82 results on '"Kamiyama F"'
Search Results
2. Popliteal pseudoaneurysm simulating soft-tissue sarcoma: complication of osteochondroma resection
- Author
-
Otsuka, T., Yonezawa, M., Kamiyama, F., Matusita, Y., and Matui, N.
- Published
- 2001
- Full Text
- View/download PDF
3. Development of a novel transdermal patch containing sumatriptan succinate for the treatment of migraine: in vitro and in vivo characterization
- Author
-
Wu, D., Tanaka, Y., Jin, Y., Yoneto, K., Alama, T., Quan, Y., Kamiyama, F., Kusamori, K., Katsumi, H., Sakane, T., and Yamamoto, A.
- Published
- 2014
- Full Text
- View/download PDF
4. Inter‐ and intralaboratory variation of in vitro diffusion cell measurements: An international multicenter study using quasi‐standardized methods and materials
- Author
-
Chilcott, R.P., primary, Barai, N., additional, Beezer, A.E., additional, Brain, S.I., additional, Brown, M.B., additional, Bunge, A.L., additional, Burgess, S.E., additional, Cross, S., additional, Dalton, C.H., additional, Dias, M., additional, Farinha, A., additional, Finnin, B.C., additional, Gallagher, S.J., additional, Green, D.M., additional, Gunt, H., additional, Gwyther, R.L., additional, Heard, C.M., additional, Jarvis, C.A., additional, Kamiyama, F., additional, Kasting, G.B., additional, Ley, E.E., additional, Lim, S.T., additional, Mcnaughton, G.S., additional, Morris, A., additional, Nazemi, M.H., additional, Pellett, M.A., additional, DU Plessis, J., additional, Quan, Y.S., additional, Raghavan, S.L., additional, Roberts, M., additional, Romonchuk, W., additional, Roper, C.S., additional, Schenk, D., additional, Simonsen, L., additional, Simpson, A., additional, Traversa, B.D., additional, Trottet, L., additional, Watkinson, A., additional, Wilkinson, S.C., additional, Williams, F.M., additional, Yamamoto, A., additional, and Hadgraft, J., additional
- Published
- 2005
- Full Text
- View/download PDF
5. Thermodynamik und Konformationseigenschaften von Styrol/Methyhneth-acrylat-Blockcopolymeren in verdünnter Lösung
- Author
-
Kamiyama F., Inagaki, H., and Kotaka, T.
- Published
- 1974
- Full Text
- View/download PDF
6. A Fully Automatic Method for Analysis of Individual Bile Acids in the Serum Using High-Performance Liquid Chromatography for Clinical Use.
- Author
-
Hasegawa, S., Uenoyaraa, R., Takeda, F., Chuma, J., Suzuki, K., Kamiyama, F., Yamazaki, K., and Baba, S.
- Published
- 1984
- Full Text
- View/download PDF
7. Inter‐ and intralaboratory variation of in vitrodiffusion cell measurements: An international multicenter study using quasi‐standardized methods and materials
- Author
-
Chilcott, R.P., Barai, N., Beezer, A.E., Brain, S.I., Brown, M.B., Bunge, A.L., Burgess, S.E., Cross, S., Dalton, C.H., Dias, M., Farinha, A., Finnin, B.C., Gallagher, S.J., Green, D.M., Gunt, H., Gwyther, R.L., Heard, C.M., Jarvis, C.A., Kamiyama, F., Kasting, G.B., Ley, E.E., Lim, S.T., Mcnaughton, G.S., Morris, A., Nazemi, M.H., Pellett, M.A., DU Plessis, J., Quan, Y.S., Raghavan, S.L., Roberts, M., Romonchuk, W., Roper, C.S., Schenk, D., Simonsen, L., Simpson, A., Traversa, B.D., Trottet, L., Watkinson, A., Wilkinson, S.C., Williams, F.M., Yamamoto, A., and Hadgraft, J.
- Abstract
In vitromeasurements of skin absorption are an increasingly important aspect of regulatory studies, product support claims, and formulation screening. However, such measurements are significantly affected by skin variability. The purpose of this study was to determine inter‐ and intralaboratory variation in diffusion cell measurements caused by factors other than skin. This was attained through the use of an artificial (silicone rubber) rate‐limiting membrane and the provision of materials including a standard penetrant, methyl paraben (MP), and a minimally prescriptive protocol to each of the 18 participating laboratories. “Standardized” calculations of MP flux were determined from the data submitted by each laboratory by applying a predefined mathematical model. This was deemed necessary to eliminate any interlaboratory variation caused by different methods of flux calculations. Average fluxes of MP calculated and reported by each laboratory (60 ± 27 μg cm−2h−1, n = 25, range 27–101) were in agreement with the standardized calculations of MP flux (60 ± 21 μg cm−2h−1, range 19–120). The coefficient of variation between laboratories was approximately 35% and was manifest as a fourfold difference between the lowest and highest average flux values and a sixfold difference between the lowest and highest individual flux values. Intralaboratory variation was lower, averaging 10% for five individuals using the same equipment within a single laboratory. Further studies should be performed to clarify the exact components responsible for nonskin‐related variability in diffusion cell measurements. It is clear that further developments of in vitromethodologies for measuring skin absorption are required. © 2005 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:632–638, 2005
- Published
- 2005
- Full Text
- View/download PDF
8. Determination of Compositional Heterogeneity in Copolymers by Thin Layer Chromatography. I. Preliminary Results for Styrene-Acrylate Copolymers
- Author
-
Inagaki, H., primary, Matsuda, H., additional, and Kamiyama, F., additional
- Published
- 1968
- Full Text
- View/download PDF
9. Study on the Beating motionless Power loom
- Author
-
Kamiyama, F., primary and Suematsu, M., additional
- Published
- 1952
- Full Text
- View/download PDF
10. A Note on Fractionation of Polymers by Thin Layer Chromatography
- Author
-
Inagaki, H., primary, Kamiyama, F., additional, and Yagi, T., additional
- Published
- 1971
- Full Text
- View/download PDF
11. Intratumoral delivery of a highly active form of XCL1 enhances antitumor CTL responses through recruitment of CXCL9-expressing conventional type-1 dendritic cells.
- Author
-
Kamei M, Matsuo K, Yoshida Y, Shimada K, Otsuki M, Fujimoto N, Ishibashi M, Quan YS, Kamiyama F, Hara Y, Takamura S, and Nakayama T
- Subjects
- Humans, Mice, Animals, T-Lymphocytes, Cytotoxic, Killer Cells, Natural, Dendritic Cells, CD8-Positive T-Lymphocytes, Chemokine CXCL9 metabolism, Melanoma metabolism, Chemokines, C genetics
- Abstract
Conventional type 1 dendritic cells (cDC1s) play a crucial role in antitumor immunity through the induction and activation of tumor-specific CD8
+ cytotoxic T cells (CTLs). The chemokine XCL1 is a major chemotactic factor for cDC1s and its receptor XCR1 is selectively expressed on cDC1s. Here, we investigated the effect of intratumoral delivery of a highly active form of murine XCL1 (mXCL1-V21C/A59C) on cDC1-mediated antitumor immunity using a hydrophilic gel patch. The hydrophilic gel patch containing mXCL1-V21C/A59C increased cDC1 accumulation in the tumor masses and promoted their migration to the regional lymph nodes, resulting in enhanced induction of tumor-specific CTLs. Tumor-infiltrating cDC1s not only expressed XCR1 but also produced CXCL9, a ligand for CXCR3 which is highly expressed on CTLs and NK cells. Consequently, CTLs and NK cells were increased in the tumor masses of mice treated with mXCL1-V21C/A59C, while immunosuppressive cells such as monocyte-derived suppressive cells and regulatory T cells were decreased. We also confirmed that anti-CXCL9 treatment decreased the tumor infiltration of CTLs. The intratumoral delivery of mXCL1-V21C/A59C significantly decreased tumor growth and prolonged survival in E.G7-OVA and B16-F10 tumor-bearing mice. Furthermore, the antitumor effect of mXCL1-V21CA59C was enhanced in combination with anti-programmed cell death protein 1 treatment. Finally, using The Cancer Genome Atlas database, we found that XCL1 expression was positively correlated with tumor-infiltrating cDC1s and a better prognosis in melanoma patients. Collectively, our findings provide a novel therapeutic approach to enhance tumor-specific CTL responses through the selective recruitment of CXCL9-expressing cDC1s into the tumor masses., (© 2024 UICC.)- Published
- 2024
- Full Text
- View/download PDF
12. Enantioselective Synthesis of 1,2-Benzothiazine 1-Imines via Ru II /Chiral Carboxylic Acid-Catalyzed C-H Alkylation/Cyclization.
- Author
-
Huang LT, Kitakawa Y, Yamada K, Kamiyama F, Kojima M, Yoshino T, and Matsunaga S
- Abstract
Sulfondiimines are diaza-analogues of sulfones with a chiral sulfur center. Compared to sulfones and sulfoximines, their synthesis and transformations have so far been studied to a lesser extent. Here, we report the enantioselective synthesis of 1,2-benzothiazine 1-imines, i.e., cyclic sulfondiimine derivatives from sulfondiimines and sulfoxonium ylides via C-H alkylation/cyclization reactions. The combination of [Ru(p-cymene)Cl
2 ]2 and a newly developed chiral spiro carboxylic acid is key to achieving high enantioselectivity., (© 2023 Wiley-VCH GmbH.)- Published
- 2023
- Full Text
- View/download PDF
13. Synthesis of Polysubstituted Enamides by Hydrogen Atom Transfer Alkene Isomerization Using Dual Cobalt/Photoredox Catalysis.
- Author
-
Seino Y, Yamaguchi Y, Suzuki A, Yamashita M, Kamei Y, Kamiyama F, Yoshino T, Kojima M, and Matsunaga S
- Abstract
M-HAT isomerization is a highly reliable method to access thermodynamically stable alkenes with high functional group tolerance. However, synthesis of heteroatom-substituted alkenes by M-HAT isomerization reaction is still underdeveloped. Herein, we report an enamide synthesis using M-HAT via a combination of cobalt and photoredox catalysis. This method tolerates a variety of functional groups including haloarenes, heteroarenes, free hydroxy groups, non-protected indoles, and drug derivatives. Furthermore, this method can isomerize styrene derivatives in good yield and E/Z selectivity., (© 2023 Wiley-VCH GmbH.)
- Published
- 2023
- Full Text
- View/download PDF
14. Transcutaneous Administration of Imiquimod Promotes T and B Cell Differentiation into Effector Cells or Plasma Cells.
- Author
-
Hirobe S, Yamasaki T, Ito S, Quan YS, Kamiyama F, Tachibana M, and Okada N
- Abstract
We are interested in promoting the development of transcutaneous immunization using microneedle technology and attempting to apply an adjuvant with transcutaneous immunization to improve the efficacy and reduce the amount of antigen and number of administrations needed. In this study, we collected basic information to help elucidate the mechanism responsible for the transcutaneous adjuvant activity of imiquimod (IMQ), which is a ligand of toll-like receptor (TLR) 7. In mouse groups administered ovalbumin (OVA), the OVA-specific IgG antibody titer of the IMQ-adjuvanted group was higher than that of the group administered OVA alone. No immune response bias due to transcutaneous IMQ administration was observed in terms of IgG1 (T helper cell [Th]2-type IgG subclass) and IgG2c (Th1-type IgG subclass) antibody titers. After the initial immunization, the IMQ-adjuvanted group showed increased migration of Langerhans cells to draining lymph nodes (dLNs) and active proliferation of OVA-specific CD4
+ T cells. Transcutaneously administered IMQ did not affect the direction of CD4+ T cell differentiation, while promoted B cell activation and germinal center (GC) B cell differentiation. Immune staining revealed greater GC formation in the dLNs with the IMQ-adjuvanted group than in the OVA-alone group. In the secondary immune response, effector T cells increased in the dLNs and spleen, and effector memory T cells also increased in the spleen in the IMQ-adjuvanted group. In addition, our results suggested that the administration of IMQ enhanced B cell differentiation into plasma cells and GC B cells in the dLNs and spleen. In this study, we partially clarified the mechanism underlying the adjuvant activity of transcutaneously administered IMQ, which is required for the practical application of transcutaneous immunization with IMQ.- Published
- 2022
- Full Text
- View/download PDF
15. CCR4 Involvement in the Expansion of T Helper Type 17 Cells in a Mouse Model of Psoriasis.
- Author
-
Matsuo K, Kitahata K, Kaibori Y, Arima Y, Iwama A, Ito M, Hara Y, Nagakubo D, Quan YS, Kamiyama F, Oiso N, Kawada A, Yoshie O, and Nakayama T
- Subjects
- Animals, Cell Communication drug effects, Cell Communication immunology, Cell Proliferation drug effects, Cells, Cultured, Coculture Techniques, Dendritic Cells immunology, Disease Models, Animal, Humans, Imiquimod administration & dosage, Imiquimod immunology, Mice, Mice, Transgenic, Primary Cell Culture, Psoriasis drug therapy, Psoriasis pathology, Receptors, CCR4 antagonists & inhibitors, Receptors, CCR4 genetics, Skin immunology, Th17 Cells drug effects, Th17 Cells metabolism, Psoriasis immunology, Receptors, CCR4 metabolism, Skin pathology, Th17 Cells immunology
- Abstract
Psoriasis is a chronic skin disease associated with T helper (Th)17-mediated inflammation. Because CCR4 is a major chemokine receptor expressed on Th17 cells, we investigated the role of CCR4 in a modified imiquimod-induced psoriasis model that showed enhanced skin infiltration of Th17 cells. CCR4-deficient mice had less severe skin disease than wild-type mice. Th17 cells were decreased in the skin lesions and regional lymph nodes of CCR4-deficient mice. In the regional lymph nodes of wild-type mice, CD44
+ memory Th17 cells expressing CCR4 were found to be clustered with dendritic cells expressing CCL22, a ligand for CCR4. Such dendritic cell‒Th17 cell clusters were significantly decreased in CCR4-deficient mice. Similar results were obtained using the IL-23‒induced psoriasis model. In vitro, compound 22, a CCR4 antagonist, significantly reduced the expansion of Th17 cells in the coculture of CD11c+ dendritic cells and CD4+ T cells separately prepared from the regional lymph nodes of wild-type mice with psoriasis. In vivo, compound 22 ameliorated the psoriasis-like skin disease in wild-type mice with significant decreases of Th17 cells in the regional lymph nodes and skin lesions. Collectively, CCR4 is likely to play a role in the pathogenesis of psoriasis through the expansion of Th17 cells., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
16. Characteristics of immune induction by transcutaneous vaccination using dissolving microneedle patches in mice.
- Author
-
Hirobe S, Susai R, Takeuchi H, Eguchi R, Ito S, Quan YS, Kamiyama F, and Okada N
- Subjects
- Administration, Cutaneous, Animals, Drug Delivery Systems, Immunization, Mice, Skin, Vaccination
- Abstract
Transcutaneous immunization (TCI) is an appealing vaccination method. Compared with conventional injectable immunization, TCI is easier and less painful. We previously developed a dissolving microneedle (MN) patch and demonstrated that TCI using MN patches demonstrates high vaccination efficacy without adverse events in humans. In this study, we investigated the immune induction mechanism of TCI using our MN patch, focusing on inflammatory responses in the skin and on the dynamics, activation, and differentiation of various immunocompetent cells in draining lymph nodes (dLNs). We demonstrate that inflammatory cytokines such as IL-6 and TNF-α increased in the skin at an early stage after MN patch application, inducing the infiltration of macrophages and neutrophils and promoting the activation and migration of skin-resident antigen-presenting cells (Langerhans and Langerin
- dermal dendritic cells) to dLNs. Moreover, the activated antigen-presenting cells reaching the dLNs enhanced the differentiation of T (Teff , Tem , and Tcm ) and B (plasma and memory) cells. This may contribute to the efficient antigen-specific antibody production induced by TCI using MN patches. We believe that our findings reveal a part of the immune induction mechanism by TCI and provide useful information for the development and improvement of TCI formulations based on the immune induction mechanism., (Copyright © 2021 Elsevier B.V. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
17. Transcutaneous immunization with a highly active form of XCL1 as a vaccine adjuvant using a hydrophilic gel patch elicits long-term CD8 + T cell responses.
- Author
-
Kamei M, Matsuo K, Imanishi H, Hara Y, Quen YS, Kamiyama F, Oiso N, Kawada A, Okada N, and Nakayama T
- Subjects
- Animals, Antigens, CD, Cell Line, Dendritic Cells immunology, Gels, Hydrophobic and Hydrophilic Interactions, Integrin alpha Chains, Mice, Inbred C57BL, Ovalbumin administration & dosage, Ovalbumin immunology, Time Factors, Adjuvants, Immunologic administration & dosage, CD8-Positive T-Lymphocytes immunology, Cancer Vaccines administration & dosage, Chemokines, C administration & dosage, Chemokines, C immunology, Immunization methods, Transdermal Patch
- Abstract
Memory CD8
+ cytotoxic T-lymphocytes (CTLs) play a key role in protective immunity against infection and cancer. However, the induction of memory CTLs with currently available vaccines remains difficult. The chemokine receptor XCR1 is predominantly expressed on CD103+ cross-presenting dendritic cells (DCs). Recently, we have demonstrated that a high activity form of murine lymphotactin/XCL1 (mXCL1-V21C/A59C), a ligand of XCR1, can induce antigen-specific memory CTLs by increasing the accumulation of CD103+ DCs in the vaccination site and the regional lymph nodes. Here, we combined a hydrophilic gel patch as a transcutaneous delivery device and mXCL1-V21C/A59C as an adjuvant to further enhance memory CTL responses. The transcutaneous delivery of ovalbumin (OVA) and mXCL1-V21C/A59C by the hydrophilic gel patch increased CD103+ DCs in the vaccination site and the regional lymph nodes for a prolonged period of time compared with the intradermal injection of OVA and mXCL1-V21C/A59C. Furthermore, the hydrophilic gel patch containing OVA and mXCL1-V21C/A59C strongly induced OVA-specific memory CTLs and efficiently inhibited the growth of OVA-expressing tumors more than the intradermal injection of OVA and mXCL1-V21C/A59C. Collectively, this type of hydrophilic gel patch and a high activity form of XCL1 may provide a useful tool for the induction of memory CTL responses., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
18. Characteristic of K3 (CpG-ODN) as a Transcutaneous Vaccine Formulation Adjuvant.
- Author
-
Ito S, Hirobe S, Kawakita T, Saito M, Quan YS, Kamiyama F, Ishii KJ, Nagao M, Fujisawa T, Tachibana M, and Okada N
- Abstract
Transcutaneous immunization (TCI) is easy to use, minimally invasive, and has excellent efficacy in vaccines against infections. We focused on toll-like receptor (TLR) ligands as applicable adjuvants for transcutaneous formulations and characterized immune responses. TCI was performed using poke-and-patch methods, in which puncture holes are formed with a polyglycolic acid microneedle on the back skin of mice. Various TLR ligands were applied to the puncture holes and covered with an ovalbumin-loaded hydrophilic gel patch. During the screening process, K3 (CpG-oligonucleotide) successfully produced more antigen-specific antibodies than other TLR ligands and induced T helper (Th) 1-type polarization. Transcutaneously administered K3 was detected in draining lymph nodes and was found to promote B cell activation and differentiation, suggesting a direct transcutaneous adjuvant activity on B cells. Furthermore, a human safety test of K3-loaded self-dissolving microneedles (sdMN) was performed. Although a local skin reaction was observed at the sdMN application site, there was no systemic side reaction. In summary, we report a K3-induced Th1-type immune response that is a promising adjuvant for transcutaneous vaccine formulations using MN and show that K3-loaded sdMN can be safely applied to human skin.
- Published
- 2020
- Full Text
- View/download PDF
19. Immunogenicity of Milk Protein-Containing Hydrophilic Gel Patch for Epicutaneous Immunotherapy for Milk Allergy.
- Author
-
Ito S, Hirobe S, Kuwabara Y, Nagao M, Saito M, Quan YS, Kamiyama F, Fujisawa T, and Okada N
- Subjects
- Administration, Cutaneous, Animals, Cattle, Child, Child, Preschool, Disease Models, Animal, Female, Humans, Hydrophobic and Hydrophilic Interactions, Immunoglobulin E analysis, Immunotherapy, Male, Mice, Microinjections, Milk Proteins administration & dosage, Needles, Pilot Projects, Skin metabolism, Treatment Outcome, Acrylic Resins chemistry, Immunoglobulin E immunology, Milk Hypersensitivity immunology, Milk Proteins immunology, Transdermal Patch
- Abstract
Purpose: Epicutaneous immunotherapy (EPIT) involving the skin's immune system is easy to use, painless and has a low risk of systemic side effects; it can be applied to food allergies that have a high morbidity rate in children. In this study, we evaluated the safety and efficacy of hydrophilic gel patch (HG) for EPIT., Methods: Milk protein concentrate (MPC)-containing HG was applied to the skin that maintained a barrier function or formed puncture holes with microneedle, and MPC-specific antibodies were measured. The clinical study was conducted involving patients with severe milk allergy., Results: No specific immune response was induced when immunizing to intact skin, and antibody production was observed by forming puncture holes. It was suggested that MPC contained in HG has immunogenicity and a very small amount of MPC was delivered to intact skin. In the clinical study, the symptom induction threshold increased in four of eight subjects, allowing them to consume milk and switch to oral immunotherapy. Although local skin reactions and temporary elevation of specific IgE antibodies were observed, no systemic side effects appeared throughout the study., Conclusions: EPIT using HG is a safe method to enable oral administration even in patients with severe milk allergies.
- Published
- 2020
- Full Text
- View/download PDF
20. C-H γ,γ,γ-Trifluoroalkylation of Quinolines via Visible-Light-Induced Sequential Radical Additions.
- Author
-
Kumagai Y, Murakami N, Kamiyama F, Tanaka R, Yoshino T, Kojima M, and Matsunaga S
- Abstract
The photocatalyst-free C-H γ,γ,γ-trifluoroalkylation of quinolines under visible light irradiation is reported. By the combination of readily available alkenes and Umemoto's reagent II, a variety of γ,γ,γ-trifluoroalkyl groups were installed into quinolines via chemoselective sequential radical processes. This transformation provides rapid access to a variety of quinoline derivatives with scarcely explored fluoroalkyl groups, affording a novel library of N-heteroaromatic compounds and versatile building blocks for applications in medicinal chemistry.
- Published
- 2019
- Full Text
- View/download PDF
21. A CCR4 antagonist ameliorates atopic dermatitis-like skin lesions induced by dibutyl phthalate and a hydrogel patch containing ovalbumin.
- Author
-
Matsuo K, Hatanaka S, Kimura Y, Hara Y, Nishiwaki K, Quan YS, Kamiyama F, Oiso N, Kawada A, Kabashima K, and Nakayama T
- Subjects
- Animals, Chemokine CCL17 metabolism, Chemokine CCL22 metabolism, Cytokines metabolism, Dermatitis, Atopic metabolism, Eosinophils drug effects, Eosinophils metabolism, Immunoglobulin E metabolism, Mast Cells drug effects, Mast Cells metabolism, Mice, Mice, Inbred BALB C, Skin metabolism, Th2 Cells drug effects, Th2 Cells metabolism, Thymic Stromal Lymphopoietin, Dermatitis, Atopic drug therapy, Dibutyl Phthalate pharmacology, Hydrogels pharmacology, Ovalbumin pharmacology, Receptors, CCR4 antagonists & inhibitors, Skin drug effects
- Abstract
CCR4 is a chemokine receptor highly expressed by Th2 cells, and regarded as a potential therapeutic target for atopic dermatitis (AD). CCL17 and CCL22 are the CCR4 ligands, and thymic stromal lymphopoietin (TSLP) is shown to promote the expression of CCL17 and CCL22 by dendritic cells. Here, by using dibutyl phthalate (DBP), a TSLP inducer, and a hydrogel patch as a transcutaneous delivery device for ovalbumin, we developed a novel murine AD model and investigated the effect of Compound 22, a CCR4 antagonist. We first found that the mRNA expression of TSLP together with CCL17 and CCL22 was increased in the skins treated with DBP. Furthermore, the topical application of ovalbumin and DBP efficiently and rapidly induced AD-like skin lesions in BALB/c mice, which were characterized by ear swelling accompanied by infiltration of eosinophils, mast cells, and CCR4-expressing Th2 cells in the skin lesions, and elevated total IgE levels in the sera. Using this AD model, we demonstrated that cutaneous administration of Compound 22 inhibited Th2 cell infiltration and ameliorated the AD-like skin lesions. These results suggest that our AD model could be useful for studying new therapeutic strategies. Collectively, CCR4 antagonists may be a promising approach for treating AD., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
22. Self-Dissolving Microneedle Arrays for Transdermal Absorption Enhancement of Human Parathyroid Hormone (1-34).
- Author
-
Naito C, Katsumi H, Suzuki T, Quan YS, Kamiyama F, Sakane T, and Yamamoto A
- Abstract
Human parathyroid hormone (1-34) (PTH) has been widely used as the subcutaneous injection formulation for the treatment of osteoporosis. In the present study, we developed an efficient transdermal delivery system of PTH by using dissolving microneedle arrays (MNs) composed of hyaluronic acid (HA) for the treatment of osteoporosis. PTH-loaded MNs, with needle length 800 µm, were fabricated via a micro-molding method. The stability of PTH in MNs was found to be 6-fold higher than that of PTH solution when stored at room temperature (15⁻20 °C) for one month. Micron-scale pores were clearly visible in rat skin following application of PTH-loaded MNs. PTH-loaded MNs were completely dissolved by 60 min following application to rat skin. The bioavailability (BA) of PTH relative to subcutaneous injection was 100 ± 4% following application of PTH-loaded MNs in rats. In addition, PTH-loaded MNs were found to effectively suppress decreases in bone density in a rat model of osteoporosis. Furthermore, no skin irritation was observed at the site of application in rats. These findings indicate that our dissolving MNs have a potential use in formulations for the transdermal delivery of PTH and for the treatment of osteoporosis., Competing Interests: The authors declare no competing financial interest. Y.-s.Q. and F.K. are working in CosMED Pharmaceutical Co., Ltd. since 2001. The fund had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the result.
- Published
- 2018
- Full Text
- View/download PDF
23. CCR4 Is Critically Involved in Skin Allergic Inflammation of BALB/c Mice.
- Author
-
Matsuo K, Nagakubo D, Komori Y, Fujisato S, Takeda N, Kitamatsu M, Nishiwaki K, Quan YS, Kamiyama F, Oiso N, Kawada A, Yoshie O, and Nakayama T
- Subjects
- Animals, Bacterial Toxins administration & dosage, Bacterial Toxins immunology, Dermatitis, Atopic pathology, Disease Models, Animal, Eosinophils immunology, Humans, Mast Cells immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Ovalbumin administration & dosage, Ovalbumin immunology, Receptors, CCR4 antagonists & inhibitors, Receptors, CCR4 genetics, Receptors, CCR4 metabolism, Skin cytology, Skin immunology, Skin pathology, Th17 Cells metabolism, Th2 Cells metabolism, Dermatitis, Atopic immunology, Receptors, CCR4 immunology, Th17 Cells immunology, Th2 Cells immunology
- Abstract
Atopic dermatitis is a chronic inflammatory skin disease involving T-helper (Th) 2 cells, eosinophils, and mast cells. Although CCR4 is a major chemokine receptor expressed on Th2 cells and regarded as a potential therapeutic target for allergic diseases, its role in atopic dermatitis remains unclear. Here, by using a hydrogel patch as a transcutaneous delivery device for ovalbumin (an antigen) and Staphylococcus aureus δ-toxin (a mast cell activator), we efficiently induced acute atopic dermatitis-like skin lesions in BALB/c mice, a strain prone to Th2 responses, which were characterized by increased numbers of eosinophils, mast cells, and CCR4-expressing Th2 cells in the skin lesions; elevated levels of total and ovalbumin-specific IgE in the sera; and increased expression of IL-4, IL-17A, IL-22, CCL17, CCL22, and CCR4 in the skin lesions. Of note, the same model was less efficient in C57BL/6 mice, a strain prone to Th1 responses. Using this atopic dermatitis model in BALB/c mice, we demonstrated that CCR4-deficiency or a CCR4 antagonist ameliorated the allergic responses. Collectively, these results demonstrate that CCR4 plays a pivotal role in skin allergic inflammation of BALB/c mice by recruiting CCR4-expressing Th2 cells and Th17 cells., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
24. Correction: Development of Novel Faster-Dissolving Microneedle Patches for Transcutaneous Vaccine Delivery. Pharmaceutics, 2017, 9(3), 27.
- Author
-
Ono A, Ito S, Sakagami S, Asada H, Saito M, Quan YS, Kamiyama F, Hirobe S, and Okada N
- Abstract
The authors wish to make a change to their published paper [1].[...].
- Published
- 2017
- Full Text
- View/download PDF
25. Development of novel double-decker microneedle patches for transcutaneous vaccine delivery.
- Author
-
Ono A, Azukizawa H, Ito S, Nakamura Y, Asada H, Quan YS, Kamiyama F, Katayama I, Hirobe S, and Okada N
- Subjects
- Administration, Cutaneous, Adult, Animals, Antigens administration & dosage, Antigens immunology, Female, Hemagglutinins, Viral administration & dosage, Hemagglutinins, Viral immunology, Humans, Immunoglobulin G blood, Influenza Vaccines administration & dosage, Influenza Vaccines adverse effects, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Middle Aged, Rats, Wistar, Skin metabolism, Skin Irritancy Tests, Young Adult, Drug Delivery Systems adverse effects, Microinjections adverse effects, Needles adverse effects, Transdermal Patch adverse effects, Vaccination instrumentation
- Abstract
Microneedle (MN) patches have great potential as transcutaneous vaccine delivery devices because MNs can effectively deliver vaccine antigen into the skin through the micropores formed in the stratum corneum by low-invasive and painless skin puncturing. This study aims to develop novel double-decker MN patches which have not only high safety and efficacy but also broad applicability to various vaccine antigens. We developed two types of MN patches (PGA-MN and Nylon-MN) that are made from polyglycolic acid and Nylon-6. In pre-clinical studies, both MN patches could demonstrably deliver antigens into resected human dermal tissue, prolong antigen deposition and increase antigen-specific IgG levels after vaccination compared with conventional injections. We demonstrated both MN patches could be safely applied to human skin because no broken MNs or significant skin irritation were observed after applications in the clinical research. PGA-MN was suggested to be superior to Nylon-MN regarding human skin puncturability based on measurements of transepidermal water loss and needle failure force. A high content of tetravalent influenza hemagglutinin antigens loaded on PGA-MN could stably maintain HA titers at 35°C for 1year. Overall, double-decker MN patches can reliably and safely puncture human skin and are promising as effective transcutaneous vaccine delivery devices., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
26. Efficient Transdermal Delivery of Alendronate, a Nitrogen-Containing Bisphosphonate, Using Tip-Loaded Self-Dissolving Microneedle Arrays for the Treatment of Osteoporosis.
- Author
-
Katsumi H, Tanaka Y, Hitomi K, Liu S, Quan YS, Kamiyama F, Sakane T, and Yamamoto A
- Abstract
To improve the transdermal bioavailability and safety of alendronate (ALN), a nitrogen-containing bisphosphonate, we developed self-dissolving microneedle arrays (MNs), in which ALN is loaded only at the tip portion of micron-scale needles by a dip-coating method (ALN(TIP)-MN). We observed micron-scale pores in rat skin just after application of ALN(TIP)-MN, indicating that transdermal pathways for ALN were created by MN. ALN was rapidly released from the tip of MNs as observed in an in vitro release study. The tip portions of MNs completely dissolved in the rat skin within 5 min after application in vivo. After application of ALN(TIP)-MN in mice, the plasma concentration of ALN rapidly increased, and the bioavailability of ALN was approximately 96%. In addition, the decrease in growth plate was effectively suppressed by this efficient delivery of ALN in a rat model of osteoporosis. Furthermore, no skin irritation was observed after application of ALN(TIP)-MN and subcutaneous injection of ALN, while mild skin irritation was induced by whole-ALN-loaded MN (ALN-MN)-in which ALN is contained in the whole of the micron-scale needles fabricated from hyaluronic acid-and intradermal injection of ALN. These findings indicate that ALN(TIP)-MN is a promising transdermal formulation for the treatment of osteoporosis without skin irritation., Competing Interests: The authors declare no conflict of interest.
- Published
- 2017
- Full Text
- View/download PDF
27. Development of Novel Faster-Dissolving Microneedle Patches for Transcutaneous Vaccine Delivery.
- Author
-
Ono A, Ito S, Sakagami S, Asada H, Saito M, Quan YS, Kamiyama F, Hirobe S, and Okada N
- Abstract
Microneedle (MN) patches are promising for transcutaneous vaccination because they enable vaccine antigens to physically penetrate the stratum corneum via low-invasive skin puncturing, and to be effectively delivered to antigen-presenting cells in the skin. In second-generation MN patches, the dissolving MNs release the loaded vaccine antigen into the skin. To shorten skin application time for clinical practice, this study aims to develop novel faster-dissolving MNs. We designed two types of MNs made from a single thickening agent, carboxymethylcellulose (CMC) or hyaluronan (HN). Both CMC-MN and HN-MN completely dissolved in rat skin after a 5-min application. In pre-clinical studies, both MNs could demonstrably increase antigen-specific IgG levels after vaccination and prolong antigen deposition compared with conventional injections, and deliver antigens into resected human dermal tissue. In clinical research, we demonstrated that both MNs could reliably and safely puncture human skin without any significant skin irritation from transepidermal water loss measurements and ICDRG (International Contact Dermatitis Research Group) evaluation results., Competing Interests: The authors declare no conflict of interest.
- Published
- 2017
- Full Text
- View/download PDF
28. Clinical study of a retinoic acid-loaded microneedle patch for seborrheic keratosis or senile lentigo.
- Author
-
Hirobe S, Otsuka R, Iioka H, Quan YS, Kamiyama F, Asada H, Okada N, and Nakagawa S
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Keratolytic Agents administration & dosage, Keratolytic Agents adverse effects, Keratosis, Seborrheic pathology, Lentigo pathology, Male, Middle Aged, Needles, Skin metabolism, Skin pathology, Tretinoin administration & dosage, Tretinoin adverse effects, Keratolytic Agents therapeutic use, Keratosis, Seborrheic drug therapy, Lentigo drug therapy, Skin drug effects, Transdermal Patch adverse effects, Tretinoin therapeutic use
- Abstract
Aims: Pigmented lesions such as of seborrheic keratosis and senile lentigo, which are commonly seen on skin of people>50years of age, are considered unattractive and disfiguring because of their negative psychological impact. Drug therapy using all-trans retinoic acid (ATRA) is an attractive option for self-treatment at home. We have developed an ATRA-loaded microneedle patch (ATRA-MN) and confirmed the pharmacological effects of ATRA-MN application in mice. Here, we describe a clinical study to evaluate the safety and efficacy of ATRA-MN in subjects with seborrheic keratosis or senile lentigo., Main Methods: ATRA-MN was applied to the lesion site of each subject for 6h once per week for 4weeks. The skin irritation reaction was scored to assess adverse reactions and blood tests were performed to evaluate the presence of systemic adverse reactions. To assess the treatment effect using ATRA-MN, the desquamation and whitening ability of the investigational skin was observed., Key Findings: Desquamation of the stratum corneum was observed following four ATRA-MN applications at 1-week intervals, but ATRA-MN applications did not induce severe local or systemic adverse effects., Significance: These results showed that ATRA-MN treatment is promising as a safe and effective therapy for seborrheic keratosis and senile lentigo., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
29. Permeation of sumatriptan succinate across human skin using multiple types of self-dissolving microneedle arrays fabricated from sodium hyaluronate.
- Author
-
Wu D, Katsumi H, Quan YS, Kamiyama F, Kusamori K, Sakane T, and Yamamoto A
- Subjects
- Animals, Drug Delivery Systems instrumentation, Equipment Design, Humans, In Vitro Techniques, Male, Permeability, Rats, Wistar, Serotonin 5-HT1 Receptor Agonists pharmacokinetics, Skin Absorption, Skin Irritancy Tests, Solubility, Sumatriptan pharmacokinetics, Drug Delivery Systems methods, Hyaluronic Acid chemistry, Needles, Serotonin 5-HT1 Receptor Agonists administration & dosage, Skin metabolism, Sumatriptan administration & dosage
- Abstract
Available formulations of sumatriptan succinate (SS) have low bioavailability or are associated with site reactions. We developed various types of self-dissolving microneedle arrays (MNs) fabricated from sodium hyaluronate as a new delivery system for SS and evaluated their skin permeation and irritation in terms of clinical application. In vitro permeation studies with human skin, physicochemical properties (needle length, thickness and density), and penetration enhancers (glycerin, sodium dodecyl sulfate and lauric acid diethanolamide) were investigated. SS-loaded high-density MNs of 800 µm in length were the optimal formulation and met clinical therapeutic requirements. Penetration enhancers did not significantly affect permeation of SS from MNs. Optical coherence tomography images demonstrated that SS-loaded high-density MNs (800 µm) uniformly created drug permeation pathways for the delivery of SS into the skin. SS-loaded high-density MNs induced moderate primary skin irritations in rats, but the skin recovered within 72 h of removal of the MNs. These findings suggest that high-density MNs of 800 µm in length are an effective and promising formulation for transdermal delivery of SS. To our knowledge, this is the first report of SS permeation across human skin using self-dissolving MNs.
- Published
- 2016
- Full Text
- View/download PDF
30. Development of a drug-coated microneedle array and its application for transdermal delivery of interferon alpha.
- Author
-
Kusamori K, Katsumi H, Sakai R, Hayashi R, Hirai Y, Tanaka Y, Hitomi K, Quan YS, Kamiyama F, Yamada K, Sumida S, Kishi K, Hashiba K, Sakane T, and Yamamoto A
- Subjects
- Administration, Cutaneous, Animals, Equipment Design, Equipment Failure Analysis, Injections, Subcutaneous adverse effects, Male, Microinjections adverse effects, Miniaturization, Pain etiology, Rats, Rats, Wistar, Coated Materials, Biocompatible administration & dosage, Injections, Subcutaneous instrumentation, Interferon-alpha administration & dosage, Microinjections instrumentation, Needles, Pain prevention & control
- Abstract
Interferon alpha (IFNα) is one of the most famous drugs for the treatment of chronic hepatitis C and various types of human malignancy. Protein drugs, including IFNα, are generally administered by subcutaneous or intramuscular injection due to their poor permeability and low stability in the bloodstream or gastrointestinal tract. Therefore, in the present study, novel IFNα-coated polyvinyl alcohol-based microneedle arrays (IFNα-MNs) were fabricated for the transdermal delivery of IFNα without the painful injection. IFNα was rapidly released from MNs in phosphate buffered solution and these MNs presented piercing ability in the rat skin. Slight erythema and irritation were observed when MNs were applied to the rat skin, but these skin damages completely disappeared within 24 h after removing the IFNα-MNs. Furthermore, the pharmacokinetic parameters of IFNα-MNs were similar to those of IFNα subcutaneous administration. Finally, IFNα-MNs showed a significant antitumor effect in tumor bearing mice similar to that of IFNα subcutaneous administration. These results indicate that IFNα-MNs are a useful biomaterial tool for protein drug therapy and can improve the quality of life in patients by avoidance of painful injections.
- Published
- 2016
- Full Text
- View/download PDF
31. Improvement of Transdermal Delivery of Exendin-4 Using Novel Tip-Loaded Microneedle Arrays Fabricated from Hyaluronic Acid.
- Author
-
Liu S, Wu D, Quan YS, Kamiyama F, Kusamori K, Katsumi H, Sakane T, and Yamamoto A
- Subjects
- Animals, Exenatide, Male, Rats, Rats, Wistar, Skin Absorption, Administration, Cutaneous, Hyaluronic Acid chemistry, Peptides administration & dosage, Peptides chemistry, Venoms administration & dosage, Venoms chemistry
- Abstract
The purpose of this study was to evaluate the characteristics of exendin-4 tip-loaded microneedle arrays and to compare their acute efficacy with subcutaneous injections in type 2 diabetic GK/Slc rats. Fluorescein isothiocyanate labeled dextran with an average molecular weight of 4,000 (FD4) was selected as a model drug, and FD4 tip-loaded microneedle arrays were prepared in this study. In addition, intraperitoneal glucose tolerance tests after application of exendin-4 tip-loaded microneedle arrays were also compared with those after subcutaneous injection in type 2 diabetic GK/Slc rats. The release of FD4 from the tip-loaded microneedle arrays was very rapid, particularly in the initial 30 s, and most of the FD4 was released within 5 min. In addition, glucose tolerance was improved and the insulin secretion was enhanced after application of exendin-4 tip-loaded microneedle arrays, and these effects were comparable to those after subcutaneous injection of exendin-4. Similar plasma concentration profiles were seen after application of exendin-4 tip-loaded microneedle arrays, as was the case with subcutaneous injection in type 2 diabetic GK/Slc rats. These findings indicate that exendin-4 tip-loaded microneedle arrays can be used as an alternative to achieve sufficient delivery of exendin-4 for treatment of type 2 diabetes. To our knowledge, this is the first report of transdermal exendin-4 delivery using tip-loaded microneedle arrays.
- Published
- 2016
- Full Text
- View/download PDF
32. Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch.
- Author
-
Hirobe S, Azukizawa H, Hanafusa T, Matsuo K, Quan YS, Kamiyama F, Katayama I, Okada N, and Nakagawa S
- Subjects
- Administration, Cutaneous, Adult, Animals, Antibody Formation, Chickens, Hemagglutinins administration & dosage, Hemagglutinins adverse effects, Hemagglutinins immunology, Humans, Immunization adverse effects, Immunization instrumentation, Influenza Vaccines adverse effects, Influenza Vaccines immunology, Influenza, Human immunology, Male, Middle Aged, Solubility, Young Adult, Hyaluronic Acid chemistry, Influenza A Virus, H1N1 Subtype immunology, Influenza A Virus, H3N2 Subtype immunology, Influenza A virus immunology, Influenza Vaccines administration & dosage, Influenza, Human prevention & control, Transdermal Patch adverse effects
- Abstract
Transcutaneous immunization (TCI) is an attractive vaccination method compared with conventional injectable vaccines because it is easier to administer without pain. We developed a dissolving microneedle patch (MicroHyala, MH) made of hyaluronic acid and showed that transcutaneous vaccination using MH induced a strong immune response against various antigens in mice. In the present study, we investigated the clinical safety and efficacy of a novel transcutaneous influenza vaccine using MH (flu-MH), which contains trivalent influenza hemagglutinins (15 μg each). Subjects of the TCI group were treated transcutaneously with flu-MH, and were compared with subjects who received subcutaneous injections of a solution containing 15 μg of each influenza antigen (SCI group). No severe local or systemic adverse events were detected in either group and immune responses against A/H1N1 and A/H3N2 strains were induced equally in the TCI and SCI groups. Moreover, the efficacy of the vaccine against the B strain in the TCI group was stronger than that in the SCI group. Influenza vaccination using MH is promising for practical use as an easy and effective method to replace conventional injections systems., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
33. Improvement of transdermal delivery of sumatriptan succinate using a novel self-dissolving microneedle array fabricated from sodium hyaluronate in rats.
- Author
-
Wu D, Quan YS, Kamiyama F, Kusamori K, Katsumi H, Sakane T, and Yamamoto A
- Subjects
- Administration, Cutaneous, Animals, Biological Availability, Chemistry, Pharmaceutical, Humans, Male, Migraine Disorders drug therapy, Rats, Wistar, Skin metabolism, Solubility, Sumatriptan blood, Sumatriptan therapeutic use, Drug Carriers, Drug Liberation, Hyaluronic Acid metabolism, Microinjections, Needles, Skin Absorption, Sumatriptan administration & dosage
- Abstract
The purpose of the present study was to develop an alternative transdermal formulation containing sumatriptan succinate (SS) for the treatment of migraine. Novel self-dissolving SS-loaded microneedle arrays (MNs) were fabricated from sodium hyaluronate and their efficacy for transdermal delivery of SS was characterized. The resulting MNs maintained their skin piercing abilities for at least 30 min after being placed at a high relative humidity of 75%. Rapid release of SS from the MNs was also observed in vitro. Optical coherence tomography images demonstrated that MNs were able to successfully pierce into rat skin without any bending or cracking, and needles were completely dissolved within 1 h. MNs significantly increased transepidermal water loss; however, skin barrier function gradually recovered to control levels within 24 h, in contrast to the skin damage observed after tape stripping treatment. These findings indicated that the micropores created by MNs quickly resealed, and that the skin damage was reversible. Furthermore, a dose-dependent plasma concentration of SS was obtained after transdermal delivery using SS-loaded MNs in rats. Absorption of SS delivered by MNs was similar to that observed after subcutaneous injection and was associated with high bioavailability (ca. 90%), which was much higher than that produced by oral administration. These findings suggested that application of SS-loaded MNs to the skin provided an effective alternative approach to enhance the transdermal delivery of SS without serious skin damage, and would be likely to improve patient compliance.
- Published
- 2015
- Full Text
- View/download PDF
34. Transdermal delivery of relatively high molecular weight drugs using novel self-dissolving microneedle arrays fabricated from hyaluronic acid and their characteristics and safety after application to the skin.
- Author
-
Liu S, Jin MN, Quan YS, Kamiyama F, Kusamori K, Katsumi H, Sakane T, and Yamamoto A
- Subjects
- Administration, Cutaneous, Animals, Dextrans administration & dosage, Dextrans chemistry, Drug Delivery Systems methods, Fluorescein-5-isothiocyanate administration & dosage, Fluorescein-5-isothiocyanate analogs & derivatives, Fluorescein-5-isothiocyanate chemistry, Humans, Microinjections methods, Molecular Weight, Needles, Permeability, Rats, Safety, Skin Absorption, Hyaluronic Acid administration & dosage, Hyaluronic Acid chemistry, Pharmaceutical Preparations administration & dosage, Pharmaceutical Preparations chemistry, Skin metabolism
- Abstract
The purpose of this study was to develop novel dissolving microneedle arrays fabricated from hyaluronic acid (HA) as a material and to improve the transdermal permeability of relatively high molecular weight drugs. In this study, fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4kDa (FD4) was used as a model drug with a relatively high molecular weight. The microneedle arrays significantly increased transepidermal water loss (TEWL) and reduced transcutaneous electrical resistance (TER), indicating that they could puncture the skin and create drug permeation pathways successfully. Both TEWL and TER almost recovered to baseline levels in the microneedle array group, and relatively small pathways created by the microneedles rapidly recovered as compared with those created by a tape stripping treatment. These findings confirmed that the microneedle arrays were quite safe. Furthermore, we found that the transdermal permeability of FD4 using the microneedle arrays was much higher than that of the FD4 solution. Furthermore, we found that the microneedle arrays were much more effective for increasing the amount of FD4 accumulated in the skin. These findings indicated that using novel microneedle arrays fabricated from HA is a very useful and effective strategy to improve the transdermal delivery of drugs, especially relatively high molecular weight drugs without seriously damaging the skin., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
35. Vaccine efficacy of transcutaneous immunization with amyloid β using a dissolving microneedle array in a mouse model of Alzheimer's disease.
- Author
-
Matsuo K, Okamoto H, Kawai Y, Quan YS, Kamiyama F, Hirobe S, Okada N, and Nakagawa S
- Subjects
- Administration, Cutaneous, Alzheimer Disease blood, Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid beta-Peptides blood, Amyloid beta-Protein Precursor genetics, Animals, Brain metabolism, Disease Models, Animal, Escape Reaction physiology, Exploratory Behavior physiology, Humans, Immunoglobulin G blood, Maze Learning physiology, Mice, Mice, Transgenic, Mutation genetics, Peptide Fragments blood, Presenilin-1 genetics, Reaction Time physiology, Time Factors, Alzheimer Disease therapy, Amyloid beta-Peptides immunology, Immunotherapy, Active methods, Peptide Fragments immunology
- Abstract
Vaccine therapy for Alzheimer's disease (AD) based on the amyloid cascade hypothesis has recently attracted attention for treating AD. Injectable immunization using amyloid β peptide (Aβ) comprising 1-42 amino-acid residues (Aβ1-42) as antigens showed therapeutic efficacy in mice; however, the clinical trial of this injected Aβ1-42 vaccine was stopped due to the incidence of meningoencephalitis caused by excess activation of Th1 cells infiltrating the brain as a serious adverse reaction. Because recent studies have suggested that transcutaneous immunization (TCI) is likely to elicit Th2-dominant immune responses, TCI is expected to be effective in treating AD without inducing adverse reactions. Previously reported TCI procedures employed complicated and impractical vaccination procedures; therefore, a simple, easy-to-use, and novel TCI approach needs to be established. In this study, we investigated the vaccine efficacy of an Aβ1-42-containing TCI using our novel dissolving microneedle array (MicroHyala; MH) against AD. MH-based TCI induced anti-Aβ1-42 immune responses by simple and low-invasive application of Aβ1-42-containing MH to the skin. Unfortunately, this TCI system resulted in little significant improvement in cognitive function and Th2-dominant immune responses, suggesting the need for further modification., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
36. [Development of a novel transdermal delivery system of peptide and protein drugs using microneedle arrays].
- Author
-
Katsumi H, Quan YS, Kamiyama F, Kusamori K, Sakane T, and Yamamoto A
- Subjects
- Administration, Cutaneous, Animals, Drug Design, Humans, Microarray Analysis instrumentation, Needles, Microarray Analysis methods, Peptides metabolism, Proteins metabolism
- Abstract
Transdermal delivery of peptide and protein drugs may be limited by the stratum corneum, which is a protective barrier against the entry of microorganisms and water. Many approaches have been utilized to promote peptide and protein drugs delivery across the stratum corneum, including chemical enhancer modification and physical disruption of barrier function. However, it has been difficult to achieve therapeutic levels of peptide and protein drugs via this route without any skin irritation. Recently, attention has been paid to the possibility of using microneedle arrays in delivering peptide and protein drugs into the skin. As a novel and minimally invasive approach, microneedle arrays are capable of creating superficial pathways across the skin for peptide and protein drugs to achieve enhanced transdermal drug delivery. This method combines the efficacy of conventional injection needles with the convenience of transdermal patches, while minimizing the disadvantages of these administration methods. Therefore, microneedle arrays are a very useful alternative method for delivering peptide and protein drugs from the skin into the systemic circulation without any serious damage to skin. In this review, recent challenges in the developments of microneedle arrays for the delivery of peptide and protein drugs are summarized. Then, future developments of microneedle arrays for the delivery of peptide and protein drugs are also discussed in order to improve their therapeutic efficacy and safety.
- Published
- 2014
- Full Text
- View/download PDF
37. Development of a novel therapeutic approach using a retinoic acid-loaded microneedle patch for seborrheic keratosis treatment and safety study in humans.
- Author
-
Hiraishi Y, Hirobe S, Iioka H, Quan YS, Kamiyama F, Asada H, Okada N, and Nakagawa S
- Subjects
- Adult, Animals, Collagen metabolism, Cytokines genetics, Dermatologic Agents adverse effects, Female, Heparin-binding EGF-like Growth Factor, Humans, Hyperplasia chemically induced, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Keratosis, Seborrheic drug therapy, Male, Mice, Mice, Hairless, Microinjections, Middle Aged, Needles, RNA, Messenger metabolism, Receptors, Retinoic Acid genetics, Skin drug effects, Skin metabolism, Skin Irritancy Tests, Transdermal Patch, Tretinoin adverse effects, Dermatologic Agents administration & dosage, Drug Delivery Systems, Tretinoin administration & dosage
- Abstract
Seborrheic keratosis is one of the most common skin benign tumors in humans with a high occurrence rate of 80%-100% in people > 50 years of age; however, its pathogenesis is still unclear. The standard treatment includes cryotherapy and laser surgery for physically removing lesions. Drug therapy for this condition has not been well established. We aimed to evaluate the use of all-trans retinoic acid (ATRA)-loaded microneedle (MN) patches as a simple, alternative therapeutic option to traditional surgical treatments. This therapeutic strategy was designed to induce the proliferation of basal keratinocytes and accelerate stratum corneum turnover, leading to the lesion falling off the surface of the skin. The MN patch induced epidermal hyperplasia and marked expression of heparin-binding epidermal growth factor-like growth factor mRNA and protein corresponding to ATRA activity in the skin of HR-1 hairless mice. The acceleration of stratum corneum turnover was also observed by the dansyl chloride method. The skin irritation study in mice and safety study in humans support the safety findings of our study. Overall, MN patches can offer an effective and safe means of ATRA delivery into the skin, and the ATRA-loaded MN patch appears to be an effective pharmaceutical product providing a novel therapeutic option for seborrheic keratosis., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
38. Development and clinical study of a self-dissolving microneedle patch for transcutaneous immunization device.
- Author
-
Hirobe S, Azukizawa H, Matsuo K, Zhai Y, Quan YS, Kamiyama F, Suzuki H, Katayama I, Okada N, and Nakagawa S
- Subjects
- Adult, Animals, Diphtheria Toxoid administration & dosage, Drug Delivery Systems methods, Electric Impedance, Equipment Design, Female, Guinea Pigs, Humans, Immunoglobulin G blood, Male, Mice, Mice, Inbred BALB C, Middle Aged, Rats, Rats, Wistar, Skin metabolism, Skin pathology, Skin Irritancy Tests, Tetanus Toxoid administration & dosage, Vaccination methods, Drug Delivery Systems instrumentation, Skin immunology, Transdermal Patch adverse effects, Vaccination instrumentation
- Abstract
Purpose: We previously reported the safety and efficacy in animal experiments of transcutaneous immunization (TCI) using a self-dissolving microneedle patch (MicroHyala; MH) made of hyaluronic acid and collagen. However, this MH was an unsuitable TCI device for the human skin, as collagen is suspected to induce inflammation. In this study, we developed an improved collagen-free MH (new-MH) and conducted clinical study to evaluate the fundamental properties and safety in human., Methods: Microneedle dissolution, skin irritation, and antigen-specific antibody production about new-MH were measured in mice and/or rats. On the basis of the results, the clinical study was conducted in healthy volunteers to evaluate local and systemic adverse events caused by new-MH application., Results: We confirmed that the microneedles of new-MH, as well as those on our old-MH that contained collagen, could easily pierce stratum corneum without severe skin irritation, and that TCI using new-MH efficiently increased antibody titer with comparable to TCI using old-MH. Application of new-MH caused no severe adverse reactions in 20 healthy volunteers enrolled in a clinical study., Conclusions: These results verified that new-MH is a safe TCI device in human, and greatly encouraged us to advance PI/PII clinical studies of antigen-loaded new-MH.
- Published
- 2013
- Full Text
- View/download PDF
39. Analysis of transcutaneous antigenic protein delivery by a hydrogel patch formulation.
- Author
-
Matsuo K, Ishii Y, Kawai Y, Saiba Y, Quan YS, Kamiyama F, Hirobe S, Okada N, and Nakagawa S
- Subjects
- Administration, Cutaneous, Animals, Antigens immunology, Antigens metabolism, Female, Humans, Immunity, Active, Mice, Mice, Inbred BALB C, Vaccination, Vaccines immunology, Vaccines pharmacokinetics, Antigens administration & dosage, Hydrogel, Polyethylene Glycol Dimethacrylate chemistry, Skin metabolism, Transdermal Patch, Vaccines administration & dosage
- Abstract
We have developed a hydrogel patch, which could promote antigen penetration through stratum corneum (SC), and have demonstrated its safety and efficacy in animals and humans. For the availability improvement of our system, it is important to develop a device, which enhances antigen penetration through SC more efficiently. In this study, we have tried to collect the basic information involved in transcutaneous antigen delivery by investigating the immune event induced by our system and examining the effect of physical property of antigens or patch component on antigen penetration. A hydrogel patch delivered antigens through SC into skin, and some of Langerhans cells captured antigens, activated, and migrated to regional lymph nodes. We also showed that protein distribution into SC was regulated by various complexly-intertwined factors of proteins but not one particular parameter. Additionally, glycerin as the patch component contributed to the formation of SC hydration by patch application, which might be one of the factors of acceleration of protein penetration. On the basis of the present information, we are planning to modify the patch composition and establish the antigen modification technology for improvement in the efficacy of transcutaneous immunization., (Copyright © 2013 Wiley Periodicals, Inc.)
- Published
- 2013
- Full Text
- View/download PDF
40. Performance and characteristics evaluation of a sodium hyaluronate-based microneedle patch for a transcutaneous drug delivery system.
- Author
-
Hiraishi Y, Nakagawa T, Quan YS, Kamiyama F, Hirobe S, Okada N, and Nakagawa S
- Subjects
- Administration, Cutaneous, Animals, Diphtheria Toxoid administration & dosage, Diphtheria Toxoid chemistry, Drug Combinations, Drug Stability, Drug Storage, Female, Fluorescein-5-isothiocyanate chemistry, Fluorescent Dyes chemistry, Humidity, Mice, Mice, Hairless, Mice, Inbred ICR, Microinjections, Needles, Ovalbumin chemistry, Rats, Rats, Wistar, Tetanus Toxoid administration & dosage, Tetanus Toxoid chemistry, Time Factors, Transdermal Patch, Tretinoin chemistry, Drug Delivery Systems, Hyaluronic Acid chemistry, Ovalbumin administration & dosage, Tretinoin administration & dosage
- Abstract
The MicroHyala(®) microneedle (MN) patch was developed to provide a simple, safe, and effective drug delivery system. In this study, we examined the performance and characteristics of our fabricated MN patch to identify potential quality issues with future commercial application. Mechanical failure force analysis identified that the strength of the MN patch was affected by environmental humidity, because higher moisture levels weakened the strength of the MN. Incorporation of all-trans retinoic acid (ATRA) or ovalbumin (OVA) into the MN patch decreased the mechanical failure force by almost 50% of the strength of placebo (without drug) patches. ATRA-loaded MN patches displayed good stability after storage at 4 °C, with more than 90% and 85% of the drug remaining in the patch after 8 and 24 weeks of storage, respectively. Tetanus toxoid- and diphtheria toxoid-loaded MN patches stored for 12 months induced robust antigen-specific immune responses similar to the responses by freshly prepared MN patches. Fluorescence imaging findings suggested that prolonged antigen deposition was induced by MN-mediated fluorescein isothiocyanate-labeled (FITC)-OVA vaccination. Overall, although the strength of MN requires improvement, our developed MN patch appears to be an effective pharmaceutical product providing a simple, safe, and relatively painless approach., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
41. Development of a novel self-dissolving microneedle array of alendronate, a nitrogen-containing bisphosphonate: evaluation of transdermal absorption, safety, and pharmacological effects after application in rats.
- Author
-
Katsumi H, Liu S, Tanaka Y, Hitomi K, Hayashi R, Hirai Y, Kusamori K, Quan YS, Kamiyama F, Sakane T, and Yamamoto A
- Subjects
- Administration, Cutaneous, Alendronate chemistry, Alendronate pharmacokinetics, Alendronate toxicity, Animals, Biological Availability, Bone Density Conservation Agents chemistry, Bone Density Conservation Agents pharmacokinetics, Bone Density Conservation Agents toxicity, Chemistry, Pharmaceutical, Disease Models, Animal, Dosage Forms, Female, Growth Plate pathology, Male, Miniaturization, Needles, Osteoporosis etiology, Osteoporosis pathology, Ovariectomy, Permeability, Rats, Rats, Sprague-Dawley, Rats, Wistar, Skin drug effects, Skin pathology, Solubility, Technology, Pharmaceutical methods, Alendronate administration & dosage, Bone Density Conservation Agents administration & dosage, Drug Delivery Systems instrumentation, Growth Plate drug effects, Hyaluronic Acid chemistry, Osteoporosis drug therapy, Skin metabolism, Skin Absorption
- Abstract
Alendronate is a nitrogen-containing bisphosphonate that is widely used for the treatment of osteoporosis. In this study, we developed a novel self-dissolving micron-size needle array (microneedle array) containing alendronate, which was fabricated by micromodeling technologies using hyaluronic acid as a basic material. Micron-scale pores in the skin were seen after the application of the alendronate-loaded microneedle array, verifying establishment of transdermal pathways for alendronate. The absorption of alendronate after the application of alendronate-loaded microneedle array was almost equivalent to that after subcutaneous administration, and the bioavailability of alendronate was approximately 90% in rats. Furthermore, delivery of alendronate via this strategy effectively suppressed the decrease in the width of the growth plate in a rat model of osteoporosis. Although mild cutaneous irritation was observed after the application of the alendronate-loaded microneedle array, it resolved by day 15. These findings indicate that this alendronate-loaded microneedle array is a promising transdermal formulation for the treatment of osteoporosis., (Copyright © 2012 Wiley Periodicals, Inc.)
- Published
- 2012
- Full Text
- View/download PDF
42. The development and characteristics of novel microneedle arrays fabricated from hyaluronic acid, and their application in the transdermal delivery of insulin.
- Author
-
Liu S, Jin MN, Quan YS, Kamiyama F, Katsumi H, Sakane T, and Yamamoto A
- Subjects
- Administration, Cutaneous, Animals, Blood Glucose analysis, Diabetes Mellitus, Experimental blood, Hyaluronic Acid chemistry, Hypoglycemic Agents blood, Hypoglycemic Agents pharmacokinetics, Insulin blood, Insulin pharmacokinetics, Male, Rats, Rats, Wistar, Diabetes Mellitus, Experimental drug therapy, Drug Delivery Systems, Hypoglycemic Agents administration & dosage, Insulin administration & dosage, Needles
- Abstract
The aim of the present study was to develop novel insulin-loaded microneedle arrays (MNs) fabricated from hyaluronic acid (HA), and characterize their applicability in the transdermal delivery of insulin. The shape of MNs was observed via scanning electron microscopy. The characteristics of these novel insulin-loaded MNs, including hygroscopy, stability, drug release profiles, and dissolution properties, were evaluated from a clinical application point-of-view. Transepidermal water loss (TEWL) was measured to investigate the piercing properties of MNs, and the recovery of the skin barrier after the removal of MNs to confirm their safety. Additionally, the transdermal absorption of insulin from MNs was examined via an in vivo absorption study in diabetic rats. The length of MNs was 800 μm with a base diameter of 160 μm and a tip diameter of 40 μm. MNs were found to maintain their skin piercing abilities for at least 1h, even at a relative humidity of 75%. After storing insulin-loaded MNs for a month at -40, 4, 20, and 40 °C, more than 90% of insulin remained in MNs at all temperatures, indicating that insulin is highly stable in MNs at these storage conditions. It was also found that insulin is rapidly released from MNs via an in vitro release study. These findings were consistent with the complete dissolution of MNs within 1h of application to rat skin in vivo. Therefore, the novel HA MNs possess self-dissolving properties after their dermal application, and insulin appears to be rapidly released from these MNs. A significant increase in TEWL was observed after the application of MNs. However, this parameter recovered back to baseline within 24h after the removal of MNs. These findings indicate that the transdermal transport pathway of insulin, which was created by the MNs, disappeared within 24h, and that the skin damage induced by the MNs was reversible. Furthermore, a dose-dependent hypoglycemic effect and transdermal delivery of insulin were observed after a dermal treatment with insulin-loaded MNs in vivo. A continuous hypoglycemic effect was observed after 0.25 IU of insulin was administered to skin via MNs. Additionally, lower peak plasma insulin levels, but higher plasma insulin concentrations after 2 h, were achieved with 0.25 IU of insulin administered via MNs as compared to the subcutaneous administration of insulin of the same dose. Pharmacodynamic and pharmacokinetic parameters indicated that insulin administered via MNs was almost completely absorbed from the skin into the systemic circulation, and that the hypoglycemic effect of insulin-loaded MNs was almost similar to that of the subcutaneous injection of insulin. These findings indicate that the novel insulin-loaded MNs fabricated from HA are a very useful alternative method of delivering insulin via the skin into the systemic circulation without inducing serious skin damage. Therefore, HA MNs may be an effective and safe method of transdermal insulin delivery in the clinic., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
43. A low-invasive and effective transcutaneous immunization system using a novel dissolving microneedle array for soluble and particulate antigens.
- Author
-
Matsuo K, Yokota Y, Zhai Y, Quan YS, Kamiyama F, Mukai Y, Okada N, and Nakagawa S
- Subjects
- Adenoviridae immunology, Adenoviridae Infections prevention & control, Administration, Cutaneous, Animals, Antigens immunology, Cell Line, Female, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Ovalbumin immunology, Rats, Rats, Wistar, Transdermal Patch, Antigens administration & dosage, Drug Delivery Systems instrumentation, Hyaluronic Acid chemistry, Skin metabolism, Vaccination instrumentation
- Abstract
Transcutaneous immunization (TCI) is a promising needle-free, easy-to-use, and low-invasive vaccination method. The hydrogel patch-based TCI system induced immune responses against soluble antigens (Ags) like toxoids, but could not induce immune responses against particulate Ags. Here, as an effective TCI system against every form of Ag, we developed a dissolving microneedle array of three lengths (200, 300, or 800 μm) made of hyaluronate as a novel TCI device. Unlike conventional microneedles, the microneedles of our dissolving microneedle arrays dissolved in the skin after insertion. Each dissolving microneedle array effectively delivered both soluble and particulate Ags under the stratum corneum. TCI using these dissolving microneedle arrays induced effective immune responses in rats regardless of the Ag form that were comparable to conventional vaccination using subcutaneous immunization. In addition, application of these dissolving microneedle arrays caused only slight skin irritation. These findings suggest that our TCI system can simply, safely, and effectively improve protective immune responses for every vaccine Ag., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
44. Transcutaneous immunization using a dissolving microneedle array protects against tetanus, diphtheria, malaria, and influenza.
- Author
-
Matsuo K, Hirobe S, Yokota Y, Ayabe Y, Seto M, Quan YS, Kamiyama F, Tougan T, Horii T, Mukai Y, Okada N, and Nakagawa S
- Subjects
- Administration, Cutaneous, Animals, Antigens, Protozoan administration & dosage, Diphtheria Toxin administration & dosage, Female, Hemagglutinin Glycoproteins, Influenza Virus administration & dosage, Immunization methods, Mice, Mice, Inbred BALB C, Mice, Inbred ICR, Rats, Rats, Hairless, Tetanus Toxin administration & dosage, Diphtheria Toxoid administration & dosage, Immunization instrumentation, Influenza Vaccines administration & dosage, Malaria Vaccines administration & dosage, Needles, Tetanus Toxoid administration & dosage
- Abstract
Transcutaneous immunization (TCI) is an attractive alternative vaccination route compared to the commonly used injection systems. We previously developed a dissolving microneedle array for use as a TCI device, and reported that TCI with the dissolving microneedle array induced an immune response against model antigens. In the present study, we investigated the vaccination efficacy against tetanus and diphtheria, malaria, and influenza using this vaccination system. Our TCI system induced substantial increases in toxoid-specific IgG levels and toxin-neutralizing antibody titer and induced the production of anti-SE36 IgG, which could bind to malaria parasite. On influenza HA vaccination, robust antibody production was elicited in mice that provided complete protection against a subsequent influenza virus challenge. These findings demonstrate that TCI using a dissolving microneedle array can elicit large immune responses against infectious diseases. Based on these results, we are now preparing translational research for human clinical trials., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
45. Clinical study of transcutaneous vaccination using a hydrogel patch for tetanus and diphtheria.
- Author
-
Hirobe S, Matsuo K, Quan YS, Kamiyama F, Morito H, Asada H, Takaya Y, Mukai Y, Okada N, and Nakagawa S
- Subjects
- Adult, Aged, Animals, Antibodies, Bacterial blood, Diphtheria prevention & control, Female, Humans, Hydrogels pharmacology, Immunoglobulin G blood, Male, Mice, Middle Aged, Skin immunology, Tetanus prevention & control, Young Adult, Diphtheria Toxoid administration & dosage, Hydrogels administration & dosage, Tetanus Toxoid administration & dosage, Transdermal Patch adverse effects, Vaccination methods
- Abstract
Transcutaneous immunization (TCI) is a non-invasive and easy-to-use vaccination method. We demonstrated the efficacy and safety of a transcutaneous vaccine formulation using a hydrogel patch in animal experiments. In the present study, we performed a clinical study to apply our TCI formulation for vaccination against tetanus and diphtheria in human. The TCI device was a hydrogel patch (antigen-free) applied to the left brachial medial skin of 22 healthy volunteers for 48 h. Next, the hydrogel patch, containing 2mg tetanus toxoid (TT) and 2mg diphtheria toxoid (DT) as the TCI formulation, was applied to 27 healthy volunteers for 24h and some volunteers were vaccinated again by TCI formulation. For safety assessment, the patch application site was observed to assess local adverse events, and systemic adverse events were determined by a blood test. The antigen-free hydrogel patch and TCI formulation containing TT and DT did not induce local or systemic severe adverse events. For vaccine efficacy estimation, toxoid-specific serum antibody titers were determined by ELISA and the toxin-neutralizing activity of the induced antibody was evaluated in a passive-challenge experiment. The anti-TT IgG titer and the anti-DT IgG titer increased, and a significant effect was detected by paired t-test. The antibody titers were maintained at higher level than that before vaccination for at least 1 year. Moreover, toxoid-specific antibodies were produced by the second vaccination in some subjects. Antibodies induced by application of the TCI formulation neutralized the toxin and prevented toxic death in mice. In addition, changes in the skin condition due to application of the TCI formulation were observed under in vivo confocal Raman spectroscopy. The amount of water and patch components in the stratum corneum increased after application of the TCI formulation, suggesting that the change in the skin condition was related to antigen penetration. These data indicate that this easy-to-use TCI system induces an immune response without severe adverse reactions in humans. This easy-to-use and safe TCI formulation enables mass treatment in an outbreak setting and increased vaccination rates in developing countries, and will greatly contribute to worldwide countermeasures against infectious diseases., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
46. Transcutaneous vaccination using a hydrogel patch induces effective immune responses to tetanus and diphtheria toxoid in hairless rat.
- Author
-
Matsuo K, Ishii Y, Quan YS, Kamiyama F, Mukai Y, Yoshioka Y, Okada N, and Nakagawa S
- Subjects
- Animals, Chemistry, Pharmaceutical, Diphtheria Toxin immunology, Enzyme-Linked Immunosorbent Assay, Female, Guinea Pigs, Immunoglobulin G blood, Immunologic Memory immunology, Mice, Mice, Inbred ICR, Rats, Rats, Hairless, Tetanus Toxin immunology, Th1 Cells immunology, Th2 Cells immunology, Transdermal Patch, Diphtheria Toxoid administration & dosage, Diphtheria Toxoid immunology, Hydrogels, Tetanus Toxoid administration & dosage, Tetanus Toxoid immunology, Vaccination methods
- Abstract
Transcutaneous immunization (TCI) targeting the Langerhans cells (LCs) of the epidermal layer is a promising needle-free, easy-to-use, and non-invasive vaccination method. We developed a hydrogel patch formulation to promote the penetration of antigenic proteins into the stratum corneum. Here, we investigated the characteristics of the immune responses induced by this vaccination method and the vaccine efficacy of TCI using a hydrogel patch containing tetanus and diphtheria toxoids. Our TCI system induced toxoid-specific IgG production in an antigen dose-, patch area-, and application period-dependent manner. Moreover, IgG subclass analysis indicated that our TCI predominantly elicited a Th2-type immune response rather than a Th1-type immune response. Importantly, our TCI system induced antigen-specific immune memory based on the booster effect and showed potent efficacy, comparable to that of subcutaneous immunization in toxin-challenge experiments. On the basis of these results, we are now performing translational research to apply TCI for tetanus and diphtheria., (Copyright © 2010 Elsevier B.V. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
47. Compositional optimization and safety assessment of a hydrogel patch as a transcutaneous immunization device.
- Author
-
Matsuo K, Ishii Y, Quan YS, Kamiyama F, Asada H, Mukai Y, Okada N, and Nakagawa S
- Subjects
- Administration, Cutaneous, Animals, Antigens toxicity, Diphtheria Toxin administration & dosage, Diphtheria Toxin toxicity, Female, Humans, Hydrogel, Polyethylene Glycol Dimethacrylate toxicity, In Vitro Techniques, Male, Ovalbumin administration & dosage, Ovalbumin toxicity, Rats, Rats, Hairless, Rats, Wistar, Skin drug effects, Skin Tests, Tetanus Toxin administration & dosage, Tetanus Toxin toxicity, Antigens administration & dosage, Hydrogel, Polyethylene Glycol Dimethacrylate administration & dosage, Transdermal Patch adverse effects, Vaccination methods
- Abstract
The development of a simple, easy-to-use, and non-invasive vaccination system is in high demand. For transcutaneous immunization (TCI), we previously developed a hydrogel patch formulation that accelerates the penetration of an antigen (Ag) through the stratum corneum (SC) and effectively elicits Ag-specific immune responses. The present studies were performed to optimize the composition and assess the safety of the patch formulation. A hydrogel patch with a water content ratio of 5% more effectively induced an immune response compared to patches with a different composition, suggesting that the moisture content of the hydrogel patch formulation has optimal ratio for SC hydration to promote Ag penetration through the SC. TCI using a hydrogel patch induced few local and systemic adverse reactions. Based on these results, we are now advancing translational research to evaluate the safety and efficacy of our novel TCI system in humans.
- Published
- 2011
- Full Text
- View/download PDF
48. Characterization of transcutaneous protein delivery by a hydrogel patch in animal, human, and tissue-engineered skin models.
- Author
-
Matsuo K, Ishii Y, Quan YS, Kamiyama F, Mukai Y, Okada N, and Nakagawa S
- Subjects
- Animals, Female, Guinea Pigs, Humans, Male, Mice, Mice, Inbred Strains, Models, Animal, Proteins administration & dosage, Tissue Engineering, Hydrogel, Polyethylene Glycol Dimethacrylate, Proteins metabolism, Skin metabolism, Transdermal Patch, Vaccination methods
- Abstract
The development of a simple, easy-to-use, and noninvasive vaccination system is in high demand. For transcutaneous immunization (TCI), we previously reported that a hydrogel patch was an effective TCI device that accelerates antigen penetration through the stratum corneum in mouse and rat models. The present study was performed to characterize the transcutaneous protein delivery induced by the hydrogel patch in mouse, guinea pig, LWD pig, human, or tissue-engineered skin models, and to assess the activity of proteins delivered into the skin. The hydrogel patch promoted protein penetration through the stratum corneum in all skin models, indicating that our original hydrogel patch might have practical application for use in humans. In addition, proteins delivered into the skin by the hydrogel patch retained their activity, suggesting that the hydrogel patch is applicable for the delivery of therapies for other diseases as well. On the basis of these results, translational research in human is now in progress.
- Published
- 2011
- Full Text
- View/download PDF
49. Development of a novel transdermal patch of alendronate, a nitrogen-containing bisphosphonate, for the treatment of osteoporosis.
- Author
-
Kusamori K, Katsumi H, Abe M, Ueda A, Sakai R, Hayashi R, Hirai Y, Quan YS, Kamiyama F, Sakane T, and Yamamoto A
- Subjects
- Alendronate blood, Alendronate pharmacokinetics, Animals, Bone Density Conservation Agents blood, Bone Density Conservation Agents pharmacokinetics, Butylated Hydroxytoluene pharmacology, Calcium blood, Female, Growth Plate drug effects, Growth Plate pathology, Humans, Hypercalcemia blood, Hypercalcemia complications, Hypercalcemia drug therapy, Hypercalcemia prevention & control, Osteoporosis blood, Osteoporosis complications, Ovariectomy, Permeability drug effects, Rats, Rats, Sprague-Dawley, Rats, Wistar, Skin drug effects, Skin pathology, Skin Irritancy Tests, Alendronate administration & dosage, Alendronate therapeutic use, Bone Density Conservation Agents administration & dosage, Bone Density Conservation Agents therapeutic use, Nitrogen therapeutic use, Osteoporosis drug therapy, Transdermal Patch
- Abstract
Bisphosphonates are widely used for the treatment and prevention of bone diseases, including Paget disease, hypercalcemia of malignancy, and postmenopausal osteoporosis. In this study, we developed a novel transdermal patch of alendronate, a nitrogen-containing bisphosphonate, for the treatment of bone diseases. The maximum permeation fluxes of alendronate through rat and human skin after application of this patch were 1.9 and 0.3 µg/cm(2) per hour, respectively. The bioavailability (BA) of alendronate in rats was approximately 8.3% after the application of alendronate patch and approximately 1.7% after oral administration. These results indicated that the transdermal permeation of alendronate using this patch system was sufficient for the treatment of bone diseases. The plasma calcium level was effectively reduced after application of the alendronate patch in 1α-hydroxyvitamin D(3) -induced hypercalcemia model rats. The alendronate patch also effectively suppressed the decrease in bone mass in model rats with osteoporosis. Modest alendronate-induced erythema of rat skin was observed after application of the alendronate patch. Incorporation of butylhydroxytoluene in the alendronate patch almost completely suppressed this alendronate-induced skin damage while maintaining the transdermal permeation and pharmacologic effects of alendronate. These findings indicate that our novel transdermal delivery system for alendronate is a promising approach to improve compliance and quality of life of patients in the treatment of bone diseases., (Copyright © 2010 American Society for Bone and Mineral Research.)
- Published
- 2010
- Full Text
- View/download PDF
50. Trypsin as a novel potential absorption enhancer for improving the transdermal delivery of macromolecules.
- Author
-
Li YZ, Quan YS, Zang L, Jin MN, Kamiyama F, Katsumi H, Tsutsumi S, and Yamamoto A
- Subjects
- Administration, Cutaneous, Animals, Dextrans administration & dosage, Dextrans pharmacokinetics, Fluorescein-5-isothiocyanate administration & dosage, Fluorescein-5-isothiocyanate analogs & derivatives, Fluorescein-5-isothiocyanate pharmacokinetics, Humans, In Vitro Techniques, Insulin administration & dosage, Insulin pharmacokinetics, Male, Microscopy, Fluorescence, Permeability, Rats, Rats, Wistar, Skin drug effects, Skin metabolism, Swine, Excipients chemistry, Skin Absorption, Trypsin chemistry
- Abstract
Objectives: The aim was to assess the effect of trypsin on the transdermal delivery of macromolecules by applying its specific biochemical properties to the stratum corneum of the skin., Methods: Fluorescein isothiocyanate (FITC)-labelled dextrans (FDs), with molecular weights of 4 to 250 kDa, and FITC-insulin were used as model macromolecules and a model polypeptide, and the in-vitro transdermal permeation experiments, with or without trypsin (0.1-2.5%), were carried out using rat skin and cultured human epidermis. The mechanism for the enhancement of trypsin was also studied using fluorescence and conventional light microscopy., Key Findings: Trypsin significantly increased the transdermal permeability of all FDs through the rat skin (2.0- to 10.0-fold). It also markedly enhanced the permeation of FD4 through three-dimensional cultured human epidermis (3.1-fold), which was used to evaluate the transport pathways other than the transfollicular route. Furthermore, the permeation flux of FITC-insulin was increased by 10.0-fold with trypsin pretreatment (from 0.02 +/- 0.00 to 0.20 +/- 0.07 microg/cm(2) per h). Mechanistic studies indicated that trypsin affects both the intercellular pathway and the hair follicular route, and may alter stratum corneum protein structures, thereby affecting skin barrier properties., Conclusions: This study suggests that trypsin could be effective as a biochemical enhancer for the transdermal delivery of macromolecules including peptide and protein drugs.
- Published
- 2009
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.