WO2012101746A1 - Activateur de tie-2, agent pour la maturation, la normalisation, ou la stabilisation des vaisseaux sanguins, agent de stabilisation des vaisseaux lymphatiques, agent de prévention/d'amélioration des rides, et agent d'amélioration/de prévention des œdèmes - Google Patents

Activateur de tie-2, agent pour la maturation, la normalisation, ou la stabilisation des vaisseaux sanguins, agent de stabilisation des vaisseaux lymphatiques, agent de prévention/d'amélioration des rides, et agent d'amélioration/de prévention des œdèmes Download PDF

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WO2012101746A1
WO2012101746A1 PCT/JP2011/051245 JP2011051245W WO2012101746A1 WO 2012101746 A1 WO2012101746 A1 WO 2012101746A1 JP 2011051245 W JP2011051245 W JP 2011051245W WO 2012101746 A1 WO2012101746 A1 WO 2012101746A1
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agent
tie2
vascular
normalization
stabilization
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PCT/JP2011/051245
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English (en)
Japanese (ja)
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大田　正弘
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株式会社資生堂
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • 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
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • 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
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • 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
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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

Definitions

  • the present invention includes Eleutheroside E, Eleutheroside E1, Sesamin, Eudesmine, Sylvatesmin, Pinoresinol, Yangambin, Forsythinol, and Coumarin.
  • a novel Tie2 (Tyrosine Kinase with Ig and EGF Homology Domain 2) activator (Tie2 phosphorylating agent) consisting of one or more compounds selected from the group consisting of, vascular maturation, normalization or stabilization, Provided are a lymphatic stabilizer, a wrinkle prevention / improvement agent, and a swelling improvement / prevention agent.
  • vascular smooth muscle cells and pericytes collectively called vascular wall cells are adhered to vascular endothelial cells via the extracellular matrix or directly from the outer cavity surface of vascular endothelial cells.
  • the ratio of adhesion between endothelial cells and wall cells differs depending on the size of the blood vessel diameter.
  • one layer of endothelial cells is lined with multiple layers of wall cells.
  • one wall cell is lined with one cell, and in a blood vessel having a smaller diameter, one wall cell adheres to a plurality of endothelial cells.
  • the lining of wall cells against vascular endothelial cells is important for the structural “maturation” process of blood vessels.
  • adhesion between vascular endothelial cells can form adhesion spots between endothelial cells so that intravascular environmental factors (cells and humoral factors) do not easily leak out of the blood vessel. It is important for the “maturation” process. Furthermore, depending on the demand for oxygen and nutrients in the tissue, especially when they are deficient, the blood vessels increase blood flow by expanding the lumen so that oxygen and nutrients can be adequately distributed to the tissue. Adjust. In other words, the process of controlling the permeability by controlling adhesion by forming adhesion spots between vascular endothelial cells, structurally stabilizing vascular endothelial cells with wall cell lining, and controlling the vascular cavity to large, medium and small , Defined as “blood vessel maturation”.
  • blood vessels with disordered structures are constructed, and immature blood vessels in which adhesion between endothelial cells is suppressed or adhesion of wall cells to endothelial cells is formed.
  • These cause disordered increase in vascular permeability, thereby causing abnormal humoral factors and cellular traffic in the tissues and blood vessels.
  • Increased permeability causes tissue edema, causes tissue dysfunction, and causes inflamed inflammatory cell infiltration, resulting in inflammation.
  • mural cells suppress sprouting of blood vessels from existing blood vessels, sprouting of blood vessels becomes excessive from blood vessels not accompanied by mural cells, and disordered sprouting of blood vessels is induced, resulting in worsening of the disease state.
  • Such a phenomenon is observed in pathological conditions represented by diabetic retinopathy, tumor, and inflammation.
  • blood vessels that have broken vascular permeability and abnormal blood vessels that cause disordered growth of blood vessels are promoted by lining the endothelial cells to the endothelial cells by increasing adhesion between the endothelial cells, thereby making the blood vessels normal.
  • the state is defined as “normalization of blood vessels”.
  • abnormal blood vessels such as those described above may cause changes in the internal and external blood flow factors, such as diabetes, hyperlipidemia, and hypertension, which may cause damage (cell death, etc.) to endothelial cells and mural cells, as well as cancer and inflammation. This triggers an excessive increase in the production of angiogenesis-promoting factors.
  • blood vessel stabilization to suppress damage to existing blood vessels, suppress dissociation of endothelial cells, or suppress dissociation of endothelial cells and wall cells.
  • This stabilization also includes a mechanism for suppressing cell death of endothelial cells.
  • Angiogenesis is a phenomenon in which a new blood vessel network is formed from existing blood vessels, and is deeply related to diseases mainly consisting of vascular lesions such as tumors, rheumatoid arthritis, diabetic retinopathy, hyperlipidemia, and hypertension.
  • VEGF vascular endothelial growth factor
  • VEGF family and angiopoietin (Angiopoietin; Ang) family molecules have been identified one after another as factors that act specifically on angiogenesis. It was. 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 regulates adhesion between vascular endothelial cells and vascular wall cells such as pericytes (pericytes) and vascular smooth muscle cells via the receptor tyrosine kinase Tie-2 expressed in vascular endothelial cells. It functions in structural stabilization (Non-patent Document 1: Experimental Medicine Vol.20, No.8-8 (2002) pp.52-57).
  • Ang-1 and Ang-2 are present in both humans and mice, but Ang-3 is present in mice and Ang-4 is present in humans.
  • Ang-1, -4 secreted from mural cells stimulates Tie-2 and induces autophosphorylation of intracellular tyrosine kinase domain, integrin activation, focal adhesion kinase (focal adhesion kinase; FAK) activation
  • FAK focal adhesion kinase
  • FAK focal adhesion kinase
  • PI3K / Akt phosphatidylinositol-3-kinase
  • PI3K serine-threonine kinase: Akt
  • Non-Patent Document 3 Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, McDonald DM.
  • Non-patent Document 5 Takakura
  • N Huang XL, Naruse T, Hamaguchi I, Dumont DJ, Yancopoulos GD, Suda T.
  • hematopoietic stem cells By inducing cell adhesion, hematopoietic stem cells can be induced to maintain anchorage-dependent survival in vivo and externally by activation of Tie2. Furthermore, recent reports have suggested that Tie2 is expressed in cancer stem cells that are considered to be the most malignant in cancer tissues and are involved in cancer recurrence (non- Patent Document 6: Lee OH, Xu J, Fueyo J, Fuller GN, Aldape KD, Alonso MM, Piao Y, Liu TJ, Lang FF, Bekele BN, Gomez-Manzano C. Expression of the receptor Trosie is associated with integrin beta1-dependent adhesion to the extracellular matrix. Mol Cancer Res.
  • lymphatic dilation has been observed due to ultraviolet inflammation, and experiments with dye injection have revealed that lymphatic function is impaired. It is considered that lymphatic vessels are expanding and collecting interstitial fluid as water leaks into the dermis due to vasodilation.
  • Congenital lymphedema includes Milroy disease, Meige disease, and lymphedema-distichiasis syndrome. Milroy's disease has been reported to be aplastic and hypoplastic, while lymphedema-distichiasis syndrome has been reported to be hyperplastic. 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 11: Experimental Medicine Vol. 24, No. 18 (2006), pp. 139-143).
  • the object of the present invention is to provide a novel Tie2 activator, and in turn to maintain and enhance the recovery function of the lymphatic vessel by stabilizing the vascular maturation, normalization, stabilizing agent and lymphatic vessel To provide an effective medicine to do.
  • a Tie2 activator comprising one or a plurality of compounds selected from the group consisting of eleuteroside E, eleuteroside E1, sesamin, eudesmin, silvathesmin, pinoresinol, Yangan bin, forcytinol, and coumarin.
  • a lymphatic stabilizer comprising one or more compounds selected from the group consisting of eleuteroside E, eleuteroside E1, sesamin, eudesmin, silvathesmin, pinoresinol, yangambin, forcytinol and coumarin.
  • a swelling improving / preventing agent comprising the lymphatic vessel stabilizer of (5).
  • a cosmetic method for improving or preventing swelling, comprising applying a lymphatic vessel stabilizer of (5) to a subject.
  • a method for maturation, normalization, or stabilization of blood vessels wherein a subject in need of maturation, normalization, or stabilization of blood vessels is treated with eleuteroside E, eleuteroside E1, sesamin, eudesmin, silvathesmin, pinoresinol Applying a Tie2 activator consisting of one or more compounds selected from the group consisting of: Yanggambin, forcitinol and coumarin.
  • Tie2 Activator in one aspect, relates to Tie2 activity comprising one or more compounds selected from the group consisting of eleuteroside E, eleuteroside E1, sesamin, eudesmin, silvathesmin, pinoresinol, yangambin, forcytinol and coumarin. Providing an agent.
  • Eleuteroside E, eleuteroside E1, sesamin, eudesmin, silvathesmin, pinoresinol, yangambin, forcytinol are components contained in cereal and sesame seed lipids, and are known to have antioxidative and cholesterol lowering effects.
  • the chemical structural formulas of eleuteroside E, eleuteroside E1, sesamin, eudesmin, silvathesmin, pinoresinol, yangambin and forcytinol are shown below.
  • Coumarin is well known as an aromatic compound derived from legumes and cereals.
  • the chemical structural formula of coumarin is shown below. All of these compounds are known to have effects such as Tie2 activation, vascular maturation, normalization or stabilization associated with Tie2 activation, or lymphatic vessel stabilization, as well as improvement of wrinkles and swelling. It is not done.
  • the compound may be optically pure or a mixture of optical isomers.
  • the compound 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.
  • Activating Tie2 refers to the ability to convert Tie2 into its active form (phosphorylated Tie2) by phosphorylating it.
  • phosphorylated Tie2 As an activator of Tie2, angiopoietin 1 (Ang-1) has been known to activate Tie2.
  • Eleuteroside E, eleuteroside E1, sesamin, eudesmin, silvathesmin, pinoresinol, yangambin, forcytinol and coumarin can be used alone or in combination as a Tie2 activator. Moreover, since Tie2 activation action is shown in a concentration-dependent manner, the compounding amounts of eleuteroside E, eleuteroside E1, sesamin, eudesmin, silvathesmin, pinoresinol, yangambin, forcytinol and coumarin are included in the total amount of the composition formulated as an agent. 0.1 ppM to 100 mM, preferably 1 ppM to 100 mM, 10 ppM to 10 mM.
  • the present invention relates to one or more selected from the group consisting of eleuteroside E, eleuteroside E1, sesamin, eudesmin, silvathesmin, pinoresinol, yangambin, forcytinol and coumarin.
  • a vascular maturation, normalization or stabilization agent comprising a plurality of compounds is provided.
  • the vascular maturation, normalization or stabilization agent according to the present invention can be used as a pharmaceutical or cosmetic effective for prevention and improvement of various diseases and aging caused by vascular structural changes.
  • the vascular maturation, normalization or stabilization agent of the present invention induces normalization and stabilization of blood vessels, thereby causing various inflammatory diseases, immune diseases, adult diseases, etc., for example, various infectious diseases. It can be used as a drug for improving lesions throughout the body accompanied by neovascularization or vascular rupture in rheumatoid arthritis, gout, hypertension, diabetes, arteriosclerosis, atopic dermatitis, etc.
  • vascular permeability in organs, organs and various tissues including the skin, such as inflammatory and immune diseases, vascular edema due to adult diseases, UV exposure, insect bites, allergies, etc. It can be used as a pharmaceutical or cosmetic to improve symptoms such as edema and itching caused by hypersensitivity.
  • the vascular maturation, normalization, or stabilizing agent of the present invention promotes wound healing, such as trauma or itch, by vascular maturation or enlargement of the vascular cavity, vascular maturation in revascularization medicine, ischemic
  • It can be used in pharmaceuticals as an ameliorating agent for diseases such as cerebral infarction and myocardial infarction, and can also be used as an internal medicine and external medicine for low back pain, frostbite, alopecia, etc. by utilizing the effect of improving blood flow.
  • application to dementia is also possible.
  • It can also be used as a cosmetic for alopecia.
  • cancer it can be used as a therapeutic agent for inducing dormancy of cancer cells, and in stem cells as a maintenance agent in vivo and in vivo.
  • photoaging is rough skin, wrinkle formation, spot coloration, soil coloration, sagging formation, onset of telangiectasia, development of mole, onset of purpura, vulnerable, atrophy, fibrosis It can be specified as the occurrence of a pigment removal region, the development of a pre-malignant tumor, a malignant tumor, and the like.
  • Photoaging usually occurs in skin that is habitually exposed to sunlight, such as the face, ears, head, neck, and hands.
  • photoaging due to skin damage or exposure to ultraviolet rays is the main cause, but this Tie2 phosphorylating agent can be used to improve photoaging by suppressing vascular damage that causes photoaging.
  • 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 irradiation, filaria, surgery, malignancy, inflammation, and congenital lymphedema, such as Milroy disease, Meige disease, and lymphedema-distichiasis syndrome.
  • the dose, usage, and dosage form of the Tie2 activator, vascular maturation, normalization or stabilization agent, and lymphatic vessel stabilizer according to the present invention can be appropriately determined according to the intended use.
  • the administration form of the vascular maturation, normalization or stabilizer and lymphatic vessel stabilizer of the present invention is not particularly limited, and may be oral, parenteral, external, etc., but preferably external It is an agent.
  • Examples of 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 extracts and syrups can be mentioned, and can also be blended in foods such as tablets, drinks and cookies.
  • 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 extracts and syrups can be mentioned, and can also be blended in foods such as tablets, drinks and cookies.
  • the compounding amount of one or more kinds of compounds can be appropriately determined according to the use, but is generally 0.1 ppM to 100 mM, preferably 1 ppM to 100 mM, 10 ppM to 10 mM in the total amount of the composition to be compounded.
  • vascular maturation, normalization or stabilization agent and lymphatic vessel stabilization agent of the present invention may be selected from the group consisting of eleuteroside E, eleuteroside E1, sesamin, eudesmin, silvathesmin, pinoresinol, yanganbin, forcytinol and coumarin.
  • excipients for example, excipients, moisture-proofing agents, preservatives, strengthening agents, thickeners, emulsifiers, antioxidants, sweeteners, acidity used in normal foods and pharmaceuticals
  • Whitening agent moisturizer, oily component, ultraviolet absorber, surfactant, thickener, alcohols, powder component, colorant, aqueous component, which are usually used in cosmetics, seasonings, colorants, fragrances, etc. Water, various skin nutrients, and the like can be appropriately blended as necessary.
  • disodium edetate trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, sequestering agents, caffeine, tannin, verapamil, tranexamic acid and its derivatives, licorice Extracts, hot water extract of glabrizine, karin fruit, various herbal medicines, drugs such as tocopherol acetate, glycyrrhizic acid and its derivatives or salts thereof, vitamin C, magnesium ascorbate phosphate, glucoside ascorbate, arbutin, kojic acid, etc.
  • Whitening agent glucose, fructose, mannose, , Sugars trehalose, retinoic acid, retinol, retinol acetate, can also be suitably incorporated, such as vitamin A such as retinol palmitate.
  • the amount of vascular maturation, normalization or stabilizer or lymphatic vessel stabilizer to be added to the external preparation for skin can be determined as appropriate, but generally 0.1ppM to the total amount of the composition to be added 100 mM, preferably 1 ppM to 100 mM, 10 ppM to 10 mM.
  • the present invention provides a cosmetic method for preventing and improving wrinkles, comprising applying a vascular maturation, normalization or stabilizing agent to a subject.
  • the cosmetic method according to the present invention can be applied to facial skin where fine lines are likely to be formed, particularly skin such as the corners of the eyes, the lower eyelid, or the mouth, but is not limited to these parts.
  • the present invention provides a cosmetic method for improving or preventing swelling, comprising applying a lymphatic vessel stabilizer to a subject.
  • the cosmetic method according to the present invention is intended to reduce or prevent 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.
  • Total protein the RC DC Protein Assay Kit (BIO-RAD, Hercules, CA) and quantified by and detected by Western blotting as follows. SDS-PAGE was performed on 7.5% acrylamide gel (NPU-7.5L, ATTO, Japan) with the same amount of total protein, and the expression of Tie2 and phosphorylated Tie2 protein was confirmed by antibody (Santa Cruz Biotechnology, Santa Cruz, The color was developed with ECL Kit. The results are shown in FIG.
  • Formulation Example of Tie2 Activator Formulation examples of tablets, soft capsules, granules, drinks, candy, and cookies containing the Tie2 activator according to the present invention are shown below. These formulation examples are listed for the purpose of illustration, and are not intended to limit the technical scope of the present invention.
  • Formulation Example 2 (tablet) (Composition) Formulation amount (mg / tablet) Sucrose ester 70 Crystalline cellulose 74 Methylcellulose 36 Glycerin 25 Tie2 activator of the present invention 475 N-acetylglucosamine 200 Hyaluronic acid 150 Vitamin E 30 Vitamin B6 20 Vitamin B2 10 ⁇ -Lipoic acid 20 Coenzyme Q10 40 Ceramide (konjac extract) 50 L-proline 300 1500
  • Formulation Example 4 (soft capsule) (Composition) Blending amount (mg / 1 capsule) Brown rice germ oil 659 Tie2 activator of the present invention 500 Resveratrol 1 Lotus germ extract 100 Elastin 180 DNA 30 Folic acid 30 1500
  • Formulation Example 5 (granule) (Composition) Blending amount (mg / pack) Tie2 activator of the present invention 400 Vitamin C 100 Soy isoflavone 250 Reduced lactose 300 Soybean oligosaccharide 36 Erythritol 36 Dextrin 30 Fragrance 24 Citric acid 24 1200 Formulation Example 6 (Drink) (Composition) Compounding amount (in g / 60 mL) Eucommia extract 1.6 Carrot extract 1.6 Tie2 activator of the present invention 1.6 Reduced maltose starch syrup 28 Erythritol 8 Citric acid 2 Fragrance 1.3 N-acetylglucosamine 1 Hyaluronic acid Na 0.5 Vitamin E 0.3 Vitamin B6 0.2 Vitamin B2 0.1 ⁇ -Lipoic acid 0.2 Coenzyme Q10 1.2 Ceramide (konjac extract) 0.4 L-proline 2 Purified water residue 60
  • Formulation Example 7 (candy) (Composition) Compounding amount (% by weight) Sugar 50 Minamata 48 Tie2 activator of the present invention 1 Fragrance 1 100
  • Formulation Example 8 (Cookie) (Composition) Compounding amount (% by weight) Soft flour 45.0 Butter 17.5 Granulated sugar 20.0 Tie2 activator of the present invention 4.0 Egg 12.5 Fragrance 1.0 100.0

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Abstract

La présente invention concerne: un activateur de Tie-2 comportant un ou des type(s) de composés choisi(s) parmi un groupe constitué d'Éleuthéroside E, d'Éleuthéroside E1, de Sésamine, d'Eudesmine, de Sylvatesmin, de Pinorésinol, de Yangambine, de Forsythinol, et de Coumarine; un agent pour la maturation, la normalisation, ou la stabilisation des vaisseaux sanguins, un agent de stabilisation des vaisseaux lymphatique qui contient l'activateur ; un agent de prévention/d'amélioration des rides, et un agent d'amélioration/de prévention des œdèmes qui sont caractérisés en ce qu'ils sont une combinaison des agents.
PCT/JP2011/051245 2011-01-24 2011-01-24 Activateur de tie-2, agent pour la maturation, la normalisation, ou la stabilisation des vaisseaux sanguins, agent de stabilisation des vaisseaux lymphatiques, agent de prévention/d'amélioration des rides, et agent d'amélioration/de prévention des œdèmes WO2012101746A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103816172A (zh) * 2014-03-11 2014-05-28 苏州大学附属第二医院 刺五加苷e在制备治疗类风湿性关节炎药物中的应用
JPWO2020003363A1 (ja) * 2018-06-25 2021-06-24 学校法人近畿大学 ニコチン摂取の影響による血管の劣化を防止するための健康食品または医薬組成物

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