Development of a Low-dose Doxycycline Gel for the Treatment of Oral Ulcers

Objective: Recurrent oral ulceration is a common and painful condition that lasts 7-14 days without treatment. Topical steroids have been the principal drugs of choice but few therapeutic advances have been made in recent years. Tetracycline and its derivatives have been shown to be inhibitors of matrix metallo-proteinases (MMP) that are part of the inflammatory response and contribute to the breakdown of tissue in the ulcer. This study aimed to develop a muco-adhesive gel to deliver MMP inhibitor to the oral ulcer. Methods: A gel has been developed and tested with respect to adhesion, release of active drug, stability, inhibition of MMP in vitro and for its effect on oral commensal flora in vitro. The aim of treatment is to inhibit MMP activity using a low dose of doxycycline without having a significant inhibitory effect on the commensal oral flora. Results: MMP-2 and MMP-9 activity was completely inhibited with 300µM and 50µM concentrations of doxycycline respectively. The gel demonstrated good adherence to mucosa in vitro and the preparation has been found to be stable after one year of storage. Release of the active ingredient from the gel was rapid, about 20% being released in 15 min. but the preparation had only minimal effect on the commensal oral flora. Conclusion: MMP enzymes can be inhibited by low doses of doxycycline below levels likely to disrupt the oral flora. Incorporation of doxycycline in a muco-adhesive gel has potential as a means of treating recurrent oral ulceration. Supported by the Icelandic Research Council and Biogels Pharmaceuticals