Chang S C, Chien D S, Bundgaard H, Lee V H
University of Southern California, School of Pharmacy, Los Angeles 90033.
Exp Eye Res. 1988 Jan;46(1):59-69. doi: 10.1016/s0014-4835(88)80093-9.
The effectiveness of the prodrug approach in maximizing the ratio of ocular to systemic absorption of topically applied timolol was compared with that based on viscous solutions. The pigmented rabbit was the experimental animal. o-Butyryl timolol, a lipophilic ester prodrug of timolol, was found to be twice as effective as hyaluronic acid and poly(vinyl alcohol) solutions in enhancing the ocular absorption of timolol. In addition, it was slightly more effective than retaining the instilled dose in the conjunctival sac for 240 min via nasolacrimal blockade. On the other hand, due to its inability to minimize contact of the instilled dose with the nasal mucosa, o-butyryl timolol was less capable than the viscous solutions in reducing systemic drug absorption. But this could be corrected by reducing the instilled solution volume from 25- to 5 microliter, resulting in a nine-fold reduction in plasma timolol levels while still providing the same amount of drug in the aqueous humor as a five times higher dose of timolol. The net result was a 15-fold improvement in the ratio of ocular to systemic drug absorption, which was also achieved upon retaining the instilled dose in the conjunctival sac for 240 min. It thus appears that the approach based on improved corneal absorption would be as effective as that based on improved retention in the conjunctival sac in maximizing the ratio of ocular to systemic drug absorption, so long as a smaller instilled dose volume of the prodrug is used.
将前药方法在使局部应用的噻吗洛尔的眼部与全身吸收比率最大化方面的有效性与基于粘性溶液的方法进行了比较。有色家兔为实验动物。噻吗洛尔的亲脂性酯前药邻丁酰噻吗洛尔在增强噻吗洛尔的眼部吸收方面被发现比透明质酸和聚乙烯醇溶液有效两倍。此外，通过鼻泪管阻塞将滴入剂量在结膜囊中保留240分钟，它的效果略好。另一方面，由于其无法使滴入剂量与鼻黏膜的接触最小化，邻丁酰噻吗洛尔在减少全身药物吸收方面比粘性溶液的能力弱。但这可以通过将滴入溶液体积从25微升减少到5微升来纠正，这导致血浆噻吗洛尔水平降低九倍，同时在房水中仍提供与五倍高剂量噻吗洛尔相同量的药物。最终结果是眼部与全身药物吸收比率提高了15倍，这在将滴入剂量在结膜囊中保留240分钟时也能实现。因此，只要使用较小的前药滴入剂量体积，基于改善角膜吸收的方法在使眼部与全身药物吸收比率最大化方面似乎与基于改善在结膜囊中保留的方法一样有效。
