Suzuki Hiroki, Ueno Kodai, Mizumoto Takahiro, Seto Yoshiki, Sato Hideyuki, Onoue Satomi
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Sales Department, ILS Inc., 1-2-1 Kubogaoka, Moriya, Ibaraki 302-0104, Japan.
Eur J Pharm Sci. 2017 Jan 1;96:107-114. doi: 10.1016/j.ejps.2016.09.015. Epub 2016 Sep 12.
The present study aimed to develop an inhalable self-micellizing solid dispersion of cyclosporine A (SMSD/CsA) for the direct delivery to the respiratory system with improved therapeutic efficacy and minimized systemic exposure. SMSD/CsA was obtained by wet-milling, and then jet-milled SMSD/CsA was blended with lactose carrier, producing a respirable powder of SMSD/CsA (SMSD/CsA-RP). The physicochemical, pharmacological, and pharmacokinetic properties of SMSD/CsA-RP were characterized, and the hepatotoxic and nephrotoxic potentials were investigated by biomarker analysis. Cascade impactor analysis demonstrated that SMSD/CsA-RP had high in vitro inhalation performance, with a fine particle fraction of 36%. In simulated lung fluid, the SMSD/CsA exhibited better dissolution behavior than amorphous CsA. Pretreatment with SMSD/CsA-RP resulted in significant suppression of antigen-evoked inflammatory events in rats. After intratracheal administration of SMSD/CsA-RP at a pharmacologically effective dose (100μg-CsA/rat), the AUC value was <1% of that after oral administration of Neoral at a toxic dose (10mg-CsA/kg). Compared with oral Neoral, insufflated SMSD/CsA-RP showed 99% reductions of CsA concentrations in both liver and kidney. No significant increases of biomarker levels in plasma were observed even after repeated intratracheal administration of SMSD/CsA-RP for 7days. From these findings, SMSD/CsA-RP might be a favorable dosage form for effective and safe inhalation therapy of CsA.
本研究旨在开发一种可吸入的环孢素A自微乳化固体分散体（SMSD/CsA），用于直接递送至呼吸系统，以提高治疗效果并使全身暴露最小化。通过湿磨获得SMSD/CsA，然后将喷射研磨的SMSD/CsA与乳糖载体混合，制得可吸入的SMSD/CsA粉末（SMSD/CsA-RP）。对SMSD/CsA-RP的物理化学、药理和药代动力学性质进行了表征，并通过生物标志物分析研究了其肝毒性和肾毒性潜力。级联撞击器分析表明，SMSD/CsA-RP具有较高的体外吸入性能，细颗粒分数为36%。在模拟肺液中，SMSD/CsA表现出比无定形环孢素A更好的溶解行为。用SMSD/CsA-RP预处理可显著抑制大鼠抗原诱发的炎症事件。以药理有效剂量（100μg-环孢素A/大鼠）气管内给予SMSD/CsA-RP后，AUC值低于以毒性剂量（10mg-环孢素A/kg）口服Neoral后的1%。与口服Neoral相比，吹入SMSD/CsA-RP后肝脏和肾脏中环孢素A的浓度降低了99%。即使在气管内重复给予SMSD/CsA-RP 7天后，血浆中生物标志物水平也未观察到显著升高。基于这些发现，SMSD/CsA-RP可能是环孢素A有效和安全吸入治疗的理想剂型。
