TTI Ellebeau Inc.

Shinagawa-ku, Japan

TTI Ellebeau Inc.

Shinagawa-ku, Japan
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Hama S.,Kyoto Pharmaceutical University | Takahashi K.,Kyoto Pharmaceutical University | Inai Y.,Kyoto Pharmaceutical University | Shiota K.,Kyoto Pharmaceutical University | And 6 more authors.
Journal of Pharmaceutical Sciences | Year: 2012

Astaxanthin (Asx) would be expected to prevent ultraviolet (UV)-induced skin damage, as it is regarded as a potent antioxidative carotenoid in biological membranes. However, it is difficult to administer Asx topically to skin because of its poor water solubility. In this study, we attempted to solve this problem by preparing liposomes containing Asx (Asx-lipo), which were dispersible in the water phase, and therefore, suitable for topical application to the skin. Asx-lipo was shown to have potent scavenging ability against chemiluminescence-dependent singlet oxygen production in the water phase. When Asx-lipo was applied to skin before UV exposure, UV-induced skin thickening was prevented. Interestingly, collagen reduction induced by UV exposure was also prevented by preadministration of Asx-lipo. In addition, topical administration of Asx-lipo containing cationic lipid inhibited melanin production in skin exposed to UV. Consequently, we succeeded in preventing UV-induced skin damage using a topical application of a liposomal formulation containing Asx. © 2012 Wiley Periodicals, Inc.


Kigasawa K.,Hokkaido University | Miyashita M.,Hokkaido University | Kajimoto K.,Hokkaido University | Kanamura K.,TTI Ellebeau Inc. | And 2 more authors.
Biological and Pharmaceutical Bulletin | Year: 2012

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. © 2012 The Pharmaceutical Society of Japan.


Kajimoto K.,Hokkaido University | Yamamoto M.,Hokkaido University | Watanabe M.,Hokkaido University | Kigasawa K.,Hokkaido University | And 3 more authors.
International Journal of Pharmaceutics | Year: 2011

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/cm2, duration: 1 h) for effective iontophoretic delivery of aqueous solution, which cannot 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 h after administration. These lower blood glucose levels were maintained for up to 24 h. Significant amount of insulin were also detected in plasma 18 h 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. © 2010 Elsevier B.V. All rights reserved.


Kigasawa K.,Hokkaido University | Kigasawa K.,TTI ellebeau Inc. | Kajimoto K.,Hokkaido University | Hama S.,Kyoto Pharmaceutical University | And 3 more authors.
International Journal of Pharmaceutics | Year: 2010

Topical application of siRNA to the skin should be an effective treatment for serious skin disorders, such as atopic dermatitis. However, it is difficult to introduce hydrophilic macromolecules, including siRNA, into the skin by conventional methods. For efficient delivery of siRNA, we examined an iontophoretic technique, since it is suitable for the delivery of charged molecules. Naked siRNA effectively accumulated in the epidermis (and not in the dermis) after iontophoretic delivery. In contrast, siRNA did not penetrate tape-stripped skin by passive diffusion. In a rat model of atopic dermatitis, skin was sensitized with ovalbumin to stimulate IL-10 mRNA expression as observed in skin lesions. Iontophoretic delivery of anti-IL-10 siRNA significantly reduced (73%) the level of IL-10 mRNA. In conclusion, we successfully delivered naked siRNA into the epidermis and concomitantly suppressed the expression of an endogenous immuno-regulatory cytokine. © 2009 Elsevier B.V. All rights reserved.


Kigasawa K.,Hokkaido University | Kajimoto K.,Hokkaido University | Nakamura T.,Hokkaido University | Hama S.,Kyoto Pharmaceutical University | And 3 more authors.
Journal of Controlled Release | Year: 2011

Oligodeoxynucleotides containing unmethylated cytosine-phosphate-guanosine motifs (CpG-ODN) possess immunostimulatory effects and potential antitumor activity. Since the skin is an easily available site of administration of CpG-ODN due to its accessibility and the presence of abundant antigen presenting cells, it is expected that the application of CpG-ODN to the skin would induce systemic immune response and antitumor activity. However, it is difficult to deliver hydrophilic macromolecules including CpG-ODN through the skin. We have previously demonstrated that small interfering RNA (siRNA) was efficiently delivered into rat epidermis by iontophoresis. In this report, we investigate the effect of transdermal iontophoretic delivery of CpG-ODN on the induction of immune responses and antitumor activity against B16F1 melanoma in mice. Iontophoresis promoted CpG-ODN delivery into the epidermis and dermis. Furthermore, iontophoretic delivery of CpG-ODN to the skin induced the expression of proinflammatory and Th1-type cytokines in the skin and draining lymph node. Finally, transdermal iontophoretic delivery of CpG-ODN led to antitumor activity against B16F1 melanoma. Interestingly, the CpG-ODN administration site is not restricted to the tumor area. In conclusion, CpG-ODN delivered transdermally induced potent antitumor activity, and our system is expected to serve as a simple and noninvasive approach for cancer immunotherapy. © 2011 Elsevier B.V. All rights reserved.


Takasuga S.,TTI Ellebeau Inc. | Yamamoto R.,TTI Ellebeau Inc. | Mafune S.,TTI Ellebeau Inc. | Sutoh C.,TTI Ellebeau Inc. | And 4 more authors.
Journal of Pharmacy and Pharmacology | Year: 2011

Objectives The feasibility of transdermal delivery of tramadol, a centrally acting analgesic, by anodal iontophoresis using Ag/AgCl electrodes was investigated in vitro and in vivo. Methods To examine the effect of species variation and current strength on skin permeability of tramadol, in-vitro skin permeation studies were performed using porcine ear skin, guinea-pig abdominal skin and hairless mouse abdominal skin as the membrane. In an in-vivo pharmacokinetic study, an iontophoretic patch system was applied to the abdominal skin of conscious guinea pigs with a constant current supply (250 μA/cm 2) for 6 h. An intravenous injection group to determine the pharmacokinetic parameters for estimation of the transdermal absorption rate in guinea pigs was also included. Key findings The in-vitro steady-state skin permeation flux of tramadol current-dependently increased without significant differences among the three different skin types. In the in-vivo pharmacokinetic study, plasma concentrations of tramadol steadily increased and reached steady state (336 ng/ml) 3 h after initiation of current supply, and the in-vivo steady-state transdermal absorption rate was 499 μg/cm 2 per h as calculated by a constrained numeric deconvolution method. Conclusions The present study reveals that anodal iontophoresis provides current-controlled transdermal delivery of tramadol without significant interspecies differences, and enables the delivery of therapeutic amounts of tramadol. © 2011 Royal Pharmaceutical Society.


Yamamoto R.,TTI Ellebeau Inc. | Takasuga S.,TTI Ellebeau Inc. | Yoshida Y.,TTI Ellebeau Inc. | Mafune S.,TTI Ellebeau Inc. | And 7 more authors.
International Journal of Pharmaceutics | Year: 2012

Aim: The feasibility of transdermal delivery of naloxone, an opioid antagonist, by anodal iontophoresis patches using Ag/AgCl electrodes was investigated. Methods: To examine the effect of current strength, species variation and drug concentration on skin permeability of naloxone, in vitro skin permeation studies were performed using rat dorsal skin and porcine ear skin as the membrane. To determine in vivo transdermal absorption rate of naloxone, the iontophoretic patch system was applied to the dorsal skin of conscious rat with a constant current supply for 24 h. Results: The in vitro steady-state skin permeation flux of naloxone current-proportionally (0-360 μA/cm 2) increased without significant differences between these two different skin types. The in vitro delivery rate through the porcine skin was found to be independent of the concentration of naloxone hydrochloride dehydrate in the donor patch over the range from 1 to 10% (w/v). In the in vivo pharmacokinetic study, plasma concentrations of naloxone steadily increased and sustained steady-state levels from 4 h to 24 h after the initiation of current application. In vivo steady-state transdermal absorption rates at 90 and 180 μA/cm 2 were 136 and 305 μg/h/cm 2, respectively. Conclusion: These results suggest that the transdermal delivery rates of naloxone by anodal iontophoresis are sufficient for the management of intoxication in opioid-overdosed patients. © 2011 Elsevier B.V.


Ito F.,Tokyo Metroplitan University | Takahashi T.,TTI ellebeau Inc. | Kanamura K.,Tokyo Metroplitan University | Kawakami H.,Tokyo Metroplitan University
Drug Development and Industrial Pharmacy | Year: 2013

The optimized preparation of Poly-(lactide-co-glycolic acid) (PLGA) nanospheres containing ubiquinone (UQ) for cosmetic products was pursued. By investigating various conditions for the preparation of UQ/PLGA nanospheres such as the molecular weight of PLGA, PLGA concentration, and UQ concentration, UQ/PLGA nanospheres with increased stability and slower drug release at a higher drug loading efficiency were prepared. Permeation tests on the prepared nanospheres using iontophoresis via electric dermal administration on membrane filters (200 nm pore size) and hairless mouse skin samples were also carried out. After iontophoresis, the nanospheres choked the membrane filter and remained on the horny layer of the hairless mouse skin, even after washing. Therefore, the prepared UQ/PLGA nanospheres and the established iontophoresis technique with the PLGA nanospheres in the present study can be applied to the future development of cosmetics. © 2013 Informa Healthcare USA, Inc.


PubMed | TTI ellebeau Inc.
Type: Journal Article | Journal: Chemical & pharmaceutical bulletin | Year: 2013

The aim of the present study was to evaluate the feasibility of transdermal delivery of glycyrrhizin, an agent used in the treatment of chronic hepatitis C, by cathodal iontophoresis using Ag/AgCl electrodes in vitro. The effects of donor pH (pH 4-7), concentration of drug (0.025-0.2% (w/v)), concentration of external chloride ions (Cl(-)) (0-133 mM), current strength (0-0.5 mA/cm(2)), and permeation enhancers (urea and Tween 80) on the skin permeability of glycyrrhizin were examined in in vitro skin permeation studies using porcine ear skin as the membrane. The cumulative amount of permeated glycyrrhizin and the steady-state skin permeation flux of glycyrrhizin across porcine skin increased in a pH-dependent manner. The skin permeability of glycyrrhizin was independent of the concentration of drug and competed only with a high external Cl(-) concentration. The skin permeation flux of glycyrrhizin increased with the current (R(2)=0.8955). The combination of iontophoresis and enhancers provided an additive or synergistic effect, and a skin permeation flux of about 60 g/h/cm(2) was achieved. The plasma concentration of glycyrrhizin in humans, extrapolated from the in vitro steady-state permeation flux across porcine skin, was within the therapeutic level. These results suggest that cathodal iontophoresis can be used as a transdermal drug delivery system for glycyrrhizin using reasonable patch sizes and acceptable levels of current intensity.


PubMed | TTI ellebeau Inc.
Type: Journal Article | Journal: The Journal of pharmacy and pharmacology | Year: 2011

The feasibility of transdermal delivery of tramadol, a centrally acting analgesic, by anodal iontophoresis using Ag/AgCl electrodes was investigated in vitro and in vivo.To examine the effect of species variation and current strength on skin permeability of tramadol, in-vitro skin permeation studies were performed using porcine ear skin, guinea-pig abdominal skin and hairless mouse abdominal skin as the membrane. In an in-vivo pharmacokinetic study, an iontophoretic patch system was applied to the abdominal skin of conscious guinea pigs with a constant current supply (250 A/cm(2)) for 6 h. An intravenous injection group to determine the pharmacokinetic parameters for estimation of the transdermal absorption rate in guinea pigs was also included.The in-vitro steady-state skin permeation flux of tramadol current-dependently increased without significant differences among the three different skin types. In the in-vivo pharmacokinetic study, plasma concentrations of tramadol steadily increased and reached steady state (336 ng/ml) 3 h after initiation of current supply, and the in-vivo steady-state transdermal absorption rate was 499 g/cm(2) per h as calculated by a constrained numeric deconvolution method.The present study reveals that anodal iontophoresis provides current-controlled transdermal delivery of tramadol without significant interspecies differences, and enables the delivery of therapeutic amounts of tramadol.

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