CN102233089B - 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 refers to that menstruation stops more than 1 year fully, claims menopause.One occurred between 45～65 years old.Climacteric women approximately 1/3 can reach new balance and asymptomatic by neuroendocrine self regulation, and the symptom of a series of gonadal hormone due to reducing then can appear in 2/3 women, is referred to as clinically climacteric syndrome.At home and abroad western medical treatment and prevention climacteric syndrome mostly adopt Hormone Replacement Therapy, but with simultaneously, and some researchs find also that this treatment measure also might be with and serve unfavorable factor, 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 therefore senile appearance and loss of fecundity are also ", think that exhaustion of kidney-essence with promoting reproductive function is the Basic disease cause 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, therefore see hectic fever, spontaneous perspiration; The kidney failing to nourish the liver, stagnation of QI due to depression of the liver is therefore see fidgety irritability; Menses gradually exhausts, and yin and yang imbalance is therefore see menoxenia; Kidney qi can not the replenishing vital QI with drugs of warm nature the five internal organs, therefore see the 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 the technique such as extracting, refining.Said composition can be used for the endocrine disturbance, the diseases such as women's infertility, leucorrhea abnormal.But because its complicated components, can't specific aim regulate nerve, the reproductive endocrine system of " climacteric " women's disorder, also very little to the improvement effect of the symptoms such as involutional agitation, insomnia.
In view of this special proposition the present invention.
Summary of the invention
The first purpose of the present invention is to provide a kind of Chinese medicine composition.
The 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 the 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 pharmaceutically acceptable adjuvant.
Described oral formulations is granule, and described adjuvant is dextrin.
For realizing the second purpose of the present invention, the present invention adopts following technical scheme:
A kind of preparation method of as mentioned above Chinese medicine composition, this preparation method comprises the steps:
1) with for subsequent use 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) the 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 is combined with pharmaceutically acceptable conventional adjuvant and is further made 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: the 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; The 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 pharmaceutically acceptable adjuvant, 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 pharmaceutically acceptable adjuvant in the extract extractum, fully mixing is put 55-65 ℃ of drying and crushing; Mixing, granulation, drying, tabletting, and get final product.
The preparation method of described capsule is:
Add an amount of pharmaceutically acceptable adjuvant in the extract extractum, stir, pulverize behind the vacuum drying, sieve, granulate, drying, fill and get final product.
Described pharmaceutically acceptable adjuvant is starch, dextrin, lactose, Carboxymethyl cellulose sodium, micropowder silica gel, stearate or Pulvis Talci.
1, Process Route Planning
(1) physicochemical property of each flavour of a drug in the side
(1) Radix Rehmanniae Preparata: this product is the fresh tuber Preparation process product of scrophulariaceae rehmannia glutinosa plant Rehmannia glutinosa Libosch..
Concocting method: get clean Radix Rehmanniae, steam to black profit according to steaming method (II D of Chinese Pharmacopoeia version in 2000), take out, when dry in the sun is slightly dried to crust mucus, cut sheet or piece, drying, and get final product.
(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 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 fleshy stem 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.
In the side take Radix Rehmanniae Preparata as monarch, 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 refreshing loose person, 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, 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 and is transferred punching to appoint.Radix Codonopsis, the Radix Astragali are again consolidating superficial resistance of invigorating middle warmer, 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 take tonifying kidney-yin as main, is played YIN nourishing and the merit of heat clearing away altogether.
We suit pathogen and pathology of tcm theory and pharmacology of Chinese medical formulae theory, 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.
Above nine flavor Chinese medicines all should meet pertinent regulations under each medical material item of Chinese Pharmacopoeia version in 2000.
Above nine flavor Chinese medicines, medical material is made through clean, and feeding intake with decoction pieces gets final product.
Radix Rehmanniae Preparata contains the compositions such as catalpol, rehmanin, aucubin, rehmannioside and polysaccharide; The Rhizoma Anemarrhenae contains saponin component; Radix Codonopsis contains saponin, saccharide 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
Can find out from the physicochemical property of the above-mentioned medicine of respectively distinguishing the flavor of, in the equal water soluble of most of flavour of a drug compositions, therefore, this process using water boiling and extraction technique.In the trial test process, the inventor notices that the employing decocting boils the method extraction, and is very large on the impact 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, the research of extraction process technology condition
2.1 the selection of Herba Epimedii ethanol extraction condition
The present invention determines to affect 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 in conjunction with practical situation for each factor, 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 impact on result of the test to investigate above four factor three levels.
(1) preparation of sample liquid
Precision takes by weighing Herba Epimedii 10g, presses respectively reflux, extract, of table 1 condition, 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 respectively 0.5,1.0,1.5,2.0,2.5ml 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 as a result variance analysis 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
Found out by table 2, each factor to the importance of result of the test is: D＞C＞A＞B.Table 3 variance analysis shows, 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, namely 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 at 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 desirable 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 technique, prepares three duplicate samples liquid, and sample liquid and epimedium herb are measured respectively content, 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,, Recycled ethanol, residue add water and are settled to 100ml.This test triplicate.
Determination of Content of Icariin 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, uses 70% ethanol 200ml eluting again, 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, namely get need testing solution.Precision is drawn each 10 μ l of reference substance solution (containing icariin 0.11mg among every 1ml) and need testing solution respectively, and the injection liquid chromatography is measured peak area, with external standard method calculating, and get final product.
Determination of Content of Icariin in the epimedium herb: get approximately 1g of epimedium herb powder (crossing 40 mesh sieves), accurately weighed, put in the 100ml tool plug conical flask, the accurate Diluted Alcohol 50ml that adds, close plug, weighed weight, supersound process 1 hour, weighed weight again, supply the weight of less loss with Diluted Alcohol, shake up, filter, get subsequent filtrate, namely get need testing solution.Precision is drawn each 10 μ l of reference substance solution (containing icariin 0.11mg among every 1ml) and need testing solution respectively, and the injection liquid chromatography is measured peak area, with external standard method calculating, and get final product.
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, illustrates that the extracting method extraction comparison that optimizes is complete, and extraction process is feasible.4.2.3.2 the selection of the 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 affect 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 in conjunction with practical situation for each factor, 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 impact on 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.
Determination of Astragaloside: precision is drawn the extracting solution of 20ml respectively, 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, lets cool, by D101 macroporous adsorptive resins (internal diameter 1.5cm, long 12cm), with water 100ml eluting, discard water liquid.Use 40% ethanol 80ml eluting again, discard 40% ethanol elution, continue with 70% ethanol 100ml eluting, collect eluent, 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, take lower floor's solution of chloroform-methanol-water (13: 6: 2) (below 10 ℃ place spend the night) as developing solvent, launch, take out, dry, spray is with 10% ethanol solution of sulfuric acid, 100 ℃ of bakings approximately 5～7 minutes, to clear spot, take out, cover onesize glass plate at lamellae, 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 as a result variance analysis sees Table 7,9.
Table 5, decocting method extract medical material and investigate the factor level table
Table 6, orthogonal experiments (take the astragaloside extracted amount as investigating index)
Table 7, variance analysis (take the astragaloside extracted amount as investigating index)
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 (take paste-forming rate as investigating index)
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: take the astragaloside extracted amount as investigating 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
Take paste-forming rate as investigating 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) has 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
3Namely 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 the 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.Particularly preferably; The 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 the 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 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.
The 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.
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 most manufacturing enterprise to have ready conditions and carry out, and the control temperature is no more than 70 ℃, is lower than temperature in the medicinal material extract process, composition can be because of dry not destroyed in this process therefore can make the thing that is dried.
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, behind concentrated 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 complexity processed, the granule character of making, melting and stability (plastic bag packaging, place at ambient temperature a month moisture absorption situation) be index, investigate the problem that clear paste adds the adjuvant amount.Get respectively 3 parts of 5 times of recipe quantity medical materials, prepare three parts of clear paste (relative density is 1.30～1.35,80 ℃ of surveys) by above-mentioned definite extraction process, take dextrin as example, add the dextrin of different proportion, drying under reduced pressure, be ground into fine powder, wet granulation, 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 (such 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, affects 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, after the present invention is concentrated with extracting solution, adds appropriate amount of auxiliary materials and drying under reduced pressure and become dried cream, be ground into fine powder, granulation.
Adopt respectively 85% ethanol, 95% ethanol and dehydrated alcohol to carry out wet method granule processed as wetting agent in the test.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, 95% ethanol granule effect processed is better, so the present invention adopts 95% ethanol granule processed.
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 greatly strengthens its curative effect, safe without toxic side effect;
(2) preparation method of Chinese medicine composition provided by the present invention is simple, and active constituent content is high, 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 the spirit and scope of the present invention 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 for subsequent use.
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;
The 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.
The liquid medicine decocting to thick ointment such as Herba Epimedii ethanol extraction thick paste and Radix Rehmanniae Preparata are mixed to get extract extractum.
In extract extractum, add an amount of micropowder silica gel, mixing, drying under reduced pressure (60-80 ℃) is ground into fine powder, and granulation 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 for subsequent use.
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.
The 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.
The liquid medicine decocting to thick ointment such as Herba Epimedii ethanol extraction thick paste and Radix Rehmanniae Preparata are mixed to get extract extractum.
In extract extractum, add an amount of dextrin, mixing, drying under reduced pressure (60-80 ℃) is ground into fine powder, and granulation 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 for subsequent use.
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.
The 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.
The liquid medicine decocting to thick ointment such as Herba Epimedii ethanol extraction thick paste and Radix Rehmanniae Preparata are mixed to get extract extractum.
Add appropriate amount of starch in the 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, packs and get final product.
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 for subsequent use.
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.
The 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.
The liquid medicine decocting to thick ointment such as Herba Epimedii ethanol extraction thick paste and Radix Rehmanniae Preparata are mixed to get extract extractum.
In extract extractum, add appropriate amount of starch, stir, pulverize behind the vacuum drying, sieve, granulate, drying, fill becomes 1000 of capsules, packs and get final product.
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 for subsequent use.
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.
The 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.
The liquid medicine decocting to thick ointment such as Herba Epimedii ethanol extraction thick paste and Radix Rehmanniae Preparata are mixed to get extract extractum.In extract extractum, add an amount of dextrin, stir, pulverize behind the vacuum drying, sieve, granulate, drying, fill becomes 1000 of capsules, packs and get final product.
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 test example 1-3.
The acute toxicity test research of test example 1 embodiment of the invention 1:
One, experiment purpose:
In this experimental observation mice one day repeatedly gavage give the embodiment of the invention the 1 rear acute toxic reaction that produces and death condition, for Pharmacodynamics research and long term toxicity test provide science 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, the 40ml/kg gavage gave 60% embodiment 1 suspension, mice state after the observation administration, mortality rate in the week.Activity reduces after found that the mice administration, and accelerated breathing is crawled motionless, and stool colour is deepened, and slightly rare, tail vein pipe color is normal, and eye, nose have no secretions, and second day recovers normally after the administration, and feed is normal.Nothing is dead in one week.
2. maximum tolerance determination in the mice one day
Since Cmax (60%) in the mice one day, (40%) gavage of maximum volume give embodiment in 1, one week without dead, 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, give administration secondary in 60% embodiment 1, a day by the 40ml/kg gavage, mice state after the administration is observed, mortality rate in the week in interval 6 hours.Activity reduces after found that the mice administration, and accelerated breathing is crawled motionless, stool colour intensification, slightly rare, and tail vein pipe color is normal, and eye, nose have no secretions, and second day recovers normally after the administration, and feed is normally.Nothing is dead in one week.The administration cumulative volume is 80ml/kg in one day, and the administration total amount is 48g/kg (123.5g crude drug/kg).
Four, conclusion
Mice gives embodiment 124g/kg by gavage of 40ml/kg, and (the 61.7g crude drug/kg), nothing is dead in the week.
Maximum volume (40ml/kg) in the mice one day, Cmax (60%), the secondary gastric infusion, mice has no the overt toxicity reaction, nothing is dead in one week, the administration cumulative volume is 80ml/kg in one day, and the administration total amount is 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: after experimental animal observation ward in Jilin Prov. Inst. of Chinese Medicine and Chinese Medical Science adapts to a week, begin experiment after animal is bought.Condition is: ventilates, and 20～23 ℃ of temperature, humidity 40～45%, the cage tool is sterilized weekly once, regularly feeding feedwater.
Tested medicine: embodiment 1 is the dark-brown powder, and every gram contains crude drug 2.57 grams, for not containing excipient dry powder before granulating, faces the time spent is made into desired concn with distilled water suspension, 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 blood rheological 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 48g/kg (123.5g crude drug/kg), the pharmacodynamics effective dosage ranges is 5g/kg～1.25g/kg, drafting clinical practice per 1 course for the treatment of is 1 month, take 1～3 course for the treatment of by state of an illness weight, restriction determines that the rat chronic 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 large Female Rats, be divided at random four groups, 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, by above-mentioned dosage gavage every day once, administration is 6 days weekly, and in continuous 26 weeks, matched group gives with volume distilled water (30ml/kg).
Sample time: during 13 week, each group is put to death 10 animals in administration, and sampling is made indices and measured, and all the other animals continue administration.Each organizes 20 animals of execution during 26 week in administration, and sampling is made indices and measured.All the other animals stop administration, under equal conditions continue to raise 2 all rear each groups and put to death 10 animals, the recovery situation of observation indices.
Inspection item: (1) one observation: at whole duration of test, observe at any time and record the variation of behavior, outward appearance activity and the defecation of animal; 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, and dyeing is counted 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 the 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 rear 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 first ready Bao Shi liquid, 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 126 weeks of embodiment, heavy dose of group (16g/kg) rat, and hair color gloss is relatively poor, and stool colour is darker, and all the other have no obvious change.Other dosage group has no the ANOMALOUS VARIATIONS such as outward appearance, behavioral activity.
On growth, ingest and the impact of amount of drinking water: after gavage gave embodiment 1 continuously, 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 with the matched group basic simlarity.Each is organized food-intake and approaches.The high dose group water yield is more.Drug withdrawal 2 all high dose group body weight gains are obviously accelerated.
3. on the impact of routine blood test: rat continuous 26 all gavages give embodiment 1, RBC, Hb, WBC, PLT each period of administration all within normal range, leukocyte differential count and clotting time have no significant change, also without significant change, show that the peripheral hemogram that long-term gavage gives 1 pair of rat of embodiment has no significant effect after 2 weeks of drug withdrawal.
4. serum biochemistry is learned the impact of indices: after the continuous gavage of rat gives embodiment 1, learn every detection index all without obviously changing at administration serum biochemistry in each in period, 2 weeks also had no any change after the drug withdrawal, and the result shows: long-term gavage gives 1 pair of biochemical indices of rat blood serum of embodiment and has no significant effect.
5. on the impact of major organs weight: the continuous gavage of rat gives 126 weeks of embodiment, administration is respectively organized each organ coefficient and relatively have no significant change with matched group each period, 2 weeks of drug withdrawal are also without obviously changing, the result shows, long-term gavage gives 1 pair of rat of embodiment rat main organs weight is had no significant effect.
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. on the impact of organ-tissue pathomorphism: rat oral gavage gives 113 weeks of embodiment and 26 all matched groups and each administration group Some Animals 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.Each other tissue of dosage group of matched group and administration has no obvious pathological change, has no drug-induced toxicity, drug withdrawal after one month all internal organs pathological examination results all normal.
Above-mentioned result of the test shows, rat continuous 26 all gavages give embodiment 1, and heavy dose of treated animal body weight gain obviously slows down, food-intake more slightly has minimizing with matched group, amount of drinking water has increase trend, and showing that body weight slows down may to organize drug level larger with heavy dose, and the absorption that affects food is relevant; The amount of drinking water increase may be pressed the feedwater of 30ml/kg gavage for matched group, and the high dose group gavage gives the medicine of high concentration, and the gavage confluent reduces for matched group, and therefore natural water uptake increases; All other index Non Apparent Abnormalities of high dose group change.In, the indices such as the behavior of low dose group outward appearance, body weight gain, routine blood test, serum biochemistry, main organs weight, histopathological examination is with the more equal no significant difference of matched group, has no 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 react without overt toxicity rat, high, medium and low dosage group is equivalent to respectively clinical plan with 84.8 times, 42.4 times, 21.2 times of dosage (people presses 70kg and calculates), show that said preparation toxicity is very low, clinical practice is safer.
The pharmacodynamic study of test example 3 embodiment of the invention 1
Tested medicine:
1, embodiment 1, and dark-brown powder, every gram contain crude drug 2.57 grams, for not containing excipient dry powder before granulating;
2, Geng Nian An Capsules 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, take the A prescription as 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, do not contain excipient dry powder before the granulation according to embodiment 1 described method preparation, every gram contains crude drug 2.61g;
5, take the B prescription as 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, 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 domestic analytical reagent.
Instrument: spectrofluorophotometer, model: the RF-540 type, Japanese Shimadzu Corporation produces; Chemiluminescence Apparatus, U.S. beckman company produces; Multifunctional mouse 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 end 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 the 4.5th, 6.7 days are by only carrying out vaginal smear examination, and be complete to determine ovariectomy, and postoperative was chosen anestrus on the 7th day and changed rat and be divided at random five groups.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, Normal group is implemented sham-operation, gavage gives the consubstantiality distilled water, all the other 7 groups (castrations) are respectively model control group (20ml/kg water), Geng Nian An Capsules 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 organize rat respectively at last give hot Chinese medicine after 1 hour gavage give said medicine, continuous 10 days once a day.
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, pap staining, and Microscopic observation keratinization degree, 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, keratinocyte and the shared percent of keratinocyte not in 100 epithelial cells of numeration under the mirror.
3.2. anus temperature measurement
Rat was measured Rat-rectum temperature (probe gos deep into approximately 3cm of anus) in 1 hour behind 4,6,8,10 days the medicine after giving tested medicine, 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 represents (mg/g) with the uterus weight number 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 postoperative 5,7,9 days vaginal smears are got oophorectomize and be used for experiment without the mice that emotionally changes fully.
2. grouping and administration
Mice is divided into 8 groups at random, Normal group is implemented sham-operation, all the other 7 groups are respectively model control group (20ml/kg water), Geng Nian An Capsules 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 gavage 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 Multifunctional mouse autonomic activities instrument record 10min in 1 hour after the last administration.
3.2 the 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 Sex Hormones and the hypothalamus that neurotransmitter levels is obviously disorderly, climacteric model obviously form.
2. embodiment 1 the results are shown in Table 13. to the impact of " climacteric " rat anus temperature
Table 13. embodiment 1 is on " the impact 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, give obviously reduction of the anus temperature that different time administration group rat raises behind the tested medicine, after the administration 2 groups of coolings of 8 days 5g/kg embodiment 1 and 1.2g/kg Geng Nian An Capsules obviously, 4 groups of 10 days 5～1.25g/kg embodiment 1 and 1.2g/kg Geng Nian An Capsules all have obvious cooling effect after the administration.
3. embodiment 1 the results are shown in Table 14. to the impact of " climacteric " rat uterus weight and uterus keratinization degree
Table 14. embodiment 1 is on the impact of " climacteric " rat uterus weight and keratinization degree
With the model matched group relatively: * P＜0.05, * * P＜0.01.
The result shows, the uterus weight that the continuous gastric infusion of embodiment 15～1.25g/kg and Geng Nian An Capsules 1.2g/kg can make rat model alleviate in 14 days obviously increases, and obviously increases vaginal epithelial cell keratinization degree.
4. embodiment 1 the results are shown in Table 15 to the impact of castration mouse autonomic activities
Table 15. embodiment 1 is on the impact of castration mouse autonomic activities
With the model matched group relatively: * P＜0.05.x ± S
The result shows, embodiment 16g/kg, 3g/kg and Geng Nian An Capsules 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, embodiment 16g/kg, 3g/kg and Geng Nian An Capsules 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 large impact in therapeutic effect on 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 reproductive endocrine system sex hormones secretion is disorderly, and ovary weakens the stress ability of promoting sexual gland hormone, the estrogen decrease of secretion, feedback cause that hypothalamus, pituitary are hyperfunction, gonadotrophin secretion is too much, causes autonomic nervous dysfunction, and then the 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.The monoamine neurotransmitter Noradrenaline Contents 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, serum estradiol content there is certain increasing action, 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 obvious Pasitive Regulation Effect of Genseng, 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 obvious reducing effect, shows that it has obvious inhibitory action 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 " central nervous system of rats monoamine neurotransmitter disorder, and then improve the disorderly symptom of autonomic nervous system, the 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 obvious Pasitive Regulation Effect of Genseng, and the symptoms such as climacteric agitation, insomnia are all improved significantly.For its clinical research provides pharmacological basis.The inventor drops into the present invention clinical use on above-mentioned Research foundation, the result shows, take the granule of embodiment 1 as example, oral, one time 1 bag, every day 2 times is take 14 days as 1 course for the treatment of, can obviously improve the symptoms such as climacteric women is vexed, gas is dry, hectic fever sweating, vertigo and tinnitus, be the drug of first choice for the treatment of climacteric syndrome.
Other embodiment of the present invention are done above-mentioned experiment, all obtain same effect.
Claims (14)
1. Chinese medicine composition that is used for climacteric syndrome, it is characterized in that: the raw material of 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.
2. Chinese medicine composition according to claim 1, it is characterized in that: the raw material of described compositions has following proportioning by weight:
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.
3. Chinese medicine composition according to claim 2, it is characterized in that: the raw material of described compositions has following proportioning by weight:
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.
4. each described Chinese medicine composition according to claim 1-3, it is characterized in that: described Chinese medicine composition is the extract of above-mentioned raw materials, the oral formulations made from pharmaceutically acceptable adjuvant.
5. Chinese medicine composition according to claim 4, it is characterized in that: described oral formulations is granule, described adjuvant is dextrin.
6. the preparation method of each described Chinese medicine composition of claim 1-4, it is characterized in that: this preparation method comprises the steps:
1) with for subsequent use 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) the 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 is combined with pharmaceutically acceptable conventional adjuvant and is further made oral formulations.
7. preparation method according to claim 6, 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 and relative density 1.28～1.36 thick pastes when being evaporated to 80 ℃.
8. preparation method according to claim 7, it is characterized in that: step 2 is: Herba Epimedii adds 15 times of amount 70% alcohol reflux 2 times, each 1.5 hours, merge extractive liquid,, filter filtrate recycling ethanol and relative density 1.30～1.35 thick pastes when being evaporated to 80 ℃.
9. preparation method according to claim 6, it is characterized in that: described step 3 is: the eight flavor medicines such as Radix Rehmanniae Preparata, the Rhizoma Anemarrhenae, Radix Codonopsis add 8-12 times of medical material water gaging and decoct 2-5 time, and each 0.5-2 hour, collecting decoction, filter relative density 1.28～1.36 thick pastes when filtrate is concentrated into 80 ℃.
10. preparation method according to claim 9, it is characterized in that: described step 3 is: the 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, filter relative density 1.30～1.35 thick pastes when filtrate is concentrated into 80 ℃.
11. preparation method according to claim 6 is characterized in that: described oral formulations is tablet, granule and capsule.
12. preparation method according to claim 11 is characterized in that: the preparation method of described granule is: add an amount of pharmaceutically acceptable adjuvant, mixing in extract extractum, drying under reduced pressure under the 60-80 ℃ of condition, be ground into fine powder, granulate, packing forms.
13. preparation method according to claim 11 is characterized in that: the preparation method of described tablet is: add an amount of pharmaceutically acceptable adjuvant in extract extractum, fully mixing is put 55-65 ℃ of drying and crushing; Mixing, granulation, drying, tabletting, and get final product; The preparation method of described capsule is: add an amount of pharmaceutically acceptable adjuvant in the extract extractum, stir, pulverize behind the vacuum drying, sieve, granulate, drying, fill and get final product.
14. each described preparation method according to claim 12-13, it is characterized in that: described pharmaceutically acceptable adjuvant is starch, dextrin, lactose, Carboxymethyl cellulose sodium, micropowder silica gel, stearate or Pulvis Talci.
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| CN101269150A (en) * | 2008-05-15 | 2008-09-24 | 天科仁祥技术（北京）有限责任公司 | Pharmaceutical composition for treating climacteric syndrome and preparation method thereof |
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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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