Engineering polymethacrylic microparticles for oral drug delivery

pH responsive microparticles provide a valid alternative to conventional modified release systems for site-specific drug delivery. However, there is a lack of fundamental science in this area which hinders further development and commercialization of this platform technology. The aim of this work was to investigate the utility of a novel pH responsive microparticle technology prepared by the emulsion solvent evaporation process. Specifically, we endeavoured to explore the gastric resistance of enteric microparticles, to tailor drug release in intestinal conditions, to study the rate of solvent evaporation during particle formation, drug-polymer interactions and a potential in vivo application, and to develop an alternative approach for preparing microparticles using spray drying.;Drug tendency to crystallization during microparticle formation was investigated through thermal analysis and FTIR and was found to be directly related to drug: polymer ratio, drug solubility in the inner phase and the nature of the polymer. Moreover, the determination of glass transition temperature and measurement of crystallization inhibition after melt-quenching suggested that drug-polymer interaction might have inhibited drug crystallization.;The in vivo performance of this microparticle system was investigated in Wistar rats. The poorly soluble basic drug, cinnarizine, was successfully encapsulated into Eudragit L microparticles. The suspension of these microparticles and a suspension of the drug for comparison purposes were orally dosed to the rats (n=5). The oral bioavailability of the cinnarizine loaded Eudragit L microparticles was over 2-fold higher than that of the cinnarizine suspension (p<0.05), hence demonstrating the potential of this technology to enhance the bioavailability of poorly soluble basic drugs.;As an attempt to substitute the evaporation process used above, a novel method to produce enteric microparticles from aqueous solutions through spray drying was reported. Spherical microparticles were successfully fabricated; Eudragit S and Eudragit L microparticles showed significant gastric resistance of drug release. Upon changing the pH to intestinal values, rapid and complete drug release was reported from both sets of microparticles. The development of this novel aqueous based microparticle system can offer obvious economic and environmental advantages.;A library of nine drugs with different physicochemical properties was incorporated into methacrylic (Eudragit S and Eudragit L) microparticles (drug: Eudragit ratio 1:10). The microparticles had the desirable properties of spherical morphology, smooth surface, small particle size (< 100m) and a uniform size distribution. Drug molecular weight was deemed more important than drug acid solubility in controlling drug release in gastric conditions and a minimum molecular weight threshold of 300 Da was necessary to meet USP requirements for delayed release formulations. To favour better local treatment in the distal intestine, extended drug release is preferred to an immediate burst effect. Therefore, pH dependant and pH independent polymers were blended into microparticles. Thermal analysis and confocal laser scanning microscopy was used to study the distributions and interactions of these polymers within the microparticle and correlated to the pattern of in vitro drug release.