Westmeier Regina, Steckel Hartwig
Department of Pharmaceutics and Biopharmaceutics, Christian Albrecht University of Kiel, Gutenbergstr. 76, 24118 Kiel, Germany.
J Pharm Sci. 2008 Jun;97(6):2299-310. doi: 10.1002/jps.21154.
A precipitation process is used to produce combined particles consisting of two antiasthmatic drugs: salmeterol xinafoate and fluticasone propionate. To control the crystallisation of these particles, a micromixer is used to mix solvent and antisolvent flow. To produce particles in the respirable range, crystal growth inhibitors are added to the antisolvent flow. The obtained suspension is spray-dried afterwards to get a dry powder which can be further processed into inhalation drug products. It is found that a combination of polysorbate 80 and hydroxypropylmethyl cellulose (HPMC) represents the best excipient combination. It is supposed that the smaller molecule polysorbate rapidly stabilises the particle surface and with this inhibits crystal growth, whereas HPMC is observed to produce spherical particles during the spray-drying process acting as lubricant and dispersion-modifier. The processed particles show a needlelike habit and, therefore, tend to form aggregates. When dispersed from an inhaler device, they are only moderately disaggregated. The deposition of the single drugs salmeterol xinafoate and fluticasone propionate on the stages of the NGI shows a very uniform distribution, indicating that both drugs are evenly dispensed, with an FPF of about 22% for the combined particles which corresponds to the deposition of the marketed product.
昔萘酸沙美特罗和丙酸氟替卡松。为了控制这些颗粒的结晶过程，使用微混合器来混合溶剂流和反溶剂流。为了制备可吸入范围内的颗粒，在反溶剂流中加入晶体生长抑制剂。随后将得到的悬浮液进行喷雾干燥，得到干粉，该干粉可进一步加工成吸入用药品。研究发现，聚山梨酯80和羟丙基甲基纤维素（HPMC）的组合是最佳的辅料组合。据推测，较小分子的聚山梨酯能迅速稳定颗粒表面，从而抑制晶体生长，而在喷雾干燥过程中观察到HPMC能产生球形颗粒，起到润滑剂和分散改性剂的作用。加工后的颗粒呈现针状习性，因此容易形成聚集体。当从吸入装置中分散出来时，它们只是适度地解聚。昔萘酸沙美特罗和丙酸氟替卡松这两种单一药物在下一代撞击器（NGI）各级上的沉积显示出非常均匀的分布，这表明两种药物都能均匀分布，复合颗粒的细颗粒分数（FPF）约为22%，与市售产品的沉积情况相当。
