JP2011148837A - Lipase inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a safe and effective lipase inhibitor even by taking continuously for a long period, since the lipase is an enzyme catalyzing the decomposition of lipids in digestive tract, and on inhibiting its activity, the decomposition of the lipid is inhibited or delayed and the absorption of the lipid can be suppressed, the lipase inhibitor suppresses the elevation of serum lipid and accumulation of the lipids in a body and is useful for the prevention or improvement of hyperlipemia, obesity, etc. <P>SOLUTION: The lipase inhibitor is obtained by blending one or two or more kinds selected from the group consisting of crude medicines derived from plants such as dried leaves of Rhododendron spp., dried Biota orientalis, dried fruits of Alpinia oxyphylla, dried Polygonum multiflorum roots, dried seeds of Prunus persica, dried roots of Sanguisorba officinalis, dried flowers of Inula britannica, dried roots of Bolboschoenus fluviatilis. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

The present invention relates to a lipase inhibitor that is safe and effective even when taken for a long period of time.

In recent years, lifestyle-related diseases, for which lifestyle habits such as eating habits, exercise habits, rest, smoking, and alcohol consumption are thought to affect the onset and progression of the disease, have attracted attention. In developed countries, increases in obesity, hyperlipidemia, non-insulin dependent diabetes mellitus (type II diabetes), high blood pressure, etc., which are said to be related to eating habits and exercise habits, have hindered people's health maintenance. Not only does it lead to a decline in quality of life (QOL), but it has also become a major social problem, causing a rapid increase in national medical expenses.

Lipase secreted from the pancreas (pancreatic lipase) is a lipid digestive enzyme in the digestive tract. Of the lipids ingested by diet, triglycerides are broken down into fatty acids and monoglycerides by pancreatic lipase and absorbed from the small intestine. Therefore, a composition that inhibits the activity of pancreatic lipase not only inhibits lipid absorption from the gastrointestinal tract but also suppresses lipid accumulation in the body, so that it is effective in preventing or improving hyperlipidemia, obesity, etc. Conceivable.

Conventionally, orlistat (tetrahydrolipostatin) has been developed as a lipase inhibitor, but there are many reports of side effects such as gastrointestinal disorders and fatty stool, and a safer drug is required.

As a lipase inhibitor derived from natural products, a lipase inhibitor (Patent Document 1) containing a solvent extract of asen, guava leaves, and medusait leaves, lemongrass, allspice, cinnamon, clove plants or Lipase inhibitor containing the extract as an active ingredient (Patent Document 2), alfalfa extract, bitter tea extract, gold-silver flower extract, peppermint extract, clove extract, squirrel extract, olive extract and rafuma A lipase inhibitor (Patent Document 3) containing tea extract as an active ingredient is disclosed.

Bowie (prevented) is the dried stem and rhizome of Sinomenium acutum (Hanho already), the dried root of Cocculus trilobus (prevented tree), Stephania tetrandra ) Dried roots (powder-prevented), dried roots of Aristolochia fanchi of the family Alasolochia fanchi (wide-prevented), and dried Aristolochia heterophylla roots (prevented in Hanchu). The pharmacological action includes blood pressure lowering, central depression, anti-allergy and anti-inflammation, etc. In Kampo, its use as a diuretic or analgesic is known. The Aristolochia genus plant contains a component called aristolochiic acid, and it has been reported that this aristolochiic acid induces renal damage. It is desirable to use wood-resistant and powder-proofed materials, and more preferably, Han-proofed or powder-proofed materials.

Sekinanyou (Shinami leaf) is a dried leaf of the rose family, Photinia serrulata, or Rhododendron spp. Rhododendron leaves are known to have antihypertensive, emetic, and intestinal motility effects, but there are few pharmacological reports of rosaceae. It is also known as an analgesic, diuretic and tonic, applied to gout, rheumatic pain, kidney disease and the like.

Sakuhakuyo (Tsubaki orientalis) is a dried branch of the leaves of the cypress family Thuja orientalis = Biota orientalis, and is known for its use as an astringent, analgesic and hemostatic agent.

Yakuchi is a dried fruit of Alpinia oxyphylla from the ginger family, and is known for its use as an aromatic bitter stomachic medicine and intestinal adjuster.

Kashuu is a dried tuberous root of the Polygonum multiflorum, and is known for its use as a tonic, strong, blood replacement and laxative.

Chiyu is a dried root and rhizome, such as rosaceae (Sangusorba officinalis), has antibacterial action as a pharmacological action, and is known to be used as an astringent and hemostatic agent.

Sempukuka (dried flower) is a dried small head flower of Inula britannica and I. britannica subsp. Lineariaefolia. Are known.

Kokusanryo (Kurosan Ryuji) is a dried rhizome of the cyperaceae, Bolboschoenus fluviatilis, and is known for its use as a vaginal, antitussive and analgesic.

Tonin (Momojin) is a dried seed of rose peach (Prunus persica) and peach (P. persica var. Davidiana), and is known for its use as an anti-inflammatory antipigant (non- Patent Documents 1 and 2).

However, these natural products are not known to have a lipase inhibitory action and an action for improving obesity and hyperlipidemia based on the lipase inhibitory action.

JP2000-103741 JP2001-120237 JP2003-26585

Namba Tsuneo, Encyclopedia of Japanese and Chinese Medicine [I], Yogosha, p.9-10, p.70-71, p.77, p.78-81, p.272-273, p.238-239, 1993 Namba Tsuneo, Encyclopedia of Japanese and Chinese Medicine [II], Yoikusha, p.83-86, p.89-91, p.121-122, 1994

An object of the present invention is to provide a lipase inhibitor that is safe and effective even when taken continuously for a long period of time.

As a result of intensive studies to solve the above problems, the present inventors have found that certain herbal medicines or extracts thereof have excellent lipase inhibitory activity, and further suppress the increase in serum lipid concentration in oil-loaded rats and It was found that the increase in serum lipid concentration in genetically obese mice was suppressed, and further, the increase in body weight and increase in serum lipid concentration in dietary obese rats were suppressed, and the present invention was completed.

That is, the present invention
1) A lipase inhibitor comprising one or more selected from the group consisting of sequinanyo, sakuhakuyo, yakuchi, kashu, tonin, chiyu, sempukka and kokusanrioun.
2) A prophylactic or ameliorating agent for hyperlipidemia, comprising one or more selected from the group consisting of Sekinanyou, Sakuhakuyo, Yakuchi, Kashu, Tonin, Chiyu, Sempukuka and Kokusanryo.
3) The preventive or ameliorating agent according to 2), wherein the hyperlipidemia is hypertriglyceridemia.
4) A prophylactic or ameliorating agent for obesity characterized by containing one or more selected from the group consisting of Sekinanyou, Sakuhakuyo, Yakuchi, Kashou, Tonin, Chiyu, Sempukuka and Kokusan Ryo.
It is.

The present invention is effective in preventing or improving obesity and hyperlipidemia since it is effective in inhibiting lipid absorption based on a lipase inhibitory action.

Sekinanyou, Sakuhakuyo, Yakuchi, Kashu, Chiyu, Senpukuka, Kokusanryo and Tonin according to the present invention can be used as a crude drug powder as it is, or as an extract extracted with water, polar solvents, mixed solvents thereof, etc. An extract extracted with a solvent in which equal amounts of water and alcohol are mixed is preferable. Moreover, a dry extract, a flow extract, etc. can also be used for an extract.

The herbal medicine components used in the present invention can be used alone or in combination.

The dose of the lipase inhibitor of the present invention can be appropriately increased or decreased in consideration of age, sex, etc., but can be used usually in an adult range of 100 mg to 50 g as an active ingredient equivalent per day, preferably 500 mg. ~ 30 g.

The present invention is a qualitative and quantitative range that does not impair the effects of the invention, vitamins, xanthine derivatives, amino acids, excipients, pH adjusting agents, cooling agents, suspending agents, antifoaming agents, viscous agents, Solubilizing agents, disintegrating agents, binders, lubricants, antioxidants, coating agents, coloring agents, flavoring agents, surfactants, plasticizers, fragrances, etc. are blended, and liquids, tablets, Oral or parenteral preparations such as granules, powders, capsules, dry syrups, chewable tablets and transmucosal agents can be used.

It was found that the herbal medicine component of the present invention has an excellent lipase inhibitory action. In addition, it was found that the increase in serum lipid concentration in oil-loaded rats and the increase in serum lipid concentration in genetically obese mice were suppressed, and further, the increase in body weight and increase in serum lipid concentration in dietary obese rats were suppressed.

The present invention will be specifically described below with reference to examples and test examples.

After chopping kanbowei, 10 times the amount of 50% ethanol was added, extracted by heating at about 80 ° C., filtered to remove ethanol under reduced pressure, and further concentrated to obtain an extract.

In addition, Sekinanyou, Sakuhakuyo, Yakuchi, Kashou, Chiyu, Sempukuka, Kokusan Ryo and Tonin were extracted by the same extraction method to produce an extract.

Test Example 1 (Measurement of lipase inhibitory action)
25 μL of each herbal extract (dissolved in 2.5% DMSO) obtained in Example 1 and 25 μl of enzyme solution (100 U / mL pancreatic lipase, Type VI-S from porcine pancreas) were added to 50 μl of a substrate solution (0.2 mM 4-methylumbelliferyl oleate). . After reacting at 37 ° C. for 15 minutes, 150 μL of 0.1M hydrochloric acid and 25 μL of 0.1M sodium citrate were added, and fluorescence at an excitation wavelength of 320 nm and a fluorescence wavelength of 450 nm was measured. Each crude drug extract was added at final concentrations of 12.5, 25, 50, and 100 μg / mL.

Table 1 and FIG. 1 show the results of expressing the fluorescence of the herbal extract combination group as the inhibition rate (%) when the crude drug extract-free group is 100%.

As is clear from the tables and figures, Bowie, Sekinanyou, Sakuhakuyou, Yakuchi, Kashu, Chiyu, Sempukuka, Kokusan Ryo, and Tonin have lipase inhibitory effects and may have preventive or ameliorating effects on hyperlipidemia and obesity. It was revealed.

Test Example 2 (Measurement of inhibitory effect on serum lipid concentration after olive oil administration)
Each male herb extract obtained in Example 1 was orally administered at a dose of 300 or 500 mg / kg (in terms of dry extract) to SD male rats (6 to 7 weeks old, Nippon Charles River Co., Ltd.) fasted for 18 to 20 hours. 30 minutes later, 1 mL of olive oil was orally administered. 120 minutes later, blood was collected from the posterior vena cava under ether anesthesia, and serum was separated by centrifugation (3000 rpm, 20 ° C., 15 minutes). The triglyceride concentration in the serum was quantified using Triglyceride E-Test Wako (Wako Pure Chemical Industries, Ltd.).
The results are shown in Table 2 and FIG.

As is clear from the tables and figures, Bowie, Sekinanyou, Sakuhakuyo, Yakuchi and Kashu significantly suppressed the increase in serum triglyceride concentration by olive oil administration. From these results, it was revealed that Bowie, Sekinanyou, Sakuhakuyou, Yakuchi and Kashu inhibit lipid absorption and have a preventive or ameliorating action on hyperlipidemia and obesity.

Test Example 3 (Measurement of serum lipid concentration increase inhibitory effect in ob / ob mice)
The ob / ob mouse (6 weeks old, male, Nippon Charles River Co., Ltd.) was orally administered once a day for 8 weeks at a dose of 300 mg / kg (converted to dry extract) at a dose of 300 mg / kg. After the final administration, the animals were fasted for 18 to 20 hours, blood was collected from the posterior vena cava under ether anesthesia, and serum was separated by centrifugation (3000 rpm, 20 ° C., 15 minutes). The serum triglyceride concentration and free fatty acid concentration were quantified using triglyceride E-Test Wako and NEFAC-Test Wako (both Wako Pure Chemical Industries, Ltd.).

The results are shown in Table 3 and FIG.
As is clear from the tables and figures, it was revealed that Sekinanyou and Sakuhakuyo significantly suppressed the increase in serum lipids in ob / ob mice and prevented or ameliorated hyperlipidemia and obesity.

Test Example 4 (Measurement of body weight and serum lipid elevation inhibitory action of diet-induced obesity model rats)
SD male rats (8 weeks old, Nippon Charles River Co., Ltd.) were fed a high calorie diet, and at the same time, the extract obtained in Example 1 was administered once a day at a dose of 300 mg / kg (in terms of dry extract). Orally administered for a week. The normal group was fed with a normal diet. After the final administration, the animals were fasted for 18 to 20 hours, blood was collected from the posterior vena cava under pentobarbital anesthesia, and serum was separated by centrifugation (3000 rpm, 20 ° C., 15 minutes). Visceral fat was collected and weighed. The serum triglyceride concentration and free fatty acid concentration were quantified using triglyceride E-Test Wako and NEFAC-Test Wako (both Wako Pure Chemical Industries, Ltd.).

The results are shown in Table 4 and FIG.

As is clear from the tables and figures, Bowie significantly suppressed body weight gain and serum triglyceride concentration increase due to high-calorie diet. Sakuhakuyo significantly suppressed the increase in serum free fatty acid concentration. Kash also significantly suppressed body weight gain and serum triglyceride concentration, and also showed a tendency to suppress the increase in visceral fat weight. That is, it has been clarified that Bowie, Sakuhakuyo and Kashou are effective in preventing or improving hyperlipidemia and obesity.

Since the component of the present invention has an excellent lipase inhibitory action, it can be used for pharmaceuticals, foods, functional foods and the like for the treatment or prevention of hyperlipidemia, obesity, and excess body fat.

It is the figure which showed the lipase activity inhibition rate about each crude drug extract of this invention, and showed the inhibition rate on each vertical axis | shaft, and the density | concentration on each horizontal axis. It is the figure which showed the effect | action with respect to the serum lipid rise at the time of the olive oil load about each crude drug extract of this invention, and the serum triglyceride density | concentration was shown on each vertical axis | shaft, and the crude drug name was shown on each horizontal axis | shaft. Also, # or ## in the figure represents a p value of 0.05 or less or 0.01 or less when t-test is performed between the normal group and the control group, respectively. * Or ** indicates t between the control group and the herbal extract group. The p-value when tested represents 0.05 or less or 0.01 or less, respectively. It is the figure which showed the effect | action with respect to the serum lipid rise of b / ob mouse | mouth about each crude drug extract of this invention, The serum triglyceride density | concentration or the serum free fatty acid density | concentration was shown on each vertical axis | shaft, and the crude drug name was shown on each horizontal axis | shaft. In addition, ## in the figure represents a p value of 0.01 or less when the t test is performed between the normal group and the control group, and * or ** indicates a p value when the t test is performed between the control group and the herbal extract group. Represents 0.05 or less or 0.01 or less, respectively. It is a diagram showing the action on dietary obese rat body weight, visceral fat weight and serum lipid elevation for each herbal extract of the present invention, the vertical axis is body weight, serum triglyceride concentration, serum free fatty acid concentration or visceral fat weight, Each abscissa indicates the name of the crude drug. Also, # or ## in the figure represents a p value of 0.05 or less or 0.01 or less when t-test is performed between the normal group and the control group, respectively. * Or ** indicates t between the control group and the herbal extract group. The p-value when tested represents 0.05 or less or 0.01 or less, respectively.

Claims (4)

A lipase inhibitor characterized by comprising one or more selected from the group consisting of Sekinanyou, Sakuhakuyo, Yakuchi, Kashu, Tonin, Chiyu, Sempukuka and Kokusan Ryo. A prophylactic or ameliorating agent for hyperlipidemia, comprising one or more selected from the group consisting of Sekinanyou, Sakuhakuyo, Yakuchi, Kashu, Tonin, Chiyu, Sempukuka and Kokusanryo. The preventive or ameliorating agent according to claim 2, wherein the hyperlipidemia is hypertriglyceridemia. A preventive or ameliorating agent for obesity, comprising one or more selected from the group consisting of Sekinanyou, Sakuhakuyo, Yakuchi, Kashu, Tonin, Chiyu, Sempukuka and Kokusanryo.

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