JP4907280B2 - Lipase inhibitor - Google Patents

Description

  The present invention relates to lipase inhibitors. More specifically, obesity that does not digest and absorb lipids in vivo, can effectively contribute to the suppression and prevention of obesity and hyperlipidemia by effectively inhibiting pancreatic lipase, the key to hyperlipidemia, The present invention relates to a highly safe lipase inhibitor that is effective in preventing and treating skin diseases such as acne, dermatitis, and dandruff caused by bacterial lipase.

  Hyperlipidemia with abnormal fat deposition in the body adipose tissue and various organs, resulting in abnormally high levels of serum lipids, is caused by various lifestyle-related diseases such as hypertension, arteriosclerosis and diabetes It is thought to be closely involved in the development of Obesity is said to be caused by constitutional factors, dietary factors, mental factors, central factors, metabolic factors, lack of exercise, etc., resulting in caloric intake exceeding calorie consumption and fat accumulation. ing. Dietary lipids are broken down by pancreatic lipase and absorbed from the small intestine. Therefore, it is thought that obesity can be prevented or hyperlipidemia can be suppressed by using a lipase inhibitor having a function of inhibiting the activity of lipase in order to suppress lipid absorption.

  From such a point of view, various natural products that can be ingested on a daily basis are vigorously searched for components having strong lipase inhibitory activity, that is, natural components having lipid absorption inhibitory activity. So far, phosphatidylcholine (Non-patent document 1), soy protein (Non-patent document 2; Non-patent document 3), tannin (Non-patent document 4), peonies, oren, psyllium, button pi, gentian pepper, tea, kujin, etc. Solvent extract of herbal medicine (patent document 1), green pepper, pumpkin, shimeji, maitake, fujiki, green tea, black tea and oolong tea water extract (patent document 2), dokkatsu, ryokyo, areca, yobaihi, ketsumeishi extract (Patent Document 3) and the like have been reported as having lipase inhibitory activity, but are still not sufficient in terms of the properties and effects of the substance itself. Furthermore, in such a search, there is a high content in the raw material, and a substance suitable for industrial production is expected, but no substance that sufficiently satisfies such conditions has been found so far. .

  In addition, bacterial lipases in the human body include lipases produced by microorganisms (Propionibacterium acnes, Pityrosporum ovale, Micrococcus sp., Etc.) that are resident on the skin surface. Lipase decomposes triglyceride contained in sebum to produce free fatty acids. Free fatty acids cause an irritating inflammatory reaction to the skin and are considered as one of the causes of skin diseases such as acne, dermatitis and dandruff. In particular, there is a correlation between the number of Propionibacterium acnes, the cause of acne, and the amount of free fatty acids produced. It is thought to cause formation (Non-Patent Document 5).

However, the development of a drug that inhibits bacterial lipase to suppress or prevent diseases has not yet been advanced, and 2-Pyridylmethyl-2- (P- (2-methylpropyl) -phenyl) propionate (common name: ibuprofen) Piconol) (Non-patent document 6), tetracycline and metal salt (patent document 4), loquat leaf extract (patent document 5), cora de caballo extract (patent document 6) and the like as plant extracts have been reported. However, the lipase inhibitory action cannot be exhibited due to the relationship with other compounding components, and it is not always satisfactory in terms of safety and effectiveness in topical application.
JP-A 64-90131 JP 3-219872 JP 5-255100 A JP 59-186919 JP 10-265364 A JP 11-228338 A K. Taniguti et al., Bull. Facul. Agric. Meiji Univ. 73, 9-26 (1986) K. Satouchi et al., Agric. Biol. Chem. 38, 97-101 (1974) K. Satouchi et al., Agric. Biol. Chem. 40, 889-897 (1976) S.Ahimura et al., Solar Eclipse, 41, 561-564 (1994) McGinley, K, J. et al., J. Clin. Microbiol. 12: 672-675 (1980) Seishin skin, 47, 5, 888-898, 899-908 (1985)

  An object of the present invention is to provide an effective and highly safe lipase inhibitor which has a function of inhibiting the activity of lipase action and does not cause side effects even when used continuously. Another object of the present invention is to prevent skin diseases such as acne by preventing obesity, suppressing hyperlipidemia, or inhibiting lipase produced by skin resident bacteria such as Propionibacterium acnes. An object of the present invention is to provide an effective and safe anti-obesity agent, hyperlipidemia-improving agent, and acne skin-improving agent that are effective for prevention or treatment and that do not cause side effects even when used continuously. Another object of the present invention is to provide foods, medicines and cosmetics containing these lipase inhibitors, anti-obesity agents, hyperlipidemia improving agents, and acne skin improving agents.

The inventor of the present invention has found a strong lipase inhibitory activity in a specific kind of plant, and has completed the present invention.
That is, the present invention includes the following: red diola sacra; ), Turmeric pine (Limonium wrigbitii O. Kuntze), green tense (Maytenus laevis), cats claw (Uncaria tomeotosa), cinnamon (Cinnamomum zeylanicum), yam (Zanthoxylum piperitum), Bendens biternate, wolf x (Fragaria ananassa), Morge (Schinus molle), Rose (Rosa hybrida), Salmon (Diospyros kaki Thunb.), Hypericum perforatum, Eucommia ulmoides, and White tea Lipase inhibitor containing at least one selected from the above Beauty lipid absorption inhibitors containing them, anti-obesity agents, hyperlipemia-improving agents, anti-acne skin improvement agents, furthermore, foods containing them are pharmaceutical and cosmetics.

  Since the plant of the present invention strongly inhibits lipase activity, it can contribute to suppression and prevention of obesity and hyperlipidemia, and prevention of skin diseases such as acne, dermatitis and dandruff caused by bacterial lipase. It is effective for treatment.

  The plants used in the present invention are: Rhodiola sacra, Rhodiola rosea, Saponalia officinalis, Bord (Peumus boldus), Pasaca (Geranium ayabacense Knuth), Tormentilla (Potentilla tormentilla Scbrank), El Campuri (Gentianella alborocea), Turmeric pine (Limonium wrigbitii O. Kuntze), Chutenashi (Maytenus laevis), Cats claw (Uncaria tomeotosa), Cinnamon (Cinnamomum zeylanicum), Zanthoxylum piperitum, Bendens biterie (Bidens biternate) ), Strawberry (Fragaria ananassa), Morge (Schinus molle), Rose (Rosa hybrida), Salmon (Diospyros kaki Thunb.), Hypericum perforatum, Eucommia ulmoides and White tea is there. These plants may be those usually used for food.

  The “Rhodiola sacra.” In the present invention is a plant belonging to the family Aceraceae, and its underground part is used for hemostasis, clean fever, etc. as one of the source plants of Chinese medicine. It is attracting attention as it has the effect of enhancing memory.

  In the present invention, Rhodiola rosea is a plant belonging to the family Aceraceae and is also called Golden Root. It is a natural herb that lives in Eastern Siberia. It works at the cellular level, suppresses side effects caused by stress, and normalizes body functions. It has been said that it has the effect of improving the immunity.

  In the present invention, Saponalia officinalis is a perennial plant that is cultivated for use in medicinal plants and for flower beds, and for purposes such as diuresis, relaxation, promotion of bile secretion, and expectoration of raw leaves and dried rhizomes. Is a plant that is used in

  Bold (Peumus boldus) in the present invention is an evergreen tree of the family Mimamiidae, which is cultivated for firewood charcoal, equipment, medicinal use, etc. The leaves are traditionally diuretic, anti-inflammatory, antiseptic, and tonic It is used.

  The pastaca (Geranium ayabacense Knuth) in the present invention is a perennial plant belonging to the family Aceraceae, inhabiting at an altitude of 4,000 meters in Cajamarca, and being used privately in Peru as a hypoglycemic agent, diabetes treatment aid, and pancreatic function enhancement. It is.

  Tormentilla (Potentilla tormentilla) in the present invention is a plant belonging to the family Rosaceae, which has been chopped and washed and dried to prevent diarrhea against acute or nervous diarrhea, and sore throat, laryngitis, gums, etc. It is used for the improvement of symptoms such as bleeding and mouth ulcers, and for external use for hemorrhoids.

  The Elcampuri (Gentianella alborocea) in the present invention is a perennial plant inhabiting at an altitude of 4,000 meters in the Andes, and is traditionally used for gastric medicine, chronic gastritis and the like in South America and Peru.

  In the present invention, turmeric pine (Limonium wrigbitii O. Kuntze) is a small shrub-like perennial plant of the dicotyledonaceae family, and is distributed from Izu Nanto, Yakushima and south to Taiwan and Ogasawara. So it is also called a ridge.

  In the present invention, the term “chuenashi” (Maytenus laevis) is a dicotyledonous plant belonging to the family Nymphalidae, inhabiting the Amazon region such as Peru, Colombia, and Ecuador. It is used for the treatment of.

  Cats Claw (Uncaria tomeotosa) in the present invention is a dicotyledonous plant of Rubiaceae native to Peru and is also called Unya de Kato. It improves rheumatism, anti-inflammatory, anti-allergy, and immunity improvement / enhancement on the bark and leaves. Because it has an effect, it is used as a health food in Japan.

  The cinnamon (Cinnamomum zeylanicum) in the present invention is an evergreen tree of the camphor family, which is also called Nikkei or cinnamon, and is generally used as a spice for cookies, bread, cakes, etc. It has been used as a wind, sweat, and antipyretic.

  According to the present invention, the potato (Zanthoxylum piperitum) is a deciduous shrub of the mandarin family, and the dried fruit is used as a spice, as well as a healthy stomach, intestine, diuresis, and an antipruritic drug. It is used for roundworm.

  The term “Bidens biternate” in the present invention is a dicotyledon of the family Asteraceae, generally called marigold, or demon needle in China. In China, the whole plant is antipyretic, detoxification, diarrhea, hepatitis, nephritis. Young shoots are used as food for digestive diseases.

  In the present invention, ukogi (Acanthopanax sieboldianus) is a deciduous shrub of the family Rubiaceae, which is obtained by drying leaves and root bark in Kampo, used as nutritional tonic, as an analgesic, for abdominal pain, fatigue recovery, coldness, etc. It is.

  Strawberry (Fragaria ananassa) in the present invention is a dicotyledonous plant belonging to the family Rosaceae, and uses fruits as raw foods and processed products as jams, juices, and syrups.

  In the present invention, Mosier (Schinus molle) is a tree of the Ursiaceae native to Peru, inhabiting the lowlands and semi-arid areas of the Andes. It is used for the treatment of atopic dermatitis, hay fever, asthma and rheumatism, and for drying. The fruit is used as a spice.

  The rose (Rosa hybrida) in the present invention is a dicotyledon plant belonging to the family Rosaceae and is generally cultivated for horticulture and appreciation. In recent years, it has been used as an antiallergic material in health foods as a flavoring material. is there.

  The cocoon (Diospyros kaki Thunb.) In the present invention is a deciduous tree of the oyster family, the fruit is used for food, the leaves are used for hypertension, arteriosclerosis, frosty, rash, bleeding due to trauma, etc. It has been.

  Hypericum perforatum according to the present invention is a perennial plant belonging to the genus Pleuroaceae, also called St. John's wort, and is generally used as an antidepressant in the West and as a health food for antidepressant action in Japan. It is widely used.

  Eucommia ulmoides in the present invention is a deciduous tree of the Brassicaceae family, the bark has a blood pressure lowering action, and as a tonic, strong, and analgesic, it has weakened energy, low back pain, leg knee In addition to being used for soft and miscarriage, the leaves are drunk as Tochu tea.

  The white tea in the present invention is a fermented tea obtained by fermenting several percent of tea. It is made from a special variety with a lot of white hair in the bud and is known by the name of white peony. Tea used for drinking in the provinces.

  The plant in the present invention can use all parts such as leaves, stems, buds, flowers, woody parts, bark parts (bark) and the like, and underground parts such as roots and tubers, seeds, fruits and resins.

  The plant in the present invention includes a dried product obtained by drying the plant itself, a pulverized product thereof, a juice obtained by squeezing and extracting the product itself, a crude extract using water or an organic solvent such as alcohol, ether, acetone, and the like. It includes all extract fractions obtained by stepwise purification by various chromatographies such as partitioning and column chromatography. These may be used alone or in combination of two or more.

  For example, an extract obtained by adding an ethanol solvent to a dried plant of Rhodiola rosea and immersing it overnight at room temperature is a lipase inhibitor, a lipid absorption inhibitor containing them, an anti-obesity agent, You may use as a hyperlipidemia improving agent and a skin improving agent for acne, and you may use what was refine | purified combining various chromatography.

  It has not been known at all that dried products or extracts of these specific plants have a lipase inhibitory activity, which is a new finding obtained by the present invention.

  The plant according to the present invention has excellent lipase inhibitory activity, and is used as a lipid absorption inhibitor, anti-obesity agent, hyperlipidemia improving agent, acne skin improving agent, and foods, medicines and cosmetics containing them. It can be used.

  As the administration method of the lipase inhibitor, lipid absorption inhibitor, anti-obesity agent, hyperlipidemia improving agent and medicament containing these of the present invention, either oral administration or parenteral administration can be adopted. In administration, the active ingredient can be mixed with a solid or liquid nontoxic pharmaceutical carrier suitable for administration methods such as oral administration, rectal administration, and injection, and administered in the form of a conventional pharmaceutical preparation. Examples of such preparations include solid preparations such as tablets, granules, powders and capsules, solutions such as solutions, suspensions and emulsions, freeze-dried preparations, and the like. It can be prepared by conventional means. Examples of the non-toxic pharmaceutical carrier include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, amino acid, gelatin, Examples include albumin, water, and physiological saline. Further, if necessary, conventional additives such as a stabilizer, a wetting agent, an emulsifier, a binder, and an isotonic agent can be appropriately added.

  The food of the present invention is a health food or food material useful for the treatment and prevention of hyperlipidemia or obesity by adding the above-mentioned plant as it is, or by adding various nutritional components, or by including it in foods and drinks. It is eaten as. For example, after adding the above-mentioned appropriate auxiliary agent to the above-mentioned plant, using conventional means, it is formed into an edible form, for example, granular, granular, tablet, capsule, paste, etc. It may also be used and added to various foods such as processed foods such as ham and sausage, fishery processed foods such as kamaboko and chikuwa, bread, confectionery, butter, powdered milk, fermented milk products, and water. It may be used by adding to beverages such as fruit juice, milk and soft drinks.

  The effective dose of the plant of the present invention is appropriately selected and determined according to the patient's age, weight, symptoms, patient grade, administration route, administration schedule, formulation form, strength of the inhibitory activity of the material, etc. In the case of oral administration, it is generally about 0.001 to 1000 mg / kg body weight per day, and in the case of Tormentilla hot water extract, it is about 5 to 300 mg / kg body weight per day. Good.

In addition, when the plant of the present invention is contained and used as a lipase inhibitor-containing cosmetic or cosmetic material, for example, a dried product or an extract of turmeric pine (Limonium wrigbitii O. Kuntze) is used as wheat germ oil or olive oil. It can be added to form a lipase inhibitor-containing composition, which can be used as a cosmetic material. The added amount of the dried product or extract of the plant of the present invention is not particularly limited, but as an example, 0.1 wt% or more and 60 wt% or less, preferably 0.1 wt% or less, preferably 0.5% by weight or more and 50% by weight or less is appropriate.
In addition, the above lipase inhibitor-containing composition can be used directly as a cosmetic ingredient to produce a cosmetic having a lipase inhibitory action.

  The cosmetic containing the lipase inhibitor-containing composition obtained by the method of the present invention is not particularly limited, but from the functional aspect, for example, emulsion, cosmetic liquid, face cream, hand cream, lotion, essence. , Shampoo, rinse and the like are preferred.

  Such a cosmetic can be produced according to a conventional method. The amount of the dried product or extract of the plant of the present invention added to the cosmetic is not particularly limited, but for example, it is suitably about 0.01% by weight to 20% by weight of the total weight of the cosmetic. .

  Since the plant of the present invention is a natural product, its toxicity is low. For example, even if a hot water extract of Potentilla tormentilla is orally administered to a rat over a long period of 1000 mg / kg every day for 100 days, it will die. There were no examples and no change in body weight was observed.

  Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

Production Example 1
[Plant extraction]
Rhodiola sacra, Rhodiola rosea, Saponalia officinalis, Bord (Peumus boldus), Paschaka (Geranium ayabacense Knuth), Tormentilla (Potentilla tormentilla Scbrank), Elcampuri (Gentianella alborocea), Gentianella alborocea wrigbitii O. Kuntze, Maytenus laevis, Cats Claw (Uncaria tomeotosa), Cinnamon (Cinnamomum zeylanicum), Zanthoxylum piperitum, Sendensunga (Bidens biternate), Silkworm (Acanthopanax sieboldianrag), Strawberry (Schinus molle), rose (Rosa hybrida), persimmon (Diospyros kaki Thunb.), Hypericum perforatum, Eucommia ulmoides, white tea (3 kg) each with 3 L of distilled water, 100 ° C, 1500 P Each hot water extractor is boiled for 20 minutes at .SI and then freeze-dried. To obtain a dry product 1400,1860,1330,1580,990,1040,2514,2320,4950,3210,2354,782,1423,2653,4521,2562,3265,1473,1023,2105,2538mg.

Pharmacological test 1
[Lipase inhibitory activity test]
{Preparation of substrate (10% soybean oil / gum arabic emulsion)}
Dissolve 1 g of gum arabic in about 5 ml of distilled water and dialyze against 5 L of distilled water overnight. Then, the gum arabic is taken out from the dialysis tube into a 20 ml metric glass and made into 20 ml while washing together. Also, weigh 1 g of soybean oil into a 50 ml beaker. To this, 10 ml of 5% gum arabic was added and stirred well with a stirrer.

{Preparation of copper mixture}
6.45% copper nitrate (II) trihydrate 100 ml, 1M triethanolamine 90 ml, 1N acetic acid 10 ml were added to prepare a copper mixture 200 ml.

{Preparation of coloring reagent (0.1% DEDC)}
10 mg of sodium N, N-diethyldithiocarbamate trihydrate was dissolved in 10 ml of butanol.

{Inhibitory activity test}
The lipase inhibitory activity was measured by the Duncombe method according to the method of K. Satouchi et al. (Agric. Biol. Chem. 40, 889-897 (1976)).
Specifically, 50 μl of 0.5 M Tris-HCl (pH 7.4) buffer, 50 μl of 10% soybean oil emulsion as a substrate, 100 μl of 5 mM calcium acetate, and various concentrations (1, 0.5, 0.1, After adding 100 μl of 0.05, 0.01, 0.005, 0.001 mg / ml) aqueous solution, add distilled water to make 450 μl. This was preincubated at 37 ° C. and 65 rpm for 5 minutes, lipase (Sigma, bovine pancreas derived) (1 mg / ml) (50 μl) was added, and incubated at 37 ° C. and 125 rpm for 20 minutes. Thereafter, 3.5 ml of chloroform is added to remove the upper layer, 1.5 ml of the copper mixture is added to the remaining lower layer, and the mixture is stirred for 15 minutes with a concentrator, and then the upper layer is removed. After adding 0.5 ml of a coloring reagent (0.1% DEDC) to the remaining lower layer, the amount of released fatty acid was measured for absorbance at 440 nm to measure lipase inhibitory activity, and IC ₅₀ value (enzyme activity was 50%) The results expressed in terms of the concentration to be inhibited (μg / 0.5 ml) are shown in Table 1.
In addition, as a comparative example, the same test was also performed on Ketsumeishi and Kola de Cavallo, which have already been reported to have lipase inhibitory activity. The results are also shown in Table 1.

  As can be seen from Table 1, according to the present invention, Rhodiola sacra, Rhodiola rosea, Saponalia officinalis, Borudo (Peumus boldus), Pasaca (Geranium ayabacense Knuth), Tormentilla tormentilla Scbrank , Elcampuri (Gentianella alborocea), Turmeric pine (Limonium wrigbitii O. Kuntze), Chuenshi (Maytenus laevis), Cats claw (Uncaria tomeotosa), Cinnamon (Cinnamomum zeylanicum), Zanthoxylum piperitum, Bend, nate Extraction of Acanthopanax sieboldianus, Strawberry (Fragaria ananassa), Morge (Schinus molle), Rose (Rosa hybrida), Persimmon (Diospyros kaki Thunb.), Hypericum perforatum, Eucommia ulmoides, White tea It can be seen that the solution has high lipase inhibitory activity.

Formulation Example 1
[Manufacture of tablets]
Tablets having the following composition were produced in accordance with a conventional method using hot water extraction of turmeric pine (Limonium wrigbitii O. Kuntze) obtained in Production Example.
(Composition) (Composition: Weight%)
Turmeric Isopine Extract 24
Lactose 63
Cornstarch 12
Guar gum 1

Formulation Example 2
[Manufacture of juice]
A juice having the following composition was produced in accordance with a conventional method using the hot water extract of the red diol (Rhodiola sacra) obtained in the production example.
(Composition) (Composition: Weight%)
Frozen concentrated Wenzhou orange juice 5.0
Fructose glucose liquid sugar 11.0
Citric acid 0.2
L-ascorbic acid 0.02
Fragrance 0.2
Dye 0.1
Hongjing heaven extract 0.2
Wed 83.28

Formulation Example 3
[Manufacture of face cream]
Using the hot water extract of rose (Rosa hybrida) obtained in the production example, a face cream having the following composition was produced according to a conventional method.
(Composition) (Composition: Weight%)
Isopropyl isostearate 8.0
Jojoba oil 6.0
Cetanol 8.0
Stearyl alcohol 2.0
Polyoxyethylene lauryl ether 1.5
Propylene glycol 6.0
Sorbitol 1.0
Paraben 0.4
Rose extract 0.5
Vitamin E 0.5
Fragrance 0.1
Purified water 66.0

Claims (6)

  A lipase inhibitor containing hot water extract of Savonso as an active ingredient.   Lipid absorption inhibitor containing hot water extract of Savonso as an active ingredient.   An anti-obesity agent containing hot water extract of Savonso as an active ingredient.   An antihyperlipidemic agent comprising hot water extract of bonito as an active ingredient.   A skin disease ameliorating agent for acne, comprising hot water extract of savanna as an active ingredient. An acne cosmetic comprising the agent according to claim 5 .