WO2012101741A1 - Activateur de tie-2, agent pour la maturation, la normalisation, ou la stabilisation de vaisseaux sanguins, agent de stabilisation des vaisseaux lymphatiques, agent de prévention/amélioration des rides, et agent d'amélioration/prévention de l'œdème. - Google Patents

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

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WO2012101741A1
WO2012101741A1 PCT/JP2011/051234 JP2011051234W WO2012101741A1 WO 2012101741 A1 WO2012101741 A1 WO 2012101741A1 JP 2011051234 W JP2011051234 W JP 2011051234W WO 2012101741 A1 WO2012101741 A1 WO 2012101741A1
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agent
extract
tie2
normalization
vascular
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PCT/JP2011/051234
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Japanese (ja)
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大田　正弘
智子 齋藤
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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
    • 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)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/483—Gleditsia (locust)
    • 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)
    • A61K36/42—Cucurbitaceae (Cucumber family)
    • A61K36/428—Trichosanthes
    • 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)
    • A61K36/74—Rubiaceae (Madder family)
    • A61K36/746—Morinda
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8969—Polygonatum (Solomon's seal)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9771—Ginkgophyta, e.g. Ginkgoaceae [Ginkgo family]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9794—Liliopsida [monocotyledons]
    • 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
    • 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
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations

Definitions

  • the present invention relates to a novel Tie2 (Tyrosine Kinase with Ig and EGF Homology Domain 2) activator (Tie2 phosphorylating agent), vascular maturation, normal, comprising extracts of hornworm, horsetail, goose, caronin and / or vulture.
  • Tie2 Teyrosine Kinase with Ig and EGF Homology Domain 2 activator
  • Tie2 phosphorylating agent Tie2 phosphorylating agent
  • vascular maturation normal, comprising extracts of hornworm, horsetail, goose, caronin and / or vulture.
  • 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
  • endothelial cells maintain their adhesion between endothelial cells and mural cells by Ang-1, -4, which is constantly secreted by mural cells, but when hypoxia occurs locally, Ang-1 , -4 antagonist Ang-2, -3 production is increased, Tie2 activation is temporarily suppressed, and adhesion between endothelial cells and wall cells lining it is suppressed. Endothelial cells proliferate by the dissociation of mural cells and initiate sprouting angiogenesis, leading to the formation of new vascular networks. Tie2 activation induces adhesion between endothelial cells and mural cells, thereby contributing to the stabilization of the vascular structure, and promotes adhesion between endothelial cells to control vascular permeability.
  • Non-patent Document 2 Cho CH, Kammerer RA, Lee HJ, Yasunaga K, Kim KT, Choi HH, Kim W , Kim SH, Park SK, Lee GM, Koh GY.
  • Designed angiopoietin-1 variant, COMP-Ang1 protects against radiation-induced endothelial cell apoptosis. Proc Natl Acad Sci U S A. 2004 A15 -8), with respect to environmental factors disrupting the vascular structures of various intracellular and extracellular, by inducing activation of Tie2, thereby suppressing the instability of the vessel, it is stabilized and normalize blood vessel Is possible.
  • Non-Patent Document 3 Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, McDonald DM.
  • Tie2 activation has been reported to enlarge the vascular lumen, and in ischemic diseases caused by vascular narrowing or suppression of vasodilation By activating Tie2, it is possible to enlarge the vascular cavity and improve the disease state.
  • Angptl Angiopoietin-like protein
  • Non-Patent Document 4 Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, Ito K, Koh GY, Suda T. Tie2 / angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004 Jul 23; 118 (2): 149-61).
  • 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.
  • the lymphatic vessels form 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.
  • lymphatic endothelial cells In mouse ears infected with adenovirus expressing VEGF-A, remarkable lymphangiogenesis was observed, but along with the structural abnormalities, lymphoid recovery function was also remarkable from experiments in which colloidal carbon was injected into the ear (Non-patent document 9: Nagy et al., (2002) Vascular permeability factor / vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196: 1497-1506). 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".
  • 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.
  • Non-Patent Document 10 Kajiya K., Hirakawa S., and Detmar M., (2006) VEGF -A mediates UVB-induced impairment of lymphatic vessel function. Am J Pathol 169: 1496-1503). That is, it is considered that “stabilization of lymphatic vessels” that does not induce excessive expansion of lymphatic vessels is necessary for rapid recovery of interstitial fluid.
  • 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.
  • the Tie2 activator according to (1) wherein the extract is an extract with one or more solvents selected from ethanol, methanol, 1,3-butylene glycol, and water.
  • a vascular maturation, normalization, or stabilization agent comprising an extract of hornbill, horsetail, gourd, caronin and / or vulture.
  • a wrinkle-preventing / improving agent comprising the blood vessel maturation, normalization or stabilization agent of (3).
  • a cosmetic method for preventing and improving wrinkles comprising applying to the subject the vascular maturation, normalization or stabilizing agent of (3).
  • a lymphatic vessel stabilizer comprising an extract of hornworm, horsetail, gyokuchi, caronine and / or vulture.
  • a swelling improving / preventing agent comprising the lymphatic vessel stabilizer of (6).
  • a cosmetic method for improving or preventing swelling, comprising applying the lymphatic vessel stabilizer of (6) to a subject.
  • Tie2 activator comprising extracts of seeds, horseshoe (Polygonatum sibiricum Red.), Gyokuchiku (Polygonatum officinalle), caroten [fruits and seeds of Trichosanthes kirilowii Maxim] and / or baleen tenn (Morinda officinalis How.) Applying the method.
  • (11) For maturation, normalization or stabilization of blood vessels, hornworm (Gleditsia sinensis Lam.
  • Tie2 activator consisting of an extract of crow uri (Trichosanthes kirilowii Maxim) and / or baleen chiten (Morinda officinalis How.).
  • the extract is an extract using one or more solvents selected from ethanol, methanol, 1,3-butylene glycol, and water.
  • extracts of hornworms, horseshoe, garlic, carotenine and / or vultures activate Tie2, whereby the blood vessels are matured, normalized or stabilized and / or the lymphatic vessels are stabilized, As a result, wrinkles and swelling are improved.
  • FIG. 3 is a western blot diagram showing phosphorylation of Tie2 in normal human umbilical vein endothelial cells (HUVEC) when a bald quit extract is added.
  • Tie2 Activator In one aspect, the present invention provides a Tie2 activator comprising an extract of Sowakushi, Gansei, Gokoku, Caronin and / or Vulture.
  • Sokakushi are the stems and seeds of legumes (Leguminosae) and pearl beetle (Gleditsia sinensis Lam.), And the extract is known for its effects such as antitumor, detoxification and drainage.
  • Horseshoe Polygonatum sibiricum Red. Is a plant belonging to the lily family ( ⁇ Liliaceae), and its extract is known for its effects such as nourishment, tonic blood pressure lowering and blood sugar lowering.
  • Gyokuchiku (Tamatake) (Polygonatum officinalle) is a plant belonging to Liliaceae, the extract is well known to have a tonic effect.
  • Caronin is a mature fruit and seed of Cucurbitaceae and Trichosanthes kirilowii Maximum, and its extract is known for its effects such as anti-inflammatory, antipyretic and analgesic.
  • Hagekiten Morinda officinalis How. Is a plant belonging to the Rubiaceae (Rubiaceae), is well known that it has a tonic effect. In the case of horsetail, gyakuchiku, and bald kid, whole grass may be used as the extraction site. None of these extracts 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. unknown.
  • the extract can be obtained by a conventional method, for example, by immersing or heated refluxing room temperature or with heating to together with a part or the whole extraction solvent of the plant to be its origin, filtered, it can be obtained by concentrating .
  • the extraction site Prior to solvent extraction, the extraction site may be dried.
  • the extraction solvent any solvent can be used as long as it is usually used for extraction.
  • organic solvents such as alcohols such as methanol, ethanol, propylene glycol, 1,3-butylene glycol and glycerin, hydrous alcohols , Chloroform, dichloroethane, carbon tetrachloride, acetone, ethyl acetate, hexane, or an aqueous solvent such as water, physiological saline, phosphate buffer, borate buffer, etc., either alone or in combination. it can.
  • one or more kinds selected from water, methanol, ethanol, and 1,3-butylene glycol are preferably 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
  • 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.
  • the extract itself can be used as a Tie2 activator.
  • the compounding amount of the extract of Sokukakushi, seisei, gyokuchiku, caronine and / or vulture in the Tie2 activator of the present invention is a composition formulated as an agent. In the total amount, it is 0.0001 to 20.0 mass%, preferably 0.0001 to 10.0 mass% as a dry product.
  • the present invention provides a vascular maturation, normalization or stabilization agent comprising an extract of hornworm, horsetail, goose, caronin and / or vulture. To do.
  • 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.
  • Tie2 phosphorylating agent is a cell death of endothelial cells induced by various factors, for example, inflammatory diseases, immune diseases, adult diseases, such as various infectious diseases, cancer, rheumatoid arthritis, gout, hypertension, It can be used as a pharmaceutical or a cosmetic that can suppress the destabilization of blood vessels by suppressing the death of endothelial cells due to diabetes, arteriosclerosis, radiation damage, various drugs or ultraviolet rays.
  • 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.
  • UVB ultraviolet rays
  • UVB intermediate UV
  • the amount of UVB exposure necessary to cause photoaging is currently unknown.
  • repeated exposure to UVB at levels that cause erythema and sunburn usually leads to photoaging.
  • 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.
  • Lymphatic vessel stabilizing agent in another aspect, provides a lymphatic vessel stabilizing agent comprising an extract of horn beetle, horsetail, gyle, caronin and / or vulture.
  • 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 Agent, food.
  • 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 blending amount of the extract of mokukaku, seisei, kakutoku, caronin and / or vulture in the vascular maturation, normalization or stabilizing agent and lymphatic vessel stabilizer of the present invention can be appropriately determined according to the use, Generally, it is 0.0001 to 20.0% by mass, preferably 0.0001 to 10.0% by mass, as the dry residue of the plant extract in the total amount of the agent.
  • the blood vessel maturation, normalization or stabilization agent and lymphatic vessel stabilization agent of the present invention include, for example, ordinary foods and pharmaceuticals, in addition to the extract of kokushikushi, seisei, kakutiku, caronin and / or vulture.
  • Excipients used moisture-proofing agents, preservatives, reinforcing agents, thickeners, emulsifiers, antioxidants, sweeteners, sour agents, seasonings, coloring agents, fragrances, etc., whitening agents usually used in cosmetics,
  • a humectant, an oil component, an ultraviolet absorber, a surfactant, a thickener, an alcohol, a powder component, a colorant, an aqueous component, water, various skin nutrients, and the like can be appropriately blended as necessary.
  • vascular maturation, normalization or stabilization agent or lymphatic vessel stabilization agent of the present invention is used as a skin external preparation such as a wrinkle prevention / amelioration agent or swelling improvement / prevention agent, Conventional auxiliaries, e.g.
  • 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 blended in the external preparation for skin can be determined as appropriate, but generally 0% as a dry product in the total amount of the blended composition. It is 0.0001 to 20.0 mass%, preferably 0.0001 to 10.0 mass%.
  • 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.
  • gyokuchi extract 11.0 g and 13.1 g of dried gyokuchi were added to methanol (100%) and hot water 80 ml (90 ° C.) for 1 week at room temperature, respectively. Subsequently, methanol or water was distilled off from the extract obtained by filtration with filter paper, and 1.82 g (yield 17%) of methanol extract and 8.04 g (yield 61%) of hot water extract were obtained from each.
  • 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 1 (tablet) (Composition) Formulation amount (mg / tablet) Tie2 activator of the present invention (as dry residue of plant extract) 360.5 Lactose 102.4 Carboxymethylcellulose calcium 29.9 Hydroxypropylcellulose 6.8 Magnesium stearate 5.2 Crystalline cellulose 10.2 515.0
  • 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 (as dry residue of plant extract) 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 3 soft capsule) (Composition) Blending amount (mg / 1 capsule) Edible soybean oil 530 Eucommia extract 50 Carrot extract 50 Tie2 activator of the present invention (as dry residue of plant extract) 100 Royal Jelly 50 Maca 30 GABA 30 Beeslow 60 Gelatin 375 Glycerin 120 Glycerin fatty acid ester 105 1500
  • Formulation Example 4 soft capsule) (Composition) Blending amount (mg / 1 capsule) Brown rice germ oil 659 Tie2 activator of the present invention (as dry residue of plant extract) 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 (as dry residue of plant extract) 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 (as dry residue of plant extract) 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 (as dry residue of plant extract) 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 (as dry residue of plant extract) 4.0 Egg 12.5 Fragrance 1.0 100.0

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Abstract

La présente invention concerne : un activateur de TIE-2 comprenant les extraits de tige, branche ou graine de sokakushi (Gleditsia sinensis Lam.), rhizome de polygonatum (Polygonatum sibiricum Red.), sceau de Salomon (Polygonatum officinalle), fruit ou graine de Trichosanthes (Trichosanthes kirilowii Maxim), et/ou de pomme-chien (Morinda officinalis How.) ; un agent pour la maturation, la normalisation, ou la stabilisation de vaisseaux sanguins et un agent de stabilisation des vaisseaux lymphatiques ; et un agent de prévention/amélioration des rides et un agent d'amélioration/prévention de l'œdème qui sont caractérisés en ce qu'ils sont une combinaison de l'activateur et d'agents.
PCT/JP2011/051234 2011-01-24 2011-01-24 Activateur de tie-2, agent pour la maturation, la normalisation, ou la stabilisation de vaisseaux sanguins, agent de stabilisation des vaisseaux lymphatiques, agent de prévention/amélioration des rides, et agent d'amélioration/prévention de l'œdème. WO2012101741A1 (fr)

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PCT/JP2011/051234 WO2012101741A1 (fr) 2011-01-24 2011-01-24 Activateur de tie-2, agent pour la maturation, la normalisation, ou la stabilisation de vaisseaux sanguins, agent de stabilisation des vaisseaux lymphatiques, agent de prévention/amélioration des rides, et agent d'amélioration/prévention de l'œdème.

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CN102935133A (zh) * 2012-12-08 2013-02-20 南京正宽医药科技有限公司 一种用于治疗风湿性关节炎的中药组合物及其制备方法和应用
CN103301246A (zh) * 2013-06-20 2013-09-18 史凤娥 一种治疗风寒湿腰痛的药物及其制备方法
CN103432279A (zh) * 2013-08-07 2013-12-11 许春桂 一种利用药渣制备防治痛风泡洗剂的方法及制品
CN103549652A (zh) * 2013-11-20 2014-02-05 红塔烟草(集团)有限责任公司 一种复合烟用添加剂及制备方法和应用
JP2014097977A (ja) * 2012-10-17 2014-05-29 Maruzen Pharmaceut Co Ltd 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
CN105924540A (zh) * 2016-07-11 2016-09-07 福建农林大学 一种同步提取巴戟天中蒽醌和多糖的方法
CN110622649A (zh) * 2019-11-01 2019-12-31 雅安三九中药材科技产业化有限公司 浸种液、浸种方法、育苗方法和瓜蒌的种植方法
CN111317691A (zh) * 2020-02-12 2020-06-23 南京中医药大学 一种具有美白效果的栝楼果瓤总黄色素及其制备方法与应用

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Publication number Priority date Publication date Assignee Title
JP2014097977A (ja) * 2012-10-17 2014-05-29 Maruzen Pharmaceut Co Ltd 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
CN102935133A (zh) * 2012-12-08 2013-02-20 南京正宽医药科技有限公司 一种用于治疗风湿性关节炎的中药组合物及其制备方法和应用
CN103301246A (zh) * 2013-06-20 2013-09-18 史凤娥 一种治疗风寒湿腰痛的药物及其制备方法
CN103432279A (zh) * 2013-08-07 2013-12-11 许春桂 一种利用药渣制备防治痛风泡洗剂的方法及制品
CN103549652A (zh) * 2013-11-20 2014-02-05 红塔烟草(集团)有限责任公司 一种复合烟用添加剂及制备方法和应用
CN105924540A (zh) * 2016-07-11 2016-09-07 福建农林大学 一种同步提取巴戟天中蒽醌和多糖的方法
CN110622649A (zh) * 2019-11-01 2019-12-31 雅安三九中药材科技产业化有限公司 浸种液、浸种方法、育苗方法和瓜蒌的种植方法
CN111317691A (zh) * 2020-02-12 2020-06-23 南京中医药大学 一种具有美白效果的栝楼果瓤总黄色素及其制备方法与应用

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