High bioavailability opioid formulations

Abstract

A high bioavailability opioid depot precursor formulation comprising: a) a controlled-release matrix; b) at least oxygen containing organic solvent; c) at least one active agent selected from buprenorphine and salts thereof. Typically such a precursor formulation will form a depot composition upon administration to the body of a subject.

1 . A high bioavailability opioid depot precursor formulation comprising:
 a) a controlled-release matrix;   b) at least oxygen containing organic solvent;   c) at least one active agent selected from buprenorphine and salts thereof.   
     
     
         2 . The high bioavailability opioid depot precursor formulation of  claim 1  which forms a depot composition upon administration to the body of a subject. 
     
     
         3 . The high bioavailability opioid depot precursor formulation of  claim 1  having a bioavailability, measured as the area under a curve of plasma concentration against time in a human subject, of no less than 7 hours*ng/ml per mg of administered buprenorphine. 
     
     
         4 . The high bioavailability opioid depot precursor formulation of  claim 1  wherein the controlled release matrix component a) comprises a lipid controlled release formulation. 
     
     
         5 . The high bioavailability opioid depot precursor formulation of  claim 4  wherein the lipid controlled release formulation comprises:
 i) least one neutral diacyl lipid and/or a tocopherol; and 
 ii) at least one phospholipid; 
 
     
     
         6 . The high bioavailability opioid depot precursor formulation of  claim 5  wherein component i) comprises at least 50% of components C16 to C18 acyl groups and having zero, one or two unsaturations. 
     
     
         7 . The high bioavailability opioid depot precursor formulation of  claim 5  wherein component ii) comprises at least 50% of components C16 to C18 acyl groups and having zero, one or two unsaturations. 
     
     
         8 . The high bioavailability opioid depot precursor formulation of  claim 1  wherein component b) comprises NMP. 
     
     
         9 . The high bioavailability opioid depot precursor formulation of  claim 1  for a once-weekly administration having a dose in the range 3 to 40 mg buprenorphine (calculated as buprenorphine free base). 
     
     
         10 . The high bioavailability opioid depot precursor formulation of  claim 1  for a once-fortnightly administration having a dose in the range 6 to 60 mg buprenorphine. 
     
     
         11 . The high bioavailability opioid depot precursor formulation of  claim 1  for once-monthly administration having a dose in the range 10 to 80 mg buprenorphine. 
     
     
         12 . The high bioavailability opioid depot precursor formulation of  claim 1  wherein the precursor formulation is in ready-to-administer form. 
     
     
         13 . The high bioavailability opioid depot precursor formulation of  claim 12  wherein the precursor formulation is stable to storage in ready-to-administer form. 
     
     
         14 . The high bioavailability opioid depot precursor formulation of  claim 1  containing greater than 30% by weight buprenorphine (calculated as buprenorphine free base). 
     
     
         15 . A depot composition formed by administration to a subject the depot precursor formulation as claimed in  claim 1 . 
     
     
         16 . The depot composition of  claim 15  which provides a Cmax (maximum concentration) in the blood plasma of said subject after a single administration of no more than 0.3 ng/ml per mg of administered buprenorphine. 
     
     
         17 . The depot composition of  claim 15  which, upon administration to said subject provides linearity of the AUC dose in comparison with the administered dose of buprenorphine. 
     
     
         18 . The depot composition of  claim 15  wherein a half-life plasma concentration experienced by the subject after Cmax is be greater than 1 day. 
     
     
         19 . The depot composition of  claim 15  wherein the steady-state Cmax concentration in said subject is no more than 20 times the corresponding Cmin plasma concentration. 
     
     
         20 . The depot composition of  claim 15  wherein the variation between Cmin and Cmax at a steady-state of administration of the precursor formulation as claimed in  claim 1  both fall with the range of between 0.4 ng/mL and 10 ng/mL. 
     
     
         21 . A depot composition as claimed in  claim 15  which comprises:
 a) a controlled-release matrix; 
 b) optionally at least oxygen containing organic solvent; 
 c) at least one active agent selected from buprenorphine and salts thereof; 
 d) optionally at least one aqueous fluid. 
 
     
     
         22 . A method of sustained delivery of an opioid bioactive agent to a human or non-human animal body, this method comprising administering a high bioavailability opioid depot precursor formulation comprising:
 a) a controlled-release matrix;   b) at least oxygen containing organic solvent;   c) at least one active agent selected from buprenorphine and salts thereof.   
     
     
         23 . A method for the formation of a high bioavailability opioid depot composition comprising exposing a precursor formulation comprising:
 a) a controlled-release matrix;   b) at least oxygen containing organic solvent;   c) at least one active agent selected from buprenorphine and salts thereof.   
       to an aqueous fluid in vivo. 
     
     
         24 . A method of treatment or prophylaxis of a human or non-human animal subject comprising administration of a precursor formulation of  claim 1 . 
     
     
         25 . A method of  claim 24  for the treatment of pain 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 
     
     
         26 . A method of transitioning of a subject from daily sublingual buprenorphine to a sustained buprenorphine formulation comprising administering to said subject a weekly buprenorphine depot precursor formulation comprising 0.5 to 3 times his previous daily buprenorphine dose.