| The solvent removal method developed in our group was revised to make it possible to fabricate single-phase microspheres from a variety of polymers as well as produce multi-phase microspheres from selected two-polymeric combinations. The microspheres were developed with the final target of releasing anti-cancer agents such as antide, a gonadotropin releasing hormone (GnRH) antagonist, and monoclonal antibodies. The delivery system was optimized by analyzing the effects on protein release made by changes in the particle size, the polymer solution concentration, the polymer ratio in multi-phase microspheres, the protein loading, and the polymer into which the protein was loaded. The non-solvent viscosity and the solvent:non-solvent balance were studied and the viscosity was determined to have less effect on the success of sphere fabrication than the concentration of solvent in the non-solvent mixture. The experimental morphological results of the fabrication of multi-phase microspheres were compared to the theoretical predictions described by the Harkin's equation. The Harkin's equation was found to be invalid in predicting the morphology of microspheres fabricated via the solvent removal method. The in vitro as well as the in vivo degradation processes of poly(L-lactic)acid:poly(fumaric-co-sebacic)anhydride (PLLA:P(FA:SA)) multi-phase microspheres were investigated. The P(FA:SA) phase of the microspheres was found to degrade much faster than the PLLA phase, leaving only some of the sebacic portion of the polymer in addition to other oligomeric fractions after 16 weeks. The method of introduction of the drug was studied to determine the effect of protein infiltration on the initial burst and release profile. Finally, we used the polymeric delivery system to deliver anti-cancer agents in rats. We were able to achieve castration for 11 weeks using 5% loaded antide multi-phase microspheres. The 20% loaded multi-phase microspheres resulted in castration through 49 days. Both of these delivery systems resulted in lower antide dosage per time-point than the subcutaneous antide administration, and lengthened the duration of castration. We obtained fairly constant IgG serum levels through ∼35 days. Maintaining fairly constant drug levels within a specified therapeutic range is advantageous to prevent side effects, which could result from repeated bolus injections of drug. |
