Pharmaceutical composition containing complex extract of Crataegi fructus and Citri pericarpium as an active ingredient for treating or preventing obesity or lipid-related metabolic diseases

Abstract

The present invention provides a pharmaceutical or health functional food containing, as an active ingredient, a complex extract of Crataegi Fructus and Citri Pericarpium. The complex extract has the effects of reducing body weight and lipids in blood vessels.

Claims

1. A pharmaceutical composition for reducing the concentration of blood triglycerides or blood total cholesterol and/or for reducing body weight comprising an effective amount of a complex extract, wherein the complex extract is a synergistic combination of extracts obtained by extraction of Crataegi Fructus and Citri Pericarpium with ethanol, wherein the ratio of Crataegi Fructus and Citri Pericarpium is 5:3 or 1:1, and wherein the composition is in the form of a tablet, a pill, or a capsule.

2. The pharmaceutical composition of claim 1, wherein the complex extract is present in an amount of 0.1 to 50 wt % with respect to the total weight of the composition.

3. A method for reducing the concentration of blood triglyceride or blood total cholesterol in a subject in need thereof, comprising administering an effective amount of the pharmaceutical composition of claim 1 to said subject.

4. A method for reducing body weight in a subject in need thereof, comprising administering an effective amount of the pharmaceutical composition of claim 1 to said subject.

Description

DESCRIPTION OF DRAWINGS

(1) FIG. 1 is a diagram showing the change in weight of high-fat diet obese animal models.

(2) FIG. 2 is a diagram showing the change in concentration of blood triglyceride in high-fat diet obese animal models.

(3) FIG. 3 is a diagram showing the change in concentration of blood total cholesterol in high-fat diet obese animal models.

BEST MODE FOR CARRYING OUT THE INVENTION

(4) Hereinafter, the present invention will be described in detail.

(5) The present invention provides a composition comprising a complex extract of Crataegi Fructus and Citri Pericarpium as an active ingredient.

(6) Method of Preparing Complex Extract of Crataegi Fructus and Citri Pericarpium

(7) The complex extract of the present invention is preferably prepared by a method comprising the following steps, but not limited thereto:

(8) (1) drying and crushing Crataegi Fructus and Citri Pericarpium;

(9) (2) extracting an extract by adding an extraction solvent to the crushed Crataegi Fructus and Citri Pericarpium;

(10) (3) cooling and filtering the extract; and

(11) (4) concentrating the filtered extract under reduced pressure and drying the concentrated extract.

(12) The Crataegi Fructus and Citri Pericarpium used in step (1) may be those grown or commercially available without any limitation.

(13) The extraction in step (2) may be performed by shaking extraction, Soxhlet extraction or reflux extraction, but not limited thereto. The extraction temperature may preferably be 40 to 100 C., more preferably 60 to 80 C. Moreover, the extraction time may preferably be 2 to 24 hours, and the number of extractions may preferably be 1 to 5 times, more preferably more than 2 times.

(14) The extraction solvent used in step (2) may be water, alcohol, or a mixture thereof. The alcohol may preferably be C1-C4 lower alcohol, more preferably methanol or ethanol. The concentration of the alcohol may preferably be 0 to 100%, more preferably 30%. Moreover, the extraction may preferably be performed by adding the extraction solvent in a weight or volume of 5 to 15 times the Crataegi Fructus and Citri Pericarpium prepared in step (1), more preferably 10 times.

(15) The concentration under reduced pressure in step (4) may preferably be performed using a vacuum reduced-pressure concentrator or vacuum rotary evaporator, and the drying may preferably be performed by drying under reduced-pressure, vacuum drying, boiling drying, spray drying, or freeze drying, but not limited thereto.

(16) Pharmaceutical Composition

(17) The present invention provides a pharmaceutical composition comprising a complex extract of Crataegi Fructus and Citri Pericarpium as an active ingredient for treating or preventing obesity.

(18) The pharmaceutical composition has the effect of minimizing body weight gain even in an obese environment due to high-fat diet, which can be seen from FIG. 1. Accordingly, the pharmaceutical composition of the present invention can be used to control an obese patient's weight to be close to a normal weight or prevent a normal person from being an obese patient.

(19) Moreover, the present invention provides a pharmaceutical composition comprising a complex extract of Crataegi Fructus and Citri Pericarpium as an active ingredient for treating or preventing lipid-related metabolic diseases.

(20) The lipid-related metabolic diseases may be at least one disease selected from the group consisting of diabetes, hyperlipidemia, hypertension, arteriosclerosis, fatty liver, stroke, and cardiovascular disease.

(21) The pharmaceutical composition has the effects of reducing the concentration of blood triglyceride and the concentration of blood total cholesterol, which can be seen from FIGS. 2 and 3. Accordingly, the pharmaceutical composition of the present invention can be used to treat or prevent lipid-related metabolic diseases.

(22) The complex extract of Crataegi Fructus and Citri Pericarpium in the pharmaceutical composition as an active ingredient of the present invention may preferably be contained in an amount of 0.1 to 50 wt % with respect to the total weight of the composition.

(23) The pharmaceutical composition of the present invention may be administered in various dosage forms such as oral and parenteral dosage forms during actual clinical administration. For formulation, the pharmaceutical composition can be formulated with generally used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc.

(24) Solid dosage forms for oral administration may include tablets, pills, powders, granules, and capsules, and these solid dosage forms are prescribed by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose, and gelatin. Moreover, lubricants such as magnesium stearate, talc, etc. can be used in addition to simple excipients.

(25) Liquid dosage forms for oral administration may include suspensions, liquids for internal use, emulsions, and syrups, and various excipients such as wetting agents, sweeteners, flavoring agents, preservatives, etc. can be used in addition to generally used simple diluents such as water, liquid paraffin, etc.

(26) Dosage forms for parenteral administration may include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the non-aqueous solvents and suspensions may include vegetable oils such as propylene glycol, polyethylene glycol, and olive oil and injectable esters such as ethyl oleate. Examples of suppository bases may include Witepsol, macrogol, Tween 61, cocoa butter, laurin butter, glycerol, gelatin, etc. For parenteral administration, the pharmaceutical composition of the present invention can be administered via subcutaneous injection, intravenous injection, or intramuscular injection.

(27) The dose of the pharmaceutical composition may vary depending on a patient's state and weight, the severity of disease, the form of drug, and administration route and duration and can be appropriately selected by those skilled in the art. However, for a desired effect, the pharmaceutical composition of the present invention may preferably be administered at a dose of 0.0001 to 100 mg/kg per day. The daily dose may be administered once a day or in equally divided doses. However, the dose does not limit the scope of the present invention.

(28) Health Functional Food

(29) The present invention provides a health functional food comprising a complex extract of Crataegi Fructus and Citri Pericarpium as an active ingredient for ameliorating or preventing obesity.

(30) The health functional food has the effect of controlling an obese patient's weight to be close to a normal weight or preventing a normal person from being an obese patient.

(31) Moreover, the present invention provides a health functional food comprising a complex extract of Crataegi Fructus and Citri Pericarpium as an active ingredient for ameliorating or preventing lipid-related metabolic diseases.

(32) The health functional food has the effect of reducing the lipid concentration and thus ameliorating or preventing lipid-related metabolic diseases.

(33) The health functional food of the present invention may comprise the complex extract of the present invention as it is or can be used in combination with other foods or food ingredients and can be appropriately used according to a conventional method.

(34) The content of the active ingredient in the health functional food can be determined appropriately depending on the purpose of use (prevention, healthy or therapeutic treatment). In general, during the production of food or beverage, the complex extract of the present invention may be added in an amount of 0.01 to 15 wt % with respect to the total weight of the food.

(35) The type of the health functional food is not particularly limited. Example of the health functional food to which the complex extract of the present invention can be added may include beverages, gums, vitamin complexes, health drinks, etc. and may encompass all health functions foods in a general sense.

(36) The health functional food of the present invention may comprise various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheeses, chocolates, etc.), pectic acid and its salts, alginic acid and its salts, organic acid, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohol, carbonizing agents used in carbonated drinks, etc.

MODE FOR INVENTION

Examples

(37) Next, preferred Examples will be provided to facilitate understanding of the present invention. However, the following Examples are provided for better understanding of the present invention, and the scope of the present invention is not limited by the Examples.

Example 1: Preparation of Complex Extract

(38) Crataegi Fructus and Citri Pericarpium were purchased from Yaksudang (Dongdaemun-gu, Seoul). 30% ethanol was added to 62.5 g of Crataegi Fructus and 37.5 g of Citri Pericarpium in a weight of 10 times the total weight of each ingredient and extracted at 80 C. for 3 hours twice. Filtrates of the extracts were concentrated under reduced pressure to 60 Brix, freeze-dried in the form of power, and then mixed.

Example 2: Preparation of Complex Extract

(39) Extract was prepared and mixed by the same method as Example 1, except that 50 g of Crataegi Fructus and 50 g of Citri Pericarpium were used.

(40) The contents of Crataegi Fructus and Citri Pericarpium contained in the complex extracts of Examples 1 and 2 are shown in the following Table 1:

(41) TABLE-US-00001 TABLE 1 Crataegi Citri Fructus Pericarpium Example 1 Weight (g) 62.5 37.5 Weight ratio 5 3 Example 2 Weight (g) 50 50 Weight ratio 1 1

Comparative Example 1: Preparation of Crataegi Fructus Extract

(42) Extract was prepared by the same method as Example 1, except that 100 g of Crataegi Fructus was used.

Comparative Example 1: Preparation of Citri Pericarpium Extract

(43) Extract was prepared by the same method as Example 1, except that 100 g of Citri Pericarpium was used.

(44) The contents of Crataegi Fructus and Citri Pericarpium contained in the extracts of Comparative Examples 1 and 2 are shown in the following Table 2:

(45) TABLE-US-00002 TABLE 2 Crataegi Citri Fructus Pericarpium Comparative Weight (g) 100 0 Example 1 Weight ratio 1 0 Comparative Weight (g) 0 100 Example 2 Weight ratio 0 1

Example 3: Determination of Effects of Complex Extract on Weight Loss and Lipid Reduction

(46) 1. Overview of Experiments

(47) Animal models, diet-induced obesity (DIO) white rat models, which exhibit a similar process to the case where a person becomes obese, were used.

(48) 2. Experimental Animals

(49) Animal experiments were performed on Sprague-Dawley (SAMTAKO BIO Korea) male white rats weighing 80 to 100 g.

(50) 3. Selection of Experimental Groups Normal group (AIN-93G, Normal diet+fed with secondary distilled water); Control group (60% Kcal high-fat diet+fed with secondary distilled water); Positive control group (60% Kcal high-fat diet+administered with 390 mg/kg of HCA); Crataegi Fructus extract-administered group (high-fat diet+administered with 100 mg/kg of theCrataegi Fructus extract of Comparative Example 1); Citri Pericarpium extract-administered group (high-fat diet+administered with 100 mg/kg of the Citri Pericarpium extract of Comparative Example 2); and Complex extract-administered group (high-fat diet+administered with 100 mg/kg of the complex extract of Example 1 or 2).

(51) 4. Experimental Conditions

(52) The temperature was 222 C., the relative humidity was 5010%, and the dark-light cycle (light on at 07:00light off at 19:00) was controlled with fluorescent lighting.

(53) All the experimental groups were orally administered twice a day for 8 weeks, and during the experiments, the measurement of weight was performed once a day, and the measurement of feed intake was performed every three days. Moreover, all the experimental groups were sacrificed after 8 weeks to collect blood samples, serums were separated from the blood samples, and the blood triglyceride (mg/dL) and the total cholesterol (mg/dL) were analyzed using a biochemical analyzer (VetTest 8008, IDEXX, USA).

(54) 5. Experimental Results

(55) After administration to each group for 8 weeks, the reduction in the rate of body weight gain (g) in the groups administered with 100 mg/kg of the Crataegi Fructus extract and the Citri Pericarpium extract, respectively, was 3.2% and 5.7%, which were statistically insignificant compared to the control group.

(56) However, the reduction in the rate of body weight gain (g) in the group administered with 100 mg/kg of the complex extract was significantly reduced by 13% (359.310.5 g VS 311.518.5 g, P<0.01) (meanSD), which was higher than the positive control group administered with 390 mg/kg of HCA (see FIG. 1).

(57) Moreover, after all the experimental groups were sacrificed after 8 weeks to collect blood samples and the serums separated from the blood samples were analyzed, the concentration of blood triglyceride (mg/dL) in the groups administered with 100 mg/kg of the Crataegi Fructus extract and the Citri Pericarpium extract, respectively, was reduced by 12.7% and 10%, which, however, were statistically insignificant compared to the control group.

(58) However, the concentration of blood triglyceride (mg/dL) in the group administered with 100 mg/kg of the complex extract was significantly reduced by 21.7% (158.423.9 mg/dL VS 1245.8 mg/dL, P<0.05), which was higher than the control group (see FIG. 2).

(59) Moreover, the concentration of blood total cholesterol (mg/dL) in the group administered with 100 mg/kg of the Crataegi Fructus extract was reduced by 2.5% compared to the control group, but the group administered with 100 mg/kg of the Citri Pericarpium extract showed no reduction in the total cholesterol concentration.

(60) However, the concentration of blood total cholesterol in the group administered with 100 mg/kg of the complex extract was reduced by 28.4%, which was significantly higher than the control group (72.913.6 mg/dL VS 52.28.7 mg/dL, P<0.01) (see FIG. 3).

(61) The above experimental results are summarized in the following Tables 3 and 4:

(62) TABLE-US-00003 TABLE 3 Reduction in rate Body weight gain of body weight gain (g) (%) Negative control (Saline) 359.3 16.6 Positive control (HCA) 333.2 12.2* 7.3* Comparative Example 1 347.7 10.8 3.2 Comparative Example 2 338.7 20.5 5.7 Example 1 311.5 15.2** 13.3** Example 2 312.6 9.1* 13*

(63) TABLE-US-00004 TABLE 4 Total triglyceride Total cholesterol (mg/dL) (mg/dL) Negative control (Saline) 158.4 23.9 72.9 13.6 Positive control (HCA) 134.2 21.3 59.8 11.2* Comparative Example 1 138.3 23.5 71.1 12.1 Comparative Example 2 142.5 9.2 78.2 10.3 Example 1 .sup.124 5.8* 52.2 8.7** Example 2 126.7 19.1* 52.6 9.7** (*P < 0.05, **P < 0.01)

Formulation Example 1: Preparation of Tablets

(64) TABLE-US-00005 The complex extract of Example 1 200 mg Lactose 100 mg Starch 100 mg Magnesium stearate q.s

(65) The above ingredients were mixed and compressed to prepare tablets according to a conventional tablet preparation method.

Formulation Example 2: Preparation of Capsules

(66) TABLE-US-00006 The complex extract of Example 1 200 mg Lactose 50 mg Starch 50 mg Talc 2 mg Magnesium stearate q.s

(67) The above ingredients were mixed and filled into gelatin capsules to prepare capsules according to a conventional capsule preparation method.

Formulation Example 3: Preparation of Liquids

(68) TABLE-US-00007 The complex extract of Example 1 1,000 mg Sugar 20 g Isomerized glucose syrup 20 g Lemon flavor q.s

(69) Purified water was added to make a total of 1,000 mL. The above ingredients were mixed, filled into brown bottles, and sterilized to prepare liquids according to a conventional liquid preparation method.

(70) The above ratio illustrates a preferred example of mixing ingredients relatively suitable for a beverage, but it can be arbitrarily changed according to regional and national preferences such as demand classes, demand nations, uses, etc.

Formulation Example 4: Preparation of Health Functional Food

(71) TABLE-US-00008 The complex extract of Example 1 1,000 mg Vitamin mixture q.s Vitamin A acetate 70 g Vitamin E 1.0 mg Vitamin B1 0.13 mg Vitamin B2 0.15 mg Vitamin B6 0.5 mg Vitamin B12 0.2 g Vitamin C 10 mg Biotin 10 g Nicotinic acid amide 1.7 mg Folic acid 50 g Calcium pantothenate 0.5 mg Mineral mixture q.s Ferrous sulfate 1.75 mg Zinc oxide 0.82 mg Magnesium carbonate 25.3 mg Potassium monophosphate 15 mg Potassium diphosphate 55 mg Potassium citrate 90 mg Calcium carbonate 100 mg Magnesium chloride 24.8 mg

(72) The above ratio of vitamins and minerals illustrates a preferred example of mixing ingredients relatively suitable for a health functional food, but it can be arbitrarily changed. According to a conventional health functional food preparation method, the above ingredients are mixed and used for preparation of a health functional food composition by a conventional method (e.g., nutrient candies).

Formulation Example 5: Preparation of Health Functional Beverage

(73) TABLE-US-00009 The complex extract of Example 1 1,000 mg Citric acid 1,000 mg Oligosaccharide 100 g Plum extract 2 g Taurine 1 g Total with purified water added 900 mL

(74) According to a conventional health functional beverage preparation method, the above ingredients were mixed, stirred and heated at 85 C. for about 1 hour, and the prepared solution was filtered, filled into 2 L sterile bottles, sealed, sterilized, and kept under refrigeration, and then used for preparation of a health functional beverage composition.

(75) The above ratio illustrates a preferred example of mixing ingredients relatively suitable for a beverage, but it can be arbitrarily changed according to regional and national preferences such as demand classes, demand nations, uses, etc.

INDUSTRIAL APPLICABILITY

(76) As described above, the present invention can provide a composition for treating or preventing obesity or lipid-related metabolic diseases.