Injectable buprenorphine formulation

Abstract

The present invention provides an injectable liquid formulation with controlled release comprising: a) a lipid controlled-release matrix comprising at least 50% triacyl lipids; b) at least one oxygen containing organic solvent; c) at least 16% by weight of at least one active agent selected from buprenorphine and salts thereof, calculated as buprenorphine free base. The invention also provides a method for the treatment of pain, for opioid maintenance therapy or for the treatment of opioid dependence by detoxification and/or maintenance or for the treatment or prophylaxis of the symptoms of opioid withdrawal and/or cocaine withdrawal by injecting such a liquid composition.

1 - 28 . (canceled) 
     
     
         29 . An injectable liquid formulation comprising:
 a) a lipid controlled-release matrix comprising at least 50% triacyl lipids;   b) at least one oxygen containing organic solvent;   c) at least 16% by weight of at least one active agent selected from buprenorphine and salts thereof, calculated as buprenorphine free base.   
     
     
         30 . The injectable liquid formulation of  claim 29 , wherein the formulation forms a controlled-release composition upon administration to the body of a subject. 
     
     
         31 . The injectable liquid formulation of  claim 29 , wherein the at least one active agent selected from buprenorphine and salts thereof is present at a level of greater than 21% (e.g., greater than 30%, such as 31 to 50%) by weight buprenorphine (calculated as buprenorphine free base). 
     
     
         32 . The injectable liquid formulation of  claim 29 , wherein component a) forms 10% to 60% of the total precursor formulation and at least 50% of said component a) is formed of triacyl lipids. 
     
     
         33 . The injectable liquid formulation of  claim 29 , wherein 50% to 100%, preferably 60 to 90%, more preferably 70 to 90% of said lipid controlled release matrix is formed of triacyl lipids. 
     
     
         34 . The injectable liquid formulation of  claim 29 , wherein component a) comprises at least 80% triglycerides. 
     
     
         35 . The injectable liquid formulation of  claim 29 , wherein the lipid controlled release formulation further comprises:
 i) at least one neutral diacyl lipid   ii) at least one tocopherol; and/or   iii) at least one phospholipid.   
     
     
         36 . The injectable liquid formulation of  claim 29 , wherein component a) comprises at least 50% by weight of triacyl lipids comprising C16 to C20 acyl groups having zero, one or two unsaturations, especially C16:0, C16:1, C18:0, C18:1, C18:2, C18:3 and/or C20:1 acyl groups. 
     
     
         37 . The injectable liquid formulation of  claim 29 , wherein component a) comprises at least 60% of triglycerides. 
     
     
         38 . The injectable liquid formulation of  claim 29 , wherein component a) comprises at least 60% of triacyl lipids having C16 to C18 acyl groups with zero, one or two unsaturations. 
     
     
         39 . The injectable liquid formulation of  claim 29 , wherein component b) is present at 15 to 50% by weight of the precursor formulation, preferably 25 to 40% by weight. 
     
     
         40 . The injectable liquid formulation of  claim 29 , wherein component b) comprises at least one amide and/or at least one sulphoxide. 
     
     
         41 . The injectable liquid formulation of  claim 29 , wherein component b) comprises NMP, DMSO or mixtures thereof. 
     
     
         42 . The injectable liquid formulation of  claim 29  for administration no more frequently than once every 28 days, such as once every 28 to 32 days, once every 56 to 62 days, or once every 82 to 95 days. 
     
     
         43 . The injectable liquid formulation of  claim 29  having a dose in the range 20 to 600 mg buprenorphine (calculated as free base) particularly 30 to 300 mg, more preferably 40 to 140 mg. 
     
     
         44 . The injectable liquid formulation of  claim 29  having a dose in the range 20 to 240 mg buprenorphine (calculated as free base) per month of release duration and having a release duration of 1 to 4 months. 
     
     
         45 . The injectable liquid formulation  claim 29 , wherein the formulation is in ready-to-administer form. 
     
     
         46 . The injectable liquid formulation of  claim 29  having a viscosity of 20 to 600 mPas at 20° C., preferably 50 to 400 mPas at 20° C., most preferably 60 to 300 mPas at 20° C. 
     
     
         47 . The injectable liquid formulation of  claim 29 , wherein the formulation is stable to storage in ready-to-administer form. 
     
     
         48 . The injectable liquid formulation of  claim 29 , wherein the ratio of triacyl lipid(s):phospholipid(s) (w/w) in the lipid controlled-release matrix a) is in the range of 90:10 to 100:0, preferably in the range of 95:5 to 100:0. 
     
     
         49 . The injectable liquid formulation of  claim 29 , wherein the level of phospholipid in the formulation as a whole is less than 8 wt.%, such as 6 wt % or less, or 4 wt % or less. 
     
     
         50 . A controlled-release composition formed by administration to a (preferably human) subject of an injectable liquid formulation of  claim 29 . 
     
     
         51 . The controlled-release composition of  claim 50 , wherein following administration to said subject of an injectable liquid formulation once monthly for at least 6 months, mean Cmin and Cmax at a steady-state both fall within the range of between 0.3 ng/mL to 12 ng/mL, preferably 0.4 ng/mL and 5 ng/mL, in a population of at least 10 subjects. 
     
     
         52 . The controlled-release composition of  claim 50 , wherein the composition comprises:
 a) a lipid controlled-release matrix comprising at least 50% triacyl lipids;   b) optionally at least one oxygen containing organic solvent;   c) at least 16% by weight of at least one active agent selected from buprenorphine and salts thereof, calculated as buprenorphine free base; and   d) optionally at least one aqueous fluid.   
     
     
         53 . A method of sustained delivery of buprenorphine to a human or non-human animal body, said method comprising administering an injectable liquid formulation comprising:
 a) a lipid controlled-release matrix comprising at least 50% triacyl lipids;   b) at least one oxygen containing organic solvent; and   c) at least 16% by weight of at least one active agent selected from buprenorphine and salts thereof, calculated as buprenorphine free base.   
     
     
         54 . A method for the formation of a controlled-release composition comprising exposing an injectable liquid formulation comprising:
 a) a lipid controlled-release matrix comprising at least 50% triacyl lipids;   b) at least one oxygen containing organic solvent; and   c) at least 16% by weight of at least one active agent selected from buprenorphine and salts thereof, calculated as buprenorphine free base;   to an aqueous fluid in vivo.   
     
     
         55 . A method of treatment or prophylaxis of a human or non-human animal subject comprising administration of an injectable liquid formulation of  claim 29 . 
     
     
         56 . A method of  claim 55  for the treatment of pain, for opioid maintenance therapy or for the treatment of opioid dependence by detoxification and/or maintenance or for the treatment or prophylaxis of the symptoms of opioid withdrawal and/or cocaine withdrawal.