| Summary: | Paclitaxel is a drug of choice for the treatment of ovarian cancer but despite its
widespread usage, the solid state properties of paclitaxel are not clearly understood.
There is speculation that several solid forms may exist because of the wide range of
reported values for the water solubility of paclitaxel. In this work, two distinct anhydrous
crystalline forms, a dihydrate and an amorphous solid form were identified. Dissolution
profiles of the as received anhydrous form showed a maximum apparent solubility of
3.5 μg/ml after 2 hours that decreased to 1 μ/ml after 20 hours due to conversion of the
anhydrous form to the dihydrate.
Microsphere delivery systems for paclitaxel were developed using poly(L-lactic
acid) (PLLA) polymers in order to provide controlled release of the drug. The ability to
resuspend microspheres, the total content of paclitaxel in microspheres, and polymer
thermal properties all varied with polymer molecular weight. The greatest changes in
these properties occurred in the molecular weight range of lk to 4k g/mol. For
microspheres manufactured from 100k g/mol PLLA, surface morphology, thermal
properties and paclitaxel release profiles were dependent on the microsphere size range
and on the paclitaxel loading level. Microspheres were manufactured in the size ranges
of 1-10, 10-35, and 35-105 pm and had theoretical loading levels between 10 and 30%.
Addition of paclitaxel to the microspheres resulted in a dimpled surface morphology
which was believed to be due to paclitaxel's effect on the formation of the outer surface
of the microspheres. Depression of the glass and melting transition temperatures of the
polymer by up to 6°C indicated that paclitaxel was dissolved in the amorphous phase of
the semicrystalline polymer matrix. In vitro release profiles of paclitaxel from 100k g/mol PLLA microspheres showed an initial rapid phase of release for 3 days,
followed by a slower phase of apparently zero-order release. The rate and extent of
release increased with increasing paclitaxel loading levels and decreasing particle size.
In order to alter the release profiles for paclitaxel from PLLA microspheres the
polymer matrix was modified by blending low and high molecular weight PLLA
polymers. Blends of 2k and 50 g/mol PLLA and lk and 100k g/mol PLLA were
prepared with blend compositions between 0 and 100% of the low molecular weight
component and their thermal properties were characterised. Both blend systems
exhibited a single glass transition over the entire range of compositions, indicating that
the polymers were miscible. As the amount of low molecular PLLA increased, the
melting temperature of the polymer blend decreased from 175°C to 145°C and from
175°C to 110°C for the 2k/50k g/mol and lk/lOOk g/mol PLLA blends, respectively.
Microspheres made from all blends of 2k/50k g/mol PLLA were spherical and easily
resuspended from the dry state. However, for lk/lOOk g/mol PLLA blends, 60% was the
highest proportion of lk g/mol PLLA that could be used to form spherical microspheres
that were resuspendable. The blend containing 60% lk g/mol PLLA (PB60) was
therefore selected for the formulation of paclitaxel loaded polymer blend microspheres.
Thermal properties and paclitaxel release profiles from PB60 microspheres were
dependent on the microsphere size range and on the paclitaxel loading level. The
incorporation of paclitaxel into PB60 microspheres did not result in the dimpled
appearance observed for 100k g/mol PLLA microspheres. Depression of the melting
transition temperature of the polymer by up to 6°C indicated that paclitaxel was dissolved
in the PB60 polymer matrix. However, the glass transition temperature of the blend was increased by the addition of paclitaxel, indicating that the amorphous phase was stiffened
by the addition of the drug. In vitro release profiles for paclitaxel released from PB60
microspheres showed an initial rapid phase of release for 3 days, followed by a constant
rate of diffusion controlled release until day 21 of the release study. Around day 21,
PB60 microspheres in all size ranges and paclitaxel loadings exhibited a sudden increase
in the release rate due to the onset of erosion of the matrix.
Microspheres made from 100k g/mol PLLA were used in two sets of in vivo
studies in rats. The first study determined the size of microspheres that would be retained
in the peritoneal cavity. The second study determined the efficacy of intraperitoneal
paclitaxel loaded microspheres in preventing 9L glioblastoma tumour growth following a
tumour cell spill. To simulate the spill two million tumour cells were injected into the
peritoneal cavity through an incision in the abdomen of rats.
Microspheres with diameters of less than 24 μm were observed in the lymphatic
system of rats. It is believed that these microspheres passed from the peritoneal cavity to
the lymphatic system through fenestrations in the diaphragm. Microspheres in the size
range of 35-105 μrn were selected for the efficacy study to ensure that they would be
retained in the peritoneum. A dose of 100 mg of 30% loaded microspheres, administered
at the time of the simulated tumour cell spill, was efficacious in preventing tumour cell
implantation and growth for up to six weeks.
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