RECOMBINANT HUMAN GROWTH-HORMONE POLY(LACTIC-CO-GLYCOLIC ACID) MICROSPHERE FORMULATION DEVELOPMENT

The development of a sustained release formulation of recombinant huma n growth hormone (rhGH) has focused on a depot preparation using the b iodegradable polymer, poly(lactic-co-glycolic acid) (PLGA), for micros phere production. These formulations have been designed to assure the maintenance of protein integrity both during the microencapsulation pr ocess and upon subsequent release in vitro and in vivo. In addition, a nimal models were developed to assess both the in vivo release kinetic s and the potency of the released protein. These studies emphasized th e importance of obtaining a correlation between the in vivo and in vit ro release at an early stage of development. Juvenile rhesus monkey st udies revealed that continuous rhGH administration resulted in a great er total insulin-like growth factor-I (IGF-I) response than daily rhGH administration, indicating that a continuous rhGH dose may provide co mparable efficacy to daily dosing at a lower total dose of rhGH. The u se of a conventional water-in-oil-in-water process yielded a triphasic release of biologically active and non-immunogenic rhGH, while the no vel cryogenic process achieved a continuous release of rhGH that is bi ologically active and non-immunogenic. The rhGH PLGA formulation produ ced 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 futur e development of PLGA formulations for therapeutic proteins. (C) 1997 Elsevier Science B.V.