CN101816747B - Medicinal preparation for preventing and treating mental diseases such as insomnia and the like and preparation method thereof - Google Patents

Abstract

The invention provides a medicinal preparation for preventing and treating mental diseases such as insomnia and the like and a preparation method thereof. The medicinal preparation is mainly prepared from camellia branch, thin-leaf milkwort root-bark, dwarf lilyturf tuber and tuber fleeceflower stem serving as raw medicaments, or is compatible with partial or total medicinal materials comprising valeriana root, hawthorn fruit and aleppo avens. Compared with the prior art, the formula provided by the invention can be prepared into an oral preparation by a conventional preparation process; and the preparation has the effects of tranquilizing by nourishing the heart, nourishing yin and tonifying spleen, has good curative effect on symptoms such as insomnia, melancholy, amnesia and the like caused by heart-kidney imbalance and spleen-stomach yin deficiency, is safe to use, has no toxic or side effect, does not produce medicament resistance, has no influence on driving, high-altitude work and the like, and is a safe, effective and quality-controllable new Chinese medicament for preventing and treating the mental diseases such as the insomnia and the like.

Description

A kind ofly prevent and treat pharmaceutical preparation of the mental sickness such as insomnia and preparation method thereof

Technical field

The present invention relates to and a kind ofly prevent and treat pharmaceutical preparation of the mental sickness such as insomnia and preparation method thereof, belong to technical field of Chinese medicines.

Background technology

The sleeping problems such as insomnia have become the ubiquitous serious public health problem in countries in the world.World Health Organization (WHO) was once investigated in 14 countries, and the people of about 27% has sleeping problems.The investigation display of U.S.'s sleep foundation, the American of about 50% can have weekly several days time to occur at least one insomnia symptom.In Europe, the people of nearly 4% ~ 22% is subject to having a strong impact on of insomnia, and the sickness rate of the current insomnia of China is also up to 10% ~ 20%.Chinese Medical Association psychosis association of China once in Shanghai, Beijing, Guangzhou, Beijing, the ground such as Hangzhou and the Shandong sleeping problems that carried out once having people more than 10,000 to participate in investigate.In surveyee, exist the sleeping problems such as easily wake up, wake up too early, the length of one's sleep is not enough, sleep quality is bad up to 42.5%.Have a sleepless night and become in order to a very general problem in China, particularly with women and old man in the majority.

Depression is called as in west " blue secret worry ", and according to relevant investigation display, in China, depression rate is about 3%-5%, has had at present and has suffered from depression more than 2,600 ten thousand people.Along with the development of society, live in the metropolitan white collars such as Beijing, Shanghai and Guangzhou and become for this reason sick group of people at high risk rapidly under the environment of high pressure height competition.Form distinct contrast with high incidence regrettably, current national prefectural level is to go to the hospital to the discrimination of depression less than 20%.In existing patients with depression, only receive relevant Drug therapy less than the people of 10%.World Health Organization's latest survey statistical analysis, the incidence rate of global depression is about 3.1%, and in developed country close to about 6%, 2002 years existing more than 8,900 ten thousand people of global Serious depression patient, and the patients with depression in the whole world reaches 3.4 hundred million.In the adult population of 20 years old, patients with depression just increases with the speed of annual 11.3%.Expect 2005, depression rate will rise to 8 ~ 10% in developed country; Be easy to caused function residue to the year two thousand twenty principal characteristic and will rise to the 2nd of the total class of disease, be only second to ischemic heart desease.Depression also allows of no optimist in the situation of China, and current depression is approximately 4% at the sickness rate of China.Show according to the new classification of diseases of application and diagnostic system some areas Epidemiological study data of carrying out, China's depression prevalence is about 10 ‰ ~ about 15 ‰, close with developed country statistical result.Neuropsychiatric disease ranks first in China's disease is always born, and account for that disease always bears 20%.Calculate according to World Health Organization (WHO), Chinese neuropsychiatric disease bears the year two thousand twenty will rise to disease always bears 1/4.Have data to show, the people of China 70% is in sub-health state, and the Disease relevant to psychological stress accounts for crowd's 5% ~ 10%, and somatopsychic illness, mental maladjustment have become frequently-occurring disease, commonly encountered diseases.Within 2002, key cities of China typical hospital nervous system charges for drug has reached about 14.20 hundred million yuan, and the metropolitan proportion of Beijing,Shanghai and Guangzhou three accounts for 63.28%, and antidepressants account for 1/5.

The pathogenic factor of amnesia is various, and its topmost reason is the age, and nearest amnesia sickness rate becomes younger trend, but versus young people, the person in middle and old age of more than 40 years old more easily suffer from amnesia.The best memory of people appears at 20 years old front and back, and then the function of brain starts fall off, and before and after 25 years old, memory starts formal decline, and the age, larger memory was lower.Therefore the people of two teens and three teens is perplexed the thing that neither wonder by amnesia.In addition, amnesia also have its external cause, it is tired that lasting pressure and anxiety can make brain cell produce, and amnesia is worsened.Excessive smoking, drink, being deficient in vitamin etc. to cause temporary memory to worsen.Recently, expert also starts to notice, psychological factor also has the impact that can not be ignored on the formation of amnesia, and the amesiac gone to see a doctor has and much has symptoms of depression.Once people is absorbed in depression, will only pay close attention to doggedly depressed itself and to the people in society and thing unconcerned, so the energy of brain is low, and bring out amnesia.According to statistics, in amesiac, women account for 60%, and housewife more than 80% has amnesia to experience.

Insomnia is one of common clinical card, though do not belong to critical illness, normal hinders people orthobiosis, work, study and health, and can increase the weight of or bring out the diseases such as cardiopalmus, the thoracic obstruction, dizzy, headache, apoplexy.Obstinate insomnia, brings long-term misery to patient, even form the dependence to sleeping medicine, and the sleeping medicine of long-term taking can cause iatrogenic disease.Chinese medicine passes through the function of adjustment viscera negative and positive of qi and blood, often energy obviously improving water flood situation, and does not cause drug dependence and iatrogenic illness, thus rather well received.Up to the present, the mental sickness such as insomnia there is no medicine safely and effectively, calm class medicine clinically, this quasi drugs energy quick symptom relief, but also cure the symptoms, not the disease, this quasi drugs toxic and side effects is comparatively large, long-term taking simultaneously, cause drug dependence and iatrogenic illness to human body, applying such medicine can increase and occur that motor vehicle accident, death, fracture, mortality are poisoning, physiological function declines and the danger of cognitive impairment.In order to develop the Chinese medicine of energy safety, effective anti-treatment goat, applicant carried out a large amount of explorations and research.

Summary of the invention

Technical problem to be solved by this invention is to provide pharmaceutical preparation of the mental sickness such as a kind of energy safety, effectively control insomnia and preparation method thereof, medicine effect of the present invention is fast, have no side effect, and is the new Chinese medicine of the mental sickness such as a kind of safe, effective, quality controllable control insomnia.

In order to solve the problems of the technologies described above, the present invention adopts following technical scheme: control insomnia waits the medicine of mental sickness, is mainly made up of the crude drug of following weight percents: Semen Pittospori Glabrati tea 10% ~ 45%, Radix Polygalae 15% ~ 20%, Radix Ophiopogonis 15% ~ 30%, Caulis Polygoni Multiflori 25% ~ 40%.

The medicine of the mental sickness such as above-mentioned control insomnia, the consumption of each crude drug is preferably: Semen Pittospori Glabrati tea 26.7%, Radix Polygalae 17.8%, Radix Ophiopogonis 22.2%, Caulis Polygoni Multiflori 33.3%.

The preparation method of the medicine of the mental sickness such as above-mentioned control insomnia is: get Semen Pittospori Glabrati tea, Radix Polygalae, Radix Ophiopogonis, Caulis Polygoni Multiflori four Chinese medicine material, add 5 ~ 12 times of soak by water 1 ~ 3 time of prescription total amount, each decoction 1 ~ 3 hour, filter, it is the extractum of 1.20 ~ 1.40 that filtrate is concentrated into 60 DEG C of relative densities, and then preparation process makes different pharmaceutical preparation routinely.

Aforementioned control insomnia waits the medicine of mental sickness, in order to reach better therapeutic effect, can also add Rhizoma valerianae latifoliae, Fructus Crataegi, Radix seu Herba Gei aleppici three taste raw medicinal material, the part by weight of each crude drug is: Semen Pittospori Glabrati tea 5% ~ 40%, Radix Polygalae 5% ~ 13%, Radix Ophiopogonis 10% ~ 15%, Caulis Polygoni Multiflori 15% ~ 22%, Rhizoma valerianae latifoliae 10% ~ 15%, Fructus Crataegi 10% ~ 15%, Radix seu Herba Gei aleppici 10% ~ 15%.

The medicine of the mental sickness such as above-mentioned control insomnia, the consumption of each component is preferably: Semen Pittospori Glabrati tea 16%, Radix Polygalae 10.7%, Radix Ophiopogonis 13.3%, Caulis Polygoni Multiflori 20%, Rhizoma valerianae latifoliae 13.3%, Fructus Crataegi 13.3%, Radix seu Herba Gei aleppici 13.3%.

The preparation method of the medicine of the mental sickness such as above-mentioned control insomnia is: get Semen Pittospori Glabrati tea, Radix Polygalae, Radix Ophiopogonis, Caulis Polygoni Multiflori, Rhizoma valerianae latifoliae, Fructus Crataegi, Radix seu Herba Gei aleppici seven flavor medicine material, add 5 ~ 12 times of soak by water 1 ~ 3 time of prescription total amount, each decoction 1 ~ 3 hour, filter, it is the extractum of 1.20 ~ 1.40 that filtrate is concentrated into 60 DEG C of relative densities, and then preparation process makes different pharmaceutical preparation routinely.

Medicine of the present invention can be prepared into oral formulations, comprises decoction, granule, oral liquid, syrup, soft extract, pill, tablet, hard capsule or soft capsule etc.

We are according to theory of Chinese medical science, utilize the mental sickness such as interior application treatment insomnia, in line with the basic principle of " have heresy and the person's of being insomnia eliminating the pathogen and god from peace ", the method for thus treatment is worked as head and is got mind tranquilizing and the heart calming, void person is aided with the method for nourishing the blood and yin QI invigorating, and real person controls with the method for eliminating phlegm heat clearing and blood circulation promoting.Control from specimen deficiency and excess opinion, Cure for insomnia, determined curative effect, effect obviously.

Prescription medicine characteristic of the present invention: Rhizoma valerianae latifoliae: pungent, micro-hardship, temperature.Promoting digestion and invigorating the stomach, regulating QI to relieve pain, removing toxic substances of dispeling the wind.To treat for stomachache abdominal distention, dyspepsia, infantile malnutrition, gastroenteritis, dysentery, rheumatalgia, soreness of the waist and knees.Semen Pittospori Glabrati tea: property is cold, bitter in the mouth, peppery.Enter hot warp.Heat clearing away, wind-damp dispelling, calms the nerves; Jaundice, rheumatalgia, insomnia.Radix Polygalae: bitter, pungent, tepor.GUIXIN, kidney, lung meridian.To calm the nerves Fructus Alpiniae Oxyphyllae, eliminate the phlegm, detumescence.For the insomnia and dreamful sleep that disarmony between the heart and kidney causes, forgetful palpitation with fear, staring spells, expectoration is not well, sore swollen toxin, breast swell and pain.Fructus Crataegi: sour in the mouth, sweet, slightly warm in nature.Appetite-stimulating indigestion-relieving, change stagnant removing food stagnancy, promoting blood circulation to remove blood stasis, circulation of qi promoting of reducing phlegm.For meat stagnant long-pending, lump in the abdomen, abdominal distention feeling of fullness, stasis blocking stomachache, phlegm retention, have loose bowels, discharging fresh blood stool etc.Radix Ophiopogonis: sweet, micro-hardship, is slightly cold.GUIXIN, lung, stomach warp.YIN nourishing and the production of body fluid promoting, lung moistening clears away heart-fire.For dryness of the lung dry cough, chronic consumptive disease is coughed, and Tianjin wound is thirsty, and vexed insomnia, interior-heat is quenched one's thirst, dryness of the intestine constipation, pharyngeal diphtheria.Caulis Polygoni Multiflori: property is put down, sweet in the mouth.Enter the heart, spleen, liver, kidney channel.Nourish heart, calm the nerves, dredging collateral, dispel the wind, control insomnia, impairment caused by overstrain, hyperhidrosis, blood deficiency general pain, carbuncle, scrofula, wind skin ulcer scabies.Radix seu Herba Gei aleppici: pungent, bitter is flat.Analgesia, blood pressure lowering, regulating menstruation, expelling wind and removing dampness.For hypertension, dizziness headache, menoxenia, lower abdominal pain, leucorrhea, infantile convulsion, lumbago, skelalgia of rheumatism; Carbuncle furuncle and phyma poison is controlled in external, traumatic injury.

Prescription side of the present invention separates: have a sleepless night not enough with the length of one's sleep, Depth of sleep not and can not allaying tiredness, to regain one's strength with energy be main syndromes feature.Wherein the length of one's sleep, deficiency person can show as difficulty falling asleep, and sleep night and easily wake up, be difficult to sleep after waking up, severe patient is insomnia even all night again.Depth of sleep inadequate person sleeps when waking up when often showing as night, sleep then disintoxicated, or dream of sleeping night is many.Inadequate due to the length of one's sleep and degree of depth quality, causing after waking up can not allaying tiredness, shows as dizziness, headache, spiritlessness and weakness, cardiopalmus, forgetful, even malaise etc.Due to individual variation, also not identical with the requirement of quality to the length of one's sleep, thus clinical judgment insomnia not only will according to sleep time and quality, the more important thing is with can allaying tiredness, regain one's strength with energy as foundation.At reinforce insufficiency and reduce excessiveness, the basis of adjustment internal organs negative and positive of qi and blood is aided with the base therapy method that tranquilizing the mind is primary disease.The suitable reducing for the excess syndrome of excess syndrome, as dispersing the stagnated live-QI to relieve the stagnation of QI, pathogenic fire reducing clearing away phlegm, promoting digestion and regulating the middle JIAO.The suitable tonifying for deficiency syndrome of deficiency syndrome, as benefiting QI and nourishing blood, spleen invigorating, tonifying liver, kidney tonifying.With the passing of time, QI and blood consumption wound, also can transfer deficiency syndrome to, simulataneous insufficiency and excessive person to excess syndrome, and controlling should reinforcement and elimination in combination.The use of tranquilizing the mind method in conjunction with clinical, will be selected the concrete method for the treatment of such as nourishing blood to tranquillize the mind, tranquillizing the mind by relieving convulsion, clearing away heart-fire for tranquillization, and notes coordinating spiritual healing respectively, to eliminate nervous anxiety, keeps spirit happy.We cure mainly disarmony between the heart and kidney institute induced insomnia, melancholy, the card such as forgetful, based on Semen Pittospori Glabrati tea, Radix Polygalae in side, focus on Fructus Alpiniae Oxyphyllae of calming the nerves; With YIN nourishing and the production of body fluid promoting Radix Ophiopogonis, lung moistening clears away heart-fire; Caulis Polygoni Multiflori nourishes heart, and calms the nerves, and two medicines are with the power of principal drug assistance tranquilizing by nourishing the heart; With Radix seu Herba Gei aleppici analgesia blood pressure lowering; With Rhizoma valerianae latifoliae, Fructus Crataegi two taste strengthening the spleen and stomach, regulate the flow of vital energy; All medicines share, and adopt heart and tranquilizing mind altogether, the merit of YIN nourishing spleen invigorating, vexed insomnia difficulty can be made to sleep, melancholy, forgetful all diseases must control.

Function of the present invention cures mainly: medicine of the present invention has tranquilizing by nourishing the heart, YIN nourishing spleen invigorating effect.The insomnia caused for disarmony between the heart and kidney, deficiency of YIN of the spleen and stomach, melancholy, the card such as forgetful.And use safety, having no side effect, do not produce drug resistance, on driving, work high above the ground etc. without impact, is the new Chinese medicine of the mental sickness such as a kind of safe, effective, quality controllable anti-Cure for insomnia.

In order to verify that medicine of the present invention has good therapeutic effect, applicant carried out series of experimental research, specific as follows:

one, clinical practice

1, physical data: clinically accept patient 120 example altogether for medical treatment, male 52 example, women 68 example, older person 65 years old, reckling 23 years old, the most elder of the course of disease 6 years, the shortest person 15 days.Basis is clinical is divided into treatment group 80 example, matched group 40 example, two groups of no significant differences at random.

2, Therapeutic Method

2.1 treatment groups: treat, syndrome by " disease of tcm Standardization of diagnosis and curative effect ": disarmony between the heart and kidney institute induced insomnia, melancholy, forgetful etc. see dizziness, headache, spiritlessness and weakness, cardiopalmus, forgetful, the even disease such as malaise.Control and clear away heart-fire with yin nourishing, Fructus Alpiniae Oxyphyllae of calming the nerves.Method of administration: Semen Pittospori Glabrati tea 12g, Radix Polygalae 8g, Radix Ophiopogonis 10g, Caulis Polygoni Multiflori 15g, Rhizoma valerianae latifoliae 10g, Fructus Crataegi 10g, Radix seu Herba Gei aleppici 10g.Decoct soup take orally, one day 1 dose, within 30 days, be a course for the treatment of.

2.2 matched groups: by NAOLEJING KELI, nourish heart, brain-strengthening, mind-easing function.For depressed, easily frightened insomnia, irritated and children's's night restlessness is slept.Warm boiled water, a 14 ~ 42g, 3 times on the one.

3, observation of curative effect

3.1 observation items: before and after treatment, all patients all makes routine blood test, routine urinalysis, blood urea nitrogen, blood pressure detecting.

3.2 criterions of therapeutical effect: effectively: primary symptom insomnia all disappears, other transference cures, lab testing recovers normal; Effective: primary symptom insomnia and other symptoms alleviate, and lab testing is improved; Invalid: primary symptom insomnia and other symptom lab testings unchanged.

3.3 results: treatment group 80 example, effective 36 examples, effective 38 examples, invalid 6 examples, total effective rate is 92.5%; Matched group 40 example, effective 14 examples, effective 20 examples, invalid 6 examples, total effective rate is 85%.Treatment group curative effect is apparently higher than matched group.

The clinical total effects of table 1

4, discuss: the psychotic disorders such as insomnia are internal medicine refractory disease, the satisfaction not of Western medicine curative effect, and side effect is large.Chinese medicine is at psychotic disorder satisfactory effects such as Cure for insomnias, and the party has the effect such as tranquilizing by nourishing the heart, YIN nourishing spleen invigorating, and demonstrate,prove insomnia, melancholy, forgetful etc. and have good curative effect, clinic is applied.

two, preliminary drug effect and formula contrast test

1, experiment material

1.1 laboratory animals: Kunming mouse, cleaning grade, body weight 18-22g.

1.2 medicines and reagent: by reagent: No. 1, invention formulation extract and No. 2, Kweiyang spring section's Pharmaceutical research and development company limited provides, specification: each 2 bags × 100g, clinical usage and consumption: 3 times on the one, 1.2g/ time (being equivalent to primary crude drug 10.5g), facing the used time, to be made into suspension with distilled water for subsequent use.Contrast medicine: sedative jujube kernel capsule; Pentobarbital sodium.

1.3 experiment equipments: BS110S precision electronic balance (Beijing Sai Duolisi joint-stock company), SHA-C temperature controlled water bath oscillator (all over the country industrial corporation in Shenzhen), timer (Kweiyang is permanent in biotech firm).

2, method and result are on the impact of pentobarbital sodium syngignoscism: white mice is divided into 8 groups at random, No. 1, invention formulation extract and No. 2 high, medium and low dosage groups, sedative jujube kernel capsule group and blank group, every day gavage once, continuous 4 days.Within after last administration l hour, respectively organize equal ip pentobarbital sodium 30mg.Observe righting reflex loss in mice 1 hour more than the Mus number of 1min and dropping asleep latency, non-sleeper in 1 hour, dropping asleep latency is by 60 points of calculating, calculate sleep rate and the length of one's sleep, result shows that invention formulation extract obviously can increase sleep rate and the dropping asleep latency of white mice, extends the length of one's sleep.No. 1, invention formulation extract and No. 2 compare, and No. 2 results are better than No. 1.

The synergism of table 2 pair pentobarbital sodium hypnosis

The synergism of table 3 pair pentobarbital sodium sleep

three, preparation process thereof research

1, preparation technology

1.1 prescriptions:semen Pittospori Glabrati tea 12g, Radix Polygalae 8g, Radix Ophiopogonis 10g, Caulis Polygoni Multiflori 15g, Rhizoma valerianae latifoliae 10g, Fructus Crataegi 10g, Radix seu Herba Gei aleppici 10g.

1.2 preparation technologies:above seven flavor medicine material, decocts with water twice, adds water 10 times at every turn, each decoction 3 hours, filter, merging filtrate, being evaporated to relative density is 1.25 ~ 1.30(60 DEG C) extractum, vacuum drying, pulverizes, and crosses 80 mesh sieves, add right amount of auxiliary materials, mixing, granulate, drying, granulate, sieves, fill, makes capsule, to obtain final product.

1.3 dosage forms:original formulation usage is taken for decocting soup, and the preliminary test of pesticide effectiveness also shows, water extraction dry extract obviously increases sleep rate and the dropping asleep latency of white mice, and extend the length of one's sleep, therefore, consideration dosage form is oral formulations.This experiment carries out technical study with hard capsule.

1.4 technological process

2, Study on Preparation

2.1 process routes are determined:this product prescription is made up of Semen Pittospori Glabrati tea, Radix Polygalae, Radix Ophiopogonis, Caulis Polygoni Multiflori, Rhizoma valerianae latifoliae, Fructus Crataegi, Radix seu Herba Gei aleppici 7 taste medicine, takes to decoct soup.The determination of process route should take into full account the character of each medical material in prescription.In this project prescription, the character of each medical material is as follows: (1) Rhizoma valerianae latifoliae: pungent, the micro-hardship of this product, temperature.There is promoting digestion and invigorating the stomach, regulating QI to relieve pain, removing toxic substances of dispeling the wind.For abdominal distention of having a stomachache, dyspepsia, infantile malnutrition, soreness of the waist and knees.This product main component is bornival; Also contain the alkaloids such as valerianine, chatinine, valerianae alkaloid A, valerianae alkaloid B, actinidine, valerianine containing australene.There is sedation, can corticocerebral process of inhibition be strengthened, lower reflex excitability, remove smooth muscle spasm.(2) Semen Pittospori Glabrati tea: this product is bitter, tepor.Have promoting blood circulation to remove obstruction in the collateral, synthetism is subsided a swelling, removing toxic substances pain relieving.For hypertension, neurasthenia, emission, cough, limbs fatigue, hematuria.(3) Radix Polygalae: this product is bitter, pungent, tepor.There is Fructus Alpiniae Oxyphyllae of calming the nerves, eliminate the phlegm, detumescence.For the insomnia and dreamful sleep that disarmony between the heart and kidney causes, forgetful palpitation with fear, staring spells.This product main component is bessisterol glucoside, bessisterol glucoside 6 '-O cetylate, stigmasterol, and (2-8Z) three chemical composition of tetradecenoic acid, has the effect of Fructus Alpiniae Oxyphyllae of calming the nerves.(4) Fructus Crataegi: this product sour in the mouth, sweet, slightly warm in nature.There is appetite-stimulating indigestion-relieving, change stagnant removing food stagnancy, promoting blood circulation to remove blood stasis, circulation of qi promoting of reducing phlegm.For meat stagnant long-pending, lump in the abdomen, abdominal distention feeling of fullness, stasis blocking stomachache, phlegm retention, have loose bowels, discharging fresh blood stool etc.The main component of Fructus Crataegi is Flavonoid substances, mainly contains containing the flavonoid glycoside of carbon bond, flavonol and glycoside thereof, dioxygen flavonoid glycoside, polymerization flavonoid.The composition of another kind of outbalance is triterpene substance, has heart tonifying, increases coronary blood flow, improves the important function such as blood circulation.In addition, organic acid is contained in Fructus Crataegi as chlorogenic acid, caffeic acid and tannin, acid anhydride of tanning, epicatechol, choline, acetylcholine, Sitosterolum, carotene and a large amount of Vit C etc.Can prevention and cure of cardiovascular disease, there is blood vessel dilating, increase coronary flow, improve heart vigor, stimulating central nervous system system, reduce blood pressure and cholesterol, vessel softening and diuresis and sedation.(5) Radix Ophiopogonis: sweet, the micro-hardship of this product, is slightly cold.Have YIN nourishing and the production of body fluid promoting, lung moistening clears away heart-fire.For dryness of the lung dry cough, Tianjin wound is thirsty, and vexed insomnia, interior-heat is quenched one's thirst.In this product, Total saponin, total amino acids low dose all have significant positive inotropic and increase cardiac output effect, and coronary flow is increased; And the Total saponin of heavy dose, total amino acids and total sugar all produce suppression to heart, myocardial contraction is weakened, cardiac output reduces.Total saponin, total amino acids and total sugar have no significant effect heart rate.To dual regulation and the antibacterial action of blood glucose, immunologic function.(6) Caulis Polygoni Multiflori: the sweet micro-hardship of this product is flat.Have and nourish heart, calm the nerves, dredging collateral, dispel the wind.For insomnia, impairment caused by overstrain, hyperhidrosis, blood deficiency general pain.Stem, containing Anthraquinones, is mainly emodin, chrysophanol or physcione, all exists with conjunction type.(7) Radix seu Herba Gei aleppici: this product is pungent, bitter is flat.There is analgesia, blood pressure lowering, regulating menstruation, expelling wind and removing dampness.For hypertension, dizziness headache, menoxenia, lower abdominal pain, leucorrhea, infantile convulsion, lumbago, skelalgia of rheumatism.This product contains the chemical compositions such as gein, volatile oil, tannin, resin.For Guizhou Province commonly uses traditional herbal medicine, market one's own products, output is larger.There is vigorate qi and replenish the blood, tonifying YANG tonify deficiency, the function of yin nourishing strengthening the spleen and stomach, therefore have a dizzy spell for folk therapy and key medicine that tonify deficiency is weak, be therefore referred to as again dizzy medicine.

In sum, in conjunction with the character feature of medical material each in prescription, this preparation determines to adopt water extraction, existing by as follows for its experimental results report.

2.2 decocting process researchs

(1) factor level is established: the factor that impact decocts mainly contains the following aspects: amount of water, decocting time, decoction number of times etc.Therefore we have carried out the orthogonal investigation of 3 factor 3 levels to these three principal elements, with preferred optimal processing parameter.The factor level table of orthogonal test is in table 4:

Table 4 decocts orthogonal test factor level table

(2) choose targets: in we, multi-flavor medicine contains flavone compound, modern study shows, chromocor compound is to cardiac-cerebral ischemia damage, hepatic injury, ARR protective effect and analgesia thereof, therefore free radical resisting and antitumor etc. act on, using its extracted amount as orthogonal test evaluation index; Prescription Chinese crude drug is also containing fat-soluble active ingredients such as alkaloids, and in order to fully reflect extraction effect, we measure the content of 60% ethanol soluble extraction in extract, and also make orthogonal test evaluation index with it; In addition, dried cream yield is also the conventional index evaluating extraction effect, and it directly affects the regulation taking dosage and single oral dose day, therefore also using it as one of orthogonal test evaluation index.This test intended adopts comprehensive scoring method to carry out process conditions preferably, because dried cream yield and effective amount are not proportional, specifies that its balance is divided into 30 points; 60% ethanol soluble extraction balance is divided into 30 points; Effective ingredient in the total flavones side of being, directly can reflect extraction effect, therefore specifies that the balance of this index divides and be 40 points.

(3) sample preparation: get 1 recipe quantity medical material, amount to 75g, carry out water extraction by each orthogonal test condition of table 4, medicinal liquid, with after 300 order filter-cloth filterings, concentrates and is settled to 100ml.For subsequent use.

(4) dried cream yield measure: precision get each orthogonal test concentrate after medicinal liquid 25ml, put respectively and be dried in the evaporating dish of constant weight, water bath method, residue in 105 DEG C of dryings 3 hours, take out, put in exsiccator place 30 minutes, weigh, calculate dried cream yield.

(5) 60% ethanol soluble extractions measure: precision get each orthogonal test concentrate after medicinal liquid 50ml, adding ethanol respectively makes alcohol content reach 60%, leave standstill cold preservation 24 hours, filter, filtrate water bath method, residue was in 105 DEG C of dryings 3 hours, take out, be placed in exsiccator to place 30 minutes, weigh, calculate extractum yield.

(6) Determination of Total Flavonoids

The preparation of reference substance solution: it is appropriate that precision takes the control substance of Rutin being dried to constant weight at 120 DEG C, puts in 25ml measuring bottle, adds methanol appropriate, put slight fever in water-bath and make dissolving, let cool, add methanol to scale, shake up; Precision measures 10ml, puts in 100ml measuring bottle, adds water to scale, shake up, and makes the solution containing rutin 0.20192 mg in every lml, obtains reference substance solution;

Prepared by standard curve: precision measures reference substance solution 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, put respectively in 25ml measuring bottle, respectively add water to 6.0ml, add 5% sodium nitrite solution 1ml, shake up, place 6 minutes, add 10% aluminum nitrate solution 1ml, place 6 minutes, hydro-oxidation sodium test solution 10ml, then add water to scale, shaking up, place 15 minutes, take corresponding reagent as blank; According to ultraviolet visible spectrophotometry, measure absorbance at 510nm wavelength place, take absorbance as vertical coordinate, concentration is abscissa, drawing standard curve;

The preparation of need testing solution: get this product under content uniformity item, mixing, get 0.2g, accurately weighed, put in tool plug conical flask, precision adds 70% ethanol 25ml, weigh, ultrasonic 10min, places room temperature, less loss weight is supplied with 70% ethanol, filter, in accurate absorption subsequent filtrate 1ml to 25ml volumetric flask, add water to 5ml, method under sighting target directrix curve preparation, with the obtained need testing solution of method operation from " adding water to 6.0ml ", measure absorbance in accordance with the law, read the weight containing anhydrous rutin in need testing solution from standard curve, calculate, to obtain final product.Orthogonal experiments and interpretation of result are in table 5, table 6.

Table 5 decocts orthogonal experiments table

Note: dried cream yield scoring=(dried cream yield/maximum dried cream yield) × 30

60% ethanol soluble extraction scoring=(extractum yield/maximum extractum yield) × 30

Total flavones extracted amount scoring=(extracted amount/maximum extracted amount) × 40

Comprehensive grading=dried cream yield scoring+60% ethanol soluble extraction scoring+total flavones taken amount scoring

Table 6 decocts analysis of variance table

From table 5,6 analysis results, each factor effect primary and secondary is A > B > C; A, B, C factor all has significant difference, A in A factor ₃> A ₂> A ₁, so select A ₃; B in B factor ₃> B ₁> B ₂, so select B ₃; C in C factor ₂> C ₃> C ₁, so select C ₂.Therefore optimised process is A ₃b ₃c ₂.Namely add 10 times of water gagings, each decoction 3 hours, decocts twice.

2.3 best decocting process checkings:because preferred optimised process is not included in 9 tests of orthogonal array, therefore it is verified.Get orthogonal test with a collection of medical material, by A ₃b ₃c ₂test, verify 3 batches altogether, the result is in table 7:

Table 7 decocts optimised process the result

The result shows, this technique extractum yield, 60% ethanol soluble extraction content and total flavones extracted amount are all more stable, can be used as the optimised process of extraction.

2.4 concentration technologies are investigated:the method for concentration that workshop is conventional has normal pressure to concentrate and concentrating under reduced pressure.Concentrating under reduced pressure have consuming time less, feature that thickening temperature is low, therefore destroy less to heat-sensitive ingredients, along with improving constantly of pharmaceutical equipment manufacturing technology, present Chinese medicine workshop more adopts concentrating under reduced pressure to be main.In order to combine closely with production is actual, the condensing mode of this product adopts concentrating under reduced pressure method.

Get 2 times of recipe quantity medical materials, extract by best decocting process, decoction liquor concentrating under reduced pressure (-0.06 ~-0.08 Mpa, 80 DEG C), to thick extractum, record now extractum relative density and be about 1.25(60 DEG C), get extractum appropriate, the same method measures wherein general flavone content, and result of the test is in table 8.

Determination of total flavonoids result in table 8 concentrated extract

Result of the test shows: adopt pressure reducing mode to concentrate this product extracting solution, in prescription, general flavone content is stablized, and illustration method is feasible.

2.5 drying processes:normal pressure and drying under reduced pressure two kinds of modes are adopted to investigate drying process respectively, thick extractum mixing during concentration technology is investigated, be divided into 3 parts, drying is carried out respectively by table 9 conditional, with the content of gained extract powder total flavones, color and luster, drying time for investigating object, carry out preferably, the results are shown in Table 9 to drying mode with this.

The different drying mode investigation table of table 9

Upper watch test result shows, drying mode and drying condition have no significant effect puerarin content, but constant pressure and dry extractum color and luster is comparatively dark, required time is long, by contrast, adopts decompression 70 DEG C to be that Drying Technology Parameter is more suitable.

2.6 extract characteristic research

(1) character of extract powder: this product extract powder is the pitchy powder be prepared into after drying under reduced pressure, in order to grasp the character of extract powder, is convenient to preparation research, we determine Moisture percentage and the mobility of extract powder.

(2) Moisture percentage measures: get proper amount of dry extractum, pulverize, cross 80 mesh sieves, put P2O5 exsiccator inner drying 48 hours, the glass desicator simultaneously bottom being filled NaCl supersaturated solution puts into the calorstat 24 hours of 25 DEG C, and its internal relative humidity (RH) is 75%.In the weighing botle of dry constant weight, add appropriate extract powder, thickness is about 2mm, and precise weighing is placed in above-mentioned glass desicator, opens weighing bottle cap; Timing weighs, and is calculated as follows Moisture percentage:

Table 10 extract powder Moisture percentage measurement result table

(3) measure angle of repose: adopt fixed funnel method to measure extract powder (80 order) angle of repose: 3 funnels are connected and is fixed on height (3cm) suitable on the graph paper of horizontal positioned, carefully extract powder is poured in uppermost funnel along hopper walls, until the extract powder apex partis petrosae termination that graph paper is formed contacts bottom bell mouth, measure conical base diameter, be calculated as follows out a angle of repose:

Table 11 extract powder measurement result angle of repose

Extract powder Moisture percentage and angle of repose measurement result show, extract powder moisture resistance is poor, and mobility is bad, is unsuitable for direct granulation, should add appropriate amount of auxiliary materials adjustment.

2.7 adjuvant screenings

2.7.1 supplementary product kind screening: the kind of adjuvant directly determines hygroscopicity and the mobility of granule.The adjuvant being commonly used to improve granule hygroscopicity and mobility has lactose, starch and dextrin etc.Getting above-mentioned 3 kinds of adjuvants respectively by table 12 adds in extract powder, mixing, with 75% ethanol soft material, crosses 10 orders and makes granule, 65 DEG C of dry 15min, after crossing 10 mesh sieve granulate, then in 65 DEG C of dryings.Moisture percentage and the angle of repose of granule is measured by preceding method.The results are shown in Table 12,13.

Table 12 different auxiliary material and extract powder compatibility table

Table 13 different auxiliary material obtains the index checking of granule

Table 14 different auxiliary material proportioning obtains the Moisture percentage of granule

As seen from table, after different auxiliary material mixes in varing proportions with dried cream powder, 3 groups of sample hydroscopicity orders are 1 > 3 > 2.The wherein hydroscopicity minimum (60h) of No. 2 prescriptions (alone starch), good fluidity; No. 3 micro-tides of prescription (alone dextrin) granule.Consider lower selection No. 2 prescriptions.

2.7.2 supplementary product consumption screening: the consumption of adjuvant should under the prerequisite meeting formulation requirements, and reduce consumption is principle as far as possible.Getting starch respectively by table 15 adds in extract powder, measures Moisture percentage and the angle of repose of granule by preceding method after granulating.The results are shown in Table 15,16.

Table 15 supplementary product consumption compatibility table

The Moisture percentage of table 16 different auxiliary material consumption granule

The angle of repose of table 17 different starch consumption granule

Above-mentioned result of the test shows, add adjuvant amount more, the anti-wettability power of granule and mobility better, wherein every 20g extractum adds adjuvant 10g and to add 12g effect suitable, in order to save production cost, we select every 20g extract powder to add adjuvant 10g is supplementary product consumption parameter.

2.8 preparations shaping technical studiesthe present invention is extraction process by water, the gained extractum moisture absorption, make granule more suitable, but adopt conventional granulation to be difficult to realize, so use certain density alcohol granulation, concentration of alcohol is selected: get extract powder 20g, add starch 10g, mixing, uses 60%, 75%, 95% alcohol granulation respectively, investigating granulates is difficult to the quality of degree and obtained granule, the results are shown in Table 18.

Table 18 different concentration ethanol granulation information slip

Experimental result shows, obtains granular mass the best with 75% ethanol, therefore, selects 75% ethanol to be this product granulation solvent.

2.9 preparation prescriptions and the amount of making are determined:by the laws and regulations requirement that new drug is declared, new drug prescription must by 1000 preparation unit statements, and be about 11% according to 3 batches of pilot scale dried cream yield and calculate, this product preparation prescription calculates that process is as follows:

(1) each taste dose in preparation prescription: original prescription ratio is Semen Pittospori Glabrati tea 1.2, Radix Polygalae 0.8, Radix Ophiopogonis 1, Caulis Polygoni Multiflori 1.5, Rhizoma valerianae latifoliae 1, Fructus Crataegi 1, Radix seu Herba Gei aleppici 1, calculating each medical material amount in this product preparation prescription in this ratio is: Semen Pittospori Glabrati tea 420g, Radix Polygalae 280g, Radix Ophiopogonis 350g, Caulis Polygoni Multiflori 525g, Rhizoma valerianae latifoliae 350g, Fructus Crataegi 350g, Radix seu Herba Gei aleppici 350g.Namely preparation prescription is 2625g containing crude drug total amount.

(2) every capsules is containing crude drug total amount: every containing crude drug total amount=crude drug total amount ÷ preparation unit; That is: every contains crude drug total amount=2625g ÷ 1000=2.625g

(3) adjuvant amount is added in production process

1. every prescription dry extract receipts amount: preparation prescription is 2625g containing crude drug total amount, if be about 10% calculating according to dried cream yield, then every prescription dry extract receipts amount is: every prescription dry extract receipts amount=prescription is containing crude drug total amount × dried cream yield.That is: every prescription dry extract receipts amount=2625g × 11%=288.8g

2. supplementary product consumption is determined: from front test, and in this product production process, dry extract and the ratio that adds starch are 20: 10, and calculating starch consumption is thus: every prescription starch consumption=every dry cream receipts amount × 10 ÷ 20 of prescription.That is: starch consumption=288.8g × 10 ÷ 20=144.4g.It is dry extract receipts amount and starch consumption sum that every prescription obtains content amount, and from 1., 2., this product obtains content 433.2g.Consider that medical material collecting season is different with the place of production, and the impact of production technology, dry extract receipts amount can slightly fluctuate, and supplementary product consumption is described as by we: add right amount of auxiliary materials, makes the obtained amount of content be 450g.

2.10 finished product loading amounts are determined:finished product loading amount =the content obtained amount ÷ amount of making; That is: finished product loading amount =450g ÷ 1000=0.45g/ grain.

2.11 pilot scale researchget 10 times of recipe quantity medical materials, by work out process route carries out scale up test, comprehensive assessment is carried out to production technology index, performance rating is carried out to medical material and finished product, the results are shown in Table 19.

Table 19 pilot plant test result

Pilot plant test result of study shows, the every technical parameter of product of the present invention is stablized, and feasible process is described, is applicable to batch production.

the preparation technology of 2.12 Some dosage forms of the present invention

(1) preparation technology of hard capsule: the formula getting claim 2 or claim 4, decocts with water twice, adds water 10 times at every turn, each decoction 3 hours, filter, merging filtrate, being evaporated to relative density is 1.25 ~ 1.30(60 DEG C) extractum, vacuum drying, pulverizes, and crosses 80 mesh sieves, add right amount of auxiliary materials, mixing, granulate, drying, granulate, sieves, fill, makes 1000, to obtain final product.

(2) preparation technology of tablet: the formula getting claim 2 or claim 4, decocts with water twice, adds water 10 times at every turn, each decoction 3 hours, filters, merging filtrate, being evaporated to relative density is 1.25 ~ 1.30(60 DEG C) extractum, add right amount of auxiliary materials, mixing, granulate, dry, add moderate lubrication agent, mixing, tabletting, film coating, make 1000, to obtain final product.

(3) preparation technology of soft capsule: the formula getting claim 2 or claim 4, decoct with water twice, add water 10 times at every turn, each decoction 3 hours, filter, merging filtrate, being evaporated to relative density is 1.15 ~ 1.20(60 DEG C) extractum, add ethanol, alcohol content is made to reach 60%, leave standstill 24 hours, get supernatant, filter, reclaim ethanol and to be concentrated into relative density be 1.25 ~ 1.30(60 DEG C) extractum, vacuum drying, pulverizes, sieves, add right amount of auxiliary materials, grind well, be pressed into 1000, obtain final product.

(4) preparation technology of oral liquid: the formula getting claim 2 or claim 4, decocts with water twice, adds water 10 times at every turn, each decoction 3 hours, filters, merging filtrate, being evaporated to relative density is 1.15 ~ 1.20(60 DEG C) extractum, add ethanol, make alcohol content reach 60%, leave standstill 24 hours, get supernatant, filter, filtrate recycling ethanol, to without alcohol taste, adds appropriate correctives, appropriate antiseptic, supply with boiled water, make 1000ml, to obtain final product.

(5) preparation technology of granule: the formula getting claim 2 or claim 4, decocts with water twice, adds water 10 times at every turn, each decoction 3 hours, filter, merging filtrate, being evaporated to relative density is 1.25 ~ 1.30(60 DEG C) extractum, add right amount of auxiliary materials, mixing, granulates, dry, make 300g(Sugarless type), 1000g(sugar-containing type), to obtain final product.

four, Pharmacodynamic test of active extract research

1, experiment material

1.1 medicines:by reagent: invention formulation semi-finished product (medicated powder), Kweiyang spring section's Pharmaceutical research and development company limited provides, specification: 8kg/ bag, clinical usage and consumption: 3 times on the one, and 1.35g/ time, facing the used time, to be made into suspension with distilled water for subsequent use; Positive control drug: sedative jujube kernel capsule, Guizhou Tongjitang Chinese Medicines C., clinical usage and consumption: 3 times on the one, 2.25g/ time, facing the used time, to be made into suspension with distilled water for subsequent use; Pentobarbital sodium; Chlorpromazine HCL injection; Caffeine and sodium benzoate injection; Morphine.

1.2 animals:white mice, body weight 18-22g.Wistar rat, 180-220g.

1.3 instruments:photoelectric counting instrument; WMZ-707l type temperature indicator.

2, method and result

2.1 on the impact of white mice autonomic activitiesget mice 50, be divided into 5 groups at random, often organize 10, blank group (distilled water), positive control sedative jujube kernel capsule group (4.5g/kg), invention formulation high dose group (3.0g/kg), middle dosage group (1.5g/kg), low dose group (0.75g/kg), respectively organize gastric infusion, every day 1 time, for three days on end, after last administration 1 hour, measure each Mus 10min autonomic activities number of times (each 5rnin of left and right dish merges statistics) with photoelectricity calculating instrument.Result shows in table 20, and the high, medium and low dosage group of the present invention compares ambulatory activity count with blank group and all obviously reduces (P<0.01).

Table 20 is on the impact of mice autonomic activities

2.2 impacts on pentobarbital sodium syngignoscismget mice 50, be divided into 5 groups at random, grouping with 2.1, every day gavage once, continuous 4 days.Within after last administration l hour, respectively organize equal ip pentobarbital sodium 30mg.Observe righting reflex loss in mice 1 hour more than the Mus number of 1rain and dropping asleep latency, non-sleeper in 1 hour, dropping asleep latency, by 60 points of calculating, calculating sleep rate and the length of one's sleep, the results are shown in Table 21, table 22.

The synergism of table 21 pair pentobarbital sodium hypnosis

The synergism of table 22 pair pentobarbital sodium sleep

Result shows, high, the middle dosage group of the present invention obviously can increase sleep rate and the dropping asleep latency of white mice, extends the length of one's sleep.

2.3 impacts on chlorpromazine syngignoscismget mice 50, be divided into 5 groups at random, often organize 10, grouping is with 2.1, gastric infusion, every day 1 time, continuous 4 days, after last administration 1 hour, each group of ip chlorpromazine 12.8mg/kg, observes each group righting reflex loss in 1 hour and, more than the Mus number of 1min, calculates dropping asleep latency and sleep rate, last sleeper in 1 hour, incubation period is by 60 points of calculating.In table 23.Show that invention formulation can significantly improve sleep rate, and have the trend extending dropping asleep latency.

The synergism of table 23 pair chlorpromazine hypnosis

2.4 collaborative pentobarbital sodiums suppress the effect of caffeine and sodium benzoate central excitationby mice 60, be divided into 6 groups at random: blank group, model control group, positive control sedative jujube kernel capsule group (4.5g/kg), invention formulation high dose group (3.0g/kg), middle dosage group (1.5g/kg), low dose group (0.75g/kg).Equal gastric infusion, once a day, continuous 4 days.Before last administration, 40min is except blank group, all the other 5 groups equal sc caffeine and sodium benzoate 0.19g/kg, and after last gastric infusion 40min, 6 groups of equal ip pentobarbital sodium 37mg/kg, then survey dropping asleep latency, the length of one's sleep and sleep rate.Non-sleep person in 1 hour, presses 60min incubation period and calculates, and sleep, more than 1 hour, is pressed 60min the length of one's sleep and calculated.The results are shown in Table 24.Model group compares with Normal group, and dropping asleep latency obviously extends and the length of one's sleep shortens, and shows that caffeine and sodium benzoate causes central excitation.Invention formulation is respectively organized and is compared dropping asleep latency with caffeine and sodium benzoate group and significantly shorten, and the length of one's sleep, significant prolongation, showed that invention formulation can suppress the central excitation effect of caffeine and sodium benzoate.

Table 24 suppresses the central excitation effect of caffeine and sodium benzoate to collaborative pentobarbital sodium

2.5 analgesic activity

(1) hot plate method: get mice 60, be divided into 6 groups at random, often organize 10, blank group, model control group, positive control sedative jujube kernel capsule group (4.5g/kg), invention formulation high dose group (3.0g/kg), middle dosage group (1.5g/kg), low dose group (0.75g/kg).Gastric infusion, every day 1 time, for three days on end, after last medication 1 hour, aluminum matter hot plate is placed in the water-bath of 55 DEG C ± 0.5 DEG C, licks metapedes for the 1st time for index with mice and survey the threshold of pain, positive controls subcutaneous injection morphine 25mg/kg, survey the threshold of pain after 30min, the results are shown in Table 25, show that invention formulation has obvious analgesic activity.

The analgesic activity (hot plate method) of table 25 pair mice

(2) writhing method: get mice 60, grouping and medication are with (1), and last administration gives white mice ip1% acetic acid 0.2ml/10g in 1 hour respectively, observes the writhing number of times in 10min, the results are shown in Table 26, show that invention formulation has obvious analgesic activity.

The analgesic activity (writhing method) of table 26 pair mice

2.6 impacts that myocardial ischemia is testedget mice 50, be divided into 5 groups at random.That is: often 10 are organized, blank group, positive control sedative jujube kernel capsule group (4.5g/kg), invention formulation high dose group (3.0g/kg), middle dosage group (1.5g/kg), low dose group (0.75g/kg).Successive administration l0.After administration in the 9th day, fasting 20 hours, freely drinks water, after administration in the 10th day 40 minutes, and the equal subcutaneous injection isoprenaline of each group mice, after 15 minutes, puts into the 250ml ground wide mouthed bottle that 15g sodica calx is housed by mice, observe mouse diing time.The results are shown in Table 27.Invention formulation high dose group obviously can extend the time-to-live of mouse cardiac muscle anoxia, compares P<0.01 with blank group, and low dose group also shows good effect trend, but compares with positive controls without difference statistically.

Table 27 is on the impact of mouse cardiac muscle anoxia

2.7 anti-myocardial ischemia in rats effectsget rat 50, be divided into 5 groups at random: blank group, positive control sedative jujube kernel capsule group (2.7g/kg), invention formulation high dose group (2.0g/kg), middle dosage group (1.0g/kg), low dose group (0.5g/kg).Every day gastric infusion, the ordinary water of blank group gavage same volume, continuous gavage one week, respectively at the 6th day and the 7th day lumbar injection isoprenaline after administration, then gets blood on automatic clinical chemistry analyzer, measures serum CPK value, the results are shown in Table 28.Result shows, the high, medium and low dosage group of invention formulation all can reduce CPK value in serum, compares to have to show sex differernce (P<0.001) with blank group, and its effect is better than sedative jujube kernel glue group.

Table 28 is on the impact of rat blood serum creatine phosphokinase (CPK)

2.8 impacts on mouse anti-reflecting fatigue abilityget mice 50, be divided into 5 groups at random: blank group, positive control sedative jujube kernel capsule group (4.5g/kg), invention formulation high dose group (3.0g/kg), middle dosage group (1.5g/kg), low dose group (0.75g/kg).Successive administration 10 days, fasting 20 hours before experiment, can't help water, mice, after 30 minutes, is dropped into (room temperature) in ordinary water, carries out parallel observations by administration next day, the time of the water surface that avales from overboard beginning to nostril with stopwatch calculating, the results are shown in Table 29.Result is visible, and the high, medium and low dosage group of invention formulation is organized with blank and contrasted, and all can extend the swimming time of mice, have antifatigue effect.

Table 29 is on the impact of mouse anti-reflecting fatigue

2.9 impacts on mouse immune organget mice 50, be divided into 5 groups at random: blank group, positive control sedative jujube kernel capsule group (4.5g/kg), invention formulation high dose group (3.0g/kg), middle dosage group (1.5g/kg), low dose group (0.75g/kg).Successive administration 10 days, the next day after last administration, eye socket sacrificed by exsanguination, gets spleen, thymus is weighed, and represents with organ index, and t checks the significance of each group difference.The results are shown in Table 30.From table, invention formulation has obvious effect of gain to the spleen of mice and thymus, compares with blank group, has significant difference (P<0.001).Its effect is better than sedative jujube kernel capsule group.

Table 30 is on the impact of mouse immune organ

3, conclusiondragon Fructus Jujubae capsule has obvious sedation, the autonomic activities number of times of white mice can be reduced, strengthen the syngignoscism of pentobarbital sodium, obvious shortening pentobarbital sodium dropping asleep latency, improve mice sleep rate, extend the length of one's sleep, strengthen the syngignoscism of chlorpromazine, improve the sleep rate of chlorpromazine, the central excitation effect of pentobarbital sodium antagonism caffeine and sodium benzoate can be worked in coordination with.Also have obvious analgesic activity in addition, extend the time-to-live of myocardial ischemia, function of resisting myocardial ischemia, antifatigue effect, strengthen immunization etc.

By above Pharmacodynamic test of active extract, prompting invention formulation has good preventive and therapeutic effect to mental sickness such as insomnias, for clinical application provides reference frame.

five, toxicity test research

1, acute toxicity test

1.1 test medicine: invention formulation medicated powder, the sodium carboxymethyl cellulose with 1% is mixed with the suspension (being equivalent to every 100ml containing crude drug 135g) of 20%.

1.2 animal subjects: white mice, male and female half and half, body weight 18 ~ 22g.

1.3 test methods and result: according to preliminary result, expectation can not measure LD ₅₀, therefore measure the mtd test of single-dose.The invention formulation suspension of clinical administration approach gastric infusion 20% is pressed to 20 healthy mices, 0.8ml/20g, dosage is 13.5g/kg, is equivalent to crude drug in whole 54g/kg, to behave 200 times of clinical consumption per day (0.0675g/kg), after administration, animal activity reduces, and after about 2 ~ 3 hours, full recovery is normal, activity freely, behavior, diet, defecation show no obvious abnormalities, and continue observation 14 days, without dead.

1.4 conclusions: the minimum lethal dose of invention formulation is greater than 54g/kg crude drug, are equivalent to 200 times of clinical people's consumption, show that this medicine is without overt toxicity effect.

below in conjunction with detailed description of the invention, the present invention is further illustrated.

Detailed description of the invention

Embodiment 1: get Semen Pittospori Glabrati tea 12g, Radix Polygalae 8g, Radix Ophiopogonis 10g, Caulis Polygoni Multiflori 15g.Adding decocting becomes decoction to take.Usage and dosage: every day 1 dose, point 3 clothes.

Embodiment 2: get Semen Pittospori Glabrati tea 12g, Radix Polygalae 8g, Radix Ophiopogonis 10g, Caulis Polygoni Multiflori 15g, Rhizoma valerianae latifoliae 10g, Fructus Crataegi 10g, Radix seu Herba Gei aleppici 10g.Adding decocting becomes decoction to take.Usage and dosage: every day 1 dose, point 3 clothes.

Embodiment 3: get Semen Pittospori Glabrati tea 420g, Radix Polygalae 280g, Radix Ophiopogonis 350g, Caulis Polygoni Multiflori 525g.Decoct with water 2 times, add water 10 times at every turn, each decoction 3 hours, filter, merging filtrate, being evaporated to relative density is 1.25 ~ 1.35(60 DEG C) extractum, add starch appropriate, mixing, granulate, drying, adds Magnesium Stearate proper quantity, mixing, tabletting, coating, makes 1000, obtains Tablets.Specification: the heavy 0.25g of every sheet.Usage and dosage: oral, one time 4,3 times on the one.

Embodiment 4: get Semen Pittospori Glabrati tea 8.4kg, Radix Polygalae 5.6kg, Radix Ophiopogonis 7kg, Caulis Polygoni Multiflori 10.5kg.Decoct with water 2 times, add water 10 times at every turn, each decoction 3 hours, filter, merging filtrate, being evaporated to relative density is 1.25 ~ 1.35(60 DEG C) extractum, add starch appropriate, mixing, granulate, drying, adds Magnesium Stearate proper quantity, mixing, tabletting, coating, makes 20000, obtains Tablets.Specification: the heavy 0.25g of every sheet.Usage and dosage: oral, one time 4,3 times on the one.

Embodiment 5: get Semen Pittospori Glabrati tea 708.75g, Radix Polygalae 236.25g, Radix Ophiopogonis 236.25g, Caulis Polygoni Multiflori 393.75g.Decoct with water 3 times, add water 5 times at every turn, each decoction 1 hour, filter, merging filtrate, being evaporated to relative density is 1.30 ~ 1.35(60 DEG C) extractum, add starch appropriate, mixing, granulate, drying, adds Magnesium Stearate proper quantity, mixing, tabletting, coating, makes 1000, obtains Tablets.Specification: the heavy 0.25g of every sheet.Usage and dosage: oral, once sheet, 3 times on the one.

Embodiment 6: get Semen Pittospori Glabrati tea 157.5g, Radix Polygalae 315g, Radix Ophiopogonis 472.5g, Caulis Polygoni Multiflori 630g.Decoct with water 1 time, add water 12 times, decoct 3 hours, filter, merging filtrate, being evaporated to relative density is 1.25 ~ 1.30(60 DEG C) extractum, add starch appropriate, mixing, granulate, dry, add Magnesium Stearate proper quantity, mixing, tabletting, coating, makes 1000, obtains Tablets.Specification: the heavy 0.25g of every sheet.Usage and dosage: oral, one time 4,3 times on the one.

Embodiment 7: get Semen Pittospori Glabrati tea 420g, Radix Polygalae 280g, Radix Ophiopogonis 350g, Caulis Polygoni Multiflori 525g.Decoct with water 3 times, add water 8 times at every turn, each decoction 1 hour, filters, merging filtrate, being evaporated to relative density is 1.30 ~ 1.35(60 DEG C) extractum, add right amount of auxiliary materials, mixing, drying, makes 1000, obtains capsule of the present invention, specification: every dress 0.25g.Usage and dosage: oral, one time 4,3 times on the one.

Embodiment 8: get Semen Pittospori Glabrati tea 168g, Radix Polygalae 112g, Radix Ophiopogonis 140g, Caulis Polygoni Multiflori 210g.Decoct with water 3 times, add water 8 times at every turn, each decoction 1 hour, filter, merging filtrate, being evaporated to relative density is 1.30 ~ 1.35(60 DEG C) extractum, add right amount of auxiliary materials, mixing, granulate, dry, make 300g(Sugarless type), 1000g(sugar-containing type), obtain granule of the present invention, specification: every packed 3g(Sugarless type), 10g(sugar-containing type).Usage and dosage: oral, one time 1 bag, 3 times on the one.

Embodiment 9: get Semen Pittospori Glabrati tea 1682g, Radix Polygalae 1121g, Radix Ophiopogonis 1399g, Caulis Polygoni Multiflori 2098g.Decoct with water 2 times, add water 10 times at every turn, each decoction 2 hours, filter, merging filtrate, hold over night, gets supernatant and is evaporated to about 800ml, add right amount of auxiliary materials, and mixing, adds water and make 10000ml, obtain oral liquid of the present invention, specification: every bottled 10ml.Usage and dosage: oral, one time 1 bottle, 3 times on the one.

Embodiment 10: get Semen Pittospori Glabrati tea 4200g, Radix Polygalae 2800g, Radix Ophiopogonis 3500g, Caulis Polygoni Multiflori 5250g.Decoct with water 2 times, add water 10 times at every turn, each decoction 3 hours, filters, filtrate reduced in volume to relative density is 1.25 ~ 1.35(60 DEG C) extractum, dry, pulverize into fine powder, add right amount of auxiliary materials, grind well, be pressed into 10000, obtain soft capsule of the present invention, specification: every dress 0.4g.Usage and dosage: oral, one time 4,3 times on the one.

Embodiment 11: get Semen Pittospori Glabrati tea 4200g, Radix Polygalae 2800g, Radix Ophiopogonis 3500g, Caulis Polygoni Multiflori 5250g.Decoct with water 2 times, add water 12 times at every turn, each decoction 1 hour, filter, merging filtrate, being evaporated to relative density is 1.30 ~ 1.35(60 DEG C) extractum, add starch appropriate, mixing, granulate, drying, adds Magnesium Stearate proper quantity, mixing, tabletting, coating, makes 10000, obtains Tablets.Specification: the heavy 0.25g of every sheet.Usage and dosage: oral, one time 4,3 times on the one.

Embodiment 12: get Semen Pittospori Glabrati tea 8.4kg, Radix Polygalae 5.6kg, Radix Ophiopogonis 7.0kg, Caulis Polygoni Multiflori 10.5kg.Decoct with water 2 times, add water 10 times at every turn, each decoction 1.5 hours, filters, merging filtrate, being evaporated to relative density is 1.25 ~ 1.30(60 DEG C) extractum, add right amount of auxiliary materials, mixing, drying, makes 10000, obtains capsule of the present invention, specification: every dress 0.25g.Usage and dosage: oral, one time 4,3 times on the one.

Embodiment 13: get Semen Pittospori Glabrati tea 420g, Radix Polygalae 280g, Radix Ophiopogonis 350g, Caulis Polygoni Multiflori 525g, Rhizoma valerianae latifoliae 350g, Fructus Crataegi 350g, Radix seu Herba Gei aleppici 350g.Decoct with water 2 times, add water 10 times at every turn, each decoction 3 hours, filter, merging filtrate, being evaporated to relative density is 1.25 ~ 1.30(60 DEG C) extractum, add starch appropriate, mixing, granulate, drying, adds Magnesium Stearate proper quantity, mixing, tabletting, coating, makes 1000, obtains Tablets.Specification: the heavy 0.45g of every sheet.Usage and dosage: oral, one time 4,3 times on the one.

Embodiment 14: get Semen Pittospori Glabrati tea 8400g, Radix Polygalae 5600g, Radix Ophiopogonis 7000g, Caulis Polygoni Multiflori 10500g, Rhizoma valerianae latifoliae 7000g, Fructus Crataegi 7000g, Radix seu Herba Gei aleppici 7000g.Decoct with water 2 times, add water 10 times at every turn, each decoction 3 hours, filter, merging filtrate, being evaporated to relative density is 1.25 ~ 1.35(60 DEG C) extractum, add starch appropriate, mixing, granulate, drying, adds Magnesium Stearate proper quantity, mixing, tabletting, coating, makes 20000, obtains Tablets.Specification: the heavy 0.45g of every sheet.Usage and dosage: oral, one time 4,3 times on the one.

Embodiment 15: get Semen Pittospori Glabrati tea 1050g, Radix Polygalae 131.2g, Radix Ophiopogonis 262.5g, Caulis Polygoni Multiflori 393.8g, Rhizoma valerianae latifoliae 262.5g, Fructus Crataegi 262.5g, Radix seu Herba Gei aleppici 262.5g.Decoct with water 3 times, add water 8 times at every turn, each decoction 1 hour, filter, merging filtrate, being evaporated to relative density is 1.30 ~ 1.35(60 DEG C) extractum, add starch appropriate, mixing, granulate, drying, adds Magnesium Stearate proper quantity, mixing, tabletting, coating, makes 1000, obtains Tablets.Specification: the heavy 0.45g of every sheet.Usage and dosage: oral, one time 4,3 times on the one.

Embodiment 16: get Semen Pittospori Glabrati tea 131.2g, Radix Polygalae 341.1g, Radix Ophiopogonis 393.8g, Caulis Polygoni Multiflori 577.5g, Rhizoma valerianae latifoliae 393.8g, Fructus Crataegi 393.8g, Radix seu Herba Gei aleppici 393.8g.Decoct with water 1 time, add water 12 times at every turn, each decoction 3 hours, filter, merging filtrate, being evaporated to relative density is 1.30 ~ 1.35(60 DEG C) extractum, add starch appropriate, mixing, granulate, drying, adds Magnesium Stearate proper quantity, mixing, tabletting, coating, makes 1000, obtains Tablets.Specification: the heavy 0.45g of every sheet.Usage and dosage: oral, one time 4,3 times on the one.

Embodiment 17: get Semen Pittospori Glabrati tea 420g, Radix Polygalae 280g, Radix Ophiopogonis 350g, Caulis Polygoni Multiflori 525g, Rhizoma valerianae latifoliae 350g, Fructus Crataegi 350g, Radix seu Herba Gei aleppici 350g.Decoct with water 2 times, add water 10 times at every turn, each decoction 3 hours, filters, merging filtrate, being evaporated to relative density is 1.25 ~ 1.30(60 DEG C) extractum, add right amount of auxiliary materials, mixing, drying, makes 1000, obtains capsule of the present invention, specification: every dress 0.45g.Usage and dosage: oral, one time 4,3 times on the one.

Embodiment 18: get Semen Pittospori Glabrati tea 840g, Radix Polygalae 560g, Radix Ophiopogonis 7000g, Caulis Polygoni Multiflori 10500g, Rhizoma valerianae latifoliae 7000g, Fructus Crataegi 7000g, Radix seu Herba Gei aleppici 7000g.Decoct with water 3 times, add water 8 times at every turn, each decoction 2 hours, filters, merging filtrate, being evaporated to relative density is 1.30 ~ 1.35(60 DEG C) extractum, add right amount of auxiliary materials, mixing, drying, makes 20000, obtains capsule of the present invention, specification: every dress 0.45g.Usage and dosage: oral, one time 4,3 times on the one.

Execute example 19: get Semen Pittospori Glabrati tea 10500g, Radix Polygalae 1312.5g, Radix Ophiopogonis 2625g, Caulis Polygoni Multiflori 3937.5g, Rhizoma valerianae latifoliae 2625g, Fructus Crataegi 2625g, Radix seu Herba Gei aleppici 2625g.Decoct with water 3 times, add water 10 times at every turn, each decoction 1 hour, filters, merging filtrate, being evaporated to relative density is 1.20 ~ 1.25(60 DEG C) extractum, add right amount of auxiliary materials, mixing, drying, makes 10000, obtains capsule of the present invention, specification: every dress 0.45g.Usage and dosage: oral, one time 4,3 times on the one.

Execute example 20: get Semen Pittospori Glabrati tea 1312.5g, Radix Polygalae 3411.5g, Radix Ophiopogonis 3937.5g, Caulis Polygoni Multiflori 5775g, Rhizoma valerianae latifoliae 3937.5g, Fructus Crataegi 3937.5g, Radix seu Herba Gei aleppici 3937.5g.Decoct with water 1 time, add water 10 times at every turn, each decoction 3 hours, filters, merging filtrate, being evaporated to relative density is 1.30 ~ 1.40(60 DEG C) extractum, add right amount of auxiliary materials, mixing, drying, makes 10000, obtains capsule of the present invention, specification: every dress 0.45g.Usage and dosage: oral, one time 4,3 times on the one.

Embodiment 21: get Semen Pittospori Glabrati tea 1680g, Radix Polygalae 1120g, Radix Ophiopogonis 1400g, Caulis Polygoni Multiflori 2100g, Rhizoma valerianae latifoliae 1400g, Fructus Crataegi 1400g, Radix seu Herba Gei aleppici 1400g.Decoct with water 3 times, add water 8 times at every turn, each decoction 1 hour, filter, merging filtrate, being evaporated to relative density is 1.30 ~ 1.35(60 DEG C) extractum, add right amount of auxiliary materials, mixing, granulate, dry, make 3000g(Sugarless type), 10000g(sugar-containing type), obtain granule of the present invention, specification: every packed 3g(Sugarless type), 10g(sugar-containing type).Usage and dosage: oral, one time 1 bag, 3 times on the one.

Embodiment 22: get Semen Pittospori Glabrati tea 1680g, Radix Polygalae 1120g, Radix Ophiopogonis 1400g, Caulis Polygoni Multiflori 2100g, Rhizoma valerianae latifoliae 1400g, Fructus Crataegi 1400g, Radix seu Herba Gei aleppici 1400g.Decoct with water 2 times, add water 10 times at every turn, each decoction 2 hours, filter, merging filtrate, hold over night, getting supernatant, to be evaporated to relative density be 1.15 ~ 1.20(60 DEG C) extractum, add ethanol, make alcohol content reach 60%, leave standstill 24 hours, get supernatant, filter, be evaporated to about 8000ml, add right amount of auxiliary materials, mixing, add water and make 10000ml, obtain oral liquid of the present invention, specification: every bottled 10ml.Usage and dosage: oral, one time 1 bottle, 3 times on the one.

Embodiment 23: get Semen Pittospori Glabrati tea 4200g, Radix Polygalae 2800g, Radix Ophiopogonis 3500g, Caulis Polygoni Multiflori 5250g, Rhizoma valerianae latifoliae 3500g, Fructus Crataegi 3500g, Radix seu Herba Gei aleppici 3500g.Decoct with water 3 times, add water 8 times at every turn, each decoction 1 hour, filters, filtrate reduced in volume to relative density is 1.15 ~ 1.20(60 DEG C) extractum, add ethanol, make alcohol content reach 60%, leave standstill 24 hours, get supernatant, filter, reclaim ethanol and to be concentrated into relative density be 1.25 ~ 1.30(60 DEG C) extractum, vacuum drying, pulverizes, sieve, add right amount of auxiliary materials, grind well, be pressed into 10000, obtain soft capsule of the present invention, specification: every dress 0.4g.Usage and dosage: oral, one time 4,3 times on the one.

Embodiment 24: get Semen Pittospori Glabrati tea 840g, Radix Polygalae 560g, Radix Ophiopogonis 700g, Caulis Polygoni Multiflori 1050g, Rhizoma valerianae latifoliae 700g, Fructus Crataegi 700g, Radix seu Herba Gei aleppici 700g.Decoct with water 2 times, add water 10 times at every turn, each decoction 2 hours, filter, merging filtrate, hold over night, getting supernatant, to be evaporated to relative density be 1.15 ~ 1.20(60 DEG C) extractum, add ethanol, make alcohol content reach 60%, leave standstill 24 hours, get supernatant, filter, being evaporated to relative density is 1.20(20 DEG C) clear paste, spraying dry, fine powder is for subsequent use; Add in the polyethylene glycol 6000 of melting, stir evenly, in instillation methyl-silicone oil, take out, drop pill absorbs condensed fluid, dry, makes 10000, obtains drop pill of the present invention.Specification: every heavy 40mg.Usage and dosage: oral, one time 10,3 times on the one.

Embodiment 25: get Semen Pittospori Glabrati tea 1680g, Radix Polygalae 1120g, Radix Ophiopogonis 1400g, Caulis Polygoni Multiflori 2100g, Rhizoma valerianae latifoliae 1400g, Fructus Crataegi 1400g, Radix seu Herba Gei aleppici 1400g.Decoct with water 2 times, add water 10 times at every turn, each decoction 2 hours, filter, merging filtrate, hold over night, getting supernatant, to be evaporated to relative density be 1.15 ~ 1.20(60 DEG C) extractum, add ethanol, make alcohol content reach 60%, leave standstill 24 hours, get supernatant, filter, be evaporated to about 8000ml, add sucrose 100g, Mel 100g, sodium benzoate 2g, stir evenly, be heated to boil, put to room temperature, add Fructus Citri tangerinae essence 1ml again, add water to 10000ml, stir evenly, filter, fill, obtains syrup of the present invention, specification: every bottled 100ml.Usage and dosage: oral, a 10ml, 3 times on the one.

Embodiments of the present invention are not limited to above-described embodiment, and the various changes made under the prerequisite not departing from present inventive concept all belong within protection scope of the present invention.

Claims (4)

1. prevent and treat a pharmaceutical preparation for insomnia mental sickness, it is characterized in that: it is made up of the crude drug of following weight ratio example: Semen Pittospori Glabrati tea 5% ~ 40%, Radix Polygalae 5% ~ 13%, Radix Ophiopogonis 10% ~ 15%, Caulis Polygoni Multiflori 15% ~ 22%, Rhizoma valerianae latifoliae 10% ~ 15%, Fructus Crataegi 10% ~ 15%, Radix seu Herba Gei aleppici 10% ~ 15%.

2., according to the pharmaceutical preparation of control insomnia mental sickness according to claim 1, it is characterized in that: the consumption of each component is: Semen Pittospori Glabrati tea 16%, Radix Polygalae 10.7%, Radix Ophiopogonis 13.3%, Caulis Polygoni Multiflori 20%, Rhizoma valerianae latifoliae 13.3%, Fructus Crataegi 13.3%, Radix seu Herba Gei aleppici 13.3%.

3. the preparation method of the pharmaceutical preparation of control insomnia mental sickness described in claim 1 or 2, it is characterized in that: get Semen Pittospori Glabrati tea, Radix Polygalae, Radix Ophiopogonis, Caulis Polygoni Multiflori, Rhizoma valerianae latifoliae, Fructus Crataegi, Radix seu Herba Gei aleppici seven flavor medicine material, add 5 ~ 12 times of soak by water 1 ~ 3 time of prescription total amount, each decoction 1 ~ 3 hour, filter, it is the extractum of 1.20 ~ 1.40 that filtrate is concentrated into 60 DEG C of relative densities, and then preparation process makes different pharmaceutical preparation routinely.

4., according to the preparation method of the pharmaceutical preparation of control insomnia mental sickness described in claim 3, it is characterized in that: described pharmaceutical preparation is decoction, granule, oral liquid, syrup, soft extract, pill, tablet, hard capsule or soft capsule.