AU2021201353B1

AU2021201353B1 - Dosage form providing prolonged release of a salt of Tapentadol with L-(+)-tartaric acid

Info

Publication number: AU2021201353B1
Application number: AU2021201353A
Authority: AU
Inventors: Ulrike Bertram; Christian Grosse; Carmen HARTMANN; Ulrich Reinhold
Original assignee: Gruenenthal GmbH
Current assignee: Gruenenthal GmbH
Priority date: 2020-11-10
Filing date: 2021-03-02
Publication date: 2022-04-21
Anticipated expiration: 2041-03-02
Also published as: PL3995135T3; EP3995135A1; HRP20221136T1; DK3995135T3; LT3995135T; ES2927147T3; RS63521B1; EP3995135B1; HUE059465T2; PT3995135T

Abstract

Dosage Form Providing Prolonged Release of a Salt of Tapentadol with L-(+)-Tartaric Acid Abstract: The invention relates to a tablet providing prolonged release of Tapentadol, wherein Tapentadol is present in the form of a salt with tartaric acid, in particular in the form of a salt with L-(+)-tartaric acid. The tablet has satisfactory mechanical properties, for example, with regard to breaking strength and friability, and it can be produced under considerably facilitated tableting conditions, in particular at reduced compression force.

Description

Dosage Form Providing Prolonged Release of a Salt of Tapentadol with L-(+)-Tartaric

Acid

Cross Reference

[1] The present application claims priority to European Patent Application No. EP

20206800.3, filed 10 November 2020, the contents of which is incorporated herein by

reference in its entirety.

[la] The invention relates to a tablet providing prolonged release of Tapentadol,

wherein Tapentadol is present in the form of a salt with tartaric acid, in particular L-(+)-tartaric

acid. The tablet has satisfactory mechanical properties, for example, with regard to breaking

strength and friability, and it can be produced under considerably facilitated tableting

conditions, in particular in the case of reduced compression force.

[2] Any reference to publications cited in this specification is not an admission that

the disclosures constitute common general knowledge in Australia.

[3] Tablets are produced in that a compression force is allowed to act on a powder,

and the powder in the forming die of a press is consolidated into a compacted form. In the

production of a tablet, two processes occur simultaneously: compaction and compression.

According to the definition, compaction is an increase in the mechanical strength of the power

under exposure to force due to the consolidation of the particles. Compaction is thus connected

with particle consolidation and bonding, which has a direct effect on the breaking strength of

the tablet. Compression, on the other hand, is defined as a reduction of the bulk volume of the

powder under exposure to a force by displacement of air between the particles. Compression

leads to a reduction of empty space between solid particles, which means a decrease in the porosity of a tablet (for more precise information, see, for example, Y. Qiu et al., Developing

Solid Oral Dosage Forms, Pharmaceutical Theory & Practice, 2nd edition, Elsevier, 2017, pp.

940-942).

[4] Tablet production is influenced by a series of mutually dependent parameters

including

- the desired properties of the tablet (for example, mechanical strength, weight

variability, disintegration time, size, and shape),

- the constitution and the amount of the excipients of the solid material to be

formed into tablets, and

- the conditions in the tableting machine (for example, compression force,

tableting speed, residence time of the punch in the forming die, punch geometry, tool material,

etc.

[5] As far as the desired properties of the tablet are concerned, they depend to a

great extent on pharmacological, i.e., pharmacokinetic and pharmacodynamic, considerations.

The drug dose to be contained in a tablet is determined by the potency of the drug and the

envisaged frequency of administration. The release characteristics determine the constitution

and the amount of excipients as well as the total distribution of excipients in the tablet. A matrix

delaying, for example, requires considerable amounts of prolonged-release matrix material in

which the drug is embedded. A sufficient mechanical strength is necessary in order to enable,

for example, the expulsion of the compacted forms from the forming die in the tableting process

and the release of tablets from an appropriate packaging such as a blister pack.

[6] As far as the constitution and amount of excipients is concerned, powder

excipients are used as binders for the cohesion, as fillers for the tensile strength of the tablet,

as lubricant for successful processing of a mixture or of a granulate into a tablet, as disintegrant

for facilitating the in vivo disintegration of the tablet, as materials for controlled release for delayed dissolution, and sometimes as glidant for mixtures with poor flowability. The excipients are in each case predominantly elastic or plastic or friable. Elastic particles undergo deformation during the compression up to their elastic limit and then break. Before reaching this elasticity limit, the deformation of the elastic material is reversible. After removal of the compression forces, elastic powders expand (relaxation). In plastic deformation, the shape is preserved after removal of the compression forces and therefore undergoes deformation without recovery of the initial state, thereby providing good particle bonding. A friable component will break under a compression load if the force exceeds the deformation limit.

While, after a friable rupture, a larger surface area forms, this also leads to greater friction and

to greater resistance to movement in the forming die during the compression. Plastic and friable

excipients provide physical forms and give the shape stability after compression.

[7] As far as the conditions in the tableting machine are concerned, in modern

highly developed tableting machines, in each case the same general operating concepts are

used: filling of the forming die, compression of the tablet, expulsion of the tablet, and scraping

of the table. The quality of the compacted form depends on the compression and consolidation

of the powder composition, the decompression of the compacted form, the expulsion from the

forming die, and the subsequent scraping of the lower punch. Since these viscoelastic properties

are time-dependent, the tablet quality is influenced both by the size and also by the rate of

application (and the release) of the compression force.

[8] Tableting punches are used for compressing a mixture or a granulate into a

compacted unit dose.

[9] In tableting machines for roller compaction (rotary tablet presses), first the

lower punch is lowered, so that the feed device can deliver powder into a forming die. With a

scraper, excess powder is removed, so that the formulation is flush with the upper margin of

the forming die. The amount of powder in the forming die is the filling amount. The upper punch is then lowered into the forming die. The precompression rollers exert pressure, by means of which the filling amount in the forming die is freed of air, in that the particles are forced closer together. Then, the main compression rollers exert force, by means of which the powder is compressed into a compacted form. The upper punch is then pulled by the upper lifting cam out of the forming die. Subsequently, the lower punch is shifted upward by the expulsion cam upward, whereby the compacted form is expelled from the forming die, so that it can be removed by a scraper. The compression enables particle-to-particle bonding for the purpose of producing a tablet having sufficient cohesive strength or hardness to maintain its shape and appearance.

[10] In tableting machines with eccentric press (eccentric tablet presses), there is no

precompression and the force is not transmitted via compression rollers. However, the overall

principle of compression and compaction is very similar.

[11] If powder is introduced into an forming die, then there is empty space between

the particles. It has been shown that the particles consolidate during compression of the powder

and that the powder filling amount is freed of air. The movement of the powder is prevented

by the forming die, and time is provided for the cohesive bonding of particles to one another.

Then follow rearrangement of the particles, plastic and elastic deformation, and subsequently

fragmentation of the friable components after their deformation limit has been reached. The

pressure enables the formation of bonds between the particles, which give the compacted form

tensile strength. After the expulsion from the forming die, the compacted form undergoes a

kind of elastic relaxation, in which the elastic materials in part regain their shapes before the

compression. Due to the cohesion of the compressed particles, the shape of the compacted form

is maintained after compression.

[12] Some of the deformation characteristics are time-dependent and therefore

machine characteristics can have a great influence on the tableting performance. These characteristics determine the rate of force application, the residence time (i.e., the time of maximum compression force, which depends on the diameter of the surface of the punch head and the tangential speed and the decompression rate. In materials which undergo plastic deformation, in the case of increased machine speed, typically less time is available for the stress relaxation.

[13] Tablets have to be capable of withstanding the stresses of production,

packaging, shipping and distribution. According to the Quality Attribute Considerations for

Chewable Tablets, Guidance for the Industry of the FDA of August 2018, chewable tablets

should have a hardness of < 12 kp (- 19.6 N), wherein one is aware of the fact that the tablet

size and shape are important in establishing an acceptable tablet hardness. In the case of a very

small tablet, for example, a hardness value of 20 N could be quite high. Moreover, it has been

recommended that tablets that disintegrate rapidly with immediate release of the drug should

have a hardness of approximately 70 to 100 N, while tablets with prolonged release of the drug

should have a hardness of approximately 100 to 200 N. The larger the tablets are, the harder

they have to be, in order to withstand wear during production, packaging, shipping and

distribution. With regard to prolonged-release tablets, the tablet hardness therefore should be

at least 100 N, preferably at least 150 N.

[14] Within certain limits, the tablet hardness is a function of the compression force;

the higher the compression force is, the higher the tablet hardness is. In the case of a given

excipient mixture, an increased tablet hardness can thus frequently be achieved in that the

compression force is increased. However, this can at the same time require a reduction of the

machine speed, in order to correctly set the residence time, whereby the total tablet yield per

hour is reduced. The reason for this is that both the bonding between the particles and also the

adhesive bonding can be influenced not only by the compression force but also the punch

residence time during which the powder in the forming die is compressed. The residence time relates to the time period during which a punch compresses powder in the forming die. It is a function of the machine speed, wherein a more rapid tableting enables a shorter time period for compressing the powder in the forming die by the punch. If the residence time is increased, more time is available for particle deformation, for fragmentation in order to increase the surface area, and for forming bonds between particles. If the compression force is changed, then one must in addition take into consideration that not only the tablet hardness is influenced thereby. Harder tablets can have longer disintegration times and dissolution rates. In seeking a compromise between compression force and residence time, tablet attributes must be taken into consideration (more precise information can be found, for example, in M. T. Ende et al.,

Chemical Engineering In The Pharmaceutical Industry, Drug Product Design, Development,

and Modeling, 2"d edition, Wiley, 2019, pp. 228-232; J. Swarbrick, M. Bogda, Encyclopedia

of Pharmaceutical Technology, 3 rd edition, Informa Healthcare, 2007, Tablet Compression:

Machine Theory, Design and Process Troubleshooting, 3611-2629).

[15] An increase of the compression force for improving the tablet hardness can thus

require a reduction of the machine speed, which leads to economic disadvantages due to a

reduced output.

[16] Moreover, due to material properties (tool-related limitations), the compression

forces cannot be increased ad ultimo. The tablet tool strength is a function of the size, the shape,

and the filling weight of the tablet. Therefore, there are multiple tablet shapes and sizes that

allow the maximum compression strength of less than 10 kN. Consequently, tableting machines

which are provided with punches of such a size and shape already operate at compression forces

close to their maximum tool force, and, under these conditions, there is less maneuvering room

for increasing the compression force in order to increase the tablet hardness (more precise

information can be found, for example, in L. L. Augsburger et al., Pharmaceutical Dosage

Forms: Tablets, 3 rd edition, informa healthcare, 2008, pp. 26-30; J. Zheng, Formulation and

Analytical Development for Low-Dose Oral Drug Products, Wiley 2009, 150-155).

[17] From the prior art, different Tapentadol-containing tablets are known.

[18] WO 2003/035054 Al relates to a pharmaceutical formulation which is

characterized by a delayed release of Tapentadol HCl in a matrix with delayed release of the

active ingredient. This matrix contains between 1 and 80 wt.-% of at least one hydrophilic or

hydrophobic polymer as agent forming a pharmaceutically acceptable matrix. The granulate

was compressed on an EKO eccentric press (Korsch) into elongate tablets having a size of 6 x

mm and a break score.

[19] EP 2 942 054 Al relates to a pharmaceutical formulation with slow release,

which contains Tapentadol HCl in a slow release matrix, wherein the matrix contains between

and 50 wt.-% mono, di- and triglycerides of saturated fatty acids with a chain length between

16 and 22 carbon atoms or a mixture thereof. The influence of compression force and tablet

dimensions on the tablet hardness and the dissolution behavior was examined. At a constant

force of 27 kN, a tablet hardness of only 53 to 79 N could be achieved, while lower forces

yielded an even poorer tablet hardness.

[20] WO 2008/051617 A2 relates to a method for producing a dry granulate

composition, in which a pharmaceutical composition is compressed to a hardness of 800 to 900

kPa, thereby forming one or more blanks, and the one or more blanks are ground using an

oscillating granulator, thereby forming a granulate. An example of a pharmaceutical

formulation contains Tapentadol HCl, hypromellose, microcrystalline cellulose, colloidal

silicon dioxide, and magnesium stearate. In Figures 7 to 9, the influence of the compression

force on the tablet hardness is shown. In the case of compression forces of 2000 to 3000 lbs

(-8.9 to -13.3 kN), tablets with a hardness of approximately 7 to 20 kp (-69to-196 N) were

obtained.

[21] In WO 2015/014980 Al, a pharmaceutical composition is disclosed, which includes (a) dissolved Tapentadol HCl, (b) organic solvent with a boiling point of 1100 to 350

°C and (c) solid carrier. If a rotary press is used for producing the tablets, then the main

compression force can be in the range of 1 to 50 kN, preferably 3 to 40 kN. The tablets obtained

can have a hardness of 30 to 400 N, particularly preferably of 50 to 250 N, especially preferably

of 30 to 180 N and even more preferably of 40 to 150 N.

[22] D. V. Reddy et al., Journal of Pharmacy Research 2014. 8(10), 1368-1374,

describe the production of Tapentadol HCl tablets with delayed release using combinations of

hydrophilic and hydrophobic polymers, produced by wet granulation.

[23] S. M. Afzal et al., Int J A PS BMS 2017, 6(1), 1-21 relates to the production of

Tapentadol HCl tablets with a sustained release matrix by means of a sintering method.

[24] S. K. Paramasivan et al., GSC Biological and Pharmaceutical Sciences, 2018,

04(03), 042-048 relates to Tapentadol-containing tablets which are produced by direct

compression in a rotary tablet press.

[25] The known Tapentadol-containing tablets are not satisfactory in this regard

particularly since the compression of tablets from the starting material requires considerable

compression forces in order to achieve a satisfactory mechanical strength, for example,

hardness.

[26] It would be desirable to provide oral dosage forms of Tapentadol that are easy

to produce and do not require e.g., thermal forming or multiple coating steps. The oral dosage

forms should preferably be provided in the form of tablets, preferably monolithic tablets, i.e.

the production of a plurality of particles should not be necessary. The production of the oral

dosage forms should be possible on standard equipment at industrial high throughput scale,

preferably by compression of powder mixtures, possibly involving granulation (dry granulation

or wet granulation), but preferably by direct compression of powder mixtures.

[27] There is a need for formulations of Tapentadol that can be compressed by means of conventional tableting machines at high machine speeds into tablets which provide satisfactory tablet properties, particularly with regard to hardness, and which allow a wide variety of tablet sizes and shapes without reaching the tool strength limits of the conventional tableting apparatus.

[28] Disclosed herein are pharmaceutical dosage forms of Tapentadol that may have one or more advantages compared to the pharmaceutical dosage forms of the prior art.

SUMMARY OF THE INVENTION

[28a] In a first embodiment there is provided a pharmaceutical dosage form comprising Tapentadol for twice daily administration; wherein Tapentadol is present as a salt with tartaric acid; wherein the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form is in the range of 10 to 300 mg relative to the free base of Tapentadol; wherein the dosage form is a tablet; wherein the dosage form provides a prolonged release of Tapentadol; and wherein Tapentadol is embedded in a prolonged-release matrix.

[28b] In a second embodiment there is provided a method of treating pain, comprising administering the pharmaceutical dosage form according to the first embodiment to a subject in need thereof.

[28c] In a third embodiment there is provided use of the pharmaceutical dosage form according to the first embodiment, for the manufacture of a medicament for treating pain.

[28d] In a fourth embodiment there is provided a method for the preparation of a pharmaceutical dosage form according to the first embodiment, wherein the method comprises the following steps: (a) providing a mixture containing substantially the entire amount of Tapentadol to be contained in the dosage form and at least one prolonged-release matrix material, optionally together with one or more excipients; (b) optionally granulating the mixture provided in step (a), thereby obtaining a granulate; (c) optionally mixing the granulate obtained in step (b) with one or more excipients, thereby obtaining a granulate mixture; (d) compressing the mixture provided in step (a) or the granulate obtained in step (b) or the granulate mixture obtained in step (c) into tablets; (e) optionally, film coating the tablets compressed in step (d).

9a

[29] The invention provides a pharmaceutical dosage form comprising Tapentadol for oral administration twice daily; wherein Tapentadol is present as a salt with tartaric acid, in particular L-(+)-tartaric acid; wherein the dosage form provides prolonged release of Tapentadol; and wherein the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form is in the range of 10 to 300 mg relative to the free base of Tapentadol (Mr = 221.3 g/mol).

[30] It has been surprisingly found that salts of Tapentadol with tartaric acid, in particular L-(+)-tartaric acid, are particularly useful for pharmaceutical dosage forms providing prolonged-release of Tapentadol. It has been surprisingly found that, in comparison to conventional Tapentadol hydrochloride, the production of compressed tablets comprising salts of Tapentadol with tartaric acid, in particular L-(+)-tartaric acid, requires significantly reduced compression forces, in order to achieve a desired target breaking strength of the tablets. This effect depends advantageously neither upon the particle size of the salts of Tapentadol with tartaric acid, nor on the polymorphic form of the salt of Tapentadol with tartaric acid. In particular, this effect is also observed with various other excipients, i.e. it is attributable to the properties of the salt of Tapentadol with tartaric acid, in particular L-(+)-tartaric acid, as such.

[31] A crystalline product of Tapentadol with tartaric acid is known from WO

2017/085734 Al. However, the reduction of the compression forces for reaching a desired

target breaking strength of the tablets in not addressed this citation.

[32] Dosage forms providing prolonged release of Tapentadol are also known, e.g.

from WO 03/035053 Al, WO 2006/002886 Al, and WO 2009/092601 Al. But the reduction

of the compression forces for reaching a desired target breaking strength of the tablets is not

addressed in this citation.

[33] According to the instructions for use, the commercial Tapentadol tablets

Palexia ®retard contain Tapentadol as hydrochloride salt, wherein the tablet core additionally

contains hypromellose, microcrystalline cellulose, highly dispersed silicon dioxide, and

magnesium stearate. Thus, Palexia ®retard tablets contain a prolonged-release matrix of

hypromellose. The tablet cores are film coated with a composition comprising hypromellose,

lactose monohydrate, talc, macrogol 6000 and colorants. These tablets are in accordance with

WO 03/035053 Al and the comparative examples contained herein in the experimental section.

BRIEF DESCRIPTION OF THE DRAWINGS

[34] Figure 1 shows the XRPD diffractogram of the crystalline form of Tapentadol

and L-(+)-tartaric acid as obtained according to WO 2017/085734 Al.

[35] Figure 2 shows the infrared spectrum of the crystalline form of Tapentadol and

L-(+)-tartaric acid as obtained according to WO 2017/085734 Al.

[36] Figure 3 shows the XRPD diffractogram of the crystalline form of Tapentadol

tartrate according to Example 1.

DETAILED DESCRIPTION OF THE INVENTION

[37] A first aspect of the invention relates to a pharmaceutical dosage form

comprising Tapentadol for oral administration twice daily; wherein Tapentadol is present as a

salt with tartaric acid, in particular L-(+)-tartaric acid; wherein the dosage form provides

prolonged release of Tapentadol; and wherein the weight equivalent dose of Tapentadol that is

contained in the pharmaceutical dosage form is in the range of 10 to 300 mg relative to the free

base of Tapentadol.

[38] Tapentadol, i.e. (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2

methylpropyl)phenol, is a synthetic, centrally acting analgesic which is effective in the

treatment of moderate to severe, acute or chronic pain. The synthesis of the free base of

Tapentadol is known e.g. from EP-A 693 475.

[39] The pharmaceutical dosage form according to the invention contains

Tapentadol as a salt with tartaric acid, in particular L-(+)-tartaric acid. While it is considered

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), preferably the entire amount of Tapentadol that is contained in the

pharmaceutical dosage form is present as a salt with tartaric acid, in particular L-(+)- tartaric

acid.

[40] The inventive salts of Tapentadol with tartaric acid in principle include the salts

with L-(+)-tartaric acid, D-(-)-tartaric acid, DL-(+)-tartaric acid and meso tartaric acid. L-(+)

Tartaric acid is also referred to as (2R,3R)-tartaric acid, D-(-)-tartaric acid is also referred to as

(2S,3S)-tartaric acid, and DL-(+)-tartaric acid is also referred to as (2RS,3SR)-tartaric acid.

The corresponding salts are referred to as L-(+)-tartrates , D-(-)-tartrates as well as DL-(±)

tartrates.

[41] Preferably, the salt of Tapentadol with tartaric acid is salt of Tapentadol with L

(+)-tartaric acid which can optionally be solvated (for example, hydrated) or ansolvated (for

example, anhydrated). The salt of Tapentadol can be in the form of an individual polymorphic

form or in the form of a mixture of different polymorphic forms in any mixing ratio.

[42] According to a preferred embodiment, the salt of Tapentadol with tartaric acid

is the salt with L-(+)-tartaric acid which is present substantially in pure crystalline form of

Tapentadol-L-(+)-tartrate.

[43] It is taken into consideration that, in the salt of Tapentadol with tartaric acid, in

particular L-(+)-tartaric acid, these two components are present in a ratio of 1:0.4 to 1:2.1.

[44] Salts with a substantially 2:1 stoichiometry of Tapentadol to tartaric acid, in

particular L-(+)-tartaric acid, are also referred to as hemi-salts and they are also covered.

[45] According to a preferred embodiment, the salt of Tapentadol with tartaric acid

is a crystalline L-(+)-tartaric acid salt, for example, Tapentadol L-(+)-tartrate, with

characteristic X-ray powder diffraction peaks at 14.1, 20.0, 21.1 and 23.7 degrees 20 ( 0.2

degrees 20); preferably characterized by one or more additional X-ray powder diffraction

peaks at 12.7, 18.6, 21.6, 22.1, 25.6 and/or 28.5 degrees 20 ( 0.2 degrees 20).

[46] Alternatively, the crystalline Tapentadol L-(+)-tartrate can also be characterized

by the following X-ray powder diffraction peaks in degrees 20+0.2 degrees 20: 12.7, 14.1,

18.6, 20.0, 21.1, 21.6, 22.1, 23.7, 25.6 and/or 28.5.

[47] X-ray powder diffraction measurements are carried out with Cu, Ka radiation at

room temperature. A suitable apparatus is, for example, D8 ADVANCE Eco, Bruker. DSC

measurements are carried out according to ASTM D3418. IR spectra are obtained on an FTIR

spectrometer.

[48] Also, alternatively, the crystalline Tapentadol L-(+)-tartrate can be

characterized in that it has an endothermal transition at 132 °C±3 °C in the differential scanning calorimetry.

[49] Furthermore, alternatively, crystalline Tapentadol L-(+)-tartrate can be

characterized by absorption bands in the infrared spectrum at 3319, 3237, 2960, 1731, 1597,

1305, 1263, 1213, 791, 679 and 485 cm-'.

[50] A corresponding crystalline Tapentadol L-(+)-tartrate as well as method for the

production thereof and methods for the characterization thereof are known from WO

2017/085734 Al.

[51] For the purposes of the description, reference to "Tapentadol" should include

the salt of Tapentadol with tartaric acid.

[52] The salt of Tapentadol with tartaric acid, in particular L-(+)-tartaric acid, can be

present in the form of any solvate, for example, hydrate, ansolvate, for example, anhydrate,

and any polymorphic form, for example, crystalline form and/or amorphous form.

[53] The weight equivalent dose of Tapentadol that is contained in the

pharmaceutical dosage form according to the invention is in the range of 10 to 300 mg relative

to the free base of Tapentadol, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg. The

free base of Tapentadol (i.e. the free molecule) has a molecular weight of 221.3 g/mol. Thus,

mg of the free base of Tapentadol correspond to 0.0452 mmol, while 300 mg of the free

base of Tapentadol correspond to 1.3556 mmol. Thus, in other words, the pharmaceutical

dosage form contains a mole equivalent dose of Tapentadol in the range of 0.0452 to 1.3556

mmol.

[54] The hydrochloride salt of Tapentadol (anhydrate) has a molecular weight of

257.8 g/mol, while the tartaric acid salt of Tapentadol (anhydrate) has a molecular weight of

371.4 g/mol. Thus, when the pharmaceutical dosage form according to the invention contains

e.g. a weight equivalent dose of 100 mg relative to the free base of Tapentadol (0.4518 mmol),

it actually contains 167.8 mg tartaric acid salt of Tapentadol (0.4518 mmol).

[55] Unless expressly stated otherwise, dose information for Tapentadol is thus

expressed as equivalent weight relative to the free base of Tapentadol, i.e. the non-salt form,

the non-solvate form, the non-cocrystal form, and the non-aggregate form of Tapentadol with

any other molecules. It is contemplated that the form of Tapentadol, i.e. salt of Tapentadol with

tartaric acid, that is actually contained in the pharmaceutical dosage form, i.e. the salt of

Tapentadol with tartaric acid, in particular L-(+)-tartaric acid, may be present in form of any

polymorph and/or solvate and/or cocrystal and/or any other aggregate of such salt with other

molecules.

[56] Unless expressly stated otherwise, all percentages are weight percent and are

related to the total weight of the pharmaceutical dosage form. When the pharmaceutical dosage

form is coated, the weight of the coating is included in the total weight of the pharmaceutical

dosage form.

[57] While it is contemplated that besides Tapentadol the pharmaceutical dosage

form according to the invention may contain additional pharmacologically active ingredients,

Tapentadol is preferably the sole pharmacologically active ingredient that is contained in the

pharmaceutical dosage form.

[58] Preferably, Tapentadol is homogeneously distributed over the pharmaceutical

dosage form according to the invention.

[59] The pharmaceutical dosage form according to the invention is devoted for oral

administration, preferably by swallowing the pharmaceutical dosage form as a whole. Thus,

the pharmaceutical dosage form according to the invention is preferably not devoted for buccal

or sublingual administration where the pharmaceutical dosage form would be devoted to

remain within the oral cavity.

[60] The pharmaceutical dosage form according to the invention is devoted for

administration twice daily. Thus, the pharmaceutical dosage form according to the invention contains 50% of the daily dose of Tapentadol that is intended for administration in order to bring about the desired therapeutic effect.

[61] Administration twice daily may proceed at intervals of about every 12 hours,

although such regimen is not to be strictly followed. For the purpose of the specification, twice

daily shall also encompass any administration regimen where two pharmaceutical dosage forms

according to the invention are administered during a period of about 24 hours, where the two

administrations must be separated from one another by at least 4 hours, preferably at least 8

hours.

[62] The pharmaceutical dosage form according to the invention provides prolonged

release of Tapentadol. For the purpose of the specification, prolonged release means not

immediate release. Prolonged release includes controlled release, delayed release, extended

release, staggered release, repeat action release, sustained release and evenly sustained release.

Prolonged release preferably means a release with a reduced release rate, to obtain a therapeutic

effect upright, to reduce toxic effects or for some other therapeutic purpose.

[63] Prolonged release may be based upon different technologies that are known to

the skilled person. In a preferred embodiment, prolonged release is based upon prolonged

release coating materials with which the pharmaceutical dosage form as such or with which a

multitude of particles may be coated. In another preferred embodiment, prolonged release is

based upon a prolonged-release matrix in which Tapentadol is preferably embedded. It is

further contemplated in accordance with the invention that prolonged release may be achieved

by alternative concepts such as ion exchange resins, osmotic dosage forms, and the like.

[64] Preferably, the pharmaceutical dosage form according to the invention after oral

administration provides plasma levels of Tapentadol providing pain relief (analgesia) for a

duration of at least 6 hours, preferably at least 8 hours, more preferably at least 10 hours, most

preferably at least 12 hours.

[65] Preferably, the pharmaceutical dosage form according to the invention provides

an in vitro dissolution profile, measured by the USP Paddle Method at 50 rpm in 900 mL

aqueous phosphate buffer at pH 6.8 at 37 °C, wherein

- after 0.5 hour 2020 wt.-%; preferably 2015 wt.-%; more preferably 2010

wt.-%;

- after 4 hours 60+20 wt.-%; preferably 60+15 wt.-%; more preferably 60+10 wt.

%; and

- after 12 hours at least 60 wt.-%; preferably at least 70 wt.-%; more preferably

at least 80 wt.-%

of the Tapentadol that was originally contained in the dosage form have been released.

[66] Preferably, the pharmaceutical dosage form according to the invention provides

aqueous phosphate buffer at pH 6.8 at 37 °C, wherein

- after 1 hour 25+15 wt.-%; preferably 25+10 wt.-%; more preferably 25+5.0 wt.

0.

- after 2 hours 3520 wt.-%; preferably 3510 wt.-%; more preferably 355.0

wt.-%;

- after 4 hours 5020 wt.-%; preferably 5010 wt.-%; more preferably 505.0

wt.-%;

- after 8 hours 8020 wt.-%; preferably 8010 wt.-%; more preferably 805.0

wt.-%;

[67] Preferably, the pharmaceutical dosage form according to the invention provides

aqueous buffer at pH 4.5 at 37 °C, wherein

- after 0.5 hour 20±20 wt.-%; preferably 2015 wt.-%; more preferably 2010 wt.-%;

- after 4 hours 6020 wt.-%; preferably 60+15 wt.-%; more preferably 6010 wt.-%; and

- after 12 hours at least 60 wt.-%; preferably at least 70 wt.-%; more preferably at least

wt.-%

[68] Preferably, the pharmaceutical dosage form according to the invention provides

aqueous buffer at pH 4.5 at 37 °C, wherein

- after 1 hour 25+15 wt.-%; preferably 25+10 wt.-%; more preferably 25+5.0 wt.

0.

- after 2 hours 3520 wt.-%; preferably 3510 wt.-%; more preferably 355.0

wt.-%;

- after 4 hours 5020 wt.-%; preferably 5010 wt.-%; more preferably 505.0

wt.-%;

- after 8 hours 8020 wt.-%; preferably 8010 wt.-%; more preferably 805.0

wt.-%;

[69] Preferably, the pharmaceutical dosage form according to the invention provides

an in vitro dissolution profile, measured by the USP Paddle Method at 50 rpm in 900 mL 0.1

N HCl at pH 1.0 and 37 °C, wherein

- after 0.5 hour 2020 wt.-%; preferably 2015 wt.-%; more preferably 2010

wt.-%;

- after 4 hours 60+20 wt.-%; preferably 60+15 wt.-%; more preferably 60+10 wt.

%; and

- after 12 hours at least 60 wt.-%; preferably at least 70 wt.-%; more preferably at least 80 wt.-% of the Tapentadol that was originally contained in the dosage form have been released.

[70] Preferably, the pharmaceutical dosage form according to the invention provides

N HCl at pH 1.0 and 37 °C, wherein

- after 1 hour 2510 wt.- % ; preferably 2510 wt.- % ; more preferably 255.0 wt.- % ;

- after 2 hours 4030 wt.- %; preferably 4010 wt.- % ; more preferably 405.0 wt.- % ;

- after 4 hours 6020 wt.- %; preferably 6010 wt.- % ; more preferably 605.0 wt.- % ;

- after 8 hours 8020 wt.-%; preferably 8010 wt.-%; more preferably 805.0 wt.-%;

[71] The pharmaceutical dosage form according to the invention preferably provides

resistance to ethanol-induced dose-dumping.

[72] Preferably, the pharmaceutical dosage form according to the invention provides

a slower in vitro dissolution of Tapentadol in an aqueous medium containing ethanol than in a

medium not containing ethanol.

[73] Preferably, the pharmaceutical dosage form according to the invention provides

a slower dissolution of Tapentadol in 0.1 N HCl with 5.0 vol.-% ethanol (pH 1.0) than in 0.1

N HCl without 5.0 vol.-% ethanol (pH 1.0), in each case measured by the USP Paddle Method

at 50 rpm in 900 mL at 37 C.

[74] Preferably, the pharmaceutical dosage form according to the invention provides

a slower dissolution of Tapentadol in 0.1 N HC1 with 20 vol.-% ethanol (pH 1.0) than in 0.1 N

HCl without 20 vol.-% ethanol (pH 1.0), in each case measured by the USP Paddle Method at

rpm in 900 mL at 37 °C.

[75] Preferably, the pharmaceutical dosage form according to the invention provides

a slower dissolution of Tapentadol in 0.1 N HCl with 40 vol.-% ethanol (pH 1.0) than in 0.1 N

HCl without 40 vol.-% ethanol (pH 1.0), in each case measured by the USP Paddle Method at

rpm in 900 mL at 37 °C.

[76] According to preferred embodiments of the pharmaceutical dosage form

according to the invention, the weight equivalent dose of Tapentadol that is contained in the

pharmaceutical dosage form is 25 mg, 50 mg, or 100 mg, in each case relative to the free base

of Tapentadol. Preferably, the pharmaceutical dosage form according to the invention has a

total weight in the range of 150 to 750 mg.

[77] In preferred embodiments with the pharmaceutical dosage form according to

the invention, the weight equivalent dose of Tapentadol that is contained in the pharmaceutical

dosage form is 150 mg, 200 mg or 250 mg, in each case relative to the free base of Tapentadol.

Preferably, the pharmaceutical dosage form according to the invention has a total weight in the

range of 300 to 1200 mg.

[78] Preferably, the pharmaceutical dosage form according to the invention

comprises one, two or more physiologically acceptable excipients.

[79] Pharmaceutical excipients are known to the skilled person (cf. e.g. R. C. Rowe

et al., Handbook of Pharmaceutical Excipients, Pharmaceutical Press; 6th edition 2009; E.-M.

Hoepfner et al., Fiedler-Encyclopedia of Excipients, Editio Cantor, 6th edition 2008). For the

purpose of the specification, a "pharmaceutical excipient" is preferably to be regarded as any

pharmacologically inactive substance typically used as a carrier for the active ingredients of a

medication. The pharmaceutical excipient may have a physiological effect, e.g. like a vitamin,

but not a pharmacological effect, like a drug. Typical examples of pharmaceutical excipients

include antiadherents, binders, coating materials, disintegrants, fillers, diluents, flavors,

colorants, glidants, lubricants, preservatives, sorbents, surfactants, sweeteners, dyes, pigments,

and the like.

[80] Any of the foregoing excipients can be divided into subgroups. For example, preservatives can be divided into antioxidants, buffers, antimicrobial substances and the like; while binders can be divided into solution binders and dry binders. Several excipients simultaneously exhibit different properties so that they can serve different purposes. For example, polyethylene glycol can be used as binder, plasticizer and the like.

[81] Preferably, the pharmaceutical dosage form according to the invention,

preferably the prolonged-release matrix, comprises a binder.

[82] Preferably, the binder is selected from the group consisting of cellulose,

magnesium-aluminum silicates (e.g. bentonite), mono-, oligo- and poylsaccharides (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; more preferably silicified microcrystalline cellulose.

[83] Preferably, the weight content of the binder is at least 5.0 wt.-%, more

preferably at least 10 wt.-%, still more preferably at least 15 wt.-%, yet more preferably at least

wt.-%, even more preferably at least 25 wt.-%, most preferably at least 30 wt.-%, and in

particular at least 35 wt.-%, in each case relative to the total weight of the pharmaceutical

dosage form.

[84] Preferably, the weight content of the binder is at most 85 wt.-%, more preferably

at most 82.5 wt.-%, still more preferably at most 80 wt.-%, yet more preferably at most 77.5

wt.-%, even more preferably at most 75 wt.-%, most preferably at most 72.5 wt.-%, and in

particular at most 70 wt.-%, in each case relative to the total weight of the pharmaceutical

dosage form.

[85] Preferably, the weight content of the binder is in the range of5230 wt.-%, more

preferably 52+27.5 wt.-%, still more preferably 52+25 wt.-%, yet more preferably 5222.5 wt.

%, even more preferably 52+20 wt.-%, most preferably 52+17.5 wt.-%, and in particular 5215 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.

[86] When the pharmaceutical dosage form contains more than one binder, the above

percentages refer to the total content of all binders that are contained in the pharmaceutical

dosage form.

[87] Preferably, the pharmaceutical dosage form according to the invention

comprises a lubricant.

[88] Preferably, the lubricant is selected from the group consisting of salts of fatty

acids (e.g. magnesium stearate, calcium stearate, zinc stearate), fatty acids (e.g. stearic acid,

palmitic acid), glyceryl fatty acid esters (e.g. glyceryl monostearate, glyceryl monobehenate,

glyceryl dibehenate, glyceryl tribehenate), sorbitan monostearate, sucrose monopalmitate,

sodium stearyl fumarate, hydrated magnesium silicate, and talc; preferably magnesium

stearate.

[89] Preferably, the weight content of the lubricant is at least 0.20 wt.-%, more

preferably at least 0.25 wt.-%, still more preferably at least 0.30 wt.-%, yet more preferably at

least 0.35 wt.-%, even more preferably at least 0.40 wt.-%, most preferably at least 0.45 wt.

%, and in particular at least 0.50 wt.-%, in each case relative to the total weight of the

pharmaceutical dosage form.

[90] Preferably, the weight content of the lubricant is at most 3.0 wt.-%, more

preferably at most 2.8 wt.-%, still more preferably at most 2.6 wt.-%, yet more preferably at

most 2.40 wt.-%, even more preferably at most 2.20 wt.-%, most preferably at most 2.00 wt.

%, and in particular at most 1.80 wt.-%, in each case relative to the total weight of the

pharmaceutical dosage form.

[91] Preferably, the weight content of the lubricant is in the range of 0.11.0 wt.-%,

more preferably 0.50+0.45 wt.-%, still more preferably 0.50+0.40 wt.-%, yet more preferably

0.50+0.35 wt.-%, even more preferably 0.500.30 wt.-%, most preferably 0.500.25 wt.-%, and in particular 0.50+0.20 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.

[92] According to preferred embodiments of the pharmaceutical dosage form

according to the invention, the dosage form contains prolonged-release coating with prolonged

release which includes a prolonged-release coating material selected from the group consisting

of hydrophobic cellulose ethers, acrylic polymers, shellac, zein, hydrophobic wax-like products

and mixtures thereof.

[93] It is taken into consideration that the dosage form is a monolith which includes

such a prolonged-release coating. According to a preferred embodiment, the dosage form is

multiparticulate, wherein the individual particles (granules, pellets and the like) include such a

prolonged-release coating.

[94] The number of particles contained in the dosage form is not particularly limited

and can be in the range of 1, 2, 3, 4 or 5 to 10, 20, 30, 40 to 100, 200 and more.

[95] Preferably, the particles have substantially the same weight, the same size and

the same composition.

[96] According to a preferred embodiment, the particles contain a core which

substantially comprises the entire amount of Tapentadol, optionally together with one or more

excipients, and a prolonged-release coating encapsulating the core.

[97] According to another preferred embodiment, the particles contain an inert core

which contains no Tapentadol (for example, sugar beads), a drug coating which encapsulates

the core and substantially includes the entire amount of Tapentadol, optionally together with

one or more excipients, and a prolonged-release coating encapsulating the core and the drug

coating layer.

[98] The prolonged-release coating material is preferably selected from the group

consisting of acrylic acid and methacrylic acid copolymers, aminoalkyl methacrylate copolymers, cyanoethyl methacrylates, ethoxyethyl methacrylates, ethylcellulose, methacrylic acid alkylamide copolymers, methacrylic acid copolymers, methyl methacrylates, methyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid) (anhydride), poly(methacrylic acid), glycidyl methacrylate copolymers, poly(methyl methacrylate), poly(methyl methacrylate) copolymers, polyacrylamide and polymethacrylate.

[99] According to preferred embodiments, the acrylic polymer consists of one or

more ammoniomethacrylate copolymers, i.e., copolymers of acrylic and methacrylic acid esters

with a low content of quaternary ammonium groups. To obtain a desirable dissolution profile,

it may be necessary to include two or more ammoniomethacrylate copolymers with different

physical properties, such as different molar ratios of quaternary ammonium groups with respect

to neutral (meth)acrylic acid esters.

[100] The coating is preferably produced from an aqueous dispersion or an organic

dispersion or an organic solution of a hydrophobic polymer. The coating preferably comprises

an effective amount of a plasticizer which is also present in the aqueous dispersion of the

hydrophobic polymer. The plasticizer further improves the physical properties of the film.

Since, for example, ethylcellulose has a relatively high glass transition temperature and under

normal coating conditions does not form flexible films, it is necessary to plasticize the

ethylcellulose before its use as coating material. In general, the amount of plasticizer added to

a coating solution is based on the concentration of the film former, for example, most

commonly approximately 1 to approximately 50 weight percent of the film former.

[101] Examples of suitable plasticizers for ethylcellulose include water-insoluble

plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and

triacetin, although it is possible to use other water-insoluble plasticizers (such as acetylated

monoglycerides, phthalate ester, castor bean oil, etc.). Triethyl citrate is a particularly preferred

plasticizer for the aqueous dispersions of ethylcelllulose of the present invention.

[102] Examples of suitable plasticizers for the acrylic polymers of the present

invention include, although this is not limiting, citric acid esters such as triethyl citrate NF XVI,

tributyl citrate, dibutyl phthalate and optionally 1,2-propylene glycol. Other plasticizers which

have been found to be suitable for improving the elasticity of the films formed by acrylic films,

such as Eudragit RL/RS lacquer solutions, include polyethylene glycols, polypropylene

glycols, diethyl phthalate, castor oil and triacetin. Triethyl citrate is a particularly preferred

plasticizer for the aqueous dispersions of ethylcellulose of the present invention.

[103] The addition of talc reduces the tendency of the aqueous dispersions to adhere

during processing and acts as a polishing agent.

[104] In addition to modifying the dissolution profile by changing the relative

amounts of the different acrylic resin lacquers, the dissolution profile of the product obtained

in the end can also be modified in that, for example, by increasing or reducing the thickness of

the delayed release coating. If one uses the aqueous dispersion of the hydrophobic polymer for

coating inert pharmaceutical beads, then, subsequently a plurality of obtained stabilized solid

beads with prolonged release can be added to a gelatin capsule in an amount which is sufficient

upon ingestion and contact with gastric juice for providing an effective prolonged-release dose.

[105] The prolonged-release profile can be changed, for example, by varying the

amount of coating with the aqueous dispersion of the hydrophobic polymer, by changing the

manner in which the plasticizer is added to the aqueous dispersion of the hydrophobic polymer,

by varying the amount of plasticizer relative to the hydrophilic polymer, by including

additional ingredients or excipients, by changing the production method, etc.

[106] The coating preferably contains, in addition to the film former, plasticizers and

solvent system (i.e., water), a colorant for providing elegance and product differentiation.

Suitable ingredients for providing color for the formulation when using an aqueous dispersion

of an acrylic polymer include titanium dioxide and color pigments such as iron oxide pigments.

However, the inclusion of pigments can increase the delaying effect of the coating.

[107] The plasticized aqueous dispersion or organic dispersion or organic solution of

the hydrophobic polymer can be applied by spraying onto substrate comprising the Tapentadol

using any suitable spraying device known in the prior 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 brings about drying during the spraying of the acrylic polymer coating. Preferably,

for obtaining a predetermined controlled release of Tapentadol in case of exposure of the coated

substrate to aqueous solutions, for example, gastric juice, a sufficient amount of the aqueous

dispersion of the hydrophobic polymer is applied, taking into consideration the manner in

which the plasticizer was incorporated, etc. After the coating with the hydrophobic polymer,

an additional coating of a film former such as Opadry@ can optionally be applied to the beads.

This coating is only provided, if it is provided at all, in order to considerably reduce the

agglomeration of the beads.

[108] The release of Tapentadol from the prolonged-release formulation can

furthermore be influenced, i.e. set at a desired rate, by addition of one or more release

modifying agents or by providing one or more passages through the coating. The ratio of

hydrophobic polymer with respect to water-soluble material, in addition to other factors, is

determined by the required release rate and the solubility characteristics of the selected

materials. The release-modifying agents functioning as pore formers can be organic or

inorganic and include materials which can be dissolved, extracted or leached out of the coating

in the application environment. Pore formers can include one or more hydrophilic polymers

such as hydroxypropylmethylcellulose. The controlled release coatings can additionally

include erosion-promoting agents such as starches and gums. The controlled release coatings

for the controlled release according to the present invention can moreover include materials

which are suitable for the formation of microporous lamina in the application environment, such as polycarbonates consisting of linear chain carbonic acid polyesters in which the carbonate groups in the polymer chain recur.

[109] According to a preferred embodiment, the dosage form is multiparticulate,

wherein the individual particles (granules, pellets and the like) with a prolonged-release coating

are contained in a capsule, optionally together with additional excipients which can be

contained in the capsule in powder form or likewise in the form of particles (granules, pellets

and the like). In the latter case, the capsules contain at least two different types of particles,

namely particles which contain Tapentadol and particles which contain no Tapentadol.

[110] According to another preferred embodiment, the dosage form is

multiparticulate, wherein the individual particles (granules, pellets and the like) with a

prolonged-release coating are contained in a tablet which contains an extraparticulate material

(Multiple Unit Pellet System, MUPS). The extraparticulate material preferably contains at least

one excipient selected from binders, disintegrants and lubricants.

[111] According to preferred embodiments of the pharmaceutical dosage form

according to the invention, the Tapentadol is embedded in a prolonged-release matrix.

[112] Preferably, the pharmaceutical dosage form according to the invention,

preferably the prolonged-release matrix, contains at least one physiologically acceptable

polymer which is used for delaying the release of the pharmacological active ingredient from

the pharmaceutical dosage form. The at least one physiologically acceptable polymer is thus

part of the prolonged-release matrix of the pharmaceutical dosage form according to the

invention.

[113] The prolonged-release matrix preferably comprises or substantially consists of

at least one prolonged-release matrix material selected from the group consisting of hydrophilic

or hydrophobic polymers and hydrocarbons.

[114] According to preferred embodiments of the pharmaceutical dosage form according to the invention, the prolonged-release matrix comprises or substantially consists of at least one polymer selected from the group consisting of

- polysaccharides or gums (e.g. xanthan gum, guar gum, karaya gum, locust bean

gum, sodium alginate, carob gum, chitosan, polysaccharides of mannose and galactose, pectin,

tragacanth, agar-agar);

- cellulose ethers (e.g. HPMC, HPC, HEC, MC, EC);

- cellulose esters (e.g. cellulose acetate, cellulose acetate succinate, cellulose

acetate phthalate, cellulose acetate butyrate);

- polyalkylene glycols and polyalkylene oxides;

- polyvinylalcohol (PVA), cross-linked polyvinylalcohol (PVA),

polyvinylpyrrolidone (PVP), cross-linked polyvinylpyrrolidone (PVP), polyvinylpyrrolidone

vinylacetate copolymers, polyvinyl chloride (PVC), polyethylene vinyl acetate (PVAc),

polydimethylsiloxane (PDS), polyether urethane (PEU), polylactic acid (PLA), polyglycolic

acid (PGA), polycaprolactone (PCL), polyanhydrides, polyorthoesters;

- acrylic resins (e.g. cross-linked homopolymers and copolymers of acrylic acids,

acrylic acid and methacrylic acid copolymers, aminoalkyl methacrylate copolymer, cyanoethyl

methacrylate, ethoxyethyl methacrylate, methacrylic acid-alkyl amide copolymers,

methacrylic acid copolymers, methyl methacrylates, methyl methacrylate copolymers,

poly(acrylic acid), poly(methacrylic acid), poly(methacrylic acid anhydride), glycidyl

methacrylate copolymers, poly(methylmethacrylate), poly(methylmethacrylate) copolymers,

polyacrylamide, polyhydroxyethylmethacrylate (PHEMA) and polymethacrylate); and

- protein derived materials.

[115] Preferably, the prolonged-release matrix comprises or substantially consists of

at least one hydrocarbon selected from the group consisting of long chain (C-Co, especially

C 12-C 4 0) fatty acids, long chain fatty alcohols, glyceryl esters of long chain fatty acids, mineral oils, vegetable oils, and waxes.

[116] Preferably, the prolonged-release matrix comprises or substantially consists of

a prolonged-release matrix material selected from the group consisting of (i)

hydroxypropylmethylcellulose (HPMC); (ii) hydroxypropylcellulose (HPC); (iii)

hydroxyethylcellulose (HEC); (iv) microcrystalline cellulose (MCC); (v) ethylcellulose (EC);

(vi) polyvinyl acetate (PVAc); (vii) polyvinylpyrrolidone (PVP); (viii) polyvinylpyrrolidone

vinylacetate copolymer (PVP/PVAc); (ix) poly(ethylacrylate-co-methylmethacrylate-co

trimethylammonioethylmethacrylate chloride); (x) poly(butyl methacrylate-co-(2

dimethylaminoethyl)methacrylate-co-methylmethacrylate);(xi)poly(methylmethacrylate-co

methacrylic acid); (xii) poly(ethylacrylate-co-methacrylic acid); (xiii) poly(methylacrylate-co

methylmethacrylate-co-methacrylic acid); (xiv) poly(ethylacrylate-co-methylmethacrylate);

(xv) poly(ethylene oxide) (PEO); (xvi) polyethylene glycol (PEG); (xvii) long chain fatty

alcohol having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated

or unsaturated, linear or branched; (xviii) cetostearyl alcohol; (xix) stearyl alcohol; (xx) cetyl

alcohol; (xxi) hydrocarbon selected from the group consisting of long chain fatty acids having

8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated,

linear or branched; glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils,

and waxes; (xxii) xanthan gum; (xxiii) sodium alginate; (xxiv) guar gum; (xxv) locust bean

gum; and any mixtures of the foregoing. Preferably, the content of the prolonged-release matrix

material is in the range of 1510 wt.-%, or 2010 wt.-%, or 2510 wt.-%, or 3010 wt.-%, or

+10 wt.-%, or 40+10 wt.-%, or 45+10 wt.-%, or 50+10 wt.-%, or 5510 wt.-%, or 6010

wt.-%, or 65+10 wt.-%, or 70+10 wt.-%, or 75+10 wt.-%, or 80+10 wt.-%, in each case relative

to the total weight of the dosage form.

[117] Preferably, the pharmaceutical dosage forms according to the invention

comprise neither poly(alkylene oxide), e.g. poly(ethylene oxide), nor ethylene-vinylacetate copolymers (EVA). For the purpose of the specification, poly(alkylene oxide) is distinguished from poly(alkylene glycol) by its molecular weight; polymers having a weight average molecular weight Mw of less than 100,000 g/mol are to be regarded as poly(alkylene glycol), while polymers having a weight average molecular weight Mw of 100,000 g/mol or more are to be regarded as poly(alkylene oxide).

[118] Preferably, the prolonged-release matrix comprises a cellulose derivative

selected from cellulose ethers and cellulose esters or a poly(meth)acrylate or copolymer

thereof.

[119] Preferably, the cellulose derivative is a cellulose ether selected from the group

consisting of methylcellulose, ethylcellulose, propylcellulose, hydroxyethylcellulose,

hydroxypropylcellulose and hydroxypropylmethylcellulose; preferably

hydroxypropylmethylcellulose.

[120] Preferably, the cellulose derivative is hydroxypropylmethylcellulose.

Preferably, the hydroxypropylmethylcellulose is selected from hypromellose type 1828, 2208,

2906 and 2910 according to USP having the following methoxyl content hydroxypropoxyl

content:

Methoxyl (%) Hydroxypropoxyl (%)

Type min max min max

1828 16.5 20.0 23.0 32.0

2208 19.0 24.0 4.0 12.0

2906 27.0 30.0 4.0 7.5

2910 28.0 30.0 7.0 12.0

[121] Preferably, the viscosity of the physiologically acceptable polymer, preferably cellulose derivative, more preferably hydroxypropylmethylcellulose, is in the range of

100,00080,000 mPa-s, more preferably 100,00060,000 mPa-s, still more preferably

100,00040,000 mPa-s, yet more preferably 100,000+20,000 mPa-s.

[122] Preferably, the number average molecular weight Mn of the physiologically

acceptable polymer, preferably cellulose derivative, more preferably

hydroxypropylmethylcellulose, is not more than 220,000 g/mol, more preferably not more than

180,000 g/mol, still more preferably not more than 140,000 g/mol, yet more preferably not

more than 120,000 g/mol, even more preferably not more than 110,000 g/mol, most preferably

not more than 86,000 g/mol, and in particular not more than 63,000 g/mol.

[123] Preferably, the weight content of the physiologically acceptable polymer,

preferably cellulose ether, is at least 2.0 wt.-%, more preferably at least 3.0 wt.-%, still more

preferably at least 4.0 wt.-%, yet more preferably at least 5.0 wt.-%, even more preferably at

least 6.0 wt.-%, most preferably at least 7.0 wt.-%, and in particular at least 8.0 wt.-%, in each

case relative to the total weight of the pharmaceutical dosage form.

[124] Preferably, the weight content of the physiologically acceptable polymer,

preferably cellulose ether, is at most 62.5 wt.-%, more preferably at most 60 wt.-%, still more

preferably at most 57.5 wt.-%, yet more preferably at most 55 wt.-%, even more preferably at

most 52.5 wt.-%, most preferably at most 50 wt.-%, and in particular at most 47.5 wt.-%, in

each case relative to the total weight of the pharmaceutical dosage form.

[125] Preferably, the weight content of the physiologically acceptable polymer,

preferably cellulose ether, is in the range of 3028 wt.-%, more preferably 3026 wt.-%, still

more preferably 30+24 wt.-%, yet more preferably 30+22 wt.-%, even more preferably 3020

wt.-%, most preferably 3018 wt.-%, and in particular 30+16 wt.-%, in each case relative to

the total weight of the pharmaceutical dosage form.

[126] When the pharmaceutical dosage form contains more than one physiologically acceptable polymer serving the purpose of significantly retarding the release of the pharmacologically active ingredient from the pharmaceutical dosage form, preferably cellulose ether, the above percentages refer to the total content of all such physiologically acceptable polymers, preferably cellulose ethers, that are contained in the pharmaceutical dosage form.

[127] In a particularly preferred embodiment, the pharmaceutical dosage form

according to the invention comprises a weight equivalent dose of Tapentadol in the range of

to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case relative to

the free base of Tapentadol, and a prolonged-release matrix in which the salt of Tapentadol

with tartaric acid, preferably the salt of Tapentadol with L-(+)-tartaric acid salt, is embedded;

wherein the prolonged-release matrix comprises as prolonged-release matrix material

hydroxypropylmethylcellulose (HPMC) preferably in an amount of from 5.0 to 60 wt.-%, e.g.

1510 wt.-%, or 20+10 wt.-%, or 25+10 wt.-%, or 30+10 wt.-%, or 3510 wt.-%, or 4010

wt.-%, or 45+10 wt.-%, or 5010 wt.-%,in each case relative to the total weight of the dosage

form.

[128] In a particularly preferred embodiment, the pharmaceutical dosage form

hydroxypropylcellulose (HPC)preferably in an amount of from 10 to 50 wt.- % , e.g. 20+10 wt.

%, or 25+10 wt.-%, or 30+10 wt.-%, or 35+10 wt.-%, or 40+10 wt.-%, in each case relative to

the total weight of the dosage form.

[129] In a particularly preferred embodiment, the pharmaceutical dosage form

according to the invention comprises a weight equivalent dose of Tapentadol in the range of to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case relative to the free base of Tapentadol, and a prolonged-release matrix in which the salt of Tapentadol with tartaric acid, preferably the salt of Tapentadol with L-(+)-tartaric acid salt, is embedded; wherein the prolonged-release matrix comprises as prolonged-release matrix material hydroxyethylcellulose (HEC)preferably in an amount of from 5.0 to 50 wt.-%, e.g. 15+10 wt.

%, or 20+10 wt.-%, or 25+10 wt.-%, or 30+10 wt.-%, or 35+10 wt.-%, or 40+10 wt.-%, in each

case relative to the total weight of the dosage form.

[130] In a particularly preferred embodiment, the pharmaceutical dosage form

microcrystalline cellulose (MCC) preferably in an amount of from 10 to 70 wt.-%, e.g. 2010

wt.-%, or 25+10 wt.-%, or 30+10 wt.-%, or 35+10 wt.-%, or 40+10 wt.-%, or 4510 wt.-%, or

+10 wt.-%, or 5510 wt.-%, or 6010 wt.-%, in each case relative to the total weight of the

dosage form.

[131] In a particularly preferred embodiment, the pharmaceutical dosage form

ethylcellulose (EC)preferably in an amount of from 5.0 to 30 wt.-%, e.g. 1510 wt.-%, or

+10 wt.-%, in each case relative to the total weight of the dosage form.

[132] In a particularly preferred embodiment, the pharmaceutical dosage form

polyvinyl acetate (PVAc) preferably in an amount of from 25 to 70 wt.-%, e.g. 3510 wt.-%,

or 40+10 wt.-%, or 45+10 wt.-%, or 50+10 wt.-%, or 55+10 wt.-%, or 60+10 wt.-%, in each

case relative to the total weight of the dosage form. Preferably, the polyvinyl acetate is

employed in form of a blend with polyvinylpyrrolidone (povidone). Such a preferred blend is

commercially available e.g. as Kollidon* SR (80 wt.-% polyvinyl acetate, 19 wt.-% povidone,

0.8 wt.-% sodium lauryl sulfate, and 0.2 wt.-% silicic acid).

[133] In a particularly preferred embodiment, the pharmaceutical dosage form

polyvinylpyrrolidone (PVP) preferably in an amount of from 2.0 to 21 wt.-%, e.g. 10+5.0 wt.

%, or 15+5.0 wt.-%, in each case relative to the total weight of the dosage form.

[134] In a particularly preferred embodiment, the pharmaceutical dosage form

with tartaric acid, preferably the salt of Tapentadol with L-(+)-tartaric acid, is embedded; wherein the prolonged-release matrix comprises as prolonged-release matrix material polyvinylpyrrolidone-vinylacetate copolymer (PVP/PVAc) preferably in an amount of from

1.0 to 30 wt.-%, e.g. 15+10 wt.-%, or 20+10 wt.-%, in each case relative to the total weight of

the dosage form.

[135] In a particularly preferred embodiment, the pharmaceutical dosage form

with tartaric acid, preferably the salt of Tapentadol with L-(+)-tartaric acid, is embedded;

poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethylmethacrylate chloride)

preferably in an amount of from 5.0 to 45 wt.-%, e.g. 1510 wt.-%, or 2010 wt.-%, or 2510

wt.-%, or 30+10 wt.-%, or 3510 wt.-%, in each case relative to the total weight of the dosage

form. Poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate

chloride) is commercially available e.g. as Eudragit* RS and Eudragit* RL.

[136] In a particularly preferred embodiment, the pharmaceutical dosage form

poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate)

form. Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) is commercially available e.g. as Eudragit* E.

[137] In a particularly preferred embodiment, the pharmaceutical dosage form

poly(methyl methacrylate-co-methacrylic acid) preferably in an amount of from 5.0 to 45 wt.

%, e.g. 15+10 wt.-%, or 20+10 wt.-%, or 25+10 wt.-%, or 3010 wt.-%, or 3510 wt.-%, in

each case relative to the total weight of the dosage form. Poly(methyl methacrylate-co

methacrylic acid) is commercially available e.g. as Eudragit* L.

[138] In a particularly preferred embodiment, the pharmaceutical dosage form

poly(ethyl acrylate-co-methacrylic acid) preferably in an amount of from 5.0 to 45 wt.-%, e.g.

1510 wt.-%, or 20+10 wt.-%, or 25+10 wt.-%, or 30+10 wt.-%, or 35+10 wt.-%, in each case

relative to the total weight of the dosage form. Poly(ethyl acrylate-co-methacrylic acid) is

commercially available e.g. as Eudragit* S.

[139] In a particularly preferred embodiment, the pharmaceutical dosage form

the free base of Tapentadol, and a prolonged-release matrix in which the salt of Tapentadol with tartaric acid, preferably the salt of Tapentadol with L-(+)-tartaric acid, is embedded; wherein the prolonged-release matrix comprises as prolonged-release matrix material poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) preferably in an amount of from 5.0 to 45 wt.-%, e.g. 1510 wt.-%, or 2010 wt.-%, or 2510 wt.-%, or 3010 wt.-%, or

+10 wt.-%, in each case relative to the total weight of the dosage form. Poly(methyl acrylate

co-methyl methacrylate-co-methacrylic acid) is commercially available e.g. as Eudragit* FS.

[140] In a particularly preferred embodiment, the pharmaceutical dosage form

poly(ethyl acrylate-co-methyl methacrylate) preferably in an amount of from 5.0 to 45 wt.-%,

e.g. 15+10 wt.-%, or 20+10 wt.-%, or 25+10 wt.-%, or 30+10 wt.-%, or 35+10 wt.-%, in each

case relative to the total weight of the dosage form. Poly(ethyl acrylate-co-methyl

methacrylate) is commercially available e.g. as Eudragit* NE.

[141] In a particularly preferred embodiment, the pharmaceutical dosage form

poly(ethylene oxide) (PEO) preferably in an amount of from 25 to 65 wt.-%, e.g. 35+10 wt.

%, or 40+10 wt.-%, or 45+10 wt.-%, or 50+10 wt.-%, or 55+10 wt.-%, in each case relative to

the total weight of the dosage form.

[142] In a particularly preferred embodiment, the pharmaceutical dosage form

polyethylene glycol (PEG) preferably in an amount of from 5.0 to 35 wt.-%, e.g. 1510 wt.-%,

or 20+10 wt.-%, or 25+10 wt.-%, in each case relative to the total weight of the dosage form.

[143] In a particularly preferred embodiment, the pharmaceutical dosage form

wherein the prolonged-release matrix comprises as prolonged-release matrix material a long

chain fatty alcohol having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may

be saturated or unsaturated, linear or branched, preferably in an amount of from 15 to 40 wt.

%, e.g. 25+10 wt.-%, or 30+10 wt.-%, in each case relative to the total weight of the dosage

form.

[144] In a particularly preferred embodiment, the pharmaceutical dosage form

cetostearyl alcohol preferably in an amount of from 15 to 40 wt.-%, e.g. 2510 wt.-%, or 3010 wt.-%, in each case relative to the total weight of the dosage form.

[145] In a particularly preferred embodiment, the pharmaceutical dosage form

wherein the prolonged-release matrix comprises as prolonged-release matrix material stearyl

alcohol preferably in an amount of from 15 to 40 wt.-%, e.g. 2510 wt.-%, or 3010 wt.-%, in

each case relative to the total weight of the dosage form.

[146] In a particularly preferred embodiment, the pharmaceutical dosage form

wherein the prolonged-release matrix comprises as prolonged-release matrix material cetyl

each case relative to the total weight of the dosage form.

[147] In a particularly preferred embodiment, the pharmaceutical dosage form

wherein the prolonged-release matrix comprises as prolonged-release matrix material a

hydrocarbon selected from the group consisting of long chain fatty acids having 8 to 50 carbon

atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated, linear or branched; glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils, and waxes; in each case preferably in an amount of from 5.0 to 70 wt.-%, e.g. 1510 wt.-%, or 2010 wt.

%, or 25+10 wt.-%, or 30+10 wt.-%, or 35+10 wt.-%, or 4010 wt.-%, or 4510 wt.-%, or

dosage form.

[148] In a particularly preferred embodiment, the pharmaceutical dosage form

wherein the prolonged-release matrix comprises as prolonged-release matrix material xanthan

gum preferably in an amount of from 15 to 40 wt.-%, e.g. 2510 wt.-%, or 3010 wt.-%, in

each case relative to the total weight of the dosage form.

[149] In a particularly preferred embodiment, the pharmaceutical dosage form

wherein the prolonged-release matrix comprises as prolonged-release matrix material sodium

alginate preferably in an amount of from 15 to 40 wt.-%, e.g. 2510 wt.-%, or 3010 wt.-%, in

each case relative to the total weight of the dosage form.

[150] In a particularly preferred embodiment, the pharmaceutical dosage form

the free base of Tapentadol, and a prolonged-release matrix in which the salt of Tapentadol with tartaric acid, preferably the salt of Tapentadol with L-(+)-tartaric acid, is embedded; wherein the prolonged-release matrix comprises as prolonged-release matrix material guar gum preferably in an amount of from 5.0 to 35 wt.-%, e.g. 1510 wt.-%, or 2010 wt.-%, or 2510 wt.-%, in each case relative to the total weight of the dosage form.

[151] In a particularly preferred embodiment, the pharmaceutical dosage form

wherein the prolonged-release matrix comprises as prolonged-release matrix material locust

bean gum preferably in an amount of from 5.0 to 35 wt.-%, e.g. 1510 wt.-%, or 2010 wt.-%,

or 25+10 wt.-%, in each case relative to the total weight of the dosage form.

[152] In addition to the above ingredients, a prolonged-release matrix may also

contain suitable amounts of other materials, e.g. diluents, lubricants, binders, granulating aids,

colorants, flavors and glidants that are conventional in the pharmaceutical art.

[153] Pharmaceutical dosage forms containing prolonged-release matrices in which

Tapentadol is embedded may be produced by conventional methods that are known to the

skilled person such as blending and direct compression, dry granulation, wet granulation,

extrusion, and the like.

[154] According to a preferred embodiment, the pharmaceutical dosage form according

to the invention is a capsule which preferably contains a plurality of particles containing a

prolonged-release coating.

[155] According to another preferred embodiment, the pharmaceutical dosage form

according to the invention is a tablet. Preferably, the tablet is monolithic. Monolithic tablets

according to the invention are tablets that are optionally film coated, wherein the core of the tablets contains a compressed powder and/or granulate mixture. In particular (i), tablets produced by direct compression of powder mixtures, (ii) tablets produced by compression of mixtures comprising granules obtained by dry granulation and optionally extragranular excipients, (iii) tablets produced by compression of mixtures comprising granules obtained by wet granulation and optionally extragranular excipients, and (iv) tablets produced by compression of mixtures comprising granules obtained by extrusion granulation and optionally extragranular excipients are all to be regarded as monolithic tablets in accordance with the invention. Multiple unit pellet systems (MUPS) or other dosage forms in which a plurality of particles of specific design, weight and shape are mixed with an outer matrix material and subsequently compressed into tablets, wherein the outer matrix material forms a continuous phase in which the pellets or particles are embedded, are preferably not to be regarded as monolithic tablets. Of course, capsules filled with a plurality of loose particles are naturally not to be regarded as monolithic either.

[156] Preferably, the tablet has a breaking strength of at least 100 N, preferably at

least 150 N, more preferably at least 200 N. The breaking strength is preferably determined in

accordance with Ph. Eur. 10, chapter 2.9.8. "Resistanceto Crushingof Tablets".

[157] Another aspect of the invention relates to a method for producing a

pharmaceutical dosage form according to the invention as described above.

[158] If the pharmaceutical dosage form contains a prolonged-release coating

comprising particles, then the production method according to the invention according to a

preferred embodiment comprises the following steps:

(A) providing inner starting pellets, for example, sugar beads, which contain one or

more excipients but no Tapentadol;

(B) providing a solution or dispersion of Tapentadol (including the salt of tartaric

acid, in particular L-(+)-tartaric acid) in water or an organic solvent or a mixture thereof, optionally with the one or more excipients, wherein the organic solvent is preferably selected from ethanol and acetone;

(C) coating the inner starting pellet provided in step (A) with the solution or

dispersion of Tapentadol provided in step (B), preferably in a fluidized bed, thereby obtaining

intermediate product particles which include an inner core containing no Tapentadol and a drug

coating layer encapsulating the core, which substantially includes the entire amount of

Tapentadol which is to be contained in the dosage form, optionally together with the one or

more excipients;

(D) optionally drying the intermediate product particles obtained in step (C),

thereby obtaining dried intermediate product particles;

(E) providing a solution or dispersion of a prolonged-release coating material in

water or an organic solvent or a mixture thereof, optionally with the one or more excipients,

wherein the organic solvent is preferably selected from ethanol and acetone;

(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

prolonged-release coating material provided in step (E), preferably in a fluidized bed, thereby

obtaining prolonged-release particles which contain an inner core containing no Tapentadol, a

drug coating layer encapsulating the core, which includes substantially the entire amount of

Tapentadol, optionally together with the one or more excipients, and a prolonged-release

coating encapsulating the core and the drug coating layer;

(G) optionally drying the prolonged-release particles obtained in step (F), thereby

obtaining dried prolonged-release particles; and

(H) either filling the prolonged-release particles obtained in step (F) or the dried

prolonged-release particles obtained in step (G) into capsules; or mixing the prolonged-release

particles obtained in step (F) or the dried prolonged-release particles obtained in step (G) with extraparticulate excipients and compressing of the mixture into tablets (Multiple Unit Pellet

Systems, MUPS).

[159] Another aspect of the invention relates to a pharmaceutical dosage form which

can be obtained by this preferred method according to the invention as described above.

[160] If the pharmaceutical dosage form contains a prolonged-release coating

preferred embodiment includes the following steps:

(A) providing a mixture containing substantially the entire amount of Tapentadol

(including the salt with tartaric acid, in particular L-(+)-tartaric acid) which is to be contained

in the dosage form, optionally together with one or more excipients;

(B) producing drug pellets from the mixture provided in step (A) by dry granulation,

wet granulation or extrusion, wherein the wet granulation preferably comprises the use of a

solvent selected from water, ethanol, acetone and any desired mixture thereof;

(C) optionally drying and/or spheronizing the drug pellets produced in step (B),

thereby obtaining dried and/or spheronized drug pellets;

(D) providing a solution or dispersion of a prolonged-release coating material in

wherein the organic solvent is preferably selected from ethanol and acetone;

(E) coating the drug pellets produced in step (B) or the dried and/or spheronized

drug pellets obtained in step (C) with the solution or dispersion of the prolonged-release coating

material provided in step (D), preferably in a fluidized bed, thereby obtaining prolonged

release particles which contain a core substantially including the entire amount of Tapentadol,

optionally together with one or more excipients, and a prolonged-release coating encapsulating

the core;

(F) optionally drying the prolonged-release particles obtained in step (E), thereby obtaining dried prolonged-release particles; and

(G) either filling the prolonged-release particles obtained in step (E) or the dried

prolonged-release particles obtained in step (F) into capsules; or mixing the prolonged-release

particles obtained in step (E) or the dried prolonged-release particles obtained in step (F) with

extraparticulate excipients and compressing the mixture into tablets (Multiple Unit Pellet

Systems, MUPS).

[161] Another aspect of the invention relates to a pharmaceutical dosage form which

[162] If the pharmaceutical dosage form contains a prolonged-release matrix, in

which the Tapentadol (including the salt with tartaric acid, in particular L-(+)-tartaric acid) is

embedded, then the production method according to the invention according to a preferred

embodiment includes the following steps:

(including the salt with tartaric acid, in particular L-(+)-tartaric acid) to be contained in the

dosage form and at least one prolonged-release matrix material, optionally together with one

or more excipients;

(b) optionally granulating the mixture provided in step (a), thereby obtaining a

granulate, wherein the granulation preferably comprises the following: (i) wet granulation by

means of a solvent selected preferably from water, ethanol, acetone and any mixture thereof,

optionally followed by drying; (ii) dry granulation; or (iii) extrusion;

(c) optionally mixing the granulate obtained in step (b) with one or more excipients,

thereby obtaining a granulate mixture;

(d) compressing the mixture provided in step (a) or the granulate obtained in step

(b) or the granulate mixture obtained in step (c) into tablets;

(e) optionally film coating the tablets compressed in step (d).

[163] The compressing in step (d) of the method according to the invention occurs

preferably by applying a compression force of not more than 20 kN, particularly preferably not

more than 15 kN, even more preferably not more than 10 kN, even more preferably not more

than 9.5 kN, even more preferably not more than 9.0 kN, most preferably not more than 8.75

kN, and particularly not more than 8.5 kN.

[164] The compressing instep (d) of the method according to the invention preferably

occurs under conditions wherein the compressed tablet has a breaking strength of at least 100

N, particularly preferably at least 150 N, even more preferably at least 200 N.

[165] The pharmaceutical dosage form according to the invention is preferably not

produced by thermal forming such as melt extrusion.

[166] Preferably, the pharmaceutical dosage form according to the invention does not

contain a plurality of particles or pellets with specific design, specific shape and specific

weight, which are optionally compressed into tablets, in which the particles or pellets form a

discontinuous phase in a continuous phase of an outer matrix material.

[167] Preferably, the pharmaceutical dosage form according to the invention contains

no opioid antagonists. Opioid antagonists are units which modify the response of opioid

receptors. Opioid antagonists include naloxone, naltrexone, diprenorphin, etorphin,

dihydroetorphin, nalinefen, cyclazacin, levallorphan, pharmaceutically acceptable salts and

mixtures thereof.

[168] Another aspect of the invention relates to the above-described pharmaceutical

dosage form according to the invention for use in the treatment of pain, wherein the dosage

form is administered orally, preferably twice daily.

[169] Another aspect of the invention relates to the use of a salt of Tapentadol with

tartaric acid, of Tapentadol with L-(+)-tartaric acid, for producing a pharmaceutical dosage

form according to the invention as described above for treating pain, wherein the dosage form is administered orally, preferably twice daily.

[170] Another aspect of the invention relates to a method for the treatment of pain,

which includes the step of oral, preferably twice daily, administration of a pharmaceutical

dosage form according to the invention as described above to a subject in need of it.

[171] Preferably, the pain is chronic pain.

[172] According to preferred embodiments, the pharmaceutical dosage form

according to the invention provides, in a patient population of at least 10 patients, preferably

at least 50 patients, after oral administration, an average value of Tmax in the range of 5.03.0

hours.

[173] According to preferred embodiments of the pharmaceutical dosage form

pharmaceutical dosage form is 50 mg relative to the free base of Tapentadol, wherein the

dosage form after oral administration in a patient population of at least 50 patients provides an

average value of

- Cmaxin the range of 12+3 ng/mL; and/or

- AUCiast in the range of 204+50 ng-h/mL; and/or

- AUC. in the range of 214+50 ng-h/mL.

[174] According to preferred embodiments of the pharmaceutical dosage form

pharmaceutical dosage form is 100 mg relative to the free base of Tapentadol, wherein the

average value of

- Cmaxin 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.

[175] According to preferred embodiments of the pharmaceutical dosage form

pharmaceutical dosage form is 150 mg relative to the free base of Tapentadol, wherein the

average value of

- Cmaxin 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.

[176] According to preferred embodiments of the pharmaceutical dosage form

pharmaceutical dosage form is 200 mg relative to the free base of Tapentadol, wherein the

average value of

- Cmaxin the range of 64+12 ng/mL; and/or

- AUCiast in the range of 890+200 ng-h/mL; and/or

- AUC. in the range of 895+200 ng-h/mL.

[177] According to preferred embodiments of the pharmaceutical dosage form

pharmaceutical dosage form is 250 mg relative to the free base of Tapentadol, wherein the

average value of

- Cmaxin the range of 85+15 ng/mL; and/or

- AUCiast in the range of 1141+250 ng-h/mL; and/or

- AUC. in the range of 1145+250 ng-h/mL.

[178] Particularly preferred embodiments of the invention are summarized as paragraphs 1 to 67 hereinafter:

Paragraph 1. A pharmaceutical dosage form comprising Tapentadol for administration

twice daily;

wherein Tapentadol is present as a salt with tartaric acid; wherein the dosage form

provides prolonged release of Tapentadol; and wherein the weight equivalent dose of

Tapentadol that is contained in the pharmaceutical dosage form is in the range of 10 to 300 mg,

relative to the free base of Tapentadol.

Paragraph 2. The pharmaceutical dosage form according to paragraph 1, wherein the

salt is the salt of Tapentadol with L-(+)-tartaric acid, a solvate, an ansolvate, and/or a

polymorphic form thereof.

Paragraph 3. The pharmaceutical dosage form according to paragraph 1 or 2, which

includes one, two or more physiologically acceptable excipients.

Paragraph 4. The pharmaceutical dosage form according to any of the preceding

paragraphs, which after oral administration provides plasma levels of Tapentadol that provide

pain relief for a duration of at least 6 hours.

Paragraph 5. The pharmaceutical dosage form according to any of the preceding

paragraphs, which provides an in vitro dissolution profile, measured by the USP Paddle Method

at 50 rpm in 900 mL aqueous phosphate buffer at pH 6.8 at 37 C, in which after 0.5 hour

2020 wt.-%; preferably 2015 wt.-%; particularly preferably 2010 wt.-%; after 4 hours

+20 wt.-%; preferably 60+15 wt.-%; particularly preferably 60+10 wt.-%; and after 12 hours

at least 60 wt.-%; preferably at least 70 wt.-%; particularly preferably at least 80 wt.-% of the

Tapentadol that was originally contained in the dosage form have been released.

Paragraph 6. The pharmaceutical dosage form according to any of the preceding

at 50 rpm in 900 mL aqueous phosphate buffer at pH 6.8 at 37 °C, in which - after 1 hour 25+15 wt.-%;- after 2 hours 35+20 wt.-%; - after 4 hours 50+20 wt.-%; - after 8 hours 8020 wt.-% of the Tapentadol that was originally contained in the dosage form have been released.

Paragraph 7. The pharmaceutical dosage form according to any of the preceding

at 50 rpm in 900 mL aqueous buffer at pH 4.5 at 37 °C, in which after 0.5 hour 2020 wt.-%;

preferably 2015 wt.-%; particularly preferably 2010 wt.-%; after 4 hours 6020 wt.-%;

preferably 6015 wt.-%; particularly preferably 6010 wt.-%; and after 12 hours at least 60

wt.-%; preferably at least 70 wt.-%; particularly preferably at least 80 wt.-%

Paragraph 8. The pharmaceutical dosage form according to any of the preceding

at 50 rpm in 900 mL aqueous buffer at pH 4.5 at 37 °C, in which - after 1 hour 2515 wt.-%;

after 2 hours 35+20 wt.-%;- after 4 hours 50+20 wt.-%;- after 8 hours 8020 wt.-% of the

Tapentadol that was originally contained in the dosage form have been released.

Paragraph 9. The pharmaceutical dosage form according to any of the preceding

at 50 rpm in 900 mL 0.1 N HCl at pH 1.0 and 37 °C, in which after 0.5 hour 2020 wt.-%;

wt.-%; preferably at least 70 wt.-%; more preferably at least 80 wt.-% of the Tapentadol that

was originally contained in the dosage form have been released.

Paragraph 10. The pharmaceutical dosage form according to any of the preceding

at 50 rpm in 900 mL 0.1 N HCl at pH 1.0 and 37 °C, in which - after 1 hour 25+10 wt.-%;

after 2 hours 40+30 wt.-%; - after 4 hours 60+20 wt.-%; - after 8 hours 80+20 wt.-% of the

Tapentadol that was originally contained in the dosage form have been released.

Paragraph 11. The pharmaceutical dosage form according to any of the preceding

paragraphs, which provides resistance against ethanol induced dose dumping.

Paragraph 12. The pharmaceutical dosage form according to paragraph 11, which

provides slower in vitro dissolution of Tapentadol in aqueous medium containing ethanol than

in aqueous medium not containing ethanol.

Paragraph 13. The pharmaceutical dosage form according to paragraph 11 or 12, which

provides a slower dissolution of Tapentadol in 0.1 N HCl with 40 vol.-% of ethanol (pH 1.0)

than in 0.1 N HCl without 40 vol.-% of ethanol (pH 1.0), in each case measured by the USP

Paddle Method at 50 rpm in 900 mL at 37 °C.

Paragraph 14. The pharmaceutical dosage form according to any one of the preceding

paragraphs, in which the weight equivalent dose of Tapentadol that is contained in the

of Tapentadol.

Paragraph 15. The pharmaceutical dosage form according to paragraph 14, wherein the

dosage form has a total weight in the range of 150 to 750 mg.

Paragraph 16. The pharmaceutical dosage form according to one of paragraphs I to 13,

wherein the weight equivalent dose of Tapentadol that is contained in the pharmaceutical

Paragraph 17. The pharmaceutical dosage form according to paragraph 16, wherein the

dosage form has a total weight in the range of 300 to 1200 mg.

Paragraph 18. The pharmaceutical dosage form according to any of the preceding

paragraphs, wherein the dosage form contains a prolonged-release coating comprising a

prolonged-release coating material selected from the group consisting of hydrophobic cellulose

ethers, acrylic polymers, shellac, zein, hydrophobic waxy products, and mixtures thereof.

Paragraph 19. The pharmaceutical dosage form according to paragraph 18, wherein the

prolonged-release coating material is selected from the group consisting of acrylic acid and

methacrylic acid copolymers, aminoalkyl methacrylate copolymers, cyanoethyl methacrylates,

ethoxyethyl methacrylates, ethylcellulose, methacrylic acid-alkylamide copolymers,

methacrylic acid copolymers, methylmethacrylates, methylmethacrylate copolymers,

poly(acrylic acid), poly(methacrylic acid) (anhydride), poly(methacrylic acid), glycidyl

polyacrylamide and polymethacrylate.

Paragraph 20. The pharmaceutical dosage form according to any of the preceding

paragraphs, wherein Tapentadol is embedded in a prolonged-release matrix.

Paragraph 21. The pharmaceutical dosage form according to paragraph 20, wherein the

prolonged-release matrix comprises or substantially consists of at least one prolonged-release

matrix material selected from the group consisting of hydrophilic or hydrophobic polymers and

hydrocarbons.

Paragraph 22. The pharmaceutical dosage form according to paragraph 21, wherein the

prolonged-release matrix comprises or substantially consists of at least one polymer selected

from the group consisting of polysaccharides or gums (e.g. xanthan gum, guar gum, karaya

gum, locust bean gum, sodium alginate, carob gum, chitosan, polysaccharides of mannose and

galactose, pectin, tragacanth, agar-agar); cellulose ethers (e.g. HPMC, HPC, HEC, MC, EC);

cellulose esters (e.g. cellulose acetate, cellulose acetate succinate, cellulose acetate phthalate);

polyalkylene glycols and polyalkylene oxides; polyvinylalcohol (PVA), cross-linked

polyvinylalcohol (PVA), polyvinylpyrrolidone (PVP), cross-linked polyvinyl-pyrrolidone

(PVP), polyvinylpyrrolidone-vinylacetate copolymers, polyvinylchloride (PVC), polyethylene

vinyl acetate (PVA), polydimethylsiloxane (PDS), polyether urethane (PEU), polylactic acid

(PLA), polyglycolic acid (PGA), polycaprolactone (PCL), polyanhydrides, polyorthoesters; acrylic resins (e.g. cross-linked homopolymers and copolymers of acrylic acid, acrylic acid and methacrylic acid copolymers, aminoalkylmethacrylate copolymers, cyanoethyl methacrylate, ethoxyethyl methacrylates, methacrylic acid alkyl amide copolymers, methacrylic acid copolymers, methyl methacrylates, methyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), poly(methacrylic acid anhydride), glycidylmethacrylate copolymers, poly(methylmethacrylate), poly(methylmethacrylate) copolymers, polyacrylamide, polyhydroxyethylmethacrylate (PHEMA) and polymethacrylate) and materials obtained from proteins.

Paragraph 23. The pharmaceutical dosage form according to paragraph 21 or 22,

wherein the prolonged-release matrix comprises or substantially consists of at least one

hydrocarbon selected from the group consisting of long chain (C8-C50, especially C12-C40)

fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral oils, vegetable oils, and waxes.

Paragraph 24. The pharmaceutical dosage form according to any of paragraphs 20 to

23, wherein the prolonged-release matrix comprises or substantially consists of a prolonged

release matrix material selected from the group consisting of (i) hydroxypropylmethylcellulose

(HPMC); (ii) hydroxypropyl cellulose (HPC); (iii) hydroxyethylcellulose (HEC); (iv)

microcrystalline cellulose (MCC); (v) ethylcellulose (EC); (vi) polyvinyl acetate (PVAc); (vii)

polyvinylpyrrolidone (PVP); (viii) polyvinylpyrrolidone-vinylacetate copolymer

(PVP/PVAc); (ix) poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl

methacrylate chloride); (x) poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate

co-methyl methacrylate); (xi) poly(methyl methacrylate-co-methacrylic acid); (xii) poly(ethyl

acrylate-co-methacrylic acid); (xiii) poly(methyl acrylate-co-methyl methacrylate-co

methacrylic acid); (xiv) poly(ethyl acrylate-co-methyl methacrylate); (xv) poly(ethylene oxide)

(PEO); (xvi) polyethylene glycol (PEG); (xvii) long chain fatty alcohol having 8 to 50 carbon

atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated, linear or branched; (xviii) cetostearyl alcohol; (xix) stearyl alcohol; (xx) cetyl alcohol; (xxi) hydrocarbon selected from the group consisting of long chain fatty acids having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated, linear or branched; glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils, and waxes;

(xxii) xanthan gum; (xxiii) sodium alginate; (xxiv) guar gum; (xxv) locust bean gum; and any

mixtures of the above; wherein preferably, the content of prolonged-release matrix material is

in the range of 1510 wt.-%, or 2010 wt.-%, or 2510 wt.-%, or 3010 wt.-%, or 3510 wt.

%, or 40+10 wt.-%, or 45+10 wt.-%, or 50+10 wt.-%, or 55+10 wt.-%, or 6010 wt.-%, or

6510 wt.-%, or 7010 wt.-%, or 7510 wt.-%, or 8010 wt.-%, in each case relative to the

total weight of the dosage form.

Paragraph 25. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material

hydroxypropylmethylcellulose (HPMC) in an amount of 5.0 to 50 wt.-%, e.g. 1510 wt.-%, or

+10 wt.-%, or 25+10 wt.-%, or 30+10 wt.-%, or 35+10 wt.-%, or 40+10 wt.-%, in each case

relative to the total weight of the dosage form.

Paragraph 26. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material hydroxypropyl

cellulose (HPC) in an amount of 10 to 50 wt.-%, e.g. 2010 wt.-%, or 2510 wt.-%, or 3010

wt.-%, or 35+10 wt.-%, or 4010 wt.-%, in each case relative to the total weight of the dosage

form.

Paragraph 27. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material

hydroxyethylcellulose (HEC)in an amount of 5.0 to 50 wt.-%, e.g. 1510 wt.-%, or 2010 wt.

the total weight of the dosage form.

Paragraph 28. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material microcrystalline

cellulose (MCC) in an amount of 10 to 70 wt.-%, e.g. 2010 wt.-%, or 2510 wt.-%, or 3010

wt.-%, or 35+10 wt.-%, or 40+10 wt.-%, or 45+10 wt.-%, or 50+10 wt.-%, or 5510 wt.-%, or

+10 wt.-%, in each case relative to the total weight of the dosage form.

Paragraph 29. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material ethylcellulose (EC)

in an amount of 5.0 to 30 wt.-%, e.g. 1510 wt.-%, or 2010 wt.-%, in each case relative to the

total weight of the dosage form.

Paragraph 30. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material polyvinyl acetate

(PVAc) in an amount of 25 to 70 wt.-%, e.g. 3510 wt.-%, or 4010 wt.-%, or 4510 wt.-%,

or 50+10 wt.-%, or 55+10 wt.-%, or 60+10 wt.-%, in each case relative to the total weight of

the dosage form.

Paragraph 31. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material polyvinylpyrrolidone

(PVP) in an amount of 2.0 to 21 wt.-%, e.g. 105.0 wt.-%, or 155.0 wt.-%, in each case

relative to the total weight of the dosage form.

Paragraph 32. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material

polyvinylpyrrolidone-vinylacetate copolymer (PVP/PVAc) in an amount of 1.0 to 30 wt.-%,

e.g. 15+10 wt.-%, or 20+10 wt.-%, in each case relative to the total weight of the dosage form.

Paragraph 33. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material poly(ethyl acrylate

co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) in an amount of 5.0 to 45 wt.-%, e.g. 15+10 wt.-%, or 2010 wt.-%, or 2510 wt.-%, or 3010 wt.-%, or 3510 wt.-%, in each case relative to the total weight of the dosage form.

Paragraph 34. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material

poly(butylmethacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methylmethacrylate) in

an amount of 5.0 to 45 wt.-%, e.g. 1510 wt.-%, or 2010 wt.-%, or 2510 wt.-%, or 3010

wt.-%, or 3510 wt.-%, in each case relative to the total weight of the dosage form.

Paragraph 35. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material poly(methyl

methacrylate-co-methacrylic acid) in an amount of 5.0 to 45 wt.-%, e.g. 1510 wt.-%, or 2010

wt.-%, or 2510 wt.-%, or 3010 wt.-%, or 35+10 wt.-%, in each case relative to the total

weight of the dosage form.

Paragraph 36. The pharmaceutical dosage form according to paragraph 24, wherein the

co-methacrylic acid) in an amount of 5.0 to 45 wt.-%, e.g. 1510 wt.-%, or 2010 wt.-%, or

+10 wt.-%, or 3010 wt.-%, or 3510 wt.-%, in each case relative to the total weight of the

dosage form.

Paragraph 37. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material poly(methyl acrylate

co-methyl methacrylate-co-methacrylic acid) in an amount of 5.0 to 45 wt.-%, e.g. 15+10 wt.

%, or 20+10 wt.-%, or 25+10 wt.-%, or 30+10 wt.-%, or 35+10 wt.-%, in each case relative to

the total weight of the dosage form.

Paragraph 38. The pharmaceutical dosage form according to paragraph 24, wherein the

co-methyl methacrylate) in an amount of 5.0 to 45 wt.-%, e.g. 1510 wt.-%, or 2010 wt.-%, or 25+10 wt.-%, or 30+10 wt.-%, or 3510 wt.-%, in each case relative to the total weight of the dosage form.

Paragraph 39. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material poly(ethylene oxide)

(PEO) in an amount of 25 to 65 wt.-%, e.g. 3510 wt.-%, or 4010 wt.-%, or 4510 wt.-%, or

+10 wt.-%, or 5510 wt.-%, in each case relative to the total weight of the dosage form.

Paragraph 40. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material polyethylene glycol

(PEG) in an amount of 5.0 to 35 wt.-%, e.g. 1510 wt.-%, or 2010 wt.-%, or 2510 wt.-%, in

each case relative to the total weight of the dosage form.

Paragraph 41. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material a long chain fatty

or unsaturated, linear or branched, in an amount of 15 to 40 wt.-%, e.g. 2510 wt.-%, or 3010

wt.-%, in each case relative to the total weight of the dosage form.

Paragraph 42. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material cetostearyl alcohol

in an amount of 15 to 40 wt.-%, e.g. 2510 wt.-%, or 3010 wt.-%, in each case relative to the

total weight of the dosage form.

Paragraph 43. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material stearyl alcohol in an

amount of 15 to 40 wt.-%, e.g. 25+10 wt.-%, or 30+10 wt.-%, in each case relative to the total

weight of the dosage form.

Paragraph 44. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material cetyl alcohol in an amount of 15 to 40 wt.-%, e.g. 25+10 wt.-%, or 30+10 wt.-%, in each case relative to the total weight of the dosage form.

Paragraph 45. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material a hydrocarbon

selected from the group consisting of long chain fatty acids having 8 to 50 carbon atoms,

preferably 12 to 40 carbon atoms, which may be saturated or unsaturated, linear or branched;

glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils, and waxes; in each

case in an amount of 5.0 to 70 wt.-%, e.g. 1510 wt.-%, or 2010 wt.-%, or 2510 wt.-%, or

+10 wt.-%, or 35+10 wt.-%, or 40+10 wt.-%, or 45+10 wt.-%, or 50+10 wt.-%, or 5510

wt.-%, or 6010 wt.-%, in each case relative to the total weight of the dosage form.

Paragraph 46. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material xanthan gum in an

weight of the dosage form.

Paragraph 47. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material sodium alginate in

an amount of 15 to 40 wt.-%, e.g. 2510 wt.-%, or 30+10 wt.-%, in each case relative to the

total weight of the dosage form.

Paragraph 48. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material guar gum in an

amount of 5.0 to 35 wt.-%, e.g. 1510 wt.-%, or 2010 wt.-%, or 25+10 wt.-%, in each case

relative to the total weight of the dosage form.

Paragraph 49. The pharmaceutical dosage form according to paragraph 24, wherein the

prolonged-release matrix comprises as prolonged-release matrix material locust bean gum in

an amount of 5.0 to 35 wt.-%, e.g. 1510 wt.-%, or 2010 wt.-%, or 25+10 wt.-%, in each case relative to the total weight of the dosage form.

Paragraph 50. The pharmaceutical dosage form according to any of the preceding

paragraphs, in which it is a capsule.

Paragraph 51. The pharmaceutical dosage form according to any of paragraphs 1 to 49,

in which it is a tablet.

Paragraph 52. The pharmaceutical dosage form according to any of paragraph 51,

wherein the tablet is monolithic.

Paragraph 53. The pharmaceutical dosage form according to paragraph 51 or 52,

wherein the tablet has a breaking strength of at least 100 N.

Paragraph 54. The dosage form according to any of the preceding paragraphs for use in

the treatment of pain, wherein the dosage form is orally administered twice daily.

Paragraph 55. The pharmaceutical dosage form according to paragraph 54, wherein the

pain is chronic pain.

Paragraph 56. The dosage form for use according to paragraph 54 or 55, which, in a

patient population of at least 10 patients, after oral administration, provides an average value

of Tmaxin the range of 5.0+3.0 hours.

Paragraph 57. The dosage form for use according to any of paragraphs 54 to 56, wherein

the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form

is 50 mg, relative to the free base of Tapentadol, and wherein the dosage form after oral

administration in a patient population of at least 10 patients provides an average value of Cmax

in the range of 123 ng/mL; and/or AUClast in the range of 20450 ng-h/mL; and/or AUCoo

in the range of 21450 ng-h/mL.

Paragraph 58. The dosage form foruse according to any of paragraphs 54 to 56, wherein

is 100 mg, relative to the free base of Tapentadol, and wherein the dosage form after oral administration in a patient population of at least 10 patients provides an average value of Cmax in the range of 296 ng/mL; and/or AUClast in the range of 440100 ng-h/mL; and/or AUCo in the range of 447100 ng-h/mL.

Paragraph 59. The dosage form for use according to any of paragraphs 54 to 56, wherein

is 150 mg, relative to the free base of Tapentadol, and wherein the dosage form after oral

in the range of 479 ng/mL; and/or AUClast in the range of 662150 ng-h/mL; and/or AUCo

in the range of 665150 ng-h/mL.

Paragraph 60. The dosage form for use according to any of paragraphs 54 to 56, wherein

is 200 mg, relative to the free base of Tapentadol, and wherein the dosage form after oral

in the range of 6412 ng/mL; and/or AUClast in the range of 890200 ng-h/mL; and/or AUCo

in the range of 895200 ng-h/mL.

Paragraph 61. The dosage form for use according to any of paragraphs 54 to 56, wherein

is 250 mg, relative to the free base of Tapentadol, and wherein the dosage form after oral

in the range of 8515 ng/mL; and/or AUClast in the range of 1141250 ng-h/mL; and/or

AUCoo in the range of 1145+250 ng-h/mL.

Paragraph 62. A method for the preparation of a pharmaceutical dosage form according

to any of the preceding paragraphs, which contains particles comprising a prolonged-release

coating, wherein the method comprises the following steps: (A) providing inner starter pellets

which contain one or more excipients but no Tapentadol; (B) providing a solution or dispersion of Tapentadol in water or an organic solvent or a mixture thereof, optionally together with the one or more excipients; (C) coating the inner starter pellets provided in step (A) with the solution or dispersion of Tapentadol provided in step (B), thereby obtaining intermediate particles including an inner core not containing any Tapentadol and a drug coating layer encapsulating the core and comprising substantially the entire amount of Tapentadol to be contained in the dosage form, optionally together with the one or more excipients; (D) optionally, drying the intermediate particles obtained in step (C), thereby obtaining dried intermediate particles; (E) providing a solution or dispersion of a prolonged-release coating material in water or an organic solvent or a mixture thereof, optionally together with the one or more excipients; (F) coating the intermediate particles obtained in step (C) or the dried intermediate particles obtained in step (D) with the solution or dispersion of prolonged-release coating material provided in step (E), thereby obtaining prolonged-release particles containing an inner core not containing any Tapentadol, a drug coating layer encapsulating the core and comprising substantially the entire amount of Tapentadol, optionally together with the one or more excipients, and a prolonged-release coating encapsulating the core and said drug coating layer; (G) optionally, drying the prolonged-release particles obtained in step (F), thereby obtaining dried prolonged-release particles; and (H) either filling the prolonged-release particles obtained in step (F) or the dried prolonged-release particles obtained in step (G) into capsules; or mixing the prolonged-release particles obtained in step (F) or the dried prolonged release particles obtained in step (G) with extraparticulate excipients and compressing the mixture tablets.

Paragraph 63. A pharmaceutical dosage form that can be obtained by the method

according to paragraph 62.

Paragraph 64. A method for the preparation of a pharmaceutical dosage form according

to any one of paragraphs 1 to 61, which contains particles comprising a prolonged-release coating, wherein the method comprises the following the steps: (A) providing a mixture containing substantially the entire amount of Tapentadol to be contained in the dosage form, optionally together with one or more excipients; (B) preparing drug pellets from the mixture provided in step (A) by dry granulation, wet granulation or extrusion; (C) optionally, drying and/or spheronizing the drug pellets prepared in step (B), thereby obtaining dried and/or spheronized drug pellets; (D) providing a solution or dispersion of a prolonged-release coating material in water or an organic solvent or a mixture thereof, optionally with one or more excipients; (E) coating the drug pellets prepared in step (B) or the dried and/or spheronized drug pellets obtained in step (C) with the solution or dispersion of prolonged-release coating material provided in step (D), thereby obtaining prolonged-release particles containing a core comprising substantially the entire amount of Tapentadol, optionally together with one or more excipients, and a prolonged-release coating encapsulating the core; (F) optionally, drying the prolonged-release particles obtained in step (E), thereby obtaining dried prolonged-release particles; and (G) either filling the prolonged-release particles obtained in step (E) or the dried prolonged-release particles obtained in step (F) into capsules; or mixing the prolonged-release particles obtained in step (E) or the dried prolonged-release particles obtained in step (F) with extraparticulate excipients and compressing the mixture into tablets.

Paragraph 65. A pharmaceutical dosage form that can be obtained by the method

according to paragraph 64.

Paragraph 66. A method for the preparation of a pharmaceutical dosage form according

to any of paragraphs 1 to 61, which contains a prolonged-release matrix in which the

Tapentadol is embedded, wherein the method comprises the following steps: (a) providing a

mixture containing substantially the entire amount of Tapentadol to be contained in the dosage

form and at least one prolonged-release matrix material, optionally together with one or more

excipients; (b) optionally granulating the mixture provided in step (a), thereby obtaining a granulate; (c) optionally mixing the granulate obtained in step (b) with one or more excipients, thereby obtaining a granulate mixture; (d) compressing the mixture provided in step (a) or the granulate obtained in step (b) or the granulate mixture obtained in step (c) into tablets; (e) optionally, film coating the tablets compressed in step (d).

Paragraph 67. The method according to paragraph 66, wherein compressing in step (d)

is performed at a compression force of not more than 20 kN, particularly preferably not more

than 15 kN, even more preferably not more than 10 kN, even more preferably not more than

9.5 kN, even more preferably not more than 9.0 kN, most preferably not more than 8.75 kN,

and in particular not more than 8.5 kN.

EXAMPLES

[179] The following examples explain the invention in further detail but should not

be interpreted as limiting the scope of the invention.

[180] Commercially available Palexia ®retard Tapentadol tablets contain Tapentadol

as hydrochloride salt, wherein the tablet core additionally contains hypromellose,

microcrystalline cellulose, highly dispersed silicon dioxide and magnesium stearate. Palexia®

retard tablets thus contain hypromellose as prolonged-release matrix with Prolonged release.

These tablets correspond to WO 03/035053 Al and the comparison examples described below.

Example 1 - Preparation of the salt of Tapentadol with L-(+)-tartaric acid

30 g Tapentadol base were introduced with 20.4 g L-(+)-tartaric acid in a 1 L reactor.

400 mL acetone were added, and the preparation was heated under vigorous stirring at 50 °C

and stirred for 3 h. In the process, a sticky paste formed. Subsequently, the mixture was cooled

to 25 °C, and 200 mL cyclohexane were added. The preparation was cooled to 5 °C and stirred at this temperature for an additional hour. The preparation was heated again to 50 °C, stirred for 1 h and subsequently cooled to 5 °C. The preparation was stirred for an additional 16 h at

°C. The solid obtained was separated by filtration and dried at 50 °C at reduced pressure for

6 h. 48.1 g Tapentadol tartrate were obtained (yield 95.5%, 1:1 stoichiometry determined by

1H-NMR, XRPD according to Figure 3, DSC: Tonset 131.4 °C, Tpeak 134.2 °C, TGA: 0% weight

loss (37 °C - 172 C)).

Example 2 - intrinsic dissolution (dissolution rate):

[181] 100 mg Tapentadol, either in the form of the hydrochloride salt or of the salt

with L-(+)-tartaric acid, were compressed with a compression force of 200 kg (gravitational)

on a surface of 0.5 cm2 for 1 minute. The resulting compressed samples were studied in a Wood

apparatus at 37 °C in 900 mL dissolution medium at different pH values and a paddle rotational

speed of 50 rpm in order to determine their dissolution rate.

[182] The experimental results for Tapentadol hydrochloride and for the salt with L

(+)-tartaric acid are compiled in the table below:

Tapentadol hydrochloride Salt of Tapentadol with L-(+)

[%] (comparison) tartaric acid

(according to Example 1)

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 19 20 18 19

3 95 91 65 79 51 51 44 44

5 99 95 80 92 77 77 65 67

Example 3 - Thermodynamic solubility:

[183] The thermodynamic solubility of Tapentadol hydrochloride and of the salt of

Tapentadol with L-(+)-tartaric acid was determined as saturation solubility at different pH

values in different media. The solutions were stirred for 24 hours at 25 °C, and the pH values

of the solutions at the start and at the end of the experiments were measured. The dissolved

amount of Tapentadol was quantified by HPLC (free base of Tapentadol). The experimental

results are compiled in the table below:

Salt of Tapentadol with L-(+) Tapentadol hydrochloride tartaric acid (comparison) (according to Example 1)

Assay expressed pH Assay expressed as base pH as base

Start End g/100 mL Start End g/100 mL

0.1 M HCl 1.11 0.83 31.2 1.15 3.39 26.7

Acetate pH 4.5 4.54 4.29 32.7 4.51 3.53 26.6

Water n.d. 4.63 33.0 6.19 3.38 26.4

SIF sp pH 6.8 6.82 6.23 32.4 6.83 3.55 12.6

Phosphate pH 7.4 n.d. n.d. n.d. 7.53 3.56 12.9

Citrate pH 7.4 7.39 6.33 31.9 n.d. n.d. n.d.

n.d. = not determined

Example 4 - In vitro dissolution profiles of pharmaceutical dosage forms:

[184] Tablets with the following composition were prepared by mixing all the

components and compressing the resulting mixtures:

Comparison According to the invention

C-1 I-1

[mg]

Tapentadol hydrochloride 250.00

2 Salt of Tapentadol with L-(+)-tartaric acid' - 250.00

Hydroxypropylmethylcellulose 100.00 100.00 100,000 mPa-s Type 2208

Silicified microcrystalline cellulose 304.80 304.80 (Prosolv HD90)

Magnesium stearate 4.00 4.00

Mean breaking strength, Ph. Eur. 2.9.8. [N] 222 239

Mean compression force, upper punch [kN] 12.8 8.0

Mean compression force, lower punch [kN] 11.3 7.0

equivalent dose relative to the free base of Tapentadol; 2 according to Example 1.

[185] From the above comparison data, it is apparent that for tablets of identical dose

strength of Tapentadol, in order to obtain tablets with improved breaking strength, a

significantly lower compression force is necessary, if Tapentadol as salt with L-(+)-tartaric

acid is used instead of hydrochloric acid, (see, for example, C-1 vs. I-1). Tablets C-1 and I-1,

for example, have a mean breaking strength of 222 or 239 N; the hydrochloride salt requires

tableting forces of 12.8 kN or 11.3 kN, while the L-(+)-tartaric acid salt requires only 8.0 kN

or 7.0 kN.

The in vitro dissolution of Tapentadol from the tablets was measured with a paddle

apparatus equipped with a sinker according to Ph. Eur. at a rotational speed of 50 rpm at 37 °C

in 900 mL of various dissolution media at different pH values. The experimental results are compiled in the following tables:

Tapentadol hydrochloride (n = 3):

[%] C-1

Difference between Time pH 1.0 pH 6.8 pH 4.5 pH 1.0 pH 1.0 and pH 1.0

[min] 40 vol.-% ethanol 40 vol.-% ethanol

0 0 0 0 0 0

30 17 19 18 14 4

60 26 28 27 22 5

90 33 36 34 28 6

120 39 42 40 33 7

240 58 63 60 50 10

480 82 87 84 73 11

720 93 96 95 87 8

Salt of Tapentadol with L-(+)-tartaric acid (n = 3):

[%] I-1

Difference between Time pH 1.0 pH 6.8 pH 4.5 pH 1.0 pH 1.0 und pH 1.0

[min] 40 vol.-% ethanol 40 vol.-% ethanol

0 0 0 0 0 0

30 15 14 17 11 6

60 24 23 28 20 8

90 31 30 36 26 10

120 37 36 43 32 11

240 57 56 64 50 14

480 83 82 90 75 15

720 96 95 99 91 8

Example 5 - In vitro dissolution profiles of pharmaceutical dosage forms:

[186] Tablets with the following composition were prepared by mixing all the

components and compressing the mixtures obtained:

Comparison According to the

invention

[mg] C-2 1-2

Tapentadol hydrochloride 250.00

2 Salt of Tapentadol with L-(+)-tartaric acid' - 250.00

Kollidon® SR 320.00 320.00

Aerosil200 6.80 6.80

Magnesium stearate 3.20 3.20

Mean breaking strength, Ph. Eur. 2.9.8. [N] 237 271

Mean compression force, upper punch [kN] 12.4 8.1

Mean compression force, lower punch [kN] 9.9 6.5

equivalent dose relative to the free base of Tapentadol; 2 according to Example 1

[187] The in vitro dissolution of Tapentadol from tablets was measured in a paddle

in 900 mL 0.1 N HCl without ethanol (pH 1.0) and in 0.1 N HC with 40 vol.-% ethanol (pH

1.0). The experimental results are compiled in the table below:

Tapentadol hydrochloride (n = 3): Salt of Tapentadol with L-(+)-tartaric

[%] acid (n =3):

C-2 1-2

Difference Difference pH 1.0 between pH 1.0 pH 1.0 Time between pH 1.0 pH 1.0 40 vol.-% and pH 1.0 pH 1.0 40 vol.-%

[min] and pH 1.0 ethanol 40 Vol.-% ethanol 40 vol.-% ethanol ethanol

0 0 0 0 0 0 0

30 24 14 10 33 15 18

60 33 21 12 46 24 22

90 40 27 13 55 31 24

120 45 32 13 63 37 26

240 60 51 9 84 61 23

480 79 78 1 100 95 5

720 90 92 -2 103 102 1

[188] From the above comparison data, it is apparent that the reduced compression

force of the L-(+)-tartaric acid salt of Tapentadol in comparison to the hydrochloride salt of

Tapentadol does not depend on the other excipients of the tablet (C-1, I-1 both

hydroxypropylmethylcellulose), but rather is also observed with Kollidon* SR. Again, for

tablets of identical dose strength of Tapentadol, a significantly lower compression force is

necessary if Tapentadol as salt with L-(+)-tartaric acid is used instead of hydrochloric acid for

preparing tablets with improved breaking strength (see C-2 vs. 1-2). The tablets C-2 and 1-2 both have a mean breaking strength of approximately 237 or 271 N; the hydrochloride salt requires tableting forces of 12.4 kN or 9.9 kN, while the salt of L-(+)-tartaric acid requires only

8.1 kN or 6.5 kN.

Claims

Claims:

1. A pharmaceutical dosage form comprising Tapentadol for twice daily administration; wherein Tapentadol is present as a salt with tartaric acid; wherein the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form is in the range of 10 to 300 mg relative to the free base of Tapentadol; wherein the dosage form is a tablet; wherein the dosage form provides a prolonged release of Tapentadol; and wherein Tapentadol is embedded in a prolonged-release matrix.

2. The pharmaceutical dosage form according to claim 1, wherein the salt is the salt of Tapentadol with L-(+)-tartaric acid, a solvate, an ansolvate and/or a polymorphic form thereof, a crystalline form and/or an amorphic form thereof

3. The pharmaceutical dosage form according to claim 1 or 2, wherein the tablet is monolithic.

4. The pharmaceutical dosage form according to any one of the preceding claims, wherein the tablet has a breaking strength of at least 100 N.

5. The pharmaceutical dosage form according to any one of the preceding claims, wherein the weight equivalent dose of Tapentadol contained in the pharmaceutical dosage form is 25 mg, 50 mg or 100 mg, in each case relative to the free base of Tapentadol; and wherein the dosage form has a total weight in the range of 150 to 750 mg.

6. The pharmaceutical dosage form according to any one of claims 1 to 4, wherein the weight equivalent dose of Tapentadol contained in the pharmaceutical dosage form is 150 mg, 200 mg or 250 mg, in each case relative to the free base of Tapentadol; and wherein the dosage form has a total weight in the range of 300 to 1200 mg.

7. The pharmaceutical dosage form according to any one of the preceding claims, wherein the prolonged-release matrix comprises or substantially consists of a prolonged release matrix material selected from the group consisting of (i) hydroxypropylmethylcellulose (HPMC); (ii) hydroxypropylcellulose (HPC); (iii) hydroxyethylcellulose (HEC); (iv) microcrystalline cellulose (MCC); (v) ethylcellulose (EC); (vi) polyvinyl acetate (PVAc); (vii) polyvinylpyrrolidone (PVP); (viii) polyvinylpyrrolidone-vinylacetate copolymer (PVP/PVAc); (ix) poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride); (x) poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate); (xi) poly(methyl methacrylate-co-methacrylic acid); (xii) poly(ethyl acrylate-co-methacrylic acid); (xiii) poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid); (xiv) poly(ethyl acrylate-co-methyl methacrylate); (xv) poly(ethylene oxide) (PEO); (xvi) polyethylene glycol (PEG); (xvii) long chain fatty alcohol having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated and linear or branched; (xviii) cetostearyl alcohol; (xix) stearyl alcohol; (xx) cetyl alcohol; (xxi) hydrocarbon selected from the group consisting of long chain fatty acids having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated and linear or branched; glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils, and waxes; (xxii) xanthan gum; (xxiii) sodium alginate; (xxiv) guar gum; (xxv) locust bean gum; and any mixtures ofthe above.

8. The pharmaceutical dosage form according to claim 7, wherein the content of prolonged-release matrix material is preferably in the range of 15+10 wt.- % or 2010 wt. ,

%, or 25+10 wt.-%, or 30+10 wt.-%, or 35+10 wt.-%, or 4010 wt.-%, or 4510 wt.-%, or +10 wt.-%, or 55+10 wt.-%, or 60+10 wt.-%, or 65+10 wt.-%, or 7010 wt.-%, or 7510 wt.-%, or 80+10 wt.-%, in each case relative to the total weight of the dosage form.

9. A method of treating pain, comprising administering the pharmaceutical dosage form according to any one of the preceding claims to a subject in need thereof

10. The method according to claim9, wherein the dosage form is orally administered.

11. The method according to claim 9 or 10, wherein the dosage form is administered twice daily.

12. The method according to any one of claims 9 to 11, which, after oral administration, provides plasma levels of Tapentadol providing pain relieffor a duration of at least 6 hours.

13. The method according to any one of claims 9 to 12, wherein the pain is chronic pain.

14. Use of the pharmaceutical dosage form according to any one of claims 1 to 8, for the manufacture of a medicament for treating pain.

15. The use according to claim 14, wherein the dosage form is orally administered.

16. The use according to claim 14 or 15, wherein the dosage form is administered twice daily.

17. The use according to any one of claims 14 to 16, which, after oral administration, provides plasma levels of Tapentadol providing pain relief for a duration of at least 6 hours.

18. The use according to any one of claims 14 to 17, wherein the pain is chronic pain.

19. A method for the preparation of a pharmaceutical dosage form according to any one of claims I to 8, wherein the method comprises the following steps: (a) providing a mixture containing substantially the entire amount of Tapentadol to be contained in the dosage form and at least one prolonged-release matrix material, optionally together with one or more excipients; (b) optionally granulating the mixture provided in step (a), thereby obtaining a granulate; (c) optionally mixing the granulate obtained in step (b) with one or more excipients, thereby obtaining a granulate mixture; (d) compressing the mixture provided in step (a) or the granulate obtained in step (b) or the granulate mixture obtained in step (c) into tablets; (e) optionally, film coating the tablets compressed in step (d).

20. The method according to claim 19, wherein the compression in step (d) occurs with a compression force of not more than 20 kN, particularly preferably not more than 15 kN, even more preferably not more than 10 kN, even more preferably not more than 9.5 kN, even more preferably not more than 9.0 kN, most preferably not more than 8.75 kN and in particular not more than 8.5 kN. Grunenthal GmbH

Patent Attorneys for the Applicant/Nominated Person SPRUSON&FERGUSON