Lipids present in the oral mucous membrane offer the main barrier to the permeability of hydrophilic drugs. On the other hand, well-hydrated connective tissues provide resistance to lipophilic drugs. Thus, the potential transport path across the oral mucous membrane may be either polar or non-polar. Non-polar molecules cross through the lipid regions of the epithelium, while polar molecules travel through ionic channels present in the intercellular spaces of the epithelium, or aqueous pores present in the epithelial cells. For this reason, an understanding of a drug’s lipophilic or hydrophilic nature during the developmental stage of the drug product appears to be the most useful index for evaluating its suitability for absorption across the oral mucosa.
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For efficient absorption through the oral mucosa, the drug must be hydrophobic enough to partition into the lipid bilayer, but not so hydrophobic such that once it is in the bilayer, it will not partition out again. Satisfactory oral absorption of drugs has been observed over a wide range of log P (octanol/water partition coefficient) values of 1 to 5. As the log P value increases beyond 5, the solubility in saliva is usually not enough to provide adequate concentration for diffusion through the lipid bilayer (39). According to the diffusive model of absorption, the flux across the lipid bilayer is directly proportional to the concentration gradient. Therefore, lower solubility in saliva results in lower absorption rates and vice versa. In general, a drug formulated for sublingual or buccal administration should have a molecular weight of less than 500 (as free base) to facilitate its diffusion (39).
Because drugs diffuse through the lipid bilayer in the unionized form, based on the pH-partition theory, the pKa of drugs also plays a crucial role in drug transport across the oral mucous membrane. It is important to note that the oral cavity, unlike the gastrointestinal tract, has a narrow range of pH, usually from 5.6 to 7.6. Thus, a basic drug administered as a salt, predominantly exists as a free unionized base if the pH is raised above its pKa value and this increase in the unionized fraction of a drug increases its bioavailability (40). For this reason, the inclusion of a suitable buffer in the formulation of an ionizable drug makes it possible to control the pH of aqueous saliva in a range most appropriate for the optimal absorption of such drugs. Drugs that do not contain ionizable groups are not affected by changes in pH.