UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Poly(e-caprolactone) and methoxypolyethylene glycol blends as a surgical paste delivery system for paclitaxel Winternitz, Charles


A biodegradable, polymeric surgical paste formulation was developed in which the anticancer drug paclitaxel was incorporated by mixing into a blend of poly(e-caprolactone) (PCL) and methoxypolyethylene glycol, M W 350, (MePEG). The potential application of this paste formulation is to a surgical cavity following tumour resection surgery. The paste would be applied in the molten state and would solidify to form a solid depot for the slow release of paclitaxel to prevent regrowth of cancerous tissue which may not have been surgically removed. The MePEG was used to modify the thermal and mechanical properties of PCL, specifically to reduce the melting point and melt viscosity, and to increase the time taken to crystallization from the melt. The effect of the incorporation of MePEG into PCL on the physical and chemical properties of polymer matrix was investigated. The melt viscosity at 60° C of PCL:MePEG blends was decreased from 120 to 11 poise as the MePEG concentration was increased from 0 to 40%. X-ray analysis revealed that PCL was a semicrystalline polymer, and the incorporation of MePEG did not alter the crystalline form of the PCL crystallites. Differential scanning calorimetry showed that the melting points of PCL and MePEG were 59° C and -1° C respectively, so at room temperature, PCL crystallites could form but MePEG would still be above its melting point. On cooling paste blends from the melt to -100° C, recrystallization of both PCL and MePEG occurred. At all blend compositions tested, only one glass transition (Tg) was observed and it was intermediate between the Tg's of the individual components indicating that the components were miscible. The observed Tg's deviated from those predicted by the Fox equation and this was thought to be due to the blend not being completely amorphous. Blend composition did not affect the degree of crystallinity of either component. Blend composition had no effect on either the crystallization or melting temperature of MePEG but melting point depression was observed with the PCL crystallites. Analysis of the melting point depression indicated that the stability parameters of PCL crystallites in the presence of between 0 and 30% MePEG did not change, but the equilibrium melting point of the PCL crystallites was decreased from 59.4° to 55.2° C. A Flory interaction parameter value of -0.16 was calculated for the PCL:MePEG blend and the melting point depression of PCL was shown to be due, at least in part, to an interaction between the melting PCL chains and the liquid MePEG present in the matrix. Microscopic analysis of PCL spherulites crystallizing in blends with MePEG at 37° C showed that the spherulites impinged on each other, suggesting that the MePEG was incorporated intraspherulitically. Measurement of spherulite growth across divisions in a micrometer etched in the microscope eyepiece as a function of time, revealed that the presence of MePEG did not affect the growth rate of PCL spherulites. The effect of MePEG blending on the tensile strength of PCL tablets was measured using a CT-40 tablet hardness tester. MePEG was found to decrease the tensile strength of PCL from 179.4 to 26.7 N/cm². Incubation of PCL and PCL:MePEG 80:20 at 4°, 25° and 37° C and in phosphate buffered saline at 37° C over 13 weeks showed that no degradation of PCL occurred in the samples stored dry, but that in buffer, the PCL molecular weight was decreased from 20k to 14k (100% PCL) and 17k (PCL:MePEG 80:20). Storage for 13 weeks also resulted in an increase in both the melting point and degree of crystallinity of PCL , both alone or in a blend with MePEG. In vitro release studies of 20% paclitaxel loaded PCL and PCL:MePEG 80:20 in phosphate buffered saline with albumin showed a biphasic pattern of paclitaxel release consisting of a burst phase of about 1 day, followed by a period of slow sustained release lasting at least 3 months. Paclitaxel release followed a diffusion model and sterilization by gamma irradiation did not affect the release profile of paclitaxel. The presence of MePEG in the surgical paste formulation decreased the rate and extent of paclitaxel release by about 50% although the percentage of MePEG in the polymer matrix, between 1 and 30% MePEG, did not change the paclitaxel release. When paste samples were incubated in an aqueous solution, it was found that the MePEG diffused out of the paste leaving a PCL matrix containing channels into which water could diffuse. It was suggested that the formation of water channels in the PCL:MePEG formulations contributed to the precipitation of a more stable form of paclitaxel crystals, paclitaxel dihydrate, within the polymer matrix resulting in altered release profiles. Formulations of paclitaxel in PCL and PCL:MePEG 80:20 were shown to result in inhibition of angiogenesis using a chick chorioallantoic membrane (CAM) model. Molten surgical paste, which subsequently solidified as pellets, containing 3H-paclitaXel was injected subcutaneously in mice at a dose of 25 mg paclitaxel. The distribution of 3H-paclitaxel in the mice over 1 month was measured using a radioassay. Analysis of the surgical paste pellet remaining in the mice showed that 35% of the 3H-paclitaxel was released from the pellet in vivo over 15 days. Treated mice did not show any obvious signs of gross toxicity due to treatment, although inhibition of wound healing at the injection site was observed. The 3H-paclitaxel was found to distribute to the liver and to the muscle tissue adjacent to the injected pellet, which was analyzed to represent the site of action for the drug. The level of 3H-paclitaxel detected on the muscle tissue remained above the minimum level required for activity for at least 30 days.

Item Media

Item Citations and Data


For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.

Usage Statistics