CN1785234A - Medicine composition and its prepn. method - Google Patents
Medicine composition and its prepn. method Download PDFInfo
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- CN1785234A CN1785234A CNA200410096969XA CN200410096969A CN1785234A CN 1785234 A CN1785234 A CN 1785234A CN A200410096969X A CNA200410096969X A CN A200410096969XA CN 200410096969 A CN200410096969 A CN 200410096969A CN 1785234 A CN1785234 A CN 1785234A
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Landscapes
- Medicines Containing Plant Substances (AREA)
- Medicinal Preparation (AREA)
Abstract
A composite Chinese medicine in the form of coated tablet or capsule for treating prostatoplasia and kidney-deficiency blood stasis is prepared from psoralea fruit and dung beetle through reflux extracting in alcohol, concentrating, cold storage of the concentrated liquid of dung beetle for removing fat, mixing, spray drying, granulating, coating, and loading in capsules.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and preparation method thereof, particularly relate to a kind of pharmaceutical composition for the treatment of hyperplasia of prostate and preparation method thereof.
Background technology
Hyperplasia of prostate (BPH) is the urology department common clinical.The hyperplasia of prostate sickness rate is in rising trend in recent years, and its Therapeutic Method has medicine, thermotherapy, operation etc., is the gerontal patient but suffer from hyperplasia of prostate, and complication is more, and it is very necessary to explore ideal medicine.Simultaneously, about the bibliographical information of the hyperplasia of prostate of Catharsii molossi treatment seldom, effective ingredient wherein is still indeterminate, does not see the pharmacological experiment study of its treatment hyperplasia of prostate, and effective extractum and preparation technology's thereof research.
Summary of the invention
The object of the present invention is to provide a kind of new pharmaceutical composition; The present invention also aims to provide a kind of preparation of drug combination method; The present invention also aims to provide the new purposes of this pharmaceutical composition.
The present invention seeks to be achieved through the following technical solutions.
Pharmaceutical composition of the present invention is to make by following materials of weight proportions medicine:
Fructus Psoraleae 1～5 weight portion Catharsii molossi 1～5 weight portion;
The optimum ratio of pharmaceutical composition of the present invention is:
Fructus Psoraleae 1 weight portion Catharsii molossi 1 weight portion;
The optimum ratio of pharmaceutical composition of the present invention is:
Fructus Psoraleae 1 weight portion Catharsii molossi 4 weight portions;
The optimum ratio of pharmaceutical composition of the present invention is:
Fructus Psoraleae 2 weight portion Catharsii molossis 3 weight portions;
Get the invention described above pharmaceutical composition, press the pharmaceutics common process, directly or add conventional adjuvant and be prepared into clinical acceptable any dosage form, include but not limited to a kind of in the middle of the following dosage form: tablet, capsule, pill, granule, drop pill etc.
Preparation of drug combination method of the present invention is:
Take by weighing Fructus Psoraleae, Catharsii molossi; Fructus Psoraleae adds 70%～90% alcohol reflux 2～3 times, and each 1.0～2.0 hours extraction times, each ethanol consumption by volume weight ratio is 6～10 times of medical material amounts, filters; Merging filtrate reclaims ethanol, and relative density is 1.05～1.10 when being concentrated into 60 ℃; Catharsii molossi adds 85%～95% alcohol reflux 1～3 time, each 1.0～3.0 hours extraction times, each ethanol consumption by volume weight ratio is 6～10 times of medical material amounts, filter, merging filtrate reclaims ethanol, relative density is 1.10～1.15 when being concentrated into 60 ℃, surface fat is removed in cold preservation, merges with the Fructus Psoraleae concentrated solution; Spray drying gets pharmaceutical composition powdered extract powder of the present invention; Get the powdered extract powder routinely prepared become any clinical acceptable solid preparation: tablet, capsule, pill, granule, drop pill etc.
Drying process with atomizing in the above-mentioned preparation method can be undertaken by following condition: fluid temperature: 50 ℃; Feed liquor speed: 200-300ml/min; Inlet temperature: 135～145 ℃; Leaving air temp: 80-90 ℃.
The preparation of capsule of the present invention: prepare the powdered extract powder by above-mentioned preparation method, get the powdered extract powder, ethanol with 95% is wetting agent system soft material, cross 40 mesh sieves, 50～60 ℃ of hot air dryings are again with 40 mesh sieve granulate, Opadry solution with 15% carries out fluidized bed coating, get the dry coationg granule, fill No. 1 capsule, promptly.
Fluidized bed coating can be undertaken by following condition in the preparation method of the invention described above capsule: feed liquor speed 40-50ml/min; Atomisation pressure 0.3 (MPa); Steam pressure 0.5 (MPa); Temperature of charge 55～50 (℃); Inlet temperature 78～68 (℃); Leaving air temp 40～35 (℃).
The method of quality control of capsule of the present invention contains one or more in following discrimination method and/or the content assaying method.
Differentiate: A. gets capsule content 0.5g of the present invention, adds ethyl acetate 20ml, and ultrasonic 15 minutes, filter, filtrate evaporate to dryness, residue add ethyl acetate 1ml dissolving, as need testing solution; Other gets psoralen, isopsoralen reference substance, adds ethyl acetate and makes the mixed solution that every 1ml contains 2mg, in contrast product solution; Test according to thin layer chromatography, draw each 4 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, with ratio is that benzene-ethyl acetate that 4: 1 normal hexane-ethyl acetate or ratio are 9: 1 is developing solvent, launch, take out, dry, spray is put under the 365nm uviol lamp and is inspected with 10% potassium hydroxide methanol solution; In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the fluorescence speckle of same color;
B. get capsule content 0.5g of the present invention, other gets Catharsii molossi control medicinal material fine powder 1g, adds 50ml distilled water supersound extraction 30 minutes respectively, filter, after filtrate is transferred PH2-3 with hydrochloric acid, by the strong acid cation exchange resin column of 2 * 10cm, earlier with 200ml distillation washing, flow velocity 1ml/min discards water lotion, and reuse 100ml concentration is the sodium hydroxide solution eluting of 1mol/L, flow velocity 1ml/min, collect the alkali eluent, transfer PH4-5, be concentrated into 10ml with hydrochloric acid, add isopyknic ethanol precipitation, the filtrate evaporate to dryness is filtered in cold preservation 24 hours, residue is with 50% dissolve with ethanol, filter, be settled to 2ml, make test sample and control medicinal material solution liquid; Test according to thin layer chromatography, draw each 5 μ l of above-mentioned solution, point sample is on same silica gel g thin-layer plate, with ratio is that n-butyl alcohol-acetic acid-water that 75: 15: 10 n-butyl alcohol-formic acid-water or ratio are 70: 20: 10 is developing solvent, launch, take out, dry, spray is with the istain test solution, and it is clear to be heated to the speckle colour developing at 105 ℃; In the test sample chromatograph, with control medicinal material chromatograph relevant position on, show the speckle of same color;
Assay: " Chinese pharmacopoeia (one one) appendix VID in 2000 measures according to high performance liquid chromatography;
Chromatographic condition and system suitability test: C
18(250mm * 4.6mm, 5 μ m) post; Mobile phase: ratio is 60: 40 a methanol-water; Flow velocity: 0.8ml/min: column temperature: 35 ℃; Detect wavelength 245nm;
The preparation of reference substance solution: take by weighing psoralen, isopsoralen reference substance, add methanol and make concentration and respectively be the mixing reference substance solution of 0.03mg/ml; The preparation of need testing solution: get capsule content 10g of the present invention under the content uniformity item, grind well, take by weighing 0.5g and place a conical flask, the accurate methanol 50ml that adds, claim to decide weight, ultrasonic 40min is put cold, claim to decide weight once more, replenish lost methanol filters, and gets subsequent filtrate, filter with 0.45 μ m microporous filter membrane, promptly;
Algoscopy: draw each 10 μ l of need testing solution and reference substance solution,, measure peak area, calculate, promptly according to the high performance liquid chromatography test;
Capsule of the present invention contains psoralen must not be lower than the 0.39mg/ grain, and isopsoralen must not be lower than the 0.42mg/ grain.
A little less than the granule hygroscopicity that preparation of drug combination method cost of the present invention is low, easy to operate, make, be suitable for industrialized great production.The present invention carries out having determined effective extractum, and its extraction process being studied about treating the pharmacological experiment study of hyperplasia of prostate to Catharsii molossi.
Capsule of the present invention is made up of Fructus Psoraleae, Catharsii molossi, has the function of the kidney invigorating warming YANG, blood circulation promoting and blood stasis dispelling, tonneau water channel, cures mainly hyperplasia of prostate, the blood stasis due to renal deficiency syndrome.
Results of pharmacodynamic test shows: capsule of the present invention can obviously resist experimental rat, mice prostatic hyperplasia; Can suppress prostate glandular cell and smooth muscle cell proliferation, induce the prostatic cell accent to die and dwindle prostate volume; Increase the expression of prostate Interstitial cell iNOS and reduce its smooth muscle tension force; Can improve hemorheological property and microcirculation disturbance; What can prolong the incubation period of acetic acid induced mice pain outbreak and reduce stomachache turns round the body number of times.
In sum, capsule capsule for treating hyperplasia of prostate curative effect of the present invention certainly.Clinical effectiveness shows the capsule of the present invention dysuria symptom that has clear improvement, and improves the urine flow rate, reduces effects such as residual urine volume, has curative effect certainly, advantages such as safe and reliable, taking convenience.
Following experimental example is used to further specify but is not limited to the present invention.
Experimental example 1: the research of the effective extractum of Catharsii molossi
1. the preparation of sample: adopt different solvents that Catharsii molossi is extracted, get Catharsii molossi medical material 100g (totally 4 parts), use petroleum ether, chloroform, ethanol, the water reflux 1 hour of 500ml respectively, filter, reclaim solvent, concentrate, ligroin extraction (sample A), chloroform extract (sample B), ethanol extraction (sample C), water extract (sample D) carry out pharmacodynamic study with above-mentioned sample A, B, C, D.
2. the pharmacodynamics test of Catharsii molossi:
The influence that the rabbit trigone of bladder flesh that each extraction part of table 1 Catharsii molossi is brought out NE shrinks (X ± S)
| Group | Sample number (N) | Suppression ratio (%) |
| A B C D hytrin distilled water tween 80 | 10 10 10 10 10 10 10 | 3.1850±6.0103 21.4730±9.1559* 16.0400±4.4572* 7.3300±5.7068 47.9650±11.1554** 0.5510±8.7201 2.8740±8.2263 |
* compare with distilled water, tween 80 group P＜0.05 * * P＜0.01
Statistical result: in each extract part of Catharsii molossi, B (chloroform extract), the suppression ratio and blank group that trigone of bladder flesh shrinks brought out to NE in C (ethanol extraction) position, tween group relatively there were significant differences .A (ligroin extraction), D (water extract) two parts relatively do not have significant difference with blank group and tween 80 group, the chloroform extraction position of Catharsii molossi is described, the ethanol extraction position is an effective extract, feasibility according to above result of the test and actual production, select for use ethanol to extract Catharsii molossi, be to guarantee the effectiveness of preparation, the different concentration ethanol extract of Catharsii molossi is carried out pharmacodynamic experiment.
3. the pharmacodynamics test of Catharsii molossi different concentration ethanol extract
Take by weighing Catharsii molossi 100g (totally three parts), added 95%, 85%, 75% ethanol 500ml reflux, extract, respectively 1 hour, filter, reclaim ethanol, concentrate extractum, investigate the influence of the rabbit trigone of bladder flesh that Catharsii molossi different concentration ethanol extract brings out NE by above-mentioned experimental technique, the results are shown in Table 2
The influence that the rabbit trigone of bladder flesh that table 2 Catharsii molossi different concentration ethanol extract brings out NE shrinks (X ± S)
| Group | Sample number (N) | Suppression ratio (%) |
| 95% ethanol extraction, 85% ethanol extraction, 75% ethanol extraction hytrin distilled water tween 80 | 10 10 10 10 10 10 | 16.5400±5.1736* 14.8650±4.2022* 10.5480±8.4710 45.1720±13.1645** 2.1290±7.0687 3.6700±7.7491 |
* compare with distilled water, tween 80 group P＜0.05 * * P＜0.01
The result shows, 95%, 85% the ethanol extraction of Catharsii molossi has significant inhibitory effect to the rabbit trigone of bladder flesh that epinephrine brings out, and 75% ethanol does not have significant inhibitory effect, the inhibitory action there was no significant difference of 95%, 85% ethanol extraction.
4. Catharsii molossi fat sites and non-fat sites pharmacodynamics test
The preparation of sample: get Catharsii molossi 100g, added 500ml concentration and be 85% alcohol reflux 1 hour, filter, filtrate recycling ethanol leaves standstill to 100ml, cold preservation 24 hours, release surface fat, sample F, aqueous solution is condensed into thick extractum and gets sample E.
The pharmacodynamics test of sample E and F:
The influence that the rabbit trigone of bladder flesh that table 3 grease removal position (E) and fat sites (F) are brought out NE shrinks (X ± S)
| Group | Sample number (N) | Suppression ratio (%) |
| E F hytrin distilled water tween 80 | 10 10 10 10 10 | 32.5780±12.9652* 9.7830±7.9924 44.4040±14.4813** 3.2040±8.5191 5.3890±9.5622 |
* compare with distilled water, tween 80 group P＜0.05 * * P＜0.01
Result: analyze by statistics, E (grease removal part) and blank group, tween 80 group and F (fats portion) have significant difference, with the hytrin there was no significant difference, effect is best: F (fats portion) and blank group, tween 80 there was no significant difference, parmacodynamics-less activity, for the ease of the drying and the molding of extractum, fat is removed.
Experimental example 2: Fructus Psoraleae extraction process Study on Conditions
1. the optimization Test of alcohol reflux extracting process condition:
Take by weighing Fructus Psoraleae 20 grams (totally 9 parts), extract, filter by process conditions in the Orthogonal Experiment and Design table, merging filtrate, standardize solution is in the 1000ml measuring bottle.
Adopting alcohol reflux, is evaluation index with psoralen, isopsoralen content, and comprehensive grading is respectively 50 and 50, and principal element concentration of alcohol, alcohol adding amount, extraction time and the extraction time that influences alcohol reflux carried out L
9(3
4) the orthogonal test screening.Experimental design, arrange to see Table 4, table 5.
Table 4 ethanol extraction factor level table
| Level | Factor | |||
| A concentration of alcohol (%) | B amount of alcohol (doubly) | C extraction time (hour) | D extraction time (inferior) | |
| 1 2 3 | 70 80 90 | 6 8 10 | 1.0 1.5 2.0 | 1 2 3 |
Table 5 L
9(3
4) orthogonal test arrangement, result and analytical table
| Sequence number | A | B | C | D | Evaluation index psoralen content (mg/g) | Isopsoralen content (mg/g) | Comprehensive grading | |
| 1 2 3 4 5 6 7 8 9 | 1 1 1 2 2 2 3 3 3 | 1 2 3 1 2 3 1 2 3 | 1 2 3 2 3 1 3 1 2 | 1 2 3 3 2 1 2 3 1 | 0.880 0.967 0.989 0.929 0.919 0.949 0.992 0.980 0.793 | 0.725 0.825 0.835 0.787 0.776 0.800 0.828 0.840 0.662 | 87.49 97.85 99.55 93.66 92.51 95.45 99.29 99.40 79.37 | |
| K1 K2 K3 R SS | 284.89 281.62 278.06 6.83 7.78 | 280.44 289.76 274.37 15.39 40.06 | 282.34 270.88 291.35 20.47 70.17 | 262.31 289.55 292.61 30.30 488.04 | Comprehensive grading psoralen content/0.992 * 50+ isopsoralen content/0.840 * 50 | |||
Table 6 analysis of variance table
| Source of error | SS | f | MS | F | P |
| B C D A (error) | 40.06 70.17 488.04 7.78 | 2 2 2 2 | 20.03 35.08 244.02 3.89 | 5.51 9.02 62.73 | * |
F
0.05(2，2)＝19.00；F
0.01(2，2)＝99.00
By the orthogonal experiments intuitive analysis, four factors are D (extraction time) maximum to extracting effect, are C (extraction time), B (alcohol adding amount) and A (determining alcohol) secondly, and optimum extraction process is A
1B
2C
3D
3
By variance analysis as can be known, D (extraction time) has significant difference, but extracts twice and three there was no significant differences of extraction, and other three factor affecting do not have significance, for reducing production costs, determine that last extraction process is A
1B
1C
1D
2, promptly add 6 times and measure 70% alcohol reflux twice, each 1 hour.
2. demonstration test: for guaranteeing the rationally feasible of extraction process, optimum process condition is carried out demonstration test three times, the result is as follows.
Table 7 ethanol extraction optimum process demonstration test
| Sample | Psoralen content (mg/g) | Isopsoralen content (mg/g) |
| 123 is average | 0.951 0.950 0.951 0.951 | 0.789 0.774 0.775 0.779 |
As seen from the above table, demonstration test is favorable reproducibility as a result, illustrates that the extraction process condition is basicly stable.
Experimental example 3: Catharsii molossi extraction process Study on Conditions
1. alcohol reflux extracting process condition optimizing test
Take by weighing Catharsii molossi 100g (totally 9 parts), carry out reflux, extract,, filter by the Orthogonal Experiment and Design table, filtrate recycling ethanol leaves standstill to 100ml, cold preservation 24 hours, release surface fat, solution is settled to 200ml, respectively gets 20ml, water bath method, residue added the 50ml chloroform ultrasonic 30 minutes, filtered, filtrate is put in the evaporating dish of constant weight, water bath method, and residue was in 105 ℃ of bakings 3 hours, place exsiccator cooling 0.5 hour, weigh rapidly.
Adopting alcohol reflux, is index with the chloroform extractum, and principal element concentration of alcohol, alcohol adding amount, extraction time, the extraction time that influences the second reflux, extract, carried out L
9(3
4) the orthogonal test screening.Experimental design, arrange to see Table 8, table 9.
Table 8 ethanol extraction factor level table
| Level | Factor | |||
| A concentration of alcohol (%) | B alcohol adding amount (doubly) | C extraction time (inferior) | D extraction time (h) | |
| 1 2 3 | 75 85 95 | 6 8 10 | 1 2 3 | 1 2 3 |
Table 9 L
9(3
4) orthogonal test arrangement, result and analytical table
| Sequence number | A | B | C | D | Evaluation index (chloroform extractum g) |
| 1 2 3 4 5 6 7 8 9 | 1 1 1 2 2 2 3 3 3 | 1 2 3 1 2 3 1 2 3 | 1 2 3 2 3 1 3 1 2 | 1 2 3 3 2 1 2 3 1 | 0.0308 0.0356 0.0414 0.0752 0.0687 0.0476 0.0734 0.0508 0.0591 |
| K1 K2 K3 R SS | 0.035933 0.063833 0.061100 0.02790 0.001419 | 0.059800 0.051700 0.049367 0.01040 0.000180 | 0.043067 0.056633 0.061167 0.01810 0.000532 | 0.05287 0.05220 0.05580 0.00360 0.000022 |
Table 10 analysis of variance table
| Source of error | SS | f | MS | F | P |
| A B C D (error) | 0.001419 0.000180 0.000532 0.000022 | 2 2 2 2 | 0.000710 0.000090 0.000266 0.000011 | 64.5067 8.1773 24.1900 | ** * |
F
0.05(2，2)＝19.00；F
0.01(2，2)＝99.00
By the orthogonal experiments intuitive analysis, four factors are A (determining alcohol) maximum to extracting effect, secondly are C (extraction time), B (adding pure multiple) and D (extraction time), and optimum extraction process is A
2B
1C
3D
3
By variance analysis as can be known, D (extraction time), B (alcohol adding amount) there was no significant difference, A (determining alcohol), C (extraction time) have significant difference, for reducing production costs, determine that last extraction process is A
2B
1C
3D
1, promptly add 6 times of amount alcohol reflux of 85% 3 times, each 1 hour.
2. demonstration test is guarantee extraction process rationally feasible, and optimum process condition is carried out demonstration test three times, and the result is as follows.
Table 11 ethanol extraction optimum process demonstration test
| Sample | The chloroform extractum |
| 123 is average | 0.0687 0.0672 0.0699 0.0686 |
As seen from the above table, demonstration test is favorable reproducibility as a result, illustrates that the extraction process condition is basicly stable.
Experimental example 4: the particulate coating research of capsule of the present invention
For improving particulate hygroscopicity, adopt Opadry damp-proof coating material that granule is carried out coating.
1. the investigation of coating solution concentration
The solid concentration influence bigger to being formed with of coating membrane for this solid concentration to different coating solutions screens, the results are shown in Table 12 in the coating solution.
The solid concentration of the different coating solutions of table 12 to coating after the hygroscopic influence of granule
| Tested number | Solid concentration in the coating solution | The coating situation | The granule hygroscopicity |
| 1 2 3 | 10％ 15％ 20％ | Droplet is even, nonchoking nozzle, and the time, long droplet was even, and the nonchoking nozzle droplet is inhomogeneous, plug nozzle | Stronger than power |
As can be known from the above table, when solid concentration in the coating solution is 15%, convenient coating operation, granule hygroscopicity a little less than.
2. the investigation of coating material consumption
The consumption of coating material directly influences the thickness of coating membrane, thereby influence the effect of granule protection against the tide, for reducing dose and reducing production costs, under the prerequisite that guarantees moisture effect, should reduce the consumption of coating material as far as possible, investigate for this consumption (with the percentage ratio of particle weight), the results are shown in Table 13 coating material.
Table 13 coating material consumption to coating after the hygroscopic influence of granule
| Tested number | The consumption of coating material | The granule hygroscopicity |
| 1 2 3 | 3％ 5％ 7％ | A little less than power |
As can be known from the above table, when the coating material consumption is particulate 5% the time, particulate moisture pick-up properties improves, hygroscopicity a little less than.
3. the hydroscopicity of coated granule is investigated
Be the stable of the examination quality of the pharmaceutical preparations, the granule behind the film coating is carried out the mensuration of hydroscopicity, method is measured with the extract powder hydroscopicity.The results are shown in Table 14.
The hydroscopicity of table 14 coated granule is investigated
| The moisture absorption time (h) | 1 | 2 | 8 | 12 | 24 | 48 | 72 | 96 |
| Hydroscopicity (%) | 1.43 | 2.27 | 3.35 | 3.82 | 5.01 | 5.15 | 5.25 | 5.28 |
As can be seen from the above table, the hygroscopicity of coated granule is improved greatly, hygroscopicity a little less than.
Experimental example 5: capsule pilot scale research of the present invention
According to the process conditions that filter out, pilot plant amplifies production in Enwei Chinese Medicine Inst., Sichuan Prov., manufactures experimently test agent in three batches continuously, the results are shown in following table.
The Opadry consumption calculates with the amount of spray powder.</entry></row></tbody></tgroup></table></tables>
The result shows, this technology quantity-produced good stability, and process conditions are easy to control feasible.The Device-General pharmaceutical equipment is fit to commercial production.
Experimental example 6: capsule of the present invention causes the influence of rat prostate model of hyperplasia to testosterone propionate
1. be subjected to the reagent thing
Capsule of the present invention is provided by Enwei Chinese Medicine Inst., Sichuan Prov.'s pilot plant, lot number 990601, specification: 0.36g/ grain, 1.67g crude drug in whole/grain; Consumption and instructions about how to take medicine: 60kg body weight adult is each oral 4 clinically, and 3 times on the one, promptly dosage is: (4/time * 3 times/day * 1.67g crude drug in whole/grain) ÷ 60kg body weight=0.33g crude drug in whole/kg body weight Coming-of-Age Day; 30 days is a course of treatment.Compound method during test: face the time spent with distilled water be made into the desired concn medicinal liquid for the experiment usefulness, see Table 16.
Proscar, every contains 4 one nitrogen steroid hormone chemical compound 5mg, produce by U.S. MSD Corp., lot number: 990541, clinical adult's dose every day is 5mg (5mg/ sheet, every day 1 time, each 1), be 0.083mg/Kg, the rat dosage is 1.67mg/Kg in the experiment, is equivalent to 20 times of people's consumption.Various medicines face with preceding and all are mixed with suspension by its dosage with distilled water, press the 10ml/Kg administration.
Capsular compound method of table 16 the present invention and dosage calculate
| Be subjected to test product | Drug level (the g crude drug in whole/dl) | Administration volume (ml/kg) | Dosage (the g crude drug in whole/dl) | The multiple (doubly) that is equivalent to clinical dosage |
| Capsule of the present invention capsule of the present invention capsule proscar of the present invention sheet normal saline | 66.6 33.3 16.7 0.0167 - | 10 10 10 10 10 | 6.66 3.33 1.67 0.00167 - | 20 10 5 20 - |
2. experimental technique
The blank group of the preparation of BPH animal model and medication rat is after 3 ‰ pentobarbital sodiums are with 10ml/Kg dosage intraperitoneal injection of anesthesia, and aseptic operation cuts hypogastric region, free testis, but do not excise testis, postoperative recovered the back in 5 days naturally as blank group.Treatment group and model group rat are after 3 ‰ pentobarbital sodiums are with 10ml/Kg dosage intraperitoneal injection of anesthesia, and aseptic excision bilateral testes after recovering naturally in 5 days, is divided into 5 groups at random by body weight.Wherein, testosterone propionate adds capsule in high dose group of the present invention, testosterone propionate and adds that dosage group, testosterone propionate add capsule low dose group of the present invention in the capsule of the present invention, testosterone propionate adds the proscar group: equal percutaneous every day injection testosterone propionate 0.5mg down, and according to the listed dosage administration of table 16,1 time/d; Model group: every day, percutaneous was injected testosterone propionate 0.5mg down, and the filling stomach gives distilled water 10ml/Kg, 1 time/d; Blank group: every day, percutaneous was injected water for injection 0.1ml down, and the filling stomach gives distilled water 10ml/Kg, 1 time/d.Successive administration 30d (centre is weighed 1 time weekly to adjust dosage), behind last administration 24h, claim rat body weight after the femoral artery sacrificed by exsanguination is won prostate, weigh, and measure prostate volume (water method of substitution) and prostate index (every 100g body weight prostate is heavy).
3. experimental result
3.1 influence to rat prostate weight, volume
The results are shown in Table 17.
Table 17 capsule of the present invention is to rat prostate weight, volume, exponential influence (X ± SD)
| Group | n | Rat body weight (g) | Weight of prostate (g) | Prostate volume (ml) | Prostate index (%) |
| Dosage group capsule low dose group of the present invention proscar group in the blank group model group capsule in high dose group of the present invention capsule of the present invention | 10 10 10 10 9 10 | 309.00±19.69 313.5±19.59 317±24.06 311.5±17.49 307.78±13.26 310.5±17.23 | 0.86±0.2 △△△ 1.49±0.33 0.92±0.09 △△△ 0.99±0.19 △△△ 1.12±0.24 △△ 0.94±0.12 △△△ | 0.75±0.13 △△△ 1.32±0.29 0.81±0.12 △△△ 0.90±0.20 △△△ 1.02±0.20 △△ 0.87±0.13 △△△ | 0.28±0.06 △△△ 0.50±0.15 0.29±0.04 △△△ 0.32±0.06 △△△ 0.36±0.08 △△ 0.31±0.05 △△△ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01, △ △ △ P＜0.001 with model group through the t check
By table 17 as seen, respectively organize the rat body weight there was no significant difference after the modeling.Model group rat prostate weight, volume, prostate index show the modeling success apparently higher than blank group (P＜0.001).Capsule 6.66g crude drug/kg of the present invention, 3.33g crude drug/kg group reaches proscar group and model group relatively, can extremely significantly reduce weight of prostate, dwindles prostate volume, reduces prostate index (P＜0.001).Capsule 1.67g crude drug of the present invention/kg group can significantly reduce weight of prostate, dwindles prostate volume, reduces prostate index (P＜0.01).
3.2 influence to the rat prostate organizational structure
Get the same area prostata tissue.With 10% dipped into formalin 3d.The routine paraffin wax embedding, serial section, slice thickness 4 μ m, wherein conventional H E dyeing is done in first section, observes the prostata tissue structural change.Model group is compared the body of gland dense arrangement with the blank group, and it is big that the body of gland chamber becomes, glandular epithelium thickening, the expansion of part body of gland, part is mamillary dashes forward to intracavity, and the luminal sectetion thing increases, and epithelial cell partly is multiple layer, nucleus circle or be ovum garden type, visible kernel, the little vasodilation hyperemia of a matter; Between the matter smooth muscle increase.Each dosage group of capsule of the present invention and the visible lumen of gland diameter of proscar group and lumen of gland wall thickness are little than model group, and the luminal sectetion thing reduces, and the stroma smooth muscle is more loose.
3.3 to rat prostate body of gland, a matter area, the influence of glandular epithelium thickness etc.
Body of gland number in 5 visuals field is calculated with MIAS-2000 type graph image analytical system in 5 visuals field of picked at random under 40 * mirror, measures each body of gland girth, measures body of gland, a matter area, gland walls area, gland walls nuclear degree.Calculate a body of gland and a matter area again than (a body of gland area/matter area), body of gland cumulative volume, a matter cumulative volume.Statistical result is shown in table 18,19,20,21.
Table 18 capsule of the present invention is to the influence of rat prostate body of gland number, girth, area (X ± SD)
| Group | n | Body of gland number (individual) | Body of gland girth (μ m) | Body of gland area (μ m 2) |
| Dosage group capsule low dose group of the present invention proscar group in the blank group model group capsule in high dose group of the present invention capsule of the present invention | 10 10 10 10 9 10 | 21.75±4.83 △ 13.13±1.81 25.63±3.99 △△ 24.13±3.27 △△ 23.13±2.64 △△ 26.88±3.83 △△ | 637.31±25.34 △△ 866.46±82.67 640.31±61.77 △△ 659.83±45.01 △△ 649.35±52.04 △△ 640.41±29.51 △△ | 27622.49±4978.95 △△ 48199.79±5001.63 26462.84±5401.59 △△ 27112.97±2797.95 △△ 27390.64±3676.22 △△ 25812.95±3913.77 △△ |
Annotate:, compare △ P＜0.05 with model group, △ △ P＜0.01 through the t check.
By table 18 as seen, model group body of gland average perimeter, area all obviously increase than blank group, and the blank group of body of gland number obviously reduces in 5 visuals field.Capsule 6.66g crude drug/kg of the present invention, 3.33g crude drug/kg, 1.67g crude drug/kg group and proscar group are compared with model group, all can significantly reduce body of gland average area, average perimeter, and significantly increase body of gland total number in 5 visuals field (P＜0.01).
Table 19 capsule of the present invention is to body of gland, a matter gross area in 5 visuals field, and the influence of gland plastid stroma ratio (X ± SD)
| Group | n | The body of gland gross area (μ m 2) | Between the matter gross area (μ m 2) | A body of gland/matter area ratio |
| Dosage group capsule small dose group of the present invention proscar group in the heavy dose of group of the blank group model group capsule of the present invention capsule of the present invention | 10 10 10 10 9 10 | 919095.80±49080.81 △△ 1055111.00±49144.10 1003549.00±67053.71 1031446.02±51004.89 994952.10±60005.83 993740.80±70394.63 | 400613.30±48081.03 △△ 265303.30±49144.10 316864.60±67053.71 288967.80±51004.89 325461.90±60005.83 326673.30±70394.63 | 2.34±0.40 △ 4.13±0.93 3.31±0.79 3.70±0.85 3.17±0.73 3.21±0.93 |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with model group through the t check
By table 19 as seen, the blank group of the body of gland gross area is obvious in 5 visuals field of model group rat prostate increases (P＜0.01), and the blank group of a matter gross area significantly reduces, so gland plastid stroma area ratio is obviously greater than the blank group.Each the dosage group of capsule of the present invention and the proscar group body of gland gross area, gland plastid stroma area are compared the trend that reduction is arranged than with model group, a matter gross area is compared the trend that increases with model group, but equal not statistically significant.
The influence overall to prostate body of gland, a matter of table 20 capsule of the present invention (X ± SD)
| Group | n | Body of gland cumulative volume (ml) | Between matter cumulative volume (ml) |
| Dosage group capsule low dose group of the present invention proscar group in the blank group model group capsule in high dose group of the present invention capsule of the present invention | 10 10 10 10 9 10 | 0.51±0.13 △△ 1.10±0.17 0.59±0.16 △△ 0.61±0.11 △△ 0.67±0.15 △△ 0.69±0.16 △△ | 0.22±0.05 △ 0.29±0.09 0.18±0.03 △△ 0.18±0.05 △△ 0.22±0.07 △ 0.22±0.06 △ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with model group through the t check.
By table 20 as seen, model group rat prostate body of gland, a matter cumulative volume are all obviously greater than the blank group.Each dosage group of capsule of the present invention and proscar group are compared with model group, can obviously reduce the prostate body of gland and between matter cumulative volume (P＜0.01, P＜0.05).
Associative list 19 and table 20, model group rat body of gland area are higher than blank group and a matter area is lower than blank group, but model group rat prostate body of gland and between the matter cumulative volume all be higher than blank group and more obvious with the body of gland area.The prostatic hyperplasia that explanation is caused by testosterone, body of gland and stroma hypertrophy all occurs and based on glandular hyperplasia.Each dosage group of capsule of the present invention and proscar group all can reduce the volume of prostate body of gland and stroma, and gland plastid stroma area is not influenced than having.
Table 21 capsule of the present invention is to the influence of rat prostate gland walls nuclear degree, area, integral optical density (X ± SD)
| Group | n | Gland wall area (μ m 2) | Gland wall nuclear degree | Gland wall integral optical density (IU) |
| Dosage group capsule low dose group of the present invention proscar group in the blank group model group capsule in high dose group of the present invention capsule of the present invention | 10 10 10 10 9 10 | 3189.75±990.92 △△ 8613.87±2758.64 4549.88±761.23 △ 4521.24±814.11 △ 3650.81±1669.14 △ 3963.39±1160.25 △ | 99.67±10.41 △ 121.78±9.36 123.84±4.30 117.46±6.25 117.43±7.62 116.86±9.12 | 626814.50±191528.60 △△ 1297336.01±436458.50 659125.80±108514.10 △△ 694196.20±120324.10 △△ 664627.60±125778.80 △△ 614867.70±161349.20 △△ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with model group through the t check.
Gland walls nuclear degree and integral optical density are represented epithelioglandular dense degree.By table 21 as seen, model group gland walls area, nuclear degree and integral optical density all obviously increase than blank group.Each dosage group of capsule of the present invention and proscar group gland wall area and integral optical density all reduce than model group, show that each dosage group of capsule of the present invention and proscar group gland walls area and glandular epithelium dense degree all reduce than model group.
3.4 capsule of the present invention is to the stereology research of prostata tissue structure influence
5 visuals field of picked at random under 40 * mirror, the unit volume average particle diameter (D), average curvature (K), the particle surface that calculate body of gland and body of gland chamber with MIAS-2000 type graph image analytical system amass/particle volume (R
Sv), number density (N
v), bulk density (Vv), unit volume particle average surface area (S), unit volume particle average external volume (V), surface area density (Sv), spherical factor indexs such as (S.g).
1. capsule of the present invention is to the influence of rat prostate body of gland stereology
(1) capsule of the present invention is to the influence of body of gland density parameter, and the result is shown in table 22.
Table 22 capsule of the present invention is to the influence of Vv, Sv and Nv (X ± SD)
| Group | n | Body of gland number density (l/mm 3) | The body of gland bulk density | Gland surface amasss density (l/mm) |
| Blank group | 10 | 258.17±78.05 △ | 1.37±0.11 | 40.83±5.53 |
| Model group | 10 | 119.09±22.81 | 1.48±0.11 | 33.92±3.66 |
| Capsule in high dose group of the present invention | 10 | 319.96±77.91 △△ | 1.59±0.12 | 48.65±3.63 △△ |
| Dosage group in the capsule of the present invention | 10 | 296.56±56.08 △△ | 1.53±0.09 | 47.51±4.70 △△ |
| Capsule low dose group of the present invention | 9 | 278.35±52.06 △△ | 1.47±0.07 | 44.78±2.93 △ |
| The proscar group | 10 | 346.16±83.40 △△ | 1.61±0.09 | 51.92±5.90 △△ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with model group through the t check
Number density (Nv) refers to unit with reference to certain the phase population that contains in the volume, surface area density (Sv) refer to unit with reference to certain mutually shared surface area in the volume what, bulk density (Vv) refers to that unit is with reference to certain mutually shared volume in the volume.By table 22 as seen, the blank group of model group body of gland Nv reduces, and each dosage group of capsule of the present invention and proscar Nv group are than the equal showed increased of model group.Model group body of gland Vv compares with the blank group with Sv, all not statistically significant.Each dosage group of capsule of the present invention and proscar group Nv and Sv all increase (P＜0.01) than model group, but Vv compares there was no significant difference with model group.
Illustrate, body of gland number, the long-pending increase of gland surface in each dosage group of capsule of the present invention and the proscar group unit volume, but the body of gland volume does not have significant change in the unit volume.
(2) capsule of the present invention is to the influence of body of gland form parameter, and the result is shown in table 23.
Table 23 capsule of the present invention is to the influence of Rsv, S.g, S, K (X ± SD)
| Group | n | Particle surface amasss/particle volume (l/mm) | Average curvature (l/mm) | Unit volume particle average surface area (μ m 2) | The spherical factor |
| Dosage group capsule low dose group of the present invention proscar group in the blank group model group capsule in high dose group of the present invention capsule of the present invention | 10 10 10 10 9 10 | 29.75±2.56 △△ 23.014±2.25 31.40±3.43 △△ 31.11±1.71 △△ 30.43±2.52 △△ 32.38±3.94 △△ | 7.83±0.91 △△ 5.74±0.49 7.77±0.76 △△ 7.51±0.49 △△ 7.65±0.66 △△ 7.65±0.35 △△ | 165734.96±29873.69 △△ 289198.74±30009.81 158777.13±32409.51 △△ 162677.83±16787.72 △△ 164343.85±22057.35 △△ 154877.73±23483.20 △△ | 0.79±0.05 0.76±0.11 0.75±0.05 0.72±0.05 0.76±0.07 0.72±0.07 |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with model group through the t check.
Particle surface is long-pending/and particle volume (Rsv) refers to the surface area of certain phase structure and the ratio of its volume, it is specific surface, the degree of average curvature (K) reaction surface bending, unit volume particle average surface area (S) refers to the meansigma methods of the long-pending size of a certain particle surface in the unit volume, the spherical factor (S.g) expression shape of particle and spheric degree of closeness, S.g is more near 1, and particle shape is got over subglobular.
By table 23 as seen, body of gland and spheric degree of closeness zero difference between each group.The blank group of model group body of gland specific surface and body of gland degree of crook reduces, and the blank group of unit volume inner gland body surface area increases.Each dosage group of capsule of the present invention and proscar group body of gland specific surface and body of gland degree of crook enlarge markedly (P＜0.01) than model group, and the body of gland average surface area significantly reduces (P＜0.01) than model group in the unit volume.
Illustrate, the interior body of gland average surface area of unit volume is significantly reduced, and degree of crook and specific surface are enlarged markedly.
(3) capsule of the present invention the results are shown in Table 24 to the influence of body of gland dimensional parameters.
Table 24 capsule of the present invention is to the influence of body of gland D, V (X ± SD)
| Group | n | Unit volume particle average external volume (μ m 3) | Unit volume average particle diameter (μ m) |
| Dosage group capsule low dose group of the present invention proscar group in the blank group model group capsule in high dose group of the present invention capsule of the present invention | 10 10 10 10 9 10 | 5674785.56±1433398.86 △△ 12742519.58±2304848.81 5218002.18±1715342.56 △△ 5262372.28±769586.94 △△ 5474942.36±1109622.71 △△ 4921213.80±1337466.81 △△ | 202.97±17.01 △△ 262.93±25.28 193.27±22.79 △△ 193.36±10.08 △△ 198.30±15.88 △△ 187.72±22.85 △△ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with model group through the t check.
Unit volume average particle diameter (D) refers to that average diameter, the unit volume particle average external volume (V) of certain three dimensional particles in the unit volume refer to the average external volume of certain class particle in the unit volume.By table 24 as seen, model group D and V all obviously increase than blank group, and each dosage group of capsule of the present invention and proscar group D and V all reduce than model group.Illustrate, give capsule of the present invention and proscar after, the body of gland average external volume is dwindled, body of gland average diameter diminish (P＜0.01).
Consolidated statement 22,23,24 as seen, after the treatment of each dosage of capsule of the present invention and proscar, body of gland average external volume, average diameter and average surface area dwindle, body of gland number and surface area increase in the unit volume, body of gland degree of crook and specific surface increase.
2. capsule of the present invention is to the influence of rat prostate gland walls stereology.
(1) capsule of the present invention is to the influence of rat prostate gland walls density parameter, and the result is as shown in Table 25.
Table 25 capsule of the present invention is to the influence of gland walls Sv, Vv and Nv (X ± SD)
| Group | n | Surface area density (l/mm) | Bulk density | Number density (l/mm 3) |
| Dosage group capsule small dose group of the present invention proscar group in the heavy dose of group of the blank group model group capsule of the present invention capsule of the present invention | 10 10 10 10 9 10 | 78.98±15.99 △ 55.56±7.60 84.03±15.27 △△ 85.22±14.15 △△ 81.49±6.28 △ 93.37±19.08 △△ | 0.16±0.03 △△ 0.27±0.09 0.27±0.04 0.25±0.03 0.24±0.05 0.25±0.08 | 28088.61±17689.90 △ 3546.305±2976.75 7202.00±3732.38 11040.06±7249.55 11914.42±7477.81 14409.29±10781.49 |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with model group through the t check.
By table 25 as seen, the blank group of model group gland walls Sv and Nv reduces, and the blank group of Vv increases.Each dosage group of capsule of the present invention and proscar group Sv are than model group showed increased (P＜0.01), and Nv compares the trend that increases with model group, and Vv compares the trend that reduction is arranged with model group, but equal not statistically significant.
Illustrate, give each dosage of capsule of the present invention and proscar after, the gland walls surface area increases in the unit volume.
(2) capsule of the present invention is to the influence of gland walls form parameter, and the result is shown in table 26.
Table 26 capsule of the present invention is to the influence of gland walls Rsv, S.g, S, K (X ± SD)
| Group | n | Particle surface amasss/particle volume (l/mm) | Average curvature (l/mm) | Unit volume particle average surface area (μ m 2) | The spherical factor |
| Dosage group capsule small dose group of the present invention proscar group in the heavy dose of group of the blank group model group capsule of the present invention capsule of the present invention | 10 10 10 10 9 10 | 495.66±139.07 △△ 231.73±83.78 310.52±44.68 346.58±96.93 363.02±90.60 △ 404.09±136.67 △△ | 24.55±11.11 △△ 9.24±3.85 9.96±3.53 12.41±3.39 14.29±5.91 12.59±5.49 | 4586.38±3771.85 △△ 23286.26±11811.91 13753.56±4775.22 △△ 10596.84±5497.46 △△ 9170.20±4665.57 △△ 10435.55±7319.40 △△ | 0.15±0.06 0.13±0.05 0.10±0.03 0.11±0.01 0.12±0.03 0.10±0.03 |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with model group through the t check.
By table 26 as seen, gland walls and spheric degree of closeness zero difference between each group.The blank group of model group gland walls specific surface and gland walls degree of crook reduces, and the blank group of gland walls average surface area increases in the unit volume.Capsule small dose group of the present invention and proscar group gland walls specific surface enlarge markedly than model group, and the gland walls average surface area reduces (P＜0.01) than model group in each dosage group of capsule of the present invention and the proscar group unit volume.And the gland walls degree of crook is compared zero difference with model group.
Illustrate, after each dosage of capsule of the present invention and proscar treatment, can make gland walls average surface area reduction in the unit volume, and the gland walls specific surface is increased, but not have influence to the gland walls degree of crook and with spheric degree of closeness.
(3) capsule of the present invention the results are shown in Table 27 to the influence of body of gland dimensional parameters.
Table 27 capsule of the present invention is to the influence of gland walls D, V (X ± SD)
| Group | n | Unit volume particle average external volume (μ m 3) | Unit volume average particle diameter (μ m) |
| Blank group | 10 | 11475.13±12009.42 △△ | 12.95±3.50 △△ |
| Dosage group capsule small dose group of the present invention proscar group in the heavy dose of group of the model group capsule of the present invention capsule of the present invention | 10 10 10 9 10 | 130478.08±100924.47 46305.66±20658.23 △△ 36139.22±26178.49 △△ 28575.17264±17267.49 △△ 37553.19±43451.82 △△ | 29.46±11.61 19.70±3.07 △△ 18.43±4.69 △△ 17.40±4.05 △△ 17.02±7.64 △△ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with model group through the t check.
By table 27 as seen, model group D and V all obviously increase than blank group, and each dosage group of capsule of the present invention and proscar group D and V all reduce (P＜0.01) than model group.Illustrate that after capsule of the present invention and the proscar treatment, the gland walls average external volume is dwindled, the gland walls average diameter diminishes.
Consolidated statement 25,26,27 as seen, after the treatment of each dosage of capsule of the present invention and proscar, gland walls average external volume and average surface area dwindle, and the gland walls surface area increases in the unit volume.But capsule low dose of the present invention and proscar knob gland walls specific surface increase.
4 conclusions
4.1 the BPH modeling method (the injection testosterone causes the BPH molding method after the rat castration) of generally acknowledging is adopted in this experiment of evaluation of animal model.The result shows that model group rat prostate weight, volume, index all increase than blank group, and light microscopic and stereology result of study all conform to above-mentioned conclusion.After animal pattern gave proscar, above-mentioned every index all was able to recovery in various degree.Human BPH interstitial proliferation is more obvious, and the also obvious hypertrophy of matter illustrates that this model and people BPH meet between this rat model, and model is successful.
4.2 the capsular therapeutic evaluation animal pattern of the present invention gives each dosage group of capsule of the present invention and proscar all can dwindle prostate volume, reduces weight of prostate and index.Observe and calculate under the mirror each dosage group of capsule of the present invention as can be known and proscar group can dwindle body of gland and between the matter cumulative volume, dwindle body of gland area, girth, the gland walls area reduces the epithelial dense degree of body of gland.Stereology studies show that the average external volume of body of gland and gland walls, average diameter, average surface area dwindle, and body of gland and gland walls area, number, specific surface increase in the unit volume.Illustrate that capsule of the present invention has tangible antagonism for the rat prostate model of hyperplasia due to the testosterone propionate.
Experimental example 7: capsule of the present invention causes the influence of rat prostate model of hyperplasia prostatic cell proliferation to testosterone propionate
1. experimental technique
1.1BPH the preparation of animal model and medication: see experimental example 6.
1.2 immunohistochemical staining
The operation of test kit description press in SP method dyeing, with the positive contrast of positive sheet that provides in the test kit, with PBS liquid substitute one anti-, two resist as negative control.200 * mirror is observed down, and 5 visuals field are got in every section, and occurring brown yellow granule in the cell karyon is the Ki-67 positive cell, and several 100 cells on each specimen calculate positive cell number, calculate corresponding index; The positive cell stained area and the painted depth are analyzed with MIAS-2000 type graph image analytical system.
2. result
The Ki-67 positive is colored as nucleus and pale brown color.Ki-67 is positive painted in glandular epithelium in the normal rat prostata tissue; Positive main painted in epithelium holostrome and stroma at model group Ki-67, it is darker to dye; Castration group glandular epithelium and stroma Ki-67 are positive, and stained area is less, and it is more shallow to dye; Capsule 6.66g crude drug/kg of the present invention, 3.33g crude drug/kg, 1.67g crude drug/kg group and proscar group Ki-67 are positive main painted in glandular epithelium, but dyeing is more shallow, is starkly lower than model group.Shown in table 28.
Table 28 capsule of the present invention is organized the influence (X ± SD) of Ki-67 to rat prostate
| Group | n | Index (%) | Average blackness | Average area (μ m 2) | Integral optical density (IU) |
| Dosage group capsule small dose group of the present invention proscar group in the blank group model group capsule in high dose group of the present invention capsule of the present invention | 10 10 10 10 9 10 | 11.50±2.73 41.88±12.67 △△ 21.38±3.58 △※※ 21.88±4.44 △※※ 24.75±5.28 △※※ 23.88±4.55 △※※ | 97.40±22.31 116.19±3.24 △ 99.12±6.79 ※ 94.20±8.14 ※ 93.08±8.55 ※ 100.83±5.32 ※ | 139.31±20.48 211.37±42.54 △ 144.62±24.34 ※ 146.01±14.28 ※ 132.18±15.50 ※ 115.66±15.26 △※※ | 34229.68±16416.27 142208.20±69749.06 △△ 56459.79±15023.75 ※※ 58306.39±13974.00 ※※ 60984.09±8494.75 △※※ 46543.63±7069.07 △※※ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with the blank group through the t check; Compare ※ P＜0.05, ※ ※ P＜0.01 with model group.
As seen from the above table, model group Ki-67 index, positive cell nuclear average area, Ki-67 dyeing blackness, integral optical density all are higher than blank group; Capsule 6.66g crude drug/kg of the present invention, 3.33g crude drug/kg, 1.67g crude drug/kg group and the above-mentioned every index of proscar group all are lower than model group.It is relevant to show that mechanism that animal pattern gives to dwindle behind the capsule of the present invention of each dosage and the proscar prostate volume and its can suppress prostatic cell proliferation.
3 conclusions
This research shows in conjunction with the result that the computer image analysis system carries out quantitative analysis with SABC, capsule 6.66g crude drug/kg of the present invention, 3.33g crude drug/kg, 1.67g crude drug/kg group has all obviously suppressed the expression of Ki-67 in the prostata tissue (P＜0.01), and then has suppressed the propagation of prostatic epithelium and Interstitial cell.
Experimental example 8: capsule of the present invention causes the influence of rat prostate model of hyperplasia prostata tissue bcl-2 protein expression to testosterone propionate
1. experimental technique
1.1BPH the preparation of animal model and medication are seen experimental example 6.
1.2 immunohistochemical staining
The operation of test kit description press in SP method dyeing, with the positive contrast of positive sheet that provides in the test kit, with PBS liquid substitute one anti-, two resist as negative control.20 times of mirrors are observed down, and 10 visuals field are got in every section, and occurring brown yellow granule in the cell cytosol is the bcl-2 positive cell.Analyze with MIAS-2000 type graph image analytical system.
2. result
The bcl-2 protein positive is colored as cytoplasm and pale brown color.The bcl-2 protein positive is painted in the normal rat prostata tissue distributes along the glandular epithelium basal cell layer; The bcl-2 protein positive is painted in epithelium holostrome and stroma in model group rat prostate tissue, and it is darker to dye; Main painted in each dosage group of capsule of the present invention and proscar group bcl-2 protein positive in glandular epithelium, but dyeing is more shallow, is starkly lower than model group.It is shown in table 29 that each organizes in the prostata tissue bcl-2 protein expression situation.
Table 29 capsule of the present invention is organized the influence (X ± SD) of bcl-2 to rat prostate
| Group | n | Average blackness | The positive cell gross area (μ m 2) | Integral optical density (* 10 7IU) |
| Dosage group capsule small dose group of the present invention proscar group in the blank group model group capsule in high dose group of the present invention capsule of the present invention | 10 10 10 10 9 10 | 66.97±8.31 90.99±7.15 △△ 80.35±5.81 △△※※ 81.08±6.71 △△※※ 77.50±7.61 △△※※ 81.60±765 △△※ | 17366.75±6188.80 68552.13±37850.12 △△ 15062.38±5679.18 ※ 17766.88±9809.76 ※ 19730.25±5564.69 ※ 30968.13±9080.42 ※ | 0.49±0.16 1.43±0.68 △△ 0.40±0.13 ※※ 0.48±0.25 ※※ 0.53±0.14 ※※ 0.77±0.20 ※※ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with the blank group through the t check; Compare ※ P＜0.05, ※ ※ P＜0.01 with model group.
3. conclusion
This research shows in conjunction with the result that the computer image analysis system carries out quantitative analysis with SABC, capsule 6.66g crude drug/kg of the present invention, 3.33g crude drug/kg, 1.67g crude drug/kg group has all obviously suppressed the proteic expression of bcl-2 (P＜0.01) in the prostata tissue, and then has induced the apoptosis of prostatic epithelium and Interstitial cell.
Experimental example 9: capsule of the present invention causes the influence of rat prostate model of hyperplasia prostate smooth muscle tissue to testosterone propionate
1. experimental technique
1.1BPH the preparation of animal model and medication are seen experimental example 6.
1.2 immunohistochemical staining
The operation of test kit description press in SP method dyeing, with the positive contrast of positive sheet that provides in the test kit, with PBS liquid substitute one anti-, two resist as negative control.20 times of mirrors are observed down, and 10 visuals field are got in every section, and occurring brown yellow granule in the cell cytosol is α-SMA positive cell.Analyze with MIAS-2000 type graph image analytical system.
2. result
α-SMA positive is colored as cytoplasm and pale brown color.α in the normal rat prostata tissue-SMA protein positive is painted in a matter smooth muscle cell; α in model group rat prostate tissue-SMA is positive painted in a matter smooth muscle cell and glandular epithelium basal cell, it is darker to dye: positive main painted in a matter smooth muscle cell and glandular epithelium basal cell in each dosage group of capsule of the present invention and proscar group α-SMA, but it is more shallow to dye, and is starkly lower than model group.It is shown in table 30 that each organizes α in the prostata tissue-SMA expression.
Table 30 capsule of the present invention is organized the influence (X ± SD) of a-SMA to rat prostate
| Group | n | Average blackness | The positive cell gross area (μ m 2) | Integral optical density (IU) |
| Dosage group capsule low dose group of the present invention proscar group in the blank group model group capsule in high dose group of the present invention capsule of the present invention | 10 10 10 10 9 10 | 90.43±4.22 92.10±6.36 83.43±4.40 △△※※ 85.55±6.56 △※ 83.38±303 △△※※ 85.63±3.42 ※ | 50885.75±19484.48 206608.63±88195.31 △ 43861.50±25048.04 ※ 50742.13±17034.55 ※ 37638.13±10924.82 ※ 41011.00±12866.93 ※ | 12785045.22±440415.35 43882560.14±189440.58 △△ 11568247.48±557043.60 ※※ 12103648.44±377655.92 ※※ 9492615.36±256338.52 ※※ 10852246.69±286055.19 ※※ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with the blank group through the t check; Compare ※ P＜0.05, ※ ※ P＜0.01 with model group.
3. conclusion
Originally studies show that, testosterone causes the obvious hypertrophy of prostate smooth muscle tissue of rat prostate model of hyperplasia, give capsule 6.66g crude drug/kg of the present invention, 3.33g crude drug/kg, 1.67g crude drug/kg smooth muscle composition obviously reduces (P＜0.01), illustrate that capsule of the present invention can suppress the hypertrophy of prostate smooth muscle cell, and then alleviate the firm static factor of BPH.
Experimental example 10: capsule of the present invention causes the influence that rat prostate model of hyperplasia interstitial tissue of prostate inducible nitric oxide synthase (iNOS) is expressed to testosterone propionate
1. experimental technique
1.1BPH the preparation of animal model and medication are seen experimental example 6.
1.2 immunohistochemical staining
The operation of test kit description press in SP method dyeing, with the positive contrast of positive sheet that provides in the test kit, with PBS liquid substitute one anti-, two resist as negative control.20 times of mirrors are observed down, and 10 visuals field are got in every section, and occurring brown yellow granule in the cell cytosol is the iNOS positive cell.Analyze with MIAS-2000 type graph image analytical system;
2. result
The iNOS positive is colored as cytoplasm and pale brown color.Experiment organizes respectively that inducible nitric oxide synthase (iNOS) all has expression in the stroma.It is as shown in the table that each organizes in the prostata tissue iNOS expression.
Table 31 capsule of the present invention is to the influence of rat prostate stroma iNOS (X ± SD)
| Group | n | Average blackness | The positive cell gross area (μ m 2) | Integral optical density (* 10 7IU) |
| Dosage group capsule low dose group of the present invention proscar group in the blank group model group capsule in high dose group of the present invention capsule of the present invention | 10 10 10 10 9 10 | 94.26±8.64 87.97±7.03 107.89±6.83 △△※※ 96.53±10.99 ※ 119.55±9.68 △△※※ 116.27±10.95 △△※※ | 137289.50±58216.60 55041.25±35300.12 △△ 117269.50±50149.42 ※※ 66976.50±21405.07 △△ 82578.38±43626.28 △ 137710.25±55676.46 ※※ | 2.63±0.8 1.22±0.7 △△ 2.05±0.7 ※※ 1.36±0.3 △△※ 1.52±0.8 △△※ 2.4±0.9 ※※ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with the blank group through the t check; Compare ※ P＜0.05, ※ ※ P＜0.01 with model group.
As above shown in the table, iNOS is positive painted more shallow in the blank group rat prostate stroma, and stained area is less; And the blank group of the positive painted blackness of iNOS is shallow in the model group rat prostate stroma, and the blank group of stained area is little, and the blank group of integral optical density is low; The positive painted blackness of each dosage group of capsule of the present invention and proscar group iNOS, area and integral optical density all are significantly higher than model group.
3. conclusion
This research shows in conjunction with the result that the computer image analysis system carries out quantitative analysis with SABC, capsule 6.66g crude drug/kg of the present invention, 3.33g crude drug/kg, 1.67g crude drug/kg group all can increase the expression of iNOS in the interstitial tissue of prostate, one of mechanism of action that capsule for treating BPH of the present invention is described is to have the NOS of mediation to alleviate the dynamic property factor of BPH by increasing to the prostate smooth muscle loosening.
Experimental example 11: capsule of the present invention causes the influence that rat prostate model of hyperplasia prostatic epithelium organizes inducible nitric oxide synthase (iNOS) to express to testosterone propionate
1. experimental technique
1.1 the preparation of BPH animal model and medication
See experimental example 6.
1.2 immunohistochemical staining
The operation of test kit description press in SP method dyeing, with the positive contrast of positive sheet that provides in the test kit, with PBS liquid substitute one anti-, two resist as negative control.20 times of mirrors are observed down, and 10 visuals field are got in every section, and occurring brown yellow granule in the cell cytosol is the iNOS positive cell.Analyze with MIAS-2000 type graph image analytical system.
2. result
The iNOS positive is colored as cytoplasm and pale brown color.It is all positive painted in the glandular epithelium holostrome that iNOS is respectively organized in experiment, and it is as shown in the table that each organizes in the prostatic epithelium tissue iNOS expression.
Table 32 capsule of the present invention is organized the influence (X ± SD) of iNOS to rat prostate
| Group | n | Average blackness | The positive cell gross area (μ m 2) | Integral optical density (* 10 7IU) |
| Dosage group capsule low dose group of the present invention proscar group in the blank group model group capsule in high dose group of the present invention capsule of the present invention | 10 10 10 10 9 10 | 116.16±7.21 97.07±9.55 △ 113.50±2.61 ※ 110.33±5.22 ※ 113.45±8.11 ※ 111.44±11.71 ※ | 303273.63±115330.67 133700.25±58973.89 △△ 274815.63±74446.60 ※※ 228822.13±82908.87 ※ 197807.50±70981.70 △ 295826.50±29558.86 ※※ | 4.46±1.6 2.32±0.7 △△ 4.20±1.1 ※※ 3.63±1.1 3.12±1.0 4.54±0.3 ※※ |
Annotate:, compare △ AP＜0.05, △ △ P＜0.01 with the blank group through the S-N-K check; Compare ※ P＜0.05, ※ ※ P＜0.01 with model group.
As above shown in the table, model group prostatic epithelium tissue staining is more shallow, and stained area is less, and integral optical density is less.Each dosage group of capsule of the present invention and proscar group iNOS dye average blackness apparently higher than model group; Capsule 6.66g crude drug/Kg of the present invention, 3.33g crude drug/Kg group and the proscar group positive cell gross area are big than model group.Capsule 6.66g crude drug group of the present invention and proscar group inte gration optical density are big than model group, and capsule 3.33g crude drug of the present invention, 1.67g crude drug group inte gration optical density are compared there was no significant difference with model group.
3. conclusion
This research shows in conjunction with the result that the computer image analysis system carries out quantitative analysis that with SABC capsule of the present invention has obviously suppressed the expression of iNOS in the prostatic epithelium tissue.One of mechanism of action that capsule for treating BPH of the present invention is described is the expression that increases iNOS in the prostatic epithelium tissue, induces its apoptosis, and dwindles prostate volume, and then alleviate the firm static factor of BPH.
Experimental example 12: capsule of the present invention causes the influence of mice prostatic hyperplasia model to testosterone propionate
1. experimental technique
Select 110 of healthy qualified complete male Kunming mouses for use, be divided into model group and blank group, 84 of model group, 26 of blank groups at random by body weight.Model group subcutaneous injection every day 10mg/kg testosterone propionate, blank is organized in subcutaneous injection isometric(al) water for injection, injects altogether 10 days.After 10 days model group and normal group are respectively randomly drawed 12 mices and put to death, take off prostate, weighing is also calculated prostate and is heavily reached the prostate index to determine the modeling success.To remain the model group mice then and be divided into 5 groups more at random, be respectively capsule of the present invention large, medium and small dosage group, model group and proscar matched group.Each reagent group is by irritating stomach (model group is irritated appearance normal saline such as stomach) and every day shown in the table 33 in the standard injection testosterone propionate of the subcutaneous 10mg/kg of pressing.Blank is organized in subcutaneous injection isometric(al) water for injection and is irritated stomach simultaneously and gives the isometric(al) normal saline.Continuous 20 days.Put to death all animals after 20 days, weighing is also write down body weight and the weight of prostate of every mice, calculates the prostate index.
Capsular compound method of table 33 the present invention and dosage calculate
| Be subjected to test product | Drug level (the g crude drug in whole/dl) | Administration volume (ml/kg) | Dosage (the g crude drug in whole/kg) | The multiple (doubly) that is equivalent to clinical dosage |
| Capsule of the present invention capsule of the present invention capsule proscar of the present invention sheet normal saline | 66.6 33.3 16.7 0.0167 - | 10 10 10 10 10 | 6.66 3.33 1.67 0.00167 - | 20 10 5 20 - |
Get the same area prostata tissue, with 10% dipped into formalin 3d.Routine paraffin wax embedding, section, slice thickness 4 μ m do conventional H E dyeing, observe the prostata tissue structural change under 40 * mirror.And calculate each body of gland girth, area, equivalent diameter, maximum gauge in 1 visual field with MIAS-2000 type graph image analytical system.Measure again in the whole visual field all body of gland areas (the body of gland gross area), all between matter area (a matter gross area), and calculate body of gland and a matter area than (a body of gland area/matter area).
2. result
2.1 capsule of the present invention is to mice weight of prostate and exponential influence
The results are shown in Table 34,35
Table 34 modeling heavy, exponential comparison of prostate of mice prostate after 10 days (X ± SD)
| Group | n | Body weight | Prostate is heavy | The prostate index |
| The blank group of model group | 12 12 | 31.13±2.26 28.47±4.53 | 0.099±0.033 0.057±0.016 △△ | 0.032±0.0097 0.020±0.0058 △△ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with model group through the t check.
As above shown in the table, make and touch the back model group and compare body weight with the blank group and do not have marked difference; The model group modeling after 10 days heavy, the prostate index of prostate all be significantly higher than blank group, the success of modeling type be described.
Table 35 capsule of the present invention is heavy to the mice prostate, the exponential influence of prostate (X ± SD)
| Group | n | Mice body weight (g) | Weight of prostate (g) | Prostate index (%) |
| Dosage group capsule low dose group of the present invention proscar group in the blank group model group capsule in high dose group of the present invention capsule of the present invention | 12 13 11 12 12 12 | 32.90±3.42 34.04±5.05 32.97±3.84 34.64±4.45 35.88±5.45 35.53±2.66 | 0.063±0.015 △△ 0.088±0.024 0.064±0.015 △△ 0.063±0.017 △△ 0.066±0.018 △ 0.068±0.019 △ | 0.019±0.0057 △ 0.026±0.0078 0.020±0.0054 △ 0.019±0.0046 △ 0.018±0.0041 △△ 0.019±0.0051 △ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with model group through the t check
As above shown in the table, model group mice weight of prostate, prostate index are organized apparently higher than blank, and the success of modeling type is described.Capsule 6.66g crude drug/kg of the present invention, 3.33g crude drug/kg, 1.67g crude drug/kg group and proscar group can obviously reduce weight of prostate, prostate index (P＜0.05,0.01).
2.2 capsule of the present invention is to the influence of mice prostata tissue structure
Model group is compared the body of gland dense arrangement with the blank group, and it is big that the body of gland chamber becomes, the glandular epithelium thickening, it is prominent to intracavity that the expansion of part body of gland, part are mamillary, and the luminal sectetion thing increases, epithelial cell partly is multiple layer, nucleus circle or be ovum garden type, the little vasodilation hyperemia of a matter; Between the matter smooth muscle increase.Each dosage group of capsule of the present invention and the visible lumen of gland diameter of proscar group and lumen of gland wall thickness are little than model group, and the luminal sectetion thing reduces, and the stroma smooth muscle is more loose.
2.3 capsule of the present invention is to the influence of mice prostate body of gland average area, girth
The results are shown in Table 36
Table 36 capsule of the present invention is to the influence of mice prostate body of gland average area and girth (X ± SD)
| Group | n | Body of gland area (μ m 2) | Body of gland girth (μ m) |
| Dosage group capsule small dose group of the present invention proscar group in the heavy dose of group of the blank group model group capsule of the present invention capsule of the present invention | 12 13 11 12 12 12 | 2808.91±1276.62 △△ 5228.63±2579.36 2712.15±851.73 △△ 3487.44±919.62 △△ 3169.16±803.24 △△ 3131.41±1165.51 △△ | 209.76±57.33 △△ 283.00±72.64 203.21±36.98 △△ 224.47±30.36 △△ 208.84±25.67 △△ 210.70±41.83 △△ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with model group through the t check.
As above shown in the table, model group body of gland average area, girth all than blank group big (P＜0.01), illustrate that model is successful.Each dosage group of capsule of the present invention and proscar group are compared with model group, can significantly reduce body of gland average area, average perimeter (P＜0.01).Illustrate that each dosage group of capsule of the present invention and proscar group all can dwindle body of gland and lumen of gland area.
2.4 capsule of the present invention is to the influence of mice prostate body of gland equivalent diameter and maximum gauge
The results are shown in Table 37
Table 37 capsule of the present invention is to the influence of mice prostate body of gland equivalent diameter and maximum gauge (X ± SD)
| Group | n | Body of gland equivalent diameter (μ m) | Body of gland maximum gauge (μ m) |
| Dosage group capsule small dose group of the present invention proscar group in the heavy dose of group of the blank group model group capsule of the present invention capsule of the present invention | 12 13 11 12 12 12 | 52.08±12.54 △△ 69.85±12.33 52.22±9.05 △△ 58.06±7.99 △ 54.92±5.91 △△ 57.28±10.44 △△ | 73.06±15.93 △△ 99.63±27.69 72.94±11.68 △△ 78.91±10.97 △△ 71.25±7.98 △△ 77.87±16.10 △△ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with model group through the t check.
As above shown in the table, model group body of gland equivalence garden diameter and maximum gauge illustrate that all apparently higher than blank group (P＜0.01) model is successful.Each dosage group of capsule of the present invention and proscar group are compared with model group, all can significantly reduce average equivalent diameter of body of gland and maximum gauge (P＜0.05,0.01).
2.5 capsule of the present invention is to the influence of the mice prostate body of gland gross area, a matter gross area and gland plastid stroma area ratio
The results are shown in Table 38
Table 38 capsule of the present invention is to the influence of the body of gland gross area, a matter gross area, gland plastid stroma area ratio (X ± SD)
| n | The body of gland gross area (μ m 2) | Between the matter gross area (μ m 2) | Gland plastid stroma area ratio | |
| Dosage group capsule small dose group of the present invention proscar group in the heavy dose of group of the blank group model group capsule of the present invention capsule of the present invention | 12 13 11 12 12 12 | 69475.25±18945.32 87961.38±28811.71 85025.91±25675.07 75845.75±19333.21 84907.33±25359.36 70820.00±17901.52 | 154783.80±45857.02 △△ 107556.70±35404.23 134266.50±34380.72 124544.40±50784.98 147902.20±42341.21 △△ 129426.30±41397.85 | 0.49±0.19 △△ 0.97±0.64 0.68±0.24 0.70±0.30 0.65±0.31 △ 0.61±0.27 △ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with model group through the t check.
It is as shown in the table: blank group of the body of gland gross area increases in the model group rat prostate visual field, and the blank group of a matter gross area significantly reduces, so gland plastid stroma area ratio is obviously greater than the blank group.Each the dosage group of capsule of the present invention and the proscar group body of gland gross area, gland plastid stroma area are compared the trend that reduction is arranged than with model group, a matter gross area is compared the trend that increases with model group, but not statistically significant.
3. conclusion:
Capsule 6.66g crude drug/kg of the present invention, 3.33g crude drug/kg, 1.67g crude drug/kg group and proscar group all can reduce mice weight of prostate and index.Observe and calculate each dosage group of capsule of the present invention as can be known and proscar group under the mirror and can dwindle body of gland area, girth, equivalent garden diameter, maximum gauge, can make the stroma smooth muscle loose simultaneously.Each dosage group of capsule of the present invention and proscar group do not make significant difference to body of gland, a matter gross area and gland plastid stroma area ratio in the visual field, point out each dosage group of capsule of the present invention and proscar group when dwindling the prostate body of gland matter also to be had certain dwindling.Show that capsule of the present invention causes the mice prostatic hyperplasia model to testosterone propionate and has significant antagonism.
Experimental example 14: capsule of the present invention is to the influence of " blood stasis " rat blood rheological characteristic
60 of the SD rats of body weight 140～180g, male and female half and half after this laboratory is fed a week, are divided into 6 groups at random by sex, body weight.Press the listed dosage gastric infusion of table 39, once a day, successive administration 7 days, administration volume are 1ml/100g, and model group and matched group gavage isometric(al) 4% starch solution.After the last administration 1 hour, inject 10% high molecular dextran 0.7ml/kg fast from the tail vein, get blood in the anticoagulant heparin pipe from rat eye socket venous plexus after 1 hour, measure the hemorheology many index with R-80A hemorheology instrument.
The compound method of table 39 capsule of the present invention and Radix Salviae Miltiorrhizae Tabellae and dosage calculate
| Be subjected to test product | Drug level (the g crude drug in whole/kg) | Administration volume (ml/kg) | Dosage (the g crude drug in whole/kg) | The multiple (doubly) that is equivalent to clinical dosage |
| Capsule of the present invention capsule of the present invention capsule FUFANG DANSHEN PIAN of the present invention normal saline | 66.6 33.3 16.7 30/dl- | 10 10 10 10 10 | 6.66 3.33 1.67 3- | 20 10 5 20 - |
Experimental result sees Table 40,41.
Table 40 capsule of the present invention is to the influence of " blood stasis " rat plasma viscosity, packed cell volume (X ± SD)
| Group | n | Plasma viscosity (mpos) | Packed cell volume (L/L) |
| Dosage group capsule small dose group of the present invention FUFANG DANSHEN PIAN group in the heavy dose of group of the blank group model group capsule of the present invention capsule of the present invention | 10 10 10 10 10 10 | 1.47±0.05 2.0±0.04 △△△ 1.90±0.03 *** 1.90±0.08 *** 1.95±0.03 *** 1.77±0.07 *** | 0.41±0.22 0.54±0.05 △△△ 0.54±0.05 0.55±0.05 0.54±0.04 0.53±0.05 |
△ △ △ represents to compare with blank group: p＜0.01.* * represents to compare p＜0.01 with model group.
Table 41 capsule of the present invention is to the influence of " blood stasis " rat whole blood viscosity (X ± SD)
| Group | n | 1/200s | 1/30s | 1/5s | 1s |
| Dosage group capsule small dose group of the present invention FUFANG DANSHEN PIAN group in the heavy dose of group of the blank group model group capsule of the present invention capsule of the present invention | 10 10 10 10 10 10 | 4.35±0.31 6.54±0.78 △△△ 5.75±1.05 6.45±1.22 6.04±0.27 5.20±0.82 *** | 5.99±0.49 9.09±1.28 △△△ 8.23±1.21 8.98±1.72 8.31±1.07 6.93±1.11 *** | 10.93±1.17 17.15±3.30 △△△ 15.87±1.83 16.66±3.49 15.10±1.72 11.99±2.04 *** | 26.05±3.61 42.30±10.27 △△△ 39.98±4.67 40.34±9.67 35.87±3.93 27.05±5.09 *** |
△ △ △ represents to compare with blank group: p＜0.01.* * represents to compare p＜0.01 with model group.
The result shows: behind the rat injection high molecular dextran, the obvious change of hemorheological properties occurs, whole blood viscosity, plasma viscosity, packed cell volume all significantly increase (P＜0.01).Capsule 6.66g crude drug/kg of the present invention, 3.33g crude drug/kg, 1.67g crude drug/kg all can significantly reduce the plasma viscosity (P＜0.01) of " blood stasis " rat.
Experimental example 15: capsule of the present invention is to the microcirculatory influence of mice mesentery
60 of Kunming mouses, male and female half and half are divided into 5 groups at random by sex, body weight, 12 every group.Press the listed dose value gastric infusion of table 42, the administration volume is 0.2ml/10g, and matched group gavages isometric(al) 4% starch suspension.Be administered once every day, successive administration 7 days, and the last administration with pentobarbital sodium 50mg/kg intraperitoneal injection of mice, made it anesthesia after 1 hour, cut open the belly, and pulled out mesentery gently and was placed on the lucite observation platform, splashed into an amount of tyrode's solution (37 ℃ of constant temperature).Observe the open number of blood capillary earlier with WX-6 type multi-section position microcirculation instrument, measure third level branch arteriole (A
3) and thin vein (V
3) caliber, observe blood fluidised form (adopt the Tian Shi quantitative method, divides seven grades and corresponding power to divide: linear flow 0, line grain stream 0.2, grain linear flow 0.4, grain stream 0.8, grain unhurried current 1.6, grain pendulum stream 4, stagnate 6, divide by power and measure).Drip 1: 10000 epinephrine (Adr) 15 μ l in same position immediately, A after 1,5,10,15 minute behind the following observation Adr of mirror
3, V
3Caliber changes.
The compound method of table 42 capsule of the present invention and Radix Salviae Miltiorrhizae Tabellae and dosage calculate
| Be subjected to test product | Drug level (the g crude drug in whole/kg) | Administration volume (ml/kg) | Dosage (the g crude drug in whole/kg) | The multiple (doubly) that is equivalent to clinical dosage |
| Capsule of the present invention capsule of the present invention capsule FUFANG DANSHEN PIAN of the present invention | 33.3 16.7 8.35 15/dl | 20 20 20 20 | 6.66 3.33 1.67 3/Kg | 20 10 5 20 |
Experimental result sees Table 43, table 44, table 45, table 46.
Table 43 capsule of the present invention is to the influence of the open number of blood capillary (X ± SD)
| Group | Dosage (the g crude drug in whole/kg) | Number of animals (only) | The open number (propping up) of blood capillary | |
| Before dripping Adr | After dripping Adr | |||
| Edition with parallel text invention capsule capsule of the present invention capsule FUFANG DANSHEN PIAN of the present invention | -6.66 3.33 1.67 3/kg | 12 12 12 12 12 | 6.8±1.6 8.2±2.0 7.3±1.8 8.1±2.1 8.1±1.8 | 6.8±1.4 8.8±3.4 8.1±2.6 8.6±3.2 9.0±2.6 * |
Compare * P＜0.05 with matched group
Table 44 capsule of the present invention is to the influence of blood fluidised form (X ± SD)
| Group | Dosage (the g crude drug in whole/kg) | Number of animals (only) | Fluidised form power score value | ||||
| Before dripping Adr | Drip (branch) behind the Adr | ||||||
| 1 | 5 | 10 | 15 | ||||
| Edition with parallel text invention capsule capsule of the present invention capsule FUFANG DANSHEN PIAN of the present invention | -6.66 3.33 1.67 3/kg | 12 12 12 12 12 | 0±0 0±0 0±0 0±0 0±0 | 1.3±0.9 0.7±0.4 * 0.7±0.2 * 0.7±0.2 * 0.6±0.4 * | 1.4±0.9 0.6±0.4 * 0.7±0.5 * 0.7±0.3 * 0.6±0.4 * | 1.0±0.4 0.6±0.4 * 0.5±0.4 * 0.7±0.6 0.4±0.4 ** | 0.5±0.4 0.3±0.3 0.5±0.4 0.4±0.4 0.3±0.3 |
Compare with matched group: * P＜0.05, * * P＜0.01.
Table 45 capsule of the present invention is to A
3The influence of caliber (X ± SD)
| Group | Dosage (g crude drug/kg | Number of animals (only) | A 3Caliber (μ m) | ||||
| Before dripping Adr | Drip (branch) behind the Adr | ||||||
| 1 | 5 | 10 | 15 | ||||
| Edition with parallel text invention capsule capsule of the present invention capsule FUFANG DANSHEN PIAN of the present invention | -6.66 3.33 1.67 3/kg | 12 12 12 12 12 | 56.9±18.5 61.4±22.6 63.6±15.1 61.3±10.9 59.0±17.2 | 1.9±1.5 7.4±5.0 ** 5.7±3.3 ** 6.3±5.4 * 8.2±5.5 ** | 9.0±6.3 13.0±6.1 12.6±9.6 13.4±7.0 18.2±11.1 * | 26.3±17.0 31.8±18.1 23.1±16.5 26.8±21.5 41.2±21.0 | 37.6±20.3 56.1±26.3 38.4±23.8 43.6±22.9 50.3±25.0 |
Compare with matched group: * P＜0.05, * * P＜0.01.
Table 46 capsule of the present invention is to the influence of V3 caliber (X ± SD)
| Group | Dosage (the g crude drug/kg) | Number of animals (only) | V 3Caliber (μ m) | ||||
| Before dripping Adr | Drip (branch) behind the Adr | ||||||
| 1 | 5 | 10 | 15 | ||||
| Edition with parallel text invention capsule capsule of the present invention capsule FUFANG DANSHEN PIAN of the present invention | -6.66 3.33 1.67 3/kg | 12 12 12 12 12 | 101.4±33.8 93.6±31.2 99.9±35.2 110.3±26.9 90.9±27.8 | 62.2±25.8 54.5±38.7 50.1±27.9 63.7±35.5 50.9±23.3 | 60.1±25.8 44.6±20.6 51.5±33.0 63.2±36.1 57.5±15.2 | 77.4±29.1 60.6±30.4 54.6±34.4 72.1±32.1 77.6±21.0 | 37.6±20.3 89.3±36.4 56.8±44.7 81.9±37.2 86.3±25.6 |
The result shows capsule 6.66g crude drug/kg of the present invention, and 3.33g crude drug/kg, 1.67g crude drug/kg all can significantly alleviate the contraction (P＜0.05) of Adr to blood vessel, improve blood status, and antagonism Adr is to A
3Contraction (P＜0.01), and increase the open number of blood capillary.
Experimental example 16: the influence of capsule Dichlorodiphenyl Acetate induced mice pain of the present invention
Get 50 of Kunming mouses, be divided into 5 groups at random, 10 every group by body weight.Be respectively the large, medium and small dosage group of capsule of the present invention, positive controls and blank group.Press the listed dosage gastric infusion of table 47.Continuous three days.Last was irritated stomach after 1 hour, and room temperature is constant about 20 ℃, in the acetum 0.2ml/ of the lumbar injection 0.6% of every animal subject only, observed the mouse writhing reaction, and index is that the abdominal part indent appears in mice, trunk and hind leg extension, hips up.Observe the incubation period (injection finished to the time that body occurs turning round for the first time) of every mouse writhing reaction, in 30 minutes every mice turn round the body number of times, and be calculated as follows and turn round the body suppression ratio.The results are shown in Table 47.
Capsular compound method of table 47 the present invention and dosage calculate
| Be subjected to test product | Drug level (the g crude drug in whole/dl) | Administration volume (ml/kg) | Dosage (the g crude drug in whole/kg) | The multiple (doubly) that is equivalent to clinical dosage |
| Capsule of the present invention capsule of the present invention capsule tramadol hydrochloride of the present invention normal saline | 66.6 33.3 16.7 0.1 - | 10 10 10 10 10 | 6.66 3.33 1.67 0.01 - | 20 10 5 - - |
Table 48 capsule Dichlorodiphenyl Acetate of the present invention solution induced mice is turned round the influence (X ± SD) of body
| Group | n | Body weight (g) | Turn round body incubation period (s) | Turn round the body number of times in 30 minutes | Suppression ratio |
| Dosage group capsule small dose group of the present invention positive controls in the heavy dose of group of the blank group capsule of the present invention capsule of the present invention | 10 10 10 10 10 | 25.36±2.38 26.09±2.49 25.07±2.29 24.97±2.77 25.47±2.31 | 126.60±45.85 373.10±110.06 △△ 227.00±54.39 △△ 235.70±73.95 △△ 701.10±461.66 △△ | 27.20±10.66 18.00±4.32 △ 20.09±4.19 25.00±5.35 7.60±6.15 △△ | ---- 33.82％ 23.16％ 8.09％ 72.59％ |
Annotate:, compare △ P＜0.05, △ △ P＜0.01 with the blank group through the t check
It is as shown in the table, capsule 6.66g crude drug/kg of the present invention, and 3.33g crude drug/kg, 1.67g crude drug/kg group is compared it and is turned round body all there were significant differences (P＜0.01) incubation period with the blank group.Capsule 6.66g crude drug of the present invention/kg group is turned round the body number of times and is compared with the blank group that there were significant differences (P＜0.05) in 30 minutes.
The result shows that each dosage group of capsule of the present invention can obviously prolong the incubation period of acetic acid induced mice pain outbreak; What capsule 6.66g crude drug of the present invention/kg group can also reduce acetic acid induced mice stomachache turns round the body number of times.
Experimental example 16: capsule clinical research of the present invention
For of curative effect and the safety of assessment capsule of the present invention, year March 30 routine BPH have been carried out clinical observation in JIUYUE, 1999 to 2000 to benign prostate hyperplasia (BPH).January is observed in treatment.Case choice criteria, prostatic hyperplasia diagnostic criteria are all with reference to " new Chinese medicine clinical research guideline " (1997).Clinical test results is as follows.
1. total effects: produce effects 11 examples (36.67%), progressive 15 examples (50%), invalid 4 examples (13.33%).
2.I-PSS, the variation of quality of life index (QOL):
Table 49 I-PSS and QOL change
| n | I-PPS (branch) | QOL (branch) | ||
| Before the treatment | After the treatment | Before the treatment | After the treatment | |
| 30 | 23.4±6.2 | 8.9±6.3** | 3.8±0.8 | 2.6±0.8** |
Notes: * represents and treats preceding relatively p＜0.05 that * * represents and preceding p＜0.01 (down together) of comparing of treatment.
3. the variation of urine flow rate
Table 50 Qmax (Qmax), AFR (AFR) are relatively
| n | Qmax(ml/s) | AFR(ml/s) | ||
| Before the treatment | After the treatment | Before the treatment | After the treatment | |
| 30 | 9.3±2.8 | 15.2±3.7** | 5.4±2.2 | 9.5±2.3** |
Annotate: the p value representation is the same.
4. the variation of residual urine volume (PVR)
Table 51 residual urine volume (PVR) relatively
| N | Before the treatment | After the treatment |
| 30 | 56.0±21.5 | 29.8±14.2** |
Annotate: the p value representation is the same.
5. prostate volume changes
Table 52 prostate volume (ml) relatively
| N | Before the treatment | After the treatment |
| 30 | 35.5±11.5 | 34.2±9.2 |
6. tcm symptom changes
The tcm symptom integration compares (branch) before and after table 53 treatment
| n | Before the treatment | After the treatment | |
| Nocturia frequency urine wire condition lower abdomen symptom | 30 30 30 | 1.82±0.81 1.87±0.77 1.63±0.98 | 0.72±0.45* 0.76±0.38* 0.74±0.41* |
Annotate: the P value representation is the same
Can find out from last table, restrain infirmity capsule traditional Chinese medical science cardinal symptom nocturia frequency, dysuria, the effect of having clear improvement of lower abdomen symptom.
Experimental result shows that patient's subjective symptom obviously improves, and the I-PSS scoring reduces by 62.0%, quality of life index (QoL) 31.9% (p＜0.01) that descends; Qmax (MRF) and AFR (AFR) improve 63.7%, 75.1% (p＜0.01) respectively; 24 routine residual urines (PVR) decline, 46.8% (p＜0.01).10 patients before treatment and when end treatment detected its blood, urine, stool routine examination, and liver function, kidney merit, electrocardiogram.Have no significant change.Untoward reaction does not appear during the treatment.Think that capsule for treating BPH of the present invention is safe and effective.
The following embodiment of the present invention all can reach the effect of above-mentioned experimental example.
Embodiment 1:
Get 1 kilogram of Fructus Psoraleae, 4 kilograms of Catharsii molossis, add adjuvant, conventional preparation technology makes tablet by pharmaceutics.
Embodiment 2:
Get 5 kilograms of Fructus Psoraleaes, 1 kilogram of Catharsii molossi, add adjuvant, conventional preparation technology makes pill by pharmaceutics.
Embodiment 3:
Get 2 kilograms of Fructus Psoraleaes, 3 kilograms of Catharsii molossis, add adjuvant, conventional preparation technology makes capsule by pharmaceutics, every 0.36 gram, every day 3 times, each 4.
Embodiment 4:The preparation of capsule of the present invention
Take by weighing Fructus Psoraleae 836g, Catharsii molossi 836g, Opadry 17.1g;
Fructus Psoraleae adds 70% alcohol reflux 2 times, adds 7 times of amounts for the first time, extracts filtration 1 hour; For the second time add 6 times of amounts, extracted 1 hour, filter; Merging filtrate reclaims ethanol, is concentrated into relative density 1.05 (60 ℃);
Catharsii molossi adds 85% alcohol reflux 3 times, adds 7 times of amounts for the first time, extracts filtration 1 hour; For the second time add 6 times of amounts, extracted 1 hour, filter; Add 6 times of amounts for the third time again, extracted 1 hour, filter; Merging filtrate reclaims ethanol, is concentrated into relative density 1.10 (60 ℃); Surface fat is removed in cold preservation 24 hours, merges with the Fructus Psoraleae concentrated solution, adds ethanol, makes concentration of alcohol reach 40%; Carry out spray drying by following condition, fluid temperature: 50 ℃; Feed liquor speed: 200-300ml/min; Inlet temperature: 135～145 ℃; Leaving air temp: 80-90 ℃;
Collect the powdered extract powder, the ethanol with 95% is wetting agent system soft material, crosses 40 mesh sieves, and 50～60 ℃ of hot air dryings are again with 40 mesh sieve granulate; Opadry solution with 15% carries out fluidized bed coating by following condition to granule, feed liquor speed 40-50ml/min; Atomisation pressure 0.3 (MPa); Steam pressure 0.5 (MPa): temperature of charge 55～50 (℃); 78～68 ℃ of inlet temperature); 40～35 ℃ of leaving air temps); Get the dry coationg granule, fill No. 1 capsule, promptly get 1000 of capsules (0.36g/ grain).Oral, one time 4,3 times on the one.
Embodiment 5:The preparation of tablet of the present invention
Get 1 kilogram of Fructus Psoraleae, 4 kilograms of Catharsii molossis;
Fructus Psoraleae adds 90% alcohol reflux 3 times, 1.0 hours extraction times of the first time, ethanol consumption by volume weight ratio is 10 times of medical material amounts, 1.0 hours extraction times of the second time, ethanol consumption by volume weight ratio is 8 times of medical material amounts, for the third time 2.0 hours extraction times, ethanol consumption by volume weight ratio is 6 times of medical material amounts, filters; Merging filtrate reclaims ethanol, and relative density is 1.05 when being concentrated into 60 ℃;
Catharsii molossi adds 95% alcohol reflux 1 time, and 3.0 hours extraction times, ethanol consumption by volume weight ratio is 8 times of medical material amounts, filters; Merging filtrate reclaims ethanol, and relative density is 1.10 when being concentrated into 60 ℃; Surface fat is removed in cold preservation 24 hours, merges with the Fructus Psoraleae concentrated solution; Carry out spray drying by following condition, fluid temperature: 50 ℃; Feed liquor speed: 200-300ml/min; Inlet temperature: 135～145 ℃; Leaving air temp: 80-90 ℃, get pharmaceutical composition powdered extract powder of the present invention; Get the powdered extract powder, prepared becomes tablet routinely.
Embodiment 6:The preparation of pill of the present invention
Get 2 kilograms of Fructus Psoraleaes, 3 kilograms of Catharsii molossis;
Take by weighing Fructus Psoraleae, Catharsii molossi, Fructus Psoraleae adds 80% alcohol reflux 2 times, and each 2.0 hours extraction times, each ethanol consumption by volume weight ratio is 8 times of medical material amounts, filters; Merging filtrate reclaims ethanol, and relative density is 1.10 when being concentrated into 60 ℃;
Catharsii molossi adds 90% alcohol reflux 2 times, each 2 hours extraction times, by volume weight ratio for the first time the ethanol consumption be 10 times of medical material amounts, the ethanol consumption is 8 times of medical material amounts for the second time, filters; Merging filtrate reclaims ethanol, and relative density is 1.10 when being concentrated into 60 ℃; Surface fat is removed in cold preservation, merges with the Fructus Psoraleae concentrated solution; Carry out spray drying by following condition, fluid temperature: 50 ℃; Feed liquor speed: 200-300ml/min; Inlet temperature: 135～145 ℃; Leaving air temp: 80-90 ℃, get pharmaceutical composition powdered extract powder of the present invention; Get the powdered extract powder, prepared becomes pill routinely.
Claims (19)
1, a kind of pharmaceutical composition is characterized in that this pharmaceutical composition is to be made by following materials of weight proportions medicine:
Fructus Psoraleae 1～5 weight portion Catharsii molossi 1～5 weight portion.
2, pharmaceutical composition as claimed in claim 1 is characterized in that this pharmaceutical composition is to be made by following materials of weight proportions medicine:
Fructus Psoraleae 1 weight portion Catharsii molossi 4 weight portions.
3, pharmaceutical composition as claimed in claim 1 is characterized in that this pharmaceutical composition made by following materials of weight proportions medicine:
Fructus Psoraleae 2 weight portion Catharsii molossis 3 weight portions.
4, pharmaceutical composition as claimed in claim 1 is characterized in that this pharmaceutical composition made by following materials of weight proportions medicine:
Fructus Psoraleae 1 weight portion Catharsii molossi 1 weight portion.
5, as claim 1,2,3 or 4 described pharmaceutical compositions, its feature is being got this pharmaceutical composition, directly or add conventional adjuvant, be prepared into clinical acceptable solid preparation by the pharmaceutics common process: tablet, capsule, pill, granule or drop pill.
6, as claim 1,2,3 or 4 described preparation of drug combination methods, it is characterized in that this method is:
Take by weighing Fructus Psoraleae, Catharsii molossi; Fructus Psoraleae adds 70%～90% alcohol reflux 2～3 times, and each 1.0～2.0 hours extraction times, each ethanol consumption by volume weight ratio is 6～10 times of medical material amounts, filters; Merging filtrate reclaims ethanol, and relative density is 1.05～1.10 when being concentrated into 60 ℃; Catharsii molossi adds 85%～95% alcohol reflux 1～3 time, and each 1.0～3.0 hours extraction times, each ethanol consumption by volume weight ratio is 6～10 times of medical material amounts, filters; Merging filtrate reclaims ethanol, and relative density is 1.10～1.15 when being concentrated into 60 ℃; Surface fat is removed in cold preservation, merges with the Fructus Psoraleae concentrated solution; Spray drying gets pharmaceutical composition powdered extract powder of the present invention; Get the powdered extract powder routinely prepared become clinical acceptable solid preparation: tablet, capsule, pill, granule or drop pill.
7, preparation of drug combination method as claimed in claim 6 is characterized in that this method is:
Take by weighing Fructus Psoraleae, Catharsii molossi; Fructus Psoraleae adds 90% alcohol reflux 3 times, 1.0 hours extraction times of the first time, ethanol consumption by volume weight ratio is 10 times of medical material amounts, 1.0 hours extraction times of the second time, ethanol consumption by volume weight ratio is 8 times of medical material amounts, for the third time 2.0 hours extraction times, ethanol consumption by volume weight ratio is 6 times of medical material amounts, filters; Merging filtrate reclaims ethanol, and relative density is 1.05 when being concentrated into 60 ℃; Catharsii molossi adds 95% alcohol reflux 1 time, and 3.0 hours extraction times, ethanol consumption by volume weight ratio is 8 times of medical material amounts, filters; Merging filtrate reclaims ethanol, and relative density is 1.10 when being concentrated into 60 ℃; Surface fat is removed in cold preservation, merges with the Fructus Psoraleae concentrated solution; Spray drying gets pharmaceutical composition powdered extract powder of the present invention; Get the powdered extract powder routinely prepared become tablet.
8, preparation of drug combination method as claimed in claim 6 is characterized in that this method is:
Take by weighing Fructus Psoraleae, Catharsii molossi, Fructus Psoraleae adds 80% alcohol reflux 2 times, and each 2.0 hours extraction times, each ethanol consumption by volume weight ratio is 8 times of medical material amounts, filters; Merging filtrate reclaims ethanol, and relative density is 1.10 when being concentrated into 60 ℃; Catharsii molossi adds 90% alcohol reflux 2 times, each 2 hours extraction times, by volume weight ratio for the first time the ethanol consumption be 10 times of medical material amounts, the ethanol consumption is 8 times of medical material amounts for the second time, filters; Merging filtrate reclaims ethanol, and relative density is 1.15 when being concentrated into 60 ℃; Surface fat is removed in cold preservation, merges with the Fructus Psoraleae concentrated solution; Spray drying gets pharmaceutical composition powdered extract powder of the present invention; Get the powdered extract powder routinely prepared become pill.
9, preparation of drug combination method as claimed in claim 6 is characterized in that this method is:
Take by weighing Fructus Psoraleae, Catharsii molossi; Fructus Psoraleae adds 70% alcohol reflux 2 times, adds 7 times of amounts for the first time, extracts filtration 1 hour; For the second time add 6 times of amounts, extracted 1 hour, filter; Merging filtrate reclaims ethanol, and relative density is 1.05 when being concentrated into 60 ℃; Catharsii molossi adds 85% alcohol reflux 3 times, adds 7 times of amounts for the first time, extracts filtration 1 hour; For the second time add 6 times of amounts, extracted 1 hour, filter; Add 6 times of amounts for the third time again, extracted 1 hour, filter, merging filtrate reclaims ethanol, and relative density is 1.10 when being concentrated into 60 ℃, and surface fat is removed in cold preservation, merges with the Fructus Psoraleae concentrated solution; Carry out spray drying, collect the powdered extract powder, the ethanol with 95% is wetting agent system soft material, crosses 40 mesh sieves, and 50～60 ℃ of hot air dryings are again with 40 mesh sieve granulate; With 15% Opadry solution granule is carried out fluidized bed coating, the dry coationg granule, fill No. 1 capsule, promptly.
10, as claim 1,2, the application of 3 or 4 described pharmaceutical compositions in preparation treatment prostatic hyperplasia disease drug.
11, the application of pharmaceutical composition as claimed in claim 10 in preparation treatment hyperplasia of prostate blood stasis due to renal deficiency card medicine.
12, has application in the medicine of the proliferation function that suppresses prostatic epithelium and Interstitial cell as claim 1,2,3 or 4 described pharmaceutical compositions in preparation.
13, the propagation of inhibition prostatic epithelium as claimed in claim 12 and Interstitial cell is meant the expression that suppresses Ki-67 in the prostata tissue.
14, as claim 1,2,3 or 4 described pharmaceutical compositions preparation have suppress the proteic expression of bcl-2 in the prostata tissue or induce prostatic epithelium and the medicine of Interstitial cell apoptotic effect in application.
15, has application in the medicine of the proliferative effect that suppresses the prostate smooth muscle cell as claim 1,2,3 or 4 described pharmaceutical compositions in preparation.
16, has application in the medicine that increases the expressional function of iNOS in the interstitial tissue of prostate as claim 1,2,3 or 4 described pharmaceutical compositions in preparation.
17, has application in the medicine that reduces the plasma viscosity effect as claim 1,2,3 or 4 described pharmaceutical compositions in preparation.
18, as claim 1,2,3 or 4 described pharmaceutical compositions preparation have alleviate Adr to the contraction of blood vessel or antagonism Adr to A
3Application in the medicine of the contraction of receptor.
19, has application in the medicine of analgesic activity as claim 1,2,3 or 4 described pharmaceutical compositions in preparation.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB200410096969XA CN100348213C (en) | 2004-12-07 | 2004-12-07 | Medicine composition and its prepn. method |
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| CNB200410096969XA CN100348213C (en) | 2004-12-07 | 2004-12-07 | Medicine composition and its prepn. method |
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| CN1785234A true CN1785234A (en) | 2006-06-14 |
| CN100348213C CN100348213C (en) | 2007-11-14 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102302521A (en) * | 2010-10-14 | 2012-01-04 | 中国科学院昆明植物研究所 | Catharsius molossus extract, anti-anxiety medicament which takes catharsius molossus extract as active ingredient and preparation method and application thereof |
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2004
- 2004-12-07 CN CNB200410096969XA patent/CN100348213C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102302521A (en) * | 2010-10-14 | 2012-01-04 | 中国科学院昆明植物研究所 | Catharsius molossus extract, anti-anxiety medicament which takes catharsius molossus extract as active ingredient and preparation method and application thereof |
| CN102302521B (en) * | 2010-10-14 | 2012-11-07 | 中国科学院昆明植物研究所 | Catharsius molossus extract, anti-anxiety medicament which takes catharsius molossus extract as active ingredient and preparation method and application thereof |
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| CN100348213C (en) | 2007-11-14 |
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