MULTIPARTICULATE ORAL DOSAGE FORM PROVIDING PROLONGED RELEASE OF TAPENTADOL

Abstract

The invention relates to an oral pharmaceutical dosage form comprising a plurality of coated particles, wherein said coated particles comprise a core which comprises a Tapentadol component and which is coated with a controlled release coating material, wherein the controlled release coating material comprises a lubricant component and a polymer component, wherein the polymer component comprises one or more cellulose ethers and/or one or more acrylates, and wherein the pharmaceutical dosage form provides controlled release of the Tapentadol component.

Claims

1. An oral pharmaceutical dosage form comprising a plurality of coated particles, wherein said coated particles comprise a core which comprises a Tapentadol component, wherein under in vitro conditions the pharmaceutical dosage form provides controlled release of the Tapentadol component, and wherein the core is coated (i) with a controlled release coating material, wherein the controlled release coating material comprises a lubricant component and a polymer component, wherein the polymer component comprises one or more cellulose ethers and/or one or more acrylates; and/or (ii) with a tamper resistant coating material providing resistance against ethanolic dose dumping.

2. The dosage form according to claim 1, wherein the controlled release coating material essentially consists of the lubricant component and the polymer component.

3. The dosage form according to claim 1, wherein the polymer component comprises or essentially consists of a cellulose ether selected from the group consisting of ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, and mixtures thereof

4. The dosage form according to claim 3, wherein the cellulose ether is ethylcellulose.

5.-7. (canceled)

8. The dosage form claim 1, wherein the lubricant component comprises or essentially consists of a fatty acid, a metallic salt of a fatty acid, a fatty acid ester, an inorganic material, a polymeric lubricant, or a mixture thereof.

9. The dosage form according to claim 8, wherein the fatty acid is selected from stearic acid, myristic acid, palmitic acid, and mixtures thereof; and/or the metallic salt of a fatty acid is selected from magnesium stearate, calcium stearate, zinc stearate, and mixtures thereof; and/or the fatty acid ester is selected from glyceride esters; and sugar esters; and mixtures thereof; and/or the inorganic material is talc; and/or the polymeric lubricant is macrogol.

10. The dosage form according to claim 1, wherein the weight content of the controlled release coating material, relative to the total weight of the coated particles, is within the range of from 5.0 wt.-% to 21 wt.-%.

11.-13. (canceled)

14. The dosage form according to claim 1, wherein the coated particles comprise a core which comprises a drug coat and a controlled release coat, wherein the drug coat comprises the Tapentadol component and wherein the controlled release coat comprises the controlled release coating material.

15. The dosage form according to claim 14, wherein the drug coat and the controlled release coat are in intimate contact with one another.

16.-25. (canceled)

26. The dosage form according to claim 1, wherein the coated particles have an average weight per particle within the range of 100?90 ?g.

27.-33. (canceled)

34. The dosage form according to claim 1, wherein the relative weight ratio of the polymer component to the lubricant component is within the range of from 5.0:1.0 to 2.1:1.0.

35.-41. (canceled)

42. The dosage form according to claim 1, wherein the weight content of the polymer component, relative to the total weight of the coated particles, is within the range of 10.0?9.0 wt.-%.

43.-47. (canceled)

48. The dosage form according to claim 1, wherein the weight content of the lubricant component, relative to the total weight of the coated particles, is within the range of 3.0?2.5 wt.-%.

49.-54. (canceled)

55. The dosage form according to claim 1, which is a filled capsule comprising the plurality of coated particles.

56. (canceled)

57. The dosage form according to claim 55, wherein the capsule is a sprinkle capsule.

58.-96. (canceled)

97. A method of treating pain in a patient in need thereof, said method comprising administering to said patient at least one dosage form according to claim 1.

98.-102. (canceled)

103. A process for the manufacture of a pharmaceutical dosage form according to claim 1, the process comprising the step of (b) applying a controlled release coating material, which comprises a lubricant component and a polymer component, to a plurality of cores, which comprise a Tapentadol component.

104. (canceled)

105. The process according to claim 103, comprising the preceding step of (a) applying a drug coat, which comprises the Tapentadol component, to a plurality of starter pellets thereby providing the plurality of cores.

106.-107. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0252] The invention will now be described with reference to the drawings, wherein:

[0253] Preferred embodiments of the coated particles according to the invention are schematically illustrated in FIGS. 1A to 7B.

[0254] FIG. 1A schematically illustrates a coated particle (1) comprising an inert core (2) essentially comprising no Tapentadol component (e.g. nonpareil). The inert core (2) is coated with a drug coat (4) comprising the Tapentadol component and overcoated with a controlled release coat (5) comprising the controlled release coating material. FIG. 1B schematically illustrates a variant of the embodiment shown in FIG. 1A, wherein the coated particle (1) comprises a core (3) comprising the Tapentadol component, but no additional drug coat. The Tapentadol component is homogeneously distributed over the core (3).

[0255] FIGS. 2A and 2B schematically illustrate a variant of the embodiment shown in Figures 1A and 1B, respectively, wherein in each case the controlled release coat (5) is overcoated with a tamper resistant coat (6) comprising tamper resistant coating material.

[0256] FIGS. 3A and 3B schematically illustrate a variant of the embodiment shown in FIGS. 2A and 2B, respectively, wherein in each case a tamper resistant coat (6) comprising tamper resistant coating material is overcoated with the controlled release coat (5).

[0257] FIGS. 4A and 4B schematically illustrate a variant of the embodiment shown in FIGS. 2A and 2B, respectively, wherein the tamper resistant coat (6) is composed of an inner layer (6a) comprising alginate salt and an outer layer (6b) comprising acrylate polymer.

[0258] FIGS. 5A and 5B schematically illustrate another variant of the embodiment shown in FIGS. 4A and 4B, respectively, wherein in each case a tamper resistant coat (6), which is composed of an inner layer (6a) comprising alginate salt and an outer layer (6b) comprising acrylate polymer, is overcoated with the controlled release coat (5).

[0259] FIGS. 6A and 6B schematically illustrate a variant of the embodiment shown in FIGS. 2A and 2B, respectively, wherein the tamper resistant coat (6) provides controlled release of the Tapentadol component such that no additional controlled release coat (5) is necessary.

[0260] FIGS. 7A and 7B schematically illustrate a variant of the embodiment shown in FIGS. 4A and 4B, respectively, wherein the tamper resistant coat (6) provides controlled release of the Tapentadol component such that no additional controlled release coat (5) is necessary.

[0261] FIG. 8 shows in vitro release profiles of inventive embodiments of Example 1 in comparison to a commercial tablet comprising Tapentadol.

[0262] FIGS. 9 and 10 graph pharmacokinetic parameters of inventive embodiments of Example 1 in comparison to a commercial tablet comprising Tapentadol. FIG. 9 depicts the results in the fasted state. FIG. 10 depicts the results in the fed state.

[0263] In a preferred embodiment, the coated particles comprise or essentially consist of a core which comprises a drug coat, a controlled release coat, and a tamper resistant coat, wherein the drug coat comprises the Tapentadol component, wherein the controlled release coat comprises the controlled release coating material, and wherein the tamper resistant coat comprises the tamper resistant coating material.

[0264] Preferably, the drug coat and the controlled release coat are in intimate contact with one another, and/or the controlled release coat and the tamper resistant coat are in intimate contact with one another.

[0265] Preferably, the weight content of the tamper resistant coating material, relative to the total weight of the coated particles, is not more than 45.5 wt.-% or not more than 49 wt.-%, more preferably not more than 47.5 wt.-% or not more than 45 wt.-%, still more preferably not more than 42.5 wt.-% or not more than 40 wt.-%, yet more preferably not more than 37.5 wt.-% or not more than 35 wt.-%, even more preferably not more than 32 wt.-% or not more than 31 wt.-%, most preferably not more than 30 wt.-% or not more than 29 wt.-%, and in particular not more than 28 wt.-% or not more than 27 wt.-%.

[0266] Preferably, the weight content of the tamper resistant coating material, relative to the total weight of the coated particles, is not more than 26 wt.-% or not more than 25 wt.-%, more preferably not more than 24 wt.-% or not more than 23 wt.-%, still more preferably not more than 22 wt.-% or not more than 21 wt.-%, yet more preferably not more than 20 wt.-% or not more than 19 wt.-%, even more preferably not more than 18 wt.-% or not more than 17 wt.-%, most preferably not more than 16 wt.-% or not more than 15 wt.-%, and in particular not more than 14 wt.-% or not more than 13 wt.-%.

[0267] Preferably, the weight content of the tamper resistant coating material, relative to the total weight of the coated particles, is within the range of from 5.0 wt.-% to 21 wt.-%, more preferably from 7.0 wt.-% to 19 wt.-%.

[0268] In preferred embodiments, the weight content of the tamper resistant coating material, relative to the total weight of the coated particles, is within the range of 9.0?8.0 wt.-%, or 9.0?7.0 wt.-%, or 9.0?6.0 wt.-%, or 9.0?5.0 wt.-%, or 9.0?4.0 wt.-%, more preferably 9.0?3.5 wt.-%, still more preferably 9.0?3.0 wt.-%, yet more preferably 9.0?2.5 wt.-%, even more preferably 9.0?2.0 wt.-%, most preferably 9.0?1.5 wt.-%, and in particular 9.0?1.0 wt.-% or 9.0?0.5 wt.-%.

[0269] In preferred embodiments, the weight content of the tamper resistant coating material, relative to the total weight of the coated particles, is within the range of 11.0?8.0 wt.-%, or 11.0?7.0 wt.-%, or 11.0?6.0 wt.-%, or 11.0?5.0 wt.-%, or 11.0?4.0 wt.-%, more preferably 11.0?3.5 wt.-%, still more preferably 11.0?3.0 wt.-%, yet more preferably 11.0?2.5 wt.-%, even more preferably 11.0?2.0 wt.-%, most preferably 11.0?1.5 wt.-%, and in particular 11.0?1.0 wt.-% or 11.0?0.5 wt.-%.

[0270] In preferred embodiments, the weight content of the tamper resistant coating material, relative to the total weight of the coated particles, is within the range of 13.0?8.0 wt.-%, or 13.0?7.0 wt.-%, or 13.0?6.0 wt.-%, or 13.0?5.0 wt.-%, or 13.0?4.0 wt.-%, more preferably 13.0?3.5 wt.-%, still more preferably 13.0?3.0 wt.-%, yet more preferably 13.0?2.5 wt.-%, even more preferably 13.0?2.0 wt.-%, most preferably 13.0?1.5 wt.-%, and in particular 13.0?1.0 wt.-% or 13.0?0.5 wt.-%.

[0271] In preferred embodiments, the weight content of the tamper resistant coating material, relative to the total weight of the coated particles, is within the range of 15.0?8.0 wt.-%, or 15.0?7.0 wt.-%, or 15.0?6.0 wt.-%, or 15.0?5.0 wt.-%, or 15.0?4.0 wt.-%, more preferably 15.0?3.5 wt.-%, still more preferably 15.0?3.0 wt.-%, yet more preferably 15.0?2.5 wt.-%, even more preferably 15.0?2.0 wt.-%, most preferably 15.0?1.5 wt.-%, and in particular 15.0?1.0 wt.-% or 15.0?0.5 wt.-%.

[0272] In preferred embodiments, the weight content of the tamper resistant coating material, relative to the total weight of the coated particles, is within the range of 17.0?8.0 wt.-%, or 17.0?7.0 wt.-%, or 17.0?6.0 wt.-%, or 17.0?5.0 wt.-%, or 17.0?4.0 wt.-%, more preferably 17.0?3.5 wt.-%, still more preferably 17.0?3.0 wt.-%, yet more preferably 17.0?2.5 wt.-%, even more preferably 17.0?2.0 wt.-%, most preferably 17.0?1.5 wt.-%, and in particular 17.0?1.0 wt.-% or 17.0?0.5 wt.-%.

[0273] In preferred embodiments, the weight content of the tamper resistant coating material, relative to the total weight of the coated particles, is within the range of 19.0?8.0 wt.-%, or 19.0?7.0 wt.-%, or 19.0?6.0 wt.-%, or 19.0?5.0 wt.-%, or 19.0?4.0 wt.-%, more preferably 19.0?3.5 wt.-%, still more preferably 19.0?3.0 wt.-%, yet more preferably 19.0?2.5 wt.-%, even more preferably 19.0?2.0 wt.-%, most preferably 19.0?1.5 wt.-%, and in particular 19.0?1.0 wt.-% or 19.0?0.5 wt-%.

[0274] In preferred embodiments, the weight content of the tamper resistant coating material, relative to the total weight of the coated particles, is within the range of 22.5?8.0 wt.-%, or 22.5?7.0 wt.-%, or 22.5?6.0 wt.-%, or 22.5?5.0 wt.-%, or 22.5?4.0 wt.-%, more preferably 22.5?3.5 wt.-%, still more preferably 22.5?3.0 wt.-%, yet more preferably 22.5?2.5 wt.-%, even more preferably 22.5?2.0 wt.-%, most preferably 22.5?1.5 wt.-%, and in particular 22.5?1.0 wt.-% or 22.5?0.5 wt.-%.

[0275] In preferred embodiments, the weight content of the tamper resistant coating material, relative to the total weight of the coated particles, is within the range of 25.0?8.0 wt.-%, or 25.0?7.0 wt.-%, or 25.0?6.0 wt.-%, or 25.0?5.0 wt.-%, or 25.0?4.0 wt.-%, more preferably 25.0?3.5 wt.-%, still more preferably 25.0?3.0 wt.-%, yet more preferably 25.0?2.5 wt.-%, even more preferably 25.0?2.0 wt.-%, most preferably 25.0?1.5 wt.-%, and in particular 25.0?1.0 wt.-% or 25.0?0.5 wt.-%.

[0276] Preferably, the coated particles have an average weight per particle of at least 5.0 ?g, more preferably at least 7.5 ?g, still more preferably at least 10 ?g, yet more preferably at least 15 ?g, even more preferably at least 20 ?g, most preferably at least 25 ?g, and in particular at least 30 ?g.

[0277] Preferably, the coated particles have an average weight per particle of not more than 500 ?g, more preferably not more than 450 ?g, still more preferably not more than 400 ?g, yet more preferably not more than 350 ?g, even more preferably not more than 300 ?g, most preferably not more than 250 ?g, and in particular not more than 200 ?g.

[0278] Preferably, the coated particles have an average weight per particle within the range of 100?90 ?g, more preferably 100?80 ?g, still more preferably 100?70 ?g, yet more preferably 100?60 ?g, even more preferably 100?50 ?g, most preferably 100?40 ?g, and in particular 100?30 ?g.

[0279] The shape of the coated particles is not particularly limited. While the shape of the particles may be oval or oblong, the shape of the coated particles is preferably round and essentially spherical.

[0280] Preferably, the coated particles have an average diameter of at least 50 ?m, more preferably at least 100 ?m, still more preferably at least 150 ?m, yet more preferably at least 200 ?m, even more preferably at least 250 ?m, most preferably at least 300 ?m, and in particular at least 350 ?m.

[0281] Preferably, the coated particles have an average diameter of not more than 1000 ?m, more preferably not more than 900 ?m, still more preferably not more than 800 ?m, yet more preferably not more than 700 ?m, even more preferably not more than 600 ?m, most preferably not more than 550 ?m, and in particular not more than 500 ?m.

[0282] Preferably, the coated particles have an average diameter within the range of 400?300 ?m, more preferably 400?260 ?m, still more preferably 400?220 ?m, yet more preferably 400?180 ?m, even more preferably 400?140 ?m, most preferably 400?100 ?m, and in particular 400?60 ?n.

[0283] Preferably, the plurality of coated particles has a particle size distribution such that upon sieve analysis at least 80 wt.-%, more preferably at least 82 wt.-%, still more preferably at least 84 wt.-%, yet more preferably at least 86 wt.-%, even more preferably at least 88 wt.-%, most preferably at least 90 wt.-%, and in particular at least 92 wt.-% of the coated particles have of size within the range of from 355 ?m to 560 ?m.

[0284] Preferably, the plurality of coated particles has a particle size distribution such that upon sieve analysis not more than 99.9 wt.-%, more preferably not more than 99.7 wt.-%, still more preferably not more than 99.5 wt.-%, yet more preferably not more than 99.3 wt.-%, even more preferably not more than 99.0 wt.-%, most preferably not more than 98.8 wt.-%, and in particular not more than 98.6 wt.-% of the coated particles have of size within the range of from 355 ?m to 560 ?m.

[0285] Preferably, the plurality of coated particles has a particle size distribution such that upon sieve analysis 90.0?9.9 wt.-% more preferably 90.0?9.5 wt.-%, still more preferably 90.0?9.0 wt.-%, yet more preferably 90.0?8.5 wt.-%, even more preferably 90.0?8.0 wt.-%, most preferably 90.0?7.5 wt.-%, and in particular 90.0?7.0 wt.-% of the coated particles have of size within the range of from 355 ?m to 560

[0286] In a preferred embodiment, the plurality of coated particles has a particle size distribution such that upon sieve analysis [0287] 0.1 to 5.0 wt.-% of the coated particles have of size within the range of from 355 ?m to 400 ?m; [0288] 40 to 95 wt.-% of the coated particles have a size within the range of from 401 ?m to 500 ?m; and [0289] 5.0 to 50 wt.-% of the coated particles have a size within the range of from 501 ?m to 560 ?m.

[0290] Preferably, the Tapentadol component is Tapentadol free base of a physiologically acceptable salt of Tapentadol.

[0291] Preferably, the Tapentadol component is Tapentadol hydrochloride.

[0292] While it is principally possible that the dosage form according to the invention comprises one or more additional pharmacologically active ingredients, the Tapentadol component is preferably the only pharmacologically active ingredient that is contained in the dosage form.

[0293] Preferably, the weight content of the Tapentadol component, relative to the total weight of the coated particles and expressed as weight equivalents relative to Tapentadol free base, 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.-%.

[0294] Preferably, the weight content of the Tapentadol component, relative to the total weight of the coated particles and expressed as weight equivalents relative to Tapentadol free base, is not more than 30 wt.-%, or not more than 27.5 wt.-%, or not more than 25 wt.-%, or not more than 22.5 wt.-%, or not more than 20 wt.-% , more preferably not more than 19 wt.-%, still more preferably not more than 18 wt.-%, yet more preferably not more than 17 wt.-%, even more preferably not more than 16 wt.-%, most preferably not more than 15 wt.-%, and in particular not more than 14 wt.-%.

[0295] Preferably, the weight content of the Tapentadol component, relative to the total weight of the coated particles and expressed as weight equivalents relative to Tapentadol free base, is within the range of 11.0?8.0 wt.-%, more preferably 11.0?7.0 wt.-%, still more preferably 11.0?6.0 wt.-%, yet more preferably 11.0?5.0 wt.-%, even more preferably 11.0?4.0 wt.-%, most preferably 11.0?3.0 wt.-%, and in particular 11.0?2.0 wt.-%.

[0296] The dosage form according to the invention may contain excipients that are conventionally used for the manufacture of oral dosage forms.

[0297] 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., FiedlerEncyclopedia of Excipients, Editio Cantor, 6th edition 2008).

[0298] 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. Typical examples of pharmaceutical excipients include but are not limited to antiadherents, binders, coating materials, disintegrants, fillers, diluents, flavours, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, and the like. Binders and glidants are preferred.

[0299] In a preferred embodiment, the dosage form comprises a binder, preferably hydroxy-propylmethylcellulose (hypromellose). Other suitable binders include but are not limited to saccharides and their derivatives such as disaccharides (e.g. sucrose or lactose), polysaccharides and their derivatives (e.g. starches, cellulose or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC)), sugar alcohols such as xylitol, sorbitol or maltitol; proteins such as gelatin; synthetic polymers such as polyvinylpyrrolidone (PVP) or polyethylene glycol (PEG). Preferably, the binder is contained in the coated particles, more preferably in a drug coat also comprising the Tapentadol component.

[0300] Preferably, the weight content of the binder, relative to the total weight of the coated particles, is at least 0.01 wt.-%, more preferably at least 0.05 wt.-%, still more preferably at least 0.1 wt.-%, yet more preferably at least 0.2 wt.-%, even more preferably at least 0.3 wt.-%, most preferably at least 0.4 wt.-%, and in particular at least 0.5 wt.-%.

[0301] Preferably, the weight content of the binder, relative to the total weight of the coated particles, is not more than 5.0 wt.-%, more preferably not more than 4.5 wt.-%, still more preferably not more than 4.0 wt.-%, yet more preferably not more than 3.5 wt.-%, even more preferably not more than 3.0 wt.-%, most preferably not more than 2.5 wt.-%, and in particular not more than 2.0 wt.-%.

[0302] Preferably, the weight content of the binder, relative to the total weight of the coated particles, is within the range of 0.65?0.60 wt.-%, more preferably 0.65?0.55 wt.-%, still more preferably 0.65?0.50 wt.-%, yet more preferably 0.65?0.45 wt.-%, even more preferably 0.65?0.40 wt.-%, most preferably 0.65?0.35 wt.-%, and in particular 0.65?0.30 wt.-%.

[0303] In a preferred embodiment, the dosage form comprises a glidant, preferably silicon dioxide. Other suitable glidants include but are not limited to starch, talc, silaceous material like colloidal silica, pyrogenic silica, hydrated sodium silicoaluminate, and magnesium carbonate. Preferably, the glidant is contained in the coated particles, more preferably in a drug coat also comprising the Tapentadol component.

[0304] Preferably, the weight content of the glidant, relative to the total weight of the coated particles, is at least 0.01 wt.-%, more preferably at least 0.05 wt.-%, still more preferably at least 0.1 wt.-%, yet more preferably at least 0.2 wt.-%, even more preferably at least 0.3 wt.-%, most preferably at least 0.4 wt.-%, and in particular at least 0.5 wt.-%.

[0305] Preferably, the weight content of the glidant, relative to the total weight of the coated particles, is not more than 5.0 wt.-%, more preferably not more than 4.5 wt.-%, still more preferably not more than 4.0 wt.-%, yet more preferably not more than 3.5 wt.-%, even more preferably not more than 3.0 wt.-%, most preferably not more than 2.5 wt.-%, and in particular not more than 2.0 wt.-%.

[0306] Preferably, the weight content of the glidant, relative to the total weight of the coated particles, is within the range of 0.65?0.60 wt.-%, more preferably 0.65?0.55 wt.-%, still more preferably 0.65?0.50 wt.-%, yet more preferably 0.65?0.45 wt.-%, even more preferably 0.65?0.40 wt.-%, most preferably 0.65?0.35 wt.-%, and in particular 0.65?0.30 wt.-%.

[0307] The dosage form according to the invention may principally be any type of dosage form suitable for oral administration. Examples include but are not limited to tablets, coated tablets, coated minitablets, coated pellets, coated granules, powders, suspensions, dragees, capsules or sachets filled with coated pellets or with powder or with granules, and the like.

[0308] The term coated tablet includes pellet-containing tablets or compressed tablets and is well known to a skilled person. Such a tablet may have a size of around 5 to 25 mm for instance. Usually, defined pluralities of small Tapentadol component containing pellets are compressed therein together with binding excipients to give the well known tablet form. After oral ingestion and contact with the body fluid the tablet form is disrupted and the pellets are set free. The compressed tablet combines the advantage of the single dose form for ingestion with the advantages of a multiple forms, for instance the dosage accuracy.

[0309] The term coated minitablet is well known to the skilled person. A minitablet is smaller than the traditional tablet and may have a size of around 1 to 4 mm. The minitablet is, like a pellet, a single dosage form to be used in multiple dosages. In comparison to pellets, which may be in the same size, minitablets usually have the advantage of having more regular surfaces which can be coated more accurately and more uniformly. Minitablets may be provided enclosed in capsules, such as gelatine capsules. Such capsules disrupt after oral ingestion and contact with the gastric or intestinal fluids and the minitablets are set free. Another application of minitablets is the individual fine adjustment of the Tapentadol component dosage. In this case the patient may ingest a defined number of minitablets directly which matches to the severe of the decease to cure but also to his individual body weight. A minitablet is different from pellet-containing compressed tablet as discussed above.

[0310] The term sachet is well known to the skilled person. It refers to small sealed package which contains the Tapentadol component in particle containing form. The sachet itself is only the package form is not intended to be ingested. The content of the sachet may be dissolved in water or as an advantageous feature may be soaked or ingested directly without further liquid. The latter is advantageous feature for the patient when the dosage form shall be ingested in a situation where no water is available. The sachet is an alternative dosage form to tablets, minitablets or capsules.

[0311] In a preferred embodiment, the dosage form according to the invention is provided in form of a sachet comprising the plurality of coated particles.

[0312] In another preferred embodiment, the dosage form according to the invention is provided in form of a MUPS (multiple unit pellet system) formulation, wherein the plurality of coated particles is contained in a matrix material and compressed to a tablet.

[0313] In still another preferred embodiment, the dosage form according to the invention is provided in form of a filled capsule comprising the plurality of coated particles.

[0314] Preferably, the filled capsule essentially consists of the capsule and the plurality of coated particles.

[0315] In a particularly preferred embodiment, the capsule is a sprinkle capsule. Sprinkle capsules are patient-centric capsules specifically designed to meet the needs of a rapidly growing number of patients that have difficulty swallowing. Sprinkle capsules have an innovative closure that needs less force to open so it can be opened much easier and safer. Based on the trusted design, it can be filled on the same machines as traditional capsules but will remain in place during packaging and transportation. Sprinkle capsules are commercially available (e.g. Coni-Snap?).

[0316] The dosage form according to any of the invention provides prolonged release of the Tapentadol component.

[0317] In a preferred embodiment, the dosage form according to the invention provides an in vitro release profile measured with the paddle method according to Ph. Eur. at 50 rpm in 900 ml phosphate buffer pH 6.8 and 37? C., such that [0318] after 60 min 15?10 wt.-%; more preferably 15?8.0 wt.-%; still more preferably 15?6.0 wt.-%; [0319] after 120 min 50?30 wt.-%; more preferably 50?25 wt.-%; still more preferably 50?15 wt.-%; [0320] after 240 min 70?20 wt.-%; more preferably 70?15 wt.-%; still more preferably 70?10 wt.-%; [0321] after 360 min 80?15 wt.-%; more preferably 80?12.5 wt.-%; still more preferably 80?10 wt.-%; and [0322] after 720 min 90?10 wt.-%; more preferably 90?7.5 wt.-%; still more preferably 90?5.0 wt.-%; [0323] of the Tapentadol component that was originally contained in the dosage form have been released.

[0324] In another preferred embodiment, the dosage form according to the invention provides an in vitro release profile measured with the paddle method according to Ph. Eur. at 50 rpm in 900 ml phosphate buffer pH 6.8 and 37? C., such that [0325] after 60 min 3.2?3.0 wt.-%; more preferably 3.2?3.0 wt.-%; still more preferably 3.2?3.0 wt.-%; [0326] after 120 min 35?30 wt.-%; more preferably 35?30 wt.-%; still more preferably 35?30 wt.-%; [0327] after 240 min 65?30 wt.-%; more preferably 65?30 wt.-%; still more preferably 65?30 wt.-%; [0328] after 360 min 76?14 wt.-%; more preferably 76?14 wt.-%; still more preferably 76?14 wt.-%; and [0329] after 720 min 89?11 wt.-%; more preferably 89?11 wt.-%; still more preferably 89?11 wt.-%; [0330] of the Tapentadol component that was originally contained in the dosage form have been released.

[0331] The volume of the phosphate buffer of 900 ml may be reduced to 500 ml when the dose strength is reduced as well. In particular, when the dose strength is 25 mg, a buffer volume of 900 ml is preferred, whereas when the dose strength is 6.25 mg, a buffer volume of 500 ml is preferred.

[0332] In a preferred embodiment of the dosage form according to the invention, the dose of the Tapentadol component, expressed as weight equivalents relative to Tapentadol free base, is within the range of 25?5 mg.

[0333] According to this preferred embodiment, the number of the plurality of coated particles that is contained in the dosage form, e.g. in the capsule, is preferably within the range from 1000 to 1500.

[0334] According to this embodiment, the dosage form according to the invention preferably provides under fasted conditions mean (?standard deviation) pharmacokinetic parameters of [0335] AUC within the range of 65.1?17.6 h.Math.ng/ml; more preferably 65.1?12.3 h.Math.ng/ml; and/or [0336] C.sub.max within the range of 5.22?1.83 ng/ml; more preferably 5.22?1.28 ng/ml; and/or [0337] t.sub.max within the range of 5.61?0.783 h; more preferably 5.61?0.548 h.

[0338] Alternatively, according to this embodiment, the dosage form according to the invention preferably provides under fasted conditions mean (?standard deviation) pharmacokinetic parameters of [0339] AUC within the range of 65.1?17.6 h.Math.ng/ml; and/or [0340] C.sub.max within the range of 5.22?1.83 ng/ml; and/or [0341] t.sub.max within the range of 5.61?0.783 h.

[0342] According to this embodiment, the dosage form according to the invention preferably provides under fed status conditions mean (?standard deviation) pharmacokinetic parameters of [0343] AUC within the range of 101?21.1 h.Math.ng/ml; more preferably 101?14.8 h.Math.ng/ml; and/or [0344] C.sub.max within the range of 10.1?2.37 ng/ml; more preferably 10.1?1.66 ng/ml; and/or [0345] t.sub.max within the range of 4.79?0.658 h; more preferably 4.79?0.460 h.

[0346] Alternatively, according to this embodiment, the dosage form according to the invention preferably provides under fed status conditions mean (?standard deviation) pharmacokinetic parameters of [0347] AUC within the range of 102 ?21.0 h.Math.ng/ml; and/or [0348] C.sub.max within the range of 10.2 ?2.39 ng/ml; and/or [0349] t.sub.max within the range of 4.78 ?0.672 h.

[0350] In another preferred embodiment of the dosage form according to the invention, the dose of the Tapentadol component, expressed as weight equivalents relative to Tapentadol free base, is within the range of 50?5 mg.

[0351] According to this preferred embodiment, the number of the plurality of coated particles that is contained in the dosage form, e.g. in the capsule, is preferably within the range from 2000 to 3000.

[0352] According to this embodiment, the dosage form according to the invention preferably provides under fasted conditions mean (?standard deviation) pharmacokinetic parameters of [0353] AUC within the range of 130.2?35.2 h.Math.ng/ml; more preferably 130.2?24.6 h.Math.ng/ml; and/or [0354] C.sub.max within the range of 10.44?3.66 ng/ml; more preferably 10.44?2.56 ng/ml.

[0355] In still another preferred embodiment of the dosage form according to the invention, the dose of the Tapentadol component, expressed as weight equivalents relative to Tapentadol free base, is within the range of 100?5 mg.

[0356] According to this preferred embodiment, the number of the plurality of coated particles that is contained in the dosage form, e.g. in the capsule, is preferably within the range from 3000 to 4500.

[0357] According to this embodiment, the dosage form according to the invention preferably provides under fasted conditions mean (?standard deviation) pharmacokinetic parameters of [0358] AUC within the range of 260.4?70.4 h.Math.ng/ml; more preferably 260.4?49.3 h.Math.ng/ml; and/or [0359] C.sub.max within the range of 20.9?7.32 ng/ml; more preferably 20.9?5.12 ng/ml.

[0360] In another preferred embodiment of the dosage form according to the invention, the dose of the Tapentadol component, expressed as weight equivalents relative to Tapentadol free base, is within the range of 150?5 mg.

[0361] In another preferred embodiment of the dosage form according to the invention, the dose of the Tapentadol component, expressed as weight equivalents relative to Tapentadol free base, is within the range of 200?5 mg.

[0362] In another preferred embodiment of the dosage form according to the invention, the dose of the Tapentadol component, expressed as weight equivalents relative to Tapentadol free base, is within the range of 250?5 mg.

[0363] In a preferred embodiment, the dosage form according to the invention comprises the Tapentadol component as the only pharmacologically active ingredient that is contained in the pharmaceutical dosage form. In a preferred embodiment, the Tapentadol component is exclusively provided in form of the coated particles according to the invention as described above. In another preferred embodiment, the pharmaceutical dosage form contains the coated particles according to the invention as described above as well as subunits which differ from the coated particles according to the invention and which contain Tapentadol component as well. For example, said subunits may provide a different in vitro release profile, e.g. immediate release, such that the overall release profile of the Tapentadol component from the dosage form, i.e. from the coated particles and from the subunits, may be modified, e.g. bimodal.

[0364] In further preferred embodiments, the dosage form according to the invention provides preferably under fasted conditions a mean value for AUC within the range of 150?100 h.Math.ng/ml; or 200?150 h.Math.ng/ml, more preferably 200?100 h.Math.ng/ml; or 250?200 h.Math.ng/ml, more preferably 250?150 h.Math.ng/ml, still more preferably 250?100 h.Math.ng/ml; or 300?250 h.Math.ng/ml, more preferably 300?200 h.Math.ng/ml, still more preferably 300?150 h.Math.ng/ml, yet more preferably 300?150 h.Math.ng/ml; or 400?250 h.Math.ng/ml, more preferably 400?200 h.Math.ng/ml, still more preferably 400?150 h.Math.ng/ml, yet more preferably 400?150 h.Math.ng/ml; or 500?250 h.Math.ng/ml, more preferably 500?200 h.Math.ng/ml, still more preferably 500?150 h.Math.ng/ml, yet more preferably 500?150 h.Math.ng/ml; or 600?250 h.Math.ng/ml, more preferably 600?200 h.Math.ng/ml, still more preferably 600?150 h.Math.ng/ml, yet more preferably 600?150 h.Math.ng/ml; or 700?250 h.Math.ng/ml, more preferably 700?200 h.Math.ng/ml, still more preferably 700?150 h.Math.ng/ml, yet more preferably 700?150 h.Math.ng/ml; or 800?250 h.Math.ng/ml, more preferably 800?200 h.Math.ng/ml, still more preferably 800?150 h.Math.ng/ml, yet more preferably 800?150 h.Math.ng/ml or 900?250 h.Math.ng/ml, more preferably 900?200 h.Math.ng/ml, still more preferably 900?150 h.Math.ng/ml, yet more preferably 900?150 h.Math.ng/ml.

[0365] In further preferred embodiments, the dosage form according to the invention provides preferably under fasted conditions a mean value for C.sub.max within the range of 5.0?2.5 ng/ml; or 7.5?5.0 ng/ml; more preferably 7.5?2.5 ng/ml; or 10.0?7.5 ng/ml, more preferably 10.0?5.0 ng/ml, still more preferably 10.0?2.5 ng/ml; or 12.5?10.0 ng/ml, more preferably 12.5?7.5 still more preferably 12.5?5.0 ng/ml, yet more preferably 12.5?2.5 ng/ml; or 15.0?10.0 ng/ml, more preferably 15.0?7.5 ng/ml, still more preferably 15.0?5.0 ng/ml, yet more preferably 15.0?2.5 ng/ml, or 17.5?10.0 ng/ml, more preferably 17.5?7.5 ng/ml, still more preferably 17.5?5.0 ng/ml, yet more preferably 17.5?2.5 ng/ml; or 20.0?10.0 ng/ml, more preferably 20.0?7.5 ng/ml, still more preferably 20.0?5.0 ng/ml, yet more preferably 20.0?2.5 ng/ml; or 25.0?10.0 ng/ml, more preferably 25.0?7.5 ng/ml, still more preferably 25.0?5.0 ng/ml, yet more preferably 25.0?2.5 ng/ml; or 30.0?10.0 ng/ml, more preferably 30.0?7.5 ng/ml, still more preferably 30.0?5.0 ng/ml, yet more preferably 30.0?2.5 ng/ml; or 35.0?10.0 ng/ml, more preferably 35.0?7.5 ng/ml, still more preferably 35.0?5.0 ng/ml, yet more preferably 35.0?2.5 ng/ml; or 40.0?10.0 ng/ml, more preferably 40.0?7.5 ng/ml, still more preferably 40.0?5.0 ng/ml, yet more preferably 40.0?2.5 ng/ml; or 45.0?10.0 ng/ml, more preferably 45.0?7.5 ng/ml, still more preferably 45.0?5.0 ng/ml, yet more preferably 45.0?2.5 ng/ml; or 50.0?10.0 ng/ml, more preferably 50.0?7.5 ng/ml, still more preferably 50.0?5.0 ng/ml, yet more preferably 50.0?2.5 ng/ml.

[0366] In further preferred embodiments, the dosage form according to the invention provides preferably under fasted conditions a mean value for t.sub.max within the range of 4.0?2.5 h; more preferably 4.0?2.0 h, still more preferably 4.0?1.5 h, yet more preferably 4.0?1.0 h; or 5.0?2.5 h; more preferably 5.0?2.0 h, still more preferably 5.0?1.5 h, yet more preferably 5.0?1.0 h; or 6.0?2.5 h; more preferably 6.0?2.0 h, still more preferably 6.0?1.5 h, yet more preferably 6.0?1.0 h; or 7.0?2.5 h; more preferably 7.0?2.0 h, still more preferably 7.0?1.5 h, yet more preferably 7.0?1.0 h.

[0367] Another aspect of the invention relates to a dosage form according to the invention as described above for use in the treatment of pain.

[0368] Another aspect of the invention relates to the use of a Tapentadol component for the manufacture of a dosage form according to the invention as described above for treatment of pain.

[0369] Another aspect of the invention relates to a method of treating pain comprising administering to a subject in need thereof a dosage form according to the invention as described above.

[0370] Preferably, the pain is moderate to severe. Preferably, the pain is acute pain or chronic pain. Preferably, the pain is nociceptive pain or neuropathic pain.

[0371] In a preferred embodiment, the dosage form according to the invention is for administration to a pediatric patient, preferably having an age of from 2 to 8 years, more preferably 2 to 6 years.

[0372] In another preferred embodiment, the dosage form according to the invention is for administration to a geriatric patient, preferably having an age of at least 70 years, more preferably at least 75 years.

[0373] In yet another preferred embodiment, the dosage form according to the invention is for administration to an adult, preferably having an age of at least 14 years, more preferably at least 18 years.

[0374] In still another preferred embodiment, the dosage form according to the invention is for administration to a patients with gastric or duodenal tubes.

[0375] Preferably, the dosage form according to the invention is for administration once daily, twice daily or thrice daily. Preferably, the dosage form according to the invention is for administration twice daily.

[0376] The dosage form according to the invention is an oral dosage form. Thus, the dosage form according to the invention is preferably devoted for peroral administration, optionally after removing the coated particles from the remainder of the original dosage form, e.g. from the sprinkle capsule.

[0377] Particularly preferred embodiments A.sup.1 to A.sup.24 of the dosage form according to the invention are summarized in the tables here below, wherein all values are provided in wt.-%, relative to the total weight of the coated particles:

TABLE-US-00003 Ingredient [wt.-%] A.sup.1 A.sup.2 A.sup.3 A.sup.4 A.sup.5 A.sup.6 A.sup.7 A.sup.8 Core - Inert carrier 73 ? 20 73 ? 18 73 ? 16 73 ? 14 73 ? 12 73 ? 10 73 ? 8 73 ? 6 Tapentadol 13 ? 10 13 ? 9 13 ? 8 13 ? 7 13 ? 6 13 ? 5 13 ? 4 13 ? 3 component Polymer 10 ? 8 10 ? 7 10 ? 6 10 ? 5 10 ? 4 10 ? 3 10 ? 2 10 ? 1 component Lubricant 3.0 ? 2.5 3.0 ? 2.2 3.0 ? 1.9 3.0 ? 1.6 3.0 ? 1.3 3.0 ? 1.0 3.0 ? 0.7 3.0 ? 0.4 component Ingredient [wt.-%] A.sup.9 A.sup.10 A.sup.11 A.sup.12 A.sup.13 A.sup.14 A.sup.15 A.sup.16 Core - Inert carrier 73 ? 20 73 ? 18 73 ? 16 73 ? 14 73 ? 12 73 ? 10 73 ? 8 73 ? 6 Tapentadol HCl 13 ? 10 13 ? 9 13 ? 8 13 ? 7 13 ? 6 13 ? 5 13 ? 4 13 ? 3 Ethylcellulose 10 ? 8 10 ? 7 10 ? 6 10 ? 5 10 ? 4 10 ? 3 10 ? 2 10 ? 1 Magnesium stearate 3.0 ? 2.5 3.0 ? 2.2 3.0 ? 1.9 3.0 ? 1.6 3.0 ? 1.3 3.0 ? 1.0 3.0 ? 0.7 3.0 ? 0.4 Ingredient [wt.-%] A.sup.17 A.sup.18 A.sup.19 A.sup.20 A.sup.21 A.sup.22 A.sup.23 A.sup.24 Microcrystalline 73 ? 20 73 ? 18 73 ? 16 73 ? 14 73 ? 12 73 ? 10 73 ? 8 73 ? 6 cellulose Tapentadol HCl 13 ? 10 13 ? 9 13 ? 8 13 ? 7 13 ? 6 13 ? 5 13 ? 4 13 ? 3 Ethylcellulose 10 ? 8 10 ? 7 10 ? 6 10 ? 5 10 ? 4 10 ? 3 10 ? 2 10 ? 1 Magnesium stearate 3.0 ? 2.5 3.0 ? 2.2 3.0 ? 1.9 3.0 ? 1.6 3.0 ? 1.3 3.0 ? 1.0 3.0 ? 0.7 3.0 ? 0.4

[0378] Another aspect of the invention relates to a process for the manufacture of a pharmaceutical dosage form according to the invention as described above, the process comprising the step of: [0379] (b) applying a controlled release coating material, which comprises a lubricant component and a polymer component, to a plurality of cores, which comprise a Tapentadol component.

[0380] Preferably, the controlled release coating material is applied in form of an ethanolic composition.

[0381] Preferably, the process according to the invention comprises the preceding step of [0382] (a) applying a drug coat, which comprises the Tapentadol component, to a plurality of starter pellets thereby providing the plurality of cores.

[0383] Preferably, the drug coat is applied In form of an aqueous composition.

[0384] Preferably, in step (a) the drug coat and/or in step (b) the controlled release coat is applied by fluid-bed coating.

[0385] The following examples further illustrate the invention but are not to be construed as limiting its scope.

[0386] Tapentadol prolonged release granules were developed, considering that the used excipients have to be acceptable for pediatric use. Only excipients were selected which were sufficiently tested to be non-hazardous for children in the respective age group of 2 to 6 years.

COMPARATIVE EXAMPLE 1

[0387] A comparative formulation development approach was based on a purely aqueous film-coating process. Therefore, pellets were produced via an extrusion/spheronization process and further processed by an aqueous solvent based prolonged release film-coating step.

[0388] The obtained granules demonstrated prolonged-release characteristics in vitro in aqueous dissolution media, but the dissolution profiles were not stable during storage, leading to accelerated drug release over time. Tapentadol HCl is a highly soluble drug substance which is known to alter the prolonged-release behavior of a formulation due to the migration into the film-coat in an aqueous environment.

COMPARATIVE EXAMPLE 2

[0389] The manufacturing process was switched from aqueous to organic solvent based prolonged-release film coating. An initial drug layering was performed followed by a second organic solvent based coating step.

[0390] Ethanol 96% was used for the organic solvent based coating process. The solvent was removed during processing, and was therefore of no toxicological concern.

[0391] Different excipients e.g. cellulose acetate and ethylcellulose were investigated regarding their prolonged-release capability. Further, additives such as talcum were assessed as in the coating suspension to minimize agglomeration and electrostatic charging of the pellets during manufacturing.

[0392] All batches were evaluated based on their manufacturability, their dissolution and (short refill) stability characteristics.

[0393] However, these formulations were not satisfactory in every respect. For example, the combination of ethylcellulose and talcum showed substantial disadvantages with respect to electrostatic charging during processing and an insufficient robustness.

EXAMPLE 1

[0394] For clinical trials, three prototype formulations with different prolonged-release dissolution profiles were developed. This was achieved by applying different amounts of functional coating layer (all weight percent after drying).

[0395] Three different controlled release granules were manufactured as pluralities of coated particles. Each plurality of coated particles comprised a total dose of 29.12 mg Tapentadol hydrochloride (corresponding to 15.00 mg Tapentadol free base). The quantitative compositions of the three different formulations are provided in the table here below:

TABLE-US-00004 Quantity per unit [mg] Component Function 1-1 1-2 1-3 Microcrystalline starter pellet 162.17 162.17 162.17 cellulose Ph. Eur. (Cellets? 350) Tapentadol HCl active ingredient 29.12 29.12 29.12 Hypromellose Ph. Eur. binder 1.46 1.46 1.46 Silicon dioxide glidant 1.46 1.46 1.46 Ph. Eur. Ethylcellulose Ph. Eur. polymer component 22.40 29.87 37.34 Magnesium stearate lubricant component 6.73 8.97 11.22 Ph. Eur. Total 223.35 233.05 242.76

[0396] The polymer component and the lubricant component were applied as controlled release coating material. The relative weight contents of the three different formulations are provided in the table here below:

TABLE-US-00005 Percentage per unit [wt.-%] Component Arrangement 1-1 1-2 1-3 Microcrystalline starter pellet 72.61 69.59 66.80 cellulose Ph. Eur. (Cellets? 350) Tapentadol HCl drug coat 13.04 12.50 12.00 Hypromellose Ph. Eur. 0.65 0.63 0.60 Silicon dioxide Ph. Eur. 0.65 0.63 0.60 Sub-total drug coat 14.34 13.76 13.20 Ethylcellulose Ph. Eur. controlled 10.03 12.82 15.38 Magnesium stearate Ph. Eur. release coat 3.01 3.85 4.62 Sub-Total controlled 13.04 16.67 20.00 release coat Total 100.00 100.00 100.00

[0397] The controlled release granules differed from one another essentially in the amounts of controlled release coating material.

[0398] Relative to the total weight of the controlled release granules, the granules of Example 1-1 contained about 13.0 wt.-% controlled release coating material, the granules of Example 1-2 contained about 16.7 wt.-% controlled release coating material, and the granules of Example 1-3 contained about 20.0 wt.-% controlled release coating material.

[0399] Relative to the partial weight of the starter pellet and the drug coat, the granules of Example 1-1 contained 15.0 wt.-% controlled release coating material, the granules of Example 1-2 contained 20.0 wt.-% controlled release coating material, and the granules of Example 1-3 contained 25.0 wt.-% controlled release coating material.

[0400] The manufacture involved two individual coating steps. In a first step, a drug layer was applied to starter pellets in an aqueous based coating step leading to Tapentadol immediate release granules. These Tapentadol immediate release granules were then further processed in a second, organic coating step to obtain Tapentadol prolonged release granules.

[0401] The manufacturing process involved only standard techniques of blending, fluid-bed coating and filling into glass vials.

[0402] Starter pellets of microcrystalline cellulose (28.390 kg) were coated with a composition comprising the following components in order to apply a drug coat:

TABLE-US-00006 Tapentadol HCl 5.098 kg Hypromellose 0.256 kg Silicon dioxide 0.256 kg Purified water 22.431 kg

[0403] The thus obtained coated starter pellets (Tapentadol immediate release granules) were overcoated with a composition comprising the following components in order to apply a controlled release coat:

TABLE-US-00007 1-1 1-2 1-3 coated starter pellets 4000.0 g 4000.0 g 4000.0 g Ethylcellulose 461.4 g 615.2 g 769.0 g Magnesium stearate 138.6 g 184.8 g 231.0 g Ethanol 96% 5400.0 g 7200.0 g 9000.0 g Total 4600.0 g 4800.0 g 5000.0 g

[0404] The prolonged release granules of Examples 1-1 and 1-3 were tested for storage stability, for 8 months at 25? C./60% r.h. as well as for 8 months at 40? C./75% r.h. A shelf-life of at least 8 months was observed.

[0405] The in vitro release profiles are displayed in FIG. 8 in comparison to a commercial tablet comprising the same amount of the Tapentadol component. The measurement was performed with the paddle method according to Ph. Eur. at 50 rpm in 900 ml phosphate buffer pH 6.8 and 37? C.

[0406] The measured values for composition 1-1 are also provided in the table here below (mean, n=6):

TABLE-US-00008 min % released 0 0.00 30 0.06 60 3.26 90 19.76 120 35.24 150 45.80 180 53.73 210 59.78 240 64.52 270 68.39 300 71.55 330 74.17 360 76.41 390 78.35 420 80.04 450 81.50 480 82.79 510 83.93 540 84.95 570 85.89 600 86.67 630 87.43 660 88.09 690 88.71 720 89.31

[0407] Size and size distribution of the coated particles was investigated for several samples by sieve analysis. In the following table all values are provided as [wt.-%] where every line represents the measurement on one sample (?=?m):

EXAMPLE 1-1

[0408]

TABLE-US-00009 >315? >355? >400? >500? >560? >630? >710? >800? >900? >1000? 0 0.9 89.2 9.7 0.2 0.4 0.1 0.2 0 0 0 0.7 58.4 32.4 2.2 1.1 3.5 1.1 0.3 0.1 0 1.08 68.01 27.07 1.08 0.79 1.48 0.3 0.1 0 0 1.39 55.22 34.73 1.89 1.19 3.78 1.19 0.4 0.2 0.1 1.47 55.5 35.07 1.57 1.28 3.14 1.08 0.49 0.1 0.1 1.58 59.29 32.91 1.48 0.89 2.47 0.69 0.2 0.2 0.2 1.29 57.96 32.74 1.68 1.38 3.46 0.89 0.1 0 0.2 1.47 59.61 33.24 1.47 0.78 2.06 0.59 0.29 0.2 0.2 1.48 61.71 32.09 1.18 0.69 1.67 0.69 0.1 0.2 0.1 1.28 55.77 40.08 0.79 0.39 0.89 0.3 0.1 0.2 0 0.8 59.12 36.69 1 0.6 1.3 0.2 0.1 0.1

EXAMPLE 1-2

[0409]

TABLE-US-00010 >315? >355? >400? >500? >560? >630? >710? >800? >900? >1000? 0.1 0.5 85.7 13.1 0.3 0.3 0.3 0 0 0 0 0.9 85.5 12.8 0.3 0.3 0.2 0 0 0

EXAMPLE 1-3

[0410]

TABLE-US-00011 >315? >355? >400? >500? >560? >630? >710? >800? >900? >1000? 0.1 0.2 78.5 20.1 0.5 0.1 0.3 0.2 0 0 0 0.5 73.9 21.3 1 1 1.9 0.4 0 0 0.1 0.5 71.7 19.4 1.0 2.7 3.5 0.8 0.2 0.1

[0411] The average number of pellets was also determined thus allowing to provide an average weight of one coated particle (n=3):

[0412] 125.6 mg of plurality coated particles=1202 coated particles 125.6 mg of plurality coated particles=1143 coated particles 126.3 mg of plurality coated particles=1291 coated particles

[0413] Thus, an average of 125.83 mg of plurality coated particles corresponded to an average number of 1212 pellets. Accordingly, the average weight per particle was 103.82 ?g.

[0414] The pharmacokinetic parameters were determined in a clinical trial for the fasted status as well as for the fed status. The results are displayed in FIG. 9 (fasted state) and FIG. 10 (fed state) and are compiled in the table here below:

TABLE-US-00012 Tablet (comparative) 1-1 1-2 1-3 Fasted Fed Fasted Fed Fasted Fed Fasted t.sub.lag [h] Mean ? SD 0.065 ? 0.172 0.197 ? 0.251 1.33 ? 0.287 1.07 ? 0.172 1.83 ? 0.243 1.59 ? 0.248 2.61 ? 0.499 (% CV) (264%) (128%) (21.6%) (16.2%) (13.3%) (15.6%) (19.1%) Median 0.000 0.000 1.50 1.00 2.00 1.50 3.00 (Range) (0.000-0.500) (0.000-0.533) (1.00-2.00) (1.00-1.50) (1.50-2.00) (1.00-2.03) (2.00-3.00) t.sub.max [h] Mean ? SD 5.24 ? 1.91 3.98 ? 1.59 5.61 ? 0.783 4.78 ? 0.672 6.61 ? 1.27 5.39 ? 0.840 7.30 ? 1.96 (% CV) (36.4%) (40.0%) (13.9%) (14.0%) (19.2%) (15.6%) (26.9%) Median 5.00 4.00 6.00 5.00 7.00 5.00 7.00 (Range) (1.50-10.0) (1.50-8.00) (4.00-7.00) (3.00-6.00) (5.00-10.0) (4.00-8.00) (5.00-12.0) C.sub.max Mean ? SD 4.88 ? 1.74 10.0 ? 2.01 5.22 ? 1.83 10.2 ? 2.39 4.99 ? 1.51 8.59 ? 2.25 4.68 ? 1.65 [ng/mL] (% CV) (35.6%) (20.1%) (35.1%) (23.4%) (30.2%) (26.2%) (35.1%) Median 4.66 9.85 4.88 10.2 4.53 8.19 4.47 (Range) (2.70-8.97) (7.01-14.8) (2.86-10.1) (6.88-14.9) (2.76-7.83) (4.89-12.8) (2.18-8.12) t.sub.last [h] Mean ? SD 29.6 ? 3.76 28.5 ? 4.72 31.3 ? 2.30 31.0 ? 2.75 31.3 ? 2.31 31.7 ? 1.66 31.7 ? 1.67 (% CV) (12.7%) (16.5%) (7.36%) (8.90%) (7.36%) (5.25%) (5.27%) Median 32.0 32.0 32.0 32.0 32.0 32.0 32.0 (Range) (24.0-32.0) (16.0-32.0) (24.0-32.0) (24.0-32.0) (24.0-32.0) (24.0-32.0) (24.0-32.0) AUC.sub.0-t Mean ? SD 67.7 ? 19.0 104 ? 25.3 61.0 ? 17.2 98.3 ? 20.9 64.3 ? 18.5 93.3 ? 21.9 67.9 ? 20.3 [h*ng/mL] (% CV) (28.0%) (24.4%) (28.1%) (21.2%) (28.7%) (23.4%) (29.9%) Median 68.7 102 54.9 92.9 64.8 89.8 68.9 (Range) (37.6-104) (64.1-154) (35.4-107) (53.5-136) (28.4-115) (49.4-143) (30.8-108) AUC Mean ? SD 73.5 ? 20.7 107 ? 25.2 65.1 ? 17.6 102 ? 21.0 69.8 ? 18.5 100 ? 24.0 76.1 ? 20.1 [h*ng/mL] (% CV) (28.2%) (23.5%) (27.1%) (20.6%) (26.6%) (24.0%) (26.4%) Median 74.9 105 58.4 95.9 70.2 92.7 75.3 (Range) (43.3-118) (68.0-157) (41.4-115) (57.1-138) (35.6-120) (51.6-152) (42.3-120) t.sub.1/2 [h] Mean ? SD 6.95 ? 1.87 5.35 ? 1.02 6.99 ? 0.957 5.96 ? 1.04 7.33 ? 1.42 6.96 ? 1.68 8.27 ? 2.15 (% CV) (26.9%) (19.0%) (13.7%) (17.4%) (19.4%) (24.1%) (26.1%) Median 6.94 5.64 6.94 5.80 7.03 6.77 8.11 (Range) (3.42-11.5) (2.90-6.61) (5.32-9.48) (4.58-8.78) (5.48-11.1) (4.33-10.4) (4.98-15.1) Cl/F [L/h] Mean ? SD 368 ? 107 245 ? 55.0 408 ? 98.3 256 ? 57.5 383 ? 105 265 ? 68.2 351 ? 93.3 (% CV) (29.2%) (22.5%) (24.1%) (22.5%) (27.5%) (25.7%) (26.6%) Median 334 237 428 261 356 270 332 (Range) (212-578) (160-368) (217-604) (181-438) (208-703) (164-485) (208-591) V.sub.z/F [L] Mean ? SD 3641 ? 1312 1887 ? 559 4156 ? 1356 2235 ? 857 4115 ? 1603 2613 ? 722 4287 ? 1886 (% CV) (36.0%) (29.6%) (32.6%) (38.3%) (39.0%) (27.6%) (44.0%) Median 3442 1847 3654 2017 3763 2431 3815 (Range) (1825-6155) (1050-2868) (2464-7822) (1195-5440) (1724-8729) (1624-4121) (1742-8992) MRT [h] Mean ? SD 13.1 ? 2.27 9.85 ? 1.25 13.5 ? 1.35 11.2 ? 0.910 15.2 ? 2.00 13.8 ? 2.15 17.6 ? 2.90 (% CV) (17.3%) (12.7%) (10.1%) (8.12%) (13.1%) (15.6%) (16.4%) Median 13.0 10.2 13.4 11.2 15.1 13.7 17.4 (Range) (7.32-18.7) (6.98-11.2) (11.8-16.6) (9.30-13.0) (11.5-19.8) (10.3-19.2) (13.6-26.9) HVD [h] Mean ? SD 13.4 ? 3.09 8.63 ? 1.57 9.89 ? 2.04 7.61 ? 1.89 11.2 ? 2.12 8.75 ? 2.68 13.9 ? 3.07 (% CV) (23.1%) (18.2%) (20.7%) (24.9%) (18.9%) (30.6%) (22.1%) Median 13.4 8.38 10.3 7.23 11.3 7.88 12.6 (Range) (8.57-19.6) (6.19-12.2) (3.45-13.2) (3.38-11.6) (7.34-14.4) (4.57-14.1) (10.4-20.6)

[0415] The influence of food intake was determined for the coated pellets of Examples 1-1 and 1-2 and comped with the commercial tablet. The results are compiled in the following table:

TABLE-US-00013 Parameter Treatment Fasted Fed C.sub.max Tablet (comparative) 4.88 9.99 [ng/mL] 1-1 5.22 10.2 1-2 4.99 8.59 AUC.sub.0-t Tablet (comparative) 67.7 104 [ng * h/mL] 1-1 61.0 98.3 1-2 64.3 93.3 AUC [ng * h/mL Tablet (comparative) 73.5 107 1-1 65.1 102 1-2 69.8 99.8

LIST OF REFERENCE NUMERALS

[0416] 1coated particle [0417] 2inert core essentially comprising no Tapentadol component (e.g. nonpareil) [0418] 3core comprising Tapentadol component [0419] 4drug coat comprising Tapentadol component [0420] 5controlled release coat comprising controlled release coating material [0421] 6tamper resistant coat comprising tamper resistant coating material [0422] 6ainner layer of tamper resistant coat comprising alginate salt [0423] 6bouter layer of tamper resistant coat comprising acrylate polymer

EXAMPLE 2

[0424] Two sets of controlled release granules were manufactured in accordance with Example 1-1. The only difference of the two sets was the particle size of the lubricant component (magnesium stearate) in the controlled release coating. All other parameters were identical such as content of Tapentadol, nature and content of further excipients, structure of granules and manufacturing conditions.

[0425] The particle size distribution of the magnesium stearate was measured according to different laser diffraction methods and the in vitro release of Tapentadol from the controlled release granules was determined in accordance with Example 1. The results are compiled in the table here below:

TABLE-US-00014 Example 2-1 not micronized Example 2-2 Beckmann Coulter micronized wet wet wet (Scharrsol D 80) dry, (H.sub.2O, (Scharrsol dry, Beckmann Coulter [?m] MasterSizer 1% Triton), D 80) MasterSizer #1 #2 #3 #4 Dx(10) 1.310 0.276 Dx(20) 2.270 0.499 Dx(30) 3.330 0.896 Dx(40) 4.310 1.290 Dx(50) 5.300 1.650 Dx(60) 6.440 2.030 Dx(70) 7.920 2.460 Dx(80) 10.400 3.010 Dx(90) 18.000 3.860 Dx(100) 144.000 8.490 D[3,2] 2.560 0.772 D[4,3] 8.520 1.880 mean 14.54 14.97 1.596 1.684 1.720 1.765 SD 13.65 12.84 0.808 0.859 0.827 0.917 median 9.968 1.456 1.539 1.605 1.614 maximum 8.537 8.537 1.748 1.919 1.919 2.107 d.sub.10 3.075 d.sub.50 9.610 d.sub.90 35.73 <10% 3.137 0.651 0.677 0.719 0.686 <50% 9.968 1.456 1.539 1.605 1.614 <75% 22.01 2.129 2.241 2.275 2.365 <90% 35.09 2.773 2.917 2.901 3.090 <95% 41.92 3.133 3.320 3.257 3.494 <99% 53.08 3.741 3.990 3.841 4.199 <100% 83.90 5.111 5.610 5.611 6.159 <2 ?m 3.59% 71.0% 67.5% 65.9% 64.0% <4 ?m 15.9% 99.6% 99.0% 99.4% 98.2% release after 2% (2-2%) 35% (34-37%) 60 min release after 44% (43-44%) 72% (71-73%) 150 min release after 91% (90-91%) 97% (96-99%) 720 min