Predictive models for intra-articular drug delivery

: (Alternative format thesis).

Abstract

Intra-articular (IA) administration is used for the symptomatic treatment of disorders such as Osteoarthritis (OA) and Rheumatoid Arthritis (RA) providing a local effect while avoiding systemic side effects. For appropriate IA formulations to be developed and for quality control purposes, appropriate dissolution models have significant importance. Developing these models poses a great challenge, while at the moment, there is no regulatory approved standard methods for testing drug dissolution from parenteral formulations. The principal aim of this thesis is the development of appropriate in-vitro compendial and biorelevant dissolution models of drug absorption after IA administration. A vast number of dissolution methods were investigated, based on their potential and suitability as compendial methods (USP apparatus I, II, III and IV, dialysis methods and bi-phasic models) and their applicability in simulating in- vivo conditions for the biorelevant dissolution aspect (Side-Bi-Side diffusion cells and bi- phasic models). Various parameters of the setups were successfully evaluated towards their effect in drug dissolution. The discrimination ability of the USP apparatus IV was demonstrated showing the significant potential of this method in order to be considered for compendial testing. For the biorelevant dissolution testing, biorelevant synovial fluids (BSFs) of healthy and disease states were developed according to performed in-vivo studies of physicochemical properties and solubility values of Triamcinolone Acetonide (TA). These media were also used in biorelevant dissolution testing, showing the ability of the tested systems to discriminate between these media. Finally, surface dissolution imaging has permitted direct visualisation of the solvation and dissolution of TA with a detailed insight in the characterisation of the dissolution process by evaluating the effect of surfactants and increased viscosity of the medium. Overall, this thesis provides essential information on the potential of dissolution models for being the primary method upon which the drug dissolution of IA formulations may be established.

Date of Award	31 Mar 2018
Original language	English
Awarding Institution	University of Bath
Supervisor	Nikoletta Fotaki (Supervisor)