Drug delivery vehicles, methods of manufacture, and methods of use thereof

Abstract

Drug delivery vehicles that release one or more drugs, e.g., an opioid antagonist and/or an opioid, in response to changes in the chemistry of body fluids, specifically in response to changes in the partial pressure of CO 2 in the environment of the hydrogel are described. The drug delivery vehicles include hydrogels that swell or shrink in response to changes in the partial pressure of CO 2 in their environment, thus regulating release of an entrapped drug.

What is claimed is: 
     
         1 . A drug delivery vehicle wherein drug release is stimulated by an increase in the concentration of CO 2  in environment of the drug delivery vehicle, wherein the drug delivery vehicle is a hydrogel comprising a CO 2 -sensitive group and is derived from polymerization of a composition comprising 75-99 mol % 2-hydroxyethyl methacrylate, and 1 to 25 mol % of a bis(meth)acrylamide acetal of Formula 1 
       
         
           
           
               
               
           
         
         wherein each R is independently hydrogen or methyl, R 10  is a branched or unbranched C 1-10  alkylene, a C 2-10  alkenylene, or a phenyl group, each of which can be unsubstituted or substituted with a hydroxy, carboxy, C 1-4  alkoxy, phenyl, or phenoxy group; 
         or 1 to 20 mol % 2-hydroxyethyl methacrylate, and 80 to 99 mol % of a divinyl diacetal of Formula 3 
       
       
         
           
           
               
               
           
         
         wherein. n comprises 0 to 10 carbon atoms and is optionally substituted with a oxygen, nitrogen, or sulfur. 
       
     
     
         2 . The drug delivery vehicle of  claim 1 , wherein the bis(meth)acrylamide acetal is of Formula 2 
       
         
           
           
               
               
           
         
       
       wherein R 11  is hydrogen, C 1-4  alkoxy, or —O—(C n H 2n O) m CH 3 , where n=2-3 and m=0-9); and the divinyl acetal is of Formula 4. 
       
         
           
           
               
               
           
         
       
     
     
         3 . A drug delivery vehicle wherein drug release is stimulated by an increase in the concentration of CO 2  in environment of the drug delivery vehicle, wherein the drug delivery vehicle is a hydrogel comprising a CO 2 -sensitive group and is derived from polymerization of a composition comprising
 75 to 99 mol % of an acetal (meth)acrylate of Formula 5   
       
         
           
           
               
               
           
         
         wherein R is hydrogen or methyl, and each R 4  and R 5  is independently a straight chain or branched C 1-4  alkyl group optionally, or R 4  and R 5  together form a cycloaliphatic ring having a total of 5 to 7 carbon atoms; 
         and 1 to 25 mol % of a di(meth)acrylate crosslinker of Formula 6 
       
       
         
           
           
               
               
           
         
         each R is independently hydrogen or methyl, n is 1 to 4, and R 6  and R 7  is independently hydrogen or a straight or branched chain C 1-3  alkyl group optionally substituted with a, or R 6  and R 7  together form a cycloaliphatic ring having a total of 5 to 6 carbon atoms or a cycloheteroaliphatic ring having 4 to 6 carbon atoms and an oxygen or sulfur ring atom. 
       
     
     
         4 . The drug delivery vehicle of  claim 3 , wherein the acetal (meth)acrylate is 2-tetrahydropyranyl methacrylate, and the di(meth)acrylate crosslinker is of Formula 8 
       
         
           
           
               
               
           
         
         wherein n is 1 to 4. 
       
     
     
         5 . A drug delivery vehicle wherein release of the drug from the drug delivery vehicle is substantially CO 2 -independent, or is decreased by an increase in the concentration of CO 2  in the environment of the drug delivery vehicle, wherein the drug delivery vehicle is a hydrogel comprising
 25 to 50 mol % of the aminoalkyl (meth)acrylate of Formula 9   
       
         
           
           
               
               
           
         
         or an acid salt thereof, wherein G is oxygen or NR′ where R′ is hydrogen or C 1-3  alkyl group, R is hydrogen or methyl, R 1  is a straight chain or branched C 1-4  alkylene group, and each R 2  is independently hydrogen, C 1-4  alkyl, or a labile group removable under additional reaction conditions, e.g., an acyl group, 
         40 to 70 mol % of an acetal (meth)acrylate of Formula 5 
       
       
         
           
           
               
               
           
         
         wherein R is hydrogen or methyl, and each R 4  and R 5  is independently a straight chain or branched C 1-4  alkyl group, or R 4  and R 5  together form a cycloaliphatic ring having a total of 5 to 7 carbon atoms; 
         and 1 to 5 mol % of a crosslinker of Formula 6 
       
       
         
           
           
               
               
           
         
         wherein each R is independently hydrogen or methyl, n is 1 to 4, and R 6  and R 7  is independently hydrogen or a straight or branched chain C 1-3  alkyl group, or R 6  and R 7  together form a cycloaliphatic ring having a total of 5 to 6 carbon atoms or a cycloheteroaliphatic ring having 4 to 6 carbon atoms and an oxygen or sulfur ring atom. 
       
     
     
         6 . The drug delivery vehicle of  claim 5 , wherein the aminoalkyl (meth)acryate is 2-(dimethylamino)ethyl methacrylate or its hydrochloride salt, the acetal (meth)acrylate is 2-tetrahydropyranyl methacrylate, and the crosslinker is of Formula 8 
       
         
           
           
               
               
           
         
         wherein n=1 to 4.