lontophoretic Delivery of a Telomeric Oligonucleotide

Purpose. To evaluate the feasibility of iontophoretically enhanced transdermal delivery of a phosphorothioate oligonucleotide across hairless mouse skin. Methods. The phosphorothioate sequence, 5-d(TTAGGG)-3 (TAG-6) which mimics the repeat sequence of the telomere was used as a model compound. Iontophoresis was performed on hairless mouse skin using an in vitro flow-through diffusion system. Both 5-FITC and uniformly ³⁵S labeled oligonucleotide were used to monitor transdermal flux. Results. Cathodal delivery of TAG-6 resulted in substantial oligonucleotide flux. The molecular label did not alter transport properties. No flux was measured with either anodal or passive delivery. The oligonucleotide was not degraded as it crossed the skin. Molecular transport was donor condition dependent, with pH and salt concentration both having significant effects. Pre-treating the skin with ethanol reduced iontophoretic transport. Conclusions. These data demonstrate that iontophoresis can enhance transdermal flux of an intact phosphorothioate oligonucleotide and that this penetration is donor condition dependent. Furthermore, iontophoretically enhanced transdermal delivery is a feasible apprach to the administration of phosphorothioate oligonucleotides.     

Mechanism of Transport Enhancement of LHRH Through Porcine Epidermis by Terpenes and Iontophoresis: Permeability and Lipid Extraction Studies

Purpose. The purpose of this study was to investigate the effect of 5% terpenes (i.e., limonene, carvone, thymol, and cineole)/ethanol (EtOH) and iontophoresis on the in vitro permeability of luteinizing hormone releasing hormone (LHRH) through the porcine epidermis and biophysical changes in the stratum corneum (SC) lipids by fourier transform infrared (FT-IR) spectroscopy. Methods. The porcine epidermis was pretreated with enhancer for 2 h. The permeability measurement system included Franz diffusion cells, Ag/AgCl electrodes, and SCEPTOR^® iontophoretic power source. FT-IR spectroscopy was performed to assess the possible contribution of lipid extraction to the transport enhancement of LHRH. Results. Terpenes in combination with EtOH significantly (p < 0.05) increased the flux of LHRH in comparison with the control (epidermis which was not enhancer treated). Iontophoresis further enhanced (p < 0.05) the flux of LHRH through terpenes/EtOH treated epidermis in comparison with their passive permeability. Reversibility studies showed that the post-recovery passive flux of LHRH through 5% limonene in EtOH/iontophoresis treated epidermis was significantly (p < 0.05) decreased but did not significantly recover to the baseline flux (i.e., flux through control epidermis). The SC treated with terpenes/ EtOH showed a decrease in peak heights and areas for both asymmetric and symmetric C-H stretching absorbances in comparison to untreated SC. A greater percent decrease in peak heights and areas was obtained by limonene/EtOH. However, treatment of the SC with terpenes/EtOH followed by iontophoresis did not further decrease the percentage of peak height and area over and above terpene/EtOH suggesting that iontophoresis alone does not cause SC lipid extraction. Conclusions. Terpenes/EtOH increased LHRH permeability by enhancing the extraction of the SC lipids. Iontophoresis synergistically enhanced the permeability of LHRH through terpenes/EtOH treated epidermis. Thus, terpenes can be used as chemical enhancers in combination with iontophoresis to enhance the transdermal delivery of peptides such as LHRH.     

Localization of a FITC-Labeled Phosphorothioate Oligodeoxynucleotide in the Skin After Topical Delivery by Iontophoresis and Electroporation

Purpose. The aim of this study was to verify the hypothesis that the application of high voltage to the skin enhances both stratum corneum and keratinocyte permeability. Therefore, the transport of FITC labelled phosphorothioate oligonucleotides (FITC-PS) administered by passive diffusion, iontophoresis or electroporation was localized. Methods. Fluorescent microscopy and laser scanning confocal microscopy were used to visualize the FITC-PS transport at the tissue and cell level respectively in hairless rat skin after electroporation (5 × (200 V 500 ms) or iontophoresis (same amount of charges transferred). Results. FITC-PS did not penetrate the viable skin by passive diffusion. Molecular transport in the skin upon electroporation or iontophoresis was localized and implied mainly hair follicles for iontophoresis. In the stratum corneum, the pathways for FITC-PS transport were more transcellular during electroporation and paracellular during iontophoresis. FITC-PS were detected in the nucleus of the keratinocytes a few minutes after pulsing. In contrast, iontophoresis did not lead to an uptake of the oligomer. Conclusions. The internalization of FITC-PS in the keratinocytes after electroporation confirms the hypothesis and suggests that electroporation, which allows both efficient topical delivery and rapid cellular uptake of the oligonucleotides, might be useful for antisense therapy of epidermal diseases.     

Transdermal Delivery of Fentanyl by Electroporation II. Mechanisms Involved in Drug Transport

Purpose. The aim of the present report was to systematically analyze the mechanisms involved in fentanyl transdermal transport by skin electroporation. Methods. The study was performed in vitro with full-thickness hairless rat skin, skin electroporation being carried out with five exponentially-decaying pulses of 100 V applied voltage and around 600 ms pulse duration. Results. Transport during and after pulsing are both important in transdermal delivery of fentanyl by skin electroporation. Rapid transport occurred during pulsing due to electrophoresis and diffusion through highly permeabilized skin. No electroosmosis was observed. The slow post-pulse passive transport was explained by lasting changes in skin permeability. Measurements of fentanyl quantities in the skin demonstrated that pulses rapidly loaded the viable part of the skin with fentanyl and hence rapidly overcame skin barrier. Conclusions. The different contributions of the transport mechanisms appear to depend on the physicochemical parameters of the transported molecule as well as the solution, suggesting that mechanistic analysis and careful consideration of formulation variables are essential for the development and optimization of drug delivery by skin electroporation.     

Transdermal Delivery of Fentanyl by Electroporation I. Influence of Electrical Factors

Purpose. Electroporation, a method of reversibly permeabilizing lipid bilayers by the application of an electric pulse, has been shown to induce increased transdermal passage of molecules. The aim of the present report was to study in vitro with hairless rat skin the potential of electroporation for transdermal delivery of fentanyl. Results. The application of electric pulses can strongly promote transdermal delivery of fentanyl compared to passive diffusion through untreated skin. We also point out that the choice of the waveform of the electric pulses is important: at the same applied energy, a few exponentially-decaying (ED) pulses increased fentanyl permeation more than a few square-wave pulses and to the same extent as the repeated application of higher voltage-shorter duration ED pulses. A factorial design showed that the voltage, duration, and number of ED pulses allowed control of the quantity of drug transported through the skin. Conclusions. Skin electroporation could be a good way to improve the transdermal diffusion of fentanyl.     

Effect of Electroporation on Transdermal lontophoretic Delivery of Luteinizing Hormone Releasing Hormone (LHRH) in Vitro

Electroporation, the creation of transient, enhanced membrane permeability using short duration (microseconds to millisecond) electrical pulses, can be used to increase transdermal drug delivery. The effect of an (electroporative) electric pulse (1000 V, = 5 msec) on the iontophoretic transport of LHRH through human skin was studied in vitro. Fluxes achieved with and without a pulse under different current densities (0- 4 mA/cm²) were compared. The results indicated that the application of a single pulse prior to iontophoresis consistently yielded higher fluxes (5—10 times the corresponding iontophoretic flux). For example, at 0.5 mA/cm² fluxes were 0.27 ± 0.08 and 1.62 ± 0.05 µg/hr/cm² without and with the pulse, respectively. At each current density studied, the LHRH flux decreased after iontophoresis, approaching pre-treatment values. The results show that electroporation can significantly and reversibly increase the flux of LHRH through human skin. These results also indicate the therapeutic utility of using electroporation for enhanced transdermal transport.     

X-ray microanalysis of cryopreserved human skin to study the effect of iontophoresis on percutaneous ion transport

Purpose. To study at the ultrastructural level which part of the skin is associated with percutaneous iodide transport by passive diffusion and iontophoresis. Methods. Following passive diffusion or iontophoresis of iodide, the morphology and the ion distribution of the skin was preserved by rapid freezing. The skin was kept frozen until and during examination by transmission electron microscopy (TEM) and X-ray microanalysis (XRMA). The intrinsic electron absorbing characteristics of cryopreserved skin allow direct TEM examination without additional staining. XRMA can be used to obtain in a relatively nondestructive way in situ information on ion distributions across the skin. Results. After passive diffusion, iodide was mainly found in the stratum corneum (SC), whereas there was little iodide in the viable epidermis. Iontophoresis up to 300 A/cm² did not significantly affect this distribution. With iontophoresis at 1000 A/cm², the amount of iodide increased dramatically and was equally distributed over the SC and viable epidermis. The presence of iodide in the SC suggests that iodide is present inside corneocytes. Conclusions. Iontophoresis up to 300 A/cm² does not significantly perturb skin structures in contrast to iontophoresis at 1000 A/cm². The presence of iodide inside corneocytes suggests the possibility of transcellular percutaneous iodide transport.     

Transdermal Delivery of Macromolecules Using Skin Electroporation

Purposes. (1) To evaluate the feasibility of transdermal delivery ofmacromolecules by skin electroporation. (2) To assess the influenceof the molecular weight of the permeant on transport and examinewhether there exists a cut-off value of molecular weight. (3) Tolocalize the transport pathways of the macromolecules in the skin. Methods. FITC-dextran (FD) of increasing molecular weight (4.4, 12and 38 kDa) were used as model macromolecules to study the extentof transport across hairless rats skin in vitro and to localize theirdistribution in the skin by confocal scanning laser microscopy. Results. Electroporation enhanced the transport of the macromoleculesas compared to passive diffusion. The transdermal delivery by skinelectroporation of FITC and FD 4.4 was equivalent whereas transportof higher molecular weight FD was lower but significant. FITC and FD38 were observed in the epidermis both around and in the keratinocytes. Conclusions. Transdermal and topical delivery of macromolecules ofat least 40 kDa can be achieved by skin electroporation.     

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.     

Macromolecules as Novel Transdermal Transport Enhancers for Skin Electroporation

Purpose. Macromolecules were investigated as chemical enhancers of transdermal transport by skin electroporation. Although unable to enhance passive or iontophoretic transport, macromolecules are proposed to enhance electroporation-assisted delivery by stabilizing the increased permeability caused by high-voltage pulses. Methods. To test this hypothesis, we examined the timescale of transport, the influence of electrical protocol and the influence of macromolecule size, structure, and charge on enhancement of transdermal mannitol transport in vitro by heparin, dextran-sulfate, neutral dextran, and poly-lysine. Results. Skin electroporation increased transdermal mannitol delivery by approximately two orders of magnitude. The addition of macromolecules further increased transport up to five-fold, in support of the proposed hypothesis. Macromolecules present during pulsing enhanced mannitol transport after pulsing for hours, apparently by a macromolecule-skin interaction. No enhancement was observed during passive diffusion or low-voltage iontophoresis, suggesting that macromolecules interact specifically with transport pathways created at high voltage. Although all macromolecules studied enhanced transport, those with greater charge and size were more effective. Conclusions. This study demonstrates that macromolecules can be used as trandermal transport enhancers uniquely suited to skin electroporation.     

Iontophoretic in Vivo Transdermal Delivery of β-Blockers in Hairless Rats and Reduced Skin Irritation by Liposomal Formulation

Purpose. To demonstrate the in vivo transdermal delivery and establish the comparative pharmacokinetics of five -blockers in hairless rat. Methods. Intravenous dosing was initially done via jugular cannula. For iontophoretic delivery, current (0.1 mA/cm²) was applied for 2 h through a drug reservoir patch containing the -blocker (10 mg/ml). Blood samples were collected and analyzed by stereoselective HPLC assays. Any irritation resulting from patch application was quantified by a chromameter. Multilamellar liposomal formulation was prepared by the thin-film hydration method and converted to unilamellar liposomes by extrusion. Results. With transdermal iontophoresis, therapeutically relevant amounts of propranolol (83.78 ± 7.4 ng/ml) were delivered within an hour and lasted for up to 4 h. C_max (185.1 ± 56.8 ng/ml) was reached at hour 3. A significantly higher amount (p < 0.05) of sotalol HCl was delivered compared to other -blockers. There was no significant difference in the S/R ratio of AUC_0-t for enantiomers after both intravenous and transdermal delivery. Skin irritation was significantly reduced (p < 0.05) when a liposomal formulation of the propranolol base was used rather than the base itself. Conclusions. The comparative pharmacokinetics of intravenous and transdermal iontophoretic delivery of five -blockers in hairless rats was established. It was shown that there is no stereoselective permeation.     

Electronically facilitated transdermal delivery of human parathyroid hormone (1-34)

Electronically facilitated transdermal delivery of human parathyroid hormone (1-34), hPTH (1-34), was investigated in vitro, using dermatomed porcine skin. The effect of iontophoretic current density, electroporative pulse voltages and also electroporation followed by iontophoresis was investigated on the in vitro percutaneous absorption of hPTH (1-34). Iontophoresis at 0.5 mA/cm2 current density significantly enhanced (P<0.05) the flux of hPTH (1-34) in comparison to passive flux. Electroporation pulses of 100, 200 and 300 V significantly increased (P<0.05) the flux of hPTH (1-34) in comparison with the passive as well as iontophoretic flux at 0.5 mA/cm2. The electroporative flux of hPTH (1-34) was found to vary linearly (R2 = 0.97) with the pulse amplitude. The principal barrier of the skin, stratum corneum, was found perturbed following the pulses as evident by light microscopy studies. The application of electroporation pulses followed by iontophoresis further increased the flux by several fold. The flux of hPTH (1-34) with the electroporation pulses of 100 and 300 V followed by iontophoresis at 0.2 mA/cm2 was 10- and 5-fold higher, respectively, in comparison to the flux with corresponding pulses alone. This shows the synergistic effect of iontophoresis in combination with electroporation on skin permeability of hPTH (1-34). The results indicate the possibility of designing controlled transdermal delivery systems for hPTH (1-34) using electroporation followed by iontophoresis.     

Iontophoretic Delivery of Apomorphine In Vitro: Physicochemic Considerations

Purpose. To examine the mechanisms of transdermal iontophoretic delivery of apomorphine. Methods. Anodal iontophoresis of R-apomorphine across human stratum corneum was determined in vitro. The effects on the flux of the following parameters were studied: stability of drug, pH of donor solution, concentration of NaCl, and type of Na⁺ co-ions. Results. Ascorbic acid was effective to prevent apomorphine degradation. The iontophoretic transport of apomorphine was strongly influenced by the pH of the donor formulation. Increasing the pH from 3 to 6 resulted in an increase in the iontophoretic apomorphine flux from 27.9 ± 4.4 nmol/cm²*h to 78.2 ± 6.9 nmol/cm²*h. Upon decreasing NaCl concentration from 8 to 2 g/L, the iontophoretic flux was not significantly changed. Replacing NaCl in the donor formulation by tetraethylammonium chloride or tetrabutylammonium chloride resulted in 1.3 fold greater steady-state flux. Conclusions. For optimized apomorphine iontophoretic delivery, a constant pH of the donor formulation is of great importance. The results suggest that although flux enhancement during iontophoresis is largely due to the electrical potential gradient, secondary effects, such as convective flow and electroosmosis may also contribute.     

Transepidermal Transport Enhancement of Insulin by Lipid Extraction and Iontophoresis

Purpose. To study the effect of Ethyl acetate (EtAc), 1:1 ratio of EtAc and Ethanol (EtOH) and 2:1 ratio of chloroform (C) and methanol (M) on the extent of lipid extraction from the stratum corneum (SC) and in vitro passive and iontophoretic transport of insulin through porcine epidermis. Methods. The porcine epidermis was pretreated for 40 min with the following solvents: 1) EtAc or EtAc:EtOH (1:1) and 2) C:M (2:1), which is a standard solvent combination for lipid extraction. Franz diffusion cells and Scepter^TM iontophoretic power source were used for the transport studies. Cathodal iontophoresis was performed at 0.2 mA/cm² current density. Fourier transform infrared spectroscopy (FTIR) studies were performed to assess the extent of lipid extraction. Thin layer chromatography (TLC) and gas chromatography (GC) were used to quantitate the different classes of lipid and identify the composition of the fatty acids, respectively, extracted by solvent(s) treatments. Results. Insulin flux was found to be significantly (P < 0.05) greater through solvent pretreated epidermis compared to untreated controls during both passive and iontophoretic transport. Pretreatment with EtAc:EtOH (1:1) exhibited an insulin flux of 15.29 × 10^–8 nmoles/ cm²/h compared to 52.71 × 10^–8 nmoles/ cm²/h during passive and iontophoretic transport, respectively. The passive and iontophoretic flux of insulin through EtAc:EtOH (1:1) pretreated epidermis was significantly greater (P < 0.05) than EtAc treated epidermis. The SC treated with solvents showed a decrease in peak areas of C-H stretching absorbances in comparison to untreated SC. A greater percent decrease in peak areas was obtained by EtAc:EtOH(1:1), in comparison to EtAc alone. Epidermal resistance measurements revealed its strong correlation with the amount of lipids present in the epidermis. The lipids extracted consisted of six series of ceramides, fatty acids, triglycerides, cholesterol, cholesterol esters, cholesterol sulfate and phospholipids. Conclusions. The SC lipid extraction using suitable solvents followed by iontophoresis can synergistically enhance the transepidermal transport of insulin.     

Transport Mechanisms in Iontophoresis. III. An Experimental Study of the Contributions of Electroosmotic Flow and Permeability Change in Transport of Low and High Molecular Weight Solutes

The objective of this research was to provide in vitro transport data designed to clarify the relative importance of permeability increase and electroosmotic flow in flux enhancement via iontophoresis, Iontophoretic fluxes were measured with both anode and cathode donor cells, and passive fluxes were measured both before iontophoresis (Passive 1) and after iontophoresis (Passive 2). Data were generated for three uncharged low molecular weight solutes (glycine, glucose, and tyrosine) and two high molecular weight anionic species (carboxy inulin and bovine serum albumin). Flux enhancement is greater for anodic delivery than for cathodic delivery, even for the negatively charged molecules, and anodic flux of glucose decreases as the concentration of NaCl increases. Both observations are consistent with a mass transfer mechanism strongly dependent on electroosmotic flow. Steady-state anodic flux at 0.32 mA/cm², expressed as equivalent donor solution flux (in µl/hr cm²), ranged from 6.1 for glycine to about 2 for the large anions. As expected, iontophoretic flux is higher at 3.2 mA/cm² than at 0.32 mA/cm², and passive flux measured after iontophoresis is about a factor of 10 greater than the corresponding flux measured before the skin was exposed to electric current. There are two mechanisms for flux enhancement relative to passive flux on fresh hairless mouse skin: (1) the effect of the voltage in increasing mass transfer over the passive diffusion level, the effect of electroosmotic flow dominating this contribution in the systems studied in this report; and (2) the effect of prior current flow in increasing the intrinsic permeability of the skin. Both effects are significant. Based on theoretical results given elsewhere, theoretical values for flux were calculated and compared with the experimental data. While agreement between theory and experiment was only qualitative in several cases, most of the data are predicted quantitatively by the theory.     

Constant voltage ‘Iron’tophoresis

The objective of this study was to investigate the feasibility of rapid administration of iron via transdermal route as an alternative to parenteral route of administration. In vitro drug delivery studies were carried out using porcine epidermis mounted on Franz diffusion cells. The effect of chemical permeation enhancers and physical techniques (constant voltage iontophoresis, electroporation and combination of electroporation with iontophoresis) on the transport of ferric pyrophosphate (FPP) was studied. Transepidermal water loss (TEWL) and electrical resistance were measured in order to see the effect of these techniques on the skin barrier function. The amount of FPP permeated was not enhanced significantly with the use of any of the enhancers (P?>?0.05). It was found that constant voltage iontophoresis (0.5, 2 or 4?V) for about 30?min across electroporated epidermis (120?V, 100 pulses, 10?ms at 5 Hz) enhanced the delivery of FPP over control in the range of 2- to 42-fold. Hence, a therapeutically required dose of iron could be delivered by transdermal route using electrically-mediated techniques.     

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.     

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.     

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.     

Transdermal Reverse Iontophoresis of Valproate: A Noninvasive Method for Therapeutic Drug Monitoring

Purpose. The objectives of this work were (a) to explore the potential of transdermal reverse iontophoresis for therapeutic drug monitoring and (b) to develop an internal standard calibration procedure so as to render the technique completely noninvasive. Methods. A series of in vitro iontophoresis experiments was performed in which the subdermal concentration of sodium valproate was varied from 21 M to 1 mM. Glutamic acid was also introduced into the subdermal donor at a fixed concentration to act as an internal standard for the calibration method. Results. Both valproate and glutamate anions were recovered, as expected, at the anodal receptor chamber. The iontophoretic extraction flux of valproate was linearly correlated with the subdermal concentration. Glutamate flux was constant. It follows that the ratio of extracted fluxes (valproate/glutamate) was directly dependent upon (a) the subdermal valproate concentration and (b) the subdermal concentration ratio (valproate/glutamate), offering a means, thereby, to a completely noninvasive methodology. Conclusions. This work demonstrates the potential of reverse iontophoresis for noninvasive therapeutic monitoring. The simultaneous quantification of the analyte of interest and of an internal standard renders the withdrawal of a blood sample unnecessary.