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Purpose <p>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 <i>in vitro</i> permeation test (IVPT) approach designed to quantitatively relate the nasal permeation behavior of naloxone to its clinical pharmacokinetic (PK) performance through an <i>in vitro</i>–<i>in vivo</i> relationship (IVIVR).</p> Methods <p>Naloxone hydrochloride (Narcan®, 4&#xa0;mg/0.1&#xa0;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&#xa0;min (F₂₀ and F₁₂₀, respectively) was correlated with clinical maximum plasma concentration (C<sub>max</sub>) and area under the curve from time zero to infinity (AUC₀<sub>–∞</sub>) to construct IVIVR models, supplemented by exploratory point-to-point <i>in vitro</i>–<i>in vivo </i>extrapolation (IVIVE) using Wagner–Nelson deconvolution.</p> Results <p>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 &gt; 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.</p> Conclusion <p>These findings indicate that a tissue-based IVPT–IVIVR framework may provide a translational tool for relating <i>in vitro</i> permeation behavior to systemic exposure, supporting its utility in formulation development and BE risk assessment of rapidly acting IN naloxone products.</p> Graphical Abstract <p>Schematic representation of intranasal naloxone <i>in vitro</i> permeation test using artificial membranes and EpiAirway™ tissues, integrated with a Level C IVIVR and point-to-point IVIVE analysis to predict systemic exposure.</p> <p></p>

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Development of an In Vitro Permeation Test Framework For Naloxone Hydrochloride Intranasal Spray: Establishing IVIVR for Bioequivalence Assessment

  • 期刊论文

  • 发表日期：

    2026年7月30日

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  • Tasmin Ara Sultana,
  • Manar Al-Ghabeish,
  • Steven Chopski,
  • Ross Walenga,
  • Diaa Shakleya,
  • Bryan Newman,
  • Muhammad Ashraf,
  • Ahmed Zidan

摘要

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.

Graphical Abstract

Schematic representation of intranasal naloxone in vitro permeation test using artificial membranes and EpiAirway™ tissues, integrated with a Level C IVIVR and point-to-point IVIVE analysis to predict systemic exposure.