Overnight use of oral appliance with sirolimus sustained-release varnish delivery system: a clinical note and an observational study.

OBJECTIVE: Maintaining appropriate salivary levels of an active ingredient is challenging. Intraoral trays can be used to deliver medications for localized treatment. Based on previous successful daytime studies with a slow-release sirolimus varnish, the aim was to optimize intraoral appliances/trays for overnight use to deliver slow-release medications in a manner that maintains therapeutic salivary levels of the active ingredient to treat oral conditions. METHOD AND MATERIALS: An acrylic tray appliance containing 0.5 mg of sirolimus in a sustained-release varnish was placed on six anterior teeth for 12 hours, in ten healthy volunteers. Whole unstimulated saliva was collected at 1, 2, 10, and 12 hours after application. Blood was collected at the time of recruitment to confirm eligibility, and 12 hours after device removal to measure sirolimus levels. Drug levels in the blood and saliva were analyzed. Slow- and fast-release formulations, varnish position (buccal, palatal, or lingual), and tray placement (mandibular or maxillary) were qualitatively compared. Participants evaluated the varnish and tray. RESULTS: Moderate concentrations of sirolimus were detected in the saliva when the fast-release formulation was used. The highest levels were from the mandibular tray with lingual varnish application. Sialometry of all participants was within normal range, and the highest drug levels were detected when low flow was measured. No traces of the medication were found in the blood. CONCLUSIONS: Salivary concentrations of medications applied to an intraoral appliance are affected by the placement in the maxilla or mandible, varnish formulation, location of varnish, and salivation rate. These results may help optimize medication release following application to various oral devices. (Quintessence Int 2023;54:242-249; doi: 10.3290/j.qi.b3604821).

Levels of sirolimus in saliva and blood following oral topical sustained-release varnish delivery system application.

PURPOSE: Sirolimus (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 METHODS: Sirolimus 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. RESULTS: After 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. CONCLUSIONS: After 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.

Levels of Sirolimus in saliva vs. blood--the rationale of topical oral use for oral malignancy.

BACKGROUND: Sirolimus is a potent blocker of mammalian target of Rapamycin (MTOR), with anti proliferative activity. Its potential for the management of oral cancer has been suggested. Our aim was to establish an analytical method for determining sirolimus levels in human saliva and to calculate the blood vs. saliva ratio in individuals using sirolimus chronically in order to evaluate the total oral tissue exposure. PATIENTS AND METHODS: Chemiluminescent microparticle immunoassay technology (CMIA) was used to determine the blood and saliva levels of sirolimus in four transplant patients chronically-treated with sirolimus. RESULTS: An analytical method for determining sirolimus levels in human saliva was established. We demonstrated that saliva levels were on average six times lower than blood levels. CONCLUSION: The specific sensitive analytical method showed that the saliva levels of sirolimus are significantly lower than blood levels, thus reinforcing the rationale for the use of topical oral sirolimus to enhance availability, efficacy and safety for treating oral malignancies.