(19)
(11)EP 3 653 219 A1

(12)EUROPEAN PATENT APPLICATION
published in accordance with Art. 153(4) EPC

(43)Date of publication:
20.05.2020 Bulletin 2020/21

(21)Application number: 17872232.8

(22)Date of filing:  08.11.2017
(51)Int. Cl.: 
A61K 36/258  (2006.01)
A61K 36/185  (2006.01)
A61K 36/234  (2006.01)
A61K 36/36  (2006.01)
A61K 36/481  (2006.01)
A61K 36/488  (2006.01)
A61K 36/64  (2006.01)
A61K 36/708  (2006.01)
A61K 36/752  (2006.01)
A61K 36/8945  (2006.01)
A61K 36/076  (2006.01)
A61K 36/233  (2006.01)
A61K 36/284  (2006.01)
A61K 36/40  (2006.01)
A61K 36/482  (2006.01)
A61K 36/537  (2006.01)
A61K 36/704  (2006.01)
A61K 36/734  (2006.01)
A61K 36/815  (2006.01)
(86)International application number:
PCT/JP2017/040244
(87)International publication number:
WO 2018/092654 (24.05.2018 Gazette  2018/21)
(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 18.11.2016 JP 2016224986

(71)Applicant: Nasu, Masanori
Tokyo 141-0021 (JP)

(72)Inventors:
  • LIU, Da Qi
    Beijing City 100062 (CN)
  • NASU, Masanori
    Tokyo 1410021 (JP)

(74)Representative: Schmitz, Joseph 
Isler & Pedrazzini AG Giesshübelstrasse 45 Postfach 1772
8027 Zürich
8027 Zürich (CH)

  


(54)COMPOSITION FOR TREATING FATTY LIVER


(57) A composition for treating fatty liver which comprises extracts of ginseng, Atractylodes rhizome, Crataegus cuneate, Alisma tuber and Cassia obtusifolia L.


Description

[Technical Field]



[0001] The invention relates to a therapeutic composition for treating fatty liver prescribed based on Clinical Traditional Chinese Medicine.

[Background Art]



[0002] In many cases, liver dysfunction that, it is said, one out of four Japanese suffer from, is fatty liver. Fatty liver is one of lifestyle-related diseases, and patients notice it first, in many cases, only when the fatty liver is found in a health examination or comprehensive medical examination because most cases are asymptomatic. Fatty liver may progress to cirrhosis and hepatitis when it is left untreated.

[0003] Treatment of fatty liver includes a dietary therapy, exercise therapy, pharmacological treatment and the like. Though dietary therapy and exercise therapy are important for patients with fatty liver, these therapies require the patients to change their lifestyle and therefore it is quite difficult for the patients to pursue these therapies.

[0004] Ursodeoxycholic acid (referred to as "Urso"), polyenephosphatidylcholine, diisopropylamine dichloroacetate and the like are known as therapeutic drugs for treating fatty liver in Western medicine. Urso is a hepatoprotector for chronic hepatitis and does not actually treat fatty liver. In addition, polyenephosphatidylcholine and diisopropylamine dichloroacetate are used for indirectly improving the condition of fatty liver and not for treating fatty liver itself.

[0005] In Kampo (Japan's assimilated version of Traditional Chinese Medicine (TCM)), there are known prescriptions that treat fatty liver. Frequently used prescriptions include Divaricate Saposhnikovia Miraculous Powder, Major Bupleurum Decoction, and Peach Kemel Purgative Decoction. However, these prescriptions do not have direct therapeutic effects on the fatty liver, it is said that their primary effects are general health-promotion benefits.

[0006] Furthermore, in certain cases, neither pharmacological treatment in conventional Western medicine nor Kampo medicine has significantly improved the condition of fatty liver.

[Summary of Invention]



[0007] An object of the invention is to provide a therapeutic composition (Kampo prescription) which can significantly improve the condition of fatty liver even in cases where there is no improvement by conventional dietary therapy, exercise therapy and/or pharmacological treatment.

[0008] Furthermore, an object of the invention is, by classifying fatty liver into plural types, to provide a therapeutic composition (Kampo prescription) that is more effective for treating each type of fatty liver.

[0009] According to the invention, the following therapeutic compositions for fatty liver are provided.
  1. 1. A therapeutic composition for treating fatty liver comprising the extracts of Ginseng, Atractylodes Rhizome, Crataegus Fruit, Alisma Tuber and Cassia Seed.
  2. 2. The therapeutic composition for treating fatty liver according to 1, further comprising the extracts of Poria Sclerotium, Rhubarb, Citrus Unshiu Peel, Bupleurum Root and Astragalus Root.
  3. 3. The therapeutic composition for treating fatty liver according to 2, wherein the composition is used for treating fatty liver unaccompanied by a disease other than fatty liver.
  4. 4. The therapeutic composition for treating fatty liver according to 1, further comprising the extracts of Salvia Miltiorrhiza Root, Pueraria Root, Polygonum Root, Vaccaria Segetalis and Cnidium Rhizome.
  5. 5. The therapeutic composition for treating fatty liver according to 4, wherein the composition is used for treating fatty liver accompanied by cardiovascular disorder.
  6. 6. The therapeutic composition for treating fatty liver according to 1, further comprising the extract of Eucommia Bark, Lycium Fruit, Cistanche Herb, Dioscorea Rhizome and Comus Fruit.
  7. 7. The therapeutic composition for treating fatty liver according to 6, wherein the composition is used for treating fatty liver accompanied by diabetes mellitus.


[0010] According to the invention, a therapeutic composition (Kampo prescription) for treating fatty liver that can significantly improve the condition of the fatty liver can be provided.

[0011] According to the invention, fatty liver can be classified into plural types, and an effective therapeutic composition (Kampo prescription) can be provided for each type of fatty liver.

[Description of Embodiments]



[0012] A therapeutic composition for treating fatty liver according to the invention (hereinafter, referred to as a composition of the invention) is characterized by comprising the extracts of Ginseng, Atractylodes Rhizome, Crataegus Fruit, Alisma Tuber and Cassia Seed.

[0013] In this description, the term "extract" means an extracted material.

[0014] In Western medicine, fatty livers are regarded as in one category, and often treated alike using a single uniform pharmacological treatment. However, in Kampo medicine, fatty liver is classified into five types, and medical treatment using an optimized prescription is performed for each type.

[0015] To treat fatty liver using the composition of the invention, an optimized prescription is prepared depending on the type of fatty liver, and contains at least five kinds of ingredients mentioned above.

[0016] Among patient groups with fatty liver classified into the five types, the invention mainly provides suitable prescriptions particularly for the following three types of fatty liver.
  1. A. Standard type: A group of patients without any disease or history of any disease other than fatty liver
  2. B. Cardiovascular disorder type: A group of patients with cardiovascular disease or the history of cardiovascular disease other than fatty liver
  3. C. Diabetes mellitus type: A group of patients with diabetes mellitus other than fatty liver


[0017] A therapeutic composition for treating fatty liver according to the invention to treat a standard type of fatty liver (hereinafter, referred to as a composition for a standard type of fatty liver) comprises the extracts of Poria Sclerotium, Rhubarb, Citrus Unshiu Peel, Bupleurum Root, and Astragalus Root, in addition to the five kinds of ingredients mentioned above.

[0018] A therapeutic composition for treating fatty liver according to the invention to treat a cardiovascular disorder type of fatty liver (hereinafter, referred to as a composition for a cardiovascular disorder type of fatty liver) comprises the extracts of Salvia Miltiorrhiza Root, Pueraria Root, Polygonum Root, Vaccaria Segetalis and Cnidium Rhizome in addition to the five kinds of ingredients mentioned above.

[0019] A therapeutic composition for treating fatty liver according to the invention to treat a diabetes mellitus type of fatty liver (hereinafter, referred to as a composition for the diabetes mellitus type of fatty liver) comprises the extracts of Eucommia Bark, Lycium Fruit, Cistanche Herb, Dioscorea Rhizome and Comus Fruit in addition to the five kinds of ingredients mentioned above.

[0020] According to the composition of the invention, the improvement in liver functions was significantly recognized for patients with fatty liver for which improvement was not seen by conventional treatment.

[0021] Specifically, the increase in adiponectin level in the blood, a protein secreted by adipocytes, and the reduction of transaminase level in the blood, which is abundant in the hepatocytes, were confirmed. The details will be explained in Test examples later.

[0022] The compositions of the invention contain various kinds of Kampo crude drugs, and a therapeutic effect for treating fatty liver can be obtained by the synergetic effect of these multiple ingredients. The inventors of the invention formulated the compositions of the invention, namely the combination of Kampo crude drugs, based on their knowledge and experience on Kampo medicine.

[0023] Liu Da Qi, one of the inventors of the invention, devised a Kampo prescription of the invention. Currently, Liu is a leading Chinese scholar in the world's only established operation of a custom-made medicine system by Rokushin/Juchi therapy (composed of six diagnoses and ten treatments) and the classic nutrition study, that is, dietary therapy (prophylaxis and treatment of diseases by a dietary regimen) based on Clinical Traditional Chinese Medicine.

[0024] Also, Masanori Nasu, another inventor of the invention, is an expert in procuring, processing, obtaining extracts, and performing the quality control of Kampo crude drugs. Nasu achieved to produce the compositions of the invention by using Kampo prescriptions formulated by Liu and optimizing them as extracts to be administered to patients.

[0025] The name of each Kampo crude drug used in the scope of patent claims of the application is based on the gloss index of "Kampo Igaku Daijiten 1 Yakubutsu-hen (Kampo Medicine Dictionary 1 pharmacological drug section)" (Edited by People's Medical Publishing House Co. Ltd., published by Yukonsha Co. Ltd.). As can be seen from the following description, the same Kampo crude drug may have plural another names. Therefore, even if a Kampo crude drug used in the invention is written in another name, the Kampo crude drug is the same as the Kampo crude drug used in the invention. The Table shown below summarizes the names of Kampo crude drugs used in the scope of patent claims and another name of them.
[Table 1]
Name of Kampo crude drugAnother name
Ginseng  
Atractylodes Rhizome  
Cragaegus Fruit  
Alisma Tuber  
Cassia Seed  
Poria Sclerotium  
Rhubarb  
Citrus Unshiu Peel  
Bupleurum Root  
Astragalus Root  
Salvia Miltiorrhiza Root  
Pueraria Root  
Polygonum Root  
Vaccaria Segetalis  
Cnidium Rhizome  
Eucommia Bark  
Lycium Fruit  
Cistanche Herb  
Dioscorea Rhizome  
Comus Fruit  


[0026] Hereinafter, Kampo crude drugs used for the composition of the invention will be explained individually on their original plant source, main ingredient, place of harvest, taste and nature, efficacy, effect, clinical application and the like. Efficacy, effect and clinical application are described for each crude drug alone. The efficacy and the like are not for combination of crude drugs.

1. Commonly used ingredients


Ginseng:



[0027] 
  • Original plant source: The root of Panax ginseng in the family Araliaceae
  • Ingredients: More than 13 types of panaxosides (it is also called as ginsenoside), Main ingredient is saponin.
  • Place of harvest: Jilin, Liaoning and the like
  • Nature and taste: Sweet, slightly bitter, warm. Qi enters the spleen/lung meridians.
  • Efficacy: To fortify the deficit of qi and stabilize a prostration state, fortify the lung functions and replenish the spleen. To promote the excretion of saliva or body fluid, to relieve uneasiness of mind and body tranquilization, to activate the cerebral functions
  • Effect: It is able to enhance nonspecific resistance (immune response) of the human body, and modify the predisposition to the onset of diseases, and can restore aberrant conditions to a normal state of health.


[0028] Ginseng used for the composition of the invention is preferably Chinese ginseng (Panax ginseng C.A.Mey.) (referred to as Korean ginseng or Goryeo ginseng) and Kojin (red ginseng) that are thought to have high efficacy.

Atractylodes Rhizome:



[0029] 
  • Original plant source: Root of Atractylodes Ovata DC. in the family Compositae
  • Ingredients: Main ingredients are atractylol, atractylon and the like
  • Place of harvest: Zhejiang, Anhui and the like
  • Nature and taste: Sweet, bitter, warm. Qi enters the spleen/stomach meridians.
  • Efficacy: To fortify the spleen, to replenish qi, to relieve dampness from the body, to disperse phlegm, to regulate water metabolism in the body, to suppress sweating
  • Clinical applications: Treatment for weak spleen and stomach, small appetite and fatigue, dyspepsia, distension, diarrhea, general term of phlegm and fluid. abnormal fluids stagnated in the body, dizziness, edema, jaundice, arthritis with fixed pain caused by dampness, to decrease in urinary volume, oliguria, excessive perspiration and threatened miscarriage.

Crataegus Fruit:



[0030] 
  • Original plant source: Fruit of Crataegus pinnatifida Bge. or Crataegus cuneate Sieb. et Zucc. in the family Rosaceae
  • Ingredients: The fruits of Crataegus pinnatifida contain crategolic acid, tartaric acid, citric acid, malic acid, flavonoid, lactone, glucoside, vitamin C, tannin, bioquercetin, and the like. The fruits of Crataegus cuneate contain crategolic acid, citric acid, malic acid, tannin, saponin, vitamin C, and the like.
  • Place of harvest: Shandong, Hebei, Henan, Jiangsu and the like
  • Nature and taste: Sour/sweet, lukewarm. Qi enters the spleen/stomach/liver meridians.
  • Efficacy: To relieve gastrointestinal undigested substances and promote digestion, to improve the blood stasis. It helps digestion by increasing digestive enzymes in the gastric juice, and slightly decreases the fat levels in the blood.
  • Clinical applications: Treatment for symptoms that food and drink stagnate due to overeating meats, such as heavy stomach, loss of appetite, odorous eructation, nausea, diarrhea with abdominal pain, bacillary dysentery, food and drink don't go down to the stomach smoothly, discomfort and distension, acid regurgitation, jaundice, and hemia/testis swelling and pain; and Treatment of hyperlipemia.

Alisma Tuber:



[0031] 
  • Original plant source: Groundnut of Alisma orientalis (Sam.) Juzep. in the family Alismataceae
  • Ingredients: Triterpenoids such as alisol and acetate ester thereof and the like, essential oil, alkaloids, resin, asparagine, and the like
  • Place of harvest: Fujian, Sichuan, Jiangxi
  • Nature and taste: Sweet, cold. Qi enters the kidney/bladder meridians.
  • Efficacy: to regulate water metabolism in the body, Removal of the body fluid, purge heat, diuresis, anti-fatty liver
  • Clinical applications: Treatment for to decrease in urinary volume, oliguria, edema and bloating with excess of body fluid, beriberi, diarrhea, general term of phlegm and fluid. abnormal fluids stagnated in the body, dizziness, gonorrhea, hematuria, and leukorrhea.

Cassia Seed:



[0032] 
  • Original plant source: Seeds of Cassia obtusifolia L. or Cassia tora L. in the family Leguminosae
  • Ingredients: Anthraquinones such as chrysophanol, emodin-6-methyl ether, obtusifolin, obtusin, aurantio-obtusin, chrysoobtusin, chrysophanic acid-9-anthrone and the like, and carotene
  • Place of harvest: Anhui, Jiangsu, Zhejiang, Guangxi, Guangdong, Sichuan, and the like
  • Nature and taste: Bitter, cool. Qi enters the liver/kidney meridians.
  • Efficacy: To clear the liver-heat and restore the function of the eyes, to moisten intestine and stimulate bowel movements to excrete waste products
  • Clinical applications: Treatment for congestion of the eyes with swelling and pain, tears responding to the bright light (epiphora), glaucoma and cataract, corneal ulcer, cephalalgia attributed to hypertension, dizziness, hepatitis, and habitual constipation.

2. Additional ingredients corresponding to the type of fatty liver


A. Additional Kampo crude drugs for the standard type


Poria Sclerotium:



[0033] 
  • Original plant source: Dried sclerotium of Poria cocos (Schw.) Wolf in the family Polyporaceae
  • Place of harvest: Anhui, Hubei, Henan, Yunnan
  • Ingredients: Triterpene ingredients such as tumulosic acid, pachymic acid, and eburicoic acid, dehydroeburicoic acid, pnicoline acid and the like, β-pachyman, ergosterol, lecithin and the like
  • Nature and taste: Sweet/light, flat (neutral). Qi enters the heart/spleen/kidney meridians.
  • Efficacy: To relieve excessive water from the body, to solve the stomach problem using the drug for spleen, and to ease anxious thought and stabilize psychological conditions.
  • Clinical applications: Treatment for to decrease in urinary volume, oliguria, edema and bloating with excess of body fluid, cough due to abnormal fluids stagnated in the body), lost appetite and abdominal discomfort, diarrhea, dizziness, pulsation, and insomnia.

Rhubarb:



[0034] 
  • Original plant source: Roots or rhizome of Rheum palmatum L., Rheum officinale Baill., or Rheum tangticum Maxim. et Regel in the family Polygonaceae
  • Ingredients: Anthraquinone derivatives such as Sennosides A-F, aloe-emodin, rhein, chrysophanol and the like. Others; phenolic torachrysone, catechol such as catechol tannin, and the like
  • Place of harvest: Gansu, Qinghai, Sichuan
  • Nature and taste: Bitter, cold. Qi enters the stomach/large intestine/liver meridians.
  • Efficacy : To regulate excessive heat and fever, to eliminate waste materials accumulated in the body, and to relieve congestion and hematogenous disorder
  • Clinical applications: Treatment for moisture (body fluid) in the body will be consumed by heat, the inside of the intestines will dry and moisture will cease, so the feces will solidify, making delirious sounds, derangement, indigestion and stagnation, abdominal pain and diarrhea, jaundice due to dampness and fever, dysuria and turbid urine, hematuria, blotch and swelling, congested swollen eye with pain; and Treatment for hematemesis, epistaxis, menopause due to blood stasis, and abdominal mass.

Citrus Unshiu Peel:



[0035] 
  • Original plant source: Ripe peel of Citrus reticulata Blanco in the family Rutaceae or its variants
  • Ingredients: Limonene, hesperidin, neo-hesperidin, tangeretin, citromitin, 5-norcitromitin
  • Place of harvest: Sichuan, Zhejiang, Fujian, and the like
  • Nature and taste: Acrid/bitter, warm. Qi enters the spleen/lung meridians.
  • Efficacy: To tonify qi and restore the functions of qi, to fortify the spleen, to relieve dampness from the body, and to relieve phlegm.
  • Clinical applications: Treatment for stagnation in the spleen and stomach, abdominal fullness and distention, dyspepsia, vomiting, and hiccup; and Treatment for stagnation or clogging of phlegm, discomfort and distention in the chest area and diaphragm, and cough with copious phlegm.

Bupleurum Root:



[0036] 
  • Original plant source: Roots of Bupleurum chinense DC. (Manshumishimasaiko/Hirohamishimasaiko) or Bupleurum scorzonerifolium Willd. and the like in the family Umbelliferae
  • Ingredients: The roots of Bupleurum chinense contain saikosaponins A/C/D, rutin, adonitol, α-spinasterol, essential oil and the like. The roots of Bupleurum scorzonerifolium Willd. contain saponin, adonitol, α-spinasterol, essential oil and the like.
  • Place of harvest: Liaoning, Gansu, Hebei, Henan, Hubei, Jiangsu, Sichuan and the like
  • Nature and taste: Bitter, slight cold. Qi enters the liver/gallbladder meridians.
  • Efficacy : Harmonize the exterior and interior), soothing the liver, and invigorating the vital function of spleen.
  • Clinical applications: Treatment for upper respiratory infections, malaria, fevers and chills, chest stuffiness and hypochondriac pain, hepatitis, biliary tract infections, cholecystitis, irregular menstruation, uterine prolapse, and anal prolapse.

Astragalus Root:



[0037] 
  • Original plant source: Roots of Astragalus membranaceus (Fisch.) Bge. or Astragalus mongholicus Bge. in the family Leguminosae.
  • Ingredients: Choline, glycinebetaine, coumarin, flavonoid compounds, saponin, amino acid, trace amount of folic acid, and the like
  • Place of harvest: Gansu, Inner Mongolia and regions of Northeast China
  • Nature and taste: Sweet, lukewarm. Qi enters the spleen/lung meridians.
  • Efficacy: To tonify the functions of the spleen and stomach using the drug for spleen, to consolidate the superficial resistance, to regulate water metabolism in the body, to promote discharge of pus and toxin, and to promote regeneration of tissue
  • Clinical applications: Treatment for weak spleen and stomach, inappetency, weariness, deficiency of qi (vital energy) and vibrancy, and losing blood, uterine bleeding; metrorrhagia and metrostaxis, leukorrhea, chronic diarrhea, anal prolapse, uterine prolapse, gastroptosis, and nephroptosis; Apply for spontaneous sweating due to exterior deficiency, night sweat; Treatment for edema due to deficiency of qi (vital energy), and chronic nephritis; Treatment for malignant skin boil, that does not erupt for a long time, or not heal for a long time after crushed; and Treatment for peptic ulcer.

B. Additional Kampo crude drugs for the cardiovascular disorder type


Salvia Miltiorrhiza Root:



[0038] 
  • Original plant source: Roots of Salvia miltiorrhiza Bge. in the family Labiatae
  • Ingredients: Tanshinone I/IA/B, cryptotanshinone, hydroxytanshinone IIA, dihydrotanshinone, metacutanshinonate, miltirone, danshexinkumA/B/C, β-sitosterol, 3,4-dihydroxybenzaldehyde, catechin, rutin, vitamin E and the like
  • Place of harvest: Hebei, Anhui, Jiangsu, Sichuan and the like
  • Nature and taste: Bitter, cool. Qi enters the heart/liver meridians.
  • Efficacy: To tonify the blood circulation and relieve congestion, and to stabilize unstable psychological state
  • Clinical applications: Treatment for irregular menstruation, menopause, postpartum poor blood circulation and abdominal pain, coronary heart disease, angina pectoris, mass in abdominal area (tumor), diseases affected on muscles or joints such as rheumatoid arthritis etc. and splenalgia, palpitation, and insomnia.

Pueraria Root:



[0039] 
  • Original plant source: Roots of Pueraria lobata (Willd.) Ohwi in the family Leguminosae
  • Ingredients: It contains flavones such as puerarin, puerarin xyloside, daidzein, daidzin and the like, as well as β-sitosterol, arachidonic acid and the like.
  • Place of harvest: Henan, Hunan, Zhejiang, Sichuan
  • Nature and taste: Sweet/acrid, flat (neutral). Qi enters the spleen/stomach meridians.
  • Efficacy: to relieve muscles to expel heat, to promote eruption, to promote the excretion of saliva or body fluid, and to stop diarrhea
  • Clinical applications: Treatment for cold and onset of fever, headache, muscle stiffness in the back neck with symptoms of difficulty of moving the neck, treatment used for malfunction due to measles in the early phase, febrile illness with thirst, diarrhea, dysentery; and Treatment for neck pain and angina pectoris that are attributed to hypertension.

Polygonum Root:



[0040] 
  • Original plant source: Groundnut root of Polygonum multiflorum Thunb. in the family Polygonaceae
  • Ingredients: Chrysophanol, emodin, rhein, physcion, chrysophanic acid anthrone, lecithin and the like
  • Place of harvest: Henan, Hubei, Guizhou, Sichuan, Jiangsu, Guangxi and the like
  • Nature and taste: Bitter/sweet, astringent, lukewarm. Qi enters the liver/kidney meridians.
  • Efficacy: to tonify liver and kidney, to nourish the blood and arrest seminal emission; Treatment for blood deficiency, dizziness, tinnitus, agrypnia, gray hair in young age, weak waist and knee, paralysis of four extremities, pain of joints, wet dream, spermatorrhoea, uterine bleeding; metrorrhagia and metrostaxis, leukorrhea, lingering dysentery, hypertension, chronic hepatitis, pruritus in skin, to moisten intestine and stimulate bowel movements to excrete waste products, detoxification, ague, malaria, constipation due to intestinal dryness, scrofula, struma, and chronic malaria.

Vaccaria Segetalis



[0041] 
  • Original plant source: Seeds of Vaccaria Segetalis (Neck.) Garcke in the family Caryophyllaceae
  • Ingredients: vacsegoside, vaccarin and the like
  • Place of harvest: Hebei, Shandong, Liaoning
  • Nature and taste: Bitter, flat (neutral). Qi enters the liver/stomach meridians.
  • Efficacy: To improve the blood circulation and induce or increase menstruation, and to detumescence by lactogenesis
  • Clinical applications: Treatment for menopause, galactostasis, mastitis, orchitis, and furunculosis; deep-rooted boil, malignant boil.

Cnidium Rhizome:



[0042] 
  • Original plant source: Rhizome of Ligusticum chuanxiong Hort in the family Umbelliferae
  • Ingredients: Essential oil, alkaloids, butylphthalide, sedanonic acid lactone, ferulic acid, phenylacetic acid methacrylate and the like
  • Place of harvest: Sichuan
  • Nature and taste: Acrid, warm. Qi enters the liver/liver/pericardium meridians.
  • Efficacy: To improve the circulation of blood and qi (vital energy), and to improve heat (hot/cold) and moisture (damp/dry), and release the pain
  • Clinical applications: Treatment for irregular menstruation, postpartum poor blood circulation and abdominal pain, algomenorrhea, menopause, distension and pain in the chest area, coronary heart disease, angina pectoris; and Treatment for cold with chill, migraine and general headache, pain or numbness of joints and muscles by cold, swelling and ulcer on the body surface, and bruise.

C. Additional Kampo crude drugs for the diabetes mellitus type


Eucommia Bark



[0043] 
  • Original plant source: Bark of Eucommia ulmoides Oliv. in the family Eucommiaceae
  • Ingredients: Gutta-percha, pinoresinol diglucoside, eucommiol, ajugoside, harpagide and the like
  • Place of harvest: Sichuan, Shaanxi, Hubei, Henan, Guizhou, Yunnan
  • Nature and taste: Sweet/slightly acrid, warm. Qi enters the liver/kidney meridans.
  • Efficacy: To tonify liver and kidney, to fortify muscle and bone, miscarriage prevention, and lowering blood pressure
  • Clinical applications: Treatment for pain of waist and knee, limp wilting muscle and bone, impotence, frequent urination, a warning sign of miscarriage, and hypertension.

Lycium Fruit



[0044] 
  • Original plant source: Fruit of Lycium barbarum L. or Lycium chinense Mill. in the family Solanaceae
  • Ingredients: Betaine, physalien and the like
  • Place of harvest: Ningxia, Gansu, Hebei and the like
  • Nature and taste: Sweet, flat (neutral). Qi enters the liver/kidney meridians.
  • Efficacy: To tonify kidney and replenish essence of life, and to nourish the liver to improve visual acuity
  • Clinical applications: Treatment for deficiency of blood and body fluid in the liver and kidney, dulness and aching of waist and knee, dizziness, visual loss, and frequent drinking and urination, and spermatorrhea

Cistanche Herb:



[0045] 
  • Original plant source: Scale-like pulpy substance of Cistanche deserticola Y. C. Ma in the family Orobanchaceae
  • Ingredients: Alkaloids, crystalline neutral material and the like
  • Place of harvest: Inner Mongolia and the like
  • Nature and taste: Sweet/salty, warm. Qi enters the kidney/large intestine meridians.
  • Efficacy: To tonify the function of the kidney, to boost essence blood, and to moisten intestine and stimulate bowel movements to excrete waste products
  • Clinical applications: Treatment for premature ejaculation, spermatorrhea, infertility, enuresis, dulness and aching of waist and knee, limp wilting muscle and bone, and constipation due to exhaustion of blood.

Dioscorea Rhizome



[0046] 
  • Original plant source: Rhizome of Dioscorea batatas Decne. in the family Dioscoreaceae
  • Ingredients: Dopamine, abscisin II, choline, tannin and a variety of amino acids and the like
  • Place of harvest: Henan, Shanxi, Hebei, Shaanxi and the like
  • Nature and taste: Sweet, flat (neutral). Qi enters the spleen/lung/kidney meridians.
  • Efficacy: To tonify spleen and stomach, to fortify lung and kidney), and to fortify weak constitution.
  • Clinical applications : Treatment for deficiency of the functions of spleen, and severe diarrhea, coughing due to deficiency of body liquid in the lung, frequent drinking and urination, urinary frequency, spermatorrhea, emaciation due to deficiency of the functions of the five internal organs, small appetite and fatigue, chronic nephritis, child enuresis, and leukorrhea.

Comus Fruit:



[0047] 
  • Original plant source: Fruits of Comus officinalis Sieb. et Zucc. in the family Comaceae
  • Ingredients: Morroniside, 7-methyl-morroniside, sweroside, loganin, comin, ursolic acid, gallic acid, malic acid, tartaric acid, tannin, saponin, and the like
  • Place of harvest: Zhejiang, Henan, Anhui, Shaanxi, Shanxi, Shandong, Sichuan, and the like
  • Nature and taste: Sour, lukewarm. Qi enters the liver/kidney meridians.
  • Efficacy: To tonify kidney and liver, and to arrest seminal emission and sweating.
  • Clinical applications: dizzy, dizziness, tinnitus, dulness and aching of waist and knee, spermatorrhea and lingering diarrhea, enuresis, senile frequent urination and incontinence, persistent abnormal sweating due to general debility, hypermenorrhea, and persistent metrostaxis.


[0048] Next, a method for producing the compositions of the invention will be explained.

[0049] Specifically, the compositions of the invention are mixtures of extracts from the Kampo crude drugs mentioned above.

[0050] Each crude drug is processed to a size suitable for extraction and mixed at a predetermined ratio. Subsequently, the mixture is extracted to obtain the desired extract.

[0051] The extract of the Kampo crude drug used in the invention is the one extracted with water.

[0052] In the process of the extraction of the crude drug extracts, it is preferable to use a bag to bundle up the mixed crude drugs in one for an efficient extraction process. It is necessary that the bag does not disturb the extraction process, and that it has robust strength so that it is not torn out even if it is squeezed with strong power.

[0053] A preferable bag material is, for example, one used as "Medical supply 04, Formed article, General medical device, Medical gauze, Type 1 (100% cotton, 30 cm in width × 10 m in length)".

[0054] A rectangular bag is made in an appropriate size (e.g., 18 cm in width × 25 cm in height) by processing the bag materials mentioned above. In the process of squeezing a crude drug, strong pressure is applied to the bag used for the extraction. Therefore, it is desirable to make the above-mentioned bag material (gauze) in three layers so that the bag is not ripped.

[0055] In addition, similar bag material is desirable to prepare a three-layered string in a suitable size (e.g., 1.5 cm in width × 60 cm in length), which ties up the mouth (upper part) of the bag.

[0056] For the extraction process of the extract, it is preferable to soak the crude drug for 12 hours in water from which a chlorine component was removed beforehand. Next, the mixture is heated and kept in a boiling state until a crude drug ingredient is sufficiently extracted. As for the duration of the boiling state, it is usually 5 to 10 hours, and may be adjusted as appropriate.

[0057] The blending ratio of each crude drug extract in the composition of the invention should be appropriately adjusted depending on the quality and the like of available crude drugs. As for essential crude drugs, for example, the weight ratio of each crude drug to be mixed is within the following ranges.
Name of crude drugRange of weight ratio
Ginseng 1 to 10, preferably 3 to 8
Atractylodes Rhizome 5 to 20, preferably 8 to 15
Crataegus Fruit 10 to 40, preferably 15 to 40
Alisma Tuber 10 to 30, preferably 15 to 30
Cassia Seed 5 to 20, preferably 8 to 20


[0058] For a blending ratio of each crude drug extract to be added in the case of the standard-type fatty liver, for example, the weight ratio of each crude drug to be mixed is within the following ranges.
Name of crude drugRanqe of weight ratio
Poria Sclerotium 5 to 20, preferably 8 to 20
Rhubarb 1 to 10, preferably 2 to 5
Citrus Unshiu Peel 5 to 20, preferably 5 to 15
Bupleurum Root 1 to 10, preferably 3 to 8
Astragalus Root 10 to 30, preferably 15 to 30


[0059] For a blending ratio of each crude drug extract to be added in the case of the cardiovascular disorder type fatty liver, for example, the weight ratio of each crude drug to be mixed is within the following ranges.
Name of crude drugRanqe of weight ratio
Salvia Miltiorrhiza Root 10 to 30, preferably 15 to 30
Pueraria Root 5 to 20, preferably 8 to 20
Polygonum Root 5 to 20, preferably 8 to 20
Vaccaria Segetalis 5 to 20, preferably 8 to 20
Cnidium Rhizome 5 to 20, preferably 8 to 20


[0060] For a blending ratio of each crude drug extract to be added in the case of the diabetic mellitus type of fatty liver, for example, the weight ratio of each crude drug to be mixed is within the following ranges.
Name of crude drugRanqe of weight ratio
Eucommia Bark 10 to 30, preferably 15 to 30
Lycium Fruit 5 to 20, preferably 8 to 20
Cistanche Herb 5 to 20, preferably 8 to20
Dioscorea Rhizome 10 to 30, preferably 10 to 25
Comus Fruit 10 to 30, preferably 10 to 25


[0061] Additives that are commonly used in pharmaceutical products including Kampo medicines may be added to the composition of the invention in a range (types and quantities) not affecting the treatment of fatty liver.

[0062] For example, the additives that may be optionally added include a sweetener to adjust the taste of the composition of the invention. Specifically, natural sweeteners such as honey, brown sugar, sugar beet and the like are included. However, in the case of the diabetes mellitus type of fatty liver, the addition of sugars mentioned above is not permitted.

[0063] The blending amount of any additives mentioned above may be acceptable in an amount not affecting the therapeutic effect of fatty liver. For example, it is preferable to be in 5 to 10 parts by weight per 100 parts by weight as the predetermined total amount of crude drug extract mentioned above.

[0064] The dosage form of the composition of the invention is not limited in particular as long as it is in a form for oral administration. The dosage form is basically a liquid formulation, and it may be transformed into powder or granules by means such as freeze-drying, or may be in the form of tablets or capsules.

[0065] The dosage when the composition of the invention is given orally as a liquid formulation is not limited in particular, and is usually about 200 mL a day. The daily frequency of dose is not limited in particular, and it is desirable to be administered, for example, twice a day, before breakfast and before bedtime, and in both cases administration should be conducted during the fasting state.

[0066] In addition, it is preferable to avoid a diet for about 30 minutes after the administration.

[0067] The administration period will be continued until the improvement of the fatty liver can be recognized. According to the following study, a significant improvement was seen after an administration for about three months.

[Examples]



[0068] The invention will be explained more specifically by showing test examples in which the composition of the invention was manufactured and the improvement of the status of the fatty liver was confirmed for the composition actually administered to patients.

[0069] For the extraction of crude drug extracts, an "extraction machine HRS-705" made by SHOWATSUSHO Co., Ltd., an Kampo drug extraction machine, which has an overwhelming domestic market share in Japan, was used.

Example A: Preparation of an extract for type A (standard type)



[0070] In the preparation of the extract, the following two extraction processes and one concentration process were conducted using the extraction machine mentioned above.

[0071] In the first "crude drug extract extraction process", crude drugs of the composition for type A as shown in the following Table 2 were mixed at a predetermined ratio, and the total of 120 g of crude drug mixtures is placed in a bag (18 cm in width × 25 cm in height made with three-layered gauze). After immersing two of the bag (120 g × 2) into 5,000 mL of water for 12 hours, the mixture was charged into the crude drug extraction machine, and the extraction operation time on the thermoswitch was set for 180 minutes (three hours).

[0072] When the temperature inside the tank reaches 92°C, the crude drug extraction machine was set so that the thermoswitch indicating the extraction time was automatically turned on and started to operate. In addition, it takes about 80 seconds to raise the temperature inside the tank by 1°C. Since the temperature of the mixed water was 12°C, it took about 106 minutes until the temperature reached 92°C and the thermoswitch started to operate. The temperature inside the tank rose up to a maximum temperature of 106°C after the thermoswitch was operated.

[0073] Thus, for the extraction time of the first crude drug extract, it took 106 minutes to prepare the operation of the machine, then 180 minutes for extracting the crude drug extract, and a total of 286 minutes (four hours 46 minutes).

[0074] At the point when the switch of the crude drug extraction machine was turned OFF, 3,000 mL of the extract liquid was taken out of the tank. At that time, the bag of the mixed crude drugs and extract residual liquid was left in the tank of the extraction machine.

[0075] By the first extraction, the amount of vapor released to the outside of the tank was about 1,200 mL.

[0076] For the second "extraction of the crude drugs", 3,000 mL of water was newly poured into the tank and the thermoswitch was set at 120 minutes.

[0077] Since the temperature in the tank was 55°C when the second extraction was initiated, it took about 50 minutes to prepare the operation of the machine until the thermoswitch was turned ON, then 120 minutes for extracting the crude drug extract, and a total of 170 minutes (2 hours 50 minutes).

[0078] All the extract liquid was taken out of the tank when the thermoswitch mentioned above was turned OFF, then the bag of crude drugs was taken out and squeezed, and the extract liquid squeezed was added to the second extract liquid.

[0079] By the second extraction, the amount of vapor released out of the tank was about 800 mL, and the mixed crude drug residue including the moisture after squeezing was about 600 g. Therefore, the extraction amount obtained by the second extraction was about 2,400 mL.

[0080]  In the concentration process, a total of 5,400 mL of the crude drug extract liquid obtained by the first and second extractions was re-charged into the extraction machine. Subsequently, the thermoswitch was set to 90 minutes, and the extract liquid was concentrated.

[0081] Since about 600 mL of vapor was released in the concentration process, about 4,800 mL of crude drug extract liquid was finally obtained.

[0082] This crude drug extract liquid was filled in an aluminum pack for each 100 mL. The aluminum pack filled with the crude drug extract was subjected to heat sterilization for 40 minute at 100°C by steam convection process.

Example B: Preparation of an extract for Type B (hypertension complication type)



[0083] The preparation was conducted in a similar way to Example A except that the crude drugs shown in the following Table 2 were used at the weight indicated in Table 2, respectively, to obtain about 4,800 mL of the extract for Type B.

Example C: Preparation of an extract for Type C (diabetes mellitus complication type)



[0084] The preparation was conducted in a similar way to Example A except that the crude drugs shown in the following Table 2 were used at the weight indicated in Table 2, respectively, to obtain about 4,700 mL of the extract for Type C.
[Table 2]
Name of crude drugExtract for Type AExtract for Type BExtract for Type C
Ginseng 5 5 5
Atractylodes Rhizome 10 10 10
Cragaegus Fruit 30 20 30
Alisma Tuber 20 20 20
Cassia Seed 10 10 10
Poria Sclerotium 10 - -
Rhubarb 3 - -
Citrus Unshiu Peel 7 - -
Bupleurum Root 5 - -
Astragalus Root 20 - -
Salvia Miltiorrhiza Root - 20 -
Pueraria Root - 10 -
Polygonum Root - 10 -
Vaccaria Segetalis - 10 -
Cnidium Rhizome - 10 -
Eucommia Bark - - 20
Lycium Fruit - - 10
Cistanche Herb - - 10
Dioscorea Rhizome - - 15
Comus Fruit - - 15
Total amount 120 g 125 g 145 g

Test example



[0085] In the following study, the classification of the type of subjects, laboratory data and clinical findings were provided by Professor Takeshi Kurihara, M.D. at Tokyo Women's Medical University.

Subjects



[0086] Fifteen patients who had fatty liver based on diagnosis by abdominal ultrasonography, and the values of either AST (aspartate aminotransferase) or ALT (alanine aminotransferase) exceeding their reference values of 20 IU/L, were selected as subjects. None of them had shown therapeutic effects after dietary therapy and exercise therapy.

[0087] Fifteen patients were classified into the following three types in consideration of the five kinds of classification based on Clinical Chinese Traditional Medicine and from the viewpoint of Western medicine.

Type A: Patients who shows only fatty liver (3 cases)

Type B: Patients complicated by hypertension (7 cases) (patients who are administered an antihypertensive agent, and show 140 mmHg or more of systolic blood pressure or 90 mmHg or more of diastolic blood pressure (based on the guideline of the Japanese Society of Hypertension 2004 version))

Type C: Patients complicated by diabetes mellitus (7 cases) (patients who show 126 mg/dL or more of fasting blood glucose levels or 200 mg/dL or more of casual blood glucose levels (based on the guideline of the Japan Diabetes Society 2006 through 2007))


Administration method



[0088] An extract for each type produced in Examples A to C mentioned above was orally administered twice daily (morning and evening) for three months. In addition, in case where the administration twice daily was impossible, the drink was administered once daily instead.

[0089] The administration period was set for three months from the beginning of dosage.

[0090] During the administration period, subjects were not given any special dietary instructions, alcohol drinking regulation nor exercise therapy, but left on a voluntary basis.

Follow-up



[0091] Before starting the test and every month during the test, a hematological examination was carried out over time, and significant difference was tested with a statistical analysis. Results from the analysis was shown in the following Table 3 for Type A subjects of, the following Table 4-1 and 4-2 for Type B subjects, and the following Tables 5-1 and 5-2 for Type C subjects.
[Table 3]
SubjectsS.MI.WM.H
GenderMFM
Age692460
Examination datePreAfter 1m.After 2m.After 3m.PreAfter 1m.After 2m.After 3m.PreAfter 1m.After 2m.After 3m.
Body weight 63 62.2 60.3 59.9 90.3 87.5 87.1 87.3 62.4 61.8 61.3 60.5
Systolic blood pressure 122 118 122 120 122 116 120 122 128 120 134 126
Diastolic blood 76 72 70 78 72 70 70 70 78 82 80 76
Total protein 7.8 7.8 7.7 7.8 7.7 8.2 8 7.9 7.6 7.9 7.7 7.9
Albumin 4.5 4.6 4.4 4.6 4.5 4.7 4.7 4.7 4.4 4.5 4.5 4.6
AST 39 38 34 29 50 43 40 39 52 29 38 30
ALT 67 64 48 40 117 91 88 82 46 28 34 27
yGTP 115 127 122 108 66 56 54 49 223 220 289 337
Blood glucose 100 99 101 93 87 77 86 73 106 105 102 101
HbAlc 5.6 5.5 5.5 5.7 4.9 5 4.5 4.5 5 5 4.9 5.1
T-Cho 157 160 156 153 172 152 144 157 193 212 207 189
HDL-C 32 34 33 32 62 51 53 63 54 56 52 50
LDL-C 111 117 115 109 108 100 94 103 66 87 78 70
TG 189 156 191 177 95 157 63 90 441 500 478 398
Adiponectin 9.1 - - 11.6 3.7 - - 6.5 3.7 - - 5.8
CT visceral 107.7 - - - 95.6 - - - - - - -
subcutaneous 110.8 - - - 100.8 - - - - - - -
Waist 82.4 - - - 79.4 - - - - - - -
Findings Diarrhea symptoms started at week 2 after initiaing the test, discontinued medication temporary at week 3, later started the administration once a day at week 5. No symptoms of diarrhea was recognized. The improvement of liver functions and the body weight loss and reduction of visceral fat were also confirmed in CT. The improvement of liver functions was remarkable compared to the body weight loss. The body weight decreased, and liver functions tended to improve.
[Table 4-1]
SubjectsF.KO.TA.H
GenderMMF
Age395562
Examination datePreAfter 1m.After 2m.After 3m.PreAfter 1m.After 2m.After 3m.PreAfter 1m.After 2m.After 3m.
Body weight 103.8 104.4 103.7 104.9 84.5 81.4 81.3 80.5 83.8 83.9 84.2 84.8
Systolic blood 152 150 136 142 135 118 114 124 168 146 142 142
Diastolic blood 100 100 100 96 100 82 80 84 100 94 90 90
Total protein 7.9 8.2 7.9 8 6.9 7.1 7.2 7.1 7.9 8 7.9 8.1
Albumin 4.9 5.1 4.8 5 4.4 4.6 4.7 4.6 4.9 5.1 5 5.1
AST 42 34 37 31 39 21 19 21 38 32 22 24
ALT 87 80 77 69 48 23 25 19 46 33 25 26
yGTP 68 61 68 63 107 64 67 67 53 47 43 45
Blood glucose 125 138 169 186 107 100 128 100 110 75 93 98
HbAlc 6.7 6.5 6.8 6.9 5.4 5.4 4.8 5.4 5.4 5.5 5.7 5.7
T-Cho 285 244 250 233 165 190 168 233 233 246 234 243
HDL-C 61 53 62 59 51 45 49 44 52 52 60 57
LDL-C 190 167 161 158 99 119 108 152 162 160 165 178
TG 267 234 212 154 241 166 69 267 261 294 179 202
Adiponectin 5.7 - - 6.9 7.8 - - 11.7 4.8 - - 7.1
CT visceral 248.8 - - - - - - - - - - -
subcutaneous 298.5 - - - - - - - - - - -
Waist 111.7 - - - - - - - - - - -
Findings The liver functions showed a tendency to improve although the body weight tended to increase and the blood glucose level increased due to overeating. The blood pressure also tended to decline. T he body weight decreased sharply. In the second half of medication, triglyceride and cholesterol increased due to overeating tendency, but ALT declined. The blood pressure also declined. The liver functions improved, although the body weight tended to increase and HbA1c also aggravated. The blood pressure also tended to decrease.
[Table 4-2]
SubjectsY.MA.NS.T
GenderMMM
Age675566
Examination datePreAfter 1m.After 2m.After 3m.PreAfter 1m.After 2m.After 3m.PreAfter 1m.After 2m.After 3m.
Body weight 74.8 74.1 73.9 74.7 97.4 97.7 98.2 97.6 74 74.6 74.1 73.7
Systolic blood 178 146 142 146 158 134 124 126 146 132 130 138
Diastolic blood 108 94 86 84 96 84 82 86 88 84 82 84
Total protein 8.2 8.3 8.3 8.3 7.7 8 7.6 7.7 6.9 6.9 7.1 6.6
Albumin 4.4 4.4 4.3 4.4 4.4 4.4 4.4 4.4 4.4 4.4 4.4 4.2
AST 70 65 60 56 46 28 23 26 48 39 43 43
ALT 46 35 32 32 55 51 37 44 47 32 41 37
yGTP 288 249 207 203 86 83 78 90 255 281 288 243
Blood glucose 103 103 105 99 102 112 106 102 125 115 112 97
HbAlc 5.9 5.6 6 5.9 5.6 5.5 5.5 5.5 4.8 4.7 4.7 4.7
T-Cho 271 261 303 256 204 206 213 208 156 158 168 149
HDL-C 115 103 124 98 43 43 45 42 40 45 38 42
LDL-C 140 143 153 134 133 120 120 117 67 66 66 59
TG 84 119 91 75 339 204 246 311 416 335 535 394
Adiponectin 10.4 - - 12.3 2.2 - - 3.2 5.9 - - 6.6
CT visceral - - - - - - - - - - - -
subcutaneous - - - - - - - - - - - -
Waist - - - - - - - - - - - -
Findings Although the body weight was unchanged, and the lipid level fluctuated, the function of the liver tended to improve mildly. The blood pressure was improved. Increase or decrease in the body weight was not observed, but the function of the liver tended to improve. In the second half of the medication, the amount of alcohol drinking increased, and γ GTP, TG levels were elevated. However, the blood pressure decreased. Increase or decrease in the body weight was not observed, and the laboratory data was slightly improved, but it was almost invariable.
[Table 5-1]
SubjectsS.MN.FW.T
GenderMFM
Age613948
Examination datePreAfter 1m.After 2m.After 3m.PreAfter 1m.After 2m.After 3m.PreAfter 1m.After 2m.After 3m.
Body weight 65.1 64.5 64.1 63.2 78.9 80.6 81.3 81 123.1 122.9 121.7 119.8
Systolic blood pressure 130 120 124 128 124 118 118 128 136 132 140 136
Diastolic blood pressure 80 80 82 84 92 90 82 86 98 92 88 94
Total protein 7.2 7.6 7 7.3 7.8 8.1 7.8 7.9 7.4 7.3 7.4 7
Albumin 4.7 5.1 4.6 4.6 4.5 4.7 4.6 4.6 4.7 4.6 4.7 4.3
AST 21 19 13 15 112 78 68 72 86 49 48 42
ALT 19 11 8 11 147 129 112 119 82 53 50 47
yGTP 81 70 64 68 76 70 63 68 152 141 139 129
Blood glucose 195 107 182 222 181 141 149 158 139 130 132 140
HbAlc 8.9 8.6 8.9 9.3 6.4 6.2 6.3 6.1 7 6.9 6.8 6.6
T-Cho 165 178 135 163 250 313 248 239 221 204 219 200
HDL-C 95 57 64 62 65 59 65 62 72 60 71 70
LDL-C 93 98 69 97 163 200 174 181 150 127 142 118
TG 95 158 119 72 174 279 175 193 214 226 209 254
Adiponectin 2.6 - - 3.9 3.9 - - 5.3 2.9 - - 5.1
Leptin - - - - - - - - - - - -
CT visceral 100.1 - - 95.8 - - - - - - - -
subcutaneous 91.3 - - 93.5 - - - - - - - -
Waist 81.3 - - 80.1 - - - - - - - -
Findings The liver functions showed an improving tendency. CT showed a decrease of visceral fat. Despite the body weight gain, the liver functions and the blood glucose level were improved. Both the liver functions and the blood glucose level improved along with the body weight loss.
[Table 5-2]
SubjectsS.MN.FW.T
GenderMFM
Aqe613948
Examination datePreAfter 1m.After 2m.After 3m.PreAfter 1After 2m.After 3m.PreAfter 1 m.After 2m.After 3m.
Body weight 65.1 64.5 64.1 63.2 78.9 80.6 81.3 81 123.1 122.9 121.7 119.8
Systolic blood pressure 130 120 124 128 124 118 118 128 136 132 140 136
Diastolic blood pressure 80 80 82 84 92 90 82 86 98 92 88 94
Total protein 7.2 7.6 7 7.3 7.8 8.1 7.8 7.9 7.4 7.3 7.4 7
Albumin 4.7 5.1 4.6 4.6 4.5 4.7 4.6 4.6 4.7 4.6 4.7 4.3
AST 21 19 13 15 112 78 68 72 86 49 48 42
ALT 19 11 8 11 147 129 112 119 82 53 50 47
γGTP 81 70 64 68 76 70 63 68 152 141 139 129
Blood glucose 195 107 182 222 181 141 149 158 139 130 132 140
HbAlc 8.9 8.6 8.9 9.3 6.4 6.2 6.3 6.1 7 6.9 6.8 6.6
T-Cho 165 178 135 163 250 313 248 239 221 204 219 200
HDL-C 95 57 64 62 65 59 65 62 72 60 71 70
LDL-C 93 98 69 97 163 200 174 181 150 127 142 118
TG 95 158 119 72 174 279 175 193 214 226 209 254
Adiponectin 2.6 - - 3.9 3.9 - - 5.3 2.9 - - 5.1
Leptin - - - - - - - - - - - -
CT visceral 100.1 - - 95.8 - - - - - - - -
subcutaneous 91.3 - - 93.5 - - - - - - - -
Waist 81.3 - - 80.1 - - - - - - - -
Findings The liver functions showed an improving tendency. CT showed a decrease of visceral fat. Despite the body weight gain, the liver functions and the blood glucose level were improved. Both the liver functions and the blood glucose level improved along with the body weight loss.


[0092] For the examination items in the Tables mentioned above were determined using the conventional laboratory procedure that has been clinically used. The units of each measurement value are described in the parentheses.

Total protein: total protein amount (g/dL) in the blood

Albumin: albumin amount (g/dL) in the blood

AST: aspartate aminotransferase (U/L)

ALT: alanine aminotransferase (U/L)

γGTP: γ-glutamyl transpeptidase (U/L)

HbA1c: glycohemoglobin A1c (%)

T-Cho: total cholesterol (mg/dL)

HDL-C: high-density cholesterol (mg/dL)

LDL-C: low-density cholesterol (mg/dL)

TG: triglyceride (mg/dL)

CT visceral: area of visceral fat (cm2) measured by using computed tomography (CT)

Subcutaneous: area of subcutaneous fat (cm2) measured by using computed tomography (CT)

Waist: waist circumference (cm)


Discussions



[0093] In all the subjects, the AST level (P = 0.011) and the maximum blood pressure (P = 0.025) were significantly decreased three months after the administration of the extract compared to the levels before the administration.

[0094] In addition, a tendency to decrease was found in the ALT level (P = 0.066), and the adiponectin level (0.063) showed a tendency to increase.

[0095] Any particular changes in the measured values except the above results were not recognized, and no value became exacerbated.

[0096] In two subjects, the area of the visceral fat in the umbilical part was measured by CT. Subsequent observation of their outcome revealed that the area of the visceral fat decreased in both cases.

[0097] It was thought that the decrease of AST and ALT was a result of the decline of the extent of fatty deposition in the liver. In addition, the presentation of a rising trend in the adiponectin level, a marker of metabolic syndrome, indicates a decrease in visceral fat. In other words, it is expected that adiponectin, beneficial adipocytokine, produced in visceral fat cells increases, and the activation of glycometabolism and the suppression of obesity occur.

[0098] Obesity was examined by measuring the body weight, but no change in the body weight was observed. Even though no changes in the body weight were observed, the decline of fat deposits in the liver demonstrates most clearly that the extract used in the invention is useful for treating fatty liver.

[0099] When each case was individually examined (referred as Tables), in many subjects, the body weight, or HbA1c, TG (triglyceride) was elevated, however, the decrease of AST and ALT was recognized.

[0100] In addition, although the test was carried out under severe conditions in which all the restrictions such as diet, alcohol drinking, exercise therapy, and the like by the subjects were on a voluntary basis, the improvement effect on fatty liver or liver functions was recognized. Through such an objective fact, it can be said that the composition of the invention has an extremely advantageous effect compared to medicines currently prescribed.

[Industrial applicability]



[0101] The composition of the invention (extract) is very useful for the treatment of fatty liver.

[0102] The composition of the invention (extract) is very useful for the treatment of fatty liver that is not improved by dietary therapy, exercise therapy, medical treatment by Western medicine.

[0103] The composition of the invention (extract) is expected to show a tremendous therapeutic effect if it is used in conjunction with diet therapy and/or exercise therapy.

[0104] Some embodiments and/or Examples of the invention were explained in details above. For those skilled in the art, it is easy to add many modifications to the embodiments and/or Examples, which are only for exemplification, substantially not apart from the new teach and effects of the invention. Therefore, these many modifications are included within the scope of the invention.

[0105] The entire content of the references cited in the description and the description of the Japanese Patent Application that serves as the basis for the right of priority provided for in the Paris Convention is incorporated herein by reference.


Claims

1. A therapeutic composition for treating fatty liver comprising an extract of Ginseng, Atractylodes Rhizome, Crataegus Fruit, Alisma Tuber and Cassia Seed.
 
2. The therapeutic composition for treating fatty liver according to claim 1, further comprising an extract of Poria Sclerotium, Rhubarb, Citrus Unshiu Peel, Bupleurum Root and Astragalus Root.
 
3. The therapeutic composition for treating fatty liver according to claim 2, wherein the composition is used for treating fatty liver unaccompanied by a disease other than fatty liver.
 
4. The therapeutic composition for treating fatty liver according to claim 1, further comprising an extract of Salvia Multiorrhiza Root, Pueraria Root, Polygonum Root, Vaccaria Segetalis and Cnidium Rhizome.
 
5. The therapeutic composition for treating fatty liver according to claim 4, wherein the composition is used for treating fatty liver accompanied by cardiovascular disorder.
 
6. The therapeutic composition for treating fatty liver according to claim 1, further comprising an extract of Eucommia Bark, Lycium Fruit, Cistanche Herb, Dioscorea Rhizome and Comus Fruit.
 
7. The therapeutic composition for treating fatty liver according to claim 6, wherein the composition is used for treating fatty liver accompanied by diabetes mellitus.
 














REFERENCES CITED IN THE DESCRIPTION



This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Non-patent literature cited in the description