CN108785314A - Drug and combinations thereof for treating and preventing alcoholic liver disease - Google Patents
Drug and combinations thereof for treating and preventing alcoholic liver disease Download PDFInfo
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- CN108785314A CN108785314A CN201710303185.7A CN201710303185A CN108785314A CN 108785314 A CN108785314 A CN 108785314A CN 201710303185 A CN201710303185 A CN 201710303185A CN 108785314 A CN108785314 A CN 108785314A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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Abstract
The invention discloses the pharmaceutical composition of Kaempferol, cupreol and/or Tanshinone I composition and its preparing the application in preventing and treating alcoholic liver medicine.Pharmaceutical composition includes Kaempferol（3-55%）, cupreol（10-60%）And Tanshinone I（20-80%）；The drug that can be used alone includes Kaempferol（0.5-70%）, cupreol（0.03-70%）Or Tanshinone I（1.5-99%）.By implementing Alcoholic Hepatic Injury model, the therapeutic effect of Kaempferol, cupreol, Tanshinone I and its pharmaceutical composition to alcoholic liver disease is confirmed respectively.Said medicine and composition can effectively mitigate hepatic disease；It is embodied in liver enlargement and Gain weight significantly reduces, serum aminotransferase activity is significantly lowered；Content of triglyceride is substantially reduced in liver；Fat aggregation, inflammatory infiltration degree significantly improve in tissue.Said medicine can prevent and treat alcoholic liver disease；It can combine or independent patent medicine, and for developing relative medicine and health products.
Description
Technical field
The invention belongs to field of medicaments.More particularly, to Kaempferol, cupreol and Tanshinone I and its arbitrary drug
Application of the composition in preparing prevention and treatment alcoholic liver medicine and health products.
Background technology
Alcoholic liver disease (Alcoholic liver disease, ALD) is the liver damage caused by long-term heavy drinking
Evil, including alcoholic fatty liver (Alcoholic fatty liver, AFL), alcoholic hepatitis (Alcoholic
Hepatitis, AH), alcoholic fibrosis (Alcoholic Fibrosis, AF) and alcoholic cirrhosis (Alcoholic
cirrhosis,AC)；Three is often mixed.Clinically, 80%~90% hepatic sclerosis cause of disease is caused by drinking.The U.S.
There are more than 20,000 people to die of alcoholic cirrhosis every year.In recent years, China's trend of drinking increases suddenly with the improvement of living, alcoholic liver
The incidence of disease is also in ascendant trend year by year；Have become the second largest cause of disease after virus hepatitis.
For these reasons, it establishes most important with mankind's alcoholic liver disease close copy.Some alcoholic liver disease of past
There is damage slightly in animal model, induced pathologies index is single, can not simulate mixed type alcoholic liver disease, it is difficult to the disadvantages such as operation
End.In the recent period by U.S. National Institutes alcohol abuse and alcoholism research institute hepatopathy research department (National
Institution on alcohol abuse and alcoholism, NIAAA) new model (2013 issue) established, i.e.,
Chronic Alcohol is fed plus the alcoholic liver disease mouse model (Gao-Binge models) of alcohol gavage, closer to drinking for the mankind
Mode.It is that maximally efficient alcoholic fatty liver generally acknowledged at present merges hepatitis modeling mode.It can cause and clinically consistent disease
Manage index：1) hepatomegaly；2) fat lesion, inflammatory cell infiltration occur for liver cell；3) liver cell is in balloon sample lesion and transparent
Venereal disease becomes；4) serum transaminase based on AST, ALT increases；5) serum and liver tg raising etc..
It is believed that the generation of alcoholic liver disease and duration of alcohol consumption length, intake and nutritional status are closely related.So
And pathomechanism not yet all illustrates；And have no special efficacy or targeted drug.It is with auxiliary and ethanol withdrawal therapy mainly
It is main；Including choline, methionine, glutathione and vitamin etc..Therefore, clinically there is an urgent need for find other to prevent or treat wine
The drug of essence hepatopathy.
Kaempferol belongs to plant flavone alcohol component, has very strong physiologically active.It is present in Chinese medicine hawthorn, radix bupleuri
In food onion.With anticancer, inhibit fertility, anti-epileptic, anti-inflammatory, antioxidant, spasmolysis, antiulcer, cholagogic diuretics and
The effects that cough-relieving.However, not having report for its research for treating or preventing alcoholic liver disease.Currently, controlling about Kaempferol
Treatment effect has following publication：(1) patent CN103951645B (application number 201310302501.0) provides a kind of utilize and grows
The method of white larch root extraction dihydroquercetin.Extract includes：Dihydroquercetin, aromadendrin, eriodictyol, Quercetin and
Kaempferol etc..(2) patent CN1329043C (application number 02125413.3) discloses a kind of and natural hippophae fruit effective active
The more close sea-buckthorn whole fruit extract of ingredient and the method for extracting the whole fruit agent, and obtained in preparing treatment hepatitis medicament
Using.Above-mentioned two invention primary treatment disease is the chemical damage of tetrachloro-methane induction, and alcoholic liver disease is treated to it
Effect do not study.Simultaneously as extract component is complicated, Kaempferol content is very low；Targetedly medicine is not carried out to it
Activity of science is inquired into.(3) patent CN1919257B (application number 200610041486.9) discloses Hawk tea ethanol extract and exists
Prepare the application in the drug of prevention alcoholic liver disease.Flavonoid drugs, respectively Quercetin-are mainly contained in extract
3 β-D- galactosides (I, 2~4%), -3 β of Kaempferol-D-Glucose glycosides (II, 12~14%), isoquercitrin (III, 5~
8%), Kaempferol galactoside (IV, 3~5%)；Flavanol compound be respectively catechin (28~30%) and epicatechin (2~
3%).The invention extract component is complicated, is not studied one by one compound monomer.And in extract only include Kaempferol
Glucoside compound；The pharmacological activity of Kaempferol itself is not inquired into.(4) patent CN101167805B (application numbers
200710170416.8) it discloses medicinal composition made of lotus leaf, hypericum japonicum total flavone extraction and its is preparing anti-hepatitis B
New application in virus drugs.Inside contain chemical composition：Quercetin, Quercetin -3-O- β-D- galactopyranoses, isoquercitin,
Kaempferol etc..The compound of the extractive of general flavone is through In vitro cell model and internal animal model test, it was demonstrated that it has
Anti-hepatitis virus and liver-protective activity.The invention is liver inflammation caused by virus mainly for disease, and drug is compound
Object complicated component does not carry out pharmaceutical research to single compound.
Cupreol (β-sitosterol) is one of phytosterols content, belongs to three note class compound of Fourth Ring, wide
In the vegetable seeds such as general each vegetable oil, the nut being present in nature, exist in certain plants medicine such as hawthorn.Research
Show that it has effects that be substantially reduced serum cholesterol, however the effect that alcoholic liver disease is treated to it is not reported.Currently,
Therapeutic effect about cupreol has following publication：(1) patent CN103602550B (application numbers
201310604338.3) it by plurality of Chinese is raw material, Composite fermentation type dogwood fruit health liquor and its production technology to disclose a kind of,
Include the nutriments such as ursolic acid, gallic acid, Fructus Corni saponin(e, cupreol, betulic acid, Iq7613.Though the invention
Right production technology is relatively advanced, but extract component is extremely complex；Physiology is not carried out to the treatment of invention or health care to comment
Valence does not more carry out pathology to single ingredient and pharmacology is inquired into.(2) patent CN1307131C (application numbers
200510036625.4) a kind of extracorporeal anti-tumor extract of Chinese fan palm is disclosed, diosgenin, cupreol, beans steroid are included
Ketone, β-daucosterol, hexacosyl alcohol etc., and more detailed discussion has been carried out to its extracting method；It is verified by pharmacology,
Confirm the growth inhibition effect of 7 class tumor cell line of Chinese fan palm extract pair.The patent main emphasis is extracting method, although
There is cellular pharmacology to prove, does not conduct a research to whole animal effect.Meanwhile the invention is mainly for property treatment disease
Tumour does not evaluate alcoholic liver disease or fatty liver relevant disease.
Tanshinone I belongs to one kind of total-tanshinone；It is the fat-soluble phenanthrene with bacteriostasis extracted from salviamiltiorrhizabung
Naphtoquinone compounds.Total-tanshinone includes：Tanshinone I, tanshinone IIA, tanshinone ⅡB, Cryptotanshinone, different Cryptotanshinone etc. more than 10
Radix Salviae Miltiorrhizae one monomers.Currently, it is more for the research of total-tanshinone on the market, include mainly antibacterial, anti-inflammatory, promoting blood circulation and removing blood stasis, promotion
The effects that wound healing, treatment cardiovascular and cerebrovascular disease；The effect that alcoholic liver disease is treated to it does not have report.In contrast, right
The cognition of Tanshinone I only rests on bacteriostasis；The effect that alcoholic liver disease is treated to it is more rarely known by the people.Currently, about
The therapeutic effect of Tanshinone I has following publication：(1) patent CN100404040C (application number 03144300.1) discloses one
The Pharmaceutical composition that kind is made of Chinese medical extract or its active ingredient, crude drug therein include just Radix Salviae Miltiorrhizae, Radix Notoginseng or ginseng, dragon
Brain perfume or yellow cinnamon leaf.It is prepared into a kind of pharmaceutical composition for treating heart disease.The patent, which only has studied, controls heart disease
Treatment acts on, and the factors such as existence component is excessive, drug effect specific aim is indefinite.(2) patent CN1210025C (application numbers
01819760.4) a kind of tanshinone compound containing dihydrofuran ring structure is disclosed or containing any type among them
Pharmaceutical compositions manufacture and for preventing and treating chronic hepatitis and hepatic sclerosis cause hyperammonemia, including caused by hyperammonemia
Hepatic encephalopathy and subclinical hepatic encephal drug.The patent is hyperammonemia and hepatic encephalopathy for treatment disease；And pathology
The appraisement system of index slightly owes complete, and other internal parameters are short of in addition to blood ammonia levels.(3) (the Shens patent CN101394860A
It number please 200780007383.3) provide and weaken the method that proinflammatory cytokine and NO are discharged from mammalian cell.Also provide
The method for inhibiting or treating inflammatory cytokine cascade in mammal.Indication includes pyemia, septicaemia and/or endotoxin
Property shock.The invention is various inflammation caused by septicopyemia, septicemia, shock and macrophage disorder mainly for disease,
It is not related to the discussion to lipid disorders, obesity and liver class disease.(4) patent CN101036637B (application numbers
200710087032.X) disclose the new application of Tanshinone I sodium sulfonate in medicine preparation.The invention is proposed Tanshinone I sulphur
Sour sodium is applied in preparing treatment coronary heart disease, anticancer drug, and the drug of oral and injection a variety of dosage forms can be made.This is specially
Sharp primary treatment disease is coronary heart disease and tumor disease, is not related to the discussion to lipid disorders, obesity and liver class disease.(5)
Patent CN103958490B (application number 201280056730.2) discloses novel 2- alkyl or the Tanshinone I of aromatic radical substitution
Derivative or its pharmaceutically acceptable salt, prepare the methods of these compounds, the pharmaceutical composition comprising the compound and its
Purposes in the preparation of antitumor drugs.The patent only relates to the application to preparing tumour medicine, does not inquire into the related disease of fat
The therapeutic effect of disease and liver class disease.And there are pathological index appraisement systems slightly to owe the factors such as complete.
Invention content
The present invention overcomes the limitation of existing alcoholic liver injury prevention and treatment drug, and it is specific to disclose it by zoopery
Effect.In addition to pharmaceutical composition beyond the region of objective existence, pharmacology one by one also is carried out to its individual compound and is verified.There is provided Kaempferol, cupreol,
The application of Tanshinone I and its arbitrary pharmaceutical composition in preparing prevention and treatment alcoholic liver medicine and health products.
Present invention aims at provide Kaempferol, cupreol, Tanshinone I and its pharmaceutical composition to prevent and control preparing
Treat the application in alcoholic liver medicine and health products.
Above-mentioned purpose of the present invention is achieved by the following technical programs：
First, the present invention provides a variety of for preventing and/or treating the pharmaceutical compositions of alcoholic liver disease, includes in composition
Kaempferol, cupreol or Tanshinone I any one or a few；It is main with Kaempferol, cupreol and/or Tanshinone I
Active constituent；And the preparation that pharmaceutically acceptable auxiliary material or complementary ingredient are prepared is added.It is described pharmaceutically acceptable
Auxiliary material or complementary ingredient include (1) peroral dosage form auxiliary material：Starch, modified starch, 1% magnesium stearate, various auxiliary materials are fine
Dimension element, α galactolipins and beta cyclodextrin etc.；(2) injection type auxiliary material：Water for injection and various solubilizer, cosolvent, antioxidant and
Isotonic regulator such as glucose and sodium chloride etc..The preparation includes oral preparation and ejection preparation.The oral preparation is piece
Agent, capsule or granule.Ejection preparation is injection.
Preferably, the pharmaceutical composition for preventing and/or treating alcoholic liver disease, including Kaempferol 0.5-
70%, weight percent.It is furthermore preferred that described pharmaceutical composition further includes pharmaceutically acceptable auxiliary material or complementary ingredient.
Preferably, the pharmaceutical composition for preventing and/or treating alcoholic liver disease, including cupreol 0.03-
70%, weight percent.It is furthermore preferred that described pharmaceutical composition further includes pharmaceutically acceptable auxiliary material or complementary ingredient.
Preferably, the pharmaceutical composition for preventing and/or treating alcoholic liver disease, including Tanshinone I 1.5-
99%, weight percent.It is furthermore preferred that described pharmaceutical composition further includes pharmaceutically acceptable auxiliary material or complementary ingredient.
The pharmaceutical composition for preventing and/or treating alcoholic liver disease, including Kaempferol, cupreol and Radix Salviae Miltiorrhizae
Ketone I wherein, including Kaempferol 0.5-70%；Cupreol 0.03-70%；Tanshinone I 1.5-99%；It is weight percentage.
It is furthermore preferred that the pharmaceutical composition for preventing and/or treating alcoholic liver disease, following group of selection of composition
One kind of conjunction：1) Kaempferol 5-55%, cupreol 10-60%, Tanshinone I 20-80%；2) Kaempferol 3-30%, β-paddy steroid
Alcohol 6-30%, Tanshinone I 10-50%, Quercetin 25-65%；It is weight percentage.It can arbitrarily be combined limiting in range
Drug total amount is set to reach 100%.
Described pharmaceutical composition further includes pharmaceutically acceptable auxiliary material or complementary ingredient.
It is furthermore preferred that aforementioned pharmaceutical compositions further include pharmaceutically acceptable auxiliary material or complementary ingredient.This field skill
Art personnel can according to actual needs or the form of preparation selects the content of pharmaceutically acceptable auxiliary material or complementary ingredient；
The content of pharmaceutically acceptable auxiliary material or complementary ingredient is generally the 1% to 90% or so of composition total weight, the medicine
Acceptable auxiliary material or complementary ingredient include 1) oral preparation auxiliary material on：It is starch, modified starch, 1% magnesium stearate, each
Kind auxiliary material cellulose, α galactolipins and beta cyclodextrin etc..2) ejection preparation auxiliary material：Water for injection and various solubilizer, hydrotropy
Agent, antioxidant, isotonic regulator such as glucose and sodium chloride etc..For example, described for preventing and/or treating alcoholic liver disease
Pharmaceutical composition, one kind of composition selection following combination：1) Kaempferol (0.35-54.5%)+cupreol (0.7-
59.4%)+Tanshinone I (1.4-79.2%)；Pharmaceutically acceptable auxiliary material or complementary ingredient 1-93%；2) Kaempferol
(0.3-29.7%)+cupreol (0.6-29.7%)+Tanshinone I (1-49.5%)+Quercetin (2.5-64.35%), pharmacy
Upper acceptable auxiliary material or complementary ingredient 1-90.0%；It is weight percentage.Can limit range in arbitrarily combination make it is auxiliary
Material and drug reach 100%.
Aforementioned pharmaceutical compositions are preparing the application in preventing and/or treating alcoholic liver medicine and/or health products
Within protection scope of the present invention.Including pharmaceutical composition of the present invention is preparing prevention and/or treatment alcoholic liver
Application, pharmaceutical composition of the present invention in the drug of disease are preparing the health products for preventing and/or treating alcoholic liver disease
In application；Also include that can not only be used for the application that drug also can be used as health products in above application.
Above-mentioned alcoholic liver disease refers to alcoholic liver injury caused by long-term heavy drinking.The long-term heavy drinking
It is more than 5g/kg to refer to average daily Ethanol intake amount, and the time is more than 10 days.
Above-mentioned alcoholic liver disease refers to the alcoholic liver injury that alcohol is fed plus alcohol gavage is induced.The alcohol is fed
It supports plus alcohol gavage refers to：Liquid feed containing 5% (volume ratio) alcohol is fed plus the alcohol of 5g/kg dosage fills once or several times
Stomach.
The prevention and treatment alcoholic liver disease refers to mitigating liver volume enlargement and quality in Alcoholic Liver Disease Model
Increase；Serum alt and AST activity are reduced, hepatic tissue fat aggregation, bubble sample lesion and inflammatory infiltration degree are mitigated, is reduced
Triglycerides (TG) content in serum and liver.
Secondly, the present invention provide above-mentioned each traditional Chinese medicine monomer prepare prevent and/or treatment alcoholic liver disease drug and/
Or the application in health products.
The application includes：
The present invention provides Kaempferols to prepare the application in preventing and/or treating the drug and/or health products of alcoholic liver disease.
Including：Kaempferol prepare prevent and/or treatment alcoholic liver disease drug in application, Kaempferol prepare prevent and/or
Treat the application in the health products of alcoholic liver disease；Also include that can not only be used for drug in above application also to can be used as answering for health products
With.It is characterized in that, using Kaempferol as active constituent, after being mixed with pharmaceutically acceptable auxiliary material or complementary ingredient, system
At the oral preparation of prevention and/or treatment alcoholic liver disease, ejection preparation.
The present invention provides cupreols in the drug and/or health products for preparing prevention and/or treatment alcoholic liver disease
Application.Cupreol is preparing the application in preventing and/or treating the drug of alcoholic liver disease, cupreol in preparation prevention
And/or the application in the health products for the treatment of alcoholic liver disease；Also include that can not only be used for drug in above application also to can be used as health care
The application of product.It is characterized in that, using cupreol as active constituent, it is mixed with pharmaceutically acceptable auxiliary material or complementary ingredient
After conjunction, prevention is made and/or treats the oral preparation of alcoholic liver disease, ejection preparation.
The present invention provides Tanshinone Is in the drug and/or health products for preparing prevention and/or treatment alcoholic liver disease
Using.Including：Tanshinone I prepare prevent and/or the drug for the treatment of alcoholic liver disease in application, Tanshinone I prepare it is pre-
Application in anti-and/or treatment alcoholic liver disease health products；Also include that can not only be used for drug in above application also to can be used as guarantor
The application of strong product.It is characterized in that, using Tanshinone I as active constituent, with pharmaceutically acceptable auxiliary material or complementary ingredient
After mixing, prevention is made and/or treats the oral preparation of alcoholic liver disease, ejection preparation.
It is furthermore preferred that the present invention also provides Kaempferol, cupreol or Tanshinone Is or composition of the present invention to exist
Prepare the purposes in liver organization lesion inhibitor；Kaempferol, cupreol or Tanshinone I or composition of the present invention
Preparing the application in inhibiting serum glutamic pyruvic transminase and the raised drug of aspartate aminotransferase；Kaempferol, β-paddy steroid
The application of alcohol or Tanshinone I or composition of the present invention in preparing serum and the raised inhibitor of liver tg.
The present invention is fed by alcohol first plus alcohol gavage causes mouse Alcoholic Liver Disease Model, collaboration to give the drug of various dose
Monomer (Kaempferol：5mg/kg,15mg/kg,30mg/kg；Cupreol：10mg/kg,20mg/kg,30mg/kg；Tanshinone I：
15mg/kg, 30mg/kg, 60mg/kg) or pharmaceutical composition after, can effectively mitigate liver volume enlargement in Alcoholic Liver Disease Model
Increase with quality；It reduces in liver and TG is horizontal in serum, mitigate hepatic tissue fat aggregation, bubble sample lesion and inflammatory infiltration journey
Degree.The result shows that drug can prophylactic treatment alcohol feed plus the alcoholic liver injury that is induced of alcohol gavage.Therefore, according to this
Tanshinone I can be used to prepare the drug or health products for clinically preventing or treating alcoholic liver disease by result of study.
The invention has the advantages that：
The present invention overcomes the limitations that existing alcoholic liver injury prevents and treats drug, provide Kaempferol, cupreol or pellet
Join ketone I and using its application as main active in preparing prevention and treatment alcoholic liver medicine (or health food).
Be found that Kaempferol, cupreol or Tanshinone I can prophylactic treatment long term alcohol feed plus the alcohol that is induced of alcohol gavage
Property hepatic injury.
First, it is fed by alcohol plus alcohol gavage causes murine chronic Alcoholic Liver Disease Model, collaboration to give different doses
After the drug monomer or pharmaceutical composition of amount, it can effectively mitigate hepar damnification and reduce lipid lesion levels, be embodied in small
Volume, weight and the liver of mouse liver are again than obviously lowering, and serum alt and AST activity significantly reduce, and TG contains in serum and liver
Amount significantly reduces, and hepatic tissue fat aggregation, vacuole sample lesion and inflammatory infiltration degree significantly mitigate.On the other hand, configuration contains
After the pharmaceutical composition of Tanshinone I, above-mentioned mouse hepatopathy model is repeated, liver weight increase can be effectively relieved；It reduces in serum
AST and ALT activity；Reduce TG contents in serum and liver.Improve hepatic tissue fat aggregation and vacuole sample lesion degree.
Therefore, according to this research as a result, can be by Kaempferol, cupreol, Tanshinone I and its arbitrary pharmaceutical composition
For the prevention or treatment of clinically alcoholic liver disease, and good effect, without obvious toxic-side effects.Meanwhile above-mentioned traditional Chinese medicine monomer exists
Content is higher in medicinal material, at low cost, easily obtains, and has good application value.
In conjunction at present for treating the pharmaceutical composition and Kaempferol of alcoholic liver disease, cupreol and Tanshinone I
Research, the present invention have following advantage：
1. the present invention makes full use of Kaempferol and cupreol to act on the reduction of triglycerides and cholesterol, in conjunction with Tanshinone I
Anti-inflammatory effect；Alcoholic liver disease caused by comprehensive alleviation long term alcohol intake.It is wide to treat indication range, significant effect.
2. pharmaceutical composition of the present invention is targeted drug monomer, non-Chinese medicine combination；Definite ingredients, effect are more
Obviously.
3. Kaempferol is present in many foods and medicinal plant, in hawthorn, radix bupleuri and onion, derive from a wealth of sources；It is adapted to
It is prepared on a large scale.Since drug effect is notable, toxic side effect is small；It can be applied in food, drug and health products, be highly advantageous to exploitation.
4. currently, the application for treating and preventing alcoholic liver disease for Kaempferol is not yet excavated.
It is the main component of Sitosterols compound 5. cupreol is present in hawthorn；Have in terms of reducing cholesterol
Special effect, toxic side effect are small；It is many pharmacy additives to have sent out exploitation.
6. currently, the effect for treating alcoholic liver disease to cupreol has no research.
7. Tanshinone I drug effect is mildly apparent, long-term use has no toxic side effect.Oral and drug administration by injection all may be used；Its semi-annular jade pendantization is produced
Object Tanshinone I sodium sulfonate is water-soluble good；It is very beneficial for developing practical preparation.
8. Tanshinone I is present in Radix Salviae Miltiorrhizae rhizome, fruit and herb.Extraction process is simple, can also be according to other similar
Object chemical synthesis；It is adapted to be prepared on a large scale.
9. although had been reported with estrogen-like pharmacological action for Tanshinone I is antibacterial；It at present can be pre- for Tanshinone I
There has been no researchs for anti-and treatment alcoholic liver disease and various fatty liver relevant diseases.
Obviously, the above-mentioned technology of the present invention is not being departed from conjunction with ordinary skill and customary means according to the above
Under the premise of thought, the modification, replacement or change of other diversified forms can also be made.Form is specific by the following examples
Mode is described in further detail the above of the present invention again.But this should not be interpreted as to the above range of the present invention
It is only limitted to following instance.The techniques implemented on the basis of the foregoing are all within the scope of the present invention.
Description of the drawings：
Fig. 1 is that the Kaempferol of various dose mitigates the result figure of liver enlargement and weightening caused by NIAAA models.Ns is indicated without significantly
Sex differernce, P<0.05 is considered significant difference.Wherein * indicates the P compared with contrast groups<0.05, * * is indicated and contrast groups ratio
Compared with P<0.01, * * * indicate the P compared with contrast groups<0.001.Wherein liver again than for：The ratio of liver divided by weight.In mouse reality
In testing, 4.5-5% can become the auxiliary judgment condition of fatty liver.
Fig. 2 is that the Kaempferol of various dose mitigates the knot of hepatic tissue fat aggregation and vacuole sample lesion caused by NIAAA models
Fruit is schemed.Color relatively depth is effect after fat stains in figure.Vacuole sample lesion is marked by arrow.
Fig. 3 is that the Kaempferol of various dose reverses the raised result of mice serum AST and ALT index caused by NIAAA models
Figure.AST is the abbreviation of aspartate amino transferase, is once called as glutamic-oxalacetic transaminease (GOT), is that one of liver function test is important
Index, for judging whether liver is damaged.Glutamic-oxalacetic transaminease normal value is 4-40U/L (every liter of unit).ALT, liver function
One kind, i.e., " glutamic-pyruvic transaminase ".
Fig. 4 is that the Kaempferol of various dose reverses mice serum and the raised result of liver TG contents caused by NIAAA models
Figure.Triglycerides (Triglyceride, abridge TG) is long chain fatty acids and the fat molecule that glycerine is formed.
Fig. 5 is that the cupreol of various dose mitigates the result figure of liver enlargement and weightening caused by NIAAA models.
Fig. 6 is that the cupreol of various dose mitigates hepatic tissue fat aggregation caused by NIAAA models and vacuole sample lesion
Result figure.
Fig. 7 is that the cupreol of various dose reverses the raised knot of mice serum AST and ALT index caused by NIAAA models
Fruit is schemed.
Fig. 8 is that the cupreol of various dose reverses mice serum and the raised knot of liver TG contents caused by NIAAA models
Fruit is schemed.
Fig. 9 is that the Tanshinone I of various dose mitigates the result figure of liver enlargement and weightening caused by NIAAA models.
Figure 10 is that the Tanshinone I of various dose mitigates hepatic tissue fat aggregation caused by NIAAA models and vacuole sample lesion
Result figure.
Figure 11 is that the Tanshinone I of various dose reverses the raised knot of mice serum AST and ALT index caused by NIAAA models
Fruit is schemed.
Figure 12 is that the Tanshinone I of various dose reverses mice serum and the raised knot of liver TG contents caused by NIAAA models
Fruit is schemed.
Figure 13 is the result figure that pharmaceutical composition mitigates liver enlargement and weightening caused by NIAAA models.
Figure 14 is the result figure that pharmaceutical composition mitigates hepatic tissue fat aggregation and vacuole sample lesion caused by NIAAA models.
Figure 15 is that pharmaceutical composition reverses the raised result figure of mice serum AST and ALT index caused by NIAAA models.
Figure 16 is that pharmaceutical composition reverses mice serum and the raised result figure of liver TG contents caused by NIAAA models.
Figure 17 is the result figure that pharmaceutical composition mitigates liver enlargement and weightening caused by NIAAA models.
Specific implementation mode
Effective effect of the present invention is proved below by way of pharmacodynamics test.But the present invention is not limited thereto.
Embodiment 1
The Kaempferol of various dose is used to prevent and treat the alcoholic liver disease caused by NIAAA models.
1, instrument and material：
Key instrument：All-wave length microplate reader (Thermo companies of the U.S.).
Drug and reagent：Liquid feed (Lieber-DeCarli diet ad libitum) and liquid alcohol feed (south
Tong Teluofei feed technologies Co., Ltd)；Alcohol (Burdick&Jackson)；Kaempferol (>=98%, Chengdu Man Site biology
Science and Technology Ltd.)；ALT, AST, TG detection kit (Bioengineering Research Institute is built up in Nanjing)；Other reagents are analysis
Pure rank.
2, experimental animal and dosage regimen：
C57BL/6 mouse, male, week old 8~9 weeks are provided by Traditional Chinese Medicine University Of Guangzhou's Experimental Animal Center, according to different groups
Using control liquid feed or liquid alcohol forage feed.Using control liquid feed (Lieber-DeCarli diet ad
Libitum mouse) is fed 5 days；Adapt it to liquid feed.Hereafter, mouse is randomly divided into 6 groups, every group 6, group is sky
White control liquid feed group (Lieber-DeCarli diet ad libitum), alcohol modeling group (Lieber-DeCarli
Alcohol is added in diet ad libitum；Final concentration of 5% (volume/volume)), Kaempferol+alcohol modeling group；It feeds 10 days altogether.
Wherein Kaempferol+alcohol modeling group is Kaempferol (5/15/30mg/kg), with alcohol modeling gastric infusion.Disposable wine after 10 days
Smart gavage (5g/kg) waits heats dextrin；And mouse is dissected in 9h processing thereafter, is clapped in vitro liver morphology after dissection
According to partial liver tissue is placed in 10% (v/v) formaldehyde and fixes by collection serum and liver, and other samples are freezed at -80 DEG C
It saves backup.
3, hepatic tissue and serum chemistry detect
Hepatic tissue section, H&E and oil red dyeing are completed by Wuhan Seville bio tech ltd, ALT, AST in serum,
TG detection methods are completed according to the specification of kit.
4, data statistics
Each group experimental data is indicated with mean ± S.E.M., for statistical analysis using 5 softwares of GraphPad Prism, is adopted
Two comparison among groups, P are carried out with unpaired Student ' s t test<0.05, it is considered significant difference.Wherein * is indicated
The P compared with contrast groups<0.05, * * indicates the P compared with contrast groups<0.01, * * * indicate the P compared with contrast groups<0.001.
5, experimental result：
Ordinary circumstance：Alcohol group mouse appetite is deteriorated, feeds reduction, weight loss, fur gloss difference；Naked eyes can be apparent after solution plane
Observe liver volume become larger, rough surface, color change.Negative control group and the above-mentioned pathological reaction of administration group are obviously improved；
Liver enlargement is significantly alleviated.In addition to this, there is also othernesses for liver weight variation：Alcohol group liver mass is apparently higher than control
Group and Kaempferol group (P<0.05).Again than alcohol group highest, Kaempferol takes second place liver；Control feed group is minimum；And there are statistics
Difference.It is shown in Table 1 and Fig. 1.
Table 1
Wherein * indicates the P compared with alcohol modeling group<0.05, * * indicates P<0.01, * * * indicate P<0.001.
Histopathology slide：Oil red coloring pathological section confirms that fat drop is rare in cellular control unit；Alcohol group endochylema
Inside there are the fat drips to differ in size (black and white picture is grey black spot).Fat drips shape is obviously reduced after administration.Bush Yihong
(Hematoxylin and eosin；H&E) coloring pathological section is shown：Normal group mouse lobuli hepatis is clear, and the arrangement of cell rope is whole
Together, intracellular is without lesion.Compared with negative control group, the hepatic pathology section of alcohol group can obviously observe lesion tissue；Liver is thin
Being dispersed in and sheet balloon sample lesion occur in born of the same parents (shown in arrow), it is seen that inflammatory cell infiltration, swelling of liver cell, endochylema is interior to be occurred more
Unrestrained property fat drips, karyon is smudgy.Kaempferol group can significantly mitigate murine liver tissue fat aggregation and cytopathy.See Fig. 2.
Serum glutamic pyruvic transminase (ALT) and aspartate aminotransferase (AST)：It is compared with control group, alcohol group serum
ALT increase three times of (P<0.05).AST/ALT is significantly greater than 1.After administration above-mentioned pathological index significantly improve and with alcohol group
Compare with significant difference (P<0.05)；Improve when 15mg/kg, 30mg/kg is administered the most apparent.It is shown in Table 2 and Fig. 3.
Table 2
Wherein * indicates the P compared with alcohol modeling group<0.05, * * indicates P<0.01, * * * are indicated and P<0.001.
Serum and the horizontal variation of liver tg (TG)：It is compared with control feed group, serum TG increases 1.2 times；Liver
Interior TG significantly increases nearly 5 times of (P<0.05).Above-mentioned pathological index significantly improves and has compared with alcohol group notable after administration
Sex differernce (P<0.05)；The improvement degree highest of pathological index when 30mg/kg is administered.It is shown in Table 3 and Fig. 8-9.
Table 3
Wherein * indicates the P compared with alcohol modeling group<0.05, * * indicates P<0.01, * * * indicate P<0.001.
Embodiment 2
Cupreol is used to prevent and treat the alcoholic fatty liver caused by NIAAA models.
1, instrument and material
Cupreol (>=98%, the Chengdu bio tech ltd Man Site)；Remaining is the same as embodiment 1.
2, experimental animal and dosage regimen
Mouse is randomly divided into 3 groups, and every group 6, group is blank control liquid feed group, alcohol modeling group, alcohol modeling collaboration
Administration group.Wherein alcohol modeling cooperativing medicine-feeding group includes cupreol (10/20/30mg/kg)；Remaining is the same as embodiment 1.
Hepatic tissue is detected with serum chemistry, and mathematical statistics is the same as embodiment 1.
3, experimental result
Ordinary circumstance：Compared with compareing liquid feed group, naked eyes can obviously observe that liver volume becomes after alcohol modeling group solution plane
Greatly, rough surface, color change.Pathological reaction is obviously improved after collaboration awards cupreol；Liver enlargement is significantly alleviated.Together
When, cupreol can also significantly alleviate the liver weight that alcohol induces and liver again than increasing.It is shown in Table 4 and Fig. 5.
Table 4
Wherein * indicates the P compared with alcohol modeling group<0.05, * * indicates P<0.01, * * * are indicated and P<0.001.
Histopathology slide：Oil red coloring pathological section shows size occur not in liver cell endochylema after alcohol modeling
Deng fat drips (black and white picture be grey black spot).Fat drips shape is obviously reduced after cupreol is given in collaboration.With negative control
Group is compared, and the hepatic pathology section of alcohol group can obviously observe balloon sample lesion (shown in arrow) and inflammatory cell infiltration,
Occur diffusivity fat drips in endochylema, karyon is smudgy.Give after pharmaceutical composition fat aggregation and cell in murine liver tissue
Lesion degree is greatly reduced.See Fig. 6.
Serum glutamic pyruvic transminase (ALT) and aspartate aminotransferase (AST)：It is compared with control group, alcohol group serum
ALT increases nearly three times of (P<0.05).Wherein, AST/ALT is significantly greater than 1.The above-mentioned pathological index of cupreol is given to greatly improve
And with significant difference (P compared with alcohol group<0.05)；When 20mg/kg is administered, overall target is best.It is shown in Table 5 and Fig. 7.
Table 5
Wherein * indicates the P compared with alcohol modeling group<0.05, * * indicates P<0.01, * * * are indicated and P<0.001.
Serum and the horizontal variation of liver tg (TG)：It is compared with control feed group, serum TG slightly increases；In liver
TG significantly increases nearly 6 times of (P<0.05).After giving cupreol, serum TG is less than control feed group, and liver TG indexs are significantly
Improve and compared with alcohol group with significant difference (P<0.05), the best results in 20mg/kg.It is shown in Table 6 and Fig. 8.
Table 6
Wherein * indicates the P compared with alcohol modeling group<0.05, * * indicates P<0.01, * * * indicate P<0.001.
Embodiment 3
Tanshinone I is used to prevent and treat the alcoholic fatty liver caused by NIAAA models.
1, instrument and material
Tanshinone I (>=98%, the Chengdu bio tech ltd Man Site)；Remaining is the same as embodiment 1.
2, experimental animal and dosage regimen
Mouse is randomly divided into 5 groups, and every group 6, group is blank control liquid feed group, alcohol modeling group, alcohol modeling collaboration
Administration group:Wherein Tanshinone I dosage is：15mg/kg, 30mg/kg, 60mg/kg, remaining is the same as embodiment 1.
Hepatic tissue is detected with serum chemistry, and data statistics is the same as embodiment 1.
Experimental result：
Compared with compareing liquid feed group, alcohol modeling group solution plane after naked eyes can obviously observe liver volume become larger, surface it is thick
Rough, color change.Above-mentioned pathological reaction is obviously improved after collaboration awards above-mentioned dosage；Liver enlargement is significantly alleviated.Meanwhile Radix Salviae Miltiorrhizae
Ketone I can significantly alleviate liver mass caused by alcohol and increase；And reach optimum curative effect when 30mg/kg.It is shown in Table 7 and Fig. 9.
Table 7
Wherein * indicates the P compared with alcohol modeling group<0.05, * * indicates P<0.01, * * * indicate P<0.001.
Hepatic pathology section shows occur a large amount of fat drips after alcohol modeling in liver cell；Oil red dyeing is visible not of uniform size
Peony drop (black and white picture be grey black spot)；Quantity is reduced after giving Tanshinone I；Area reduces.H&E pathology is cut
Piece shows occur apparent vacuole sample lesion (arrow expression) in alcohol modeling group hepatic tissue；Collaboration awards lesion after Tanshinone I
Degree significantly mitigates.See Figure 10.
It is compared with control group, the Serum ALT and AST of alcohol group significantly increase；Wherein, AST/ALT is significantly greater than 1.Administration
Above-mentioned pathological index significantly improves and compared with alcohol group with significant difference (P afterwards<0.05)；When 30mg/kg is administered
Effect is the most apparent.It is shown in Table 8 and Figure 11.
Table 8
Wherein * indicates the P compared with alcohol modeling group<0.05, * * indicates P<0.01, * * * are indicated and P<0.001.
It is compared with control feed group, serum and liver tg (TG) horizontal significant changes of alcohol group.Wherein, liver
TG significantly increases nearly 5 times of (P<0.05).Above-mentioned pathological index significantly improves and has compared with alcohol group after giving Tanshinone I
Significant difference (P<0.05)；The improvement degree highest of pathological index when 60mg/kg is administered.It is shown in Table 9 and Figure 12.
Table 9
Wherein * indicates the P compared with alcohol modeling group<0.05, * * indicates P<0.01, * * * indicate P<0.001.
Embodiment 4
The pharmaceutical composition of Kaempferol, cupreol and Tanshinone I composition is used to prepare prevention and treatment alcoholic liver disease.
1, instrument and material
Quercetin (>=98%, the Chengdu bio tech ltd Man Site)；Remaining is the same as embodiment 1.
2, experimental animal and dosage regimen
Mouse is randomly divided into 4 groups, and every group 6, group is blank control liquid feed group, alcohol modeling group, alcohol modeling collaboration
Administration group.Administration group includes two kinds of pharmaceutical compositions：Wherein, pharmaceutical composition I is：Kaempferol 15mg/kg, cupreol
20mg/kg, Tanshinone I 30mg/kg, dosage is 65mg/kg in total；Pharmaceutical composition II is：Kaempferol 15mg/kg, β-paddy
Sterol 20mg/kg, Tanshinone I 30mg/kg, Quercetin 50mg/kg, dosage is 115mg/kg in total；Remaining is the same as embodiment 1.
Hepatic tissue is detected with serum chemistry, and data statistics is the same as embodiment 1.
Experimental result：
Compared with compareing liquid feed group, alcohol modeling group solution plane after naked eyes can obviously observe liver volume become larger, surface it is thick
Rough, color change.Above-mentioned pathological reaction is obviously improved after collaboration awards pharmaceutical composition, and liver enlargement, which is significantly alleviated, (to be seen below
Figure).Pharmaceutical composition I and II can significantly alleviate liver mass caused by alcohol and increase；Pharmaceutical composition II curative effects are best.See
Table 10 and Figure 13.
Table 10
Wherein * indicates the P compared with alcohol modeling group<0.05, * * indicates P<0.01, * * * indicate P<0.001.
Hepatic pathology section shows occur a large amount of fat drips after alcohol modeling in liver cell；Oil red dyeing is visible not of uniform size
Peony drop (black and white picture be grey black spot)；After giving composition I and II, oil droplet quantity substantially reduces；And face
Product reduces.H&E pathological sections show occur apparent vacuole sample lesion (arrow expression) in alcohol modeling group hepatic tissue；Collaboration
Lesion degree significantly mitigates after awarding composition, the best results of composition II.See Figure 14.
It is compared with control group, the serum glutamic pyruvic transminase (ALT) and aspartate aminotransferase (AST) of alcohol group are notable
It increases；Wherein, AST/ALT is significantly greater than 1.Above-mentioned pathological index significantly improves and has compared with alcohol group notable after administration
Sex differernce (P<0.05)；Wherein, the effect of composition I becomes apparent.It is shown in Table 11 and Figure 15.
Table 11
Wherein * indicates the P compared with alcohol modeling group<0.05, * * indicates P<0.01, * * * are indicated and P<0.001.
It is compared with control feed group, serum and liver tg (TG) horizontal significant changes of alcohol group.Wherein, liver
TG significantly increases 4.6 times of (P<0.05).Above-mentioned pathological index significantly improves and has compared with alcohol group after giving composition I
Significant difference (P<0.05)；The improvement degree highest of pathological index when giving pharmaceutical composition II.It is shown in Table 12 and Figure 16.
Table 12
First, the equivalent drug dose of the human body such as table 13 derived according to zoopery dosage.
Method is originated from Anhui Province clinical evaluation of drug center (Huang Jihan, 2004).Secondly, dosage form is made according to human dose
Medicament contg be shown in Table 13-15.According to EXPERIMENTAL EXAMPLE 1-4, following preparation can be prepared；Method therefor is conventional preparation side
Method.
Embodiment 5 prepares the oral preparation for including 0.5-70% Kaempferols
Prepare the tablet for including 0.5-70% Kaempferols：Kaempferol (or Kaempferol pharmaceutical composition) dried powder is taken, 60- is crossed
100 mesh sieve is spare.The one or more that tablet often uses auxiliary material are added；It is tabletted through tablet press machine.Make every 5.5- containing Kaempferol
66mg, piece weight 0.1-1g.Auxiliary material used can be：Starch, modified starch, 1% magnesium stearate, microcrystalline cellulose, Methyl cellulose
Element, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose etc..
Prepare the capsule for including 0.5-26.4%：Kaempferol (or Kaempferol pharmaceutical composition) dried powder is taken, 60- is crossed
100 mesh sieve is spare.Capsule, which is added, often uses auxiliary material one or more of, granulation, and whole grain is encapsulated.Contain Kaempferol in every capsule
5.5-66mg capsule weight 0.25-1g.Auxiliary material used can be：Modified starch, microcrystalline cellulose, methylcellulose, carboxymethyl
Cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose etc..
In addition to this, the granule comprising Kaempferol, suspension etc. can also be prepared.
Embodiment 6 prepares the oral preparation for including 1-70% cupreols
Prepare the tablet for including 1-70% cupreols：Take cupreol (or cupreol pharmaceutical composition) dried powder, mistake
60-100 mesh sieve is spare.The one or more that tablet often uses auxiliary material are added；It is tabletted through tablet press machine.Every is set to contain cupreol
5.5-66mg piece weight 0.1-1g.Auxiliary material used can be：Starch, modified starch, 1% magnesium stearate, microcrystalline cellulose, methyl
Cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose etc..
Prepare the capsule for including 1-26.4% cupreols：Take cupreol (or cupreol pharmaceutical composition) dry
It is spare to cross 60-100 mesh sieve for powder.Capsule, which is added, often uses auxiliary material one or more of, granulation, and whole grain is encapsulated.Every capsule
In 10-66mg containing cupreol, capsule weight 0.25-1g.Auxiliary material used can be：Modified starch, microcrystalline cellulose, Methyl cellulose
Element, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose etc..
In addition to this, the granule (5-10g) comprising 10-66mg cupreols, suspension (20-30ml) can also be prepared
Deng.The content of final cupreol is granule 0.1-1.32%, suspension 0.03%-0.33%.
Embodiment 7 prepares the oral preparation for including 1.5-99% Tanshinone Is
Prepare the tablet for including 1.5-99% Tanshinone Is：Take Tanshinone I (or Tanshinone I pharmaceutical composition) dried powder, mistake
60-100 mesh sieve is spare.The one or more that tablet often uses auxiliary material are added；It is tabletted through tablet press machine.Every is set to contain 15-396mg
Tanshinone I, piece weight 0.1-1g.Auxiliary material used can be：Starch, modified starch, 1% magnesium stearate, microcrystalline cellulose, methyl are fine
Tie up element, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose etc..
Prepare the capsule for including 1.5-99% Tanshinone Is：Take Tanshinone I (or Tanshinone I pharmaceutical composition) xeraphium
It is spare to cross 60-100 mesh sieve for end.Capsule, which is added, often uses auxiliary material one or more of, granulation, and whole grain is encapsulated.In every capsule
Containing 15-396mg, capsule weight 0.25-1g.Auxiliary material used can be：Modified starch, microcrystalline cellulose, methylcellulose, carboxymethyl
Cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose etc..
Embodiment 8 prepares the ejection preparation for including 0.008-20% Tanshinone I sodium sulfonates
Using Tanshinone I sodium sulfonate as main active component, ejection preparation can be prepared.Including intramuscular dose, intravenous injection,
Intravenous infusion injection and freeze-dried powder etc..Commonly auxiliary material includes：PH adjusting agent including：Sodium bicarbonate, sodium hydroxide, hydroxide
Potassium etc.；Freeze-dried excipient；The auxiliary materials such as isotonic regulator such as glucose and sodium chloride.Usage and dosage is 40mg-200mg/ times, one day
Once.Wherein intravenous injection can use 5% glucose injection agent with 25% glucose injection 20ml dilutions, intravenous drip
250-500ml dilutes.
Embodiment 9 prepares the oral preparation for including pharmaceutical composition I
The ultimate constituent is Kaempferol (0.35-54.5%)+cupreol (0.7-59.4%)+Tanshinone I (1.4-79.2%)；Medicine
Acceptable auxiliary material or complementary ingredient 1-93% on.It is weight percentage.Limit in range arbitrarily combination make it is overall at
It is divided into 100%.Now state one by one as follows：
Prepare the tablet for including 7-99% pharmaceutical compositions I：Kaempferol, cupreol and Tanshinone I dried powder are taken, 60- is crossed
100 mesh sieve is spare.The one or more that tablet often uses auxiliary material are added；It is tabletted through tablet press machine.Make every 70- containing composition
150mg, piece weight 0.1-1g.Auxiliary material used can be：Starch, modified starch, 1% magnesium stearate, microcrystalline cellulose, Methyl cellulose
Element, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose etc..
Prepare the capsule for including 7-99% pharmaceutical compositions I：Kaempferol, cupreol and Tanshinone I dried powder are taken,
It is spare to cross 60-100 mesh sieve.Capsule, which is added, often uses auxiliary material one or more of, granulation, and whole grain is encapsulated.Drug containing in every capsule
Compositions 70-150mg, capsule weight 0.25-1g.Auxiliary material used can be：Modified starch, microcrystalline cellulose, methylcellulose,
Carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose etc..
Embodiment 10 prepares the oral preparation for including pharmaceutical composition II
The ultimate constituent is Kaempferol (0.3-29.7%)+cupreol (0.6-29.7%)+Tanshinone I (1-49.5%)+quercitrin
Plain (2.5-64.35%), pharmaceutically acceptable auxiliary material or complementary ingredient 1-90.0%.It is weight percentage.Limit model
Enclosing interior arbitrary combination makes overall composition be 100%.Now state one by one as follows：
Prepare the tablet for including 10-99% pharmaceutical compositions II：Take Kaempferol, cupreol, Tanshinone I and Quercetin xeraphium
It is spare to cross 60-100 mesh sieve for end.The one or more that tablet often uses auxiliary material are added；It is tabletted through tablet press machine.Make every drug containing
Compositions 100-260mg, piece weight 0.1-1g.Auxiliary material used can be：Starch, modified starch, 1% magnesium stearate, crystallite are fine
Tie up element, methylcellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose etc..
Prepare the capsule for including 10-99% pharmaceutical compositions II：Take Kaempferol, cupreol, Tanshinone I and Quercetin
It is spare to cross 60-100 mesh sieve for dried powder.Capsule, which is added, often uses auxiliary material one or more of, granulation, and whole grain is encapsulated.Every
Drug containing compositions 100-260mg in capsule, capsule weight 0.25-1g.Auxiliary material used can be：Modified starch, microcrystalline cellulose,
Methylcellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose etc..
Table 13- human bodies and the equivalent drug dose of animal
According to table 7, each daily minimum and highest intake of drug monomer selection adult (60kg)：
(1) Kaempferol minimum intake 33mg, highest intake 198mg daily；
(2) cupreol minimum intake 66mg, highest intake 198mg daily；
(3) Tanshinone I minimum intake 99mg, highest intake 396mg daily.
Therefore, according to result of calculation, oral preparation content (being shown in Table 8) is calculated.
Table 14 is by taking oral preparation as an example
Therefore, 1. using Kaempferol as in the drug and health products of main active, excipient substance is counted, content limits
For 0.55%-66%.Range is suitably widened and is limited to 0.5-70%.2. using cupreol as the drug of main active and
In health products, excipient substance is counted, content is limited to 1.1%-66%.Range is suitably widened and is limited to 1-70%.
3. using Tanshinone I as in the drug and health products of main active, excipient substance is counted, content is limited to 1.65-
99%.Range is suitably widened and is limited to 1.5-99%.4. using pharmaceutical composition I as the drug of main active and health products
In, excipient substance is counted, content is limited to 7.15-99%.Range is suitably widened and is limited to 7-99%.5. with drug
Composition II is to be counted excipient substance, content is limited to 12.65- in the drug and health products of main active
99%.Range is suitably widened and is limited to 10-99%.
Table 12 is by taking Tanshinone I sodium sulfonate-injection as an example
With reference to tanshinone IIA sodium sulfonate injection, dosage are generally 40-80mg on the market
In conjunction with this patent content, dosage is set as 40-200mg.
Table 15
It is verified by experiments, the preparation of embodiment 5-10, there is similar pharmacological effect effect with the composition of embodiment 4.
Compared with compareing liquid feed group, alcohol modeling group solution plane after naked eyes can obviously observe liver volume become larger, table
Face is coarse.Pathological reaction is obviously improved after collaboration awards aforementioned pharmaceutical compositions, and liver enlargement is significantly alleviated.Embodiment 5-10's
Preparation can significantly alleviate liver mass caused by alcohol and increase (P<0.05).
Hepatic pathology section shows occur a large amount of fat drips after alcohol modeling in liver cell；Oil red dyeing is visible not of uniform size
Peony drop (black and white picture be grey black spot)；After the preparation for giving embodiment 5-10, oil droplet quantity substantially reduces；And
And area reduces.H&E pathological sections show occur apparent vacuole sample lesion in alcohol modeling group hepatic tissue.
It is compared with control group, the ALT and AST of alcohol group are significantly increased；Wherein, AST/ALT is significantly greater than 1.To embodiment
Above-mentioned pathological index significantly improves and compared with alcohol group with significant difference (P after the preparation of 5-10<0.05).
It is compared with control feed group, the serum and the horizontal significant changes of liver TG of alcohol group.Wherein, liver TG is significantly increased
4-5 times of (P<0.05).Above-mentioned pathological index significantly improves and has compared with alcohol group after giving the preparation of embodiment 5-10
Significant difference (P<0.05).
Claims (13)
1. a kind of pharmaceutical composition, which is characterized in that include the arbitrary of Kaempferol, cupreol and/or Tanshinone I in composition
It is one or more of；Using Kaempferol, cupreol and/or Tanshinone I as main active；And it is added pharmaceutically acceptable auxiliary
The preparation that material or complementary ingredient are prepared.
2. pharmaceutical composition as described in claim 1, which is characterized in that the pharmaceutically acceptable auxiliary material or it is complementary at
It includes peroral dosage form auxiliary material or injection type auxiliary material to divide；The preparation includes oral preparation and ejection preparation.
3. pharmaceutical composition as claimed in claim 2, which is characterized in that peroral dosage form auxiliary material includes：Starch, modified starch,
1% magnesium stearate, various auxiliary material celluloses, α galactolipins and/or beta cyclodextrin；Injection type auxiliary material includes：Water for injection, increasing
Solvent, cosolvent, antioxidant, isotonic regulator；Isotonic regulator is selected from glucose and/or sodium chloride.
4. pharmaceutical composition as claimed in claim 2 or claim 3, which is characterized in that the oral preparation be tablet, capsule or
Granula；Ejection preparation is injection.
5. pharmaceutical composition according to any one of claims 1-4, which is characterized in that described for preventing and treating Alcoholic
The pharmaceutical composition of hepatopathy, selected from one of following combination object：
1）Including Kaempferol 0.5-70%, weight percent；
2）Including cupreol 0.03-70%, weight percent；
3）Including Tanshinone I 1.5-99%, weight percent；
4）Including Kaempferol 0.5-70%；Cupreol 0.03-70%；Tanshinone I 1.5-99%；It is weight percentage.
6. pharmaceutical composition as claimed in claim 5, which is characterized in that described for preventing and/or treating alcoholic liver disease
Pharmaceutical composition, composition selection following combination one kind：1）Kaempferol 5-55%, cupreol 10-60%, Tanshinone I
20-80%；2）Kaempferol 3-30%, cupreol 6-30%, Tanshinone I 10-50%, Quercetin 25-65%；It is weight hundred
Divide ratio；The percentage composition summation of composition is 100%.
7. such as pharmaceutical composition described in claim 5 or 6, which is characterized in that described pharmaceutical composition further includes pharmaceutically may be used
The auxiliary material of receiving or complementary ingredient.
8. pharmaceutical composition as claimed in claim 7, which is characterized in that described for preventing and/or treating alcoholic liver disease
Pharmaceutical composition, composition selection following combination one kind：
1）Kaempferol 0.35-54.5%, cupreol 0.7-59.4%, Tanshinone I 1.4-79.2%；It is pharmaceutically acceptable auxiliary
Material or complementary ingredient 1-93%；
2）Kaempferol 0.3-29.7%, cupreol 0.6-29.7%, Tanshinone I 1-49.5%, Quercetin 2.5-64.35%, medicine
Acceptable auxiliary material or complementary ingredient 1-90.0% on；It is weight percentage,
The percentage composition summation of composition is 100%.
9. as claim 1-8 any one of them pharmaceutical compositions application, described pharmaceutical composition prepare prevent and/or
Treat the application in alcoholic liver medicine and/or health products.
10. the application of pharmaceutical composition as claimed in claim 9, the application include：
Claim 1-8 any one of them pharmaceutical composition is in the drug for preparing prevention and/or treatment alcoholic liver disease
Using, claim 1-8 any one of them pharmaceutical composition prepare prevent and/or the health products for the treatment of alcoholic liver disease in
Application；Also include that can not only be used for the application that drug also can be used as health products in above application.
11. the application of pharmaceutical composition as claimed in claim 8 or 9, which is characterized in that the application is：Kaempferol, β-paddy
Sterol or Tanshinone I or claim 1-8 any one of them pharmaceutical composition are preparing liver organization fat lesion inhibitor
In purposes.
12. the application of pharmaceutical composition as claimed in claim 8 or 9, which is characterized in that the application is：Kaempferol, β-paddy
Sterol or Tanshinone I or claim 1-8 any one of them pharmaceutical composition are preparing inhibition serum glutamic pyruvic transminase and door
Application in the winter raised drug of histidine amino group transferase.
13. the application of pharmaceutical composition as claimed in claim 8 or 9, which is characterized in that the application is：Kaempferol, β-paddy
Sterol or Tanshinone I or claim 1-8 any one of them pharmaceutical composition are preparing serum and liver tg raising
Inhibitor in application.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20040084482A (en) * | 2003-03-28 | 2004-10-06 | 학교법인 원광학원 | A composition for treating hepatic fibrosis or cirrhosis containing tanshinone Ⅰ |
| CN101394860A (en) * | 2006-01-13 | 2009-03-25 | 范斯坦医药研究院 | Inhibition of inflammatory cytokine production with tanshinones |
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2017
- 2017-05-03 CN CN201710303185.7A patent/CN108785314A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20040084482A (en) * | 2003-03-28 | 2004-10-06 | 학교법인 원광학원 | A composition for treating hepatic fibrosis or cirrhosis containing tanshinone Ⅰ |
| CN101394860A (en) * | 2006-01-13 | 2009-03-25 | 范斯坦医药研究院 | Inhibition of inflammatory cytokine production with tanshinones |
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| 周海明等: "β-谷甾醇与豆甾醇对非酒精性脂肪肝作用的体外研究", 《营养学报》 * |
| 续洁琨等: "丹参酮类化合物对小鼠应激性肝损伤的保护作用", 《药学学报》 * |
| 郭媛媛: "山奈酚对急性肝衰竭模型的作用及对内质网应激诱导肝细胞凋亡的研究", 《万方数据知识服务平台》 * |
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Application publication date: 20181113 |