Pharmaceutical compositions

专利摘要:

公开号:AU2009209629A1
申请号:U2009209629
申请日:2009-01-28
公开日:2009-08-06
发明作者:Graham Jackson；Werner Oberegger；Edwin Walsh；Jin Xiaopin
申请人:Biovail Laboratories International Srl；
IPC主号:A61K9-32

专利说明:
WO 2009/095395 PCT/EP2009/050924 PHARMACEUTICAL COMPOSITIONS RELATED APPLICATIONS [0001] This application claims priority to U.S. provisional patent application Ser. No. 61/023,951 filed January 28, 2008, the contents of which are hereby incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] The present invention relates to novel once daily pharmaceutical compositions comprising combinations of escitalopram and bupropion or citalopram and bupropion and their use for the treatment of central nervous system disorders, such as for example mood disorders (e.g., major depressive disorder (MDD)- also known as major depression, unipolar depression, unipolar disorder, or clinical depression) and anxiety disorders (general anxiety disorder, social anxiety disorder, post traumatic stress disorder, or panic disorder). The present invention also relates to novel once daily pharmaceutical compositions comprising a combination of bupropion and quetiapine fumarate. BACKGROUND OF THE INVENTION [00031 The burden of mental illness and neurological disorders worldwide is significant. According to the World Health Organization, neuropsychiatric disorders account for 3 1% of the disability in the world, affecting both rich and poor nations alike (World Health Report 2001: Mental Health: New Understanding, New Hope. World Health Organization (WHO). January 2001. Geneva, Switzerland). It is estimated that the incidence of major depression in the general population is around 5% and its lifetime prevalence is about 20% (Weissman, M.M., et al. (1996) Am Med Ass 276: 293-299). Similarly, the incidence of anxiety disorders in the general population is widespread and high, with lifetime prevalence rates ranging between about 14% and 29% in Western countries (Michael, T et al. (2007). Psychiatry, 6 (4): 136-142). This study also found co-morbidity among individuals with an anxiety disorder to be high, with three out of four individuals with a lifetime anxiety disorder experiencing at least one other mental disorder. These FIG.ures, together with the conclusion that unipolar depression accounted for the fourth leading cause of worldwide Disability Adjusted Life Years (Murray C.J et al. (1997). Lancet 349: 1436-1442), makes neuropsychiatric disorders, particularly MDD, a significant global health issue, which needs to be treated.
WO 2009/095395 PCT/EP2009/050924 [0004] Today, physicians have about 20 FDA approved medications as effective options for treating depressed patients. However, no one treatment is universally effective. While some patients respond to one antidepressant, others respond to another, and some patients may require a combination of medications. [0005] The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the largest and longest study conducted to date, assessed the effectiveness of antidepressant treatments in patients diagnosed with MDD (Rush AJ et al. (2006). Am JPsychiatry 163: 1905 1917). STAR*D was divided into four levels, each of which assessed the effectiveness of a different medication or combination of medications. [0006] Patients who did not become symptom free in one level of treatment moved on to the next level. Level 1 evaluated the effectiveness of the antidepressant citalopram alone. Citalopram and escitalopram (the s-enantiomer of citalopram) currently marketed in the United States as Celexa* and Lexapro respectively, belong to the class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs). Citalopram was chosen as the first line of treatment because of its superior efficacy, ease of administration (once-a-day), and safety profile in older patients. Patients who did not become symptom free over a 12 to 14 week period after being treated with Celexa* moved on to level 2. [0007] Level 2 patients had the option of switching to a different medication or adding on to the existing Celexa* treatment. Patients who opted for the "add-on" group were prescribed either bupropion-SR (Wellbutrin* SR), or buspirone (BuSpar®). Buspirone itself is not an antidepressant, but enhances the action of antidepressants. Bupropion, on the other hand, is an antidepressant belonging to the chemical class of aminoketones. Bupropion, marketed in the U.S. as Wellbutrin*, Wellbutrin* SR, or Wellbutrin* XL, is classified as an atypical antidepressant. Bupropion was chosen as the antidepressant of choice in Level 2 possibly for several reasons. For one, clinical studies have confirmed the efficacy of bupropion for MDD. (Fava M. et al. (2005). Prim Care Companion J Clin Psychiatry 7(3): 106-113). For another, bupropion, in contrast to nearly all other antidepressants, does not cause weight gain or sexual dysfunction (Zimmerman M. et al. (2005). J Clin Psychiatry 66(10): 1336-1339; Clayton AH. (2003). Primary Psychiatry 10(1): 55-61) and is more effective than SSRIs at improving symptoms of hypersomnia and fatigue in depressed patients (Baldwin et al. (2006). J Clin Psychiatry 67(suppl 6): 9-15). Further, a survey of clinicians found bupropion to be the preferred "add-on" antidepressant for patients not responding to SSRIs as the first line of treatment (Zisook S et al. (2006). Biol Psychiatry 59(3): 203-210; Lam R. W. (2004). J Clin Psychiatry 65(3): 33 7-340). 2 WO 2009/095395 PCT/EP2009/050924 [00081 One of the conclusions of the STAR*D study is that patients resistant to citalopram and subsequently treated with a combination of citalopram and bupropion faired much better than patients on citalopram or bupropion alone. The study also indicated a possibility of a higher remission rate in citalopram non-responders when bupropion was added on to the existing citalopram treatment rather than when switched to bupropion (30% vs. 20%). [0009] One of the major problems in treating depression with SSRls is the two to three week delay in onset of their action. This is believed to be a consequence of the mechanism of action of S SRls (Pifneyro G. and Blier P. (1999) Pharmacol Rev 51(3): 533-591). Citalopram, primarily through its S-enantiomer, escitalopram, mediates its antidepressant effects by inhibiting re-uptake of serotonin (5-hydroxytryptamine [5-HT]) released into the synaptic cleft (Brcestrup C. and Sanchez C. (2004). Int JPsychiatry Clin Practice 8 supplyl 1): 11-13). A result of the inhibition of this uptake is that 5-HT persists in the synaptic cleft thereby stimulating receptors of postsynaptic neurons for an extended period in patients suffering from MDD. [0010] Current research suggests that early in the SSRI antidepressant response, 5-HT1A autoreceptors, located at the cell body of neurons, exert a negative feedback response on the firing activity of serotonergic (5-HT) neurons by binding to excess 5-HT. These autoreceptors, after a period of time of treatment with the SSRI, become desensitized and allow 5-HT neurons to regain their normal firing rate in the presence of sustained reuptake inhibition (Blier, P. (2003) European Neuropsychopharmacology 13: 57-66). The time taken to desensitize 5-HT1A autoreceptors, about two to three weeks, is believed to represent the delay in onset of action of SSRls. Several lines of evidence suggest, however, that the time to desensitization of 5-HT1A autoreceptors can be reduced, and hence the delay in the onset of action of SSRls can be shortened, when SSRls are administered in combination with other antidepressants, like mirtazapine and bupropion. [0011] The mechanism of action of bupropion is not clearly understood. Bupropion has the ability to increase synaptic availability of norepinephrine (NE) and differentially effect dopamine (DA) release in various parts of the brain (Dong J and Blier P. (2001). Psychopharmacology 155: 52-57; Mansari M.E. et al. (2008). Neuropharmacology 55: 1191 1198). It is believed that this enhanced NE release results in an attenuation of firing of NE neurons due to an increased activation of inhibitory somatodendritic a 2 -adrenoceptors located on NE neurons rather than due to the re-uptake inhibition of NE as previously thought. NE neurons gradually re-initiate firing to normal levels over a two-week period of bupropion administration as the a 2 -adrenoceptors become desensitized. 3 WO 2009/095395 PCT/EP2009/050924 [0012] Although SSRIs and bupropion exert their action via different neuronal systems it appears that these systems work in concert in the antidepressant response. In fact, 5-HT and NE neurons have reciprocal connections. Mansari et al. have recently demonstrated that bupropion leads to a rapid and sustained increase in the firing rate of 5-HT neurons and conclude that this is a result of the desensitization of the 5-HTiA autoreceptors after only two days of administration (Mansari et al. (2008). Neuropharmacology 55: 1191-1198). Additionally, long-term SSRI administration has been shown to gradually attenuate NE neuronal firing (Szabo S. T. et al. (2000). Int JNeuropsychopharmacol 3: 1-11). Given this interplay between SSRI and bupropion, it has been postulated that a combination of an SSRI, such as citalopram, and bupropion should exert a synergistic effect on both 5-HT and NE systems. The rapid desensitization of the 5-HT1A autoreceptors by bupropion should override the two to three week suppression of serotonergic neurons induced by SSRIs in as little as two days. Additionally, the enhanced NE releasing action by bupropion should counteract the decreased firing rate of NE neurons produced by long term administration of SSRIs. Intuitively then, treatment methods that affect both 5-HT and NE neuronal systems might be expected to benefit depressed patients regardless of whether their depression is a result of 5-HT and/or NE deficiency. [00131 Preliminary clinical evidence has provided support for the efficacy of combining bupropion and escitalopram for depressed patients (CITATION). Patients were treated for 8 weeks with a combination of escitalopram and bupropion in escalating doses up to 40mg/d and 450 mg/d respectively. This study did not conduct a head-to-head comparison of combination versus monotherapy. Nevertheless, of 43 patients who took part in the study, 34% remitted within 2 weeks and 61 % remitted after 8 weeks. Historically, according to the study, 10% of patients remit after two weeks and 410% remit after 2 weeks on monotherapy. Further support for a combination of SSRI and bupropion was recently demonstrated in an animal model. Prica et al. evaluated the effects of co-administration of bupropion and SSRIs in mice using the forced swimming test, which is predictive of the antidepressant activity of drugs (Prica et al. Behav. Brain Res. (2008). 194: 92-99). The results suggest that bupropion might enhance the effectiveness of SSRIs and SNRIs but not NRIs. Their results also suggest that bupropion enhances only the serotonergic system, which is in agreement with the pre-clinical studies presented above. [0014] Taken together, basic research and preliminary clinical studies support the notion that a combination of antidepressant drugs having complementary mechanisms of action on 5-HT and NE systems, such as citalopram and escitalopram in combination with bupropion, have the potential of producing a more robust and/or rapid response, and hence a more efficacious 4 WO 2009/095395 PCT/EP2009/050924 outcome with possibly a lower side-effect profile. It is further reasonable to assume that the synergistic effects of these drugs can be maximized if both these drugs can be administered such that the drugs can act on the 5-HT/NE neuronal network at or about the same time. It would therefore be a significant advance in the art if a pharmaceutical composition can be manufactured such that both citalopram or escitalopram and bupropion can be formulated into a single composition, which provides for the release of both drugs such that the drugs might be able to act on the 5-HT and NE neuronal systems at or about the same time to maximize the expected synergistic antidepressant outcome. [0015] Pharmaceutical compositions for the delivery of combinations of drugs are not new in the art of drug delivery. For example, US Pat. No. 4,449,983, (the '983 application) refers to 'an osmotic device for delivering two beneficial drugs to an environment of use'. The patent refers to a tri-layer tablet coated with a semi-permeable membrane with two separate orifices to allow for drug release. The semi-permeable membrane is substantially impermeable to the drugs. The first tablet layer contains the first active ingredient, the second tablet layer forms a swellable (hydrogel) partition barrier and the third tablet layer contains the second drug. The tablet is then coated with a semi-permeable membrane to form two drug-containing compartments in one tablet. Two separate orifices are then formed across the membrane to communicate each drug containing compartment with the environment such that drug is delivered separately from each compartment. The swellable (hydrogel) partition layer acts as a 'driving' layer. As the partition layer hydrates it expands and reduces the volume of each drug-containing compartment. The rate of drug release from this device is controlled by an osmotic pressure gradient within each drug containing compartment. [00161 US Pat. No. 4,455,143, refers to a similar osmotic device to that described in the '983 patent, the difference being the composition of the tablet partition layer. Instead of a swellable (hydrogel) layer, the partition layer is made of a material 'selected from the group consisting essentially of semi-permeable, microporous and impermeable materials'. The function of the partition layer is to 'maintain the integrity of the first and second compartments', (i.e. the drug containing compartments). The rate of drug release is controlled by the osmotic pressure within the drug compartment. [0017] US Pat. No. 4,601,894, refers to a matrix tablet composition for the controlled release of the triple drug combination of acetaminophen, pseudoephedrine sulfate and dexbrompheniramine maleate. The matrix composition contains the three actives but a choice of polymers (preferably hydroxypropyl methylcellulose (HPMC) ethers and ethyleellulose. The patent refers to a simple combination dosage form with unexpected release rates (based on very 5 WO 2009/095395 PCT/EP2009/050924 different drug solubilities) specific to three actives, 'acetaminophen, pseudoephedrine or a pharmaceutically acceptable salt thereof and dexbrompheniramine or a pharmaceutically acceptable salt thereof.' The matrix tablet composition referred to is an uncoated matrix tablet, with drug release controlled by a combination of drug diffusion and polymer erosion. [00181 US Pat. No. 4,662,880, refers to an osmotic device for the controlled delivery of the two pharmaceutical actives pseudoephedrine and brompheniramine. Both actives are formulated in one tablet core; a semi-permeable membrane, which is substantially impermeable to the passage of drug, is applied followed by an immediate release active coat containing both pharmaceutical actives. [0019] US Pat. No. 4,844,907, refers to a 'multiphase (especially a bi-layered, optionally coated) tablet' composition for the delivery of a combination of a narcotic analgesic and a non steroidal anti-inflammatory. The patent refers to a bi-layer tablet consisting of two separate controlled release matrix layers, each layer containing one of the actives individually. There is no partition layer between the two active layers. US Pat. No. 5,866,164, refers to a similar method for the controlled delivery of an opioid and an opioid antagonist. [0020] US Pat. Nos. 4,814,181, and 4,915,954 refer to an osmotic pump dosage form for delivering actives at two different rates. The patents refer to a bi-layer tablet core coated with a semi-permeable membrane with a single passageway for osmotic drug release. The semi permeable membrane is substantially impermeable to the passage of the drug. The first drug layer (closest to the passageway) releases drug rapidly while the second drug layer releases active over a prolonged period of time. [0021] US Pat. Application No. 11/355,315 refers to an osmotic dual delivery technology containing a bi-layered core. The application purports to teach a dual controlled release of both drugs from a controlled release bi-layered core osmotic device. The arrangement of the layers of the bi-layer core can be stacked or the second layer can surround the first. The application refers to a first and second drug which can be released sequentially or in an overlapping manner when the osmotic device is exposed to an aqueous environment in a timed, targeted, pseudo-first order, first order, pseudo-zero order, zero-order, and/or delayed release profile. [0022] PCT International Application Number PCT/US2007/011186 (WO 2007/133583) refers to a solid dosage form for delivery of water-soluble pharmaceutical agents. The solid dosage form comprises a matrix core containing the pharmaceutical agent and a hydrophobic material, and a coating containing a hydrophilic pore-forming agent and a hydrophobic polymer. The dosage form exhibits a zero-order release profile upon dissolution. 6 WO 2009/095395 PCT/EP2009/050924 [0023] US Pat. Application Nos. 11/582,164 (the '164 application) and 11/549,714 both refer to stable once-a-day oral dosage forms containing escitalopram or pharmaceutically acceptable salt thereof and bupropion and pharmaceutically acceptable salt thereof. The '164 application teaches that the escitalopram and bupropion are preferably physically separated. The applicants teach that commercial escitalopram oxalate compositions, which are normally stable up to about 12 months, degrade significantly more rapidly when stored in intimate contact with bupropion hydrochloride such that each drug degrades by more than 10% in potency after just one month of storage at 40'C and 75% relative humidity. Accordingly, the applicants teach that compositions comprising the drugs may be separated into separate discrete zones such as separate layers or the compositions may take the form of a plurality of escitalopram beads or tablets and a plurality of bupropion tablets or beads, where ate least one or both of the bead or tablet populations are coated. [0024] US Pat. No. 7,241,805 (the '805 patent) refers to combinations of bupropion hydrobromide with a second drug, which may be citalopram or escitalopram. In particular, the '805 patent refers to controlled release microparticulate compositions wherein combination products can be made by providing an overcoat comprising a second drug substantially surrounding a control-releasing coat of each microparticle core comprising bupropion hydrobromide. In certain embodiments, a pulsatile release of at least one other drug is achieved from the coated microparticles. The overcoat can be an immediate release overcoat that includes at least one other drug. As such, this composition can provide an immediate release of at least one other drug from the overcoat in a first phase of drug release, and then a subsequent controlled release of the bupropion hydrobromide from the control-releasing coated microparticle in a second phase of drug release. [0025] While the above referenced prior art refers to pharmaceutical compositions suitable for the delivery of combinations of drugs, they are either complicated or costly to manufacture. Further, the ability of the above referenced pharmaceutical compositions to release two drugs, such as bupropion and citalopram or escitalopram, at about the same rate to maximize the expected synergistic antidepressant outcome, is further hampered by the significantly different physicochemical characteristics of the two drugs, which vary across the physiological pH range. Accordingly, there is a need to develop a once-a-day pharmaceutical composition capable of delivering bupropion and citalopram or escitalopram at about the same rate independent of the pH of the environment of use. 7 WO 2009/095395 PCT/EP2009/050924 SUMMARY OF THE INVENTION [0026] The present invention relates to a once-daily pharmaceutical composition comprising a tablet core comprising a combination of actives selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, bupropion hydrobromide and escitalopram oxalate, and bupropion hydrobromide and quetiapine fumarate, optionally a stabilizer in an effective stabilizing amount, and at least one pharmaceutically acceptable excipient, and a control-releasing coat surrounding the tablet core, wherein said composition surprisingly provides for a synchronous release of the combination of active agents across the pH range i.e., 0. IN HCl, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer in-vitro. The once daily pharmaceutical composition surprisingly also provides for enhanced absorption of bupropion hydrobromide when administered to a subject in need of such administration. The once-daily pharmaceutical composition provides an about 15-25% increase in the bioavailability of bupropion when compared to co-administration of single active agent pharmaceutical compositions of bupropion hydrobromide and citalopram hydrochloride or bupropion hydrobromide and escitalopram oxalate. [0027] The synchronous release of the combination of actives comprising the once-daily pharmaceutical compositions of the present invention is particularly surprising when one considers that the differing physicochemical characteristics of the active ingredients and the likely differences in the permeability coefficients for the combination of active drugs would result in a differing rate and extent of drug release for each of the drugs chosen to be part of the combination. Accordingly, it was expected that it would be difficult to optimize the release kinetics of the combination of drugs contemplated without one drug potentially negatively influencing the release kinetics of the other drug of the combination. However, it was surprisingly found that despite the differing physicochemical characteristics (shown below) for the actives used in the combinations described herein, the in-vitro rate and extent of drug release was substantially synchronous across the pH range. Bupropion Physichochemistry Bupropion HCl Bupropion HBr Molecular Weight 276.2 320.7 pKa 7.8 7.8 Solubility (37 0 C) 0.lN HCl 416 190 pH 4.5 437 180 pH 6.8 437 200 8 WO 2009/095395 PCT/EP2009/050924 Escitalopram Physicochemistry Escitalopram Oxalate Molecular Weight 414.4 pKa 9.5 Solubility (37 0 C) 0.1N HCl 183 pH 4.5 111 pH 6.8 121 Quetiapine Fumarate Physicochemistry Quetiapine Fumarate Molecular Weight 883.11 pKa 3.3, 6.87 Solubility (37 0 C) 0.1N HCl 41 pH 4.5 3 pH 6.8 0.3 [0028] Accordingly, at least one embodiment of the present invention provides for a once-daily pharmaceutical composition comprising a homogenous core comprising a therapeutically effective combination of active agents selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, and bupropion hydrobromide and escitalopram oxalate, a stabilizer in an effective stabilizing amount, and at least one pharmaceutically acceptable excipient, and a control releasing coating surrounding said core, said coating comprising a water-insoluble water permeable film-forming polymer, a water-soluble polymer and at least one plasticizer; wherein said composition provides for a synchronous release of the combination of active agents. [0029] In at least one embodiment of the present invention, the pharmaceutical compositions provide for a synchronous release of the combination of actives in 0. IN HCl, pH 4.5 acetate buffer, pH 6.8 phosphate buffer when measured in 900 ml of each aqueous solution at 37 0 C using USPI apparatus at 75 rpm. [00301 In at least one embodiment of the invention, the stabilizer comprises at least one suitable pharmnaceutically acceptable inorganic acid, at least one suitablem pharmaceutically acceptable organic acid, at least one suitable pharmaceutically acceptable salt of an organic base, at least one suitable pharmaceutically acceptable salt of an inorganic acid, at least one suitable pharmaceutically acceptable acid salt of an amino acid, potassium metabisulfite, sodium bisulfite, 9 WO 2009/095395 PCT/EP2009/050924 or at least one suitable pharmaceutically acceptable phenylated antioxidant, or any combination thereof. [00311 In at least one embodiment of the present invention, stabilizer comprises at least one suitable inorganic acid, which at a concentration of about 0.310% w/w/ forms an aqueous solution having a pH of from about 0.5 to about 0.4. [0032] In at least one embodiment of the present invention, the stabilizer comprises hydrochloric acid, phosphoric acid, nitric acid, or sulfuric acid, or any combination thereof. [00331 In at least one embodiment of the present invention, the stabilizer comprises at least one suitable organic acid that has a solubility in water at 20'C of less than about 1Og/100g water and that at a concentration of about 60% w/w forms an aqueous suspension having a pH of from about 0.9 to about 4.0. [0034] In at least one embodiment of the present invention, the stabilizer comprises at least one suitable dicarboxylic acid that has a solubility in water at 20'C of less than about 1Og/1OOg water and that at a concentration of about 60% w/w forms an aqueous suspension having a pH of from about 0.9 to about 4.0. [0035] In at least one embodiment of the present invention, the stabilizer comprises hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid, or any combination thereof. [00361 In at least one embodiment of the present invention, the stabilizer comprises at least one suitable pharmaceutically acceptable salt of an organic base having an aqueous pH of from about 2.70 to about 3.10 at a concentration of about 10% w/w. [0037] In at least one embodiment of the present invention, the stabilizer comprises creatinine hydrochloride. [00381 In at least one embodiment of the present invention, the stabilizer comprises at least one suitable pharmaceutically acceptable salt of an organic base having an aqueous pH of from about 2.95 to about 3.05, at a concentration of about 20% w/w. [00391 In at least one embodiment of the present invention, the stabilizer comprises thiamine hydrochloride. [0040] In at least one embodiment of the present invention, the stabilizer comprises sat least one salt of an organic base having an aqueous pH of from about 2.70 to about 2.72, at a concentration of about 20% w/w. [0041] In at least one embodiment of the present invention, the stabilizer comprises thiamine hydrochloride. [0042] In at least one embodiment of the invention, the stabilizer is citric acid. 10 WO 2009/095395 PCT/EP2009/050924 [0043] In at least one embodiment of the present invention, the stabilizer comprises at least one suitable pharmaceutically acceptable salt of an inorganic acid having an aqueous pH of from about 4.20 to about 4.30 at a concentration of about 10 w/w. [0044] In at least one embodiment of the present invention, the stabilizer comprises potassium phosphate monobasic. [0045] In at least one embodiment of the present invention, the stabilizer comprises at least one suitable pharmaceutically acceptable acid salt of an amino acid. [00461 In at least one embodiment of the present invention, the stabilizer comprises L cysteine hydrochloride, L-cystine dihydrochloride, glycine hydrochloride or any combination thereof. [0047] In at least one embodiment of the present invention, the stabilizer comprises potassium metabisulfite, sodium bisulfite, or any combination thereof. [00481 In at least one embodiment of the invention, the stabilizer comprises at least one suitable pharmaceutically acceptable phenylated antioxidant. [0049] In at least one embodiment of the invention, the stabilizer comprises butlylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or any combination thereof. [0050] In at least one embodiment of the present invention, the stabilizer comprises butylated hydroxytoluene. [0051] In at least one embodiment of the present invention, the stabilizer comprises a combination of citric acid and butylated hydroxytoluene. [0052] In at least one embodiment of the present invention, the once-daily pharmaceutical composition comprises at least one pharmaceutically acceptable excipient selected from the group consisting of a binder, a lubricant, a filler, a glidant, or any combinations thereof. [00531 In at least one embodiment of the present invention, the water-insoluble water permeable film-forming polymer comprises at least one cellulose ether, cellulose ester, methacrylic acid derivative, aqueous ethyleellulose dispersion, aqueous acrylic enteric system, or polyvinyl derivative, or any combination thereof. [0054] In at least one embodiment of the present invention, the water-soluble polymer comprising the control-releasing coat comprises at least one methyleellulose, hydroxypropyleellulose, hydroxypropylmethyleellulose, hydroxyethyleellulose, polyvinyl alcohol, or polyvinylpyrrolidone, or any combination thereof. [0055] In at least one embodiment of the present invention, the at least one plasticizer comprises a combination of two plasticizers. 11 WO 2009/095395 PCT/EP2009/050924 [0056] In at least one embodiment of the present invention, the at least one plasticizer comprises at least one ester, or a polyalkylene glycol, or any combination thereof. [0057] In at least one embodiment of the invention, the plastizer is a combination of polyethylene glycol 3350 and dibutyl sebacate. [00581 In at least one embodiment of the invention, the once-daily pharmaceutical composition is in the form of a tablet. [0059] In at least one embodiment, the once-daily pharmaceutical composition when administered to a subject in need of such administration can provide an about 15-25% increase in the bioavailability of bupropion when compared to co-administration of single active agent pharmaceutical compositions of bupropion hydrobromide and citalopram hydrochloride or bupropion hydrobromide and escitalopram oxalate. [00601 At least one embodiment of the present invention provides for a method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject any one of the pharmaceutical compositions of the invention. [00611 At least one embodiment of the present invention provides for a method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering a once daily pharmaceutical composition comprising a homogenous core comprising a therapeutically effective combination of active agents selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, and bupropion hydrobromide and escitalopram oxalate, a stabilizer in an effective stabilizing amount, and at least one pharmaceutically acceptable excipient, and a control-releasing coating surrounding said core, said coating comprising a water-insoluble water permeable film-forming polymer, a water-soluble polymer and at least one plasticizer. [0062] At least one embodiment of the present invention provides for a method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering a once daily pharmaceutical composition comprising a homogenous core comprising a therapeutically effective combination of active agents selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, and bupropion hydrobromide and escitalopram oxalate, a stabilizer in an effective stabilizing amount, and at least one pharmaceutically acceptable excipient, and a control-releasing coating surrounding said core, said coating comprising a water-insoluble water permeable film-forming polymer, a water-soluble polymer and at least one plasticizer, wherein said composition provides an about 15-25% increase in the bioavailability of bupropion when 12 WO 2009/095395 PCT/EP2009/050924 compared to co-administration of single active agent pharmaceutical compositions of bupropion hydrobromide and citalopram hydrochloride or bupropion hydrobromide and escitalopram oxalate. [00631 At least one embodiment of the present invention provides for a method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering a once daily pharmaceutical composition comprising a homogenous core comprising a therapeutically effective combination of active agents selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, and bupropion hydrobromide and escitalopram oxalate, a stabilizer in an effective stabilizing amount, and at least one pharmaceutically acceptable excipient, and a control-releasing coating surrounding said core, said coating comprising a water-insoluble water permeable film-forming polymer, a water-soluble polymer and at least one plasticizer; wherein said composition provides for a synchronous release of the combination of active agents. [0064] At least one embodiment of the present invention provides for a pharmaceutical composition comprising a controlled release matrix core, said controlled release matrix core comprising at least one hydrophilic control-releasing polymer present in a control-releasing amount, a therapeutically effective combination of active agents selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, and bupropion hydrobromide and escitalopram oxalate, a stabilizer, and at least one pharmaceutically acceptable excipient; wherein said pharmaceutical composition provides for a synchronous release of the combination of active agents. [0065] In at least one embodiment of the present invention, the at least one hydrophilic control-releasing polymer comprising the controlled-release matrix core comprises at least one hydrophilic cellulose, ethyleellulose, polysaccharide, polyvinylpyrrolidone, polymethacrylate, or a mixture of polyvinyl acetate and polyvinylpyrrolidone, or any combination thereof. [00661 At least one embodiment of the present invention provides for a method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject a pharmaceutical composition comprising a controlled release matrix core, said controlled release matrix core comprising at least one hydrophilic control-releasing polymer present in a control-releasing amount, a therapeutically effective combination of active agents selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, and bupropion hydrobromide and escitalopram oxalate, a stabilizer, and at least one pharmaceutically acceptable 13 WO 2009/095395 PCT/EP2009/050924 excipient; wherein said composition provides for a synchronous release of the combination of actives. [0067] At least one embodiment of the present invention provides for a method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject a pharmaceutical composition comprising a controlled release matrix core, said controlled release matrix core comprising at least one hydrophilic control-releasing polymer present in a control-releasing amount, a therapeutically effective combination of active agents selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, and bupropion hydrobromide and escitalopram oxalate, a stabilizer, and at least one pharmaceutically acceptable excipient. [00681 At least one embodiment of the present invention provides for a method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject a pharmaceutical composition comprising a controlled release matrix core, said controlled release matrix core comprising at least one hydrophilic control-releasing polymer present in a control-releasing amount, a therapeutically effective combination of active agents selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, and bupropion hydrobromide and escitalopram oxalate, a stabilizer, and at least one pharmaceutically acceptable excipient, wherein said composition provides an about 15-25% increase in the bioavailability of bupropion when compared to co-administration of single active agent pharmaceutical compositions of bupropion hydrobromide and citalopram hydrochloride or bupropion hydrobromide and escitalopram oxalate. [00691 At least one embodiment provides for a pharmaceutical composition comprising a core comprising a first immediate release layer comprising a therapeutically effective amount of an active agent selected from the group consisting of bupropion hydrochloride and bupropion hydrobromide, optionally a stabilizer and at least one pharmaceutically acceptable excipient in direct contact with a second immediate release layer comprising an active agent selected from the group consisting of citalopram hydrochloride and escitalopram oxalate, optionally a stabilizer, and at least one pharmaceutically acceptable excipient, and a control-releasing coating surrounding said core, said coating comprising a water-insoluble water-permeable film-forming polymer, a water-soluble polymer and at least one plasticizer, wherein said composition provides for a synchronous release of the active agents. 14 WO 2009/095395 PCT/EP2009/050924 [00701 At least one embodiment of the present invention provides for a method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject a pharmaceutical composition comprising a core comprising a first immediate release layer comprising a therapeutically effective amount of an active agent selected from the group consisting of bupropion hydrochloride and bupropion hydrobromide, optionally a stabilizer and at least one pharmaceutically acceptable excipient in direct contact with a second immediate release layer comprising an active agent selected from the group consisting of citalopram hydrochloride and escitalopram oxalate, optionally a stabilizer, and at least one pharmaceutically acceptable excipient, and a control-releasing coating surrounding said core, said coating comprising a water-insoluble water-permeable film-forming polymer, a water-soluble polymer and at least one plasticizer, wherein said composition provides for a synchronous release of the active agents. [0071] At least one embodiment of the present invention provides for a method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject a pharmaceutical composition comprising administering once daily to said subject a pharmaceutical composition comprising a core comprising a first immediate release layer comprising a therapeutically effective amount of an active agent selected from the group consisting of bupropion hydrochloride and bupropion hydrobromide, optionally a stabilizer and at least one pharmaceutically acceptable excipient in direct contact with a second immediate release layer comprising an active agent selected from the group consisting of citalopram hydrochloride and escitalopram oxalate, optionally a stabilizer, and at least one pharmaceutically acceptable excipient, and a control-releasing coating surrounding said core, said coating comprising a water-insoluble water-permeable film-forming polymer, a water-soluble polymer and at least one plasticizer. [0072] At least one embodiment of the present invention provides for a method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject a pharmaceutical composition comprising administering once daily to said subject a pharmaceutical composition comprising a core comprising a first immediate release layer comprising a therapeutically effective amount of an active agent selected from the group consisting of bupropion hydrochloride and bupropion hydrobromide, optionally a stabilizer and at least one pharmaceutically acceptable excipient in direct contact with a second immediate release layer comprising an active agent selected from the group consisting of citalopram hydrochloride and escitalopram oxalate, optionally a stabilizer, and at least one pharmaceutically acceptable excipient, and a control-releasing coating surrounding said core, said 15 WO 2009/095395 PCT/EP2009/050924 coating comprising a water-insoluble water-permeable film-forming polymer, a water-soluble polymer and at least one plasticizer, wherein said composition provides an about 15-25% increase in the bioavailability of bupropion when compared to co-administration of single active agent pharmaceutical compositions of bupropion hydrobromide and citalopram hydrochloride or bupropion hydrobromide and escitalopram oxalate. [00731 In at least one embodiment of the present invention, the once-daily pharmaceutical compositions of the invention avoid dose dumping of the combination of actives in the presence of food and/or alcohol. [0074] In at least one embodiment of the present invention, the once-daily pharmaceutical compositions of the invention are free of food-effect. [0075] At least one embodiment of the present invention provides for a method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering a once daily pharmaceutical composition comprising a homogenous core comprising a therapeutically effective combination of active agents selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, and bupropion hydrobromide and escitalopram oxalate, a stabilizer in an effective stabilizing amount, and at least one pharmaceutically acceptable excipient, and a control-releasing coating surrounding said core, said coating comprising a water-insoluble water permeable film-forming polymer, a water-soluble polymer and at least one plasticizer, wherein said composition provides an about 15-25% increase in the bioavailability of bupropion when compared to co-administration of single active agent pharmaceutical compositions of bupropion hydrobromide and citalopram hydrochloride or bupropion hydrobromide and escitalopram oxalate and is free of food effect. [00761 At least one embodiment of the present invention provides for a method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject a pharmaceutical composition comprising a controlled release matrix core, said controlled release matrix core comprising at least one hydrophilic control-releasing polymer present in a control-releasing amount, a therapeutically effective combination of active agents selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, and bupropion hydrobromide and escitalopram oxalate, a stabilizer, and at least one pharmaceutically acceptable excipient, wherein said composition provides an about 15-25% increase in the bioavailability of bupropion when compared to co-administration of single active agent pharmaceutical 16 WO 2009/095395 PCT/EP2009/050924 compositions of bupropion hydrobromide and citalopram hydrochloride or bupropion hydrobromide and escitalopram oxalate and is free of food effect. [0077] At least one embodiment of the present invention provides for a method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject a pharmaceutical composition comprising administering once daily to said subject a pharmaceutical composition comprising a core comprising a first immediate release layer comprising a therapeutically effective amount of an active agent selected from the group consisting of bupropion hydrochloride and bupropion hydrobromide, optionally a stabilizer and at least one pharmaceutically acceptable excipient in direct contact with a second immediate release layer comprising an active agent selected from the group consisting of citalopram hydrochloride and escitalopram oxalate, optionally a stabilizer, and at least one pharmaceutically acceptable excipient, and a control-releasing coating surrounding said core, said coating comprising a water-insoluble water-permeable film-forming polymer, a water-soluble polymer and at least one plasticizer, wherein said composition provides an about 15-25% increase in the bioavailability of bupropion when compared to co-administration of single active agent pharmaceutical compositions of bupropion hydrobromide and citalopram hydrochloride or bupropion hydrobromide and escitalopram oxalate and is free of food effect. [00781 At least one embodiment of the present invention provides for a method of manufacturing a pharmaceutical composition, said method comprising the steps of: a) granulating an active agent selected from the group consisting of bupropion hydrobromide and bupropion hydrochloride by homogenously blending with a solution of at least one suitable binder and optionally a suitable stabilizer; b) drying said granules comprising either bupropion hydrobromide or bupropion hydrochloride and retaining said granules of a size between about 355 m and about 800 Jm; c) granulating an active agent selected from the group consisting of citalopram hydrochloride, escitalopram oxalate, and quetiapine fumarate by homogenously blending with a solution of at least one suitable binder and optionally at least one suitable stabilizer; d) drying said granules comprising either citalopram hydrochloride, escitalopram oxalate, and quetiapine fumarate and retaining said granules of a size between about 355 m and about 800 Jm; e) homogenously blending the granules in (b) and (d) in an amount equivalent to the desired dosage strength of each of the actives selected in (a) and (c) with at least one suitable lubricant; (f) compressing the homogenously blended mixture obtained in (e) into a homogenously blended tablet core; and coating said homogenously blended tablet core with a control-releasing coat comprising a water-insoluble water-permeable film-forming polymer, a 17 WO 2009/095395 PCT/EP2009/050924 water-soluble polymer and at least one plasticizer; wherein said pharmaceutical composition provides for a synchronous release of the actives selected in (a) and (b). [0079] At least one embodiment of the present invention provides for a method of manufacturing a pharmaceutical composition comprising the steps of: a) granulating a first active selected from the group consisting of bupropion hydrochloride and bupropion hydrobromide with a second active selected from the group consisting of citalopram hydrochloride, escitalopram oxalate and quetiapine fumarate, in an amount equivalent to the desired dosage strength the first and second active by homogenously blending with a solution of at least one suitable binder and optionally at least suitable stabilizer; b) drying the granules obtained in (a) and retaining granules of < 1.00 tim) homogenously blending the granules obtained in (b) with at least one suitable lubricant; d) compressing the homogenously blended mixture obtained in (c) into a homogenous tablet core; and d) coating said homogenously blended tablet core with a control-releasing coat comprising a water-insoluble water-permeable film-forming polymer, a water-soluble polymer and at least one plasticizer; wherein said pharmaceutical composition provides for a synchronous release of the first and second actives. [00801 In certain embodiments of the present invention, the amount of bupropion hydrobromide present is at least about 10% less than a single active agent pharmaceutical composition comprising bupropion hydrobromide. [00811 In certain embodiments of the present invention, the amount of bupropion hydrobromide present is at least about 10% less than a single active agent pharmaceutical composition comprising 348mg bupropion hydrobromide. BRIEF DESCRIPTION OF THE DRAWINGS [0082] The present invention will be further understood from the following detailed description with references to the following drawings. [00831 FIG. 1A is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 1. [0084] FIG. 1B is a graph depicting the dissolution profile in 900 ml of pH 4.5 acetate buffer using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 1. [0085] FIG. IC is a graph depicting the dissolution profile in 900 ml of pH 6.8 phosphate buffer using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 1. [00861 FIG. 2A is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 2. 18 WO 2009/095395 PCT/EP2009/050924 [00871 FIG. 2B is a graph depicting the dissolution profile in 900 ml of pH 4.5 acetate buffer using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 2. [0088] FIG. 2C is a graph depicting the dissolution profile in 900 ml of pH 6.8 phosphate buffer using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 2. [00891 FIG. 3A is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 3. [0090] FIG. 3B is a graph depicting the dissolution profile in 900 ml of pH 4.5 acetate buffer using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 3. [0091] FIG. 3C is a graph depicting the dissolution profile in 900 ml of pH 6.8 phosphate buffer using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 3. [0092] FIG. 4 is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 4. [00931 FIG. 5 is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 5. [0094] FIG. 6 is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 6. [0095] FIG. 7 is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 7. [00961 FIG. 8 is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 8. [0097] FIG. 9 is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 9. [00981 FIG. 10 is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 10. [0099] FIG. 11 is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 11. [00100] FIG. 12 is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 12. [00101] FIG. 13 is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 13. [00102] FIG. 14 is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 14. 19 WO 2009/095395 PCT/EP2009/050924 [001031 FIG. 15 is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 15. [00104] FIG. 16 is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 16. [00105] FIG. 17A is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 17. [00106] FIG. 17B is a graph depicting the dissolution profile in 900 ml of pH 6.8 phosphate buffer using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 17. [001071 FIG. 18 is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 18. [001081 FIG 19 is a graph depicting the dissolution profile in 900 ml of 0.lN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 19. [00109] FIG 20A is a graph depicting the dissolution profile in 900 ml of 0. IN HCl using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 20. [00110] FIG. 20B is a graph depicting the dissolution profile in 900 ml of pH 6.8 phosphate buffer using USP Apparatus 1 at 75 rpm at 37'C of the composition described in Example 20. [00111] FIG. 21A is a graph depicting the mean plasma bupropion concentration versus time profile for the study described in Example 21 (linear scale (n=23)). [00112] FIG. 21B is a graph depicting the mean plasma hydroxybupropion concentration versus time profile for the study described in Example 21 (linear scale (n=23)). [001131 FIG. 21C is a graph depicting the mean plasma bupropion threoamino alcohol concentration versus time profile for the study described in Example 21 (linear scale (n=23)). [00114] FIG. 21D is a graph depicting the mean plasma bupropion erythroamino alcohol concentration versus time profile for the study described in Example 21 (linear scale (n=23)). [00115] FIG. 21E is a graph depicting the mean plasma PAWC concentration versus time profile for the study described in Example 21 (linear scale (n=23)). [001161 FIG. 22A is a graph depicting the mean concentration-time profiles of citalopram during steady-state dosing of Celexa* 20 mg alone and Celexa 20 mg plus Wellbutrin XL 300 mg for the study described in Example 22 (linear scales (n=26)). [00117] FIG. 22B is a graph depicting the mean concentration-time profile of desmethyleitalopram during steady-state dosing of Celexa* 20 mg alone and Celexa* 20 mg plus Wellbutrin XL® 300 mg for the study described in Example 22 (linear scales (n=26)). 20 WO 2009/095395 PCT/EP2009/050924 [001181 FIG. 22C is a graph depicting the mean concentration time profile for didesmethyleitalopram during steady-state dosing of Celexa* 20 mg alone and Celexa* 20 mg plus Wellbutrin XL* 300 mg for the study described in Example 22 (linear scales (n=26)). [00119] FIG. 22D is a graph depicting the mean concentration time for bupropion, rrythro-hydrobupropion, hydroxybupropion, and threo-hydrobupropion during steady-state dosing of Celexa* 20 mg plus Wellbutrin XL® 300 mg for the study described in Example 22 (linear scales (n=26)). [00120] FIG. 23A is a graph depicting the mean plasma bupropion concentration versus time profile for the study described in Example 23 (linear scale, Group 1 (n=1 1)). [00121] FIG. 23B is a graph depicting the mean plasma hydroxybupropion concentration versus time profile for the study described in Example 23 (linear scale, Group 1 (n=1 1)). [00122] FIG. 23C is a graph depicting the mean plasma bupropion threoamino alcohol concentration versus time profile for the study described in Example 23 (linear scale, Group 1 (n= 11)). [001231 FIG. 23D is a graph depicting the mean plasma bupropion erythroamino alcohol concentration versus time profile for the study described in Example 23 (linear scale, Group 1 (n= 11)). [00124] FIG. 23E is a graph depicting the mean plasma PAWC concentration versus time profile for the study described in Example 23 (linear scale, Group 1 (n=1 1)). [00125] FIG. 23F is a graph depicting the mean plasma citalopram concentration versus time profile for the study described in Example 23 (linear scale, Group 1 (n=1 1)). [001261 FIG. 23G is a graph depicting the mean plasma demethyleitalopram concentration versus time profile for the study described in Example 23 (linear scale, Group 1 (n= 11)). [00127] FIG. 23H is a graph depicting the mean plasma didemethyleitalopram concentration versus time profile for the study described in Example 23 (linear scale, Group 1 (n= 11)). [001281 FIG. 231 is a graph depicting the mean plasma bupropion concentration versus time profile for the study described in Example 23 (linear scale, Group 2 (n=10)). [00129] FIG. 23J is a graph depicting the mean plasma hydroxybupropion concentration versus time profile for the study described in Example 23 (linear scale, Group 2 (n=10)). [001301 FIG. 23K is a graph depicting the mean plasma bupropion threoamino alcohol concentration versus time profile for the study described in Example 23 (linear scale, Group 2 (n= 10)). 21 WO 2009/095395 PCT/EP2009/050924 [001311 FIG. 23L is a graph depicting the mean plasma bupropion erythroamino alcohol concentration versus time profile for the study described in Example 23 (linear scale, Group 2 (n= 10)). [00132] FIG. 23M is a graph depicting the mean plasma PAWC concentration versus time profile for the study described in Example 23 (linear scale, Group 2 (n=10)). [001331 FIG. 23N is a graph depicting the mean plasma citalopram concentration versus time profile for the study described in Example 23 (linear scale, Group 2 (n= 10)). [00134] FIG. 230 is a graph depicting the mean plasma demethyleitalopram concentration versus time profile for the study described in Example 23 (linear scale, Group 2 (n= 10)). [00135] FIG. 23P is a graph depicting the mean plasma didemethyleitalopram concentration versus time profile for the study described in Example 23 (linear scale, Group 2 (n= 10)). [001361 FIG. 24A is a graph depicting the mean plasma bupropion concentration versus time profile for the study described in Example 24 (linear scale, Group 1 (n=13)). [00137] FIG. 24B is a graph depicting the mean plasma hydroxybupropion concentration versus time profile for the study described in Example 24 (linear scale, Group 1 (n=13)). [001381 FIG. 24C is a graph depicting the mean plasma bupropion threoamino alcohol concentration versus time profile for the study described in Example 24 (linear scale, Group 1 (n= 13)). [001391 FIG. 24D is a graph depicting the mean plasma bupropion erythroamino alcohol concentration versus time profile for the study described in Example 24 (linear scale, Group 1 (n= 13)). [00140] FIG. 24E is a graph depicting the mean plasma PAWC concentration versus time profile for the study described in Example 24 (linear scale, Group 1 (n= 13)). [00141] FIG. 24F is a graph depicting the mean plasma citalopram concentration versus time profile for the study described in Example 24 (linear scale, Group 1 (n=13)). [00142] FIG. 24G is a graph depicting the mean plasma demethyleitalopram concentration versus time profile for the study described in Example 24 (linear scale, Group 1 (n= 13)). [001431 FIG. 24H is a graph depicting the mean plasma didemethyleitalopram concentration versus time profile for the study described in Example 24 (linear scale, Group 1 (n= 13)). 22 WO 2009/095395 PCT/EP2009/050924 [00144] FIG. 241 is a graph depicting the mean plasma bupropion concentration versus time profile for the study described in Example 24 (linear scale, Group 2 (n=13)). [00145] FIG. 24J is a graph depicting the mean plasma hydroxybupropion concentration versus time profile for the study described in Example 24 (linear scale, Group 2 (n=13)). [00146] FIG. 24K is a graph depicting the mean plasma bupropion threoamino alcohol concentration versus time profile for the study described in Example 24 (linear scale, Group 2 (n= 13)). [00147] FIG. 24L is a graph depicting the mean plasma bupropion erythroamino alcohol concentration versus time profile for the study described in Example 24 (linear scale, Group 2 (n= 13)). [001481 FIG. 24M is a graph depicting the mean plasma PAWC concentration versus time profile for the study described in Example 24 (linear scale, Group 2 (n=13)). [00149] FIG. 24N is a graph depicting the mean plasma citalopram concentration versus time profile for the study described in Example 24 (linear scale, Group 2 (n= 13)). [00150] FIG. 240 is a graph depicting the mean plasma demethyleitalopram concentration versus time profile for the study described in Example 24 (linear scale, Group 2 (n= 13)). [00151] FIG. 24P is a graph depicting the mean plasma didemethyleitalopram concentration versus time profile for the study described in Example 24 (linear scale, Group 2 (n= 13)). [00152] FIG. 25A is a graph depicting the mean plasma bupropion concentration versus time profile for the study described in Example 25 (linear scale, n=14). [00153] FIG. 25B is a graph depicting the mean plasma hydroxybupropion concentration versus time profile for the study described in Example 25 (linear scale, n=14). [00154] FIG. 25C is a graph depicting the mean plasma bupropion threoamino alcohol concentration versus time profile for the study described in Example 25 (linear scale, n=14). [00155] FIG. 25D is a graph depicting the mean plasma bupropion erythroamino alcohol concentration versus time profile for the study described in Example 25 (linear scale, n=14). [00156] FIG. 25E is a graph depicting the mean plasma PAWC concentration versus time profile for the study described in Example 25 (linear scale, n=14). [00157] FIG. 25F is a graph depicting the mean plasma escitalopram concentration versus time profile for the study described in Example 25 (linear scale, n=13). [00158] FIG. 25G is a graph depicting the mean plasma S-demethyleitalopram concentration versus time profile for the study described in Example 25 (linear scale, n=13). 23 WO 2009/095395 PCT/EP2009/050924 [001591 FIG. 25H is a graph depicting the mean plasma S-didemethyleitalopram concentration versus time profile for the study described in Example 25 (linear scale, n=13). [001601 FIG. 26A is a graph depicting the mean plasma bupropion concentration versus time profile for the study described in Example 26 (linear scale, n=13). [001611 FIG. 26B is a graph depicting the mean plasma hydroxybupropion concentration versus time profile for the study described in Example 26 (linear scale, n=13). [00162] FIG. 26C is a graph depicting the mean plasma bupropion threoamino alcohol concentration versus time profile for the study described in Example 26 (linear scale, n=13). [001631 FIG. 26D is a graph depicting the mean plasma bupropion erythroamino alcohol concentration versus time profile for the study described in Example 26 (linear scale, n=13). [00164] FIG. 26E is a graph depicting the mean plasma PAWC concentration versus time profile for the study described in Example 26 (linear scale, n=13). [00165] FIG. 26F is a graph depicting the mean plasma escitalopram concentration versus time profile for the study described in Example 26 (linear scale, n=14). [001661 FIG. 26G is a graph depicting the mean plasma S-demethyleitalopram concentration versus time profile for the study described in Example 26 (linear scale, n=14). [00167] FIG. 26H is a graph depicting the mean plasma S-didemethyleitalopram concentration versus time profile for the study described in Example 26 (linear scale, n=14). [001681 FIG. 27 is a graph depicting the dissolution profile in 900 ml of pH 7.5 phosphate buffer using USP Apparatus 1 at 75 rpm at 37C of the composition described in Example 27. [001691 FIG. 28 is a graph depicting the dissolution profile in 900 ml of pH 7.5 phosphate buffer using USP Apparatus 1 at 75 rpm at 37C of the composition described in Example 28. [00170] FIG. 29A is a graph depicting the dissolution profile in 900 ml of 0.1N HCl using USP Apparatus 1 at 75 rpm at 37C of the composition described in Example 29. [00171] FIG. 29B is a graph depicting the dissolution profile in 900 ml of pH 6.8 phosphate buffer using USP Apparatus 1 at 75 rpm at 37C of the composition described in Example 29. DEFINITIONS [00172] The term "a" or "an" as used herein means "one" or "one or more". [001731 The term "about" or "approximately" as used herein means within an acceptable range for the particular value as determined by one of ordinary skill in the art. An accetable range 24 WO 2009/095395 PCT/EP2009/050924 may depend on how the value is measured or determined, i.e., the limitations of the measurement system or on the desired properties sought to be obtained by the present invention. [00174] The term "active", "active agent", "active pharmaceutical agent", "active drug" or "drug" as used herein means the active pharmaceutical ingredient ("API"), which can be either bupropion hydrobromide, bupropion hydrochloride, citalopram hydrochloride, escitalopram oxalate, or quetiapine fumarate alone or in combination. The terms also include the anhydrous, hydrated, solvated forms, prodrugs, as well as polymorphs of the API. [00175] The term "tablet core" as used herein refers to the part of the once-daily pharmaceutical composition comprising the active agents, at least one pharmaceutically acceptable excipient, and optionally at least one stabilizer minus the control-releasing coat. More specifically, a tablet core can be a homogenous core, a controlled-release matrix core, or a bi layered core. [001761 The term "homogenous core" as used herein refers to a composition in which the combination of active agents selected from the group consisting of bupropion hydrochloride (bupropion HCl) and escitalopram oxalate (escitalopram Ox), bupropion hydrobromide (bupropion HBr) and citalopram hydrochloride (citalopram HCl), bupropion HBr and escitalopram Oxalate, or bupropion hydrobromide and quetiapine fumarate are blended together with at least one other pharmaceutically acceptable excipient to form a homogenous solid core which has a uniform structure or composition throughout and is free of discreet zones or layers of the active agent combinations. The homogenous core does not have any controlled-release properties and hence can also be referred to as "non-controlled release matrix homogenous cores". The homogenous core is preferably manufactured into a unitary core. [00177] The term "controlled release matrix core" as used herein refers to a composition comprising at least one hydrophilic control-releasing polymer present in a control-releasing amount, a combination of active agents selected from the group consisting of bupropion HCl and escitalopram Oxalate, bupropion HBr and citalopram HCl, bupropion HBr and escitalopram Oxalate, or bupropion hydrobromide and quetiapine fumarate, and at least one pharmaceutically acceptable excipient. Examples of such control-releasing polymers can include, for example, hydrophilic celluloses, ethyleellulose, polysaccharides, polyvinylpyrrolidone, zein, ethyleellulose, polymethacrylates, and mixtures of polyvinyl acetate and polyvinylpyrrolidone, commercially available as Kollidon* SR. The controlled release matrix core may comprise at least one other pharmaceutically acceptable excipient present in amounts that do not contribute to the control release of the combination of actives, but are present for the ease of manufacture of the controlled release matrix core. The ingredients are blended together to form a homogenous solid core, which 25 WO 2009/095395 PCT/EP2009/050924 has a uniform structure or composition throughout and is free of discreet zones or layers of the active agent combinations. [001781 The terms "therapeutically effective", "pharmaceutically effective", or "effective amount" as used herein refers to the amount or quantity of the combination of active agents enough for the required or desired therapeutic response or the amount which is sufficient to elicit an appreciable biological response, when administered to a patient in need of administration of the combination of drugs. The exact amount of the combination of active agents required will vary from subject to subject, depending on age, general condition of the subject, the severity of the condition being treated, and the particular combination of drugs administered. Thus, it is not possible to specify and exact "therapeutically effective" amount. As is well known, the specific dosage for a given patient under specific conditions and for a specific disease will routinely vary, but determination of the optimum amount in each case can readily be accomplished by simple routine procedures. Thus, an appropriate "therapeutically effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. [00179] The term "dose dumping" as used herein refers to the unintended rapid release of the entire amount or a significant fraction of the active agents in a short period of time from a controlled release or modified-release dosage form in a fixed time relative to the release of the active agents that occurs when the same controlled release or modified-release dosage form is not subject to conditions which induces dose dumping. Conditions that may induce dose dumping include for concomitant ingestion of alcohol or food. [001801 The term "control-releasing coating" or "sustained release coating" as used herein refers to a functional coating which when applied onto a core comprising an active or combination of actives does not result in the immediate release of the active or combination of actives. The coating is permeable to the active or combination of actives in the absence of any monomeric pore forming agents and is free of any pre-formed pores. The coating when applied onto a core comprising an active or combination of actives, modifies or controls the release of the active agents when compared to an uncoated core comprising the same active or combination of actives. The term "controlled release" includes any nonimmediate release pharmaceutical composition. A "controlled release" or "sustained release" pharmaceutical composition, when administered orally or when placed in dissolution media, does not result in the immediate release of the active or combination of actives from the once-daily pharmaceutical composition. [001811 The term "synchronous release" as used herein refers to the substantially similar rate of release of the combination of active agents from the once-daily pharmaceutical composition in dissolution media in-vitro regardless of pH. 26 WO 2009/095395 PCT/EP2009/050924 [00182] The term "plasticizer" as used herein includes any compound or combination of compounds capable of plasticizing or softening a polymer or binder used in the present invention, The use of plasticizers is optional, and can be included in the dosage form to modify the properties of and characteristics of the polymers used in the control-releasing coating for convenient processing of the coat during manufacture of the coated pharmaceutical composition. Once the coated, plasticized pharmaceutical composition has been manufactured, the plasticizer can function to increase the hydrophilicity of the coat in the environment of use. During manufacture of the coated, plasticized pharmaceutical composition, the plasticizer(s) can lower the melting temperature or glass transition temperature (softening point temperature) of the polymer or combination of polymers used in the manufacture of the control-releasing coat. The plasticizer(s) can also broaden the average molecular weight of a polymer or combination of polymers used in the manufacture of the control-releasing coat, thereby also lowering the glass transition temperature of the control-releasing coat. Plasticizers can also reduce the viscosity of a polymer or combinations of polymers for convenient processing of the coat solution when manufacturing the control-releasing coat. [001831 The term "tablet" as used herein refers to a single dosage form comprising the combination of active agents to be administered to a patient in need of such administration. The term "tablet" also includes a tablet that may be a combination of one or more minitablets. [00184] The term "single active agent pharmaceutical compositions" as used herein refers to pharmaceutical compositions comprising only one active agent. For example, a single active agent pharmaceutical composition of bupropion HBr contains only bupropion HBr and no other active agent. A single active agent pharmaceutical composition of bupropion HCl contains only bupropion HCl and no other active agent. The single active agent pharmaceutical composition of bupropion HCl described herein is commercially available as Wellbutrin® XL in 150 mg and 300 mg dosage strengths in the US. Similarly, the single active agent pharmaceutical composition of citalopram HCl contains only citalopram HCl and no other active agent. The single active agent pharmaceutical composition of citalopram HCl described herein is commercially available as Celexa® in the US and is available in dosage strengths of 10 mg, 20 mg, and 40 mg of the base. The single active agent pharmaceutical composition of escitalopram Oxalate described herein contains escitalopram Oxalate as the sole active agent and is commercially available as Lexapro® in the US in dosage strengths of 5 mg, 10 mg, and 20 mg of the base. [00185] The term "co-administration" as used herein refers to administering to a patient in need of such administration a first single active agent pharmaceutical composition together with a second single active agent pharmaceutical composition which may containing the same 27 WO 2009/095395 PCT/EP2009/050924 single active agent as the first single active agent pharmaceutical composition or a different single active agent pharmaceutical composition simultaneously. For example, co-administration of 300 mg Wellbutrin* XL and 20 mg Lexapro* means that one 300 mg Wellbutrin* XL tablet and one 20 mg Lexapro* tablet are administered to a patient in need of such administration at the same time. [001861 The term "immediate-release coat" as used herein is defined to mean a coat, which has substantially no influence on the rate of release of an active or combination of actives from the once-daily pharmaceutical composition in-vitro or in-vivo when compared to a pharmaceutical composition comprising the same active or combination of actives. The excipients comprising the immediate release coat have no substantial controlled release, swelling, erosion, or erosion and swelling properties, which could lead to the non-immediate release of the active or combination of actives from the once-daily pharmaceutical composition. The immediate release coat can enhance the chemical, biological, physical stability, or the physical appearance of the once-daily pharmaceutical composition. [00187] The term "immediate release core" or "immediate release layer" as used herein refers to a core or immediate release layer within a core, which has substantially no influence on the rate of release of an active or combination of actives from the once-daily pharmaceutical composition in-vitro or in-vivo when compared to a controlled release matrix core comprising the same active or combination of actives. The excipients comprising the immediate release core or immediate release layer within a core have no substantial controlled release, swelling, erosion, or erosion and swelling properties, which could lead to the non-immediate release of the active or combination of actives from the immediate release core or immediate release layer within a core. [001881 "Stabilizer", as the term is used herein, means a compound when present in an effective stabilizing amount inhibits or prevents the degradation of the active agents, so that the stabilizer can be used in the once-daily pharmaceutical composition while retaining much of the active agents' potency over time. Stabilizers useful in accordance with the present invention retain at least about 80% of the potency of the active agents and preferably over 90% of potency after one year of storage at room temperature (59 - 77 0 C) at 35-60% humidity. When used herein, the term "potency" means the weight of the active agent remaining in a pharmaceutical composition after a period of time has elapsed, for example about a year under ambient conditions or about 12 weeks at about 40C and about 75% relative humidity, expressed as a percentage of the initial weight of the active agents in the composition. The weight is measured by suitable quantitative analytical techniques known to one of ordinary skill in the art, such as for example an HPLC. 28 WO 2009/095395 PCT/EP2009/050924 [001891 "Free of food effect" as used herein means that the bioavailability of the desired combination of drug actives when administered using the once-daily pharmaceutical compositions of the present invention is not statistically significantly different between a fed and fasted study as described in the Guidance for Industry:Food-Effect Bioavailability and Fed Bioequivalence Studies, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), December 2002. DETAILED DESCRIPTION OF THE INVENTION [00190] The present invention relates to a pharmaceutical composition comprising a tablet core comprising a combination of actives selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, bupropion hydrobromide and escitalopram oxalate, and bupropion hydrobromide and quetiapine fumarate, and at least one pharmaceutically acceptable excipient, and a control-releasing coat surrounding the tablet core, wherein said composition surprisingly provides for a synchronous release of the combination of active agents across the pH range i.e., 0.1N HCl, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer in-vitro. The once-daily pharmaceutical composition surprisingly also provides for enhanced absorption of bupropion hydrobromide when administered to a subject in need of such administration. The once-daily pharmaceutical composition provides an about 15-25% increase in the bioavailability of bupropion when compared to co-administration of single active agent pharmaceutical compositions of bupropion hydrobromide and citalopram hydrochloride or bupropion hydrobromide and escitalopram oxalate. [00191] The Tablet Cores [00192] In certain embodiments of the present invention, the tablet core comprises a combination of actives selected from the group consisting of a therapeutically effective combination of active agents selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, bupropion hydrobromide and escitalopram oxalate, bupropion hydrobromide and quetiapine fumarate, and optionally a stabilizer, and at least one pharmaceutically acceptable excipient. [001931 In embodiments where the tablet core comprises a combination of bupropion hydrochloride and escitalopram oxalate, the amount of bupropion hydrochloride present in the homogenous tablet core can can be about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 99% w/w of the dry tablet core weight, and the amount of escitalopram oxalate can be present at about 0.l1%, about 0.2%, about 0.4%, 29 WO 2009/095395 PCT/EP2009/050924 about 0.6%, about 0.8%, about 1%, about 2%, about 4%, about 6%, ablout 8%, about 10%, about 20%, about 30%, about 40%, or about 50% w/w of the dry tablet core weight. In at least one embodiment of the present invention, the amount of bupropion hydrochloride is about 300 mg and the amount of escitalopram oxalate is about 20 mg (16mg escitalopram free base). [00194] In embodiments where the tablet core comprises a combination of bupropion hydrobromide and escitalopram oxalate, the amount of bupropion hydrobromide present in the homogenous tablet core can can be about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 99% w/w of the dry tablet core weight, and the amount of escitalopram oxalate can be present at about 0. 1%, about 0.2%, about 0.4%, about 0.6%, about 0.8%, about 1%, about 2%, about 4%, about 6%, ablout 8%, about 10%, about 20%, about 30%, about 40%, or about 50% w/w of the dry tablet core weight. In at least one embodiment of the present invention, the amount of bupropion hydrobromide is about 325 mg and the amount of escitalopram oxalate is about 16 mg. In at least one other embodiment of the present invention, the amount of bupropion hydrobromide is about 156 mg and the amount of escitalopram oxalate is about 8 mg. [00195] In embodiments where the tablet core comprises a combination of bupropion hydrobromide and citalopram hydrochloride, the amount of bupropion hydrobromide present in the homogenous tablet core can can be about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 99% w/w of the dry tablet core weight, and the amount of escitalopram oxalate can be present at about 0. 1%, about 0.2%, about 0.4%, about 0.6%, about 0.8%, about 1%, about 2%, about 4%, about 6%, ablout 8%, about 10%, about 20%, about 30%, about 40%, or about 50% w/w of the dry tablet core weight. In at least one embodiment of the present invention, the amount of bupropion hydrobromide is about 348 mg and the amount of citalopram hydrochloride is about 22.2 mg. [001961 In embodiments where the tablet core comprises a combination of bupropion hydrobromide and quetiapine fumarate, the amount of bupropion hydrobromide present in the homogenous tablet core can can be about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 99% w/w of the dry tablet core weight, and the amount of quetiapine fumarate can be present at about 1%, about 2%, about 4%, about 6%, about 8%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% w/w of the dry tablet core weight. In at least one embodiment of the present invention, the amount of bupropion hydrobromide is about 348 mg and the amount of quetiapine fumarate is about 23 mg. 30 WO 2009/095395 PCT/EP2009/050924 [001971 In certain embodiments of the present invention, the tablet core can comprise a pharmaceutically acceptable suitable stabilizer. Stabilizers are used to inhibit degradation of the combination of active agents, thereby maintaining their potency over time (at least 12-months) and increasing shelf life of the finished pharmaceutical compositions of the invention. Stabilizers for bupropion hydrochloride or bupropion hydrobromide are optional. Stabilizers suitable for inhibiting degradation of bupropion hydrochloride or bupropion hydrobromide may be chosen based on the stabilizer's ability to provide an acidic environment in the once-daily pharmaceutical composition. Stabilizers suitable for inhibiting degradation of bupropion hydrochloride or bupropion hydrobromide, in embodiments where such stabilizers are utilized include, for example, pharmaceutically acceptable inorganic acids, which at a concentration of about 0.3 1% w/w/ form an aqueous solution having a pH of from about 0.5 to about 0.4. Examples of such inorganic acids include, but are not limited to, hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid, or combinations thereof. Pharmaceutically acceptable suitable organic acids that have a solubility in water at 20C of less than about 10g/100g water and that at a concentration of about 60% w/w form an aqueous suspension having a pH of from about 0.9 to about 4.0 can also function as suitable stabilizers. Examples of such organic acids include, but are not limited to, dicarboxylic acids, such as for example, lactic, formic, acetic, oxalic, succinic, adipic, fumaric, and phthalic acid, or combinations thereof. Citric acid is another example of a suitable organic acid hat can be used as an effective stabilizer. Other non-limiting examples of suitable stabilizers include salts of organic bases such as, creatinine hydrochloride, preferably having an aqueous pH of from about 2.70 to about 3.10 at a concentration of about 10% w/w, thiamine hydrochloride, preferably having an aqueous pH of from about 2.95 to about 3.05, at a concentration of about 20% w/w, pyridoxine hydrochloride, preferably having an aqueous pH of from about 2.70 to about 2.72, at a concentration of about 20% w/w, or combinations thereof. Suitable salts of inorganic acids can also function as stabilizers. An example of such a salt includes, but is not limited to potassium phosphate monobasic, preferably having an aqueous pH of from about 4.20 to about 4.30 at a concentration of about 10 w/w. Other stabilizers suitable for use include acid salts of amino acids such as L-cysteine hydrochloride, L-cystine dihydrochloride and glycine hydrochloride, or combinations thereof and sulfites such as potassium metabisulfite and sodium bisulfite, or combinations thereof. The amount of stabilizer appropriate for inhibiting degradation of bupropion hydrochloride or bupropion hydrobromide can be about 0.l1%, about 0.2%, about 0.4%, about 0.6%, about 0.8%, about 1%, about 2%, about 4%, about 6%, about 8%, about 10%, about 15%, about 20%, about 25%, or about 30% w/w of the dry tablet core weight. In at least one embodiment of the present invention, the amount of stabilizer appropriate for inhibiting 31 WO 2009/095395 PCT/EP2009/050924 degradation of bupropion hydrochloride or bupropion hydrobromide can be about 5% w/w of the dry tablet core. Stabilizers for citalopram hydrochloride and escitalopram oxalate are optional. Pharmaceutically acceptable suitable stabilizers can be added to stabilize the citalopram hydrochloride or escitalopram oxalate when the citalopram hydrochloride or escitalopram oxalate is in intimate contact with either bupropion hydrochloride or bupropion hydrobromide. In embodiments of the present invention that utilize stabilizers for citalopram hydrochloride or escitalopram oxalate, the suitable stabilizers can be selected from the class of phenylated antioxidants. Non-limiting examples of such phenylated antioxidants include butlylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or combinations thereof. In certain embodiments of the present invention, BHT is the preferred stabilizer and can be present at about 0.01%, about 0.02%, about 0.04%, about 0.06%, about 0.08%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% w/w of the dry tablet core weight. In at least one embodiment of the present invention, BHT comprises about 0.l1% w/w of the dry tablet core weight. [001981 In certain embodiments of the present invention, the tablet core can comprise at least one pharmaceutically acceptable excipient conventional in the pharmaceutical arts. Such pharmaceutically acceptable excipients include spheronization aids, solubility enhancers, disintegrating agents, diluents, lubricants, binders, fillers, glidants, etc. Depending on the intended main function, excipients to be used in formulating compositions are subcategorized into different groups. However, one excipient can affect the properties of a composition in a series of ways, and many excipients used in compositions can thus be described as being multifunctional. [00199] In certain embodiments of the present invention, the tablet cores can comprise at least one diluent. Any suitable diluent conventional in the pharmaceutical art can be used. Non limiting examples of diluents suitable for use in the present invention include, lactose, microcrystalline cellulose, mannitol, and combinations thereof. In embodiments comprising lactose, the lactose can be lactose anhydrous (direct tabletting). In embodiments comprising microcrystalline cellulose, the microcrystalline cellulose can be, for example, AVICEL®, such as AVICEL® PH101 or AVICEL® PH 102. [00200] In certain embodiments of the present invention, the tablet cores can comprise at least one binder. Any suitable binder conventional in the pharmaceutical art can be used. A binder (also sometimes called adhesive) can be added to a drug-filler mixture to increase the mechanical strength of the tablet cores. Binders can be added to the formulation in different ways: (1) as a dry powder, which is mixed with other ingredients before wet agglomeration, (2) as a solution, which is used as agglomeration liquid during wet agglomeration, and is referred to as a 32 WO 2009/095395 PCT/EP2009/050924 solution binder, and (3) as a dry powder, which is mixed with the other ingredients before compaction. In this form the binder is referred to as a dry binder. Solution binders are a common way of incorporating a binder into granules. In certain embodiments, the binder used in the tablet cores is in the form of a solution binder. Non-limiting examples of binders useful for the tablet cores include hydrogenated vegetable oil, castor oil, paraffin, higher aliphatic alcohols, higher alphatic acids, long chain fatty acids, fatty acid esters, wax-like materials such as fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic polymers having hydrocarbon backbones, and mixtures thereof. Specific examples of water-soluble polymer binders include modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives (such as for example hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC)), polyvinyl alcohol and mixtures thereof. In certain embodiments of the invention the binder is polyvinylpyrrolidone (KOLLIDON* 90F, KOLLIDON* K29/32, or combinations thereof). The amount of binder present can be present at about 0.10%, about 0.2%, about 0.4%, about 0.6%, about 0.8%, about 1%, about 2%, about 4%, about 6%, about 8%, about 10%, about 12%, about 14%, about 16%, about 18%, or about 20% w/w of the dry tablet core weight. In at least one embodiment, the binder is present at about 3% w/w of the tablet dry weight. [00201] Certain embodiments of the present invention can comprise at least one lubricant. Any suitable lubricant conventional in the pharmaceutical art may be used. Non-limiting examples of lubricants useful for the tablet cores include glyceryl behenate, stearic acid, hydrogenated vegetable oils (such as hydrogenated cottonseed oil (STEROTEX*), hydrogenated soybean oil (STEROTEX* HM) and hydrogenated soybean oil & castor wax (STEROTEX*K), stearyl alcohol, leucine, polyethylene glycol (MW 1450, suitably 4000, and higher), magnesium stearate, glyceryl monostearate, stearic acid. polyethylene glycol, ethylene oxide polymers (CARBOWAX*), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, mixtures thereof and others as known in the art. In certain embodiments of the present invention, the lubricant can be glyceryl behenate (for example, COMPRITOL*888 ATO). The amount of lubricant present can be about 0.10%, about 0.2%, about 0.4%, about 0.6%, about 0.8%, about 1%, about 2%, about 4%, about 6%, about 8%, or about 10% w/w of the dry tablet core weight. In at least one embodiment, the lubricant is present at about 3% w/w of the tablet dry weight. [00202] In certain embodiments, one or both active agents may be granulated for use in this invention to manufacture the tablet core. Well known granulation methods can be used to manufacture the tablet core, including wet mass granulation (such as high shear and top-spray 33 WO 2009/095395 PCT/EP2009/050924 granulation), dry granulation (such as roller compaction and slugging) and hot-melt granulation. In certain embodiments, the active agents can be granulated individually and then combined, in order to be compressed into a tablet core or they can be co-granulated (both actives granulated together into the one granule) for incorporation into a tablet core. [002031 If the characteristics of both active agents are suitable and granulation is not required, both pharmaceutical actives may be incorporated directly into the tablet blend. Alternatively, one active may need to be granulated (as described above) while the second active is added directly to the tablet blend. If both actives are granulated, the active granules (either dispensed separately or as a co-granule) are incorporated into the tablet blend. The tablet blend is made using conventional tablet blend technologies (e.g. low shear blending using v-blenders or bowl blenders or high-shear blending). The actives are combined with a tablet lubricant. The tablet blend is compressed to the required shape, weight and hardness using a standard tablet press. [00204] In embodiments where the active agents are granulated separately, the bupropion hydrochloride or bupropion hydrochloride is uniformly granulated by spraying the active agents with an aqueous mixture comprising a binder, such as for example polyvinyl alcohol, and optionally a stabilizer, such as for example citric acid in a fluid bed processor or other suitable apparatus known in the art. The bupropion hydrochloride or bupropion hydrobromide granules thus formed are then dried and screened for granules between about 355 Pim and about 800 Pim. These appropriately seized bupropion hydrochloride or bupropion hydrobromide granules are retained for manufacture of the tablet core. Similarly, the citalopram hydrochloride or escitalopram oxalate is uniformly granulated by spraying the active agents with solvent based mixture comprising a binder, such as for example polyvinylpyrrolidone, and optionally a stabilizer, such as for example BHT in a fluid bed processor or other suitable apparatus known in the art. The citalopram hydrochloride or citalopram hydrobromide granules thus formed are then dried and screened for granules between about 355 pm and about 800 pm. In certain embodiments comprising quetiapine fumarate, the quetiapine fumarate can be granulated by spraying with an aqueous solution of polyvinyl alcohol in a suitable granulating apparatus and subsequently dried. The resulting granules are screened and granules between about 355 Pim about 800 pm are retained for use in the tablet core. [00205] In embodiments where a homogenous tablet core is desired, an appropriate amount of each of the sized granulated active agents, equivalent to the dosage strength desired, for the combination is mixed uniformly with a lubricant, such as for example glyceryl behenate, to obtain a homogenous mixture of granules of the two actives and lubricant. The homogenous 34 WO 2009/095395 PCT/EP2009/050924 mixture is then compressed into a homogenous tablet core using a tablet press to a hardness of about 130N using 9mm round normal concave shaped tablet tooling. The resulting immediate release homogenous tablet core is ready to be coated with a control-releasing coat. [002061 In embodiments where the combination of actives are co-granulated, the granulation solution is first prepared by combining an aqueous solution of a binder, such as for example, polyvinyl alcohol and optionally a stabilizer, such as for example, citric acid together with a solvent based solution comprising a binder, such as for example, polyvinylpyrrolidone and optionally a stabilizer, such as for example BHT. When combining the aqueous based and solvent-based solutions together, the BHT becomes finely dispersed in the PVA/citric acid solution. The combination of active agents is charged to the granulation chamber of a suitable apparatus in the required ratio to give the desired final dosage strengths of each active. The combination of active agents are then sprayed and simultaneously uniformly mixed for a period of time with the granulation solution to obtain a homogenously mixed co-granulate of the combination of active agents. The granules thus obtained are screened through a 1.00mm screen, and the material < 1.00mm retained for use in the tablet core. [00207] In embodiments where a homogenous tablet core using a co-granulated combination of actives is desired, the dried co-granules obtained by the above described co granulation method, are then uniformly combined with a lubricant (e.g., glyceryl behenate) to obtain a homogenous tablet core which is then compressed to a target tablet hardness of 130N using 9mm round normal concave shaped tablet tooling. The resulting immediate release homogenous tablet core is ready to be coated with a control-releasing coat. [002081 In certain embodiments of the present invention, the control-releasing coated homogenous tablet cores of the present invention can avoid the dose dumping of the combination of active agents in the presence of food and/or alcohol regardless of whether the homogenous tablet core is manufactured by the separate granulation or co-granulation methods described herein. [00209] In certain embodiments, the tablet core comprises a controlled-release matrix core. A controlled release matrix core is provided from which the kinetics of drug release from the matrix core are dependent at least in part upon the diffusion and/or erosion properties of excipients within the tablet core. In embodiments where the pharmaceutical composition comprises a tablet core comprising a controlled-release matrix core, the controlled release matrix core comprises a therapeutically effective amount of a combination of bupropion hydrochloride or bupropion hydrobromide and citalopram hydrochloride or escitalopram oxalate, bupropion hydrochloride, or bupropion hydrobromide and quetiapine fumarate, optionally a stabilizer, and at 35 WO 2009/095395 PCT/EP2009/050924 least one pharmaceutically acceptable excipient. The amount of the bupropion salt present in the controlled release matrix can be about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80% w/w of the dry controlled-release matrix core. The amount of the citalopram hydrochloride or escitalopram oxalate present in the controlled release matrix can be about 0.1%, about 0.2%, about 0.4%, about 0.6%, about 0.8%, about 1%, about 2%, about 4%, about 6%, about 8%, about 10%, about 20%, about 30%, about 40%, or about 50% w/w of the dry controlled-release matrix core. The amount of quetiapine fumarate present in the controlled release matrix can be about 0.1%, about 0.2%, about 0.4%, about 0.6%, about 0.8%, about 1%, about 2%, about 4%, about 6%, about 8%, about 10%, about 20%, about 30%, about 40%, or about 50% w/w of the dry controlled-release matrix core. The controlled release matrix is preferably uniparticulate, and can be uncoated or further coated with at least one control-releasing or non-functional coating. Functional coatings can include, by way of example, controlled release polymeric coatings, enteric polymeric coatings, and the like. Non-functional coatings are coatings that do not affect drug release but which affect other properties (e.g., they may enhance the chemical, biological, or the physical appearance of the controlled release formulation). Those skilled in the pharmaceutical art and the design of medicaments are well aware of controlled release matrices conventionally used in oral pharmaceutical compositions adopted for controlled release and means for their preparation. Examples of controlled release matrices are described in U.S. Pat. Nos. 6,326,027; 6,340,475; 6,905,709; 6,645,527; 6,576,260; 6,326,027; 6,254,887; 6,306,438; 6,129,933; 5,891,471; 5,849,240; 5,965,163; 6,162,467; 5,567,439; 5,552,159; 5,510,114; 5,476,528; 5,453,283; 5,443,846; 5,403,593; 5,378,462; 5,350,584; 5,283,065; 5,273,758; 5,266,331; 5,202,128; 5,183,690; 5,178,868; 5,126,145; 5,073,379; 5,023,089; 5,007,790; 4,970,075; 4,959,208; 4,59,208; 4,861,598; 4,844,909; 4,834,984; 4,828,836; 4,806,337; 4,801,460; 4,764,378; 4,421,736; 4,344,431; 4,343,789; 4,346,709; 4,230,687; 4,132,753; 5,591,452; 5,965,161; 5,958,452; 6,254,887; 6,156,342; 5,395,626; 5,474,786; and 5,919,826. [00210] Suitable excipient materials for use in such controlled release matrices include, by way of example, release-resistant or controlled release materials such as hydrophobic polymers, hydrophilic polymers, lipophilic materials and mixtures thereof. Non-limiting examples of hydrophobic, or lipophilic components include glyceryl monostearate, mixtures of glyceryl monostearate and glyceryl monopalmitate (Myvaplex, Eastman Fine Chemical Company), glycerylmonooleate, a mixture of mono, di and tri-glycerides (ATMUL 84S), glycerylmonolaurate, paraffin, white wax, long chain carboxylic acids, long chain carboxylic acid esters, long chain carboxylic acid alcohols, and mixtures thereof. The long chain carboxylic acids 36 WO 2009/095395 PCT/EP2009/050924 can contain from 6 to 30 carbon atoms; in certain embodiments at least 12 carbon atoms, and in other embodiments from 12 to 22 carbon atoms. In some embodiments this carbon chain is fully saturated and unbranched, while others contain one or more double bonds. In at least one embodiment the long chain carboxylic acids contain 3-carbon rings or hydroxyl groups. Non limiting examples of saturated straight chain acids include n-dodecanoic acid, n-tetradecanoic acid, n-hexadecanoic acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, montanic acid and melissic acid. Also useful are unsaturated monoolefinic straight chain monocarboxylic acids. Non-limiting examples of these include oleic acid, gadoleic acid and erucic acid. Also useful are unsaturated (polyolefinic) straight chain monocaboxyic acids. Non-limiting examples of these include linoleic acid, linolenic acid, arachidonic acid and behenolic acid. Useful branched acids include, for example, diacetyl tartaric acid. Non-limiting examples of long chain carboxylic acid esters include glyceryl monostearates; glyceryl monopalmitates; mixtures of glyceryl monostearate and glyceryl monopalmitate (Myvaplex 600, Eastman Fine Chemical Company); glyceryl monolinoleate; glyceryl monooleate; mixtures of glyceryl monopalmitate, glyceryl monostearate glyceryl monooleate and glyceryl monolinoleate (Myverol 18-92, Eastman Fine Chemical Company); glyceryl monolinolenate; glyceryl monogadoleate; mixtures of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, glyceryl monolinoleate, glyceryl monolinolenate and glyceryl monogadoleate (Myverol 18-99, Eastman Fine Chemical Company); acetylated glycerides such as distilled acetylated monoglycerides (Myvacet 5-07, 7-07 and 9-45, Eastman Fine Chemical Company); mixtures of propylene glycol monoesters, distilled monoglycerides, sodium stearoyl lactylate and silicon dioxide (Myvatex TL, Eastman Fine Chemical Company); mixtures of propylene glycol monoesters, distilled monoglycerides, sodium stearoyl lactylate and silicon dioxide (Myvatex TL, Eastman Fine Chemical Company) d-alpha tocopherol polyethylene glycol 1000 succinate (Vitamin E TPGS, Eastman Chemical Company); mixtures of mono- and diglyceride esters such as Atmul (Humko Chemical Division of Witco Chemical); calcium stearoyl lactylate; ethoxylated mono- and di-glycerides; lactated mono- and di-glycerides; lactylate carboxylic acid ester of glycerol and propylene glycol; lactylic esters of long chain carboxylic acids; polyglycerol esters of long chain carboxylic acids, propylene glycol mono- and di-esters of long chain carboxylic acids; sodium stearoyl lactylate; sorbitan monostearate; sorbitan monooleate; other sorbitan esters of long chain carboxylic acids; succinylated monoglycerides; stearyl monoglyceryl citrate; stearyl heptanoate; cetyl esters of waxes; cetearyl octanoate; C1O-C30 cholesterol/lavosterol esters; sucrose long chain carboxylic acid esters; and mixtures thereof. 37 WO 2009/095395 PCT/EP2009/050924 [00211] In certain embodiments, alcohols useful as excipient materials for controlled release matrices can include the hydroxyl forms of the carboxylic acids exemplified above and also cetearyl alcohol. [00212] In certain other embodiments, waxes can be useful alone or in combination with the materials listed above, as excipient materials for the controlled release matrix embodiments of the present invention. Non-limiting examples of these include white wax, paraffin, microcrystalline wax, carnauba wax, and mixtures thereof. [002131 The lipophilic agent can be present in an amount of from 5% to 90% by weight of the controlled release matrix dosage form. For example, in certain embodiments the lipophilic agent is present in an amount of from 10% to 85%, and in other embodiments from 30% to 60% by weight of the controlled release matrix dosage form. [00214] Non-limiting examples of hydrophilic polymers that can be used in certain embodiments of the controlled release matrix dosage form include hydroxypropylmethyleel lulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethyleeflulose (HEC), carboxymethylcellulose (CMC) or other cellulose ethers, polyoxyethylene, alginic acid, acrylic acid derivatives such as polyacmylic acid, Carbopol (B. F. Goodrich, Cleveland, Ohio). polymethacrylate polymer such as EUDRAGIT* RL, RS, R. S, NE and E (Rhome Pharma, Darmstadt, Germany), acrylic acid polymer, methacrylic acid polymer, hydroyethyl methacrylic acid (HEMA) polymer, hydroxymethyl methacrylic acid (HMMA) polymer, polyvinyl alcohols. In at least one embodiment of the present invention, the control-release matrix core is uncoated and comprises hydroxypropyl cellulose as the hydrophilic polymer. [00215] The hydrophilic polymer can be present in an amount of from 10% to 90% by weight of the controlled release matrix tablet core. For example, in certain embodiments the hydrophilic polymer can be present in an amount of from 20% to 75%, and in other embodiments from 30% to 60% by weight of the controlled release matrix tablet core. [002161 In certain embodiments, the controlled release matrix tablet core can comprise hydroxypropylmethylcellulose (HPMC). Non-limiting examples of hydroxypropyl methyleelluloses that are commercially available include METHOCEL* E (USP type 2910), METHOCEL* F (USP type 2906), METHOCEL* J (USP type 1828), METHOCEL*K (USP type 2201), and METHOCEL*3 10 Series, products of The Dow Chemical Company, Midland, Mich., USA. The average degree of methoxyl substitution in these products can range from 1.3 to 1.9 (of the three positions on each unit of the cellulose polymer that are available for substitution) while the average degree of hydroxypropyl substitution per unit expressed in molar terms can range from 0.13 to 0.82. The controlled release matrix tablet core can comprise different HPMC 38 WO 2009/095395 PCT/EP2009/050924 grades having different viscosities. The size of a HPMC polymer is expressed not as molecular weight but instead in terms of its viscosity as a 2% solution by weight in water. Different HPMC grades can be combined to achieve the desired viscosity characteristics. For example, the at least one pharmaceutically acceptable polymer can comprise two HPMC polymers such as for example METHOCEL*K3 LV (which has a viscosity of 3 cps) and METHOCEL*K100M CR (which has a viscosity of 100,000 cps). In addition, the polymer can comprise two hydroxypropyleellulose forms such as KLUCEL*LF and KLUCEL*EF. In addition, the at least one polymer can comprise a mixture of a KLUCEL* and a METHOCEL*. [00217] In certain embodiments the controlled release matrix tablet core can comprise a polyethylene oxide (PEO). PEO is a linear polymer of unsubstituted ethylene oxide. In certain embodiments poly(ethylene oxide) polymers having viscosity-average molecular weights of 100,000 daltons and higher can be used. Non-limiting examples of poly(ethylene oxide)s that are commercially available include: POLYOX* NF, grade WSR Coagulant, molecular weight 5 million; POLYOX* grade WSR 301, molecular weight 4 million; POLYOX* grade WSR 303, molecular weight 7 million; POLYOX® grade WSR N-60 K, molecular weight 2 million; and mixtures thereof. These particular polymers are products of Dow Chemical Company, Midland, Mich., USA. Other examples of polyethylene oxides exist and can likewise be used. The required molecular weight for the PEO can be obtained by mixing PEO of differing molecular weights that are available commercially. [002181 In certain embodiments of the controlled release matrix tablet core, PEO and HPMC can be combined within the same controlled release matrix. In certain embodiments, the polyethylene oxides can have molecular weights ranging from 2,000,000 to 10,000,000 Da. For example, in certain embodiments the polyethylene oxides can have molecular weights ranging from 4,000,000 to 7,000,000 Da. In certain embodiments the HPMC polymers have a viscosity within the range of 4,000 centipoise to 200,000 centipoise. For example, in certain embodiments, the HPMC polymers can have a viscosity of from 50,000 centipoise to 200,000 centipoise, and in other embodiments from 80,000 centipoise to 120,000 centipoise. The relative amounts of PEO and HPMC within the controlled release matrix tablet core can vary within the scope of the invention. In at least one embodiment the PEO:HPMC weight ratio can be from about 1:3 to about 3:1. For example, in certain embodiments the PEO:HPMC weight ratio is from about 1:2 to about 2:1. As for the total amount of polymer relative to the entire controlled release matrix tablet core, this can vary as well and can depend on the desired drug loading. In at least one embodiment the total amount of polymer in the controlled release matrix tablet core can constitute from 15% to 90% by weight of the controlled release matrix tablet core. For example, 39 WO 2009/095395 PCT/EP2009/050924 in certain embodiments the total amount of polymer in the controlled release matrix tablet core can be from 20% to 75%, in other embodiments from 30% to 60%, and in still other embodiments from 10% to 20% by weight of the controlled release matrix tablet core. [00219] In certain embodiments of the invention the controlled release matrix tablet core can comprise a hydrophobic polymer such as ethyleellulose. The viscosity of ethyleellulose can be selected in order to influence of rate the drug release. In certain embodiments the ethyleellulose has a viscosity from 7 to 100 cP (when measured as a 5% solution at 25.degree. C. in an Ubbelohde viscometer, using a 80:20 toluene:ethanol solvent.) In certain embodiments the hydrophobic polymer can constitute from 10% to 90% by weight of the controlled release matrix core. For example, in certain embodiments the hydrophobic polymer can constitutes from 20% to 7 5 %, and in other embodiments from 30% to 60% by weight of the controlled release matrix dosage tablet core. [00220] In certain embodiments of the invention the controlled release matrix tablet core can comprise at least one lubricant. Non-limiting examples of lubricants include stearic acid, hydrogenated vegetable oils (such as hydrogenated cottonseed oil (STEROTEX®), hydrogenated soybean oil (STEROTEX® HM) and hydrogenated soybean oil & castor wax (STEROTEX®K)) stearyl alcohol, leucine, polyethylene glycol (MW 1450, suitably 4000, and higher), magnesium stearate, glyceryl monostearate, stearic acid, glycerylbehenate, polyethylene glycol, ethylene oxide polymers (for example, available under the registered trademark CARBOWAX* from Union Carbide, Inc., Danbury, Conn.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, and mixtures thereof. A lubricant can be present in an amount of from 0 to 4% by weight of the compressed uncoated matrix. For example, in certain embodiments the lubricant can be present in an amount of from 0 to 2.5% by weight of the controlled release matrix tablet core. [00221] In certain embodiments of the invention the controlled release matrix tablet core comprises a plasticizer. Non-limiting examples of plasticizers include dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, triacetin, citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, 1,2-propylene glycol, polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, acetylated monoglycerides, phthalate esters, and mixtures thereof. In certain embodiments of the invention, the plasticizer can be present in an amount of from 1% to 70% by weight of the controlled release polymer in the controlled release matrix tablet core. For example, in certain embodiments the plasticizer can be present in an amount of from 5% to 50%, and in other embodiments from 10% to 40% by weight of the controlled release polymer in the controlled release matrix tablet core. 40 WO 2009/095395 PCT/EP2009/050924 [00222] In certain embodiments of the invention the controlled release matrix tablet core can comprise at least one diluent, non-limiting examples of which include dicalcium phosphate, calcium sulfate, lactose or sucrose or other disaccharides, cellulose, cellulose derivatives, kaolin, mannitol, dry starch, glucose or other monosaccharides, dextrin or other polysaccharides, sorbitol, inositol, sucralfate, calcium hydroxyl-apatite, calcium phosphates and fatty acid salts such as magnesium stearate. In certain embodiments the diluent can be added in an amount so that the combination of the diluent and the combination of active agent comprises up to 60%, and in other embodiments up to 50%, by weight of the composition. [002231 In certain embodiments of the invention the controlled release matrix tablet core can comprise a solubilizer. The solubilizer can act to increase the instantaneous solubility of the bupropion salt. The solubilizer can be selected from hydrophilic surfactants or lipophilic surfactants or mixtures thereof. The surfactants can be anionic, nonionic, cationic, and zwitterionic surfactants. The hydrophilic non-ionic surfactants can be selected from the group comprised of, but not limited to: polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group from triglycerides, vegetable oils, and hydrogenated vegetable oils such as glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide, d-ca-iocopheryl polyethylene glycol 1000 succinate. The ionic surfactants can be selected from the group comprised of, but not limited to: alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkyisulfates ; fatty acid salts; sodium docusate; acyl lactylates; mono and di-acetylated tartaric acid esters of mono- and di- glycericles; succinylated mono-and di glycerides; citric acid esters of mono-and di- glycerides; and mixtures thereof. The lipophilic surfactants can be selected from the group comprised of, but not limited to: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives: polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono-and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group from glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil soluble vitamins/vitamin derivatives; PEG sorbitan fatty acid esters, PEG glycerol fatty acid esters, polyglycerized fatty acid, polyoxycihylene-polyoxypropylene block copolymers, sorbitan 41 WO 2009/095395 PCT/EP2009/050924 fatty acid esters; and mixtures thereof. In certain embodiments, the solubilizer can be selected from: PEG-20-glyceryl stearate, PEG-40 hydrogenated castor oil, PEG 6 corn oil, lauryl macrogol-32 glyceride, stearoyl macrogol glyceride, polyglyceryl-10 mono dioleate, propylene glycol olcate, Propylene glycol dioctanoate, Propylene glycol caprylate/caprate, Glyceryl monooleate, Glycerol monolinoleate, Glycerol monostearate, PEG-20 sorbitan monolaurate, PEG-4 lauryl ether, Sucrose distearate, Sucrose monopalmitate, polyoxyethylene polyoxypropylene block copolymer, polyethylene glycol 660 hydroxystearate, Sodium lauryl sulfate, Sodium dodecyl sulphate, Dioctyl suphosuccinate, L-hydroxypropyl cellulose, hydroxylethyleellulose, hydroxyl propyleellulose, Propylene glycol alginate, sodium taurochol ate, sodium glycocholate, sodium deoxycholate, betains, polyethylene glycol, d-a-tocopheryl polyethylene glycol 1000 succinate, and mixtures thereof. In at least one other embodiment the solubilizer can be selected from PEG-40 hydrogenated castor oil, lauryl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-20 sorbitan monolaurate, PEG-4 lauryl ether, polyoxyethylene polyoxypropylene block copolymer, Sodium lauryl sulphate, Sodium dodecyl sulphate, polyethylene glycol, and mixtures thereof. [00224] In certain embodiments of the invention the controlled release matrix tablet core comprises a swelling enhancer. Swelling enhancers are members of a special category of excipients that swell rapidly to a large extent resulting in an increase in the size of the tablet. At lower concentrations, these excipients can be used as superdisintegrants; however at concentrations above 5% w/w these agents can function as swelling enhancers and help increase the size of the controlled release matrix tablet core. According to certain embodiments of the controlled release matrix tablet core of the invention, examples of swelling enhancers include but are not limited to: low-substituted hydroxypropyl cellulose, microcrystalline cellulose, cross linked sodium or calcium carboxymethyl cellulose, cellulose fiber, cross-linked polyvinyl pyrrolidone, cross-linked polyacrylic acid, cross-linked amberlite resin, alginates, colloidal magnesium-aluminum silicate, corn starch granules, rice starch granules, potato starch granules, pregelatinised starch, sodium carboxymethyl starch and mixtures thereof. In certain embodiments comprising the controlled release matrix tablet core, the swelling enhancer is cross-linked polyvinylpyrrolidone. The amount of the swelling enhancer can be from 5% to 90% by weight of the controlled release matrix tablet core. For example, in certain embodiments the swelling enhancer is present in an amount of from 10% to 70%, and in other embodiments from 15% to 50% by weight of the controlled release matrix tablet core. [00225] In certain embodiments of the invention, the controlled release matrix tablet core comprises additives for allowing water to penetrate into the core of the preparation (hereinafter 42 WO 2009/095395 PCT/EP2009/050924 referred to as "hydrophilic base"). In certain embodiments, the amount of water required to dissolve 1 g of the hydrophilic base is not more than 5 ml, and in other embodiments is not more than 4 ml at the temperature of 20'C ± 5'C. The higher the solubility of the hydrophilic base in water, the more effective is the base in allowing water into the core of the preparation. The hydrophilic base includes, inter alia, hydrophilic polymers such as polyethylene glycol (PEG); (e.g. PEG400, PEG 1500, PEG4000, PEG6000 and PEG20000, produced by Nippon Oils and Fats Co.) and polyvinylpyrrolidone (PVP); (e.g. PVP K30, of BASF), sugar alcohols such as D sorbitol, xylitol, or the like, sugars such as sucrose, anhydrous maltose, D-fructose, dextran (e.g. dextran 40), glucose or the like, surfactants such as polyoxyethylene-hydrogenated castor oil (HCO; e.g. Cremophor RH40 produced by BASF, HCO-40 and HCO-60 produced by Nikko Chemicals Co.), polyoxyethylene-polyoxypropylene glycol (e.g. Pluronic F68 produced by Asahi Denka Kogyo K.K.), polyoxyethylene-sorbitan high molecular fatty acid ester (Tween; e.g. Tween 80 produced by Kanto Kagaku K.K.), or the like; salts such as sodium chloride, magnesium chloride, or the like; organic acids such as citric acid, tartaric acid, or the like; amino acids such as glycine, p-alanine, lysine hydrochloride, or the like; and amino sugars such as meglumine. In at least one embodiment the hydrophilic base is PEG6000, PVP, D-sorbitol, or mixtures thereof. [002261 The controlled release matrix tablet core of the present invention can further contain one or more pharmaceutically acceptable excipients such as, granulating aids or agents, colorants, flavorants, pH adjusters, anti-adherents, glidants and like excipients conventionally used in pharmaceutical compositions. [00227] In at least one other embodiment of the invention there is provided a controlled release matrix tablet core comprising the combination of actives incorporated within the homogeneous controlled release matrix tablet core, which include effective amounts of at least two polymers having opposing wettability characteristics, wherein at least one polymer is selected which demonstrates a stronger tendency towards hydrophobicity and the other polymer(s) is selected such that it demonstrates a stronger tendency towards hydrophilicity. In at least one embodiment the polymer demonstrating a stronger tendency towards hydrophobicity can be ethylcellulose (EC) whereas the polymer demonstrating a stronger tendency towards hydrophilicity can be hydroxyethylcellulose (HEC) and/or hydroxypropyl methyleellulose (HPMC). [002281 In certain embodiments, the pharmaceutical composition of the present invention can be provided as a controlled release matrix tablet core, which can be optionally encased in the controlled-release coating described herein. Such coated controlled-release matrix core tablets 43 WO 2009/095395 PCT/EP2009/050924 avoid the dose dumping of the combination of active agents in the presence of food and/or alcohol. Certain embodiments of the present invention provide for a method for preparing the controlled release of the combination of actives, the method comprising blending the combination of actives with 5% to 25% by weight of hydrophillic polymer, and 1% to 25% by weight of hydrophobic polymer, adding suitable pharmaceutical excipients, surface active agents and lubricants, granulating the mixture with solvents such as isopropyl alcohol, drying the granular mixture, milling the dried mixture, adding from 5% to 70% by weight of ethyleellulose, adding a lubricant and optionally a glidant and compressing the granules into matrices. The controlled release matrices can optionally be encased in a gastrointestinal resistant coat or a pharmaceutically acceptable film coat. [00229] In certain embodiments of the present invention, a swellable controlled release matrix tablet core is provided in which the combination of actives is dispersed in a polymeric matrix that is water-swellable rather than merely hydrophilic, that has an erosion rate that is substantially slower than its swelling rate, and that releases the combination of actives primarily by diffusion. The rate of diffusion of the combination of actives out of the swellable matrix can be slowed by increasing the drug particle size, by the choice of polymer used in the matrix, and/or by the choice of molecular weight of the polymer. The swellable matrix can comprise a relatively high molecular weight polymer that swells upon ingestion. In at least one embodiment the swellable matrix swells upon ingestion to a size that is at least twice its unswelled volume, and that promotes gastric retention during the fed mode. Upon swelling, the swellable matrix can also convert over a prolonged period of time from a glassy polymer to a polymer that is rubbery in consistency, or from a crystalline polymer to a rubbery one. The penetrating fluid then causes release of the combination of actives in a gradual and prolonged manner by the process of solution diffusion, i.e., dissolution of the combination of actives in the penetrating fluid and diffusion of the dissolved combination of actives back out of the swellable matrix. The swellable matrix itself is solid prior to administration and, once administered, remains undissolved in (i.e., is not eroded by) the environment of use for a period of time sufficient to permit the majority of the combination of actives to be released by the solution diffusion process during the fed mode. The rate-limiting factor in the release of the combination of actives from the swellable matrix is therefore controlled diffusion of the combination of actives from the swellable matrix rather than erosion, dissolving or chemical decomposition of the swellable matrix. [002301 The combination of actives in the swellable matrix can be present in a therapeutically effective amount of from 0. 1% to 99% by weight of the dried controlled release matrix tablet core in a ratio according to the desired dosage strengths. In certain other 44 WO 2009/095395 PCT/EP2009/050924 embodiments the combination of actives is present in the swellable matrix in an amount of from 5% to 90%, in still other embodiments from 10% to 80%, and in even still other embodiments from 25% to 80% by weight of the swellable matrix in a ratio according to the desired dosage strengths. [002311 The water-swellable polymer forming the swellable matrix tablet core in accordance with the embodiments of the present invention can be any polymer that is non-toxic, that swells in a dimensionally unrestricted manner upon imbibition of water, and that provides for a synchronous release of the combination of actives. Non-limiting examples of polymers suitable for use in the swellable matrix include cellulose polymers and their derivatives (such as for example, hydroxyethyleellulose, hydroxypropylcellulose, carboxymethyleellulose, and microcrystalline cellulose, polysaccharides and their derivatives, polyalkylene oxides, polyethylene glycols, chitosan, poly(vinyl alcohol), xanthan gum, maleic anhydride copolymers, poly(vinyl pyrrolidone), starch and starch-based polymers, poly (2-ethyl-2-oxazoline), poly(ethyleneimine), polyurethane hydrogels, and crosslinked polyacrylic acids and their derivatives, and mixtures thereof. Further examples include copolymers of the polymers listed in the preceding sentence, including block copolymers and grafted polymers. Specific examples of copolymers include PLURONIC* and TECTONIC® which are polyethylene oxide-polypropylene oxide block copolymers available from BASF Corporation, Chemicals Div., Wyandotte, Mich., USA. [00232] The controlled release matrices of the present invention can be manufactured by methods known in the art such as those described in the patents listed above (e.g. U.S. Pat. No. 5,965,161). Other examples of methods of manufacturing controlled release matrices include wet granulation, dry granulation (e.g. slugging, roller compaction), direct compression, melt granulation, and rotary granulation. [002331 In certain embodiments of the present invention the controlled release matrix tablet cores can optionally be coated with the control-releasing coat or a non-functional aesthetic coat using well-known coating methods. [00234] In certain embodiments of the present invention, the tablet core can comprise a bi-layer tablet core, wherein the first layer comprises an immediate release composition comprising one drug of the desired combination, optionally a stabilizer and at least one pharmaceutically acceptable excipient and the second layer comprises an immediate release composition comprising the second drug of the desired combination, optionally a stabilizer, and at least one pharmaceutically acceptable excipient. The two layers are in direct contact. This bi layer tablet core can subsequently be coated with a control-releasing coat such as the one 45 WO 2009/095395 PCT/EP2009/050924 described herein. The layers can be manufactured according to the separately granulated method described herein and subsequently compressed into a bi-layer tablet core using methods and equipment well known in the art (e.g., using a bi-layer press). Alternatively, each layer can be directly compressed using methods well known in the art and subsequently compressed to form the bi-layer tablet core using methods and equipment well known in the art. The immediate release bi-layer tablet core is subsequently coated with a control-releasing coat. The pharmaceutical compositions comprising a bi-layer tablet core avoid dose dumping of the combination of active agents in the presence of food and/or alcohol regardless of whether the homogenous tablet core is manufactured by the separate granulation or co-granulation methods described herein. [00235] The Control-Releasing Coat [002361 In at least one embodiment, the control-releasing coat is a semipermeable coat, which comprises a water-insoluble water-permeable film forming polymer, a water-soluble polymer and at least one plasticizer. The coat is permeable to both the passage of the actives and water and is free of any preformed pores. [00237] In certain embodiments, the water-insoluble water-permeable film-forming polymer can include, a cellulose ether, such as for example, ethyleellulose; a cellulose ester, such as for example, cellulose acetate; methacrylic acid derivatives, such as for example EUDRAGIT* NE30D or NE40D; aqueous ethyleellulose dispersions, such as for example, Surelease*; aqueous acrylic enteric systems, such as for example, Acryl-EZE*, Kollicoat* MAE30DP, and Kollicoat* MAE 1OOP; and polyvinyl derivatives, such as for example, Kollidon® SR, Kollicoat® SR3OD, and Kollicoat® EMM30D. Combinations of these water-insoluble water-permeable film-forming polymers can also be used. In at least one embodiment, ethyleellulose is used as the water insoluble, water-permeable film-forming polymer. Ethyleelluloses of a variety of viscosities can be utilized. Non-limiting examples of the ethylcellulose that can be used include, for example,
ETHOCEL
TM Standard Premium 4, 7, 10, 20, 45 and 100 or ETHOCEL TM Standard FP Premium 7, 10, and 100. Any combination of these ethyleelluloses can be used. In at least one embodiment of the invention, ETHOCELTM Standard FP Premium 100 is the water-insoluble water-permeable film-forming polymer. Depending on the viscosity of the water-insoluble water permeable film-forming polymer used, the amount of the water-insoluble, water-permeable film forming polymer can be present at about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% w/w of the dry coat weight. In at least one embodiment of the present invention, the amount of water-insoluble water-permeable film 46 WO 2009/095395 PCT/EP2009/050924 forming polymer, such as for example ETHOCELTM Standard FP Premium 100, used can be about 50%, about 50.5%, about 51%, about 51.5%, or about 52% w/w of the dry coat weight. In at least one embodiment of the present invention, the amount of ETHOCELTM Standard FP Premium 100, used is about 51.2% w/w of the dry coat weight. [00238] In certain embodiments, the water-soluble polymer can be a partially or substantially water-soluble hydrophilic substance intended to modulate film permeability to both the medium and the actives in the environment of use. Non-limiting examples of the water soluble polymers can be water-soluble cellulose ethers, vinylic polymers and combinations thereof. Non-limiting examples of the water-soluble cellulose ethers that can be used in the manufacture of the control-releasing coat can include, for example, cellulose ethers such as methyleellulose, hydroxypropylmethyleellulose, non-ionic water-soluble cellulose ethers, and any combinations thereof. Non-limiting examples of the vinylic polymers that can be used in the manufacture of the control-releasing coat include, for example, polyvinyl alcohol, polyvinylpyrrolidone, and any combinations thereof. The amount of the water-soluble polymer present can be about 1%, about 2%, about 4%, about 6%, about 8%, about 10%, about 20%, about 30%, about 40%, about 50% or about 60% w/w of the dry coat weight. In at least one embodiment of the present invention, the preferred water-soluble polymer is polyvinylpyrrolidone, such as for example, KOLLIDON* as supplied by BASF and is present at about 32% w/w of the dry coat weight. Similar polyvinylpyrrolidones are also available from other suppliers. [002391 Plasticizers are generally added to film coatings to modify the physical properties of a polymer or polymer combinations used during manufacture of a particular coating system. The amount and choice of the plasticizer contributes to the hardness of the tablet and can even affect its dissolution or disintegration characteristics, as well as the chemical and physical stability of the coated tablet. Certain plasticizers can increase the elasticity and/or pliability of a coat, thereby decreasing the coat's brittleness. Once a pharmaceutical composition or dosage form is manufactured, certain plasticizers can function to increase the hydrophilicity of the coat in the environment of use. Therefore, plasticizers can function to enhance processing of coating formulations during manufacture as well as affect release characteristics of a coating system. Non-limiting examples of plasticizers that can be used in the control-releasing coat described herein include acetylated monoglycerides; acetyltributyl citrate, butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; tripropioin; diacetin; dibutyl phthalate; acetyl monoglyceride; acetyltriethyl citrate, polyethylene glycols; castor oil; rape seed oil, olive oil, sesame oil, triethyl 47 WO 2009/095395 PCT/EP2009/050924 citrate; polyhydric alcohols, glycerol, glycerin sorbitol, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidized tallate, triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate, diethyloxalate, diethylmalate, diethylfumerate, dibutylsuccinate, diethylmalonate, dibutylphthalate, dibutylsebacate, glyceroltributyrate, polyols (e.g. polyethylene glycol) of various molecular weights, and mixtures thereof. It is contemplated and within the scope of the invention, that a combination of plasticizers can be used in the present composition. In certain embodiments of the invention, the plastizer is a combination of polyethylene glycol 3350 and dibutyl sebacate. In certain other embodiments, the plasticizer is dibutyl sebacate. The amount of plasticizer can be present at about 0.1%, about 0.2%, about 0.4%, about 0.6%, about 0.8%, about 1%, about 2%, about 4%, about 6%, about 8%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% w/w of the dry coat weight. In at least one embodiment of the present invention where the plasticizer used is a combination of polyethylene glycol 3350 and dibutyl sebacate, the amount of plasticizer used can be present at about 3%, about 5%, about 7%, about 9%, about 11%, about 12%, or about 15% of the dry coat weight in a ratio of about 2:1 (polyethylene glycol 3350 : dibutyl sebacate). In embodiments where the plasticizer is dibutyl sebabcate, the amount of dibutyl sebacate is about 5% w/w of the dry coat weight. [00240] It will be readily apparent to the skilled artisan that the permeability of the control-releasing coating will affect the release profile of the actives from the immediate release tablet cores described herein. This is true even if a controlled-releasing coat is applied onto the controlled-release matrix core described herein. Not only can the relative proportions of the preferred polymer coat ingredients, notably the ratio of the water-insoluble water-permeable film forming polymer : plasticizer : water-soluble polymer, be varied to alter the permeability of the control-releasing coat, but so can the type and viscosity of the polymers used as well as the thickness of coating applied. Thus, if a more controlled i.e., a slower release is desired, the ratio of water-insoluble water-permeable film-forming polymer: water-soluble polymer and/or the amount of coating applied would be increased. Also, if the polymers being used are of a lower viscosity, the amount of coating to be applied can be increased to obtain the desired release profile when compared to a control-release coating formulation with a higher viscosity polymer. Addition of other excipients to the tablet core can also alter the permeability of the control releasing coat. For example, if it is desired that the tablet cores described herein further comprise 48 WO 2009/095395 PCT/EP2009/050924 an expanding agent, the amount of plasticizer in the control-releasing coat should be increased to make the coat more pliable as the pressure exerted on a less pliable control-releasing coat by the expanding agent would rupture the coat. Other excipients such as taste masking agents and pigments can also be added to the control-releasing coat. [00241] Depending on the desired in-vitro or in-vivo release profile of the actives, the weight gained after coating the tablet cores with the control-releasing coat can be about 4%, about 6%, about 8%, about 10%, about 12%, about 14%, about 16%, about 18%, about 20%, about 22%, about 24%, or about 25% w/w of the dry tablet core. In at least one embodiment of the present invention, the weight gained is about 5% of the dry coat weight. [00242] Preparation and application of the control-releasing coat are well known in the art. Nevertheless, an exemplary process for preparing the coating solution can be as follows. The water-insoluble water-permeable film-forming polymer (e.g. ethyleellulose), and the plasticizer or plasticizers (e.g. PEG 3350 or PEG 3350 and dibutyl sebacate), can be dissolved in an organic solvent (e.g. ethyl alcohol) or a mixture of organic solvents and water (e.g. ethyl alcohol, propanol, and water). The water-soluble polymer (e.g. polyvinylpyrrolidone) is added next until a homogenous mixture is achieved. The resulting solution can be, if necessary, homogenized by passing it through a high-pressure homogenizer. The coating solution is then spray coated onto the tablet cores using a tablet coater, fluidized bed apparatus, or any other suitable coating apparatus known in the art until the desired weight gain is achieved. The tablet cores coated with the control-releasing mixture are subsequently dried. [002431 The controlled-release pharmaceutical formulations prepared by the process described above surprisingly exhibit a synchronous release of the combination of actives at least in-vitro. In certain embodiments the synchronous release is observed in 900 ml of 0. IN HCl, pH4.5 acetate buffer, or pH 6.8 phosphate buffer using a USP Apparatus 1 at 75 rpm at 37'C. In certain embodiments, the control-release pharmaceutical compositions of the invention surprisingly also provide an about 15% to about 26% enhanced absorption of bupropion hydrobromide in the plasma when compared to co-administration of single active agent pharmaceutical compositions of bupropion hydrobromide and citalopram hydrochloride or bupropion hydrobromide and escitalopram oxalate. [00244] In certain embodiments of the present invention, the pharmaceutical compositions of the invention can avoid the dose-dumping phenomenon when the compositions are administered with food and/or alcohol. [00245] Examples for manufacturing the pharmaceutical compositions of the invention are described below. It should be understood that these examples are intended to be exemplary 49 WO 2009/095395 PCT/EP2009/050924 and that the specific constituents, amounts thereof, and methods described may be varied therefrom by the skilled artisan based on his/her skill and knowledge in the art of drug delivery without undue experimentation in order to achieve the desired in-vitro dissolution and pharmacokinetic parameters described and claimed herein. [002461 The embodiments of the invention and variations thereof relating to the pharmaceutical compositions of the invention will be apparent to those versed in the drug delivery art from the above description and the following examples taken in conjunction with the accompanying claims. EXAMPLE 1 [00247] Homogenous Tablet Core Composition and Method of Manufacture - Separate Granulation Method. [002481 A. Bupropion HBr Granulation: Bupropion HBr Granule Composition Component %w/w Bupropion HBr 91.72 Polyvinyl Alcohol 3.24 Citric Acid 5.04 [00249] The pharmaceutical active, bupropion HBr, was top-spray granulated using a Glatt GPCG 1 (6 inch chamber). The theoretical batch size was 3270.6g. An aqueous (purified water) solution of polyvinyl alcohol (PVA) (4.82% of solution) and citric acid (7.5% of solution) was sprayed onto 3 kg of bupropion HBr to a weight gain of 9.02% to produce a granule comprising of 91.73% bupropion HBr, 3.23% PVA, and 5.04% citric acid. The powder bed temperature was maintained between 38-45'C, and the liquid spray rate maintained between 5-7 g/min throughout the granulation process. When spraying of the granulation solution was stopped, the granules were fluid bed dried to an LOD (loss on drying) level of < 1%. The granules were screened and the granules with a particle size of between about 355 Jim and about 800 im were retained for manufacture of the homogenous tablet core. [00250] B. Citalopram HCl Granulation: Citalopram HCl Granule Composition Component %w/w Citalopram HCl 93.28 Kollidon* 90F 5.60 Butylated hydroxytoluene 1.12 50 WO 2009/095395 PCT/EP2009/050924 [002511 The pharmaceutical active, citalopram HCl, was top-spray granulated using a Glatt GPCG 1 (6 inch chamber). The theoretical batch size was 3216g. An organic solvent (2 propanol) solution of Kollidon* 90F (10% of solution) and butylated hydroxytoluene (BHT) (2% of solution) was sprayed onto about 3 kg of citalopram HCl to a weight gain of about 7.2% to produce a granule comprising of about 93.28% citalopram HCl, 5.60% Kollidon* 90F, and 1.12% BHT. The powder bed temperature was maintained between 20-35'C, and the liquid spray rate maintained between 13 - 17 g/min throughout the granulation process. When spraying of the granulation solution was stopped, the granules were fluid bed dried to an LOD (loss on drying) level of < 1%. The granules were screened and the granules with a particle size of between about 355 m and about 800 Jim were retained for manufacture of the homogenous tablet core. [00252] C. Homogenous Tablet Core Composition and Method of Manufacture [002531 To manufacture the homogenous tablet core comprising about 348mg of bupropion HBr (equivalent to about 260mg of bupropion base) and about 22.2mg of citalopram HCl (equivalent to about 20mg citalopram base), a blend with the following composition was prepared: about 91.3% bupropion HBr granules (manufactured as described above), about 5.8% citalopram HCl granules (manufactured as described above) and about 2.9% Compritol 888 ATO (screened through a 500 Jim screen). A homogenous blend of about 1500g was manufactured by dispensing about 1369.5g of bupropion HBr granules, about 87.Og of citalopram HCl granules, and about 43.5g of the screened Compritol 888 ATO. The material was added to a v-blender (15 litre shell of a Pharmatech AB-050 v-blender) in the following order: 1. about 12 of the bupropion HBr granules 2. All of the citalopram HCl granules 3. All of the Compritol 888 ATO 4. The remaining bupropion HBr granules The tablet core components were homogenously blended for about 10 minutes, with the v-shell speed set to 25 rpm and the intensifier bar turned off. The homogenous blend was discharged from the v-shell and charged to a tablet press (Riva Picolla 10 station rotary tablet press) and compressed to a target tablet weight of about 416mg and a target tablet hardness of about 130N using 9mm round normal concave shaped tablet tooling. The resulting product comprises the homogenous tablet core, which at this point is an immediate release core having the following composition: 51 WO 2009/095395 PCT/EP2009/050924 Homogenous Tablet Core Composition Component mg/tablet %w/w Bupropion HBr 348.36 83.74 Citalopram HCl 22.51 5.41 PVA 12.31 2.96 Citric Acid 19.14 4.60 BHT 0.27 0.06 Kollidon* 90F 1.35 0.32 Compritol 888 ATO 12.06 2.90 [00254] Tablet Coat Composition And Method of Manufacture Tablet Control-Releasing Coat Composition Component %w/w Ethocel 100 FP Premium 4.61 Kollidon* 90F 2.86 PEG 3350 1.03 Dibutylsebacate 0.50 2-Propanol 8.68 Absolute Ethanol 81.86 Purified water 0.46 [002551 The homogenous IR tablet cores were coated with an ethyleellulose based film by preparing an organic solvent solution consisting of about 4.610% ethocel standard 1 OOFP premium, about 2.86% Kollidon* 90F, about 1.03% carbowax sentry polyethylene glycol 3350 granular NF FCC grade, about 0.5% dibutyl sebacate NF, about 8.68% 2-propanol, about 81.86% absolute ethanol, and about 0.46% purified water. The plasticized polymer solution was applied to about 1 kg of the final tablet cores using an O'Hara Labcoat I tablet coating machine (12" pan) until about a 10% weight gain was obtained. The product temperature was maintained between about 3 8-44'C, and the liquid spray rate was maintained between about 7 - 9 g/min throughout the coating process. The controlled release coated tablets were then cured for about 10 minutes (inlet air is set at about 35'C, pan speed set at 5 rpm). [002561 The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Tables 1A, iB, and IC. The results of the dissolution testing are presented as a % of the total bupropion HBr and citalopram HCl in the controlled release tablet (batch no. 0612087) and are also depicted in FIGs. 1A, iB, and IC. 52 WO 2009/095395 PCT/EP2009/050924 Table 1A Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Citalopram HCl 1 12 13 2 29 33 3 45 50 4 59 64 5 73 77 6 84 87 7 93 95 8 100 101 9 103 104 10 104 105 11 104 106 12 104 106 13 103 105 14 103 105 15 102 105 16 102 104 Table 1B Dissolution Conditions: 900 ml pH 4.5 acetate buffer, USP Apparatus 1, 75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Citalopram HCl 1 12 15 2 28 34 3 43 49 4 57 63 5 70 75 6 81 85 7 91 94 8 98 100 9 103 104 10 105 106 11 106 107 12 106 107 13 106 107 14 106 107 15 105 107 16 105 106 53 WO 2009/095395 PCT/EP2009/050924 Table IC Dissolution Conditions: 900 ml pH 6.8 phosphate buffer, USP Apparatus 1, 75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Citalopram HCl 1 12 16 2 27 35 3 42 52 4 56 66 5 69 79 6 80 90 7 88 97 8 95 101 9 98 104 10 100 106 11 100 107 12 100 107 13 101 107 14 100 107 15 99 106 16 99 106 EXAMPLE 2 [002571 Homogenous Tablet Core Composition and Method of Manufacture - Separate Granulation Method [00258] A. Bupropion HBr Granulation: [002591 The bupropion HBr granules were prepared as described in Example 1. [00260] B. Escitalopram Oxalate Granulation: Escitalopram Oxalate Granule Composition Component %w/w Escitalopram Ox 91.74 Kollidon* 90F 6.88 Butylated hydroxytoluene 1.38 [00261] The pharmaceutical active, escitalopram Oxalate, was top-spray granulated using a Glatt GPCG 1 (6 inch chamber). The theoretical batch size was 2725g. An organic solvent (2 propanol) solution of Kollidon* 90F (6% of solution) and butylated hydroxytoluene (BHT) (1 .2% of solution) was sprayed onto 2.5 kg of escitalopram Oxalate to a weight gain of 9% to produce a granule comprising of 91.74% escitalopram oxalate, 6.88% Kollidon* 90F, and 1.38% BHT. The powder bed temperature was maintained between 15-30'C, and the liquid spray rate maintained between 15 - 19 g/min throughout the granulation process. When spraying of the granulation solution was stopped, the 54 WO 2009/095395 PCT/EP2009/050924 granules were fluid bed dried to an LOD (loss on drying) level of < 1%. The granules were screened and the granules with a particle size of between about 355 m and about 800 Jim were retained for use to manufacture the homogenous tablet core. [00262] C. Homogenous Tablet Core Composition and Method of Manufacture [002631 To manufacture the homogenous tablet core comprising 348mg of bupropion HBr (equivalent to 260mg of bupropion base) and 25.5mg of escitalopram Oxalate (equivalent to 20mg escitalopram base), a homogenous tablet blend with the following composition was prepared; 90.46% bupropion HBr granules (manufactured as outlined in Example 1), 6.63% escitalopram Oxalate granules (manufactured as outlined above) and 2.91% Compritol 888 ATO (screened through a 500 m screen). A homogenous tablet blend of 1500g was manufactured by dispensing 1356.90g of bupropion HBr granules, 99.45g of escitalopram Oxalate granules, and 43.65g of the screened Compritol 888 ATO. The material was added to a v-blender (15 litre shell of a Pharmatech AB-050 v-blender) in the following order: 1. 1 2 of the bupropion HBr granules 2. All of the escitalopram Oxalate granules 3. All of the Compritol 888 ATO 4. The remaining bupropion HBr granules The tablet components were blended for 10 minutes, with the v-shell speed set to 25 rpm and the intensifier bar turned off. The homogenous tablet blend was discharged from the v-shell and charged to a tablet press (Riva Bilayer 11 station rotary tablet press) and compressed to a target tablet weight of 419.4mg and a target tablet hardness of 1OON using 9mm round normal concave shaped tablet tooling. The resulting product comprises the homogenous tablet core, which at this point is an immediate release core having the following composition: Homogenous Tablet Core Composition Component mg/tablet %w/w Bupropion HBr 347.98 82.97 Escitalopram Ox 25.51 6.08 PVA 12.29 2.93 Citric Acid 19.12 4.56 BHT 0.38 0.09 Kollidon* 90F 1.91 0.46 Compritol 888 ATO 12.21 2.91 [00264] Tablet Coat Composition And Method of Manufacture 55 WO 2009/095395 PCT/EP2009/050924 [002651 The homogenous IR tablet cores were next coated with the control-releasing coat as described in Example 1. [002661 The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Tables 2A, 2B, and 2C. The results of the dissolution testing are presented as a % of the total bupropion HBr and escitalopram Oxalate in the controlled release tablet (batch no. 0705037) and are also depicted in FIGs. 2A, 2B, and 2C. Table 2A Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HBr escitalopram Ox 1 12 15 2 29 35 4 61 68 8 100 99 12 103 102 16 102 101 Table 2B Dissolution Conditions: 900 ml pH 4.5 acetate buffer, USP Apparatus 1, 75 rpm, 37 0 C % Released Time (hr) Bupropion HBr escitalopram Ox 1 12 15 2 28 35 4 57 64 8 97 97 12 102 101 16 101 100 Table 2C Dissolution Conditions: 900 ml pH 6.8 phosphate buffer, USP Apparatus 1, 75 rpm, 37 0 C % Released Time (hr) Bupropion HBr escitalopram Ox 1 11 14 2 27 33 4 55 61 8 94 92 12 97 96 16 96 96 56 WO 2009/095395 PCT/EP2009/050924 EXAMPLE 3 [002671 Homogenous Tablet Core Composition and Method of Manufacture - Co Granulation Method [002681 A. Bupropion HBr /Escitalopram Oxalate Co-Granulation: Bupropion HBr /Escitalopram Oxalate Co-Granulation Composition Component %w/w Bupropion HBr 85.40 Escitalopram Ox 6.25 Butylatedhydroxytoluene 0.09 PVA 3.23 Citric Acid 5.03 [00269] The pharmaceutical actives, bupropion HBr and escitalopram Oxalate, were top spray granulated using a Glatt GPCG 1 (6 inch chamber). The theoretical batch size was 3273.9g. The granulation solution was prepared in 3 steps: 1.) an aqueous (purified water) solution of polyvinyl alcohol (PVA) (4.91% of solution) and citric acid (7.64% of solution) was prepared 2.) a solvent (2-propanol) solution of BHT (7.73% of solution) was prepared 3.) the BHT solvent solution was added to the aqueous PVA/citric acid solution and mixed for a minimum of 20 minutes. The BHT became finely dispersed in the PVA / citric acid solution. The final composition of the granulation suspension was 4.82% PVA, 7.50% citric acid, 1.67% 2 propanol, 0.14% BHT, 85.87% purified water. [00270] The buproion HBR and escitalopram Oxalate were charged to the granulation chamber in the required ratio to give the desired final dosage strengths of each active. For a 348mg dose of bupropion HBr and a 25.5mg dose of escitalopram Oxalate the actives were dispensed such that the material in the granulation chamber consisted of 93.2% bupropion HBr and 6.8% escitalopram Ox. In this example 3kg of material was granulated, 2796g of bupropion HBr mixed with 204g of escitalopram Ox. Approximately half of the bupropion HBr was charged to the granulation chamber, followed by all of the escitalopram Oxalate, and the remainder of the bupropion HBr. The granulation suspension was sprayed onto the 3 kg mix of bupropion HBr to a weight gain of 9.13% to produce a granule comprising of 85.40% bupropion HBr, 6.23% 57 WO 2009/095395 PCT/EP2009/050924 escitalopam Oxalate, 3.24% PVA, 5.04% citric acid, and 0.09% BHT. The powder bed temperature was maintained between 40-45'C, and the liquid spray rate maintained between 5 7 g/min throughout the granulation process. When spraying of the granulation solution was stopped, the granules were fluid bed dried to an LOD (loss on drying) level of < 1%. The granules were screened through a 1.00mm screen, and the material < 1.00mm retained for manufacture of the homogenous tablet core. [00271] B. Homogenous Tablet Core Composition and Method of Manufacture [00272] To manufacture a homogenous tablet core comprising 348mg of bupropion HBr (equivalent to 260mg of bupropion base) and 25.5mg of escitalopram Oxalate (equivalent to 20mg escitalopram base), a homogenous tablet blend with the following composition was prepared; 97.l1% bupropion HBr / escitalopram Oxalate co-granules (manufactured as outlined above), and 2.9% Compritol 888 ATO (screened through a 500 m screen). A homogenous tablet blend of 1500g was manufactured by dispensing 1456.5g of bupropion HBr / escitalopram Oxalate co-granules, and 43.5g of the screened Compritol 888 ATO. The material was added to a v-blender (15 litre shell of a Pharmatech AB-050 v-blender) in the following order: 1. ~ half of the bupropion HBr / escitalopram Oxalate co-granules 2. All of the Compritol 888 ATO 3. The remaining bupropion HBr / escitalopram Oxalate co-granules The tablet components were blended for 10 minutes, with the v-shell speed set to 25 rpm and the intensifier bar turned off. The homogenous tablet blend was discharged from the v-shell and charged to a tablet press (Riva Bilayer 11 station rotary tablet press) and compressed to a target tablet weight of 420mg and a target tablet hardness of 130N using 9mm round normal concave shaped tablet tooling. The resulting product comprises the homogenous tablet core, which at this point is an immediate release core has the following composition: Homogenous Tablet Core Composition Component mg/tablet %w/w Bupropion HBr 348.28 82.92 Escitalopram Ox 25.49 6.07 PVA 13.17 3.14 Citric Acid 20.51 4.88 BHT 0.37 0.09 Compritol 888 ATO 12.18 2.90 [002731 Tablet Coat Composition And Method of Manufacture 58 WO 2009/095395 PCT/EP2009/050924 [00274] The homogenous IR tablet cores were next coated with the control-releasing coat as described in Example 1. [00275] The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Tables 3A, 3B, and 3C. The results of the dissolution testing are presented as a % of the total bupropion HBr and escitalopram Oxalate in the controlled release tablet (batch no. 0704028) and are also depicted in FIGs. 3A, 3B, and 3C. Table 3A Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Escitalopram Ox 1 13 14 2 31 32 4 62 63 8 102 102 12 104 106 16 103 105 Table 3B Dissolution Conditions: 900 ml pH 4.5 acetate buffer, USP Apparatus 1, 75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Escitalopram Ox 1 12 13 2 28 29 4 58 57 8 99 96 12 103 102 16 102 101 Table 3C Dissolution Conditions: 900 ml pH 6.8 phosphate buffer, USP Apparatus 1, 75 rpm, 37 0 C % Released Time (hr) Bupropion HBr escitalopram Ox 1 11 13 2 27 29 4 57 59 8 98 99 12 100 104 16 99 104 59 WO 2009/095395 PCT/EP2009/050924 EXAMPLE 4 [00276] Homogenous Tablet Core Composition and Method of Manufacture. [002771 A. Homogenous Tablet Core Composition and Method of Manufacture [00278] The homogenous tablet core composition comprises a mixture of bupriopion HBr (348 mg) and citalopram HCl (22.2 mg). The homogenous tablet core was made according to the co-granulation method described in Example 3 with citalopram HCl instead of escitalopram Ox. The resulting product comprises the homogenous tablet core, which at this point is an immediate release tablet core has the following composition: Homogenous Tablet Core Composition Component mg/tablet %w/w Bupropion HBr 348.36 83.74 Citalopram HCl 22.51 5.41 PVA 12.31 2.96 Citric Acid 19.14 4.60 BHT 0.27 0.06 Kollidon* 90F 1.35 0.32 Compritol 888 ATO 12.06 2.90 [00279] Tablet Coat Composition And Method of Manufacture [00280] The control-releasing coat was manufactured according to the method described in Example 1 in the absence of the plasticizer PEG 3350. The resulting control-releasing coat has the following composition: Control-releasing Coat Composition Minus PEG 3500 Component %w/w Ethocel 100 FP Premium 4.61 Kollidon 90F 2.86 Dibutylsebacate 0.50 2-Propanol 8.68 Absolute Ethanol 82.89 Purified water 0.46 [002811 The dissolution profile of the above pharmaceutical composition (batch no. E2240) was determined under the dissolution conditions described below in Table 4. The result of the dissolution testing is presented as a % of the total bupropion HBr and citalopram HCl in the controlled release tablet and is also depicted in FIG. 4. 60 WO 2009/095395 PCT/EP2009/050924 Table 4 Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Citalopram HCl 1 11 12 2 27 30 4 56 60 8 97 93 12 105 101 16 103 99 EXAMPLE 5 [00282] Homogenous Tablet Core Composition and Method of Manufacture. [00283] The homogenous tablet core was manufactured according to the method described in Example 3 with the following bupropion HBr/escitalopram Oxalate co-granule and homogenous tablet core composition: Bupropion HBr /Escitalopram Oxalate Co-Granulation Composition Component %w/w Bupropion HBr 86.88 Escitalopram Ox 4.78 Butylatedhydroxytoluene 0.07 PVA 3.24 Citric Acid 5.03 Homogenous Tablet Core Composition Component mg/tablet %w/w Bupropion HBr 325.02 84.36 Escitalopram Ox 17.88 4.64 PVA 12.12 3.15 Citric Acid 18.82 4.88 BHT 0.26 0.07 Compritol 888 ATO 11.17 2.90 [00284] Tablet Coat Composition and Method of Manufacture [002851 The control-releasing coat was manufactured according to the method described in Example 1 accept that the polyvinylpyrrolidone (Kollidon* 90F) was replaced with the lower viscosity Kollidon* K29/32 at the same %w/w. The resulting control-releasing coat has the following composition: 61 WO 2009/095395 PCT/EP2009/050924 Control-releasing Coat Composition with a lower viscosity PVP (Kollidon*K29/32) Component %w/w Ethocel 100 FP Premium 4.61 Kollidon* K29/32 2.86 PEG 3350 1.03 Dibutylsebacate 0.50 2-Propanol 8.68 Absolute Ethanol 81.86 Purified water 0.46 [002861 The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Table 5. The result of the dissolution testing is presented as a % of the total bupropion HBr and escitalopram Oxalate in the controlled release tablet and is also depicted in FIG. 5. Table 5 Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Escitalopram Ox 1 9 13 2 20 26 4 43 49 8 82 81 12 98 97 16 99 98 EXAMPLE 6 [002871 Homogenous Tablet Core Composition and Method of Manufacture. [00288] The homogenous tablet core was manufactured according to the method described in Example 3 with the following co-granule and homogenous tablet core composition: Bupropion HBr /Escitalopram Oxalate Co-Granulation Composition Component %w/w Bupropion HBr 86.88 Escitalopram Ox 4.78 Butylatedhydroxytoluene 0.07 PVA 3.24 Citric Acid 5.03 62 WO 2009/095395 PCT/EP2009/050924 Homogenous Tablet Core Composition Component mg/tablet %w/w Bupropion HBr 325.02 84.36 Escitalopram Ox 17.88 4.64 PVA 12.12 3.15 Citric Acid 18.82 4.88 BHT 0.26 0.07 Compritol 888 ATO 11.17 2.90 [00289] Tablet Coat Composition and Method of Manufacture [00290] The control-releasing coat was manufactured according to the method described in Example 1 accept that the grade of ethyleellulose polymer was changed from Ethocel Std 100 PREM (Dow Chemical Company) to the lower viscosity grade, Ethocel Std 10 PREM. The resulting control-releasing coat has the following composition: Control-releasing Coat Composition with a lower viscosity grade Ethylcellulose (Ethocel Std 10 PREM) Component %w/w Ethocel Std 10 FP Premium 4.61 Kollidon* K29/32 2.86 PEG 3350 1.03 Dibutylsebacate 0.50 2-Propanol 8.68 Absolute Ethanol 81.86 Purified water 0.46 [00291] The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Table 6. The result of the dissolution testing is presented as a % of the total bupropion HBr and escitalopram Oxalate in the controlled release tablet (batch no. E2828) and is also depicted in FIG. 6. Table 6 Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Escitalopram Ox 1 13 16 2 30 34 4 61 63 8 98 97 12 100 100 16 100 100 63 WO 2009/095395 PCT/EP2009/050924 EXAMPLE 7 [00292] Homogenous Tablet Core Composition and Method of Manufacture. [00293] The homogenous tablet core was manufactured according to the method and composition described in Example 2. [00294] Tablet Coat Composition and Method of Manufacture [00295] The homogenous IR tablet cores were coated with a polymethacrylate based film by preparing an aqueous suspension consisting of about 26.97% aqueous disperion of Eudragit NE30D, 5.3% Tale, 2.47% Hydroxypropyl Methyleellulose, 2.25% PEG4000, 0.31 % Somethicone C, 0.23% Tween 80 and 62.47% purified water. Approximately 60% of the required water was heated to approximately 65C using a paddle mixer, to which the hydroxypropyl methyleellulose, Tween* 80 and Simethicone* C were added. Tale was added to the remaining water in a separate vessel under conditions of high shear, and the suspension mixed under high shear for approximately 20 minutes, following which the tale suspension was added to the other vessel. Upon cooling, the NE30D dispersion was added directly to the coating suspension, and the entire suspension mixed for approximately 30 minutes, following which the suspension was sieved through a 150pm screen to remove lumps. The plasticized polymer solution was applied to about 1 kg of the final tablet cores using an O'Hara Labcoat I tablet coating machine (12" pan) until about a 10% weight gain was obtained. The product temperature was maintained between about 30'C, and the liquid spray rate maintained between about 7 - 9 g/min throughout the coating process. The controlled release coated tablets were then cured for about 24 hours at 40C in a conventional tray drying oven [002961 The control-releasing coating formulation has the following composition: Component %w/w Eudragit NE 30 D 26.97 Talc 1889 5.30 Hydroxypropyl Methyleellulose 2.47 (Pharmacoat 606) PEG 4000 2.25 Simethicone C 0.31 Tween 80 0.23 Water 62.47 [00297] The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Table 7. The result of the dissolution testing 64 WO 2009/095395 PCT/EP2009/050924 is presented as a % of the total bupropion HBr and escitalopram oxalate in the controlled release tablet is also depicted in FIG. 7. Table 7 Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Escitalopram Ox 1 2 2 2 5 7 4 14 19 8 36 44 12 57 63 16 74 77 EXAMPLE 8 [00298] BUPROPION HBR (3 25MG) / ESCITALOPRAM OXALATE (17.9MG) PHARMACEUTICAL COMPOSITION [00299] Homogenous Tablet Core Composition and Method of Manufacture. [00300] The homogenous tablet core was manufactured according to the method and composition described in Example 5. [00301] Tablet Coat Composition and Method of Manufacture [00302] The control-releasing coat was manufactured according to the method described in Example 1 accept that the polyvinylpyrrolidone (Kollidon* 90F) was reduced by 50%. The resulting control-releasing coat has the following composition: Control-releasing Coat Composition with 50% less PVP (Kollidon* 90F) Component %w/w Ethocel 100 FP Premium 4.61 Kollidon* 90F 1.43 PEG 3350 1.03 Dibutylsebacate 0.50 2-Propanol 8.68 Absolute Ethanol 83.29 Purified water 0.46 [00303] The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Table 8. The result of the dissolution testing 65 WO 2009/095395 PCT/EP2009/050924 is presented as a % of the total bupropion HBr and escitalopram oxalate in the controlled release tablet and is also depicted in FIG. 8. Table 8 Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Escitalopram Ox 1 0 0 2 1 1 4 4 6 8 13 19 12 22 31 16 31 40 EXAMPLE 9 [00304] Homogenous Tablet Core Composition and Method of Manufacture. [00305] A. Bupropion HBr /Escitalopram Oxalate Co-Granulation: Bupropion HBr /Escitalopram Oxalate Co-Granulation Composition Component %w/w Bupropion HBr 86.0 Escitalopram Oxalate 5.6 Butylatedhydroxytoluene 0.1 PVA 3.3 Citric Acid 5.0 [00306] The pharmaceutical actives, bupropion HBr and escitalopram oxalate, were top spray granulated using a Glatt GPCG 1 (6 inch chamber). The theoretical batch size was 3273.9g. The granulation solution was prepared in 3 steps: 4.) an aqueous (purified water) solution of polyvinyl alcohol (PVA) (5.6% of solution) and citric acid (8.7% of solution) was prepared 5.) a solvent (2-propanol) solution of BHT (5.9% of solution) was prepared 6.) the BHT solvent solution was added to the aqueous PVA/citric acid solution and mixed for a minimum of 20 minutes. The BHT became finely dispersed in the PVA / citric acid solution. The final composition of the granulation 66 WO 2009/095395 PCT/EP2009/050924 suspension was 4.82% PVA, 7.50% citric acid, 1.67% 2 propanol, 0.1% BHT, 85.91% purified water. [003071 The bupropion HBR and escitalopram oxalate were charged to the granulation chamber in the required ratio to give the desired final dosage strengths of each active. For a 312mg dose of bupropion HBr and a 16mg dose of escitalopram oxalate the actives were dispensed such that the material in the granulation chamber consisted of 93.6% bupropion HBr and 6.4% escitalopram oxalate. In this example 3kg of material was granulated, 2815.5g of bupropion HBr mixed with 193.73g of escitalopram oxalate. Approximately half of the bupropion HBr was charged to the granulation chamber, followed by all of the escitalopram oxalate, and next the remainder of the bupropion HBr was charged to the chamber. The granulation suspension was sprayed onto the 3 kg mix of bupropion HBr to a weight gain of 9.1% to produce a granule comprising of 86% bupropion HBr, 5.6% escitalopam oxalate, 3.3% PVA, 5.0% citric acid, and 0. 1% BHT. The powder bed temperature was maintained between 40 - 45'C, and the liquid spray rate maintained between 5 - 7 g/min throughout the granulation process. When spraying of the granulation solution was stopped, the granules were fluid bed dried to an LOD (loss on drying) level of < 1%. The granules were screened through a 1.00mm screen, and the material < 1.00mm retained for manufacture of the homogenous tablet core. [003081 B. Homogenous Tablet Core Composition and Method of Manufacture [003091 To manufacture a homogenous tablet core comprising 312mg of bupropion HBr (equivalent to 234mg of bupropion base) and 16mg of escitalopram oxalate (equivalent to 12.5mg escitalopram base), a homogenous tablet blend with the following composition was prepared; 97% bupropion HBr / escitalopram oxalate co-granules (manufactured as outlined above), and 3% Compritol 888 ATO (screened through a 500 m screen). A homogenous tablet blend of 1500g was manufactured by dispensing 1455g of bupropion HBr / escitalopram oxalate co granules, and 45g of the screened Compritol 888 ATO. The material was added to a v-blender (15 litre shell of a Pharmatech AB-050 v-blender) in the following order: 4. ~ half of the bupropion HBr / escitalopram oxalate co-granules 5. All of the Compritol 888 ATO 6. The remaining bupropion HBr / escitalopram oxalate co-granules The tablet components were blended for 10 minutes, with the v-shell speed set to 25 rpm and the intensifier bar turned off. The homogenous tablet blend was discharged from the v-shell and charged to a tablet press (Riva Bilayer 11 station rotary tablet press) and compressed to a target tablet weight of 373.5mg and a target tablet hardness of 130N using 9mm round normal concave 67 WO 2009/095395 PCT/EP2009/050924 shaped tablet tooling. The resulting product comprises the homogenous tablet core, which at this point is an immediate release core having the following composition: Homogenous Tablet Core Composition Component mg/tablet %w/w Bupropion HBr 312 84 Escitalopram Oxalate 20.4 5 PVA 11.68 3 Citric Acid 18.21 5 BHT 0.36 0.09 Compritol 888 ATO 10.83 3 [003101 Tablet Coat Composition And Method of Manufacture [003111 The homogenous IR tablet cores were coated with Kollicoat SR30D (a polyvinyl acetate dispersion with 27% polyvinyl acetate, 2.7% povidone and 0.3% sodium lauryl sulfate) by preparing an aqueous suspension consisting of about 50% aqueous disperion of Kollidon SR30D, 3.5% Tale, 1.5% Triethyl citrate and 45% purified water. Tale was added to approximately 80% of the water and the dispersion mixed with high shear for approximately 15 minutes. In a separate vessel triethyl citrate was added to the Kollicoat SR30D, and the suspension mixed, following which the Tale dispersion was added to the other vessel and the coating suspension made up to volume with the remaining water. The entire suspension was mixed overnight prior to use in coating. The plasticized polymer solution was applied to about 1 kg of the final tablet cores using an O'Hara Labcoat I tablet coating machine (12" pan) until about a 12% weight gain was obtained. The product temperature was maintained between about 30'C, and the liquid spray rate was maintained between about 3 - 5 g/min throughout the coating process. [00312] The resulting control-releasing coat has the following composition: Control-releasing Coat Composition with Kollicoat* SR30D Component %w/w Kollicoat" SR30D 50 Triethyl Citrate 1.5 Tale 2.5 Purified water 45 [003131 The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Table 9. The result of the dissolution testing 68 WO 2009/095395 PCT/EP2009/050924 is presented as a % of the total bupropion HBr and escitalopram oxalate in the controlled release tablet and is also depicted in FIG. 9. Table 9 Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Escitalopram Ox 1 17 17 2 49 48 3 76 74 4 94 93 6 105 104 8 105 103 10 104 103 EXAMPLE 10 [00314] Homogenous Tablet Core Composition and Method of Manufacture. [003151 The homogenous tablet core was manufactured according to the method described in Example 3 with the following co-granule and homogenous tablet core composition: Bupropion HBr (325 mg) / Escitalopram Oxalate (17.9 mg) Co-Granule Composition Component %w/w Bupropion HBr 86.88 Escitalopram Ox 4.78 Butylatedhydroxytoluene 0.07 PVA 3.24 Citric Acid 5.03 Homogenous Tablet Core Composition Component mg/tablet %w/w Bupropion HBr 325.02 84.36 Escitalopram Ox 17.88 4.64 PVA 12.12 3.15 Citric Acid 18.82 4.88 BHT 0.26 0.07 Compritol 888 ATO 11.17 2.90 [00316] Tablet Coat Composition and Method of Manufacture [003171 The control-releasing coat was manufactured according to the method and composition described in Example 1. 69 WO 2009/095395 PCT/EP2009/050924 [003181 The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Table 10. The result of the dissolution testing is presented as a % of the total bupropion HBr and escitalopram Oxalate in the controlled release tablet and is also depicted in FIG. 10. Table 10 Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Escitalopram Ox 0 1 13 14 2 30 32 4 59 59 8 97 94 12 102 99 16 101 99 EXAMPLE 11 [00319] Homogenous Tablet Core Composition and Method of Manufacture. [00320] The homogenous tablet core was manufactured according to the method described in Example 3 with the following co-granule and homogenous tablet core composition: Bupropion HBr (400 mg) / Escitalopram Oxalate (19.2 mg) Co-Granule Composition Component %w/w Bupropion HBr 87.45 Escitalopram Ox 4.20 Butylatedhydroxytoluene 0.08 PVA 3.24 Citric Acid 5.03 Homogenous Tablet Core Composition Component mg/tablet %w/w Bupropion HBr 400.03 84.92 Escitalopram Ox 19.21 4.07 PVA 14.82 3.15 Citric Acid 23.00 4.88 BHT 0.37 0.08 Compritol 888 ATO 13.66 2.90 [00321] Tablet Coat Composition and Method of Manufacture 70 WO 2009/095395 PCT/EP2009/050924 [00322] The control-releasing coat was manufactured according to the method and composition described in Example 1. [003231 The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Table 11. The result of the dissolution testing is presented as a % of the total bupropion HBr and escitalopram Oxalate in the controlled release tablet and is also depicted in FIG. 11. Table 11 Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Escitalopram Ox 1 15 16 2 30 33 4 55 56 8 93 88 12 103 97 16 102 97 EXAMPLE 12 [00324] Homogenous Tablet Core Composition and Method of Manufacture. [00325] The homogenous tablet core was manufactured according to the method described in Example 3 with the following co-granule and homogenous tablet core composition: Bupropion HBr (171.3 mg) / Escitalopram Oxalate (171.3 mg) Co-Granule Composition Component %w/w Bupropion HBr 45.78 Escitalopram Ox 45.78 Butylatedhydroxytoluene 0.10 PVA 3.26 Citric Acid 5.08 Homogenous Tablet Core Composition Component mg/tablet %w/w Bupropion HBr 171.32 44.45 Escitalopram Ox 171.32 44.45 PVA 12.20 3.17 Citric Acid 19.01 4.93 BHT 0.37 0.10 Compritol 888 ATO 11.18 2.90 71 WO 2009/095395 PCT/EP2009/050924 [003261 Tablet Coat Composition and Method of Manufacture [003271 The control-releasing coat was manufactured according to the method and composition described in Example 1. [003281 The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Table 12. The result of the dissolution testing is presented as a % of the total bupropion HBr and escitalopram Oxalate in the controlled release tablet and is also depicted in FIG. 12. Table 12 Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Escitalopram Ox 1 13 8 2 36 29 3 57 47 4 75 63 5 90 77 6 103 92 7 106 98 8 107 102 EXAMPLE 13 [00329] Homogenous Tablet Core Composition and Method of Manufacture. [00330] The homogenous tablet core was manufactured according to the method described in Example 3 with the following co-granule and homogenous tablet core composition: Bupropion HBr (156 mg) / Escitalopram (8 mg) Co Granule Composition Component %w/w Bupropion HBr 86.03 Escitalopram Ox 5.63 Butylatedhydroxytoluene 0.1 PVA 3.22 Citric Acid 5.02 Homogenous Tablet Core Composition Component mg/tablet %w/w Bupropion HBr 156.0 83.5 Escitalopram Ox 10.2 5.46 PVA 5.84 3.12 Citric Acid 9.11 4.88 72 WO 2009/095395 PCT/EP2009/050924 BHT 0.18 0.9 Compritol 888 ATO 5.42 3.0 [003311 Tablet Coat Composition and Method of Manufacture [00332] The control-releasing coat was manufactured according to the method and composition described in Example 1, except that the plasticized polymer solution was applied until about a 18% weight gain was obtained. [003331 The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Table 13. The result of the dissolution testing is presented as a % of the total bupropion HBr and escitalopram Oxalate in the controlled release tablet and is also depicted in FIG. 13. Table 13 Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Escitalopram Ox 1 9 9 2 25 28 3 42 45 4 58 60 6 84 83 8 96 96 10 99 99 12 99 100 16 99 100 EXAMPLE 14 [00334] Homogenous Tablet Core Composition and Method of Manufacture. [003351 The homogenous tablet core was manufactured according to the method described in Example 3 with the following co-granule and homogenous tablet core composition: Bupropion HBr (312 mg) / Escitalopram Oxalate (16 mg) Co-Granule Composition Component %w/w Bupropion HBr 86.03 Escitalopram Ox 5.63 Butylatedhydroxytoluene 0.1 PVA 3.22 Citric Acid 5.02 73 WO 2009/095395 PCT/EP2009/050924 Homogenous Tablet Core Composition Component mg/tablet %w/w Bupropion HBr 312.0 83.5 Escitalopram Ox 20.4 5.46 PVA 11.68 3.12 Citric Acid 18.21 4.88 BHT 0.36 0.96 Compritol 888 ATO 10.83 3.0 [003361 Tablet Coat Composition and Method of Manufacture [003371 The control-releasing coat was manufactured according to the method and composition described in Example 1, except that the plasticized polymer solution was applied until about a 12% weight gain was obtained. [003381 The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Table 14. The result of the dissolution testing is presented as a % of the total bupropion HBr and escitalopram Oxalate in the controlled release tablet and is also depicted in FIG. 14. Table 14 Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Escitalopram Ox 1 9 12 2 24 29 3 39 43 4 51 56 6 73 76 8 90 92 10 97 99 12 98 102 16 99 102 EXAMPLE 15 [003391 Pharmaceutical compositions comprising a homogenous controlled-release matrix comprising about 300mg of bupropion HCl (equivalent to about 260mg of bupropion base) and about 25.5mg of escitalopram oxalate (equivalent to about 20mg escitalopram base) were prepared by direct blending of Bupropion HCl granule fines (initially manufactured as granules described in Example 18 and screened through a 45 mesh screen. Particles < 355 m 74 WO 2009/095395 PCT/EP2009/050924 were retained for the manufacturing the controlled-release matrix pharmaceutical composition) with escitalopram oxalate powder and other excipients with the following compositon. Homogenous Controlled-Release Matrix Composition Component mg/tablet %w/w Bupropion HCl 300.0 39.56 Escitalopram Oxalate 25.5 3.36 Polyvinyl Alcohol 10.6 1.40 Hydroxypropyl 200.0 26.37 cellulose Lactose DT 125.0 16.48 Microcrystalline 72.2 9.52 cellulose Silicon dioxide 2.5 0.33 Magnesium stearate 22.5 2.97 [00340] A homogenous blend of about 150g was manufactured by dispensing about 61.44 g of bupropion HCl granule fines, about 5.04g of escitalopram oxalate, about 39.56g of hydroxypropyl cellulose, about 24.73g of lactose, about 14.28g of microcrystalline cellulose, about 0.49g of silicon dioxide, and about 4.45g of magenisium stearate. All the excipients were pre-screened through the 30mesh screen prior to dispensing. Manual bag mixing was applied according to the following order. 1. Pre-mix active escitalopram oxalate with a small portion of hydroxypropyl cellulose, lactose and microcrystalline cellulose. 2. Add approximately half of the Bupropion HCl granules and mix 3. Add approximately half of the remaining hydroxypropyl cellulose, lactose and microcrystalline cellulose, and mix 4. Add the remaining Bupropion HCl granules, and mix 5. Add the remaining hydroxypropyl cellulose, lactose and microcrystalline cellulose, and mix 6. Add silicon dioxide and magnesium stearate, and mix for 2 minutes. [00341] The homogenous blend was further compressed using Natoli Single Station Press equipped with 0.706" x 0.329" capsule shaped tablet tooling. The target tablet weight was 758.3 mg. The hardness of the table was about 2 ION. 2.25 tons of compression force was applied. [00342] The dissolution results of the homogenous controlled-release matrix pharmaceutical copmposition (batch no. BUPHCL/ESC-300/25.5-03-07) was determined under 75 WO 2009/095395 PCT/EP2009/050924 the dissolution conditions described below in Table 15. The result of the dissolution testing is presented as a % of the total bupropion HCl and escitalopram oxalate in the controlled release composition. The dissolution profile determined under the dissolution conditions is also depicted in Figure 15. Table 15 Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HCl Escitalopram Oxalate 1 21.88 18.19 2 34.15 28.44 3 43.59 36.45 4 52.04 44.01 5 57.92 49.35 6 64.57 55.56 7 69.02 59.87 8 73.09 63.96 EXAMPLE 16 [00343] Bi-layer Tablet Core Composition and Method of Manufacture [00344] To manufacture the bi-layer tablet core comprising about 150mg of bupropion HCl (equivalent to about 130mg of bupropion base) and about 150mg of escitalopram oxalate (equivalent to about 118mg escitalopram base), two separate blends with the following compositions were prepared separately: 1) about 47.23% bupropion HCl granules (manufactured according to the separate granulation method) with about 1.52% Compritol 888 ATO (screened through a 500 m screen); 2) about 49.73% escitalopram oxalate granules (manufactured according to the separate granulation method, potency of the escitalopram oxalate granules is 90.1%) with about 1.52% Compritol 888 ATO (screened through a 500im screen). The theoretical batch size was about 100g. About 47.2g of bupropion HCl granules were lubricated with about 1.52g of the screened Compritol 888 ATO by bag mixing for 2 minutes, and about 49.7g of escitalopram oxalate granules were lubricated with about 1.52g of the screened Compritol 888 ATO by bag mixing for 2 minutes. [00345] The bi-layer tablet cores were prepared using Natoli Single Station Press equipped with 9mm round concave shaped tablet tooling by pre-compressing the lubricated escitalopram oxalate granules as the first layer and followed by compressing the lubricated bupropion HCl granules as second layer. The target tablet weight was 332 mg and the target 76 WO 2009/095395 PCT/EP2009/050924 tablet hardness was about 175N. 0.5 tons of pre-compression force and 3 tons of compression force was applied. The resulting product comprises the bi-layer tablet core (batch no. BUPHCL/ESC-150-150-01-07), which at this point is an immediate release core having the following composition: Bi-Layer Tablet Core Composition Component mg/tablet %w/w Bupropion HCl 150.0 45.62 Escitalopram oxalate 150.0 45.62 PVA 5.3 1.61 BHT 2.3 0.70 Kollidon* 90F 11.2 3.41 Compritol 888 ATO 10.0 3.04 [00346 Tablet Coat Composition And Method of Manufacture Tablet Control-releasing Coat Composition Component %w/w Ethocel 100 FP Premium 4.61 Kollidon* 90F 2.86 PEG 3350 1.03 Dibutylsebacate 0.50 2-Propanol 8.68 Absolute Ethanol 81.86 Purified water 0.46 [00347] The bi-layer tablet cores were coated separately with an ethyleellulose based film by preparing an organic solvent solution consisting of about 4.610% ethocel standard 1 OOFP premium, about 2.86% Kollidon* 90F, about 1.03% carbowax sentry polyethylene glycol 3350 granular NF FCC grade, about 0.5% dibutyl sebacate NF, about 8.68% 2-propanol, about 81.86% absolute ethanol, and about 0.46% purified water. The plasticized polymer solution is applied to about 1.53 kg of the tablet cores, including about 35g of active tablet cores and about 1.5kg placebo tablets (comprising 69% lactose monohydrate, 30% microcrystalline cellulose and 1% magnesium stearate), using an O'Hara Labcoat II-X tablet coater (15" pan) until about a 10% weight gain is obtained. The product temperature is maintained between about 30-33'C, and the liquid spray rate is maintained between about 20-22 g/min throughout the coating process. The controlled release coated tablets are then cured for about 25 minutes (inlet air is set at about 50'C, pan speed set at 3 rpm). The dissolution profile of the controlled release coated bi-layer tablets 77 WO 2009/095395 PCT/EP2009/050924 (batch no. BUPHCL/ESC-150-150-02-07) was determined under the dissolution conditions described below in Table 16. The result of the dissolution testing is presented as a % of the total bupropion HCl and escitalopram oxalate in the controlled release tablet and is also depicted in FIG. 16. Table 16 Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) (Bi-layer Tablets) Bupropion HCl Escitalopram Oxalate 1 16.36 9.47 2 33.56 27.06 3 49.54 45.32 4 65.00 60.81 5 79.63 74.22 6 88.97 83.48 7 94.82 90.11 8 97.06 93.47 EXAMPLE 17 [00348] Homogenous Tablet Core Composition and Method of Manufacture. [00349] A. Bupropion HBr Granulation: [003501 Bupropion HBr granules were manufactured as described in example 1. [003511 B. Quetiapine Fumarate Granulation: Quetiapine Fumarate Granule Composition Component %w/w Quetiapine Fumarate 96.62 Polyvinyl Alcohol 3.38 [00352] The pharmaceutical active, Quetiapine fumarate, was top-spray granulated using a Glatt GPCG 1 (6 inch chamber). The theoretical batch size was 2070g. An aqueous (purified water) solution of polyvinyl alcohol (PVA) (4.8% of solution) was sprayed onto 2 kg of Quetiapine fumarate to a weight gain of 3.5% to produce a granule comprising of 96.62% Quetiapine fumarate, and 3.38% PVA. The powder bed temperature was maintained between 38 - 45'C, and the liquid spray rate maintained between 5 - 10 g/min throughout the granulation process. When spraying of the granulation solution was stopped, the granules were fluid bed dried 78 WO 2009/095395 PCT/EP2009/050924 for 10 minutes with a product temperature of-45'C. The granules were screened and the granules with a particle size below 800 m and above 355gm are retained for use in the tablet core. [003531 C. Homogenous Tablet Core Composition and Method of Manufacture [00354] To manufacture a tablet core containing 348mg of Bupropion HBr (equivalent to 260mg of Bupropion base) and 23mg of Quetiapine fumarate (equivalent to 20mg quetiapine base), a homogenous tablet blend with the following composition was prepared; 90.79% Bupropion HBr granules (manufactured as outlined in Example 1), 5.710% Quetiapine fumarate granules (manufactured as outlined above), 3.40% Compritol 888 ATO, and 0. 1% lake green blend. A homogenous tablet blend of 400g was manufactured by dispensing 363.16g of Bupropion HBr granules, 22.84g of Quetiapine fumarate granules, 13.60g of Compritol 888 ATO, and 0.40g of lake green blend. The material was added to a v-blender (4 quart shell of a PK labmaster v-blender) in the following order: 1. ~ half of the Bupropion HBr granules 2. All of the Quetiapine fumarate granules 3. All of the Compritol 888 ATO 4. All of the lake green blend 5. The remaining Bupropion HBr granules The tablet components were blended for 10 minutes, with the intensifier bar turned off. The homogenous tablet blend was discharged from the v-shell and charged to a tablet press (Riva Bilayer 11 station rotary tablet press) and compressed to a target tablet weight of 418mg and a target tablet hardness of 120N using 9mm round deep concave shaped tablet tooling. The resulting product comprises the homogenous tablet core, which at this point is an immediate release core having the following composition: Homogenous Tablet Core Composition Component mg/tablet %w/w Bupropion HBr 348.08 83.27 Quetiapine Fumarate 23.06 5.52 PVA 13.10 3.13 Citric Acid 19.13 4.58 Lake Green Blend 0.42 0.10 Compritol 888 ATO 14.21 3.40 [00355] Tablet Coat Composition And Method of Manufacture [003561 The homogenous IR tablet cores were next coated with the control-releasing coat as described in Example 1. 79 WO 2009/095395 PCT/EP2009/050924 [003571 The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Tables 17A and 17B. The results of the dissolution testing are presented as a % of the total bupropion HBr and quetiapine fumarate in the controlled release tablet and are also depicted in FIGs. 17A and 17B. Table 17A Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Quetiapine Fumarate 1 14 18 2 31 39 4 61 69 8 99 98 12 102 97 16 100 96 Table 17B Dissolution Conditions: 900 ml pH 6.8 phosphate buffer, USP Apparatus 1, 75 rpm, 37 0 C % Released Time (hr) Bupropion HBr Quetiapine Fumarate 1 7 2 2 17 10 4 39 41 8 71 76 12 90 93 16 92 95 EXAMPLE 18 [00358] Homogenous IR Tablet Core Composition and Method of Manufacture Separate Granulation Method. [003591 A. Bupropion HCl Granulation: Bupropion HCl Granule Composition Component %w/w Bupropion HCl 96.59 Polyvinyl Alcohol 3.41 [00360] The pharmaceutical active, bupropion HCl, was top-spray granulated using an Aromatic MP8 Fluid Bed. The theoretical batch size was 310.6kg. An aqueous (purified water) solution of polyvinyl alcohol (PVA) (4.82% of solution) was sprayed onto 300.0 kg of bupropion 80 WO 2009/095395 PCT/EP2009/050924 HCl to a weight gain of 3.4 1% to produce a granule comprising of 96.59% bupropion HCl, 3.41% PVA. The powder bed temperature was maintained between 48-52'C, and the liquid spray rate maintained between 1500 g/min throughout the granulation process. When spraying of the granulation solution was stopped, the granules were fluid bed dried to a LOD (loss on drying) level of < 1%. The granules were screened and the granules with a particle size of between about 355 m and about 850 Jim were retained for manufacture of the homogenous tablet core. [003611 B. Escitalopram Oxalate Granulation: Citalopram HCl Granule Composition Component %w/w Escitalopram Oxalate 91.74 Kollidon* 90F 6.88 Butylated hydroxytoluene 1.38 [00362] The pharmaceutical active, escitalopram oxalate, was top-spray granulated using an Aeromatic fluid bed MPl. The theoretical batch size was 1943.5g. An organic solvent (2 propanol) solution of Kollidon* 90F (6.0% of solution) and butylated hydroxytoluene (BHT) (1.2% of solution) was sprayed onto about 1783.0 g of escitalopram oxalate to a weight gain of about 8.3% to produce a granule comprising of about 91.
74 % citalopram HCl, 6.88% Kollidon* 90F, and 1.38% BHT. The powder bed temperature was maintained between 35-45'C, and the liquid spray rate maintained between 13 - 17 g/min throughout the granulation process. When spraying of the granulation solution was stopped, the granules are fluid bed dried to a LOD (loss on drying) level of < 1%. The granules were screened and the granules with a particle size of between about 355 m and about 850 m were retained for manufacture of the homogenous tablet core. [003631 C. Homogenous IR Tablet Core Composition and Method of Manufacture [00364] To manufacture the homogenous tablet core comprising about 300mg of bupropion HCl (equivalent to about 260mg of bupropion base) and about 25.5mg of escitalopram oxalate (equivalent to about 20mg escitalopram base), a blend with the following composition was prepared: about 88.9% bupropion HCl granules (manufactured as described above), about 8.1% escitalopram oxalate granules (manufactured as described above, potency of the escitalopram oxalate granules is 90.1%) and about 3.0% Compritol 888 ATO (screened through a 500 im screen). A homogenous blend of about 10OOg was manufactured by dispensing about 889.Og of bupropion HCl granules, about 81.Og of escitalopram oxalate granules, and about 30.3g 81 WO 2009/095395 PCT/EP2009/050924 of the screened Compritol 888 ATO. The material was added to a 8 qt. v-blender in the following order: 1. about half of the bupropion HCl granules 2. All of the escitalopram oxalate granules 3. All of the Compritol 888 ATO 4. The remaining bupropion HCl granules The tablet core components were homogenously blended for about 10 minutes, with the v-shell speed set to 25 rpm. The homogenous blend was discharged from the v-shell and charged to a tablet press (Manesty Betapress 16 station) and compressed to a target tablet weight of about 349.5mg and a target tablet hardness of about 130N using 9mm round normal concave shaped tablet tooling. The resulting product comprises the homogenous tablet core, which at this point is an immediate release core having the following composition: Homogenous IR Tablet Core Composition Component mg/tablet %w/w Bupropion HCl 300.0 85.96 Escitalopram oxalate 25.5 7.31 Polyvinyl Alcohol 10.6 3.03 Butylated hydroxytoluene 0.38 0.11 Kollidon* 90F 1.91 0.55 Compritol 888 ATO 10.6 3.03 [00365 Tablet Coat Composition And Method of Manufacture Tablet Control-releasing Coat Composition Component %w/w Ethocel 100 FP Premium 4.61 Kollidon* 90F 2.86 Polyethylene Glyol 3350 1.03 Dibutylsebacate 0.50 2-Propanol 8.68 Absolute Ethanol 81.86 Purified water 0.46 [003661 The homogenous IR tablet cores were coated with an ethyleellulose based film by preparing an organic solvent solution consisting of about 4.61% ethocel standard 100FP premium, about 2.86% Kollidon* 90F, about 1.03% carbowax sentry polyethylene glycol 3350 82 WO 2009/095395 PCT/EP2009/050924 granular NF FCC grade, about 0.5% dibutyl sebacate NF, about 8.68% 2-propanol, about 81.86% absolute ethanol, and about 0.46% purified water. The plasticized polymer solution is applied to about 1.7 kg of the tablet cores, including about 0.2kg of active tablet cores and about 1.5kg placebo tablets (comprising 69% lactose monohydrate, 30% microcrystalline cellulose and 1% magnesium stearate), using an O'Hara Labcoat II-X tablet coater (15" pan) until about a 10% weight gain is obtained. The product temperature is maintained between about 30-33'C, and the liquid spray rate is maintained between about 20-22 g/min throughout the coating process. The controlled release coated tablets are then cured for about 25 minutes (inlet air is set at about 50'C, pan speed set at 3 rpm). [003671 The dissolution results of the above coated tablets are presented in Table 18 as a % of the total bupropion HCl and escitalopram oxalate in the controlled release tablet (batch no. BUPHCL/ESC-300/25.5-02-07). The dissolution profile was determined under the dissolution conditions shown in Table 18 and is also depicted in Figure 18. Table 18 Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Bupropion HCl Escitalopram Oxalate 1 15.77 26.30 2 34.68 48.19 3 52.34 63.33 4 67.21 74.10 5 81.76 83.56 6 92.94 90.30 7 99.19 95.04 8 101.69 95.74 EXAMPLE 19 [003681 Homogenous Tablet Core Composition and Method of Manufacture [003691 The homogenous tablet core comprising about 225mg of bupropion HCl (equivalent to about 195mg of bupropion base) and about 75mg of escitalopram oxalate (equivalent to about 58.8mg escitalopram base) was prepared by blending and tabletting the following compositions: about 71.42% bupropion HCl granules (manufactured according to the separate granulation method)), and about 25.5 1 % escitalopram oxalate granules (manufactured according to the separate granulation method), potency of the escitalopram oxalate granules is 90.1%), and about 3.07% Compritol 888 ATO (screened through a 500 m screen). A 83 WO 2009/095395 PCT/EP2009/050924 homogenous blend of about 1OOg was manufactured by dispensing about 71.4g of bupropion HCl granules, about 25.5g of escitalopram oxalate granules, and about 3.07g of the screened Compritol 888 ATO, and manually bag mixing for 2 minutes. [00370] The bulk blend was compressed using Natoli Single Station Press equipped with 9mm round concave shaped tablet tooling to a target tablet weight of about 326mg and a target tablet hardness of about 140N. 3 tons of compression force was applied. The resulting homogenous tablet core (batch no. BUPHCL/ESC-225-75-01-07) has the following composition. Homogenous Tablet Core Composition Component mg/tablet %w/w Bupropion HCl 225.0 68.98 Escitalopram oxalate 75.0 23.0 PVA 7.94 2.43 BHT 1.37 0.42 Kollidon* 90F 6.84 2.10 Compritol 888 ATO 10.0 3.07 [00371] Tablet Coat Composition And Method of Manufacture Tablet Control-releasing Coat Composition Component %w/w Ethocel 100 FP Premium 4.61 Kollidon* 90F 2.86 PEG 3350 1.03 Dibutylsebacate 0.50 2-Propanol 8.68 Absolute Ethanol 81.86 Purified water 0.46 [00372] The homogenous tablet cores were coated separately with an ethyleellulose based film by preparing an organic solvent solution consisting of about 4.61 % ethocel standard 100FP premium, about 2.86% Kollidon* 90F, about 1.03% carbowax sentry polyethylene glycol 3350 granular NF FCC grade, about 0.5% dibutyl sebacate NF, about 8.68% 2-propanol, about 81.86% absolute ethanol, and about 0.46% purified water. The plasticized polymer solution was applied to about 1.53 kg of the tablet cores, including about 30g of active tablet cores and about 1.5kg placebo tablets (comprising 69% lactose monohydrate, 30% microcrystalline cellulose and 1% magnesium stearate), using an O'Hara Labcoat II-X tablet coater (15" pan) until about a 10% weight gain is obtained. The product temperature was maintained between about 30-33'C, and 84 WO 2009/095395 PCT/EP2009/050924 the liquid spray rate was maintained between about 20-22 g/min throughout the coating process. The controlled release coated tablets were then cured for about 25 minutes (inlet air is set at about 50'C, pan speed set at 3 rpm). [003731 The the dissolution results of the coated homogenous tablets (batch no. BUPHCL/ESC-225-75-02-07) are presented as a % of the total bupropion HCl and escitalopram oxalate released under the conditions described in Table 19. The dissolution profile is also depicted in Fig.19. Table 19 Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released (Homogenous Tablets) Time (hr) Bupropion HCl Escitalopram Oxalate 1 16.63 16.65 2 39.40 40.32 3 60.60 59.61 4 78.36 75.31 5 90.30 86.68 6 96.38 94.46 7 99.14 99.30 8 100.26 101.01 EXAMPLE 20 [00374] Homogenous Tablet Core Composition and Method of Manufacture. [003751 To manufacture a homogenous tablet core comprising about 300mg of tramadol HCl (equivalent to about 263.5mg of tramadol base) and about 25.5mg of escitalopram oxalate (equivalent to about 20mg escitalopram base), a blend with the following composition was prepared: about 88.9% tramadol HCl powder, about 7.6% escitalopram oxalate powder, about 3.1% Compritol 888 ATO (screened through a 500 im screen) and 0.5% magnesium stearate (screened through a 500 im screen). A homogenous blend of about 93.4g was manufactured by dispensing about 83.Og of tramadol HCl powder, about 7. Ig of escitalopram oxalate, about 2.9g of the screened Compritol 888 ATO, and about 0.47g of magnesium stearate. The material was manually blended by bag mixing for 2 minutes. [003761 The homogenous blend was compressed using Natoli Single Station Press equipped with 9mm round concave shaped tablet tooling to a target tablet weight of about 85 WO 2009/095395 PCT/EP2009/050924 337.5mg and a target tablet hardness of about 90N. 1.75 tons of compression force is applied. The resulting homogenous tablet core (batch no. 08029T) has the following composition. Homogenous Tablet Core Composition Component mg/tablet %w/w Tramadol HCl 300.00 88.89 Escitalopram Oxalate 25.50 7.56 Compritol 888 ATO 10.30 3.05 Magnesium Stearate 1.69 0.50 [00377] Tablet Coat Composition And Method of Manufacture Tablet Control-releasing Coat Composition Component %w/w Ethocel 100 FP Premium 4.61 Kollidon* 90F 2.86 PEG 3350 1.03 Dibutylsebacate 0.50 2-Propanol 8.68 Absolute Ethanol 81.86 Purified water 0.46 [003781 The homogenous IR tablet cores were coated with an ethyleellulose based film by preparing an organic solvent solution consisting of about 4.610% ethocel standard 1 OOFP premium, about 2.86% Kollidon* 90F, about 1.03% carbowax sentry polyethylene glycol 3350 granular NF FCC grade, about 0.5% dibutyl sebacate NF, about 8.68% 2-propanol, about 81.86% absolute ethanol, and about 0.46% purified water. The plasticized polymer solution was applied to about 1.84 kg of the tablet cores, including about 40.8g of active tablet cores and about 1.8kg placebo tablets (comprising 69% lactose monohydrate, 30% microcrystalline cellulose and 1% magnesium stearate), using an O'Hara Labcoat II-X tablet coater (15" pan) until about a 10% weight gain is obtained. The product temperature was maintained between about 30-34'C, and the liquid spray rate was maintained between about 20-22 g/min throughout the coating process. The controlled release coated tablets were then cured for about 25 minutes (inlet air is set at about 48'C, pan speed set at 3 rpm). [00379] The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Table 20A and 20B. The results of the dissolution testing as presented as a % of the total tramadol HCl and escitalopram Oxalate in the controlled release tablet (batch no. 08029C) and is also depicted in Fig.20A and 20B. 86 WO 2009/095395 PCT/EP2009/050924 Table 20A Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Tramadol HCl Escitalopram Oxalate 0.5 10 6 1 33 24 2 73 63 3 96 84 4 104 98 5 106 102 6 106 102 8 106 102 10 105 102 12 105 101 Table 20B Dissolution Conditions: 900 ml pH 6.8 phosphate buffer, USP Apparatus 1, 75 rpm, 37 0 C % Released Time (hr) Tramadol HCl Escitalopram Oxalate 0.5 9 4 1 32 23 2 75 60 3 98 83 4 105 93 5 107 98 6 107 99 8 107 101 10 107 101 12 107 101 EXAMPLE 21 [00380] A STEADY STATE DRUG INTERACTION STUDY OF WELLBUTRIN XL* TABLETS AND CELEXA® TABLETS IN HEALTHY, NON-SMOKING MALE AND FEMALE SUBJECTS. [00381] This study was a single period, 2 treatment, open-label, multiple-dose, drug interaction study under fed conditions. The objective of this study was to evaluate the potential drug interaction of citalopram (Celexa* 40 mg Tablets) on bupropion (Wellbutrin XL* 300 mg Tablets) under steady state conditions. Normal, healthy, non-smoking male and female subjects between the ages of 18 and 55 years were included in the study. 87 WO 2009/095395 PCT/EP2009/050924 [00382] Following an overnight fast of at least 10 hours, and 1 hour after the start of a standard breakfast, subjects received 1 Wellbutrin XL* 150 mg Tablet (Lot #: 06E065P) daily on Days I to 3, 1 Wellbutrin XL* 300 mg Tablet (Lot #: 06E002P) daily on Days 4 to 13, 1 Wellbutrin XL* 300 mg Tablet (Lot #: 06E002P) and 1 Celexa* 20 mg Tablet (Lot #: M0512M) daily on Days 14 to 19, 1 Wellbutrin XL* 300 mg Tablet (Lot #: 06E002P) and 1 Celexa* 40 mg Tablet (Lot #: M0606A) daily on Days 20 to 33, and 1 Celexa* 20 mg Tablet (Lot #: M0512M) on Days 34 to 36. All treatments were administered orally with 240 mL of ambient temperature water. [003831 26 subjects were dosed in the study, 23 of whom completed the study. One subject was dismissed because of adverse events (AEs), two subjects withdrew for personal reasons. Pharmacokinetic and statistical analyses were performed on the 23 subjects who completed the study. [00384] During the study, 31 blood samples were collected from each subject at the following time points: Days 1, 10, 11, 12, 30, 31, and 32: 0.00 hour (pre-dose) Day 13: 0.00 (pre-dose), 1.00, 2.00, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00, and 24.00 hours post-dose. Day 33: 0.00 (pre-dose), 1.00, 2.00, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00, and 24.00 hours post-dose. [00385] Bupropion and its metabolites - hydroxybupropion, bupropion erythroamino alcohol, and bupropion threoamino alcohol, and the internal standard, 1-(3-chlorophenyl) piperazine, were extracted by solid phase extraction into an organic media from 0.50 mL of human plasma. An aliquot of this extract was injected into a High Performance Liquid Chromatography system and detected using a tandem mass spectrometer. The analytes were separated by reverse phase chromatography. Evaluation of the assay was carried out by the construction of an eight-point calibration curve (excluding zero concentration) covering the range of 1.000 ng/mL to 1023.900 ng/mL for bupropion, 3.907 ng/mL to 4001.200 ng/mL for hydroxybupropion, 1.000 ng/mL to 1024.310 ng/mL for bupropion erythroamino alcohol, and 1.000 ng/mL to 1023.850 ng/mL for bupropion threoamino alcohol in human plasma. The slope and intercept of the calibration curves were determined through weighted linear regression analysis (1/area ratio.
2 ) Two calibration and duplicate QC samples (at three concentration levels) were analyzed along with each batch of the study samples. Peak area ratios were used to 88 WO 2009/095395 PCT/EP2009/050924 determine the concentration of the standards, quality control samples, and the unknown study samples from the calibration curves. [003861 Citalopram and its metabolites - demethyleitalopram and didemethyleitalopram, and the internal standards, citalopram analog, demethyleitalopram analog, and didemethyleitalopram analog, were extracted by liquid-liquid extraction into an organic media from 1.00 mL of human plasma. An aliquot of this extract was injected into a High Performance Liquid Chromatography system and detected using a tandem mass spectrometer. The analytes were separated by reverse phase chromatography. Evaluation of the assay was carried out by the construction of an eight-point calibration curve (excluding zero concentration) covering the range of 0.250 ng/mL to 64.023 ng/mL for citalopram, 0.050 ng/mL to 12.812 ng/mL for demethyleitalopram, and 0.050 ng/mL to 12.796 ng/mL for didemethyleitalopram in human plasma. The slope and intercept of the calibration curves were determined through weighted linear regression analysis (1/cone.
2 ). Two calibration curves and duplicate QC samples (at three concentration levels) were analyzed along with each batch of the study samples. Peak area ratios were used to determine the concentration of the standards, quality control samples, and the unknown study samples from the calibration curves. [00387] The pharmacokinetic analysis was performed on 23 subjects who completed the study. The safety assessment was performed on all subjects who received at least 1 dose during the course of the study. [003881 The following pharmacokinetic parameters for bupropion, bupropion erythroamino alcohol, bupropion threoamino alcohol, hydroxybupropion, and PAWC were calculated by standard non-compartmental methods: AUC, Cmax, Cmin, Cavg, Tmax, % Fluctuation, % Swing, Mean Residence Time (MRT), CL/F, and (Metabolite/Parent) M/P ratio. Citalopram and its metabolites concentrations were taken to show that 1) Subjects did take the citalopram products, and 2) Systemic levels of citalopram and its metabolites were present due to Celexa*® administration on Days 14 - 36. [003891 Using General Linear Model (GLM) procedures in Statistical Analysis System (SAS), analysis of variance (ANOVA) was performed on In-transformed AUC, Cmax, Cmin, and Cav9 and on untransformed % Fluctuation, % Swing, MRT M/P ratio and CL/F at the significance level of 0.05. The intra-subject coefficient of variation (CV) was calculated using the Mean Square Error (MSE) from the ANOVA table. The ratio of geometric means and the 90% geometric confidence interval (90% C.I.) were calculated based on the difference in the Least Squares Means of the ln-transformed AUC, Cmax, and Cmin between the test and reference formulations. Tmax was analyzed using nonparametric methods. 89 WO 2009/095395 PCT/EP2009/050924 [003901 Data for the pharmacokinetic parameters for bupropion and citalopram and its metabolites is presented in the tables below and in FIGs. 2 1A-E. Pharmacokinetic Parameters for Bupropion Pharmacokinetic Geometric Mean (%CV) Parameters Arithmetic Mean SD p-Value Treatment A (n=23) Treatment B (n=23) AUC, -hr/mL) 1551.73 (22.74) 1418.22 (24.45) 0.2095 (ng1591.23 + 361.82 1459.93 + 357.01 C.ax(ng/mL) 148.70 (26.29) 148.12 (25.55) 0.9604 153.57+ 40.38 153.24+ 39.15 Cmi. (ng/mL) 25.84 (32.17) 24.13 (31.75) 0.4705 27.17 + 8.74 25.27 + 8.02 C., (n/mL) 64.66 (22.74) 59.09 (24.45) 0.2095 66.30 + 15.08 60.83 + 14.88 Tmax (hr)* 6.00 (3.00 - 10.00) 5.00 (2.00 - 6.00) 0.015 Degree of Fluctuation 191.16 + 37.69 212.90 + 50.88 0.1067 Degree of 501.57 + 180.74 548.70 + 207.50 0.4159 Swing (%) MRT (hr) 10.00 + 0.61 9.77 + 0.43 0.1442 CL/F 26.45 + 6.29 29.05 + 7.26 0.2019 * median (min - max) TREATMENT A: Day 13, Wellbutrin XL* 300 mg Tablet alone TREATMENT B: Day 33, Wellbutrin XL* 300 mg Tablet and Celexa* 40 mg Tablet administered concomitantly Relative Bioavailability Assessments for Bupropion Parameter 90% C.I. Ratio of Means Intra-Subject CV AUC, 81.17% to 102.92% 91.40% 24.31% Cmax 87.28% to 113.68% 99.61% 27.15% Cmi. 79.73% to 109.37% 93.38% 32.73% Pharmacokinetic Parameters for Hydroxybupropion Pharmacokinetic Geometric Mean (%CV) Parameters Arithmetic Mean ± SD p-Value Treatment A (n=23) Treatment B (n=23) AUC, -hr/mL) 23059.77 (28.43) 24303.78 (28.58) 0.5209 (ng23910.83 + 6797.16 25231.86 + 7210.51 C.a (ng/mL) 1142.95 (28.61) 1202.83 (27.82) 0.5270 1185.68 + 339.19 1245.98 + 346.67 Cmi. /mL) 849.10 (31.17) 890.49 (31.92) 0.5952 (ng 886.37 + 276.27 932.34 + 297.61 C, (ng/mL) 960.82 (28.43) 1012.66 (28.58) 0.5209 996.28 + 283.21 1051.33 + 300.44 Tmax (hr)* 10.00 (1.00 - 12.00) 6.00 (3.00 - 12.00) 0.004 Degree of Fluctuation (%) 30.54 + 9.83 30.80 + 10.22 0.9301 Degree of Swing (%) 35.20 + 12.91 35.77 + 14.27 0.8892 MRT (hr) 11.80 + 0.23 11.72 + 0.23 0.2276 M/P Ratio 14.99 6.05 17.08 + 5.95 0.2435 * median (min - max) TREATMENT A: Day 13, Wellbutrin XL* 300 mg Tablet alone TREATMENT B: Day 33, Wellbutrin XL* 300 mg Tablet and Celexa* 40 mg Tablet administered concomitantly Relative Bioavailability Assessments for Hydroxybupropion Parameter 90% C.I. Ratio of Means Intra-Subject CV AUC, 91.96% to 120.80% 105.39% 28.06% Cmax 91.99% to 120.40% 105.24% 27.66% 90 WO 2009/095395 PCT/EP2009/050924 Cmi. 90.32% to 121.77% 104.87% 30.85o Pharmacokinetic Parameters for Bupropion Threoamino Alcohol Pharmacokinetic Geometric Mean (%CV) Parama etc Arithmetic Mean SD p-Value Treatment B (n=23) Treatment B (n=23) 10586.56 (38.17) 10277.50 (41.17) AUC, (ng-hr/mL) 11321.06 + 4320.85 11083.99 + 4563.35 0.7954 Cmax(ng/mL) 540.16 (34.92) 529.62 (35.49) 0.8468 571.88 + 199.67 560.62 + 198.96 C (ng/mL) 371.01 (42.80) 364.30 (45.59) 0.8843 """ m403.25 + 172.60 398.40 + 181.63 C. n/mL) 441.11 (38.17) 428.23 (41.17) 0.7954 Cv ( L 471.71 + 180.04 461.83 + 190.14 Tmax (hr)* 8.00 (5.00 - 16.00) 6.00 (5.00 - 12.00) 0.048 Degree of Fluctuation 38.33 + 11.96 38.78 + 13.37 0.9050 Degree of Swing (%) 46.55 + 17.32 46.45 + 18.39 0.9844 MRT (hr) 11.83 + 0.29 11.74z+ 0.25 0.2713 M/P Ratio 7.14 + 2.36 7.56 +2.54 0.5617 * median (min - max) TREATMENT A: Day 13, Wellbutrin XL* 300 mg Tablet alone TREATMENT B: Day 33, Wellbutrin XL* 300 mg Tablet and Celexa* 40 mg Tablet administered concomitantly Relative Bioavailability Assessments for Bupropion Threoamino Alcohol Parameter 90% C.I. Ratio of Means Intra-Subject CV AUC, 80.22% to 117.49% 97.08% 39.99% Cmax 82.69% to 116.26% 98.05% 35.43% Cmi. 79.64% to 121.06% 98.19% 44.21% Pharmacokinetic Parameters for Bupropion Erythoamino Alcohol Pharmacokinetic Geometric Mean (%CV) Parameters Arithmetic Mean ± SD p-Value Treatment B (n=23) Treatment B (n=23) ALJC,(ng-hr/mL) 2175.39 (30.56) 2194.09 (32.58) 0.9264 2271.60 + 694.27 2306.73 + 751.53 C.ax(ng/mL) 104.88 (30.07) 107.19 (30.59) 0.8056 109.43 + 32.91 111.94 + 34.24 Cmii (ng/mL) 83.23 (30.69) 84.25 (36.01) 0.9017 87.03 + 26.71 89.42 + 32.20 C (ng/mL) 90.64 (30.56) 91.42 (32.58) 0.9264 "n/L94.65 + 28.93 96.11 + 31.31 Tmax (hr)* 10.00 (2.00 - 16.00) 6.00 (5.00 - 12.00) 0.112 Degree of Fluctuation 23.80 8.64 25.05 + 10.61 0.6633 (%) Degree of Swing (%) 26.45 + 10.81 27.88 + 13.19 0.6898 MRT (hr) 11.91 + 0.23 11.84 + 0.23 0.2821 M/P Ratio 1.46 + 0.44 1.60 + 0.44 0.2923 * median (min - max) TREATMENT A: Day 13, Wellbutrin XL* 300 mg Tablet alone TREATMENT B: Day 33, Wellbutrin XL* 300 mg Tablet and Celexa* 40 mg Tablet administered concomitantly Relative Bioavailability Assessments for Bupropion Erythroamino Alcohol Parameter 90% C.I. Ratio of Means Intra-Subject CV AUC, 86.38% to 117.76% 100.86% 32.05% Cmax 88.14% to 118.52% 102.21% 30.56% Cmi. 85.93% to 119.23% 101.22% 33.98% 91 WO 2009/095395 PCT/EP2009/050924 Pharmacokinetic Parameters for PAWC Data Pharmacokinetic Geometric Mean (%CV) Parameters Arithmetic Mean ± SD p-Value Treatment B (n=23) Treatment B (n=23) AUC, uM-hr 72.19 (22.98) 74.24 (24.46) 0.6877 73.98 + 17.00 76.37 + 18.68 Cmax (uM) 3.76 (22.20) 3.94 (21.94) 0.4614 3.85 + 0.85 4.03 + 0.89 Cm.i (uM) 2.51 (27.27) 2.59 (28.65) 0.6868 2.60 + 0.71 2.70 + 0.77 Cag (UM) 3.01 (22.98) 3.09 (24.46) 0.6877 3.08 + 0.71 3.18 + 0.78 Tmax (hr)* 8.00 (3.00 - 10.00) 5.00 (3.00 - 8.00) 0.003 Degree of Fluctuation 41.68 + 11.69 43.75 + 12.47 0.5646 Degree of Swing (%) 50.80 + 16.63 53.05 + 18.48 0.6657 MRT (hr) 11.64 + 0.25 11.56 + 0.21 0.2816 * median (min - max) TREATMENT A: Day 13, Wellbutrin XL* 300 mg Tablet alone TREATMENT B: Day 33, Wellbutrin XL* 300 mg Tablet and Celexa* 40 mg Tablet administered concomitantly Relative Bioavailability Assessments for PAWC Data Parameter 90% C.I. Ratio of Means Intra-Subject CV AUC, 91.56% to 115.50% 102.84% 23.76% Cmax 94.23% to 116.62% 104.83% 21.77% Cmi. 90.15% to 118.51 % 103.36% 28.14% EXAMPLE 22 [003911 AFFECT OF BUPROPION HCl ON STEADY-STATE PHARMACOKINETICS OF CITALOPRAM HBr IN HEALTHY NON-SMOKING VOLUNTEERS. [003921 The intent of this steady-state drug interaction study was to determine if a 300 mg dose of bupropion (Wellbutrin XL® 300 mg Tablets, GlaxoSmithKline, USA) would affect the pharmacokinetics of a 20 mg dose of Citalopram (Celexa® 20 mg Tables, Forrest Laboratories, Inc. USA). This study followed a single period, 2 treatments with up- and down titration phases, open-label, multiple-dose design pharmacokinetic design study in which 28 subjects were scheduled to receive multiple dose administrations of Bupropion HCl (Wellbutrin XL*) and Citalopram HBr (Celexa®). [003931 Healthy adult male or female volunteers, 18-55 years of age, BMI greater than or equal to 18.5 kg/m 2 and less than or equal to 29.9 kg/m 2 were included in this study. [003941 Duration, dose, and mode of administration was as follows: Daily oral dose of one Celexa® 20 mg Tablet (Lot: M0512) on Days 1-14; Daily oral dose of one Celexa® 20 mg tablet and one Wellbutrin XL® 150 mg tablet (Lot: 06E065P) on days 15-17; Daily oral dose of one Celexa® 20 mg tablet and one Wellbutrin XL® 300 mg tablet (Lot: 06E002P) on Days 18-27; and Daily oral dose of Celexa® 10 mg tablet (Lot: M0517 J) and Wellbutrin XL® 150 mg tablet on Days 28-30. 92 WO 2009/095395 PCT/EP2009/050924 [003951 Data from the 26 subjects who completed the study were included in the pharmacokinetic and statistical analyses. The concentration-time data were transferred from Watson directly to WinNonlin Enterprise Edition (Version 4.0, Pharsight Corporation) using the Custom Query Builder option for analysis. Data were analyzed by noncompartmental methods in WinNonlin. In the pharmacokinetic analysis, BLQ concentrations were treated as zero from time-zero up to the time at which the first quantifiable concentration was observed; embedded and/or terminal BLQ concentrations were treated as "missing." Full precision concentration data (not rounded to three significant figures) and actual sample times were used for all pharmacokinetic and statistical analyses. Bupropion, hydroxybupropion, erythro hydrobupropion, threo-hydrobupropion, citalopram, desmethyleitalopram (demethycitalopram), and didesmethylcitalopram (didemethyleitaopram) were included in the analysis. PAWC (potency corrected molar concentration summed for bupropion and its metabolites) at each time point was calculated by multiplying the molar concentrations of bupropion, hydroxybupropion, threo-hydrobupropion, and erythro-hydrobupropion by relative potency (1.0, 0.6, 0.2, and 0.2, respectively) and adding all four concentrations. PAWC data were also included in the pharmacokinetic analysis. [003961 The following pharmacokinetic parameters for bupropion and its metabolites hydroxybupropion, bupropion erythroamino alcohol, and bupropion threoamino alcohol, including pharmacologic activity-weighted composite (PAWC), and citalopram and its metabolites, demethylcitalopram and didemethylcitalopram were calculated by standard non compartmental methods: AUCo-t, AUCo-inf, Cmax, Tm., Kei, t/, MRT, and M/P ratio. [00397] The following M/P ratios were considered: Bupropion Erythroamino Alcohol / Bupropion, Bupropion Threoamino Alcohol / Bupropion, Hydroxybupropion / Bupropion, Demethyleitalopram / Citalopram, Didemethylcitalopram / Citalopram. [003981 To test for a potential drug interaction between Celexa* and Wellbutrin XL*, pharmacokinetic parameters of citalopram, desmethyleitalopram, and didemethylcitalopram were compared. Analysis of variance (ANOVA) and the Schuirmann's two one-sided t-test procedures at the 5% significance level were applied to the natural log-transformed pharmacokinetic exposure parameters Cma, Cmin, Cavg, and AUCinf and on untransformed values of % fluctuation, % swing, MRT, and M/P ratio. Pharmacokinetic parameters were analyzed for differences between treatments using an ANOVA model with factors for sequence, subject within sequence, period, and treatment. The 90% confidence interval for the ratio of the geometric means (Celexa* + Wellbutrin XL* / Celexa* alone) was calculated, using Celexa® alone as a reference. A lack of significant drug interaction was demonstrated if the lower and upper confidence 93 WO 2009/095395 PCT/EP2009/050924 intervals of the log-transformed parameters were within 80% to 125%. Tm values of citalopram, demethyleitalopram, and didemethyleitalopram were compared (Celexa* + Wellbutrin XL* vs. Celexa* alone) using nonparametric methods; a significant difference was defined a priori as p < 0.05. [003991 Data for the pharmacokinetic parameters for bupropion and citalopram and its metabolites is presented in the tables below and in FIGs. 22A-D. Pharmacokinetic Parameters of Citalopram During Steady-State Dosing of Celexa* 20 mg Alone Parameter n Mean SD CV% AUCo., (hr*ng/mL) 26 1219 321.6 26.38 Cmax(ng/mL) 26 67.9 17.0 25.04 Tmax(hr) 26 3.96 2.03 51.23 C.. (ng/mL) 26 39.5 11.5 29.13 C.,g(ng/mL) 26 50.8 13.4 26.38 Fluctuation (%) 26 57.22 13.31 23.27 Swing (%) 26 75.55 23.10 30.58 CL/F (L/hr) 26 17.66 5.214 29.52 Vss/F (L) 26 749.6 172.0 22.95 MRT (hr) 26 48.62 13.96 28.71 M/P Ratio 26 1.000 0.000 0.00 Pharmacokinetic Parameters of Desmethyleitalopram During Steady-State Dosing of Celexa* 20 mg Alone Parameter n Mean SD CV% AUCo.,(hr*ng/mL) 26 445.9 112.9 25.31 Cmax(ng/mL) 26 21.7 5.97 27.45 T.ax(hr) 26 5.46 3.69 67.58 Cmi. (ng/mL) 26 16.3 4.25 26.03 Cg (ng/mL) 26 18.6 4.70 25.31 Fluctuation (%) 26 28.93 6.18 21.38 Swing (%) 26 33.09 7.53 22.75 CL/F (L/hr) Vss/F (L) MRT (hr) 26 98.54 41.21 41.82 M/P Ratio 26 0.4062 0.1330 32.75 Pharmacokinetic Parameters of Didesmethyleitalopram During Steady-State Dosing of Celexa* 20 mg Alone Parameter n Mean SD CV% AUCo., (hr*ng/mL) 25 92.04 50.09 54.42 Cmax(ng/mL) 25 4.40 2.44 55.35 Tmax(hr) 25 6.41 4.30 67.17 Cm..(ng/mL) 25 3.42 1.91 55.73 Cg (ng/mL) 25 3.84 2.09 54.42 Fluctuation (%) 25 26.43 14.71 55.64 Swing (%) 25 29.97 17.95 59.90 CL/F (L/hr) Vss/F (L) MRT (hr) 25 258.96 260.91 100.75 M/P Ratio 25 0.09587 0.07202 75.12 Pharmacokinetic Parameters of Citalopram During Steady-State Dosing of Celexa* 20 mg Plus Wellbutrin XL* 300 mg Parameter n Mean SD CV% AUCo., (hr*ng/mL) 26 1877 369.3 19.68 Cmax(ng/mL) 26 99.4 20.1 20.23 94 WO 2009/095395 PCT/EP2009/050924 Tmax(hr) 26 3.77 1.37 36.23 Cmi.i(ng/mL) 26 61.6 12.5 20.32 C.,g (ng/mL) 26 78.2 15.4 19.68 Fluctuation (%) 26 48.46 9.08 18.73 Swing (%) 26 62.15 14.13 22.74 CL/F (L/hr) 26 11.04 2.097 18.98 Vss/F (L) 26 604.3 277.5 45.92 MRT (hr) 26 57.21 23.18 40.51 M/P Ratio 26 1.000 0.000 0.00 Pharmacokinetic Parameters of Desmethylcitalopram During Steady-State Dosing of Celexa® 20 mg Plus Wellbutrin XL® 300 mg Parameter n Mean SD CV% AUCo., (hr*ng/mL) 26 485.2 113.6 23.41 Cma (ng/mL) 26 23.6 6.69 28.39 Tmax(hr) 26 7.12 3.47 48.70 Cmi.(ng/mL) 26 17.3 4.15 24.06 Cg (ng/mL) 26 20.2 4.73 23.41 Fluctuation (%) 26 30.39 8.73 28.72 Swing (%) 26 35.98 11.68 32.48 CL/F (L/hr) Vss/F (L) MRT (hr) 26 85.78 35.06 40.87 M/P Ratio 26 0.2814 0.09099 32.33 Pharmacokinetic Parameters of Didesmethylcitalopram During Steady-State Dosing of Celexa® 20 mg Plus Wellbutrin XL® 300 mg Parameter n Mean SD CV% AUCo., (hr*ng/mL) 25 16.39 8.055 49.15 Cmax(ng/mL) 25 0.781 0.395 50.62 Tmax(hr) 25 5.72 3.92 68.52 Cmi. (ng/mL) 25 0.591 0.271 45.78 Cg (ng/mL) 25 0.683 0.336 49.15 Fluctuation (%) 25 26.66 6.91 25.91 Swing (%) 25 30.90 9.25 29.94 CL/F (L/hr) Vss/F (L) MRT (hr) 24 110.87 72.21 65.13 M/P Ratio 25 0.01029 0.006047 58.77 Pharmacokinetic Parameters of Bupropion During Steady-State Dosing of Celexa* 20 mg Plus Wellbutrin XL* 300 mg Parameter n Mean SD CV% AUCo.,(hr*ng/mL) 26 1356 311.1 22.93 Cmax(ng/mL) 26 142 38.5 27.11 Tmax(hr) 26 4.81 0.85 17.67 Cmu.(ng/mL) 26 19.7 8.48 43.11 Cg (ng/mL) 26 56.5 13.0 22.93 Fluctuation (%) 26 218.86 41.63 19.02 Swing (%) 26 795.19 622.18 78.24 CL/F (L/hr) 26 232.9 54.31 23.32 Vss/F (L) 26 3041 1065 35.03 MRT (hr) 26 15.83 3.04 19.19 M/P Ratio 26 1.000 0.000 0.00 Pharmacokinetic Parameters of Erythro-Hydrobupropion During Steady-State Dosing of Celexa* 20 mg Plus Wellbutrin XL* 300 mg Parameter n Mean SD CV% AUCo., (hr*ng/mL) 26 2239 889.3 39.73 Cmax (ng/mL) 26 110 43.1 39.18 Tmax(hr) 26 8.89 3.26 36.64 Cmi. (ng/mL) 26 77.3 34.9 45.17 Cg (ng/mL) 26 93.3 37.1 39.73 Fluctuation (%) 26 38.06 17.80 46.76 Swing (%) 26 51.68 42.25 81.75 95 WO 2009/095395 PCT/EP2009/050924 CL/F (L/hr) Vss/F (L) MRT (hr) 25 97.66 70.54 72.22 M/P Ratio 26 1.622 0.4313 26.59 Pharmacokinetic Parameters of Hydroxybupropion During Steady-State Dosing of Celexa* 20 mg Plus Wellbutrin XL* 300 mg Parameter n Mean SD CV% AUCo., (hr*ng/mL) 26 26620 8713 32.74 Cmax (ng/mL) 26 1320 448 33.99 Tmax(hr) 26 7.42 2.83 38.14 Cmi.(ng/mL) 26 918 357 38.85 C., (ng/mL) 26 1110 363 32.74 Fluctuation (%) 26 37.32 17.83 47.76 Swing (%) 26 50.52 42.97 85.05 CL/F (L/hr) Vss/F (L) MRT (hr) 26 89.99 48.99 54.44 M/P Ratio 26 19.06 6.515 34.18 Pharmacokinetic Parameters of Threo-Hydrobupropion During Steady-State Dosing of Celexa* 20 mg Plus Wellbutrin XL* 300 mg Parameter n Mean SD CV% AUCo., (hr*ng/mL) 26 10750 4719 43.90 Cmax(ng/mL) 26 553 237 42.90 Tmax(hr) 26 7.93 2.83 35.72 Cmi. (ng/mL) 26 352 186 52.87 Cg (ng/mL) 26 448 197 43.90 Fluctuation (%) 26 50.12 22.25 44.40 Swing (%) 26 75.49 68.58 90.86 CL/F (L/hr) Vss/F (L) MRT (hr) 25 56.01 21.70 38.74 M/P Ratio 26 7.856 2.969 37.79 Pharmacokinetic Parameters of PAWC During Steady-State Dosing of Celexa* 20 mg Plus Wellbutrin XL* 300 mg Parameter n Mean SD CV% AUCo., (hr*nmol/L) 26 78860 22910 29.05 Cmax(nmol/L) 26 4130 1190 28.80 Tmax(hr) 26 6.19 2.47 39.82 Cmi. (nmol/L) 26 2620 966 36.82 Cg (nmol/L) 26 3290 955 29.05 Fluctuation (%) 26 47.76 17.02 35.63 Swing (%) 26 66.14 45.71 69.11 CL/F (L/hr) Vss/F (L) MRT (hr) 26 65.23 28.69 43.98 Statistical Analysis of the Log-Transformed Systemic Exposure Parameters of Citalopram Dependent Geometric Mean" Ratio (%)b 90% CIC Power Variable Test Ref (Test/Ref) Lower Upper 1846.90 1175.60 157.10 140.27 175.95 0.9447 ln(AUCo.,) ln(Cmax) 97.71 65.80 148.51 133.44 165.27 0.9626 60.47 37.70 160.38 141.47 181.83 0.9009 In(Ca) 76.95 48.98 157.10 140.27 175.95 0.9447 'Geometric Mean for Celexa* 20 mg plus Wellbutrin XL* 300 mg (Test) and Celexa* 20 mg alone (Ref) based on Least Squares Mean of 96 WO 2009/095395 PCT/EP2009/050924 log-transformed parameter values b Ratio(%) = Geometric Mean (Test)/Geometric Mean (Ref) 90% Confidence Interval Statistical Analysis of the Log-Transformed Systemic Exposure Parameters of Desmethylcitalopram Dependent Geometric Mean" Ratio (%)b 90% CIC Power Variable Test Ref (Test/Ref) Lower Upper 473.82 433.72 109.24 98.32 121.38 0.9667 ln(AUCo-) ln(C.ax) 22.83 21.05 108.50 96.55 121.93 0.9337 16.84 15.84 106.29 95.36 118.46 0.9587 19.74 18.07 109.24 98.32 121.38 0.9667 a Geometric Mean for Celexa* 20 mg plus Wellbutrin XL* 300 mg (Test) and Celexa* 20 mg alone (Ref) based on Least Squares Mean of log-transformed parameter values b Ratio(%) = Geometric Mean (Test)/Geometric Mean (Ref) 90% Confidence Interval Statistical Analysis of the Log-Transformed Systemic Exposure Parameters of Didesmethylcitalopram Dependent Geometric Mean" Ratio (%)b 90% CIC Power Variable Test Ref (Test/Ref) Lower Upper 14.99 82.11 18.26 14.69 22.70 0.5179 ln(AUCO-) ln(Cmax) 0.71 3.93 18.08 14.55 22.46 0.5193 0.54 3.05 17.89 14.42 22.19 0.5244 0.62 3.42 18.26 14.69 22.70 0.5179 'Geometric Mean for Celexa* 20 mg plus Wellbutrin XL* 300 mg (Test) and Celexa* 20 mg alone (Ref) based on Least Squares Mean of log-transformed parameter values b Ratio(%) = Geometric Mean (Test)/Geometric Mean (Ref) 90% Confidence Interval EXAMPLE 23 [004001 A TWO-PART, TWO-WAY CROSSOVER, OPEN-LABEL, SINGLE-DOSE, FASTING AND FOOD-EFFECT, PHARMACOKINETIC STUDY OF BUPROPION HBR XL 348 MG/CITALOPRAM HCL IR 20 MG TABLETS VERSUS BUPROPION HBR XL 348 MG TABLETS GIVEN CONCOMITANTLY WITH CELEXA TM (CITALOPRAM HBR) 20 MG TABLETS IN NORMAL, HEALTHY, NON-SMOKING MALE AND FEMALE SUBJECTS. [004011 This study was a two-part, two-way crossover, randomized, open-label, single dose, fasting and food-effect, Phase I study. The objectives of this study were: a) to determine and compare the rate and extent of absorption of bupropion and citalopram from a test fixed dose combination tablet formulation of Bupropion HBr XL (sustained release) 348 mg/Citalopram HCl Immediate Release (IR) 20 mg versus Bupropion HBr XL 348 mg tablets given concomitantly with CelexaTM 20 mg tablets under fasting conditions, (Group 1) and, b) to determine the effect of food on the rate and extent of absorption of a fixed dose combination tablet formulation of Bupropion HBr XL 348 mg/Citalopram HCl IR 20 mg (Group 2). The bupropion HBr XL 97 WO 2009/095395 PCT/EP2009/050924 (sustained release) tablet used in this study was manufactured as described in US Patent No. 7,241,805. To obtain the fixed dose combination tablet formulation of bupropion HBr XL (sustained release) 348 mg/citalopram HCl Immediate Release (IR) 20 mg, the bupropion HBr XL tablet is over coated with an immediate release coating comprising 20 mg citalopram HCl according to methods well known in the art. Normal, healthy, non-smoking male and female subjects between the ages of 18 and 55 years were included in the study. [00402] Following an overnight fast of at least 10 hours, and 30 minutes after the start of a high fat content meal, 1 Bupropion HBr XL 348 mg/Citalopram HCl IR 20 mg Tablet, Lot #: 0608055 [otency value = citalopram (95.2%) and bupropion (98.8%) of label claim], administered orally with 240 mL of ambient temperature water. Following an overnight fast of at least 10 hours, 1 Bupropion HBr XL 348 mg Tablet, Lot #: 06C159P (potency value = 97.8 % of label claim) and 1 Celexa T M 20 mg Tablet, Lot #: M0512M (potency value = 97.9 % of label claim) administered orally with 240 mL of ambient temperature water. [004031 There were 13 subjects dosed in Group 1, 11 of whom completed the study. One subject was dismissed after emesis within 24.00 hours of dosing, and 1 subject was dismissed because of administrative reasons. Pharmacokinetic and statistical analyses were performed on 11 subjects who completed the study. [00404] There were 14 subjects dosed in Group II, 10 of whom completed the study. Two subjects were dismissed after emesis within 24.00 hours of dosing, and 2 subjects withdrew for personal reasons. Pharmacokinetic and statistical analyses were performed on 10 subjects who completed the study. [00405] During each study period, 25 blood samples (10 mL each as 1 x 4 mL tube and 1 x 6 mL tube for each time-point) were collected from each subject at the following timepoints: 0.00 (pre-dose), 0.50, 1.00, 1.50, 2.00, 3.00, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00, 96.00, 120.00, 144.00, 168.00, 192.00, 216.00, and 240.00 hours post dose. [004061 Bupropion, its metabolites - hydroxybupropion, bupropion erythroamino alcohol, and bupropion threoamino alcohol, and the internal standard, 1-(3-chlorophenyl)-piperazine, were extracted by solid phase extraction into an organic media from 0.50 mL of human plasma. An aliquot of this extract was injected into a High Performance Liquid Chromatography system and detected using a tandem mass spectrometer. The analytes were separated by reverse phase chromatography. Evaluation of the assay was carried out by the construction of an eight (8) point calibration curve (excluding zero concentration) covering the range of 1.000 ng/mL to 1023.900 ng/mL for bupropion, 3.907 ng/mL to 4001.200 ng/mL for hydroxybupropion, 98 WO 2009/095395 PCT/EP2009/050924 1.000 ng/mL to 1024.310 ng/mL for bupropion erythroamino alcohol, and 1.000 ng/mL to 1023.850 ng/mL for bupropion threoamino alcohol in human plasma. The slope and intercept of the calibration curves were determined through weighted linear regression analysis (1/area ratio.
2 ). Two calibration curves and duplicate QC samples (at three concentration levels) were analyzed along with each batch of the study samples. Peak area ratios were used to determine the concentration of the standards, quality control samples, and the unknown study samples from the calibration curves. [00407] Citalopram, its metabolites - demethyleitalopram and didemethyleitalopram, and the internal standards, citalopram analog, demethyleitalopram analog, and didemethyleitalopram analog, were extracted by liquid-liquid extraction into an organic media from 1.00 mL of human plasma. An aliquot of this extract was injected into a High Performance Liquid Chromatography system and detected using a tandem mass spectrometer. The analytes were separated by reverse phase chromatography. Evaluation of the assay was carried out by the construction of an eight (8) point calibration curve (excluding zero concentration) covering the range of 0.250 ng/mL to 63.944 ng/mL for Citalopram, 0.050 ng/mL to 12.812 ng/mL for demethyleitalopram, and 0.050 ng/mL to 12.796 ng/mL for didemethyleitalopram in human plasma. The slope and intercept of the calibration curves were determined through weighted linear regression analysis (1/cone.
2 ). Two calibration curves and duplicate QC samples (at three concentration levels) were analyzed along with each batch of the study samples. Peak area ratios were used to determine the concentration of the standards, quality control samples, and the unknown study samples from the calibration curves. [004081 The pharmacokinetic analysis was performed on 21 subjects who completed the 2 study periods (11 subjects in Group 1 and 10 subjects in Group 2). The safety assessment was performed on all subjects who received at least 1 dose during the course of the study. [00409] The following pharmacokinetic parameters for bupropion and its metabolites hydroxybupropion, bupropion erythroamino alcohol, and bupropion threoamino alcohol, including pharmacologic activity-weighted composite (PAWC), and citalopram and its metabolites, demethylcitalopram and didemethyleitalopram were calculated by standard non compartmental methods: AUCo-t, AUCo-inf, Cmax, Tm., Kei, t/, MRT, and M/P ratio. [00410] Statistical analysis was carried out using General Linear Model (GLM) procedures in Statistical Analysis System (SAS), analysis of variance (ANOVA) was performed on ln-transformed AUCo-t, AUCo-inf, and Cm,, and on untransformed Kei, t/, MRT, and M/P ratio at the significance level of 0.05. The intra-subject coefficient of variation (CV) was calculated using the Mean Square Error (MSE) from the ANOVA table. The ratio of geometric means and 99 WO 2009/095395 PCT/EP2009/050924 the 90% geometric confidence interval (90% C.I.) were calculated based on the difference in the Least Squares Means of the In-transformed AUCo-t, AUCo-xf, and Cmax between the test and reference formulations. Tmax was analyzed using nonparametric methods. [00411] Data for the pharmacokinetic parameters for bupropion and citalopram and their metabolites is presented in the tables below and in FIGs. 23A-P. Pharmacokinetic Parameters Bupropion (Group 1) Geometric Mean (%CV) Arithmetic Mean ± SD Pharmacokinetic Parameters Bupropion HBr XL 348 mg/Citalopram HCl Bupropion HBr XL 348 mg Tablets and IR 20 mg Tablets (A) (fasting conditions) Celexa TM 20 mg Tablets (B) (fasting conditions) (n=11) AUCo, (ng-hr/mL) 1306.88 (28.24) 1246.49 (32.72) 1355.50 + 382.79 1301.77 + 425.92 AUC ng-hr/mL) 1352.18 (27.47) 1288.48 (32.09) A Jo rm1399.78 + 384.47 1343.41 + 431.13 C (ng/mL) 110.13 (47.04) 114.67 (30.63) '"" mL124.00 + 58.33 119.58 + 36.62 Tmax (hr)* 5.00 (2.00 - 5.02) 3.00 (2.00 - 5.00) t 1 2 (hr) 21.41 + 8.32 19.55 + 7.39 Ked (hr-') 3.96E-02 + 2.19E-02 4.16E-02 + 1.90E-02 MRT (hr) 21.15 +6.19 20.36 +6.33 * median (min - max) Relative Bioavailability Assessments for Bupropion (Group 1) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCo., 88.13% to 125.53% 105.18% 22.82% AUCOi.f 88.82% to 124.82% 105.29% 21.93% Cmax 70.81% to 133.09% 97.08% 41.88% Parameter Potency Corrected Data AUCo., 87.24 % to 124.26 % 104.12% AUCOi.f 87.92 % to 123.56 % 104.23% Cmax 70.10 % to 131.74 % 96.10% Pharmacokinetic Parameters for Hydroxybupropion (Group 1) Geometric Mean (%CV) Arithmetic Mean ± SD Pharmacokinetic Parameters Bupropion HBr XL 348 mg/Citalopram HCl Bupropion HBr XL 348 mg Tablets and IR 20 mg Tablets (A) (fasting conditions) Celexa TM 20 mg Tablets (B) (fasting conditions) (n=11) AUCo, (ng-hr/mL) 19769.84 (43.38) 17749.81 (52.24) 21212.19 + 9202.72 19742.73 + 10313.94 AUC ng-hr/mL) 19991.61 (43.01) 17973.86 (51.79) A Jo /m21424.72 + 9214.70 19951.68 + 10332.15 C (ng/mL) 450.03 (27.74) 393.57 (33.64) ""gL468.22 + 129.87 415.16 + 139.64 Tmax (hr)* 8.00 (7.00 - 24.00) 8.00 (5.00 - 24.00) t 1 2 (hr) 25.04 + 6.12 24.56 + 6.03 Ked (hr-') 2.91E-02 + 6.63E-03 2.98E-02 + 7.07E-03 MRT (hr) 39.38 + 7.67 39.40 + 7.84 M/P Ratio 14.82 6.20 14.35 7.97 * median (min - max) Relative Bioavailability Assessments for Hydroxybupropion (Group 1) Parameter 90% C.I. I Ratio of Means Intra-Subject CV AUCo., 97.13% to 130.18% 112.45% 18.82% AUCo-i.f 97.21% to 129.69% 112.28% 18.52% 100 WO 2009/095395 PCT/EP2009/050924 Cmax | 94.88% to 139.31% | 114.97% 24.84% Pharmacokinetic Parameters for Bupropion Threoamino Alcohol (Group 1) Geometric Mean (%CV) Arithmetic Mean ± SD Pharmacokinetic Parameters Bupropion HBr XL 348 mg/Citalopram HCl Bupropion HBr XL 348 mg Tablets and IR 20 mg Tablets (A) (fasting conditions) Celexa TM 20 mg Tablets (B) (fasting 2 t() (conditions) (n=11) 6781.91 (39.37) 6721.27 (54.76) AUCo(ng-hr/mL) 7277.11 + 2865.28 7614.66 + 4169.98 7379.72 (40.50) 7142.17 (54.16) AUJCo~i 1 (nghr/mL) 8015.86 + 3 24 6 .55t 8106.20 + 4390.12 C (ng/mL) 138.27 (39.58) 128.32 (40.64) "" mL149.64 + 59.23 139.06 + 56.51 Tmax (hr)* 7.00 (5.00 - 24.00) 6.00 (3.00 - 12.00) t 11
/
2 (hr) 68.95 + 50.0 6 61.63 + 12.49 Ked (hr-') 1.33E-02 + 5.42E-03t 1.17E-02 + 2.30E-03 MRT (hr) 79.83 +E 32.07t 78.61 +E 17.93 M/P Ratio 5.85 + 2.53t 5.83 + 2.38 * median (min - max) t n= 10 Relative Bioavailability Assessments for Bupropion Threoamino Alcohol (Group 1) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 85.35% to 120.65% 101.47% 22.32% AUCo-i.f 83.93% to 124.82% 102.36% 24.20% Cmax 84.68% to 142.18% 109.73% 33.93% Pharmacokinetic Parameters for Bupropion Eryhthroamino Alcohol (Group 1) Geometric Mean (%CV) Arithmetic Mean ± SD Pharmacokinetic Parameters Bupropion HBr XL 348 mg/Citalopram HCl Bupropion HBr XL 348 mg Tablets and IR 20 mg Tablets (A) (fasting conditions) Celexa TM 20 mg Tablets (B) (fasting 2 t() (conditions) (n=11) 1202.67 (32.03) 1154.00 (49.06) AUC., (ng-hr/mL) 1266.30 + 405.65 1276.47 + 626.26 AUCO-i. (ng-hr/mL) 1269.58 (30.77) 1222.29 (48.02) 1331.59 + 409.70 1344.73 + 645.78 22.82 (24.43) 21.28 (21.62) Cmax(ng/mL) 23.44 + 5.73 21.76 + 4.70 Tmax (hr)* 8.00 (7.00 - 24.00) 8.00 (5.00 - 24.00) t 1 1
/
2 (hr) 31.24 + 7.88 33.57 + 9.70 Ked (hr-') 2.37E-02 + 7.02E-03 2.24E-02 + 6.94E-03 MRT (hr) 51.70+ 12.47 53.60+ 14.03 M/P Ratio 0.96 + 0.25 0.97 + 0.27 * median (min - max) Relative Assessments for Bupropion Erythroamino Alcohol (Group 1) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 87.85% to 124.74% 104.68% 22.61% AUCo-i.f 88.21% to 123.03% 104.17% 21.43% Cmax 87.56% to 132.77% 107.82% 26.99% Pharmacokinetic Parameters for PAWC (Group 1) Geometric Mean (%CV) Arithmetic Mean ± SD Pharmacokinetic Parameters Bupropion HBr XL 348 mg/Citalopram HCl Bupropion HBr XL 348 mg Tablets and IR 20 mg Tablets (A) (fasting conditions) Celexa TM 20 mg Tablets (B) (fasting 2 t() (conditions) (n=11)(n=11) 59.69 (36.13) 54.79 (43.74) AUJC., (uM-hr) 62.72 + 22.66 59.34 + 25.96 60.05 (36.27) 55.05 (44.08) AUJCo~.
1 (uM-hr) 63.12 + 22.90 59.68 + 26.30 101 WO 2009/095395 PCT/EP2009/050924 C uM 1.59 (27.50) 1.40 (26.06) '" (1.65 + 0.45 1.45 + 0.38 Tmax (hr)* 5.00 (4.00 - 10.00) 5.00 (4.00 - 12.00) t 11
/
2 (hr) 43.90 + 28.03 33.52 + 5.25 Ke (hr-) 1.95E-02 + 7.8 1E-03 2.12E-02 3.49E-03 MRT (hr) 40.67 + 7.48 40.58 + 7.73 * median (min - max) Relative Bioavailability Assessments for PAWC (Group 1) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 94.69% to 127.38% 109.82% 19.06% AUCOi.f 94.69% to 127.67% 109.95% 19.21% Cmax 91.08% to 144.95% 114.90% 30.26% Phrmcokinetic Parameters for Citalopram (Group 1) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Bupropion HBr XL 348 mg/Citalopram HCi Bupropion HBr XL 348 mg Tablets and Celexa TM 20 IR 20 mg Tablets (A) (fasting conditions) mg Tablets (B) (fasting conditions) (n=11) (n=11) AUCo, (ng-hr/mL) 1243.68 (29.90) 1310.90 (33.48) 1298.07 + 388.17 1376.28 + 460.76 AUCO-i. (ng-hr/mL) 1308.68 (31.80) 1371.57 (35.69) 1373.05 + 436.59 1448.18 + 516.91 C ng/mL) 23.89 (21.76) 26.28 (23.38) Cmx ( L 24.47 + 5.32 26.91 + 6.29 Tmax (hr)* 5.00 (2.00 - 8.00) 5.00 (3.00 - 8.00) t 1 1
/
2 (hr) 58.25 + 16.80 54.75 + 9.44 Ked (hr-') 1.28E-02 + 3.5 1E-03 1.30E-02 + 2.46E-03 MRT (hr) 73.81 + 14.08 71.88 + 12.49 * median (min - max) Relative Bioavailability Assessments for Citalopram (Group 1) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCo., 90.26% to 100.49% 95.24% 6.85% AUCOi.f 90.42% to 101.39% 95.75% 7.31% Cmax 83.61%to 99.39% 91.16% 11.04% Parameter Potency Corrected Data 90% C.I. Ratio of Me ans AUCo., 92.82 % to 103.34 % 97.940% AUCOi.f 92.98 % to 104.27 % 98.470% Cmax 85.98 % to 102.20 % 93.740% Pharmacokinetic Parameters for Demetheylcitalopram (Group 1) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Bupropion HBr XL 348 mg/Citalopram HCl Bupropion HBr XL 348 mg Tablets and Celexa TM 20 IR 20 mg Tablets (A) (fasting conditions) mg Tablets (B) (fasting conditions) (n=11) (n=11) AUCo., (ng-hr/mL) 329.83 (21.36) 349.57 (21.08) 337.60 + 72.12 358.21 + 75.50 ALJCO-f(nghr/mL) 352.35 (8.86) 442.09 (19.62) 353.53 + 31.32: 448.82 + 88.08: C (ng/mL) 2.22 (25.49) 2.38 (27.71) Cmx n2.30 + 0.59 2.49 + 0.69 Tmax (hr)* 48.00 (8.00 - 96.00) 36.00 (10.00 - 36.03) t 11
/
2 (hr) 59.70 + 8.76: 77.33 + 15.85: Ked (hr-') 1.18E-02+ 1.74E-03t 9.29E-03 + 1.89E-03t MRT (hr) 117.28 + 18.17: 128.01 +26.80: M/P Ratio 0.35 + 0.13: 0.39 + 0.08: * median (min - max) Relative Bioavailability Assessments for Demethylcitalopram (Group 1) 102 WO 2009/095395 PCT/EP2009/050924 Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 90.20% to 99.07% 94.53% 5.98% AUCO-i.f 55.06% to 152.04% 91.50% 9.31% Cmax 87.90% to 97.97% 92.80% 6.92% Pharmacokinetic Parameters for Didemethylcitalopram (Group 1) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Bupropion HBr XL 348 mg/Citalopram HCi Bupropion HBr XL 348 mg Tablets and Celexa TM 20 IR 20 mg Tablets (A) (fasting conditions) mg Tablets (B) (fasting conditions) (n=11) (n=11) AUCo, -hr/mL) 27.72 (84.96) 31.08 (75.70) (ng38.58 + 32.78 41.36 + 31.31 AUCOi.f (ng-hr/mL) NC NC 0.25 (128.93) 0.24 (62.84) Cmax(ng/mL) 0.31 + 0.40 0.26 + 0.16 Tmax (hr)* 144.00 (48.00 - 216.00)§ 132.10 (96.00 - 216.00)t t 11
/
2 (hr) NC NC Ke (hr-') NC NC MRT (hr) NC NC M/P Ratio NC NC * median (min - max) §n-9 tn= 10 NC = No Calculation Relative Bioavailability Assessments for Didemethylcitalopram (Group 1) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 36.51% to 98.89% 60.09% 56.44% AUCOi.f NC 60.09% NC Cmax 63.80% to 151.20% 98.21% 48.01% Pharmacokinetic Parameters for Bupropion (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Bupropion HBr XL 348 mg/Citalopram HCl Bupropion HBr XL 348 mg/Citalopram HCl IR 20 IR 20 mg Tablets (A) (fasting conditions) mg Tablets (C) (fed conditions) (n=10) (n=10) 1683.03 (24.53) 1512.58 (35.95) AUC., (ng-hr/mL) 1728.43 + 424.01 1599.22 + 574.93 1729.27 (24.35) 1555.02 (35.50) AUJCo~.
1 (nghr/mL) 1775.06 + 432.18 1640.96 + 582.47 C (ng/mL) 141.59 (32.39) 109.86 (39.28) "a" /L149.11 + 48.29 119.88 + 47.09 Tmax (hr)* 4.50 (3.00 - 10.00) 5.00 (2.00 - 8.00) t 11
/
2 (hr) 23.70 + 5.97 20.70 + 7.63 Ked (hr-') 3.14E-02 + 9.70E-03 3.73E-02 + 1.20E-02 MRT (hr) 22.27 +6.15 22.09 +6.96 * median (min - max) Relative Bioavailability Assessments for Bupropion (Group 2) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCo., 79.81% to 101.21% 89.87% 14.36% AUCOi.f 80.17% to 100.86% 89.92% 13.87% Cmax 63.13% to 95.36% 77.59% 25.19% Pharmacokinetic Parameters for Hydroxybupropion (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Bupropion HBr XL 348 mg/Citalopram HCl Bupropion HBr XL 348 mg/Citalopram HCl IR 20 IR 20 mg Tablets (A) (fasting conditions) mg Tablets (C) (fed conditions) (n=10) (n=10) 24257.00 (37.65) 21904.96 (53.59) AUC., (ng-hr/mL) 25952.95 + 9771.48 25096.58 + 13449.54 103 WO 2009/095395 PCT/EP2009/050924 24490.88 (37.48) 22142.07 (53.35) AUJCo~.
1 (nghr/mL) 26183.71 + 9812.76 25322.65 + 13510.55 C (ng/mL) 466.81 (33.07) 421.37 (45.63) '"" mL488.11 + 161.41 466.37 + 212.79 Tmax (hr)* 9.00 (7.00 - 24.00) 12.00 (8.00 - 36.00) t 11
/
2 (hr) 26.27 + 6.08 27.45 + 6.09 Ked (hr-') 2.79E-02 + 7.15E-03 2.64E-02 + 5.74E-03 MRT (hr) 44.92 + 10.09 44.93 + 8.66 M/P Ratio 14.06 + 4.99 14.25 + 5.61 * median (min - max) Relative Bioavailability Assessments for Hydroxybupropion (Group 2) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 79.80% to 102.19% 90.30% 14.95% AUCOi.f 80.05% to 102.110% 90.41% 14.72% Cmax 80.44% to 101.29% 90.27% 13.92% Pharmacokinetic Parameters for Bupropion Threoamino Alcohol (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Bupropion HBr XL 348 mg/Citalopram HCl Bupropion HBr XL 348 mg/Citalopram HCl IR 20 IR 20 mg Tablets (A) (fasting conditions) mg Tablets (C) (fed conditions) (n=10) (n=10) 9052.10 (41.63) 7946.73 (45.82) AUC., (ng-hr/mL) 9695.24 + 4035.97 8695.70 + 3984.62 9664.70 (45.82) 8489.87 (48.32) AUJCo~i 1 (nghr/mL) 10511.83 + 4816.41 9395.31 + 4540.05 C (ng/mL) 168.34 (25.85) 134.83 (40.31) '"" /L173.22+±44.78 145.82+±58.78 Tmax (hr)* 7.00 (5.00 - 10.00) 10.00 (6.00 - 36.00) t 1 1
/
2 (hr) 58.30 + 21.53 62.13 + 16.94 Ked (hr-') 1.39E-02 + 6.46E-03 1.20E-02 + 3.65E-03 MRT (hr) 80.09 + 22.79 81.49 + 20.47 M/P Ratio 5.80 + 2.04 5.88 + 2.98 * median (min - max) Relative Bioavailability Assessments for Bupropion Threoamino Alcohol (Group 2) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 75.33% to 102.30% 87.79% 18.56% AUCo-i.f 74.69% to 103.310% 87.84% 19.69% Cmax 66.26% to 96.82% 80.10% 23.10% Pharmacokinetic Parameters for Bupropion Erythroamino Alcohol (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Bupropion HBr XL 348 mg/Citalopram HCl Bupropion HBr XL 348 mg/Citalopram HCl IR 20 IR 20 mg Tablets (A) (fasting conditions) mg Tablets (C) (fed conditions) (n=10) (n=10) AUCo, (ng-hr/mL) 1597.56 (33.52) 1380.30 (36.03) 1680.63 + 563.35 1457.66 + 525.14 1664.27 (32.70) 1453.53 (34.45) AUJCo~.
1 (nghr/mL) 1746.86 + 571.29 1528.45 + 526.55 26.81 (22.05) 23.80 (26.45) Cmax(ng/mL) 27.30 + 6.02 24.61 + 6.51 Tmax (hr)* 8.00 (6.00 - 24.00) 11.00 (10.00 - 36.00) t 1 1
/
2 (hr) 33.17 + 7.58 34.67 + 10.38 Ke (hr-') 2.20E-02 5.48E-03 2.18E-02 + 7.23E-03 MRT (hr) 56.09 + 12.79 56.55 + 13.91 M/P Ratio 0.98 + 0.22 0.95 + 0.20 * median (min - max) Relative Bioavailability for Bupropion Erythoamino Alcohol (Group 2) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 73.23% to 101.93% 86.40% 20.08% AUCo-i.f 74.38% to 102.56% 87.34% 19.50% Cmax 76.27% to 103.33% 88.78% 18.41% 104 WO 2009/095395 PCT/EP2009/050924 Pharmacokinetic Parameters for PAWC (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Bupropion HBr XL 348 mg/Citalopram HCi Bupropion HBr XL 348 mg/Citalopram HCi IR 20 IR 20 mg Tablets (A) (fasting conditions) mg Tablets (C) (fed conditions) (n=10) (n=10) AUCo. (uM-hr) 74.24 (31.23) 66.95 (47.43) 77.70 + 24.27 74.13 + 35.16 AUCO-i. (uM-hr) 74.73 (31.51) 67.40 (47.71) 78.27 + 24.67 74.70 + 35.64 C uM 1.73 (25.00) 1.42 (39.90) '" (1.78 + 0.44 1.53 + 0.61 Tmax (hr)* 5.50 (4.00 - 12.00) 10.00 (4.00 - 36.00) t 1 2 (hr) 30.34 + 10.99 34.85 + 17.95 Ked (hr-') 2.63E-02 + 1.1 IE-02 2.36E-02 + 9.23E-03 MRT (hr) 45.14 + 10.49 45.44 + 9.04 * median (min - max) Relative Bioavailability Assessments for PAWC (Group 2) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 79.87% to 101.84% 90.19% 14.69% AUCOi.f 79.77% to 101.99% 90.20% 14.85% Cmax 72.53% to 92.60% 81.95% 14.77% Pharmacokinetic Parameters for Citalopram (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Bupropion HBr XL 348 mg/Citalopram HCl Bupropion HBr XL 348 mg/Citalopram HCl IR 20 IR 20 mg Tablets (A) (fasting conditions) mg Tablets (C) (fed conditions) (n=10) (n=10) AUCo., (ng-hr/mL) 1204.03 (15.08) 1185.17 (15.02) 1216.86 + 183.46 1197.82 + 179.96 AUC -hr/mL) 1261.16 (15.59) 1249.49 (15.23) L -i 1 (ngh/m1275.36 + 198.81 1263.33 + 192.37 C (ng/mL) 22.41 (20.18) 23.80 (18.23) '"" /L22.80 + 4.60 24.13 + 4.40 Tmax (hr)* 5.00 (3.00 - 7.00) 4.00 (2.00 - 6.00) t 1 2 (hr) 58.24 + 9.70 61.99 + 13.28 Ked (hr-') 1.22E-02 + 2.09E-03 1.16E-02 + 2.36E-03 MRT (hr) 73.00 + 9.19 73.59 + 8.44 * median (min - max) Relative Bioavailability Assessments for Citalopram (Group 2) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 95.60% to 101.35% 98.43% 3.51% AUCo-i.f 96.24% to 102.00% 99.07% 3.50% Cmax 99.30% to 113.59% 106.21% 8.09% Pharmacokinetic Parameters for Demethylcitalopram (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Bupropion HBr XI 348 mg/Citalopram HCl Bupropion HBr XL 348 mg/Citalopram HCl IR 20 IR 20 mg Tablets (A) (fasting conditions) mg Tablets (C) (fed conditions) (n=10) (n=10) AUCo., (ng-hr/mL) 310.98 (20.51) 297.01 (22.54) 316.79 + 64.99 304.48 + 68.63 350.62 (22.44) 365.75 (22.53) AUCO-i. (ng-hr/mL) 357.86 + 80.30A 374.08 + 84.27: C (ng/mL) 2.25 (21.56) 2.04 (24.70) '"" /L2.30 + 0.50 2.10 + 0.52 Tmax (hr)* 36.00 (7.00 - 96.00) 24.01 (5.00 - 48.30) t 1 2 (hr) 79.40 + 11.89A 76.85 + 13.06: Ked (hr-') 8.92E-03 + 1.46E-03A 9.25E-03 + 1.65E-03t MRT (hr) 131.77+ 17.94A 132.77+ 18.04: M/P Ratio 0.29 + 0.09A 0.31 + 0.061 105 WO 2009/095395 PCT/EP2009/050924 * median (min - max) :n-6 A n-=8 An =8 Relative Bioavailability Assessments for Demethylcitalopram (Group 2) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 87.01% to 104.84% 95.51% 11.24% AUCo-i.f :d 81.310% to 132.92% 103.96% 16.28% Cmax 83.45% to 98.85% 90.83% 10.21% Pharmacokinetic Parameters for Didemethylcitalopram (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Bupropion HBr X 348 mg/Citalopram HCl Bupropion HBr XL 348 mg/Citalopram HC IR 20 IR 20 mg Tablets (A) (fasting conditions) mg Tablets (C) (fed conditions) (n=10) (n=10) AUCo-, (ng-hr/mL) 38.65 (75.94) 33.81 (74.08) 34.29 + 26.04 29.76 + 22.04 AUCOi.f (ng-hr/mL) NC NC Cma (ng/mL) 0.22 (77.48) 0.19 (74.14) 0.20 + 0.15 0.17 + 0.12 Tmax (hr)* 120.00 (96.00 - 216.75) A 144.00 (72.03 - 192.00)^ t 1 2 (hr) NC NC Kd (hr-') NC NC MRT (hr) NC NC M/P Ratio NC NC * median (min - max) An =8 NC = No Calculation Relative Bioavailability Assessments for Didemethylcitalopram (Group 2) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 75.91% to 98.91% 86.65% 13.24% AUCo-i.f NC 86.65% NC Cmax 77.81% to 92.95% 85.04% 8.88% EXAMPLE 24 [004121 A PILOT, SINGLE-DOSE, PHARMACOKINETIC STUDY OF A CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION OF THE INVENTION COMPRISING BUPROPION HBR 348 MG/CITALOPRAM HCL 22.2 MG TABLETS IN HEALTHY, NON-SMOKING MALE AND FEMALE SUBJECTS [004131 This was a two-way crossover, randomized, open-label, single-dose, fasting and food-effect, Phase I study. The objectives of this study were a) to determine and compare the rate and extent of absorption of bupropion and citalopram from a test pharmaceutical composition manufactured according to Example 1 versus Bupropion HBr (XL) 348 mg Tablets described in US Patent No. 7,241,805 co-administered with Celexa* 20 mg Tablets under fasting conditions, and b) to determine the effect of food on the rate and extent of absorption of a fixed dose combination pharmaceutical composition of Example 1. Normal, healthy, non-smoking male and female subjects between the ages of 18 and 55 years were included in the study. [004141 The test formulation used was: Treatment A: One (1) Pharmaceutical Composition of Example 1, Lot #: 0612087, administered orally under fasting conditions, and 106 WO 2009/095395 PCT/EP2009/050924 Treatment C: One (1) Pharmaceutical Composition of Example 1, Lot #: 0612087, administered orally under fed conditions. [00415] The reference formulation used was: Treatment B: One (1) Bupropion HBr XL 348 mg Tablet as described in US Patent No. 7,241,805, Lot #: 06M064P and 1 Celexa*20 mg Tablet, Lot #: M0512M administered orally under fasting conditions. [00416] There were 14 subjects dosed in Group 1, 13 of whom completed the study. One subject was dismissed after emesis within 24.00 hours of dosing. Pharmacokinetic and statistical analyses were performed on 13 subjects who completed the study. There were 14 subjects dosed in Group II, 13 of whom completed the study. One subject withdrew for personal reasons. Pharmacokinetic and statistical analyses were performed on 13 subjects who completed the study. [00417] During each study period, 27 blood samples were collected from each subject at the following time points: 0.00 (pre-dose), 0.50, 1.00, 1.50, 2.00, 3.00, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00, 96.00, 120.00, 144.00, 168.00, 192.00, 216.00, 240.00, 264.00 and 288.00 hours post-dose. [004181 The pharmacokinetic analysis was performed on 26 subjects who completed the 2 study periods. The safety assessment was performed on all subjects who received at least 1 dose during the course of the study. [00419] The following pharmacokinetic parameters for bupropion and its metabolites hydroxybupropion, bupropion erythroamino alcohol, and bupropion threoamino alcohol, including pharmacologic activity-weighted composite (PAWC), and citalopram and its metabolites, demethylcitalopram and didemethyleitalopram were calculated by standard non compartmental methods: AUCo-t, AUCo-inf, Cmax, Tmax, Kei, t/, Mean Residence Time (MRT), and Metabolite/Parent (M/P) ratio. [00420] Statistical methods used General Linear Model (GLM) procedures in Statistical Analysis System (SAS), analysis of variance (ANOVA) was performed on In-transformed AUCo_ t, AUCo-inf, and Cmax and on untransformed Kei, t, MRT, and M/P ratio at the significance level of 0.05. The intra-subject coefficient of variation (CV) was calculated using the Mean Square Error (MSE) from the ANOVA table. The ratio of geometric means and the 90% geometric confidence interval (90% C.I.) were calculated based on the difference in the Least Squares Means of the ln-transformed AUCo-t, AUC-inf, and Cmax between the test and reference formulations. Tmax was analyzed using nonparametric methods. [00421] Bupropion and its metabolites, hydroxybupropion, bupropion erythroamino alcohol, bupropion threoamino alcohol and the internal standard, 1-(3-chlorophenyl)- piperazine, were extracted by solid phase extraction into an organic media from 0.50 mL of human plasma. 107 WO 2009/095395 PCT/EP2009/050924 An aliquot of this extract was injected into a High Performance Liquid Chromatography system and detected using a tandem mass spectrometer. Evaluation of the assay was carried out by the construction of an eight (8) point calibration curve (excluding zero concentration) covering the range of 1.000 ng/mL to 1023.900 ng/mL for bupropion, 3.905 ng/mL to 3998.970 ng/mL for hydroxybupropion, 1.000 ng/mL to 1024.000 ng/mL for bupropion erythroamino alcohol, and 1.000 ng/mL to 1024.000 ng/mL for bupropion threoamino alcohol in human plasma. The slope and intercept of the calibration curves were determined through weighted linear regression analysis (1/area ratio.
2 ). Two calibration curves and duplicate QC samples (at three concentration levels) were analyzed along with each batch of the study samples. Peak area ratios were used to determine the concentration of the standards, quality control samples, and the unknown study samples from the calibration curves. [00422] Citalopram, its metabolites - demethyleitalopram and didemethyleitalopram, and the internal standards, citalopram analog, demethyleitalopram analog, and didemethyleitalopram analog, were extracted by liquid-liquid extraction into an organic media from 1.00 mL of human plasma. An aliquot of this extract was injected into a High Performance Liquid Chromatography system and detected using a tandem mass spectrometer. The analytes were separated by reverse phase chromatography. Evaluation of the assay was carried out by the construction of an eight (8) point calibration curve (excluding zero concentration) covering the range of 0.250 ng/mL to 64.034 ng/mL for citalopram, 0.050 ng/mL to 12.8 10 ng/mL for demethyleitalopram, and 0.050 ng/mL to 12.791 ng/mL for didemethyleitalopram in human plasma. The slope and intercept of the calibration curves were determined through weighted linear regression analysis (1/cone.
2 ). Two calibration curves and duplicate QC samples (at three concentration levels) were analyzed along with each batch of the study samples. Peak area ratios were used to determine the concentration of the standards, quality control samples, and the unknown study samples from the calibration curves. [004231 Data for the pharmacokinetic parameters for bupropion and citalopram and their metabolites is presented in the tables below and in FIGs. 24A-P. Pharmacokinetic Parameters for Bupropion (Group 1) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Bupropion HBr XL 348 mg Tablets and Celexa* 20 Example 1 (A) [fasting conditions] mg Tablets (B) [fasting conditions] (n=13) (n= 13) AUCo- (ng-hr/mL) 1570.10 (33.74) 1264.46 (32.84) 1660.28 + 560.15 1331.74 + 437.31 AUCoa r -hr/mL) 1628.89 (32.43) 1315.88 (31.87) "(ngh1713.92 + 555.80 1381.81 + 440.42 141.29 (24.80) 107.70 (30.78) Cux(ng/mL) 145.74 + 36.15 112.77 + 34.71 108 WO 2009/095395 PCT/EP2009/050924 Tmax (hr)* 5.00 (4.00 - 7.00) 4.00 (2.00 - 5.00) t 1 2 (hr) 25.03 + 5.56 21.85 + 5.41 Ke (hr-') 2.91E-02+7.08E-03 3.37E-02 9.18E-03 MRT (hr) 21.45 + 4.47 22.14 +5.33 * median (min - max) Relative Bioavailability Assessments (A vs B) for Bupropion (Group 1) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV
AUC
1 99.67% to 152.59% 123.32% 30.84% AUCo-i.f 100.10% to 151.00% 122.95% 29.72% Cmax 109.43% to 153.88% 129.76% 24.48% Parameter Potency Corrected Data AUCo, 96.91% to 148.36% 119.91% AUCOi.f 97.33% to 146.82% 119.54% Cmax 106.40% to 149.62% 126.17% Pharmacokinetic Parameters for Hydroxybupropion (Group 1) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Bupropion HBr XL 348 mg Tablets and Celexa* Example 1 (A) [fasting conditions] 20 mg Tablets (B) [fasting conditions] (n=13) (n= 13) 23529.49 (41.42) 18413.09 (46.25) AUJC, (ng-hr/mL) 25590.82 + 10600.46 20410.99 + 9439.43 AUCoi.
1 f(ng-hr/mL) 23753.82 (41.18) 18617.18 (45.86) 25803.36 + 10626.20 20596.42 + 9445.45 510.83 (27.27) 375.83 (39.88) Cmax(ng/mL) 531.47 + 144.94 403.42 + 160.90 Tmax (hr)* 10.00 (5.03 - 12.00) 8.00 (5.00 - 12.00) t 1 (hr) 25.58 +7.44 24.47 +4.56 Ked (hr-') 2.89E-02 + 6.95E-03 2.93E-02 + 5.60E-03 MRT (hr) 41.71 + 8.13 40.87 + 7.13 M/P Ratio 14.30 +4.15 13.90 +4.23 * median (min - max) Relative Bioavailability Assessments (A vs B) for Hydroxybupropion (Group 1) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCo., 101.24% to 158.47% 126.67% 32.52% AUCo-i.f 101.23% to 158.07% 126.50% 32.34% Cmax 114.13% to 160.12% 135.18% 24.31% Pharmacokinetic Parameters for Bupropion Threoamino Alcohol (Group 1) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Bupropion HBr XL 348 mg Tablets and Celexa" 20 Example 1 (A) [fasting conditions] mg Tablets (B) [fasting conditions] (n=13) (n= 13) 7551.59 (71.70) 5908.31 (55.22) AUC., (ng-hr/mL) 8885.47 + 6370.75 6697.79 + 3698.44 AUC -hr/mL) 6936.64 (39.91) 6106.99 (59.82) L -i 1 (ngh/m7471.68 + 2982.15 7024.33 + 4202.27 160.20 (49.22) 111.90 (31.85) Cmax(ng/mL) 177.47 + 87.35 118.65 + 37.79 Tmax (hr)* 7.00 (5.00 - 10.00) 6.00 (5.00 - 8.00) t 1 2 (hr) 48.99 + 17.20t 51.54 + 16.00 Ked (hr-') 1.57E-02 + 4.97E-03t 1.45E-02 + 3.72E-03 MRT (hr) 67.81 + 18.80t 73.63 + 26.80 M/P Ratio 4.62 + 1.60t 5.01 + 2.36 * median (min - max); n -12 Relative Bioavailability Assessments (A vs B) for Bupropion Threoamino Alcohol (Group 1) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV 109 WO 2009/095395 PCT/EP2009/050924 AUC., 101.81% to 158.62% 127.08% 32.17% AUCo-i.f 96.53% to 152.17% 121.20% 31.04% Cmax 115.35% to 176.72% 142.77% 30.89% Pharmacokinetic Parameters for Bupropion Erythroamino Alcohol (Group 1) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Bupropion HBr XL 348 mg Tablets and Celexa* Example 1 (A) [fasting conditions] 20 mg Tablets (B) [fasting conditions] (n=13) (n= 13) AUCo-, (ng-hr/mL) 1240.23 (72.45) 962.02 (51.81) 1519.16 + 1100.65 1103.04 + 571.47 1319.17 (70.35) 1027.55 (49.98) AUJCo~ 1 f(ng-hr/mL) 1591.01 + 1119.21 1163.50 + 581.51 25.84 (38.01) 18.75 (28.79) Cmax (ng/mL) 27.46 + 10.44 19.57 + 5.63 Tmax (hr)* 10.00 (5.03 -16.00) 7.00 (5.00 - 16.00) t 11
/
2 (hr) 31.68 + 10.63 29.30 + 6.44 Ke (hr-1) 2.36E-02 + 5.90E-03 2.45E-02 + 4.41E-03 MRT (hr) 49.91 + 12.19 48.65 + 12.48 M/P Ratio 0.88 + 0.39 0.84 + 0.33 * median (min - max) Relative Bioavailability Assessments (A vs B) for Bupropion Erythroamino Alcohol (Group 1) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCo., 99.18% to 165.51% 128.12% 37.47% AUCo-i.f 100.68% to 161.99% 127.71% 34.64% Cmax 113.39% to 167.08% 137.64% 27.96% Pharmacokinetic Parameters for PAWC (Group 1) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Bupropion HBr XL 348 mg Tablets and Celexa* 20 Example 1 (A) [fasting conditions] mg Tablets (B) [fasting conditions] (n=13) (n= 13) AUCo.t (uM-hr) 70.42 (39.85) 55.31 (41.83) 75.85 + 30.23 60.12 + 25.15 AUCo 1 i.
1 (uM-hr) 70.70 (40.25) 55.46 (41.82) 76.22 + 30.68 60.29 + 25.21 C uM 1.84 (22.53) 1.34 (31.92) '""M1.89 + 0.43 1.40 + 0.45 Tmax (hr)* 7.00 (5.00 - 8.00) 5.00 (4.00 - 8.00) t 1 1
/
2 (hr) 39.22 + 24.12 32.28 + 15.17 Ked (hr-') 2.48E-02 + 1.42E-02 2.61E-02 + 1.13 E-02 MRT (hr) 42.42 + 9.64 41.36 + 8.78 * median (min - max) Relative Bioavailability Assessments (A vs B) for PAWC (Group 1) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 101.38% to 157.32% 126.29% 31.86% AUCo-i.f 101.52% to 157.50% 126.45% 31.85% Cmax 115.68% to 161.47% 136.67% 23.94% Pharmacokinetic Parameters for Citalopram (Group 1) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Bupropion HBr XL 348 mg Tablets and Celexa* 20 Example 1 (A) [fasting conditions] mg Tablets (B) [fasting conditions] (n=13) (n= 13) AUCo-, (ng-hr/mL) 909.34 (44.20) 1024.06 (27.26) 992.44 + 438.68 1060.55 + 289.09 942.09 (45.70) 1052.26 (28.16) AUJCi.f (ng-hr/mL) 1029.79 + 470.62 1091.04 + 307.26 15.21 (20.97) 20.05 (14.19) Cmax (ng/mL) 15.53 + 3.26 20.24 + 2.87 Ito WO 2009/095395 PCT/EP2009/050924 Tmax (hr)* 12.00 (5.00 - 16.00) 5.00 (4.00 - 6.00) t 11
/
2 (hr) 54.95 + 13.02 52.50 + 12.07 Ked (hr-') 1.32E-02 + 2.60E-03 1.38E-02 + 2.85E-03 MRT (hr) 71.76 + 13.63 67.16 + 12.09 * median (min - max) Relative Bioavailability Assessments (A vs B)for Citalopram (Group 1) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCOL 72.72% to 108.10% 88.66% 28.62% AUCoij.f 73.58% to 108.59% 89.39% 28.08% Cmax 68.03% to 84.62% 75.87% 15.53% Pharmacokinetic Parameters for Demethylcitalopram (Group 1) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Bupropion HBr XL 348 mg Tablets and Celexa* 20 Example 1 (A) [fasting conditions] mg Tablets (B) [fasting conditions] (n=13) (n= 13) AUCo, (ng-hr/mL) 242.98 (30.83) 293.58 (24.56) 253.57 + 78.17 302.30 + 74.26 AUCO. ng-hr/mL) 255.23 ( 2 8
.
4 8 ) 318.43 (25.71)
"
1 (ngh264.42 + 75.31 328.57 + 84.48 1.62 (35.69) 2.01 (28.37) Cmax(ng/mL) 1.71 + 0.61 2.09 + 0.59 Tmax (hr)* 36.50 (36.00 - 72.10) 36.00 (8.00 - 72.00) t 11
/
2 (hr) 72.22 + 15.19' 69.25 + 13.88 Ked (hr-') 1.0 1E-02 + 2.48E-03t 1.03E-02 + 1.62E-03 MRT (hr) 128.38 + 14.12i 123.03 + 18.91 M/P Ratio 0.32 + 0.12t 0.33 + 0.12 * median (min - max); t n = 12 Relative Bioavailability Assessments (A vs B) for Demethylcitalopram (Group 1) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCo, 70.35% to 96.71% 82.48% 22.81% AUCoij.f 68.33% to 96.92% 81.38% 23.61% Cmax 69.21% to 93.34% 80.38% 21.41% Pharmacokinetic Parameters for Didemetheylcitalopram (Group 1) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Bupropion HBr XL 348 mg Tablets and Celexa* 20 Example 1 (A) [fasting conditions] mg Tablets (B) [fasting conditions] (n=13) (n= 13) AUCo, (ng-hr/mL) 31.09 (47.73) 40.92 (38.77) 34.01 + 16.24 44.00 + 17.06 AUCO_; y(ng-hr/mL) 57.29 (NC) t 76.64 (NC) t 57.29 + NC 76.64 + NC 0.16 (42.87) 0.20 (39.39) Cmax(ng/mL) 0.17 + 0.07 0.22 + 0.08 Tmax (hr)* 144.00 (72.00 - 240.00) 120.03 (72.07 - 240.00) t 11
/
2 (hr) 88.31 + NCt 87.50 + NCt Ked (hr-') 7.85E-03 + NCt 7.92E-03 + NCt MRT (hr) 189.53 + NCt 175.85 + NCt M/P Ratio 0.10 + NCt 0.11 + NCt * median (min - max);' n = 1; NC = No Calculation 111 WO 2009/095395 PCT/EP2009/050924 Relative Bioavailability Assessments for Didemethylcitalopram (Group 1) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCo., 68.47% to 84.12% 75.89% 14.65% AUCO-I.f NC NC NC Cmax 71.29% to 88.24% 79.31% 15.18% NC = No Calculation Pharmacokinetic Parameters for Bupropion (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Pharmaceutical Composition according to Example 1 Example 1 (A) [fasting conditions] (C) [fed conditions] (n= 13) (n= 13) 1430.25 (29.21) 1793.34 (19.73) AUC., (ng-hr/mL) 1488.54 + 434.88 1827.81 + 360.54 1485.63 (28.48) 1845.33 (19.58) AUJCo~i 1 (nghr/mL) 1542.82 + 439.38 1880. 14 +E 368.17 112.22 (34.48) 144.31 (17.58) Cmax(ng/mL) 117.99 + 40.69 146.37 + 25.73 Tmax (hr)* 5.00 (4.00 - 12.00) 5.00 (5.00 - 7.00) t 11
/
2 (hr) 23.70 + 5.98 24.62 + 4.82 Ked (hr-') 3.14E-02 + 9.65E-03 2.92E-02 + 5.88E-03 MRT (hr) 21.65 +4.41 21.57 +3.87 * median (min - max) Relative Bioavailability Assessments (Fed vs Fasting (C vs A) ) for Bupropion (Group 2) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCo., 109.66% to 141.16% 124.42% 18.01% AUCOi.f 109.16% to 139.23% 123.28% 17.35% Cmax 103.65% to 155.19% 126.83% 29.16% Pharmacokinetic Parameters for Hydroxybupropion (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Pharmaceutical Composition according to Example 1 Example 1 (A) [fasting conditions] (C) [fed conditions] (n= 13) (n= 13) 19905.35 (55.57) 21620.85 (35.78) AUJC, (ng-hr/mL) 23223.14 + 12904.38 23226.52 + 8310.59 AUC (ng-hr/mL) 20166.01 (55.02) 21871.10 (35.47) AJfi"23431.66 + 12892.50 23456.76 + 8319.25 417.94 (48.54) 454.81 (34.81) Cmax(ng/mL) 476.51 + 231.30 492.18 + 171.35 Tmax (hr)* 12.00 (8.00 - 16.00) 12.00 (8.00 - 24.00) t 1 1
/
2 (hr) 26.75 + 5.12 26.63 + 5.08 Ke (hr-') 2.68E-02 + 5.15E-03 2.68E-02 + 4.42E-03 MRT (hr) 41.65 + 6.53 42.83 + 6.01 M/P Ratio 14.44 + 6.48 12.28 + 4.92 * median (min - max) Relative Bioavailability Assessments(Fed vs Fasting (C vs A) ) for Hydroxybupropion (Group 2) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCo, 93.72% to 123.00% 107.36% 19.42% AUCOi.f 93.85% to 122.52% 107.23% 19.04% Cmax 94.59% to 122.05% 107.44% 18.19% Pharmacokinetic Parameters for Bupropion Threoamino Alcohol (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Pharmaceutical Composition according to Example 1 Example 1 (A) [fasting conditions] (C) [fed conditions] (n= 13) (n= 13) 112 WO 2009/095395 PCT/EP2009/050924 7522.59 (47.43) 8692.42 (31.12) AUC., (ng-hr/mL) 8176.10 + 3877.66 9046.50 + 2814.88 AUC (ng-hr/mL) 7767.17 (50.35) 8996.27 (32.35) -i" (8496.38 + 4277.79 9396.06 + 3040.00 136.93 (36.47) 163.81 (25.26) Cmax(ng/mL) 145.99 + 53.24 168.28 + 42.51 Tmax (hr)* 10.00 (5.00 - 12.00) 8.00 (5.00 - 12.00) t1/2 (hr) 53.77 + 13.61 61.46 + 19.76 Ke (hr-') 1.37E-02 + 3.50E-03 1.25E-02 + 4.62E-03 MRT (hr) 76.86 + 18.02 77.31 + 17.82 M/P Ratio 5.38 + 1.55 5.01 + 1.47 * median (min - max) Relative Bioavailability Assessments (Fed vs Fasting (C vs A) ) for Bupropion Threoamino Alcohol (Group 2) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCo., 101.77% to 129.310% 114.72% 17.07% AUCOi.f 102.12% to 129.52% 115.01% 16.94% Cmax 101.80% to 137.59% 118.35% 21.56% Pharmacokinetic Parameters for Bupropion Erythroamino Alcohol (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Pharmaceutical Composition according to Example 1 Example 1 (A) [fasting conditions] (C) [fed conditions] (n= 13) (n= 13) 1277.83 (61.07) 1493.34 (43.69) AUC., (ng-hr/mL) 1451.80 + 886.65 1597.68 + 698.05 1343.22 (59.16) 1561.88 (42.33) AUJCo~i 1 (nghr/mL) 1516.13 + 896.90 1665.50 + 704.99 C.a (ng/mL) 25.11 (27.00) 28.53 (20.72) 26.18 + 7.07 29.06 + 6.02 Tmax (hr)* 12.00 (8.00 - 16.03) 12.00 (8.00 - 16.00) t 11
/
2 (hr) 30.55 + 7.65 32.09 + 7.62 Ked (hr-') 2.40E-02 + 5.70E-03 2.28E-02 + 5.55E-03 MRT (hr) 50.16+ 13.62 51.48 + 10.29 M/P Ratio 0.95 + 0.34 0.89 + 0.34 * median (min - max) Relative Bioavailability Assessments (Fed vs Fasting (C vs A)) for Bupropion Erythroamino Alcohol (Group 2) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCo., 99.90% to 134.28% 115.83% 21.16% AUCOi.f 100.32% to 132.61% 115.34% 19.94% Cmax 98.96% to 127.47% 112.32% 18.06% Pharmacokinetic Parameters for PAWC (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Pharmaceutical Composition according to Example 1 Example 1 (A) [fasting conditions] (C) [fed conditions] (n= 13) (n= 13) AUCO-, (uM-hr) 61.80 (49.03) 68.49 (27.96) 68.91 + 33.79 71.18 + 19.91 AUCO-i. (uM-hr) 62.01 (49.01) 68.75 (27.86) 69.11 + 33.87 71.42 + 19.90 C uM 1.52 (34.30) 1.67 (25.47) "U1.61 + 0.55 1.74 + 0.44 Tmax (hr)* 8.00 (5.00 - 12.00) 8.00 (5.00 - 12.00) t 11
/
2 (hr) 46.97 + 20.35 52.22 + 24.12 Ke (hr-') 1.8 1E-02 + 9.36E-03 1.69E-02 + 1.01E-02 MRT (hr) 42.32 + 7.31 43.19 + 6.67 * median (min - max) Relative Bioavailability Assessments (Fed vs Fasting (C vs A)) for PAWC (Group 2) 113 WO 2009/095395 PCT/EP2009/050924 Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV
AUC
0 ., 96.52% to 124.43% 109.59% 18.12% AUCo-i.f 96.62% to 124.35% 109.61% 18.00% Cmax 94.39% to 124.73% 108.50% 19.92% Pharmacokinetic Parameters for Citalopram (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Pharmaceutical Composition according to Example 1 Example 1 (A) [fasting conditions] (C) [fed conditions] (n= 13) (n= 13) 880.17 (41.69) 1026.46 (25.16) AUC., (ng-hr/mL) 951.81 + 396.81 1052.52 + 264.82 909.29 (42.25) 1057.35 (26.24) AUJCi.f (ng-hr/mL) 983.67 + 415.60 1085.96 + 284.96 13.67 (28.83) 16.15 (11.95) Cmax (ng/mL) 14.23 + 4.10 16.25 + 1.94 Tmax (hr)* 12.00 (6.00 - 16.00) 12.00 (6.00 - 16.00) t 1 2 (hr) 51.00 + 12.09 53.86 + 14.81 Ked (hr-') 1.43E-02 + 3.30E-03 1.38E-02 + 3.78E-03 MRT (hr) 73.11 + 12.92 73.48 + 13.08 * median (min - max); Relative Bioavailability Assessments (Fed vs Fasting (C vs A) ) for Citalopram (Group 2) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCo., 101.45% to 133.49% 116.37% 19.61% AUCOi.f 101.53% to 132.67% 116.06% 19.10% Cmax 102.57% to 133.54% 117.03% 18.84% Pharmacokinetic Parameters for Demethylcitalopram (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Pharmaceutical Composition according to Example 1 Example 1 (A) [fasting conditions] (C) [fed conditions] (n= 13) (n= 13) 266.04 (36.92) 296.07 (34.31) AUJCo.(ng-hr/mL) 284.13 + 104.90 311.92 + 107.00 AUC -hr/mL) 307.20 ( 3 1.
2 7 ) t 318.99 ( 3 5.
6 9 ) t L -i", 1 (ngh320.62 + 100.26 337.06 + 120.28 C (ng/mL) 1.71 (34.71) 1.89 (33.51) '"" /L1.80 + 0.62 1.98 + 0.66 Tmax (hr)* 36.07 (24.00 - 72.02) 36.00 (16.00 - 96.05) t 12 (hr) 73.60 + 22.83t 70.51 22 Ked (hr-') 1.03E-02 + 3.36E-03t 1.06E-02 + 3.05E-03t MRT (hr) 136.19 + 27.81t 131.71 + 25.36t M/P Ratio 0.37 + 0.13i 0.34 +0.12 * median (min- max);T n= 11 Relative Bioavailability Assessments (Fed vs Fasting (C vs A) ) for Demethylcitalopram (Group 2) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCo., 99.59% to 123.94% 111.10% 15.57% AUCOi.f 99.77% to 118.41% 108.69% 10.12% Cmax 99.19% to 123.23% 110.56% 15.44% Pharmacokinetic Parameters for Didemethylcitalopram (Group 2) Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Pharmaceutical Composition according to Example 1 Example 1 (A) [fasting conditions] (C) [fed conditions] (n= 11) (n= 11) AUCo., (ng-hr/mL) 43.47 (51.49) 45.45 (49.86) 49.19 + 25.33 52.15 + 26.00 114 WO 2009/095395 PCT/EP2009/050924 AUCO-i.f(ng-hr/mL) 89.06 (NC)t 51.20 (NC)t 89.06 + NC 51.20 + NC 0.22 (56.74) 0.23 (53.18) Cmax (ng/mL) 0.25 + 0.14 0.27 + 0.14 Tmax (hr)* 144.00 (72.00 - 192.17) 144.00 (72.00 - 192.00) t 1 m (hr) 73.00 + NC' 84.53 + NC' K. (hr-') 9.49E-03 + NCI 8.20E-03 + NCI MRT (hr) 192.53 + NCT 188.05 + NCt M/P Ratio 0.09 + NCI 0.07 + NC * median (min - max); n = 1; NC = No Calculation Relative Bioavailability Assessments (Fed vs Fasting (C vs A) ) for Didemethylcitalopram (Group 2) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCoL 88.70% to 124.37% 105.03% 21.03% AUCOi.f NC NC NC Cmax 92.92% to 128.57% 109.30% 20.18% EXAMPLE 25 [004241 A FOUR-WAY, PILOT, SINGLE DOSE, FASTING STUDY OF A CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION OF THE INVENTION COMPRISING BUPROPION HBR (348MG)/ESCITALOPRAM OXALATE (25.5MG). [004251 This was a 4-way crossover, randomized, open-label, single-dose, fasting, pilot, phase I (comparative bioavailability) study. The objective of this study was to evaluate the relative peak and systemic exposure of 2 controlled-release pharmaceutical compositions of the invention comprising Bupropion HBr (348mg)/Escitalopram Oxalate (25.5mg (Formulations A (manufactured according to Example 3 (Batch No. 0704028) and B (manufactured according to Example 2 (Batch No. 0705037)) to Bupropion HBr XL 348 mg Tablets manufactured according to US Patent No. 7,241,805 (Lot # 07D042P) and Lexapro® 20 mg Tablets (Lot M0603M) given concomitantly (i.e., co-administered) under single dose fasting conditions. The secondary objective was to determine whether there was a drug-by-formulation (i.e., different method of manufacture (separate granulation vs co-granulation) interaction with respect to the escitalopram component. Normal, healthy, non-smoking male and female subjects between the ages of 18 and 55 years were included in the study. [00426] The following treatments were administered in this study: Treatment A: One (1) Bupropion HBr (348 mg) / Escitalopram Oxalate (25.5 mg) SR Tablet [Formulation A], Lot #: 0704028, administered orally; Treatment B: One (1) Bupropion HBr (348 mg) / Escitalopram Oxalate (25.5 mg) SR Tablet [Formulation B], Lot #: 0705037, administered orally; Treatment C: One (1) Bupropion HBr XL 349 mg Tablet, Lot # 07D042P and one (1) Lexapro® 20 mg Tablet, Lot#: M0603M, administered orally; AND Treatment D: One (1) Lexapro® 20 mg Tablet, Lot M0603M, administered orally 115 WO 2009/095395 PCT/EP2009/050924 [004271 There were 24 subjects dosed in Period I, 13 of whom completed the study. Two subjects withdrew because of adverse events (AEs) (Subject #007, who experienced dizziness, nausea, sweating, shakiness and weakness; Subject #013, who experienced a laceration on his right hand). One subject (Subject #0 10) was dismissed due to an AE (low hemoglobin levels). Two subjects (Subjects #002 and #006) were dismissed after emesis within 24.00 hours of dosing. Two subjects were dismissed because of administrative reasons (Subject #0 14, whose personal residence was infested with bedbugs, and Subject #024 who tested positive for benzodiazepines at checking for Period III). Four subjects (Subjects #008, 009, #020 and #022) withdrew for personal reasons. [00428] During each study period, 23 blood samples were collected from each subject at the following timepoints: 0.00 (pre-dose), 1.00, 2.00, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00, 96.00, 120.00, 144.00, 168.00, 192.00, 216.00, 240.00, 264.00 and 288.00 hours post-dose. [00429] The following pharmacokinetic parameters for bupropion and its metabolites hydroxybupropion, bupropion threoamino alcohol, bupropion erythroamino alcohol, and PAWC as well as escitalopram and its metabolites S-demethyleitalopram and S-didemethyleitalopram were calculated by standard non-compartmental methods: AUCo-t, AUCo-inf, Cmax, Tmax, t/, Kei, MRT, and M/P ratio. [004301 Using General Linear Model (GLM) procedures in Statistical Analysis System (SAS), analysis of variance (ANOVA) was performed on In-transformed AUCo-t, AUCo-inf, and Cmax and on untransformed t, Kei, MRT, and M/P ratio at the significance level of 0.05. The intra-subject coefficient of variation (CV) was calculated using the Mean Square Error (MSE) from the ANOVA table. The ratio of geometric means and the 90% geometric confidence interval (90% C.I.) were calculated based on the difference in the Least Squares Means of the ln-transformed AUCo-t, AUC-inf, and Cmax between the test and reference formulations. Tmax was analyzed using nonparametric methods. [004311 Bupropion and its metabolites and citalopram and its metabolites were assayed as follows. Bupropion, hydroxybupropion, bupropion erythroamino alcohol, bupropion threoamino alcohol, and the internal standard, 1-(3-chlorophenyl)-piperazine, were extracted from human plasma (0.50 mL), by solid phase extraction (SPE) into an organic medium. The analytes were separated by High Performance Liquid Chromatography (HPLC) system using reverse phase chromatography conditions, detected using an API 3000 tandem mass spectrometer. Method sensitivity and selectivity were achieved by detecting distinct precursor to production mass transitions for bupropion (240.3-184.0), hydroxybupropion (256.3-238.0), bupropion 116 WO 2009/095395 PCT/EP2009/050924 erythroamino alcohol (242.4-* 168.1), bupropion threoamino alcohol (242.4-* 168.1) and the internal standard, 1-(3-chlorophenyl)-piperazine (197.3-.153.8), at defined retention time. Evaluation of the assay, using defined acceptance criteria, was carried out by the construction of an eight (8) point calibration curve (excluding zero concentration) covering the range of 1.000 ng/ml to 1023.900 ng/ml for bupropion, 3.907 ng/ml to 4000.320 ng/ml for hydroxybupropion, 1.000 ng/ml to 1024.000 ng/ml for bupropion erythroamino alcohol, and 1.000 ng/ml to 1024.000 ng/ml for bupropion threoamino alcohol in human plasma. the slope and intercept of the calibration curves were determined through weighted linear regression analysis (1/peak area ratio 2 ). Two calibration curves and duplicate QC samples (at three or five concentration levels) were analyzed along with each batch of the study samples. Peak area ratios were used to determine the concentration of the standards, quality control samples, and the unknown study samples from the calibration curves. The concentrations of escitalopram, S demethyleitalopram and S-didemthyleitalopram were measured using an achrial LC-MS/MS method for citalopram, demethylcitalopram and didemethyleitalopram. Citalopram, demethyleitalopram, didemethylcitalopram and the internal standards, citalopram analog, demethyleitalopram analog, and didemethyleitalopram analog, were extracted from human plasma (0.75 mL), using sodium heparin as an anticoagulant, by liquid-liquid extraction into an organic medium followed by back extraction into a dilute acid. An aliquot of this extract was injected into a High Performance Liquid Chromatography system and detected using a TSQ Quantum tandem mass spectrometer. The analytes were separated by reverse phase chromatography. Method sensitivity and selectivity were achieved by detecting distinct precursor to product ion mass transitions for citalopram (325.1-).109.0), demethylcitalopram (311. 1-*109.0), didemethylcitalopram (297.1-.109.0 and 297.1-.260.0), and the internal standards, citalopram analog (341.1 -*125.0), demethylcitalopram analog (327.1 -. 125.0), and didemethylcitalopram analog (313.1 -125.0), at defined retention time. Evaluation of the assay, using defined acceptance criteria, was carried out by the construction of an eight (8) point calibration curve (excluding zero concentration) covering the range of 0.251 ng/ml to 64.020 ng/ml for citalopram, 0.126 ng/ml to 32.013 ng/ml for demethyleitalopram, and 0.025 ng/ml to 6.397 ng/ml for didemetyleitalopram in human plasma. The slope and intercept of the calibration curves were determined through weighted linear regression analysis (1/cone.
2 ). Two calibration curves and duplicate QC samples (at three concentration levels) were analyzed along with each batch of the study samples. Peak area ratios were used to determine the concentration of the standards, quality control samples, and the unknown study samples from the calibration curves. 117 WO 2009/095395 PCT/EP2009/050924 [00432] The pharmacokinetic and statistical analyses were performed on data for bupropion and its metabolites from 14 subjects, 13 of who completed the 4 study periods and 1 for whom there were sufficient data in at least 2 periods to potentially allow for a meaningful analysis. The pharmacokinetic and statistical analysis was performed data for citalopram and its metabolites on 13 subjects who completed the 4 study periods. [004331 Data for the pharmacokinetic parameters for bupropion and citalopram and its metabolites is presented in the tables below and in FIGs. 25A-H. Pharmacokinetic Parameters for Bupropion Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition Pharmaceutical Composition Bupropion HBr XL 348 mg according to Example 3 according to Example 2 Tablets and Lexapro* 20 mg [Formulation A] (A) (n=14) [Formulation B] (B) (n=14) Tablets (C) (n=14) AUCo., ng-hr/mL) 1592.27 (29.72) 1674.66 (28.35) 1401.39 (25.50) 1665.89 + 495.03 1733.70 + 491.44 1444.53 + 368.32 AUCO-i. (ng-hr/mL) 1646.47 (28.85) 1726.12 (27.75) 1448.54 (24.96) 1718.79 + 495.92 1784.69 + 495.25 1491.40 + 372.29 C /mL) 108.41 (22.58) 108.97 (25.09) 121.53 (33.25) max(ng/ 111.42 + 25.16 112.38 + 28.20 127.76 + 42.47 Tmax (hr)* 6.00 (3.00-10.00) 4.00 (3.02-8.00) 4.00 (2.00-6.00) t 1 2 (hr) 24.59 + 6.00 24.99 + 6.13 23.43 + 5.74 K. (hr-') 3.07E-02 + 1.20E-02 2.97E-02 + 8.87E-03 3.14E-02 + 8.04E-03 MRT (hr) 22.63 + 3.42 23.01 + 4.15 21.53 + 4.36 * median (min - max) Relative Bioavailability Assessments For Bupropion (A vs C) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 103.98% to 140.410% 120.83% 18.06% AUCOi.f 104.59% to 139.92% 120.97% 17.49% Cmax 78.28% to 110.88% 93.17% 20.99% Relative Bioavailability Assessments For Bupropion (B vs C) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 108.810% to 140.84% 123.79% 18.06% AUCOi.f 108.98% to 139.95% 123.50% 17.49% Cmax 79.11% to 106.70% 91.87% 20.99% Relative Bioavailability Assessments For Bupropion (B vs A) Parameter Ratio of Means AUCo., 102.45% AUCOi.f 102.09% Cmax 98.61% Pharmacokinetic Parameters for Hydroxybupropion Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition of Pharmaceutical Composition of Bupropion HBr XL 348 mg Example 3 [Formulation A] (A) Example 2 [Formulation B] (B) Tablets and Lexapro* 20 mg (n=14) (n=14) Tablets (C) (n=14) 118 WO 2009/095395 PCT/EP2009/050924 22649.81 (36.33) 24259.45 (28.61) 20951.94 (24.98) AUC., (ng-hr/mL) 24149.14 + 8773.57 25264.47 + 7227.97 21698.92 + 5420.94 AUC (ng-hr/mL) 22862.02 (36.11) 24462.97 (28.44) 21163.98 (24.80) AL i" m24358.34 + 8795.64 25464.13 + 7243.12 21902.02 + 5432.04 Cmax (ng/mL) 479.62 (29.20) 492.08 (22.35) 459.12 (22.85) 501.27 + 146.38 506.09 + 113.13 472.84 + 108.06 Tmax (hr)* 11.00 (8.00-24.00) 12.00 (8.00 - 16.05) 6.00 (4.00 - 24.00) t 1 1
/
2 (hr) 25.61 + 3.60 25.86 + 3.08 25.07 + 3.41 Ke (hr-') 2.76E-02 + 3.91E-03 2.72E-02 + 3.56E-03 2.81E-02 + 3.60E-03 MRT (hr) 42.00 + 5.20 42.39 + 6.22 40.13 + 5.15 M/P Ratio 13.28 + 2.79 13.60 + 3.02 14.09 + 3.51 * median (min - max) Relative Bioavailability Assessments For Hydroxybupropion (A vs C) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 95.69% to 136.26% 114.19% 21.31% AUCo-i.f 95.78% to 136.09% 114.17% 21.18% Cmax 96.30% to 125.86% 110.09% 16.07% Relative Bioavailability Assessments For Hydroxybupropion (B vs C) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 102.58% to 138.99% 119.41% 21.31% AUCOi.f 102.54% to 138.67% 119.24% 21.18% Cmax 98.42% to 123.88% 110.41% 16.07% Relative Bioavailability Assessments For Hydroxybupropion (B vs A) Parameter Ratio of Means AUCo, 104.57% AUCOi.f 104.44% Cmax 100.29% Pharmacokinetic Parameters for Bupropion Threoamino Alcohol Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition Pharmaceutical Composition Bupropion HBr XL 348 mg according to Example 3 according to [Formulation B] Tablets and Lexapro* 20 mg [Formulation A] (A) (n=14) (B) (n=14) Tablets (C) (n=14) 7554.14 (39.64) 8053.81 (35.18) 6090.33 (38.15) AUJC, (ng-hr/mL) 8137.89 +E 3225.77 8584.81 +E 3020.41 6547.74 +E 2498.29 7744.52 (39.30) 8326.17 (34.81) 6228.78 (37.98) AUJCo~.
1 (nghr/mL) 8333.68 + 3275.03 8874.78 + 3089.23 6692.84 + 2542.17 154.51 (40.88) 154.75 (38.37) 137.07 (45.52) Cmax (ng/mL) 167.29 + 68.40 165.90 + 63.66 150.98 + 68.73 Tmax (hr)* 8.02 (6.00 - 24.00) 10.00 (6.00 - 16.05) 6.00 (4.00 - 16.07) t 1 1
/
2 (hr) 56.32 + 15.32 63.55 + 28.76 51.21 + 13.10 Ked (hr-') 1.32E-02 + 3.89E-03 1.21E-02 + 3.18E-03 1.43E-02 + 3.41E-03 MRT (hr) 68.01 + 13.43 72.06 + 19.85 64.70 + 11.64 M/P Ratio 4.83 + 1.29 4.99 + 1.44 4.47 + 1.39 * median (min - max) Relative Bioavailability Assessments For Bupropion Threoamino Alcohol (A vs C) Parameter 90% C.I. Ratio of Intra-Subject CV Means AUCo, 105.72% to 159.52% 129.86% 24.91% AUCo-i.f 105.55% to 159.53% 129.76% 25.02% Cmax 98.32% to 144.38% 119.14% 23.22% 119 WO 2009/095395 PCT/EP2009/050924 Relative Bioavailability Assessments For Bupro ion Threoamino Alcohol (B vs C) Parameter 90% C.I. Ratio of Intra-Subject CV AUCo., 113.69% to 161.90% 135.67% 24.91% AUCo-i.f 114.61% to 163.45% 136.87% 25.02% Cmax 98.72% to 137.35% 116.45% 23.22% Relative Bioavailability Assessments For Bupropion Threoamino Alcohol (B vs A) Parameter Ratio of Means AUCo, 104.47% AUCOi.f 105.48% Cmax 97.74% Pharmacokinetic Parameters for Bupropion Erythroamino Alcohol Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition Pharmaceutical Composition Bupropion HBr XL 348 mg according to Example 3 according to Example 2 Tablets and Lexapro* 20 mg [Formulation A] (A) (n=14) [Formulation B] (B) (n=14) Tablets (C) (n=14) 1399.37 (39.81) 1505.89 (34.93) 1088.96 (36.24) AUC., (ng-hr/mL) 1509.83 + 601.09 1609.12 + 562.08 1164.97 + 422.23 AUCO-i. (ng-hr/mL) 1468.79 (37.99) 1574.95 (33.82) 1162.77 (34.29) 1573.77 + 597.87 1674.54 + 566.25 1233.20 + 422.86 25.82 (26.80) 26.94 (23.10) 21.56 (28.77) Cmax (ng/mL) 26.73 + 7.16 27.68 + 6.39 22.43 + 6.45 Tmax (hr)* 10.00 (8.00 - 24.00) 12.00 (10.00 - 16.05) 8.00 (4.00 - 16.07) t 1 (hr) 33.08 +4.13 31.82 +4.10 31.40 +4.26 K. (hr-') 2.12E-02 + 2.56E-03 2.21E-02 + 3.03E-03 2.25E-02 + 3.13E-03 MRT (hr) 53.61 + 7.20 53.12 +7.36 50.14+ 6.28 M/P Ratio 0.92 + 0.24 0.95 + 0.28 0.83 + 0.26 * median (min - max) Relative Bioavailability Assessments For Bupropion Erythroamino Alcohol (A vs C) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 108.01% to 168.46% 134.89% 26.98% AUCo-i.f 107.24% to 163.72% 132.50% 25.64% Cmax 105.93% to 145.48% 124.14% 19.09% Relative Bioavailability Assessments For Bupropion Erythroamino Alcohol (B vs C) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 117.39% to 171.99% 142.09% 26.98% AUCo-i.f 116.01% to 166.87% 139.13% 25.64% Cmax 111.22% to 146.08% 127.46% 19.09% Relative Bioavailability Assessments For Bupropion Erythroamino Alcohol (B vs A) Parameter Ratio of Means AUCo, 105.34% AUCOi.f 105.00% Cmax 102.67% Pharmacokinteic Parameters for PAWC Geometric Mean (%CV) Arithmetic Mean ± SD Pharmacokinetic Pharmaceutical Composition of Pharmaceutical Bupropion HBr XL 348 mg Tablets Parameters Example 3 [Formulation A] (A) Composition of Example 2 and Lexapro 20 mg Tablets (C) (n=14) Tablets [Formulation B] (B) (n=14) (n=14) AUCo, M-hr) 67.86 (34.18) 72.59 (26.77) 61.56 (23.84) 71.85 + 24.56 75.17 + 20.13 63.56 + 15.15 67.99 (34.11) 72.80 (26.60) 61.65 (23.84) AUJCo~.
1 (pM-hr) 71.96+ 24.55 75.35 + 20.04 63.64 + 15.17 120 WO 2009/095395 PCT/EP2009/050924 1.59 (25.87) 1.61 (21.37) 1.60 (24.85) Cm"x (PM) 1.65 + 0.43 1.65 + 0.3 5 1.66 + 0.41 Tmax (hr)* 8.02 (4.00 - 24.00) 8.00 (4.12 - 12.09) 6.00 (4.00 - 10.00) t 1 1
/
2 (hr) 43.58 + 23.09 47.19 + 35.90 38.34 + 21.55 Ked (hr-') 2.06E-02 + 1.06E-02 2.07E-02 + 9.86E-03 2.29E-02 + 1.03E-02 MRT (hr) 41.30 + 5.02 42.27 + 5.73 39.08 + 5.09 * median (min - max) Relative Bioavailability Assessments For PAWC (A vs C) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 98.110% to 137.79% 116.27% 20.47% AUCOi.f 98.17% to 137.83% 116.33% 20.45% Cmax 92.17% to 118.78% 104.63% 15.21% Relative Bioavailability Assessments For PAWC (B vs C) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 105.00% to 140.60% 121.50% 20.47% AUCOi.f 105.17% to 140.77% 121.67% 20.45% Cmax 92
.
74 % to 11 5
.
3 1% 10 3
.
4 1% 15.21% Relative Bioavailability Assessments For PAWC (B vs A) Parameter Ratio of Means AUCo., 104.50% AUCO-i.f 104.60% Cmax 98.83% Pharmacokinetic Parameters for Escitalopram Geometric Mean (%CV) Arithmetic Mean ± SD Pharmacokinetic Pharmaceutical Pharmaceutical Bupropion HBr Parameters Composition according to Composition XL 348 mg Lexapro* (20 mg) (D) Example 3 [Formulation according to Example Tablets and (n=13) A] (A) (n=13) 2 [Formulation B] (B) Lexapro® 20 mg (n=13) Tablets (C) (n=13) AUCo. (ng-hr/mL) 1007.64 (33.18) 1036.88 (32.87) 1083.76 (26.12) 809.59 (35.50) 1062.98 + 352.70 1087.81 + 357.52 1120.42 + 292.62 858.14 + 304.67 AUC ng-hr/mL) 1025.87 (32.88) 1055.23 (32.55) 1101.96 (25.84) 828.03 (35.21) A -"g/m1080.89 + 355.43 1106.25 + 360.14 1138.28 + 294.09 876.81 + 308.72 C (ng/mL) 16.11 (24.35) 16.87 (20.54) 25.13 (21.81) 22.06 (25.13) Cm"x 16.57 + 4.03 17.18 + 3.53 25.68 + 5.60 22.68 + 5.70 Tmax (hr)* 12.00 (6.00 - 24.00) 16.00 (6.00 - 24.00) 4.00 (2.00 - 6.00) 4.00 (2.00 - 6.00) t 1 1
/
2 (hr) 35.81 + 6.28 36.58 + 5.81 37.33 + 6.15 37.90 + 10.63 Kei (hr-') 1.98E-02 + 3.02E-03 1.94E-02 + 3.08E-03 1.90E-02 3 .22E- 1.93E-02 + 4.30E-03 (lit')03 MRT (hr) 61.61 + 9.50 60.09 + 9.16 53.90 + 8.73 48.79 + 10.27 *median (max-min) Relative Bioavailability Assessments For Escitalopram (A vs C) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo, 86.89% to 100.30% 93.35% 10.68% AUCOi.f 87.07% to 100.31% 93.45% 10.53% Cmax 58.98% to 69.86% 64.19% 12.62% Relative Bioavailability Assessments For Escitalopram (A vs D) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 110.27% to 127.91% 118.76% 10.68% AUCOi.f 109.85% to 127.17% 118.19% 10.53% Cmax 65.45% to 77.98% 71.44% 12.62% 121 WO 2009/095395 PCT/EP2009/050924 Relative Bioavailability Assessments For Escitalopram (B vs C) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 93.50% to 108.46% 100.70% 10.68% AUCo-i.f 93.65% to 108.42% 100.76% 10.53% Cmax 64.37% to 76.69% 70.26% 12.62% Relative Bioavailability Assessments For Escitalopram (B vs D) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 119.24% to 137.64% 128.11% 10.68% AUCo-i.f 118.73% to 136.78% 127.43% 10.53% Cmax 71.85% to 85.11% 78.20% 12.62% Relative Bioavailability Assessments For Escitalopram (C vs D) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 118.12% to 137.02% 127.22% 10.68% AUCOi.f 117.54% to 136.07% 126.47% 10.53% Cmax 101.97% to 121.48% 111.30% 12.62% Relative Bioavailability Assessments For Escitalopram (B vs A) Parameter Ratio of Means AUCo., 107.87% AUCOi.f 107.82% Cmax 109.47% Pharmacokinetic Parameters for S-Demethylcitalopram Geometric Mean (%CV) Arithmetic Mean ± SD Pharmacokinetic Pharmaceutical Pharmaceutical Bupropion HBr Parameters Composition according Composition according XL 348 mg Tablets Lexapro* (20 mg) (D) to Example 3 to Example 2 and Lexapro® 20 (n=13) [Formulation A] (A) [Formulation B] (B) mg Tablets (C) (n=13) (n=13) (n=13) AUCo, (ng-hr/mL) 264.27 (35.79) 271.43 (25.68) 314.78 (30.02) 330.98 (22.37) 276.25 + 98.88 278.68 + 71.55 325.97 + 97.86 337.85 + 75.58 AUC ng-hr/mL) 279.36 (36.24) 286.48 (25.13) 329.65 (29.24) 345.20 (22.67) A Jofn/292.24 + 105.91 293.73 + 73.81 340.74 + 99.64 352.43 + 79.88 C (ng/mL) 1.82 (34.15) 1.93 (31.30) 2.53 (30.27) 2.96 (24.35) ""gL1.91 + 0.65 2.01 + 0.63 2.64 + 0.80 3.04 + 0.74 Tmax (hr)* 36.00 (16.00 - 72.03) 48.00 (16.00 - 96.00) 10.00 (3.00 - 48.02) 16.00 (2.00 - 36.32) t 1 2 (hr) 54.73 + 8.35 55.43 + 7.00 54.29 + 8.75 54.14 + 12.30 K (hr-') 1.30E-02 2.19E-03 1.27E-02 1.60E-03 1.31E-02 32.21E- 1.34E-02+±2.83E-03 MRT (hr) 114.39 + 13.77 112.08 + 12.71 100.93 + 13.69 93.96 + 16.50 M/P ratio 0.30 +0.11 0.30 +0.12 0.33 + 0.12 0.47 + 0.18 *median (max-min) Relative Bioavailability Assessments For S-demethylcitalopram (A vs C) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo, 79.52% to 90.65% 84.90% 9.75% AUCOi.f 80.15% to 91.57% 85.67% 9.91% Cmax 68.89% to 78.81 % 73.68% 10.01% Relative Bioavailability Assessments For S-demethylcitalopram (A vs D) Parameter 90% C.I. Ratio of Means Intra-Subject CV 122 WO 2009/095395 PCT/EP2009/050924 AUCo., 73.81% to 84.53% 78.99% 9.75% AUCo-i.f 74.61% to 85.64% 79.93% 9.91% Cmax 57.37% to 65.93% 61.50% 10.01% Relative Bioavailability Assessments For S-demethylcitalopram (B vs C) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCO., 82.77% to 94.78% 88.57% 9.75% AUCOi.f 83.29% to 95.60% 89.23% 9.91% Cmax 73.35% to 84.30% 78.64% 10.01% _ Relative Bioavailability Assessments For S-demethylcitalopram (B vs D) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCO., 77.17% to 87.98% 82.40% 9.75% AUCOi.f 77.89% to 88.99% 83.26% 9.91% Cmax 61.37% to 70.20% 65.64% 10.01% Relative Bioavailability Assessments For S-demethylcitalopram (C vs D) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCO., 86.94% to 99.55% 93.03% 9.75% AUCo-i.f 87.09% to 99.96% 93.30% 9.91% Cmax 77.86% to 89.48% 83.47% 10.01% Relative Bioavailability Assessments For S-demethylcitalopram (B vs A) Parameter Ratio of Means AUCo., 104.32% AUCo-i.f 104.16% Cmax 106.73% Pharmacokinetic Parameters for S-Didemethylcitalopram Geometric Mean (%CV) Arithmetic Mean SD PharaceuicalBupropion HBr Pharmacokinetic Pharmaceutical Pharmaceutical XL 348 mg Parameters Composition a Composition according to Tablets and Lexapro (20 mg) (D) toEm le 3 Example 2 [Formulation Lexapro 20 mg (n=13) [Formulation A] (A)B](B)(n=13) Tablets (C) B](B1n3(n=13) 17.86 (67.01) 18.83 (58.38) 25.50 (68.89) 47.34 (69.19) 23.37 + 15.66 22.83 + 13.33 31.22 + 21.51 62.42 + 43.19 AUCO.(ng-hr/mL) 27.65 (33.72) t 35.84 (38.51) t 35.91 (69.32) $ 66.16 (58.94) 76.22 29.01 + 9.78 37.83 + 14.57 42.67 + 29.57 44.92C C /mL) 0.10 (61.69) 0.11 (52.10) 0.14 (62.79) 0.30 (68.55) max(ng/ 0.12 + 0.08 0.12 + 0.06 0.17 + 0.10 0.38 + 0.26 Tmax (hr)* 120.00 (72.00-168.00) 120.02 (72.00 - 168.10) 96.00 (12.02- 72.00 (36.00 - 96.00) __________________168.00) t 1 m (hr) 69.57 +2.11t 84.44 + 11.68 t 74.45 + 14.23 $ 63.52 + 10.016 Ka (hr-') 9.97E-03 + 3.11 E-04t 8.35E-03 + 1.22E-031 9.65E-033+ 2.0SF- 1.12E-02 + 1.87E-036 MRT (hr) 171.76x+ 14.40t 187.03 + 12.541 166.30 + 19.71$ 135.38 + 9.77C M/P ratio 0.04 + 0.01t 0.05 + 0.021 0.05+0.03 $ 0.12+0.08 C *median (max-min); t n =4; In = 6; $:n = 8; Cn = 11 Relative Bioavailability Assessments For S-didemethylcitalopram (A vs C) Parameter 90% C.I. Ratio of Means Intra-Subject CV 123 WO 2009/095395 PCT/EP2009/050924 AUCo., 64.15% to 81.95% 72.50% 18.33% AUCo-i.f 64.25% to 98.83% 79.68% 14.60% Cmax 61.74% to 90.43% 74.72% 28.89% Relative Bioavailability Assessments For S-didemethylcitalopram (A vs D) Parameter Potency Uncorrected Data 90% C.I. Ratio of Means Intra-Subject CV AUCo., 34.86% to 44.91% 39.57% 18.33% AUCOi.f 39.46% to 58.94% 48.23% 14.60% Cmax 31.31% to 46.46% 38.14% 28.89% Relative Bioavailability Assessments For S-didemethylcitalopram (B vs C) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 65.92% to 84.92% 74.82% 18.33% AUCOi.f 60.78% to 87.61% 72.97% 14.60% Cmax 60.68% to 90.05% 73.92% 28.89% Relative Bioavailability Assessments For S-didemethylcitalopram (B vs D) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 36.12% to 46.15% 40.83% 18.33% AUCOi.f 38.05% to 51.26% 44.16% 14.60% Cmax 31.18% to 45.67% 37.73% 28.89% Relative Bioavailability Assessments For S-didemethylcitalopram (C vs D) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 48.08% to 61.94% 54.57% 18.33% AUCOi.f 52.67% to 69.55% 60.52% 14.60% Cmax 41.91% to 62.18% 51.05% 28.89% Relative Bioavailability Assessments For S-didemethylcitalopram (B vs A) Parameter Ratio of Means AUCo., 103.20% AUCOi.f 91.57% Cmax 98.93% EXAMPLE 26 [004341 A PILOT THREE-WAY, SINGLE-DOSE, FASTING STUDY OF A PHARMACEUTICAL COMPOSITION OF THE INVENTION COMPRISING BUPROPION HBR (325 MG)/ESCITALOPRAM OXALATE (17.9 MG) [004351 This was a 3-way crossover, randomized, open-label, single-dose, fasting, pilot, Phase I (comparative bioavailability) study. The objective of this study was to evaluate the relative peak and systemic exposure of a test formulation of the pharmaceutical composition manufactured according to Example 10 to Bupropion HBr Extended Release (XL) 348 mg Tablets described in US Patent No. 7,241,805 and Lexapro® 20 mg Tablets when co 124 WO 2009/095395 PCT/EP2009/050924 administered under fasting conditions. Normal, healthy, non-smoking male and female subjects between the ages of 18 and 55 years were included in the study. [004361 The test formulation used was one (1) pharmaceutical composition of Example 10, Batch #: 0707050, administered orally. The reference formulation was One (1) Bupropion HBr XL 348 mg Tablet as described in US Patent No. 7,241,805 Batch #: 07H044P, administered orally and one (1) Lexapro® 20 mg Tablet, Lot #: M0603M, administered orally. [00437] There were 18 subjects dosed in Period I, 13 of whom completed the study. One subject was dismissed because of an adverse event (AE, decreased hemoglobin), 1 subject was dismissed after emesis within 24.00 hours of dosing with Treatment B, and 3 subjects withdrew for personal reasons. Pharmacokinetic and statistical analyses were performed on 13 subjects who completed the study for bupropion and its metabolites. Pharmacokinetic and statistical analyses were performed on 14 subjects (13 subjects who completed the study and 1 subject for whom there were sufficient data for a meaningful analysis) for escitalopram and its metabolite. [004381 During each study period, 23 blood samples were collected from each subject at the following timepoints: 0.00 (pre-dose), and at 1.00, 2.00, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00, 96.00, 120.00, 144.00, 168.00, 192.00, 216.00, 240.00, 264.00 and 288.00 hours post-dose. [004391 Pharmacokinetic and statistical analyses were performed on 13 subjects who completed the study for bupropion and its metabolites. Pharmacokinetic and statistical analyses were performed on 14 subjects (13 subjects who completed the study and 1 subject for whom there were sufficient data for a meaningful analysis) for escitalopram and its metabolites. The safety assessment was performed on all subjects who received at least 1 dose during the course of the study. [00440] The following pharmacokinetic parameters for bupropion, hydroxybupropion, bupropion threoamino alcohol, bupropion erythroamino alcohol, Pharmacologic Activity Weighted Composite (PAWC), escitalopram, S-demethylcitalopram, and S-didemethyleitalopram were calculated by standard non-compartmental methods: AUCo-t, AUCoiff, Cmax, Tmax, t/, Kei, MRT, and M/P ratio. [00441] Bupropion, hydroxybupropion, bupropion erythroamino alcohol, bupropion threoamino alcohol, and the internal standard, 1-(3-chlorophenyl)-piperazine, were extracted from human plasma (0.50 mL), by solid phase extraction (SPE) into an organic medium. The analytes were separated by High Performance Liquid Chromatography (HPLC) system using reverse phase chromatography conditions, detected using an API 3000 tandem mass spectrometer. Method sensitivity and selectivity were achieved by detecting distinct precursor to production 125 WO 2009/095395 PCT/EP2009/050924 mass transitions for bupropion (240.3 -*184.0), hydroxybupropion (256.3-.238.0), bupropion erythroamino alcohol (242.4-* 168.1), bupropion threoamino alcohol (242.4-* 168.1) and the internal standard, 1-(3-chlorophenyl)-piperazine (197.3-.153.8), at defined retention time. [00442] For standards prepared on July 25, 2007, evaluation of the assay, using defined acceptance criteria, was carried out by the construction of an eight (8) point calibration curve (excluding zero concentration) covering the range of 1.000 ng/mL to 1023.900 ng/mL for bupropion, 3.905 ng/mL to 3998.970 ng/mL for hydroxybupropion, 1.000 ng/mL to 1024.000 ng/mL for bupropion erythroamino alcohol, and 1.000 ng/mL to 1024.000 ng/mL for bupropion threoamino alcohol in human plasma. For standards prepared on September 27, 2007, evaluation of the assay, using defined acceptance criteria, was carried out by the construction of an eight (8) point calibration curve (excluding zero concentration) covering the range of 1.000 ng/mL to 1023.900 ng/mL for bupropion, 3.907 ng/mL to 4000.320 ng/mL for hydroxybupropion, 1.000 ng/mL to 1024.000 ng/mL for bupropion erythroamino alcohol, and 1.000 ng/mL to 1024.000 ng/mL for bupropion threoamino alcohol in human plasma. The slope and intercept of the calibration curves were determined through weighted linear regression analysis (1/peak area ratio 2 ). Two calibration curves and duplicate QC samples (at three or five concentration levels) were analyzed along with each batch of the study samples. Peak area ratios were used to determine the concentration of the standards, quality control samples, and the unknown study samples from the calibration curves. The Concentration of escitalopram, S-demethylcitalopram and S-didemethylcitalopram were measured using an archiral LC-MS/MS method for citalopram, demethyleitalopram, didemethyleitalopram. citalopram, demethyleitalopram, didemethyleitalopram and the internal standards, citalopram analog, demethylcitalopram analog, and didemethylcitalopram analog, were extracted from human plasma (0.75 mL), using sodium heparin as an anticoagulant, by liquid-liquid extraction into an organic medium followed by back extraction into a dilute acid. An aliquot of this extract was injected into a High Performance Liquid Chromatography system and detected using a TSQ Quantum tandem mass spectrometer. The analytes were separated by reverse phase chromatography. Method sensitivity and selectivity were achieved by detecting distinct precursor to production mass transitions for citalopram (325.1 -*109.0), demethylcitalopram (311.1 -*109.0), didemethylcitalopram (297.1-*109.0 and 297.1-.260.0), and the internal standards, citalopram analog (341.1-.125.0), demethyleitalopram analog (327.1 -*125.0), and didemethylcitalopram analog (313.1 -*125.0), at defined retention time. [004431 Evaluation of the assay, using defined acceptance criteria, was carried out by the construction of an eight (8) point calibration curve (excluding zero concentration) covering the 126 WO 2009/095395 PCT/EP2009/050924 range of 0.251 ng/mL to 64.020 ng/mL for citalopram, 0.126 ng/mL to 32.013 ng/mL for demethyleitalopram, and 0.025 ng/mL to 6.397 ng/mL for didemetyleitalopram in human plasma. The slope and intercept of the calibration curves were determined through weighted linear regression analysis (1/cone.
2 ). Two calibration curves and duplicate QC samples (at three or four concentration levels) were analyzed along with each batch of the study samples. Peak area ratios were used to determine the concentration of the standards, quality control samples, and the unknown study samples from the calibration curves. [00444] Pharmacokinetic and statistical analyses were performed on 13 subjects who completed the study for bupropion and its metabolites. Pharmacokinetic and statistical analyses were performed on 14 subjects (13 subjects who completed the study and 1 subject for whom there were sufficient data for a meaningful analysis) for escitalopram and its metabolites. The safety assessment was performed on all subjects who received at least 1 dose during the course of the study. [00445] The following pharmacokinetic parameters for bupropion, hydroxybupropion, bupropion threoamino alcohol, bupropion erythroamino alcohol, Pharmacologic Activity Weighted Composite (PAWC), escitalopram, S-demethyleitalopram, and S-didemethyleitalopram were calculated by standard non-compartmental methods: AUCo-t, AUCo-if, Cma, Tmax, t/, Kel, MRT, and M/P ratio. [004461 Data for the pharmcokinetic parameters for bupropion and citalopram and their metabolites is presented in the tables below and in FIGs. 26A-H. Pharmacokinetic Parameters for Bupropion Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition according to Bupropion HBr XL 348 mg Tablets (B) (n=13) Example 10 (A) (n=13) Batch #: 07H044P Batch #: 0707050 AUQo, (ng-hr/mL) 1540.44 (42.08) 1306.14 (24.03) 1682.56 + 708.04 1342.18 + 322.57 AUCo-i.f ng-hr/mL) 1588.39 (40.98) 1363.51 (22.80) 1726.27 + 707.35 1396.89 + 318.46 114.98 (30.47) 103.18 (29.69) Cmax(ng/mL) 119.83 + 36.51 108.30 + 32.16 Tmax (hr)* 4.00 (3.00 - 6.02) 4.00 (3.00 - 6.00) t 1 2 (hr) 21.71 + 6.75 23.24 + 7.87 Kd (hr-') 3.46E-02 + 9.52E-03 3.29E-02 + 1.03E-02 MRT (hr) 19.98 + 4.42 23.13 + 5.50 * median (min - max) Relative Bioavailability Assessments for Bupropion (A vs B) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCoL 99.28% to 136.83% 116.55% 22.43% AUCo-i.f :d 98.58% to 134.69% 115.23% 21.81% Cmax 96.59% to 124.44% 109.63% 17.63% 127 WO 2009/095395 PCT/EP2009/050924 Pharmacokinetic Parameters for Hydroxybupropion Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition According to Bupropion HBr XL 348 mg Tablets (B) (n=13) Example 10 (A) (n=13) Batch #: 07H044P Batch #: 0707050 25490.93 (43.68) 23053.82 (36.28) AUC., (ng-hr/mL) 28065.86 + 12259.79 24480.15 + 8881.54 25732.33 (43.33) 23288.15 (36.18) AUJCo~.
1 (nghr/mL) 28286.16 + 12257.45 24717.94 + 8943.32 531.88 (30.91) 443.18 (33.63) Cmax(ng/mL) 556.01 + 171.88 464.00 + 156.03 Tmax (hr)* 10.00 (6.00 - 24.00) 10.05 (6.00 - 16.00) t 1 1
/
2 (hr) 26.74 + 5.19 26.26 + 5.38 Ked (hr-') 2.68E-02 + 4.79E-03 2.73E-02 + 4.83E-03 MRT (hr) 42.91 + 5.69 43.87 + 6.50 M/P Ratio 15.47 3.03 16.47 3.85 * median (min - max) Relative Bioavailability Assessments For Hydroxybupropion (A vs B) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 93.58% to 127.93% 109.41% 21.85% AUCo-i.f 93.52% to 127.76% 109.31% 21.80% Cmax 105.36% to 136.24% 119.81% 17.90% Pharmacokinetic Parameters for Bupropion Threoamino Alcohol Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition According to Bupropion HBr XL 348 mg Tablets (B) (n=13) Example 10 (A) (n=13) Batch #: 07H044P Batch #: 0707050 7079.68 (53.12) 6911.03 (22.19) AUC., (ng-hr/mL) 8074.61 + 4289.60 7074.21 + 1569.85 AUCO-i. (ng-hr/mL) 7350.60 (52.90) 7106.82 (22.14) 8387.70 + 4437.17 7273.18 + 1610.27 145.38 (45.89) 128.08 (28.91) Cmax(ng/mL) 159.05 + 72.99 133.02 + 38.46 Tmax (hr)* 10.00 (6.00 - 12.02) 8.00 (3.00 - 10.00) t 1 1
/
2 (hr) 60.92 + 19.38 56.08 + 13.20 Ked (hr-') 1.27E-02 + 4.82E-03 1.3 1E-02 + 3.53E-03 MRT (hr) 74.50 + 18.13 72.24 + 16.32 M/P Ratio 4.77 + 1.40 5.28 + 1.14 * median (min - max) Relative Bioavailability Assessments For Bupropion Threoamino Alcohol (A vs B) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo 0 , 79.64% to 127.13% 100.62% 33.16% AUCo-i.f 80.41% to 127.84% 101.39% 32.86% Cmax 89.70% to 138.99% 111.66% 30.95% 128 WO 2009/095395 PCT/EP2009/050924 Pharmacokinetic Parameters for Bupropion Erythroamino Alcohol Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Bupropion HBr (325 mg)/Escitalopram Bupropion HBr XL 348 mg Tablets (B) (n=13) Oxalate (17.9 mg) SR Tablets (A) (n=13) Batch #: 0711044P Batch #: 0707050 1299.62 (48.00) 1313.17 (22.29) AUC., (ng-hr/mL) 1449.54 + 695.84 1343.05 + 299.34 AUCO i. (ng-hr/mL) 1370.88 (46.20) 1369.92 (22.09) - m1517.67 + 701.16 1400.60 + 309.40 25.29 (33.84) 23.76 (22.13) Cmax (ng/mL) 26.67 + 9.03 24.30 + 5.38 Tmax (hr)* 10.00 (6.00 - 24.00) 10.00 (6.00 - 16.00) t 11
/
2 (hr) 32.39 + 5.61 29.71 + 5.49 Ke (hr-') 2.2 1E-02 4.21E-03 2.40E-02 4.13E-03 MRT (hr) 52.35 + 8.97 51.51 + 9.53 M/P Ratio 0.88 + 0.20 1.02 + 0.22 * median (min - max) Relative Bioavailability Assessments For Bu ropion Erythroamino Alcohol (A vs B) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 77.31% to 123.34% 97.65% 33.12% AUCo-i.f 78.57% to 123.77% 98.61% 32.17% Cmax 86.21% to 126.76% 104.54% 27.10% Pharmacokinetic Parameters for PAWC Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition According to Bupropion HBr XL 348 mg Tablets (B) Example 10 (A) (n=13) (n=13) Batch #: 0707050 Batch #: 07H044P AUCo, M.hr) 73.87 (42.70) 67.15 (31.81) 80.98 + 34.58 70.32 + 22.37 AUCO-i.f (pM.hr) 74.05 (42.61) 67.26 (31.75) 81.16 + 34.58 70.43 + 22.36 1.70 (29.51) 1.45 (34.69) Cmax (PM) 1.76 + 0.52 1.52 + 0.53 Tmax (hr)* 10.00 (4.00 - 12.02) 6.00 (4.00 - 10.05) t 1 1
/
2 (hr) 37.98 + 23.54 35.58 + 17.38 Ked (hr-') 2.48E-02 + 1.26E-02 2.4 1E-02 + 1.09E-02 MRT (hr) 42.31 + 5.69 43.35 + 5.86 * median (min - max) Relative Bioavailability Assessments For PAWC (A vs B) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 92.92% to 127.38% 108.79% 22.05% AUCo-i.f 92.98% to 127.47% 108.87% 22.05% Cmax 101.40% to 134.02% 116.57% 19.44% 129 WO 2009/095395 PCT/EP2009/050924 Pharmacokinetic Parameters For Escitalopram Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition According to Lexapro* 20 mg Tablets (C) (n=14) Examle 10 (A) (n=14) Lot #: M0603M Batch #: 0707050 AUCo, (ng.hr/mL) 606.10 (41.90) 751.78 (25.80) 661.94 + 277.35 774.39 + 199.81 AUC (ng.hr/mL) 625.05 (41.30) 767.40 (25.59) fi"f m680.63 + 281.08 790.08 + 202.21 C (ng/mL) 10.79 (24.93) 21.56 (22.86) "" mL11.14 + 2.78 22.04 + 5.04 Tmax (hr)* 12.00 (6.00 - 16.00) 6.00 (2.02 - 8.00) t1/2 (hr) 36.15 +8.36 31.85 +7.08 Ked (hr-') 2.01E-02 + 4.45E-03 2.29E-02 + 5.42E-03 MRT (hr) 56.89 + 10.51 42.51 + 8.99 * median (min - max) Relative Bioavailability Assessments For Escitalopram (A vs C) Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 69.49% to 103.47% 84.80% 27.18% AUCo-i.f 70.27% to 103.82% 85.42% 26.63% Cmax 45.12% to 59.43% 51.78% 18.63% Pharmacokinetic Parameters For S-demethylcitalopram Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Bupropion HBr (325 mg)/Escitalopram Lexapro* 20 mg Tablets (C) (n=14) Oxalate (17.9 mg) SR Tablets (A) (n=14) Lot #: M0603M Batch #: 0707050 AUCo. ng.hr/mL) 184.49 (25.46) 346.32 (13.42) 191.48 + 48.75 349.33 + 46.88 AUCO. ( .hr/mL) 198.12 (24.54) 358.80 (12.90) " (ng/204.94 + 50.29 361.61 + 46.63 C (ng/mL) 1.39 (23.98) 3.23 (17.15) '"" /L1.44 + 0.34 3.27 + 0.56 Tmax (hr)* 42.00 (24.02 - 72.00) 16.00 (8.00 - 48.00) t 11
/
2 (hr) 56.20 + 16.03 46.57 + 8.83 Ked (hr-') 1.33E-02 + 3.88E-03 1.55E-02 + 3.56E-03 MRT (hr) 109.23 + 19.06 84.48 + 15.83 M/P Ratio 0.34 + 0.10 0.50 + 0.13 * median (min - max) Relative Bioavailability Assessments For S-demethylcitalopram Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 48.67% to 61.57% 54.74% 15.86% AUCo-i.f 50.64% to 64.01% 56.93% 15.81% Cmax 39.85% to 48.34% 43.89% 13.00% 130 WO 2009/095395 PCT/EP2009/050924 Pharmacokinetic Parameters For S-didemethylcitalopram Geometric Mean (%CV) Pharmacokinetic Arithmetic Mean ± SD Parameters Pharmaceutical Composition According to Lexapro* 20 mg Tablets (C) (n=14) Example 10 (A) (n=14) Lot #: M0603M Batch #: 0707050 AUCo., (ng.hr/mL) 17.80 (42.15) 73.99 (34.64) 19.62 + 8.27 79.34 + 27.49 AUCO-i.f (ng.hr/mL) 27.31 ( 3 1.
6 3 ) 80.34 (33.33) 28.40 + 8.98 85.66 + 28.55 0.10 (36.95) 0.46 (40.41) Cmax(ng/mL) 0.11 + 0.04 0.51 + 0.20 Tmax (hr)* 120.00 (72.00 - 144.00) 72.00 (36.00 - 120.00) t 1 2 (hr) 68.43 7.71t 62.45 + 14.59 K. (hr-') 1.03E-02 1.26E-03t 1.18E-02 + 3.44E-03 MRT (hr) 160.29 20.47t 132.86 22.77 M/P Ratio 0.06 0.02t 0.13 0.06 * median (min - max); n = 7 Relative Bioavailability Assessments for S-demethylcitalopram Parameter 90% C.I. Ratio of Means Intra-Subject CV AUCo., 21.07% to 26.80% 23.76% 16.24% AUCo-i.f 23.62% to 32.01% 27.49% 12.80% Cmax 17.910% to 24.71 % 21.04% 21.84% COMPARATIVE EXAMPLES EXAMPLE 27 [004471 Homogenous Tablet Core Composition and Method of Manufacture-Separate Granulation Method. [004481 A. Tramadol HCl Granulation and Bulk Blend Tramadol HCl Granules Composition Tramadol HCl ER Bulk Blend Composition Component %w/w % w/w 97.09 96.16 Tramadol HCl Aerosil 200 (Colloidal 0.97 0.96 Silicone Dioxide) Polyvinyl alcohol (PVA) 1.94 1.92 Pruv (Sodium Searyl - 0.96 Fumarate) [004491 The pharmaceutical active, tramadol HCl, was top-spray granulated using Aeromatic 4/5 Fluid Bed granulator. The theoretical batch size was 66.950kg. An aqueous (purified water) solution of polyvinyl alcohol (PVA, 4.59% solution) was sprayed onto 65.000kg of tramadol HCl and 0.650kg of Aerosil 2000 (colloidal silicone dioxide) to a weight gain of 131 WO 2009/095395 PCT/EP2009/050924 1.98% to produce granules comprising 97.09% of tramadol HCL, 0.97% Aerosil 200 and 1.94% PVA. The powder bed temperature was maintained between 25-35'C, and the liquid spray was maintained between 150-300g/min throughout the granulation process. When spraying of the granulation solution was completed, the granules were fluid bed dried to an LOD of < 1%. The granules were then sieved through 1.5mm screen using Sweco sifter. The oversized granules were passed at 1000rpm through a Comill fitted with 1.57mm screen. The resulting granules were added to the sifted granules to make one granule batch. These granules were then blended for 10 minutes with 0.635kg of screened Pruv (sodium stearyl fumarate screened through 0.590mm size) using a V blender. The total blend batch size was 65.995kg. [004501 B. Meloxicam Granulation Meloxicam Granule Composition Component %w/w Meloxicam 98.74 Polyvinyl alcohol (PVA) 1.26 [00451] The pharmaceutical active, meloxicam, was granulated using high shear mixer. The theoretical batch size after granulation was 303.9g. An aqueous solution of polyvinyl alcohol (4.6% solution) was sprayed onto about 300g of meloxicam to a weight gain of about 1.3% weight gain to produce granules comprising about 98.72% meloxicam and 1.28% polyvinyl alcohol. The granules were tray dried at 45C to an LOD of 0.1%. The resulting granules were co-milled through 1143 .tm screen for manufacture of the homogenous tablet core. [00452] C. Homogenous Tablet Core Composition and Method of Manufacture [004531 To manufacture the homogenous tablet core comprising of about 120mg of tramadol and about 6mg of meloxicam, a blend with the following composition was prepared: about 95.36% tramadol HCl granules (manufactured as described above, but milled again through a 991 m comill screen to obtain comparable particle size granules as meloxicam), and 4.64% meloxicam granules (manufactured as described above). A homogenous blend of about 2000g was manufactured by dispensing about 1907.2g of tramadol HCL granules, and about 92.8g of meloxicam granules. The material was added to a v-blender (4 quart shell) in the following order: 1. About half of the tramadol HCl granules 2. All of the meloxicam granules 3. The remaining of tramadol HCl granules 132 WO 2009/095395 PCT/EP2009/050924 The tablet core components were homogenously blended for about 10 minutes, with the intensifier bar turnedd off. The homogenous blend was discharged from the shell and charged onto a tablet press (Piccola 10 station rotary press) and compressed to a target weight of about 131mg and a target hardness of about 60N using 6.5mm round standard concave tablet tooling. The resulting product comprises the homogenous tablet core, which at this point is an immediate release (IR) having the following composition: Homogenous Tablet Core Composition Component Mg/tablet %w/w 120.11 91.69 Tramadol HCl 6.08 4.64 Meloxicam Aerosil 2000 (Colloidal Silicone 1.21 0.92 Dioxide) Polyvinyl alcohol (PVA) 2.40 1.83 Pruv (Sodium Stearyl Fumarate) 1.21 0.92 [00454] D. Tablet Coating Composition And Method of Manufacture Tablet Control-Release Coating Composition Component %w/w 4.61 Ethocel 100 FP Premium 2.86 Kollidon@ 90F Polyethylene Glycol 3350 (PEG) 1.03 Dibutyl sebacate (DBS) 0.50 2-Propanol 8.68 Absolute Ethanol 81.86 Purified Water 0.46 [00455] The homogenous IR tablet core was coated with an ethyleellulose based system by preparing an organic solvent solution consisting of about 4.61% ethocel standard 100 FP premium, 2.86% Kollidon 90F, 1.03% carbowax sentry polyethylen glycol 3350 granular NF/ FCC grade, 0.5% dibutyl sebacate NF, 8.68% 2-propanol, 81.86% absolute ethanol, and 0.46% purified water. The plasticized polymer solution was applied to 700g of tablet core using O'Hara Labcoat 1 fitted with 12"pan until about 17% weight gain was obtained. During spraying, the product temperature was maintained between 39-44'C, and the liquid spray rate was maintained 133 WO 2009/095395 PCT/EP2009/050924 between 10-22g/min. The controlled release coated tablets were then dried for a further 30 minutes (inlet air set to 43C, pan speed set at 5rpm jog mode). [004561 The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Table 27. The result of the dissolution testing is presented as a % of the total tramadol HCl and meloxicam in the controlled release tablet (batch 1258-171) and also depicted in Fig 27 Table 27 Dissolution Conditions: 900ml Phosphate Buffer, pH 7.5, Apparatus 1, 75rpm, 37C % Release Time (hrs) Tramadol HCl Meloxicam 2 51 10 4 70 20 8 96 39 10 100 50 16 100 74 EXAMPLE 28 [004571 A homogenous tablet core was prepared according to the method and composition described in Example 27. The homogenous cores thus obtained were coated according to the following method and composition: Control-Release Coating Composition (Kollicoat SR30D based) Component %w/w Kollicoat SR 30D (30% dispersion) 36.97 Triethylcitrate 0.55 Pharmacoat 606 (Hydroxypropylmethyl cellulose) 2.77 Tale 3.59 Purified Water 56.12 [00458] The homogenous IR tablet core was coated wih Kollicoat SR 30D based system by preparing an aqueous coating suspension consisting of about 36.97% Kollicoat SR 30D (30% dispersion), 055% triethyleitrate (TEC), 2.77% pharmacot 606, 3.59% tale, and 56.12% purified water. The plasticized polymer suspension was applied to 700g of tablet core using O'Hara Labcoat 1 fitted with 12"pan until about 40% weight gain was obtained. During spraying, the product temperature was maintained between 35-41 C, and the liquid spray rate maintained 134 WO 2009/095395 PCT/EP2009/050924 between 9-17g/min. The controlled release coated tablets were then cured for 3 hours (inlet air set to 67C, pan speed set at 3.3rpm jog mode). [00459] The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Table28. The result of the dissolution testing is presented as a % of the total tramadol HCl and meloxicam in the controlled release tablet (batch 1258-175) and also depicted in Fig 28. Table 28 Dissolution Conditions: 900ml Phosphate Buffer, pH 7.5, Apparatus 1, 75rpm, 37C % Release Time (hrs) Tramadol HCl Meloxicam 2 0 0 4 7 0 8 61 18 10 74 21 16 84 23 EXAMPLE 29 [00460] Homogenous CR Tablet Core Composition and Method of Manufacture [00461] The homogenous CR tablets comprising about 300mg of tramadol HCl (equivalent to about 263.5mg of tramadol base) and about 20mg of meloxicam were prepared by direct blending of about 40.4% tramadol HCl powder, about 2.7% meloxicam powder, about 26.9% hydroxypropyl cellulose, about 16.8% lactose, about 9.7% microcrystalline cellulose, about 0.3% silicon dioxide, and about 3.0% magenisium stearate. [00462] A homogenous blend of about 150g was manufactured by dispensing about 60.63g of tramadol HCl, about 4.04g of meloxicam, about 40.42 of hydroxypropyl cellulose, about 25.26g of lactose, about 14.59g of microcrystalline cellulose, about 0.51g of silicon dioxide, and about 4.55g of magenisium stearate. The silicon dioxide and magenisium stearate were pre-screened through the 30mesh screen prior to dispensing. Manual bag mixing was applied for 2 minutes. [00463] The homogenous blend was further compressed using Natoli Single Station Press equipped with 0.706" x 0.329" capsule shaped tablet tooling. The target tablet weight was 742.2 mg. The hardness of the table was about 160 N. 1.75 tons of compression force was applied. The resulting product comprises the homogenous tablet core, which at this point is an controlled release core having the following composition: 135 WO 2009/095395 PCT/EP2009/050924 Homogenous CR Tablet Core Composition Component mg/tablet %w/w Tramadol HCl 300.0 40.42 Meloxicam 20.0 2.69 Hydroxypropyl 200.0 26.95 cellulose Lactose DT 125.0 16.84 Microcrystalline 72.2 9.73 cellulose Silicon dioxide 2.5 0.34 Magnesium stearate 22.5 3.03 [00464] The dissolution profile of the above pharmaceutical composition was determined under the dissolution conditions described below in Table 29A and 29B. The result of the dissolution testing is presented as a % of the total tramadol HCl and meloxicam in the controlled release tablet (batch no. 08070T) and is also depicted in FIGs. 29A and 29B. Table 29A Dissolution Conditions: 900 ml 0.1N HCl, USP Apparatus 1,75 rpm, 37 0 C % Released Time (hr) Tramadol HCl Meloxicam 0.5 18 0 1 28 0 2 42 0 3 53 0 4 62 0 5 70 0 6 76 0 8 86 0 10 93 0 12 97 0 Table 29B Dissolution Conditions: 900 ml pH 6.8 phosphate buffer, USP Apparatus 1, 75 rpm, 37 0 C % Released Time (hr) Tramadol HCl Meloxicam 0.5 19 2 1 29 3 2 44 7 3 55 11 4 65 14 5 72 18 6 79 22 136 WO 2009/095395 PCT/EP2009/050924 8 90 29 10 98 37 12 102 44 137

权利要求:
Claims (85)
[1] 1. A pharmaceutical composition comprising: a) a homogenous core comprising a therapeutically effective combination of active agents selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, and bupropion hydrobromide and escitalopram oxalate, at least one stabilizer in an effective stabilizing amount, and at least one pharmaceutically acceptable excipient, and b) a control-releasing coating surrounding said core, said coating comprising a water insoluble water-permeable film-forming polymer, a water-soluble polymer and optionally at least one plasticizer.
[2] 2. The pharmaceutical composition of claim 1 wherein said pharmaceutical composition provides for a synchronous release of the combination of actives independent of pH of dissolution media.
[3] 3. The pharmaceutical composition of claim 1 wherein said combination of actives is bupropion hydrobromide and escitalopram oxalate.
[4] 4. The pharmaceutical composition of claim 1, wherein said stabilizer is selected from the group consisting at least one suitable pharmaceutically acceptable inorganic acid, at least one suitable pharmaceutically acceptable organic acid, at least one suitable pharmaceutically acceptable salt of an organic base, at least one suitable pharmaceutically acceptable salt of an inorganic acid, at least one suitable pharmaceutically acceptable acid salt of an amino acid, potassium metabisulfite, sodium bisulfite, or at least one suitable pharmaceutically acceptable phenylated antioxidant, or any combination thereof.
[5] 5. The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one suitable inorganic acid, which at a concentration of about 0.31% w/w/ forms an aqueous solution having a pH of from about 0.5 to about 0.4.
[6] 6. The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one suitable organic acid that has a solubility in water at 20 0 C of less than about 1 Og/1 OOg 138 WO 2009/095395 PCT/EP2009/050924 water and that at a concentration of about 60% w/w forms an aqueous suspension having a pH of from about 0.9 to about 4.0.
[7] 7. The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one suitable dicarboxylic acid that has a solubility in water at 20 0 C of less than about lOg/1Og water and that at a concentration of about 60% w/w forms an aqueous suspension having a pH of from about 0.9 to about 4.0.
[8] 8. The pharmaceutical composition of claim 1 wherein said stabilizer comprises at least one suitable pharmaceutically acceptable salt of an organic base having an aqueous pH of from about 2.70 to about 3.10 at a concentration of about 10% w/w.
[9] 9. The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable salt of an organic base having an aqueous pH of from about 2.95 to about 3.05, at a concentration of about 20% w/w.
[10] 10. The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one salt of an organic base having an aqueous pH of from about 2.70 to about 2.72, at a concentration of about 20% w/w.
[11] 11. The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable salt of an inorganic acid having an aqueous pH of from about 4.20 to about 4.30 at a concentration of about 10 w/w.
[12] 12. The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable acid salt of an amino acid.
[13] 13. The pharmaceutical composition of claim 1 wherein said at least one stabilizer is selected from the group consisting of potassium metabisulfite, sodium bisulfite, and any combination thereof.
[14] 14. The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable phenylated antioxidant. 139 WO 2009/095395 PCT/EP2009/050924
[15] 15. The pharmaceutical compositon of claim 14 wherein said at least one stabilizer is selected from the group consisting of butlylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and any combination thereof.
[16] 16. The pharmaceutical compositon of claim 1 wherein said at least one stabilizer comprises butlylated hydroxytoluene.
[17] 17. The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises citric acid.
[18] 18. The pharmaceutical compositon of claim 1 wherein said at least one stabilizer comprises a combination of citric acid and butylayed hydroxytoluene.
[19] 19. The pharmaceutical composition of claim 1, wherein said at least one pharmaceutically acceptable excipient is selected from the group consisting of a binder, a lubricant, a filler, a glidant, and any combinations thereof.
[20] 20. The pharmaceutical composition of claim 1, wherein said water-insoluble water permeable film-forming polymer is selected from the group consisting of cellulose ethers, cellulose esters, methacrylic acid derivatives, aqueous ethylcellulose dispersions, aqueous acrylic enteric systems, polyvinyl derivatives, and any combination thereof.
[21] 21. The pharmaceutical composition of claim 1, wherein said water-soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and any combination thereof.
[22] 22. The pharmaceutical composition of claim 1, wherein said at least one plasticizer, when said plasticizer is present, is selected from the group consisting of an ester, a polyalkylene glycol and any combination thereof.
[23] 23. The pharmaceutical composition of claim 1, wherein said at least one plasticizer, when said plasticizer is present, comprises a combination of two plasticizers. 140 WO 2009/095395 PCT/EP2009/050924
[24] 24. The pharmaceutical composition of claimI, wherein said composition is in the form of a tablet.
[25] 25. The pharmaceutical composition of claim 1, when administered to a subject in need of such administration provides a about 15-25% increase in the bioavailability of bupropion when compared to co-administration of single active agent pharmaceutical compositions of bupropion hydrobromide and citalopram hydrochloride or bupropion hydrobromide and escitalopram oxalate.
[26] 26. The pharmaceutical compositon of claim 3 whererin said bupropion hydrobromide is present at an amount at least about 10% less than a single active agent pharmaceutical composition comprising 348 mg bupropion hydrobromide.
[27] 27. A method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject the pharmaceutical composition of claim 1.
[28] 28. A pharmaceutical composition comprising a controlled release matrix core, said controlled release matrix core comprising at least one hydrophilic control-releasing polymer present in a control-releasing amount, a therapeutically effective combination of active agents selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, and bupropion hydrobromide and escitalopram oxalate, at least one stabilizer present in an effective stabilizing amount, and at least one pharmaceutically acceptable excipient.
[29] 29. The pharmaceutical composition of claim 28 wherein said pharmaceutical composition provides for a synchronous release of the combination of actives independent of pH of dissolution media.
[30] 30. The pharmaceutical composition of claim 28 wherein said combination of actives is bupropion hydrobromide and escitalopram oxalate.
[31] 31. The pharmaceutical composition of claim 28, wherein said stabilizer is selected from the group consisting at least one suitable pharmaceutically acceptable inorganic acid, at least one 141 WO 2009/095395 PCT/EP2009/050924 suitable pharmaceutically acceptable organic acid, at least one suitable pharmaceutically acceptable salt of an organic base, at least one suitable pharmaceutically acceptable salt of an inorganic acid, at least one suitable pharmaceutically acceptable acid salt of an amino acid, potassium metabisulfite, sodium bisulfite, or at least one suitable pharmaceutically acceptable phenylated antioxidant, or any combination thereof.
[32] 32. The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one suitable inorganic acid, which at a concentration of about 0.31% w/w/ forms an aqueous solution having a pH of from about 0.5 to about 0.4.
[33] 33. The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one suitable organic acid that has a solubility in water at 20 0 C of less than about lOg/100g water and that at a concentration of about 60% w/w forms an aqueous suspension having a pH of from about 0.9 to about 4.0.
[34] 34. The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one suitable dicarboxylic acid that has a solubility in water at 20 0 C of less than about lOg/100g water and that at a concentration of about 60% w/w forms an aqueous suspension having a pH of from about 0.9 to about 4.0.
[35] 35. The pharmaceutical composition of claim 28 wherein said stabilizer comprises at least one suitable pharmaceutically acceptable salt of an organic base having an aqueous pH of from about 2.70 to about 3.10 at a concentration of about 10% w/w.
[36] 36. The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable salt of an organic base having an aqueous pH of from about 2.95 to about 3.05, at a concentration of about 20% w/w.
[37] 37. The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one salt of an organic base having an aqueous pH of from about 2.70 to about 2.72, at a concentration of about 20% w/w. 142 WO 2009/095395 PCT/EP2009/050924
[38] 38. The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable salt of an inorganic acid having an aqueous pH of from about 4.20 to about 4.30 at a concentration of about 10 w/w.
[39] 39. The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable acid salt of an amino acid.
[40] 40. The pharmaceutical composition of claim 28 wherein said at least one stabilizer is selected from the group consisting of potassium metabisulfite, sodium bisulfite, and any combination thereof.
[41] 41. The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable phenylated antioxidant.
[42] 42. The pharmaceutical compositon of claim 41 wherein said at least one stabilizer is selected from the group consisting of butlylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and any combination thereof.
[43] 43. The pharmaceutical compositon of claim 28 wherein said at least one stabilizer comprises butlylated hydroxytoluene.
[44] 44. The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises citric acid.
[45] 45. The pharmaceutical compositon of claim 28 wherein said at least one stabilizer comprises a combination of citric acid and butylayed hydroxytoluene.
[46] 46. The pharmaceutical composition of claim 28, wherein said at least one hydrophilic control-releasing polymer is selected from the group consisting of hydrophilic celluloses, ethylcellulose, polysaccharides, polyvinylpyrrolidone, ethylcellulose, polymethacrylates, and mixtures of polyvinyl acetate and polyvinylpyrrolidone, and any combination thereof. 143 WO 2009/095395 PCT/EP2009/050924
[47] 47. The pharmaceutical composition of claim 28, wherein said at least one pharmaceutically acceptable excipient is selected from the group consisting of a binder, a lubricant, a filler, a glidant, and any combination thereof.
[48] 48. The pharmaceutical composition of claim 28, wherein said composition is in the form of a tablet.
[49] 49. The pharmaceutical composition of claim 28 further comprising a control-releasing coating surrounding said core, said coating comprising a water-insoluble water-permeable film forming polymer, a water-soluble polymer and optionally at least one plasticizer.
[50] 50. The pharmaceutical composition of claim 49, wherein said water-insoluble water permeable film-forming polymer is selected from the group consisting of cellulose ethers, cellulose esters, methacrylic acid derivatives, aqueous ethylcellulose dispersions, aqueous acrylic enteric systems, polyvinyl derivatives, and any combination thereof.
[51] 51. The pharmaceutical composition of claim 49, wherein said water-soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and any combination thereof.
[52] 52. The pharmaceutical composition of claim 49, wherein said at least one plasticizer, when said plasticizer is present, is selected from the group consisting of an ester, a polyalkylene glycol and any combination thereof.
[53] 53. The pharmaceutical composition of claim 49, wherein said at least one plasticizer, when said plasticizer is present, comprises a combination of two plasticizers.
[54] 54. The pharmaceutical composition of claim 49, wherein said composition is in the form of a tablet.
[55] 55. The pharmaceutical composition of claim 49 wherein said combination of actives is bupropion hydrobromide and escitalopram oxalate. 144 WO 2009/095395 PCT/EP2009/050924
[56] 56. The pharmaceutical compositon of claim 30 whererin said bupropion hydrobromide is present at an amount at least about 10% less than a single active agent pharmaceutical composition comprising 348 mg bupropion hydrobromide.
[57] 57. The pharmaceutical compositon of claim 55 wherein said bupropion hydrobromide is present at an amount at least about 10% less than a single active agent pharmaceutical composition comprising 348 mg bupropion hydrobromide.
[58] 58. A method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject the pharmaceutical composition of claim 28.
[59] 59. A method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject the pharmaceutical composition of claim 49.
[60] 60. A pharmaceutical composition comprising: a) a core comprising a first immediate release layer comprising a therapeutically effective amount of an active agent selected from the group consisting of bupropion hydrochloride and bupropion hydrobromide, optionally a stabilizer in an effective stabilizing amount, and at least one pharmaceutically acceptable excipient in direct contact with a second immediate release layer comprising an active agent selected from the group consisting of citalopram hydrochloride and escitalopram oxalate, optionally a stabilizer, and at least one pharmaceutically acceptable excipient, and b) a control-releasing coating surrounding said core, said coating comprising a water insoluble water-permeable film-forming polymer, a water-soluble polymer and at least one plasticizer.
[61] 61. The pharmaceutical composition of claim 60 wherein said pharmaceutical composition provides for a synchronous release of the combination of actives independent of pH of dissolution media.
[62] 62. The pharmaceutical composition of claim 60 wherein said combination of actives is bupropion hydrobromide and escitalopram oxalate. 145 WO 2009/095395 PCT/EP2009/050924
[63] 63. The pharmaceutical composition of claim 60, wherein said stabilizer, when said stabilizer is present, for the first immediate release layer is selected from the group consisting of at least one suitable pharmaceutically acceptable inorganic acid, at least one suitable pharmaceutically acceptable organic acid, at least one suitable pharmaceutically acceptable salt of an organic base, at least one suitable pharmaceutically acceptable salt of an inorganic acid, at least one suitable pharmaceutically acceptable acid salt of an amino acid, potassium metabisulfite, sodium bisulfite, and any combination thereof.
[64] 64. The pharmaceutical composition of claim 63 wherein said at least one stabilizer comprises at least one suitable inorganic acid, which at a concentration of about 0.31% w/w/ forms an aqueous solution having a pH of from about 0.5 to about 0.4.
[65] 65. The pharmaceutical composition of claim 63 wherein said at least one stabilizer comprises at least one suitable organic acid that has a solubility in water at 20 0 C of less than about lOg/100g water and that at a concentration of about 60% w/w forms an aqueous suspension having a pH of from about 0.9 to about 4.0.
[66] 66. The pharmaceutical composition of claim 63 wherein said at least one stabilizer comprises at least one suitable dicarboxylic acid that has a solubility in water at 20 0 C of less than about lOg/100g water and that at a concentration of about 60% w/w forms an aqueous suspension having a pH of from about 0.9 to about 4.0.
[67] 67. The pharmaceutical composition of claim 63 wherein said stabilizer comprises at least one suitable pharmaceutically acceptable salt of an organic base having an aqueous pH of from about 2.70 to about 3.10 at a concentration of about 10% w/w.
[68] 68. The pharmaceutical composition of claim 63 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable salt of an organic base having an aqueous pH of from about 2.95 to about 3.05, at a concentration of about 20% w/w.
[69] 69. The pharmaceutical composition of claim 63 wherein said at least one stabilizer comprises at least one salt of an organic base having an aqueous pH of from about 2.70 to about 2.72, at a concentration of about 20% w/w. 146 WO 2009/095395 PCT/EP2009/050924
[70] 70. The pharmaceutical composition of claim 63 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable salt of an inorganic acid having an aqueous pH of from about 4.20 to about 4.30 at a concentration of about 10 w/w.
[71] 71. The pharmaceutical composition of claim 63 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable acid salt of an amino acid.
[72] 72. The pharmaceutical composition of claim 63 wherein said at least one stabilizer is selected from the group consisting of potassium metabisulfite, sodium bisulfite, and any combination thereof.
[73] 73. The pharmaceutical compositon of claim 63 wherein said at least one stabilizer, when said stabilizer is present comprises citric acid.
[74] 74. The pharmaceutical composition of claim 60, wherein said stabilizer, when said stabilizer is present, for the second immediate release layer comprises at least one suitable pharmaceutically acceptable phenylated antioxidant.
[75] 75. The pharmaceutical compositon of claim 74 wherein said at least one stabilizer is selected from the group consisting of butlylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and any combination thereof.
[76] 76. The pharmaceutical compositon of claim 60 wherein said at least one stabilizer, when said stabilizer is present, in the first immediate release layer comprises citric acid and said at least one stabilizer, when said stabilizer is present, in the second immediate release layer comprises butylated hydroxytoluene.
[77] 77. The pharmaceutical composition of claim 60, wherein said at least one pharmaceutically acceptable excipient is selected from the group consisting of a binder, a lubricant, a filler, a glidant, and any combination thereof.
[78] 78. The pharmaceutical composition of claim 60, wherein said water-insoluble water permeable film-forming polymer is selected from the group consisting of cellulose ethers, 147 WO 2009/095395 PCT/EP2009/050924 cellulose esters, methacrylic acid derivatives, aqueous ethylcellulose dispersions, aqueous acrylic enteric systems, polyvinyl derivatives, and any combination thereof.
[79] 79. The pharmaceutical composition of claim 60, wherein said water-soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and any combination thereof.
[80] 80. The pharmaceutical composition of claim 60, wherein said at least one plasticizer, when said plastizer is present, comprises a combination of two plasticizers.
[81] 81. The pharmaceutical composition of claim 60, wherein said at least one plasticizer, when said plasticizer is present, is selected from the group consisting of an ester, a polyalkylene glycol and any combination thereof.
[82] 82. The pharmaceutical composition of claim 60, wherein said composition is in the form of a tablet.
[83] 83. The pharmaceutical composition of claim 60, when administered to a subject in need of such administration provides a about 15-25% increase in the bioavailability of bupropion when compared to co-administration of single active agent pharmaceutical compositions of bupropion hydrobromide and citalopram hydrochloride or bupropion hydrobromide and escitalopram oxalate.
[84] 84. The pharmaceutical compositon of claim 62 wherein said bupropion hydrobromide is present at an amount at least about 10% less than a single active agent pharmaceutical composition comprising 348 mg bupropion hydrobromide.
[85] 85. A method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject the pharmaceutical composition of claim 60. 148

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公开号 | 公开日

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IL206487D0|2010-12-30|

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

US4132753A|1965-02-12|1979-01-02|American Cyanamid Company|Process for preparing oral sustained release granules|

---

US4344431A|1969-03-24|1982-08-17|University Of Delaware|Polymeric article for dispensing drugs|

---

US4230687A|1978-05-30|1980-10-28|Griffith Laboratories U.S.A., Inc.|Encapsulation of active agents as microdispersions in homogeneous natural polymeric matrices|

---

CA1146866A|1979-07-05|1983-05-24|Yamanouchi Pharmaceutical Co. Ltd.|Process for the production of sustained releasepharmaceutical composition of solid medicalmaterial|

---

US4346709A|1980-11-10|1982-08-31|Alza Corporation|Drug delivery devices comprising erodible polymer and erosion rate modifier|

---

US4449983A|1982-03-22|1984-05-22|Alza Corporation|Simultaneous delivery of two drugs from unit delivery device|

---

US4455143A|1982-03-22|1984-06-19|Alza Corporation|Osmotic device for dispensing two different medications|

---

US4421736A|1982-05-20|1983-12-20|Merrel Dow Pharmaceuticals Inc.|Sustained release diethylpropion compositions|

---

US4629621A|1984-07-23|1986-12-16|Zetachron, Inc.|Erodible matrix for sustained release bioactive composition|

---

US4601894A|1985-03-29|1986-07-22|Schering Corporation|Controlled release dosage form comprising acetaminophen, pseudoephedrine sulfate and dexbrompheniramine maleate|

---

GB8521350D0|1985-08-28|1985-10-02|Euro Celtique Sa|Analgesic composition|

---

US4764378A|1986-02-10|1988-08-16|Zetachron, Inc.|Buccal drug dosage form|

---

US4662880A|1986-03-14|1987-05-05|Alza Corporation|Pseudoephedrine, brompheniramine therapy|

---

DE3612212A1|1986-04-11|1987-10-15|Basf Ag|METHOD FOR PRODUCING SOLID PHARMACEUTICAL FORMS|

---

GB8613689D0|1986-06-05|1986-07-09|Euro Celtique Sa|Pharmaceutical composition|

---

AT107857T|1986-06-10|1994-07-15|Euro Celtique Sa|COMPOSITION WITH CONTROLLED RELEASE OF DIHYDROCODEIN.|

---

US4861598A|1986-07-18|1989-08-29|Euroceltique, S.A.|Controlled release bases for pharmaceuticals|

---

US4970075A|1986-07-18|1990-11-13|Euroceltique, S.A.|Controlled release bases for pharmaceuticals|

---

GB8626098D0|1986-10-31|1986-12-03|Euro Celtique Sa|Controlled release hydromorphone composition|

---

US4915954A|1987-09-03|1990-04-10|Alza Corporation|Dosage form for delivering a drug at two different rates|

---

US4814181A|1987-09-03|1989-03-21|Alza Corporation|Dosage form comprising fast agent delivery followed by slow agent delivery|

---

US4959208A|1987-10-19|1990-09-25|Ppg Industries, Inc.|Active agent delivery device|

---

JP2681373B2|1988-07-18|1997-11-26|塩野義製薬株式会社|Method for manufacturing sustained-release preparation|

---

DE3830353A1|1988-09-07|1990-03-15|Basf Ag|METHOD FOR THE CONTINUOUS PRODUCTION OF SOLID PHARMACEUTICAL FORMS|

---

US5178868A|1988-10-26|1993-01-12|Kabi Pharmacia Aktiebolaq|Dosage form|

---

US5202128A|1989-01-06|1993-04-13|F. H. Faulding & Co. Limited|Sustained release pharmaceutical composition|

---

US5007790A|1989-04-11|1991-04-16|Depomed Systems, Inc.|Sustained-release oral drug dosage form|

---

US5126145A|1989-04-13|1992-06-30|Upsher Smith Laboratories Inc|Controlled release tablet containing water soluble medicament|

---

EP0418596A3|1989-09-21|1991-10-23|American Cyanamid Company|Controlled release pharmaceutical compositions from spherical granules in tabletted oral dosage unit form|

---

IE65045B1|1990-04-28|1995-10-04|Takeda Chemical Industries Ltd|Granulated preparations and method of producing the same|

---

US5183690A|1990-06-25|1993-02-02|The United States Of America, As Represented By The Secretary Of Agriculture|Starch encapsulation of biologically active agents by a continuous process|

---

DE4031881C2|1990-10-08|1994-02-24|Sanol Arznei Schwarz Gmbh|Solvent-free, oral sustained-release pharmaceutical preparation and process for its preparation|

---

US5403593A|1991-03-04|1995-04-04|Sandoz Ltd.|Melt granulated compositions for preparing sustained release dosage forms|

---

US5273758A|1991-03-18|1993-12-28|Sandoz Ltd.|Directly compressible polyethylene oxide vehicle for preparing therapeutic dosage forms|

---

DE4138513A1|1991-11-23|1993-05-27|Basf Ag|SOLID PHARMACEUTICAL RETARD FORM|

---

US5266331A|1991-11-27|1993-11-30|Euroceltique, S.A.|Controlled release oxycodone compositions|

---

US5681585A|1991-12-24|1997-10-28|Euro-Celtique, S.A.|Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer|

---

US5350584A|1992-06-26|1994-09-27|Merck & Co., Inc.|Spheronization process using charged resins|

---

DE4227385A1|1992-08-19|1994-02-24|Kali Chemie Pharma Gmbh|Pancreatin micropellets|

---

US5891471A|1993-11-23|1999-04-06|Euro-Celtique, S.A.|Pharmaceutical multiparticulates|

---

IL119660A|1993-05-10|2002-09-12|Euro Celtique Sa|Controlled release formulation comprising tramadol|

---

KR100354702B1|1993-11-23|2002-12-28|유로-셀티크 소시에떼 아노뉨|Manufacturing method and sustained release composition of pharmaceutical composition|

---

IT1265074B1|1993-05-18|1996-10-30|Istituto Biochimico Italiano|SLOW-RELEASE PHARMACEUTICAL COMPOSITION CONTAINING A BILIARY ACID AS THE ACTIVE SUBSTANCE|

---

US5567439A|1994-06-14|1996-10-22|Fuisz Technologies Ltd.|Delivery of controlled-release systems|

---

US5476528A|1993-12-20|1995-12-19|Tennessee Valley Authority|System for improving material release profiles|

---

US5395626A|1994-03-23|1995-03-07|Ortho Pharmaceutical Corporation|Multilayered controlled release pharmaceutical dosage form|

---

US5965161A|1994-11-04|1999-10-12|Euro-Celtique, S.A.|Extruded multi-particulates|

---

DK0914097T3|1996-03-12|2002-04-29|Alza Corp|Composition and dosage form comprising opioid antagonist|

---

US5919826A|1996-10-24|1999-07-06|Algos Pharmaceutical Corporation|Method of alleviating pain|

---

ES2248908T7|1997-06-06|2014-11-24|Depomed, Inc.|Dosage forms of drugs orally and gastric retention for continued release of highly soluble drugs|

---

US6306438B1|1997-07-02|2001-10-23|Euro-Celtique, S.A.|Stabilized sustained release tramadol formulations|

---

US6156342A|1998-05-26|2000-12-05|Andex Pharmaceuticals, Inc.|Controlled release oral dosage form|

---

CA2388560A1|1999-08-31|2001-03-08|Grunenthal Gmbh|Sustained-release form of administration containing tramadol saccharinate|

---

US20050112198A1|2003-10-27|2005-05-26|Challapalli Prasad V.|Bupropion formulation for sustained delivery|

---

US20050250838A1|2004-05-04|2005-11-10|Challapalli Prasad V|Formulation for sustained delivery|

---

ZA200711123B|2005-06-27|2009-08-26|Biovail Lab Int Srl|Modified-release formulations of a bupropion salt|

---

ZA200804086B|2005-10-14|2009-07-29|Lundbeck & Co As H|Stable pharmaceutical formulations containing escitalo-pram and bupropion|

---

WO2007053796A2|2005-10-14|2007-05-10|Forest Laboratories, Inc.|Methods of treating central nervous system disorders with a low dose combination of escitalopram and bupropion|

---

ES2627127T3|2006-05-09|2017-07-26|Mallinckrodt Llc|Solid dosage forms of zero-order modified release|PT2271348T|2008-03-28|2018-04-16|Paratek Pharm Innc|Oral tablet formulation of tetracycline compound|

---

PT2389923E|2010-05-19|2013-03-28|Uni Pharma Kleon Tsetis Pharmaceutical Lab S A|Stable ready to use injectable paracetamol formulation|

法律状态:
2013-01-24| MK1| Application lapsed section 142(2)(a) - no request for examination in relevant period|

优先权:

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申请号 | 申请日 | 专利标题

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US2395108P| true| 2008-01-28|2008-01-28||

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US61/023,951||2008-01-28||

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PCT/EP2009/050924|WO2009095395A2|2008-01-28|2009-01-28|Pharmaceutical compositions|

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