Pharmaceutical research · 2026
Development of an In Vitro Permeation Test Framework For Naloxone Hydrochloride Intranasal Spray: Establishing IVIVR for Bioequivalence Assessment.
СтатьяНазвание и аннотация: Перевод в очереди
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Sultana Tasmin Ara, Al-Ghabeish Manar, Chopski Steven, Walenga Ross, Shakleya Diaa, Newman Bryan, Ashraf Muhammad, Zidan Ahmed
Аннотация
PURPOSE: Intranasal (IN) naloxone achieves rapid systemic exposure necessary for effective opioid overdose reversal; yet establishing bioequivalence (BE) for fast-acting drug-device combination products remains challenging due to the interplay of formulation attributes, device performance, and nasal physiology. This study developed an in vitro permeation test (IVPT) approach designed to quantitatively relate the nasal permeation behavior of naloxone to its clinical pharmacokinetic (PK) performance through an in vitro-in vivo relationship (IVIVR).
METHODS: Naloxone hydrochloride (Narcan®, 4 mg/0.1 mL) was deposited onto artificial membranes and EpiAirway™ mucociliary tissues using a controlled aerosol-deposition system (VITROCELL® Cloud Alpha 12). Naloxone permeation was assessed under sink conditions using a validated LC-MS/MS method. Cumulative permeation at 20 and 120 min (F₂₀ and F₁₂₀, respectively) was correlated with clinical maximum plasma concentration (Cmax) and area under the curve from time zero to infinity (AUC₀-∞) to construct IVIVR models, supplemented by exploratory point-to-point in vitro-in vivo extrapolation (IVIVE) using Wagner-Nelson deconvolution.
RESULTS: Permeation profiles differed by substrate, with the hydrophilic membranes showing higher dissolution rates and EpiAirway™ tissues demonstrating dose-proportional transport despite lower deposited mass. The tissue-based IVIVR models showed strong linearity (R2 > 0.98) and mean prediction errors within accepted limits (≤ 10%), while artificial membranes consistently overpredicted the systemic exposure. IVIVE analysis further supported close temporal agreement with clinical absorption patterns.
CONCLUSION: These findings indicate that a tissue-based IVPT-IVIVR framework may provide a translational tool for relating in vitro permeation behavior to systemic exposure, supporting its utility in formulation development and BE risk assessment of rapidly acting IN naloxone products.
METHODS: Naloxone hydrochloride (Narcan®, 4 mg/0.1 mL) was deposited onto artificial membranes and EpiAirway™ mucociliary tissues using a controlled aerosol-deposition system (VITROCELL® Cloud Alpha 12). Naloxone permeation was assessed under sink conditions using a validated LC-MS/MS method. Cumulative permeation at 20 and 120 min (F₂₀ and F₁₂₀, respectively) was correlated with clinical maximum plasma concentration (Cmax) and area under the curve from time zero to infinity (AUC₀-∞) to construct IVIVR models, supplemented by exploratory point-to-point in vitro-in vivo extrapolation (IVIVE) using Wagner-Nelson deconvolution.
RESULTS: Permeation profiles differed by substrate, with the hydrophilic membranes showing higher dissolution rates and EpiAirway™ tissues demonstrating dose-proportional transport despite lower deposited mass. The tissue-based IVIVR models showed strong linearity (R2 > 0.98) and mean prediction errors within accepted limits (≤ 10%), while artificial membranes consistently overpredicted the systemic exposure. IVIVE analysis further supported close temporal agreement with clinical absorption patterns.
CONCLUSION: These findings indicate that a tissue-based IVPT-IVIVR framework may provide a translational tool for relating in vitro permeation behavior to systemic exposure, supporting its utility in formulation development and BE risk assessment of rapidly acting IN naloxone products.