Long-acting polymeric delivery systems

Abstract

Compositions comprised of a delivery vehicle or delivery system and an active agent dispersed within the delivery vehicle or system, wherein the delivery vehicle or system contains a polyorthoester polymer and a polar aprotic solvent. Also disclosed are low viscosity delivery systems for administration of active agents. The low viscosity delivery systems have a polyorthoester polymer, a polar aprotic solvent and a solvent containing a triglyceride viscosity reducing agent. Compositions described include an amide- or anilide-type local anesthetic of the “caine” classification, and a non-steroidal anti-inflammatory drug (NSAID), along with related methods, e.g., for treatment of post-operative pain or for prophylactic treatment of pain. The compositions are suitable for delivery via, e.g., direct application and instillation, intradermal injection, subcutaneous injection, and nerve block (perineural).

It is claimed: 
     
         1 . A composition, comprising:
 a delivery system comprising a polyorthoester and a solvent in which the polyorthoester is miscible to form a single phase;   an amide local anesthetic; and   a non-steroidal anti-inflammatory drug (NSAID);   
       wherein the amide local anesthetic and NSAID are present in the composition at a ratio ranging from about 10:1 to 50:1. 
     
     
         2 . The composition according to  claim 1 , wherein the solvent is selected from dimethyl sulfoxide, dimethyl acetamide and N-methyl pyrrolidone. 
     
     
         3 . The composition according to  claim 1 , wherein the polyorthoester is represented by the structure shown as Formula I: 
       
         
           
           
               
               
           
         
       
       where:
 R* is a C 1-4  alkyl, 
 n is an integer ranging from 5 to 400, and 
 A is a diol, where A is R 1  and/or R 3 , where the fraction of A units that are of formula R 1  is between 0 and 25 mole percent, where when A is R 3 , R 3  is 
 
       
         
           
           
               
               
           
         
       
       where x is 2; and
 when A is R 1 , R 1  is 
 
       
         
           
           
               
               
           
         
         R 5  is H, and R 6  is 
       
       
         
           
           
               
               
           
         
       
       the sum of p and q is, on average, 2 and s is 2,
 where the resulting component of the polyorthoester comprises the subunit 
 
       
         
           
           
               
               
           
         
       
     
     
         4 . The composition according to  claim 1 , wherein the amide local anesthetic is bupivacaine or ropivacaine. 
     
     
         5 . The composition according to  claim 1 , wherein the NSAID is selected from meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam. 
     
     
         6 . The composition according to  claim 1 , wherein the delivery system further comprises an organic acid having a molecular weight less than about 300 Da. 
     
     
         7 . A method for producing analgesia or pain relief in a subject in need thereof, comprising: administering to the subject the composition according to  claim 1 . 
     
     
         8 . A method for managing pain or for prophylactic treatment of pain in a subject, comprising administering to the subject the composition according to  claim 1 . 
     
     
         9 . A composition, comprising:
 a delivery system;   an amide local anesthetic; and   a non-steroidal anti-inflammatory drug (NSAID);   wherein the delivery system comprises a bioerodible or biodegradable polymer, a solvent in which the polymer is miscible to form a single phase, a triglyceride viscosity reducing agent comprising three fatty acid groups, and an organic acid having a molecular weight less than about 300 Da.   
     
     
         10 . The composition according to  claim 9 , wherein the amide local anesthetic and NSAID are present in the composition at a ratio ranging from about 10:1 to 50:1. 
     
     
         11 . The composition according to  claim 9 , wherein the triglyceride viscosity reducing agent comprises three fatty acid groups each independently comprising between 1-7 carbon atoms. 
     
     
         12 . The composition according to  claim 9 , wherein the triglyceride viscosity reducing agent is triacetin. 
     
     
         13 . The composition according to  claim 9 , wherein the organic acid is selected from the group consisting of fumaric or maleic acid, ethanoic acid, propanoic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, benzoic acid, salicylic acid and acetyl salicylic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, and pimelic acid. 
     
     
         14 . The composition according to  claim 9 , wherein the bioerodible or biodegradable polymer is a polyorthoester represented by the structure shown as Formula I: 
       
         
           
           
               
               
           
         
       
       where:
 R* is a C 1-4  alkyl, 
 n is an integer ranging from 5 to 400, and 
 A is a diol, where A is R 1  and/or R 3 , where the fraction of A units that are of formula R 1  is between 0 and 25 mole percent, where
 when A is R 3 , R 3  is 
 
 
       
         
           
           
               
               
           
         
       
       where x is 2; and
 when A is R 1 , R 1  is 
 
       
         
           
           
               
               
           
         
         R 5  is H, and R 6  is 
       
       
         
           
           
               
               
           
         
       
       the sum of p and q is, on average, 2 and s is 2,
 where the resulting component of the polyorthoester comprises the subunit 
 
       
         
           
           
               
               
           
         
       
     
     
         15 . A method for producing analgesia or pain relief in a subject in need thereof, comprising: administering to the subject the composition according to  claim 9 . 
     
     
         16 . A method for managing pain or for prophylactic treatment of pain in a subject, comprising administering to the subject the composition according to  claim 9 . 
     
     
         17 . A composition, comprising:
 a delivery system comprising a bioerodible or biodegradable polyorthoester, a polar aprotic solvent, and a triglyceride viscosity reducing agent;   an amide local anesthetic; and   a non-steroidal anti-inflammatory drug (NSAID);   wherein the amide local anesthetic and NSAID are present in the composition at a ratio ranging from about 10:1 to 50:1.   
     
     
         18 . The composition according to  claim 17 , wherein the delivery system consists essentially of the bioerodible or biodegradable polyorthoester, the polar aprotic solvent, the triglyceride viscosity reducing agent, and an organic acid having a molecular weight less than about 300 Da. 
     
     
         19 . A method for producing analgesia or pain relief in a subject in need thereof, comprising: administering to the subject the composition according to  claim 17 . 
     
     
         20 . A method for managing pain or for prophylactic treatment of pain in a subject, comprising administering to the subject the composition according to  claim 17 .