JP5806324B2 - スチラキスリグノリドaまたはそのアグリコンを有効成分として含む喘息の予防または治療用組成物 - Google Patents
スチラキスリグノリドaまたはそのアグリコンを有効成分として含む喘息の予防または治療用組成物 Download PDFInfo
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- JP5806324B2 JP5806324B2 JP2013539765A JP2013539765A JP5806324B2 JP 5806324 B2 JP5806324 B2 JP 5806324B2 JP 2013539765 A JP2013539765 A JP 2013539765A JP 2013539765 A JP2013539765 A JP 2013539765A JP 5806324 B2 JP5806324 B2 JP 5806324B2
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- homoegonol
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- stylakislignolide
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate 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
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- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
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- 230000000069 prophylactic effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
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- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 235000013580 sausages Nutrition 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
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- 229960002920 sorbitol Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
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- 239000008107 starch Substances 0.000 description 1
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- 150000003431 steroids Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 238000000194 supercritical-fluid extraction Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 235000015193 tomato juice Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
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- 238000003809 water extraction Methods 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
Images
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7016—Disaccharides, e.g. lactose, lactulose
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- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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Description
と呼ばれ薬用に用い、漢方では駆虫、殺虫、興奮性除痰、喉頭炎、防腐剤などに用いて、清化、風通し、除湿の効能があって喉痛、牙痛、歯痛、風湿関節炎、四肢痛などを治療すると知られている。
[本発明1001]
スチラキスリグノリド(Styraxlignolide)A化合物、そのアグリコン(aglycone)、またはその薬学的に許容可能な塩を有効成分として含む、喘息予防及び治療用薬学的組成物。
[本発明1002]
前記スチラキスリグノリドA化合物が、下記の化学式1で表されることを特徴とする、本発明1001の喘息予防及び治療用薬学的組成物
[化1]
。
[本発明1003]
前記アグリコンが、下記の化学式2で表されるホモエゴノール(homoegonol)であることを特徴とする、本発明1001の喘息予防及び治療用薬学的組成物
[化2]
。
[本発明1004]
前記スチラキスリグノリドA化合物が、エゴノキ(Styrax japonica)から分離されることを特徴とする、本発明1001の喘息予防及び治療用薬学的組成物。
[本発明1005]
前記喘息が、気道リモデリングが進行した喘息であることを特徴とする、本発明1001の喘息予防及び治療用薬学的組成物。
[本発明1006]
スチラキスリグノリドA化合物、そのアグリコン、またはその薬学的に許容可能な塩を有効成分として含む、喘息予防及び改善用健康食品用組成物。
[本発明1007]
前記スチラキスリグノリドA化合物が、下記の化学式1で表されることを特徴とする、本発明1006の喘息予防及び改善用健康食品用組成物
[化1]
。
[本発明1008]
前記アグリコンが、下記の化学式2で表されるホモエゴノールであることを特徴とする、本発明1006の喘息予防及び改善用健康食品用組成物
[化2]
。
[本発明1009]
前記スチラキスリグノリドA化合物が、エゴノキから分離されることを特徴とする、本発明1006の喘息予防及び改善用健康食品用組成物。
[本発明1010]
前記喘息が、気道リモデリングが進行した喘息であることを特徴とする、本発明1006の喘息予防及び改善用健康食品用組成物。
[本発明1011]
薬学的に有効な量のスチラキスリグノリドA化合物、そのアグリコン、またはその薬学的に許容可能な塩を有効成分として含む薬学的組成物を個体に投与する工程を含む、喘息の予防方法。
[本発明1012]
薬学的に有効な量のスチラキスリグノリドA化合物、そのアグリコン、またはその薬学的に許容可能な塩を有効成分として含む薬学的組成物を個体に投与する工程を含む、喘息の治療方法。
[本発明1013]
喘息予防及び治療用薬学的組成物に用いるためのスチラキスリグノリドA化合物、そのアグリコン、またはその薬学的に許容可能な塩。
[本発明1014]
喘息予防及び改善用健康食品用組成物に用いるためのスチラキスリグノリドA化合物、そのアグリコン、またはその薬学的に許容可能な塩。
1)エゴノキを水、C1〜C2の低級アルコールまたはそれらの混合溶媒で抽出する工程、
2)前記工程1)の抽出物を、追加でヘキサン及びエチルアセテートを順に加えて系統分画する工程、及び
3)前記工程2)でエチルアセテート層を分離して残りの水溶液層にカラムクロマトグラフィーを遂行して前記化学式1で表される化合物を得る工程
を含む方法で製造することができるが、それに限定されない。
エゴノキ(S.japonica Sieb. Et Zucc.,Styracaceae)の幹及び樹皮120kgを採取して(済州、韓国)、5Lのメタノール(MeOH)で4回抽出した。抽出液を得て蒸留水に懸濁した後、再びヘキサンを加えてヘキサン層を分離し、残った水層に再びエチルアセテートを加えてエチルアセテート層を分離し、残った水層をDiaion HP−20カラムに通過させて蒸留水8L、50%MeOH及び100%MeOHに溶解して分離した。得られたメタノール溶解性画分(MeOH-soluble fraction)は、RP C−18カラムクロマトグラフィーを経て50%MeOH、25%MeOH、100%MeOHで溶解してスチラキスリグノリドAを分離した。
ホモエゴノールの合成は、既存の報告された方法(Xue Fei Yang and Ling Yi Kong,Chinese Chemical Letters,2007年,第18巻,p.380-382参照)を活用するが、新規な工程(工程3)を追加する合成経路を通じて製造した。まず、工程1で中間体4を合成し、工程2で中間体4と8を縮合した後、トリメトキシエゴノール前駆体である化合物10を製造した。最後に、工程3で中間体10のカルボン酸エステルをアルコールで還元して所望する最終化合物11(ホモエゴノール)を得た(図20)。
気管支喘息誘導実験動物を製作するために、平均体重20g内外の6週齢Balb/cメスのマウスを用いた。1週間の適応期間を有した後、基本的な身体検査上で異常が観察されない個体を対象にした。2週間間隔で水酸化アルミニウム(A8222,Sigma,St. Louis,MO)2mg及び卵白アルブミン20μg(A5503,Sigma,St. Louis,MO)を懸濁したリン酸緩衝食塩水(PBS)(pH7.4)200μlを腹腔に注入して感作させた。最初の卵白アルブミン腹腔投与後28日目から30日目まで、1%卵白アルブミンを超音波噴霧器を用いて30分間吸入させた。最後の抗原投与24時間後に、気道過敏性を測定し、48時間後に致死量のペントバルビタール(エントバル(登録商標)、翰林製薬株式会社)を投与した後、体重を測定して気管支切開を実施して総1.2mlの生理食塩水で気管支肺胞洗浄を実施した後、検体を回収した。正常対照群(NC)では、卵白アルブミンを投与及び吸入しない群、喘息誘導群(OVA)では卵白アルブミンを投与及び吸入して気管支喘息を誘導した群、比較群1(DEXA)では卵白アルブミン吸入1時間前にデキサメタゾン(3mg/kg,PO:D4902,Sigma,St. Louis,MO)を経口投与した群、比較群2(Monte)では卵白アルブミン吸入1時間前にモンテルカスト(montelukast)(30mg/kg,PO)を経口投与した群、スチラキスリグノリドAに対する実験群では卵白アルブミン吸入1時間前にスチラキスリグノイドA(30mg/ml,PO)を経口投与した群で実験を進行し、各群当たり8匹のマウスを用い、ホモエゴノールに対する実験群では卵白アルブミン吸入1時間前にホモエゴノールを7.5mg/kgを経口投与した群(hE7.5)、15mg/kgを経口投与した群(hE15)、30mg/kgを経口投与した群(hE30)で実験を進行し、各群当たり5匹のマウスを用いた。
スチラキスリグノリドAの、喘息誘導マウス体重減少に及ぼす効果を確認するために、前記<実施例2>で製作したそれぞれのマウスに対する体重を測定した。以下、すべての測定値の統計分析については、いくつかの変数による平均値と標準誤差(mean±S.E.)を計算し、各集団間の比較は、SPSS10.0を用いてマン・ホイットニーのU検定を行なって分析した。統計的にp値が0.05未満の場合に有意な差があると判定した。
スチラキスリグノリドAの、喘息発生による気道過敏性に対する効果の有無は、単一チャンバー体積変動測定機(one chamber plethysmography,All Medicus,ソウル)を用いた気道抵抗測定で確認し、気道抵抗の程度はPenh数値を測定して評価した。Penh数値の測定は、正常呼吸状態で基底値を測定した後、PBSを超音波噴霧器を用いて3分間吸入させた後に3分間測定した。以後、気管支喘息を診断する一般的な方法として使用されるヒスタミン剤メタコリン(A2251,Sigma,St,Louis,MO)を12、25、50mg/mlの濃度で徐々に増加させながら吸入させた後、Penh数値を測定し、結果として得られるPenh数値は下記の数式1で示し、結果として得られる数値は各濃度のメタコリン吸入後のPenhの増加百分率で表現し、基底Penh(生理食塩水投与)は100%で表示した。
前記<実施例2>の各実験群の個体から気管支肺胞洗浄液を回収して、回収後直ちにトリパンブルーで染色して死滅細胞を除いた総細胞数を血球計数器を用いて計算した後、サイトスピン(Cytospin)IIで標本塗抹後ディフ・クイック染色(Sysmex、Switzerland)を実施して好酸球とそれ以外の炎症細胞を鑑別計算した。
スチラキスリグノリドA投与による血清及び気管支肺胞洗浄液の卵白アルブミン特異的IgEの濃度を測定するために、免疫酵素法を用いた。卵白アルブミンを20μg/ml/の濃度でpH8.3の0.1M NAHCO3緩衝液に溶解してこれを96ウェルフラットボトムELISAプレートに入れて4℃で一晩中コーティングさせた後、1%ウシ血清アルブミンを含有したPBSで非特異的反応を抑制させて、血清検体を1:400に希釈して室温で2時間反応させた。その後、それをよく洗浄した後、抗マウスIgE単一クローン抗体を300倍に希釈して2時間反応させた。そうして、ペルオキシダーゼが結合されたHRP結合されたヤギ抗ラットIgGポリクローナル抗体を4000倍に希釈して室温で1時間反応させた後に洗浄した。発色は、3,3',5,5'-テトラメチルベンジジン基質で反応させた後、650nmで分光吸光度を測定した。
スチラキスリグノリドAの投与による反応性酸素生成量を測定するために、前記<実施例2>の各個体の一部気管支肺胞洗浄液をPBSで洗浄した後、10μM 2,7-ジクロロフルオレセインジアセテート(35845,Sigma,,St.Louis,MO)を添加して10分間常温暗室に放置した後、分光蛍光計で測定した(Ex=480nm,Em=522nm)。
スチラキスリグノリドAの肝毒性を確認するために、市販のELISAキット(BECKMAN Coulter,Inc.,Fullerton,CA,米国)を用いて、血清内アラニンアミノトランスフェラーゼ(ALT)及びアスパラギン酸アミノトランスフェラーゼ(AST)を測定した。
<7−1>気道粘膜内炎症細胞浸潤抑制
それぞれの個体から摘出された肺は、一般的なホルマリン固定とパラフィン包埋を経て4μmの厚さで永久組織切片を製作して、ヘマトキシリンとエオジン(H&E)染色を実施した。H&E染色後、各個体の組織切片当たり無作為に5ヶ所部位の炎症指数を測定して平均を出した。炎症指数0は気管支周辺に炎症細胞が発見されない場合、炎症指数1は間欠的に炎症細胞が観察される場合、炎症指数2は大部分の気管支周辺に一層から二〜三層の間の薄い炎症細胞層が観察される場合、炎症指数3は大部分の気管支周辺に二〜三層から五層以下の炎症細胞層が観察される場合、炎症指数4は大部分の気管支周辺に五層以上の厚い炎症細胞層が観察される場合として評価した。
それぞれの個体から摘出された肺は、一般的なホルマリン固定とパラフィン包埋を経て4μmの厚さで永久組織切片を製作して、過ヨウ素酸シッフ(PAS)染色を通じて鑑別された杯状細胞が気管支上皮細胞で占める比率を測定して、杯状細胞増殖程度を評価した。
気管支下部の線維化程度を測定するために、それぞれの個体から摘出された肺は一般的なホルマリン固定とパラフィン包埋を経て4μmの厚さで永久組織切片を製作してマッソントリクローム染色を実施して上皮下に染色される細胞外基質部位の面積を測定した後、基底膜周囲の長さ100μm当たりの線維化染色部位の面積を計算した。すべての測定には、コンピューター化された画像解析プログラムを用いた。
ホモエゴノールの、喘息誘導マウス体重減少に及ぼす効果を確認するために、前記<実施例2>で製作したそれぞれのマウスに対する体重を測定した。以下、すべての測定値の統計分析については、いくつかの変数による平均値と標準誤差(mean±S.E.)を計算し、各集団間の比較はSPSS10.0を用いて、マン・ホイットニーのU検定を行なって分析した。統計的に、p値が0.05未満の場合に有意な差があると判定した。
ホモエゴノールの喘息発生による気道過敏性有無を確認するために、前記<実験例2>の方法でPenh値を測定した。
ホモエゴノールの喘息に対する効果を調べるために、喘息の重症度と係わり合いがあるIgE濃度を測定するために、前記<実験例4>の方法によって血清及び気管支肺胞洗浄液内のIgEを測定した。
ホモエゴノールの喘息に対する効果を調べるために、前記<実験例3>の方法によって喘息と関連がある炎症細胞数の増減を測定した。
ホモエゴノールの気道リモデリングに対する効果を調べるために、気管支肺胞洗浄液内TGF−β1及びIL−17生成を測定した。
ホモエゴノールの喘息に対する効果を調べるために、気管支肺胞洗浄を行なっていない肺を分離して、前記実験例<7−1>の方法によって組織病理学的検査を行なった。ここで、抗原が惹起された気管支では好酸球、好中球及び大食細胞からなる炎症性細胞の浸潤が観察されるので、これを検出しようとした。
前記実験例<7−2>の方法によって、過ヨウ素酸シッフ染色を通じて鑑別された杯状細胞(goblet cell)が気管支上皮細胞で占める比率を測定して、杯状細胞増殖程度を評価した。
前記実験例<7−3>の方法によって、気管支下部の線維化程度を測定するためにマッソントリクローム染色を行なって、上皮下に染色される細胞外基質部位の面積を測定した後、基底膜周囲の長さ100μm当たりの線維化染色部位の面積を計算した。
<1−1>散剤の製造
本発明のスチラキスリグノリドA化合物 2mg
乳糖 1g
前記の成分を混合して気密包に充填して散剤を製造した。
本発明のスチラキスリグノリドA化合物 100mg
コーンスターチ 100mg
乳糖 100mg
ステアリン酸マグネシウム 2mg
前記の成分を混合した後、通常の錠剤の製造方法にしたがって打錠して錠剤を製造した。
本発明のホモエゴノール化合物 100mg
コーンスターチ 100mg
乳糖 100mg
ステアリン酸マグネシウム 2mg
前記の成分を混合した後、通常のカプセル剤の製造方法にしたがってゼラチンカプセルに充填してカプセル剤を製造した。
本発明のホモエゴノール化合物 1mg
乳糖 1.5g
グリセリン 1g
キシリトール 0.5g
前記の成分を混合した後、通常の方法によって1丸薬当たり4gになるように製造した。
本発明のホモエゴノール化合物 150mg
大豆抽出物 50mg
ブドウ糖 200mg
澱粉 600mg
前記の成分を混合した後、30%エチルアルコール100mgを添加して摂氏60℃で乾燥して顆粒を形成した後、包みに充填した。
本発明のスチラキスリグノリドA化合物を含む食品を下記のように製造した。
本発明のスチラキスリグノリドA化合物0.5〜5.0重量部を小麦粉に添加して、その混合物を用いてパン、ケーキ、クッキー、クラッカー及び麺類を製造した。
本発明のスチラキスリグノリドA化合物0.1〜5.0重量部をスープ及び肉汁に添加して健康増進用肉加工製品、麺類のスープ及び肉汁を製造した。
本発明のスチラキスリグノリドA化合物10重量部を牛ひき肉に添加して健康増進用牛ひき肉を製造した。
本発明のスチラキスリグノリドA化合物5〜10重量部を牛乳に添加して、前記牛乳を用いてバター及びアイスクリームのような多様な乳製品を製造した。
玄米、麦、もち米、鳩麦を公知の方法でアルファ化させて乾燥させたものを焙煎した後、粉砕機で粒度60メッシュの粉末に製造した。
種実類(えごま7重量部、黒豆8重量部、黒ごま7重量部)、
スチラキスリグノリドA化合物(3重量部)、
霊芝(0.5重量部)、
地黄(0.5重量部)。
<3−1>健康飲料の製造
液状果糖(0.5%)、オリゴ糖(2%)、砂糖(2%)、食塩(0.5%)、水(75%)などの副材料と本発明のホモエゴノール5mgを均質に配合して瞬間殺菌をした後、それをガラス瓶、ペットボトルなど小包装容器に包装して製造した。
本発明のホモエゴノール化合物5mgをトマトまたはにんじんジュース1,000mlに加えて野菜ジュースを製造した。
本発明のホモエゴノール化合物1mgをリンゴまたはブドウジュース1,000mlに加えて果物ジュースを製造した。
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KR10-2011-0120160 | 2011-11-17 | ||
KR1020110120160A KR101322391B1 (ko) | 2010-11-17 | 2011-11-17 | 스티락스리그놀리드 a 또는 이의 비당체를 유효성분으로 함유하는 천식의 예방 또는 치료용 조성물 |
PCT/KR2011/008805 WO2012067447A2 (ko) | 2010-11-17 | 2011-11-17 | 스티락스리그놀리드 a 또는 이의 비당체를 유효성분으로 함유하는 천식의 예방 또는 치료용 조성물 |
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EP (1) | EP2641604B1 (ja) |
JP (1) | JP5806324B2 (ja) |
KR (1) | KR101322391B1 (ja) |
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WO2015137775A1 (ko) * | 2014-03-13 | 2015-09-17 | 한국생명공학연구원 | 벤조퓨란계 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 천식 예방 및 치료용 조성물 |
WO2015147597A1 (ko) * | 2014-03-27 | 2015-10-01 | 한국생명공학연구원 | 호모에고놀을 유효성분으로 함유하는 만성폐쇄성 폐질환 예방 및 치료용 약학적 조성물 |
CN106176967B (zh) * | 2016-07-19 | 2017-09-01 | 中南民族大学 | 一种舒张气管平滑肌的药物组合物 |
EP3516397A1 (en) * | 2016-09-23 | 2019-07-31 | Ventana Medical Systems, Inc. | Methods and systems for scoring extracellular matrix biomarkers in tumor samples |
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2011
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- 2011-11-17 WO PCT/KR2011/008805 patent/WO2012067447A2/ko active Application Filing
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KR101322391B1 (ko) | 2013-10-29 |
EP2641604A4 (en) | 2014-06-18 |
JP2013544252A (ja) | 2013-12-12 |
WO2012067447A3 (ko) | 2012-07-12 |
WO2012067447A2 (ko) | 2012-05-24 |
CN103313717A (zh) | 2013-09-18 |
US8980846B2 (en) | 2015-03-17 |
CN103313717B (zh) | 2015-04-29 |
KR20120089784A (ko) | 2012-08-13 |
EP2641604A2 (en) | 2013-09-25 |
US20130244959A1 (en) | 2013-09-19 |
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