Mechanisms Involved in lontophoretic Transport of Angiotensin

Purpose. The feasibility of using iontophoresis to enhance the permeation rate of a model peptide was investigated in vitro using hairless mouse skin. Methods. Angiotensin 2 (AT 2) was employed as a permeant probe, using optimum iontophoresis conditions. A number of physicochemical parameters (donor ionic strength; valence of competitive ions; pH of donor solution) were studied with the aim of exploring the mechanisms involved in the iontophoretic transport through the skin: electrokinetic transport or convective transport. For this purpose, the magnitude of the convective solvent flow was also evaluated by the permeation of (³H) H₂O. The interest of pulsed currents for peptide delivery was also investigated and the effect of current density and frequency was studied. Results. AT 2 transport was found to be enhanced 20-fold in comparison to passive permeation and was found to be proportional to the current density with direct currents as with pulsed currents. Conclusions. Although the flux enhancement of ions during iontophoresis is due principally to the electrical potential gradient, secondary effects such as convective solvent flow contribute also to flux enhancement of peptide delivery. This effect is dependent of physicochemical conditions of formulation.     

Iontophoresis Enhances the Transport of Acyclovir Through Nude Mouse Skin by Electrorepulsion and Electroosmosis

Purpose. Iontophoresis was employed for enhancing the transdermal delivery of acyclovir through nude mouse skin in vitro, with the aim of understanding the mechanisms responsible for drug transport, in order to properly set the conditions of therapeutical application. Methods. Experiments were done in horizontal diffusion cells, using as donor a saturated solution of acyclovir at two different pH values (3.0 and 7.4). Different electrical conditions (current density and polarity) were employed. Results. At pH 3.0, acyclovir anodal transport was due to electrorepulsion, since acyclovir was 20% in the protonated form. In acyclovir anodal iontophoresis at pH 7.4 the main mechanism involved was electroosmosis, since the drug was substantially unionized and the negative charge of the skin at this pH caused the electroosmotic flow to be from anode to cathode. In the case of cathodal iontophoresis at pH 3.0, acyclovir transport was enhanced approx. seven times, due to the presence of an electroosmotic contribution caused by the reversal of the charge of the skin. At pH 7.4 during cathodal iontophoresis acyclovir transport was not enhanced because the electroosmotic flow was in the opposite direction, compared to drug electric transport, i.e. anode to cathode. The increased skin permeability caused by current application was demonstrated to be less important than electrorepulsion and electroosmosis. Conclusions. Anodal iontophoresis shows potential applicability for enhancing acyclovir transport to the skin, considering that both electric transport and electroosmosis can be used by appropriately setting the pH of the donor.     

Iontophoretic Delivery of Ropinirole Hydrochloride: Effect of Current Density and Vehicle Formulation

Purpose. The objectives of this work were 1) to establish the feasibility of the transdermal iontophoretic delivery of ropinirole hydrochloride; 2) to investigate the possibility of delivering therapeutic doses of this drug; and 3) to determine the key factors that control ropinirole electrotransport. Methods. A series of in vitro transdermal iontophoretic experiments were instituted to study the effects of drug concentration, co-ion concentration, intensity of current, and application time on ropinirole flux. The convective contribution to ropinirole electrotransport was evaluated by following the transport of the electroosmotic marker mannitol. Results. Ropinirole flux decreased dramatically in the presence of competing ions. This effect was observed even when the molar fraction of the two competing cations was kept constant. Anodal flux of mannitol decreased with drug concentration, indicating a possible alteration of the skin permselectivity. In the absence of competing co-ions, ropinirole transport number reached a maximum value (8-13%). In these conditions, the main factor controlling drug delivery was the intensity of current applied. Conclusions. Transdermal iontophoresis allowed the delivery of therapeutic doses of ropinirole. The dose administered and the input rate were controlled by the judicious choice of the key delivery factors here described.     

Controlled delivery of ropinirole hydrochloride through skin using modulated iontophoresis and microneedles

Abstract

The objective of this study was to investigate the effect of modulated current application using iontophoresis- and microneedle-mediated delivery on transdermal permeation of ropinirole hydrochloride. AdminPatch® microneedles and microchannels formed by them were characterized by scanning electron microscopy, dye staining and confocal microscopy. In vitro permeation studies were carried out using Franz diffusion cells, and skin extraction was used to quantify drug in underlying skin. Effect of microneedle pore density and ions in donor formulation was studied. Active enhancement techniques, continuous iontophoresis (74.13?±?2.20?µg/cm²) and microneedles (66.97?±?10.39?µg/cm²), significantly increased the permeation of drug with respect to passive delivery (8.25?±?2.41?µg/cm²). Modulated iontophoresis could control the amount of drug delivered at a given time point with the highest flux being 5.12?±?1.70?µg/cm²/h (5–7?h) and 5.99?±?0.81?µg/cm²/h (20–22?h). Combination of modulated iontophoresis and microneedles (46.50?±?6.46?µg/cm²) showed significantly higher delivery of ropinirole hydrochloride compared to modulated iontophoresis alone (84.91?±?9.21?µg/cm²). Modulated iontophoresis can help in maintaining precise control over ropinirole hydrochloride delivery for dose titration in Parkinson’s disease therapy and deliver therapeutic amounts over a suitable patch area and time.     

Electrically Modulated Transdermal Delivery of Fentanyl

Purpose. Test to determine if iontophoresis and electroporation, alone or in combination, can be used for rapid and modulated delivery of fentanyl. Methods. Fentanyl citrate (5 mg/ml) dissolved in pH 4.0 citrate buffer was delivered in vitro across human epidermis. For iontophoresis, a current of 0.5 mA/cm² was applied for 5 h, using silver/silver chloride electrodes. Electroporation protocol consisted of applying 15 exponential pulses of 500V (applied voltage) and 200 msec duration at the rate of 1 pulse per minute at time zero and, in some cases, repeating at 1.5 and 2.5 h. Results. There was no measurable permeation of fentanyl through human epidermis under passive conditions. A significant flux (about 80 g/cm²-hr) was achieved using iontophoresis and decreased once the current was turned off. A 4-fold higher flux and shorter lag time was observed with electroporation as compared to iontophoresis. The flux was found to recover quickly (within 1 h) following pulsing. Modulation of transdermal delivery of fentanyl was demonstrated by both iontophoresis and electroporation. Conclusions. Electrically assisted transdermal delivery of fentanyl significantly increased transport compared to passive delivery. Also, rapid and modulated delivery was shown to be feasible by programming the electrical parameters.     

In vitro and in vivo evaluation of a hydrogel-based prototype transdermal patch system of alfuzosin hydrochloride

The first-line therapy for moderate to severe benign prostatic hyperplasia is the oral therapy by alfuzosin hydrochloride. Unfortunately, the oral therapy of alfuzosin is associated with several route-specific systemic side-effects. The current study was aimed to develop a prototype transdermal patch system for alfuzosin using a hydrogel polymer and optimize the drug delivery through the skin for systemic therapy. The prospective of different chemical enhancers (polyethylene glycol (PEG 400), isopropyl myristate, propylene glycol, menthol and L-methionine; 5% w/v) and iontophoresis (0.3?mA/cm²) in the alfuzosin delivery across the full thickness rat skin was assessed in vitro. In vivo iontophoretic studies were carried out using selected patch system (PEG 400) for a period of 6?h in Sprague-Dawley rats. Passive permeation studies indicated that the incorporation of chemical agents have moderate effect (~?4- to 7-fold) on the alfuzosin skin permeability and reduced the lag time. Combined approach of iontophoresis with chemical enhancers significantly augmented the drug transport (~ 43- to 72-fold). In vivo pharmacokinetic parameters revealed that the iontophoresis (transdermal patch with PEG 400) significantly enhanced the C_max (~ 3-fold) and AUC_0-α (~ 4-fold), when compared to control. The current study concludes that the application of iontophoresis (0.3?mA/cm²) using the newly developed agaorse-based prototype patch with PEG 400 could be utilized for the successful delivery of alfuzosin by transdermal route.     

Transdermal and intradermal iontophoretic delivery of dexamethasone sodium phosphate: quantification of the drug localized in skin

In this study, the effect of iontophoresis on the transdermal and intradermal delivery of dexamethasone sodium phosphate (DEX-P) was examined in vitro and in vivo in the hairless rat model by skin permeation studies, tape stripping, and skin extraction. Cathodal or anodal iontophoresis (ITP) was performed and samples were analyzed by HPLC. In vitro experiments revealed that cathodal ITP significantly enhanced the cumulative amount of DEX-P permeating through the skin when compared to passive and anodal delivery. Tape stripping and skin extraction studies performed in vivo after ITP showed enhanced deposition of the drug in the stratum corneum and underlying skin when compared to passive delivery. The DEX-P and DEX depot formed in the stratum corneum and underlying skin were retained for at least 48?h and 24?h, respectively. In conclusion, ITP demonstrated potential as a feasible enhancement technique to drive the drug into and through the skin in significant amounts as compared to passive delivery.     

Compartmental Modeling of Transdermal Iontophoretic Transport II: <Emphasis Type="Italic">In Vivo</Emphasis> Model Derivation and Application

No HeadingPurpose. This study was aimed to develop a family of compartmental models to describe in a strictly quantitative manner the transdermal iontophoretic transport of drugs in vivo. The new models are based on previously proposed compartmental models for the transport in vitro.Methods. The novel in vivo model considers two separate models to describe the input into the systemic circulation: a) constant input and b) time-variant input. Analogous to the in vitro models, the in vivo models contain four parameters: 1) kinetic lag time (t_L), 2) steady-state flux during iontophoresis (J_ss), 3) skin release rate constant (K_R), and 4) passive flux in the post-iontophoretic period (J_pas). The elimination from the systemic circulation is described by a) the one-compartment and b) the two-compartment pharmacokinetic models. The models were applied to characterize the observed plasma concentration vs. time data following single-dose iontophoretic delivery of growth hormone-releasing factor (GRF) and R-apomorphine. Moreover, the models were also used to simulate the observed plasma concentration vs. time profiles following a two-dose transdermal iontophoretic administration of alniditan.Results. The time-variant input models were superior to the constant input models and appropriately converged to the observed data of GRF and R-apomorphine allowing the estimation of J_ss, K_R, and J_pas. In most cases, the values of t_L were negligible. The estimated J_ss and the in vivo flux profiles of GRF and R-apomorphine were similar to those obtained using the deconvolution method. The two-dose iontophoretic transport of alniditan was properly simulated using the proposed time-variant input model indicating the utility of the model to predict and to simulate the drug transport by a multiple-dose iontophoresis. Moreover, the use of the compartmental modeling approach to derive an in vitro-in vivo correlation for R-apomorphine was demonstrated. This approach was also used to identify the optimum in vitro model that closely mimics the in vivo iontophoretic transport of R-apomorphine.Conclusions. The developed in vivo models demonstrate their consistency and capability to describe the in vivo iontophoretic drug transport. This compartmental modeling approach provides a scientific basis to examine in vitro-in vivo correlations of drug transport by iontophoresis.     

Insights into drug delivery across the nail plate barrier

Abstract

Topical therapy is at the forefront in treating nail ailments (especially onychomycosis and nail psoriasis) due to its local effects, which circumvents systemic adverse events, improves patient compliance and reduces treatment cost. However, the success of topical therapy has been hindered due to poor penetration of topical therapeutics across densely keratinized nail plate barrier. For effective topical therapy across nail plate, ungual drug permeation must be enhanced. Present review is designed to provide an insight into prime aspects of transungual drug delivery viz. nail structure and physiology, various onychopathies, techniques of nail permeation enhancement and in vitro models for trans-nail drug permeation studies. Updated list of drug molecules studied across the nail plate and key commercial products have been furnished with sufficient depth. Patents pertinent to, and current clinical status of transungual drug delivery have also been comprehensively reviewed. This is the first systematic critique encompassing the detailed aspects of transungual drug delivery. In our opinion, transungual drug delivery is a promising avenue for researchers to develop novel formulations, augmenting pharmaceutical industries to commercialize the products for nail disorders.     

Permeability Profiles of M-Alkoxysubstituted Pyrrolidinoethylesters of Phenylcarbamic Acid Across Caco-2 Monolayers and Human Skin

Purpose. The purpose of the present research was to study 10 m-alkoxysubstituted pyrrolidinoethylesters of phenylcarbamic acid—potential local anesthetics. The relationships between the structure of the molecule, its physicochemical parameters (log D_oct, log k, R_M, solubility) were correlated to the permeability data obtained from permeation experiments in Caco-2 monolayers and excised human skin in vitro. Methods. The extent and mechanism(s) of permeability of the series were studied through a Caco-2 monolayer in the apical-to-basolateral (a-b) and basolateral-to-apical (b-a) directions. The MTT test was performed to determine cellular damage. In vitro transdermal permeability data were obtained from permeation experiments on excised human skin by using side-by-side chambers. Passive diffusion and iontophoretically enhanced permeability were measured. Results. In Caco-2 monolayers, similar results in the shape of the permeability curves were obtained for the two directions. In the b-a direction, the values of P_app were 2-6 times greater than in the a-b direction. A plot of drug permeability vs. the number of carbons in the alkoxychain plateaued first, after which the permeability decreased by the increasing lipophilicity of the drug. If the log D_oct of the ester was 3.4 and the MW > 385 Da, no measurable Caco-2 permeability was found. Cell damage was also higher by the more lipophilic compounds. In excised human skin, the relationship between the passive diffusion of the drugs and the number of carbons in the alkoxychain was parabolic (r ² = 0.95). Introducing low-level electrical current (iontophoresis), transdermal permeability of the more hydrophilic phenylcarbamic acid esters increased clearly. Conclusions. Lipophilicity and solubility of a compound have crucial roles in the permeation process. A very high lipophilicity has, however, a negative influence on the permeability, both intestinally and transdermally. Iontophoresis significantly increases the diffusion of small and less lipophilic compounds.     

Iontophoresis of Bases,Nucleosides, and Nucleotides

Purpose. To investigate whether transdermal iontophoresis may be potentially useful for delivery of oligonucleotide drugs, the electro-transport of representative bases (uracil and adenine), nucleosides (uridine and adenosine) and nucleotides (AMP, ATP, GTP and imido-GTP) across mammalian skin in vitro has been considered. Methods. While the passive permeability of all compounds investigated (from 1 mM solutions at pH 7.4) was very low, the application of constant current iontophoresis (0.55 mA/cm²) significantly enhanced the transport of both charged and uncharged species. Results. The efficiency of delivery depended only weakly upon lipophilicity, varied quite linearly with concentration (for AMP and ATP), was inversely sensitive to molecular weight, and was strongly influenced by charge. Neutral solutes were delivered better from the anode than the cathode, as expected; post-iontophoresis, passive permeabilities were greater than those of the untreated controls, suggesting that iontophoretically-induced changes in barrier function cannot be completely repaired in in vitro model systems. The triphosphate nucleotides, ATP and GTP, were essentially completely metabolized (presumably to their corresponding mono-phosphates) during their iontophoretic delivery, while imido-GTP was apparently resistant to enzymatic attack; however, comparison of the transport data from AMP and ATP suggested that ATP metabolism occurred primarily after the rate-limiting step of iontophoresis. Conclusions. The results obtained are consistent with the general patterns of behavior previously observed in investigations of amino acid and peptide electrotransport. It remains to be seen whether extension of the research described here to larger oligonucleotide species is a feasible long-term objective.     

Optimizing Iontophoretic Drug Delivery: Identification and Distribution of the Charge-Carrying Species

Purpose. To identify and quantify, in vitro and in vivo (in humans), the charge-carrying species during transdermal iontophoresis of lidocaine hydrochloride as a function of the concentration of drug relative to that of sodium chloride in the anodal solution. Methods. In vitro experiments in standard diffusion cells quantified lidocaine delivery and the outward migration of chloride across the skin. Electrotransport of Na⁺ was inferred by difference, allowing transport numbers of the three main charge-carrying species to be deduced. In vivo, outward electrotransport of Cl^– was measured and compared to the corresponding in vitro results. Results. The transport number of lidocaine increased linearly with increasing mole fraction and reached 0.15-0.20 at X_L = 1.0. In the absence of Na⁺, most of the charge was carried by Cl^– (>80%) despite the skin retaining its net negative charge and cation permselectivity. In vivo data correlated very well with in vitro results. Conclusions. The mole faction of drug (relative to competing ions of like polarity) is the crucial determinant of the extent to which it can carry charge across the skin during iontophoresis. The outward electromigration of Cl^–, in the sense opposite to drug delivery, may offer a useful means by which to optimize iontophoretic efficiency in the absence of competing cations in the anode formulation.     

An <Emphasis Type="BoldItalic">Ex Vivo</Emphasis> Toe Model Used to Assess Applicators for the Iontophoretic Ungual Delivery of Terbinafine

Purpose  An ex vivo intact toe model was developed to assess two different applicator designs for iontophoretic delivery of terbinafine into the nail only or the nail and surrounding skin. Methods  Iontophoretic permeation studies were carried out on intact cadaver toes using nail-only and nail/skin applicators with a current dose of 10 mA*min (0.5 mA for 20 min). Results  Iontophoresis enhanced drug permeation and tissue loading with both applicators tested. Greater drug delivery was observed with the nail/skin applicator due to the additional terbinafine being delivered directly through the lower impedance skin area surrounding the nail. The concentration of drug loaded into the contact area of the nail with the nail-only and nail/skin applicator was ~13 and ~7 fold higher than their respective passive delivery levels but equivalent from each other in total drug mass delivered over the whole nail plate. In vitro release of drug from the iontophoretically loaded nails into agar suggests that a single treatment could have a prolonged effect (>50 days). Conclusions  This study demonstrates that the ex vivo toe model was useful in assessing the functionality of the different applicator designs. These results suggest that iontophoresis can significantly enhance the delivery of drugs to both the hard and soft tissues of the toe for the treatment of onychomycosis and other nail disorders.     

Transscleral passive and iontophoretic transport: theory and analysis

Introduction: The sclera is considered the ‘static barrier,’ a main barrier for transscleral drug delivery. The characterization of passive and iontophoretic transport across the sclera in vitro is the first step toward our ability to predict transscleral drug delivery. Although previous studies have investigated this topic, the quantitative structure permeation relationships (QSPR) for passive and iontophoretic transscleral transport are not available.

Areas covered: This review evaluated previous results of transscleral passive and iontophoretic transport in vitro and examined QSPR for transscleral permeation of small permeants and macromolecules. Passive permeation data in the literature were compared with respective to the animal species employed in the studies. Data variability was investigated. Electrotransport theory and the mechanisms of iontophoresis were reviewed and used to analyze the iontophoresis data.

Expert opinion: QSPR was examined for passive transscleral permeation, showing correlations between logarithm of permeability coefficient and logarithm of molecular weight. Potential causes of data variability were proposed. QSPR were established for electroosmosis using the molecular weight of neutral permeants and for iontophoresis enhancement using the molecular weight and charge of ionic permeants. However, QSPR for charged macromolecules were empirical; iontophoretic flux enhancement was significantly smaller than Nernst-Planck model prediction due to complicating factors.     

Enhancement of the in Vitro Skin Permeability of Azidothymidine (AZT) via Iontophoresis and Chemical Enhancer

Azidothymidine (AZT) was used as a model drug to study the effect of iontophoresis on the skin permeation of a neutral compound. The rate of in vitro permeation across hairless rat skin was low and highly variable. With iontophoresis treatment the permeation rate was two- to threefold greater than by passive diffusion. The addition of varying amounts of sodium chloride to the donor enhanced the iontophoretic permeation rate an additional two- to threefold possibly due to convective forces. The addition of N-decylmethyl sulfoxide (C₁₀MSO) to the donor increased the permeation rate by several hundred-fold over passive diffusion for hairless rat skin and approximately 75-fold for human skin. No additional enhancement was observed with the combination of C₁₀MSO and iontophoresis treatment at constant current or constant voltage. It may be that the presence of C₁₀MSO lowers the zeta potential of the skin, thus enhancement due to convective flow is minimized.     

Transdermal Iontophoretic Delivery of Propofol: A General Anaesthetic in the Form of its Phosphate Salt

The main objective of this study was to investigate the feasibility of delivery of propofol phosphate (PP), a prodrug of propofol, via transdermal route using iontophoresis in combination with chemical permeation enhancers (CPEs). PP, a prodrug, was synthesized and its structure was characterized. In vitro passive and iontophoretic drug transport studies were carried out using Franz diffusion cell across freshly excised hairless rat skin at different concentrations of PP in combination with CPE. Among all the CPEs screened, 0.1% sodium dodecyl sulfate (SDS) increased the passive transdermal flux to 13.43 ± 0.73 μg/(cm² h) from 8.52 ± 0.82 μg/(cm² h) (control). Cathodal iontophoresis in combination with 0.1% SDS synergistically enhanced the flux [249.24 ± 6.12μg/(cm² h)] of PP. The Pharmacokinetic studies were performed in rat model to assess the feasibility of transdermal delivery of PP. The amount of propofol present in plasma samples in control group (passive) was below the detectable levels at all the time points during the study. The plasma concentration—time profile of iontophoresis group of rats was fit to a noncompartmental model and the pharmacokinetic parameters were calculated. These studies suggest the plausibility of achieving therapeutically relevant levels of propofol when delivered via transdermal route by combining iontophoresis with CPE.     

The Electrical Characteristics of Human Skin in Vivo

Purpose. The objectives of this study were to investigate the impedance properties of human skin in vivo and to examine the effect of iontophoresis upon them. Methods. Having established the intra- and inter-individual variation in basal values of skin impedance, the effect of varying iontophoretic current density, ionic strength and counter-ion on the rate of recovery of skin impedance after iontophoresis was investigated. Results. Passage of an iontophoretic current caused a significant reduction in the magnitude of the skin impedance. Increasing the current density caused an even greater reduction in the value of the skin impedance and slowed the rate of recovery. Reduction of the ionic strength resulted in an increase in the rate of recovery following iontophoresis. A significant increase in the rate of recovery was observed when CaCl₂ replaced NaCl as the electrolyte. Although visual inspection revealed the presence of greater erythema when CaCl₂ was used, there was an absence of the mild sensation experienced by volunteers when using NaCl. The last part of the study established a correlation between transepidermal water loss and impedance analysis as complementary methods for probing skin barrier function in vivo. The data were fitted to an equivalent circuit consisting of a resistor in parallel with a constant-phase element and a mechanistic model proposed to explain the electrical properties of the skin. Conclusions. The first comprehensive investigation of the effect of iontophoresis on the electrical properties of human skin in vivo has been described. It would appear from the results, and from their interpretation, that impedance spectroscopy may be an effective method to quantify the impact of iontophoresis on the skin, and to determine the extent to which proposed drug delivery regimens will perturb skin barrier function.     

Ungual and trans-ungual iontophoretic delivery of terbinafine for the treatment of onychomycosis

The application of iontophoresis was demonstrated in the nail drug delivery of terbinafine (TH) recently. This study explored a systematic assessment of this approach to enhance the drug delivery using a novel topical formulation, and the subsequent release of TH from the drug loaded nails. For the first time, a nail on-agar plate model was used to study the release of drug from the iontophoresis (0.5 mA/cm²) loaded nails. In addition, the activity of the drug released from the drug loaded nail plate was studied against Trichophyton rubrum. An increase in applied current density and current duration enhanced the transport of TH into and through the nail plate. In vitro release of drug from the iontophoretic loaded nails into agar plates exhibited 2-phase release pattern. The amount of drug released in both of the in vitro models was comparable, and the nails loaded using iontophoresis continued to release levels of TH > 2 orders of magnitude above the minimum inhibitory concentration over at least 52 days. Results indicate that iontophoresis enhances the delivery of terbinafine into and through the nail plate and suggest that the use of this treatment approach could result in a safe and more efficacious outcome with less frequent treatments. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4130–4140, 2009     

Basic principles and current status of transcorneal and transscleral iontophoresis

Introduction: Iontophoresis is an active non-invasive drug delivery technique that can increase the transport of charged and neutral molecules into and across biological membranes. Most research to-date has focused on (per)cutaneous iontophoretic drug delivery. However, recent studies illustrate its potential for drug delivery to the eye: corneal iontophoresis may enable targeted topical therapy of intracorneal diseases, whereas transscleral iontophoresis may enable non-invasive intraocular drug delivery.

Areas covered: We describe iontophoretic principles in the context of ocular delivery before providing a summary of recent preclinical studies involving transcorneal and transscleral iontophoresis in vitro and in vivo. Subsequently, an overview of clinical applications with special focus on the transcorneal iontophoresis of riboflavin for corneal cross-linking and transscleral iontophoresis of corticosteroids for the treatment of posterior segment diseases is provided.

Expert opinion: The feasibility of using iontophoresis for ocular drug delivery has been demonstrated. Drug formulation development and the ability to design iontophoretic applicators will now determine its success in the clinic. The specificities of the ocular globe must be taken into account; in particular, its unique morphology, and the smaller surface area available for drug diffusion and the fact that it is more susceptible to irritation and less robust than the skin.     

Response Surface Method: A Novel Strategy to Optimize lontophoretic Transdermal Delivery of Thyrotropin-releasing Hormone

Purpose. To maximize the iontophoretic transdermal delivery rate of thyrotropin-releasing hormone (TRH) facilitated by periodically monophase-pulsed current across excised skin. Methods. The pH of the buffer, the ionic strength in the solution, the frequency of the periodically monophase-pulsed current and the current on/off ratio were chosen as the key variables. A response surface method was applied to optimize the transdermal delivery rate of TRH under different operational conditions. Results. The optimum operating conditions were achieved via experimentation based on the response surface method by systematically adjusting the pH of the buffer, the ionic strength in the solution, the current amplitude, frequency and the active temporal ratio of the pulsed current. The rate of permeation of TRH crossing the skin during iontophoresis varied from two to ten-fold, depending on operating conditions. Conclusions. Only a few steps, two in this work, were needed to reach the optimal. The response surface near the region of the maximal point was thoroughly described with a quadratic function. A maximal transdermal rate of permeation of TRH, 103.2 µg h^–1 cm^–2, was obtained when the donor solution was at pH = 7.0, ionic strength = 0.037, and with a periodically monophase-pulsed current iontophoresis with duty cycle = 75%. The effect of pulse frequency was not statistically significant.