In vitro and in vivo characterization on amorphous solid dispersion of cyclosporine A for inhalation therapy.
In vitro and in vivo characterization on amorphous solid dispersion of cyclosporine A for inhalation therapy.
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DOI：
10.1016/j.jconrel.2009.04.014
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发表时间：
2009-08
期刊：
影响因子：
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通讯作者：
S. Onoue;Hideyuki Sato;Yohei Kawabata;T. Mizumoto;N. Hashimoto;S. Yamada
中科院分区：
文献类型：
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作者：
S. Onoue;Hideyuki Sato;Yohei Kawabata;T. Mizumoto;N. Hashimoto;S. Yamada
环孢菌素A（CsA）作为免疫抑制剂在临床上得到了广泛的应用，同时也为治疗气道炎症提供了新的途径。但CsA全身暴露后不良反应严重，溶解性差，限制了其临床应用。本研究利用湿磨CsA固体分散体（WM/CsA）研制了一种新型CsA可吸入粉剂（RP），并对WM/CsA及其RP制剂的理化和药理性质进行了表征。通过X射线粉末衍射和差示扫描量热法，发现CsA在固体分散体中是无定形的。与活性药物成分相比，它表现出改善的溶出行为。新开发的WM/CsA-RP，包括喷射研磨WM/CsA和乳糖载体的激光衍射和级联冲击器分析，建议高分散和沉积在呼吸器官中的发射剂量和细颗粒分数分别为96和54%。在实验性炎症大鼠中，WM/CsA-RP（100 µg CsA）经鼻给药导致支气管肺泡灌洗液和肺组织中的粒细胞募集分别减少71%和85%，与毒性浓度（10 mg/kg）的CsA口服剂型相比，血浆CsA的AUC和Cmax值降低约102倍。因此，WM/CsA-RP可能是临床治疗气道炎症的有效剂型，且全身副作用最小。
Cyclosporine A (CsA) has been clinically used as immunosuppressant, and new application for airway inflammation was also proposed. However, the clinical use of CsA was limited due to severe adverse effects after systemic exposure and the poor solubility. In the present investigation, novel respirable powder (RP) of CsA was developed for pulmonary administration with use of solid dispersion of wet-milled CsA (WM/CsA), and the physicochemical and pharmacological properties of the WM/CsA and its RP formulation were characterized. CsA in the solid dispersion was found to be amorphous by X-ray powder diffraction and differential scanning calorimetry. It exhibited the improved dissolution behavior as compared to active pharmaceutical ingredients. Laser diffraction and cascade impactor analysis of newly developed WM/CsA-RP, consisting of jet-milled WM/CsA and lactose carriers, suggested high dispersion and deposition in the respiratory organs with the emitted dose and the fine particle fraction of 96 and 54%, respectively. Intratracheal administration of WM/CsA-RP (100 µg CsA) in experimental inflammatory rats led to 71 and 85% reduction of granulocyte recruitment in bronchoalveolar lavage fluids and lung tissues, respectively, with showing ca 102-fold reduced AUC and Cmaxvalues of plasma CsA as compared to the oral dosage form of CsA at toxic concentration (10 mg/kg). Upon these findings, WM/CsA-RP would be efficacious dosage form for clinical treatment of airway inflammations with minimal systemic side effects.