KR20170067303A - Composition of Ginsenoside Compound K Having Enhanced Water Solubility - Google Patents

Abstract

The present invention discloses a composition of a ginsenoside compound K improved in water solubility. Specifically, the present invention includes a cyclodextrin or taurine which can improve water solubility in addition to the ginsenoside compound K, so that a water solubility of at least 16 to 40 times higher than that of a simple compound K solution to which cyclodextrin is not added And a water solubility of 2.5 to 5.1 times higher than that of a simple compound K aqueous solution to which no taurine is added.

Description

Composition of Ginsenoside Compound K Having Enhanced Water Solubility}

The present invention relates to a composition in which the water solubility of the ginsenoside K is improved. Specifically, the present invention relates to a composition of a compound (K) having improved water solubility by adding cyclodextrin or taurine to the compound (K).

Ginseng is known throughout the world as a perennial Paper 6-7, the current Korean Ginseng (Panax ginseng CA MEYER), Guangdong American ginseng (Panax quinquefolium L.), Chinese ginseng ( Panax notoginseng and Japanese Panax japonicus CA MEYER) have been used as medicines. The root (Ginseng radix) is divided into Ginseng Radix alba and Ginseng Radix Rubra according to the processing method. White ginseng is dried without the raw sunshine (natural ginseng) Roots are steamed by steam or steam, and they are dark yellowish brown or reddish brown. The color of white ginseng and other red ginseng is that the ginseng starch is gelatinized by heat treatment when the red ginseng is matured and the color of the contents texture is changed by amino carbonyl reaction.

These ginsengs have been used widely in East Asian countries such as China, Korea, and Japan for about 2,000 years as a safeguard for medicines and health promotion. The main active ingredient of ginseng saponin (ginsenoside) is ginsenoside, which is an active ingredient of ginsenoside, which is used as a medicament for enhancing immunity, antiinflammatory action, antiallergic action, anticancer effect, effect on erectile dysfunction, hypotensive action, anticholesterol action, (J. Immunol., 148: 1519-25, 1992; Lee FC., Facts about ginseng, the elixir of life. Hollyn International. New Jersey, 1992; Huang KC Pharm. Bull. 17: 635-9, 1994; < RTI ID = 0.0 > Pharmacology < / RTI > Biol., Pharm. Bull., 18: 1197-1202, 1995).

The ginseng saponin is a saponin which is a major component of physiological activity in ginseng. The ginseng saponin is a neutral component of bidesemic acid, which is bound with glucose, arabinose, xylose and rhamnose to a triterpenoid-based dammarane skeleton. It is a glycoside. They are named Ginsenoside Rx according to the order of polarity by column chromatography. To date, more than 40 kinds of ginsenosides have been isolated and identified. These ginsenosides are divided into PPD (protopanaxadiol) series and PPT (Protopanaxatriol) series. The basic chemical structural formula thereof is as follows. As shown in the following Table 1, the PPD-based saponin has a basic structure of PPD with R ₂ as hydrogen (H), and ginsenosides Rb1, Rb2, Rg3, Rc, Rd, F2, , PPT series saponin has R ₁ as hydrogen (H), PPT as basic structure, and ginsenosides Re, Rf, Rg1, Rh1 and so on.

[Chemical Formula 1]

In general, many glycoside compounds present in nature exhibit a tendency to increase physiological activity when the sugar is degraded to become an unglycoside rather than itself (Med. Pharm. Soc. 1992, 9: 1-13). In the case of ginseng saponin, ginsenosides Rg1, Rb2, Rd, and ginsenosides Rg3, Rh1, Rh2, F2, Compound Y, and Compound K produced by hydrolysis of some sugars rather than Re, (Ginseng Res. 2003, 27: 129-134). It is believed that the effect of the present invention on the absorption and physiological activity of the protein is remarkable. For example, the PPD saponins Rb1, Rb2, and Rc are metabolized by the intestinal bacteria of a human to K (FGM1, M1, IH-901, 20-O-β-D-glucopyranosyl-20 (S) -protopanaxadiol) PPT saponins Re and Rg1 are hydrolyzed into Rh1 or F1 by intestinal bacteria (Planta Medica 62: 463-40, 1997; Drug Metab. Dispos. 31: 1065-71, 2003) 453-7, 1996, Drug Metab. Dispos., 31: 1065-71, 2003).

 Resin 9 has been known to inhibit the invasion of cancer cells or prevent chromosomal aberration and tumor formation, thereby inducing antitumor or anticancer effects, especially liver cancer suppressing action and immune enhancing action (Oncol. Res. 9: 411-7, Cancer Lett. 144: 39-43, 1999).

 Rh1 is a cytotoxic effect on growth of various cancer cells (Cancer Res. 45: 2781-4, 1985; Cancer Res. 47: 3863-7, 1987; Lee HY, et al., Differentiation mechanism of ginsenosides in cultured murine F9 teratocarcinoma Allergy Immunol, 133: 113-120, 2004), and the like, and it is also known that the anti-allergic effect and anti-inflammatory activity (Int. F1 is known to protect human HaCaT keratinocytes by inhibiting the expression of Bcl-2 and Brn-3a from apoptosis by irradiation with ultraviolet B (J. Invest. Dermatol. 121: 607-13 , 2003).

Compound K, which has excellent inhibitory action and immunity against various tumors including hepatocellular carcinoma, is hydrophobic. Therefore, it is soluble in organic solvents such as alcohols such as methanol and ethanol, and organic solvents such as pyridine, but the solubility in water is very low. It has been difficult to commercialize such products as drinks. In order to overcome this difficulty, there has been reported a covalent bond with a compound K of glycol chitosan, which is a hydrophilic substance. (Carbohydr Polym. 2014 Nov 4; 112: 359-66).

The present invention discloses a technique capable of increasing the solubility of Compound (K) in water by using cyclodextrin or the like.

It is an object of the present invention to provide a composition of the ginsenoside compound K improved in water solubility.

Other and further objects of the present invention will be described below.

As shown in the following Examples and Experimental Examples, the inventors of the present invention prepared an aqueous solution containing only the compound K, and prepared an aqueous solution containing the compound K as -cyclodextrin, -cyclodextrin, -cyclodextrin -cyclodextrin) or taurine was added to the aqueous solution to prepare an aqueous solution, and the concentration of the compound K in each aqueous solution was measured by HPLC. In the case of the aqueous solution prepared by adding cyclodextrin, as compared with the simple aqueous solution of the compound K in which cyclodextrin was not added It was confirmed that the concentration of the compound K was increased at least 16 times or at most 40 times.

In the case of aqueous solution prepared by adding taurine to compound K, the concentration of compound K increased from about 2.5 times to 5.1 times.

The present invention provides, on the basis of these experimental results, the composition of the water-improving ginsenoside compound K of the present invention, which comprises a ginsenoside compound K and contains water as a solvent, And cyclodextrin or taurine capable of improving water solubility.

In the present specification, "ginsenoside K" follows the same meaning as it is known in the art. Specifically, PPD saponins derived from ginseng are produced by elimination of sugar by intestinal microorganisms. -beta-d-glucopyranosyl-20 (S) -protopanaxadiol. The chemical structural formula thereof can be confirmed in the following formula (1).

[Chemical Formula 1]

As used herein, the term "cyclodextrin" is a food additive listed in the Food Additive Ordinance according to the Food Hygiene Act, which is widely used for increasing the stickiness and viscosity of foods and stabilizing flavoring agents and coloring agents. It follows the meaning of what is known in the industry. Specifically, glucose means oligosaccharide which is cyclized through -1,4-glycosidic bond. There are three types of cyclodextrins: cyclodextrin (molecular weight 972.85) consisting of 6 glucose, cyclodextrin (molecular weight 1134.99) consisting of 7 glucose, and cyclodextrin (molecular weight 1297.14) composed of 8 glucose.

As used herein, "taurine" means a compound having the formula C ₂ H ₇ NO ₃ S and having a molecular weight of 125.14. Taurine, like cyclodextrin, is a food additive listed in the Food Additives Ordinance according to the Food Hygiene Act. It is known to be an organic acid that is common in animal tissues including humans, and has antioxidant activity and obesity inhibitory activity.

In the composition of the present invention, the addition amount of cyclodextrin or taurine depends on the concentration of the compound K, the purity of the compound K, the presence or absence of heating in the aqueous solution preparation step, the presence or absence of stirring, Food, cosmetics, or medicines, and specifically refers to beverages in the case of foods), and in a specific product form, it may be determined in consideration of a desirable amount of the compound K, an effective amount, and the like. As the addition amount of cyclodextrin or taurine increases, the water solubility of the compound K will increase. Therefore, in order to increase the solubility of the compound K, it may be preferable to increase the addition amount of cyclodextrin or taurine in proportion thereto. The amount of such cyclodextrin or taurine to be added can be determined experimentally within the ordinary skill in the art. Considering the following examples and experimental examples, it is preferable that the addition amount of cyclodextrin is at least 10 times (weight) or more, especially 20 times (weight) or more than that of compound K.

In the composition of the present invention, the compound K may be contained at a concentration lower than its saturation concentration at room temperature when the addition amount of cyclodextrin or taurine is determined. The saturation concentration or the titratable amount of the compound K may also be determined within the ordinary skill of those skilled in the art in consideration of the purity of the compound K, the desired amount of the compound K, the effective amount, and the like.

The composition of the present invention may be heated or stirred in its production step regardless of its product form in order to increase the solubility of the compound K.

The composition of the present invention may be prepared in a food composition in a specific embodiment.

When the composition of the present invention is prepared as a food composition, the food composition may be classified into any product category according to the use of the food. Specifically, the food composition may be a health functional food, a health supplement food, a special nutrition supplement food, . The form of the food may be any form as long as the water can be contained as a solvent. Examples of the form of the food include drinks such as tea, juice, carbonated drink, ionic drink, milk such as milk, route required, paste, syrup, Semi-solid formulations and the like. In the case of semi-solid products made of water such as pastes, syrups, and gels, these products may be used as they are without additional processing, or water may be added as a solvent.

The food composition of the present invention may contain sweetening agents, flavoring agents, physiologically active ingredients, minerals and the like in addition to the active ingredients thereof.

Sweetening agents may be used in an amount that sweetens the food in a suitable manner, and may be natural or synthetic. Preferably, natural sweeteners are used. Examples of natural sweeteners include sugar sweeteners such as corn syrup solids, honey, sucrose, fructose, lactose and maltose.

Flavors may be used to enhance taste or flavor, both natural and synthetic. Preferably, a natural one is used. When using natural ones, the purpose of nutritional fortification can be performed in addition to the flavor. Examples of natural flavoring agents include those obtained from apples, lemons, citrus fruits, grapes, strawberries, peaches, and the like, or those obtained from green tea leaves, Asiatica, Daegu, Cinnamon, Chrysanthemum leaves and Jasmine. It may also be obtained from ginseng (red ginseng), bamboo shoots, aloe vera, banks and the like. The natural flavoring agent may be a liquid concentrate or a solid form of extract. Synthetic flavors may be used depending on the case, and synthetic flavors such as esters, alcohols, aldehydes, terpenes and the like may be used.

Examples of the physiologically active substance include catechins such as catechin, epicatechin, gallocatechin and epigallocatechin, and vitamins such as retinol, ascorbic acid, tocopherol, calciferol, thiamine and riboflavin.

As the mineral, calcium, magnesium, chromium, cobalt, copper, fluoride, germanium, iodine, iron, lithium, magnesium, manganese, molybdenum, phosphorus, potassium, selenium, silicon, sodium, sulfur, vanadium and zinc can be used.

In addition, the food composition of the present invention may further contain preservatives, acidifiers, thickeners, and the like in addition to the above sweeteners.

It is preferable that such a preservative or the like is added and used in a small amount so long as it can attain the use to which it is added. Trace amounts, when expressed numerically, range from 0.005% to about 0.5% by weight, based on the total weight of the food composition.

Preservatives that can be used include calcium sorbate, sodium sorbate, potassium sorbate, calcium benzoate, sodium benzoate, potassium benzoate, and EDTA (ethylenediaminetetraacetic acid).

Examples of the acidulant that can be used include acid, malic acid, fumaric acid, adipic acid, phosphoric acid, gluconic acid, tartaric acid, ascorbic acid, acetic acid, and phosphoric acid. Such an acidulant may be added so that the food composition has a proper acidity for the purpose of inhibiting the growth of microorganisms other than the purpose of enhancing the taste.

Agents that may be used include suspending agents, sedimentation agents, gel formers, bulking agents and the like.

Food additives and food additives according to the Food Sanitation Law can be referred to in relation to other food types or additives which are required to be used depending on the type of food.

The compositions of the present invention a ginsenoside compound K is true due to the biosynthesis inhibitory activity of gelatinase tea tyrosinase (Korea Patent Registration No. 10-1140039 call), etc. or skin wrinkles, skin whitening activity (jeongseonyoung, Lactobacillus brevis that biomolecule Synoveide Compound K and F1 conversion and tyrosinase inhibitory effect, Kyung Hee University, master's thesis, 2014). Therefore, in other specific embodiments, it can also be produced as a cosmetic composition.

When the composition of the present invention is prepared by a cosmetic composition, the cosmetic composition may be classified into any product category according to the use of the cosmetic composition. Specifically, the cosmetic composition may be a functional cosmetic having a use such as skin whitening, . As long as water is used as a solvent in the form of a product, it may be in any product form, and may be in the form of a liquid product such as an aqueous solution or a suspension, or a semi-solid product such as paste, gel, cream, .

When the composition of the present invention is prepared with a cosmetic composition, it may contain ingredients conventionally used in cosmetic compositions, such as stabilizers, vitamins, colorants, conventional adjuvants such as antioxidants, and carriers.

Specifically, when the composition of the present invention is prepared from a liquid cosmetic composition such as a solution or suspension, it may contain, in addition to water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, Butyl glycol oil, glycerol aliphatic ester, polyethylene glycol, fatty acid ester of sorbitan, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and the like.

When the composition of the present invention is made of a semi-solid cosmetic composition such as a paste, a cream, a lotion or a gel, it may contain starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, Zinc, and the like.

The cosmetic composition of the present invention can be manufactured to include skin whitening ingredients, skin wrinkle improving ingredients, ultraviolet ray protecting ingredients, and the like known in the art in order to reinforce and add skin-related activities. Specific examples of such components may refer to the functional cosmetic products according to the Cosmetic Act. Examples of skin whitening ingredients include arbutin, niacinamide, ascorbyl glucoside, alpha-bisabolol, and oil soluble licorice (Glycyrrhiza) extract.

The composition of the present invention can also be prepared as a pharmaceutical composition when the ginsenoside compound K, which is a physiologically active substance thereof, is used as a raw material for medicines such as anticancer drugs.

When the composition of the present invention is prepared from a pharmaceutical composition, the pharmaceutical composition may be formulated into oral formulations according to the route of administration by conventional methods known in the art, including pharmaceutically acceptable carriers in addition to water and compound K, cyclodextrin Or parenteral formulations. The term "pharmaceutically acceptable" as used herein means that the application (prescribing) subject does not have the above-mentioned toxicity that is adaptable without inhibiting the activity of the active ingredient.

When the pharmaceutical composition of the present invention is prepared into an oral formulation, it may be formulated into a liquid, a gel, a syrup, a suspension or the like according to a method known in the art together with a suitable carrier in addition to water as a solvent. Examples of suitable pharmaceutically acceptable carriers include sugars such as lactose, glucose, sucrose, dextrose, sorbitol, mannitol, xylitol, starch such as corn starch, potato starch and wheat starch, cellulose, methylcellulose, ethylcellulose, Cellulose derivatives such as sodium carboxymethyl cellulose and hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, methylhydroxybenzoate, propylhydroxybenzoate, magnesium stearate, mineral oil, malt, gelatin, talc, polyol, . In case of formulation, a diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and / or an excipient may be formulated according to need.

When the pharmaceutical composition of the present invention is prepared into a parenteral formulation, it may be formulated in an injectable form according to a method known in the art together with a suitable carrier. Examples of suitable carriers for the preparation of injections include sterilized water, polyols such as ethanol, glycerol and propylene glycol, and mixtures thereof. Preferred examples of the carrier include phosphate buffered saline (PBS) containing Ringer's solution and triethanolamine, Sterile water, isotonic solution such as 5% dextrose, and the like.

As described above, according to the present invention, by including cyclodextrin or taurine capable of improving the water solubility of the ginsenoside K, in addition to containing the ginsenoside compound K and containing water as a solvent, To provide a composition of Senocide K.

Since the composition of the present invention contains the ginsenoside compound K having improved water solubility, it is possible to adjust the amount of the ginsenoside compound K, the effective amount, and the like, so that the amount of the ginsenoside compound K can be adjusted by the manufacturer or the user, Of cosmetics such as medicines, skin lotions, and the like.

Hereinafter, the present invention will be described with reference to Examples and Experimental Examples. However, the scope of the present invention is not limited to these examples and experimental examples.

< Example > Gin Senocide  Preparation of aqueous solution of compound K

Example 1 Production of aqueous solution of ginsenoside K

10 mg of a ginsenoside compound K (CK crystal) having a purity of 98% or more was placed in a 250 ml beaker, and 100 ml of water was added thereto. The mixture was placed on a hot plate and stirred for 20 minutes while boiling. At this time, when the volume of water evaporated, the volume of evaporated volume was added during the heating. This was left overnight at room temperature, transferred to a 100 ml volumetric flask the following day, and scaled with water. It was filtered with a 0.20 μm filter and 20 μl was taken and used in the HPLC analysis experiment below.

<Example 2> Preparation of binary aqueous solution of ginsenoside Compound K Example 2

1 g of? -Cyclodextrin,? -Cyclodextrin or? -Cyclodextrin was added to 10 mg or 20 mg of CK crystals, which was then placed in a 250 ml beaker and 100 ml of water was added. Then, the same manufacturing method as in <Example 1> was followed.

&Lt; Example 3 > Preparation Example 3 of aqueous solution of ginsenoside K

An aqueous solution of ginsenoside K was prepared in the same manner as in Example 1, except that 25 mg of a compound having a purity of about 40% (CK-40) was used as the innose compound K.

Example 4 Production Example 4 of aqueous solution of ginsenoside K

1 g of? -Cyclodextrin,? -Cyclodextrin or? -Cyclodextrin was added to prepare an aqueous solution of ginsenoside K in the same manner as in Example 2, except that 25 mg of GK or 40 mg of ginsenoside K was used Respectively.

<Example 5> Preparation of binary aqueous solution of ginsenoside Compound K Example 5

After adding 1 g of taurine to 10 mg of CK crystals, it was put into a 250 ml beaker and 100 ml of water was added. Then, the same manufacturing method as in <Example 1> was followed.

However, to break the micelle structure formed by taurine and CK before HPLC, some of the 100 ml aqueous solution was added, and the same amount of 95% alcohol was added. After filtration with 0.2 μm filter, 20 ul of the filtrate was analyzed by HPLC.

Example 6 Production Example 6 of aqueous solution of ginsenoside K

An aqueous solution of ginsenoside K was prepared in the same manner as in Example 5, except that 25 mg of CK-40 was used.

< Comparative Example > Gin Senocide  Compound K Alcohol  Preparation of solution

10.0 mg of CK crystals or 25.0 mg of CK-40 was dissolved in alcohol (95% ethanol), transferred to a 100 ml volumetric flask, and the scale was adjusted with alcohol. The solution was filtered with a 0.20 탆 filter and 20 쨉 l of the filtrate was taken, HPLC analysis.

< Experimental Example > Gin Senocide  Solubility measurement of compound K

HPLC (JASCO, LC-Net / ADC) C18 column (4.6 × 250 mm, 5 μm) was used to measure the solubility of the ginsenoside compound K in the aqueous solution or alcohol solution samples prepared in the above Examples and Comparative Examples And the UV absorbance of the detector was measured at 203 nm using a UV detector. The mobile phase was separated by gradient elution using water and acetonitrile and the flow rate was maintained at 1 ml / min.

HPLC analysis conditions time water acetonitrile 0 25% 75% 10 25% 75% 15 0% 100% 20 0% 100%

From the above HPLC analysis, the peak area of the 7th minute was calculated as the valley to valley from the HPLC results of the solution of the CK crystals dissolved in alcohol (comparative example), and this area (standard area) was calculated to correspond to the CK concentration of 100 / / ml , And the same 7-minute peak area was obtained by the same method in the remaining HPLC results, and the area ratio was calculated to the standard area to calculate the CK concentration. The results are shown in [Table 3] and [Table 4] below.

HPLC results of CK crystals
division
CK crystal
[mg] additive
[1g]
solvent dilution before
HPLC CK concentration
[[Mu] g / ml] Comparative Example 10 0 95% ethanol One 100 Example 1 10 0 water One 4.4

Example 2 10 alpha-cyclodextrin water One 75.4 20 alpha-cyclodextrin water One 113 10 β-cyclodextrin water One 77.9 20 β-cyclodextrin water One 104 10 γ-cyclodextrin water One 91.9 20 γ-cyclodextrin water ½ * 167 Example 5 10 taurine water ½ 11.0   * Before HPLC, the sample was diluted with water twice and then measured by HPLC

HPLC results of CK-40
division
CK-40
[mg] food additive
[1g] solvent
dilution before
HPLC CK concentration
[[Mu] g / ml] Comparative Example 25 0 95% ethanol One 114 Example 3 25 0 water One 5.3

Example 4 25 alpha-cyclodextrin water One 84.5 50 alpha-cyclodextrin water One 144 25 β-cyclodextrin water One 87.1 50 β-cyclodextrin water One 146 25 γ-cyclodextrin water One 106 50 γ-cyclodextrin water ½ * 212 Example 6 25 taurine water ½ 27.1  * Before HPLC, the sample was diluted with water twice and then measured by HPLC

Referring to [Table 3] and [Table 4], it can be seen that the solubility is significantly increased when cyclodextrin or the like is used. Specifically, the concentration of CK in Example 1 in which cyclodextrin was not added was 4.4 μg / ml. When cyclodextrin was added, the concentration of CK crystals (Example 2) was 75.4 to 167 μg / ml, about 17 to 38 times , And in the case of CK-40 (Example 3 and Example 4), it increased about 16 to 40 times from 5.3 to 84.5 to 212 g / ml at 5.3 g / ml.

When 1 g of taurine was added to 10 mg of CK crystals, the CK concentration was increased 2.5 times. When 1 g of taurine was added to 25 mg of CK-40, the CK concentration was increased 5.1 times. However, the aqueous solution to which taurine was added became an emulsion. Therefore, when the filter was filtered with 0.2 filter, all of the emulsion particles were caught in the filter. Therefore, in order to obtain a transparent solution by crushing the emulsion particle, an equal volume of 95% alcohol was added before HPLC and the filtrate was subjected to HPLC.

Claims (6)

A composition of improved water-solubility ginsenoside K, comprising cyclodextrin or taurine capable of improving the water solubility of the ginsenoside K, in addition to containing ginsenoside K and containing water as a solvent.
The method according to claim 1,
Wherein the cyclodextrin is? -Cyclodextrin,? -Cyclodextrin,? -Cyclodextrin, or a mixture thereof.
The method according to claim 1,
Wherein the composition is a food composition.
The method according to claim 1,
Wherein the composition is a beverage.
The method according to claim 1,
Wherein the composition is a cosmetic composition.
The method according to claim 1,
Wherein the composition is a pharmaceutical composition.