Poloxamer-based thermoresponsive ketorolac tromethamine in situ gel preparations: Design, characterisation, toxicity and transcorneal permeation studies
Poloxamer-based thermoresponsive ketorolac tromethamine in situ gel preparations: Design, characterisation, toxicity and transcorneal permeation studies
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DOI：
10.1016/j.ejpb.2017.01.008
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发表时间：
2017-05-01
影响因子：
4.9
通讯作者：
Alany, Raid G.
中科院分区：
文献类型：
--
作者：
Fathalla, Zeinab M. A.;Vangala, Anil;Alany, Raid G.
本研究旨在制备、表征和评价基于两种亲水性聚合物即泊洛沙姆407（P407）和泊洛沙姆188（P188）的共混物的原位凝胶制剂，用于酮咯酸氨丁三醇（KT）的持续眼部递送。用DSC和FT-IR研究了药物与聚合物的相互作用，考察了凝胶的凝胶化温度、凝胶化时间、流变性、粘膜粘附特性、经角膜渗透性、眼刺激性和毒性。DSC和FT-IR研究表明，药物和所用聚合物之间可能存在静电相互作用。与仅含有P407的制剂相比，P188修饰了P407的T-溶胶/凝胶，使其接近眼睛温度（35 ℃）。此外，包含P407和P188的凝胶在不同浓度下表现出假塑性行为。此外，使用粘蛋白盘的粘膜粘附研究表明，原位凝胶制剂在增加P407的浓度时具有良好的粘膜粘附特性。当比较制剂PP 11和PP 12时，粘附功从377.9 +/- 7.79 mN mm显著降低（P < 0.001）至272.3 +/- 6.11 mN mm。体外释放和离体渗透实验表明，原位凝胶能够延长和控制KT释放，因为在12 h内仅48%的KT释放。此外，HET-CAM和BCOP试验证实了载KT原位凝胶的无刺激性，HET-CAM试验证实了对强刺激物质的眼保护能力。对原代角膜上皮细胞的MM试验表明，与对照样品相比，装载有KT的原位凝胶制剂显示出合理且可接受的细胞活力百分比。(C)2017爱思唯尔B. V.保留所有权利。
This study was aimed at preparing, characterising and evaluating in situ gel formulations based on a blend of two hydrophilic polymers i.e. poloxamer 407 (P407) and poloxamer 188 (P188) for a sustained ocular delivery of ketorolac tromethamine (KT). Drug-polymer interaction studies were performed using DSC and FT-IR. The gelation temperature (Tsoi-gei), gelation time, rheological behaviour, mucoadhesive characteristics of these gels, transcorneal permeation and ocular irritation as well as toxicity was investigated. DSC and FT-IR studies revealed that there may be electrostatic interactions between the drug and the polymers used. P188 modified the T-sol/gel of P407 bringing it close to eye temperature (35 degrees C) compared with the formulation containing P407 alone. Moreover, gels that comprised P407 and P188 exhibited a pseudoplastic behaviour at different concentrations. Furthermore, mucoadhesion study using mucin discs showed that in situ gel formulations have good mucoadhesive characteristics upon increasing the concentration of P407. When comparing formulations PP11 and PP12, the work of adhesion decreased significantly (P < 0.001) from 377.9 +/- 7.79 mN mm to 272.3 +/- 6.11 mN mm. In vitro release and ex vivo permeation experiments indicated that the in situ gels were able to prolong and control KT release as only 48% of the KT released within 12 h. In addition, the HET-CAM and BCOP tests confirmed the non-irritancy of KT loaded in situ gels, and HET-CAM test demonstrated the ability of ocular protection against strongly irritant substances. MM. assay on primary corneal epithelial cells revealed that in situ gel formulations loaded with KT showed reasonable and acceptable percent cell viability compared with control samples. (C) 2017 Elsevier B.V. All rights reserved.