Controlled release of U-86983 from double-layer biodegradable matrices: effect of additives on release mechanism and kinetics

Abstract

Effects of additives on the drug release kinetics from biodegradable matrices is an important determinant in designing a drug delivery system. These experiments introduced the influence of an array of additives on the drug release from double-layered poly(lactic-co-glycolic acid) (PLGA) matrices. Various additives such as l-tartaric acid dimethyl ester (DMT), Pluronic® F127 (F127); 2-hydroxypropyl derivative of β-cyclodextrin (HPB), methyl derivative of β-cyclodextrin (MMB) and Beeswax (Wax), differing in molecular size, hydrophilicity and steric configuration were selected for this study. An antiproliferative 2-aminochromone, U-86983 (U-86, Pharmacia and Upjohn), was used as a model agent because of our interest in investigating local drug delivery systems for the inhibition of restenosis. The in vitro release of U-86 from PLGA matrices without additive showed a typical biphasic release kinetics, i.e. a slow diffusion release (Phase I) followed by a fast erosion-mediated release (Phase II). The water-soluble additives in PLGA matrices changed the biphasic release pattern to a near monophasic profile by increasing the release rate of the Phase I. Increasing the ratio of additives to PLGA in matrices causes a significant increase in the U-86 release rates. The high molecular weight water-soluble additive, Pluronic® F127, resulted in a matrix showing perfect zero-order release kinetics. The water-soluble cyclodextrin derivative, HPB, gave the highest release rate among all the matrices formulated. A hydrophobic additive, Beeswax, however showed biphasic release kinetics comparable to PLGA control matrices, but delayed the onset of the Phase II by 4 days. The U-86 release profiles were in good agreement with the mass loss profiles of these matrices except for the matrices with F127 and HPB additives. The morphologic evaluation of matrices using scanning electron microscopy indicates that the water-soluble additives are leachable and thus generate a highly porous structure in the matrices. The matrix pore configuration (e.g. interconnected or closed) created with different additives determined the mechanism of drug release kinetics from the various matrix formulations. In conclusion, the feasibility of modulating release rates and kinetics of an agent from PLGA monolithic matrices by utilizing various types of additives is demonstrated. Water-solubility, molecular size and steric configuration of the additives are the important determinants in generating various types of pore structures in polymer matrix which in turn affect the release mechanism and release kinetics.