DE202020103814U1 - Extended release dosage forms of tapentadol phosphoric acid salt - Google Patents

Abstract

A pharmaceutical dosage form comprising tapentadol;
wherein tapentadol is present as a salt with phosphoric acid;
wherein the dosage form provides sustained release of tapentadol;
wherein the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is in the range from 10 to 300 mg, based on the free base of tapentadol;
wherein the dosage form is multiparticulate; and
wherein the individual particles comprise an extended release coating comprising an extended release coating material.

Description

According to §5 (1) sentence 1 GebrMG, the relevant filing date for the European patent application No. 20 160 420.4, filed on March 2, 2020, is used for the present property right, whereby this European patent application is hereby carried out in full for all purposes Reference is incorporated.

The invention relates to a pharmaceutical dosage form which provides a prolonged release of tapentadol, tapentadol being in the form of a salt with phosphoric acid (orthophosphoric acid), preferably as a dihydrogen phosphate salt. The dosage form according to the invention provides improved prolonged release properties, is particularly resistant to ethanol-induced can dumping and, in addition to such resistance, provides additional safety features with regard to the associated use of ethanol, e.g. B. alcoholic beverages, ready.

Several formulations with sustained release can be subject to an ethanol-induced dose dumping (also referred to as alcohol-induced dose dumping, alcoholic can dumping, ethanolic dose dumping and the like), which is known as "unintended, rapid drug release in a short period of time of the entire amount or a significant fraction of the drug contained in a modified release dosage form "[unintentional, rapid release of drug within a short period of the total amount or a significant proportion of the drug contained in a modified-release dosage form].

Of the numerous classes of drugs commercially available as sustained release products, opioids, centrally acting drugs, and drugs with a narrow therapeutic index are at particular risk of dose dumping, despite being formulated in such a way that the drug released in a tailored or delayed manner. The awareness of ethanol-induced can dumping has led to regulatory withdrawals of some products on the market and black box warnings for others. Since then, considerable effort has focused on providing robustness to a formulation when ingested with alcohol. The risk for the patient is considered to be low if the formulation and its effect are not impaired 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 of alcohol-induced dose dumping, AAPS Open (2017) 3: 5, 1-20).

In the most pronounced case, the simultaneous intake of the previously available analgesic Palladone ™ (Purdue Pharma; hydromorphone hydrochloride capsules with sustained release) with alcohol led to significantly higher plasma levels of hydromorphone (up to 16 times higher), especially when fasting. This finding led to the product being discontinued and withdrawn from the market. In vitro studies with another long-acting opioid, Avinza ^® (Pfizer Inc; sustained-release morphine sulfate capsules), showed an accelerated release of morphine based on alcohol concentration. Warning on the box of Avinza ^® and other sustained-release opioids or long-acting opioids warn patients not to drink alcoholic beverages or take prescription or non-prescription drugs containing alcohol during therapy, as this will result in rapid release and absorption of a potentially fatal opioid dose.

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 Food and Drug Administration currently recommends investigating the risk of alcohol-induced dose dumping with opioids and non-opioid drugs with a narrow therapeutic index. Of particular interest are, in particular, sustained release formulations which offer a reduced frequency of administration and a prolonged therapeutic effect due to higher drug levels. For example, in the treatment of (chronic) pain, opioid controlled-release dosage forms have been used as the formulation of choice. However, when patients experience pain, they often turn to alcohol in order to endure the stress of the pain and to reduce the perception of pain.

The most harmful effect is the first to occur due to a rapid dose escalation. Thus, when the dosage form is taken with ethanol, drug release can increase immediately, resulting in an overdose and leading to respiratory depression followed by hypoxia and even death. In addition to the side effects associated with ethanol, the mechanistic understanding of oro-gastrointestinal absorption and metabolism in the liver is important. After the oral Administration of a formulation which is sensitive to dose dumping and is taken at the same time as ethanol, a large part of the drug dissolves immediately in the stomach. After a sufficient retention time in the stomach, the entire amount of the dissolved drug will be uncontrollably emptied into the small intestine. This leads to absorption, which can lead to high plasma concentrations.

In order to avoid these effects, it is desirable to provide dosage forms with release characteristics in which the release in aqueous ethanol is essentially not accelerated compared to the release in a non-ethanolic medium (resistance to ethanol-induced dose dumping).

However, the above consequences of a first burst of drug release are not the only risk associated with ethanol co-ingestion. It is known that the ingestion of alcoholic beverages can prolong the rate of emptying of the stomach and thus the onset of absorption of the drug due to the caloric content of alcohol, which is comparable to the slightly nourished state after ingesting a meal (further details can be found also in 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 mechanisms by which alcohol changes the pharmacokinetic properties of long-lasting opioids are poorly understood. Several studies have shown that the associated consumption of alcohol increases the maximum plasma concentration (C _max ) of certain opioids and reduces the time to reach C _max (t _max ), despite the lack of evidence of dose dumping. Fatal poisoning with prescription opioids is often associated with alcohol use and is likely due to combined CNS and respiratory depressant effects. It has been reported that opioids can significantly reduce the ventilatory response to hypercapnia when administered with ethanol, even when no pharmacokinetic interaction has been observed (see Gudin et al., Risks, Management, and Monitoring of Combination Opioid, Benzodiazepines, and / or Alcohol Use, Postgrad Mes 2013 125 (4) 115-130).

Thus, even if pharmaceutical dosage forms can be provided which are resistant to ethanol-induced can-dumping, i. H. which do not show accelerated dissolution in aqueous ethanol compared to a non-ethanolic medium and which therefore do not provide an initial burst when taken together with ethanol, additional safety concerns related to the effects of ethanol. There is a need for pharmaceutical dosage forms that can provide additional safety features beyond mere resistance to ethanol-induced can-dumping. It would be particularly desirable to provide pharmaceutical dosage forms which not only provide non-accelerated dissolution, but which provide slowed dissolution in aqueous ethanol as compared to a non-ethanolic medium. It is expected that such pharmaceutical dosage forms will be less associated with the risks associated with drug interaction with concomitantly ingested ethanol, since at any given point in time, due to the slowed dissolution, less opioid will be made available to the organism and with the concomitantly consumed ethanol can interact.

Tapentadol (Nucynta ^® , Palexia ^® ) is an oral opioid analgesic from the benzenoid class with a dual mechanism of action similar to tramadol; it is a µ-opioid receptor agonist and also inhibits the reuptake of norepinephrine. Tapentadol is currently available as an oral dosage form containing tapentadol hydrochloride salt and offering immediate release or prolonged release.

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, several sustained-release opioid formulations were used after simultaneous Ingestion with alcohol observed increased absorption. In Table 3 on page 8, the authors provide the following comparison of alcohol interaction data for sustained-release opioid products on the market: Opioid Mean increase in the C _max ratio to medicinal product taken with 0% alcohol Maximum individual C _max ratio with 40% alcohol Hydromorphone 1.37 2.51 Oxymorphone 1.70 2.70 Hydrocodone 2.3 3.9 Tapentadol 100 mg 1.48 4.38 Tapentadol 250 mg 1.28 2.67 Morphine / naltrexone 2.0 5.0 Morphine 1.0 4.54

According to the FDA Draft Guidance for Tapentadol Hydrochloride (available at URL: https://www.accessdatafda.gov/drugsatfda - docs / psg / Tapentadol_% 20ERTabs_200533_RC09-10.pdf), the agency is currently requesting due to concerns about dose dumping of the drug from this medicinal product when ingested with alcohol, that additional dissolution tests with different concentrations of ethanol in the dissolution medium must be carried out.

The pharmaceutical dosage forms of tapentadol currently on the market already offer sufficient resistance to ethanol-induced dose dumping. In an in vivo cross-over study, the effect of alcohol (240 ml, 40%) on the bioavailability of a single dose of 100 mg and 250 mg Nucynta ^® tablets with sustained release was investigated in 19 healthy fasting test subjects. After simultaneous administration of a 100 mg Nucynta ^® sustained release tablet with alcohol, the mean C _max value increased by 48% compared to the control (ingestion with water instead of alcohol), with a range of 0.99- times up to 4.38 times. In addition, the 3 subjects (15%) with the highest C _max values were a factor of at least 2.3 above the mean C _max value of the control. The mean AUC _last and AU-C _inf for tapentadol were increased by 17%; T _max and t _1/2 were relatively unchanged. After simultaneous administration of a 250 mg Nucynta ^® sustained release tablet with alcohol, the mean C _max value increased by 28% compared to the control, with a range from 0.90-fold to 2.67-fold . The individual C _max values of 2 of these subjects (10%) were greater than the mean C _max value of the control by a factor of at least 2.6. The mean AUCiast and AUC _inf for tapentadol were increased by 16%; T _max and t _1/2 were relatively unchanged.

Nevertheless, the simultaneous consumption of alcohol should be avoided, as it is to be expected that Nucynta ^® Extended-Release has additive effects when used in conjunction with alcohol (see PRODUCT MONOGRAPH, Nucynta ^® Extended-Release Tapentadol, October 28, 2013, revised: March 1, 2018).

Therefore, the prescribing information for Nucynta ^® and Palexia ^® includes instructions not to consume alcohol or products containing alcohol while taking the medication, despite providing satisfactory resistance to ethanol-induced can-dumping.

Several attempts to provide pharmaceutical dosage forms containing strong opioids such as tapentadol with a further reduced potential for ethanol-induced dose dumping have been described in the literature.

WO 2015/004245 A1 relates to a tamper-evident oral pharmaceutical dosage form comprising a pharmacologically active ingredient with psychotropic effects and an ethylene vinyl acetate (EVA) polymer which provides resistance to solvent extraction, resistance to abrasion and resistance to can dumping in aqueous ethanol. 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 require the application of heat and pressure to manufacture. The particles are preferably extruded pellets, ie they are produced by thermal molding with the aid of an extruder. All examples relate to multiparticulate dosage forms in which the particles are produced by melt extrusion.

WO 2018/219897 A1 relates to an oral pharmaceutical dosage form comprising a plurality of coated particles, the coated particles comprising a core comprising a tapentadol component and which is coated with a coating material for a controlled release, wherein the coating material for the controlled release 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 enables the controlled release of the tapentadol component. The controlled release coating material serves the purpose of controlled release of the tapentadol component from the coated particles. The controlled release coating from the controlled release coating material may form the outer surface of the particles or be coated with one or more layers of different or identical coating materials, e.g. B. to make the particles resistant to ethanol-induced can dumping. If the particles are made from sugar globules, they are coated with a drug coating comprising tapentadol. These particles can additionally be coated with a controlled release coating comprising a coating material for the controlled release. If the coated particles offer resistance to ethanol-induced can dumping, then they contain at least two further coating layers, namely an inner layer which comprises an alginate salt and an outer layer which comprises an anionic acrylate polymer.

However, known concepts for avoiding ethanol-induced can dumping are not completely satisfactory and there is a need for improved concepts. It would be desirable to provide oral dosage forms of tapentadol which are easy to manufacture and which e.g. B. require no thermal shaping or no multiple coating steps. The oral dosage forms should preferably be provided in the form of tablets, preferably monolithic tablets, i.e. H. it should not be necessary to produce a large number of particles. The production of the oral dosage forms should be possible on standard equipment on a large industrial scale with a high throughput, preferably by pressing powder mixtures, possibly with granulation (dry granulation or wet granulation), but preferably by pressing powder mixtures directly.

It would be particularly desirable to provide additional safety features, namely the availability of pharmaceutical dosage forms that not only show approximately the same dissolution profile in aqueous ethanol and nonethanolic medium, but that in view of the different effects of simultaneously ingested ethanol on the pharmacological profile for an even more retarded dissolution in aqueous ethanol versus non-ethanol medium. It would also be desirable to reduce the amount of excipient required to provide sustained release tapentadol, e.g. In terms of twice daily oral administration.

The object of the invention is to provide pharmaceutical dosage forms of tapentadol which offer advantages compared to the pharmaceutical dosage forms from the prior art. The pharmaceutical dosage forms should be safe and easy to manufacture in an economical manner, should offer advantageous patient compliance and resistance to ethanol-induced dose dumping, should offer additional safety features with regard to simultaneously ingested ethanol, in particular a more delayed dissolution in aqueous ethanol compared to a non-ethanolic one Medium so that it is less likely that changes in the pharmacological profile will occur due to concomitant ingestion of ethanol.

This problem was solved by the subject matter of the claims for protection.

SUMMARY OF THE INVENTION

The invention provides a pharmaceutical dosage form comprising tapentadol for twice daily oral administration; 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 is in the range from 10 to 300 mg, based on the free base of tapentadol (M _r = 221.3 g / mol).

It has surprisingly been found that salts of tapentadol with phosphoric acid (H ₃ PO ₄ ) are of particular use for pharmaceutical dosage forms that provide sustained release of tapentadol. It has surprisingly been found that salts of tapentadol with dosage forms containing phosphoric acid provide a slower release of tapentadol in vitro in an ethanol medium than in a non-ethanol medium. It is therefore to be expected that this Dosage forms further prolong drug release in vivo when ingested with ethanol. This effect depends neither on the particle size of the salts of tapentadol with phosphoric acid nor on the polymorphic form of the salts of tapentadol with phosphoric acid. Furthermore, this effect is observed at extended release matrices, different template materials sustained release (for. Example, Hypromellose or Kollidon ^® SR) comprise, it can ie the characteristics of the salt of phosphoric acid with tapentadol be attributed as such.

It has also been surprisingly found that, compared to tapentadol hydrochloride contained in the sustained release pharmaceutical dosage forms of tapentadol currently on the market, such salts of tapentadol with phosphoric acid have a lower thermodynamic solubility and a slower intrinsic dissolution rate. Because of these dissolution properties of the phosphate salts of tapentadol, they are particularly suitable for the manufacture of sustained release dosage forms. Such dosage forms can contain reduced amounts of sustained release matrix material while maintaining the same dissolution profile as the dosage forms currently on the market with tapentadol hydrochloride.

Salts of tapentadol with phosphoric acid are known, e.g. B. off WO 2010/096045 , WO 2012/010316 A1 , WO 2012/051246 A1 and WO 2017/182438 A1 . However, none of these references addresses the use of the salts to avoid ethanol-induced can dumping.

Dosage forms that provide sustained release of tapentadol are also known, e.g. B. off WO 03/035053 A1 , WO 2006/002886 A1 and WO 2009/092601 A1 . However, none of these references address the avoidance of ethanol-induced can dumping, and none of these references disclose salts of tapentadol with phosphoric acid.

According to the instructions for use, the commercially available tapentadol tablets Palexia ^® retard tapentadol as the hydrochloride salt, the tablet core also containing hypromellose, microcrystalline cellulose, finely divided silicon dioxide and magnesium stearate. Palexia ^® retard tablets thus contain hypromellose as a matrix with extended release. The tablet cores are film-coated with a composition comprising hypromellose, lactose monohydrate, talc, macrogol 6000 and coloring agents. These tablets match WO 03/035053 A1 and the comparative examples contained here in the experimental section.

Figure list

• 1 shows the XRPD spectrum of tapentadol dihydrogen phosphate (mixed form) obtained according to Example 1.1.
• 2 shows the XRPD spectrum of tapentadol dihydrogen phosphate hemihydrate obtained according to Example 1.4.
• 3 shows the DSC curve of tapentadol dihydrogen phosphate hemihydrate obtained according to Example 1.4.
• 4th shows the XRPD spectrum of tapentadol dihydrogen phosphate anhydrate obtained according to Example 1.6.
• 5 shows the DSC curve of tapentadol dihydrogen phosphate anhydrate obtained according to Example 1.6.
• 6 shows three photographs of different particle sizes of the salt of tapentadol with phosphoric acid ( 6A shows relatively fine particles, 6B relatively coarse particles) and the salt of tapentadol with hydrochloric acid ( 6C ).
• In 7th the in vitro dissolution profiles of a conventional tablet containing tapentadol hydrochloride and a tablet according to the invention containing the salt of tapentadol with phosphoric acid in 0.1 N HCl (pH 1.0) and in 0.1 N HCl (pH 1.0) compared to 40% by volume of ethanol.
• In 8th the in vitro dissolution profiles of a conventional tablet containing tapentadol hydrochloride and a tablet according to the invention containing the salt of tapentadol with phosphoric acid are compared at a pH of 4.5 in aqueous buffer (without ethanol).
• In 9 the in vitro dissolution profiles of a conventional tablet containing tapentadol hydrochloride are compared at pH 1.0, pH 4.5 and pH 6.8, in each case in aqueous buffer without ethanol, and at pH 1.0 in 40% by volume of ethanol .
• In 10 the in vitro dissolution profiles of a tablet according to the invention containing the salt of tapentadol with phosphoric acid at pH 1.0, pH 4.5 and pH 6.8, in each case without ethanol, and at pH 1.0 in 40% by volume Compared to ethanol.
• In 11 the in vitro dissolution profiles of a tablet according to the invention containing the 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 of ethanol compared.

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the invention relates to a pharmaceutical dosage form comprising tapentadol for twice daily oral administration; 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 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 used in the treatment of moderate to severe acute or chronic pain works. The synthesis of the tapentadol free base is e.g. B. off EP-A 693 475 known.

The pharmaceutical dosage form of the invention contains tapentadol as a salt with phosphoric acid. It is contemplated that the pharmaceutical dosage form of the invention may contain mixtures of various salts of tapentadol or mixtures of salt (s) of the tapentadol free base (e.g. the non-salt form of tapentadol), but preferably the total amount is in the pharmaceutical Dosage form contained tapentadol as a salt with phosphoric acid.

Salts of tapentadol with phosphoric acid according to the invention include in principle the orthophosphate salts (PO ₄ ^3- ), the monohydrogen phosphate salts (HPO ₄ ^2- ) and the dihydrogen phosphate (H ₂ PO ₄ ^- ). Condensation products of phosphoric acid such as metaphosphate salts or pyrophosphate salts are also contemplated but are less preferred. The tapentadol dihydrogen phosphate salts are particularly preferred.

Preferably, the salt of tapentadol with phosphoric acid is the dihydrogen phosphate salt of tapentadol, which can optionally be solvated (e.g. hydrated) or solvated (e.g. anhydrated). Preferably, the dihydrogen phosphate salt of tapentadol is selected from the group consisting of the solvated dihydrogen phosphate salt of tapentadol, the anhydrated dihydrogen phosphate salt of tapentadol, the solvated dihydrogen phosphate salt of tapentadol, the hydrated dihydrogen phosphate salt of tapentadol, and any mixtures of the above. The salt of tapentadol can be in the form of a single polymorphic form or as a mixture of different polymorphic forms in any mixing ratio.

According to a preferred embodiment, the salt of tapentadol with phosphoric acid is the dihydrogen phosphate salt, which is in the essentially pure crystalline form of tapentadol dihydrogen phosphate hemihydrate salt.

According to a preferred embodiment, the salt of tapentadol with phosphoric acid is the dihydrogen phosphate salt that is present in the essentially pure crystalline form of tapentadol dihydrogen phosphate anhydrate salt.

According to 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 2Θ (± 0.2 degrees 2Θ ); preferably characterized by one or more further X-ray powder diffraction peaks at 8.7, 17.6, 20.3, 22.1 and / or 23.4 degrees 2Θ (± 0.2 degrees 2Θ). Alternatively, the crystalline dihydrogen phosphate salt can be characterized by the following X-ray powder diffraction peaks at degrees 2Θ ± 0.2 degrees 2Θ (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 (11), 21.0 (25), 21.6 (9), 22.1 (18), 23.4 (14), 24.8 (7), 25.0 (17th ), 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 be characterized by the following X-ray powder diffraction peaks at Degree 2Θ ± 0.2 Degree 2Θ: 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.

According to 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 2Θ (± 0.2 degrees 2Θ); preferably characterized by one or more further X-ray powder diffraction peaks at 8.9, 20.5, 22.4, 23.5 and / or 24.3 degrees 2Θ (± 0.2 degrees 2Θ). Alternatively, the crystalline dihydrogen phosphate salt can be characterized by the following X-ray powder diffraction peaks at degrees 2Θ ± 0.2 degrees 2Θ (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 (3rd ), 26.2 (12), 26.4 (13), 26.7 (5), 27.3 (2), 28.2 (5), 28.8 (8), 29.1 (11) , 29.4 (5) and 29.6 (5). Alternatively, the crystalline dihydrogen phosphate salt may be characterized by the following X-ray powder diffraction peaks at Degree 2Θ ± 0.2 Degree 2Θ: 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.

Preferably, the salt of tapentadol with phosphoric acid has an average particle size expressed as a mean surface area D [3.2] (Sauter diameter) and determined by laser diffraction in dry mode according to ISO 13320: 2020 , in the range from 5.0 to 500 µm, preferably 50 ± 40 µm, or 75 ± 40 µm, or 100 ± 40 µm, or 125 ± 40 µm, or 150 ± 40 µm, or 175 ± 40 µm, or 200 ± 40 µm, or 225 ± 40 µm, or 250 ± 40 µm, or 275 ± 40 µm, or 300: L40 µm, or 325 ± 40 µm, or 350 ± 40 µm, or 375 ± 40 µm, or 400 ± 40 µm , or 425 ± 40 µm, or 450 ± 40 µm.

According to a preferred embodiment, the salt of tapentadol with phosphoric acid is in crystalline form. According to another preferred embodiment, the salt of tapentadol with phosphoric acid is in amorphous form. It is further contemplated that the pharmaceutical dosage form 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 amount of the salt of tapentadol with phosphoric acid present in the pharmaceutical dosage form is crystalline.

For the purposes of the description, the dihydrogen phosphate salt of tapentadol is to be regarded as the acid addition salt of 1 mol of orthophosphoric acid with 1 mol of tapentadol. It is believed that one proton of orthophosphoric acid (H ₃ PO ₄ ) protonates the amino group of tapentadol and thus forms an ammonium ion, while the rest of the orthophosphoric acid, i.e. the dihydrogen phosphate anion (HzPO ₄ ^- ), forms the counterion:

For the purposes of description, a reference to "tapentadol" is intended to include the salt of tapentadol with phosphoric acid.

The salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol, can be in the form of any solvate, e.g. B. hydrates, ansolvates, e.g. Anhydrate, and any polymorphic form, e.g. B. crystalline form and / or amorphous form. With regard to these forms and their preparation WO 2012/010316 A1 and WO 2017/182438 A1 referenced.

The equivalent dose by weight of tapentadol contained in the pharmaceutical dosage form according to the invention is in the range from 10 to 300 mg, based on the free base of tapentadol, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg. The tapentadol free base (i.e. the free molecule) has a molecular weight of 221.3 g / mol. 10 mg of the free base of tapentadol thus correspond to 0.0452 mmol, while 300 mg of the free base of tapentadol correspond to 1.3556 mmol. In other words, the pharmaceutical dosage form 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. B. a weight equivalent dose of 100 mg based on the free base of tapentadol (0.4518 mmol), it actually contains 144.3 mg of the dihydrogen phosphate salt of tapentadol (0.4518 mmol).

Unless expressly stated otherwise, the dose information for tapentadol is thus given as equivalent weight based on the free base of tapentadol, i.e. H. the non-salt form, the non-solvate form, the non-cocrystalline form and the non-aggregate form of tapentadol expressed with any other molecules. It is contemplated that the actual form of tapentadol contained in the pharmaceutical dosage form; H. the salt of tapentadol with phosphoric acid, can be in the form of any polymorphic form and / or any solvate and / or any cocrystal and / or any other aggregate of such a salt with other molecules.

Unless expressly stated otherwise, all percentages are percentages by weight and relate 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.

It is contemplated that the pharmaceutical dosage form according to the invention may contain additional pharmacological active ingredients in addition to tapentadol; however, tapentadol is preferably the only pharmacologically active ingredient contained in the pharmaceutical dosage form.

Tapentadol is preferably distributed homogeneously over the pharmaceutical dosage form according to the invention.

The pharmaceutical dosage form of the invention is intended for oral administration, preferably by swallowing the pharmaceutical dosage form as a whole. The pharmaceutical dosage form according to the invention is therefore preferably not intended for buccal or sublingual administration in which the pharmaceutical dosage form would remain in the oral cavity.

The pharmaceutical dosage form according to the invention is intended for twice daily administration. The pharmaceutical dosage form according to the invention thus contains 50% of the daily dose of tapentadol intended for administration to bring about the desired therapeutic effect.

Twice-daily administration can be given approximately every 12 hours, although such a protocol does not need to be strictly followed. For the purposes of the description, an administration protocol should also include twice a day in which the two pharmaceutical dosage forms according to the invention are administered over a period of about 24 hours, the two administrations having to be at least 4 hours apart, preferably at least 8 hours.

The pharmaceutical dosage form of the invention provides sustained release of tapentadol. For purposes of description, extended release means non-immediate release. The prolonged release includes controlled release, sustained release, sustained release, gradual release, repeated release, sustained release, and steady release. Prolonged release preferably means a release with a reduced release rate, to maintain a therapeutic effect, to reduce toxic effects or for another therapeutic purpose.

The prolonged release can be based on various techniques known to those skilled in the art. According to a preferred embodiment, the sustained release is based on sustained release coating materials with which the pharmaceutical dosage form as such or with which a plurality of particles can be coated. According to another preferred embodiment, the extended release is based on a matrix with extended release in which tapentadol is preferably embedded. According to the invention, it is further contemplated that extended release can be achieved through alternative concepts such as ion exchange resins, osmotic dosage forms and the like.

After oral administration, the pharmaceutical dosage form according to the invention preferably provides plasma levels of tapentadol which provide pain relief (analgesia) over a period of at least 6 hours, preferably at least 8 hours, particularly preferably at least 10 hours, most preferably at least 12 hours.

• - nach 0,5 Stunden 20±20 Gew.-%; vorzugsweise 20±15 Gew.-%; besonders bevorzugt 20±10 Gew.-%;
• - nach 4 Stunden 60±20 Gew.-%; vorzugsweise 60±15 Gew.-%; besonders bevorzugt 60±10 Gew.-% und
• - nach 12 Stunden mindestens 60 Gew.-%; vorzugsweise mindestens 70 Gew.-%; besonders bevorzugt mindestens 80 Gew.-%

des ursprünglich in der Dosierungsform enthaltenen Tapentadol freigesetzt worden sind.The pharmaceutical dosage form according to the invention preferably provides an in vitro dissolution profile in which, measured according to the USP paddle method at 50 rpm in 900 ml of aqueous phosphate buffer at a pH of 6.8 at 37 ° C,

• - after 0.5 hours 20 ± 20% by weight; preferably 20 ± 15% by weight; particularly preferably 20 ± 10% by weight;
• - after 4 hours 60 ± 20% by weight; preferably 60 ± 15% by weight; particularly preferably 60 ± 10% by weight and
• - after 12 hours at least 60% by weight; preferably at least 70% by weight; particularly preferably at least 80% by weight

of the tapentadol originally contained in the dosage form have been released.

• - nach 1 Stunde 25±15 Gew.-%; vorzugsweise 25±10 Gew.-%; besonders bevorzugt 25±5,0 Gew.-%;
• - nach 2 Stunden 35±20 Gew.-%; vorzugsweise 35±10 Gew.-%; besonders bevorzugt 35±5,0 Gew.-%;
• - nach 4 Stunden 50±20 Gew.-%; vorzugsweise 50±10 Gew.-%; besonders bevorzugt 50±5,0 Gew.-%;
• - nach 8 Stunden 80±20 Gew.-%; vorzugsweise 80±10 Gew.-%; besonders bevorzugt 80±5,0 Gew.-%;

des ursprünglich in der Dosierungsform enthaltenen Tapentadol freigesetzt worden sind.The pharmaceutical dosage form according to the invention preferably provides an in vitro dissolution profile in which, measured according to the USP paddle method at 50 rpm in 900 ml of aqueous phosphate buffer at a pH of 6.8 at 37 ° C,

• - after 1 hour 25 ± 15% by weight; preferably 25 ± 10% by weight; particularly preferably 25 ± 5.0% by weight;
• - after 2 hours 35 ± 20% by weight; preferably 35 ± 10 wt%; particularly preferably 35 ± 5.0% by weight;
• - after 4 hours 50 ± 20% by weight; preferably 50 ± 10% by weight; particularly preferably 50 ± 5.0% by weight;
• - after 8 hours 80 ± 20% by weight; preferably 80 ± 10% by weight; particularly preferably 80 ± 5.0% by weight;

of the tapentadol originally contained in the dosage form have been released.

• - nach 0,5 Stunden 20±20 Gew.-%; vorzugsweise 20±15 Gew.-%; besonders bevorzugt 20±10 Gew.-%;
• - nach 4 Stunden 60±20 Gew.-%; vorzugsweise 60±15 Gew.-%; besonders bevorzugt 60±10 Gew.-% und
• - nach 12 Stunden mindestens 60 Gew.-%; vorzugsweise mindestens 70 Gew.-%; besonders bevorzugt mindestens 80 Gew.-%

des ursprünglich in der Dosierungsform enthaltenen Tapentadol freigesetzt worden sind.The pharmaceutical dosage form according to the invention preferably provides an in vitro dissolution profile in which, measured by the USP paddle method at 50 rpm in 900 ml of aqueous buffer at a pH of 4.5 at 37 ° C,

• - after 0.5 hours 20 ± 20% by weight; preferably 20 ± 15% by weight; particularly preferably 20 ± 10% by weight;
• - after 4 hours 60 ± 20% by weight; preferably 60 ± 15% by weight; particularly preferably 60 ± 10% by weight and
• - after 12 hours at least 60% by weight; preferably at least 70% by weight; particularly preferably at least 80% by weight

of the tapentadol originally contained in the dosage form have been released.

• - nach 1 Stunde 25±15 Gew.-%; vorzugsweise 25±10 Gew.-%; besonders bevorzugt 25±5,0 Gew.-%;
• - nach 2 Stunden 35±20 Gew.-%; vorzugsweise 35±10 Gew.-%; besonders bevorzugt 35±5,0 Gew.-%;
• - nach 4 Stunden 50±20 Gew.-%; vorzugsweise 50± 10 Gew.-%; besonders bevorzugt 50±5,0 Gew.-%;
• - nach 8 Stunden 80±20 Gew.-%; vorzugsweise 80±10 Gew.-%; besonders bevorzugt 80±5,0 Gew.-%;

des ursprünglich in der Dosierungsform enthaltenen Tapentadol freigesetzt worden sind.The pharmaceutical dosage form according to the invention preferably provides an in vitro dissolution profile in which, measured by the USP paddle method at 50 rpm in 900 ml of aqueous buffer at a pH of 4.5 at 37 ° C,

• - after 1 hour 25 ± 15% by weight; preferably 25 ± 10% by weight; particularly preferably 25 ± 5.0% by weight;
• - after 2 hours 35 ± 20% by weight; preferably 35 ± 10 wt%; particularly preferably 35 ± 5.0% by weight;
• - after 4 hours 50 ± 20% by weight; preferably 50 ± 10% by weight; particularly preferably 50 ± 5.0% by weight;
• - after 8 hours 80 ± 20% by weight; preferably 80 ± 10% by weight; particularly preferably 80 ± 5.0% by weight;

of the tapentadol originally contained in the dosage form have been released.

• - nach 0,5 Stunden 20±20 Gew.-%; vorzugsweise 20±15 Gew.-%; besonders bevorzugt 20±10 Gew.-%;
• - nach 4 Stunden 60±20 Gew.-%; vorzugsweise 60±15 Gew.-%; besonders bevorzugt 60±10 Gew.-% und
• - nach 12 Stunden mindestens 60 Gew.-%; vorzugsweise mindestens 70 Gew.-%; besonders bevorzugt mindestens 80 Gew.-%

des ursprünglich in der Dosierungsform enthaltenen Tapentadol freigesetzt worden sind.The pharmaceutical dosage form according to the invention preferably provides an in vitro dissolution profile in which, measured by the USP paddle method at 50 rpm in 900 ml of 0.1 N HCl at a pH of 1.0 and 37 ° C,

• - after 0.5 hours 20 ± 20% by weight; preferably 20 ± 15% by weight; particularly preferably 20 ± 10% by weight;
• - after 4 hours 60 ± 20% by weight; preferably 60 ± 15% by weight; particularly preferably 60 ± 10% by weight and
• - after 12 hours at least 60% by weight; preferably at least 70% by weight; particularly preferably at least 80% by weight

of the tapentadol originally contained in the dosage form have been released.

• - nach 1 Stunde 25±10 Gew.-%; vorzugsweise 25±10 Gew.-%; besonders bevorzugt 25±5,0 Gew.-%;
• - nach 2 Stunden 40±30 Gew.-%; vorzugsweise 40±10 Gew.-%; besonders bevorzugt 40±5,0 Gew.-%;
• - nach 4 Stunden 60±20 Gew.-%; vorzugsweise 60±10 Gew.-%; besonders bevorzugt 60±5,0 Gew.-%;
• - nach 8 Stunden 80±20 Gew.-%; vorzugsweise 80±10 Gew.-%; besonders bevorzugt 80±5,0 Gew.-%;

des ursprünglich in der Dosierungsform enthaltenen Tapentadol freigesetzt worden sind.The pharmaceutical dosage form according to the invention preferably provides an in vitro dissolution profile in which, measured by the USP paddle method at 50 rpm in 900 ml of 0.1 N HCl at a pH of 1.0 and 37 ° C,

• - after 1 hour 25 ± 10% by weight; preferably 25 ± 10% by weight; particularly preferably 25 ± 5.0% by weight;
• - after 2 hours 40 ± 30% by weight; preferably 40 ± 10 wt%; particularly preferably 40 ± 5.0% by weight;
• - after 4 hours 60 ± 20% by weight; preferably 60 ± 10% by weight; particularly preferably 60 ± 5.0% by weight;
• - after 8 hours 80 ± 20% by weight; preferably 80 ± 10% by weight; particularly preferably 80 ± 5.0% by weight;

of the tapentadol originally contained in the dosage form have been released.

The pharmaceutical dosage form of the invention preferably provides resistance to ethanol-induced can dumping.

The pharmaceutical dosage form of the invention preferably provides a slower in vitro dissolution of tapentadol in aqueous ethanol-containing medium than in non-ethanol-containing medium.

The pharmaceutical dosage form according to the invention preferably provides a slower dissolution of tapentadol in 0.1 N HCl with 5.0% by volume of ethanol (pH 1.0) than in 0.1 N HCl without 5.0% by volume of ethanol (pH 1.0) ready, each measured according to the USP paddle method at 50 rpm in 900 ml at 37 ° C.

The pharmaceutical dosage form according to the invention preferably provides a slower dissolution of tapentadol in 0.1 N HCl with 20% by volume of ethanol (pH 1.0) than in 0.1 N HCl without 20% by volume of ethanol (pH 1.0). ready, each measured according to the USP paddle method at 50 rpm in 900 ml at 37 ° C.

The pharmaceutical dosage form according to the invention preferably provides a slower dissolution of tapentadol in 0.1 N HCl with 40% by volume of ethanol (pH 1.0) than in 0.1 N HCl without 40% by volume of ethanol (pH 1.0). ready, each measured according to the USP paddle method at 50 rpm in 900 ml at 37 ° C.

According to preferred embodiments with the pharmaceutical dosage form according to the invention, the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 25 mg, 50 mg or 100 mg, based in each case on the free base of tapentadol. The pharmaceutical dosage form of the invention preferably has a total weight in the range from 150 to 750 mg.

According to preferred embodiments with the pharmaceutical dosage form according to the invention, the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 150 mg, 200 mg or 250 mg, based in each case on the free base of tapentadol. The pharmaceutical dosage form of the invention preferably has a total weight in the range from 300 to 1200 mg.

The pharmaceutical dosage form according to the invention preferably comprises one, two or more physiologically acceptable excipients.

Pharmaceutical excipients are known to the person skilled in the art (cf. BRC Rowe et al., Handbook of Pharmaceutical Excipients, Pharmaceutical Press; 6th edition 2009; E.-M. Hoepfner et al., Fiedler-Encyclopedia of Excipients, Editio Cantor, 6th edition 2008 ). For the purposes of description, a “pharmaceutical excipient” is preferably viewed as any pharmacologically inactive substance that is typically used as a carrier for the active ingredients of a medicament. The pharmaceutical excipient can have a physiological effect, e.g. B. like a vitamin, but no pharmacological effect like a drug. Typical examples of pharmaceutical excipients include anti-stick agents, binders, coating materials, disintegrants, fillers, diluents, flavoring agents, coloring agents, lubricants, lubricants, preservatives, sorbents, surfactants, sweeteners, colorants, pigments and the like.

Any of the above excipients can be divided into subgroups, respectively. For example, preservatives can be divided into antioxidants, buffers, antimicrobials, and the like, while binders can be divided into solvent binders and dry binders. Several excipients simultaneously show different properties, making them different purposes can serve. For example, polyethylene glycol can be used as a binder, plasticizer, and the like.

The pharmaceutical dosage form of the invention, preferably the sustained release matrix, preferably comprises a binder.

The binder is preferably selected from cellulose, magnesium aluminum silicates (e.g. bentonite), mono-, oligo- and polysaccharides (e.g. dextrose, lactose, mannose), sugar alcohols (e.g. lactitol, mannitol), starches ( e.g., pregelatinized starch, hydrolyzed starch, modified starch), calcium phosphate, polyvinylpyrrolidone and vinylpyrrolidone-vinyl acetate copolymers; preferably microcrystalline cellulose; particularly preferably silicified microcrystalline cellulose, existing group selected.

The content of binder by weight is preferably at least 5.0% by weight, particularly preferably at least 10% by weight, even more preferably at least 15% by weight, even more preferably at least 20% by weight, even more preferably at least 25% by weight, most preferably at least 30% by weight and in particular at least 35% by weight, in each case based on the total weight of the pharmaceutical dosage form.

The content of binder by weight is preferably at most 85% by weight, particularly preferably at most 82.5% by weight, even more preferably at most 80% by weight, even more preferably at most 77.5% by weight, even more preferably at most 75% by weight, most preferably at most 72.5% by weight and in particular at most 70% by weight, in each case based on the total weight of the pharmaceutical dosage form.

The content of binder by weight is in the range of 52 ± 30% by weight, particularly preferably 52 ± 27.5% by weight, even more preferably 52 ± 25% by weight, even more preferably 52 ± 22 , 5% by weight, even more preferably from 52 ± 20% by weight, most preferably from 52 ± 17.5% by weight and in particular from 52 ± 15% by weight, each based on the total weight of the pharmaceutical Dosage form.

If the pharmaceutical dosage form contains more than one binder, the above percentages relate 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 salts of fatty acids (e.g. magnesium stearate, calcium stearate, zinc stearate), fatty acids (e.g. stearic acid, palmitic acid), glyceryl fatty acid esters (e.g. glyceryl monostearate, glyceryl monobehenate, glyceryl dibehenate, glyceryl tribitehenate), sorbic acid Sucrose monopalmitate, sodium stearyl fumarate, hydrated magnesium silicate and talc and is preferably magnesium stearate.

The content of lubricant by weight is at least 0.20% by weight, particularly 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 , even more preferably at least 0.40% by weight, most preferably at least 0.45% by weight and in particular at least 0.50% by weight, in each case based on the total weight of the pharmaceutical dosage form.

The content of lubricant by weight is at most 3.0% by weight, particularly 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 , even more preferably at most 2.20% by weight, most preferably at most 2.00% by weight and in particular at most 1.80% by weight, in each case based on the total weight of the pharmaceutical dosage form.

The content of lubricant by weight is preferably in the range of 0.1 ± 1.0% by weight, particularly preferably 0.50 ± 0.45% by weight, even more preferably 0.50 ± 0.40% by weight %, even more preferably from 0.50 ± 0.35% by weight, even more preferably from 0.50 ± 0.30% by weight, most preferably from 0.50 ± 0.25% by weight % and in particular from 0.50 ± 0.20% by weight, in each case based on the total weight of the pharmaceutical dosage form.

According to preferred embodiments of the pharmaceutical dosage form of the invention, the dosage form contains an extended release coating comprising a coating material extended release selected from the group consisting of hydrophobic cellulose ethers, acrylic polymers, shellac, zein, hydrophobic waxy products, and mixtures thereof.

The dosage form is contemplated to be a monolith comprising such a sustained release coating. In a preferred embodiment, the dosage form is multiparticulate, the individual particles (granules, pellets, and the like) comprising such a sustained release coating.

The number of particles contained in the dosage form is not particularly limited and can range from 1, 2, 3, 4 or 5 to 10, 20, 30, 40 to 100, 200 and more.

The particles are preferably of substantially the same weight, size and composition.

According to a preferred embodiment, the particles contain a core which essentially comprises the total amount of tapentadol, optionally together with one or more excipients, and a coating encapsulating the core with extended release.

According to another preferred embodiment, the particles contain an inert core that does not contain tapentadol (e.g. sugar globules), a drug coating layer which encapsulates the core and comprises substantially the entire amount of tapentadol, optionally together with one or more excipients, and a sustained release coating encapsulating the core and drug coating layer.

The extended release coating material is preferably selected from the group consisting of ethyl cellulose, 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, 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, methyl methacrylate copolymer , Poly (methyl methacrylate), poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride) and glycidyl methacrylate copolymers are selected.

In preferred embodiments, the acrylic polymer consists of one or more ammonio methacrylate copolymers; H. Copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. To obtain a desirable dissolution profile, it may be necessary to include two or more ammoniomethacrylate copolymers with different physical properties such as different molar ratios of quaternary ammonium groups to neutral (meth) acrylic acid esters.

The coating is preferably produced from an aqueous dispersion or from an organic dispersion or from an organic solution of a hydrophobic polymer. The coating preferably comprises an effective amount of a plasticizer that is also present in the aqueous dispersion of the hydrophobic polymer. The plasticizer further improves the physical properties of the film. Since, for example, ethyl cellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is necessary to plasticize the ethyl cellulose before it is used as a coating material. In general, the amount of plasticizer added to a coating solution is based on the concentration of the film former, e.g. B. most commonly from about 1 to about 50 percent by weight of the film former.

Examples of suitable plasticizers for ethyl cellulose include water-insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin, although it is possible to use other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.). Triethyl citrate is a particularly preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers 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 that have been found useful in improving the elasticity of films formed by acrylic films such as Eudragit® RL / RS paint solutions include polyethylene glycols, propylene glycols, diethyl phthalate, castor oil and triacetin. Triethyl citrate is a particularly preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.

The addition of talc reduces the tendency of the aqueous dispersion to stick during processing and acts as a polishing agent.

In addition to modifying the dissolution profile by changing the relative amounts of the various acrylic varnishes, the dissolution profile of the final product can also be modified by, for example, increasing or reducing the thickness of the retardant coating. If the aqueous dispersion of the hydrophobic polymer is used to coat inert pharmaceutical beads, then a large number of the stabilized solid beads obtained with extended release can then be used in an amount which, when ingested and in contact with gastric juice, is sufficient to provide an effective dose with extended release in give a gelatin capsule.

The prolonged release profile can be determined, for example, by varying the amount of coating with the aqueous dispersion of the hydrophobic polymer, changing the manner in which the plasticizer is added to the aqueous dispersion of the hydrophobic polymer, by varying the amount of plasticizer relative to the hydrophobic polymer by adding additional ingredients or excipients, by changing the manufacturing process, etc.

The coating preferably contains a dye in addition to the film former, plasticizer and solvent system (i.e. water) to provide elegance and product demarcation. Suitable ingredients for providing color to the formulation using an aqueous dispersion of an acrylic polymer include titanium dioxide and color pigments such as iron oxide pigments. However, the absorption of pigments can increase the retarding effect of the coating.

The plasticized aqueous dispersion or organic dispersion or organic solution of the hydrophobic polymer can be applied to the substrate comprising tapentadol by spraying using any suitable spray device known in the art. In a preferred process, a Wurster fluidized bed system is used in which a jet of air introduced from below fluidizes the core material and causes drying when the acrylic polymer coating is sprayed on. Preferably one brings about a predetermined controlled release of tapentadol upon exposure of the coated substrate to aqueous solutions, e.g. B. gastric juice, sufficient amount of the aqueous dispersion of the hydrophobic polymer, taking into account the manner in which the plasticizer was incorporated, etc. After coating with the hydrophobic polymer, a further coating of a film former such as Opadry® can optionally be applied to the beads . This conversion is only provided, if at all, to substantially reduce the agglomeration of the beads.

The release of tapentadol from the sustained release formulation can be further influenced by adding one or more release modifying agents or by providing one or more passages through the coating, i.e. by adding one or more release modifying agents. H. set to a desired rate. The ratio of hydrophobic polymer to water soluble material is determined, among other factors, by the rate of release required and the solubility characteristics of the materials chosen. The release modifying agents which act as pore formers can be organic or inorganic and include materials that can be dissolved, extracted or leached from the coating in the environment of use. The pore formers can comprise one or more hydrophilic polymers such as hydroxypropylmethyl cellulose. The controlled release coatings can also include anti-erosion agents such as starches and gums. The controlled release coatings of the present invention may also include materials suitable for the formation of microporous lamina in the environment of use, such as straight chain carbonated polyester polycarbonates in which the carbonate groups reappear in the polymer chain.

According to a preferred embodiment, the dosage form is multiparticulate, the individual particles (granules, pellets and the like) being contained in a capsule with a coating for a prolonged release, optionally together with additional excipients, which are contained in the capsule in powder form or also in the form of Particles (granules, pellets and the like) can be included. In the latter case, the capsules contain at least two different types of particles, namely particles that contain tapentadol and particles that do not contain tapentadol.

According to another preferred embodiment, the dosage form is multiparticulate, the individual particles (granules, pellets and the like) being contained with a coating for a prolonged release in a tablet which contains an extra-particulate material (Multiple Unit Pellet System, MUPS). The extra-particulate material preferably contains at least one excipient selected from binders, disintegrants and lubricants.

According to preferred embodiments of the pharmaceutical dosage form according to the invention, the tapentadol is embedded in a matrix with extended release.

The pharmaceutical dosage form according to the invention, preferably the matrix with prolonged release, preferably contains at least one physiologically harmless polymer which serves to delay the release of the pharmacologically active substance from the pharmaceutical dosage form. The at least one physiologically harmless polymer is thus part of the matrix for the prolonged release of the pharmaceutical dosage form according to the invention.

The prolonged release matrix preferably comprises or consists essentially of at least one prolonged release matrix material selected from the group consisting of hydrophilic or hydrophobic polymers and hydrocarbons.

• - Polysacchariden oder Gummen (z. B. Xanthan, Guaran, Karayagummi, Johannisbrotkernmehl, Natriumalginat, Karobgummi, Chitosan, Polysacchariden von Mannose und Galactose, Pektin, Tragant, Agar);
• - Celluloseethern (z. B. HPMC, HPC, HEC, MC, EC);
• - Celluloseestern (z. B. Celluloseacetat, Celluloseacetatsuccinat, Celluloseacetatphthalat, Celluloseacetatbutyrat);
• - Polyalkylenglykolen und Polyalkylenoxiden;
• - Polyvinylalkohol (PVA), quervernetztem Polyvinylalkohol (PVA), Polyvinylpyrrolidon (PVP), quervernetztem Polyvinylpyrrolidon (PVP), Polyvinylpyrrolidon-Vinylacetat-Copolymeren, Polyvinylchlorid (PVC), Polyethylenvinylacetat (PVAc), Polydimethylsiloxan (PDS), Polyetherurethan (PEU), Polylmilchsäure (PLA), Polyglykolsäure (PGA), Polycaprolacton (PCL), Polyanhydriden, Polyorthoestern;
• - Acrylharzen (z. B. quervernetzten Homopolymeren und Copolymeren von Acrylsäure, Acrylsäure- und Methacrylsäure-Copolymeren, Methacrylsäure-Copolymeren, Methylmethacrylat-Copolymeren, Ethoxyethylmethacrylaten, Cyanoethylmethacrylat, Methylmethacrylat-Copolymeren, Methacrylsäure-Copolymeren, Methylmethacrylat-Copolymeren, Methylmethacrylat-Copolymeren, Methylmethacrylat-Copolymeren, Methacrylsäure-Copolymer, Aminoalkylmethacrylat-Copolymer, Methacrylsäure-Copolymeren, Methylmethacrylat-Copolymeren, Poly(acrylsäure), Poly(methacrylsäure, methacrylsäurealkylamid-Copolymer, Poly(methylmethacrylat), Poly(methacrylsäure) (anhydrid), Methylmethacrylat, Polymethacrylat, Methylmethacrylat-Copolymer, Poly(methylmethacrylat), Poly(methylmethacrylat)-Copolymer, Polyacrylamid, Aminoalkylmethacrylat-Copolymer, Poly(methacrylsäureanhydrid) und Glycidylmethacrylat-Copolymeren, Polyhydroxyethylmethacrylat (PHEMA), Polyacrylamid); und
• - aus Proteinen gewonnenen Materialien.

According to preferred embodiments of the pharmaceutical dosage form according to the invention, the matrix with extended release comprises at least one polymer selected from the group consisting of or the matrix with extended release consists essentially of at least one polymer selected from the group consisting of

• - Polysaccharides or gums (e.g. xanthan, guar, karaya gum, locust bean gum, sodium alginate, diamond gum, chitosan, polysaccharides of mannose and galactose, pectin, tragacanth, agar);
• - Cellulose ethers (e.g. HPMC, HPC, HEC, MC, EC);
• Cellulose esters (e.g. cellulose acetate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate);
• - polyalkylene glycols and polyalkylene oxides;
• - Polyvinyl alcohol (PVA), cross-linked polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), cross-linked polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymers, polyvinyl chloride (PVC), polyethylene vinyl acetate (PVAc), polydimethylsiloxane (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), polyanhydrides, polyorthoesters;
• - Acrylic resins (e.g. 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 acrylate copolymers, methyl acrylate copolymers -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, methyl methacrylate -Copolymer, poly (methyl methacrylate), poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride) and glycidyl methacrylate copolymers, polyhydroxyethyl methacrylate (PHEMA), polyacrylamide); and
• - materials derived from proteins.

Preferably, the extended-release matrix comprises at least one hydrocarbon selected from the group consisting of long-chain (C ₈ -C ₅₀ , especially C ₁₂ -C ₄₀ ) fatty acids, long-chain fatty alcohols, glyceryl esters of long-chain fatty acids, mineral oils, vegetable oils and waxes or consists essentially from it.

The sustained release matrix preferably comprises a sustained release matrix material selected from the group consisting of (i) hydroxypropylmethyl cellulose (HPMC); (ii) hydroxypropyl cellulose (HPC); (iii) hydroxyethyl cellulose (HEC); (iv) microcrystalline cellulose (MCC); (v) ethyl cellulose (EC); (vi) polyvinyl acetate (PVAc); (vii) polyvinyl pyrrolidone (PVP); (viii) polyvinylpyrrolidone-vinyl acetate copolymer (PVP / PVAc); (ix) poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl 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 can be saturated or unsaturated and straight-chain 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 can be saturated or unsaturated and straight-chain or branched; Glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils and waxes; (xxii) xanthan gum; (xxiii) sodium alginate; (xxiv) guaran; (xxv) locust bean gum; and any mixtures of the above, or consists essentially of them. The content of matrix material with extended release is preferably in the range of 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 or 65 ± 10% by weight or 70 ± 10% by weight or 75 ± 10% by weight or 80 ± 10% by weight, in each case based on the total weight of the dosage form.

The pharmaceutical dosage forms of the invention preferably do not comprise poly (alkylene oxide), e.g. B. poly (ethylene oxide), nor ethylene-vinyl acetate copolymers (EVA). For purposes of description, poly (alkylene oxide) differs from poly (alkylene glycol) by its molecular weight; Polymers with a weight average molecular weight M _w of less than 100,000 g / mol are regarded as poly (alkylene glycol), while polymers with a weight average molecular weight M _w of 100,000 g / mol or more are regarded as poly (alkylene oxide).

The sustained release matrix preferably comprises a cellulose derivative selected from cellulose ethers and cellulose esters or a poly (meth) acrylate or copolymer thereof.

The cellulose derivative is preferably a cellulose ether selected from the group consisting of methyl cellulose, ethyl cellulose, propyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose; preferably hydroxypropylmethyl cellulose.

The cellulose derivative is preferably hydroxypropylmethyl cellulose. The hydroxypropyl methylcellulose is preferably selected from the hypromellose types 1828, 2208, 2906 and 2910 according to USP with the following methoxyl content and hydroxypropoxyl content: Methoxyl (%) Hydroxypropoxyl (%) Type min Max min Max 1828 16.5 20.0 23.0 32.0 2208 19.0 24.0 4.0 12.0 2906 27.0 30.0 4.0 7.5 2910 28.0 30.0 7.0 12.0

The viscosity of the physiologically harmless polymer, preferably cellulose derivative, particularly preferably hydroxypropylmethyl cellulose, is preferably in the range of 100,000 ± 80,000 mPas, particularly preferably 100,000 ± 60,000 mPas, even more preferably 100,000 ± 40,000 mPas, even more preferably 100,000 ± 20000 mPas.

The number average molecular weight M _{n of} the physiologically harmless polymer, preferably cellulose derivative, particularly preferably hydroxypropylmethylcellulose, is preferably not more than 220,000 g / mol, particularly 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, even 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.

The content of physiologically harmless polymer, preferably cellulose ether, by weight is preferably at least 2.0% by weight, particularly preferably at least 3.0% by weight, even more preferably at least 4.0% by weight, even more preferably at least 5.0% by weight, even more preferably at least 6.0% by weight, most preferably at least 7.0% by weight and in particular at least 8.0% by weight, in each case based on the total weight of the pharmaceutical dosage form .

The content of physiologically harmless polymer, preferably cellulose ether, by weight is preferably at most 62.5% by weight, particularly preferably at most 60% by weight, even more preferably at most 57.5% by weight, even more preferably at most 55% by weight .-%, more preferably at most 52.5% by weight, most preferably at most 50% by weight and in particular at most 47.5% by weight, based in each case on the total weight of the pharmaceutical dosage form.

The content of physiologically harmless polymer, preferably cellulose ether, by weight is preferably in the range of 30 ± 28% by weight, particularly preferably 30 ± 26% by weight, even more preferably 30 ± 24% by weight, even more preferably from 30 ± 22% by weight, even more preferably from 30 ± 20% by weight, most preferably from 30 ± 18% by weight and in particular from 30 ± 16% by weight, each based on the total weight of the pharmaceutical dosage form.

If the pharmaceutical dosage form contains more than one physiologically harmless 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 relate to the total content of all such physiologically harmless polymers, preferably cellulose ethers, which contained in the pharmaceutical dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , wherein the sustained release matrix comprises, as sustained release matrix material, hydroxypropylmethylcellulose (HPMC), preferably in an amount of 5.0 to 60% by weight, e.g. B. 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, each based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , wherein the sustained release matrix comprises, as sustained release matrix material, hydroxypropyl cellulose (HPC), preferably in an amount of 10 to 50% by weight, e.g. B. 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 based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , wherein the sustained release matrix comprises, as sustained release matrix material, hydroxyethyl cellulose (HEC), preferably in an amount of 5.0 to 50% by weight, e.g. B. 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, each based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , wherein the sustained release matrix as sustained release matrix material comprises microcrystalline cellulose (MCC), preferably in an amount of 10 to 70% by weight, e.g. B. 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, each based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , is embedded, wherein the extended release matrix as the extended release matrix material comprises ethyl cellulose (EC), preferably in an amount of 5.0 to 30 wt%, e.g. B. 15 ± 10 wt .-% or 20 ± 10 wt .-%, each based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , wherein the extended release matrix comprises polyvinyl acetate (PVAc) as the extended release matrix material, preferably in an amount of 25 to 70 wt%, e.g. B. 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, each based on the total weight of the dosage form. The polyvinyl acetate is preferably used in the form of a mixture with polyvinylpyrrolidone (povidone). Such a preferred mixture is commercially available, e.g. B. as Kollidon ^® SR (80 wt .-% polyvinyl acetate, 19 wt .-% povidone, 0.8 wt .-% sodium lauryl sulfate and 0.2 wt .-% silica).

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , wherein the extended release matrix comprises polyvinylpyrrolidone (PVP) as the extended release matrix material, preferably in an amount of 2.0 to 21% by weight, e.g. B. 10 ± 5.0 wt .-% or 15 ± 5.0 wt .-%, each based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , wherein the extended release matrix as the extended release matrix material comprises polyvinylpyrrolidone-vinyl acetate copolymer (PVP / PVAc), preferably in an amount of 1.0 to 30% by weight, e.g. B. 15 ± 10 wt .-% or 20 ± 10 wt .-%, each based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , wherein the extended release matrix as the extended release matrix material comprises poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride), preferably in an amount of 5.0 to 45% by weight, e.g. B. 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 based on the total weight of the dosage form. Poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) is commercially available e.g. B. available as Eudragit ^® RS and Eudragit ^® RL.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , is embedded, wherein the extended release matrix as the extended release matrix material comprises poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), preferably in an amount of 5.0 to 45 wt .-%, e.g. . B. 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 based on the total weight of the dosage form. Poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) is commercially available e.g. B. available as Eudragit ^® E.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , is embedded, the extended-release matrix as Extended release matrix material comprises poly (methyl methacrylate-co-methacrylic acid), preferably in an amount of from 5.0 to 45% by weight, e.g. B. 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 based on the total weight of the dosage form. Poly (methyl methacrylate-co-methacrylic acid) is commercially available e.g. B. available as Eudragit ^® L.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , is embedded, wherein the extended release matrix as the extended release matrix material comprises poly (ethyl acrylate-co-methacrylic acid), preferably in an amount of 5.0 to 45 wt .-%, e.g. B. 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 based on the total weight of the dosage form. Poly (ethyl acrylate-co-methacrylic acid) is commercially available e.g. B. as Eudragit ^® S available.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , is embedded, wherein the extended release matrix as the extended release matrix material comprises poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid), preferably in an amount of 5.0 to 45 wt .-%, e.g. B. 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 based on the total weight of the dosage form. Poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid) is commercially available e.g. B. available as Eudragit ^® FS.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , is embedded, wherein the extended release matrix as the extended release matrix material comprises poly (ethyl acrylate-co-methyl methacrylate), preferably in an amount of 5.0 to 45 wt .-%, e.g. B. 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 based on the total weight of the dosage form. Poly (ethyl acrylate-co-methyl methacrylate) is commercially available e.g. B. available as Eudragit ^® NE.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , wherein the sustained release matrix comprises, as sustained release matrix material, poly (ethylene oxide) (PEO), preferably in an amount of 25 to 65% by weight, e.g. B. 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 based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , wherein the extended release matrix as the extended release matrix material comprises polyethylene glycol (PEG), preferably in an amount of 5.0 to 35 wt.%, e.g. B. 15 ± 10 wt .-% or 20 ± 10 wt .-% or 25 ± 10 wt .-%, each based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , is embedded, the extended-release matrix being a long-chain fatty alcohol having 8 to 50 carbon atoms as the extended-release matrix material, preferably 12 to 40 carbon atoms, which can be saturated or unsaturated and straight-chain or branched, preferably in an amount of 15 to 40% by weight, e.g. B. 25 ± 10 wt .-% or 30 ± 10 wt .-%, each based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , is embedded, wherein the extended release matrix as the extended release matrix material comprises cetostearyl alcohol, preferably in an amount of 15 to 40 wt .-%, e.g. B. 25 ± 10 wt .-% or 30 ± 10 wt .-%, each based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , is embedded, wherein the extended release matrix as the extended release matrix material comprises stearyl alcohol, preferably in an amount of 15 to 40 wt .-%, e.g. B. 25 ± 10 wt .-% or 30 ± 10 wt .-%, each based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , is embedded, wherein the extended release matrix as the extended release matrix material comprises cetyl alcohol, preferably in an amount of 15 to 40 wt .-%, e.g. B. 25 ± 10 wt .-% or 30 ± 10 wt .-%, each based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , is embedded, wherein the matrix with extended release as the matrix material with extended release is a hydrocarbon selected from the group of long chain fatty acids having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which can be saturated or unsaturated and straight-chain or branched, glyceryl esters of such long-chain Fatty acids, mineral oils, vegetable oils and waxes, each preferably in an amount of 5.0 to 70% by weight, e.g. B. 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 based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , wherein the extended release matrix comprises xanthan gum as the extended release matrix material, preferably in an amount of 15 to 40% by weight, e.g. B. 25 ± 10 wt .-% or 30 ± 10 wt .-%, each based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , the sustained release matrix comprising, as sustained release matrix material, sodium alginate, preferably in an amount of 15 to 40% by weight, e.g. B. 25 ± 10 wt .-% or 30 ± 10 wt .-%, each based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , wherein the sustained release matrix comprises guaran as sustained release matrix material, preferably in an amount of 5.0 to 35% by weight, e.g. B. 15 ± 10 wt .-% or 20 ± 10 wt .-% or 25 ± 10 wt .-%, each based on the total weight of the dosage form.

According to 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. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a matrix with extended release in which the salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate salt of tapentadol , wherein the sustained release matrix comprises, as sustained release matrix material, locust bean gum, preferably in an amount of from 5.0 to 35% by weight, e.g. B. 15 ± 10 wt .-% or 20 ± 10 wt .-% or 25 ± 10 wt .-%, each based on the total weight of the dosage form.

In addition to the above ingredients, an extended release matrix may also contain suitable amounts of other materials, e.g. B. customary in pharmacy diluents, lubricants, binders, granulating auxiliaries, colorants, flavorings and accompanying agents.

Pharmaceutical dosage forms containing extended release matrices in which tapentadol is embedded can be prepared by conventional methods 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 of the invention is a capsule that preferably contains a plurality of particles containing a sustained release coating.

According to another preferred embodiment, the pharmaceutical dosage form according to the invention is a tablet. The tablet is preferably monolithic. According to the invention, monolithic tablets are optionally film-coated tablets in which the tablet cores contain a compressed powder and / or a mixture of granules. In particular, (i) tablets produced by direct compression of powder mixtures, (ii) tablets produced by compression of granules obtained by dry granulation and optionally mixtures containing extra-granular excipients, (iii) tablets produced by pressing granules obtained by wet granulation and optionally mixtures containing extra-granular excipients and (iv) tablets produced by compressing granules obtained by extrusion granulation and optionally mixtures comprising extra-granular excipients are all to be regarded as monolithic tablets according to the invention. Multiple Unit Pellet Systems (MUPS) or other dosage forms in which a large number of particles with a specific design, specific weight and specific shape are mixed with an outer matrix material and then pressed into tablets, the outer matrix material forming a continuous phase in which the Pellets or particles are embedded, are preferably not viewed as monolithic tablets. Capsules that are filled with a large number of loose particles are of course also not to be regarded as monolithic.

The tablet preferably has a breaking strength of at least 100 N, preferably at least 150 N, particularly preferably at least 200 N. The breaking strength is preferably in accordance with Ph. Eur. 10, Chapter 2.9.8. "Resistance to Crushing of Tablets" determined.

Another aspect of the invention relates to a method for producing a pharmaceutical dosage form according to the invention as described above.

1. (A) die Bereitstellung innerer Ausgangspellets, z. B. Zuckerkügelchen, die einen oder mehrere Exzipienten, jedoch kein Tapentadol enthalten;
2. (B) die Bereitstellung einer Lösung oder Dispersion von Tapentadol (einschließlich des Salzes mit Phosphorsäure) in Wasser oder einem organischen Lösungsmittel oder einer Mischung davon, gegebenenfalls mit dem einen oder den mehreren Exzipienten, wobei das organische Lösungsmittel vorzugsweise aus Ethanol und Aceton ausgewählt ist;
3. (C) das Beschichten der in Schritt (A) bereitgestellten inneren Ausgangspellets mit der in Schritt (B) bereitgestellten Lösung oder Dispersion von Tapentadol, vorzugsweise in einer Wirbelschicht, unter Erhalt von Zwischenproduktpartikeln, die einen kein Tapentadol enthaltenden inneren Kern und eine den Kern verkapselnde Arzneimittelüberzugsschicht, die im Wesentlichen die gesamte Menge an Tapentadol, die in der Dosierungsform enthalten sein soll, umfasst, gegebenenfalls zusammen mit dem einen oder den mehreren Exzipienten umfassen;
4. (D) gegebenenfalls das Trocknen der in Schritt (C) erhaltenen Zwischenproduktpartikel unter Erhalt getrockneter Zwischenproduktpartikel;
5. (E) die Bereitstellung einer Lösung oder Dispersion eines Überzugsmaterials mit verlängerter Freisetzung in Wasser oder eines organischen Lösungsmittels oder einer Mischung davon, gegebenenfalls mit dem einen oder den mehreren Exzipienten, wobei das organische Lösungsmittel vorzugsweise aus Ethanol und Aceton ausgewählt ist;
6. (F) das Beschichten der in Schritt (C) erhaltenen Zwischenproduktpartikel oder der in Schritt (D) erhaltenen getrockneten Zwischenproduktpartikel mit der in Schritt (E) bereitgestellten Lösung oder Dispersion des Überzugsmaterials mit verlängerter Freisetzung, vorzugsweise in einer Wirbelschicht, unter Erhalt von Partikeln mit verlängerter Freisetzung, die einen kein Tapentadol enthaltenden inneren Kern, eine den Kern verkapselnde Arzneimittelüberzugsschicht, die im Wesentlichen die gesamte Menge an Tapentadol umfasst, gegebenenfalls zusammen mit dem einen oder den mehreren Exzipienten, und einen den Kern und die Arzneimittelüberzugsschicht verkapselnden Überzug mit verlängerter Freisetzung enthalten;
7. (G) gegebenenfalls das Trocknen der in Schritt (F) erhaltenen Partikel mit verlängerter Freisetzung unter Erhalt getrockneter Partikel mit verlängerter Freisetzung; und
8. (H) entweder das Abfüllen der in Schritt (F) erhaltenen Partikel mit verlängerter Freisetzung oder der in Schritt (G) erhaltenen getrockneten Partikel mit verlängerter Freisetzung in Kapseln; oder das Mischen der in Schritt (F) erhaltenen Partikel mit verlängerter Freisetzung oder der in Schritt (G) erhaltenen getrockneten Partikel mit verlängerter Freisetzung mit extrapartikulären Exzipienten und das Verpressen der Mischung zu Tabletten (Multiple Unit Pellet Systems, MUPS).

If the pharmaceutical dosage form contains particles comprising a coating with a prolonged release, the manufacturing method of the invention in a preferred embodiment comprises the following steps:

1. (A) the provision of internal output pellets, e.g. B. sugar globules containing one or more excipients but no tapentadol;
2. (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 with the one or more excipients, the organic solvent preferably being selected from ethanol and acetone;
3. (C) coating the inner starting pellets provided in step (A) with the solution or dispersion of tapentadol provided in step (B), preferably in a fluidized bed, to obtain intermediate product particles which have an inner core which does not contain tapentadol and an inner core which encapsulates the core A drug coating layer comprising substantially all of the amount of tapentadol to be included in the dosage form, optionally together with the one or more excipients;
4. (D) if appropriate, drying the intermediate product particles obtained in step (C) to obtain dried intermediate product particles;
5. (E) providing a solution or dispersion of a sustained release coating material in water or an organic solvent or a mixture thereof, optionally with the one or more excipients, the organic solvent preferably being selected from ethanol and acetone;
6. (F) coating the intermediate product particles obtained in step (C) or the dried intermediate product particles obtained in step (D) with the solution or dispersion of the coating material provided in step (E) with prolonged release, preferably in a fluidized bed, to obtain particles with sustained release comprising an inner core not containing tapentadol, a core-encapsulating drug coating layer which comprises substantially the entire amount of tapentadol, optionally together with the one or more excipients, and a sustained release coating encapsulating the core and the drug coating layer ;
7. (G) optionally drying the prolonged release particles obtained in step (F) to obtain dried prolonged release particles; and
8. (H) either filling the sustained release particles obtained in step (F) or the dried sustained release particles obtained in step (G) into capsules; or mixing the extended release particles obtained in step (F) or the dried extended release particles obtained in step (G) with extra-particulate excipients and compressing the mixture into tablets (Multiple Unit Pellet Systems, MUPS).

Another aspect of the invention relates to a pharmaceutical dosage form obtainable by this preferred method according to the invention as described above.

1. (A) das Bereitstellen einer im Wesentlichen die gesamte Menge an Tapentadol (einschließlich des Salzes mit Phosphorsäure), die in der Dosierungsform enthalten sein soll, enthaltenden Mischung, gegebenenfalls zusammen mit einem oder mehreren Exzipienten;
2. (B) die Herstellung von Arzneimittelpellets aus der in Schritt (A) bereitgestellten Mischung durch Trockengranulation, Nassgranulation oder Extrusion, wobei die Nassgranulation vorzugsweise die Verwendung eines aus Wasser, Ethanol, Aceton und einer beliebigen Mischung davon ausgewählten Lösungsmittels umfasst;
3. (C) gegebenenfalls das Trocknen und/oder Sphäronisieren den Schritt (B) hergestellten Arzneimittelpellets unter Erhalt getrockneter und/oder sphäronisierter Arzneimittelpellets;
4. (D) die Bereitstellung einer Lösung oder Dispersion eines Überzugsmaterials mit verlängerter Freisetzung in Wasser oder einem organischen Lösungsmittel oder einer Mischung davon, gegebenenfalls mit einem oder mehreren Exzipienten, wobei das organische Lösungsmittel vorzugsweise aus Ethanol und Aceton ausgewählt ist;
5. (E) das Beschichten der in Schritt (B) hergestellten Arzneimittelpellets oder der in Schritt (C) erhaltenen getrockneten und/oder sphäronisierten Arzneimittelpellets mit der in Schritt (D) bereitgestellten Lösung oder Dispersion des Überzugsmaterials mit verlängerter Freisetzung, vorzugsweise in einer Wirbelschicht, unter Erhalt von Partikeln mit verlängerter Freisetzung, die einen im Wesentlichen die Gesamtmenge an Tapentadol umfassenden Kern, gegebenenfalls zusammen mit einem oder mehreren Exzipienten, und einen den Kern verkapselnden Überzug mit verlängerter Freisetzung enthalten;
6. (F) gegebenenfalls das Trocknen der in Schritt (E) erhaltenen Partikel mit verlängerter Freisetzung unter Erhalt getrockneter Partikel mit verlängerter Freisetzung; und
7. (G) entweder das Abfüllen der in Schritt (E) erhaltenen Partikel mit verlängerter Freisetzung oder der in Schritt (F) erhaltenen getrockneten Partikel mit verlängerter Freisetzung in Kapseln; oder das Mischen der in Schritt (E) erhaltenen Partikel mit verlängerter Freisetzung oder den Schritt (F) erhaltenen getrockneten Partikel mit verlängerter Freisetzung mit extrapartikulären Exzipienten und das Verpressen der Mischung zu Tabletten (Multiple Unit Pellet Systems, MUPS).

If the pharmaceutical dosage form contains particles comprising a coating with a prolonged release, the manufacturing method of the invention in a preferred embodiment comprises the following steps:

1. (A) providing a mixture containing substantially all of the amount of tapentadol (including the salt with phosphoric acid) to be included in the dosage form, optionally together with one or more excipients;
2. (B) the production of drug pellets from the mixture provided in step (A) by dry granulation, wet granulation or extrusion, the wet granulation preferably comprising the use of a solvent selected from water, ethanol, acetone and any mixture thereof;
3. (C) optionally drying and / or spheronizing drug pellets produced in step (B) to obtain dried and / or spheronized drug pellets;
4. (D) providing a solution or dispersion of a sustained release coating material in water or an organic solvent, or a mixture thereof, optionally with one or more excipients, the organic solvent preferably being selected from ethanol and acetone;
5. (E) coating the medicament pellets produced in step (B) or the dried and / or spheronized medicament pellets obtained in step (C) with the solution provided in step (D) or dispersion of the coating material with prolonged release, preferably in a fluidized bed, to obtain particles with prolonged release which contain a core comprising essentially the total amount of tapentadol, optionally together with one or more excipients, and a coating encapsulating the core with prolonged release ;
6. (F) optionally drying the extended-release particles obtained in step (E) to obtain dried extended-release particles; and
7. (G) either filling the extended release particles obtained in step (E) or the dried extended release particles obtained in step (F) into capsules; or mixing the extended-release particles obtained in step (E) or the dried extended-release particles obtained in step (F) with extra-particulate excipients and compressing the mixture into tablets (Multiple Unit Pellet Systems, MUPS).

Another aspect of the invention relates to a pharmaceutical dosage form obtainable by this preferred method according to the invention as described above.

1. (a) das Bereitstellen einer im Wesentlichen die gesamte Menge an Tapentadol (einschließlich des Salzes mit Phosphorsäure), die in der Dosierungsform enthalten sein soll, und mindestens ein Matrixmaterial mit verlängerter Freisetzung enthaltenden Mischung, gegebenenfalls zusammen mit einem oder mehreren Exzipienten;
2. (b) gegebenenfalls das Granulieren der in Schritt (a) bereitgestellten Mischung unter Erhalt eines Granulats, wobei das Granulieren vorzugsweise Folgendes umfasst: (i) Nassgranulation mittels eines vorzugsweise aus Wasser, Ethanol, Aceton und einer beliebigen Mischung davon ausgewählten Lösungsmittels, gegebenenfalls gefolgt von Trocknen; (ii) Trockengranulation; oder (iii) Extrusion;
3. (c) gegebenenfalls das Mischen des in Schritt (b) erhaltenen Granulats mit einem oder mehreren Exzipienten unter Erhalt einer Granulatmischung;
4. (d) das Verpressen der in Schritt (a) bereitgestellten Mischung oder des in Schritt (b) erhaltenen Granulats oder der in Schritt (c) erhaltenen Granulatmischung zu Tabletten;
5. (e) gegebenenfalls das Filmbeschichten der in Schritt (d) verpressten Tabletten.

If the pharmaceutical dosage form contains a matrix with prolonged release in which the tapentadol (including the salt with phosphoric acid) is embedded, the manufacturing method according to the invention, in a preferred embodiment, comprises the following steps:

1. (a) providing a mixture containing substantially all of the tapentadol (including the salt with phosphoric acid) to be included in the dosage form and at least one sustained release matrix material, optionally together with one or more excipients;
2. (b) optionally granulating the mixture provided in step (a) to obtain granules, wherein the granulating preferably comprises the following: (i) wet granulation using a solvent preferably selected from water, ethanol, acetone and any mixture thereof, optionally followed by Dry; (ii) dry granulation; or (iii) extrusion;
3. (c) if appropriate, mixing the granules obtained in step (b) with one or more excipients to obtain a granule mixture;
4. (d) compressing the mixture provided in step (a) or the granulate obtained in step (b) or the granulate mixture obtained in step (c) to give tablets;
5. (e) optionally film-coating the tablets compressed in step (d).

The pressing in step (d) of the method according to the invention is preferably carried out with a compression force of not more than 20 kN, particularly preferably not more than 15 kN, even more preferably not more than 10 kN, even more preferably not more than 9.5 kN, even 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.

The compression in step (d) of the method according to the invention is preferably carried out under conditions in which the compressed tablet has a breaking strength of at least 100N, particularly preferably at least 150N, even more preferably at least 200N.

The pharmaceutical dosage form of the present invention is preferably not manufactured by thermal molding such as melt extrusion.

The pharmaceutical dosage form according to the invention preferably does not contain a large number of particles or pellets with a specific design, specific shape and specific weight, which may be compressed into tablets in which the particles or pellets form a discontinuous phase in a continuous phase of an external matrix material.

The pharmaceutical dosage form according to the invention preferably does not contain an opioid antagonist. Opioid antagonists are units that modify the response of opioid receptors. Opioid antagonists include naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, nalinefen, cyclazacin, levallorphan, pharmaceutically acceptable salts thereof, and mixtures thereof.

Another aspect of the invention relates to the pharmaceutical dosage form according to the invention as described above for use in the treatment of pain, the dosage form being 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 the treatment of pain, the dosage form being administered orally, preferably twice daily.

Another aspect of the invention relates to a method for the treatment of pain, which comprises the step of oral, preferably twice daily, administration of a pharmaceutical dosage form according to the invention as described above to a subject in need thereof.

The pain is preferably chronic pain.

According to preferred embodiments, the pharmaceutical dosage form according to the invention provides an average T _max value within the range of 5.0 ± 3.0 hours in a patient population of at least 10 patients, preferably at least 50 patients, after oral administration.

• - C_max im Bereich von 12±3 ng/ml; und/oder
• - AUC_last im Bereich von 204±50 ng·h/ml; und/oder
• - AUC_∞ im Bereich von 214±50 ng·h/ml bereitstellt.

According to preferred embodiments of the pharmaceutical dosage form according to the invention, the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 50 mg, based on the free base of tapentadol, the dosage form after oral administration in a patient population of at least 50 patients an average of

• - C _max in the range of 12 ± 3 ng / ml; and or
• - AUC _last in the range of 204 ± 50 ng.h / ml; and or
• - Provides AUC _∞ in the range of 214 ± 50 ng.h / ml.

• - C_max im Bereich von 29±6 ng/ml; und/oder
• - AUC_last im Bereich von 440±100 ng·h/ml; und/oder
• - AUC_∞ im Bereich von 447±100 ng·h/ml bereitstellt.

According to 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, the dosage form after oral administration in a patient population of at least 50 patients an average of

• - C _max in the range of 29 ± 6 ng / ml; and or
• - AUC _last in the range of 440 ± 100 ng.h / ml; and or
• - AUC _∞ in the range of 447 ± 100 ng.h / ml.

• - C_max im Bereich von 47±9 ng/ml; und/oder
• - AUC_last im Bereich von 662±150 ng·h/ml; und/oder
• - AUC_∞ im Bereich von 665±150 ng·h/ml bereitstellt.

According to preferred embodiments of the pharmaceutical dosage form according to the invention, the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 150 mg, based on the free base of tapentadol, the dosage form after oral administration in a patient population of at least 50 patients an average of

• - C _max in the range of 47 ± 9 ng / ml; and or
• - AUC _load in the range of 662 ± 150 ng.h / ml; and or
• - AUC _∞ in the range of 665 ± 150 ng.h / ml.

• - C_max im Bereich von 64±12 ng/ml; und/oder
• - AUC_last im Bereich von 890±200 ng·h/ml; und/oder
• - AUC_∞ im Bereich von 895±200 ng·h/ml bereitstellt.

According to 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, the dosage form after oral administration in a patient population of at least 50 patients an average of

• - C _max in the range of 64 ± 12 ng / ml; and or
• - AUC _last in the range of 890 ± 200 ng.h / ml; and or
• - AUC _∞ in the range of 895 ± 200 ng.h / ml.

• - C_max im Bereich von 85±15 ng/ml; und/oder
• - AUC_last im Bereich von 1.141±250 ng·h/ml; und/oder
• - AUC_∞ im Bereich von 1.145±250 ng·h/ml bereitstellt.

According to 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, the dosage form after oral administration in a patient population of at least 50 patients an average of

• - C _max in the range of 85 ± 15 ng / ml; and or
• - AUC _load in the range of 1,141 ± 250 ng.h / ml; and or
• - AUC _∞ in the range of 1,145 ± 250 ng.h / ml.

• Paragraph 1. Eine Tapentadol umfassende pharmazeutische Dosierungsform für die zweimal tägliche Verabreichung;
• wobei Tapentadol als ein Salz mit Phosphorsäure vorliegt; wobei die Dosierungsform eine verlängerte Freisetzung von Tapentadol bereitstellt; und wobei die in der pharmazeutischen Dosierungsform enthaltene gewichtsäquivalente Dosis von Tapentadol im Bereich von 10 bis 300 mg liegt, bezogen auf die freie Base von Tapentadol.

Particularly preferred embodiments of the invention are summarized below as paragraphs 1 to 67:

• Paragraph 1. A pharmaceutical dosage form comprising tapentadol for twice daily administration;
• 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 is in the range of 10 to 300 mg, based on the free base of tapentadol.

Paragraph 2. The pharmaceutical dosage form according to Paragraph 1, wherein the salt is the dihydrogen phosphate salt of tapentadol, a solvate, an ansolvate and / or a polymorphic form thereof.

Paragraph 3. The pharmaceutical dosage form according to Paragraph 1 or 2, which comprises one, two or more physiologically acceptable excipients.

Paragraph 4. The pharmaceutical dosage form of any preceding paragraph which, after oral administration, provides plasma levels of tapentadol that provide for pain relief over a period of at least 6 hours.

Paragraph 5. The pharmaceutical dosage form according to one of the preceding paragraphs, which has an in vitro dissolution 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, provides at which after 0.5 hours 20 ± 20% by weight; preferably 20 ± 15% by weight; particularly preferably 20 ± 10% by weight; after 4 hours 60 ± 20% by weight; preferably 60 ± 15% by weight; particularly preferably 60 ± 10% by weight; and after 12 hours at least 60% by weight; preferably at least 70% by weight; particularly preferably at least 80% by weight of the tapentadol originally contained in the dosage form have been released.

Paragraph 6. The pharmaceutical dosage form according to any one of the preceding paragraphs, which has an in vitro dissolution 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, in which - after 1 hour 25 ± 15% by weight; - after 2 hours 35 ± 20% by weight; - after 4 hours 50 ± 20% by weight; - after 8 hours 80 ± 20% by weight % of the tapentadol originally contained in the dosage form has been released.

Paragraph 7. The pharmaceutical dosage form according to any of the preceding paragraphs, which has an in vitro dissolution profile, measured by the USP paddle method at 50 rpm in 900 ml of aqueous buffer at a pH of 4.5 at 37 ° C, provides at which after 0.5 hours 20 ± 20% by weight; preferably 20 ± 15% by weight; particularly preferably 20 ± 10% by weight; after 4 hours 60 ± 20% by weight; preferably 60 ± 15% by weight; particularly preferably 60 ± 10% by weight; and after 12 hours at least 60% by weight; preferably at least 70% by weight; particularly preferably at least 80% by weight
of the tapentadol originally contained in the dosage form have been released.

Paragraph 8. The pharmaceutical dosage form according to any of the preceding paragraphs, which has an in vitro dissolution profile measured by the USP paddle method at 50 rpm in 900 ml of aqueous buffer at a pH of 4.5 at 37 ° C, in which - after 1 hour 25 ± 15% by weight; - after 2 hours 35 ± 20% by weight; - after 4 hours 50 ± 20% by weight; - after 8 hours 80 ± 20% by weight % of the tapentadol originally contained in the dosage form has been released. Paragraph 9. The pharmaceutical dosage form according to any of the preceding paragraphs which has an in vitro dissolution profile measured by the USP paddle method at 50 rpm in 900 ml of 0.1 N HCl at pH 1.0 and 37 ° C, at which after 0.5 hours 20 ± 20% by weight; preferably 20 ± 15% by weight; particularly preferably 20 ± 10% by weight; after 4 hours 60 ± 20% by weight; preferably 60 ± 15% by weight; particularly preferably 60 ± 10% by weight; and after 12 hours at least 60% by weight; preferably at least 70% by weight; particularly preferably at least 80% by weight of the tapentadol originally contained in the dosage form have been released.

Paragraph 10. The pharmaceutical dosage form according to any of the preceding paragraphs which has an in vitro dissolution profile measured by the USP paddle method at 50 rpm in 900 ml of 0.1 N HCl at a pH of 1.0 and 37 ° C, at which - after 1 hour 25 ± 10% by weight; - after 2 hours 40 ± 30% by weight; - after 4 hours 60 ± 20% by weight; - after 8 hours 80 ± 20 Wt .-% of the tapentadol originally contained in the dosage form have been released.

Paragraph 11. The pharmaceutical dosage form of any preceding paragraph that provides resistance to ethanol-induced can-dumping.

Paragraph 12. The pharmaceutical dosage form of Paragraph 11 which provides slower in vitro dissolution of tapentadol in aqueous ethanol-containing medium than in aqueous non-ethanol-containing medium.

Paragraph 13. The pharmaceutical dosage form according to Paragraph 11 or 12, which allows a slower dissolution of tapentadol in 0.1 N HCl with 40% by volume of ethanol (pH 1.0) than in 0.1 N HCl without 40% by volume. Ethanol (pH 1.0), each measured according to the USP paddle method at 50 rpm in 900 ml at 37 ° C.

Paragraph 14. The pharmaceutical dosage form according to one of the preceding paragraphs, in which 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. Paragraph 15. The pharmaceutical dosage form of Paragraph 14, wherein the dosage form has a total weight in the range of 150 to 750 mg.

Paragraph 16. The pharmaceutical dosage form according to one of Paragraphs 1 to 13, in which 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.

Paragraph 17. The pharmaceutical dosage form of Paragraph 16, wherein the dosage form has a total weight in the range of 300 to 1200 mg.

Paragraph 18. The pharmaceutical dosage form of any preceding paragraph, wherein the dosage form comprises an extended release coating comprising an extended release coating material selected from the group consisting of hydrophobic cellulose ethers, acrylic polymers, shellac, zein, hydrophobic waxy products, and mixtures thereof, contains.

Paragraph 19. The pharmaceutical dosage form of Paragraph 18, wherein the extended release coating material is preferably composed of ethyl cellulose, acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, methyl methacrylate copolymers, methacrylic acid copolymers, methyl methacrylates -Copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methacrylic acid copolymers, aminoalkyl methacrylate copolymers, 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) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride) and glycidyl methacrylate copolymers.

Paragraph 20. The pharmaceutical dosage form of any preceding paragraph, wherein tapentadol is embedded in a sustained release matrix.

Paragraph 21. The pharmaceutical dosage form of Paragraph 20, wherein the sustained release matrix comprises or consists essentially of at least one sustained release matrix material selected from the group consisting of hydrophilic or hydrophobic polymers and hydrocarbons.

Paragraph 22. The pharmaceutical dosage form of Paragraph 21, wherein the sustained release matrix comprises at least one polymer selected from the group consisting of polysaccharides or gums (e.g., xanthan, guar, karaya gum, locust bean gum, sodium alginate, karob gum, chitosan, polysaccharides of mannose and galactose, pectin, tragacanth, 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), cross-linked Polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), cross-linked polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymers, polyvinyl chloride (PVC), polyethylene vinyl acetate (PVA), polydimethylsiloxane (PDS), polyacrylic acid (polyglycolic acid, polyglycolic acid, polyga ), Polycaprolactone (PCL), polyanhydrides, polyorthoesters; Acrylic resins (e.g. 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 Copolymers, methacrylic acid copolymers, aminoalkyl methacrylate copolymers, 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) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride) and glycidyl methacrylate copolymers, polyhydroxyethyl methacrylate (PHEMA), polyacrylamide); and comprises or consists of protein-derived materials.

Paragraph 23. The pharmaceutical dosage form of Paragraph 21 or 22, wherein the matrix sustained release at least one hydrocarbon selected from the group consisting of long chain (C8-C50, especially C12-C40) fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral oils, vegetable oils and Comprises or consists essentially of growth. Paragraph 24. The pharmaceutical dosage form of any one of Paragraphs 20 to 23, wherein the extended release matrix is an extended release matrix material selected from the group consisting of (i) hydroxypropylmethyl cellulose (HPMC); (ii) hydroxypropyl cellulose (HPC); (iii) hydroxyethyl cellulose (HEC); (iv) microcrystalline cellulose (MCC); (v) ethyl cellulose (EC); (vi) polyvinyl acetate (PVAc); (vii) polyvinyl pyrrolidone (PVP); (viii) polyvinylpyrrolidone-vinyl acetate copolymer (PVP / PVAc); (ix) poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl 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 can be saturated or unsaturated and straight-chain 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 can be saturated or unsaturated and straight-chain or branched; Glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils and waxes; (xxii) xanthan gum; (xxiii) sodium alginate; (xxiv) guaran; (xxv) locust bean gum; and any mixtures of the above; wherein the content of matrix material with extended release is preferably in the range of 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 or 65 ± 10% by weight or 70 ± 10% by weight or 75 ± 10% by weight or 80 ± 10% by weight is, comprises or essentially consists of, in each case based on the total weight of the dosage form.

Paragraph 25. The pharmaceutical dosage form of Paragraph 24 wherein the extended release matrix is used as the extended release matrix material is hydroxypropylmethyl cellulose (HPMC) in an amount of 5.0 to 50% by weight, e.g. B. 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, each based on the total weight of the dosage form.

Paragraph 26. The pharmaceutical dosage form of Paragraph 24 wherein the extended release matrix is used as the extended release matrix material is hydroxypropyl cellulose (HPC) in an amount of 10 to 50% by weight, e.g. B. 20 ± 10% by weight or 25 ± 10% by weight or 30 ± 10% by weight or 35 ± 10% by weight or 40 ± 10% by weight, each based on the total weight of the dosage form, includes.

Paragraph 27. The pharmaceutical dosage form of Paragraph 24, wherein the extended release matrix is used as the extended release matrix material is hydroxyethyl cellulose (HEC) in an amount of 5.0 to 50% by weight, e.g. B. 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, each based on the total weight of the dosage form.

Paragraph 28. The pharmaceutical dosage form of Paragraph 24 wherein the extended release matrix is used as the extended release matrix material of microcrystalline cellulose (MCC) in an amount of 10 to 70% by weight, e.g. B. 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 based on the total weight of the dosage form, includes.

Paragraph 29. The pharmaceutical dosage form of Paragraph 24, wherein the extended release matrix is used as the extended release matrix material is ethyl cellulose (EC) in an amount of 5.0 to 30% by weight, e.g. B. 15 ± 10 wt .-% or 20 ± 10 wt .-%, each based on the total weight of the dosage form comprises.

Paragraph 30. The pharmaceutical dosage form of Paragraph 24, wherein the sustained release matrix is used as sustained release matrix material polyvinyl acetate (PVAc) in an amount of 25 to 70% by weight, e.g. B. 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, each based on the total weight of the dosage form.

Paragraph 31. The pharmaceutical dosage form of Paragraph 24, wherein the extended release matrix is used as the extended release matrix material polyvinylpyrrolidone (PVP) in an amount of 2.0 to 21% by weight, e.g. B. 10 ± 5.0 wt .-% or 15 ± 5.0 wt .-%, each based on the total weight of the dosage form comprises.

Paragraph 32. The pharmaceutical dosage form according to Paragraph 24, wherein the extended release matrix is used as the extended release matrix material polyvinylpyrrolidone-vinyl acetate copolymer (PVP / PVAc) in an amount of 1.0 to 30% by weight, e.g. B. 15 ± 10 wt .-% or 20 ± 10 wt .-%, each based on the total weight of the dosage form comprises.

Paragraph 33. The pharmaceutical dosage form of Paragraph 24, wherein the extended release matrix is used as the extended release matrix material poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) in an amount of 5.0 to 45% by weight, e.g. B. 15 ± 10% by weight or 20 ± 10% by weight or 25 ± 10% by weight or 30 ± 10% by weight or 35 ± 10% by weight, each based on the total weight of the dosage form, includes.

Paragraph 34. The pharmaceutical dosage form of Paragraph 24, wherein the extended release matrix is used as the extended release matrix material poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) in an amount of 5.0 to 45 wt. %, e.g. B. 15 ± 10% by weight or 20 ± 10% by weight or 25 ± 10% by weight or 30 ± 10% by weight or 35 ± 10% by weight, each based on the total weight of the dosage form, includes.

Paragraph 35. The pharmaceutical dosage form of Paragraph 24, wherein the extended release matrix is used as the extended release matrix material poly (methyl methacrylate-co-methacrylic acid) in an amount of 5.0 to 45% by weight, e.g. B. 15 ± 10% by weight or 20 ± 10% by weight or 25 ± 10% by weight or 30 ± 10% by weight or 35 ± 10% by weight, each based on the total weight of the dosage form, includes.

Paragraph 36. The pharmaceutical dosage form of Paragraph 24, wherein the extended release matrix is used as the extended release matrix material poly (ethyl acrylate-co-methacrylic acid) in an amount of 5.0 to 45% by weight, e.g. B. 15 ± 10% by weight or 20 ± 10% by weight or 25 ± 10% by weight or 30 ± 10% by weight or 35 ± 10% by weight, each based on the total weight of the dosage form, includes.

Paragraph 37. The pharmaceutical dosage form of Paragraph 24, wherein the extended release matrix is used as the extended release matrix material poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid) in an amount of 5.0 to 45% by weight, e.g. B. 15 ± 10% by weight or 20 ± 10% by weight or 25 ± 10% by weight or 30 ± 10% by weight or 35 ± 10% by weight, each based on the total weight of the dosage form, includes.

Paragraph 38. The pharmaceutical dosage form of Paragraph 24, wherein the extended release matrix is used as the extended release matrix material poly (ethyl acrylate-co-methyl methacrylate) in an amount of 5.0 to 45% by weight, e.g. B. 15 ± 10% by weight or 20 ± 10% by weight or 25 ± 10% by weight or 30 ± 10% by weight or 35 ± 10% by weight, each based on the total weight of the dosage form, includes.

Paragraph 39. The pharmaceutical dosage form of Paragraph 24, wherein the extended release matrix is used as the extended release matrix material is poly (ethylene oxide) (PEO) in an amount of 25 to 65% by weight, e.g. B. 35 ± 10% by weight or 40 ± 10% by weight or 45 ± 10% by weight or 50 ± 10% by weight or 55 ± 10% by weight, each based on the total weight of the dosage form, includes.

Paragraph 40. The pharmaceutical dosage form of Paragraph 24 wherein the extended release matrix is used as the extended release matrix material is polyethylene glycol (PEG) in an amount of 5.0 to 35% by weight, e.g. B. 15 ± 10 wt .-% or 20 ± 10 wt .-% or 25 ± 10 wt .-%, each based on the total weight of the dosage form comprises.

Paragraph 41. The pharmaceutical dosage form according to Paragraph 24, wherein the sustained release matrix as sustained release matrix material is a long chain fatty alcohol having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which can be saturated or unsaturated and straight chain or branched, in an amount from 15 to 40% by weight, e.g. B. 25 ± 10 wt .-% or 30 ± 10 wt .-%, each based on the total weight of the dosage form comprises. Paragraph 42. The pharmaceutical dosage form of Paragraph 24 wherein the extended release matrix is used as the extended release matrix material of cetostearyl alcohol in an amount of 15 to 40% by weight, e.g. B. 25 ± 10 wt .-% or 30 ± 10 wt .-%, each based on the total weight of the dosage form comprises.

Paragraph 43. The pharmaceutical dosage form of Paragraph 24, wherein the sustained release matrix is used as sustained release matrix material of stearyl alcohol in an amount of 15 to 40% by weight, e.g. B. 25 ± 10 wt .-% or 30 ± 10 wt .-%, each based on the total weight of the dosage form comprises.

Paragraph 44. The pharmaceutical dosage form of Paragraph 24, wherein the sustained release matrix is used as sustained release matrix material of cetyl alcohol in an amount of 15 to 40% by weight, e.g. B. 25 ± 10 wt .-% or 30 ± 10 wt .-%, each based on the total weight of the dosage form comprises.

Paragraph 45. The pharmaceutical dosage form according to Paragraph 24, wherein the matrix with extended release as matrix material with extended release is a hydrocarbon selected from the group of long-chain fatty acids having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which is saturated or unsaturated and straight-chain or branched may be, glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils and waxes, each in an amount of 5.0 to 70 wt .-%, e.g. B. 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 based on the total weight of the dosage form. Paragraph 46. The pharmaceutical dosage form of Paragraph 24 wherein the extended release matrix is used as the extended release matrix material xanthan gum in an amount of 15 to 40% by weight, e.g. B. 25 ± 10 wt .-% or 30 ± 10 wt .-%, each based on the total weight of the dosage form comprises.

Paragraph 47. The pharmaceutical dosage form of Paragraph 24 wherein the sustained release matrix is used as sustained release matrix material of sodium alginate in an amount of 15 to 40% by weight, e.g. B. 25 ± 10 wt .-% or 30 ± 10 wt .-%, each based on the total weight of the dosage form comprises.

Paragraph 48. The pharmaceutical dosage form of Paragraph 24, wherein the sustained release matrix is used as sustained release matrix material guaran in an amount of 5.0 to 35% by weight, e.g. B. 15 ± 10 wt .-% or 20 ± 10 wt .-% or 25 ± 10 wt .-%, each based on the total weight of the dosage form comprises.

Paragraph 49. The pharmaceutical dosage form of Paragraph 24, wherein the sustained release matrix is used as sustained release matrix material. Locust bean gum in an amount of 5.0 to 35% by weight, e.g. B. 15 ± 10 wt .-% or 20 ± 10 wt .-% or 25 ± 10 wt .-%, each based on the total weight of the dosage form comprises.

Paragraph 50. The pharmaceutical dosage form according to any preceding paragraph which is a capsule.

Paragraph 51. The pharmaceutical dosage form according to any one of Paragraphs 1 to 49 which is a tablet.

Paragraph 52. The pharmaceutical dosage form of Paragraph 51, wherein the tablet is monolithic.

Paragraph 53. The pharmaceutical dosage form of Paragraph 51 or 52, wherein the tablet has a breaking strength of at least 100N.

Paragraph 54. The dosage form of any preceding paragraph for use in the treatment of pain, which dosage form is administered orally twice daily. Paragraph 55. The dosage form for use in Paragraph 54 wherein the pain is chronic pain.

Paragraph 56. The dosage form for use under Paragraph 54 or 55 which, in a patient population of at least 10 patients, provides an average T _max within the range of 5.0 ± 3.0 hours after oral administration.

Paragraph 57. The 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 of at least 10 patients had a mean value of Cmax in the range of 12 ± 3 ng / ml; and / or AUClast in the range of 204 ± 50 ng.h / ml; and / or AUC _∞ in the range of 214 ± 50 ng.h / ml.

Paragraph 58. The 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 had a mean value of Cmax in the range of 29 ± 6 ng / ml; and / or AUClast in the range of 440 ± 100 ng.h / ml; and / or AUC∞ in the range of 447 ± 100 ng.h / ml.

Paragraph 59. The dosage form for use according to any 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 of at least 10 patients had a mean value of Cmax in the range of 47 ± 9 ng / ml; and / or AUClast in the range of 662 ± 150 ng.h / ml; and / or AUC∞ in the range of 665 ± 150 ng.h / ml.

Paragraph 60. The 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 had a mean value of Cmax in the range of 64 ± 12 ng / ml; and / or AUClast in the range of 890 ± 200 ng.h / ml; and / or AUC∞ in the range of 895 ± 200 ng.h / ml.

Paragraph 61. The dosage form for use according to any 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 of at least 10 patients had a mean value of Cmax in the range of 85 ± 15 ng / ml; and / or AUClast in the range of 1141 ± 250 ng.h / ml; and / or AUC∞ in the range of 1,145 ± 250 ng.h / ml.

Paragraph 62. A process for the manufacture of a pharmaceutical dosage form comprising a sustained release coating comprising particles according to any preceding paragraph, the process comprising the steps of: (A) providing internal starting pellets containing one or more excipients but not tapentadol ; (B) the provision of a solution or dispersion of tapentadol in water or an organic solvent or a mixture thereof, optionally with the one or more excipients; (C) the coating of the inner starting pellets provided in step (A) with the solution or dispersion of tapentadol provided in step (B), to obtain intermediate product particles which have an inner core which does not contain tapentadol and a drug coating layer which encapsulates the core, which essentially comprises the entire amount of tapentadol to be included in the dosage form, optionally together with the one or more excipients; (D) if appropriate, drying the intermediate product particles obtained in step (C) to obtain dried intermediate product particles; (E) providing a solution or dispersion of a sustained release coating material in water or an organic solvent or mixture thereof, optionally with the one or more excipients; (F) coating the intermediate product particles obtained in step (C) or the dried intermediate product particles obtained in step (D) with the solution or dispersion of the coating material with extended release provided in step (E), to obtain particles with extended release which have a an inner core not containing tapentadol, a core-encapsulating drug coating layer comprising substantially the entire amount of tapentadol, optionally together with the one or more excipients, and a sustained release coating encapsulating the core and the drug coating layer; (G) optionally drying the prolonged release particles obtained in step (F) to obtain dried prolonged release particles; and (H) either filling the sustained release particles obtained in step (F) or the dried sustained release particles obtained in step (G) into capsules; or mixing the prolonged release particles obtained in step (F) or the dried prolonged release particles obtained in step (G) with extra-particulate excipients and compressing the mixture into tablets.

Paragraph 63. A pharmaceutical dosage form obtainable by the method of Paragraph 62.

Paragraph 64. A process for preparing a pharmaceutical dosage form comprising a sustained release coating comprising particles according to any one of Paragraphs 1 to 61, the process comprising the steps of: (A) providing substantially all of the amount of tapentadol contained in the dosage form is to be contained, containing mixture, optionally together with one or more excipients; (B) the production of pharmaceutical pellets from the mixture provided in step (A) by dry granulation, wet granulation or extrusion; (C) optionally drying and / or spheronizing the drug pellets produced in step (B) to obtain dried and / or spheronized drug pellets; (D) providing a solution or dispersion of a sustained release coating material in water or an organic solvent or mixture thereof, optionally with one or more excipients; (E) coating the drug pellets produced in step (B) or the dried and / or spheronized drug pellets obtained in step (C) with the solution or dispersion of the coating material with prolonged release provided in step (D), to obtain particles with prolonged release Releases containing a core comprising substantially the entire amount of tapentadol, optionally together with one or more excipients, and a sustained release coating encapsulating the core; (F) optionally drying the extended-release particles obtained in step (E) to obtain dried extended-release particles; and (G) either filling the extended release particles obtained in step (E) or the dried extended release particles obtained in step (F) into capsules; or mixing the extended release particles obtained in step (E) or the dried extended release particles obtained in step (F) with extra-particulate excipients and compressing the mixture into tablets.

Paragraph 65. A pharmaceutical dosage form obtainable by the method of Paragraph 64.

Paragraph 66. A method of making a pharmaceutical dosage form containing a sustained release matrix in which tapentadol is embedded, according to any one of Paragraphs 1 to 61, the method comprising the steps of: (a) providing substantially all of the amount tapentadol to be included in the dosage form and at least one mixture containing matrix material with sustained release, optionally together with one or more excipients; (b) optionally granulating the mixture provided in step (a) to obtain a granulate, (c) optionally mixing the granulate obtained in step (b) with one or more excipients to obtain 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) to give tablets; (e) optionally film-coating the tablets compressed in step (d).

Paragraph 67. The method according to Paragraph 66, wherein the pressing in step (d) with a compression force of not more than 20 kN, particularly preferably not more than 15 kN, even more preferably not more than 10 kN, even more preferably not more than 9.5 kN, even 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.

EXAMPLES

The following examples illustrate the invention in more detail, but should not be construed as limiting its scope.

Commercially available tapentadol tablets Palexia ^® retard contain tapentadol as the hydrochloride salt, the tablet core also containing hypromellose, microcrystalline cellulose, finely divided silicon dioxide and magnesium stearate. Palexia ^® retard tablets thus contain hypromellose as a matrix with extended release. These tablets match 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 produced, one batch of essentially pure tapentadol dihydrogen phosphate hemihydrate, one batch of essentially pure tapentadol dihydrogen phosphate anhydrate and one batch comprising a mixture of the two polymorphic forms (= mixed form).

Example 1.1 - tapentadol dihydrogen phosphate, mixed form:

Tapentadol base (200 mg) was mixed thoroughly with phosphoric acid (104 mg, 61.7 μl, 85% by weight) using a spatula. The resulting mixture was ripened for 4 days at 20 ° C to 25 ° C to give 292 mg of a white crystalline solid. The product obtained was analyzed by X-ray powder diffraction ( 1 ). In the case of TGA, a weight loss of 2.8% was found on heating to 172 ° C.

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 (81 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 suspension immediately formed. After 45 minutes of mixing at 60 ° C, the suspension was cooled to 5 ° C over 45 minutes. After mixing for a further 45 minutes at 5 ° C., the solid obtained was isolated by vacuum filtration and dried (20 ° C. to 25 ° C., vacuum, 2 h). The obtained product (9.5 g, white crystalline powder) was analyzed by X-ray powder diffraction. In the case of the TGA, a weight loss of 3.1% was found when heated to 113 ° C.

Example 1.3 - tapentadol dihydrogen phosphate, mixed form:

Tapentadol base (7.5 g) was dissolved in a mixture of tetrahydrofuran (80 g, 90 ml) and water (10 mg, 10 μl) at 20 ° C. to 25 ° C. 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 suspension immediately formed. After 45 minutes of mixing at 60 ° C, the suspension was cooled to 5 ° C over 45 minutes. After mixing for a further 45 minutes at 5 ° C., the solid obtained was isolated by vacuum filtration and dried (20 ° C. to 25 ° C., vacuum, 2 h). The obtained product (9.6 g, white crystalline powder) was analyzed by X-ray powder diffraction. In the case of the TGA, a weight loss of 1.9% was found on heating to 120 ° C.

Example 1.4 - tapentadol dihydrogen phosphate hemihydrate:

Tapentadol base (497 mg) was dissolved in a mixture of acetone (2.72 g, 3.44 ml) and water (50 mg, 50 μl) at 20 ° C. to 25 ° C., which gave a clear solution. Phosphoric acid (259 mg, 153 µl, 85% by weight) was added and after a short time the clear solution became a suspension. The suspension was mixed for 30 minutes at 20 ° C to 25 ° C and then cooled to 5 ° C and mixed for a further 30 minutes at 5 ° C. The solid obtained was isolated by vacuum filtration and dried (20 ° C to 25 ° C, vacuum, 30 min). The product obtained (404 g, white crystalline powder) was determined by X-ray powder diffraction ( 2 ) and DSC ( 3 ) analyzed. The first DSC peak had a normalized integral of 149.2 J · g ^-1 , with an initial temperature of 56.7 ° C and a peak temperature of 89.2 ° C. The second DSC peak had a normalized integral of 22.0 J · g ⁻¹ , with an initial temperature of 130.1 ° C and a peak temperature of 133.4 ° C. At about 200 ° C it decomposed. In the case of TGA, a weight loss of 3.7% was found on heating to 119 ° C.

Example 1.5 - tapentadol dihydrogen phosphate hemihydrate (coarse material):

Tapentadol base (60 g) was dissolved in a mixture of tetrahydrofuran (1.5 kg, 1.641) and water (82 g, 82 ml) at 20 ° C to 25 ° C. 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 suspension. The suspension obtained was cooled to 10 ° C. over 30 minutes. The mixture was heated to 35 ° C. and mixed for 30 minutes, followed by cooling to 5 ° C. over 30 minutes, and the suspension was mixed at 5 ° C. for 45 minutes. The solid obtained was isolated by vacuum filtration and dried (20 ° C to 25 ° C, vacuum, 2 h). The product obtained (84.6 g, white crystalline solid) was analyzed by powder X-ray diffraction. In the TGA, a weight loss of 4.5% was found on heating to 113 ° C.

Example 1.6 - tapentadol dihydrogen phosphate anhydrate:

Tapentadol base (150 mg) was suspended in 1-butanol (1.2 g, 1.5 ml) at 20 ° C to 25 ° C. The suspension was heated to 50 ° C., whereby a clear solution was obtained. 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 suspension. The suspension obtained was heated to 115 ° C. To keep the suspension miscible, 1-butanol (400 mg, 0.5 ml) was added and mixing was continued for 45 min at 115 ° C. The mixture was then cooled to 30 ° C. over 3 hours. The solid obtained was isolated by vacuum filtration and dried (20 ° C to 25 ° C, vacuum, 30 min). The product obtained (157 mg, white crystalline powder) was determined by powder X-ray diffraction ( 4th ) and DSC ( 5 ) analyzed. The DSC peak had a normalized integral of 72.1 Jg ^-1 , with an initial temperature of 146.5 ° C and a peak temperature of 149.1 ° C. At about 200 ° C it decomposed. In the case of the TGA, a weight loss of 0.9% was found on heating to 134 ° C.

Example 1.7 - tapentadol dihydrogen phosphate anhydrate:

Tapentadol dihydrogen phosphate (500 mg, mixture of hemihydrate and anhydrate) was suspended in 2-butanone (4.8 g, 6 ml) and water (5 mg, 5 μl) at 20 ° C. to 25 ° C. The reaction mixture was heated to 60 ° C. and mixed for 3 hours. The resulting solid was isolated by hot filtration under vacuum and dried (20 ° C to 25 ° C, vacuum, 30 min). The obtained product (452 mg, white crystalline powder) was analyzed by powder X-ray diffraction. In the case of the TGA, a weight loss of 1.0% was found when heated to 129 ° C.

6 shows three photographs of various salts of tapentadol that were used to make tablets. 6A shows relatively fine particles of the mixed form of tapentadol dihydrogen phosphate (average particle size when visually inspected about 10-20 µm). 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 inspection about 100-200 μm). 6C shows relatively coarse particles of tapentadol hydrochloride (average particle size on visual inspection about 100-150 µm).

Example 2 - intrinsic dissolution (dissolution rate):

100 mg 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 pressed with a compression force of 200 kg (gravitational) with a surface area of 0.5 cm ^{2 for} 1 minute . The compressed samples obtained in this way were examined for their rate of dissolution in a Wood apparatus at 37 ° C. in 900 ml of dissolution medium at various pH values and a paddle rotation speed of 50 rpm.

The experimental results for tapentadol hydrochloride and for tapentadol dihydrogen phosphate (mixed form) are summarized in the table below: [%] Tapentadol hydrochloride (comparison) Tapentadol dihydrogen phosphate (mixed form) (according to the invention) min pH 1.0 pH 4.5 pH 7.4 pH 6.8 pH 1.0 pH 4.5 pH 7.4 pH 6.8 0 0 0 0 0 0 0 0 0 1 52 60 27 38 14th 12th 12th 11 3 95 91 65 79 35 30th 30th 29 5 99 95 80 92 56 49 46 48 7th 99 95 89 94 78 73 63 66 9 99 96 92 94 84 86 78 77

From the comparative experimental data in the table above it can be seen that tapentadol dihydrogen phosphate (mixed form) under all experimental conditions i.e. H. at all pH values tested, has a significantly slower rate of dissolution than tapentadol hydrochloride.

The experimental results for tapentadol dihydrogen phosphate hemihydrate and for tapentadol dihydrogen phosphate anhydrate are summarized in the table below [%] Tapentadol dihydrogen phosphate (according to the invention) Hemihydrate Anhydrate min pH 6.8 pH 1.2 pH 6.8 pH 1.2 0 0 0 0 0 1 12th 14th 13 15th 3 36 37 36 37 5 66 54 66 57 7th 80 72 90 75 9 83 84 96 85

From the comparative experimental data in the table above it can be seen that the slower rate of dissolution 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 the 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 at the end of the experiments were measured. The dissolved amount of tapentadol was quantified by HPLC (tapentadol free base). The experimental results are summarized in the table below: Tapentadol hydrochloride (comparison) Tapentadol dihydrogen phosphate (mixed form) (according to the invention) pH Assay expressed as base pH Assay expressed as base begin The End g / 100 ml begin The End g / 100 ml 0.1 M HCl 1.11 0.83 31.2 1.11 2.55 24.3 Acetate pH 4.5 4.54 4.29 32.7 4.54 2.81 21.2 water nb 4.63 33.0 nb 2.75 21.4 Citrate pH 6.8 6.83 6.17 31.8 6.83 3.15 19.3 SIF sp pH 6.8 6.82 6.23 32.4 6.82 2.81 20.2 Citrate pH 7.4 7.39 6.33 31.9 7.39 3.16 19.0 0.15N NaOH 13.08 8.21 6.6 13.08 8.09 6.5 nb = not determined

From the comparative experimental data in the table above, it can be seen that under all conditions tested, the thermodynamic solubility of tapentadol dihydrogen phosphate (mixed form) is below that of tapentadol hydrochloride.

Example 4 - In Vitro Dissolution Profiles of Pharmaceutical Dosage Forms:

Tablets with the following composition were prepared by mixing all the ingredients and compressing the resulting mixtures: comparison according to the invention C-1 C-2 I-1 I-2 1-3 [mg] Tapentadol hydrochloride ¹ 250.00 25.00 - - - fine tapentadol dihydrogen phosphate ^1,2,3 - - 250.00 25.00 - coarse tapentadol dihydrogen phosphate ⁴ - - - - 250.00 Hydroxypropyl methyl cellulose 100000 mPas type 2208 100.00 100.00 100.00 100.00 100.00 silicified microcrystalline cellulose (Prosoly HD90) 304.80 79.79 304.80 79.79 304.80 Magnesium stearate 4.00 1.09 4.00 1.09 4.00 medium breaking strength, Ph. Eur. 2.9.8. [N] 222 209 222 218 205 medium tabletting force, upper punch [kN] 12.8 9.3 7.4 6.3 8.3 medium tabletting force, lower punch [kN] 11.3 8.1 5.0 4.9 4.3 ¹ equivalent dose based on the tapentadol free base ² mixed form ³ relatively fine particle size (average diameter about 10-20 µm when visually inspected) ⁴ relatively coarse particle size (average diameter about 100-200 µm with visual inspection)

The in vitro dissolution of tapentadol from the tablets (drug load 250 mg, C-1, 1-1 and 1-3) was carried out in a paddle apparatus equipped with a sinker according to Ph. Eur. At a rotation speed of 50 rpm at 37 ° C measured in 900 ml of different dissolution media with different pH values. The experimental results are summarized in the table below: [%] Tapentadol hydrochloride (n = 3): Tapentadol dihydrogen phosphate (n = 3): C-1 I-1 1-3 Time [min] pH 6.8 pH 4.5 pH 1.0 pH 1.0 40% by volume ethanol pH 6.8 pH 4.5 pH 1.0 pH 1.0 40% by volume ethanol pH 4.5 0 0 0 0 0 0 0 0 0 0 30th 17th 19th 18th 14th 14th 15th 16 10 15th 60 26th 28 27 22nd 23 23 26th 18th 23 90 33 36 34 28 30th 30th 33 24 30th 120 39 42 40 33 35 36 39 29 36 150 45 48 46 38 41 41 45 33 41 180 49 54 51 42 45 46 50 36 46 210 54 58 55 46 49 50 54 40 50 240 58 63 60 50 53 54 58 43 54 270 62 67 64 53 57 58 62 46 58 300 66 71 67 57 61 62 66 48 61 330 69 74 71 60 64 65 69 51 64 360 72 77 74 63 67 68 72 53 67 390 75 80 77 65 70 71 75 55 70 420 78 83 79 68 73 74 78 58 73 450 80 85 82 70 75 77 80 60 76 480 82 87 84 73 78 79 83 62 78 510 84 89 86 75 80 82 85 64 81 540 86 91 88 77 82 84 87 65 83 570 88 92 89 79 84 86 88 67 86 600 89 93 91 81 86 88 90 69 88 630 90 94 92 82 88 90 91 71 90 660 92 95 93 84 89 91 93 72 91 690 93 96 94 85 91 92 94 74 93 720 93 96 95 87 92 93 95 76 94

From the above data it can be seen that the in vitro dissolution profile of the tablets according to the invention according to Examples 1-1 and 1-3 at pH 4.5 is almost identical. Thus, as shown, the particle size of the salt of tapentadol with phosphoric acid (Example 1-1 relatively fine, Example 1-3 relatively coarse) does not significantly change the in vitro dissolution profile.

The in vitro dissolution profiles in 0.1 N HCl (pH 1.0) and in 0.1 N HCl with 40% by volume aqueous ethanol (pH 1.0) are in 7th shown. Out 7th it can be seen that in 0.1 N HCl (pH 1.0) the in vitro dissolution of tapentadol dihydrogen phosphate is very similar to the in vitro dissolution of tapentadol hydrochloride. It is still off 7th It can be seen that in 0.1 N HCl (pH 1.0) with 40% by volume of ethanol, the in vitro dissolution of both tapentadol dihydrogen phosphate and tapentadol hydrochloride is retarded compared to pH 1.0. The dosage forms thus show no ethanol-induced dose dumping and even provide additional retardation in aqueous ethanol.

However, this additional retarding effect is much stronger with tapentadol dihydrogen phosphate than with tapentadol hydrochloride. Since the dosage forms contained the same excipients in the same amounts, this effect of the salt form of tapentadol (dihydrogen phosphate / Hydrochloride). As shown, tapentadol dihydrogen phosphate thus provides additional safety features with regard to the simultaneous intake of ethanol, e.g. B. alcoholic beverages, ready.

The in vitro dissolution profiles at pH 4.5 in aqueous buffer (without ethanol) are in 8th shown. Out 8th it can be seen that at pH 4.5 the difference in the in vitro dissolution of tapentadol dihydrogen phosphate compared to tapentadol hydrochloride is more pronounced than at pH 6.8 (see 7th , Δ / ▲). At pH 4.5 a release of z. B. 70% achieved significantly earlier with tapentadol hydrochloride than with tapentadol dihydrogen phosphate, the time difference being more than 1 hour. Since the dosage forms contained the same excipients in the same amounts, it can be concluded that tapentadol dihydrogen phosphate requires a matrix material with a less prolonged release (e.g. HPMC) to achieve the same in vitro dissolution as tapentadol hydrochloride. Thus, as shown, the lower intrinsic dissolution (dissolution rate) of tapentadol dihydrogen phosphate allows a reduction in the amount of excipient, particularly the amount of sustained release matrix material, to achieve the desired in vitro dissolution profile.

In 9 the in vitro dissolution profiles of a conventional tablet containing tapentadol hydrochloride at pH 1.0, pH 4.5 and pH 6.8, in each case in aqueous buffer without ethanol and in 0.1 N HCl with 40% by volume of ethanol ( pH 1.0).

In 10 the in vitro dissolution profiles of the tablet according to the invention containing the salt of tapentadol with phosphoric acid at pH 1.0, pH 4.5 and pH 6.8, each in an aqueous buffer without ethanol and in 0.1 N HCl with 40 vol .-% ethanol (pH 1.0), compared.

Example 5 - In Vitro Dissolution Profiles of Pharmaceutical Dosage Forms:

Tablets with the following composition were prepared by mixing all the ingredients and compressing the resulting mixtures: comparison according to the invention [mg] C-3 1-4 Tapentadol hydrochloride ¹ 250.00 - Tapentadol dihydrogen phosphate ^1,2,3 - 250.00 Kollidon ^® SR 320.00 320.00 Aerosil 200 6.80 6.80 Magnesium stearate 3.20 3.20 medium breaking strength, Ph. Eur. 2.9.8. [N] 237 230 medium tabletting force, upper punch [kN] 12.4 8.1 medium tabletting force, lower punch [kN] 9.9 4.4 ¹ equivalent dose based on the free base of Tapentadol ² mixed form ³ relatively fine particle size (average diameter about 20 µm when visually inspected)

The in vitro dissolution of tapentadol from the tablets (drug loading 250 mg, 1-4) was measured in a paddle apparatus according to Ph. Eur. At a speed of rotation of 50 rpm at 37 ° C. in 900 ml 0.1 N HCl without ethanol (pH 1.0) and measured in 0.1 N HCl with 40% by volume of ethanol (pH 1.0). The experimental results are summarized in the table below: Time [min] pH 1.0 [%] pH 1.0 40 vol .-% ethanol [%] 0 0 0 30th 30th 14th 60 40 21st 90 47 26th 120 53 30th 150 58 34 180 63 38 210 67 42 240 71 45 270 75 49 300 78 53 330 81 56 360 84 60 390 87 63 420 89 67 450 91 71 480 92 76 510 94 81 540 95 85 570 96 87 600 97 89 630 97 91 660 98 93 690 98 94 720 98 95

From the above data it can be seen that in 0.1 N HCl (pH 1.0) with 40% by volume of ethanol the in vitro dissolution is retarded compared to pH 1.0. The dosage form thus shows no ethanol-induced dose dumping and even provides additional retardation in aqueous ethanol. This additional retarding effect is thus attributable to the salt of tapentadol with phosphoric acid and is observed with various dosage forms, e.g. B. with matrices based on hypromellose with extended release (see Examples 1-1 and 1-3) and also with matrices based on Kollidon ^® SR (mixture with polyvinyl acetate and povidone) based matrices with extended release.

In 11 the in vitro dissolution profiles of a tablet according to the invention containing the 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 of ethanol compared.

QUOTES INCLUDED IN THE DESCRIPTION

This list of the documents listed by the applicant was generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Patent literature cited

• WO 2015/004245 A1 [0019]
• WO 2018/219897 A1 [0020]
• WO 2010/096045 [0028]
• WO 2012/010316 A1 [0028, 0044]
• WO 2012/051246 A1 [0028]
• WO 2017/182438 A1 [0028, 0044]
• WO 03/035053 A1 [0029, 0030, 0232]
• WO 2006/002886 A1 [0029]
• WO 2009/092601 A1 [0029]
• EP 693475 A [0032]

Non-patent literature cited

• ISO 13320: 2020 [0040]
• B. R. C. Rowe et al., Handbook of Pharmaceutical Excipients, Pharmaceutical Press; 6th edition 2009; E.-M. Hoepfner et al., Fiedler-Encyclopedia of Excipients, Editio Cantor, 6th edition 2008 [0071]

Claims (49)

A pharmaceutical dosage form comprising tapentadol; wherein tapentadol is present as a salt with phosphoric acid; wherein the dosage form provides sustained release of tapentadol; wherein the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is in the range from 10 to 300 mg, based on the free base of tapentadol; wherein the dosage form is multiparticulate; and wherein the individual particles comprise an extended release coating comprising an extended release coating material. The pharmaceutical dosage form according to Claim 1 wherein the sustained release coating material is selected from the group consisting of hydrophobic cellulose ethers, acrylic polymers, shellac, zein, hydrophobic waxy products, and mixtures thereof. The pharmaceutical dosage form according to Claim 1 or 2 , the coating material with extended release preferably from that of ethyl cellulose, 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, aminoalkyl (acrylic methacrylate ), Poly (methacrylic acid, methacrylic acid alkylamide) copolymer, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, poly (methyl methacrylate), poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic acid anhydride ) and glycidyl methacrylate copolymers is selected. The pharmaceutical dosage form of any preceding claim, wherein the acrylic polymer consists of one or more ammonio methacrylate copolymers. The pharmaceutical dosage form according to Claim 4 , there being two or more ammonio methacrylate copolymers with different physical properties. The pharmaceutical dosage form according to any one of the preceding claims, wherein the coating has been produced from an aqueous dispersion or from an organic dispersion or from an organic solution of a hydrophobic polymer. The pharmaceutical dosage form according to Claim 6 wherein the coating comprises an effective amount of a plasticizer that was also present in the aqueous dispersion of the hydrophobic polymer. The pharmaceutical dosage form according to Claim 7 wherein the hydrophobic polymer is ethyl cellulose and wherein the plasticizer is selected from the group consisting of dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin. The pharmaceutical dosage form according to Claim 6 wherein the hydrophobic polymer is an acrylic polymer and wherein the plasticizer is selected from the group consisting of citric acid esters, dibutyl phthalate, 1,2-propylene glycol, polyethylene glycols, diethyl phthalate, castor oil and triacetin. The pharmaceutical dosage form of any preceding claim, wherein the coating comprises one or more release modifying agents, or wherein there are one or more passages through the coating. The pharmaceutical dosage form according to Claim 10 wherein the release modifying agents are organic or inorganic and act as pore formers. The pharmaceutical dosage form according to Claim 11 , wherein the pore formers comprise one or more hydrophilic polymers such as, preferably hydroxypropylmethyl cellulose. The pharmaceutical dosage form according to any one of the preceding claims, wherein the salt of tapentadol is the dihydrogen phosphate salt of tapentadol, a solvate, an ansolvate and / or a polymorphic form thereof. The pharmaceutical dosage form according to Claim 13 wherein the salt of tapentadol is the dihydrogen phosphate salt which is in the substantially pure crystalline form of tapentadol dihydrogen phosphate hemihydrate salt. The pharmaceutical dosage form according to Claim 14 wherein the salt of tapentadol is the dihydrogen phosphate salt which is in the substantially pure crystalline form of tapentadol dihydrogen phosphate anhydrate salt. The pharmaceutical dosage form according to Claim 13 , wherein the salt of tapentadol 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 2Θ (± 0.2 degrees 2Θ). The pharmaceutical dosage form according to Claim 16 , wherein the crystalline dihydrogen phosphate salt is characterized by one or more additional X-ray powder diffraction peaks at 8.7, 17.6, 20.3, 22.1 and / or 23.4 degrees 2Θ (± 0.2 degrees 2 Θ). The pharmaceutical dosage form according to Claim 13 , wherein the salt of tapentadol 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 2Θ (± 0.2 degrees 2Θ). The pharmaceutical dosage form according to Claim 18 , wherein the crystalline dihydrogen phosphate salt is characterized by one or more further X-ray powder diffraction peaks at 8.9, 20.5, 22.4, 23.5 and / or 24.3 degrees 2Θ (± 0.2 degrees 2Θ). The pharmaceutical dosage form of any preceding claim which provides an in vitro dissolution profile measured at 50 rpm in 900 ml of aqueous phosphate buffer at pH 6.8 at 37 ° C, at which - after 0.5 hours 20 ± 20% by weight; preferably 20 ± 15% by weight; particularly preferably 20 ± 10% by weight; - after 4 hours 60 ± 20% by weight; preferably 60 ± 15% by weight; particularly preferably 60 ± 10% by weight; and - after 12 hours at least 60% by weight; preferably at least 70% by weight; particularly preferably at least 80% by weight of the tapentadol originally contained in the dosage form have been released. The pharmaceutical dosage form of any preceding claim which provides an in vitro dissolution profile measured at 50 rpm in 900 ml of aqueous phosphate buffer at pH 6.8 at 37 ° C, at which - after 1 hour 25 ± 15% by weight; - after 2 hours 35 ± 20% by weight; - after 4 hours 50 ± 20% by weight; and - after 8 hours 80 ± 20% by weight of the tapentadol originally contained in the dosage form have been released. The pharmaceutical dosage form of any preceding claim which provides an in vitro dissolution profile measured at 50 rpm in 900 ml of aqueous buffer at pH 4.5 at 37 ° C, at which - after 0.5 hours 20 ± 20% by weight; preferably 20 ± 15% by weight; particularly preferably 20 ± 10% by weight; - after 4 hours 60 ± 20% by weight; preferably 60 ± 15% by weight; particularly preferably 60 ± 10% by weight; and - after 12 hours at least 60% by weight; preferably at least 70% by weight; particularly preferably at least 80% by weight of the tapentadol originally contained in the dosage form have been released. The pharmaceutical dosage form according to any one of the preceding claims, which provides an in vitro dissolution profile measured at 50 rpm in 900 ml aqueous buffer at pH 4.5 at 37 ° C, at which - after 1 hour 25 ± 15 wt%; - after 2 hours 35 ± 20% by weight; - after 4 hours 50 ± 20% by weight; - after 8 hours 80 ± 20% by weight of the tapentadol originally contained in the dosage form have been released. The pharmaceutical dosage form of any preceding claim which provides an in vitro dissolution profile measured at 50 rpm in 900 ml of 0.1 N HCl at pH 1.0 and 37 ° C, at which - after 0.5 hours 20 ± 20% by weight; preferably 20 ± 15% by weight; particularly preferably 20 ± 10% by weight; - after 4 hours 60 ± 20% by weight; preferably 60 ± 15% by weight; particularly preferably 60 ± 10% by weight; and - after 12 hours at least 60% by weight; preferably at least 70% by weight; particularly preferably at least 80% by weight of the tapentadol originally contained in the dosage form have been released. The pharmaceutical dosage form of any preceding claim which provides an in vitro dissolution profile measured at 50 rpm in 900 ml of 0.1 N HCl at pH 1.0 and 37 ° C, at which - after 1 hour 25 ± 10% by weight; - after 2 hours 40 ± 30% by weight; - after 4 hours 60 ± 20% by weight; - after 8 hours 80 ± 20% by weight of the tapentadol originally contained in the dosage form have been released. The pharmaceutical dosage form of any preceding claim which provides resistance to ethanol-induced can dumping. The pharmaceutical dosage form according to Claim 26 which provides slower in vitro dissolution of tapentadol in aqueous ethanol-containing medium than in aqueous non-ethanol-containing medium. The pharmaceutical dosage form according to Claim 26 or 27 , which provides a slower dissolution of tapentadol in 0.1 N HCl with 40% by volume of ethanol (pH 1.0) than in 0.1 N HCl without 40% by volume of ethanol (pH 1.0) at 50 rpm in 900 ml at 37 ° C. The pharmaceutical dosage form according to any one of the preceding claims, wherein the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 25 mg, 50 mg or 100 mg, each based on the free base of tapentadol. The pharmaceutical dosage form according to Claim 29 wherein the dosage form has a total weight ranging from 150 to 750 mg. The pharmaceutical dosage form according to any of the Claims 1 to 28 , at which 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. The pharmaceutical dosage form according to Claim 31 wherein the dosage form has a total weight in the range of 300 to 1200 mg. The pharmaceutical dosage form according to one of the preceding claims, which is a capsule in which the individual particles are contained with a coating for a prolonged release, optionally together with additional excipients, which in the capsule in powder form or also in the form of Particles may be included. The pharmaceutical dosage form according to Claim 33 wherein the sustained release coating material is selected from the group consisting of hydrophobic cellulose ethers, acrylic polymers, shellac, zein, hydrophobic waxy products, and mixtures thereof. The pharmaceutical dosage form according to Claim 33 or 34 , the coating material with extended release preferably from that of ethyl cellulose, 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, aminoalkyl (acrylic methacrylate ), Poly (methacrylic acid, methacrylic acid alkylamide) copolymer, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, poly (methyl methacrylate), poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic acid anhydride ) and glycidyl methacrylate copolymers is selected. The pharmaceutical dosage form according to any of the Claims 33 to 35 wherein the acrylic polymer consists of one or more ammonio methacrylate copolymers. The pharmaceutical dosage form according to Claim 36 , there being two or more ammonio methacrylate copolymers with different physical properties. The pharmaceutical dosage form according to any of the Claims 33 to 37 wherein the coating was produced from an aqueous dispersion or from an organic dispersion or from an organic solution of a hydrophobic polymer. The pharmaceutical dosage form according to Claim 38 wherein the coating comprises an effective amount of a plasticizer that was also present in the aqueous dispersion of the hydrophobic polymer. The pharmaceutical dosage form according to Claim 39 wherein the hydrophobic polymer is ethyl cellulose and wherein the plasticizer is selected from the group consisting of dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin. The pharmaceutical dosage form according to Claim 38 wherein the hydrophobic polymer is an acrylic polymer and wherein the plasticizer is selected from the group consisting of citric acid esters, dibutyl phthalate, 1,2-propylene glycol, polyethylene glycols, diethyl phthalate, castor oil and triacetin. The pharmaceutical dosage form according to any of the Claims 33 to 41 wherein the coating comprises one or more release modifying agents, or wherein there are one or more passages through the coating. The pharmaceutical dosage form according to Claim 42 wherein the release modifying agents are organic or inorganic and act as pore formers. The pharmaceutical dosage form according to Claim 43 , wherein the pore formers comprise one or more hydrophilic polymers such as, preferably hydroxypropylmethyl cellulose. The pharmaceutical dosage form according to any of the Claims 1 to 32 , which is a tablet containing the individual particles with a sustained release coating and containing an extra-particulate material. The pharmaceutical dosage form according to Claim 45 wherein the extra-particulate material contains at least one excipient selected from binders, disintegrants and lubricants. The pharmaceutical dosage form of any preceding claim, wherein the particles - an inert core that does not contain tapentadol, a drug coating layer encapsulating the core and comprising substantially the entire amount of tapentadol, optionally together with one or more excipients, and - contain a sustained release coating encapsulating the core and the drug coating layer. The pharmaceutical dosage form according to any of the Claims 1 to 46 wherein the particles contain - a core which essentially comprises the entire amount of tapentadol, optionally together with one or more excipients, and - a coating encapsulating the core with extended release. The pharmaceutical dosage form of any preceding claim which is for twice daily administration.

Images