Self-micellizing solid dispersion of cyclosporine A for pulmonary delivery: Physicochemical, pharmacokinetic and safety assessments

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• 作者：Hiroki Suzuki^a ; Kodai Ueno^a ; Takahiro Mizumoto^b ; Yoshiki Seto^a ; Hideyuki Sato^a ; Satomi Onoue^a ; ^{onoue@u-shizuoka-ken.ac.jp}
• 关键词：AUC ; area under the curve of blood concentration versus time curve ; BALF ; bronchoalveolar lavage fluid ; BUN ; blood urea nitrogen ; Cmax ; maximum concentration ; CsA ; cyclosporine A ; CsA-RP ; amorphous cyclosporine A-based respirable powder ; FPD ; fine particle dose ; FPF ; fine particle fraction ; HPMC ; hydroxypropyl methylcellulose ; MPO ; myeloperoxidase ; OVA ; ovalbumin ; OVA-RP ; ovalbumin-based respirable powder ; PBS ; phosphate buffer solution ; RP ; respirable powder ; SMSD/CsA-RP ; self-micellizing solid
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：96
• 期：Complete
• 页码：107-114
• 全文大小：866 K
• 卷排序：96

文摘

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 (100 μg-CsA/rat), the AUC0–24 value was < 1% of that after oral administration of Neoral® at a toxic dose (10 mg-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 7 days. From these findings, SMSD/CsA-RP might be a favorable dosage form for effective and safe inhalation therapy of CsA.