Safety comparison of additives in antiglaucoma prostaglandin (PG) analog ophthalmic formulations

Masamichi Fukuda, Shinsuke Shibata, Naoko Shibata, Kenta Hagihara, Hiromoto Yaguchi, Hiromi Osada, Nobuo Takahashi, Eri Kubo, Hiroshi Sasaki

Department of Ophthalmology, Kanazawa Medical University, Uchinada, Japan

Purpose: To investigate the safety of five types of antiglaucoma prostaglandin analog ophthalmic formulations, and to clarify their differences in accordance with contained additives (preservatives and surface-active agents).
Methods: The following five types of ophthalmic solutions and three types of additives were investigated: latanoprost (Xalatan^®; latanoprost), tafluprost (Tapros^®; tafluprost), bimatoprost (Lumigan^®; bimatoprost), travoprost (Travatan^®; travoprost), travoprost (Travatan Z^®; travoprost-Z), benzalkonium chloride (BAK), polyoxyethylene hardening castor oil 40 (HCO-40), and polysorbate 80 (P-80). These experimental solutions were exposed to the cultured cells of a rabbit-derived corneal cell line for a certain time, and the exposure time causing 50% cell damage (CD50), indicated by the ratio of viable cells to total cells was calculated (in vitro). In addition, corneal resistance (CR) was measured and CR ratio (post-treatment CR/pretreatment CR × 100) was calculated (in vivo).
Results: CD50 of each ophthalmic solution was the longest with tafluprost, followed by travoprost-Z, bimatoprost, travoprost, and latanoprost. CD50 of 0.005%, 0.01%, and 0.02% BAK was 14.5 minutes, 8.1 minutes, and 4.0 minutes, respectively. The number of viable cells decreased to 60%, 8 minutes after exposure with HCO-40, and 30 minutes after being exposed to P-80. The CR ratio was 81.0% with travoprost and 82.0% with latanoprost, indicating a significant posttreatment reduction of CR (P < 0.05). The CR ratio did not decrease after treatment with tafluprost, travoprost-Z, or bimatoprost. The CR ratio of 0.005%, 0.01%, and 0.02% BAK was 105.0%, 90.5%, and 68.7%, respectively, and that of HCO-40 and P-80 was 108.7% and 114.2%, respectively.
Conclusion: BAK, HCO-40, and P-80 were thought to be involved in corneal injuries caused by each ophthalmic solution. Corneal injuries due to surface action were observed when using HCO-40 and P-80. When HCO-40 was combined with BAK, it induced micellar BAK and reduced corneal injuries by BAK.

Keywords: corneal resistance measuring device, additives, prostaglandin analogs, surface-active agents, corneal epithelial injury

A Letter to the Editor has been received and published for this article.