DE102021119130A1 - Ethylcellulose-coated particles containing a salt of tapentadol and phosphoric acid - Google Patents

Abstract

The invention relates to a pharmaceutical dosage form comprising a multiplicity of coated particles; said coated particles comprising a salt of tapentadol with phosphoric acid and having a tapentadol sustained release coating comprising ethyl cellulose; the dosage form releases tapentadol in a delayed manner; and wherein the weight equivalent dose of tapentadol contained in the dosage form is in the range of 10 to 300 mg, based on tapentadol free base.

Description

The priority of the German utility model application No. 20 2020 104 285.8 , filed July 24, 2020, claimed.

The invention relates to a pharmaceutical dosage form comprising a multiplicity of coated particles; said coated particles comprising a salt of tapentadol with phosphoric acid and having a tapentadol sustained release coating comprising ethyl cellulose; the dosage form releases tapentadol in a delayed manner; and wherein the weight equivalent dose of tapentadol contained in the dosage form is in the range of 10 to 300 mg, based on tapentadol free base.

Tapentadol (Nucynta ^® , Palexia ^® ) is an oral opioid analgesic of the benzenoid class with a dual mechanism of action similar to tramadol; it is a µ-opioid receptor agonist and also inhibits norepinephrine reuptake. Tapentadol is currently available as a tablet containing tapentadol and offering immediate release or sustained release. Dose strengths of 25 mg, 50 mg, 100 mg, 150 mg, 200 mg and 250 mg are currently available (each expressed as a weight equivalent dose of tapentadol based on tapentadol free base), with the prolonged-release tablets intended for twice-daily dosing are.

Matrix tablets are by far the most common concept for the pharmaceutical formulation of sustained-release opioid analgesics. Sustained-release formulations of conventional opioids, such as morphine, oxycodone, hydromorphone and tramadol, are largely available as matrix tablets.

The previously commercially available slow-release formulations of tapentadol are also exclusively matrix tablets. The tapentadol tablets (Palexia ^® retard) available in Germany contain hypromellose as a delayed-release matrix, while the tapentadol tablets (Nucynta ^® Extended-Release) available in the USA also contain polyethylene oxide in the matrix.

The matrix tablets (Palexia ^® retard) were approved in Germany in August 2010. ^{Palexia ®} retard has been among the most prescribed drugs since 2011 (U. Schwabe et al., Arzneiverordnungsreport 2019, Springer). In 2017, Palexia ^® retard ranked No. 162 of the 300 most prescribed drugs for private patients (Ch. O.Jacket et al., Drug supply of privately insured 2019, Scientific Institute of PKV, WIP analysis 5/2019). In 2019, Palexia ^® retard was prescribed more than morphine after a further increase in prescriptions (U. Schwabe et al., Arzneiverordnungsreport 2020, Springer).

There is a need for new sustained-release dosage forms for oral administration of tapentadol. For regulatory reasons, the oral dosage forms for sustained-release tapentadol should be bioequivalent to the products already on the market.

With regard to the development of new sustained-release formulations of tapentadol, tablets with matrix release are generally the most promising galenic concept.

If you switch instead from the established monolithic matrix tablets (Palexia ^® retard, Nucynta ^® extended release) to multiparticulate concepts such as capsules, the structure of the dosage forms changes fundamentally. Only minor changes compared to the approved product are not possible in this case, but a fundamental new development is required, mostly with other additives in different quantities and using other manufacturing processes.

A fundamental change in the formulation concept harbors the considerable risk of a fundamentally changed release profile and thus ultimately also the loss of bioequivalence. There are significant differences in bioavailability between "single-unit" forms (e.g. monolithic tablets) and "multiple-unit" forms (e.g. polydisperse or pellet preparations compressed into tablets), so that - especially in the case of modified-release preparations - of therapeutic interchangeability can only be assumed in special cases (H. Blume et al., Deutsche Pharmazeutische Gesellschaft, guideline, Gute Substitutionspraxis, February 24, 2014).

In addition, the change in the formulation concept can lead to an increased occurrence of pain as a result of the changed galenics, especially at the end of the administration interval. Even if prolonged-release formulations ensure that the plasma level of the analgesic is as uniform as possible, this phenomenon, known as "end-of-dose failure", is sometimes observed in the course of the aut-idem regulation or discount agreements when one prolonged-release form is uncritically substituted for another prolonged-release form (S. Reichl, Pharmazeutische Zeitung issue 31/2009, July 31, 2009). Additional requirements may also arise from a regulatory point of view when changing the formulation concept.

With regard to the development of new sustained-release formulations of tapentadol, it should also be noted that tapentadol is a highly effective drug for which special safety criteria must be observed. When the matrix tablets of tapentadol were approved in Germany in August 2010, it was already known that sustained-release dosage forms of opioids can entail particular risks if they are taken with alcoholic beverages. For example, the slow-release effect of the dosage form can be canceled by taking alcohol at the same time, which can lead to dangerously high active substance concentrations in the systemic circulation (ethanol-induced dose dumping).

Of the many classes of drugs commercially available as sustained release products, opioids are at particular risk from dose dumping. Awareness of ethanol-induced can dumping has led to regulatory withdrawals of some marketed products and black-box warnings to others. Since then, considerable effort has focused on providing the robustness of a formulation when ingested with alcohol. The risk to the patient is considered low if the formulation and its effects are unaffected in the presence of 0-40% alcohol under in vivo and in vitro conditions (see D'Souza et al., AAPS Open ( 2017) 3:5, 1-20).

Increased absorption has been observed for several sustained-release opioid formulations when taken concomitantly with alcohol. Alcohol interaction data for marketed sustained-release opioid products were compared (Farr et al., Clinical Pharmacology: Advances and Applications 2015:7 1-9): opioid Mean increase in C _max ratio to drug 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

The matrix tablets with delayed release of tapentadol currently on the market already offer sufficient resistance to ethanol-induced dose dumping. Nevertheless, the simultaneous intake of alcohol should be avoided. Therefore, while providing satisfactory resistance to ethanol-induced can dumping, the prescribing information for Nucynta ^® and Palexia ^® includes instructions not to consume alcohol or alcohol-containing products when taking the medication.

With regard to the development of new sustained-release formulations of tapentadol, which also ensure satisfactory resistance to ethanol-induced dose dumping, tablets with matrix release are generally the most promising concept.

So far, problems with regard to ethanol-induced dose dumping have been observed, particularly in the case of multiparticulate retard formulations of opioids. In the most severe case, concomitant use of the previously available analgesic Palladone™ (Purdue Pharma; multiparticulate Formulation of hydromorphone hydrochloride as sustained-release capsules) with alcohol resulted in significantly higher plasma levels of hydromorphone (up to 16-fold higher), particularly in the fasted state. This finding led to product discontinuation and withdrawal from the market (S. Fava et al., Drug Invention Today, 2020, 13(1), 190). In vitro studies with another long-acting opioid, Avinza ^® (Pfizer Inc; multiparticulate formulation of morphine sulfate in sustained-release capsules), demonstrated an alcohol concentration-dependent accelerated release of morphine. Box warning for Avinza ^® and other controlled-release and long-acting opioids warns patients not to drink alcoholic beverages or take prescription or non-prescription medications containing alcohol while on therapy, as this can prevent rapid release and absorption of a potentially fatal opioid dose (D'Souza et al., AAPS Open (2017) 3:5, 1-20).

In contrast to such multiparticulate concepts, monolithic matrix tablets have the advantage that they can inherently guarantee a certain protection against ethanol-induced dose dumping based on the embedding of the active ingredient in a polymer matrix. Hydrophilic matrix polymers are preferred which are poorly soluble or insoluble in ethanol, such as polyethylene oxide (PEO), starch, carbomer or hypromellose (HPMC). The selection of suitable matrix polymers and their mixtures therefore plays an important role in the development of new matrix formulations of tapentadol. The methods of manufacturing such matrix formulations may also have an impact on protection against ethanol-induced can-dumping. In particular, melt extrusion and injection molding are promising technologies for the production of such matrix formulations. The sustained-release formulations of tapentadol (Nucynta ^® Extended-Release) marketed in the USA are matrix tablets which are produced by melt extrusion and in which the active ingredient is embedded in a matrix of PEO and HPMC (cf. N. Jedinger et al., Eur. J. Pharm. Biopharm., 2014, 87(2), 217-26).

However, if you switch from the established monolithic matrix tablets (Palexia ^® retard, Nucynta ^® extended release) to multiparticulate concepts such as capsules, further difficulties arise, especially if the delayed release is controlled by a film coating. On the one hand, the process engineering effort for the production of such film-coated particles is considerable and the storage stability of the formulations is generally only low. On the other hand, such film-coated multiparticulate systems often require significant amounts of excipients, which limits the maximum drug loading.

This is also a particular disadvantage with regard to tapentadol, because tapentadol has a comparatively low specific activity and because oral bioavailability is reduced because of a pronounced first-pass effect; usual equivalent doses of tapentadol are therefore in the range of 25 mg to 250 mg. Together with the required amounts of excipients, this results in considerable total weights of the formulations, especially for the larger dosage strengths, which can only be accommodated in large capsules or provided in loose form, e.g. as sachets. It is known that many patients experience problems when taking large capsules, which adversely affects patient compliance.

Furthermore, tapentadol tends to migrate and can diffuse from the particle core into the film coating. There is therefore a risk that the retardation properties of the film coating will change during storage as a result of the plasticizing effect, with unforeseeable effects on the release profile.

Furthermore, the release mechanism from film-coated multiparticles is fundamentally different from the release mechanism from a matrix tablet. The individual properties of the active substance and the excipients play a different role here, so that the release kinetics are also different.

This is further complicated by the different dose strengths. If one wants to develop a film-coated multiparticulate formulation that is bioequivalent to a marketed matrix tablet, this bioequivalence must be achieved for every dosage strength. In the case of film-coated multiparticles, different dose strengths can be set simply by adjusting the amount of particles. After ingestion, possibly after rapid dissolution of the capsule, the particles then behave essentially in the same way, ie the release profile is essentially identical regardless of the respective dose strength. In contrast, matrix tablets of different dosage strengths are usually of different sizes. With the different size comes a different ratio of surface to volume, which affects the release profile; the release profile of the active substance from a small tablet with a dose of eg 50 mg is therefore often different than the release profile from a large tablet with a dose of eg 250 mg. If, for example, it was possible to produce a film-coated multiparticulate formulation whose release profile roughly corresponds to that of the small tablet (50 mg), it is by no means to be expected that the release profile of five times the amount of film-coated multiparticulates will necessarily also approximately correspond to the release profile of the large tablet ( 250 mg). Rather, it is to be expected that a specifically adapted film-coated multiparticulate formulation will have to be developed for each dosage strength in order to ensure the required bioequivalence with the corresponding matrix tablet of the same dosage strength.

The salt form of the active ingredient also plays a role in the development of new sustained-release formulations of tapentadol. The matrix tablets on the market (Palexia ^® retard, Nucynta ^® Extended Release) contain tapentadol as the hydrochloride salt.

When changing from the established salt form (tapentadol hydrochloride, Palexia ^® retard, Nucynta ^® Extended-Release) to another salt form, numerous regulatory requirements have to be met. When changing the salt, a complete evaluation of the new salt form in vitro and in vivo may be necessary, especially with regard to toxicology, solubility, tolerability and polymorphism. It depends on the interim experimental results whether further studies are necessary or not (cf. European Medicines Agency, ICH Topic Q 6 A, decision tree #4). The extent of the investigations that will ultimately be required cannot therefore be predicted from the beginning, but depends on the experimental interim results that are collected during the development. This additional regulatory effort is not only associated with additional costs, but can ultimately also lead to delayed market entry. When developing new dosage forms, it is therefore fundamentally much more promising to start with the salt form that is established on the market, especially if, as in the case of tapentadol hydrochloride, this has proven to be easily soluble, well tolerated, safe and without problems with regard to polymorphs.

In addition, it should be noted that the type of salt also contributes to the weight of the active substance and thus to the total weight and size of the dosage form. Thus, 250 mg of tapentadol free base in the form of the hydrochloride has an equivalent weight of approximately 291 mg. Other physiologically tolerable salts of tapentadol have an even higher equivalent weight. For example, 250 mg of tapentadol free base in the form of the salt of tapentadol with phosphoric acid in a 1:1 stoichiometric ratio (dihydrogen phosphate) has an equivalent weight of about 361 mg. If one wants to provide such salts of tapentadol in formulations with delayed release, the difficulties associated with the considerable total weight and thus also the considerable size with regard to patient compliance are even more pronounced, particularly in the case of the higher dose strengths.

Phosphate salts of active ingredients are generally uncommon. Today, phosphate salts are more likely to be avoided in oral dosage forms. In patients with impaired renal function, especially dialysis patients, phosphate salts can be problematic. Of the 101 salt forms of active ingredients approved by the FDA in the years 1995 to 2006, only 2 were phosphates, but 54 were hydrochlorides (A.T.M. Serajuddin, Adv Drug Deliv Rev 2007, 30, 59(7), 603-16). Phosphate salts are also not the usual salt forms of opioids. The only opioid available in Germany, including in the form of a phosphate salt, is codeine, although as a phosphate salt this has only a short storage stability (MF Powell, J Pharm Sci. 1986, 75(9), 901-3).

In addition, phosphate salts tend to form hydrates with varying water content, which complicates their formulation (PH Stahl et al., Handbook of Pharmaceutical Salts, 2nd edition, Wiley-VCH, 2011). Because of polyvalent anions and the associated mixed salt forms, defined phosphate salts are much more complicated to produce than hydrochlorides. Phosphate salts are also rather unfavorable with regard to stability problems, crystallization of other salts (eg calcium phosphate), decompensation and possible interactions with other active substances. In addition, phosphate salts often tend towards pronounced polymorphism. Various polymorphs of phosphate salts of tapentadol are already known ( WO 2017/182438 A1 ).

If one accepts the disadvantages associated with changing the salt form, then instead of phosphate salts, more promising alternatives are poorly soluble salts of tapentadol, in which the delayed release of the active substance is controlled by the poorer solubility than such ( DE 101 09 763 ; D. Gupta et al., Molecules 2018, 23, 1719).

SUMMARY OF THE INVENTION

The invention provides a pharmaceutical dosage form comprising a multiplicity of coated particles; said coated particles comprising a salt of tapentadol with phosphoric acid and having a tapentadol sustained release coating comprising ethyl cellulose; the dosage form releases tapentadol in a delayed manner; and wherein the weight equivalent dose of tapentadol contained in the dosage form is in the range of 10 to 300 mg, based on tapentadol free base (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 which provide sustained release of tapentadol. It has surprisingly been found that dosage forms containing salts of tapentadol with phosphoric acid provide in vitro a slower release of tapentadol in ethanolic medium than in non-ethanolic medium. It is therefore to be expected that these dosage forms will further prolong drug release in vivo when co-administered 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.

It was also surprisingly found that, compared to tapentadol hydrochloride, which is 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. These dissolving properties of the phosphate salts of tapentadol make them particularly suitable for the manufacture of sustained-release dosage forms.

Furthermore, it was surprisingly found that the salt of tapentadol with phosphoric acid can be formulated in multiparticulate dosage forms which do not control the retardation by a matrix of pharmaceutical excipients but by a coating (coating retardation). Since the release kinetics can be controlled by the amount, in particular layer thickness, of the coating, differently coated particles can be produced in a comparatively simple manner, which differ from one another in terms of their respective release kinetics. By mixing suitable amounts of such differently coated particles, bioequivalence to the products already on the market can be achieved if necessary. However, bioequivalence can also be achieved by essentially the same coated particles, provided that the type and amount of coating are chosen correctly.

In addition, it has surprisingly been found that patient compliance is particularly advantageous despite the higher equivalent weight of the salt of tapentadol with phosphoric acid. Thus, patients who have difficulties taking dosage forms, especially in the case of the higher dosage strengths, can take the coated particles contained in the dosage form individually and separately without the delayed release of the active substance being impaired as a result. For example, hard gelatine capsules containing a large number of coated particles can be opened without difficulty and the individual coated particles can be removed from them. Since these individual coated particles are much lighter in weight and therefore also much smaller in size than the dosage form as such, there are hardly any difficulties in taking the individual coated particles. In this way, tapentadol can even be administered orally to patients who have injuries in the mouth or throat.

Salts of tapentadol with phosphoric acid are known, for example from WO 2010/096045 , WO 2012/010316 A1 , WO 2012/051246 A1 and WO 2017/182438 A1 .

Dosage forms which provide a delayed release of tapentadol are also known, for example from WO 03/035053 A1 , WO 2006/002886 A1 and WO 2009/092601 A1 .

character 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.
• 4 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, i.e. the hydrochloride ( 6C ).

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the invention relates to a pharmaceutical dosage form comprising a multiplicity of coated particles; said coated particles comprising a salt of tapentadol with phosphoric acid and having a tapentadol sustained release coating comprising ethyl cellulose; the dosage form releases tapentadol in a delayed manner; and wherein the weight equivalent dose of tapentadol contained in the dosage form is in the range of 10 to 300 mg, based on tapentadol free base.

The dosage form according to the invention contains a large number of coated particles.

In a preferred embodiment, the dosage form according to the invention comprises only those coated particles which are essentially of the same nature, i.e. have essentially the same structure and contain the same ingredients in essentially the same amounts. Accordingly, the coated particles preferably have essentially the same weight, the same size and the same composition.

For the purpose of the description, “substantially” preferably means that the mean quantitative deviation is no more than 5%, preferably no more than 2%.

In another preferred embodiment, the dosage form according to the invention comprises at least two different types of coated particles which differ from one another in at least one property. The at least one property is preferably selected from the group consisting of content of salt of tapentadol with phosphoric acid, type of pharmaceutical excipient, content of a pharmaceutical excipient, and content of coating for the delayed release of tapentadol.

• - anderen beschichteten Partikeln mit retardierter Freisetzung von Tapentadol;
• - Partikeln mit spontaner Freisetzung von Tapentadol; und/oder
• - Tapentadol oder dem Salz von Tapentadol mit Phosphorsäure in Pulverform.

Thus, specific release profiles can be set if particles coated according to the invention with delayed release of tapentadol are mixed with

• - other coated particles with controlled release of tapentadol;
• - Particles with spontaneous release of tapentadol; and or
• - Tapentadol or the salt of tapentadol with phosphoric acid in powder form.

The number of coated particles contained in the dosage form can be in the range from 1, 2, 3, 4 or 5 to 10, 20, 30, 40 to 100, 200 and more.

The size of the coated particles is preferably in the range from 0.2 to 3.5 mm; preferably 0.2 to 1.2 mm; or 0.7 to 1.7 mm; or 1.2 to 2.2 mm; or 1.7 to 2.7 mm; or 2.2 to 3.2 mm. In preferred embodiments, the size of the coated particles ranges from 0.2 to 0.6 mm; or 0.3 to 0.7 mm; or 0.4 to 0.8 mm; or 0.5 to 0.9 mm; or 0.6 to 1.0 mm; or 0.7 to 1.1 mm; or 0.8 to 1.2 mm; or 0.9 to 1.3 mm; or 1.0 to 1.4 mm; or 1.1 to 1.5 mm; or 1.2 to 1.6 mm; or 1.3 to 1.7 mm; or 1.4 to 1.8 mm; or 1.5 to 1.9 mm; or 1.6 to 2.0 mm; or 1.7 to 2.1 mm; or 1.8 to 2.2 mm; or 1.9 to 2.3 mm; or 2.0 to 2.4 mm; or 2.1 to 2.5 mm; or 2.2 to 2.6 mm; or 2.3 to 2.7 mm; or 2.4 to 2.8 mm; or 2.5 to 2.9 mm; or 2.6 to 3.0 mm; or 2.7 to 3.1 mm; or 2.8 to 3.2 mm; or 2.9 to 3.3 mm; or 3.0 to 3.4 mm; or 3.1 to 3.5 mm.

According to a preferred embodiment, the coated particles contain a core, which essentially comprises the total amount of the salt of tapentadol with phosphoric acid, optionally together with one or more pharmaceutical excipients, and a coating encapsulating the core for the sustained release of tapentadol.

According to another preferred embodiment, the particles contain an inert core which does not contain a salt of tapentadol with phosphoric acid (e.g. sugar spheres), an active substance layer which encapsulates the inert core and comprises substantially all of the salt of tapentadol with phosphoric acid, optionally together with one or more pharmaceutical excipients, and a coating encapsulating the core and the active substance layer for the delayed release of tapentadol.

In preferred embodiments, the pharmaceutical dosage form according to the invention is a capsule (e.g. hard gelatine capsule, HPMC capsule, etc.), a sachet, a stick pack, etc., in which the coated particles are each contained, optionally together with additional pharmaceutical excipients which in powder form or also in the form of particles. In the latter case the capsules contain at least two different types of particles, namely particles containing tapentadol and particles which do not contain tapentadol.

In other preferred embodiments, the pharmaceutical dosage form according to the invention is a tablet which contains the coated particles and which contains an extraparticulate material. The delayed-release coated particles then preferably form an immediately disintegrating matrix with the pharmaceutical excipients of the extraparticulate material, which matrix was compressed to form MUPS tablets (Multiple Unit Pellet Systems). The extraparticulate material preferably contains at least one pharmaceutical excipient selected from binders, disintegrants and lubricants.

Tapentadol, ie (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, is a synthetic centrally acting analgesic useful in the treatment of moderate to severe acute or chronic pain works. For example, the synthesis of the free base of tapentadol is from EP-A 693 475 known.

The pharmaceutical dosage form according to 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 different salts of tapentadol or mixtures of salt(s) of tapentadol free base (e.g. the non-salt form of tapentadol), but preferably the total amount of tapentadol contained in the pharmaceutical dosage form is 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 phosphates are particularly preferred.

Preferably the salt of tapentadol with phosphoric acid has a stoichiometric ratio of tapentadol: phosphoric acid in the range 2.0:1.0 to 1.0:2.0, more preferably in the range 1.5:1.0 to 1.0 : 1.5.

In preferred embodiments, the salt of tapentadol with phosphoric acid is a mixed salt which contains at least one other cation in addition to the protonated form of tapentadol, the other cation preferably being selected from the group consisting of NH ₄ ⁺ , Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ and Ca ²⁺ or mixtures thereof.

Such mixed salts are described, inter alia, in WO2017182438A1 . In a preferred embodiment of the invention the salt of tapentadol with phosphoric acid is in combination with MHPO ₄ or M(H ₂ PO ₄ ) ₂ , where M is a divalent cation, or in combination with M'(H ₂ PO ₄ ) or M' ₂ HPO ₄ where M' is a monovalent cation. MHPO ₄ , M(H ₂ PO ₄ ) ₂ , M'(H ₂ PO ₄ ) or M' ₂ HPO ₄ can each be hydrates. In a preferred embodiment, the monovalent cation M' may be a cation of an alkali metal. Examples of alkali metals are lithium, sodium and potassium. In a more preferred embodiment, the salt of tapentadol with phosphoric acid is in combination with MHPO ₄ where M is a is divalent cation. In a preferred embodiment, the divalent cation M can be a cation of an alkaline earth metal. Examples of alkaline earth metals are magnesium or calcium. Calcium is particularly preferred. In another preferred embodiment, the molar ratio of tapentadol and M(H ₂ PO ₄ ) ₂ or MXH ₂ PO ₄ ) is 2:1 to 1:1.7, preferably 1.8:1 to 1:1.5, more preferably 1 .7:1 to 1:1.

Preferably the salt of tapentadol with phosphoric acid is the dihydrogen phosphate of tapentadol which may optionally be solvated (e.g. hydrated) or ansolvated (e.g. anhydrated). Preferably, the tapentadol dihydrogen phosphate is selected from the group consisting of solvated tapentadol dihydrogen phosphate, anhydrated tapentadol dihydrogen phosphate, solvated tapentadol dihydrogen phosphate, hydrated tapentadol dihydrogen phosphate, and any mixtures thereof.

The salt of tapentadol with phosphoric acid may be in the form of a single polymorph or a mixture of different polymorphs in any mixing ratio.

In a preferred embodiment, the salt of tapentadol with phosphoric acid is the dihydrogen phosphate present in the substantially pure crystalline form of tapentadol dihydrogen phosphate hemihydrate.

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

According to a preferred embodiment, the salt of tapentadol with phosphoric acid is a crystalline dihydrogen phosphate 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 may be characterized by the following X-ray powder diffraction peaks at degree 2θ ± 0.2 degree 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 (17 ), 25.3 (12), 26.0 (9), 26.5 (7), 26.8 (9), 28.0 (5), 28.4 (4), 28.9 (10) , 29.2 (6), 29.4 (4) and 29.6 (2). Alternatively, the crystalline dihydrogen phosphate 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 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 may be characterized by the following X-ray powder diffraction peaks at degree 2θ ± 0.2 degree 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 (3 ), 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 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.

X-ray powder diffraction measurements are performed with Cu K _α radiation at room temperature. A suitable device is eg D8 ADVANCE Eco, Bruker. DSC measurements are performed according to ASTM D3418.

Preferably, the salt of tapentadol with phosphoric acid has an average particle size, expressed as mean surface area D[3.2] (Sauter diameter) and determined by laser diffraction in dry mode according to ISO 13320:2020, ranging from 5.0 to 500 µm, preferably 50±40 µm, or 75±40 µm, or 100±40 µm, or 125±40 µm, or 150:L40 µm, or 175±40 µm, or 200:L40 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:L40 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. For example, the salt of tapentadol with phosphoric acid can be dissolved in suitable solvents together with suitable binders (eg hydroxypropylmethylcellulose or polyvinylpyrrolidone) and applied to an inert core (composite pellets). A suitable type and quantity of binder can be used to ensure that the salt of tapentadol with phosphoric acid does not crystallize when the solvent evaporates, but instead is deposited in amorphous form together with the binder (solid solution) as a layer of active substance on the inert core.

It is further contemplated that the pharmaceutical dosage form may contain mixtures of crystalline tapentadol salt with phosphoric acid with amorphous tapentadol salt with phosphoric acid in any mixing ratio. Preferably, substantially all of the salt of tapentadol with phosphoric acid present in the pharmaceutical dosage form is crystalline.

For the purposes of description, the dihydrogen phosphate of tapentadol is to be considered as the acid addition salt of 1 mole of orthophosphoric acid with 1 mole of tapentadol. It is believed that a proton of orthophosphoric acid (H ₃ PO ₄ ) protonates the amino group of tapentadol, thus forming an ammonium ion, while the rest of the orthophosphoric acid, i.e. the dihydrogen phosphate anion (H ₂ PO ₄ ^- ), forms the counter ion:

For 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 of tapentadol, may be in the form of any solvate, eg hydrate, ansolvate, eg anhydrate, and any polymorphic form, eg crystalline form and/or amorphous form. With regard to these forms and their preparation WO 2012/010316 A1 and WO 2017/182438 A1 referred.

The weight equivalent dose of tapentadol contained in the pharmaceutical dosage form according to the invention is in the range of 10 to 300 mg, based on the free base of tapentadol, for example 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg. Tapentadol free base (i.e. the free molecule) has a molecular weight of 221.3 g/mol. Thus, 10 mg of tapentadol free base corresponds to 0.0452 mmol, while 300 mg of tapentadol free base corresponds 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.

Tapentadol hydrochloride (anhydrate) has a molecular weight of 257.8 g/mol, while tapentadol (anhydrate) dihydrogen phosphate has a molecular weight of 319.3 g/mol. Thus, if the pharmaceutical dosage form according to the invention contains, for example, a dose equivalent by weight of 100 mg in terms of tapentadol free base (0.4518 mmol), it actually contains 144.3 mg of tapentadol dihydrogen phosphate (0.4518 mmol).

Thus, unless expressly stated otherwise, the dose information for tapentadol is presented as an equivalent weight in terms of the free base of tapentadol, i. H. expressing the non-salt form, the non-solvate form, the non-cocrystal form and the non-aggregated form of tapentadol with any other molecules. It is contemplated that the form of tapentadol actually contained in the pharmaceutical dosage form, i.e. H. the salt of tapentadol with phosphoric acid, can be in the form of any polymorph 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 are based on the total weight of the pharmaceutical dosage form.

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

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

In addition, it is contemplated that the dosage form of the invention may contain, in addition to the salt of tapentadol with phosphoric acid, other forms of tapentadol, for example tapentadol free base or additional salts of tapentadol, for example tapentadol hydrochloride, but the salt of tapentadol with phosphoric acid is preferably the only form of tapentadol contained in the pharmaceutical dosage form.

It is further contemplated that the dosage form of the present invention will contain several different salts of tapentadol with phosphoric acid; however, the pharmaceutical dosage form preferably contains only a single salt of tapentadol with phosphoric acid

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

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

Twice-daily dosing can be done at intervals of about every 12 hours, although such a protocol need not be strictly followed. For purposes of description, twice daily is also intended to encompass an administration regimen in which the two pharmaceutical dosage forms of the invention are administered over a period of about 24 hours, with the two administrations being separated by at least 4 hours, preferably at least 8 hours.

The pharmaceutical dosage form according to the invention provides a delayed release of tapentadol. For purposes of description, sustained release means non-immediate release. Sustained release includes controlled release, delayed release, extended release, staged release, repeated release, sustained release, and uniformly sustained release. Prolonged release preferably means release at a reduced release rate, to maintain a therapeutic effect, to reduce toxic effects, or for some other therapeutic purpose.

The sustained release is based on a coating coated on the plurality of particles comprising ethyl cellulose.

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, more 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 Darreichungsform enthaltenen Tapentadol freigesetzt worden sind.The pharmaceutical dosage form of the present invention preferably provides an in vitro dissolution profile where, measured by the USP paddle method at 50 rpm in 900 mL of aqueous phosphate buffer at pH 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 Darreichungsform enthaltenen Tapentadol freigesetzt worden sind.The pharmaceutical dosage form of the present invention preferably provides an in vitro dissolution profile where, measured by the USP paddle method at 50 rpm in 900 mL of aqueous phosphate buffer at pH 6.8 at 37°C,

• - after 1 hour 25±15% by weight; preferably 25±10% by weight; more preferably 25±5.0% by weight;
• - after 2 hours 35±20% by weight; preferably 35±10% by weight; more preferably 35±5.0% by weight;
• - after 4 hours 50±20% by weight; preferably 50±10% by weight; 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 Darreichungsform enthaltenen Tapentadol freigesetzt worden sind.The pharmaceutical dosage form of the present invention preferably provides an in vitro dissolution profile where, as measured by the USP paddle method at 50 rpm in 900 mL of aqueous buffer at pH 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 Darreichungsform enthaltenen Tapentadol freigesetzt worden sind.The pharmaceutical dosage form of the present invention preferably provides an in vitro dissolution profile where, as measured by the USP paddle method at 50 rpm in 900 mL of aqueous buffer at pH 4.5 at 37°C,

• - after 1 hour 25±15% by weight; preferably 25±10% by weight; more preferably 25±5.0% by weight;
• - after 2 hours 35±20% by weight; preferably 35±10% by weight; more preferably 35±5.0% by weight;
• - after 4 hours 50±20% by weight; preferably 50±10% by weight; 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 Darreichungsform enthaltenen Tapentadol freigesetzt worden sind.The pharmaceutical dosage form of the present invention preferably provides an in vitro dissolution profile where, as measured by the USP paddle method at 50 rpm in 900 mL of 0.1N HCl at pH 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 Darreichungsform enthaltenen Tapentadol freigesetzt worden sind.The pharmaceutical dosage form of the present invention preferably provides an in vitro dissolution profile where, as measured by the USP paddle method at 50 rpm in 900 mL of 0.1N HCl at pH 1.0 and 37°C,

• - after 1 hour 25±10% by weight; preferably 25±10% by weight; more preferably 25±5.0% by weight;
• - after 2 hours 40±30% by weight; preferably 40±10% by weight; 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 according to the invention preferably provides resistance to ethanol-induced dose dumping.

The pharmaceutical dosage form according to 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 0.1N HCl with 5.0% by volume ethanol (pH 1.0) than in 0.1N HCl without 5.0% by volume ethanol (pH 1.0) ready, each measured by 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 0.1N HCl with 20% by volume ethanol (pH 1.0) than in 0.1N HCl without 20% by volume ethanol (pH 1.0) ready, each measured by 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 0.1N HCl with 40% by volume ethanol (pH 1.0) than in 0.1N HCl without 40% by volume ethanol (pH 1.0) ready, each measured by the USP paddle method at 50 rpm in 900 ml at 37°C.

According to preferred embodiments, 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. The pharmaceutical dosage form according to the invention preferably has a total weight in the range from 150 to 750 mg.

According to preferred embodiments, 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 according to 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 pharmaceutical excipients.

Pharmaceutical excipients are known to those skilled in the art (cf., for example, RC Rowe et al., Handbook of Pharmaceutical Excipients, Pharmaceutical Press; 6th edition 2009; E.-M. Hoepfner et al., Fiedler-Encyclopedia of Excipients, Editio Cantor, 6. edition 2008). For purposes of description, a "pharmaceutical excipient" is preferably considered to be any pharmacologically inactive substance typically used as a carrier for the active ingredients of a medicament. The pharmaceutical excipient can have a physiological effect, e.g. like a vitamin, but not a pharmacological effect like a drug. Typical examples of pharmaceutical excipients include anti-adhesive agents, binders, film formers (coating materials), disintegrating agents, fillers, diluents, flavoring agents, colorants, flow regulators (lubricants), lubricants, preservatives, sorbents, surfactants, sweeteners, colorants, pigments and the like.

Any of the above pharmaceutical excipients can each be divided into subgroups. For example, preservatives can be divided into antioxidants, buffers, antimicrobials, and the like, while binders can be divided into solution binders and dry binders. Several pharmaceutical excipients show different properties at the same time, so they can serve different purposes. For example, polyethylene glycol can be used as a binder, plasticizer, and the like.

Binders preferred according to the invention are selected from the group consisting of cellulose, cellulose derivatives (eg cellulose ethers), magnesium aluminum silicates (eg 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, silicified microcrystalline cellulose and/or hydroxypropyl cellulose.

According to the invention, preferred cellulose derivatives are cellulose ethers, preferably selected from the group consisting of methyl cellulose, ethyl cellulose, propyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose and salts thereof.

Lubricants preferred according to the invention are selected from the group consisting of 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 tribehenate), sorbitan monostearate, sucrose monopalmitate, sodium stearyl fumarate, hydrated magnesium silicate and talc; preferably magnesium stearate.

Flow control agents preferred according to the invention are selected from the group consisting of silica gel, colloidal silicon dioxide, precipitated silicon dioxide, talc, kaolin and glycerol monostearate; preferably colloidal anhydrous silicon dioxide.

Film formers preferred according to the invention are selected from the group consisting of cellulose ethers and polyvinylpyrrolidone; preferably hydroxypropylmethyl cellulose or ethyl cellulose.

According to the invention, preferred plasticizers for the coating, which comprises ethyl cellulose, are selected from the group consisting of dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin; preferably triethyl citrate. Other water-insoluble plasticizers are acetylated monoglycerides, phthalate esters, castor oil, etc.

• (i) Pellets, welche durch Extrusion und gegebenenfalls anschließende Sphäronisierung;
• (ii) Mikrotabletten, welche durch Verpressen von Pulvermischungen oder Granulaten
• (iii) Pellets, welche durch Pulverbeschichtung inerter Kügelchen (Zucker / Maisstärke) (sog. „Non-Pareilles“ oder „Nu-Pareilles“) in Beschichtungspfannen;
• (iv) Pellets, welche durch Beschichten inerter Kügelchen (Zucker / Maisstärke) (sog. „Non-Pareilles“ oder „Nu-Pareilles“) mit Lösungen oder Suspensionen;
• (v) Pellets, welche durch Beschichten von Cellulosekügelchen (sog. „Cellets“); oder
• (vi) Pellets, welche durch Beschichten von groben Laktosekristallen;

erhalten wurden.The coated particles contained in the pharmaceutical dosage form according to the invention can have different structures. In preferred embodiments, these are coated with the coating for the sustained release of tapentadol

• (i) pellets obtained by extrusion and optionally subsequent spheronization;
• (ii) Microtablets obtained by compressing powder mixtures or granules
• (iii) Pellets obtained by powder coating inert (sugar/cornstarch) beads (so-called “Non-Pareilles” or “Nu-Pareilles”) in coating pans;
• (iv) pellets made by coating inert beads (sugar/cornstarch) (so-called "Non-Pareilles" or "Nu-Pareilles") with solutions or suspensions;
• (v) pellets, which are obtained by coating cellulose beads (so-called "cellets"); or
• (vi) pellets obtained by coating coarse lactose crystals;

were received.

Here, embodiments (i) and (ii) have in common that the core of the coated particles contains the salt of tapentadol with phosphoric acid, preferably in homogeneous distribution, whereas embodiments (iii), (iv), (v) and (vi) have in common that the core is inert and encapsulated by a layer of active substance containing the salt of tapentadol with phosphoric acid (reconstructive pellets).

• - einen Kern, welcher im Wesentlichen die Gesamtmenge des Salzes von Tapentadol mit Phosphorsäure umfasst, gegebenenfalls zusammen mit einem oder mehreren pharmazeutischen Hilfsstoffen, und
• - den Überzug zur retardierten Freisetzung von Tapentadol, welcher den Kern verkapselt.

In preferred embodiments of the pharmaceutical dosage form according to the invention, in particular with regard to embodiments (i) and (ii), the coated particles contain

• - a core comprising substantially all of the salt of tapentadol with phosphoric acid, optionally together with one or more pharmaceutical excipients, and
• - the prolonged-release coating of tapentadol, which encapsulates the core.

The salt of tapentadol with phosphoric acid is preferably distributed homogeneously in the core.

The content of the salt of tapentadol with phosphoric acid in the core is preferably in the range from 50 to 90% by weight, based on the total weight of the core.

The core preferably contains one or more binders, which are preferably independently selected from the group consisting of cellulose, cellulose derivatives, magnesium aluminum silicates, mono-, oligo- and polysaccharides, sugar alcohols, starches, calcium phosphate, polyvinylpyrrolidone and vinylpyrrolidone-vinyl acetate copolymers; preferably microcrystalline cellulose, silicified microcrystalline cellulose and/or hydroxypropyl cellulose. The total content of all binders in the core is preferably in the range from 5.0 to 50% by weight, based on the total weight of the core.

Preferably, the core contains one or more lubricants, preferably independently selected from the group consisting of salts of fatty acids, fatty acids, glyceryl fatty acid esters, sorbitan monostearate, sucrose monopalmitate, sodium stearyl fumarate, hydrated magnesium silicate, and talc; preferably magnesium stearate. The total content of all lubricants in the core is preferably in the range from 0.1 to 5.0% by weight, based on the total weight of the core.

In preferred embodiments, the core comprises extruded and optionally spheronized pellets (cf. embodiment (i)).

In other preferred embodiments, the core comprises microtablets (see embodiment (ii)).

In preferred embodiments, the core contains microcrystalline cellulose in an amount in the range from 5.0 to 25% by weight based on the total weight of the core and hydroxypropyl cellulose in an amount in the range from 5.0 to 25% by weight on the total weight of the core.

In other preferred embodiments, the core contains silicified microcrystalline cellulose in an amount in the range from 5.0 to 50% by weight, based on the total weight of the core, and magnesium stearate in an amount in the range from 0.1 to 5.0% by weight. -% based on the total weight of the core.

1. (A) Bereitstellen einer im Wesentlichen die gesamte Menge an Salz von Tapentadol mit Phosphorsäure, welche in der Darreichungsform enthalten sein soll, enthaltenden Mischung, gegebenenfalls zusammen mit einem oder mehreren pharmazeutischen Hilfsstoffen;
2. (B) Herstellen von Arzneimittelpellets oder Mikrotabletten aus der in Schritt (A) bereitgestellten Mischung durch Trockengranulation, Nassgranulation, Extrusion oder Direktverpressung;
3. (C) gegebenenfalls Trocknen und/oder Sphäronisieren der in Schritt (B) hergestellten Arzneimittelpellets oder Mikrotabletten unter Erhalt getrockneter und/oder sphäronisierter Arzneimittelpellets bzw. Mikrotabletten;
4. (D) Bereitstellen einer Lösung oder Dispersion eines Überzugsmaterials zur retardierten Freisetzung von Tapentadol, welches Ethylcellulose enthält, in Wasser oder in einem organischen Lösemittel oder einer Mischung davon, gegebenenfalls mit einem oder mehreren pharmazeutischen Hilfsstoffen;
5. (E) Beschichten der in Schritt (B) hergestellten Arzneimittelpellets bzw. Mikrotabletten oder der in Schritt (C) erhaltenen getrockneten und/oder sphäronisierten Arzneimittelpellets bzw. Mikrotabletten mit der in Schritt (D) bereitgestellten Lösung oder Dispersion des Überzugsmaterials unter Erhalt von beschichteten Partikeln mit retardierter Freisetzung, welche einen im Wesentlichen die Gesamtmenge an Salz von Tapentadol mit Phosphorsäure umfassenden Kern, gegebenenfalls zusammen mit einem oder mehreren pharmazeutischen Hilfsstoffen, und einen den Kern verkapselnden Überzug zur retardierten Freisetzung von Tapentadol enthalten;
6. (F) gegebenenfalls Trocknen der in Schritt (E) erhaltenen beschichteten Partikel unter Erhalt getrockneter beschichteter Partikel; und
7. (G) entweder Abfüllen der in Schritt (E) erhaltenen beschichteten Partikel oder der in Schritt (F) erhaltenen getrockneten beschichteten Partikel in Kapseln; oder Mischen der in Schritt (E) erhaltenen beschichteten Partikel oder der in Schritt (F) erhaltenen getrockneten beschichteten Partikel mit extrapartikulären pharmazeutischen Hilfs-stoffen und Verpressen der Mischung zu Tabletten.

In preferred embodiments, the pharmaceutical dosage form can be obtained by a method which comprises the following steps:

1. (A) providing a mixture containing substantially all of the amount of salt of tapentadol with phosphoric acid to be contained in the dosage form, optionally together with one or more pharmaceutical excipients;
2. (B) producing drug pellets or microtablets from the mixture provided in step (A) by dry granulation, wet granulation, extrusion or direct compression;
3. (C) optionally drying and/or spheronizing the drug pellets or microtablets produced in step (B) to obtain dried and/or spheronized drug pellets or microtablets;
4. (D) providing a solution or dispersion of a coating material for the sustained release of tapentadol, which contains ethyl cellulose, in water or in an organic solvent or a mixture thereof, optionally with one or more pharmaceutical excipients;
5. (E) coating the drug pellets or microtablets produced in step (B) or the dried and/or spheronized drug pellets or microtablets obtained in step (C) with the solution or dispersion of the coating material provided in step (D) to obtain coated particles with sustained release, which contain a core comprising essentially the total amount of salt of tapentadol with phosphoric acid, optionally together with one or more pharmaceutical excipients, and a core encapsulating coating for the sustained release of tapentadol;
6. (F) optionally drying the coated particles obtained in step (E) to obtain dried coated particles; and
7. (G) either filling the coated particles obtained in step (E) or the dried coated particles obtained in step (F) into capsules; or mixing the coated particles obtained in step (E) or the dried coated particles obtained in step (F) with extraparticulate pharmaceutical excipients and compressing the mixture into tablets.

• - einen inerten Kern, welcher kein Salz von Tapentadol mit Phosphorsäure enthält,
• - eine Wirkstoffschicht, welche den inerten Kern verkapselt und im Wesentlichen die gesamte Menge des Salzes von Tapentadol mit Phosphorsäure umfasst, gegebenenfalls zusammen mit einem oder mehreren pharmazeutischen Hilfsstoffen, und
• - den Überzug zur retardierten Freisetzung von Tapentadol, welcher den Kern und die Wirkstoffschicht verkapselt.

In other preferred embodiments of the pharmaceutical dosage form according to the invention, in particular with regard to embodiments (iii), (iv), (v) and (vi), the coated particles contain

• - an inert core, which does not contain a salt of tapentadol with phosphoric acid,
• - a drug layer encapsulating the inert core and comprising substantially all of the salt of tapentadol with phosphoric acid, optionally together with one or more pharmaceutical excipients, and
• - the coating for the sustained release of tapentadol, which encapsulates the core and the active substance layer.

The inert core is preferably formed by a bead of sugar and/or corn starch (cf. embodiments (iii) and (iv)), beads of microcrystalline cellulose (cf. embodiment (v)) or lactose crystal (cf. embodiment (vi)). .

The salt of tapentadol with phosphoric acid is preferably distributed homogeneously in the active substance layer.

The content of the salt of tapentadol with phosphoric acid in the active substance layer is preferably in the range from 50 to 90% by weight, based on the total weight of the inert core and the active substance layer.

Preferably, the drug layer contains one or more flow regulators, which are preferably independently selected from the group consisting of silica gel, colloidal silicon dioxide, precipitated silicon dioxide, talc, kaolin and glycerol monostearate; preferably colloidal anhydrous silicon dioxide. The total content of all flow regulators in the active substance layer is preferably in the range from 0.1 to 5.0% by weight, based on the total weight of the inert core and the active substance layer.

The layer of active substance preferably contains one or more film formers, which are preferably selected independently of one another from the group consisting of cellulose ethers and polyvinylpyrrolidone; preferably hydroxypropylmethyl cellulose or ethyl cellulose. The total content of all film formers in the active substance layer is preferably in the range from 0.5 to 10% by weight, based on the total weight of the inert core and the active substance layer.

In preferred embodiments, the inert core forms a build-up pellet with the layer of active substance which encapsulates the inert core (cf. embodiments (iii), (iv), (v) and (vi)).

In preferred embodiments, the drug layer contains colloidal anhydrous silica in an amount ranging from 0.1 to 5.0% by weight based on the total weight of the inert core and drug layer, and ethyl cellulose in an amount ranging from 0.5 to 10% by weight, based on the total weight of the inert core and the active substance layer.

In other preferred embodiments, the drug layer contains colloidal anhydrous silicon dioxide in an amount in the range of 0.1 to 5.0% by weight based on the total weight of the inert core and drug layer, and hydroxypropylmethylcellulose in an amount in the range of 0.5 up to 10% by weight, based on the total weight of the inert core and the active substance layer.

1. (A) Bereitstellen inerter Kerne, welche einen oder mehrere pharmazeutische Hilfsstoffe, jedoch kein Salz von Tapentadol mit Phosphorsäure enthalten;
2. (B) Bereitstellen einer Zusammensetzung umfassend das Salz von Tapentadol mit Phosphorsäure gegebenenfalls zusammen mit einem oder mehreren pharmazeutischen Hilfsstoffen;
3. (C) Beschichten der in Schritt (A) bereitgestellten inerten Kerne mit der in Schritt (B) bereitgestellten Zusammensetzung unter Erhalt von Zwischenproduktpartikeln, welche einen kein Salz von Tapentadol mit Phosphorsäure enthaltenden inerten Kern und eine den inerten Kern verkapselnde Wirkstoffschicht, welche im Wesentlichen die gesamte Menge des Salzes von Tapentadol mit Phosphorsäure, welche in der Darreichungsform enthalten sein soll, umfasst, gegebenenfalls zusammen mit dem einen oder den mehreren pharmazeutischen Hilfsstoffen umfasst;
4. (D) gegebenenfalls Trocknen der in Schritt (C) erhaltenen Zwischenproduktpartikel unter Erhalt getrockneter Zwischenproduktpartikel;
5. (E) Bereitstellen einer Lösung oder Dispersion eines Überzugsmaterials zur retardierten Freisetzung von Tapentadol, welches Ethylcellulose enthält, in Wasser oder in einem organischen Lösemittel oder einer Mischung davon, gegebenenfalls mit einem oder mehreren pharmazeutischen Hilfsstoffen;
6. (F) 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 unter Erhalt von beschichteten Partikeln mit retardierter Freisetzung, welche einen kein Salz von Tapentadol mit Phosphorsäure enthaltenden inerten Kern, eine den inerten Kern verkapselnde Wirkstoffschicht, welche im Wesentlichen die gesamte Menge des Salzes von Tapentadol mit Phosphorsäure umfasst, gegebenenfalls zusammen mit dem einen oder den mehreren pharmazeutischen Hilfsstoffen, und einen den inerten Kern und die Wirkstoffschicht verkapselnden Überzug zur retardierten Freisetzung von Tapentadol enthalten;
7. (G) gegebenenfalls Trocknen der in Schritt (F) erhaltenen beschichteten Partikel unter Erhalt getrockneter beschichteter Partikel; und
8. (H) entweder Abfüllen der in Schritt (F) erhaltenen beschichteten Partikel oder der in Schritt (G) erhaltenen getrockneten beschichteten Partikel in Kapseln; oder Mischen der in Schritt (F) erhaltenen beschichteten Partikel oder der in Schritt (G) erhaltenen getrockneten beschichteten Partikel mit extrapartikulären pharmazeutischen Hilfsstoffen und Verpressen der Mischung zu Tabletten.

In preferred embodiments, the pharmaceutical dosage form can be obtained by a method which comprises the following steps:

1. (A) providing inert cores which contain one or more pharmaceutical excipients but no salt of tapentadol with phosphoric acid;
2. (B) providing a composition comprising the salt of tapentadol with phosphoric acid, optionally together with one or more pharmaceutical excipients;
3. (C) Coating the inert cores provided in step (A) with the composition provided in step (B) to obtain intermediate product particles which contain an inert core which does not contain a salt of tapentadol with phosphoric acid and an active substance layer encapsulating the inert core which essentially contains the total amount of the salt of tapentadol with phosphoric acid, which in to be included in the dosage form, optionally together with the one or more pharmaceutical excipients;
4. (D) optionally drying the intermediate product particles obtained in step (C) to obtain dried intermediate product particles;
5. (E) providing a solution or dispersion of a coating material for the sustained release of tapentadol, which contains ethyl cellulose, in water or in an organic solvent or a mixture thereof, optionally with one or more pharmaceutical excipients;
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) to obtain coated sustained-release particles which do not contain a salt of tapentadol with an inert core containing phosphoric acid, an active substance layer encapsulating the inert core, which essentially comprises the entire amount of the salt of tapentadol with phosphoric acid, optionally together with the one or more pharmaceutical excipients, and a coating encapsulating the inert core and the active substance layer for the sustained release release of tapentadol included;
7. (G) optionally drying the coated particles obtained in step (F) to obtain dried coated particles; and
8. (H) filling either the coated particles obtained in step (F) or the dried coated particles obtained in step (G) into capsules; or mixing the coated particles obtained in step (F) or the dried coated particles obtained in step (G) with extraparticulate pharmaceutical excipients and compressing the mixture into tablets.

Preferably the composition provided in step (B) is a dispersion or solution in water or in an organic solvent or a mixture thereof.

In preferred embodiments, step (C) is carried out by powder coating in a coating pan (cf. embodiment (iii), optionally also (v) and (vi)).

In other preferred embodiments, step (C) is carried out by spraying the inert cores in a fluidized bed coater (cf. embodiment (iv), optionally also (v) and (vi)).

The coated particles contained in the pharmaceutical dosage form according to the invention have a coating for the delayed release of tapentadol which contains ethyl cellulose. Compositions containing ethylcellulose and are suitable for the production of coatings for the delayed release of active compounds, are commercially available (for example, Ethocel ^® 20, Aquacoat ^® ECD 30, Surelease ^® B NF).

The ethyl cellulose preferably has an ethoxy content in the range from 48 to 49.5% by weight.

The release of tapentadol can be controlled, among other things, by the type and amount of plasticizers, the molecular weight of the ethyl cellulose and the layer thickness of the coating (i.e. the weight applied).

The coating for the delayed release of tapentadol preferably comprises, in addition to ethyl cellulose, one or more plasticizers, which are preferably selected independently of one another from the group consisting of dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin; preferably triethyl citrate. The total content of all plasticizers in the coating for the sustained release of tapentadol is preferably in the range from 5.0 to 20% by weight, based on the total weight of the coating.

• - im Bereich von 3 bis 5,5 mPa·s (z.B. Ethocel^® 4 Premium),
• - im Bereich von 6 bis 8 mPa·s (z.B. Ethocel^® 7 Premium),
• - im Bereich von 9 bis 11 mPa·s (z.B. Ethocel^® 10 Premium),
• - im Bereich von 18 bis 22 mPa·s (z.B. Ethocel^® 20 Premium),
• - im Bereich von 41 bis 49 mPa·s (z.B. Ethocel^® 45 Premium), oder
• - im Bereich von 90 bis 110 mPa·s (z.B. Ethocel^® 100 Premium).

In preferred embodiments, the ethyl cellulose has a viscosity

• - in the range from 3 to 5.5 mPa s (e.g. Ethocel ^® 4 Premium),
• - in the range of 6 to 8 mPa s (e.g. Ethocel ^® 7 Premium),
• - in the range of 9 to 11 mPa s (e.g. Ethocel ^® 10 Premium),
• - in the range of 18 to 22 mPa s (e.g. Ethocel ^® 20 Premium),
• - in the range of 41 to 49 mPa·s (e.g. Ethocel ^® 45 Premium), or
• - in the range from 90 to 110 mPa·s (e.g. Ethocel ^® 100 Premium).

• - 5,0 bis 20 Gew.-%;
• - 15 bis 30 Gew.-%;
• - 25 bis 40 Gew.-%;
• - 35 bis 50 Gew.-%; oder
• - 45 bis 60 Gew.-%;

jeweils bezogen auf das Gesamtgewicht der beschichteten Partikel.In preferred embodiments, the sustained release coating content of tapentadol is in the range of

• - 5.0 to 20% by weight;
• - 15 to 30% by weight;
• - 25 to 40% by weight;
• - 35 to 50% by weight; or
• - 45 to 60% by weight;

in each case based on the total weight of the coated particles.

The release of tapentadol can optionally be influenced by adding one or more release modifying agents or by providing one or more passages through the coating, ie. H. set to a desired rate. The release modifying agents acting as pore formers can be organic or inorganic and can include materials which can be leached, extracted or leached from the coating in the environment of use. The ratio of ethyl cellulose to water soluble material is determined by the release rate required and the solubility characteristics of the materials chosen, among other factors. The pore formers may comprise one or more hydrophilic polymers such as hydroxypropyl methyl cellulose. The sustained release coatings may also include erosion promoting agents such as starches and gums. The sustained release coatings can also include materials suitable for forming microporous laminae in the environment of use, such as polycarbonates made from straight chain carbonic polyesters in which the carbonate groups recur in the polymer chain.

The coating for the delayed release of tapentadol preferably contains talc in addition to ethylcellulose, preferably in significant amounts. Preferably, the relative weight ratio of ethylcellulose:talc ranges from 2:1 to 1:20; preferably 2:1 to 1:2, or 1:8 to 1:12.

According to the invention, the coating for the delayed release of tapentadol can be applied to the cores of the particles in different ways. The coating is preferably applied directly to the cores (cf. embodiments (i) and (ii)) or to the layer of active substance which encapsulates the inert cores (cf. embodiments (iii), (iv), (v) and (vi). )). Accordingly, there is preferably no further layer of a different material between the coating and the core or the active substance layer, although such embodiments with a further layer are not excluded according to the invention.

In preferred embodiments, the coating material, which forms the coating for the delayed release of tapentadol, is applied in the form of ethanolic solutions or aqueous dispersions, with the solvent (ethanol or water) being evaporated during the application.

The plasticized aqueous dispersion or organic dispersion or organic solution may be applied to the substrate comprising the salt of tapentadol with phosphoric acid by spraying using any suitable spraying equipment known in the art. A preferred method uses a Wurster fluidized bed system in which a jet of air introduced from below fluidizes the core material and causes drying as the coating is sprayed on. Preferably, an amount of the aqueous dispersion or organic dispersion or organic solution sufficient to obtain a predetermined sustained release of tapentadol upon exposure of the coated substrate to aqueous solutions, e.g. gastric juice, is applied, taking into account the manner in which the plasticizer has been incorporated, etc . After coating with the coating for the delayed release of tapentadol may be Opadry ^® apply optionally a further coating of a film-former, such as on the particles. If at all, this conversion is only provided to substantially reduce agglomeration of the particles.

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 a day.

Another aspect of the invention relates to the use of a salt of tapentadol with phosphoric acid for the manufacture 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 a day.

The pain is preferably chronic pain.

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

• - Cmax 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 having an average value of

• - Cmax 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 having an average value 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
• - Provides 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 having an average value of

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

• - Cmax 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 having an average value of

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

• - Cmax 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 having an average value of

• - Cmax in the range of 85±15 ng/ml; and or
• - AUC _last in the range of 1,141±250 ng·h/ml; and or
• - Provides AUC _∞ in the range of 1,145±250 ng h/mL.

EXAMPLES

The following examples further illustrate the invention but should not be construed as limiting the scope thereof.

Example 1 - Preparation of Tapentadol Dihydrogen Phosphate Salt:

Three different batches of tapentadol dihydrogen phosphate were prepared, a batch of essentially pure tapentadol dihydrogen phosphate hemihydrate, a batch of essentially pure tapentadol dihydrogen phosphate anhydrate and a batch comprising a mixture of the two polymorphs (=mixed form).

Example 1.1 - Tapentadol dihydrozene phosphate, mixed form:

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

Example 1.2 - Tapentadol dihydrozene phosphate, mixed form:

Tapentadol base (7.5 g) was suspended in a mixture of ethyl acetate (81 g, 90 ml) and water (10 mg, 10 µl) at 20°C to 25°C. The mixture was heated to 55°C resulting in a clear solution. Then crystalline tapentadol dihydrogen phosphate (10 mg) and phosphoric acid (3.9 g, 2.3 ml, 85 wt%) were added. A white suspension formed immediately. After mixing at 60°C for 45 min, the suspension was cooled to 5°C over 45 min. After an additional 45 min of mixing at 5°C, the resulting solid was isolated by vacuum filtration and dried (20°C to 25°C, vacuum, 2 h). The product obtained (9.5 g, white crystalline powder) was analyzed by X-ray powder diffraction. TGA showed a 3.1% weight loss when heated to 113°C.

Example 1.3 - Tapentadol dihydrozene 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 resulting in a clear solution. Then crystalline tapentadol dihydrogen phosphate (10 mg) and phosphoric acid (3.9 g, 2.3 ml, 85 wt%) were added. A white suspension formed immediately. After mixing at 60°C for 45 min, the suspension was cooled to 5°C over 45 min. After an additional 45 min of mixing at 5°C, the resulting solid was isolated by vacuum filtration and dried (20°C to 25°C, vacuum, 2 h). The product obtained (9.6 g, white crystalline powder) was analyzed by X-ray powder diffraction. The TGA showed a 1.9% weight loss when heated to 120°C.

Example 1.4 - Tapentadol dihydrozene 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 to give a clear solution. Phosphoric acid (259 mg, 153 µl, 85 wt%) was added and after a short time the clear solution became a suspension. The suspension was mixed at 20°C to 25°C for 30 min and then cooled to 5°C and mixed at 5°C for a further 30 min. The resulting solid was isolated by vacuum filtration and dried (20°C to 25°C, vacuum, 30 min). The product obtained (404 g, white crystalline powder) was determined by X-ray powder diffraction ( 2 ) and DSC ( 3 ) analyzed. The first DSC peak had a normalized integral of 149.2 Jg ^-1 , with an onset temperature of 56.7°C and a peak temperature of 89.2°C. The second DSC peak had a normalized integral of 22.0 ^{Jg -1} , with an onset temperature of 130.1°C and a peak temperature of 133.4°C. Decomposition occurred at around 200 °C. The TGA showed a 3.7% weight loss when heated to 119°C.

Example 1.5 - Tapentadol dihydrocene phosphate hemihydrate (coarse material):

Tapentadol base (60g) was dissolved in a mixture of tetrahydrofuran (1.5kg, 1.64L) and water (82g, 82ml) at 20°C to 25°C. Phosphoric acid (31.25 g, 18.5 mL, 85 wt%) and crystalline Tapentadol dihydrogen phosphate (5 mg) was added. During the addition, the solution became a white suspension. The resulting suspension was cooled to 10°C over 30 min. The mixture was heated to 35°C and mixed for 30 min followed by cooling to 5°C over 30 min. The suspension was mixed at 5°C for 45 min. The resulting solid was isolated by vacuum filtration and dried (20°C to 25°C, vacuum, 2 h). The product obtained (84.6 g, white crystalline solid) was analyzed by X-ray powder diffraction. The TGA showed a 4.5% weight loss when heated to 113°C.

Example 1.6 - Tapentadol dihydrozene 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, resulting in a clear solution. Phosphoric acid (78.1 mg, 46.3 µl, 85 wt%) 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 mixed at 115°C for a further 45 min. The mixture was then cooled to 30°C over 3 hours. The resulting solid 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 X-ray powder diffraction ( 4 ) and DSC ( 5 ) analyzed. The DSC peak had a normalized integral of 72.1 Jg ^-1 , with an onset temperature of 146.5°C and a peak temperature of 149.1°C. Decomposition occurred at around 200 °C. The TGA showed a weight loss of 0.9% when heated to 134°C.

Example 1.7 - Tapentadol dihydrozene 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 product obtained (452 mg, white crystalline powder) was analyzed by X-ray powder diffraction. The TGA showed a 1.0% weight loss when heated to 129°C.

6 Figure 12 shows three photographs of different salts of tapentadol used to make tablets. 6A shows relatively fine particles of the mixed form of tapentadol dihydrogen phosphate (average particle size by visual inspection 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 by visual inspection about 100-150 µm).

Example 2 - intrinsic resolution (dissolution rate):

100 mg of tapentadol, either in the form of the hydrochloride salt or the dihydrogen phosphate salt (mixed form [fine particle batch], pure hemihydrate or pure anhydrate) was compressed with a compression force of 200 kg (gravitational) at a surface area of 0.5 cm ^{2 for} 1 minute . The pressed samples thus obtained were tested 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) at least 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 14 12 12 11 3 95 91 65 79 35 30 30 29 5 99 95 80 92 56 49 46 48 7 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. 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 at least pH 6.8 pH 1.2 pH 6.8 pH 1.2 0 0 0 0 0 1 12 14 13 15 3 36 37 36 37 5 66 54 66 57 7 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 dissolution rate of tapentadol dihydrogen phosphate compared to tapentadol hydrochloride is independent of the polymorphic form of tapentadol dihydrogen phosphate.

Example 3 - Thermodynamic solubility:

The thermodynamic solubility of tapentadol hydrochloride and of tapentadol dihydrogen phosphate (mixed form, fine particle batch) was determined as the saturation solubility in various media at various pH values. The solutions were stirred at 25°C for 24 hours and the pH values of the solutions at the beginning and 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 end g/100ml begin end g/100ml 0.1M 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
na = 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 lower than that of tapentadol hydrochloride.

Example 4 - pharmaceutical dosage forms:

Six different multiparticulate dosage forms according to the invention are produced.

Example 4-1: Extrusion spheronization of pellets with retarding coating

ingredients Range [%] Salt of tapentadol with phosphoric acid per batch [g] per 100 mg equivalent dose of tapentadol free base [mg] pellet cores Salt of tapentadol with phosphoric acid 50 - 90 4000 143.8 Microcrystalline cellulose (mean particle size 20 µm, Avicel ^® PH 105, FMC) 5-25 500 18.0 low substituted hydroxypropyl cellulose (L-HPC LH-31, Shin Etsu) 5-25 500 18.0 Retarding coating Ethyl cellulose 20 mPa.s (Ethocel ^® 20, Dupont) 5-50 278 10.0 talc 50-95 2780 100.0

Extrusion spheronization of pellet cores:

Salt of tapentadol with phosphoric acid and the excipients are mixed in a Diosna P25 high shear granulator for 10 minutes, followed by granulation with 950 ml of water for about 10 minutes. The wet mass is extruded through a 1 x 2 mm die plate using a NICA E140 extruder and spheronized on a NICA S450 spheronizer for about 10 min at 900 rpm in portions of about 3 kg. The rounded pellets are dried in a fluid bed drier and then graded into a range of 0.63 to 1.4 mm.

Retarding coating based on ethyl cellulose:

The coating solution is prepared with an excess of about 20% (334 g ethyl cellulose, 3336 g talc). Ethyl cellulose is dissolved in about 50 liters of ethanol (96%) with stirring. After dissolving ethyl cellulose, the talc is dispersed in the solution with stirring. The classified pellets are loaded into a fluidized bed coater equipped with a Wurster column and sprayed from below with the coating suspension until an increase in pellet weight of about 61% is achieved.

In order to achieve different doses of the tapentadol base, the prolonged-release coated pellets are filled into appropriately sized hard gelatin capsules or sachets with the following quantities: Equivalent dose of tapentadol free base Weight of the retarding coated pellets 50 mg 144.9 mg 100 mg 289.8 mg 150 mg 434.7 mg 200 mg 579.6 mg 250 mg 724.5 mg

Alternatively, delayed-release coated pellets can be mixed with excipients that form an immediately disintegrating matrix and compressed into MUPS (Multiple Unit Pellet Systems) tablets.

Example 4-2: Pan Coated Pellets, Retardant Coated

ingredients Salt of tapentadol with phosphoric acid per batch [g] per 100 mg equivalent dose of tapentadol free base [mg] pellet cores Salt of tapentadol with phosphoric acid 4000 143.8 Neutral sugar spheres 0.5-0.6 mm diameter (sucrose, corn starch) 1000 35.8 Colloidal Anhydrous Silicon Dioxide (Aerosil ^® 200) 20 0.7 Ethylcellulose 20 mPa·s part 1 (Ethocel ^® 20, Dupont) 230 8.3 retarding coating Ethylcellulose 20 mPa·s Part 2 (Ethocel ^® 20, Dupont) 420 15.0 talc 4200 150.0

Powder coating of pellets:

Salt of tapentadol with phosphoric acid and colloidal anhydrous silicon dioxide are mixed in a Bohle tank mixer (20 L tank) for 10 minutes. Ethylcellulose Part 1 is dissolved in approximately 1200mL of ethanol (96% v/v). The sugar globules are placed in a coating pan, rotated, and warm air is blown through the coating pan. The ethyl cellulose solution is added in portions to the sugar spheres. After each wetting of the balls, the tapentadol-silica mixture is poured into portio added and partially dried. This process is repeated until all of the ethyl cellulose solution and tapentadol powder are added to the spheres and the spheres are dried. The balls grow to a diameter of 0.8 - 1.5 mm.

Retarding coating based on ethyl cellulose:

The coating solution is prepared with an excess of about 20% (504 g ethyl cellulose). Ethyl cellulose is dissolved in about 7 liters of ethanol (96%) with stirring. The ethyl cellulose is sprayed onto the tapentadol pellets which are rotating in a coating pan at a spray rate which results in a wet surface. To prevent the moist pellets from sticking to one another, talc is continuously dosed onto the pellets. Spray rate and talc addition rate are synchronized with each other. The process is continued until an increase in pellet weight of about 92% is achieved.

Release coated pellets can be filled into hard gelatin capsules, HPMC capsules, sachets, stick packs, etc. Alternatively, delayed-release coated pellets can be mixed with excipients that form an immediately disintegrating matrix and compressed into MUPS (Multiple Unit Pellet Systems) tablets.

Example 4-3: Coating on sugar spheres in a fluidized bed coater, retarding coating

ingredients Salt of tapentadol with phosphoric acid per batch [g] per 100 mg equivalent dose of tapentadol free base [mg] pellet cores Salt of tapentadol with phosphoric acid 2000 143.8 Neutral sugar globules 0.4-0.6 mm diameter (sucrose, corn starch) 1000 72.0 Hypromellose 3 mPa s (Pharmacoat 603, Shin Etsu) 100 7.2 Colloidal Anhydrous Silicon Dioxide 50 3.6 retarding coating Ethylcellulose dispersion 30% (Aquacoat ECD 30, Dupont), weight as dry substance 1667 (30% dispersion = 500 g dry substance) 30.8 (dry matter) triethyl citrate 150 9.2 talc 450 27.7

Layer structure of pellets:

5 liters of water are heated to 60°C, hypromellose is added with stirring and, after dispersing, 10 liters of water at room temperature are added. Salt of tapentadol with phosphoric acid and colloidal anhydrous silicon dioxide are mixed in a Bohle tank mixer (20 L tank) for 10 minutes and then added to the hypromellose solution with stirring. The sugar spheres are placed in a fluid bed coater equipped with a Wurster column and the tapentadol dispersion sprayed onto the pellets.

Retarding coating based on ethyl cellulose:

The coating solution is prepared with an excess of about 20% (about 2100 g Aquacoat, 158 g triethyl citrate, 525 g talc). Triethyl citrate is added with gentle stirring over a few hours. Talc is suspended in about 1 liter of water with vigorous stirring and added to the Aquacoat dispersion with gentle stirring. The suspension is sprayed onto the tapentadol pellets in a fluid bed coater equipped with a Wurster column. The process is continued until an increase in pellet weight of about 30% is achieved.

Release coated pellets can be filled into hard gelatin capsules, HPMC capsules, sachets, stick packs, etc. Alternatively, delayed-release coated pellets can be mixed with excipients that form an immediately disintegrating matrix and compressed into MUPS (Multiple Unit Pellet Systems) tablets.

Example 4-4 Coating on cellulose beads in a fluidized bed coater, retarding coating

ingredients Salt of tapentadol with phosphoric acid per batch [g] per 100 mg equivalent dose of tapentadol free base [mg] pellet cores Salt of tapentadol with phosphoric acid 2000 143.8 Microcrystalline cellulose beads 0.35-0.5 mm diameter (Cellets ^® 350, Rake) 1000 72.0 Hypromellose 3 mPa s (Pharmacoat 603, Shin Etsu) 100 7.2 Colloidal Anhydrous Silicon Dioxide 50 3.6 retarding coating Ethyl cellulose 20 mPa.s (Ethocel ^® 20, Dupont) 175 12.6 talc 1750 125.8

Layer structure of pellets:

5 liters of water are heated to 60°C, hypromellose is added with stirring and, after dispersing, 10 liters of water at room temperature are added. Salt of tapentadol with phosphoric acid and colloidal anhydrous silicon dioxide are mixed in a Bohle tank mixer (20 L tank) for 10 minutes and then added to the hypromellose solution with stirring. The cellulose beads are placed in a fluid bed coater equipped with a Wurster column and the tapentadol dispersion sprayed onto the pellets.

Retarding coating based on ethyl cellulose:

The coating solution is prepared with an excess of about 20% (210 g ethyl cellulose, 2100 g talc). Ethyl cellulose is dissolved in about 30 liters of ethanol (96%) with stirring. After dissolving ethyl cellulose, the talc is dispersed in the solution with stirring. The classified pellets are loaded into a fluid bed coater equipped with a Wurster column and sprayed from below with the coating suspension until an increase in pellet weight of about 63% is achieved.

Release coated pellets can be filled into hard gelatin capsules, HPMC capsules, sachets, stick packs, etc. Alternatively, delayed-release coated pellets can be mixed with excipients that form an immediately disintegrating matrix and compressed into MUPS (Multiple Unit Pellet Systems) tablets.

Example 4-5: Coating on lactose crystals in a fluidized bed coater, delayed release coating

ingredients Salt of tapentadol with phosphoric acid per batch [g] per 100 mg equivalent dose of tapentadol free base [mg] pellet cores Salt of tapentadol with phosphoric acid 3000 143.8 Lactose monohydrate crystals D50 = 150 µm (Lactochem ^® coarse crystals, DFE) 1000 47.9 Hypromellose 3 mPa s (Pharmacoat 603, Shin Etsu) 300 14.4 Colloidal Anhydrous Silicon Dioxide 75 3.6 retarding coating Ethyl cellulose 20 mPa.s (Ethocel ^® 20, Dupont) 250 12.0 talc 2500 119.8

Coating of crystals:

7.5 liters of water are heated to 60° C., hypromellose is added with stirring and, after dispersing, 15 liters of water at room temperature are added. Salt of tapentadol with phosphoric acid and colloidal anhydrous silicon dioxide are mixed in a Bohle tank mixer (20 L tank) for 10 minutes and then added to the hypromellose solution with stirring. The lactose crystals are placed in a fluid bed coater equipped with a Wurster column and the tapentadol dispersion is sprayed onto the crystals.

Retarding coating based on ethyl cellulose:

The coating solution is prepared with an excess of about 20% (300 g ethyl cellulose, 3000 g talc). Ethyl cellulose is dissolved in about 40 liters of ethanol (96%) with stirring. After dissolving ethyl cellulose, the talc is dispersed in the solution with stirring. The classified pellets are loaded into a fluid bed coater equipped with a Wurster column and sprayed from below with the coating suspension until an increase in pellet weight of about 63% is achieved.

Release coated pellets can be filled into hard gelatin capsules, HPMC capsules, sachets, stick packs, etc. Alternatively, delayed-release coated pellets can be mixed with excipients that form an immediately disintegrating matrix and compressed into MUPS (Multiple Unit Pellet Systems) tablets.

Example 4-6: Microtablets, delayed-release coating

ingredients Salt of tapentadol with phosphoric acid per batch [g] per microtablet [mg] per 100 mg equivalent dose of tapentadol free base [mg] pellet cores Salt of tapentadol with phosphoric acid 3595.5 5.75 143.8 Silicified microcrystalline cellulose (PROSOLV ^® SMCC, JRS Pharma) 1354.5 2:17 47.9 magnesium stearate 50.0 0.08 14.4 retarding coating Ethyl cellulose 20 mPa.s (Ethocel ^® 20, Dupont) 70 0.11 2.80 talc 700 1:12 28.00

Production of microtablets:

Salt of tapentadol with phosphoric acid and silicified microcrystalline cellulose are mixed in a Bohle tank mixer (20 liter tank) for 30 minutes and then magnesium stearate is added and mixed for an additional 5 minutes. The mixture is compressed into microtablets weighing 8 mg on a tabletting machine equipped with punches and dies for 2mm diameter microtablets.

Retarding coating based on ethyl cellulose:

The coating solution is prepared with an excess of about 20% (300 g ethyl cellulose, 3000 g talc). Ethyl cellulose is dissolved in about 40 liters of ethanol (96%) with stirring. After dissolving ethyl cellulose, the talc is dispersed in the solution with stirring. The microtablets are loaded into a GS rotating pan coater and sprayed with the coating suspension until an increase in pellet weight of about 15% is achieved.

In order to achieve different doses of the tapentadol base, the prolonged-release coated pellets are filled into pouches containing the following number of prolonged-release coated microtablets: Equivalent dose of tapentadol free base Number of delayed-release coated microtablets 50 mg 10 100 mg 20 150 mg 30 200 mg 40 250 mg 50

Alternative retarding coating:

The uncoated micro-tablets are treated with a solution of 5% ethylcellulose 20 mPa.s (Ethocel ^® 20, DuPont) in ethanol coated 96% (V / V) until a weight gain of 8% was reached.

QUOTES INCLUDED IN DESCRIPTION

This list of documents cited 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

• DE 202020104285 [0001]
• WO 2017/182438 A1 [0028, 0035, 0068]
• DE 10109763 [0029]
• WO 2010/096045 [0035]
• WO 2012/010316 A1 [0035, 0068]
• WO 2012/051246 A1 [0035]
• WO 03/035053 A1
• WO 2006/002886 A1 [0036]
• WO 2009/092601 A1 [0036]
• EP 693475A [0049]
• WO 2017182438 A1 [0054]

Claims (68)

A pharmaceutical dosage form comprising a plurality of coated particles; said coated particles comprising a salt of tapentadol with phosphoric acid and having a tapentadol sustained release coating comprising ethyl cellulose; the dosage form releases tapentadol in a delayed manner; and wherein the weight equivalent dose of tapentadol contained in the dosage form is in the range of 10 to 300 mg, based on the free base of tapentadol. The pharmaceutical dosage form claim 1 , wherein the dosage form comprises only those coated particles which are essentially of the same nature. The pharmaceutical dosage form claim 1 , wherein the dosage form comprises at least two different types of coated particles, which differ from one another in at least one property. The pharmaceutical dosage form claim 3 wherein the at least one property is selected from the group consisting of content of salt of tapentadol with phosphoric acid, type of pharmaceutical excipient, content of pharmaceutical excipient, and content of coating for sustained release of tapentadol. The pharmaceutical dosage form according to any one of the preceding claims, wherein the salt of tapentadol with phosphoric acid has a stoichiometric ratio of tapentadol: phosphoric acid in the range of 2.0:1.0 to 1.0:2.0, preferably in the range of 1.5 : 1.0 to 1.0: 1.5. The pharmaceutical dosage form according to any one of the preceding claims, wherein the salt of tapentadol with phosphoric acid is a mixed salt which contains at least one further cation in addition to the protonated form of tapentadol. The pharmaceutical dosage form claim 6 , wherein the further cation is selected from the group consisting of NH ₄ ⁺ , Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ and Ca ²⁺ . The pharmaceutical dosage form according to any one of the preceding claims, wherein the salt of tapentadol with phosphoric acid is amorphous. The pharmaceutical dosage form according to one of Claims 1 until 7 , where the salt of tapentadol with phosphoric acid is crystalline. The pharmaceutical dosage form according to any one of the preceding claims, wherein the salt of tapentadol is a dihydrogen phosphate, a solvate, an solvate and/or a polymorph thereof. The pharmaceutical dosage form claim 10 wherein the salt of tapentadol is the dihydrogen phosphate which is in the substantially pure crystalline form of tapentadol dihydrogen phosphate hemihydrate. The pharmaceutical dosage form claim 10 wherein the salt of tapentadol is the dihydrogen phosphate which is in the substantially pure crystalline form of tapentadol dihydrogen phosphate anhydrate. The pharmaceutical dosage form claim 10 , where the salt of tapentadol is a crystalline dihydrogen phosphate 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 Claim 13 , wherein the crystalline dihydrogen phosphate is 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). The pharmaceutical dosage form claim 10 , where the salt of tapentadol is a crystalline dihydrogen phosphate 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 claim 15 , wherein the crystalline dihydrogen phosphate 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 according to any one of the preceding claims, which is a capsule containing the coated particles, optionally together with additional pharmaceutical excipients, which are contained in the capsule in powder form or also in the form of particles. The pharmaceutical dosage form according to one of Claims 1 until 16 which is a tablet incorporating the coated particles and which contains an extraparticulate material. The pharmaceutical dosage form Claim 18 , wherein the extraparticulate material contains at least one pharmaceutical excipient selected from binders, disintegrants and lubricants. The pharmaceutical dosage form according to any one of the preceding claims, wherein the dosage form does not contain any forms of tapentadol other than the salt of tapentadol with phosphoric acid. The pharmaceutical dosage form according to any one of the preceding claims, wherein the coated particles - a core comprising substantially all of the salt of tapentadol with phosphoric acid, optionally together with one or more pharmaceutical excipients, and - contain the tapentadol sustained release coating which encapsulates the core. The pharmaceutical dosage form Claim 21 , wherein the salt of tapentadol with phosphoric acid is homogeneously distributed in the core. The pharmaceutical dosage form Claim 21 or 22 wherein the content of the salt of tapentadol with phosphoric acid in the core ranges from 50 to 90% by weight based on the total weight of the core. The pharmaceutical dosage form according to one of Claims 21 until 23 , wherein the core contains one or more binders. The pharmaceutical dosage form Claim 24 wherein the binder or binders are independently selected from the group consisting of cellulose, cellulose derivatives, magnesium aluminum silicates, mono-, oligo- and polysaccharides, sugar alcohols, starches, calcium phosphate, polyvinylpyrrolidone and vinylpyrrolidone-vinyl acetate copolymers; preferably microcrystalline cellulose, silicified microcrystalline cellulose and/or hydroxypropyl cellulose. The pharmaceutical dosage form Claim 24 or 25 , wherein the total content of all binders in the core is in the range from 5.0 to 50% by weight, based on the total weight of the core. The pharmaceutical dosage form according to one of Claims 21 until 26 , wherein the core contains one or more lubricants. The pharmaceutical dosage form Claim 27 wherein the one or more lubricants are independently selected from the group consisting of salts of fatty acids, fatty acids, glyceryl fatty acid esters, sorbitan monostearate, sucrose monopalmitate, sodium stearyl fumarate, hydrated magnesium silicate, and talc; preferably magnesium stearate. The pharmaceutical dosage form Claim 27 or 28 wherein the total content of all lubricants in the core ranges from 0.1 to 5.0% by weight based on the total weight of the core. The pharmaceutical dosage form according to one of Claims 21 until 29 wherein the core comprises extruded and optionally spheronized pellets. The pharmaceutical dosage form according to one of Claims 21 until 29 , wherein the core comprises microtablets. The pharmaceutical dosage form according to one of Claims 21 until 31 , wherein the core comprises microcrystalline cellulose in a content in the range from 5.0 to 25% by weight, based on the total weight of the core, and hydroxypropyl cellulose in a content in the range from 5.0 to 25% by weight, based on the total weight of the core. The pharmaceutical dosage form according to one of Claims 21 until 31 , wherein the core contains silicified microcrystalline cellulose with a content in the range from 5.0 to 50% by weight, based on the total weight of the core, and magnesium stearate with a content in the range from 0.1 to 5.0% by weight, based on the total weight of the core. The pharmaceutical dosage form according to one of Claims 21 until 33 , wherein the pharmaceutical dosage form is obtainable by a process comprising the following steps: (A) providing a mixture containing essentially the entire amount of salt of tapentadol with phosphoric acid to be contained in the dosage form, optionally together with one or several pharmaceutical excipients; (B) producing drug pellets or microtablets from the mixture provided in step (A) by dry granulation, wet granulation, extrusion or direct compression; (C) optionally drying and/or spheronizing the drug pellets or microtablets produced in step (B) to obtain dried and/or spheronized drug pellets or microtablets; (D) providing a solution or dispersion of a coating material for the sustained release of tapentadol, which contains ethyl cellulose, in water or in an organic solvent or a mixture thereof, optionally with one or more pharmaceutical excipients; (E) coating the drug pellets or microtablets produced in step (B) or the dried and/or spheronized drug pellets or microtablets obtained in step (C) with the solution or dispersion of the coating material provided in step (D) to obtain coated particles with sustained release, which contain a core comprising essentially the total amount of salt of tapentadol with phosphoric acid, optionally together with one or more pharmaceutical excipients, and a core encapsulating coating for the sustained release of tapentadol; (F) optionally drying the coated particles obtained in step (E) to obtain dried coated particles; and (G) filling either the coated particles obtained in step (E) or the dried coated particles obtained in step (F) into capsules; or mixing the coated particles obtained in step (E) or the dried coated particles obtained in step (F) with extraparticulate pharmaceutical excipients and compressing the mixture into tablets. The pharmaceutical dosage form according to one of Claims 1 until 20 , wherein the coated particles - an inert core, which does not contain a salt of tapentadol with phosphoric acid, - an active substance layer, which encapsulates the inert core and comprises essentially the entire amount of the salt of tapentadol with phosphoric acid, optionally together with one or more pharmaceutical excipients , and - contain the coating for the delayed release of tapentadol, which encapsulates the core and the active substance layer. The pharmaceutical dosage form Claim 35 , where the inert core is formed by a sugar sphere, microcrystalline cellulose sphere or lactose crystal. The pharmaceutical dosage form Claim 35 or 36 , wherein the salt of tapentadol with phosphoric acid is distributed homogeneously in the active substance layer. The pharmaceutical dosage form according to one of Claims 35 until 37 , wherein the content of the salt of tapentadol with phosphoric acid in the drug layer is in the range from 50 to 90% by weight based on the total weight of the inert core and the drug layer. The pharmaceutical dosage form according to one of Claims 35 until 38 , wherein the active substance layer contains one or more flow regulators. The pharmaceutical dosage form Claim 39 wherein the or more flow control agents are independently selected from the group consisting of silica gel, colloidal silica, precipitated silica, talc, kaolin and glycerol monostearate; preferably colloidal anhydrous silicon dioxide. The pharmaceutical dosage form Claim 39 or 40 , wherein the total content of all flow control agents in the active substance layer is in the range from 0.1 to 5.0% by weight, based on the total weight of the inert core and the active substance layer. The pharmaceutical dosage form according to one of Claims 35 until 41 , wherein the active ingredient layer contains a film former or more film formers. The pharmaceutical dosage form Claim 42 wherein the film former or multiple film formers are independently selected from the group consisting of cellulose ethers and polyvinylpyrrolidone; preferably hydroxypropylmethyl cellulose or ethyl cellulose. The pharmaceutical dosage form Claim 42 or 43 , wherein the total content of all film formers in the active substance layer is in the range from 0.5 to 10% by weight, based on the total weight of the inert core and the active substance layer. The pharmaceutical dosage form according to one of Claims 35 until 44 , wherein the inert core with the active substance layer, which encapsulates the inert core, forms a build-up pellet. The pharmaceutical dosage form according to one of Claims 35 until 45 , wherein the drug layer comprises colloidal anhydrous silicon dioxide in a content ranging from 0.1 to 5.0% by weight based on the total weight of the inert core and the drug layer, and ethyl cellulose in a content ranging from 0.5 to 10% by weight % based on the total weight of the inert core and the active substance layer. The pharmaceutical dosage form according to one of Claims 35 until 45 , wherein the drug layer comprises colloidal anhydrous silicon dioxide with a content in the range from 0.1 to 5.0% by weight, based on the total weight of the inert core and the drug layer, and hydroxypropylmethylcellulose with a content in the range from 0.5 to 10% by weight % based on the total weight of the inert core and the active substance layer. The pharmaceutical dosage form according to one of Claims 35 until 47 wherein the pharmaceutical dosage form is obtainable by a process comprising the following steps: (A) providing inert cores which contain one or more pharmaceutical excipients but no salt of tapentadol with phosphoric acid; (B) providing a composition comprising the salt of tapentadol with phosphoric acid, optionally together with one or more pharmaceutical excipients; (C) Coating the inert cores provided in step (A) with the composition provided in step (B) to obtain intermediate product particles which contain an inert core which does not contain a salt of tapentadol with phosphoric acid and an active substance layer encapsulating the inert core which essentially contains the total amount of the salt of tapentadol with phosphoric acid to be contained in the dosage form, optionally together with the one or more pharmaceutical excipients; (D) optionally drying the intermediate product particles obtained in step (C) to obtain dried intermediate product particles; (E) providing a solution or dispersion of a coating material for the sustained release of tapentadol, which contains ethyl cellulose, in water or in an organic solvent or a mixture thereof, optionally with one or more pharmaceutical excipients; (F) Coating of the intermediate particles obtained in step (C) or those obtained in step (D). dried intermediate product particles with the solution or dispersion of the coating material provided in step (E) to obtain coated particles with sustained release, which do not contain a salt of tapentadol with phosphoric acid-containing inert core, an active substance layer encapsulating the inert core, which essentially contains the entire amount of salt of tapentadol with phosphoric acid, optionally together with the one or more pharmaceutical excipients, and a coating encapsulating the inert core and the active substance layer for the delayed release of tapentadol; (G) optionally drying the coated particles obtained in step (F) to obtain dried coated particles; and (H) filling either the coated particles obtained in step (F) or the dried coated particles obtained in step (G) into capsules; or mixing the coated particles obtained in step (F) or the dried coated particles obtained in step (G) with extraparticulate pharmaceutical excipients and compressing the mixture into tablets. The pharmaceutical dosage form Claim 48 wherein the composition provided in step (B) is a dispersion or solution in water or in an organic solvent or a mixture thereof. The pharmaceutical dosage form Claim 48 or 49 wherein step (C) is carried out by powder coating in a coating pan. The pharmaceutical dosage form Claim 48 or 49 , wherein step (C) takes place by spraying the inert cores in a fluidized bed coater. The pharmaceutical dosage form according to any one of the preceding claims, wherein the coating for the sustained release of tapentadol contains talc in addition to ethylcellulose. The pharmaceutical dosage form Claim 52 wherein the relative weight ratio of ethylcellulose:talc is in the range of 2:1 to 1:20; preferably 2:1 to 1:2, or 1:8 to 1:12. The pharmaceutical dosage form according to any one of the preceding claims, wherein the coating for the delayed release of tapentadol comprises one or more plasticizers in addition to ethyl cellulose. The pharmaceutical dosage form Claim 54 wherein the plasticizer or plasticizers are independently selected from the group consisting of dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin; preferably triethyl citrate. The pharmaceutical dosage form Claim 54 or 55 wherein the total content of all plasticizers in the tapentadol sustained release coating is in the range of 5.0 to 20% by weight based on the total weight of the coating. The pharmaceutical dosage form according to any one of the preceding claims, wherein the content of the coating for the delayed release of tapentadol is in the range from 5.0 to 20% by weight, based on the total weight of the coated particles. The pharmaceutical dosage form according to one of Claims 1 until 56 , wherein the content of the coating for the sustained release of tapentadol is in the range from 15 to 30% by weight, based on the total weight of the coated particles. The pharmaceutical dosage form according to one of Claims 1 until 56 , wherein the content of the coating for the sustained release of tapentadol is in the range from 25 to 40% by weight, based on the total weight of the coated particles. The pharmaceutical dosage form according to one of Claims 1 until 56 , wherein the content of the coating for the sustained release of tapentadol is in the range from 35 to 50% by weight, based on the total weight of the coated particles. The pharmaceutical dosage form according to one of Claims 1 until 56 , wherein the content of the coating for the sustained release of tapentadol is in the range from 45 to 60% by weight, based on the total weight of the coated particles. The pharmaceutical dosage form of any one of the preceding claims which provides an in vitro dissolution profile measured at 50 rpm in 900 ml aqueous phosphate buffer at pH 6.8 at 37°C in 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 has been released. The pharmaceutical dosage form of any one of the preceding claims which provides an in vitro dissolution profile measured at 50 rpm in 900 ml aqueous phosphate buffer at pH 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; and - After 8 hours, 80±20% by weight of the tapentadol originally contained in the dosage form has been released. The pharmaceutical dosage form of any one of the preceding claims which provides an in vitro dissolution profile, measured at 50 rpm in 900 ml of aqueous buffer at pH 4.5 at 37°C, in 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 has been released. The pharmaceutical dosage form of any one of the preceding claims which provides an in vitro dissolution profile, measured at 50 rpm in 900 ml of aqueous buffer at pH 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. The pharmaceutical dosage form of any one of the preceding claims which provides an in vitro dissolution profile measured at 50 rpm in 900 ml of 0.1N HCl at pH 1.0 and 37°C in 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 has been released. The pharmaceutical dosage form of any one of the preceding claims which provides an in vitro dissolution profile measured at 50 rpm in 900 ml of 0.1N HCl at pH 1.0 and 37°C in 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 has been released. The pharmaceutical dosage form of any one of the preceding claims which is for twice daily oral administration.

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