DE202020104285U1 - Ethyl cellulose-coated particles containing a salt of tapentadol and phosphoric acid - Google Patents

Abstract

A pharmaceutical dosage form comprising a plurality of coated particles;
wherein the coated particles contain a salt of tapentadol with phosphoric acid and have a coating for the sustained release of tapentadol which contains ethyl cellulose;
the dosage form releasing tapentadol in a retarded manner; and
the weight-equivalent dose of tapentadol contained in the dosage form being in the range from 10 to 300 mg, based on the free base of tapentadol.

Description

The invention relates to a pharmaceutical dosage form comprising a large number of coated particles; wherein the coated particles contain a salt of tapentadol with phosphoric acid and have a coating for the sustained release of tapentadol which contains ethyl cellulose; the dosage form releasing tapentadol in a retarded manner; and wherein the weight-equivalent dose of tapentadol contained in the dosage form is in the range from 10 to 300 mg, based on the free base of tapentadol.

Tapentadol (Nucynta ^® , Palexia ^® ) is an oral opioid analgesic from the benzenoid class with a dual mechanism of action similar to tramadol; it is a µ-opioid receptor agonist and also inhibits the reuptake of norepinephrine. Tapentadol is currently available as a tablet which contains tapentadol hydrochloride and offers 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 the weight-equivalent dose of tapentadol based on the tapentadol free base), the tablets being intended for twice daily administration.

According to the instructions for use, the commercially available tapentadol tablets Palexia ^® retard contain tapentadol as hydrochloride, with the tablet core also containing hypromellose, microcrystalline cellulose, finely divided silicon dioxide and magnesium stearate. Palexia ^® retard tablets thus contain hypromellose as a matrix with sustained release. The tablet cores are film-coated with a composition comprising hypromellose, lactose monohydrate, talc, macrogol 6000 and coloring agents.

The tablets with sustained release contain tapentadol hydrochloride in a polymer matrix from which the active ingredient is released in a sustained manner (matrix sustained release). The polymer matrix is formed from pharmaceutical excipients, which must be present in a certain minimum amount in order to develop the desired retarding effect. As a consequence of this, the higher-dose tablets in particular have a considerable overall weight and thus also a considerable size, which in some patients means that they have difficulty ingesting them, especially when swallowing them. The type of salt (hydrochloride) also contributes to the weight of the active ingredient and thus to the total weight and size of the tablets. For example, 250 mg of the free base of tapentadol in the form of the hydrochloride has an equivalent weight of approx. 291 mg.

Other physiologically compatible salts of tapentadol have an even higher equivalent weight. 250 mg of the free base of tapentadol, for example in the form of the salt of tapentadol with phosphoric acid in a stoichiometric ratio of 1: 1 (dihydrogen phosphate), has an equivalent weight of approx. 361 mg. If it is desired to provide such salts of tapentadol in formulations with sustained release, the difficulties with regard to patient compliance associated with the considerable total weight and thus also the considerable size are even more pronounced, especially at the higher dose strengths.

There is a need for dosage forms for the oral administration of tapentadol with sustained release which do not contain tapentadol in the form of the hydrochloride, but as salts with other acids, in particular phosphoric acid, without the associated weight gain adversely affecting patient compliance. For regulatory reasons, the dosage forms for the oral administration of tapentadol with sustained release should be bioequivalent to the products already on the market.

It is an object of the invention to provide pharmaceutical dosage forms of tapentadol which offer advantages compared to the pharmaceutical dosage forms from the prior art. The pharmaceutical dosage forms should be safe and easy to manufacture in an economical manner and should offer advantageous patient compliance.

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

SUMMARY OF THE INVENTION

The invention provides a pharmaceutical dosage form comprising a plurality of coated particles; wherein the coated particles contain a salt of tapentadol with phosphoric acid and have a coating for the sustained release of tapentadol which contains ethyl cellulose; the dosage form releasing tapentadol in a retarded manner; and wherein the contained in the dosage form weight equivalent dose of tapentadol is in the range from 10 to 300 mg, based on the free base of tapentadol (M _r = 221.3 g / mol).

It has surprisingly been found that salts of tapentadol with phosphoric acid (H ₃ PO ₄ ) are of particular use for pharmaceutical dosage forms which provide a delayed release of tapentadol. It has surprisingly been found that salts of tapentadol with administration forms containing phosphoric acid provide a slower release of tapentadol in vitro in an ethanol medium than in a non-ethanol medium. It is therefore to be expected that these dosage forms will further prolong the drug release in vivo when taken at the same time as 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 found, surprisingly, that compared to tapentadol hydrochloride, which is contained in the pharmaceutical dosage forms of tapentadol with delayed release currently on the market, such salts of tapentadol with phosphoric acid have a lower thermodynamic solubility and a slower intrinsic dissolution rate. Because of these dissolution properties of the phosphate salts of tapentadol, they are particularly suitable for the production of dosage forms with sustained release.

Furthermore, it has surprisingly been found that the salt of tapentadol with phosphoric acid can be formulated in multiparticulate dosage forms which control the retardation not by a matrix of pharmaceutical excipients but by a coating (coating retardation). Since the release kinetics can be controlled by the amount, in particular the layer thickness of the coating, differently coated particles can be produced in a comparatively simple manner, which particles differ from one another with regard to 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. Bioequivalence can, however, also be achieved using essentially identical coated particles, provided that the type and amount of the coating are correctly selected.

In addition, it was surprisingly 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 in taking dosage forms, especially with the higher dose strengths, can take the coated particles contained in the dosage form individually and separately, without the delayed release of active ingredient being impaired as a result. For example, hard gelatine capsules which contain 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 have a much lower weight and thus also a much smaller size than the dosage form as such, the ingestion of the individual coated particles presents hardly any difficulties. In this way, tapentadol can even be administered orally to patients who have injuries to 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 .

Figure list

• 1 shows the XRPD spectrum of tapentadol dihydrogen phosphate (mixed form) obtained according to Example 1.1.
• 2 shows the XRPD spectrum of tapentadol dihydrogen phosphate hemihydrate obtained according to Example 1.4.
• 3 shows the DSC curve of tapentadol dihydrogen phosphate hemihydrate obtained according to Example 1.4.
• 4th shows the XRPD spectrum of tapentadol dihydrogen phosphate anhydrate obtained according to Example 1.6.
• 5 shows the DSC curve of tapentadol dihydrogen phosphate anhydrate obtained according to Example 1.6.
• 6 shows three photographs of different particle sizes of the salt of tapentadol with phosphoric acid ( 6A shows relatively fine particles, 6B relatively coarse particles) and the salt of tapentadol with hydrochloric acid, 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; wherein the coated particles contain a salt of tapentadol with phosphoric acid and have a coating for the sustained release of tapentadol which contains ethyl cellulose; the dosage form releasing tapentadol in a retarded manner; and wherein the weight-equivalent dose of tapentadol contained in the dosage form is in the range from 10 to 300 mg, based on the free base of tapentadol.

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. essentially have the same structure and contain the same ingredients in essentially the same amounts. The coated particles accordingly preferably have essentially the same weight, the same size and the same composition.

For the purpose of the description, “essentially” preferably means that the mean quantitative deviation is not more than 5%, preferably not 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 the content of the salt of tapentadol with phosphoric acid, the type of pharmaceutical excipient, the content of a pharmaceutical excipient, and the content of the coating for the sustained 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.

Certain release profiles can thus be set if particles coated according to the invention with sustained release of tapentadol are mixed with

• - other coated particles with sustained 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 is in the range 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 (for example sugar globules), an active substance layer which encapsulates the inert core and essentially comprises the entire amount 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 ingredient layer for the sustained release of tapentadol.

In preferred embodiments, the pharmaceutical dosage form according to the invention is a capsule (e.g. hard gelatin capsule, HPMC capsule, etc.), a bag, a stick pack, etc., in which the coated particles are each contained, optionally together with additional pharmaceutical excipients which are contained 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 which contain 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 extra-particulate material. The particles with a retarding coating then preferably form an immediately disintegrating matrix with the pharmaceutical excipients of the extra-particulate material, which matrix is compressed to form MUPS tablets (Multiple Unit Pellet Systems). The extra-particulate 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 which is used in the treatment of moderate to severe acute or chronic pain works. The synthesis of the free base of tapentadol is eg 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 according to the invention may contain mixtures of different salts of tapentadol or mixtures of salt (s) of the free base of tapentadol (e.g. the non-salt form of tapentadol), but the total amount of tapentadol contained in the pharmaceutical dosage form is preferably 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.

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

In preferred embodiments, the salt of tapentadol with phosphoric acid is a mixed salt which, in addition to the protonated form of tapentadol, contains at least one further cation, the further 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 'can 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 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 a further preferred embodiment, the molar ratio of tapentadol and M (H ₂ PO ₄ ) ₂ or M '(H 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.

The salt of tapentadol with phosphoric acid is preferably the dihydrogen phosphate of tapentadol, which can optionally be solvated (eg hydrated) or solvated (eg anhydrated). The dihydrogen phosphate of tapentadol is preferably selected from the group consisting of the solvated dihydrogen phosphate of tapentadol, the anhydrated Tapentadol dihydrogen phosphate, tapentadol solvated dihydrogen phosphate, tapentadol hydrated dihydrogen phosphate, and any mixtures thereof.

The salt of tapentadol with phosphoric acid can be in the form of a single polymorphic form or as a mixture of different polymorphic forms in any mixing ratio.

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

According to a preferred embodiment, the salt of tapentadol with phosphoric acid is the dihydrogen phosphate that is present in an 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 can be characterized by the following X-ray powder diffraction peaks at degrees 2Θ ± 0.2 degrees 2Θ (intensity%): 5.1 (100), 8.7 (10), 10.1 (1), 12.5 (3), 13.4 (4), 14.4 (37), 15.3 (4), 17.6 (12), 17.7 (15), 18.3 (27), 19.1 ( 7), 20.3 (11), 21.0 (25), 21.6 (9), 22.1 (18), 23.4 (14), 24.8 (7), 25.0 (17th ), 25.3 (12), 26.0 (9), 26.5 (7), 26.8 (9), 28.0 (5), 28.4 (4), 28.9 (10) , 29.2 (6), 29.4 (4) and 29.6 (2). Alternatively, the crystalline dihydrogen phosphate can be characterized by the following X-ray powder diffraction peaks at degrees 2Θ ± 0.2 degrees 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 can be characterized by the following X-ray powder diffraction peaks at degrees 2Θ ± 0.2 degrees 2Θ (intensity%): 5.1 (100), 8.9 (3), 12.4 (5), 13.5 (4), 14.3 (42), 15.2 (4), 17.6 (21), 18.5 (18), 19.1 (7), 20.5 (14), 21.1 ( 28), 21.7 (9), 22.4 (14), 23.5 (15), 24.3 (6), 24.9 (19), 25.1 (16), 25.8 (3rd ), 26.2 (12), 26.4 (13), 26.7 (5), 27.3 (2), 28.2 (5), 28.8 (8), 29.1 (11) , 29.4 (5) and 29.6 (5). Alternatively, the crystalline dihydrogen phosphate can be characterized by the following X-ray powder diffraction peaks at degrees 2Θ ± 0.2 degrees 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 carried out with Cu K _α radiation at room temperature. A suitable device is, for example, D8 ADVANCE Eco, Bruker. DSC measurements are carried out according to ASTM D3418.

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

According to a preferred embodiment, the salt of tapentadol with phosphoric acid is in crystalline form.

According to another preferred embodiment, the salt of tapentadol with phosphoric acid is in amorphous form. For example, the salt of tapentadol with phosphoric acid together with suitable binders (e.g. hydroxypropylmethylcellulose or polyvinylpyrrolidone) can be dissolved in suitable solvents and applied to an inert core (build-up pellets). A suitable type and amount of binder can ensure that the salt of tapentadol with phosphoric acid does not crystallize when the solvent evaporates, but is deposited in amorphous form together with the binder (solid solution) as an active ingredient layer on the inert core.

It is further contemplated that the pharmaceutical dosage form can contain mixtures of crystalline salt of tapentadol with phosphoric acid with amorphous salt of tapentadol with phosphoric acid in any mixing ratio. Preferably, essentially the entire amount of the salt of tapentadol with phosphoric acid present in the pharmaceutical dosage form is crystalline.

For the purposes of the description, the dihydrogen phosphate of tapentadol is to be regarded as the acid addition salt of 1 mol of orthophosphoric acid with 1 mol of tapentadol. It is believed that one proton of orthophosphoric acid (H ₃ PO ₄ ) protonates the amino group of tapentadol and thus forms an ammonium ion, while the remainder of the orthophosphoric acid, i.e. the dihydrogen phosphate anion (H ₂ PO ₄ ^- ), forms the counterion:

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

The salt of tapentadol with phosphoric acid, preferably the dihydrogen phosphate of tapentadol, can 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 referenced.

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

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

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

Unless expressly stated otherwise, all percentages are percentages by weight and relate to the total weight of the pharmaceutical dosage form.

It is envisaged that the pharmaceutical dosage form according to the invention can contain additional pharmacological active ingredients in addition to tapentadol; however, tapentadol is preferably the only pharmacological 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 units that modify the response of opioid receptors. Opioid antagonists include naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, nalinefen, cyclazacin, levallorphan, pharmaceutically acceptable salts thereof, and mixtures thereof.

In addition, it is considered that the dosage form according to the invention contains, in addition to the salt of tapentadol with phosphoric acid, also other forms of tapentadol, for example the free base of tapentadol or additional salts of tapentadol, for example tapentadol hydrochloride; however, the salt of tapentadol with phosphoric acid is preferably the only form of tapentadol contained in the pharmaceutical dosage form.

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

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

The delayed release is based on a coating with which the multiplicity of particles is coated and which comprises 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, particularly preferably at least 10 hours, most preferably at least 12 hours.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The pharmaceutical dosage form according to the invention preferably provides a slower dissolution of tapentadol in 0.1 N HCl with 40% by volume of ethanol (pH 1.0) than in 0.1 N HCl without 40% by volume of ethanol (pH 1.0) , each measured according to 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, 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 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 auxiliaries.

Pharmaceutical auxiliaries are known to the person 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 that is 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 no pharmacological effect like a drug. Typical examples of pharmaceutical excipients include anti-stick agents, binders, film formers (coating materials), disintegrating agents, fillers, diluents, flavoring agents, coloring agents, flow regulating agents (lubricants), lubricants, preservatives, sorbents, surfactants, sweeteners, coloring agents, 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 solvent binders and dry binders. Several pharmaceutical excipients show different properties at the same time, so that 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 (e.g. cellulose ethers), magnesium aluminum silicates (e.g. bentonite), mono-, oligo- and polysaccharides (e.g. dextrose, lactose, mannose), sugar alcohols (e.g. lactitol, mannitol), starches ( e.g. pregelatinized starch, hydrolyzed starch, modified starch), calcium phosphate, polyvinylpyrrolidone and vinylpyrrolidone-vinyl acetate copolymers; preferably microcrystalline cellulose, silicified microcrystalline cellulose and / or hydroxypropyl cellulose.

Cellulose derivatives preferred according to the invention 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 their salts.

Lubricants preferred according to the invention are selected from the group consisting of salts of fatty acids (for example magnesium stearate, calcium stearate, zinc stearate), fatty acids (for example stearic acid, palmitic acid), glyceryl fatty acid esters (for example glyceryl monostearate, glyceryl monobehenate, glyceryl dibehenate, glyceryl dibehenate, glyceryl dibehenate, glyceryl tribehenate, sodium stearate monoumarate, sodium stearyl tribehenate, sodium stearyl stearate, sorbitanate and talc; preferably magnesium stearate.

Flow regulators 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.

1. (i) Pellets, welche durch Extrusion und gegebenenfalls anschließende Sphäronisierung;
2. (ii) Mikrotabletten, welche durch Verpressen von Pulvermischungen oder Granulaten
3. (iii) Pellets, welche durch Pulverbeschichtung inerter Kügelchen (Zucker / Maisstärke) (sog. „Non-Pareilles“ oder „Nu-Pareilles“) in Beschichtungspfannen;
4. (iv) Pellets, welche durch Beschichten inerter Kügelchen (Zucker / Maisstärke) (sog. „Non-Pareilles“ oder „Nu-Pareilles“) mit Lösungen oder Suspensionen;
5. (v) Pellets, welche durch Beschichten von Cellulosekügelchen (sog. „Cellets“); oder
6. (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 those coated with the coating for the sustained release of tapentadol

1. (i) Pellets which are produced by extrusion and, if appropriate, subsequent spheronization;
2. (ii) Micro-tablets, which are produced by pressing powder mixtures or granules
3. (iii) Pellets, which are powder coated with inert spheres (sugar / corn starch) (so-called “Non-Pareilles” or “Nu-Pareilles”) in coating pans;
4. (iv) Pellets obtained by coating inert spheres (sugar / corn starch) (so-called "Non-Pareilles" or "Nu-Pareilles") with solutions or suspensions;
5. (v) Pellets, which are produced by coating cellulose spheres (so-called “cellets”); or
6. (vi) pellets made by coating coarse lactose crystals;

were obtained.

Embodiments (i) and (ii) have in common that the core of the coated particles contains the salt of tapentadol with phosphoric acid, preferably in a homogeneous distribution, whereas embodiments (iii), (iv), (v) and (vi) have in common that the core is inert and encapsulated by an active ingredient layer that contains the salt of tapentadol with phosphoric acid (build-up 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 which essentially comprises the total amount of the salt of tapentadol with phosphoric acid, optionally together with one or more pharmaceutical excipients, and
• - The coating for the delayed release 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 binder or several binders, which are preferably selected independently of one another 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.

The core preferably contains one lubricant or more lubricants, which are preferably selected independently of one another 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 (cf. embodiment (ii)).

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

In other preferred embodiments, 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.

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 is obtainable by a method which comprises the following steps:

1. (A) providing a mixture containing essentially the entire amount of salt of tapentadol with phosphoric acid which is to be contained in the dosage form, optionally together with one or more pharmaceutical excipients;
2. (B) producing drug pellets or micro-tablets 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 delayed release, which contain a core comprising essentially 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 delayed release of tapentadol;
6. (F) if appropriate, 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 extra-particulate pharmaceutical auxiliaries and compressing the mixture to form 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 that does not contain a salt of tapentadol with phosphoric acid,
• an active substance layer which encapsulates the inert core and essentially comprises the entire amount of the salt of tapentadol with phosphoric acid, optionally together with one or more pharmaceutical excipients, and
• - The coating for the delayed release of tapentadol, which encapsulates the core and the active ingredient layer.

The inert core is preferably formed by a globule of sugar and / or corn starch (cf. embodiments (iii) and (iv)), globules of microcrystalline cellulose (see embodiment (v)) or lactose crystal (see 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 ingredient layer is preferably in the range from 50 to 90% by weight, based on the total weight of the inert core and the active ingredient layer.

The active ingredient layer preferably contains a flow regulating agent or several flow regulating agents, which are preferably selected independently of one another 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 active substance layer preferably contains a film-forming agent or several film-forming agents, 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 ingredient 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 ingredient layer.

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

In preferred embodiments, the active ingredient layer contains 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 active ingredient layer, and also ethyl cellulose 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 ingredient layer.

In other preferred embodiments, the active ingredient layer contains 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 active ingredient layer, as well as hydroxypropylmethylcellulose with a content in the range 0.5 up to 10% by weight, based on the total weight of the inert core and the active ingredient 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 is obtainable 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 is to be contained in the dosage form, optionally together with the one or more pharmaceutical excipients;
4. (D) if appropriate, drying the intermediate product particles obtained in step (C) to obtain dried intermediate product particles;
5. (E) providing a solution or dispersion of a 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 particles with sustained release which do not contain a salt of tapentadol with an inert core containing phosphoric acid, an active ingredient 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 ingredient layer for retarded purposes Release of tapentadol included;
7. (G) if appropriate, drying the coated particles obtained in step (F) to obtain dried coated particles; and
8. (H) either filling 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 extra-particulate pharmaceutical excipients and compressing the mixture to form tablets.

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

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

In other preferred embodiments, step (C) takes place by spraying the inert cores in a fluidized bed coater (cf. embodiment (iv), if appropriate also (v) and (vi)).

The coated particles which are 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 ethoxyl 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).

In addition to ethyl cellulose, the coating for the sustained release of tapentadol preferably comprises a plasticizer 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 mPas (e.g. Ethocel ^® 4 Premium),
• - in the range from 6 to 8 mPas (e.g. Ethocel ^® 7 Premium),
• - in the range from 9 to 11 mPas (e.g. Ethocel ^® 10 Premium),
• - in the range from 18 to 22 mPas (e.g. Ethocel ^® 20 Premium),
• - in the range from 41 to 49 mPa · s (eg Ethocel ^® 45 Premium), or
• - in the range from 90 to 110 mPa · s (eg 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 content of the sustained release coating for tapentadol is in the range of

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

each 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; H. set to a desired rate. The release modifying agents that act as pore formers can be organic or inorganic and include materials that 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, among other factors, by the required release rate and the solubility characteristics of the materials chosen. The pore formers can comprise one or more hydrophilic polymers such as hydroxypropylmethyl cellulose. The sustained release coatings can also include anti-erosion agents such as starches and gums. The sustained release coatings can also include materials suitable for the formation of microporous lamina in the environment of use, such as straight chain carbonated polyester polycarbonates in which the carbonate groups reappear in the polymer chain.

For the sustained release of tapentadol, the coating preferably contains, in addition to ethyl cellulose, talc, preferably in considerable amounts. The relative weight ratio of ethyl cellulose: talc is preferably in the range from 2: 1 to 1:20; preferably 2: 1 to 1: 2, or 1: 8 to 1:12.

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

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

The plasticized aqueous dispersion or organic dispersion or organic solution can be applied to the substrate comprising the salt of tapentadol with phosphoric acid by spraying using any suitable spray device known in the art. In a preferred method, a Wurster fluidized bed system is used in which an air jet introduced from below fluidizes the core material and causes drying when the coating is sprayed on. Preferably, a sufficient amount of the aqueous dispersion or organic dispersion or organic solution is applied to obtain a predetermined sustained release of tapentadol upon exposure of the coated substrate to aqueous solutions, e.g. gastric juice, taking into account the manner in which the plasticizer was 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. This conversion is only provided, if at all, in order to substantially reduce the 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 production of a pharmaceutical dosage form according to the invention as described above for the treatment of pain, the dosage form being administered orally, preferably twice daily.

The pain is preferably chronic pain.

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

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

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

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

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

According to preferred embodiments of the pharmaceutical dosage form according to the invention, the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 100 mg, based on the free base of tapentadol, the dosage form after oral administration in a patient population of at least 50 patients an average of

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

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

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

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

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

According to preferred embodiments of the pharmaceutical dosage form according to the invention, the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 200 mg, based on the free base of tapentadol, the dosage form after oral administration in a patient population of at least 50 patients an average of

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

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

According to preferred embodiments of the pharmaceutical dosage form according to the invention, the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 250 mg, based on the free base of tapentadol, the dosage form after oral administration in a patient population of at least 50 patients an average of

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

EXAMPLES

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

Example 1 - Preparation of tapentadol dihydrogen phosphate salt:

Three different batches of tapentadol dihydrogen phosphate were produced, one batch of essentially pure tapentadol dihydrogen phosphate hemihydrate, one batch of essentially pure tapentadol dihydrogen phosphate anhydrate and a batch comprising the two polymorphic forms (= mixed form).

Example 1.1 - Tapentadol dihydrogen phosphate, mixed form:

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

Example 1.2 - Tapentadol dihydrogen phosphate, mixed form:

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

Example 1.3 - Tapentadol dihydrogen phosphate, mixed form:

Tapentadol base (7.5 g) was dissolved in a mixture of tetrahydrofuran (80 g, 90 ml) and water (10 mg, 10 μl) at 20 ° C. to 25 ° C. The mixture was heated to 55 ° C to give a clear solution. Then crystalline tapentadol dihydrogen phosphate (10 mg) and phosphoric acid (3.9 g, 2.3 ml, 85% by weight) were added. A white suspension immediately formed. After 45 minutes of mixing at 60 ° C, the suspension was cooled to 5 ° C over 45 minutes. After mixing for a further 45 minutes at 5 ° C., the solid obtained was isolated by vacuum filtration and dried (20 ° C. to 25 ° C., vacuum, 2 h). The obtained product (9.6 g, white crystalline powder) was analyzed by X-ray powder diffraction. In the case of the TGA, a weight loss of 1.9% was found on heating to 120 ° C.

Example 1.4 - Tapentadol dihydrogen phosphate hemihydrate:

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

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

Tapentadol base (60 g) was dissolved in a mixture of tetrahydrofuran (1.5 kg, 1.641) and water (82 g, 82 ml) at 20 ° C to 25 ° C. Phosphoric acid (31.25 g, 18.5 ml, 85 wt%) and crystalline tapentadol dihydrogen phosphate (5 mg) were added. During the addition the solution became a white suspension. The suspension obtained was cooled to 10 ° C. over 30 minutes. The mixture was heated to 35 ° C. and mixed for 30 minutes, followed by cooling to 5 ° C. over 30 minutes, and the suspension was mixed at 5 ° C. for 45 minutes. The solid obtained was isolated by vacuum filtration and dried (20 ° C. to 25 ° C., vacuum, 2 h). The product obtained (84.6 g, white crystalline solid) was analyzed by powder X-ray diffraction. In the TGA, a weight loss of 4.5% was found on heating to 113 ° C.

Example 1.6 - Tapentadol dihydrogen phosphate anhydrate:

Tapentadol base (150 mg) was suspended in 1-butanol (1.2 g, 1.5 ml) at 20 ° C to 25 ° C. The suspension was heated to 50 ° C., whereby a clear solution was obtained. Phosphoric acid (78.1 mg, 46.3 µl, 85% by weight) and crystalline tapentadol dihydrogen phosphate (5 mg) were added at 50 ° C. During the addition the clear solution became a white suspension. The suspension obtained was heated to 115 ° C. To keep the suspension miscible, 1-butanol (400 mg, 0.5 ml) was added and mixing was continued for 45 minutes at 115 ° C. The mixture was then cooled to 30 ° C. over 3 hours. The solid obtained was isolated by vacuum filtration and dried (20 ° C to 25 ° C, vacuum, 30 min). The product obtained (157 mg, white crystalline powder) was determined by powder X-ray diffraction ( 4th ) and DSC ( 5 ) analyzed. The DSC peak had a normalized integral of 72.1 J · g ^-1 , with an initial temperature of 146.5 ° C and a peak temperature of 149.1 ° C. At about 200 ° C it decomposed. In the case of the TGA, a weight loss of 0.9% was found on heating to 134 ° C.

Example 1.7 - Tapentadol dihydrogen phosphate anhydrate:

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

6 shows three photographs of various salts of tapentadol which were used to make tablets. 6A shows relatively fine particles of the mixed form of tapentadol dihydrogen phosphate (average particle size when visually inspected about 10-20 µm). 6B shows relatively coarse particles of the pure hemihydrate of tapentadol dihydrogen phosphate according to Example 1.5 (needle-like crystals, average particle size on visual inspection about 100-200 μm). 6C shows relatively coarse particles of tapentadol hydrochloride (average particle size on visual inspection about 100-150 µm).

Example 2 - intrinsic dissolution (dissolution rate):

100 mg tapentadol, either in the form of the hydrochloride salt or the dihydrogen phosphate salt (mixed form [batch with fine particles], pure hemihydrate or pure anhydrate) were pressed with a compression force of 200 kg (gravitational) with a surface area of 0.5 cm ^{2 for} 1 minute . The compressed samples obtained in this way were examined for their rate of dissolution in a Wood apparatus at 37 ° C. in 900 ml of dissolution medium at various pH values and a paddle rotation speed of 50 rpm.

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

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

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

From the comparative experimental data in the table above it can be seen that the slower rate of dissolution of tapentadol dihydrogen phosphate compared to tapentadol hydrochloride is independent of the polymorphic form of tapentadol dihydrogen phosphate.

Example 3 - Thermodynamic Solubility:

The thermodynamic solubility of tapentadol hydrochloride and tapentadol dihydrogen phosphate (mixed form, batch with fine particles) was determined as the saturation solubility in different media at different pH values. The solutions were stirred for 24 hours at 25 ° C. and the pH values of the solutions at the beginning and at the end of the experiments were measured. The dissolved amount of tapentadol was quantified by HPLC (tapentadol free base). The experimental results are summarized in the table below: Tapentadol hydrochloride (comparison) Tapentadol dihydrogen phosphate (mixed form) (according to the invention) pH Assay expressed as base pH Assay expressed as base begin The End g / 100 ml begin The End g / 100 ml 0.1 M HCl 1.11 0.83 31.2 1.11 2.55 24.3 Acetate pH 4.5 4.54 4.29 32.7 4.54 2.81 21.2 water nb 4.63 33.0 nb 2.75 21.4 Citrate pH 6.8 6.83 6.17 31.8 6.83 3.15 19.3 SIF sp pH 6.8 6.82 6.23 32.4 6.82 2.81 20.2 Citrate pH 7.4 7.39 6.33 31.9 7.39 3.16 19.0 0.15N NaOH 13.08 8.21 6.6 13.08 8.09 6.5 nb = not determined

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

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 Retardant coating Ethyl cellulose 20 mPas (Ethocel ^® 20, Dupont) 5-50 278 10.0 Talk 50-95 2780 100.0

Extrusion spheronization of pellet cores:

Tapentadol salt 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 moist mass is extruded through a 1 × 2 mm nozzle plate using a NICA E140 extruder and rounded in portions of about 3 kg on a NICA S450 spheronizer for about 10 minutes at 900 rpm. The rounded pellets are dried in a fluidized bed dryer and then divided into a range from 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 l of ethanol (96%) with stirring. After the ethyl cellulose has dissolved, the talc is dispersed in the solution with stirring. The classified pellets are filled into a fluidized bed coater equipped with a Wurster column and sprayed from below with the coating suspension until an increase in the pellet weight of about 61% is reached.

In order to achieve different doses of the tapentadol base, the retardant coated pellets are filled in hard gelatine capsules of suitable size or in bags with the following quantities: Equivalent dose of tapentadol free base Weight of the retarded 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, pellets with a retarding coating can be mixed with auxiliaries which form an instantly disintegrating matrix and compressed to form MUPS tablets (Multiple Unit Pellet Systems).

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 globules 0.5-0.6 mm in diameter (sucrose, corn starch) 1000 35.8 Colloidal anhydrous silicon dioxide (Aerosil ^® 200) 20th 0.7 Ethyl cellulose 20 mPas part 1 (Ethocel ^® 20, Dupont) 230 8.3 retarding coating Ethyl cellulose 20 mPas part 2 (Ethocel ^® 20, Dupont) 420 15.0 Talk 4200 150.0

Powder coating of pellets:

Tapentadol salt with phosphoric acid and colloidal anhydrous silicon dioxide are mixed in a Bohle container mixer (20 liter container) for 10 minutes. Ethyl cellulose part 1 is dissolved in approximately 1200 ml of ethanol (96% v / v). The sugar globules are placed in a coating pan, rotated and warm air is passed through the coating pan. The ethyl cellulose solution is added to the sugar globules in portions. After each wetting of the spheres, the tapentadol-silica mixture is added in portions and partially dried. This process is repeated until all of the ethyl cellulose solution and all of the tapentadol powder have been added to the balls and the balls have 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 of 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 rotate in a coating pan at a spray speed that results in a moist surface. In order to prevent the moist pellets from sticking to one another, talc is continuously dosed onto the pellets. The spray rate and talc addition rate are synchronized with one another. The process is continued until an increase in pellet weight of about 92% is achieved.

Retardant coated pellets can be filled into hard gelatine capsules, HPMC capsules, bags, stick packs etc. Alternatively, pellets with a retarding coating can be mixed with auxiliaries which form an immediately disintegrating matrix and compressed to form MUPS tablets (Multiple Unit Pellet Systems).

Example 4-3: Coating on sugar spheres in a fluidized bed coater, retarded 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 in diameter (sucrose, corn starch) 1000 72.0 Hypromellose 3 mPas (Pharmacoat 603, Shin Etsu) 100 7.2 Colloidal anhydrous silicon dioxide 50 3.6 retarding coating Ethyl cellulose dispersion 30% (Aquacoat ECD 30, Dupont), weight as dry substance 1667 (30% dispersion = 500 g dry matter) 30.8 (dry matter) Triethyl citrate 150 9.2 Talk 450 27.7

Layer structure of pellets:

5 l of water are heated to 60 ° C., hypromellose is added with stirring and, after dispersing, 10 l of water at room temperature are added. Tapentadol salt with phosphoric acid and colloidal anhydrous silicon dioxide are mixed in a Bohle container mixer (20 liter container) for 10 minutes and then added to the hypromellose solution with stirring. The sugar globules are placed in a fluidized bed coater equipped with a Wurster column and the tapentadol dispersion is 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 over a few hours with gentle stirring. 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 fluidized bed coater equipped with a Wurster column. The process is continued until an increase in pellet weight of about 30% is achieved.

Retardant coated pellets can be filled into hard gelatine capsules, HPMC capsules, bags, stick packs etc. Alternatively, pellets with a retarding coating can be mixed with auxiliaries which form an instantly disintegrating matrix and compressed to form MUPS tablets (Multiple Unit Pellet Systems).

Example 4-4: Coating on cellulose spheres in a fluidized bed coater, retarded 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, Harke) 1000 72.0 Hypromellose 3 mPas (Pharmacoat 603, Shin Etsu) 100 7.2 Colloidal anhydrous silicon dioxide 50 3.6 retarding coating Ethyl cellulose 20 mPas (Ethocel ^® 20, Dupont) 175 12.6 Talk 1750 125.8

Layer structure of pellets:

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

Retarding coating based on ethyl cellulose:

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

Retardant coated pellets can be filled into hard gelatine capsules, HPMC capsules, bags, stick packs etc. Alternatively, pellets with a retarding coating can be mixed with auxiliaries which form an immediately disintegrating matrix and compressed to form MUPS tablets (Multiple Unit Pellet Systems).

Example 4-5: Coating on lactose crystals in a fluidized bed coater, retarded 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 mPas (Pharmacoat 603, Shin Etsu) 300 14.4 Colloidal anhydrous silicon dioxide 75 3.6 retarding coating Ethyl cellulose 20 mPas (Ethocel ^® 20, Dupont) 250 12.0 Talk 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. Tapentadol salt with phosphoric acid and colloidal anhydrous silicon dioxide are mixed in a Bohle container mixer (20 liter container) 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 approx. 20% (300 g ethyl cellulose, 3000 g talc). Ethyl cellulose is dissolved in about 40 l of ethanol (96%) with stirring. After the ethyl cellulose has dissolved, the talc is dispersed in the solution with stirring. The classified pellets are filled into a fluidized bed coater equipped with a Wurster column and sprayed with the coating suspension from below until an increase in the pellet weight of about 63% is reached.

Retardant coated pellets can be filled into hard gelatine capsules, HPMC capsules, bags, stick packs etc. Alternatively, pellets with a retarding coating can be mixed with auxiliaries which form an immediately disintegrating matrix and compressed to form MUPS tablets (Multiple Unit Pellet Systems).

Example 4-6: Micro-tablets, retarded coating

Ingredients Salt of tapentadol with phosphoric acid per batch [g] per micro-tablet [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 mPas (Ethocel ^® 20, Dupont) 70 0.11 2.80 Talk 700 1.12 28.00

Production of micro tablets:

Tapentadol salt with phosphoric acid and silicified microcrystalline cellulose are mixed in a Bohle container mixer (20-1 container) for 30 minutes and then magnesium stearate is added and mixed for an additional 5 minutes. The mixture is compressed on a tablet machine equipped with punches and dies for micro-tablets with a diameter of 2 mm to form micro-tablets with a weight of 8 mg.

Retarding coating based on ethyl cellulose:

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

In order to achieve different doses of the tapentadol base, the retarded coated pellets are filled into bags with the following number of retarded coated micro-tablets: Equivalent dose of tapentadol free base Number of micro-tablets with a retarded coating 50 mg 10 100 mg 20th 150 mg 30th 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 THE DESCRIPTION

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

Patent literature cited

• WO 2010/096045 [0014]
• WO 2012/010316 A1 [0014, 0047]
• WO 2012/051246 A1 [0014]
• WO 2017/182438 A1 [0014, 0047]
• WO 03/035053 A1 [0015]
• WO 2006/002886 A1 [0015]
• WO 2009/092601 A1 [0015]
• EP 693475 A [0028]
• WO 2017182438 A1 [0033]

Non-patent literature cited

• ISO 13320: 2020 [0041]

Claims (68)

A pharmaceutical dosage form comprising a plurality of coated particles; wherein the coated particles contain a salt of tapentadol with phosphoric acid and have a coating for the sustained release of tapentadol which contains ethyl cellulose; the dosage form releasing tapentadol in a retarded manner; and the weight-equivalent dose of tapentadol contained in the dosage form being in the range from 10 to 300 mg, based on the free base of tapentadol. The pharmaceutical dosage form according to Claim 1 , the dosage form only comprising those coated particles which are essentially of the same nature. The pharmaceutical dosage form according to 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 according to Claim 3 , the at least one property being selected from the group consisting of the content of the salt of tapentadol with phosphoric acid, the type of pharmaceutical excipient, the content of a pharmaceutical excipient, and the content of the coating for the delayed 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 from 2.0: 1.0 to 1.0: 2.0, preferably in the range from 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, in addition to the protonated form of tapentadol, contains at least one further cation. The pharmaceutical dosage form according to Claim 6 , the further cation being 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 the Claims 1 to 7th , the salt of tapentadol with phosphoric acid being 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 ansolvate and / or a polymorphic form thereof. The pharmaceutical dosage form according to 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 according to 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 according to Claim 10 , wherein 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 according to 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 according to Claim 10 , wherein 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 according to 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 one of the preceding claims, which is a capsule in which the coated particles are contained, 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 the Claims 1 to 16 , which is a tablet that contains the coated particles and that contains an extra-particulate material. The pharmaceutical dosage form according to Claim 18 wherein the extra-particulate material contains at least one pharmaceutical excipient selected from binders, disintegrants and lubricants. The pharmaceutical dosage form according to one of the preceding claims, wherein the dosage form contains no other forms of tapentadol besides 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 which essentially comprises the total amount of the salt of tapentadol with phosphoric acid, optionally together with one or more pharmaceutical excipients, and - contain the coating for the sustained release of tapentadol, which encapsulates the core. The pharmaceutical dosage form according to Claim 21 , the salt of tapentadol with phosphoric acid being distributed homogeneously in the core. The pharmaceutical dosage form according to Claim 21 or 22nd , the content of the salt of tapentadol with phosphoric acid in the core being in the range from 50 to 90% by weight, based on the total weight of the core. The pharmaceutical dosage form according to one of the Claims 21 to 23 wherein the core contains one or more binders. The pharmaceutical dosage form according to Claim 24 , wherein the binder or the plurality of binders are selected independently of one another 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 according to Claim 24 or 25th , the total content of all binders in the core being 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 the Claims 21 to 26th wherein the core contains one or more lubricants. The pharmaceutical dosage form according to Claim 27 wherein the lubricant or 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 according to Claim 27 or 28 wherein the total content of all lubricants in the core is in the range of 0.1 to 5.0% by weight based on the total weight of the core. The pharmaceutical dosage form according to one of the Claims 21 to 29 wherein the core comprises extruded and optionally spheronized pellets. The pharmaceutical dosage form according to one of the Claims 21 to 29 wherein the core comprises microtablets. The pharmaceutical dosage form according to one of the Claims 21 to 31 , the core being microcrystalline cellulose with a content in the range from 5.0 to 25% by weight, based on the total weight of the core, and hydroxypropyl cellulose with 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 the Claims 21 to 31 , wherein the core silicified microcrystalline cellulose with a content in the range from 5.0 to 50 wt .-%, based on the total weight of the core, and magnesium stearate with a content in the range from 0.1 to 5.0 wt .-%, based on the total weight of the core. The pharmaceutical dosage form according to one of the Claims 21 to 33 , wherein the pharmaceutical dosage form is obtainable by a method which comprises the following steps: (A) providing a mixture containing essentially the entire amount of salt of tapentadol with phosphoric acid which is to be contained in the dosage form, optionally together with one or several pharmaceutical excipients; (B) producing drug pellets or micro-tablets 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 delayed release, which contain a core comprising essentially 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 delayed release of tapentadol; (F) if appropriate, drying the coated particles obtained in step (E) to obtain dried coated particles; and (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 extra-particulate pharmaceutical excipients and compressing the mixture to form tablets. The pharmaceutical dosage form according to one of the Claims 1 to 20th The coated particles - an inert core which does not contain a salt of tapentadol with phosphoric acid, - an active ingredient layer which encapsulates the inert core and essentially comprises the entire amount 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 ingredient layer. The pharmaceutical dosage form according to Claim 35 wherein the inert core is formed by a sugar bead, microcrystalline cellulose bead or a lactose crystal. The pharmaceutical dosage form according to Claim 35 or 36 , the salt of tapentadol with phosphoric acid being distributed homogeneously in the active ingredient layer. The pharmaceutical dosage form according to one of the Claims 35 to 37 , the content of the salt of tapentadol with phosphoric acid in the active ingredient layer being in the range from 50 to 90% by weight, based on the total weight of the inert core and the active ingredient layer. The pharmaceutical dosage form according to one of the Claims 35 to 38 , wherein the active ingredient layer contains one or more flow regulators. The pharmaceutical dosage form according to Claim 39 wherein the flow control agent or agents are 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 pharmaceutical dosage form according to Claim 39 or 40 , the total content of all flow regulators in the active ingredient layer being in the range from 0.1 to 5.0% by weight, based on the total weight of the inert core and the active ingredient layer. The pharmaceutical dosage form according to one of the Claims 35 to 41 , wherein the active ingredient layer contains one or more film formers. The pharmaceutical dosage form according to Claim 42 wherein the film former or the plurality of film formers are independently selected from the group consisting of cellulose ethers and polyvinylpyrrolidone; preferably hydroxypropylmethyl cellulose or ethyl cellulose. The pharmaceutical dosage form according to Claim 42 or 43 , the total content of all film formers in the active ingredient layer being in the range from 0.5 to 10% by weight, based on the total weight of the inert core and the active ingredient layer. The pharmaceutical dosage form according to one of the Claims 35 to 44 , the inert core forming a build-up pellet with the active ingredient layer which encapsulates the inert core. The pharmaceutical dosage form according to one of the Claims 35 to 45 , wherein the active ingredient layer is 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 active ingredient layer, and ethyl cellulose 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 ingredient layer. The pharmaceutical dosage form according to one of the Claims 35 to 45 , wherein the active ingredient layer is 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 active ingredient 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 ingredient layer. The pharmaceutical dosage form according to one of the Claims 35 to 47 , wherein the pharmaceutical dosage form is obtainable by a process which comprises 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 which is to be contained in the dosage form, optionally together with the one or more pharmaceutical excipients; (D) if appropriate, drying the intermediate product particles obtained in step (C) to obtain dried intermediate product particles; (E) providing a solution or dispersion of a 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 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 particles with sustained release which do not contain a salt of tapentadol with an inert core containing phosphoric acid, an active ingredient 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 ingredient layer for retarded purposes Release of tapentadol included; (G) if appropriate, drying the coated particles obtained in step (F) to obtain dried coated particles; and (H) either filling 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 extra-particulate pharmaceutical excipients and compressing the mixture to form tablets. The pharmaceutical dosage form according to Claim 48 , the composition provided in step (B) being a dispersion or solution in water or in an organic solvent or a mixture thereof. The pharmaceutical dosage form according to Claim 48 or 49 , wherein step (C) is carried out by powder coating in a coating pan. The pharmaceutical dosage form according to Claim 48 or 49 wherein step (C) is carried out by spraying the inert cores in a fluidized bed coater. The pharmaceutical dosage form according to one of the preceding claims, wherein the coating for the delayed release of tapentadol contains talc in addition to ethyl cellulose. The pharmaceutical dosage form according to Claim 52 wherein the relative weight ratio of ethyl cellulose: 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 one of the preceding claims, wherein the coating for the sustained release of tapentadol comprises, in addition to ethyl cellulose, one or more plasticizers. The pharmaceutical dosage form according to Claim 54 wherein the plasticizer or the plurality of plasticizers are selected independently of one another from the group consisting of dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin; preferably triethyl citrate. The pharmaceutical dosage form according to Claim 54 or 55 , wherein the total content of all plasticizers in the coating for the sustained release of tapentadol is in the range of 5.0 to 20 wt .-%, based on the total weight of the coating. The pharmaceutical dosage form according to one of the preceding claims, wherein the content of the coating for the sustained 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 the Claims 1 to 56 , the content of the coating for the delayed release of tapentadol being 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 the Claims 1 to 56 , the content of the coating for the sustained release of tapentadol being 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 the Claims 1 to 56 , the content of the coating for the delayed release of tapentadol being 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 the Claims 1 to 56 , the content of the coating for the sustained release of tapentadol being in the range from 45 to 60% by weight, based on the total weight of the coated particles. The pharmaceutical dosage form according to one of the preceding claims, which provides an in vitro dissolution profile, measured at 50 rpm in 900 ml of aqueous phosphate buffer at a pH of 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 have been released. The pharmaceutical dosage form according to any one of the preceding claims, which provides an in vitro dissolution profile, measured at 50 rpm in 900 ml of aqueous phosphate buffer at a pH of 6.8 at 37 ° C, at which - after 1 hour 25 ± 15% by weight; - after 2 hours 35 ± 20% by weight; - after 4 hours 50 ± 20% by weight; and - after 8 hours 80 ± 20% by weight of the tapentadol originally contained in the dosage form have been released. The pharmaceutical dosage form according to any one of the preceding claims, which provides an in vitro dissolution profile measured at 50 rpm in 900 ml of aqueous buffer at a pH of 4.5 at 37 ° C, at which - after 0.5 hours 20 ± 20% by weight; preferably 20 ± 15% by weight; particularly preferably 20 ± 10% by weight; - after 4 hours 60 ± 20% by weight; preferably 60 ± 15% by weight; particularly preferably 60 ± 10% by weight; and - after 12 hours at least 60% by weight; preferably at least 70% by weight; particularly preferably at least 80% by weight of the tapentadol originally contained in the dosage form have been released. The pharmaceutical dosage form according to any one of the preceding claims, which provides an in vitro dissolution profile measured at 50 rpm in 900 ml of aqueous buffer at a pH of 4.5 at 37 ° C, at which - after 1 hour 25 ± 15% by weight; - after 2 hours 35 ± 20% by weight; - after 4 hours 50 ± 20% by weight; - after 8 hours 80 ± 20% by weight of the tapentadol originally contained in the dosage form have been released. The pharmaceutical dosage form according to any one of the preceding claims, which provides an in vitro dissolution profile measured at 50 rpm in 900 ml 0.1 N HCl at a pH of 1.0 and 37 ° C, at which - after 0.5 hours 20 ± 20% by weight; preferably 20 ± 15% by weight; particularly preferably 20 ± 10% by weight; - after 4 hours 60 ± 20% by weight; preferably 60 ± 15% by weight; particularly preferably 60 ± 10% by weight; and - after 12 hours at least 60% by weight; preferably at least 70% by weight; particularly preferably at least 80% by weight of the tapentadol originally contained in the dosage form have been released. The pharmaceutical dosage form according to any one of the preceding claims, which provides an in vitro dissolution profile measured at 50 rpm in 900 ml 0.1 N HCl at a pH of 1.0 and 37 ° C, at which - after 1 hour 25 ± 10% by weight; - after 2 hours 40 ± 30% by weight; - after 4 hours 60 ± 20% by weight; - after 8 hours 80 ± 20% by weight of the tapentadol originally contained in the dosage form have been released. The pharmaceutical dosage form according to any one of the preceding claims which is intended for twice daily oral administration.

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