Controlled transdermal iontophoresis by ion-exchange fiber.

The objective of this study was to assess the transdermal delivery of drugs using iontophoresis with cation- and anion-exchange fibers as controlled drug delivery vehicles. Complexation of charged model drugs with the ion-exchange fibers was studied as a method to achieve controlled transdermal drug delivery. Drug release from the cation-exchange fiber into a physiological saline was dependent on the lipophilicity of the drug. The release rates of lipophilic tacrine and propranolol were significantly slower than that of hydrophilic nadolol. Permeation of tacrine across the skin was directly related to the iontophoretic current density and drug concentration used. Anion-exchange fiber was tested with anionic sodium salicylate. The iontophoretic flux enhancement of sodium salicylate from the fiber was substantial. As the drug has to be released from the ion-exchange fiber before permeating across the skin, a clear reduction in the drug fluxes from the cationic and anionic fibers were observed compared to the respective fluxes of the drugs in solution. Overall, the ion-exchange fibers act as a drug reservoir, controlling the release and iontophoretic transdermal delivery of the drug.     

Effect of electroporation on the electroosmosis across hairless mouse skin in vitro.

The effect of electroporation on the iontophoresis-produced electroosmosis across the skin was evaluated by measuring the permeability of hairless mouse skin, to mannitol, a non-electrolyte, in vitro. Immediately after electroporation by squared pulses (10 times/s) at 100, 150 or 200 V for 1 ms, anodal iontophoretic permeations were determined at 0.4 mA/cm2 for 4 h. The observed iontophoretic permeability of mannitol was higher with electroporation pretreatment than without pretreatment. The enhanced flux of mannitol induced by electroporation, however, was due to increased passive diffusion. The contribution of convective or osmotic flow caused by anodal iontophoresis on skin permeation of mannitol was decreased by the pretreatment. In addition, osmotic flow was decreased with an increase in the applied voltage for electroporation. In contrast, mannitol flux during cathodal iontophoresis at 0.4 mA/cm2 after 150 or 200 V electroporation was higher than without electroporation as well as anodal iontophoresis, but cathodal iontophoretic flux after electroporation was lower than without iontophoresis. The neutral high-molecular compound dextran rhodamine B was also used as a second model. Anodal iontophoresis alone did not increase skin permeability of the compound. However, electroporation pretreatment before anodal iontophoresis enhanced the skin permeation of dextran rhodamine B, which was due to increased osmotic flow induced by this combination. These results suggest that electroporation decreases the electroosmosis produced by iontophoresis, and that electroporation increases skin permeability to neutral low and high model compounds (mannitol and dextran rhodamine B) probably due to an enlarged permeation pathway. Thus, electroporation affects osmotic flow from the anode to cathode during iontophoresis. Therefore, one has to pay attention to the change in electroosmosis produced by iontophoresis for the combined use of electroporation and iontophoresis to attain a high skin-penetration enhancing effect.     

The effect of electroporation on iontophoretic transdermal delivery of calcium regulating hormones.

Electrically-assisted delivery by iontophoresis and/or electroporation was used in vitro to deliver the calcium regulating hormones, salmon calcitonin (sCT) and parathyroid hormone (1-34) (PTH) through human epidermis. Such delivery could be useful for chronic treatment of post-menopausal osteoporosis and other clinical indications as a superior alternative to parenteral delivery. sCT (50 microg/ml) or PTH (1-34) (100 microg/ml) formulation was prepared in citrate buffer (pH 4.0 or 5.0, respectively). Epidermis separated from human cadaver skin was used. Iontophoresis was applied using a constant current power source and electroporation with an exponential pulse generator. Silver/silver chloride electrodes were used. A combination of electroporation and iontophoresis resulted in higher transdermal permeation than either one technique alone. Electroporation also shortened the lag time of iontophoretic transdermal delivery of salmon calcitonin. Pulsing at lower voltages followed by iontophoresis did not result in increased transport (over iontophoresis alone), perhaps because the transdermal voltage was very low. The transdermal transport of salmon calcitonin by pulsing with 15 pulses (1 ppm) of 500 V (200 ms) followed by iontophoresis led to a quick input and high flux. The average transdermal voltage was only about 50 V for a 500 V study.     

Electrically-assisted transdermal delivery of buprenorphine.

The objective of this study was to explore the electrically assisted transdermal delivery of buprenorphine. Oral delivery of buprenorphine, a synthetic opiate analgesic, is less efficient due to low absorption and large first-pass metabolism. While transdermal delivery of buprenorphine is expected to avoid the first-pass effect and thereby be more bioavailable, use of electrical enhancement techniques (iontophoresis and/or electroporation) could provide better programmability. Another use of buprenorphine is for opiate addiction therapy. However, a patch type device is subject to potential abuse as it could be removed by the addict. This abuse can be prevented if drug particles are embedded in the skin. The feasibility of doing so was investigated by electro-incorporation. Buprenorphine HCl (1 mg/ml) in citrate buffer (pH 4.0) was delivered in vitro across human epidermis via iontophoresis using a current density of 0.5 mA/cm(2) and silver-silver chloride electrodes. Electroporation pulses were also applied in some experiments. For electro-incorporation, drug microspheres or particles were driven into full thickness human skin by electroporation. It was observed that the passive transdermal flux of buprenorphine HCl was significantly enhanced by iontophoresis under anodic polarity. The effectiveness of electro-incorporation seemed inconclusive, with pressure also playing a potential role. Delivery was observed with electro-incorporation, but the results were statistically not different from the corresponding controls.     

基于STC12C5S60S2单片机经皮给药系统的设计

背景:经皮给药技术为蛋白质多肽类药物的导入提供了一种方便有效的方式。目的:研制一种基于微控制器的经皮给药系统,实现药物经皮无创导入的同时维持药物的活性,提高药物的生物利用度。方法:经皮给药系统以微控制器为核心,采用电致孔导入技术,电离导入技术和超声波导入技术从不同角度克服皮肤屏障,促进药物经皮吸收,在软硬件上合理的设计实现3种机制的协同作用,提高药物导入的效率。结果与结论:试制出经皮给药系统样机,该系统操作简便,以无创的方式经皮给药可以提高患者的依从性,通过各治疗参数的调节,可用于多种药物的经皮导入,为实现个体化治疗提供可能。     

Electrically assisted skin delivery of liposomal estradiol; phospholipid as damage retardant.

This work investigated transdermal penetration of a model lipophilic drug (estradiol) through human epidermis from phosphatidylcholine (PC)-based liposomes and saturated aqueous estradiol solution (control). Representative examples of cholate-containing ultradeformable (Transfersomes), non-rigid (pure PC) and membrane-stabilized (cholesterol-containing) vesicles were used. The unilamellar vesicles' diameters and zeta potentials were determined. Transdermal penetration studies involved occluded passive penetration for 12 h and cathodic iontophoresis (0.8 mA/cm(2)) for 8 h for all systems. Combined electroporation (5 pulses, 100 V, 100 ms, 1 min spacing) and iontophoresis (0.8 mA/cm(2), for 2 h) was also employed for ultradeformable vesicles and control. Estradiol penetration parameters (flux and skin deposition) from different formulations were compared. All vesicles had essentially the same particle size, with ultradeformable liposomes showing the highest negative zeta potential (-29 mV). Occluded passive penetration improved estradiol skin penetration from liposomes relative to control. Iontophoretic studies revealed the superiority of ultradeformable vesicles regarding drug skin penetration and deposition compared to traditional liposomes. Combination of electroporation and iontophoresis did not markedly improve estradiol penetration for ultradeformable vesicles. The combination results implied repair of the skin barrier due to the penetration retarding effect of PC monomers released from liposomes.     

Transdermal delivery of insulin from poloxamer gel: ex vivo and in vivo skin permeation studies in rat using iontophoresis and chemical enhancers.

Gels are considered to be the most suitable delivery vehicle for iontophoresis, as they can be easily amalgamated with the iontophoretic delivery system and can also match the contours of the skin. Insulin was used as a model peptide for large peptides in the molecular weight range of 3-7 kDa. A gel formulation of insulin was formulated using poloxamer 407 and was evaluated by ex vivo and in vivo skin permeation studies in rat with chemical enhancer and/or iontophoresis. The poloxamer gel was physically and chemically stable during the storage period. In ex vivo studies, both linoleic acid and menthone in combination with iontophoresis showed a synergistic enhancement of insulin permeation. The plasma insulin concentration (PIC) was highest with linoleic acid pre-treatment, in agreement with ex vivo permeation studies, but the reduction in plasma glucose levels (PGL) was comparable to iontophoresis. Menthone pre-treatment resulted in rapid attainment of peak PIC, but the reduction in PGL was less than other treatment groups. There was no direct relation between PIC and PGL and is attributed to the fact that the action of insulin in mediated by a cascade of cellular mechanisms, before a reduction in PGL is observed. However, iontophoresis either alone or in combination with linoleic acid produced a reduction in PGL to the extent of 36-40%. A combination of chemical enhancers and iontophoresis caused greater skin irritation than when either of them was used alone.     

The electrostability and electrically assisted delivery of an organophosphate pretreatment (physostigmine) across human skin in vitro.

Physostigmine is a tertiary carbamate that is utilised as a pretreatment against organophosphate intoxication. Oral delivery of physostigmine is not practical due to high first pass metabolism and short elimination half life. Transdermal administration of physostigmine may circumvent such problems. The aim of this study was to assess the electrostability of physostigmine and the feasibility of electrically assisted transdermal drug delivery of physostigmine through isolated human skin in vitro. Buffered solutions of physostigmine (free base, salicylate and sulphate) were electrostable under conditions of iontophoresis and electroporation as measured by HPLC, although instability of the chloridised silver electrodes was observed. Physostigmine sulphate was chosen for further study as it appeared to prevent degradation of the electrodes. Under conditions of iontophoresis (0.8 mA cm(-2), applied for 5- or 2.5-min durations for a maximum period of 45 min over 8 h), the total quantity of physostigmine sulphate that penetrated was 6.5+/-2.3% and 3.9+/-1.7% (pH 5.0 and pH 5.5) of the total applied dose (2 mg). Physostigmine did not penetrate the skin when electroporated at a frequency of 0.1 Hz or 10 Hz (100 V, 1 ms pulse width, duration 1 s, repetition 5-10 s), but significant amounts were delivered at a frequency of 100 Hz, being 11.3+/-2.9% and 5.8+/-2.5% of the applied dose (pH 5.0 and pH 5.5, respectively). These data indicate that iontophoretic and electroporative drug delivery of physostigmine sulphate was buffer-dependent, an effect tentatively attributed to a combination of co-ion competition, mono/di-cation ratio and applied charge effects.     

Transdermal delivery of cyclosporin-A using electroporation

Topical delivery of cyclosporin A (CSA) is desirable for treating psoriasis, but it is hindered by the barrier property of stratum corneum, and the physicochemical properties of CSA. Attempts to deliver CSA from a solution prepared in 40% ethanol (EtOH) in phosphate buffered saline (PBS) using iontophoresis did not result in any significant increase in drug delivery, compared to passive. However, the use of electroporation pulses as a physical penetration enhancer enabled delivery of a significant amount of CSA. Single pulse electroporation study indicated that the amount of EtOH delivered across the skin increased as the applied electrode voltage (U_electrode) was increased. However, it did not translate into a proportional increase in the delivery of CSA and only a three to four times increase, compared to passive delivery, was seen with the single pulse electroporation. The drug contact duration had a varying effect in the efficiency of transdermal delivery of CSA. Four hour contact duration was chosen for the multiple pulse study. Use of multiple pulses (25 pulses, 10 ms each) at U_electrode 200 V resulted in a sixty-fold increase, compared to passive, in the delivery of CSA to the skin. Transdermally delivered CSA was mostly bound to the skin and only a small amount was seen to cross the full skin into the receiver compartment. In a study of solvent transport, the flux of water was up to three times larger than that of EtOH after electroporation.     

Enhancement of skin permeation of high molecular compounds by a combination of microneedle pretreatment and iontophoresis.

A combination of microneedle pretreatment and iontophoresis was evaluated for the potential to increase skin permeation of drugs. Two model compounds with low and high molecular D(2)O and fluorescein isothiocyanate (FITC)-dextrans (FD-4, FD-10, FD-40, FD-70 and FD-2000; average molecular weight of 3.8, 10.1, 39.0, 71.2 and 200.0 kDa), respectively, were used and the effect of microneedle pretreatment and iontophoresis on their in vitro permeability was evaluated using excised hairless rat skin with a 2-chamber diffusion cell. Convective solvent flow through the skin was measured using a set of calibrated capillaries attached to the diffusion cell. The following results were obtained: (1) convective solvent flow (electroosmosis) during iontophoresis through microneedle-pretreated skin, 2.62+/-0.32 microL/cm(2)/h, was almost the same as through intact skin, 2.71+/-0.25 microL/cm(2)/h, and (2) the combination of microneedle pretreatment and subsequent iontophoresis significantly enhanced FD flux compared with microneedle pretreatment alone or iontophoresis alone, whereas no synergistic effect was found on the flux of D(2)O. These results suggest that the combination of iontophoresis with microneedle pretreatment may be a useful means to increase skin permeation of high molecular compounds.     

Transdermal iontophoresis of insulin. V. Effect of terpenes.

To increase the skin permeation of large peptides like insulin, it is necessary to utilize a combination of enhancement strategies. In this regard, this study investigated the effect of terpenes/EtOH combination in comparison to EtOH and neat terpene on transdermal iontophoretic permeation of insulin. Ex-vivo experiments were conducted using full thickness rat skin after pre-treatment for 2 h with 5% of menthol, menthone, cineole and pulegone in EtOH; EtOH alone; neat menthone with and without iontophoresis (0.5 mA/cm(2); 6 h). FT-IR studies were carried out using rat epidermal sheets after pre-treatment with enhancer solution for 2 h and tritiated water permeation studies was used to investigate the alteration in skin barrier property after enhancer or current treatment. The lag time was significantly reduced (P<0.05) with terpene/EtOH pre-treatment in comparison to passive control and EtOH pre-treatment, although there was no significant difference (P>0.05) among the terpenes. Synergistic enhancement in flux was observed with terpene/EtOH, and menthone/EtOH showed highest enhancement among the terpene/EtOH combinations. On the other hand, enhancement with neat menthone was higher than with menthone/EtOH. FT-IR studies showed that terpene/EtOH, EtOH and neat terpene act at the intercellular lipids. The skin barrier property was significantly (P<0.05) compromised with neat menthone treatment. Iontophoresis had a lesser effect on skin barrier property compared to chemical enhancer pre-treatment. Terpene/EtOH caused synergistic enhancement of insulin permeation when combined with iontophoresis and was influenced by the type and concentration of terpene.     

In vitro and in vivo iontophoresis of a tripeptide across nude rat skin

The iontophoretic delivery across nude rat skin of a tripeptide (Threonme-Lysine-Proline), which is positively charged at pH 7.4, has been measured in vitro and in vivo. The peptide was delivered from a poloxamer gel which demonstrated thermoreversible properties: the gel is a liquid at room temperature, a feature which facilitates preparation, whereas, at 37°C, the gel solidifies and provides a welldefined delivery system. The in vitro studies showed that: (a) iontophoresis significantly enhanced peptide delivery compared to passive transport; (b) peptide delivery was directly proportional to the applied continuous direct current density over the range 0.18–0.36 mA/cm²; (c) following 6 h of iontophoresis, minimal degradation of the peptide in either the donor or receptor phases of the diffusion cell (by electrolysis and/or metabolism) was observed; (d) exposure of the skin to direct current prior to the application (without current) of the tripeptide lowered the barrier function to the passive transport of Thr-Lys-Pro. In vivo, a single intravenous injection of radiolabeled tripeptide was rapidly eliminated (primarily in the urine) with an apparent half-life of less than 30 min. When the peptide was delivered by iontophoresis, considerable enhancement over passive diffusion was again achieved; the cumulative delivery of tripeptide in vivo was predictable from the in vitro results. In addition, and once more in parallel to the in vitro findings, pre-exposure of the skin to the iontophoretic current lowered barrier function to the subsequent passive delivery of the peptide. Skin sectioning and radioassay demonstrated that, relative to passive diffusion, iontophoresis produced (i) greater localization of the peptide in the skin, and (ii) delivery of peptide to deeper layers of the skin. Finally, histological and electron microscopical examination or rat skin following 3 hours of iontophoresis (at 0.36 mA/ cm²) in vivo did not reveal any gross morphological changes.     

Iontophoretic delivery of calcium for experimental hydrofluoric acid burns

OBJECTIVE: To examine the efficacy of iontophoretic delivery of calcium to experimental hydrofluoric acid burns. DESIGN: Prospective, controlled study. SETTING: Institutional laboratory. SUBJECTS: Male nude rats. INTERVENTIONS: For the in vitro experiment, a full-thickness skin from the back was set in a vertical flow-through diffusion cell. Calcium chloride was applied to the donor chamber, and transdermal transport of calcium was examined with or without a voltage gradient of 1.5 V. Either intact skin or skin whose stratum corneum was stripped with adhesive tapes was used. For the in vivo experiment, hydrofluoric acid burns were induced by dispensing 50% hydrofluoric acid (50 microL) on the backs of the nude rats, who were under pentobarbital anesthesia. Rats were divided into four groups (n = 5 for each group): control group (burned but not treated); topical group (treated with calcium gluconate jelly); infiltration group (intradermal and subcutaneous injection of calcium gluconate); and iontophoresis group (treated with iontophoresis of calcium chloride at 1.5 V). Burn areas were measured and pathologic findings were classified microscopically into five stages at 1 wk: stage 1, epidermal burn; stage 2, superficial dermal burn; stage 3, deep dermal burn; stage 4, full-thickness burn; and stage 5, burn affecting the skeletal muscle. MEASUREMENTS AND MAIN RESULTS: In the in vitro experiment, calcium concentrations increased significantly only in stripped skins with a 1.5-V gradient. In the in vitro experiment, burn areas were reduced significantly in the iontophoresis group compared with the other three groups. Pathologic findings were significantly improved in the iontophoresis group compared with the control group. This efficacy of iontophoresis was observed when it was initiated within 30 mins after hydrofluoric acid burn. CONCLUSIONS: These results show that transdermal transport of calcium was enhanced in stripped skins by iontophoresis and that iontophoresis was more efficacious than topical or infiltration therapy for experimental hydrofluoric acid burns. Iontophoretic delivery of calcium seems to be easier than intra-arterial infusion and may be effective for the lesions where intra-arterial infusion is difficult.     

In vitro acyclovir distribution in human skin layers after transdermal iontophoresis

The purpose of the present work was to study the in vitro distribution of acyclovir in human skin layers after iontophoresis, applied in order to increase the amount of drug in the basal epidermis, site of Herpes simplex infections. Experiments were done with Franz diffusion cells applying, as donor, acyclovir solutions (pH values: 3.0 and 7.4) or a commercial cream. Quantification of drug at different skin depths was performed by horizontal slicing of frozen skin, and drug extraction and analysis by high-performance liquid chromatography. Seven h of transdermal iontophoresis (0.5 mA cm⁻²) induced an accumulation of acyclovir in epidermis and dermis ranging from 80 to 150 μg cm⁻³, characterized by homogeneous distribution of the drug in skin layers. After short current application time (30 min) however, the concentration profile of drug in skin was not significantly different from that obtained after seven h of passive diffusion, employing pH 3.0 donor solution. After 30 min of iontophoresis, the acyclovir reservoir on the skin was maintained for up to five h producing a dramatic increase of drug concentration in skin, evening out over 80 μg cm⁻³ until a depth of 300 μm. Acyclovir can be accumulated at target site more quickly and maintained at higher level through application of a iontophoretic pulse and by keeping the drug reservoir on skin.     

Iontophoretic delivery of 5-aminolevulinic acid and its methyl ester using a carbopol gel as vehicle.

The aim of this study was to evaluate a Carbopol gel as a vehicle for iontophoretic delivery of 5-aminolevulinic acid (ALA) and its methyl ester (m-ALA). The formulation was characterized rheologically and the passive diffusion of ALA and m-ALA in the gels was measured. Addition of ALA and m-ALA did not change the rheological behavior of the gel and the diffusion coefficients of ALA and m-ALA were 4.4 +/- 1.2 x 10(-6) and 3.08 +/- 0.7 x 10(-7) cm2 s(-1), respectively. The anodal iontophoretic transport of ALA and m-ALA through porcine skin in vitro was followed for 15 h at a constant current of 0.4 mA. When incorporating ALA in the gel, the steady-state was reached in 10-12 h at a flux level of approx. 65 nmol cm(-2) h(-1) compared to 2.5-4 h and a level of approximately 145 nmol cm(-2) h(-1) for m-ALA. The total amount of m-ALA delivered after 15 h of iontophoresis resulted in a six-fold enhancement over ALA delivery. Iontophoretic delivery from the gel formulation seems to be better than, or comparable to, the passive delivery from formulations commonly used clinically, in spite of the 10-20 times lower concentration of the drug in the gel formulation. The skin uptake after iontophoresis for m-ALA showed a nine-fold increase over that of ALA in the stratum corneum (SC).     

Gene packaging with lipids, peptides and viruses inhibits transfection by electroporation in vitro.

To develop improved methods of gene delivery, packaging DNA in chemical or viral vectors could increase electroporation-mediated transfection. To test this hypothesis, electroporation was applied to DU145 prostate cancer cells incubated with green fluorescent protein-encoded DNA plasmid either naked or packaged with cationic lipid (Lipofectin), polycationic peptide (salmon protamine) or retroviral vectors (Moloney murine leukemia viruses) and then assayed for gene expression and cell viability. Cationic lipid or electroporation alone each significantly increased transfection, but their combination was less effective. Addition of protamine peptide during electroporation was also less effective than electroporation alone. The combination of retroviral vectors and electroporation transfected fewer cells than retrovirus alone. We conclude that the combination of electroporation with chemical or viral vectors does not improve gene transfection in vitro.     

Emerging technologies in transdermal therapeutics

Until very recently, the only drugs that could permeate transdermally were those possessing a very narrow and specific combination of physicochemical properties. However, rapid advances in bioengineering have led to the emergence of various new "active" enhancement technologies designed to transiently circumvent the barrier function of the stratum corneum. These novel systems, using iontophoresis, sonophoresis, electroporation, or microneedle arrays, will greatly expand the range of drugs that can be delivered transdermally. Crucially, the delivery of macromolecules will become possible and the transdermal flux of other molecules could be enhanced by several orders of magnitude. This article sequentially reviews the basis of each of the new enhancement techniques and discusses how these emerging technologies will influence transdermal therapy in the coming years.     

Effects of iontophoresis current magnitude and duration on dexamethasone deposition and localized drug retention

BACKGROUND AND PURPOSE: Iontophoresis is a process that uses bipolar electric fields to propel molecules across intact skin and into underlying tissue. The purpose of this study was to describe and experimentally examine an iontophoresis drug delivery model. SUBJECTS AND METHODS: A mechanistic model describing delivery was studied in vitro using agarose gels and was further tested in vivo by evaluation of cutaneous vasoconstriction following iontophoresis in human volunteers. RESULTS: In vitro cathodic iontophoresis at 4 mA and 0.1 mA each delivered dexamethasone/dexamethasone phosphate (DEX/DEX-P) from a 4-mg/mL donor solution to a depth of 12 mm following a 40 mA minute stimulation dosage. Delivery of DEX/DEX-P to at least the depths of the vasculature in humans was confirmed by observation of cutaneous vasoconstriction. This cutaneous vasoconstriction was longer lasting and greater in magnitude when using low-current, long-duration (approximately 0.1 mA) iontophoresis compared with equivalent dosages delivered by higher-current, shorter-duration (1.5-4.0 mA) iontophoresis. DISCUSSION AND CONCLUSION: From data gathered with the gel model, the authors developed a model of a potential mechanism of drug depot formation following iontophoresis. The authors believe this drug depot formation to be due to exchange of drug ions for chloride ions as the ionic current carriers. Furthermore, diffusion, not magnitude of current, appears to govern the depth of drug penetration. Although the authors did not address the efficacy of the drug delivered, the results of human experiments suggest that current magnitude and duration should be considered as factors in treating musculoskeletal dysfunctions with iontophoresis using DEX/DEX-P at a concentration of 4 mg/mL.     

DNA electrotransfer into the skin using a combination of one high- and one low-voltage pulse.

Electroporation is an effective alternative to viral methods to significantly improve DNA transfection after intradermal and topical delivery. The aim of the study was to check whether a combination of a short high-voltage pulse (HV) to permeabilize the skin cells and a long low-voltage pulse (LV) to transfer DNA by electrophoresis was more efficient to enhance DNA expression than conventional repeated HV or LV pulses alone after intradermal injection of DNA plasmid. GFP and luciferase expressions in the skin were enhanced by HV+LV protocol as compared to HV or LV pulses alone. The expression lasted for up to 10 days. Consistently, HV+LV protocol induced a higher Th2 immune response against ovalbumin than HV or LV pulses. Standard methods were used to assess the effect of electric pulses on skin: the application of a combination of HV and LV pulses on rat skin fold delivered by plate electrodes was well tolerated. These data demonstrate that a combination of one HV (700 to 1000 V/cm; 100 micros) followed by one LV (140 to 200 V/cm; 400 ms) is an efficient electroporation protocol to enhance DNA expression in the skin.     

Transdermal iontophoretic delivery of apomorphine in patients improved by surfactant formulation pretreatment.

The objective of the present study is to evaluate the efficacy and the safety of transdermal iontophoretic delivery of R-apomorphine, a potent dopamine agonist, in combination with surfactant pretreatment in patients with advanced Parkinson's disease. Iontophoresis patches were applied in 16 patients for 3.5 h, with 0.5 h of passive delivery followed by 3 h of current application at a current density of 250 microA/cm2. Eight of these patients were treated with a surfactant formulation prior to iontophoresis. The pharmacokinetics, pharmacodynamic effects, systemic and local side effects of R-apomorphine were assessed. The plasma concentration vs. time profiles upon iontophoresis of R-apomorphine were described successfully by a novel pharmacokinetic model. The model suggests that only 1.9% of the dose that has been released from the patch accumulated in the skin. The patients treated with the surfactant formulations showed a statistically significant increase of bioavailability (from 10.6+/-0.8% to 13.2+/-1.4%) and of the steady state input rate (from 75.3+/-6.6 to 98.3+/-12.1 nmol/cm2 h) compared to the control patients (iontophoresis without absorption enhancers). In five out of eight patients in the study group and in three out of eight patients in the control group, clinical improvement was observed.