Pharmaceutical formulations comprising opioid receptor agonist as active ingredients, methods of manufacture and therapeutic uses thereof

Abstract

Formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof as the sole active ingredient, a viscosity enhancer, and a buffering agent in an amount to provide a pH of from 5.0 to 7.0 are useful for treating opioid withdrawal syndrome.

1 . A ready-to-use pharmaceutical formulation in form of aqueous solution for sublingual and buccal administration, said formulation comprising:
 (1) from 0.005 to 0.02% w/v, based on the volume of the formulation, of buprenorphine or a pharmaceutically acceptable salt thereof as the sole active ingredient;   (2) from 0.6 to 10% w/v, based on the volume of the formulation, of a thickening agent; and   (3) a buffering agent in an amount sufficient to provide a pH of 5.0 to 7.0.   
     
     
         2 . The formulation according to  claim 1 , wherein said buprenorphine is in form of its hydrochloride salt. 
     
     
         3 . The formulation according to  claim 1 , which has a pH of from 5.2 to 6.8. 
     
     
         4 . The formulation according to  claim 1 , which has a pH of from 5.5 to 6.5. 
     
     
         5 . The formulation according to  claim 1 , which has a viscosity of from 500 to 2300 mPas at 25±2° C. 
     
     
         6 . The formulation according to  claim 5 , which has a viscosity of from 700 to 2100 mPas at 25±2° C. 
     
     
         7 . The formulation according to  claim 1 , wherein said thickening agent is a cellulose derivative. 
     
     
         8 . The formulation according to  claim 7 , wherein said thickening agent is hydroxyethylcellulose or sodium carboxymethylcellulose. 
     
     
         9 . The formulation according to  claim 1 , wherein said buffering agent is made of citric acid and sodium citrate. 
     
     
         10 . The formulation according to  claim 1 , which further comprises a sweetener and/or a flavoring agent. 
     
     
         11 . A formulation according to  claim 1 , consisting essentially of:
 0.05-0.01% w/v, based on the volume of the formulation, of buprenorphine hydrochloride expressed as a base;   1.5% w/v, based on the volume of the formulation, of hydroxyethylcellulose or 6.0% w/v, based on the volume of the formulation, of sodium carboxymethylcellulose;   0.12% w/v, based on the volume of the formulation, of anhydrous citric acid;   1.13% w/v, based on the volume of the formulation, of sodium citrate anhydrous; and   water for injection.   
     
     
         12 . A process for preparing a ready-to-use formulation according to  claim 1 , comprising:
 (i) dissolving a suitable amount of buprenorphine or a pharmaceutically acceptable salt thereof in water in a glass container to obtain a buprenorphine concentrated clear solution;   (ii) optionally, sterilizing the obtained solution in step (i) by filtration;   (iii) in parallel, dissolving an appropriate amount of a buffering agent in water in a volumetric glass container to obtain a clear buffering agent solution;   (iv) optionally, sterilizing the obtained solution in step (iii) by heating;   (v) adding an appropriate volume of buprenorphine concentrated solution to said buffering agent solution to obtain a final desired concentration of buprenorphine while mixing under continuous stirring; and   (vi) slowly adding a proper amount of a thickening agent to the solution of step (v) under continuous stirring until the thickening agent is completely dissolved and a clear and homogenous solution is obtained.   
     
     
         13 . A method of treating opioid withdrawal syndrome, comprising administering to a subject in need thereof an effective amount of a formulation according to  claim 1 . 
     
     
         14 . The method according to  claim 13 , wherein said opioid withdrawal syndrome is the neonatal opioid withdrawal syndrome. 
     
     
         15 . A syringe pre-filled with a formulation according to  claim 1 . 
     
     
         16 . A package, containing a formulation according to  claim 1  in the form of either ready-to-use aqueous solution or powder to be reconstituted in a suitable aqueous vehicle, in combination with a syringe, and instructions to orally administer said pharmaceutical formulation to a patient suffering from opioid withdrawal syndrome. 
     
     
         17 . The package according to  claim 16 , wherein said patient is a neonate suffering from neonatal opioid withdrawal syndrome.