Πολυμερικά συστήματα ελεγχόμενης αποδέσμευσης

Abstract

This study focuses on the physical and chemical properties of the matrix controlled release (MCR) devices in which drug release is activated by the ingress of solvent (water) and is controlled by swelling of the polymer (swelling controlled systems). We also examine the possibility of designing a novel system of polymer matrix containing both the drug and a contrast agent used in clinical MR imaging. The purpose of this work is to achieve simultaneous release and an equal delivery rate. This work also aims at contributing to the optimization of the design of these systems, with the following main objectives: the experimental study of a typical model system composed of a polymer matrix, the active ingredient, and water, focusing on understanding the mechanisms which control the functioning of the system and simulation of the kinetics of drug release and concurrent water sorption on the basis of a theoretical model previously developed in our lab. We chose to use poly(vinyl alcohol) [PVA] due to its low toxicity, biocompatibility and a wide range of biomedical applications. As an active ingredient we chose a model drug –diphylline– and Gd-DTPA, a widely used contrast agent. The first step was to examine the effect of thermal treatment on the polymer properties using DSC and water sorption experiments. Heat treatment (at 130oC for 20 min) results in increase of crystallinity of the polymer matrix and dramatic reduction of the water sorption capacity. Moreover, the solubility of the polymer matrix in water is significantly reduced. The transport parameters of water were determined by application of a model taking into account the coupling of the diffusion process with the relaxation of the swelling glassy polymer matrix. The deduced values of water diffusion coefficients DW and βW, indicate a variation with heat treatment.. The release kinetics of diphylline from dry matrices was studied at drug loadings 1–40% by wt. In all cases deviations from Fickian release kinetics, were observed (i.e. sigmoidal curves in plots vs. t1/2, while the release rate remains constant for a prolonged time period), as expected from the fact that solute release occurs at comparable time scales with the ingress of water in the matrix. By increasing the initial content of the drug the release rate was accelerated due to plasticization of the polymer. It was also observed that increase of the initial amount of the drug leads to an increase of the water imbibition rate. Moreover, the increase on the experiment’s temperature from 25o to 37oC led to the anticipated acceleration of the release kinetics without, on the other hand, materially affecting the release rate. It should also be noted that at high drug loadings, microscopic cracks were observed attributable to differential swelling stresses caused by excessive polymer swelling. Comparison of the release kinetics from Gd-DTPA-loaded, and from diphylline-loaded, matrices indicates that the two solutes are released at comparable time scales, in line with the similar diffusion coefficients and the rate of release is relatively stable for more than 50% of the loaded drug. Release of diphylline from PVA is accelerated, in the presence of Gd-DTPA in the matrix, probably due to enhanced hydration of the matrix in this case. DSC analysis of the dry matrices indicated that the incorporation of Gd- DTPA does not materially affect the crystallinity of PVA, nor it has a plasticizing effect through reduction of the Tg of the polymer. Thus, the observed acceleration of diphylline release could be possibly due to enhanced hydration of the matrix. The computer simulation study of diphylline release from dry PVA matrices was highly successful considering that it proved possible to simulate closely the kinetics of both drug release and concurrent water uptake. Values of the relevant input model parameters were derived from independent experimental measurements of the sorption and diffusion properties of drug and water, performed in the present work.