KR19990079922A - Lipid metabolism improving and blood pressure lowering composition comprising jujube extract and citrus peel extract - Google Patents

Abstract

The present invention relates to a composition for improving lipid metabolism and lowering blood pressure, comprising a jujube extract and a citrus peel extract, and the composition of the present invention includes a pharmaceutical and food composition. The composition of the present invention comprising a jujube extract and a citrus peel extract may exhibit effects such as liver disease, hypertension, arteriosclerosis, hyperlipidemia and other diseases such as cancer and cancer.

Description

Lipid metabolism improving and blood pressure lowering composition comprising jujube extract and citrus peel extract

The present invention relates to a composition for improving lipid metabolism and lowering blood pressure, which includes jujube extract and citrus peel extract.

Jujube has been used as a herbal medicine since ancient times for mental stability, relieving stress, treating insomnia, promoting liver detoxification and sanitary agents (Song Hyo-jung, Sanya Herbal Treatment , 228 , (1994)). It has been found by the present inventors that a protein (cholesterol ester transfer protein (CETP)) inhibitor is included (Korean Patent Application Nos. 97-59425 and 97-59426). In addition, it has also been found by the present inventors that the citrus peel extract and the hesperidin or naringin isolated therefrom are excellent in preventing atherosclerosis (Korean Patent Application Nos. 97-55578, 97-55579 and 97-55580). number).

Citrus peels are known to have various pharmacological activities, for example, lipid metabolism improving effects associated with cardiovascular disease, anticancer and antiviral effects. For example, hesperetin obtained by removing glycosides from hesperidin or hesperidin is known to have capillary potentiation, decreased permeability, lowered blood pressure, lowered blood cholesterol, antiplatelet aggregation, anti-inflammatory and antiviral action. (Meyer, OC, Angiology, 45 , 579-584 (1994); Struckmann JR, et al., Angiol., 45 , 419-428 (1994); Matsubara, Y., et al., Japan Organic Synthesis Chem. Association Journal., 52 , 318-327 (1994. Mar.); Galati EM, et al., Farmaco., 51 (3) , 219-221 (1996, Mar.); Monforte MT., Et al., Farmaco ., 50 (9) , 595-599 (1995, Sep.); JP 95-86929; JP 95-86930; Chung, MI, et al., Chin. Pharm. J. (Taipei) ., 46 , 429- 437 (1994, Nov.); Galati, EM, et al., Farmaco., 40 (11) , 709-712 (1994, Nov.); and Emim JA, et al., J. Pharm.Pharmacol ., 46 (2), 118-122 (1994)), various bioflavonoids are known to have antioxidant, hypotensive, anticancer and antiviral effects (Saija, A., et al., Free Radical Biol. Med., 19 , 481-486 (1995); Matsubara, Y., et al., Supra; Galati EM, et al., Supra; Felicia V., et al., Nutr. Cancer, 26 , 167-181 (1996); EP 0352147 A2 (1990.1.24); and Kaul, TN, et al., J. Med. Virol., 15, 71-79 (1985)). Naringenin, obtained by removing glycosides from naringin or naringin, is known to act as a cholesterol lowering, anticancer and antigastric ulcer (protect from alcohol) (Monforte MT., Et al., Supra; JP 95-86929; JP 95-86930; Felicia V., et al., Supra; EP 0352147 A2 (1990.1.24); and Martin MJ, et al., Pharmacol., 49, 144-150 (1994)).

In addition, there are limonoid-based substances in the skin and seeds of tangerines, which have been shown to have anticancer activity (Lam, LKT, et al., Inhibition of chemically induced carcinogenesis by citrus limonoids.In Food Phytochemicals for Cancer Prevention, Vol. I, ACS Symposium series No. 546, Huang, MT, O. Osawa, CT Ho, R. Rosen (ed). 1993).

Therefore, the present inventors continue to research the development of ingredients that are effective in improving lipid metabolism and lowering blood pressure, when administering a composition of citrus peel and jujube extract to animals, improving lipid metabolism and lowering blood pressure The present invention has been completed by discovering the effect of the present invention.

An object of the present invention to provide a pharmaceutical and food composition for improving lipid metabolism and lowering blood pressure, including jujube extract and citrus peel extract.

In the present invention, jujube extract and citrus rind extract are mixed in a weight ratio of 1: 1 to 100: 1, there is provided a composition for improving lipid metabolism and lowering blood pressure.

The present invention also provides a composition for improving lipid metabolism and lowering blood pressure, in which the jujube extract and hesperidin, hesperetin, naringin, naringenin or a mixture thereof are mixed in a weight ratio of 1: 0.001 to 1: 0.1.

In addition, the present invention provides a pharmaceutical and food composition for improving lipid metabolism and lowering blood pressure, each containing an effective amount of the composition as an active ingredient.

Method for extracting the active ingredient from the jujube in the present invention is as follows. That is, after washing the jujube with water, add 2 to 5 L of 70 to 95% ethanol or water per 1 kg of jujube, 1 to 24 hours at 50 ℃-60 ℃ for ethanol, 70 to 121 for water The active substance may be extracted by heating at 30 ° C. for 30 minutes to 12 hours. In general, when extracting the jujube using water or ethanol, the composition of the extract may vary depending on the reaction time, reaction temperature, alcohol concentration, jujube maturity. In particular, the jujube used in the present invention serves to improve the smell and taste of the pharmaceutical and food composition.

Citrus fruits in the present invention refers to a mandarin orange, sugar citron, orange, lemon, citrus, grapefruit or citron. In order to obtain citrus peels used in the present invention, citrus fruits must first be produced without pesticide treatment or by using low pollution pesticides or biological control agents that are harmless to humans.

In the present invention, the following methods are used to prepare the citrus peel extract. That is, after drying the citrus peel, 3 to 30 l of 20 to 95% ethanol per kg of dried peel was added, extracted at 25 to 80 ° C. for 1 to 12 hours, and then the extract was filtered and the filtrate was concentrated in vacuo. Extracts can be obtained.

On the other hand, after drying the citrus peel, 0.1 to 2% Ca (OH) ₂ or 5 to 30 L of NaOH per 1 kg of dried peel is added and extracted at 25 to 60 ° C. for 1 to 5 hours, and then the extract is extracted. After filtering, 1N HCl solution was added to the filtrate to adjust the pH of the mixed solution to 4.0 to 7.0, and the resultant precipitate was recovered by drying in a refrigerating chamber for 10 to 48 hours, followed by drying.

Jujube extract obtained as above; And citrus peel extracts, or mixtures of hesperidin, hesperetin, naringin or naringenin, lower blood cholesterol and blood pressure in rats. Toxicity studies studied so far showed that jujube extract and citrus rind extract had little toxicity when administered orally to rats at a dose of 1,000 mg / kg, respectively. In addition, jujube extract and citrus rind extract do not show any side effects on the function of organs, including liver.

The mixture of extracts obtained from jujube and citrus peels according to the method of the present invention shows an effect of improving lipid metabolism and lowering blood pressure when administered to rats in an amount of 0.05 to 5 g / kg.

In addition, jujube and hesperidin, hesperetin, naringin, naringenin or mixtures thereof according to the method of the present invention show an effect of improving lipid metabolism and lowering blood pressure when administered to rats in an amount of 0.01 to 1 g / kg. .

In order to improve lipid metabolism and lower blood pressure, the composition of the present invention may be mixed with a pharmaceutically acceptable carrier as an active ingredient to prepare a pharmaceutical composition for improving lipid metabolism and lowering blood pressure. When hesperidin, hesperetine, naringin or naringenin, which are flavonoids isolated from citrus peels, is used in place of citrus peel extracts, jujube extracts and hesperidin, hesperetin, naringin, naringenin or mixtures thereof may be used. The pharmaceutical composition may further include conventionally used excipients, disintegrants, sweeteners, lubricants, flavoring agents, etc., tablets, capsules, powders, granules, suspensions, emulsifiers, syrups, liquids by conventional methods Or in dosage unit forms or as multi-dose pharmaceutical preparations, such as preparations for parenteral administration.

Jujube extract and citrus peel extract, hesperidin, hesperetine, naringin or naringenin of the present invention, the composition for improving lipid metabolism and lowering blood pressure can be administered parenterally or orally, as desired. 0.1 g to 5 g, preferably 0.5 to 1 g and citrus peel extract 0.1 g to 10 g, preferably 0.5 to 2 g or hesperidin, hesperetin, naringin naringenin or mixtures thereof It may be administered in one to several portions to be administered in an amount of 1 mg to 2000 mg, preferably 2 mg to 20 mg. Dosage levels for a particular patient may vary depending on the patient's weight, age, sex, health condition, diet, time of administration, method of administration, rate of excretion, severity of the disease, and the like.

The composition of the present invention mixed with the jujube extract and the citrus peel extract may also be added to the food in an amount of 1 to 100% by weight for the purpose of improving lipid metabolism and lowering blood pressure.

In addition, the composition of the present invention mixed with jujube extract and hesperidin, hesperetin, naringin, naringenin or a mixture thereof may be added to the food in an amount of 1 to 100% by weight for the purpose of improving lipid metabolism and lowering blood pressure. . Foods to which the mixture of the present invention may be added for the development of dietary supplements include, for example, various foods, meats, beverages, chocolates, snacks, confectionery, pizzas, ramen noodles, other noodles, gums, ice creams, Alcoholic beverages, vitamin complexes, and health supplements.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following Examples are only for illustrating the present invention, and the scope of the present invention is not limited to these.

Example 1 Preparation of Jujube Extract

(1) ethanol extraction

15 L of 95% ethanol was added to 5 kg of jujube and extracted twice in a water bath at 50-60 ° C. for 3 hours. The extracted ethanol solution was filtered and the filtrate was concentrated under reduced pressure to obtain 2 kg of ethanol extract.

(2) water extraction

15 L of water was added to 5 kg of jujube, and the mixture was boiled at 100 ° C. for 2 hours, filtered to remove solids, and the filtrate was concentrated under reduced pressure to obtain 3 kg of jujube extract.

Example 2 Effects of Jujube Extract on Plasma Cholesterol Concentrations and Changes in Serum Total Cholesterol

(Step 1) Effect of Jujube Extract on Plasma Cholesterol Concentration in Rats

30 Sprague-Dawley rats of 3 weeks of age were purchased from the Korean Experimental Animal Center in Negative Chungcheongbuk-do and were bred for 1 week in experimental animal feed, and at 4 weeks of age (90-110 g), Divided into three groups by randomized block design. Three groups of rats each had three different high cholesterol diets, namely 1% cholesterol (control) in normal diet (AIN-76 experimental animal diet); 1% cholesterol and 1.2% jujube ethanol extract (jujube ethanol extract group); And the diet containing 1% cholesterol and 1.5% jujube water extract (jujube water extract group), respectively. The composition of the diets ingested in the three groups is shown in Table 1 below.

All diets corresponded to the high cholesterol diet (1%, wt / wt) and the experimental diet contained 1.2 or 1.5% jujube extracts. Cellulose, mineral mixtures and vitamin mixture components in the AIN-76 dietary composition of rats were purchased from TEKLAD premier, Madison, Wisconsin.

All dietary rats were given free diet with water for 6 weeks. The dietary intake was recorded daily and weighed every 7 days. After the animal breeding was completed, the data on the breeding journals were analyzed.

(Step 2) Determination of total cholesterol, HDL-cholesterol and neutral lipid content in blood of experimental animals

The effect of jujube extract on the blood cholesterol and triglyceride content in rats was investigated as follows.

Blood samples were taken from three dietary rats, and plasma HDL fractions were isolated from the HDL-cholesterol reagent (Sigma Chemical Co. Cat. No. 352-3) including dextran-sulfate. Total cholesterol and HDL-cholesterol concentrations were measured by enzymatic coloration using Sigma's Total Cholesterol Kit (Cat. No. 352-100) (Allain et al., Clin. Chem., 20 , 470-475 (1974)). It was. Neutral lipid concentrations were measured using Sigma Diagnostic Kit (Cat. No. 339-50) (Bucolo, G. and David, H., Clin. Chem., 19 , 476-482 (1973)). The results are shown in Table 2 below, plasma total cholesterol concentration was reduced by 28% compared to the control group in the 1.2% jujube ethanol extract administration group, 30% compared to the control group in the 1.5% jujube water extract administration group.

Example 3 Confirmation of Blood Pressure Control Effect of Jujube Extract

(Step 1) Extraction of Blood Pressure Regulator from Jujube

4 kg of jujube was poured into 4 L of water, and 6 L of acetone was added thereto and stirred for 18 hours. After filtering by filter paper to remove solids, and concentrated the liquid phase under reduced pressure, 4 L of hexane was added thereto to separate the water layer and the hexane layer. In the same manner, the hexane layer was separated two more times to remove the fatty acid-based material contained in the hexane layer. Equal amount of ethyl acetate was added to the collected water layer, and the mixture was separated into a water layer and an ethyl acetate layer. The ethyl acetate layer was collected and concentrated to dryness under reduced pressure to obtain 7.3 g of a yellowish brown material. Jujube extract thus obtained was used for blood pressure control experiment.

(Step 2) Check the blood pressure control effect of jujube extract

Congenital hypertensive rats (SHR) were purchased from Charles River, Japan. Male Sprague-Dawley rats were 4 weeks old at the Korea Institute of Chemistry and were raised in the absence of specific pathogens (SPF). 12 weeks of age and 350-weight weight, respectively, were fed to feed and water freely in a normal breeding room (12 hours, 12 hours cancer cycle) maintained at a constant temperature (22 ℃) and humidity (55 ± 5%). When 450g was used for the experiment.

100 mg deoxycorticosterone acetate pellets (Innovative Research of America, USA) were implanted into the right femoral subcutaneous of Sprague Dawley rats and sutured with autoclips. After four weeks of oral administration of 1% NaCl to the rats to establish DOCA / saline hypertensive rats, rats with elevated mean arterial pressure above 170 mmHg were used for the evaluation of hypotensive action.

Sprague Dawley rats (350-450 g) were anesthetized with ether, incised about 1 cm in the left abdomen, and the renal artery close to the abdominal aorta was carefully separated. The muscle layer and skin were sutured with a ligated and needled suture. After 6-8 days of ligation, animals with systolic blood pressure greater than 180 mmHg were used in the experiments as a model of renal hypertensive rat (RHR).

DOCA / saline hypertensive rats, SHR and RHR rats prepared as described above were anesthetized by intraperitoneal administration of ketamine hydrochloride in an amount of 125 mg / kg, followed by PE10 to polyethylene tubing 50 (PE50). A cannula was inserted into the femoral artery by filling a heparinized saline solution in a catheter connected to the catheter. The other end of the catheter was pulled behind the neck subcutaneously and fixed.

After the rats were stabilized in the blood pressure measuring cage, a cannula was inserted into the femoral artery of the animal that awoke from the anesthesia the next day. blood pressure and heart rate were measured using a processing center (Modular, USA). After confirming that the blood pressure was stabilized for about 1 hour, orally administer the jujube extract prepared in step 1 by dose, and then measure blood pressure and heart rate until 24 hours after administration at regular intervals. It is expressed as the rate of change for.

The results are shown in Tables 3, 4 and 5, jujube extract showed a continuous blood pressure lowering effect for 24 hours when administered to rats in the amount of 0.3-1.0g / kg.

Effect of Jujube Extract on Blood Pressure and Heart Rate in DOCA Rats Average blood pressure (%) time Control 0.3 g / kg jujube extract 1 g / kg jujube extract 0 0.00 0.00 0.00 10 minutes 0.30 7.70 2.50 20 minutes -0.20 3.80 -4.70 30 minutes 0.20 -0.20 -9.50 60 mins -3.10 -11.50 -21.20 90 mins -1.30 -11.50 -22.90 2 hours -6.00 -10.20 -25.10 4 hours -6.60 -18.60 -29.90 6 hours -7.20 -13.30 -30.20 22 hours -3.20 -25.30 -14.30 24 hours -6.40 -24.40 -18.30 Baseline (mmHg) 144.00 158.00 173.00

Average heart rate (%) time Control 0.3 g / kg jujube extract 1 g / kg jujube extract 0 0.00 0.00 0.00 10 minutes 0.00 -0.20 4.50 20 minutes 2.00 2.80 4.60 30 minutes 2.80 -1.10 4.60 60 mins -1.50 -8.90 -3.20 90 mins -2.80 -10.60 -8.20 2 hours -4.70 -12.50 -3.60 4 hours -1.80 -16.70 -10.10 6 hours -5.00 -12.50 -13.80 22 hours -11.90 -24.20 -3.60 24 hours -12.00 -19.40 -2.70 Baseline (mmHg) 184.00 298.00 290.00

Effect of Jujube Extract on Blood Pressure and Heart Rate in SHR Average blood pressure (%) time Control 1g / kg jujube extract 0 0.00 0.00 10 minutes -0.20 3.00 20 minutes -1.90 -5.00 30 minutes -3.20 -8.80 60 mins -2.30 -11.40 90 mins -3.00 -8.30 2 hours -1.00 -7.60 4 hours -0.60 -12.20 6 hours -0.90 -13.70 22 hours -7.30 24 hours -0.10 -15.90 Baseline (mmHg) 150.00 139.00

Average heart rate (%) time Control 1 g / kg jujube extract 0 0.00 0.00 10 minutes 8.40 -0.80 20 minutes 7.10 -4.70 30 minutes 2.50 -7.20 60 mins -0.50 -11.30 90 mins 1.70 -10.40 2 hours -0.80 -6.40 4 hours -5.00 -10.30 6 hours -7.50 -12.70 22 hours -11.10 24 hours -10.10 -10.30 Baseline (mmHg) 366.00 310.00

Effect of Jujube Extract on Blood Pressure and Heart Rate in RHR Average blood pressure (%) time Control 1 g / kg jujube extract 3 g / kg jujube extract 0 0.00 0.00 0.00 10 minutes -2.20 -2.20 -6.20 20 minutes -0.60 -2.80 -6.30 30 minutes -0.30 -2.10 -4.10 60 mins -1.20 -0.80 0.00 90 mins 1.80 -3.00 -1.30 2 hours 3.00 -5.40 0.00 4 hours -3.10 -6.20 -3.60 6 hours -4.30 -8.60 0.10 22 hours -1.50 -16.60 -11.90 24 hours -0.20 -17.50 -10.40 Baseline (mmHg) 182.00 163.00 171.00

Average heart rate (%) time Control 1 g / kg jujube extract 3 g / kg jujube extract 0 0.00 0.00 0.00 10 minutes 5.90 4.30 10.00 20 minutes 6.50 2.80 2.50 30 minutes 2.00 2.30 -1.60 60 mins -0.10 0.60 1.40 90 mins 0.10 5.20 8.60 2 hours 5.80 2.80 5.20 4 hours 5.10 3.20 0.00 6 hours -2.20 -0.80 4.30 22 hours 0.80 3.40 4.60 24 hours -5.80 -0.50 2.90 Baseline (mmHg) 393.00 363.00 354.00

Example 4 Extraction and Quantification of Bioflavonoids from Citrus Peel Extracts and Preparation of Citrus Peel Extracts

(Step 1) Extraction and Quantification of Bioflavonoids

The peels of oranges, grapefruits and lemons, which were produced in Jeju, South Korea, were imported from citrus fruits, tangerines, citrons and imported citrus fruits from Jeonnam, and then powdered to a particle size of 100 μm-200 μm. 500 mg of this powder was precisely weighed, and 50 ml of methanol was added thereto, followed by extraction with a water bath at 50 ° C. for 6 hours, followed by cooling, filtration, and addition of methanol to make a 50 ml solution. If necessary, the mixture was diluted to have a concentration within the range used for preparing the calibration curve.

In order to investigate the components of the skin extract obtained as described above, HPLC analysis was performed under the following conditions. 5.0 μl of the sample solution was injected into an HPLC equipped with a Lichrosorb RP-8 column (5 μm, 4 × 250 mm) previously equilibrated with 37% methanol. The temperature of the column was adjusted to 30 ° C. and eluted at a flow rate of 1.0 ml / min using 37% methanol as the mobile phase. Separately, hesperidin and nargine (Sigma Co.) standards were dissolved in methanol and standard solutions were prepared so that the final concentrations were 0.1, 0.2, 0.3, 0.4 and 0.5 mg / ml, respectively, and HPLC was performed under the same conditions. The eluate was detected at 280 nm using a UV-VIS spectrophotometer, and the content was calculated by comparing the area of the HPLC profile of the extract with the calibration curve and the content of hesperidin and naringin in the extract extracted from the extract. The content was as follows.

Content of Hesperidin and Naringin in Various Citrus Peels Citrus varieties Hesperidin Narinjin Orange Tangerine Orange Lemon Lemon Tangerine Grapefruit -0.402.101.402.10-0.80 3.403.90 Micro Trace Micro Trace 4.700.80

(Step 2) Preparation of Citrus Peel Extract

(1) Method using ethanol

After drying the citrus peel from Jeju Island, 5 l of 30% ethanol solution was added to 500 g of dried citrus peel and extracted at 60 ° C. for 5 hours. The extract was filtered using cotton cloth, and the filtrate was concentrated in vacuo to obtain 190 g of syrupy extract. As a result of measuring the content of hesperidin in the extract in the same manner as in step 1, 190 g of the hesperidin was contained in the extract. As a result of analyzing the components of the extract using HPLC, it consisted of trace components such as water 65%, sugar 28% (11% fructose, glucose 11%, sucrose 6%), hesperidin 2.7% and other ash.

(2) Method using Ca (OH) ₂

After the Jeju citrus peel was dried, 5 l of 0.5% Ca (OH) ₂ solution was added to 500 g of dried citrus peel, and the mixture was stirred for 1 hour while stirring at room temperature. The extract was filtered with cotton fabric and 1N HCl solution was added to the filtrate to make the pH of the mixed solution 4.0 to 4.5, or 6.80 to 7.0, and then left in a 5 ° C. cold room for 24 hours. At this time, the resulting precipitate was recovered and dried to obtain 5 g and 10 g of dried powder, respectively. The precipitated powder was quantitatively analyzed by HPLC as in Step 1, containing 3.2 g and 6.55 g of hesperidin, respectively, so that the purity of hesperidin was 64% and 65%, respectively.

(3) Method using NaOH

After drying the citrus peel from Jejudo, 5 l of 0.5% NaOH was added to 500 g of the dried citrus peel and stirred at room temperature for 1 hour, followed by filtration with cotton fabric. 1N HCl solution was added to the filtrate to bring the pH of the mixed solution to 4.0-4.5 or 6.8-7.0, and then left in a 5 ° C. refrigerator for 24 hours. At this time, the resulting precipitate was recovered and dried to obtain 44 g and 49 g of dry powder, respectively. 13.6 g and 9.8 g of hesperidin, respectively, were recovered from the dry powder by HPLC (purity: 31% and 20%, respectively).

Example 5 Animal Dose Experiment of Citrus Peel Extract with Dietary Composition of Alcohol and Alcohol

Two 20-week-old Sprague-Dawley rats were purchased from the Korean Experimental Animal Center in Eumseong-gun, Chungbuk, and were bred for one week in experimental animal feed, and at 4 weeks of age (90-110 g), Divided into two groups by randomized block design. Two groups of rats each had three different high cholesterol diets, namely 1% cholesterol (control) in normal diet (AIN-76 experimental animal diet); A diet containing the tangerine rind extract prepared in step 2 (1) of Example 4 corresponding to 1% cholesterol and 0.1% hesperidine was consumed. The composition of the diets ingested in both groups is shown in Table 7 below.

* 0.1% hesperidin equivalent

All diets correspond to a high cholesterol diet (1%, wt / wt). Hesperidin and naringin were purchased from Sigma Chemical company, St. Louis, Mo. AIN-76, a laboratory diet of experimental rats. Cellulose, mineral mixtures and vitamin mixture components in the dietary composition were purchased from TEKLAD premier, Madison, Wisconsin, USA.

All dietary rats were given free diet with water for 6 weeks. The dietary intake was recorded daily and weighed every 7 days. After the animal breeding was finished, the data on the breeding journal showed that there was no significant difference between the two groups in terms of dietary intake and weight gain.

Example 6 Determination of Total Cholesterol, HDL-Cholesterol and Neutral Lipid Contents in Experimental Animals

The effects of citrus peel extract on blood cholesterol and triglyceride content in rats were investigated as follows.

Blood samples were taken from the rats of both diets, from which plasma HDL fractions were separated using HDL-cholesterol reagent (Sigma Chemical Co. Cat. No. 352-3) including dextran-sulfate. Total cholesterol and HDL-cholesterol concentrations were measured by enzymatic coloration using Sigma's Total Cholesterol Kit (Cat. No. 352-100) (Allain et al., Clin. Chem., 20 , 470-475 (1974)). It was. Neutral lipid concentrations were measured using Sigma Diagnostic Kit (Cat. No. 339-50) (Bucolo, G. and David, H., Clin. Chem., 19 , 476-482 (1973)). The results are shown in Table 8 below, plasma total cholesterol concentration was reduced by 35% compared to the control group in the citrus peel extract administration group.

Example 7 Oral Toxicity Test of Jujube and Citrus Peel Extracts

Specific pathogens free of 7-8 weeks of age, 12 females weighing 25-29 g and 12 males weighing 34-38 g, temperature 22 ± 1 ° C, humidity 55 ± 5%, illumination 12L / 12D was bred in the animal room. Mice were allowed to acclimate for about a week before being used in the experiment. Feed for experimental animals (Jeil Jedang Co., Ltd., mice and rats) and drinking water were supplied after sterilization and free ingestion.

The jujube extract obtained in Example 1 (1) and the tangerine peel extract obtained in Step 2 (1) of Example 4 were each prepared at a concentration of 100 mg / ml using 0.5% Tween 80 as a solvent, and then, each 20 g of mouse body weight. 0.2 ml was administered orally. Samples were administered orally once and observed for side effects or lethality for 10 days after administration. That is, on the day of dosing, changes in general symptoms and the presence or absence of dead animals were observed at least once in the morning, at least once every afternoon from 1 hour, 4 hours, 8 hours, 12 hours after the administration and from the next day until the 10th. In addition, the animals were killed and dissected at 10 days of administration, and the internal organs were visually examined. The change in body weight was measured every day from the day of administration to observe the weight loss phenomenon of the animal by jujube and citrus extract.

The purpose of this study was to provide information on available doses in general pharmacology and drug efficacy tests and to derive basic data on toxicity by identifying the degree of acute toxicity in jujube and citrus peel extracts. The following results were obtained.

In the case of acute oral toxicity, no lethal animals were observed for 10 days at the dose of 1,000 mg / kg citrus peel extract. An autopsy of the surviving animals was performed 10 days later, and there were no gross lesions, and normal body weight gain was observed without any weight loss for 10 days from the day after the administration.

In conclusion, the jujube and citrus peel extracts were not toxic upon oral administration.

Example 8 Pharmaceutical Composition Containing Jujube Extract and Citrus Peel Extract Produce

Jujube extract and citrus rind extract, or naringin, naringenin, hesperidin, hesperetin, or a mixture thereof prepared in the above examples, a pharmaceutical composition for improving lipid metabolism and lowering blood pressure was prepared.

(1) 500 mg jujube extract

Citrus Peel Extract 500 mg

500 mg of carrier or excipient (starch, lactose, pectin, etc.)

Total 1,500 mg

(2) 500 mg jujube extract

Citrus Peel Extract 100 mg

Carrier or excipient (starch, lactose, pectin, etc.) 900 mg

Total 1,500 mg

(3) 200 mg of jujube extract

Naringin or naringenin 100 mg

Carrier or excipient (starch, lactose, pectin, etc.) 200 mg

500 mg total

(4) 200 mg jujube extract

Hesperidin or Hesperetin 100 mg

Carrier or excipient (starch, lactose, pectin, etc.) 200 mg

500 mg total

(5) 200 mg jujube extract

Naringin 50 mg

Hesperidin 50 mg

Carrier or excipient (starch, lactose, pectin, etc.) 200 mg

500 mg total

Example 9 Preparation of Food Composition Using Jujube Extract and Citrus Peel Extract

Jujube extract and citrus rind extract, or naringin, naringenin, hesperidin, hesperetin, or a mixture thereof prepared in the above examples, a pharmaceutical composition for improving lipid metabolism and lowering blood pressure was prepared.

(1) 300g of ground beef used in the production of hamburgers was prepared by adding 50g of jujube extract and 10g of citrus peel.

(2) To 300 g of ground beef used in the production of hamburgers, 50 g of jujube extract and 5 g of citrus peel were prepared.

(3) To 300 g of ground beef used in the manufacture of hamburgers, 50 g of jujube extract and 300 mg of naringin or naringenin were added.

(4) Jujube in 300 g of ground beef used for making hamburgers

Prepared by adding 50 g of extract and 300 mg of hesperidin or hesperetin.

5) To 300 g of ground beef used in the manufacture of hamburgers, 50 g of jujube extract, 150 mg of naringin and 150 mg of hesperidine were added.

The composition of the present invention comprising jujube extract and citrus rind extract containing naringin and hesperidin, or when administered to an animal, may exhibit effects such as liver disease, hypertension, arteriosclerosis, hyperlipidemia and other diseases such as cancer and cancer. .

Claims (12)

A pharmaceutical composition for improving lipid metabolism and lowering blood pressure, comprising a mixture of jujube extract and citrus peel extract as an effective amount of an active ingredient in a weight ratio of 1: 1 to 100: 1 together with a pharmaceutically acceptable carrier. The method of claim 1, The jujube extract is prepared by a method comprising adding 2 to 5 L of 70 to 95% ethanol per 1 kg of jujube and extracting for 1 to 24 hours at 50 ℃ -60 ℃. The method of claim 1, The jujube extract is prepared by a method comprising adding 2 to 5 L of water per kg of jujube and extracting at 70 to 121 ° C. for 30 minutes to 12 hours. The method of claim 1, The citrus fruit is a mandarin orange, sugar, orange, lemon, citrus, grapefruit or citron composition. The method of claim 1, After the citrus peel extract dries the citrus peel, 3 to 30 l of 20 to 95% ethanol per kg of dried peel is added, extracted at 25 to 80 ° C. for 1 to 12 hours, and then the extract is filtered and the filtrate is filtered. A composition, which is prepared by a method comprising vacuum concentration. The method of claim 1, The effective amount of the jujube extract and the citrus peel extract is 0.1 g to 5 g / kg body weight / day and 0.1 g to 10 g / kg body weight / day, respectively. A lipid comprising a jujube extract as an effective amount of an active ingredient and a mixture of hesperidin, hesperetin, naringin, naringenin or a mixture thereof in a weight ratio of 1: 0.001 to 1: 0.1 with a pharmaceutically acceptable carrier Pharmaceutical composition for improving metabolism and lowering blood pressure. The method of claim 7, wherein The jujube extract is prepared by a method comprising adding 2 to 5 L of 70 to 95% ethanol per 1 kg of jujube and extracting for 1 to 24 hours at 50 ℃ -60 ℃. The method of claim 7, wherein The jujube extract is prepared by a method comprising adding 2 to 5 L of water per kg of jujube and extracting at 70 to 121 ° C. for 30 minutes to 12 hours. The method of claim 7, wherein An effective amount of the jujube extract and hesperidin, hesperetin, naringin, naringenin or a mixture thereof is equivalent to 0.1 g to 5 g / kg body weight / day and 1 mg to 2000 mg / kg body weight / day, respectively. A food composition for improving lipid metabolism and lowering blood pressure, comprising a jujube extract and a citrus peel extract in a weight ratio of 1: 1 to 100: 1. A jujube extract and hesperidin, hesperetin, naringin, naringenin or a mixture thereof in a weight ratio of 1: 0.001 to 1: 0.1 food composition for improving lipid metabolism and lowering blood pressure.