RESUMO
The development of a sustained release formulation of recombinant human growth hormone (rhGH) has focused on a depot preparation using the biodegradable polymer, poly(lactic-co-glycolic acid) (PLGA), for microsphere production. These formulations have been designed to assure the maintenance of protein integrity both during the microencapsulation process and upon subsequent release in vitro and in vivo. In addition, animal models were developed to assess both the in vivo release kinetics and the potency of the released protein. These studies emphasized the importance of obtaining a correlation between the in vivo and in vitro release at an early stage of development. Juvenile rhesus monkey studies revealed that continuous rhGH administration resulted in a greater total insulin-like growth factor-I (IGF-I) response than daily rhGH administration, indicating that a continuous rhGH dose may provide comparable efficacy to daily dosing at a lower total dose of rhGH. The use of a conventional water-in-oil-in-water process yielded a triphasic release of biologically active and non-immunogenic rhGH, while the novel cryogenic process achieved a continuous release of rhGH that is biologically active and non-immunogenic. The rhGH PLGA formulation produced by the novel cryogenic process was manufactured under aseptic GMP conditions and was shown to be safe in growth hormone-deficient adults. This protein and these studies should serve as a model for the future development of PLGA formulations for therapeutic proteins.
RESUMO
Polymer microspheres have shown great potential as a next generation adjuvant to replace or complement existing aluminum salts for vaccine potentiation. Microsphere-based systems can now be made to deliver subunit protein and peptide antigens in their native form in a continuous or pulsatile fashion for periods of weeks to months with reliable and reproducible kinetics, often obviating the need for booster immunizations in animal models. Microspheres have also shown potential as carriers for oral vaccine delivery due to their protective effects on encapsulated antigens and their ability to be taken up by the Peyer's patches in the intestine. The potency of these optimal depot formulations for antigen may be enhanced by the co-delivery of vaccine adjuvants, including cytokines, that are either entrapped in the polymer matrix or, alternatively, incorporated into the backbone of the polymer itself and released concomitantly with antigen as the polymer degrades. In this article we review the use of polymer microspheres for single-step immunization and discuss future applications for the improvement of vaccines and immunotherapies by utilizing encapsulation technology.
