Injectable flowable 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. A method for treating opioid dependence in a subject in need thereof, the method comprising administering to the subject by subcutaneous injection a therapeutically effective amount of an injectable flowable pharmaceutical composition comprising:
(i) 10 wt % to about 50 wt % of buprenorphine in the form of a free base or a pharmaceutically acceptable salt;
(ii) about 5 wt % to about 70 wt % of a poly(lactide-co-glycolide) copolymer; and
(iii) N-methyl-2-pyrrolidone,
wherein the method produces (a) buprenorphine plasma concentration levels in the subject from about 1.82 ng/mL to about 12.1 ng/mL for about 28 days; (b) buprenorphine plasma concentration levels in the subject from about 2.18 ng/mL to about 3.26 ng/mL from the third day to the twenty-fourth day after the first injection; and/or (c) a twenty-four hour buprenorphine burst release in the subject of less than 10%.
2. The method of claim 1 , wherein the method produces buprenorphine plasma concentration levels in the subject from about 1.82 ng/mL to about 12.1 ng/mL for about 28 days.
3. The method of claim 1 , wherein the method produces buprenorphine plasma concentration levels in the subject from about 2.18 ng/mL to about 3.26 ng/mL from the third day to the twenty-fourth day after the first injection.
4. The method of claim 1 , wherein the method produces a twenty-four hour buprenorphine burst release in the subject of less than 10%.
5. The method of claim 1 , comprising subcutaneously administering the composition once every twenty-eight days.
6. The method of claim 1 , comprising subcutaneously administering the composition once per month.
7. The method of claim 1 , wherein the composition comprises from 10 wt % to about 30 wt % of the buprenorphine.
8. The method of claim 1 , wherein the composition comprises from about 15 wt % to about 20 wt % of the buprenorphine.
9. The method of claim 1 , wherein the composition comprises about 18 wt % of the buprenorphine.
10. The method of claim 1 , wherein the buprenorphine is in the form of the free base.
11. The method of claim 1 , wherein the composition comprises from about 3 mg to about 900 mg of the buprenorphine free base.
12. The method of claim 1 , wherein the composition comprises 300 mg of the buprenorphine free base.
13. The method of claim 1 , wherein the composition comprises from about 15 wt % to about 70 wt % of the poly(lactide-co-glycolide) copolymer.
14. The method of claim 1 , wherein the poly(lactide-co-glycolide) copolymer is a 50/50, 55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10, or 95/5 poly(lactide-co-glycolide) copolymer.
15. The method of claim 1 , wherein the poly(lactide-co-glycolide) copolymer is a 50/50 poly(lactide-co-glycolide) copolymer.
16. The method of claim 1 , wherein the poly(lactide-co-glycolide) copolymer has a carboxy terminal group.
17. The method 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.
18. The method of claim 1 , wherein the composition is a solution.
19. The method of claim 1 , wherein the composition transforms in situ into an implant by contact with water, a bodily fluid, or other aqueous medium.
20. The method of claim 1 , wherein the composition has a volume from about 0.10 mL to about 2.0 mL.
21. The method of claim 1 , wherein the composition comprises about 30 wt % to about 70 wt % of a biocompatible organic liquid comprising: (i) N-methyl-2-pyrrolidone and (ii) glycerin, propylene glycol, polyethylene glycol, or a combination of two or more thereof.
22. The method of claim 1 , wherein the composition comprises about 18 wt % of buprenorphine free base, about 32 wt % of a poly(lactide-co-glycolide) copolymer; and about 50 wt % of N-methyl-2-pyrrolidone.