Bioavailability and anticataract effects of a topical ocular drug delivery system containing disulfiram and...

To test the effect of aqueous eye drops containing a high concentration of disulfiram (DSF) in a cyclodextrin- based drug delivery system. This system increases both the drug solubility in aqueous eye drops and the permeability of drug into the rabbit eye, by the formation of a drug-cyclodextrin inclusion complex, and so enhances the ocular bioavailability and anti-cataract effect of DSF.

The DSF and hydroxypropyl-beta-cyclodextrin (HPbetaCD) inclusion (DSF/HPbetaCD) was studied using solubility methods, IR spectra and X-ray diffraction patterns. Suitable formulations for DSF eye drops were first identified by a trans-corneal penetration experiment in vitro. Finding a new p-bromophenacyl bromide (p-BPB) derivative reagent for diethyldithiocarbamic acid (DDC), which was a metabolite of DSF, allowed precise determination of the contents of DSF in aqueous humor. The ocular bioavailability was calculated by a transcorneal experiment of DSF in vivo. The lens opacity of a selenite-induced cataract in rat pups was monitored using a slit lamp with an anterior eye segment analysis system.

The formation of DSF/HPbetaCD inclusion and the addition of hydroxypropylmethylcellulose (HPMC), as a penetration enhancer, played very important roles in increasing the ocular bioavailability of DSF. DSF eye drops, with a formulation of 1.26% (w/v) DSF/HPbetaCD inclusion, 0.01% (w/v) HPMC, 0.005% (w/v) benzalkonium chloride and 0.9% (w/v) sodium chloride, inhibited the onset of selenite-induced cataracts effectively.

The cyclodextrin-based drug delivery system enhances both the solubility of DSF in aqueous eye drops and permeability of the drug into the rabbit eye. DSF ocular bioavailability in rabbit aqueous humor exceeded those reported for the DSF ophthalmic preparation. DSF eye drops effectively prevent the development of selenite-induced cataracts.