Topical aldose reductase inhibitor formulations for effective lens drug delivery in a rat model for sugar cataracts.
OBJECTIVE
In the topical delivery of drugs to the lens, drug retention on the eye surface is considered to be important because increased retention on the ocular surface should lead to increased ocular absorption of a drug through the cornea into the aqueous humor and subsequently the lens. The aim of this study was to investigate whether increasing the viscosity of a topical aldose reductase inhibitor suspension increases the lenticular bioavailability of the inhibitor and whether such a formulation can arrest sugar cataract formation.


METHODS
Five topical suspensions of 3% 2-methylsorbinil (2-MS) were prepared using (1) hydroxypropyl methylcellulose (HPMC, 0.5% w/v), (2) xanthan gum (0.5% w/v), (3) gellan gum (0.5% w/v), (4) carbopol (0.25% w/v), and (5) carbopol (0.25% w/v)--hydroxypropyl methylcellulose (HPMC) (0.25% w/v). Viscosity measurements were conducted with a viscometer. Lenticular levels of 2-MS were determined in the lenses from young Sprague Dawley rats receiving 1 drop of selected topical suspension twice-daily for 7 days. The efficacy of the suspensions to arrest sugar cataract formation was evaluated by administering the suspensions for 21 days to similar rats fed a diet containing 50% galactose. Lens changes were examined by portable slit lamp following mydriasis.


RESULTS
Lenticular levels of 2-MS was highest in rats administered suspensions containing 0.25% carbopol + 0.25% HPMC as vehicles followed by 0.5% gellan gum, 0.5% HPMC, 0.25% carbopol, and 0.5% xanthan gum. All untreated rats fed a 50% galactose diet developed hypermature cataracts within 15 days; however, none of the topical treated rats demonstrated cortical vacuole formation after 21 days of galactose feeding.


CONCLUSIONS
In the suspensions examined, no direct relationship between the lenticular drug levels of 2-MS and either viscosity or pH of the vehicles were observed. The observed arrest of sugar cataract formation indicated that therapeutically adequate lenticular levels of 2-MS were provided by all topical suspensions.
Kador
Peter F
PF
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6025, USA. pkador@unmc.edu
Randazzo
James
J
Babb
Thomas
T
Koushik
Kavitha
K
Takamura
Yoshihiro
Y
Zhu
Wenjun
W
Blessing
Karen
K
Kompella
Uday B
UB
D000287:Administration, Topical; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001082:Aqueous Humor; D001682:Biological Availability; D001692:Biological Transport; D002386:Cataract / Q000139:chemically induced / Q000188:drug therapy*; D003315:Cornea; D004337:Drug Carriers; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005690:Galactose; D006863:Hydrogen-Ion Concentration; D048289:Imidazolidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007908:Lens, Crystalline / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D015878:Mydriasis; D009883:Ophthalmic Solutions / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014677:Pharmaceutical Vehicles; D051381:Rats; D017207:Rats, Sprague-Dawley; D014617:Vacuoles; D014783:Viscosity
D004337:Drug Carriers; D004791:Enzyme Inhibitors; D048289:Imidazolidines; D009883:Ophthalmic Solutions; D014677:Pharmaceutical Vehicles; C037070:M 79175; D000449:Aldehyde Reductase; D005690:Galactose