| Summary: | Novel amphiphilic graft copolymers with hydrophilic hydroxypropylcellulose
(HPC) and dextrans (Dx) as main chains and hydrophobic poly(ε-caprolactone) (PCL) as
side chains were synthesized and characterized. Paclitaxel loaded polymeric films based
on these graft copolymers were developed and characterized for the prevention of
surgical adhesions.
Hydroxypropylcellulose-graft-poly(s-caprolactone) (HPC-g-PCL) and dextrangraft-
poly(ε -caprolactone) (Dx-g-PCL) were synthesized via a "graft from" process, in
which the PCL side chains were formed by a ring-opening polymerization of scaprolactone
(CL) initiated by the hydroxyl groups on the main chains of HPC or
dextrans. HPC-g-PCL with a molar substitution of CL (MSCL) in the range of 8.6 to 10.1
was synthesized by bulk polymerization without using any catalyst. Dx-g-PCLs were
synthesized by solution polymerization using dimethyl sulfoxide as a solvent and
stannous 2-ethylhexanoate as a catalyst. Dextrans with two different molecular weights,
70,000 (Dx70) and 500,000 (Dx500), were used as the main chains and the MSCL was
determined to be in the range of 1.2 to 1.3.
The films of the copolymers with or without paclitaxel were cast from
tetrahydrofuran (THF) solutions. Both paclitaxel and the graft copolymers could be
readily dissolved in THF and homogenous film formulations with paclitaxel loading up to
10% (w/w) were obtained. Due to the higher MSCL of HPC-g-PCL, PCL-rich microcrystalline
regions formed in the HPC-g-PCL films. Films of HPC-g-PCL were more
hydrophobic than the Dx-g-PCL films and showed less water uptake and swelling.
Controlled release of paclitaxel from the copolymer films was achieved. An increase in initial paclitaxel loading resulted in an increase in the release rate for all the copolymer
films. At 1% paclitaxel loading, the release rate from the Dx-g-PCL films was
significantly higher than from the HPC-g-PCL films due to increased swelling and
therefore greater diffusion rate of paclitaxel in the Dx-g-PCL matrices. At loadings of 5%
and 10%, crystallization of paclitaxel occurred in the Dx-g-PCL matrices during
incubation in the release media. The onset of this crystallization event led to a reduction
in paclitaxel release rate from the films. At 10% loading, release rates from the Dx-g-
PCL and HPC-g-PCL films were similar.
No significant degradation was detected after the HPC-g-PCL films were
incubated in aqueous media at 37 °C for 3 months and this was considered unsuitable for
a surgical adhesion formulation. Dx-g-PCL films with or without paclitaxel were
evaluated in rat models of surgical adhesions. The films were biocompatible and showed
good handling characteristics when being applied to a surgical site. In a rat cecal abrasion
model, Dx500-g-PCL films with paclitaxel loadings of 0.1% and 0.5% significantly
reduced adhesion formation. Dx500-g-PCL films with no paclitaxel showed a barrier
effect and reduced the incidence of adhesion formation. === Pharmaceutical Sciences, Faculty of === Graduate
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