CN1709475A - Chinese medicine formulation for treating extensive anxiety, and its preparing method - Google Patents

Abstract

The present invention relates to a Chinese medicine preparation for effectively curing extensive anxiety neurosis. Said Chinese medicine preparation can be made into various dosage forms of granules, capsule, tablet, dripping pills, soft capsule preparation, oral liquor, syrup, dispersing tablet and gel preparation, and is made up by using 11 Chinese medicinal materials of white peony root, spiny jujube kernel, biota seed, mother-of-pearl, lily bulb and others and adding aspartame through a certain preparation process.

Description

Chinese medicine preparation of treatment generalized anxiety disorder and preparation method thereof

Technical field: the present invention relates to a kind of Chinese medicine preparation for the treatment of generalized anxiety disorder and preparation method thereof, belong to technical field of medicaments.

Background technology: along with the progress and the expanding economy of society, human living standard has had large increase, but also is accompanied by recessive stress, cause depressed, feel guilty, detest give birth to, lose, irritated, dejected, anxiety and emotion and Mental Subnormality.Investigation shows, the sickness rate of China's anxiety neurosis is 2%～4.7%, and along with all multifactor influences such as work and the quickening of rhythm of life, intensified competitions, the sickness rate of anxiety neurosis is the trend that increases year by year, anxiety neurosis has more than 2,600 ten thousand people at the sickness rate of China every year according to incompletely statistics, has brought great trouble for people's life and work.Treatment to anxiety neurosis mainly is Drug therapy and psychotherapy at present.Modern study thinks that the generation development of anxiety neurosis and many-sides such as neurotransmitter, receptor, neuroendocrine system, immune system, blood circulation and gene expression adjusting all have relation, and anxiety neurosis pathogeny complexity, and clinical symptom is various.Existing doctor trained in Western medicine adopts tricyclic antidepressants, B-adrenergic receptor blocker, oxidase inhibitor to anxiety patient.But these medicines can not very fast control anxiety attack, and longly just makes effect stability service time, and toxic and side effects is big, and the careless slightly drawback that promptly stays drug dependence to patient makes a lot of patients be difficult to acceptance.The Chinese medicine anxiety is then many according to etiology and pathogenesis and clinical experience, patient is carried out the Chinese and western medicine medicine typing, and tcm treatment according to syndrome differentiation in addition on this basis, curative effect is better, have the motility of principle-method-recipe-medicines and the characteristics such as safety of drug effect, be used as medicine with decoction but traditional Chinese medicine is many, comparatively loaded down with trivial details, inconvenient, be difficult to take medicine in time rapidly, time is longer, the performance that affects the treatment, and dose is big, preserves, transport, carry and take inconvenience.It is reported that the Chinese patent medicine that can treat anxiety has Semen Ziziphi Spinosae mixture, refreshing healthy and free from worry etc., but up to the present, also do not occur special for treating on the market, excessive rising of liver-YANG, malaise and the Chinese patent medicine of the generalized anxiety disorder that causes because of deficiency of YIN-blood.

Summary of the invention: the objective of the invention is to: a kind of Chinese medicine preparation for the treatment of generalized anxiety disorder and preparation method thereof is provided, this product has determined curative effect, have no side effect, steady quality and preserve, transport, carry and characteristics such as taking convenience, to solve the problem that prior art exists.

The present invention constitutes like this: according to listed as parts by weight, it is by the Radix Paeoniae Alba 600～900, Semen Ziziphi Spinosae 400～700, Semen Platycladi 300～600, Concha Margaritifera 400～700, Bulbus Lilii 200～400, Radix Rehmanniae Preparata 300～600, Concha Ostreae 400～700, Fructus Schisandrae Chinensis 200～400, Radix Et Caulis Acanthopanacis Senticosi 300～600, Poria 300～600, Flos Albiziae 200～400, Flos Chrysanthemi 100～300 is prepared from, specifically, according to listed as parts by weight, it is by Radix Paeoniae Alba 726g, Semen Ziziphi Spinosae 592g, Semen Platycladi 484g, Concha Margaritifera 592g, Bulbus Lilii 393g, Radix Rehmanniae Preparata 484g, Concha Ostreae 592g, Fructus Schisandrae Chinensis 393g, Radix Et Caulis Acanthopanacis Senticosi 484g, Poria 484g, Flos Albiziae 393g, Flos Chrysanthemi 296g is prepared from;

Its preparation method is: take by weighing the Radix Paeoniae Alba, Semen Ziziphi Spinosae, Semen Platycladi, Concha Margaritifera, Bulbus Lilii, Radix Rehmanniae Preparata, Concha Ostreae, Fructus Schisandrae Chinensis, Radix Et Caulis Acanthopanacis Senticosi, Poria, Flos Albiziae, Flos Chrysanthemi, get Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis, be ground into coarse powder, extract 1～3 time with 50%～80% alcohol heating reflux, each 1～3 hour, merge alcohol extract, filter, decompression recycling ethanol, the survey relative density is 0.8～1.30 clear paste when being concentrated into 60 ℃, and is standby; Concha Margaritifera, Concha Ostreae decoct with water and extracted 0.5～2 hour, filter, and filtrate device is in addition collected; The residue and the Radix Paeoniae Alba, Semen Ziziphi Spinosae, Semen Platycladi, Poria, Flos Albiziae, Flos Chrysanthemi, Bulbus Lilii, Radix Rehmanniae Preparata merge, decoct with water and extract 1～4 time, each 0.5～3 hour, collecting decoction, filter, centrifugal, the survey relative density was 0.8～1.30 clear paste when centrifugal medicinal liquid was concentrated into 60 ℃, got a part of medicine liquid spray drying, make extract powder, with remaining medicinal liquid mixing granulation, obtain the active component of medicine of the present invention again, then the active component that makes is prepared into required preparation according to a conventional method.

Above-mentioned preparation is granule, capsule, tablet, drop pill, soft capsule preparation, oral liquid, syrup preparation, dispersible tablet.

Specifically: the granular preparation of this product is preparation like this: take by weighing Radix Paeoniae Alba 726g, Semen Ziziphi Spinosae 592g, Semen Platycladi 484g, Concha Margaritifera 592g, Bulbus Lilii 393g, Radix Rehmanniae Preparata 484g, Concha Ostreae 592g, Fructus Schisandrae Chinensis 393g, Radix Et Caulis Acanthopanacis Senticosi 484g, Poria 484g, Flos Albiziae 393g, Flos Chrysanthemi 296g and aspartame 65g; Get Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis, be ground into coarse powder, extract 2 times with 70% alcohol heating reflux, each 2 hours, merge alcohol extract, filter, decompression recycling ethanol, the survey relative density is 1.1 clear paste when being concentrated into 60 ℃, and is standby; Concha Margaritifera, Concha Ostreae decoct with water and extracted 1 hour, filter, and filtrate device is in addition collected; The residue and the Radix Paeoniae Alba, Semen Ziziphi Spinosae, Semen Platycladi, Poria, Flos Albiziae, Flos Chrysanthemi, Bulbus Lilii, Radix Rehmanniae Preparata merge, and decoct with water and extract each 1 hour 3 times, collecting decoction filters, and is centrifugal, the survey relative density was 1.1 clear paste when centrifugal medicinal liquid was concentrated into 60 ℃, added above-mentioned clear paste and aspartame, merged, mixing is got a part of medicine liquid spray drying, makes extract powder, get the residue medicinal liquid again and do binding agent, boiling granulating in fluid bed is made 1000g, promptly.

This product has YIN nourishing blood, suppressing the hyperactive liver sun, mind calming god's effect.Be used for deficiency of YIN-blood, excessive rising of liver-YANG, the generalized anxiety disorder that malaise causes, disease is seen frightened frightened cautious, cardiopalmus, insomnia, dreaminess are on tenterhooks, frightened and restless, absentminded, disease such as have a dizzy spell.

Chinese medicine does not have " anxiety neurosis " saying, and the traditional Chinese medical science claims that psychotic disorder is an emotional disorder, and it is the important component part of " theory on three categories of etiologic factors " in the tcm causa morbi scientific principle opinion system that feelings will is caused a disease, the analysis etiology and pathogenesis, and traditional Chinese medical science melancholia has much in common with depressed, anxiety neurosis.Primary disease may be relevant with diseases such as " melancholia ", " shying ", " fearing ", " cardiopalmus ", " palpitation with a distress feelings ".Belong to traditional Chinese medical science palpitation with a distress feeling, palpitation with fear category.It is how relevant with factors such as Nervous and Mental Factors, deficiency of heart-blood, liver and gall weakness, deficiency of kidney-QI that the formation of severe palpitation, palpitation with fear, motherland's medical science are thought.As " a Ling Shu Miraculous Pivot or Divine Axis passages through which vital energy circulates piece of writing " cloud: " kidney meridian of Foot-SHAO YIN ... QI-insufficiency is susceptible to fear then." " Prescriptions for Succouring the Sick severe palpitation opinion " cloud: " the severe palpitation person, this deficiency of heart-blood is also." wherein more complete with " miscellaneous diseases source and course rhinoceros candle severe palpitation source and course " record: " and the severe palpitation person, deficiency of heart-blood is also ... painstaking effort disappear it, and the manner fall is then hollow in the heart, and disgruntled shaking is much troubled, always does, and name is said severe palpitation; Or by the yang-energy interior-deficiency, or by cloudy blood in-fighting, or be stopped under the heart by diseases caused by retention of fluid, aqueous vapor is taken advantage of the heart; Or accident is heavy diverse and complicated, and motive is labor too; Or by the stagnation of QI should not and cause aroused in interest, more than all due to the palpitation with a distress feeling by also." make a general survey of each family and discuss, be many with deficiency syndrome, and internal organs such as the heart of many duties, liver, kidney, gallbladder.Have anxiety neurosis is divided into 8 types by the course of disease.1. malaise: timid usually people because suddenly frightened causes the frightened god of the heart and shakes, can not be autonomous, gradually to frightened slightly or do not have frightened then frightened nervous, be on tenterhooks.2. deficiency of kidney-essence: probably for kidney will, if cross consumption because of prolonged illness consumption of essence, exhaustion due to sexual indulgence, lose in the vital essence, it is rather then not frightened and restless to cause kidney will.As " a Ling Shu Miraculous Pivot or Divine Axis passages through which vital energy circulates piece of writing " cloud: " kidney meridian of Foot-SHAO YIN ... QI-insufficiency is susceptible to fear then." 3. insufficiency of vital energy and blood: motherland's medical science think heart master god, if weakness due to chronic disease or severe loss of blood or excessive thinking not only consume sad blood but also influence transformation coming from spleen, it is foster that deficiency of both QI and blood, the heart are become homeless, thus refreshing uneasiness and will is not peaceful alarmedly fear, nervous.4. liver and gall deficiency: blood stored in the liver house soul, with refreshing and toward the soul of person that has come's meaning.If plain body weakness, essence is activating QI not, and liver and gall deficiency then liver is not hidden soul, and gallbladder loses to be made a decision, performance susceptible to fear anxiety.Say as " General Treatise on the Cause and Symptoms of Diseases ": " deficiency of the liver is then feared ... conscience is empty and be subjected to ailment said due to cold or exposure, courage again a little less than, and taken advantage of by wind, probably catch it as the people." the 5. heart and gallbladder deficiency of vital energy: the heart being a vital viscus like a king of the body, here gods go out.Gallbladder is the fu-viscera with decisive character, makes a decision here.Motive easiness, courage is unhappy.Frightened to some extent because of thing, or see out-phase or thought is infinite, dream is not understood, it is impaired then to cause courage, and malaise is easily frightened, uneasy in either sitting or lying, fear probably in the heart.As " Longevity and Life Preservation " cloud: " being frightened with palpitation ... timid fast under the heart is as people's tip probably, all due to the timidness due to deficiency of the heart." 6. hepatic depression and blood deficiency: feelings will is smooth, stagnation of liver-QI is not relaxed, the fire-transformation Tianjin of burning, liver blood is impaired, and then painstaking effort are also lost, and cause liver and do not hide soul, and the heart is main refreshing, and the state of mind is at random, easily frightened uneasiness.7. the heart disturbed by phlegm-fire: plain body abundant expectoration, or rage impairing the liver, stagnated QI transforming into fire, fluid transformed into phlegm by fire are disturbed on the phlegm-fire, irritability, easily frightened irritability, insecure 8. excessive fire in heart: how because of the heart has excess-fire, fire is contained blood disorderly, and refreshing nothing is given up and sent out terrified, carry as " element ask the most pure virginity will discuss greatly ": " soreness is frightened, all belongs to fire." to have primary disease be that 6 types are summarized as follows: 1. liver qi stagnation type; 2. stagnated QI transforming into fire type; 3. malaise type; 4. disturb type on the expectorant heat; 5. deficiency of both the heart and spleen; 6. type of hyperactivity of fire caused by deficiency of YIN.Also having primary disease is 5 types.Be summarized as follows: 1. malaise type, QIYINLIANGXU type; 2. liver-Yang sthenia type; 3. liver qi stagnation type; 4. type of hyperactivity of fire caused by deficiency of YIN; 5. kidney-yang deficiency type.Also having primary disease is 4 types.Be summarized as follows: 1. the liver heart is with sick type; 2. disturb in the expectorant heat, gallbladder discomfort in the stomach type; 3. weakness of the spleen and stomach, the wet stationary form of food; 4. be stranded type in deficiency of kidney-essence, the phlegm-damp.By being as seen, the mental symptom of primary disease is similar mostly, is difficult to difference, but follows somatization that characteristics are respectively arranged.

We's mentality of designing with Radix Paeoniae Alba cold nature and bitter in the mouth, acid, can be returned liver, spleen two warps promptly based on above-mentioned logos in the side, kind energy suppressing the hyperactive liver, the yin fluid astringing that nourishes blood, " herbal classic " calls it: " main pathogen stomachache; remove arthralgia due to stagnation of blood, broken hard amassing ", " medicine origin " says it: " control stomachache; and blood; eliminating pathogen in the liver ", " the southern regions of the Yunnan Province book on Chinese herbal medicine " says it again: " it is painful to receive adverse flow of liver-QI, takes good care of conscience spleen channel blood; relax through sending down the abnormal ascending QI, end irritability pain "; Semen Ziziphi Spinosae, liver, gallbladder, all warps of the heart are returned in the flat and sweet in the mouth of property, acid, are good at tonifying liver, mind calming, " not record " calls it: " all vexatious insomnia, the liver benefiting gas help cloudy gas ", Wang Haogu is said it: " control milk-livered sleeplessness, cold also, fry and obey ".Two medicines share, and gather the merit of monarch drug altogether.Semen Platycladi in the side, property is put down and sweet in the mouth, GUIXIN, kidney, large intestine channel, kind energy tranquilizing by nourishing the heart, with auxiliary acid Semen Ziziphi Spinosae reinforcing the heart blood, the effect of nourishing the heart to keep a sound mind, " herbal classic " calls it: " main palpitation with fear, An Wuzang ", Compendium of Material Medica is said it: " gas that nourishes heart, Fructus Alpiniae Oxyphyllae is allayed excitement "; Concha Margaritifera, cold in nature and salty in the mouth is returned liver, heart channel, be longer than suppressing the hyperactive liver and subsiding YANG, arresting convulsion is used together with the Radix Paeoniae Alba, to strengthen Radix Paeoniae Alba suppressing liver-YANG, tranquillizing and subduing sedative action, " Chinese medicine voluminous dictionary " calls it: " liver nourishing the moon, clearing away liver-fire; control demented infantile convulsion; dizziness, tinnitus ", and " decoction pieces is newly joined " claims it: " suppressing the hyperactive liver and subsiding YANG; the soul of calming the nerves, arresting convulsion epilepsy "; Bulbus Lilii, warm in nature and acrid in the mouth, little hardship can be returned spleen, kidney, heart channel, are good at clearing away heart-fire for tranquillization, and " property of medicine opinion " claims it: " removing spasm in the epigastrium, full, bitterly ", " Japan hanako materia medica " said again: " feel at ease, decide gallbladder, beneficial will is controlled insane heresy and wept, madly cries, palpitates with fear "; Radix Rehmanniae Preparata, slightly warm in nature and sweet in the mouth is returned liver, kidney channel, be longer than nourishing YIN and supplementing blood, the benefit essence is filled out marrow, and the Radix Paeoniae Alba is played assosting effect, and " not Lu " calls it: " main man's five kinds of strain and seven kinds of impairment; woman's damaging the spleen and stomach; tonifying five ZANG-organs, internal injury deficiency, physical strength profiting ", " Japan hanako materia medica " says it: " it is bad to control palpitation with fear labor, and cardiopulmonary decrease ".Four medicines share, and gather the merit of ministerial drug altogether.Concha Ostreae in the side, cold nature and salty in the mouth, return liver, gallbladder, kidney channel, be longer than tranquillization with heavy prescription, the YANG hyperactivity suppressing nourishing YIN is share with Concha Margaritifera and can be strengthened the effect that its suppressing the hyperactive liver and subsiding YANG is calmed the nerves, and " Haiyao Bencao, Oversea Materia Medica " says it: " can take a tonic or nourishing food to build up one's health and calm the nerves; control child's infantile convulsion ", and " modern practical Chinese medicine " claims it: " it is moving cautious to control cardiopalmus "; Fructus Schisandrae Chinensis, warm in nature and sour in the mouth, sweet can be returned lung, the heart, kidney channel are good at kidney calming, convergence, supplementing QI for promoting the production of body fluid, " not record " calls it: " support the five internal organs, give birth to the moon ", " explaining abstruseness of the canon of materia medica " said again: " controlling nocturnal emission with astringent drugs, arresting sweating "; Radix Et Caulis Acanthopanacis Senticosi, warm in nature and acrid in the mouth, little hardship are returned spleen, kidney, heart channel, are longer than replenishing QI to invigorate the spleen, tonifying the kidney for tranquilization, " 2000 editions pharmacopeia of the People's Republic of China (PRC) " claim it: " being used for deficiency of spleen-YANG and kidneyYANG, insomnia and dreamful sleep "; Poria, the flat and sweet in the mouth, light of property, GUIXIN, lung, spleen, all warps of kidney are longer than the spleen invigorating mind calming, and " herbal classic " says it: " the contrary gas of the main breast side of body, the frightened heresy of melancholy Gui is probably throbbed with fear ", " not record " said again: " opening the breast internal organs, during guarantor god keeps "; Flos Albiziae, the flat and sweet in the mouth of property, GUIXIN, Liver Channel are good at resolving stagnation for tranquilization, and " Sichuan Chinese medicinal herbal " claims it: " can close will, resolving depression is controlled the insomnia of having a guilty conscience ", Jiangxi " Chinese herbology " said again: " resolving stagnation for tranquilization is controlled melancholy and discomfort, forgetful insomnia "; Flos Chrysanthemi, cold nature and sweet in the mouth, hardship are returned lung, Liver Channel, are longer than the wind heat clearing away of loosing, suppressing the hyperactive liver, " detailed outline is picked up any lost article from the road " claims it: " make eye bright and dispel the wind, search irritability, control and have a dizzy spell ".Six medicines share, and gather the merit of adjuvant drug altogether.

Take a broad view of full side, have the cloudy blood of the nourishing the liver and kidney and the heart, suppressing the hyperactive liver and subsiding YANG, tranquillizing and allaying excitement, the merit that QI invigorating is emboldened.

Compared with prior art, this product good effect, take safety, have determined curative effect, have no side effect, and preserve, transport, carry and advantage such as taking convenience and the used Chinese crude drug of this product all are common medical materials, aboundresources, production cost is low.

The correlational study of this product:

1, study of pharmacy:

1.1 quality standard research: this product is by the extract of Chinese medicines such as the Radix Paeoniae Alba, Fructus Schisandrae Chinensis, Radix Et Caulis Acanthopanacis Senticosi and the granule that an amount of correctives is prepared from, so select the thin layer chromatography discrimination method for use.When differentiating, consider that the prescription flavour of a drug are more, complicated component, interference factor is many etc., and therefore, monarch drug and flavour of a drug with diagnostic characteristics are studied in the side of being primarily aimed at.The result of the test conclusive evidence, the discrimination method that this standard body is recorded is easy, and repeatability and specificity are good.Monarch drug in the Radix Paeoniae Alba side of being is measured wherein paeoniflorin content and is controlled this product quality, can effectively control product quality, has drafted the method for assay, has formulated coherence check project etc.

1.2 stability study: get test agent in 3 batches, the method that adopts room temperature to keep sample and investigate, by the quality standard of declaring (draft) and " Chinese pharmacopoeia version appendix in 2000 method has been carried out 12 months study on the stability, the result: the equal conformance with standard of projects such as sample character, granularity, melting, limit test of microbe, discriminating and assay regulation.

1.3 pharmacological toxicology research:

1.3.1 main pharmacodynamics research: this product is given mouse gavaging once with 60.3g, 40.5g, 20.2g (crude drug)/kg, 60.3,40.5g (crude drug)/kg dosage group can obviously suppress the number of times that the spontaneous activity number of times of mice and mice are lifted two forelimbs, shortens walking about the time of mice.This product is given mouse gavaging once with 60.3g, 40.5g, 20.2g (crude drug)/kg, and 60.3,40.5g (crude drug)/kg dosage group can obviously shorten the time for falling asleep of mice and prolong mouse sleep time.This product is given mouse gavaging with 60.3g, 40.5g, 20.2g (crude drug)/kg, and once a day, continuous 7 days, 60.3g (crude drug)/kg dosage group can make sleeping mice Mus number increase.This product 40.5,20.3 and 10.2g (crude drug)/kg dosage group can improve the effect of mice pentetrazole CD50 value, and improving percentage rate respectively is 13.88%, 12.05% and 17.65%.20.3 and 10.2g (crude drug)/kg dosage group energy highly significant reaches and resists mice electrofit incidence rate significantly.This product 40.5,20.3 and 10.2g (crude drug)/kg dosage group can obviously prolong atropine and cause the incubation period that the acquired obstacle mice of memory is made a mistake.30g, 10g (crude drug)/kg dosage group after to the anaesthetized dog blood pressure administration each time point and administration before no difference of science of statistics relatively.The granule 30 of this product, 10g (crude drug)/kg dosage group cause anesthetized dog DP and the obviously influence of AP rising nothing to dopamine hydrochloride, but 10g (crude drug)/kg dosage group causes anesthetized dog SP rising to dopamine hydrochloride inhibitory action are arranged.

1.3.2 toxicologic study: (1) acute toxicity: this product is given mouse gavaging, and twice (the upper and lower noon respectively once) observed 14 days continuously in one day, and its maximum tolerated dose is 240g (crude drug)/kg or LD ₅₀＞240g (crude drug)/kg.This product to the mouse peritoneal injection was once observed its LD 14 days continuously ₅₀Be 5.4158g (crude drug)/kg.(2) long term toxicity research: this product was irritated stomach rat 120,60,30g.kg in continuous 180 days ^-1.d crude drug (large, medium and small) three dosage groups, matched group is given distilled water, and drug withdrawal convalescent period observed 30 days.Successive administration 180 days, the outward appearance sign of three dosage treated animals, behavioral activity Non Apparent Abnormality.The feedstuff day consumption increases with body weight, and each treated animal does not have significant difference to feed consumption.(0 day) ratio before administration 180 days and the administration, weight average increases: heavy dose of 205.35g, middle dosage 207.24g, low dose of 218.92g, matched group 240.63g, heavy dose of group body weight is slightly low than low dose and matched group, with middle dosage group basically identical.Administration 90,180 days, drug withdrawal was observed 30 days, and large, medium and small dosage group peripheral hemogram is checked relatively all no difference of science of statistics (P＞0.05) of index and 10 indexs of blood biochemistry checking and matched group, peripheral hemogram, blood biochemistry checking, data all fluctuate in normal range, no abnormality seen.Each treated animal of anatomic observation, except that have the individual animal lung tissue have naked eyes as seen unusually, other is organized does not all have the visible pathological changes of naked eyes; More equal no difference of science of statistics between each organ coefficient group; Administration 90,180 days, drug withdrawal 30 days, histopathological examination, heavy dose of group and matched group, the heart, liver, spleen, lung, kidney, brain (cerebellum), spinal cord, hypophysis, esophagus, trachea, lymph node, thyroid, thymus,, pancreas, adrenal gland, testis (epididymis), prostate, uterus, ovary, stomach, duodenum, return, colon, bladder body, more than all acellular form of each organs and tissues, textural anomaly changes.

1.4 comprehensive conclusion: in sum, the quality standard of this product is controlled, and end product quality is basicly stable; Acute toxicity testing shows that this product oral administration is 240g (crude drug)/kg or LD to the mice maximum tolerated dose ₅₀＞240g (crude drug)/kg, lumbar injection are once to the LD of mice ₅₀Be 5.4158g (crude drug)/kg; 180 days long term toxicity test shows this medicine safety non-toxic.Therefore, result of study meets the new drug requirement substantially.

2, technical study

2.1 dosage form selection: according to the clinical application needs, square taste of Chinese medicine character and active ingredient physicochemical property thereof and day clothes crude drug amount in conjunction with factors such as the market demands, are selected dosage form.This prescription should be developed into dosage forms such as granule, capsule, tablet, drop pill, soft capsule preparation, oral liquid, syrup preparation or dispersible tablet, and they can satisfy the clinical day big needs of clothes dosage, and preserve, transport, carry and taking convenience.

2.2 medical material buying and processing: institute is purchased in Heilungkiang except that Radix Et Caulis Acanthopanacis Senticosi with medical material, all the other medical materials are all purchased five stone medical material markets in Chengdu, all meet " relevant regulations under 2000 editions each medical material items of Chinese pharmacopoeia through identifying, and make only and process by concocting the general rule regulation, made feeding intake that institute needs, standby.

2.3 technological design and process route are drafted: we are made up of 12 flavor medicines such as the Radix Paeoniae Albas, are mainly effective ingredient such as saponins, flavonoid, aminoacid, trace element, organic acid, polysaccharide.From prescription analysis and bibliographical information, Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis adopt ethanol extraction; Concha Margaritifera, Concha Ostreae belong to shell, and tradition is used as medicine requirement and should be decocted first as if going into decoct; Flavour of a drug such as all the other Radix Paeoniae Albas, Semen Ziziphi Spinosae decoct and extract.Because of we's day clothes crude drug amount is big, when technological design,, remove invalid components for preserving effective ingredient to greatest extent, flavour of a drug water extract-alcohol precipitations such as the Radix Paeoniae Alba, Semen Ziziphi Spinosae are to reduce leaching rate.Trial test records water extract extractum yield and is about 20%, surveys its extractum yield about 12% behind precipitate with ethanol.It is as follows to draft process route:

But when granulating, the extractum behind the discovery water extract-alcohol precipitation is heated easier to be softening, and being clamminess is difficult to molding.Though this explanation aqueous extraction-alcohol precipitation technology has reduced the extractum yield, unfavorable molding.After test adopts high speed centrifugation to remove impurity, spray drying makes extract powder, puts boiling granulating in the fluid bed again.The process route of drafting had both shortened production technology, had reduced supplementary product consumption again, was beneficial to molding.

2.4 process conditions research:

2.4.1 medical material pre-treatment: clean processing: medical material mainly adopts the method for selecting to remove assorted bits, and medical materials such as Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis are smashed the coarse granule into about 5mm again to pieces, and are standby.

2.4.2 Study on extraction: 1. flavour of a drug such as the Radix Paeoniae Alba decoct the extraction conditions screening: use orthogonal experiment, factors such as examination amount of water, soak time, decoction number of times, decocting time, to decocting the extraction effect influence, select with experimental establishment research as follows about factor level: (1) factor level is selected: learn according to long-term practice, the performance that Chinese medicine leaches the preparation curative effect depends primarily on extraction, and extraction effect is subjected to extracting the factors such as solvent, extraction time and time, soak time and the influence of factor varying level.Extract when investigating so decoct, choose amount of water, soak time, decocting time, decoction number of times as factor, the varying level of high spot reviews factor is to decocting the influence of extraction effect.Take all factors into consideration selection factor level design table 1 in conjunction with aspects such as production cost, the energy.

Table 1 factor level table

Level	Factor
					Amount of water (doubly) A	Soak time B	Decocting time (little C	Decoct number of times D
	??1 ??2 ??3	??6 ??8 ??10	??0 ??1.5 ??3.0	?1.0 ?1.5 ?2.0					??1 ??2 ??3

(2) index is determined: selecting extractum recovery rate and two of content is evaluation index, its reason and assay method are as follows: 1. extractum recovery rate: extractum is the material base of solid preparation performance curative effect, its yield height directly influences preparation process, is reasonable, effective control device so be chosen as the extraction index.Assay method: 103g feed intake (remove Radix Et Caulis Acanthopanacis Senticosi and Fructus Schisandrae Chinensis, altogether heavy) decoct merge extractive liquid,, filter, adjustment is settled to 500ml, therefrom gets 50ml again, in the dry evaporating dish of weighing of impouring, water-bath is concentrated into dried, moved into 105 ℃ of oven dryings 3 hours, and took out, put and cool off after 30 minutes in the exsiccator, taking-up is weighed, and calculates.

2. paeoniflorin content: extractum yield height can not reflect fully that active ingredient extracts situation, thus in selecting simultaneously to write out a prescription the contained main component paeoniflorin content of the Radix Paeoniae Alba as screening index.

(3) orthogonal test: select orthogonal table, test arrangement and the results are shown in Table 2.

Table 2 test arrangement and analysis of results table

Tested number	Row number				Result of the test
								??1	??2	??3	??4
	Factor											The extractum yield	Paeoniflorin content	Comprehensive grading
					??A	??B	??C	??D	??Y 1(％)	??Y 2(mg/ml)	??Y
	??1 ??2 ??3 ??4 ??5 ??6 ??7 ??8 ??9	??1 ??1 ??1 ??2 ??2 ??2 ??3 ??3 ??3	??1 ??2 ??3 ??1 ??2 ??3 ??1 ??2 ??3	??1 ??2 ??3 ??2 ??3 ??1 ??3 ??1 ??2								??1 ??2 ??3 ??3 ??1 ??2 ??2 ??3 ??1	??12.21 ??16.96 ??19.68 ??17.93 ??14.11 ??16.52 ??19.55 ??17.77 ??14.17	??0.3294 ??0.4072 ??0.3731 ??0.4046 ??0.4252 ??0.4043 ??0.4129 ??0.4463 ??0.4637	??67.4358 ??87.1576 ??88.2769 ??88.2769 ??83.6982 ??85.8852 ??93.1626 ??93.8631 ??88.8036
??I ??II ??III ? I ? ? II ? ? III ??R					??242.8703 ??257.8603 ??275.8293 ??80.95677 ? ??85.95343 ? ??91.94310 ??10.9863	??248.8753 ??264.7189 ??262.9657 ??82.95843 ? ??88.23963 ? ??87.65523 ??5.2812	??247.1841 ??264.2381 ??265.1377 ??82.39470 ? ??82.39470 ? ??88.37923 ??5.9845	??239.9376 ??266.2054 ??270.4169 ??79.97920 ? ??79.97920 ? ??90.13897 ??10.1598

Remarks: 1. paeoniflorin content is the contained peoniflorin total amount of 1ml extracting solution.

2. aggregative weighted is marked by formula:

$Y={Y_1}^{\′}+{Y_2}^{\′}=40\×\frac{Y_1}{19.68}+60\×\frac{Y_2}{0.4637}$

Extractum yield design 19.68 is an ideal value, counts 40%; Paeoniflorin content design 0.4637mg/ml is an ideal value, counts 60%.

Table 3 analysis of variance table

Soruces of variation	Sum of deviation square	Degree of freedom	Variance	The F value	Significance
						??A ??B ??C	??181.5423 ??50.29250 ??68.22000	??2 ??2 ??2	??90.77115 ??25.14626 ??34.11000

??D

??181.8580

??2

??90.92899

Interpretation of result: as seen by table 2 evaluation directly perceived, from comprehensive grading, the factor size order that influences extraction effect is A＞D＞C＞B, it is amount of water＞extraction time＞decocting time＞soak time, be comprehensive extractum yield, peoniflorin yield angle, factor A (amount of water) has considerable influence to it, secondly is factor D (extraction time) and factor C (decocting time), and factor B (soak time) influences minimum.Determine about level: at first,, should select A3 the selection of principal element A (amount of water) level; Secondly, factor D (extraction time) should select D3 from comprehensive grading value size; Determining of factor C (decocting time) level, should select C3, but consider from peoniflorin yield and actual production, this prescription flavour of a drug have colored class medical material, and the effective ingredient good water solubility is more fried, needn't decoct for a long time, should optimize technology, selects C1 promptly to decoct 1 hour; The level of factor B is selected, and selects B2 (soaking 1.5 hours).The extraction optimal conditions is: A3B2C1D3.Consider that Concha Margaritifera, Concha Ostreae belong to shell, tradition is used as medicine requirement if going into decoct should be decocted first, and is decocted first 1 hour so determine Concha Margaritifera, Concha Ostreae, and medicinal residues and other medical material (soaking after 1.5 hours) merge, and decoct to extract three times, add 10 times of water gagings, each 1.0 hours at every turn.And carry out repeated authentication according to this condition and test.

(4) repeated authentication experiment: carry out repeated confirmatory experiment by above extraction process condition, it is 4 as follows that experimental result is tabulated:

Table 4 repeated experiment result

Scheme	Tested number	Extractum yield (%)	Paeoniflorin content (mg/ml)
				? ??A3B2C1D3	??1 ??2 ??3	??17.56 ??17.47 ??17.53	??0.4487 ??0.4384 ??0.4552

Remarks: investigation amount 103g

Extract by visible this optimum organization condition of the result of repeated confirmatory experiment that extractum yield and paeoniflorin content fluctuation are little as a result, the extractum yield coefficient of variation is about 2.59%, the peoniflorin yield coefficient of variation is about 1.89%, and as seen this extraction process condition is reasonable, feasible and stable.2. Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis alcohol reflux conditional filtering: according to documents and materials, Radix Et Caulis Acanthopanacis Senticosi, the most alcohol reflux that adopt of Fructus Schisandrae Chinensis.Select orthogonal experiment for use, factors such as examination ethanol consumption, concentration of alcohol, extraction time, extraction time, to the reflux, extract, influential effect, select with experimental establishment research as follows about factor level: (1) factor level is selected: learn according to long-term practice, the performance that Chinese medicine leaches the preparation curative effect depends primarily on extraction, and extraction effect is subjected to extracting the factors such as solvent, extraction time and time and the influence of factor varying level.So when reflux, extract, is investigated, choose ethanol consumption, concentration of alcohol, extraction time, extraction time as factor, the varying level of high spot reviews factor is to the influence of reflux, extract, effect.Take all factors into consideration in conjunction with aspects such as production cost, the energy, the design of selection factor level sees Table 5.

Table 5 factor level table

Level	Factor
					Ethanol consumption (doubly) A	Concentration of alcohol (%) B	Extraction time (inferior) C	Extraction time (hour) D
	??1 ??2 ??3	??4 ??6 ??8	??50 ??70 ??90	??1 ??2 ??3					??1.0 ??1.5 ??2.0

(2) index is determined: selecting extractum yield and two of content is evaluation index, its reason and assay method are as follows: 1. extractum yield: extractum is the material base of solid preparation performance curative effect, its yield height directly influences preparation process, is reasonable, effective control device so be chosen as the extraction index.Assay method: Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis 72g altogether feed intake reflux, extract,, merge extractive liquid,, filter, adjustment is settled to 500ml, therefrom gets 50ml again, in the dry evaporating dish of weighing of impouring, water-bath is concentrated into dried, moved into 105 ℃ of oven dryings 3 hours, and took out, put and cool off after 30 minutes in the exsiccator, taking-up is weighed, and calculates.2. schisandrin content: extractum yield height can not reflect fully that active ingredient extracts situation, thus in selecting simultaneously to write out a prescription the contained main component schisandrin of Fructus Schisandrae Chinensis content as screening index.

(3) orthogonal test: select orthogonal table L ₉(3 ⁴), test arrangement and the results are shown in Table 6, The results of analysis of variance sees Table 7.

Table 6 test arrangement and analysis of results table

Tested number	Row number				Result of the test
								??1	??2	??3	??4
	Factor											The extractum yield	Schisandrin content	Comprehensive grading
					??A	??B	??C	??D	??Y 1(％)	??Y 2(mg/ml)	??Y
	??1 ??2 ??3 ??4 ??5 ??6 ??7 ??8 ??9	??1 ??1 ??1 ??2 ??2 ??2 ??3 ??3 ??3	??1 ??2 ??3 ??1 ??2 ??3 ??1 ??2 ??3	??1 ??2 ??3 ??2 ??3 ??1 ??3 ??1 ??2								??1 ??2 ??3 ??3 ??1 ??2 ??2 ??3 ??1	??8.93 ??12.98 ??14.54 ??13.49 ??16.41 ??11.02 ??15.08 ??13.55 ??14.32	??0.1262 ??0.2446 ??0.2918 ??0.2317 ??0.2650 ??0.1935 ??0.1977 ??0.2183 ??0.2238	??47.7143 ??81.9333 ??95.4426 ??80.5218 ??94.4894 ??66.6457 ??77.4042 ??77.9142 ??80.9186
??I ??II ??III ? I ? II ? III ??R					??225.0902 ??241.6569 ??236.237 ??75.0301 ??80.5523 ??78.7457 ??5.5222	??205.6403 ??254.3369 ??243.0069 ??68.5468 ??84.7790 ??81.0023 ??16.2322	??192.2742 ??243.3737 ??267.3362 ??64.0914 ??81.1246 ??89.1121 ??25.0207	??223.1223 ??225.9832 ??253.8786 ??74.3741 ??75.3277 ??84.6262 ??10.2521

Remarks: aggregative weighted is marked by formula:

$Y={Y_1}^{\′}+{Y_2}^{\′}=40\×\frac{Y_1}{16.41}+60\×\frac{Y_2}{0.2918}$

Extractum yield design 16.4120% is an ideal value, counts 40%; Schisandrin content design 0.2918mg/ml is an ideal value, counts 60%.

Table 7 analysis of variance table

Soruces of variation	Sum of deviation square	Degree of freedom	Variance	The F value	Significance
						??A ??B ??C ??D	??47.56467 ??432.8878 ??979.9627 ??192.4765	??2 ??2 ??2 ??2	??23.78233 ??216.4439 ??489.9813 ??96.23823	??9.10 ??20.60 ??4.05	? ? ??*

F0.05(2，2)＝19.0??F0.10(2，2)＝9.0

Interpretation of result: as seen by the evaluation directly perceived of last table, from comprehensive grading, the factor primary and secondary is in proper order: C＞B＞D＞A, wherein the C influence is bigger, be comprehensive extractum yield, schisandrin yield angle, factor C (extraction time) has considerable influence to it, secondly is factor B (concentration of alcohol) and factor D (extraction time), A (ethanol consumption).From the result of variance analysis, C has significant difference, and for influencing the principal element of extraction effect, A, B and D then do not have the significance meaning, are secondary cause.Determine about level: at first,,, should select C3, but, select C2 in conjunction with production reality and cost consideration from comprehensive grading C3＞C2＞C1 value size to the selection of principal element C; The level of factor B (concentration of alcohol) is selected, and from comprehensive grading B2＞B3＞B1 value size, should select B2; The level of factor D (extraction time) is selected, and from comprehensive grading D3＞D2＞D1 value size, should select D3; The level of factor A (ethanol consumption) is selected, and from comprehensive grading actinium 2＞A3＞A1 value size, selects 6 times of amounts.So determine that extracting optimal conditions is A2B2C2D3, promptly extract secondary, each 2 hours, add 6 times of amount 70% ethanol at every turn.And carry out repeated authentication according to this condition and test.(4) repeated authentication experiment: carry out repeated confirmatory experiment by above extraction process condition, it is 8 as follows that experimental result is tabulated:

Table 8 repeated experiment result

Scheme	Tested number	Extractum yield (%)	Schisandrin content (mg/ml)
				? ??A2B2C2D3	??1 ??2 ??3	??14.75 ??14.36 ??14.52	??0.2972 ??0.2837 ??0.2984

Extract extractum yield (%), the fluctuation of schisandrin content as a result not quite by visible this optimum organization condition of the result of repeated confirmatory experiment, the extractum yield coefficient of variation is about 1.35%, the yield coefficient of variation is about 2.78%, and as seen this extraction process condition is reasonable, feasible and stable.

2.4.3 isolation and purification technical study: the former prescription of this product day clothes crude drug amount is big, therefore should discard the dross and select the essential as far as possible, alcohol extraction part since in the medicinal liquid contained solid particle and macromolecular substances less, so only need filter gained filtrate employing decompression recycling ethanol with 260 order filter clothes.It is more that water is carried the part impurities, as macromolecular substances and solid particles such as protein, phlegmatic temperaments.Adopt ultracentrifugal (12000 rev/mins) method, reach impurity-eliminating effect.

2.4.4 concentration technology research: method for concentration is selected, for the ease of production operation control with avoid loss of effective components, water to carry medicinal liquid and the alcohol extraction medicinal liquid all adopts concentrating under reduced pressure, relative density be the clear paste of 1.10 (60 ℃).Water is put forward the spissated condition of medicinal liquid (supernatant behind the high speed centrifugation): temperature is 80 ℃, and vacuum is 0.08～0.1Mpa.The condition of alcohol extraction medicinal liquid concentrating under reduced pressure is: temperature is 70 ℃, and vacuum is 0.08～0.1Mpa.

2.4.5 drying process research: drying means, once adopted the drying baker convection drying, easily bonding is softening because of extractum, and length consuming time is not succeeded; After reelect spray drying because have that its rate of drying is fast, production process is simple, the material heated time is short, product quality easy to control.Through test, obtain being fit to the process operation parameter of this product: relative density of medicine liquid is 1.10 (60 ℃); Atomizing pressure 0.25Mpa; Inlet temperature should be decided to be 200～220 ℃, leaving air temp should be decided to be 80～86 ℃.

2.4.6 Study on Forming: 1. prescription design: because of this product prescription usage and dosage is: oral, a daily dose primary crude drug 121g.Now make granule, relate to the formulation usage and dosage, inevitable relevant with Chinese medical concrete amount and supplementary product consumption.Yin Qiri clothes crude drug dosage is big, should consider not add or add less as far as possible adjuvant, and preparation process research should stress pilot plant test and investigate Chinese medical concrete yield, granule melting and mouthfeel.One daily dose primary crude drug 121g, paste volume be 18.7g (in), by taking every day 2 times, take 1 bag at every turn, then specification is the 10g/ bag, adjuvant need add 1.3g.According to last calculating, preparation prescription is: extract part medical material 6050g, paste volume is that 935g makes granule 1000g altogether, and adjuvant need add 65g.2. supplementary product kind and consumption thereof are investigated: correctives is selected: bitter because of this taste, need to select suitable correctives.Consult pertinent literature and done the mouthfeel debugging, the results are shown in Table 9 and table 10 at this product.

Table 9 function as sweeteners comparison sheet

Kind	Sucrose	Aspartame	Cyclamate
				The safety of sugariness flavor quality and price lattice consumption	1, (standard of comparison) 1, (standard of comparison) is unrestricted, (but diabetes are avoided usefulness) is good	180～300 times 80 times unrestricted good	50 times have the low consumption of metalloid aftertaste cost limited, generally are no more than 0.1% better

Through relatively comprehensive, selected aspartame is made the correctives of this product, and institute's expense per os sense is debugged and got.Screening experiment: get extract powder 40g, be divided into four parts, portion does not add any adjuvant, and three parts add 1%, 2%, 3% aspartame mixing respectively in addition, adds an amount of boiled water and takes after mixing it with water, and tastes its flavor through many people, judges the quality of mouthfeel, and it the results are shown in Table 10.

Table 10 aspartame scale

Tested number	??1	?2	?3	?4
					Addition	Do not add adjuvant	Add 1% aspartame	Add 2% aspartame	Add 3% aspartame
Mouthfeel	Pained (-)	The sweet slightly bitterness (+) that still has	Sugariness moderate (++)	Cross sweet (+++)

The result shows, adds 2% aspartame, and mouthfeel is moderate.

2.5 granulating process research: (1) method of granulating is investigated: method of granulating once adopted wet granulation, selected for use Different concentrations of alcohol and PVP to granulate, easily bonding is softening because of extractum, and operating difficulties is so abandon this kind method.Boiling method in the fluid bed is adopted in the back, for mix homogeneously, after water extract and alcohol extract merging, adds an amount of correctives, and mixing is got a part of medicine liquid spray drying, makes extract powder, and get the residue medicinal liquid again and do binding agent, boiling granulating in fluid bed, promptly.(2) the granulating process condition is investigated: 1. spray drying extractum and the investigation of boiling granulating extractum ratio are consistent because of spray drying extractum and boiling granulating extractum relative density, extracting solution can be concentrated into 1.10 (60 ℃), press the different proportion separated into two parts again, a part is carried out spray drying, a part is as binding agent, and its ratio investigation situation sees Table 11.

Table 11 spray drying extractum and boiling granulating extractum ratio are investigated

Spray drying extractum: boiling granulating extractum (Kg: Kg)	The granulation situation
		??2∶1 ??2∶3 ??1∶1	Easily granulate, granular size is suitable, evenly the granulation time long, the big granulation time of gained granule is long, the gained granule is big, bed easily collapses

2. the investigation of fluidized granulating important technological parameters is screened the fluidized granulating important technological parameters, and concrete outcome sees Table 12.

Table 12 fluidized granulating important technological parameters is investigated

Feed liquor speed (ml/min)	??55～60	??50～55	??45～50	??40～45
					Atomisation pressure (Mpa) steam pressure (Mpa) temperature of charge (℃) inlet temperature (℃) leaving air temp (℃) the granulation situation	0.15 0.5 65～60 98～88 50～45 granules are inhomogeneous, easily bonding	0.15 0.5 60～55 80～100 60～65 uniform particles are easily granulated	0.15 0.5 55～50 78～68 40～35 uniform particles, but the granulation time is long	0.15 0.5 50～45 68～58 35～30 uniform particles, but the granulation time is long

The important technological parameters of fluidized granulating is as seen from table: feed liquor speed 50～55ml/min; Atomisation pressure 0.15Mpa; 55～60 ℃ of temperature of charge; 80～100 ℃ of inlet temperature; 60～65 ℃ of leaving air temps; 20 ℃ of indoor temperatures, relative humidity 50%.

2.6 critical relative humidity (CRH) is measured: affected by environment during the examination packing, especially humidity effect has carried out the granule critical relative humidity and has measured.Concrete operations are as follows: get 14 parts of granules respectively, and every part of about 1g, the accurate title, decide, put in the weighing botle, open bottle cap, putting into relative humidity respectively is 22.45%, 33.00%, 42.76%, 57.70%, in 75.28%, 84.26%, 92.48% the environment, in 25 ℃ of incubators, placed 84 hours, take out weighing botle, add a cover the accurate title in back and decide, calculate its moisture absorption percentage rate.The results are shown in Table 13.

Particulate moisture absorption percentage rate (%) under the different relative humiditys of table 13

The saturated salt solution kind	Relative humidity (%)	Moisture absorption percentage rate (%)
			??CH3COOK.1.5H 20 ??MgCl 2.6H 20 ??K 2CO 3.2H 2O ??NaBr.2H 2O ??NaCl ??KCl ??KNO 3	??22.45 ??33.00 ??42.76 ??57.70 ??75.28 ??84.26 ??92.48	??2.05 ??4.72 ??8.87 ??15.87 ??26.18 ??37.26 ??43.77

To moisture absorption percentage rate (%) mapping, the results are shown in accompanying drawing 1 with relative humidity (CRH).Its CRH% about 59% as shown in Figure 1.

2.7 the selection of packaging material: selecting suitable packaging material is the important means that prevent the solid preparation moisture absorption.The packaging material of solid preparation of Chinese medicine mainly contain glass, plastics, fine aluminium composite membrane and plastic-aluminum etc. at present.The Different Package material is widely different to the preparation stability influence.The first-selected two In Aluminium Foil Packings of granule packing also are evacuated.This product is satisfying under the prescription prerequisite, selects to pack with the aluminized complex film bag, proves that by stability test these packaging material are feasible.

2.8 packing:, get product with the granule of the one-step palletizing aluminized complex film bag of packing into.

3, pilot scale trial-production and run-of-the-mill inspection: feed intake by above-mentioned technology and to carry out several batches of investigations of pilot scale trial-production, wherein three batch datas and run-of-the-mill check result see Table 14.

Three batches of pilot scale trial-production of table 14 data

Lot number		??020301	??020302	??020303
					Inventory	Chinese crude drug (Kg)	??60.50	??60.50	??60.50
Extractum gross weight (Kg)		??37.67	??37.73	??37.39
					Spraying	Extractum relative density (60 ℃)	??1.10	??1.10	??1.10
Spray drying extractum amount (Kg)	??25.10	??25.15	??24.93

Dry	Powdered extract powder (Kg)	??6.13	??6.12	??6.05
					Fluidized granulating	Extractum relative density (60 ℃)	??1.10	??1.10	??1.10
Fluidized granulating extractum amount (Kg)	??12.57	??12.58	??12.46
				Fluidized granulating carrier (Kg)		??6.13	??6.12	??6.05
Dried particles weight (Kg)	??9.17	??9.08	??9.11
				Theoretical yield (Kg)		??10	??10	??10
Actual production (Kg)		??9.17	??9.08						??9.11
				Yield rate (%)		??91.7	??90.8	??91.1

By the analysis of pilot-scale experiment, the process route of working out has operability, and is basicly stable, and pilot scale extractum yield is more lower slightly than laboratory result as can be known simultaneously, probably 15～16%.Determine about the granule usage and dosage, took raw medicinal herbs 121g on 1st, be equivalent to extractum amount 121g * 15%～121g * 16%=18.15g～19.36g, it is an amount of to add correctives again, adjusts total amount to 20g, with the packing of aluminized complex film bag, every packed 10g.

Test agent run-of-the-mill check result in the table 15

Lot number	Granularity	Moisture (%)	Melting	Content uniformity (%)	Limit test of microbe	Assay (mg/g)
							??020301 ??020302 ??020303	Up to specification up to specification	??2.4 ??2.6 ??2.8	Qualified qualified	??-3.0～3.0 ??-2.0～3.0 ??-2.0～3.0	Up to specification up to specification	??4.921 ??4.658 ??5.110

As seen from the above table, the sample of three batches of trial-productions all meets the requirements according to the inspection of granule general rule, and the technology of drafting is reasonable, feasible.

Description of drawings: Fig. 1 is the figure that the present invention is done moisture absorption percentage rate (%) with relative humidity (CRH), and wherein abscissa is that relative humidity (%), vertical coordinate are moisture absorption percentage rate (%).

The specific embodiment:

Embodiments of the invention 1: take by weighing Radix Paeoniae Alba 726g, Semen Ziziphi Spinosae 592g, Semen Platycladi 484g, Concha Margaritifera 592g, Bulbus Lilii 393g, Radix Rehmanniae Preparata 484g, Concha Ostreae 592g, Fructus Schisandrae Chinensis 393g, Radix Et Caulis Acanthopanacis Senticosi 484g, Poria 484g, Flos Albiziae 393g, Flos Chrysanthemi 296g and aspartame 65g, get Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis, be ground into coarse powder, extract 2 times with 70% alcohol heating reflux, each 2 hours, merge alcohol extract, filter, decompression recycling ethanol, the survey relative density is 1.1 clear paste when being concentrated into 60 ℃, and is standby; Concha Margaritifera, Concha Ostreae decoct with water and extracted 1 hour, filter, and filtrate device is in addition collected; The residue and the Radix Paeoniae Alba, Semen Ziziphi Spinosae, Semen Platycladi, Poria, Flos Albiziae, Flos Chrysanthemi, Bulbus Lilii, Radix Rehmanniae Preparata merge, and decoct with water and extract each 1 hour 3 times, collecting decoction filters, and is centrifugal, the survey relative density was 1.1 clear paste when centrifugal medicinal liquid was concentrated into 60 ℃, added above-mentioned clear paste and an amount of aspartame, merged, mixing is got a part of medicine liquid spray drying, makes extract powder, get the residue medicinal liquid again and do binding agent, boiling granulating in fluid bed is made 1000g, promptly gets granular preparation of the present invention.

Embodiments of the invention 2: take by weighing Radix Paeoniae Alba 600g, Semen Ziziphi Spinosae 400g, Semen Platycladi 300g, Concha Margaritifera 400g, Bulbus Lilii 200g, Radix Rehmanniae Preparata 300g, Concha Ostreae 400g, Fructus Schisandrae Chinensis 200g, Radix Et Caulis Acanthopanacis Senticosi 300g, Poria 300g, Flos Albiziae 200g, Flos Chrysanthemi 100g and aspartame 40g, get Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis, be ground into coarse powder, extract 1 with 50% alcohol heating reflux, each 3 hours, merge alcohol extract, filter, decompression recycling ethanol, the survey relative density is 0.8 clear paste when being concentrated into 60 ℃, and is standby; Concha Margaritifera, Concha Ostreae decoct with water and extracted 0.5 hour, filter, and filtrate device is in addition collected; The residue and the Radix Paeoniae Alba, Semen Ziziphi Spinosae, Semen Platycladi, Poria, Flos Albiziae, Flos Chrysanthemi, Bulbus Lilii, Radix Rehmanniae Preparata merge, and decoct with water and extract each 3 hours 1 time, collecting decoction filters, and is centrifugal, the survey relative density was 0.8 clear paste when centrifugal medicinal liquid was concentrated into 60 ℃, added above-mentioned clear paste and aspartame, merged, mixing, get a part of medicine liquid spray drying, make extract powder, encapsulated, make 1000, promptly obtain capsule preparations of the present invention.

Embodiments of the invention 3: take by weighing Radix Paeoniae Alba 900g, Semen Ziziphi Spinosae 700g, Semen Platycladi 600g, Concha Margaritifera 700g, Bulbus Lilii 400g, Radix Rehmanniae Preparata 600g, Concha Ostreae 700g, Fructus Schisandrae Chinensis 400g, Radix Et Caulis Acanthopanacis Senticosi 600g, Poria 600g, Flos Albiziae 400g, Flos Chrysanthemi 300g and aspartame 70g, get Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis, be ground into coarse powder, extract 3 times with 80% alcohol heating reflux, each 1 hour, merge alcohol extract, filter, decompression recycling ethanol, the survey relative density is 1.30 clear paste when being concentrated into 60 ℃, and is standby; Concha Margaritifera, Concha Ostreae decoct with water and extracted 2 hours, filter, and filtrate device is in addition collected; The residue and the Radix Paeoniae Alba, Semen Ziziphi Spinosae, Semen Platycladi, Poria, Flos Albiziae, Flos Chrysanthemi, Bulbus Lilii, Radix Rehmanniae Preparata merge, and decoct with water and extract each 0.5 hour 4 times, collecting decoction filters, and is centrifugal, the survey relative density was 1.30 clear paste when centrifugal medicinal liquid was concentrated into 60 ℃, added above-mentioned clear paste and aspartame, merged, mixing, get a part of medicine liquid spray drying, make extract powder, and then with remaining medicinal liquid mixing granulation, tabletting promptly obtains tablet of the present invention.

Embodiments of the invention 4: take by weighing Radix Paeoniae Alba 700g, Semen Ziziphi Spinosae 500g, Semen Platycladi 500g, Concha Margaritifera 600g, Bulbus Lilii 300g, Radix Rehmanniae Preparata 500g, Concha Ostreae 600g, Fructus Schisandrae Chinensis 300g, Radix Et Caulis Acanthopanacis Senticosi 500g, Poria 500g, Flos Albiziae 300g, Flos Chrysanthemi 200g and aspartame 50g, get Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis, be ground into coarse powder, extract 2 times with 60% alcohol heating reflux, each 1.5 hours, merge alcohol extract, filter, decompression recycling ethanol, the survey relative density is 1.2 clear paste when being concentrated into 60 ℃, and is standby; Concha Margaritifera, Concha Ostreae decoct with water and extracted 1.5 hours, filter, and filtrate device is in addition collected; The residue and the Radix Paeoniae Alba, Semen Ziziphi Spinosae, Semen Platycladi, Poria, Flos Albiziae, Flos Chrysanthemi, Bulbus Lilii, Radix Rehmanniae Preparata merge, and decoct with water and extract each 2 hours 2 times, collecting decoction filters, and is centrifugal, the survey relative density was 1.2 clear paste when centrifugal medicinal liquid was concentrated into 60 ℃, added above-mentioned clear paste and aspartame, merged, mixing, get a part of medicine liquid spray drying, make extract powder, mix, add vegetable oil substrate with remaining medicinal liquid again, pill promptly obtains drop pill of the present invention.

Embodiments of the invention 5: take by weighing Radix Paeoniae Alba 726g, Semen Ziziphi Spinosae 592g, Semen Platycladi 484g, Concha Margaritifera 592g, Bulbus Lilii 393g, Radix Rehmanniae Preparata 484g, Concha Ostreae 592g, Fructus Schisandrae Chinensis 393g, Radix Et Caulis Acanthopanacis Senticosi 484g, Poria 484g, Flos Albiziae 393g, Flos Chrysanthemi 296g, get Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis, be ground into coarse powder, extract 2 times with 70% alcohol heating reflux, each 2 hours, merge alcohol extract, filter, decompression recycling ethanol, surveying when being concentrated into 60 ℃ density is 1.1 clear paste, standby; Concha Margaritifera, Concha Ostreae decoct with water 1 hour, filter, and filtrate device is in addition collected; The residue and the Radix Paeoniae Alba, Semen Ziziphi Spinosae, Semen Platycladi, Poria, Flos Albiziae, Flos Chrysanthemi, Bulbus Lilii, Radix Rehmanniae Preparata merge, and decoct with water and extract each 1 hour 3 times, collecting decoction, filter, centrifugal, the survey relative density was 1.1 clear paste when centrifugal medicinal liquid was concentrated into 60 ℃, get a part of medicine liquid spray drying, make extract powder,, add propylene glycol again with remaining medicinal liquid mixing granulation, mix homogeneously promptly obtains soft capsule preparation of the present invention with being pressed into soft capsule after the colloid mill grinding.

Embodiments of the invention 6: take by weighing Radix Paeoniae Alba 600g, Semen Ziziphi Spinosae 400g, Semen Platycladi 300g, Concha Margaritifera 400g, Bulbus Lilii 200g, Radix Rehmanniae Preparata 300g, Concha Ostreae 400g, Fructus Schisandrae Chinensis 200g, Radix Et Caulis Acanthopanacis Senticosi 300g, Poria 300g, Flos Albiziae 200g, Flos Chrysanthemi 100g, get Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis, be ground into coarse powder, extract 3 times with 50% alcohol heating reflux, each 1 hour, merge alcohol extract, filter, decompression recycling ethanol, the survey relative density is 0.8 clear paste when being concentrated into 60 ℃, and is standby; Concha Margaritifera, Concha Ostreae decoct with water and extracted 0.5 o'clock, filter, and filtrate device is in addition collected; The residue and the Radix Paeoniae Alba, Semen Ziziphi Spinosae, Semen Platycladi, Poria, Flos Albiziae, Flos Chrysanthemi, Bulbus Lilii, Radix Rehmanniae Preparata merge, decoct with water and extract 1 time, each 3 hours, collecting decoction filtered, centrifugal, the survey relative density was 0.8 clear paste when centrifugal medicinal liquid was concentrated into 60 ℃, got a part of medicine liquid spray drying, made extract powder, mix, add solvent with remaining medicinal liquid again, promptly obtain oral liquid formulations of the present invention.

Embodiments of the invention 7: take by weighing Radix Paeoniae Alba 900g, Semen Ziziphi Spinosae 700g, Semen Platycladi 600g, Concha Margaritifera 700g, Bulbus Lilii 400g, Radix Rehmanniae Preparata 600g, Concha Ostreae 700g, Fructus Schisandrae Chinensis 400g, Radix Et Caulis Acanthopanacis Senticosi 600g, Poria 600g, Flos Albiziae 400g, Flos Chrysanthemi 300g, get Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis, be ground into coarse powder, extract 1 time with 80% alcohol heating reflux, each 3 hours, merge alcohol extract, filter, decompression recycling ethanol, the survey relative density is 1.30 clear paste when being concentrated into 60 ℃, and is standby; Concha Margaritifera, Concha Ostreae decoct with water and extracted 2 hours, filter, and filtrate device is in addition collected; The residue and the Radix Paeoniae Alba, Semen Ziziphi Spinosae, Semen Platycladi, Poria, Flos Albiziae, Flos Chrysanthemi, Bulbus Lilii, Radix Rehmanniae Preparata merge, decoct with water and extract 4 times, each 0.5 hour, collecting decoction filtered, centrifugal, the survey relative density was 1.30 clear paste when centrifugal medicinal liquid was concentrated into 60 ℃, got a part of medicine liquid spray drying, made extract powder, add glycerol and grind well back adding syrup, promptly obtain syrup preparation of the present invention.

Embodiments of the invention 8: take by weighing Radix Paeoniae Alba 800g, Semen Ziziphi Spinosae 600g, Semen Platycladi 500g, Concha Margaritifera 600g, Bulbus Lilii 300g, Radix Rehmanniae Preparata 500g, Concha Ostreae 600g, Fructus Schisandrae Chinensis 300g, Radix Et Caulis Acanthopanacis Senticosi 500g, Poria 500g, Flos Albiziae 300g, Flos Chrysanthemi 200g, get Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis, be ground into coarse powder, extract 2 times with 60% alcohol heating reflux, each 2 hours, merge alcohol extract, filter, decompression recycling ethanol, the survey relative density is 1.0 clear paste when being concentrated into 60 ℃, and is standby; Concha Margaritifera, Concha Ostreae decoct with water and extracted 1.5 hours, filter, and filtrate device is in addition collected; The residue and the Radix Paeoniae Alba, Semen Ziziphi Spinosae, Semen Platycladi, Poria, Flos Albiziae, Flos Chrysanthemi, Bulbus Lilii, Radix Rehmanniae Preparata merge, and decoct with water and extract each 2 hours 2 times, collecting decoction filters, and is centrifugal, the survey relative density was 1.0 clear paste when centrifugal medicinal liquid was concentrated into 60 ℃, get a part of medicine liquid spray drying, make extract powder, again with remaining medicinal liquid mixing granulation, spray into volatile oil or volatile oil clathrate compound, add sodium carboxymethyl cellulose, tabletting promptly obtains dispersible tablet of the present invention.

Claims (6)

1, a kind of Chinese medicine preparation for the treatment of generalized anxiety disorder, it is characterized in that: according to listed as parts by weight, it is prepared from for 100～300 parts by 600～900 parts of the Radix Paeoniae Albas, 400～700 parts of Semen Ziziphi Spinosaes, 300～600 parts of Semen Platycladi, 400～700 parts of Concha Margaritiferas, 200～400 parts of Bulbus Liliies, 300～600 parts of Radix Rehmanniae Preparata, 400～700 parts of Concha Ostreaes, 200～400 parts of Fructus Schisandrae Chinensis, 300～600 parts of Radix Et Caulis Acanthopanacis Senticosis, 300～600 parts in Poria, 200～400 parts of Flos Albiziaes and Flos Chrysanthemi.

2, according to the Chinese medicine preparation of the described treatment generalized anxiety disorder of claim 1, it is characterized in that: calculate according to weight, it is prepared from by Radix Paeoniae Alba 726g, Semen Ziziphi Spinosae 592g, Semen Platycladi 484g, Concha Margaritifera 592g, Bulbus Lilii 393g, Radix Rehmanniae Preparata 484g, Concha Ostreae 592g, Fructus Schisandrae Chinensis 393g, Radix Et Caulis Acanthopanacis Senticosi 484g, Poria 484g, Flos Albiziae 393g, Flos Chrysanthemi 296g.

3, according to the Chinese medicine preparation of claim 1 or 2 described treatment generalized anxiety disorders, it is characterized in that: described preparation is granule, capsule, tablet, drop pill, soft capsule preparation, oral liquid, syrup preparation or dispersible tablet.

4, as the preparation method of the Chinese medicine preparation of treatment generalized anxiety disorder as described among the claim 1-3 any, it is characterized in that: take by weighing the Radix Paeoniae Alba, Semen Ziziphi Spinosae, Semen Platycladi, Concha Margaritifera, Bulbus Lilii, Radix Rehmanniae Preparata, Concha Ostreae, Fructus Schisandrae Chinensis, Radix Et Caulis Acanthopanacis Senticosi, Poria, Flos Albiziae, Flos Chrysanthemi, get Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis, be ground into coarse powder, extract 1～3 time with 50%～80% alcohol heating reflux, each 1～3 hour, merge alcohol extract, filter, decompression recycling ethanol, the survey relative density is 0.8～1.30 clear paste when being concentrated into 60 ℃, and is standby; Concha Margaritifera, Concha Ostreae decoct with water and extracted 0.5～2 hour, filter, and filtrate device is in addition collected; The residue and the Radix Paeoniae Alba, Semen Ziziphi Spinosae, Semen Platycladi, Poria, Flos Albiziae, Flos Chrysanthemi, Bulbus Lilii, Radix Rehmanniae Preparata merge, decoct with water and extract 1～4 time, each 0.5～3 hour, collecting decoction, filter, centrifugal, the survey relative density was 0.8～1.30 clear paste when centrifugal medicinal liquid was concentrated into 60 ℃, added above-mentioned clear paste and an amount of correctives, merged, mixing, get a part of medicine liquid spray drying, make extract powder, again with remaining medicinal liquid mixing granulation, obtain the active component of medicine of the present invention, then the active component that makes is prepared into required preparation according to a conventional method.

5, according to the preparation method of the Chinese medicine preparation of the described treatment generalized anxiety disorder of claim 4, it is characterized in that: take by weighing the Radix Paeoniae Alba, Semen Ziziphi Spinosae, Semen Platycladi, Concha Margaritifera, Bulbus Lilii, Radix Rehmanniae Preparata, Concha Ostreae, Fructus Schisandrae Chinensis, Radix Et Caulis Acanthopanacis Senticosi, Poria, Flos Albiziae, Flos Chrysanthemi, get Radix Et Caulis Acanthopanacis Senticosi, Fructus Schisandrae Chinensis, be ground into coarse powder, extract 2 times with 70% alcohol heating reflux, each 2 hours, merge alcohol extract, filter decompression recycling ethanol, the survey relative density is 1.1 clear paste when being concentrated into 60 ℃, and is standby; Concha Margaritifera, Concha Ostreae decoct with water and extracted 1 hour, filter, and filtrate device is in addition collected; The residue and the Radix Paeoniae Alba, Semen Ziziphi Spinosae, Semen Platycladi, Poria, Flos Albiziae, Flos Chrysanthemi, Bulbus Lilii, Radix Rehmanniae Preparata merge, and decoct with water and extract each 1 hour 3 times, collecting decoction filters, and is centrifugal, the survey relative density was 1.1 clear paste when centrifugal medicinal liquid was concentrated into 60 ℃, added above-mentioned clear paste and aspartame, merged, mixing is got a part of medicine liquid spray drying, makes extract powder, get the residue medicinal liquid again and do binding agent, boiling granulating in fluid bed is made 1000g, promptly gets granular preparation of the present invention.

6, according to the preparation method of the Chinese medicine preparation of the described treatment generalized anxiety disorder of claim 5, it is characterized in that: the consumption of aspartame is 65g, or with stevioside or cyclamate, consumption still is 65g.

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