KR101408170B1 - Pharmaceutical composition and functional food for prevention or treatment of restenosis comprising the lactic acid bacteria ferment of soshihotang - Google Patents

Abstract

The present invention relates to a fermentation product of a natural product extract which is effective for prevention or treatment of vascular restenosis, and more particularly, to a pharmaceutical composition for preventing or treating vascular restenosis comprising an active ingredient of a fermented product of lactic acid bacteria of Soshiho Tang, .

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition and a functional food for prevention or treatment of vascular restenosis comprising an active ingredient of a lactic acid fermented product of Soshiho Tang,

The present invention relates to a pharmaceutical composition and a health functional food for preventing or treating vascular restenosis comprising a fermented product of lactic acid bacteria of Soshifohang as an effective ingredient.

The incidence of cardiovascular (coronary) disease, represented by angina, myocardial infarction, and sudden death, has increased dramatically and has seen remarkable progress over the last decade in terms of treatment. In addition to medication, various treatments such as coronary artery bypass grafting and a stent insertion procedure in which the narrowed blood vessels are connected by a surgical method are developed and the coronary arteries become narrow due to arteriosclerosis, giving hope to the suffering patients And became a new electricity in the treatment of heart disease.

Medication can not fundamentally resolve the stenosis, and should continue to take antianxiety medication. There is a limit to medication, so even if you take medication, you may still have chest pain due to angina. On the other hand, coronary artery dilatation hemorrhage is a non-invasive method that can be used to treat narrowed blood vessels, is effective in relieving the symptoms of angina, and does not need to reduce the use of anti-angina drugs.

In addition, percutaneous transluminal coronary angioplasty was introduced by Adreas Gruentzig in 1977 for the first time in clinical practice and was thought to be a revolutionary treatment for coronary artery and carotid stenosis. The restenosis occurred in%. Despite these limitations, percutaneous coronary intervention has been used to treat patients with ischemic heart disease.

A stent for the prevention of vascular restenosis was developed and first introduced into the coronary artery by Sigwart et al. In 1986, and vascular restenosis was reduced to 20 to 30%. However, despite the introduction of new devices and advances in technology and efforts to prevent vascular reoccurrence, vascular restenosis after coronary intervention or stenting still remains a problem.

Coronary artery stenosis due to atherosclerosis develops slowly over the years to decades, while vascular restenosis results from several molecular and cellular biologic cascades within the vessel wall due to dilatation of the coronary arteries, resulting in only a few weeks to months . Therefore, the pathophysiological characteristics of vascular restenosis are different from the occurrence of general atherosclerosis, and an artificial mechanical damage is applied to the vessel wall during coronary artery intervention, and as a natural healing process, numerous vasoactive substances, Substances and cleavage promoting substances are secreted, resulting in intense cellular reactions. As a result, neointimal hyperplasia occurs, resulting in narrowing of the lumen and eventual restenosis of the upper, lower, left and right vessels. Recent studies have shown that the majority of neovascular hypertrophic episodes consist of the following two important steps [Tung R., et al., Narrative review: drug-eluting stents for a management of restenosis: a critical appraisal of the evidence. Ann. Intern. Med. vol. 144 (12): 913-919 (2006)).

The first stage is the inflammation phase, which is a healing process of blood vessels damaged by the plasty procedure or stent insertion, causing local thrombus formation, which causes inflammatory cells to actively infiltrate into the vascular endothelium. Infiltration of inflammatory cells occurs mainly 3-7 days after the procedure. The second stage is a proliferative phase in which the infiltrating inflammatory cells stimulate vascular smooth muscle cells to induce excessive cell proliferation, usually occurring one week after the procedure. Therefore, in order to effectively prevent vascular restenosis, at least one of the above two steps must be effective. The immunosuppressant sirolimus [rapamucin], a drug currently used to prevent vascular restenosis, has the greatest effect in the second step described above. These drugs can not be produced in large quantities, so they are treated as expensive drugs, and they are being antagonized by multinational pharmaceutical companies. Therefore, development of more economical and more stable drugs and compositions for preventing vascular restenosis is required.

Accordingly, the inventors of the present invention have been studying natural medicines for preventing or treating vascular restenosis as described above, wherein the fermented product of lactic acid bacteria of the mixed herbal medicine extract of Seiho, Golden, Ginseng, Licorice, And thus the present invention has been completed.

It is an object of the present invention to provide a pharmaceutical composition or health functional food composition containing as an active ingredient fermented lactic acid bacteria of Soshiho Tang, which can prevent or treat vascular restenosis.

In order to solve the above-mentioned problems, the present invention provides a pharmaceutical composition for preventing or treating vascular restenosis, which comprises a fermented product of lactic acid bacteria of Soshiho Tang as an active ingredient.

The term " Soshihokuto " as used in the present invention refers to a mixture of ginseng root, ginseng, ginseng, licorice, half summer, ginger, And a control (大 大). It means a herbal medicine-derived herbal medicine having effects such as hepatitis improvement, anti-allergic action, anti-inflammatory action, fatty liver improvement, digestive disorder improvement and nervous stability effect. The Soshifotang of the present invention is preferably a hydrothermal extract of Shiho, Golden, Ginseng, Licorice, Banha, Ginger and Contrast.

The term " fermented product of lactic acid bacteria " used in the present invention means the result of culture obtained from a culture obtained by inoculating lactic acid bacterium into a medium in which lactic acid bacteria can grow. The fermented product of lactic acid bacteria of the present invention is preferably fermented at a temperature of 35 ° C to 45 ° C and for a period of 1 day to 3 days under an aerobic atmosphere by inoculating lactic acid bacteria into the Soshiho Tang.

Preferably, the lactic acid bacterium belongs to the genus Lactobacillus, and the genus of Lactobacillus is selected from the group consisting of Lactobacillus plantarum, Lactobacillus amylophilus, Lactobacillus casei, , Lactobacillus curvatus, Lactobacillus delbrueckii subsp. Lactis, and Lactobacillus bulgaricus. [0033] The term " Lactobacillus bulgaricus "

The lactic acid bacteria may be, but not limited to, Bifidobacterium, Streptococcus, Leuconostoc, Pediococcus or Lactococcus.

The term " vascular restenosis " used herein refers to a process in which smooth muscle cells are excessively proliferated and restenosis of blood vessels, which means undesirably excessive healing process caused by damage to the inner lining of the coronary artery.

In the present invention, it has been confirmed that a composition containing the fermented product of lactic acid bacteria of Soshiho Tang is effective for preventing or treating vascular restenosis. According to one embodiment of the present invention, it was confirmed that the inhibitory effect of proliferation of smooth muscle cells, which is an index of vascular restenosis, is effective for preventing or treating vascular restenosis.

The term " prevention " used in the present invention means all the actions of inhibiting or delaying the disease by administration of the composition containing the lactic acid fermented product of Soshiho Tang. The term " treatment " used in the present invention means all the actions of improving or alleviating symptoms of the disease by administration of the composition containing the lactic acid fermented product of Soshiho Tang.

The composition of the present invention may contain, for administration, a pharmaceutically acceptable carrier, excipient or diluent in addition to the above-described effective ingredients. The carrier, the beating agent and the diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium and stearate, and mineral oil.

The composition of the present invention may be formulated in the form of oral, granule, tablet, capsule, suspension, emulsion, syrup, aerosol or the like oral preparation, external preparation, suppository or sterilized injection solution according to a conventional method. In detail, when formulating it, it can be prepared using diluents or excipients such as fillers, weighing agents, binders, humectants, disintegrants, surfactants and the like which are generally used. Solid formulations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, and the like. Such a solid preparation can be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin and the like in the fermented product of lactic acid bacteria of Soshiho Tang. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration, liquid paraffin, various excipients such as wetting agents, sweetening agents, fragrances, preservatives and the like. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and tasks. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. As a base for suppositories, it is possible to use witepsol, macrosole, tween 61, cacao paper, laurin, glycerogelatin and the like.

The composition of the present invention may be administered or parenterally administered (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may be determined depending on the condition and the weight of the patient, The mode of administration, the route of administration, and the time, but may be suitably selected by those skilled in the art. The daily dose of the lactic acid bacterium fermented product of Soshiho Tang is preferably 1 mg / kg to 500 mg / kg, and may be administered once to several times per day as needed.

In addition, the present invention provides a health functional food composition for preventing or ameliorating vascular restenosis, which comprises a fermented product of lactic acid bacteria of Soshiho Tang as an active ingredient.

The health functional food may contain flavoring agents such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and enhancers (cheese, chocoline etc.), pectic acid and its salts, alginic acid and its salts, Organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. It can also contain natural fruit juices and pulp for the production of fruit juices and vegetable drinks. These components may be used independently or in combination. In addition, the health functional food may be any one of meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen gum, ice cream, soup, beverage, tea, functional water, drink, alcohol and vitamin have.

In addition, the health functional food may further include food additives, and the suitability of the food functional food as a "food additive" is not limited to the corresponding items in general rules and general test methods approved by the Food and Drug Administration Shall be determined according to the relevant standards and standards.

Examples of the products that have been used in the above-mentioned "food additives" include natural products such as ketones, chemical products such as glycine, potassium citrate, nicotinic acid and cinnamic acid, sensory coloring matter, licorice extract, crystalline cellulose, high- - Mixed preparations such as a sodium glutamate preparation, a noodle-added alkaline agent, a preservative preparation, a tar coloring agent and the like.

At this time, the lactic acid fermented product of Soshiho Tang according to the present invention, which is added to the food containing beverages in the course of manufacturing the health functional food, may be appropriately added or decreased as required, By weight to 15% by weight.

The present invention is a fermented lactic acid fermented product of Soshiho Tang, which is effective for prevention or treatment of vascular restenosis, and can be used not only as a pharmaceutical composition for preventing or treating vascular restenosis but also as a health functional food.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the results of suppressing the proliferation inhibition of Soshihotang and Soshihotang fermented products on abnormal proliferation induced by PDGF (Platelet-derived Growth Factor) -BB in vascular smooth muscle cells according to an embodiment of the present invention.
FIG. 2 is a graph showing an effect of inhibiting abnormal proliferation of vascular smooth muscle cells by Soshihotang and Soshihotang fermented products obtained by cell counting using a hemocyte according to an embodiment of the present invention.

Hereinafter, the present invention will be described in more detail with reference to the following Production Examples and Examples. However, the following Preparation Examples and Examples are for illustrating the present invention, but the scope of the present invention is not limited thereto.

Example : Soshihotan  Lactobacillus Fermentation product  Produce

1) Manufacture of Soshihotang (CH)

Soshihotang is a oriental herbal medicine which is made by extracting Seoho, Golden, Ginseng, Licorice, Banha, Ginger and Contrast. The mixture was prepared at a ratio of 12 g of Seoho, 8 g of gold, 4 g of ginger, 1.49 g of ginger, 4 g of ginseng, 2 g of control, and 2 g of licorice. The total content of 50 kinds of medicinal herbs was 1,674 g, which was extracted with 16.74 ℓ of distilled water for 10 minutes and extracted with hot water for 150 minutes and then filtered using a standard testing sieve (Aperture 500 ㎛ and 150 ㎛) .

2) Production of fermented lactic acid bacteria from Soshiho-tang

Lactobacillus was inoculated into Soshiho Tang prepared in Example 1) and fermented to prepare a fermented product of Soshihotang lactic acid bacteria. 1% v / v lactic acid bacteria (1 x 10 ⁸ to 5 x 10 ⁸ CFU / ml) was inoculated into the Soshiho Tang prepared in Example 1), fermented at 37 ° C for 48 hours, Followed by filtration to produce a lactic acid fermented product of Soshiho Tang. Lactobacillus plantarum (KFRI 144), lactobacillus amylopyrus (KFRI 161) and lactobacillus bulgaricus (KFRI 344) were used as the lactic acid bacteria. The prepared Soshihotang lactobacillus fermented product was lyophilized and stored at 4 ° C until use.

Experimental Example : Effect of Aortic Smooth Muscle Cells on Growth Inhibition

The inhibitory effect of Soshiho Tang prepared in Example 1) and Example 2 on the inhibition of smooth muscle cell proliferation of fermented lactic acid bacteria was measured. The fermented lactic acid bacteria of Soshiho-tang and Soshiho-tang produced in Example 1) and Example 2) were mixed with CH (Soshiho-tang), CH con (sterilized Soshohokutan), CH 144 (KFRI 144 Soshihotang fermented product) 161 (KFRI 161 Soshihotang fermented product) and CH 344 (KFRI 344 Soshihotang fermented product). Aortic smooth muscle cells (4.0 × 10 ⁴ cells / ml) were transferred to a 96-well plate and incubated with 0.5% (v / v) fetal bovine serum And cultured in DMEM medium for 24 hours. Then, the medium was treated with CH, CH3 con, CH144, CH161 and CH344 at a concentration of 500 μg / ml, and further cultured for another 24 hours. After that, the cells were treated with a platelet-derived prowth factor (PDGF-BB), treated with CCK-8 (Dojindo, Japan) kit 22 hours later, and the antiproliferative efficacy against vascular smooth muscle cells And the results are shown in FIG.

As shown in FIG. 1, it was confirmed that CH 144, CH 161 and CH 344, which are fermented products of Soshiho-tang lactic acid bacteria, effectively inhibited abnormal proliferation of aortic smooth muscle cells by the platelet-derived growth factor. Among them, CH 144 not only enhanced the antiproliferative effect but also the most excellent antiproliferation effect as compared with the control group containing CH.

The number of cells isolated using a hemocytometer was counted to determine whether the fermentations of Lactobacillus bacteria of Soshiho Tang in Example 2 were inhibiting the growth of aortic smooth muscle cells. To determine whether or not the fermentations of aortic smooth muscle cells inhibited the growth of aortic smooth muscle cells, 4.0 × 10 ⁴ cells / The cells were transferred to a 12-well plate and cultured in DMEM medium containing 0.5% (v / v) fetal bovine serum for 24 hours. Then, the medium was treated with CH, CH3 con, CH144, CH161 and CH344 at a concentration of 500 μg / ml, and further cultured for another 24 hours. The cells were then treated with platelet-derived prowth factor (PDGF-BB) and treated with trypsin 24 hours later to separate the cells from the bottom. Separated cells were counted using a hemocytometer, and the results are shown in FIG.

As shown in FIG. 2, it was confirmed that the CH 144, CH 161 and CH 344 fermented by Soshihotang lactic acid bacteria inhibited the abnormal proliferation of aortic smooth muscle cells by the platelet-derived growth factor. Among the results, CH 144 was a control group , CH 161 and CH 344, respectively. In addition, it was confirmed that CH 144 enhanced the inhibitory effect on the aortic smooth muscle cells compared with CH and CH con, and it was confirmed that it did not decrease compared with the normal aortic smooth muscle cells not treated with the platelet-derived growth factor, The inhibitory effect was confirmed.

Claims (10)

A pharmaceutical composition for the prevention or treatment of vascular restenosis, which comprises a fermented product of lactic acid bacteria of Soshiho Tang as an active ingredient.
[Claim 2] The pharmaceutical composition according to claim 1, wherein the Soshifohang is a hot-water extract of Shiho, Golden, Ginseng, Licorice, Half, Ginger and Contrast.
[Claim 2] The pharmaceutical composition according to claim 1, wherein the lactic acid bacteria fermented product is inoculated with the lactic acid bacteria in the Soshifohtang and fermented under an aerobic atmosphere at a temperature of 35 [deg.] C to 45 [deg.] C for 1 to 3 days.
4. The pharmaceutical composition according to claim 3, wherein the lactic acid bacterium belongs to the genus Lactobacillus.
The method according to claim 4, wherein the Lactobacillus genus is selected from the group consisting of Lactobacillus plantarum, Lactobacillus amylophilus, Lactobacillus casei, Lactobacillus cabbage, wherein the composition is at least one selected from the group consisting of Lactobacillus delbrueckii subsp. lactis and Lactobacillus bulgaricus.
A health functional food composition for preventing or ameliorating vascular restenosis comprising Soshohotang's fermented product of lactic acid bacteria as an active ingredient.
[Claim 7] The health functional food composition according to claim 6, wherein the Soshifohang is a hot-water extract of Shiho, Golden, Ginseng, Licorice, Half, Ginger and Contrast.
The health functional food composition according to claim 6, wherein the fermented lactic acid bacteria is fermented at a temperature of 35 ° C to 45 ° C for 1 to 3 days under inoculated aerobic bacteria by inoculating lactic acid bacteria into the Soshiho Tang .
The health functional food composition according to claim 8, wherein the lactic acid bacterium belongs to the genus Lactobacillus.
10. The method of claim 9, wherein the Lactobacillus genus is selected from the group consisting of Lactobacillus plantarum, Lactobacillus amylophilus, Lactobacillus casei, Lactobacillus cabbage, wherein the composition is at least one selected from the group consisting of Lactobacillus delbrueckii subsp. lactis and Lactobacillus bulgaricus.

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