Delayed-release formulation for reducing the frequency of urination and method of use thereof

专利摘要:
Methods and compositions for reducing the frequency of urination are disclosed. One method comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an analgesic agent formulated in a delayed-release formulation. Another method comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising multiple active ingredients. Yet another method comprises administering to a subject in need thereof an effective amount of a diuretic followed with another administration of an pharmaceutical composition comprising an analgesic agent.
公开号:AU2012363788A1
申请号:U2012363788
申请日:2012-08-22
公开日:2014-07-17
发明作者:David A. Dill
申请人:Wellesley Pharmaceuticals LLC；
IPC主号:A61K31-192

专利说明:
WO 2013/103389 PCT/US2012/051859 TITLE DELAYED-RELEASE FORM NATION FOR REDUC] ING TH1 E FREQU&JENCY OF URINATION AND METHOD OF USE THEREOF 100011 This application claims the priority from U.S. Patent Application Serial No. 13/487,343, filed on June 4, 2012, U.S. Application Serial No. 13/423,949,. filed on March 19, 2012, and U.S. Patent Application Serial No. 13/343,349, filed on January 4,2012, FIELD 100021 The present application generally relates to methods and compositions for inhibiting the contraction of muscles and, in particular, to methods and compositions for inhibiting the contraction of smooth muscles of the urinary bladder. BACKGROU ND 100031 The detrusor muscle is a layer of the urinary bladder wall made of smooth muscle fibers arranged in spiral, longitudinal, and circular bundles. When the bladder is stretched, this signals the parasympathetic nervous system to contract the detrusor muscle. This encourages the bladder to expel urine through the urethra. 100041 For the urine to exit the bladder, both the autonomically controlled internal sphincter and the voluntarily controlled external sphincter must be opened. Problems with these muscles can lead to incontinence. If the amount of urine reaches 100% of the urinary bladder's absolute capacity, the voluntary sphincter becomes involuntary and the urine will be ejected instantly. 100051 The human adult urinary bladder usually holds about 300-350 ml of urine (the working volume), but a full adult bladder may hold up to about 1000 ml (the absolute volume), varying among individuals, As urine accumulates, the ridges produced by folding of the wall of the bladder (rugae) flatten and the wall of the bladder thins as it stretches, allowing the bladder to store larger amounts of urine without a significant rise in internal pressure. [0006] In most individuals, the desire to urinate usually starts when the volume of urine in the bladder reaches around 200 ml. At this stage it is easy for the subject, if desired, to resist the urge to urinate. As the bladder continues to fill, the desire to urinate becomes stronger and harder to ignore. Eventually, the bladder will fill to the point where the urge to urinate becomes overwhelming, and the subject will no longer be able to ignore it. In some 1 WO 2013/103389 PCT/US2012/051859 individuals, this desire to urinate starts when the bladder is less than 100% full in relation to its working volume. Such increased desire to urinate may interfere with nonnal activities, including the ability to sleep for sufficient uninterrupted periods of rest. In some cases, this increased desire to urinate may be associated with medical conditions such as benign prostate hyperplasia or prostate cancer in men, or pregnancy in women. However, increased desire to urinate also occurs in individuals, both male and female, who are not affected by another medical condition. 100071 Accordingly, there exists a need for compositions and methods for the treatment of male and female subjects who suffer from a desire to urinate when the bladder is less than 100% fill of urine in relation to its working volume. Said compositions and methods are needed for the inhibition of muscle contraction in order to allow in said subjects the desire to urinate to start when the volume of urine in the bladder exceeds around 100% of its working volume. SUMMARY 100081 One aspect of the present application relates to a method for reducing the frequency of urination. In one embodiment, the method comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a first analgesic agent selected from the group consisting of aspirin, ibuprofeni, naproxen sodium, and acetaminophen, wherein the pharmaceutical composition is formulated in a delayed release formulation arid wherein said first analgesic agent is administered orally at a daily dose of 5 mg to 2000 mg. 100091 In another embodiment, the method comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a plurality of active ingredients, wherein the plurality of active ingredients comprises (1) one or more analgesic agents and/or (2) one or more antimuscarinic agents and wherein the one or more analgesic agents are administered orally at a combined daily dose of 5 mg to 2000 mg. In some embodiments, the one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen sodium and acetaminophen. Examples of the antimuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darifenacin, fesoterodine, tolterodine, trospium and atropine. 100101 Another aspect of the present application relates to a pharmaceutical composition, comprising: one or more analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen, and acetaminophen; one or more antidiuretics; and a pharmaceutically acceptable carrier, wherein at least one of said one or more analgesic agents WO 2013/103389 PCT/US2012/051859 is formulated for delayed-release. BRIEF DESCRIPTION OF DRAWINGS [00111 Figure l1A and IB are diagrams showing that analgesies regulate expression of co-stimulatory molecules by Raw 264 macrophage cells in the absence (Figure IA) or presence (Figure 113) of LPS. Cells were cultures for 24 hrs in the presence of analgesic alone or together with Salmonella typhy/urium LPS (0.05 pg/ml). Results are mean relative % of CD40- CD80+ cells. DETAILED DESCRIPTION 100121 The following detailed description is presented to enable any person skilled in the art to make and use the invention. For purposes of explanation, specific nomenclature is set forth to provide a thorough understanding of the present invention. However, it will be apparent to one skilled in the art that these specific details are riot required to practice the invention. Descriptions of specific applications are provided only as representative examples. The present invention is not intended to be limited to the embodiments shown, but is to be accorded the broadest possible scope consistent with the principles and features disclosed herein. 100131 As used herein, the term "effective amount" means an amount necessary to achieve a selected result. 100141 As used herein, the term "analgesic" refers to agents, compounds or drugs used to relieve pain and inclusive of anti-inflamrmatory compounds. Exemplary analgesic and/or anti-inflamrnmatory agents, compounds or drugs include, but are not limited to, the following substances: non-steroidal anti-inflammatory drugs (NSAIDs), salicylates, aspirin, salicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, para aminophenol derivatives, acetanilide, acetaminophen, phenacetin, fenamates, mefenamic acid, meclofenamate, sodium meclofenamate, heteroaryl acetic acid derivatives, tolmetin, ketorolac, diclofenac, propionic acid derivatives, ibuprofen, naproxen sodium, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin; enolic acids, oxicam derivatives, piroxicam, meloxicamn, tenoxicam, amnpiroxicam, droxicamn, pivoxicam, pyrazolon derivatives, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, dipyrone, coxibs, celecoxib, rofecoxib, nabumetone, apazone, indomethacin, sulindac, etodolac, isobutylphenyl propionic acid, lumiracoxib, etoricoxib, parecoxib, valdecoxib, tiracoxib, etodolac, darbufelone, dexketoprofen, aceclofenac. licofelone, bromfenac, pranoprofen, loxoprofen, piroxicam, nimesulide, cizolirine, 3-formylamino-7-methylsulfonvlamino-6-phenoxy-4H-1-I -benzopyran 3 WO 2013/103389 PCT/US2012/051859 4-one, meloxicam, lomoxicam, d-indobufen, mofezolac, amtolmetin, pranoprofen, tolfenamic acid, flurbiprofen, suprofen, oxaprozin, zaltoprofen, alminoprofen, tiaprofenic acid, pharmacological salts thereof, hydrates thereof, and solvates thereof. 100151 As used herein, the terms "coxib" and "COX inhibitor" refer to a composition of compounds that is capable of inhibiting the activity or expression of CO)X2 enzymes or is capable of inhibiting or reducing the severity, including pain and swelling, of a severe inflammatory response. 100161 The urinary bladder has two important functions: storage of urine and emptying. Storage of urine occurs at low pressure, which implies that the detrusor niuscle relaxes during the filling phase. Emptying of the bladder requires a coordinated contraction of the detrusor muscle and relaxation of the sphincter muscles of the urethra. Disturbances of the storage function may result in lower urinary tract symptoms, such as urgency, frequency, and urge incontinence, the components of the overactive bladder syndrome. The overactive bladder syndrome, which may be due to involuntary contractions of the smooth muscle of the bladder (detrusor) during the storage phase, is a common and underreported problem, the prevalence of which has only recently been assessed. 100171 One aspect of the present application relates to a method for reducing the frequency of urination by administering to a person in need thereof a pharmaceutical composition formulated in a delayed-release formulation. The pharmaceutical composition comprises one or more analgesic agents and, optionally, one or more antimuscarinic agents. 100181 As used herein, the term "delayed-release" refers to a medication that does not immediately disintegrate and release the active ingredient(s) into the body. In some embodiments, the term "delayed-release" is used with reference to a drug formulation having a release profile in which there is a predetermined delay in the release of the drug following administration. In some embodiments, the delayed-release formulation includes an enteric coating, which is a barrier applied to oral medication that prevents release of medication before it reaches the small intestine. Delayed-release formulations, such as enteric coatings, prevent drugs having an irritant effect on the stomach, such as aspirin, from dissolving in the stomach. Such coatings are also used to protect acid-unstable drugs from the stomach's acidic exposure, delivering them instead to a basic p-I environment (intestine's pH 5.5 and above) where they do not degrade, and give their desired action. 100191 The term "pulsatile release" is a type of delayed-release, which is used herein with reference to a drug formulation that provides rapid and transient release of the drug within a short time period immediately after a predetermined lag period, thereby producing a 4 WO 2013/103389 PCT/US2012/051859 "pulsed" plasma profile of the drug after drug administration. Formulations may be designed to provide a single pulsatile release or multiple pulsatile releases at predetermined time intervals following administration. 100201 Most enteric coatings work by presenting a surface that is stable at the highly acidic p-I found in the stomach, but breaks down rapidly at a less acidic (relatively more basic) pH. Therefore, an enteric coated pill will not dissolve in the acidic juices of the stomach (p-I -3), but they will in the alkaline (piH 7-9) environment present in the small intestine, Examples of enteric coating materials include, but are not limited to, methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methaerylate-rnethacrylic acid copolymers, sodium alginate and stearic acid. 100211 In some embodiments, the pharmaceutical composition is orally administered from a variety of drug formulations designed to provide delayed-release. Delayed oral dosage forms include, for example, tablets, capsules, caplets, and may also comprise a plurality of granules, beads, powders or pellets that may or may not be encapsulated. Tablets and capsules represent the most convenient oral dosage forms, in which case solid pharmaceutical carriers are employed. 100221 In a delayed-release formulation, one or more barrier coatings may be applied to pellets, tablets, or capsules to facilitate slow dissolution and concomitant release of drugs into the intestine. Typically, the barrier coating contains one or more polymers encasing, surrounding, or forming a layer, or membrane around the therapeutic composition or active core. 100231 In some embodiments, the active agents are delivered in a formulation to provide delayed-release at a pre-determined time following administration. The delay may be up to about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, or longer. 100241 A delayed-release composition may comprise 100% of the total dosage of a given active agent administered in a single unit dose. Alternatively, a delayed-release composition may be included as a component in a combined release profile formulation may provide about 30-95% of the total dosage of the active agent(s) to be delivered by the pharmaceutical formulation. For example, the immediate-release component may provide about 5-70%, or about 50% of the total dosage of the active agent(s) to be delivered by the pharmaceutical formulation. In alternate embodiments, the delayed-release component 5 WO 2013/103389 PCT/US2012/051859 provides about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95% of the total dosage of the active agents) to be delivered by the formulation, 100251 A delayed-release formulation typically comprises a barrier coating that delays the release of the active ingredient(s). The barrier coating may consist of a variety of different materials, depending on the objective. In addition, a formulation may comprise a plurality of barrier coatings to facilitate release in a temporal manner. The coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methyleellul ose, methyleellulose, methyl hydroxyethylcellulose, hydroxypropyicellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or a coating based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methyicellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose. Furthermore, the formulation may additionally include a time delay material such as, for example, glyceryl monostearate or glyceryl distearate. 100261 In some embodiments, the delayed-release formulation includes an enteric coating comprised one or more polymers facilitating release of active agents in proximal or distal regions of the gastrointestinal tract. As used herein, the term "enteric polymer coating" a coating comprising of one or more polymers having a pH dependent or pH-independent release profile. Typically the coating resists dissolution in the acidic medium of the stomach, but dissolves or erodes in more distal regions of the gastrointestinal tract, such as the small intestine or colon, An enteric polymer coating typically resists releases of the active agents until some time after a gastric emptying lag period of about 3-4 hours after administration. 100271 pH dependent enteric coatings comprising one or more pH-dependent or pH sensitive polymers that maintain their structural integrity at low p1, as in the stomach, but dissolve in higher pH environments in more distal regions of the gastrointestinal tract, such as the small intestine, where the drug contents are released. For purposes of the present invention, "pH dependent" is defined as having characteristics (e.g., dissolution) which vary according to environmental p1. Exemplary p1:1-dependent polymers include, but are not limited to, methacarylic acid copolymers, methacrylic acid-methyl methacrylate copolymers (e.g., EUDRAGIT* [100 (Type A), EUDRAGIT* S100 (Type B), Rohm GmbH, Germany; methacrylic acid-ethyl acrylate copolymers (e.g., EUDRAG IT" LI 00-55 (Type C) and EUDRAGIT* L3OD-55 copolymer dispersion, Rohm GmbH, Germany); copolymers of methacrylic acid-methyl methacrylate and methyl methacrylate (EUDRAGIT *' FS) terpolymers of methacrylic acid, methacrylate, and ethyl acrylate; cellulose acetate phthalates (CAP); hydroxypropyl methylcellulose phthalate (HPMCP) (e.g., HP-55, HP-50, HP-55S, 6 WO 2013/103389 PCT/US2012/051859 Shinetsu Chemical, Japan); polyvinyl acetate phthalates (PVAP) (e.g., COATERIC", OPADRY enteric white OY-P-7171); cellulose acetate succinates (CAS); hydroxypropyl methylcellulose acetate succinate (HIPMCAS), e.g., HPMCAS LF Grade, MF Grade, HF Grade, including AQOAT* LF and AQOAT* MF (Shin-Etsu Chemical, Japan); Shinetsu Chemical, Japan); shellac (e.g., MarcoatTMl 125 & MarcoatTM 125N); carboxymethyl ethylcellulose (CMEC, Freund Corporation, Japan), cellulose acetate phthalates (CAP)(e.g., AQUATER IC"); cellulose acetate trimellitates (CAT); and mixtures of two or more thereof at weight ratios between about 2:1 to about 5:1, such as, for instance, a mixture of EUDRAGIT* L 100-55 and EUDRAGIT* S 100 at a weight ratio of about 3:1 to about 2:1, or a mixture of EUDRAGIT* L 30 D-55 and EUDRAGIT* FS at a weight ratio of about 3:1 to about 5:1. 100281 pH-dependent polymers typically exhibit a characteristic pH optimum for dissolution. In some embodiments, the pH-dependent polymer exhibits a pH optimum between about 5.0 and 5.5, between about 5.5 and 6.0, between about 6.0 and 6.5, or between about 6.5 and 7.0. In other embodiments, the pH-dependent polymer exhibits a pH optimum of >5.0, of >5.5, of >6.0, of >6.5, or of >7.0. 100291 In other embodiments, the enteric coating may comprise one or more pH independent polymers. These polymers provide for release of the drug after a certain time, independent of the pH. For purposes of the present invention, "pH independent" is defined as having characteristics (e.g., dissolution) which are substantially unaffected by pH, pH] independent polymers are often referred to in the context of "time-controlled" or "time dependent" release profiles. 100301 A p-I independent polymer may be water-insoluble or water soluble. Exemplary water insoluble pH independent polymers include, but are not limited to, neutral methacrylic acid esters with a small portion of trimethylammonioethyl methacrylate chloride (e.g., EUDRAGIT*R RS and EUDRAGIT* RL; neutral ester dispersions without any functional groups (e.g., EUDRAGIT* NE30D and EUDRAGIT* N E30); cellulosic polymers, such as ethylcellulose, hydroxyl ethyl cellulose, cellulose acetate or mixtures and other pH independent coating products. Exemplary water soluble p-I independent polymers include OPADRY amb. 100311 In some embodiments, the pH independent polymers contain one or more polysaccharides that are resistant to erosion in both the stomach and intestine, Such polymers can be only degraded in the colon, which contains a large microflora containing biodegradable enzymes breaking down, for example, the polysaccharide coatings to release WO 2013/103389 PCT/US2012/051859 the drug contents in a controlled, time-dependent manner. 100321 In certain embodiment, the coating methodology employs the blending of one or more pH-dependent and one or more pH-independent polymers. The blending of pH dependent and p1-i-independent polymers can reduce the release rate of active ingredients once the soluble polymer has reached its optimum p1-i of solubilization. 100331 In some embodiments, a "time-controlled" or "time-dependent" release profile can be obtained using a water insohible capsule body containing one or more active agents, wherein the capsule body closed at one end with an insoluble, but permeable and sellable hydrogel plug. Upon contact with gastrointestinal fluid or dissolution medium, the plug swells, pushing itself out of the capsule and releasing the drugs after a pre-determined lag time, which can be controlled by e.g., the position and dimensions of the plug. The capsule body may be further coated with an outer pH-dependent enteric coating keeping the capsule intact until it reaches the small intestine. Suitable plug materials include, for example, polymethacrylates, erodible compressed polymers (e.g., HPMC, polyvinyl alcohol), congealed melted polymer (e.g., glyceryl mono oleate) and enzymatically controlled erodible polymers (e.g., polysaccharides, such as amylose, arabinogalactan, chitosan, chondroitin sulfate, cyclodextrin, dextran, guar gum, pectin and xylan). 100341 In other embodiments, capsules or bilayered tablets may be formulated to contain a drug-containing core, covered by a swelling layer, and an outer insoluble, but semi permeable polymer coating or membrane. The lag time prior to rupture can be controlled by the permeation and mechanical properties of the polymer coating and the swelling behavior of the swelling layer. Typically, the swelling layer comprises one or more swelling agents, such as swel[able hydrophilic polymers that swell and retain water in their structures. 100351 Exemplary water swellable materials include, but are not limited to, polyethylene oxide (having e.g., an average molecular weight between 1,000,000 to 7,000,000, such as POLYOX"), methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose; polvalkylene oxides having a weight average molecular weight of 100,000 to 6,000,000, including but not limited to poly(methylene oxide), poly(butylene oxide); poly(hydroxy alkyl methacrylate) having a molecular weight of from 25,000 to 5,000,000; poly(vinyl)alcohol, having a low acetal residue, which is cross-linked with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization of from 200 to 30,000; mixtures of methyl cellulose, cross-linked agar and carboxymethyl cellulose; hydrogel forming copolymers produced by forming a dispersion of a finely divided copolymer of mbaleic anhydride with styrene, ethylene, propylene, butylene or isobutylene 8 WO 2013/103389 PCT/US2012/051859 cross-linked with from 0.001 to 0.5 moles of saturated cross-linking agent per mole of maleic anyhydride in the copoly mer; CARBOPOL* acidic carboxy polymers having a molecular weight of 450,000 to 4,000,000; CYANAMER* polyacrylamides; cross-linked water swellable indenemaleicanhydride polymers; GOODRITE * polyacrylic acid having a molecular weight of 80,000 to 200,000; starch graft copolymers; AQUA-KEEPS' acrylate polymer polysaccharides composed of condensed glucose units such as diester cross-linked polyglucan; carbomers having a viscosity of 3,000 to 60,000 mPa as a 0.5%-t1 w/v aqueous solution; cellulose ethers such as hydroxypropylcellulose having a viscosity of about 1000 7000 mPa s as a 1% w/w aqueous solution (25" C); hydroxypropyl methylcellulose having a viscosity of about 1000 or higher, preferably 2,500 or higher to a maximum of 25,000 mPa as a 2% w/v aqueous solution; polyvinylpyrrolidone having a viscosity of about 300-700 mPa s as a 10% w/v aqueous solution at 200 C: and combinations thereof. 100361 The enteric layer may further comprise anti-tackiness agents, such as tale or glyceryl monostearate and/or plasticizers such as. The enteric layer may further comprise one or more plasticizers including, but not limited to, triethyl citrate, acetyl triethyl cirate, acetyltributyl citrate, polyethylene glycol acetylated monoglycerides, glycerin, triacetin, propylene glycoi, phthalate esters (e.g., diethyl phthalate, dibutyl phthalate), titanium dioxide, ferric oxides, castor oil, sorbitol and dibutyl sebacate. 100371 In another embodiment, the delay release formulation employs a water permeable but insoluble film coating to enclose the active ingredient and an osmotic agent utilizing a enclosing. As water from the gut slowly diffuses through the film into the core, the core swells until the film bursts, thereby releasing the active ingredients. The film coating may be adjusted to permit various rates of water permeation or release time. 100381 Alternatively, the release time of the drugs can be controlled by a disintegration lag time depending on the balance between the tolerability and thickness of a water insoluble polymer membrane (such as ethyl cellulose, EC) containing predefined micropores at the bottom of the body and the amount of a swellable excipient, such as low substituted hydroxypropyl cellulose (L-HPC) and sodium glycolate. After oral administration, GI fluids permeate through the micropores, causing swelling of the swellable excipients, which produces an inner pressure disengaging the capsular components, including a first capsule body containing the swellable materials, a second capsule body containing the drugs, and an outer cap attached to the first capsule body. 100391 In other embodiments, the drugs may be released by an osmotic mechanism. By way of example, a capsule may be formulated with a single osmotic unit or it may 9 WO 2013/103389 PCT/US2012/051859 incorporate 2, 3, 4, 5, or 6 push-pull units encapsulated within a hard gelatin capsule, whereby each bilayer push pull unit contains an osmotic push layer and a drug layer, both surrounded by a semi-permeable membrane. One or more orifices are drilled through the membrane next to the drug layer. This membrane may be additionally covered with a p-i dependent enteric coating to prevent release until after gastric emptying. The gelatin capsule dissolves immediately after ingestion. As the push pull unit(s) enter the small intestine, the enteric coating breaks down, which then allows fluid to flow through the semi-penneable membrane, swelling the osmotic push compartment to force to force drugs out through the orifice(s) at a rate precisely controlled by the rate of water transport through the semi permeable membrane. Release of drugs can occur over a constant rate for up to 24 hours or more. 100401 The osmotic push layer comprises one or more osmotic agents creating the driving force for transport of water through the semi-permeable membrane into the core of the delivery vehicle. One class of osmotic agents includes water-swellable hydrophilic polymers, also referred to as "osmopolymers" and "hydrogels," including, but not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2 hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PIVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, iVAIPVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC). hydroxypropyl methyl cellulose (1-HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate. [0041] Another class of osmotic agents includes osmogens, which are capable of imbibing water to effect an osmotic pressure gradient across the semi-permeable membrane. Exemplary osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartari acid; urea; and mixtures thereof, 10 WO 2013/103389 PCT/US2012/051859 100421 Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking, 100431 In another embodiment, the delay release formulation employs a water impermeable tablet coating whereby water enters through a controlled aperture in the coating until the core bursts, When the tablet bursts, the drug contents are released immediately or over a longer period of time. These and other techniques may be modified to allow for a pre determined lag period before release of drugs is initiated, 100441 Various coating techniques may be applied to granules, beads, powders or pellets, tablets, capsules or combinations thereof containing active agents to produce different and distinct release profiles. In some embodiments, the pharmaceutical composition is in a tablet or capsule form containing a single coating layer. In other embodiments, the pharmaceutical composition is in a tablet or capsule form containing multiple coating layers. 100451 In some embodiments, the pharmaceutical composition comprises a plurality of active ingredients selected from the group consisting of analgesics, antimuscarinic agents, antidiuretics and spasmolytics. Examples of spasmolytics include, but are not limited to, carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, methocarbamol, clonidine, clonidine analog, and dantrolene. In some embodiments, the phannaceutical composition comprises one or more analgesics, In other embodiments, the pharmaceutical composition comprises (1) one or more analgesics, and (2) one or more other active ingredients selected from the group consisting of antimuscarinic agents, antidiuretics and spasmolytics, In another embodiment, the pharmaceutical composition comprises (1) one or two analgesics and (2) one or two antimuscarinic agents. In another embodiment, the pharmaceutical composition comprises (1) one or two analgesics and (2) one or two antidiuretics, In another embodiment, the pharmaceutical composition comprises (1) one or two analgesics and (2) one or two spasmolytics, In yet another embodiment, the pharmaceutical composition comprises (1) one or two analgesics, (2) one or two antimuscarinic agents, and (3) one or two antidiuretics. [0046] In one embodiment, the plurality of active ingredients are formulated for immediate-release, In other embodiment, the plurality of active ingredients are formulated for delayed-release. In other embodiment, the plurality of active ingredients are formulated for both immediate-release and delayed-release (e.g., a first portion of each active ingredient is formulated for immediate-release and a second portion of each active ingredient is
II
WO 2013/103389 PCT/US2012/051859 formulated for delayed-release). In yet other embodiment, some of the plurality of active ingredients are formulated for immediate-release and some of the plurality of active ingredients are formulated for delayed-release (e.g., active ingredients A, B, C are formulated for immediate-release and active ingredients C and D are formulated for delayed release). 100471 In certain embodiments, the pharmaceutical composition comprises an immediate-release component and a delayed-release component. The immediate-release component may comprise one or more active ingredients selected from the group consisting of analgesics, antimuscarinic agents, antidi uretics and spasmolytics.. The delayed-release component may comprise one or more active ingredients selected from the group consisting of analgesics, antimuscarinic agents, antidiuretics and spasmolytics.. In some embodiments, the imnmediate-release component and the delayed-release component have exactly the same active ingredients. In other embodiments, the immediate-release component and the delayed release component have different active ingredients. In yet other embodiments, the immediate-release component and the delayed-release component have one or more common active ingredients. 100481 In one embodiment, the pharmaceutical composition comprises two active ingredients (e.g., two analgesic agents, or a mixture of one analgesic agent and one antimuscarinic agent or antiuretic or spasmolytic), formulated for immediate-release at about the same time. In another embodiment, the pharmaceutical composition comprises two active ingredients, formulated for delayed-release at about the same time. In another embodiment, the pharmaceutical composition comprises two active ingredients formulated as two delayed release components, each providing a different delayed-release profile. For example, a first delayed-release com ponent releases a first active ingredient at a first time point and a second delayed-release component releases a second active ingredient at a second time point. In another embodiment, the pharmaceutical composition comprises two active ingredients, one is formulated for immediate-release and the other is formulated for delayed-release. 100491 In other embodiments, the pharmaceutical composition comprises two active ingredients (e.g., two analgesic agents, or a mixture of one analgesic agent and one antimuscarinic agent or antiuretic or spasmolytic) formulated for immediate-release, and (2) two active ingredients (e.g., two analgesic agents, or a mixture of one analgesic agent and one antimuscarinic agent or antiuretic or spasmolytic) formulated for delayed-release. In other embodiments, the pharmaceutical composition comprises three active ingredients formulated for innediate-release, and (2) three active ingredients formulated for delayed-release. In 12 WO 2013/103389 PCT/US2012/051859 other embodiments, the pharmaceutical composition comprises four active ingredients formulated for inunediate-release, and (2) four active ingredients fornulated for delayed release. In these embodiments, the active ingredient(s) in the immediate-release component can be the same as, or different from, the active ingredients) in the delayed-release component. 100501 The term "immediate-release" is used herein with reference to a drug formulation that does not contain a dissolution rate controlling material. There is substantially no delay in the release of the active agents following administration of an immediate-release formulation. An immediate-release coating may include suitable materials immediately dissolving following administration so as to release the drug contents therein. Exemplary inniediate-release coating materials include gelatin, polyvinyl alcohol polyethylene glycol (PVA-PEG) copolymers (e.g., KOLLICOAT*) and various others materials known to those skilled in the art. 100511 An immediate-release composition may comprise 100% of the total dosage of a given active agent administered in a single unit dose. Alternatively, an immediate-release component may be included as a component in a combined release profile formulation that may provide about 1% to about 50% of the total dosage of the active agent(s) to be delivered by the pharmaceutical formulation, For example, the immediate-release component may provide at least about 5%, or about 10% to about 30%, or about 45% to about 50% of the total dosage of the active agent(s) to be delivered by the formulation. The rest of the active agents) may be delivered in a delayed-release formulation. in alternate embodiments, the immediate-release component provides about 10, 15, 20, 25, 30, 35, 40, 45 or 50% of the total dosage of the active agent(s) to be delivered by the formulation. The delayed-release component provides about 90, 85, 80, 75, 70, 65, 60, 55 or 50% of the total dosage of the active agent(s) to be delivered by the formulation. 100521 In some embodiments, the inmediate-release or delayed-release formulation comprises an active core comprised of one or more inert particles, each in the form of a bead, pellet, pill, granular particle, microcapsule, microsphere, microgranule, nanocapsule, or nanosphere coated on its surfaces with drugs in the form of e.g., a drug-containing film forming composition using, for example, fluid bed techniques or other methodologies known to those of skill in the art. The inert particle can be of various sizes, so long as it is large enough to remain poorly dissolved. Alternatively, the active core may be prepared by granulating and milling and/or by extrusion and spheronization of a polymer composition containing the drug substance, 13 WO 2013/103389 PCT/US2012/051859 100531 The amount of drug in the core will depend on the dose that is required, and typically varies from about 5 to 90 weight %. Generally, the polymeric coating on the active core will be from about 1 to 50% based on the weight of the coated particle, depending on the lag time and type of release profile required and/or the polymers and coating solvents chosen. Those skilled in the art will be able to select an appropriate amount of drug for coating onto or incorporating into the core to achieve the desired dosage. In one embodiment, the inactive core may be a sugar sphere or a buffer crystal or an encapsulated buffer crystal such as calcium carbonate, sodium bicarbonate, fumaric acid., tartaric acid., etc. which alters the microernvironient of the drug to facilitate its release. 100541 In some embodiments, the delayed-release formulation is formed by coating a water soluble/dispersible drug-containing particle, such as a bead, with a mixture of a water insoluble polymer and an enteric polymer, wherein the water insoluble polymer and the enteric polymer may be present at a weight ratio of from 4:1 to 1:1, and the total weight of the coatings is 10 to 60 weight % based on the total weight of the coated beads, The drug layered beads may optionally include an inner dissolution rate controlling membrane of ethyleellulose. The composition of the outer layer, as well as the individual weights of the inner and outer layers of the polymeric membrane are optimized for achieving desired circadian rhythm release profiles for a given active, which are predicted based on in vitro/in viVo correlations. 100551 In other embodiments the formulations comprise a mixture of immediate release drug-containing particles without a dissolution rate controlling polymer membrane and delayed-release beads exhibiting, for example, a lag time of 2-4 hours following oral administration, thus providing a two-pulse release profile. In yet other embodiments the formulations comprise a mixture of two types of delayed-release beads: a first type that exhibits a lag time of 1-3 hours and a second type that exhibits a lag time of 4-6 hours. 100561 In some embodiments, the active core is coated with one or more layers of dissolution rate-controlling polymers to obtain desired release profiles with or without a lag time. An inner layer membrane can largely control the rate of drug release following imbibition of water or body fluids into the core, while the outer layer membrane can provide for a desired lag time (the period of no or little drug release following imbibition of water or body fluids into the core). The inner layer membrane may comprise a water insoluble polymer, or a mixture of water insoluble and water soluble polymers. 100571 The polymers suitable for the outer membrane, which largely controls the lag time of up to 6 hours may comprise an enteric polymer, as described above, and a water 14 WO 2013/103389 PCT/US2012/051859 insoluble polymer at 10 to 50 weight %. The ratio of water insoluble polymer to enteric polymer may vary from 4:1 to 1:2, preferably the polymers are present at a ratio of about 1:1. The water insoluble polymer typically used is ethylcellulose. 100581 Exemplary water insoluble polymers include ethyicellulose, polyvinyl acetate (Kollicoat SR#0D from BASF), neutral copolymers based on ethyl acrylate and methylmethaciylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups such as EUDRAGIT* NE, RS and RS3OD, RL or RL3OD and the like. Exemplary water soluble polymers include low molecular weight HPMC, HPC, methylcellulose, polyethylene glycol (PEG of molecular weight>3000) at a thickness ranging from I weight % up to 10 weight % depending on the solubility of the active in water and the solvent or latex suspension based coating fornulation used. The water insoluble polymer to water soluble polymer may typically vary from 95:5 to 60:40, preferably from 80:20 to 65:35. 100591 Preferably, the formulations are designed with release profiles to limit interference with restful sleep, wherein the formulation releases the medicine when the individual would normally be awakened by an urge to urinate. For example, consider an individual who begins sleeping at II PM and is normally awakened at 12:30 AM, 3:00 AM, and 6:00 AM to urinate. A delayed-release vehicle could deliver the medicine at 12:15 AM, thereby delaying the need to urinate for perhaps 2-3 hours. 100601 The pharmaceutical composition may be administered daily or administered on an as needed basis. In certain embodiments, the pharmaceutical composition is administered to the subject prior to bedtime. In some embodiments, the pharmaceutical composition is administered immediately before bedtime. In some embodiments, the pharmaceutical composition is administered within about two hours before bedtime, preferably within about one hour before bedtime. In another embodiment, the pharmaceutical composition is administered about two hours before bedtime. In a further embodiment, the pharmaceutical composition is administered at least two hours before bedtime. In another embodiment, the pharmaceutical composition is administered about one hour before bedtime. In a further embodiment, the pharmaceutical composition is administered at least one hour before bedtime. In a still further embodiment, the phannaceutical composition is administered less than one hour before bedtime. In still another embodiment, the pharmaceutical composition is administered immediately before bedtime. Preferably, the pharmaceutical composition is administered orally. 100611 The appropriate dosage ("therapeutically effective amount") of the active agent(s) in the immediate-component or delayed-release component will depend, for 15 WO 2013/103389 PCT/US2012/051859 example, the severity and course of the condition, the mode of administration, the bioavailability of the particular agent(s), the age and weight of the patient, the patient's clinical history and response to the active agent(s), discretion of the physician, etc. 100621 As a general proposition, the therapeutically effective amount of the active agent(s) in the immediate-release component or the delayed-release component is administered in the range of about 100 pg/kg body weight/day to about 100 mg/kg body weight/day whether by one or more administrations. In some embodiments, the range of each active agent administered daily is from about 100 pg/kg body weight/day to about 50 mg/kg body weight/day, 100 pg/kg body weight/day to about 10 mg/kg body weight/day, 100 pAg/kg body weight/day to about I mg/kg body weight/day, 100 pag/kg body weight/day to about 10 mg/kg body weight/day, 500 pg/kg body weight/day to about 100 mg/kg body weight/day, 500 pg/kg body weight/day to about 50 mg/kg body weight/day, 500 pg/kg body weight/ day to about 5 mg/kg body weight/ day, 1 mg/kg body weight/day to about 100 mg/kg body weight/day, 1 mg/kg body weight/day to about 50 mg/kg body weight/ day,I mg/kg body weight/day to about 10 mg/kg body weight/day, 5 mg/kg body weight/dose to about 100 mg/kg body weight/day, 5 mug/kg body weight/dose to about 50 mg/kg body weight/day, 10 mg/kg body weight/day to about 100 mg/kg body weight/day, and 10 mg/kg body weight/day to about 50 mg/kg body weight/day. 100631 The active agent(s) described herein may be included in an immediate-release component or a delayed-release component or combinations thereof for daily oral administration at a single dose or combined dose range of I mg to 2000 mg, 5 mg to 2000 mg, 10 mg to 2000 mg, 50 mg to 2000 mg, 100 mg to 2000 mg, 200 mg to 2000 mg, 500 mg to 2000 mg, 5 mg to 1800 mg. 10 mg to 1600 mg. 50 mg to 1600 mg, 100 mg to 1500 mg, 150 mg to 1200 mg, 200 mg to 1000 mg, 300 mg to 800 mg, 325 mg to 500 mg, I mg to 1000 mg, I mg to 500 mg. 1 mg to 200 mg, 5 mg to 1000 mg, 5 mg to 500 mg, 5 mg to 200 mg, 10 mg to 1000 mg, 10 mg to 500 mg, 10 mg to 200 mg, 50 mg to 1000 mg, 50 mg to 500 mg, 50 mg to 200 img, 100 mg to 250 mg, 100 mg to 500 mg, 250 mg to 1000 img, 250 mg to 500 mg, 500 mg to 1000 mg, 500 mg to 2000 mg. As expected, the dosage will be dependant on the condition, size, age and condition of the patient. [0064] In some embodiments, the pharmaceutical composition comprises a single analgesic agent. In one embodiment, the single analgesic agent is aspirin. In another embodiment, the single analgesic agent is ibuprofen. In another embodiment, the single analgesic agent is naproxen sodium. In another embodiment, the single analgesic agent is indomethacin. In another embodiment, the single analgesic agent is nabumetone. In another 16 WO 2013/103389 PCT/US2012/051859 embodiment, the single analgesic agent is acetaminophen. 100651 In some embodiments, the single analgesic agent is given at a daily dose of I mg to 2000 mg, 5 mg to 2000 mg, 20 mg to 2000 mg, 5 mg to 1000 mg, 20 mg to 1000 mg, 50 Ig to 500 mg, 100 mg to 500 ig, 250 Ig to 500 ig, 250 Ig to 1000 Ig or 500 mg to 1000 mg. In certain embodiments, the pharmaceutical composition comprises acetylsalicylic acid, ibuprofen, naproxen sodium, indomethancin, nabumetone or acetaminophen as a single analgesic agent and the analgesic agent is administered orally at a daily dose in the range of 5 mg to 2000 mg, 20 mg to 2000 mg, 5 mg to 1000 mg, 20 mg to 1000 mg, 50 mg to 500 mg, 100 mg to 500 Ig, 250 Ig to 500 mg, 250 Ig to 1000 Ig or 500 mg to 1000 mg. In some embodiments, a second analgesic agent is given at a daily dose of mg to 2000 mg, 5 mg to 2000 ig, 20 rug to 2000 tng, 5 mg to 1000 rmg, 20 mg to 1000 rmg, 50 mg to 500 mg, 100 mg to 500 mg, 1250 mg to 500 mg, 250 mg to 1000 mg or 500 mg to 1000 mg. 100661 In other embodiments, the phanraceutical composition comprises a pair of analgesic agents. Examples of such paired analgesic agents include, but are not limited to, acetylsalicylic acid and ibuprofen, acetylsalicylic acid and naproxen sodium, acetylsalicylic acid and nabumetone, acetylsalicylic acid and acetaminophen, acetylsalicylic acid and indomethancin, ibuprofen and naproxen sodium, ibuprofen and nabumetone, ibuprofen and acetaminophen, ibuprofen and indomethancii, naproxen sodium and nabumetone, naproxen sodium and acetaminophen, naproxen sodium and indomethancin, nabumetone and acetaminophen, nabutrietorie and indomethancin, and acetaminophen and indotriethancin. The paired analgesic agents are mixed at a weight ratio in the range of 0.1:1 to 10:1, 0.2:1 to 5:1 or 0.3:1 to 3:1, with a combined dose in the range of 5 mg to 2000 mg, 20 mg to 2000 mg, 100 tug to 2000 tug, 200 tug to 2000 mg, 500 mg to 2000 mg, 5 tug to 1500 tug, 20 mg to 1500 mg, 100 mg to 1500 mg, 200 mg to 1500 mg, 500 mg to 1500 mg, 5 mg to 1000 mg, 20 mg to 1000 mg, 100 mg to 1000 mg, 250 mg to 500 mg, 250 mg to 1000 mg, 250 mg to 1500 mg, 500 mg to 1000 mg, 500 mg to 1500 mg, 1000 mg to 1500 mg, and 1000 mg to 2000 mg. In one emribodirient, the paired analgesic agents are mixed at a weight ratio of 1:1, 100671 In some other embodiments, the pharmaceutical composition of the present application further comprises one or more antimuscarinic agents. Examples of the antitnuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darifenacm, fesoterodine, tolterodine, trospium and atropine. The daily dose of antimuscarinic agent is in the range of 0.01 tug to 100 mg, 0.1 mg to 100 mg. I mg to 100 tug, 10 mg to 100 tmg, 0.01 mg to 25 mg, 0.1 mg to 25 mg, I mg to 25 mg, 10 mg to 25 mg, 0.01 mg to 10 mg, 0.1 mg to 10 rmg, 1 mg to 10 mg, 10 Ig to 100 ig and 10 Ig to 25 tng. 17 WO 2013/103389 PCT/US2012/051859 100681 Another aspect of the present application relates to a method for reducing the frequency of urination by administering to a person in need thereof a pharmaceutical composition formulated in an immediate-release formulation. In some embodiments, the pharmaceutical composition comprises one or more analgesic agents and one or more antimuscarinic agents. In other embodiments, the pharmaceutical composition comprises one or more analgesic agents and one or more antidiuretic agents. In yet other embodiments, the pharmaceutical composition comprises one or more analgesic agents, one or more antimuscarinic agents. and one or more antidiuretic agents. 100691 In other embodiments, the pharmaceutical composition of the present application ftirther comprises one or more spasmolytics. Examples of spasmolytics include, but are not limited to, carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, methocarbamol, clonidine, clonidine analog, and dantrolene. In some embodiments, the spasmolytics is used at a daily dose of 1 mg to 1000 mg, I mg to 100 mg. 10 mg to 1000 mg, 10 mg to 100 mug, 20 mg to 1000 mug, 20 mg to 800 mg, 20 mg to 500 mg, 20 mg to 200 mg, 50 mg to 1000 mg, 50 mg to 800 mg. 50 mg to 200 mg, 100 mg to 800 mg, 100 mg to 500 mg, 200 mg to 800 mg, and 200 mg to 500 mg. The spasmolytics may be formulated, alone or together with other active ingredient(s) in the pharmaceutical composition, for immediate release, delayed-extended release or combinations thereof. 100701 In certain embodiments, the pharmaceutical composition comprises two or more analgesic agents. In other embodiments, the pharmaceutical composition comprises one or more analgesic agents and one or more antimuscarinic agents and/or antidiuretic agents. The pharmaceutical composition may be formulated into a tablet, capsule, dragee, powder, granulate, liquid, gel or emulsion form. Said liquid, gel or emulsion may be ingested by the subject in naked form or contained within a capsule. [0071] In certain embodiments, the analgesic agent is selected from the group consisting of salicylates, aspirin, salicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, para-aminophenol derivatives, acetanilide, acetaminophen, phenacetin, fenamates, mefenamic acid, meclofenamate, sodium meclofenamate, heteroaryl acetic acid derivatives, toinetin, ketorolac, diclofenac, propionic acid derivatives, ibuprofen, naproxen sodium, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin; enolic acids, oxicam derivatives, piroxicam, meloxicam, tenoxicam, ampiroxicam, droxicam, pivoxicam, pyrazolon derivatives, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, dipyrone, coxibs, celecoxib, rofecoxib, nabumetone, apazone, nimesulide, indomethacin, sulindac, etodolac, and isobutylphenyl propionic acid. The antimuscarinic agent is selected from the 18 WO 2013/103389 PCT/US2012/051859 group consisting of oxybutynin, solifenacin, darifenacin and atropine. 100721 In some embodiments, the pharmaceutical composition comprises a single analgesic agent and a single antimuscarinic agent. In one embodiment, the single analgesic agent is aspirin. in another embodiment, the single analgesic agent is ibuprofen. In another embodiment, the single analgesic agent is naproxen sodium. In another embodiment, the single analgesic agent is indomethacin. In another embodiment, the single analgesic agent is nabumetone, In another embodiment, the single analgesic agent is acetaminophen. The analgesic agent and anti-muscarinic agent may be given at doses in the ranges described above. 100731 Another aspect of the present application relates to a method for treating nocturia by administering to a subject in need thereof (1) one or more analgesic agents and (2) one or more antidiuretic agents. In certain embodiments, the antidiuretic agent(s) act to: (1) increase vasopressin secretion; (2) increase vasopressin receptor activation; (3) reduce secretion of atrial natriuretic peptide (ANP) or C-type natriuretic peptide (CNP); or (4) reduce ANP and/or CNP receptor activation. [0074] Exemplary antidiuretic agents include, but are not limited to, antidiuretic hormone (ADlH), angiotensin II, aldosterone, vasopressin, vasopressin analogs (e.g., desmnopressin argipressin, lypressin, felypressin, ornipressin, terlipressin); vasopressin receptor agonists, atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) receptor (i.e., NPRi, NPR2, NPR3)) antagonists (e.g., HS-142-1, isatin, [Asu7,23']b-ANP-(7 28)], anantin, a cyclic peptide from Streptomyces coerulescens, and 3G12 monoclonal antibody); somatostatin type 2 receptor antagonists (e.g., somatostatin), and pharmaceutically-acceptable derivatives, analogs, salts, hydrates, and solvates thereof. 100751 In certain embodiments, the one or more analgesic agent and one or more antidiuretic agents are formulated for delayed-rel ease. 100761 Another aspect of the present application relates to a method for treating nocturia by administering to a person in need thereof a first phannaceutical composition comprising a diuretic, followed with a second pharmaceutical composition comprising one or more analgesic agents. The first pharmaceutical composition is dosed and formulated to have a diuretic effect within 6 hours of administration and is administered at least 8 hours prior to bedtime, The second pharmaceutical composition is administered within 2 hours prior to bedtime. 100771 Examples of diuretics include, but are not limited to, acidifying salts, such as CaCl 2 and NH 4 Ci; arginine vasopressin receptor 2 antagonists, such as amphotericin B and 19 WO 2013/103389 PCT/US2012/051859 lithium citrate; aquaretics, such as Goldenrod and Junipe; Na-H exchanger antagonists, such as dopamine; carbonic anhydrase inhibitors, such as acetazolamide and dorzolamide; loop diuretics, such as bumetanide, ethacrynic acid, furosemide and torsemide; osmotic diuretics, such as glucose and mannitol; potassium-sparing diuretics, such as amiloride, spironolactone, triamterene, potassium canrenoate; thiazides, such as bendroflumethiazide and hydrochlorothiazide; and xanthines, such as caffeine, theophylline and theobromine. [00781 In some embodiments, the second pharmaceutical composition further comprises one or more antmuscarnic agents. Examples of the antimuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darifenacin, fesoterodine, tolterodine, trospium and atropine. The second pharmaceutical composition may be formulated in immediate-release formulation or delayed-release formulation. In one embodiment, the first pharmaceutical composition is formulated for immediate-release and the second pharmaceutical composition is formulated for delayed-release. 100791 In some other embodiments, the second pharmaceutical composition further comprises one or more antidiuretic agents. 100801 Another aspect of the present application relates to a pharmaceutical composition comprising a plurality of active ingredients and a pharmaceutically acceptable carrier. In some embodiments, the plurality of active ingredients comprise two or more analgesics. In other embodiments, the plurality of active ingredients comprise one or more analgesics arid one or more antimuscarinic agents. In other embodiments, the plurality of active ingredients comprise one or more analgesics and one or more antidiuretic agents. In yet other embodiments, the plurality of active ingredients comprise one or more analgesics, one or more antidiuretic agents, and one or more antimuscarinic agents. In other embodiments. at least one of said plurality of active ingredients is formulated for delayed release. 100811 In some embodiments, the pharmaceutical composition comprises two analgesics selected from the group consisting of cetylsalicylic acid, ibuprofen, naproxen sodium, nabumetone, acetaminophen and indomethancin. In other embodiments, the pharmaceutical composition comprises one or more analgesics selected from the group consisting of cetyIsalicylic acid, ibuprofen, naproxen sodium, nabumetone, acetaminophen and indomethancin; and an antimuscarinic agent selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine. 100821 As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and 20 WO 2013/103389 PCT/US2012/051859 absorption delaying agents, sweeteners and the like. The pharmaceutically acceptable carriers may be prepared from a wide range of materials including, but not limited to, flavoring agents, sweetening agents and miscellaneous materials such as buffers and absorbents that may be needed in order to prepare a particular therapeutic composition, The use of such media and agents with pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. 100831 Another aspect of the present application relates to a method for reducing the frequency of urination by administering to a subject in need thereof, two or more analgesic agents alternatively to prevent the development of drug resistance. In one embodiment, the method comprises administering a first analgesic agent for a first period of tine and then administering a second analgesic agent for a second period of time. In another embodiment, the method further comprises administering a third analgesic agent for a third period of time. The first, second and third analgesic agents are different from each other and may be selected from the group consisting of: salicylates, aspirin, salicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, para-aminophenol derivatives, acetanilide, acetaminophen, phenacetin, fenamates, mefenamic acid, meclofenamate, sodium meclofenamate, heteroaryl acetic acid derivatives, tolmetin, ketorolac, diclofenac, propionic acid derivatives, ibuprofen, naproxen sodium, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin; enolic acids, oxicam derivatives, piroxicam, meloxicam, tenoxicam, ampiroxicam, droxicam, pivoxicam, pyrazolon derivatives, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, dipyrone, coxibs, celecoxib, rofecoxib, nabumetone, apazone, nimesulide. indomethacin, sulindac, etodolac, and isobutylphenyl propionic acid. 100841 In one embodiment, the first analgesic agent is acetaminophen, the second analgesic agent is ibuprofen and the third analgesic agent is naproxen sodium. The length of each period may vary depending on the subject's response to each analgesic agent. In some eibodiients, each period lasts from 3 days to three weeks. In another embodiment, one or more of the first, second and third analgesic is fonrulated for delayed-release. 100851 The present invention is further illustrated by the following example which should not be construed as limiting. The contents of all references, patents and published patent applications cited throughout this application are incorporated herein by reference, EXAM PLE 1: INHIBITION OF TH E URGE TO URINATE 100861 Twenty volunteer subjects, both male and female were enrolled, each of which experienced premature urge or desire to urinate, interfering with their ability to sleep for a 21 WO 2013/103389 PCT/US2012/051859 sufficient period of time to feel adequately rested. Each subject ingested 400-800 mg of ibuprofen as a single dose prior to bedtime. At least 14 subjects reported that they were able to rest better because they were not being awakened as frequently by the urge to urinate. 100871 Several subjects reported that after several weeks of nightly use of ibuprofen, the benefit of less frequent urges to urinate was no longer being realized. However, all of these subjects further reported the return of the benefit after several days of abstaining from taking the dosages. EXAMPLE 2: EFFECT OF ANALGESIC AGENTS, BOTULINUM NEUROTOXIN AND ANTIMIJSCAR]NICAGENTS ON M ACROPHAGE RESPONSES TO INFLAMMATORY AND N ON-INFLAMMATORY STIMULI Experimental Desiun 100881 This study is designed to determine the dose and in vitro efficacy of analgesics and antimuscarinic agents in controlling macrophage response to inflammatory and non inflammatory stimuli mediated by Cox-2 and prostaglandins (PGE, PGH, etc.). It establishes baseline (dose and kinetic) responses to inflammatory and non-inflammatory effectors in bladder cells. Briefly, cultured cells are exposed to analgesic agents and/or antimuscarinic agents in the absence or presence of various effectors. 100891 The effectors include: lipopolysaccharide (LPS), an inflammatory agent and COX2 inducer, as inflammatory stimuli: carbachol or acetylcholine. a stimulator of smooth muscle contraction, as non-inflammatory stimuli; botulinum neurotoxin A, a known inhibitor of acetylcholine release, as positive control; and arachidonic acid (AA), gamma linolenic acid (DGLA) or eicosapentaenoic acid (EPA) as precursors of prostaglandins, which are produced following the sequential oxidation of AA, DGLA or EPA inside the cell by cyclooxygenases (COXI and COX2) and terminal prostaglandin syntheses. [0090] The analgesic agents include: Salicylates such as aspirin, iso-butyl-propanoic phenolic acid derivative (ibuprofen) such as Advil, Motrin, Nuprin, and Medipren, naproxen sodium such as Aleve, Anaprox, Antalgin, Feminax Ultra, Flanax, Inza, Midol Extended Relief, Nalgesin, Naposin, Naprelan, Naprogesic, Naprosyn, Naprosyn suspension, EC Naprosyn, Narocin, Proxen, Synflex and Xenobid, acetic acid derivative such as indomethacin (Indocin), I -naphthaleneacetic acid derivative such as nabumetone or relafen, N-acetyl-para-aminophenol (APAP) derivative such as acetaminophen or paracetamol (Tylenol) and Celecoxib. 100911 The antimuscarinic agents include: oxybutynin, solifenacin, darifenacin and atropine. 22 WO 2013/103389 PCT/US2012/051859 100921 Macrophages are subjected to short term (1-2 hrs) or long term (24-48 hrs) stimulation of with: 1) Each analgesic agent alone at various doses. (2) Each analgesic agent at various doses in the presence of LPS. (3) Each analgesic agent at various doses in the presence of carbachol or acetylcholine. (4) Each analgesic agent at various doses in the presence of AA, DGLA, or EPA. (5) Botulinum neurotoxin A alone at various doses. (6) Botulinum neurotoxin A at various doses in the presence of LPS. (7) Botulinum neurotoxin A at various doses in the presence of carbachol or acetylcholine. (8) Botulinum neurotoxin A at various doses in the presence of AA, DGLA, or EPA. (9) Each antimuscarinic agent alone at various doses. (10) Each antimuscarinic agent at various doses in the presence of LPS, (11) Each antimuscarinic agent at various doses in the presence of carbachol or acetylcholine. (12) Each antimuscarinic agent at various doses in the presence of AA, DGLA, or EPA. 100931 The cells are then analyzed for the release of PGH 2 , PGE, PGE, Prostacydin, Thromnboxane, IL- 3, IL-6, TNF-a, the COX2 activity, the production of cAMP and cGM P, the production of IL-1 IL-6, TNF-a and COX2 mRNA, and surface expression of CD80, CD86 and MHC class II molecules. Materials and AMethods Macrophage cells [0094] Murine RAW264.7 or J774 macrophage cells (obtained from ATCC) were used in this study. Cells were maintained in a culture medium containing RPMI 1640 supplemented with 10 % fetal bovine serum (FBS), 15 mM 1-EPES, 2 inM L-glutamine, 100 U/ml penicillin, and 100 pg / ml of streptomycin. Cells were cultured at 37' C in a 5 % CO 2 atmosphere and split (passages) once a week, In vitro treatment of macrophage cells with analgesics 100951 RAW264.7 macrophage cells were seeded in 96-well plates at a cell density of 1.5x10 6 cells per well in 100 l of the culture medium, The cells were treated with (1) various concentrations of analgesic (acetaminophen, aspirin, ibuprophen or naproxen), (2) various concentrations of lipopolysaccharide (LPS), which is an effector of inflamniatory 23 WO 2013/103389 PCT/US2012/051859 stimuli to macrophage cells, (3) various concentrations of carbachol or acetylcholine, which are effectors of non-inflammatory stimuli, (4) analgesic and LPS or (5) analgesic and carbachol or acetylcholine. Briefly, the analgesics were dissolved in FBS-free culture medium (i.e., RPMI 1640 supplemented with 15 nM HEPES, 2 mM L-glutamine, 100 U / ml penicillin, and 100 qg / ml of streptomycin), and diluted to desired concentrations by serial dilution with the same medium. For cells treated with analgesic in the absence of LPS, 50 pl of analgesic solution and 50 l1 of FBS-free culture medium were added to each well. For cells treated with analgesic in the presence of LPS, 50 pl of analgesic solution and 50 pl of LPS (from Salmonella typhimurium) in FBS-free culture medium were added to each well. All conditions were tested in duplicates. 100961 After 24 or 48 hours of culture, 150 pl of culture supernatants were collected, spun down for 2 min at 8,000 rpm at 4 0 C to remove cells and debris and stored at -70 C for analysis of cytokine responses by ELISA. The cells were collected and washed by centrifugation (5 min at 1,500 rpm at 4 0 C) in 500 p of Phosphate buffer (PBS). Half of the cells were then snap frozen in liquid nitrogen and stored at -70'C. The remaining cells were stained with fluorescent monoclonal antibodies and analyzed by flow cytometry. Flow cytometry analysis of co-stimulatory molecule expression 100971 For flow cytometry analysis, macrophages were diluted in 100 pl of FACS buffer (phosphate buffered saline (PBS) with 2% bovine serum albumin (BSA) and 0.01% NaN 3 ) and stained 30 min at 4 0 C by addition of FITC-conjugated anti-CD40, PE-conjugated anti-CD80, PE-conjugated anti-CD86 antibody, anti MHC class II (I-A ) PE (BD Bioscience). Cells were then washed by centrifugation (5 min at 1,500 rpm at 4'C) in 300 p1 of FACS buffer. After a second wash, cells were re-suspended in 200 p] of FACS buffer and the percentage of cells expressing a given marker (single positive), or a combination of markers (double positive) were analyzed with the aid of an Accuri C6 flow cytometer (131) Biosciences). Analysis of cytokine responses by ELISA 100981 Culture supernatants were subjected to cytokine-specific ELISA to determine IL-1 I3, IL-6 and TNF-a responses in cultures of macrophages treated with analgesic, LPS alone or a combination of LPS and analgesic. The assays were performed on Nunc MaxiSorp Immunoplates (Nunc) coated overnight with 100 pl of anti-mouse IL-6, TNF-a mAbs (BD Biosciences) or IL-Ip mAb (R&D Systems) in 0.1 M sodium bicarbonate buffer (pH 9.5). After two washes with PBS (200 pl per well), 200 pl of PBS 3% BSA were added in each 24 WO 2013/103389 PCT/US2012/051859 well (blocking) and the plates incubated for 2 hours at room temperature. Plates were washed again two times by addition of 200 p1 per well, 100 pl of cytokine standards and serial dilutions of culture supernatants were added in duplicate and the plates were incubated overnight at 4 0 C. Finally, the plates were washed twice and incubated with 100 pl1 of secondary biotinylated anti-mouse IL-6, TNFa mAbs (BD Biosciences) or IL-IfP (R&D Systems) followed by peroxidase-labelled goat anti-biotin mAb (Vector Laboratories). The colorimetric reaction was developed by the addition of2,2'-azino-bis (3) ethylbenzylthiazoline-6-sulfonic acid (ABTS) substrate and H202 (Sigma) and the absorbance measured at 415 nm with a Victor V rnultilabel plate reader (PerkinElmer). Determination of COX2 activity and the production of cAMP and cGM P 100991 The COX2 activity in the cultured macrophages is determined by COX2 activity assay. The production of cAMP and cGM1P is determined by the cAMP assay and cGMP assay. These assays are performed routinely in the art. Results 101001 Table I summarizes the experiments performed with Raw 264 macrophage cell line and main findings in terms of the effects of analgesics on cell surface expression of costimulatory molecules CD40 and CD80. Expression of these molecules is stimulated by COX2 and inflammatory signals and thus, was evaluated to determine functional consequences of inhibition of COX2. 101011 As shown in Table 2, acetaminophen, aspirin, ibuprophen and naproxen inhibit basal expression of co-stimulatory molecules CD40 and (D80 by macrophages at all the tested doses (i.e., 5x 10 nM, 5x 104 nM, 5x 10 nM, 5x 10- nM, 50 nM and 5 nM), except for the highest dose (i.e., 5x 106 nM), which appears to enhance, rather than inhibit, expression of the co-stimulatory molecules. As shown in Figures lA and 1D, such inhibitory effect on CD40 and CD50 expression was observed at analgesic doses as low as 0.05 nM (i.e., 0.00005 pM). This finding supports the notion that a controlled release of small doses of analgesic may be preferable to acute delivery of large doses. The experiment also revealed that acetaminophen, aspirin, ibaprophen and naproxen have a similar inhibitory effect on LPS induced expression of CD40 and CD80. 25 WO 2013/103389 PCT/US2012/051859 Table . Summary of experiments LPS Control Salmonella typhimurium Acetaninophen Aspirin Ibuprophen Naproxen TESTS 1 X 2 X Dose responses (0, 5, 50, 1000) ng/mL 3 X Dose responses (0, 5, 50, 500, 5x10 3 , 5x10', 5x10 5 , 5x10) nM 4 X X (5 ng/mL) Dose responses X (50 ng/mL (0, 5 50, 500, 5.10, 5.104, 5105, 5,106) nM X (1000 ng/inL) ANALYSIS a Characterization of activation/stimulatory status: Flow cytornetry analysis of CD40, CD8O CD86 and MHC class II b Mediators of inflammatory responses: ELISA analysis of IL-1 , IL-6, TNF-a Table 2. Summary of main findings Effectors IX Positive Negative LPS iDose analgesic (nM) Control 5 ng/mi 5.106 510 5. 10* 5.10 500 50 CD40+CD80* 20.6 77.8 Acetaminophen CD40*CD80* 63 18 12 9.8 8 9,5 7.5 Aspirin C)40+CD80 t 44 11 10.3 8.3 8 10.5 7.5 Ibuprophen CD40*CD80* ND* 6.4 7.7 7.9 6.0 4.9 5,8 Naproxen CD40+CD80* 37 9.6 7.7 6.9 .2 68 5.2 Analgesic plus LPS Acetaminnophen CD40CD80 95.1 82.7 72.4 68.8 66.8 66.2 62.1 Aspirin CD40*CD80* 84.5 80 78.7 74.7 75 J8 70,1 65.7 Ibuprophlen CD40+C)80* ND 67 77.9 72.9 11 63.7 60,3 Naproxen CD40*CD80 66.0 74.1 77.1 71.0 68.8 72 73 ND: not done (toxicity) 10102] Table 3 summarizes the results of several studies that measured serum levels of analgesic after oral therapeutic doses in adult humans. As shown in Table 3, the maximum serum levels of analgesic after an oral therapeutic dose are in the range of 10" to 10 nM. Therefore, the doses of analgesic tested in vitro in Table 2 cover the range of concentrations 26 WO 2013/103389 PCT/US2012/051859 achievable in vivo in human. Table 3. Serum levels of analgesic in human blood after oral therapeutic doses Maximum serum Analgesic drug Molecular levels after oral References weight therapeutic doses mo/L nM Acetaminophen 15116 11-18 7.2x10'- BMC Clinical Pharmacology.2010, 10:10 (Tlenol) 1.19x10 5 Anaesth Intensive Care. 2011, 39:242 Aspirin 181.66 30-100 1.65x10- * Disposition of Toxic Drugs and Chemicals in (Acetylsalicylic acid) 5.5x10 5 Man, 8th Edition, Biomedical Public, Foster City CA, 2008, pp. 22-25 * J Lab Cl in Med. 1984 Jun; 103:869 Ibuprofen 206.2 9 24-32 116x10 * BMC Clinical Pharnacology2010, 10:10 (Advil, Motrin) 1,55 x105 * J Clin Pharmacol. 2001, 41:330 Naproxen 3 0.2 6 Up to Up to * J Clin Pharmacol. 2001, 41:330 (Aleve) 60 2,6x10 EXAMPLE 3: EFFECT OF ANALGESIC AGENTS BOTULINUM NEUROTOXIN AND ANTIMUSCARINIC AGENTS ON BLADDER SMOOTH MUSCLE CELL RESPONSES TO INFLAMMATORY AND NON-INFLAMMATORY STIMULI Experirnenta! Design 10103] This study is designed to characterize how the optimal doses of analgesic determined in Example 2 affect bladder smooth muscle cells in cell culture or tissue cultures, and to address whether different classes of analgesics can synergize to more efficiently inhibit COX2 and PGE2 responses. 101041 The effectors, analgesic agents and antimuscarinic agents are described in Example 2. 101051 Primary culture of mouse bladder smooth muscle cells are subjected to short term (1-2 hrs) or long tenr (24-48 hrs) stimulation of with: (1) Each analgesic agent alone at various doses. (2) Each analgesic agent at various doses in the presence of LPS. 27 WO 2013/103389 PCT/US2012/051859 (3) Each analgesic agent at various doses in the presence of carbachol or acetylcholine. (4) Each analgesic agent at various doses in the presence of AA, DGLA, or EPA. (5) Botulinum neurotoxin A alone at various doses. (6) Botulinum neurotoxin A at various doses in the presence of LPS. (7) Botulinum neurotoxin A at various doses in the presence of carbachol or acetylcholine. (8) Botulinum neurotoxin A at various doses in the presence of AA, DGLA, or EPA. (9) Each antimuscarinic agent alone at various doses, (10) Each antimuscarinic agent at various doses in the presence of LPS. (11) Each antimuscarinic agent at various doses in the presence of carbachol or acetylcholine. (12) Each antimuscarinic agent at various doses in the presence of AA, DGLA, or EPA. 101061 The cells are then analyzed for the release of PGH2, PGE, PGE 2 , Prostacydin, Thromboxane, IL-I J3, [L-6, TNF-a, the COX2 activity, the production of cAMP and cGMP, the production of IL- I, IL-6, TNF-a and COX2 mRNA, and surface expression of CD80, CD86 and MHC class II molecules. Materials and Methods Isolation and purification of murine bladder cells 101071 Bladder cells were removed from euthanized animals C57BL/6 mice (8-12 weeks old) and cells were isolated by enzymatic digestion followed by purification on a Percoll gradient. Briefly, bladders from 10 mice were minced with scissors to fine slurry in 10 ml of digestion buffer (RPMI 1640, 2% fetal bovine serum, 0.5 mg/ml collagenase, 30 pg/ml DNase). Bladder slurries were enzymatically digested for 30 minutes at 37 3 C. Undigested fragments were further dispersed through a cell-trainer. The cell suspension was pelleted and added to a discontinue 20%, 40% and 75% Percoll gradient for purification on mononuclear cells. Each experiment used 50-60 bladders. 10108] After washes in RPMI 1640, bladder cells were resuspended RPMI 1640 supplemented with 10 % fetal bovine serum, 15 m M HEPES, 2 mN L-glutamine, 100 U/ml penicillin, and 100 pg / ml of streptomycin and seeded in clear-bottom black 96-well cell culture microculture plates at a cell density of 3x10 4 cells per well in 100 pl. Cells were cultured at 37 C in a 5 % CO 2 atmosphere. 28 WO 2013/103389 PCT/US2012/051859 In vitro treatment of cells with analgesics 10109] Bladder cells were treated with analgesic solutions (50 pl/ well) either alone or together with carbachol (10-Molar, 50 p1/ well), as an example of non-inflammatory stimuli, or lipopolysaccharide (LPS) of S(almonella tvphimurium (1 pg/ml, 50 pl/ well), as an example of non-inflammatory stimuli. When no other effectors were added to the cells, 50 Pl of RPM I 1640 without fetal bovine serum were added to the wells to adjust the final volume to 200 ul. 101101 After 24 hours of culture, 150 l1 of culture supernatants were collected, spun down for 2 min at 8,000 rpm at 4 0 C to remove cells and debris and stored at -70 C for analysis of Prostaglandin E2 (PGE 2 ) responses by ELISA. Cells were fixed, permeabilized and blocked for detection of Cyclooxygenase-2 (COX2) using a fluorogenic substrate. In selected experiment cells were stimulated 12 hours in vitro for analysis of COX2 responses. Analysis of COX2 responses 10111] COX2 responses were analyzed by a Cell-Based ELISA using Human/mouse total COX2 immunoassay (R&D Systems), following the instructions of the manufacturer. Briefly, after cells fixation and permeabilization, a mouse anti-total COX2 and a rabbit anti total GA PDH were added to the wells of the clear-bottom black 96-well cell culture microculture plates. After incubation and washes, an HRP-conjugated anti-mouse igG and an AP-conjugated anti-rabbit IgG were added to the wells, Following another incubation and set of washes, the HRP- and AP-fluorogenic substrates were added. Finally, a Victor* V multilabel plate reader (PerkinElmer) was used to read the fluorescence emitted at 600 nm (COX2 fluorescence) and 450 nm (GAPDH fluorescence). Results are expressed as relative levels of total COX2 as determined by relative fluorescence unit (RFUs) and nomalized to the housekeeping protein GAPDH. Analysis of PGE2 responses 10112] Prostaglandin E2 responses were analyzed by a sequential competitive ELISA (R&D Systems). More specifically, culture supernatants or PGE2 standards were added to the wells of a 96-well polystyrene microplate coated with a goat anti-mouse polyclonal antibody. After one hour incubation on a microplate shaker, an HRP-conjugated PGE2 was added and plates incubated for an additional two hours at room temperature. The plates were then washed and HRP substrate solution added to each well. The color was allowed to develop for 30 min and the reaction stopped by addition sulfuric acid before reading the plate at 450 nm with wavelength correction at 570 nm. Results are expressed as mean pg/ml of PGE2. Other assays 10113] The release of PGHI- 2 , PGE, Prostacydin, Thromboxane, IL-i 13, IL-6, and TNF 29 WO 2013/103389 PCT/US2012/051859 a, the production of cAMP and cGM P. the production of IL-I P, IL-6, TNF-a and COX2 mRiNA, and surface expression of CD80, CD86 and MHC class II molecules are determined as described in Example 2. Results Analgesics inhibit COX2 responses of urine bladder cells to an inflammatory stimuli 101141 Several analgesics acetaminophene, aspirin, ibuprofen and naproxen) were tested on mouse bladder cells at the concentration of 5 pM or 50 pM to determine whether the analgesics could induce COX2 responses. Analysis of 24-hour cultures showed that none of the analgesics tested induced COX2 responses in murine bladder cells in vitro. 101151 The effect of these analgesics on the COX2 responses of murine bladder cells to carbachol or LPS stimulation in vitro was also tested. As indicated in Table 1, the dose of carbachol tested has no significant effect on COX2 levels in murine bladder cells. On the other hand, LPS significantly increased total COX2 levels. Interestingly, acetaminophen, aspirin, ibuprofen and naproxen could all suppress the effect of LPS on COX2 levels. The suppressive effect of the analgesic was seen when these drugs were tested at either 5 pM or 50 pM (Table 4). Table 4. COX2 expression by murine bladder cells after in vitro stimulation and treatment with analgesics Stimuli Analgesic Total COX2 levels (Normalized RF Us) None None 158± 18 Carbachol (mM) None 149 ± 21 LPS (1pg/mi) None 420 ± 26 LPS (Ipg/ml) Acetarninophen (5 pM) 275 ± 12 LiPS (Ipg/mi) Aspirin (5 pM) 240 ± 17 LPS (1pg/ml) Ibuprofen (5 pM)) 253 ± 32 LPS (ipg/ml) Naproxen (5 p M) 284± 11 LPS (lpg/ml) Acetaminophen (50 pM) 243 ± 15 LPS (lpg/ml) Aspirin (50 pM) 258 + 21 LPS (Ipg/ml) Ibuprofen (50 pM) 266 19 LP'S (1pg/ml) Naproxen (50 pM) 279 ± 23 30 WO 2013/103389 PCT/US2012/051859 Analgesics inhibit PGE2 responses of murine bladder cells to an inflanamatory stimuli 10116] The secretion of PGE2 in culture supernatants of niurine bladder cells was measured to detennine the biological significance of the alteration of murine bladder cell COX2 levels by analgesics. As shown in Table 5, PGE2 was not detected in the culture supernatants of unstimulated bladder cells or bladder cells cultured in the presence of carbachol. Consistent with COX2 responses described above, stimulation of urine bladder cells with LPS induced the secretion of high levels of PGE2. Addition of the analgesics acetaminophen, aspirin, ibuprofen and naproxen suppressed the effect of LPS on PGE2 secretion and no difference was seen between the responses of cells treated with the 5 or 50 pM dose of analgesic. Table 5. PGE2 secretion by niurine bladder cells after in vitro stimulation and treatment with analgesics Stimuli Analgesic PGE2 levels (pg/ml) None None < 205 Carbachol (mM) None < 20 5 LPS (1 pg/ml) None 925 ± 55 LPS (1 pg/ml) Acetaminophen (5 M) 619 32 LPS (1pg/ml) Aspirin (5 pM) 588 ± 21 LPS (1pg/ml) Ibuprofen (5 pMN)) 593 ± 46 LPS (1pg/ml) Naproxen (5 pM) 597±19 LPS (1 pg/ml) Acetaminophen (50 pM) 600 ± 45 LPS (1pg/ml) Aspirin (50 pM) 571 ± 53 LPS (lpg/ml) Ibuprofen (50 pM) 568 + 32 LPS (1pg/ml) Naproxen (50 pM) 588 + 37 10117] In summary, these data show that the analgesics alone at 5 pM or 50 pM do not inchce COX2 and PGE2 responses in murine bladder cells. The analgesics at 5 pM or 50 pM, however, significantly inhibit COX2 and PGE2 responses of murine bladder cells stimulated in vitro with LPS (1 pg/nil). No significant effect of analgesics was observed on COX2 and PGE2 responses of murine bladder cells stimulated with carbachol (1 mlM). EXAMPLE 4: EFFECT OF ANALGESIC AGENTS, BOTULINUM NEUROTOXIN AND ANTIMUSCARINIC AGENTS ON BLADDER SMOOTH MUSCLE CELL 31 WO 2013/103389 PCT/US2012/051859 CONTRACTION Experiment tai Design 101181 Cultured mouse or rat bladder smooth muscle cells and mouse or rat bladder srnooth muscle tissue are exposed to inflammatory stimuli and non-inflanmatory stimuli in the presence of analgesic agent and/or antimuscarinic agent at various concentrations. The stimuli-induced muscle contraction is measured to evaluate the inhibitory effect of the analgesic agent and/or antimuscarinic agent. 10119] The effectors, analgesic agents and antimuscarinic agents are described in Example 2. 101201 Primary culture of mouse bladder smooth muscle cells are subjected to short term (1-2 hrs) or long term (24-48 hrs) stimulation of with: (1) Each analgesic agent alone at various doses. (2) Each analgesic agent at various doses in the presence of LPS. (3) Each analgesic agent at various doses in the presence of carbachol or acetylcholine. (4) Each analgesic agent at various doses in the presence of AA, DGLA, or EPA. (5) Botulinum neurotoxin A alone at various doses. (6) Botulinum neurotoxin A at various doses in the presence of LPS. (7) Botulinum neurotoxin A at various doses in the presence of carbachol or acetylcholine. (8) Botulinum neurotoxin A at various doses in the presence of AA, DGLA, or EPA. (9) Each antimuscarinic agent alone at various doses. (10) Each antimuscarinic agent at various doses in the presence of LPS, (11) Each antimuscarinic agent at various doses in the presence of carbachol or acetylcholine. (12) Each antimuscarinic agent at various doses in the presenceof AA, DGLA, or EPA. Materials and Methods 10121] Primary mouse bladder cells are isolated as described in Example 3. In selected experiments, cultures of bladder tissue are used. Bladder smooth muscle cell contractions are recorded with a Grass polygraph (Quincy Mass, USA). EXAMPLE 5: EFFE /CT OF ORAL ANALGESIC AGENTS AND ANTIMU SCARNIQ AGENTS ON COX2 AND PGE2 RESPONSES OF BLADDER SMOOTH MUSCLE CELLS. 32 WO 2013/103389 PCT/US2012/051859 Experimental design: 10122] Normal mice and mice with over active bladder syndrome are given oral doses of aspirin, naproxen sodium, Ibuprofen, Indocin, nabumetone, Tylenol, Celecoxib, oxybutynin, solifenacin, darifenacin, atropine and combinations thereof. Control groups include untreated normal mice and untreated OA3 mice without over active bladder syndrome. Thirty (30) min after the last doses, the bladders are collected and stimulated ex vivo with carbachol or acetylcholine. In selected experiments the bladders are treated with botulinum neurotoxin A before stimulation with carbachol. Animals are maintained in metabolic cages and frequency (and volume) of urination are evaluated. Bladder outputs are determined by monitoring water intake and cage litter weight. Serum PGH 2 , PGE, PGE 2 , Prostacydin, Thromboxane, IL-1 f3, IL-6, TNF-a, cAMP, and cGMP levels are determined by ELISA. CD80, CD86, MHC class II expression in whole blood cells are determined by flow cytometry. 10123] At the end of the experiment, animals are euthanized and ex vivo bladder contractions are recorded with a Grass polygraph. Portions of bladders are fixed in formalin, and COX2 responses are analyzed by immunohistochemistry. EXAMPLE 6: EFFECT OF ANALGESIC AGENTS, BOTULINUM NEUROTOXIN AND ANTIMIUSCARINIC AGENTSON HUMAN BLADDER SMOOTH MUSCLECELL RESPONSES TO INFLAMMATORY AND NON-INFLAMMATORY STIMULI Experimenta/ Desian 101241 This study is designed to characterize how the optimal doses of analgesics determined in Examiples 1-5 affect human bladder smooth muscle cells in cell culture or tissue cultures, and to address whether different classes of analgesics can synergize to more efficiently inhibit COX2 and PGE2 responses. [0125] The effectors, analgesic agents and antimuscarinic agents are described in Example 2. 10126] Human bladder smooth muscle cells are subjected to short term (1-2 hrs) or long tenn (24-48 hrs) stimulation of with: (1) Each analgesic agent alone at various doses, (2) Each analgesic agent at various doses in the presence of LPS. (3) Each analgesic agent at various doses in the presence of carbachol or acetylcholine. (4) Each analgesic agent at various doses in the presence of AA, DGLA, or EPA. (5) Botulinum neurotoxin A alone at various doses, 33 WO 2013/103389 PCT/US2012/051859 (6) Botulinum neurotoxin A at various doses in the presence of LPS. (7) Botulinum neurotoxin A at various doses in the presence of carbachol or acetylcholine. (8) Botulinum neurotoxin A at various doses in the presence of AA, DGLA, or EPA, (9) Each antimuscarinic agent alone at various doses. (10) Each antimuscarinic agent at various doses in the presence of LPS. (11) Each antinuscarinic agent at various doses in the presence of carbachol or acetylcholine. (12) Each antimuscarinic agent at various doses in the presence of AA, DGLA, or EPA. 10127] The cells are then analyzed for the release of PGI-, PGE, PGE2, Prostacydin, Thromboxane, IL- I 3, IL-6, TNF-a, the COX2 activity, the production of cAMP and cGMP, the production of IL- I 3, IL-6, TNF-a. and COX2 mRNA, and surface expression of CD80, CD86 and MIC class II molecules. EXAMPLE 7: EFFECT OF ANALGESIC AGENTS. BOTULINUM NEUROTOXIN AND ANTIMUSCARINIC AGENTS ON HUMAN BLADDER SMOOTH MUSCLE CELL CONT RACTION. ExLperimental Desizn 101281 Cultured human bladder smooth muscle cells are exposed to inflammatory stimuli and non-inflammniatory stimuli in the presence of analgesic agent and/or antimuscarinic agent at various concentrations. The stimuli-induced muscle contraction is measured to evaluate the inhibitory effect of the analgesic agent and/or antimuscarinic agent 10129] The effectors, analgesic agents and antimuscarinic agents are described in Example 2. [0130] Human bladder smooth muscle cells are subjected to short term (1-2 hrs) or long term (24-48 hrs) stimulation of with: (1) Each analgesic agent alone at various doses. (2) Each analgesic agent at various doses in the presence of LPS. (3) Each analgesic agent at various doses in the presence of carbachol or acetylcholine. (4) Each analgesic agent at various doses in the presence of AA, DGLA, or EPA. (5) Botulinum neurotoxin A alone at various doses. (6) Botulinum neurotoxin A at various doses in the presence of LPS. (7) Botulinum neurotoxin A at various doses in the presence of carbachol or 34 WO 2013/103389 PCT/US2012/051859 acetylcholine. (8) Botulinum neurotoxin A at various doses in the presence of AA, DGLA, or EPA. (9) Each antimuscarinic agent alone at various doses. (10) Each antimuscarinic agent at various doses in the presence of LPS, (11) Each antimuscarinic agent at various doses in the presence of carbachol or acetylcholine. (12) Each antimuscarinic agent at various doses in the presence of AA, DGLA, or EPA. 10131] Bladder smooth muscle cell contractions are recorded with a Grass polygraph (Quincy Mass, USA). EXAMPLE 8: EFFECT OF ANALGESIC AGENTS ON NORMAL HUMAN BLADDER SMOOTH MUSCLE CELL RESPONSES TO INFLAMMATORY AND NON INFLAMMATORY SIGNALS EXPERIMENTAL DESIGN Culture of normal human bladder smooth muscle cells [0132] Normal human bladder smooth muscle cells were isolated by enzymatic digestion from macroscopically normal pieces of human bladder. Cells were expended in vitro by culture at 37' C in a 5 % CO 2 atmosphere in RPMI 1640 supplemented with 10 % fetal bovine serum, 15 mM HEPES, 2 mM IL-glutamine, 100 U/mIl penicillin, and 100 mg / ml of streptomycin and passage once a week by treatment with trypsin to detach cells followed by reseeding in a new culture flask. The first week of culture, the culture medium was supplemented with 0.5 ng/mI epidermal growth factor, 2 ng/ml fibroblast growth factor, and 5 pg/ml insulin. Treatment of normal human bladder smooth muscle cells with analgesics in vitro 10133] Bladder smooth muscle cells typsinized and seeded in microculture plates at a cell density of 3x10 4 cells per well in 100 pl were treated with analgesic solutions (50 pl/ well) either alone or together carbachol (10-Molar, 50 pl/ well), as an example of non inflammatory stimuli, or lipopolysaccharide (LPS) of Salnonella typhimurium (1 ig/ml, 50 pl/ well), as an example of non-inflammatory stimuli. When no other effectors were added to the cells, 50 pl of RPM 11640 without fetal bovine serum were added to the wells to adjust the final volume to 200 pL. 101341 After 24 hours of culture, 150 pl of culture supernatants were collected, spun down for 2 min at 8,000 rpm at 4 0 C to remove cells and debris and stored at -70 0 C for WO 2013/103389 PCT/US2012/051859 analysis of Prostaglandin E2 (PGE 2 ) responses by ELISA. Cells were fixed, permeabilized and blocked for detection of COX2 using a fluorogenic substrate. In selected experiments cells were stimulated 12 hours in vitro for analysis of COX2, PGE2 and cytokine responses. Analysis of COX2, PGE2 and cytokine responses 10135] COX2 and PGE2 responses were analyzed as described in Example 3. Cytokine responses were analyzed as described in Example 2 RESULTS 101361 Analgesics inhibit COX2 responses of normal human bladder smooth muscle cells to inlammatory and non- injIammatory stimuli - Analysis of cells and culture supernatants after 24 hours of cultures showed that none of the analgesics tested alone induced COX2 responses in normal human bladder smooth muscle cells. However, as summarized in Table 6, carbachol induced low, but significant COX2 responses in normal human bladder smooth muscle cells. On the other hand, LPS treatment resulted in higher levels of C()X2 responses in normal human bladder smooth muscle cells, Acetaminophen, aspirin, ibuprofen and naproxen could all suppress the effect of carbachol and LPS on COX2 levels. The suppressive effect of the analgesics was seen on LPS-induced responses when these drugs were tested at either 5 pM or 50 pM. Table 6. COX2 expression by normal human bladder smooth muscle cells after in vitro stimulation with inflammatory and non- inflammatory stimuli and treatment with analgesic Total COX2 levels Total COX2 levels Stimuli Analgesic (Normalized RFUs) (Normalized ReUs) subject 1 subject 2 None None 230 199 Carbachol 10" M Acetaminophen (50 piM) 437 462 Carbachol 10- M Aspirin (50 piM) 298 310 Carbachol 10! M Ibiprofen (50 pM) 312 297 Carbachol 0- 3 M Napi)roxen (50 uM) 309 330 Carbachol 1M Acetaninophen (50 pM) 296 354 LPS (10 pg/ln) None 672 633 LPS (10 pg/ml) Acetaminophen (5 pM) 428 457 LPS (10 p/mil) Aspirin (5 pM) 472 491 LPS (10 pg/mln) Ibuprofen (5 pM) 417 456 LPS (10 pg/ml) Naproxen (5 pM 458 50 1 36 WO 2013/103389 PCT/US2012/051859 LPS (10 pg/mi) Acetaminophen (50 pM) 399 509 LPS (10 Ig/ml) Aspirin (50 pM) 413 484 1PS (10 pg/mi) Ibuprofen (50 uM) 427 466 LPS (10 pm) Naproxen (50 pM) 409 458 4 Data are expressed as mean of duplicates 10137] Analgesics inhibit PGE2 responses of normal human bladder smooth muscle cells to inflammatory and non- inflammatory stimuli - Consistent with the induction of COX2 responses described above, both carbachol and LPS induced production of PGE2 by normal human bladder smooth muscle cells. Acetaminophen, aspirin, ibuprofen and naproxen were also found to suppress the LPS-induced PGE2 responses at either 5 PM or 50 pM (Table 7). Table 7. PGE2 secretion by normal human bladder smooth muscle cells after in vitro stimulation with inflammatory and non- inflammatory stimuli and treatment with analgesic Stimuli Analgesic PGE2 levels 5 (pg/nml) PGE2 levels (pg/ml) Subject I Subject 2 None None <20.5 < 20.5 Carbachol 10 3 M Acetaminophen (50 M) 129 104 Carbachol 1 M Aspirin (50 paM) 76 62 Carbachol 10 3 M Ibuprofen (50 pM) 89 59 Carbachol 10- M Naproxen (50 piM) 84 73 Carbachol 10-' M Acetaminophen (50 piM) 77 66 LPS (10 g/ml) None 1125 998 LPS (10 pg/ml) Acetaminophen (5 pM) 817 542 LPS (10 pg/mi) Aspirin (5 pM) 838 598 LPS (0 pg/mI) Ibuprofen (5 pM) 824 527 LPS (10 p ig/m) Naproxen (5 pM 859 506 LPS (10 pg/mi) Acetaminophen (50 ;M) 803 540 LPS (10 pg/mI) Aspirin (50 pM) 812 534 LPS (10 pg/mi) lbuprofen (50 pM) 821 501 LPS (10 pg/ml) Naproxen (50 pM) 819 523 Data are expressed as mean of duplicates 101381 Analgesics inhibit cytokine responses of normal human bladder cells to an inflammatory stimuli - Analysis of cells and culture supernatants after 24 hours of cultures showed that none the analgesics tested alone induced IL-6 or TNFct secretion in normal human bladder smooth muscle cells. As shown in Tables 8 and 9, the dose of carbachol tested induced low, but significant TNFa- and IL-6 responses in normal human bladder 37 WO 2013/103389 PCT/US2012/051859 smooth muscle cells. On the other hand, LPS treatment resulted in massive induction of these proinflammatory cytokines, Acetaminophen, aspirin, ibuprofen and naproxen suppress the effect of carbachol and LPS on TNFct and IL-6 responses. The suppressive effect of the analgesic on LPS-induced responses was seen when these drugs were tested at either 5 iM or 50 pM. Table 8. TNFa secretion by normal human bladder smooth muscle cells after in vitro stimulation with inflammatory and non- inflammatory stimuli and treatment with analgesic Stimuli Analgesic TNFa (pg/mi) TNFa (pg/ml) Subject I Subject 2 None None < 5 < 5 Carbachol 10 3 M None 350 286 Carbachol 10- M Acetaminophen (50 pM) 138 164 Carbachol 10 M Aspirin (50 pM) 110 142 Carbachol i0- 3 M Ibuprofen (50 pM) 146 121 Carbachol 10- M Naproxen (50 pM) 129 137 LPS (10 pg/mi) None 5725 4107 LPS (10 pg/ml) Acetaininophen (5 pM) 2338 2267 LPS (10 pg/mi) Aspirin (5 pM) 2479 2187 LPS (10 pg/ml) Ibuprofen (5 pM) 2733 2288 LPS (10 pg/ml) Naproxen (5 pM 2591 2215 IPS (10 pg/mi) Acetaminophen (50 pM) 2184 2056 LPS (10 pg/ml) Aspirin (50 pM) 2266 2089 LPS (10 pg/ml) Ibuprofen (50 pM) 2603 1997 LPS (10 pg/ml) Naproxen (50 pM) 2427 2192 "Data are expressed as mean of duplicates. Table 9. IL-6 secretion by normal human bladder smooth muscle cells after in vitro stimulation with inflammatory and non- inflammatory stimuli and treatment with analgesic Stimuli Analgesic IL-6 (pg/ml)" IL-6 (pg/ml) Subject I Subject 2 None None < 5 < 5 Carbachol 10-M None 232 278 Carbachol I10 M Acetaminophen (50 pM) 119 135 Carbachol i0- 3 M Aspirin (50 pM) 95 146 Carbachol 103 M Ibuprofen (50 pM) 107 118 Carbachol 10 M Naproxen (50 pM) 114 127 38 WO 2013/103389 PCT/US2012/051859 LPS (10 pg/m) None 4838 4383 1PS (10 pg/mal) Acetaminophen (5 PM) 2012 2308 LPS (10 pm) Aspirin (5 pM) 2199 2089 LPS (10 pg/ul) Ibuprofen (5 pM) 2063 2173 LPS (10 pg/ml) Naproxen (5 pM 2077 2229 LPS (10 pg/lrI) Acetaminophen (50 pM) 2018 1983 LPS (10 Lg/ul) Aspirin (50 aM) 1987 2010 LPS (10 pg/ml) lbuprofen (50 pM) 2021 1991 LPS (10 g/ml) Naproxen (50 pM) 2102 2028 4 Data are expressed as mean of duplicates 10139] Primary normal human bladder smooth muscle cells were isolated, cultured and evaluated for their responses to analgesics in the presence of non-inflanmatory (carbachol) and inflammatory (LPS) stimuli. The goal of this study was to determine whether or not nonnal human bladder smooth muscle cells recapitulate the observations previously made with murine bladder cells. 10140] The above-described experiment will be repeated with analgesic agents and/or antimuscarinic agents in delayed-release, or extended-release formulation or delayed-and extended-release formulations. [0141] The above description is for the purpose of teaching the person of ordinary skill in the art how to practice the present invention, and it is not intended to detail all those obvious modifications and variations of it which will become apparent to the skilled worker upon reading the description. It is intended, however, that all such obvious modifications and variations be included within the scope of the present invention, which is defined by the following claims. The claims are intended to cover the claimed components and steps in any sequence which is effective to meet the objectives there intended, unless the context specifically indicates the contrary. 39

权利要求:
Claims (30)
[1] 1. A method for reducing the frequency of urination, comprising: administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a first analgesic agent, wherein said pharmaceutical composition is formulated in delayed-release formulation and wherein said first analgesic agent is administered orally at a daily dose of 5 mg to 2000 mg.
[2] 2. The method of Claim 1, wherein said delayed-release formulation comprises a material selected from the group consisting of hydroxypropyl methylcellulose, methyleellulose, methyl hydroxyethylcellulose, hydroxypropyleellulose, carboxymethyle ellulose, acrylate copolyiners, polyethylene glycols, polyvinylpyrrolidone, methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and ethylcellulose.
[3] 3. The method of Claim 2, wherein said delayed-release formulation further comprises glyceryl monostearate or glyceryl distearate.
[4] 4, The method of Claim 1, wherein said delayed-release formulation comprises a water insoluble capsule body closed at one end with an insoluble, but permeable and swellable hydrogel plug, wherein said plug comprises a material selected from the group consisting of polyrnethacrylates, erodible compressed polymers, congealed melted polymer and enzymatically controlled erodible polymers.
[5] 5. The method of Claim 1, wherein said delayed-release formulation comprises an enteric coating.
[6] 6. The method of Claim 1, wherein said first analgesic agent is selected from the group consisting of aspirin, ibuprofen, naproxen, and acetaminophen, and wherein said first analgesic agent is administered orally at a daily dose of 50 ing to 500 mg.
[7] 7. The method of Claim 6, wherein said first analgesic agent is administered orally at a daily dose of 100 mg to 500 mg.
[8] 8. The method of Claim 7, wherein said first analgesic agent is administered orally at a daily dose of 250 mg to 500 mg.
[9] 9. The method of Claim 1, wherein said first analgesic agent is administered orally at a daily dose of 250 ig to 1000 ig.
[10] 10. The method of Claim 1, wherein said pharmaceutical composition further comprises: 40 WO 2013/103389 PCT/US2012/051859 a second analgesic agent selected from the group consisting of acetaminophen, aspirin, ibuprofen, and naproxen, wherein said second analgesic agent is different from said first analgesic agent and is administered orally at a daily dose of 5 mg to 2000 mg.
[11] 11, The method of Claim 10, wherein said second analgesic agent is administered orally at a daily dose of 50 mg to 500 mg.
[12] 12. The method of Claim 11, wherein said second analgesic agent is administered orally at a daily dose of 100 mg to 500 mg.
[13] 13. The method of Claim 12, wherein said second analgesic agent is administered orally at a daily dose of 250 mg to 500 mg.
[14] 14. The method of Claim 10, wherein said second analgesic agent is administered orally at a daily dose of 250 mg to 1000 mg.
[15] 15. The method of Claim 1, wherein said pharmaceutical composition farther comprises one or more antimuscarinic agents selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine.
[16] 16. The method of Claim 1, wherein said pharmaceutical composition further comprises one or more antidiuretics.
[17] 17. The method of Claim 1, wherein said pharmaceutical composition further comprises one or more spasmolytics.
[18] 18. The method of Claim 1, further comprising: administering to said subject a diuretic; wherein said diuretic is administered at least 8 hours prior to a target time, and wherein said pharmaceutical composition is administered within 2 hours prior to said target time.
[19] 19. A method for reducing the frequency of urination, comprising: administering orally to a subject in need thereof an effective amount of a pharmaceutical composition comprising a plurality of active ingredients, wherein said plurality of active ingredients comprises: (1) one or more analgesic agents and (2) one or more antimuscarinic agents, and wherein said one or more analgesic agents are administered at a combined daily dose of 5 mg to 2000 mg.
[20] 20. The method of Claim 19, wherein said pharmaceutical composition is formulated for immediate-release of said plurality of active ingredients. 41 WO 2013/103389 PCT/US2012/051859
[21] 21. The method of Claim 19, wherein said pharmaceutical composition contains two active ingredients, one is formulated for immediate-release and the other one is formulated for delayed-release.
[22] 22. The method of Claim 19, wherein said pharmaceutical composition contains two active ingredients, both active ingredients are formulated for immediate-release and delayed release.
[23] 23. The method of Claim 19, wherein said pharmaceutical composition contains two active ingredients, one is formulated for delayed-release at a first time point and the other one is formulated for delayed-release at a second time point.
[24] 24. The method of Claim 19, wherein said one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen, and acetaminophen, and wherein said one or more antimuscarinic agents are selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine.
[25] 25, The method of Claim 19, wherein said plurality of active ingredients consist of two analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen, and acetaminophen.
[26] 26. The method of Claim 19, wherein said plurality of active ingredients further comprise one or more antidiuretics.
[27] 27. The method of Claim 19, wherein said plurality of active ingredients further comprise one or more spasmolytics.
[28] 28. A pharmaceutical composition, comprising: one or more analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen, and acetaminophen; one or more antidiuretics; and a pharmaceutically acceptable carrier, wherein at least one of said one or more analgesic agents is formulated for delayed release.
[29] 29. The pharmaceutical composition of Claim 28.
[30] 30. The pharmaceutical composition of Claim 28, further comprise one or more spasmolytics. 42

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法律状态:
2014-07-24| DA3| Amendments made section 104|Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 24 JUN 2014 |

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2017-07-06| FGA| Letters patent sealed or granted (standard patent)|

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2020-04-02| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|

优先权:

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申请号 | 申请日 | 专利标题

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US13/343,349||2012-01-04||

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US13/343,349|US20120141554A1|2010-07-08|2012-01-04|Delayed release formulation for reducing the frequency of urination and method of use thereof|

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US13/423,949|US8236856B2|2010-07-08|2012-03-19|Delayed release formulation for reducing the frequency of urination and method of use thereof|

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US13/423,949||2012-03-19||

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US13/487,343||2012-06-04||

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US13/487,343|US20120237574A1|2010-07-08|2012-06-04|Delayed-release formulation for reducing the frequency of urination and method of use thereof|

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PCT/US2012/051859|WO2013103389A1|2012-01-04|2012-08-22|Delayed-release formulation for reducing the frequency of urination and method of use thereof|

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