Polymeric particles for sustained and local drug delivery

Abstract

Controlled drug delivery systems have been extensively investigated as means to prolong the action of drugs in the body. In this regard, a drug is incorporated into a carrier (e.g., polymeric material) in such a way that the drug is released from the matrix in a controlled manner for an extended period of time. As of 1970th, the Food and Drug Administration (FDA) has approved >70 new products based on the drug delivery systems. In particular a number of biodegradable polyesters, such as poly(lactic-co-glycolic acid) (PLGA), has been frequently used for the development of controlled drug delivery systems. PLGA-based particulate systems (i.e., nanoparticles and microparticles) are suitable systems for controlled release of small molecules as well as macromolecular biotherapeutics. These drug-loaded particulate systems can be injected in/or adjacent to the targeted organs ensuring relatively high drug concentrations in the targeted organs/tissues and minimizing drug distribution into other untargeted and healthy organs/tissues. Besides different cancer types, ophthalmic diseases affecting both anterior and posterior segments of the eye can greatly benefit from local drug delivery. Due to the presence of many ocular barriers (e.g., tear film, corneal and conjunctival epithelia, efflux pumps, blood retinal and blood aqueous barriers) delivering and maintaining drug concentrations at therapeutic levels in the eye is challenging. Aim of the thesis This thesis focuses on the preparation of particulate systems based on biodegradable aliphatic polyesters and their application for sustained and local delivery of low molecular weight hydrophilic and amphiphilic drugs. Outline of the thesis Chapter 2 gives an overview of strategies for efficient encapsulation of small molecule drugs into polymeric microspheres. This chapter addresses the challenges and formulation-related aspects for efficient encapsulation of small hydrophilic and amphiphilic molecules into PLGA microspheres using conventional as well as novel emulsification methods. Chapter 3 reviews the localized drug delivery approaches using polymeric drug-depots for the treatment of various cancers including brain, lung, peritoneum, and liver. Chapter 4 describes formulation of imatinib-loaded PLGA microspheres and investigates the in vitro release of this small amphiphilic drug from the microspheres. In Chapter 5 a series of novel multi-block copolymers composed of amorphous blocks of poly-(d,l-lactide) (PDLLA) and poly(ethylene glycol) (PEG) and of semi-crystalline poly-(l-lactide) (PLLA) blocks were synthesized. Sunitinib, an antiangiogenic multitargeted tyrosine kinase inhibitor, was loaded into microspheres by a single O/W emulsion method. A chicken chorioallantoic membrane (CAM) assay was performed to study the effect of sunitinib-loaded microspheres on angiogenesis. In Chapter 6 PLGA and PLGA-PEG copolymers were used for preparation of sunitinib microspheres. The effects of polymer blend as well as different preparation methods (O/W and W1/O/W2) on the physicochemical properties and release kinetics of the microspheres were investigated. Chapter 7 describes the improved ocular retention and aqueous humoral drug availability of ganciclovir when administered via topical instillation of chitosan-coated PLGA nanoparticles into the rabbit eye. Chapter 8 summarizes the findings and conclusions of this thesis. Furthermore, perspectives and suggestions for future research are given.