Methods and compositions for administration of therapeutic reagents

Abstract

Methods and compositions are taught that may be used to administer specific bioactive polypeptides, known as T20 and T1249 to a patient, e.g., as a method of treating a disease or disease state. In particular, the invention teaches carrier hydrogel composition that contain (a) a polymer material and (b) an effective dose of T20, T1249 or a derivative thereof. The polymer materials used in the carrier hydrogel composition preferably have reverse gelation properties and exist as a liquid, aqueous solution at temperatures below physiological temperatures (e.g., below the body temperature of a patient) but form hydrogels under physiological conditions (e.g., at temperatures at or near the body temperature of a patient). The carrier hydrogel compositions may thus be administered to a patient by injection while they are in a liquid state. Upon administration the carrier hydrogel compositions then form hydrogels with the T20 and/or T1249 polypeptides embedded therein. The T20 and/or T1249 polypeptides are thereby released with improved pharmacokinetic properties and bioavailability. The invention thus provides methods for administering T20 and T1249 polypeptides to a patient by administering the T20 and/or T1249 polypeptides in the carrier hydrogel composition of the invention. Methods of treating various diseases and disease states, particularly HIV infection, are also provided that involve administering an effective dose of T20 and/or T1249 polypeptides to a patient in the carrier hydrogel composition of the invention.

What is claimed is:  
     
         1 . A composition comprising: 
 (a) a polymer material that forms a hydrogel at physiological temperatures, and    (b) a polypeptide having the amino acid sequence 
 X-YLTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-Z (SEQ ID NO.: 1), or  
 X-WQEWEQKITALLEQAQIQQEKNEYELQKLDKWASLWEWF-X (SEQ ID NO.:2); wherein 
 X comprises an amino group, an acetyl group, a 9-fluorenylmethoxy-carbonyl group, a T-butoxycarbonyl group, or a macromolecular carrier group; and  
 Z comprises a carboxyl group, an amido group, a T-butoxycarbonyl group or a macromolecular carrier group.  
 
   
     
     
         2 . The composition of  claim 1  wherein said composition is a liquid at temperatures below physiological temperatures.  
     
     
         3 . The composition of  claim 2  wherein said composition is a liquid below 30° C.  
     
     
         4 . The composition of  claim 3  wherein said composition is a liquid below 25° C.  
     
     
         5 . The composition of  claim 4  wherein said composition is a liquid below 15° C.  
     
     
         6 . The composition of  claim 5  wherein said composition is a liquid below 10° C.  
     
     
         7 . The composition of  claim 6  wherein said composition is a liquid below 5° C.  
     
     
         8 . The composition of  claim 1  wherein the polymer material is Poloxamer 407.  
     
     
         9 . The composition of  claim 8  wherein Poloxamer 407 is present in an amount between 20 and 30% by weight.  
     
     
         10 . The composition of  claim 8  wherein Poloxamer 407 is present in an amount of 20% by weight.  
     
     
         11 . The composition of  claim 8  wherein Poloxamer 407 is present in an amount of 30% by weight.  
     
     
         12 . The composition of  claim 1  wherein the polymer material is methyl cellulose.  
     
     
         13 . The composition of  claim 12  wherein methyl cellulose is present in an amount of between 4% and 8% by weight.  
     
     
         14 . The composition of  claim 13  wherein methyl cellulose is present in an amount of 5% by weight.  
     
     
         15 . The composition of  claim 1  wherein said composition comprises at least one other therapeutic reagent.  
     
     
         16 . The composition of  claim 15  wherein the other therapeutic reagent is an antiviral reagent.  
     
     
         17 . The composition of  claim 16  wherein the antiviral reagent is another polypeptide.  
     
     
         18 . The composition of  claim 16  wherein the antiviral reagent is a cytokine.  
     
     
         19 . The composition of  claim 16  wherein the antiviral reagent is an inhibitor of reverse transcriptase.  
     
     
         20 . The composition of  claim 16  wherein the antiviral reagent is an inhibitor of viral mRNA capping.  
     
     
         21 . A method for sustained release of a peptide in a patient comprising administering to the patient a composition comprising: 
 (a) a polymer material that forms a hydrogel at physiological temperatures, and    (b) a polypeptide having the amino acid sequence 
 X-YLTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-Z (SEQ ID NO.: 1), or  
 X-WQEWEQKITALLEQAQIQQEKNEYELQKLDKWASLWEWF-X (SEQ ID NO.:2);  
 such that the composition acts as a sustained release matrix for the polypeptide, and wherein  
   X comprises an amino group, an acetyl group, a 9-fluorenylmethoxy-carbonyl group, a T-butoxycarbonyl group, or a macromolecular carrier group; and    Z comprises a carboxyl group, an amido group, a T-butoxycarbonyl group or a macromolecular carrier group.    
     
     
         22 . The method of  claim 21  wherein the composition is a liquid at temperatures below physiological temperatures.  
     
     
         23 . The method of  claim 21  wherein the composition is administered to the patient in a liquid state by subcutaneous, intramuscular or intraperitoneal injection.  
     
     
         24 . The method of  claim 21  wherein the injection is subcutaneous.  
     
     
         25 . A method for ameliorating a symptom associated with an HIV infection comprising administering to an HIV infected patient a pharmaceutical composition comprising: 
 (a) a polymer material that forms a hydrogel at physiological temperatures, and    (b) a sufficient amount of a polypeptide having the amino acid sequence 
 X-YLTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-Z (SEQ ID NO.:1), or  
 X-WQEWEQKITALLEQAQIQQEKNEYELQKLDKWASLWEWF-X (SEQ ID NO.:2);  
 such that an effective dose of the polypeptide is released from the polymer at a sustained rate, and wherein  
   X comprises an amino group, an acetyl group, a 9-fluorenylmethoxy-carbonyl group, a T-butoxycarbonyl group, or a macromolecular carrier group; and    Z comprises a carboxyl group, an amido group, a T-butoxycarbonyl group or a macromolecular carrier group.    
     
     
         26 . The method of  claim 25  wherein the pharmaceutical composition further comprises at least one other therapeutic reagent.  
     
     
         27 . The method of  claim 26  wherein the other therapeutic reagent is another antiviral agent.  
     
     
         28 . The method of  claim 27  wherein the antiviral reagent is another polypeptide.  
     
     
         29 . The method of  claim 25  wherein the antiviral reagent is a cytokine.  
     
     
         30 . The method of  claim 25  wherein the antiviral reagent is an inhibitor of reverse transcriptase.  
     
     
         31 . The method of  claim 25  wherein the antiviral reagent is an inhibitor of viral mRNA capping.