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Promoting activity of menthol derivatives containing sulfur atom on the percutaneous absorption of drugs

Research Project

Project/Area Number 08457597
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Physical pharmacy
Research InstitutionHoshi University

Principal Investigator

NAGAI Tsuneji  Hoshi University Pharmaceutics, Professor, 薬学部, 教授 (40061270)

Co-Investigator(Kenkyū-buntansha) HIGASHIYAMA Kimio  Hoshi University Organic Chemistry, Assistant Professor, 薬学部, 講師 (70101582)
TAKAYAMA Kozo  Hoshi University Pharmaceutics, Associate Professor, 薬学部, 助教授 (00130758)
SUZUKI Tsutomu  Hoshi University Pharmacology, Associate Professor, 薬学部, 助教授 (90130757)
Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 1997: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1996: ¥3,900,000 (Direct Cost: ¥3,900,000)
KeywordsAbsorption promoter / Menthol / Thiomenthol / Ketoprofen / Rat / Skin irritation / log P value / Chemical shift / log P値 / O-エチルメントール
Research Abstract

Thiomenthol derivatives were synthesized and their promoting activity on the percutaneous absorption of ketoprofen from hydrogels was evaluated in rats. The apparent penetration rate (R_p) of ketoprofen absorbed from the hydrogel was estimated by the pharmacokinetic model derived under the assumption of a constant penetration rate through the skin after a lag time. As an index of promoting activity of thiomenthol derivatives, an enhancement factor (E_f) was defined as the ratio of the R_p value with enhancer to the value obtained with the control not containing enhancer. Skin irritancy evoked by these derivatives was investigated microscopically by using a cross section of the excised skin on to which ketoprofen hydrogel was applied. Total irritation score (TIS) was estimated by summation of each irritation score in several parts of the skin. The physicochemical parameters of thiomenthol derivatives such as a partition coefficient (log P) and a steric energy were calculated and the quantitative relationships between these parameters and the E_f values or TIS values were investigated on the basis of multiple regression analysis. As a result, a parabolic relationship between log P and E_f was noted. A similar relationship was also observed in the case of TIS.The structure parameters of thiomenthol derivatives such as chemical shifts were measured by NMR spectroscopy, and the quantitative relationships between these parameters and the Ef values or TIS values were investigated. It was concluded that the chemical shift at C-2 and C-6 positions of thiomenthol derivatives negatively affected the promoting activity of enhancers, but those of C-4 and H-1 positions positively affected it. A similar relationship was also observed in the case of TIS.These results is effective in order to design chemical structure of enhancers with strong promoting activity.

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Y.Takanashi: "Thiomenthol derivatives as novel percutaneous absroption enhancers" Drug Dev.Ind.Pharm.(in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] J.Takahara: "Multi-objective simultaneous optimization based on artificial neural network in a ketoprofen hydrogel formula containing-O-ethylmenthol as a percutaneous absorption enhancer" Int.J.Pharm.158. 203-210 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 大草 貴之: "オキシブチニンの皮膚透過におけるメントール誘導体の影響" Drug Delivery System. 12. 327-333 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] T.Suzuki: "Involvement of dopamine-dependent and -independent mechanisms in rewarding effects mediated by δ opoid receptor subtypes in mice" Brain Res.744. 327-334 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] T.Suzuki: "Involvement of δ1 and δ2 opioid receptor subtypes in the development of physical dependence on morphine in mice" Pharmacol.Biochem.Behav.57. 293-299 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] H.Poerwono: "Facile diastereoselective reaction of chiral 1,3-oxazolidines with Grignard reagents ; Asymmetric synthesis of 2-substituted and 2,6-disubstituted piperidines" Heterocycles. 46. 385-400 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Y.Takanashi, K.Higashiyama, H.Komiya, K.Takayama, T.Nagai: "Thiomenthol derivatives as novel percutaneous absorption enhancers" Drug Dev.Ind.Pharm.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] J.Takahara, K.Takayama, K.Isowa, T.Nagai: "Multi-objective simultaneous optimization based on artificial neural network in a ketoprofen hydrogel formula containing O-ethylmenthol as a percutaneous absorption enhancer" Int.J.Pharm.158. 203-210 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] T.Okusa, Y.Obata, K.Takayama, K.Higashiyama, T.Nagai: "Effect of menthol derivatives on skin permeation of oxybutynin" Drug Delivery System. 12. 327-333 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] T.Suzuki, M.Tsuji, T.Mori, H.Ikeda, M.Misawa, H.Nagase: "Involvement of dopamine-dependent and -independent mechanisms in the rewarding effects mediated by delta opioid receptor subtypes in mice" Brain Res.744. 327-334 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] T.Suzuki, M.Tsuji, T.Mori, M.Misawa, H.Nagase: "Involvement of delta1 and delta2 opioid receptor subtypes in the development of physical dependence on morphine in mice" Pharmacol.Biochem.Behav.57. 293-299 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] H.Poerwono, K.Higashiyama, T.Yamauchi, H.Takahashi: "Facile diastereoselective reaction of chiral 1,3-oxazolidines with Grignard reagents ; Asymmetric synthesis of 2-substituted and 2,6-disubstituted piperidines" Heterocycles. 46. 385-400 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Y.Takanashi: "Thiomenthol derivatives as novel percutaneous absroption enhancers" Drug Dev.Ind.Pharm.(印刷中).

    • Related Report
      1997 Annual Research Report
  • [Publications] J.Takahara: "Multi-objective simultaneous optimization based on artificial neural network in a ketoprofen hydrogel formula containing O-ethylmenthol as a percutaneous absorption enhancer" Int.J.Pharm.158. 203-210 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 大草貴之: "オキシプチニンの皮膚透過におけるメントール誘導体の影響" Drug Delivery System. 12. 327-333 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] T.Suzuki: "Involvement of dopamine-dependent and -independent mechanisms in rewarding effects mediated by δ opoid receptor subtypes in mice" Brain Res.744. 327-334 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] T.Suzuki: "Involvement of δ1 and δ2 opioid receptor subtypes in the development of physical dependence on morphine in mice" Pharmacol.Biochem.Behav.57. 293-299 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] H.Poerwono: "Facile diastereoselective reaction of chiral 1,3-oxazolidines with Grignard reagents;Asymmetric synthesis of 2-substituted and 2,6-disubstituted piperidines" Heterocycles. 46. 385-400 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Y.Nakamura: "Promoting effect of O-ethylmenthol on the percutaneous absorption of ketoprofen" Int.J.Pharm.,in press.

    • Related Report
      1996 Annual Research Report
  • [Publications] N.Ohara: "Combined effect of penetration enhancer and temperature on skin irritation in rats" S.T.P.Pharma Sci.6. 142-147 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] T.Suzuki: "Effects of the highly selective nonpeptide δ opioid receptor agonist TAN 67 on the morphine-induced place prefence in mice" J.Pharmacol.Exp.Ther.279. 177-185 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] T.Suzuki: "Formalin-and carrageenan-induced inflammation attenuates place preferences produced by morphine,methanphetamine and cocaine" Life Sci.59. 1667-1674 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] J.Akimoto: "Evaluation of skin irritation of percutaneous absorption promoters by means of fractal dimension of rat skin structure" Int.J.Pharm. 128. 251-260 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 大原長夫喜: "ケトプロフェンの経皮吸収における温熱と吸収促進剤の適用条件の最適化" 薬剤学. 56. 40-48 (1996)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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