Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, University of Shizuoka, Shizuoka, Japan.
Eur J Pharm Biopharm. 2012 Jan;80(1):54-60. doi: 10.1016/j.ejpb.2011.10.003. Epub 2011 Oct 8.
The main purpose of the present study was to develop a novel respirable powder (RP) formulation of cyclosporine A (CsA) using a spray-dried O/W-emulsion (DE) system. DE formulation of CsA (DE/CsA) was prepared by spray-drying a mixture of erythritol and liquid O/W emulsion containing CsA, polyvinylpyrrolidone, and glyceryl monooleate as emulsifying agent. The DE/CsA powders were mixed with lactose carriers to obtain an RP formulation of DE/CsA (DE/CsA-RP), and its physicochemical, pharmacological, and pharmacokinetic properties were evaluated. Spray-dried DE/CsA exhibited significant improvement in dissolution behavior with ca. 4500-fold increase of dissolution rate, and then, nanoemulsified particles were reconstituted with a mean diameter of 317 nm. Laser diffraction analysis on the DE/CsA-RP suggested high dispersion of DE/CsA on the surface of the lactose carrier. Anti-inflammatory properties of the inhaled DE/CsA-RP were characterized in antigen-sensitized asthma/COPD-model rats, in which the DE/CsA-RP was more potent than the RP formulation of physical mixture containing CsA and erythritol in inhibiting inflammatory responses, possibly due to the improved dissolution behavior. Pharmacokinetic studies demonstrated that systemic exposure of CsA after intratracheal administration of the DE/CsA-RP at a pharmacologically effective dose (100 μg-CsA/rat) was 50-fold less than that of the oral CsA dosage form at a toxic dose (10 mg/kg). From these findings, use of inhalable DE formulation of CsA might be a promising approach for the treatment of airway inflammatory diseases with improved pharmacodynamics and lower systemic exposure.
本研究的主要目的是开发一种新型的环孢素 A（CsA）可吸入粉末（RP）制剂，采用喷雾干燥的 O/W-乳液（DE）系统。通过喷雾干燥含有 CsA、聚乙烯吡咯烷酮和甘油单油酸酯的赤藓糖醇和液体 O/W 乳液混合物来制备 CsA 的 DE 制剂（DE/CsA）。将 DE/CsA 粉末与乳糖载体混合以获得 DE/CsA 的 RP 制剂（DE/CsA-RP），并对其理化性质、药理学和药代动力学性质进行了评价。喷雾干燥的 DE/CsA 表现出显著改善的溶解行为，溶解速率约增加了 4500 倍，然后纳米乳粒再重构为平均直径为 317nm 的颗粒。对 DE/CsA-RP 的激光衍射分析表明，DE/CsA 高度分散在乳糖载体的表面上。在抗原致敏哮喘/COPD 模型大鼠中，研究了吸入 DE/CsA-RP 的抗炎特性，其中 DE/CsA-RP 比含有 CsA 和赤藓糖醇的物理混合物的 RP 制剂更能抑制炎症反应，这可能是由于改善了溶解行为。药代动力学研究表明，在以药理学有效剂量（100μg-CsA/大鼠）经气管内给予 DE/CsA-RP 后，CsA 的全身暴露量比毒性剂量（10mg/kg）的口服 CsA 剂型低 50 倍。从这些发现来看，使用可吸入的 DE 制剂的 CsA 可能是一种有前途的治疗气道炎症性疾病的方法，可改善药效学和降低全身暴露量。
