Recombinant human growth hormone poly(lactic-co-glycolic acid) microsphere formulation development.

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.