KR101816601B1 - Pharmaceutical composition for blood vessel disease prevention or treatment comprising substance extracted from the fruits of acanthopanax sessiliflorus and method for manufacturing thereof - Google Patents
Pharmaceutical composition for blood vessel disease prevention or treatment comprising substance extracted from the fruits of acanthopanax sessiliflorus and method for manufacturing thereof Download PDFInfo
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Abstract
The present invention relates to a pharmaceutical composition for prevention or inhibition of angiogenesis, which comprises an omega-fruit-derived material, and more particularly to a pharmaceutical composition for preventing or inhibiting angiogenesis, The present invention can provide a pharmaceutical composition and health functional food containing the omega fruit-derived material suitable for use in prevention or inhibition of aging of blood vessels.
Description
The present invention relates to a pharmaceutical composition for preventing or inhibiting angiogenesis, which comprises an omega fruit-derived material, and a method for preparing the same, and more particularly, to a pharmaceutical composition for preventing or inhibiting angiogenesis, And to a method for preparing the same.
Acanthopanax spp is a perennial broad-leaved shrub belonging to Araliaceae. Acantho is a tree with thorns. Panax means healing a panacea. It is a cold tolerant plant with height of 2-3m and disappearing in October. 17 species are distributed throughout Korea (Yook, 2000). Ogaki is similar in appearance to ovine and is also called siberian ginseng in Russia and Europe. Acanthoside-A, B, C, D (acanthoside-A, B, C, D) and lignan glycosides such as sesamin and savinin, chiisanoside, polyacetylene, beta-sitosterol, stigmasterol, campesterol, vitamins and minerals, and yellowing agents such as yellowing agents A, B, C, D, I , K, and M (eleutherosides A, B, C, D, I, K, and M) have been attracting attention as a good medicinal product (Hirata et al. Especially, many researches have been made on these compounds, such as eleutheroside B and E, and the gingival capsules extracted from the leaves and stems of the leaves have a property of preserving the biological functions of basic metabolism and acting extensively, Its main effects are known to be effective for arthritis, hypertension, gastric ulcer, ischemic heart disease, hepatitis and so on.
In recent years, it has been reported that the administration of sessiloside, chiisanoside and saponin derived from Ogaki leaves inhibits the activity of pancreatic lipase and inhibits the weight gain induced by high-fat diets, It has been reported that adenosine diphosphate (ADP) -induced platelet aggregation inhibitory activity has been reported (Yoshizumi et al. 2006; Yang et al .. 2009). In recent years, a variety of beneficial foods have been emerging due to increased interest in functional foods. The research on ogapi has been started from the pharmacological point of view rather than from the food aspect, and the physiological activity of the lignan- (Lee et al., 2004). In addition, studies on ogapi so far have been studied with leaves, stems, and roots as the main ingredients.
However, ogafi fruit can be used as food, and it is easy to secure fuel by self-cultivation and cultivation in all regions of Korea, but there is little research on its function and efficacy as a functional food.
On the other hand, the efforts to find a substance that suppresses aging by the wind of all people are continuing from the past to the present, in which aging is delayed and the degenerative disease does not develop and the person lives long without disease. Oxidation by active oxygen species such as superoxide, hydrogen peroxide, hydroxyl group and singlet oxygen is one of the factors promoting aging. Free radicals generated by the metabolites of reactive oxygen species act on proteins, biomembranes, and DNA in vivo and cause oxidative damage. Many studies have been conducted on antioxidant components to suppress these effects, Researches are being actively conducted at home and abroad to search for new materials having action. However, since the aging phenomenon is not only caused by oxidation but is known to be influenced by numerous factors such as telomerase, cell replication ability, gene damage and recovery ability, it is necessary to evaluate the antioxidative effect of natural products and drugs, A method of using aging is needed.
Cell senescence is a phenomenon in which normal somatic cells can no longer divide after a certain number of divisions, contributing to the aging of individuals and tissues, and is an important mechanism for inhibiting abnormal cell proliferation and cancer formation. Cell senescence is caused by the shortening of the telomere at the end of the chromosome due to repeated somatic cell division, the increase of the activity of the cancer gene or the cancer suppressor gene, the excessive oxidative stress, the cytotoxic substance such as ultraviolet ray or radiation, And the like.
The senescence-associated β-galactosidase (SA-β-gal) activity increases with the morphological features that aged cells become larger, flattened, increase in heterochromatin in the nucleus, (IGFBPs), interleukin-6 (interleukin-6), and transforming growth factor-beta (IGFBPs), which increase the amount of proteins that inhibit cell growth such as p53, p16INK4, transforming growth factor-β, TGF-β, and interferon.
In particular, the correlation between the activity of SA-β-gal and the diseases caused by cell senescence associated therewith is well known, and Korean Patent No. 1062616 discloses this relationship in detail.
Cell senescence not only contributes to the aging of individuals and tissues, but also plays an important role in the pathogenesis of various diseases. Aging cells are frequently observed in inflammatory lesions such as rheumatoid arthritis, osteoarthritis, hepatitis, chronic skin injured tissue, and arteriosclerotic vascular tissue. In addition, cell senescence is observed in proliferative hyperplasia, hepatitis, and liver cancer.
As the aging cells accumulate, the aging cells do not divide well. Therefore, not only the damaged tissues can not be properly restored but also the enzymes that decompose the surrounding tissues and the cytokines such as inflammatory cytokines are accelerated, And contributes to the pathogenesis of the disease associated with the disease.
Since cellular aging is considered to be an essential cause of aging, efforts have been made to develop methods for delaying cellular aging. Among them, some researches have been conducted to search for substances capable of regulating cell senescence and to utilize them for the prevention and treatment of diseases.
In the prior art, Patent Document 10-2013-0139512 discloses a composition for preventing or treating an aging-related or senescence-related disease comprising an MDM2 (mouse double minute 2) inhibitor as an active ingredient.
Furthermore, Patent Document 10-2013-0046115 discloses a composition for inhibiting angiogenesis, which comprises syringaresinol as an active ingredient, which increases the expression of
In addition, a well known method of delaying blood vessel aging has been calorie restriction.
However, such conventional agents for inhibiting blood vessel aging and methods thereof are not only expensive, but also have limited efficacy.
DISCLOSURE OF THE INVENTION The present invention has been conceived to solve the above-mentioned problems. The first problem to be solved by the present invention is to provide a method for preventing or inhibiting aging of blood vessels by inhibiting SA-β-Gal activity, And a method for producing the same.
A second object to be solved by the present invention is to provide a pharmaceutical composition comprising the compound purified from the fruit fruit fraction having an excellent effect as compared with the compounds preventing or inhibiting the known vascular aging.
A third problem to be solved by the present invention is to provide a health functional food containing the compound purified from the fruit fruit fraction.
In order to solve the above-described first problem,
(1) extracting an acacia fruit with a C 1 -C 4 alcohol solvent to obtain an alcohol extract, and (2) extracting the alcohol extract with an extraction solvent containing ethyl acetate to obtain an ethyl acetate fraction The present invention provides a method for producing an ocher fruit fraction for preventing or inhibiting vascular aging.
According to a preferred embodiment of the present invention, the present invention provides an acacia fruit fraction for preventing or inhibiting vascular aging comprising an ethyl acetate fraction for an alcohol extract of acacia fruit.
In order to solve the above-mentioned second problem, the present invention provides a pharmaceutical composition for preventing or inhibiting angiogenesis, which comprises a compound represented by the following
[Chemical Formula 1]
According to a preferred embodiment of the present invention, there is provided a pharmaceutical composition for preventing or inhibiting angiogenesis, which comprises a compound represented by the following formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient .
(2)
According to a preferred embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof may be derived from an acacia fruit.
According to another preferred embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof may inhibit SA-beta-Gal activity.
According to another preferred embodiment of the present invention, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be contained at a concentration of 5 to 15 占 퐂 / ml.
According to another preferred embodiment of the present invention, the compound represented by Formula 2 or a pharmaceutically acceptable salt thereof may be contained at a concentration of 0.5 to 1.5 占 퐂 / ml.
According to another preferred embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of skin aging, rheumatoid arthritis, osteoarthritis, hepatitis, chronic skin damaged tissue, arteriosclerosis, prostatic hyperplasia, It is possible to prevent or suppress the disease of the species or more.
Further, in order to solve the above-mentioned third problem, the present invention provides a health functional food for preventing or inhibiting blood vessel aging, which comprises a compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient to provide.
According to a preferred embodiment of the present invention, there is provided a health functional food for preventing or inhibiting blood vessel aging, which comprises the compound represented by the general formula (2) or a pharmaceutically acceptable salt thereof as an active ingredient.
According to another preferred embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof may be derived from Ogaki fruit.
The pharmaceutical composition for prevention or inhibition of angiogenesis, which comprises the omega fruit-derived material of the present invention, is less expensive than conventional angiostatic inhibitor and method, and inhibits SA-beta-Gal activity, , Thereby providing a pharmaceutical composition containing the omega fruit-derived material suitable for use in preventing or inhibiting blood vessel aging and a health functional food.
FIG. 1 is an optical microscope photograph of
FIG. 2 is a graph showing a percentage of
FIG. 3 is an optical microscope photograph of Compound 2 according to one preferred embodiment of the present invention, which measures the activity of inhibiting angiogenesis.
FIG. 4 is a graph showing a percentage of Compound 2 according to a preferred embodiment of the present invention measured for its anti-aging activity.
Hereinafter, the present invention will be described in more detail.
As described above, Ogphi has been studied mainly on leaves, stems, and roots of Ogphi, and the function and efficacy of Ogphi fruit have been limited. In particular, the results of inhibiting the cell senescence of the fruit extract of Ogaki fruit extracted from Ogaki fruit have not been reported.
In addition, the conventional anti-aging agents and methods are not only prohibitively expensive, but also have limited efficacy.
Accordingly, the present invention provides a process for producing an alcohol extract, comprising the steps of (1) extracting an acacia fruit with a C 1 -C 4 alcohol solvent to obtain an alcohol extract, and (2) extracting the alcohol extract with an extraction solvent containing ethyl acetate, The present invention has been made to solve the above-mentioned problems by a method for producing an ocherfat fraction for preventing or inhibiting blood vessel aging comprising the step of obtaining a fraction. Through this, an acacia fruit fraction for prevention or inhibition of vascular aging including a substance having an effect of inhibiting senescence-associated beta -galactosidase (SA-beta-Gal) activity was obtained.
First, in step (1), the oak fruit is extracted with a C 1 -C 4 alcohol solvent to obtain an alcohol extract. The acacia to be used in the present invention is acacia fruit. The reason for using OGA Fruits in the present invention is that compounds capable of inhibiting aging of blood vessels or pharmaceutically acceptable salts thereof can be obtained by inhibiting SA-beta-Gal activity, which will be described later, from OGA Fruits. Furthermore, if ocher leaves, stems, and roots are used except for Ogaki fruit, it is difficult to achieve the effect of inhibiting the aging of blood vessels by inhibiting SA-beta-Gal activity, which is the object of the present invention.
The oak fruit used in the present invention can be used by being pulverized to an appropriate size in a dried state.
Any alcohol selected from the group consisting of C 1 -C 4 lower alcohols may be used as the alcohol solvent used as the extraction solvent for the fruit of Ogaki fruit, preferably ethanol may be used. The alcohol solvent of the present invention means alcohol, and may be 100% alcohol or mixed with other solvent. In this case, water, ethyl acetate, chloroform, hexane and the like can be preferably used as other solvents. When water is used as a solvent for the alcohol solvent, the concentration is 50 to 90% by weight, preferably 60 to 80% It is very advantageous to use an aqueous alcohol solution to maximize extraction efficiency. In other words, if more than 90% by weight or less than 50% by weight of a C 1 -C 4 alcohol aqueous solution is used, the oacup fruit-derived material contained in the alcohol extract can be reduced.
When the oacup fruit of the present invention is C 1 -C 4 Extraction with an alcohol solvent can be carried out at room temperature, and various conventional extraction methods obvious to those skilled in the art can be used. In addition, the oak fruit is referred to as C 1 -C 4 In extracting with an alcoholic solvent, the extraction temperature is 18-27 ° C, preferably 20-25 ° C. The extraction time is 20-28 hours, preferably 22-26 hours, the extraction frequency is 1-4 times, preferably 2 ~ 3 times.
Further, in a preferred embodiment for increasing the extraction efficiency of the fruit material derived from alcohol, the dried fruit is pulverized and mixed with a 60 to 80% by weight aqueous solution of C 1 to C 4 alcohol and extracted at room temperature , The extract is filtered, and the remaining material is extracted twice more by the same method, which can be concentrated under reduced pressure to produce an alcoholic extract. The alcohol extract prepared by such a method may include 0.02 to 0.025 part by weight of an oak fruit-derived material per 100 parts by weight of an aqueous alcohol solution, but is not limited thereto.
Next, in step (2), the alcohol extract is extracted with an extraction solvent containing ethyl acetate (EtOAc) to obtain an ethyl acetate fraction. The reason why ethyl acetate is used as an extraction solvent for the alcohol extract in step (2) is that the alcohol extract must be extracted using an ethyl acetate solvent to form a fraction represented by the following formula (1) and / or As possible salts thereof are obtained. In other words, if the alcohol extract is extracted using water or other alcohol solvent in addition to the ethyl acetate solvent, the compound represented by the formula (1) and / or the formula (2) or the pharmaceutically acceptable salt thereof is not obtained in the fraction.
Specifically, in a preferred embodiment of the present invention, the alcohol extract extracted in step (1) is divided and extracted with ethyl acetate (2 L × 2) and water (H 2 O) (2 L) n-BuOH) (2.5 L x 2), and concentrated under reduced pressure to obtain ethyl acetate fraction, water fraction and n-butanol fraction. In other words, the ethyl acetate fraction as well as the water fraction and the n-butanol fraction can be prepared through the step (2). In this case, the ethyl acetate fraction may contain a compound represented by the following
Next, the ethyl acetate fraction obtained in step (2) may be subjected to a purification method of step (3) to obtain a compound represented by the following formula (1) and / or (2) or a pharmaceutically acceptable salt thereof. The compound represented by the formula (1) and / or the formula (2) obtained through such a purification method or a pharmaceutically acceptable salt thereof may be used as an active ingredient to inhibit SA-β-Gal activity and prevent or inhibit angiogenesis And is used for producing a pharmaceutical composition and a health functional food. These uses of the compound represented by the formula (1) and / or the compound represented by the formula (2) or the pharmaceutically acceptable salt thereof have been discovered for the first time by the present inventors. Specifically, the compound represented by the formula (1) and / or the formula (2) or a pharmaceutically acceptable salt thereof will be described later.
In the step (3), which is the ethyl acetate fraction purification step, the ethyl acetate fraction can be purified by column chromatography to obtain the compound represented by the
Next, the pharmaceutical composition for prevention or inhibition of angiogenesis according to the present invention prepared by the above-mentioned method comprises a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[Chemical Formula 1]
In addition, the pharmaceutical composition for preventing or inhibiting angiogenesis according to the present invention prepared by the above method comprises a compound represented by the following formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient.
(2)
The pharmaceutical composition for preventing or inhibiting angiogenesis comprising the compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient provides an excellent anti-aging effect by inhibiting SA-β-Gal activity . 1 and 2, which show the degree of SA-β-Gal activity of a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention, the compound represented by the formula (1) It can be confirmed that the acceptable salt thereof has SA-beta-Gal activity inhibitory effect similar to n-acetylcysteine (NAC) and rapamycin, which are commonly known as anti-angiogenic substances. In particular, when the concentration of the compound represented by the formula (1) or the pharmaceutically acceptable salt thereof was 10 μg / ml, it showed an excellent SA-β-Gal inhibitory effect as compared with 1 μg / ml. Therefore, the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may be extremely advantageous in maximizing activity when it is contained at a concentration of 5 to 15 μg / ml. As described above, when the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is contained at a concentration of 5 to 15 占 퐂 / ml, it was firstly confirmed that the compound inhibits SA-beta-Gal activity and has an excellent effect of inhibiting angiogenesis. In other words, as shown in FIG. 1 and FIG. 2, when the concentration of the compound represented by the formula (1) or the pharmaceutically acceptable salt thereof is less than 5 / / ml, the effect of inhibiting SA-? -Galactosidase activity is insufficient The cell deterioration inhibiting effect is inferior. When the concentration exceeds 15 占 퐂 / ml, there is a problem that efficiency is lowered because there is little improvement in the effect due to the increase in concentration.
On the other hand, as described above, the correlation between the inhibition of SA-beta-gal activity and the prevention or inhibition of angiogenesis is already known, and the direct correlation between such angiogenesis and diseases related to blood vessel aging, which will be described later, It is known. Therefore, the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has a very excellent effect for inhibiting SA-β-Gal activity, and thereby, the effect on the prevention or inhibition of vascular aging is directly related thereto It is obvious to those skilled in the art to have a direct effect on diseases.
In addition, the pharmaceutical composition for preventing or inhibiting angiogenesis comprising the compound represented by the formula (2) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient inhibits SA-beta-Gal activity, to provide. 3 and 4, which show the degree of SA-beta-Gal activity of a compound represented by formula 2 of the present invention or a pharmaceutically acceptable salt thereof, a compound represented by formula 2 of the present invention or a compound represented by formula It can be confirmed that the acceptable salt thereof has SA-beta-Gal activity inhibitory effect similar to n-acetylcysteine (NAC) and rapamycin, which are commonly known as anti-angiogenic substances. In particular, when the concentration of the compound represented by the formula (2) or the pharmaceutically acceptable salt thereof was 1 μg / ml, the SA-β-Gal inhibitory activity was superior to that of the case of 0.1 μg / ml. Accordingly, the compound represented by the formula (2) of the present invention or a pharmaceutically acceptable salt thereof may be administered at a dose of 0.5 to 1.5 占 퐂 / ml Concentration may be very advantageous in maximizing the activity. As described above, when the compound represented by the formula (2) or the pharmaceutically acceptable salt thereof is contained at a concentration of 0.5 to 1.5 占 퐂 / ml , the inhibition of SA-? In other words, as shown in FIG. 3 and FIG. 4, when the concentration of the compound represented by the general formula (2) or the pharmaceutically acceptable salt thereof is less than 0.5 μg / ml, the effect of inhibiting SA-? -Galactosidase activity is insufficient The cell deterioration inhibiting effect is inferior. When the concentration exceeds 1.5 / / ml, the efficiency may not be improved due to the increase in the effect due to the increase in the concentration.
On the other hand, as described above, the correlation between the inhibition of SA-beta-gal activity and the prevention or inhibition of angiogenesis is already known, and the direct correlation between such angiogenesis and diseases related to blood vessel aging, which will be described later, It is known. Therefore, the compound represented by the general formula (2) of the present invention or a pharmaceutically acceptable salt thereof has a very excellent effect for inhibiting SA-beta-Gal activity, and thereby the effect on the prevention or inhibition of angiogenesis is directly related to the effect It is obvious to those skilled in the art to have a direct effect on diseases.
The compound represented by the formula (1) and / or the compound represented by the formula (2) or a pharmaceutically acceptable salt thereof is not particularly limited as long as it can be usually prepared and / or purchased, but preferably it may be derived from an Omega fruit.
In addition, the pharmaceutically acceptable salts thereof may include a compound represented by formula (1) and / or (2). Further, the pharmaceutical compositions may be lyophilized and include such agents or salts thereof that can be reconstituted to form pharmaceutically acceptable agents for administration, such as intravenous, intramuscular, or subcutaneous injection.
In addition, the disease related to the blood vessel aging is not particularly limited as long as it is a disease that can usually be caused by aging and / or loss of elasticity of blood vessels, but is preferably a skin aging, rheumatoid arthritis, osteoarthritis, hepatitis, , Arteriosclerosis, prostate hyperplasia, liver cancer, and the like. Such correlation with diseases due to the mechanism of vascular aging is well known, and in particular, Korean Patent No. 1062616 discloses this relationship in detail.
The pharmaceutically acceptable carriers contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol ), Starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, But are not limited to, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).
The pharmaceutical composition of the present invention can be administered orally or parenterally. In the case of parenteral administration, intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, And the like. When administered orally, the protein or peptide is extinguished and the oral composition should be formulated to coat the active agent or protect it from degradation from above. The pharmaceutical composition may also be administered by any device capable of transferring the active agent to the target cell.
The appropriate dosage of the pharmaceutical composition of the present invention varies depending on factors such as the formulation method, the administration method, the age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate and responsiveness of the patient, Usually, a skilled physician can readily determine and prescribe dosages effective for the desired treatment or prophylaxis. According to a preferred embodiment of the present invention, the daily dosage of the pharmaceutical composition of the present invention is 0.001 to 100 mg / kg. As used herein, the term "pharmaceutically effective amount" means an amount sufficient to prevent or treat vascular disease and / or an amount sufficient to inhibit angiogenesis.
The pharmaceutical composition of the present invention may be formulated into a unit dosage form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. Here, the formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, suppositories, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.
In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used.
Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, sucrose), lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included .
Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the non-aqueous solvent or suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like.
The base of suppositories may be witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.
The pharmaceutical composition of the present invention may be administered as an individual prophylactic agent or a therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents.
Further, the present invention provides a health functional food for preventing or inhibiting vascular aging comprising the compound represented by the general formula (1) and / or the general formula (2) or a salt thereof as an active ingredient.
The compound represented by the general formula (1) and / or the general formula (2) or a salt thereof is not particularly limited as far as it can be usually prepared and / or purchased, but it may preferably be one derived from an acacia fruit.
The kind of health functional food is not particularly limited as long as it is usually produced and / or sold. For example, dairy products such as meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums and ice cream, soups, drinks, tea, drinks, alcoholic beverages, And can be used in the form of pills, powders, granules, infusions, tablets, capsules or beverages, all of which include health functional foods in the conventional sense.
The health beverage composition of the present invention is not particularly limited as far as it contains the compound represented by the formula (1) and / or the formula (2) or the pharmaceutically acceptable salt thereof, and there is no particular limitation to the liquid ingredient, and various flavors or natural carbohydrates As an additional component. Examples of the above-mentioned natural carbohydrates include monosaccharides, polysaccharides such as disaccharides such as glucose and fructose such as maltose and sucrose, Such as dextrin, cyclodextrin and the like and sugar alcohols such as xylitol, sorbitol and erythritol. (Flavorings such as thaumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavorings (for example, (Saccharin, aspartame, etc.) can be advantageously used.
In addition to the above, the health functional food of the present invention may contain various kinds of nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and heavies (cheese, chocolate etc.), pectic acid and its salts, And salts thereof, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like.
In addition, the health functional foods of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks. These components may be used independently or in combination.
Hereinafter, the present invention will be described in detail with reference to examples. However, these examples are intended to further illustrate the present invention, and the scope of the present invention is not limited to these examples.
Example
EXAMPLES Example 1. Extraction and fractionation of fruit-derived materials from Ogaki
1-1. Manufacture of ethanol extracts containing Ogaki fruit-derived material
10 kg of dried fruit was pulverized to an appropriate size, and 36 L of a 70 wt% ethanol aqueous solution was added thereto. The mixture was repeatedly extracted three times at room temperature for 24 hours, filtered through a filter paper, and concentrated under reduced pressure to obtain an ethanol extract of 2012 g.
1-2. It is an ethanol extract containing ougi fruit-derived material. Fraction Produce
The ethanol extract containing the oaci fruit-derived material prepared in Example 1-1 was subjected to partitioning and extraction with ethyl acetate (2L x 2) and water (2L), and water was further dispensed into n-butanol (2.5L x 2) . The ethylacetate layer, the water layer and the n-butanol layer produced by the partitioned extraction were concentrated under reduced pressure to prepare ethyl acetate fraction, water fraction and n-butanol fraction.
1-3. Preparation of compounds from solvent fractions
Carried out by silica gel column chromatography in Example 1-2 ethyl acetate fractions were 100g (SiO 2 column chromatography obtained in, Kieselgel 60 (70 ~ 230 mesh ), 3 to 12 × 25 cm, CHCl 3 and MeOH respectively L 15: 1 → 13 (100 ml) was applied to a thin layer (1: 1 → 12: 1 → 11: 1 → 10: 1 → 7: 1 → 5: 1 → 3: 1 → 1: 14 fractions (ASFE-1 to ASFE-14) were obtained by thin layer chromatography (TLC).
Among them, ASFE-8 fractions with respect to 8.98g was purified by silica gel column chromatography (SiO 2 column chromatography, Kieselgel 60 (70 ~ 230 mesh), 4 × 12 cm, CHCl 3, by respectively 2.5L of MeOH and
Next, ASFE-9 fraction with respect to 5.8g silica gel column chromatography (SiO 2 column chromatography, Kieselgel 60 (70 ~ 230 mesh), 4 × 12 cm, CHCl 3, MeOH and
Comparative Example One.
The water soluble fraction obtained in Example 1 was treated in the same manner as in Example 1-3 to separate and purify the water fraction. As a result, the
Comparative Example 2
The butanol fraction obtained from Example 1 was fractionated and purified by the same method as Example 1-3. As a result, the
Experimental Example 1: Analysis of Structure of
As a result, the following chemical structure of
Compound 1:
1) 1 H-NMR (400 MHz, pyridine- d 5, δ) 6.32 (1H, d, J = 8.0 Hz, H-1 '), 4.93 (1H, br.s, H-23a), 4.79 (1H , br.s, H-29a), 4.75 (1H, br.s, H-23b), 4.70 (1H, br.s, H-29b), 4.41 (1H, dd, J = 12.0, 2.0 Hz, H -6'a), 4.32 (1H, dd , J = 12.0, 4.4 Hz, H-6'b), 4.27 (2H, overlap, H-3 ', 4'), 4.11 (1H, dd, J = 8.0 , 8.0, H-2 '), 4.00 (1H, m, H-5'), 3.47 (1H, ddd, J = 9.6,9.6,4.4 Hz, H- ), 1.62 (3H, s, H-24), 1.06 (3H, s, H-26), 1.00 (3H, s, H-25), 0.66 (3H, s, H-27). 13 C-NMR (100 MHz, pyridine- d 5 ,?) 178.68 (C-3), 173.06 (C-28), 151.16 (C- (C-23), 96.02 (C-1 '), 79.35 (C-5'), 78.45 (C-3 '), 74.13 (C-18), 47.72 (C-19), 43.23 (C-10), 41.07 (C-9), 40.72 14), 39.55 (C-8), 38.59 (C-13), 37.53 (C-1), 34.36 ), 30.31 (C-2), 29.17 (C-15), 26.04 (C-6), 24.95 (C-12), 23.63 , 19.67 (C-30), 16.35 (C-26), 14.90 (C-27).
Experimental Example 2: Analysis of Structure of Compound 2
As a result, the following chemical structure of
Compound 2:
One)
Preparation Example 1. Cell culture
(Lonza, Walkersville, MD, USA), 10% fetal bovine calf serum (Weljin, Taegu, Korea) and EGM-2 (Endotherial cell Growth Media) Were subdivided into 1 × 10 5 umbilical cord blood cells. Then, the cells were cultured in a 5% carbon dioxide incubator at 37 ° C. for 3 days. When cells were cultured in 80-90% of the culture dish, the cells were treated with 1 ml of 2.5 × trypsin-ethylenediaminetetraacetic acid (EDTA) . Subsequently, some of the isolated cells were maintained in a culture dish containing calf fetal serum and EGM-2, and some were used for the experiment.
The cells used for the experiment were washed twice with EGM-2 medium containing 1% penicillin-streptomycin solution (Weljin, Daegu, Korea) and then incubated with 500 nM adriamycin (Ildong Pharm, Seoul, Korea) was treated for 4 hours.
The number of cell divisions was determined by measuring population doublings (PDs) while subculturing the cells. PD was calculated using PD = log2F / log2I (F, final cell number, I), and the umbilical cord blood cells were used for adriamycin treatment of PD < 30 cells, Cells of old cells used PD cells of PD> 50.
Experimental Example 3: Evaluation of cell aging inhibition through SA-beta-Gal active staining
In Preparative Example 1, adriamycin-treated cord blood cells were treated with 1 ml of 2.5 x trypsin-EDTA, and the cord blood cells were separated from the culture dish. The cells were then divided into 12-well culture dishes or 24-well culture dishes.
Specifically, the umbilical cord blood cells obtained in Preparation Example 1 were added to a 50 ml tube of EGM-2 culture medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution (Weljin, Daegu, Republic of Korea) And the cells and the culture solution were dispensed into each well. Finally, in the 12-well culture vessels, 7,000 cells were placed in the umbilical cord blood vessels per well, and 5000 cells were placed in the 24-well culture vessels per well.
The cells were cultured in a 5% CO 2 incubator at 37 ° C for one day. Then, EGM-2 culture medium containing 10% fetal bovine serum and 1% antibiotic was changed into each well, and the reagent was treated.
The reagents were dissolved in dimethyl sulfoxide (DMSO) as a negative control, 5 mM of N-acetylcysteine (NAC) and 500 mM of rapamycin as a positive control, The extracted
After incubation for 3 days at 37 ° C in a 5% CO 2 incubator, the cells were washed twice with phosphate buffer, fixed with 3.7% paraformaldehyde for 1 min, and then fixed. The cells were then stained with SA-β-gal staining solution (40 mM citric acid / phosphate [pH 5.8], 5 mM potassium ferrocyanide, 5 mM potassium ferricyanide, 150 mM NaCl, mM MgCl 2, X-gal ( 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside) 1 ㎎ / ㎖) the 12-well culture plate, the 1000 ㎕ or 24-well culture plate, the 500 ㎕ per well Was added.
Subsequently, the culture container to which the SA-β-gal staining solution was added was wrapped in silver foil and reacted at 37 ° C. for 16 hours, washed twice with phosphate buffered saline (PBS) , St. Louis, MO, USA) for 1 minute. When crystals were formed during the dyeing, crystals were dissolved by DMSO. After the staining, the cells were washed twice with phosphate buffer, and then blue-stained cells were observed under an optical microscope to examine the effect on vascular cell senescence. The degree of SA-β-gal activity was expressed in percentage (%) by measuring the number of cells stained blue in the cytoplasm among 50-100 cells in total. The results of optical microscopic observation of cells in umbilical cord blood are shown in Fig. 1, and the measured percentage of cells in umbilical cord blood was shown in Fig. 2 shows the anti-angiogenic activity of
As can be seen in Figures 1 and 2, the cells treated with
Based on this, it can be seen that
Experimental Example 4: Evaluation of cytotoxicity by SA-β-Gal active staining
In Preparative Example 1, adriamycin-treated cord blood cells were treated with 1 ml of 2.5 x trypsin-EDTA, and the cord blood cells were separated from the culture dish. The cells were then divided into 12-well culture dishes or 24-well culture dishes.
Specifically, cells in cord blood obtained in Preparation Example 1 were added to a 50 ml tube of EGM-2 culture medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution (Wulin, Daegu, Korea) And the cells and the culture solution were dispensed into each well. Finally, in the 12-well culture vessels, 7,000 cells were placed in the umbilical cord blood vessels per well, and 5000 cells were placed in the 24-well culture vessels per well.
The cells were cultured in a 5% CO 2 incubator at 37 ° C for one day. Then, EGM-2 culture medium containing 10% fetal bovine serum and 1% antibiotic was changed into each well, and the reagent was treated.
The reagents were dissolved in dimethyl sulfoxide (DMSO) as a negative control, 5 mM of N-acetylcysteine (NAC) and 500 mM of rapamycin as positive controls, Was added. 0.1 μg / ml or 1 μg / ml of Compound 2 of Example 1-3 was added.
After incubation for 3 days at 37 ° C in a 5% CO 2 incubator, the cells were washed twice with phosphate buffer, fixed with 3.7% paraformaldehyde for 1 min, and then fixed. The cells were then stained with SA-β-gal staining solution (40 mM citric acid / phosphate [pH 5.8], 5 mM potassium ferrocyanide, 5 mM potassium ferricyanide, 150 mM NaCl, mM MgCl 2, X-gal ( 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside) 1 ㎎ / ㎖) the 12-well culture plate, the 1000 ㎕ or 24-well culture plate, the 500 ㎕ per well Was added.
Subsequently, the culture container to which the SA-β-gal staining solution was added was wrapped in silver foil and reacted at 37 ° C. for 16 hours, washed twice with phosphate buffered saline (PBS) , St. Louis, MO, USA) for 1 minute. When crystals were formed during the dyeing, crystals were dissolved by DMSO. After the staining, the cells were washed twice with phosphate buffer, and then blue-stained cells were observed under an optical microscope to examine the effect on vascular cell senescence. The degree of SA-β-gal activity was expressed in percentage (%) by measuring the number of cells stained blue in the cytoplasm among 50-100 cells in total. Among the results of the optical microscopic observation, the cells in the umbilical cord blood were shown in FIG. 3, and the cells in the umbilical cord blood among the measured percentage results are shown in FIG. In Fig. 4, the anti-angiogenic activity of DMSO, a positive control group, NAC, a positive control group, rapamycin, V, 0.1 μg / ml of
As can be seen in Figures 3 and 4, the cells treated with Compound 2 of Example 1 had significantly fewer blue stained cells than the cells treated with DMSO alone, / Ml decreased the SA-b-Gal activity by about 20%, confirming the anti-angiogenic activity similar to NAC and rapamvcin, which are conventionally known anti-aging agents.
Based on this, Compound 2 of the present invention can prevent or inhibit angiogenesis by inhibiting vascular endothelial cell senescence.
As described above,
[ Manufacturing example ]
Manufacturing example 1: Preparation of pharmaceutical composition
The preparation examples of the pharmaceutical composition comprising the
Manufacturing example 1-1. Sanje Produce
Lactose 1 g
The above components were mixed and packed in airtight bags to prepare powders.
Manufacturing example 1-2. Manufacture of tablets
100 mg of milk
Magnesium stearate 2 mg
After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.
Manufacturing example 1-3. Preparation of capsules
100 mg of milk
2 mg of magnesium stearate
After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.
Manufacturing example 1-4. Manufacture of rings
Lactose 1.5 g
Glycerin 1 g
0.5 g of xylitol
After mixing the above components, they were prepared so as to be 4 g per one ring according to a conventional method.
Manufacturing example 1-5. Manufacture of granules
Soybean extract 50 mg
200 mg of glucose
600 mg of starch
After mixing the above components, 100 mg of 30% ethanol was added and the mixture was dried at 60 캜 to form granules, which were then filled in a capsule.
Manufacturing example 2: Preparation of health functional foods.
Manufacturing example 2-1. Manufacture of Health Functional Foods
70 [mu] g of vitamin A acetate
Vitamin E 1.0 mg
0.13 mg vitamin B1
0.15 mg of vitamin B2
10 mg vitamin C
Biotin 10 μg
50 ㎍ of folic acid
Calcium pantothenate 0.5 mg
1.75 mg of ferrous sulfate
0.82 mg of zinc oxide
Magnesium carbonate 25.3 mg
15 mg of potassium phosphate monobasic
Potassium citrate 90 mg
Although the composition ratio of the above-mentioned vitamin and mineral mixture is relatively mixed with a suitable preparation for health food, the compounding ratio may be arbitrarily changed, and the above ingredients may be mixed according to a conventional method for producing healthy food , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.
Manufacturing example 2-2. Manufacture of health drinks
Citric acid 1000 mg
100 g of oligosaccharide
Plum concentrate 2 g
Taurine 1 g
Purified water was added to a total of 900 ml
The above components were mixed according to a conventional health drink manufacturing method, and the mixture was heated for about 1 hour at 85 ° C with stirring. The resulting solution was filtered and sterilized in a sterilized 2 liter container, sealed, It is used in the manufacture of the health functional beverage composition of the invention.
Although the composition ratio is relatively mixed with the ingredients suitable for the favorite beverage as a preferable preparation example, the blending ratio may be arbitrarily modified according to the local or national preference such as the demand class, demand country, use purpose, and the like.
Claims (12)
[Chemical Formula 1]
Wherein said compound or a pharmaceutically acceptable salt thereof is derived from an ethyl acetate fraction for an alcoholic extract of acacia fruit.
The pharmaceutical composition for preventing or inhibiting angiogenesis-induced diseases, wherein the compound or a pharmaceutically acceptable salt thereof inhibits SA-beta-Gal activity.
Wherein the compound or a pharmaceutically acceptable salt thereof is contained at a concentration of 5 to 15 占 퐂 / ml. The pharmaceutical composition for preventing or inhibiting a disease caused by aging of blood vessels,
[Chemical Formula 1]
Wherein the compound or a pharmaceutically acceptable salt thereof is derived from an ethyl acetate fraction for an alcohol extract of an acacia fruit.
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| KR20220065116A (en) | 2020-11-12 | 2022-05-20 | 한국식품연구원 | Composition Comprising the Extract of Senna Alata for Preventing or Inhibiting Vascular Aging |
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