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

Figures & data

Table 1 Composition of five types of antiglaucoma PG analog ophthalmic formulations

Opthalmic solution	Xalatan^® ophthalmic solution 0.005%	Tapros^® ophthalmic solution 0.0015%	Lumigan^® ophthalmic solution 0.03%	Travatan^® ophthalmic solution 0.004%	Travatan-Z^® ophthalmic solution 0.004%
Active ingredient	Latanoprost 50 ìg/mL	Tafluprost 15 ìg/mL	Bimatoprost 0.3 mg/mL	Travoprost 40 ìg/mL	Travoprost 40 ìg/mL
Additives	Benzalkonium chloride (0.02%), hydrogen phosphate sodium, sodium dihydrogen-phosphate, tonicity adjusting agents	Benzalkonium chloride (0.001%), sodium dihydrogen-phosphate hydrate, EDTA, strong glycerin, polysorbate 80, pH regulator	Benzalkonium chloride (0.005%), hydrogen phosphate sodium hydrate, sodium chloride, citric acid hydrate, hydrochloric acid, sodium hydroxide	Benzalkonium chloride (0.015%), polyoxyethylene hydrogenated castor oil 40, trometamol, boric acid, mannitol, pH regulator, EDTA	Polyoxyethylene hydrogenated castor oil 40, propylene glycol, boric acid, D-sorbitol, zinc chloride, pH regulator

Abbreviations: PG, prostaglandin; EDTA, ethylenediaminetetraacetic acid.

Figure 1 Evaluation of five types of antiglaucoma PG analog ophthalmic formulations using cultured cells of a rabbit-derived corneal cell line (in vitro).

Notes: ▲: latanoprost; •: tafluprost; ×: bimatoprost; □: travoprost; ■: travoprost-Z. The CD50 of each ophthalmic solution was the longest with tafluprost, followed by travoprost-Z, bimatoprost, travoprost, and latanoprost.
Abbreviations: CD50, exposure time causing 50% cell damage; PG, prostaglandin.

Figure 2 Evaluation of BAK using cultured cells of a rabbit-derived corneal cell line (in vitro).

Notes: •: 0.0025% BAK; ■: 0.005% BAK; ▲: 0.01% BAK; ×: 0.02% BAK. CD50 of 0.005%, 0.01%, and 0.02% BAK was 14.5 minutes, 8.1 minutes, and 4.0 minutes, respectively.
Abbreviations: BAK, benzalkonium chloride; CD50, exposure time causing 50% cell damage.

Figure 3 Evaluation of surface-active agents (HCO-40 and P-80) using cultured cells of a rabbit-derived corneal cell line (in vitro).

Notes: ■: HCO-40 (0.1%); •: P-80 (0.1%); *P < 0.05. The cell survival rate with HCO-40 (0.1%) decreased to 60%, and that of P-80 (0.1%) decreased to 80% until 8 minutes after exposure, which indicated a difference in the decreasing speed between them.
Abbreviations: HCO-40, polyoxyethylene hardening castor oil 40; P-80, polysorbate 80.

Table 2 CD50 (minutes), Cr ratio (%), and the relation to AD classification of each ophthalmic solution and additive

Ophthalmic solution	CR (%)	CDT50 (minutes)	AD classification
Latanoprost (Xalatan^®)	82.0	11.6	A1D2
Tafluprost (Tapros^®)	113.2	>60	A0D0
Bimatoprost (Lumigan^®)	118.0	50.5	A0D0
Travoprost (Travatan^®)	81.0	25.3	A1D1
Travoprost (Travatan Z^®)	96.6	51.0	A0D0
BAK (0.005%)	105.0	14.5	A0D0
BAK (0.01%)	90.5	8.1	A1D1
BAK (0.02%)	68.7	4.0	A2D2
HCO-40 (0.1%)	108.7	24.6	A0D0
P-80 (0.1%)	114.2	37.2	A0D0

Notes: Cell injuries were the most severe with BAK, followed by P-80 and HCO-40. The CR ratio (%) significantly decreased with latanoprost (82.0%, 2 minutes after instillation) and with travoprost (81.0%, 30 minutes after instillation), but recovered as time advanced (P < 0.05). On the other hand, a decrease in the Cr ratio was rarely observed with travoprost-Z. The CR ratio with tafluprost or bimatoprost did not decrease, and tended to be slightly higher after instillation.

Abbreviations: CD50, exposure time causing 50% cell damage; Cr, corneal resistance; AD, area density; BAK, benzalkonium chloride; P-80, polysorbate 80; HCO-40, polyoxyethylene hardening castor oil 40.

Figure 4 Evaluation of five types of antiglaucoma PG analog ophthalmic formulations using corneal resistance measuring device (in vivo).

Notes: (A) ▲: latanoprost; (B) •: tafluprost; (C) ×: bimatoprost; (D) □: travoprost; (E) ■: travoprost-Z; *P < 0.05; N = 4, (mean ± SD). CR ratio (%) significantly decreased with latanoprost (82.0%, 2 minutes after instillation) and with travoprost (81.0%, 30 minutes after instillation), but recovered as time advanced (P < 0.05). On the other hand, a decrease in the CR ratio was rarely observed with travoprost-Z. The CR ratio with tafluprost or bimatoprost did not decrease, and tended to be slightly higher after instillation.
Abbreviations: PG, prostaglandin; Cr, corneal resistance; SD, standard deviation.