Development of a novel sustained release formulation of recombinant human growth hormone using sodium hyaluronate microparticles

Abstract

A novel sustained release formulation of recombinant human growth hormone (SR-rhGH) was developed as a once-a-week injection formulation using sodium hyaluronate. SR-rhGH was produced in the form of solid microparticles by spray drying technology. A single administration of a prototype formulation of SR-rhGH with a ratio of hGH:HA=1:1 to cynomolgus monkeys through a fine 26-gauge needle induced continuous elevation of serum IGF-I level for 6 days demonstrating the bioactivity of hGH released from the prototype formulation. For expanded pre-clinical and clinical developments, a pilot-scale process under aseptic condition was established and used for the preparation of the optimized formulation of SR-rhGH with a ratio of hGH:HA=1:3. When the ratio of hGH to HA changed from 1:1 to 1:3, hGH released more slowly in vitro from SR-rhGH with almost complete release of hGH loaded. According to pharmacokinetic and pharmacodynamic studies in beagle dogs, sustained release of hGH from the optimized formulation of SR-rhGH continued for a more extended period longer than 72 h with a lower C(max) than those of prototype formulations. The single administration resulted in an elevation of serum insulin-like growth factor-I (IGF-I) level for 6 days with a maximum value higher than the baseline level by ca. 350 ng/mL, which supported the possibility of SR-rhGH as a once-a-week injection formulation of hGH. The bioavailability of both formulations was comparable to that of hGH daily injection formulation. Finally, toxicity studies revealed no evidence of adverse effect in both cynomolgus monkeys and beagle dogs.