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Paclitaxel-loaded microspheres incorporated into chitosan and hyaluronic acid films for prevention of post-surgical adhesions Wang, Jin Fang


Post-surgical adhesions are abnormal attachments between tissues or organs, which frequently occur following surgical trauma. They are currently treated using either barriers or drugs. In this work, drug-loaded barriers were developed using paclitaxel as a drug and chitosan and hyaluronic acid (HA) as film matrices. Our novel approach was to disperse paclitaxel-loaded poly (L-lactic acid) (PLLA) microspheres in chitosan and crosslinked HA film matrices (hydrogel systems) to avoid the precipitation of hydrophobic paclitaxel in hydrophilic hydrogel matrices. Microspheres were prepared using low molecular weight (2k g/mol) PLLA and employing the solvent evaporation method. Paclitaxel-loaded microspheres possessed higher than theoretical drug content due to the water-soluble component of PLLA diffusing into the aqueous phase during microsphere preparation. Differential scanning calorimetry (DSC) scans showed that compared to control microspheres, the glass transition temperature increased by 7 °C for 10% paclitaxel-loaded microspheres. The melting temperature of PLLA microspheres decreased as paclitaxel loading increased, with a decrease of 7 °C for 25% paclitaxel-loaded microspheres. This is evidence that the paclitaxel was miscible with PLLA in the microspheres. Microsphere-loaded films were prepared by dispersing the microspheres in chitosan and HA solutions using 0.01% polysorbate 80. The HA was crosslinked using 1- ethyl-3-(3-dimethyl amino-propyl) carbodiimide hydrochloride (EDAC) and the cast films were dried at room temperature. SEM micrographs revealed uniform dispersion and no aggregates of the microspheres in the film matrices. Degradation studies were carried out in phosphate buffered saline with albumin (PBS-A), pH 7.4 at 37 °C. The increased retention time of PLLA in microspheres with incubation in PBS-A on gel permeation chromatography (GPC) indicated the decrease in MW and shortening of polymer chains due to hydrolysis. The erosion of both PLLA microspheres alone and microsphere-loaded film matrices started after 2-4 hours incubation in PBS-A as shown by SEM data. In vitro release of paclitaxel from PLLA microspheres was biphasic. An initial rapid phase of release was likely due to the diffusional release of paclitaxel from the superficial surface region of the microspheres. The slower phase of release may be due to the increased crystallinity of the matrix, with slower water uptake, decreased paclitaxel diffusivity and decreased degradation rate. The release of paclitaxel from the film matrices involved the release of paclitaxel from PLLA microspheres and then diffusion through film matrices to the external medium. For both microspheres and film matrices containing microspheres, increased drug loading led to a faster release rate and an increased extent of release. This work demonstrated that by dispersing paclitaxel-loaded microspheres in chitosan and HA films, elegant formulations could be achieved in which there was a uniform dispersion of paclitaxel through the film matrices. The hydrogel films exerted a small controlling effect on the release of paclitaxel from microsphere-loaded film matrices.

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