Kendall, Richard Andrew; (2007) Novel pH-sensitive microparticles for site-specific drug delivery to the gastrointestinal tract. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Conventional delayed release formulations which utilise pH-sensitive polymers, and take advantage of the aboral increase in gastrointestinal pH, to deliver drugs to either the small intestine or colonic region often suffer from poor site-specificity of drug release in man. This has been attributed to physiological factors including gastrointestinal transit times, pH and free fluid volume within the lumen of the gastrointestinal tract. pH-sensitive microparticles are expected to offer improved gastrointestinal transit and control of drug release compared to conventional delayed release dosage forms. The aim of this study was to formulate pH-sensitive microparticles to target different regions of the gastrointestinal tract, and to characterise the resulting microparticles both in vitro and in vivo. The emulsification/solvent evaporation technique was successfully optimised for the production of Eudragit L55 and L microparticles for small intestinal targeting, and Eudragit S microparticles for colonic targeting. Optimised microparticles were observed by scanning electron microscopy to be spherical and monodisperse, in the size range 30-50μm. Eudragit L55 microparticles aggregated in acidic media during in vitro dissolution testing, which was thought to be due to the low glass transition temperature of the polymer. However, Eudragit L and S microparticles suspended freely without aggregation, and retarded release of a model drug, prednisolone, at acidic pH for a period of two hours, but released it rapidly at small intestinal and colonic pH, respectively, due to the large surface area to volume ratio of the microparticulate dosage forms and, possibly, the amorphous nature of the entrapped prednisolone. To assess the in vivo drug absorption from the microparticulate dosage forms, prednisolone-loaded Eudragit L and S microparticles and a prednisolone control suspension were administered orally to rats which were bled over a period of 8 hours. A faster Tmax was achieved with Eudragit L microparticles than with control suspension due to the release of drug in a presolubilised form, close to the absorption window of prednisolone in the small intestine. The relative bioavailability of prednisolone-loaded Eudragit S microparticles was 0.35 compared to the prednisolone suspension. This suggests that drug absorption was incomplete from the Eudragit S microparticles, which was possibly due to the limited fluid volumes in the gastrointestinal tract, demonstrating the limited usefulness of the rat as a model for man.

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