CN102688230B - New applciation of procyanidine B2 - Google Patents

Abstract

The invention relates to the technical field of medicines, healthcare products and the like, and particularly to a new application of procyanidine B2 related to active Chinese medicine components in preparation of products, especially medicines and healthcare products for preventing, diagnosing, detecting, protecting, treating and researching vascular dementia, alzheimer disease and diseases directly related to vascular dementia and alzheimer disease. Experiments prove that the procyanidine B2 can enhance the learning and memory capabilities of a mouse with vascular dementia caused by global cerebral ischemia reperfusion injury, a rat with vascular dementia caused by cerebral ischemia reperfusion injury, and a rat with alzheimer disease caused by beta amyloid protein. The compound is strong in action, obvious in effect, abundant in source, stable in property, safe in use, especially wide in use range, and capable of furthest exerting the action thereof. The incidence rate of dementia continuously rises, and the new applciation of procyanidine B2 can generate remarkable social benefits and economic benefits in a short time after being popularized.

Description

The purposes of procyanidin B 2

Technical field

The present invention relates to medicine, food, health product and technical field of beverage, specifically relate to a kind of new purposes of Effective Component of Chinese Medicine, more particularly relate to a kind of new purposes of procyanidin compounds, then relate in particular to procyanidin B 2 (title again: procyanidin B ₂) new purposes.

Background technology

One, the research overview of procyanidin B 2

1, anthocyanidin

Anthocyanidin (Anthocyanins) is a kind of water colo(u)r, can change color along with the soda acid of Cell sap.It is partially red that Cell sap is acidity, and it is partially blue that Cell sap is alkalescence.Anthocyanidin is one of main pigment forming petal and fruit color.Generate via phenylpropionic acid class synthesis path (phenylpropanoid pathway) and the raw route of synthesis of flavonoid (flavonoids biosynthetic pathway).

The factor that affects anthocyanidin colour generation comprises the structure of anthocyanidin, pH value, is total to color effect (copigmentation) etc.Peel colour generation is subject to the impact of inherence, extrinsic factor and cultivation technique.Light can increase anthocyanidin content; High temperature can make anthocyanidin degraded.Anthocyanidin is plant secondary metabolism product, plays the part of important role on physiology.The color of petal and fruit can attract animal to pollinate and seed dispersal (Stintzing and Carle, 2004).In the tissue of common what flower, fruit and epidermis cell and the following table cortex of stem and leaf.Part fruit determines the fruit market price with shade.

Anthocyanidin belongs to the flavonoid class (flavonoids) in what phenolic compound.Basic structure comprises two phenyl ring, and links (C by the unit of 3 carbon ₆-C ₃-C ₆).Anthocyanidin generates via phenylpropionic acid path and the raw route of synthesis of flavonoid, by much ferment regulation and control catalysis.Taking pelargonidin (pelargonidin), cyanidin (cyanidin), delphinidin (delphinidin), peonidin (peonidin), petunidin (petunidin) and six kinds of non-glycoside bodies of enidin (malvidin) (aglycone) as main.Anthocyanidin presents different colours (model and Qiu, 1998) because of factors such as hydroxyl number (OH), methylate (methylation) of institute, candy base (glycosylation) number, candy kind and link positions.The performance of color is because of the change of biochemical environmental condition, as is subject to the impact (Clifford, 2000) of pH value in anthocyanidin concentration, color effect altogether, vacuole.

Orange and yellow is the effect of carotene.Within 1910, in Radix Dauci Sativae, find beta-carotene, found altogether other 2 kinds of carotene isomers later, respectively: α, β, tri-kinds of isomers of γ.Beta-carotene patented (US2849495, on August 26th, 1958, patentee: Hoffmann La Roche) in 1958 mainly extracts at present from ocean, also can synthetic.

2, procyanidin B 2

Procyanidin compounds (Oligomeric Proantho Cyanidins, be called for short: OPCs or OPC), claim again concentrated gene (Pycnjogenols), it is a kind of bioflavonoids that has special molecular structure, efficient cofactor, be that generally acknowledge in the world at present, active the strongest, remove the most effective Natural antioxidant of people's interior free yl, remove free radical with and the material of anti-aging effects.Be generally rufous powder, feeble QI, puckery, water-soluble and most organic solvent.Be generally Semen Vitis viniferae extract or French coast Cortex Pini Massonianae extract.

Procyanidin compounds is a kind of new and effective antioxidant, is the most potent free radical scavenger found so far, has very strong activity in vivo.The free radical resisting oxidability that experiment showed, OPCs is 50 times of vitamin E, ascorbic 20 times, and absorb rapidly completely, within oral 20 minutes, can reach the highest haemoconcentration, metabolic half life is for 7 hours.

Procyanidin compounds is rich in the plant flavonoids material (flavonoids) the most useful to human body---proanthocyanidin glycosides (Proanthocyanidin) or title procyanidin (Procyanidin or Procyanidins are called for short PC).

Procyanidin is present in plant widely, a kind of by procyanidin monomers (being mainly catechin, epicatechin etc.), Oligomeric Proanthocyanidins (two, three, four polymeric acceptors of monomer, English is Oligomeric procyanidins, PCO) and the high procyanidin that gathers (more than pentamer be called for short:, English is Procyanidolic polymers, is called for short: the PPC) compound of composition.The most basic procyanidin monomers, one is catechin, and another kind is epicatechin, and these two kinds of monomers can form oligomer or polymer by polymerization, conventionally two～tetramer are called to oligomer by the size of the degree of polymerization, and pentamer is called high polymer above.

Wherein, dimer distributes the widest in all kinds of procyanidins, and antioxidant activity is the strongest, is a most important class.Dimer, because of conformation or the condensation key mapping difference of 2 monomers, has multiple isomer, 8 kinds of isomers now having identified, and in 8 kinds of isomers, procyanidin B 2 is an active the strongest dimer.Its structural formula is as follows:

3, source

Procyanidin compounds, is generally Semen Vitis viniferae extract.Although procyanidin compounds has effect of mystery like this, human body cannot produce procyanidin compounds, and procyanidin compounds focuses mostly at the skin of plant, shell, seed, leaf, the first-class position of bar, as Semen Vitis viniferae, skin etc.; And best resource is picked up from fruit nymphaeaceous and leaf, with the OPC purity of Nelumbonaceae plant extract can be higher than more than 98% (that extracts in general Semen Vitis viniferae, skin can only reach 90% at most).

In recent years, physicochemical property and the biological nature of countries in the world scholar to OPCs carried out a large amount of research work, and makes a breakthrough, in Semen Vitis viniferae extract, OPCs has higher content, and the content height of oligomer has ensured the high curative effect of the procyanidin compounds of unit quantity.And from the bioflavonoids OPCs extracting Semen Vitis viniferae compared with most of flavone, structure is special, good water solubility, effectiveness is high, bioavailability, more than 90%, is very easily absorbed by the body, and is the most potent natural antioxidant of finding up to now.

According to the achievement in research of 1951 ~ 1971 years and 1972 ~ 1978 years Jacques Masquelier, Semen Vitis viniferae is the source of the OPCs that is considered to best, is rich in 92 ~ 95% OPCs.Simultaneously scientific research result shows, grape seed extract OPC s is following important defying age and anticancer natural product, and Semen Vitis viniferae extract obtains medical licence in France.

In present market, OPCs all size emerges, and only has monomer more than 10%, procyanidin is more than 95%, and polyphenol more than 90% is only real grape seed extract OPC s, if monomer is lower than 3%, polyphenol 60 ~ 70% even reaches 90%, generally thinks procyanidin PPC.

It should be noted that skin, shell, seed, leaf, the processing of bar un-extracted of occurring in nature, OPC wherein can not extract out, and natural human body can not absorb.

4, the various health-care of procyanidin compounds

Prove through theoretical research for many years, procyanidin compounds has plurality of health care functions, comprising:

1. by the blood circulation of three approach protection human bodies: remove the oxygen-derived free radicals existing in blood; Help body to stop the generation of oxygen-derived free radicals; Strengthen the integrity of blood vessel wall.

2. prevent collagenase and the elastoser Degradation to connective tissue, thereby be conducive to keep the elasticity of skin, effect of performance anti aging effect.

3. can strengthen the microcirculation of optical fundus retinal capillary and extremity tip blood capillary.

4. by maintaining the health of blood vessel and improving microcirculation, make each Organ and tissue obtain more sufficient blood supply.

5. can strengthen immunologic function, show that anthocyanidin improves the immunne response ability of feeding the white mice of ethanol and the white mice cytokine 2 of retroviral infection.

6. procyanidin compounds also can strengthen ascorbic effect, and the time of effect occurs prolongation vitamin C in human body.

7. the dissolubility of procyanidin compounds in water is very good, and oral rear good absorbing enter human body interior rapid-action, and action time is lasting.

8. as health food, safety is extremely important.The result of many animals experiment and experimental system research proves, procyanidin compounds is nontoxic, without mutagenicity, non-carcinogenesis, nothing cause birth defect, without sensitization, therefore anthocyanidin is safe.Specifically be described below:

(1) blood circulation

In Europe, in order to improve blood circulation, treat diabetic retinopathy, alleviate edema and suppress varicosis etc., anthocyanidin is for clinical treatment decades.Anthocyanidin can be strengthened blood capillary, tremulous pulse and vein blood vessel, therefore, and effect that it has detumescenceization to become silted up.The drag reduction of blood capillary and permeability improve, and make cell more easily absorb nutrient and get rid of refuse.This is the function of blood circulation with transporting refuse to carry nutrient.Heart is responsible for taking out pressure blood; Tremulous pulse and vein blood vessel pumping blood; And be responsible for transporting nutrition to cell, what transport again refuse is blood capillary.Anthocyanidin can scavenger cell film in water solublity and fat-soluble free radical, therefore, suppressed to discharge some enzyme and go to injure the process of capillary wall.

The nourishing effects of anthocyanidin can be observed in a short period of time.Professor HenriChoussat of Dogue de Bordeaux university has done single test, and experimenter has 47 people, and the age, everyone took 100 milligrams of anthocyanidin from 37 years old to 85 years old.After 27 hours find, the drag reduction of blood capillary 40%.

(2) vision protection

Diabetic retinopathy is the sign of diabetes, and it is micro-hemorrhage the causing of eyes blood capillary, be grow up blind person commonly encountered diseases because of.France allow with anthocyanidin treat this disease much year.This method has significantly reduced eyes capillary hemorrhage, has improved vision.Anthocyanidin has also been used for preventing the complication after Operation of Cataract in Diabetics.

1998, brainstrust selected many people that there is no oculopathy eye wound to do experiment, and investigates anthocyanidin and whether can alleviate nyctalopia.Participant is divided into two groups, and one group is the driver who drives evening, and one group is that all day and computer screen are companion's people.After four weeks, reexamine their resistance to blind ability, 98% experimenter has had improvement.

(3) alleviating edemas

Edema is that moisture, the electrolyte etc. in blood infiltered tissue and cause, its normally injury swelling.Sit to such an extent that Healthy People excessively of a specified duration has edema, have edema before woman in menstrual period, the injured edema that often causes of moving, may have edema after some operation, and some diseases also can cause edema.

Research shows, takes anthocyanidin every day one time, and edema can obviously be alleviated.Clinical trial was done by Dogue de Bordeaux university, and having investigated the mean age is 60 years old, had 40 patients of edema disease.Participant is divided into two groups, patient be in 60 days every day take the anthocyanidin of 300 milligrams, proprietary disease alleviates.After 30 days, 26% patient's swelling disappears.After 60 days, the edema recovery from illness of experimenter's shank of 63%.

(4) skin care

People from Europe claims that anthocyanidin is youth nutriment, skin vitamin, oral cosmetics.Because it can recover collagen protein vigor, make skin level and smooth and flexible.Collagen protein is the fundamental component of skin, and is that a kind of our health that makes becomes as a whole colloid substance.Vitamin C is the nutriment of biochemical synthetic collagen protein necessity.Anthocyanidin comes into force more vitamin C, this means, vitamin C can more easily go its all functions (comprising that collagen protein produces).Anthocyanidin is connected on collagen protein, can stop those to destroy the harm of the enzyme of collagen protein.Anthocyanidin not only helps collagen fabric to form cross-linked structure, and can help to recover because of the injured and caused excessively crosslinked infringement of free radical.Excessively be cross-linked and can make connective tissue suffocate and harden, thereby skin is corrugated and premature aging.Anthocyanidin also protects human body to avoid sunlight injury, promotes to cure psoriasis and senile plagues.Anthocyanidin is also the fabulous additive of the skin cream of local application.

(5) cholesterol

Cholesterol is the fundamental component of cell membrane, and for producing hormone and promoting transporting of fatty acid to say, it has played pivotal role.But too much cholesterol is a potential bad sign.Anthocyanidin and ascorbic combination can make cholesterol decomposition, become bile salts, and then get rid of external.Anthocyanidin has been accelerated decomposition and the eliminating of harmful cholesterol.Here, the conspiracy relation between vitamin C and anthocyanidin is confirmed again.

(6) heart protective agent

Anthocyanidin not only helps to recover skin elasticity, and helps joint, tremulous pulse and other tissue (as heart) to maintain normal function.Vascular system is responsible for blood flow, and blood is delivered to all cells and tissue.Therefore, no matter be that anthocyanidin is all that find so far, best heart protective agent from long-term and short run effect.Anthocyanidin also suppresses histamine and produces, thereby can reduce inflammation, and helps tremulous pulse to resist the impact of those initiations cardiovascular diseases's mutagen.

Although Frenchman eats food rich in fat conventionally far more than American, it is a lot of less that Frenchman dies from cardiopathic ratio American, and Frenchman is famous to like to drink, and normally has meal and must drink.The number that France drink gentleman suffers from coronary heart disease is also low by 30% to 40% than the crowd who is not stained with wine, and this is because contain anthocyanidin in Bordeaux Rouge.

(7) allergy and inflammation

Anthocyanidin not only helps to slow down cardiovascular inflammation, and also helps treatment numerous disease, for example, and allergy, asthma, bronchitis, Hay Fever, rheumatoid arteritis, injured, the pressure ulcers of moving etc.When human body inflammation, will discharge a kind of compound that is named as histamine, it can bring out all symptoms of above-mentioned disease.Anthocyanidin suppresses to produce the enzyme that histamine needs, and prevents from generating histamine, thus dephlogistication.Anthocyanidin is the famous inhibitor of histamine, but it does not hinder other enzyme.Now, our health has born chemical substance and the pollutant from food, drinking water, air and animals and plants (as pollen) too much, and its result, just allergy has become very general disease.About the ability of anthocyanidin antiallergic and anti-inflammatory, many documents are all on the books.Athlete appreciates anthocyanidin very much because anthocyanidin make joint flexibly, can repair the collagen protein in connective tissue, and alleviate edema.Also have report, anthocyanidin improves many people's arthritis.

(8) varicosis

Cirsoid disease, can comprise pain, scratches where it itches, burns, fatigue.Serious varicosis can cause heart disease, apoplexy, thrombophlebitis, pulmonary infarction etc.Doctor Haake did clinical research in Hamburg, Germany, found that anthocyanidin is of value to varicosis patient.The patient who participates in test has 110 people, and wherein 41 people have crus spasm disease.Patient's every day oral 90 milligrams of anthocyanidin, 77% experimenter has major improvement.In addition, 93% crus spasm patient's disease disappears.

(9) brain function

Anthocyanidin can help to promote memory, the risk of delaying senility and apoplexy.Even, after apoplexy occurs, anthocyanidin can help improve memory and brain function, and this fact is proved by clinical research.For example, for child's hyperfunctioning disease (or hyperkinetic syndrome), be often to cure with the Western medicine that is called Ritilan.This Western medicine has the side effect that hinders child's growth, and patient may produce dependency to it, once cut out, patient will produce appetite to be increased, the diseases such as depression and lethargy.Some the report recommends, substitute Ritilan not only effectively but also safety with anthocyanidin natural tonic.

(10) improve anoxia

Anoxia just refers to and lacks for a long time oxygen, and this has irremediable injury to health.Old people's anoxia, may cause problem mentally and physically, as suffered from Alzheimer(A Erchamo) disease.Aged people, blood circulation is often not so good.Anthocyanidin has been removed free radical, has suppressed the destruction of capillary rupture and surrounding tissue.Anthocyanidin has also improved blood capillary state, the cerebripetal blood circulation of enhanced flow, and therefore, brain can obtain more oxygen.

(11) premenstrual syndrome

Clinical experiment result shows, anthocyanidin can alleviate premenstrual (anxiety) syndrome that torments women.Because hormone disequilibrium, on psychological and health, there will be and permitted various disease conditions.Body fluid retention effects blood proper flow, result, brain, ovary and uterus can not get enough oxygen.Hypoglycemia may be also a kind of factor of bringing out premenstrual syndrome.This disease may show as any or whole diseases below: mammary swelling and tenderness, sore waist and aching in the waist and the back, abdominal part bulge, muscle spasm, personality change and (as fly into a rage, fly into a rage, even want to commit suiside), depressed, tired, faint, insomnia, arthralgia, headache, urine retention.

In the research of a premenstrual syndrome, there is the anthocyanidin of oral 200 milligrams 165 women's every days.After two months, 60% body of women disappearance of disease.After four months, 80% women's physical symptom has not had, and the disease of half women's psychological aspects has not also existed.

Much nourish the body about anthocyanidin in addition, wholesome research report, it comprises following (but not limiting to) these aspects: improved liver function, reduced the risk of phlebitis and cancer, improved multiple sclerosis and prevention etc.

4, the safety of anthocyanidin

Masquelier professor and many scientists utilize anthocyanidin, done the research of various clinical, chemical examination, toxicity and pharmacokinetics for many years.

Extensive experimentation has proved that anthocyanidin is tonic nontoxic, not carcinogenic, that do not have antigenicity, unlikely fetal anomaly.Professor Masquelier points out, he had four more than ten years with anthocyanidin preventing and treating diseases, never saw direct or indirect toxicity.

5, taking dose

In the many clinical reports of large number, adult takes the anthocyanidin between 100 and 200 milligrams every day.Expert advice, maximal dose is to calculate in the body weight ratio of a milligram one pound of every day, be one to fortnight the course for the treatment of.Then dosage reduces, and maintains every day between 50 and 100 milligrams.In the time of sick or unexpected allergy, there is a roughly method, every day oral 150 to 300mg, until crisis is gone over.Child's dosage is adult's half normally.

Two, the research overview of vascular dementia

Dull-witted (Dementia) is the acquired and persistence disturbance of intelligence syndrome producing due to disordered brain function, comprises that memory, language, visual space function, abnormality of personality and cognitive competence in various degree reduce.Dull-witted main Types is to comprise vascular dementia (vascular dementia, be called for short: senile dementia VD), in senile dementia (Alzheimer ' s Disease, or title alzheimer's disease, or claim to be called for short Alzheimer, Alzheimer's disease: AD) etc.

Vascular dementia is caused by cerebrovascular, is mainly caused by cerebral hypoxia ischemia.

Because AD falls ill in more than 60 years old old people well, so custom is called as senile dementia or degenerative brain disorder.

VD is the type such as common multi-infarct dementia, massive cerebral infarction dementia, thalamic dementia and the concurrent dementia of hemorrhagic cerebrovaseular and Mixed dementia clinically.Clinical manifestation is depression, delirium, aphasia etc.Pathological change is that multiple lacuna sexually transmitted disease (STD) becomes or large area infarct and atherosclerotic lesion (referring to neurological, the 4th edition, People's Health Publisher).Clinical treatment can use cholinergic inhibitor, blood vessel dilating, increase cerebral blood flow, or utilize cerebral protective agent-antioxidant or free radical scavenger can improve ischemia, the caused pathology damage minimizing brain cell necrosis of anoxia and apoptosis, protection cerebral tissue.

Vascular dementia person only shows nearly dysmnesia in early days, and memory far away keeps better relatively; With the increase of the course of disease, memory ability far away is lost gradually, and hypophrenia is gradual and increases the weight of.

And alzheimer disease just shows far and near dysmnesia in early days, hypophrenia presents one progression (Guo Mingying slowly, Korea S's tinkling of pieces of jade, etc. the comparative study of alzheimer disease and vascular dementia disturbance of intelligence. the journal .2007 of Qinghai Medicine College, 28 (2): 125-127.).

Vascular risk factor is all being played the part of key player in the morbidity of vascular dementia and Alzheimer, so there is theory to think that Alzheimer and vascular dementia may not be two independent illness.The general character research of Alzheimer and vascular dementia is carried out widely in various aspects such as risk factor, pathogenesis, Pathophysiology, Imageologies.

Vascular dementia is the carrying out property decline property disease by the acquired Premium Features of cerebral cortex due to repeatedly apoplexy or long-term chronic cerebral ischemia.

Show in America and Europe's investigation, dementia incidence rate approximately 1.1% in 55 years old above old men, wherein Alzheimer disease accounts for top priority (incidence rate approximately 7.7 ‰), be about 50%～60% of dull-witted total number of persons, and VD occupies time (incidence rate approximately 1.5 ‰), account for 10%～20%, and with age, VD proportion significantly increases (1. Ott A, Breteler MMB, Harskamp F, Stijnen T, Hofman A.Incidence and risk of dementia:the Rotterdam study.Am.J.Epidemiol., 1998,147 (6): 574 – 580.; 2. Di Carlo A, Baldereschi M, Amaducci L, et al.Incidence of dementia, Alzheimer'sdisease, and vascular dementia in Italy.The ILSA Study.J.Am.Geriatr.Soc., 2002; 50:41-48.).

The nearest research of China also shows; AD incidence rate approximately 3.5% in the old man of over-65s; VD incidence rate 1.1%(Zhang ZX; Zahner GE; Roman GC, et al.Dementia subtypes in China:prevalence in Beijing, Xian; Shanghai, and Chengdu.Arch Neurol.2005; 62 (3): 447-453.).

Owing to also lacking at present the cognitive impairment pattern that is applicable to diagnose VD, for discriminating and " mixed type " dull-witted (AD+ cerebrovascular of the diagnosis of AD and VD, be called for short: diagnosis AD+CVD) still has certain challenge (1. fourth element chrysanthemum, Li Yunxia. the clinical diagnosis of vascular dementia and treatment. countries in the world medical science: cerebrovascular disease fascicle .2005,13 (9): 676-680; 2. Erkinjuntti T:Vascular dementia:challenge of clinical diagnosis.Int Psychogeriatr.1997; 9:51 – 58.), so someone thinks that vascular dementia may be dull-witted type the most common in old people, mainly because a lot " mixed type " dull-witted (AD+CVD) may be diagnosed as 1. Rom á n GC.Vascular dementia may be the most common form of dementia in the elderly.J Neurol Sci.2002 of AD(, 203-204:7-10; 2. fourth element chrysanthemum. vascular dementia. Aged in China is learned magazine .2003; 23 (4): 200-202.).

The incidence rate of VD is at men and women's no significant difference (Anderson K; Launer LJ; Dewey ME, et al.Gender differences in the incidence of AD and vascular dementia:the EURODEM studies.Neurology.1999; 53:1992 – 1997.); its the most significant risk factor is age [Hebert R.; Lindsay J.; Verreault R.; Rockwood K.; Hill G, Dubois MF.Vascular dementia:incidence and risk factors in the Canadian study of health and aging.Stroke, 2000; 31 (7): 1487-1493.],, according to Epidemiological study, in the crowd who is greater than 60 years old, the sickness rate of 5 years old VD of every increase of age just increases by 1 times.

Two main causes that cause VD are apoplexy and ischemic heart desease (ischemic heart disease, abbreviation: IHD), and the two is all commonly encountered diseases in old people.Only with regard to apoplexy, the now annual whole world newly increases apoplexy patient 1,000 ten thousand, wherein just there are 2,000,000 (1. Feigin VL in China, Lawes CMM, Bennett DA, et al.Stroke epidemiology:a review of population-based studies of incidence, prevalence, and case-fatality in the late 20thcentury.Lancet Neurol., 2003,2 (1): 43-53; 2. Wu Zhao Soviet Union, Yao Chonghua, Zhao Dong. the epidemiological study of Chinese population Cerebral Haemorrhage Invasion Rate, mortality rate. Chinese epidemiology magazine, 2003; 24 (3): 236-239.), in old people, sickness rate is especially high, thereby causes the concurrent VD of a lot of patients.The national dull-witted epidemiology statistics data of China also shows along with the aging of population, the change of dietary structure, and the morbidity of VD is and increases progressively trend.

Along with the aging of population, the sickness rate of cardiovascular and cerebrovascular disease raises year by year, and concurrent VD patient also increases gradually.VD is grievous injury patient health not only, brings long-term misery to patient, affects patient's quality of life, brings white elephant also to society and family, has caused the common concern of countries in the world, and it is an important topic in geriatrics field.Generally believe that the age affects by many-side the effect of VD, the aging change of the self-regulation of for example brain, the metabolism of cell, blood brain barrier and autonomic function aspect makes cerebrovascular be easy to suffer damage, and encephaloclastic accumulative total effect is also one of reason.

The diagnosis of vascular dementia must meet three conditions: 1. dull-witted; 2. cerebrovascular; 3. more than, the two is closely related.Dull-witted and apoplexy is maintained close ties with in time, conventionally after apoplexy, in 3 months, occurs dull-witted.Cardinal symptom is: 1. histopathology form changes; 2. hypomnesis.

About the treatment of VD, there is no at present sure Therapeutic Method and can change the whole course of disease, because brain cell downright bad after cerebral infarction can not reverse, be mainly that the treatment of the brain cell to blood supply insufficiency is to alleviate stage of attack symptom, to prevent infringement again etc.The method etc. that normal employing actively improves brain cell oxygen supply, improve microcirculation, prevent new thrombosis and re-infarction.Improve cerebral circulation treatment conventional have 9,10-Dihydroergotoxine class, calcium ion antagonist, nicotinic acid class, other medicament for expanding vascellum and a medicament for resisting platelet aggregation.Cholinesterase inhibitor is developed recently dementia treatment medicine comparatively rapidly, example hydrochloric acid donepezil and rivastigmine-hydrogentartrate.Also often apply clinically Cerebral protection medicine as calcium ion antagonist (nimodipine and western pyrrole spirit); Free radical scavenger (vitamin E, vitamin C and gingko leaf preparation) etc.But from present clinical effect of said medicine, curative effect is general, and major part is only all anti symptom treatment, can not improve mortality rate.Some Chinese medicine preparation, as the preparations such as Folium Ginkgo, Herba Erigerontis, Radix Et Caulis Acanthopanacis Senticosi exist the weak points such as active component is unclear, mechanism of action not clear, quality is unstable, toxic and side effects is large mostly, are difficult to meet clinical needs at present.

Therefore; at present countries in the world there is no effective ways and medicine to controlling this sick course advancement, the drug research and development of prevention, treatment and the prognosis of VD become the research topic paid much attention to various countries (1. fourth element chrysanthemum. vascular dementia. Aged in China is learned magazine .2003; 23 (4): 200-202; 2. Chen Chunlei, Qiu Zhihui, Su Shixin, Zheng Zhongcheng, Chen Peifen, Ye Zhiping. the therapeutic advance of vascular dementia. the new medical science .2007 of forum of China, 7 (7): 59-62.).

Three, the progress of AD

1, general introduction

In senile dementia, topmost disease type is AD.AD is a kind of chronic former, taking brain aging as basis, carrying out property cerebral degeneration's old central nervous system degenerative disease, it is the progressive neurodegenerative diseases of one that betides geratic period or presenium, be the common stiff reaction of one entering after the declining years, belong to the presenile dementia disease of improper aging state.

AD is a kind of serious, degeneration brain illness.AD is with hypomnesis, cognitive disorder, personality changes, dystropy and linguistic competence lose for feature, main manifestations is that comprehensive obstacle and the cognitive function of the acquired Premium Features of cerebral cortex is obviously impaired, cerebral functional deterioration decline, be rapidly decay and identification ability obstacle of memory function, and with the change of behavior or personality aspect.Its Clinical symptoms is carrying out property cognitive dysfunction, and clinical manifestation is amnesia, cognitive disorder, personality changes, and its pathological characters is that neurofibrillary tangles in neuron, extracellular senile plaque deposition and neuronal quantity reduce.During due to people or other Animal Aging, many degeneration can occur body itself changes, and therefore, AD is as Senile disease, and it occurs there is substantial connection with aging.

Along with population in the world aging, the sickness rate of alzheimer disease also increases thereupon.According to Rotterdarm result of study, 65～69 years old annual sickness rate of old people is that 1.4%, 70～74 years old person is that 3.9%, 75～79 years old person is 16.7 ‰, during by 85 years old, increases to 45.4 ‰.This sick genesis mechanism has various theories, but the definite cause of disease there is no final conclusion.

At present, the whole world approximately has more than 5,000 ten thousand old people to suffer from alzheimer disease, and there is the trend of continuous rejuvenation, become the social problem that can not be ignored and domestic problem (Zhang Juntian. the pathogenesis of senile dementia and control medicine. medical Leader, 2002,21 (8): 469.471).And the mean survival time (MST) of senile dementia patients is 5.5 years, make this disease become one of main lethal disease of modern society old people.

But because the cause of disease of AD is not exclusively clear and definite, there is no so far effectively preventing medicine, this disease is still one of comparatively thorny disease in the whole world at present, the control of AD has become outstanding, urgently to be resolved hurrily medical treatment and a social problem, and it is an instant thing that active research is developed new Therapeutic Method.Such disease course is generally longer, is about 3～20 years.Being huge to the long-term nurse fees of AD patient, not only the medical security system of entire society being had to very big impact, is also great challenge to nuclear family's pattern of Chinese Future Society.Therefore, it occurs all to have brought heavy financial burden and mental burden to society, family, brings great misery also to patient self.

2, pathological manifestations and pathogenesis

The main pathological manifestations of AD is the formation at Basal forebrain, Hippocampus and cerebral cortex extracellular neuritis's speckle, and in cell, the appearance of neurofibrillary tangles and neurocyte and number of synapses object reduce.Speckle mainly (is called for short: (Beta-Amyloid Protein is called for short: A β) assemble composition protein hydrolysate amyloid-beta APP) by amyloid precursor protein.Under normal circumstances, APP hydrolyzate is the A β of solubility ₄₀, and under pathological conditions, APP hydrolyzate is the A β of the easy formation fiber of length _1-42, it first exists with a kind of speckle form immature, non-fibrous dispersion, finally passes through conformational change, aggregates into a kind of poisonous fibrous material, forms speckle.Neurofibrillary tangles is mainly present in the neuronic born of the same parents of taper and in abnormal neural axon, it is a water-insoluble structure, its chief component is that the Double helix fibre structure of diameter 10nm (is called for short: PHF), main component is a kind of microtubule bindin, it is Protein tau, the interaction that normal Protein tau can be stablized tubulin, the Protein tau in PHFs exists with the form that surpasses phosphorylation.

The etiology complexity of AD, mainly contains two kinds of hypothesis at present: Protein tau hypothesis and amyloid hypothesis.The main argument of Protein tau hypothesis is: because the super phosphorylation of Protein tau causes the unstable of tubulin, cause that Golgi body structure changes, thereby affect the metabolism of APP, produce excessive A β.This hypothesis is not also confirmed at cell or animal individual level.The main argument of amyloid hypothesis is: the gathering of amyloid around extracellular neuropathy occurs, causes the formation of neuritis's speckle and the formation of neurofibrillary tangles subsequently.Therefore, amyloid is the cause of AD pathology chain formation.Support that the evidence of amyloid hypothesis is very extensive.

The senile plaque that amyloid-beta abnormal deposition forms is the typical pathological characters of AD.The speckle around activation prompting A β of significant neuron degeneration and glial cell may be the reason that causes neuron loss and inflammatory reaction in AD.In nerve retrograde affection, the activation of glial cell and neuronic death have effect of equal importance, and exist and necessarily contact (referring to Bales KR between the two, Du Y, et al.The NF-kappaB/Rel family of proteins mediates Abeta-induced neurotoxicity and glial activation.Brain Res Mol Brain Res.1998; 57 (1): 63-72.).Remove after amyloid-beta speckle by inoculation, the nervous system lesion relevant to AD can be repaired.This fact provides strong evidence for amyloid-beta theory.Other evidences of amyloid-beta theory comprise: trisomy 21 syndrome patient is because A β produces too much, can there is in early days AD sample nervous system lesion, the only nervous system disease of its young patient becomes diffusivity A β deposition, illustrates that amyloid beta deposition may be neuro pathology's change the earliest; Remove after amyloids by some measures, nervous system lesion can reverse as neuron shrinkage, microglial activation.These evidences explanation amyloid beta depositions be AD morbidity key link (referring to Zhou Huifang, Xue Bing, Wang Xiaomin, sick progress-amyloid-beta the theory of Alzheimer and main control strategy, natural science progress, 2003,13(2): 121-125.).

3, Epidemiology

Along with developed country and the raising of developing country's average life span, the old number of suffering from dementia increases sharply.In all dementias, the ratio shared with AD the highest (approximately 50% ~ 60%).

According to document announcement, with advancing age, under the impact of and gene aging in tissue, the incidence rate of dull-witted phenomenon constantly raises; Wherein, AD sharply rises with old, from 60 years old, within every 4 years ~ 5 years, rises one times; The sickness rate of AD accounts for 10% in the old people of one's mid-60s, in the old people more than 85 years old, accounts for 47%, has become the mankind's No. four killer.

Past academia once thought that China was the low dangerous country of AD, but in the Second Committee Chinese Aged dementia of holding in Tunxi, Anhui in the early time and depression scientific seminar and international senile dementia scientific seminar, this viewpoint is challenged.Have 5 parts of research reports to show, China is also the high-risk country of AD.

Patient AD in the whole world estimates in 1,200 ten thousand left and right at present, and Chinese existing old dementia patients is approximately 3,000,000～4,000,000, and is rapid ascendant trend, makes a definite diagnosis in latter general approximately 7 years ~ 9 years dead.Have data to show, more than 60 years old population of China has reached 1.2 hundred million as far back as 1998, and with average annual 3.2% speed increase, is much higher than the rate of population increase.Within 75 years old, above old man has more than 2,000 ten thousand, 80 years old old man to have 8,000,000, and increases with average annual 5.4% speed, and middle period next century can reach 400,000,000 left and right, will become the maximum country of the aged in the world.

Sino-U.S.'s Shanghai investigation in 1988 shows, the dementia incidence rate of aged people over 65 years old in China is 4.6%, wherein the proportion of AD is 63%, and multi-infarct dementia is 28%, and the dementia that the poisoning and nervous system disorder of brain tissue impairment sequela, chemicals or malnutrition cause accounts for 10%.

The Epidemiological study demonstration in Shanghai, the prevalence of China 55 years old, over-65s dementia is respectively 2.57% and 4.6%.The investigation discovery of senile disease medical research center, Beijing to 2788 the more than 60 years old old men in Beijing area, has 208 old men to suffer from dementia, and prevalence reaches 7.5%.Wherein female patients 139 people, prevalence reaches 9.7%, is significantly higher than male's 5.8%.Their research also shows, advanced age, low educational level, lives in the high risk factor that rural area is senile dementia.And PLA General Hospital shows 1728 retired veteran cadres' investigation, have in dull-witted family history, " Culture Revolution " be afflicted by persecution, electromagnetic field exposes, cerebral trauma is also the risk factor of senile dementia.In the investigation of Guangzhou City more than 75 years old elderly dementia prevalence, AD prevalence is 7.49%.

4, the medicine of AD

AD is one of common complaint among the elderly, is a kind of gradual function of nervous system's degenerative deficiency disorder, and the cause of disease of primary disease is not yet thrown a flood of light at present, is a thorny problem in treatment always.

The research and development of antidementia agent has caused the great attention of countries in the world the world of medicine.In recent years, along with to the deepening continuously of the aspect researchs such as old people's nervous physiology, biochemistry, pharmacology, cause the developmental research of related drugs constantly to make progress.Calendar year 2001 has 1270 multiple products to put on market, and in these products, 90% is that the discovery eighties, the research and development nineties are successful, and the new product of this type of drug development has outnumbered the number of any other treatment class drug development.

The medicine for the treatment of senile dementia mainly contains cholinesterase inhibitor at present, cerebral vasodilator, and calcium antagonists, prevents A β deposition medicine, suppresses β, gamma secretase medicine and anti-inflammatory agent etc.Main application cholinergic drug or choline vinegar enzyme inhibitor are treated, and the medicine of U.S. FDA approval listing treatment AD is cholinesterase inhibitor.Now there are tacrine, donepezil (donepezil) and huperzine first-class for clinical cholinesterase inhibitor.This type of medicine is early stage and to improve cognitive dysfunction effective to dementia, but also has certain side effect and act on the shortcomings such as of short duration, and especially tacrine is serious to hepar damnification.Also often apply clinically Cerebral protection medicine as calcium ion antagonist (nimodipine and western pyrrole spirit); Free radical scavenger (vitamin E, vitamin C and gingko leaf preparation) etc.But at present clinical curative effect is general from said medicine, and major part is only all anti symptom treatment, can not improve mortality rate, and toxic and side effects is large, and effect is often not satisfactory.

Through clinical the showing of nearly 10 years, acetylcholinesterase (is called for short: AChE) inhibitor has certain therapeutical effect to AD, this bright, donepezil, galantamine of its main medicine tacrine, profit has been the representative kind in this field, thereby also promoted the development process of dementia treatment drug market.

5, the future develop of AD

Within 2000, the large drug market in the world seven shows, AD drug market has increased nearly one times from more than 400,000,000 dollar of the mid-90, calendar year 2001 nearly 1,200,000,000 dollars of whole world AD market value; Countries in the world analyst prediction AD patient within Future Ten year will be increased to 20% left and right, and the growth rate of AD drug market is by the rising having by a relatively large margin.

Due to being on the increase of patient, the market sales revenue of AD medicine is also always in steady-state growth.The nineties, such medicine became situation of selling well medicine, nineteen ninety-five world's sales volume reached 5,000,000,000 dollars.At the beginning of 21 century, the sales volume of such medicine has exceeded the share in the treatment cardiovascular disease treating medicine, treatment gastrointestinal disease medicine and the anti-infectives market that are arranged in first three, and its growth momentum is good.

At present, such disease is more and more subject to China national and social great attention, and because such disease is similar to the affluenza such as diabetes, equally needs long-term taking medicine, therefore its medication market expands gradually along with aged tendency of population, and market prospect is good.Based on this, for understanding in time the market situation of China treatment AD medicine, state food and drug administration south medication economics institute information centre chooses various schools of thinkers sampling hospital, 60 doctor experts and 120 consumers of China six main medication cities (Beijing, Shanghai, Guangzhou, Nanjing, Hangzhou, Chengdu), to Chinese Domestic Old dementia disease medication market (1999 and 2000) and mainly compete kind and carried out comprehensive market survey activity.

The treatment of AD accounts for the 7th of world's drug market, is worth 6,100,000,000 dollars to the end of the year 2005.And if current anti-AD drug main relief of symptoms is not contained the development of the state of an illness.Therefore; working out a kind of effective Therapeutic Method, to stop potential pathogenic process be very necessary, thus it is considered herein that development for the product that prevents, diagnose, detect, protect and treat the aspects such as AD particularly medicine can there is significant Social benefit and economic benefit.

Therefore, in conjunction with Chinese Chinese traditional herbs, therefrom excavate effectively, the medicine of low toxicity, inexpensive treatment vascular dementia, have very important significance.

But by literature search etc., up to the present, not yet find the report using procyanidin B 2 as dementia product application aspect.

Summary of the invention

The technical problem that will solve required for the present invention is to disclose one to come from middle the effective elements of the medicine procyanidin B ₂new purposes, the above-mentioned defect existing to overcome prior art.

That is to say, object of the present invention is intended to clear and definite one and comes from middle the effective elements of the medicine procyanidin B ₂new purposes, it is the activity of dementia, comprise vascular dementia disease, Alzheimer, or early stage, mid-term of the disease such as the mixing disease of vascular dementia disease and senile dementia and late period etc. application aspect activity, and then by procyanidin B 2 for the preparation of dementia product, comprise vascular dementia disease, Alzheimer, or early stage, mid-term of the disease such as the mixing disease of vascular dementia disease and senile dementia and late period etc. aspect product;

Described procyanidin B 2 refers to an active the strongest isomer in the dimer that procyanidin monomers (comprising: catechin and epicatechin) forms by polymerization, and its structural formula is shown in Instructions Page 2 middle part.

Described dementia product refers to the product for preventing, diagnose, detect, protect, treat and study dementia disease and directly related disease thereof; to comprise one or more in medicine, reagent, food, health product etc.; preferred agents and health product, further preferred health product.

Described dementia disease and directly related disease thereof refer to and comprise vascular dementia disease, Alzheimer, or one or more in early stage, mid-term of the disease such as the mixing disease of vascular dementia disease and senile dementia and late period etc., the present invention has good prevention and therapeutic effect to vascular dementia disease and the early stage mild cognitive impairment of Alzheimer, hypomnesis or the symptom such as forgetful.

The medicinal raw material that described procyanidin B 2 uses refers to many natural plants that procyanidin B 2 extensively exists, as one or more in Semen Vitis viniferae, Fructus Hippophae, black currant, cacao bean, Fructus Fragariae Ananssae, Semen Ginkgo, Semen arachidis hypogaeae or Fructus Crataegi etc., preferably Semen Vitis viniferae, Fructus Hippophae, Semen Ginkgo, Semen arachidis hypogaeae or Fructus Crataegi, further preferred Fructus Hippophae.

(1) technical conceive

Independent development original new drug is a current urgent task of China, Chinese medicine and pharmacy has a long history, prevent and treat disease aspect also to have accumulated rich experience with Chinese herbal medicine, therefore from Chinese medicine, finding effective active component is an effective approach, is also the place of the advantage of Chinese original new drug development.

Procyanidin compounds is the plant polyphenol compounds being rich in various plants, due to its unique physiological hygiene function, in recent years extremely people's concern.Procyanidin compounds wide material sources extensively exist in many natural plants Semen Vitis viniferae, Fructus Hippophae, black currant etc.Countries in the world are more about the bioactivity research of procyanidin; due to its extremely strong antioxidant activity; procyanidin compounds becomes the focus of research aspect anticancer, antiinflammatory, antioxidation, radioprotective, mutation, antiallergic, protection cardiovascular and anti-ageing the waiting for a long time of improving looks in recent years, and it is a kind of the have treatment of potentiality and the medicine of prevention and health care, food and health product for various diseases.

Procyanidin compounds can obtain by extracting in natural product, can prepare by chemistry route is synthetic, can be obtained by microorganism, enzyme fermentation, can be prepared by molecular biology method, prepares extracting method various and simple to operate.

The inventor is on the basis of the procyanidin compounds research in early stage, effective ingredient has wherein been carried out to deep experimentation, find that the procyanidin B 2 in procyanidin compounds is the main component of drug action, the drug effect of this single component is compared with procyanidin compounds, can significantly can improve cerebral ischemia-reperfusion in mice/Focal Cerebral Ischemia-Reperfusion in Rats model learning memory ability, thereby show that this procyanidin B 2 has good therapeutical effect to vascular dementia, to dull-witted Early manifestation mild cognitive impairment, hypomnesis or forgetfully also have a therapeutical effect, can significantly can improve amyloid and cause Model of Dementia in Rats ability of learning and memory, thereby show that this procyanidin B 2 has good therapeutical effect to Alzheimer, to dull-witted Early manifestation mild cognitive impairment, hypomnesis or forgetfully also have a therapeutical effect,

Inventor, by procyanidin compounds being carried out to the experimentation of system, screens and proves new activity and the new purposes of this procyanidin B 2.According to literature search, inventor found through experiments active site procyanidin compounds and has multiple significant pharmacologically active, inventor infers that procyanidin compounds is in prevention, diagnosis, the dull-witted clinical drug effect that comprises the aspect such as vascular dementia and Alzheimer activity of protection and treatment, also should be mainly to bring into play by the drug effect of procyanidin B 2, and through chemical composition and animal experiment study, also prove and confirmed that procyanidin B 2 has significant pharmacologically active, main onset composition in active site procyanidin compounds is procyanidin B 2.

Dementia has become the important death cause of Aged in China population and great society and family burden; development treatment and prevention dementia medicine; especially medicine, food and the health product that prevent, diagnose, protect and treat the aspects such as dementia disease particularly medicine have significant social benefit, economic benefit; economic pressures and the monitoring burden that can obviously alleviate family, also can obviously improve patient's life quality.

(2) activity of procyanidin B 2 and effect

The present invention has carried out many-sided test to procyanidin B 2 in the activity of the aspects such as prevention, diagnosis, protection, treatment and the research of vascular dementia and alzheimer disease.

Procyanidin B 2 is in the test of the aspects such as prevention, diagnosis, protection and treatment vascular dementia disease and alzheimer disease

1, the protective effect to vascular dementia due to Mouse Whole Brain ischemical reperfusion injury

Group:

Blank group: give and the isopyknic normal saline of medicine group (that is: positive controls, trial drug group).

Positive controls: give medicine Folium Ginkgo, procyanidin.

Trial drug group: basic, normal, high 3 the dosage groups of procyanidin B 2.

Method: by injected in mice anesthesia, neck median incision, separates left and right side common carotid artery, the bulldog clamp blocking-up bilateral common carotid arteries blood flow some time.Removing bulldog clamp pours into again.Sham operated rats is not pressed from both sides bulldog clamp, and all the other steps are the same.Gastric infusion when reper-fusion, sham operated rats and model group (that is: blank group) gavage gives pure water.Mice gavage every day, carries out Morris water maze test after gavage 23d continuously.

Water maze test in mice:

Formed by the positive circular channels of a black lucite, in tank, have one, can stand for mice.Before experiment, in labyrinth, pour water, the depth of water there was not platform, and water temperature is moderate.Be placed in some seconds on platform the first day mice of training, make its existence of understanding this safety zone, then by mice in order head put into water, timing from four quadrants successively towards tank, mice is found platform and stops thereon after some seconds, and timing stops automatically.Within the 5th day, remove platform, the swimming starting point of mice is two quadrantal points away from platform, the incubation period of recording mice platform in 2 minutes.

Result shows that procyanidin B 2 has therapeutical effect to vascular dementia, improves its learning and memory function.

2, the protective effect to vascular dementia rats due to Focal Cerebral Ischemia Reperfusion

Blank group: give and the isopyknic normal saline of medicine group.

Positive controls: give medicine Folium Ginkgo, procyanidin.

Trial drug group: basic, normal, high 3 the dosage groups of procyanidin B 2.

Animal: rat

Method: by rats by intraperitoneal injection anesthesia, line bolt method is made middle cerebral artery occlusion (MCAO method) and prepared focal cerebral ischemia in rats 2h, and then perfusion.Gastric infusion when rat is poured into again, sham operated rats and model group gavage give pure water.Rat gavage every day, gavage 27 days, then carries out rat water maze test continuously.

Rat water maze test:

Formed by the positive circular channels of a black lucite, in tank, have one, can stand for rat.Before experiment, in labyrinth, pour water, the depth of water there was not platform, and water temperature is moderate.

Be placed in some seconds on platform the first day rat of training, make its existence of understanding this safety zone, then by rat in order head put into water from four quadrants successively towards tank, timing some minutes, rat is found platform and stops thereon after some seconds, and timing stops automatically.

Within the 5th day, remove platform, the swimming starting point of rat is two quadrantal points away from platform, records the incubation period of rat platform in certain hour.

Result shows that procyanidin B 2 has therapeutical effect to vascular dementia, improves its learning and memory function.

3. pair amyloid beta (is called for short: the effect of Alzheimer's Disease Rats A β)

Blank group: give and the isopyknic normal saline of medicine group.

Positive controls: give medicine Folium Ginkgo, procyanidin.

Trial drug group: basic, normal, high 3 the dosage groups of procyanidin B 2.

Animal: rat

Method: rats by intraperitoneal injection chloral hydrate anesthesia, be fixed on brain multiplex, determine entry point coordinate.The A β that injects state of aggregation with microsyringe is to tricorn, and sham operated rats is injected isometric(al) normal saline, after injection, fills up pin hole with dental base acrylic resin powder.Gastric infusion subsequently, sham operated rats and model group gavage give pure water.After some days of successive administration, carry out water maze test.

Result shows that procyanidin B 2 has therapeutical effect to Alzheimer, improves its learning and memory function.

By experiment research, all prove procyanidin B 2 of the present invention, with and pharmaceutical composition be a kind of safe, efficient, stable, inexpensive control dementia disease and the medicine of directly related disease thereof.

Of the present invention addressed procyanidin B 2 can be applied to the patient who needs treatment with the form of compositions, and said compositions comprises treats the procyanidin B 2 of effective dose and pharmaceutically acceptable carrier.

(3) purposes of procyanidin B 2

1, general introduction

The object of this invention is to provide one and comprise vascular dementia disease for preventing, diagnose, detect, protect, treat and studying dementia; Alzheimer; or early stage, mid-term of the disease such as the mixing disease of vascular dementia disease and senile dementia and late period etc. disease and the product of directly related disease thereof; comprise one or more in medicine, reagent, food etc.; preferred agents and health product, further preferred health product.

Completed acute toxicity testing proves, mouse stomach administration exceedes 3.0g/kg to the maximum tolerated dose of this active site, shows that this effective site is safe and reliable, solved the problem that Chinese medicine ingredients complexity, active constituent content are low and contain toxic component.Therefore, procyanidin B 2 and compositions thereof can be used for preparing dementia and comprise vascular dementia and Alzheimer disease product, the medicine being preferably prepared from taking procyanidin B 2 of the present invention as raw material and health product, further preferred health product.

2, the using method of procyanidin B 2 and compositions thereof and requirement

Procyanidin B 2 of the present invention can be combined use separately or with other active component; comprise for the preparation of the product for preventing, diagnose, detect, protect, treat and study dementia disease and directly related disease thereof; comprise medicine, reagent, food, health product etc., especially medicine and health product.

In concrete use, procyanidin B 2 of the present invention can use separately, can also use together with other many chemical substances.No matter whether these chemical substances have biological activity or have the function for the treatment of disease, comprise miscellaneous function as collaborative amplification, antagonism or alleviate the side effect etc. of procyanidin B 2, these chemical substances are to comprise one or more in pharmaceutically acceptable carrier, food, natural product, chemical synthetic drug or mankind's medication etc.; Preferably include one or more in pharmaceutically acceptable carrier or food etc.; Further preferred pharmaceutically acceptable carrier.

" pharmaceutically acceptable carrier " used herein comprises one or more in the applicable solvent of any and all physiology, disperse medium, afterbirth, antibacterial and antifungal, isotonic agent or absorption delay agent etc.The example of pharmaceutically acceptable carrier comprises one or more in one or more water, saline, phosphate-buffered saline, glucose, glycerol or ethanol etc. and compositions thereof.In many cases, in said composition, preferably include isotonic agent, for example, sugar, such as one or more in polyhydric alcohol or the sodium chloride etc. of mannitol, sorbitol, sorbitol.Pharmaceutically acceptable carrier can also comprise a small amount of auxiliary substance, such as, in wetting agent or emulsifying agent, antiseptic or buffer etc. one or more, and they have strengthened effect duration or the effect of this procyanidin B 2.

From concrete classification, said pharmaceutically acceptable carrier refers to the pharmaceutical carrier of medicine and pharmacology field routine, comprises excipient, as one or more in starch or water etc.; Lubricant, as one or more in glycerol or magnesium stearate etc.; Disintegrating agent, as microcrystalline Cellulose etc.; Filler, as one or more in starch or lactose etc.; Bonding agent, as one or more in pregelatinized Starch, dextrin, cellulose derivative, alginate, gelatin or polyvinylpyrrolidone etc.; Osmotic pressure regulator, as one or more in glucose, sucrose, sorbitol or mannitol etc.; Diluent, as water etc.; Disintegrating agent, as one or more in agar, calcium carbonate or sodium bicarbonate etc.; Absorption enhancer, as quaternary ammonium compound etc.; Surfactant, as hexadecanol etc.; Absorption carrier, as one or more in Kaolin or soap clay etc.; Lubricant, as one or more in Pulvis Talci, calcium stearate, magnesium stearate or Polyethylene Glycol etc.; In addition, can also in compositions, add other adjuvant, as one or more in flavouring agent or sweeting agent etc.

For example, active component procyanidin B 2 is dissolved, suspendible or (be for example emulsifiable in suitable aqueous solvent, distilled water, one or more in normal saline or Green's solution etc.) or oil-based solvent in (for example, vegetable oil is olive oil such as, Oleum sesami, Oleum Gossypii semen, one or more in Semen Maydis oil or propylene glycol etc.) in, can make ejection preparation, wherein in solvent, (for example can contain dispersant, polyoxyethylene sorbitan monoleate, polyoxyethylene hardened castor oil 60, Polyethylene Glycol, benzyl alcohol, one or more in chlorobutanol or phenol etc.), osmotic pressure regulator (for example, sodium chloride, glycerol, D9-mannose, one or more in D-glucitol or glucose etc.).In this case, if necessary, can add additive, for example solubilizing agent (for example, one or more in sodium salicylate or sodium acetate etc.), stabilizing agent (for example, human serum albumin etc.), analgesic (for example, benzyl alcohol etc.) etc.

Of the present invention and procyanidin B 2 can also combine use with the form of compositions, particularly with by other chemical substance animal especially mammal is comprised to people or other animals treat compositions used or similar compositions as medicine.Described mammal, comprise one or more in people, mice, rat, sheep, monkey, cattle, pig, horse, rabbit, dog, chimpanzee, baboon, Adeps seu carnis Rhiopithecus roxellanae, macaque or Rhesus Macacus etc., preferably one or more in people, mice, rat, monkey, pig, rabbit or dog etc., one or more in further preferred people, rat or monkey etc.For example, procyanidin B 2 of the present invention can be added be suitable for to curee's Pharmaceutical composition in.Conventionally, this Pharmaceutical composition comprises procyanidin B 2 of the present invention and pharmaceutically acceptable carrier.

The compositions of procyanidin B 2 particularly pharmaceutical composition can have various forms, comprises one or more in the dosage forms such as such as liquid, semisolid and solid; Wherein said pharmaceutical composition comprises that the procyanidin B 2 for the treatment of effective dose is active component, and one or more pharmaceutically acceptable carriers.

The pharmaceutical composition of procyanidin B 2 can adopt conventional production method well known in the art to make various dosage forms, for example, make active component mix with one or more carriers, is then made into required dosage form.For example, procyanidin B 2 of the present invention can be by adding the dosage forms such as the further granulation agent of suitable adjuvant, capsule, tablet, pill, and described adjuvant can be selected from one or more in starch, dextrin, lactose, silicon dioxide, calcium hydrogen phosphate, cyclodextrin, microcrystalline Cellulose, sodium carboxymethyl cellulose, magnesium stearate, Pulvis Talci etc.

Described dosage form comprises one or more in tablet, capsule, granule, suspensoid, Emulsion, solution, syrup or injection etc., takes one or more route of administration in oral or injection (comprise in intravenous injection, intravenous drip, intramuscular injection or subcutaneous injection etc. one or more) etc. to carry out prevention, diagnosis, detection, protection, treatment or the scientific research of dementia disease and directly related disease thereof.

It is 0.5% ~ 99% active component procyanidin B 2 that pharmaceutical composition preferably contains weight ratio, further preferably contains weight ratio and be 36% ~ 99% active component procyanidin B 2, most preferably contains weight ratio and be 90% ~ 99% active component procyanidin B 2.

The pharmaceutical composition of procyanidin B 2 generally must be aseptic and stable under production condition of storage.Said composition can be mixed with to the ordered structure that solution, microemulsion, dispersion liquid, liposome or other are suitable for high drug level.By being added in suitable solvent and then carry out aseptic filtration together with a kind of of required mentioned component or combination, this procyanidin B 2 of aequum prepares aseptic parenteral solution.Generally speaking, prepare dispersion liquid by this procyanidin B 2 being added in the aseptic solvent that contains basic disperse medium and required above-mentioned other composition.In the case of the sterile powder for the preparation of aseptic parenteral solution, the preparation method of recommendation is vacuum drying and lyophilized preparation.For example, by the coating such as lecithin, the dispersion liquid in the situation that by keeping required granular size and by using surfactant, can keeping the adequate liquidity of solution.For example, by comprising that in said composition the medicament (Monostearate or gelatin) that postpones to absorb can reach the prolongation absorption of injectable composition.

During for patient, procyanidin B 2 dosage of the present invention is 5 ~ 200mg/kgd, and this dosage or consumption decide according to the situation of the age of patient or user and body weight and health or patient's symptom conventionally.

Procyanidin B 2 of the present invention and Pharmaceutical composition thereof can comprise the procyanidin B 2 of the present invention of " treatment effective dose " or " prevention effective dose "." treatment effective dose " refers to the amount that effectively reaches required therapeutic effect under necessary dosage and time.The treatment effective dose of procyanidin B 2 can cause that at this individuality the factors such as the ability of required reaction change according to the patient's condition such as individual, age, sex and body weight and this procyanidin B 2.Treatment effective dose also refers to that the useful therapeutic effect of this procyanidin B 2 exceedes the amount of its any toxicity or harmful effect." prevention effective dose " refers to the amount that effectively reaches required preventive effect under necessary dosage and time.Because preventive dose is for the ill front or early stage curee of disease, prevention effective dose is less than treatment effective dose conventionally.The typical non-limiting scope of the treatment of procyanidin B 2 of the present invention or prevention effective dose is 5 ~ 200mg/kg, more preferably 20 ~ 100mg/kg.Should note, dose value will change according to the disease type of wanting to alleviate and seriousness, while that is to say for patient, procyanidin B 2 dosage of the present invention or consumption, decide according to the situation of the age of patient or user and body weight and health or patient's symptom conventionally.In addition; should understand; for any specific curee; should along with the time according to individual need and give with or supervision to adjusting given dose system with the people's of described compositions professional judgement; and the dosage range of setting is herein only illustrative, can't limit scope or the practice of claimed compositions.

That is to say, need to be according to object, route of administration, disease and the situation etc. for the treatment of for the treatment of, change dosage or the consumption of the each and/or every day of procyanidin B 2 of the present invention.For example, give mammal through vein, especially adult (as body weight 60kg), the single dose of described procyanidin B 2 is about 50～200mg, preferred about 100mg, preferably administration every day 1～3 time.Can adjust dosage unit, for example, so that best required reaction (, treatment or prevention are replied) to be provided.For example, can single-bolus high-dose administration, can within a period of time, give several divided doses or reduce in proportion or increase dosage according to the urgency for the treatment of situation.The non-intestinal compositions that preparation is easy to administration and the unified dosage unit form of dosage is especially favourable.Dosage unit form used herein, refers to be suitable for the physical separation unit of the dosage unit of the mammalian subject of wish treatment; The calculating that each unit contains scheduled volume is for together producing the active matter procyanidin B 2 of required therapeutic effect with required pharmaceutical carrier.The specification of dosage unit form of the present invention, be determined by the following and directly depend on the specific characteristic of following (a) this procyanidin B 2 and particular treatment or the preventive effect of wanting to reach, and (b) interior restriction of mixing in this technology that is used for the treatment of individual sensitivity procyanidin B 2.

3, the pharmaceutical dosage form of procyanidin B 2 and compositions thereof and route of administration

Procyanidin B 2 of the present invention and compositions thereof prepare for preventing, diagnose, detect, protect, treat and study the product of dementia disease and directly related disease thereof, the product of wherein preparing according to the requirement of beverage, food technology field can be used in prevention, protection and treatment dementia disease and directly related disease thereof; The product of preparing according to the requirement of medical technical field can be used in patient's treatment or health care, can either be directly used in separately the medicine of preparation treatment or health care, also can mix or combine with many chemical substances, directly or indirectly for the preparation of the medicine for the treatment of or keeping healthy.Chemical substance described here and this section are above described identical.

In the present invention, required material comprises raw material of the present invention, above-mentioned matching used chemical substance etc., all should, according to practical situation and needs, adopt the material of food stage or pharmaceutical grade.

Procyanidin B 2 of the present invention and compositions thereof, can be with the whole bag of tricks administration known in the art, although route of administration/administering mode of recommending in many therapeutic use is spray or oral administration.But technical staff will appreciate that route of administration/administering mode changes with required result.In some concrete enforcement, this reactive compound can with this compound of protection avoid the carrier that discharges fast together preparation example as empty release formulation, comprise that graft transmission system, transdermal paste one or more in transmission system or microcapsule transmission system etc.In addition, can also use biodegradable, biocompatible polymer, such as, in ethylene-ethyl acetate, polyanhydride, polyglycolic acid, collagen protein, polyorthoesters or polylactic acid etc. one or more.Prepare the equal patent applied for of many methods of this preparation or generally known to those skilled in the art (referring to for example Sustained and Controlled Release Drug Delivery Systems, J.R.Robinson edits, Marcel Dekker, Inc., New York, 1978).

Procyanidin B 2 of the present invention and compositions thereof, conventionally by one or more modes in oral or parenteral etc., be applied to the patient who needs this treatment.

When oral, can be made into conventional solid preparation as one or more in tablet, powder, granule or capsule etc.In the time implementing, procyanidin B 2 of the present invention can be together oral with for example inert diluent or assimilable edible carrier.This procyanidin B 2 (with its composition altogether, if needed) can also be wrapped in hard or soft shell gelatin capsules, is pressed into tablet or directly adds in curee's meals.About oral therapeutic administration, described procyanidin B 2 can be added together with excipient and use with one or more forms in edible tablet, buccal tablet agent, lozenge, capsule, suspension, syrup or wafer etc.

For to give procyanidin B 2 of the present invention outside parenterai administration, may need with preventing that the material of its inactivation from together giving to this procyanidin B 2 coating or with this procyanidin B 2.Supplementary reactive compound can also be added in said composition.In the specific implementation, procyanidin B 2 of the present invention and one or more other medicines that can be used for the treatment of disease are prepared altogether and/or given altogether.Thisly combine use, can utilize primely this medicine giving compared with low dosage, therefore avoid possible toxicity or the complication relevant to various monotherapies.

Make liquid preparation as one or more in water preparation, oil-suspending agent or other liquid preparation, as one or more in syrup, tincture or elixir etc.; When the parenteral, can be made into one or more in solution, water preparation or the oiliness suspending agent etc. of injection.

In above-described type of service, preferred form is one or more in tablet, coated tablet, capsule or injection etc., further one or more in preferred tablet, capsule or injection etc., particularly preferably tablet.

In addition; the medicinal raw material that procyanidin B 2 uses also can be directly used in separately the product for the preparation of prevention, diagnosis, detection, protection, treatment and research dementia disease and directly related disease thereof in some cases; also can mix or combine with many chemical substances, with the form of compositions directly or indirectly for the preparation of the product for preventing, diagnose, detect, protect, treat and study dementia disease and directly related disease thereof.Chemical substance described here and this section are above described identical.

The powder of the medicinal raw material that for example, procyanidin B 2 uses is for the preparation of prevention, diagnosis, detect, protection, the particularly various dosage forms of medicine of product for the treatment of and research dementia disease and directly related disease thereof, or the powder of the medicinal raw material that uses of procyanidin B 2 and relevant adjuvant are for the preparation of for preventing, diagnosis, detect, protection, the especially various dosage forms of medicine of product for the treatment of and research dementia disease and directly related disease thereof, or the powder of the medicinal raw material that uses of procyanidin B 2 with relevant for the preparation of prevention, diagnosis, detect, protection, the product for the treatment of and research dementia disease and directly related disease thereof as together with medicine for the preparation of for prevention, diagnosis, detect, protection, the product for the treatment of and research dementia disease and directly related disease thereof is as the various dosage forms of medicine, or the powder of the medicinal raw material that uses of procyanidin B 2 and relevant ancillary drug are together for the preparation of for prevention, diagnosis, detect, protection, the product for the treatment of and research dementia disease and directly related disease thereof is as the various dosage forms of medicine, as tablet, one or more in capsule or injection etc., preferred tablet.

One of described method is that the powder filling of medicinal raw material that procyanidin B 2 is used is for capsule or be pressed into tablet; Two of method be medicinal raw material that procyanidin B 2 is used powder with relevant for the preparation of prevention, diagnosis, detect, the product of protection, treatment and research dementia disease and directly related disease thereof is if fill together with medicine is for capsule or be pressed into tablet; Three of method be the powder of medicinal raw material that procyanidin B 2 is used with relevant ancillary drug together fill for capsule or be pressed into tablet; Four of method be medicinal raw material that procyanidin B 2 is used powder and relevant adjuvant together according to a conventional method fill for capsule or directly to press be tablet; Five of method be medicinal raw material that procyanidin B 2 is used powder, relevant for the preparation of prevention, diagnosis, detect, the product of protection, treatment and research dementia disease and directly related disease thereof as together with medicine with relevant adjuvant according to a conventional method fill for capsule or directly to press be tablet; Six of method be the powder of medicinal raw material that procyanidin B 2 is used, relevant ancillary drug together with relevant adjuvant according to a conventional method fill for capsule or directly to press be tablet etc.

Except six kinds of above-mentioned basic skills, can also select other forms of the medicinal raw material that procyanidin B 2 uses or the medicinal raw material that anthocyan compound is used to carry out after method processing well known in the art, prepare the product that contains the medicinal raw material that procyanidin B 2 uses of various dosage forms as medicine.But, in it should be noted that the medicinal raw material using at above-mentioned direct use procyanidin B 2, should be first according to the dosage requirement of used procyanidin B 2, convert and obtain the consumption of the medicinal raw material that the procyanidin B 2 of required use uses.

In sum, procyanidin B 2 of the present invention and compositions thereof can be used for the product of prevention, diagnosis, detection, protection, treatment and research dementia disease and directly related disease thereof, preferred agents and health product, further preferred health product.

(4) technology speciality

The present invention has expanded new medical usage to procyanidin B 2, also for prevention, diagnosis, detect, protection, treatment and research dementia disease and directly related disease thereof provide a kind of new medicament sources.Procyanidin B 2 safety and low toxicity of the present invention, pharmacological action is stronger, and its raw material sources are abundant, inexpensive, and preparation technology is simple, can be used for the product of preparation prevention, diagnosis, detection, protection, treatment and research dementia disease and directly related disease thereof.

The present invention studies procyanidin B 2 targetedly, and procyanidin B 2 pharmacological action is stronger, and its raw material sources are abundant, and preparation technology is simple, and yield is high; And use safety, particularly can one-object-many-purposes, brought into play to greatest extent effect, and the scope of application is wide especially, therefore easily applies, and can have a tremendous social and economic benefits in the short period of time.

Procyanidin B 2 stable in properties; use the quality of the pharmaceutical preparations of preparation stable; prevention, diagnosis, detect, the successful of protection, treatment and research dementia disease and directly related disease thereof, therefore its be more suitable for prevention, diagnosis, detect, the suitability for industrialized production of protection, treatment and research dementia disease and directly related disease product thereof.

In a word, active adaption of the present invention modern medical service and the job demand of scientific research field and the needs of human nature service, be the safe raw material for preventing, diagnose, detect, protect, treat and study the aspect such as dementia disease and directly related disease thereof.

Detailed description of the invention

The present invention has studied new pharmacological action and the new purposes of the procyanidin B 2 in existing procyanidin compounds; a kind of raw material that can be used in the products such as preparation prevention, diagnosis, detection, protection, treatment and research dementia disease and directly related disease thereof is provided, has been convenient to medical industry and relevant industries as the safe handling in the fields such as food, beverage, health product.

(1) test of procyanidin B 2 aspect prevention, diagnosis, protection and treatment dementia disease and directly related disease thereof

In order to set forth better activity of the present invention and effect, be described in detail below by example, wherein the content in procyanidin B 2 is in 95% situation.

1, the protective effect of procyanidin B 2 to vascular dementia due to Mouse Whole Brain ischemical reperfusion injury

Group:

Blank group: give and the isopyknic normal saline of medicine group.

Positive controls: give medicine Folium Ginkgo (Dr Willmar Schwabe) 48mg/kg, procyanidin (Jianfeng Natural Product R&D Development Co., Ltd., Tianjin) 40mg/kg.

Trial drug group: procyanidin B 2 (Jianfeng Natural Product R&D Development Co., Ltd., Tianjin), basic, normal, high 3 dosage 20,40,80mg/kg.

Method: by kunming mice, 28～32g, with 3% chloral hydrate 10ml/kg intraperitoneal injection of anesthesia, neck median incision, separates left and right side common carotid artery, bulldog clamp blocking-up bilateral common carotid arteries blood flow 30 minutes.Removing bulldog clamp pours into again.Sham operated rats is not pressed from both sides bulldog clamp, and all the other steps are the same.Gastric infusion when reper-fusion, sham operated rats and model group gavage give pure water (0.1ml/10g).1 time/d of mouse stomach, starts to carry out water maze test in mice after gavage 23d continuously.

Water maze test in mice:

Formed by the positive circular channels of a black lucite (d=90cm), in tank, have one, can stand for mice.Before experiment, in labyrinth, pour water, the depth of water there was not platform 2cm, 24 ± 1 DEG C of water temperatures.Be placed in platform upper 10 second the first day mice of training, make its existence of understanding this safety zone, then by mice in order head put into water from four quadrants successively towards tank, timing 2min, mice is found platform and stops thereon after 10s, and timing stops automatically.Within the 5th day, remove platform, the swimming starting point of mice is two quadrantal points away from platform, the incubation period of recording mice platform in 2 minutes.

After pouring into 23d again, water maze test result demonstration Mouse Whole Brain ischemia 30min causes mouse models with vascular dementia, model group learning and memory of little mouse function is impaired, the 5th day water maze time incubation period remarkable increase (P<0.01) compared with sham operated rats of undergoing training, the basic, normal, high dosage group of procyanidin B 2 significantly reduces the time of fourth ventricle in mice with vascular dementia water maze escape latency, compared with model group, difference has significant (P<0.05, P<0.01).The effect of procyanidin B 2 is better than the effect of procyanidin.The results are shown in Table 1.

The impact on fourth ventricle in mice with vascular dementia water maze escape latency of table 1, procyanidin B 2 (n=10, )

With model group comparison, * P<0.05; * P<0.01.

Result shows that procyanidin B 2 has therapeutical effect to vascular dementia, improves its learning and memory function.

2, the protective effect of procyanidin B 2 to vascular dementia rats due to Focal Cerebral Ischemia Reperfusion

Blank group: give and the isopyknic normal saline of medicine group.

Positive controls: give medicine Folium Ginkgo (Dr Willmar Schwabe) 24mg/kg, procyanidin (spike Natural products research development corporation, Ltd. of Jinshi City) 20mg/kg.

Trial drug group: procyanidin B 2 (Jianfeng Natural Product R&D Development Co., Ltd., Tianjin), basic, normal, high 3 dosage 10,20,40mg/kg.

Animal: SD rat

Method: by SD rat, 220～250g, with 3% chloral hydrate 10ml/kg intraperitoneal injection of anesthesia, neck median incision, separates common carotid artery, internal carotid artery, line bolt method is made middle cerebral artery occlusion (MCAO method) and is prepared focal cerebral ischemia in rats 2h, and then perfusion.Gastric infusion when rat is poured into again (positive drug is Folium Ginkgo 24mg/kg, procyanidin 40mg/kg for basic, normal, high 3 dosage 10,20 of procyanidin B 2,40mg/kg), sham operated rats and model group gavage give pure water.1 time/d of rat oral gavage, gavage 27d, then carries out rat water maze test continuously.

Rat water maze test:

Formed by the positive circular channels of a black lucite (d=150cm), in tank, have one, can stand for rat.Before experiment, in labyrinth, pour water, the depth of water there was not platform 2cm, 24 ± 1 DEG C of water temperatures.

Be placed in platform upper 10 second the first day rat of training, make its existence of understanding this safety zone, then by rat in order head put into water from four quadrants successively towards tank, timing 2min, rat is found platform and stops thereon after 20s, and timing stops automatically.

Within the 5th day, remove platform, the swimming starting point of rat is two quadrantal points away from platform, the incubation period of recording rat platform in 2 minutes.

After pouring into 27d again, water maze test result demonstration rat cerebral ischemia 2h causes vascular dementia rats model, model group's learning and memory function is impaired, the 5th day water maze escape latency time remarkable increase (P<0.01) compared with sham operated rats of undergoing training.The basic, normal, high dosage group of procyanidin B 2 water maze is hidden and is compared equal significance shortening aspire to model group, has significant difference (P<0.05, P<0.01) compared with model group.The effect of procyanidin B 2 is better than the effect of procyanidin.The results are shown in Table 2.

The impact on vascular dementia rats water maze escape latency of table 2, procyanidin B 2 (n=10, )

With model group comparison, * P<0.05; * P<0.01.

3. the effect of procyanidin B 2 to Alzheimer's Disease Rats due to amyloid beta (A β)

" aging " of 3.1A β processed the A β (25-35) of synthetic is dissolved in aseptic double-distilled water, and concentration is 1mg/ml, hatches 4 days for 37 DEG C, makes it reach aging coherent condition.

Chloral hydrate (0.35g/kg) anesthesia of the making SD rats by intraperitoneal injection 10% of 3.2 animal models, is fixed on brain multiplex, head unhairing, and sterilization skin, head median incision, exposes anterior fontanelle.Determine that entry point coordinate is: 0.8mm after bregma, left 1.5mm place is point of puncture, cranium (diameter 1mm) is worn in boring, from brain surface inserting needle 3.8mm to tricorn.Inject the A β 5 μ 1(1mg/ml of state of aggregation with microsyringe) to tricorn, sham operated rats is injected isometric(al) normal saline.The per injection time is 5min, and let the acupuncture needle remain at a certain point 5min fills up pin hole, postoperative a little sterilizing sulfa powder skin suture of spreading in wound with dental base acrylic resin powder.Gastric infusion after 24h (positive drug is Folium Ginkgo 24mg/kg, procyanidin 40mg/kg for basic, normal, high 3 dosage 20,40 of procyanidin B 2,80mg/kg), sham operated rats and model group gavage give pure water.21d after successive administration, then carries out water maze test.

Water maze test result shows that the beta induced Model of Dementia in Rats type of A group learning and memory function is impaired, the 5th day water maze escape latency time remarkable increase (P<0.01) compared with sham operated rats of undergoing training.Compared with model group, the basic, normal, high dosage group water maze of procyanidin B 2 significance incubation period shortens, and difference has statistical significance (P<0.05, P<0.01).The effect of procyanidin B 2 is better than the effect of procyanidin.The results are shown in Table 3.

Table 3, procyanidin B 2 on alzheimer disease rat water maze escape latency, wear platform number of times impact (n=10, )

With model group comparison, * P<0.05

Above specific experiment is given an example and other experiments of the present invention all prove, procyanidin B 2 of the present invention, and pharmaceutical composition is medicine or the health product of a kind of safe, efficient, stable, inexpensive control dementia disease and directly related disease thereof.

(2) dosage form of procyanidin B 2 aspect the anti-angiogenic dementia of preparation and Alzheimer product

Procyanidin B 2 can adopt method well known in the art to make various dosage forms, as tablet, capsule, granule, suspensoid, Emulsion, solution, syrup, injection etc., take the route of administration such as oral or injection (comprising intravenous injection, intravenous drip, intramuscular injection, subcutaneous injection), mucosa dialysis to carry out the control of dementia disease and directly related disease thereof.

During for patient, dosage determines according to the situation of patient's age, body weight, route of administration and symptom.

The present invention prepares injectable powder and generally adopts conventional freeze-drying, using water as solvent, the steps include: to get procyanidin B 2, adds excipient, is dissolved in water, and adds active carbon, filtration sterilization, and fill, partly rolls plug, lyophilization, lid is rolled in tamponade.Excipient used is selected from one or more in mannitol, gelatin hydrolysate, glucose, lactose, dextran etc.Every bottle containing procyanidin B ₂10 ~ 100mg.

The present invention prepares injectable powder also can adopt spray drying method, using water as solvent, the steps include: to get procyanidin B 2, adds or do not add excipient (excipient is the same), be dissolved in water, add active carbon, filtration sterilization, spraying is dry, and aseptic subpackaged, lid is rolled in tamponade.Every bottle containing procyanidin B ₂10 ~ 100mg.

When the present invention prepares small-volume injection, using water for injection as solvent, preparation, also can add appropriate amount of auxiliary materials, and adjuvant is selected from one or more in ethanol, propylene glycol, glycerol, Polyethylene Glycol, benzyl benzoate, dimethyl acetylamide.Every containing procyanidin B ₂10 ~ 100mg.

The present invention prepares glucose infusion liquid or sodium chloride transfusion, using water for injection as solvent, add appropriate glucose or sodium chloride preparation, also can add appropriate amount of auxiliary materials, adjuvant is selected from one or more in ethanol, propylene glycol, glycerol, Polyethylene Glycol, benzyl benzoate, dimethyl acetylamide.Every bottle containing procyanidin B ₂10 ~ 100mg.

The present invention prepares the oral formulations such as tablet, capsule, granule, oral liquid, and adjuvant can be lactose, starch, dextrin, stearate etc., technology preparation routinely.

As for procyanidin B ₂preparation method be ripe method, delivered at public publications such as multiple periodicals and magazines and patent documentations, just repeat no more in the present invention.

In the present invention, the example of above-described detailed description of the invention and the following stated is all in order to set forth better the present invention, is not for limiting scope of invention.

Below by the mode of embodiment, further the present invention is described in detail.

The preparation of embodiment 1, procyanidin B 2 tablet

Prescription:

Technique:

Procyanidin B 2 is crossed to 80 mesh sieves, mix with starch, lactose, carboxymethyl starch sodium, add starch slurry and make soft material.Granulate through 16 mesh sieves, 60 DEG C following dry, and granulate, adds magnesium stearate to mix rear tabletting.Can be made into the 1000 every tablet tablet containing 100mg procyanidin B 2.

The preparation of embodiment 2, procyanidin B 2 capsule

Prescription:

Technique:

Procyanidin B 2 is crossed 80 mesh sieves, mixes with starch, the micropowder silica gel of recipe quantity, directly incapsulates, and can be made into every capsule containing 100mg procyanidin B 2.

The preparation of embodiment 3, procyanidin B 2 injection

Prescription:

Technique:

Get 20 DEG C of ethanol (95%) 2000g, add active carbon 5g to stir, through core group filtration under diminished pressure, for subsequent use.Getting recipe quantity procyanidin B 2 adds in above-mentioned ethanol 2000g, be heated to approximately 40 DEG C, fully stir, make it to dissolve clear and bright, then add recipe quantity propylene glycol, add again fresh water for injection to make full dose become 10000ml, fully stir, mix, add active carbon 3g, clear and bright through core group filtration under diminished pressure, filtrate before and after merging, more clear and bright with special core fine straining.Check content and the qualified rear embedding of clarity, 100 DEG C of circulation steam sterilization 30min, obtain the injection of every 10ml containing PB1 0mg.

Claims (5)

1. Procyanidin B 2 as unique active component in the application of preparing in dementia product, described dementia product refers to the product of prevention, diagnosis, detection, protection, treatment and research dementia disease and directly related disease thereof, and described dementia disease and directly related disease thereof are one or more in early stage, mid-term or late period of mixing disease of vascular dementia disease and senile dementia; The structural formula of described procyanidin B 2 is as follows:
2. Procyanidin B 2 as the compositions of unique active component in the application of preparing in dementia product; described dementia product refers to the product of prevention, diagnosis, detection, protection, treatment and research dementia disease and directly related disease thereof; described dementia disease and directly related disease thereof are one or more in early stage, mid-term or late period of mixing disease of vascular dementia disease and senile dementia, and the structural formula of described procyanidin B 2 is as follows:
3. 3. application according to claim 1 and 2, is characterized in that, described dementia product is to comprise one or more in medicine, reagent, food, health product.
4. 4. application according to claim 3, is characterized in that, described dementia product is health product.
5. 5. application according to claim 1 and 2, is characterized in that, described dementia disease and directly related disease thereof are early stage mild cognitive impairment, the hypomnesis or forgetful of the mixing disease of vascular dementia disease and Alzheimer.