研究室

生物薬剤学[研究者の方向け]

主な研究テーマ

当研究室では薬物投与の最適化を目指して、薬物の有効性・安全性を高める投与剤形の開発、投与計画の設定に関する研究を行っている。

  1. 薬物の体内動態の解析:
    生理活性を有する薬物を医薬品として開発する際、その体内動態の解析は必須である。当教室では主にラットを用いて各種薬物の体内動態の解析を行っている。
  2. 新しい薬物投与剤形 (DDS) の開発:
    薬物が薬理効果を発揮するためには、その薬物の作用部位に必要な濃度が得られなければならない。1)の検討の結果、バイオアベイラビリティが不十分であるなど、体内動態の欠点が見つかれば、その原因を解析し、改善手段を見出して適用する。それらに関連して、種々の研究テーマを展開中である。

    (1)薬物の消化管吸収制御因子の解析とその結果に基づく経口投与製剤の改善
    (溶解性、安定性、粘膜透過性、消化管滞留性の最適化)
    (2)薬物の新投与経路の開発と評価(皮膚、鼻粘膜、大腸粘膜)
    (3)抗がん剤内封ナノ粒子製剤の腫瘍組織への到達性改善による抗腫瘍効果の増強
    (4)薬物吸収の速度論的解析と予測
    (5)薬物の体内消失過程の速度論的解析

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最近の主な発表論文

  1. Appearance of double peaks in plasma concentration – time profile after oral administration depends on gastric emptying profile and weight function. Y. Metsugi, Y. Miyaji, K. Ogawara, K. Higaki and T. Kimura: Pharm. Res., 25 (4) 886-895 (2008).
  2. Evaluation of in-vivo dissolution behavior and GI transit of griseofulvin, a BCS class II drug. Y. Fujioka, Y. Metsugi, K. Ogawara, K. Higaki and T. Kimura: Int. J. Pharm., 352 (1-2) 36-43 (2008).
  3. Albumin-conjugated PEG liposome enhances tumor distribution of liposomal doxorubicin in rats. J. Yokoe, S. Sakuragi, K. Yamamoto, T. Teragaki, K. Ogawara, K. Higaki, N. Katayama, T. Kai, M. Sato and T. Kimura: Int. J. Pharm., 353 (1-2) 28-34 (2008).
  4. Correlation of cyclosporine blood concentration-dose ratio and biochemical parameters in living-donor lung transplant patients. M. Ishii, Y. Kawakami, H. Date, K. Higaki, T. Sendo and T. Kimura: Jpn. J. Pharm. Healthcare Sci., 34 (4) 381-385 (2008).
  5. Effect of percutaneous endoscopic gastrostomy on gastrointestinal motility: evaluation by gastric-emptying scintigraphy. H. Wakamatsu, S. Nagamachi, R. Nishii, K. Higaki, K. Kawai, K. Kamimura, S. Fujita, S. Futami and S. Tamura: Nucl. Med. Commun., 29 (6) 562-567 (2008).
  6. Mechanistic understanding of time-dependent oral absorption based on gastric motor activity in humans. K. Higaki, S. Y. Choe, R. Löbenberg, L. S. Welage and G. L. Amidon: Eur. J. Pharm. Biopharm., 70 (1) 313-325 (2008).
  7. Determinants for in-vivo anti-tumor effects of PEG liposomal doxorubicin: Importance of vascular permeability within tumors. K. Ogawara, K. Un, K. Minato, K. Tanaka, K. Higaki and T. Kimura: Int. J. Pharm., 359 (1-2) 234-240 (2008).
  8. Prolongation of residence time of liposome by surface-modification with mixture of hydrophilic polymers. T. Shehata, K. Ogawara, K. Higaki and T. Kimura: Int. J. Pharm., 359 (1-2) 272-279 (2008).
  9. In vitro-in vivo correlation for wet-milled tablet of poorly water-soluble cilostazol. J. Jinno, N. Kamada, M. Miyake, K. Yamada, T. Mukai, M. Odomi, H. Toguchi, G. G. Liversidge, K. Higaki and T. Kimura: J. Controlled Rel., 130 (1) 29-37 (2008).
  10. Quantitative evaluation of PEPT1 contribution to oral absorption of cephalexin in rats. T. Hironaka, S. Itokawa, K. Ogawara, K. Higaki and T. Kimura: Pharm. Res., 26 (1) 40-50 (2009).
  11. In vivo anti-tumor effect of PEG liposomal doxorubicin (DOX) in DOX-resistant tumor-bearing mice: Involvement of cytotoxic effect on vascular endothelial cells. K. Ogawara, K. Un, K. Tanaka, K. Higaki and T. Kimura: J. Controlled Rel., 133 (1) 4-10 (2009).
  12. Novel oral absorption system containing polyamines and bile salts enhances drug transport via both transcellular and paracellular pathways across Caco-2 cell monolayers. F. Mukaizawa, K. Taniguchi, M. Miyake, K. Ogawara, M. Odomi, K. Higaki and T. Kimura: Int. J. Pharm., 367 (1-2) 103-108 (2009).
  13. Effect of adrenergic stimulation on drug absorption via passive diffusion in Caco-2 cells. T. Kimoto, M. Takanashi, H. Mukai, K. Ogawara, T. Kimura and K. Higaki: Int. J. Pharm., 368 (1-2) 31-36 (2009).
  14. Amino acids suppress apoptosis induced by sodium laurate, an absorption enhancer. C. Takayama, F. Mukaizawa, T. Fujita, K. Ogawara, K. Higaki and T. Kimura: J. Pharm. Sci., 98 (12) 4629-4638 (2009).
  15. Emusion generating microchannel device oscillated by 2.25 MHz ultrasonic vibrator. T. Harada, T. Kanda, O. Suzumori, T. Ono, S. Iwabuchi, K. Ito, K. Ogawara and K. Higaki: Jpn. J. Appl. Phys., 49 07HE13-1 – 07HE13-6 (2010).
  16. The Design and evaluation of emulsion generation device using ultrasonic vibration and microchannel. T. Kanda, T. Harada, Y. Tominaga, K. Suzumori, T. Ono, S. Iwabuchi, K. Ito, K. Ogawara, K. Higaki and Y. Yoshizawa: Jpn. J. Appl. Phys., 50 07HE24 -1 – 07HE24‐6 (2011).
  17. PEG liposomalization of paclitaxel improved its in-vivo disposition and anti-tumor efficacy. Y. Yoshizawa, Y. Kono, K. Ogawara, T. Kimura and K. Higaki: Int. J. Pharm., 412 (1-2) 132-141 (2011).
  18. Antimalarial activity of endoperoxide compound 6-(1,2,6,7-tetraoxaspiro [7.11]nonadec-4-yl)hexan-1-ol. A. Sato, A. Hiramoto, M. Morita, M. Matsumoto, Y. Komichi, Y. Nakase, N. Tanigawa, O. Hiraoka, K. Hiramoto, H. Hayatsu, K. Higaki, A. Kawai, A. Masuyama, M. Nojima, Y. Wataya and H.-S. Kim: Parasitol. Int., 60 (3) 270-273 (2011).
  19. Sex differences in pharmacokinetics of cilostazol in rats. N. Kamada, K. Yamada, M. Odomi, T. Mukai, T. Nishibayashi, K. Ogawara, T. Kimura and K. Higaki: Xenobiotica, 41 (10) 903-913 (2011).
  20. Antimalarial activity of 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) and its carboxylic acid derivatives. A. Sato, S. Kawai, A. Hiramoto, M. Morita, N. Tanigawa, Y. Nakase, Y. Komichi, M. Matsumoto, O. Hiraoka, K. Hiramoto, H. Tokuhara, A. Masuyama, M. Nojima,  K. Higaki, H. Hayatsu, Y. Wataya and H.-S. Kim: Parasitol. Int., 60 (4) 488-492 (2011).
  21. Development of transdermal therapeutic formulation of CNS5161, a novel NMDA receptor antagonist, by utilizing pressure-sensitive adhesives I. M. Naruse, K. Ogawara, T. Kimura, R. Konishi and K. Higaki: Biol. Pharm. Bull., 35 (3) 321-328 (2012).
  22. Evaluation of factors affecting gastrointestinal absorption of a novel anticoagulant FX-93 for development of oral formulation.  S. Takemura, H. Kondo, K. Suzumura, K. Ogawara, S. Watanabe, K. Sako and K. Higaki: J. Pharm. Sci., 101 (6) 2134-2142 (2012).
  23. In vitro evaluation of nasal mucociliary clearance using excised rat nasal septum. D. Inoue, T. Furubayashi, K. Ogawara, T. Kimura, K. Higaki, H. Katsumi, T. Sakane, A. Yamamoto and Y. Higashi: Biol. Pharm. Bull., 35 (6) 889-894 (2012).
  24. Formulation and evaluation of paclitaxel-loaded polymeric nanoparticles composed of polyethylene glycol and polylactic acid block copolymer. T. Araki, Y. Kono, K. Ogawara, T. Watanabe, T. Ono, T. Kimura and K. Higaki: Biol. Pharm. Bull., 35 (8) 1306-1313 (2012).
  25. Novel comb-shaped PEG modification enhances the osteoclastic inhibitory effect and bone delivery of osteoprotegerin after intravenous administration in ovariectomized rats. Y. Miyaji, Y. Kasuya, Y. Furuta, A. Kurihara, M. Takahashi, K. Ogawara, T. Izumi, O. Okazaki and K. Higaki: Pharm. Res., 29 (11) 3143-3155 (2012).
  26. Deeper penetration into tumor tissues and enhanced in-vivo anti-tumor activity of liposomal paclitaxel by pre-treatment with angiogenesis inhibitor SU5416. Y. Yoshizawa, K. Ogawara, A. Fushimi, S. Abe, K. Ishikawa,T. Araki, G. Molema, T. Kimura and K. Higaki: Mol. Pharm., 9 (12) 3486-3494 (2012).
  27. Establishment of novel prediction system of intestinal absorption in humans using human intestinal tissues. M. Miyake, H. Toguchi, T. Nishibayashi, K. Higaki, A. Sugita, K. Koganei, N. Kamada, N-T. Kitazume, T. Hisamatsu, T. Sato, S. Okamoto, T. Kanai and T. Hibi: J. Pharm. Sci., 102 (8) 2564-2571 (2013).
  28. In vitro evaluation of the ciliary beat frequency of the rat nasal epithelium using a high-speed digital imaging system. D. Inoue, T. Furubayashi, K. Ogawara, T. Kimura, K. Higaki, T. Shingaki, S. Kimura, A. Tanaka, H. Katsumi, T. Sakane, A. Yamamoto and Y. Higashi: Biol. Pharm. Bull., 36 (6) 966-973 (2013).
  29. Aminoalkylmethacrylate copolymer E improves oral bioavailability of YM466 by suppressing drug – bile Interaction. S. Takemura, H. Kondo, S. Watanabe, K. Sako, K. Ogawara and K. Higaki: J. Pharm. Sci., 102 (9) 3128-3135 (2013).
  30. Regulation system of serine protease production in Vibrio vulnificus strain NCIMB 2137, a metalloprotease-gene negative strain isolated from a diseased eel. A. Elgaml, K. Higaki and S. Miyoshi: Aquaculture, 416-417 315-321 (2013).
  31. Effects of temperature, growth phase and luxO-disruption on regulation systems of toxin production in Vibrio vulnificus strain L-180, a human clinical isolate. A. Elgaml, K. Higaki and S. Miyoshi: World J. Microbiol. Biotechnol., 30 (2) 681-691 (2014).
  32. Development of transdermal therapeutic formulation of CNS5161, a novel NMDA receptor antagonist, by utilizing pressure-sensitive adhesives II: Improved transdermal absorption and evaluation of efficacy and safety. M. Naruse, K. Ogawara, T. Kimura, R. Konishi and K. Higaki: Eur. J. Pharm. Sci., 52 86-94 (2014).
  33. Pharmacokinetics and Safety of Resveratrol Derivatives in Humans after Oral Administration of Melinjo (Gnetum gnemon L.) Seed Extract Powder. H. Tani, S. Hikami, S. Iiduna, M. Yoshimatsu, T. Asama, H. Ota, Y. Kimura, T. Tatefuji, K. Hashimoto and K. Higaki: J. Agric. Food Chem., 62 (9) 1999-2007 (2014).
  34. Assessment of Tacrolimus Absorption from the Human Intestinal Tract: Open Label, Randomized, Four-way Crossover Study. D. Tsunashima, A. Kawamura, M. Murakami, T. Sawamoto, N. Undre, M. Brown, A. Groenewoud, J. Keirns, J. Holman, A. Connor, H. Wylde, I. Wilding, K. Ogawara, K. Sako, K. Higaki and R. First: Clin. Ther., 36 (5) 748-759 (2014).
  35. 小腸における難吸収性薬物の吸収改善に関する検討(Absorption Improvement of Poorly Absorbable Drug from Small Intestine): 三宅 正晃、向井 正志、檜垣 和孝: J. Pharm. Sci. Technol. Japan (薬剤学), 74 (5) 361-365 (2014).
  36. Determinants for in vivo anti-tumor effect of angiogenesis inhibitor SU5416 formulated in PEGylated emulsion. K. Ogawara, S. Abe, K. Un, Y. Yoshizawa, T. Kimura and K. Higaki: J. Pharm. Sci., 103 (8) 2464-2469 (2014).
  37. A novel approach to overcome multidrug resistance: Utilization of P-gp mediated efflux of paclitaxel to attack neighboring vascular endothelial cells in tumors. Y. Yoshizawa, K. Ogawara, T. Kimura and K. Higaki: Eur. J. Pharm. Sci., 62 274-280 (2014).
  38. Augmented EPR effect by photo-triggered tumor vascular treatment improved therapeutic efficacy of liposomal paclitaxel in mice bearing tumors with low permeable vasculature. T. Araki, K. Ogawara, H. Suzuki, R. Kawai, T. Watanabe, T. Ono and K. Higaki: J. Controlled Rel., 200 (1) 106-114 (2015).
  39. Improvement of oral bioavailability of N-251, a novel antimalarial drug, by increasing lymphatic transport with long-chain fatty acid-based self-nanoemulsifying drug delivery system. C. Imada, T. Takahashi, M. Kuramoto, K. Masuda, K. Ogawara, A. Sato, Y. Wataya, H-S. Kim and K. Higaki: Pharm. Res., 32 (8) 2595-2608 (2015).
  40. Analysis of intra- and inter-subject variability in oral drug absorption in human bioequivalence studies of 131 generic products. M. Sugihara, S. Takeuchi, M Sugita, K. Higaki, M. Kataoka and S. Yamashita: Mol. Pharm., 12 (12) 4405-4413 (2015).
  41. Efficient anti-tumor effect of photodynamic treatment with polymeric nanoparticles composed of polyethylene glycol and polylactic acid block copolymer encapsulating hydrophobic porphyrin derivative. K. Ogawara, T. Shiraishi, T. Araki, T. Watanabe, T. Ono and K. Higaki: Eur. J. Pharm. Sci., 82 154-160 (2016).
  42. Preparation of extended release solid dispersion formulations of tacrolimus using ethylcellulose and hydroxypropylmethylcellulose by solvent evaporation method. D. Tsunashima, K. Yamashita, K. Ogawara, K. Sako, and K. Higaki: J. Pharm. Pharmacol., 68 (3) 316-323 (2016).
  43. In-vivo disposition characteristics of PEG niosome and its interaction with serum proteins. T. Shehata, T. Kimura, K. Higaki and K. Ogawara: Int. J. Pharm., 512, 322-328 (2016).
  44. Biomarker discovery for drug-induced phospholipidosis: phenylacetylglycine to hippuric acid ratio in urine and plasma as potential markers. H. Kamiguchi, M. Murabayashi, I. Mori, A. Horinouchi and K. Higaki: Biomarkers, 22, 178-188 (2016).
  45. Evaluation of pharmacokinetic-pharmacodynamic indices of topical ophthalmic gatifloxacin against Staphylococcus aureus utilizing an in-vitro aqueous humour pharmaco- kinetic (AHPK) model. S. Kozai, T. Wada, K. Ogawara, T. Kida, H. Tokushige and K. Higaki: Int. J. Antimicrobial Agents, 49, 113-115 (2017).
  46. Development of safe and potent oil-in-water emulsion of paclitaxel to treat peritoneal dissemination. K. Ogawara, Y. Fukuoka, Y. Yoshizawa, T. Kimura and K. Higaki: J. Pharm. Sci., 106, 1143-1148 (2017).
  47. Development of extended release solid dispersion granules of tacrolimus: Evaluation of release mechanism and human oral bioavailability: D. Tsunashima, K. Yamashita, K. Ogawara, K. Sako, T. Hakomori and K. Higaki: J. Pharm. Pharmacol., 69, 1697-1706 (2017).
  48. The relationship between in vivo nasal drug clearance and in vitro nasal mucociliary clearance: Application to the prediction of nasal drug absorption: D. Inoue, A. Tanaka, S. Kimura, A. Kiriyama, H. Katsumi, A. Yamamoto, K. Ogawara, T. Kimura, K. Higaki, R. Yutani, T. Sakane, T. Furubayashi: Eur. J. Pharm. Sci., 117, 21-26 (2018).

教員紹介

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檜垣 和孝 教授
Kazutaka HIGAKI
専門分野 生物薬剤学、消化管吸収、肝•腎消失動態解析
所属学会 日本薬物動態学会、日本薬剤学会、日本DDS学会、日本薬学会、創剤フォーラム、Controlled Release Society (CRS)、American Association of Pharmaceutical Scientists (AAPS)、International Society for the Study of Xenobiotics (ISSX)
uid000006_2010071213172940f30426
大河原 賢一 准教授
Ken-ichi OGAWARA
専門分野 薬剤学、ドラッグデリバリーシステム(DDS)
所属学会 日本薬学会、日本薬剤学会、日本DDS学会、日本薬物動態学会

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