In vitro and in vivo characterization of a newly developed clonidine transdermal patch for treatment of attention deficit hyperactivity disorder in children

The aim of this study was to characterize a newly developed clonidine transdermal patch, KBD-transdermal therapeutic system (TTS), for the treatment of attention deficit hyperactivity disorder in children. In vitro release, penetration, and in vivo pharmacokinetics in rabbits were investigated. The smaller size of KBD-TTS (2.5 mg/2.5 cm2) showed a similar in vitro penetration to those of Catapres-TTS (2.5 mg/3.5 cm2, a clonidine transdermal patch used for the treatment of hypertension, Alza Corporation, U.S.A.). The transdermal penetration rate of clonidine was mainly controlled by the ethylene vinylacetate membrane used in the patch. The skin layer may be only a minor rate-limiting barrier after the topical skin layer at the dosing site is saturated with penetrating clonidine in the initial phase (0 to 12 h). A sensitive liquid chromatography-mass spectrometry method for the quantification of clonidine in rabbit plasma was developed using solid-phase extraction and gradient elution on LC combined with the selected-ion monitoring (SIM) mode. A single dose of clonidine transdermal patch (KBD-TTS) or Catapres-TTS was transdermally administered to rabbits (n=6 each) and removed after 168 h. The average half-life, Tmax, Cmax and Css values of clonidine in rabbits following administration of KBD-TTS were 19.27+/-4.68 h, 52.56+/-25.77 h, 27.39+/-9.03 ng/ml, and 25.82+/-9.34 ng/ml, similar to those of Catapres-TTS, respectively. The clonidine plasma concentration of KBD-TTS reached a steady state at 24 h through 168 h. The in vitro release rate of the clonidine from KBD-TTS significantly correlated with the in vivo absorption rate (p<0.001).     

Kinetic Analysis of Transdermal Nitroglycerin Delivery

The current success of transdermal nitroglycerin delivery systems has focussed much attention upon the skin as a portal of drug entry into the systemic circulation. Although there are multiple potential problems associated with this administration route to elicit central effects, considerable efforts are being made to identify transdermal drug delivery candidates and to determine whether a sufficient percutaneous input rate can be achieved such that therapeutic levels in the biophase may be maintained. The purpose of this work is to develop a physically-based kinetic model of percutaneous absorption, which includes delivery system input. Both zero-order and first-order situations are considered and the model is employed to analyze nitroglycerin plasma concentration vs. time data following transdermal delivery both from a controlled-release patch and from an ointment. The kinetic model includes rate parameters which relate to drug transport across the stratum corneum, to further diffusion across the viable epidermis and to the competition for substrate between these two layers of skin tissue. We show how these kinetic constants may be determined physicochemically and used, in conjunction with designated (delivery system) input rates and established systemic elimination kinetics, to predict plasma concentrations as a function of time. The agreement with human in vivo data for nitroglycerin, delivered from either a patch or a more conventional vehicle, is good and suggests that the simulation proposed may enable facile estimation of the feasibility of transdermal drug delivery.     

In vivo iontophoretic administration of ropinirole hydrochloride

This work explores the possibility of achieving therapeutic levels of the anti-Parkinsonian drug, ropinirole hydrochloride (RHCl), by transdermal iontophoretic delivery. An in vivo study was performed in hairless rats during which RH(+) was delivered at one current intensity (0.58 mA identical with 0.12 mA/cm(2)) and at three different drug concentrations (25, 125, and 250 mM). In vivo RH(+) flux and transport number were deduced from the steady-state plasma concentration values. Plasma concentration profiles and RH(+) transport numbers were independent of the drug donor concentration. The average iontophoretic input rate was about 3 micromol/h. Postiontophoresis transepidermal water loss (TEWL) was monitored and biopsies were histologically examined to identify any effects of iontophoresis on the skin. TEWL was elevated only at the anodal sites. TEWL recovery was faster for the "no-drug" control anodal sites, which suggests a combined effect of the drug and current on the skin. In conclusion, (1). the in vivo iontophoretic transport of RH(+) is independent of the drug donor concentration, and (2). iontophoresis can deliver therapeutic amounts of RH(+).     

Clinical pharmacokinetics of clonidine

Clonidine is a centrally active antihypertensive agent effective in the treatment of mild, moderate and severe hypertension, alone or in combination with other drugs. Use of oral clonidine has often been limited by side effects which include dry mouth and drowsiness. Transdermal clonidine was therefore developed as an alternative to oral therapy. Ideally, a drug administered at a constant rate into the systemic circulation should attain steady-state concentrations with less peak-to-trough fluctuation than that associated with intermittent oral dosing. In theory, transdermal administration should thus minimise the adverse effects associated with peak plasma drug concentration, while avoiding the potential for decreased efficacy associated with trough levels. Clonidine has been incorporated into a small, pliable adhesive cutaneous delivery device designed to provide therapeutically effective doses of drug at a constant rate for at least 7 days. The transdermal therapeutic system is a laminate consisting of an external film impermeable to moisture and to the drug, a thin layer of active drug dispersed within a highly drug-permeable matrix, a membrane with a controlled intrinsic permeability regulating the rate of delivery of drug to the skin, and an adhesive coating that attaches the system to the skin surface. The permeation of drug through the skin occurs primarily by diffusion. Application of the clonidine transdermal system to both normotensive and hypertensive subjects has consistently reduced systolic and diastolic blood pressures. Maximum reduction in blood pressure occurs 2 to 3 days after initial application, and is maintained for at least 7 days or until the system is removed. The rate at which clonidine is presented to the skin surface is controlled by the microporous membrane: this rate is the same for all strengths of transdermal clonidine, the amount of clonidine released being proportional to its surface area. Thus, the daily dose is regulated by the area of skin covered. Typically, steady-state plasma concentrations are reached on the fourth day after initial transdermal system application. The lack of dose dependency in half-life and renal clearance estimates emphasise that the transdermal absorption of clonidine is linear. The plasma clonidine concentration produced by a particular transdermal dose varies considerably between individuals as a result of interindividual variation in renal clearance. For this reason, it is recommended that dosages be titrated up from the smallest system (3.5 cm2) until the desired pharmacological effect has been obtained.(ABSTRACT TRUNCATED AT 400 WORDS)     

Permeation enhancer strategies in transdermal drug delivery

Abstract

Today, ～74% of drugs are taken orally and are not found to be as effective as desired. To improve such characteristics, transdermal drug delivery was brought to existence. This delivery system is capable of transporting the drug or macromolecules painlessly through skin into the blood circulation at fixed rate. Topical administration of therapeutic agents offers many advantages over conventional oral and invasive techniques of drug delivery. Several important advantages of transdermal drug delivery are prevention from hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. Human skin surface, as a site of drug application for both local and systemic effects, is the most eligible candidate available. New controlled transdermal drug delivery systems (TDDS) technologies (electrically-based, structure-based and velocity-based) have been developed and commercialized for the transdermal delivery of troublesome drugs. This review article covers most of the new active transport technologies involved in enhancing the transdermal permeation via effective drug delivery system.     

Naltrexone salt selection for enhanced transdermal permeation through microneedle-treated skin

The passive delivery rate of naltrexone (NTX) through intact skin is too slow to achieve therapeutic plasma levels in humans from a reasonably sized transdermal patch. A physical enhancement method--microneedles (MNs)--has been shown to afford a substantial increase in the percutaneous flux of NTX hydrochloride in vitro. However, for better therapeutic effect and decrease in the transdermal patch area, further enhancement is desired. The purpose of this study was to identify a NTX salt that would (1) provide elevated in vitro percutaneous drug transport across MN-treated skin as compared with that of the NTX hydrochloride and (2) prove nonirritating to the skin in vivo. The pH-solubility profiles of NTX salts were investigated with three drug salts showing improved solubility at physiologically relevant skin surface pH of 5.0. The skin-irritation potential of NTX glycolate and lactate gels was not greater than that of placebo gel in the guinea pig model. Additionally, in vitro diffusion studies indicated that NTX glycolate provides around 50% enhancement in the flux through MN-treated skin at the cost of doubling the drug concentration in the donor solution. Overall, a new NTX glycolate salt appears to be a promising candidate for MN-assisted transdermal drug delivery system.     

Feasibility of proniosomes-based transdermal delivery of frusemide: formulation optimization and pharmacotechnical evaluation

The aim of the present study was to formulate non-ionic surfactant vesicles of frusemide to enhance its skin permeation and to develop a transdermal therapeutic system using provesicular approach. The effect of various formulation variables on the transdermal flux, amount of drug deposited in skin, and plasma level of drug were studied. The skin permeation studies were conducted on rat skin and human skin for quantification of permeation parameters. With PGS3 formulation [Span 40:soyalecithin:cholesterol (4.5:4.5:1)], the plasma level in the rats had reached to a level of 0.42 +/- 0.13 microg/mL at the sampling interval of 4 hr and remained within the therapeutic concentration range (1.66-0.3 microg/mL) for the next 12 hr. Results showed that proniosomal formulation was able to sustain the drug level in the blood and offer a promising means for non-invasive delivery of frusemide.     

Feasibility of Proniosomes-Based Transdermal Delivery of Frusemide: Formulation Optimization and Pharmacotechnical Evaluation

The aim of the present study was to formulate non-ionic surfactant vesicles of frusemide to enhance its skin permeation and to develop a transdermal therapeutic system using provesicular approach. The effect of various formulation variables on the transdermal flux, amount of drug deposited in skin, and plasma level of drug were studied. The skin permeation studies were conducted on rat skin and human skin for quantification of permeation parameters. With PGS3 formulation [Span 40:soyalecithin:cholesterol (4.5:4.5:1)], the plasma level in the rats had reached to a level of 0.42 ± 0.13 µg/mL at the sampling interval of 4 hr and remained within the therapeutic concentration range (1.66–0.3 µg/mL) for the next 12 hr. Results showed that proniosomal formulation was able to sustain the drug level in the blood and offer a promising means for non-invasive delivery of frusemide.     

In vivo evaluation of limonene-based transdermal therapeutic system of nicorandil in healthy human volunteers

Hydroxypropyl methylcellulose (HPMC) gel drug reservoir system prepared with 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene was effective in promoting the in vitro transdermal delivery of nicorandil. The objective of the present study was to fabricate and evaluate a limonene-based transdermal therapeutic system (TTS) for its ability to provide the desired steady-state plasma concentration of nicorandil in human volunteers. The in vitro permeation of nicorandil from a limonene-based HPMC gel drug reservoir was studied across excised rat skin (control), EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite to account for their effect on the desired flux of nicorandil. The flux of nicorandil from the limonene-based HMPC drug reservoir across EVA2825 membrane decreased to 215.8 +/- 9.7 microg/cm(2).h when compared to that obtained from control, indicating that EVA2825 was effective as a rate-controlling membrane. The further decrease in nicorandil flux across adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite showed that the adhesive coat and skin also controlled the in vitro transdermal delivery. The limonene-based drug reservoir was sandwiched between adhesive-coated EVA2825-release liner composite and a backing membrane. The resultant sandwich was heat-sealed as circle-shaped patch (20 cm(2)), trimmed and subjected to in vivo evaluation in human volunteers against immediate-release tablets of nicorandil (reference formulation). The fabricated limonene-based TTS of nicorandil provided a steady-state plasma concentration of 21.3 ng/ml up to 24 h in healthy human volunteers. It was concluded that the limonene-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations and improved bioavailability.     

In vivo efficacy and safety of skin electroporation

This article reviews the studies on skin electroporation carried out in vivo in animals and emphasizes its potential therapeutic applications for transdermal and topical drug delivery. In agreement with in vitro studies, transport across skin due to high-voltage pulses in vivo was shown to increase by orders of magnitude on a timescale of minutes. Increased transdermal transport was measured by systemic blood uptake and/or pharmacological response, and demonstrated for calcein, a fluorescent tracer, fentanyl, a potent analgesic and flurbiprofen, an antiinflammatory drug. Combined electroporation with iontophoresis was shown to provide rapidly responsive transdermal transport of luteinizing hormone releasing hormone ex vivo as well. These data underline the potential of skin electroporation for improving the delivery profile of existing conventional transdermal patches, but also for replacing the injectable route.High-voltage pulses can increase drug permeation within and across skin but are also an efficient tool to permeabilize the membrane of cells of the cutaneous or subcutaneous tissue. This was shown beneficial for targeting cutaneous cells with oligonucleotides or genes and might open new opportunities for gene therapy and DNA vaccination.The safety of the application of high-voltage pulses on skin was assessed in vivo, using histological and visual scores, and bioengineering methods. While changes in skin barrier and function were observed, the irritation was mild and short-lived. Further optimization of the electrode configuration for improved targeting of the stratum corneum should still improve tolerance and levels of sensation.     

Diagnostic and therapeutic applications of iontophoresis

Owing to the excellent barrier properties of the stratum corneum, transdermal delivery remains a challenge for a high number of molecules. Iontophoresis is a noninvasive technique which uses a low current to administer polar and charged species through the skin, thereby enlarging the range of drug candidates for transdermal administration. Unlike other techniques of transdermal delivery enhancement, iontophoresis acts on the molecule itself allowing a better control of the dose applied. The symmetry of the technique can be employed for controlled extraction, allowing a relation to be established between extracted flux and subdermal concentration. This opened the way for innovative applications, notably in the field of noninvasive monitoring of glucose and xenobiotics. Rather than being an extensive review of the literature, this article summarizes the basic rules governing iontophoretic transport, discusses advantages and limitations of the technique, and provides an overview of promising therapeutic applications.     

Dermal Drug Delivery Systems: A Review

Abstract

Systems that deliver drugs through intact skin at a controlled rate are now in routine clinical use. They include a nitroglycerin system for the prophylaxis of angina, and a scopolamine system for the prevention of motion sickness. In addition, there are also published reports on rate-controlled transdermal forms of clonidine and estradiol. Since the trans-dermal mode of drug administration can provide continuity of delivery and precise control of drug plasma concentrations, it offers particular advantages for drugs with short half-lives or narrow therapeutic indices. It is also useful when the oral route is unsuitable. Transdermal rate-controlled therapy appears on the brink of rapid expansion for the administration of potent, nonirritating, nonallergenic agents with suitable physi-cochemical properties. In the case of new agents, rate-controlled transdermal administration may render some drugs routinely usable that otherwise would produce unacceptable side effects or require impractical regimens. Some older agents will gain an increased margin of safety and convenience—as well as expanded therapeutic usefulness—compared with their administration in conventional dosage forms. Owing to constraints arising from drug potency, skin permeability, and/or topical reactions, however, transdermal administration is not expected to become the preferred dosage form for a high percentage of drugs.     

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.     

Pharmacokinetics and efficacy of phenazepam after transdermal and enteral administration in rats

The concentration of fenazepam in the blood plasma of rats upon application of the transdermal therapeutic system (TTS) fenapercuten was very low, incomparable to the drug concentration (recalculated to equal input doses) upon intravenous or enteral administration. Nevertheless, the TTS exhibited a pronounced anxiolytic and weak sedative action in the absence of any side myorelaxant effect. The agent responsible for adverse side effects (3-hydroxyfenazepam) was not determined in the blood plasma upon the TTS application. A steady-state concentration of fenazepam in the blood plasma of rats was observed between 2nd and 8th hours upon fenapercuten application, which agrees with the duration of anxiolytic action of the parent drug.     

Prediction of plasma concentration of GTS-21 in hairless rats following monolithic transdermal delivery

The transdermal therapeutic systems (TTS) usually achieve constant plasma concentration for an extended period of time. This is because a sufficient drug stored in the device can keep the constant concentration on the surface of the stratum corneum during the system application. When the drug molecules are not enough to provide the constant surface concentration, the rate of drug penetration decreases with time because of decreased supply of the drug molecules from the delivery device. This paper has proposed an empirical simple approach to predict the plasma concentration for such a TTS. A novel compound, GTS-21, for Alzheimers' disease currently under development was used as a model drug. In vivo and in vitro experiments were carried out in hairless rats. The in vivo plasma concentration-time profile in hairless rats following the application of TTS well agreed with the predicted profile based on the skin pharmacokinetic model together with the model parameters determined from the in vitro experiment.     

Development of matrix-membrane transdermal drug delivery system for atenolol

A polymer matrix system for transdermal delivery of Atenolol was developed for its prolonged and controlled release systemic availability. To achieve the desired and controlled release rate, different combinations of Eudragit RL with polyvinyl pyrrolidone and polyethylene glycol 4000 were used in the preparations of polymeric matrix system. These preparations were evaluated for in vitro release and permeation of the drug across pig skin. The desired systems exhibited linear relationship between drug release (Q) versus ne^0.8(hr^0.8). The product exhibiting required skin permeation 64 mcg/h/cm² to achieve an effective plasma concentration was selected for the in vivo performance evaluation. The drug plasma profile was compared with the plasma profile obtained following the administration of a conventional oral dose of Atenolol. The study revealed that the designed polymeric matrix transdermal drug delivery system of Atenolol could be successful with improved performance.     

Controlled transdermal delivery of model drug compounds by MEMS microneedle array

This article reports an in vitro study of microneedle-array-enhanced transdermal transport of model drug compounds dispersed in chitosan films. Each microneedle array has 400 out-of-plane, needle-shaped microstructures fabricated using micro-electro-mechanical systems (MEMS) technology to ensure adequate mechanical strength and high precision, and consistency. A nanometer coating on the microneedles ensured the biocompatibility that is important in the application of transdermal drug delivery. Model drugs selected to investigate skin permeation in vitro were calcein, a small molecule (molecular weight, 623 d) that has little skin penetration, and bovine serum albumin (BSA) (molecular weight, 66,000 d), a hydrophilic biological macromolecule. A Franz permeation cell was used to characterize the permeation rate of calcein and BSA through the rat skin. The transdermal transport behavior of BSA was investigated from solid films coated on the surface of microneedle arrays with various chitosan concentrations, film thicknesses, and BSA contents. The BSA permeation rate decreased with the increase of the chitosan concentration; the thicker the film, the slower the permeation rate. In addition, the permeation rate increased with the increase of BSA loading dose. A linear relationship existed between the permeation rate and the square root of the BSA loading dose. Results showed that the chitosan hydrophilic polymer film acts as a matrix that can regulate the BSA release rate. The controlled delivery of BSA can be achieved using the BSA-containing chitosan matrix film incorporated with the microneedle arrays. This will provide a possible way for the transdermal delivery of macromolecular therapeutic agents such as proteins and vaccines.     

In vitro and in vivo characterization of novel biomaterial for transdermal application

Polymers have become an indispensable part in the design of a conventional as well as novel drug delivery system. Gum Copal (GC), a novel biomaterial obtained from Agathis species, is evaluated in the present study for its potential application as a matrix former in transdermal drug delivery systems. GC was initially characterized for various physicochemical properties and then mechanical characterization of the Plasticized films of GC was investigated. Verapamil hydrochloride (VH), owing to its pharmacokinetic properties, was selected as the model drug for the present work. Matrix type transdermal films of VH with GC, alone and in combination with polyvinyl pyrrolidone (PVP K-30), were developed and evaluated for various physicochemical properties. In-vitro drug release study was carried out using paddle over disk method and in-vitro skin permeation study was performed using human cadaver skin. On the basis of physicochemical properties, in-vitro drug release study and permeation performance, formulation F5 containing GC: PVP K-30 (60:40) was selected as an optimized formulation for in vivo study. Animal studies were carried out using Dawley rats and the data obtained from the plasma drug analysis showed that peak drug concentration of about 244.94 ± 1.25 ng/mL was achieved in 6 h after the application of the patch and plasma drug concentration was maintained till 24 h. Skin irritancy test results proved the suitability of the biomaterial for transdermal application. The drug polymer interaction studies carried out using UV, FTIR and TLC analysis indicated that drug and polymer were compatible. Due to reasonably good mechanical properties, low water vapor transmission and sustained release capability, GC seems to be a promising film former for transdermal drug delivery.     

Veterinary drug delivery: potential for skin penetration enhancement

A range of topical products are used in veterinary medicine. The efficacy of many of these products has been enhanced by the addition of penetration enhancers. Evolution has led to not only a highly specialized skin in animals and humans, but also one whose anatomical structure and skin permeability differ between the various species. The skin provides an excellent barrier against the ingress of environmental contaminants, toxins, and microorganisms while performing a homeostatic role to permit terrestrial life. Over the past few years, major advances have been made in the field of transdermal drug delivery. An increasing number of drugs are being added to the list of therapeutic agents that can be delivered via the skin to the systemic circulation where clinically effective concentrations are reached. The therapeutic benefits of topically applied veterinary products is achieved in spite of the inherent protective functions of the stratum corneum (SC), one of which is to exclude foreign substances from entering the body. Much of the recent success in this field is attributable to the rapidly expanding knowledge of the SC barrier structure and function. The bilayer domains of the intercellular lipid matrices within the SC form an excellent penetration barrier, which must be breached if poorly penetrating drugs are to be administered at an appropriate rate. One generalized approach to overcoming the barrier properties of the skin for drugs and biomolecules is the incorporation of suitable vehicles or other chemical compounds into a transdermal delivery system. Indeed, the incorporation of such compounds has become more prevalent and is a growing trend in transdermal drug delivery. Substances that help promote drug diffusion through the SC and epidermis are referred to as penetration enhancers, accelerants, adjuvants, or sorption promoters. It is interesting to note that many pour-on and spot-on formulations used in veterinary medicine contain inert ingredients (e.g., alcohols, amides, ethers, glycols, and hydrocarbon oils) that will act as penetration enhancers. These substances have the potential to reduce the capacity for drug binding and interact with some components of the skin, thereby improving drug transport. However, their inclusion in veterinary products with a high-absorbed dose may result in adverse dermatological reactions (e.g., toxicological irritations) and concerns about tissue residues. These are important considerations when formulating a veterinary transdermal product when such compounds are added, either intentionally or otherwise, for their penetration enhancement ability.     

Iontophoretic delivery of apomorphine: from in-vitro modelling to the Parkinson patient

Apomorphine is a mixed dopamine D1/D2 receptor agonist which is potentially useful in the treatment of Parkinson's disease. The delivery of apomorphine is however complicated because it is not absorbed orally and other delivery routes with the exception of the intravenous route seem to fail. The most interesting route for controlled delivery of apomorphine is transdermal iontophoresis because this could enable the Parkinson patient to directly control the needed amount of apomorphine by increasing or decreasing the drug input in order to achieve optimal drug therapy ('on-demand') with a minimum of toxic side effects. The typical features of Parkinson's disease could be used to monitor the needed drug input and even more elegantly by means of suitable chip sensors which are able to directly measure bradykinesia, akinesia and/or tremor and to regulate in such a way the drug input. Such a chip-controlled iontophoretic system would be the first closed-loop system monitoring not pharmacokinetic data (blood levels) but more importantly externally measurable pharmacodynamic effects of Parkinson's disease. This scenario is more feasible as skin irritation and toxicity studies have proven that iontophoresis is a safe route of treatment. This review describes the basics of iontophoresis and the development of a transdermal iontophoretic delivery system on the basis of integrated pharmacokinetic/pharmacodynamic (PK/PD) investigations in patients with idiopathic Parkinson's disease. Transdermal iontophoretic transport of apomorphine was studied both in vitro with human stratum corneum using a newly developed iontophoretic continuous flow-through transport cell and in vivo in a first exploratory study in patients with Parkinson's disease. These studies showed that the delivery of apomorphine is feasible and furthermore the rate of delivery can be controlled by variation of the current densities. Additionally the pretreatment of the skin either with a mono-surfactant or a vesicular suspension of elastic liquid-state vesicles may be useful to further increase the apomorphine flux across the skin in combination with iontophoresis.