Sustained Release Buprenorphine Microshperes (SRBM) and Methods of Use Thereof
The present invention is directed to a sustained release buprenorphine microsphere (SRBM) formulation capable of delivering buprenorphine, a metabolite, or a prodrug thereof for a duration of about 7 days to about 6 months.
1 . A method for treating opioid dependence and/or pain in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a sustained release buprenorphine microsphere (SRBM) formulation, wherein the SRBM formulation comprises: buprenorphine and poly(D,L-lactide-co-glycolide) having a MW of 24,000-38,000, wherein the SRBM formulation provides plasma concentration of buprenorphine in the subject that does not exceed 10 ng/ml in the 12 hours after administration.
2 . The method of claim 1 wherein the formulation comprises:
buprenorphine and poly(D,L-lactide-co-glycolide) having a MW of 7,000-17,000.
3 . The method of claim 1 , wherein the SRBM formulation comprises buprenorphine and poly(D,L-lactide-co-glycolide) having a MW of 24,000-38,000 and poly(D,L-lactide-co-glycolide) having a MW of 7,000-17,000.
4 . The method of claim 1 , wherein the SRBM formulation further comprises polyvinyl alcohol or ethyl acetate.
5 . (canceled)
6 . (canceled)
7 . The method of claim 1 , wherein the pain is chronic pain in an opioid dependent subject.
8 . The method of claim 1 , wherein the plasma concentration of buprenorphine remains substantially within the therapeutic range for 29 or 30 days, and wherein the therapeutic range comprises from about 1 ng/mL to about 8 ng/mL for the treatment of opioid dependence or for the treatment of pain in opioid dependent subjects.
9 .- 12 . (canceled)
13 . The method of claim 1 , wherein the SRBM formulation comprises from about 1 milligram to about 600 milligrams of buprenorphine.
14 . The method of claim 1 , wherein the buprenorphine is in the form of a free base or a pharmaceutically acceptable salt.
15 . The method of claim 1 , wherein the method comprises administering the SRBM formulation to the subject by injection once about every 7 days, once about every 30 days, once about every 60 days, once about every 120 days or once about every 180 days.
16 .- 19 . (canceled)
20 . The method of claim 1 , wherein the SRBM formulation has a substantially linear release profile of buprenorphine that lasts for 30 days after administration to the subject.
21 . The method of claim 1 , wherein the SRBM formulation is administered a second time at least about 15 days, 30 days, 45 days, 60 days, 90 days, 120 days or 180 days after first administration.
22 . The method of claim 1 , wherein the SRBM formulation is administered by a subcutaneous injection or an intramuscular injection.
23 . (canceled)
24 . (canceled)
25 . The method of claim 1 , wherein the plasma concentration of buprenorphine in the subject within the first hour after administration is less than 10 ng/mL, or less than 7.5 ng/mL.
26 . The method of claim 1 , wherein the plasma concentration of buprenorphine in the subject within the first twelve hours after administration does not exceed about 10 ng/mL, 9 ng/mL, 8 ng/mL, 7.5 ng/mL, 7 ng/mL, 6.5 ng/mL, 6 ng/mL, 5.5 ng/mL or 5 ng/mL.
27 .- 34 . (canceled)
35 . The method of claim 1 , wherein the plasma concentration of buprenorphine in the subject within the first twelve hours after administration does not exceed about 10 ng/mL or about 9 ng/mL.
36 . (canceled)
37 . The method of claim 1 , wherein the plasma concentration of buprenorphine from 1 hour to 12 hours after administration of the SRBM formulation to the subject does not vary by more than 8 ng/mL (from the lowest to the highest concentration achieved).
38 . The method of claim 1 , wherein the plasma concentration of buprenorphine from 30 minutes to about 12 hours after administration of the SRBM formulation to the subject does not vary by more than 7.5 ng/mL.
39 . The method of claim 1 , wherein the plasma concentration of buprenorphine reaches and is maintained at or near a therapeutic level within 6 hours after administration of the SRBM formulation to the subject.
40 . The method of claim 1 , wherein the plasma concentration of buprenorphine in the subject remains near a therapeutic level from day 2 through day 30 after administration of the SRBM formulation to the subject.
41 . (canceled)
42 . The method of claim 40 , wherein the therapeutic level comprises from about 1 ng/ml to about 8 ng/ml of buprenorphine for the treatment of opioid dependence, or for the treatment of pain in opioid dependent subjects.
43 . (canceled)
44 . (canceled)
45 . The method of claim 1 , wherein the plasma concentration of buprenorphine in the subject remains at a substantially therapeutic level from about day 2 through day 30, from about 12 hours through about day 35, or from about day 5 through about day 40 after administration of the SRBM formulation to the subject.
46 . (canceled)
47 . (canceled)
48 . The method of claim 1 , wherein the plasma concentration of buprenorphine in the subject remains at a substantially therapeutic level from about day 2 through about day 30, or about day 40, or about day 60, or about day 120, or about day 180 after administration of the SRBM formulation to the subject, or
wherein the plasma concentration of buprenorphine remains at a substantially therapeutic level from about 12 hours through about day 30, or about day 40, or about day 60, or about day 120, or about day 180 after administration of the SRBM formulation to the subject.
49 . (canceled)
50 . The method of claim 1 , wherein the SRBM formulation provides C max of burprenorphine that does not exceed 10 ng/mL, 9 ng/mL, 8 ng/mL, 7 ng/mL, 6.25 ng/mL, 6 ng/mL, 5.75 ng/mL, 5.5 ng/mL, 5.25 ng/mL, 5 ng/mL, 4.75 ng/mL, 4 ng/mL, 3 ng/mL, or 2 ng/mL.
51 . The method of claim 1 , further comprising administering a second or subsequent effective amount of a sustained release buprenorphine microsphere (SRBM) formulation, wherein the C max of buprenorphine provided by the SRBM formulation after the second or subsequent administration is less than 10 ng/mL.
52 . The method of claim 51 , wherein the C max of buprenorphine after the second or subsequent administration includes the residual amount from the first or previous administrations, and wherein the effective amount is between about 1 mg and about 600 mg.
53 . (canceled)
54 . The method of claim 1 , wherein the SRBM formulation comprises particles having diameters between about 12 to about 100 μm, or between about 15 to about 80 μm, or between about 20 and about 40 μm.
55 . (canceled)
56 . (canceled)