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Preparation and characterization of paclitaxel-loaded poly(d,l-lactide-co-glycolide) microspheres for intra-articular injection Guan, Dechi

Abstract

Paclitaxel has been shown to cause significant regression of existing rheumatoid arthritis and to prevent the induction of collagen-induced arthritis (CIA) in animal models. Paclitaxel suppresses arthritis because rapidly proliferating inflammatory pannus cells in the joint are susceptible to the phase-specific cytotoxic effects of paclitaxel. Intra-articular therapy using anti-inflammatory steroids is used for patients in whom rheumatoid arthritis manifests itself in only a limited number of joints. The objective of the research was to prepare and characterize paclitaxel-loaded microspheres using lactide:glycolide (LA:GA) polymers, which might potentially be suitable for the intra-articular delivery of paclitaxel in arthritis. Paclitaxel-loaded poly(J,/-lactide-co-glycolide) (PLG) microspheres were prepared using the solvent evaporation method. PLG polymers having different compositions of lactide and glycolide as well as having different molecular weights with the same lactide and glycolide composition were chosen to study the influences of these factors on the paclitaxel release rate. The effects of paclitaxel loading in the polymer matrix and the sizes of the microspheres on the paclitaxel in vitro release behavior were also assessed. Paclitaxel was loaded into PLG microspheres with encapsulation efficiencies of over 90% due to the hydrophobicity of the drug. Differential scanning calorimetry (DSC) thermograms indicated that the glass transition temperatures increased with an increase in paclitaxel loading in the PLG matrices, which was believed to be due to an interaction involving the formation of hydrogen bonds between paclitaxel and PLG polymers. X-ray diffraction data showed only the presence of an amorphous matrix, with no evidence by either X-ray diffraction or DSC, of crystalline paclitaxel present in the microspheres matrix. Degradation studies of both control and paclitaxel-loaded microspheres in phosphate buffered saline (PBS) containing albumin at 37°C showed that the molecular weights of P L G microspheres with a 50:50 lactide:glycolide composition decreased rapidly with time. The molecular weights of PLG microspheres with higher lactide content (> 50 mole% of lactide) did not decrease significantly until after 3 weeks of incubation in PBS-albumin. The release profiles of paclitaxel from all PLG microsphere formulations showed a burst phase of release, followed by a phase of relatively steady release. The burst phase was caused by rapid release of paclitaxel from the superficial surface layers of the microspheres. The release rates of paclitaxel from PLG50:50 microspheres were influenced by paclitaxel loading and molecular weights of the PLG50:50 polymers. Increased loading and decreased molecular weight led to faster paclitaxel release rates. PLG microspheres prepared from polymers with LA : GA ratios of 85:15, 75:25 and 65:35 showed that the LA : GA compositions had minimal effect on paclitaxel release rates. The two size ranges of microspheres showed minimal effects on the rates of paclitaxel releases from the microspheres.

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