JPH0477427A - Theradeutic agent for hepatic disease containing alisol a-relating compound as active component - Google Patents
Theradeutic agent for hepatic disease containing alisol a-relating compound as active componentInfo
- Publication number
- JPH0477427A JPH0477427A JP19042390A JP19042390A JPH0477427A JP H0477427 A JPH0477427 A JP H0477427A JP 19042390 A JP19042390 A JP 19042390A JP 19042390 A JP19042390 A JP 19042390A JP H0477427 A JPH0477427 A JP H0477427A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- active component
- agent
- compound
- chloroform
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000019423 liver disease Diseases 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 title abstract description 6
- 229930188824 alisol Natural products 0.000 title description 3
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- BLYMKZZHAHHGBK-UHFFFAOYSA-N 13,17-epoxyalisol A Natural products C1CC(=O)C(C)(C)C2CCC3(C)C4(C)CCC(C(CC(O)C(O)C(C)(C)O)C)(O5)C45CC(O)C3C21C BLYMKZZHAHHGBK-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000004480 active ingredient Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 241000422842 Chamaecyparis pisifera Species 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 6
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- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 2
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- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 2
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- 238000004949 mass spectrometry Methods 0.000 description 2
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- BUPJOLXWQXEJSQ-QLFBSQMISA-N (1r,3as,8as)-1-methyl-4-methylidene-7-propan-2-yl-2,3,3a,5,6,8a-hexahydroazulen-1-ol Chemical compound C=C1CCC(C(C)C)=C[C@@H]2[C@@](O)(C)CC[C@@H]21 BUPJOLXWQXEJSQ-QLFBSQMISA-N 0.000 description 1
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 description 1
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- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
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- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
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- 238000001816 cooling Methods 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
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- 239000007884 disintegrant Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
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- 239000002552 dosage form Substances 0.000 description 1
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- 239000000839 emulsion Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- DOVBXGDYENZJBJ-ONMPCKGSSA-N lactosamine Chemical compound O=C[C@H](N)[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O DOVBXGDYENZJBJ-ONMPCKGSSA-N 0.000 description 1
- 235000019860 lauric fat Nutrition 0.000 description 1
- 230000002475 laxative effect Effects 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 150000004667 medium chain fatty acids Chemical class 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
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- 229940126585 therapeutic drug Drugs 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
[産業上の利用分野1
本発明は、澤瀉から得られる16−ケトアリソールA又
は13.17−エポキシアリソールAを有効成分とする
肝臓疾患治療薬に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application 1] The present invention relates to a drug for treating liver diseases, which contains 16-ketoalisol A or 13.17-epoxyalisol A obtained from Sawabori as an active ingredient.
13.17−エポキシアリソールA
[従来の技術]
澤瀉はオモダカ科[Al i smataceae)に
属するサシオモダカ(AI+sma plantago
−aqatica Linne varOrlenta
le SamuelSSOn )の根茎から調製される
生薬で古来漢方の薬物療法において利尿、1喝なとの効
用が有るとされ、いくつかの処方に配合される重要生薬
である。澤瀉には澱粉、有機酸、カリウム塩、ビタミン
類、揮発油の他、プロトスタン型のトリテルペンである
アリソール関連化合物及びセスキテルペンのアリスモー
ルなどが含まれ、有効成分としてはコリン、アリソール
A、アリソールA24−アセテート、アリソール823
−アセテート、アリソールC23−アセテート(以上抗
脂肪肝作用)、アリソールB(利尿作用)、16−メド
キシアリソールB23−アセテート、16−ヒトロキシ
アリソール823−アセテート(以上冠動脈拡張作用)
、アリスモール(降圧作用)等がそれぞれ報告されてい
るか、いまだ肝臓疾患治療作用については知られていな
い。13.17-Epoxy Alisole A [Prior Art] Sawa-sara is a plantago that belongs to the family Al i smataceae.
-aquatica Linne varOrlenta
This herbal medicine is prepared from the rhizome of Le Samuel SS On) and is said to have diuretic and laxative effects in ancient Chinese medicine, and is an important herbal medicine that is included in some prescriptions. In addition to starch, organic acids, potassium salts, vitamins, and volatile oil, Sawasha contains alisol-related compounds, which are protostane-type triterpenes, and alismol, a sesquiterpene.The active ingredients include choline, alisol A, Alisol A24-acetate, Alisol 823
- Acetate, Alisol C23-acetate (anti-fatty liver effect), Alisol B (diuretic effect), 16-medoxyallysole B23-acetate, 16-hydroxyallysole 823-acetate (coronary artery dilator effect)
, Arithmol (hypertensive effect), etc. have been reported, but its therapeutic effect on liver diseases is still unknown.
[発明が解決しようとする課題]
本発明者らは、肝臓疾患治療薬探索を目的として生薬中
に含まれる有効成分に関して検討を行なってきたところ
、澤瀉の抽出物かラット初代培養肝細胞のD−ガラクト
サミン障害による団v+troの系及びD−力ラクトサ
ミン肝障害ラットを用いた10vivoの系それぞれに
おいて効果を示すことを発見し、その活性成分か16−
ケトアリソールA又は13.17−エポキシアリソール
Aであることを究明し、本発明に到達した。[Problems to be Solved by the Invention] The present inventors have been conducting studies on the active ingredients contained in crude drugs for the purpose of searching for therapeutic drugs for liver diseases, and found that extracts from Sawabori or primary cultured rat hepatocytes. It was discovered that the active ingredient 16-tro was effective in both the D-galactosamine-induced hepatotoxicity-induced group v+tro system and the 10-vivo system using D-galactosamine liver-impaired rats.
It was determined that it was ketoalisol A or 13.17-epoxyalisol A, and the present invention was achieved.
[課題を解決するための手段]
本発明によれば、16−ケトアリソールA又は1311
−エポキシアリソールAを有効成分とする肝臓疾患治療
剤が提供される。[Means for Solving the Problems] According to the present invention, 16-ketoalisole A or 1311
- A liver disease therapeutic agent containing epoxy alysole A as an active ingredient is provided.
本発明に使用する16−ケトアリソールA又は13.1
7−エポキシアリソールAは、澤瀉をクロロホルム又は
60%エタノールで抽出し、これらの抽出物を適当な混
合液を溶出液とする段階的溶出法【ごよるシリカゲルカ
ラムクロマトグラフィー、[)DSカラムクロマトグラ
フィー又は005分取高性能液体クロマトグラフィー(
以下HPLCという)等に付し、精製することにより製
造することかできる。16-Ketoalisol A or 13.1 used in the present invention
7-Epoxy alysole A can be obtained using a stepwise elution method (silica gel column chromatography, [) DS column] in which sawawa is extracted with chloroform or 60% ethanol, and an appropriate mixture of these extracts is used as the eluent. Chromatography or 005 preparative high performance liquid chromatography (
It can be produced by subjecting it to HPLC (hereinafter referred to as HPLC) and purifying it.
溶出液はヘキサン、ペンセン、クロロホルム若しくは酢
酸エチル等の疎水性有機溶媒、アセトン、D−ブタノー
ル、エタノール若しくはメタノール等の親水性有機溶媒
、又は水から選択し適当なハ]合で混合する。なお、本
発明において、その他の生薬から抽出され又は化学合成
される16−ケトアリソールA又は13.17−エポキ
シアリソール△も使用することができることは言うまで
もない。The eluate is selected from hydrophobic organic solvents such as hexane, pentene, chloroform or ethyl acetate, hydrophilic organic solvents such as acetone, D-butanol, ethanol or methanol, or water, and mixed in a suitable combination. It goes without saying that in the present invention, 16-ketoalisol A or 13.17-epoxyalisol Δ extracted from other crude drugs or chemically synthesized can also be used.
[作用及び発明の効果]
16−ケトアリソールA又は13.17−エポキシアリ
ソールAの肝臓疾患治療作用を以下に詳述する。[Actions and Effects of the Invention] The therapeutic action of 16-ketoalisol A or 13.17-epoxyalisol A on liver diseases will be described in detail below.
−1nVitrO−の系
ラット初代培養肝細胞のD−ガラクトサミン障害モデル
ラット肝細胞を分離し、D−ガラクトサミン1mM存在
下、被験化合物と共に002インキユヘーター中で31
℃、42時間培養した。培養終了後、培養液中に遊離し
てきたGOT活性をセントリフィケム660自動分析機
(ベーカー社製)で測定した。-1nVitrO- system D-galactosamine injury model of rat primary cultured hepatocytes Rat hepatocytes were isolated and incubated with the test compound in a 002 incubator in the presence of 1mM D-galactosamine.
The cells were cultured at ℃ for 42 hours. After the culture was completed, the GOT activity released in the culture solution was measured using a Centrificem 660 automatic analyzer (manufactured by Baker).
肝細胞障害抑制率を以下の式で求め、その結果を表1に
示した。The hepatocyte damage inhibition rate was determined using the following formula, and the results are shown in Table 1.
[+C0nt]GOT−[S]GOT
抑制率(%)・ X 100[+
contlGOT−[−contlGOT[+cont
lGO丁:O−ガラクトサミンlnM添加コントロール
系のGOT
[−contlGOT : D−ガラクトサミン1mM
無添加コントロール系のGOT
[5lGOT:D−ガラクトサミン1mM+試料添加系
のGOT
(以下余白)
−invivo−の系
D−ガラクトサミン肝障害ラット
24時間絶食させた1star系雄性ラツト(7適齢、
日本タレア社製)に生理食塩水に溶解させたD−ガラク
トサミン(pH7)を400#Irj/Ngの割合て腹
腔的投与した。引き続き24時間絶食させた後、エーテ
ル麻酔上心臓採血し、得られた血清(3000rpmで
20分間遠心分離)について、GOT及びGPT活性を
セントリフイケム600自動分析装置(ベーカー社製)
で測定した。なお、被験化合物は、0−力ラクトサミン
投与2時間前に301rlfl/Klの割合で腹腔的投
与した。結果を表2に示す。[+C0nt]GOT-[S]GOT Suppression rate (%)・X 100[+
contlGOT-[-contlGOT[+cont
lGOT: GOT with O-galactosamine lnM addition control system [-contlGOT: D-galactosamine 1mM
Additive-free control system GOT [5lGOT: D-galactosamine 1mM + sample addition system GOT (blank below) -in vivo system D-galactosamine liver-damaged rats 1 star male rats fasted for 24 hours (7 years old,
D-galactosamine (pH 7) dissolved in physiological saline (manufactured by Nippon Talea Co., Ltd.) was intraperitoneally administered at a ratio of 400 #Irj/Ng. After a subsequent 24-hour fast, cardiac blood was collected under ether anesthesia, and the GOT and GPT activities of the obtained serum (centrifuged at 3000 rpm for 20 minutes) were measured using a Centrifuichem 600 automatic analyzer (manufactured by Baker).
It was measured with The test compound was intraperitoneally administered at a rate of 301 rlfl/Kl 2 hours before the administration of 0-force lactosamine. The results are shown in Table 2.
表2
急性毒性試験
動物はICR雌性マウス(5〜6週齢、日本チャールス
・リバー社製)を使用し、16−ケトアリソールA 2
00.300.400.4BOmy/ Kg、13.1
7−エポキシアリソールA 300.450I11g/
Klを、それぞれ腹腔的投与した。被験試料は1%丁
ween80/ 0.5%CHC混和液に投与液量が2
Ornll/に9となるように調製した。投与後、3日
間にわたって一般症状の観察及び体重変化の測定を行っ
た。Table 2 Acute toxicity test animals used were ICR female mice (5-6 weeks old, manufactured by Charles River Japan), and 16-ketoalisole A 2
00.300.400.4BOmy/Kg, 13.1
7-Epoxy Alisole A 300.450I11g/
Kl was administered intraperitoneally, respectively. The test sample was a 1% Vienna 80/0.5% CHC mixture with a dose of 2.
Ornll/ was adjusted to 9. After administration, general symptoms were observed and body weight changes were measured for 3 days.
最小致死量(HL[))値は、16−ケトアリソールA
400#l!iF/N#以上、13.17−エポキシア
リソールA4501rl’J/に’j以上で’il)ツ
た。The lowest lethal dose (HL[)) value is 16-ketoalisole A.
400#l! iF/N# or above, 13.17-Epoxy Alisole A4501rl'J/'j or above'il).
上述の各試験結果を考慮すれば、16−ケトアリソール
A又は13.17−エポキシアリソールAを有効成分と
する薬剤は優れた肝臓疾患治療剤でおるということかで
きる。患者への用量は、年齢、症状等により異なるか、
一般に成人に対し、1日あたり経口で1〜1000mg
、好ましくは、10〜600■、これを1〜6回、好ま
しくは、1〜3回に分けて用いるのが望ましい。Considering the above test results, it can be said that drugs containing 16-ketoalisol A or 13.17-epoxyalisol A as an active ingredient are excellent therapeutic agents for liver diseases. Dosage for patients varies depending on age, symptoms, etc.
Generally for adults, 1 to 1000 mg orally per day
, preferably from 10 to 600 cm, and is preferably divided into 1 to 6 times, preferably 1 to 3 times.
本発明においては、16−ケトアリソールA又は131
7−エポキシアリソールAに通常の製剤担体を配合する
ことにより、錠剤、ハート若しくはソフトカプセル剤、
顆粒剤、散剤、細粒剤若しくは末剤等の固形製剤又は注
射剤、シロップ剤、水剤、懸濁剤若しくは乳剤等の液剤
に調製することができる。固形製剤にあっては、腸溶性
製剤又は徐放性製剤等に調製してもよい。配合する製剤
担体としては、所望の剤型に応じ例えば、賦形剤、結合
剤、崩壊剤、滑沢剤、被覆剤、溶解補助剤、乳化剤、懸
濁剤、界面活性剤、吸収助剤、安定化剤又は溶剤等を適
宜選択して使用すればよい。具体的な製剤担体としては
、澱粉類、デキストリン類、α、β若しくはγ−シクロ
デキストリン、ブドウ糖、乳糖、ショ糖、マンニット、
ソルビトール、部分α化澱粉、メチルセルロース、エチ
ルセルロース、ヒドロキシエチルセルロース、カルホキ
ジメチルセルロース、カルホキジメチルセルロースカル
シウム
トリウム、結晶セルロース、低置換度ヒドロキシプロピ
ルセルロース、ステアリン酸カルシウム、ステアリン酸
マグネシウム、アルギン酸ナトリウム、ケイ酸マグネシ
ウム、リン酸水素カルシウム、炭酸カルシウム、炭酸マ
グネシウム、メタケイ酸アルミン酸マグネシウム、ウイ
テプゾールW35、ウイテプゾールE85、ウイテプゾ
ールH15、ポリビニルアルコール、無水ケイ酸、合成
ケイ酸アルミニウム、酸化チタン、タルク、ワックス類
、ヒドロキシプロピルセルロース、ヒドロキシプロピル
メチルセルロース、ヒドロキシエチルメチルセルロース
、カルホキジメチルエチルセルロース、セルロースアセ
テートフタレート、セルロースアセテートマレエート、
ヒドロキシプロピルメチルセルロースフタレート、ヒド
ロキシプロピルメチルセルロースアセテートサクシネー
ト、ポリビニルアルコールフタレート、スチレン無水マ
レイン酸共重合体、ポリビニルアセタルジエチルアミン
アセテート、メタアクリル酸・メタアクリル酸メチルコ
ポリマー、メタアクリル酸・アクIノル酸エチルコポリ
マー、メタアクリル酸メタアクリル酸ブチル及びメタア
クリル酸ジメチルアミンエチルコポリマー、アクリル酸
エチル・メタアクリル酸メチル及びメタアクリル酸塩化
トリメチルアンモニウムエチルコポリマー、ゼラチン、
グリセリン、プロピレングリコール、ラウリルFjM酸
ナトリウム、中鎖脂肪酸トリグリセライド、レシチン、
ソルビタンモノオレエート、ソルビタンセスキオレエー
ト、ポリオキシエチレンソルビタンモノオレエート、グ
リセリルモノステアレート、グリセリルモノオレエート
、ポリオキシエチレンセチルエーテル、ポリオキシエチ
レン硬化ヒマシ油、ショ糖脂肪酸エステル、ポリグリセ
リン脂肪酸エステル、ポリオキシエチレン・ポリオキシ
プロピレンブロック重合体、ポリエチレングリコール、
ポリご二ルピロリドン、架橋ポリビニルピロリドン又は
カカオ脂、ラウリン脂、グリセロゼラチン等の油脂類等
が挙げられる。In the present invention, 16-ketoalisole A or 131
By blending 7-epoxy alysole A with a usual pharmaceutical carrier, tablets, hearts or soft capsules,
It can be prepared into solid preparations such as granules, powders, fine granules, powders, etc., or liquid preparations such as injections, syrups, solutions, suspensions, and emulsions. In the case of solid preparations, enteric-coated preparations or sustained-release preparations may be prepared. Depending on the desired dosage form, carriers for the formulation include, for example, excipients, binders, disintegrants, lubricants, coating agents, solubilizing agents, emulsifiers, suspending agents, surfactants, absorption aids, What is necessary is just to select and use a stabilizer, a solvent, etc. suitably. Specific pharmaceutical carriers include starches, dextrins, α, β or γ-cyclodextrin, glucose, lactose, sucrose, mannitol,
Sorbitol, partially pregelatinized starch, methylcellulose, ethylcellulose, hydroxyethylcellulose, carboxydimethylcellulose, carboxydimethylcellulose calcium thorium, crystalline cellulose, low-substituted hydroxypropylcellulose, calcium stearate, magnesium stearate, sodium alginate, magnesium silicate, Calcium hydrogen phosphate, calcium carbonate, magnesium carbonate, magnesium aluminate metasilicate, Witepsol W35, Witepsol E85, Witepsol H15, polyvinyl alcohol, silicic anhydride, synthetic aluminum silicate, titanium oxide, talc, waxes, hydroxypropyl cellulose, Hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxydimethylethylcellulose, cellulose acetate phthalate, cellulose acetate maleate,
Hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl alcohol phthalate, styrene maleic anhydride copolymer, polyvinyl acetal diethylamine acetate, methacrylic acid/methyl methacrylate copolymer, methacrylic acid/ac I ethyl norate copolymer , butyl methacrylate and dimethylamine ethyl methacrylate copolymer, ethyl acrylate/methyl methacrylate and trimethylammonium ethyl methacrylate copolymer, gelatin,
Glycerin, propylene glycol, sodium lauryl FjM acid, medium chain fatty acid triglyceride, lecithin,
Sorbitan monooleate, sorbitan sesquioleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, polyoxyethylene cetyl ether, polyoxyethylene hydrogenated castor oil, sucrose fatty acid ester, polyglycerin fatty acid ester , polyoxyethylene/polyoxypropylene block polymer, polyethylene glycol,
Examples include polygonylpyrrolidone, crosslinked polyvinylpyrrolidone, and fats and oils such as cacao butter, lauric fat, and glycerogelatin.
16−ケトアリソールA及び13.17−エポキシアリ
ソールAの製造例及び具体的製剤例をもって本発明を更
に説明する。The present invention will be further explained using production examples and specific formulation examples of 16-ketoalisol A and 13.17-epoxyalisol A.
[製造例]
注湯(紀伊国屋漢薬局 Lot IH940905Y及
びIH282826Y > 1.5Hgを1回につき
7Jlのクロロホルムで60℃で60分間、計2回抽出
し、クロロホルム抽出液を調製した。その後濃縮乾固し
、クロロホルム抽出画分54!iFを得た。これを更に
一次シリカゲルカラムクロマトグラフィーに付し、ベン
セン(2〕)及びベンゼン7/アセトン(容量比10.
1〜5.1)の混合液から順次溶出し、粗物質7.9g
を得た。これを二次シリカゲルカラムクロマトグラフィ
ーに付し、酢酸エチルへ酢酸エチル/エタノール(容量
比3:2)混合液から順次溶出し、酢酸エチルで溶出さ
れた粗物質2.79を得た。これをODSカラムクロマ
トグラフィーに付し、60〜100%メタノールで順次
溶出じ、16〜ケトア1ノソールAを含有する画分68
0Irtg及び13.17−■ポキシアリソールAを含
有する画分440ηを得た。これらをそれぞれODS分
取HPLCに付しく展開溝!11 ; 70% メタ/
−ル) 、16−ケトアリソールA 340m5及び1
3.17−エポキシアリソールA230!qを得た。[Production example] Pouring water (Kinokuniya Chinese Pharmacy Lot IH940905Y and IH282826Y > 1.5 Hg was extracted twice with 7 Jl of chloroform each time at 60°C for 60 minutes to prepare a chloroform extract. Then, concentrated to dryness. A chloroform extracted fraction of 54!iF was obtained. This was further subjected to primary silica gel column chromatography, and benzene (2) and benzene 7/acetone (volume ratio 10.
Sequentially eluted from the mixture of 1 to 5.1), 7.9 g of crude material
I got it. This was subjected to secondary silica gel column chromatography and sequentially eluted from a mixture of ethyl acetate and ethanol (volume ratio 3:2) to ethyl acetate to obtain 2.79 of a crude substance eluted with ethyl acetate. This was subjected to ODS column chromatography and sequentially eluted with 60 to 100% methanol to obtain a fraction 68 containing 16 to 1-ketoalinosole A.
A fraction 440η containing 0Irtg and 13.17-■ poxyalisol A was obtained. Add these to ODS preparative HPLC and develop them! 11; 70% Meta/
), 16-ketoalisole A 340m5 and 1
3.17-Epoxy Alisole A230! I got q.
16−ケトアリソールAの物性
性状:無色微細立方体結晶
融点: 101.3〜102.9℃
旋光度[(X ] ’t0: +72.5° (c:0
.51%、 in MeOH)。Physical properties of 16-ketoalisol A: Colorless fine cubic crystals Melting point: 101.3-102.9°C Optical rotation [(X]'t0: +72.5° (c: 0
.. 51% in MeOH).
質量分析スペクトル(m/z):
504(M” )、486(1)、468(5L450
(45)、409(36)396(4B)、367(6
2)。Mass spectrometry spectrum (m/z): 504 (M"), 486 (1), 468 (5L450
(45), 409 (36) 396 (4B), 367 (6
2).
赤外線吸収スペクトル(KBr、C771) :343
62961.292216901642,1463,1
380゜1169、1045.1008.679゜1H
−核磁気共鳴スペクトル(CDCl3. ppm) :
0.90(3H,S) 、 1.08〜1.34(3
Hx 7)。Infrared absorption spectrum (KBr, C771): 343
62961.292216901642,1463,1
380°1169, 1045.1008.679°1H
-Nuclear magnetic resonance spectrum (CDCl3.ppm):
0.90(3H,S), 1.08~1.34(3
Hx7).
2.72(IH,d、J=9.281−12)、 2
.88(IH,brs) 。2.72 (IH, d, J=9.281-12), 2
.. 88 (IH, brs).
3.02(d、J=8.3Hz)、 3.21(1N
、q、J=14.16゜5.86H2)、 3.52
(IH,d、J=2.93H2)、 3.62(1N
。3.02 (d, J=8.3Hz), 3.21 (1N
, q, J=14.16°5.86H2), 3.52
(IH, d, J=2.93H2), 3.62 (1N
.
q、J=10.25,2.93Hz)、 4.06(
IH,m)。q, J=10.25, 2.93Hz), 4.06(
IH, m).
13C−核磁気共鳴スペクトル(CDCl3.pl)m
:19.34 q 、 19.88 t)、 1
9.98 q)、 23.09(Q 。13C-Nuclear Magnetic Resonance Spectrum (CDCl3.pl)m
:19.34 q, 19.88 t), 1
9.98 q), 23.09 (Q.
23.41 a 、 25.30 q)、 25.83
d)、 26.22(q 。23.41 a, 25.30 q), 25.83
d), 26.22 (q.
26.97 Q 、 29.47 q)、 30.7
5 t)、 33.53ft 。26.97 Q, 29.47 q), 30.7
5t), 33.53ft.
34.86 t 、 35.97 t)、 36.86
5)、 39.56(t 。34.86 t, 35.97 t), 36.86
5), 39.56 (t.
39.90 s 、 45.31 t)、 46.91
s)、 48.18(d 。39.90 s, 45.31 t), 46.91
s), 48.18 (d.
4B、38 d 、 49.97 S)、 69.25
6)、 69.43(d 。4B, 38 d, 49.97 S), 69.25
6), 69.43 (d.
73.92(S)、77.23(d)、 139.
95(S)。73.92(S), 77.23(d), 139.
95(S).
177.86(s)、 209.45(s)、 2
20.06(s)。177.86 (s), 209.45 (s), 2
20.06(s).
13.17−エポキシアリソールAの物性性状:無色微
細結晶
融点=111〜112.5℃
旋光度[a ] io: +100.4°(C;0.4
4. in CDCl3 )。13. Physical properties of 17-Epoxy Alisole A: Colorless fine crystals Melting point = 111-112.5°C Optical rotation [a] io: +100.4° (C; 0.4
4. in CDCl3).
質量分析スペクトル(n+/z):
506(M )、488(1)、47([1)、45
2(3)、450(6)。Mass spectrometry spectrum (n+/z): 506 (M), 488 (1), 47 ([1), 45
2(3), 450(6).
434(10)、380(23)、338(19)。434(10), 380(23), 338(19).
赤外線吸収スペクトル(KBr、(,7) :3450
298017001460.13751240.116
0゜1100、1000,950.910.800゜1
H−核磁気共鳴スペクトル(CDCl3. ppm)
:1.05〜1.12(3Hx 6)、 1.26(3
H,s)。Infrared absorption spectrum (KBr, (,7): 3450
298017001460.13751240.116
0°1100, 1000,950.910.800°1
H-nuclear magnetic resonance spectrum (CDCl3.ppm)
:1.05~1.12(3Hx6), 1.26(3
H,s).
1.30(3H,s)、 2.70(IH,m)、
3.09(2H,brs)3.50(IH,brs)
、 3.65(1H,brs)4.04(IH,br
Q)、 4.16(IN、brd)13C−核磁気共
鳴スペクトル(CDCl3. Dpm) :17.48
q 、 19.25 G 、 19.93 a
、 20.06 t)。1.30 (3H, s), 2.70 (IH, m),
3.09 (2H, brs) 3.50 (IH, brs)
, 3.65 (1H, brs) 4.04 (IH, br
Q), 4.16 (IN,brd)13C-nuclear magnetic resonance spectrum (CDCl3.Dpm): 17.48
q, 19.25 G, 19.93 a
, 20.06 t).
24.62 Q 、 25.67 Q 、 26.4
6 t 、 26.59 Q 。24.62 Q, 25.67 Q, 26.4
6 t, 26.59 Q.
26.72 Q 、 29.57 Q 、 30.5
7ft 、 30.78 d 。26.72 Q, 29.57 Q, 30.5
7ft, 30.78d.
30.85 t 、 33.53 t 、 34.
73 t 、 35.53 t 。30.85 t, 33.53 t, 34.
73 t, 35.53 t.
36.89 s 、 3B、69 t 、 40
.34 S 、 46.89 S 。36.89 s, 3B, 69 t, 40
.. 34 S, 46.89 S.
4B、71 d 、 48.88 d 、 50.
02 s 、 6B、39 d 。4B, 71 d, 48.88 d, 50.
02s, 6B, 39d.
68.53 d)、 73.31 S)、 73.
54[S 、 77.00 d 。68.53 d), 73.31 S), 73.
54 [S, 77.00 d.
78.455)、 220.09(S)。78.455), 220.09 (S).
[製剤例1] (錠剤)
重量(%)
(1) 16−ケトアリソールA 40.0
(2)乳糖 25.0(3)ト
ウモロコシ澱粉 15.0(4)結晶セル
ロース 15.0(5)ヒドロキシプロ
ピルセルロース 3.0(6)ステアリン酸マグネシウ
ム 1.0(7)ポリオキシエチレン(40)モノ
ステアレート1.0
ioo、。[Formulation Example 1] (Tablet) Weight (%) (1) 16-ketoalisole A 40.0
(2) Lactose 25.0 (3) Corn starch 15.0 (4) Crystalline cellulose 15.0 (5) Hydroxypropyl cellulose 3.0 (6) Magnesium stearate 1.0 (7) Polyoxyethylene (40) Monostearate 1.0 ioo.
上述の(1)〜(5)を混合し、(7)を溶解した水を
添加して造粒し、ついで乾燥した。得られた顆粒を整粒
したのち、(6)を加えて混合し、これらを圧縮成形し
て1錠250IIPJの錠剤を調製した。The above (1) to (5) were mixed, water in which (7) was dissolved was added to form granules, and then dried. After sizing the obtained granules, (6) was added and mixed, and these were compression molded to prepare tablets each weighing 250 IIPJ.
[製剤例2コ (ハードカプセル剤)
16−ケトアリソールA
乳糖
トウモロコシ澱粉!粉
ヒドロキシプロピルセルロース
重量(%)
33.0
41.5
20、0
3.0
(5)合成ケイ酸アルミニウム 1.0(6)ス
テアリン酸マグネシウム 1.0(7)ポリオキシ
エチレン(20)ソルビタンモノオレエート
0.5100.0
常法に従って、上述の(1)〜(4)を混合し、これに
(7)を溶解したエタノールを加えて混和したのち乾燥
し顆粒とした。この顆粒に(5)及び(6)を添加混合
し、ついでハードカプセルに充填し、’1(11300
■のハードカプセル剤を調製した。[Formulation Example 2 (Hard Capsule) 16-Ketoalisole A Lactose Corn Starch! Powdered hydroxypropyl cellulose weight (%) 33.0 41.5 20,0 3.0 (5) Synthetic aluminum silicate 1.0 (6) Magnesium stearate 1.0 (7) Polyoxyethylene (20) Sorbitan mono Oleate
0.5100.0 According to a conventional method, the above (1) to (4) were mixed, ethanol in which (7) was dissolved was added and mixed, and then dried to form granules. (5) and (6) were added to and mixed with the granules, and then filled into hard capsules.
Hard capsules of (2) were prepared.
[製剤例3] (顆粒剤)
重量(%)
(1) 13.17−ニポキシアリソールA 10
.0(2)乳糖 73.0(
3)低置換ヒドロキシプロピルセルロースio、 。[Formulation Example 3] (Granule) Weight (%) (1) 13.17-Nipoxyalisol A 10
.. 0(2) Lactose 73.0(
3) Low substituted hydroxypropyl cellulose io,.
(4)ポリビニルピロリドン 5.0(5)
ラウリルt1酸ナトリウム 2.0100、0
上述の(1)〜(5)を混合し、水を加えて練合したの
ら押出造粒機を用いて円柱顆粒を調製した。(4) Polyvinylpyrrolidone 5.0 (5)
Sodium lauryl t1 acid 2.0100,0 The above (1) to (5) were mixed, water was added and kneaded, and then cylindrical granules were prepared using an extrusion granulator.
「製剤例4] (ソフトカプセル剤)
重M(%)
(1) 13.17−ニポキシアリソールA 25
.0(2)ポリエチレングリコール400 67.0
(3)ポリオキシエチレン(20)ソルビタンモノオレ
エート 5.0(4)精製水
3.0100.0
上述の(1)〜(4)を加熱下に良く混合し、得られた
分散液を常法によりソフトカプセルに充填し、1個40
0■のソフトカプセル剤を調製した。“Formulation Example 4” (Soft capsule) Heavy M (%) (1) 13.17-Nipoxyalisol A 25
.. 0(2) Polyethylene glycol 400 67.0
(3) Polyoxyethylene (20) Sorbitan monooleate 5.0 (4) Purified water
3.0100.0 The above-mentioned (1) to (4) are thoroughly mixed under heating, and the resulting dispersion is filled into soft capsules using a conventional method.
Soft capsules of 0.0 mm were prepared.
(4)レシチン 10100.
0
上述の(1)〜(4)を加熱下に良く混合し、ついて冷
却、固化した。これを50〜60’Cて熔融し、32〜
35℃にまで冷却したのち末剤型に注入し、放冷、固化
し、1個2gの末剤を調製した。(4) Lecithin 10100.
0 The above (1) to (4) were thoroughly mixed under heating, and then cooled and solidified. Melt this at 50-60'C, and
After cooling to 35° C., the mixture was poured into a powder mold, left to cool, and solidified to prepare a powder weighing 2 g each.
特許出願人 東京田辺製蕎株式会社Patent applicant: Tokyo Tanabe Seiso Co., Ltd.
Claims (2)
徴とする16−ケトアリソールAの製造方法(3)16
−ケトアリソールA又は13,17−エポキシアリソー
ルAを有効成分とする肝臓疾患治療薬(2) A method for producing 16-ketoalisol A, characterized by obtaining 16-ketoalisol A from sawara (3) 16
- Liver disease treatment containing ketoalisol A or 13,17-epoxyalisol A as an active ingredient
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP19042390A JPH0477427A (en) | 1990-07-20 | 1990-07-20 | Theradeutic agent for hepatic disease containing alisol a-relating compound as active component |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP19042390A JPH0477427A (en) | 1990-07-20 | 1990-07-20 | Theradeutic agent for hepatic disease containing alisol a-relating compound as active component |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH0477427A true JPH0477427A (en) | 1992-03-11 |
Family
ID=16257891
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP19042390A Pending JPH0477427A (en) | 1990-07-20 | 1990-07-20 | Theradeutic agent for hepatic disease containing alisol a-relating compound as active component |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0477427A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111624267A (en) * | 2020-04-30 | 2020-09-04 | 广东经典名方科技有限公司 | High performance liquid detection method for 16-oxo-alisol A in alisma orientale |
CN113960213A (en) * | 2021-11-09 | 2022-01-21 | 上海海虹实业(集团)巢湖今辰药业有限公司 | Alisma orientale component selection method based on alisma orientale decoction |
-
1990
- 1990-07-20 JP JP19042390A patent/JPH0477427A/en active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111624267A (en) * | 2020-04-30 | 2020-09-04 | 广东经典名方科技有限公司 | High performance liquid detection method for 16-oxo-alisol A in alisma orientale |
CN113960213A (en) * | 2021-11-09 | 2022-01-21 | 上海海虹实业(集团)巢湖今辰药业有限公司 | Alisma orientale component selection method based on alisma orientale decoction |
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