Process for the preparation of amphiphilic poly(n-vinyl-2-pyrrolidone) block copolymers

Abstract

The instant invention provides a two-step polymerization process for preparing amphiphilic poly(N-vinyl-2-pyrrolidone), (PVP)-block-polyester copolymers and other diblock and triblock copolymers consisting of PVP as one block. The block copolymers of the invention can be used as vehicles for drug delivery.

1 - 62 . (canceled)  
   
   
       63 . A process for preparing diblock and triblock copolymers comprising the steps of: 
 (a) performing radical polymerization of N-vinyl-2-pyrrolidone in the presence of a radical initiator and an alcoholic solvent to form hydroxy-terminated poly(N-vinylpyrrolidone) wherein said hydroxy-terminated poly(N-vinylpyrrolidone) is isolated by dissolution and precipitation and    (b) performing ionic polymerization of monomers or comonomers selected from the group consisting of 3,6-dimethyl-1,4-dioxane-2,5-dione, ε-caprolactone, γ-caprolactone, poly(D,L-lactide), poly(D-lactide), poly(L-lactide), poly(ε-caprolactone) and poly(γ-caprolactone) in the presence of a catalyst and a macroinitiator wherein said macroinitiator is the hydroxy-terminated poly(N-vinylpyrrolidone) formed in step (a) thereby preparing said diblock and triblock copolymers, wherein said copolymers self-assemble in polymeric micelles or stabilized nanoparticles in aqueous solution.    
   
   
       64 - 68 . (canceled)  
   
   
       69 . The process in accordance with  claim 63  wherein said alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, -butanol, 2-butanol, tert-butanol, 1-pentanol and 2-pentanol.  
   
   
       70 . The process in accordance with  claim 63  wherein said radical initiator is an azo derivative selected from the group consisting of 2,2′-azobis(2-methyl-N-(2-hydroyethyl)-propionamide); 2,2′-azobis(2-methyl-N-[2-(1-hydroxybutyl)]propionamide and 1,1′-azobis(cyclohexane-carbonitrile).  
   
   
       71 . The process in accordance with  claim 63  wherein said catalyst is aluminum or tin alkoxides.  
   
   
       72 . The process in accordance with  claim 63  wherein said poly(N-vinylpyrrolidone) formed in step (a) comprises a hydroxyl group on at least one chain end.  
   
   
       73 . (canceled)  
   
   
       74 . The process in accordance with  claim 63  wherein the solvent for said dissolution is selected from the group consisting of methanol, ethanol, isopropanol (isopropyl alcohol), acetone, 2-butanone, 4-methyl-2-pentanone, dichloromethane and tetrahydrofuran.  
   
   
       75 . The process in accordance with  claim 74  wherein at least two solvents are combined for said dissolution.  
   
   
       76 . The process in accordance with  claim 63  wherein the solvent for said precipitation is selected from the group consisting of diethyl ether, tert-butyl methyl ether, hexane derivatives, heptane derivatives, ethyl acetate, isopropyl acetate, toluene and xylene derivatives.  
   
   
       77 . The process in accordance with  claim 76  wherein at least two solvents are combined for said precipitation.  
   
   
       78 . The process in accordance with  claim 63  wherein said poly(N-vinylpyrrolidone) formed in step (a) is dried under vacuum at a final temperature over 100° C.  
   
   
       79 . The process in accordance with  claim 63  wherein said poly(N-vinylpyrrolidone) formed in step (a) is dried by azeotropic distillation using an inert organic solvent.  
   
   
       80 . The process in accordance with  claim 79  wherein said inert organic solvent is selected from the group consisting of toluene, xylene derivatives and heptane derivatives.  
   
   
       81 . The process in accordance with  claim 63  wherein said diblock and triblock copolymers are isolated by precipitation using an inert organic solvent.  
   
   
       82 . The process in accordance with  claim 81  wherein said inert organic solvent is selected from the group consisting of diethyl ether, tert-butyl methyl ether, hexane derivatives, heptane derivatives, ethyl acetate, isopropyl acetate, toluene and xylene derivatives.  
   
   
       83 . The process in accordance with  claim 82  wherein at least two inert organic solvents are combined for said precipitation.  
   
   
       84 . The process in accordance with  claim 63  wherein said diblock and triblock copolymers are purified by charcoal treatment.  
   
   
       85 . The process in accordance with  claim 63  wherein said poly(N-vinylpyrrolidone) formed in step (a) has a molecular weight between 1,000 D and 700 kD.  
   
   
       86 . The process in accordance with  claim 63  wherein said diblock and triblock copolymers have a molecular weight between 2,000 D and 700 kD.  
   
   
       87 - 88 . (canceled)  
   
   
       89 . The diblock copolymer prepared by the process of  claim 63 .  
   
   
       90 . The diblock copolymer of  claim 89  wherein said diblock copolymer is poly(N-vinylpyrrolidone)-block-poly (D,L-lactide).  
   
   
       91 . The triblock copolymer prepared by the process of  claim 63 .  
   
   
       92 . The triblock copolymer of  claim 91  wherein said triblock copolymer is poly(D,L-lactide)-block-poly (N-vinylpyrrolidone)-block-poly(D,L-lactide).  
   
   
       93 - 123 . (canceled)