Buprenorphine formulations for intranasal delivery

Abstract

Aqueous formulations suitable for intranasal administration comprise buprenorphine or a physiologically acceptable salt or ester thereof and (a) a pectin having a degree of esterification of less than 50%, (b) chitosan and a polyoxyethylene-poly-oxypropylene copolymer (poloxamer) or (c) chitosan and hydroxypropylmethylcellulose. Such formulations can induce rapid and prolonged analgesia when delivered intranasally to a patient. The buprenorphine or buprenorphine salt or ester may be delivered to the bloodstream to produce within 30 minutes a therapeutic plasma concentration of buprenorphine, C ther , of 0.2 ng/ml or greater which is maintained for a duration T maint of at least 2 hours.

1 . An aqueous solution suitable for intranasal administration, which comprises from 0.1 to 10 mg/ml of buprenorphine or a physiologically acceptable salt or ester thereof and from 5 to 40 mg/ml of a pectin having a degree of esterification of less than 50%; which solution has a pH of from 3 to 4.2, is substantially free from divalent metal ions and gels on the nasal mucosa. 
   
   
       2 . A solution according to  claim 1 , wherein the buprenorphine or buprenorphine salt or ester is present in an amount of from 0.5 to 8 mg/ml. 
   
   
       3 . A solution according to  claim 2 , wherein the buprenorphine or buprenorphine salt or ester is present in an amount of from 1 to 6 mg/ml calculated as buprenorphine. 
   
   
       4 . A solution according to  claim 1 , which comprises buprenorphine hydrochloride. 
   
   
       5 . A solution according to  claim 1 , wherein the pectin is present in an amount of from 10 to 30 mg/ml. 
   
   
       6 . A solution according to  claim 1 , wherein the pectin has a degree of esterification of from 10 to 35%. 
   
   
       7 . A solution according to  claim 1 , wherein the pH is from 3.5 to 4.0. 
   
   
       8 . A solution according to  claim 1 , wherein the pH has been adjusted by means of hydrochloric acid. 
   
   
       9 . A solution according to  claim 1 , which comprises a preservative. 
   
   
       10 . A solution according to  claim 9 , which comprises phenylethyl alcohol and propyl hydroxybenzoate as preservatives. 
   
   
       11 . A solution according to  claim 1 , which has an osmolality of from 0.35 to 0.5 osmol/kg. 
   
   
       12 . A solution according to  claim 1 , which contains dextrose as a tonicity adjustment agent. 
   
   
       13 . An aqueous solution suitable for intranasal administration, which has a pH of from 3.5 to 4.0, which is substantially free from divalent metal ions and which comprises:
 (a) from 1 to 6 mg/ml of buprenorphine or a physiologically acceptable salt or ester thereof, calculated as buprenorphine,   (b) from 10 to 40 mg/ml of a pectin which has a degree of esterification from 10 to 35%, and   (c) dextrose as a tonicity adjustment agent.   
   
   
       14 . A process for the preparation of an aqueous solution as defined in  claim 1 , which process comprises dissolving buprenorphine or a physiologically acceptable salt or ester thereof in water; mixing the resulting solution with a solution in water of a pectin having a degree of esterification of less than 50% such that the mixed solution comprises from 0.1 to 10 mg/ml of buprenorphine or said salt or ester thereof and from 5 to 40 mg/ml of the pectin; and adjusting the pH of the solution to a value from 3 to 4.2 if desired. 
   
   
       15 . A process according to  claim 14 , wherein the resulting solution is introduced into a nasal delivery device. 
   
   
       16 . An aqueous solution suitable for intranasal administration, which comprises:
 (a) from 0.1 to 10 mg/ml of buprenorphine or a physiologically acceptable salt or ester thereof,   (b) from 0.1 to 20 mg/ml of a chitosan, and   (c) from 0.1 to 15 mg/ml of hydroxypropylmethylcellulose;   which solution has a pH of from 3 to 4.8.   
   
   
       17 - 18 . (canceled) 
   
   
       19 . An aqueous solution suitable for intranasal administration, which comprises:
 (a) from 0.1 to 10 mg/ml of buprenorphine or a physiologically acceptable salt or ester thereof,   (b) from 0.1 to 20 mg/ml of a chitosan, and   (c) from 50 to 200 mg/ml of a polyoxyethylene-polyoxypropylene copolymer of the general formula HO(C 2 H 4 O) a (C 3 H 6 O) b (C 2 H 4 O) a H wherein a is from 2 to 130 and b is from 15 to 67;   which solution has a pH of from 3 to 4.8.   
   
   
       20 - 37 . (canceled) 
   
   
       38 . A nasal delivery device loaded with a solution as claimed in  claim 1 . 
   
   
       39 . A device according to  claim 38 , which is a spray device. 
   
   
       40 . (canceled) 
   
   
       41 . A method of inducing analgesia in a patient in need thereof, which method comprises intranasally administering an aqueous solution as defined in  claim 1 . 
   
   
       42 - 47 . (canceled) 
   
   
       48 . A pharmaceutical composition suitable for use as an analgesic which comprises buprenorphine or a physiologically acceptable salt or ester thereof and a delivery agent whereby, on introduction into the nasal cavity of a patient to be treated, the buprenorphine or salt or ester thereof is delivered to the bloodstream to produce within 30 minutes a therapeutic plasma concentration C ther  of 0.2 ng/ml or greater which is maintained for a duration T maint  of at least 2 hours. 
   
   
       49 . A method of inducing analgesia in a patient in need thereof, which method comprises administering intranasally to said patient a pharmaceutical composition which comprises buprenorphine or a physiologically acceptable salt or ester thereof and a delivery agent whereby, on introduction into the nasal cavity of said patient to be treated, the buprenorphine or salt or ester thereof is delivered to the bloodstream to produce within 30 minutes a therapeutic plasma concentration C ther  of 0.2 ng/ml or greater which is maintained for a duration T maint  of at least 2 hours. 
   
   
       50 . A method according to  claim 49 , wherein a unit dosage of 0.1 to 0.6 mg of buprenorphine or buprenorphine salt or ester, calculated as buprenorphine, is administered intranasally. 
   
   
       51 . A method according to  claim 49  wherein T maint  is up to 6 hours. 
   
   
       52 . A method according to  claim 51  wherein C ther  is 0.5 to 5 ng/ml. 
   
   
       53 . A method according to  claim 52  wherein T maint  is up to 12 hours. 
   
   
       54 . A method according to  claim 49  wherein the time to reach the peak plasma concentration T max  is 10 to 30 minutes. 
   
   
       55 . A method according to  claim 54  where T max  is 15 to 25 minutes. 
   
   
       56 . A method according to  claim 54  wherein the peak plasma concentration C max  is 1 to 5 ng/ml. 
   
   
       57 . A method according to  claim 49  wherein C ther  is 0.4 ng/ml or more and is attained within a time of 2 to 15 minutes.