CN1931212A - Medicine for preventing and treating senile dementia and its prepn and use - Google Patents
Medicine for preventing and treating senile dementia and its prepn and use Download PDFInfo
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Abstract
The present invention is one kind of medicine for preventing and treating senile dementia and its preparation and use. The medicine has epimedium as the single ingredient, which is treated through solvent extraction, macroporous resin elution, drying and other technological steps to obtain epimedium total flavone used as the main component. The medicine is used in preventing and treating vascular dementia, Alzheimer disease and other senile dementia. It may be prepared into tablet, capsule, soft capsule, granule, dripping pill and other preparation forms.
Description
Technical field:
The present invention relates to medicine and the preparation and the purposes of a kind of prevention and treatment senile dementia, the Herba Epimedii total flavones and the preparation thereof that are specifically related to extract in the Chinese medicine material Herba Epimedii prevent and treat the medicine of senile dementia, the application in the health product in preparation.
Background technology:
Senile dementia is a kind of central nervous system's constitutional degeneration disease, and onset is slow, and the course of disease is chronic carrying out, and average 5～10 years is feature with comprehensive progressive dementia.It is mainly clinical to be chronic brain syndrome mutually, mainly shows as senior neural activity obstacles such as memory, language, judgement, understanding, thinking, behavior, personality and emotion, companion's aphasia, apraxia, agnosia, logagraphia and alexia etc.Senile dementia mainly can be divided into dementia of the Alzheimer type, cerebrovascular property senile dementia, mixed type and other type.Wherein much more to see with Alzheimer (AD) and vascular dementia (VD).Alzheimer senile dementia (AD) is a kind of chronic brain degeneration disease, and its unknown etiology as yet has characteristic europathology and neuro chemistry and changes.Since cerebrovascular disorders caused is the disease of main clinic symptoms with the dementia, just be referred to as vascular dementia (Vascluardementia, VD).From neuro pathology's angle, VD comprises that ischemia and hemorrhagic apoplexy and asystole cause the cerebral hypoxia ischemia infringement and the dementia that causes.China is more to the research of vascular dementia, thinks that multi-infarct dementia (MID) is the most common, is that the interior majority of brain that cerebrovascular causes is dispersed in infraction or the lacunar infarction kitchen range causes.Except cerebral infarction can take place the dementia, cerebral hemorrhage can cause dementia equally, comprises chronic subdural hematoma, subarachnoid hemorrhage sequela and cephalophyma, all can cause the generation of vascular dementia.The mixed type senile dementia is meant the symptom that has senile dementia and vascular dementia simultaneously, differentiates very difficult sometimes.The dementia that other reasons causes is classified as other type dementia.
It is reported that in the aging population, dull-witted prevalence accounts for 4%～5% of total population, the old people more than 80 years old can account for 17%～20%.Wherein the brain degenerative disease cause dementia---Alzheimer accounts for more than 50%, the vascular dementia that cerebrovascular causes accounts for 20%, the Combination dementia accounts for 20%, the dementia that other reasons causes accounts for 10%.In the U.S., the ill population of AD is 4,000,000, will rise to 1,100 ten thousand to this numeral of middle period next century, and annual cost is 10,000,000,000 dollars.The reconnaissance information in 27 town and country of China shows: more than 60 years old the patient of old man's medium vessels dementia to lead be 3,24/,100,000 populations, Alzheimer is 2,38/,100,000 populations; The prevalence city of vascular dementia is higher than the rural area, Alzheimer antithesis, the rural area is more than the city.According to estimates, by 2025, the ill population of AD was 2,200 ten thousand in the world wide.AD is the 4th cause of death after heart disease, cancer, apoplexy as the main type of senile dementia.Therefore the control of AD has been caused the extensive attention of the medical circle and even the whole society.
The medicine of senile dementia; Western medicine mainly contains the cholinergic precursor load and urgees releasing agent, cholinesterase inhibitor, cholinergic agonist class, antioxidant and neuroprotective, Hormone Replacement Therapy (ERT), anti-inflammatory agent; can also use neurotrophic factor, anti-neuronal apoptosis agent and short neurocyte metabolism medicine for the treatment of senile dementia in addition; calcium channel blocker, correction calcium homeostasis imbalance medicine; anti-4 amyloid forms medicine; metabolism reinforcing agent; the cell membrane regulator; cerebrolysin, medicines such as glutamate receptor antagonist.Main clinical medication at present has physostigmine, liquor epinephrinae bitartratis ophthalmicus Kalarba spit of fland, galantamine, donepezil, tacrine, huperzine A, selegiline, nimodipine etc.Though these medicines have certain therapeutical effect to senile dementia, these medicines all have toxic and side effects in various degree, and for example a lot of patients of physostigmine are difficult to bear its gastrointestinal side effect, as feel sick, vomiting, hemorrhage etc.; The tacrine acting duration is long than physostigmine, the main adverse reaction of this medicine is liver toxicity and gastrointestinal symptom, especially cause that transaminase (ALT and AST) level raises, gastrointestinal symptom comprises nausea,vomiting,diarrhea, dyspepsia, anorexia and weight loss, other untoward reaction comprise frequent micturition, sialorrhea, hyperhidrosis, dizzy and erythra etc., because this product toxic and side effects is bigger, at present domestic clinically stop using; Taking the common untoward reaction in liquor epinephrinae bitartratis ophthalmicus Kalarba spit of fland has nausea,vomiting,diarrhea, dizzy and headache etc., side effect of digestive tract such as that galantamine also has is nauseating, vomiting and diarrhoea; Donepezil and huperzine are first-class, and this type of medicine is early stage and to improve cognitive dysfunction effective to dementia, but certain untoward reaction is also arranged and act on shortcomings such as of short duration.
Along with the development of society, pace of population aging's quickening, senile dementia will cause more and more that people pay attention to.There is 20% people to suffer from this disease in Europe, the Japan and the U.S. population more than 70 years old at present, has more than 5,000 ten thousand people to suffer from different types of dementia in the population of whole world over-65s.It is predicted that the care of patients with senile dementia number in developed country in 2005 will increase by 50%.To this, still there is not more effective Therapeutic Method at present.But this phenomenon has caused the concern of countries in the world pharmaceuticals industries, and is is researching and developing medicine energetically, and its quantity of developing new product has surpassed the quantity of any other treatment class drug development.Yet although a large amount of funds has been dropped into to the research and development of medicine of treatment senile dementia in countries in the world, effect is not very satisfactory.Most of kind has certain therapeutical effect, and short-term can be improved patient's cognitive function, but long-term efficacy and toxic and side effects but allow of no optimist.So increasing people turns one's attention to traditional Chinese herbal medicine, wishes therefrom to seek out the medicine that can effectively prevent and treat senile dementia.
The name of disease of not having " alzheimer disease " in the ancient Chinese medicine, but that the description of similar dementia symptom can sporadically appear is silly in slow-witted card, literary composition, in the diseases such as force is silly, forgetful, language is put upside down, dementia, depressive psychosis, mania syndrome." left side pass " meaning: " not intelligent, unparalleled so-called idiot ", " become 18 years, Zhou Zi has brother and do not have intelligently, can not distinguish the bean wheat, does not know the branch domesticated dog ".The elaboration of similar disease is arranged, as " Ling Shu Miraculous Pivot or Divine Axis sea opinion " " the soreness of the shank dizziness, order does not have finding, slack peacefully sleeping for deficiency of marrow-reservoir, vertigo and tinnitus then " in " interior warp "; " kidney governing bones is given birth to marrow and is led in brain ".Not from the deficiency and excess two ends, see more by double the holding under the arm of deficiency in origin and excess in superficiality to the understanding of dull-witted etiology and pathogenesis for the modern Chinese medicine scholar.It is few that void comprises that mainly deficiency of kidney-essence and QI and blood decline; Actually comprise that phlegm-damp is hoodwinked, the resistance of blood stasis numbness.Visceral dysfunctions such as the kidney liver heart spleen of pathogenesis duty, kidney essense lose and fill, and insufficiency of vital energy and blood, brains lose supports, and phlegm and blood stasis is hoodwinked key clearly.The void of dementia, though it is all dirty extensively to involve kidney, spleen, the heart, liver, it is basic into it to suffer from a deficiency of the kidney, deficiency of kidney-essence, the brains deficiency runs through this sick overall process all the time.In view of of the classics explaination of above-mentioned motherland traditional medicine to the treatment theory of dementia, we have carried out detailed research to the part Chinese herbal medicine, ten several expections are demonstrate,proved medicative Chinese crude drug to dementia and extract has carried out drug effect and toxicological study by a large amount of animals and cell pharmacology screening experiment, the final Chinese crude drug Herba Epimedii total flavones of finding can obviously improve the animal pattern dysmnesia, improve learning capacity, can effectively improve, regulate cholinergic nerve of centrum, regulate multiple effects such as Radical Metabolism, to comprising Alzheimer's disease, various senile dementias such as vascular dementia all have definite curative effect.
Summary of the invention:
The objective of the invention is at the deficiencies in the prior art, provide a kind of Herba Epimedii total flavones that from traditional single medicinal material material Herba Epimedii, extracts to prevent and treat the medicine of senile dementia, the application in the health product in preparation.
Another object of the present invention is to provide the pharmaceutical preparation that is used to prevent and treat senile dementia that is prepared from by Herba Epimedii total flavones and appropriate drug adjuvant.
Herba Epimedii is stem, the leaf of Berberidaceae plant Herba Epimedii (Epimedium brevicornum Maxim.), arrow leaf Herba Epimedii [Epimediumsagittatum (Sieb.et Zucc.) Maxim], Epimedium wushanense (Epimedium wushanenes T.S.Ying), Herba Epimedii (Epimedium koreanum Nakai), pubescence Herba Epimedii (Epimedium pubescens Maxim.) etc.Herba Epimedii acrid in the mouth, sweet, warm in nature.Return kidney, Liver Channel.Have effects such as kidney invigorating and YANG supporting, strengthening the tendons and bones, expelling wind and removing dampness.The tradition medication is usually used in treating impotence and seminal emission, and cold caused by deficiency is sterile, the frequent micturition incontinence, and dyspnea and cough due to deficiency of the kidney, soreness of the waist and knees, rheumatic arthralgia, hemiplegia, extremity are meciless etc.Modern pharmacological research shows that Herba Epimedii has short sexual function effect, improves immunologic function, protects myocardial ischemic injury, increases multiple pharmacological effect such as coronary flow, slow down aging.We have carried out intensive research to aspects such as the chemical constituent of Chinese crude drug Herba Epimedii, pharmacological action, mechanism of action, find that Herba Epimedii total flavones can significantly improve Model of Dementia learning and memory in rats and mice obstacle, also has radical metabolism in the brain of raising, regulate the metabolic effect of monoamine neurotransmitter, senile dementias such as Alzheimer's disease, vascular dementia, mixed type dementia are all had tangible prevention and therapeutical effect.
The present invention can use the Chinese crude drug Herba Epimedii, it is extracted processing, with Herba Epimedii total flavones is main medicinal component, adds the suitable adjuvant that is used for, and is prepared into prevention and treatment that suitable preparation is used for various senile dementias such as vascular dementia, Alzheimer's disease.
The present invention also can buy ready-made Herba Epimedii total flavones, adds suitable pharmaceutic adjuvant, is prepared into prevention and treatment that suitable preparation is used for senile dementia.
1, the Herba Epimedii total flavones that extracts from the Chinese crude drug Herba Epimedii described in the present invention is to be prepared from according to following preparation technology, and its processing step is:
(1) the Chinese crude drug Herba Epimedii is cleaned, drying is ground into coarse powder, adds 5～12 times of amount 50～95% ethanol, and reflux, extract, 2～3 times each 0.5～2 hour, is filtered merge extractive liquid;
(2) concentrated extracting solution reclaims ethanol to there not being the alcohol flavor;
(3) in concentrated solution, add the organic solvent extraction 2～3 times of 1/3～1/5 volume, divide and get organic solvent layer, merge, be concentrated into paste, reclaim organic solvent; Or with concentrated solution by macroporous adsorptive resins, water be eluted to eluent colourless after, reuse 30%～90% alcoholic solution carries out eluting, collects ethanol elution, merges, concentrated extract reclaims ethanol to paste;
(4), beat powder and promptly get Herba Epimedii total flavones with the paste extract drying of step (3) gained.
Organic solvent is used in extraction described in the step (3), can be fatty acid esters such as ethyl acetate, Ethyl formate, halogenated hydrocarbons such as chloroform, dichloromethane, aliphatic alcohols such as n-butyl alcohol.
Drying means described in the step (4) can be proper method such as boulton process, freeze-drying, forced air drying method, spray drying method, the common seasoning of normal pressure, infrared drying method.
What make with this method is the epimedium flavone that comprises various active compositions such as epimedium flavone glycoside, epimedium flavone time glycoside, and wherein the content of Herba Epimedii total flavones is more than 50%.
The contained medicinal component of preparation per unit of the present invention is 1mg～1000mg.Administration as required.Because Herba Epimedii total flavones does not have obvious toxic-side effects, so be not very strict.The doctor can be according to the order of severity of disease, the patient's that receives treatment body weight, give and want frequency, adjust dosage for the individual difference of wanting approach and the course of treatment and patient, change flexibly.
The used pharmaceutical preparation of the present invention can be in accordance with known methods, with preparations such as one or more pharmaceutically useful carriers or diluent.Said preparation can be the form of oral, non-intestinal, rectum, intranasal administration, also can make the form of administrations such as aerosol, inhalant.
The solid pharmaceutical preparation of oral administration can be tablet, hard capsule, soft capsule, drop pill, granule, powder, pill etc.Can be prepared from the adjuvant that use can be medicinal in the process of preparation according to their conventional preparation method.For example, in the preparation process of tablet or capsule, can use filler (for example starch, dextrin, sucrose, lactose, calcium sulfate, calcium carbonate, little smart cellulose etc.), adhesive (as methylcellulose, ethyl cellulose, polyvinylpyrrolidone, carboxymethyl starch sodium, gelatin, corn starch etc.), disintegrating agent (as dry starch, crosslinked carboxymethyl fecula sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose etc.), lubricant (as magnesium stearate, stearic acid, micropowder silica gel, Polyethylene Glycol, Pulvis Talci etc.).Tablet can also be according to present known method coating.Granule also needs to select for use corresponding correctives (as sucrose, syrupus citri etc.).Used diluent includes but not limited to one or more in vegetable oil, mineral oil, propylene glycol, tween, the Polyethylene Glycol (PEG) (200～8000) in the preparation of soft capsule.Suspending agent includes but not limited to cellulose family such as Carboxymethyl cellulose sodium, hyetellose, ethyl cellulose, hydroxyethylmethyl-cellulose, hyprolose, methylcellulose, hydroxypropyl emthylcellulose etc.; Gum class such as arabic gum etc.; Other are as in carbomer, the polyvinyl alcohol etc. one or more.Emulsifying agent comprises but is not limited in sodium stearate, enuatrol, spans (20～80), Tweens (20～80), glyceryl monostearate, hydroxylated lecithin, diacetyl monoglyceride, diethylene glycol stearate, orthoformic acid, ethylene glycol monostearate, the Cera Flava one or more.Used antiseptic includes but not limited to one or more in sorbic acid methyl ester, benzoic acid, sorbic acid, methyl parahydroxybenzoate, Nepal's tortoise beetle ester, nipagin ester, the benzyl alcohol.In the preparation of drop pill, substrate includes but not limited to Polyethylene Glycol (PEG) 6000, Polyethylene Glycol (PEG) 4000, Polyethylene Glycol (PEG) 1000, Polyethylene Glycol (PEG) 1500, sodium stearate, glycerin gelatine, stearic acid, poloxamer etc.; Condensed fluid includes but not limited to dimethicone, liquid paraffin, plant wet goods.
Oral liquid can be mixture (oral liquid), syrup, Emulsion, suspensoid, elixir or suspension, can also be that water or other suitable carriers reconstitute the dry products of taking before it uses.These liquid preparations can be according to known method preparation itself, in the process of preparation, can use medical additive, as suspending agent (as cellulose derivative, glucose/sucrose syrup, sorbitol syrups etc.), emulsifying agent (as arabic gum, soybean phospholipid, lecithin, gelatin, Tweens etc.), suspending agent (as glycerol, simple syrup, aluminum monostearate vegetable oil, colloid sulphuric acid magnalium etc.), antiseptic (as benzoic acid, methyl hydroxybenzoate, nipasol, sorbic acid etc.).Can also add flavoring material, fragrant composition, sweeting agent etc. as required.
Non-intestinal drug delivery agent can be prepared into injection, preferred intravenous, subcutaneous, intramuscular injection.Can be with the ampoule form, also can add antiseptic and be prepared into the transfusion form.Said preparation can be solution, suspension or the emulsion form in aqueous or the oiliness carrier, can also add the reagent of suitable suspending agent, stabilizing agent, dispersant or adjusting osmotic pressure etc.In addition, active component can be made the solid sterile powder, dissolves with suitable carrier preparation before using.
The present invention can also be prepared into rectally preparation suppository etc.The substrate of suppository can be selected WitepsolH, S and E, and Polyethylene Glycol, glycerin gelatine, tween 61, poloxamer etc.Also can be prepared into preparations such as suitable aerosol, spray, drop.
The Herba Epimedii total flavones that extracts in the single medicinal material material Herba Epimedii provided by the invention can also be used to prepare food supplement and/or health food, can be prepared into the various dosage forms of health food, for example tablet, capsule, oral liquid, health beverage, health tea etc.; Also can be used as food additive, be applied to food (as bread, noodles etc.), health tea, health beverage etc.
The present invention compares with prior art has following remarkable novelty and advance: at first, the present invention is to serve as that prescription is formed with single medicinal material material Herba Epimedii, with Herba Epimedii total flavones as main medicinal component, active component is clear and definite, avoid the kinds of traditional Chinese medicines material to be used as medicine simultaneously, caused the indefinite deficiency of active component of medicine; Secondly, the present invention has adopted the modern extraction process of Chinese medicine, optimal design by technology, selected with solvent extraction, solvent extraction/processing steps such as macroporous adsorbent resin eluting separation, to medical material extract, remove impurity, refining, the Herba Epimedii total flavones that obtains effective ingredient, effective site enrichment is as main medicinal component, and preparation technology has repeatability and controllability; The 3rd, because the medicinal component of the present invention is clearer and more definite, can carry out qualitative, quantitative by modern analysis means such as methods such as uv analysis method, high performance liquid chromatogram and measure, drug quality is controlled, meets the modern medicine development definite ingredients that development proposes to Chinese medicine, quality controllable requirement; The 4th, the present invention is the research and development object to traditional kidney-nourishing yang-strengthening medicine Herba Epimedii, to its chemical constituent, pharmacological action, particularly the pharmacology pharmacodynamic based on the modern pharmacology experiment has carried out deep research and exploration, find that Herba Epimedii total flavones can significantly improve the dysmnesia of senile dementia, cognitive disorder, can also improve the metabolism of oxygen-derived free radicals in the brain, regulate the monoamine neurotransmitter metabolism, improve the material base of the learning and memory of senile dementia, thereby changed the medication direction of Herba Epimedii traditional " kidney invigorating and YANG supporting ", opened up it and be used for the vascular senile dementia, the new medicinal direction and the effect of the prevention of various senile dementias such as Alzheimer's disease and treatment; The 5th, the present invention is prevention and the treatment that its composition with medical active is used for senile dementia with the modern medicines preparation as carrier, various preparations all are according to the needs of preparation itself and characteristics, adopt modern preparation technique to be prepared from, embodied the science and the multiformity of modern Chinese medicine preparation, also met requirement and the selection of modern simultaneously pharmaceutical preparation.
Description of drawings:
Fig. 1 is the process chart of embodiment 1;
Fig. 2 is the process chart of embodiment 2;
Fig. 3 is the experimental result to the influence of AD rat model passive learning memory;
Fig. 4 is the experimental result to the influence of AD rat model active learning and memory;
Fig. 5 is the experimental result to the influence of AD rat model hippocampal tissue monoamine neurotransmitter content;
Fig. 6 is to the experimental result of the influence of AD rat model temporo side cerebral tissue monoamine neurotransmitter content;
Fig. 7 is the experimental result to the influence of VD rat model study capacitation;
Fig. 8 is that the experimental result of the influence of ability is consolidated in memory to the VD rat model;
Fig. 9 is the experimental result to the influence of VD rat model cerebral tissue SOD vigor;
Figure 10 is the experimental result to the influence of dementia mice brain cholinergic system due to the D-galactose.
In order further to understand the present invention, the present invention is further illustrated and explaination with embodiment below, but the present invention is not limited in cited embodiment.
Specific embodiment:
The preparation technology of embodiment 1 Herba Epimedii total flavones (extraction is refining)
The Chinese crude drug Herba Epimedii is cleaned, and drying is behind the coarse powder, add 10 times of amount 75% ethanol, reflux, extract,, 1.5 hours extraction times, filter, in medical material, add 8 times of amount 70% ethanol again, reflux, extract, twice, 1 hour extraction time for the first time, 0.5 hour extraction time of the second time, filter, merge three times reflux extracting liquid, discard medicinal residues; Amalgamation liquid is evaporated to no ethanol flavor, and reclaims ethanol; In concentrated solution, add the organic solvent ethyl acetate of 1/3 volume, fully leave standstill separating and extracting layer and water layer behind the mixing; The ethyl acetate that adds 1/4 volume, 1/5 volume in water layer successively extracts 2 times again, separates water layer, merges the extraction liquid layer of three gained, and concentrating under reduced pressure reclaims ethyl acetate, and the extract obtained vacuum drying oven of putting into is dry under 60 ℃ of temperature, beats powder promptly.
Figure of description 1 is seen in its technological process.
The preparation technology of embodiment 2 Herba Epimedii total flavones (macroporous resin column separating purification);
The Chinese crude drug Herba Epimedii is cleaned, and drying is behind the coarse powder, add 10 times of amount 75% ethanol, reflux, extract,, 1.5 hours extraction times, filter, in medical material, add 8 times of amount 70% ethanol again, reflux, extract, twice, 1 hour extraction time for the first time, 0.5 hour extraction time of the second time, filter, merge three times reflux extracting liquid, discard medicinal residues; Amalgamation liquid is evaporated to no ethanol flavor, and reclaims ethanol; Concentrated solution is by macroporous adsorptive resins, water be eluted to eluent colourless after, reuse 70% alcoholic solution carries out eluting, collects ethanol elution, concentrating under reduced pressure reclaims ethanol; With the extract obtained vacuum drying oven of putting into, dry under 60 ℃ of temperature, beat powder and promptly get Herba Epimedii total flavones.
Figure of description 2 is seen in its technological process.
Embodiment 3 oral tablets
Herba Epimedii total flavones 0.05～0.40 gram/sheet
0.1～0.3 milligram/sheet of magnesium stearate
4～12 milligrams/sheet of carboxymethyl starch sodium
50～100 milligrams/sheet of microcrystalline Cellulose
Herba Epimedii total flavones is mixed with carboxymethyl starch sodium, microcrystalline Cellulose, sieve, make its mixing, add an amount of water or the alcohol granulation of suitable concentration, after the drying, granulate adds an amount of magnesium stearate, and the decompressor of using suitable diameter then is with the granule tabletting.
Embodiment 4 hard capsules
Herba Epimedii total flavones 0.05～0.40 gram/grain
4～12 milligrams/of carboxymethyl starch sodium
0.1～0.3 milligram/of magnesium stearate
50～100 milligrams/of starch
Herba Epimedii total flavones is sieved, mix with carboxymethyl starch sodium, starch, sieve, add an amount of water or the alcohol granulation of suitable concentration, after the drying, granulate adds an amount of magnesium stearate, with suitable device this mixture is packed in the hard gelatin capsule.By changing net weight, and change capsular size as required and can prepare different capsules.
Embodiment 5 granules
Herba Epimedii total flavones 2～20 gram/bags
Dextrin 2～10 grams
Sucrose 2～15 grams
Correctives is an amount of
Sweeting agent is an amount of
With medicinal component and sucrose, dextrin, correctives, sweeting agent mix homogeneously, add an amount of water or the alcohol granulation of suitable concentration, after the drying, granulate, packing.
Embodiment 6 soft capsules
Herba Epimedii total flavones 0.05～0.40 gram/grain
300～450 milligrams/of diluent
5～7.5 milligrams/of suspending agents
5～7.5 milligrams/of emulsifying agents
60～90 milligrams/in water
The component and the content of every softgel shell are as follows:
100～150 milligrams in gelatin
30～50 milligrams of glycerol
100～150 milligrams in water
Antiseptic is an amount of
Gelatin is placed the glue jar, add the purified water of solubilized gelatin amount, glue jar temperature is suitable, after dissolving, adds glycerol, antiseptic, stirs, and insulation is left standstill after the vacuumize degassing; In proportion with Herba Epimedii total flavones and diluent, emulsifying agent, suspending agent mix homogeneously, content and the gelatin for preparing are put rotation press the capsule machine, be pressed into soft capsule, typing, dry getting final product.Can change the soft capsule that content is prepared into different size according to different needs.
Embodiment 7 drop pill
2～20 milligrams/of Herba Epimedii total flavones
40～80 milligrams of substrate
Condensed fluid methyl-silicone oil (in right amount)
Add water and make even pasty state in Herba Epimedii total flavones, add molten matrix liquid again, heating and melting becomes supernatant liquid, pour in the drop pill device of preheating, control is dripped the system temperature and is dripped speed, splashes in the condensed fluid, blot condensed fluid after becoming ball, collect drop pill, put in the exsiccator promptly.
Embodiment 8 syrups
20～100 milligrams of Herba Epimedii total flavones
Hydroxypropyl emthylcellulose is an amount of
Buffer agent is an amount of
Correctives is an amount of
Antiseptic is an amount of
Sweeting agent is an amount of
Coloring agent is an amount of
Purified water to 10～100 milliliter
Hydroxypropyl emthylcellulose is dispersed in the hot water, cooling, then with contain active component and preparation in the aqueous suspension of other compositions mix.The modulation of gained solution is needed volume and mix homogeneously, sterilization back packing.
Embodiment 9 injections
5～100 milligrams/unit of Herba Epimedii total flavones
Injection 0.9% sodium chloride solution to 5～10 milliliters
Medicinal component is dissolved in the sodium chloride for injection solution, solution is transferred to needed volume, regulate pH value, heat sterilization at high temperature after the fill.
Herba Epimedii total flavones 0.05～0.40 gram/sheet
Can press 40～80 milligrams/sheet of sucrose
0.1～0.3 milligram/sheet of magnesium stearate
With Herba Epimedii total flavones after suitable sieve sieves with other composition mix homogeneously, and with suitable decompressor tabletting.Can be by ratio that changes active component and carrier or the tablet that is prepared into varying strength by the change compressing weight.
The suppository of embodiment 11 rectallies
Herba Epimedii total flavones 0.05～0.40 gram/sheet
Witepsol H15 0.5～2 gram
The suspension of preparation medicinal component in fusion Witepsol H15, and proper device is with in its 1 gram suppository mold of packing into.
Further specify the present invention with pharmacological evaluation below.
One, to the influence of Model of Dementia learning and memory in rats effect
(1) influence of Alzheimer's disease (AD) rat model learning and memory
1, experimental technique: get 60 of healthy Wistar male rats, 3～4 monthly ages, body weight 200～250g.Be divided into 10 of sham operated rats at random, 10 of AD model group, 10 of administration low dose group (0.01g/kg), dosage group (0.03g/kg) in the administration, 10 of administration high dose group (0.06g/kg), 10 of YINKELUO PIAN (Folium Ginkgo 0.02g/kg) matched groups.With 1.0ml/100g body weight, gastric infusion.Sham operated rats and AD model group are irritated capacity drinking waters such as stomach, every day gastric infusion once, continuous irrigation stomach 15 days.Formal administration the previous day, with rat with 1% pentobarbital sodium 3ml/kg with intraperitoneal anesthesia, cut off calvarium cutout regions hair, be fixed on the brain solid positioner.Get rat calvarium median incision, with reference to the brain stereotaxic atlas (tail side 1.4mm, each side 3.1mm, 6.9mm deeply) of rat, to both sides Hippocampus CA
1Behind the three-dimensional location, district, use electric dental engine, bore and open skull, with the vertical inserting needle of microsyringe, will use 0.01mol/L, the quinolinic acid 2 μ l (containing the 150nmol quinolinic acid) of PH7.4PBS buffer solution slowly inject Hippocampus CA
1The district.Sham operated rats is injected the PBS buffer solution of equivalent.Injection rate is 0.05 μ l/min, let the acupuncture needle remain at a certain point 10min, then in 10min in gradual slow pin is extracted.After the partly sterilised,, and give rats by intraperitoneal injection penicillin injection liquid 120000U/kg with the boring of dentistry cemented, skin suture.
Rose in the 14th day, after the administration 1 hour, with multi-functional avoidance conditioned reflex instrument, adopt the diving tower method to carry out the passive learning memory training, to observe animal and jump off the incubation period of electric grid and the errors number that shocked by electricity from platform, test next day; Adopted the method for shuttling back and forth to carry out the training of active learning and memory on the 14th day on the same day, observe the active avoidance phase (Tl), initiatively avoid number of times (Nl), passive avoidance incubation period (Ts), passive avoidance number of times (Ns), the 15th day and 16 days, follow-on test 2 days.Behind the neuroethology EOT, put to death animal, dissect and get rat hippocampal tissue and temporo side tissue, place respectively weigh on the template after, put into the acid n-butyl alcohol that pre-cooling is housed, under the condition of ice bath, the preparation homogenate, adjusting homogenate concentration with acid n-butyl alcohol is 0.1g/3ml.Homogenate is poured in the tool plug centrifuge tube, concussion 5min, centrifugal 10min (rotating speed 3000) gets suitable n-butyl alcohol liquid, carries out the extraction and the mensuration of norepinephrine (NE), dopamine (DA), 5-hydroxy tryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA) with the chemiluminescence algoscopy.Experimental result is calculated with the method for X ± S.
2, experimental result:
Experimental result shows: compare with sham operated rats, the test phase diving tower errors number of AD model group animal obviously increases, have remarkable meaning (
*P＜0.05); Compare with the AD model group, big or middle, the administration group of dosage and the diving tower errors number of Ginkgo Biloba Leaf Preparation group rat all have obvious minimizing, the extremely significant statistical significance of performance (
* *P＜0.01).After showing administration, the passive learning memory ability of animal is significantly increased.
Compare with sham operated rats, the test of AD animal pattern initiatively avoid incubation period (Tl) and initiatively avoid number of times (Nl) all obviously reduce (
*P＜0.01); And all obviously increases of passive avoidance incubation period (Ts) and passive avoidance number of times (Ns) (
*P＜0.01,
*P＜0.05), shows extremely significantly meaning; Compare with the AD model group, each dosed administration group and Ginkgo Biloba Leaf Preparation group to Tl and Nl all have remarkable increase effect (
*P＜0.01), to Ts and Ns have obvious minimizing effect (
* *P＜0.01), demonstrates extremely significant statistical significance.After showing administration, the active ability of learning and memory of animal is significantly improved.
Compare with sham operated rats, the NE content of AD model group rat hippocampus have significance reduce (
*P＜0.05), 5-HT content also has more obviously minimizing, but compares with sham operated rats, does not see significant statistical significance; Compare with the AD model group, the administration group and the Ginkgo Biloba Leaf Preparation group of each dosage all can significantly improve NE content, significant difference (
*P＜0.05); Low dose of administration group can significantly improve DA and 5-HT content, reduces 5-HIAA content; In the dosage group 5-HIAA content is also had remarkable reduction effect, also can improve DA and 5-HT content (
*P＜0.05,
* *P＜0.01); High dose group also has tangible regulating action to the content of above-mentioned monoamine neurotransmitter, shown be the content that increases rat hippocampus NE, DA, 5-HT with the increase of dosage to medicine.
Compare with sham operated rats, AD rat model temporo side cerebral tissue 5-HT content obviously reduces, statistical significance significantly (
*P＜0.05); Compare with the AD model group, administration small dose group, middle dosage group can significantly improve 5-HT content (
*P＜0.05), DA, 5-HIAA content are had certain regulating action, heavy dose of group also has to a certain degree regulating action to DA, 5-HT, 5-HIAA, but significant difference is not very remarkable.
Experimental result to the influence of AD rat model passive learning memory sees Figure of description 3 for details;
To the AD rat model initiatively the experimental result of the influence of learning and memory see Figure of description 4 for details;
Experimental result to the influence of AD rat model hippocampal tissue monoamine neurotransmitter content sees Figure of description 5 for details;
Experimental result to the influence of AD rat model temporo side cerebral tissue monoamine neurotransmitter content sees Figure of description 6 for details.
(2) influence of vascular dementia (VD) rat model learning and memory
1, laboratory animal and grouping: get 60 of adult male SD rats, SPF level, body weight 180～220g.Animal grouping situation; Be divided into six groups at random according to the water maze training achievement: 1) sham operated rats is 10; 2) positive drug group (piracetam group) is 10; 3) 10 of administration group (is the extract group of main component with the Herba Epimedii total flavones) low dose group; 4) the dosage group is 10 in; 5) high dose group is 10; 6) model group is 10.
2, modeling and administration: by 4% pentobarbital sodium 1ml/kg, ip after the anesthesia, separates the exposure bilateral common carotid arteries with rat.After nitre Pu Na closes bilateral common carotid arteries 10min with noinvasive bulldog clamp folder after by the 2.5mg/kg lumbar injection at once, logical again 10min, folder closes 10min once more, and logical again back is sewed up.Make rat anus temperature remain on 37 ± 0.3 ℃ in the real process, to prevent the protective effect of low temperature to the rat cerebral ischemia damage, the postoperative insulation is raised.After the modeling, treat that the clear-headed back of animal promptly began administration the same day.Positive controls is given piracetam, presses the 0.4g/100g body weight and irritates stomach; Model group and sham operated rats give the normal saline of same dose and irritate stomach, every day 1 time, continuous 15 days.
3, experimental technique: the water maze laboratory device has three place's cecums, has only a ladder that leads to outlet.During experiment, train four times for every.The time of writing down its covering the race the 5th time, with the VD rat from the needed to terminal time of water maze starting point trip with enter the number of times (errors number) of cecum midway, as weighing the index of learning capacitation.If when 3min, do not find ladder yet, then be decided to be and can not finish learning training, promptly there is tangible learning capacity low.The retest These parameters is consolidated the index of ability behind the 24h as memory.Rat enters cecum in water maze number of times more less and the short more animal learning memory ability that shows of the time of swimming out of strong more.Dispose animal, get brain after rat is put to death, isolate left hippocampus and cortex, ice normal saline flushing blood is weighed after filter paper is dried, and adds 10 times of amount normal saline, grinds to form 10% homogenate in the pressure-even pulp crusher, and is centrifugal, gets supernatant.Adopt the Coomassie brilliant blue albuminometry to carry out protein determination.Computing formula is: protein content (g/L)=mensuration pipe absorbance/standard pipe absorbance * standard pipe concentration.SOD measures, assay method is according to used SOD test kit description, computing formula: protein content (U/mgpro) in SOD vigor in the homogenate=(control tube absorbance-mensuration pipe absorbance) afterreaction liquid cumulative volume/control tube absorbance * 50% * sampling amount (ml) * tissue.
4, experimental result: each treated animal perform the operation back 15 days and 16 days recording learning and memory achievement respectively.Model group is compared with sham operated rats: the former covering the race time, enter the cecum number of times and the time obviously increase (
*P＜0.01).The administration group is compared with model group: the former covering the race time, enter the cecum number of times and the time obviously reduce (
*P＜0.05); The administration group is compared with positive controls: both differences are not very remarkable, not statistically significant.
SOD is that body is removed the more important enzyme in the free radical enzyme system, and its ability of removing free radical is directly proportional with the activity of enzyme, can constantly remove unnecessary free radical, guarantees the organism metabolism balance.This experimental result shows that the vigor of model group cerebral tissue SOD obviously descends the free radical resisting ability drop; And administration group and positive controls can improve the SOD vigor, have the free radical resisting damaging action, and are excellent with the curative effect of administration group.Compare with model group
*Compare with sham operated rats P＜0.001
*P＜0.01; Compare with positive controls
* *P＜0.05.
The experimental result of the VD rat model being learnt the influence of capacitation sees Figure of description 7 for details;
The experimental result of the VD rat model being remembered the influence of the ability of consolidating sees Figure of description 8 for details;
Experimental result to the influence of VD rat model cerebral tissue SOD vigor sees Figure of description 9 for details.
(3) to the influence of dementia mice brain cholinergic system due to the D-galactose
1, experimental technique: select 100 of female kunming mices of three monthly ages, body weight 40 ± 5g is divided into the normal control group at random, model group, administration is little, in, heavy dose of group (60,180,600mg/kg), Ginkgo Biloba Leaf Preparation group (12mg/kg).Every day, gastric infusion was 1 time, capacity 0.5mL/20g, and normal control group and model group wait the capacity distilled water.Except that the normal control group, all the other respectively organize mice in administration every day, all in back subcutaneous injection 5%D-galactose (0.5mL/ only).Capacity normal saline such as normal control group mouse subcutaneous injection.More than equal successive administrations 60 days.
Acetylcholinesterase (AchE) determination of activity: after the last administration 1 hour, animal all takes off cervical vertebra put to death, and gets brain immediately, weighs, and prepares 10% brain homogenate with normal saline in the ice bath, measures the AchE activity.The AchE activity is represented (μ mol/ml) with the content of choline that generates.
Choline acetyltransterase (ChAT) determination of activity: after the last administration 1 hour, animal takes off cervical vertebra put to death, and gets brain immediately, weighs, add 18 times of phosphate buffers (PBS, 75mmol/L, pH7.4), homogenate in ice bath, get homogenate 10 μ L, add the atural object buffer and (contain NaCl1600mmol/L, MgCl
240mmol/L, physostigmine 2.0mmol/L,
3H-S-acetyl-coenzyme-A 0.88mmol/L), after 37 ℃ of temperature are bathed 40min, add the heptane ketone that 150 μ L contain sodium tetraphenylborate 70mg/mL, jolting, centrifugal, get upper organic phase, measure its radioactivity in Beckman LS Analyzer, it is an amount of to get homogenate simultaneously, measures protein content with the Coomassie brilliant blue method.Acetylcholine [nmol/ (mgh) albumen] expression of ChAT activity to form.
2, experimental result:
Show that the administration group can obviously reduce the D-galactose and cause the Model of Dementia mouse brain and organize cholinesterase activity, obviously improve its cerebral tissue choline acetyl transfers enzyme activity.Prompting this product can play the dull-witted effect of treatment by improving the disorder of central cholinergic system function.Annotate: compare with the normal control group
*P＜0.01; Compare with model group
*P＜0.05.
Its experimental result sees Figure of description 10 for details.
Claims (7)
1, Herba Epimedii total flavones is used for preparing prevention and the medicine of treatment senile dementia or the purposes of health product.
2, Herba Epimedii total flavones according to claim 1 is formed through solvent extraction, organic solvent extraction or macroporous resin column are refining by single medicinal material material Herba Epimedii, and its preparation technology is as described below:
(1) the Chinese crude drug Herba Epimedii is cleaned, drying is ground into coarse powder, adds 5～12 times of amount 50～95% ethanol, and reflux, extract, 2～3 times each 0.5～2 hour, is filtered merge extractive liquid;
(2) concentrated extracting solution reclaims ethanol to there not being the alcohol flavor;
(3) in concentrated solution, add the organic solvent extraction 2～3 times of 1/3～1/5 volume, divide and get organic solvent layer, merge, be concentrated into paste, reclaim organic solvent; Or with concentrated solution by macroporous adsorptive resins, water be eluted to eluent colourless after, reuse 30%～90% alcoholic solution carries out eluting, collects ethanol elution, merges, concentrated extract reclaims ethanol to paste;
(4), beat powder and promptly get Herba Epimedii total flavones with the paste extract drying of step (3) gained.
3, Herba Epimedii total flavones according to claim 2 is characterized in that it being the total flavones that comprises various active compositions such as epimedium flavone glycoside, epimedium flavone time glycoside, and wherein content of total flavone is more than 50%.
4, the purposes of Herba Epimedii total flavones according to claim 1 is characterized in that the application that can be used for preparing prevention and treat the medicine of various senile dementias such as vascular dementia, Alzheimer, mixed type dementia.
5, the purposes of Herba Epimedii total flavones according to claim 4 is characterized in that being mainly used in the application in the medicine for the treatment of Alzheimer's disease.
6,, it is characterized in that to be used to being prepared into the medicine of all form of medication such as oral, rectum, intramuscular, intravenous, nasal cavity according to the purposes of claim 4 or 5 described Herba Epimedii total flavones.
7, the preparation that contains Herba Epimedii total flavones according to claim 6 is characterized in that described preparation comprises pharmaceutically acceptable preparations such as conventional tablet, buccal tablet, slow releasing tablet, controlled release tablet, dispersible tablet, hard capsule, soft capsule, granule, drop pill, pill, injection, Emulsion, inhalant, aerosol or suppository.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103781466A (en) * | 2011-09-08 | 2014-05-07 | 罗蒂株式会社 | Oral composition |
| CN108354961A (en) * | 2018-04-23 | 2018-08-03 | 长江大学 | Purposes of the Shorthorned Epimedium P.E after preparing treatment radiation in the drug of Cranial nerve injury as birth trauma and cognitive disorder |
| CN110251549A (en) * | 2019-06-24 | 2019-09-20 | 浙江省肿瘤医院 | Application of the barren wort total chromocor extract in the drug or health care product of preparation prevention and treatment Hashimoto thyroiditis |
| CN110638823A (en) * | 2019-10-25 | 2020-01-03 | 贵州中医药大学 | Application of icariin in preparation of medicine for treating vascular dementia |
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2005
- 2005-09-16 CN CN 200510094412 patent/CN1931212A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103781466A (en) * | 2011-09-08 | 2014-05-07 | 罗蒂株式会社 | Oral composition |
| US10201493B2 (en) | 2011-09-08 | 2019-02-12 | Lotte Co., Ltd. | Method of reducing oral biofilm |
| CN108354961A (en) * | 2018-04-23 | 2018-08-03 | 长江大学 | Purposes of the Shorthorned Epimedium P.E after preparing treatment radiation in the drug of Cranial nerve injury as birth trauma and cognitive disorder |
| CN108354961B (en) * | 2018-04-23 | 2021-05-04 | 长江大学 | Application of epimedium extract in preparing medicine for treating postradiation cranial nerve injury and cognitive disorder |
| CN110251549A (en) * | 2019-06-24 | 2019-09-20 | 浙江省肿瘤医院 | Application of the barren wort total chromocor extract in the drug or health care product of preparation prevention and treatment Hashimoto thyroiditis |
| CN110251549B (en) * | 2019-06-24 | 2021-12-03 | 浙江省肿瘤医院 | Application of epimedium total flavone extract in preparing medicine for preventing and treating hashimoto thyroiditis |
| CN110638823A (en) * | 2019-10-25 | 2020-01-03 | 贵州中医药大学 | Application of icariin in preparation of medicine for treating vascular dementia |
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