• Zakhar Nudelman, Mordechai Findler, Dinorah Barasch, Alina Nemirovski, Anna Pikovsky, David Kirmayer, Maamoun Basheer, J Silvio Gutkind, Michael Friedman, and Rakefet Czerninski.
• Department of Pharmaceutics, Faculty of Medicine, The Institute for Drug Research, School of Pharmacy, The Hebrew University, POB 12065, 91120, Jerusalem, Israel.
• Cancer Chemother. Pharmacol. 2015 May 1;75(5):969-74.

PurposeSirolimus (rapamycin) is a mammalian target of rapamycin pathway blocker. The efficacy of sirolimus is currently studied for its antiproliferative properties in various malignancies and particularly in squamous cell carcinoma and other oral disorders. Topical application at the oral cavity can augment sirolimus availability at the site of action by increasing sirolimus levels in saliva and hence efficacy, along with improved safety (low levels in the blood to avoid side effects) and compliance. Our purpose was to evaluate the release profile and safety of a topical sirolimus sustained-release varnish drug delivery system.Subjects And MethodsSirolimus sustained-release varnish drug delivery system containing a total of 0.5 mg of the drug was applied to nine healthy male volunteers. Saliva and blood levels were determined utilizing mass spectrometry and chemiluminescent microparticle immunoassay, respectively. The prolonged release profile and safety were evaluated for the oral topical delivery system.ResultsAfter the application of the drug delivery system, a sustained-release profile was observed in the oral cavity. We have measured moderate sirolimus levels for up to 12 h. The safety was confirmed, and systemic sirolimus blood levels were negligible.ConclusionsAfter an application of sirolimus sustained-release varnish drug delivery system, prolonged drug levels can be achieved in the saliva. The oral topical sirolimus concentrations were potentially therapeutic along with minimal systemic exposure. These results broaden the potential clinical use of sustained-release oral topical rapalogs.

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