WO2015071248A1

WO2015071248A1 - Abuse-proofed extended release pharmaceutical composition comprising tapentadol

Info

Publication number: WO2015071248A1
Application number: PCT/EP2014/074246
Authority: WO
Inventors: Denny Johan Marijn HEUVEL VAN DEN; Henricus Cornelis Willibrordus SWAANS
Original assignee: Synthon B.V.
Priority date: 2013-11-15
Filing date: 2014-11-11
Publication date: 2015-05-21

Abstract

The present invention relates to an abuse-proofed extended release pharmaceutical composition suitable for oral administration of tapentadol and/or a salt thereof.

Description

ABUSE-PROOFED EXTENDED RELEASE PHARMACEUTICAL COMPOSITION COMPRISING TAPENTADOL The invention relates to an abuse-proofed extended release pharmaceutical composition comprising the compound tapentadol as the active pharmaceutical ingredient.

BACKGROUND OF THE INVENTION

Tapentadol, chemically 3-((lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl)-phenol of formula (1)

is a centrally acting analgesic with a dual mode of action: μ-opioid receptor agonism and noradrenaline reuptake inhibition. Its dual mode of action provides analgesia at similar levels of more potent narcotic analgesics such a hydrocodone, oxycodone, and morphine with a more tolerable side effect profile. Tapentadol hydrochloride is used for the treatment of moderate to severe acute and/or chronic pain and for pain associated with diabetic peripheral neuropathy under the names Palexia and Yantil in Europe and Nucynta in the US. Tapentadol and its salts were first disclosed in EP 0693475. Specifically, tapentadol hydrochloride and its crystalline polymorphic forms A and B are disclosed in EP 1612203. Crystalline Form A has the same pharmacological activity as Form B, but is more stable under ambient conditions.

The traditional formulations of tapentadol for oral administration lead to a rapid release of the drug in the gastrointestinal tract and hence its analgesic action begins rapidly.

However, a rapid reduction in the analgesic activity is observed. Therefore, treatment with tapentadol requires repeated administration of the pharmaceutical composition at relatively short intervals. The need for repeated dosing can lead to errors in administration and inability to maintain desirable concentrations in the plasma, which are detrimental to patient compliance and the therapeutic objectives, particularly if the condition is chronic pain or a pain related condition.

Several approaches to obtain extended release formulations of tapentadol have been disclosed in the prior art.

WO 03/035053 is first to disclose a delayed release formulation comprising tapentadol, in which the matrix comprises between 1 and 80% of one or more hydrophilic or

hydrophobic polymers. Preferred polymers are cellulose ethers and cellulose esters.

The prolonged release composition disclosed in WO 2011/124953 is multilayered, comprising a wide range of hydrophilic and hydrophobic release controlling agents and maintaining the desired tapentadol serum concentration of at least 20 ng/ml for at least 17 hours after oral administration.

In WO 2013/092589, a multi unit pellet tablet formulation provides a substantially constant rate of release over an extended period of time. These pellets preferably comprise cellulose ethers as the retardant material.

Due to its pharmacological activity, tapentadol is prone to be used by abusers, for example, to induce a state of narcosis or euphoria. Since extended release formulations do not usually give rise to the kick desired by the abuser when taken orally even in abusively high quantities, these dosage forms for example in the form of tablets or capsules are often crushed and ingested, crushed or vaporised and snorted, or injected intravenously after attempted extraction of the active pharmaceutical ingredient.

WO 2006/002886 discloses an abuse-proofed, oral dosage form with controlled release of tapentadol for once daily administration, comprising at least one synthetic or natural polymer having a breaking strength of at least 500 N, whereas WO 2009/092601 provides controlled release tablets with a breaking strength of at least 500 N in the longitudinal direction and less than 500 N in the transversal direction, effected by the shape of the tablet and not by the choice of its polymer excipients.

WO 2007/087452 discloses oral multimodal abuse resistant extended release formulations comprising opioid agents, including tapentadol, and one or more abuse deterrent extended release compounds chosen from hydrogenated Type I or Type II vegetable oils, polyoxyethylene stearates and distearates, glycerol monostearate or poorly water soluble, high melting point waxes. Similar formulations have been disclosed in WO 2008/027442 and WO 2008/134071.

WO 2010/140007 teaches that a dosage form with melt-extruded particulates comprising an opioid agonist, including tapentadol, and a matrix comprising various polymers may be tamper resistant. This formulation possesses alcohol-extraction resistance properties (i.e. tamper resistance) as well as crush resistance. Similar formulations have been disclosed in WO 2012/076907.

WO 2011/009602 provides hot-melt extruded tablets with controlled release of an active pharmaceutical ingredient, e.g., tapentadol, embedded in a polymer matrix. This tablet has an increased breaking strength, e.g., at least 300 N, resulting from a specified extrusion direction.

In summary, the prior art teachings indicate that tapentadol may be formulated in abuse-proofed extended release formulations. The approaches tried include the inclusion of suitable synthetic or natural polymers, i.e., those which have a breaking strength of at least 500 N, applying a specific tablet shape and hot-melt extrusion. Clearly, there is a need for tapentadol formulations that simultaneously provide robust abuse deterrence properties and an extended release pharmacokinetic profile suitable for every 12 or 24 hour oral administration. There is also a need for extended release formulations of tapentadol that are stable (i.e., do not dose dump) when used in conjunction with alcohol.

SUMMARY OF THE INVENTION

The present invention relates to an extended release pharmaceutical composition suitable for oral administration of tapentadol and/or a salt thereof, which provides robust abuse deterrence properties and is stable (i.e., does not dose dump) when used in conjunction with alcohol.

In one aspect, the present invention relates to an extended release pharmaceutical composition comprising tapentadol or a pharmaceutically acceptable salt thereof, glyceryl behenate or glyceryl palmitostearate and, optionally, a diluent.

Preferably, tapentadol or a pharmaceutically acceptable salt thereof is molecularly dispersed in glyceryl behenate or glyceryl palmitostearate.

Preferably, the pharmaceutically acceptable salt of tapentadol is tapentadol

hydrochloride. Even more preferably, the pharmaceutically acceptable salt is tapentadol hydrochloride crystalline Form B, amorphous tapentadol hydrochloride or a mixture thereof.

Preferably, glyceryl behenate or glyceryl palmitostearate is present in the composition in 10 to 80% by weight.

Preferably, the weight ratio tapentadol : glyceryl behenate or tapentadol : glyceryl palmitostearate is from between 1 : 2 to 2 : 1, wherein tapentadol is calculated as the free base.

Preferably, the diluent is selected from the group consisting of dicalcium phosphate or a hydrate thereof, tricalcium phosphate, lactose or a mixture thereof.

Preferably, the composition further comprises a lubricant, which is preferably magnesium stearate. Preferably, the composition consists of 5 to 89% by weight of tapentadol or a pharmaceutically acceptable salt thereof, 10 to 75% by weight of glyceryl behenate or glyceryl palmitostearate, 1 to 45% by weight of dicalcium phosphate or a hydrate thereof, tricalcium phosphate, lactose or a mixture thereof, and 0 to 10% by weight of a lubricant.

In a third aspect, the invention relates to an extended release pharmaceutical dosage form comprising the aforementioned pharmaceutical composition. The dosage form is preferably in the form of a powder, granulate, capsule or compressed tablet for oral administration.

Preferably, the dosage form has a specific in vitro dissolution profile, when measured in USP phosphate buffer, pH 6.8 using USP Apparatus II at 100 rpm, such that

15-82% by weight of tapentadol is released after 3 hours,

30-97% by weight of tapentadol is released after 6 hours,

more than 50% by weight of tapentadol is released after 12 hours,

more than 80% by weight of tapentadol is released after 24 hours.

In a fourth aspect, the invention relates to a process for making said pharmaceutical composition, comprising the steps of:

a) melting glyceryl behenate or glyceryl palmitostearate;

b) adding tapentadol or a pharmaceutically acceptable salt to the glyceryl behenate or glyceryl palmitostearate;

c) cooling down, screening, milling and/or granulating the mixture obtained in step b); and

d) optionally mixing the mixture from step c) with a diluent. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Dissolution assay of tapentadol 150 mg extended release tablets with glyceryl behenate

Figure 2: Dissolution assay of tapentadol 150 mg extended release capsules with glyceryl behenate

Figure 3: Dissolution assay of tapentadol 150 mg extended release capsules with glyceryl palmitostearate

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an abuse-proofed extended release oral pharmaceutical composition, and oral dosage forms, comprising tapentadol. "Tapentadol" is a generically used name for 3-((lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl)-phenol and will be so used throughout this specification, unless expressly stated differently.

Tapentadol comprises a basic amino-group and may accordingly form acid addition salts with organic or inorganic acids. In accordance with its intended use, pharmaceutically acceptable acids are preferred. A preferred pharmaceutically acceptable salt is tapentadol hydrochloride.

Solid state tapentadol and/or a salt thereof may exist as a crystalline or an amorphous material. Crystalline materials may exist in different polymorphic modifications. In addition, they may be substantially anhydrous or may exist in the form of a hydrate and/or a solvate. Any such modifications are included within the terms "tapentadol" and "tapentadol salt" throughout this specification.

Tapentadol or a salt thereof are either commercially available or may be obtained by processes known in the art. The essential features of the extended release compositions of the present invention are tapentadol or a salt thereof, glyceryl behenate or glyceryl palmitostearate and, optionally, a diluent.

The "extended release compositions or dosage forms" or compositions or dosage forms which exhibit an "extended release" of drug as used herein is defined to mean compositions or dosage forms administered once or twice daily that release drug slowly, so that plasma concentrations of the drug are maintained at a therapeutic level for an extended period of time such that the composition or dosage form provides therapeutic benefit over about a 12-hour to 24-hour period.

Glyceryl behenate is a known compound approved in particular for use in cosmetics, foods, and oral pharmaceutical formulations. In pharmaceutical formulations, glyceryl behenate is mainly used as a tablet and capsule lubricant and as a lipidic coating excipient. In amongst, glyceryl behenate has been investigated for use in the preparation of sustained release tablets as a matrix-forming agent for the controlled release of water-soluble drugs. Glyceryl behenate is a mixture of glyceryl esters of behenic acid made from glycerine and behenic acid. The mixture contains predominantly glyceryl dibehenate. Glyceryl behenate meets the following specifications: 10 to 20% monobehenate, 47 to 59% dibehenate, 26 to 38% tribehenate, and not more than 2.5% free fatty acids.

Preferably, commercially available Compritol 888 ATO is used as the glyceryl behenate. Compritol 888 ATO has the following specifications: 18% monobehenate, 52% dibehenate, 28% tribehenate, and 2% free fatty acids.

Glyceryl palmitostearate is a known compound approved in particular for use in foods and oral pharmaceutical formulations. In pharmaceutical formulations, glyceryl

palmitostearate is mainly used as a tablet and capsule lubricant. In amongst, glyceryl palmitostearate has been investigated for use in the preparation of sustained release tablet and capsule formulations as a matrix-forming agent. Glyceryl palmitostearate is a mixture of mono-, di-, and triglyceryl esters of palmitic and stearic acids made from glycerin, palmitic acid, and stearic acid.

Preferably, commercially available Precirol® ATO 5 is used as the glyceryl palmitostearate. Precirol® ATO 5 has the following specifications: < 1.0% free glycerol content, 8.0 to 22.0% total monoglycerides content, 40.0 to 60.0% total diesters content, 25.0 to 35.0% total triesters content, 40.0 to 60.0% palmitic acid (C₁₆), and 40.0 to 60.0% stearic acid (C₁₈). The sum of palmitic and stearic acids is > 90.0%.

It was found out by the present inventor that amounts of glyceryl behenate or glyceryl palmitostearate exceeding the commonly used quantities for a lubricant, i.e. 1 to 5%, formed stable extended release compositions with tapentadol or salts thereof. Preferably, glyceryl behenate or glyceryl palmitostearate serves as matrix wherein tapentadol or a

pharmaceutically acceptable salt thereof is molecularly dispersed. The stability of such compositions in long-term storage tests is at least comparable with that of the currently marketed products. The compositions of the present invention exhibit good handling properties, e.g. flowability, content uniformity, etc. for making powders or granulates for both direct oral administration or for encapsulation or tabletting. Furthermore, it was found that these compositions provide robust abuse deterrence properties and are stable (i.e., do not dose dump) when used in conjunction with alcohol.

Accordingly, the present invention provides for an abuse-proofed extended release solid composition for oral administration comprising tapentadol or a salt thereof and glyceryl behenate or glyceryl palmitostearate, wherein tapentadol or its salt is preferably molecularly dispersed in glyceryl behenate or glyceryl palmitostearate. Glyceryl behenate or glyceryl palmitostearate is present in the composition in 10 to 80% by weight, with respect to the total weight of the composition, when tapentadol in the mixture is calculated as tapentadol free base. Preferably, the composition comprises 10-75% by weight of glyceryl behenate or glyceryl palmitostearate, more preferably 20-70% by weight, and even more preferably 25- 70% by weight. Most preferably, the weight ratio tapentadol (calculated as the free base) : glyceryl behenate or tapentadol (calculated as the free base) : glyceryl palmitostearate is from between 1 : 2 to 2 : 1.

The glyceryl behenate or glyceryl palmitostearate matrix is a non-erodible, non- swelling lipid matrix. Drug release from the matrix is diffusion controlled.

The composition preferably further comprises a diluent, which will act as a pore former and enhance release from the lipid matrix. Suitable diluents include lactose, microcrystalline cellulose, dicalcium phosphate or a hydrate thereof, tricalcium phosphate, sucrose, starch, mannitol, ethylcellulose, hydroxypropyl cellulose, or a combination thereof. Preferably, the diluent is selected from the group consisting of dicalcium phosphate or a hydrate thereof, tricalcium phosphate, lactose or a mixture thereof. The amount of diluent is typically about 1- 45 weight % with respect to the total weight of the composition.

The composition preferably further comprises a lubricant, which improves the flow of the composition and minimizes adherence to walls of equipment. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, zinc stearate or a mixture of any of the above. Preferably, the lubricant is magnesium stearate. The amount of lubricant is typically about 1-10 weight % with respect to the total weight of the composition.

In an advantageous embodiment, the composition does not comprise, besides tapentadol or its pharmaceutically acceptable salt, any other ingredients than glyceryl behenate or glyceryl palmitostearate, diluent and, optionally, a lubricant. Thus, in a specific aspect, the invention provides for a pharmaceutical composition consisting of 5 to 89 weight % tapentadol or a pharmaceutically acceptable salt thereof, 10 to 75 weight % of glyceryl behenate or glyceryl palmitostearate, 1 to 45 weight % of dicalcium phosphate or a hydrate thereof, tricalcium phosphate, lactose or a mixture thereof and, optionally, 0 to 10 weight % of a lubricant.

The use of other excipients is not excluded, however. In particular, the composition may optionally comprise a binder. Suitable binders may include cellulose or a cellulose derivative, e.g. hydroxypropyl cellulose or hydroxypropylmethyl cellulose. The amount of binder may typically be from 0.05 to 5 weight % with respect to the total weight of the composition.

As is known from the prior art, tapentadol hydrochloride exists in two crystalline polymorphic forms, namely Form A and Form B. Crystalline Form A has the same pharmacological activity as Form B, but is more stable under ambient conditions. We have experienced in our laboratory that it is rather difficult to prepare extended release pharmaceutical compositions wherein tapentadol hydrochloride is kept in crystalline Form B without any conversion in time to crystalline Form A. Surprisingly, it was found that both glyceryl behenate and glyceryl palmitostearate stabilises tapentadol hydrochloride crystalline Form B. It was shown in stability experiments that even after 1 month Form B did not convert into Form A. In a similar way, both glyceryl behenate and glyceryl palmitostearate are able to stabilise amorphous tapentadol hydrochloride or mixtures of amorphous tapentadol hydrochloride and tapentadol hydrochloride Form B. Stability experiments prove the absence of conversion into Form A.

In summary, there has been manifested a suitability and advantage of using glyceryl behenate or glyceryl palmitostearate in making stable pharmaceutical compositions comprising tapentadol hydrochloride crystalline Form B, tapentadol hydrochloride in amorphous form or mixtures thereof.

The composition of the present invention may be formulated to final extended release dosage forms for oral administration. Such dosage forms may comprise a dose of powder or granulate comprising the composition of the invention, which is filled in a (hard-shell) capsule or in a sachet. Such dosage form may also comprise the composition of the invention compressed into a tablet. The tablet is preferably a swallowable tablet. It may optionally be coated with a film coat comprising, in essence, any suitable inert coating material known in the art. The dosage form advantageously comprises a unit dose of tapentadol, which may be from 50 to 250 mg of tapentadol, preferably 50, 100, 150, 200, or 250 mg of tapentadol, calculated as the free base. In total, a single dosage form may advantageously comprise from 50 to 500 mg of the composition. A preferred dosage form is an oral tablet.

The dosage forms of the invention exhibit good, first-order extended release of tapentadol. Generally, the average dissolution curve of the dosage forms in USP phosphate buffer pH 6.8 meets the following time/release relationships:

3 hours - 15-82% of dose released;

6 hours - 30-97% of dose released;

12 hours - more than 50% of dose released; and

24 hours - more than 80% of dose released.

In some embodiments, the dosage forms of the invention exhibit an average in vitro dissolution of tapentadol in USP phosphate buffer pH 6.8 using USP Apparatus II at 100 rpm, such that:

3-35% by weight (referred to 100 % by weight of active constituent) of tapentadol is released after 30 minutes;

5-50% by weight of tapentadol is released after 1 hour

10-75% by weight of tapentadol is released after 2 hours;

15-82% by weight of tapentadol is released after 3 hours;

30-97% by weight of tapentadol is released after 6 hours;

more than 50% by weight of tapentadol is released after 12 hours; more than 70% by weight of tapentadol is released after 18 hours; and

more than 80% by weight of tapentadol is released after 24 hours.

The dosage forms of the present invention can be made by any known granulation, dispersion or compression technique. Suitable techniques include direct compression, wet granulation and roller compaction, but also melt and mix, spray cooling, hot melt extrusion and melt granulation. Direct compression procedures generally comprise mixing the solid ingredients in one or more stages and compressing the uniform mixture into tablets. In general, wet granulation comprises mixing the tapentadol salt with the glyceryl behenate or glyceryl palmitostearate in the presence of a granulating liquid. The liquid, which is typically water or an organic solvent, such as ethanol or isopropylalcohol, is removed from the formed granules by drying. The granules are then sieved and/or milled and combined with the remaining excipients in one or more steps and then, optionally, compressed into tablets. Roller compaction procedures generally comprise mixing the solid ingredients (except lubricants), compacting the mixture in a roller-compactor, milling the compacted mass, screening the milled granules, mixing with a lubricant and, optionally, compressing the mixture into tablets.

In granulation through melt and mix, spray cooling or via hot melt granulation and/or hot melt extrusion, one or more of the solid ingredients become fluid under elevated temperatures. This enables an intense mixing and homogenization of all materials. After cooling, the material solidifies and can be processed further, similar to the techniques mentioned above. This heating/cooling mixing process can be automated via a hot melt fluid bed process, hot melt granulation in a high shear mixer or hot melt extruder.

In another aspect, the invention relates to a process for producing a pharmaceutical composition as defined hereinabove, comprising the steps of

a) melting glyceryl behenate or glyceryl palmitostearate;

b) adding tapentadol or a pharmaceutically acceptable salt thereof to the glyceryl behenate or glyceryl palmitostearate; c) cooling down, screening, milling and/or granulating the mixture obtained in step b); and

d) optionally mixing the mixture from step c) with a diluent.

More particularly, the composition as discussed above may be produced by this process.

Sub a)

Typically, the glyceryl behenate melts at a temperature of 65-77°C, whereas glyceryl palmitostearate melts at a temperature of 52-56°C. When preparing hot melt filled capsules, further (solid) excipients, such as a diluent, may optionally be added to the melt at this stage and mixed with top stirrer, high shear mixer or extruder.

Sub b)

Tapentadol or a pharmaceutically acceptable salt thereof, typically tapentadol hydrochloride may optionally be milled and/or pre-screened before mixing in step b) in order to remove lumps. Advantageously, the particles of the treated product pass a screen with 400- 800 μιη (0.4-0.8 mm) mesh size.

The weight ratio of glyceryl behenate or glyceryl palmitostearate to tapentadol or a salt thereof is advantageously from 10:90 to 80:20, more preferably from 30:70 to 70:30, calculated as tapentadol free base.

The mixing step b) may advantageously comprise mixing of components in any suitable blender at, e.g. 5 to 30 revolutions per minute. The mixing step b) also comprises mixing per partes, i.e. when the glyceryl behenate or glyceryl palmitostearate is mixed first with a small amount of tapentadol component, e.g. from 5 to 50 per cent of the total charge of tapentadol, in order to form a pre-mix. Subsequently the remaining amount of tapentadol is added to the pre-mix in one or more doses. Sub C)

The purpose of the step c) is to suitably modify the physical properties of the mixture from step b) for its formulation in medicinal dosage forms. If appropriate, the mixture may be screened, advantageously through a screen of mesh size of about 600 μιη, and/or optionally milled on a suitable mill. If appropriate, the mixture may be granulated in a suitable high sheer mixer- granulator and/or in a fluid bed granulator. A drying step may be included as well, e.g., within the granulation process.

When preparing hot melt filled capsules, the hot mixture of step b) is directly filled into capsules and then cooled down.

Sub d)

Mixing with a suitable diluent, preferably selected from the group consisting of dicalcium phosphate or a hydrate thereof, tricalcium phosphate, lactose or a mixture thereof, provides a free-flowing particulate composition suitable for use in making the solid-state final forms as discussed above. The diluent is preferably pre-screened, e.g. with a screen of 500- 850 μιη mesh size.

In accordance with the invention, the hot melt mixture of step b), wherein tapentadol or a pharmaceutically acceptable salt thereof is molecularly dispersed in glyceryl behenate or glyceryl palmitostearate, or the free-flowing composition obtained in step d), which is typically in the form of a powder or granulate, is then formulated into medicinal final dosage forms. Suitable final dosage forms have been discussed above.

The pharmaceutical compositions of the present invention and/or final dosage forms comprising them are useful, for treating or preventing a disease or condition treatable by tapentadol. The "disease or condition treatable by tapentadol" as used herein may comprise, without limitation: - treatment of moderate to severe acute pain;

- treatment of moderate to severe chronic pain;

- treatment of pain associated with diabetic peripheral neuropathy.

The invention will be further illustrated by the following non-limiting examples.

EXAMPLES

Example 1 - Tablet and capsule compositions

150 mg tapentadol extended release tablets were prepared using glyceryl behenate or lyceryl palmitostearate. The table below shows the quantitative compositions.

Direct compression process (tablet formulation):

The materials are weighed. Mix all ingredients, with the exception of magnesium stearate, for 15 minutes at 22 rpm using a turbula mixer. Magnesium stearate is screened over 600 μηι, added to the mixture and stirring is continued for 5 minutes at 22 rpm. 540 mg tablets are compressed by using EK-0 with 16*8 mm oblong punches.

Hot melt granulation process (capsule formulation):

The materials are weighed. Glyceryl behenate or glyceryl palmitostearate is melted. Tapentadol is added and the mixture is stirred until homogeneous. The mixture is filled into capsules and then cooled down.

Dissolution

Dissolution of the tablet is shown in Figure 1.

Dissolution of capsule I is shown in Figure 2.

Dissolution of capsule II is shown in Figure 3.

The reference product is the marketed Palexia SR batch no. 113D04 (150 mg tapentadol SR tablet).

Example 2 - Tablet compositions

150 mg tapentadol extended release tablets were prepared using glyceryl behenate. The table below shows the quantitative compositions.

Hot melt granulation process;

The materials are weighed. Glyceryl behenate is melted and Tapentadol hydrochloride and half the amount of tricalciumphosphate is added and the mixture is stirred until homogeneous. After cooling, the remaining amount of tricalciumphosphate and lactose is added and mixed. Magnesium stearate is screened over 600 μιη, added to the mixture and stirring is continued for 5 minutes at 22 rpm. Tablets are compressed by using EK-0.

Dissolution

The tablets obtained show similar dissolution profiles when compared to the tablets obtained in example 1 and shown in Figure 1 and the reference product Palexia SR.

Claims

1. An extended release pharmaceutical composition comprising tapentadol or a

pharmaceutically acceptable salt thereof, glyceryl behenate or glyceryl palmitostearate and, optionally, a diluent.

2. The composition according to claim 1, wherein tapentadol or a pharmaceutically

acceptable salt thereof is molecularly dispersed in glyceryl behenate or glyceryl palmitostearate.

3. The composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt of tapentadol is tapentadol hydrochloride crystalline Form B.

4. The composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt of tapentadol is tapentadol hydrochloride in amorphous form.

5. The composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt of tapentadol is a mixture of amorphous and crystalline Form B tapentadol hydrochloride.

6. The composition according to any one of claims 1 to 5, wherein glyceryl behenate or glyceryl palmitostearate is present in 10 to 80% by weight.

7. The composition according to any one of claims 1 to 6, wherein the weight ratio

tapentadol : glyceryl behenate or tapentadol : glyceryl palmitostearate is from between

1 : 2 to 2 : 1, and tapentadol is calculated as the free base.

8. The composition according to any one of claims 1 to 7, wherein the diluent is selected from the group consisting of dicalcium phosphate or a hydrate thereof, tricalcium phosphate, lactose or a mixture thereof.

9. The composition according to any one of claims 1 to 8, further comprising a lubricant, preferably magnesium stearate.

10. The composition according to any one of claims 1 to 9, wherein the composition consists of 5 to 89% by weight of tapentadol or a pharmaceutically acceptable salt thereof, 10 to 75% by weight of glyceryl behenate or glyceryl palmitostearate, 1 to 45% by weight of dicalcium phosphate or a hydrate thereof, tricalcium phosphate, lactose or a mixture thereof and 0 to 10% by weight of a lubricant.

11. An extended release pharmaceutical dosage form comprising the composition

according to any one of claims 1 to 10, wherein the dosage form is in the form of a powder, granulate, capsule or compressed tablet for oral administration.

12. The dosage form according to claim 10 in the form of a tablet.

13. The dosage form according to claim 10 or 11, wherein said dosage form exhibits an average in vitro dissolution of tapentadol, when measured in USP phosphate buffer, pH 6.8 using USP Apparatus II at 100 rpm, such that

15-82% by weight of tapentadol is released after 3 hours;

30-97% by weight of tapentadol is released after 6 hours;

more than 50% by weight of tapentadol is released after 12 hours; and

more than 80% by weight of tapentadol is released after 24 hours.

14. A process for producing the composition according to any one of claims 1 to 10,

comprising the steps of

a) melting glyceryl behenate or glyceryl palmitostearate;

b) adding tapentadol or a pharmaceutically acceptable salt thereof to the glyceryl behenate or glyceryl palmitostearate;

d) optionally mixing the mixture from step c) with a diluent.

15. The process according to claim 14 further comprising the addition of at least one further excipient to the melted glyceryl behenate or glyceryl palmitostearate of step a).

16. The process according to claim 14 or 15 further comprising a step of formulating the composition into a pharmaceutical dosage form according to any one of claims 11 to 13.