ABSTRACT

This thesis is focused on fabrication of biodegradable implantable devices for extended localized drug release. Paclitaxel (PT) was used as cancer drug in the study. Poly lactic –co- glycolic acid (PLGA) is a polymer used for drug elution. In this work, the role of enzymes on the degradation of PLGA, Effect of different pH on the degradation of PLGA and the kinetics of drug release was elucidated. PLGA ratios of 75:25 and 85:15 were used. The enzyme used in the study is lipase enzyme. The pH used was 4.0, 6.0, 6.5, 7.0 and 7.4. From the study, it was observed that lipase enzyme increased the rate of polymer degradation and thus the rate of drug release from PLGA. This experiment also shows that PLGA degrades faster in acidic medium. This also caused the kinetics of drug release to be higher in acidic medium than in alkaline or neutral medium.

Chapter One

1.0 Introduction

In 2008, the World Health Organization (WHO) estimated all global deaths arising from cancer to be up to 84 million (WHO, 2008). In recent years, the increasing incidence of cancer has been associated with high cancer mortality rates across the globe (WHO, 2014). It was also reported that the different types of cancer causes more deaths than those due to HIV/AIDS, tuberculosis and malaria all combined (WHO, 2014). In any case, early detection and improved treatment are crucial for a successful management of cancer (Anand P et al., 2008). However, it is difficult to detect breast cancer at the early stages. This causes late detection and reduces the chances of effective treatments especially for cases in which the metastatic stage, before detection.

Furthermore, the current cancer treatment methods such as bulk systemic chemotherapy (American Cancer Society (ACS), 2013; Kushi et al., 2012; Parkin et al., 2011; WHO, 2014) and radiotherapy (Gotzsche and Jorgensen, 2013; National Cancer Institute (NCI), 2014) have severe side effects. Such severe side effects can be reduced by a sustained and controlled release of cancer drugs into regions containing cancer cells/tissue (NCI, 2014; WHO 2014). There is, therefore, a strong interest in the localized delivery of cancer drugs from implantable drug delivery systems (NCI, 2014; WHO 2014WHO, 2014; Dubas and Ingraffea, 2013). Recent work focused on the development of implantable non-resolvable systems for cancer drug delivery (ACS, 2014). However, such systems remain in the body, or require surgical removal, after drug release. Hence there is a need for resorbable structures for the controlled release of cancer drugs (Cakir et al., 2012; Jemal et al., 2011; ACS, 2013; WHO, 2014) to tumor regions. Such resorbable structures have been studied over the past decade (ACS, 2014), using biodegradable polymers that facilitate the controlled release of cancer drugs. These include polymers, such as poly (lactic-acid) (PLA) and poly(glycolic-acid) (PGA), and their copolymers (PLGA)

Biodegradable microparticles have also been formulated from PLA or PLGA for controlled drug release (National Cancer Institute, NCI, 2013). PLA or PLGA have also been shown to be biocompatible and biodegradable (NCI 2013; Hanahan and Weinberg, 2000). Furthermore by altering their molecular weight, sample size and surface morphologies (Hanahan and Weinberg, 2011) well-defined degradation rates can be achieved and used to control the release of encapsulated therapeutic agents. This will be explored in the current study of minirods of PLGA that encapsulate PT.The degradation and drug release kinetics are studied using a combination of optical microscopy and UV-Vis spectrophotometry. The implications of the results are also discussed for the development of resorbable/implantable devices for multipulse cancer drug delivery