Institute of Pharmaceutical Science, King's College London, London SE1 9NH, UK.
School of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
Int J Pharm. 2023 Mar 5;634:122676. doi: 10.1016/j.ijpharm.2023.122676. Epub 2023 Feb 3.
Given the environmental compulsion to reformulate pressurised metered dose inhalers (pMDI) using new propellants with lower global warming potential, this study investigated how non-volatile excipients can be used to engineer aerosol particle microphysics and drug release. The dynamics of change in particle size, wetting and physical state were measured for single particles (glycerol/ethanol/beclomethasone dipropionate; BDP) in the aerosol phase at different relative humidity (RH) using an electrodynamic balance. BDP dissolution rates were compared for aerosols from pMDI containing different ratios of BDP:glycerol or BDP:isopropyl myristate (IPM). In 45 % RH, ethanol loss was followed by evaporation of condensed water to generate spherical particles with solid inclusions or compact irregular-shaped solid particles, according to the presence or absence of glycerol. In RH > 95 %, condensed water did not evaporate and BDP formed solid inclusions in water/glycerol or water droplets. Varying the non-volatile component, 0-50 % w/w, in pMDI resulted in a concentration-dependent 4-8-fold reduction in BDP dissolution rate. These findings demonstrate that non-volatile excipients provide a means of engineering aerosol properties and, modifying the rate of drug release from aerosol medicines. We also demonstrated differences between particles formed in vitro in ambient humidity versus higher humidity, more like that encountered during oral inhalation.
鉴于环境压力需要用全球变暖潜能值较低的新型推进剂来重新配方压力定量吸入器（pMDI），本研究探讨了如何使用非挥发性赋形剂来设计气溶胶颗粒微观物理学和药物释放。使用电动天平在不同相对湿度（RH）下测量了单个颗粒（甘油/乙醇/丙酸倍氯米松；BDP）在气溶胶相中的粒径、润湿和物理状态变化的动力学。比较了含有不同比例 BDP:甘油或 BDP:肉豆蔻酸异丙酯（IPM）的 pMDI 产生的气雾剂中 BDP 的溶解速率。在 45% RH 下，随着乙醇的损失，浓缩水蒸发，生成含有固体包裹物的球形颗粒或含有致密不规则固体颗粒，这取决于是否存在甘油。在 RH>95%下，浓缩水不会蒸发，BDP 在水/甘油或水滴中形成固体包裹物。在 pMDI 中，非挥发性成分（0-50% w/w）的变化导致 BDP 溶解速率呈浓度依赖性降低 4-8 倍。这些发现表明，非挥发性赋形剂提供了一种设计气溶胶性质的手段，并可调节气雾剂药物的释放速率。我们还证明了在环境湿度下与在较高湿度下（更类似于口服吸入期间遇到的湿度）形成的颗粒之间的差异。
