(T1030-04-26) Oral Cavity Permeability Assessment Using Sublingual and Buccal In Vitro Tissue Models

Purpose: The oral cavity is a viable route for administration of drugs that exhibit significant hepatic first-pass extraction. Following intraoral administration, absorption of dissolved drug occurs predominantly by passive diffusion via the buccal and sublingual mucosa resulting in local and/or systemic pharmacological effects. The aim of this study was to quantitatively assess mucosal permeation properties of selected active pharmaceutical ingredients (APIs) from oral cavity drug products approved by the U.S. Food and Drug Administration using in vitro models of the sublingual and buccal tissue barriers.

Methods: Time-dependent transmucosal flux of acyclovir, apomorphine, asenapine, buprenorphine, fentanyl, naloxone, sufentanil, and zolpidem was measured up to 120 minutes using filter-grown human HO-1-U-1 cells as an in vitro tissue model of the sublingual mucosa and the organotypic EpiOral™ tissue model (MatTek Corp., Ashland, MA) for assessing in vitro buccal permeability. Transport experiments were initiated by apical addition of a filtered drug solution that was obtained after 20 min dissolution of the API (as per labelled dose of respective drug products) in 5 mL of artificial saliva, pH 6.8. The receiver compartment was filled with Hanks' Balanced Salt Solution, pH 7.4 (HBSS). All experiments were performed at least in triplicate using a shaking water bath maintained at 37°C (50 rpm). At predetermined time intervals, an aliquot was removed from the receiver compartment and stored at -20°C until quantitative analysis. The volume removed was replaced with fresh, prewarmed HBSS. At the end of the experiment, samples from tissue barrier and donor compartment were removed for mass-balance calculations. Drug concentrations were quantified by high-performance liquid chromatography using either UV or mass spectroscopy detection. Apparent permeability coefficient (Papp) values were calculated from the linear flux according to: Papp = dQ/dt × 1/A×C₀
where dQ/dt = the linear mass appearance rate in receiver compartment, Co = initial drug concentration in donor compartment, and A = surface area available for diffusion in cm².

Results: Calculated Papp values for the selected APIs across the sublingual HO-1-U-1 tissue model ranged from 2.72 ± 0.06 × 10^-5 cm/s for asenapine to 6.21 ± 2.60 × 10^-5 cm/s for naloxone. Tissue-associated dose fraction recovered at the end of the transport experiment varied between 0.4% for naloxone and 6.6% for asenapine, while overall mass-balance was >80%. In contrast, Papp values estimated for the same API across the buccal EpiOral™ tissue model demonstrated a significantly greater diversity ranging over two orders of magnitude (Papp = 0.33 ± 0.08 × 10^-6 cm/s for acyclovir and Papp = 25.60 ± 6.80 × 10^-6 cm/s for sufentanil, respectively). Tissue-associated dose fraction recovered at the end of the transport experiment across this in vitro model of the buccal mucosa varied between 0.1% for acyclovir and 8.5% for sufentanil, with a greater variability in overall mass-balance between 50.1% for buprenorphine and 110.2% for acyclovir.

Conclusion: Permeation assessment of the selected APIs that varies in lipophilicity from logP = -1.2 to 4.5 and in molecular weight from 225.3 Da to 764.9 Da reveals greater discrimination power with the buccal than the sublingual in vitro tissue model. This result appears to correlate with the difference in tissue barrier thickness reported for these two in vitro models. Tissue-associated drug fraction recovered at the end of the transport experiment across the thicker, organotypic EpiOral™ buccal tissue model is greater for lipophilic, high-permeability than for hydrophilic, low-permeability solutes. This implies that solutes predicted to permeate this tissue barrier predominantly via the paracellular pathway exhibit limited binding with cellular components of this in vitro model of the buccal mucosa. Physicochemical properties of APIs appear to have a greater impact on the rate and extent of the drug fraction absorbed via the buccal route when compared to the sublingual route.

Acknowledgements: The project was funded by a contract from the U.S. Food and Drug Administration (contract # 75F40120C00150). The views expressed here do not reflect official policies of the U.S. FDA or the Department of Health and Human Services, nor does any mention of trade names imply endorsement by the U.S. Government.