Mechanisms of Isoniazid Release from Poly(d,I-lactide-co-glycolide) Matrices Prepared by Dry-Mixing and Low Density Polymeric Foam Methods

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Abstract
The release mechanisms of a small molecular drug from biodegradable poly(d,l-lactide-co-glycolide) (PLGA) cylindrical matrices were investigated. Isoniazid (INH), one of the most effective drugs against tuberculosis (TB), was selected as the model drug. Controlled-release matrices consisting of the drug and polymer were fabricated by two methods. The first of these, the dry-mixing method, involved the extrusion of a mixture of micronized drug and polymer particles as rods. In the second technique, the low density polymeric foam method, drug particles were enclosed in the cells of porous polymeric foams prior to extrusion. In vitro, the dry-mixed matrices released INH more rapidly than the polymeric foam matrices. The Roseman-Higuchi diffusion model, which had previously been found to be effective in analyzing the release kinetics of INH from the dry-mixed matrices, also fit the kinetics of INH released from matrices prepared from polymeric foams. This indicated that the release was still diffusion-controlled rather than degradation-controlled. The release mechanisms were further investigated, and two diffusion mechanisms, pore diffusion and lattice diffusion, were proposed for the INH controlled-release matrices according to the way in which they were prepared. Matrices prepared by the dry-mixing method appear to segregate drug particles along polymer grain boundaries and thus have a pore diffusion mechanism, while matrices prepared by the foam method entrap drug within the porous structure of foams and thus display a lattice diffusion mechanism. Theoretically, these two diffusion mechanisms can be identified by their activation energies for diffusion. With varying in vitro temperature, the activation energies were calculated from plots of ln (DIT) vs T-1 and in D vs T-1, where D is the diffusivity and T is the in vitro temperature in K. According to the results, we concluded that the INH from the dry-mixed matrices diffused through the drug channels filled with the medium, while the INH from the foam matrices diffused through the polymer lattice.