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In Vitro and In Vivo Evaluation of a Preservative-Free Cationic Emulsion of Latanoprost in Corneal Wound Healing Models

Liang, Hong MD, PhD*,†,‡,§; Baudouin, Christophe MD, PhD*,†,‡,§,¶,‖; Daull, Philippe PhD**; Garrigue, Jean-Sébastien PharmD, MSc, MBA**; Buggage, Ronald MD**; Brignole-Baudouin, Françoise MD, PhD*,†,‡,§,¶,#

doi: 10.1097/ICO.0b013e318255a7f8
Basic Investigation

Purpose: Cationic emulsions (CEs), developed as vehicles for lipophilic drugs, have been shown to be safe and effective for the treatment of dry eye. The aim of this study was to investigate the effects of a preservative-free latanoprost 0.005% CE (latanoprost-CE) in in vitro and in vivo models of corneal wound healing.

Methods: An in vitro wound was made by scraping through a confluent layer of human corneal epithelial cells. Cytotoxicity, cell migration, and proliferation were analyzed after an exposure to phosphate-buffered saline, CE, latanoprost-CE, 0.02% benzalkonium chloride (0.02%BAK), and Xalatan (0.02%BAKlatanoprost). In vivo, the recovery and integrity of corneal wound healing were assessed in rat eyes instilled twice a day for 5 days with the above treatments after deepithelialization of the superior cornea.

Results: In vitro wound distances decreased at 2 and 24 hours for human corneal epithelial cells exposed to CE, latanoprost-CE, and phosphate-buffered saline, whereas they progressively increased for 0.02%BAK-treated and 0.02%BAKlatanoprost-treated cells. The greater wound closure was associated with a higher number of Ki67-positive cells. In CE- and latanoprost-CE-treated rats, reepithelialization of the cornea was enhanced, restoring normal appearance and function. In contrast, 0.02%BAK or 0.02%BAKlatanoprost delayed corneal healing, induced inflammation, and decreased MUC5-AC expression.

Conclusions: Both models effectively evaluated the cytotoxicity and dynamic recovery of corneal wound healing, and their correlation supports the potential of the in vitro model as a reliable alternative to in vivo ocular toxicity tests. Both models demonstrated that in the face of corneal injury, CEs favored corneal healing, whereas BAK was deleterious.

*INSERM, U968, Department of Therapy, Paris, France

UPMC University Paris 06, UMR_S 968, Institut de la Vision, Paris, France

CNRS, UMR_7210, Paris, France

§Department of Service, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France

Assistance Publique - Hôpitaux de Paris Hôpital Ambroise Paré, Service d'Ophtalmologie, Boulogne-Billancourt, France

Université Versailles Saint-Quentin-en-Yvelines, Versailles, France

**Novagali Pharma, Evry, France

#Laboratoire de Toxicologie, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France.

Reprints: Hong Liang, Institute of Vision Paris, Paris F-75012, France (e-mail:

Supported by an unrestricted grant from Novagali Pharma, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, and INSERM, UMR_S968, Institut de la Vision.

The authors state that they have no conflicts of interest to disclose.

Received June 12, 2011

Accepted February 27, 2012

© 2012 Lippincott Williams & Wilkins, Inc.