In situ forming hydrogels for intra-articular delivery of celecoxib: from polymer design to in vivo studies

Abstract

The main topic of this thesis was the development and evaluation of an injectable in situ forming gel made of acylated PCLA-PEG-PLCA copolymers for the local and sustained release of celecoxib, which is to date the drug of choice for the treatment of OA (Chapter 1). As shown in this thesis, the advantageous properties of gels composed of acylated PCLA-PEG-PCLA copolymers is the straightforward preparation and the versatility in the rheological and degradation/release properties as well as ease of injection and good tolerability/biodegradability. Rheological and degradation/release properties can easily be modulated by the polymer composition and microstructure (Chapter 2 & 3). The ease to modulate properties combined with the possibility of functionalizing the end groups with, for instance, iodine-containing groups allowing longitudinal imaging by computed tomography shows that the systems have potential for in vivo applications (Chapter 4). Also, celecoxib is released from the gel in a sustained manner after subcutaneous injection in rats (Chapter 5) and also locally after intra-articular injection in horses (Chapter 6). The systemic exposure and duration is low and short and, plasma concentrations are a factor 150-330 lower than the levels in synovial fluid. This demonstrates clearly the potential of the system for local drug delivery with relatively high local drug concentrations and very low systemic leaching.