JP6448754B2 - Tie2 activator, blood vessel maturation agent, blood vessel stabilizer, and food and drink - Google Patents

Description

  The present invention relates to a Tie2 activator, an angiogenesis inhibitor, a blood vessel maturation agent, a blood vessel normalizing agent, a blood vessel stabilizer, and food and drink.

  A blood vessel has a structure in which vascular endothelial cells and vascular wall cells (vascular smooth muscle cells and perisite) adhere indirectly or directly via an extracellular matrix, and oxygen and nutrients are absorbed by living bodies. It has a function of supplying waste tissue and removing waste from living tissue.

  In general, the formation of blood vessels consists of vasculogenesis where new blood vessels are formed, and angiogenesis where new blood vessels are formed by the elongation and branching of existing blood vessels. And divided into two stages. In the former, vascular endothelial growth factor (VEGF) acts and is involved in a very wide range of angiogenesis from the initial development of blood vessels called angiogenesis to the subsequent angiogenesis, and the latter is angiopoietin. (Ang) acts and participates in the control of adhesion between vascular endothelial cells and vascular wall cells and the structural stabilization of blood vessels.

  Under normal oxygen conditions, blood vessel endothelial cells and blood vessel wall cells that line the periphery of blood vessels are firmly adhered to each other, and the blood vessel structure is kept stable. Cells can detach from vascular endothelial cells and proliferate disordered blood vessels. Such a phenomenon (angiogenesis) is often observed in diseases mainly composed of vascular lesions such as tumors, rheumatoid arthritis, diabetic retinopathy, hyperlipidemia, and hypertension.

  It is known that these angiogenesis are suppressed by activating a receptor tyrosine kinase Tie2 (Tyrosine kinase with Ig and EGF homology domain 2) expressed in vascular endothelial cells (see, for example, Patent Document 1). ). In an ischemic disease caused by suppression of blood vessel narrowing or blood vessel enlargement, it has been reported that the blood vessel cavity is enlarged by activation of Tie2 (see, for example, Non-Patent Document 1). It has also been reported that the activation of Tie2 suppresses cell death of vascular endothelial cells (see, for example, Non-Patent Document 2).

Thus, it is known that the activation of Tie2 not only suppresses angiogenesis but also matures, normalizes, and stabilizes blood vessels.
For example, in vascular regenerative medicine, it is known that the activation of Tie2 induces adhesion between vascular endothelial cells and vascular wall cells in a blood vessel to mature the blood vessel.
For example, in diseases where vascular wall cells observed in tumors, diabetic retinopathy, etc. do not adhere to vascular endothelial cells, disordered blood vessels grow. By activation of Tie2, vascular wall cells become endothelial cells. It is known to adhere and normalize blood vessels.
For example, with respect to environmental factors that disrupt various intracellular and external vascular structures, activation of Tie2 is known to suppress vascular destabilization and stabilize blood vessels.

  As a naturally occurring substance that suppresses angiogenesis by activation of Tie2, cinnamon extract is known (for example, see Patent Document 1), but there is a problem that the activity is insufficient. Moreover, although suramin is known as a substance which suppresses angiogenesis (for example, refer patent document 2), there exists a problem that it is not excellent in safety.

  Accordingly, there is a strong demand for rapid development of highly safe substances having excellent Tie2 activation action, angiogenesis inhibition action, blood vessel maturation action, blood vessel normalization action, and blood vessel stabilization action. is the current situation.

JP 2009-263358 A JP-T 9-503488

Science. 1999. Dec. 24; 286 (5449): 2511-4. P. N. A. S. 2004. Apr. 13; 101 (15): 5553-8.

  An object of the present invention is to solve the conventional problems and achieve the following objects. That is, an object of the present invention is to provide a Tie2 activator having an excellent Tie2 activation action and high safety. Another object of the present invention is to provide a highly safe angiogenesis inhibitor having an excellent angiogenesis inhibitory action. Another object of the present invention is to provide a highly safe vascular maturation agent having an excellent vascular maturation action. Another object of the present invention is to provide a blood vessel normalizing agent having a blood vessel normalizing action and high safety. Another object of the present invention is to provide a highly safe blood vessel stabilizer having a blood vessel stabilizing action. In addition, the present invention has an excellent Tie2 activation action, angiogenesis inhibition action, vascular maturation action, vascular normalization action, and vascular stabilization action, and is highly safe. The purpose is to provide food and drink.

  As a result of intensive studies by the inventor in order to solve the above-mentioned problems, the following extract has excellent Tie2 activation action, angiogenesis inhibition action, blood vessel maturation action, blood vessel normalization action, and blood vessel stabilization. The present invention has been completed by finding that it has an action.

This invention is based on the said knowledge by this inventor, and as a means for solving the said subject, it is as follows. That is,
<1> At least one of Kiraya extract, twilight extract, ginkgo extract, oyster extract, turmeric extract, chrysanthemum extract, jujube extract, wolfberry extract, chamomile extract, and butcher bloom extract It is a Tie2 activator characterized by containing an extract as an active ingredient.
<2> At least one of Kiraya extract, twilight extract, ginkgo extract, oyster extract, turmeric extract, chrysanthemum extract, jujube extract, wolfberry extract, chamomile extract, and butcher bloom extract An angiogenesis inhibitor characterized by containing an extract as an active ingredient.
<3> At least one of Kiraya extract, twilight extract, ginkgo extract, oyster extract, turmeric extract, chrysanthemum extract, jujube extract, wolfberry extract, chamomile extract, and butcher bloom extract A vascular maturation agent, vascular normalization agent, or vascular stabilization agent characterized by containing an extract as an active ingredient.
<4> The Tie2 activator according to <1>, the angiogenesis inhibitor according to <2>, the vascular maturation agent, the blood vessel normalizing agent or the blood vessel stabilization according to <3> A pharmaceutical composition containing at least one of the agents.

According to the Tie2 activator of the present invention, it is possible to solve the conventional problems and to provide a highly safe Tie2 activator having an excellent Tie2 activation action.
According to the angiogenesis inhibitor of the present invention, the conventional problems can be solved, and an angiogenesis inhibitor having an excellent angiogenesis inhibitory action and high safety can be provided.
According to the blood vessel maturation agent, blood vessel normalization agent, and blood vessel stabilization agent of the present invention, the conventional problems are solved, and an excellent blood vessel maturation action, blood vessel normalization action, and blood vessel It is possible to provide a vascular maturation agent, a vascular normalization agent, and a vascular stabilization agent having a stabilizing action and high safety.
According to the food and drink of the present invention, the conventional problems are solved, and at least any of the excellent Tie2 activation action, angiogenesis inhibition action, blood vessel maturation action, blood vessel normalization action, and blood vessel stabilization action Therefore, it is possible to provide a highly safe food and drink.

(Tie2 activator, angiogenesis inhibitor, blood vessel maturation agent, blood vessel normalizing agent, blood vessel stabilizer, and food and drink)
Tie2 activator, angiogenesis inhibitor, blood vessel maturation agent, blood vessel normalizing agent, blood vessel stabilizer, and pharmaceutical composition of the present invention are Kiraya extract, jaundice extract, ginkgo extract , Oyster extract, turmeric extract, chrysanthemum extract, jujube extract, wolfberry extract, chamomile extract, and butcher bloom extract as an active ingredient, and other if necessary It contains.

  The Tie2 activator has a Tie2 activating action of phosphorylating Tie2 to convert it into its active form (phosphorylated Tie2). When Tie2 is activated, it induces autophosphorylation of intracellular tyrosine kinase domain and induces adhesion between vascular endothelial cells and vascular wall cells. In an ischemic disease caused by suppression of vascular narrowing or vasodilation, the vascular cavity is expanded by activation of Tie2. In addition, activation of Tie2 suppresses cell death of vascular endothelial cells.

  The angiogenesis inhibitor has an angiogenesis inhibitory action that suppresses a network of new blood vessels formed from existing blood vessels. In the hypoxic state, the activation of Tie2 is temporarily suppressed, the adhesion between the vascular endothelial cell and the vascular wall cell is dissociated, and a new blood vessel network is formed from the vascular endothelial cell from which the adhesion is dissociated. An angiogenesis inhibitor can suppress the disordered growth of blood vessels caused by the adhesion of such vascular wall cells to endothelial cells.

  The vascular maturation agent induces adhesion between vascular endothelial cells and vascular wall cells, and between vascular endothelial cells such that intravascular environmental factors (cells and humoral factors) do not easily leak out of the blood vessel. It has a maturation effect to form adhesion spots. In vascular regenerative medicine, activation of Tie2 can induce adhesion between vascular endothelial cells and vascular wall cells in the blood vessel, thereby allowing the blood vessel to mature.

  The blood vessel normalizing agent increases the adhesion between vascular endothelial cells and promotes the lining of the vascular wall cells to the vascular endothelial cells, thereby leading to disordered growth of blood vessels and blood vessels in which vascular permeability is broken. It has a normalizing action to make abnormal blood vessels normal. Also, in diseases where vascular wall cells observed in tumors, diabetic retinopathy, etc. do not adhere to vascular endothelial cells and proliferate disordered blood vessels, Tie2 activation activates vascular wall cells to become endothelial cells. It is possible to adhere and normalize the blood vessels.

  The above-mentioned blood vessel stabilizer has an action to suppress damage to existing blood vessels, dissociation between vascular endothelial cells, and dissociation between vascular endothelial cells and vascular wall cells, and a stabilizing effect to suppress cell death of vascular endothelial cells. Have. In addition, with respect to environmental factors that break down various vascular structures inside and outside cells, activation of Tie2 can suppress vascular instability and stabilize blood vessels.

  The pharmaceutical composition is a composition comprising at least one of the Tie2 activator, the angiogenesis inhibitor, the vascular maturation agent, the vascular normalization agent, and the vascular stabilization agent, It has at least one of Tie2 activation action, angiogenesis inhibitory action, vascular maturation action, vascular normalization action, and vascular stabilization action.

<Quillaja extract>
The quilla is an evergreen small tree belonging to the genus Kiraya of the Rosaceae family, and its scientific name is Quillaja saponaria . Kiraya is native to the Chile, Bolivia, and Peru regions of South America and is readily available from these regions. The bark contains tannins and triterpene saponins. Quillaja saponin (Quillaja saponin) is known to have superior surface activity and homogeneity compared to saponins obtained from other plants, solubilizing food emulsifiers, vitamin E, flavors, It is also widely used in industrial fields such as toothpaste and beverage foaming agents, toiletry products, and photographic films.

The extraction part of the quilla is not particularly limited and may be appropriately selected depending on the purpose.For example, a leaf part, a branch part, a trunk part, a bark part, a flower part, a fruit part, a root part, and the like may be mentioned. Among these, a bark part is preferable.
As a method for preparing the extraction part of the kiraya, it can be obtained by drying each part and then pulverizing it as it is or using a crusher and subjecting it to solvent extraction. The drying may be performed in the sun, or may be performed using a commonly used dryer.

  The Quillaja extract can be easily obtained by a method generally used for plant extraction. There is no restriction | limiting in particular as said quilla extract, According to the objective, it can select suitably, For example, the dilution liquid of an extract, a concentrate, the dried product of an extract, etc. are mentioned.

  The extraction method of the kiraya is not particularly limited and may be appropriately selected depending on the purpose. For example, the extraction portion of the kiraya that is an extraction raw material is put into a treatment tank filled with an extraction solvent, and necessary. Accordingly, there may be mentioned a method of obtaining an extract by eluting soluble components while stirring appropriately and then filtering to remove the extraction residue.

  There are no particular limitations on the extraction conditions (extraction time and extraction temperature) of the kiraya and the amount of the extraction solvent used for the kiraya, which can be appropriately selected according to the purpose.

  There is no restriction | limiting in particular as an extraction solvent of the said kiraya, According to the objective, it can select suitably, For example, water, a hydrophilic solvent, or these mixed solvents are mentioned. The water is not particularly limited and may be appropriately selected according to the purpose.For example, pure water, tap water, well water, mineral spring water, mineral water, hot spring water, spring water, fresh water, purified water, hot water, Examples include ion-exchanged water, physiological saline, phosphate buffer, and phosphate buffered saline. There is no restriction | limiting in particular as said hydrophilic solvent, According to the objective, it can select suitably, For example, C1-C5 lower alcohols, such as methanol, ethanol, propyl alcohol, isopropyl alcohol; Acetone, methyl ethyl ketone, etc. Lower aliphatic ketones; C2-C5 polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin. There is no restriction | limiting in particular as said mixed solvent, Although it can select suitably according to the objective, When using a lower alcohol, 1 mass part-90 mass parts with respect to 10 mass parts of water, a lower aliphatic ketone. 1 to 40 parts by mass with respect to 10 parts by mass of water, and when using polyhydric alcohol, 1 to 90 parts by mass with respect to 10 parts by mass of water is preferably added. . Further, it is preferable that the extraction solvent for Kiraya is used at a temperature from room temperature to the boiling point of the solvent. Among these, it is preferable to extract using hot water.

  There is no restriction | limiting in particular as a refinement | purification method of the said Quillaja extract, According to the objective, it can select suitably, For example, purification methods, such as liquid-liquid partition extraction, various chromatography, and membrane separation, are mentioned.

  There is no restriction | limiting in particular as a density | concentration of the said quilla extract, Although it can select suitably according to the objective, 6.25 microgram / mL-12.5 microgram / mL are preferable.

<Twilight extract>
The jaundice is an evergreen tree belonging to the genus Jatrophaceae, and its scientific name is Engelhardtia chrysolepis . The jaundice grows naturally in areas in southern China and is readily available from these areas. The twilight leaves have a weak sweet taste and have been drunk for the purpose of antipyretic, reduced obesity, detoxification and the like.

The extraction site of the jaundice is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include leaves, branches, trunks, barks, flowers, fruits, and roots. Of these, the leaves are preferred.
As a method for preparing the extraction site of jaundice, it can be obtained by drying each site and then pulverizing it as it is or using a crusher and subjecting it to solvent extraction. The drying may be performed in the sun, or may be performed using a commonly used dryer.

  The jaundice extract can be easily obtained by a method generally used for plant extraction. There is no restriction | limiting in particular as said jaundice extract, According to the objective, it can select suitably, For example, the dilution liquid of an extract, a concentrated liquid, the dried product of an extract, etc. are mentioned.

  The method for extracting jaundice is not particularly limited and can be appropriately selected according to the purpose.For example, the extraction site of the jaundice that is an extraction raw material is put into a treatment tank filled with an extraction solvent, Examples include a method of obtaining an extract by eluting soluble components while appropriately stirring as necessary and then filtering to remove the extraction residue.

  The extraction conditions (extraction time and extraction temperature) of the jaundice and the amount of the extraction solvent used for the jaundice are not particularly limited and can be appropriately selected according to the purpose.

  The extraction solvent for jaundice is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include water, a hydrophilic solvent, and a mixed solvent thereof. The water is not particularly limited and may be appropriately selected according to the purpose.For example, pure water, tap water, well water, mineral spring water, mineral water, hot spring water, spring water, fresh water, purified water, hot water, Examples include ion-exchanged water, physiological saline, phosphate buffer, and phosphate buffered saline. There is no restriction | limiting in particular as said hydrophilic solvent, According to the objective, it can select suitably, For example, C1-C5 lower alcohols, such as methanol, ethanol, propyl alcohol, isopropyl alcohol; Acetone, methyl ethyl ketone, etc. Lower aliphatic ketones; C2-C5 polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin. There is no restriction | limiting in particular as said mixed solvent, Although it can select suitably according to the objective, When using a lower alcohol, 1 mass part-90 mass parts with respect to 10 mass parts of water, a lower aliphatic ketone. 1 to 40 parts by mass with respect to 10 parts by mass of water, and when using polyhydric alcohol, 1 to 90 parts by mass with respect to 10 parts by mass of water is preferably added. . Further, the jaundice extraction solvent is preferably used at a temperature between room temperature and the boiling point of the solvent. Among these, it is preferable to extract using hot water.

  There is no restriction | limiting in particular as a purification method of the said jaundice extract, According to the objective, it can select suitably, For example, purification methods, such as liquid-liquid partition extraction, various chromatography, and membrane separation, are mentioned.

  There is no restriction | limiting in particular as a density | concentration of the said jaundice extract, Although it can select suitably according to the objective, 200 microgram / mL-400 microgram / mL are preferable.

<Ginkgo extract>
The ginkgo is a deciduous tree of the genus Ginkgo genus, and its scientific name is Ginkgo biloba . The ginkgo is distributed around the world by artificial transplantation and is easily available from these regions. The height of the stem of the ginkgo is 20 to 30 m, which is a kind of gymnosperm. The ginkgo ingredients include gingolide, flavonoids, etc., and are blended as health foods.

The extraction part of the ginkgo is not particularly limited and can be appropriately selected according to the purpose.For example, a leaf part, a branch part, a trunk part, a bark part, a flower part, a fruit part, a root part, and the like can be mentioned. Among these, a leaf part is preferable.
As a method for preparing the extraction part of the ginkgo, it can be obtained by drying each part and then pulverizing it as it is or using a crusher and subjecting it to solvent extraction. The drying may be performed in the sun, or may be performed using a commonly used dryer.

  The ginkgo extract can be easily obtained by a method generally used for plant extraction. There is no restriction | limiting in particular as said Ginkgo extract, According to the objective, it can select suitably, For example, the diluted solution of an extract, a concentrated liquid, the dried product of an extract, etc. are mentioned.

  The extraction method of the ginkgo is not particularly limited and can be appropriately selected according to the purpose. For example, the extraction site of the ginkgo as an extraction raw material is put into a treatment tank filled with an extraction solvent, and necessary. Accordingly, there may be mentioned a method of obtaining an extract by eluting soluble components while stirring appropriately and then filtering to remove the extraction residue.

  The extraction conditions (extraction time and extraction temperature) of the ginkgo and the amount of the extraction solvent used for the ginkgo are not particularly limited and can be appropriately selected depending on the purpose.

  There is no restriction | limiting in particular as an extraction solvent of the said ginkgo, According to the objective, it can select suitably, For example, water, a hydrophilic solvent, or these mixed solvents are mentioned. The water is not particularly limited and may be appropriately selected according to the purpose.For example, pure water, tap water, well water, mineral spring water, mineral water, hot spring water, spring water, fresh water, purified water, hot water, Examples include ion-exchanged water, physiological saline, phosphate buffer, and phosphate buffered saline. There is no restriction | limiting in particular as said hydrophilic solvent, According to the objective, it can select suitably, For example, C1-C5 lower alcohols, such as methanol, ethanol, propyl alcohol, isopropyl alcohol; Acetone, methyl ethyl ketone, etc. Lower aliphatic ketones; C2-C5 polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin. There is no restriction | limiting in particular as said mixed solvent, Although it can select suitably according to the objective, When using a lower alcohol, 1 mass part-90 mass parts with respect to 10 mass parts of water, a lower aliphatic ketone. 1 to 40 parts by mass with respect to 10 parts by mass of water, and when using polyhydric alcohol, 1 to 90 parts by mass with respect to 10 parts by mass of water is preferably added. . The ginkgo extraction solvent is preferably used at a temperature between room temperature and the boiling point of the solvent. Among these, it is preferable to extract using hot water.

  There is no restriction | limiting in particular as a purification method of the said ginkgo extract, According to the objective, it can select suitably, For example, purification methods, such as liquid-liquid partition extraction, various chromatography, and membrane separation, are mentioned.

  There is no restriction | limiting in particular as a density | concentration of the said ginkgo extract, Although it can select suitably according to the objective, 100 microgram / mL-200 microgram / mL are preferable.

<Oyster extract>
The oyster is a collective term for bivalves belonging to the order of the mussel family. The oysters are collected from Hiroshima Prefecture, but can be easily obtained from coastal regions around the world. The oysters contain a lot of high-quality proteins, taurine, glycogen, zinc and minerals, and have been widely used as a raw material for traditional Chinese medicine.

  The oyster extract can be easily obtained by a method generally used for oyster extraction. There is no restriction | limiting in particular as an extract of the said oyster, According to the objective, it can select suitably, For example, the diluted solution of an extract, a concentrate, the dried product of an extract, etc. are mentioned.

  There is no restriction | limiting in particular as the extraction method of the said oyster, According to the objective, it can select suitably, For example, (1) The refrigerated raw oyster and the frozen oyster are prepared to an extraction can, and hot water of 80 to 100 degreeC is added. (2) The oyster hot water extraction residue is charged into a reaction kettle equipped with a stirring blade and subjected to protease enzymatic decomposition at 30 ° C to 50 ° C. And a method obtained by heating at 90 ° C., deactivation, clarification and filtration, and concentration under reduced pressure.

  There is no restriction | limiting in particular as an extraction solvent of the said oyster, According to the objective, it can select suitably, For example, water, a hydrophilic solvent, or these mixed solvents are mentioned. The water is not particularly limited and may be appropriately selected according to the purpose.For example, pure water, tap water, well water, mineral spring water, mineral water, hot spring water, spring water, fresh water, purified water, hot water, Examples include ion-exchanged water, physiological saline, phosphate buffer, and phosphate buffered saline. There is no restriction | limiting in particular as said hydrophilic solvent, According to the objective, it can select suitably, For example, C1-C5 lower alcohols, such as methanol, ethanol, propyl alcohol, isopropyl alcohol; Acetone, methyl ethyl ketone, etc. Lower aliphatic ketones; C2-C5 polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin. There is no restriction | limiting in particular as said mixed solvent, Although it can select suitably according to the objective, When using a lower alcohol, 1 mass part-90 mass parts with respect to 10 mass parts of water, a lower aliphatic ketone. 1 to 40 parts by mass with respect to 10 parts by mass of water, and when using polyhydric alcohol, 1 to 90 parts by mass with respect to 10 parts by mass of water is preferably added. . The oyster extraction solvent is preferably used at a temperature between room temperature and the boiling point of the solvent. Among these, it is preferable to extract using hot water.

  There is no restriction | limiting in particular as the usage-amount of the extraction solvent of the said oyster, According to the objective, it can select suitably.

  There is no restriction | limiting in particular as a purification method of the said oyster extract, According to the objective, it can select suitably, For example, purification methods, such as liquid-liquid partition extraction, various chromatography, and membrane separation, are mentioned.

  There is no restriction | limiting in particular as a density | concentration of the said oyster extract, Although it can select suitably according to the objective, 200 microgram / mL-400 microgram / mL are preferable.

<Turmeric extract>
The turmeric is a perennial plant belonging to the genus Curcuma (turmeric), and the scientific name is Curcuma longa . The turmeric is distributed in tropical Asia and is cultivated in India, Okinawa, Southeast China and Southeast Asia, and can be easily obtained from these regions. It is known that the yellow curcumin contained in the root mass part of the turmeric has an antioxidant action, a liver function improving action, a prostate hypertrophy suppressing action and the like. On the other hand, the turmeric also contains an essential oil component called sesquiterpene. The fleshy rhizome of turmeric is used not only for medicinal purposes but also as an important flavor for curry powder, and as a yellow pigment.

The extraction part of the turmeric is not particularly limited and may be appropriately selected depending on the purpose. Examples thereof include leaves, stems, flower parts, fruit parts, rhizome parts, root parts, and the like. Of these, the rhizome is preferred.
As the method for preparing the extraction part of the turmeric, after each part is dried, it can be obtained by subjecting it to solvent extraction as it is or after pulverization using a crusher. The drying may be performed in the sun, or may be performed using a commonly used dryer.

  The turmeric extract can be easily obtained by a method generally used for plant extraction. The turmeric extract is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a diluted solution of the extract, a concentrated solution, and a dried product of the extract.

  The method for extracting the turmeric is not particularly limited and may be appropriately selected depending on the purpose. For example, the extraction part of the turmeric as an extraction raw material is put into a treatment tank filled with an extraction solvent, and is necessary. Accordingly, there may be mentioned a method of obtaining an extract by eluting soluble components while stirring appropriately and then filtering to remove the extraction residue.

  The extraction conditions (extraction time and extraction temperature) of the turmeric and the amount of the extraction solvent used for the turmeric are not particularly limited and may be appropriately selected depending on the purpose.

  There is no restriction | limiting in particular as an extraction solvent of the said turmeric, According to the objective, it can select suitably, For example, water, a hydrophilic solvent, or these mixed solvents are mentioned. The water is not particularly limited and may be appropriately selected according to the purpose.For example, pure water, tap water, well water, mineral spring water, mineral water, hot spring water, spring water, fresh water, purified water, hot water, Examples include ion-exchanged water, physiological saline, phosphate buffer, and phosphate buffered saline. There is no restriction | limiting in particular as said hydrophilic solvent, According to the objective, it can select suitably, For example, C1-C5 lower alcohols, such as methanol, ethanol, propyl alcohol, isopropyl alcohol; Acetone, methyl ethyl ketone, etc. Lower aliphatic ketones; C2-C5 polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin. There is no restriction | limiting in particular as said mixed solvent, Although it can select suitably according to the objective, When using a lower alcohol, 1 mass part-90 mass parts with respect to 10 mass parts of water, a lower aliphatic ketone. 1 to 40 parts by mass with respect to 10 parts by mass of water, and when using polyhydric alcohol, 1 to 90 parts by mass with respect to 10 parts by mass of water is preferably added. . The turmeric extraction solvent is preferably used at a temperature between room temperature and the boiling point of the solvent. Among these, it is preferable to extract using hot water.

  There is no restriction | limiting in particular as a purification method of the said turmeric extract, According to the objective, it can select suitably, For example, purification methods, such as liquid-liquid partition extraction, various chromatography, and membrane separation, are mentioned.

  There is no restriction | limiting in particular as a density | concentration of the said turmeric extract, Although it can select suitably according to the objective, 25 microgram / mL-40 microgram / mL are preferable.

<Chrysanthemum extract>
The chrysanthemum is a short-day plant belonging to the genus Asteraceae, and its scientific name is Chrysanthhemum morifolium syn. It is. The chrysanthemums grow naturally in Japan and are readily available. The chrysanthemum flower has been used for medicinal purposes in China for a long time, and it is also used in Japan for tea and liquor and as a food for cooking, and is effective for dizziness, headache, eye fatigue, etc. It is said.

The extraction part of the chrysanthemums is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include leaf parts, stem parts, flower parts, fruit parts, root parts, etc. Among them, flowers Part is preferred.
The method for preparing the chrysanthemum extraction site can be obtained by drying each site and then pulverizing it as it is or using a crusher and subjecting it to solvent extraction. The drying may be performed in the sun, or may be performed using a commonly used dryer.

  The chrysanthemum extract can be easily obtained by a method generally used for plant extraction. There is no restriction | limiting in particular as said chrysanthemum extract, According to the objective, it can select suitably, For example, the dilution liquid of an extract, a concentrated liquid, the dried product of an extract, etc. are mentioned.

  The chrysanthemum extraction method is not particularly limited and can be appropriately selected according to the purpose. For example, the extraction part of the chrysanthemum as an extraction raw material is put into a treatment tank filled with an extraction solvent, and necessary. Accordingly, there may be mentioned a method of obtaining an extract by eluting soluble components while stirring appropriately and then filtering to remove the extraction residue.

  The chrysanthemum extraction conditions (extraction time and temperature) and the amount of chrysanthemum extraction solvent used are not particularly limited and may be appropriately selected depending on the intended purpose.

  There is no restriction | limiting in particular as said chrysanthemum extraction solvent, According to the objective, it can select suitably, For example, water, a hydrophilic solvent, or these mixed solvents are mentioned. The water is not particularly limited and may be appropriately selected according to the purpose.For example, pure water, tap water, well water, mineral spring water, mineral water, hot spring water, spring water, fresh water, purified water, hot water, Examples include ion-exchanged water, physiological saline, phosphate buffer, and phosphate buffered saline. There is no restriction | limiting in particular as said hydrophilic solvent, According to the objective, it can select suitably, For example, C1-C5 lower alcohols, such as methanol, ethanol, propyl alcohol, isopropyl alcohol; Acetone, methyl ethyl ketone, etc. Lower aliphatic ketones; C2-C5 polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin. There is no restriction | limiting in particular as said mixed solvent, Although it can select suitably according to the objective, When using a lower alcohol, 1 mass part-90 mass parts with respect to 10 mass parts of water, a lower aliphatic ketone. 1 to 40 parts by mass with respect to 10 parts by mass of water, and when using polyhydric alcohol, 1 to 90 parts by mass with respect to 10 parts by mass of water is preferably added. . The chrysanthemum extraction solvent is preferably used at a temperature between room temperature and the boiling point of the solvent. Among these, it is preferable to extract using hot water.

  There is no restriction | limiting in particular as a purification method of the said chrysanthemum extract, According to the objective, it can select suitably, For example, purification methods, such as liquid-liquid partition extraction, various chromatography, and membrane separation, are mentioned.

  There is no restriction | limiting in particular as a density | concentration of the said chrysanthemum extract, Although it can select suitably according to the objective, 200 microgram / mL-400 microgram / mL are preferable.

<Jujube extract>
The jujube is a deciduous tree belonging to the genus Legumeaceae, and the scientific name is Zizihus jujuba . The jujube is native to North Africa and western Europe and is readily available from these regions. The fruit of the jujube has been used for medicinal purposes since ancient times, and contains vitamin C and the like as its components.

The extraction part of the jujube is not particularly limited and can be appropriately selected according to the purpose.For example, a leaf part, a branch part, a trunk part, a bark part, a flower part, a fruit part, a root part, etc. Among these, a fruit part is preferable.
The jujube extraction site can be prepared by drying each site and then pulverizing it as it is or using a crusher and subjecting it to solvent extraction. The drying may be performed in the sun, or may be performed using a commonly used dryer.

  The jujube extract can be easily obtained by a method generally used for plant extraction. The jujube extract is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a diluted solution of an extract, a concentrated solution, and a dried extract.

  The jujube extraction method is not particularly limited and may be appropriately selected depending on the purpose.For example, the jujube extraction site of the jujube as an extraction raw material is put into a treatment tank filled with an extraction solvent, and is necessary. Accordingly, there may be mentioned a method of obtaining an extract by eluting soluble components while stirring appropriately and then filtering to remove the extraction residue.

  The jujube extraction conditions (extraction time and extraction temperature) and the amount of the jujube extraction solvent used are not particularly limited and may be appropriately selected depending on the purpose.

  There is no restriction | limiting in particular as an extraction solvent of the said jujube, According to the objective, it can select suitably, For example, water, a hydrophilic solvent, or these mixed solvents are mentioned. The water is not particularly limited and may be appropriately selected according to the purpose.For example, pure water, tap water, well water, mineral spring water, mineral water, hot spring water, spring water, fresh water, purified water, hot water, Examples include ion-exchanged water, physiological saline, phosphate buffer, and phosphate buffered saline. There is no restriction | limiting in particular as said hydrophilic solvent, According to the objective, it can select suitably, For example, C1-C5 lower alcohols, such as methanol, ethanol, propyl alcohol, isopropyl alcohol; Acetone, methyl ethyl ketone, etc. Lower aliphatic ketones; C2-C5 polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin. There is no restriction | limiting in particular as said mixed solvent, Although it can select suitably according to the objective, When using a lower alcohol, 1 mass part-90 mass parts with respect to 10 mass parts of water, a lower aliphatic ketone. 1 to 40 parts by mass with respect to 10 parts by mass of water, and when using polyhydric alcohol, 1 to 90 parts by mass with respect to 10 parts by mass of water is preferably added. . The jujube extraction solvent is preferably used at a temperature between room temperature and the boiling point of the solvent. Among these, it is preferable to extract using hot water.

  The method for purifying the jujube extract is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include purification methods such as liquid-liquid partition extraction, various chromatography and membrane separation.

  There is no restriction | limiting in particular as a density | concentration of the said jujube extract, Although it can select suitably according to the objective, 200 microgram / mL-400 microgram / mL are preferable.

<Wolfberry extract>
The wolfberry is a deciduous shrub belonging to the genus Cucurbitaceae, and the scientific name is Lycine chinense . The wolfberry is distributed in Japan, Korea, China, Taiwan, and the like, and is easily available from these regions. The fruit of the wolfberry is used as a raw meal, dried fruit, and a bowl of rice cake as well as being drunk in sake. The soft young leaves of wolfberry are widely used for food.

The wolfberry extraction site is not particularly limited and can be appropriately selected according to the purpose.For example, leaf, branch, stem, bark, flower, fruit, root, etc. Among these, a fruit part is preferable.
The method for preparing the wolfberry extraction sites can be obtained by drying each site and then pulverizing it as it is or using a crusher and subjecting it to solvent extraction. The drying may be performed in the sun, or may be performed using a commonly used dryer.

  The wolfberry extract can be easily obtained by a method generally used for plant extraction. There is no restriction | limiting in particular as said wolfberry extract, According to the objective, it can select suitably, For example, the dilution liquid of an extract, a concentrated liquid, the dried product of an extract, etc. are mentioned.

  The extraction method of the wolfberry is not particularly limited and can be appropriately selected according to the purpose. For example, the extraction site of the wolfberry as an extraction raw material is put into a treatment tank filled with an extraction solvent, and is necessary. Accordingly, there may be mentioned a method of obtaining an extract by eluting soluble components while stirring appropriately and then filtering to remove the extraction residue.

  The wolfberry extraction conditions (extraction time and extraction temperature) and the amount of the wolfberry extraction solvent used are not particularly limited and may be appropriately selected depending on the purpose.

  The wolfberry extraction solvent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include water, a hydrophilic solvent, and a mixed solvent thereof. The water is not particularly limited and may be appropriately selected according to the purpose.For example, pure water, tap water, well water, mineral spring water, mineral water, hot spring water, spring water, fresh water, purified water, hot water, Examples include ion-exchanged water, physiological saline, phosphate buffer, and phosphate buffered saline. There is no restriction | limiting in particular as said hydrophilic solvent, According to the objective, it can select suitably, For example, C1-C5 lower alcohols, such as methanol, ethanol, propyl alcohol, isopropyl alcohol; Acetone, methyl ethyl ketone, etc. Lower aliphatic ketones; C2-C5 polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin. There is no restriction | limiting in particular as said mixed solvent, Although it can select suitably according to the objective, When using a lower alcohol, 1 mass part-90 mass parts with respect to 10 mass parts of water, a lower aliphatic ketone. 1 to 40 parts by mass with respect to 10 parts by mass of water, and when using polyhydric alcohol, 1 to 90 parts by mass with respect to 10 parts by mass of water is preferably added. . The wolfberry extraction solvent is preferably used at a temperature between room temperature and the boiling point of the solvent. Among these, it is preferable to extract using hot water.

  There is no restriction | limiting in particular as a purification method of the said wolfberry extract, According to the objective, it can select suitably, For example, purification methods, such as liquid-liquid partition extraction, various chromatography, and membrane separation, are mentioned.

  There is no restriction | limiting in particular as a density | concentration of the said wolfberry extract, Although it can select suitably according to the objective, 100 microgram / mL-400 microgram / mL are preferable.

<Chamomile extract>
The chamomile is a cold-tolerant annual plant belonging to the genus Asteraceae, and its scientific name is Matricaria chamomill (aka: chamomile). The origin of the chamomile is a region from Europe to West Asia, and is easily available from these regions. The chamomile leaves are feathery compound leaves, the flowers have a diameter of about 3 cm, the central tubular flower is yellow, the tongue-like flower is white, and has a unique strong scent similar to an apple. The chamomile is used as a herb for a stomachic agent, a sweating agent, an anti-inflammatory agent, a gynecological drug, and the like.

  There is no restriction | limiting in particular as an extraction site | part of the said chamomile, According to the objective, it can select suitably, For example, a leaf part, a stem part, a flower part, a fruit part, a root part etc. are mentioned, A flower part is preferable.

  A method for preparing the chamomile extraction site can be obtained by drying each site and then pulverizing it as it is or using a crusher and subjecting it to solvent extraction. The drying may be performed in the sun, or may be performed using a commonly used dryer.

  The chamomile extract can be easily obtained by a method generally used for plant extraction. The chamomile extract is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include an extract diluted solution, a concentrated solution, and a dried extract.

  The chamomile extraction method is not particularly limited and can be appropriately selected according to the purpose.For example, the chamomile extraction site as an extraction raw material is put into a treatment tank filled with an extraction solvent, and is necessary. Accordingly, there may be mentioned a method of obtaining an extract by eluting soluble components while stirring appropriately and then filtering to remove the extraction residue.

  The chamomile extraction conditions (extraction time and temperature) and the amount of chamomile extract solvent used are not particularly limited and may be appropriately selected according to the purpose.

  There is no restriction | limiting in particular as an extraction solvent of the said chamomile, According to the objective, it can select suitably, For example, water, a hydrophilic solvent, or these mixed solvents are mentioned. The water is not particularly limited and may be appropriately selected according to the purpose.For example, pure water, tap water, well water, mineral spring water, mineral water, hot spring water, spring water, fresh water, purified water, hot water, Examples include ion-exchanged water, physiological saline, phosphate buffer, and phosphate buffered saline. There is no restriction | limiting in particular as said hydrophilic solvent, According to the objective, it can select suitably, For example, C1-C5 lower alcohols, such as methanol, ethanol, propyl alcohol, isopropyl alcohol; Acetone, methyl ethyl ketone, etc. Lower aliphatic ketones; C2-C5 polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin. There is no restriction | limiting in particular as said mixed solvent, Although it can select suitably according to the objective, When using a lower alcohol, 1 mass part-90 mass parts with respect to 10 mass parts of water, a lower aliphatic ketone. 1 to 40 parts by mass with respect to 10 parts by mass of water, and when using polyhydric alcohol, 1 to 90 parts by mass with respect to 10 parts by mass of water is preferably added. . The chamomile extraction solvent is preferably used at a temperature between room temperature and the boiling point of the solvent. Among these, it is preferable to extract using hot water.

  There is no restriction | limiting in particular as a purification method of the said chamomile extract, According to the objective, it can select suitably, For example, purification methods, such as liquid-liquid partition extraction, various chromatography, and membrane separation, are mentioned.

  There is no restriction | limiting in particular as a density | concentration of the said chamomile extract, Although it can select suitably according to the objective, 200 microgram / mL-400 microgram / mL are preferable.

<Butcher Bloom extract>
The Butcher bloom is evergreen shrub Liliaceae butcher's broom genus perennial, scientific name, Ruscus aculeatus (Japanese name: Butcher's Broom, aka Butchers Broom) is. The butcher bloom originates in Europe and is readily available from these regions. The Butcher Bloom is a hermaphrodite, with flowers blooming from spring to summer and red fruits in winter. The butcher bloom leaves are degenerated, the stem at the end is flat like a leaf, and the tip has sharp spines.

  The extraction site of the butcher bloom is not particularly limited and may be appropriately selected according to the purpose. Examples thereof include a leaf part, a stem part, a flower part, a fruit part, a root part, and a rhizome part. Of these, the rhizome is preferred.

  As a method for preparing the extraction part of the butcher bloom, it can be obtained by drying each part and then pulverizing it as it is or using a crusher and subjecting it to solvent extraction. The drying may be performed in the sun, or may be performed using a commonly used dryer.

  The butcher bloom extract can be easily obtained by a method generally used for plant extraction. There is no restriction | limiting in particular as an extract of the said butcher bloom, According to the objective, it can select suitably, For example, the diluted solution of an extract, a concentrate, the dried product of an extract, etc. are mentioned.

  The extraction method of the butcher bloom is not particularly limited and can be appropriately selected according to the purpose.For example, the extraction site of the butcher bloom as an extraction raw material is charged into a processing tank filled with an extraction solvent, Examples include a method of obtaining an extract by eluting soluble components while appropriately stirring as necessary and then filtering to remove the extraction residue.

  The extraction conditions (extraction time and extraction temperature) of the butcher bloom and the amount of the extraction solvent used for the butcher bloom are not particularly limited and may be appropriately selected depending on the purpose.

  There is no restriction | limiting in particular as an extraction solvent of the said butcher bloom, According to the objective, it can select suitably, For example, water, a hydrophilic solvent, or these mixed solvents are mentioned. The water is not particularly limited and may be appropriately selected according to the purpose.For example, pure water, tap water, well water, mineral spring water, mineral water, hot spring water, spring water, fresh water, purified water, hot water, Examples include ion-exchanged water, physiological saline, phosphate buffer, and phosphate buffered saline. There is no restriction | limiting in particular as said hydrophilic solvent, According to the objective, it can select suitably, For example, C1-C5 lower alcohols, such as methanol, ethanol, propyl alcohol, isopropyl alcohol; Acetone, methyl ethyl ketone, etc. Lower aliphatic ketones; C2-C5 polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin. There is no restriction | limiting in particular as said mixed solvent, Although it can select suitably according to the objective, When using a lower alcohol, 1 mass part-90 mass parts with respect to 10 mass parts of water, a lower aliphatic ketone. 1 to 40 parts by mass with respect to 10 parts by mass of water, and when using polyhydric alcohol, 1 to 90 parts by mass with respect to 10 parts by mass of water is preferably added. . The butcher bloom extraction solvent is preferably used at a temperature between room temperature and the boiling point of the solvent. Among these, it is preferable to extract using hot water.

  There is no restriction | limiting in particular as a purification method of the said butcher bloom extract, According to the objective, it can select suitably, For example, purification methods, such as liquid-liquid partition extraction, various chromatography, and membrane separation, are mentioned.

  There is no restriction | limiting in particular as a density | concentration of the said butcher bloom extract, Although it can select suitably according to the objective, 50 micrograms / mL-200 micrograms / mL are preferable, and 100 micrograms / mL-200 micrograms / mL are more preferable.

<Other ingredients>
The other components are not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include excipients, moisture-proofing agents, preservatives, reinforcing agents, thickeners, emulsifiers, antioxidants, and sweeteners. , Sour, seasoning, coloring, flavoring, whitening agent, moisturizer, oil component, UV absorber, surfactant, thickener, alcohol, powder component, colorant, aqueous component, water, skin nutrition Agents and the like.
The other components are not particularly limited and may be appropriately selected depending on the purpose. Specifically, hyaluronic acid, hyaluronic acid hydrolyzate, collagen, collagen hydrolyzate, ascorbic acid, ascorbine Acid derivatives, ascorbic acid glycosides, coenzyme Q10, propolis, royal jelly, royal jelly proteolysate, fucoidan, aloe powder, aloe extract, blueberry powder, blueberry extract, isoflavone, noni powder, noni extract, garlic powder, garlic Extract, Turmeric powder, Chitosan, Glucosamine, Chlorella powder, Chlorella extract, Carnitine, Maca powder, Maca extract, Cassis powder, Cassis extract, Hanabiratake powder, Hanabiratake extract, and other plants that are said to be effective for beauty Powder and / or extract of And the like.

<Application>
The Tie2 activator, angiogenesis inhibitor, blood vessel maturation agent, blood vessel normalizing agent, blood vessel stabilizer, and pharmaceutical composition of the present invention have excellent Tie2 activation action, angiogenesis inhibition action, Diseases mainly composed of vascular lesions such as tumors, rheumatoid arthritis, diabetic retinopathy, hyperlipidemia, hypertension, and atopy due to vascular maturation, vascular normalization, and vascular stabilization It can be suitably used as a pharmaceutical for allergic diseases such as dermatitis and hay fever, and as a safe preventive agent for these diseases, and its blending amount, usage, and dosage form are appropriately determined according to the purpose of use. You can choose.

  It has been confirmed that the Tie2 activator, angiogenesis inhibitor, blood vessel maturation agent, blood vessel normalizing agent, and blood vessel stabilizer of the present invention are not digestible in the digestive tract. Therefore, it can use suitably as food / beverage products, such as beauty food / beverage products and health food / beverage products, and it can select suitably as the compounding quantity, usage, and dosage form according to the intended purpose.

  The blending amount can be adjusted as appropriate depending on the physiological activity of the extract, etc., but the kiraya extract, the jaundice extract, the ginkgo extract, the oyster extract, the turmeric extract, the chrysanthemum extract 0.0001% by mass to 20% by mass in terms of a purified product of the product, the jujube extract, the wolfberry extract, the chamomile extract, and the butcher bloom extract, More preferred is 10% by mass.

  There is no restriction | limiting in particular as said usage, According to the objective, it can select suitably, For example, oral, parenteral, administration forms, such as external use, are mentioned.

  The dosage form is not particularly limited and may be appropriately selected depending on the intended purpose. For example, oral dosage forms such as tablets, powders, capsules, granules, extracts, and syrups, injections, and infusions And parenteral agents such as suppositories, ointments, creams, emulsions, lotions, packs, and external preparations such as bath preparations and hair cosmetics.

  Examples of the present invention will be described below, but the present invention is not limited to these examples.

[Test Example 1: Tie2 activation action (immunoassay) test]
(Example 1: Kiraya extract)
Normal human umbilical vein endothelial cells (HUVEC) cultured to confluence were seeded in a 96-well plate at 2.0 × 10 ⁴ cells / 0.1 mL / well, and a medium for low serum vascular endothelial cell proliferation (Kurashiki Spinning) The culture was carried out overnight using Humedia-EG2). Next, the HUVEC after overnight culture was replaced with 0.1 mL of vascular endothelial cell basal medium (Humdia-EB2 manufactured by Kurashiki Boseki Co., Ltd.) 3 hours before cell stimulation (addition of test sample) and cultured again. Went. Thereafter, 0.1 mL of Kiraya extract (manufactured by Maruzen Pharmaceutical Co., Ltd.) prepared as a test sample at the concentration shown in Table 1 was added as a test sample and incubated for 10 minutes. After the incubation, the amount of phosphorylated Tie2 and total Tie2 in the cells were measured according to the protocol using an immunoassay kit (manufactured by R & D Systems, Human Phospho-Tie2 (Y992) Immunoassay). The ratio was calculated.
For dimethyl sulfoxide (DMSO) used as a negative control, the ratio of phosphorylated Tie2 to total Tie2 was calculated in the same manner.
And Tie2 activation rate was calculated according to following formula (1), and phosphorylation action was evaluated. The results are shown in Table 1.
Tie2 activation rate (%) =
[{(Measured value of phosphorylated Tie2 when test sample is added) / (Measured value of total Tie2 when test sample is added)} / {(Measured value of phosphorylated Tie2 with negative control) / (With negative control) Measured value of total Tie2)}] × 100 (1)

(Example 2: Jaundice extract)
In Example 1, the Kiraya extract was changed to a yellow cocoon extract (manufactured by Maruzen Pharmaceutical Co., Ltd., yellow coconut leaf extract powder MF), and the concentrations shown in Table 1 were used. Tested. The results are shown in Table 1.

(Example 3: Ginkgo extract)
In Example 1, the Kiraya extract was changed to a Ginkgo extract (Maruzen Pharmaceutical Co., Ltd., Ginkgo biloba extract F), and the concentrations shown in Table 1 were used. Tested. The results are shown in Table 1.

(Example 4: Oyster extract)
In Example 1, the Kiraya extract was changed to an oyster extract (manufactured by Maruzen Pharmaceutical Co., Ltd., oyster extract powder) and tested in the same manner as in Example 1 except that the concentrations shown in Table 1 were used. . The results are shown in Table 1.

(Example 5: Turmeric extract)
In Example 1, the Kiraya extract was changed to a turmeric extract (manufactured by Maruzen Pharmaceutical Co., Ltd., turmeric concentrated extract powder M), and the concentrations shown in Table 1 were used. Tested. The results are shown in Table 1.

(Example 6: Chrysanthemum extract)
In Example 1, the Kiraya extract was changed to a chrysanthemum extract (manufactured by Maruzen Pharmaceutical Co., Ltd., chrysanthemum extract powder MF), except that the concentrations shown in Table 1 were used. Tested. The results are shown in Table 1.

(Example 7: jujube extract)
In Example 1, the Quillaja extract was changed to a jujube extract (manufactured by Maruzen Pharmaceutical Co., Ltd., Tisoura extract powder MF), except that the concentrations shown in Table 1 were used. Tested. The results are shown in Table 1.

(Example 8: wolfberry extract)
In Example 1, the Kiraya extract was changed to a wolfberry extract (manufactured by Maruzen Pharmaceutical Co., Ltd., Kukosi extract powder MF), except that the concentrations shown in Table 1 were used. Tested. The results are shown in Table 1.

(Example 9: Chamomile extract)
In Example 1, the kiraya extract was changed to a chamomile extract (manufactured by Maruzen Pharmaceutical Co., Ltd., chamomile extract powder MF), except that the concentrations shown in Table 1 were used. Tested. The results are shown in Table 1.

(Example 10: Butcher Bloom extract)
In Example 1, the Kiraya extract was changed to a Butcher Bloom extract (Maruzen Pharmaceutical Co., Ltd., Butchers Bloom extract), and the concentrations shown in Table 1 were used. Thus, Example 5 was obtained. The results are shown in Table 1.

(Reference Example 1: Positive control)
In Example 1, the Quillaja extract was changed to Angiopoietin-1 (manufactured by R & D system) as a positive control, and the concentrations shown in Table 1 were used. It was. The results are shown in Table 1.

[Test Example 1: Test results]
The test result of Tie2 activation action (immunoassay) will be described.
When the Tie2 activation action was evaluated using the immunoassay kit, it was confirmed that Tie2 was phosphorylated and activated by the extract used in the examples. In the system to which DMSO as a negative control was added, no significant phosphorylation of Tie2 was observed. Moreover, in the system which added Angiopoietin-1 which is a positive control of Reference Example 1, it was confirmed that Tie2 was phosphorylated and activated. Here, it is known that phosphorylation of Tie2 leads to vascular maturation, vascular normalization, and vascular stabilization, and angiogenesis is suppressed.
From the above, it was suggested that the extract used in the Examples has Tie2 phosphorylation action, angiogenesis is suppressed, and vascular maturation, vascular normalization, and vascular stabilization are induced. .

The Tie2 activator, angiogenesis inhibitor, blood vessel maturation agent, blood vessel normalizing agent, blood vessel stabilizer, and pharmaceutical composition of the present invention have excellent Tie2 activation action, angiogenesis inhibition action, Drugs related to diseases mainly composed of vascular lesions such as tumors, rheumatoid arthritis, diabetic retinopathy, hyperlipidemia, hypertension and the like because they have vascular maturation action, vascular normalization action, and vascular stabilization action It can be widely used as a safe preventive drug for these diseases.
It was also confirmed that the Tie2 activator, angiogenesis inhibitor, blood vessel maturation agent, blood vessel normalizing agent, and blood vessel stabilizer of the present invention are not digested in the digestive tract. Therefore, it can be widely used as food and drink such as beauty food and drink and health food and drink.

Claims (3)

Water extract of the leaves of the ginkgo, hydrophilic solvent extracts, and Tie2 activators characterized by containing at least one as an active ingredient of a mixed solvent extract of water and a hydrophilic solvent. It contains at least one of a water extract of leaves of a ginkgo, a hydrophilic solvent extract, and a mixed solvent extract of water and a hydrophilic solvent as an active ingredient, and a blood vessel maturation action based on a Tie2 activation action or A blood vessel maturation agent or a blood vessel stabilization agent characterized by having a blood vessel stabilization effect. A food or drink used for at least one of activation of Tie2, vascular maturation, and vascular stabilization,
A food or drink comprising at least one of the Tie2 activator according to claim 1, the vascular maturation agent according to claim 2, and the vascular stabilizer according to claim 2.