Sensitivity of Pharmacokinetics to Differences in the Particle Size Distribution for Formulations of Locally Acting Mometasone Furoate Suspension-Based Nasal Sprays

To assess bioequivalence of locally acting suspension-based nasal sprays, the U.S. FDA currently recommends a weight-of-evidence approach. In addition to in vitro and human pharmacokinetic (PK) studies, this includes a comparative clinical endpoint study to ensure equivalent bioavailability of the a...

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Published in:Molecular pharmaceutics 2023-11, Vol.20 (11), p.5690-5700
Main Authors: Amini, Elham, Berger, Simon M., Schilling, Uta, Jiao, Yuanyuan, Chen, Mong-Jen, Bachhav, Sagar, Baumstein, Sandra M., Tang, Yufei, Al-Humiari, Mohammed, Leon Astudillo, Carmen E., Drescher, Stefanie, Iley, Teresa, Shur, Jagdeep, Price, Robert, Carrasco, Cynthia, Conti, Denise S., Delvadia, Renishkumar, Oguntimein, Oluwamurewa, Witzmann, Kimberly, Absar, Mohammad, Luke, Markham C., Boc, Susan, Dhapare, Sneha, Saluja, Bhawana, Bielski, Elizabeth, Newman, Bryan, Bulitta, Jürgen B., Hochhaus, Günther
Format: Article
Language:English
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Summary:To assess bioequivalence of locally acting suspension-based nasal sprays, the U.S. FDA currently recommends a weight-of-evidence approach. In addition to in vitro and human pharmacokinetic (PK) studies, this includes a comparative clinical endpoint study to ensure equivalent bioavailability of the active pharmaceutical ingredient (API) at the site of action. The present study aimed to assess, within an in vitro/in vivo correlation paradigm, whether PK studies and dissolution kinetics are sensitive to differences in drug particle size for a locally acting suspension-based nasal spray product. Two investigational suspension-based nasal formulations of mometasone furoate (MF-I and MF-II; delivered dose: 180 μg) differed in API particle size and were compared in a single-center, double-blind, single-dose, randomized, two-way crossover PK study in 44 healthy subjects with oral charcoal block. Morphology-directed Raman spectroscopy yielded volume median diameters of 3.17 μm for MF-I and 5.50 μm for MF-II, and dissolution studies showed that MF-II had a slower dissolution profile than MF-I. The formulation with larger API particles (MF-II) showed a 45% smaller C max and 45% smaller AUC0‑inf compared to those of MF-I. Systemic bioavailability of MF-I (2.20%) and MF-II (1.18%) correlated well with the dissolution kinetics, with the faster dissolving formulation yielding the higher bioavailability. This agreement between pharmacokinetics and dissolution kinetics cross-validated both methods and supported their use in assessing potential differences in slowly dissolving suspension-based nasal spray products.
ISSN:1543-8384
1543-8392
DOI:10.1021/acs.molpharmaceut.3c00553