In vitro
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- 作者：Satomi Onoue ; Hideyuki Sato ; Yohei Kawabata ; Takahiro Mizumoto ; Naofumi Hashimoto ; Shizuo Yamada
- 关键词：Cyclosporine A ; Dry powder inhaler ; Solid dispersion ; Asthma ; Anti-inflammation
- 刊名：Journal of Controlled Release
- 出版年：2009
- 出版时间：19 August 2009
- 年：2009
- 卷：138
- 期：1
- 页码：16-23
- 全文大小：969 K
文摘
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 Cmax values 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.