JP4125011B2 - Excess iron-induced liver injury prevention / treatment agent and excess iron-induced liver injury prevention / treatment - Google Patents

Description

【００３３】
この結果、図６に示されるように、８週間後の血中鉄分濃度は各群とも９４．６±１．５μｇ／ｄＬに収束した。
以上の点から、本被験飲料の継続的摂取は、血中ヘモグロビン濃度や赤血球数に影響を与えず、貧血を起こさせることもなく、それでいて血中鉄分濃度を効果的に降下せしめることができることが確かめられた。
【００３４】
（実施例1）
以下の処方で過剰鉄起因肝障害予防・治療剤としてのタブレットを作成した。
【００３５】
茶抽出物（テアフラン90S又はテアフラン30A） … １２０ｍｇ
ビタミンC … ５０ｍｇ
乳化オリゴ糖 … ９０ｍｇ
造粒剤 … ６０ｍｇ
結晶セルロース … ８０ｍｇ
還元麦芽糖水飴 … ９０ｍｇ
スクロース … １００ｍｇ
香料 … 適量
【００３６】
（実施例２）
以下の処方で血中鉄分濃度安定化効果を備えた飲食物としての飲料を作成した。
【００３７】
茶抽出物（テアフラン90S又はテアフラン30A） … ２５０ｍｇ
ビタミンC … ５０ｍｇ
果糖ぶどう液糖 … １０ｇ
水溶性食物繊維 … ５００ｍｇ
香料 … 適量
イオン交換水 … １００ｍＬに調整
【図面の簡単な説明】
【図１】 被験者の血中鉄分濃度を経時的に示したグラフである。
【図２】 被験者のγ−ＧＴＰ値を経時的に示したグラフである。
【図３】 平均血中鉄分濃度と平均γ−ＧＴＰ値の相関関係を示したグラフである。
【図４】 被験者の血中ヘモグロビン濃度を経時的に示したグラフである。
【図５】 被験者の赤血球数を経時的に示したグラフである。
【図６】 別の３群の被験者の血中鉄分濃度を経時的に示したグラフである。[0001]
[Industrial application fields]
The present invention relates to a new use of tea polyphenol obtained by extracting tea (Camellia sinensis), and more particularly to a new use related to metabolism of blood iron.
[0002]
[Prior art]
Various pharmacological actions have been discovered for tea polyphenols extracted from tea and have already been used for various purposes.
[0003]
For example, Japanese Patent Application Laid-Open No. 05-017364 discloses a sucrose activity inhibitor containing tea polyphenol as an active ingredient, and Japanese Patent Application Laid-Open No. 06-263648 is a body alcohol containing catechin, which is one of tea polyphenols, and its metabolite. JP-A 06-122626 discloses an agent for improving renal function based on the fact that tea polyphenols suppress the proliferation of mesangial cells and have an effect of improving renal function.
[0004]
JP 06-65085 discloses a tyrosinase activity inhibitor containing tea polyphenols as an active ingredient, and JP 06-9391 discloses a hyaluronidase activity inhibitor containing tea polyphenols as an active ingredient. No. 56686 discloses an anti-atherosclerotic agent that can be phagocytosed by macrophages to prevent LDL from reaching foam cells.
[0005]
Japanese Patent Application Laid-Open No. 09-59154 discloses an antidote containing tea catechin as an active ingredient, that is, excessive alcohol consumption resulting in an excessive increase in the concentration of acetic acid or acetone in the body resulting in acidemia, causing unpleasant symptoms such as nausea and dizziness. Disclosed is an antidote that can promote the metabolism of acetic acid and acetone in the body if it is ingested, effectively reduce the concentration in the body and eliminate the symptoms in a short time,
Japanese Patent Application Laid-Open No. 10-175858 has found that tea catechin has an effect of suppressing the generation of active oxygen, and an active oxygen generation inhibitor and an active oxygen-induced disease preventive agent, ie, active oxygen-induced diseases such as periodontal disease, pneumonia, aging and cancer It is proposed to be used as a preventive agent to prevent.
[0006]
Japanese Patent Laid-Open No. 10-147525 discloses a human papillomavirus-derived wart condyloma therapeutic agent mainly composed of tea catechin, and Japanese Patent Laid-Open No. 10-36260 added tea catechins and / or theaflavins to an anticancer agent. Then, it is disclosed that the effect of enhancing the efficacy of anticancer agents can be obtained,
JP-A-11-193239 proposes a gastrin secretion inhibitor and a gastric acid secretion inhibitor containing tea catechin as an active ingredient, and suppresses gastrin secretion and gastric acid excess secretion in the gastric body by ingestion. It discloses that gastrointestinal diseases such as duodenal ulcer, gastric ulcer, and gastric cancer can be prevented.
[0007]
Furthermore, Japanese Patent Laid-Open No. 2000-60427 discloses that a main catechin composition containing catechin exhibits a liver injury protecting effect (liver function improving effect), and Japanese Patent Laid-Open No. 2001-226276 is a polyphenol derived from green tea. An apoptosis-inducing anti-leukemia cell agent containing as an active ingredient is disclosed.
[0008]
[Problems to be solved by the invention]
Iron in the body plays a role in oxygen transport, oxygen fixation in the muscle, energy regeneration and metabolism, defense against oxygen poison, body temperature maintenance, and the like. Most of the iron in the body exists as a complex protein bound with protein, 60 to 70% of which is present in hemoglobin in erythrocytes, and the rest is stored in the liver and serum.
[0009]
The effects of excessive iron concentrations are serious. If iron is excessive for some reason, it is said that iron deposits in each tissue in the body, and its chronic toxicity leads to diseases such as diabetes, liver dysfunction, and sexual dysfunction due to tissue damage and fibrosis. For example, it is known that iron deposition in the heart causes myocardial damage, iron deposition in the pancreas causes diabetes, and iron deposition in the pituitary gland promotes a decrease in gonadotropin secretion. In particular, the effect on the liver is significant, and iron deposition in the liver leads to cirrhosis from fibrosis, and it has recently been clarified that iron is an aversion factor for liver damage, particularly an aversion factor for viral activity in chronic hepatitis C. It was. In addition, it has been reported that iron ions abnormally increased in the liver are a major factor in liver damage (Abstracts of the 53rd Annual Meeting of the Japanese Cancer Association, page 91, 1994).
[0010]
The absorption of iron in the healthy body is strictly regulated, and the absorption efficiency naturally decreases in the body when the necessary amount of iron is exceeded. Nonetheless, the causes of iron overload are known to include blood transfusion, iron overabsorption, iron overdose, high alcohol intake of alcoholic beverages, long-term parenteral iron intake, and liver disease (Pippard MJ: Iron deficiency and overload. In. Oxford Textbook of Medicine. Pp. 19.83-19.91 Oxford University Press. 1990) and other genetic causes. Aceruloplasminemia is an autosomal recessive genetic disease that causes excessive deposition of iron in systemic organs such as the brain, liver, and pancreas due to abnormalities in the ceruloplasmin gene.
[0011]
As a treatment for removing excess iron, phlebotomy is generally performed. The hemoptysis is a treatment method for extracting blood from a patient's vein, and is performed, for example, by repeatedly collecting blood of about 200 to 400 mL while supplying water by infusion.
However, repeated hemoptysis tends to result in iron deficiency, which is a difficult treatment for those with anemia. In addition, it has been reported that nails are deformed, weakness is caused by excessive hemoptysis, and liver damage is caused. Furthermore, since it is necessary to prepare appropriate equipment for hemoptysis, it is difficult to perform it at home as a maintenance therapy to maintain an appropriate blood iron concentration, and there is a problem that the burden on the patient is heavy. Was.
[0012]
On the other hand, when iron content is insufficient, blood hemoglobin decreases, oxygen does not reach the body enough, and various symptoms such as anemia, fatigue, fatigue, headache, dizziness, palpitation / shortness of breath, loss of appetite, etc. Various adverse effects such as decreased resistance to illness and decreased body temperature maintenance function. And it is said that many modern people, especially Japanese people, do not have the necessary iron intake and have “iron deficiency anemia”.
[0013]
By the way, drinks containing tannins such as tea and coffee have long been said to have an effect of inhibiting iron absorption, and in medical practice, guidance to avoid intake of tannin-containing drinks for iron deficiency patients for many years. (Pharmacy Vol. 39, No. 1 (1988) "In vivo kinetics of drugs (13)").
On the other hand, recently there have been reports of denying the influence of tea etc. on iron absorption and reports that anemia can be recovered sufficiently even when iron and tea are used in combination. JP-A-2001-139481 also obtained a result of promoting the absorption of iron preparations as a result of taking in a young woman a container-packed tea drink and an iron preparation. An iron absorption promoter as an active ingredient is disclosed.
[0014]
The present invention proposes a new use of tea polyphenol based on the knowledge obtained as a result of intensive studies on the influence of tea extract on blood iron metabolism, especially the influence of tea polyphenol.
[0015]
[Means for Solving the Problems]
As a result of earnest research on the influence of tea extract components on iron metabolism, the present inventors newly newly introduced tea extract components, particularly tea polyphenols, with the action of lowering the blood iron concentration when blood iron content is excessive, Found that there is an action to stabilize the blood iron concentration when the blood iron content is no longer excessive, based on this finding, the present invention, that is, a prophylactic and therapeutic agent for excess iron-induced liver injury containing tea polyphenol as an active ingredient, and We propose food and drink for preventing and treating excess iron-induced liver damage. In the present invention, “iron” includes a complex protein in which iron and protein are bound.
[0016]
The agent for preventing and treating excess iron-induced liver damage and the food and drink for preventing or treating excess iron-induced liver damage according to the present invention, when the blood iron concentration is high, removes excess blood iron by simply ingesting orally. While the iron concentration can be effectively reduced, when the blood iron concentration is relatively low, it can be absorbed with iron to promote iron absorption and suppress the decrease in blood iron concentration ( Control action). Moreover, it has been confirmed that there is no significant effect on the red blood cell count and hemoglobin concentration, and anemia, malaise, fatigue, headache, dizziness, palpitation / shortness of breath, loss of appetite, etc. even if the iron concentration in the blood is reduced. It does not cause various adverse effects due to a decrease in red blood cell count and hemoglobin.
From these points, the agent for preventing and treating excess iron-induced liver injury and the food and drink for excess iron-induced liver injury according to the present invention are caused by excess iron without causing various diseases and diseases caused by iron deficiency. Treatment and prevention of symptoms and diseases (tissue disorders and fibrosis, diabetes, liver dysfunction, sexual dysfunction, myocardial damage, decreased gonadotropin secretion). Moreover, since it does not have a significant effect on the red blood cell count and hemoglobin concentration, and if the blood iron concentration is low as described above, further reduction is suppressed. Without reducing the concentration, for example, it is particularly effective for maintenance treatment after hemoptysis and iron removal treatment for anemia.
Furthermore, since the active ingredient of the present invention is an ingredient derived from tea that has been drunk on a daily basis and can be safely consumed by anyone since ancient times, it can be taken comfortably and safely for a long period of time. Therefore, it is particularly effective for long-term treatment and prevention, such as the fundamental treatment / prevention of symptoms and diseases caused by chronic iron excess, and maintenance treatment after hemoptysis treatment.
[0017]
DETAILED DESCRIPTION OF THE INVENTION
Excess iron-induced liver injury prevention / treatment agent and excess iron-induced liver injury prevention / treatment food and drink according to the present invention may be blended with “tea polyphenol” obtained by extracting tea at an appropriate concentration, or high concentration of tea polyphenol Can be produced by blending the “tea extract” contained in
[0018]
Here, the “tea polyphenol” in the present invention includes any of the following a) to d).
a) (-)-epicatechin, (-)-epigallocatechin, (-)-epicatechin gallate, (-)-epigallocatechin gallate, (±) -catechin, (-)-gallocatechin, (-)- Any one compound selected from the group consisting of catechin gallate, (−)-gallocatechin gallate, free theaflavin, theaflavin monogallate A, theaflavin monogallate B and theaflavin digallate,
b) any one polymer selected from the group a),
c) a copolymer comprising a combination of any two or more selected from the group of a),
d) a mixture comprising any combination of two or more selected from the group consisting of any compound of a), any polymer of b) and any copolymer of c),
[0019]
However, among the above a) to d), tea catechins or polymers thereof or copolymers thereof, in particular, (−)-epicatechin gallate, (−)-epigallocatechin gallate and polymers thereof. And what contains 50% or more of copolymer in a total amount is preferable as an active ingredient of this invention.
It is known that when a mixture containing tea catechins is sterilized by retort, a polymer or copolymer of these tea catechins is produced.
[0020]
These “tea polyphenols” should be extracted from tea obtained from leaves, stems, xylem, roots, fruits, or a mixture of two or more of these obtained from Camellia sinensis The tea can be any of fresh tea leaves, fermented teas such as black tea and puer tea, semi-fermented teas such as oolong tea and baked tea, green tea, potted green tea, non-fermented tea such as hojicha, or these The mixture obtained by extracting from each tea (single) or the mixture extracted from each tea can be used. As an extraction method, extraction and purification may be performed by any currently known method, and a commercially available tea polyphenol can also be used.
[0021]
As the “tea extract” containing tea polyphenols at a high concentration, for example, the above tea is extracted with water, hot water or hot water, preferably hot water of 90 ° C. to 100 ° C. even in hot water of 40 ° C. to 100 ° C. In order to increase the tea catechin content by purification means such as resin adsorption, ultrafiltration / reverse osmosis filtration, or partition extraction using ethyl acetate, etc. The tea extract obtained by refining can be used, or the tea extract obtained by concentrating or drying these tea extracts. In this case, the concentration of tea polyphenol is 25 to 97%, preferably 30 to 90%. As a specific example of this tea extract, green tea is subjected to hot water extraction treatment, and the extract is dried to obtain a tea catechin concentration. 30% green tea extract (product name: Teaflan 30A, manufactured by ITO EN) and green tea are extracted with hot water, and this extract is processed by the column method and dried to exclude components other than tea catechins. An example is a green tea extract (trade name: Tea Franc 90S manufactured by ITO EN) with a tea polyphenol concentration of about 85 to 95%.
[0022]
The above-mentioned “tea polyphenol” or “tea extract” is the only active ingredient, and other ingredients are added as necessary to prevent or treat excess iron-induced liver injury and treatment. Although it is possible to prepare foods and drinks, it is mixed with materials that have already or in the future been recognized to have a blood iron concentration lowering action or iron absorption action, and these are used as active ingredients to prevent or treat excess iron-induced liver damage. It is also possible to prepare foods for preventing and treating excess iron-induced liver damage.
In addition, when blended as the only active ingredient, for example, "tea polyphenol" or "tea extract" is dissolved in purified water or physiological saline in the form of a refined product, crude refined product, tea extract or the like It is also possible to provide it as a drug (for example, oral administration agent, intraperitoneal administration agent, intracerebral administration agent, etc.).
[0023]
The agent for preventing or treating excess iron-induced liver injury of the present invention is an orally or parenterally administered agent (for intramuscular injection, intravenous injection, subcutaneous administration, rectal administration, transdermal administration, nasal administration, etc. It is preferable that the composition and dosage form are suitable for each administration.
Speaking of dosage forms, for example, for oral administration, it can be prepared in the form of solutions, tablets, powders, granules, dragees, capsules, suspensions, emulsions, pills, etc. It can be prepared in the form of injection, ampoule, rectal administration, oily suppository, water-soluble suppository and the like.
Regarding formulation (formulation), commonly used excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubilizers, It can be produced by a conventional method using a preservative, a flavoring agent, a soothing agent, a stabilizer and the like. Also, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or salts thereof, gum arabic, polyethylene glycol, syrup, petrolatum, glycerin, ethanol, propylene Non-toxic additives such as glycol, citric acid, sodium chloride, sodium sulfite, and sodium phosphate can be blended.
[0024]
Further, the agent for preventing or treating excess iron-induced liver injury of the present invention can be provided as a pharmaceutical, a quasi-drug, other drugs for non-human animals, food additives, feeds, feed additives, and the like. . For example, by preparing as a quasi-drug and making it into a drinking form such as a bottled drink or a form such as a tablet, capsule, granule, etc., it can be a preventive agent that is easy to ingest.
[0025]
On the other hand, the food and drink for preventing and treating excess iron-induced liver injury of the present invention can be provided as a health food, health drink, food for specified health use, and functional food having a pharmacological effect.
[0026]
In addition, the active ingredients of the present invention include carbonic acid, excipients (including granulating agents), diluents, or sweeteners, flavors, flours, starches, sugars, fats and other various proteins, carbohydrate raw materials and vitamins, Mixing one or two or more selected from minerals, for example, sports drinks, fruit drinks, milk drinks, tea drinks, vegetable juices, milk drinks, alcoholic drinks, jelly, jelly drinks, carbonated drinks, chewing gum, chocolate, It can be provided as foods and drinks in various forms such as candy, biscuits, snacks, bread, dairy products, fish paste products, livestock meat products, frozen desserts, dried foods and supplements.
[0027]
The content of the active ingredient in the present invention varies depending on the use, but in the case of a pharmaceutical, it is preferably 0.001 to 1% by weight, particularly 0.01 to 0.5% by weight in terms of catechin dry weight. If it is a food or drink, it is preferably added in an amount of 0.001 to 1% by weight, particularly 0.01 to 0.5% by weight in terms of dry weight of catechin. Particularly in the case of a beverage form, it is preferably adjusted to a concentration of 1.4 to 8 times that of tea that is usually drunk.
The amount of intake is 10 to 5000 mg per day in terms of dry weight of catechin, preferably about 100 to 1500 mg.
[0028]
(Volunteer Exam 1)
In this study, 8 volunteers 20 years of age or older (all volunteers have γ-GTP of 50 IU / L or more (reference value) or more) were allowed to take the following test beverage three times a day for 8 weeks, one for each meal. It was.
[0029]
As a test beverage, a beverage comprising 272 mg of Tearfuran 90S (trade name, manufactured by ITO EN) per 190 mL of can, and a slight amount of cyclodextrin, vitamin C and flavoring are added to improve the taste. did. The tea polyphenol concentration in this beverage was 0.132%, the total catechin concentration was 0.090%, and the EGCg and ECg concentrations were 0.072% and 0.019%, respectively.
The teafuran 90S had a tea polyphenol content of 92% and a tea catechin content of 63% (of which EGCg was 50% and ECg was 13%). Moreover, since the test beverage is sterilized by retort, it is a mixed beverage containing a polymer or isomer of tea catechins.
[0030]
As a result, as shown in FIG. 1 and FIG. 2, a significant decrease in the γ-GTP value was observed with a decrease in blood iron concentration, and the value at the 8th week compared to the beginning of intake was the blood iron concentration, γ -Both GTP values decreased significantly. On the other hand, as shown in FIG. 4 and FIG. 5, the blood hemoglobin concentration and the number of red blood cells were not significantly changed, and no volunteer had anemia.
In addition, as shown in FIG. 3, it was found that there is a significant correlation between the blood iron concentration and the average value of the γ-GTP value when the blood iron concentration is in the range of 90 to 132 μg / dL (r = 0.989561).
[0031]
(Volunteer Exam 2)
In this study, 42 male volunteers over the age of 20 were divided into 3 groups of 14 each (Group A, Group B, and Group C). In Group A, 190 g of placebo drinks were taken 3 times a day for 8 weeks. In group B, 190 g of tea polyphenol-containing beverage having the following composition was ingested two times a day for 8 weeks, and in group C, 190 g of tea polyphenol-containing beverage having the following composition was ingested three times a day for 8 weeks.
[0032]
[Table 1]

[0033]
As a result, as shown in FIG. 6, the blood iron concentration after 8 weeks converged to 94.6 ± 1.5 μg / dL in each group.
In view of the above, continuous intake of this test beverage does not affect blood hemoglobin concentration or red blood cell count, does not cause anemia, and can effectively lower blood iron concentration. It was confirmed.
[0034]
(Example 1)
A tablet was prepared as an agent for preventing and treating excess iron-induced liver injury with the following prescription.
[0035]
Tea extract (teafuran 90S or teafuran 30A) ... 120mg
Vitamin C ... 50mg
Emulsified oligosaccharide ... 90mg
Granulating agent 60mg
Crystalline cellulose ... 80mg
Reduced maltose starch syrup ... 90mg
Sucrose ... 100mg
Perfume ... appropriate amount [0036]
(Example 2)
A beverage as a food and drink having the effect of stabilizing blood iron concentration was prepared with the following formulation.
[0037]
Tea extract (teafuran 90S or teafuran 30A)… 250mg
Vitamin C ... 50mg
Fructose grape sugar: 10g
Water-soluble dietary fiber: 500mg
Fragrance ... Appropriate amount of ion-exchanged water ... Adjust to 100 mL [Brief description of the drawings]
FIG. 1 is a graph showing blood iron concentration of a subject over time.
FIG. 2 is a graph showing γ-GTP values of subjects over time.
FIG. 3 is a graph showing the correlation between the average blood iron concentration and the average γ-GTP value.
FIG. 4 is a graph showing the blood hemoglobin concentration of a subject over time.
FIG. 5 is a graph showing the number of red blood cells of a subject over time.
FIG. 6 is a graph showing blood iron concentrations of subjects in another three groups over time.

Claims (2)

(−)-Epicatechin gallate and (−)-epigallocatechin gallate are combined to contain at least 50% of the total catechin amount, and the blood iron concentration is decreased when the blood iron content is excessive. A prophylactic / therapeutic agent for excess iron-induced liver injury, which has the effect of stabilizing blood iron concentration when blood iron content is no longer excessive. (−)-Epicatechin gallate and (−)-epigallocatechin gallate are combined to contain at least 50% of the total catechin amount, and the blood iron concentration is decreased when the blood iron content is excessive. A prophylactic / therapeutic agent for excess iron-induced liver injury that has an action that does not substantially change the blood hemoglobin concentration and the number of red blood cells.

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