Method: Menthol was conjugated to pyrophosphate (PPi) via a glycolic acid linker to obtain the dentotropic menthol (Menthol-PPi). 1H NMR was used evaluate the binding potential and kinetics of Menthol-PPi to hydroxyapatite (HA, the model tooth surface). Surface-enhanced Raman spectroscopy was used to further confirm the binding of Menthol-PPi to the HA surface. Human saliva was isolated for the in vitro menthol release study according to an approved IRB protocol. For the in vitro release study, a Menthol-PPi solution in fresh human saliva (5 mg/mL) was prepared. The solution was incubated at 37°C. Samples (1 mL) were withdrawn at predetermined time points, after which they were extracted with chloroform (1 mL) and analyzed for menthol content using GC/MS.
Result: The chemical structure of Menthol-PPi is confirmed with 1H NMR and 31P NMR. Menthol-PPi was found to bind to HA immediately (< 1 min). Approximately 25% of Menthol-PPi in the saliva solution was found to bind to HA powder (10 mg) within 2 minutes. Addition of HA powder (10 mg) would increase the binding by ~10%. Minimal binding is observed with menthol alone. A close to linear releasing profile was found with Menthol-PPi in human saliva at 37°C over the course of 24 hours.
Conclusion: A dentotropic (tooth-binding) menthol derivative (Menthol-PPi) was successfully synthesized and characterized. It can bind to the model tooth surface (HA) quickly and gradually release menthol in the presence of human saliva. When incorporated into dentifrice formulations, we believe such a functionalized flavoring agent can provide sustained fresh breath and clean sensation, which may further improve the product performance and patient compliance to routine oral hygienic procedures.