Basic principles and current status of transcorneal and transscleral iontophoresis

References

• Järvinen K, Järvinen T, Urtti A. Ocular absorption following topical delivery. Adv Drug Deliv Rev. 1995;16:3–19.
   Web of Science ®Google Scholar
• Gaudana R, Jwala J, Boddu SH, et al. Recent perspectives in ocular drug delivery. Pharm Res. 2009;26:1197–1216.
   PubMed Web of Science ®Google Scholar
• Urtti A. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv Drug Deliv Rev. 2006;58:1131–1135.
   PubMed Web of Science ®Google Scholar
• Lee VH, Robinson JR. Mechanistic and quantitative evaluation of precorneal pilocarpine disposition in albino rabbits. J Pharm Sci. 1979;68:673–684.
   PubMed Web of Science ®Google Scholar
• Duvall B, Kershner RM. Ophthalmic medications and pharmacology. 2nd ed. New Jersey, USA:SLACK; 2006.
   Google Scholar
• Patel A, Cholkar K, Agrahari V, et al. Ocular drug delivery systems: an overview. World J Pharmacol. 2013;2:47–64.
   PubMedGoogle Scholar
• Stepien KE, Eaton AM, Jaffe GJ, et al. Increased incidence of sterile endophthalmitis after intravitreal triamcinolone acetonide in spring 2006. Retina. 2009;29:207–213.
   PubMed Web of Science ®Google Scholar
• Sampat KM, Garg SJ. Complications of intravitreal injections. Curr Opin Ophthalmol. 2010;21:178–183.
   PubMed Web of Science ®Google Scholar
• Jonas JB, Spandau UH, Schlichtenbrede F. Short-term complications of intravitreal injections of triamcinolone and bevacizumab. Eye. 2008;22:590–591.
   PubMed Web of Science ®Google Scholar
• Gratieri T, Kalia YN. Mathematical models to describe iontophoretic transport in vitro and in vivo and the effect of current application on the skin barrier. Adv Drug Deliv Rev. 2013;65:315–329.
   PubMed Web of Science ®Google Scholar
• Patel SR, Zhong H, Sharma A, et al. Controlled non-invasive transdermal iontophoretic delivery of zolmitriptan hydrochloride in vitro and in vivo. Eur J Pharm Biopharm. 2009;72:304–309.
   PubMed Web of Science ®Google Scholar
• Kalia YN, Naik A, Garrison J, et al. Iontophoretic drug delivery. Adv Drug Deliv Rev. 2004;56:619–658.
   PubMed Web of Science ®Google Scholar
• Leduc S Introduction of medicinal substances into the depth of tissues by electric current. Ann Electrobiol. 1900;3:545–560.
   Google Scholar
• Zempsky WT, Sullivan J, Paulson DM, et al. Evaluation of a low-dose lidocaine iontophoresis system for topical anesthesia in adults and children: a randomized, controlled trial. Clin Ther. 2004;26:1110–1119.
   PubMed Web of Science ®Google Scholar
• Viscusi ER, Siccardi M, Damaraju CV, et al. The safety and efficacy of fentanyl iontophoretic transdermal system compared with morphine intravenous patient-controlled analgesia for postoperative pain management: an analysis of pooled data from three randomized, active-controlled clinical studies. Anesth Analg. 2007;105:1428–1436.
   PubMed Web of Science ®Google Scholar
• Garnock-Jones KP. Sumatriptan iontophoretic transdermal system: a review of its use in patients with acute migraine. Drugs. 2013;73:1483–1490.
   PubMed Web of Science ®Google Scholar
• Yamamoto R, Takasuga S, Yoshida Y, et al. In vitro and in vivo transdermal iontophoretic delivery of naloxone, an opioid antagonist. Int J Pharm. 2012;422:132–138.
   PubMed Web of Science ®Google Scholar
• Gratieri T, Kalia YN. Targeted local simultaneous iontophoresis of chemotherapeutics for topical therapy of head and neck cancers. Int J Pharm. 2014;460:24–27.
   PubMed Web of Science ®Google Scholar
• De Caro V, Giandalia G, Siragusa MG, et al. New prospective in treatment of Parkinson’s disease: studies on permeation of ropinirole through buccal mucosa. Int J Pharm. 2012;429:78–83.
   PubMed Web of Science ®Google Scholar
• Lerner EN, Van Zanten EH, Stewart GR. Enhanced delivery of octreotide to the brain via transnasal iontophoretic administration. J Drug Target. 2004;12:273–280.
   PubMed Web of Science ®Google Scholar
• Patane MA, Schubert W, Sanford T, et al. Evaluation of ocular and general safety following repeated dosing of dexamethasone phosphate delivered by transscleral iontophoresis in rabbits. J Ocul Pharmacol Ther. 2013;29:760–769.
   PubMed Web of Science ®Google Scholar
• Nicoli S, Ferrari G, Quarta M, et al. In vitro transscleral iontophoresis of high molecular weight neutral compounds. Eur J Pharm Sci. 2009;36:486–492.
   PubMed Web of Science ®Google Scholar
• Gratieri T, Gelfuso GM, Thomazini JA, et al. Excised porcine cornea integrity evaluation in an in vitro model of iontophoretic ocular research. Ophthalmic Res. 2010;43:208–216.
   PubMed Web of Science ®Google Scholar
• Amichai B, Nitzan B, Mosckovitz R, et al. Iontophoretic delivery of terbinafine in onychomycosis: a preliminary study. Br J Dermatol. 2010;162:46–50.
   PubMed Web of Science ®Google Scholar
• Le QV, Howard A. Dexamethasone iontophoresis for the treatment of nail psoriasis. Australas J Dermatol. 2013;54:115–119.
   PubMed Web of Science ®Google Scholar
• Horwath-Winter J, Schmut O, Haller-Schober E-M, et al. Iodide iontophoresis as a treatment for dry eye syndrome. Br J Ophthalmol. 2005;89:40–44.
   PubMed Web of Science ®Google Scholar
• Patane MA, Cohen A, From S, et al. Ocular iontophoresis of EGP-437 (dexamethasone phosphate) in dry eye patients: results of a randomized clinical trial. Clin Ophthalmol. 2011;5:633–643.
   PubMedGoogle Scholar
• Cohen AE, Assang C, Patane MA, et al. Evaluation of dexamethasone phosphate delivered by ocular iontophoresis for treating noninfectious anterior uveitis. Ophthalmology. 2012;119:66–73.
   PubMed Web of Science ®Google Scholar
• Vinciguerra P, Randleman JB, Romano V, et al. Transepithelial iontophoresis corneal collagen cross-linking for progressive keratoconus: initial clinical outcomes. J Refract Surg. 2014;30:746–753.
   PubMed Web of Science ®Google Scholar
• Bikbova G, Bikbov M Standard corneal collagen crosslinking versus transepithelial iontophoresis-assisted corneal crosslinking, 24 months follow-up: randomized control trial. Acta Ophthalmol. 2016;94:e600-e606.
   PubMed Web of Science ®Google Scholar
• Eljarrat-Binstock E, Domb AJ Iontophoresis: A non-invasive ocular drug delivery. J Control Release. 2006;110:479–489.
   PubMed Web of Science ®Google Scholar
• Phipps JB, Padmanabhan RV, Lattin GA. Iontophoretic delivery of model inorganic and drug ions. J Pharm Sci. 1989;78:365–369.
   PubMed Web of Science ®Google Scholar
• Abla N, Naik A, Guy RH, et al. Contributions of electromigration and electroosmosis to peptide iontophoresis across intact and impaired skin. J Control Release. 2005;108:319–330.
   PubMed Web of Science ®Google Scholar
• Ledger PW. Iontophoresis Skin biological issues in electrically enhanced transdermal delivery. Adv Drug Deliv Rev. 1992;9:289–307.
   Web of Science ®Google Scholar
• Hughes L, Maurice DM. A fresh look at iontophoresis. Arch Ophthalmol. 1984;102:1825–1829.
   PubMedGoogle Scholar
• Parkinson TM, Ferguson E, Febbraro S, et al. Tolerance of ocular iontophoresis in healthy volunteers. J Ocul Pharmacol Ther. 2003;19:145–151.
   PubMed Web of Science ®Google Scholar
• Rootman DS, Jantzen JA, Gonzalez JR, et al. Pharmacokinetics and safety of transcorneal iontophoresis of tobramycin in the rabbit. Invest Ophthalmol Vis Sci. 1988;29:1397–1401.
   PubMed Web of Science ®Google Scholar
• Choi TB, Lee DA. Transscleral and transcorneal iontophoresis of vancomycin in rabbit eyes. J Ocul Pharmacol. 1988;4:153–164.
   PubMedGoogle Scholar
• Mencucci R, Ambrosini S, Paladini I, et al. Early effects of corneal collagen cross-linking by iontophoresis in ex vivo human corneas. Graefes Arch Clin Exp Ophthalmol. 2014;253:277–286.
   PubMed Web of Science ®Google Scholar
• Behar-Cohen FF, El Aouni A, Gautier S, et al. Transscleral Coulomb-controlled iontophoresis of methylprednisolone into the rabbit eye: influence of duration of treatment, current intensity and drug concentration on ocular tissue and fluid levels. Exp Eye Res. 2002;74:51–59.
   PubMed Web of Science ®Google Scholar
• Lam TT, Fu J, Tso MOM. A histopathologic study of retinal lesions inflicted by transscleral iontophoresis. Graefes Arch Clin Exp Ophthalmol. 1991;229:389–394.
   PubMed Web of Science ®Google Scholar
• Li SK, Jeong EK, Hastings MS. Magnetic resonance imaging study of current and ion delivery into the eye during transscleral and transcorneal iontophoresis. Invest Ophthalmol Vis Sci. 2004;45:1224–1231.
   PubMed Web of Science ®Google Scholar
• Marro D, Guy RH, Delgado-Charro MB. Characterization of the iontophoretic permselectivity properties of human and pig skin. J Control Release. 2001;70:213–217.
   PubMed Web of Science ®Google Scholar
• Rojanasakul Y, Robinson JR. Transport mechanisms of the cornea: characterization of barrier permselectivity. Int J Pharm. 1989;55:237–246.
   Web of Science ®Google Scholar
• Güngör S, Delgado-Charro MB, Ruiz-Perez B, et al. Trans-scleral iontophoretic delivery of low molecular weight therapeutics. J Control Release. 2010;147:225–231.
   PubMed Web of Science ®Google Scholar
• Pikal MJ. The role of electroosmotic flow in transdermal iontophoresis. Adv Drug Deliv Rev. 2001;46:281–305.
   PubMed Web of Science ®Google Scholar
• Hao J, Li SK, Liu C-Y, et al. Electrically assisted delivery of macromolecules into the corneal epithelium. Exp Eye Res. 2009;89:934–941.
   PubMed Web of Science ®Google Scholar
• Murtomäki L, Vainikka T, Pescina S, et al. Drug adsorption on bovine and porcine sclera studied with streaming potential. J Pharm Pharm Sci. 2013;102:2264–2272.
   Web of Science ®Google Scholar
• Monti D, Saccomani L, Chetoni P, et al. Effect of iontophoresis on transcorneal permeation ‘in vitro’ of two β-blocking agents, and on corneal hydration. Int J Pharm. 2003;250:423–429.
   PubMed Web of Science ®Google Scholar
• Frangie JP. Clinical Pharmacokinetics of various topical ophthalmic delivery systems. Clin Pharmacokinet. 2012;29:130–138.
   Web of Science ®Google Scholar
• Vaka SR, Sammeta SM, Day LB, et al. Transcorneal iontophoresis for delivery of ciprofloxacin hydrochloride. Curr Eye Res. 2008;33:661–667.
   PubMed Web of Science ®Google Scholar
• O’Brien TP. Management of bacterial keratitis: beyond exorcism towards consideration of organism and host factors. Eye. 2003;17:957–974.
   PubMed Web of Science ®Google Scholar
• Amescua G, Miller D, Alfonso EC. What is causing the corneal ulcer? Management strategies for unresponsive corneal ulceration. Eye. 2012;26:228–236.
   PubMed Web of Science ®Google Scholar
• Von Sallmann L Sulfadiazine iontophoresis in pyocyaneus infection of rabbit cornea. Am J Ophthalmol. 1942;25:1292–1300.
   Google Scholar
• Hobden JA, Rootman DS, O’Callaghan RJ, et al. Iontophoretic application of tobramycin to uninfected and Pseudomonas aeruginosa-infected rabbit corneas. Antimicrob Agents Chemother. 1988;32:978–981.
   PubMed Web of Science ®Google Scholar
• Grossman RE, Chu DF, Lee DA. Regional ocular gentamicin levels after transcorneal and transscleral iontophoresis. Invest Ophthalmol Vis Sci. 1990;31:909–916.
   PubMed Web of Science ®Google Scholar
• Frucht-Pery J, Solomon A, Doron R, et al. Efficacy of iontophoresis in the rat cornea. Graefes Arch Clin Exp Ophthalmol. 1996;234:765–769.
   PubMed Web of Science ®Google Scholar
• Frucht-Pery J, Mechoulam H, Siganos CS, et al. Iontophoresis-gentamicin delivery into the rabbit cornea, using a hydrogel delivery probe. Exp Eye Res. 2004;78:745–749.
   PubMed Web of Science ®Google Scholar
• Eljarrat-Binstock E, Raiskup F, Frucht-Pery J, et al. Hydrogel probe for iontophoresis drug delivery to the eye. J Biomater Sci Polym Ed. 2004;15:397–413.
   PubMed Web of Science ®Google Scholar
• Eljarrat-Binstock E, Raiskup F, Stepensky D, et al. Delivery of gentamicin to the rabbit eye by drug-loaded hydrogel iontophoresis. Invest Ophthalmol Vis Sci. 2004;45:2543–2548.
   PubMed Web of Science ®Google Scholar
• Frucht-Pery J, Raiskup F, Mechoulam H, et al. Iontophoretic treatment of experimental pseudomonas keratitis in rabbit eyes using gentamicin-loaded hydrogels. Cornea. 2006;25:1182–1186.
   PubMed Web of Science ®Google Scholar
• Eljarrat-Binstock E, Raiskup F, Frucht-Pery J, et al. Transcorneal and transscleral iontophoresis of dexamethasone phosphate using drug loaded hydrogel. J Control Release. 2005;106:386–390.
   PubMed Web of Science ®Google Scholar
• Grossman R, Lee DA. Transscleral and transcorneal iontophoresis of ketoconazole in the rabbit eye. Ophthalmology. 1989;96:724–729.
   PubMed Web of Science ®Google Scholar
• Yoo SH, Dursun D, Dubovy S, et al. Iontophoresis for the treatment of paecilomyces keratitis. Cornea. 2002;21:131–132.
   PubMed Web of Science ®Google Scholar
• Asahara T, Shinomiya K, Naito T, et al. Induction of gene into the rabbit eye by iontophoresis: preliminary report. Jpn J Ophthalmol. 2001;45:31–39.
   PubMed Web of Science ®Google Scholar
• Voigt M, De Kozak Y, Halhal M, et al. Down-regulation of NOSII gene expression by iontophoresis of anti-sense oligonucleotide in endotoxin-induced uveitis. Biochem Biophys Res Commun. 2002;295:336–341.
   PubMed Web of Science ®Google Scholar
• Berdugo M, Valamanesh F, Andrieu C, et al. Delivery of antisense oligonucleotide to the cornea by iontophoresis. Antisense Nucleic Acid Drug Dev. 2003;13:107–114.
   PubMedGoogle Scholar
• Andrieu-Soler C, Doat M, Halhal M, et al. Enhanced oligonucleotide delivery to mouse retinal cells using iontophoresis. Mol Vis. 2006;12:1098–1107.
   PubMed Web of Science ®Google Scholar
• Bejjani RA, Andrieu C, Bloquel C, et al. Electrically assisted ocular gene therapy. Surv Ophthalmol. 2007;52:196–208.
   PubMed Web of Science ®Google Scholar
• Bai J-H, Su S, Huang L, et al. In vitro extraction of intra-corneal iron using reverse iontophoresis and vitamin C. Graefes Arch Clin Exp Ophthalmol. 2014;252:1245–1258.
   PubMed Web of Science ®Google Scholar
• Mastropasqua L Collagen cross-linking: when and how? A review of the state of the art of the technique and new perspectives. Eye Vis (Lond). 2015;2:19.
   PubMedGoogle Scholar
• Arboleda A, Kowalczuk L, Savoldelli M, et al. Evaluating in vivo delivery of riboflavin with coulomb-controlled iontophoresis for corneal collagen cross-linking: a pilot study. Invest Ophthalmol Vis Sci. 2014;55:2731–2738.
   PubMed Web of Science ®Google Scholar
• Mastropasqua L, Nubile M, Calienno R, et al. Corneal cross-linking: intrastromal riboflavin concentration in iontophoresis-assisted imbibition versus traditional and transepithelial techniques. Am J Ophthalmol. 2014;157:623–630.
   PubMed Web of Science ®Google Scholar
• Lombardo M, Serrao S, Rosati M, et al. Biomechanical changes in the human cornea after transepithelial corneal crosslinking using iontophoresis. J Cataract Refract Surg. 2014;40:1706–1715.
   PubMed Web of Science ®Google Scholar
• Lombardo M, Serrao S, Carbone G, et al. Corneal light backscattering after transepithelial corneal crosslinking using iontophoresis in donor human corneal tissue. J Cataract Refract Surg. 2015;41:635–643.
   PubMed Web of Science ®Google Scholar
• Cassagne M, Laurent C, Rodrigues M, et al. Iontophoresis transcorneal delivery technique for transepithelial corneal collagen crosslinking with riboflavin in a rabbit model. Invest Ophtalmol Vis Sci. 2016;57:594–603.
   PubMed Web of Science ®Google Scholar
• Gore DM, O’Brart DP, French P, et al. A Comparison of Different Corneal Iontophoresis Protocols for Promoting Transepithelial Riboflavin Penetration. Invest Ophtalmol Vis Sci. 2015;56:7908–7914.
   PubMed Web of Science ®Google Scholar
• Gore DM, O’Brart D, French P, et al. Transepithelial riboflavin absorption in an Ex Vivo Rabbit Corneal Model. Invest Ophtalmol Vis Sci. 2015;56:5006–5011.
   PubMed Web of Science ®Google Scholar
• Bikbova G, Bikbov M. Transepithelial corneal collagen cross-linking by iontophoresis of riboflavin. Acta Ophtalmol. 2014;92:30–34.
   PubMed Web of Science ®Google Scholar
• Buzzonetti L, Petrocelli G, Valente P, et al. Iontophoretic transepithelial corneal cross-linking to halt keratoconus in pediatric cases: 15-month follow-up. Cornea. 2015;34:512–515.
   PubMed Web of Science ®Google Scholar
• Lombardo M, Serrao S, Raffa P, et al. Novel Technique of Transepithelial Corneal Cross-Linking Using Iontophoresis in Progressive Keratoconus. J Ophthalmol. 2016;11. doi:10.1155/2016/7472542
   Web of Science ®Google Scholar
• Vinciguerra P, Romano V, Rosetta P, et al. Transepithelial Iontophoresis Versus Standard Corneal Collagen Cross-linking: 1-Year Results of a Prospective Clinical Study. J Refract Surg. 2016;32:672–678.
   PubMed Web of Science ®Google Scholar
• Molokhia SA, Jeong EK, Higuchi WI, et al. Examination of barriers and barrier alteration in transscleral iontophoresis. J Pharm Sci. 2008;97:831–844.
   PubMed Web of Science ®Google Scholar
• Kim H, Robinson MR, Lizak MJ, et al. Controlled drug release from an ocular implant: an evaluation using dynamic three-dimensional magnetic resonance imaging. Invest Ophthalmol Vis Sci. 2004;45:2722–2731.
   PubMed Web of Science ®Google Scholar
• Ranta V-P, Mannermaa E, Lummepuro K, et al. Barrier analysis of periocular drug delivery to the posterior segment. J Control Release. 2010;148:42–48.
   PubMed Web of Science ®Google Scholar
• Molokhia SA, Jeong E-K, Higuchi WI, et al. Transscleral iontophoretic and intravitreal delivery of a macromolecule: study of ocular distribution in vivo and postmortem with MRI. Exp Eye Res. 2009;88:418–425.
   PubMed Web of Science ®Google Scholar
• Vollmer DL, Szlek MA, Kolb K, et al. In vivo transscleral iontophoresis of amikacin to rabbit eyes. J Ocul Pharmacol Ther. 2002;18:549–558.
   PubMed Web of Science ®Google Scholar
• Barza M, Peckman C, Baum J. Transscleral iontophoresis of cefazolin, ticarcillin, and gentamicin in the rabbit. Ophthalmology. 1986;93:133–139.
   PubMed Web of Science ®Google Scholar
• Kondo M, Araie M. Iontophoresis of 5-fluorouracil into the conjunctiva and sclera. Invest Ophthalmol Vis Sci. 1989;30:583–585.
   PubMed Web of Science ®Google Scholar
• Eljarrat-Binstock E, Domb AJ, Orucov F, et al. Methotrexate delivery to the eye using transscleral hydrogel iontophoresis. Curr Eye Res. 2007;32:639–646.
   PubMed Web of Science ®Google Scholar
• Sarraf D, Equi RA, Holland GN, et al. Transscleral iontophoresis of foscarnet. Am J Ophthalmol. 1993;115:748–754.
   PubMed Web of Science ®Google Scholar
• Volz C, Pauly D. Antibody therapies and their challenges in the treatment of age-related macular degeneration. Eur J Pharm Biopharm. 2015;95:158–172.
   PubMed Web of Science ®Google Scholar
• Stitt AW, Curtis TM, Chen M, et al. The progress in understanding and treatment of diabetic retinopathy. Prog Retin Eye Res. 2016;51:156–186.
   PubMed Web of Science ®Google Scholar
• Tratta E, Pescina S, Padula C, et al. In vitro permeability of a model protein across ocular tissues and effect of iontophoresis on the transscleral delivery. Eur J Pharm Biopharm. 2014;88:116–122.
   PubMed Web of Science ®Google Scholar
• Chopra P, Hao J, Li SK. Iontophoretic transport of charged macromolecules across human sclera. Int J Pharm. 2010;388:107–113.
   PubMed Web of Science ®Google Scholar
• Pescina S, Antopolsky M, Santi P, et al. Effect of iontophoresis on the in vitro trans-scleral transport of three single stranded oligonucleotides. Eur J Pharm Sci. 2013;49:142–147.
   PubMed Web of Science ®Google Scholar
• Souied EH, Reid SN, Piri NI, et al. Non-invasive gene transfer by iontophoresis for therapy of an inherited retinal degeneration. Exp Eye Res. 2008;87:168–175.
   PubMed Web of Science ®Google Scholar
• Pescina S, Ferrari G, Govoni P, et al. In-vitro permeation of bevacizumab through human sclera: effect of iontophoresis application. J Pharm Pharmacol. 2010;62:1189–1194.
   PubMed Web of Science ®Google Scholar
• Lam TT, Edward DP, Zhu XA, et al. Transscleral iontophoresis of dexamethasone. Arch Ophthalmol. 1989;107:1368–1371.
   PubMedGoogle Scholar
• Behar-Cohen FF, Parel JM, Pouliquen Y, et al. Iontophoresis of dexamethasone in the treatment of endotoxin-induced-uveitis in rats. Exp Eye Res. 1997;65:533–545.
   PubMed Web of Science ®Google Scholar
• Halhal M, Renard G, Courtois Y, et al. Iontophoresis: from the lab to the bed side. Exp Eye Res. 2004;78:751–757.
   PubMed Web of Science ®Google Scholar
• Pescina S, Martini D, Santi P, et al. In vitro trans-scleral iontophoresis of methylprednisolone hemisuccinate with short application time and high drug concentration. Int J Pharm. 2013;451:12–17.
   PubMed Web of Science ®Google Scholar
• Eljarrat-Binstock E, Orucov F, Frucht-Pery J, et al. Methylprednisolone delivery to the back of the eye using hydrogel iontophoresis. J Ocul Pharmacol Ther. 2008;24:344–350.
   PubMed Web of Science ®Google Scholar
• Eljarrat-Binstock E, Orucov F, Aldouby Y, et al. Charged nanoparticles delivery to the eye using hydrogel iontophoresis. J Control Release. 2008;126:156–161.
   PubMed Web of Science ®Google Scholar
• Chopra P, Hao J, Li SK. Sustained release micellar carrier systems for iontophoretic transport of dexamethasone across human sclera. J Control Release. 2012;160:96–104.
   PubMed Web of Science ®Google Scholar
• Chopra P, Hao J, Li SK. Influence of drug lipophilicity on drug release from sclera after iontophoretic delivery of mixed micellar carrier system to human sclera. J Pharm Sci. 2013;102:480–488.
   PubMed Web of Science ®Google Scholar