大竹　裕子 （オオタケ　ヒロコ）

コミュニケーション情報 byコメンテータガイド

• コメント

  吸入剤の製剤設計および適正使用に関する研究を行っています。

研究者情報

学位

• 博士 (薬学)（名城大学 薬学部）

ホームページURL

https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201701017612785873

J-Global ID

• 201701017612785873

研究キーワード

• 吸入剤   経肺デリバリー   

現在の研究分野（キーワード）

吸入剤の製剤設計および適正使用に関する研究を行っています。

研究分野

• ライフサイエンス / 医療薬学

学歴

• 2022年04月 - 現在   近畿大学   薬学部   医療薬学科 講師
• 2017年04月 - 2022年03月   近畿大学   薬学部   医療薬学科 助教
• 2016年04月 - 2017年03月   名城大学   薬学部 研究員
• 2012年04月 - 2016年03月   名城大学大学院   薬学研究科   薬学専攻

所属学協会

• 日本医療薬学会   粉体工学会   日本薬学会   日本薬剤学会   日本白内障学会   

研究活動情報

論文

• Design of an Oral Tablet Containing Furosemide Nanoparticles with Elevated Bioavailability.

  Noriaki Nagai; Fumihiko Ogata; Reita Kadowaki; Saori Deguchi; Hiroko Otake; Yosuke Nakazawa; Manju Misra; Naohito Kawasaki

  Journal of oleo science 73 4 563 - 571 2024年 

  The solubility and permeability of the Biopharmaceutics Classification System (BCS) class IV drugs, such as furosemide (FUR), are low. Thus, the oral bioavailability of these drugs needs to be augmented. Here, we aimed to design orally disintegrating tablets containing FUR nanoparticles to improve bioavailability after oral administration. The FUR nanoparticles were generated by bead-milling in water containing 0.5% methylcellulose and 0.5% 2-hydroxypropyl-β-cyclodextrin (w/w%). Particle size was approximately 47-350 nm (mean particle size, 188 nm). An orally disintegrating tablet (FUR-NP tablet) comprising FUR nanoparticles (1%) was successfully produced by employing suspensions outlined above that incorporated additives (4% D-mannitol, 0.4% polyvinylpyrrolidone, and 16% gum Arabic, w/w%), followed by freeze-drying. The FUR-NP tablet disaggregated after only 5 s in water, liberating nano-sized FUR particles (172 nm). Experiments using rats showed the absorption of the FUR-NP tablet was significantly improved by comparison with a FUR tablet containing microparticles. In summary, the orally disintegrating tablet containing FUR nanoparticles markedly enhanced the bioavailability of FUR. We anticipate this formulation will also improve the bioavailability of other BCS class IV drugs.
• Recovery from indomethacin-induced gastrointestinal bleeding by treatment with teprenone.

  Saori Deguchi; Ayusa Iwakami; Mizuki Tujigiwa; Hiroko Otake; Yu Mano; Naoki Yamamoto; Yosuke Nakazawa; Manju Misra; Noriaki Nagai

  Journal of pharmaceutical health care and sciences 9 1 44 - 44 2023年11月 

  BACKGROUND: Gastrointestinal injuries caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is a serious side effect in patients with rheumatoid arthritis (RA). However, effective therapeutic strategies have yet to be established. In this study, we investigated the therapeutic effects of teprenone (TEP), a gastric mucosal protective drug, on NSAID-induced gastrointestinal injuries in rats with RA (AA rats). METHODS: Gastrointestinal injury was induced by oral administration of indomethacin (IMC), a typical NSAID. TEP was orally administered after IMC-induced gastrointestinal bleeding, and the stomach, jejunum, and ileum were excised. RESULTS: On day 14 of IMC administration, lesion areas in the stomach, jejunum, and ileum were significantly larger in AA rats than in normal rats. When TEP was orally administered to AA rats, the lesion areas in the stomach, jejunum, and ileum significantly decreased compared with those in control rats (IMC-induced AA rats). Therefore, we measured NOS2 mRNA and NO levels, which were significantly decreased in rats with IMC-induced AA after treatment with TEP. CONCLUSIONS: These results suggest that the oral administration of TEP may be useful for the treatment of NSAID-induced gastrointestinal injuries in patients with RA.
• ジヒドロピリジン系カルシウム拮抗薬ニルバジピンのナノ結晶点眼液調製と水晶体硬化に対する有用性評価

  出口 粧央里; 門脇 玲太; 浅井 拓己; 大竹 裕子; 岡本 紀夫; 中澤 洋介; Misra Manju; 長井 紀章

  日本眼薬理学会プログラム・抄録集 43回 43 - 43 日本眼薬理学会 2023年11月
• Skin absorption of felbinac solid nanoparticles in gel formulation containing l-menthol and carboxypolymethylene.

  Reita Kadowaki; Fumihiko Ogata; Aoi Fushiki; Saki Daimyo; Saori Deguchi; Hiroko Otake; Mayumi Nagata; Hiroshi Sasaki; Naohito Kawasaki; Noriaki Nagai

  Journal of pharmaceutical health care and sciences 9 1 20 - 20 2023年06月 

  BACKGROUND: It is important to design an effective formulation to enhance the skin penetration, and nanotechnologies have been used in dermal and transdermal drug delivery. In this study, we prepared formulations (gels) containing l-menthol and felbinac (FEL) solid nanoparticles (FEL-NP gel) for topical application, and investigated the local and systemic absorption of the prepared FEL-NP gel. METHODS: FEL solid nanoparticles were obtained by bead milling of FEL powder (microparticles), and a topical formulation (FEL-NP gel) consisting of 1.5% FEL solid nanoparticles), 2% carboxypolymethylene, 2% l-menthol, 0.5% methylcellulose, and 5% 2-hydroxypropyl-β-cyclodextrin (w/w %) were prepared. RESULTS: The particle size of FEL nanoparticles was 20-200 nm. The released FEL concentration from FEL-NP gel was significantly higher than that from FEL gel without bead mill treatment (carboxypolymethylene gel in which FEL microparticles (MPs) instead of FEL nanoparticles were incorporated, FEL-MP gel), and FEL was released as nanoparticles from the gel. Moreover, both transdermal penetration and percutaneous absorption of FEL-NP gel were significantly increased compared with those of FEL-MP gel, and the area under the FEL concentration-time curve (AUC) of FEL-NP gels was 1.52- and 1.38-fold of commercially available FEL ointment and FEL-MP gel, respectively. In addition, after 24 h of treatment, the FEL content in rat skin treated with FEL-NP gels was 1.38- and 2.54-fold higher than that when treated with commercially available FEL ointment and FEL-MP gel, respectively. Moreover, the enhanced skin penetration of FEL-NP gels was significantly attenuated by inhibition of energy-dependent endocytosis, such as clathrin-mediated endocytosis. CONCLUSIONS: We successfully prepared a topically applied carboxypolymethylene gel containing FEL nanoparticles. In addition, we observed that the endocytosis pathway was mainly related to the high skin penetration of FEL nanoparticles, and FEL-NP gel application resulted in high local tissue concentration and systemic absorption of FEL. These findings provide useful information for the design of topically applied nanoformulations against inflammation by providing local and systemic effects.
• Poly(oxyethylene)/Poly(oxypropylene) butyl ether prolongs the repellent effect of N,N-diethyl-3-toluamide on the skin.

  Mayu Kawaguchi; Kana Matsumoto; Joji Yoshitomi; Hiroko Otake; Kanta Sato; Atsushi Taga; Tatsuji Sasabe; Kenji Nobuhara; Akira Matsubara; Noriaki Nagai

  PloS one 18 10 e0292447  2023年 

  N,N-diethyl-meta-toluamide (DEET) is a widely used insect repellent, with minimal skin permeation and sustained repellent activity in the superficial layers of the skin. In this study, we prepared a 10% DEET formulation consisting of 40% ethanol with or without 2% poly(oxyethylene)/poly(oxypropylene) butyl ether (POE-POP), an amphiphilic random copolymer. Further, we demonstrated the effects of POE-POP on tensile stress (stickiness), hydrophobicity, skin retention, permeation, and repellent activity of DEET. Stickiness was measured in male ICR mice (7-week old), and skin retention and permeation were evaluated in male Wistar rats (7-week old). In addition, female Aedes albopictus were used to measure the repellent action of DEET. The addition of POE-POP did not affect stickiness, volatility, and degradability but decreased logP and increased viscosity of DEET. Next, we demonstrated the behavior of DEET formulations in the rat skin. POE-POP prolonged the retention of DEET in the superficial layers of the rat skin (skin surface and stratum corneum) and decreased the penetration of DEET into rat skin tissues (epithelium and dermis). The repellent effect of DEET was also enhanced by the addition of POE-POP. However, severe skin damage was not observed after repetitive treatment with DEET formulations containing POE-POP for one month (twice a day). In conclusion, we demonstrated that a 10% DEET formulation consisting of 40% ethanol and 2% POE-POP attenuated the skin penetration and prolonged the repellent action of DEET without causing stickiness and skin damage. We conclude that the combination of ethanol and POE-POP is useful as a safe and effective delivery system for the development of insect repellent formulations containing DEET.
• Nasal Absorption Enhancement of Mometasone Furoate Nanocrystal Dispersions.

  Shuya Masuda; Saori Deguchi; Fumihiko Ogata; Joji Yoshitomi; Hiroko Otake; Kazutaka Kanai; Naohito Kawasaki; Noriaki Nagai

  International journal of nanomedicine 18 5685 - 5699 2023年 

  PURPOSE: We designed a 0.05% mometasone furoate (MF) nanocrystal dispersion and investigated whether the application of MF nanocrystals in nasal formulations enhanced local absorption compared to traditional nasal MF formulations (CA-MF). METHODS: MF nanocrystal dispersions (MF-NPs) were prepared by bead milling MF microcrystal dispersions (MF-MPs) consisting of MF, 2-hydroxypropyl-β-cyclodextrin, methylcellulose, and purified water. Pluronic F-127 combined with methylcellulose, Pluronic F-68, or carbopol was used as a base for in situ gelation (thickener). MF concentrations were measured using high-performance liquid chromatography, and nasal absorption of MF was evaluated in 6 week-old male Institute of Cancer Research (ICR) mice. RESULTS: The particle size range of MF prepared with the bead mill treatment was 80-200 nm, and the nanoparticles increased the local absorption of MF, which was higher than that of CA-MF and MF-MPs. In addition, unlike the results obtained in the small intestine and corneal tissue, the high absorption of nanocrystalline MF in the nasal mucosa was related to a pathway that was not derived from energy-dependent endocytosis. Moreover, the application of the in situ gelling system attenuated the local absorption of MF-NPs, owing to a decrease in drug diffusion in the dispersions. CONCLUSION: We found that nanoparticulation of MF enhances local intranasal absorption, and nasal bioavailability is higher than that of CA-MF. In addition, we demonstrate that viscosity regulation is an important factor in the design of nasal formulations based on MF nanocrystals. These findings provide insights for the design of novel nanomedicines with enhanced nasal bioavailability.
• Therapeutic Effects of Hydrogel Formulations Incorporating Troxipide Nanoparticles on Oral Mucositis in Hamsters.

  Reita Kadowaki; Fumihiko Ogata; Miku Nishida; Miri Komatsu; Hiroko Otake; Yosuke Nakazawa; Naoki Yamamoto; Naohito Kawasaki; Noriaki Nagai

  Drug design, development and therapy 17 3349 - 3361 2023年 

  PURPOSE: Medical therapies, such as the use of anti-inflammatory agents, are commonly used for the treatment of oral mucositis (OM). However, these treatments have limited efficacy in treating severe cases of OM. In this study, we aimed to develop a carbopol gel incorporating troxipide (TRO) nanoparticles and methylcellulose (TRO-NP gel) and demonstrate its efficacy in accelerating wound healing in a hamster model of OM (OM model) induced by acetic acid injection. METHODS: TRO nanoparticles were prepared using bead milling. The crystalline form was determined by powder X-ray diffraction, and the particle size was measured using a NanoSight LM10 instrument. The drug release was determined using a Franz diffusion cell, and the hamsters injected with acetic acid were selected to evaluate the therapeutic effect of OM. RESULTS: After preparing TRO nanoparticles, we observed a mixture of crystals and amorphous TRO, and the particle size of TRO in the TRO-NP gel ranged from 50 to 280 nm. The TRO-NP gel exhibited a more uniform TRO distribution and viscosity compared to the Carbopol gel containing TRO microparticles (TRO-MP gel). However, the solubility of TRO was comparable in both TRO-MP and TRO-NP gels. The TRO-NP gel released a higher amount of TRO than that from the TRO-MP gel, with detectable release of TRO nanoparticles. TRO levels in the cheek pouches of hamsters treated with TRO-NP gel were higher than those treated with TRO-MP gel. The increased TRO levels in the cheek pouches of hamsters treated with TRO-NP gel were attenuated by treatment with 40 μM dynasore, an inhibitor of clathrin-dependent endocytosis (CME). Moreover, the therapeutic effect of the TRO-NP gel was superior to that of the TRO-MP gel in the hamster model of OM. CONCLUSION: We have designed a TRO-NP gel, and this gel showed excellent TRO delivery into the cheek pouch tissue through the CME pathway. Moreover, the TRO-NP gel treatment enhanced wound healing after acetic acid injection.
• Orally disintegrating tablets containing famotidine nanoparticles provide high intestinal absorbability via the energy-dependent endocytosis pathway.

  Noriaki Nagai; Fumihiko Ogata; Reita Kadowaki; Saori Deguchi; Hiroko Otake; Yosuke Nakazawa; Mayumi Nagata; Hiroshi Sasaki; Naohito Kawasaki

  Frontiers in bioengineering and biotechnology 11 1167291 - 1167291 2023年 

  The permeability of the Biopharmaceutics Classification System (BCS) class III drugs are low, and their oral bioavailability needs to be improved. In this study, we attempted to design oral formulations containing famotidine (FAM) nanoparticles to overcome the limitations of BCS class III drugs. Dispersions containing FAM nanoparticles with a particle size of approximately 50-220 nm were produced by the bead-milling treatment. Moreover, we succeeded in preparing an orally disintegrating tablet containing FAM nanoparticles using the dispersions described above, additives (D-mannitol, polyvinylpyrrolidone, and gum arabic), and freeze-dry treatment (FAM-NP tablet). The FAM-NP tablet was disaggregated 3.5 s after addition to purified water, and the FAM particles in the redispersion of the FAM-NP tablet stored for 3 months were nano-sized (141 ± 6.6 nm). The ex-vivo intestinal penetration and in vivo absorption of FAM in rats applied with the FAM-NP tablet were significantly higher than those in rats applied with the FAM tablet containing microparticles. In addition, enhanced intestinal penetration of the FAM-NP tablet was attenuated by an inhibitor of clathrin-mediated endocytosis. In conclusion, the orally disintegrating tablet containing FAM nanoparticles improved low mucosal permeability and low oral bioavailability and overcame these issues of BCS class III drugs as oral formulations.
• Effect of Ointment Base on the Skin Wound-Healing Deficits in Streptozotocin-Induced Diabetic Rat.

  Hiroko Otake; Yu Mano; Saori Deguchi; Fumihiko Ogata; Naohito Kawasaki; Noriaki Nagai

  Biological & pharmaceutical bulletin 46 5 707 - 712 2023年 

  Wound-healing deficits of the skin, one of the most common complications in patients with diabetes, delay wound healing, significantly reducing the patient's QOL. Therefore, the topical treatment of wound areas with drug-containing ointments and dressings is important. In this study, we investigated the effect of various ointment bases on skin wound healing in normal and streptozotocin-induced diabetic rats (STZ rats). Three ointment bases were used: white ointment (oil-based), absorbent cream (emulsion-based, w/o), and macrogol ointment (water-based). Skin wound healing in STZ rats was delayed compared with that in normal rats. Each of the three ointment bases was applied to the skin wound area in normal rats, and there was no difference in the therapeutic effect. The therapeutic effect of both white ointment and absorbent cream was higher in the STZ rats group than that in the non-treated group, and delayed wound healing was observed in STZ rats treated with macrogol ointment. In conclusion, skin wound healing in STZ rats is affected by the properties of the ointment base, and it is important to use an ointment base that controls the drying of the wound area in STZ rats. These findings provide information for the selection of ointment bases useful for application to skin wounds in patients with diabetes.
• MPCポリマーの併用は市販ジクアホソルナトリウムまたはヒアルロン酸ナトリウム点眼液のドライアイ治療効果を高める

  長井 紀章; 後藤 涼花; 渡辺 彩花; 油納 美和; 小坂 太陽; 大竹 裕子; 鷲見 梓; 笹木 友美子; 原 真佐夫; 原田 英治

  医療薬学 48 12 545 - 550 (一社)日本医療薬学会 2022年12月 

  著者等はこれまでドライアイ症状を軽減できる物質のスクリーニングを行い、MPCポリマー(生体適合性ポリマー)の点眼が有効な可能性を示してきた。また、涙液崩壊時間短縮型ドライアイに対し、市販ドライアイ治療薬のレバミピド懸濁点眼液とMPCポリマー溶液(MPCP溶液)を併用することで、各々の単独使用群よりも治療効果が高まることを明らかにした。今回、レバミピド懸濁点眼液とは作用機序が異なる市販ドライアイ治療薬(ジクアホソルナトリウム点眼液およびヒアルロン酸ナトリウム点眼液)とMPCP溶液の併用による効果について、眼表面ムチン被覆障害ウサギモデルを用いて検討した。結果、ジクアホソルナトリウム点眼液(DIQ点眼液)、ヒアルロン酸ナトリウム点眼液ともそれぞれ単独使用した群よりもMPCP溶液を併用した群で治療効果が高く、特にDIQ点眼液にMPCP溶液を併用した群では有意に治療効果が高まった。
• Novel drug delivery systems for the management of dry eye.

  Noriaki Nagai; Hiroko Otake

  Advanced drug delivery reviews 191 114582 - 114582 2022年12月 

  Dry eye disease (DED) is a frequently observed eye complaint, which has recently attracted considerable research interest. Conventional therapy for DED involves the use of artificial tear products, cyclosporin, corticosteroids, mucin secretagogues, antibiotics and nonsteroidal anti-inflammatory drugs. In addition, ocular drug delivery systems based on nanotechnology are currently the focus of significant research effort and several nanotherapeutics, such as nanoemulsions, nanosuspensions, microemulsions, liposomes and nanomicelles, are in clinical trials and some have FDA approval as novel treatments for DED. Thus, there has been remarkable progress in the design of nanotechnology-based approaches to overcome the limitations of ophthalmic formulations for the management of anterior eye diseases. This review presents research results on diagnostic methods for DED, current treatment options, and promising pharmaceuticals as future therapeutics, as well as new ocular drug delivery systems.
• Design of a Transdermal Sustained Release Formulation Based on Water-Soluble Ointment Incorporating Tulobuterol Nanoparticles.

  Noriaki Nagai; Fumihiko Ogata; Saori Deguchi; Aoi Fushiki; Saki Daimyo; Hiroko Otake; Naohito Kawasaki

  Pharmaceutics 14 11 2022年11月 

  We aimed to investigate which base was suitable for preparing transdermal formulations incorporating tulobuterol (TUL) nanoparticles (30-180 nm) in this study. Three bases (water-soluble, absorptive, and aqueous ionic cream) were selected to prepare the transdermal formulations, and TUL nanoparticles were prepared with a bead-milling treatment. In the drug release study, the TUL release from the water-soluble ointment was higher than that from the other two ointments. Moreover, the addition of l-menthol enhanced TUL nanoparticle release from the ointment, and the rat skin penetration of the TUL water-soluble ointment was also significantly higher than that of the other two ointments. In addition, the drug penetration of the TUL water-soluble ointment with l-menthol sustained zero-order release over 24 h, and the skin permeability of TUL increased with TUL content in the ointment. On the other hand, this penetration was significantly inhibited by treatment with a caveolae-mediated endocytosis inhibitor (nystatin). In conclusion, we found that the water-soluble base incorporating TUL nanoparticles and l-menthol was the best among those assessed in this study. Furthermore, the pathway using caveolae-mediated endocytosis was related to the skin penetration of TUL nanoparticles in the TUL water-soluble ointment with l-menthol. These findings are useful for the design of a transdermal sustained-release formulation based on TUL nanoparticles.
• シクロデキストリンとカチオン性基からなる共重合体CDQAポリマーはレバミピドの角膜含有量を高める

  長井 紀章; 門脇 玲太; 後藤 涼花; 出口 粧央里; 吉富 丈二; 大竹 裕子; 松田 将; 小林 滉; 原田 英治

  日本眼薬理学会プログラム・抄録集 42回 62 - 62 日本眼薬理学会 2022年10月
• Combination of Lanosterol and Nilvadipine Nanosuspensions Rescues Lens Opacification in Selenite-Induced Cataractic Rats.

  Saori Deguchi; Reita Kadowaki; Hiroko Otake; Atsushi Taga; Yosuke Nakazawa; Manju Misra; Naoki Yamamoto; Hiroshi Sasaki; Noriaki Nagai

  Pharmaceutics 14 7 2022年07月 

  It has recently been reported that lanosterol (LAN) plays a preventive role against lens opacification through the reversal of crystalline aggregation. However, the effect of LAN is not sufficient to restore lens transparency. In this study, we designed ophthalmic nanosuspensions (LAN-ONSs and NIL-ONSs) based on LAN and nilvadipine (NIL), which can counteract cataract-related factors (e.g., enhanced Ca2+ and calpain levels), and investigated whether the combination of LAN-ONSs and NIL-ONSs can restore the nuclear lens opacity in sodium-selenite-induced cataractic rats (cataractic rats). The mean particle sizes of the LAN-ONSs and NIL-ONSs were 108.8 nm and 89.0 nm, respectively. The instillation of the LAN-ONSs or NIL-ONSs successfully delivered the drugs (LAN or NIL) into the lenses of the rats, although the instillation of LAN-ONSs or NIL-ONSs alone did not increase lens transparency in the cataractic rats. On the other hand, the cataract-related factors (enhanced Ca2+ and calpain levels) were significantly alleviated by the combination of LAN-ONSs and NIL-ONSs; furthermore, the perinuclear refractile ring in the lens nucleus and enhanced number of swollen fibers were attenuated by the LAN-ONS and NIL-ONS combination. Moreover, the opacity levels in the cataractic rats were reduced after treatment with the combination of LAN-ONSs and NIL-ONSs. It is possible that the combination of LAN and NIL will be useful for the treatment of lens opacification in the future.
• レバミピド懸濁点眼液とMPCポリマーの併用処理によるドライアイ治療効果の有用性評価

  後藤 涼花; 勢力 諒太朗; 渡辺 彩花; 油納 美和; 大竹 裕子; 櫻井 俊輔; 原田 英治; 長井 紀章

  あたらしい眼科 39 7 982 - 987 (株)メディカル葵出版 2022年07月 

  本研究では市販ドライアイ治療薬であるレバミピド懸濁点眼液(REB点眼液)と生体適合性MPCポリマー(MPCP)を併用処理した際のドライアイに対する治癒効果について検討した。REB点眼液点眼5分後にMPCPを処理することで、涙液中REB濃度の滞留性向上が確認され、そのREB眼表面滞留時間の延長はREB点眼液単独処理群と比較し有意に高値であった。次に、N-アセチルシステイン処理ウサギ(眼表面ムチン被覆障害モデル)を用い、REB点眼液とMPCP併用処理時のドライアイに対する治療効果を検討したところ、併用処理により、眼表面ムチン被覆障害モデルの涙液層破壊とムチン量低下は改善され、その効果はREB点眼液単独処理群に比べ高値であった。以上、MPCP併用により、REBの涙液中薬物滞留性が高まるとともに、ムチン被覆改善作用が向上する可能性が示唆された。(著者抄録)
• 口腔粘膜炎の早期治療を可能とするトロキシピドナノゲル製剤の開発

  出口 粧央里; 吉岡 涼; 西田 未来; 小松 美莉; 大竹 裕子; 長井 紀章

  日本薬学会年会要旨集 142年会 27H - am03S (公社)日本薬学会 2022年03月
• ブリンゾラミドナノ点眼製剤化に伴う眼内薬物移行性の改善と緑内障治療効果の向上

  後藤 涼花; 衣川 美宇; 矢野 詩歩; 大竹 裕子; 岡本 紀夫; 長井 紀章

  日本薬学会年会要旨集 142年会 27L - am09S (公社)日本薬学会 2022年03月
• 噴霧急速凍結乾燥法を用いたトラニラストナノ結晶懸濁液からの微粉末体作成と吸入製剤への応用性

  大竹 裕子; 辜 瓊雅; 福本 航; 長井 紀章

  日本薬学会年会要旨集 142年会 28F - am10 (公社)日本薬学会 2022年03月
• 芍薬甘草湯エキス顆粒における粗大・コロイド・分子分散体の同定とその消化管吸収性の評価

  吉富 丈治; 大竹 裕子; 遠藤 雄一; 小竹 武; 長井 紀章

  日本薬学会年会要旨集 142年会 28J - am07S (公社)日本薬学会 2022年03月
• BCSクラス3薬物を対象としたナノ結晶製剤の開発研究 再分散可能なファモチジンナノ固化成形体の調製

  門脇 玲太; 池 彩里; 下前 憂梨咲; 大迫 華乃; 大竹 裕子; 長井 紀章

  日本薬学会年会要旨集 142年会 27PO7 - 05S (公社)日本薬学会 2022年03月
• Effect of inner physical properties on powder adhesion in inhalation capsules in case of a high resistance device.

  Hiroko Otake; Misa Minami; Mizuki Yamaguchi; Sawako Akiyama; Kazunori Inaba; Noriaki Nagai

  Experimental and therapeutic medicine 22 6 1353 - 1353 2021年12月 [査読有り]
   

  The inhalation performance of a dry powder inhaler (DPI) depends on the inhalation patterns of patients, inhalation particle characteristics and inhalation devices. In capsule-based DPIs, the capsule plays an important role in the dispersion of inhalation particles. The present study investigated the effects of inner physical properties of capsules on drug release from capsules-based DPIs with high resistance device. Atomic force microscopy (AFM) was used to evaluate the capsule physical properties, such as the capsule inner structure and surface potential, of three capsules with different compositions (G-Cap, PEG/G-Cap, and HPMC-Cap). As a model dry powder for capsule-based DPIs, the dry powder in Spiriva® Inhalation Capsules containing tiotropium bromide was used. Inhalation performance was evaluated using a twin-stage liquid impinge and Handihaler® (flow rate 30 l/min). The results indicated that the capsule inner surface presented with numerous valleys and mountains, regardless of the capsule type. Furthermore, the valley and mountain areas on the capsule inner surface showed a significantly higher or lower surface potential. Following inhalation of capsule-based DPIs, the drug remained in the valleys on the capsule inner surface; however, no significant difference was observed in the drug release from capsule and lung drug delivery. Therefore, inhalation performance in capsule-based DPIs when a high resistance device, such as Handihaler®, is used at an appropriately flow rate is not markedly affected by the physical properties of the capsule inner surface due to capsule composition.
• Instillation of Ophthalmic Formulation Containing Nilvadipine Nanocrystals Attenuates Lens Opacification in Shumiya Cataract Rats.

  Ryoka Goto; Shigehiro Yamada; Hiroko Otake; Yosuke Nakazawa; Mikako Oka; Naoki Yamamoto; Hiroshi Sasaki; Noriaki Nagai

  Pharmaceutics 13 12 2021年11月 

  We developed ophthalmic formulations based on nilvadipine (NIL) nanocrystals (NIL-NP dispersions; mean particle size: 98 nm) by using bead mill treatment and investigated whether the instillation of NIL-NP dispersions delivers NIL to the lens and prevents lens opacification in hereditary cataractous Shumiya cataract rats (SCRs). Serious corneal stimulation was not detected in either human corneal epithelial cells or rats treated with NIL-NP dispersions. The NIL was directly delivered to the lens by the instillation of NIL-NP dispersions, and NIL content in the lenses of rats instilled with NIL-NP dispersions was significantly higher than that in the ophthalmic formulations based on NIL microcrystals (NIL-MP dispersions; mean particle size: 21 µm). Moreover, the supply of NIL prevented increases in Ca2+ content and calpain activity in the lenses of SCRs and delayed the onset of cataracts. In addition, the anti-cataract effect in the lens of rats instilled with NIL-NP dispersions was also significantly higher than that in NIL-MP dispersions. NIL-NPs could be used to prevent lens opacification.
• ストレプトゾトシン誘発視機能障害に対するブリンゾラミドナノ点眼液の有用性評価

  南 実沙; 後藤 涼花; 櫻井 達真; 明和 亮伍; 衣川 美宇; 出口 粧央里; 大竹 裕子; 長井 紀章

  日本眼薬理学会プログラム・抄録集 41回 37 - 37 日本眼薬理学会 2021年11月
• Balance of Drug Residence and Diffusion in Lacrimal Fluid Determine Ocular Bioavailability in In Situ Gels Incorporating Tranilast Nanoparticles.

  Misa Minami; Hiroko Otake; Yosuke Nakazawa; Norio Okamoto; Naoki Yamamoto; Hiroshi Sasaki; Noriaki Nagai

  Pharmaceutics 13 9 2021年09月 [査読有り]
   

  We previously designed ophthalmic formulations (nTRA) containing tranilast nanoparticles (Tra-NPs) with high uptake into ocular tissues. In this study, we used in situ gel (ISG) bases comprising combinations of pluronic F127 (F127) and methylcellulose (MC/F127), pluronic F68 (F68/F127), and Carbopol (Car/F127), and we developed in situ gels incorporating Tra-NPs (Tra-NP-incorporated ISNGs) such as nTRA-F127, nTRA-MC/F127, nTRA-F68/F127, and nTRA-Car/F127. Moreover, we demonstrated the therapeutic effect on conjunctival inflammation using lipopolysaccharide-induced rats. Each Tra-NP-incorporated ISNG was prepared by the bead mill method, the particle size was 40-190 nm, and the tranilast release and diffusion from formulation were nTRA > nTRA-F127 > nTRA-F68/F127 > nTRA-Car/F127 > nTRA-MC/F127. In the Tra-NP-incorporated ISNGs, the tranilast residence time in the lacrimal fluid, cornea, and conjunctiva was prolonged, although the Cmax was attenuated in comparison with nTRA. On the other hand, no significant difference in conjunctival inflammation between non- and nTRA-F127-instilled rats was found; however, the nTRA-F68/F127, nTRA-Car/F127, and nTRA-MC/F127 (combination-ISG) attenuated the vessel leakage, nitric oxide, and tumor necrosis factor-α expression. In particular, nTRA-F68/F127 was significant in preventing the conjunctival inflammation. In conclusion, we found that the combination-ISG base prolonged the residence time of Tra-NPs; however, Tra-NP release from the formulation was attenuated, and the Tmax was delayed longer than that in nTRA. The balance of drug residence and diffusion in lacrimal fluid may be important in providing high ocular bioavailability in formulations containing solid nanoparticles.
• Nanocrystalline Suspensions of Irbesartan Enhance Oral Bioavailability by Improving Drug Solubility and Leading Endocytosis Uptake into the Intestine.

  Saori Deguchi; Fumihiko Ogata; Masaki Watanabe; Hiroko Otake; Naoki Yamamoto; Naohito Kawasaki; Noriaki Nagai

  Pharmaceutics 13 9 2021年09月 [査読有り]
   

  We attempted to design irbesartan nanocrystalline (IRB-NC) suspensions by the bead mill method, and we evaluated the bioavailability (BA) in the oral administration of the nanocrystalline drug. The mean particle size of the IRB-NC suspensions was approximately 140 nm, and the crystalline structure of irbesartan in these suspensions was different using the bead mill method. The aggregation and degradation of irbesartan were not observed for one month, and the solubility increased. Moreover, the inclusion complex formation of IRB-NC suspensions with 2-hydroxypropyl-β-cyclodextrin was higher than that in traditional IRB powder (IRB-P). In addition, the intestinal absorption of IRB-NC suspensions was higher than that of IRB-P suspensions, and the reducing effect on blood pressure in spontaneously hypertensive SHR-SP rats orally administered IRB-NC suspensions was significantly higher than in those administered IRB-P suspensions. On the other hand, the intestinal penetration of IRB-NC suspensions was attenuated by the inhibitors of clathrin-dependent endocytosis (CME). In conclusion, we improved the low oral BA of irbesartan by preparing IRB-NC suspensions and showed that both the solubility and CME are related to the enhanced intestinal absorption of IRB-NC suspensions, resulting in an increase in their antihypertensive effect. These findings provide significant information for the development of oral nanomedicines.
• Energy-Dependent Endocytosis Is Responsible for Skin Penetration of Formulations Based on a Combination of Indomethacin Nanoparticles and l-Menthol in Rat and Göttingen Minipig.

  Hiroko Otake; Mizuki Yamaguchi; Fumihiko Ogata; Saori Deguchi; Naoki Yamamoto; Hiroshi Sasaki; Naohito Kawasaki; Noriaki Nagai

  International journal of molecular sciences 22 10 2021年05月 [査読有り]
   

  We previously designed a Carbopol gel formulation (N-IND/MEN) based on a combination of indomethacin solid nanoparticles (IND-NPs) and l-menthol, and we reported that the N-IND/MEN showed high transdermal penetration. However, the detailed mechanism for transdermal penetration of IND-NPs was not clearly defined. In this study, we investigated whether endocytosis in the skin tissue of rat and Göttingen minipig is related to the transdermal penetration of IND-NPs using pharmacological inhibitors of endocytosis. The pharmacological inhibitors used in this study are as follows: 54 µM nystatin, a caveolae-mediated endocytosis (CavME) inhibitor; 40 µM dynasore, a clathrin-mediated endocytosis (CME) inhibitor; and 2 µM rottlerin, a micropinocytosis (MP) inhibitor. The N-IND/MEN was prepared by a bead mill method, and the particle size of solid indomethacin was 79-216 nm. In both rat and Göttingen minipig skin, skin penetration of approximately 80% IND-NPs was limited by the stratum corneum (SC), although the penetration of SC was improved by the combination of l-menthol. On the other hand, the treatment of nystatin and dynasore decreased the transdermal penetration of indomethacin in rats and Göttingen minipigs treated with N-IND/MEN. Moreover, in addition to nystatin and dynasore, rottlerin attenuated the transdermal penetration of IND-NPs in the Göttingen minipigs' skin. In conclusion, we found that l-menthol enhanced the SC penetration of IND-NPs. In addition, this study suggests that the SC-passed IND-NPs are absorbed into the skin tissue by energy-dependent endocytosis (CavME, CME, and/or MP pathways) on the epidermis under the SC, resulting in an enhancement in transdermal penetration of IND-NPs. These findings provide significant information for the design of nanomedicines in transdermal formulations.
• Transdermal System Based on Solid Cilostazol Nanoparticles Attenuates Ischemia/Reperfusion-Induced Brain Injury in Mice.

  Hiroko Otake; Mizuki Yamaguchi; Fumihiko Ogata; Saori Deguchi; Naoki Yamamoto; Hiroshi Sasaki; Naohito Kawasaki; Noriaki Nagai

  Nanomaterials (Basel, Switzerland) 11 4 2021年04月 [査読有り]
   

  Cilostazol (CIL) exerted a protective effect by promoting blood-brain barrier integrity as well as improving the status of neurological dysfunctions following cerebral ischemia/reperfusion (I/R) injury. We attempted to design a 0.5% CIL carbopol gel using solid nanoparticles (CIL-Ngel), and then investigated the relationships between energy-dependent endocytosis and the skin penetration of CIL-Ngel in this study. In addition, we evaluated whether the CIL-Ngel attenuated I/R-induced brain injury in a middle cerebral artery occlusion (MCAO)/reperfusion model mouse. The particle size of CIL was decreased using a bead mill, and the CIL particles (14.9 × 1014 particles/0.3 g) in the CIL-Ngel were approximately 50-180 nm. The release of CIL in the CIL-Ngel was higher than that in gel containing CIL powder (CIL-Mgel), and the CIL particles were released from the CIL-Ngel as nanoparticles. In addition, the percutaneous absorption of CIL from the CIL-Ngel was higher in comparison with that from CIL-Mgel, and clathrin-dependent endocytosis and caveolae-dependent endocytosis were related to the enhanced skin penetration of CIL-NPs. In the traditional (oral administration of CIL powder, 3 mg/kg) and transdermal administration (CIL-Ngel, 0.3 g) for 3 days (once a day), the area under the plasma CIL concentration-time curves (AUC) was similar, although the CIL supplied to the blood by the CIL-Ngel was more sustained than that via oral administration of CIL powder. Furthermore, the CIL-Ngel attenuated the ischemic stroke. In conclusion, we designed a gel using solid CIL-NPs, and we showed that the sustained release of CIL by CIL-Ngel provided an effective treatment for ischemic stroke in MCAO/reperfusion model mice. These findings induce the possibilities of developing novel applications of CIL solid nanoparticles.
• Prevention of Postprandial Hyperglycemia by Ophthalmic Nanoparticles Based on Protamine Zinc Insulin in the Rabbit.

  Saori Deguchi; Fumihiko Ogata; Takumi Isaka; Hiroko Otake; Yosuke Nakazawa; Naohito Kawasaki; Noriaki Nagai

  Pharmaceutics 13 3 2021年03月 [査読有り]
   

  Postprandial hyperglycemia, a so-called blood glucose spike, is associated with enhanced risks of diabetes mellitus (DM) and its complications. In this study, we attempted to design nanoparticles (NPs) of protamine zinc insulin (PZI) by the bead mill method, and prepare ophthalmic formulations based on the PZI-NPs with (nPZI/P) or without polyacrylic acid (nPZI). In addition, we investigated whether the instillation of the newly developed nPZI and nPZI/P can prevent postprandial hyperglycemia in a rabbit model involving the oral glucose tolerance test (OGTT). The particle size of PZI was decreased by the bead mill to a range for both nPZI and nPZI/P of 80-550 nm with no observable aggregation for 6 d. Neither nPZI nor nPZI/P caused any noticeable corneal toxicity. The plasma INS levels in rabbits instilled with nPZI were significantly higher than in rabbits instilled with INS suspensions (commercially available formulations, CA-INS), and the plasma INS levels were further enhanced with the amount of polyacrylic acid in the nPZI/P. In addition, the rapid rise in plasma glucose levels in OGTT-treated rabbits was prevented by a single instillation of nPZI/P, which was significantly more effective at attenuating postprandial hyperglycemia (blood glucose spike) in comparison with nPZI. In conclusion, we designed nPZI/P, and show that a single instillation before OGTT attenuates the rapid enhancement of plasma glucose levels. These findings suggest a better management strategy for the postprandial blood glucose spike, which is an important target of DM therapy.
• イルベサルタンナノ結晶を用いた経口用固形製剤の設計 固化成形体の調製と薬物吸収性評価

  南 実沙; 渡辺 雅輝; 池 彩里; 下前 憂梨咲; 大竹 裕子; 長井 紀章

  日本薬学会年会要旨集 141年会 29P01 - 270S (公社)日本薬学会 2021年03月
• モメタゾンフランカルボン酸エステルのナノ粒子化と点鼻製剤への応用

  出口 粧央里; 吉富 丈治; 大竹 裕子; 長井 紀章

  日本薬学会年会要旨集 141年会 29P01 - 277S (公社)日本薬学会 2021年03月
• フェノフィブラートナノ点眼薬の開発と眼後部への薬物送達能評価

  後藤 涼花; 長岡 泰司; 出口 粧央里; 森本 泰光; 大竹 裕子; 長井 紀章

  日本薬学会年会要旨集 141年会 29P01 - 278S (公社)日本薬学会 2021年03月
• トラニラストナノ結晶を用いた結膜炎治療薬の開発 メチルセルロースは超微粒子の滞留性を高める

  南 実沙; 山崎 由夏; 大竹 裕子; 金井 一享; 長井 紀章

  日本眼薬理学会プログラム・抄録集 40回 42 - 42 日本眼薬理学会 2021年02月
• 眼科領域における生体適合性ポリマーの応用性 MPCポリマーはベンザルコニウム塩化物の角膜傷害性を軽減する

  長井 紀章; 南 実沙; 山崎 由夏; 大竹 裕子; 櫻井 俊輔; 原田 英治

  日本眼薬理学会プログラム・抄録集 40回 46 - 46 日本眼薬理学会 2021年02月
• Fixed-Combination Eye Drops Based on Fluorometholone Nanoparticles and Bromfenac/Levofloxacin Solution Improve Drug Corneal Penetration.

  Hiroko Otake; Ryoka Goto; Fumihiko Ogata; Takumi Isaka; Naohito Kawasaki; Shinichiro Kobayakawa; Toru Matsunaga; Noriaki Nagai

  International journal of nanomedicine 16 5343 - 5356 2021年 

  Purpose: The multi-instillation of three commercially available (CA) eye drops [fluorometholone (FL)-, bromfenac (BF)- and levofloxacin (LV)-eye drops] has been used to manage pain and inflammation post-intraocular surgery. However, the multi-instillation of these three eye drops causes corneal damage, and the FL drops have the disadvantage of low ocular bioavailability. To overcome these problems, we prepared fixed-combination eye drops based on FL nanoparticles (FL-NPs) and BF/LV solution (nFBL-FC), and evaluated the corneal toxicity and transcorneal penetration of the nFBL-FC eye drops. Methods: FL powder was mixed in 2-hydroxypropyl-β-cyclodextrin solution containing benzalkonium chloride, mannitol and methylcellulose, and milled with a Bead Smash 12 (5500 rpm for 30 s×30 times). The BF/LV solution was then added to the milled-dispersions to be used as nFBL-FC. The FL, BF and LV concentrations were measured by HPLC methods, and transcorneal penetration was evaluated in rabbits. Results: The FL particle size in nFBL-FC was 40-150 nm, with only 0.0018% in liquid form. No aggregation of FL particles in the nFBL-FC was observed for 1 month. The viability of human corneal epithelial cells treated with nFBL-FC was remarkably higher than that of cells subjected to the multi-instillation of the corresponding three CA-eye drops. In addition, the corneal penetrations (AUC) of the FL, BF and LV in nFBL-FC were 4.9-, 1.8-, and 7.1-fold those of the corresponding CA-eye drops, respectively. Moreover, the caveolae-dependent endocytosis (CavME) inhibitor (nystatin) significantly prevented the transcorneal penetration of these drugs. Conclusion: We prepared fixed-combination eye drops based on FL-NPs and BF/LV solution (nFBL-FC), and show that high levels of FL-NPs and dissolved BF/LV (liquid drugs) can be delivered into the aqueous humor by the instillation of nFBL-FC. Further, we show that CavME is mainly related to the enhancement of transcorneal penetration of both the solid (NPs) and liquid drugs.
• In Situ Gelling Systems Using Pluronic F127 Enhance Corneal Permeability of Indomethacin Nanocrystals.

  Noriaki Nagai; Takumi Isaka; Saori Deguchi; Misa Minami; Mizuki Yamaguchi; Hiroko Otake; Norio Okamoto; Yosuke Nakazawa

  International journal of molecular sciences 21 19 2020年09月 [査読有り]
   

  We previously designed an ophthalmic dispersion containing indomethacin nanocrystals (IMC-NCs), showing that multiple energy-dependent endocytoses led to the enhanced absorption of drugs from ocular dosage forms. In this study, we attempted to prepare Pluronic F-127 (PLF-127)-based in situ gel (ISG) incorporating IMC-NCs, and we investigated whether the instillation of the newly developed ISG incorporating IMC-NCs prolonged the precorneal resident time of the drug and improved ocular bioavailability. The IMC-NC-incorporating ISG was prepared using the bead-mill method and PLF-127, which yielded a mean particle size of 50-150 nm. The viscosity of the IMC-NC-incorporating ISG was higher at 37 °C than at 10 °C, and the diffusion and release of IMC-NCs in the IMC-NC-incorporating ISG were decreased by PLF-127 at 37 °C. In experiments using rabbits, the retention time of IMC levels in the lacrimal fluid was enhanced with PLF-127 in the IMC-NC-incorporating ISG, whereby the IMC-NC-incorporating ISG with 5% and 10% PLF-127 increased the transcorneal penetration of the IMCs. In contrast to the results with optimal PLF-127 (5% and 10%), excessive PLF-127 (15%) decreased the uptake of IMC-NCs after instillation. In conclusion, we found that IMC-NC-incorporating ISG with an optimal amount of PLF-127 (5-10%) resulted in higher IMC corneal permeation after instillation than that with excessive PLF-127, probably because of the balance between higher residence time and faster diffusion of IMC-NCs on the ocular surface. These findings provide significant information for developing ophthalmic nanomedicines.
• In Situ Gel Incorporating Disulfiram Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka Long-Evans Tokushima Fatty Rats.

  Saori Deguchi; Fumihiko Ogata; Mizuki Yamaguchi; Misa Minami; Hiroko Otake; Kazutaka Kanai; Naohito Kawasaki; Noriaki Nagai

  Cells 9 10 2020年09月 [査読有り]
   

  We attempted to design an ophthalmic in situ gel formulation incorporating disulfiram (DIS) nanoparticles (Dis-NPs/ISG) and demonstrated the therapeutic effect of Dis-NPs/ISG on retinal dysfunction in 15-month-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a rat model of diabetes. The DIS particles were crushed using a bead mill to prepare the nanoparticles, and the Dis-NPs/ISG was prepared using a combination of the DIS nanoparticles and an in situ gelling system based on methylcellulose (MC). The particle size of the Dis-NPs/ISG was 80-250 nm, and there was no detectable precipitation or aggregation for 1 month. Moreover, the Dis-NPs/ISG was gelled at 37 °C, and the drug was delivered into the retina by instillation. Only diethyldithiocarbamate (DDC) was detected in the retina (DIS was not detected) when the Dis-NPs/ISG was instilled in the right eye, and the DDC levels in the right retina were significantly higher than those in the left retina. In addition, the retinal residence time of the drug was prolonged by the application of the in situ gelling system, since the DDC levels in the retinas of rats instilled with Dis-NPs/ISG were higher than those in DIS nanoparticles without MC. Furthermore, repetitive instillation of the Dis-NPs/ISG attenuated the deterioration of electroretinograms (ERGs) in 15-month-old OLETF rats by preventing the collapse of ATP production via excessive nitric oxide and recovered the decrease in retinal function. These findings provide important information for the development of novel therapeutic approaches to diabetic retinopathy.
• Ophthalmic In Situ Gelling System Containing Lanosterol Nanoparticles Delays Collapse of Lens Structure in Shumiya Cataract Rats.

  Noriaki Nagai; Kazuki Umachi; Hiroko Otake; Mikako Oka; Noriko Hiramatsu; Hiroshi Sasaki; Naoki Yamamoto

  Pharmaceutics 12 7 2020年07月 [査読有り]
   

  We attempted to prepare ophthalmic in situ gel formulations containing lanosterol (Lan) nanoparticles (LA-NPs/ISG) and investigated the characteristics, delivery pathway into the lens, and anti-cataract effects of LA-NPs/ISG using SCR-N (rats with slight lens structure collapse) and SCR-C (rats with a combination of remarkable lens structure collapse and opacification). LA-NPs/ISG was prepared by bead milling of the dispersions containing 0.5% Lan powder, 5% 2-hydroxypropyl-β-cyclodextrin, 0.5% methylcellulose, 0.005% benzalkonium chloride, and 0.5% mannitol. The particle size distribution of Lan was 60-250 nm. The LA-NPs/ISG was gelled at 37 °C, and the LA-NPs/ISG was taken into the cornea by energy-dependent endocytosis and then released to the intraocular side. In addition, the Lan contents in the lenses of both SCR-N and SCR-C were increased by the repetitive instillation of LA-NPs/ISG (twice per day). The space and structure collapse in the lens of SCR-N with aging was attenuated by the instillation of LA-NPs/ISG. Moreover, the repetitive instillation of LA-NPs/ISG attenuated the changes in cataract-related factors (the enhancement of nitric oxide levels, calpain activity, lipid peroxidation levels, Ca2+ contents, and the decrease of Ca2+-ATPase activity) in the lenses of SCR-C, and the repetitive instillation of LA-NPs/ISG delayed the onset of opacification in the SCR-C. It is possible that the LA-NPs/ISG is useful in maintaining lens homeostasis.
• Hydrogel Formulations Incorporating Drug Nanocrystals Enhance the Therapeutic Effect of Rebamipide in a Hamster Model for Oral Mucositis.

  Noriaki Nagai; Ryotaro Seiriki; Saori Deguchi; Hiroko Otake; Noriko Hiramatsu; Hiroshi Sasaki; Naoki Yamamoto

  Pharmaceutics 12 6 2020年06月 [査読有り]
   

  A mouthwash formulation of rebamipide (REB) is commonly used to treat oral mucositis; however, this formulation does not provide sufficient treatment or prevention in cases of serious oral mucositis. To improve treatment, we attempted to design a hydrogel incorporating REB nanocrystals (R-NPs gel). The R-NPs gel was prepared by a bead mill method using carbopol hydrogel, methylcellulose and 2-hydroxypropyl-β-cyclodextrin, and another hydrogel incorporating REB microcrystals (R-MPs gel) was prepared following the same protocol but without the bead mill treatment. The REB particle size in the R-MPs gel was 0.15-25 μm, and while the REB particle size was 50-180 nm in the R-NPs gel. Next, we investigated the therapeutic effect of REB nanocrystals on oral mucositis using a hamster model. Almost all of the REB was released as drug nanocrystals from the R-NPs gel, and the REB content in the cheek pouch of hamsters treated with R-NPs gel was significantly higher than that of hamsters treated with R-MPs gel. Further, treatment with REB hydrogels enhanced the healing of oral wounds in the hamsters. REB accumulation in the cheek pouch of hamsters treated with the R-NPs gel was prevented by an inhibitor of clathrin-dependent endocytosis (CME) (40 μM dynasore). In conclusion, we designed an R-NPs gel and found that REB nanocrystals are taken up by tissues through CME, where they provide a persistent effect resulting in an enhancement of oral wound healing.
• メロキシカムナノ製剤の開発とその消化管吸収機構の解明

  山口 瑞季; 池田 瑠璃; 渡辺 雅輝; 大竹 裕子; 長井 紀章

  日本薬剤学会年会講演要旨集 35年会 148 - 148 (公社)日本薬剤学会 2020年05月
• Clinical Academic Topics 薬物ナノ結晶と眼内薬物送達技術

  大竹 裕子; 長井 紀章

  アレルギーの臨床 40 5 385 - 387 (株)北隆館 2020年05月 

  主な眼アレルギー疾患として結膜炎やぶどう膜炎があり、病変部位は眼前〜眼後部まで広範囲にわたる。一般的な治療法として点眼療法が選択されるが、点眼直後に涙液による薬物の希釈、眼房水による速やかな薬物排出などを生じるため、薬物眼内移行性が低く、従来の溶液型または懸濁液型点眼液では、眼内の疾患に対しては十分な治療効果を得ることは難しいのが現状である。これら背景から、アレルギー性眼疾患領域においても、眼内移行性を高めた点眼製剤の開発が切望されている。本稿では、薬物ナノ結晶を用いた点眼製剤を開発するとともに、眼内への薬物送達の可能性について検討を行った。(著者抄録)
• Enhancement of Amyloid β1-43 Production in the Lens Epithelium of Japanese Type 2 Diabetic Patients.

  Yu Mano; Hiroko Otake; Teppei Shibata; Eri Kubo; Hiroshi Sasaki; Noriaki Nagai

  Biomedicines 8 4 2020年04月 [査読有り]
   

  We investigated whether the accumulation of amyloid β-protein (Aβ) is enhanced in the lenses of diabetic patients. Lens epithelium samples were collected from Japanese patients during cataract surgery, and the Aβ levels and gene expression of Aβ-producing and -degrading enzymes in the samples were measured by ELISA and real-time RT-PCR, respectively. The Aβ 1-43 levels in lenses of non-diabetic patients were low (0.11 pmol/g protein), while the levels in lenses of diabetic patients were significantly (6-fold) higher. Moreover, the Aβ1-43/total-Aβ ratio in the lenses of diabetic patients was also significantly higher than non-diabetic patients (p < 0.05). In addition, the mRNA levels for Aβ-producing enzymes were also enhanced in the lenses of diabetic patients. In contrast to the results for Aβ-producing enzymes, the mRNAs for the Aβ-degrading enzymes in the lenses of diabetic patients were significantly lower than in non-diabetic patients (p < 0.05). Furthermore, Aβ 1-43/total-Aβ ratio in lenses was found to increase with plasma glucose level. In conclusion, these results suggest that high glucose levels cause both an increase in Aβ production and a decrease in Aβ degradation, and these changes lead to the enhancement in Aβ1-43 accumulation in the lenses of diabetic patients. These findings are useful for developing therapies for diabetic cataracts and for developing anti-cataract drugs.
• Development of Sustained-Release Ophthalmic Formulation Based on Tranilast Solid Nanoparticles.

  Misa Minami; Ryotaro Seiriki; Hiroko Otake; Yosuke Nakazawa; Kazutaka Kanai; Tadatoshi Tanino; Noriaki Nagai

  Materials (Basel, Switzerland) 13 7 2020年04月 [査読有り]
   

  Eye drops containing Tranilast (TL), N-(3,4-dimethoxycinnamoyl) anthramilic acid, are used as an anti-allergic conjunctivitis drug in the ophthalmic field. Traditional eye drops are very patient compliant, although the bioavailability (BA) of most eye drops is low since eye drops cannot be instilled beyond the capacity of the conjunctival sac due to its limited volume. Thus, traditional eye drops have low BA and a short duration of the drug on the ocular surface, so solutions to these problems are highly anticipated. In this study, we designed a sustained-release drug-delivery system (DDS) for TL nanoparticles. TL nanoparticles were prepared by bead mill treatment, and the gel formulations containing TL nanoparticles (TL-NPs-Gel, particle size 50 nm-100 nm) were provided by carboxypolymethylene. The crystal structure of TL with and without bead mill treatment is the same, but the TL solubility in formulations containing nanoparticles was 5.3-fold higher compared with gel formulations containing TL microparticles (TL-MPs-Gel). The photo and thermal stabilities of TL-NPs-Gel are also higher than those of dissolved TL. Moreover, when TL-NPs-Gel is applied to the upper eyelid skin (outside), the TL is released as nanoparticles, and delivered to the lacrimal fluid through the meibomian glands. In addition, the TL release profile for TL-NPs-Gel was sustained over 180 min after the treatment. These findings can be used to develop a sustained-release DDS in the ophthalmic field.
• Oral Administration System Based on Meloxicam Nanocrystals: Decreased Dose Due to High Bioavailability Attenuates Risk of Gastrointestinal Side Effects.

  Noriaki Nagai; Fumihiko Ogata; Hiroko Otake; Naohito Kawasaki

  Pharmaceutics 12 4 2020年04月 [査読有り]
   

  Meloxicam (MLX) is widely applied as a therapy for rheumatoid arthritis (RA); however, it takes far too long to reach its peak plasma concentration for a quick onset effect, and gastrointestinal toxicity has been observed in RA patients taking it. To solve these problems, we designed MLX solid nanoparticles (MLX-NPs) by the bead mill method and used them to prepare new oral formulations. The particle size of the MLX-NPs was approximately 20-180 nm, and they remained in the nano-size range for 1 month. The tmax of MLX-NPs was shorter than that of traditional MLX dispersions (MLX-TDs), and the intestinal penetration of MLX-NPs was significantly higher in comparison with MLX-TDs (P < 0.05). Caveolae-dependent endocytosis (CavME), clathrin-dependent endocytosis (CME), and micropinocytosis (MP) were found to be related to the high intestinal penetration of MLX-NPs. The area under the plasma MLX concentration-time curve (AUC) for MLX-NPs was 5-fold higher than that for MLX-TDs (P < 0.05), and the AUC in rats administered 0.05 mg/kg MLX-NPs were similar to rats administered the therapeutic dose of 0.2 mg/kg MLX-TDs. In addition, the anti-inflammatory effect of the MLX-NPs was also significantly higher than that of MLX-TDs at the corresponding dose (P < 0.05), and the therapeutic effect of 0.2 mg/kg MLX-TDs and 0.05 mg/kg MLX-NPs in adjuvant-induced arthritis (AA) rats showed no difference. Furthermore, the gastrointestinal lesions in AA rats treated repetitively with 0.05 mg/kg MLX-NPs were fewer than in rats receiving 0.2 mg/kg MLX-TDs (P < 0.05). In conclusion, we demonstrate that MLX solid nanoparticles allow a quick onset of therapeutic effect and that three endocytosis pathways, CavME, CME, and MP, are related to the high absorption of solid nanoparticles. In addition, we found that MLX solid nanoparticles make it possible to reduce the amount of orally administered drugs, and treatment with low doses of MLX-NPs allows RA therapy without intestinal ulcerogenic responses to MLX. These findings are useful for designing therapies for RA patients.
• Oral Administration System Based on Meloxicam Nanocrystals: Decreased Dose Due to High Bioavailability Attenuates Risk of Gastrointestinal Side Effects.

  Noriaki Nagai; Fumihiko Ogata; Hiroko Otake; Naohito Kawasaki

  Pharmaceutics 12 4 2020年04月 [査読有り]
   

  Meloxicam (MLX) is widely applied as a therapy for rheumatoid arthritis (RA); however, it takes far too long to reach its peak plasma concentration for a quick onset effect, and gastrointestinal toxicity has been observed in RA patients taking it. To solve these problems, we designed MLX solid nanoparticles (MLX-NPs) by the bead mill method and used them to prepare new oral formulations. The particle size of the MLX-NPs was approximately 20-180 nm, and they remained in the nano-size range for 1 month. The tmax of MLX-NPs was shorter than that of traditional MLX dispersions (MLX-TDs), and the intestinal penetration of MLX-NPs was significantly higher in comparison with MLX-TDs (P < 0.05). Caveolae-dependent endocytosis (CavME), clathrin-dependent endocytosis (CME), and micropinocytosis (MP) were found to be related to the high intestinal penetration of MLX-NPs. The area under the plasma MLX concentration-time curve (AUC) for MLX-NPs was 5-fold higher than that for MLX-TDs (P < 0.05), and the AUC in rats administered 0.05 mg/kg MLX-NPs were similar to rats administered the therapeutic dose of 0.2 mg/kg MLX-TDs. In addition, the anti-inflammatory effect of the MLX-NPs was also significantly higher than that of MLX-TDs at the corresponding dose (P < 0.05), and the therapeutic effect of 0.2 mg/kg MLX-TDs and 0.05 mg/kg MLX-NPs in adjuvant-induced arthritis (AA) rats showed no difference. Furthermore, the gastrointestinal lesions in AA rats treated repetitively with 0.05 mg/kg MLX-NPs were fewer than in rats receiving 0.2 mg/kg MLX-TDs (P < 0.05). In conclusion, we demonstrate that MLX solid nanoparticles allow a quick onset of therapeutic effect and that three endocytosis pathways, CavME, CME, and MP, are related to the high absorption of solid nanoparticles. In addition, we found that MLX solid nanoparticles make it possible to reduce the amount of orally administered drugs, and treatment with low doses of MLX-NPs allows RA therapy without intestinal ulcerogenic responses to MLX. These findings are useful for designing therapies for RA patients.
• I-メントールによるインドメタシンナノ結晶製剤の経皮吸収促進効果とその透過機序の解明

  山口 瑞季; 福岡 侑也; 永福 紡; 川口 陽菜子; 原 雅紀; 大竹 裕子; 長井 紀章

  日本薬学会年会要旨集 140年会 26K - am07S (公社)日本薬学会 2020年03月
• 食後高血糖の制御を目的とした新剤形の確立 インスリンナノ点眼薬は血糖値スパイクを抑制する

  長井 紀章; 畠中 優斗; 井阪 匠; 出口 粧央里; 大竹 裕子; 金井 一享; 岡本 紀夫; 下村 嘉一

  日本薬学会年会要旨集 140年会 26P - pm169 (公社)日本薬学会 2020年03月
• ナノ結晶点眼製剤による新規結膜炎治療薬の確立 トラニラストナノ結晶点眼液の抗炎症効果

  南 実沙; 山崎 由夏; 蛭子 小春; 宇野 樹; 大竹 裕子; 長井 紀章

  日本薬学会年会要旨集 140年会 27Y - pm15S (公社)日本薬学会 2020年03月
• ブレオマイシン誘発性肺線維症モデルマウスにおけるトラニラストナノ結晶分散液の肺内投与時における有用性評価

  大竹 裕子; 秋山 紗和子; 片山 理沙; 福本 航; 長井 紀章

  日本薬学会年会要旨集 140年会 28P - pm082 (公社)日本薬学会 2020年03月
• Novel Sustained-Release Drug Delivery System for Dry Eye Therapy by Rebamipide Nanoparticles.

  Noriaki Nagai; Miyu Ishii; Ryotaro Seiriki; Fumihiko Ogata; Hiroko Otake; Yosuke Nakazawa; Norio Okamoto; Kazutaka Kanai; Naohito Kawasaki

  Pharmaceutics 12 2 2020年02月 [査読有り]
   

  The commercially available rebamipide ophthalmic suspension (CA-REB) was approved for clinical use in patients with dry eye; however, the residence time on the ocular surface for the traditional formulations is short, since the drug is removed from the ocular surface through the nasolacrimal duct. In this study, we designed a novel sustained-release drug delivery system (DDS) for dry eye therapy by rebamipide nanoparticles. The rebamipide solid nanoparticle-based ophthalmic formulation (REB-NPs) was prepared by a bead mill using additives (2-hydroxypropyl-β-cyclodextrin and methylcellulose) and a gel base (carbopol). The rebamipide particles formed are ellipsoid, with a particle size in the range of 40-200 nm. The rebamipide in the REB-NPs applied to eyelids was delivered into the lacrimal fluid through the meibomian glands, and sustained drug release was observed in comparison with CA-REB. Moreover, the REB-NPs increased the mucin levels in the lacrimal fluid and healed tear film breakup levels in an N-acetylcysteine-treated rabbit model. The information about this novel DDS route and creation of a nano-formulation can be used to design further studies aimed at therapy for dry eye.
• The Intravitreal Injection of Lanosterol Nanoparticles Rescues Lens Structure Collapse at an Early Stage in Shumiya Cataract Rats.

  Noriaki Nagai; Yuya Fukuoka; Kanta Sato; Hiroko Otake; Atsushi Taga; Mikako Oka; Noriko Hiramatsu; Naoki Yamamoto

  International journal of molecular sciences 21 3 2020年02月 [査読有り]
   

  We designed an intravitreal injection formulation containing lanosterol nanoparticles (LAN-NPs) via the bead mill method and evaluated the therapeutic effect of LAN-NPs on lens structure collapse and opacification using two rat cataract models (SCR-N, rats with slight lens structure collapse; SCR-C, rats with the combination of a remarkable lens structure collapse and opacification). The particle size of lanosterol in the LAN-NPs was around 50-400 nm. A single injection of LAN-NPs (0.5%) supplied lanosterol into the lens for 48 h, and no irritation or muddiness was observed following repeated injections of LAN-NPs for 6 weeks (once every 2 days). Moreover, LAN-NPs repaired the slight collapse of the lens structure in SCR-N. Although the remarkable changes in the lens structure of SCR-C were not repaired by LAN-NP, the onset of opacification was delayed. In addition, the increase of cataract-related factors (Ca2+ contents, nitric oxide levels, lipid peroxidation and calpain activity levels) in the lenses of SCR-C was attenuated by the repeated injection of LAN-NPs. It is possible that a deficiency of lanosterol promotes the production of oxidative stress. In conclusion, it is difficult to improve serious structural collapse with posterior movement of the lens nucleus with a supplement of lanosterol via LAN-NPs. However, the intravitreal injection of LAN-NPs was found to repair the space and structural collapse in the early stages in the lenses.
• An in situ Gelling System Based on Methylcellulose and Tranilast Solid Nanoparticles Enhances Ocular Residence Time and Drug Absorption Into the Cornea and Conjunctiva.

  Noriaki Nagai; Misa Minami; Saori Deguchi; Hiroko Otake; Hiroshi Sasaki; Naoki Yamamoto

  Frontiers in bioengineering and biotechnology 8 764 - 764 2020年 [査読有り]
   

  We previously developed ophthalmic formulations containing tranilast nanopartaicles (ophthalmic TL-NPs formulations), and found them to show high uptake into ocular tissues. In this study, we aimed to design an in situ gel incorporating TL-NPs with 0.5-3% methylcellulose (MC, type SM-4) to ensure long residence time of the drug at the ocular surface. The ophthalmic TL-NPs formulations were prepared by the bead mill method, which yielded a mean particle size of ~93 nm with or without MC (0.5-3%). Although the dispersibility of TL particles in ophthalmic formulations increased with the MC content, the diffusion behavior of TL particles in the dispersion medium decreased with MC content. In an in vivo study using rats, the TL content in the lacrimal fluid was enhanced with MC content in the ophthalmic TL-NPs formulations, and the optimum amount of MC (0.5-1.5%) enhanced the TL content in the cornea and conjunctiva, and an anti-inflammatory effect of TL in rats instilled with ophthalmic TL-NPs formulations was observed. On the other hand, excessive MC (3%) prevented the corneal uptake of TL-NPs after instillation, and the anti-inflammation effect of TL was lower than that of ophthalmic TL-NPs formulations with optimum MC (0.5-1.5%). In conclusion, we found that gel formulations of TL-NPs with 0.5 and 1.5% MC provided a prolonged pre-corneal and pre-conjunctival contact time of TL, and resulted in higher TL contents in the cornea and conjunctiva following instillation in comparison with TL-NPs with or without 3% MC. This is probably due to the balance between the higher residence time and faster diffusion of TL-NPs on the ocular surface. These findings provide significant information that can be used to design further studies aimed at developing ophthalmic nanomedicines.
• Effects of the Ophthalmic Additive Mannitol on Antimicrobial Activity and Corneal Toxicity of Various Preservatives.

  Kazunori Inaba; Misa Minami; Mizuki Yamaguchi; Ryoka Goto; Hiroko Otake; Takeshi Kotake; Noriaki Nagai

  Chemical & pharmaceutical bulletin 68 11 1069 - 1073 2020年 [査読有り]
   

  Ophthalmic preservatives are indispensable in eye drop formulations, but may be toxic to corneal structures. Corneal damage necessitates the discontinuation of treatment with ophthalmic solutions. Therefore, the development of a new and safe preservative system without corneal toxicity is needed. The present study investigated the effects of mannitol on the antimicrobial activities and corneal toxicities of various preservatives using Escherichia coli and a human corneal epithelial cell line (HCE-T cells). The following preservatives were examined: boric acid (BA), benzalkonium chloride (BAC), methyl parahydroxybenzoate (MP), propyl parahydroxybenzoate (PP), sodium chlorite (SC), and zinc chloride (ZC). The antimicrobial activities and HCE-T-cell toxicities of 50 µg/mL BA, MP, PP, SC, and ZC were reduced by a co-treatment with mannitol (0-300 µg/mL). The suppressed antimicrobial activities of BA, MP, PP, and SC by the co-treatment with mannitol were restored by the application of a mannitol content higher than 500 µg/mL. In contrast to these 5 preservatives, the addition of mannitol did not affect the antimicrobial activity of BAC and attenuated its HCE-T cell toxicity. Therefore, the balance between the contents of mannitol and preservatives is important in co-treatments. The present results will serve as a guide for the future development of eye drop formulations without corneal toxicity.
• Retinal proteomic evaluation of rats following streptozotocin‑injection using shotgun proteomics.

  Otake H; Yamamoto T; Deguchi S; Taga A; Nagai N

  Molecular medicine reports 21 1 379 - 386 2020年01月 [査読有り]
   

  It is important to elucidate how retinal stimulation leads to retinal protection and dysfunction. The current study aimed to identify factors that are up‑ and downregulated in the retinas of streptozotocin (STZ)‑induced diabetic rats with acute retinal dysfunction. Retinal function was measured and changes in protein expressions were determined using electroretinograms (ERGs) and liquid chromatography/mass spectroscopy‑based shotgun proteomics, respectively. The results revealed that the plasma glucose levels of STZ rats were markedly higher when compared with normal rats. Furthermore, levels of a‑waves, b‑waves and oscillatory potential amplitudes on ERGs in STZ rats were decreased compared with healthy animals. With use of shotgun proteomics, 391 proteins were identified in the retinas of normal rats and 541 proteins were found in the retinas of STZ rats. Of the 560 proteins identified in rat retinas, 372 (66.4%) were present in both normal and STZ rats. Of these, 19 (3.39%) were unique to normal rats and 169 (30.1%) were unique to STZ rats. Gene Ontology analysis was performed on the candidate proteins that were differentially regulated in the retinas of STZ rats and focused on those classified as 'protein binding', which serve important roles in retinal neurodegeneration. The results revealed an excessive expression of retinol‑binding protein 1 (RBP1) and a negative expression of rod outer segment membrane protein 1 (Rom-1) in the retinas of STZ rats. Therefore, retinal function may be decreased with STZ‑induced injury, and expressions of Rom‑1 and RBP1 may be altered in the retinas of STZ rats.
• 医薬品適正使用の取り組み セレン含有院内製剤の水剤から錠剤への剤型変更後の評価

  覚野 律; 大橋 香菜子; 桑原 明日香; 脇 啓子; 仲村 弥栄子; 田邨 保之; 森 惠子; 木原 理絵; 中村 明美; 都市 美晴; 川端 成佐; 中尾 元紀; 大竹 裕子; 松野 純男; 緒方 文彦; 川崎 直人; 長井 紀章

  国立病院総合医学会講演抄録集 73回 WS11 - 4 国立病院総合医学会 2019年11月 [査読有り]
  
• Solid Nanocrystals of Rebamipide Promote Recovery from Indomethacin-Induced Gastrointestinal Bleeding.

  Noriaki Nagai; Ryusuke Sakamoto; Seiji Yamamoto; Saori Deguchi; Hiroko Otake; Tadatoshi Tanino

  International journal of molecular sciences 20 20 2019年10月 [査読有り]
   

  Indomethacin (IMC)-induced gastrointestinal (GI) injuries are more common in rheumatoid arthritis (RA) patients than in other IMC users, and the overexpression of nitric oxide (NO) via inducible NO synthase (iNOS) is related to the seriousness of IMC-induced GI injuries. However, sufficient strategies to prevent IMC-induced GI injuries have not yet been established. In this study, we designed dispersions of rebamipide (RBM) solid nanocrystals (particle size: 30-190 nm) by a bead mill method (RBM-NDs), and investigated whether the oral administration of RBM-NDs is useful to prevent IMC-induced GI injuries. The RBM nanocrystals were spherical and had a solubility 4.71-fold greater than dispersions of traditional RBM powder (RBM-TDs). In addition, the RBM-NDs were stable for 1 month after preparation. The RBM contents in the stomach, jejunum, and ileum of rats orally administered RBM-NDs were significantly higher than in rats administered RBM-TDs. Moreover, the oral administration of RBM-NDs decreased the NO levels via iNOS and area of the GI lesions in IMC-stimulated RA (adjuvant-induced arthritis rat) rats in comparison with the oral administration of RBM-TDs. Thus, we show that the oral administration of RBM-NDs provides a high drug supply to the GI mucosa, resulting in a therapeutic effect on IMC-induced GI injuries. Solid nanocrystalline RBM preparations may offer effective therapy for RA patients.
• Combination with l-Menthol Enhances Transdermal Penetration of Indomethacin Solid Nanoparticles.

  Noriaki Nagai; Fumihiko Ogata; Mizuki Yamaguchi; Yuya Fukuoka; Hiroko Otake; Yosuke Nakazawa; Naohito Kawasaki

  International journal of molecular sciences 20 15 2019年07月 [査読有り]
   

  This study designed the transdermal formulations containing indomethacin (IMC)-1% IMC was crushed with 0.5% methylcellulose and 5% 2-hydroxypropyl-β-cyclodextrin by the bead mill method, and the milled IMC was gelled with or without 2% l-menthol (a permeation enhancer) by Carbopol® 934 (without menthol, N-IMC gel; with menthol, N-IMC/MT gel). In addition, the drug release, skin penetration and percutaneous absorption of the N-IMC/MT gel were investigated. The particle sizes of N-IMC gel were approximately 50-200 nm, and the combination with l-menthol did not affect the particle characterization of the transdermal formulations. In an in vitro experiment using a Franz diffusion cell, the skin penetration in N-IMC/MT gel was enhanced than the N-IMC gel, and the percutaneous absorption (AUC) from the N-IMC/MT gel was 2-fold higher than the N-IMC gel. On the other hand, the skin penetration from the N-IMC/MT gel was remarkably attenuated at a 4 °C condition, a temperature that inhibits all energy-dependent endocytosis. In conclusion, this study designed transdermal formulations containing IMC solid nanoparticles and l-menthol, and found that the combination with l-menthol enhanced the skin penetration of the IMC solid nanoparticles. In addition, the energy-dependency of the skin penetration of IMC solid nanoparticles was demonstrated. These findings suggest the utility of a transdermal drug delivery system to provide the easy application of solid nanoparticles (SNPs).
• Changes in mitochondrial cytochrome c oxidase mRNA levels with cataract severity in lens epithelia of Japanese patients.

  Noriaki Nagai; Yu Mano; Hiroko Otake; Teppei Shibata; Eri Kubo; Hiroshi Sasaki

  Molecular medicine reports 19 6 5464 - 5472 2019年06月 [査読有り]
   

  We previously reported that the collapse of ATP production via mitochondrial damage causes ATPase dysfunction, resulting in the onset or progression of lens opacification in cataracts in model rats. In the present study, it was investigated whether the mRNA expression levels of the three subtypes of mitochondrial cytochrome c oxidase (MTCO)1, 2 and 3 and ATP content change with the type and severity of cataracts in human lens. Samples of lens epithelium were collected from Japanese patients during cataract surgery, and the type and severity of the cataracts (grade) were determined according to the WHO classification [cortical (COR), nuclear (NUC), posterior subcapsular (PSC) opacification]. The MTCO1‑3 mRNA expression levels in patients with grade‑1 COR, NUC and PSC opacification were significantly enhanced compared with those of normal patients. The enhanced MTCO1‑3 mRNA levels subsequently decreased in patients with COR, and the MTCO1‑3 mRNA levels and ATP levels in patients with grade‑3 COR were similar to those in normal patients. However, the mRNA expression levels of MTCO3 in patients with grade 3‑NUC opacification and MTCO1‑3 in patients with grade‑3 PSC opacification, along with the ATP content, were significantly lower than in patients without cataracts. In conclusion, it was revealed that ATP production in lens epithelium is enhanced in early‑stage cataracts (grade‑1) in Japanese patients with COR, NUC and PSC opacification. In addition, in severe cataracts (grade‑3), ATP production and content are strongly decreased in Japanese patients with PSC opacification. ATP depletion in human lens epithelium with PSC opacification may promote lens opacification by ATPase dysfunction.
• Therapeutic Potential of a Combination of Magnesium Hydroxide Nanoparticles and Sericin for Epithelial Corneal Wound Healing.

  Noriaki Nagai; Yoshie Iwai; Saori Deguchi; Hiroko Otake; Kazutaka Kanai; Norio Okamoto; Yoshikazu Shimomura

  Nanomaterials (Basel, Switzerland) 9 5 2019年05月 [査読有り]
   

  We previously found the instillation of sericin to be useful as therapy for keratopathy with or without diabetes mellitus. In this study, we investigated whether a combination of solid magnesium hydroxide nanoparticles (MHN) enhances epithelial corneal wound healing by sericin using rabbits, normal rats and type 2 diabetes mellitus rats with debrided corneal epithelium (ex vivo and in vivo studies). Ophthalmic formulations containing sericin and MHN (N-Ser) were prepared using a bead mill method. The mean particle size of the N-Ser was 110.3 nm at the time of preparation, and 148.1 nm one month later. The instillation of N-Ser had no effect on the amount of lacrimal fluid in normal rabbits (in vivo), but the MHN in N-Ser was found to expand the intercellular space in ex vivo rat corneas. In addition, the instillation of N-Ser increased the phosphorylation of Extracellular Signal-regulated Kinase (ERK)1/2, a factor involved in cell adhesion and cell proliferation in the corneal epithelium, in comparison with the instillation of sericin alone. The combination with MHN enhanced epithelial corneal wound healing by sericin in rat debrided corneal epithelium (in vivo). This study provides significant information to prepare potent drugs to cure severe keratopathy, such as diabetic keratopathy.
• Energy-Dependent Endocytosis is Involved in the Absorption of Indomethacin Nanoparticles in the Small Intestine.

  Miyu Ishii; Yuya Fukuoka; Saori Deguchi; Hiroko Otake; Tadatoshi Tanino; Noriaki Nagai

  International journal of molecular sciences 20 3 2019年01月 [査読有り]
   

  We previously reported that oral formulations containing indomethacin nanoparticles (IND-NPs) showed high bioavailability, and, consequently, improved therapeutic effects and reduced injury to the small intestine. However, the pathway for the transintestinal penetration of nanoparticles remained unclear. Thus, in this study, we investigated whether endocytosis was related to the penetration of IND-NPs (72.1 nm) using a transcell set with Caco-2 cells or rat intestine. Four inhibitors of various endocytosis pathways were used [nystatin, caveolae-dependent endocytosis (CavME); dynasore, clathrin-dependent endocytosis (CME); rottlerin, macropinocytosis; and cytochalasin D, phagocytosis inhibitor], and all energy-dependent endocytosis was inhibited at temperatures under 4 °C in this study. Although IND-NPs showed high transintestinal penetration, no particles were detected in the basolateral side. IND-NPs penetration was strongly prevented at temperatures under 4 °C. In experiments using pharmacological inhibitors, only CME inhibited penetration in the jejunum, while in the ileum, both CavME and CME significantly attenuated penetration. In conclusion, we found a novel pathway for the transintestinal penetration of drug nanoparticles. Our hypothesis was that nanoparticles would be taken up into the intestinal epithelium by endocytosis (CME in jejunum, CavME and CME in ileum), and dissolved and diffused in the intestine. Our findings are likely to be of significant use for the development of nanomedicines.
• Drug Delivery System Based On Minoxidil Nanoparticles Promotes Hair Growth In C57BL/6 Mice.

  Noriaki Nagai; Yoshie Iwai; Akane Sakamoto; Hiroko Otake; Yoshihiro Oaku; Akinari Abe; Tohru Nagahama

  International journal of nanomedicine 14 7921 - 7931 2019年 [査読有り]
   

  Purpose: We designed formulations based on minoxidil (MXD) nanoparticles (N-MXD) and examined whether N-MXD can increase drug delivery into the follicles. In addition, we investigated the effect of N-MXD on hair growth in C57BL/6 mice. Methods: N-MXD (1%) was prepared as follows: methylcellulose, p-hydroxyalkylbenzoates, mannitol, and MXD were dispersed in purified water and milled using zirconia beads under refrigeration (5500 rpm, 30 s×15 times, intermittent milling). C57BL/6 mice were used to evaluate hair-growth effects. The expression levels of mRNA and protein for vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) were determined by real-time PCR and ELISA methods, respectively. Results: The ratio of solid-MXD was approximately 60% in N-MXD, and the MXD nanoparticles (90-300 nm) were oblong in shape. For the design of nanomedicines, usability is important. Therefore, we measured the stability and toxicity after N-MXD treatment. No agglutination of MXD nanoparticles was detected for 2 weeks, and no redness or MXD powder residue was observed in the skin after repetitive applications of N-MXD. Next, we evaluated hair-growth effects by N-MXD treatment. MXD contents in the skin tissue from N-MXD were lower than for commercially available MXD formulations (CA-MXD). Conversely, MXD contents in the hair bulbs were higher for N-MXD than for CA-MXD, and the drug efficacy of N-MXD was also higher than that of CA-MXD. In addition, the mRNA and protein levels of IGF-1 and VEGF were enhanced by the repetitive application of N-MXD and CA-MXD, and the enhanced IGF-1 and VEGF levels were significantly higher for N-MXD than for CA-MXD. Conclusion: We designed a novel nanomedicine based on MXD nanoparticles and showed that N-MXD can deliver MXD into hair bulbs via hair follicles and that the therapeutic efficiency for hair growth is higher than for CA-MXD (solution type).
• [Effect of Methylcellulose (Cellulose Derivatives) on Ibuprofen-crushing Efficiency in Nano Pulverizer NP-100].

  Noriaki Nagai; Yuka Yamasaki; Tsubasa Nakamura; Hiroko Otake; Naoya Okamoto

  Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 139 1 123 - 130 2019年 [査読有り]
   

  It is expected that drug systems using nanoparticles will improve the problem of poor water solubility and bioavailability of lipophilic drugs. However, it is difficult to prepare the formulations containing nanoparticles, and it is important to determine the concentration and kind of additives to prepare the formulations. We previously reported that a nano pulverizer NP-100 is possible to prepare drug nanoparticles for the 2-3 min, and the cellulose derivatives (metolose®, methylcellulose) is usefulness to prepare the nanoparticles by the mill method. In this study, we investigated the relationships of methylcellulose type and crushing efficiency in NP-100. First, we demonstrated the effect of viscosity in the various methylcellulose on the ibuprofen (IBU, lipophilic drug) particle size, and showed that the viscosity did not relate the crushing efficiency by the NP-100. Next, we measured the changes of cumulative size frequency curve in IBU particles by the combination of the NP-100 and 0.1-2.0% methylcellulose (SM-4, 400 and 4000). The appropriate addition reached IBU nanoparticles, although, the appropriate addition amount of methylcellulose was different in the SM-4 (0.5%), 400 (1.0%) and 4000 (1.2%). In addition, the IBU became meringue-like when subjected to the bead mill method in the less of methylcellulose, and excessive addition of methylcellulose increased the ratio of coarse particle. In conclusion, this results show that the appropriate addition amount of methylcellulose is different in the type of methylcellulose, and these changes of cumulative size frequency curve is useful as index to determine the concentration and type of additives in the nanoparticle production.
• Evaluation of Dissolution Profile between Original and Generic Products of Zolpidem Tartrate by Microdialysis-HPLC.

  Kazunori Inaba; Toshiharu Oie; Hiroko Otake; Takeshi Kotake; Noriaki Nagai

  Chemical & pharmaceutical bulletin 67 2 120 - 124 2019年 [査読有り]
   

  The evaluation of the dissolution profile of hypnotic drugs is important to promote switching from original products to generic products by removing distrust in generic hypnotics. In this study, we investigated differences in the dissolution profiles between original and generic products (GE-D, GE-S, and GE-T) in commercially available zolpidem tartrate (ZOL) products using the HPLC method using a connected microdialysis probe (microdialysis-HPLC method). Although the degree of hardness and the disintegration time were not different among the original, GE-S, and GE-T, GE-D was 1.4 times harder than the other products. The disintegration time of GE-D was approximately twice as long as that of the original product. Generic products dissolved rapidly as compared with the original product, however, the dissolution rate in the ZOL powder (milled ZOL product) was not different between the original and generic products. Macrogol 6000 (polyethylene glycol (PEG)-6000) was used in the generic products, and this additive was the only PEG difference from the original product. We investigated whether the PEG in the product affected the solubility of ZOL and found that the addition of PEG-4000 or PEG-6000 significantly increased the dissolution rate. These results suggest that the solubility of ZOL may be increased by PEG when the product is disintegrated, resulting in the increased dissolution rate in the generic products. In conclusion, we found that the difference of PEG affected the dissolution profile in the disintegration process using the microdialysis-HPLC method. This finding can help ensure the safety of milled products and the selection of additives.
• Energy-dependent endocytosis is responsible for drug transcorneal penetration following the instillation of ophthalmic formulations containing indomethacin nanoparticles.

  Noriaki Nagai; Fumihiko Ogata; Hiroko Otake; Yosuke Nakazawa; Naohito Kawasaki

  International journal of nanomedicine 14 1213 - 1227 2019年 [査読有り]
   

  Purpose: We previously found that ophthalmic formulations containing nanoparticles prepared by a bead mill method lead to an increase in bioavailability in comparison with traditional formulations (solution type). However, the transcorneal penetration pathway for ophthalmic formulations has not been explained yet. In this study, we investigated the mechanism of transcorneal penetration in the application of ophthalmic formulations containing indomethacin nanoparticles (IMC-NPs). Materials and methods: IMC-NPs was prepared by the bead mill method. For the analysis of energy-dependent endocytosis, corneal epithelial (HCE-T) cell monolayers and removed rabbit cornea were thermoregulated at 4°C, where energy-dependent endocytosis is inhibited. In addition, for the analysis of different endocytosis pathways using pharmacological inhibitors, inhibitors of caveolae-mediated endocytosis (54 µM nystatin), clathrin-mediated endocytosis (40 µM dynasore), macropinocytosis (2 µM rottlerin) or phagocytosis (10 µM cytochalasin D) were used. Results: The ophthalmic formulations containing 35-200 nm sized indomethacin nanoparticles were prepared by treatment with a bead mill, and no aggregation or degradation of indomethacin was observed in IMC-NPs. The transcorneal penetration of indomethacin was significantly decreased by the combination of nystatin, dynasore and rottlerin, and the decreased penetration levels were similar to those at 4°C in HCE-T cell monolayers and rabbit cornea. In the in vivo experiments using rabbits, dynasore and rottlerin tended to decrease the transcorneal penetration of indomethacin (area under the drug concentration - time curve in the aqueous humor [AUCAH]), and the AUCAH in the nystatin-treated rabbit was significantly lower than that in non-treatment group. In addition, the AUCAH in rabbit corneas undergoing multi-treatment was obviously lower than that in rabbit corneas treated with each individual endocytosis inhibitor. Conclusion: We found that three energy-dependent endocytosis pathways (clathrin-dependent endocytosis, caveolae-dependent endocytosis and macropinocytosis) are related to the trans-corneal penetration of indomethacin nanoparticles. In particular, the caveolae-dependent endocytosis is strongly involved.
• A Proteomic Approach for Understanding the Mechanisms of Delayed Corneal Wound Healing in Diabetic Keratopathy Using Diabetic Model Rat.

  Tetsushi Yamamoto; Hiroko Otake; Noriko Hiramatsu; Naoki Yamamoto; Atsushi Taga; Noriaki Nagai

  International journal of molecular sciences 19 11 2018年11月 [査読有り]
   

  Diabetes mellitus is a widespread metabolic disorder, and long-term hyperglycemia in diabetics leads to diabetic keratopathy. In the present study, we used a shotgun liquid chromatography/mass spectrometry-based global proteomic approach using the cornea of streptozotocin-induced diabetic (STZ) rats to examine the mechanisms of delayed corneal wound healing in diabetic keratopathy. Applying a label-free quantitation method based on spectral counting, we identified 188 proteins that showed expression changes of >2.0-fold in the cornea of STZ rats. In particular, the level of lumican expression in the cornea of STZ rats was higher than that of the normal rats. In the cornea of the normal rat, the expression level of lumican was elevated during the wound healing process, and it returned to the same expression level as before cornea injury after the wound was healed completely. On the other hand, a high expression level of lumican in the cornea of STZ rats was still maintained even after the wound was healed completely. In addition, adhesion deficiency in corneal basal cells and Bowman's membrane was observed in the STZ rat. Thus, abnormally overexpressed lumican may lead to adhesion deficiency in the cornea of STZ rats.
• Involvement of Endocytosis in the Transdermal Penetration Mechanism of Ketoprofen Nanoparticles.

  Noriaki Nagai; Fumihiko Ogata; Miyu Ishii; Yuya Fukuoka; Hiroko Otake; Yosuke Nakazawa; Naohito Kawasaki

  International journal of molecular sciences 19 7 2138  2018年07月 

  We previously designed a novel transdermal formulation containing ketoprofen solid nanoparticles (KET-NPs formulation), and showed that the skin penetration from the KET-NPs formulation was higher than that of a transdermal formulation containing ketoprofen microparticles (KET-MPs formulation). However, the precise mechanism for the skin penetration from the KET-NPs formulation was not clear. In this study we investigated whether energy-dependent endocytosis relates to the transdermal delivery from a 1.5% KET-NPs formulation. Transdermal formulations were prepared by a bead mill method using additives including methylcellulose and carbopol 934. The mean particle size of the ketoprofen nanoparticles was 98.3 nm. Four inhibitors of endocytosis dissolved in 0.5% DMSO (54 μM nystatin, a caveolae-mediated endocytosis inhibitor; 40 μM dynasore, a clathrin-mediated endocytosis inhibitor; 2 μM rottlerin, a macropinocytosis inhibitor; 10 μM cytochalasin D, a phagocytosis inhibitor) were used in this study. In the transdermal penetration study using a Franz diffusion cell, skin penetration through rat skin treated with cytochalasin D was similar to the control (DMSO) group. In contrast to the results for cytochalasin D, skin penetration from the KET-NPs formulation was significantly decreased by treatment with nystatin, dynasore or rottlerin with penetrated ketoprofen concentration-time curves (AUC) values 65%, 69% and 73% of control, respectively. Furthermore, multi-treatment with all three inhibitors (nystatin, dynasore and rottlerin) strongly suppressed the skin penetration from the KET-NPs formulation with an AUC value 13.4% that of the control. In conclusion, we found that caveolae-mediated endocytosis, clathrin-mediated endocytosis and macropinocytosis are all related to the skin penetration from the KET-NPs formulation. These findings provide significant information for the design of nanomedicines in transdermal formulations.
• Involvement of Endocytosis in the Transdermal Penetration Mechanism of Ketoprofen Nanoparticles.

  Noriaki Nagai; Fumihiko Ogata; Miyu Ishii; Yuya Fukuoka; Hiroko Otake; Yosuke Nakazawa; Naohito Kawasaki

  International journal of molecular sciences 19 7 2018年07月 [査読有り]
   

  We previously designed a novel transdermal formulation containing ketoprofen solid nanoparticles (KET-NPs formulation), and showed that the skin penetration from the KET-NPs formulation was higher than that of a transdermal formulation containing ketoprofen microparticles (KET-MPs formulation). However, the precise mechanism for the skin penetration from the KET-NPs formulation was not clear. In this study we investigated whether energy-dependent endocytosis relates to the transdermal delivery from a 1.5% KET-NPs formulation. Transdermal formulations were prepared by a bead mill method using additives including methylcellulose and carbopol 934. The mean particle size of the ketoprofen nanoparticles was 98.3 nm. Four inhibitors of endocytosis dissolved in 0.5% DMSO (54 μM nystatin, a caveolae-mediated endocytosis inhibitor; 40 μM dynasore, a clathrin-mediated endocytosis inhibitor; 2 μM rottlerin, a macropinocytosis inhibitor; 10 μM cytochalasin D, a phagocytosis inhibitor) were used in this study. In the transdermal penetration study using a Franz diffusion cell, skin penetration through rat skin treated with cytochalasin D was similar to the control (DMSO) group. In contrast to the results for cytochalasin D, skin penetration from the KET-NPs formulation was significantly decreased by treatment with nystatin, dynasore or rottlerin with penetrated ketoprofen concentration-time curves (AUC) values 65%, 69% and 73% of control, respectively. Furthermore, multi-treatment with all three inhibitors (nystatin, dynasore and rottlerin) strongly suppressed the skin penetration from the KET-NPs formulation with an AUC value 13.4% that of the control. In conclusion, we found that caveolae-mediated endocytosis, clathrin-mediated endocytosis and macropinocytosis are all related to the skin penetration from the KET-NPs formulation. These findings provide significant information for the design of nanomedicines in transdermal formulations.
• Therapeutic Effect of Ophthalmic Formulation containing Nilvadipine Nanoparticles on Retinal Dysfunction in Rats Injected with Streptozotocin

  Nagai Noriaki; Deguchi Saori; Ishii Miyu; Fukuoka Yuya; Otake Hiroko; Nakazawa Yosuke

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 59 9 2018年07月 [査読有り]
  
• カプセル組成の変更に伴う吸入粉末剤の薬物放出性制御に関する研究

  大竹 裕子; 石井 美有; 福岡 侑也; 長井 紀章

  日本薬剤学会年会講演要旨集 33年会 243 - 243 (公社)日本薬剤学会 2018年05月
• Instillation of Sericin Enhances Corneal Wound Healing through the ERK Pathway in Rat Debrided Corneal Epithelium.

  Noriaki Nagai; Yuya Fukuoka; Miyu Ishii; Hiroko Otake; Tetsushi Yamamoto; Atsushi Taga; Norio Okamoto; Yoshikazu Shimomura

  International journal of molecular sciences 19 4 2018年04月 [査読有り]
   

  Sericin is a major constituent of silk produced by silkworms. We previously found that the instillation of sericin enhanced the proliferation of corneal epithelial cells, and acted to promote corneal wound healing in both normal and diabetic model rats. However, the mechanisms by which sericin promotes the proliferation of corneal cells have not been established. In this study, we investigated the effects of sericin on Akt and ERK activation in a human corneal epithelial cell line (HCE-T cells) and rat debrided corneal epithelium. Although Akt phosphorylation was not detected following the treatment of HCE-T cells with sericin, ERK1/2 phosphorylation was enhanced. The growth of HCE-T cells treated with sericin was significantly increased, with the cell growth of sericin-treated HCE-T cells being 1.7-fold higher in comparison with vehicle-treated HCE-T cells. On the other hand, both of an ERK inhibitor U0126 (non-specific specific inhibitor) and SCH772984 (specific inhibitor) attenuated the enhanced cell growth by sericin, and the growth level in the case of co-treatment with sericin and ERK1/2 inhibitor was similar to that of cells treated with ERK1/2 inhibitor alone. In an in vivo study using rat debrided corneal epithelium, the corneal wound healing rate was enhanced by the instillation of sericin, and this enhancement was also attenuated by the instillation of U0126. In addition, the corneal wound healing rate in rats co-instilled with sericin and U0126 was similar to that following the instillation of U0126 alone. In conclusion, we found that the instillation of sericin enhanced cell proliferation via the activation of the MAPK/ERK pathway, resulting in the promotion of corneal wound healing in rat eyes. These findings provide significant information for designing further studies to develop potent corneal wound-healing drugs.
• 水溶性薬物の角膜透過性向上を目指して：チモロールマレイン酸・マグネシウムヒドロキシドナノ粒子配合剤の開発

  長井紀章; 緒方文彦; 大竹裕子; 川崎 直人; 中澤洋介; 金井一享; 岡本紀夫; 下村嘉一

  日本眼科学会雑誌 122 1 61 - 62 2018年01月
• Enhancement in Corneal Permeability of Dissolved Carteolol by Its Combination with Magnesium Hydroxide Nanoparticles.

  Noriaki Nagai; Sakie Yamaoka; Yuya Fukuoka; Miyu Ishii; Hiroko Otake; Kazutaka Kanai; Norio Okamoto; Yoshikazu Shimomura

  International journal of molecular sciences 19 1 2018年01月 [査読有り]
   

  We prepared magnesium hydroxide (MH) nanoparticles, and investigated their effect when combined with dissolved carteolol on the bioavailability and intraocular pressure (IOP)-reducing effect of carteolol. The carteolol was solved in saline containing additives (0.5% methylcellulose, 0.001% benzalkonium chloride, 0.5% mannitol; CRT-solution). MH nanoparticles were prepared by a bead mill method with additives. Then carteolol/MH microparticle and carteolol/MH nanoparticle fixed combinations (mCMFC and nCMFC) were prepared by mixing the CRT-solution and MH particles. The transcorneal penetration and IOP-reducing effect of carteolol was evaluated in rabbits. The mean particle size of mCMFC was 7.2 μm, and the particle size was reduced to 73.5-113.5 nm by the bead mill treatment. The MH particles in nCMFC remained in the nano size range for 8 days after preparation, and the amounts of lacrimal fluid and corneal damage were unchanged by repetitive instillation of nCMFC (twice a day for 4 weeks). The transcorneal penetration of carteolol was enhanced by the combination with MH nanoparticles, and the IOP-reducing effect of nCMFC was significantly higher than that of CRT-solution or mCMFC. In conclusion, we designed nCMFC, and showed that the high levels of dissolved carteolol can be delivered into the aqueous humor by the instillation of nCMFC. Combination with MH nanoparticles may achieve an enhancement of corneal penetration for water-soluble drugs. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma eye drugs.
• Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment.

  Noriaki Nagai; Fumihiko Ogata; Hiroko Otake; Yosuke Nakazawa; Naohito Kawasaki

  International journal of nanomedicine 13 5215 - 5229 2018年 [査読有り]
   

  Purpose: In the clinical setting, raloxifene, a second-generation selective estrogen receptor modulator, is administered orally; however, the bioavailability (BA) is only 2% because of its poor solubility in aqueous fluids and its extensive first-pass metabolism. Therefore, it is expected that the development of a transdermally delivered formulation may reduce the necessary dose without compromising its therapeutic efficacy. In this study, we designed transdermal formulations containing raloxifene nanoparticles and evaluated their usefulness for osteoporosis therapy. Methods: Raloxifene was crushed with methylcellulose by the bead mill method, and the milled raloxifene was gelled with or without menthol (a permeation enhancer) by Carbopol® 934 (without menthol, Ral-NPs; with menthol, mRal-NPs). The drug release and transdermal penetration were measured using a Franz diffusion cell, and the therapeutic evaluation of osteoporosis was determined in an ovariectomized rat model. Results: The mean particle size of raloxifene in the transdermal formulation (Ral-NPs) was 173.7 nm. Although the raloxifene released from Ral-NPs remained in the nanoparticle state, the skin penetration of raloxifene nanoparticles was prevented by the stratum corneum in rat. On the other hand, inclusion of menthol in the formulation attenuated the barrier function of the stratum corneum and permitted the penetration of raloxifene nanoparticles through the skin. Moreover, macropinocytosis relates to the skin penetration of the formulation including menthol (mRal-NPs), since penetration was inhibited by treatment with 2 µM rottlerin, a macropinocytosis inhibitor. In addition, the application of 0.3% mRal-NPs (once a day) attenuated the decreases in calcium level and stiffness of the bones of ovariectomized rat. Conclusion: We prepared raloxifene solid nanoparticles by a bead mill method and designed a novel transdermal formulation containing nanoparticles and permeation enhancers. These trans-dermal formulations overcome the barrier properties of the skin and show high drug penetration through the transdermal route (BA 8.5%). In addition, we found that raloxifene transdermal formulations are useful for the treatment of osteoporosis in ovariectomized rat.
• [Design of Microdialysis-CLC Method for Measurement of Drug Behavior in Lacrimal Fluid after Instillation].

  Noriaki Nagai; Akina Ueno; Miyu Ishii; Yuya Fukuoka; Hiroko Otake

  Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 138 8 1111 - 1117 2018年 [査読有り]
   

  The ophthalmic application is the main route for the therapy of glaucoma, and is well-accepted by glaucoma patients. Therefore, it is important to measure the drug behavior in lacrimal fluid after instillation of eye drops. In this study, we used ophthalmic formulation (eye drops) containing timolol maleate (TM), in anti-glaucoma eye drops, and attempted to measure the drug behavior after instillation of TM eye drops. First, we collected the lacrimal fluid (5 μL) every 10 time after instillation using micropipette, and measured by the HPLC method. The TM concentration in lacrimal fluid was 21.2 μg/mL at 5 min after the instillation, and the TM was remained for 30 min after the instillation. Next, we collected the lacrimal fluid via the dialysis prove, and measured by the HPLC method. The retention of TM in lacrimal fluid was observed for 45 min after the instillation, and the measurement accuracy was enhanced by system with an automatic injection of TM solution via dialysis prove (microdialysis-HPLC method). In addition, the measurement accuracy increased more by using a capillary liquid chromatography (CLC) instead of an HPLC (microdialysis-CLC method), and the retention time of TM in lacrimal fluid was extended to 75 min after the instillation. In conclusion, we showed that the microdialysis-CLC method was suitable to measure the drug behavior in lacrimal fluid after instillation. These findings provide significant information that can be used in the design and evaluation of ophthalmic formulation.
• Ophthalmic Formulation Containing Nilvadipine Nanoparticles Prevents Retinal Dysfunction in Rats Injected with Streptozotocin.

  Saori Deguchi; Hiroko Otake; Yosuke Nakazawa; Noriko Hiramatsu; Naoki Yamamoto; Noriaki Nagai

  International journal of molecular sciences 18 12 2017年12月 [査読有り]
   

  Retinopathy leads to irreparable vision loss via capillary closure and areas of nonperfusion. However, the current instillation systems do not allow a sufficient amount of drug required to treat retinopathy to reach the posterior segment (retina); therefore, a new formulation targeting the posterior segment is expected as therapy for retinopathy. We prepared ophthalmic formulations containing nilvadipine nanoparticles (NILnano), and demonstrated whether the instillation of NILnano can prevent retinal dysfunction in rats injected with excessive streptozotocin (STZ rats) in this study. NILnano (mean particle size, 77 nm) was prepared by wet bead mill treatment, with the inclusion of various additives (2-hydroxypropyl-β-cyclodextrin, benzalkonium chloride, d-mannitol, and methylcellulose). Retinal dysfunction was observable two weeks after rats received intraperitoneal injections of streptozotocin (100 mg/kg × 2, consecutive days, STZ rat). Changes in retinal function were evaluated by electroretinogram (ERG) and immunological methods. The retinal thickness, measured as the distance between the ganglion cell layer and the distal border of the outer nuclear layer, increased two weeks after the injection of streptozotocin, resulting in decreases in the levels of a-waves, b-waves, and oscillatory potential amplitudes in ERG of rats. The instillation of NILnano allowed the topical supplement of nilvadipine into the retina, and repeated instillation of NILnano (2 times/day) attenuated the retinal disorders led by the excessive streptozotocin. In conclusion, we found that retinal dysfunction in rats injected with streptozotocin can be prevented by the NILnano instillation. These results are useful in further studies aimed at the therapeutic treatment of retinopathy.
• Co-instillation of nano-solid magnesium hydroxide enhances corneal permeability of dissolved timolol.

  Noriaki Nagai; Fumihiko Ogata; Hiroko Otake; Naohito Kawasaki; Yosuke Nakazawa; Kazutaka Kanai; Norio Okamoto; Yoshikazu Shimomura

  Experimental eye research 165 118 - 124 2017年12月 [査読有り]
   

  We prepared magnesium hydroxide (MH) nanoparticles by a bead mill method, and investigated whether the co-instillation of MH nanoparticles improves the low transcorneal penetration of water-soluble drugs, such as the anti-glaucoma eye drug timolol maleate (TM). MH particle size was decreased by the bead mill treatment to a mean particle size of 71 nm. In addition, the MH nanoparticles were highly stable. Next, we demonstrated the effect of MH nanoparticles on the corneal surface. MH shows only slight solubility in lacrimal fluid, and the instillation of MH nanoparticles for 14 days did not affect the behavior (balance of secretion and excretion) of the lacrimal fluid in rabbit corneas. Moreover, there was no observable corneal toxicity of MH nanoparticles, and treatment with MH nanoparticles enhanced the intercellular space ratio in the eyes of rats. MH alone did not permeate into the cornea; however, the co-instillation of MH nanoparticles and dissolved TM (nMTFC) enhanced the corneal penetration of TM. In addition, the intraocular pressure (IOP)-reducing effect of nMTFC was significantly higher than those of the TM solution or the co-instillation of MH microparticles and TM. In conclusion, we found that MH nanoparticles enhance the corneal penetration of dissolved TM with no observable corneal stimulation or obstruction of the nasolacrimal duct by the MH nanoparticles. It is possible that the co-instillation of MH nanoparticles may provide a useful way to improve the bioavailability of water-soluble drugs in the ophthalmic field. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma eye drugs.
• Therapeutic effect of cilostazol ophthalmic nanodispersions on retinal dysfunction in streptozotocin-induced diabetic rats

  Noriaki Nagai; Saori Deguchi; Hiroko Otake; Noriko Hiramatsu; Naoki Yamamoto

  International Journal of Molecular Sciences 18 9 2017年09月 [査読有り]
   

  We previously prepared ophthalmic formulations containing cilostazol (CLZ) nanoparticles by bead mill methods (CLZnano), and found that instillation of CLZnano into rat eyes supplies CLZ into the retina. In this study, we investigated changes in the electroretinograms (ERG) of streptozotocin-induced diabetic rats (STZ rats), a model of diabetes mellitus. In addition, we demonstrated that dispersions containing CLZ nanoparticles attenuate changes in the ERG of STZ rats. The instillation of CLZnano had no effect on body weight or plasma glucose and insulin levels. Furthermore, no corneal toxicity was observed in the in vivo study using STZ rats. The a-wave and b-wave levels in addition to oscillatory potentials (OP) amplitude decreased in STZ rats two weeks after the injection of streptozotocin, with the instillation of CLZnano attenuating these decreases. In addition, the level of vascular endothelial growth factor (VEGF) in the retinas of STZ rats was 9.26-fold higher than in in normal rats, with this increase also prevented by the instillation of CLZnano Thus, we have found that a-wave and b-wave levels in addition to OP amplitude are decreased in rats following the injection of excessive streptozotocin. Furthermore, the retinal disorders associated with diabetes mellitus are attenuated by the instillation of CLZnano. These findings provide significant information that can be used to design further studies aimed at developing anti-diabetic retinopathy drugs.
• Therapeutic Effect of Cilostazol Ophthalmic Nanodispersions on Retinal Dysfunction in Streptozotocin-Induced Diabetic Rats.

  Noriaki Nagai; Saori Deguchi; Hiroko Otake; Noriko Hiramatsu; Naoki Yamamoto

  International journal of molecular sciences 18 9 2017年09月 [査読有り]
   

  We previously prepared ophthalmic formulations containing cilostazol (CLZ) nanoparticles by bead mill methods (CLZnano), and found that instillation of CLZnano into rat eyes supplies CLZ into the retina. In this study, we investigated changes in the electroretinograms (ERG) of streptozotocin-induced diabetic rats (STZ rats), a model of diabetes mellitus. In addition, we demonstrated that dispersions containing CLZ nanoparticles attenuate changes in the ERG of STZ rats. The instillation of CLZnano had no effect on body weight or plasma glucose and insulin levels. Furthermore, no corneal toxicity was observed in the in vivo study using STZ rats. The a-wave and b-wave levels in addition to oscillatory potentials (OP) amplitude decreased in STZ rats two weeks after the injection of streptozotocin, with the instillation of CLZnano attenuating these decreases. In addition, the level of vascular endothelial growth factor (VEGF) in the retinas of STZ rats was 9.26-fold higher than in in normal rats, with this increase also prevented by the instillation of CLZnano Thus, we have found that a-wave and b-wave levels in addition to OP amplitude are decreased in rats following the injection of excessive streptozotocin. Furthermore, the retinal disorders associated with diabetes mellitus are attenuated by the instillation of CLZnano. These findings provide significant information that can be used to design further studies aimed at developing anti-diabetic retinopathy drugs.
• Amyloid β1-43 Accumulates in the Lens Epithelium of Cortical Opacification in Japanese Patients.

  Nagai N; Mano Y; Otake H; Shibata T; Kubo E; Sasaki H

  Investigative ophthalmology & visual science 58 7 3294 - 3302 2017年06月 [査読有り]
   

  Purpose: We investigated the accumulation of amyloid β (Aβ1-40, Aβ1-42, Aβ1-43) in the lens epithelium of patients with opacification of five different types (cortical cataract [COR]; nuclear cataract [NUC]; posterior subcapsular cataract [PSC]; retrodots [RD]; and water clefts [WC]). Methods: Samples were collected from Japanese patients taken during cataract surgery; Aβ levels and mRNA expression were determined by ELISA and a real-time RT-PCR method, respectively. Results: Levels of Aβ1-40 and Aβ1-42 in the lens epithelium of patients with COR, NUC, PSC, RD, and WC showed no significant differences in comparison with transparent lens epithelium. Levels of Aβ1-43 in the lens epithelium of patients with PSC and WC were not detected, and NUC and RD were slightly elevated. In contrast to the results in these cataract types, high Aβ1-43 levels were observed in the lens epithelium of patients with COR, and a close relationship was observed between Aβ1-43 levels and the degree of lens opacification (R = 0.8229, n = 6). The levels of Aβ1-43 were also higher in the lens epithelium of patients with mixed-cataract showing cortical opacification, and the Aβ1-43 levels in the lens epithelium of mixed-cataract patients with cortical opacification was significantly higher than in that of mixed-cataract patients without cortical opacification. In addition, the level of an amyloid precursor protein mRNA in the lens epithelium of mixed-cataract patients with cortical opacification was significantly higher than in transparent lens and mixed-cataract patients without cortical opacification. Conclusions: We found high levels of Aβ1-43 accumulation in the lens epithelium of Japanese patients with cortical opacification.
• 網膜電図及び免疫組織染色によるストレプトゾトシン誘発糖尿病ラットの網膜機能障害の評価

  平松 範子; 出口 粧央里; 吉岡 千晶; 大竹 裕子; 山本 直樹; 長井 紀章

  薬学雑誌. 乙号 137 9 1169 - 1175 公益社団法人 日本薬学会 2017年 [査読有り]
   

   Streptozotocin-induced diabetic rat (STZ rat) was used in many studies for the diabetic mellitus. In this study, we demonstrated whether the electroretinograms (ERG) was changed in the retina of STZ rats. In addition, we investigated the histopathological alteration in the retina of STZ rats by using the immunological method. The 100 mg/kg of STZ was injected continuously for 2 d (100 mg/kg×2). The insulin level was decreased, and the glucose level was enhanced 14 d after the injection of STZ. Moreover, the levels of a-wave, b-wave and OP amplitude were decreased in the rat at 14 d after the injection of STZ. Although, the damage and apoptosis was not observed in the retinal ganglion cell of STZ rats by the immunological experiment using the phospho-H2A.X and cleaved caspase-3, the distance between cell and cell was increased in both of outer- and inner- nuclear (granule) layer in retina of STZ rats. In conclusion, we showed that the enhanced thickening in retina was caused by the injection of excessive STZ. The thickening in retina of STZ rats may lead to the dysfunction of retina, resulting in the decrease in ERG. These findings provide significant information that can be used in the design of a model of diabetic retinopathy.
  
• Inhalable Spray-Freeze-Dried Powder with L-Leucine that Delivers Particles Independent of Inspiratory Flow Pattern and Inhalation Device.

  Hiroko Otake; Tomoyuki Okuda; Daiki Hira; Haruyoshi Kojima; Yasuhiro Shimada; Hirozazu Okamoto

  Pharmaceutical research 33 4 922 - 31 2016年04月 [査読有り]
   

  PURPOSE: The purpose of this study was to develop inhalable particles that can reach deep into the lungs efficiently independent of inhalation patterns of patients and inhalation devices. We prepared porous particles including L-leucine (Leu), a dispersive agent, by a spray-freeze-drying (SFD) method and examined the influence of inspiratory flow patterns and inhalation devices with various inhalation resistances. METHODS: Four types of SFD powder with different Leu contents (0-10%) were prepared. Scanning electron microscopy and laser diffraction were used to measure the morphology and size distribution of the powders. In-vitro inhalation characteristics were determined using a twin-stage liquid impinger equipped with an inspiratory flow pattern simulator. The effects of Leu on the adhesion force and electrostatic property of the particles were evaluated. RESULTS: The inhalation performance of the powders was improved by the addition of Leu. The powders with Leu showed a high inhalation performance regardless of inspiratory flow patterns and devices. The addition of Leu decreased the adhesion force and increased the surface potential of the powders. CONCLUSIONS: The SFD particles with Leu showed high inhalation performance regardless of the inhalation patterns and devices, which was attributed to the decreased adhesion force between particles and increased dispersibility.
• Development of Spray-Freeze-Dried Powders for Inhalation with High Inhalation Performance and Antihygroscopic Property.

  Hiroko Otake; Tomoyuki Okuda; Hirokazu Okamoto

  Chemical & pharmaceutical bulletin 64 3 239 - 45 2016年 [査読有り]
   

  Spray-freeze-drying (SFD) is a unique powderization technique to produce highly porous dry powders with a low density. The characteristic morphology can markedly contribute to the superior inhalation performances of SFD powders. Due to the increased specific surface area of the powders, however, moisture adsorption may readily occur, subsequently leading to losses of their inhalation potentials. In this study, hydrophobic amino acids were newly applied as pharmaceutical excipients to obtain SFD powders with both a favorable inhalation performance and antihygroscopic property. SFD powders composed of several hydrophobic amino acids were prepared. The morphology, particle size distribution, and crystallinity of the prepared powders were evaluated by scanning electron micrography, laser diffraction, and X-ray powder diffraction, respectively. The inhalation characteristics of the SFD powders were examined using a twin-stage liquid impinger equipped with an inspiratory pattern simulator and devices. To investigate their antihygroscopicity, moreover, the SFD powders were stored under a humidified condition to assess the morphology, crystallinity, and inhalation performance as described above. It was demonstrated that a SFD powder composed of L-leucine, L-isoleucine, or L-phenylalanine showed a superior inhalation performance, which was sufficiently maintained after storage under the humidified condition, strongly indicating their antihygroscopicity. These results indicated that the hygroscopicity of SFD powders can be effectively improved by the application of hydrophobic amino acids as excipients.

書籍

• 臨床製剤学 第5版

  内田, 享弘; 鈴木, 豊史; 四方, 敬介 (担当:分担執筆範囲:)南江堂 2022年03月 ISBN: 9784524403936 xiv, 428p
• エンタイア製剤学・物理薬剤学

  長井, 紀章; 大竹, 裕子 京都廣川書店 2021年03月 ISBN: 9784909197795 ix, 253p
• 次世代吸入製剤とデバイスの開発

  大竹 裕子 (担当:分担執筆範囲:第Ⅲ編 製剤開発 第3章 吸入粉末剤開発における微粒子調製法と疎水性アミノ酸の組み合わせによる吸入効率改善アプローチ)シーエムシー出版 2018年11月

MISC

• レバミピド懸濁点眼液とMPCポリマーの併用処理によるドライアイ治療効果の有用性評価

  後藤 涼花; 勢力 諒太朗; 渡辺 彩花; 油納 美和; 大竹 裕子; 櫻井 俊輔; 原田 英治; 長井 紀章 あたらしい眼科 39 (7) 982 -987 2022年07月
• 口腔粘膜炎の早期治療を可能とするトロキシピドナノゲル製剤の開発

  出口 粧央里; 吉岡 涼; 西田 未来; 小松 美莉; 大竹 裕子; 長井 紀章 日本薬学会年会要旨集 142年会 27H -am03S 2022年03月
• ブリンゾラミドナノ点眼製剤化に伴う眼内薬物移行性の改善と緑内障治療効果の向上

  後藤 涼花; 衣川 美宇; 矢野 詩歩; 大竹 裕子; 岡本 紀夫; 長井 紀章 日本薬学会年会要旨集 142年会 27L -am09S 2022年03月
• 噴霧急速凍結乾燥法を用いたトラニラストナノ結晶懸濁液からの微粉末体作成と吸入製剤への応用性

  大竹 裕子; 辜 瓊雅; 福本 航; 長井 紀章 日本薬学会年会要旨集 142年会 28F -am10 2022年03月
• 芍薬甘草湯エキス顆粒における粗大・コロイド・分子分散体の同定とその消化管吸収性の評価

  吉富 丈治; 大竹 裕子; 遠藤 雄一; 小竹 武; 長井 紀章 日本薬学会年会要旨集 142年会 28J -am07S 2022年03月
• BCSクラス3薬物を対象としたナノ結晶製剤の開発研究 再分散可能なファモチジンナノ固化成形体の調製

  門脇 玲太; 池 彩里; 下前 憂梨咲; 大迫 華乃; 大竹 裕子; 長井 紀章 日本薬学会年会要旨集 142年会 27PO7 -05S 2022年03月
• ストレプトゾトシン誘発視機能障害に対するブリンゾラミドナノ点眼液の有用性評価

  南 実沙; 後藤 涼花; 櫻井 達真; 明和 亮伍; 衣川 美宇; 出口 粧央里; 大竹 裕子; 長井 紀章 日本眼薬理学会プログラム・抄録集 41回 37 -37 2021年11月
• イルベサルタンナノ結晶を用いた経口用固形製剤の設計 固化成形体の調製と薬物吸収性評価

  南 実沙; 渡辺 雅輝; 池 彩里; 下前 憂梨咲; 大竹 裕子; 長井 紀章 日本薬学会年会要旨集 141年会 29P01 -270S 2021年03月
• モメタゾンフランカルボン酸エステルのナノ粒子化と点鼻製剤への応用

  出口 粧央里; 吉富 丈治; 大竹 裕子; 長井 紀章 日本薬学会年会要旨集 141年会 29P01 -277S 2021年03月
• フェノフィブラートナノ点眼薬の開発と眼後部への薬物送達能評価

  後藤 涼花; 長岡 泰司; 出口 粧央里; 森本 泰光; 大竹 裕子; 長井 紀章 日本薬学会年会要旨集 141年会 29P01 -278S 2021年03月
• トラニラストナノ結晶を用いた結膜炎治療薬の開発 メチルセルロースは超微粒子の滞留性を高める

  南 実沙; 山崎 由夏; 大竹 裕子; 金井 一享; 長井 紀章 日本眼薬理学会プログラム・抄録集 40回 42 -42 2021年02月
• 眼科領域における生体適合性ポリマーの応用性 MPCポリマーはベンザルコニウム塩化物の角膜傷害性を軽減する

  長井 紀章; 南 実沙; 山崎 由夏; 大竹 裕子; 櫻井 俊輔; 原田 英治 日本眼薬理学会プログラム・抄録集 40回 46 -46 2021年02月
• MPCポリマーが点眼用保存剤ベンザルコニウム塩化物の角膜傷害性および薬物眼内移行性へ与える影響

  南 実沙; 山口 瑞季; 山崎 由夏; 大竹 裕子; 櫻井 俊輔; 原田 英治; 長井 紀章 あたらしい眼科 37 (10) 1309 -1314 2020年10月
• 経眼瞼適用レバミピドナノゲル製剤によるドライアイ治療

  南 実沙; 石井 美有; 勢力 諒太朗; 大竹 裕子; 平松 範子; 山本 直樹; 長井 紀章 日本薬剤学会年会講演要旨集 35年会 148 -148 2020年05月
• トラニラストの超微細化と肺内投与による肺線維化抑制効果

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• Clinical Academic Topics 薬物ナノ結晶と眼内薬物送達技術

  大竹 裕子; 長井 紀章 アレルギーの臨床 40 (5) 385 -387 2020年05月
• メロキシカムナノ製剤の開発とその消化管吸収機構の解明

  山口 瑞季; 池田 瑠璃; 渡辺 雅輝; 大竹 裕子; 長井 紀章 日本薬剤学会年会講演要旨集 35年会 148 -148 2020年05月
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  南 実沙; 石井 美有; 勢力 諒太朗; 大竹 裕子; 平松 範子; 山本 直樹; 長井 紀章 日本薬剤学会年会講演要旨集 35年会 148 -148 2020年05月
• トラニラストの超微細化と肺内投与による肺線維化抑制効果

  大竹 裕子; 秋山 紗和子; 片山 理沙; 福本 航; 長井 紀章 日本薬剤学会年会講演要旨集 35年会 163 -163 2020年05月
• I-メントールによるインドメタシンナノ結晶製剤の経皮吸収促進効果とその透過機序の解明

  山口 瑞季; 福岡 侑也; 永福 紡; 川口 陽菜子; 原 雅紀; 大竹 裕子; 長井 紀章 日本薬学会年会要旨集 140年会 26K -am07S 2020年03月
• 食後高血糖の制御を目的とした新剤形の確立 インスリンナノ点眼薬は血糖値スパイクを抑制する

  長井 紀章; 畠中 優斗; 井阪 匠; 出口 粧央里; 大竹 裕子; 金井 一享; 岡本 紀夫; 下村 嘉一 日本薬学会年会要旨集 140年会 26P -pm169 2020年03月
• ナノ結晶点眼製剤による新規結膜炎治療薬の確立 トラニラストナノ結晶点眼液の抗炎症効果

  南 実沙; 山崎 由夏; 蛭子 小春; 宇野 樹; 大竹 裕子; 長井 紀章 日本薬学会年会要旨集 140年会 27Y -pm15S 2020年03月
• ブレオマイシン誘発性肺線維症モデルマウスにおけるトラニラストナノ結晶分散液の肺内投与時における有用性評価

  大竹 裕子; 秋山 紗和子; 片山 理沙; 福本 航; 長井 紀章 日本薬学会年会要旨集 140年会 28P -pm082 2020年03月
• 点眼液の刺激性評価のためのpH変化を指標とした新規in vitro評価方法の提案

  稲葉 一訓; 本多 公貴; 大竹 裕子; 岡本 紀夫; 下村 嘉一; 小竹 武; 長井 紀章 医療薬学 46 (2) 93 -99 2020年02月
• 一酸化窒素-アミロイドβポジティブフィードバックはヒト水晶体上皮細胞でのミトコンドリア障害を増悪する

  長井 紀章; 福岡 侑也; 石井 美有; 大竹 裕子; 柴田 哲平; 久保 江理; 佐々木 洋 日本眼薬理学会プログラム・抄録集 39回 43 -43 2019年09月
• ナノ結晶を基盤とした経口製剤化に伴うNSAIDs消化管障害発現頻度の軽減

  福岡 侑也; 大竹 裕子; 長井 紀章 BIO Clinica 34 (7) 746 -748 2019年07月
• 【私の研究を聞いて欲しい】薬物眼内移行性の向上を目的としたナノ点眼製剤の開発

  大竹 裕子; 真野 裕; 長井 紀章 日本白内障学会誌 31 (1) 33 -35 2019年06月
• 認知症患者組織を用いた水晶体中アミロイドβ関連mRNA量の測定

  長井 紀章; 福岡 侑也; 真野 裕; 大竹 裕子; 柴田 哲平; 久保 江理; 佐々木 洋 日本白内障学会誌 31 (1) 53 -57 2019年06月
• 【私の研究を聞いて欲しい】薬物眼内移行性の向上を目的としたナノ点眼製剤の開発

  大竹 裕子; 真野 裕; 長井 紀章 日本白内障学会誌 31 (1) 33 -35 2019年06月
• 認知症患者組織を用いた水晶体中アミロイドβ関連mRNA量の測定

  長井 紀章; 福岡 侑也; 真野 裕; 大竹 裕子; 柴田 哲平; 久保 江理; 佐々木 洋 日本白内障学会誌 31 (1) 53 -57 2019年06月
• インドメタシンナノ粒子に対する経皮吸収促進剤l-メントールの有用性評価

  福岡 侑也; 氏原 慎太郎; 梁 宇紀; 山口 瑞季; 大竹 裕子; 長井 紀章 日本薬剤学会年会講演要旨集 34年会 158 -158 2019年05月
• レバミピドナノゲル製剤の開発と口腔粘膜炎治療への応用

  石井 美有; 勢力 諒太朗; 大竹 裕子; 平松 範子; 山本 直樹; 長井 紀章 日本薬剤学会年会講演要旨集 34年会 161 -161 2019年05月
• トラニラストナノ結晶を用いた新規吸入剤の調製とその体内動態評価

  大竹 裕子; 秋山 紗和子; 片山 理沙; 石井 美有; 福岡 侑也; 長井 紀章 日本薬剤学会年会講演要旨集 34年会 195 -195 2019年05月
• インドメタシンナノ製剤の開発とその消化管吸収機序の解明

  長井 紀章; 中村 翼; 池田 瑠璃; 渡辺 雅輝; 大竹 裕子 日本薬剤学会年会講演要旨集 34年会 204 -204 2019年05月
• カプセル組成の変更に伴う吸入粉末剤の薬物放出制御に関する研究 カプセル表面の形状および電位差が薬物放出性に与える影響

  大竹 裕子; 片山 理沙; 秋山 紗和子; 石井 美有; 福岡 侑也; 長井 紀章 日本薬学会年会要旨集 139年会 (4) 127 -127 2019年03月
• 眼科適用ラノステロールナノ製剤を用いた新規白内障治療法の確立を目指して

  福岡 侑也; 渡邉 菜摘; 大竹 裕子; 佐藤 完太; 多賀 淳; 岡 美佳子; 平松 範子; 山本 直樹; 長井 紀章 日本薬学会年会要旨集 139年会 (4) 127 -127 2019年03月
• 就寝中に目を修復!持続性薬物供給システムの開発 ナノ結晶技術はドライアイを改善する

  長井 紀章; 石井 美有; 勢力 諒太朗; 大竹 裕子; 金井 一享; 岡本 紀夫; 下村 嘉一 日本薬学会年会要旨集 139年会 (4) 128 -128 2019年03月
• 添加物メチルセルロースが遊星ボールミルによるイブプロフェン微粒子化へ与える影響

  長井 紀章; 山崎 由夏; 中村 翼; 大竹 裕子; 岡本 直也 薬学雑誌 139 (1) 123 -130 2019年01月
• 認知症患者水晶体におけるアミロイドβ関連遺伝子発現量の測定

  眞野裕; 福岡侑也; 石井美有; 出口粧央里; 大竹裕子; 柴田哲平; 久保江理; 佐々木洋; 長井紀章 日本白内障学会総会・水晶体研究会プログラム・講演抄録集 58th-45th 2019年
• 高血糖は自然発症糖尿病モデルOLETFラット水晶体におけるアミロイドβ蓄積を高める

  大竹裕子; 石井美有; 福岡侑也; 眞野裕; 佐々木洋; 長井紀章 日本白内障学会総会・水晶体研究会プログラム・講演抄録集 58th-45th 2019年
• 2型糖尿病白内障患者における水晶体混濁度とアミロイドβ蓄積の相関性評価

  石井美有; 眞野裕; 福岡侑也; 大竹裕子; 柴田哲平; 久保江理; 佐々木洋; 長井紀章 日本白内障学会総会・水晶体研究会プログラム・講演抄録集 58th-45th 2019年
• 添加物メチルセルロースが遊星ボールミルによるイブプロフェン微粒子化へ与える影響

  長井 紀章; 山崎 由夏; 中村 翼; 大竹 裕子; 岡本 直也 薬学雑誌 139 (1) 123 -130 2019年01月
• 添加物メチルセルロースが遊星ボールミルによるイブプロフェン微粒子化へ与える影響

  長井紀章; 山崎由夏; 中村翼; 大竹裕子; 岡本直也 薬学雑誌(Web) 139 (1) 123 -130 2019年
• 難溶性医薬品ナノ粒子化に伴う生体膜透過能の向上効果

  石井美有; 國松紬; 蛭子小春; 大竹裕子; 長井紀章 電気学会研究会資料 (OQD-18-071-079) 11‐15 2018年12月
• 新規院内製剤セレン含有口腔内崩壊錠の作製と実用化についての検討

  中尾 元紀; 松尾 世為子; 大橋 香菜子; 田邨 保之; 永井 聡子; 覺野 律; 中村 明美; 福永 聖子; 川端 成佐; 寺倉 智子; 松野 純男; 緒方 文彦; 川崎 直人; 大竹 裕子; 長井 紀章 国立病院総合医学会講演抄録集 72回 656 -656 2018年11月
• 涙液中薬物動態研究に向けたマイクロダイアリシス-キャピラリー液体クロマトグラフィー法の開発

  長井 紀章; 上野 祥奈; 石井 美有; 福岡 侑也; 大竹 裕子 薬学雑誌 138 (8) 1111 -1117 2018年08月
• 涙液中薬物動態研究に向けたマイクロダイアリシス-キャピラリー液体クロマトグラフィー法の開発

  長井 紀章; 上野 祥奈; 石井 美有; 福岡 侑也; 大竹 裕子 薬学雑誌 138 (8) 1111 -1117 2018年08月
• レバミピドナノ口腔内崩壊錠の製造とレバミピドの薬剤性消化管障害治療への応用

  福岡 侑也; 上田 純也; 大竹 裕子; 長井 紀章 日本薬剤学会年会講演要旨集 33年会 116 -116 2018年05月
• ドライアイ治療への応用を目指した新規経眼瞼レバミピドナノ製剤の開発

  石井 美有; 上野 祥奈; 大竹 裕子; 長井 紀章 日本薬剤学会年会講演要旨集 33年会 129 -129 2018年05月
• ラロキシフェンを用いたナノ経皮吸収製剤の開発と骨粗鬆症治療への有用性評価

  出口 粧央里; 梁 宇紀; 大竹 裕子; 緒方 文彦; 川崎 直人; 長井 紀章 日本薬剤学会年会講演要旨集 33年会 145 -145 2018年05月
• レバミピドナノ口腔内崩壊錠の製造とレバミピドの薬剤性消化管障害治療への応用

  福岡 侑也; 上田 純也; 大竹 裕子; 長井 紀章 日本薬剤学会年会講演要旨集 33年会 116 -116 2018年05月
• ドライアイ治療への応用を目指した新規経眼瞼レバミピドナノ製剤の開発

  石井 美有; 上野 祥奈; 大竹 裕子; 長井 紀章 日本薬剤学会年会講演要旨集 33年会 129 -129 2018年05月
• ラロキシフェンを用いたナノ経皮吸収製剤の開発と骨粗鬆症治療への有用性評価

  出口 粧央里; 梁 宇紀; 大竹 裕子; 緒方 文彦; 川崎 直人; 長井 紀章 日本薬剤学会年会講演要旨集 33年会 145 -145 2018年05月
• 重合度の異なるセルロース誘導体が自転・公転ナノ粉砕機の薬物破砕効率へ与える影響

  長井 紀章; 中村 翼; 山崎 由夏; 大竹 裕子; 高塚 隆之 日本薬剤学会年会講演要旨集 33年会 202 -202 2018年05月
• カプセル組成の変更に伴う吸入粉末剤の薬物放出性制御に関する研究

  大竹 裕子; 石井 美有; 福岡 侑也; 長井 紀章 日本薬剤学会年会講演要旨集 33年会 243 -243 2018年05月
• 重合度の異なるセルロース誘導体が自転・公転ナノ粉砕機の薬物破砕効率へ与える影響

  長井 紀章; 中村 翼; 山崎 由夏; 大竹 裕子; 高塚 隆之 日本薬剤学会年会講演要旨集 33年会 202 -202 2018年05月
• ショットガンプロテオミクス解析を用いた糖尿病白内障要因の解析

  大竹 裕子; 山本 哲志; 三田村 邦子; 多賀 淳; 長井 紀章 日本薬学会年会要旨集 138年会 (3) 243 -243 2018年03月
• 毛根を標的とした新規薬物送達技術の開発 ナノ結晶技術はミノキシジルの発毛効果を高める

  長井 紀章; 岩井 淑恵; 川瀬 七愛; 坂本 茜; 大竹 裕子; 緒方 文彦; 川崎 直人 日本薬学会年会要旨集 138年会 (4) 158 -158 2018年03月
• ショットガンプロテオミクス解析を用いた糖尿病白内障要因の解析

  大竹 裕子; 山本 哲志; 三田村 邦子; 多賀 淳; 長井 紀章 日本薬学会年会要旨集 138年会 (3) 243 -243 2018年03月
• 毛根を標的とした新規薬物送達技術の開発 ナノ結晶技術はミノキシジルの発毛効果を高める

  長井 紀章; 岩井 淑恵; 川瀬 七愛; 坂本 茜; 大竹 裕子; 緒方 文彦; 川崎 直人 日本薬学会年会要旨集 138年会 (4) 158 -158 2018年03月
• ヒト白内障患者におけるミトコンドリア障害と水晶体白濁の関係

  長井紀章; 真野裕; 福岡侑也; 石井美有; 大竹裕子; 柴田哲平; 久保江理; 佐々木洋 日本白内障学会総会・水晶体研究会プログラム・講演抄録集 57th-44th 2018年
• 網膜電図及び免疫組織染色によるストレプトゾトシン誘発糖尿病ラットの網膜機能障害の評価

  平松 範子; 出口 粧央里; 吉岡 千晶; 大竹 裕子; 山本 直樹; 長井 紀章 薬学雑誌 137 (9) 1169 -1175 2017年09月
• 網膜電図および免疫組織染色によるストレプトゾトシン誘発糖尿病ラットの網膜機能障害の評価

  長井 紀章; 平松 範子; 出口 粧央里; 大竹 裕子; 山本 直樹 日本眼薬理学会プログラム・抄録集 37回 43 -43 2017年09月
• PADE式を用いた市販吸入粉末剤の吸入特性評価

  大竹 裕子; 奥田 知将; 岡本 浩一 日本薬剤学会年会講演要旨集 32年会 106 -106 2017年05月
• 薬物粒子径変更に伴うレバミピド懸濁性点眼液の製剤機能の向上

  長井 紀章; 川崎 真緒; 上野 祥奈; 大竹 裕子; 岡本 紀夫; 下村 嘉一 日本薬剤学会年会講演要旨集 32年会 172 -172 2017年05月
• PADE式を用いた市販吸入粉末剤の吸入特性評価

  大竹裕子; 大竹裕子; 奥田知将; 岡本浩一 日本薬剤学会年会講演要旨集(Web) 32nd ROMBUNNO.11‐2‐01 (WEB ONLY) -106 2017年05月
• 薬物粒子径変更に伴うレバミピド懸濁性点眼液の製剤機能の向上

  長井紀章; 川崎真緒; 上野祥奈; 大竹裕子; 岡本紀夫; 下村嘉一 日本薬剤学会年会講演要旨集(Web) 32nd ROMBUNNO.13‐3‐02 (WEB ONLY) -172 2017年05月
• 日本人白内障患者を対象とした新たな白濁要因の模索:アミロイドβ蓄積は皮質混濁を増悪する

  長井紀章; 真野裕; 大竹裕子; 柴田哲平; 久保江理; 佐々木洋 日本医療薬学会年会講演要旨集(Web) 27 2017年
• 粉末吸入剤の吸入特性評価におけるACIとAPSの相関性

  藤原 大輝; 大竹 裕子; 奥田 知将; 岡本 浩一 日本薬学会年会要旨集 136年会 (4) 194 -194 2016年03月
• 噴霧乾燥サブミクロン粒子の構造・吸入特性に及ぼす調製用溶媒の効果

  渡邊 晃平; 奥田 知将; 坂 晃輔; 藤原 大輝; 大竹 裕子; 岡本 浩一 日本薬剤学会年会講演要旨集 30年会 104 -104 2015年05月
• L‐ロイシン添加による噴霧急速凍結乾燥微粒子の吸入特性・吸湿性改善効果に及ぼす表面特性の影響

  大竹裕子; 奥田知将; 岡本浩一 製剤と粒子設計シンポジウム講演要旨集 31st 168 -169 2014年10月
• 噴霧急速凍結乾燥微粒子の気中構造崩壊/保持性による吸入特性への影響

  大竹 裕子; 奥田 知将; 涌井 裕梨; 小川 昌樹; 渡邊 晃平; 岡本 浩一 日本薬剤学会年会講演要旨集 29年会 127 -127 2014年05月
• サブミクロン粉末微粒子の構造および吸入特性に及ぼすエタノールの効果

  川瀬 佑紀; 奥田 知将; 小川 昌樹; 渡辺 晃平; 大竹 裕子; 岡本 浩一 日本薬剤学会年会講演要旨集 29年会 126 -126 2014年05月
• ヒト吸入パターン再現装置を用いた吸入方法の違いによる吸入エアゾール剤の吸入特性解析

  稲垣 翠; 水野 愛; 大竹 裕子; 奥田 知将; 岡本 浩一 日本薬学会年会要旨集 134年会 (4) 66 -66 2014年03月
• ヒト吸入パターン再現装置によるスペーサー使用時の吸入エアゾール剤の吸入特性解析

  大竹 裕子; 稲垣 翠; 水野 愛; 奥田 知将; 岡本 浩一 日本薬学会年会要旨集 134年会 (4) 66 -66 2014年03月
• 噴霧急速凍結乾燥法による吸入粉末剤開発における疎水性アミノ酸の有用性

  大竹 裕子; 奥田 知将; 岡本 浩一 日本薬剤学会年会講演要旨集 28年会 202 -202 2013年04月
• ヒト吸入パターン再現装置を用いた市販吸入粉末剤の吸入特性評価

  水野 愛; 冨田 奈央; 大竹 裕子; 奥田 知将; 岡本 浩一 日本薬学会年会要旨集 133年会 (4) 57 -57 2013年03月
• 吸湿性薬物の吸入用噴霧急速凍結乾燥微粒子の開発

  山田裕実子; 大竹裕子; 小島晴義; 奥田知将; 岡本浩一; 平大樹 製剤と粒子設計シンポジウム講演要旨集 29th 162 -163 2012年10月
• 非侵襲性バイタルサイン測定による粉末吸入製剤のin vivo障害性評価

  大竹 裕子; 岡崎 真貴; 奥田 知将; 岡本 浩一 日本薬剤学会年会講演要旨集 26年会 168 -168 2011年05月
• 近赤外蛍光標識siRNA粉末微粒子による肺内投与後のsiRNA体内動態および遺伝子発現抑制効果の評価

  奥田 知将; 鬼頭 大輔; 大竹 裕子; 岡崎 真貴; 岡本 浩一 Drug Delivery System 26 (3) 301 -301 2011年05月
• 近赤外蛍光標識siRNAによる肺内投与後の体内動態および遺伝子発現抑制効果の評価

  鬼頭 大輔; 大竹 裕子; 奥田 知将; 岡本 浩一 日本薬学会年会要旨集 131年会 (4) 233 -233 2011年03月
• 噴霧急速凍結乾燥法における高送達/高導入型遺伝子粉末吸入剤の開発

  細江慎吾; 浅井歩; 大竹裕子; 奥田知将; 岡本浩一 薬剤学 70 (Supplement) 146 2010年04月
• 噴霧急速凍結乾燥法における高速達/高導入型遺伝子粉末吸入剤の開発

  細江 慎吾; 浅井 歩; 大竹 裕子; 奥田 知将; 岡本 浩一 薬剤学: 生命とくすり 70 (Suppl.) 146 -146 2010年04月

受賞

• 2023年03月 日本薬学会 物理系薬学部会 令和5年度 日本薬学会物理系薬学部会 奨励賞
   ナノ化技術を基盤とした経皮吸収型製剤の開発と薬物送達機構の解明 

  受賞者: 大竹裕子
• 2021年01月 日本薬学会関西支部 奨励賞 クリスタルエンジニアリングを基盤とした吸入用ナノ結晶製剤の開発と肺線維症治療への応用
   

  受賞者: 大竹裕子
• 2018年07月 第57回 日本白内障学会・第44回 水晶体研究会 トラベルアワード
   薬物眼内移行性向上を目的としたナノ点眼製剤の開発
• 2017年10月 日本薬学会近畿支部総会・大会 優秀ポスター賞
   NSAIDs起因性消化管障害の制御を目指した製剤工夫：メロキシカムナノ結晶製剤の開発 

  受賞者: 石井美有;大竹裕子;長井紀章
• 2017年08月 日本眼科学会 セッション優秀賞
   ラノステロールを用いた白内障治療の開発：ナノ製剤はSCR水晶体混濁を改善する 

  受賞者: 福岡侑也;出口粧央里;大竹裕子;佐藤完太;多賀 淳;岡 美佳子;平松範子;山本直樹;長井紀章
• 2013年05月 日本薬剤学会 永井財団大学院生スカラシップ
   

  受賞者: 大竹 裕子
• 2013年05月 日本薬剤学会 最優秀発表者賞
   噴霧急速凍結乾燥法による吸入粉末剤開発における疎水性アミノ酸の有用性 

  受賞者: 大竹 裕子

共同研究・競争的資金等の研究課題

• 肺がん治療への応用を目的とした吸入用抗がん剤ナノ粒子の創製

  日本学術振興会：科学研究費助成事業 若手研究

  研究期間 : 2019年04月 -2023年03月 

  代表者 : 大竹 裕子

   

  昨年度と同様にナノサイズまでの破砕が可能な湿式ビーズミル法を基盤とし、肺がん吸入用治療薬としての吸入用パクリタキセル（PTX）ナノ粒子（PTX-NPs）の創製に向けて、添加物の種類・添加割合・ビーズミル条件が異なる種々のナノ粒子を調製し、ナノ粒子の粒子径測定および粒子形状評価の結果に基づいた処方・調製条件の最適化を行った。処方・調製条件の最適化において、メチルセルロース(MC)の添加濃度を変化させることで薬物の破砕効率が変化することを明らかにしてきたが、肺へ直接投与した場合におけるMC由来の毒性が懸念された。そこで、添加物を含有せずPTXのみで湿式ビーズミル法によるナノ粒子化を試みた。その結果、MC添加により調製したPT-NPs懸濁液と比較して、ナノ化されているものの得られたPTX-NPs懸濁液中のPTX濃度が低く、PTXがほとんどナノ化されていないことが示された。そこで、吸入製剤の添加物として使用されるとともに添加濃度により粘度変化を示すアルギン酸ナトリウムやヒアルロン酸ナトリウムなどを用いて吸入用PTX-NPsの調製を行うとともに、調製した吸入用PTX-NPsの粉末製剤化を試みた。その結果、粉末回収時にべとつきが生じ、製剤回収量の低下および吸入時の薬物分散性の不良が予想された。今後、L-ロイシンやL-フェニルアラニンなどを始めとする分散補助剤を添加することで肺および肺深部送達性が良好な吸入用PTX-NPs含有粉末の調製を行い、マウスに経肺投与した際の体内動態評価および肺転移がんモデルマウスを用いた際の治療効果評価について検討を行う。
• 肺胞標的型吸入用薬物ナノ粒子の創製と肺線維症治療への応用

  日本私立学校振興・共済事業団：女性研究者奨励金

  研究期間 : 2018年05月 -2019年05月 

  代表者 : 大竹 裕子
• 肺深部送達・沈着性に優れた呼吸器内膨張性吸入粉末剤の開発

  公益財団法人 堀科学芸術振興財団：第24回 研究助成 一般の部 創薬の研究

  研究期間 : 2015年05月 -2016年05月 

  代表者 : 大竹 裕子

担当経験のある科目

創薬科学実習1近畿大学
総合演習2近畿大学
医薬品物性・製剤学実習近畿大学
卒業研究近畿大学
基礎ゼミ近畿大学
製剤工学近畿大学
生命の科学近畿大学
創薬科学実習4近畿大学

その他

• 2021年04月 - 2022年03月  肺深部を標的とした次世代型吸入用薬物ナノ粒子の創製と肺がん治療への有用性評価 

  近畿大学 学内研究助成金 奨励研究助成金 SR15 研究内容：本研究は、肺がん治療薬として知られている各種抗がん剤とナノサイズまでの破砕が可能な湿式ビーズミル法を基盤とし、肺がん治療薬としての吸入用抗がん剤ナノ粒子の創製を試みた。ビーズミルの調製条件および処方条件を適宜変化させることで、ナノサイズを示す吸入用抗がん剤ナノ粒子を調製し、その物理化学的性質（粒子径および粒子形状等）を評価した。
• 2018年04月 - 2018年04月  肺深部治療を指向した新規ナノ吸入製剤の開発 

  近畿大学学内研究助成金 奨励研究助成金 SR02 研究内容: 本研究は、肺線維症治療薬としての開発が望まれるトラニラストをナノサイズまで破砕が可能な湿式ビーズミル法を基盤とし、肺線維症の病変部位である肺深部を標的とした吸入用薬物ナノ粒子の調製条件の確立を試みたものである。また、ビーズミルの調製条件および処方条件を適宜変化させることで、100 nm 以下の吸入用トラニラストナノ粒子を調製し、マウスへの肺内投与による体内動態や肺障害性について評価を行うとともに、肺線維症モデルマウスへの治療効果について検討を行っている。

その他のリンク

researchmap

https://researchmap.jp/hotake