IN-VIVO CHARACTERIZATION OF SUSTAINED-RELEASE FORMULATIONS OF HUMAN GROWTH-HORMONE

Long-acting formulations of recombinant human growth hormone (rhGH) we re prepared by stabilizing and encapsulating the protein into three di fferent injectable, biodegradable microsphere formulations composed of polymers of lactic and glycolic acid. The formulations were compared in juvenile rhesus monkeys by measuring the serum levels of rhGH and t wo proteins induced by hGH, insulin-like growth factor-I and IGF bindi ng protein-3 (IGFBP-3) after single s.c. administration. All three for mulations, which differed principally in the composition of the polyme r, provided sustained elevated levels of all three proteins for severa l weeks, and the rate of release of rhGH differed among the formulatio ns consistent with the molecular weight of the polymer used. All three formulations induced a higher level of insulin-like growth factor-I a nd insulin-like growth factor binding protein than was induced by dail y injections of the same amount of rhGH in solution. After three month ly injections of one of the formulations, both the rhGH and IGF-I leve ls remained elevated for nearly 90 days. Immunogenicity of the rhGH re leased from this formulation, as assessed by the incidence of seroconv ersion to hGH and the titer of anti-hGH antibody in both the rhesus mo nkeys and transgenic mice expressing rhGH, was no greater than that of the unencapsulated protein. In addition, the microsphere injection si tes appeared normal by macroscopic evaluation between 1 to 2 mo after microsphere administration and by microscopic evaluation between 2 to 3 mo. These results show that serum levels of a therapeutic protein ca n be sustained for an extended period when encapsulated into different formulations of injectable, biodegradable microspheres.