Vartiainen Ville, Bimbo Luis M, Hirvonen Jouni, Kauppinen Esko I, Raula Janne
Faculty of Medicine, University of Helsinki, Clinicum, P.O. Box 22, FI-00014, Helsinki, Finland.
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5E), FI-00014, Helsinki, Finland.
Pharm Res. 2017 Jan;34(1):25-35. doi: 10.1007/s11095-016-2035-9. Epub 2016 Sep 7.
PURPOSE: The purpose of this study was to assess the feasibility of hydroxypropyl-β-cyclodextrin as a solubilizer for the corticosteroids prednisolone and fludrocortisone acetate in dry powder inhalation formulations. METHODS: The dry particles were simultaneously produced and coated with nanosized L-leucine crystals using an aerosol flow reactor method. The aerosolization performances of carrier-free powders were studied using Easyhaler® and Twister™ at 2 and 4 kPa pressure drops over the inhalers. Drug permeation properties of the formulations were tested across a Calu-3 cell monolayer. Toxicity and reactive oxygen species induction were tested against Calu-3 and A549 cell lines. RESULTS: The hydroxypropyl-β-cyclodextrin in the powders promoted the dissolution of fludrocortisone the most, followed by that of prednisolone. Fine particle fractions were 52-70% from emitted doses which showed good repeatability with a coefficient variation of 0.9-0.17. In addition, hydroxypropyl-β-cyclodextrin enhanced the permeation of the corticosteroids. The powders showed no statistically significant toxicity nor reactive oxygen species induction in the tested cell lines. CONCLUSIONS: This study demonstrated the preparation and function of fine powder formulations which combine improved dissolution of poorly soluble drugs with good aerosolization performance. These results are expected to promote particle engineering as a way to develop new types of therapeutic pulmonary powders.
目的:本研究旨在评估羟丙基-β-环糊精作为皮质类固醇泼尼松龙和醋酸氟氢可的松在干粉吸入制剂中的增溶剂的可行性。 方法:使用气溶胶流动反应器方法同时制备干燥颗粒并用纳米级L-亮氨酸晶体进行包衣。使用Easyhaler®和Twister™在吸入器上2和4 kPa的压降下研究无载体粉末的雾化性能。在Calu-3细胞单层上测试制剂的药物渗透特性。针对Calu-3和A549细胞系测试毒性和活性氧诱导情况。 结果:粉末中的羟丙基-β-环糊精对醋酸氟氢可的松的溶解促进作用最大,其次是泼尼松龙。细颗粒分数占发射剂量的52 - 70%,显示出良好的重复性,变异系数为0.9 - 0.17。此外,羟丙基-β-环糊精增强了皮质类固醇的渗透。在测试的细胞系中,这些粉末没有显示出统计学上显著的毒性或活性氧诱导。 结论:本研究证明了细粉制剂的制备和功能,该制剂将难溶性药物的改善溶解与良好的雾化性能相结合。这些结果有望促进颗粒工程作为开发新型治疗性肺部粉末的一种方式。
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