Polypeptide synthesis for drug delivery

Abstract

The present invention provides improved methods for the synthesis of polypeptide or peptide-linked compounds via a NCA-based polymerization reaction that produces high product yields in much less time. Such improved methods are achieved by application of a higher temperature and/or reduced pressure to the reaction such that an NCA-containing monomer melts.

1 . A method, comprising the following steps:
 (a) combining one or more initiators and one or more NCA-containing monomers in a reaction vessel to form a reaction mixture; and   (b) heating the reaction mixture to an elevated temperature at or above the melting point of at least one of the NCA-containing monomers, wherein at least one of the NCA-containing monomers melts at the elevated temperature during step (b).   
     
     
         2 . The method of  claim 1 , wherein the elevated temperature is in the range of from about 50° to about 75° C. 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the heating step (b) is carried out until the reaction reaches or nears completion. 
     
     
         5 . The method of  claim 4 , wherein the heating step (b) is carried out until evolution of CO 2  from the reaction mixture is no longer visible. 
     
     
         6 . The method of  claim 4 , wherein the heating step (b) is carried out until a visible solid precipitate is formed in the reaction mixture. 
     
     
         7 . The method of  claim 1 , wherein the one or more initiators comprises two or more different types of initiators. 
     
     
         8 . The method of  claim 1 , wherein the one or more NCA-containing monomers comprises two or more different types of NCA-containing monomers. 
     
     
         9 . The method of  claim 1 , wherein at least one of the one or more initiators is an L-amino acid, D-amino acid, or derivative thereof. 
     
     
         10 . The method of  claim 1 , wherein at least one of the one or more initiators is water. 
     
     
         11 . The method of  claim 1 , wherein at least one of the one or more initiators is an active agent or drug. 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the base monomer of at least one of the one or more NCA-containing monomers is an active agent or drug. 
     
     
         14 . The method of  claim 13 , wherein the active agent or drug is L-DOPA, 3,5,3′,5′-tetraiodothyronine (T4), or 3,5,3′-triiodo-L-thyronine (T3). 
     
     
         15 . The method of  claim 1 , wherein the combining step (a) further comprises combining an aprotic solvent as part of the reaction mixture. 
     
     
         16 - 17 . (canceled) 
     
     
         18 . The method of  claim 15 , wherein the aprotic solvent has a boiling point below the melting point of at least one NCA-containing monomer melted during step (b). 
     
     
         19 . The method of  claim 15 , wherein the aprotic solvent comprises one or more of the following: perfluorohexane, pentane, hexane, cyclohexane, carbon tetrachloride, benzene, carbon disulfide, diisopropyl ether, diethyl ether, t-butyl methyl ether (MTBE), chloroform, ethyl acetate, tetrahydrofuran (THF), methylene chloride, 2-butanone, acetone, acetonitrile, dichloromethane, or nitrobenzene. 
     
     
         20 . The method of  claim 1 , further comprising step (c) of applying a reduced pressure to the reaction mixture. 
     
     
         21 . The method of  claim 20 , wherein the reduced pressure is between zero inches of Hg to about 20 inches of Hg. 
     
     
         22 . The method of  claim 20 , wherein step (c) is performed after step (a). 
     
     
         23 . The method of  claim 20 , wherein step (c) is performed during step (b).