Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
Lonza AG, Basel, Switzerland.
Int J Pharm. 2018 Mar 1;538(1-2):119-129. doi: 10.1016/j.ijpharm.2018.01.019. Epub 2018 Jan 12.
Semifluorinated alkanes (SFAs) are amphiphilic liquids that can dissolve hydrophobic drugs to form clear solutions. This study evaluated the potential of two SFAs to act as vehicle for topical ocular drug delivery. After confirming ocular safety, an ex vivo corneal penetration model was developed to determine drug distribution and corneal bioavailability. Hydrophobic dye distribution in the different corneal layers was visualised under a confocal microscope. Corneal bioavailability of cyclosporine A (CsA) dissolved in perfluorobutylpentane (F4H5) or perfluorohexyloctane (F6H8) was compared to commercially available CsA ophthalmic emulsions, Restasis® and Ikervis®. Precorneal residence of the four test vehicles containing the hydrophobic dye was also compared using an ex vivo corneal tissue model. Preferential accumulation of the hydrophobic dye in the corneal epithelium was observed with higher amounts detectable when delivered via the SFAs compared to Restasis or Ikervis. A significant improvement in corneal CsA penetration was observed after application of a single dose of 0.05% CsA in F4H5 and F6H8 when compared to Restasis with the area under curve over 4 h (AUC) being at least 8-fold greater for both SFAs (p < .0001). Moreover, the AUC of 0.1% CsA in F4H5 was almost 5-fold greater than Ikervis (p < .0001). Finally, the precorneal residence time of both SFA solutions was significantly longer than that of the commercial emulsions with the AUC being 2- to 11-fold greater. This study demonstrated that SFAs can significantly improve the local bioavailability of hydrophobic drugs by increasing corneal penetration as well as prolonging precorneal residence. They therefore offer a promising new platform for topical drug delivery to the eye.
全氟辛烷（SFAs）是一种两亲性液体，可溶解疏水性药物形成澄清溶液。本研究评估了两种 SFAs 作为局部眼部药物递送载体的潜力。在确认眼部安全性后，开发了一种离体角膜渗透模型，以确定药物分布和角膜生物利用度。使用共聚焦显微镜观察疏水性染料在不同角膜层中的分布。比较了全氟丁基戊烷（F4H5）或全氟己基辛烷（F6H8）中溶解的环孢素 A（CsA）与市售的 CsA 眼用乳液 Restasis®和 Ikervis®的角膜生物利用度。还使用离体角膜组织模型比较了含有疏水性染料的四种测试载体的角膜前驻留时间。与 Restasis 或 Ikervis 相比，观察到疏水性染料在角膜上皮中的优先积累，通过 SFAs 给药时可检测到更高的量。与 Restasis 相比，F4H5 和 F6H8 中单次给予 0.05%CsA 后，观察到角膜 CsA 穿透率显著提高，在 4 小时内（AUC）至少增加了 8 倍（p<.0001）。此外，F4H5 中 0.1%CsA 的 AUC 几乎是 Ikervis 的 5 倍（p<.0001）。最后，两种 SFA 溶液的角膜前驻留时间均明显长于商业乳液，AUC 增加 2-11 倍。本研究表明，SFAs 可通过增加角膜穿透率和延长角膜前驻留时间，显著提高疏水性药物的局部生物利用度。因此，它们为眼部局部药物递送提供了一个有前途的新平台。
