Pharmaceutical compositions for the administration of aptamers

Abstract

Pharmaceutical compositions comprising an aptamer and an amino acid ester or amide or an aptamer; a divalent metal cation; and a carboxylic acid, a phospholipid, a phosphatidyl choline, or a sphingomyelin. Methods of treating or preventing a condition in an animal comprising administering to the animal the pharmaceutical compositions.

1 - 84 . (canceled) 
     
     
         85 . A pharmaceutical composition comprising:
 (i) an amino acid ester of formula:   
       
         
           
           
               
               
           
         
       
       wherein
 R is the amino acid side chain; and 
 R 1  is a C 1  to C 22  hydrocarbon group; or 
 
       an amino acid amide of formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R is the amino acid side chain; 
 R 3  is a C 1  to C 22  hydrocarbon group; and 
 R 4  is hydrogen or a C 1  to C 22  hydrocarbon group; 
 (ii) a protonated aptamer, optionally conjugated to a polymer; and 
 (iii) a pharmaceutically acceptable organic solvent, 
 wherein the protonated aptamer is dissolved in the pharmaceutically acceptable organic solvent to provide a concentration of the aptamer in the pharmaceutically acceptable organic solvent of at least 2 percent by weight of the pharmaceutical composition or about 2 percent by weight of the pharmaceutical composition, and 
 wherein the composition is suitable for administration to an animal by injection. 
 
     
     
         86 . The pharmaceutical composition of  claim 85 , wherein the pharmaceutical composition forms a precipitate when injected into water. 
     
     
         87 . The pharmaceutical composition of  claim 85 , wherein the pharmaceutical composition forms a depot when administered to an animal. 
     
     
         88 . The pharmaceutical composition of  claim 85 , wherein the pharmaceutical composition does not form a precipitate when injected into water. 
     
     
         89 . The pharmaceutical composition of  claim 85 , further comprising water. 
     
     
         90 . The pharmaceutical composition of  claim 85 , wherein there is more than 1 equivalent of basic groups on the amino acid ester or amino acid amide per equivalent of acidic groups on the protonated aptamer. 
     
     
         91 . The pharmaceutical composition of  claim 90 , further comprising at least one of a carboxylic acid, a phospholipid, a sphingomyelin, or a phosphatidyl choline. 
     
     
         92 . The pharmaceutical composition of  claim 91 , wherein the at least one of a carboxylic acid, a phospholipid, a sphingomyelin, or a phosphatidyl choline is a carboxylic acid. 
     
     
         93 . The pharmaceutical composition of  claim 92 , wherein the pharmaceutical composition forms a precipitate when injected into water. 
     
     
         94 . The pharmaceutical composition of  claim 92 , wherein the pharmaceutical composition forms a depot when administered to an animal. 
     
     
         95 . The pharmaceutical composition of  claim 92 , wherein the pharmaceutical composition does not form a precipitate when injected into water. 
     
     
         96 . The pharmaceutical composition of  claim 92 , wherein the carboxylic acid is a fatty acid. 
     
     
         97 . The pharmaceutical composition of  claim 92 , wherein the carboxylic acid is a polycarboxylic acid. 
     
     
         98 . The pharmaceutical composition of  claim 85 , wherein the amino acid ester or amide is an ester or amide of lysine. 
     
     
         99 . The pharmaceutical composition of  claim 98 , wherein the pharmaceutical composition forms a precipitate when injected into water. 
     
     
         100 . The pharmaceutical composition of  claim 98 , wherein the pharmaceutical composition forms a depot when administered to an animal. 
     
     
         101 . The pharmaceutical composition of  claim 98 , wherein the pharmaceutical composition does not form a precipitate when injected into water. 
     
     
         102 . The pharmaceutical composition of  claim 98 , further comprising water. 
     
     
         103 . The pharmaceutical composition of  claim 98 , wherein there is more than 1 equivalent of basic groups on the amino acid ester or amino acid amide per equivalent of acidic groups on the protonated aptamer. 
     
     
         104 . The pharmaceutical composition of  claim 103 , further comprising at least one of a carboxylic acid, a phospholipid, a sphingomyelin, or a phosphatidyl choline. 
     
     
         105 . The pharmaceutical composition of  claim 104 , wherein the at least one of a carboxylic acid, a phospholipid, a sphingomyelin, or a phosphatidyl choline is a carboxylic acid. 
     
     
         106 . The pharmaceutical composition of  claim 105 , wherein the pharmaceutical composition forms a precipitate when injected into water. 
     
     
         107 . The pharmaceutical composition of  claim 105 , wherein the pharmaceutical composition forms a depot when administered to an animal. 
     
     
         108 . The pharmaceutical composition of  claim 105 , wherein the pharmaceutical composition does not form a precipitate when injected into water. 
     
     
         109 . The pharmaceutical composition of  claim 105 , wherein the carboxylic acid is a fatty acid. 
     
     
         110 . The pharmaceutical composition of  claim 105 , wherein the carboxylic acid is a polycarboxylic acid. 
     
     
         111 . The pharmaceutical composition of  claim 85 , wherein the amino acid ester or amide is an ester or amide of aspartic acid or glutamic acid. 
     
     
         112 . The pharmaceutical composition of  claim 111 , wherein the pharmaceutical composition forms a precipitate when injected into water. 
     
     
         113 . The pharmaceutical composition of  claim 111 , wherein the pharmaceutical composition forms a depot when administered to an animal. 
     
     
         114 . The pharmaceutical composition of  claim 111 , wherein the pharmaceutical composition does not form a precipitate when infected into water. 
     
     
         115 . The pharmaceutical composition of  claim 111 , further comprising water. 
     
     
         116 . The pharmaceutical composition of  claim 111 , wherein there is more than 1 equivalent of basic groups on the amino acid ester or amino acid amide per equivalent of acidic groups on the protonated aptamer. 
     
     
         117 . The pharmaceutical composition of  claim 116 , further comprising at least one of a carboxylic acid, a phospholipid, a sphingomyelin, or a phosphatidyl choline. 
     
     
         118 . The pharmaceutical composition of  claim 117 , wherein the at least one of a carboxylic acid, a phospholipid, a sphingomyelin, or a phosphatidyl choline is a carboxylic acid. 
     
     
         119 . The pharmaceutical composition of  claim 118 , wherein the pharmaceutical composition forms a precipitate when injected into water. 
     
     
         120 . The pharmaceutical composition of  claim 118 , wherein the pharmaceutical composition forms a depot when administered to an animal. 
     
     
         121 . The pharmaceutical composition of  claim 118 , wherein the pharmaceutical composition does not form a precipitate when injected into water. 
     
     
         122 . The pharmaceutical composition of  claim 118 , wherein the carboxylic acid is a fatty acid. 
     
     
         123 . The pharmaceutical composition of  claim 118 , wherein the carboxylic acid is a polycarboxylic acid. 
     
     
         124 . The pharmaceutical composition of  claim 85 , wherein the pharmaceutically acceptable organic solvent is selected from the group consisting of N-methyl-2-pyrrolidone, polyethylene glycol, propylene glycol, glycerol formal, isosorbide dimethyl ether, ethanol, dimethyl sulfoxide, tetraglycol, tetrahydrofurfuryl alcohol, triacetin, propylene carbonate, dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, and combinations thereof. 
     
     
         125 . The pharmaceutical composition of  claim 98 , wherein the pharmaceutically acceptable organic solvent is selected from the group consisting of N-methyl-2-pyrrolidone, polyethylene glycol, propylene glycol, glycerol formal, isosorbide dimethyl ether, ethanol, dimethyl sulfoxide, tetraglycol, tetrahydrofurfuryl alcohol, triacetin, propylene carbonate, dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, and combinations thereof. 
     
     
         126 . The pharmaceutical composition of  claim 111 , wherein the pharmaceutically acceptable organic solvent is selected from the group consisting of N-methyl-2-pyrrolidone, polyethylene glycol, propylene glycol, glycerol formal, isosorbide dimethyl ether, ethanol, dimethyl sulfoxide, tetraglycol, tetrahydrofurfuryl alcohol, triacetin, propylene carbonate, dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, and combinations thereof. 
     
     
         127 . The composition of  claim 86 , wherein the precipitate releases the aptamer over time. 
     
     
         128 . The composition of  claim 85 , wherein the aptamer is not conjugated to a polymer. 
     
     
         129 . The composition of  claim 85 , wherein the aptamer is conjugated to a polymer. 
     
     
         130 . A pharmaceutical composition comprising a complex between:
 (i) an amino acid ester of formula:   
       
         
           
           
               
               
           
         
       
       wherein
 R is the amino acid side chain; and 
 R 1  is a C 1  to C 22  hydrocarbon group; or 
 
       an amino acid amide of formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R is the amino acid side chain; 
 R 3  is a C 1  to C n  hydrocarbon group; and 
 R 4  is hydrogen or a C i  to C n  hydrocarbon group; and 
 (ii) a protonated aptamer, optionally conjugated to a polymer; and 
 (iii) a pharmaceutically acceptable organic solvent, 
 
       wherein the composition forms micelle or a liposome structures when injected into water. 
     
     
         131 . The pharmaceutical composition of  claim 130 , further comprising water. 
     
     
         132 . The pharmaceutical composition of  claim 130 , wherein the aptamer is present in an amount of at least 2 percent by weight of the pharmaceutical composition or about 2 percent by weight of the pharmaceutical composition. 
     
     
         133 . The pharmaceutical composition of  claim 130 , wherein the composition is suitable for administration to an animal by injection. 
     
     
         134 . The composition of  claim 130 , wherein the aptamer is not conjugated to a polymer. 
     
     
         135 . The composition of  claim 130 , wherein the aptamer is conjugated to a polymer.