Stabilized sustained release tramadol formulations

• US 6,306,438 B1
• Filed: 07/02/1998
• Issued: 10/23/2001
• Est. Priority Date: 07/02/1997
• Status: Expired due to Term

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Euroceltique SA
• Inventors: Oshlack, Benjamin, Huang, Hua-Pin, Goldenheim, Paul, Chasin, Mark
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): WARE, TODD
• Application Number:
  US09/109,615
• Time in Patent Office: 1,209 Days
• Field of Search: 424/468, 424/469, 424/470, 424/476, 424/484, 424/485, 424/486, 424/487, 424/488, 424/400
• US Class Current: 424/468
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• 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: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

A stabilized sustained release oral solid dosage form which includes an effective amount of tramadol or a pharmaceutically acceptable salt thereof dispersed in a matrix of a hydrophobic material comprising a wax-like substance which was melted or softened during the preparation of the matrix, is cured at a temperature from about 35° C. to about 65° C. for a time period from about 4 to about 72 hours, such that the formulation, when subjected to in-vitro dissolution after exposure to accelerated storage conditions of at least one month at 40° C./75% RH, releases an amount of tramadol which does not vary at any given dissolution time point by more than about 20% of the total amount of tramadol released when compared to in-vitro dissolution conducted prior to subjecting the dosage form to the accelerated storage conditions.

Claims

1. A stabilized sustained release oral solid dosage form containing tramadol as the active agent, comprising an effective amount of tramadol or a pharmaceutically acceptable salt thereof dispersed in a matrix of a hydrophobic material comprising a substance which was melted or softened during the preparation of said matrix, said substance being selected from the group consisting of hydrogenated vegetable oil, hydrogenated castor oil, paraffin, higher aliphatic alcohols, higher aliphatic acids, long chain fatty acids, fatty acid esters, and mixtures thereof, said solid dosage form being subjected to a separate curing step at a temperature from about 35 °

C. to about 65 °

C. for a sufficient time such that an endpoint is reached at which said solid dosage form provides a stable dissolution profile, said endpoint being determined by comparing the dissolution profile of said solid dosage form immediately after curing to the dissolution profile of said solid dosage form after eposure to accelerated storage conditions of at least one month at 40°

C. and 75% relative humidity.

2. The stabilized sustained release oral solid dosage form of claim 1, wherein the curing is conducted at a temperature from about 40°

C. to about 60°

C. for a time period from about 4 to about 72 hours.

3. The stabilized sustained release oral solid dosage form of claim 1, wherein the curing is conducted at a temperature from about 45°

C. to about 55°

C. for a time period from about 4 to about 72 hours.

4. The stabilized sustained release oral solid dosage form of claim 1, wherein the curing is conducted for a time period of about 24 hours.

5. The stabilized sustained release oral solid dosage form of claim 1, wherein said hydrophobic material further comprises a hydrophobic polymer selected from the group consisting of acrylic polymers, alkylcelluloses and mixtures thereof.

6. The stabilized sustained release oral solid dosage form of claim 1, further comprising a hydrophilic polymer.

8. The stabilized sustained release oral solid dosage form of claim 1, wherein said matrix comprises tramadol, a higher aliphatic alcohol, and a hydrophobic polymer selected from the group consisting of acrylic polymers, alkylcelluloses and mixtures thereof.

9. The stabilized sustained release oral solid dosage form of claim 1, wherein said matrix comprises trarnadol and hydrogenated vegetable oil.

10. The stabilized sustained release oral solid dosage of claim 1, which is a tablet.

11. The stabilized sustained release oral solid dosage form of claim 1, which releases an amount of tramadol which does not vary at any given dissolution time point by more than about 20% of the total amount of tramadol released at that dissolution time point, when compared to in-vitro dissolution conducted prior to said accelerated storage conditions.

12. The stabilized sustained release oral solid dosage form of claim 5, wherein said hydrophobic polymer comprises from about 0% to about 80% by weight, of the hydrophobic material.

13. The stabilized sustained release oral solid dosage form of claim 5, wherein said hydrophobic polymer comprises from about 30% to about 50% by weight, of the hydrophobic material.

24. The stabilized sustained release oral solid dosage form of claim 8, wherein said solid dosage form is subjected to curing after said matrix is tableted.

25. The stabilized sustained release oral solid dosage form of claim 24, wherein said matrix comprises tramadol, a higher aliphatic alcohol, and a hydrophobic polymer selected from the group consisting of acrylic polymers, alkylcelluloses and mixtures thereof.

26. The stabilized sustained release oral solid dosage form of claim 24, wherein said cured tablet is coated with a hydrophobic material to a weight gain form about 1 to about 30 percent.

27. The stabilized sustained release oral solid dosage form of claim 1, wherein said matrix further comprises a cellulose ether.

34. The stabilized sustained release oral solid dosage form of claim 1 wherein said hydrophobic material is selected from the group consisting of lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol and cetostearyl alcohol.

35. The stabilized sustained release oral solid dosage form of claim 1 wherein said hydrophobic material is a C₁₂-C₃₆ aliphatic alcohol.

7. The stabilized sustained release oral solid dosage form of claim wherein said hydrophilic polymer is a cellulose ether.

14. A process for prepaing a stabilized sustained release oral solid dosage form containing tramadol as the active agent, comprising:

preparing a matix comprising tramadol or a pharmaceutically acceptable salt thereof dispersed in a matrix of a hydrophobic material comprising a substance which is melted or softened during the preparation of said matrix, said substance being selected from the group consisting of hydrogenated vegetable oil, hydrogenated castor oil, paraffin, higher aliphatic alcohols, higher aliphatic acids, long chain fatty acids, fatty acid esters, and mixtures thereof; and

thereafter curing said matrix at a temperature from about 35°

C. to about 65°

C. for a sufficient time such that an endpoint is reached at which said matrix provides a stable dissolution profile, said endpoint being determined by comparing the dissolution profile of said matrix immediately after curing to the dissolution profile of said matrix after exposure to accelerated storage conditions of at least one month at 40°

C. and 75% relative humidity.

15. The process of claim 14, further comprising compressing said matrix into a tablet prior to said curing step.

16. The process of claim 15, wherein said tablets are prepared by feeding said tramadol and said hydrophobic material, together with further optional pharmaceutical excipients, into an extruder at elevated temperatures sufficient to soften or melt said substance;

extruding the mixture;

granulating the mixture;

lubricating the granulate; and

then compressing the granulate into tablets.

17. The process of claim 15, wherein said tablets are prepared by spraying a hydrophobic polymer dispersion onto a mixture of tramadol and an inert diluent in a fluid bed dryer to obtain granulates;

mixing said substance in a molten state into the granulates in a high shear mixer;

passing the mixture through a screen and mixing with talc;

lubricating the resultant material; and

compressing the lubricated granulates into tablets.

18. The process of claim 15, wherein said tablets are prepared by pouring said substance in a molten state onto the tramadol in a pharmaceutically suitable mixer;

allowing the mixture to congeal and cool; and

thereafter milling the mixture;

lubricating the mixture; and

compressing lubricated granulation into tablets.

19. The process of claim 15, wherein said tablets are prepared by melting and granulating said substance;

hydrating a cellulose ether and granulating the same;

blending the tramadol with either the granulated melt, the granulated cellulose ether, or a mixture thereof;

drying the granules; and

thereafter optionally mixing with an appropriate amount of a inert pharmaceutically acceptable diluent and compressing the mixture tablets.

20. The process of claim 15, wherein said hydrophobic material comprises a hydrophilic or hydrophobic polymer in addition to said substance, and said tablets are prepared by (a) wet granulating said hydrophobic or hydrophilic polymer and optional diluents with or without said tramadol;

(b) drying and sizing the resultant granulate;

(c) combining said tramadol with the granulate if not previously accomplished in step (a);

incorporating said substance in a molten state into said granules using a suitable mixer;

(d) cooling and sizing the granules; and

thereafter (e) lubricating the granules compressing the lubricated granules into tablets.

21. The process of claim 14, wherein the curing is conducted at a temperature from about 40°

C. to about 60°

C. for a time period from about 4 to about 72 hours.

22. The process of claim 14, wherein the curing is conducted at a temperature from about 45°

C. to about 55°

C. for a time period from about 4 to about 72 hours.

23. The process of claim 14, wherein the curing is conducted for a time period of about 24 hours.

28. A stabilized sustained release tablet containing tramadol as an active ingredient, comprising an effective amount of tramadol or a pharmaceutically acceptable salt thereof dispersed in a matrix of a hydrophobic material comprising a substance which was melted or softened during the preparation of said matrix, said substance being selected from the group consisting of hydrogenated vegetable oil, hydrogenated castor oil, paraffin, higher aliphatic alcohols, higher aliphatic acids, long chain fatty acids, fatty acid esters, and mixtures thereof, said tablet being cured at a temperature from about 35 °

C. to about 65°

C. for a sufficient time such that an endpoint is reached at which said solid dosage form provides an in-vitro dissolution profile after said dosage form is subjected to accelerated storage conditions of at least one month at 40°

C. and 75% relative humidity in which the total amount of tramadol released does not vary at any given dissolution time point by more than about 20% of the total amount of tramadol released at that dissolution time point prior to subjecting said dosage form to accelerated storage conditions.

29. The stabilized sustained release tablet of claim 28, wherein said hydrophobic material further comprises a hydrophobic polymer selected from the group consisting of acrylic polymers, alkylcelluloses and mixtures thereof.

30. The stabilized sustained release tablet of claim 28, wherein said matrix comprises tramadol, a higher aliphatic alcohol, and a hydrophobic polymer selected from the group consisting of acrylic polymers, alkylcelluloses and mixtures thereof.

31. The stabilized sustained release tablet of claim 28, wherein said matrix further comprises a cellulose ether.

32. The stabilized sustained release tablet of claim 28, wherein said cured tablet is coated with a hydrophobic material to a weight gain form about 1 to about 30 percent.

33. The stabilized sustained release tablet of claim 28, wherein the substance has a melting point from about 350 to about 140°

C.

36. A stabilized sustained release oral solid dosage form containing tramadol as the active agent, comprising an effective amount of tramadol or a pharmaceutically acceptable salt thereof dispersed in a matrix of a hydrophobic material comprising a substance which was melted or softened during the preparation of said matrix, said substance being selected from the group consisting of a natural wax, a natural oil, a synthetic wax, a synthetic oil, and mixtures of any of the foregoing, said solid dosage form being subjected to a sepaate curing step at a temperature from about 35°

C. to about 65°

C. for a sufficient time such that an endpoint is reached at which said solid dosage form provides a stable dissolution profile, said endpoint being determined by comparing the dissolution profile of said solid dosage form immediately after curing to the dissolution profile of said solid dosage form after exposure to accelerated storage conditions of at least one month at 40°

C. and 75% relative humidity.

37. A process for preparing a stabilized sustained release oral solid dosage form containing tramadol as the active agent, comprising

preparing a matrix comprising tramadol or a pharmaceutically acceptable salt thereof dispersed in a matrix of a hydrophobic material comprising a substance which is melted or sofened during the preparation of said matrix said substance being selected from the group consisting of a natural wax, a natural oil, a synthetic wax, a synthetic oil, and mixtures of any of the foregoing;

and thereafter curing said matrix at a temperature from about 35°

C. to about 65°

C. for a sufficient time such that an endpoint is reached at which said matrix provides a stable dissolution profile, said endpoint being determined by comparing the dissolution profile of said matrix immediately after curing to the dissolution profile of said matrix after exposure to accelerated storage conditions of at least one month at 40°

C. and 75% relative hmidity.

38. A stabilized sustained release tablet containing tramadol as an active ingredient, comprising an effective amount of tramadol or a phabmaceutically acceptable salt thereof dispersed in a matrix of a hydrophobic materal comprising a substance which was melted or softened during the preparation of said matrix, said substance being selected from the group consisting of a natural wax, a natural oil, a synthetic wax, a synthetic oil, and mixtures of any of the foregoing, said tablet being cured at a temperature from about 35°

C. to about 65°

C. for a sufficient time such that an endpoint is reached at which said solid dosage form provides an in-vitro dissolution profile after said dosage form is subjected to accelerated storage conditions of at least one month at 40°

C. and 75% relative humidity in which the total amount of tranadol released does not vary at any given dissolution time point by more than about 20% of the total amount of tramadol released at that dissolution time point prior to subjecting said dosage form to accelerated storage conditions.