CN102233089A - Traditional Chinese medicine composition and preparation method thereof - Google Patents
Traditional Chinese medicine composition and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a traditional Chinese medicine composition and a preparation method thereof. The traditional Chinese medicine composition comprises the following components in parts by weight: 330-390 parts of prepared rehmannia root, 85-145 parts of anemarrhena, 185-245 parts of dangshen, 85-145 parts of wolfberry bark, 185-245 parts of angelica sinensis, 85-145 parts of epimedium, 115-175 parts of astragalus root, 185-245 parts of desertliving cistanche and 185-245 parts of wild jujube seed. The traditional Chinese medicine composition has obvious positive regulating effects on disordered nerves and reproductive endocrine systems of climacteric women, and has obvious effects on improving the symptoms such as restlessness, insomnia and the like due to climacteric. The preparation method disclosed by the invention is simple to operate and suitable for industrial big production.
Description
Technical field
The present invention relates to the field of Chinese medicines and Chinese medicine manufacture field, be specifically related to a kind of Chinese medicine composition and preparation method thereof.
Background technology
Climacteric is that the women's ovary function disappeared gradually to a transition period of complete obiteration, and menopause is meant that menstruation stops more than 1 year fully, claims menopause.One occurred between 45～65 years old.Climacteric women about 1/3 can reach new balance and asymptomatic by neuroendocrine self regulation, and the symptom due to a series of gonadal hormone minimizings then can appear in 2/3 women, is referred to as climacteric syndrome clinically.At home and abroad western medical treatment and prevention climacteric syndrome mostly adopt Hormone Replacement Therapy, but with simultaneously, some researchs find that also this treatment measure also might bring some unfavorable factors, and one of them is the incidence rate that possible increase some gynecologic malignant tumor.
Climacteric syndrome belongs to it " all diseases before and after the menopause " category of the traditional Chinese medical science, " interior warp " thought: " woman's seventy-seven exhaustion of kidney-essence with promoting reproductive function; menopause are so senile appearance and loss of fecundity are also ", think that exhaustion of kidney-essence with promoting reproductive function is the basic cause of disease of primary disease, the woman is to climacteric, kidney qi degradation, kidney qi can not faint-hearted nourishing liver-YIN, excessive rising of liver-YANG, so see hectic fever, spontaneous perspiration; The kidney failing to nourish the liver, stagnation of QI due to depression of the liver is so see fidgety irritability; Menses gradually exhausts, and yin and yang imbalance is so see menoxenia; Kidney qi can not the replenishing vital QI with drugs of warm nature the five internal organs, so see diseases such as cardiopalmus, insomnia.
Chinese patent 200810101870.2 discloses Chinese medicine composition of a kind of enriching yin and nourishing kidney and preparation method thereof, this Chinese medicine composition is by following crude drug: Radix Astragali, Poria, Radix Bupleuri, the Rhizoma Anemarrhenae, Cortex Eucommiae (parched), Radix Rehmanniae, Radix Rehmanniae Preparata, Radix Angelicae Sinensis, Radix Codonopsis, Cortex Lycii, Rhizoma Atractylodis Macrocephalae (parched), Radix Ophiopogonis, Flos Chrysanthemi process through technology such as extracting, refining.Said composition can be used for the endocrine disturbance, diseases such as women's infertility, leucorrhea abnormal.But because its component complexity, can't specific aim regulate nerve, the reproductive endocrine system of " climacteric " women's disorder, also very little to the improvement effect of symptoms such as involutional agitation, insomnia.
In view of this special proposition the present invention.
Summary of the invention
First purpose of the present invention is to provide a kind of Chinese medicine composition.
Second purpose of the present invention is to provide the preparation method of above-mentioned Chinese medicine composition, and this prescription and preparation technology are feasible, are suitable for large-scale production.
For realizing first purpose of the present invention, the present invention adopts following technical scheme:
A kind of Chinese medicine composition, described compositions have following proportioning by weight:
Radix Rehmanniae Preparata 330-390, Rhizoma Anemarrhenae 85-145, Radix Codonopsis 185-245, Cortex Lycii 85-145, Radix Angelicae Sinensis 185-245,
Herba Epimedii 85-145, Radix Astragali 115-175, Herba Cistanches 185-245, Semen Ziziphi Spinosae 185-245;
Preferably:
Radix Rehmanniae Preparata 345-375, Rhizoma Anemarrhenae 100-130, Radix Codonopsis 200-230, Cortex Lycii 100-130, Radix Angelicae Sinensis 200-230, Herba Epimedii 100-130, Radix Astragali 130-160, Herba Cistanches 200-230, Semen Ziziphi Spinosae 200-230;
More preferably:
Radix Rehmanniae Preparata 357, the Rhizoma Anemarrhenae 114, Radix Codonopsis 214, Cortex Lycii 114, Radix Angelicae Sinensis 214,
Herba Epimedii 114, the Radix Astragali 143, Herba Cistanches 214, Semen Ziziphi Spinosae 214.
Described Chinese medicine composition is the extract of above-mentioned raw materials, the oral formulations made from acceptable accessories.
Described oral formulations is a granule, and described adjuvant is a dextrin.
For realizing second purpose of the present invention, the present invention adopts following technical scheme:
A kind of preparation method of Chinese medicine composition as mentioned above, this preparation method comprises the steps:
1) with standby after described 9 kinds of pretreatments of raw material;
2) Herba Epimedii ethanol extraction, after extracting solution filtered, filtrate decompression was concentrated into thick paste;
3) eight flavor medicines such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis decoct with water, and decoction liquor filters, and filtrate is concentrated into thick paste;
4) step 3 gained thick paste and Herba Epimedii ethanol extraction thick paste are mixed into extract extractum, this extract extractum combines with pharmaceutically acceptable conventional adjuvant and further makes oral formulations.
Step 2 is: Herba Epimedii adds 12-18 and doubly measures the 60-80% alcohol reflux 1-3 time, and each 1-3 hour, merge extractive liquid, filtered, and filtrate recycling ethanol also is evaporated to relative density 1.28～1.36 (80 ℃) thick paste; Preferably: Herba Epimedii adds 15 times of amount 70% alcohol reflux 2 times, and each 1.5 hours, merge extractive liquid, filtered, and filtrate recycling ethanol also is evaporated to relative density 1.30～1.35 (80 ℃) thick paste.
Described step 3 is: eight flavor medicines such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis add 8-12 medical material water gaging and decoct 2-5 time, and each 0.5-2 hour, collecting decoction filtered, and filtrate is concentrated into relative density 1.28～1.36 (80 ℃) thick paste, and is preferred; Eight flavor medicines such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis add 10 times of medical material water gagings and decoct 3 times, and each 1 hour, collecting decoction filtered, and filtrate is concentrated into relative density 1.30～1.35 (80 ℃) thick paste.
Described oral formulations is tablet, granule and capsule.
The preparation method of described granule is:
In extract extractum, add an amount of acceptable accessories, mixing, drying under reduced pressure (60-80 ℃) is ground into fine powder, granulates, and packing forms.
The preparation method of described tablet is:
Add an amount of acceptable accessories in extract extractum, fully mixing is put 55-65 ℃ of drying and crushing; Mixing, granulation, drying, tabletting, promptly.
The preparation method of described capsule is:
In extract extractum, add an amount of acceptable accessories, stir, pulverize behind the vacuum drying, sieve, granulate, drying, fill is promptly.
Described acceptable accessories is starch, dextrin, lactose, Carboxymethyl cellulose sodium, micropowder silica gel, stearate or Pulvis Talci.
1, process route design
(1) physicochemical property of each flavour of a drug in the side
(1) Radix Rehmanniae Preparata: this product is that the fresh tuber of scrophulariaceae rehmannia glutinosa plant Rehmannia glutinosa Libosch. is concocted processed goods.
Concocting method: get clean Radix Rehmanniae, steam to black profit according to steaming method (II D of Chinese Pharmacopoeia version in 2000), take out, dry in the sun when dried slightly, is cut sheet or piece to crust mucus, drying, promptly.
(2) Rhizoma Anemarrhenae: this product is the dry rhizome of liliaceous plant Rhizoma Anemarrhenae Anemarrhena asphodeloides Bge..
(3) Radix Codonopsis: this product is the dry root of campanulaceae plant Radix Codonopsis Codonopsis pilosula (Franch.) Nannf..
(4) Cortex Lycii: this product is the dry root bark of matrimony vine of solanaceae plant Lycium chinense Mill. or lycium barbarum Lycium barbarum L..
(5) Radix Angelicae Sinensis: this product is the dry root of umbelliferae angelica Angelica sinensis (Oliv.) Diels.
(6) Herba Epimedii: this product is the dry aerial parts of Berberidaceae plant Herba Epimedii Epimedium wushanense T.S.Ying.
(7) Radix Astragali: this product is the dry root of leguminous plant Radix Astagali Astragalus membranaceus (Fisch.) Bge.var.mongholicus (Bge.).
(8) Herba Cistanches: this product is the chylocaulous of the dry zone phosphorus leaf of orobanchaceae plant cistanche Cistanche deserticola Y.C.Ma.
(9) Semen Ziziphi Spinosae: this product is the dry mature seed of Rhamnaceae plant acid Semen Ziziphi Spinosae Ziziphhus jujubaMill.Var.spinosa (Bunge) HuexH.F.Chou.
Be monarch with the Radix Rehmanniae Preparata in the side, nourishing the blood and yin, vital essence replenishing and marrow benifiting, tonifying for deficiency syndrome is to effect a permanent cure." book on Chinese herbal medicine is just ": " deficiency of YIN and the refreshing person that looses, the keeping of non-Radix Rehmanniae Preparata, be not enough to poly-it; The deficiency of YIN and the fiery person of liter, non-Radix Rehmanniae Preparata is heavy, supplies to fall it; The deficiency of YIN is restless, and non-Radix Rehmanniae Preparata quiet is not enough to press down it; The deficiency of YIN and firm anxious person, non-Radix Rehmanniae Preparata sweet, be not enough to slow it ".Ministerial drug is selected the Rhizoma Anemarrhenae for use, and clearing away heat-fire is nourshing Yin and drynsessmoistening prescription.The Cortex Lycii removing heat from blood moves back steaming, kind clearind deficient heat.This two flavors ministerial drug, clearing away heat and nourishing YIN, flat its wins partially to take stopgap measures.Adjuvant drug is selected the Chinese angelica blood supplementing nourishing the liver for use and is transferred to dash and appoint.Radix Codonopsis, the Radix Astragali are invigorating middle warmer consolidating superficial resistance again, and QI invigorating rises Tianjin Hang Shui, mend and appoint the sky congenital to support.The Herba Cistanches reinforcing the kidney and supporting YANG is mended and not dry." book on Chinese herbal medicine converges and says ": " support the gate of vitality, nourishing kidney gas, the medicine of replenishing vital essence and blood is also." the Herba Epimedii kidney invigorating and YANG supporting, share with Herba Cistanches, be among nourishing YIN, to be equipped with YANG invigorating, get " meaning for the treatment of YIN within YANG ".The Semen Ziziphi Spinosae Fructus Alpiniae Oxyphyllae of calming the nerves, the liver benefiting that nourishes blood, arresting sweating.The same usefulness of Six-element adjuvant drug, the heart, liver,spleen,kidney are with mending, and gas, blood, yin, yang are taken into account, and make the unlikely too bitter cold of the monarch and his subjects' nourishing YIN heat clearing away.Full side's medication based on tonifying kidney-yin, is played YIN nourishing and the merit of heat clearing away altogether.
We suit the theoretical and pharmacology of Chinese medical formulae theory of pathogen and pathology of tcm, select YAOJING good, and prescription is ingenious, and medical knowledge is profound, can be rated as effective good recipe for the treatment of climacteric syndrome.
More than nine the flavor Chinese medicines all should meet pertinent regulations under each medical material item of Chinese Pharmacopoeia version in 2000.
More than nine flavor Chinese medicines, medical material is through clean system, feeding intake with decoction pieces gets final product.
Radix Rehmanniae Preparata contains compositions such as catalpol, rehmanin, aucubin, rehmannioside and polysaccharide; The Rhizoma Anemarrhenae contains saponin component; Radix Codonopsis contains saponin, saccharide trace alkaloid and triterpenoid compound; Cortex Lycii contains betanin, saponin etc.; Radix Angelicae Sinensis contains volatile oil, ferulic acid, polysaccharide etc.; Herba Epimedii contains flavones ingredient; The Radix Astragali contains saponin, polysaccharide etc.; The Herba Cistanches alkaloid, boschnaloside etc.; Semen Ziziphi Spinosae contains flavonoid and triterpenes components.
(2) intend the extracting method take
From the physicochemical property of the above-mentioned medicine of respectively distinguishing the flavor of as can be seen, in the equal water soluble of most of flavour of a drug compositions, therefore, this process using water boiling and extraction technology.In the trial test process, the inventor notices that the employing decocting boils the method extraction, and is very big to the influence of the effective ingredient Herba Epimedii total flavones extraction ratio in the epimedium herb, therefore, the suitable concentration ethanol extraction adopted in the extraction of epimedium herb.
2, extraction process technology Study on Conditions
2.1 the selection of Herba Epimedii ethanol extraction condition
The present invention determines to influence four factors, i.e. A of Herba Epimedii ethanol extraction effect: extraction time; B: extraction time; C: alcohol adding amount; D: concentration of alcohol.And determined three levels for each factor in conjunction with practical situation, see Table 1.
Table 1, Herba Epimedii ethanol extraction condition are investigated the factor level table
On the investigation index of orthogonal test is determined, measure the Herba Epimedii total flavones extracted amount for investigating index, press L
9(3
4) orthogonal table tests, and changes influence to result of the test to investigate above four factor three levels.
(1) preparation of sample liquid
Precision takes by weighing Herba Epimedii 10g, presses table 1 condition reflux, extract, respectively, filters, and filtrate is flung to ethanol, adds ethyl acetate extraction 4 times, each 50ml, and evaporate to dryness behind the anhydrous sodium sulfate dehydration, residue adds dissolve with methanol, and is settled in the 25ml volumetric flask.
(2) mensuration of investigation index
The preparation precision of standard curve takes by weighing icariin 4mg, puts in the 25ml volumetric flask, adds dissolve with methanol and is diluted to scale.Draw 0.5,1.0,1.5,2.0 respectively, 2.5ml icariin reference substance solution, put in the 25ml volumetric flask, add dissolve with methanol and be diluted to scale.Measure its trap in the 267nm place, the calculating regression equation is Y=3.5010C-0.0087 (r=0.9987)
The accurate sample liquid 1ml that draws of sample determination puts in the 25ml volumetric flask, and the methanol dilution also is settled to scale.Draw this solution 1ml, put in the 25ml volumetric flask, the methanol dilution also is settled to scale.Press and measure its trap under the standard curve item, and calculate content.
(3) result of the test: orthogonal experiments sees Table 2, and variance analysis as a result sees Table 3.
Table 2, orthogonal experiments
Table 3, variance analysis
F
0.10(2，2)＝9.0；F
0.05(2，2)＝19.0；F
0.01(2，2)＝99.0
Find out that by table 2 each factor to the importance of result of the test is: D＞C＞A＞B.Table 3 ANOVA showed significant, concentration of alcohol, ethanol consumption and extraction time must have been measured appreciable impact to Herba Epimedii total flavones.According to the intuitive analysis result, best water extraction process should be A
3B
2C
3D
2, promptly Herba Epimedii is with 70% alcohol reflux 2 times, and each 1.5 hours, alcohol adding amount was 15 times.On this basis, the inventor has carried out the expansion of an amount of scope to extraction conditions, think that on a large amount of experiment basis Herba Epimedii adds 12-18 and doubly measures the 60-80% alcohol reflux 1-3 time, each 1-3 hour, merge extractive liquid,, filter, filtrate recycling ethanol also is evaporated to relative density 1.28～1.36 (80 ℃) thick paste and still can obtains ideal extraction effect, wherein preferred: Herba Epimedii adds 15 times of amount 70% alcohol reflux 2 times, each 1.5 hours, collecting decoction filters, and filtrate recycling ethanol also is evaporated to relative density 1.30～1.35 (80 ℃) thick paste.
(4) optimised process demonstration test
In order further to investigate above-mentioned selection process, the present invention adopts above-mentioned technology, prepares three duplicate samples liquid, and sample liquid and epimedium herb are measured content respectively, calculates the rate of transform of icariin.
The preparation of sample liquid: get epimedium herb 50g, with 70% alcohol reflux 2 times, each 1.5 hours, alcohol adding amount was 15 times.Merge extractive liquid, reclaims ethanol, and residue adds water and is settled to 100ml.This test triplicate.
Icariin assay in the sample liquid: accurate each sample liquid 2ml that draws, on the D that handled well
101(1.5cm * 10cm), water 200ml eluting discards water liquid to macroporous resin, reuse 70% ethanol 200ml eluting, collect eluent, evaporate to dryness, residue add methanol makes dissolving in right amount, quantitatively is transferred in the 50ml measuring bottle, add methanol to scale, shake up, promptly get need testing solution.Accurate respectively each the 10 μ l of reference substance solution (containing icariin 0.11mg among every 1ml) and need testing solution that draw inject chromatograph of liquid, measure peak area, calculate with external standard method, promptly.
Icariin assay in the epimedium herb: get the about 1g of epimedium herb powder (crossing 40 mesh sieves), the accurate title, decide, and puts in the 100ml tool plug conical flask, the accurate Diluted Alcohol 50ml that adds, close plug claims to decide weight, supersound process 1 hour, claim to decide weight again, supply the weight that subtracts mistake with Diluted Alcohol, shake up, filter, get subsequent filtrate, promptly get need testing solution.Accurate respectively each the 10 μ l of reference substance solution (containing icariin 0.11mg among every 1ml) and need testing solution that draw inject chromatograph of liquid, measure peak area, calculate with external standard method, promptly.
Three batch sample icariin rate of transform measurement results: as calculated, the rate of transform measurement result of three batch sample icariin sees Table 4.
The rate of transform measurement result of table 4, three batch sample icariin
The icariine rate of transform is 84.4% as a result, and it is more complete to illustrate that the extracting method that optimizes extracts, and extraction process is feasible.4.2.3.2 the selection of eight flavor medical material decocting conditions such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis, Cortex Lycii, Radix Angelicae Sinensis, the Radix Astragali
The present invention determines to influence three factors, i.e. A of extraction effect: each amount of water during decoction; B: decoct number of times; C: each decocting time, and determined three levels for each factor in conjunction with practical situation, see Table 5.
On the investigation index of orthogonal test was determined, astragaloside extracted amount and paste-forming rate were pressed L for investigating index in the decocting liquid
9(3
4) orthogonal table tests, and changes influence to result of the test to investigate above three factor levels.
(1) preparation of sample liquid
In prescription 1/10 ratio, accurately take by weighing eight flavor medical material (Radix Rehmanniae Preparata 35.7g, Rhizoma Anemarrhenae 11.4g, Radix Codonopsis 21.4g, Cortex Lycii 11.4g, Radix Angelicae Sinensis 21.4g, Radix Astragali 14.3g, Herba Cistanches 21.4g, Semen Ziziphi Spinosae 21.4g) totally 9 parts, extract operation by the listed condition of table 4, decocting boils, filter, merging filtrate is concentrated into 100ml (1.584g crude drug/ml) be sample liquid to make 9 duplicate samples liquid.
(2) mensuration of investigation index
The mensuration of paste-forming rate: accurate each sample liquid 20ml that draws, to the evaporating dish of having weighed, water bath method according to dry weight-loss method (appendix of Chinese Pharmacopoeia version in 2000) gravimetry, calculates paste-forming rate.
Astragaloside content is measured: the accurate respectively extracting solution of drawing 20ml, extract (30,30,30ml) 3 times with the water-saturated n-butanol jolting, merge n-butanol extracting liquid, extract (30,30ml) 2 times with ammonia solution, discard ammoniacal liquor, n-butyl alcohol liquid evaporate to dryness, residue add water 5ml makes dissolving, puts cold, by D101 macroporous adsorptive resins (internal diameter 1.5cm, long 12cm), with water 100ml eluting, discard water liquid.Reuse 40% ethanol 80ml eluting discards 40% ethanol elution, continues with 70% ethanol 100ml eluting, collects eluent, and evaporate to dryness with dissolve with methanol and be transferred in the 2ml measuring bottle, adds methanol and is diluted to scale, shakes up, as need testing solution.Other gets the astragaloside reference substance, adds methanol and makes the solution that 1ml contains 0.76mg, in contrast product solution.Test according to thin layer chromatography (an appendix VI of Chinese Pharmacopoeia version in 2000 B), draw need testing solution 5 μ l, reference substance solution 2 μ l, 5 μ l, put respectively on same silica gel g thin-layer plate, lower floor's solution with chloroform-methanol-water (13: 6: 2) (place below 10 ℃ and spend the night) is developing solvent, launch, take out, dry, spray is with 10% ethanol solution of sulfuric acid, about 5～7 minutes of 100 ℃ of bakings, to clear spot, take out, on lamellae, cover onesize glass plate, use immobilization with adhesive tape on every side, (an appendix VI of Chinese Pharmacopoeia version in 2000 B) scans according to thin layer chromatography, wavelength X S=500nm, λ R=700nm measures test sample trap integrated value and reference substance trap integrated value, calculates content.
(3) result of the test: orthogonal experiments sees Table 6,8, and variance analysis as a result sees Table 7,9.
Table 5, decocting method extract medical material and investigate the factor level table
Table 6, orthogonal experiments (serves as to investigate index with the astragaloside extracted amount)
Table 7, variance analysis (serves as to investigate index with the astragaloside extracted amount)
F
0.10(2，2)＝9.0；F
0.05(2，2)＝19.0；F
0.01(2，2)＝99.0
Table 8, orthogonal experiments (is to investigate index with the paste-forming rate)
F
0.10(2，2)＝9.0；F
0.05(2，2)＝19.0；F
0.01(2，2)＝99.0
(4) brief summary
Above-mentioned The results of analysis of variance shows: with the astragaloside extracted amount serves as to investigate index, factor A (amount of water) has significant difference (P＜0.05), factor B (extraction time) there was no significant difference (P＞0.05), factor C (extraction time) has significant difference (P＜0.01), according to the intuitive analysis result, best water extraction process should be A
3B
3C
3
With the paste-forming rate is to investigate index, factor A (amount of water) there was no significant difference (P＞0.05), factor B (extraction time) there was no significant difference (P＞0.05), factor C (extraction time) have significant difference (P＞0.05), according to the intuitive analysis result, best water extraction process should be A
3B
3C
3
Comprehensive above-mentioned two aspect results, best water extraction process should be A
3B
3C
3, consider factor B (extraction time) there was no significant difference, be energy savings, extraction time B
3Be adjusted into B
1, be A
3B
1C
3Just decocting boils three times, and each amount of water is 10 times, and each decocting time is 1 hour.On the basis of this optimised process, the inventor has carried out the expansion of an amount of scope to extraction conditions, after having carried out sufficient experimental verification, think that eight flavor medicines such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis add 8-12 medical material water gaging and decoct 2-5 time, each 0.5-2 hour, collecting decoction filters, and filtrate is concentrated into relative density 1.28～1.36 (80 ℃) thick paste all can reach the optimum extraction effect.Preferred especially; Eight flavor medicines such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis add 10 times of medical material water gagings and decoct 3 times, and each 1 hour, collecting decoction filtered, and filtrate is concentrated into relative density 1.30～1.35 (80 ℃) thick paste.
(5) investigation of medical material decocting paste-forming rate
In order to understand the paste-forming rate after eight flavor medical materials such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis extract by this preparation technology, the present invention gets the medical material of 2 times of except that Herba Epimedii recipe quantities, decoct extraction, filtration, drying under reduced pressure, weigh by determined extraction conditions, the paste-forming rate of examination decocting part medical material the results are shown in Table 10.
Eight flavor medical material decoctings such as table 10, Radix Rehmanniae, the Rhizoma Anemarrhenae, Radix Codonopsis boil paste-forming rate examination result
5 separate, concentrate and drying process research
1. filter method: decompression (or pressurization) filters, and it is filter material that filtration the present invention of medicinal residues and extracting solution selects 200 order nylon screens for use.
2. method for concentration: the present invention all adopts low, the fireballing concentrating under reduced pressure method of temperature.
Concentrating degree: for the concentrating degree before dry, the principle that the present invention holds is the maximum relative density when concentrated solution can be emitted from concentration tank smoothly, is 1.28-1.36 after measured, preferred 1.30～1.35 (80 ℃).
3. the selection of drying means:
It is 1.28-1.36 that medicinal liquid is concentrated into relative density, the thick paste of preferred 1.30～1.35 (80 ℃), hypobaric drying method (60～70 ℃) preparation dried cream powder.The drying under reduced pressure that the present invention selects for use present most of manufacturing enterprise to have ready conditions and carry out, and control temperature be no more than 70 ℃, be lower than temperature in the medicinal material extract process, thus can make be dried thing in this process composition can because of the drying not destroyed.
6 preparations shaping Journal of Sex Researchs
6.1 adjuvant is selected and the investigation of addition
With the medical material water boiling and extraction, concentrate behind the clear paste, add appropriate amount of auxiliary materials, drying under reduced pressure.Described adjuvant can be starch, dextrin, lactose, Carboxymethyl cellulose sodium, micropowder silica gel, stearate or Pulvis Talci.Yin Ben prescription Chinese medicine (not have too bitter flavour of a drug) and be the characteristics of being grown up and taking needn't add correctives.Take every day guaranteeing nondecreasing while of crude drug amount, in order to make taking dose the least possible, with granule character, melting and the stability (plastic bag packaging is placed a month moisture absorption situation at ambient temperature) of making the granule complexity, make is index, investigates the problem that clear paste adds the adjuvant amount.Getting 3 parts of 5 times of recipe quantity medical materials respectively, by above-mentioned definite extraction process preparation three parts of clear paste (relative density is 1.30～1.35,80 ℃ of surveys), is example with the dextrin, adds the dextrin of different proportion, and drying under reduced pressure is ground into fine powder, wet granulation, and the investigation situation is as follows.
The investigation result of table 11, adjuvant dextrin addition
* room temperature condition: 20～25 ℃ of temperature, relative humidity 60～70%
Investigation is the result show, (2), (3) condition all can be made qualified sugar type granules, be that each recipe quantity adds 320～360g dextrin and get final product, so the present invention considers the factor of preparation specification, the quantity of each recipe quantity adding adjuvant dextrin is defined as 340g.The addition of other adjuvants also can be with reference to dextrin.
6.2 the selection of method of granulating
One is to be concentrated into the clear paste of certain density after the medicinal material extract for the preparation of Chinese medicine granules, adds adjuvant (as dextrin, starch etc.), mixes wet method or dry granulation thoroughly.Because it is consistent that the density of clear paste is difficult to control, influences supplementary product consumption and method of granulating, also make in the finished product every gram granule contain the crude drug amount and differ greatly.Therefore, the present invention adds appropriate amount of auxiliary materials and drying under reduced pressure and becomes dried cream after extracting solution is concentrated, and is ground into fine powder, makes granule.
Adopt 85% ethanol, 95% ethanol and dehydrated alcohol to carry out wet method system granule in the test respectively as wetting agent.Investigate the granule situation that makes of said method from granulation complexity, degree of dissolving, granularity, grain color several respects, the results are shown in Table 12.
Table 12, granulating process comparative test result
Result of the test shows that 95% ethanol system granule effect is better, so the present invention adopts 95% ethanol system granule.
Adopt technique scheme, the present invention compared with prior art has following beneficial effect:
(1) Chinese medicine composition prescription provided by the present invention is scientific and reasonable, and the flavor of 9 in prescription crude drug is not only simple stack, and every medical material drug effect complements each other, and strengthens its curative effect greatly, safe without toxic side effect;
(2) preparation method of Chinese medicine composition provided by the present invention is simple, and the active constituent content height is fit to large-scale production.
Description of drawings
Fig. 1 is the process chart of preparation method of the present invention
The specific embodiment
Below in conjunction with embodiment the present invention is described in more detail.But embodiment is described the preferred embodiments of the present invention; be not that design of the present invention and scope are limited; under the prerequisite that does not break away from design philosophy of the present invention; the various changes and modifications that the professional and technical personnel makes technical scheme of the present invention in this area all belong to protection scope of the present invention.
Embodiment 1 granule
Clean Radix Rehmanniae Preparata 357g, Rhizoma Anemarrhenae 114g, Radix Codonopsis 214g, Cortex Lycii 114g, Radix Angelicae Sinensis 214g, Herba Epimedii 114g, Radix Astragali 143g, Herba Cistanches 214g, Semen Ziziphi Spinosae 214g standby.
Herba Epimedii adds 15 times of amount 70% alcohol reflux 2 times, each 1.5 hours.Merge extractive liquid, filters, and filtrate recycling ethanol also is evaporated to relative density 1.30～1.35 (80 ℃) thick paste;
Eight flavor medicines such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis add 10 times of medical material water gagings and decoct 3 times, and each 1 hour, collecting decoction filtered, and filtrate is concentrated into relative density 1.30～1.35 (80 ℃) thick paste.
With Herba Epimedii ethanol extraction thick paste mix with liquid medicine decocting to thick ointment such as Radix Rehmanniae Preparata extract extractum.
In extract extractum, add an amount of micropowder silica gel, mixing, drying under reduced pressure (60-80 ℃) is ground into fine powder, makes granule 1000g, is packaged into 100 bags, every bag of 10g.
Embodiment 2 granules
Clean Radix Rehmanniae Preparata 330g, Rhizoma Anemarrhenae 85g, Radix Codonopsis 185g, Cortex Lycii 85g, Radix Angelicae Sinensis 185g, Herba Epimedii 85g, Radix Astragali 115g, Herba Cistanches 185g, Semen Ziziphi Spinosae 185g standby.
Herba Epimedii adds 12-18 and doubly measures 60% alcohol reflux 3 times, and each 3 hours, merge extractive liquid, filtered, and filtrate recycling ethanol also is evaporated to relative density 1.28～1.33 (80 ℃) thick paste.
Eight flavor medicines such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis add 8 medical material water gagings and decoct 2 times, and each 2 hours, collecting decoction filtered, and filtrate is concentrated into relative density 1.28～1.33 (80 ℃) thick paste.
With Herba Epimedii ethanol extraction thick paste mix with liquid medicine decocting to thick ointment such as Radix Rehmanniae Preparata extract extractum.
In extract extractum, add an amount of dextrin, mixing, drying under reduced pressure (60-80 ℃) is ground into fine powder, makes granule 1000g, is packaged into 100 bags, every bag of 10g.
Embodiment 3 tablets
Clean Radix Rehmanniae Preparata 390g, Rhizoma Anemarrhenae 145g, Radix Codonopsis 245g, Cortex Lycii 145g, Radix Angelicae Sinensis 245g, Herba Epimedii 145g, Radix Astragali 175g, Herba Cistanches 245g, Semen Ziziphi Spinosae 245g standby.
Herba Epimedii adds 18 times of amount 80% alcohol reflux 3 times, and each 3 hours, merge extractive liquid, filtered, and filtrate recycling ethanol also is evaporated to relative density 1.30～1.35 (80 ℃) thick paste.
Eight flavor medicines such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis add 12 medical material water gagings and decoct 5 times, and each 2 hours, collecting decoction filtered, and filtrate is concentrated into relative density 1.30～1.35 (80 ℃) thick paste.
With Herba Epimedii ethanol extraction thick paste mix with liquid medicine decocting to thick ointment such as Radix Rehmanniae Preparata extract extractum.
Add appropriate amount of starch in extract extractum, fully mixing is put 55-65 ℃ of drying and crushing; Add appropriate amount of starch and disintegrating agent carboxymethyl base Starch Sodium, mixing, granulation, drying add moderate lubrication agent magnesium stearate again, and mixing is pressed into 1000 in tablet, and packing is promptly.
Embodiment 4 capsules
Clean Radix Rehmanniae Preparata 345g, Rhizoma Anemarrhenae 100g, Radix Codonopsis 200g, Cortex Lycii 100g, Radix Angelicae Sinensis 200g, Herba Epimedii 100g, Radix Astragali 130g, Herba Cistanches 200g, Semen Ziziphi Spinosae 200g standby.
Herba Epimedii adds 12-18 and doubly measures 70% alcohol reflux 2 times, and each 2.5 hours, merge extractive liquid, filtered, and filtrate recycling ethanol also is evaporated to relative density 1.33～1.36 (80 ℃) thick paste.
Eight flavor medicines such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis add 10 medical material water gagings and decoct 4 times, and each 1.5 hours, collecting decoction filtered, and filtrate is concentrated into relative density 1.33～1.36 (80 ℃) thick paste.
With Herba Epimedii ethanol extraction thick paste mix with liquid medicine decocting to thick ointment such as Radix Rehmanniae Preparata extract extractum.
In extract extractum, add appropriate amount of starch, stir, pulverize behind the vacuum drying, sieve, granulate, drying, fill becomes 1000 of capsules, and packing is promptly.
Embodiment 5 capsules
Clean Radix Rehmanniae Preparata 375g, Rhizoma Anemarrhenae 130g, Radix Codonopsis 230g, Cortex Lycii 130g, Radix Angelicae Sinensis 230g, Herba Epimedii 130g, Radix Astragali 160g, Herba Cistanches 230g, Semen Ziziphi Spinosae 230g standby.
Herba Epimedii adds 12 times of amount 80% alcohol reflux 1 time, and each 3 hours, merge extractive liquid, filtered, and filtrate recycling ethanol also is evaporated to relative density 1.30～1.35 (80 ℃) thick paste.
Eight flavor medicines such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis add 12 medical material water gagings and decoct 3 times, and each 1 hour, collecting decoction filtered, and filtrate is concentrated into relative density 1.30～1.35 (80 ℃) thick paste.
With Herba Epimedii ethanol extraction thick paste mix with liquid medicine decocting to thick ointment such as Radix Rehmanniae Preparata extract extractum.In extract extractum, add an amount of dextrin, stir, pulverize behind the vacuum drying, sieve, granulate, drying, fill becomes 1000 of capsules, and packing is promptly.
In order to verify Chinese medicine composition of the present invention to the application on the treatment climacteric syndrome, the inventor has further done a large amount of toxicity and pharmacodynamics test with the embodiment of the invention 1 described granule, the results are shown in the routine 1-3 of test.
The acute toxicity test research of test example 1 embodiment of the invention 1:
One, experiment purpose:
This experimental observation mice is repeatedly irritated stomach and gives the embodiment of the invention 1 acute toxic reaction and death condition that the back is produced in one day, for main pharmacodynamics is studied and long term toxicity test provides scientific and reliable dosage foundation.
Two, experiment material:
Medicine: the embodiment of the invention 1, be the dark-brown powder, every gram contains crude drug 2.57 grams.Time spent is made into the suspension of desired concn with distilled water.
Animal: Kunming mouse, 20～22g, female, available from high-new medical experiment zooscopy center, Changchun.The quality certification number: SCXK-(Ji) 2003-0004.
Three, experimental technique and result
1. maximum dosage-feeding of mice is measured
Get 10 of female mices, hungry 16 hours, 40ml/kg irritated stomach and gives 60% embodiment 1 suspension, mice state after the observation administration, mortality rate in the week.Activity reduces after found that the mice administration, accelerated breathing, and it is motionless to crawl, and stool colour is deepened, and rare slightly, tail vein pipe color is normal, and eye, nose are not seen secretions, recover normally in second day after the administration, feed is normal.Do not have dead in one week.
2. maximum tolerance determination in the mice one day
Because Cmax (60%) in the mice one day, maximum volume (40%) are once irritated stomach and given embodiment and do not have deadly in 1, one week, can't measure median lethal dose(LD 50), therefore survey gastric infusion maximum tolerated dose in the mice one day.
Get 30 of female mices, hungry 16 hours, irritate stomach by 40ml/kg and give administration secondary in 60% embodiment 1, a day, 6 hours at interval, observe mice state after the administration, mortality rate in the week.Activity reduces after found that the mice administration, accelerated breathing, and it is motionless to crawl, stool colour intensification, rare slightly, tail vein pipe color is normal, and eye, nose are not seen secretions, recover normally in second day after the administration, and feed is normally.Do not have dead in one week.The administration cumulative volume is 80ml/kg in one day, and the administration total amount is a 48g/kg (123.5g crude drug/kg).
Four, conclusion
Mice is once irritated stomach by 40ml/kg and gives embodiment 124g/kg (61.7g crude drug/kg), do not have dead in the week.
Maximum volume (40ml/kg) in the mice one day, Cmax (60%), the secondary gastric infusion, mice does not see the overt toxicity reaction, do not have dead in one week, the administration cumulative volume is 80ml/kg in one day, and the administration total amount is a 48g/kg (123.5g crude drug/kg), be 255 times (people presses 70kg and calculates) of a clinical consumption per day.Show that embodiment 1 toxicity is very low.
The rat long term toxicity test of test example 2 embodiment of the invention 1
Experiment material
The animal strain: the Wistar rat, 80～100g, female.High-new medical animal experiment research center, Changchun provides, and the animal quality certification number is: the lucky moving full word: SCXK-(Ji) 2003-0004.
The care of animal condition: (1) feedstuff: the experimental animal full-valence pellet feed, high-new medical animal experiment research center, Changchun provides.(2) management: animal is bought the back and begin experiment after experimental animal observation ward in Jilin Prov. Inst. of Chinese Medicine and Chinese Medical Science adapts to a week.Condition is: ventilates, and 20～23 ℃ of temperature, humidity 40～45%, the cage tool is sterilized weekly once, regularly feeding feedwater.
Be subjected to reagent thing: embodiment 1 to be the dark-brown powder, every gram contains crude drug 2.57 grams, for not containing excipient dry powder before granulating, faces the time spent to be made into the suspension of desired concn with distilled water, and gastric infusion, matched group give with volume distilled water (30ml/kg).
Measure reagent: all serum biochemistries are learned to measure and are all used test kit, Beijing Zhongsheng Biological Engineering High Technology Company's product.
Instrument: automatic clinical chemistry analyzer, Olympus 2700 types; Blood counting instrument, U.S. Coulter Corporation product; Paracetamol moral BV-100 type hemorheology instrument, Beijing paracetamol moral Institute for New Technologies; Electronic balance, Beijing Sai Duolisi balance company limited.
Test method
The dosage of embodiment 1: median lethal dose(LD 50) is not measured in the administration of this product mouse stomach, maximum tolerated dose is a 48g/kg (123.5g crude drug/kg), the pharmacodynamics effective dosage ranges is 5g/kg～1.25g/kg, drafting clinical practice per 1 course of treatment is 1 month, take 1～3 course of treatment by state of an illness weight, restriction determines that the rat long term toxicity test cycle was 26 weeks according to above-mentioned condition and drug level, and dosage is 16g/kg, 8g/kg, 4g/kg (three dosage groups of 41.2g crude drug/kg, 20.6g crude drug/kg, 10.3g crude drug/kg).
Animal grouping: get 160 of big female Mus, be divided into four groups at random, 40 every group, be respectively matched group (30ml/kg distilled water), high dose group (16g/kg), middle dosage group (8g/kg), low dose group (4g/kg).
Medication: gastric infusion.In June, 2003～2004 year January, irritate stomach once every day by above-mentioned dosage, administration is 6 days weekly, and in continuous 26 weeks, matched group gives with volume distilled water (30ml/kg).
Sample time: during 13 weeks, each group is put to death 10 animals in administration, and every index determining is made in sampling, and all the other animals continue administration.Each organizes 20 animals of execution during 26 weeks in administration, and every index determining is made in sampling.All the other animals stop administration, under equal conditions continue to raise 2 each group of all backs and put to death 10 animals, observe the recovery situation of every index.
Inspection item: (1) one observation: during whole test, observe and write down the variation of behavior, outward appearance activity and the defecation of animal at any time; Record food-intake, amount of drinking water.(2) body weight: weigh once weekly, and adjust dosage according to body weight.(3) blood routine examination: comprise erythrocyte (RBC), leukocyte (WBC), hemoglobin (Hb), platelet (PLT) and clotting time.Other gets blood smear, and is fixing, dyeing, meter leukocyte classification under optical microscope.(4) blood biochemical is learned and is checked: comprise aspartic acid aminotransferase (AST), ALT (ALT), alkali phosphatase (ALP), total protein (TP), albumin (ALB), blood urea nitrogen (BUN), T-CHOL (TCHO), blood glucose (GLU), creatinine (Crea), total bilirubin (TBIL).(5) to the inspection of major organs weight: different time behind the rat successive administration, win main organs such as brain, the heart, liver, spleen, lung, kidney, adrenal gland, thymus, thyroid, uterus+ovary and weigh, observe its weight change situation.(6) system's postmortem and histopathological examination: system's postmortem: administration finishes back 24 hours, and the sacrificed by exsanguination animal performs an autopsy on sb immediately, its situation of change of perusal.Microscopy: after the postmortem, get linked groups's organ and put into and give ready Bao Shi liquid earlier, through embedding, section, fixing and dyeing.Examine under a microscope pathological change, histoorgan to be checked comprises: brain, the heart, liver, spleen, lung, kidney, stomach, duodenum, colon, ileum, rectum, pancreas, adrenal gland, thyroid, thymus, hypophysis, optic nerve, oblongata, breastbone, bladder, lymph node, ovary, uterus.
Experimental result
1. one situation: rat oral gavage gives embodiment 126 weeks, heavy dose of group (16g/kg) rat, and hair color gloss is relatively poor, and stool colour is darker, and all the other do not see obvious change.Other dosage group ANOMALOUS VARIATIONS such as sight, behavioral activity of not regarding sb. as an outsider.
To growth, ingest and the influence of amount of drinking water: after the continuous irrigation stomach gave embodiment 1, heavy dose of group rat body weight increased and obviously slows down, and comparing with matched group, there are notable difference in the 5th～8 week, 19～20 weeks after administration.In, low dose group is similar substantially with matched group.It is approaching that each organizes food-intake.The high dose group water yield is more.Drug withdrawal 2 all high dose group body weight gains are obviously accelerated.
3. to the influence of routine blood test: continuous 26 weeks of rat irritate stomaches and give embodiment 1, RBC, Hb, WBC, PLT each period of administration all in normal range, leukocyte differential count and clotting time have no significant change, drug withdrawal does not have significant change after 2 weeks yet, shows that the peripheral hemogram that long-term filling stomach gives 1 pair of rat of embodiment does not have obvious influence.
4. serum biochemistry is learned the influence of every index: after rat continuous irrigation stomach gives embodiment 1, learn every detection index at administration serum biochemistry in each in period and all do not have obvious change, 2 weeks were not seen any change yet after the drug withdrawal, and the result shows: irritate stomach for a long time and give the biochemical every index of 1 pair of rat blood serum of embodiment and do not have obvious influence.
5. to the influence of major organs weight: rat continuous irrigation stomach gives embodiment 126 weeks, administration is respectively organized each organ coefficient and relatively have no significant change with matched group each period, 2 weeks of drug withdrawal do not have obvious change yet, the result shows, irritates stomach for a long time and gives 1 pair of rat of embodiment rat main organs weight is not had obvious influence.
6. system's postmortem and histopathological examination: 1. system's postmortem: naked eyes check that to main organs matched group, the equal Non Apparent Abnormality of high, medium and low dosage group change.2. to the influence of organ-tissue pathomorphism: rat oral gavage gives 113 weeks of embodiment and 26 all matched groups and each administration group part animal interstitial lung there are cell infiltration (13 weeks of successive administration: 2 of matched groups, 2 of high dose group, 2 of middle dosage groups, 2 of low dose group; 26 weeks of successive administration: 4 of matched groups, 4 of high dose group, 3 of middle dosage groups, 4 of low dose group), be similar to because probability appears in each group, and be lower than 20%, therefore being judged as animal produces inflammation, non-drug-induced naturally.Other organizes each dosage group of matched group and administration and does not see obvious pathological change, does not see drug-induced toxicity, drug withdrawal after one month all internal organs pathological examination results all normal.
Above-mentioned result of the test shows that continuous 26 weeks of rat irritate stomach and give embodiment 1, and heavy dose of treated animal body weight gain obviously slows down, food-intake has minimizing more slightly with matched group, amount of drinking water has increase trend, and showing that body weight slows down may to organize drug level bigger with heavy dose, and the absorption that influences food is relevant; The amount of drinking water increase may be pressed 30ml/kg for matched group and be irritated the stomach feedwater, and high dose group is irritated the medicine that stomach gives high concentration, irritates the stomach confluent and reduce for matched group, and therefore natural water uptake increases; All other index Non Apparent Abnormalities of high dose group change.In, every indexs such as the behavior of low dose group outward appearance, body weight gain, routine blood test, serum biochemistry, main organs weight, histopathological examination are with the relatively equal no significant difference of matched group, do not see drug-induced any abnormal change.
In sum, embodiment 1 heavy dose (16g/kg), middle dosage group (8g/kg), low dose group (4g/kg) continuous 26 all gastric infusions do not have the overt toxicity reaction to rat, high, medium and low dosage group is equivalent to clinical plan 84.8 times, 42.4 times, 21.2 times with dosage (people presses 70kg and calculates) respectively, show that said preparation toxicity is very low, clinical practice is safer.
The pharmacodynamic study of test example 3 embodiment of the invention 1
Be subjected to the reagent thing:
1, embodiment 1, and dark-brown powder, every gram contain crude drug 2.57 grams, for not containing excipient dry powder before granulating;
2, GENGNIANAN capsule Tonghua Jinhui Pharmaceutical Co., Ltd. product, authentication code: the accurate word Z22020683 of traditional Chinese medicines, lot number: 20030218.Facing the time spent is made into the desired concn suspension with distilled water, equal gastric infusions,
3, matched group gives same volume (20ml/kg) water.
4, be Radix Rehmanniae Preparata 395g, Rhizoma Anemarrhenae 78g, Radix Codonopsis 235g, Cortex Lycii 80g, Radix Angelicae Sinensis 180g, Herba Epimedii 124g, Radix Astragali 100g, Herba Cistanches 255g, Semen Ziziphi Spinosae 224g with the A prescription, do not contain excipient dry powder before the granulation according to embodiment 1 described method preparation, every gram contains crude drug 2.61g;
5, be Radix Rehmanniae Preparata 357g, Radix Scrophulariae 114g, ditch rattan 214g, Cortex Lycii 114g, Radix Angelicae Sinensis 214g, Herba Epimedii 114g, Fructus Schisandrae Chinensis 143g, Radix Polygoni Multiflori 214g, Semen Ziziphi Spinosae 214g with the B prescription, do not contain excipient dry powder before the granulation according to embodiment 1 described method preparation, every gram contains crude drug 2.53g;
Reagent: 5-HT, 5-HIAA, Sigma company; Noradrenaline bitartrate injection, dopamine hydrochloride inj Shanghai Hefeng Pharmaceutical Co., Ltd. product; Pentobarbital sodium, Beijing chemical reagent factory product; E2, LH, FSH, PRL radioimmunological kit, U.S. beckman company produces; Other reagent is homemade analytical reagent.
Instrument: spectrofluorophotometer, model: the RF-540 type, Japanese Shimadzu Corporation produces; Chemiluminescence Apparatus, U.S. beckman company produces; Multi-functional mice autonomic activities instrument, the YLS-1A type, produce in equipment station, the Academy of Medical Sciences, Shandong; Computer numeral formula clinical thermometer, Omron (Dalian) company product; Electronic balance, Beijing Sai Duolisi balance company limited product.
Animal: Kunming mouse 25～30g, wistar rat 160～170g, female, available from Changchun High-technology Medical Animal Experiment Research Center, the quality certification number: SCXK-(Ji) 2003.
Experimental technique
One, " climacteric " rat model
1. model copy
Method according to prior art is set up model: rat is with 3% chloral hydrate intraperitoneal injection of anesthesia, the abdomen position is fixed, on midaxillary line under the most last rib, approximately apart from spinal column 2cm place, cropping, cut skin and dorsal muscles, press from both sides out ovary, fractionation of fatty group, salpingotomy bilateral ovaries under the ligation ovary, postoperative pursued and only carries out vaginal smear examination on the 4.5th, 6.7th, and is complete to determine ovariectomy, and postoperative was chosen anestrus variation rat on the 7th day and is divided into five groups at random.Each organizes the hot Chinese medicine of rats gavaged (Radix Aconiti Lateralis Preparata: Rhizoma Zingiberis=decocting made 50% in 1: 1) 20ml/kg, once a day, and continuous 14 days.
2. grouping and administration
Rat is divided into 8 groups at random, the normal control group is implemented sham-operation, irritate stomach and give the consubstantiality distilled water, all the other 7 groups (castrations) are respectively model control group (20ml/kg water), GENGNIANAN capsule 1.2g/kg (clinical equivalent dosage 5 times), embodiment 15g/kg, 2.5g/kg, 1.25g/kg (be respectively clinical equivalent dosage 4.2 times, 2.1 times, 1 times), the A 1.25g/kg that writes out a prescription, the B 1.25g/kg that writes out a prescription, each is organized rat and gives hot Chinese medicine respectively at last and irritate stomach after 1 hour and give said medicine, continuous once a day 10 days.
3. detection index
3.1. the vaginal epithelial cell keratinization detects
Respectively organized rat in 1 hour after the last administration and do vaginal smear, 95% ethanol is fixed, and pap staining, mirror are observed the keratinization degree down, and wherein dyeing is the cell of blue color, is keratinocyte not; Dyeing is middle low layer keratinization for green cell; Dyeing has a nuclear squamous cell for red, is the top layer keratinization; Dyeing is red seedless polygon squamous epithelial cancer, for crossing keratinization.With middle low layer keratinization, top layer keratinization, cross keratinization and be decided to be keratinocyte, mirror is keratinocyte and the shared percent of keratinocyte not in 100 epithelial cells of numeration down.
3.2. anus temperature measurement
Rat was measured rat rectal temperature (probe gos deep into the about 3cm of anus) in 1 hour behind 4,6,8,10 days the medicine after being subjected to the reagent thing, with rectum " ℃ " temperature is as the rectal temperature of rat.
3.3. uterus weight is measured
Behind the sacrifice of animal, cut open the belly immediately and win the uterus, claim weight in wet base with electronic balance, the result shows (mg/g) with the uterus weight numerical table of every g body weight
Two, mice castration model
1. model copy
The mice etherization cuts skin of back, peels off flesh layer and fat, and the excision bilateral ovaries was raised 9 days, and 5,7,9 days vaginal smears of postoperative are got oophorectomize and do not had the mice that emotionally changes fully and be used for testing.
2. grouping and administration
Mice is divided into 8 groups at random, the normal control group is implemented sham-operation, all the other 7 groups are respectively model control group (20ml/kg water), GENGNIANAN capsule 1.5g/kg (clinical equivalent dosage 4.2 times), embodiment 16g/kg, 3g/kg, 1.5g/kg (be respectively clinical equivalent dosage 3.5 times, 1.8 times, 0.9 times), the A 1.25g/kg that writes out a prescription, the B 1.25g/kg that writes out a prescription, each organize mice respectively at castration after 9～18 day every day irritated the stomach one-time continuous 10 days.Matched group gives same volume (20ml/kg) water.
3. detect
3.1. autonomic activities
Mice put into the movable number of times of multi-functional mice autonomic activities instrument record 10min in 1 hour after the last administration.
3.2 synergism to the threshold dose pentobarbital sodium
Respectively organize mouse peritoneal injection 40mg/kg pentobarbital sodium (threshold dose) in 1 hour after the last administration, observe 15min righting reflex loss mice number of elements, calculate the sleep rate.
Experimental result
1. " climacteric " rat model moulding result
The vagina epithelium keratinocyte obviously reduces after the rat moulding, keratinocyte showed increased not, and the anus temperature obviously raises, E in the serum
2Content obviously reduces, LH, FSH, PRL content obviously increase, uterus weight obviously alleviates, monoamine neurotransmitter NE level obviously reduces in the hypothalamus, 5-HT, 5-HIAA level obviously increase, and 5-HT/NE ratio obviously improves, and the anus temperature obviously improves, show in serum gonadal hormone and the hypothalamus that neurotransmitter levels is obviously disorderly, climacteric model obviously form.
2. the influence of 1 pair of " climacteric " rat anus of embodiment temperature the results are shown in Table 13.
Table 13. embodiment 1 is to " the influence of hot flushes in rats anus temperature
With the model matched group relatively: * P＜0.05, * * P＜0.01.
Table 13 result as seen, castration and give hot Chinese medicine after the model group rat temperature obviously increase, be subjected to the obviously reduction of anus temperature that different time administration group rat raises behind the reagent thing, after the administration 2 groups of coolings of 8 days 5g/kg embodiment 1 and 1.2g/kg GENGNIANAN capsule obviously, 10 days 5～1.25g/kg embodiment 1 and 1.2g/kg GENGNIANAN capsule all have the obvious cooling effect for 4 groups after the administration.
3. the influence of 1 pair of " climacteric " rat uterus weight of embodiment and uterus keratinization degree the results are shown in Table 14.
Table 14. embodiment 1 is to the influence of " climacteric " rat uterus weight and keratinization degree
With the model matched group relatively: * P＜0.05, * * P＜0.01.
The result shows that the uterus weight that the continuous gastric infusion of embodiment 15～1.25g/kg and GENGNIANAN capsule 1.2g/kg can make rat model alleviate in 14 days obviously increases, and obviously increases vaginal epithelial cell keratinization degree.
4. the influence of 1 pair of castration mouse autonomic activities of embodiment the results are shown in Table 15
The influence of 1 pair of castration mouse autonomic activities of table 15. embodiment
With the model matched group relatively: * P＜0.05.x ± S
The result shows that embodiment 16g/kg, 3g/kg and GENGNIANAN capsule 1.5g/kg can obviously reduce castration mouse autonomic activities number of times.
5. the synergistic result of 1 pair of castration mouse threshold dose of embodiment pentobarbital sodium sees Table 16.
The synergism of 1 pair of castration mouse sub-threshold dose of table 16. embodiment pentobarbital sodium
With the model matched group relatively
The result shows that embodiment 16g/kg, 3g/kg and GENGNIANAN capsule 1.5g/kg can obviously improve threshold dose pentobarbital sodium mice sleep rate.
Above-mentioned results of pharmacodynamic test also shows, on basis of the present invention, change the weight proportion (prescription A) of 9 flavor medical materials in the prescription, there is very big influence in therapeutic effect to medicine, in addition, according to weight proportion of the present invention, four medical materials in the prescription are changed into other medical materials (prescription B) that have same or similar drug effect in the prior art, also can't obtain the technique effect identical or close with the present invention, thereby further verified the science of the present invention's prescription, reasonability has guaranteed its effectiveness clinically.
The women enters into the climacteric period, because hypo-ovaria, hypothalamic-pituitary-ovarian axis (gonad axis) dysequilibrium, the disorder of reproductive endocrine system sex hormones secretion, ovary weakens the stress ability of promoting sexual gland hormone, and excretory estrogen reduces significantly, feedback cause hypothalamus, hypophysis hypersecretion, gonadotrophin secretion is too much, causes autonomic nervous dysfunction, and then various plants neurological disorders symptoms such as hectic fever, hyperhidrosis, dysphoria, insomnia occur.
Castration+gavage method simulating human climacteric of hot Chinese medicine is adopted in this test, the result as seen, estrogen level obviously reduces in the rat model serum, follicle stimulating hormone, lutropin, lactotropin level obviously increase, uterus weight obviously reduces, the keratinization degree obviously reduces, and shows that reproductive endocrine system is disorderly.Monoamine neurotransmitter noradrenaline cellulose content obviously reduces in the hypothalamus, serotonin, pentahydroxy-indoleacetic acid content obviously increase, 5-HT/NE ratio obviously increases, show that normal monoamine transmitters balance is broken in the hypothalamus, rat anus temperature obviously increases and shows that " interior-heat " symptom occurs.The continuous gastric infusion of embodiment 15～2.5g/kg 14 days, can obviously reduce rat model priatin FSH, LH, PRL content, the serum estrogen content there is certain increase effect, simultaneously can obviously increase the rat model uterus weight, obviously increase uterine epithelial cell keratinization degree, show that its reproductive endocrine system to " climacteric " rat disorder has tangible forward regulating action, simultaneously can directly act on the uterus, the uterus there is direct Nutrition, reduces the atrophy ager process in uterus; The anus temperature that animal pattern is raise has tangible reduction effect, shows that it has the obvious suppression effect to climacteric syndrome; Obviously reduce 5-HT, 5-HIAA content in the hypothalamus, improve NA content, reduce 5-HT/NE ratio, not obvious to DA content and the effect of 5-HIAA/5-HT ratio, show that it has part to correct the effect of " climacteric " rat maincenter monoamine neurotransmitter disorder, and then improve the disorderly symptom of autonomic nervous system, symptoms such as climacteric dysphoria, insomnia are alleviated; Obviously reduce castration mouse autonomic activities number of times, increase sub-threshold dose pentobarbital sodium mice sleep rate, show that it has certain tranquilizing effect.
In sum, nerve, the reproductive endocrine system of 1 pair of " climacteric " rat disorder of embodiment have tangible forward regulating action, and symptoms such as climacteric agitation, insomnia are all improved significantly.For its clinical research provides pharmacological basis.The inventor drops into clinical use with the present invention on above-mentioned research basis, the result shows, granule with embodiment 1 is an example, oral, one time 1 bag, be 1 course of treatment with 14 days every day 2 times, can obviously improve symptoms such as climacteric women is vexed, gas is dry, hectic fever sweating, vertigo and tinnitus, be the drug of first choice of treatment climacteric syndrome.
Other embodiment of the present invention are done above-mentioned experiment, all obtain same effect.
Claims (10)
1. Chinese medicine composition, it is characterized in that: described compositions has following proportioning by weight:
Radix Rehmanniae Preparata 330-390, Rhizoma Anemarrhenae 85-145, Radix Codonopsis 185-245, Cortex Lycii 85-145, Radix Angelicae Sinensis 185-245,
Herba Epimedii 85-145, Radix Astragali 115-175, Herba Cistanches 185-245, Semen Ziziphi Spinosae 185-245;
Preferably:
Radix Rehmanniae Preparata 345-375, Rhizoma Anemarrhenae 100-130, Radix Codonopsis 200-230, Cortex Lycii 100-130, Radix Angelicae Sinensis 200-230,
Herba Epimedii 100-130, Radix Astragali 130-160, Herba Cistanches 200-230, Semen Ziziphi Spinosae 200-230;
More preferably:
Radix Rehmanniae Preparata 357, the Rhizoma Anemarrhenae 114, Radix Codonopsis 214, Cortex Lycii 114, Radix Angelicae Sinensis 214,
Herba Epimedii 114, the Radix Astragali 143, Herba Cistanches 214, Semen Ziziphi Spinosae 214.
2. Chinese medicine composition according to claim 1 is characterized in that: described Chinese medicine composition is the extract of above-mentioned raw materials, the oral formulations made from acceptable accessories.
3. Chinese medicine composition according to claim 2 is characterized in that: described oral formulations is a granule, and described adjuvant is a dextrin.
4. the preparation method of each described Chinese medicine composition of claim 1-3, it is characterized in that: this preparation method comprises the steps:
1) with standby after described 9 kinds of pretreatments of raw material;
2) Herba Epimedii ethanol extraction, after extracting solution filtered, filtrate decompression was concentrated into thick paste;
3) eight flavor medicines such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis decoct with water, and decoction liquor filters, and filtrate is concentrated into thick paste;
4) step 3 gained thick paste and Herba Epimedii ethanol extraction thick paste are mixed into extract extractum, this extract extractum combines with pharmaceutically acceptable conventional adjuvant and further makes oral formulations.
5. preparation method according to claim 4, it is characterized in that: step 2 is: Herba Epimedii adds 12-18 and doubly measures the 60-80% alcohol reflux 1-3 time, and each 1-3 hour, merge extractive liquid,, filter, filtrate recycling ethanol also is evaporated to relative density 1.28～1.36 (80 ℃) thick paste; Preferably: Herba Epimedii adds 15 times of amount 70% alcohol reflux 2 times, and each 1.5 hours, merge extractive liquid, filtered, and filtrate recycling ethanol also is evaporated to relative density 1.30～1.35 (80 ℃) thick paste.
6. preparation method according to claim 4, it is characterized in that: described step 3 is: eight flavor medicines such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis add 8-12 medical material water gaging and decoct 2-5 time, each 0.5-2 hour, collecting decoction, filter, filtrate is concentrated into relative density 1.28～1.36 (80 ℃) thick paste, and is preferred; Eight flavor medicines such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis add 10 times of medical material water gagings and decoct 3 times, and each 1 hour, collecting decoction filtered, and filtrate is concentrated into relative density 1.30～1.35 (80 ℃) thick paste.
7. preparation method according to claim 4 is characterized in that: described oral formulations is tablet, granule and capsule.
8. preparation method according to claim 7 is characterized in that: the preparation method of described granule is: in extract extractum, add an amount of acceptable accessories, and mixing, drying under reduced pressure (60-80 ℃) is ground into fine powder, granulates, and packing forms.
9. preparation method according to claim 7 is characterized in that: the preparation method of described tablet is: add an amount of acceptable accessories in extract extractum, fully mixing is put 55-65 ℃ of drying and crushing; Mixing, granulation, drying, tabletting, promptly; The preparation method of described capsule is: in extract extractum, adds an amount of acceptable accessories, stirs, pulverize behind the vacuum drying, sieve, granulate, and drying, fill is promptly.
10. according to each described preparation method of claim 7-9, it is characterized in that: described acceptable accessories is starch, dextrin, lactose, Carboxymethyl cellulose sodium, micropowder silica gel, stearate or Pulvis Talci.
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| CN112220754A (en) * | 2020-11-18 | 2021-01-15 | 上海中医药大学 | Method for improving compression formability of traditional Chinese medicine extract powder |
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| CN101642504A (en) * | 2009-06-15 | 2010-02-10 | 张继成 | Capsule for reinforcing yin and clearing deficient heat |
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| CN102579766A (en) * | 2012-03-29 | 2012-07-18 | 翟西菊 | Anti-tumor medicine |
| CN102579766B (en) * | 2012-03-29 | 2015-02-18 | 翟西菊 | Anti-tumor medicine |
| CN112220754A (en) * | 2020-11-18 | 2021-01-15 | 上海中医药大学 | Method for improving compression formability of traditional Chinese medicine extract powder |
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