JP2009227622A - Therapeutic agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a therapeutic agent having a cranberry extract as an active ingredient which is particularly remarkably effective for various diseases other than periodontal diseases and autoimmune diseases although the applications of the cranberry extract to a periodontal disease preventing agent, an autoimmune disease therapeutic agent and the like are known. <P>SOLUTION: An antiallergic, a hyperuricemia preventing or improving agent, an anti-osteoporosis agent, an antidepressant-antistress agent, an adiponectin production promoter, and a cholesterol reducing agent comprise a cranberry extract as an active ingredient. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a therapeutic agent useful for various diseases comprising a cranberry extract as an active ingredient.

Cranberry extract is known for its use as a preventive agent for periodontal disease (Patent Document 1), an autoimmune disease therapeutic agent (Patent Document 2), and the like.
However, there is no viewpoint that the combination of the cranberry extract, in particular, the combination of the cranberry extract and the processed product of Kuzuka, is effective for various diseases applied in the present invention described below with particularly remarkable effects. .
JP 2007-91703 A International Publication WO2005 / 030200 Pamphlet

  An object of the present invention is to provide various therapeutic agents that are effective with a particularly remarkable effect on various diseases applied in the present invention described below.

The invention according to claim 1 is an antiallergic agent characterized by comprising cranberry extract as an active ingredient.
The invention according to claim 2 is a preventive or ameliorating agent for hyperuricemia, characterized by comprising a cranberry extract as an active ingredient.
The invention according to claim 3 is an anti-osteoporosis agent comprising cranberry extract as an active ingredient.
The invention according to claim 4 is an antidepressant / antistress agent characterized by comprising a cranberry extract as an active ingredient.
The invention according to claim 5 is an adiponectin production promoter characterized by comprising a cranberry extract as an active ingredient.
The invention according to claim 6 is a cholesterol-lowering agent characterized by comprising cranberry extract as an active ingredient.
The invention according to claim 7 is an antiallergic agent characterized by comprising cranberry extract and processed kuzuka as active ingredients.
The invention according to claim 8 is a prophylactic or ameliorating agent for hyperuricemia characterized by comprising a cranberry extract and a processed kuzu flower as active ingredients.
The invention according to claim 9 is an anti-osteoporosis agent characterized by comprising a cranberry extract and a processed kuzu flower as active ingredients.
The invention according to claim 10 is an antidepressant / antistress agent characterized by comprising a cranberry extract and a processed kuzu flower as active ingredients.
The invention according to claim 11 is an adiponectin production promoter characterized by comprising a cranberry extract and a processed kuzu flower as active ingredients.
The invention according to claim 12 is a cholesterol-lowering agent characterized by comprising a cranberry extract and a processed kuzu flower as active ingredients.

  According to the present invention, there are provided various therapeutic agents that are particularly effective for various diseases applied in the present invention described below with remarkable effects.

  Hereinafter, the present invention will be described in more detail.

  Cranberry (Vaccinium macrocarpon Ait.) Used in the present invention is not limited in its variety, but for example, Crowley, Stevens, Benlear, Pilgrim, Early black , Bergman and the like. Commercially available cranberry powder can also be used. For example, Early Black is manufactured under the trade name PACran from Decas Botany Synergies, USA.

  Cranberry extracts include juice obtained from cranberry fruits, fruit skin, stems, seeds, concentrates, purified products, dried products and freeze-dried products, and cranberry fruits, fruit skins, stems, seeds as solvents. An extract obtained by contacting is mentioned.

  In the latter form, examples of the solvent to be used include a polar solvent and an ambipolar solvent. For example, water, an organic solvent, a mixed solution of water and an organic solvent, or the like can be used. Examples of the organic solvent include lower alcohols represented by ethanol, methanol, propanol and butanol, ethers represented by dimethyl ether and diethyl ether, halogenated hydrocarbons represented by chloroform, carbon tetrachloride, acetonitrile, and the like. Examples include ethyl acetate and acetone. Among these, water, an aqueous ethanol solution, an aqueous acetone solution, and ethyl acetate are preferable.

  In the case of purified cranberry product, dried product, or freeze-dried product, any means known in the art may be appropriately employed. For example, the method for purifying cranberry extract using column chromatography is described in the above-mentioned patent document. 1.

  The extraction time may be a time for sufficiently extracting soluble components from the extraction raw material, and may be set as appropriate according to the extraction temperature and the like. Preferably, it is 30 minutes to 48 hours. For example, when the extraction temperature is less than 50 ° C., it can be extracted for 6 hours to 48 hours, and when it is 50 ° C. or more, it can be extracted for 30 minutes to 24 hours.

  For example, in the case of a freeze-dried product of an aqueous extract of cranberry fruit, the intake amount of the cranberry extract is preferably in the range of 50 to 2000 mg as a total amount per day for an adult, but is not particularly limited.

  In the present invention, a form in which the cranberry extract and the processed kuzu flower are used in combination is particularly preferable.

  The processed kuzu flower used in the present invention is not particularly limited as long as it is a processed product of the flower part of the kuzu plant belonging to the leguminous plant. Kuzuka includes flowers collected from the stage to the fully opened flower. It is preferable to use soot. In the present specification, the “kuzuka processed product” refers to a product obtained by performing at least one of a drying process, a pulverizing process, and an extracting process on kuzuka. The processed kuzuka product includes a dried katsuka product, a kuzu flower crushed product, a dried katsuhana product (kuzuka powder), and a kuzu flower extract. The kuzu flower extract includes an extract obtained by performing an extraction process from kuzu flower, kuzu flower crushed material, kuzu flower dried product or kuzu flower powder. The shape of the kuzu flower extract is not limited and may be liquid, paste, or powder.

  The processed Kuzuka product used in the present invention contains saponins, tryptophan glycosides and the like in addition to flavonoids such as isoflavones, and preferably can contain isoflavones and saponins. The content of these components is not particularly limited. Preferably, the isoflavones in the processed kuzuhana product are 3% by mass or more, more preferably 5% by mass to 90% by mass in terms of dry mass. The saponin is preferably 1% by mass or more, more preferably 2% by mass to 50% by mass. As such a kuzu flower processed product containing a high content of isoflavones and saponins, a kuzu flower extract is preferably used. Each effect in the processed kuzuhana product of the present invention is considered to involve components other than isoflavones contained in kuzuka, for example, a soybean extract containing the same amount of isoflavones or saponin. It is superior compared.

  Hereinafter, the preparation method of the dried katsuka, kuzuka powder and kuzuka extract, which are the kuzuka processed products, will be described.

  The dried product of Kuzuka is a dried Kuzuka, preferably Kuzuka in the cocoon stage, dried by a method such as sun drying or hot air drying. Preferably, it can be carried out until the water content is 10% by mass or less.

  The kuzu flower powder is obtained by pulverizing the dried kuzu flower. The powderization is performed by a method usually used by those skilled in the art, for example, a ball mill, a hammer mill, a roller mill, or the like.

  The kuzu flower powder can also be obtained by crushing the collected kuzu flowers using a mascolloider, slicer, comitolol, etc. to obtain a kuzu flower crushed material, and drying the kuzu flower crushed material.

  For example, the Kuzuka extract can be added as necessary by adding a solvent to the Kuzuka collection, Kuzuka crushed material, dried Katsuka or Kuzuka powder (hereinafter sometimes referred to simply as “raw material”). Extraction is performed by heating, and the extract is collected by centrifugation or filtration.

  Examples of the solvent used for the extraction include water, an organic solvent, a water-containing organic solvent, and the like, most preferably hot water and ethanol.

  The extraction temperature is not particularly limited as long as it is a temperature below the boiling point of the solvent used. The extraction temperature varies depending on the solvent to be used, but is generally 4 ° C to 130 ° C in consideration of decomposition of active ingredients. Preferably they are 50 to 130 degreeC, More preferably, it is 70 to 100 degreeC. When extracting by heating, for example, a heating extraction method such as heating under reflux, a supercritical extraction method, or the like can be employed. When heating, pressurization may be performed.

  The extraction time may be a time for sufficiently extracting soluble components from the extraction raw material, and may be set as appropriate according to the extraction temperature and the like. Preferably, it is 30 minutes to 48 hours. For example, when the extraction temperature is less than 50 ° C., it can be extracted for 6 hours to 48 hours, and when it is 50 ° C. or more, it can be extracted for 30 minutes to 24 hours.

  Moreover, the obtained extract is concentrated by a method used by those skilled in the art, such as vacuum concentration or freeze-drying, as necessary, and a kuzuhana extract is obtained by forming a liquid, a paste, or a powder. In addition, a powdery kuzu flower extract may be called an extract powder.

  Alternatively, this extract is further purified using a synthetic adsorbent (Diaion HP20, Sephabies SP825, Amberlite XAD4, MCIgelCHP20P, etc.) or dextran resin (Sephadex LH-20, etc.), and the concentration of flavonoids, saponins, etc. is high. Kuzuhana extract can be obtained.

  As for the intake of the processed kuzuhana product, it is recommended to administer about 1 to 500 mg, preferably about 3 to 300 mg, once a day for an adult.

  The therapeutic agent of the present invention can be appropriately prepared by a known method in the form of a solid or solution (hereinafter, also referred to as a preparation) such as a tablet, pill, capsule, granule, powder, powder, or liquid. That is, the solid preparation or liquid preparation useful in the present invention is produced by using a well-known preparation method that has been well established. Examples of additives include excipients, pH adjusting agents, cooling agents, suspending agents, diluents, antifoaming agents, thickeners, solubilizers, disintegrating agents, binders, lubricants, antioxidants. Agents, coating agents, coloring agents, flavoring agents, surfactants, plasticizers or fragrances.

  Examples of the excipient include sugar alcohols such as D-sorbitol, D-mannitol or xylitol, sugars such as glucose, sucrose, lactose or fructose, crystalline cellulose, carmellose sodium, calcium hydrogen phosphate, wheat starch, rice Examples thereof include starch, corn starch, potato starch, dextrin, β-cyclodextrin, light anhydrous silicic acid, titanium oxide, and magnesium aluminate metasilicate.

Examples of the pH adjuster include citric acid, malic acid, sodium hydrogen phosphate, and dipotassium phosphate.
Examples of the refreshing agent include l-menthol or mint water.
Examples of the suspending agent include kaolin, carmellose sodium, xanthan gum, methylcellulose, and tragacanth.
Examples of the diluent include purified water, ethanol, vegetable oil, and emulsifier.
Examples of the antifoaming agent include dimethylpolysiloxane or silicon antifoaming agent.

Examples of the thickener include xanthan gum, tragacanth, methylcellulose, and dextrin.
Examples of the solubilizer include ethanol, sucrose fatty acid ester, and macrogol.
Examples of the disintegrant include low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, hydroxypropyl starch, or partially pregelatinized starch.

  Examples of the binder include methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethylcellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, or propylene glycol alginate. Can be mentioned.

Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, polyoxyl stearate, cetanol, talc, hydrogenated oil, sucrose fatty acid ester, dimethylpolysiloxane, beeswax and white beeswax.
Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene (BHT), propyl gallate, butylhydroxyanisole (BHA), tocopherol, ascorbic acid, and citric acid.

Examples of the coating agent include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate. Copolymer, hydroxypropyl methylcellulose acetate succinate, methacrylic acid copolymer, polyvinyl acetate diethylaminoacetate or shellac.
Examples of the colorant include turmeric extract, riboflavin, titanium oxide, or carotene solution.

Examples of the flavoring agents include citric acid, adipic acid, ascorbic acid, fructose, D-sorbitol, glucose, sodium saccharin, simple syrup, sucrose, honey, amacha, licorice, citric acid, adipic acid, ascorbic acid, orange oil, Spruce tincture, fennel oil, mint or menthol.
Examples of the surfactant include polyoxyethylene hydrogenated castor oil, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, polyoxyethylene polyoxypropylene, polysorbates, sodium lauryl sulfate, macrogol or sucrose. Examples include fatty acid esters.
Examples of the plasticizer include triethyl citrate, polyethylene glycol, triacetin, and cetanol.
As said fragrance | flavor, synthetic fragrance | flavors, such as natural fragrance | flavors, such as an animal fragrance | flavor or a vegetable fragrance | flavor, or an isolated fragrance | flavor etc. are mentioned, for example.

  You may mix | blend the therapeutic agent of this invention with food-drinks material. Examples of such materials include solid foods such as bread, chewing gum, cookies, chocolate and cereal, jams such as jam, ice cream, yogurt and jelly, cream or gel foods, juice, coffee, cocoa and green tea. And beverages such as oolong tea and black tea. Moreover, it can also mix | blend with a seasoning, a food additive, etc.

  Furthermore, in the present invention, for example, royal jelly, propolis, vitamins (A, C, D, E, K, folic acid, pantothenic acid, biotin, derivatives thereof, etc.), minerals (iron, magnesium, calcium, zinc, etc.), Selenium, lecithin, carotenoids (lycopene, astaxanthin, zeaxanthin, lutein, etc.), saponins (gymnemic acid, soybean saponin, ginseng saponins, etc.), fatty acids, proteins (collagen, elastin, etc.), oligosaccharides (isomalto-oligosaccharides, cyclic oligosaccharides, etc.) ), Phospholipids and derivatives thereof (phosphatidylcholine, sphingomyelin, ceramide, etc.), sulfur-containing compounds (eg, alliin, sepaene, taurine, glutathione, methylsulfonylmethane), sugar alcohols, lignans (sesamin, etc.), Contains animal and plant extracts Root vegetables (turmeric, ginger, etc.), green leaves of gramineous plants such as young wheat powder, green leaves of cruciferous plants such as kale, dried leaves of cactus, terminaria berylica extract, whole potato stems and leaves, soybean Contains ceramide-like ingredients extracted from herbs, herbs such as Chancapiedra, etc.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further, this invention is not limited to these. The therapeutic agent of the present invention is extremely useful as an antiallergic agent, an agent for preventing or improving hyperuricemia, an anti-osteoporosis agent, an antidepressant / antistress agent, an adiponectin production promoter, and a cholesterol lowering agent. Hereinafter, the various medicinal effects will be described with examples.

Example 1 (Usefulness as an antiallergic agent)
Cranberry hot water extract 1 was obtained by adding 20 times the amount of hot water (80 ° C.) to the dried product of cranberry fruit and stirring for 2 hours. Cranberry hot water extract 1 was concentrated under reduced pressure and freeze-dried to obtain powder 1.

  Twenty patients (10 males and 10 females 20 to 22 years old) with food allergen positive chronic urticaria by the RAST method were administered 300 mg of the powder 1 together with one meal for 1 month. The results are shown in Table 1 below.

Example 2
Twenty patients with atopic dermatitis by RAST method (10 men and 10 women aged 20 to 22) were administered 300 mg of Powder 1 of Example 1 together with one meal for 1 month. The results are shown in Table 2 below.

Example 3
20 times the amount of hot water (80 ° C.) was added to the dried product of the katsuhana crushed material, and the mixture was stirred for 2 hours to obtain Kuzuka hot water extract 1. Katsuhana hot water extract 1 was concentrated under reduced pressure and freeze-dried to obtain powder 2.

  In Example 2, 300 mg of Powder 1 of Example 1 and 300 mg of Powder 2 of Example 3 were administered for 1 month. The rest is the same as in the second embodiment. The results are shown in Table 3 below.

Example 4 (improvement effect of hyperuricemia)
Experimental Method As test animals, Wistar rats (8 weeks old, body weight of about 180 g) were used in groups of 6 animals.
Adenine was added to the test feed at a concentration of 0.75% and fed to rats to cause inhibition of uric acid excretion into the urine from the kidney, thereby giving a model animal of hyperuricemia.
The control group was the above 0.75% adenine feed alone, and the drug administration group was the feed containing 0.75% adenine and powder 1 of Example 1. Although the feed was freely consumed, the concentration of the powder 1 in the test diet of the drug administration group was adjusted so that the intake amount was 1 mg / kg body weight. The uric acid level in the blood was measured on the test start day and 24th day.
As a result, the blood uric acid concentration on the test start day of the control group was 0.57 mg / ml, and it was 2.33 mg / ml on the 24th day. The uric acid concentration was 0.73 mg / ml.
As is clear from this result, the blood uric acid concentration in the control group was significantly increased, whereas in the drug administration group, the concentration was not increased. Therefore, it has been shown that a drug containing cranberry extract as an active ingredient is useful as an agent for preventing or improving hyperuricemia.

Example 5
In Example 4, except that the powder 2 of Example 3 was further added to the test feed of the drug administration group, and the concentration of the dry powder was adjusted so that the intake amount was 1 mg / kg body weight. Example 4 was repeated. As a result, the blood uric acid concentration on day 24 of the drug administration group was 0.60 mg / ml.

Example 6 (Anti-osteoporosis effect)
Osteoporosis Improvement Effect Test SD rat (22 weeks old) Female ovaries were surgically removed to create osteoporosis model rats. Ovariectomized rats were divided into 6 groups of 7 animals, and physiological saline so that the intake of powder 1 of Example 1 was 1 mg / kg every other day (total 17 times) during the 35-day test period. 2 ml of water-dissolved liquid was orally administered. The feed was the solid feed CRF-1 for mice, rats and hamsters from Oriental Yeast Co., Ltd. There was no difference in food intake between groups during the study period. On the 35th day after the start of the test, the weight of the rat was measured, and then the femur was removed. The femur was used for analysis with the adhesive tissue and muscle removed. After measuring the volume of the femur, it was washed three times with ethanol, then washed three times with acetone, dried overnight, and then weighed to determine the dry weight of the femur. From the volume and dry weight, the bone density (dry weight g / volume mm ³ ) was measured. In addition, as a control experiment, Table 4 shows the results together with an example (comparative example) in which the above experiment was repeated except that physiological saline not containing the powder 1 was administered to the rat.

  When Example 6 and the comparative example were compared, Example 6 showed a significant difference at a risk rate of p <0.05.

Example 7
In Example 6, in addition to the powder 1 of Example 1, 2 ml of a physiological saline-dissolved liquid was orally administered so that the intake of the powder 2 of Example 3 was 1 mg / kg. Otherwise, Example 6 was repeated. As a result, the bone density was 1.079 (mg / mm ³ ).

Example 8 (Antidepressant / Anti-stress effect)
The therapeutic effect of the powder 1 of Example 1 was examined.
Evaluation of tranquilizing effect by forced mouse swimming test The therapeutic agent of the present invention was evaluated by the forced mouse swimming test developed by Porsolt in 1977. This is one of the most frequently used animal model experiments for depression. In this test, the mouse is forced to swim in a limited space to cause “immobility”. This immobility state is thought to reflect a kind of “despair state” in which stressed animals abandon their escape from water, and is associated with depression and stress in humans. In fact, antidepressants have been found to specifically reduce the duration of immobility in this situation, and this shortening has been found to have a significant correlation with clinical titer.

The test method is as follows.
Mice are forced to swim in a plastic cylinder containing 25 ° C. water to a depth of 15 cm. After forced swimming for 5 minutes, dry in a dryer at 30 ° C. for 15 minutes and return to the home cage. On the next day, the test sample is intraperitoneally administered to the mouse, one hour later, forced swimming for 5 minutes is imposed again, and the duration of the immobility that appears is measured using a stopwatch. A state in which the mouse floats on the water and is stationary is determined as an immobile state. For the duration of stationary state, a significant difference test is performed, and a statistically significant difference is tested. For the experiment, male ddY mice are used, and there are 6 mice per group. All tests are conducted between 1pm and 6pm. A test using imipramine, an antidepressant, as a positive control will also be conducted.

  As a result, the duration of immobility in mice administered with 30 mg / kg of Powder 1 was 175.5 ± 3.9 seconds. The control (saline only) was 220.0 ± 2.2 seconds. The duration of immobility in positive control mice (30 mg / kg dose) was 176.5 ± 4.0 seconds. The duration of immobility in this example and the positive control is significantly different at a risk rate of 1%. In addition, even if it used 2-3 times amount of the powder 1, the same result was obtained.

Example 9
In Example 8, Example 8 was repeated except that Powder 1 of 30 mg / kg was administered and Powder 2 of Example 3 was further administered 30 mg / kg. As a result, the duration of immobility of the mouse was 161.2 ± 4.8 seconds.

Example 10
Adiponectin production increase confirmation test Normal human preadipocytes were used and seeded in a 96-well microplate at 1.0 × 10 ⁴ cells. Human preadipocyte basal medium was used as the seeding medium. After 24 hours, the medium was replaced with a growth medium to which the differentiation-inducing additive and the powder 1 of Example 1 were added, and further cultured for 1 week. Thereafter, the amount of adiponectin produced in the culture supernatant was quantified by ELISA. The evaluation results of each sample are shown below as relative values when the amount of adiponectin in the blank (sample not added) is 100. The added powder 1 concentration was 10 μg / ml.

  Test result: relative value = 374. This value has a significant difference at a risk rate of 1%.

Example 11
In Example 10, Example 10 was repeated except that Powder 1 of 10 μg / ml was added and Powder 2 of Example 3 was further added by 10 μg / ml. As a result, the relative value was 389.

Example 12 (cholesterol lowering action)
ICR male mice weighing about 20 g (5 per group) were given a high cholesterol-cholate diet (71.9% standard diet, 15% sucrose, 2% salt, 10% coconut oil, 0.6% cholesterol, 0.2% cholic acid, 0.3% choline chloride) was fed (free intake) from the first day to the seventh day of the test. On the 6th and 7th day of the test, 5 mg of the powder 1 of Example 1 was dissolved in distilled water and orally administered. Thereafter, fasting was performed for 24 hours, and blood was collected from the mice on the 8th day of the test, and the serum was separated.

  In addition, heparin was added to a portion of the collected serum and precipitated to obtain heparin-precipitated lipoprotein as low density lipoprotein (LDL). The total cholesterol level in serum and the cholesterol level in LDL were reported by C. C. Allain et al. (Clinical Chemistry, 1974, 20, 470-475). ) And measured.

  The value obtained by subtracting the LDL cholesterol value from the total cholesterol value in the serum was calculated as a high density lipoprotein (HDL) cholesterol value. The control group is a group not administered with the powder 1.

  The results are shown in Table 5. As is clear from Table 5, an obvious effect of lowering serum total cholesterol was observed.

Example 13
In Example 12, Example 12 was repeated except that 5 mg of Powder 2 of Example 3 was further administered in addition to 5 mg of Powder 1 above. As a result, serum total cholesterol was about 234 mg / dl, LDL cholesterol was about 122 mg / dl, and HDL cholesterol was about 112 mg / dl.

  In each of the above examples, when the hot water extract 1 of Example 1 was prepared, the extract was prepared using a 20 to 100 vol% ethanol aqueous solution or an acetone aqueous solution without using hot water. Similar results were obtained.

  The therapeutic agent of the present invention is useful as a pharmaceutical, food or feed form.

Claims (12)

  An antiallergic agent characterized by comprising cranberry extract as an active ingredient.   A preventive or ameliorating agent for hyperuricemia, characterized by comprising cranberry extract as an active ingredient.   An anti-osteoporosis agent comprising a cranberry extract as an active ingredient.   An antidepressant / anti-stress agent characterized by comprising cranberry extract as an active ingredient.   An adiponectin production promoter comprising a cranberry extract as an active ingredient.   A cholesterol-lowering agent comprising a cranberry extract as an active ingredient.   An antiallergic agent comprising a cranberry extract and a processed kuzu flower as active ingredients.   A prophylactic or ameliorating agent for hyperuricemia, comprising a cranberry extract and a processed kuzu flower as active ingredients.   An anti-osteoporosis agent comprising a cranberry extract and a processed kuzu flower as active ingredients.   An anti-depressant / anti-stress agent comprising cranberry extract and processed kuzu flower as active ingredients.   An adiponectin production promoter comprising a cranberry extract and a processed kuzu flower as active ingredients.   A cholesterol-lowering agent comprising a cranberry extract and a processed kuzu flower as active ingredients.