Effect of benzalkonium chloride on transscleral drug delivery.
OBJECTIVE
To investigate the effect and safety of benzalkonium chloride on transscleral drug delivery in the rabbit after continuous intrascleral administration.


METHODS
Betamethasone 21-phosphate (BP) aqueous solutions, with or without benzalkonium chloride (BAK), were continuously administered to albino rabbit sclera with an osmotic pump for 1 week. The BP concentrations in the aqueous humor, vitreous, and retina-choroid were measured by high-performance liquid chromatography (HPLC). To investigate the effect of BAK on scleral permeability of BP in vitro, penetration of BP aqueous solution with or without BAK across the rabbit sclera was evaluated using a two-chamber Ussing apparatus. To determine the effects of BAK on transscleral delivery of large molecules, 20- and 70-kDa fluorescein isothiocyanate (FITC)-dextran (FD-20 and -70, respectively) aqueous solutions, with or without BAK, were continuously administered to the sclera by an osmotic pump. The intensity of fluorescence in the aqueous humor, vitreous, and retina-choroid was measured by fluorescence spectrophotometry at 1 week after implantation of the pump. The retinal toxicity of BAK was evaluated electrophysiologically and histologically.


RESULTS
BAK increased concentrations of BP in the vitreous and retina-choroid compared with the control. BP was not detected in the aqueous humor. In the in vitro study, BAK did not increase the scleral permeability of BP. In the retina-choroid, BAK significantly increased concentrations of FD-20 but did not increase those of FD-70. The addition of BAK did not increase concentrations of FD-20 or -70 in the vitreous. No substantial toxic reactions were observed in the retina in electrophysiological or histologic examinations after the addition of BAK.


CONCLUSIONS
The results of this study demonstrate that BAK may improve the ocular penetration of a drug in a transscleral drug delivery system without producing toxic reactions.
Okabe
Komei
K
Department of Ophthalmology, Nagoya University, University Graduate School of Medical Sciences, Aichi 467-8061, Japan.
Kimura
Hideya
H
Okabe
Junko
J
Kato
Aki
A
Shimizu
Hideo
H
Ueda
Takashi
T
Shimada
Shouichi
S
Ogura
Yuichiro
Y
D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D001548:Benzalkonium Compounds / Q000494:pharmacology*; D001623:Betamethasone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D002829:Choroid / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003911:Dextrans / Q000378:metabolism; D016503:Drug Delivery Systems; D005123:Eye / Q000378:metabolism*; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives* / Q000378:metabolism; D005938:Glucocorticoids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015918:Infusion Pumps, Implantable; D010539:Permeability; D011310:Preservatives, Pharmaceutical / Q000494:pharmacology*; D011817:Rabbits; D012160:Retina / Q000378:metabolism; D012449:Safety; D012590:Sclera / Q000187:drug effects* / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D014822:Vitreous Body / Q000378:metabolism
D001548:Benzalkonium Compounds; D003911:Dextrans; D005938:Glucocorticoids; D011310:Preservatives, Pharmaceutical; C015219:fluorescein isothiocyanate dextran; C028994:betamethasone sodium phosphate; D001623:Betamethasone; D016650:Fluorescein-5-isothiocyanate