Macromolecular Drug Release from Porous Implants: Sources of Matrix Tortuosity

Release of the highly water-soluble proteins Bovine Serum Albumin (BSA), -lactoglobulin and lysozyme chloride from ethylene-vinyl acetate copolymer (EVAc) matrices was studied at three drug powder particle sizes and ten drug loadings. It was found that at small particles and low loadings, much of the BSA is virtually trapped inside the matrix. Even at higher loadings and particle sizes, where all drug was released, the release rate was orders of magnitude slower than would be predicted for diffusion through waterfilled channels, which have previously been shown to be the conduits for drug release. For the two smaller particle sizes it was found that as loading increases, a sharp transition occurs in the total fraction of releasable drug. This transition is similar to other transitions that are described by percolation theory. A percolation-type model was applied to the data, with qualitative agreement but quantitative disagreement. It was conjectured that the differences are due to inhomogeneities in the drug particle distribution in the matrices. Three possible mechanisms of retardation of drug release were studied theoretically. It was shown that neither the concentration dependence of the diffusion coefficient of proteins nor the random pore topology are sufficient to account for the slowness of release. However, it was shown that constricted throats connecting pores, which have previously been identified by scanning electron microscopy, can account for the retardation of release. The constricted throats are much larger in diameter than the protein molecules, so the retardation is not due to sieving or hydrodynamic effects. Rather, the constricted throats make it more difficult for diffusing molecules to find their way out of pores.