KR20230039527A - Composition for preventing, ameliorating or treating arthritis comprising Inula helenium Linne extract as effective component - Google Patents

Abstract

The present invention relates to a composition for preventing, ameliorating or treating arthritis comprising an Inula helenium Linne extract as an effective component. The Inula helenium Linne extract of the present invention reduces the content of prostaglandin E2 (PGE2), which is an inflammatory mediator, has an excellent inhibitory effect on MMPs, which is a cartilage matrix decomposing enzyme, reduces the content of GAG, exhibits an analgesic effect in pain-induced animal models, and has the effect of relieving edema. Therefore, the composition of the present invention can be usefully used for preventing, ameliorating or treating arthritis.

Description

Composition for preventing, ameliorating or treating arthritis comprising Inula helenium Linne extract as effective component}

The present invention relates to a composition for preventing, improving or treating arthritis, containing an extract of Geomokhyang as an active ingredient.

As we enter an aging society, inflammatory diseases including arthritis are socially emerging regardless of gender. Inflammatory diseases caused by this inflammatory response include gastritis, colitis, arthritis, nephritis, hepatitis, arteriosclerosis, cancer, or degenerative diseases. Among them, effective drugs or treatments for the prevention and treatment of arthritis have not yet been developed. Arthritis refers to an inflammatory change in a joint due to various causes such as aging, mechanical damage, and immune abnormality.

Among the above-mentioned arthritis, osteoarthritis (osteoarthritis) is a kind of arthritis, also called degenerative arthritis, refers to arthritis caused by degenerative changes in cartilage and surrounding bones in synovial joints. That is, osteoarthritis is a disease characterized by gradual loss of articular cartilage, hypertrophy of bones located below the cartilage, bone formation at the joint edge, and non-specific synovial inflammation. Osteoarthritis is a disease caused by damage to cartilage due to aging or excessive physical pressure (eg, obesity, trauma, etc.). Therefore, osteoarthritis shows severe pain and movement disorders in joints that receive a lot of weight, that is, knee (knee) joints, hip (hip) joints, etc., and even causes deformation of the joints when left unattended for a long period of time.

In addition, gouty arthritis is an inflammation caused by the deposition of uric acid in the space and tissues within the joint. As the concentration of uric acid (a product left after the body metabolizes a substance called purine consumed through food) increases, the uric acid (Uric acid exists in the form of uric acid in blood, body fluids, and joint fluid.) It is a disease in which crystals are deposited in joint cartilage, tendons, and surrounding tissues. This phenomenon causes inflammation of the joint, resulting in recurrent attacks with excruciating pain.

On the other hand, Inula helenium Linne is the Korean plant name Inula helenium Linne, but to avoid confusion with Inula helenium Linne as a genuine product, we decided to express the Korean plant name as Inula helenium Linne, unlike the taxonomic description. The root is conical, slightly bent, 10 to 30 cm long and 1 to 3 cm in diameter. The outer surface is yellowish brown to dark brown, and has vertical wrinkles and beard root marks. The head is thick, has a stem mark at the top, sometimes leaves are attached, and there are cone-shaped side branches around it. The quality is hard and does not break easily. The bent surface is slightly flat, yellowish white to light grayish yellow, and has a slight pitted washout. It is slightly fragrant and tastes bitter and spicy. In pharmacological experiments, it was revealed that it inhibits increased stomach movement and secretion, choleretic, anti-inflammatory, expectorant, and antibacterial effects. The ingredient allantolactone kills roundworms and exhibits antibacterial activity. It is used for bloating, stomachache, side pain, poor appetite, indigestion, diarrhea, dysentery, back pain, convulsive cough, skin itching, scabies, eczema, etc. It can also be used for intestinal tuberculosis and bronchitis.

As prior art related to geomokhyang, Korean Patent Publication No. 2017-0053770 discloses a composition for preventing, treating, or improving inflammatory bowel disease containing a mixed extract containing chamomile and health as an active ingredient, and a method for manufacturing the same. , A composition for preventing, improving or treating arthritis containing the extract of the present invention as an active ingredient has not been disclosed.

The present invention has been derived from the above needs, and the present invention provides a composition for preventing, improving or treating arthritis containing an extract of Inula helenium Linne as an active ingredient, and the extract of Inula helenium Linne of the present invention It reduces the content of prostaglandin E2 (PGE2), an inflammatory mediator, has excellent inhibitory effects on MMPs, which are cartilage matrix degrading enzymes, reduces the GAG content, exhibits analgesic effects in pain-induced animal models, and relieves swelling. By confirming that there is an effect, the present invention was completed.

In order to achieve the above object, the present invention provides a health functional food composition for preventing or improving arthritis containing Inula helenium Linne extract as an active ingredient.

In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of arthritis containing the extract of geomokhyang as an active ingredient.

In addition, the present invention provides a feed additive for the prevention or improvement of arthritis containing the geomokhyang extract as an active ingredient.

In addition, the present invention provides a veterinary composition for the prevention or treatment of arthritis containing the extract of geomokhyang as an active ingredient.

The present invention relates to a composition for preventing, improving or treating arthritis containing an extract of Inula helenium Linne as an active ingredient. , It has an excellent effect of inhibiting MMPs, which are cartilage matrix degrading enzymes, reduces the GAG content, shows an analgesic effect in pain-induced animal models, and has an effect of relieving edema.

1 is a result of confirming the change in PGE2 content according to the treatment of the geomokhyang extract of the present invention. ## indicates that the PGE2 content of the IL-1β treated group significantly increased compared to the control group (Con) not treated with anything, p<0.01. ** indicates that the PGE2 content of the Geomokhyang extract treatment group was significantly decreased compared to the IL-1β treatment group, p<0.01.
Figure 2 is the result of confirming the change in the content of MMP-1 and MMP-13 according to the treatment of the geomokhyang extract of the present invention. #### indicates that the MMP-1 and MMP-13 contents of the IL-1β treated group were significantly increased compared to the control group (Con) not treated with anything, p<0.0001. **, ***, **** indicate that the MMP-1 and MMP-13 contents of the Geomokhyang extract treatment group were significantly decreased compared to the IL-1β treatment group, ** is p<0.01, ** * is p<0.001, **** is p<0.0001.
Figure 3 is the result of confirming the change in GAG content according to the treatment of the geomokhyang extract of the present invention. ## indicates that the GAG content of the IL-1β treated group was significantly increased compared to the control group (Con) not treated with anything, p<0.01. ***, **** indicates that the GAG content of the Geomokhyang extract treatment group of the present invention was significantly decreased compared to the IL-1β treatment group, *** is p<0.001, and **** is p< is 0.0001.
Figure 4 is the result of confirming the analgesic effect on pain according to the administration of the geomokhyang extract of the present invention in an animal model. Indo is indomethacin, a positive control. *, *** are the number of times the body was twisted for 10 minutes by the positive control group (Indo) compared to the control group (con) not treated with the geomokhyang extract of the present invention or the experimental group administered with the geomokhyang extract of the present invention after inducing pain. It means that is significantly decreased, * is p <0.05, *** is p <0.001.
Figure 5 is the result of confirming the ear edema alleviation effect in an animal model inducing inflammation by arachidonic acid (AA) according to the administration of the geomokhyang extract of the present invention in an animal model. ### indicates that ear edema significantly increased in the arachidonic acid-treated group (AA) compared to the normal group (Nor) not treated with anything, p<0.001. *, ** indicates that ear edema was significantly reduced in the positive control group (Indo) or the geomokhyang extract treatment group compared to the arachidonic acid-treated group (AA), * is p<0.05, and ** is p<0.01 am.

The present invention relates to a health functional food composition for preventing or improving arthritis containing an extract of Inula helenium Linne as an active ingredient. The geomokhyang extract is preferably an extract of geomokhyang root, but is not limited thereto. The arthritis is preferably osteoarthritis, but is not limited thereto. The active ingredient is characterized by inhibiting inflammatory cytokines. The geomokhyang extract may be prepared by a method comprising the following steps, but is not limited thereto:

1) extracting by adding an extraction solvent to geomokhyang;

2) filtering the extract of step 1); and

3) preparing an extract by concentrating the filtered extract of step 2) under reduced pressure and drying it.

In step 1), the extraction solvent is preferably water, C ₁ ~ C ₄ lower alcohol or a mixture thereof, more preferably 70% (v / v) ethanol extract, but is not limited thereto. In the above production method, all conventional methods known in the art, such as filtration, hot water extraction, immersion extraction, reflux cooling extraction and ultrasonic extraction, may be used for extraction of geomokyang. The vacuum concentration in step 3) is preferably performed using a vacuum vacuum concentrator or a vacuum rotary evaporator, but is not limited thereto. In addition, drying is preferably reduced pressure drying, vacuum drying, boiling drying, spray drying or freeze drying, but is not limited thereto. The composition is preferably prepared in any one formulation selected from powder, granule, pill, tablet, capsule, candy, syrup and beverage, but is not limited thereto. When using the health functional food composition of the present invention as a food additive, the geomokhyang extract may be added as it is or used together with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient can be suitably determined according to its purpose of use (prevention, health or therapeutic treatment). In general, when preparing food or beverage, the composition of the present invention is added in an amount of 15 parts by weight or less, preferably 10 parts by weight or less, based on the raw material. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range. There is no particular limitation on the type of food. Examples of foods to which the extract or its fraction can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea , drinks, alcoholic beverages, and vitamin complexes, and includes all health functional foods in the conventional sense.

When the composition of the present invention is used as a health drink, it may contain various flavoring agents or natural carbohydrates as additional components, like conventional drinks. The aforementioned natural carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclotenstrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As the sweetener, natural sweeteners such as thaumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame may be used. The proportion of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 g of the composition of the present invention. The composition of the present invention contains various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal agents, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonic acid It may contain a carbonation agent used in beverages and the like. In addition, the composition of the present invention may contain fruit flesh for preparing natural fruit juice, fruit juice beverages and vegetable beverages. These components may be used independently or in combination. The ratio of these additives is not very important, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.

In addition, the present invention relates to a pharmaceutical composition for the prevention or treatment of arthritis containing the extract of geomokhyang as an active ingredient. The arthritis is preferably osteoarthritis, but is not limited thereto. The composition of the present invention may be prepared in any one formulation selected from capsules, powders, granules, tablets, suspensions, emulsions, syrups and aerosols, but is not limited thereto. The composition of the present invention may further include a pharmaceutically acceptable carrier, excipient, or diluent in addition to the above active ingredient, and may be in various oral or parenteral formulations. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include capsules, powders, granules, tablets, pills, and the like, and these solid preparations include at least one excipient in one or more compounds, for example, starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, emulsions, syrups, aerosols, etc., and various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included in addition to water and liquid paraffin, which are commonly used simple diluents. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending solvents. As a base for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used. In the case of parenteral administration, it is preferable to select an external skin or intraperitoneal, rectal, intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebrovascular injection method. The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the level of the effective amount depends on the type, severity, and activity of the drug of the patient's disease. , sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, factors including concomitantly used drugs, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art. The dosage of the composition of the present invention varies in its range depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate and severity of the disease, and the daily dosage is 0.01 to 2,000 mg/kg as a standard, preferably 30 to 500 mg/kg, and more preferably 50 to 300 mg/kg, and may be administered 1 to 6 times a day. The composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

In addition, the present invention relates to a feed additive for preventing or improving arthritis containing an extract of Geomokhyang as an active ingredient. The feed additive of the present invention corresponds to supplementary feed under the Feed Management Act. In the present invention, the term 'feed' may refer to any natural or artificial diet, one meal, etc., or a component of the one meal meal, suitable for or suitable for consumption by animals. The type of feed is not particularly limited, and feeds commonly used in the art may be used. Non-limiting examples of the feed include vegetable feeds such as grains, root fruits, food processing by-products, algae, fibers, pharmaceutical by-products, oils and fats, starches, meal or grain by-products; Animal feed such as proteins, inorganic materials, oils, mineral oils, oils, single cell proteins, zooplankton, or food may be mentioned. These may be used alone or in combination of two or more.

In addition, the present invention relates to a veterinary composition for the prevention or treatment of arthritis containing the extract of Geomokhyang as an active ingredient. The veterinary composition of the present invention may further include appropriate excipients and diluents according to conventional methods. Excipients and diluents that may be included in the veterinary composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, cetanol, stearyl alcohol, liquid paraffin, sorbitan monostearate , polysorbate 60, methylparaben, propylparaben and mineral oil. The veterinary composition according to the present invention may further include fillers, anti-agglomerating agents, lubricants, wetting agents, spices, emulsifiers, preservatives, and the like. Or it may be formulated using a method well known in the art to provide delayed release, and the dosage form may be a powder, granule, tablet, capsule, suspension, emulsion, solution, syrup, aerosol, soft or hard gelatin capsule, It may be in the form of a suppository, a sterile injection solution, or a sterile external preparation. An effective amount of the veterinary composition according to the present invention can be appropriately selected according to the individual animal. The severity of the disease or condition, the sensitivity to the active ingredient of the present invention according to the age, weight, health condition or sex of the subject, the route of administration, the period of administration, factors including other compositions that are combined or used simultaneously with the above composition, and other physiological or It can be determined according to factors well known in the veterinary field.

Hereinafter, the present invention will be described in more detail using examples. These examples are only for explaining the present invention in more detail, and it is obvious to those skilled in the art that the scope of the present invention is not limited thereto.

Example 1. Preparation of Geomokhyang Extract

For 1 kg of geomokhyang, 15 liters of 70% (v / v) ethanol was added, extracted at 85 ° C. for 3 hours, and then the filtrate was concentrated under reduced pressure and dried at 45 ° C. to obtain geomokhyang extract.

Example 2. Evaluation of anti-inflammatory efficacy in chondrocytes

Inhibition of MMPs (MMP-1, MMP-13), which are cartilage matrix degrading enzymes activated by changes in the content of prostaglandin E2 (PGE2), an inflammatory mediator, and increase in inflammatory cytokines, according to extract treatment in human chondrocytes (SW1353) and cartilage A change in the content of GAG (Glycosaminoglycan), a proteoglycan degradation product, was confirmed.

[Cell culture]

After culturing human chondrocytes (SW1353) using a culture medium in which 10% FBS was added to DMEM/F12 (Dulbecco's Modified Eagle Medium: Nutrient Mixture F-12), 5 to 25 ㎍/㎖ of turmeric extract was treated. and incubated for 2 hours, and treated with IL-1β (10 μg/ml) for 24 hours.

(1) Confirmation of inhibitory effect on PGE2 production induced by IL-1β

In order to evaluate the anti-inflammatory effect of the Geomokhyang extract, the inhibitory effect on the production of PGE2, an inflammatory mediator, was measured using an ELISA kit (R&D Systems).

As a result, PGE2 production was significantly increased by IL-1β treatment in chondrocytes, and PGE2 production was significantly decreased in cells pre-treated with 25 μg/ml of Geomokhyang extract (FIG. 1).

(2) Confirmation of IL-1β-mediated reduction of MMP-1 and MMP-13 expression levels

The activation and synthesis of MMPs following the secretion of inflammatory cytokines degrades cartilage matrix molecules (ECM) constituting cartilage tissue. An ELISA kit (R&D Systems) examines the effect of Geomokhyang extract on the expression of MMPs It was confirmed using .

As a result, the expression levels of MMP-1 and MMP-13 were increased in the culture supernatant treated with IL-1β for 24 hours. The expression level of was significantly decreased in a concentration-dependent manner (FIG. 2).

(3) Confirmation of GAG (Glycosaminoglycan) content change

GAG is a component constituting cartilage tissue and is a material produced by decomposition of proteoglycan. In order to confirm whether the Geomokhyang extract affects the degradation of proteoglycan, the change in GAG content was confirmed. Specifically, after treatment with IL-1β for 24 hours, the culture supernatant was reacted with blyscan dye to measure absorbance at 656 nm to measure the amount of GAG.

As a result, it was confirmed that the GAG content, which was increased due to the promotion of cartilage degradation due to IL-1β, was reduced by the treatment of the Geomokhyang extract (FIG. 3).

Example 3. Evaluation of analgesic efficacy in pain-induced animal models by acetic acid induction

After 7-week-old ICR mice were acclimatized for one week, geomokhyang extract (150mg/kg, 300mg/kg) and indomethacin (5mg/kg) as a positive control group were orally administered for 4 days, respectively. 1 hour after administration on the 4th day, 0.75% (v/v) acetic acid (acetic acid) was intraperitoneally administered to the mouse at a dose of 10 ml/kg, and fasted for more than 18 hours for intraperitoneal administration of acetic acid. Five minutes after administration of acetic acid, the number of times the mouse twisted its body was observed for 10 minutes.

As a result, intraperitoneal administration of acetic acid caused capillary damage and pain, resulting in an increase in the number of twists in the mouse, and when the extract was administered, the number of twists in the mouse was significantly reduced. (Fig. 4).

Example 4. Efficacy evaluation of ear edema relief in inflammation-induced animal models by arachidonic acid

After 7-week-old ICR mice were acclimatized for one week, geomokhyang extract (150mg/kg, 300mg/kg) and indomethacin (5mg/kg) as a positive control group were orally administered for 4 days. 1 hour after administration on the 4th day, 10 μl of 2% arachidonic acid dissolved in acetone was applied to the inner and outer surfaces of both ears, respectively. After 2 hours, they were euthanized, and ear tissue weight was measured using a 5 mm dermal biopsy punch.

As a result, it was confirmed that the ear edema was significantly reduced by the administration of the arachidonic acid-induced ear edema in the animal model of the ear edema (FIG. 5).

Claims (11)

A health functional food composition for preventing or improving arthritis, containing an extract of Inula helenium Linne as an active ingredient. According to claim 1, wherein the geomokhyang extract is a health functional food composition for the prevention or improvement of arthritis, characterized in that the extract of the geomokhyang root. The functional food composition for preventing or improving arthritis according to claim 1, wherein the arthritis is osteoarthritis. The functional food composition for preventing or improving arthritis according to claim 1, wherein the active ingredient inhibits inflammatory cytokines. The health functional food composition for preventing or improving arthritis according to claim 1, wherein the extraction solvent of the Geomokhyang extract is water, C ₁ ~ C ₄ lower alcohol, or a mixture thereof. The functional food composition for preventing or improving arthritis according to claim 1, wherein the composition is prepared in any one formulation selected from powder, granule, pill, tablet, capsule, candy, syrup and beverage. A pharmaceutical composition for the prevention or treatment of arthritis containing an extract of Geomokhyang as an active ingredient. The pharmaceutical composition for preventing or treating arthritis according to claim 7, wherein the composition further comprises a pharmaceutically acceptable carrier, excipient or diluent in addition to the active ingredient. The pharmaceutical composition for preventing or treating arthritis according to claim 7, wherein the composition is prepared in any one formulation selected from capsules, powders, granules, tablets, suspensions, emulsions, syrups and aerosols. A feed additive for the prevention or improvement of arthritis containing an extract of geomokhyang as an active ingredient. A veterinary composition for preventing or treating arthritis, containing an extract of Geomokhyang as an active ingredient.

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