Drug permeability across the buccal mucosa: Role of ionized species activity and development of a predictive model

Based on the biochemical composition and structure of the buccal mucosa, drugs can permeate by the lipoidal and/or aqueous pathways. In this regard, the buccal mucosa is similar to skin. As the unionized drug form is the major permeant across skin, flux depends predominantly on the thermodynamic activity of this species. In contrast, ionized drug has been demonstrated to contribute significantly to the permeability across the buccal mucosa due to the presence of large amounts of polar lipids. The contributions of the individual activities of these species is however, not known. Therefore, the first objective of this study was to delineate the thermodynamic activities of ionized and unionized species and to determine their role in governing the total flux across buccal membrane. The flux of model acidic (nimesulide) and basic (bupivacaine) drugs across buccal mucosa either increased (nimesulide) or decreased (bupivacaine) with pH under saturated conditions depending on an increase (nimesulide) or decrease (bupivacaine) in the degree of saturation of ionized species (DS ionized). At sub-saturated drug concentrations, a decrease in nimesulide flux and an increase in bupivacaine flux were observed with pH due to corresponding changes in DSunionized. For nimesulide and bupivacaine, the contributions of the ionized and unionized species to total flux are equal when 90% of the drug is in the ionized form. In conclusion, the contribution of the ionized form activity to flux was significant.; A lack of a specific model for predicting buccal permeability has led to the use of transdermal models such as the Potts-Guy model. However, it is hypothesized that based on the above conclusion, this model might lead to erroneous permeability predictions. In the second part of this dissertation, a specific model was developed and validated by performing permeation studies of 15 small molecules across porcine buccal mucosa. Molecular volume, lipophilicity, number of hydrogen bond donors and number of rotatable bonds were found to be the most significant descriptors governing buccal permeability (logK p) based on stepwise regression analysis. An excellent fit with an adjusted R2 of 0.946 and a Q2 of 0.882 were obtained. A good correlation was observed between the observed and predicted logKp values for an external data set.