JP2005126344A - Cell adhesion factor expression inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a cell adhesion factor expression inhibitor which is originated from a plant and has higher safety and more excellent effects than those of conventional inhibitors. <P>SOLUTION: This cell adhesion factor expression inhibitor contains a proanthocyanidin, preferably a proanthocyanidin originated from pine bark. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a cell adhesion factor expression inhibitor.

  Cell adhesion factors are a group of molecules involved in adhesion between cells or between cells and the extracellular matrix, many of which are transmembrane glycoproteins. For example, a selectin molecule group, an integrin molecule group, an immunoglobulin superfamily molecule group, and the like are known. These cell adhesion factors are involved not only in the adhesion between cells but also in various important reactions in vivo. For example, in an inflammatory reaction, leukocytes adhere to vascular endothelial cells and infiltrate a place where a foreign substance exists (inflamed area), thereby protecting the body. At this time, adhesion of leukocytes to vascular endothelial cells and infiltration into inflamed areas are controlled by respective cell adhesion factors expressed in leukocytes and vascular endothelial cells.

  Specifically, the above invasion includes (1) capture of leukocytes on vascular endothelial cells, (2) rolling of leukocytes, (3) strong adhesion of leukocytes to endothelial cells, and (4) extravasation of leukocytes. Cell adhesion factors are involved in these processes. That is, in the above (1) and (2), capture and rolling of leukocytes is caused by binding of a selectin molecule group expressed on leukocytes or vascular endothelial cells to a sugar chain antigen on leukocytes or vascular endothelial cells. Is done. In the above (3) and (4), strong adhesion of leukocytes and migration to the outside of the blood vessel are caused by the selection of the selectin molecule group, the integrin molecule group on the leukocyte, and the immunoglobulin superfamily molecule group on the vascular endothelial cell. Depends on binding. Thus, a normal biological reaction is maintained by appropriately expressing the cell adhesion factor according to the biological reaction.

  As described above, the expression of cell adhesion factor is induced by stimulation of inflammatory cytokines. Its expression is also thought to be enhanced in various lesions and may be involved in the formation of many pathological conditions such as chronic inflammation by enhancing cell adhesion or the intercellular reaction caused by this adhesion. For example, autoimmune diseases such as rheumatism, and allergic diseases such as hay fever are considered to be caused by an excessive inflammatory reaction due to enhanced cell-cell adhesion due to increased expression of cell adhesion factors. In addition, it has been reported that the above-mentioned cell adhesion factor for leukocytes and vascular endothelial cells is also involved in cancer cell metastasis and HIV infection. Other diseases involving cell adhesion factors include, for example, inflammation such as bronchial asthma, atopic dermatitis, psoriasis, ischemia-reperfusion injury, nephritis, hepatitis, ulcerative colitis, acute respiratory distress syndrome, transplant organ rejection Diseases related to blood or blood vessels (blood circulation failure due to decreased blood fluidity, arteriosclerosis, etc.); sepsis; diabetes and the like. Furthermore, it has been suggested that the epidermis is involved in blistering, keratosis, keratosis, acne, and rough skin. Control / suppression of the expression of cell adhesion factors is effective not only for suppressing excessive cell adhesion but also for the prevention and / or treatment of the above-mentioned symptoms and diseases.

In order to suppress the expression of such cell adhesion factors, various chemical compounds or animal-derived components have been proposed as pharmaceuticals to date (Patent Documents 1 to 4). However, since many of these have problems such as a narrow safe capacity range, they are limited to use as pharmaceuticals and cannot be used easily.
JP-A-10-330259 JP-A-10-87491 JP 2001-335490 A JP 2000-319278 A

  Therefore, an object of the present invention is to provide a plant-derived cell adhesion factor inhibitor having a safer and superior effect.

  The inventors of the present invention diligently studied a plant-derived substance that can effectively suppress the expression of cell adhesion factor, and found that proanthocyanidins have an excellent cell adhesion factor expression inhibitory effect, thereby completing the present invention. It was.

  That is, the cell adhesion factor expression inhibitor of the present invention contains proanthocyanidins.

  In a preferred embodiment, the cell adhesion factor is a cell adhesion factor expressed on blood cells.

  In a preferred embodiment, the proanthocyanidins are derived from pine bark.

  An excellent cell adhesion factor expression inhibitory effect can be obtained by orally or transdermally administering the cell adhesion factor expression inhibitor containing proanthocyanidins of the present invention. The inhibitor of the present invention can be used as food, pharmaceuticals, cosmetics and the like, and can be applied to the prevention and treatment of various diseases caused by the expression of cell adhesion factors.

  Hereinafter, the cell adhesion factor expression inhibitor of the present invention will be described. The configurations described below are not intended to limit the present invention, and it will be apparent to those skilled in the art that various modifications can be made within the scope of the present invention.

  The cell adhesion factor expression inhibitor of the present invention contains proanthocyanidins, and may contain other components as necessary. Hereinafter, each component will be described.

(Proanthocyanidins)
In the present specification, proanthocyanidins refer to a group of compounds consisting of a condensation polymer having a degree of polymerization of 2 or more having flavan-3-ol and / or flavan-3,4-diol as a structural unit. Proanthocyanidins are known to have various activities such as antioxidant action.

  As the proanthocyanidins used in the present invention, those containing many condensation polymers having a low degree of polymerization are suitable. The condensation polymer having a low polymerization degree is preferably a condensation polymer having a polymerization degree of 2 to 30 (2 to 30 mer), more preferably a condensation polymer having a polymerization degree of 2 to 10 (2 to 10 mer). Further, a condensation polymer (2 to 4 mer) having a polymerization degree of 2 to 4 is more preferable. This polycondensation polymer having a degree of polymerization of 2 to 4 is referred to as oligomeric proanthocyanidin (hereinafter referred to as OPC). Proanthocyanidins, a type of polyphenols, are powerful antioxidants produced by plants and are concentrated in plant leaves, bark, fruit peels or seed parts. Proanthocyanidins, especially OPCs, are specifically the bark of plants such as pine, cocoons, and wild peaches; grapes, blueberries, strawberries, avocados, black acacias, berries or seeds of barley; barley; wheat; soybeans; black soybeans; It is contained in red beans; tochi nut shells; peanut skins; ginkgo leaves. It is also known that cola nuts in West Africa, Latania roots in Peru, and Japanese green tea contain OPC. OPC is a substance that cannot be produced in the human body.

  In particular, when an extract containing proanthocyanidins having a high OPC content or proanthocyanidins having a high OPC content was used, proanthocyanidins having a low OPC content (proanthocyanidins containing a high proportion of proanthocyanidins having a high degree of polymerization) were used. In contrast to the case, an excellent cell adhesion factor expression inhibitory effect is obtained.

  As the proanthocyanidins used in the inhibitor of the present invention, materials such as the bark of the above-mentioned plants, pulverized fruits or seeds, or extracts thereof can be used. Among these, it is preferable to use the above extract, and it is particularly preferable to use an extract derived from pine bark. An extract derived from pine bark exhibits a particularly high physiological activity among extracts derived from plants containing the above-mentioned proanthocyanidins. This is considered to be because among the plants containing proanthocyanidins, pine bark is rich in OPC. Therefore, pine bark is preferably used as a raw material for proanthocyanidins.

  Hereinafter, a method for preparing an extract containing proanthocyanidins as a main component will be described with reference to an example in which pine bark rich in OPC is used as a raw material plant.

  Pine bark extracts include pinus martima, larch, black pine, red pine, Japanese pine, pine pine, Korean pine, red pine, rhubarb pine, pine pine, pine pine, pine of the Quebec region of Canada An extract of the bark of a plant belonging to is preferably used. Among them, a bark extract of French coastal pine (Pinus Martima) is preferable.

  French coastal pine is a marine pine that grows on the Atlantic coast of southern France. This French coastal pine bark contains proanthocyanidins, organic acids, and other physiologically active ingredients, and it is known that proanthocyanidins, which are the main ingredients, have a strong antioxidant action to remove active oxygen. Yes.

  The pine bark extract is obtained by extracting the pine bark with water or an organic solvent. When using water, it is preferable to use warm water or hot water. In order to improve the extraction efficiency, it is preferable to add a salt such as sodium chloride to these waters. As an organic solvent used for extraction, an organic solvent that is acceptable for the production of food or drugs is used. For example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetone, hexane, cyclohexane , Propylene glycol, hydrous ethanol, hydrous propylene glycol, methyl ethyl ketone, glycerin, methyl acetate, ethyl acetate, diethyl ether, dichloromethane, edible oil, 1,1,1,2-tetrafluoroethane, and 1,1,2-trichloroethene Is mentioned. These water and organic solvent may be used alone or in combination. In particular, water, hot water, ethanol, water-containing ethanol, and water-containing propylene glycol are preferable, and water, hot water, ethanol, and water-containing ethanol are more preferable from the viewpoint of safety when used in foods and pharmaceuticals.

  The method for extracting proanthocyanidins from pine bark is not particularly limited. For example, by adding 1 to 100 parts by weight of hot water of 50 to 120 ° C., preferably 70 to 100 ° C., with respect to 1 part by weight of the dry weight of pine bark, the bioactive action is high and the water solubility is high. High pine bark extract can be obtained. A warm extraction method, a supercritical fluid extraction method, or the like may be used.

  The supercritical fluid extraction method is a method of performing extraction using a supercritical fluid that is a fluid that exceeds the critical point (critical temperature, critical pressure) of a gas-liquid substance. As the supercritical fluid, carbon dioxide, ethylene, propane, nitrous oxide (laughing gas) or the like is used, and carbon dioxide is preferably used.

  The supercritical fluid extraction method performs an extraction process of extracting a target component with a supercritical fluid and a separation process of separating the target component and the supercritical fluid. In the separation step, any one of extraction separation by pressure change, extraction separation by temperature change, or extraction separation using an adsorbent / absorbent may be performed.

  Moreover, you may perform supercritical fluid extraction by the entrainer addition method. In this method, 2 to 20 W of ethanol, propanol, n-hexane, acetone, toluene, other aliphatic lower alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, or ketones are added to the supercritical fluid. / V% is added, and supercritical fluid extraction is performed with the obtained extraction fluid, thereby dramatically increasing the solubility of the target extract such as OPC and catechins (described later) in the extraction solvent, or separation. This is a method for enhancing the selectivity of pine bark, and a method for efficiently obtaining a pine bark extract.

  Since the supercritical fluid extraction method can be operated at a relatively low temperature, it can be applied to substances that are altered or decomposed at high temperatures; the advantage that the extraction fluid does not remain; and the recycling of the solvent is possible. There is an advantage that the process can be omitted and the process becomes simple.

  Extraction from pine bark may be performed by a liquid carbon dioxide batch method, a liquid carbon dioxide reflux method, a supercritical carbon dioxide reflux method, or the like, in addition to the above method.

  For extraction from pine bark, a plurality of extraction methods may be combined. By combining a plurality of extraction methods, it becomes possible to obtain pine bark extracts having various compositions.

  The pine bark extract obtained by the above extraction may be purified for the purpose of increasing the content of proanthocyanidins. For the purification, an organic solvent such as ethyl acetate is usually used, but from the viewpoint of safety as a food or a pharmaceutical, a method that does not use an organic solvent, such as ultrafiltration, Diaion HP-20, Sephadex -It is preferable to purify by a column method or a batch method using an adsorbent carrier such as LH20 and chitin.

  In the present invention, the pine bark extract containing proanthocyanidins as a main component is specifically prepared by the following method, but this is an example and is not limited to this method.

  1 kg of French maritime pine bark is placed in 3 L of a saturated solution of sodium chloride and extracted at 100 ° C. for 30 minutes to obtain an extract (extraction process). Thereafter, the extract is filtered, and the resulting insoluble matter is washed with 500 mL of a saturated solution of sodium chloride to obtain a washing solution (washing step). The extract and washing solution are combined to obtain a crude extract of pine bark.

  Next, 250 mL of ethyl acetate is added to the crude extract and the phases are separated to recover the ethyl acetate layer 5 times. The collected ethyl acetate solutions are combined and added directly to 200 g of anhydrous sodium sulfate for dehydration. Thereafter, the ethyl acetate solution is filtered, and the filtrate is concentrated under reduced pressure until the original volume is reduced to 1/5. The concentrated ethyl acetate solution is poured into 2 L of chloroform, and the resulting precipitate is collected by filtration. Thereafter, the precipitate is dissolved in 100 mL of ethyl acetate, and then added to 1 L of chloroform again for precipitation to perform a washing step of repeating twice. By this method, for example, about 5 g of pine bark extract containing 20% by weight or more of OPC and 5% by weight or more of catechins can be obtained.

  The extract derived from the raw material plant such as the pine bark preferably contains 40% by weight or more of proanthocyanidins. Furthermore, it is preferable to contain 20% by weight or more, and more preferably 30% by weight or more in the extract derived from the raw material plant. As described above, a pine bark extract is preferably used as a raw material containing a high proportion of proanthocyanidins.

  The plant extract such as the pine bark extract preferably contains catechins together with proanthocyanidins, particularly OPC. Catechin is a general term for polyhydroxyflavan-3-ol. As catechins, (+)-catechin (referred to as catechin in a narrow sense), (−)-epicatechin, (+)-gallocatechin, (−)-epigallocatechin, epigallocatechin gallate, epicatechin gallate, afzelechin, etc. It has been known. In addition to the above-mentioned (+)-catechin, gallocatechin, afuzerekin, 3-galloyl derivative of (+)-catechin, and 3-galloyl derivative of gallocatechin are isolated from the extract derived from the raw material plant such as pine bark. Has been. Catechins are poorly water-soluble by themselves and have low physiological activity. However, catechins have the property of being activated at the same time as water solubility increases in the presence of OPC, and act effectively when ingested with OPC.

  Catechins are preferably contained in the raw material plant extract in an amount of 5% by weight or more, preferably 10% by weight or more. More preferably, the extract contains 20% by weight or more of OPC and 5% by weight or more of catechins. For example, when the catechin content of the extract is less than 5% by weight, catechins may be added and adjusted so that the final content is 5% by weight or more. It is most preferable to use a pine bark extract containing 20% by weight or more of OPC and 5% by weight or more of catechins.

(Other ingredients)
The inhibitor of the present invention may contain ascorbic acid or a derivative thereof and various components as necessary.

  Ascorbic acid or a derivative thereof is preferably contained in the inhibitor of the present invention in that the effect of proanthocyanidins used in the present invention, particularly OPC, can be exhibited more efficiently. As ascorbic acid or a derivative thereof, ascorbic acid or a derivative thereof used as a food additive, for example, ascorbic acid glycoside, sodium ascorbate, magnesium ascorbate, or the like is used. Natural materials rich in ascorbic acid (for example, natural materials derived from fruits such as lemon, orange, and acerola, or natural materials derived from vegetables such as broccoli, me cabbage, green pepper, komatsuna, and cauliflower) are also used in the present invention. Can be used as

  When ascorbic acid or a derivative thereof is taken together with proanthocyanidins (in particular, OPC), the absorption rate of ascorbic acid and the sustainability of physiological activity also increase. In the present invention, ascorbic acid or a derivative thereof may be contained for the purpose of protecting blood vessels, particularly for enhancing the flexibility and strength of blood vessels, and for lowering cholesterol in the blood. In particular, ascorbic acid or its derivatives promotes the synthesis of collagen, which is a constituent protein of not only blood vessels but also all tissues, reduces stress (especially oxidative stress), antithrombotic activity, and enhances immunity It is known that there are not only the effect of improving blood vessel protection and blood fluidity, but also the effect of improving the whole tissue in the living body.

  There is no restriction | limiting in particular in content of ascorbic acid or its derivative (s). Preferably, it is contained in the inhibitor of the present invention so that the weight ratio of proanthocyanidins to ascorbic acid is 1: 0.1 to 1:50, more preferably 1: 0.2 to 1:20. .

  The various components include, for example, components that can be added as ordinary foods and pharmaceuticals (excipients, extenders, binders, thickeners, emulsifiers, lubricants, wetting agents, suspending agents, coloring agents, perfumes. , Nutritional ingredients, food additives, etc.). The above components may be contained alone or in combination.

  Examples of the nutritional component include, but are not limited to, a component having an effect of preventing diseases and diseases associated with cell adhesion factors; and a component that further imparts functionality.

  Examples of components having an effect of preventing diseases and diseases related to cell adhesion factors include components that suppress the expression of cell adhesion factors in the same manner as proanthocyanidins (components derived from animals such as mucopolysaccharides and amino sugars); Ingredients that have an increase in blood glucose level, an increase in blood lipids, or an action to suppress high blood pressure, an antithrombotic action, an anti-inflammatory action, an antitumor action, etc. (sulfur-containing organic compounds, vitamin K, vitamin E, chitin / chitosan and its Derivatives, collagen and the like); and components having hepatoprotective action or antioxidant action (such as hesperidin, quercetin, rutin and derivatives thereof).

  Ingredients that impart functionality include, for example, flavonoids; vitamins other than ascorbic acid such as vitamins A and B; water-soluble dietary fiber; royal jelly; protein; minerals; lecithin; chlorella powder; Etc.

  Examples of food additives include stevia powder, matcha powder, lemon powder, honey, reduced maltose, lactose, sugar solution, and seasonings.

(Cell adhesion factor expression inhibitor)
As described above, the cell adhesion factor expression inhibitor of the present invention contains proanthocyanidins, and may contain ascorbic acid or a derivative thereof and various components as necessary.

  There is no restriction | limiting in particular in content of the proanthocyanidins in the inhibitor of this invention. In the case of oral administration, it is preferably 0.001% to 50% by weight, more preferably 0.005% to 20% by weight. In the case of transdermal administration, proanthocyanidins are preferably contained in the inhibitor in an amount of 0.00001 wt% to 20 wt%, more preferably 0.0001 wt% to 20 wt%, and even more preferably 0.001 wt% to It may be contained in a proportion of 15% by weight. In the case of oral administration, the daily intake of adults is 0.001 to 1.0 g, preferably 0.002 to 0.5 g, more preferably 0.002 to 0.2 g as proanthocyanidins. To be contained.

  The inhibitor of the present invention can be prepared in various forms, for example, as foods, pharmaceuticals, quasi drugs, cosmetics, etc., depending on the purpose.

  Among the above-mentioned uses, when the inhibitor of the present invention is orally ingested (orally administered) as food, pharmaceuticals, quasi drugs, etc., the form is not particularly limited. For example, capsules such as hard capsules and soft capsules, tablets, pills, powders (powder), granules, tea bags, bowl-like viscous liquids, liquids, pastes and the like are used in a form commonly used by those skilled in the art. Depending on the shape or preference, these may be taken as they are, or may be taken by dissolving in water, hot water, milk or the like, or may be taken after leaching the ingredients.

  Even when the inhibitor of the present invention is applied to the skin as a quasi-drug, cosmetic, etc. (transdermal administration), these forms are not particularly limited, and ointments, gels, creams, emulsions, lotions, packs, Any form such as a poultice, a bath preparation, or the like that is commonly used as a skin external preparation by a person skilled in the art may be used.

  The cell adhesion factor expression inhibitor of the present invention can be administered orally (taken) or transdermally (coated), thereby allowing cell adhesion factors such as blood cells, vascular endothelial cells and fibroblasts, particularly cells on blood cells. The expression of the adhesion factor can be suppressed. Examples of the cell adhesion factor include cadherin family, immunoglobulin superfamily, integrin family, selectin family, link protein family, and sialomucin family. The inhibitor of the present invention is particularly excellent in the effect of suppressing the expression of the integrin family and selectin family. The inhibitor of the present invention can be used as foods, pharmaceuticals, quasi drugs, cosmetics, and the like, and is variously caused by expression of cell adhesion factors such as autoimmune diseases, inflammatory diseases, cardiovascular diseases, and metastasis of tumors. It can be applied to the prevention and treatment of other diseases.

  Hereinafter, the present invention will be described with reference to examples, but it goes without saying that the present invention is not limited to these examples.

(Example 1: Cell adhesion factor expression inhibitory effect)
(Preparation of human peripheral blood mononuclear cells)
First, 5 mL of blood was collected from a subject using a syringe to which heparin had been added in advance, and 5 mL of phosphate buffered physiological saline (PBS (−)) was added to this blood to prepare a blood mixture. This mixed solution was layered on 6 mL of Percoll (manufactured by Sigma) and centrifuged at 1,500 rpm for 10 minutes at room temperature to recover human peripheral blood mononuclear cells (hereinafter referred to as hPBMC). Subsequently, PBS (-) was added to the collected hPBMC so that the total amount became 12 mL, and centrifugation was again performed under the same conditions. After centrifugation, RPMI1640 (Sigma) containing 5 mL of 1% non-immobilized fetal bovine serum (FBS) was added to and suspended in hPBMC from which the supernatant was removed. After counting the number of cells contained in this suspension, 1 mL each of the above solution diluted with RPMI 1640 containing 1% FBS so as to be 1 × 10 ⁶ cells / mL was seeded. Two such 6-well plates were prepared.

(Expression suppression test)
For the two seeded plates, 80% by weight of proanthocyanidins (containing 40% by weight of OPC with respect to the whole extract) and 10% by weight of catechin in a solution containing 2 wells of each 6 wells % Pine bark extract (trade name: Flavangenol, Toyo Shinyaku Co., Ltd.) was added to a concentration of 1 ng / mL. In another 2-well cell-containing solution, the pine bark extract was added to 10 ng / mL. The remaining two-well cell-containing solution was used as a control without adding pine bark extract. These plates were cultured for 48 hours at 37 ° C. in a 5 vol% CO ₂ atmosphere. Each culture solution was collected and then centrifuged at 1,500 rpm for 10 minutes at room temperature, and the supernatant was removed. 1 mL of 5% non-immobilized FBS-containing RPMI 1640 was further added to the resulting precipitate, and the mixture was centrifuged again under the same conditions as described above, and the supernatant was removed (this operation is called a washing operation). This washing operation was performed twice in total to obtain each test cell.

  Using three types of test cells obtained from one plate (pine bark extract 1 ng / mL added cells, pine bark extract 10 ng / mL added cells, and control cells), the expression level of CD18 (integrin) was Using the three kinds of test cells obtained from the other plate, the expression level of CD62L (selectin) was measured as follows.

(Measurement of CD18 expression level)
100 μL of 0.5% non-immobilized FBS-containing RPMI1640 containing 5 μg / mL anti-CD18 antibody (MEM-18, manufactured by MONOSAN) was added to the test cells, and held at 0 ° C. for 30 minutes. Next, the mixture was centrifuged at 1,500 rpm for 10 minutes at room temperature, the supernatant was removed, and then the above washing operation was performed. After washing, 100 μL of 0.5% non-immobilized FBS-containing RPMI1640 containing 5 μg / mL FITC-labeled anti-mouse antibody (manufactured by BECTON DIKINSON) was further added and held at 0 ° C. for 30 minutes. Thereafter, after centrifugation, the supernatant was removed and the washing operation was performed as described above. The cells were suspended in 1 mL of RPMI 1640 containing 0.5% non-immobilized FBS, and then the peak of fluorescence intensity per cell was measured by flow cytometry (FACSCalibur, manufactured by BECTON DIKINSON). The average value of each test cell was determined. Furthermore, the expression suppression rate was calculated | required from the following formula | equation using the obtained fluorescence intensity average value. The results are shown in Table 1.

(Measurement of CD62L expression level)
100 μL of 0.5% non-immobilized FBS-containing RPMI1640 containing a 5 ng / mL PE-labeled anti-CD62L antibody (CL8918PE, manufactured by CEDEALLANE) was added to the test cells and held at 0 ° C. for 30 minutes. Next, the supernatant was removed by centrifugation at 1,500 rpm for 10 minutes at room temperature, and then the above washing operation was performed. For these cells, the peak of fluorescence intensity per cell was measured by flow cytometry in the same manner as described above, and the average value of fluorescence intensity and the expression suppression rate were determined. The results are shown in Table 1.

  Table 1 shows that the expression of CD18 and CD62L is suppressed in the pine bark extract-added cells. This indicates that the pine bark extract containing proanthocyanidins has an excellent inhibitory effect on cell adhesion factor expression. In particular, the expression of CD18 and CD62L was suppressed by about 20% when containing 1 ng / mL of pine bark extract and about 40% when containing 10 ng / mL. This suggests that proanthocyanidins contained in the pine bark extract can exert their effects even at very low concentrations. Therefore, it is considered that sufficient effects can be obtained by adding them in small amounts in foods and pharmaceuticals.

(Example 2: Preparation of tablet)
The following ingredients were mixed to prepare 200 mg tablets per tablet:
<Tablet ingredients>
Pine bark extract 20mg
Ascorbic acid 20mg
Vitamin mix ^{* 1} 25mg
Crystalline cellulose 40mg
Reduced maltose 50mg
Sucrose ester 5mg
Silicon dioxide 2mg
Dolomite ^{* 2} 38mg
* 1: Contains vitamin B group (Nippon Fragrance Chemicals)
* 2: Contains calcium and magnesium (Sankyo Foods Co., Ltd.)

(Example 3: Preparation of beverage)
A beverage was prepared by mixing the following ingredients:
<Beverage ingredients> Weight (per liter)
Pine bark extract 70mg
Fructose dextrose liquid sugar 20g
Lemon juice 10g
Citric acid 2g
L-ascorbic acid 2g
Fragrance 150mg
Vitamin B ₁ 0.8mg
Vitamin B ₂ 1.2mg
Vitamin B ₆ 1.8mg
Glutamic acid 100mg
Arginine 20mg
Valine 100mg
Leucine 100mg
Isoleucine 100mg
Pure water remaining

(Example 4: Preparation of external preparation for skin)
The following components were mixed to prepare a topical skin preparation:
<Ingredients for external preparation for skin> (Unit:% by weight)
Pine bark extract: 0.001
Ascorbic acid glycoside: 0.1
Glycerin: 6
1,3-butylene glycol: 4
Ethanol: 5
Polyoxyethylene lauryl ether: 1
Fragrance: Small amount Pure water: The rest

  The cell adhesion factor expression inhibitor of the present invention can suppress the expression of cell adhesion factors, particularly the expression of cell adhesion factors in blood cells, by oral administration (intake) or transdermal administration (application). The inhibitor of the present invention can be used as foods, pharmaceuticals, quasi drugs, cosmetics, and the like, and is variously caused by expression of cell adhesion factors such as autoimmune diseases, inflammatory diseases, cardiovascular diseases, and metastasis of tumors. It can be applied to the prevention and treatment of other diseases.

Claims (3)

  A cell adhesion factor expression inhibitor containing proanthocyanidins.   The inhibitor according to claim 1, wherein the cell adhesion factor is a cell adhesion factor expressed on blood cells.   The inhibitor according to claim 1 or 2, wherein the proanthocyanidins are derived from pine bark.