University of Alberta, Department of Mechanical Engineering, Edmonton, AB, Canada.
Chiesi Limited, Chippenham, Wiltshire, United Kingdom.
Int J Pharm. 2017 Mar 30;520(1-2):207-215. doi: 10.1016/j.ijpharm.2017.01.062. Epub 2017 Feb 3.
The effects of propellant type, cosolvent content, and air humidity on the morphology and solid phase of the particles produced from solution pressurized metered dose inhalers containing the corticosteroid beclomethasone dipropionate were investigated. The active ingredient was dissolved in the HFA propellants 134a and 227ea with varying levels of the cosolvent ethanol and filled into pressurized metered dose inhalers. Inhalers were actuated into an evaporation chamber under controlled temperature and humidity conditions and sampled using a single nozzle, single stage inertial impactor. Particle morphology was assessed qualitatively using field emission scanning electron microscopy and focused ion beam-helium ion microscopy. Drug solid phase was assessed using Raman microscopy. The relative humidity of the air during inhaler actuation was found to have a strong effect on the particle morphology, with solid spheroidal particles produced in dry air and highly porous particles produced at higher humidity levels. Air humidification was found to have no effect on the solid phase of the drug particles, which was predominantly amorphous for all tested formulations. A critical level of air relative humidity was required to generate porous particles for each tested formulation. This critical relative humidity was found to depend on the amount of ethanol used in the inhaler, but not on the type of propellant utilized. The results indicate that under the right circumstances water vapor saturation followed by nucleated water condensation or ice deposition occurs during particle formation from evaporating propellant-cosolvent-BDP droplets. This finding reveals the importance of condensed water or ice as a templating agent for porosity when particle formation occurs at saturated conditions, with possible implications on the pharmacokinetics of solution pMDIs and potential applications in particle engineering for drug delivery.
研究了推进剂类型、共溶剂含量和空气湿度对含有皮质类固醇倍氯米松二丙酸酯的溶液加压计量吸入器产生的颗粒的形态和固相的影响。将活性成分溶解在 HFA 推进剂 134a 和 227ea 中，其中含有不同水平的共溶剂乙醇，并将其填充到加压计量吸入器中。在受控温度和湿度条件下，将吸入器致动到蒸发室中，并使用单喷嘴、单级惯性冲击器进行采样。使用场发射扫描电子显微镜和聚焦离子束-氦离子显微镜对颗粒形态进行定性评估。使用拉曼显微镜评估药物固相。发现吸入器致动过程中的空气相对湿度对颗粒形态有很强的影响，在干燥空气中产生固体球形颗粒，在较高湿度水平下产生高度多孔的颗粒。发现空气加湿对药物颗粒的固相没有影响，所有测试配方的药物固相主要为无定形。对于每种测试配方，都需要一个临界空气相对湿度水平才能生成多孔颗粒。发现这个临界相对湿度取决于吸入器中使用的乙醇量，但与所使用的推进剂类型无关。结果表明，在适当的条件下，在蒸发的推进剂-共溶剂-BDP 液滴形成颗粒的过程中，水蒸气饱和后会发生成核水蒸气冷凝或冰沉积。这一发现揭示了在饱和条件下形成颗粒时冷凝水或冰作为多孔性模板剂的重要性，这可能对溶液 pMDIs 的药代动力学产生影响，并可能在药物输送的颗粒工程中有潜在应用。
