Poly(Lactide-co-Glycolide) in Controlled-Release Pharmaceuticals - Release Mechanisms

Abstract: Controlled-release formulations reduce the frequency of injections and better maintain plasma concentrations within the therapeutic window. Poly(D,L-lactide-co-glycolide) (PLG) is currently the most frequently used biodegradable polymer for this application. In order to be able to control the release rate, it is vital to know the underlying release mechanisms. A novel method for measuring the diffusion of proteins and other substances through PLG films was developed. Size-exclusion effects were seen when studying the simultaneous diffusion of human growth hormone and glucose through the PLG films. Divalent cations in the in vitro buffer, especially zinc cations, increased the rate of pore formation in PLG films. Encapsulated zinc acetate increased the effective diffusion coefficient of lysozyme through PLG films. The pore forming effect was probably due to Lewis-acid-catalyzed hydrolysis. Pore closure was increased in an in vitro buffer with low pH, when using a low-Mw PLG with a relatively low degree of hydrophobicity, or at high temperature. Pore closure may have been caused by: (i) polymer–polymer interactions driven by the hydrophobic effect, causing separation from water and rearrangement of the polymer chains, or (ii) polymer–water interactions that led to a more homogeneously swollen polymer mass, instead of distinct regions of polymer and pores. Polymer chain mobility is important in both cases. The highest porosity of PLG films was found at pH 5–6, probably due to rapid pore closure below and above these values and due to relatively rapid hydrolysis in this slightly acidic environment. The pH may be low during drug release due to acidic polymer degradation products and inflammatory reactions. Studies based on diffusion measurements, confocal microscopy, and scanning electron microscopy suggest that there may be considerable transport resistance inside the polymer matrix during the first stage of degradation, while the most significant transport resistance is at the surface at a later stage. Release mechanisms and processes that have been reported to govern drug release were analyzed and discussed in a review article. Diffusion through water-filled pores is the most common way in which a drug is released (in this thesis called a true release mechanism). Several processes have been found to determine the rate of drug release. Drug release is often preceded by a chain of processes, and the dominant process may change with time and space, and when a parameter is altered. This provides many ways of modifying drug release and solving specific problems during pharmaceutical development.