title: Safety comparison of additives in antiglaucoma prostaglandin (PG) analog ophthalmic formulations.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Ophthalmology, Kanazawa Medical University, Uchinada, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Fukuda
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Shibata
authors.forename: Naoko
authors.initials: N
authors.lastname: Shibata
authors.forename: Kenta
authors.initials: K
authors.lastname: Hagihara
authors.forename: Hiromoto
authors.initials: H
authors.lastname: Yaguchi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Osada
authors.forename: Nobuo
authors.initials: N
authors.lastname: Takahashi
authors.forename: Eri
authors.initials: E
authors.lastname: Kubo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sasaki
keywords: additives; corneal epithelial injury; corneal resistance measuring device; prostaglandin analogs; surface-active agents