A CORNEAL PERFUSION DEVICE FOR ESTIMATING OCULAR BIOAVAILABILITY INVITRO
A CORNEAL PERFUSION DEVICE FOR ESTIMATING OCULAR BIOAVAILABILITY INVITRO
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DOI：
10.1002/jps.2600790215
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发表时间：
1990-02-01
影响因子：
3.8
通讯作者：
TANGLIU, DDS
中科院分区：
文献类型：
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作者：
RICHMAN, JB;TANGLIU, DDS
已经开发了一种用于研究急性剂量的药物穿透角膜的体外方法。与Edelhauser及其同事使用的角膜腔室相似，用体积减小的插入物对角膜腔室的供体（上皮或泪液）侧进行了修改，使得供体侧体积约为受体（内皮或房水）腔室体积的6%。通过前房泵送液体以模拟体内生理周转。用氧气：二氧化碳（95%：5%）鼓泡接收室以使流体通气和循环。我们使用该模型研究了几种市售眼科药物制剂（0.03%氟比洛芬、0.5%左布诺洛尔、0.1和0.25%氟米龙和1%醋酸泼尼松龙）的体外眼部生物利用度。在给药后1分钟，药物从供体室洗脱的剂量周转率为12%/分钟。在所有实验中，一小部分应用的剂量穿透角膜。使用该腔室装置，对于溶液制剂，通过角膜吸收的眼部生物利用度在5%和16%之间，而对于悬浮液制剂，眼部生物利用度<0.3%。给药剂量的大部分从供体侧流出物中回收。该观察结果与眼用制剂由于体内快速角膜前冲洗而导致的眼部生物利用度低的结果一致。模型中药物作为其角膜代谢物的穿透程度与体外角膜代谢速率常数具有良好的相关性。新的模型打开了几个潜在的有用领域的研究眼睛吸收。角膜接触时间、泪液周转率、制剂含量、角膜代谢首过和眼渗透促进剂的影响可以以比以前更精确和受控的方式测定。
An in vitro method for investigating drug penetration across the cornea from acute doses has been developed. The donor (epithelial or tear) side of a corneal chamber similar to those used by Edelhauser and co-workers was modified with a reduced-volume insert so that the donor side volume approximated 6% of the receiver (endothelial or aqueous humor) chamber volume. Fluid was pumped through the anterior chamber to simulate the physiologic turnover in vivo. The receiver chamber was bubbled with oxygen:carbon dioxide (95%:5%) to aerate and circulate the fluid. We investigated the in vitro ocular bioavailability of several marketed ophthalmic drug formulations using this model (0.03% flurbiprofen, 0.5% levobunolol, 0.1 and 0.25% fluorometholone, and 1% prednisolone acetate). At 1 min after the dose administration, drug was eluted from the donor chamber at a dose turnover rate of 12%/min. In all experiments, a small percentage of the applied dose penetrated the cornea. Using this chamber device, the ocular bioavailability via corneal absorption ranged between 5 and 16% for solution formulations, whereas the ocular bioavailability for the suspension formulations was < 0.3%. The major portion of the administered dose was recovered from the donor side effluent. This observation was consistent with findings showing low ocular bioavailability of ophthalmic preparations due to the rapid precorneal washout in vivo. The extent of drug penetrating as its corneal metabolite in the model correlated well to in vitro corneal metabolism rate constants. The new model opens several potentially useful areas of research into ocular absorption. The effects of corneal contact time, tear turnover rate, formulation contents, corneal metabolic first-pass, and ocular penetration enhancers are determinable in a more precise and controlled fashion than has been done previously.