Pharmacokinetic and Pharmacodynamic Evaluation of the Anti-cataract Effect of Eye Drops Containing Disulfiram and Low-Substituted Methylcellulose Using ICR/f Rats as a Hereditary Cataract Model

Abstract

We attempted to develop anti-cataract eye drops using disulfiram (DSF) and low-substituted methylcellulose (MC), and evaluated their anti-cataract effect in terms of the lens opacification vs. age-profile curves using a one-exponential equation. The eye drops were prepared using 0.5% DSF and 2% MC (DSF eye drops), and ICR/f rats, a recessive-type hereditary cataractous strain, were used as the experimental model. Gelation of DSF eye drops containing MC was first observed at about 35°C, close to body temperature. In in vivo transcorneal penetration experiments using rabbit corneas, only diethyldithiocarbamate (DDC) was detected in the aqueous humor, while DSF was not detected. The DDC penetration level of DSF eye drops containing MC was approximately 1.3-fold higher than that of DSF eye drops. The opacification rate constant (k) of ICR/f rat instilled with DSF eye drops with or without MC was lower, and the initial time of opacification (τ) was longer than those of ICR/f rats instilled with saline. Furthermore, the k of ICR/f rats instilled with DSF eye drops with MC was lower than that of ICR/f rats instilled with DSF eye drops without MC. In conclusion, the analysis of kinetic parameters including k and τ using a one-exponential equation provided useful information for clarifying the anti-cataract effect of eye drops. ICR/f rats instilled with DSF eye drops using a low-substituted MC-based drug delivery system demonstrated a delay in cataract development, probably resulting from an increase in the retention of DSF eye drops on the cornea. Key words cataract; disulfiram; methylcellulose; 2-hydroxypropyl-β-cyclodextrin; ICR/f rat A cataract is defined as any alteration in the optical homogeneity of the lens or decrease in its transparency, 1,2) and numerous factors have been implicated in the etiology of cataracts including genetic factors, diabetes, smoking, nutrition, the cumulative effect of X-rays, UV irradiation, and alterations in both endocrine and enzymatic equilibria.2-7) In human senile cataracts, an ionic imbalance in the lens with increased levels of Ca 2+ is related to cataract development. ; however, no potent anti-cataract drugs have yet to be introduced due to uncertainties regarding efficacy and safety.Disulfiram (DSF), a dimer of diethyldithiocarbamate (DDC), has long been used to treat alcoholic syndrome without severe side effects.11) DSF is a powerful antioxidant that scavenges reactive oxygen species including hydroxyl radicals, superoxide, and peroxynitrite, and chelates metal ions in rats.12,13) However, its application in the ophthalmic field is limited due to its poor water solubility. One problem with lipophilic drugs, such as DSF, administered as aqueous eye drops is obtaining the desired drug concentration in any drug delivery system. Cyclodextrins are cyclic oligosaccharides comprising R-D-glucose linked by R-(1-4) glucosidic bonds. The potential use of natural cyclodextrins and their synthetic derivatives has been studied extensively to improve certain properties such as their solub...

An Ophthalmic Formulation of Disulfiram Nanoparticles Prolongs Drug Residence Time in Lens

“…20) Suspensions containing DSF nanoparticles (nano-DSFsuspension,pH6.5)werepreparedbyabeadsmill method according to a previous report.…”

“…15,20) Three micrograms of benzophenone was added to the samples as an internal standard, and the samples were filtered through a 0.45µm Chromatodisk 4A (Kurabo Industries Ltd., Osaka, Japan). The drug concentrations were measured on a Shimadzu LC-20AT system equipped with a column oven CTO-20 A (Shimadzu Corp.) and an Inertsil ® ODS-3 (3µm, column size: 2.1×50mm) column.…”

“…We preciously prepared a 2-hydroxypropyl-β-cyclodextrin (HPβCD) solutioncontainingDSF(DSFsolution),andfoundthatitsinstillationdelayedlensopacificationinarecessive-typehereditary cataractous strain of rats (ICR/f and UPL rats). [17][18][19][20] In addition, we reported that the induction of inducible nitric oxide synthase (iNOS) via nuclear factor-kappa B (NF-κB) produces excessive nitric oxide (NO), and that this excessive NO causes enhanced lipid peroxidation and a decrease in cytochrome c oxidase in the lenses of hereditary cataractous strains of rats during cataract development. 18,19) The enhanced lipid peroxidation and decrease in cytochrome c oxidase lead to a decrease in Ca 2+ -ATPase function, resulting in lens opacification via the enhancement of Ca 2+ content in the lens.…”

“…18,19) The ophthalmic formulation containing DSF has the ability to attenuate the expression of iNOS, resulting in a delay in cataract development. [17][18][19][20] Furthermore, we designed a high quality suspension containing DSF nanoparticles (nano-DSF suspension), and showed that the corneal penetration and corneal residence time of DSF from this nano-DSF suspension were significantly higher than from a regular DSF solution (conventional eye drops). 15) In this study, we investigate the changes in drug contents in the lenses of rats instilled with the DSF solution andnano-DSFsuspension.…”

Novel Lutein Loaded Lipid Nanoparticles on Porcine Corneal Distribution

“…However, ocular lutein delivery remains challenging because of the isolated structure of eye. The conventional eye drops are restricted to deliver lipophilic drug due to the existence of the anatomical barriers such as cornea and sclera [9]. Occasionally, intravitreal injections cause side effects such as endophthalmitis, cataract formation, and retinal detachment [10].…”