Investigation of Different Iontophoretic Currents Profiles for Short-Term Applications in Cosmetics.

This study aimed at investigating the effect of electrical current profile upon the iontophoretic transport of (i) ascorbic acid (AA) and (ii) ellagic acid (EA), into porcine skin in vitro, and the impact of the physicochemical properties of both actives on their mechanism of transport when formulated in cosmetic compositions. The experiments were performed using a proprietary iontophoretic device containing a roller to apply the formulation. Three current profiles were tested: (i) galvanic direct current (DC), (ii) square unipolar pulse current (SPC), and (iii) galvanic direct current (DC) + pulse current (PC). The skin samples were collected at different sampling points, extracted and analyzed by HPLC. Results suggested that the DC + PC mode for only 5 min was able to significantly increase the delivery of AA from o/w cosmetic compositions. The use of this current profile might improve the skin penetration of AA due to electromigration and passive diffusion, the latter being facilitated by the physical enhancement method. The SPC mode significantly improved the passage of EA in its neutral form from cosmetic o/w formulations by electroosmosis. Tailoring specific electrical current modes considering the ionization state of active ingredients would allow the design of short and personalized cosmetic treatments that significantly improve the penetration efficiency of the active ingredients and possibly reduce the doses applied.

Controlled transdermal iontophoresis for poly-pharmacotherapy: Simultaneous delivery of granisetron, metoclopramide and dexamethasone sodium phosphate in vitro and in vivo.

Iontophoresis has been used to deliver small molecules, peptides and proteins into and across the skin. In principle, it provides a controlled, non-invasive method for poly-pharmacotherapy since it is possible to formulate and to deliver multiple therapeutic agents simultaneously from the anodal and cathodal compartments. The objective of this proof-of-principle study was to investigate the simultaneous anodal iontophoretic delivery of granisetron (GST) and metoclopramide (MCL) and cathodal iontophoresis of dexamethasone sodium phosphate (DEX-P). In addition to validating the hypothesis, these are medications that are routinely used in combination to treat chemotherapy-induced emesis. Two preliminary in vitro studies using porcine skin were performed: Study 1 - effect of formulation composition on anodal co-iontophoresis of GST and MCL and Study 2 - combined anodal iontophoresis of GST (10mM) and MCL (110 mM) and cathodal iontophoresis of DEX-P (40 mM). The results from Study 1 demonstrated the dependence of GST/MCL transport on the respective drug concentrations when co-iontophoresed at 0.3 mA·cm(-2). Although they possess similar physicochemical properties, MCL seemed to be a more efficient charge carrier (JMCL=0.0591∗CMCLvs JGST=0.0414∗CGST). In Study 2, MCL permeation was markedly superior to that of GST (2324.83 ± 307.85 and 209.83 ± 24.84 µg·cm(-2), respectively); this was consistent with the difference in their relative concentrations; DEX-P permeation was 336.94 ± 71.91 µg·cm(-2). The in vivo studies in Wistar rats (10mM GST, 110 mM MCL and 40 mM DEX-P (0.5 mA·cm(-2) for 5h with Ag/AgCl electrodes and salt bridges) demonstrated that significant drug levels were achieved rapidly for each drug. This was most noticeable for dexamethasone (DEX) where relatively constant plasma levels were obtained from the 1 to 5h time-points; DEX-P was not detected in the plasma since it was completely hydrolyzed to the active metabolite. The calculated input rates in vivo (k01) for GST, MCL and DEX were 0.45 ± 0.05, 3.29 ± 0.48 and 1.97 ± 0.38 µg·cm(-2) · min(-1), respectively. The study confirmed that iontophoresis provided a controlled method for the simultaneous administration of multiple therapeutic agents and that it could be of use for poly-pharmacotherapy in general and more specifically that it was able to deliver different drugs used in the treatment of chemotherapy-induced emesis.

Comparing metoclopramide electrotransport kinetics in vitro and in vivo.

The purpose of this work was to investigate the transdermal iontophoretic delivery of metoclopramide and to determine (i) the dependence of electrotransport on current density and drug concentration, (ii) the relative contributions of electromigration and electroosmosis and (iii) the feasibility of administering therapeutic amounts of drug, using a drug-sparing iontophoretic configuration. Iontophoretic delivery of metoclopramide (MCL) across dermatomed porcine ear skin was investigated in vitro as a function of concentration (10, 20, 40, 80 and 100mM) and current density (0.1, 0.2 and 0.3mAcm(-2)) using vertical flow-through diffusion cells. In vivo studies were performed in Wistar rats (40mM MCL, 0.3mAcm(-2), 5h); the anodal and drug formulation compartments were separated by a salt bridge. Cumulative delivery in vitro after 7h of current application (40mM MCL; 0.3mAcm(-2)) in the absence of electrolyte was 624.45+/-99.45microgcm(-2) (flux - 2.55+/-0.35microgcm(-2)min(-1)). There was a linear relationship between flux and both current density and drug concentration. Co-iontophoresis of acetaminophen confirmed that electromigration was the major transport mechanism (accounting for approximately 80% of MCL delivery). Electroosmotic inhibition, albeit modest, was only observed at the highest MCL concentration (100mM). Although the delivery rate observed in vivo in male Wistar rats (1.21+/-0.55microgcm(-2)min(-1)) was lower than that observed in vitro, the results suggest that drug input rates would be sufficient to achieve therapeutic levels in humans using non-invasive transdermal iontophoresis.

Using transdermal iontophoresis to increase granisetron delivery across skin in vitro and in vivo: effect of experimental conditions and a comparison with other enhancement strategies.

The objectives of the study were (i) to investigate the effect of experimental parameters on the iontophoretic transport of granisetron, (ii) to identify the relative contributions of electromigration (EM) and electroosmosis (EO), (iii) to determine the feasibility of delivering therapeutic amounts of drug for the treatment of chemotherapy-induced nausea and vomiting and (iv) to test the in vitro results in a simple animal model in vivo. Preliminary in vitro studies using aqueous granisetron formulations investigating the effect of drug concentration (5, 10, 20 and 40 mM) and current density (0.1, 0.2, 0.3 mA cm(-2)) were performed using porcine ear skin. As expected, cumulative delivery in vitro at the 20 and 40 mM concentrations was significantly greater than that at 5 and 10mM, which were not statistically different (p<0.05). Increasing the applied current density from 0.1 to 0.3 mA cm(-2) resulted in a approximately 4.2-fold increase in iontophoretic flux. Furthermore, in the absence of Na(+) in the formulation, no dependence of iontophoretic flux on drug concentration was reported (at a granisetron concentration of 40 mM, the transport rate was 2.93+/-0.62 microg cm(-2)min(-1)). Co-iontophoresis of acetaminophen was used to show that EM was the predominant transport mechanism accounting for 71-86% of total granisetron delivery. In vivo studies in Wistar rats (40 mM granisetron; application of 0.3 mA cm(-2) for 5h with Ag/AgCl electrodes and salt bridges) showed an average iontophoretic input rate (k(input)) of 0.83+/-0.26 microg min(-1) and a maximum plasma concentration (C(max)) of 0.092+/-0.004 microg ml(-1). Based on these results and given the known pharmacokinetics, transdermal iontophoresis could achieve therapeutic drug levels for the management of chemotherapy-induced emesis using a reasonably sized (4-6 cm(2)) patch.

Design and evaluation of a self-adhesive naproxen-loaded film prepared from a nanoparticle dispersion.

Naproxen-loaded nanoparticles were used to prepare, in a one-step process, unilaminar films of Eudragit E-100 (EE-100), avoiding the use of organic solvents and assuring the homogeneity and molecular dispersion of the drug. Nanoparticle films (NP-F) and conventional films (CV-F, prepared by casting of methanolic solutions onto a Teflon disc) were assayed by their mechanical properties, skin adhesivity, and calorimetric studies to compare their behavior. Different proportions of plasticizer (triacetin) were included to evaluate the quality of the films. Film characterization included in vitro drug release studies through a cellulose membrane using Franz-type cells, and in vivo stratum corneum penetration experiments by the tape stripping technique. The results showed that NP-F were semi-transparent to transparent, suggesting a good compatibility between naproxen and EE-100. Differential calorimetric studies (DSC) confirmed a molecular dispersion of naproxen in the EE-100 matrix. Taking into account the mechanical properties of the films, a 20% triacetin concentration can be considered as optimal for both types of films. The in vitro release data obtained from both systems (NP-F and CV-F) followed the Higuchi's model for matrix systems, with the Fickian diffusion (t(0.5)) being the main release mechanism. Concerning the in vivo penetration studies, no statistical differences were found for the penetrated amount of naproxen across the stratum corneum and the depth of penetration for the two films and between the three contact times (2, 4, and 6 h). The films formulated from nanoparticle dispersions (NP-F) were shown to be effective for the transdermal administration of naproxen, and can be considered as an interesting alternative for the preparation of films with several technological advantages.

Chemical enhancers for the absorption of substances through the skin: Laurocapram and its derivatives.

Absorption enhancers are substances used for temporarily increasing a membrane's permeability (e.g., the skin and mucosa), either by interacting with its components (lipids or proteins) or by increasing the membrane/vehicle partition coefficient. This article presents the results of biophysical and permeability studies performed with Laurocapram and its analogues. As shown, Laurocapram and its analogues present different enhancing efficacies, for most of both hydrophilic and lipophilic substances. The enhancing effect of Laurocapram (Azone) is attributed to different mechanisms, such as insertion of its dodecyl group into the intercellular lipidic bilayer, increase of the motion of the alkylic chains of lipids, and fluidization of the hydrophobic regions of the lamellate structure. Toxicological studies reveal a low toxicity for Laurocapram, and for some derivatives, a relationship exists between toxicity and the number of carbons in the alkylic chain. Very important, when applied to human skin, Laurocapram shows a minimal absorption, being quickly eliminated from circulation. However, although Laurocapram and its derivatives have been shown to provide enhancement, they have not been widely accepted because of their suspected pharmacological activity or questions about their safety.

Preparation of polymeric nanocapsules containing octyl methoxycinnamate by the emulsification-diffusion technique: penetration across the stratum corneum.

Polymeric nanocapsules (NCs) containing octyl methoxycinnamate (OMC) as lipophilic molecule were prepared, and their in vivo distribution profile through the stratum corneum (SC) was determined by the tape-stripping technique. Penetration degree of OMC formulated in NCs was compared with that obtained for a nanoemulsion (NE), and a conventional oil-in-water (o/w) emulsion (EM). To produce stable cellulose acetate phthalate (CAP) nanocapsules containing the lipophilic sunscreen, a study was conducted to optimize the process of NC preparation based on the emulsification-diffusion technique. NC formation was verified by measuring their density using differential centrifugation. NC density revealed that an OMC (microL)/CAP (mg) ratio of 2.5:1 is optimal for encapsulation. High encapsulation entrapment (>96%) and excellent process efficiency (recovered quantity of NCs in relation with the initial amount of OMC and CAP >99%) were always achieved with this ratio or a higher one. The capsular structure of the NCs was evidenced with a direct SEM technique. NE was prepared by the emulsification-diffusion technique, dissolving a specific quantity of OMC in water-saturated 2-butanone and then, emulsifying with an aqueous solution of PVAL. In vivo percutaneous penetration, evaluated by the tape-stripping technique, demonstrated that NE increased the extent of OMC penetration relative to the penetration achieved by NCs or EM, with relative penetration depths through the SC of 0.86 +/- 0.1, 0.64 +/- 0.11, and 0.57 +/- 0.08, respectively. In the same manner, the accumulation in the skin of OMC was significantly greater with NE than with EM or NCs. OMC penetration depth was strongly dependent upon the size of the colloidal particles and their flexibility.