title: Lipid microparticles as sustained release system for a GnRH antagonist (Antide).
abstract: Lipid microparticles (LMs) as a sustained release system for a gonadotropin release hormone (GnRH) antagonist (Antide) were prepared and evaluated. Antide loaded microparticles (Antide-LMs) were obtained by a cryogenic micronization process starting from two different monoglycerides (glyceryl monobehenate and glyceryl monostearate) and using two different incorporation methods (co-melting and solvent evaporation). Antide-LMs, 2% (w/w) loading, were characterized for drug incorporation by RP-HPLC, particle size by laser diffractometry and surface morphology by scanning electron microscopy. In vitro peptide release and in vitro biological activity were also studied. Serum Antide and testosterone levels, as pharmacodynamic marker, were assessed following subcutaneous administration in rats. Antide-LMs showed a mean diameter of approximately 30 micro m and variable Antide release depending on lipid matrix and incorporation method. In vivo experiments demonstrated that detectable Antide plasma levels were present, in the case of Antide-LMs based on Compritol E ATO obtained by co-melting procedure, for at least 30 days after dosing. Testosterone levels were consistent with prolonged pharmacokinetic profiles. In vitro release of Antide from LMs correlated well with the in vivo release. In conclusion, LMs can sustain the release of Antide for at least 1 month. The levels of the initial 'burst' and the extent of the pharmacodynamic effect can be influenced by the lipid characteristics and by process conditions.
authors.affiliation: Industria Farmaceutica Serono, Drug Delivery Systems, BioIndustry Park, via Ribes 5, I-10010 Colleretto Giacosa, Turin, Italy. mariadorly.delcurto@serono.com
authors.forename: M D
authors.initials: MD
authors.lastname: Del Curto
authors.forename: D
authors.initials: D
authors.lastname: Chicco
authors.forename: M
authors.initials: M
authors.lastname: D'Antonio
authors.forename: V
authors.initials: V
authors.lastname: Ciolli
authors.forename: H
authors.initials: H
authors.lastname: Dannan
authors.forename: S
authors.initials: S
authors.lastname: D'Urso
authors.forename: B
authors.initials: B
authors.lastname: Neuteboom
authors.forename: S
authors.initials: S
authors.lastname: Pompili
authors.forename: S
authors.initials: S
authors.lastname: Schiesaro
authors.forename: P
authors.initials: P
authors.lastname: Esposito
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006727:Hormone Antagonists / Q000493:pharmacokinetics*; D008297:Male; D008863:Microspheres; D009842:Oligopeptides / Q000493:pharmacokinetics*; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003692:Delayed-Action Preparations; D006727:Hormone Antagonists; D009842:Oligopeptides; D007987:Gonadotropin-Releasing Hormone; C057022:iturelix