Dosage form with prolonged release of tapentadolphosphoric acid salt

专利摘要:
The invention relates to a pharmaceutical dosage form which provides sustained release of tapentadol, wherein tapentadol is present in the form of a salt with phosphoric acid (orthophosphoric acid), preferably as dihydrogen phosphate salt. The dosage form of the invention provides improved sustained release properties, is particularly resistant to ethanol-induced dose dumping, and imparts, in addition to such resistance, additional safety properties associated with concomitant use of ethanol, e.g. alcoholic beverages.
公开号:DK202100018U1
申请号:DK202100018U
申请日:2021-03-01
公开日:2021-06-09
发明作者:Bertram Ulrike；Reinhold Ulrich；Grosse Christian；Hartmann Carmen
申请人:Gruenenthal Gmbh；
IPC主号:

专利说明:

DK 2021 00018 U1 1 Introduction The invention relates to a pharmaceutical dosage form which gives prolonged release of tapentadol, where tapentadol is present in the form of a salt with phosphoric acid (orthophosphoric acid), preferably as dihydrogen phosphate salt. The dosage form of the invention provides improved sustained release properties, is particularly resistant to ethanol-induced dose dumping, and imparts, in addition to such resistance, additional safety properties associated with concomitant ethanol ingestion, e.g. alcoholic beverages.
Several depot formulations may be subject to ethanol-induced dose-dumping (also referred to as alcohol-induced dose-dumping, alcohol-dose-dumping, ethanol-dose-dumping, etc.), which has been defined as “unintentional, rapid drug release within a short period of the total amount or significant proportion of the drug. contained in a modified-release dosage form. ” Among the numerous classes of drugs available commercially as depot products, opioids, centrally acting drugs and drugs with a narrow therapeutic index present a high risk of dose dumping, even if formulated in a way that releases the drug in an individually tailored manner. and delayed show. Attention to ethanol-induced dose dumping has led to the withdrawal of some marketed products by regulators and box warnings to others. Since then, significant efforts have been made to demonstrate the robustness of a formulation when ingested with alcohol. The patient risk is considered to be low if the formulation and its properties are unimpaired in the presence of 0-40% alcohol under in vivo and in vitro conditions (see D'Souza et al., A review of in vivo and in vitro aspects or alcohol-induced dose dumping, AAPS Open (2017) 3: 5, 1-20).
In the most pronounced case, concomitant use of the previously available analgesic Palladone ™ (Purdue Pharma; hydromorphone hydrochloride prolonged-release capsules) with alcohol resulted in significantly higher plasma levels of hydromorphone (up to 16-fold higher), especially in the fasted state. This observation led to the cessation of its use as well as withdrawal from the market. In vitro studies of another long-acting opioid, Avinza® (Pfizer Inc; morphine sulphate prolonged-release capsules), showed accelerated release of morphine-dependent morphine. Box warnings on Avinza%, as well as other long-acting / long-acting opioids, do not advise patients to drink alcoholic beverages or to use prescription or over-the-counter medicines containing alcohol.
DK 2021 00018 U1 2 action, as this may result in rapid release and absorption of a potentially fatal dose of opioid. According to Jedinger et al., The design of controlled-release formulations resistant to alcohol-induced dose dumping - A review, Eur J Pharm Biopharm. 2014 Jul; 87 (2): 217-26, the US Drug Administration currently recommends that the FDA assess the risk of alcohol-induced dose dumping for opioid and non-opioid drugs with a narrow therapeutic index. In particular, depot formulations, which offer reduced dosing frequency and prolonged therapeutic effect due to higher drug volumes, are of particular interest. For example, controlled release opioid dosage forms have been used as standard formulations in the treatment of (chronic) pain. However, if patients suffer from pain, they often resort to alcohol to endure the pain-related strain and reduce the pain sensation.
The most damaging effect is the first, which can occur due to rapid dose scaling. Thus, if the dosage form is taken with ethanol, the drug release may increase immediately, resulting in an overdose and leading to respiratory failure followed by oxygen deficiency and even death. Apart from the side effects associated with ethanol, the mechanistic understanding of oro-gastrointestinal absorption and liver metabolism is important. Following oral administration of a dose-dumped formulation with ethanol, a major proportion of the drug is immediately dissolved in the stomach. After a sufficient period of gastric retention, the entire amount of the dissolved drug is uncontrollably discharged into the small intestine. Thus, absorption occurs, which can result in high plasma concentrations.
Thus, to avoid these effects, it is desirable to provide dosage forms with such release properties that release in aqueous ethanol is substantially not accelerated compared to release in non-ethanol medium (resistance to ethanol-induced dumping).
However, the above consequences of an initial wave of drug release are not the only risk associated with concomitant use of ethanol. It is known that the consumption of alcoholic beverages can prolong the rate of gastric emptying and thus the onset of drug absorption due to the caloric content of alcohol, which is comparable to the slightly saturated state after eating a meal (see also Jedinger et al., The design for further details of controlled-release formulations resistant to alcohol-induced dose dumping - A review, Eur J Pharm Biopharm. 2014 Jul; 87 (2): 217-26).
DK 2021 00018 U1 3 The modes of action by which alcohol alters the pharmacokinetic properties of long-acting opioids are poorly understood. Several studies have shown that concomitant use of alcohol increases the maximum plasma concentration (Cmax) for certain opioids and shortens the time to Cmax (tmax), although there is no evidence of dose dumping.
Fatal poisonings involving prescription opioids are often associated with alcohol use and are likely due to combined central nervous system and respiratory depressant effects. It has been reported that opioids can significantly reduce the respiratory response to hypercapnia when co-administered with ethanol, although no pharmacokinetic interaction was observed (see Gudin et al., Risks, Management, and Monitoring of Combination Opioid, Benzodiazepines, and / or Alcoho / Use, Postgrad Mes 2013 125 (4) 115-130).
Thus, although pharmaceutical dosage forms can be provided which are resistant to ethanol-induced dose dumping, i.e. which do not exhibit accelerated dissolution in aqueous ethanol compared to non-ethanol medium and therefore do not give an initial wave of drug release when they are ingested along with ethanol, there are additional safety considerations that are associated with ethanol effects. There is a demand for pharmaceutical dosage forms that offer additional safety properties that go beyond the mere resistance to ethanol-induced dose dumping. In particular, it would be desirable to provide pharmaceutical dosage forms which not only provide non-accelerated but which offer inhibited solution in aqueous ethanol compared to non-ethanol medium. It is to be expected that such pharmaceutical dosage forms are less prone to the risks associated with the co-administration of the drug with concomitant ethanol, for at any given time less opioid is made available to the organism due to inhibited solution where it could interact with concomitant ethanol.
Tapentadol (Nucynta®, Palexia®) is an oral opioid analgesic in the benzenoid class with a dual mechanism of action similar to the ditto of tramadol; it is a β-opioid receptor agonist and also inhibits the reuptake of norepinephrine. Tapentadol is currently available as an oral dosage form containing immediate-release or sustained-release tapentadol hydrochloride salt.
According to Farr et al., Effects of food and alcohol on the pharmacokinetics of an oral, extended-release formulation of hydrocodone in healthy volunteers, Clinical Pharmacology: Advances and Applications 2015: 7 1-9, increased absorption has been seen in the case of several depotopioid formulations after ingestion
DK 2021 00018 U1 4 but with alcohol. The authors show the following comparison of alcohol interaction data for marketed depotopioid products in Table 3 on page 8: Opioid Mean Increase in | Maximum individual Cmax ratio in relation to | Cmax ratio with 40% drug intake alcohol together with 0% alcohol According to the FDA's draft guidelines regarding tapentadol hydrochloride (available at the internet address: Atips.// www. Accessdata. Fda.gov/drugsetfde - docs / pso / Tepentadol 20ER7abs 200533 RCO8- 10.007), the Authority currently requires, due to a concern about drug dose dumping from this medicinal product when ingested with alcohol, that further dissolution testing be performed using different ethanol concentrations in the dissolution medium.
The pharmaceutical dosage forms of tapentadol currently on the market already provide satisfactory resistance to ethanol-induced dose dumping. An in vivo crossover study examined the effect of alcohol (240 ml, 40%) on the bioavailability of a single dose of 100 mg and 250 mg Nucynta® prolonged-release tablets in 19 healthy fasting volunteers. Following co-administration of a 100 mg Nucynta® prolonged-release tablet and alcohol, the mean Cmax value increased by 48% compared to the control sample (water intake instead of alcohol) in a range from 0.99 times up to 4.38 times. In addition, the 3 individuals (15%) with the highest Cmax values had values that were at least 2.3 times higher than the control's average Cmax value. The mean AUCist (area under concentration-time curve from dosing time to last measured concentration) and AUCs (area under curve towards infinity) increased by 17%; Tmax 0g ti, 2 were relatively unchanged. Following co-administration of a 250 mg Nucynta® prolonged-release tablet and alcohol, the mean Cmax value increased by 28% compared to the control sample in a range from 0.90 times up to 2.67 times. The individual Cmax-
DK 2021 00018 U1 value for 2 of these individuals (10%) was at least 2.6 times higher than the mean Cmax value of the control. The mean tapentadol AUCiast and AUCint increased by 16%; Tmax 0g T1.2 were relatively unchanged.
Nevertheless, concomitant use of alcohol should be avoided as Nucynta4 prolonged-release tablets are expected to have additive effects when used in conjunction with alcohol (see PRODUCT MONOGRAPH, Nucynta & Extended-Release Tapentadol, 28 October 2013, revised 1 March 2018).
Therefore, prescription information for Nucynta® and Palexia®, despite having satisfactory resistance to ethanol-induced dose dumping, contains instructions not to consume alcohol or products containing alcohol when taking the drug.
Several trials have been described in the literature regarding the provision of pharmaceutical dosage forms containing strong opioids such as tapendatol, which have a further reduced potential for ethanol-induced dose dumping.
WO 2015/004245 A1 relates to a tamper-proof, oral pharmaceutical dosage form comprising a pharmacologically active ingredient having a psychotropic effect and an ethylene vinyl acetate (EVA) polymer which imparts resistance to solvent extraction, resistance to comminution and resistance to water resistance. The pharmacologically active ingredient is preferably selected from the group consisting of oxycodone, oxymorphone, hydrocodone, hydromorphone, tramadol, tapentadol, morphine, buprenorphine and the physiologically acceptable salts thereof. The dosage forms are preferably multiparticulate and the manufacture requires the application of heat and pressure. The particles are preferably extruded small spheres, i.e. they are made by thermoforming using an extruder. All examples relate to multiparticulate dosage forms in which the particles are prepared by hot melt extrusion.
WO 2018/219897 A1 relates to an oral dosage form comprising several coated particles, wherein the coated particles comprise a core which comprises a tapentadol component and which is coated with a prolonged-release tablet coating material, wherein the prolonged-release tablet coating material comprises a lubricant component and a polymer component, wherein the polymer component comprises one or more cellulose ethers and / or one or more acrylates, and wherein the pharmaceutical dosage form provides controlled release of the tapentadol component. The prolonged-release tablet coating material serves the purpose of controlling the release of the tapentadole component from the coated particles. The prolonged-release tablets of the prolonged-release tablet
DK 2021 00018 U1 6 tablet coatings may form the outer surface of the particles or may be further coated with one or more layers of different or identical coating materials, e.g. to make the particles resistant to ethanol-induced dose dumping. When the particles are made from nonpareil sugar spheres, they are coated with a drug coating comprising tapentadol. These particles are further coated with a prolonged-release tablet coating comprising prolonged-release tablet coating material. When the coated particles provide resistance to ethanol-induced dose dumping, they contain at least two other coating layers, namely an inner layer comprising an alginate salt and an outer layer comprising an anionic acrylate polymer.
However, known concepts for avoiding ethanol-induced dose dumping are not satisfactory and there is a demand for improved concepts. It would be desirable to provide oral dosage forms of tapentadol which are easy to prepare and do not require e.g. thermoforming or multiple coating steps. The oral dosage forms should preferably be provided in the form of tablets, preferably monolithic tablets, i.e. do not require the manufacture of multiple particles. The preparation of the oral dosage forms should be possible on standard equipment on a large industrial scale, preferably by compressing powder mixtures or extensive granulation (dry granulation or wet granulation), but preferably by direct compaction of powder mixtures.
In particular, it would be desirable to provide additional safety properties, namely to make available pharmaceutical dosage forms which not only exhibit the approximately same dissolution profile in aqueous ethanol and in non-ethanol medium, but which in view of the different effects of ethanol included on the pharmacological profile provides an even more delayed solution in aqueous ethanol compared to non-ethanol medium. In addition, it would be desirable to reduce the amount of excipients required to impart delayed release of tapentadole, e.g. in connection with oral administration twice daily.
It is an object of the invention to provide pharmaceutical dosage forms of tapentadol which have advantages over the pharmaceutical dosage forms of the prior art. The pharmaceutical dosage forms should be safe and easy to manufacture economically, should provide beneficial patient survival and resistance to ethanol-induced dose dumping, should provide additional safety properties with respect to co-administration of ethanol, in particular a more delayed solution in aqueous ethanol compared to
DK 2021 00018 U1 7 non-ethanol medium, so that changes in the pharmacological profile are less likely to occur due to the inclusion of ethanol.
This object is achieved by the content of the utility model requirements.
Summary of the Product The product provides a pharmaceutical dosage form comprising tapentadol for oral administration twice daily; wherein tapentadol is present as a salt with phosphoric acid; wherein the dosage form provides sustained release of tapentadol; and wherein the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form ranges from 10 to 300 mg based on the free base of tapentadol (Mr = 221.3 g / mol). It has surprisingly been found that salts of tapendatol with phosphoric acid (H3PO4) are particularly useful for extended-release pharmaceutical dosage forms of tapentadol.
It has surprisingly been found that dosage forms containing salts of tapentadol with phosphoric acid give slower release in vitro of tapentadol in ethanol medium than in non-ethanol medium.
These dosage forms are therefore expected to further prolong the drug release in vivo upon ingestion with ethanol.
This effect does not depend on the particle size of the salts of tapentadol with phosphoric acid or on the polymorphic form of the salts of tapentadol with phosphoric acid.
Furthermore, this effect is seen in depot matrices comprising different depot matrix materials (eg hypromellose or Kollidon®SR), ie. it can be attributed to the properties of the salt of tapentadol with phosphoric acid as such.
In addition, it has surprisingly been found that compared to tapentadol hydrochloride contained in the pharmaceutical depot dosage forms currently on the market, such salts of tapentadol with phosphoric acid have a lower thermodynamic solubility as well as a lower inherent dissolution rate.
These dissolution properties of the phosphate salts of tapentadol make them particularly suitable for the preparation of sustained release dosage forms.
Such dosage forms may contain reduced amounts of depot matrix material to obtain the same solution profile as the currently marketed dosage forms containing tapentadol hydrochloride.
Salts of tapentadol with phosphoric acid are known, e.g. from WO 2010/096045, WO 2012/010316 A1, WO 2012/051246 A1 and WO 2017/182438 A1. However, none of these publications deals with the use of the salts to avoid ethanol-induced dose dumping.
Dosage forms giving sustained release of tapentadol are also known.
DK 2021 00018 U1 8 so, e.g. from WO 03/035053 a1, WO 2006/002886 A1 and WO 2009/092601 A1. However, none of these references deal with the avoidance of ethanol-induced dose dumping, and none of these documents describe salts of tapentadol with phosphoric acid.
According to the instructions for use, the commercially available tapentadol tablets contain Palexia®retard tapentadol as the hydrochloride salt, while the tablet core also contains hypromellose, microcrystalline cellulose, highly dispersed silica and magnesium stearate. Thus, Palexia® retard tablets contain a prolonged-release matrix of hypromellose. The tablet cores are film-coated with a composition comprising hypromellose, lactose monohydrate, talc, macrogol 6000 and dyes. These tablets are in accordance with WO 03/035053 A1 and with the comparative examples contained herein in the experimental section.
Brief Description of the Drawings Figure 1 shows the XRPD spectrum of tapentadol dihydrogen phosphate (mixed form) as obtained according to Example 1.1.
Figure 2 shows the XRPD spectrum of tapentadol dihydrogen phosphate hemihydrate as obtained according to Example 1.4.
Figure 3 shows the DSC plot of tapentadol dihydrogen phosphate hemihydrate as obtained according to Example 1.4.
Figure 4 shows the XRPD spectrum of tapentadol dihydrogen phosphate anhydrate as obtained according to Example 1.6 Figure 5 shows the DSC plot of tapentadol dihydrogen phosphate anhydrate as obtained according to Example 1.6.
Figure 6 shows three photographs of different particle sizes of the salt of tapentadol with phosphoric acid (Figure 6A shows relatively fine particles, Figure 6B relatively coarse particles) and of the salt of tapentadol with hydrochloric acid (Figure 6C).
Figure 7 compares the in vitro dissolution profiles of a conventional tablet containing tapentadol hydrochloride and a tablet according to the invention containing salt of tapentadol with phosphoric acid in 0.1 N HCl (pH 1.0) and in 0.1 N HCl (pH 1.0) with 40 volume percent ethanol.
Figure 8 compares the in vitro dissolution profiles of a conventional tablet containing tapentadol hydrochloride and a tablet according to the invention containing salt of tapentadol with phosphoric acid at pH 4.5 in aqueous buffer (without ethanol).
Figure 9 compares the in vitro dissolution profiles of a conventional tablet containing tapentadol hydrochloride at pH 1.0, pH 4.5, pH 6.8, in each
DK 2021 00018 U1 9 single case in aqueous buffer without ethanol, and at pH 1.0 in 40% by volume ethanol.
Figure 10 compares the in vitro dissolution profiles of a tablet according to the invention containing salt of tapentadol with phosphoric acid at pH 1.0, pH 4.5, pH 6.8, in each case without ethanol, and at pH 1.0 in 40 volumes - percent ethanol.
Figure 11 compares the in vitro dissolution profiles of a tablet according to the invention containing salt of tapentadol with phosphoric acid in 0.1 N HCl (pH 1.0) without ethanol and in 0.1 N HCl (pH 1.0) with 40% by volume ethanol.
Detailed Description of the Generation A first aspect of the invention relates to a pharmaceutical dosage form comprising tapentadol for oral administration twice daily; wherein tapentadol is present as a salt with phosphoric acid; wherein the dosage form provides sustained release of tapentadol; and wherein the weight equivalent dose of tapendatol contained in the pharmaceutical dosage form is in the range of 10 to 300 mg based on the free base of tapentadol.
Tapentadol, i.e. (-) - (1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methylpropyl) -phenol, is a synthetic, centrally acting analgesic that is effective in the treatment of moderate to severe, acute or chronic pain. The synthesis of the free base of tapentadol is known e.g. from EP-A 693475.
The pharmaceutical dosage form of the invention contains tapentadol as a salt with phosphoric acid. While it is contemplated that the pharmaceutical dosage form of the invention may contain mixtures of different salts of tapentadol or mixtures of one or more salts with the free base of tapentadol (the non-salt form of tapentadol), it is preferred that the total amount tapentadol, which is contained in the pharmaceutical dosage form, is present as a salt with phosphoric acid.
Salts of tapentadol with phosphoric acid according to the invention mainly include the orthophosphate salts (PO4-), the monohydrogen phosphate salts (HPO4 *) and the dihydrogen phosphate salts (H> PO4 '). Condensation products of phosphoric acid such as metaphosphate salts or pyrophosphate salts are also contemplated, but are less preferred. The tapentadiol dihydrogen phosphate salts are particularly preferred.
The salts of tapentadol with phosphoric acid are preferably the dihydrogen phosphate salt of tapentadol, which may optionally be present as solvate (eg hydrate) or ansolvate (eg anhydrate). Preferably, the dihydrogen phosphate salt is of
Tapentadol selected from the group consisting of dihydrogen phosphate solvate salt of tapentadol, dihydrogen phosphate anhydrate salt of tapentadol, dihydrogen phosphate solvate salt of tapentadol, dihydrogen phosphate hydrate salt of tapentadol, and any mixture of the foregoing. The tapentadole salt may be present as a single polymorph or as a mixture of different polymorphs in any mixing ratio.
In a preferred embodiment, the salt of tapentadol with the phosphoric acid is the dihydrogen phosphate salt, which is present in a substantially pure crystalline form of tapentadol dihydrogen phosphate hemihydrate salt.
In a preferred embodiment, the salt of tapentadol with the phosphoric acid is the dihydrogen phosphate salt, which is present in a substantially pure crystalline form of tapentadol dihydrogen phosphate hydrate salt.
In a preferred embodiment, the salt of tapentadol with phosphoric acid is a crystalline dihydrogen phosphate salt with characteristic X-ray powder diffraction peaks at 5.1, 14.4, 17.7, 18.3 and 21.0 degrees 20 (+ 0.2 degrees 20). ; preferably with one or more additional XRPD diffraction peaks at 8.7, 17.6, 20.3, 22.1 and / or 23.4 degrees 20 (+ 0.2 degrees 20). Alternatively, the crystalline dihydrogen phosphate salt may be peculiar at one or more XRPD diffraction peaks at degrees 20 + 0.2 degrees 20 (intensity%): 5.1 (100), 8.7 (10), 10.1 (1 ), 12.5 (3), 13.4 (4), 14.4 (37), 15.3 (4), 17.6 (12), 17.7 (15), 18.3 (27) , 19.1 (7), 20.3 (1 1), 21.0 (25), 21.6 (9), 22.1 (18), 23.4 (14), 24.8 (7) , 25.0 (17), 25.3 (12), 26.0 (9), 26.5 (7), 26.8 (9), 28.0 (5), 28.4 (4), 28.9 (10), 29.2 (6), 29.4 (4), and 29.6 (2). Alternatively, the crystalline dihydrogen phosphate salt may have one or more XRPD diffraction peaks at degrees 20 + 0.2 degrees 20: 5.1, 8.7, 10.1, 12.5, 13.4, 14.4, 15.3, 17.6, 17.7, 18.3, 19.1, 20.3, 21.0, 21.6, 22.1, 23.4, 24.8, 25.0 and 25, 3.
In another preferred embodiment, the salt of tapentadol with phosphoric acid is a crystalline dihydrogen phosphate salt with characteristic X-ray powder diffraction peaks at 5.1, 14.3, 17.6, 18.5 and 21.1 degrees 20 (+ 0.2 degrees 20); preferably with one or more additional XRPD diffraction peaks at 8.9, 20.5, 22.4, 23.5 and / or 24.3 degrees 20 (+ 0.2 degrees 20). Alternatively, the crystalline dihydrogen phosphate salt may have one or more XRPD diffraction peaks at degrees 20 + 0.2 degrees 20 (intensity%): 5.1 (100), 8.9 (3), 12.4 (5), 13.5 (4), 14.3 (42), 15.2 (4), 17.6 (21), 18.5 (18), 19.1 (7), 20.5 (14), 21.1 ( 28), 21.7 (9), 22.4 (14), 23.5 (15), 24.3 (6), 24.9 (19), 25.1 (16), 25.8 (3 ), 26.2 (12), 26.4 (13), 26.7 (5), 27.3 (2), 28.2 (5), 28.8 (8), 29.1 (1 1 ),
DK 2021 00018 U1 11 29.4 (5), and 29.6 (5). Alternatively, the crystalline dihydrogen phosphate salt may have one or more XRPD diffraction peaks at degrees 20 + 0.2 degrees 20: 5.1, 8.9, 12.4, 13.5, 14.3, 15.2, 17.6, 18.5, 19.1, 20.5, 21.1, 21.7, 22.4, 23.5, 24.3, 24.9, and 25.1.
The tapentadole salt with phosphoric acid preferably has an average particle size, expressed as surface mean value D [3,2] (Sauter Mean Diameter) and determined by laser diffraction in dry mode in accordance with ISO 13320: 2020, in the range 5.0 to 500 μm, preferably 50 + 40 um, or 75 + 40 um, or 100 + 40 um, or 125 + 40 um, or 150 + 40 um, or 175 + 40 um, or 200 + 40 um, or 225 + 40 um, or 250+ 40 um, or 275 + 40 um, or 300 + 40 um, or 325 + 40 um, or 350 + 40 um, or 375 + 40 um, or 400 + 40 um, or 425 + 40 um, or 450 + 40 um .
In a preferred embodiment, the salt of tapentadol with phosphoric acid is in crystalline form. In another preferred embodiment, the salt of tapentadol with phosphoric acid is in amorphous form. It is further contemplated that the pharmaceutical dosage forms may contain mixtures of crystalline salt of tapentadol with phosphoric acid with amorphous salt of tapentadol with phosphoric acid in any mixing ratio. Preferably, substantially all of the salt of tapentadol with phosphoric acid present in the pharmaceutical dosage form is crystalline.
For purposes of the description, the dihydrogen phosphate salt of tapentadol should be considered as the acid addition salt of 1 mole of orthophosphoric acid to 1 mole of tapentadol. It is believed that a proton from orthophosphoric acid (HsPO4) protonates the amino group in tapentadol and thereby forms an ammonium ion, while the rest of the orthophosphoric acid, i.e. the dihydrogen phosphate anion (H> PO4), forms the counterion: CH; CH; z A NH + HO i NCH;
H CH; For purposes of the description, the reference to “tapentadol” should include the salt of tapentadol with phosphoric acid.
The salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, may be present in the form of any solvate, e.g. hydrate, ansolvate, e.g. anhydrate, and polymorphic form, e.g. any
DK 2021 00018 U1 12 crystalline form and / or amorphous form. With regard to these shapes and their manufacture, reference is made to WO 2012/010316 A1 and WO 2017/182438 A1.
The weight equivalent dose of tapentadol contained in the pharmaceutical dosage form of the invention is in the range of 10 to 300 mg based on the free base of tapentadol, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg. The free base of tapentadol (ie the free molecule) has a molecular weight of 221.3 g / mol. Thus, 10 mg of the free base of tapentadol corresponds to 0.0452 mmol, while 300 mg of the free base of tapentadol corresponds to 1.3556 mmol. In other words, the pharmaceutical dosage form thus contains a molar equivalent dose of tapentadol in the range of 0.0452 to 1.3556 mmol.
The hydrochloride salt of tapentadol (anhydrate) has a molecular weight of 257.8 g / mol, while the dihydrogen phosphate salt of tapentadol (anhydrate) has a molecular weight of 319.3 g / mol. Thus, when the pharmaceutical dosage form of the invention contains e.g. a weight equivalent dose of 10 mg based on the free base of tapentadol (0.4518 mm), it actually contains 144.3 mg of dihydrogen phosphate salt of tapentadol (0.4518 mmol).
Unless otherwise expressly stated, dose information for tapentadol is thus expressed as equivalent weight relative to the free base of tapentadol, i.e. the non-salt form, the non-solvate form, the non-cocrystalline form and the non-aggregate form of tapentadol with any other molecules. It is contemplated that the form of tapentadol which is actually contained in the pharmaceutical dosage form, i.e. the salt of tapentadol with phosphoric acid, may be present in the form of any polymorph and / or solvate and / or co-crystal and / or any other aggregate of such a salt with other molecules.
Unless expressly stated otherwise, all percentages are by weight and refer to the total weight of the pharmaceutical dosage form. When the pharmaceutical dosage form is coated, the weight of the coating is included in the total weight of the pharmaceutical dosage form.
Although it is contemplated that the pharmaceutical dosage form may contain additional pharmacologically active ingredients in addition to tapentadol, tapentadol is preferably the only pharmacologically active ingredient contained in the pharmaceutical dosage form.
Tapentadol is preferably uniformly distributed in the pharmaceutical dosage form of the invention.
The pharmaceutical dosage form according to the invention is devoted to oral administration.
DK 2021 00018 U1 13 poison, preferably by swallowing the pharmaceutical dosage form as a whole. The pharmaceutical dosage form of the invention is preferably not directed to cheek or sub-tongue administration where the pharmaceutical dosage form would be referred to remain in the oral cavity.
The pharmaceutical dosage form according to the invention is directed to administration twice daily. Thus, the pharmaceutical dosage form of the invention contains 50% of the daily dose of tapentadol which is intended to be administered in order to produce the desired therapeutic effect.
Administration twice daily can take place at intervals of approximately every 12 hours, although such a program does not need to be strictly followed. For purposes of the description, twice daily should also include any administration program in which two pharmaceutical dosage forms according to the invention are administered over a period of about 24 hours, the two administrations being separated by at least 4 hours, preferably at least 8 hours. .
The pharmaceutical dosage form of the invention provides prolonged release of tapentadol. For purposes of description, extended release does not mean immediate release. Sustained release includes controlled release, delayed release, extended release, staggered release, repeated release, sustained release and evenly sustained release. Prolonged release means a release with a reduced release rate to achieve a therapeutic effect simply, to reduce toxic effects or for the sake of another therapeutic purpose.
Extended release may be based on various technologies known to those skilled in the art. In a preferred embodiment, sustained release is based on sustained release coating materials with which the pharmaceutical dosage form as such or by which a plurality of particles may be coated. In another preferred embodiment, sustained release is based on a depot matrix in which tapentadol is preferably embedded. It is further contemplated in accordance with the invention that sustained release may be achieved by alternative concepts such as ion exchange resins, osmotic dosage forms and the like.
The pharmaceutical dosage form according to the invention provides, after oral administration, a plasma content of tapentadol which provides pain relief (analgesia) of a duration of at least 6 hours, preferably at least 8 hours, more preferably at least 10 hours, most preferably at least 12 hours.
The pharmaceutical dosage form according to the invention preferably provides an in vitro solution profile, measured by the USP Paddle Method at 50 rpm in 900 ml of aqueous phosphate buffer at a pH of 6.8 at 37 ° C, where there - after 0.5 hour has been released 20 + 20% by weight; preferably 20 + 15% by weight; more preferably 20 + 10% by weight; after 4 hours 60 + 20% by weight; preferably 60 + 15% by weight; more preferably 60 + 10% by weight; and - after 12 hours at least 60% by weight; preferably at least 70% by weight; more preferably at least 80% by weight of the amount of tapentadol originally contained in the dosage form. The pharmaceutical dosage form according to the invention preferably provides an in vitro solution profile, measured by the USP Paddle Method at 50 rpm in 900 ml of aqueous phosphate buffer at a pH of 6.8 at 37 ° C, where - after 1 hour has been released 25 + 15% by weight; preferably 25 + 10% by weight; more preferably 25 + 5.0% by weight; after 2 hours 35 + 20% by weight, preferably 35 + 10% by weight; more preferably 35 + 5.0% by weight; after 4 hours 50 + 20% by weight; preferably 50 + 10% by weight; more preferably 50 + 5.0% by weight; and - after 8 hours 80 + 20% by weight; preferably 8010% by weight; more preferably 80 + 5.0% by weight of the amount of tapentadol originally contained in the dosage form.
The pharmaceutical dosage form according to the invention preferably provides an in vitro solution profile, measured by the USP Paddle Method at 50 rpm in 900 ml of aqueous phosphate buffer at a pH of 4.5 at 37 ° C, where - after 0, 5 hour has been released 20 + 20% by weight; preferably 20 + 15% by weight; more preferably 20 + 10% by weight; after 4 hours 60 + 20% by weight; preferably 60 + 15% by weight; more preferably 60 + 10% by weight; and - after 12 hours at least 60% by weight; preferably at least 70% by weight; more preferably at least 80% by weight of the amount of tapentadol originally contained in the dosage form.
The pharmaceutical dosage form according to the invention preferably provides an in vitro solution profile, measured by the USP Paddle Method at 50 rpm in 900 ml of aqueous phosphate buffer at a pH of 4.5 at 37 ° C, where there - after 1 hour has been released 25 + 15% by weight; preferably 25 + 10% by weight; more preferably 25 + 5.0% by weight; after 2 hours 35 + 20% by weight, preferably 35 + 10% by weight; more preferably 35 + 5.0% by weight; after 4 hours 50 + 20% by weight; preferably 50 + 10% by weight; more preferably 50 + 5.0% by weight; and - after 8 hours 80 + 20% by weight; preferably 8010% by weight; more preferably 80 + 5.0% by weight of the amount of tapentadol originally contained in the dosage form.
The pharmaceutical dosage form according to the invention preferably provides an in vitro solution profile, measured by the USP Paddle Method at 50 rpm in 900 ml of 0.1 N HCl at a pH of 1.0 at 37 ° C, where - after 0.5 hour has been released 20 + 20% by weight; preferably 20 + 15% by weight; more preferably 20 + 10% by weight; after 4 hours 60 + 20% by weight; preferably 60 + 15% by weight; more preferably 60 + 10% by weight; and - after 12 hours at least 60% by weight; preferably at least 70% by weight; more preferably at least 80% by weight of the amount of tapentadol originally contained in the dosage form.
The pharmaceutical dosage form according to the invention preferably provides an in vitro solution profile, measured by the USP Paddle Method at 50 rpm in 900 ml of 0.1 N HCl at a pH of 1.0 at 37 ° C, where - after 1 hour has been released 25 + 10% by weight; preferably 25 + 10% by weight; more preferably 25 + 5.0% by weight; after 2 hours 40 + 30% by weight, preferably 40 + 10% by weight; more preferably 40 + 5.0% by weight; after 4 hours 60 + 20% by weight; preferably 60 + 10% by weight; more preferably 60 + 5.0% by weight; and - after 8 hours 80 + 20% by weight; preferably 8010% by weight; more preferably 80 + 5.0% by weight of the amount of tapentadol originally contained in the dosage form.
Preferably, the pharmaceutical dosage form of the invention provides resistance to ethanol-induced dose dumping.
Preferably, the pharmaceutical dosage form according to the invention produces slower in vitro solution of tapentadol in aqueous medium containing than in aqueous medium not containing ethanol.
Preferably, the pharmaceutical dosage form according to the invention gives slower dissolution of tapentadol in 0.1 N HCl containing 5.0 volume percent ethanol (pH 1.0) than in 0.1 N HCl not containing 5.0 volume percent ethanol (pH 1). , 0), in each case measured by the USP Paddle Method at 50 0o / ml 900 ml at 37 ° C.
Preferably, the pharmaceutical dosage form according to the invention gives a slower solution of tapentadol in 0.1 N HCl containing 20% by volume of ethanol (pH 1.0) than in 0.1 N HCl not containing 20% by volume of ethanol (pH 1.0). in each case measured by the USP Paddle Method at 50 rpm 900 ml at 37 ° C.
Preferably, according to the invention, the pharmaceutical dosage form yields a slower solution of tapentadol in 0.1 N HCl containing 40% by volume ethanol (pH 1.0) than in 0.1 N HCl not containing 40% by volume ethanol (pH 1.0). in each case measured by the USP Paddle Method at 50 rpm in 900 ml at 37 ° C.
In preferred embodiments of the pharmaceutical dosage form according to the invention, the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form amounts to 25 mg, 50 mg or 100 mg, in each case based on the free base of tapentadol. The pharmaceutical dosage form according to the invention preferably has a total weight in the range 150 to 750 mg.
In preferred embodiments of the pharmaceutical dosage form according to the invention, the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form amounts to 150 mg, 200 mg or 250 mg, in each case based on the free base of tapentadol. The pharmaceutical dosage form of the invention preferably has a total weight in the range of 300 to 1200 mg.
The pharmaceutical dosage form of the invention preferably comprises one, two or more physiologically acceptable excipients.
Pharmaceutical excipients are known to those skilled in the art (see, e.g., R.C. Rowe et al., Handbook of Pharmaceutical Excipients, Pharmaceutical Press; 6th edition
DK 2021 00018 U1 17 2009; E.-M. Hoepfner et al., Fiedler-Encyclopedia of Excipients, Editio Cantor, 6th edition 2008). For purposes of the description, a "pharmaceutical excipient" should preferably be considered as any pharmacologically inactive substance typically used as a carrier for the active ingredients of a medicament. The pharmaceutical excipient may have a physiological effect, e.g. Typical examples of pharmaceutical excipients include anti-adhesives, binders, coating agents, disintegrants, fillers, diluents, flavoring agents, coloring agents, lubricants, lubricants, preservatives, sweetening agents, sweetening agents, , colors, pigments and the like.
Any of the foregoing excipients may be subdivided into subgroups. For example, preservatives can be divided into antioxidants, buffers, antimicrobial substances and the like, while binders can be divided into solvent binders and dry binders. Several excipients simultaneously exhibit different properties so that they can serve different purposes. For example, polyethylene glycol can be used as a binder, plasticizer and the like.
The binder is preferably selected from the group consisting of cellulose, magnesium-aluminum silicates (eg bentonite), mono-, oligo- and polysaccharides (eg dextrose, lactose, mannose), sugar alcohols (e.g. lactitol, mannitol), starch forms (eg pregelatinized starch, hydrolysed starch, modified starch), calcium phosphate, polyvinylpyrrolidone and vinylpyrrolidone / vinyl acetate copolymers; preferably microcrystalline cellulose; more preferably silicified microcrystalline cellulose.
Preferably the weight content of the binder is at least 5.0% by weight, more preferably at least 10% by weight, even more preferably at least 15% by weight, even more preferably at least 20% by weight, preferably preferably at least 25% by weight, most preferably at least 30% by weight and in particular at least 35% by weight relative to the total weight of the pharmaceutical dosage form.
Preferably the weight content of the binder is at most 85% by weight, more preferably at most 82.5% by weight, even more preferably at most 80% by weight, even more preferably at most 77.5% by weight, preferably at most 75% by weight , most preferably not more than 72.5% by weight and in particular not more than 70% by weight relative to the total weight of the pharmaceutical dosage form.
Preferably, the weight content of the binder is in the range 52 + 30% by weight, more preferably 52 + 27.5% by weight, even more preferably 52 + 25% by weight, even more preferably 52 + 22, 5% by weight, preferably 52 + 20% by weight, most preferably 52 + 17.5% by weight and especially 52 + 15% by weight relative to the total weight of the pharmaceutical dosage form.
When the pharmaceutical dosage form contains more than one binder, the above percentages refer to the total content of all binders contained in the pharmaceutical dosage form.
The pharmaceutical dosage form of the invention preferably comprises a lubricant.
The lubricant is preferably selected from the group consisting of salts of fatty acids (eg magnesium stearate, calcium stearate, zinc stearate), fatty acids (eg stearic acid, palmitic acid), glyceryl fatty acid esters (eg glyceryl monostearate, glyceryl monobehenate, glyceryl dibhenate), , sorbitan monostearate, sucrose monopalmitate, sodium stearyl fumarate, hydrogenated magnesium silicate, and talc; preferably magnesium stearate.
The weight content of the lubricant is preferably at least 0.20% by weight, more preferably at least 0.25% by weight, even more preferably at least 0.30% by weight, even more preferably at least 0.35% by weight, further more preferably at least 0.40% by weight, most preferably at least 0.45% by weight and especially at least 0.50% by weight, in each case relative to the total weight of the pharmaceutical dosage form.
The weight content of the lubricant is preferably at most 3.0% by weight, more preferably at most 2.8% by weight, even more preferably at most 2.6% by weight, even more preferably at most 2.40% by weight, further more preferably at most 2 , 20% by weight, most preferably not more than 2.00% by weight and in particular not more than 1.80% by weight, in each case in relation to the total weight of the pharmaceutical dosage form.
The weight content of the lubricant is preferably in the range of 0.1 to 1.0% by weight, more preferably 0.50 + 0.45% by weight, even more preferably 0.50 + 0.40% by weight, even more preferably 0.50 + 0.35% by weight, further more preferably 0.50 + 0.30% by weight, most preferably 0.50 + 0.25% by weight and especially 0.50 + 0.20% by weight , in each case in proportion to the total weight of the pharmaceutical dosage form.
In preferred embodiments of the pharmaceutical dosage form of the invention, the sustained release dosage form comprises a sustained release coating material selected from the group consisting of hydrophobic cellulose ethers, acrylic polymers, shellac, zein, hydrophobic type products. and mixtures thereof.
It is contemplated that the dosage form is a monolith comprising such a sustained release coating. In a preferred embodiment, the dosage form is multiparticulate, with the individual particles (granules, small spheres and the like) comprising such a sustained release coating.
The number of particles contained in the dosage form is not particularly limited and may range from 1, 2, 3, 4 or 5 to 10, 20, 30, 40 to 100, 200 and more.
Preferably, the particles are of substantially the same weight, size and composition.
In a preferred embodiment, the particles contain a core comprising substantially the full amount of tapentadol, optionally together with one or more excipients, and a sustained release coating encapsulating the core.
In another preferred embodiment, the particles contain an inert core which does not contain any tapentadol (e.g. nonpareil lozenges), a drug coating layer which encapsulates the core and comprises substantially the total amount of tapentadol, optionally together with one or more excipients, and a sustained release coating which encapsulates the core and drug coating layer.
The coating composition extended release is preferably selected from the group consisting of ethylcelllulose, acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, methyl methacrylate, copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methacrylic acid copolymer, aminoalkyl kylmethacrylatcopolymer, methacrylic acid copolymers, methyl methacrylate copolymers, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamide copolymer, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, methyl methacrylate copolymer, poly (methyl methacrylate), poly (methyl methacrylate), poly (methyl methacrylate) , aminoalkyl methacrylate copolymer, poly (methacrylic acid anhydride) and glycidyl methacrylate copolymers.
In preferred embodiments, the acrylic polymer comprises one or more ammonium methacrylate copolymers, i.e. copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. In order to obtain a desirable solution profile, it may be necessary to incorporate two or more ammonium methacrylate copolymers with different physical properties, such as different molar ratios between the quaternary ammonium groups and the neutral (meth) acrylic esters.
The coating is preferably prepared on the basis of an aqueous dispersion or an organic dispersion or an organic solution of a hydrophobic polymer. The coating preferably comprises an effective amount of a plasticizer which is also present in the aqueous dispersion of hydrophobic polymer. The plasticizer further enhances the physical properties of the film. For example, since ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is necessary to soften the ethylcellulose before using it as a coating material. Generally, the amount of plasticizer is included in a coating solution based on the concentration of the film former, e.g. often from about 1% to about 50% by weight of the film former.
Examples of suitable plasticizers for ethylcellulose include water-insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin, although it is possible that other water-insoluble plasticizers (such as acetylated amine phthalates, acetylated monoglycerols, etc. used. Triethyl citrate is a particularly preferred plasticizer for the aqueous dispersions of ethylcellulose according to the present invention.
Examples of suitable emollients for the acrylic polymers of the present invention include, but are not limited to, citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and optionally 1,2-propylene glycol. Other plasticizers which have been found to enhance the elasticity of the films formed from acrylic films such as Eudragit® RL / RS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, American oil and triacetin. Triethyl citrate is a particularly preferred plasticizer for the aqueous dispersions of ethylcellulose in the present invention.
Addition of talc reduces the tendency of the aqueous dispersion to adhere during processing and acts as a polishing agent.
DK 2021 00018 U1 21 In addition to modifying the dissolution profile by changing the relative amounts of different acrylic resin lacquer forms, the dissolution profile of the final product can also be modified by, for example, increasing or decreasing the thickness of the retardant coating. When the aqueous dispersion of hydrophobic polymer is used to coat inert pharmaceutical beads, several of the resulting stabilized sustained release beads can then be placed in a gelatin capsule in an amount sufficient to provide an effective depot dose upon ingestion. - contact and contact with gastric fluid.
The sustained release profile can be changed, for example, by varying the amount of coating with the aqueous dispersion of hydrophobic polymer, changing the way in which the plasticizer is added to the aqueous dispersion of hydrophobic polymer, varying the amount of plasticizer relative to hydrophobic po - glues, include additional ingredients or excipients, change the manufacturing method, etc.
The coating preferably contains, in addition to the film former, plasticizer and solvent system (i.e., water), a dye to impart elegance and product distinctiveness. Suitable ingredients for imparting color to the formulation when an aqueous dispersion of an acrylic polymer is used include titanium dioxide and color pigments such as iron oxide pigments. However, the incorporation of pigments may increase the delay effect of the coating.
The plasticized aqueous dispersion or organic dispersion or organic solution of hydrophobic polymer can be applied to the substrate comprising tapentadol by spraying using any suitable spraying equipment known in the art. In a preferred method, a fluidized bed Wurster system is used in which an air stream injected from below fluidizes the core material and causes drying while the acrylic polymer coating is sprayed on. Preferably, a sufficient amount of the aqueous dispersion of hydrophobic polymer is applied to achieve a predetermined controlled release of tapentadol when the coated substrate is exposed to aqueous solutions, e.g. gastric juice, taking into account the incorporation method of the plasticizer, etc. After coating with the hydrophobic polymer, an additional coating of a film former, such as Opadry®, is optionally applied to the beads. This coating is given, where appropriate, to substantially reduce clumping of the beads.
The release of tapentadol from the prolonged-release formulation may be further affected, ie. adjusted to a desired speed, by adding one or more additional
Release 20 modifying agents, or by providing one or more passes through the coating. The ratio of hydrophobic polymer to water-soluble material is determined, among other factors, by the required release rate and the dissolution properties of the selected materials. The release modifying agents which act as pore formers may be organic or inorganic and include materials which can be dissolved, extracted or leaked from the coating in the environment of use. The pore formers may comprise one or more hydrophilic polymers such as hydroxypropyl methylcellulose. Controlled release coatings may also include degradation promoting agents such as starch and rubber molds. The controlled release coating may also include materials useful for producing microporous laminae in the environment of use, such as polycarbonates comprising linear carbonated polyesters in which carbonate groups reappear in the polymer chain.
In a preferred embodiment, the dosage form is multiparticulate, the individual particles (granules, small spheres and the like) comprising a sustained release coating being contained in a capsule, optionally together with additional excipients which may be contained in the capsule in powder form or also in form of particles (granules, small spheres and the like). In the latter case, the capsules contain at least two different types of particles, namely particles which contain tapentadol and particles which do not contain tapentadol.
In another preferred embodiment, the dosage form is multiparticulate, wherein the individual particles (granules, small spheres and the like) comprising an extended release coating are contained in a tablet containing an extraparticulate material (multi-unit pellet system). The extraparticulate material preferably contains at least one excipient selected from binders, disintegrants and lubricants.
In preferred embodiments of the pharmaceutical dosage form according to the invention, tapentadol is embedded in a depot matrix.
Preferably, the pharmaceutical dosage form according to the invention, preferably the depot matrix, contains at least one physiologically acceptable polymer, which serves the purpose of slowing down the release of the pharmacologically active ingredient from the pharmaceutical dosage form. The at least one physiologically acceptable polymer is thus part of the depot matrix of the pharmaceutical dosage form according to the invention.
DK 2021 00018 U1 23 The depot matrix comprises or consists essentially preferably of at least one depot matrix material selected from the group consisting of hydrophilic or hydrophobic polymers and hydrocarbons.
In preferred embodiments of the pharmaceutical dosage form of the invention, the depot matrix comprises or consists essentially of at least one polymer selected from the group consisting of - polysaccharides or gum forms (e.g. xanthan gum, guar gum, karaya gum, locust bean gum, gum sodium alginate , chitosan, polysaccharides of mannose and galactose, pectin, tragacanth, agar-agar); cellulose ethers (eg HPMC, HPC, HEC, MC, EC); cellulose esters (eg cellulose acetate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate); - polyalkylene glycols and polyalkylene oxides; polyvinyl alcohol (PVA), crosslinked polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), crosslinked polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymers, polyvinylchloride (PVC), polyethylenevinylacylate, polyethylene vinyl acetate, polyether urethane (PEU), polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), polyanhydrides, polyorthoesters; acrylic resins (eg crosslinked homopolymers and copolymers of acrylic acid, acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, methyl methacrylate, copolymers, methacrylic acid acrylic copolymer; copolymer, methacrylic acid copolymers, methyl methacrylate copolymers, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamide copolymer, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, poly methacrylate, methyl methacrylate, methyl methacrylate ly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), and glycidyl methacrylate copolymers, polyhydroxyethyl methacrylate (PHEMA), polyacrylamide); and
DK 2021 00018 U1 24 - protein-derived materials.
The depot matrix essentially comprises or consists essentially of at least one hydrocarbon selected from the group consisting of long chain (Cs-C 50, especially C12-C40) fatty acids, long chain fatty alcohols, glyceryl esters of long chain fatty acids, mineral oils, vegetable oils, and wax forms.
The depot matrix comprises or consists essentially of a depot matrix material selected from the group consisting of (i) hydroxypropyl methylcellulose (HPMC); (ii) hydroxypropylcellulose (HPC); (iii) hydroxyethylcellulose (HEC); (iv) microcrystalline cellulose (MCC); (v) ethylcellulose (EC); (vi) polyvinyl acetate (PVAc); (vii) polyvinylpyrrolidone (PVP); (viii) polyvinylpyrrolidone-vinyl acetate copolymer (PVP / PVAc); (ix) poly (ethyl acrylate-co-methylmethacrylate-co-trimethylammonium ethylmethacrylate chloride); (x) poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate); (xi) poly (methyl methacrylate-co-methacrylic acid); (xii) poly (ethyl acrylate-co-methacrylic acid); (xiii) poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid); (xiv) poly (ethyl acrylate-co-methyl methacrylate); (xv) poly (ethylene oxide) (PEO); (xvi) polyethylene glycol (PEG); (xvii) long chain fatty alcohol having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated, linear or branched; (xviii) cetostearyl alcohol; (xix) stearyl alcohol; (xx) cetyl alcohol; (xxi) hydrocarbon selected from the group consisting of long chain fatty acids having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated, linear or branched; glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils and waxes; (xxii) xanthan gum; (xxiii) sodium alginate; (xxiv) guar gum; (xxv) locust bean gum; and any mixture of the foregoing. Preferably, the content of the depot matrix material is in the range of 15 + 10% by weight, or 2010% by weight, or 2510% by weight, or 30 + 10% by weight, or 35 + 10% by weight, or 40 + 10%. by weight, or 45 + 10% by weight, or 5010% by weight, or 55 + 10% by weight, or 60 + 10% by weight, or 65 + 10% by weight, or 70 + 10 9% by weight, or 75 + 10% by weight, or 80 + 10% by weight, in each case in relation to the total weight of the dosage form.
The pharmaceutical dosage forms of the invention preferably do not comprise poly (alkylene oxide), e.g. poly (ethylene oxide) or ethylene vinyl acetate copolymers (EVA). For the purpose of the description, poly (alkylene oxide) is distinguished from poly (alkylene glycol) by its molecular weight; polymers with a weight average molecular weight Mw of less than 100,000 g / mol are to be regarded as poly (alkylene glycol), while
Polymers with a weight average molecular weight Mw of 100,000 g / mol or more are to be regarded as poly (alkylene oxide).
The depot matrix preferably comprises a cellulose derivative selected from cellulose ethers and cellulose esters or a poly (meth) acrylate or a copolymer thereof.
The cellulose derivative is preferably a cellulose ether selected from the group consisting of methylcellulose, ethylcellulose, propylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose; preferably hydroxypropyl methylcellulose.
The cellulose derivative is preferably hydroxypropyl methylcellulose. The hydroxypropylmethylcellulose is preferably selected from hypromellose type 1828, 2208, 2906 and 2910 according to USP with the following methoxyl and hydroxypropoxyl content: PA re Preferably the viscosity of the physiologically acceptable polymer, preferably cellulose derivative, more preferably hydroxypropylmethylcellulose, is within the range of hydroxypropylmethylcellulose. 80,000 mPa: s, more preferably 100,000 + 60,000 mPa-s, even more preferably 100,000 + 40,000 mPa-s, even more preferred
100,000 + 20,000 mPa: s.
Preferably, the number average molecular weight Mn of the physiologically acceptable polymer, preferably cellulose derivative, more preferably hydroxypropylmethylcellulose, is not more than 220,000 g / mol, more preferably not more than
180,000 g / mol, even more preferably not more than 140,000 g / mol, even more preferably not more than 120,000 g / mol, further more preferably not more than 110,000 g / mol, most preferably not more than 86,000 g / mol, and in particular not more than 63,000 g / mol.
Preferably the weight content of the physiologically acceptable polymer, preferably cellulose ether, is at least 2.0% by weight, more preferably at least 3.0% by weight, even more preferably at least 4.0% by weight, even more preferably at least 5% by weight. , 0% by weight, further more preferably at least 6.0% by weight
DK 2021 00018 U1 26 weight, most preferably at least 7.0% by weight and in particular at least 8.0% by weight, in each individual case in relation to the total weight of the pharmaceutical dosage form.
Preferably the weight content of the physiologically acceptable polymer, preferably cellulose ether, is at most 62.5% by weight, more preferably 60% by weight, even more preferably at most 57.5% by weight, even more preferably at most 55% by weight, further more preferably at most 52.5% by weight, most preferably at most 50% by weight and most preferably at most 47.5% by weight, in each case relative to the total weight of the pharmaceutical dosage form.
Preferably the weight content of the physiologically acceptable polymer, preferably cellulose ether, is in the range 30 + 28% by weight, more preferably 30 + 26% by weight, even more preferably 30 + 24% by weight, even more preferably 30 + 22 % by weight, further more preferably 30 + 20% by weight, most preferably 30 + 18% by weight and in particular at least 30 + 16% by weight, in each case in relation to the total weight of the pharmaceutical dosage form.
When the pharmaceutical dosage form contains more than one physiologically acceptable polymer which serves the purpose of significantly delaying the release of the pharmacologically active ingredient from the pharmaceutical dosage form, preferably cellulose ether, the above percentages refer to the total content of all such physiologically acceptable polymers, preferably cellulose ethers, which are contained in the pharmaceutical dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises hydroxypropyl methylcellulose (HPMC), preferably in an amount of from 5.0 to 60% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight or 40 + 10% by weight or 45 + 10% by weight or 50 + 10% by weight, in each case in relation to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, i
Each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises hydroxypropylcellulose (HPC), preferably in an amount of from 10 to 50% by weight, e.g. 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight or 40 + 10% by weight, in each case in relation to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises hydroxyethylcellulose (HEC), preferably in an amount of from 5.0 to 50% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight or 40 + 10% by weight, in each case in relation to the dosage form total weight.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises microcrystalline cellulose (MCC), preferably in an amount of from 10 to 70% by weight, e.g. 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight or 40 + 10% by weight or 45 + 10% by weight or 50 + 10% by weight or 55 + 10% by weight or 60 + 10% by weight, in each case in relation to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises ethylcellulose (EC), preferably in an amount of from 5.0 to 30% by weight,
DK 2021 00018 U1 28 e.g. 15 + 10% by weight or 20 + 10% by weight, in each case in relation to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises polyvinyl acetate (PVAc), preferably in an amount of from 25 to 70% by weight, e.g. 35 + 10% by weight or 40 + 10% by weight or 45 + 10% by weight or 50 + 10% by weight or 55 + 10% by weight or 60 + 10% by weight, in each case in relation to the dosage form total weight. The polyvinyl acetate is preferably used in a mixture with polyvinylpyrrolidone (polyvidone / povidone). Such a preferred mixture is commercially available e.g.
as Kollidon & SR (80% by weight polyvinyl acetate, 19% by weight polyvidone, 0.8% by weight sodium lauryl sulphate and 0.2% by weight silicic acid).
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises polyvinylpyrrolidone (PVP), preferably in an amount of from 2.0 to 21% by weight, e.g. 105.0% by weight or 15 + 5.0% by weight, in each case in relation to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises polyvinylpyrrolidone-vinyl acetate copolymer (PVP / PVAc), preferably in an amount of from 1.0 to 30% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight, in each case in relation to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form of the invention comprises a weight equivalent dose of tapentadol within
DK 2021 00018 U1 29 range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises poly (ethyl acrylate-co-methyl methacrylate-co-trimethyl-ammonioethyl methacrylate chloride), preferably in an amount of from 5.0 to 45% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight, in each case in relation to the total weight of the dosage form. Poly (ethyl acrylate-co-methyl methacrylate-co-trimethyl-ammonioethyl methacrylate chloride) is commercially available e.g. such as Eudragit ® RS and Eudragit ® RL.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), preferably in an amount of from 5.0 to 45% by weight, e.g.
15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight, in each case in relation to the total weight of the dosage form. Poly (butyl methacrylate co- (2-dimethylaminoethyl) methacrylate co-methyl methacrylate) is commercially available e.g. as Eudragit & E.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises poly (methyl methacrylate-co-methacrylic acid), preferably in an amount of from 5.0 to 45% by weight, e.g. 1510% by weight or 2010% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight, in each case in relation to the total weight of the dosage form. Poly (methyl methacrylate-co-methacrylic acid) is commercially available e.g. as Eudragit & L.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises poly (ethyl acrylate-co-methacrylic acid), preferably in an amount of from 5.0 to 45% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight, in each case in relation to the total weight of the dosage form. Poly (ethyl acrylate-co-methacrylic acid) is commercially available e.g. as Eudragit & S.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid), preferably in an amount of from 5.0 to 45% by weight, e.g. 15 + 10% by weight or 20 + 10 9% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight, in each case in relation to the total weight of the dosage form. Poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid) is commercially available e.g. as Eudragit & FS.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises poly (ethyl acrylate-co-methyl methacrylate), preferably in an amount of from 5.0 to 45% by weight, e.g. 1510% by weight or 2010% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight, in each case in relation to the total weight of the dosage form. Poly (ethyl acrylate-co-methyl methacrylate) is commercially available e.g. as Eudra- git & NE.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises poly (ethylene oxide) (PEO), preferably in an amount of from 25 to 65% by weight, e.g. 35 + 10% by weight or 40 + 10% by weight or 45 + 10% by weight or 50 + 10% by weight or 55 + 10% by weight, in each case relative to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises polyethylene glycol (PEG), preferably in an amount of from 5.0 to 35% by weight, e.g. 15 + 10% by weight or 2010% by weight or 25 + 10% by weight, in each case in relation to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises a long chain fatty alcohol having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated, linear or branched, preferably in an amount of from 15 to 40% by weight, e.g. 25 + 10% by weight or 30 + 10% by weight, in each case in relation to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; where the depot matrix as depot matrix material
DK 2021 00018 U1 32 comprises cetostearyl alcohol, preferably in an amount of from 15 to 40% by weight, e.g. 25 + 10% by weight or 30 + 10% by weight, in each case in relation to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises stearyl alcohol, preferably in an amount of from 15 to 40% by weight, e.g. 25 + 10% by weight or 30 + 10% by weight, in each case in relation to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises cetyl alcohol, preferably in an amount of from 15 to 40% by weight, e.g.
25 + 10% by weight or 30 + 10% by weight, in each case in relation to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises a hydrocarbon selected from the group consisting of long chain fatty acids having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated, linear or branched; glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils and waxes; in each case preferably in an amount of from 5.0 to 70% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight or 40 + 10% by weight or 45 + 10% by weight or 50 + 10% by weight or 55 + 10% by weight or 60 + 10% by weight, in each case in relation to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises xanthan gum, preferably in an amount of from 15 to 40% by weight, e.g. 25 + 10% by weight or 30 + 10% by weight, in each case in relation to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises sodium alginate, preferably in an amount of from 15 to 40% by weight, e.g. 25 + 10% by weight or 30 + 10% by weight, in each case in relation to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises guar gum, preferably in an amount of from 5.0 to 35% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight, in each case in relation to the total weight of the dosage form.
In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention comprises a weight equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 200 mg, or 250 mg, in each case on the basis of the free base of tapentadol, and a depot matrix in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, is embedded; wherein the depot matrix as depot matrix material comprises locust bean gum, preferably in an amount of from 5.0 to 35% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight, in each case in relation to the total weight of the dosage form.
DK 2021 00018 U1 34 In addition to the above components, a depot matrix may also contain appropriate amounts of other materials, e.g. diluents, lubricants, binders, granulating aids, coloring agents, flavoring agents and lubricants which are conventional in the pharmaceutical art.
Pharmaceutical dosage forms containing depot matrices in which tapentadol is embedded can be prepared by conventional techniques well known to those skilled in the art, such as mixing and direct compression, dry granulation, wet granulation, extrusion and the like.
In a preferred embodiment, the pharmaceutical dosage form according to the invention is a capsule, preferably containing several particles containing a sustained release coating.
In another preferred embodiment, the pharmaceutical dosage form of the invention is a tablet. Preferably, the tablet is a monolith. Monolith tablets according to the invention mean tablets which are optionally film-coated, the core of the tablets containing a compressed powder and / or granulate mixture. In particular, (i) tablets prepared by direct compression of powder mixtures, (ii) tablets prepared by compression of mixtures comprising granules obtained by dry granulation and optionally extragranular excipients, (iii) tablets prepared by compression of mixtures comprising granules obtained by wet granulation and optionally extragranular excipients, and (iv) tablets prepared by compressing mixtures comprising granules obtained by extrusion granulation and optionally extragranular excipients are all considered as monolithic tablets according to the invention. However, multi-unit pellet systems or other dosage forms in which several particles of specific shape, weight and shape are mixed with an outer matrix material and subsequently compressed into tablets in which the outer matrix material forms a continuous phase in which the beads or particles are embedded, preferably not considered monolithic tablets. Of course, capsules filled with a diversity of loose particles are also not to be considered monolithic.
The tablet preferably has a breaking strength of at least 100 N, preferably at least 150 N, more preferably at least 200 N. The breaking strength is preferably determined in accordance with Ph.Eur. 10, Chapter 2.9.8. "Resistance to Crushing of Tablets".
Another aspect of the invention relates to a process for the preparation of a pharmaceutical dosage form according to the invention as described above.
When the pharmaceutical dosage form contains particles comprising a sustained release coating, the method of manufacture according to the manufacture in a preferred embodiment comprises the steps of (A) providing inert starter beads, e.g. nonpareil spheres containing one or more excipients but no tapentadol;
(B) providing a solution or dispersion of tapentadol (including the salt with phosphoric acid) in water or an organic solvent or a mixture thereof, optionally together with the one or more excipients, wherein the organic solvent is preferably selected from ethanol and acetone;
(C) coating the inert starter pellets provided in step (A) with the solution or dispersion of tapentadol provided in step (B), preferably in a fluidized bed, thereby obtaining intermediate stage particles containing an inert core containing no tapentadol.
dol, and a drug coating layer encapsulating the core and comprising substantially the total amount of tapentadol to be contained in the dosage form, optionally together with one or more excipients;
(D) optionally drying the intermediate stage particles obtained in step (C) and thereby obtaining dried intermediate stage particles;
(E) providing a solution or dispersion of a depot coating material in water or an organic solvent or a mixture thereof, optionally together with the one or more excipients, wherein the organic solvent is preferably selected from ethanol and acetone;
(F) coating the intermediate stage particles obtained in step (C) or the dried intermediate stage particles obtained in step (D) with the solution or dispersion of depot coating material provided in step (E), preferably in a fluidized bed, thereby obtaining sustained release particles containing an inert core containing no tapentadol, a drug coating layer encapsulating the core and comprising substantially the full amount of tapentadol, optionally together with the excipient (s), and a sustained release coating encapsulating the core and drug coating.
the draft;
(G) optionally drying the sustained release particles obtained in step (F) and thereby obtaining sustained release particles; and (H) either filling sustained release particles obtained in step (F) or the dried sustained release particles obtained in step (G) in capsules; or mixing the extended release particles obtained in step (F) or the dried extended release particles obtained in step (G) with extraparticulate excipients and compressing mixtures into tablets (multi-unit pellet systems).
Another aspect of the invention relates to a pharmaceutical dosage form obtainable by this preferred method of the invention as described above.
When the pharmaceutical dosage form contains particles comprising a sustained release coating, the method of manufacture according to the invention in a preferred embodiment comprises the steps of (A) providing a mixture containing substantially the total amount of tapentadol (including the salt with phosphoric acid) to be contained in the dosage form, optionally together with one or more excipients; (B) preparing drug microspheres from the mixture provided in step (A) by dry granulation, wet granulation or extrusion, wherein wet granulation preferably comprises using a solvent selected from water, ethanol, acetone and any mixture thereof; (C) optionally drying and / or spheronizing the drug beads prepared in step (B) to thereby obtain dried and / or spheronized drug beads; (D) providing a solution or dispersion of a depot coating material in water or an organic solvent or a mixture thereof, optionally together with the one or more excipients, wherein the organic solvent is preferably selected from ethanol and acetone; (E) coating the drug beads prepared in step (B) or the dried and / or spheronized drug beads obtained in step (C) with the solution or dispersion of depot coating material provided in step (D), preferably in a fluidized bed, thereby obtaining particles with elongation release containing a core comprising
Essentially the total amount of tapentadol, optionally together with one or more excipients, and a sustained release coating encapsulating the core; (F) optionally drying the sustained release particles obtained in step (E) and thereby obtaining extended release dried particles; and (G) either filling the sustained release particles obtained in step (E) or the dried sustained release particles obtained in step (F) in capsules; or mixing the extended release particles obtained in step (E) or the dried extended release particles obtained in step (F) with extraparticulate excipients and compressing the mixture into tablets (multi-unit pellet systems).
Another aspect of the invention relates to a pharmaceutical dosage form obtainable by this preferred method of the invention as described above.
When the pharmaceutical dosage form contains a depot matrix in which tapentadol (including the salt with phosphoric acid) is embedded, the method of preparation according to the production in a preferred embodiment comprises the steps of (a) providing a mixture containing substantially the total amount tapentadol (including the salt with phosphoric acid) to be contained in the dosage form and at least one depot matrix material, optionally together with one or more excipients; (b) optionally granulating the mixture provided in step (a) and thereby obtaining a granulate, the granulation preferably comprising: (i) wet granulation by means of a solvent, preferably selected from water, ethanol, acetone and any mixing thereof, optionally followed by drying; (ii) dry granulation; or (iii) extrusion, (c) optionally mixing the granulate obtained in step (b) with one or more excipients and thereby obtaining a granulate mixture; (d) compressing the mixture provided in step (a) or the granulate obtained in step (b) or the mixture obtained in step (c) into tablets; (e) optionally film-coating the tablets compressed in step (d).
Preferably, the compression is carried out in step (d) of the process according to the generation at a compressive force of not more than 20 kN, more preferably not more than 15 kN, even more preferably not more than 10 kN, even more preferably
DK 2021 00018 U1 38 pulled not more than 9.5 kN, further more preferably not more than 9.0 kN, most preferably not more than 8.75 kN and in particular not more than 8.5 kN.
Preferably, compression is carried out in step (d) of the process according to the production under such conditions that the compressed tablet has a breaking strength of at least 100 N, more preferably at least 150 N, even more preferably at least 200 N.
The pharmaceutical dosage form of the invention is preferably not prepared by thermoforming such as hot melt extrusion.
The pharmaceutical dosage form of the invention does not contain a variety of particles or pellets of specific shape, form and weight, which are optionally compressed into tablets, the particles or pellets forming a discontinuous phase within a continuous phase of an outer matrix material.
The pharmaceutical dosage form of the invention preferably does not contain an opioid antagonist. Opioid antagonists are devices that modify the response of opioid receptors. Opioid antagonists include naloxone, naltrexone, diprenorphine, etorphine, dihydroethorphine, nalinephene, cyclazacine, levallorphane, pharmaceutically acceptable salts thereof, and mixtures thereof.
Another aspect of the manufacture relates to the pharmaceutical dosage form of the manufacture as described above for use in pain treatment, wherein the dosage form is administered orally, preferably twice daily.
Another aspect of the invention relates to the use of a salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, for the preparation of a pharmaceutical dosage form according to the invention as described above for pain treatment, wherein the dosage form is administered orally, preferably twice daily.
Another aspect of the invention relates to a method of pain treatment comprising the step of administering, preferably twice daily, a pharmaceutical dosage form according to the invention as described above.
Preferably, the pain is chronic pain.
In preferred embodiments, according to the generation of a patient population of at least 10 patients, preferably at least 50 patients, the pharmaceutical dosage form provides an average value for Tmax in the range of 5.0 + 3.0 hours after oral administration.
In preferred embodiments of the pharmaceutical dosage form of the invention, the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is 50 mg based on the free base of tapentadol, and
DK 2021 00018 U1 39 where the dosage form after oral administration in a patient population of at least 50 patients gives a mean value for - Cmax within the range 12 + 3 ng / ml; and / or - AUCs: in the range 204 + 50 ng-t / ml; and / or - AUC in the range 214 + 50 ng-t / ml.
In preferred embodiments of the pharmaceutical dosage form according to the invention, the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is 100 mg based on the free base of tapentadol, and wherein the dosage form after oral administration in a patient population of at least 50 patients gives an average value of - Cmax in the range 29 + 6 ng / ml; and / or - AUCs: in the range 440 + 100 ng-t / ml; and / or - AUC in the range 447100 ng-t / ml.
In preferred embodiments of the pharmaceutical dosage form of the invention, the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is 150 mg based on the free base of tapentadol, and wherein the dosage form after oral administration in a patient population of at least 50 patients gives an average value of - Cmax in the range 47 + 9 ng / ml; and / or - AUCis: within the range 662 + 150 ng-t / ml; and / or - AUC in the range 665 + 150 ng-t / ml.
In preferred embodiments of the pharmaceutical dosage form according to the invention, the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is 200 mg based on the free base of tapentadol, and wherein the dosage form after oral administration in a patient population of at least 50 patients gives an average value of - Cmax in the range 64 + 12 ng / ml; and / or - AUCisst in the range 890 + 200 ng-t / ml; and / or - AUC in the range 895 + 200 ng-t / ml.
In preferred embodiments of the pharmaceutical dosage form according to the invention, the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is 250 mg based on the free base of tapentadol, and wherein the dosage form after oral administration in a patient population of at least 50 patients gives an average value of - Cmax in the range 85 + 15 ng / ml; and / or - AUCist in the range 1141250 ng-t / ml; and or
DK 2021 00018 U1 40 - AUC within the range 1145 + 250 ng-t / ml. Particularly preferred embodiments of the manufacture are summarized as paragraphs 1 to 67 in the following: Section 1: Pharmaceutical dosage form comprising tapentadol for oral administration twice daily; wherein tapentadol is present as a salt with phosphoric acid; wherein the dosage form provides sustained release of tapentadol; and wherein the weight equivalent dose of tapendatol contained in the pharmaceutical dosage form is in the range of 10 to 300 mg based on the free base of tapentadol. Section 2: Pharmaceutical dosage form according to section 1, wherein the salt is the dihydrogen phosphate salt of tapentadol, a solvate, an ansolvate and / or a polymorph thereof. Section 3: Pharmaceutical dosage form according to section 1 or 2, which comprises one, two or more physiologically acceptable excipients. Section 4: Pharmaceutical dosage form according to any one of the preceding paragraphs which, after oral administration, provides plasma levels of tapendatol which provide pain relief for a period of at least 6 hours.
Section 5: Pharmaceutical dosage form according to any one of the preceding paragraphs, which provides an in vitro solution profile, measured by the USP Paddle Method at 50 rpm 900 ml of aqueous phosphate buffer at a pH of 6.8 at 37 ° C, where after 0.5 hour 20 + 20% by weight has been released; preferably 20 + 15% by weight; more preferably 20 + 10% by weight; after 4 hours 60 + 20% by weight; preferably 60 + 15% by weight; more preferably 60 + 10% by weight; and after 12 hours at least 60% by weight; preferably at least 70% by weight; more preferably at least 80% by weight of the amount of tapentadol originally contained in the dosage form.
Section 6: Pharmaceutical dosage form according to any one of the preceding paragraphs, which provides an in vitro solution profile, measured by the USP Paddle Method at 50 rpm 900 ml of aqueous phosphate buffer at a pH of 6.8 at 37 ° C, where after 1 hour 25 + 15% by weight has been released; after 2 hours 35 + 20% by weight; after 4 hours 50 + 20% by weight; after 8 hours 80 + 20% by weight of the amount of tapentadol originally contained in the dosage form.
Section 7: Pharmaceutical dosage form according to any one of the preceding paragraphs, which provides an in vitro solution profile, measured by the USP Paddle Method at 50 rpm in 900 ml of aqueous phosphate buffer
DK 2021 00018 U1 41 at a pH of 4.5 at 37 ° C, where after 0.5 hour 20 + 20% by weight has been released; preferably 20 + 15% by weight; more preferably 20 + 10% by weight; after 4 hours 60 + 20% by weight; preferably 60 + 15% by weight; more preferably 60 + 10% by weight; and after 12 hours at least 60% by weight; preferably at least 70% by weight; more preferably at least 80% by weight of the amount of tapentadol originally contained in the dosage form. Section 8: Pharmaceutical dosage form according to any one of the preceding paragraphs, which provides an in vitro solution profile, measured by the USP Paddle Method at 50 rpm 900 ml of aqueous phosphate buffer at a pH of 4.5 at 37 ° C, where after 1 hour 25 + 15% by weight has been released; after 2 hours 35 + 20% by weight, after 4 hours 50 + 20% by weight; after 8 hours 80 + 20% by weight of the amount of tapentadol originally contained in the dosage form.
Section 9: Pharmaceutical dosage form according to any one of the preceding paragraphs, which provides an in vitro solution profile, measured by the USP Paddle Method at 50 rpm 900 ml of aqueous phosphate buffer at a pH of 1.0 at 37 ° C, where after 0.5 hour 20 + 20% by weight has been released; preferably 20 + 15% by weight; more preferably 20 + 10 9% by weight; after 4 hours 60 + 20% by weight; preferably 60 + 15% by weight; more preferably 60 + 10% by weight; and after 12 hours at least 60% by weight; preferably at least 70% by weight; more preferably at least 80% by weight of the amount of tapentadol originally contained in the dosage form.
Section 10: Pharmaceutical dosage form according to any one of the preceding paragraphs, which provides an in vitro solution profile, measured by the USP Paddle Method at 50 rpm in 900 ml of aqueous phosphate buffer at a pH of 1.0 at 37 ° C, where after 1 hour 2510% by weight has been released; after 2 hours 40 + 30% by weight, after 4 hours 60 + 20% by weight; after 8 hours 80 + 20% by weight of the amount of tapentadol originally contained in the dosage form.
Section 11: Pharmaceutical dosage form according to any one of the preceding paragraphs, which confers resistance to ethanol-induced dose dumping.
DK 2021 00018 U1 42 Section 12: Pharmaceutical dosage form according to section 11, which gives slower in vitro dissolution of tapentadol in aqueous medium containing ethanol than in aqueous medium not containing ethanol.
Section 13: Pharmaceutical dosage form according to section 11 or 12, which gives slower dissolution of tapentadol in 0.1 N HCl containing 40% v / v ethanol (pH 1.0) than in 0.1 N HCl not containing 40% v / v ethanol ( pH 1.0), in each case measured by the USP Paddle Method at 50 rpm 900 ml at 37 ° C.
Section 14: Pharmaceutical dosage form according to any one of the preceding paragraphs, wherein the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is 25 mg, 50 mg or 100 mg, in each case based on the free base of tapentadol.
Section 15: Pharmaceutical dosage form according to section 14, wherein the dosage form has a total weight in the range of 150 to 750 mg.
Section 16: Pharmaceutical dosage form according to any one of paragraphs 1 to 13, wherein the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is 150 mg, 200 mg or 250 mg, in each case based on the free base of tapentadol.
Section 17: A pharmaceutical dosage form according to claim 16, wherein the dosage form has a total weight in the range of 300 to 1200 mg.
Section 18: Pharmaceutical dosage form according to any one of the preceding paragraphs, wherein the dosage form contains a sustained release coating comprising a depot coating material selected from the group consisting of hydrophobic cellulose ethers, acrylic polymers, shellac, zein, hydrophobic products of waxy. type, and mixtures thereof.
Clause 19: A pharmaceutical dosage form of clause 18, wherein the de- potovertræksmaterialet is selected from the group consisting of ethylcelllulose, acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, methyl methacrylate, copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methacrylic acid copolymer , aminoalkyl methacrylate copolymer, methacrylic acid copolymers, methyl methacrylate copolymers, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamide copolymer, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, polymethacrylate -
(20 methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymers, poly (methacrylic acid anhydride) and glycidyl methacrylate copolymers. Section 20: Pharmaceutical dosage form according to any one of the preceding paragraphs, wherein tapentadol is embedded in a depot matrix.
Section 21: Pharmaceutical dosage form according to section 20, wherein the depot matrix comprises or essentially consists of at least one depot matrix material selected from the group consisting of hydrophilic and hydrophobic polymers and hydrocarbons.
Section 22: Pharmaceutical dosage form according to section 21, wherein the depot matrix comprises or consists essentially of at least one polymer selected from the group consisting of polysaccharides or gum forms (eg xanthan gum, guar gum, caraya gum, locust bean gum, sodium alginate, locust bean gum, locust bean gum) chitosan, polysaccharides of mannose and galactose, pectin, tragacanth, agar-agar); cellulose ethers (e.g. HPMC, HPC, HEC, MC, EC); cellulose esters (e.g. cellulose acetate, cellulose acetate succinate, cellulose acetate phthalate); polyalkylene glycols and polyalkylene oxides; polyvinyl alcohol (PVA), crosslinked polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), crosslinked polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymers, polyvinyl chloride (PVC), polyethylene vinyl acetate (PVA), polyimethyl acetate (PVA) ether urethane (PEU), polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), polyanhydrides, polyorthoesters; acrylic resins (eg. cross-linked homopolymers and copolymers of acrylic acid, acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, methyl methacrylate, copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methacrylic acid copolymer, aminoalkyl kylmethacrylatcopolymer, methacrylic acid copolymers, methyl methacrylate copolymers, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamide copolymer, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, methyl methacrylate copolymer, poly (methyl methacrylate copolymer, poly) methyl polyacrylamide, aminoalkyl methacrylate copolymers, poly (methacrylic acid anhydride), and glycidyl methacrylate copolymers, polyhydroxyethyl methacrylate (PHEMA), polyacrylamide); and protein-derived materials. Section 23: Pharmaceutical dosage form according to section 21 or 22, wherein the depot matrix comprises or consists essentially of at least one hydrocarbon selected from the group consisting of long chain (Cs-C 50, in particular C12-C40) fatty acids.
DK 2021 00018 U1 44 acids, fatty alcohols, glyceryl esters of fatty acids, mineral oils, vegetable oils, and waxes. Section 24: A pharmaceutical dosage form according to any one of paragraphs 20 to 23, wherein the prolonged-release matrix comprises or consists essentially of a prolonged-release matrix material selected from the group consisting of (i) hydroxypropylmethylcellulose (HPMC); (ii) hydroxypropylcellulose (HPC); (iii) hydroxyethylcellulose (HEC); (iv) microcrystalline cellulose (MCC); (v) ethylcellulose (EC); (vi) polyvinyl acetate (PVAc); (vii) polyvinylpyrrolidone (PVP); (viii) polyvinylpyrrolidone-vinyl acetate copolymer (PVP / PVAc); (ix) poly (ethyl acrylate-co-methylmethacrylate-co-trimethylammonium ethylmethacrylate chloride); (x) poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate); (xi) poly (methyl methacrylate-co-methacrylic acid); (xii) poly (ethyl acrylate-co-methacrylic acid); (xiii) poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid); (xiv) poly (ethyl acrylate-co-methyl methacrylate); (xv) poly (ethylene oxide) (PEO); (xvi) polyethylene glycol (PEG); (xvii) long chain fatty alcohol having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated, linear or branched; (xviii) cetostearyl alcohol; (xix) stearyl alcohol; (xx) cetyl alcohol; (xxi) hydrocarbon selected from the group consisting of long chain fatty acids having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated, linear or branched; glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils and waxes; (xxii) xanthan gum; (xxiii) sodium alginate; (xxiv) guar gum; (xxv) locust bean gum; and any mixture of the foregoing, wherein the content of the depot matrix material is preferably in the range of 15 + 10% by weight, or 2010% by weight, or 25 + 10% by weight, or 30 + 10% by weight, or 35+ 10% by weight, or 40 + 10% by weight, or 45 + 10% by weight, or 50 + 10% by weight, or 55 + 10% by weight, or 60 + 10% by weight, or 65 + 10% by weight, or 70 + 10% by weight, or 75 + 10% by weight, or 80 + 10% by weight, in each case relative to the total weight of the dosage form.
Section 25: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises hydroxypropyl methylcellulose (HPMC) in an amount of from 5.0 to 50% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight or 40 + 10% by weight, in each case in relation to the dosage form total weight.
Paragraph 26: Pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises hydroxypropylcellulose (HPC) in an amount of from 10 to 50% by weight, e.g. 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight or 40 + 10% by weight, in each case in relation to the total weight of the dosage form.
Section 27: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises hydroxyethylcellulose (HEC), preferably in an amount of from 5.0 to 50% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight or 40 + 10% by weight, in each case in relation to the dosage form total weight.
Section 28: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises microcrystalline cellulose (MCC), preferably in an amount of from 10 to 70% by weight, e.g. 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight or 40 + 10% by weight or 45 + 10% by weight or 50 + 10% by weight or 55 +10% by weight or 60 + 10% by weight, in each case in relation to the total weight of the dosage form.
Section 29: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises ethylcellulose (EC), preferably in an amount of from 5.0 to 30% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight, in each case in relation to the total weight of the dosage form.
Section 30: Pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises polyvinyl acetate (PVAc), preferably in an amount of from 25 to 70% by weight, e.g. 35 + 10% by weight or 40 + 10% by weight or 45 + 10% by weight or 50 + 10% by weight or 55 + 10% by weight or 60 + 10% by weight, in each case in relation to dose the total weight of the ring shape.
Paragraph 31: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises polyvinylpyrrolidone (PVP), preferably in an amount of from 2.0 to 21% by weight, e.g. 10 + 5.0% by weight or 15 + 5.0% by weight, in each case in relation to the total weight of the dosage form.
A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises polyvinylpyrrolidone-vinyl acetate copolymer (PVP / PVAc), preferably in an amount of from 1.0 to 30% after
DK 2021 00018 U1 46 weight, e.g. 15 + 10% by weight or 2010% by weight, in each case in relation to the total weight of the dosage form.
Paragraph 33: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises poly (ethyl acrylate-co-methyl methacrylate-co-trimethyl-ammonioethyl methacrylate chloride), preferably in an amount of from 5.0 to 45% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight, in each case in relation to the total weight of the dosage form.
Section 34: Pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), preferably in an amount of from 5.0 to 45% by weight, f. ex. 15 + 10% by weight or 2010% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight, in each case in relation to the total weight of the dosage form.
Paragraph 35: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises poly (methyl methacrylate-com-methacrylic acid), preferably in an amount of from 5.0 to 45% by weight, e.g. 1510% by weight or 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight, in each case in relation to the total weight of the dosage form.
Paragraph 36: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises poly (ethyl acrylate-com-methacrylic acid), preferably in an amount of from 5.0 to 45% by weight, e.g. 1510% by weight or 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight, in each case in relation to the total weight of the dosage form.
Paragraph 37: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid), preferably in an amount of from 5.0 to 45% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight, in each case in relation to the total weight of the dosage form.
Paragraph 38: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises poly (ethyl acrylate-co-methyl methacrylate), preferably in an amount of from 5.0 to 45% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight or
DK 2021 00018 U1 47 30 + 10% by weight or 35 + 10% by weight, in each case in relation to the total weight of the dosage form.
Paragraph 39: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises poly (ethylene oxide) (PEO), preferably an amount of from 25 to 65% by weight, e.g. 35 + 10% by weight or 40 + 10% by weight or 45 + 10% by weight or 5010% by weight or 55 + 10% by weight, in each case in relation to the total weight of the dosage form.
Paragraph 40: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises polyethylene glycol (PEG), preferably in an amount of from 5.0 to 35% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight, in each case in relation to the total weight of the dosage form.
Paragraph 41: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as a depot matrix material comprises a long chain fatty alcohol having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated, linear or branched, preferably in an amount of from 15 to 40 % by weight, e.g. 25 + 10% by weight or 30 + 10% by weight, in each case in relation to the total weight of the dosage form.
Section 42: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises cetostearyl alcohol, preferably in an amount of from 15 to 40% by weight, e.g. 25 + 10% by weight or 30 + 10% by weight, in each case in relation to the total weight of the dosage form.
Paragraph 43: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises stearyl alcohol, preferably in an amount of from 15 to 40% by weight, e.g. 25 + 10% by weight or 30 + 10% by weight, in each case in relation to the total weight of the dosage form.
Paragraph 44: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises cetyl alcohol, preferably in an amount of from 15 to 40% by weight, e.g. 25 + 10% by weight or 30 + 10% by weight, in each case in relation to the total weight of the dosage form.
Paragraph 45: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises a hydrocarbon selected from the group consisting of long chain fatty acids having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated, linear or branched; glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils and waxes; in each case preferably in an amount from 5.0
DK 2021 00018 U1 48 to 70% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight or 30 + 10% by weight or 35 + 10% by weight or 40 + 10% by weight or 45 + 10% by weight or 50 + 10% by weight or 55 + 10% by weight or 60 + 10% by weight, in each case in relation to the total weight of the dosage form.
Paragraph 46: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises xanthan gum, preferably in an amount of from 15 to 40% by weight, e.g. 25 + 10% by weight or 30 + 10% by weight, in each case in relation to the total weight of the dosage form.
Paragraph 47: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises sodium alginate, preferably in an amount of from 15 to 40% by weight, e.g. 25 + 10% by weight or 30 + 10% by weight, in each case in relation to the total weight of the dosage form.
Section 48: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises guar gum, preferably in an amount of from 5.0 to 35% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight, in each case in relation to the total weight of the dosage form.
Section 49: A pharmaceutical dosage form according to claim 24, wherein the depot matrix as depot matrix material comprises locust bean gum, preferably in an amount of from 5.0 to 35% by weight, e.g. 15 + 10% by weight or 20 + 10% by weight or 25 + 10% by weight, in each case in relation to the total weight of the dosage form.
Section 50: Pharmaceutical dosage form according to any one of the preceding paragraphs which is a capsule.
Section 51: Pharmaceutical dosage form according to any one of paragraphs 1 to 49, which is a tablet.
Section 52: Pharmaceutical dosage form according to section 51, wherein the tablet is monolithic.
Section 53: Pharmaceutical dosage form according to section 51 or 52, wherein the tablet has a breaking strength of at least 100 N.
Section 54: Dosage form according to any one of the preceding paragraphs for use in the treatment of pain, wherein the dosage form is administered twice daily.
Section 55: Dosage form for use according to section 54, where the pain is chronic pain.
DK 2021 00018 U1 49 Section 56: Dosage form for use according to section 54 or 55, which in a patient population of at least 10 patients gives an average value for Tmax within the range 5.0 + 3.0 hours after oral administration.
Section 57: Dosage form for use according to any one of paragraphs 54 to 56, wherein the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is 50 mg based on the free base of tapentadol, and wherein the dosage form after oral administration in a patient population with at least 10 patients, a mean Cmax value in the range of 12 + 3 ng / ml; and / or AUCist in the range 204 + 50 ng-t / ml; and / or AUCx in the range 214 + 50 ng-t / ml.
Section 58: Dosage form for use according to any one of paragraphs 54 to 56, wherein the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is 100 mg based on the free base of tapentadol, and wherein the dosage form after oral administration in a patient population of at least 10 patients gives a mean Cmax value in the range 29 + 6 ng / ml; and / or AUCist in the range 440 + 100 ng-t / ml; and / or AUCx in the range 447 + 100 ng-t / ml.
Section 59: Dosage form for use according to any one of paragraphs 54 to 56, wherein the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is 150 mg based on the free base of tapentadol, and wherein the dosage form after oral administration in a patient population with at least 10 patients, a mean Cmax value in the range 47 + 9 ng / ml; and / or AUCist in the range 662 + 150 ng-t / ml; and / or AUC »in the range 665 + 150 ng-t / ml.
Section 60: Dosage form for use according to any one of paragraphs 54 to 56, wherein the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is 200 mg based on the free base of tapentadol, and wherein the dosage form after oral administration in a patient population of at least 10 patients gives a mean Cmax value in the range 64 + 12 ng / ml; and / or AUCist in the range 890 + 200 ng-t / ml; and / or AUCx in the range 895 + 200 ng-t / ml.
Section 61: Dosage form for use according to any one of paragraphs 54 to 56, wherein the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is 250 mg based on the free base of tapentadol, and wherein the dosage form after oral administration in a patient population with at least 10 patients gives an average value of Cmax within the range
DK 2021 00018 U1 50 85 + 15 ng / ml; and / or AUCist in the range 1141 + 250 ng-t / ml; and / or AUC in the range 1145 + 250 ng-t / ml.
Section 62: A method of making a pharmaceutical dosage form according to any one of the preceding paragraphs, which contains particles comprising a sustained release coating, said method comprising the steps of (A) providing inert starter beads, f. ex. nonpareil spheres containing one or more excipients but no tapentadol; (B) providing a solution or dispersion of tapentadol in water or an organic solvent or a mixture thereof, optionally together with the one or more excipients; (C) coating the inert starter pellets provided in step (A) with the solution or dispersion of tapentadol provided in step (B), thereby obtaining intermediate stage particles containing an inert core containing no tapentadol and a drug coating layer encapsulating the core and essentially comprises the total amount of tapentadol to be contained in the dosage form, optionally together with the one or more excipients; (D) optionally drying the intermediate stage particles obtained in step (C) and thereby obtaining dried intermediate stage particles; (E) providing a solution or dispersion of a depot coating material in water or an organic solvent or a mixture thereof, optionally together with the one or more excipients; (F) coating the intermediate stage particles obtained in step (C) or the dried intermediate stage particles obtained in step (D) with the solution or dispersion of depot coating material obtained in step (E), thereby obtaining sustained release particles containing an inert a core containing no tapentadol, a drug coating layer encapsulating the core and comprising substantially the full amount of tapentadol, optionally together with the excipient (s), and a sustained release coating encapsulating the core and the drug coating layer; (G) optionally drying the sustained release particles obtained in step (F) and thereby obtaining extended release dried particles; and (H) either filling the sustained release particles obtained in step (F) or the dried extended release particles obtained in step (G) in capsules; or mixing the extended release particles obtained in step (F) or the dried extended release particles obtained in step (G) with extraparticulate excipients and compressing mixtures into tablets.
Section 63: Pharmaceutical dosage form that can be achieved according to the procedure of section 62.
Paragraph 64: A method of preparing the pharmaceutical dosage form according to any one of paragraphs 1 to 61, which contains particles comprising a sustained release coating, said method comprising the steps of (A) providing a a mixture containing substantially the total amount of tapentadol to be contained in the dosage form, optionally together with one or more excipients; (B) preparing drug pellets from the mixture provided in step (A) by dry granulation, wet granulation or extrusion; (C) optionally drying and / or spheronizing the drug pellets prepared in step (B) and thereby obtaining dried and / or spheronized drug pellets; (D) providing a solution or dispersion of a depot coating material in water or an organic solvent or a mixture thereof, optionally together with the one or more excipients; (E) coating the drug beads prepared in step (B) or the dried and / or spheronized drug beads obtained in step (C) with the solution or dispersion of depot coating material provided in step (D) and thereby obtaining extended release particles containing a core comprising substantially the total amount of tapentadol, optionally together with one or more excipients, and a sustained release coating encapsulating the core; (F) optionally drying the sustained release particles obtained in step (E) and thereby obtaining extended release dried particles; and (G) either filling the sustained release particles obtained in step (E) or the dried sustained release particles obtained in step (F) in capsules; or mixing the extended release particles obtained in step (E) or the dried extended release particles obtained in step (F) with extraparticulate excipients and compressing the mixture into tablets.
Section 65: Pharmaceutical dosage form obtainable by the method of section 64. Section 66: Process for the manufacture of a pharmaceutical dosage form according to any one of paragraphs 1 to 61, which contains a depot matrix in which tapentadol is embedded, said method comprising the steps of (a) providing a mixture containing substantially the total amount of tapentadol to be contained in the dosage form and at least one depot matrix material, optionally together with one or more excipients; (b) optionally granulating the mixture provided in step (a) and thereby obtaining a granulate; (c) optionally mixing the granulate obtained in step (b) with one or more excipients and thereby obtaining a granulate mixture; (d) compressing the mixture provided in step (a) or
The granulate obtained in step (b) or the granulate mixture obtained in step (c) for tablets; (e) optionally film coating the tablets compressed in step (d).
Section 67: The method of paragraph 66, wherein the compression in step (d) is performed at a compressive force not exceeding 20 kN, more preferably not exceeding 15 kN, even more preferably not exceeding 10 kN, even more preferably not exceeding 9.5 kN, further more preferably not more than 9.0 kN, most preferably not more than 8.75 kN and especially not more than 8.5 kN.
Examples The following examples further illustrate the creation, but are not to be construed as limiting.
The commercially available tapentadol tablets “Palexia & retard” contain tapentadol as hydrochloride salt, while the tablet core also contains hypromellose, microcrystalline cellulose, highly dispersed silica and magnesium stearate. Thus, Palexia & retard tablets contain a prolonged-release matrix of hypromellose. These tablets are in accordance with WO 03/035053 A1 and the comparative examples described below.
Example 1- Preparation of tapentadol dihydrogen phosphate salt: Three different batches of tapentadol dihydrogen phosphate were prepared, a batch of substantially pure tapentadol dihydrogen phosphate hemihydrate, a batch of substantially pure tapentadol dihydrogen phosphate hydrate and a batch comprising a mixture of the two polymers = the mixed form = the polymer.
Example 1.1 - Tapentadol dihydrogen phosphate, mixed form: Tapentadol base (200 mg) was thoroughly mixed with phosphoric acid (104 mg, 61.7 μl, 85% by weight) using a spatula. The resulting mixture was allowed to stand for 4 days at 20 ° C to 25 ° C to give a white crystalline solid. The obtained product was analyzed by X-ray powder diffraction (XRPD) (Figure 1). A weight loss of 2.8% up to 172 ° C was detected by thermogravimetric analysis (TGA).
Example 1.2 - Tapentadol dihydrogen phosphate, mixed form: Tapentadol base (7.5 g) was suspended at 20 ° C to 25 ° C in a mixture of ethyl acetate (81g, 90 ml) and water (10 mg, 10 μl). The mixture was heated to 55 ° C to give a clear solution. Then crystalline tapentadold dihydrogen phosphate (10 mg) and phosphoric acid (3.9 g, 2.3 ml, 85% by weight) were added. A white slurry formed immediately. After mixing for 45 minutes at 60 ° C, the slurry was cooled to 5 ° C for 45 minutes. After further mixing at 5 ° C for 45 minutes, the resulting solid was isolated by vacuum filtration.
DK 2021 00018 U1 53 and dried (20 ° C to 25 ° C, vacuum, 2 h). The product obtained (9.5 g, white crystalline powder) was analyzed by XRPD. A weight loss of 3.1% up to 113 ° C was detected by TGA. Example 1.3 - Tapentadol dihydrogen phosphate, mixed form: Tapentadol base (7.5 g) was suspended at 20 ° C to 25 ° C in a mixture of tetrahydrofuran (80 g, 90 ml) and water (10 mg, 10 μl). The mixture was heated to 55 ° C to give a clear solution. Then crystalline tapentadol dihydrogen phosphate (10 mg) and phosphoric acid (3.9 g, 2.3 ml, 85% by weight) were added. A white slurry formed immediately. After 45 minutes of mixing at 60 ° C, the slurry was cooled to 5 ° C for 45 minutes. After further mixing at 5 ° C for 45 minutes, the resulting solid was isolated by vacuum filtration and dried (20 ° C to 25 ° C, vacuum, 2 h). The product obtained (9.6 g, white crystalline powder) was analyzed by XRPD. A weight loss of 1.9% up to 120 ° C was detected by TGA.
Example 1.4 - Tapentadol dihydrogen phosphate hemihydrate: Tapentadol base (497 mg) was suspended at 20 ° C to 25 ° C in a mixture of acetone (2.72 g, 3.44 ml) and water (50 mg, 50 μl) to give a clear solution. Phosphoric acid (259 mg, 153 μL, 85% by weight) was added and after a short time the clear solution became a slurry. The slurry was mixed for 30 minutes at 20 ° C to 25 ° C, then cooled to 5 ° C and further mixed at 5 ° C for 30 minutes. The resulting solid was isolated by vacuum filtration and dried (20 ° C to 25 ° C, vacuum, 30 min). The product obtained (404 g, white crystalline powder was analyzed by XRPD (Figure 2) and DSC (Figure 3) The first DSC peak has a normalized integral of 149.2 .mu.g with an initial temperature of 56.7 °. C and a top temperature of 89.2 ° C. The second DSC peak had a normalized integral of 22.0 ° C with an initial temperature of 130.1 ° C and a top temperature of 133.4 ° C. Degradation occurred at approximately 200 ° C. A weight loss of 3.7% up to 119 ° C was detected by TGA.
Example 1.5 - Tapentadol dihydrogen phosphate hemihydrate (coarse material): Tapentadol base (60 g) was dissolved at 20 ° C to 25 ° C in a mixture of tetrahydrofuran (1.5 kg, 1.64 L) and water (82 g, 82 ml) . Phosphoric acid (31.25 g, 18.5 ml, 85% by weight) and crystalline tapentadol dihydrogen phosphate (5 mg) were added. During the addition, the solution became a white slurry. The resulting slurry was cooled to 10 ° C for 30 minutes. The mixture was heated to 35 ° C and mixed for 30 minutes followed by cooling to 5 ° C for 30 minutes. the slurry
DK 2021 00018 U1 54 was mixed at 5 ° C for 45 min. The resulting solid was isolated by vacuum filtration and dried (20 ° C to 25 ° C, vacuum, 2 h). The obtained product (84.6 g, white crystalline solid) was analyzed by XRPD. A weight loss of 4.5% up to 113 ° C was detected by TGA. Example 1.6 - Tapentadol dihydrogen phosphate anhydrate: Tapentadol base (150 mg) was suspended at 20 ° C to 25 ° C in 1-butanol (1.2 g, 1.5 ml). The slurry was heated to 50 to obtain a clear solution. Phosphoric acid (78.1 mg, 46.3 μL, 85% by weight) and crystalline tapentadol dihydrogen phosphate (5 mg) were added at 50 ° C. During the addition, the clear solution became a white slurry. The resulting slurry was heated to 115 ° C. To keep the slurry miscible, 1-butanol (400 mg, 0.5 ml) was added and mixing at 115 ° C was continued for 45 minutes. The mixture was then cooled to 30 ° C for 3 h. The resulting solid was isolated by vacuum filtration and dried (20 ° C to 25 ° C, vacuum, 30 min). The obtained product (157 mg, white crystalline powder) was analyzed by XRPD (Figure 4) and DSC (Figure 5). The DSC peak had a normalized integral of 72.1 J-g '!' with an initial temperature of 146.5 ° C and a peak temperature of 149.1 ° C. At about 200 ° C decomposition occurred. A weight loss of 0.9% up to 134 ° C was detected by TGA.
Example 1.7 - Tapentadol dihydrogen phosphate anhydrate Tapentadol dihydrogen phosphate (500 mg, mixture of hemihydrate and anhydrate) was suspended at 20 ° C to 25 ° C in 2-butanone (4.8 g, 6 ml) and water (5 mg, 5 μl). The reaction mixture was heated to 60 ° C and mixed for 3 h. The resulting solid was isolated by hot filtration with vacuum and dried (20 ° C to 25 ° C, vacuum, 30 min). The product obtained (452 mg, white crystalline powder) was analyzed by XRPD. A weight loss of 1.0% up to 129 ° C was detected by TGA.
Figure 6 shows three photographs of different salts of tapentadol used to make tablets. Figure 6A shows relatively fine particles of the mixed form of tapentadol dihydrogen phosphate (average particle size on visual observation about 10-20 μm). Figure 6B shows relatively coarse particles of the pure hemihydrate of tapentadol dihydrogen phosphate according to Example 1.5 (needle-like crystals, average particle size on visual observation about 100-200 μm). Figure 6C shows relatively coarse particles of tapentadol hydrochloride (average particle size on visual observation approximately 100-150 μm).
Example 2 - Intrinsic Dissolution Rate (IDR)
DK 2021 00018 U1 55 100 mg of tapentadol, either in the form of the hydrochloride salt or the dihydrogen phosphate salt (mixed form [batch with fine particles], pure hemihydrate or pure anhydrate) were compressed by a compressive force of 200 kg (gravity) for 1 minute a surface of 0.5 cm . The compressed samples thus obtained were examined for their dissolution rate in a Wood apparatus at 37 ° C in 900 ml of dissolution medium at different pH values and a stirring blade speed of 50 rpm.
The test results for tapentadol hydrochloride and tapentadol dihydrogen phosphate (mixed form) are summarized in the table below: [%] Tapentadol hydrochloride Tapentadol dihydrogen phosphate (for comparison) (mixed form) (according to the product) pH pH pH pH pH pH pH OG Ja | 60 le rf [wm [wm Jw jm A FRR] SC EC I Tw [% Jw = | FFERFPFM It is clear from the comparative experimental data in the table above that tapentadol dihydrogen phosphate (mixed form) under all experimental conditions, ie. below all tested pH values, has a significantly lower dissolution rate than tapentadol hydrochloride. The test results for tapentadol dihydrogen phosphate hemihydrate and tapentadol dihydrogen phosphate anhydrate are summarized in the table below:
FA Tee Taw 19 1919419 55 19 1 18 CA 70 190 jr 190 15 9 18 6 61% 1% |
DK 2021 00018 U1 56 It is clear from the comparative experimental data in the table above that the lower dissolution rate of tapentadol dihydrogen phosphate compared to tapentadol hydrochloride is independent of the polymorphic form of tapentadol dihydrogen phosphate.
Example 3 - Thermodynamic solubility: The thermodynamic solubility of tapentadol hydrochloride and tapentadol dihydrogen phosphate (mixed form, batch with fine particles) was determined as saturation solubility in different media at different pH values.
The solutions were stirred for 24 hours at 25 ° C and the pH values of the solutions at the beginning and end of the experiments were measured.
The dissolved amount of tapentadol was calculated by HPLC (free base of tapentadol). The experimental results are summarized in the table below: Tapentadol hydrochloride Tapentadol dihydrogen phosphate (for comparison) (mixed form (according to the product) pH Assay out- pH Assay expressed as printed as base base 0.1 MI | 1.11 0.83 31 , 2 1,11 2,55 24,3 oI Acetate | 4,54 4,29 32,7 4,54 2,81 21,2 es | Ved | fø [30 | [ib [a5 [ana | Citrate 6 .83 6.17 31.8 6.83 3.15 19.3 ol | 1 1 SIF sp | 6.82 6.23 32.4 6.82 2.81 20.2 pol | 1 1 Citrate 7.39 6.33 31.9 7.39 3.16 19.0 pl 1 1 0.15N 13.08 8.21 6.6 13.08 8.09 6.5 pøj | ib = not determined
DK 2021 00018 U1 57 It is clear from the comparative experimental data in the table above that under all tested conditions the thermodynamic solubility of tapentadol dihydrogen phosphate (mixed form) is lower than the ditto of tapentadol hydrochloride.
Example 4 In Vitro Dissolution Profiles of Pharmaceutical Dosage Forms: Tablets of the following composition were prepared by mixing all the ingredients and compressing the resulting mixtures: rr | ere - | 25000 [2500 [+ | - | Fine tapentadol dihydrogen- 250.00 | 50.00 islands | LV Coarse tapentadoldihydrogen- 250.00 mee | LE Hydroxypropylmethylcellulose 100.00 | 100.00 | 100.00 | 100.00 | 100.00 moss | | | Silicon microcrystalline 304.80 | 79.79 304.80 | 79.79 | 304.80 [sl | 1 Medium breaking strength, Ph.D. Eur. 2.9.8. | 222 209 222 218 205… 0 LL Medium tableting force, over- | 12.8 9.3 7.4 6.3 8.3 sours - | | 1 1 1 Medium tableting force, sub- | 11.3 8.1 5.0 4.9 4.3 Sr equivalent dose based on the free base of tapentadol 'mixed form 3relatively fine particle size (average diameter about 10-20 μm on visual observation) 4relatively coarse particle size (average diameter about 100- 200 μm by visual observation) The in vitro solution of tapentadol from the tablets (drug volume 250 mg, C-1, I-1 and I-3) was measured in a stirrer according to Ph.Eur., Equipped with solder, at a rotational speed at 50 rpm at 37 ° C in
DK 2021 00018 U1 58 900 ml of different dissolution media with different pH values. The experimental results are summarized in the table below: [%] Tapentadol hydrochloride Tapentadol dihydrogen phosphate (n = 3): (n = 3): or qm Te Time pH pH pH 1.0 pH pH pH pH 1.0 | pH [min] | 6.8 4.5 1.0 40 vol-% 6.8 4.5 1.0 40 vol- | 4.5 ethanol% ethanol = rede jo EC @ [% | ® [7 | = FE [% [® 5 [= [% Jw Jw [Iw 2 | = = [mw 0 [% | @ | @ [5 [1 % Jw [mm [% 0 [6 | ® | e [ma | e [sm [a EC EC EC EE CI ejes EO EE EC EE CO II EO EC | [se [6 | @ [wo [ss [sw [sw a Js
ECC EC CC EE ECO EC EO æjsppPpp [lel Je Jw Je Je js FrP sej ss sjpppe [FE FRE IF = pBpPpPpF [PjFPFE Pr 0 [7% [ws | Jw Fr [7] # 0 [Jos Jez [0 [spe [7% | 0 [[or Jes [5 [sr Eje Fr March 3 | ø [mw [ss Jee so [w [om jw [7 jet re [| So [mw Jw jm [7m [lw Jw 7 [| En [mJ jm jm [www mm En [ww or jm [mr [[m Jw Js [nw |
CE sj [sj sis RC El zpFEFPFP FFRFRFF
It is clear from the above data that the in vitro dissolution profiles of the production tablets of Examples I-1 and I-3 at pH 4.5 are almost identical. Thus, as shown, the particle size of the salt of tapentadol with phosphoric acid (Example I-1 relatively fine, Example I-3 relatively coarse) does not significantly change the in vitro dissolution profile.
The in vitro solution profiles in 0.1 N HCl (pH 1.0) and in 0.1 N HCl containing 40% by volume aqueous ethanol (pH 1.0) are shown in Figure 7. It can be seen from Figure 7, that in 0.1 N HCl (pH 1.0) the in vitro solution of tapentadol dihydrogen phosphate is very similar to the in vitro solution of tapentadol hydrochloride. In addition, Figure 7 shows that in 0.1 N HCl (pH 1.0) containing 40% by volume ethanol, the in vitro solution is lowered compared to pH 1.0 for both tapentadol dihydrogen phosphate and tapentadol hydrochloride. Thus, the dosage forms show no ethanol-induced dumping and even provide further delay in aqueous ethanol.
This additional delay effect is significantly stronger for tapentadol dihydrogen phosphate compared to tapentadol hydrochloride. Since the dosage forms contained the same excipients in the same amounts, this effect can be attributed to the salt form of tapentadol (dihydrogen phosphate vs. hydrochloride). Tapentadol dihydrogen phosphate thus has, as shown, additional safety properties in connection with the simultaneous use of ethanol, e.g. alcoholic beverages.
The in vitro solution profiles at pH 4.5 in aqueous buffer (without ethanol) are shown in Figure 8. It can be seen from Figure 8 that at pH 4.5 the difference between the in vitro solution of tapentadol dihydrogen phosphate and tapentadol hydrochloride is more pronounced than at pH 6.8 (see Figure 7, A vs.A). At pH 4.5 a release of e.g. 70% tapentadol hydrochloride significantly earlier than for tapentadol dihydrogen phosphate, the time difference being over one hour. Since the dosage forms contained the same excipients in the same amounts, it can be concluded that for tapentadol dihydrogen phosphate, less depot matrix material (eg HPMC) will be required to achieve the same in vitro solution as tapentadol hydrochloride. As shown, the lower intrinsic dissolution rate (IDR) of tapentadold dihydrogen phosphate allows to reduce the amount of excipients, in particular the amount of depot matrix material, to obtain the desired in vitro dissolution profile.
Figure 9 compares the in vitro dissolution profiles of a conventional tablet containing tapentadole hydrochloride at pH, 1.0, pH 4.5, pH 6.8, in each
DK 2021 00018 U1 60 single cases in aqueous buffer without ethanol and in 0.1 N HCl with 40% by volume of ethanol (pH 1.0). Figure 10 compares the in vitro dissolution profiles of the tablet according to the invention containing salt of tapentadol with phosphoric acid at pH 1.0, pH 4.5, pH 6.8, in each case in aqueous buffer without ethanol and in 0.1 N HCl with 40 volume percent ethanol (pH 1.0). Example 5 - In Vitro Dissolution Profile of Pharmaceutical Dosage Forms: Tablets of the following composition were prepared by mixing all ingredients and compressing the resulting mixtures: Comparative
ET renenadelydredene - 2 - | vein. [moos Medium Break Strength, Ph.D. Eur. 2.9.8. | 237 230… Medium tableting force, over- | 12.4 8.1 sweet - | Medium tableting force, sub- | 9.9 4.4 seeren - | equivalent dose based on the free base of tapentadol mixed form 3relatively fine particle size (average diameter about 20 μm on visual observation). The in vitro solution of tapentadol from the tablets (drug amount 250 mg, I-4) was measured in a stirrer according to Ph. Eur., Equipped with solder, at a rotational speed of 50 rpm at 37 ° C in 900 ml of 0.1 N HCl without ethanol (pH 1.0) and in 0.1 N HCl with 40% v / v ethanol (pH 1.0). The test results are summarized in the table below:
DK 2021 00018 U1 61 oe pe | wee wo em se ewe mee we wm I A —-———… - mo me Fem It is clear from the above data that in 0.1 N HCl (pH 1.0) containing 40% by volume of ethanol, in vitro solution is delayed compared to pH 1.0. Thus, the dosage form shows no ethanol-induced dose dumping and provides even further delay in aqueous ethanol.
This additional retarding effect can thus be attributed to the salt of tapentadol with phosphoric acid and can be seen in various dosage forms, e.g. in depot matrices based on hypromellose (see examples I-1 and I-3), and also in depot matrices based on Kollidon & SR
(mixture containing polyvinyl acetate and polyvidone).
Figure 20 compares in vitro dissolution profiles of a tablet according to the invention containing salt of tapentadol with phosphoric acid in 0.1 N HCl (pH 1.0) without ethanol and in 0.1 N HCl (pH 1.0) in 40 volume percent ethanol.

权利要求:
Claims (14)
[1]
A pharmaceutical dosage form comprising tapentadol for oral administration twice daily; wherein tapentadol is present as a salt with phosphoric acid; wherein the weight equivalent dose of tapendatol contained in the pharmaceutical dosage form is in the range of 10 to 300 mg based on the free base of tapentadol; wherein tapentadol is embedded in a depot matrix; and wherein the dosage form provides an in vitro solution profile, measured by the USP Paddle Method at 50 rpm in 900 ml of aqueous phosphate buffer at a pH of 6.8 at 37 ° C, where - after 0.5 hour, has been released 20 + 20% by weight; after 4 hours 60 + 20% by weight; and - after 12 hours at least 60% by weight of the amount of tapentadol originally contained in the dosage form.
[2]
A pharmaceutical dosage form according to claim 1, wherein the salt of tapentadol with phosphoric acid is the dihydrogen phosphate salt of tapentadol, a solvate, an anolvate and / or a polymorph thereof, a crystalline form and / or amorphous form thereof.
[3]
A pharmaceutical dosage form according to claim 1 or 2, which is a tablet.
[4]
The pharmaceutical dosage form of claim 3, wherein the tablet is monolithic.
[5]
A pharmaceutical dosage form according to claim 3 or 4, wherein the tablet has a breaking strength of at least 100 N, determined according to Ph. Eur. 2.9.8.
[6]
A pharmaceutical dosage form according to any one of the preceding claims which provides slower dissolution of tapentadol in 0.1 N HCl containing 40% by volume ethanol (pH 1.0), in each case measured by the method "USP Paddle Method ”at 50 rpm 900 ml at 37 ° C.
[7]
A pharmaceutical dosage form according to any one of the preceding claims, wherein the dosage form gives an in vitro solution profile, measured by the USP Paddle Method at up to 900 ml (i) aqueous phosphate buffer at pH 6.8, (ii) aqueous buffer at pH 4.5, and / or (iii) 0.1 N HCL at pH 1.0, in each case at 37 ° C, where - after 0.5 hour 20 + has been released 15% by weight; - after 4 hours 60 + 15% by weight; and - after 12 hours at least 70% by weight
DK 2021 00018 U1 64 of the amount of tapentadol originally contained in the dosage form.
[8]
A pharmaceutical dosage form according to any one of the preceding claims, wherein the depot matrix comprises or consists essentially of depot matrix material selected from the group consisting of (i) hydroxypropyl methylcellulose (HPMC); (ii) hydroxypropylcellulose (HPC); (iii) hydroxyethylcellulose (HEC); (iv) microcrystalline cellulose (MCC); (v) ethylcellulose (EC); (vi) polyvinyl acetate (PVAc); (vii) polyvinylpyrrolidone (PVP); (viii) polyvinylpyrrolidone-vinyl acetate copolymer (PVP / PVAC); (ix) poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride); (x) poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (xi) poly (methyl methacrylate-co-methacrylic acid); (xii) poly (ethyl acrylate-co-methacrylic acid); (xiii) poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid); (xiv) poly (ethyl acrylate-co-methyl methacrylate); (xv) poly (ethylene oxide) (PEO); (xvi) polyethylene glycol (PEG); (xvii) long chain fatty alcohol having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated, linear or branched; (xviii) cetostearyl alcohol; (xix) stearyl alcohol; (xx) cetyl alcohol; (xxi) hydrocarbon selected from the group consisting of long chain fatty acids having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated, linear or branched; glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils and waxes; (xxii) xanthan gum; (xxiii) sodium alginate;
DK 2021 00018 U1 65 (xxiv) guar gum; (xxv) locust bean gum; and any mixture of the foregoing.
[9]
A pharmaceutical dosage form according to claim 8, wherein the content of the depot matrix material is in the range of 15 + 10% by weight, or 2010% by weight, or 25 + 10% by weight, or 30 + 10% by weight, or 35 + 10% by weight, or 40 + 10% by weight, or 45 + 10% by weight, or 5010% by weight, or 55 + 10% by weight, or 60 + 10% by weight, or 65 + 10% by weight, or 70 + 10% by weight, or 75 + 10% by weight, or 80 + 10% by weight, in each case relative to the total weight of the dosage form.
[10]
A pharmaceutical dosage form according to any one of the preceding claims for use in the treatment of pain.
[11]
The pharmaceutical dosage form for use according to claim 10, wherein the dosage form is administered orally.
[12]
A pharmaceutical dosage form for use according to claim 10 or 11, wherein the dosage form is administered twice daily.
[13]
A pharmaceutical dosage form for use according to any one of claims 10 to 12, which after oral administration provides plasma levels of tapentadol which provide pain relief for a period of at least 6 hours.
[14]
A pharmaceutical dosage form for use according to any one of claims 10 to 13, wherein the pain is chronic pain.

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同族专利:

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公开号 | 公开日

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DK202100018Y3|2021-06-24|

引用文献:

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法律状态:
2021-06-09| UAT| Utility model published|Effective date: 20210602 |

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2021-06-24| UME| Utility model registered|Effective date: 20210624 |

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DKBA202100018U|DK202100018Y3|2021-03-01|2021-03-01|Dosage form with prolonged release of tapentadolphosphoric acid salt|DKBA202100018U| DK202100018Y3|2021-03-01|2021-03-01|Dosage form with prolonged release of tapentadolphosphoric acid salt|