Sustained Delivery of Dexamethasone from Thermo–responsive Poly(VPAVG) Microparticles

Abstract

Abstract: : Purpose: The aim of this work was to prepare and characterize microparticles of a thermo–responsive poly (Val–Pro–Al–Val–Gly) loaded with dexamethasone phosphate for intraocular administration. This elastin–like polymer is biocompatible and shows the so called "inverse temperature transition" (ITt). Methods: The microparticles were prepared from a solution of poly(VPAVG) in phosphate buffer solution pH7.4 (PBS) containing dexamethasone phosphate (DMP) (10mg/ml). Two polymer concentrations were assayed: 20mg/ml and 30mg/ml. Particles were formed by self–aggregation of the polymer by first cooling the solution at 4ºC and then heating at a temperature of 37ºC just over the ITt (30.7ºC). Particle size and size distributions were evaluated by photon correlation spectroscopy. In vitro release studies were carried out at 37ºC under constant agitation of suspensions of 10mg of microparticles in 1.8ml (sink conditions) of PBS. Periodically the samples were centrifuged (18000xg for 45 min at 33ºC) and then the supernatant fractions were removed at pre–determined times (0, 1, 6h and 1,7,14,21, 28 and 35 days). DMP concentrations were quantified spectrophtotometrically by measuring their absorbances at 242nm. The same volume of fresh medium was replaced to continue the release study. Cell viability assays were carried out for particles loaded with DMP and without drug, after their incubation for 16 hours. Results: The self–assembled poly(VPAVG) microparticles loaded with dexamethasone phosphate resulted in sizes lower than 3µm, releasing the drug up to 35 days . The concentration of the polymer conditioned the initial burst that resulted in 64.86% and 75.96% of the encapsulated drug for poly (VPAVG) concentrations of 30mg/ml and 20mg/ml respectively. At the end of the assay both formulations of microparticles had released almost 100% of the encapsulated drug. The microparticles did not induced cytotoxicity in peritoneal macrophages. Conclusions: The self–assembled poly(VPAVG) microparticles loaded with dexamethasone phosphate provided an in vitro sustained release of the drug up to 35 days. The formulation selected for its administration in an animal model corresponds to an initial poly (VPAVG) concentration of 30mg/ml. Supported by MCyT Grant (MAT2000–1764–C02–01)

Keywords: vitreous • corticosteroids • pharmacology