Pharmaceutical combinations of oxycodone and naloxone

• US 7,943,173 B2
• Filed: 07/18/2002
• Issued: 05/17/2011
• Est. Priority Date: 07/18/2001
• Status: Expired due to Fees

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Colucci, Robert D., Howard, Stephen A, Breder, Christopher D., Wright, Curtis, Oshlack, Benjamin
• Primary Examiner(s): TRAN, SUSAN T
• Application Number:
  US10/199,972
• Publication Number:
  US 20030069263A1
• Time in Patent Office: 3,225 Days
• Field of Search: 424/422, 424/423, 424/451, 424/452, 424/457, 424/464, 424/465, 424/468, 424/489, 514/282, 514/289
• US Class Current: 424/484
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Disclosed in certain embodiments is a pharmaceutical composition comprising from 10 to 40 mg of oxycodone or a pharmaceutically acceptable salt thereof and 0.65 to 0.90 mg naloxone or a pharmaceutically acceptable salt thereof.

Claims

1. An oral pharmaceutical sustained release composition comprising active ingredients consisting essentially of about 10 mg oxycodone hydrochloride and 0.80 to 0.90 mg naloxone hydrochloride,

wherein the oxycodone hydrochloride and the naloxone hydrochloride are interdispersed in a matrix comprising a sustained release excipient, and

the composition, when tested in-vitro by the USP Apparatus I (Basket) method of U.S. Pharmacopoeia XXIV (2000) at 100 rpm in 900 ml simulated gastric fluid (SGF) at 37°

C., provides

a dissolution rate of the oxycodone hydrochloride such that from about 20 to about 60% (by weight) oxycodone hydrochloride is released at 1 hour, from about 40 to about 90% (by weight) oxycodone hydrochloride is released at 4 hours, and greater than about 70% (by weight) oxycodone hydrochloride is released at 12 hours, and

a dissolution rate of the naloxone hydrochloride which is within about 30% of the dissolution rate of the oxycodone hydrochloride at 1 hour, 4 hours and 12 hours.

4. The pharmaceutical composition of any one of claims 1-3, wherein the formulation provides effective pain relief for at least 12 hours after steady state oral administration to human patients.

5. The pharmaceutical composition of claim 1, wherein the naloxone hydrochloride has the dissolution rate which is within about 20% of the dissolution rate of the oxycodone hydrochloride at 1 hour, 4 hours and 12 hours.

6. The pharmaceutical composition of claim 1, wherein the naloxone hydrochloride has the dissolution rate which is within about 10% of the dissolution rate of the oxycodone hydrochloride at 1 hour, 4 hours and 12 hours.

7. The pharmaceutical composition of any one of claims 1-3, wherein the dissolution rate of the oxycodone hydrochloride and naloxone hydrochloride is from about 20 to about 60% (by weight) oxycodone hydrochloride and from about 20 to about 60% (by weight) naloxone hydrochloride released at 1 hour;

from about 30 to about 75% (by weight) oxycodone hydrochloride and from about 30% to about 75% (by weight) naloxone hydrochloride released at 2 hours;

from about 40 to about 90% (by weight) oxycodone hydrochloride and from about 40 to about 90% (by weight) naloxone hydrochloride released at 4 hours;

greater than about 60% (by weight) oxycodone hydrochloride and greater than about 60% (by weight) naloxone hydrochloride released at 8 hours; and

greater than about 70% (by weight) oxycodone hydrochloride and greater than about 70% (by weight) naloxone hydrochloride released at 12 hours.

8. The pharmaceutical composition of any one of claims 1-3, wherein the dissolution rate of the oxycodone hydrochloride and naloxone hydrochloride is from about 30 to about 60% (by weight) oxycodone hydrochloride and from about 30 to about 60% (by weight) naloxone hydrochloride released at 1 hour;

from about 40 to about 70% (by weight) oxycodone hydrochloride and from about 40% to about 70% (by weight) naloxone hydrochloride released at 2 hours;

from about 55 to about 90% (by weight) oxycodone hydrochloride and from about 55 to about 90% (by weight) naloxone hydrochloride released at 4 hours;

greater than about 70% (by weight) oxycodone hydrochloride and greater than about 70% (by weight) naloxone hydrochloride released at 8 hours; and

greater than about 80% (by weight) oxycodone hydrochloride and greater than about 80% (by weight) naloxone hydrochloride released at 12 hours.

10. The pharmaceutical composition of any one of claims 1-3, which provides a mean AUC of plasma oxycodone within 80% to 125% of the mean AUC of plasma oxycodone provided by an oxycodone base equivalent amount of oxycodone hydrochloride controlled release reference standard upon single dose administration to a population of human subjects.

11. The pharmaceutical composition of any one of claims 1-3 which provides a mean AUC of plasma oxycodone within 90% to 110% of the mean AUC of plasma oxycodone provided by an oxycodone base equivalent amount of oxycodone hydrochloride controlled release reference standard upon single dose administration to a population of human subjects.

12. The pharmaceutical composition of any one of claims 1-3, which provides a mean AUC of plasma oxycodone within 95% to 105% of the mean AUC of plasma oxycodone provided by an oxycodone base equivalent amount of oxycodone hydrochloride controlled release reference standard upon single dose administration to a population of human subjects.

13. The pharmaceutical composition of any one of claims 1-3, which provides a mean Cmax of plasma naloxone which is at least 50% less than the mean Cmax of plasma naloxone provided by a naloxone base equivalent amount of pentazocine and naloxone hydrochlorides reference standard upon single dose administration to a population of human subjects.

14. The pharmaceutical composition of any one of claims 1-3, which provides a mean Cmax of plasma naloxone which is at least 65% less than the mean Cmax of plasma naloxone provided by a naloxone base equivalent amount of pentazocine and naloxone hydrochlorides reference standard upon single dose administration to a population of human subjects.

15. The pharmaceutical composition of any one of claims 1-3, which provides a mean Cmax of plasma naloxone which is at least 80% less than the mean Cmax of plasma naloxone provided by a naloxone base equivalent amount of pentazocine and naloxone hydrochlorides reference standard upon single dose administration to a population of human subjects.

16. The pharmaceutical composition of any one of claims 1-3, which provides a mean Cmax of plasma naloxone of less than 180 pg/ml upon single dose administration to a population of human subjects.

17. The pharmaceutical composition of any one of claims 1-3, which provides a mean Cmax of plasma naloxone of less than 150 pg/ml upon single dose administration to a population of human subjects.

18. The pharmaceutical composition of any one of claims 1-3, which provides a mean Cmax of plasma naloxone of less than 100 pg/ml upon single dose administration to a population of human subjects.

19. The pharmaceutical composition of any one of claims 1-3, which provides a mean Cmax of plasma naloxone of less than 50 pg/ml upon single dose administration to a population of human subjects.

20. The pharmaceutical composition of any one of claims 1-3, which provides a mean Cmax of plasma naloxone of less than 10 pg/ml upon single dose administration to a population of human subjects.

21. The pharmaceutical composition of any one of claims 1-3, which provides a mean Cmax of plasma naloxone of less than 5 pg/ml upon single dose administration to a population of human subjects.

36. The pharmaceutical composition of claim 1, wherein the composition provides sustained release of the naloxone hydrochloride.

2. An oral pharmaceutical sustained release composition comprising active ingredients consisting essentially of about 20 mg oxycodone hydrochloride and 0.80 to 0.90 mg naloxone hydrochloride,

wherein the oxycodone hydrochloride and the naloxone hydrochloride are interdispersed in a matrix comprising a sustained release excipient, and

the composition, when tested in-vitro by the USP Apparatus I (Basket) method of U.S. Pharmacopoeia XXIV (2000) at 100 rpm in 900 ml simulated gastric fluid (SGF) at 37°

C., provides

a dissolution rate of the oxycodone hydrochloride such that from about 20 to about 60% (by weight) oxycodone hydrochloride is released at 1 hour, from about 40 to about 90% (by weight) oxycodone hydrochloride is released at 4 hours, and greater than about 70% (by weight) oxycodone hydrochloride is released at 12 hours, and

a dissolution rate of the naloxone hydrochloride which is within about 30% of the dissolution rate of the oxycodone hydrochloride at 1 hour, 4 hours and 12 hours.

37. The pharmaceutical composition of claim 2, wherein the composition provides sustained release of the naloxone hydrochloride.

3. An oral pharmaceutical sustained release composition comprising active ingredients consisting essentially of about 40 mg oxycodone hydrochloride and 0.80 to 0.90 mg naloxone hydrochloride in a sustained release dosage form,

wherein the oxycodone hydrochloride and the naloxone hydrochloride are interdispersed in a matrix comprising a sustained release excipient, and

the composition, when tested in-vitro by the USP Apparatus I (Basket) method of U.S. Pharmacopoeia XXIV (2000) at 100 rpm in 900 ml simulated gastric fluid (SGF) at 37°

C., provides

a dissolution rate of the oxycodone hydrochloride such that from about 20 to about 60% (by weight) oxycodone hydrochloride is released at 1 hour, from about 40 to about 90% (by weight) oxycodone hydrochloride is released at 4 hours, and greater than about 70% (by weight) oxycodone hydrochloride is released at 12 hours, and

a dissolution rate of the naloxone hydrochloride which is within about 30% of the dissolution rate of the oxycodone hydrochloride at 1 hour, 4 hours and 12 hours.

38. The pharmaceutical composition of claim 3, wherein the composition provides sustained release of the naloxone hydrochloride.

9. An oral pharmaceutical sustained release composition comprising active ingredients consisting essentially of about 10 mg to about 40 mg oxycodone or a pharmaceutically acceptable salt thereof and 0.65 to 0.90 mg naloxone or a pharmaceutically acceptable salt thereof,

wherein the oxycodone and the naloxone are interdispersed in a matrix comprising a sustained release excipient, and

the composition, when tested in-vitro by the USP Apparatus I (Basket) method of U.S. Pharmacopeia XXIV (2000) at 100 rpm in 900 ml simulated gastric fluid (SGF) at 37°

C., provides

a dissolution rate of the oxycodone such that from about 20 to about 60% (by weight) oxycodone is released at 1 hour, from about 40 to about 90% (by weight) oxycodone is released at 4 hours, and greater than about 70% (by weight) oxycodone is released at 12 hours, and

a dissolution rate of the naloxone which is within about 20% of the dissolution rate of the oxycodone at 1 hour, 4 hours and 12 hours.

22. An oral pharmaceutical sustained release composition comprising active ingredients consisting essentially of about 10 mg to about 40 mg oxycodone or a pharmaceutically acceptable salt thereof and 0.65 to 0.90 mg naloxone or a pharmaceutically acceptable salt thereof, wherein the oxycodone and the naloxone are interdispersed in a matrix comprising a sustained release excipient, and the composition provides

a mean Cmax of plasma naloxone of less than 5 pg/ml upon single dose administration to a population of human subjects,

and when tested in-vitro by the USP Apparatus I (Basket) method of U.S. Pharmacopoeia XXIV (2000) at 100 rpm in 900 ml simulated gastric fluid (SGF) at 37°

C., provides

a dissolution rate of the oxycodone such that from about 20 to about 60% (by weight) oxycodone is released at 1 hour, from about 40 to about 90% (by weight) oxycodone is released at 4 hours, and greater than about 70% (by weight) oxycodone is released at 12 hours, and

a dissolution rate of the naloxone which is within about 30% of the dissolution rate of the oxycodone at 1 hour, 4 hours and 12 hours.

24. The pharmaceutical composition of claim 22 or 23 comprising 10 mg oxycodone hydrochloride.

25. The pharmaceutical composition of claim 22 or 23 comprising 20 mg oxycodone hydrochloride.

26. The pharmaceutical composition of claim 22 or 23 comprising 40 mg oxycodone hydrochloride.

23. An oral pharmaceutical sustained release composition comprising active ingredients consisting essentially of about 10-40 mg oxycodone or a pharmaceutically acceptable salt thereof and 0.65 to 0.75 mg naloxone or a pharmaceutically acceptable salt thereof, wherein the oxycodone and the naloxone are interdispersed in a matrix comprising a sustained release excipient, and the composition, when tested in-vitro by the USP Apparatus I (Basket) method of U.S. Pharmacopoeia XXIV (2000) at 100 rpm in 900 ml simulated gastric fluid (SGF) at 37°

C., provides

a dissolution rate of the oxycodone such that from about 20 to about 60% (by weight) oxycodone is released at 1 hour, from about 40 to about 90% (by weight) oxycodone is released at 4 hours, and greater than about 70% (by weight) oxycodone is released at 12 hours, and

a dissolution rate of the naloxone which is within about 30% of the dissolution rate of the oxycodone at 1 hour, 4 hours and 12 hours.

27. A method of treating pain in a human patient comprising orally administering a pharmaceutical sustained release composition comprising active ingredients consisting essentially of about 10 mg to about 40 mg oxycodone or a pharmaceutically acceptable salt thereof and 0.65 to 0.90 mg naloxone or a pharmaceutically acceptable salt thereof to a patient in pain,

wherein the oxycodone and the naloxone are interdispersed in a matrix comprising a sustained release excipient, and

the composition, when tested in-vitro by the USP Apparatus I (Basket) method of U.S. Pharmacopoeia XXIV (2000) at 100 rpm in 900 ml simulated gastric fluid (SGF) at 37°

C., provides

a dissolution rate of the oxycodone such that from about 20 to about 60% (by weight) oxycodone is released at 1 hour, from about 40 to about 90% (by weight) oxycodone is released at 4 hours, and greater than about 70% (by weight) oxycodone is released at 12 hours, and

a dissolution rate of the naloxone which is within about 30% of the dissolution rate of the oxycodone at 1 hour, 4 hours and 12 hours.

28. The method of claim 27, further comprising orally administering the composition every 12 hours at least until steady state is achieved.

29. A method of preparing a sustained release dosage form comprising incorporating a sustained release excipient and active ingredients consisting essentially of 0.65 to 0.90 mg naloxone or a pharmaceutically acceptable salt thereof and about 10 to about 40 mg oxycodone or a pharmaceutically acceptable salt thereof into a pharmaceutical composition,

such that the oxycodone and the naloxone become interdispersed in a matrix comprising the sustained release excipient, and the composition, when tested in-vitro by the USP Apparatus I (Basket) method of U.S. Pharmacopoeia XXIV (2000) at 100 rpm in 900 ml simulated gastric fluid (SGF) at 37°

C., provides

a dissolution rate of the oxycodone such that from about 20 to about 60% (by weight) oxycodone is released at 1 hour, from about 40 to about 90% (by weight) oxycodone is released at 4 hours, and greater than about 70% (by weight) oxycodone is released at 12 hours, and

a dissolution rate of the naloxone which is within about 30% of the dissolution rate of the oxycodone at 1 hour, 4 hours and 12 hours.

30. A method of reducing the parenteral abuse of an oxycodone sustained release product comprising incorporating active ingredients consisting essentially of 0.65 to 0.90 mg naloxone or a pharmaceutically acceptable salt thereof and about 10 to about 40 mg oxycodone or a pharmaceutically acceptable salt thereof into a sustained release product such that the oxycodone and the naloxone become interdispersed in a matrix comprising the sustained release excipient, and the composition, when tested in-vitro by the USP Apparatus I (Basket) method of U.S. Pharmacopoeia XXIV (2000) at 100 rpm in 900 ml simulated gastric fluid (SGF) at 37°

C., provides

a dissolution rate of the oxycodone such that from about 20 to about 60% (by weight) oxycodone is released at 1 hour, from about 40 to about 90% (by weight) oxycodone is released at 4 hours, and greater than about 70% (by weight) oxycodone is released at 12 hours, and

a dissolution rate of the naloxone which is within about 30% of the dissolution rate of the oxycodone at 1 hour, 4 hours and 12 hours.

31. A method of treating pain comprising administering a pharmaceutical sustained release composition comprising active ingredients consisting essentially of about 10 mg oxycodone hydrochloride and 0.65 to 0.90 mg naloxone or a pharmaceutically acceptable salt thereof, and thereafter increasing the dosage by administering a pharmaceutical sustained release composition comprising about 20 mg oxycodone hydrochloride and 0.65 to 0.90 mg naloxone or a pharmaceutically acceptable salt thereof,

wherein, in each composition, the oxycodone hydrochloride and the naloxone are interdispersed in a matrix comprising a sustained release excipient, and

each composition, when tested in-vitro by the USP Apparatus I (Basket) method of U.S. Pharmacopoeia XXIV (2000) at 100 rpm in 900 ml simulated gastric fluid (SGF) at 37°

C., provides

a dissolution rate of the oxycodone hydrochloride such that from about 20 to about 60% (by weight) oxycodone hydrochloride is released at 1 hour, from about 40 to about 90% (by weight) oxycodone hydrochloride is released at 4 hours, and greater than about 70% (by weight) oxycodone hydrochloride is released at 12 hours, and

a dissolution rate of the naloxone which is within about 30% of the dissolution rate of the oxycodone hydrochloride at 1 hour, 4 hours and 12 hours.

32. A method of treating pain comprising administering a pharmaceutical sustained release composition comprising active ingredients consisting essentially of about 20 mg oxycodone hydrochloride and 0.65 to 0.90 mg naloxone or a pharmaceutically acceptable salt thereof, and thereafter increasing the dosage by administering a pharmaceutical sustained release composition comprising about 40 mg oxycodone hydrochloride and 0.65 to 0.90 mg naloxone or a pharmaceutically acceptable salt thereof,

wherein, in each composition, the oxycodone hydrochloride and the naloxone are interdispersed in a matrix comprising a sustained release excipient, and

each composition, when tested in-vitro by the USP Apparatus I (Basket) method of U.S. Pharmacopoeia XXIV (2000) at 100 rpm in 900 ml simulated gastric fluid (SGF) at 37°

C., provides

a dissolution rate of the oxycodone hydrochloride such that from about 20 to about 60% (by weight) oxycodone hydrochloride is released at 1 hour, from about 40 to about 90% (by weight) oxycodone hydrochloride is released at 4 hours, and greater than about 70% (by weight) oxycodone hydrochloride is released at 12 hours, and

a dissolution rate of the naloxone which is within about 30% of the dissolution rate of the oxycodone hydrochloride at 1 hour, 4 hours and 12 hours.

33. A method of treating pain comprising administering a pharmaceutical sustained release composition comprising active ingredients consisting essentially of about 10 mg oxycodone hydrochloride and 0.65 to 0.90 mg naloxone or a pharmaceutically acceptable salt thereof and thereafter increasing the dosage by administering a pharmaceutical sustained release composition comprising about 20 mg oxycodone hydrochloride and 0.65 to 0.90 mg naloxone or a pharmaceutically acceptable salt thereof, and thereafter increasing the dosage by administering a pharmaceutical sustained release composition comprising about 40 mg oxycodone hydrochloride and 0.65 to 0.90 mg naloxone or a pharmaceutically acceptable salt thereof,

wherein, in each composition, the oxycodone hydrochloride and the naloxone are interdispersed in a matrix comprising a sustained release excipient, and

each composition, when tested in-vitro by the USP Apparatus I (Basket) method of U.S. Pharmacopoeia XXIV (2000) at 100 rpm in 900 ml simulated gastric fluid (SGF) at 37°

C., provides

a dissolution rate of the oxycodone hydrochloride such that from about 20 to about 60% (by weight) oxycodone hydrochloride is released at 1 hour, from about 40 to about 90% (by weight) oxycodone hydrochloride is released at 4 hours, and greater than about 70% (by weight) oxycodone hydrochloride is released at 12 hours, and

a dissolution rate of the naloxone which is within about 30% of the dissolution rate of the oxycodone hydrochloride at 1 hour, 4 hours and 12 hours.

34. A kit for the treatment of pain comprising:

a container comprising at least one formulation comprising active ingredients consisting essentially of about 10 to about 40 mg oxycodone or a pharmaceutically acceptable salt thereof in sustained release form and 0.65 to 0.90 mg naloxone or a pharmaceutically acceptable salt thereof;

the formulation, when tested in-vitro by the USP Apparatus I (Basket) method of U.S. Pharmacopoeia XXIV (2000) at 100 rpm in 900 ml simulated gastric fluid (SGF) at 37°

C., provides

a dissolution rate of the oxycodone such that from about 20 to about 60% (by weight) oxycodone is released at 1 hour, from about 40 to about 90% (by weight) oxycodone is released at 4 hours, and greater than about 70% (by weight) oxycodone is released at 12 hours, and

a dissolution rate of the naloxone which is within about 30% of the dissolution rate of the oxycodone at 1 hour, 4 hours and 12 hours; and

an indicia indicating the use of said formulation.

35. The kit of claim 34, wherein said indicia indicates that said use is to reduce the parenteral abuse of said formulation.