Mechanism of permeability-enhancing effect of EDTA and boric acid on the corneal penetration of 4-[1-hydroxy-1-methylethyl]-2-propyl-1-[4-[2-[tetrazole-5-yl]phenyl]phenyl] methylimidazole-5-carboxylic acid monohydrate (CS-088).
This study was conducted to clarify the penetration properties of 4-[1-hydroxy-1-methylethyl]-2-propyl-1-[4-[2-[tetrazole-5-yl]phenyl]phenyl]methylimidazole-5-carboxylic acid monohydrate (CS-088), an ophthalmic agent, and the mechanism of the permeability-enhancing effect of EDTA and boric acid (EDTA/boric acid) on the corneal penetration of CS-088. In the absence of additives, corneal permeability decreased with increasing concentration of CS-088 as CS-088 monomers self-associate to form dimers. Presence of EDTA/boric acid caused no significant changes in the physicochemical properties of CS-088, the apparent partition coefficient or the mean particle size of CS-088. EDTA/boric acid induced only a slight change in the zeta potential of liposomes used as a model of the biological membrane. On the other hand, EDTA/boric acid significantly increased membrane fluidity of liposomes, whereas other buffering agents tested did not. This effect was synergistic and concentration-dependent for both EDTA and boric acid as was observed in in vitro corneal penetration of CS-088. In accordance with the result, the rate of CS-088 permeation into the liposomes significantly increased by the addition of EDTA/boric acid. Therefore, it was demonstrated that EDTA/boric acid promotes corneal penetration of CS-088 through the transcellular pathway by increasing membrane fluidity. Conversely, other buffering agents decreased corneal permeability of CS-088 by inducing further self-association of CS-088 aggregates.
Pharmaceutical Development Laboratories, Sankyo Co. Ltd. 1-12-1, Shinomiya, Hiratsuka, Kanagawa 254-0014, Japan. tkikuc@sankyo.co.jp
Takayuki
T
Kikuchi
Masahiko
M
Suzuki
Akira
A
Kusai
Ken
K
Iseki
Hitoshi
H
Sasaki
Kenichiro
K
Nakashima
D020003:1-Octanol / Q000737:chemistry; D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001888:Boric Acids / Q000494:pharmacology*; D003315:Cornea / Q000187:drug effects* / Q000378:metabolism; D004357:Drug Synergism; D004492:Edetic Acid / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D008081:Liposomes; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects*; D009883:Ophthalmic Solutions / Q000737:chemistry / Q000493:pharmacokinetics; D010316:Particle Size; D010539:Permeability / Q000187:drug effects; D011817:Rabbits; D013777:Tetrazoles / Q000737:chemistry / Q000493:pharmacokinetics*
D047228:Angiotensin II Type 1 Receptor Blockers; D001888:Boric Acids; D007093:Imidazoles; D008081:Liposomes; D009883:Ophthalmic Solutions; D013777:Tetrazoles; C437965:olmesartan; D004492:Edetic Acid; D020003:1-Octanol; C032688:boric acid