Y Iontophoresis a novel approach for drug delivery to the eye

Iontophoresis is a process that increases the penetration of ionized substances into or through a tissue by application of an electrical field (Figure 9). When iontophoresis is used for drug delivery, the best candidate drug is a low molecular weight charged molecule. According to electrical principle, if the molecule is positively charged it is driven from the anode and if it is negatively charged it is driven from the cathode. Although iontophoretic delivery should be inversely dependent upon the molecular weight of the penetrant,268 it has been shown that neutral molecules and high molecular weight molecules such as proteins could be delivered across tissues by means of iontophoresis.269,270 Interestingly, although the size of the molecule is an important factor that influences iontophoretic delivery, it has been demonstrated, using oligo-

Fig. 9. Schematic representation of iontophoresis in the rabbit. The drug is placed in a cylindrical eye cup. The inner circumference of the eye cup fits within the corneoscleral limbus. The current is controlled by a rheostat on the direct current transformer. In the case illustrated here, the drug molecules (cations) have a positive charge. Therefore, the platinum electrode connected to the anode (the positively charged pole) is placed in contact with the solution. The other electrode (cathode) is connected to the ear of the rabbit to complete the circuit. The positively charged anode drives the positively drug molecules from the solution into the eye at a greater rate than would be observed with simple diffusion (adapted from Ref. 272).

Fig. 9. Schematic representation of iontophoresis in the rabbit. The drug is placed in a cylindrical eye cup. The inner circumference of the eye cup fits within the corneoscleral limbus. The current is controlled by a rheostat on the direct current transformer. In the case illustrated here, the drug molecules (cations) have a positive charge. Therefore, the platinum electrode connected to the anode (the positively charged pole) is placed in contact with the solution. The other electrode (cathode) is connected to the ear of the rabbit to complete the circuit. The positively charged anode drives the positively drug molecules from the solution into the eye at a greater rate than would be observed with simple diffusion (adapted from Ref. 272).

nucleotide penetration through the skin, that not only the base composition, but also the sequence, affects steady-state transport across biological membrane. Therefore, the molecular structure could influence iontophoretic transport as well.271

The physical and biological principles of drug penetration by iontophoresis remain unclear. Most of the investigations that have been conducted to explore the mechanisms implicated in drug penetration have been done on skin explant ex vivo, in a different arrangement from that of therapeutic iontophoresis. Several theories are hypothesized, including the Shunt pathway, the flip-flop gating mechanism and elec-troosmosis.

The shunt pathway suggests that drugs cross the stratum cornea barrier of the skin via glands, follicules and imperfections in the skin.273-275 Recently, iontophoretic pathways have been identified and quantified using confocal microscopy, within hairless mouse skin. This confirms that follicular transport enhances the delivery to a significant depth into the barrier and that the efficient follicular pathway could be considerable when the surface area is taken into account.276

The 'flip-flop' gating mechanism hypothesizes that the permeability of the skin could be altered by the current applied.2 7,278 The polypeptides of the cell membranes could follow a parallel arrangement, that allow the formation of voltage-dependent pores.270'279 During the non-conducting state, the alpha helices of the polypeptides arrange themselves in an antiparallel manner within the bilipidic layer, that could switch ('flip-flop') to parallel fashion when an electric potential is applied. However, the existence of such voltage-dependent pores has not been demonstrated. More recently Monteire-Riviere et al.280 used transdermal iontophoresis of mercuric chloride on pig skin and demonstrated by ultrastructural microscopy that an intercellular and intracellular penetration was observed. Mercury precipitate were localized in the outer membrane of the mitochondria in epidermal cells, dermal fibroblasts and capillaries, demonstrating a transdermal delivery and a systemic exposure to mercury.

Electroosmosis could be one of the mechanisms implicated in the transport of molecules through the skin. Under the influence of a direct current, the passage of a solvent can carry with it other dissolved substances. This effect is dependent upon the pH. At physiological pH, the skin carries a negative charge, which enhances the migration of cations at the anode. This migration could drag the solvent through the skin, with any dissolved substances with it.281"284 Conventional electroosmosis could be modulated by lipophilic, cationic substances, modifying the permselectivity of the skin.285

For ocular application, transconjunctival, transcorneal and transscleral iontophoresis (see Sections V.A.-V.C., respectively) have been used under variable conditions. The mechanisms of drug penetration that have been previously described to occur through the skin can hardly be extrapolated to ocular iontophoresis, each ocular tissue possessing its own characteristics. Moreover, the distribution of the drug into the eyeball, following iontophoresis is difficult to anticipate. To date, no systematic study has been conducted to elucidate the mechanisms implicated in ocular drug penetration using iontophoresis.

Since the earliest description of zinc salt transcorneal iontophoresis by Wirtz in 1908, described by Duke-Elder,286 and in spite of a century of publications, clinical use of iontophoresis has not been widespread. In fact, the absence of scientific rationale for drug penetration into or through ocular tissues, the lack of systematic pharmacokinetic studies, and the effect of pathology on the drug concentration time course; and the description of tissular lesions induced by iontophoresis using high current densities, have hindered clinical development of iontophoresis. However, iontophoresis could have potential interest in many therapeutic fields in ophthalmology particularly to treat posterior segment inflammations and infections and to deliver new potential antiangiogenic or trophic agents to the retina and/or the choroid. The innovative application of modern electronics and materials science as well as further research in ocular toxicology could help to place iontophoresis among the efficient means of treatment of the posterior segment of the eye.

V.A. Transconjunctival iontophoresis

V.A.I. Transconjunctival iontophoresis of antimitotics

Transconjunctival iontophoresis of 5-fluorouracil (5-FU), was investigated in the rabbit to inhibit sub-conjunctival and scleral fibroblast proliferation. Using 0.32 mA/cm2 current density for 30 s, the acute 5-FU concentration in the conjunctiva was 480 and 168 mg/ml in the sclera, at 10 h it was 0.6 and 1.2 mg/ml, respectively, still above ID50 levels for cultured conjunctival fibroblasts. The amount of 5-FU introduced by iontophoresis was about 0.1% of the dose given to patients by subconjunctival injections.287

V.A. 2. Transconjunctival iontophoresis of anesthetics

Sisler288 reported iontophoresis of lidocaine to tarsal conjunctiva from a cotton pad prior to surgical excision of intra- and sub-conjunctival lesions in 27 patients. The excision was painless for 24 patients, and three others required classical injection of local anesthesia.

V.B. Transcorneal iontophoresis

Transcorneal iontophoresis has been used to deliver fluorescein, antibiotics and antiviral drugs into the cornea and in the aqueous humor. Transcorneal iontophoresis results in high and sustained drug concentrations in the cornea and the aqueous humor, but in low drug concentrations in the posterior segment of phakic eyes.

V.B.I. Transcorneal iontophoresis of fluorescein for aqueous humor dynamic studies In 1966, Jones and Maurice used iontophoresis of fluorescein and a slit lamp fluor-ophotometer to measure the rate of flow of aqueous humor in the patient. Iontophoresis was performed with a 10% fluorescein solution, 2% agar, and 0.1 solution of methyl-hydroxybenzoate as a preservative.289 No corneal lesions were observed on numerous patients who received iontophoresis with a 0.2 mA current intensity for 10-15 s. The same results were obtained by Starr et al.290 with a 1 min treatment. Tonjum and Green291 assayed the effect of current intensity and duration of treatment on rabbit eyes in vitro and demonstrated that fluorescein penetration in aqueous humor was already optimal with a 0.5 mA current intensity for 10 s. In 1982, Brubaker used iontophoresis of fluorescein with a central 5 mm gel containing 2% agar and 10% fluorescein, with an intensity of 0.2 mA for 5-7 min in more than 1000 patients without any lesions except some epithelial defects.292 This abrasion was apparently caused by part of the apparatus that contained the agar and did not result as a direct consequence of iontophoresis. These studies demonstrated that under specific conditions, iontophoresis is a safe procedure on patients.

V.B.2. Transcorneal iontophoresis of antibiotics

The efficacy of transcorneal iontophoresis of antibiotics has been assayed both in pharmacokinetic studies and on corneal abcess models. Table 7 gives a summary of the main studies using transcorneal iontophoresis.

Hughes and Maurice293 reported iontophoresis of gentamicin to uninfected rabbit eyes and showed rapid and sustained efficient concentrations of drug in the cornea and the aqueous humor Fishman et al.294 iontophoresed gentamicin to aphakic rabbit eyes. The peak corneal and aqueous humor concentrations were obtained 30 min after iontophoresis (Table 7), while the peak vitreous concentration was obtained (10.4 mg/ml) at 16 h after treatment, demonstrating that transcorneal iontophoresis could potentially deliver therapeutic antibiotic concentrations for endophthalmitis in aphakic eyes. Grossman et al.295 demonstrated that the concentration of gentamicin after iontophoresis resulted in higher and longer-lasting gentamicin levels compared to subconjunctival injections. In addition, the inclusion of 2% agar solution to the 10% gentamicin led to very high drug concentrations in the cornea and the aqueous humor. Iontophoresis of tobramycin has been demonstrated to be efficient in the treatment of experimental Pseudomonas aeruginosa keratitis in the rabbit.296 Transcorneal iontophoresis performed 22 h and 27 h after inoculation resulted in 'sterile' corneas over half of the animals 1 h after the treatment. Tobramycin iontophoresis allowed on average a 6-log reduction in colony-forming units in the cornea relative to untreated corneas. Safety of tobramycin iontophoresis was demonstrated by Rootman et al.297 Iontophoresis of tobramycin delivered high concentrations both to uninfected and pseudomonas-infected corneas; 20 times more than application of fortified tobramycin (1.36%) drops.298 Moreover, iontophoresis of 2.5% tobramycin resulted in a 3-log reduction in the number of a tobramycin-resistant strain of Pseudomonas, demonstrating the power of this method to deliver very high concentrations of drug.299 Quinolone iontophoresis was also an efficient way to treat Pseudomonas keratitis.3 Interestingly, transcorneal iontophoresis of vancomycin was as efficient as subconjunctival injection. The peak concentration was 122.4 mg/ml at 2 h after iontophoresis and 14.7 mg/ ml 4 h after 2.5 mg subconjunctival injection. This was the first report that demonstrated that a high molecular weight glycopeptide (1448 Da) could be delivered by iontophoresis, into the cornea and the aqueous humor.301

In conclusion, transcorneal iontophoresis has been shown to be an efficient method that enhances aqueous and corneal antibiotic concentrations by a factor of 25-100 compared to topical applications. Except in aphakic rabbits, transcorneal iontophoresis did not result in high drug concentrations in the posterior segment of the eye.

Table 7

Transcorneal iontophoresis of antibiotics

Drug; concentration

Current density (mA/cm2)

Duration treatment (min)

Tissues measured

Time (h)

Concentration (jxg/ml)

Animal model

Refe

Tobramycin sulfate;

0 0

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