| Summary: | 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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