Evaluation of Factors Impacting Nicotine Permeation in Oral Nicotine Pouch Products

In recent years, oral nicotine pouches or "tobacco-free nicotine pouches" have emerged as potential reduced-risk alternatives to traditional tobacco products. The aim of this research was to evaluate and further develop laboratory tools to measure the nicotine release rate from nicotine pouches and its permeation through the oral mucosa. For this, we evaluated the nicotine dissolution rate and buccal permeability of three nicotine pouch brands: <i>Zyn</i>, <i>Velo</i>, and <i>Dryft</i> nicotine pouches. Dissolution testing was conducted using the United States Pharmacopeia 4 (USP-4) apparatus and an in-house developed sinker method in three different artificial salivas, one laboratory-made saliva (Buffer saliva) and two commercially available salivas (Salivea and Orthana). <i>Zyn</i> nicotine pouches yielded the fastest nicotine release rate when compared to <i>Velo</i> and <i>Dryft</i> nicotine pouches. Nicotine permeability was assessed using the Side-Bi-Side diffusion cell with the porcine buccal mucosa model. Using neat nicotine solutions, we examined the effects of nicotine concentration (0.05-0.8 mg/mL), pH (5-10) (which covers the nicotine concentration and pH range in the three product extracts), and the three artificial saliva compositions on buccal permeability over 2 h (15, 30, 60, 90, and 120 min). While nicotine concentration did not affect the apparent permeability coefficient (<i>P</i> _app) within the tested range, higher pH resulted in a higher <i>P</i> _app value. Moreover, Buffer saliva and Salivea showed higher <i>P</i> _app values than those of Orthana. We further studied nicotine permeability by testing extracts from each nicotine pouch prepared by the sinker dissolution method in biorelevant, mucin containing Orthana saliva. <i>Zyn</i> nicotine pouches provided the highest permeability (38.24 × 10^-6 cm/s), followed by <i>Dryft</i> and <i>Velo</i> nicotine pouches (31.06 × 10^-6 cm/s and 14.84 × 10^-6 cm/s, respectively). Overall, our data indicate that the pH, artificial saliva composition, and product formulation can affect nicotine buccal absorption under laboratory conditions. This research provides a valuable dissolution/permeation tool to measure the nicotine release rate from nicotine pouches and its permeation through the oral mucosa, which can inform product development and adult tobacco consumers' sensory experience.