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

A method of preparing a biodegradable polymeric delivery system for delivering a biologically active agent to a subject, wherein the biodegradable polymeric delivery system maintains a pH of greater than 3 during biodegradation of the polymeric delivery system over a period of 4 weeks, comprising:

• a) forming a polymer solution comprising a solvent and a biodegradable polymer which produces acids during biodegradation;
• b) dispersing the agent in the polymer solution;
• c) dispersing one or more basic additives selected from the group consisting of magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, zinc carbonate, zinc hydroxide, zinc phosphate, aluminum hydroxide, basic aluminum carbonate, dihyroxyaluminum sodium carbonate, dihydroxyaluminum aminoacetate, calcium phosphate, calcium carbonate, magaldrate in the polymer solution;
• and
• d) solidifying the polymer from the resulting polymer solution to provide a biodegradable polymeric system whose microclimate maintains a pH of greater than 3 during biodegradation of the polymeric system for at least 4 weeks.

A biodegradable polymeric delivery system for delivering biologically active agents encapsulated therein to a subject, wherein the biodegradable polymeric delivery system maintains a pH of greater than 3 during biodegradation of the polymeric delivery system over a period of 4 weeks, wherein said delivery system comprises

• a) a PLGA polymer
• b) from 0.5% to 20% by weight of a composition which comprises the agent or a combination of the agent and a carrier;
• and
• c) from 0.5% to 20% by weight of one or more basic additives selected from the group consisting of magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, zinc carbonate, zinc hydroxide, zinc phosphate, aluminum hydroxide, basic aluminum carbonate, dihydroxyaluminum sodium carbonate, dihydroxyaluminum aminoacetate, calcium phosphate, calcium hydroxide, magaldrate;
• and
• d) a microclimate which maintains a pH of greater than 3 during biodegradation of the polymeric delivery system for a period of 4 weeks.

A method of preparing a biodegradable polymeric delivery system for delivering a biologically active agent to a subject, wherein the biodegradable polymeric delivery system is capable of stabilizing BSA encapsulated therein during biodegradation of the polymeric delivery system over a period of 4 weeks, comprising:

• a) forming a polymer solution comprising a solvent and a biodegradable polymer which produces acid during biodegradation;
• b) optionally blending from 10% to 30% of a pore-forming agent with the polymer solution of step (a);
• c) dispersing from 0.5% to 20% (w/w) of a basic additive wherein the basic additive has a solubility in water of from about 1.24×10−13 to about 3.16×10−3 and a pH of about 6.82 to about 9.76 for a saturated aqueous solution, in the polymer solution;
• d) dispersing from 0.1% to 20% (w/w) of a composition comprising the agent or the agent plus carrier in the polymer solution;
• and
• e) solidifying the polymer from the resulting polymer solution to provide a biodegradable polymeric system wherein less than 15% of the total BSA in the polymer forms insoluble aggregates after incubation in physiological buffer at 37° C. for 4 weeks.