Purpose:
Multiple applications of a matrix metalloproteinase inhibitor (MMPi) minimise fibrosis in vitro and in vivo. We aimed to develop a new single application slow release MMPi, to determine drug release using a new pharmacokinetic chamber and to test it in vitro and in vivo in a well established model.
Methods:
A novel method was used to create sterile slow release ilomastat tablets. A flow chamber was designed to mimic bleb flow. HPLC was used to monitor the release of active ilomastat. A human Tenon’s fibroblast contraction model was used to evaluate in vitro activity. A randomized, prospective, masked-observer study with 24 NZW rabbits was conducted to evaluate the potential therapeutic effect of the tablets. Sponges with 0.2mg/ml MMC and sponges with sterile water served as positive and negative controls.
Results:
Release studies in vitro showed that sterilized ilomastat tablets achieved a constant release of active ilomastat in concentration 30µM-85µM for at least 30 days which we previously showed inhibited collagen contraction. HPLC analysis confirmed that ilomastat remained stable after sterilization or incubation in the aqueous flow chamber conditions for 30 days. Ilomastat released from the tablets significantly inhibited contraction of HTF collagen I gels vs control (p<0.01). In the in vivo study all the rabbit blebs in the ilomastat group were functional throughout the 30 day period of the experiment. This was significantly superior to the sterile water group (P<0.001) and the MMC group (P<0.01 Log Rank). No ilomastat was detectable in serum.
Conclusions:
A novel single application MMP inhibitor formulation results in long term local release of therapeutic levels without detectable blood levels, and significantly prolongs bleb survival in an aggressive experimental model of scarring. These tablets have considerable potential in glaucoma surgery and other scarring situations in the human eye and body.
Keywords: wound healing • enzymes/enzyme inhibitors • conjunctiva