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Iontophoresis is a promising technique for enhancing transdermal administration of charged drugs. However, conventional iontophoresis is not sufficient for effective delivery of large, hydrophilic, or electrically neutral molecules. In this study, we utilized charged liposomes as carriers, focused on a transfollicular route for delivery of the liposomes, and optimized iontophoretic conditions and lipid composition for this method in both in vitro and in vivo conditions.As a result, we identified the optimum condition (lipid composition:DOTAP/EPC/Chol=2:2:1, current supply: 0.45 mA/cm 2 , duration: 1 hr) for effective iontophoretic delivery of aqueous solution, which can not be transferred into the skin without charged liposomes. We also examined the pharmacological effects of iontophoresis of liposomes encapsulating insulin (INS-lipo) using a rat model of type I diabetes. Interestingly, iontophoresis of INS-lipo onto a diabetes rat skin resulted in a gradual decrease in blood glucose levels, with levels reaching 20% of initial values at 18 hr after administration. These lower blood glucose levels were maintained for up to 24 hr. Significant amount of insulin were also detected in plasma 18 hr after iontophoresis of INS-lipo. We succeeded in developing a non-invasive and persistent transfollicular drug delivery system that used a combination of liposomes and iontophoresis.

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Iontophoresis is a promising method which utilizes an electric field to enhance the delivery of charged compounds across skin.1,2) Since drug administration is readily controlled by adjustment of the applied voltage or current, iontophoresis may become a useful technique for drug therapy at home. Conventional iontophoretic systems use direct current which frequently causes skin irritation due to change in pH 3) or continuous electrical polarization of the skin.4) Moreover, changes in pH alter the ionization of organic compounds which exist in a pH-dependent equilibrium between their ionized and nonionized states. 5) Since an optimal iontophoretic effect requires maximal ionization, 6,7) effective drug transport must minimize pH changes in the drug-containing solution. In order to overcome these disadvantages, systems using a silver or silver-silver chloride electrode 8,9) or pulsed direct current 10) have been investigated. However, there have been few reports demonstrating both safety and drug availability when iontophoretic systems were used in vivo.Recently, a novel iontophoretic device was developed by TTI ellebeau Inc. to improve the capabilities of current systems (Fig. 1). This novel system transfers an ionic drug from the drug solution into the skin through an ion-exchange membrane. The counter ions are transported from the drug solution to an electrode buffer compartment, and do not pass from the skin into the drug solution due to the presence of the ion-exchange membrane. In this way, the balance between cations and anions in the drug solution can be kept constant. It is assumed that changes in pH due to oxidation and reduction reactions at the anode and cathode do not affect the conditions of the drug-containing solution, because the drug solution chamber and the electrode chamber are separated by ion-exchange membrane. It is also assumed that insults to the skin are relatively minor compared with conventional devices since the influx of endogenous ions from the skin into the drug solution is prevented by the presence of the ion-exchange membranes.Transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) by iontophoresis would be advantageous since it would avoid hepatic first-pass metabolism and considerable gastrointestinal disturbances.11,12) However, as presently configured, iontophoretic delivery of anionic compounds, such as NSAIDs, is relatively inefficient because the negative charge on the surface of the skin electrostatically repels anionic drugs.13) Therefore, further improvements in iontophoresis systems are required for efficient transdermal delivery of anionic drugs. The purpose of this study was to examine transdermal delivery of the anionic pharmacologic agent diclofenac sodium, a widely used NSAID, by a novel iontophoretic system. Previously, in vitro iontophoresis of insulin was enhanced by pretreatment of skin with a chemical A novel iontophoretic system utilizing ion-exchange membranes is effective for selective transdermal delivery of ionized drugs. In the present stu...

Superoxide dismutase (SOD) is a potent antioxidant agent that protects against UV-induced skin damage. However, its high molecular weight is a significant obstacle for efficient delivery into the skin through the stratum corneum and development of antioxidant activity. Recently, we developed a non-invasive transfollicular delivery system for macromolecules using a combination of liposomes and iontophoresis, that represents promising technology for enhancing transdermal administration of charged drugs (IJP, 403, 2011, Kajimoto et al.). In this study, in rats we attempted to apply this system to intradermal delivery of SOD for preventing UV-induced skin injury. SOD encapsulating in cationic liposomes was subjected to anodal iontophoresis. After iontophoretic treatment, the liposomes were diffused widely in the viable skin layer around hair follicles. In contrast, passive diffusion failed to transport liposomes efficiently into the skin. Iontophoretic delivery of liposomes encapsulating SOD caused a marked decrease in the production of oxidative products, such as malondialdehyde, hexanoyl lysine, and 8-hydroxi-2-deoxyguanosine, in UV-irradiated skin. These findings suggested that functional SOD can be delivered into the skin using a combination of iontophoresis and a liposomal system. In conclusion, we succeeded in developing an efficient intradermal SOD delivery system, that would be useful for delivery of other macromolecules. Key words superoxide dismutase; iontophoresis; liposome; transfollicular delivery; antioxidant activityThe skin is exposed constitutively to ultraviolet (UV) rays that cause the production of reactive oxygen species (ROS) in the skin, resulting in diverse skin disorders.1) It is well-known that the classes of UV that reach the ground are UVA and UVB. UVA readily penetrates deep layers of the skin, and causes production of melanin and wrinkling associated with destruction of collagen fiber, resulting in aging of the skin. 1)UVB causes skin inflammation and DNA damage that contribute to the pathogenesis of serious skin disorders, such as skin malignancy.1) ROS are also involved in the development of skin damage, and therefore elimination of ROS is essential for protecting the skin from UV-induced damage.Superoxide dismutase (SOD) may be used to prevent and treat ROS-induced disorders of various tissues as it has potent antioxidant activity.2) Because of its poor pharmacokinetic profile, systemic administration of free SOD does not result in induction of efficient in vivo antioxidant activity.3) In contrast, the skin is an available site for topical application of SOD due to its accessibility. Percutaneous delivery of SOD is therefore considered to be a promising method for prophylaxis or therapy of UV-induced skin damage. However, SOD are highly hydrophilic macromolecules and do not readily penetrate the deeper layers of the skin as the outer layer of the skin, the stratum corneum, functions as a significant barrier prohibiting penetration of drug molecules larger than 500 Da. 4)Iontophoresis...