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Paclitaxel loaded poly(L-lactic acid)microspheres : characterisation and intraperitoneal administration

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Title: Paclitaxel loaded poly(L-lactic acid)microspheres : characterisation and intraperitoneal administration
Author: Liggins, Richard
Degree Doctor of Philosophy - PhD
Program Pharmaceutical Sciences
Copyright Date: 1998
Abstract: 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.
URI: http://hdl.handle.net/2429/9562
Series/Report no. UBC Retrospective Theses Digitization Project [http://www.library.ubc.ca/archives/retro_theses/]

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