Gai ng Li

Transdermal iontophoresis of rotigotine across human stratum corneum in vitro: Influence of pH and NaCl concentration

AbstractPurpose. 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 (Fluxss) 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 Fluxss 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 iontophoresis of R-apomorphine across human stratum corneum. Structure-transport relationship of penetration enhancement.

To achieve a therapeutical effect of the anti-Parkinsons drug R-apomorphine via iontophoresis delivery, enhancement strategies in vitro were explored using three structurally related enhancers, lauric acid (LA), dodecyltrimethylammonium bromide (DTAB) and Laureth-3 oxyethylene ether (C(12)EO(3)). Human stratum corneum and shed snake skin were pretreated with 0.15 M each enhancer solution in propylene glycol (PG). Thereafter, passive diffusion, iontophoretic transport and post-iontophoretic passive diffusion were investigated. Compared to the control (PG pretreatment), a slight inhibition on both passive and iontophoretic delivery was observed with cationic surfactant DTAB pretreated stratum corneum. Pretreatment with anionic surfactant LA resulted in a great enhancement on passive delivery, but only a small enhancing effect on the iontophoretic delivery. Unlike the others, the nonionic surfactant C(12)EO(3) substantially increased iontophoretic transport rate of R-apomorphine by 2.3-fold, whereas passive delivery was basically unchanged or slightly affected. The magnitude of enhancing effect of C(12)EO(3) was dependent on the surfactant concentration and the pretreatment duration. Moreover, comparison of transport data through shed snake skin with human stratum corneum indicates that both shunt- and intercellular pathways are involved in the iontophoretic transport of R-apomorphine.

Cutaneous side‐effects of transdermal iontophoresis with and without surfactant pretreatment: a single‐blinded, randomized controlled trial

Background  Iontophoresis, a method that facilitates drug transport across skin by an external electrical field, offers the possibility for long‐term transdermal delivery of compounds in a well‐controlled manner. In general, the literature supports the contention that iontophoresis is a safe procedure. However, there are important medical issues concerning the epidermal and dermal effects of iontophoresis that have not been extensively investigated. Specific and strictly controlled studies on the dermal effect of iontophoresis are scarce.

Iontophoretic Delivery of Apomorphine In Vitro: Physicochemic Considerations

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

Pretreatment with a water-based surfactant formulation affects transdermal iontophoretic delivery of R-apomorphine in vitro

AbstractPurpose. To further increase the transdermal transport rate of R-apomorphine, a nonocclusive pretreatment with an aqueous surfactant formulation in combination with iontophoresis was explored in vitro. Methods. The human stratum corneum was pretreated nonocclusively with formulations composed of laureth-3 oxyethylene ether (C12EO3), laureth-7 oxyethylene ether (C12EO7), and cholesterol sulfate (CSO4) prior to iontophoresis. The effect on the flux of the following parameters was examined: the composition, the charge, and the applied amount of surfactant formulations. Results. The iontophoretic flux of R-apomorphine was appreciably increased by pretreatment with surfactant formulations. A formulation containing C12EO3/C12EO7/CSO4 at a molar ratio of 70:30:5 was very stable and increased the iontophoretic flux of R-apomorphine from 92.2 ± 13.9 nmol/cm2*h to 181.5 ± 22.6 nmol/cm2*h. When further increasing the negative charge of this formulation the iontophoretic transport rate was slightly inhibited. A dose of 40 μL/cm2 of the formulation with a total surfactant concentration of 5% (w/w) was sufficient for a maximum enhancing effect. Conclusions. The results obviously show that nonocclusive pretreatment with the surfactant formulation enhances the iontophoretic transport of R-apomorphine, and is a promising approach to achieve therapeutic concentrations of R-apomorphine.

Effect of Elastic Liquid-State Vesicle on Apomorphine Iontophoresis Transport Through Human Skin In Vitro

A major challenge in transdermal drug delivery is to overcome the skin inherent barrier. There is evidence that the primary barrier to transdermal diffusion is the stratum corneum (SC), which is the thin outmost layer of the skin. SC is composed of a regular array of protein rich cells embedded in a multilamellar lipid domain (1). The lipoid domains are the integral components of the transport barrier. Many approaches, such as iontophoresis (2) or the application of chemical enhancers (3,4) have been suggested to enhance the penetration of drugs. Recently, it was proposed to use nonionic surfactant vesicles as drug carriers, often referred to as niosomes. These vesicles have several advantages over classic liposomes, in the sense of better chemical stability, ease of preparation, and low cost (5). The most recent development is the design of elastic liquid-state vesicles, which differ from conventional niosomes and liposomes by a characteristic fluid membrane and high elasticity (6). Studies with human stratum corneum in vitro and hairless mouse in vivo have shown that pretreatment of the skin with polyoxyethylene ester PEG-8-L containing elastic vesicles in a nonocclusive way modifies the ultrastructure in deeper layers of stratum corneum compared to rigid vesicles. Consequently an enhanced passive penetration of H2O was observed (7). Apomorphine is a D1 and D2 dopamine receptor agonist, which has been proven to be very effective in the treatment of Parkinson’s disease, particularly in the management of random response-fluctuations. However, due to its inherent instability, negligible oral biovailability, and short elimination half life, it cannot be administered orally (8,9). Recently in our group we focused on how to design a controlled delivery system for apomorphine by transdermal iontophoresis (10, 11). Application of a conventional iontophoretic system, however, resulted in maximum plasma levels in a lower therapeutical range. Therefore, it is important to increase the apomorphine delivery further. In the present study, we investigated whether treatment with elastic vesicles can be used to enhance apomorphine iontophoretic delivery. To this end, an elastic liquid-state vesicle suspension was prepared from polyoxyethylene ester PEG-8-L, sucrose-ester L595, and cholesterol sulfate at a molar ratio of 70: 30: 5, respectively. Its effects on the iontophoretic transport of apomorphine were examined in human SC and freshly dermatomed human epidermis in vitro.

Combined chemical and electrical enhancement modulates stratum corneum structure

In a previous in vitro study it has been shown that pretreatment with a water-based surfactant formulation results in a two-fold increase in transdermal iontophoretic transport of R-apomorphine compared to iontophoresis only. The aim of the study presented in this paper was to unravel the mechanisms involved in the increased iontophoretic delivery. Freeze fracture electron microscopy and cryo-scanning electron microscopy were used to visualise the ultrastucture of human stratum corneum after (i) application of the surfactant formulation, (ii) iontophoresis and (iii) application of the surfactant formulation followed by iontophoresis. Non-occlusive application of the surfactant formulation did not exert any detectable changes in the ultrastructure of the stratum corneum, except for swelling of the outermost corneocyte layers. Application of a current density of 0.5 mA/cm(2) for 9 h induced a swelling of the corneocytes and the formation of water pools that were occasionally present in the intercellular regions. Application of the surfactant formulation followed by iontophoresis resulted in a further swelling of the corneocytes and a frequent presence of water pools in the intercellular regions throughout the whole stratum corneum. The observed changes in the ultrastructure of the stratum corneum can explain the increased R-apomorphine transport during iontophoresis.

Iontophoretic R-apomorphine delivery in combination with surfactant pretreatment: in vitro validation studies

To validate the efficacy and controllability of a newly developed transdermal delivery system for R-apomorphine in combination with the surfactant pretreatment, iontophoresis was performed in three-chamber continuous-flow-through diffusion cells in vitro. The transdermal iontophoretic transport of R-apomorphine was examined with both human SC and freshly dermatomed human skin, at room temperature and at 32 degrees C. Furthermore, the relationship between current density and iontophoretic flux was investigated. By increasing the temperature from 22 to 32 degrees C, the iontophoretic transport rate of R-apomorphine in human SC was increased 1.9-fold. Also the iontophoretic flux increased linearly with the increase in the current density from 100 to 500 microA/cm(2). When using dermatomed human skin instead of SC, the iontophoretic flux at a current density of 500 microA/cm(2) was decreased from 362+/-45 to 259+/-30 nmol/cm(2)h, and the corresponding lag time was prolonged from 0.8 to 2.8h. In conclusion, the combination of non-occlusive pretreatment with the surfactant formulation and iontophoresis has shown to substantially increase the transdermal transport rate of R-apomorphine. A linear relationship between current density and R-apomorphine flux indicates that the iontophoretic delivery combined with surfactant pretreatment allows a controlled and individualised administration of R-apomorphine.