JP2007314438A - Antiobestic medicine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an antiobestic medicine that comprises any of scymnol and/or a scymnol ester, cholic acid, cod liver oil and cholic acid or scymnol and/or a scymnol ester and cod liver oil so as to solve life style-related diseases such as cardiovascular disease, type 2 diabetes, cancer, etc., caused by obesity. <P>SOLUTION: The antiobestic medicine comprises any of scymnol and/or a scymnol ester, cholic acid, cod liver oil and cholic acid or scymnol and/or a scymnol ester and cod liver oil. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The invention relates to anti-obesity agents comprising either simnole and / or simnol ester, cholic acid, cod liver oil, cholic acid or simnol and / or simnol ester and cod liver oil.

Currently, life-style related diseases caused by obesity such as cardiovascular disease, type 2 diabetes and cancer will account for about 60% of deaths due to illness worldwide and increase to 73% in 2020. World Health Organization (WHO).
Lifestyle-related diseases are defined as “diseases related to the onset and progression of lifestyle habits such as eating habits, exercise habits, rest, smoking, drinking, etc.” Type 2 diabetes, obesity, hyperlipidemia (family ), Cardiovascular disease (except congenital), and hypertension.
Recently, the concept of metabolic syndrome, in which multiple risk factors (such as impaired glucose tolerance, hypertension, obesity, and abnormal lipid metabolism) accumulate in one individual and frequently develop fatal cardiovascular events, has also attracted attention.
In Japan, the number of patients with lifestyle-related diseases such as hypertension and hyperlipidemia, including 77.4 million diabetic patients, has increased from 10 million to 20 million with the westernization of lifestyles. It is clear that it goes up. As a result, nearly two-thirds of deaths are due to these lifestyle-related diseases.
Furthermore, the number of deaths due to these lifestyle-related diseases is increasing not only in developed countries but also in developing countries. At the WHO annual meeting held in Genoa in May 2004, obesity that caused lifestyle-related diseases was reported. A “global diet, exercise, and health strategy” was adopted to prevent it, emphasizing restricted intake of fat, salt and sugar, increased intake of fruits and vegetables, and increased exercise levels.
In fact, the increase in obesity is happening globally, and according to the National Audit Office (NAO), the number of obese people in the UK is three times that of 20 years ago. One in four people is said to be obese.
According to the Centers for Disease Control and Prevention (CDC) announcement, the proportion of obese people in the United States has increased by 57% since 1991, and approximately 300,000 people die each year from obesity-related diseases. ing.
Thus, obesity is currently one of the most serious social problems in the world, and obesity countermeasures are a global issue.
Since obesity is formed by an increase in the number of fat cells and enlargement of fat cells, suppressing fat cell hypertrophy or abnormal differentiation / proliferation leads to treatment and prevention of lifestyle-related diseases.
As drugs having an action of replacing enlarged fat cells with small normal fat cells, there are pioglitazone and rosiglitazone. These are PPARγ agonists, and pioglitazone is a drug that is clinically applied in Japan as a therapeutic agent for diabetes.
These PPARγ agonists promote the differentiation of preadipocytes by highly activating PPARγ and increase the size of small adipocytes, thereby promoting the production of adiponectin and consequently improving the resistance to insulin.
Furthermore, hypertrophic adipocytes that overproduce insulin resistance-inducing agents (TNF-α, free fatty acids, etc.) are reduced by apoptosis or the like.
In addition, fatty acid inflow into skeletal muscle and liver is enhanced by increasing the expression of proteins in the adipose tissue that play an important role in the incorporation of triglyceride into the tissue and strongly promoting the inflow of fatty acids into the adipose tissue. Is relatively decreased, and insulin resistance in skeletal muscle and liver is improved.
However, at the same time, there is a risk of causing weight increase and obesity associated with the differentiation promoting action of the PPARγ agonist, and it is difficult to say that it is an ideal therapeutic agent for diabetes. On the other hand, there is currently no drug aimed at inhibiting differentiation of preadipocytes.

The object of the present invention is to solve such problems.
Chinese medicine is a multi-component drug that has been widely used in Asia for over 2000 years. There are many things which have the effect | action which raises the natural healing power of the living body which a western medicine does not have, and it has shown increasing popularity as herbal medicines also in Europe and America recently.
However, the fact that its use is empirical and the mechanism of action is not sufficiently clear is a major obstacle to the spread of Kampo medicine in Western medicine.
As the term evidence-based medicine (EBM) is said to be active, establishment of Kampo EBM by accumulation of evidence is also important in Kampo medicine. Since herbs whose mechanism of action has been clarified, such as digitalis, occupy a large position in Western medicine, it can be said that it is important to elucidate the scientific basis for the use of Kampo medicines.
In Kampo medicine, the treatment policy is originally determined based on “certification”, but in recent years, with the spread of Kampo medicine to Western medicine, Kampo medicine has been prescribed based on “Disease name”.
However, since traditional Chinese medicine does not have the concept of obesity, the only Chinese medicines for which obesity is indicated are Fufutsu Seisaku and Hosei Koto.
These herbal medicines are also the ones for which the description of the classics is applied to the indication forcibly, and there is no Chinese medicine used for obesity in the true sense.
Thus, Kampo medicine has no concept of obesity, but there are many Kampo medicines that can be applied to diseases close to lifestyle-related diseases. For example, various Chinese medicines are used for hypertension, hyperlipidemia, and diabetes. The mechanism of action of these herbal medicines is unclear, but some of these may improve lifestyle-related diseases by improving obesity.
As a result of various investigations to solve such problems, the inventors of the present application have found that anti-obesity drugs targeting the differentiation process of preadipocytes that have not existed so far are simanol and / or simanol ester, cholic acid, Developed as a new anti-obesity drug by utilizing cod liver oil, cholic acid or simnol and / or simnol ester and cod liver oil.

  The invention relates to anti-obesity drugs comprising either simnole and / or simnol ester, cholic acid, cod liver oil, cholic acid or simnol and / or simnol ester and cod liver oil.

The present invention relates to an anti-obesity drug containing either simnole and / or simnol ester, cholic acid, cod liver oil, cholic acid or simnol and / or simnol ester and cod liver oil, It is possible to provide a drug for preventing obesity having an excellent effect on lifestyle-related diseases caused by obesity such as type 2 diabetes and cancer.
By preventing obesity, it is possible to simultaneously achieve prevention and treatment of diseases based on obesity.

The invention of the present application may include herbal medicines that have a corrective action, carrots, pearls, taisidins, ogis, sun yaks, taisou, licorice, kowi, seisei, zukujiou, kashi, touki, jakushak, kukosi, longanganik, jinjin. More preferred are jujujio, touki, peony, kokushi, and ryuganiku, and carrots, jinjin, ogi, sanyaku, taisou, and licorice are particularly preferred.
Physiological functions are activated by these herbal medicines, and metabolism is flourishing.

The invention of this application preferably includes a herbicidal medicinal product, peanut, crispula, chorei, takusha, inchinkou, mokuboui, bowie, casseki, tokanin, mokutsu, shazenshi, sekishozu, hanpenren, keishi (keihi), Inchinkou, Bowie, Kaseki, and Sekisho are more preferred, and peanuts, bukuryo, chorei, takusha, mokutsu, and shazenshi are particularly preferred.
Excess water in the body can be drained by the water-utilizing action of sand jellyfish.

The invention of the present application preferably includes at least one of Auren, Oat, Mao, Forsythia, Keigai, Green tea, Oolong tea, Black tea, Coffee, Kidachi aloe, Tengusa, Kanten, Pepper, Ginger, Pepper. Tengusa is more preferable, and auren, autaku, mao, green tea, oolong tea, black tea, and kidachi aloe are particularly preferable.
The adipocyte differentiation-inhibiting action of these crude drugs can further suppress adipocyte hypertrophy or abnormal differentiation / proliferation.

  The invention of this application preferably includes isoflavones and isoflavone glycosides, and the isoflavones and isoflavone glycosides are particularly preferably soybean isoflavones and soybean isoflavone glycosides contained in soybeans.

The active ingredients for this purpose contained in soybeans are several isoflavone glycosides such as soybean in (Gaidin), glycitin (Glycitin), genistin (Gaistin) and the like, and their aglycones (Daizein), glycitein There are several isoflavones such as (Glycitein) and Genistein.
Soybean is a raw material for producing soybean oil, but the demand for soybean oil is large, and soybean meal, a by-product, is produced in large quantities at the same time. A part of soybean meal is used as a raw material for producing soybean protein as a raw material for food, but it is mainly used as fertilizer and feed, and its price is extremely low. Soybean isoflavone and soybean isoflavone glycosides can be produced with high purity and low cost from soybean meal that is close to industrial waste.

The crude drug of the invention of this application may be used as it is, or an extracted one may be used.
Further, the dosage form of the anti-obesity agent drug of the present invention is not particularly limited, but it is administered as a tablet, capsule, powder, solid, liquid or the like.
Moreover, when administering, it is although it does not specifically limit, It is preferable to administer twice a day. It can also be used as a cosmetic.

The daily dose of cholic acid is preferably 1 to 1000 mg, more preferably 2 to 300 mg, and particularly preferably 10 to 100 mg.
The daily dose of simnole and / or simnol ester is preferably 0.1 to 100 mg, more preferably 0.1 to 50 mg, and particularly preferably 0.3 to 10 mg.

  The daily dose of cod liver oil is preferably 0.1 to 5000 mg, more preferably 1 to 3000 mg, and particularly preferably 2 to 1500 mg.

  The daily amount of isoflavone and isoflavone glycoside is preferably 1 to 500 mg, more preferably 5 to 300 mg, and particularly preferably 10 to 200 mg.

The daily amount of herbal medicines such as carrots, sandals, and aureans is preferably 1 to 20 g and particularly preferably 1.5 to 5 g.
The amount of the extract decocted with herbal medicine is preferably 100 to 600 mg, particularly preferably 200 to 400 mg.
Hereinafter, specific examples will be described.

Powder cod liver oil 100mg
Soybean isoflavone glycoside 125mg
Ginseng extract 300mg
White birch extract 300mg
Yellow Lotus Extract 300mg
Lactose 2460mg
Corn starch 400mg
Light anhydrous silicic acid 5mg
Magnesium stearate 10mg
Total 4000mg
(1g 1g, 2 packets, 2 times a day)
Similarly, powder was prepared using soy isoflavone instead of soy isoflavone glycoside.

Granule cod liver oil 100mg
Soybean isoflavone glycoside 125mg
Ginseng extract 300mg
White birch extract 300mg
Yellow Lotus Extract 300mg
Lactose 1800mg
Corn starch 800mg
Crystalline cellulose 260mg
Light anhydrous silicic acid 5mg
Magnesium stearate 10mg
Total 4000mg
(1g 1g, 2 packets, 2 times a day)
Similarly, granules were produced using soy isoflavones instead of soy isoflavone glycosides.

Spherical granule cod liver oil 100mg
Soybean isoflavone glycoside 125mg
Ginseng extract 300mg
White birch extract 300mg
Yellow Lotus Extract 300mg
Lactose 500mg
Corn starch 1500mg
Ume powder 475mg
Crystalline cellulose 400mg
Total 4000mg
(1g 1g, 2 packets, 2 times a day)
Similarly, spherical granules were produced using soy isoflavone instead of soy isoflavone glycoside.

Tablet cod liver oil 200mg
Soybean isoflavone glycoside 125mg
Ginseng extract 300mg
White birch extract 300mg
Yellow Lotus Extract 300mg
Lactose 3100mg
Carboxymethylcellulose calcium 320mg
Hydroxypropylcellulose 75mg
Crystalline cellulose 840mg
Carplex 30mg
Magnesium stearate 10mg
Total 5600mg
(1 tablet 560mg, 1 tablet 5 times, 2 times a day)
Similarly, tablets were produced using soy isoflavones instead of soy isoflavone glycosides.

Hard capsule cod liver oil 65mg
Soybean isoflavone glycoside 125mg
Ginseng extract 200mg
Birch extract 200mg
Yellow Lotus Extract 200mg
Corn starch 1000mg
Magnesium stearate 10mg
Total 1800mg
(1 capsule 300 mg, 3 capsules, 2 times a day)
Similarly, hard capsules were produced using soy isoflavones instead of soy isoflavone glycosides.

Soft capsule cod liver oil 1000mg
Soybean isoflavone glycoside 125mg
Ginseng extract 200mg
Birch extract 200mg
Yellow Lotus Extract 200mg
Beeswax 75mg
Total 1800mg
(1 capsule 300mg, 3 tablets, 2 times a day)
Similarly, soft capsules were produced using acetyl soybean isoflavone and soybean isoflavone instead of soybean isoflavone glycoside.

Drink agent cod liver oil 100mg
Soybean isoflavone glycoside 125mg
Ginseng extract 300mg
White birch extract 300mg
Yellow Lotus Extract 300mg
Royal Jelly 150mg
Riboflavin sodium phosphate 10mg
Ethanol 1.2ml
Paraoxybenzoic acid 4mg
Purified water appropriate amount total 50ml
(50ml per bottle, once a day, once a day)
Similarly, a drink was prepared using soy isoflavone instead of soy isoflavone glycoside.

Injection cod liver oil 20mg
JP sodium sulfite 4mg
JP Ammonia Water Appropriate amount JP JP Saline Solution Appropriate amount total 5ml
(1 vial 5 ml, 1 vial once, 1 day)

Lotion preparation cod liver oil 3g
Soy isoflavone glycoside 1.25g
Ginseng extract 3g
3g white birch extract
Yellow Lotus Extract 3g
99.5% ethanol 300 ml
Purified water appropriate amount total 1000ml
(10ml once, twice a day)
Similarly, a lotion preparation was produced using soy isoflavone instead of soy isoflavone glycoside.

Ointment cod liver oil 1.5g
Soy isoflavone glycoside 1.25g
Ginseng extract 3g
3g white birch extract
Yellow Lotus Extract 3g
99.5% ethanol 20 ml
Total amount of hydrophilic ointment 500g
(10g once, twice a day)
Similarly, an ointment was prepared using soy isoflavone instead of soy isoflavone glycoside.

Suppository cod liver oil 100mg
Soy isoflavone glycoside 625mg
Ginseng extract 1000mg
White birch extract 1000mg
Yellow Lotus Extract 1000mg
Cocoa butter or an appropriate base 10 or more suppositories.
(One agent at a time, twice a day)
Similarly, suppositories were prepared using soy isoflavones instead of soy isoflavone glycosides.

Powder simnol sulfate Na 1mg
Soybean isoflavone glycoside 125mg
Lactose 800mg
Corn starch 1064mg
Magnesium stearate 10mg
Total 2000mg
(1g 1g, 1 packet 1 time, 2 times a day)
Similarly, powder was prepared using soy isoflavone instead of soy isoflavone glycoside.

Granules cholic acid 60mg
Soybean isoflavone glycoside 125mg
Lactose 2700mg
Corn starch 800mg
Crystalline cellulose 300mg
Light anhydrous silicic acid 5mg
Magnesium stearate 10mg
Total 4000mg
(1g 1g, 2 packets, 2 times a day)
Similarly, granules were produced using soy isoflavones instead of soy isoflavone glycosides.

Tablet Simnol sulfate Na 1mg
Soybean isoflavone glycoside 125mg
Lactose 140mg
Crystalline cellulose 845mg
Magnesium stearate 6mg
Talc 3mg
Total 1120mg
(1 tablet 280mg, 2 tablets, 2 times a day)
Similarly, tablets were produced using soy isoflavones instead of soy isoflavone glycosides.

Soft capsule Simanol sulfate Na 1mg
Soybean isoflavone glycoside 125mg
Cod liver oil 815mg
Tocopherol acetate 5mg
Carrot extract 200mg
Beeswax 54mg
Total 1200mg
(1 capsule 300 mg, 2 capsules, 2 times a day)
Similarly, soft capsules were produced using soy isoflavones instead of soy isoflavone glycosides.

Hard capsule cholic acid 60mg
Soybean isoflavone glycoside 125mg
Corn starch 1005mg
Magnesium stearate 10mg
Total 1200mg
(1 capsule 300 mg, 2 capsules, 2 times a day)
Similarly, hard capsules were produced using soy isoflavones instead of soy isoflavone glycosides.

Soft capsule cholic acid 60mg
Soybean isoflavone glycoside 125mg
Beeswax 55mg
Edible oil 960mg
Total 1200mg
(1 capsule 300 mg, 2 capsules, 2 times a day)
Similarly, soft capsules were produced using soy isoflavones instead of soy isoflavone glycosides.

Soft capsule cholic acid 60mg
Soy isoflavone 75mg
Cod liver oil 805mg
Acetate floor ferrol 5mg
Carrot extract 200mg
Beeswax 55mg
Total 1200mg
(1 capsule 300 mg, 2 capsules, 2 times a day)
Similarly, soft capsules were produced using soy isoflavone glycosides instead of soy isoflavones.

Soft capsule Simanol sulfate Na 1mg
Soybean isoflavone glycoside 125mg
Cod liver oil 814mg
Acetate floor ferrol 5mg
Carrot extract 200mg
Beeswax 55mg
Total 1200mg
(1 capsule 300 mg, 2 capsules, 2 times a day)
Similarly, soft capsules were produced using soy isoflavones instead of soy isoflavone glycosides.

Pure injection cholic acid 20mg
Pure soybean isoflavone glycoside 20mg
Glucose 1000mg
PH adjuster Sodium carbonate Add an appropriate amount of distilled water for injection to make a total volume of 5 ml.
(1 vial 5 ml, 1 vial once, 1 day)
Similarly, an injection was prepared using soy isoflavone instead of soy isoflavone glycoside.

Drink agent Simnol sulfate Na 1mg
Soybean isoflavone glycoside 125mg
Ginseng extract 10mg
Giant extract 10mg
Royal Jelly 100mg
Thiamine nitrate 10mg
Riboflavin sodium phosphate 5mg
Pyridoxine hydrochloride 10mg
Anhydrous caffeine 50mg
Ethanol 1.2ml
Paraoxybenzoic acid 4mg
Purified water appropriate amount total 50ml
(50ml per bottle, once a day, once a day)
Similarly, a drink was prepared using soy isoflavone instead of soy isoflavone glycoside.

Reference Example 3T3-L1 cells are precursor cells that differentiate into adipocytes when added with a differentiation-inducing agent and cultured for about 6 days.
In the invention of this application, 3T3-L1 cells in a confluent state are placed in a differentiation-inducing medium (3-isobutyl-1-methylxanthine: IBMX, dexamethasone: DEX, insulin) for 2 days in an adipocyte medium containing insulin (5 μg / mL). Differentiation was induced by culturing for 2 days and in a normal adipocyte medium not containing insulin for 2 days. During this period (6 days), test drugs were added at various concentrations, and the effect on 3T3-L1 cell differentiation was examined.
Oil Red O staining and glycerol-3-phosphate dehydrogenase activity were measured as indicators of differentiation. In order to examine the cytotoxic effect of the test drug, MTT assay was performed, and the mechanism of the inhibitory action on differentiation was examined using Western blotting.
The results are as follows.
Screening was carried out using Oil Red O staining as an indicator, and as a result, a control group with no test drug added was added to Simnol and / or Simnol ester, cholic acid, cod liver oil, cholic acid or Simnol and / or Simnol ester and cod liver oil, In comparison, a significant differentiation-inhibiting effect was observed.
Simnole and / or simnol ester, cholic acid, cod liver oil, cholic acid or simnol and / or simnol ester and cod liver oil inhibit the differentiation into adipocytes in a concentration-dependent manner, and at a concentration of 10 μg / mL, It was suppressed to almost the same level as the differentiation control group.
As a result of examination using MTT assay, no cytotoxic effect was observed.
Next, the mechanism of action of simnole and / or simnol ester, cholic acid, cod liver oil, cholic acid or simnole and / or simnol ester and cod liver oil was examined. According to previous studies, the differentiation process of 3T3-L1 cells is considered as follows. That is, differentiation induction agents IBMX and DEX first cause transient expression induction of CCAAT / enhancer-binding protein (C / EBP) β and δ transiently in the nucleus. The two transcription factors then increase the expression of peroxisome proliferator-activated receptor (PPAR) γ and C / EBPα. The produced PPARγ and C / EBPα act to induce mutual expression and maintain the production amount of these factors, and PPARγ forms a dimer with retinoid X receptor α to induce differentiation.
Therefore, Western blotting was used to examine the effects of simnole and / or simnol ester, cholic acid, cod liver oil, cholic acid or simnol and / or simnol ester and cod liver oil on the expression of PPARγ, C / EBPα, β and δ. And examined. As a result, simnole and / or simnol ester, cholic acid, cod liver oil, cholic acid or simnol and / or simnol ester and cod liver oil almost completely reduced the expression of PPARγ and C / EBPα at concentrations that inhibit differentiation. It was revealed that it had almost no effect on the expression of C / EBPβ and δ while being suppressed.
From the above results, the differentiation inhibitory action of Korento is caused by simnole and / or simnol ester, cholic acid, cod liver oil, cholic acid or simnole and / or simnol ester and cod liver oil, and simnol and / or Alternatively, it was understood that the main action mechanism of simanol ester, cholic acid, cod liver oil, and cholic acid was suppression of PPARγ and C / EBPα expression.

  The invention of this application makes obesity a etiology by providing an anti-obesity agent comprising simnole and / or simnol ester, cholic acid, cod liver oil, cholic acid or simnol and / or simnol ester and cod liver oil The purpose is to eliminate lifestyle-related diseases.

Claims (5)

An anti-obesity drug comprising any of simnole and / or simnol ester, cholic acid, cod liver oil, cholic acid or simnole and / or simnol ester and cod liver oil. The antiobesity agent according to claim 1, comprising a crude drug having a corrective action. 3. The antiobesity agent according to claim 1 or 2, comprising a crude drug having a water-utilizing action. 4. One or more kinds of Auren, Abou, Maou, Forsythia, Keigai, Green tea, Oolong tea, Black tea, Coffee, Kidachi aloe, Tengusa, Kanten, Pepper, Ginger, Pepper Anti-obesity drugs. The anti-obesity agent according to any one of claims 1 to 4, comprising isoflavone or isoflavone glycoside.