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

Abstract

PurposeTo 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).MethodsThe 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).ResultsCD50 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.ConclusionBAK, 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.

Polyvinyl alcohol-iodine induced corneal epithelial injury in vivo and its protection by topical rebamipide treatment

“…Moreover, according to another report, PI can induce cytotoxicity at concentrations ranging from 5% to 10% in vivo and 0.08% to 0.32% in vitro [20]. Washing rabbit eyes with 1.25% PI results in superficial punctate keratitis [23]. These previous data strongly support our results.…”

“…However, this device takes more than 30 min to take a single measurement. We previously developed an electrophysiologic method that uses corneal impedance measurement to quantify corneal barrier function or damage [20, 23, 28]. This method, the CR measurement, has been shown to accurately and quantitatively evaluate fine corneal barrier function not detected by the fluorescein staining method in previous studies using rabbit eyes [12, 22, 28].…”

In Vivo Measurement of Human Corneal Impedance Value

“…We tested our device to measure the corneal resistance (CR) in rabbit eyes and confirmed ocular surface safety with reliable reproducible data. [4][5][6][7] This device enables the quantitative assessment of corneal disease, to objectively confirm its progress by the degree of corneal injury with the passage of time. 4,5 There have been several reports of similar devices in animal eyes, but to date, none in human eyes.…”

BAK additive influence on results

“…This letter is in regards to Fukuda et al1 We thank the authors for their informative contribution. The use of rabbit specimens was relevant to this study as previously alluded to by Wilhelmus, who concluded from his research that rabbit eyes were more susceptible to irritants than human eyes 2…”

“…The BAK additive could have influenced the results; however the authors did an excellent job of obtaining a more suitable measurement of the corneal damage by developing an apparatus to measure it 1. It would have been ideal if the authors had mentioned the details of the “apparatus,” so as to give the readers a little more information about how objectively the corneal damage was measured.…”