Preparation of Intra-articular Drug Delivery Systems for the Treatment of Osteoarthritis
Abstract
Osteoarthritis (OA) is a degenerative disease of the articular joints that affects over 240 million people globally. Despite its overwhelming prevalence, there is no disease modifying agent currently available to treat the disease, and many treatment options remain palliative in nature. Potentially effective treatments for OA are limited by probable systemic side effects. Intra-articular drug delivery systems present a new opportunity for the treatment of OA; encapsulated therapeutics can be injected directly into the joint, at the area of injury, thereby bypassing systemic administration and diminishing the chance for side effects. This thesis describes the research and development of novel polymeric drug delivery systems for intra-articular administration. Initially, a polymer particle delivery platform using poly(ester amide) (PEA) was developed to encapsulate the non-steroidal anti-inflammatory drug celecoxib. Drug-loaded particles were successfully prepared, and were characterized physicochemically and biologically using in vitro and in vivo techniques. Drug was released in vitro from particles over a period of months, and the particles did not cause significant cellular toxicity. The particles elicit a minimal host response in vivo when tested in an ovine model. The PEA particle delivery platform was further developed to encapsulate and deliver the small molecule, GSK3787, which had been previously implicated as a potential disease modifying agent for OA. The physicochemical properties of the particles were characterized including the measurement of the mechanical properties of individual particles by atomic force microscopy, and it was found that the modulus was in the range of articular cartilage. The drug-loaded and empty particles exhibited low toxicity to mammalian cells. In order to establish an even more prolonged release, and greater control over the system, a hybrid drug delivery system consisting of GSK3787-loaded PEA particles embedded within a thermally-responsive hydrogel was prepared. This system was evaluated to understand the effects of particle and drug incorporation on the gel properties including syneresis, Young’s modulus, degradation, and toxicity. The release of GSK3787 from the hybrid system was slower in vitro than from hydrogel into which drug was directly loaded without particles. The hybrid system is promising for further in vivo evaluation. Overall, this thesis furthered the understanding of polymer drug delivery systems for intra-articular use, and led to the development of three new systems for potential use in treating OA. Furthermore, for the first time, a means to deliver the potential disease modifying agent GSK3787 was developed.