研究者詳細 - 引間　知広

Potential of TAK-593 ophthalmic emulsion for the treatment of age-related macular degeneration 査読有り国際誌

Yasuhiro MORI, Akifumi YAMAMOTO, Ayumi NAKAGAWA, Tomohiro HIKIMA, Akiharu ISOWAKI

Biological and Pharmaceutical Bulletin ( The Pharmaceutical Society of Japan ) 46 ( 7 ) 921 - 928 2023年07月

記述言語：英語掲載種別：研究論文（学術雑誌）

Intravitreal injection therapy of anti-vascular endothelial growth factor (VEGF) antibody or steroids is the mainstream for patients with age-related macular degeneration (AMD). However, since intravitreal injection is invasive administration, side effects such as endophthalmitis are major problems. In this study, we selected eye drops as a non-invasive treatment method, and aimed to develop eye drops that can deliver TAK-593 (VEGF receptor tyrosine kinase inhibitor) to the posterior segment of the eye. Since TAK-593 is a poorly water-soluble drug, the TAK-593 emulsion was formulated. The solubility of TAK-593 in various oils was measured, and the oil used for the emulsion was selected. Furthermore, viscosity enhancers were added to the emulsion in order to improve the drug delivery into the eye. As viscosity enhancer, xanthan gum was selected based on the properties and the viscosity of the emulsion. The delivery of TAK-593 to the posterior eye was increased by the formulation concentration and the addition of viscosity enhancers. In the laser-induced choroidal neovascularization model, TAK-593 emulsion eye drops showed the same angiogenesis-suppression efficacy as anti-VEGF antibody intravitreal injection. From these results, it was revealed that TAK-593 with an effective drug concentration can be delivered to the posterior eye by non-invasive eye drop administration.

DOI： 10.1248/bpb.b23-00066

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Predicting the safety of ocular iontophoresis using reconstructed human corneal epithelial cells. 査読有り国際誌

Tomohiro HIKIMA, Haruhiko EZAKI

Biological and Pharmaceutical Bulletin ( The Pharmaceutical Society of Japan ) 46 ( 7 ) 1021 - 1023 2023年07月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

We aimed to investigate eye damage caused by ocular iontophoresis (IP) based on an in vitro eye irritation test using a reconstructed human corneal cell. In this study, the LabCyte CORNEA-MODEL was selected as the reconstructed corneal cell. The test procedure was performed according to Test Guideline No.492 of the Organisation for Economic Co-operation and Development, which was partially revised for the IP. From the relationship between the cell viability of the cornea model and the electric field intensity [current density (mA/cm2) × application time (min)] of the IP, we predicted that the intensity values of 465 mA/cm2 × min and 930 mA/cm2 × min caused reversible eye irritation and irreversible eye damage, respectively. However, further studies are required to improve the accuracy and reproducibility of the prediction. This report provides essential knowledge on the clinical safety of ocular IP.

DOI： 10.1248/bpb.b23-00096

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Suitability of high-molecular-weight tissue-derived elastin polypeptides and their particles as cosmetic biomaterials 査読有り国際誌

Toma SAKAI, Nanami SODEMOTO, Asako INOUE, Suguru TANIGUCHI, Iori MAEDA, Tomohiro HIKIMA

Journal of Peptide Science ( European Peptide Society and John Wiley & Sons, Ltd. ) 46 ( 7 ) え3472 2022年12月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

We aimed to determine the coacervation properties of high-molecular-weight (HMW) tissue-derived elastin (TDE) and to examine the potential use of TDE particles as a cosmetic biomaterial. TDE solutions were filtered and divided into three fractions (1–3) according to the molecular weight of the elastin. The turbidity of fraction 2, which contained a large portion (58%) of HMW elastin polypeptides (>100 kDa), was measured under several pH values (3.0–11.0) and NaCl concentrations (0–1000 mM) to examine its coacervation ability. HMW TDE exhibited coacervation under the physiological conditions (temperature, pH, and NaCl concentration) of the skin surface. We performed inclusion and release experiments using three model chemicals with different molecular weights and measured the size and zeta potential of the fraction 3 particles to investigate the suitability of HMW elastin polypeptides. Fraction 3, which contained a larger portion (64%) of HMW elastin polypeptides, displayed a strong coacervation property at a phase transition temperature of 19.8 ± 0.1°C. The inclusion ratio of the model chemical Biebrich Scarlet (BS) with a molecular weight of <600 was approximately 92.1 ± 0.7%. The release profiles of BS from the particles linearly increased and reached a plateau after 15 days. Moreover, the average size of the particles with BS was 474.2 ± 24.6 nm. The low-molecular-weight (LMW) elastin peptides have moisturizing and whitening functions for the skin. We concluded that TDE, as a mixture of HMW polypeptides and LMW peptides, can potentially serve as a multifunctional and effective cosmetic biomaterial.

DOI： 10.1002/psc.3472

医療用マイクロニードルアレイの研究査読有り

武井栄憲, 川端一輝, 松島俊也, 水口凌, 伊藤高廣, 引間知広, 松尾正昭, 田代康典, 原正哉, 鬼木喬玄

精密工学会学術講演会講演論文集 ( 公益社団法人精密工学会 ) 2022S ( 0 ) 219 - 220 2022年03月

記述言語：日本語掲載種別：研究論文（その他学術会議資料等）

本研究ではマイクロニードルの医療への適用を目的に研究を行っている。先行研究では生分解性材料を用いて作成したマイクロニードルの針の高さ、針本数ごとの穿刺性能の評価を行い、面積当たりの本数の最適値を実験により求めた。その結果から、本研究では生分解性材料を用いて作成した、マイクロニードルの投薬性能の評価を行うことを目的とし、薬液の塗布実験、動物実験を行い良好な結果を得た。

DOI： 10.11522/pscjspe.2022s.0_219

医療用マイクロニードルの研究査読有り

川端一輝, 松島俊也, 水口凌, 伊藤高廣, 引間知広, 村上直, 松尾正昭, 田代康典, 原正哉, 椿浩忠

精密工学会学術講演会講演論文集 ( 公益社団法人精密工学会 ) 2021A ( 0 ) 387 - 388 2021年09月

記述言語：日本語掲載種別：研究論文（その他学術会議資料等）

近年、投薬時の痛みが少なく、患者への負担の少ない投薬方法としてマイクロニードル（MN）を用いた投薬方法が注目されている。投薬性能を有し、金型を用いた射出成形による生産性の高いMNの作製を目指す。本研究では、生分解性材料を用いて、本数違いの烏口型MNを作製し、成形精度の測定と穿刺実験を行った。その結果、烏口型ＭＮの本数違いに伴って、成形精度と穿刺性能の違いが見られた。

DOI： 10.11522/pscjspe.2021a.0_387

Fabrication of novel-shaped microneedles to overcome the disadvantages of solid microneedles for the transdermal delivery of insulin 査読有り国際誌

Yuki MIZUNO, Kanae TAKASAWA, Taichi HANADA, Kyou NAKAMURA, Kazuya YAMADA, Hirotaka TSUBAKI, Masaya HARA, Yasunori TASHIRO, Masaaki MATSUO, Takahiro ITO, Tomohiro HIKIMA

Biomedical Microdevices ( Springer Nature ) 23 ( 3 ) 38 2021年09月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

In this study, we fabricated two different microneedles (MNs) — semi-hollow and bird-bill — to overcome the limitations of solid and coated MNs, respectively. The two MN arrays were developed using a general injection molding process to obtain high-quality MNs with uniform shape. The semi-hollow and bird-bill MNs could penetrate the micropores of swine skin up to depths of 178.5 ± 27.6 µm and 232.1 ± 51.3 µm, respectively. When the semi-hollow MNs were used for the transdermal delivery of insulin in diabetic rats, it was observed that the blood glucose concentration (BGC) decreased remarkably within 30 min, and the desired effect of insulin was maintained for an additional 3 h after the removal of insulin from the skin surface. The bird-bill MN was able to load a coating gel at a maximum capacity of 3.20 ± 0.21 mg per MN array, and the BGC continued to decrease significantly after MN application for up to 2–6 h. In summary, we fabricated semi-hollow and bird-bill MN arrays using the injection molding method; these can be mass produced and are capable of effectively producing micro-holes in the stratum corneum. The two MN arrays could provide effective transdermal delivery of large-molecular-weight drugs such as insulin.

DOI： 10.1007/s10544-021-00576-x

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A phase I study of high dose camostat mesylate in healthy adults provides a rationale to repurpose the TMPRSS2 inhibitor for the treatment of COVID-19 査読有り国際誌

Kitagawa J., Arai H., Iida H., Mukai J., Furukawa K., Ohtsu S., Nakade S., Hikima T., Haranaka M., Uemura N.

Clinical and Translational Science 14 ( 5 ) 1967 - 1976 2021年09月

記述言語：英語掲載種別：研究論文（学術雑誌）

Camostat mesylate, an oral serine protease inhibitor, is used to treat chronic pancreatitis and reflux esophagitis. Recently, camostat mesylate and its active metabolite 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA) were reported to inhibit the infection of cells by severe acute respiratory syndrome coronavirus 2 by inhibiting type II transmembrane serine protease. We conducted a phase I study to investigate high-dose camostat mesylate as a treatment for coronavirus disease 2019. Camostat mesylate was orally administered to healthy adults at 600 mg 4 times daily under either of the following conditions: fasted state, after a meal, 30 min before a meal, or 1 h before a meal, and the pharmacokinetics and safety profiles were evaluated. In addition, the time of plasma GBPA concentration exceeding the effective concentration was estimated as the time above half-maximal effective concentration (EC50) by using pharmacokinetic/pharmacodynamic modeling and simulation. Camostat mesylate was safe and tolerated at all dosages. Compared with the fasted state, the exposure of GBPA after a meal and 30 min before a meal was significantly lower; however, no significant difference was observed at 1 h before a meal. The time above EC50 was 11.5 h when camostat mesylate 600 mg was administered 4 times daily in the fasted state or 1 h before a meal. Based on the results of this phase I study, we are currently conducting a phase III study.

DOI： 10.1111/cts.13052

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医療用マイクロニードルアレイの作製査読有り

山田一也, 松島俊也, 水野有希, 福田龍彌, 高澤香奈衣, 伊藤高廣, 引間知広, 村上直, 椿浩忠, 原正哉, 田代康典, 松尾正昭

精密工学会学術講演会講演論文集 ( 公益社団法人精密工学会 ) 2020A ( 0 ) 472 - 473 2020年08月

記述言語：日本語掲載種別：研究論文（その他学術会議資料等）

従来の注射に代え、皮膚から体内に薬物を入れる、マイクロニードルアレイを開発した。皮膚に貼るだけで、いつでもどこで誰でも、痛みなく薬を投与できるようになる。工業的生産を目指し、作製には射出成形を用いた。マイクロニードルの先端を十分に鋭くする製造方法及び、精密金型を開発した。表面形状評価、穿刺深さの測定を行いマイクロニードルが十分な性能を持つことを確認した。

DOI： 10.11522/pscjspe.2020a.0_472

九州工業大学におけるマイクロニードルの研究開発招待有り

引間知広

三島光産技報 2020年04月

経強膜イオントフォレシスによる後眼部への高分子化合物の送達促進査読有り

引間　知広, 井上　茉莉

あたらしい眼科 ( メディカル葵出版 ) 36 ( 9 ) 1149 - 1147 2019年09月

医療用マイクロニードルアレイの研究査読有り

松島俊也, 山田一也, 福田龍彌, 水野有希, 伊藤高廣, 引間知広, 村上直, 椿浩忠, 田代康典, 原正哉, 松尾正昭

精密工学会学術講演会講演論文集 ( 公益社団法人精密工学会 ) 2019A ( 0 ) 478 - 479 2019年08月

記述言語：日本語掲載種別：研究論文（その他学術会議資料等）

患者の負担軽減のため、皮膚から痛みなく投薬できるマイクロニードルを研究している。穿刺性と薬剤付着量増加を両立できる、コーティング型マイクロニードルの新規形状を提案し、金型射出成形により実現した。新規提案形状によって、付着薬剤を従来と比較して倍以上に増やせることを、モデル薬剤を用いた実験により検証した。

DOI： 10.11522/pscjspe.2019a.0_478

乾燥肌に対するビート由来グルコシルセラミド含有物の効果査読有り

引間　知広, 木下　真梨子

Fragrance Journal ( フレグランスジャーナル社 ) ( 7月 ) 82 - 85 2019年07月

医療用マイクロニードルアレイの作製査読有り

山田一也, 花田大知, 伊藤高廣, 引間知広, 村上直, 椿浩忠, 福田龍彌, 原正哉, 田代康典, 松尾正昭

精密工学会学術講演会講演論文集 ( 公益社団法人精密工学会 ) 2019S ( 0 ) 879 - 879 2019年03月

記述言語：日本語掲載種別：研究論文（その他学術会議資料等）

既存の注射器とは異なる、マイクロニードルアレイを用いて皮膚から薬剤を体内に取り入れることで、だれでも、いつでも、痛みなく投薬できることを目標としている。独自形状によって、従来型形状に比べ、より多くの薬液を保持、投薬できるコーティング方式のマイクロニードルを提案する。烏口型の先端形状により薬液保持量を増やしている。精密金型を用いた射出成形にて作製した。実験を行い効果を評価した。

DOI： 10.11522/pscjspe.2019s.0_879

医療用マイクロニードルの作製査読有り

花田大知, 伊藤高廣, 引間知広, 福田龍彌, 村上直, 椿浩忠, 原正哉, 田代康典, 松尾正昭

精密工学会学術講演会講演論文集 ( 公益社団法人精密工学会 ) 2018A ( 0 ) 819 - 819 2018年08月

記述言語：日本語掲載種別：研究論文（その他学術会議資料等）

従来の注射に代えて、マイクロニードルアレイにより皮膚から薬剤を体内に入れ、誰でも、どこでも、いつでも、痛みなく投薬ができることを目指している。従来よりさらに多くの薬剤をワンショットで投与できるコーティング型マイクロニードル形状を新たに提案する。独自の先端形状により保持薬剤の量を増やしている。精密金型と、射出成形による作製方法を考案した。また、実験によりその効果も評価した。

DOI： 10.11522/pscjspe.2018a.0_819

Characterization of an in vitro penetration system for ocular iontophoresis 査読有り国際誌

Hikima T., Kawakami M., Tojo K.

Journal of Chemical Engineering of Japan ( 公益社団法人化学工学会 ) 51 ( 5 ) 418 - 422 2018年01月

担当区分：筆頭著者,　最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

© 2018 The Society of Chemical Engineers, Japan. We have developed an in vitro penetration cell for transcorneal iontophoretic delivery. The thickness of the diffusion boundary layer δ of this in vitro system was evaluated by benzoic acid dissolution experiments under several mixing conditions of receptor solution. The δ under the condition of magnetic stirrer at 300 rpm in the receptor solution for the present KK cell was 201.0± 20.4 μm, which is thinner than that for a Franz diffusion cell (323 μm). Moreover, the mass transfer coefficient km(= D/δ) was calculated by Sh = 2+3.45Re0.11Sc0.33; this equation gave the kmand δ for the KK cell if the value of the diffusion coefficient D, viscosity μ, and density ? of receptor solution were known. The penetration rate across cornea from pig in vitro was proportional to the voltage applied to the cornea during iontophoresis. The effect of iontophoresis on the penetration rate was quantitatively investigated after taking into consideration the hydrodynamic diffusion boundary layer.

DOI： 10.1252/jcej.17we084

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医療用マイクロニードルの作製査読有り

花田大知, 伊藤高廣, 引間知広, 村上直, 椿浩忠, 原正哉, 黒木潤二, 田代康典, 松尾正昭

精密工学会学術講演会講演論文集 ( 公益社団法人精密工学会 ) 2017A ( 0 ) 287 - 288 2017年01月

記述言語：日本語掲載種別：研究論文（その他学術会議資料等）

従来の注射に代えて、マイクロニードルアレイにより皮膚から薬剤を体内に入れ、誰でも、どこでも、いつでも、痛みなく投薬ができることを目指している。皮膚に開けた穴が塞がりにくくしたマイクロニードル形状とその製作方法を提案する。独自の窪み形状により皮膚の穴が塞がることを防ぐと同時に、薬剤の量を増やしている。精密金型と、射出成形による作製方法を考案した。また、動物実験によりその効果も評価した。

DOI： 10.11522/pscjspe.2017a.0_287

Investigation of water-soluble elastin as a multifunctional cosmetic material: Moisturizing and whitening effects 査読有り国際誌

Inoue A., Hikima T., Taniguchi S., Nose T., Maeda I.

Journal of Cosmetic Science 68 ( 1 ) 11 - 23 2017年01月

記述言語：英語掲載種別：研究論文（学術雑誌）

Elastin and collagen are extracellular matrix proteins that are widely distributed in the body. Although elastin essentially functions as a skin moisturizer, there have been few reports on its other fundamental chemical and biological functions. In this study, we investigated the moisturizing and whitening (tyrosinase inhibition) effects of elastin to examine its usefulness as a cosmetic material. Water-soluble hot alkali pig aorta (HAPA)- elastin was prepared from pig aorta using the hot alkali method. HAPA-elastin showed a widely distributed molecular weight and had a coacervation property that mediated reversible self-assembly of its molecules with increasing temperature. Amino acid analysis of HAPA-elastin showed a high content (81.5%) of hydrophobic amino acids such as Gly, Ala, Val, and Pro. Des (desmosine) and Ide (isodesmosine), which are characteristic amino acids of elastin, accounted for more than 0.4% of the total amino acid content. HAPA-elastin showed a moisture-retaining property. The water content of skin samples treated with and without HAPA-elastin was 77.2% ± 7.8% and 49.4% ± 10.1%, respectively. HAPA-elastin also inhibited tyrosinase activity by 11.3% ± 3.9%. The results obtained indicate that elastin has a useful function as a cosmetic material.