In vitro evaluation of a hydroxypropyl cellulose gel system for transdermal delivery of timolol

In this work, the development of a gel reservoir for a timolol (TM) transdermal iontophoretic delivery system is investigated. TM gel is prepared using hydroxypropyl cellulose (HPC) and the permeability of TM from the gel through an artificial membrane (Polyflux) and pig stratum corneum (SC) is studied. For a constant TM donor concentration, the TM transport across the Polyflux membrane alone decreases when the concentration of the gel increases due to increase of the gel viscosity. For constant gel concentration, however, the TM permeation across the membrane increases when the TM donor concentration increases. In addition, no effect of the electrical current (iontophoresis, current density 0.5 mA cm-2) on the TM permeation is found. For the combination of the Polyflux membrane with pig SC, the TM transport is much lower than for the membrane alone and the SC fully controls the TM delivery. In this case, the application of electrical current enhances the TM delivery 13-15 times in comparison to passive (no current) transport. According to our estimation, the daily TM dose (10-60 mg) can be delivered by an iontophoretic patch with Polyflux membrane area of 6-36 cm2 containing 20% (w/w) HPC gel and 15 mg cm-3 of TM.     

Electrically enhanced transdermal delivery of a macromolecule

The purpose of this study was to establish the delivery parameters for the enhanced transdermal delivery of dextran sulfate (MW 5000 Da). Full-thickness pig skin or epidermis separated from human cadaver skin was used. Silver-silver chloride electrodes were used to deliver the current (0.5 mA cm-2). For electroporation experiments, one or more pulses were given using an exponential decay pulse generator. The correct polarity for iontophoresis and pulsing was first established as cathode in the donor. The amount of drug delivered increased with increasing donor concentration up to a point, but not any further. The amount delivered also increased with pulse voltage, the delivery being twice as much as with iontophoresis alone (144.5+/-10.35 microg cm(-2)), when 6 pulses of 500 V were applied at time zero before iontophoresis (276+/-45.2 microg cm(-2)). It was observed that the amount delivered was a function of increasing pulse length when the apparent charge delivered was kept constant. Transport through pig skin (107.4+/-24.4 microg cm(-2)) was found to be comparable with that through human epidermis (84.9+/-18.4 microg cm(-2)). In conclusion, we have demonstrated the transdermal delivery of a 5000 Da molecular weight dextran sulfate using iontophoresis. It was also seen that iontophoretic delivery could be enhanced by simultaneous electroporation.     

Passive and iontophoretic transdermal penetration of chlorpromazine

The in vitro iontophoretic transdermal delivery of chlorpromazine (CPZ) across pig skin was investigated. Anodal iontophoresis considerably increased CPZ skin penetration and accumulation compared with the passive controls. The effect of CPZ concentration in the donor solution was studied (1.4-8.2 mM). A higher penetration was observed with an increase of the concentration. In addition, the effect of NaCl concentration was also studied (154-200 mM). As expected, CPZ iontophoretic transport decreased with NaCl content. Finally, the influence of the current density (0.20-0.50 mA/cm(2)) was investigated. The iontophoretic transport of CPZ tends to increase with current density, although this effect was not statistically significant between 0.35 and 0.5 mA/cm(2). On the whole, this work shows that iontophoresis may be used to improve the transdermal delivery of CPZ for the treatment of chronic psychosis.     

Iontophoretic enhancement of timolol across human dermatomed skin in vitro

The objective of this study was to assess the in vitro the iontophoretic delivery of Timolol across human dermatomed skin in order to determine whether therapeutic doses of this drug can be delivered. Anodal iontophoresis of Timolol was performed by manipulating the donor vehicle and the current density. It was observed that by reducing simultaneously the competitive ions (NaCl) from 8 to 4 g/l and the pH from 7.4 to 4.7, the iontophoretic flux was significantly increased by a factor of 1.5 (669+/-81 microg/cm h). In order to simulate the situation in a transdermal patch, the iontophoretic delivery of Timolol was also studied after adding an artificial porous membrane placed between the Timolol formulation and the human dermatomed skin. No significant difference was observed in the steady state flux across the skin when an artificial membrane was added. Furthermore, a linear relationship was found between current density and steady state flux. These results indicate that the iontophoretic delivery of Timolol can be accurately controlled by the applied current. Assuming a one to one in vitro/in vivo correlation the Timolol transport in vitro results in therapeutic plasma concentrations in humans with very low current densities limiting possible skin irritation.     

In vitro studies indicate that miquelianin (quercetin 3-O-beta-D-glucuronopyranoside) is able to reach the CNS from the small intestine

Miquelianin (quercetin 3-O-beta-D-glucuronopyranoside) is one of the flavonoids of St. John's wort (Hypericum perforatum L.) whose antidepressant activity has been shown by the forced swimming test, an in vivo pharmacological model with rats. However, nothing is known about its ability to reach the CNS after oral administration. We examined the pathway of miquelianin from the small intestine to the central nervous system using three in vitro membrane barrier cell systems. In the Caco-2 cell line, miquelianin showed a higher uptake (1.93 +/- 0.9 pmol x min(-1) x cm(-2)) than hyperoside (quercetin 3-O-beta-D-galactopyranoside; 0.55 +/- 0.18 pmol x min(-1) x cm(-2)) and quercitrin (quercetin 3-O-alpha-L-rhamnopyranoside; 0.22 +/- 0.08 pmol x min(-1) x cm(-2)). The permeability coefficient of miquelianin (Pc = 0.4 +/- 0.19 x 10(-6) cm/sec) was in the range of orally available drugs assuming sufficient absorption from the small intestine. Uptake and permeability of the examined compounds was increased by the MRP-2 inhibitor MK-571 indicating a backwards transport by this membrane protein. Porcine cell cultures of brain capillary endothelial cells were used as a model of the blood-brain barrier (bbb) and epithelial cells of the plexus chorioidei as a model of the blood-CSF barrier (bcb). Results indicate no active transport in one direction. Although moderate, the permeability coefficients (bbb: Pc = 1.34 +/- 0.05 x 10(-6) cm/sec; bcb: Pc = 2.0 +/- 0.33 x 10(-6) cm/sec) indicate the ability of miquelianin to cross both barriers to finally reach the CNS.     

Effect of chemical penetration enhancer and iontophoresis on the in vitro percutaneous absorption enhancement of insulin through porcine epidermis

The purpose of this study was to investigate the effect of chemical enhancers (fatty acids and limonene) and iontophoresis on the in vitro permeability enhancement of insulin through porcine epidermis. The following fatty acids were used: palmitic (C16:0), palmitoleic (C16:1), stearic (C18:0), oleic (C18:1), linoleic (C18:2), and linolenic (C18:3). Franz diffusion cells and the Scepter iontophoretic power source were used for the percutaneous absorption studies. Cathodal iontophoresis was performed at 0.2 mA/cm2 current density. Iontophoresis in combination with chemical enhancers synergistically increased (p<0.05) the in vitro permeability of insulin. Linolenic acid (C18:3) produced greater permeability of insulin through epidermis than did other fatty acids during passive (44.45 x 10(-4) cm/h) and iontophoretic (78.03 x 10(-4) cm/h) transport. Lispro insulin flux was significantly (p<0.05) greater through linolenic acid and limonene pretreated epidermis compared to untreated controls during both passive and iontophoretic transports. Using limonene as a penetration enhancer, a linear increase in the passive and iontophoretic flux of lispro insulin was observed with donor concentrations increasing from 100 IU/mL to 300 IU/mL. Iontophoretic flux through limonene-treated epidermis using 0.5 mA/cm2 current density and 300 IU/mL insulin donor solution was 45.63 IU/cm2/day. Using an iontophoretic patch size of 10 cm2, we would be able to deliver 50 IU of insulin within 3 h.     

How does the benzamide antipsychotic amisulpride get into the brain?--An in vitro approach comparing amisulpride with clozapine.

This study evaluated the disposition of the two atypical antipsychotics, amisulpride (AMS) and clozapine (CLZ), and its main metabolite N-desmethylclozapine (DCLZ), to their target structures in the central nervous system by applying an in vitro blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier based on monolayers of porcine brain microvessel endothelial cells (PMEC) or porcine choroid plexus epithelial cells (PCEC). Permeation studies through PMEC- and PCEC-monolayers were conducted for 60 min at drug concentrations of 1, 5, 10, and 30 muM applied to the donor compartment. PMEC were almost impermeable for AMS (permeation coefficient, P<1 x 10(-7) cm/s) in the resorptive direction, whereas transport in the secretory direction was observed with a P (+/-SD) of 5.2+/-3.6 x 10(-6) cm/s. The resorptive P of CLZ and DCLZ were 2.3+/-1.2 x 10(-4) and 9.6+/-5.0 x 10(-5) cm/s, respectively. For the permeation across PCEC in the resorptive direction, a P of 1.7+/-2.5 x 10(-6) cm/s was found for AMS and a P of 1.6+/-0.9 x 10(-4) and 2.3+/-1.3 x 10(-5) cm/s was calculated for CLZ and DCLZ, respectively. Both, CLZ and DCLZ, could easily pass both barriers with about a five-fold higher permeation rate of CLZ at the PCEC. The permeation of AMS across the BBB was restricted partly due to an efflux transport. It is thus suggested that AMS reaches its target structures via transport across the blood-CSF barrier.     

pH值对马来酸噻吗洛尔角膜透过性的影响

目的　研究pH值对马来酸噻吗洛尔(TM)角膜透过性的影响,为其处方设计提供理论依据。方法　测定TM的表观油水分配系数(DC_app)。用体外扩散实验考察各种pH值条件下离体兔眼角膜对TM的透过性。结果　由DC_app求得TM的分配系数和pKa分别为63.63和9.17。在生理介质中,TM的表观透过系数为1.43×10^-5cm·s^-1。随着pH值由6.65升高至9.20 ,TM透过角膜的滞后时间缩短到1/20 ,累积透过量增加1.3倍。计算得到游离型噻吗洛尔的角膜透过系数为解离型的3.3倍。结论　噻吗洛尔主要以分子状态经细胞内途径透过角膜,且角膜上皮是其扩散的主要屏障。     

Vehicle effects on in vitro release of tiaprofenic acid from different topical formulations

The aim of the present study was to investigate the in vitro release properties of tiaprofenic acid (TA) from different topical vehicles. Carbopol 940 gel, chitosan gel, two types of emulsion-based ointment formulations (o/w and w/o) and hydrophilic petrolatum USP were prepared with 2% drug content. Drug release from all vehicles through a standard cellophane membrane was evaluated by using Franz-type diffusion cells. In vitro release study results showed that the diffusion coefficients of the drug from vehicles rank according to the following order: Carbopol 940 gel (D = 3.11 x 10(-7) +/- 0.54 cm(2)/s) > chitosan gel (D = 0.27 x 10(-7) +/- 0.08 cm(2)/s) > emulsion-based ointment (o/w) (D = 0.18 x 10(-7) +/- 0.05 cm(2)/s) > emulsion-based ointment (w/o) (D = 0.13 x 10(-7) +/- 0.02 cm(2)/s) > hydrophilic petrolatum USP (D = 0.02 x 10(-7) +/- 0.01 cm(2)/s). Carbopol 940 gel base showed significantly higher drug release than other vehicles (P < 0.001). These results indicated that Carbopol 940 gel base is a good candidate for the topical delivery of TA, giving significantly higher drug release than the other vehicles.     

Penetration of ammonium perfluorooctanoate through rat and human skin in vitro

Rat and human epidermal membranes were mounted onto in vitro diffusion cells with an exposure area of 0.64 cm2, and skin integrity was confirmed using electrical impedance. Following membrane selection, Fluorad FC-118, a 20% aqueous solution of ammonium perfluorooctanoate (AFPO), was applied to the epidermal surface of each skin replicate at approximately 150 microL/cm2 and the donor chamber opening occluded with Parafilm. Serial receptor fluid samples were collected hourly from 1 to 6 h and at 12, 24, 30, and 48 h and analyzed by liquid chromatography-mass spectrometry (LC-MS) for APFO anion (PFO-). For rat skin, the time to steady-state penetration (6500+/-3000 ng APFO x cm(-2) x h(-1)) occurred in less than 12 h, which was sustained until termination (48 h). Based on the concentration of the applied test material, the permeability coefficient (Kp) for APFO in rat skin was calculated to be 3.25+/-1.51 x 10(-5) cm/h. By end of the 48-h exposure period, only a small portion of the total APFO applied (1.44+/-1.13%) had penetrated through rat skin. For human skin, steady-state penetration of APFO (190+/-57 ng APFO x cm(-2) x h(-1)) was reached by 12 h. Based on the concentration of the applied test material, the permeability coefficient for APFO in human skin was calculated to be 9.49+/-2.86 x 10(-7) cm/h. By the end of the 48-h exposure period, only a negligible amount of the total APFO applied (0.048+/-0.01%) had penetrated through human skin. Thus, under infinite dose and occlusive conditions, the steady-state penetration of APFO from a 20% solution was approximately 34-fold faster through rat skin than human skin.     

Iontophoretic transdermal delivery of haloperidol

The in vitro iontophoretic transdermal delivery of haloperidol (HP) across pig skin was investigated. Anodal iontophoresis considerably increased HP skin penetration and accumulation as compared to the passive controls.The effect of NaCl and HP concentrations on the vehicle were also studied. As expected, HP iontophoretic transport decreased with NaCl content. On the other hand, HP concentration did not modify its electrotransport in the range of concentrations between 0.4 and 0.9 mg/mL, except at 24 hours. The influence of the current density (0.20-0.50 mA/cm2) was also investigated. The iontophoretic transport of HP tends to increase with current density. On the whole, this work shows that iontophoresis may be used to improve the topical application of HP for the treatment of chronic psychosis.     

Effect of electroporation and iontophoresis on skin permeation of Defibrase--a purified thrombin-like enzyme from the venom of Agkistrodon halys ussuriensis Emelianov

The purpose of this study was to investigate electroporation and iontophoresis as a means for in vitro delivery of Defibrase--a thrombin-like enzyme (TLE) from Agkistrodon halys ussuriensis Emelianov snake venom--through human epidermis membrane (HEM). Electroporation was carried out using an exponential decay pulse generator (BioR-ad Genepulser, USA) for a period of 0.5 h, followed by a period of 5.5 h passive diffusion or iontophoresis. The results indicated that the combined use of electroporation and anodal iontophoresis in pH 6.4 permeation medium could effectively enhance the skin permeation of Defibrase, whose apparent permeability coefficient was 1.6 +/- 0.8 x 10(-4) cm.h-1. The delivery of Defibrase by the combined use of electroporation and anodal iontophoresis was more effective than by electroporation alone (P < 0.01) or by the combined use of electroporation and cathodal iontophoresis (P < 0.01). Moreover, when the pH of the permeation medium was raised from 6.4 to 7.4 the permeation of Defibrase caused by a combined use of electroporation and anodal iontophoresis showed a tendency to increase. These results implied that electroosmotic flow effect might be important for the iontophoretic (following electroporation) skin permeation of Defibrase.     

Transdermal Iontophoresis of Rotigotine Across Human Stratum Corneum in Vitro: Influence of pH and NaCl Concentration

PURPOSE: The aim of this study was to characterize the influence of pH and NaCl concentration on the transdermal iontophoretic transport of the dopamine receptor agonist rotigotine across human stratum corneum (HSC). METHODS: Rotigotine transport was studied in vitro in side by side diffusion cells according to the following protocol: 6 h of passive diffusion, 9 h of iontophoresis, and 5 h of passive diffusion. A current density of 0.5 mA cm(-2) was used. The influence of donor phase pH (4, 5, and 6) and different concentrations of NaCl (0.07 and 0.14 M) on rotigotine iontophoretic flux were examined. The acceptor phase was phosphate-buffered saline (PBS) at pH 7.4 except in one series of experiments aimed to study the effects of rotigotine solubility on its iontophoretic transport. In this study, PBS at pH 6.2 was used. In separate studies. 14C-mannitol was used as a marker to determine the role of electro-osmosis during iontophoresis. RESULTS: The estimated iontophoretic steady-state flux (Flux(ss)) of rotigotine was influenced by the pH of the donor solution. At a drug donor concentration of 0.5 mg ml(-1), the iontophoretic flux was 30.0 +/- 4.2 nmol cm(-2) h(-1) at pH 6 vs. 22.7 +/- 5.5 nmol cm(-2) h(-1) at pH 5. However, when the donor concentration was increased to 1.4 mg ml(-1), no significant difference in iontophoretic rotigotine transport was observed between pH 5 and 6. Increase of NaCl concentration from 0.07 M to 0.14 M resulted in a decrease of the rotigotine Flux(ss) from 22.7 +/- 5.5 nmol cm(-2) h(-1) to 14.1 +/- 4.9 nmol cm(-2) h(-1). The contribution of electro-osmosis was estimated less than 17%. Probably due to the lipophilic character of the drug, impeding the partitioning of rotigotine from HSC to the acceptor compartment, steady-state transport was not achieved during 9 h of iontophoresis. CONCLUSIONS: Both pH and NaCl concentration of the donor phase are crucial on the iontophoretic transport of rotigotine. Electro-repulsion is the main mechanism of the iontophoretic transport of rotigotine.     

In vitro and in vivo evaluation of the transdermal iontophoretic delivery of sumatriptan succinate.

The objective was to evaluate the transdermal delivery of the 5-HT(1B/1D) agonist, sumatriptan from an iontophoretic patch system, in vivo. Initial in vitro experiments were conducted to optimize formulation parameters prior to iontophoretic delivery in Yorkshire swine. It was found in vitro that increasing drug load in the patch from 9.7 to 39 mg had no statistically significant effect on cumulative delivery (cf. 305.6+/-172.4 vs. 389.4+/-80.4 microg cm(-2), respectively). However, for a given drug load (39 mg) increasing formulation pH from pH 4.7 to 6.8 significantly increased the cumulative amount of sumatriptan delivered across the skin (389.4+/-80.4 vs. 652.4+/-94.2 microg cm(-2)). A biphasic current profile comprising intensities of 1.8 mA from t=0 to t=180 min and 0.8 mA from t=181 min to t=360 min was used for the in vivo experiments. Drug levels in the blood were 13.7+/-4.5 and 53.6+/-10.2 ng ml(-1) at the 30 and 60 min time-points, rising to 90-100 ng ml(-1) during the 90-180 min time-period. The in vivo results show that the pharmacokinetics following transdermal iontophoretic delivery are comparable to those after oral, nasal or rectal administration, but do not match those upon subcutaneous injection.     

First-principles, structure-based transdermal transport model to evaluate lipid partition and diffusion coefficients of hydrophobic permeants solely from stratum corneum permeation experiments

To account for the effect of branched, parallel transport pathways in the intercellular domain of the stratum corneum (SC) on the passive transdermal transport of hydrophobic permeants, we have developed, from first-principles, a new theoretical model-the Two-Tortuosity Model. This new model requires two tortuosity factors to account for: (1) the effective diffusion path length, and (2) the total volume of the branched, parallel transport pathways present in the SC intercellular domain, both of which may be evaluated from known values of the SC structure. After validating the Two-Tortuosity model with simulated SC diffusion experiments in FEMLAB (a finite element software package), the vehicle-bilayer partition coefficient, K(b), and the lipid bilayer diffusion coefficient, D(b), in untreated human SC were evaluated using this new model for two hydrophobic permeants, naphthol (K(b) = 225 +/- 42, D(b) = 1.7 x 10(-7) +/- 0.3 x 10(-7) cm(2)/s) and testosterone (K(b) = 92 +/- 29, D(b) = 1.9 x 10(-8) +/- 0.5 x 10(-8) cm(2)/s). The results presented in this paper demonstrate that this new method to evaluate K(b) and D(b) is comparable to, and simpler than, previous methods, in which SC permeation experiments were combined with octanol-water partition experiments, or with SC solute release experiments, to evaluate K(b) and D(b).     

Iontophoretic enhancement of leuprolide acetate by fatty acids, limonene, and depilatory lotions through porcine epidermis

The effect of chemical enhancers (e.g., fatty acids, limonene, depilatory lotions) and iontophoresis was investigated on the in vitro permeability of leuprolide acetate through porcine epidermis. Franz diffusion cells and Scepter iontophoretic power source were used for the percutaneous absorption studies. Anodal iontophoresis was performed at 0.2 mA/cm2 current density. Fatty acids used were palmitic (C16:0), palmitoleic (C16:1), stearic (C18:0), oleic (C18:1), linoleic (C18:2), and linolenic (C18:3) acids. The passive and iontophoretic flux were significantly (p < 0.05) greater through fatty acids-treated porcine epidermis in comparison to the control (untreated epidermis) for leuprolide acetate. The passive and iontophoretic permeability of leuprolide acetate increased with increasing number of cis double bonds. Among the fatty acids tested, linolenic acid (C18:3) exhibited the maximum permeability of leuprolide acetate during passive (51.42 x 10(-4) cm/hr) and iontophoretic (318.98 x 10(-4) cm/hr) transport. The passive and iontophoretic flux of leuprolide acetate were significantly (p < 0.05) greater through the limonene and depilatory lotion treated epidermis in comparison to their respective control. In conclusion, iontophoresis in combination with chemical enhancers synergistically increased (p < 0.05) the in vitro permeability of leuprolide acetate through porcine epidermis.     

Improvement of epidermal barrier properties in cultured skin substitutes after grafting onto athymic mice

Barrier function in cultured skin substitutes (CSS) prepared from human cell sources was measured by noninvasive (surface hydration, transepidermal water loss) and invasive methods (water permeation, niacinamide flux) before and after grafting onto athymic mice. In vitro measurements were made on days 7 and 14. Although three of the four measures of barrier function improved markedly from day 7 to 14, the values obtained were still far from those obtained with native human skin controls. Additional CSS were grafted onto athymic mice on day 14, and skin was harvested 2 and 6 weeks after grafting. Grafting brought about a substantial decrease in all measurements by 2 weeks and almost complete normalization of barrier function after 6 weeks. The most sensitive measure of this recovery was niacinamide permeability, which decreased from (280 +/- 40) x 10(-4) cm/h in vitro to (17 +/- 30) x 10(-4) cm/h 2 weeks after grafting and (5 +/- 2) x 10(-4) cm/h 6 weeks after grafting, versus control values of (2 +/- 2) x 10(-4) cm/h in human cadaver skin and (0.6 +/- 0.4) x 10(-4) cm/h in human epidermal membrane prepared from freshly excised breast skin. These results demonstrate the reformation of epidermal barrier function after transplantation and provide insights for the development of a functional epidermal barrier in CSS in vitro.     

In vivo iontophoretic delivery and pharmacokinetics of salmon calcitonin

In vivo iontophoretic delivery of salmon calcitonin (SCT) in hairless rats using a self-contained wearable and disposable iontophoretic patch was investigated. Iontophoretic patches with built-in proprietary Zn/AgCl electrodes were used. SCT was formulated in citrate buffer (50mM, pH 4.0) to impart a positive charge for anodal iontophoresis. SCT was delivered intravenously to determine primary pharmacokinetic parameters. Pharmacokinetics of iontophoretic delivery of SCT was compared with subcutaneous route of administration. Blood samples were collected through tail vein and analyzed for serum SCT and calcium levels. Pharmacokinetic parameters were calculated by non-compartmental analysis. An average current of 0.43+/-0.01 mA was maintained during patch application. Iontophoretic patches delivered SCT at an average infusion rate of 177.9+/-58.7 ng/(min kg) and an average steady state concentration of 7.58+/-1.35 ng/ml was achieved. There was no difference between the calcium lowering effect of iontophoretic patch and subcutaneous injection (p>0.05). Clearance and half-life of SCT after IV administration were found to be 16.8+/-0.9 ml/(min kg) and 33.5+/-3.3 min, respectively. The iontophoretic delivery of SCT was well defined by a one-compartment model with zero-order infusion. Iontophoretic patch delivered therapeutically relevant concentrations of SCT in hairless rats and delivery was comparable to conventional routes.     

Transdermal iontophoretic delivery of methylphenidate HCl in vitro

Methylphenidate is prescribed orally for Attention Deficit Disorder in children and adults, and for narcolepsy patients. Methylphenidate has a short plasma half-life (1-2 h) and thus needs to be frequently administered for effective therapy. Such therapy has limitations in terms of patient compliance, particularly in young children. For such reasons, the development of a transdermal dosage form of methylphenidate may be useful. This study was undertaken to evaluate the passive and electrically assisted transport (iontophoresis) of methylphenidate from aqueous methylphenidate hydrochloride solutions across excised human skin. A maximum flux of 12.0 micrograms/(cm2 h) of protonated methylphenidate was estimated from the passive transport data at pH 3.5. Iontophoresis significantly enhanced protonated methylphenidate transport as compared with passive delivery. From the present experiments, the efficiency of iontophoretic delivery of methylphenidate was approximately 700 micrograms/(mA h). Based on in vitro skin flux data, the daily dose of 15-40 mg methylphenidate can be achieved using a current density of 0.5 mA/cm2 and a minimum transport area of 2-5 cm2 for 24-h application, or an area of 4-10 cm2 for 12-h (daytime) application. From methylphenidate skin flux values, methylphenidate mobility of 2.2 x 10(-4) cm2/(V s) was estimated, which compares reasonably with its free solution mobility of 6.6 x 10(-4) cm2/(V s).     

Passive and iontophoretic transdermal penetration of methotrexate

The in vitro iontophoretic transdermal delivery of methotrexate (MTX) across pig skin was investigated. Cathodal iontophoresis considerably increased MTX skin permeation and accumulation as compared to the passive controls. The effect of NaCl and MTX concentrations in the vehicle were also studied. As expected, MTX iontophoretic transport decreased with NaCl content. On the other hand, MTX concentration did not modify its electrotransport in the range of concentrations considered (4.4-6.6 mM). The influence of the current density (0.25-0.5 mA/cm2) was also investigated. The iontophoretic transport of MTX tends to increase with current density although this effect was not always statistically significant. Finally, the possibility of using anodal iontophoresis from an acid (pH 4.0-5.0) donor solution to deliver MTX was explored. This was limited due to the low solubility of MTX in acid pH. On the whole, this work that iontophoresis may be used to improve the topical application of MTX for the treatment of psoriasis.