JP2000219631A - Cyclic AMP phosphodiesterase inhibitor, external preparation for skin and food and drink - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prevent and eliminate obesity by inhibiting the action of cyclic AMP phosphodiesterase, which is an enzyme that degrades cyclic AMP involved in promoting fat metabolism, and to provide an external preparation for skin and food and drink. Provided is a cyclic AMP phosphodiesterase inhibitor, which has properties suitable for being incorporated into AMP. SOLUTION: A cyclic AMP phosphodiesterase inhibitor which is extracted from Cilletta assembly, Barberry, Fuzanshaw, Fubegonia or Himalayan rhubarb is used.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a cyclic AMP phosphodiesterase inhibitor useful for reducing excess body fat.

[0002] The present invention also relates to an external preparation for skin, which has a body fat reducing effect by adding a cyclic AMP phosphodiesterase inhibitor, and a food and drink.

[0003]

2. Description of the Related Art In recent years, as eating habits have become westernized, more and more Japanese people are suffering from circulatory diseases such as hyperlipidemia and obesity due to excessive accumulation of body fat. Hyperlipidemia
It is a disease in which one or more components among serum lipids, that is, cholesterol, triglyceride, phospholipid, free fatty acid and the like are abnormally increased and cause various disorders.

[0004] Conventionally, as a drug for lowering the blood cholesterol concentration, a drug comprising many synthetic chemical substances such as pravastatin has been developed and used for treatment. However, although they are superior in efficacy, they also have side effects and cannot be used unless prescribed by a doctor.

In order to eliminate the excess accumulation of body fat, ie, obesity, which accompanies hyperlipidemia, the action of the cyclic AMP phosphodiesterase, an enzyme that degrades cyclic AMP, which is involved in promoting fat metabolism, is suppressed. It is effective to do. That is, when the action of cyclic AMP phosphodiesterase is suppressed, intracellular cyclic AMP
Increases the concentration of fat and activates the metabolism of fat, eliminating obesity.

As a substance having a cyclic AMP phosphodiesterase inhibitory activity, extracts of soybean ash, olive, etc. are known, but the effect is not remarkable.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide a highly safe natural AMP phosphodiesterase inhibitor which is effective in preventing and eliminating obesity, and which is also suitable for use in skin preparations and foods and drinks. The object of the present invention is to provide a cyclic AMP phosphodiesterase inhibitor which is found among the constituents of a product.

Another object of the present invention is to provide the above-mentioned cyclic A
It is an object of the present invention to provide an external preparation for skin and food and drink which have an effect of promoting metabolism of fat by an MP phosphodiesterase inhibitor.

[0009]

SUMMARY OF THE INVENTION The cyclic AMP phosphodiesterase inhibitor provided by the present invention is a compound of the Gentianaceae plant Tiretta cassii (Swertia c.
hirata), barberry, barberry (M
ahonia nepalaulensis) bark,
Citrus plant, Zantoxylum
armatum), rhizomes of Saxifragaceae plant, Bhuegegonia (Bergenia cliata), and Polygonaceae plant, Himalayan rhubarb (Rheum)
cyclic AMP contained in the rhizome of Emodi)
The phosphodiesterase inhibitor is extracted as an active ingredient. (In this specification, the extraction raw material of the cyclic AMP phosphodiesterase inhibitor is indicated only by the plant name, but they mean the site containing the active ingredient of the plant. .).

[0010] Further, the external preparation for skin and the food and drink provided by the present invention are all prepared by blending the cyclic AMP phosphodiesterase inhibitor according to the present invention in an appropriate amount.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The above five kinds of plants confirmed to contain a cyclic AMP phosphodiesterase inhibitor are mainly plants that grow in mountains of Central Asia at an altitude of 1000 m or more, and all of them are ancient Hindus It has been used as a crude drug in medicine and Ayurveda. However, the purpose of use as a crude drug is irrelevant to the cyclic AMP phosphodiesterase inhibitory activity, and it has not been known that these plants contain substances that inhibit the cyclic AMP phosphodiesterase activity.

As a solvent used for extracting a cyclic AMP phosphodiesterase inhibitor from a raw material plant, water, a hydrophilic organic solvent or a mixture thereof can be used.
Preferred are lower aliphatic alcohols such as ethanol, propanol, 1,3-butylene glycol, propylene glycol, glycerin and the like.

The extraction method is optional, and the extraction can be carried out using a general apparatus at room temperature or under reflux.
Briefly, an extraction raw material is charged into a treatment tank filled with an extraction solvent, and a soluble component is eluted with occasional stirring. When the obtained extract is concentrated and dried, cyclic AMP is obtained.
An extract having a phosphodiesterase inhibitory action is obtained. If a carrier such as dextrin or cyclodextrin is mixed before drying, the hygroscopicity of the extract can be reduced.

This extract or the extract before concentration and drying can be used as it is as a cyclic AMP phosphodiesterase inhibitor. If necessary, a purification effective for improving its activity, removing coloring, unpleasant odor, off-flavor and the like can be used. It can be subjected to treatment or used as a preparation in any form, such as powder, granules, tablets, capsules, syrups, enteric agents, troches, chewables and the like, together with optional auxiliaries.

[0015] The active ingredient of the cyclic AMP phosphodiesterase inhibitor of the present invention is well absorbed orally or transdermally and is absorbed into the body to exert its action. In addition, there is almost no decrease in activity when stored in air or heated up to 100 ° C. Since the raw material, such as chilletta assembly, has been used as a crude drug since ancient times, there is no problem in safety. Therefore, the cyclic AMP phosphodiesterase inhibitor of the present invention may be added to any external preparation for skin in order to reduce the subcutaneous fat by promoting fat metabolism, and may be added to any food or drink in expectation of the slimming effect by promoting fat metabolism. In addition, it can be ingested little by little and continuously at the occasion of daily eating and drinking.

[0016] The cyclic AMP phosphodiesterase inhibitor of the present invention (or a plant extract as an active ingredient thereof) may be used as an ointment, cream, emulsion, lotion, pack,
It can be added to any skin external preparation such as a spray and a bath preparation. The preferred addition level varies depending on the content of the active ingredient and the substance to be added, but is usually 0.01 to 10% by weight when a standard unpurified extract is used.

The constituents of the external preparation for skin to be added are not limited, and any of the raw materials usually used in the production of external preparations for skin, for example, any of the following can be used in combination.

Oily components such as avocado oil, palm oil, peanut oil, tallow, rice bran oil, rice germ oil, jojoba oil, carnauba wax, lanolin, liquid paraffin, squalane, oxystearic acid, and isostearyl alcohol;
Humectants such as glycerin, 1,3-butylene glycol, sorbitol, polyethylene glycol, collagen, hyaluronic acid and its salts, chondroitic acid and its salts, chitin and chitosan; amyl paradimethylaminobenzoate, urocanic acid, and diisopropylcinnamic acid UV absorbers such as ethyl; antioxidants such as sodium erythorbate and parahydroxyanisole; surfactants such as sodium stearyl sulfate, diethanolamine cetyl sulfate, cetyltrimethylammonium chloride, polyethylene glycol isostearate, and glyceryl stearate; ethyl paraben; Preservatives such as butyl paraben;
Complex lipids such as glycerophospholipid, sphingolipid, glyceroglycolipid, glycosphingolipid; superoxide dismutase, catalase, β-carotene, oil-soluble licorice root extract, glabridine, lycochalcone A, baicalin, baicalein, ginkgo leaf extract, Kuddin extract, Hamamelis extract, Huang Gui extract and other substances having an active oxygen scavenging action; allantoin, guaia azulene, camazulene, bisabolol, glycyrrhizic acid and its salts, glycyrrhetinic acid and its derivatives, stearyl epsilon iminocaproic acid, Anti-inflammatory substances such as indomethacin, zinc oxide and hinokitiol; retinol, retinal, retinoic acid, pantothenic acid, panthenol, riboflavin, pyridoxine, tocopherol, ascorbi Vitamins such as acid, folic acid and nicotinic acid and derivatives thereof; blood circulation promoters such as γ-oryzanol and dextran sodium sulfate; antiseborrheic agents such as sulfur and thianthol; arnica extract, intinko extract, gongon extract, oakaku Extract, spinach extract, chamomile extract, liquorice root water extract, sanshishi extract, siconium extract, peonies extract, peanut extract, jujuya extract, birch extract, western horse chestnut seed extract, calendula extract Thing, peanut extract,
Skull extract, linden extract, rosemary extract, Sawtooth grass extract, mugwort extract, rock cabbage extract, yokuinin extract, aloe extract, loquat extract, peach extract, senkyu extract, sage extract Stuff, touuki extract, loofah extract, oil beetle extract, panax ginseng extract, capsicum extract, bean tea extract, tea extract, hypericum extract, malonie extract, prune extract, collagen, hydrolyzed conchiolin, elastin , Vitronectin, fibronectin,
Some favorable effects on the skin, such as placenta extract, royal jelly, bifidobacterium culture, lactic acid bacteria culture, yeast extract, litchi mycelium extract, black liquorice extract, brown algae extract, red algae extract, green algae extract, etc. Plant extract, animal extract, microorganism-derived component or algal extract expected to show: amino acids; cholesterols; plant sterols; lipoproteins; (For example, titanium yellow, carsamine, safflower red) and the like.

Examples of foods and drinks suitable for imparting a cyclic AMP phosphodiesterase inhibitory action according to the present invention include various processed livestock products, processed marine products, dairy products,
Processed vegetables and fruits (including beverages), processed grains, confectionery
There are breads and the like.

[0020]

The present invention will be described below with reference to examples. In each example, “parts” means parts by weight.

Production Example 1 An extract having a cyclic AMP phosphodiesterase inhibitory activity was obtained from Cilletta assembly, barberry, Fuzanshaw, Fuebegonia and Himalayan rhubarb by the following method.

Extraction method: Dried product of shredded raw plant 1
Add 800 ml of extraction solvent to 00 g and heat under reflux for 2 hours. The extract is separated by filtration while hot, and the residue is subjected to the same extraction treatment twice more. The obtained extracts are combined, concentrated under reduced pressure, and further dried to obtain an extract.

The above extraction was carried out using the following five kinds of extraction solvents. The yield of the extract according to each example was as shown in Table 1. Solvent A: water Solvent B: 80% ethanol (mixture with water) Solvent C: ethanol Solvent D: 1,3-butylene glycol Solvent E: 50% 1,3-butylene glycol (mixture with water)

[0024]

[Table 1]

Test Example 1 Each extract obtained in Production Example 1 was tested for cyclic AMP phosphodiesterase inhibitory activity by the following test method.

Test method: 0.1 ml of fetal serum albumin solution in 0.2 ml of Tris-HCl buffer (pH 7.5) containing 5 mM magnesium chloride and cyclic AM
0.1 ml of a P-phosphodiesterase solution is added, and 0.05 ml of a sample solution is further added, and precultured at 37 ° C. for 5 minutes. Next, 0.05 ml of a cyclic AMP solution is added and reacted at 37 ° C. for 30 minutes. The reaction is stopped by boiling on boiling water for 3 minutes, centrifuged at 4 ° C., and the reaction product, 5′-AMP, in the supernatant is quantified by high performance liquid chromatography. The same enzyme reaction and reaction product analysis are performed without adding the sample solution, and the cyclic AMP phosphodiesterase inhibition rate of the sample is determined from the ratio of the reaction product amount at the time of sample addition to the reaction product amount at the time of no sample addition. .

The above measurement was repeated while the sample concentration of the sample solution was changed stepwise, and the sample concentration that inhibits the activity of cyclic AMP phosphodiesterase by 50% was determined by interpolation. Table 2 shows the results.

[0028]

[Table 2] 50% inhibitory concentration (ppm) Tilletta assembly: water extract 80.4 80% ethanol extract 56.7 ethanol extract 59.3 1,3-butylene glycol extract 68.3 50% 1,3-butylene glycol extract 63.9 barberry: Aqueous extract 120.1 80% ethanol extract 40.3 Ethanol extract 43.2 1,3-butylene glycol extract 68.7 50% 1,3-butylene glycol extract 53.9 Fuzan shaw: water extract 115 6.6 80% ethanol extract 119.2 ethanol extract 113.1 1,3-butylene glycol extract 126.3 50% 1,3-butylene glycol extract 116.7 Fuvegonia: water extract 70.3 80% Ethanol extract 51.0 Ethanol extract 50.1 1,3-butylene glycol extraction Product 89.3 50% 1,3-butylene glycol extract 95.4 Himalayan rhubarb: water extract 78.6 80% ethanol extract 54.1 ethanol extract 68.4 1,3-butylene glycol extract 98. 4 50% 1,3-butylene glycol extract 110.3

Example 1 A cream having the following composition was produced by a conventional method. Liquid paraffin 5 g Salami beeswax 4 g Cetanol 3 g Squalane 10 g Lanolin 2 g Stearic acid 1 g Polyoxyethylene sorbitan oleate (20EO) 1.5 g Glyceryl monostearate 3 g 1,3-butylene glycol 6 g Methyl paraoxybenzoate 1.5 g Fragrance 0 .1g Himalayan rhubarb 80% ethanol extract 0.5g Purified water Remainder (total amount is 100g)

Test Example 2 An application test to humans was carried out on a control cream having the same composition as in Example 1 except that the cream and the Himalayan rhubarb extract were not blended by the following test method.

Test method: Men and women 10 from 24 to 49 years old
The subject consisting of the name is divided into two groups, and the cream of Example 1 is applied to one group, and the cream of the control example is applied to the other upper group once a day for 3 months on the left upper arm. Before and after the end of the 3-month application, the arm circumference is measured 10 cm above the center of the left upper arm elbow joint.

The test results are shown in Table 3. The slimming effect of the cream of the present invention was confirmed.

[0033]

[Table 3]

Example 2 A lotion having the following composition was produced by a conventional method. Glycerin 3g 1,3-butylene glycol 3g Polyoxyethylene sorbitan oleate (20EO) 0.5g Methyl paraoxybenzoate 0.15g Citric acid 0.1g Sodium citrate 1g Flavor 0.05g 1,3 of Tilletta assembly -Butylene glycol extract 5 g Remaining purified water (total amount is 100 g)

Example 3 An emulsion having the following composition was produced by a conventional method. Jojoba oil 4 g Olive oil 2 g Squalane 2 g Cetanol 2 g Glyceryl monostearate 2 g Polyoxyethylene cetyl ether (20 EO) 2.5 g Polyoxyethylene sorbitan oleate (20 EO) 2 g 1,3-butylene glycol 3 g Paraoxybenzoic acid Methyl 0.15 g Fragrance 0.05 g Water extract of Fuzanshaw 2 g Purified water Remainder (total amount is 100 g)

Example 4 A jelly confection having the following composition was produced by a conventional method. Sugar 2.5g Erythritol 2.5g Citric acid 0.15g Carrageenan 0.2g Locust bean gum 0.05g Calcium lactate 0.01g Water extract of fubegonias 4.0g Water balance (total 100
g)

Example 5 A beverage having the following composition was produced by a conventional method. Liquid sugar 8 g Citric acid 0.5 g Vitamin C 0.2 g Flavor 0.05 g Stevia extract 0.01 g Barberry ethanol extract 3 g Water Remainder (total amount is 100 g)

Test Example 3 A drinking test was carried out on a control drink having the same composition as in Example 5 except that the drink of Example 5 and the barberry extract were not blended in the following manner.

Test method: Male and female 10 from 25 to 48 years old
Were divided into two groups, one of which was
, And another group of control drinks, each containing 20 drinks.
Drink 0 ml 3 times a day for 3 months. Before and after 3 months of drinking, one hour from the center of the left elbow joint
Measure around arm 0 cm above. The test results are shown in Table 4, and the slimming effect of the beverage of the present invention was confirmed.

[0040]

[Table 4]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 7/00 A61K 7/00 kW 7/48 7/48 A61P 3/04 31/00 603K 3/06 603L 17/00 617 43/00 643D (72) Inventor Zhou Yuyang F-term (reference) in Maruzen Pharmaceutical Co., Ltd. 14703-10 Mukotocho, Onomichi City, Hiroshima Prefecture MF01 4B041 LC10 LD02 LK21 LP05 4C083 AA082 AA111 AA112 AB052 AC022 AC072 AC102 AC122 AC182 AC242 AC302 AC392 AC402 AC482 AD512 CC04 CC05 EE09 EE11 4C088 AB43 AB62 AB63 AB66 AB67 AC02 AC13 CA05 CA06 CA08 MA23 ZA28 ZA33

Claims (3)

[Claims] 1. A cyclic AMP phosphodiesterase inhibitor comprising, as an active ingredient, a cyclic AMP phosphodiesterase inhibitor extracted from Tilletta assembly, barberry, Fuzanshaw, Fuebegonia or Himalayan rhubarb. 2. An external preparation for skin comprising the cyclic AMP phosphodiesterase inhibitor according to claim 1. 3. A food or drink comprising the cyclic AMP phosphodiesterase inhibitor according to claim 1.