JP2004161721A - ANTIOBESITY AGENT, DIET AGENT AND alpha-GLUCOSIDASE INHIBITOR - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an agent effective for preventing and treating obesity which is a main risk factor of life-style related diseases, safely takable everyday and producible from easily available raw materials. <P>SOLUTION: The antiobesity agent and a diet agent contain dried powder or extract of pomegranate flower as an active component. The dried powder or the extract can be used as the active component of the antiobesity agent and the diet agent because they have excellent α-glucosidase inhibiting action and blood sugar level suppressing action, free from side effects, usable safely and producible from easily available raw materials. <P>COPYRIGHT: (C)2004,JPO

Description

【００４４】
当該結果によれば、ザクロ花エキスは、サラシア属の根やクワ葉エキスに対して約１／３以下の用量で同等のα−グルコシダーゼ阻害活性を示し、約３倍の阻害活性を有することが明らかにされた。
【００４５】
α−グルコシダーゼは、食餌中の炭水化物由来の二糖類等を単糖まで分解し、小腸からの吸収を促進する作用を有する。つまり、この酵素に対して活性阻害作用を有するということは、食餌中ブドウ糖の体内吸収を抑制することに繋がり、ひいてはダイエット効果等を示すことを意味する。
【００４６】
従って、ザクロ花のエキスは、腸管からのブドウ糖吸収を緩慢にして血中への取り込みを有意に抑制することから、従来、ダイエットや糖尿病予防に用いられてきたクワ葉やサラシア属生薬よりも更に優れた抗肥満剤或いはダイエット剤の有効成分となり得る。
【００４７】
その上、それぞれの乾燥物からの収率に関しては、ザクロ花エキスはサラシアオブロンガの根に対して約５倍、クワ葉に対して約２倍である。よって、ザクロ花は抗肥満剤やダイエット剤の素材として、非常に有用であることが分かる。
【００４８】
（試験例２）血糖上昇抑制効果試験
体重２８〜３０ｇの雄性マウスを一群１０匹として、２０〜２４時間絶食後、試験に用いた。
【００４９】
それぞれの検体を５％アラビアゴム水溶液に懸濁し、下表２に示す用量で経口投与した。その３０分後にショ糖１ｇ／ｋｇを経口投与して８０分後に採血し、グルコース測定キット（和光純薬製，グルコースＣＩＩ−テストワコー）で血中ブドウ糖濃度を測定した。結果を表２に示す。
【００５０】
【表２】

【００５１】
表中、「＊」は危険率５％で対照群と有意差があることを表わし、「＊＊」は１％の危険率で有意差があることを示す。
【００５２】
表２に示す結果によれば、ザクロ花のエキスは、２５ｍｇ／ｋｇという低用量の経口投与でも充分にショ糖の体内吸収を抑制し、食事後においても過度のブドウ糖血中濃度上昇を防止できることが実証された。この血糖上昇抑制効果は、従来、ダイエット剤等として使用されていたサラシア属やクワ葉のエキスよりも明らかに高い。
【００５３】
また、製造例１に示したザクロ花エキスの収率を考慮すると、茶剤として体重ｋｇ当たり約１００ｍｇもあれば、充分に食事後の血糖上昇を抑制できると考えられる。
【００５４】
従って、本発明に係るザクロ花エキスは、α−グルコシダーゼ活性を阻害するのみでなく、飲用することによって実際に血糖上昇を抑制できることから、抗肥満効果やダイエット効果を有することが明らかにされた。
【００５５】
（試験例３）急性毒性試験
体重２８〜３０ｇのｄｄ−Ｙ系雄性マウスを一群１０匹とし、製造例１で製造したザクロ花エキスを物理的に投与可能な最大用量である２０００ｍｇ／ｋｇで経口投与し、その他にエサと水は自由に与えて一週間観察した。
【００５６】
その結果、死亡例は全く観察されなかった。
【００５７】
従って、本発明のザクロ花エキスは、非常に安全性が高いことが証明された。
【００５８】
【発明の効果】
本発明に係る抗肥満剤およびダイエット剤は、α−グルコシダーゼ阻害作用と血糖上昇抑制作用を享有し、且つザクロの花を原材料とするために安全で毎日の摂取も可能であり、原料の調達も容易である。従って、本発明に係る抗肥満剤およびダイエット剤は、安全な肥満の治療または予防薬として有用であり、医薬組成物の構成成分として利用され得る。
【００５９】
また、本発明のα−グルコシダーゼ阻害剤は、上記の様に抗肥満剤およびダイエット剤として利用されるだけでなく、ガン等他の疾患の治療剤および予防剤として使用され得るものである。[0001]
TECHNICAL FIELD OF THE INVENTION
TECHNICAL FIELD The present invention relates to an anti-obesity agent and a diet agent having an effect of inhibiting the decomposition of carbohydrate-derived saccharides contained in diet and suppressing the absorption of glucose, and an α-glucosidase inhibitor.
[0002]
[Prior art]
In recent years, it has become clear that obesity is a major risk factor for cardiovascular diseases such as hyperlipidemia, hypercholesterolemia, type II diabetes, cholelithiasis, and hypertension, and lifestyle-related diseases such as colorectal cancer. Has become a major social problem. Therefore, many studies have been conducted in preparation for the development of excellent antiobesity agents, and some of them have already been supplied as pharmaceuticals.
[0003]
As such anti-obesity agents, for example, agents such as an appetite regulating system and a digestive absorption inhibiting system are known.
[0004]
Of these, anti-obesity agents of the appetite control system act on the hypothalamus of the brain to suppress appetite, and as a result, reduce nutritional intake and suppress obesity. However, appetite regulation in humans is not controlled solely by the hypothalamus, but also involves the cerebral cortex association and the limbic system that have developed in higher order, and emotions also affect the presence or absence of appetite. Drugs alone are not a complete countermeasure for obesity.
[0005]
In addition, since appetite regulating drugs act directly on the central nervous system, they may have various side effects. For example, dexfenfluramine, a serotonin (5-HT) agonist, has been discontinued in the United States because it induces pulmonary hypertension and valvular heart disease as side effects. As a catecholamine agonist, amphetamine has a weight-reducing effect, but shows dependence.
[0006]
In Japan, mazindol is marketed as an appetite suppressant (manufactured by Novartis, trade name: Sanolex) and used as an adjunct treatment for obesity, but has problems of drug resistance and rebound, and also has a similar stimulant-like dependence There are also gender issues.
[0007]
In addition, leptin, a hormone secreted by adipocytes that transmits peripheral fat reserves to the hypothalamus and regulates food intake and metabolism, has attracted attention as an antiobesity drug There is also. However, a satisfactory clinical result of leptin in simple obesity in 1999 was not obtained. At present, research on leptin resistance has been conducted, and it has not yet been put to practical use. Not in.
[0008]
On the other hand, orlistat, which inhibits the action of lipase, and acarbose, which is a carbohydrate absorption inhibitor, are commercially available as anti-obesity agents of the digestion absorption inhibition system. However, orlistat has a problem that the absorption of fat-soluble vitamins is inhibited, and acarbose may cause hypoglycemic symptoms and liver dysfunction.
[0009]
In contrast to these existing drugs, those that have been used as tea or herbal medicines are safe without the above-mentioned side effects, and if you search for those that have an absorption-inhibiting action from these, you can feel safe on a daily basis. It is considered that it can be drunk, and can be applied as one that can eliminate or prevent obesity.
[0010]
For example, Patent Literature 1 discloses that an extract of Salacia reticulata (a plant belonging to the genus Salacia), which has long been used as a traditional drug in India and Sri Lanka, has an α-glucosidase inhibitory action, and as a result, sugars from the digestive tract It describes that absorption can be favorably inhibited, and in fact, discloses the results of an experiment in which an increase in blood glucose in glucose-loaded rats was suppressed. Patent Literature 2 also describes that extracts of Salacia pulinoidis and Salacia oblonga, which are also Salacia genus plants, can inhibit α-glucosidase activity and suppress an increase in blood glucose in glucose-loaded rats.
[0011]
However, Salacia plants are not cultivated commercially in Japan, and the main use site is underground. Therefore, it is necessary to secure an amount that meets the demand as an anti-obesity agent or diet agent. It is difficult. Therefore, there is a long-awaited need for a drug having high safety as well as a plant belonging to the genus Salacia and exhibiting a higher absorption inhibitory effect.
[0012]
[Patent Document 1]
JP-A-9-301882 (Claim 1 etc.)
[Patent Document 2]
JP-A-11-116496 (Claim 1 etc.)
[0013]
[Problems to be solved by the invention]
Under the above circumstances, an object of the present invention is to provide a drug which is highly safe and has an excellent digestive absorption inhibitory action, and which can be easily procured in Japan.
[0014]
[Means for Solving the Problems]
In order to solve the above-mentioned problems, the present inventor has found that among plants that have been used as foods and crude drugs so far, those that can use renewable sites such as fruits, branches and leaves, and flowers, have excellent digestion and absorption inhibition. Investigations have been conducted to find an anti-obesity agent or a dieting agent that has an action and found that pomegranate flower powder and extract have extremely excellent α-glucosidase inhibitory action and blood glucose inhibitory action. Completed the invention.
[0015]
That is, the antiobesity agent or the dieting agent according to the present invention is characterized by using a dry powder of pomegranate (Punica granatum) flowers or an extract thereof as an active ingredient. Pomegranate has been cultivated for a long time in Japan, and if flowers are used, unlike the underground part, the plant itself does not die by sampling, and the pomegranate flower has excellent α-glucosidase inhibitory action and blood glucose elevation inhibitory action. Since it is safe and can be taken daily, it is extremely useful as an active ingredient of an antiobesity agent and a dieting agent.
[0016]
In addition, anti-obesity agents of the digestion and absorption inhibition type include lipolysis type in addition to those of the carbohydrate absorption inhibition type. However, because of the high ratio of carbohydrates (carbohydrates) in Japanese food, It is considered that a carbohydrate absorption inhibitor such as the present invention is more effective for Japanese people than a lipolytic agent.
[0017]
The extract is preferably an extract using an aqueous solvent. If it is extracted from an aqueous solvent, it is safer than the fat-soluble component because it is water-soluble, and due to the fact that α-glucosidase inhibitory action and blood glucose increase inhibitory action have been actually confirmed by experiments. .
[0018]
Further, the α-glucosidase inhibitor of the present invention comprises a dry powder of pomegranate flowers or an extract thereof as an active ingredient.
[0019]
BEST MODE FOR CARRYING OUT THE INVENTION
The greatest features of the anti-obesity agent and the diet agent of the present invention are that they exhibit excellent α-glucosidase inhibitory activity and blood glucose elevation inhibitory activity, and are highly safe and can be taken even every day. In addition to having an effect on diet and diet, it can be used as a prophylactic agent for obesity. In addition, the raw material, pomegranate, has been cultivated in Japan for a long time and is easily available.
[0020]
Hereinafter, embodiments of the present invention exhibiting such characteristics and effects thereof will be described.
[0021]
The antiobesity agent or dieting agent of the present invention comprises a dry powder of pomegranate flowers or an extract thereof as an active ingredient.
[0022]
"Pomegranate (Punica granatum)" is a plant belonging to the genus Pomegranate of the family Pomegranate, and has been used for anthelmintic purposes from ancient times due to its anthelmintic components contained in its peel, fruit, bark, and root bark. The flower is mainly used as a hemostatic agent in medicine in China, India and Arabia, but has hardly been used in Japan. However, it is easy to obtain pomegranate flowers in Japan since the cultivation has been carried out since the Heian period, and there is no need to consider the withering of plants due to harvesting because the underground part is not used.
[0023]
The method of “drying” is not particularly limited, and includes, for example, sun drying, half-day drying, shade drying, heating drying, room temperature drying, freeze drying, vacuum drying, and the like. Shading is preferred. However, the product must be sufficiently dried before being used or used. This is because the pomegranate flower is relatively thick, and if the drying is insufficient, the α-glucosidase inhibitory activity may be reduced, and pests may be generated.
[0024]
“Powder” means that it can be swallowed orally as it is, and its particle size is not particularly limited. Thus, the particle size need not be uniform and may be about 1 cm. Furthermore, those which cannot be generally referred to as "powder", but which become "dry powder" only after granulation are included in the scope of the present invention.
[0025]
As described above, the dry powder of the present invention is mainly intended for oral swallowing, but may of course be used as a tea preparation. When used as a tea agent, it is not always necessary to granulate it into a powder, and it may be decocted with a certain average particle size.
[0026]
The method of extracting the “extract” from the pomegranate flower is also not particularly limited. For example, the pomegranate flower may be extracted as it is, or may be extracted from ground and the like, or once dried. May be extracted. However, in consideration of the efficiency of the extraction, it is preferable to extract from smaller ones.
[0027]
As a solvent for extraction, an aqueous solvent is mainly used. Consideration is given to the convenience of the extraction operation, the fact that if it is extracted from an aqueous solvent, it is safe because it is water-soluble, and the safety when the solvent remains, etc. Examples of such aqueous solvents include water; lower alcohols such as methanol, ethanol, isopropanol and t-butyl alcohol; mixed solvents of water and lower alcohols. Or a mixed solvent of water and ethanol is preferred.
[0028]
The amount of the solvent to be used is generally 2 to 50 times the weight of the extracted material if it is dried, and 0.5 to 30 times if it is not dried. The extraction may be carried out at normal temperature, but it is also effective to increase the extraction efficiency by appropriately heating (preferably boiling) the solvent.
[0029]
The extraction time is not particularly limited, but is preferably 1 hour to 3 days. Further, at the time of extraction, it may be left still or stirred.
[0030]
The processing after the completion of the extraction is performed according to a conventional method. For example, the residue may be washed with the solvent used after filtration, combined with the filtrate, and then the solvent may be distilled off under reduced pressure or by heating.
[0031]
The thus-obtained dry powder and extract may be drunk as it is, or may be used as a composition for treating or preventing obesity by adding other components. There is no particular limitation on the type of such additive components, and examples thereof include fragrances, preservatives, pigments, vitamins, and excipients.
[0032]
In the present invention, a component having a therapeutic or preventive effect on obesity is not specified. However, since the pomegranate flower used in the present invention has been conventionally used as a crude drug or the like, the active ingredient is not one but a plurality of active ingredients interact additively or synergistically. Thus, it is considered that the compound exerts an excellent anti-obesity effect and the like.
[0033]
The anti-obesity agent and the diet agent of the present invention are intended to treat and prevent obesity. That is, since obstruction of digestion and absorption of sugar contained in the diet can reduce the amount of energy intake without reducing the amount of meal, obesity can be treated without impairing the quality of life of obese patients. In addition, since the antiobesity agent or the diet agent of the present invention is safe and can be constantly consumed even for those who are not obese, it can be used for the purpose of preventing obesity.
[0034]
Further, as described in Examples described later, since the dried powder of pomegranate flower and its extract have a clear α-glucosidase inhibitory action, this may be used as an α-glucosidase inhibitor. The main use of such an α-glucosidase inhibitor is as an anti-obesity agent or a dieting agent as described above, but it is also used for the treatment of diseases mediated by sugar chains possessed by cell surface membrane-bound proteins. Can be done. For example, specific sugar chain processing occurs in cancer cells, and this is related to metastasis and invasion of cancer, so that the α-glucosidase inhibitor of the present invention may be used for treatment or prevention of cancer. .
[0035]
The present invention is constituted as described above. The anti-obesity agent and the diet agent according to the present invention are safe, easy to procure raw materials, and have excellent α-glucosidase inhibitory action and increased blood glucose. Has an inhibitory effect. The dose varies depending on whether it is a dry powder or an extract, or for the purpose of preventing or treating obesity, its symptoms, the age and gender of the patient, and the like. 01 mg / kg to 1 g / kg (preferably 0.1 to 500 mg / kg) is orally administered. However, the dose is merely an example, and can be changed as appropriate while observing its effects and the like.
[0036]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Production Examples and Test Examples, but the scope of the present invention is not limited thereto.
[0037]
(Preparation Example 1) Preparation of a sample A pomegranate flower is collected in the summer, dried for several days in a well-ventilated shade (shade drying), and dried using a 60 ° C warm air dryer until the loss on drying is 5% or less. did. The dried product was roughly cut and 25 g was added to 500 ml of hot water, boiled for about 5 minutes, filtered, and the filtrate was concentrated at 40 ° C. under reduced pressure to obtain a pomegranate flower extract (extract).
[0038]
Further, as a control, the same treatment was applied to the roots and mulberry leaves of Salacia oblonga to obtain respective extracts.
[0039]
The yield of the extract was 32% from pomegranate flowers, 7% from the roots of Salacia oblonga, and 15% from mulberry leaves.
[0040]
(Test Example 1) α-Glucosidase Inhibition Activity Test 37 mM of sucrose was accurately weighed, 20 mg of each sample obtained in Production Example 1 was added thereto, and water was further added to dissolve the sample solution to make exactly 1000 ml, and the sample solution was prepared. Prepared. Also, 10 mg of α-glucosidase (manufactured by Wako Pure Chemical Industries) was dissolved in 100 ml of water, and this was used as an enzyme solution.
[0041]
0.7 ml of each sample solution and enzyme solution were weighed, mixed well, and then incubated at 37 ° C. for 30 minutes. Thereafter, 0.8 ml of water was added and the mixture was heated at 90 to 100 ° C. for 2 minutes to inactivate the enzyme and stop the reaction.
[0042]
For each reaction solution, the α-glucosidase inhibitory activity was determined as an IC ₅₀ value using a glucose measurement kit (manufactured by Wako Pure Chemical Industries, Glucose CII-Test Wako). Table 1 shows the results.
[0043]
[Table 1]

[0044]
According to the results, the pomegranate flower extract showed the same α-glucosidase inhibitory activity as the root and mulberry leaf extract of the genus Salacia at a dose of about 1/3 or less, and had about three times the inhibitory activity. Revealed.
[0045]
α-Glucosidase has an action of decomposing carbohydrate-derived disaccharides and the like in a diet into monosaccharides and promoting absorption from the small intestine. In other words, having an activity inhibiting effect on this enzyme leads to suppression of the in vivo absorption of glucose in the diet, which means that it has a diet effect and the like.
[0046]
Therefore, pomegranate flower extract slows glucose uptake from the intestinal tract and significantly suppresses uptake into the blood, so that it is more effective than conventional mulberry leaves or Salacia herbs which have been used for diet and diabetes prevention. It can be an active ingredient of an excellent antiobesity agent or diet agent.
[0047]
Moreover, with respect to the yield from each dried product, the pomegranate flower extract is about 5 times for the roots of Salacia oblonga and about 2 times for the mulberry leaves. Therefore, it turns out that pomegranate flower is very useful as a material of an anti-obesity agent and a dieting agent.
[0048]
(Test Example 2) Test for Suppressing Blood Glucose Increase A group of 10 male mice weighing 28 to 30 g was used for the test after fasting for 20 to 24 hours.
[0049]
Each specimen was suspended in a 5% aqueous solution of gum arabic and orally administered at doses shown in Table 2 below. Thirty minutes later, 1 g / kg of sucrose was orally administered and 80 minutes later, blood was collected, and blood glucose concentration was measured using a glucose measurement kit (Wako Pure Chemical Industries, Glucose CII-Test Wako). Table 2 shows the results.
[0050]
[Table 2]

[0051]
In the table, “*” indicates that there is a significant difference from the control group at a risk rate of 5%, and “**” indicates that there is a significant difference at a risk rate of 1%.
[0052]
According to the results shown in Table 2, the pomegranate flower extract can sufficiently suppress the absorption of sucrose in the body even by oral administration at a low dose of 25 mg / kg, and can prevent an excessive increase in glucose blood concentration even after a meal. Has been demonstrated. This effect of suppressing an increase in blood sugar is clearly higher than extracts of genus Salacia or mulberry, which have been conventionally used as a dieting agent or the like.
[0053]
In consideration of the yield of the pomegranate flower extract shown in Production Example 1, it is considered that if the amount of tea is about 100 mg per kg of body weight, a rise in blood glucose after a meal can be sufficiently suppressed.
[0054]
Therefore, the pomegranate flower extract according to the present invention not only inhibits α-glucosidase activity, but also can actually suppress an increase in blood glucose by drinking, and thus has an antiobesity effect and a diet effect.
[0055]
(Test Example 3) Acute toxicity test A group of 10 male dd-Y mice weighing 28 to 30 g was used, and the pomegranate flower extract prepared in Preparation Example 1 was orally administered at 2000 mg / kg, which is the maximum dose that can be physically administered. They were given food and water ad libitum and observed for a week.
[0056]
As a result, no deaths were observed.
[0057]
Therefore, the pomegranate flower extract of the present invention was proved to be extremely safe.
[0058]
【The invention's effect】
The anti-obesity agent and the diet agent according to the present invention have an α-glucosidase inhibitory effect and a blood sugar increase suppressing effect, and are safe and can be taken daily because pomegranate flowers are used as a raw material. Easy. Therefore, the anti-obesity agent and the diet agent according to the present invention are useful as safe therapeutic or preventive agents for obesity and can be used as components of pharmaceutical compositions.
[0059]
In addition, the α-glucosidase inhibitor of the present invention can be used not only as an antiobesity agent and a dieting agent as described above, but also as a therapeutic and prophylactic agent for other diseases such as cancer.

Claims (3)

An anti-obesity agent or a dieting agent comprising a dry powder of pomegranate (Punica granatum) flowers or an extract thereof as an active ingredient. The anti-obesity agent or diet agent according to claim 1, wherein the extract is an extract using an aqueous solvent. An α-glucosidase inhibitor comprising a dry powder of pomegranate flowers or an extract thereof as an active ingredient.