Injectable composition comprising buprenorphine
The present invention is directed to a buprenorphine sustained release delivery system capable of delivering buprenorphine, a metabolite, or a prodrug thereof for a duration of about 14 days to about 3 months. The buprenorphine sustained release delivery system includes a flowable composition and a solid implant for the sustained release of buprenorphine, a metabolite, or a prodrug thereof. The implant is produced from the flowable composition. The buprenorphine sustained release delivery system provides in situ 1-month and 3-month release profiles characterized by an exceptionally high bioavailability and minimal risk of permanent tissue damage and typically no risk of muscle necrosis.
1. An injectable pharmaceutical composition comprising about 20 wt% of buprenorphine free base in a formulation which comprises (i) about 40 wt% of a 50:50 poly(lactide-co-glycolide) copolymer, and (ii) about 60 wt% of N-methyl-2-pyrrolidone.
2. The composition of claim 1 , wherein the poly(lactide-co-glycolide) copolymer has an average molecular weight from about 5,000 Daltons to about 40,000 Daltons.
3. The composition of claim 1 , wherein poly(lactide-co-glycolide) copolymer has an average molecular weight from about 10,000 Daltons to about 20,000 Daltons.
4. The composition of claim 1 , wherein the poly(lactide-co-glycolide) copolymer has an average molecular weight of about 26,000 Daltons.
5. The composition of claim 1 , wherein the poly(lactide-co-glycolide) copolymer has an average molecular weight of about 12,000 Daltons.
6. The composition of claim 1 , wherein the poly(lactide-co-glycolide) copolymer has an average molecular weight of about 21,000 Daltons.
7. The composition of claim 1 , wherein the buprenorphine free present is present in an amount of about 3 grams to about 300 grams.
8. An injectable pharmaceutical composition comprising (i) about 18 wt% of buprenorphine free base; (ii) about 32 wt% of a 50:50 poly(lactide-co-glycolide) copolymer; and (iii) about 50 wt% of N-methyl-2-pyrrolidone.
9. The composition of claim 8 , wherein the poly(lactide-co-glycolide) copolymer has an average molecular weight from about 5,000 Daltons to about 40,000 Daltons.
10. The composition of claim 8 , wherein poly(lactide-co-glycolide) copolymer has an average molecular weight from about 10,000 Daltons to about 20,000 Daltons.
11. The composition of claim 8 , wherein the poly(lactide-co-glycolide) copolymer has an average molecular weight of about 15,000 Daltons.
12. The composition of claim 8 , wherein the poly(lactide-co-glycolide) copolymer has an average molecular weight of about 14,000 Daltons.
13. The composition of claim 8 , wherein the poly(lactide-co-glycolide) copolymer has a carboxy terminal group.
14. The composition of claim 8 , wherein the buprenorphine free present is present in an amount of about 3 grams to about 300 grams.
15. The composition of claim 8 , consisting of (i), (ii), and (iii).
16. An injectable pharmaceutical composition comprising:
(i) 8 wt % to about 30 wt % of buprenorphine in the form of a free base or pharmaceutically acceptable salt;
(ii) about 15 wt% to about 70 wt% of a poly(lactide-co-glycolide) copolymer; and optionally further comprising a polymer selected from the group consisting of a polylactide polymer, a polyglycolide polymer, a polycaprolactone polymer, a copolymer of polylactide and polycaprolactone, a copolymer of polyglycolide and polycaprolactone, and a terpolymer of polylactide, polyglycolide, and polycaprolactone; and
(iii) about 30 wt% to about 70 wt% of N-methyl-2-pyrrolidone; and optionally further comprising a liquid selected from the group consisting of 2-pyrrolidone, N,N-dimethylformamide, propylene carbonate, triacetin, acetic acid, lactic acid, methyl lactate, ethyl lactate, monomethyl succinate acid, monomethyl citric acid, glycofurol, glycerol formal, isopropylidene glycol, 2,2-dimethyl-1,3-dioxolone-4-methanol, solketal, dimethylformamide, dimethylacetamide, dimethylsulfoxide, dimethylsulfone, epsilon-caprolactone, butyrolactone, caprolactam, or a mixture of two or more thereof.
17. The composition of claim 16 , comprising about 3 mg to about 300 mg of buprenorphine in the form of the free base or the pharmaceutically acceptable salt.
18. The composition of claim 16 , wherein the polymer is a 50/50 poly(lactide-co-glycolide) copolymer, a 55/45 poly(lactide-co-glycolide) copolymer, a 60/40 poly(lactide-co-glycolide) copolymer, a 65/35 poly(lactide-co-glycolide) copolymer, a 70/30 poly(lactide-co-glycolide) copolymer, a 75/25 poly(lactide-co-glycolide) copolymer, an 80/20 poly(lactide-co-glycolide) copolymer, an 85/15 poly(lactide-co-glycolide) copolymer, a 90/10 poly(lactide-co-glycolide) copolymer, or a 95/5 poly(lactide-co-glycolide) copolymer.
19. The composition of claim 16 , wherein the polymer is a 50/50 poly(lactide-co-glycolide) copolymer.
20. The composition of claim 16 , wherein the polymer is a 75/25 poly(lactide-co-glycolide) copolymer or an 85/15 poly(lactide-co-glycolide) copolymer.
21. The composition of claim 16 , consisting of (i), (ii), and (iii).
22. The composition of claim 16 having a 24 hour burst release of less than 10%.
23. The composition of claim 16 which provides an average buprenorphine blood plasma concentration from about 2.33 ng/ml to about 3.62 ng/ml over a period of about 28 days.
24. The composition of claim 16 which provides an average buprenorphine blood plasma concentration from about 1.59 ng/ml to about 3.01 ng/ml over a period of about 28 days.
25. The composition of claim 16 , further comprising a sterol; a cholesteryl ester; a C 18 -C 36 monoglyceride; a C 18-36 diglyceride; a C 18-36 triglyceride; a sucrose fatty acid ester; a sorbitan fatty acid ester; a C 16 -C 18 fatty alcohol; an ester of a fatty alcohol; an ester of a fatty acid; an anhydride of a fatty acid; a phospholipid; a sphingosine; a spingomyelins; a ceramide; a glycosphingolipid; lanolin; a lanolin alcohol; or a combination of two or more thereof.
26. An injectable pharmaceutical composition comprising (i) about 18 wt% of buprenorphine free base; (ii) about 32 wt% of a 50:50 poly(lactide-co-glycolide) copolymer having a carboxy terminal group and having an average molecular weight of about 5,000 Daltons to about 20,000 Daltons; and (iii) about 50 wt% of N-methyl-2-pyrrolidone.
27. The composition of claim 26 , consisting of (i), (ii), and (iii).
28. The composition of claim 1 , consisting of (i), (ii), and (iii).
29. The composition of claim 1 , wherein the poly(lactide-co-glycolide) copolymer has an average molecular weight from about 5,000 Daltons to about 20,000 Daltons.
30. The composition of claim 8 , wherein the poly(lactide-co-glycolide) copolymer has an average molecular weight from about 5,000 Daltons to about 20,000 Daltons.
31. The composition of claim 16 , wherein the poly(lactide-co-glycolide) copolymer has an average molecular weight from about 5,000 Daltons to about 20,000 Daltons.
32. A method for treating opioid addiction in a human in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 1 to the human to treat the opioid addiction.
33. The method of claim 32 , wherein the composition is administered once per month by subcutaneous injection.
34. The method of claim 32 , wherein the composition is administered once every three months by subcutaneous injection.
35. A method for treating opioid addiction in a human in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 8 to the human to treat the opioid addiction.
36. The method of claim 35 , wherein the composition is administered once per month by subcutaneous injection.
37. The method of claim 35 , wherein the composition is administered once every three months by subcutaneous injection.
38. A method for treating opioid addiction in a human in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 16 to the human to treat the opioid addiction.
39. The method of claim 38 , wherein the composition is administered once per month by subcutaneous injection.
40. The method of claim 38 , wherein the composition is administered once every three months by subcutaneous injection.
41. A method for treating opioid addiction in a human in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 26 to the human to treat the opioid addiction.
42. The method of claim 41 , wherein the composition is administered once per month by subcutaneous injection.
43. The method of claim 41 , wherein the composition is administered once every three months by subcutaneous injection.
44. A method for treating pain in a human in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 1 to the human to treat the pain.
45. A method for treating pain in a human in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 8 to the human to treat the pain.
46. A method for treating pain in a human in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 16 to the human to treat the pain.
47. A method for treating pain in a human in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 26 to the human to treat the pain.
48. The composition of claim 1 which comprises about 9 mg to about 900 mg of the buprenorphine free base.
49. The composition of claim 8 which comprises about 9 mg to about 900 mg of the buprenorphine free base.
50. The composition of claim 16 which comprises about 9 mg to about 900 mg of the buprenorphine free base.
51. The composition of claim 26 which comprises about 3 mg to about 300 mg of the buprenorphine free base.
52. The composition of claim 26 which comprises about 9 mg to about 900 mg of the buprenorphine free base.
53. The method of claim 32 , wherein the therapeutically effective amount of the buprenorphine free base is from about 3 mg to about 300 mg.
54. The method of claim 32 , wherein the therapeutically effective amount of the buprenorphine free base is from about 9 mg to about 900 mg.
55. The method of claim 35 , wherein the therapeutically effective amount of the buprenorphine free base is from about 3 mg to about 300 mg.
56. The method of claim 35 , wherein the therapeutically effective amount of the buprenorphine free base is from about 9 mg to about 900 mg.
57. The method of claim 38 , wherein the therapeutically effective amount of the buprenorphine in the form of the free base or the pharmaceutically acceptable salt is from about 3 mg to about 300 mg.
58. The method of claim 38 , wherein the therapeutically effective amount of the in the form of the free base or the pharmaceutically acceptable salt is from about 9 mg to about 900 mg.
59. The method of claim 41 , wherein the therapeutically effective amount of the buprenorphine free base is from about 3 mg to about 300 mg.
60. The method of claim 41 , wherein the therapeutically effective amount of the buprenorphine free base is from about 9 mg to about 900 mg.