Elucidating the effects of sublingual tablets containing buprenorphine on dental caries, and development of a novel formulation.

PROJECT SUMMARY/ABSTRACT Opioid use disorder (OUD) is a severely debilitating condition affecting nearly 10 million Americans. The sublingual drug product, Suboxone, which contains buprenorphine and naloxone, is the most frequently prescribed medication to treat OUD. In 2022, the FDA released a warning after several reports of patients prescribed sublingual forms of buprenorphine that exhibited severe dental caries and tooth loss. Furthermore, these issues arose in patients without prior dental concerns. Case reports and epidemiological evidence have supported these findings; yet the reason for this association is not understood. Dental caries (ie. tooth decay) is a chronic, polymicrobial, biofilm-based disease resulting from microbial dysbiosis and environmental changes in which microbial fermentation byproducts like lactic acid accumulate, demineralize the tooth structure, and can lead to severe odontogenic infections. Certain conditions favor the growth and persistence of aciduric and acidogenic microorganisms, including the cariogenic Streptococcus mutans and the yeast pathobiont Candida albicans at the expense of health-associated microorganisms, hence forming a cariogenic, dysbiotic microbiome. Sublingual tablets containing buprenorphine also contain several pharmaceutical excipients including binders, taste enhancers, and solubilizers, including lactose, mannitol, and citric acid. Our preliminary data suggests that these excipients combined promote the growth and biofilm formation of cariogenic microorganisms S. mutans and C. albicans. Importantly, they can do so at the estimated concentrations in the oral cavity following administration of the drug product. Thus, we hypothesize that the extended use of the current marketed drug products containing fermentable sugars and acidic excipients result in a shift in the oral microbiome by favoring cariogenic species and thus promoting the development of dental caries. In this proposal, we seek to address this concern by determining whether the current sublingual tablets containing buprenorphine promote a cariogenic microbiome and developing a new oral health promoting formulation that prevents the devasting dental effects associated with the currently marketed formulations. In Aim 1, the PI will first determine the growth and acidogenicity of S. mutans and C. albicans cultures exposed to each excipient and whole tablet. Then biofilms formed by these two microorganisms in response to the tablet will be examined by performing biofilm biomass assays and confocal microscopy. Metagenomic analysis will then be performed using an ex vivo dental plaque microcosm model after exposure to the tablets. In Aim 2, the PI will formulate a novel tablet formulation that replaces identified cariogenic excipients with validated non-cariogenic and dental safe excipients. Successful completion of the proposed studies will result in an improved formulation aiding in the prevention of dental caries, thus significantly improving the health and quality of life of OUD patients, and patient's willingness to accept buprenorphine therapy. Furthermore, the proposed training plan will cultivate the PI's development into a clinician-scientist through coursework, inter-disciplinary mentorship, dental practice, and rigorous research.