(T1130-03-17) Oral Cavity Permeation of Buprenorphine Across In Vitro Models of the Buccal and Gingival Mucosa

Purpose: Buprenorphine, a semi-synthetic opioid with partial agonist activity at the mu receptor, is used to treat opioid use disorder and pain. The aim of this study was to quantitatively compare in vitro buccal and gingival permeability as well as local tissue retention measured for the active pharmaceutical ingredient (API), buprenorphine hydrochloride, when dissolved as powder in artificial saliva or released after short-term dissolution in artificial saliva from an FDA-approved oral cavity drug product. The results may provide insights into the impact of formulation excipients on permeation and local tissue deposition of this API within different mucosal regions of the oral cavity that may need consideration during development of generic drug products intended for oral cavity administration.

Methods: Transmucosal flux of the API was measured across the human-derived, organotypic tissue model of the buccal (EpiOral™) and gingival (EpiGingival™) mucosa (MatTek Corp., Ashland, MA). Transport experiments were initiated by adding the filtered drug solution that was prepared from powder in 5 mL of artificial saliva, pH 6.7, or released after a 20-min dissolution of 8 mg buprenorphine HCl sublingual tablets (Akorn Pharmaceuticals, Lake Forest, IL) in the same volume of artificial saliva to the apical compartment. Time-dependent samples from the receiver compartment that was filled with Hanks' Balanced Salt Solution, pH 7.4 (HBSS) were removed up to 120 minutes and stored at -20°C until quantitative analysis using reverse phase high-performance liquid chromatography coupled with mass spectroscopy detection. The mobile phase was comprised of 0.1% (v/v) formic acid in methanol at a flow rate of 0.8mL/min. To maintain sink conditions, the sample volume removed from the receiver compartment was always replaced with fresh, prewarmed HBSS. At the end of the experiment, the tissue model was collected and buprenorphine was extracted using 10% (v/v) acetonitrile in HBSS to quantify the cell-associated drug fraction. All experiments were performed at least in triplicate at 37°C using a shaking water bath maintained at 50 rpm. Apparent permeability coefficients (Papp) were calculated from the linear flux and compared statistically using unpaired Student’s t-test.

Results: The Papp values calculated from the linear flux of buprenorphine across the EpiGingival™ tissue model demonstrated comparable permeability of this mucosal barrier for the API when dissolved as powder in artificial saliva or released from the finished dosage form into artificial saliva (Papp = 1.36±0.06 × 10^-5 cm/s vs. Papp = 1.53±0.02 × 10^-5). Similarly, EpiOral™ permeation properties of the API dissolved as powder in artificial saliva or released from the sublingual tablet into artificial saliva were comparable (Papp = 1.39±0.08 × 10^-5 cm/s vs. Papp = 1.64±0.26 × 10^-5). While the fraction of buprenorphine retained in the EpiGingival™ tissue model after a 120 min exposure was at least 50% greater than in the Epioral™ tissue model, the results from this study revealed no significant effect of inactive formulation excipients on mucosal tissue deposition (Table 1).

Conclusion: Quantitative comparison of in vitro buccal and gingival permeation properties of buprenorphine using the human-derived, organotypic EpiOral™ and EpiGingival™ tissue models demonstrate comparable mucosal permeability for this semi-synthetic opioid. As the increased drug fraction measured after prolonged exposure in the EpiGingival™ tissue model was not affected by formulation excipients used in marketed sublingual tablets, these results. may suggest greater affinity of buprenorphine for cellular components of the gingival mucosa when compared to buccal epithelial tissue. Further research is needed to delineate whether the increased tissue concentrations of buprenorphine in gingival epithelial tissue compared to the buccal mucosa may provide a mechanistic hypothesis suitable to explain idiopathic dental problems observed with long-term use of buprenorphine-containing oral cavity drug products (FDA, 2022).

References: FDA, 2022 “Buprenorphine: Durg Safety Communication – FDA warns about dental problems with buprenorphine medicines dissolved in the mouth to treat opioid use disorders and pain” (https://www.fda.gov/safety/medical-product-safety-information/buprenorphine-drug-safety-communication-fda-warns-about-dental-problems-buprenorphine-medicines); accessed last on April 4, 2024

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.


Table 1: Buprenorphine Retention in Epithelial Tissue after a 120 min Exposure