Transbuccal delivery of acyclovir: I. In vitro determination of routes of buccal transport

PURPOSE: To determine the major routes of buccal transport of acyclovir and to examine the effects of pH and permeation enhancer on drug permeation. METHODS: Permeation of acyclovir across porcine buccal mucosa was studied by using side-by-side through diffusion cells at 37 degrees C. The permeability of acyclovir was determined at pH range of 3.3 to 8.8. Permeability of different ionic species was calculated by fitting the permeation of data to a mathematical model. Acyclovir was quantified using HPLC. RESULTS: Higher steady state fluxes were observed at pH 3.3 and 8.8. The partition coefficient (1-octanol/buffer) and the solubility of acyclovir showed the same pH dependent profile as that of drug permeation. In the presence of sodium glycocholate (NaGC) (2-100 mM), the permeability of acyclovir across buccal mucosa was increased 2 to 9 times. This enhancement was independent of pH and reached a plateau above the critical micelle concentration of NaGC. The permeabilities of anionic, cationic, and zwitterionic species were 3.83 X 10-5, 4.33 X 10-5, and 6.24 x 10-6 cm/sec, respectively. CONCLUSIONS: The in vitro permeability of acyclovir across porcine buccal mucosa and the octanol-water partitioning of the drug were pH dependent. A model of the paracellular permeation of the anionic, cationic, and zwitterionic forms of acyclovir is consistent with these data. The paracellular route was the primary route of buccal transport of acyclovir, and the enhancement of transbuccal transport of acyclovir by sodium glycocholate (NaGC) appeared to operate via this paracellular route.