KR20190085767A - Composition for preventing, ameliorating or treating hyperuricemia or metabolic disorders associated with hyperuricemia comprising extract or fraction of Hydnocarpi semen or compound derived from Hydnocarpi semen extract as effective component - Google Patents

Abstract

The present invention relates to a composition for preventing, alleviating, or treating hyperuricemia or hyperuricemia-related metabolic disorders containing a Hydnocarpi semen extract, a fraction thereof, or a compound isolated from the Hydnocarpi semen extract as an active ingredient. The Hydnocarpi semen extract, the fraction thereof, or the compound isolated from the Hydnocarpi semen extract, which is an active ingredient of the present invention, not only inhibits the activity of xanthine oxidase, but also reduce the content of uric acid in serum. In addition, since the active ingredient is derived from natural products and is safe, the composition can be usefully used as a dietary supplement or medicine for preventing, alleviating, or treating hyperuricemia or metabolic disorders related to hyperuricemia.

Description

TECHNICAL FIELD The present invention relates to a composition for preventing, ameliorating or treating hyperlipemia or metabolic disorders associated with hyperuricemia, which comprises as an active ingredient, a compound isolated from the extracts of R. aureus, fractions thereof, extract or fraction of Hydnocarpi semen or compound derived from Hydnocarpi semen extract as effective component}

The present invention relates to a composition for preventing, ameliorating, or treating hyperlipidemia or hyperlipidemia-related metabolic disorders comprising as an active ingredient, a compound isolated from the genus Majora extract, a fraction thereof,

Uric acid is a waste produced by decomposition of a nucleic acid component called purine. Most of the urine is excreted in urine and feces. Hyperuricemia is called hyperuricemia because excess uric acid is produced in the blood, body fluids or joint fluids because of excessive production or discharge.

Hyperuricemia is defined by serum uric acid levels in men over 6.8 to 7.0 mg / dL or in women over 6 mg / dL. Hyperlipidemia and hyperlipidemia-related metabolic disorders (for example, gout) occur in 3 to 5 million people in the United States. In the United States, African Americans are twice as likely to have gout than white people. In addition, gout and hyperuricemia are prevalent in China, Japan, Polynesia and sub-Saharan Africa, and the incidence of gout between 1990 and 2010 doubled, and the number of domestic gout patients increased by an annual average of 14% Trend.

Metabolic disorders associated with hyperlipidemia include not only gout but also acute, single arthritic, painful seizures of inflammatory arthritis, urinary stone calculus, nephrolithiasis and gout, due to uric acid crystals, deposits of intraurethral crystalloid crystals, Includes nephropathy. Long-term nephrolithiasis and gouty nephropathy are known to increase the risk of kidney damage and renal failure. Among the metabolic disorders associated with hyperlipidemia, gout is caused by uric acid (uric acid in the blood, body fluids, and joint fluids in the form of urate salt) as the concentration of uric acid (the product of metabolism of the substance called purine, ) Crystals are deposited on cartilage, tendons and surrounding tissues of joints. This phenomenon causes inflammation of the joints, resulting in recurrent seizures accompanied by severe pain. Deformations and deformities of the joints occur when the gout nodules are formed by the urate crystals. In addition to abnormalities of the joints, kidney disease (kidney stones) that cause kidney disease and kidney stones caused by uric acid may occur.

In addition, gout occurs through stages such as asymptomatic hyperuricemia, acute gouty arthritis, intermittent gout, and chronic nodular gout. Early asymptomatic hyperuricemia has elevated serum uric acid levels, but symptoms such as arthritic symptoms, gouty nodules, and uricosuric acne have not been reported yet. Acute gouty arthritis is a stage of gouty episodes or kidney acrosis that occurs after a period of at least 20 years of hyperuricemia. Acute episodes of acute episodes of painful arthritis are characterized by a joint It is invasive and has no systemic symptoms but progressively involves multiple joints and accompanies heat. Intermittent gout refers to a period of time without symptoms between gout attacks. Most of them experience a second seizure between 6 months and 2 years after the first seizure. Involve joints. Chronic nodular gout appears to resemble other types of arthritis when it is in a period of chronic nodular ventilation past a ventilated intermittent device. There is progressive stiffness and constant pain in the joints of the affected area.

Gout is known to be a clear and successful treatment of the disease, but it is often accompanied by other diseases such as hypertension and chronic renal failure. Therefore, side effects of medication should be carefully considered, and lifestyle changes Patients' efforts are essential to improve prognosis in long-term treatment. Gout and hyperuricemia are not included in the diagnostic criteria for metabolic syndrome, which is a complex disorder with hypertension, hyperlipidemia, hyperglycemia, abdominal obesity, and clinical manifestations that increase the risk of adult diseases such as arteriosclerotic heart disease and type 2 diabetes The metabolic syndrome is thought to be closely related. In Korea, it was reported that 44% of patients with gout were accompanied by metabolic syndrome. Gout usually occurs in the form of acute monoarthritis, but may involve small joints or rarely joints. Non-steroidal anti-inflammatory drugs (NSAIDs), which are used in the treatment of acute gout, are known to inhibit the inflammatory response and are known to inhibit the activity and migration of leukocytes, ), Steroids are all drugs that can effectively treat gout attacks, and selective cyclooxygenase (COX-2) inhibitors are known to have the same effects as the existing non-steroidal anti-inflammatory drugs.

In addition, maintaining the serum uric acid concentration below the saturated state for a long period of time can prevent the acute gouty arthritis as well as reduce the size of the already existing ventilated nodule. In the chronic phase of gout, uric acid is lowered in the blood, and the uric acid lowering agent is classified into xanthine oxidase (XO) inhibitor and uricosuric agent according to the mechanism. Allopurinol and febuxostat, which was recently developed as a new drug. Allopurinol is a xanthine oxidase (XO) inhibitor that can be effectively used regardless of the cause of hyperuricemia, but the most serious side effect of allopurinol is hypersensitivity syndrome, Eosinophilia, hepatitis, kidney failure, etc., are known to be at risk of death. Unlike xanthine oxidase inhibitor or allopurinol, febuxostat is also a non-purine selective blocker, which is metabolized mainly in the liver to form glucuronide. Most cases of gout are chronic, and even if there are no symptoms, treatment is done to lower the anti - inflammatory drug and uric acid concentration prophylactically. These preventive treatments should be used after the disease has been maintained for a period of time in a calm state, otherwise the ventilation will recur more severely. However, there is a lot of controversy about the proper period of the illness, and it is also difficult to prevent the acute onset of the gout, which is intermittently recurrent, and the gout is caused by natural products. Inhibition of the enzyme, an oxidase, is still insufficient.

On the other hand, Hydnocarpi semen is a seed of a rhododendron or a relative plant. It has a length of 2 ~ 3cm and a diameter of 1 ~ 2cm. It has a dark brown oval rhizome. When hard seed coat is removed, there is a dark brown endoderm with a lot of oil. The major components of the formulation are the free radicals and hydnocarpin, which contain hydnocarpic acid, chaulmoogric acid and gorlic acid, methoxyhydnocarpin Flavolignan such as hydnotightin, neohydnocarpin, and flavonoids such as apigenin, luteolin, and chrysoeriol.

Korean Patent Laid-Open Publication No. 2015-0025679 discloses a composition for external application for skin which contains a PPAR alpha activator for prevention, improvement or treatment of atopic dermatitis, Korean Patent Laid-Open Publication No. 2009-0119622 discloses a composition for preventing and treating ischemic diseases, which comprises extract of Zygomycorrhizae, and Korean Patent Publication No. 2009-0044979 discloses a composition for preventing and treating diabetic ulcer .

However, a composition for preventing, ameliorating, or treating hyperlipidemia or hyperlipidemia-related metabolic disorders containing the compound of the present invention as a active ingredient, a fraction thereof or a compound isolated from the extract of Larvae is not disclosed.

SUMMARY OF THE INVENTION The present invention has been made in view of the above needs, Fractions thereof; Or hydnocarpin as an active ingredient, and to provide a health functional food composition for preventing or ameliorating metabolic disorders associated with hyperlipidemia or hyperlipidemia. The composition of claim 1, But also the effect of reducing the content of uric acid in the serum, thereby completing the present invention.

In order to achieve the above object, Fractions thereof; Or hydnocarpin as an active ingredient for preventing or ameliorating hyperlipidemia or metabolic disorders associated with hyperlipidemia.

In addition, the present invention relates to a method for producing a plant extract, Fractions thereof; Or hydnocarpin as an active ingredient, for the prophylaxis or treatment of metabolic disorders associated with hyperlipidemia or hyperlipidemia.

The present invention relates to an extract of Zygomycota; Fractions thereof; The present invention relates to a health functional food composition for preventing or ameliorating hyperlipidemia or hyperlipidemia-related metabolic disorders comprising hydonocarpin as an active ingredient. The isolated compounds not only inhibit the activity of xanthine oxidase but also have an effect of reducing the content of uric acid in the serum.

FIG. 1 is a graph showing the activity of inhibiting xanthine oxidase of the extract of the genus Majorelli and its fractions of the present invention.
FIG. 2 shows the HPLC results of the ethyl acetate fraction of the extracts of the present invention.
Fig. 3 shows the result of confirming the activity of xanthine oxidase inhibition of the active ingredient of the present invention (IC ₅₀ (쨉 g / ml) = 9.9 ± 0.27).
FIG. 4 shows the results of confirming the effect of reducing the urinary output in the serum according to the administration of the extract of the present invention. NC means normal group, PO means potassium oxonate group, P392-300 means 300mg / kg extract of Daejungjae and AP10 means positive control group, 10mg / kg of allopurinol. # Indicates that the uric acid content in the serum was increased significantly in the potassium oxonate group compared to the normal group, and p <0.01. The mean uricosuric acid content in the serum was significantly lower than that in the potassium oxonate-treated group. ** indicates p <0.01 and *** indicates p <0.001.

The present invention relates to an extract of Zygomycota; Fractions thereof; Or hydnocarpin as an active ingredient. The present invention also relates to a health functional food composition for preventing or ameliorating metabolic disorders associated with hyperlipidemia or hyperuricemia.

The extract may be prepared by a method including, but not limited to, the following steps:

1) Extracting the dried powder with the extracting solvent;

2) filtering the extract of step 1); And

3) Concentrating the filtrate obtained in step 2) under reduced pressure and drying to prepare an extract.

In the step 1), the extraction solvent is preferably water, a C ₁ -C ₄ lower alcohol or a mixture thereof, more preferably ethanol, but is not limited thereto.

In the above-described production method, the extraction of the vortex can be performed by any conventional method known in the art such as filtration, hot water extraction, immersion extraction, reflux cooling extraction, and ultrasonic extraction. The vacuum concentration in step 3) may be performed using a vacuum decompression concentrator or a vacuum rotary evaporator, but is not limited thereto. The drying is preferably performed under reduced pressure, vacuum drying, boiling, spray drying or freeze drying, but not always limited thereto.

The hydnocarpin is characterized in that it is isolated from the extracts of P. vivax or its ethyl acetate fraction, but is not limited thereto.

The health functional food composition may be prepared by preparing a formulation of any one of powders, granules, pills, tablets, capsules, candies, syrups and beverages, adding it to other foods or ingredients of foods, Can be suitably manufactured.

Examples of the food to which the active ingredient of the present invention can be added include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, A tea, a drink, an alcoholic beverage, and a vitamin complex, all of which include health functional foods in a conventional sense. The health functional food may contain various nutrients, vitamins, minerals (electrolytes), synthetic and natural flavors, colorants and enhancers (cheese, chocolate etc.), pectic acid and its salts, alginic acid and its salts, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. It may also contain flesh for the production of natural fruit juices and vegetable drinks. These components may be used independently or in combination.

The health functional food composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient. The natural carbohydrates are sugar saccharides such as monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like.

In the health functional food composition, the hyperlipidemia-related metabolic disorder is preferably, but not limited to, any one selected from acute or chronic gout, gouty redness, gouty arthritis, gouty nephrolithiasis and gouty nephropathy. The gustatory redness is a symptom of reddening due to inflammation due to gout.

In addition, the present invention relates to a method for producing a plant extract, Fractions thereof; Or hydnocarpin as an active ingredient, and to a pharmaceutical composition for preventing or treating hyperlipidemia-related metabolic disorders.

The hydnocarpin is characterized in that it is isolated from the extracts of P. vivax or its ethyl acetate fraction, but is not limited thereto.

In the above pharmaceutical composition, the hyperlipidemia-related metabolic disorder is preferably, but not limited to, any one selected from acute or chronic gout, gouty fever, gouty arthritis, gouty nephrolithiasis and gouty nephropathy. The gustatory redness is a symptom of reddening due to inflammation due to gout.

In addition to the above-mentioned effective ingredients, the composition may further include an uric acid salt lowering agent. The preferred urate reducing agent is at least one selected from xanthine oxidase inhibitor, uricosuric agent, urate oxydase, urine alkalizing agent and phenobibrate And may further comprise, in addition to the active ingredient, a pharmaceutically acceptable carrier, excipient or diluent.

The pharmaceutical composition of the present invention may be various oral or parenteral formulations. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain one or more excipients such as starch, calcium carbonate, sucrose or lactose lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of non-aqueous solvents and suspensions 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, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin and the like can be used.

The composition of the present invention may be administered orally or parenterally, and it is preferable to select the intraperitoneal, rectal, rectal, intravenous, intramuscular, subcutaneous, intrauterine or intracerebral injection methods during parenteral administration.

The 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 at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts. The composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

The dosage of the composition of the present invention may be varied depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are merely illustrative of the present invention and that the scope of the present invention is not limited thereto.

EXAMPLES Example 1: Extraction of Compound and separation of Compound

Daphnia (China) was purchased from Kwangmyong Dang Pharmaceutical Co., Ltd. (Korea). (150 g) was subjected to reflux extraction and filtration in 11.5 L of 70% (v / v) ethanol at 70 to 80 ° C for 3 hours. The extract solution was concentrated under reduced pressure to obtain 6.87 g of an extract of R. anthracnose, and the yield was 4.58%.

The obtained hexane fraction was fractionated from the above extract and the remaining fractions were sequentially added with ethyl acetate and butanol to obtain the respective fractions in the order of ethyl acetate, butanol and water.

The solvent fractions yielded 1.37, 0.68, 0.66 and 4.16 g, respectively, and the yields were 20.0, 9.9, 9.6 and 60.5%. The ethyl acetate fraction obtained from the fractionation of the extract was injected into a silica gel column (1.5 ± 5 cm) and aliquots were collected while changing the concentrations of methylene chloride and methanol from 100: 0 to 0: 100. The fractions obtained by the elution were subjected to thin layer chromatography (TLC) to confirm the degree of separation of single components. At this time, as developing solvent of TLC, 0.1% of acetic acid was added at a composition ratio of methylene chloride, methanol and water of 12: 1: 0.1, and a silica gel plate was expanded to obtain a single component The degree of separation was confirmed.

The fraction obtained by performing TLC was separated and purified by using Prep-HPLC as an active ingredient hydnocarpin. At this time, C18 ODS column was used as a column for HPLC analysis, and the mobile phase was 42% acetonitrile to which 0.1% TFA (trifluoroacetic acid) was added, UV was 254 nm, flow rate) was 10 ml / min (Fig. 2).

Example  2. Xanthine  Measurement of oxidase inhibitory activity

Xanthine oxidase (XO) inhibitory activity was measured by Noro et al. 1 μl of the sample dissolved in 50 mg / ml of dimethyl sulfoxide (DMSO) was added, and 179 μl of a substrate solution in which 100 μM xanthine sodium salt was dissolved in 8.3 mM potassium phosphate buffer (pH 7.2) 20 μl of xanthine oxidase (0.4 U / ml) was added thereto and reacted at 37 ° C for 30 minutes. The uric acid content was measured at 295 nm (SpectraMax M2, Molecular Devices, USA).

The XO inhibitory activity was expressed as a percentage (%) of the absorbance reduction of the sample solution added and the no-added solution.

As a result, as shown in FIG. 1 and FIG. 3, the extract, fraction and hydrocinokine of the present invention have an inhibitory activity of xanthine oxidase. Particularly, the XO inhibition of the ethyl acetate fraction It was confirmed that the activity was remarkable.

Example  3. Goyosan  Uric acid degradation effect in animal models

In order to induce a sedentary animal model, 150 mg of SDC dissolved in 0.5% sodium carboxymethylcellulose (CMC-Na, pH 5.0) solution containing 0.1 M sodium acetate was added to the SD- / kg of potassium oxonate was intraperitoneally injected. After 1 hour of intraperitoneal injection of potassium oxonate, 300 mg / kg of the extracts of Zygomycorrhizae and positive control 10 mg / kg of allophilinol were dissolved in 0.01 M PBS containing 0.1% polyoxyethylene sorbitane monooleate ) Buffer solution for oral administration. Two hours after oral administration, blood was taken after anesthesia with anesthetics (Entobar) and uric acid was measured using a uric acid assay kit (Biovision, USA).

As a result, the amount of uric acid in the serum of the control group (PO) injected with potassium oxonate abdominal injection increased compared with that of the normal group (NC). However, It was confirmed that the content of the uric acid was remarkably decreased (Fig. 4).

Claims (10)

Macrophotomy extract; Fractions thereof; Or hydnocarpin as an active ingredient for preventing or ameliorating hyperlipidemia or metabolic disorders associated with hyperlipidemia. The health functional food composition according to claim 1, wherein the hydnocarpin is isolated from the extract or the ethylacetate fraction thereof. The composition for preventing or ameliorating hyperlipidemia or metabolic disorders associated with hyperlipidemia. [Claim 2] The composition according to claim 1, wherein the solvent of the extract is a water, a C ₁ -C ₄ lower alcohol or a mixture thereof, wherein the composition is for preventing or ameliorating metabolic disorders associated with hyperlipidemia or hyperlipidemia. The method according to claim 1, wherein the hyperlipidemia-related metabolic disorder is any one selected from acute or chronic gout, gouty redness, gouty arthritis, gouty nephrolithiasis and gouty nephropathy. Or improving health functional food composition. The method according to claim 1, wherein the composition is prepared from any one of powder, granule, ring, tablet, capsule, candy, syrup and beverage for preventing or ameliorating hyperlipidemia or metabolic disorders associated with hyperlipidemia. Health functional food composition. Macrophotomy extract; Fractions thereof; Or hydnocarpin as an active ingredient for the prophylaxis or treatment of hyperlipidemia or hyperlipidemia-related metabolic disorders. [Claim 7] The pharmaceutical composition according to claim 6, wherein the hydonocarpine is isolated from the extract or the ethylacetate fraction thereof. [Claim 7] The pharmaceutical composition according to claim 6, further comprising a carrier, an excipient or a diluent in addition to the active ingredient, for preventing or treating metabolic disorders associated with hyperlipidemia or hyperlipidemia. The pharmaceutical composition for preventing or treating hyperlipidemia or hyperlipidemia-associated metabolic disorders according to claim 6, which further comprises an uric acid-lowering agent in addition to the above-mentioned effective ingredient. 10. The method of claim 9, wherein the urate decomposition agent is at least one selected from the group consisting of xanthine oxidase inhibitor, uricosuric agent, urate oxydase, urine alkalizing agent, and phenobibrate. &Lt; / RTI &gt;

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