(T0930-04-22) Mechanistic In Vitro Oral Absorption Model to Predict Mucosal Permeability of Oral Cavity Drug Products

Purpose: Drug administration via the intraoral route offers several benefits, such as patient compliance, ease of drug administration and potential bypass of the first-pass elimination. These advantages are particularly relevant for drug products (DPs) designed for specific populations or active pharmaceutical ingredients (APIs) with high hepatic extraction rates. Given the limited surface area of the oral cavity and its distinct physiology, oral mucosal permeability is critical for effective drug absorption. The buccal absorption of five DPs and their corresponding APIs were assessed for in vitro permeability employing the organotypic EpiOral™ (ORL-200, MatTek Corp., Ashland, MA) tissue model, which mimics human buccal mucosa tissue. We developed a mechanistic in silico model that deconvolutes EpiOral™ in vitro permeability measurements into drug diffusivity (D_m) and unbound fraction in epithelium tissue (f_ut) within the oral mucosal barrier. This study compares the predicted D_m and f_ut of five DPs and their corresponding APIs to identify differences in permeation between API and DP. The analysis provides insights into possible effect of formulation on API oral mucosal permeability and enables in vitro to in vivo translation of intraoral absorption for physiologically based pharmacokinetic modelling (PBPK) framework of intraoral (IO) dosage forms.

Methods: The in silico model for EpiOral™ assay (MembranePlus™, beta version, Simulations Plus Inc., Lancaster, CA) simulates drug diffusion through the tissue layers of EpiOral™ tissue model, integrating protein binding of the drug in the media, and accumulation of the drug in the tissue and the receiver compartment. The model incorporates the impact of drug depletion through sampling and the replacement of the media [i.e., Hank's Balanced Salt Solution (HBSS) buffer pH 7.4] and non-specific loss (e.g., evaporation, drug binding to the plasticware) in the received side. The model was used to estimate D_m and f_ut in the oral mucosa tissue for five APIs and DPs [APIs: Buprenorphine HCl, Fentanyl Citrate, Sufentanil Citrate, Rizatriptan Benzoate and Zolpidem Tartrate and DPs: Zubsolv® (Buprenorphine sublingual tablet) Eq. 2 mg base, Fentora® (Fentanyl buccal tablet) Eq. 0.1 mg base, Dsuvia® (Sufentanil sublingual tablet) Eq. 0.03 mg base, Rizatriptan Benzoate (Orally disintegrating tablet) Eq. 10 mg base, and Edluar® (Zolpidem sublingual tablet ) Eq. 10 mg base] based on the in vitro permeation studies from the EpiOral™ assay. Additionally, sources of inter-batch variability in the measurements were identified through Parameter Sensitivity Analysis (PSA).

Results: The mechanistic in silico model compared the predictions of EpiOral™ D_m and f_ut for five APIs and DPs approved by U.S. Food and Drug Administration (FDA) for oral cavity administration. Simulations for four API-DP pairs indicated no excipient effect on API permeation as predicted D_m and f_ut against the experimental data obtained with API alone accurately described API permeation from DP. Among the evaluated DPs, only Fentanyl DP simulations showed that excipients may impact its permeability. This was demonstrated by a time-dependent D_m (9.63e-7 cm²/s until 0.5 hours, 3.428e-6 cm²/s, from 0.5 to 1.5 hours and 5.65e-6 cm²/s from 1.5 to 2 hours) for fentanyl when administered in a DP. For all evaluated APIs and DPs, PSA identified the tissue thickness (physiological range- 90-140um) of the organotypic EpiOral™ assay as one of the main sources of inter-batch variability of EpiOral™ tissue model.

Conclusion: Understanding the influence of excipients on APIs diffusion through the oral mucosa is vital for the successful development of oral cavity drug products. The developed in silico model offers a comprehensive estimation of organotypic EpiOral™ diffusivity and fraction unbound in the tissue for five intraoral DPs. This lays the groundwork for predictive modeling of drug absorption in the oral cavity, offering a tool for the rational design of intraoral drug products using in vitro assays. Future efforts will integrate this work to inform PBPK models for in vivo oral cavity absorption prediction, supporting the development of new and generic intraoral (IO) drug products under the model-integrated evidence framework.

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 US FDA or the Department of Health and Human Services, nor does any mention of trade names imply endorsement by the US Government.