KINDAI UNIVERSITY


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OTAKE Hiroko

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FacultyDepartment of Pharmacy
PositionAssistant Professor
DegreePh.D.in Pharmaceutical Science
Commentator Guidehttps://www.kindai.ac.jp/meikan/2076-otake-hiroko.html
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Last Updated :2020/08/10

Education and Career

Education

  •   2006 04  - 2012 03 , Meijo University, Faculty of Pharmacy
  •   2012 04  - 2016 03 , Meijo University, Graduate School of Pharmacy
  •   2016 04  - 2017 03 , Meijo University, Faculty of Pharmacy
  •   2017 04  - 現在, Kindai University, Faculty of Pharmacy

Research Activities

Research Areas

  • Life sciences, Clinical pharmacy

Published Papers

  • Retinal proteomic evaluation of rats following streptozotocin-injection using shotgun proteomics, Hiroko Otake, Tetushi Yamamoto, Saori Deguchi, Atushi Taga, Noriaki Nagai, MOLECULAR MEDICINE REPORTS, MOLECULAR MEDICINE REPORTS, 21(1), 379 - 386, Jan. 2020 , Refereed
    Summary: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.
  • [Design of Microdialysis-CLC Method for Measurement of Drug Behavior in Lacrimal Fluid after Instillation]., Nagai N, Ueno A, Ishii M, Fukuoka Y, Otake H, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 138(8), 1111 - 1117, Aug. 2018 , Refereed
  • 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, International Journal of Molecular Sciences, 19(7), 2138, Jul. 23 2018
    Summary:© 2018 by the authors. Licensee MDPI, Basel, Switzerland. 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 cytochalas
  • 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, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 59(9), Jul. 2018 , Refereed
  • Involvement of Endocytosis in the Transdermal Penetration Mechanism of Ketoprofen Nanoparticles., Nagai N, Ogata F, Ishii M, Fukuoka Y, Otake H, Nakazawa Y, Kawasaki N, International journal of molecular sciences, International journal of molecular sciences, 19(7), Jul. 2018 , Refereed
  • Instillation of Sericin Enhances Corneal Wound Healing through the ERK Pathway in Rat Debrided Corneal Epithelium., Nagai N, Fukuoka Y, Ishii M, Otake H, Yamamoto T, Taga A, Okamoto N, Shimomura Y, International journal of molecular sciences, International journal of molecular sciences, 19(4), Apr. 2018 , Refereed
  • 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, NAKAZAWA Yosuke, 日本眼科学会雑誌, 日本眼科学会雑誌, 122(1), 61 - 62, Jan. 20 2018
  • Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment., Nagai N, Ogata F, Otake H, Nakazawa Y, Kawasaki N, International journal of nanomedicine, International journal of nanomedicine, 13, 5215 - 5229, 2018 , Refereed
  • Ophthalmic Formulation Containing Nilvadipine Nanoparticles Prevents Retinal Dysfunction in Rats Injected with Streptozotocin., Deguchi S, Otake H, Nakazawa Y, Hiramatsu N, Yamamoto N, Nagai N, International journal of molecular sciences, International journal of molecular sciences, 18(12), Dec. 2017 , Refereed
  • 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, International Journal of Molecular Sciences, 18, Sep. 2017 , Refereed
    Summary:© 2017 by the authors. Licensee MDPI, Basel, Switzerland. We previously prepared ophthalmic formulations containing cilostazol (CLZ) nanoparticles by bead mill methods (CLZnano), and found that instillation of CLZnanointo 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 CLZnanohad 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 CLZnanoattenuating 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 CLZnanoThus, 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 beta(1-43) Accumulates in the Lens Epithelium of Cortical Opacification in Japanese Patients, Noriaki Nagai, Yu Mano, Hiroko Otake, Teppei Shibata, Eri Kubo, Hiroshi Sasaki, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 58(7), 3294 - 3302, Jun. 2017 , Refereed
    Summary:PURPOSE. We investigated the accumulation of amyloid beta (A beta(1- 40), A beta(1-42), A beta(1- 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; A beta levels and mRNA expression were determined by ELISA and a real- time RT-PCR method, respectively. RESULTS. Levels of A beta(1- 40) and A beta(1- 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 A beta(1- 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 A beta(1- 43) levels were observed in the lens epithelium of patients with COR, and a close relationship was observed between A beta(1- 43) levels and the degree of lens opacification (R= 0.8229, n = 6). The levels of A beta(1- 43) were also higher in the lens epithelium of patients with mixed-cataract showing cortical opacification, and the A beta(1- 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 A beta(1-43) accumulation in the lens epithelium of Japanese patients with cortical opacification.
  • 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), Materials (Basel, Switzerland), 13(7), Apr. 03 2020 , Refereed
    Summary: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, Pharmaceutics, 12(4), Apr. 2020 , Refereed
    Summary:© 2020 by the authors. Licensee MDPI, Basel, Switzerland. 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, Pharmaceutics, 12(4), Apr. 01 2020 , Refereed
    Summary: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.
  • 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, Pharmaceutics, 12(2), Feb. 14 2020 , Refereed
    Summary: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, International journal of molecular sciences, 21(3), Feb. 05 2020 , Refereed
    Summary: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.
  • 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, International journal of molecular sciences, 20(20), Oct. 09 2019 , Refereed
    Summary: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, International journal of molecular sciences, 20(15), Jul. 25 2019 , Refereed
    Summary: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, Molecular medicine reports, 19(6), 5464 - 5472, Jun. 2019 , Refereed
    Summary: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), Nanomaterials (Basel, Switzerland), 9(5), May 19 2019 , Refereed
    Summary: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, International journal of molecular sciences, 20(3), Jan. 22 2019 , Refereed
    Summary: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, International journal of nanomedicine, 14, 7921 - 7931, 2019 , Refereed
    Summary: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, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 139(1), 123 - 130, 2019 , Refereed
    Summary: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, Chemical & pharmaceutical bulletin, 67(2), 120 - 124, 2019 , Refereed
    Summary: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, International journal of nanomedicine, 14, 1213 - 1227, 2019 , Refereed
    Summary: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, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 19(11), Nov. 2018 , Refereed
    Summary: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.
  • 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, International journal of molecular sciences, 19(1), Jan. 17 2018 , Refereed
    Summary: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.
  • 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, EXPERIMENTAL EYE RESEARCH, 165, 118 - 124, Dec. 2017 , Refereed
    Summary: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 watersoluble 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 watersoluble 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. (C) 2017 Elsevier Ltd. All rights reserved.
  • Evaluation of Retinal Function in Streptozotocin-induced Diabetic Rats by Using the Electroretinography and Immunohistochemistry Methods, Noriko Hiramatsu, Saori Deguchi, Chiaki Yoshioka, Hiroko Otake, Naoki Yamamoto, Noriaki Nagai, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 137(9), 1169 - 1175, Sep. 2017 , Refereed
    Summary: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/kgX2). 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.
  • 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, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 18(9), Sep. 2017 , Refereed
    Summary:We previously prepared ophthalmic formulations containing cilostazol (CLZ) nanoparticles by bead mill methods (CLZ(nano)), and found that instillation of CLZ(nano) 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 CLZ(nano) 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 CLZ(nano) 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 CLZ(nano) 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 CLZ(nano). These findings provide significant information that can be used to design further studies aimed at developing anti-diabetic retinopathy drugs.
  • 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, PHARMACEUTICAL RESEARCH, 33(4), 922 - 931, Apr. 2016 , Refereed
    Summary: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. 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. 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. 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, CHEMICAL & PHARMACEUTICAL BULLETIN, 64(3), 239 - 245, Mar. 2016 , Refereed
    Summary: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.

Books etc

  • Development of Formulation and Devices of Next-Generation Inhalation, Hiroko Otake, Contributor,   2018 11

Misc

  • 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 07
    Summary:臨床において、非ステロイド性抗炎症薬(NSAIDs)による消化管障害は重篤な問題である。著者らは、湿式ビーズミル法を用い、平均粒子径76nmのインドメタシン(IMC)ナノ結晶経口製剤の作製法を確立した。また、本製剤は、従来の製剤と比較し、約5倍もバイオアベイラビリティが高まり、薬物投与量の減量を可能とした。さらに、これら製剤化に伴うNSAIDs投与量の減少が、薬剤の消化管粘膜直接刺激の低下を介し、障害誘発を軽減することを示した。本成果が安全なNSAIDs療法の確立に繋がることを期待する。(著者抄録)
  • 【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 06
  • 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 06
    Summary:近年、アルツハイマー病の要因であるアミロイドβ(Aβ)が水晶体にも存在することが報告され、水晶体混濁(白内障)への関与が注目されている。しかし、日本人における水晶体中Aβ産生・蓄積機構については未だ十分に解明されていない。そこで今回、日本人の非認知症患者および認知症患者水晶体を対象として、組織中のAβ産生・分解関連mRNA発現量の変化について比較検討を行った。Aβ産生(APP、BACE1、PS)および分解(ADAM10、NEP、ECE-1)関連mRNA発現量の測定にはリアルタイムPCR法を用い、ヒト試料(水晶体上皮細胞)は硝子体および白内障手術患者から得た。認知症患者の混濁水晶体では、Aβ分解を促す酵素であるNEPおよびECE-1 mRNA発現量が非認知症患者と比べて有意に低値であった。これらAβ分解能の低下は、日本人の認知症患者における水晶体混濁機構の一つであると考えられる。(著者抄録)
  • 【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 06
  • 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 06
    Summary:近年、アルツハイマー病の要因であるアミロイドβ(Aβ)が水晶体にも存在することが報告され、水晶体混濁(白内障)への関与が注目されている。しかし、日本人における水晶体中Aβ産生・蓄積機構については未だ十分に解明されていない。そこで今回、日本人の非認知症患者および認知症患者水晶体を対象として、組織中のAβ産生・分解関連mRNA発現量の変化について比較検討を行った。Aβ産生(APP、BACE1、PS)および分解(ADAM10、NEP、ECE-1)関連mRNA発現量の測定にはリアルタイムPCR法を用い、ヒト試料(水晶体上皮細胞)は硝子体および白内障手術患者から得た。認知症患者の混濁水晶体では、Aβ分解を促す酵素であるNEPおよびECE-1 mRNA発現量が非認知症患者と比べて有意に低値であった。これらAβ分解能の低下は、日本人の認知症患者における水晶体混濁機構の一つであると考えられる。(著者抄録)
  • 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 01
    Summary:遊星ボールミル法適用時における添加物選択及び添加量設定の指標を確立すべく、重合度の異なるメチルセルロースが破砕効率へ与える影響について検討した。破砕薬物としてイブプロフェン(IBU)粉末を用い、添加物をメチルセルロースに固定し、1.0%SM-4、15、25、100、400、1500、4000使用時における遊星ボールミル法の破砕効率を薬物粒子径から評価した。その結果、添加物の粘度の増加に伴い、破砕後のIBU粒子径は増大したが、両因子間において直線性は認められなかった。次に、粘度と破砕効率の関係をより詳細に評価すべく、SM-4、SM-400及びSM-4000を用い、各添加物の濃度を0.1〜1%に変更した際の破砕効率を比較評価した。その結果、SM-4使用群では粘度は低いものの、高い破砕効率が得られた。一方、SM-400使用群では低濃度(0.1%)よりも高濃度(1.0%)で破砕効率が高まり、SM-4000使用群では、低濃度(0.1%)ではIBUはナノサイズまで破砕されなかった。次にSM-4、SM-400及びSM-4000の濃度変化が、破砕後の薬物粒度分布挙動に及ぼす影響について検討を行った。その結果、粘度は破砕効率に直接影響しないものの、破砕効率に対してメチルセルロース添加濃度には最適値が存在し、これら濃度(最適値)は、重合度が高いタイプほど上昇することを示した。さらに、添加物濃度が最適値よりも低い場合には、粒度分布がテーリングのような形状を示し、過剰に添加物を使用した際にはマイクロサイズの再凝集を示すピークが確認された。
  • Effect of Methylcellulose (Cellulose Derivatives) on Ibuprofen-crushing Efficiency in Nano Pulverizer NP-100, 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(J‐STAGE),   2019 , https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201902215119825526
  • 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 01
    Summary:遊星ボールミル法適用時における添加物選択及び添加量設定の指標を確立すべく、重合度の異なるメチルセルロースが破砕効率へ与える影響について検討した。破砕薬物としてイブプロフェン(IBU)粉末を用い、添加物をメチルセルロースに固定し、1.0%SM-4、15、25、100、400、1500、4000使用時における遊星ボールミル法の破砕効率を薬物粒子径から評価した。その結果、添加物の粘度の増加に伴い、破砕後のIBU粒子径は増大したが、両因子間において直線性は認められなかった。次に、粘度と破砕効率の関係をより詳細に評価すべく、SM-4、SM-400及びSM-4000を用い、各添加物の濃度を0.1〜1%に変更した際の破砕効率を比較評価した。その結果、SM-4使用群では粘度は低いものの、高い破砕効率が得られた。一方、SM-400使用群では低濃度(0.1%)よりも高濃度(1.0%)で破砕効率が高まり、SM-4000使用群では、低濃度(0.1%)ではIBUはナノサイズまで破砕されなかった。次にSM-4、SM-400及びSM-4000の濃度変化が、破砕後の薬物粒度分布挙動に及ぼす影響について検討を行った。その結果、粘度は破砕効率に直接影響しないものの、破砕効率に対してメチルセルロース添加濃度には最適値が存在し、これら濃度(最適値)は、重合度が高いタイプほど上昇することを示した。さらに、添加物濃度が最適値よりも低い場合には、粒度分布がテーリングのような形状を示し、過剰に添加物を使用した際にはマイクロサイズの再凝集を示すピークが確認された。
  • Pharmaceutical applications of nanoparticulate drug delivery systems enhance the membrane permeability, 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 12 21 , https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201902288815854288
  • 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 11
  • 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 08
    Summary:キャピラリー液体クロマトグラフィー(CLC)とマイクロダイアリシス法を連結した手法を用い、市販チモロールマレイン酸塩(TM)点眼薬点眼後の涙液中薬物挙動の把握について検討した。マイクロダイアリシス-HPLC法における検量線は直線性を示し、r値は0.9971であった。ウサギ涙液中薬物濃度を測定したところ、点眼50分後まで薬物の検出が認められ、透析膜回収法と類似した薬物消失を示した。一方、点眼15分後の涙液中薬物量の標準誤差は2.4μg/mLと透析膜回収法と比較し、涙液中薬物量のバラツキが軽減された。TM点眼薬点眼後の涙液中薬物挙動に関して、マイクロダイアリシス-CLC法の検量線において、r値は0.9982であり、点眼後のウサギ涙液中薬物濃度変化を測定したところ、点眼75分後まで経時的な薬物の消失が確認できた。また、バッチサンプリング法や透析膜回収法に比べバラツキも少なく、高い再現性が確認された。
  • 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 08
    Summary:キャピラリー液体クロマトグラフィー(CLC)とマイクロダイアリシス法を連結した手法を用い、市販チモロールマレイン酸塩(TM)点眼薬点眼後の涙液中薬物挙動の把握について検討した。マイクロダイアリシス-HPLC法における検量線は直線性を示し、r値は0.9971であった。ウサギ涙液中薬物濃度を測定したところ、点眼50分後まで薬物の検出が認められ、透析膜回収法と類似した薬物消失を示した。一方、点眼15分後の涙液中薬物量の標準誤差は2.4μg/mLと透析膜回収法と比較し、涙液中薬物量のバラツキが軽減された。TM点眼薬点眼後の涙液中薬物挙動に関して、マイクロダイアリシス-CLC法の検量線において、r値は0.9982であり、点眼後のウサギ涙液中薬物濃度変化を測定したところ、点眼75分後まで経時的な薬物の消失が確認できた。また、バッチサンプリング法や透析膜回収法に比べバラツキも少なく、高い再現性が確認された。
  • 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 05
  • 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 05
  • 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 05
  • 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 05
  • 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 05
  • 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 05
  • 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 05
  • 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 05
  • 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 03
  • 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 03
  • 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 03
  • 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 03
  • 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 09 , 10.1248/yakushi.17-00115
    Summary:7週齢Wistar雄性ラットを用い、ラットへのストレプトゾシン(STZ)過剰頻回腹腔内投与が網膜に与える影響について検討した。100mg/kg STZ頻回投与によって、網膜神経細胞層の肥厚、特に神経節細胞層と内顆粒層の間隙が広がることが分かった。また、視機能指標であるa波、b波、Opsを含むERG全体が低下することが示された。ERGの低下は40週齢のOLETFラットのような自然発症2型糖尿病モデル動物にみられないことから、糖尿病網膜症研究およびモデル動物確立に大きく寄与し、眼後部を標的にした点眼製剤の薬効評価に有用と思われた。
  • 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 09 , 10.1248/yakushi.17-00115
  • 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・講演抄録集, 37th, 43, 43,   2017 09 , http://jglobal.jst.go.jp/public/201702262810219389
  • 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 05
  • 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 05
  • 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 05 , http://jglobal.jst.go.jp/public/201702216253653694
  • 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 05 , http://jglobal.jst.go.jp/public/201702291809075005
  • 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(CD-ROM), 136th, 4, ROMBUNNO.27AB‐PM212, 194,   2016 03 , http://jglobal.jst.go.jp/public/201602283037615380
  • 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(Web), 30th, 21B5-1 (WEB ONLY), 104,   2015 05 , http://jglobal.jst.go.jp/public/201502218636894082
  • 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 10 10 , http://jglobal.jst.go.jp/public/201502222470142229
  • 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(Web), 29th, 20E2-3 (WEB ONLY), 127,   2014 05 , http://jglobal.jst.go.jp/public/201502275002425813
  • 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(Web), 29th, 20E2-2 (WEB ONLY), 126,   2014 05 , http://jglobal.jst.go.jp/public/201502296621941351
  • 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(CD-ROM), 134th, 4, ROMBUNNO.29N-AM05S, 66,   2014 03 , http://jglobal.jst.go.jp/public/201402217366626060
  • 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(CD-ROM), 134th, 4, ROMBUNNO.29N-AM06S, 66,   2014 03 , http://jglobal.jst.go.jp/public/201402256450670819
  • 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(Web), 28th, 23-3-02 (WEB ONLY), 202,   2013 04 26 , http://jglobal.jst.go.jp/public/201302233048411273
  • 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(CD-ROM), 133rd, 4, ROMBUNNO.28Q-PM03, 57,   2013 03 , http://jglobal.jst.go.jp/public/201302238695101024
  • 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 10 19 , http://jglobal.jst.go.jp/public/201302229030855371
  • 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 Deliv Syst, 26, 3, 301, 301,   2011 05 28 , http://jglobal.jst.go.jp/public/201102291627504769
  • 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, 26th, 168, 168,   2011 05 01 , http://jglobal.jst.go.jp/public/201102205728650746
  • 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, 131st, 4, 233,   2011 03 05 , http://jglobal.jst.go.jp/public/201102224199104778
  • 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 04 20 , http://jglobal.jst.go.jp/public/201002290871796387
  • 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 04