KR20040080640A - Pharmaceutical composition comprising a fruit extract of Actinidia polygama AP having anti-gout activity - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing an extract of Actinidia polygama (S. et Z.) Max., pharmaceutically acceptable carriers or excipients is provided. The pharmaceutical composition is free from toxicity and has an excellent lowering effect on blood uric acid levels and can be used in the prevention and treatment of gout disease. CONSTITUTION: The pharmaceutical composition for the prevention and treatment of gout disease contains 0.5 to 50% by weight of an Actinidia polygama extract, pharmaceutically acceptable carriers or excipients. The Actinidia polygama extract is a crude extract which is soluble in water, lower alcohol or a mixed solvent thereof, or an extract which is soluble in a nonpolar solvent. The lower alcohol is ethanol or methanol, the nonpolar solvent is ethyl acetate, chloroform, hexane and ether. The dosage of the pharmaceutical composition is 0.1 to 100mg/kg per day. The health beverage contains 0.01 to 15% by weight of the Actinidia polygama extract.

Description

Pharmaceutical composition comprising a fruit extract of Actinidia polygama AP having anti-gout activity

The present invention relates to a pharmaceutical composition and a health functional food containing an extract effective for gout, and more particularly to a uric acid lowering agent containing the extract of Caesar.

Gout causes uric acid concentrations in the blood due to abnormalities in the purine metabolism that make up DNA, resulting in hyperuricemia, resulting in articular cartilage, synovial membranes, It refers to a disease caused by acute or chronic inflammation as a chemical and foreign inflammatory response to various places in the tissues around the joint.

Purine, which is metabolized to uric acid in the body, is derived from food, cell nucleus, or purine base synthesis in the body, and metabolism is inhibited by the genetic predisposition of hypoxanthine guanine phosphoribosyl transferase (HGPRT) enzyme, High levels of uric acid in the blood are caused by the necrosis of cells, which leads to massive destruction of the nucleus and abnormal excretion in the kidneys.

Genetic relationships can be acknowledged and overwhelmingly in men and develop in their 30s. Characteristic symptoms include red swelling of the big toe, the back of the foot, and the astragalus, showing intense pain, accompanied by severe pain, swelling, and inflammation of the joints. It may be accompanied by fever. Chronicization causes joint deformities and gout nodules in the biceps, elbows and knees. In addition, kidney stones (腎臟 結石), hypertension and diabetes may be combined.

Treatment is stable during acute gout attacks, feeds low-purine foods, and ingests enough fluid to increase urine output. Drugs are administered colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids that promote uric acid excretion. Chronic ventilation, low-purine, low-fat diet (低 脂肪 食) is fed, and drugs such as probenecid (probenecid), allopurinol (allopurinol) is used. Drug selection is selected in consideration of blood uric acid concentration, uric acid excretion, renal function, nephrolithiasis, and the like.

On the other hand, Actinidia polygama AP is a fruit of the deciduous vines of the deciduous vines belonging to the genus Tami ( Mifuri ) and (Actinidiaceae). It is known to contain vitamin A, vitamin P, etc., and the effects so far known include Jigal (,), Haebun fever (解 煩熱) and urinary stones (泌 尿 器 結石) treatments (Information and Shin Mingyo, medicinal herbs) Metabolism, Younglimsa, p386-387, 1998).

However, none of these documents describes or discloses that a leprosy extract is effective in preventing or treating gout.

In the present invention, by pharmacologically observing the therapeutic effect on the anti-gout of the dog, we focused on whether gout treatment is possible for the herbal medicine that has traditionally accumulated a lot of clinical data.

As a result, the present invention was completed by confirming that the extracts of the crab of the present invention had anti-gout activity by lowering uric acid content in blood and urine.

Accordingly, an object of the present invention is to provide a pharmaceutical composition and a health functional food containing a new extract effective in preventing and treating uric acid content and preventing gout.

1 is a view briefly showing the manufacturing process of the extract of the present invention,

Figure 2a is a diagram showing the result of measuring the amount of uric acid in the blood after the administration of the crude extract

Figure 2b is a diagram showing the area under the curve of the blood uric acid measurement graph of Figure 2a,

Figure 3a is a diagram showing the results of measuring the amount of uric acid in the blood after administration of water and ether fractions

Figure 3b is a diagram showing the area under the curve of the blood uric acid measurement graph of Figure 3a,

Figure 4 is a diagram measuring the content of uric acid in the urine after administering the water of the seaweed and the seaweed ether fraction.

In accordance with the above object, the present invention provides a pharmaceutical composition for preventing and treating gout, containing crude extract of Actinidia polygama AP having uric acid content lowering activity.

The crude extract includes water, low alcohols such as methanol and ethanol, or extracts available for a mixed solvent thereof.

The present invention also provides a pharmaceutical composition for the prevention and treatment of gout containing a non-polar solvent soluble extract of the forged dog having a uric acid content lowering activity.

The nonpolar solvent soluble extract includes a nonpolar solvent such as ethyl acetate, chloroform, hexane, ether, or the like, or a mixed solvent thereof, preferably an extract soluble in an ether solvent.

The method of separating the crude extract and the non-polar solvent soluble extract from the lees of the present invention is as follows.

Hereinafter, the present invention will be described in detail.

The extract of the present invention is about 1 to 15 times, preferably about 5 to 10 times, water, lower alcohol or about 1: 0.1 to 1:10, preferably 1: 1 to 1 times the volume of dried litterworm. A mixed solvent having a mixing ratio of 1: 3, hot water extraction, ultrasonic extraction, and reflux at about 20 to 100 ° C., preferably at about 70 to 100 ° C. for about 1 hour to 2 days, preferably about 2 hours to 1 day It can obtain by extraction methods, such as cold extraction.

The present invention provides a composition for lowering blood uric acid content and preventing and treating gout, including water extracts obtained in the extraction process, lower alcohol extracts, and soluble extracts according to a mixed solvent thereof.

Also, the non-polar solvent soluble extract of the present invention is obtained by suspending the water extract, the lower alcohol extract, and the soluble extract according to a mixed solvent thereof in water, and then fractionating the same by adding about 1 to about 10 times the volume of the non-polar solvent of the suspension. can do. It is also possible to further carry out conventional fractionation processes (Harborne JB Phytochemical methods: A guide to modern techniques of plant analysis. 3rd Ed. Pp 6-7, 1998).

Hereinafter, specifically describing the separation process of the sea wormwood extract,

For example, the first step of pulverizing the leeks and extracted with a polar solvent such as water, methanol or ethanol, or a mixed solvent thereof and then concentrated under reduced pressure or lyophilized to obtain a crude extract soluble in a polar solvent;

After adding and mixing a polar solvent, such as water, to the crude extract, mixed by adding a non-polar solvent such as 1 to 5 times ether, and left for 6 to 24 hours to fractionate, and then a polar solvent soluble portion and a non-polar solvent soluble And a second step of concentrating and lyophilizing each of them to obtain a polar solvent soluble extract and a nonpolar solvent soluble extract.

Crude extracts obtained by the above method significantly reduced blood uric acid in hyperuricemia-induced white rats, and nonpolar solvent soluble extracts were more effective in lowering uric acid and uric acid in urine than provenedide. The uric acid lowering effect was similar to that of allopurinol.

The present invention provides a nonpolar solvent soluble extract obtained by the above method and effective for treating gout.

The present invention also provides a pharmaceutical composition containing the non-polar solvent soluble extract and effective in preventing and treating gout.

The composition for preventing and treating gout of the present invention comprises 0.5 to 50% by weight of the extract based on the total weight of the composition.

The composition comprising the extract of the present invention, may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.

In order to observe the effects of gout on the gout, the results of the experiment were applied to the animal model of gout.

The composition comprising the extract of the present invention may further comprise a suitable carrier, excipient and diluent according to conventional methods.

Carriers, excipients and diluents that may be included in the composition comprising the extract of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium Phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

Compositions comprising extracts according to the invention are formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterile injectable solutions, respectively, according to conventional methods. Can be used.

The amount of the extract of the present invention may vary depending on the age, sex, and weight of the patient, but may be administered once to several times in an amount of 0.1 to 100 mg / kg. In addition, the dosage of the extract can be increased or decreased depending on the route of administration, the degree of disease, sex, weight, age and the like. Therefore, the above dosage does not limit the scope of the present invention in any aspect.

The composition containing the extract of the present invention can be used in various ways, such as drugs, food and beverages for the prevention and treatment of gout. Examples of foods to which the present extract can be added include various foods, beverages, gums, teas, vitamin complexes, and health functional foods.

Since the extract of the present invention of the present invention is almost no toxicity and side effects, it is a drug that can be used safely even for long-term administration for the purpose of prevention.

The extract of the present invention may be added to food or beverage for the purpose of preventing gout. At this time, the amount of the extract in the food or beverage is generally added to the health food composition of the present invention 0.01 to 15% by weight of the total food weight, the health beverage composition is 0.02 to 10 g, preferably based on 100 ml Can be added in the ratio of 0.3-1 g.

The health beverage composition of the present invention is not particularly limited in the liquid component except for containing the extract as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates, etc. as additional ingredients, as in general beverages. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The ratio of said natural carbohydrate is generally about 1-20 g, preferably about 5-12 g per 100 ml of the composition of the present invention.

In addition to the above, the composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid and salts thereof. , Organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. The compositions of the present invention may also contain pulp for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical but is generally selected from the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.

The present invention is described in more detail based on the following examples, although the present invention is not limited thereto.

Example 1 Preparation of Crowweed Extract

Extract 400 g of Actinidia polygama ( AP) obtained from the Korea Institute of Native Herbal Medicine with 3 liters of 70% ethanol twice at 90 ° C for 4 hours, and concentrate the filtrate obtained by filtration to a third volume using a vacuum distillation apparatus. 88 g (22% yield) of crude algae extract were obtained (see FIG. 1).

Example 2 Preparation of Literary Polar Solvent Soluble Extract (2-1) and Nonpolar Solvent Soluble Extract (2-2)

After mixing 500 ml of water into 88 g of the crude coarse extract of Example 1, adding the same amount of ether, mixing the mixture, and then, the mixture was freeze-dried and dried for 6 hours at room temperature. It was. 8.8 g of ether fraction (2-2) (yield, 2.2%) was obtained as a non-polar solvent soluble extract from 88 g of crude colic extract, and 61.6 g of water layer fraction (2-1) (yield, 15.4) as a polar solvent soluble extract. %) (See FIG. 1).

Samples were stored in a 4 ° C. refrigerator until the test.

Experimental Example 1.Anti-gout Effect Experiment of Cauliflower Extract

In order to confirm the anti-gout activity of the extract of the present invention, an experiment was performed to observe the effect of lowering uric acid content in the blood using a gout disease model.

Induced hyperuricemia by administering potassium oxonate (potassium oxonate), an urinary oxidase inhibitor, to the experimental animal rats, and probenesid, a uric acid excretion accelerator (probenecid, Hanmi Pharm) and allopurinol (allopurinol, Samil Pharm.), a uric acid synthesis inhibitor, were administered, and anti-gout efficacy was compared by measuring the amount of uric acid in the blood.

1-1. Laboratory animals

The experimental animals were Sprague-Dawley white rats (160-200 g, Hallim experimental animals, Hwaseong, Korea) with a humidity of 50 ± 5%. Animals were kept in a 24-26 ° C temperature and used for experiments after being adapted to the laboratory environment for one week with sufficient feed and water.

1-2. Experimental Effects on the Blood Uric Acid Concentration

In this experiment, uric acidase inhibitor potassium oxonate (250 mg / kg) was administered intraperitoneally 1 hour prior to sample administration to induce hyperuricemia. Prior to this, blood uric acid content of white rats was measured prior to administration of potassium oxonate in order to confirm the induction of hyperuricemia after administration of potassium oxonate. After the administration of potassium oxonate, blood uric acid content was measured again. Based on this value, blood uric acid mean in the group was divided into 5 groups of white rats. It was divided into the benedid administration group and allopurinol administration group. Prior to drug administration, blood uric acid content was measured and set to 0 hours.

The hyperuricemia control group was administered by replacing the crude extract with the same amount of solvent, and the crude extract group was dissolved 1000 g / g of the coarse extract of Example 1 dissolved in a mixture of distilled water and 0.5% sodium carboxymethyl cellulose (CMC) The dose was administered to the abdominal cavity at a concentration of kg. The drug was administered at a concentration of 50 mg / kg for the probeneid group and the concentration of 5 mg / kg for the allopurinol group.

After taking the intraperitoneal administration of each sample intraperitone-treated group, allopurinol-administered group, and coarse extract group, blood was collected from the orbital vein at intervals of 1, 2, and 6 hours, and then allowed to stir at room temperature for 1 hour, followed by centrifugation ( 2500 × g, 10 minutes) to obtain plasma (plasma), urine in blood using a kit for measurement of uric acid (UA-1, Asan Pharmaceutical, uricase peroxidase method) and a spectrometer (U3210, Hitachi, Japan) Goat was measured (see FIG. 2A). The area under the curve of blood uric acid concentration vs. time (see FIG. 2B) for 0-6 hours after drug administration was calculated by the trapezoidal method.

In this experiment, potassium oxonate (250 mg / kg) was administered 1 hour before sample administration to induce hyperuricemia, and then the level of uric acid in blood (Figure 2a) and area under the curve (Figure 2b) for up to 6 hours. Liver comparison. As shown in FIG. 2A, the control group administered potassium oxonate (250 mg / kg) significantly increased uric acid levels in the blood from 2 hours after the administration, whereas the group receiving the cortical and positive control drugs (provenedid, allopurinol) In comparison, the area under the curve showed a significant decrease compared to the control. The ethanol extract of Lilium lowered the levels of uric acid in the blood at the 1000 mg / kg dose.

1-3. Effect of Nonpolar Solvent Soluble Extracts on Serum Uric Acid Concentration

Subsequently, the same experiment was performed after dividing the ethanol extract of Caesar alba into an ether fraction and a water fraction.

In the Sprague-Dooli rats induced gout with potassium oxonate as in Experimental Example 1-2, the water and ether fraction of Example 2 of the present invention (700 mg / kg, 100 mg / kg), allopurinol 100 mg / kg, probebeneide was administered at a concentration of 20 mg / kg, and then the amount of uric acid in blood was measured at intervals of 1, 2, and 6 hours using the uric acid measurement method of Experimental Example 1-2.

As a result, as shown in Figures 3a and 3b ether fraction showed an excellent activity to lower the uric acid level in the blood almost the same size as allopurinol. On the other hand, the water fractions of the waters from the dogs showed anti-inflammatory analgesic activity did not show any difference from the hyperuricemia control group. As a result of this experiment, we confirmed that the anti-gout activity of the litter was present in the ether fraction as a fat-soluble substance.

Experimental Example 2 effect of urethra extract on uric acid levels in urine

This experiment is to examine the anti-gout activity mechanism of the larvae, which can be summarized as 1) a mechanism similar to probeneside that promotes uric acid excretion, or 2) allopurinol, which inhibits the synthesis of uric acid. In the case of mechanism, uric acid levels in the blood are lowered, but uric acid in urine tends to increase a lot, and in the case of mechanism drugs, both blood and urine uric acid levels tend to be lowered.

After 6 hours of administration to the Sprague-Dooli rats induced gout with potassium oxonate in the amount of 700 mg / kg, 100 mg / kg of the water and ether fraction of the present invention in the amount of 700 mg / kg, 100 mg / kg Urine was collected and the level of uric acid therein was measured in the same manner as in Experimental Example 1-2.

As shown in the results of FIG. 4, urine uric acid levels in the water and ether fraction administration groups compared with the other groups, the water and water fractions and the probebenid tended to be lower or higher than the control group, respectively, significant differences will be found However, the antler ether fraction showed activity to reduce uric acid levels similar to allopurinol, a uric acid synthase inhibitor. Therefore, it was confirmed that the uric acid lowering activity of the ether fraction of the cortex has anti-gout activity by inhibiting the synthesis of uric acid.

Experimental Example 3. Acute Toxicity Test

1. Oral administration

ICR-based mice and Sprague-Dawley rats were divided into four groups of 10 rats each. Oral administration of the present invention of the dog worm extract at the doses of 500, 725, 1000 and 5000 mg / kg was observed for 2 weeks. No deaths occurred in all groups and no symptoms were apparent from the control group.

2. Intraperitoneal administration

ICR-based mice (weight 25 ± 5 g) and Sprague Dooli rats were divided into four groups of 10 rats each for 24 hours after intraperitoneal administration of Caesar extract of the present invention at doses of 25, 250, 500 and 725 mg / kg, respectively. While no toxicity was observed in all four groups, no symptoms were apparent from the control group. As a result, it was confirmed that the extract of the present invention of the present invention has little acute toxicity.

Examples of the formulations of the above pharmaceutical formulations are described below, but are not intended to limit the present invention but to explain in detail only.

Formulation Example 1 Preparation of Injection

Example 2-1 Dry Extract ........ 100 mg

Sodium Metabisulfite ....... 3.0mg

Methylparaben ...... 0.8mg

Propylparaben ...... 0.1mg

Sterile distilled water for injection ..........

The above ingredients are mixed and made into 2 ml by a conventional method, and then filled into 2 ml ampoules and sterilized to prepare an injection.

Formulation Example 2 Preparation of Tablet

Example 2-2 Dry Extract ....... 200 mg

Lactose ......... 100 mg

Starch ........................ 100 mg

Magnesium stearate ........ suitable

The above components are mixed and tableted according to a conventional method for producing tablets to produce tablets.

Formulation Example 3 Preparation of Capsule

Example 2-2 Dry Extract ....... 100 mg

Lactose ............. 50 mg

Starch ........................ 50 mg

Talc ........................ 2mg

Magnesium stearate ........

Capsules are prepared by mixing the above ingredients and filling into gelatin capsules according to a conventional method for preparing capsules.

Formulation Example 4 Preparation of Liquid

Example 2-2 Dry Extract ....... 1000 mg

Sugar ......... 20g

Isomerized sugar ......... 20 g

Lemon flavor ...........

Add purified water to the whole ....... 100ml

The above components are mixed according to a conventional method for preparing a liquid, filled into a 100 ml brown bottle, and sterilized to prepare a liquid.

The pharmaceutical composition containing the extract of the wormwood having anti-gout activity according to the present invention has no problem of toxicity, and can be effectively used for the prevention and treatment of gout diseases because it has excellent uric acid content lowering activity.

Claims (8)

A pharmaceutical composition for preventing and treating gout containing crude extract of Actinidia polygama AP, and containing a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition according to claim 1, wherein the crude extract is an extract available in water, lower alcohols or a mixed solvent thereof. The pharmaceutical composition according to claim 2, wherein the lower alcohol is ethanol or methanol. A pharmaceutical composition for the prevention and treatment of gout, containing a non-polar solvent soluble extract of the algae, and containing a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition according to claim 4, wherein the nonpolar solvent is a solvent selected from ethyl acetate, chloroform, hexane, ether. 6. The pharmaceutical composition according to claim 5, wherein the nonpolar solvent is an ether. A dietary supplement for lowering uric acid content and preventing gout in the blood, including crude algae extract or non-polar solvent soluble extract and food acceptable food additive. The health functional food according to claim 7, which is a health beverage.