WO2009154237A1 - リンパ管の安定化剤 - Google Patents
リンパ管の安定化剤 Download PDFInfo
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- WO2009154237A1 WO2009154237A1 PCT/JP2009/061047 JP2009061047W WO2009154237A1 WO 2009154237 A1 WO2009154237 A1 WO 2009154237A1 JP 2009061047 W JP2009061047 W JP 2009061047W WO 2009154237 A1 WO2009154237 A1 WO 2009154237A1
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- extract
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- tie2
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- lymphatic vessel
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1891—Angiogenesic factors; Angiogenin
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- 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)
- A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
- A61K36/254—Acanthopanax or Eleutherococcus
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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)
- A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/45—Transferases (2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention provides a lymphatic vessel stabilizer comprising a Tie2 activating (phosphorylating) agent.
- a lymphatic vessel forms a drainage path for tissue fluid separately from the vascular system.
- the lymphatic vessels maintain a closed circulatory system by keeping the blood volume constant by circulating interstitial fluid, proteins, fats, cells, and the like leaked from the blood vessels in the peripheral tissues to the vascular system.
- the basement membrane surrounds the outside of the endothelial cells, and pericytes are further attached.
- capillary lymphatic vessels there is almost no basement membrane outside the endothelial cells, and pericytes are not attached. This structure is useful for efficiently taking in body fluids and cells from the interstitium (Non-Patent Document 1).
- Non-patent Document 2 vascular endothelial growth -3 factor -3 receptor
- lymphatic vessel stabilization In mouse ears infected with adenovirus expressing VEGF-A, remarkable lymphangiogenesis was observed, but along with structural abnormalities, lymphoid recovery function was also remarkable from experiments in which colloidal carbon was injected into the ear (Non-patent Document 3). That is, it is considered that lymphatic endothelial cells must be appropriately arranged and lined for the function of lymphatic vessels. We define this as “lymphatic vessel stabilization”.
- Non-patent Document 4 Non-patent Document 4
- Congenital lymphedema includes Milroy disease, Meige disease, and lymphedema-distichiasis syndrome. Milroy's disease has been reported to be aplastic or hypoplastic lymphatics, while lymphedema-distichiasis syndrome has been reported to have lymphatic hyperplasia. Also from these, it is considered necessary to maintain the recovery function not only by lymphatic neovascularization but also by stabilizing the lymphatic vessels (Non-patent Document 5).
- An object of the present invention is to provide a drug effective for stabilizing lymphatic vessels and maintaining / enhancing the recovery function of lymphatic vessels.
- VEGF angiopoietin
- Ang angiopoietin
- VEGF and its receptors are involved in a very wide range of angiogenesis, from the initial development of blood vessels called angiogenesis to subsequent angiogenesis.
- Ang functions in luminal formation accompanied by cellular phenomena such as germination, branching, insertion, and retraction by vascular endothelial cells after angiogenesis.
- Ang is a receptor-type tyrosine kinase Tie (tyrosine kinase with Ig and EGF homology domain) -2 expressed in vascular endothelial cells, and vascular endothelial cells and blood vessel walls such as pericytes (pericytes) and vascular smooth muscle cells Although it is understood that it controls adhesion to cells and functions for structural stabilization of blood vessels (Non-Patent Document 7), the relationship between Tie2 and lymphatic vessels has not been fully elucidated. .
- a lymphatic stabilizer comprising a Tie2 activator.
- the Tie2 activator is at least one selected from the group consisting of Angiopoietin 1 (Ang-1), an extract of the genus Cinnamomum, a Siberian Ginseng extract, and syringaresinol.
- the lymph vessel stabilizer of (1) which is a seed.
- the lymphatic vessel stabilizer according to (2), wherein the extract is derived from a Cinnamomum cassia Blume.
- the lymphatic vessel stabilizer according to (2) wherein the extract is derived from Keishi or Keihi.
- lymphatic vessel stabilizer makes it possible to improve and prevent swelling.
- the activator of Tie2 is not particularly limited, but is known to have an activity to activate Tie2, such as Angiopoietin 1, or an extract derived from a plant belonging to the genus Cinnamomum, Siberian carrot (SiberianiberGinseng ) Extracts or syringaresinol, which are newly found by the inventor to have the activity.
- the activation of Tie2 here refers to the ability to phosphorylate Tie2 and convert it into its active form (phosphorylated Tie2).
- Nikkei is a plant of the order Lauraceae and Lauraceae, and there are more than 300 species, such as Cinnamomumomcassia Blume, C. camphora, C. daphnoides (C. doederleinii), C. japonicum, Ogasawara bay unic (C. pseudo-pedunculatum), Nikkei (C. sieboldii), Shibaya buns kei Ceylon nicki (C. verum), Cinnamon (C. zeylanicum).
- Cinnamomumomcassia Blume C. camphora, C. daphnoides (C. doederleinii), C. japonicum, Ogasawara bay unic (C. pseudo-pedunculatum), Nikkei (C. sieboldii), Shibaya buns kei Ceylon nicki (C. verum), Cinnamon (C. zeylanicum).
- an extract derived from Cay (Cinnamomum cassia Blume), in particular, Cay nae (Keishi) or Keihi (Cinnamon), which is a young branch of Cay, is used.
- Cay Cinnamomum cassia Blume
- Cay nae Keishi
- Keihi a young branch of Cay
- an extract derived from Keihi which is the bark of Kay, is useful as an active ingredient of a hair restorer, for example (Japanese Patent Laid-Open No. 10-265350), but it has absolutely no lymphatic vessel stabilizing activity. unknown.
- Siberian carrot (Siberian Ginseng) extract is traditionally said to be nourishing and strong. It exhibits excellent efficacy in fragility, extreme fatigue, mental and physical deterioration such as poor concentration, and recovery after illness. It is used as a dietary supplement in the United States.
- the above-mentioned extract can be obtained by a conventional method, for example, it can be obtained by soaking or heating and refluxing the plant that is the origin together with the extraction solvent at room temperature or heating, followed by filtration and concentration.
- the extraction solvent can be arbitrarily used as long as it is a solvent that is usually used for extraction.
- an aqueous solvent such as water, physiological saline, phosphate buffer, borate buffer, or an organic solvent such as ethanol, Alcohols such as propylene glycol, 1,3-butylene glycol and glycerin, hydrous alcohols, chloroform, dichloroethane, carbon tetrachloride, acetone, ethyl acetate, hexane and the like can be used alone or in combination.
- water is used as the solvent.
- the extract obtained by extraction with the above solvent can be used as it is or, for example, an extract concentrated by lyophilization or the like, and if necessary, an adsorbent method, for example, an ion exchange resin removed impurities, A polymer (eg, Amberlite XAD-2) adsorbed on a column, eluted with a desired solvent, and further concentrated can be used.
- an adsorbent method for example, an ion exchange resin removed impurities,
- a polymer eg, Amberlite XAD-2
- Syringalesinol is an antioxidant lignan compound unique to plants and has an effect of improving hypertension and an effect of inhibiting Helicobacter pylori, and is therefore used in foods, beverages and pharmaceuticals (for example, Japanese Patent Application Laid-Open No. Hei 8- No. 268887, JP 2004-352652 A, etc.).
- Syringaresinol has the following chemical structure:
- Syringalesinol is a known compound, and is contained in Laurales and Lauraceae, especially in its shoots (bark) or bark (barb). It is not known at all that it has effects such as lymphatic vessel stabilization and Tie2 activation. Syringaresinol may be extracted from natural sources such as cinnamon or cinnamon, or may be synthesized.
- Syringaresinol may be an inorganic salt or an organic salt.
- the salt is not particularly limited, and examples of the inorganic salt include hydrochloride, sulfate, phosphate, hydrobromide, sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt and the like.
- Organic salts include acetate, lactate, maleate, fumarate, tartrate, citrate, methanesulfonate, p-toluenesulfonate, triethanolamine salt, diethanolamine salt, amino acid salt, etc. Can be mentioned.
- the lymphatic vessel stabilizer according to the present invention can be used as a pharmaceutical or a cosmetic effective for the treatment / prevention of various skin diseases such as edema (swelling) due to leakage of lymph fluid caused by instability of the structure of lymphatic vessels.
- skin diseases such as edema (swelling) due to leakage of lymph fluid caused by instability of the structure of lymphatic vessels.
- edema include secondary lymphedema associated with ultraviolet radiation, filaria, surgery, malignant tumors, inflammation, and congenital lymphedema such as Milroy disease, Meige disease, and lymphedema-distichiasis syndrome.
- the lymphatic vessel stabilizer according to the present invention is also used in a cosmetic method for reducing or preventing swelling and eye bags.
- This cosmetic method is applied to, for example, a site with swelling of the lymphatic vessel stabilizer according to the present invention and left as it is, or subjected to, for example, massage according to the direction of the flow of the lymphatic vessel.
- the liquid flow can be promoted.
- This part can be applied to all parts of the body such as the face, neck, limbs, and the like.
- the lymphatic vessel stabilizer according to the present invention can be appropriately determined in dosage, usage and dosage form in accordance with its intended purpose.
- the dosage form of the lymphatic vessel stabilizer of the present invention is not particularly limited, and may be oral, parenteral, external use and the like. Preferably it is an external preparation.
- the dosage form include external preparations such as ointments, creams, emulsions, lotions, packs, bath preparations, parenteral preparations such as injections, drops, or suppositories, or tablets, powders, capsules, granules, Oral administration agents such as extract and syrup can be mentioned.
- the use as a functional food etc. can also be mentioned about the lymphatic vessel stabilizer which concerns on this invention.
- the blending amount of the Tie2 activator in the lymphatic vessel stabilizer of the present invention can be appropriately determined according to the use, but is generally 0.0001 to 20.0 mol%, preferably 0.0001 to 10.0 mol% in the total amount of the agent.
- the lymphatic vessel stabilizer of the present invention includes, for example, excipients, moisture-proofing agents, preservatives, strengthening agents, thickeners, emulsifiers, and the like used in ordinary foods and pharmaceuticals.
- Components, colorants, aqueous components, water, various skin nutrients, and the like can be appropriately blended as necessary.
- auxiliary agents commonly used for external preparations for skin such as disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate
- Sequestering agents such as gluconic acid, caffeine, tannin, verapamil, tranexamic acid and its derivatives, licorice extract, grabrizine, hot water extract of karin fruit, various herbal medicines, tocopherol acetate, glycyrrhizic acid and its derivatives or their derivatives
- Drugs such as salts, whitening agents such as vitamin C, magnesium ascorbate phosphate, glucoside ascorbate, arbutin, kojic acid, sugars such as glucose, fructose, mannose, sucrose, trehalose, retinoic acid, retinol, retinol acetate, palmiticin Acid retinoic
- vitamin A like may also be appropriately blended.
- a compounding quantity is the mass%.
- Lymphatic endothelial cells were isolated from human newborn foreskin as CD31 positive CD34 negative CD45 negative cells (Non-patent Document 6). Lymphatic endothelial cells are cultured in EBM-2 (Cambrex; Verviers, Belgium) with added factors, and proteins are added in the presence of various drugs (Ang-1, Keihi extract, Siberian ginseng extract, and syringaresinol). Extraction was performed with Phosphosafe Extraction Reagent (Novagen, Madison, WI). As a control, cells added with DMSO were also prepared. The cinnamon extract and syringaresinol were prepared as shown below.
- the Siberian carrot extract (Ask Chemical) used what extracted the root of Siberian carrot with 30% ethanol. It was confirmed by HPLC that this extract contained 1.01% by mass of syringaresinol. This extract was dissolved in DMSO and used as each test sample. The total protein amount was quantified with RC DC Protein Assay Kit (BIO-RAD, Hercules, CA) and detected by Western blotting as follows. SDS-PAGE was performed on 7.5% acrylamide gel (NPU-7.5L, ATTO, Japan) with an equal amount of total protein, and protein expression of Tie2 and phosphorylated Tie2 was determined by Ang-1 antibody (Santa Cruz Biotechnology, Santa The color was developed with ECL Kit using Cruz, CA). FIG.
- FIG. 2 shows that cinnamon extract phosphorylates, ie activates Tie2, similar to Ang-1.
- FIG. 3 shows that the Siberian carrot extract phosphorylates, ie activates Tie2, similar to Ang-1.
- syringaresinol although no data is shown, it was confirmed that Tie2 was activated in the same manner as Ang-1.
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Abstract
Description
(1)Tie2活性化剤からなる、リンパ管の安定化剤。
(2)前記Tie2活性化剤が、アンジオポエチン1(Ang-1)、ニッケイ(Cinnamomum)属植物の抽出物、シベリアニンジン(Siberian Ginseng)抽出物及びシリンガレシノールからなる群から選択される少なくとも1種である、(1)のリンパ管の安定化剤。
(3)前記抽出物がケイ種植物(Cinnamomum cassia Blume)由来である、(2)のリンパ管の安定化剤。
(4)前記抽出物がケイシ又はケイヒ由来である、(2)のリンパ管の安定化剤。
(5)前記抽出物が水抽出物である、(2)~(4)のいずれかのリンパ管の安定化剤。
(6)(1)~(5)のいずれかのリンパ管の安定化剤を適用することからなる、むくみを改善又は予防するための美容学的方法。
リンパドレナージュアッセイ
8週齢のマウスの耳介部にHamiltonシリンジ(Hamilton, Reno, NV)で、マウス由来アンジオポイエチン-1(Ang-1)遺伝子をAdenoXベクターに組み込んだアデノウイルスを感染させた(1x109ifu/mouse)。コントロールとしてAdenoXベクターのみを組みこんだアデノウイルスを感染させた。感染4週間後、耳介部末端より、1ulのコロイドカーボン溶液(Kamei Co., Ltd, Japan)をHamiltonシリンジで注入してリンパの流れの経時変化を解析した。その結果、Ang1高発現マウス耳ではリンパ管の回収機能が促進されることが認められた(データーは示さない)。また、リンパ管における回収機能の変化は視感判定を行い、5段階で数値化(5:インクがすべてリンパ管にとどまった状態、1:インクがすべて回収されてリンパ管からなくなった状態)して比較し、その結果を図2に示す。この図から、Tie2の活性化剤であるAng-1の発現により、コントロールと比較して、リンパ管の回収機能の顕著な亢進が認められ、Tie2の活性化によりリンパ管の安定化が図れることがわかる。
リンパ管内皮細胞は、ヒト新生児包皮よりCD31陽性CD34陰性CD45陰性細胞として単離した(非特許文献6)。リンパ管内皮細胞は添加因子を加えたEBM-2(Cambrex; Verviers, Belgium)で培養し、各種薬剤(Ang-1、ケイヒ抽出物、シベリアニンジン抽出物及びシリンガレシノール)存在下でタンパク質をPhosphosafe Extraction Reagent(Novagen, Madison, WI)で抽出した。コントロールとしてDMSOを添加した細胞も調整した。
なお、ケイヒ抽出物及びシリンガレシノールは以降に示すとおりにして調製した。シベリアニンジン抽出物(アスク薬品)はシベリアニンジンの根を30%エタノールで抽出したものを使用した。この抽出物にはシリンガレシノールを1.01質量%含有されることがHPLCで確認された。この抽出物をDMSOにて溶解し、各試験試料とした。総タンパク量をRC DC Protein Assay Kit(BIO-RAD, Hercules, CA)にて定量し、以下のようにウエスタンブロッティングして検出した。等量の総タンパク量を7.5%アクリルアミドゲル(NPU-7.5L, ATTO, Japan)でSDS-PAGEを行い、Tie2およびリン酸化Tie2のタンパク質発現は、Ang-1抗体(Santa Cruz Biotechnology, Santa Cruz, CA)を用いて、ECL Kitにより発色した。図2はケイヒ抽出物がAng-1と同様にTie2をリン酸化、即ち活性化することを示す。図3はシベリアニンジン抽出物がAng-1と同様にTie2をリン酸化、即ち活性化することを示す。なお、シリンガレシノールについても、データーは示さないが、Ang-1と同様にTie2を活性することが確認された。
ケイシ(Cinnamomum cassia Blume)400.7gに水2Lを加え、3時間加熱抽出を行い、ろ過した。得られた残渣に水2Lを加え、同様の操作を繰り返し、加熱抽出をさらに2回行った。得られたろ液を凍結乾燥し、39.7gの熱水抽出乾燥残分を得た。
熱水抽出乾燥残分 31.0gをSephadex LH-20 (Amersham Pharmacia Biotech AB)を用いて粗分画を行った。水溶出画分(2.7g)、50%メタノール溶出画分(8.5g)、メタノール溶出画分(4.9g)、アセトン溶出画分(0.5g)、および未溶出画分(7.4g)を得た。メタノール溶出画分についてアンバーライトXAD2(オルガノ(株))カラムにより分画し、次いでHPLC分取(カラム:Capcell Pak C18 AQ(株)資生堂製, 検出: UV210nm, 移動層: CH3CN/H2O混合系)によりシリンガレシノール(2.08mg)を単離した。
Claims (6)
- Tie2(tyrosine kinase with Ig and EGF homology domain 2)活性化剤からなる、リンパ管の安定化剤。
- 前記Tie2活性化剤が、アンジオポエチン1(Ang-1)、ニッケイ(Cinnamomum)属植物の抽出物、シベリアニンジン(Siberian Ginseng)抽出物及びシリンガレシノールからなる群から選択される少なくとも1種である、請求項1記載のリンパ管の安定化剤。
- 前記抽出物がケイ種植物(Cinnamomum cassia Blume)由来である、請求項2記載のリンパ管の安定化剤。
- 前記抽出物がケイシ又はケイヒ由来である、請求項2記載のリンパ管の安定化剤。
- 前記抽出物が水抽出物である、請求項2~4のいずれか1項記載のリンパ管の安定化剤。
- 請求項1~5のいずれか1項記載のリンパ管の安定化剤を適用することからなる、むくみを改善又は予防するための美容学的方法。
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2009801216551A CN102056630B (zh) | 2008-06-18 | 2009-06-17 | 淋巴管的稳定剂 |
JP2010517947A JP4970594B2 (ja) | 2008-06-18 | 2009-06-17 | リンパ管の安定化剤 |
KR1020167024946A KR101784645B1 (ko) | 2008-06-18 | 2009-06-17 | 림프관의 안정화제 |
ES09766685.3T ES2536418T3 (es) | 2008-06-18 | 2009-06-17 | Estabilizador de vasos linfáticos |
KR1020167006380A KR20160032272A (ko) | 2008-06-18 | 2009-06-17 | 림프관의 안정화제 |
US12/737,203 US8367124B2 (en) | 2008-06-18 | 2009-06-17 | Lymphatic vessel stabilizer |
EP20090766685 EP2319537B1 (en) | 2008-06-18 | 2009-06-17 | Stabilizer for lymph vessel |
HK11106902.1A HK1152866A1 (en) | 2008-06-18 | 2011-07-05 | Stabilizer for lymph vessel |
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JP2008159623 | 2008-06-18 | ||
JP2008-159623 | 2008-06-18 |
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WO2009154237A1 true WO2009154237A1 (ja) | 2009-12-23 |
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PCT/JP2009/061047 WO2009154237A1 (ja) | 2008-06-18 | 2009-06-17 | リンパ管の安定化剤 |
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US (1) | US8367124B2 (ja) |
EP (2) | EP2319537B1 (ja) |
JP (2) | JP4970594B2 (ja) |
KR (3) | KR101784645B1 (ja) |
CN (2) | CN102056630B (ja) |
ES (2) | ES2536418T3 (ja) |
HK (1) | HK1152866A1 (ja) |
TW (2) | TWI495487B (ja) |
WO (1) | WO2009154237A1 (ja) |
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WO2012101746A1 (ja) * | 2011-01-24 | 2012-08-02 | 株式会社資生堂 | Tie2活性化剤、血管の成熟化、正常化又は安定化剤、リンパ管安定化剤並びにしわ防止・改善剤及びむくみ改善・予防剤 |
JP2014534966A (ja) * | 2011-10-18 | 2014-12-25 | 株式会社アモーレパシフィックAmorepacific Corporation | シリンガレシノールを含むsirt−1活性化剤 |
WO2015152416A1 (ja) * | 2014-04-04 | 2015-10-08 | 国立大学法人東北大学 | 眼圧降下剤 |
JP2016056196A (ja) * | 2011-05-10 | 2016-04-21 | 丸善製薬株式会社 | Tie2活性化剤、血管新生抑制剤、血管の成熟化剤、血管の正常化剤、及び血管の安定化剤、並びに医薬品組成物 |
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KR102016078B1 (ko) | 2012-11-30 | 2019-08-30 | (주)아모레퍼시픽 | 심장 질환 예방 또는 치료용 조성물 |
JP6572201B2 (ja) * | 2013-03-15 | 2019-09-04 | エアーピオ セラピューティクス インコーポレイテッド | 眼疾患を処置するための組成物、製剤、および方法 |
TWI679985B (zh) * | 2014-10-16 | 2019-12-21 | 日商三得利控股股份有限公司 | 含有橄欖果實萃取物的Tie2活化劑 |
WO2019098302A1 (ja) * | 2017-11-17 | 2019-05-23 | 株式会社資生堂 | VE-カドヘリン発現促進剤及び/又はインテグリンα5発現促進剤 |
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JP2016056196A (ja) * | 2011-05-10 | 2016-04-21 | 丸善製薬株式会社 | Tie2活性化剤、血管新生抑制剤、血管の成熟化剤、血管の正常化剤、及び血管の安定化剤、並びに医薬品組成物 |
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JP2017048221A (ja) * | 2011-10-18 | 2017-03-09 | 株式会社アモーレパシフィックAmorepacific Corporation | シリンガレシノールを含むsirt−1活性化剤 |
US9913823B2 (en) | 2011-10-18 | 2018-03-13 | Amorepacific Corporation | SIRT 1 activator including syringaresinol |
US9999611B2 (en) | 2011-10-18 | 2018-06-19 | Amorepacific Corporation | SIRT 1 activator including syringaresinol |
US10022351B2 (en) | 2011-10-18 | 2018-07-17 | Amorepacific Corporation | SIRT 1 activator including syringaresinol |
US11096921B2 (en) | 2011-10-18 | 2021-08-24 | Amorepacific Corporation | SIRT 1 activator including syringaresinol |
WO2015152416A1 (ja) * | 2014-04-04 | 2015-10-08 | 国立大学法人東北大学 | 眼圧降下剤 |
Also Published As
Publication number | Publication date |
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CN102813689A (zh) | 2012-12-12 |
EP2319537A4 (en) | 2012-02-22 |
TWI495487B (zh) | 2015-08-11 |
KR101784645B1 (ko) | 2017-10-11 |
TW201010740A (en) | 2010-03-16 |
EP2319537A1 (en) | 2011-05-11 |
ES2517491T3 (es) | 2014-11-03 |
KR20110027659A (ko) | 2011-03-16 |
CN102056630A (zh) | 2011-05-11 |
JP4970594B2 (ja) | 2012-07-11 |
CN102056630B (zh) | 2013-03-13 |
KR20160110562A (ko) | 2016-09-21 |
KR20160032272A (ko) | 2016-03-23 |
JPWO2009154237A1 (ja) | 2011-12-01 |
US20110091584A1 (en) | 2011-04-21 |
JP5221783B2 (ja) | 2013-06-26 |
EP2526955B1 (en) | 2014-08-06 |
EP2319537B1 (en) | 2015-04-29 |
US8367124B2 (en) | 2013-02-05 |
TWI532490B (zh) | 2016-05-11 |
TW201233402A (en) | 2012-08-16 |
ES2536418T3 (es) | 2015-05-25 |
CN102813689B (zh) | 2016-08-10 |
EP2526955A1 (en) | 2012-11-28 |
JP2012107041A (ja) | 2012-06-07 |
HK1152866A1 (en) | 2012-03-16 |
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