CN1241581C

CN1241581C - New application of polyphenol of natural phant as well as medication and/or health products containing polyphenol of natural plant

Info

Publication number: CN1241581C
Application number: CNB028049950A
Authority: CN
Inventors: 陈建操; 逯梅; 牛蓉
Original assignee: Individual
Current assignee: Individual
Priority date: 2001-02-21
Filing date: 2002-01-31
Publication date: 2006-02-15
Anticipated expiration: 2022-01-31
Also published as: CN1520308A; CN1370527A; WO2002092110A1

Abstract

The present invention discloses a new medicinal application of natural plant polyphenol, i.e., the new application of natural plant polyphenol on preparing medicines and health-care products for resisting protection viruses and treating and preventing spongiform encephalopathy caused by the protection viruses, particularly the medicines for treating and/or preventing mad cow disease, scrapie, creutzfeldt-jacob disease and new special creutzfeldt-jacob disease. Simultaneously, the present invention discloses medicines and/or health-care products prepared by using the natural plant polyphenol as active ingredients for resisting the protection viruses and treating and/or preventing spongiform encephalopathy caused by the protection viruses, particularly the medicines and/or health-care products for treating or preventing mad cow disease, scrapie, creutzfeldt-jacob disease and new special creutzfeldt-jacob disease.

Description

The natural plants polyphenol is in preparation treatment or prevent application in the soft virus disease medicine

Technical field

The medicine that the present invention relates to the natural plants polyphenol is newly used, be specifically related to the natural plants polyphenol and be used to prepare the medicine and/or the health product of anti-prion and treatment and prevention Protein virus associated diseases, especially preparation is treated and the prevention spongiform encephalopathy, medicine and/or health product as diseases such as bovine spongiform encephalopathy, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease belong to natural medicine field.

Prior art

Protein virus also claims toxalbumin, is to be used for defining a class to cause nervous system disease, specifically is the protein that causes diseases such as propagation (infection) property spongiform encephalopathy such as creutzfeldt-Jacob disease, new type Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, scrapie.Protein virus is present in the brain and its hetero-organization of people, domestic animal, animal usually, these organize the protein (PrPC) in the cerebral tissue especially, because the effect of cause specific causes the change of 26S Proteasome Structure and Function, thereby cause humans and animals to suffer from nervous system disease, mainly show as spongiform encephalopathy.The cerebral tissue of ill humans and animals forms spongy cavity, causes symptoms such as brain atrophy, mental disorder, dementia, and is final dead.

The protein structure that causes about Protein virus and the change of function, the scientist who has thinks protein denaturation, some scientists then think not to be protein denaturation, just protein folding is unusual, cause the change of protein function thereby make protein structure produce special change, so also claim prion disease (or toxalbumin disease) to be the protein conformation disease.

It is existing that research data is consistent thinks that Protein virus mainly contains following characteristics:

(1) Protein virus does not have nucleic acid, can make normal protein transfer to perniciously by optimum, is converted into infectivity by not having an infectivity; (2) Protein virus does not have the form of virus, is fibrous form; (3) Protein virus all has resistance to the physical chemical factor of all kill virus, and present sterilization method is invalid to it, only could be with its deactivation under the high pressure of 136 ℃ of high temperature and two hours; (4) Protein virus is long incubation period, is generally some months from infecting to morbidity, and what have reaches several years even decades, and in case symptom year 100% death half a year to one occurs; (5) difficult diagnosis does not produce immunoreation and antibody in patient's body behind the organism infection, do not generate heat, and inflammatory symptom do not occur, therefore is difficult for monitoring.

The Protein virus associated diseases is called for short TSE (transmissible spongiform encephalopathy) for can propagate the spongiform encephalopathy of (maybe can infect).The spongiform encephalopathy that animal suffers from mainly comprises: the spongiform encephalopathy of cattle (bovine spongiformencephalopathy is called for short BSE), or claim bovine spongiform encephalopathy (Mad Cow Disease); Scrapie (sheep scrapie or scrapie); Ermine infectiousness encephalopathy (TME); The Chronic consumptions of pronghorn.The spongiform encephalopathy that the people suffers from mainly comprises: creutzfeldt-Jacob disease (Creutzfeldt-Jakob disease is called for short CJD); New type Creutzfeldt-Jakob disease (new variant Creutzfeldt-Jakob disease is called for short nvCJD or vCJD); Kuru disease (claiming slows again); The special Man disease of Gus; Fatal familial insomnia.

Creutzfeldt-Jacob disease, new type Creutzfeldt-Jakob disease, Kuru disease that has now proved bovine spongiform encephalopathy, scrapie and people etc. all can be propagated by food infection.

Protein virus and due to spongiform encephalopathy, especially bovine spongiform encephalopathy, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease have caused global fear, and whole world economy particularly European and North America has been caused tremendous loss, cause suitable serious social concern thus.

Because Protein virus has unusual unique character, the whole world does not still have Transmissible spongiform encephalopathy due to active drug anti-prion and treatment and the prevention Protein virus at present.Therefore, seek and research anti-prion and treatment and prevention Protein virus due to spongiform encephalopathy, the medicine of especially treating and prevent bovine spongiform encephalopathy, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease is very urgent and important.

Plant polyphenol (Plant polyphenol) is a natural polyphenol, is that a class extensively is present in the intravital polyphenol compound of plant, and many researcheres are referred to as vegetable tannin or vegatable tannin, and its structure is existing to be identified and research fully.On chemical constitution, plant polyphenol (tannin) can be divided into hydrolysis class and condensation class two major types, and the former is the chemical compound that gallic acid and derivant thereof and glucose or polyhydric phenols mainly form by ester bond, as Gallotannin; The latter is to be the condensation substance of basic structural unit with the flavan-3-alcohol, as contained polyphenol (tannin) in the bark of dahurian larch.The characteristics of hydrolysis class polyphenol (tannin) are to meet acid, alkali or enzyme facile hydrolysis, generate the product of small-molecular weight simultaneously; And condensation class polyphenol (tannin) is easy to take place intermolecular condensation under acid, alkali or enzyme effect, produces the macromole product.Plant polyphenol (tannin) is because the polyphenol hydroxyl structure of himself has determined it to have stronger chemistry and physiologically active, and main character has: combine and and complexing of metal ion with protein, alkaloid, polysaccharide.

The kind of plant polyphenol is a lot, but then less as the polyphenol kind of extract form, as medicinal polyphenol extract still less.Medical value for these plant polyphenols and its extract mainly may be summarized to be antitumor, blood fat reducing, blood sugar lowering, blood pressure lowering, cholesterol reducing, atherosclerosis, prevention and treatment cardiovascular and cerebrovascular disease, antibiotic, anti-inflammatory, free radical resisting.In addition, some polyphenol extracts (as tea polyphenols, grape polyphenols) also use as food antioxidant.

The Chinese medicine that contains polyphenol (tannin) constituents is also more, as catechu, Radix Sanguisorbae, Pericarpium Granati, Rhizoma Polygoni Cuspidati, Ilex purpurea Hassk.[I.chinensis Sims, Cacumen Platycladi, Herba Polygoni Avicularis, Herba Agrimoniae, Herba Erodii, Radix Et Rhizoma Rhei, Galla Chinensis, Ramulus Uncariae Cum Uncis, Semen Arecae, Cortex cinnamomi japonici (Ramulus Cinnamomi), Herba Ephedrae etc.But the commodity that the Chinese medicine polyphenol extract arranged seldom.And in some Chinese medicines, polyphenol (tannin) is taken as useless refuse, often it is removed when the preparation Chinese patent medicine.Tannin in the Chinese medicine is mainly used in hemostasis, convergence (as antidiarrheal) and burn at present.In addition, some tannins in the Chinese medicine are hydrolysable tans, and toxic and side effects is bigger.

In a word, up to the present, the relevant plant polyphenol of Shang Weijian is used for spongiform encephalopathy due to anti-prion and treatment and the prevention Protein virus, especially treats and prevent the report of bovine spongiform encephalopathy, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease.

Summary of the invention

The objective of the invention is to seek spongiform encephalopathy due to a kind of anti-prion and treatment and the prevention Protein virus, especially treat and prevent the active drug composition of bovine spongiform encephalopathy, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease, a kind of new medicinal application of plant polyphenol extract is proposed, be that plant polyphenol is used to prepare spongiform encephalopathy due to medicine and/or health product anti-prion and treatment and the prevention Protein virus, especially treat and prevent the new application of bovine spongiform encephalopathy, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease.

Another object of the present invention provides with plant polyphenol or plant polyphenol extract as spongiform encephalopathy due to active component anti-prion and treatment and the prevention Protein virus, especially treats and prevent the medicine and/or the health product of bovine spongiform encephalopathy, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease.

For achieving the above object, the present invention at first provides plant polyphenol to be used to prepare spongiform encephalopathy due to medicine and/or health product anti-prion and treatment and the prevention Protein virus, especially treat and prevent the new application of diseases such as bovine spongiform encephalopathy, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease, described health product and/or medicine oral administration, external, transdermal, injection, rectum or parenterai administration;

Simultaneously, the spongiform encephalopathy due to anti-prion and treatment and the prevention Protein virus that is used for the preparation of the natural polyphenol that extracts in the plant is provided, especially treat and prevent the medicine and/or the health product of bovine spongiform encephalopathy, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease, wherein, described natural plants polyphenol is Folium Camelliae sinensis extract tea polyphenols, tea catechin, Semen Vitis viniferae and Pericarpium Vitis viniferae extract grape polyphenols, Cortex Pini Massonianae extract Pine Procyanidins, Catechu extract catechin; Described natural plants polyphenol can be plant extract tea polyphenols, tea catechin, grape polyphenols, Pine Procyanidins, catechin polymer and/or derivant separately; The polymer of described natural plants polyphenol and/or derivant are preferably tea pigment, Grape cyanidins, Pine cyins, youngster's tea pigment; Described natural plants polyphenol can also can mix and use two or more singly with a kind of, also can share with other non-polyphenol pharmaceutical compositions; The content of natural plants polyphenol is 1% to 100%, is preferably 20% to 90%.

Said medicine and/or health product, the natural plants polyphenol is main active constituent, comprise that also adding one or more is selected from excipient substances such as conventional excipient, flavoring agent, disintegrating agent, antiseptic, lubricant, wetting agent, binding agent, solvent, thickening agent, solubilizing agent, make any dosage form that is suitable for using clinically, as tablet, capsule, granule, oral liquid, injection etc.

There are some researches show that the propagation of Protein virus, replication form are the propagation of protein self and duplicate.The antibacterial of Fa Xianing, virus, the parasitic infection genetic stocks that must dependence can duplicate though Protein virus does not have this genetic stocks, still can duplicate, bred and cause fatal infection in the past.This breeding and replication form have broken through life heredity and the necessary biological central dogma that relies on nucleic acid (DNA and RNA) of breeding.No gene Protein virus (toxalbumin) does not rely on any genetic stocks, with regard to reproducible, propagation and infection.Existing theory is not made compellent explanation as yet to this, existing medicine is also powerless to prion disease.Known disease is just treated and prevented and treated to existing medicine role and model of action, and for Protein virus and due to spongiform encephalopathy, especially then effect or effect are very not little for creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease.

The present invention studies according to the characteristic of protein and Protein virus, and searching can deactivation Protein virus or prevention, delay the infectious chemical compound of Protein virus, thus the design medicine.

The essence of Protein virus is the protein of proteinic variation or variation (structure, character and function variation), no matter the protein of this variation is by which kind of reason to be caused actually, no matter whether also this proteinic initial variation has positive meaning as described in existing research, but the result of this variation finally is virulent, is fatal to people and domestic animal.Because (1) Protein virus free nucleic acid, just protein in action, (2) Bian Yi protein is the change of structure, and Protein virus still still finds no change as this person's character of protein, therefore, the mode that medicine works just should be different with other medicine, and drug effect should be directly to the protein effect, and such effect should be embodied in following one or more aspects at least: the 26S Proteasome Structure and Function of (1) recovery or reduction variant protein matter; (2) stop or delay variant protein matter and infect other protein, perhaps stop or delay the propagation of variant protein matter or duplicate; (3) consolidate the 26S Proteasome Structure and Function of normal protein matter, protect it not to be subjected to the infection of variant protein matter or delay its infection velocity.(4) with protein bound after, prevent and alleviate adhering to and adhesion of the thing that causes a disease.

To the most influential native compound of protein is plant polyphenol (polyphenol) class material, and this in theory gains public acceptance.Typical example be with plant polyphenol (vegetable tannin or vegatable tannin) with rawhide tanning finished leather, almost the whole world all with plant polyphenol as traditional tanning agent.And other plant component can not resemble the polyphenol and the effect that has influence strongly and so like this takes place protein, and oneself is fully proved in human over the past thousands of years practice for this, has in theory also obtained sufficient research.

Of particular note, in the medicinal application of plant polyphenol, the researcher of existing medicine and medicine more is to emphasize the especially antioxidation of tea polyphenols, grape polyphenols and Pine Procyanidins of plant polyphenol (polyphenol), and more this class polyphenol is used as anti-oxidation medicine and free radical scavenger.Because polyphenol has hydroxyl, and tangible hydrogen supply effect is arranged, and is a kind of antioxidant really.And the of paramount importance characteristic of polyphenol is not an antioxidation, thus but the special role that produces with protein bound.Many research datas and pharmacological action explanation, the effect of polyphenol and the mutual structure of protein, or turn into being its marked feature with proteinic crosslinked action or to proteinic tanning.Have research data to show, polyphenol and protein bound increase proteinic chemical stability and physical stability.Plant polyphenol is as medicine, and the basis of its most pharmacological actions also is the effect with the protein generation.Such as effects such as the anti-inflammatory of tea polyphenols, grape polyphenols, Pine Procyanidins, antibiotic, antiviral, anticancer, deodorization is exactly that polyphenol and protein act on typical case's performance on the pharmacology.The antibacterial action of polyphenol is that polyphenols can precipitate tropina, makes the tropina degeneration and inactivation.Research worker has been studied antibacterial, the killing action of Galla Chinensis experiment in vitro to multiple coccus (staphylococcus, streptococcus) and bacillus (typhoid fever, paratyphoid fever, dysentery, anthrax, diphtheria, green pus, escherichia coli), finds that its antibacterial action is because due to the contained tannin coagulated protein.The anticaries action of tea polyphenols also is polyphenol and cariogenic bacteria protein bound and kill the result of thalline.Have research worker that pig, chicken and slop are tested, behind two all feeding tea polyphenols, its excretory feces stink significantly alleviates, and reason is that tea polyphenols and enteral produce malodorous bacterioprotein and combine the effect that embodies.The research worker of China finds that tea polyphenols can make cancerous cell " apoptosis " when research tea polyphenols anticancer mechanism, this " apoptosis " thus phenomenon is exactly cancerous cell protein is blocked nutrient delivery by tanning of polyphenol result according to one's analysis.

Therefore, the most important character that shows of plant polyphenol (mainly referring to the condensed tannin class) mainly is that what to produce with protein bound is tannin (tannin) characteristic.

Another important result of polyphenol and protein bound is, polyphenol and protein form crosslinked after, can prevent and alleviate adhering to and adhesion of other pathogenic things.Japan studies show that, catechin in the Folium Camelliae sinensis suppresses the active mechanism of influenza virus, influenza mainly is that virus is caused a disease attached to constantly breeding on the mucomembranous cell of projection in nose and the throat, gargle through tea commonly used, catechin can cover on the mucomembranous cell of projection, prevent influenza virus and mucosa combination, and kill virus.There are some researches show that also tea polyphenols not only has cariogenic bacteria directly to be killed and inhibitory action, and it can suppress the adhesion of antibacterial at dental surface.Research is also found, can suppress the periodontitis pathogenic bacteria and stick on the Stomatocyte when using the collutory that contains tea polyphenols.There are some researches show that also polyphenol acts on mucosa and wound surface ulcer, protein precipitation is solidified, become undissolved chemical compound, and form thin film,, prevent to be subjected to new infection, also prevent the invasion and attack once again of pathogenic thing the affected part overlap.

An effect of particular importance is as if preferred mainly is the polyphenol (as tea polyphenols, grape polyphenols and Pine Procyanidins) of small-molecular weight as medicinal plant polyphenol, and human body even organism are had special optionally enthusiasm meaning.Show that this class polyphenol plays protective effect to normal cell and normal protein matter, and abnormal cell and protein thereof are played destruction.This has obtained illustrating more fully in the theoretical research of tea polyphenols, grape polyphenols and Pine Procyanidins and practical application.This class polyphenol has the therapeutical effect of wide model, and people's physiology is not found harmful effect as yet.The plant polyphenol that with the tea polyphenols is representative is in China, Japan, the Italy and the research of other numerous countries and application note this problem, with grape polyphenols and Pine Procyanidins is that the plant polyphenol (representing with procyanidin usually in theory, commercial often with " Lean, Portugal ", " pycnogenol " expression) of representative has also illustrated this problem in much national researchs and application such as Germany, France, Italy, the U.S., Japan, India, Hungary, Korea S.Be typically tea polyphenols, grape polyphenols and Pine Procyanidins and can suppress antibacterial and harmful microorganism in the body, for then not influence of beneficial microbe.Such as, tea polyphenols at the strong inhibition cariogenic bacteria, obviously reduce bacterial plaque and periodontal index in, to but not influence of other beneficial microbes in the oral cavity.Grape polyphenols, tea polyphenols have the inhibition effect to much causing human carcinogen's microorganism as bacillus botulinus, and don't the procreation of injury enteral beneficial microbe such as lactobacillus, also have the function of cleaning intestinal.Tea polyphenols combines with human cell membrane, structure that can stabilizing cell membrane, and for sick cell such as cancer cell membrane, its tanning result then has destruction.

The good effect of preferred plant polyphenol not only shows on the living body biological, and the effect that isolated cells and organ are also shown same brilliance.Japan studies show that for the preservation of zooblast and organ, by add the catechin plant polyphenol in cell culture fluid or organ preservative fluid, can make cell and organ holding time improve several times than existing preservative agent.The cell of its preservation and organ and wide model thereof, its test confirm that clearly polyphenol can make protein stability improve.

The present invention according to Protein virus and due to the characteristics of spongiform encephalopathy and plant polyphenol, be used for anti-prion and treatment and prevention Protein virus associated diseases, especially treat and prevent the plant polyphenol of human creutzfeldt-Jacob disease (CJD) and new type Creutzfeldt-Jakob disease (vCJD) to select, taken all factors into consideration all multifactorly, these factors mainly contain:

(1) polyphenol (tannin) that molecular weight is too greatly, the degree of polymerization is too high generally not can be used as medicinal, and reason is:

A, this class polyphenol act on too strong to proteinic tanning (tanning), sacrifices consisting of an ox, a sheep and a pig solid with protein bound, generally are irreversible combinations, and the physiology of humans and animals will be adversely affected or suffer damage.The Chinese scholar is after research vegatable tannin and combination of proteins, and the conclusion that draws is: the tannin molecular weight produced more firm combination greater than 500 o'clock, and the tannin molecular weight is big more usually, and is strong more with combination of proteins.And the degree of polymerization increases, and corresponding molecular weight is just big, and the tannin degree of polymerization is directly proportional with itself and combination of proteins degree.In addition, Chinese science man's research also shows, tannin can influence digestion and the absorption of humans and animals to protein, cellulose, starch and fat and some metallic elements, reduce the nutritive value of food, the principal element of influence is the binding ability of materials such as tannin and protein, and promptly the binding ability of digestibility and tannin is inversely proportional to.Therefore, should not select the too big and too high polyphenol of the degree of polymerization of molecular weight.

B, Protein virus and due to the pathogenic site or the general more brain that is present in of protein variations of spongiform encephalopathy, the plant polyphenol with the oil-soluble difference that molecular weight is bigger is difficult to by blood brain barrier (considerable tannin molecular weight is 1000-3000);

(2) preferred condensation class polyphenol (tannin), main reason is:

A, in the plant polyphenol of numerous small-molecular weights, have only part polyphenol (being generally the condensation tanninoids) to have the tannin effect, and that many hydrolysis micromolecular amount tannins (polyphenol) are not had tannin (tanning) effect or a tannin effect is very faint;

B, hydrolysable tan have suitable side effect, and existing data proves, are present in the hepatic injury that this tanninoids in the Chinese medicine has caused humans and animals.The place of some foster Trionyx sinensis Wiegmanns of China, Galla Chinensis control trionyx disease commonly used because it contains a large amount of hydrolysable tans, causes Trionyx sinensis Wiegmann serious hepatopathy to occur and death.Research proves, even the Gallotannin external when the large tracts of land time spent, can be absorbed and be poisoned by wound surface, liver is had violent toxicity, causes hepatic necrosis when serious.

(3) do not have medicine or edible historical polyphenol (tannin) generally need not or careful usefulness;

(4) harmless to brain.Because cerebral tissue is most important to humans and animals, and relatively more fragile, and medication must be careful especially, even many medicine good effects also belong to forbidding.

(5) should there be wide resource, price to accept.

Xu Shu condition to sum up can satisfy the plant polyphenol chemical compound of above condition, and its molecular weight is generally at 200-800, more the superior is 200-600, often the form with monomer and/or oligomer (2,3,4 aggressiveness) exists, and has parents' structure, can see through blood brain barrier; Have appropriate degree and the effect mutual structure of protein, can be used for improving proteinic function and stability, it is optimum the combination with combination of proteins, and is reversible combination; Harmless to brain; Has stronger antioxidation; Resource is wide, moderate; Oneself is used as medicine, health food or food (nutrition) reinforcing agent by some state approvals.

According to above-mentioned research, the plant polyphenol extract that the present invention is used to prepare medicine and health product can be selected multiple, preferably: Folium Camelliae sinensis extract-tea polyphenols (Tea polyphenols) and tea catechin; Semen Vitis viniferae and Pericarpium Vitis viniferae extract-grape polyphenols (Grapepolyphenols); Cortex Pini Massonianae extract-Pine Procyanidins (pine polyphenols); The Catechu extract catechin.It is more to contain polyphenol in the Semen Vitis viniferae, is the main source of grape polyphenols.

Tea polyphenols is the mixture of the polyphenols that extracts in the Folium Camelliae sinensis, contains multiple polyphenol component, comprises more than 30 kind of polyphenol components such as catechin, flavonoid glycosides, cyanine glycoside, phenolic acids, belongs to the phenolic hydroxyl group natural phenolic compound.

Tea catechin is the main body composition of tea polyphenols, is about the 60-80% of tea polyphenols, now has from Folium Camelliae sinensis or the product of the tea catechin that extracts from tea polyphenols.

Catechin is the main component of Chinese medicine catechu, and its effect is similar to tea catechin, and existing catechin extract commodity.

Grape polyphenols also claims Fructus Vitis viniferae procyanidin (Grape Procyanidins), and Pine Procyanidins also claims pinaster procyanidin (Pine Procyanidins), belongs to the phenolic hydroxyl group natural phenolic compound.(Procyanidins is called for short PC to procyanidin, and other once exhausted English name has proanthocyanidins, and leucoanthocyanidins pycnogenol), is the general name of an extensive big class polyphenolic substance that exists in the plant.Former system belongs to condensed tannin or flavanol compound, has now become a big class material of taking the course of its own and has been referred to as procyanidin.Generally speaking, polyphenolic substance heats in acid medium can produce anthocyanidin (cyanidins), therefore, usually this class can be produced the polyphenolic substance called after procyanidin of anthocyanidin.Procyanidin is by the catechin of varying number or epicatechin be combined into.The simplest procyanidin is the dimer of catechin or epicatechin or catechin and epicatechin formation, also has trimer, the tetramer etc. in addition until ten aggressiveness.By the size of the degree of polymerization, usually two～tetramer is called oligomer (procyanidolic oligomers is called for short OPC), will be called high polymer (procyanidolic polymers is called for short PPC) more than the pentamer.The plant polyphenol extract that the present invention is used to prepare medicine and/or health product comprises procyanidin.

The present invention is used to prepare the plant polyphenol of medicine and/or health product, also comprises the polymer and the derivant of plant polyphenol extract and its extract.Tea polyphenols, tea catechin, grape polyphenols, Pine Procyanidins, catechin polymer and derivant separately preferably arranged.

The polymer of plant polyphenol extract and derivant are obtained by methods such as physics, chemistry by plant polyphenol extract.Be typically tea pigment (Tea pigment), catechu pigment, Grape cyanidins (Grape cyanidins), Pine cyins (Pain cyanidins).

Tea pigment normally tea polyphenols or tea catechin obtains after oxidation, comprises theaflavin, thearubigins and abrownin.Tea polyphenols and catechin solution overflow when hot or under the effect of enzyme, acid, alkali, self oxidable condensation product that is condensed in various degree; The catechu pigment obtains after by the catechin oxidation; Grape cyanidins and Pine cyins heat generation by grape polyphenols (or Fructus Vitis viniferae procyanidin) and Pine Procyanidins (or pinaster procyanidin) usually in acid medium.

The preparation method of the extract of these plant polyphenols and polymer thereof, derivant has multiple, and multiple report is arranged, and belongs to known technology and maturation process, and existing commodity selling.

The plant polyphenol extract and its polymer, the derivant that obtain with these methods with additive method can be used as medicinal.

The implication of " medicine and/or health product " is meant above-named natural plants polyphenol, can be used to prepare medicine, also can be used to prepare health product; The material of certain natural plants polyphenol preparation can be used as drug use, also can be used as health product and uses.

The medicine of natural plants polyphenol of the present invention and preparation thereof and/or health product are used for anti-prion and treatment or prevention Protein virus associated diseases, comprised the spongiform encephalopathy that all Protein viruss cause, these diseases mainly contain: the diseases such as Chronic consumptions of the bovine spongiform encephalopathy that animal suffers from, scrapie, ermine infectiousness encephalopathy, pronghorn, diseases such as the creutzfeldt-Jacob disease that the people suffers from, new type Creutzfeldt-Jakob disease, Kuru disease, the special Man disease of Gus, fatal familial insomnia.

Plant polyphenol of the present invention and polyphenol extract and polymer thereof and derivant are active constituents of medicine, when medicine for preparing the present invention's proposition or health product, polyphenol and its polymer, derivant can be singly with a kind of, also can mix and use two or multiple, also can share with other non-polyphenol pharmaceutical compositions.

Plant polyphenol extract of the present invention is during as medicament active composition, preparation process according to routine, can be main active constituent with plant polyphenol, add excipient substances such as one or more conventional excipient, flavoring agent, disintegrating agent, antiseptic, lubricant, wetting agent, binding agent, solvent, thickening agent, solubilizing agent, make any dosage form that is suitable for using clinically, as tablet, capsule, granule, oral liquid, injection etc.

Plant polyphenol of the present invention is made medicine and/or health product, and the content of plant polyphenol can from 1% to 100% wait in medicine and/or the health product, generally adopts 20% to 90%.

Spongiform encephalopathy due to plant polyphenol anti-prion of the present invention and treatment and the prevention Protein virus, especially treat and prevent bovine spongiform encephalopathy, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease, available multiple administering mode, as oral, as external, transdermal, injection, rectum or parenterai administration.

Except the above-mentioned natural polyphenol extract that obtains from plant, the present invention can also directly use the former plant that comprises these natural polyphenol components.When using former plant, can be directly in people's food and animal feed, add, also former plant can be processed and add in food or beverage or the animal feed.

Because the present invention discloses spongiform encephalopathy due to plant polyphenol anti-prion and treatment and the prevention Protein virus first; especially treat and prevent the pharmacologic action of bovine spongiform encephalopathy, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease; therefore; plant polyphenol is cooperated the making medicament separately or with other medicines active constituent or adjuvant; as long as this medicament is used for spongiform encephalopathy due to anti-prion and treatment and the prevention Protein virus; especially treat and prevent bovine spongiform encephalopathy, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease, then belong to protection scope of the present invention.

Plant polyphenol of the present invention all has spongiform encephalopathy due to anti-prion and treatment and the prevention Protein virus when making any dosage form, especially treat and prevent the effect of bovine spongiform encephalopathy, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease.Any medicament; if contain plant polyphenol in its component or only prepare patent medicine with plant polyphenol; on signs such as its packing or description; and on other any propaganda materials; as long as indicate or prompting has spongiform encephalopathy due to anti-prion and treatment and the prevention Protein virus; especially treat and prevent the effect of bovine spongiform encephalopathy, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease, then fall within protection scope of the present invention.

Plant polyphenol of the present invention can be made health food and health care medicine.Health food or the health care medicine made with plant polyphenol of the present invention; if on signs such as its packing or description, indicate or prompting has spongiform encephalopathy due to anti-prion and treatment and the prevention Protein virus; especially treat and prevent the effect of bovine spongiform encephalopathy, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease, also fall within protection scope of the present invention.

The present invention also provides a kind of anti-prion and treatment or the medicine of prevention Protein virus associated diseases and/or the using method of health product, promptly adds in people's food and animal feed and contains the former plant of natural plants polyphenol and/or the polymer and the derivant of natural plants polyphenol extract and/or extract.These plants mainly contain: Folium Camelliae sinensis, Semen Vitis viniferae, Pericarpium Vitis viniferae, Cortex Pini, catechu.The extract of these plants mainly contains: tea polyphenols, tea catechin, grape polyphenols, Pine Procyanidins, catechin.The polymer and the derivant of these polyphenol extracts mainly contain: tea pigment, Grape cyanidins, Pine cyins, catechu pigment.

The a kind of of these plants or extract or polymer or derivant can be added, also two or more can be added.Its effect is a spongiform encephalopathy due to anti-prion and treatment and the prevention Protein virus, especially treatment or prevention bovine spongiform encephalopathy, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease.

The specific embodiment

Embodiment 1

Prescription

Tea polyphenols 800 grams

Lactose 200 grams

Above-mentioned component is stirred, encapsulated, every filling 0.5 gram.Make 2000 of tea polyphenols capsules, every capsules contains 400 milligrams of tea polyphenols.

Embodiment 2

Prescription

Grape polyphenols 800 grams

Lactose 200 grams

Above-mentioned component is stirred, encapsulated, every filling 0.5 gram.Make 2000 of grape polyphenols capsules, every capsules contains 400 milligrams of grape polyphenolss.

Embodiment 3

Prescription

Pine Procyanidins 800 grams

Lactose 200 grams

Above-mentioned component is stirred, encapsulated, every filling 0.5 gram.Make 2000 of Pine Procyanidins capsules, every capsules contains 400 milligrams of Pine Procyanidins.

Embodiment 4

Prescription

Tea polyphenols 400 grams

Grape polyphenols 400 grams

Lactose 200 grams

Above-mentioned component is stirred, encapsulated, every filling 0.5 gram.Make 2000 of tea polyphenols and grape polyphenols capsules, every capsules contains 400 milligrams of tea polyphenols and grape polyphenolss.

Embodiment 5

Prescription

Tea polyphenols 300 grams

Grape polyphenols 300 grams

Pine Procyanidins 200 grams

Lactose 200 grams

Above-mentioned component is stirred, encapsulated, every filling 0.5 gram.Make and mix 2000 of polyphenol capsules, every capsules contains 400 milligrams of tea polyphenols, grape polyphenols and Pine Procyanidins.

Embodiment 6

Prescription

Grape cyanidins 800 grams

Lactose 200 grams

Above-mentioned component is stirred, encapsulated, every filling 0.5 gram.Make 2000 of Grape cyanidins capsules, every capsules contains 400 milligrams of Grape cyanidins.

Embodiment 7

Prescription

Pine cyins 800 grams

Lactose 200 grams

Above-mentioned component is stirred, encapsulated, every filling 0.5 gram.Make 2000 of Pine cyins capsules, every capsules contains 400 milligrams of Pine cyinss.

Embodiment 8

Prescription

Tea pigment 800 grams

Lactose 200 grams

Above-mentioned component is stirred, encapsulated, every filling 0.5 gram.Make 2000 of tea pigment capsules, every capsules contains 400 milligrams of tea pigments.

Embodiment 9

Prescription

Tea pigment 300 grams

Grape cyanidins 500 grams

Lactose 200 grams

Above-mentioned component is stirred, encapsulated, every filling 0.5 gram.Make 2000 of tea pigment and Grape cyanidins capsules, every capsules contains 400 milligrams of tea pigment and Grape cyanidins.

Embodiment 10

Prescription

Tea polyphenols 200 grams

Grape cyanidins 300 grams

Pine cyins 300 grams

Lactose 200 grams

Above-mentioned component is stirred, encapsulated, every filling 0.5 gram.Make 2000 of tea polyphenols, Grape cyanidins and Pine cyins capsules, every capsules contains 400 milligrams of tea polyphenols, Grape cyanidins and Pine cyinss.

Embodiment 11

Prescription

Grape polyphenols 300 grams

Pine Procyanidins 300 grams

Tea pigment 200 grams

Lactose 200 grams

Above-mentioned component is stirred, encapsulated, every filling 0.5 gram.Make 2000 of grape polyphenols, Pine Procyanidins and tea pigment capsules, every capsules contains 400 milligrams of grape polyphenols, Pine Procyanidins and tea pigments.

Embodiment 12

Pine Procyanidins 250 grams

2000 milliliters of distilled water

Stevioside 1 gram

Pine Procyanidins is dissolved in stirring and evenly mixing in the distilled water, adds stevioside, stirring and evenly mixing is bottled once more, and every bottled 10 milligrams, sterilization makes the Pine Procyanidins oral liquid.

Embodiment 13

Prescription

Grape polyphenols 15 grams

White sugar 50 grams

Citric acid 5 grams

Carbonated water 930 grams

A small amount of Herba Menthae, vanilla

Various raw materials are mixed, stir, bottle, make the grape polyphenols beverage.

Embodiment 14

Tea polyphenols 130 grams

Pine Procyanidins 120 grams

2000 milliliters of distilled water

Stevioside 1 gram

Tea polyphenols and Pine Procyanidins are dissolved in stirring and evenly mixing in the distilled water, add stevioside, stirring and evenly mixing is bottled once more, and every bottled 10 milligrams, sterilization makes tea polyphenols and Pine Procyanidins oral liquid.

Embodiment 15

98 kilograms of animal feeds

2 kilograms of tea polyphenols

Mix, stir, make the feedstuff that contains tea polyphenols.

Embodiment 16

96 kilograms of animal feeds

3 kilograms of Folium Camelliae sinensis

1 kilogram of Cortex Pini

Folium Camelliae sinensis and Cortex Pini are blended, become powdered, mix, make the feedstuff that contains natural polyphenol with feedstuff.

Natural polyphenol of the present invention is as the biocompatibility of medicine

Oneself has pharmacological research and clinical practice quite fully in many countries tea polyphenols, grape polyphenols and Pine Procyanidins, and existing multiple medicine and health product commodity, illustrates that it is quite safe and effective using this class polyphenol.

The safety in utilization of preferred polyphenol: many countries mainly are that tea polyphenols, grape polyphenols and Pine Procyanidins have carried out deep toxicologic study to the small-molecular weight polyphenol.Its result confirms that it is safe that this class polyphenol uses.As China to the acute and chronic toxicological study result of tea polyphenols be: the LD50 of rat and the oral tea polyphenols of mice is 2499mg/Kg, and animal is taken the toxicity that body weight, routine blood test, hepatic and renal function and organs and tissues do not appear in tea polyphenols for a long time and changes; Many countries to the toxicological study results of grape polyphenols and Pine Procyanidins (representing with procyanidin) are: the LD50 of rat and the oral procyanidin of mice all more than 4000mg/Kg, without any side effects and well-tolerated.No teratogenesis, mutagenic action.Aspect reproduction, the jenny of taking procyanidin is all fool proof before and after fertility.

Preferred polyphenol is as the biocompatibility of medicine: US and European is to being that wide model and deep research have been done in the pharmacological action of the procyanidin class polyphenol of representative with Fructus Vitis viniferae procyanidin and pinaster procyanidin, and the existing medicine made from procyanidin separately and the effect of health food mainly contain: antiinflammatory, antihistamine, antiallergic, antiulcer, the preventive and therapeutic effect to cardiovascular disease, prophylaxis of cancer, health-care effect, treatment and prevention cataract, treatment and prevention pulmonary disease to tooth and dental bed.Wide model and deep research have been done to the pharmacological action of tea polyphenols and tea pigment in China, Japan, Europe, and only the kind of medicine made from tea polyphenols and tea pigment separately and health product relates to the many-sided disease of treatment more than 10 kinds.Wherein a kind of tea polyphenols capsule and a kind of tea pigment capsule also are approved for national two kind new medicines.With tea polyphenols is that the medicine and the health product kind of main active component is various especially.Main therapeutic efficiency has: antibiotic, antiviral, anticancer, mutation, antioxidation, treatment cardiovascular disease, antiallergic, antiinflammatory, immunomodulating, protection gastrointestinal function, blood sugar lowering.What need explain especially is that brain diseases can effectively be treated and prevent to preferred plant polyphenol.The advantage of discovering procyanidin and tea polyphenols has: absorb through stomach; Enter blood system then immediately, be distributed to each organ and tissue; The interior holding time of body is long, and the procyanidin that has can reach 72h; Dissolubility is good, does not almost have saturation, the bioavailability height; Can see through blood/brain barrier, neuroprotective tissue.The many researchs and the practical application in the U.S., Europe show, are that the procyanidin of representative can be used for the treatment of and prevent Alzheimer's disease, parkinson and Heng Ting chorea with grape polyphenols and Pine Procyanidins.Chinese scholar's research also shows, available tea polyphenols and Pine Procyanidins treatment Parkinson's disease and Alzheimer's disease (senile dementia).In China, be country's two kind new medicines " heart and brain are good for capsule " of unique composition with tea polyphenols, be used for the treatment of the cerebrovascular sclerosis disease.Therefore, preferred natural plants polyphenol can act on brain, and to not damage of brain.

Plant polyphenol of the present invention is tested as the active component anti-prion:

The agent (scrapie agent) of causing a disease of the scrapie of this experiment usefulness is the strain that mice adapts to.Derive from the pathogenic agent of the natural infectivity of sheep.The Medulla caprae seuovis extract of infected Protein virus through being transmitted, the mice of cultivating is at random obtained the test infected material.

Experiment one: polyphenol and Protein virus form structural test

With purity is 98.5% tea polyphenols, 98% grape polyphenols and 98% Pine Procyanidins, is mixed with tea polyphenols, grape polyphenols and the Pine Procyanidins solution of 300mL respectively with distilled water, and it is 5% that every kind of solution contains polyphenol concentration.The pathogenic thing of three parts of 30mL volume scrapie is put into three kinds of polyphenol solution respectively, stir.Observe after 30 minutes, the thing that as seen causes a disease combines the back rapid precipitation with polyphenol, almost all precipitate after three hours.From settling velocity, thing and the settling velocity after grape polyphenols and Pine Procyanidins combine of causing a disease faster than with settling velocity after tea polyphenols combines.Precipitate placed under the Electronic Speculum observe, visible pathogenic protein matter and polyphenol combine consumingly, and crosslinked phenomenon is arranged.Bond strength: grape polyphenols and Pine Procyanidins are better than tea polyphenols.With all sample stored refrigerated, after 3 days, as seen membranaceous in the formation of azelon surface, adhesiveness reduces.Prion protein has the phenomenon of hardening, and all after-hardening strengthen.After 15 days, the pathogenic thing of respectively polyphenol having been handled separates, and is made as test and use infected material, is numbered A1, A2, and A3 is for follow-up test usefulness.

From analysis of experiments, (1) Protein virus still can form structure and rapid precipitation with polyphenol as the variation of normal PrPC, and has the glue coproduction to give birth to.(2) the infected material protein surface produces the hardening phenomenon, with the similar phenomena of polyphenol as the astringency solidifying protein.(3) infected material protein fibre surface has produced membranaceous phenomenon, and adhesiveness reduces.The prompting Protein virus does not obviously change as proteinic person's character, and polyphenol may exert an influence to Protein virus, may alleviate with the adhesion of its hetero-organization after polyphenol and the infected material protein binding and adheres to.

Experiment two: infecting mouse controlled trial

90 mices are divided into three groups, 30 every group (male and female half and half), (1) first group of infected material A through the polyphenol processing with experiment one gained ₁, A ₂, A ₃Each inoculates 10 mices (male and female half and half).Sub-cage rearing is numbered A ₁Cage, A ₂Cage, A ₃Cage.(2) second groups 30, use the infected material inoculation mice of handling without polyphenol, divide three cages, 10 in every cage (male and female half and half) is numbered B ₁Cage, B ₂Cage, B ₃Cage.B ₁Cage every day is with food tea polyphenols, B ₂Cage every day is with food grape polyphenols, B ₃Each cage adds appetite and is gram/per kilogram every day 0.1 cage with the food Pine Procyanidins every day.Organize in contrast for (3) the 3rd groups, use the infected material of handling without polyphenol to inoculate 30 of mices, divide three cages, 10 in every cage (male and female half and half) is numbered C ₁Cage, C ₂Cage, C ₃Cage.

Conditions such as three groups of feedstuffs, drinking-water are identical.With 120 days, 240 days, 360 days and 480 days was timing statistics unit respectively.

Judge whether infect according to the prion-infected typical clinical feature of generally acknowledging, these features comprise to height noise sensitivity, dystropy, trichosis setosa, urinate irregular, One's eyesight is restrained etc.And use generally acknowledge at present to detection method in the mice body of prion-infected disease, the cerebral tissue of dead mice is carried out standard that the histology the identifies infection standard according to the prion disease of generally acknowledging.

The result:

(1) C group part mice began to occur abnormal symptom in 120 days, and same feature all occurred in 480 days, and its feature is consistent with prion-infected clinical typical characteristic, and histopathological examination has been confirmed to belong to prion-infected.3 survivals are arranged in this group, and the mice that still can not judge survival is to be caused by the inoculation error, still infects long causing incubation period.

(2) A organizes only A ₁Cage has 1 mice behavior to have slightly unusually, and time of occurrence is also later.Whether its feature only has part similar to prion-infected typical clinical feature, does not see typical Protein virus pathology feature through making histopathological examination, can not judge prion-infected.

(3) the B group is that every day is with the food polyphenol behind the inoculation infected material, only there is 1 mice that adds food tea polyphenols cage abnormal symptom to occur in the later time, but have only part similar to the typical clinical feature of prion disease, do not see typical prion disease pathological characters through histopathological examination.Whether can not confirm prion-infected disease.

Discuss: behind the infected material inoculation mice that polyphenol is handled, do not see that mice typical case Protein virus pathology feature produces, and does not have 1 death; The infected material that inoculation is handled without polyphenol, but the mice of feeding polyphenol does not see prion disease typical case pathological characters equally continuously, does not have 1 death yet; And the Clinical symptoms of prion disease all appears in 30 mices of matched group that inoculate infected material simultaneously, and 27 death are arranged, and histopathological examination is confirmed to be the infection of prion disease.The prompting polyphenol has the effect of anti-prion, maybe can delay the disease time after prion-infected and delay death time of prion-infected back mice.

Result of the test is added up 1 (the statistics natural law is interior between referring at this moment) that see the following form.

Table 1

Natural law	A organizes (polyphenol processed group)						B group (adding food polyphenol group)						C organizes (matched group)
	A organizes (polyphenol processed group)						B group (adding food polyphenol group)						C organizes (matched group)						A1 tea		The A2 Portugal	The A3 pine	B1 tea		The B2 Portugal	The B3 pine	C1		C2		C3
	Unusually	Dead	Unusually	Dead	Unusually	Dead	Unusually	Dead	Unusually	Dead	Unusually	Dead	Unusually	Dead	Unusually	Dead	Unusually	Dead	A1 tea		The A2 Portugal	The A3 pine	B1 tea		The B2 Portugal	The B3 pine	C1		C2		C3
	Unusually	Dead	Unusually	Dead	Unusually	Dead	Unusually	Dead	Unusually	Dead	Unusually	Dead	Unusually	Dead	Unusually	Dead	Unusually	Dead	120									1		1		2
240													3	1	3	2	3		120									1		1		2
240													3	1	3	2	3		360									5	2	3	1	2	1
480	1						1						1	7	3	6	3	7	360									5	2	3	1	2	1
480	1						1						1	7	3	6	3	7	Add up to	1				1				10	10	10	9	10	8

Industrial applicability

The present invention has enlarged the range of application of natural plants polyphenol, has improved its exploitation and has been worth. Prepare SE due to anti-prion and treatment and the prevention prion with natural plants polyphenol of the present invention, especially treat and prevent medicine and/or the health products of rabid ox disease, scrapie, creutzfeldt-Jacob disease and new type Creutzfeldt-Jakob disease, compound method is simple, raw material is easy to get, and has industrial applicibility.

Claims

1, the natural plants polyphenol is as preparation treatment or the medicine of prevention Protein virus associated diseases and/or the application of health product.

2, application according to claim 1 is characterized in that described Protein virus, is the variation that is present in the PrPC in people, domestic animal, animal brain and its hetero-organization, thereby causes the albumen of a series of Transmissible spongiform encephalopathy.

3, application according to claim 1 is characterized in that described Protein virus associated diseases is a series of Transmissible spongiform encephalopathy.

4,, it is characterized in that described spongy disease is a creutzfeldt-Jacob disease according to claim 2 or 3 described application.

5,, it is characterized in that described spongiform encephalopathy is a new type Creutzfeldt-Jakob disease according to claim 2 or 3 described application.

6,, it is characterized in that described spongiform encephalopathy is special Man disease of Kuru disease, Gus or fatal familial insomnia according to claim 2 or 3 described application.

7,, it is characterized in that described spongiform encephalopathy is a bovine spongiform encephalopathy according to claim 2 or 3 described application.

8,, it is characterized in that described spongiform encephalopathy is a scrapie according to claim 2 or 3 described application.

9,, it is characterized in that described spongiform encephalopathy is Chronic consumptions or the ermine infectiousness encephalopathy of pronghorn according to claim 2 or 3 described application.

10, application according to claim 1 is characterized in that described natural plants polyphenol is tea polyphenols, grape polyphenols or Pine Procyanidins.