Characterization of Ocular Iontophoretic Drug Transport of Ionic and Non-ionic Compounds in Isolated Rabbit Cornea and Conjunctiva

Abstract

Ocular iontophoresis (IP) in isolated rabbit cornea and conjunctiva was examined in terms of transport enhancement, tissue viability and integrity using electrophysiological parameters by the Ussing-type chamber technique. Lidocaine hydrochloride (LC, a cationic compound), sodium benzoate (BA, anionic compound), and fluorescein isothiocyanate labeled dextran (molecular weight 4400 Da, FD-4, hydrophilic large compound) were used as model permeants. Direct electric current was applied at 0.5-5.0 mA/cm 2 for the cornea and 0.5-20 mA/cm 2 for the conjunctiva for 30 min. LC and BA fluxes across the cornea and conjunctiva were significantly increased by the application of electric current up to 2.3-and 2.5-fold and 4.0-and 3.4-fold, respectively, and returned to their baseline level on stopping the current. Furthermore, a much higher increase by IP application was obtained for the FD-4 transport. The increased FD-4 flux in the conjunctiva returned to baseline on stopping the current, whereas the flux in the cornea was sustained at a higher level after stopping the current. The transepithelial electric resistance of the cornea and conjunctiva was lowered by electric current application but fully recovered after stopping the current up to 2.0 mA/cm 2 for the cornea and 10 mA/cm 2 for the conjunctiva, suggesting that the corneal and conjunctival viability and integrity are maintained even after application of these current densities. These results indicate that ocular IP may be a useful non-invasive technique to achieve drug delivery of hydrophilic large molecules into the eyes.Key words ocular drug delivery; physical enhancement; iontophoresis; electric current; cornea; conjunctiva Eye drops are used for treatment of ocular diseases and the drugs applied by the eye drops distribute onto the ocular surface, then penetrate into the eye through the ocular surface tissues such as cornea and conjunctiva.1) In spite of the simple and convenient dosage form of eye drops, elimination and dilution of drugs by turn-over of tear fluid and the low permeability of the surface ocular tissues are major challenges that limit the absorption of an effective amount of drugs into the eyes.2) Thus, approaches to increase drug absorption into the eyes have attracted much attention. One includes chemical approaches such as the use of prodrugs, liposomes, cyclodextrins, and chemical enhancers, while others include physical approaches such as iontophoresis (IP) and sonophoresis. 3,4)IP is known as an useful technique to increase the penetration of ionic and non-ionic compounds into the body across surface epithelial tissues including skin and the ocular surface. 5,6)This technique has a potential to regulate the drug delivery depending upon the applied current density and application time and, thus, provides an ON/OFF control. A number of in vivo ocular IP studies have shown that application of IP increases the drug concentration in the aqueous and vitreous humors compared to instillation with gentamicin, 7-9) vancomycin, 10) tobramycin, 11,12)...

Application of direct electric current to the corneal and conjunctival epithelia regulates the tight junctional assembly for ocular iontophoretic drug delivery

“…We prepared isolated rabbit cornea and conjunctiva as previously described 14 . Rabbits were anesthetized with a 20 mg/kg sodium pentobarbital solution injected into a marginal ear vein, and euthanized using a 3.3 M KCl solution injected at the same site.…”

“…We have previously examined drug transport through IP using viable rabbit cornea and conjunctiva 14 and found that the permeability of fluorescein isothiocyanate dextran (FD-4), a 4.4-kDa hydrophilic macromolecule, across these tissues significantly increased when the anode was placed on the drug reservoir side (anodal IP). This increase in permeability was dependent on the applied electric current density.…”

Recent Strategies for Ocular Drug Delivery: Promises and Challenges

“…Concerning iontophoresis, it is a technique that uses low currents to create transitory and localized pores in the cell membrane, allowing ionized molecules to pass through. Iontophoresis has been shown to boost gene or drug transport across the cell membrane by 2.3 and 2.5 times in the cornea and 4.0 and 3.4 times in the conjunctiva, respectively; however, after the current was removed, the transfer recovered to baseline levels in rabbit cornea and conjunctiva [86].…”

Ocular Gene Therapy: Literature Review

“…A direct electrical modern-day might also be utilized to the cornea at 0.5-5.0 mA/cm2, and for the conjunctiva, it may additionally be utilized at 0.5-20 mA/cm2 for 30 min. Gene or drug travelling throughout the cell membrane by iontophoresis has been said to enlarge by means of 2.3-and 2.5-fold for the cornea and 4.0-and 3.4-fold for the conjunctiva, respectively; the switch again to baseline ranges in rabbit cornea and conjunctiva as soon as the modern-day was once no longer utilized [78]. Introducing genes and capsules into the cornea utilising contemporary is carried out by using loading the electrode with, for example, riboflavin answer and connecting it to a modern generator aiming at improving corneal crosslinking in keratoconus sufferers after epithelial debridement [79].…”