JP6627141B2 - ベニバナボロギク抽出物を調製する方法、それにより調製された抽出物、及び抽出物の使用 - Google Patents
ベニバナボロギク抽出物を調製する方法、それにより調製された抽出物、及び抽出物の使用 Download PDFInfo
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- JP6627141B2 JP6627141B2 JP2018534564A JP2018534564A JP6627141B2 JP 6627141 B2 JP6627141 B2 JP 6627141B2 JP 2018534564 A JP2018534564 A JP 2018534564A JP 2018534564 A JP2018534564 A JP 2018534564A JP 6627141 B2 JP6627141 B2 JP 6627141B2
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- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/50—Methods involving additional extraction steps
- A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/50—Methods involving additional extraction steps
- A61K2236/55—Liquid-liquid separation; Phase separation
Description
[0001]本発明は、植物薬であるベニバナボロギク(Crassocephalum crepidioides)抽出物を調製する方法、及び癌の治療又は予防を必要とする対象における癌の治療又は予防におけるベニバナボロギク抽出物の使用に関する。
[0002]癌は第一位の死亡原因である。有効な治療は、最新の医薬品、医薬品会社、及び学界における研究の主要な焦点になっている。従来の癌治療として、手術、化学療法、及び標的療法が挙げられる。最初に、腫瘍組織を手術によって切除する。次に、残りの細胞を化学療法及び標的療法によって死滅させる。しかし、このような治療プログラムは、末期の癌患者に対して十分であるとは全く言えない。従来の治療法では、進行した癌患者の生存率及び生活の質を向上させることはできない。
[00010]ある態様では、本発明は、ベニバナボロギク抽出物を調製する方法に関する。
[00020]本発明は、ベニバナボロギク抽出物を調製する方法であって:
(a)ベニバナボロギク植物を70%エタノールと接触させて懸濁液を得るステップと、
(b)前記懸濁液中の固体分を液体分から分離し、次に、液体分を収集して粗抽出物を得るステップと、
(c)前記粗抽出物を60%エタノール抽出物に希釈するステップと、
(d)前記60%エタノール抽出物を、マクロ多孔性スチレン−ジビニルベンゼン樹脂と混合するステップと、
(e)前記60%エタノール抽出物とマクロ多孔性樹脂との混合物をカラムに注入するステップと、
(d)前記カラムの体積に対して約2〜10倍の体積のエタノールで前記カラムを洗浄するステップと、
(e)前記カラムをエタノール/酢酸エチル又は酢酸エチルの溶媒で溶出し、異なる時間間隔で溶出画分を収集するステップと、
(f)各溶出画分を分析し、ベニバナボロギク抽出物としていずれの画分が、1,2−ジ−O−α−リノレノイル−3−O−β−ガラクトピラノシル−sn−グリセロール(dLGG)に富んでいるか、及びフィトールを含有するかを判定するステップと
を含む方法を提供する。
カラム:シンメトリーシールド(Symmetry Shield)C18、15μm、4.6×150mm
温度:室温
溶出:H2O/CH3CN勾配
検出:UV210nm
[00031]本発明は、本発明の調製方法によって調製される、治療上有効な量のベニバナボロギク抽出物を含む医薬組成物を提供する。本発明は、本発明の調製方法によって調製される、治療上有効な量のベニバナボロギク抽出物及び治療上有効な量の化学療法剤を含む、医薬の組合せも提供する。医薬組成物/医薬の組合せは、薬学的に許容される担体又は媒体を含んでもよい。
[00036]本発明の医薬組成物/医薬の組合せは、癌の治療又は予防を必要とする対象における癌を治療又は予防するために使用することができる。
[00042]乾燥したベニバナボロギク1.02kg(植物全体)をすり潰し、乾燥した植物の総重量に対して10倍量の70%エタノール溶液に24時間浸し、次に、植物抽出物を減圧下でNO.1フィルターを用いて濾過し、第1の濾液を得た。固体残渣を、乾燥した植物の総重量に対して5倍量の70%エタノール溶液に24時間浸し、次に、植物抽出物を減圧下でNO.1フィルターを用いて濾過し、第2の濾液を得た。第1及び第2の濾液を混合し、ベニバナボロギク粗抽出物を得て、粗抽出物を減圧下で濃縮し、重量213.69g、濃度203.51mg/mL、収率20.95%の濃抽出物(extractum spissum)1.05Lを得た。
[00044]HPLCの条件
カラム:シンメトリーシールドC18、15μm、4.6×150mm
温度:室温
溶出:H2O/CH3CN勾配
検出:UV210nm
[00046]MKN45細胞を、5%FBS(Gibco(商標))を含有するRPMI−1640培地(Sigma−Aldrich)で培養した。6×103個の細胞を96ウェルプレートの各ウェルに加えた。各ウェルは、上記の培地180μLを含有していた。プレートを、37℃で4時間培養し、次に、様々な濃度の前記原抽出物、Cr−E03、及びdLGGのそれぞれ20μLを、プレートの各ウェルに加えた。各濃度について試験を3回繰り返した。37℃で48時間さらに培養した後、ウェルの培地を除去し、3−(4,5−ジメチルチアゾール−2−イル)−5−(3−カルボキシメトキシフェニル)−2−(4−スルホフェニル)−2H−テトラゾリウム(MTS)を含有する5%FBS培地180μLをウェルに加えた。37℃で1時間反応させた後、ウェルの490nmにおける吸光度の値を、ELISAリーダー(モデル680マイクロプレートリーダー(Model 680 Microplate Reader)、Bio−Rad)によって測定した。原抽出物、Cr−E03、及びdLGGそれぞれのIC25、IC50、及びIC75値は、グラフパッドプリズム(GraphPad Prism)5ソフトウェア(グラフパッドソフトウェア、Inc)を使用した計算によって得られた。IC25、IC50、及びIC75値はそれぞれ、MKN45細胞の増殖の最大阻害の25%、50%、及び75%が得られる試験サンプルの濃度として定義されている。表1に結果を示す。
[00048]異なる濃度の前記原抽出物、Cr−E03、及びdLGGそれぞれと異なる濃度の5−フルオロウラシル(5−FU)及びエピルビシンそれぞれとの組合せを調製した。試験は、実施例3と同じ手順に基づいて実施され、組合せの組合せ指数(CI)も、グラフパッドプリズム5ソフトウェアの計算によって得られた。表2に結果を示す。CI定理は、Chou T.C.及びTalalay P.によって1984年に最初に提供された(Advances in Enzyme Regulation、22:27−55、1984)。CI定理によると、CI=1が相加/加重効果を有する組合せを示し、CI<1は相乗効果を有する組合せを示し、またCI>1は拮抗作用を有する組合せを示す。
Claims (21)
- ベニバナボロギク抽出物を調製する方法であって:
(a)ベニバナボロギク植物を70%エタノールと接触させて懸濁液を得るステップと、
(b)前記懸濁液を固体分と液体分とに分離し、次に、液体分を収集して粗抽出物を得るステップと、
(c)前記粗抽出物を60%エタノール抽出物になるまで希釈するステップと、
又は、
前記粗抽出物を濃縮して濃厚抽出物を得て、次に、前記濃厚抽出物を60%エタノールに希釈して60%エタノール抽出物を得るステップと、
(d)前記60%エタノール抽出物を、マクロ多孔性スチレン−ジビニルベンゼン樹脂と混合するステップと、
(e)前記60%エタノール抽出物とマクロ多孔性スチレン−ジビニルベンゼン樹脂との混合物をカラムに注入するステップと、
(f)前記カラムの体積に対して約2〜10倍の体積のエタノールで前記カラムを洗浄するステップと、
(g)前記カラムをエタノール/酢酸エチル又は酢酸エチルの溶媒で溶出し、異なる時間間隔で溶出画分を収集するステップと、
(h)各溶出画分を分析し、ベニバナボロギク抽出物としていずれの画分が、1,2−ジ−O−α−リノレノイル−3−O−β−ガラクトピラノシル−sn−グリセロール(dLGG)に富んでいるか、及びフィトールを含有するかを判定するステップと
を含み、
前記ベニバナボロギク植物が、植物全体である、方法。 - 前記ベニバナボロギク植物が、乾燥され粉末化されている、請求項1に記載の方法。
- 前記ベニバナボロギク植物が乾燥された植物であり、ステップ(a)における乾燥した植物の重量と70%エタノール溶媒との体積の比が、約1:1〜約1:50の範囲である、請求項2に記載の方法。
- ステップ(a)における乾燥した植物の重量と70%エタノール溶媒との体積の比が、約1:10である、請求項1〜3のいずれか一項に記載の方法。
- 前記マクロ多孔性スチレン−ジビニルベンゼン樹脂が、セパビーズSP70及びセパビーズSP710から選択される、請求項1〜4のいずれか一項に記載の方法。
- 前記マクロ多孔性スチレン−ジビニルベンゼン樹脂が、セパビーズSP70である、請求項5に記載の方法。
- ステップ(g)で使用される前記溶媒が、エタノール/酢酸エチルであり、エタノールと酢酸エチルとの体積比が、約1:1である、請求項1に記載の方法。
- 請求項1〜7のいずれか一項に記載の方法から得られるベニバナボロギク抽出物。
- HPLCにより以下の条件:
カラム:シンメトリーシールドC18、15μm、4.6×150mm
温度:室温
溶出:H2O/CH3CN勾配
検出:UV210nm
で定量した場合、それぞれ12.59分、12.893分、13.828分、14.158分、14.922分、15.455分、及び16.478分の保持時間に7つの主要ピークを有する、請求項8に記載のベニバナボロギク抽出物。 - 治療上有効な量の請求項8又は9に記載のベニバナボロギク抽出物及び薬学的に許容される担体を含む医薬組成物。
- 治療上有効な量の請求項8又は9に記載のベニバナボロギク抽出物及び化学療法剤を組み合わせてなる医薬。
- 前記化学療法剤が、代謝拮抗剤、アルキル化剤、アントラサイクリン、抗生剤、有糸分裂阻害剤、及びプロテアソーム阻害剤から選択される、請求項11に記載の医薬。
- 前記化学療法剤が、5−フルオロウラシル(5−FU)又はエピルビシンである、請求項11又は12に記載の医薬。
- 癌の治療又は予防を必要とする対象における癌を治療又は予防するための医薬の製造における、請求項8又は9に記載のベニバナボロギク抽出物の、請求項10に記載の医薬組成物の、又は、請求項11〜13のいずれか一項に記載の医薬の、使用。
- 癌の治療又は予防を必要とする対象における癌を治療又は予防するための医薬の製造における、化学療法剤と組み合わせた、請求項8又は9に記載のベニバナボロギク抽出物の、又は、請求項10に記載の医薬組成物の、使用。
- 前記化学療法剤が、代謝拮抗剤、アルキル化剤、アントラサイクリン、抗生剤、有糸分裂阻害剤、及びプロテアソーム阻害剤から選択される、請求項15に記載の使用。
- 前記化学療法剤が、5−フルオロウラシル(5−FU)又はエピルビシンである、請求項15又は16に記載の使用。
- 癌の治療又は予防における使用のための、請求項8又は9に記載のベニバナボロギク抽出物、請求項10に記載の医薬組成物、又は、請求項11〜13のいずれか一項に記載の医薬。
- 化学療法剤と組み合わせた癌の治療又は予防における使用のための、請求項8又は9に記載のベニバナボロギク抽出物或いは請求項10に記載の医薬組成物。
- 前記化学療法剤が、代謝拮抗剤、アルキル化剤、アントラサイクリン、抗生剤、有糸分裂阻害剤、及びプロテアソーム阻害剤から選択される、請求項19に記載のベニバナボロギク抽出物又は医薬組成物。
- 前記化学療法剤が、5−フルオロウラシル(5−FU)又はエピルビシンである、請求項19又は20に記載のベニバナボロギク抽出物又は医薬組成物。
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