A mechanistic analysis to characterize oramucosal permeation properties

Area of Science:

• Pharmacokinetics and Drug Delivery
• Membrane Transport Mechanisms
• Oral Mucosal Permeation

Background:

• Ionizable molecule permeation is often explained by the pH-partition theory.
• Membrane-coating granules (MCG) are hypothesized to influence transport resistance.
• Understanding oral mucosal permeability is crucial for drug delivery.

Purpose of the Study:

• To validate the pH-partition theory for nicotine permeation across porcine oral mucosa.
• To compare the permeability of different oral mucosal tissues.
• To elucidate the preferred transport pathways for nicotine species based on charge.

Main Methods:

• Utilized nicotine as an ionizable model compound (pK(a) 3.4 and 8.2).
• Investigated permeation through various porcine oral mucosae (gingiva, buccal, sublingual).
• Performed mechanistic analysis using permeability ratio-pH profiles.

Main Results:

• Nicotine's permeability, partition coefficient, and diffusivity were pH-dependent, supporting the pH-partition theory.
• Keratinized gingiva exhibited higher permeability than non-keratinized tissues.
• Neutral nicotine showed greater permeability than ionized forms due to higher partition coefficient and diffusivity.
• Neutral nicotine transport occurred primarily via the transcellular pathway, correlating with MCG volume.
• Ionized nicotine species preferentially utilized the intercellular pathway at lower pH.

Conclusions:

• The pH-partition theory accurately predicts nicotine permeation across oral mucosa.
• Transport pathways (transcellular vs. paracellular) are dictated by nicotine's charge status.
• Membrane-coating granules (MCG) play a significant role in both transcellular and paracellular resistance.