Biodegradable PLGA microparticles for sustained release of a new GnRH antagonist: part II. In vivo performance.

Poly (DL-lactide-co-glycolide) microparticles (MP) containing a highly potent peptidic gonadotropin releasing hormone antagonist (degarelix) of interest in the prostate cancer indication were screened for biological performance. Efficacy was tested in a castrated male rat model at 3 doses (0.4, 1.0 and 1.5 mg/kg) and assessed as inhibition of luteinizing hormone (LH) secretion. When increasing the dose, onset of inhibition was faster, inhibition was more intense, and duration of action was prolonged. The MP type was also highly influent. If spray-dried and microextrusion particles exhibited comparable potencies, double emulsion microspheres were significantly less potent, both for onset and duration of inhibition. Interestingly, for the latter type it was found that the degarelix fraction released upon reconstitution in the solution for injection was significantly lower (max 0.3%), in comparison to spray-dried MP (max 2%) or microextrusion (max 4%). With the three types of particles, increasing peptide content was detrimental for duration of action, but only little difference was noticed between particles based on different polymers. At 1.5 mg/kg, LH inhibition was achieved over 36 days with spray-dried MP based on 75/25 lactate/glycolate copolymer. This was superior by 1 week to the performance of unformulated degarelix given at the same dose.