Semifluorinated alkanes as a liquid drug carrier system for topical ocular drug delivery
Semifluorinated alkanes as a liquid drug carrier system for topical ocular drug delivery
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DOI：
10.1016/j.ejpb.2014.05.009
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发表时间：
2014-09-01
影响因子：
4.9
通讯作者：
Schrage, N.
中科院分区：
文献类型：
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作者：
Dutescu, R. M.;Panfil, C.;Schrage, N.
半氟化烷烃（SFA，例如全氟丁基戊烷F4 H5、全氟己基辛烷F6 H8）是能够溶解亲脂性药物的惰性、无毒液体。本研究的目的是评估的生物利用度和安全性的SFAs作为药物溶剂的局部眼部应用环孢素A（CsA）。将市售CsA制剂（蓖麻油中的Restasis（R）0.05%CsA）与（a）含乙醇（0.5 w/w%）的F4 H5和（B）含乙醇（0.5 w/w%）的F6 H8中的0.05%CSA和0.05%CsA的两种新制剂进行对比测试。在人工前房上培养的兔角膜上测试制剂，所述人工前房具有恒定流量的房水补充物（离体眼刺激测试（EVEIT）系统）。在多个时间点对前房液进行采样，以通过HPLC分析单次和重复应用方案后的CsA浓度。记录荧光素钠染色角膜的照片，用于角膜毒性评价。在药物施用后，通过荧光素钠角膜扩散实验测试制剂对角膜屏障功能完整性的影响。通过分析代谢标志物葡萄糖和乳酸来评价对角膜代谢的影响，Restasis（R）在短期应用后不能通过角膜屏障，CsA在乙醇F_4H_6中在前房液样品中达到最大值152.95ng/ml，而CsA在乙醇F_6H_8中达到最大值15.12ng/ml。重复应用8小时后，Restasis（R）达到21.07 ng/ml，而F4 H5和F6 H8分别为247.62 ng/ml和174.5 ng/ml。没有观察到角膜毒性在以下应用的任何formulation.In对比市售的蓖麻油为基础的配方，CsA溶解在SFA达到治疗眼内浓度后，局部给药，可能导致取代全身应用CsA的炎症性眼病。(C)© 2014 Elsevier B. V.保留所有权利。
Semifluorinated alkanes (SFA, e.g. perfluorobutylpentane F4H5, perfluorohexyloctane F6H8) are inert, non-toxic fluids capable of dissolving lipophilic drugs. The aim of this study to assess the bioavailability and safety of SFAs as drug solvents for the topical ocular application of Cyclosporin A (CsA). A commercially available CsA formulation (Restasis (R) 0.05% CsA in castor oil) was tested against two novel formulations of 0.05% CSA in (a) F4H5 containing Ethanol (0.5 w/w%) and (b) F6H8 containing Ethanol (0.5 w/w%) with 0.05% CsA. Formulations were tested on rabbit corneas cultured on an artificial anterior chamber with a constant flow of an aqueous humour supplement (Ex Vivo Eye Irritation Test (EVEIT) system). Anterior chamber fluids were sampled at multiple time points to analyse the CsA concentration following single and repeated application regimes by HPLC. Photographs of fluorescein sodium-stained corneas were recorded for corneal toxicity evaluation. The impact of the formulations on the integrity of the corneal barrier function was tested after drug application by fluorescein sodium corneal diffusion experiments. The influence on the corneal metabolism was evaluated by analysis of the metabolic markers glucose and lactate.Restasis (R) did not pass the corneal barrier after short term application, CsA in ethanolic F4H6 reached a maximum of 152.95 ng/ml in anterior chamber fluid samples whilst CsA in ethanolic F6H8 reached a maximum of 15.12 ng/ml. After repeated applications for 8 h, Restasis (R) reached 21.07 ng/ml compared to 247.62 ng/ml and 174.5 ng/ml for F4H5 and F6H8, respectively. No corneal toxicity was observed in following application of any of the formulations.In contrast to the commercially available castor oil-based formulation, CsA dissolved in SFAs reached therapeutic inner ocular concentrations after topical administration, possibly leading to the replacement of systemic applications of CsA for inflammatory ocular disease. (C) 2014 Elsevier B.V. All rights reserved.