Matrix for sustained, invariant and independent release of active compounds
The invention concerns a storage stable pharmaceutical formulation comprising preferably two active compounds in a non-swellable diffusion matrix, whereby the compounds are released from the matrix in a sustained, invariant and, if several compounds are present, independent manner and the matrix is determined with respect to its substantial release characteristics by ethylcellulose and at least one fatty alcohol. The invention also concerns methods for producing such pharmaceutical formulations.
1. An oral pharmaceutical formulation comprising:
at least one opioid agonist selected from oxycodone and pharmaceutically acceptable salts thereof;
at least one opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof; and
a diffusion matrix containing the at least one opioid agonist and the at least one opioid antagonist and comprising ethylcellulose and at least one fatty alcohol; wherein the matrix is configured to provide sustained, invariant, and independent release of the opioid agonist and the opioid antagonist; and wherein the fatty alcohol is present in 5-30% by weight of the total formulation.
2. The pharmaceutical formulation of claim 1 , wherein the fatty alcohol is selected from lauryl alcohol, myristyl alcohol, stearyl alcohol, cetylstearyl alcohol, ceryl alcohol, and cetyl alcohol.
3. The pharmaceutical formulation of claim 1 , wherein the fatty alcohol is stearyl alcohol.
4. The pharmaceutical formulation of claim 1 , wherein the opioid agonist is oxycodone hydrochloride.
5. The pharmaceutical formulation of claim 1 , wherein the oxycodone or pharmaceutically acceptable salt thereof is present in an amount ranging from 5 to 50 mg.
6. The pharmaceutical formulation of claim 1 , wherein the opioid antagonist is naloxone hydrochloride.
7. The pharmaceutical formulation of claim 1 , wherein the naloxone or pharmaceutically acceptable salt thereof is present in an amount ranging from 1 to 40 mg.
8. The pharmaceutical formulation of claim 1 , wherein:
the opioid agonist is oxycodone hydrochloride; and
the opioid antagonist is naloxone hydrochloride.
9. The pharmaceutical formulation of claim 1 , wherein:
the oxycodone or pharmaceutically acceptable salt thereof is present in an amount ranging from 10 to 150 mg; and
the naloxone or pharmaceutically acceptable salt thereof is present in an amount ranging from 1 to 50 mg.
10. The pharmaceutical formulation of claim 9 , wherein the oxycodone or pharmaceutically acceptable salt thereof is present in an amount ranging from 10 to 80 mg.
11. The pharmaceutical formulation of claim 1 , wherein the oxycodone or pharmaceutically acceptable salt thereof is present in an amount ranging from 5 to 50 mg.
12. The pharmaceutical formulation of claim 1 , wherein the oxycodone or pharmaceutically acceptable salt thereof and the naloxone or pharmaceutically acceptable salt thereof are present in a weight ratio ranging from 25:1 to 1:1.
13. The pharmaceutical formulation of claim 1 , wherein the oxycodone or pharmaceutically acceptable salt thereof and the naloxone or pharmaceutically acceptable salt thereof are present in a weight ratio ranging from 5:1 to 1:1.
14. The pharmaceutical formulation of claim 1 , wherein the oxycodone or pharmaceutically acceptable salt thereof and the naloxone or pharmaceutically acceptable salt thereof are present in a weight ratio of 5:1, 4:1, 3:1, 2:1, or 1:1.
15. The pharmaceutical formulation of claim 1 , wherein the oxycodone or pharmaceutically acceptable salt thereof and the naloxone or pharmaceutically acceptable salt thereof are present in a weight ratio of 2:1.
16. The pharmaceutical formulation of claim 1 , wherein the ethylcellulose is present in 1-15% by weight of the total formulation.
17. The pharmaceutical formulation of claim 1 , wherein the ethylcellulose is present in 5-9% by weight of the total formulation.
18. The pharmaceutical formulation of claim 1 , wherein the fatty alcohol is present in 15-20% by weight of the total formulation.
19. The pharmaceutical formulation of claim 1 , wherein the fatty alcohol is present in 10-25% by weight of the total formulation.
20. The pharmaceutical formulation of claim 1 , wherein
the ethylcellulose is present in 1-15% by weight of the total formulation;
the fatty alcohol is stearyl alcohol and is present in 10-25% by weight of the total formulation; and
the oxycodone or pharmaceutically acceptable salt thereof and is present in an amount ranging from 10 to 80 mg;
wherein the oxycodone or pharmaceutically acceptable salt thereof and the naloxone or pharmaceutically acceptable salt thereof are present in a weight ratio of 2:1.
21. The pharmaceutical formulation of claim 20 , wherein:
the opioid agonist is oxycodone hydrochloride; and
the opioid antagonist is naloxone hydrochloride.
22. The pharmaceutical formulation of claim 1 , wherein the formulation is in the form of a tablet.
23. The pharmaceutical formulation of claim 1 , wherein the matrix is not based on a polymethacrylate.
24. The pharmaceutical formulation of claim 1 , wherein the matrix does not comprise a relevant amount of a hydroxyalkylcellulose.
25. The pharmaceutical formulation of claim 1 , wherein the sustained, invariant, and independent release characteristics of the matrix are determined by the ethylcellulose and the at least one fatty alcohol.
26. An oral pharmaceutical formulation comprising:
at least one opioid agonist selected from oxycodone and pharmaceutically acceptable salts thereof;
at least one opioid antagonist selected from naloxone and pharmaceutically acceptable salts thereof; and
a diffusion matrix containing the at least one opioid agonist and the at least one opioid antagonist and comprising ethylcellulose and at least one fatty alcohol;
wherein the matrix is configured to provide sustained, invariant, and independent release of the opioid agonist and the opioid antagonist; and wherein ethylcellulose is present in 1-15% by weight of the total formulation.
27. The pharmaceutical formulation of claim 26 , wherein the fatty alcohol is selected from lauryl alcohol, myristyl alcohol, stearyl alcohol, cetylstearyl alcohol, ceryl alcohol, and cetyl alcohol.
28. The pharmaceutical formulation of claim 26 , wherein the fatty alcohol is stearyl alcohol.
29. The pharmaceutical formulation of claim 26 , wherein the opioid agonist is oxycodone hydrochloride.
30. The pharmaceutical formulation of claim 26 , wherein the oxycodone or pharmaceutically acceptable salt thereof is present in an amount ranging from 5 to 50 mg.
31. The pharmaceutical formulation of claim 26 , wherein the opioid antagonist is naloxone hydrochloride.
32. The pharmaceutical formulation of claim 26 , wherein the naloxone or pharmaceutically acceptable salt thereof is present in an amount ranging from 1 to 40 mg.
33. The pharmaceutical formulation of claim 26 , wherein: the opioid agonist is oxycodone hydrochloride; and the opioid antagonist is naloxone hydrochloride.
34. The pharmaceutical formulation of claim 26 , wherein:
the oxycodone or pharmaceutically acceptable salt thereof is present in an amount
ranging from 10 to 150 mg; and
the naloxone or pharmaceutically acceptable salt thereof is present in an amount ranging from 1 to 50 mg.
35. The pharmaceutical formulation of claim 34 , wherein the oxycodone or pharmaceutically acceptable salt thereof is present in an amount ranging from 10 to 80 mg.
36. The pharmaceutical formulation of claim 26 , wherein the oxycodone or pharmaceutically acceptable salt thereof is present in an amount ranging from 5 to 50 mg.
37. The pharmaceutical formulation of claim 26 , wherein the oxycodone or pharmaceutically acceptable salt thereof and the naloxone or pharmaceutically acceptable salt thereof are present in a weight ratio ranging from 25:1 to 1:1.
38. The pharmaceutical formulation of claim 26 , wherein the oxycodone or pharmaceutically acceptable salt thereof and the naloxone or pharmaceutically acceptable salt thereof are present in a weight ratio ranging from 5:1 to 1:1.
39. The pharmaceutical formulation of claim 26 , wherein the oxycodone or pharmaceutically acceptable salt thereof and the naloxone or pharmaceutically acceptable salt thereof are present in a weight ratio of 5:1, 4:1, 3:1, 2:1, or 1:1.
40. The pharmaceutical formulation of claim 26 , wherein the oxycodone or pharmaceutically acceptable salt thereof and the naloxone or pharmaceutically acceptable salt thereof are present in a weight ratio of 2:1.
41. The pharmaceutical formulation of claim 26 , wherein the ethylcellulose is present in 3-12% by weight of the total formulation.
42. The pharmaceutical formulation of claim 26 , wherein the ethylcellulose is present in 5-9% by weight of the total formulation.
43. The pharmaceutical formulation of claim 26 , wherein the fatty alcohol is present in 15-20% by weight of the total formulation.
44. The pharmaceutical formulation of claim 26 , wherein the fatty alcohol is present in 10-25% by weight of the total formulation.
45. The pharmaceutical formulation of claim 26 , wherein the fatty alcohol is stearyl alcohol and is present in 10-25% by weight of the total formulation; and
the oxycodone or pharmaceutically acceptable salt thereof and is present in an amount ranging from 10 to 80 mg; and
wherein the oxycodone or pharmaceutically acceptable salt thereof and the naloxone or pharmaceutically acceptable salt thereof are present in a weight ratio of 2:1.
46. The pharmaceutical formulation of claim 45 , wherein:
the opioid agonist is oxycodone hydrochloride; and
the opioid antagonist is naloxone hydrochloride.
47. The pharmaceutical formulation of claim 26 , wherein the formulation is in the form of a tablet.
48. The pharmaceutical formulation of claim 26 , wherein the matrix is not based on a polymethacrylate.
49. The pharmaceutical formulation of claim 26 , wherein the matrix does not comprise a relevant amount of a hydroxyalkylcellulose.
50. The pharmaceutical formulation of claim 26 , wherein the sustained, invariant, and independent release characteristics of the matrix are determined by the ethylcellulose and the at least one fatty alcohol.