In-vitro Evaluation of Solution Pressurised Metered Dose Inhaler Sprays with Low-GWP Propellants.

IF 4.3 3区医学 Q2 CHEMISTRY, MULTIDISCIPLINARY Pharmaceutical Research Pub Date : 2025-02-01 Epub Date: 2025-02-12 DOI:10.1007/s11095-025-03830-6

Daniel J Duke, Lingzhe Rao, Benjamin Myatt, Phil Cocks, Stephen Stein, Nirmal Marasini, Hui Xin Ong, Paul Young

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Abstract

Purpose: The transition from high Global Warming Potential (GWP) propellants such as HFA134a to low-GWP alternatives such as HFA152a and HFO1234ze(E) in pressurised metered dose inhalers (pMDIs) poses a number of challenges for inhaled pharmaceutical product development. Changes in chemicophysical properties will alter product performance, impacting in-vitro bioequivalence metrics. This study investigates those differences using equivalent pMDI hardware and formulations.

Methods: Aerodynamic particle size distribution (APSD) measurements, laser diffraction and high-speed imaging were used to compare the performance of HFA134a, HFA152a and HFO1234ze(E) solution formulations of beclomethasone dipropionate. Propellant-only placebos, cosolvent-free solutions, and ethanol solutions at 8% and 15% w/w were investigated.

Results: HFA152a formulations had increased drug deposition on the actuator and throat while HFO1234ze(E) produced comparable APSD performance to HFA134a formulations. Plumes from HFA152a formulations spread more rapidly and were less stable and repeatable than those from HFA134a. HFO1234ze(E) plumes spread more slowly than HFA134a, but converged with HFA134a ex-mouthpiece. Differences between propellants were moderated by the addition of ethanol.

Conclusion: Plume stability is a driver of differences between formulations in the near-orifice region. Shot-to-shot repeatability differences are more pronounced ex-mouthpiece, where mixing with ambient air is dominant. Modifications to low-GWP pMDI product actuator orifice and mouthpiece geometries may provide a route to improved in-vitro product bioequivalence relative to current pMDIs. Differences between formulations are modest and may be managed through a combination of formulation, orifice and mouthpiece geometry changes. These generic formulations provide a database of benchmark data against which the performance of low-GWP products may be compared.

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低gwp推进剂溶液加压计量吸入器喷雾剂的体外评价。

目的：从高压计量吸入器（pmdi）中的高全球变暖潜能值（GWP）推进剂（如HFA134a）到低GWP替代品（如HFA152a和HFO1234ze(E)）的转变为吸入式药物产品的开发带来了许多挑战。化学物理性质的变化将改变产品性能，影响体外生物等效性指标。本研究使用等效pMDI硬件和配方来调查这些差异。方法：采用气动粒径分布（APSD）测量、激光衍射和高速成像等方法，比较HFA134a、HFA152a和HFO1234ze(E)三种二丙酸倍氯米松溶液配方的性能。研究了纯推进剂安慰剂、无助溶剂溶液和8%和15% w/w的乙醇溶液。结果：HFA152a制剂增加了致动器和喉部的药物沉积，而HFO1234ze(E)的APSD性能与HFA134a制剂相当。与HFA134a相比，HFA152a配方的羽流传播速度更快，稳定性和可重复性也更差。HFO1234ze(E)羽流扩散速度比HFA134a慢，但与HFA134a前口汇合。推进剂之间的差异被乙醇的加入所缓和。结论：羽流稳定性是近孔区配方差异的驱动因素。枪对枪的重复性差异在吸嘴前更为明显，在那里与周围空气混合是主要的。对低gwp pMDI产品致动器孔口和吹口几何形状的修改可能提供一种相对于当前pMDI改善体外产品生物等效性的途径。配方之间的差异是适度的，可以通过配方、孔口和吹口几何形状变化的组合来管理。这些通用配方提供了一个基准数据数据库，可与低gwp产品的性能进行比较。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pharmaceutical Research 医学-化学综合

CiteScore

6.60

自引率

5.40%

发文量

276

审稿时长

3.4 months

期刊介绍： Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to: -(pre)formulation engineering and processing- computational biopharmaceutics- drug delivery and targeting- molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)- pharmacokinetics, pharmacodynamics and pharmacogenetics. Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.