Controlled release formulation

• US 6,326,027 B1
• Filed: 05/24/1995
• Issued: 12/04/2001
• Est. Priority Date: 05/10/1993
• Status: Expired due to Term

• Current Assignee: Napp Pharmaceutical Group Limited (NAPP Pharmaceutical Holdings Limited), Purdue Pharma Products LP (Purdue Pharma L.P.)
• Original Assignee: Euroceltique SA
• Inventors: Prater, Derek Allan, Hahn, Udo, Winkler, Horst, Smith, Kevin John, Wimmer, Walter, Miller, Ronald Brown, Leslie, Stewart Thomas, Malkowska, Sandra Therese Antoinette
• Primary Examiner(s): BARTS, SAMUEL A
• Application Number:
  US08/449,772
• Time in Patent Office: 2,386 Days
• Field of Search: 424/468, 424/470, 424/476, 424/480, 424/488, 424/494, 424/495, 424/498, 424/499, 424/502, 514/646
• US Class Current: 424/468
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/02 without antiinflammatory effect

Abstract

A controlled release preparation for oral administration contains tramadol, or a pharmaceutically acceptable salt thereof, as active ingredient.

Claims

1. A process for the preparation of a solid, controlled release oral dosage form, comprising incorporating a therapeutically effective amount of tramadol or a pharmaceutically acceptable salt thereof in a controlled release matrix such that said dosage form provides a therapeutic effect for at least about 12 hours after oral administration.

2. A process according to claim 1, wherein from about 50 to about 800 mg of tramadol (calculated as tramadol hydrochloride) is incorporated in the dosage from.

3. A process according to claim 1, wherein the dissolution rate (measured by the Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°

C. and using UV detection at 270 mm) is as set forth below;

4. A process according to claim 1, wherein the dissolution rate (measured by the Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°

C. and using UV detection at 270 mm) is as set forth below;

5. A process according to claim 1, wherein the dissolution rate (measured by Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°

C. and using UV detection at 270 mm) is as set forth below;

6. A process according to claim 1, wherein said controlled release matrix comprises at least one C₁ to C₆ alkylcellulose, at least one C₁₂ to C₃₆ aliphatic alcohol and, optionally at least one polyalkylglycol.

7. A process according to claim 6, wherein said aliphatic alcohol is a C₁₄ to C₂₂ aliphatic alcohol.

8. A process according to claim 6, wherein said polyalkylglycol is polyethylene glycol.

9. A process according to claim 6, wherein said alkylcellulose is ethylcellulose.

10. A process according to claim 1, wherein said dosage form comprises from about 2 to 15% w/w of one or more alkylcelluloses.

11. A process according to claim 10, wherein said dosage form comprises from about 2 to about 15% w/w of one or more alkylcelluloses.

12. A process according to claim 6, wherein said dosage form comprises an aliphatic alcohol selected form the group consisting of lauryl alcohol, myristyl alcohol, stearyl alcohol, and mixtures thereof.

13. A process according to claim 6, wherein said dosage form comprises an aliphatic alcohol selected form the group consisting of cetyl alcohol, cetostearyl alcohol, and mixtures thereof.

14. A process according to claim 6, wherein said dosage form comprises from about 5 to 30% w/w of at least one aliphatic alcohol.

15. A process according to claim 14, wherein said dosage form comprises from about 10 to about 25% w/w of at least one aliphatic alcohol.

16. A process according to claim 1, further comprising:

(a) granulating a mixture comprising said tramadol or a pharmaceutically acceptable salt thereof and one or more alkylcelluloses, and

(b) mixing the resultant alkylcellulose containing granules with one or more C_12-36 aliphatic alcohols.

17. A process according to claim 1, further comprising

granulating a mixture comprising said tramadol or a pharmaceutically acceptable salt thereof, lactose and one or more alkylcelluloses with one ore more C_12-36 aliphatic alcohols.

18. A process according to claim 1, further comprising:

(a) granulating said tramadol or a pharmaceutically acceptable salt thereof with a spheronizing agent;

(b) extruding the resultant granulate to provide an extrudate;

(c) spheronizing said extrudate to produce spheroids; and

(d) coating said spheriods with a controlled release film coat.

19. A process according to claim 1, comprising:

(a) mechanically working in a high-speed mixer, a mixture of said tramadol or a pharmaceutically acceptable salt thereof in particulate form and a particulate, hydrophobic fusible material having a melting point from 35 to 140°

C. and optionally a release control component comprising a material selected from the group consisting of water soluble fusible material, a particulate soluble organic material, a particulated soluble inorganic material and mixtures thereof, at a speed and energy input which allows said carrier or diluent to melt or soften, whereby it forms agglomerates;

(b) breaking down the larger said agglomerates to give controlled release seeds;

(c) continuing mechanically working with optionally a further addition of low percentage of said hydrophobic fusible material; and

(d) optionally repeating step (c) or steps (b) and (c) one or more times.

20. A process according to claim 1, further comprising the step of forming a drug mixture of said tramadol or pharmaceutically acceptable salt thereof and said fusible material and mechanically working said mixture in a high speed mixer with an energy input sufficient to melt or soften the fusible material whereby it forms particles comprising said tramadol or pharmaceutically acceptable salt thereof.

21. A process according to claim 19, further comprising compressing the resultant controlled release particles to form a tablet.

22. A process according to claim 20, further comprising compressing the resultant controlled release particles to form a tablet.

23. A process according to claim 16 further comprising film coating said granules prepared in step (b).

24. The process according to claim 19 in which said mixture further comprises a release control component taken from the group consisting of a water soluble fusible material, a particulate soluble organic material, a particulate soluble inorganic material, a particulate insoluble organic material and a particulate insoluble inorganic material.

25. The process according to claim 19 further comprising adding an additional amount of carrier or diluent during step (c).

26. The process according to claim 1 wherein said dosage form is suitable for 12 hour administration.

27. The process according to claim 1 wherein said controlled release matrix is prepared such that said dosage form provides a therapeutic effect for about 24 hours when said dosage form in orally administered to human patients.

28. A process for the preparation of a solid, controlled release oral dosage form of tramadol, comprising incorporating a therapeutically effective amount of tramadol or a pharmaceutically acceptable salt thereof in a matrix comprising an effective amount of a controlled release material selected from the group consisting of hydrophilic polymers, hydrophobic polymers, fatty acids, fatty alcohols, glycerol esters of fatty acids, mineral oil, vegetable oils, waxes, polyalkylene glycols, and mixtures thereof, such that said dosage form has a dissolution rate (measured by the Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°

C. and using UV detection at 270 nm of between 0-50% after 1 hour;

between 0-75% after 2 hours;

between 3-95% after 4 hours;

between 0-100% after 8 hours;

between 20-100% after 12 hours;

between 30-100% after 16 hours;

between 50-100% after 24 hours; and

greater than 80% after 36 hours;

said dosage form providing a therapeutic effect for at least about 12 hours after administration.

29. The process of claim 28, wherein said dosage form has an in vitro dissolution rate when measured by the Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°

C. and using UV detection at 270 nm, such that between 5 and 50% (by weight) tramadol is released after 1 hour, between 10 and 75% (by weight) tramadol is released after 2 hours, between 20 and 95% (by weight) tramadol is released after 4 hours, between 40 and 100% (by weight) tramadol is released after 8 hours, more than 50% (by weight) tramadol is released after 12 hours, more than 70% (by weight) tramadol is released after 18 hours and more than 80% (by weight) tramadol is released after 24 hours.

30. The process of claim 28, wherein said dosage form provides a t_max at 2 to 7 hours after oral administration.

31. The process of claim 28, wherein said dosage form provides a t_max at 1.5 to 8 hours after oral administration.

32. The process of claim 28, wherein said dosage form provides a W₅₀ in the range of 7 to to 16 hours when orally administered.

33. The process of claim 28, further comprising manufacturing the dosage form as a tablet.

34. A process for the preparation of a solid, controlled release oral dosage form of tramadol suitable for dosing every 24 hours, comprising incorporation a therapeutically effective amount of tramadol or a pharmaceutically acceptable salt thereof in a matrix comprising an effective amount of a controlled release material comprising (a) between 1% and 80% by weight hydrophilic polymers, hydrophobic polymers, or mixtures thereof;

(b) from 0-60% by weight digestible C₈-C₅₀ substituted or unsubstituted hydrocarbons selected from the group consisting of fatty acids, fatty alcohols, glycerol esters of fatty acids, mineral oils, vegetable oils, waxes, and mixtures thereof; and

(c) from 0-60% by weight polyalkylene glycol, such that said dosage form has a dissolution rate (measured by Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°

C. and using UV detection at 270 nm), of between 0 and 50% tramadol released after 1 hour;

between 0 and 75% tramadol released after 2 hours;

between 3 and 95% tramadol released after 4 hours;

between 10 and 100% tramadol released after 8 hours;

between 20 and 100% tramadol released after 12 hours;

between 30 and 100% tramadol released after 16 hours;

between 50 and 1005 tramadol released after 24 hours; and

greater than 805 tramadol released after 36 hours, by weight, and provides a W₅₀ in the range of 10 to 33 hours and a therapeutic effect for about 24 hours when orally administered to human patients.

35. The process of claim 34, wherein said dosage form has a dissolution rate (measured by the Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°

C. and using UV detection at 270 nm), as set forth below;

36. The process of claim 34, wherein said dosage form has a dissolution rate (measured by the Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°

C. and using UV detection at 270 nm), as set forth below;

38. The process of claim 34, wherein said preparation provides a tmax from about 3 to about 6 hours when orally administered to human patients.

37. A process for preparation of a solid, controlled release oral dosage form, comprising incorporating a therapeutically effective amount of an opioid analgesic consisting essentially of tramadol or a pharmaceutically acceptable salt thereof in a controlled release matrix such that said dosage form provides a therapeutic effect for at least about 12 hours after oral administration.

39. A process for the preparation of a solid, controlled release oral dosage form of tramadol suitable for dosing every 12 hours, comprising incorporation a therapeutically effective amount of tramadol or a pharmaceutically acceptable salt thereof in a matrix comprising an effective amount of a controlled release material comprising (a) between 1% and 80% by weight hydrophilic polymers, hydrophobic polymers, or mixtures thereof;

(b) from 0-60% by weight digestible C₈-C₅₀ substituted or unsubstituted hydrocarbons selected from the group consisting of fatty acids, fatty alcohols, glycerol esters of fatty acids, mineral oils, vegetable oils, waxes, and mixtures thereof; and

(c) from 0-60% by weight polyalkylene glycol, such that said preparation contains up to 60% by weight of said polyalkylene glycol;

such that said dosage form has a dissolution rate (measured by the Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°

C. and using UV detection at 270 nm), of between 0 and 50% tramadol released after 1 hour;

between 0 and 75% tramadol released after 2 hours, between 3 and 95% tramadol released after 4 hours;

between 10 and 100% tramadol released after 8 hours;

between 20 and 100% tramadol released after 12 hours;

between 30 and 100% tramadol released after 16 hours;

between 50 and 100% tramadol released after 24 hours; and

greater than 80% tramadol released after 36 hours, by weight, and provides a Tmax from about 1.5 to about 8 hours and a therapeutic effect for at least about 12 hours when orally administered to human patients.

40. The process of claim 39, where said preparation provides a W₅₀ from 7 to 16 hours.

41. A process for the preparation of a solid, controlled release oral dosage form, comprising incorporation from about 50 to about 800 mg tramadol or a pharmaceutically acceptable salt thereof in a controlled release matrix to obtain a granular product containing said tramadol;

and incorporating said granular product into an orally administrable dosage form such that said dosage form provides a dissolution rate (measured by the Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°

C. and using UV detection at 270 nm of between 0-50% after 1 hour;

between 0-75% after 2 hours;

between 3-95% after 4 hours;

between 10-100% after 8 hours;

between 20-100% after 12 hours;

between 30-100% after 16 hours;

between 50-100% after 24 hours; and

greater than 80% after 36 hours and provides a therapeutic effect for at least about 12 hours after oral administration.

42. The process of claim 41, where said preparation provides a therapeutic effect for about 24 hours after oral administration.

43. The process of claim 42, where said preparation provides a W₅₀ from 7 to 16 hours.

44. The process according to claim 43, wherein said dosage form provides Tmax from 1.5 to about 8 hours.

45. The process according to claim 44, wherein said granular product comprises agglomerated particles.

46. The process according to claim 45, wherein said matrix comprises an effective amount of a controlled release material comprising (a) between 1% and 80% by weight hydrophilic polymers, hydrophobic polymers, or mixtures thereof;

(b) from 0-60% by weight digestible C₈-C₅₀ substituted or unsubstituted hydrocarbons selected from the group consisting of fatty acids, fatty alcohols, glycerol esters of fatty acids, mineral oils, vegetable oils, waxes, and mixtures thereof; and

(c) from 0-60% by weight polyalkylene glycol, such that said preparation contains up to 60% by weigh of said polyalkylene glycol;

such that said dosage form has a dissolution rate (measured by the Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°

C. and using UV detection at 270 nm), of between 0 and 50% tramadol released after 1 hour, between 0 and 75% tramadol.