The adequate absorption and transport of drugs in the body is part of optimal therapy. Drug administration perorally is easy, common and traditional, but occasionally alternative routes are required. The major obstacles of this drug delivery method are the extensive presystemic degradation processes in the gut and/or liver, resulting in inadequate or erratic absorption and low systemic bioavailability. The parenteral route is the only established way that overcomes these drawbacks, but it may not achieve the maintenance of adequate drug levels at the receptor for as long as it is needed, which results in it high costs, poor patient compliance — especially in long-term therapies — and various further inconveniences and risks. Moreover, it requires repeated administration and is potentially hazardous as rapid drug removal is unachievable.

During the last two decades, transepithelial routes have been extensively explored by pharmaceutical researchers as alternative routes of delivery. Drug application to absorptive mucosae is often chosen to reach the site of action with little systemic drug concentrations to lessen side-effects.¹

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Table 1: List of APIs investigated for buccal delivery.

Buccal absorption

The principal mechanism of buccal absorption is passive diffusion. However, this assumption may be misleading as the oral mucosa contains active, carrier-mediated transport systems for few small molecules, such as monosaccharides and amino acids.¹⁶ On occasion, absorption occurs by endocytosis where molecules are engulfed by the cells.¹² Two main pathways seem to be implicated in passive diffusion across mucosae: intracellular (or transcellular) and intercellular (or paracellular). Within the intercellular spaces there are two ways: one, hydrophobic, goes through the lipid domains; the other, hydrophilic, relates to the aqueous channels associated with the polar head groups of lipids and proteins. The intrinsic physicochemical properties of the drug, such as solubility, partitioning, stability, crystallinity, thermodynamic activity, molecular size, pKa and half-life, can constitute limiting factors to drug absorption:

• Low solubility determines a small concentration gradient to the plasma and the rate of diffusion is accordingly low.
• Highly lipophilic compounds could permeate through the transcellular route by partitioning into the lipids of the intercellular matrix while hydrophilic compounds could diffuse through the paracellular pathway. Some drugs can permeate using both routes simultaneously, but the route with the least penetration resistance is usually preferable.
• Crystalline status and thermodynamic activity of a drug are correlated with the diffusant concentration, thus affecting permeation.
• Small molecules, <~100 Da, cross the mucosa rapidly; permeability decreases as molecular size increases; high molecular weight drugs, such as peptides, oligonucleotides and hormones, usually have low permeability leading to a low bioavailability.
• The pKa is indicative of the molecule degree of ionization and affects permeability: maximum absorption occurs when molecules are not ionized and absorption decreases as the degree of ionization increases. Most drugs are weak acids or bases, and exist in solution as equilibrium between the unionized and ionized forms. Only unionized nonpolar drugs penetrate the membrane and, at equilibrium, the concentrations of the unionized species are equal on both sides of the membrane. The unionized form is assumed to be sufficiently lipophilic to cross membranes. The fraction ionized is controlled by both the environmental pH and the drug pKa.¹⁷