Formulation of controlled-release delivery systems for the alpha-melanocyte stimulating hormone analog, Melanotan-I

Abstract

The overall objective of this research was to develop controlled-release formulations of Melanotan-I (MT-I). Two polymers were used, Poloxamer 407 (P407) and Poly(D,L lactide-co-glycolide) (PLGA). First, various aqueous formulations of P407 were evaluated containing MT-I and 25% w/v P407 alone, or with one of the following additives present, i.e., polyvinylpyrrolidone, methylcellulose or hydroxypropyl methylcellulose. The in-vitro release profiles of MT-I from the P407 formulations and the dissolution of the gel were obtained simultaneously using a membraneless in vitro model and a zero-order profile was observed for both. The in-vivo release kinetics of selected formulations were analyzed in guinea pigs following intraperitoneal administration. The plasma concentration-time profiles showed an extended release of the peptide formulated with gel compared to the interperitoneal administration of MT-I in solution and exhibited potential for prolonged release up to 24 hrs only. Biodegradable implants of PLGA copolymer were prepared by a melt-extrusion method. The in vitro release of MT-I from the implants exhibited a triphasic profile with an initial rapid release followed by a secondary phase of slow release, then a tertiary phase of rapid release due to erosion of the polymer. Based on release kinetics of MT-I from different viscosity PLGA implants, the polymer having a viscosity of 0.6 dL/gm was selected for preparing an implant system with a one-month duration of release. Molecular weight reduction, mass loss and lactic acid release from PLGA implants were characterized in order to correlate the in vitro release profile of MT-I with hydrolytic degradation of the polymer. The in vivo release profile of the MT-I depot implanted subcutaneously exhibited a one-month release of the peptide and the reflectance reading obtained from a reflectometer showed a prolonged skin darkening for 3 months. A 2.5 fold increase in the melanin pigment (eumelanin) was observed in guinea pig skin biopsy samples. The results indicate that the PLGA implants are a promising delivery device for controlled-release of MT-I over a one-month period.