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 a 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.