JP2007063137A - Anti-obesity agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new anti-obesity agent eliminating life style related diseases caused by obesity such as cardiovascular diseases, type 2 diabetes and cancer. <P>SOLUTION: The anti-obesity agent is obtained by using curcumin. A crude drug having enhancing actions on immune strength is used in combination. A crude drug having hydragogue actions is used in combination. Isoflavone or an isoflavone glycoside is used combination. The blood level of curcumin is maintained at 0.5-100 μM. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  This invention relates to an anti-obesity drug containing curcumin.

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 studies to solve such problems, the inventors of the present application have developed a novel anti-obesity drug by using curcumin as an anti-obesity drug that has targeted the differentiation process of adipose precursor cells that has never existed before. Developed as

  The present invention relates to an anti-obesity drug containing curcumin.

The present invention relates to an anti-obesity drug containing curcumin, and can provide a drug for preventing obesity having an excellent effect on lifestyle-related diseases caused by obesity such as cardiovascular disease, 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.
Curcumin has the following structural formula.

The blood concentration of curcumin is preferably 0.5 to 100 μM, more preferably 5 to 30 μM, and particularly preferably 7 to 20 μM.
As an internal medicine such as a tablet, 1 mg to 200 mg is preferable per day for a human with a body weight of 60 kg, more preferably 10 mg to 60 mg, and particularly preferably 14 mg to 40 mg.
As an injection solution, the amount of curcumin in 5 mL is preferably 1 mg to 200 mg, more preferably 10 mg to 60 mg, and particularly preferably 14 mg to 40 mg.

  The daily amount of isoflavone and isoflavone glycoside is preferably 1 to 500 mg, more preferably 5 to 200 mg, and particularly preferably 10 to 100 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, the present invention will be described in detail.
The purity of the soy isoflavone and soy isoflavone glycoside used was 40%.

Powder curcumin 45mg
Soybean isoflavone glycoside 125mg
Korean carrot extract 300mg
Sandalwood extract 300mg
Ouren extract 300mg
Lactose 2500mg
Corn starch 415mg
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 curcumin 45mg
Soybean isoflavone glycoside 125mg
Korean carrot extract 300mg
Sandalwood extract 300mg
Ouren extract 300mg
Lactose 1815mg
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.

Spherical granule curcumin 45mg
Soybean isoflavone glycoside 125mg
Korean carrot extract 300mg
Sandalwood extract 300mg
Ouren extract 300mg
Lactose 515mg
Corn starch 1515mg
Plum powder 500mg
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 curcumin 45mg
Soybean isoflavone glycoside 125mg
Korean carrot extract 300mg
Sandalwood extract 300mg
Ouren 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 curcumin 30mg
Soybean isoflavone glycoside 125mg
Korean carrot extract 200mg
Sandalwood extract 200mg
Ouren extract 200mg
Corn starch 1035mg
Magnesium stearate 10mg
Total 1800mg
(1 capsule 300mg, 3 tablets, 2 times a day)
Similarly, hard capsules were produced using soy isoflavones instead of soy isoflavone glycosides.

Soft capsule curcumin 30mg
Soybean isoflavone glycoside 125mg
Korean carrot extract 200mg
Sandalwood extract 200mg
Ouren extract 200mg
Beeswax 55mg
Cooking oil 990mg
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 curcumin 45mg
Soybean isoflavone glycoside 125mg
Korean carrot extract 300mg
Sandalwood extract 300mg
Ouren 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 curcumin 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 curcumin 3g
Soy isoflavone glycoside 1.25g
Ginseng extract 3g
Sandalwood extract 3g
Ouren extract 3g
99.5% ethanol 300 ml
Purified water appropriate amount perfume appropriate amount total 1000ml
(10 ml at a time, twice a day)

Ointment curcumin 1.5g
Soy isoflavone glycoside 1.25g
Ginseng extract 3g
Sandalwood extract 3g
Ouren extract 3g
99.5% ethanol 20 ml
Hydrophilic ointment appropriate amount perfume appropriate amount total 500g
(10g at a time, twice a day)

Suppository curcumin 150mg
Soy isoflavone glycoside 625mg
Korean carrot extract 1000mg
Sandalwood extract 1000mg
Ouren extract 1000mg
Cocoa butter or an appropriate base 10 or more suppositories.
(One agent at a time, twice a day)

3T3-L1 cells are progenitor cells that are differentiated into adipocytes when cultured for about 6 days after addition of a differentiation-inducing agent.
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.
When screening was performed using Oil Red O staining as an indicator, curcumin was found to have a significant differentiation inhibitory effect as compared to the control group to which no test drug was added.
Curcumin inhibited adipocyte differentiation in a concentration-dependent manner, and was suppressed to almost the same level as the undifferentiated control group at a concentration of 10 μg / mL.
As a result of examination using MTT assay, no cytotoxic effect was observed.
Next, the action mechanism of curcumin 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.
Thus, the effect of curcumin on the expression of PPARγ, C / EBPα, β and δ was examined using Western blotting. As a result, it was clarified that curcumin almost completely suppresses the expression of PPARγ and C / EBPα at a concentration that suppresses differentiation, whereas it hardly affects the expression of C / EBPβ and δ. It was.
From the above results, it was understood that the differentiation inhibitory action of Korento was caused by curcumin, and the main action mechanism of curcumin was the suppression of the expression of PPARγ and C / EBPα.

  The object of this invention is to eliminate lifestyle-related diseases caused by obesity by providing an anti-obesity drug containing curcumin.

Claims (6)

An anti-obesity drug comprising curcumin. 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. The anti-obesity drug according to any one of claims 1 to 5, wherein the anti-obesity drug is administered so that the blood concentration of curcumin is 0.5 to 100 µM (1 mg to 200 mg / day).