Slow release protein polymers

Abstract

The invention features articles for delivery of a biologically active substance, methods for making such articles, and methods for treating an animal using the articles.

1 - 10 . (canceled)  
     
     
         11 . A biocompatible therapeutic article comprising, a macromer having polymerized end groups, precipitated insulin, and a molecule or mixture of molecules which preferentially excludes proteins, wherein said molecule or mixture of molecules is present in an amount sufficient to reduce the solubility of said insulin in said article to less than 10 mg/ml.  
     
     
         12 . The biocompatible therapeutic article of claim  1 , wherein said molecule which preferentially excludes proteins is selected from the group consisting of a macromer, poly(ethylene glycol), hyaluronic acid, and poly(vinylpyrrolidone).  
     
     
         13 . The biocompatible therapeutic article of claim  1 , wherein said macromer comprises: 
 (a) a region forming a central core;    (b) at least two degradable regions attached to said core; and    (c) at least two polymerized end groups, wherein said polymerized end groups are attached to said degradable regions.    
     
     
         14 . The biocompatible therapeutic article of claim  3 , wherein said central core comprises a polymer selected from the group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers, polysaccharides, carbohydrates, proteins, and combinations thereof.  
     
     
         15 . The biocompatible therapeutic article of claim  3 , wherein said degradable regions comprise a polymer selected from the group consisting of poly(α-hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(orthocarbonates), and poly(phosphoesters).  
     
     
         16 . The biocompatible therapeutic article of claim  1 , wherein said article comprises at least 5% insulin by dry weight.  
     
     
         17 . The biocompatible therapeutic article of claim  1 , wherein said article comprises at least 10% insulin by dry weight.  
     
     
         18 . The biocompatible therapeutic article of claim  1 , wherein said molecule or mixture of molecules is present in an amount sufficient to reduce the solubility of said insulin in said article to less than 1 mg/ml.  
     
     
         19 . The biocompatible therapeutic article of claim  1 , wherein the time at which 5% of the releasable insulin is released from the article is greater than 1/16 of t 50 .  
     
     
         20 . The biocompatible therapeutic article of claim  1 , wherein said insulin is released from said article such that t 50  is greater than or equal to ⅝ of t 80 .  
     
     
         21 . The biocompatible therapeutic article of claim  1 , wherein said articles release at least 80% of the insulin at a time 11/4 times greater than t 50 .  
     
     
         22 . The biocompatible therapeutic article of claim  1 , wherein said article has a particle size of less than about 75 microns.  
     
     
         23 . The biocompatible therapeutic article of claim  1 , wherein said macromer has a water soluble region comprising poly(ethylene glycol) of about 500 to 20,000 daltons.  
     
     
         24 . The biocompatible therapeutic article of claim  1 , wherein said mixture of molecules comprises a positively charged ion-carrying reagent.  
     
     
         25 . The biocompatible therapeutic article of claim  1 , wherein said mixture of molecules comprises a negatively charged ion-carrying reagent.  
     
     
         26 . The biocompatible therapeutic article of claim  1 , wherein said mixture of molecules comprises a surfactant.  
     
     
         27 . The biocompatible therapeutic article of claim  1 , further comprising a pharmaceutically acceptable excipient.  
     
     
         28 . The biocompatible therapeutic article of  claim 27 , wherein said excipient is a carbohydrate.  
     
     
         29 . The biocompatible therapeutic article of  claim 28 , wherein said carbohydrate is selected from mannitol, sucrose, trehalose, galactose, and lactose.