US2011105551A1PendingUtilityA1

Analgesics for nasal administration

52
Assignee: VERNALIS R&D LTDPriority: Mar 19, 2002Filed: Jan 12, 2011Published: May 5, 2011
Est. expiryMar 19, 2022(expired)· nominal 20-yr term from priority
Inventors:Phillip John BirchAnn Gail HayesPeter WattsJonathan Castile
A61P 43/00A61P 5/24A61P 27/16A61P 25/04A61P 29/00A61P 25/02A61K 9/0043A61K 47/38A61K 31/5415A61K 31/407A61K 31/196A61P 15/00A61K 31/405A61K 31/54A61K 31/485A61K 47/34A61K 47/36A61K 31/195A61K 9/08
52
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Claims

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.

Claims

exact text as granted — not AI-modified
1 .- 12 . (canceled) 
     
     
         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 .- 15 . (canceled) 
     
     
         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 .- 37 . (canceled) 
     
     
         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 any  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 .- 52 . (canceled) 
     
     
         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 .- 56 . (canceled) 
     
     
         57 . 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 opioid analgesic and a delivery agent in the form of an aqueous solution;
 whereby, on introduction of said composition into the nasal cavity of the 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, and   wherein the delivery agent is from 5 to 40 mg/ml, based on the composition, of a pectin having a degree of esterification of less than 50% provided that the composition is substantially free of divalent metal ions.   
     
     
         58 . A method according to  claim 57 , wherein on introduction of the composition into the nasal cavity of the patient to be treated, the analgesic is delivered to the bloodstream to produce within 2 to 15 minutes a therapeutic plasma concentration C ther  of 0.4 ng/ml or more which is maintained for a duration T maint  of 2 to 4 hours. 
     
     
         59 . A method according to  claim 57 , wherein the pectin has a degree of esterification of from 10 to 35%. 
     
     
         60 . A method according to  claim 57 , wherein C ther  is from 0.4 to 100 ng/ml and is produced within 1 to 15 minutes. 
     
     
         61 . A method according to  claim 57 , wherein C max  is reached 10 to 30 minutes after introduction of said composition into the nasal cavity of the patient to be treated. 
     
     
         62 . A method according to  claim 57 , wherein the composition is delivered using a nasal delivery device. 
     
     
         63 . A method according to  claim 62 , wherein on introduction of the composition into the nasal cavity of a patient to be treated, the analgesic is delivered to the bloodstream to produce within 2 to 15 minutes a therapeutic plasma concentration C ther  of 0.4 ng/ml or more which is maintained for a duration T maint  of 2 to 4 hours. 
     
     
         64 . A method according to  claim 57 , wherein the opioid analgesic is fentanyl.

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