Ru, Q.; (2011) Development and investigation of implantable tablets for wound healing modulation after trabeculectomy. Doctoral thesis , UCL (University College London).

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Abstract

Modulation of wound healing is required to inhibit scar formation after trabeculectomy. Mitomycin C and 5-fluorouracil (5-FU) are the anti-proliferative drugs currently used in the clinic. Their effectiveness is limited due to their toxicity and suboptimal local tissue pharmacokinetics caused by rapid clearance within the subconjunctival space. Therefore, prolonged release of anti-scarring agents is needed. Ilomastat is a matrix metalloproteinase inhibitor that has been shown to moderate favorably the wound healing response after surgery. However, due to rapid local tissue clearance, several injections are necessary in a clinically relevant animal model. The thesis describes the development and investigation of implantable ocular tablets for wound healing modulation after trabeculectomy. A tablet would be placed in the subconjunctival space called a bleb, which is caused by the outflow through the fistula made during surgery. While the bleb volume varies, the tablet is thought to dissolve in non-sink conditions. Tablet dissolution was evaluated in vitro using a flow chamber that mimics the liquid outflow conditions of the bleb. The in vitro release studies suggest that tablet dissolution would act to prolong drug release in comparison with injections. Tablet dissolution in the subconjunctival space is affected by many factors including the physical/chemical properties of the drug and tablet, temperature, the volume and flow rate of the dissolution media, and the surface area of the tablet. The efficacy of an excipient-free ilomastat tablet was evaluated using a clinically validated rabbit model. The tablet dissolution was examined using molecular dynamics simulations to consider the molecular interactions of ilomastat and 5-FU undergoing dissolution in non-sink conditions. A mathematical model was also developed to describe the dissolution of excipient-free tablets in the non-sink conditions with 94% confidence. In conclusion, we have established methods to investigate and simulate dissolution of excipientless tablets in non-sink conditions within the subconjunctival space.

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