Pharmacokinetic advantage of an intranasal preparation of a novel anti-osteoporosis drug, L-Asp-hexapeptide-conjugated estradiol
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概要
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We examined the usefulness of intranasal (i.n.) administration of a novel osteotropic prodrug of estradiol, estradiol-17β-succinate-(L-aspartate) 6 (E2·17D6), for selective drug delivery to bone. E2·17D6 alone or with 5% 2,6-di-O-methyl-β-cyclodextrin (DMβCD), 5% β-cyclodextrin (βCD), or 10% hydroxypropyl cellulose (HPC) as an absorption enhancer was administered to ovariectomized (OVX) mice via the i.n. route. The oral and nasal bioavailability after p.o. or i.n. administration of E2· 17D6 (3.7 μmol/kg) in mice amounted to 9.9 and 23.0% of the dose, respectively. The values of nasal bioavailability of E2· 17D6 administered with DMβCD, βCD, and HPC were 74.9, 55.8, and 49.1%, respectively. The plasma concentration of E2· 17D6 after i.n. administration of E2·17D 6-DMβCD decreased rapidly to the endogenous level by 6 h, but the concentration in the bone was about 200 times higher than that in plasma, and decreased slowly over a period of about a week. When E2 (total dose 4.4 μmol/kg, i.n., every 3rd day) was administered to OVX mice for 35 d, bone mineral density (BMD), liver weight, and uterus weight increased, whereas E2·17D6-DMβCD (total dose 0.44 to 8.8 μmol/kg, i.n., every 7th day) increased only BMD in a dose-dependent manner. In conclusion, intranasally administered E2·17D 6-DMβCD has a potent antiosteoporotic effect without side effects, and has potential to provide an improved quality of life for patients with osteoporosis. © 2006 Pharmaceutical Society of Japan.
- 公益社団法人日本薬学会の論文
- 2006-06-01
著者
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MIYAMOTO Ken-ichi
Department of Pharmacology and Pharmaceutics, Graduate School of Natural Science and Technology, Kan
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Sakura Naoki
北陸大学 薬 生物活性
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YOKOGAWA Koichi
Department of Hospital Pharmacy, School of Medicine, Kanazawa University
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Miyamoto Ken-ichi
金沢大学 薬学部臨床薬物情報
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Miyamoto Ken-ichi
Dep. Of Clinical Pharmacy Graduate School Of Natural Sci. And Technol. Kanazawa Univ.
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Sakura Naoki
Department Of Biosynthetic Chemistry Faculty Of Pharmaceutical Science Hokuriku University
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Sakura Naoki
Department Of Bio-organic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University
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TOSHIMA Katsuhiro
Department of Clinical Pharmacy, Graduate School of Natural Science and Technology, Kanazawa Univers
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YAMOTO Kayo
Department of Clinical Pharmacy, Graduate School of Natural Science and Technology, Kanazawa Univers
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NISHIOKA Tatsuo
Department of Clinical Pharmacy, Graduate School of Natural Science and Technology, Kanazawa Univers
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Yokogawa Koichi
Department Of Clinical Pharmacy Graduate School Of Natural Science And Technology Kanazawa Universit
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Yamoto Kayo
Department Of Clinical Pharmacy Graduate School Of Natural Science And Technology Kanazawa Universit
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Yokogawa Koichi
Department Of Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University
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Toshima Katsuhiro
Department Of Clinical Pharmacy Graduate School Of Natural Science And Technology Kanazawa Universit
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Miyamoto Ken-ichi
Department Of Applied Pharmacology Faculty Of Pharmaceutical Sciences Hokuriku University
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Miyamoto Kenichi
Department Of Chemistry For Materials Faculty Of Engineering And Graduate School Of Engineering Mie
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Nishioka Tatsuo
Department Of Clinical Pharmacology Faculty Of Pharmaceutical Sciences Hokuriku University
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Nishioka Tatsuo
Dep. Of Clinical Pharmacology Fac. Of Pharmaceutical Sciences Hokuriku Univ.
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Miyamoto Ken-ichi
Department of Clinical Pharmacy, Graduate School of Natural Science and Technology, Kanazawa University
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