JP5258365B2 - Pancreatic lipase inhibitor and food / beverage composition and pharmaceutical composition containing the same - Google Patents

Description

The present invention relates to a pancreatic lipase inhibitor, and more specifically, a food / beverage composition excellent in the effect of improving and preventing lifestyle-related diseases such as obesity, hyperlipidemia and diabetes induced by a high-fat diet, and the therapeutic effect of these diseases It is related with the pancreatic lipase inhibitor suitable for mix | blending with the pharmaceutical composition excellent in the. Moreover, the invention regarding the food-drinks composition and pharmaceutical composition containing the pancreatic lipase inhibitor is also included.

In recent years, with the westernization of meals, the onset of lifestyle-related diseases such as obesity, hyperlipidemia and diabetes has increased remarkably, and the response is urgently needed. In order to prevent and improve obesity, hyperlipidemia and diabetes caused by diet, lipase inhibitors have been actively developed and applied.

On the other hand, various lipase inhibitors extracted from plant seeds, leaves, rhizomes, etc. have been manufactured and tried to be formulated into cosmetics, pharmaceuticals, foods, etc. There was a problem that safety and procurement were problems.

Examples of lipase inhibitors derived from plant materials include lipase inhibitors containing extract extracts such as yucca, ginseng, jasmine tea, yamakoko, yellow ginger tea, rooibos tea, soybean germ, ginger, and chuchu tea (patent document) 1), pancreatic lipase inhibitor (see Patent Document 2) containing an extract of Quillaja saponaria MOLINA bark as an active ingredient, and a lipase inhibitor (see Patent Document 3) containing chestnut skin extract. is there.

On the other hand, cocoa beans (Cacao beans or Cacao sheeds) are used as plant-derived materials. Cocoa beans are seeds that are wrapped in pulp (fruit) in cacao fruits (Cacao Pods or Cacao fruits), which are the fruits of the cacao tree. Cocoa beans are made up of the shell, the thin skin or husk, the endosperm (Cotyledon), and the germ (Germ or germ rootlet). The one excluding the endosperm germ is called nib and is used for chocolate, cocoa and the like. The cocoa bean shell and endothelium are sometimes collectively referred to as a cocoa bean shell or cocoa husk. Moreover, it may be called the cocoa bean shell including the endothelium.

As an agent having various actions derived from cocoa beans, for example, an inhibitor of blood cholesterol elevation mainly composed of lignin of a phenolic polymer compound extracted from cocoa bean endosperm, hull, cocoa powder, etc. (Patent Documents) 1) and cholesterol gallstone formation inhibitors (see Patent Document 2). In addition, cocoa beans and / or cocoa bean shells extracted with water and / or organic solvents compatible with water have an immunostimulatory action (see Patent Document 3), or extracted with an alkaline aqueous solution Has a cancer metastasis inhibitory effect (see Patent Document 4). In addition, it has been found that an aqueous extract of the seed shell of Theobroma cacao has a cell activating effect, an ultraviolet ray damaging action and a melanin production suppressing action (see Patent Document 5). In addition, there are gastric ulcer preventive foods and beverages (see Patent Document 6) and anti-diabetic complications food and drink products (see Patent Document 7), which apply an antioxidant action derived from cocoa beans.

However, none of these techniques is derived from cocoa beans themselves, which are the seeds of cocoa trees, and it is not suggested to use cocoa pods (cocoa fruits) that are the fruits of cocoa trees.

JP 2002-275077 A JP 2006-182722 A JP 2007-145802 A JP-A-3-181494 Japanese Patent Laid-Open No. 3-18196 JP 2000-86526 A JP 2002-128865 A JP 2006-342120 A JP 7-274894 A Japanese Patent Laid-Open No. 9-234018

The purpose of the present invention is a safe, stable, inexpensive, excellent in preventing and treating and improving lifestyle-related diseases such as obesity, hyperlipidemia and diabetes induced by high-fat diet in daily life, It is in providing a suitable pancreatic lipase inhibitor by mix | blending with food-drinks composition and pharmaceutical composition. It is also a secondary object to provide a food and beverage composition and a pharmaceutical composition containing the pancreatic lipase inhibitor.

As a result of intensive studies in view of the above circumstances, the present inventors have found that an active ingredient having an antihyperlipidemic action is contained in an extract obtained from a cacao pod skin that is normally discarded. When foods were blended into food and drink compositions and pharmaceutical compositions, it was found that they have a significant effect on the improvement of lifestyle-related diseases caused in daily life. In addition, the cacao pod skin extract was a naturally-derived substance and had no safety problems and was excellent in stability.

That is, the pancreatic lipase inhibitor of the present invention is characterized by containing a solvent extract of cocoa pod skin. And as said extraction solvent, water, a water-soluble organic solvent, or these mixed solvents are suitable .

According to the present invention, a safe, stable, and inexpensive pancreatic that is excellent in preventing and treating lifestyle-related diseases such as obesity, hyperlipidemia and diabetes induced by a high-fat diet in daily life. Lipase inhibitors can be provided. And this pancreatic lipase inhibitor is suitable for blending in food and beverage compositions and pharmaceutical compositions, and this food and beverage composition is obesity, hyperlipidemia and diabetes induced by a high fat diet in daily life. This pharmaceutical composition is excellent in the therapeutic effects on lifestyle-related diseases such as obesity, hyperlipidemia and diabetes induced by a high-fat diet in daily life.

Furthermore, the cocoa pod shell used for the pancreatic lipase inhibitor of the present invention is a shell of cocoa fruits (Cacao Pods or Cacao fruits) discarded in large quantities at the time of harvest in the production area, and is a new facility for obtaining as raw materials. Is easily available. Compared to conventional agents derived from cocoa beans (Cacao beans or Cacao sheeds) themselves, and food and beverage compositions and pharmaceutical compositions containing them, they can be obtained in large quantities and at low cost, as well as waste. The environment will be considered in order to utilize In order to obtain edible cocoa beans, the cocoa tree is cultivated with attention to safety, and its outer shell can be used without any problem in safety.

Hereinafter, the present invention will be described in detail.

The cocoa pod shell used for the pancreatic lipase inhibitor of the present invention is a shell of cocoa fruit (Cacao Pods or Cacao fruits) which is a fruit of a cocoa tree. In the following description of the present invention, the term “outer skin” simply refers to the outer skin of a cacao pod (cocoa fruit). On the other hand, the shell of Cacao beans is described as “shell”.

The cacao tree is an evergreen tree belonging to the genus Theobroma, and its scientific name is called Stercurliaceae Theobroma Cacao (Linnaeus). The main production areas of cacao trees are West Africa (Cote d'Ivoire, Ghana, etc.), Southeast Asia (Indonesia, etc.), and Latin America (Dominican Republic, Venezuela, Ecuador, etc.). The cacao tree can be broadly divided into two species, the Criollo species, which are close to the original species, and the improved Forastero species, but the three main species are the combined Trinitario species, which are hybrids. As the pancreatic lipase inhibitor of the present invention, any varieties of cocoa pods including derivatives other than the above three can be used.

FIG. 1 shows the structure of a cacao pod (cocoa fruit). Kakaopo' de is covered with cocoa pod skin 2. Inside the outer skin 2, there are about 30 to 40 white pulps 3 which are pulp. Cocoa beans 4 are wrapped in each of the pulps 3. Cocoa beans 4 are surrounded by a hard and brittle shell 5. A very thin white endothelium 6 is present further inside the shell 5. The endothelium 6 covers the endosperm 7 and the germ 8 so as to divide the inside of the cacao bean 4 into several parts.

Cacao pods are cut off from the cocoa trees at harvest time. The cut cocoa pod is cut open, and the cocoa beans are extracted along with the pulp. At this stage, the cacao pod skin is no longer needed and becomes waste. In the pancreatic lipase inhibitor of the present invention, this outer skin, which usually becomes waste, is used.

In addition, the cocoa beans taken out together with the pulp are put in a jute bag after being subjected to fermentation, washing with water (sometimes not performed), and drying. The cocoa beans that have passed the inspection are shipped from the production area, and roasted, cooled, crushed and winded at the consumption area to obtain cocoa nibs. A plurality of cocoa nibs obtained from cocoa beans in different production areas are mixed, ground and finished to obtain cocoa mass. Chocolate, cocoa, etc. are processed from cacao mass. The above-mentioned conventional agents and foods and drinks having various actions derived from cocoa beans used crust, shells, endothelium, germs, etc. (also called cocoa bean shells or cocoa husks) removed by the crushing process. Is.

The solvent extract of the cocoa pod skin in the present invention is obtained by extracting the cocoa pod skin with a solvent. It does not specifically limit as an extraction method for obtaining the solvent extract of a cacao pod outer skin. When extracting with a solvent, the cocoa pod shell may be used after being dried or may be used without being dried. Further, regardless of drying, the cocoa pod skin may be used as it is, or may be used after being finely cut or pulverized. From the standpoint of extraction efficiency, it is preferable to extract the cocoa pod skin after drying and then using solvent to extract it.

The solvent used is preferably water, a water-soluble organic solvent, or a mixed solvent thereof. Examples of the water-soluble organic solvent include lower alcohols such as methanol, ethanol, propanol, and 1,3-butylene glycol, benzene, ethyl ether, chloroform, ethyl acetate, butyl acetate, and acetone. Among these, ethanol is preferable, and hydrous ethanol that is a mixed solvent with water is particularly preferable. On the other hand, when extracting using methanol, acetone, etc., the effect of pancreatic lipase inhibitory action decreases.

The apparatus used at the time of solvent extraction is not specifically limited, A normal tank and a mixer may be used, and extractors, such as a Soxhlet extractor, may be used. The temperature at the time of extraction and the extraction time are not particularly limited. After solvent extraction, impurities may be removed by filtration, treatment with an adsorbent resin, activated carbon treatment, or the like.

As the dosage form of the pancreatic lipase inhibitor of the present invention, in addition to the liquid extract obtained by solvent extraction, the liquid extract is dried or concentrated by a normal drying method such as reduced pressure drying or freeze drying, a concentration method, or the like. It may be what you did. In addition, if necessary, it may be used after purification treatment such as deodorization and decoloration within a range that does not affect its efficacy, and it is formulated in a state that is easy to use, such as granulated with an appropriate excipient. What is necessary is just to use.

An example of a method for producing a solvent extract of cocoa pod skin in the present invention will be described. Open the cocoa pod and remove the pulp from the cocoa beans. Finely cut the cocoa pod shell after removing the contents. The cut outer skin is put into a mixer, and water or a water-containing organic solvent (preferably water-containing ethanol) is added and stirred for a predetermined time. Thereafter, it is filtered through a mesh. The obtained filtrate is a solvent extract of the liquid cocoa pod skin and can be used as it is as the pancreatic lipase inhibitor of the present invention. Further, the filtrate is freeze-dried under reduced pressure, and the obtained dried product is also a solvent extract of the cocoa pod shell, and thus may be used as the pancreatic lipase inhibitor of the present invention in this state.

In the pancreatic lipase inhibitor of the present invention, in addition to the above-mentioned solvent extract of the cacao pod skin, components that are usually used in food and drink compositions or pharmaceutical compositions depending on the purpose or components that are allowed to be used, It can mix | blend suitably within the range which does not impair the effect of this invention.

The blending amount of the solvent extract of the cacao pod shell in the food / beverage composition or pharmaceutical composition containing the pancreatic lipase inhibitor of the present invention is based on the total amount of the food / beverage composition or pharmaceutical composition in terms of dry solids 0.005 wt% (abbreviation for mass%) or more and 10 wt% or less is preferable from the viewpoint of expression of effects and cost. In particular, 0.005 wt% or more and 5 wt% or less is preferable when blending and applying products.

It does not specifically limit as a form of the food-drinks composition of this invention, For example, a gel, powder, a liquid, a granule, cream form, a paste form, solid etc. can be mentioned. Further, the type of the food and beverage composition of the present invention is not particularly limited, and examples thereof include confectionery (chewing gum, candy, gummi, tablet, chocolate, jelly, etc.), ice confectionery (ice candy, ice cream, sorbet, etc.), and frozen confectionery. (Jelly, pudding, water yokan, etc.), starch-based foods such as noodles, powdered foods and drinks, beverages (soups, coffee, teas, juices, carbonated beverages, cocoa, alcoholic beverages, jelly drinks, etc.), bakery foods (Cookies, biscuits, breads, pies, cakes, etc.), fats and oils (margarine, shortening, fat spreads, etc.), dairy products (milk, yogurt, whey drinks, lactic acid bacteria beverages, butter, cream, cheese, etc.) Can do.

Each of the above-mentioned food and beverage composition of the present invention can be produced by a conventional method, and if necessary, contains the solvent extract of the cacao pod skin by appropriately selecting the following components within the range not impairing the object of the present invention. Can be combined with pancreatic lipase inhibitor. For example, sugar sweeteners (monosaccharides such as fructose, glucose, tagatose and arabinose, oligosaccharides such as lactose, oligosaccharides, maltose and trehalose, powdered starch syrup, dextrin, sugar alcohol etc.), high sweetness sweeteners (sucralose, Acesulfame K, stevia, etc.), polysaccharides such as starch, fats and oils, dairy products, stabilizers, emulsifiers, fragrances (vanillin, linalool, natural fragrances, etc.), pigments, colorants, acidulants, flavor ingredients (eggs, coffee, Tea, cocoa, fruit pulp, yogurt, alcoholic beverages, etc.), flavoring (raspberry flavor, apple flavor, coffee flavor, etc.), anti-wetting agent, electrolyte, antioxidant, preservative, wetting agent, protein, amino acid, peptide , Dietary fiber, organic acids (citric acid, malic acid, fumaric acid, malonic acid, succinic acid, tartaric acid, lactic acid, etc.), vitamins (L-Asco Binic acid, dl-α-tocopherol, vitamin B1, vitamin B2, niacin, pantothenic acid, vitamin B6, vitamin B12, folic acid, biotin, inositol, etc., mineral (zinc, iron, calcium, magnesium, chromium, selenium, potassium, Sodium, etc.), glucosamine, yeast, eggshell membrane, lycopene, astaxanthin, other carotenoids, silk, chondroitin, ceramide, placenta extract, shark fin extract, deep-sea cocoon extract, squalene, γ-aminobutyric acid, casein decapeptide, raw chestnut skin extract , Chestnut leaf extract, chestnut potato extract, chestnut pulp extract, chestnut bark extract, cabbage ferment extract, rose petal extract, grape leaf extract, grape seed extract, apple polyphenol, chamomile extract, Lychee seed extract, Gotsukola extract Moon peach leaf extract, lotus germ extract, star fruit leaf extract, mulberry leaf extract, guava tea extract, red wine, green tea, black tea, oolong tea, coffee, cocoa, chocolate, black sesame, beans, soy milk, nuts, mushrooms, Green-yellow vegetables, egg-derived raw materials such as iodine eggs, catechins, other polyphenols, raspberry ketone, low molecular weight alginic acid, psyllium seed coat, ginkgo biloba extract, pine bark extract, nattokinase, plant sterol, diacylglycerol, chitosan, Examples include hyaluronic acid, methylsulfonylmethane, kojic acid, ellagic acid, arbutin, lucinol, magnolignan, magnesium phosphate L-ascorbate, CoQ10, and α-lipoic acid.

The dosage form of the pharmaceutical composition of the present invention is not particularly limited, and it may be an oral administration formulation or a parenteral administration formulation. Specifically, aerosols, liquids, extracts, elixirs, capsules (hard capsules, soft capsules, microcapsules), granules, pills, ophthalmic ointments, transdermal preparations, suspensions, emulsions, seats Preparation (vaginal preparation), powder, spirits, tablets (plain tablet, coated tablet, special tablet), syrup, soaking agent, decoction, injection (water-soluble injection, water-insoluble injection), patch, tincture Agents, eye drops, lozenges, ointments, poultices, fragrances, liniments, limonades, flow extracts, lotions and the like. These preparations can be produced by a conventional method in the pharmaceutical technical field, for example, by the method described in the Japanese Pharmacopoeia. These preparations can be safely administered to mammals including humans.

Since the pancreatic lipase inhibitor containing the solvent extract of the cacao pod coat of the present invention is a compound having low toxicity to living organisms, it is used as it is or in combination with a pharmacologically acceptable non-toxic and inactive carrier. Then, it can be applied as a pharmaceutical composition (including animal drugs) to mammals including humans (for example, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.), fish, and the like. it can.

The pharmacologically acceptable carrier is not particularly limited, and various carrier substances known as pharmaceutical materials can be used. The carrier substance is not particularly limited, and examples of solid carrier include excipients, lubricants, binders, and disintegrants. In addition to the above carrier substances, formulation additives such as preservatives, colorants, natural pigments, sweeteners and the like can be used as necessary. These substances include lactose, hydroxypropylmethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, ethylcellulose, corn starch, crystalline cellulose, carmellose calcium, anhydrous silicic acid, synthetic aluminum silicate, magnesium stearate, talc, etc. Although it can illustrate concretely, it is not restricted to these.

The carrier substance in the liquid preparation is not particularly limited, and examples thereof include those formulated as a solvent, a solubilizing agent, a suspending agent, an isotonic agent, a buffering agent, and the like. Furthermore, formulation additives such as preservatives, colorants, water-insoluble lake pigments, sweeteners and the like can be used as necessary. These substances include isotonic agents such as mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, mannose, stabilizers such as sodium sulfite, preservatives such as benzyl alcohol and methyl parahydroxybenzoate. In addition to the above, a solubilizer, a soothing agent, a pH adjuster and the like can be specifically exemplified, but are not limited thereto.

Hereinafter, the present invention will be specifically described by illustrating examples and comparative examples. In addition, this invention is not limited at all by these Examples.

The cocoa fruit from the Dominican Republic was used as the solvent extract of the cocoa pod shell used in the examples. The cocoa pod skin is fresh after removing the pulp (pulpaceous matter) of the cocoa fruit. After the outer skin was dried and cut finely, 20 g was put into a mixer (fiber mixer MX-X107), 500 ml of water was added, and the mixture was stirred at 25 ° C. for about 10 minutes. Then, it filtered with the filter paper for analysis of a dimension of 500 mm, and obtained filtrate was freeze-dried under reduced pressure with the vacuum freeze-drying apparatus (EYELA FDU-1200). The obtained dried product is a solvent extract of the cocoa pod shell used in the following examples. In the following examples, what is simply referred to as “cocoa pod skin extract” refers to this dried product unless otherwise specified.

Examples 1-3, Comparative Example 1
<Measurement of pancreatic lipase inhibitory action>
Pancreatic lipase activity was calculated by measuring the amount of oleic acid released from triolein. Triolein (SIGMA Chemical Co. (US)) 80 mg, lecithin 10 mg (Wako Pure Chemical Industries, Ltd.), bile acid (SIGMA Chemical Co. (US)) 5 mg in 9 ml of 0.1 mol (M) TES buffer A uniform suspension was obtained by sonication in a liquid (pH 7.0) for 10 minutes, and this was used as a substrate liquid. Add 0.1 ml of porcine pancreatic lipase solution (SIGMA Chemical Co. (US)) and 0.1 ml of the test substance to 0.1 ml of the substrate solution, and react at 37 ° C. for 30 minutes. The liberated fatty acid was quantitatively measured by the copper reagent method. As the activity value, the activity value of each sample was calculated with the value of no sample being added as 100%. In Example 1, a cacao pod peel extract dissolved in purified water to 4 mg / ml was used. Examples 2 and 3 were further fractionated, and those having a molecular weight of 1000 or more were designated as Example 2, and those having a molecular weight of less than 1000 were designated as Example 3. In Comparative Example 1, only purified water was used. The measurement results are shown in Table 1.

As is clear from the results shown in Table 1, the cacao pod coat extract has an effect of inhibiting pancreatic lipase activity, and particularly has an excellent inhibitory effect on those having a molecular weight cut off of 1000 or more.

<Measurement of blood lipid fluctuation after lipid loading>
a. Preparation of emulsion of soybean oil 3 ml of soybean oil (manufactured by Junsei Co., Ltd.) with 40 mg of cholic acid (SIGMA Chemical Co. (made in USA)), 1 g of cholesterol orate (manufactured by Tokyo Chemical Industry Co., Ltd.) and 3 ml of pure water for 10 minutes The solution was subjected to sonication, and the sonicated solution was made into a soybean oil emulsion.
b. Test method for administration of cacao pod peel extract Rats were divided into two groups, 4 groups per group, a control group and an administration group of cacao pod peel extract 170 mg / kg body weight, fasted overnight, and a lipid emulsion loading test was performed. In the control group, only soybean oil emulsion was orally administered to rats under non-anaesthesia. In the administration group of cocoa pod husk extract 170 mg / kg body weight, an emulsion of soybean oil containing cocoa pod husk extract was administered. Blood was collected from the tail vein of rats before and after the administration of soybean oil emulsion until 60, 120, and 180 minutes after administration. The neutral fat content in serum was measured using a triglyceride-E-test kit manufactured by Wako Pure Chemical Industries, Ltd. The results are shown in FIG.

From this result, it was clarified that the cacao pod peel extract has an excellent pancreatic lipase inhibitory effect and can delay the intestinal absorption of lipids. As a result, it has been clarified that the composition containing the cacao pod peel extract suppresses fat accumulation and has preventive, ameliorating and therapeutic effects on various diseases.

Below, the formulation example of the food-drinks composition containing the pancreatic lipase inhibitor of this invention is shown.

Formulation Example 1 Chewing gum A chewing gum having the following composition was prepared by a conventional method.
(Component) (parts by mass)
(1) Gum base 20.0
(2) Maltitol 73.5
(3) Reduced water candy 4.0
(4) Apple flavoring 0.5
(5) Cacaopod skin extract 2.0

When a monitor suffering from weight gain took the above chewing gum, which was 1500 mg per tablet, once a day, three times a day, for three months, the increase in body weight was suppressed compared to before.

Formulation Example 2 Tablet confectionery A tablet confection having the following composition was prepared by a conventional method.
(Component) (parts by mass)
(1) Sorbitol 72.9
(2) Sucrose fatty acid ester 4.0
(3) Raspberry flavor 0.1
(4) Cacaopod skin extract 13.0

When a monitor suffering from an increase in body weight took 1 tablet of 2000 mg of the above tablet confection once a day, 3 times a day for 3 months, the increase in body weight was suppressed compared to before.

Below, the formulation example of the pharmaceutical composition containing the pancreatic lipase inhibitor of this invention is shown.

Formulation Example 4 Tablet (Pharmaceutical Composition)
(Component) (parts by mass)
(1) Cocoa pod skin extract 10.0
(2) Vitamin C 20.0
(3) Vitamin B1 0.5
(4) Vitamin B2 0.5
(5) Lactose 40.0
(6) Dextrin 23.0
(7) Synthetic aluminum silicate 5.0
(8) Magnesium stearate 1.0

(operation)
Each of the above components was mixed, and the mixture was tableted to 500 mg per tablet with a tableting machine to obtain a tablet containing 50 mg of cocoa pod extract in each tablet.

When a patient with hyperlipidemia took the above tablet once a day, 3 times a day for 3 months, the blood fat level decreased.

The pancreatic lipase inhibitor of the present invention acts as a lipolysis inhibitor, thereby suppressing digestion and absorption of fat in the body and preventing, treating, and improving fat accumulation in the body. Thus, the food and beverage composition and the pharmaceutical composition containing the pancreatic lipase inhibitor of the present invention can be used for the prevention, treatment and improvement of obesity, hyperlipidemia and fatty liver.

It is a reference schematic diagram which shows the structure of a cacao pod (cacao fruit). It is a measurement result which shows the influence which it has on the rise in blood neutral fat after lipid loading.

Explanation of symbols

2 Cacaopod skin 3 Pulp (pulp)
4 Cocoa beans 5 Shell of cocoa beans
6 Thin skin of cocoa beans
7 Cocoa Bean Endosperm (Cotyledon)
8 Germ of cacao beans
11 Only lipid (soybean oil) emulsion alone (control group)
12. Administration group of lipid emulsion and cacao pod peel extract 170 mg / kg

Claims (3)

A pancreatic lipase inhibitor comprising a solvent extract of cocoa pod hulls. The pancreatic lipase inhibitor according to claim 1, wherein the extraction solvent is water, a water-soluble organic solvent, or a mixed solvent thereof. The lipase inhibitor according to claim 1 or 2, wherein the cocoa pod shell extract has a molecular weight cut-off of 1000 or more.

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