Analgesics for nasal administration

Abstract

An analgesic and a delivery agent are combined in a pharmaceutical composition such that, on introduction into the nasal cavity of a patient to be treated, the analgesic may be 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. The analgesic may be an opioid analgesic or a non-steroidal anti-inflammatory drug.

1 . Use of an analgesic and a delivery agent for the manufacture of a medicament for administration intranasally for the treatment of pain whereby, on introduction into the nasal cavity of a patient to be treated, the analgesic 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.  
     
     
         2 . Use according to  claim 1 , wherein the analgesic is an opioid analgesic.  
     
     
         3 . Use according to  claim 2 , wherein the analgesic is buprenorphine or a physiologically acceptable salt or ester thereof.  
     
     
         4 . Use according to  claim 1 , wherein the analgesic is a non-steroidal anti-inflammatory drug.  
     
     
         5 . Use according to  claim 4 , wherein the analgesic is diclofenac, etodolac, piroxicam or meloxicam, or a physiologically acceptable salt or ester thereof.  
     
     
         6 . Use according to  claim 1 , wherein the medicament is an aqueous solution.  
     
     
         7 . Use according to  claim 1 , wherein the delivery agent is a pectin having a degree of esterification of less than 50%.  
     
     
         8 . Use according to  claim 1 , wherein the delivery agent is a chitosan.  
     
     
         9 . Use according to  claim 8 , wherein the chitosan is provided in combination with hydroxypropylmethylcellulose or 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.  
     
     
         10 . Use according to  claim 1 , wherein C ther  is from 0.4 to 100 ng/ml and is produced within 1 to 15 minutes.  
     
     
         11 . Use according to  claim 1 , wherein C max  is reached 10 to 30 minutes after introduction of said medicament into the nasal cavity of a patient to be treated.  
     
     
         12 . Use of a pharmaceutical composition which comprises an analgesic and a delivery agent for the manufacture of a nasal delivery device for use in inducing analgesia whereby, on introduction into the nasal cavity of a patient to be treated, the analgesic 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.  
     
     
         13 . A pharmaceutical composition suitable for use as an analgesic which comprises an analgesic and a delivery agent whereby, on introduction into the nasal cavity of a patient to be treated, the analgesic 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.  
     
     
         14 . A method of inducing analgesia in a patient in need thereof, which method comprises administering intranasally to said patient a pharmaceutical composition which comprises an analgesic and a delivery agent whereby, on introduction into the nasal cavity of said patient to be treated, the analgesic 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.  
     
     
         15 . A method according to  claim 14 , wherein a unit dosage of 0.1 to 0.6 mg of buprenorphine or buprenorphine salt or ester, calculated as buprenorphine, is administered intranasally.  
     
     
         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 . A solution according to  claim 16 , wherein the 
 hydroxypropylmethylcellulose has an apparent viscosity of from 3000 to 6000 cps and is present in an amount of from 0.1 to 15 mg/ml.    
     
     
         18 . A solution according to  claim 17 , wherein the 
 hydroxypropylmethylcellulose is present in an amount of from 0.5 to 10 mg/ml.    
     
     
         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 . A solution according to  claim 19 , wherein the polyoxyethylene-polyoxypropylene copolymer is present in an amount of from 80 to 120 mg/ml.  
     
     
         21 . A solution according to  claim 19 , wherein the polyoxyethylene-polyoxypropyene copolymer has a molecular weight of from 7,000 to 10,000.  
     
     
         22 . A solution according to  claim 19 , wherein the polyoxyethylene-polyoxypropylene copolymer is one in which a is 80 and b is 27.  
     
     
         23 . A solution according to  claim 16 , which has an osmolality of from 0.32 to 0.4 osmol/kg.  
     
     
         24 . A solution according to  claim 16 , wherein the buprenorphine or buprenorphine salt or ester is present in an amount of from 0.5 to 8 mg/ml.  
     
     
         25 . A solution according to  claim 24 , wherein the buprenorphine or buprenorphine salt or ester is present in an amount of from 1 to 6 mg/ml calculated as buprenorphine.  
     
     
         26 . A solution according to  claim 16 , which comprises buprenorphine hydrochloride.  
     
     
         27 . A solution according to  claim 16 , wherein the chitosan is present in an amount of from 2 to 10 mg/ml.  
     
     
         28 . A solution according to  claim 16 , wherein the chitosan is a physiologically acceptable salt of a deacetylated chitin  
     
     
         29 . A solution according to  claim 28 , wherein the salt is chitosan glutamate.  
     
     
         30 . A solution according to  claim 16 , wherein the pH is from 3.2 to 3.8.  
     
     
         31 . A solution according to  claim 16 , wherein the pH has been adjusted by means of hydrochloric acid.  
     
     
         32 . A solution according to  claim 16 , which comprises a preservative.  
     
     
         33 . A solution according to  claim 32 , wherein the preservative is benzalkonium chloride.  
     
     
         34 . A solution according to  claim 16 , which contains dextrose as a tonicity adjustment agent.  
     
     
         35 . A process for the preparation of an aqueous solution as defined in  claim 16 , which process comprises dissolving buprenorphine or a physiologically acceptable salt or ester thereof, a chitosan and hydroxypropylmethylcellulose in water to provide a solution comprising from 0.1 to 10 mg/ml of buprenorphine or said salt or ester thereof, from 0.1 to 20 mg/ml of the chitosan and from 0.1 to 15 mg/ml of hydroxypropylmethylcellulose; and adjusting the pH of the solution to a value from 3 to 4.8 as desired.  
     
     
         36 . A process for the preparation of an aqueous solution as defined in  claim 19 , which process comprises dissolving buprenorphine or a physiologically acceptable salt or ester thereof, a chitosan and 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 in water to provide a solution comprising from 0.1 to 10 mg/ml of buprenorphine or said salt or ester thereof, from 0.1 to 20 mg/ml of the chitosan and from 50 to 200 mg/ml of the polyoxyethylene-polyoxypropylene copolymer; and adjusting the pH of the solution to a value from 3 to 4.8 as desired.  
     
     
         37 . A process according to  claim 35 , wherein the resulting solution is introduced into a nasal delivery device.  
     
     
         38 . 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.  
     
     
         39 . A solution according to  claim 38 , wherein the buprenorphine or buprenorphine salt or ester is present in an amount of from 0.5 to 8 mg/ml.  
     
     
         40 . A solution according to  claim 39 , wherein the buprenorphine or buprenorphine salt or ester is present in an amount of from 1 to 6 mg/ml calculated as buprenorphine.  
     
     
         41 . A solution according to  claim 38 , which comprises buprenorphine hydrochloride.  
     
     
         42 . A solution according to  claim 38 , wherein the pectin is present in an amount of from 10 to 30 mg/ml.  
     
     
         43 . A solution according to  claim 38 , wherein the pectin has a degree of esterification of from 10 to 35%.  
     
     
         44 . A solution according to  claim 38 , wherein the pH is from 3.2 to 3.8.  
     
     
         45 . A solution according to  claim 38 , wherein the pH has been adjusted by means of hydrochloric acid.  
     
     
         46 . A solution according to  claim 38 , which comprises a preservative.  
     
     
         47 . A solution according to  claim 46 , which comprises phenylethyl alcohol and propyl hydroxybenzoate as preservatives.  
     
     
         48 . A solution according to  claim 38 , which has an osmolality of from 0.25 to 0.4 osmol/kg.  
     
     
         49 . A solution according to  claim 38 , which contains dextrose as a tonicity adjustment agent.  
     
     
         50 . 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.    
     
     
         51 . A process for the preparation of an aqueous solution as defined in  claim 38 , 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.  
     
     
         52 . A process according to  claim 51 , wherein the resulting solution is introduced into a nasal delivery device.  
     
     
         53 . A nasal delivery device loaded with a solution as claimed in  claim 16 .  
     
     
         54 . A device according to  claim 53 , which is a spray device.  
     
     
         55 . Use of a solution as defined in  claim 16  for the manufacture of a nasal delivery device for use in inducing analgesia.  
     
     
         56 . A method of inducing analgesia in a patient in need thereof, which method comprises intranasally administering an aqueous solution as defined in  claim 16  to the patient.