A Composite System Based upon Hydroxypropyl Cyclodextrins and Soft Hydrogel Contact Lenses for the Delivery of Therapeutic Doses of Econazole to the Cornea, In Vitro.
A Composite System Based upon Hydroxypropyl Cyclodextrins and Soft Hydrogel Contact Lenses for the Delivery of Therapeutic Doses of Econazole to the Cornea, In Vitro.
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基于羟丙基环糊精和软性水凝胶接触镜的复合系统用于将治疗剂量的益康唑递送至角膜的体外研究。
DOI：
10.3390/pharmaceutics14081631
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发表时间：
2022-08-04
期刊：
影响因子：
5.4
通讯作者：
Heard, Charles M.
中科院分区：
文献类型：
--
作者：
Wong, Anepmete;Fallon, Melissa;Celiksoy, Vildan;Ferla, Salvatore;Varricchio, Carmine;Whitaker, David;Quantock, Andrew J.;Heard, Charles M.
真菌性角膜炎是一种由于侵袭性真菌感染导致角膜发炎的疾病，由于现有治疗方法的选择有限，这种疾病仍然难以治疗。局部滴眼液是一线治疗方法，但由于角膜前的损失和角膜的不可穿透性，低水平的药物到达目标部位可能无效。本研究的目的是利用一种基于环糊精和软水凝胶隐形眼镜的复合给药系统，通过一种新的局部增强方法来确定益康唑的角膜给药效果。将过量硝酸唑加入到羟丙基-α-环糊精（HP-α-CD）和羟丙基-β-环糊精（HP-β-CD）溶液中，用高效液相色谱法测定其溶解度。然后用饱和溶液浸渍专有的软水凝胶隐形眼镜，并将其应用于新鲜去核的猪眼球。同样浓度的硝酸益康唑滴眼液作为对照。6 h后，切除角膜，提取药物，HPLC定量。通过分子动力学模拟研究了econazole-HP -β-CD包合作用和解离作用。测定了益康唑对四种与角膜炎相关的真菌的最低抑制浓度（MIC），并将这些数据与给药到角膜的量相关，使用平均角膜体积为0.19 mL。HP-β-CD存在时，益康唑的溶解度大大增加，HP-α-CD存在时，益康唑的溶解度增加更多（p < 0.001），比值为>> 2。与单独滴眼液相比，水凝胶隐形眼镜通过角膜传递×2.8更多的药物，当环糊精存在时，×5更多的药物传递到角膜。分子图显示了动态的益康唑释放，这将在角膜表面产生短暂的药物浓度增强。纯溶液滴剂的效果最差，对半枯镰刀菌和茄枯镰刀菌都产生了亚mic水平，因子为×0.81，对沙氏镰刀菌和夏威夷双星镰刀菌都产生了×0.40。所有其他处理对所有四种真菌都以> MIC给予econazole。对评价的给药平台进行功效排序：HP-α-CD隐形眼镜> HP-β-CD隐形眼镜>隐形眼镜= HP-α-CD滴剂> HP-β-CD滴剂>纯溶液滴剂。综上所述，本研究的结果表明，一种基于econazole-HP -β-CD包合物的复合给药系统可以显著提高隐形眼镜的角膜给药效果，并有可能改善临床反应。
Fungal keratitis, a disease in which the cornea becomes inflamed due to an invasive fungal infection, remains difficult to treat due in part to limited choices of available treatments. Topical eye drops are first-line treatment, but can be ineffective as low levels of drug reach the target site due to precorneal losses and the impenetrability of the cornea. The aim of this study was to determine the corneal delivery of econazole using a novel topical enhancement approach using a composite delivery system based upon cyclodextrins and soft hydrogel contact lenses. Excess econazole nitrate was added to hydroxypropyl-α-cyclodextrin (HP-α-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) solutions, and the solubility determined using HPLC. Proprietary soft hydrogel contact lenses were then impregnated with saturated solutions and applied to freshly enucleated porcine eyeballs. Econazole nitrate ‘eye drops’ at the same concentrations served as the control. After 6 h, the corneas were excised and drug-extracted, prior to quantification using HPLC. Molecular dynamic simulations were performed to examine econazole–HP-β-CD inclusion complexation and dissociation. The minimum inhibitory concentration (MIC) of econazole was determined against four fungal species associated with keratitis, and these data were then related to the amount of drug delivered to the cornea, using an average corneal volume of 0.19 mL. The solubility of econazole increased greatly in the presence of HP-β-CD and more so with HP-α-CD (p < 0.001), with ratios >> 2. Hydrogel contact lenses delivered ×2.8 more drug across the corneas in comparison to eye drops alone, and ×5 more drug delivered to the cornea when cyclodextrin was present. Molecular graphics demonstrated dynamic econazole release, which would create transient enhanced drug concentration at the cornea surface. The solution-only drops achieved the least satisfactory result, producing sub-MIC levels with factors of ×0.81 for both Fusarium semitectum and Fusarium solani and ×0.40 for both Scolecobasidium tshawytschae and Bipolaris hawaiiensis. All other treatments delivered econazole at > MIC for all four fungal species. The efficacies of the delivery platforms evaluated were ranked: HP-α-CD contact lens > HP-β-CD contact lens > contact lens = HP-α-CD drops > HP-β-CD drops > solution-only drops. In summary, the results in this study have demonstrated that a composite drug delivery system based upon econazole–HP-β-CD inclusion complexes loaded into contact lenses can achieve significantly greater corneal drug delivery with the potential for improved clinical responses.
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影响因子：
14
作者：
Kim, Jinah;Conway, Anthony;Chauhan, Anuj
通讯作者：
Chauhan, Anuj
影响因子：
2.6
作者：
Chen, Gaoquan;Chen, Jiao;Zhao, Hongkun
通讯作者：
Zhao, Hongkun
影响因子：
3.8
作者：
Diaz-Tome, Victoria;Luaces-Rodriguez, Andrea;Fernandez-Ferreiro, Anxo
通讯作者：
Fernandez-Ferreiro, Anxo
影响因子：
2.8
作者：
Hara H;Cooper DK
通讯作者：
Cooper DK
DOI：
10.1016/s0731-7085(00)00260-0
发表时间：
2000-08-01
影响因子：
3.4
作者：
Faucci, MT;Melani, F;Mura, P
通讯作者：
Mura, P