University of Applied Sciences Northwestern Switzerland, School of Life Sciences, Institute of Pharmaceutical Technology, Muttenz/Basel, Switzerland; University of Basel, Department of Pharmaceutical Sciences, Basel, Switzerland.
University of Applied Sciences Northwestern Switzerland, School of Life Sciences, Institute of Pharmaceutical Technology, Muttenz/Basel, Switzerland.
Eur J Pharm Biopharm. 2020 Jan;146:19-31. doi: 10.1016/j.ejpb.2019.11.003. Epub 2019 Nov 15.
We combined high-energy wet media milling and spray drying to engineer dry powders for inhalation consisting of geometrically large, low-density particles with superior aerodynamic properties and fast dissolution. Peclet number proved to be a useful instrument to guide choice of the additives and process conditions for generating low-density powders by spray drying. Composite dry powders consisted of milled and stabilized budesonide nanoparticles, leucine or albumin as matrix formers, and ammonium carbonate as a pore former. Powders of different composition showed fairly large and comparable geometric particle sizes (d, > 4.4 µm) with effective densities strongly depending on the present matrix former. Powders with lowest density reached an aerosol performance of up to 60%, which is well above most commercial, carrier-based products. It was also demonstrated that the nanomilling step was indispensable to yield such good aerosol performance. Dissolution of aerodynamically classified particle fractions showed a very fast onset and was largely completed within 30 min irrespective of the formulation and the impactor stage. Mathematical kinetic modeling was used to deduce the API dissolution rate coefficient from the results obtained using a modified USP 2 apparatus. Dissolution rate was found to be determined by the properties of the API nanoparticles rather than those of the composite particles. The employment of industrially established, solely water-based processes allows introducing the presented approach as a platform technology for the development of well-performing pulmonary formulations.
我们结合高能湿磨和喷雾干燥技术，设计了用于吸入的干粉制剂，这些干粉制剂由具有优越空气动力学特性和快速溶解性能的大尺寸低密度颗粒组成。Peclet 数被证明是一种有用的工具，可用于指导通过喷雾干燥生成低密度粉末时添加剂和工艺条件的选择。复合干粉由研磨和稳定的布地奈德纳米颗粒、亮氨酸或白蛋白作为基质形成剂以及碳酸铵作为造孔剂组成。不同组成的粉末具有相当大且可比较的几何颗粒尺寸（d，>4.4μm），有效密度强烈依赖于当前的基质形成剂。密度最低的粉末达到了高达 60%的气溶胶性能，远高于大多数商业载体产品。还证明了纳米研磨步骤对于获得如此良好的气溶胶性能是必不可少的。空气动力学分类颗粒部分的溶解显示出非常快速的起始，并且在 30 分钟内基本完成，而与配方和撞击器阶段无关。数学动力学模型用于从使用改进的 USP 2 装置获得的结果中推导出 API 溶解速率系数。发现溶解速率由 API 纳米颗粒的性质决定，而不是复合颗粒的性质决定。采用工业上已建立的、仅基于水的工艺，可以将所提出的方法作为一种平台技术，用于开发性能良好的肺部制剂。
