In vitro and in vivo characterization on amorphous solid dispersion of cyclosporine A for inhalation therapy

作者：Onoue Satomi^*; Sato Hideyuki; Kawabata Yohei; Mizumoto Takahiro; Hashimoto Naofumi; Yamada Shizuo

来源：Journal of Controlled Release, 2009, 138(1): 16-23.

DOI：10.1016/j.jconrel.2009.04.014

• Cyclosporine A
• Dry powder inhaler
• Solid dispersion
• Asthma
• Anti-inflammation

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 physicochernical 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 mu g 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 10(2)-fold reduced AUC and C(max) 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.

• 出版日期2009-8-19