Methods for stabilizing biologically active agents encapsulated in biodegradable controlled-release polymers

Abstract

Methods for reducing or inhibiting the irreversible inactivation of water-soluble biologically active agents in biodegradable polymeric delivery systems which are designed to release such agents over a prolonged period of time, such as PLGA delivery systems are provided. The method comprises preparing PLGA delivery systems whose microclimate, i.e. the pores where the active agent resides, uniformly or homogenously maintain a pH of between 3 and 9, preferably between 4 and 8, more preferably between 5 and 7.5 during biodegradation. Depending on the size of the delivery system, and the initial bulk permeability of the polymer, this result is achieved by (a) incorporating a water-soluble carrier into the delivery system, (b) incorporating a select basic additive (or antacid) into the delivery system, (c) incorporating both a water soluble carrier and a select basic additive into the delivery system, (d) adding a pore forming molecule for increasing the rate of release of low molecular weight monomers and oligomers into the delivery system, (e) using a PLGA polymer with reduced glycolide content, i.e. PLGA with from 100% to 75% lactide and 0 to 25% glycolide) (f) using a microencapsulation method that yields a more extensive pore-network, e.g. oil-in-oil emulsion-solvent extraction as opposed to water-in-oil-in water-solvent evaporation method, and (g) combinations thereof.

1 . A method of preparing a biodegradable polymeric delivery system for delivering a biologically active agent to a subject, comprising:
 a) forming a polymer solution comprising a solvent and a poly(lactide-co-glycolide) (PLGA) polymer which comprises from 50 to 100% lactide or lactic acid and from 50% to 0% glycolide or glycolic acid, wherein said lactide or lactic acid is selected from the group consisting of the L isomer, the D isomer, or a D,L racemic mixture;   b) blending a pore-forming agent selected from the group consisting of polyethylene glycol (PEG), poloxamer, and combinations thereof, with the resulting polymer solution of (a) at a level of from 10% to 30% (w/w, pore-forming agent/polymer);   c) dispersing the biologically active agent in the resulting polymer solution of (b); and   d) solidifying the polymer from the resulting polymer solution of (c),   
       wherein the method results in the formation of a polymeric system whose microclimate maintains, without the need for added bases or buffers, a pH of greater than 3 during biodegradation for a period of at least 4 weeks. 
     
     
         2 . The method of  claim 1 , wherein the organic solvent is selected from the group consisting of acetone, methylene chloride, acetonitrile, chloroform, and combinations thereof. 
     
     
         3 . The method of  claim 1 , wherein the amount of pore-forming agent blended with the resulting polymer solution of (a) is from 10 to 20% (w/w, pore-forming agent/polymer). 
     
     
         4 . The method of  claim 1 , wherein the amount of pore-forming agent blended with the resulting polymer solution of (a) is from 20 to 30% (w/w, pore-forming agent/polymer). 
     
     
         5 . The method of  claim 1 , wherein PEG has a molecular weight of from 500 to 30,000. 
     
     
         6 . The method of  claim 1 , wherein PEG has a molecular weight of from 4000 to 10,000. 
     
     
         7 . The method of  claim 1 , wherein the pore-forming agent is a water-soluble poloxamer having a molecular weight of from 500 to 30,000. 
     
     
         8 . The method of  claim 1 , wherein the poloxamer has a molecular weight of from 4000 to 10,000. 
     
     
         9 . The method of  claim 1 , wherein the polymer comprises 100% lactic acid or lactide and wherein the amount of PEG blended with the resulting polymer solution of (a) is from 10 to 20% (w/w, PEG/polymer). 
     
     
         10 . The method of  claim 1 , wherein the microclimate of the resulting biodegradable polymeric system maintains a pH of from 3 to 5 during biodegradation.