Controlled release of insulin from polyester and polyanhydride microspheres

All type I diabetics and many type II diabetics rely on various injectable insulin preparations in order to maintain their physiological insulin levels. The objective of this study was to develop a delivery system based on polyester and polyanhydride microspheres to provide basal insulin levels for one month after a single subcutaneous injection. We hypothesized that the insulin hexamer formation by self association of insulin monomers in the presence of metal ions should reduce the initial burst, modify the release rate from polymeric microspheres, and increase the stability of insulin.;Poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with insulin showed a high initial burst release followed by a slow and incomplete release in vitro. Addition of a zinc salt to insulin significantly improved encapsulation efficiencies, decreased initial bursts, altered release rates, and stabilized insulin. Subcutaneous injection of PLGA microspheres in rats controlled insulin release for 14 days. To obtain a more prolonged release, two polyanhydride copolymers, poly 1,3-bis-(p-carboxyphenoxy) propane-co-sebacic acid (p(CPP:SA)) and poly 1,6-bis-(p-carboxyphenoxy) hexane-co-sebacic acid (p(CPH:SA)), were synthesized, characterized, and used in the fabrication of microspheres. Increased hydrophobic content increased encapsulation efficiency, decreased initial bursts, and led to the formation of dimer aggregates during in vitro release. Addition of a zinc salt improved insulin stability and prevented the formation of dimer aggregates. Both CPP:SA and CPH:SA microspheres controlled insulin release over a month in vivo.;The effects of a zinc salt on the conformational stability of insulin during primary emulsification at different homogenization speeds were investigated. Presence of a zinc salt was found to improve the conformational stability of insulin and increased insulin recovery from the primary emulsion. To further increase encapsulation efficiencies and decrease initial bursts of insulin from PLGA microspheres, the influence of formulation factors, such as increased water/oil ratio, increased fabrication temperature, co-encapsulation of an additive, and polymer blends of different molecular weights, was investigated. PLGA microspheres prepared by increasing the water/oil ratio markedly increased encapsulation efficiency and showed the lowest initial burst. In conclusion, this work demonstrates that polyester- and polyanhydride-based microspheres are attractive systems for the controlled delivery of insulin.