CN101966208B - Medicament for treating tristimania and preparation method thereof - Google Patents
Medicament for treating tristimania and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a medicament for treating tristimania and a preparation method thereof. The method comprises the following steps of: cutting a medicinal material, namely hypericum perforatum, performing refluxing extraction on the cut hypericum perforatum for three times by using 30 to 80 percent ethanol or 30 to 100 percent methanol, reclaiming a solvent, and concentrating; adding water and ethanol into the extract to dilute the extract until the weight of the extract is 3 to 7 times that of the medicinal material, adjusting until the alcohol content is 0 to 20 percent, uniformly mixing and centrifuging; making the supernatant pass through a treated macroporous adsorption resin column, and stopping sampling after resin adsorption is saturated; eluting with water until the eluate is clear and removing the washing liquor; eluting with 50 to 90 percent ethanol, collecting the eluate, reclaiming the ethanol, concentrating the product, and performing spray drying to obtain a hypericum perforatum extract; and adding conventional auxiliary materials into the hypericum perforatum extract and preparing clinically acceptable formulations, such as tablets, capsules, pills, particles and the like by the conventional process.
Description
Technical field
The present invention relates to a kind of medicine and preparation method thereof, particularly extract of hypericum perforatum of a kind of Cure of depression and preparation method thereof.
Background technology
Depression is human emotion's property disease, is chronic, repeatedly outbreak, and the symptom multiformity is such as depressed, appetite and sleep disorder, world-weary and suicidal tendency etc.Along with people's rhythm of life is accelerated, social competition's aggravation, aged tendency of population is accelerated, and depression has become the important diseases of harm public health.Add up according to WHO, whole world patients with depression has accounted for 3% of total population, the sickness rate of China's depression developed into 7.6 ‰ of today from 3.6 ‰ of the seventies, the 30-70% that also has an appointment is the neurasthenia by mistaken diagnosis, and at its sickness rate of the big cities such as Beijing, Shanghai up to 3.43%, its incidence rate is cumulative year after year trend.The depression severe patient can cause pessimistic and worldweary, and its homicide rate exceeds 20 times of normal person, and patients with depression has accounted for 50% among the suicide crowd.Along with the growth of sickness rate and the rapid increase of medical expense, this disease had caused already on the impact of social stability and family's peacefulness that national governments paid much attention to.The city such as Beijing, Shanghai has been defined as it therapy of serious disease medicine that emphasis is supported, and wherein Chinese medicine, crude drug are researched and developed the especially direction of Developing.
Depression is one of main disease of mental sickness, and antidepressant drug also is the focus that each large pharmacy corporation of the whole world is paid close attention to.Show that according to the latest research report sale rank of psychotropic drug has leapt to the third-largest classification of whole world medicine.And in psychotropic drug the rank front three all are antidepressants, account for 45% of its market share.It is 2,800,000,000 dollars that 1998 New Year's gifts are come the Prozac global marketing volume of company, and the seroxat of GlaxoSmithKline PLC company then is 1,800,000,000 dollars.Expect 2005, the whole antidepressants market share will reach 19,000,000,000 dollars, increase every year on average 13%, and nine kinds of antidepressants (all being Western medicine) have just been included also in continuous expansion in the domestic market in national social security medicine catalogue.
At present, antidepressants product in the world's mainly contains: 1. oxidase inhibitor (MAOT): the non-selective inhibitor that find the fifties.2. classical antidepressants (TCAS, tricyclic antidepressants), it represents medicine and comprises imipramine, amitriptyline etc.3. selective serotonin reuptake inhibitor (SSRIS), typical medicaments comprises fluoxetine, paroxetine, Sertraline and western general peptide orchid etc.1. quasi drugs, many because of side effect, toxicity is large, existing manyly be eliminated.2. quasi drugs, its pharmacological action characteristics are heavily absorptions of monoamine neurotransmitter in the blocking-up brain, but have again in various degree cholinolytic side reaction and cardiac toxicity etc. simultaneously.For reducing side reaction and reducing toxicity, some non-tricyclic antidepressants once appearred the seventies, such as maprotiline etc., but do not overcome yet toxic and side effects fully.3. quasi drugs, its pharmacology is the specific inhibition serotonin reuptake transporter, and is very low to the affinity of other neurotransmitter receptor in the brain, little than the tricyclic antidepressants toxicity, but still has certain side effect.All there are some shortcomings in existing medicine in a word: side effect is large, and incidence rate is high, and the mechanism of action is single, and is expensive, easily recurs etc., and these have all seriously influenced popularizing and using of they.Existing product can not satisfy the demands, and therefore, the antidepressants of development of new, efficient, wide spectrum, low toxicity have become one of direction of various countries pharmaceutical manufacturer research and development.
Summary of the invention
The object of the invention is to disclose a kind of medicine of Cure of depression; The present invention also aims to disclose the preparation method of this medicine.
The present invention seeks to be achieved through the following technical solutions:
Get the chopping of Herba Hyperici Monogyni medical material, extract 2-3 time with 30-80% ethanol or 30-100% methanol eddy: add 8-12 times of weight solvent for the first time, direct reflux, extract, or immersion reflux, extract, after 2-16 hour, return time 2 hours; For the second time and/or add respectively for the third time 4-8 times of weight solvent, refluxed 1 hour at every turn; The extracting solution graded concentrated or merge after concentrate again, reclaim solvent, being concentrated into relative density is 1.00～1.05 in the time of 30 ℃; Add water and ethanol dilution to the 3-7 of medical material weight doubly, and transfer to and contain the alcohol amount and be 0-20%, mixing, centrifugal; Supernatant is crossed the nonpolarity macroporous adsorptive resins chromatographic column of the models such as D-101, XAD-7, X-5, AB-8 or NKA-12 of handling well, stops loading after resin absorption is saturated; Wash with water, till the eluent clarification, discard water lotion; Use again the 50-90% ethanol elution, collect eluent, Recycled ethanol, concentrate eluant is 1.00～1.05 to relative density 30 ℃ the time, spray drying namely gets extract of hypericum perforatum.The extract that the present invention makes adds conventional adjuvant, according to common process, makes the clinical acceptable dosage forms such as tablet, capsule, soft capsule, pill, granule.Get extract of hypericum perforatum and add one or more adjuvants wherein such as carboxymethyl starch sodium, microcrystalline Cellulose, pregelatinized Starch, magnesium stearate, mixing, with the starch slurry wet granulation of dehydrated alcohol or 5-10%, dry or direct dry granulation, granulate, encapsulated or be pressed into tablet.The capsule that extract of the present invention makes or tablet can also be made by the following method: get extract of hypericum perforatum 140-160 weight portion, add one or more in carboxymethyl starch sodium 20-50 weight portion, microcrystalline Cellulose 1-20 weight portion, pregelatinized Starch 1-20 weight portion, the magnesium stearate 1-3 weight portion, mixing, starch slurry wet granulation with dehydrated alcohol or 5-10%, dry or direct dry granulation, granulate, encapsulated or be pressed into tablet.
The raw material of above-mentioned capsule or tablet is preferably:
Extract of hypericum perforatum 152 weight portions add carboxymethyl starch sodium 38 weight portions.
The raw material of above-mentioned capsule or tablet is preferably:
Extract of hypericum perforatum 152 weight portions add carboxymethyl starch sodium 45 weight portions, microcrystalline Cellulose 10 weight portions, pre-paying starch 10 weight portions.
The raw material of above-mentioned capsule or tablet is preferably:
Extract of hypericum perforatum 152 weight portions add carboxymethyl starch sodium 27 weight portions, microcrystalline Cellulose 10 weight portions, magnesium stearate 1 weight portion.
The content of medicine per unit preparation of the present invention (every or every) is as follows: medicine per unit preparation of the present invention contains total flavones with hyperin (C with determined by ultraviolet spectrophotometry
21H
20O
12) meter, should be 70.0mg～145.0mg, should be 3.0mg～10.0mg with the high effective liquid chromatography for measuring Determination of Hyperoside, should be 0.15mg～0.6mg with the high effective liquid chromatography for measuring Determination of Hypericin from Extraction, the stripping quantity of per unit preparation is in 70% of hyperin 〉=formulation content.
The preparation method of medicine of the present invention is preferably as follows step:
Get Herba Hyperici Monogyni medical material chopping, with 55% alcohol reflux 3 times: add 10 times of weight solvents for the first time, soak extraction after 8 hours, return time 2 hours; For the second time add 6 times of weight solvents, refluxed 1 hour; Add for the third time 6 times of weight solvents, refluxed 1 hour, merge behind three extracting solution concentrated, Recycled ethanol, concentrated extracting solution to relative density is 1.00 ~ 1.05 (30 ℃); Add water and ethanol dilution to 5 times of medical material weight, and transfer to that to contain alcohol amount be 15%, mixing, centrifugal; Supernatant is crossed the macroporous adsorptive resins of the D-101 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 5 times of column volume, discards water lotion; Use again 70% ethanol elution, collect eluent, Recycled ethanol, concentrate eluant to relative density is 1.00～1.05 (30 ℃), spray drying namely gets extract of hypericum perforatum; The extract that the present invention makes adds conventional adjuvant, makes clinical acceptable dosage form according to common process.
The preparation method of medicine of the present invention is preferably as follows step:
Get Herba Hyperici Monogyni medical material chopping, with 55% alcohol reflux 3 times: add 10 times of weight solvents for the first time, soak extraction after 8 hours, return time 2 hours; For the second time add 6 times of weight solvents, refluxed 1 hour; Add for the third time 6 times of weight solvents, refluxed 1 hour, the extracting solution gradation is concentrated, Recycled ethanol, and merging three concentrated solution to concentrated solution cumulative volumes is 3 times of medical material weight, relative density is 1.00 ~ 1.05 (30 ℃); Add water and ethanol dilution to 5 times of medical material weight, and transfer to that to contain alcohol amount be 15%, mixing, centrifugal; Supernatant is crossed the macroporous adsorptive resins of the D-101 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 3 times of column volume, discards water lotion; Use again 90% ethanol elution, collect eluent, Recycled ethanol, concentrate eluant to relative density is 1.00～1.05 (30 ℃), spray drying namely gets extract of hypericum perforatum; The extract that the present invention makes adds conventional adjuvant, makes clinical acceptable dosage form according to common process.
The preparation method of medicine of the present invention is preferably as follows step:
Get Herba Hyperici Monogyni medical material chopping, with 70% alcohol reflux 2 times: add 12 times of weight solvents and directly extract return time 2 hours the first time; For the second time add 8 times of weight solvents, refluxed 1 hour; The extracting solution gradation is concentrated, Recycled ethanol, and merging twice concentrated solution to concentrated solution volume is 3.5 times of medical material weight, relative density is 1.00 ~ 1.05 (30 ℃); Add water and ethanol dilution to 4.5 times of medical material weight, and transfer to that to contain alcohol amount be 10%, mixing, centrifugal; Supernatant is crossed the macroporous adsorptive resins of the AB-8 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 3 times of column volume, discards water lotion; Use again 70% ethanol elution, collect eluent, Recycled ethanol, concentrate eluant to relative density is 1.00～1.05 (30 ℃), spray drying namely gets extract of hypericum perforatum; The extract that the present invention makes adds conventional adjuvant, makes clinical acceptable dosage form according to common process.
The preparation method of medicine of the present invention is preferably as follows step:
Get the chopping of Herba Hyperici Monogyni medical material, extract 2 times with 80% methanol eddy: add 12 times of weight solvents for the first time and directly extract return time 2 hours; For the second time add 8 times of weight solvents, refluxed 1 hour; Reclaim methanol, it is 3.5 times of medical material weight that extracting solution is concentrated into volume, and relative density is 1.00 ~ 1.05 (30 ℃); Add water and ethanol dilution to 4 times of medical material weight, and transfer to that to contain alcohol amount be 20%, mixing, centrifugal; Supernatant is crossed the macroporous adsorptive resins of the NKA-12 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 1 times of column volume, discards water lotion; Use again 80% ethanol elution, collect eluent, Recycled ethanol, concentrate eluant to relative density is 1.00～1.05 (30 ℃), spray drying namely gets extract of hypericum perforatum; The extract that the present invention makes adds conventional adjuvant, makes clinical acceptable dosage form according to common process.
The preparation method of medicine of the present invention is preferably as follows step:
Get Herba Hyperici Monogyni medical material chopping, with 55% alcohol reflux 3 times: add 10 times of weight solvents for the first time, soak extraction after 12 hours, return time 2 hours; For the second time add 6 times of weight solvents, refluxed 1 hour; Add for the third time 6 times of weight solvents, refluxed 1 hour, merge behind three extracting solution concentrated, Recycled ethanol, 1.00 ~ 1.05 (without the alcohol flavors) when concentrated extracting solution to relative density is 30 ℃; Thin up is to 6 times of medical material weight, and mixing is centrifugal; Supernatant is crossed the macroporous adsorptive resins of the D-101 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 5 times of column volume, discards water lotion; Use again 50% ethanol elution, collect eluent, Recycled ethanol, when concentrate eluant to relative density is 30 ℃ 1.00 ~ 1.05, spray drying namely gets extract of hypericum perforatum; The extract that the present invention makes adds conventional adjuvant, makes clinical acceptable dosage form according to common process.
Extract of hypericum perforatum is used for the treatment of the history of the existing centuries of depression in Europe, the nineties, state's clinical experiment such as moral, method showed, Herba Hyperici Monogyni is suitable to curative effect and fluoxetine light, moderate depressive patients, and side effect obviously reduces and incidence rate is low, and the patient is better to its tolerance.The Herba Hyperici Monogyni medical material is widely distributed in China, domestic research mainly concentrates on the basic research of the aspects such as resource distribution, Preparation process, collecting season, extracting method and analytical method, the present invention provides a kind of new medicine and preparation technology thereof on the basis of analysing in depth Herba Hyperici Monogyni active ingredients of medicinal materials and physicochemical property thereof.
Following experimental example and embodiment are used for further specifying but are not limited to the present invention.
Experimental example: extract of hypericum perforatum preparation prescription, technical study
The selection of experimental example 1 wet granulation wetting agent
After Herba Hyperici perforati extract is medicinal material extract, through the macroporous adsorbent resin separation and purification, the extract of gained after the spray drying, opaque is light, and poor fluidity is difficult to directly encapsulatedly, need to carry out the research of preparation prescription, technique.
1.1 experimental program
Relatively dehydrated alcohol, 5% starch slurry are that wetting agent is on the impact of grain forming in the wet granulation, and the amount ratio of the mixture (extract of hypericum perforatum 152 weight portions add carboxymethyl starch sodium 38 weight portions) of investigating extract of hypericum perforatum and adjuvant and different wetting agents is on the impact of grain forming.
1.2 experimental result
The results are shown in Table 1:
Table 1 wetting agent kind and use scale
Annotate: it is rear in 60 ℃ of dryings (moisture 3 ~ 4%), 16 mesh sieve granulate to granulate.
Experiment conclusion
According to result of the test, wetting agent can be selected 5% starch slurry and dehydrated alcohol, considers to answer first-selected dehydrated alcohol from amplifying the angle of producing, and wetting agent is 1: 4 with the amount of mixture ratio.
The selection of experimental example 2 disintegrating agents
2.1, the purpose selected of disintegrating agent
Find in the test Herba Hyperici perforati extract is directly loaded capsule, the capsule 's content disintegrate is slower, and is low at the in setting time capsule dissolubility, will affect medicine absorption in vivo, so need to add adjuvant in the extract to solve the problem of capsule dissolubility.
2.2, experimental program
2.2.1 preparation prescription
Select one or more adjuvants in carboxymethyl starch sodium, microcrystalline Cellulose, polyvinylpolypyrrolidone, pregelatinized Starch, lactose, Pulvis Talci, the magnesium stearate, with the extract of hypericum perforatum mixing, preparation prescription A～F combination is as follows:
A, extract of hypericum perforatum 152 weight portions add carboxymethyl starch sodium 38 weight portions;
B, extract of hypericum perforatum 152 weight portions add carboxymethyl starch sodium 45 weight portions, microcrystalline Cellulose 10 weight portions, pregelatinized Starch 10 weight portions;
C, extract of hypericum perforatum 152 weight portions add carboxymethyl starch sodium 27 weight portions, microcrystalline Cellulose 10 weight portions, magnesium stearate 1 weight portion;
D, extract of hypericum perforatum 152 weight portions add carboxymethyl starch sodium 4 weight portions, polyvinylpolypyrrolidone 3 weight portions, microcrystalline Cellulose 20 weight portions, pregelatinized Starch 10 weight portions, Pulvis Talci 1 weight portion;
E, extract of hypericum perforatum 152 weight portions add carboxymethyl starch sodium 18 weight portions, microcrystalline Cellulose 10 weight portions, lactose 10 weight portions;
F, extract of hypericum perforatum 152 weight portions add carboxymethyl starch sodium 5 weight portions, polyvinylpolypyrrolidone 15 weight portions, microcrystalline Cellulose 10 weight portions, starch 8 weight portions.
2.2.2 method of granulating
Respectively write out a prescription behind extract and the adjuvant mix homogeneously by above-mentioned, with the ratio wet granulation of dehydrated alcohol with 1: 4, dry, granulate, fill capsule No. 2, measure dissolution according to 2005 editions two appendix of Chinese Pharmacopoeia, be calculated as follows every capsules dissolution according to the stripping quantity of every capsules hyperin, to determine kind and the consumption of disintegrating agent.
2.2.3 dissolution determination condition
The dissolution determination condition: turn the basket method, dilute hydrochloric acid 24ml and ethanol 165ml add water to 1000ml, and getting 900ml is dissolution medium, and rotating speed is 100 rev/mins, the stripping quantity of 45min sampling and measuring hyperin.
2.3, instrument and reagent
2.3.1, RCZ-8A intellectual drug digestion instrument (Precision Instrument Factory, Tianjin Univ.)
2.3.2, starch, pregelatinized Starch, microcrystalline Cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, lactose, Pulvis Talci, magnesium stearate: pharmaceutical grade, meet under Chinese Pharmacopoeia version adjuvant in 2005 item and stipulate
2.4, experimental result
Measurement result sees Table 2:
The choice experiment of table 2 disintegrating agent
Annotate: the dissolution of each prescription is with the mean value calculation of 6 capsules dissolutions
According to upper table measurement result, select one or more adjuvants of carboxymethyl starch sodium, pregelatinized Starch, microcrystalline Cellulose to make disintegrating agent, its dissolution test of A～C of namely writing out a prescription meets the preparation quality standard regulation.
The comparison of experimental example 3 dry granulations and wet granulation
3.1, experimental program
Dry-pressing is granulated: by prescription A～D with extract and adjuvant mix homogeneously after, the dry-pressing granulation, the pressure during dry-pressing is 3MPa～5MPa, and makes particle diameter 30～50 order grain amount＞65%, loads No. 2 capsule.
Wet granulation: by prescription A～D with extract and adjuvant mix homogeneously after, the usefulness dehydrated alcohol is with 1: 4 ratio wet granulation, 60 ℃ of dryings, granulate is loaded No. 2 capsule.
3.2, experimental result
Experimental result sees Table 3
Table 3 is done the comparative experiments of wet method preparation process
From the interpretation of table 3, prescription A～C no matter with dry granulation or wet granulation dissolution test all＞70%, and two kinds of granulation mode difference are little, the dried wet granulation dissolution test of prescription D is all lower.
Experimental example 4 micropowders are mobile, the mensuration of bulk density
4.1, experimental program
Preparation prescription A～C presses dry granulation, granulate, loads capsule, measures mobility of particle and bulk density, and can investigation load capsule.
The micropowder flowability is with representing that the assay method of angle of repose is angle of repose: powder body freely falls the formation accumulation body from funnel, and radius is R; Measure the height H of heap body, tan θ=H/R then, the θ angle is angle of repose.θ angle more small flow is larger.
Micropowder bulk density assay method is: the micropowder filling in graduated cylinder, and vibrated by certain mode, and consistent to guarantee experiment condition, favorable reproducibility.Measure the micropowder volume, try to achieve bulk density by quality and volume, " heavy " and " lightweight " of bulk density reaction micropowder.
4.2, experimental result
Measurement result sees Table 4.
The measurement result of table 4 granule angle of repose, bulk density
Annotate: measurement result N=3
From the interpretation of result of table 4, prescription A～C press behind dry granulation, the granulate 30 ° of θ ° of ≈ angle of repose, satisfies the requirement of θ °＜40 ° of granule filling capsules, and bulk density ≈ 0.7 can satisfy the requirement of No. 2 capsules of filling.
Experimental example 5
1 test objective
Verify effectiveness and the safety of the light moderate depressive patients of Drug therapy of the present invention.
2 cases are selected
The outpatient service or the inpatient that meet CCMD-3 depression outbreak diagnostic criteria in 18-65 year.In the HMAD17 of examination and baseline period total points 〉=17 and≤24 minutes.Researcher judges that according to medical history, physical examination, electrocardiogram and clinical laboratory's check result of experimenter in the examination phase experimenter is healthy except depression.The experimenter must sign Informed Consent Form.
3 test methods
3.1 master-plan
This research is adopted at random, Double-blind double-dummy, masculine parallel comparison, polycentric test method.Investigational agent is the medicine of the present invention of embodiment 1 preparation, is divided into two groups of high and low dose; The contrast medicine is fluoxetine tablets.Effective case 450 examples are finished in this test at least, and the reason of considering to come off enters group 540 examples altogether, adopts the stratified random method, and ratio is 1: 1: 1 at random, is divided into three groups, medicine low dose group 180 examples of the present invention, high dose group 180 examples, matched group 180 examples.Whole research is finished by 10 test centers.
Table of random number is provided by the statistics personnel, utilizes the SAS software simulation to produce.By finishing the preparation that medicine is compiled blind and emergent mail with the irrelevant personnel of this clinical trial.
3.2 dosage regimen
Oral administration, in 6 weeks of the course for the treatment of, medication is as follows:
Medicine low dose group of the present invention (600mg/d):
Early: 2 of 2+fluoxetine of medicament capsule of the present invention placebo;
Evening: 1 of 2+medicament capsule placebo of the present invention of medicament capsule of the present invention;
Medicine high dose group of the present invention (750mg/d):
Early: 2 of 2+fluoxetine of medicament capsule of the present invention placebo
Evening: 3 of medicament capsules of the present invention;
Fluoxetine group (20mg/d):
Early: 2 of 2+fluoxetine tablets of medicament capsule placebo of the present invention
Evening: 3 of medicament capsule placebo of the present invention
3.3 curative effect index
The curative effect index: experimenter's ratio (being defined as recovery from illness) of HAMD17 item total points≤7 when increasing the treatment end, will be to subtract score value as major variable with non-bad effect check.
The secondary efficacy index: Hamilton anxiety scale (HAMA), clinical global impression scale (CGI) and each factor of HAMD are divided the situation of change when dividing with baseline relatively with clauses and subclauses.
3.4 Safety Evaluation Index
Comprise that treatment finishes relatively to have with baseline physical examination, vital sign, electrocardiogram and clinical laboratory's check result of clinical meaning by the spontaneous report of experimenter and the adverse events found by researcher.
3.5 the regulation of following up a case by regular visits to
Make a house call altogether 5 times :-7/-3 days, 0 day, 2 weekends, 4 weekends, 6 weekends.Mainly following up a case by regular visits to content is HAMD17, HAMA, CGI scoring, laboratory inspection, adverse events assessment.
3.6 statistical analysis plan
Statistical analysis will adopt the SAS6.12 statistical analysis software to calculate, and be finished by the statistician.
All statistical test all adopt two-sided test, and the P value is less than or equal to 0.05 difference that will be considered to check statistical significance (special instruction except).The description of quantitative target is with calculated example number, mean, standard deviation, median, minima, maximum.The description of classification indicators is with all kinds of routine number and percent.
Efficiency analysis:
(1) major variable: Hamilton depressive scale (HAMD) 17 total points, HAMD subtract minute rate and classification curative effect thereof, and the indexs such as experimenter's ratio (the being defined as cure rate) employing that total points subtracted experimenter's ratio (being defined as effective percentage) of a minute rate 〉=50% and HAMD17 item total points≤7 when the HAMD total points was than baseline when treatment finished compares three groups respectively by CMH-χ 2 analytical methods of center layering.
Describe make a house call HAMD17 item total points and relative baseline variation thereof, the changing value of the relative baseline of total points adopts analysis of covariance model to carry out three groups relatively during to 6 week, must be divided into covariant with baseline in the model at every turn, and consideration is divided into groups, the effect at center.Simultaneously, take this model as basis, least squares means and 95% credibility interval thereof of calculating per two groups difference.If the upper limit of 95% credibility interval of medicine various dose group of the present invention and fluoxetine group group difference estimated value, then can draw the non-conclusion that is inferior to contrast medicine fluoxetine of investigational agent medicine of the present invention less than 3 minutes.
(2) secondary variable: describe and to make a house call at every turn that the HAMD factor is divided, HAMA total points, the HAMA factor divide, and baseline changes relatively, the changing value of the relative baseline of total points during to 6 week adopts analysis of covariance model to carry out three groups relatively; Adopting the Kruskal-wallis rank test that each individual event of Hamilton depressive scale (HAMD) of three groups is divided with CGI compares.
Safety analysis:
When tabulation is described adverse events that this test occurs, lab test results normal/abnormal situation of change and abnormal before and after test and is changed and the relation of trial drug.
4 result of the tests
4.1 case enters group/dropping situations
Collect altogether patient's 538 examples that meet into the group standard and participate in research, medicine low dose group 179 examples of the present invention wherein, medicine high dose group 180 examples of the present invention, fluoxetine group 179 examples; Finish case totally 490 examples, medicine low dose group 164 examples of the present invention wherein, medicine high dose group 160 examples of the present invention, fluoxetine group 166 examples; The audit of ignorant of the economics attitude judges that 525 routine patient's use research medicines have also carried out safety evaluatio, medicine low dose group 177 examples of the present invention, medicine high dose group 175 examples of the present invention, fluoxetine group 173 examples; 524 routine patients enter the ITT crowd of therapeutic evaluation, medicine low dose group 177 examples of the present invention, medicine high dose group 174 examples of the present invention, fluoxetine group 173 examples; 481 examples depart from without obvious scheme, enter PP crowd, medicine low dose group 160 examples of the present invention, medicine high dose group 158 examples of the present invention, fluoxetine group 163 examples.
This test 48 examples that come off altogether, total expulsion rate is 8.92% (48/538), medicine low dose group of the present invention 15 examples that come off wherein, medicine high dose group of the present invention 20 examples that come off, fluoxetine group 13 examples that come off, the main reason that comes off is to lose to visit.Three groups of expulsion rates compare no difference of science of statistics.This clinical trial is because of adverse events 9 examples that come off, medicine low dose group 3 examples of the present invention wherein, and medicine high dose group 5 examples of the present invention, fluoxetine group 1 example, three groups are suitable because of the adverse events routine number that comes off.Good and the three treatment group compliances of all experimenters' overall drug compliance are at a little more equal no difference of science of statistics of respectively making a house call in the research.
4.2 analysis of comparable between the baseline characteristic data set
Medicine low dose group of the present invention, medicine high dose group of the present invention and fluoxetine group are at comparing difference not statistically significants such as age distribution, sex, nationality, marital status, bearing status, residential areas.Patient's First episode age, whether lived the mental hospital, live three groups of comparing differences such as mental hospital's mean age, inducement of this time outbreak, the situation of receiving treatment first and also do not have statistical significance.The demography data and the medical history data aspect that show three groups have good comparability in baseline period.
More also there was no significant difference between three groups of the total points of baseline HAMD, HAMA and CGI-S shows that three groups of disease severities have good comparability in baseline period.
4.3 drug combination situation
Three are combined medication take the sedative hypnotic as main (Benzodiazepines and Non-benzodiazepine), what medicine low dose group of the present invention merged the sedative hypnotic has 40 examples (22.35%), high dose group has 40 examples (22.22%), the fluoxetine group has 42 examples (23.46%), three to be combined the medication number suitable, merges reason and be mainly insomnia.
4.4 curative effect index evaluation result
No matter ITT or PP crowd, three groups after 6 weeks for the treatment of the HAMD17 scoring subtract than self baseline and minute statistical significance arranged all, show that medicament capsule of the present invention and fluoxetine tablets all have preferably curative effect to light moderate depressive patients patient.
ITT crowd: medicine low dose group of the present invention, medicine high dose group of the present invention and fluoxetine group subtract than baseline after 6 weeks and minute are respectively 12.37,11.89 and 12.67, three groups of comparing differences and do not have statistical significance.Least squares means (LSMEANS) and 95% credibility interval of the difference that the HAMD total points changes between two groups of calculating based on this are as follows: medicine low dose group of the present invention-fluoxetine group: 0.34 (0.79,1.48); Medicine high dose group of the present invention-fluoxetine group: 0.64 (0.50,1.78); The absolute value of the upper limit of above-mentioned 95% credibility interval is all less than the non-bad effect dividing value of scheme regulation 3 minutes, and the curative effect that medicine low dosage of the present invention and high dose group be described is non-bad the effect in the fluoxetine group all.Three groups subtract minute rate and approach, and medicine low dose group of the present invention, medicine high dose group of the present invention and fluoxetine group are respectively 61.08%, 59.37% and 63.13%; Three groups effective percentage is suitable, and being respectively does not relatively have significant difference between 77.97%, 79.31% and 81.50%, three group; Three groups of clinical recovery rates are respectively: 48.02%, more also do not have significant difference between 51.72% and 57.23%, three group.Each center result is consistent.
PP crowd: medicine low dose group of the present invention, medicine high dose group of the present invention and fluoxetine group subtract than baseline after 6 weeks and minute are respectively 12.78,12.70 and 13.08, three groups of comparing differences and do not have statistical significance.Least squares means (LSMEANS) and 95% credibility interval of the difference that the HAMD total points changes between two groups of calculating based on this are as follows: medicine low dose group of the present invention-fluoxetine group: 0.29 (0.77,1.34); Medicine high dose group of the present invention-fluoxetine group: 0.23 (0.83,1.29); The absolute value of the upper limit of above-mentioned 95% credibility interval is all less than the non-bad effect dividing value of scheme regulation 3 minutes, and the curative effect that medicine low dosage of the present invention and high dose group be described is non-bad the effect in the fluoxetine group all.Three groups subtract minute rate and approach, and medicine low dose group of the present invention, medicine high dose group of the present invention and fluoxetine group are respectively 63.16%, 63.50% and 65.10%; Three groups effective percentage is suitable, and being respectively does not relatively have significant difference between 81.25%, 85.44% and 84.66%, three group; Three groups of clinical recovery rates are respectively: 51.25%, more also do not have significant difference between 56.33% and 58.90%, three group.Each center result is consistent.
Above data show that all medicament capsule of the present invention is to non-bad the effect in fluoxetine tablets of the curative effect of light moderate depressive patients.
4.5 secondary efficacy index evaluation result
4.5.1HAMD the factor is divided
Treating for 6 weekends, the anxiety/somatization of ITT crowd HAMD17, retardance, cognitive disorder and four factors of sleep disorder divide change take baseline as covariant, the covariance analysis result of consideration center, grouping effect shows three treatment group difference not statistically significants (being P＞0.05), adopts the result of the rank test body weight factor to show also not statistically significant (P=0.9930) of three treatment group differences; In addition, three groups of patient anxiety/somatizations, body weight, retardance, cognitive disorder and sleep disorder factors are all significantly improved (P＜0.001) than the baseline period score; All fine depressive symptoms such as anxiety, cognitive disorder and sleep disorder that improve of energy of two medicines are described, the improvement degree is suitable.In addition, consideration center and the interactive analysis of covariance model result for the treatment of grouping show: non-interaction action between center and treatment, each center result is consistent.PP crowd's result is consistent with ITT.
4.5.2HAMA total points and the factor are divided
Medicine low dose group HAMA scoring of the present invention is 15.45 during ITT crowd's baseline, treatment is 5.95 during 6 week, be 14.58 during medicine high dose group baseline of the present invention, treatment is 6.29 during 6 week, be 14.96 during fluoxetine group baseline, 6 whens week for the treatment of are that comparing differences all have statistical significance (P＜0.001) before and after 5.43, three groups of treatments, show the have some improvement effect of anxiety of two medicines.Subtract score value before and after three groups of treatments and be respectively 9.49,8.29 and 9.53, three groups of differences and do not have statistical significance (P=0.125), show that medicine of the present invention is suitable with the fluoxetine angst resistance effect.Three groups of spirituality anxieties are consistent with the score variation of somatic anxiety treatment front and back and the variation of HAMA total points in addition, show that two medicines all have the effect for the treatment of preferably spirituality anxiety and somatic anxiety.PP crowd is consistent with ITT crowd result.
4.5.3CGI evaluation
Treating for 6 weekends, adopting the result of rank test to show three group difference not statistically significants (being P＞0.05), showing that the state of an illness improvement degree of medicine low dose group of the present invention, high dose group and fluoxetine group depressive patient is similar.Three groups of CGI-S and CGI-I score all significantly reduce (P＜0.001) than self baseline period in addition, show that three groups of patient's state of an illness order of severity after Drug therapy significantly alleviates, and be overall significantly progressive.PP crowd is consistent with ITT crowd result.
4.5.4HAMD17 individual event divides
Treating for 6 weekends, adopting the result of rank test to show that all individual event scores of HAMD17 change the equal not statistically significant of three group differences (being P＞0.05).In addition, three groups of all individual event scores of HAMD17 all have obvious reduction (P＜0.001) than baseline period, further illustrate medicament capsule of the present invention and fluoxetine and all have a better role to patients with depression HAMD is every.PP crowd is consistent with ITT crowd result.
4.5.5 onset time is analyzed
When treating for 2 week, medicine low dose group of the present invention, high dose group and fluoxetine group HAMD17 total points, HAMA total points and CGI-S scoring and CGI-I scoring all have the decline (P＜0.001) of significance than baseline period, show three groups of onsets after 2 weeks of administration; Along with three groups of HAMD17 total points of increase of administration time, HAMA total points and CGI-S scoring and CGI-I scoring are all minute more remarkable than subtracting of baseline period, subtracting minute rate and effective percentage, clinical recovery rate also increases gradually, but three groups of each time point CGI-S, CGI-I, efficient more equal no difference of science of statistics (P＞0.05) show that three groups of curative effects are all close at each time point.It is consistent with the HAMD total points that the HAMD17 factor is divided, individual event divides, and the HAMA factor is divided consistent with the HAMA total points.PP crowd is consistent with ITT crowd.
4.5.6 safety evaluatio result
Test has 525 routine experimenters and includes safety analysis in.Total adverse events incidence rate medicine low dose group of the present invention is 17.51%, and medicine high dose group of the present invention is 23.43%, and the fluoxetine group is 17.92%, three group incidence rate no significant difference.The incidence rate medicine low dose group of the present invention of relevant adverse events is 14.69%, and medicine high dose group of the present invention is 20.00%, and the fluoxetine group is 15.03%; Common untoward reaction is respectively xerostomia (medicine low dose group 0.56% of the present invention, medicine high dose group 4.57% of the present invention, fluoxetine group 3.47%), feeling sick, (medicine low dose group of the present invention is 1.13%, medicine high dose group of the present invention is 2.29%, the fluoxetine group is 2.89%), (medicine low dose group of the present invention is 1.13% to anorexia, medicine high dose group 1.14% of the present invention, the fluoxetine group is 2.89%), (medicine low dose group of the present invention is 2.82% to stomach discomfort, medicine high dose group of the present invention is 1.14%, the fluoxetine group is 1.16%), it is dizzy that (medicine low dose group of the present invention is 2.26%, medicine high dose group of the present invention is 1.71%, the fluoxetine group is 2.31%), (medicine low dose group of the present invention is 1.69% in headache, medicine high dose group 1.71% of the present invention, fluoxetine group 0.58%) etc., three groups of common adverse events incidence rates are all less, xerostomia, feel sick and wait medicine low dose group of the present invention to be significantly less than other two groups, anorexia medicine low dose group of the present invention and medicine high dose group of the present invention are starkly lower than the fluoxetine group.Anaphylaxis medicine low dose group 4 examples of the present invention, medicine high dose group 4 examples of the present invention, fluoxetine group 1 example appear in duration of test.Three groups of adverse events severity of symptom that occur mostly are slightly, are individually moderate.Duration of test occurs without photosensitive reaction, occurs without serious adverse events.
Two medicines are to blood, routine urinalysis, and liver, renal function, electrocardiogram and vital sign are all without significantly impact.
5 conclusions
The antidepressant of medicament capsule of the present invention, anxiety curative effect are similar to fluoxetine, and total adverse events incidence rate is all lower.The antidepressant of medicine low dose group of the present invention, anxiety curative effect slightly are lower than medicine high dose group of the present invention, and the adverse events incidence rate is lighter.Result of study proved invention medicine is a kind of safe and effective antidepressant drug.The optimal dose of clinical recommendation is 600-750mg/d.
Following embodiment all can realize the effect of above-mentioned experimental example.
The specific embodiment
Embodiment 1:
Get the segment that Herba Hyperici Monogyni medical material 100kg cuts into 2-3cm, with 55% alcohol reflux 3 times: add 10 times of weight solvents for the first time, soaks extraction after 8 hours, return time 2 hours; For the second time add 6 times of weight solvents, refluxed 1 hour; Add for the third time 6 times of weight solvents, refluxed 1 hour, merge behind three extracting solution concentratedly, Recycled ethanol is concentrated into 30 ℃ lower 1.004 of relative densities; Add water and ethanol dilution to 5 times of medical material weight, and transfer to that to contain alcohol amount be 15%, mixing, centrifugal; Supernatant is crossed the macroporous adsorptive resins of the D-101 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 5 times of column volume, discards water lotion; Use again 70% ethanol elution, collect eluent, Recycled ethanol, and concentrate eluant is lower 1.003 to 30 ℃ of relative densities, spray drying gets extract of hypericum perforatum 3.76kg.
Extract is in dry product, and total flavones is with hyperin (C
21H
20O
12) meter content 69.84%, Determination of Hyperoside 4.06%, Determination of Hypericin from Extraction 0.26%, moisture 4.5%, residue on ignition 1.67% resin residue quality testing are looked into and are met content regulation (benzene≤2ppm, toluene≤20ppm, dimethylbenzene≤20ppm, styrene≤2ppm, divinylbenzene≤20ppm, normal hexane≤20ppm, hexahydrotoluene≤20ppm).
Get extract of hypericum perforatum 152g, add carboxymethyl starch sodium 38g, mixing is wetting agent with dehydrated alcohol, wet granulation, and drying, granulate incapsulates, and makes 1000 capsules, and dissolution test is 93%.
Embodiment 2:
Herba Hyperici Monogyni medical material 100kg cuts into the segment of 2-3cm, with 55% alcohol reflux 3 times: add 10 times of weight solvents for the first time, soaks extraction after 8 hours, return time 2 hours; For the second time add 6 times of weight solvents, refluxed 1 hour; Add for the third time 6 times of weight solvents, refluxed 1 hour, the extracting solution gradation is concentrated, and merging three concentrated solution to concentrated solution volumes is 305L, relative density 1.006 (30 ℃); Add water and ethanol dilution to 5 times of medical material weight, and transfer to that to contain alcohol amount be 15%, mixing, centrifugal; Supernatant is crossed the macroporous adsorptive resins of the D-101 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 3 times of column volume, discards water lotion; Use again 70% ethanol elution, collect eluent, Recycled ethanol, and to be concentrated into relative density be 1.013 ℃, spray drying gets tan powder 3.2kg.
Extract is in dry product, and total flavones is with hyperin (C
21H
20O
12) meter content 95%, Determination of Hyperoside 4.7%, Determination of Hypericin from Extraction 0.18%, moisture 5.1%, residue on ignition 1.52% resin residue quality testing are looked into and are met the content regulation;
Get extract of hypericum perforatum 152g, add carboxymethyl starch sodium 38g, mixing, dry-pressing is granulated, and granulate incapsulates, and makes 1000 capsules, and dissolution test is 90%.
Embodiment 3:
Herba Hyperici Monogyni medical material 100kg cuts into the segment of 2-3cm, with 70% alcohol reflux 2 times: add 12 times of weight solvents for the first time and directly extract return time 2 hours; For the second time add 8 times of weight solvents, refluxed 1 hour; The extracting solution gradation is concentrated, merges twice concentrated solution to relative density 1.021 (30 ℃); Add water and ethanol dilution to 4.5 times of medical material weight, and transfer to that to contain alcohol amount be 10%, mixing, centrifugal; Supernatant is crossed the macroporous adsorptive resins of the AB-8 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 3 times of column volume, discards water lotion; Use again 70% ethanol elution, collect eluent, Recycled ethanol, and to be concentrated into relative density be 1.036 (30 ℃), spray drying gets tan powder 3.67kg;
Extract is in dry product, and total flavones is with hyperin (C
21H
20O
12) meter content 52.5%, Determination of Hyperoside 2.0%, Determination of Hypericin from Extraction 0.4%, moisture 4.8%, residue on ignition 1.76% resin residue quality testing are looked into and are met the content regulation;
Get extract of hypericum perforatum 152g, add carboxymethyl starch sodium 18g, microcrystalline Cellulose 10g, pregelatinized Starch 10g mixing is used the dehydrated alcohol wet granulation, drying, granulate, the lubricants such as adding magnesium stearate are an amount of, are pressed into 1000, and dissolution test is 80%.
Embodiment 4:
Herba Hyperici Monogyni medical material 100kg cuts into the segment of 2-3cm, extracts 2 times with 80% methanol eddy: add 12 times of weight solvents for the first time and directly extract return time 2 hours; For the second time add 8 times of weight solvents, refluxed 1 hour; Extracting solution is concentrated into relative density 1.035 (30 ℃); Add water and ethanol dilution to 4 times of medical material weight, and transfer to that to contain alcohol amount be 20%, mixing, centrifugal; Supernatant is crossed the macroporous adsorptive resins of the NKA-12 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 1 times of column volume, discards water lotion; Use again 80% ethanol elution, collect eluent, Recycled ethanol, and to be concentrated into relative density be 1.041 (30 ℃), spray drying gets tan powder 2.95kg;
Extract is in dry product, and total flavones is with hyperin (C
21H
20O
12) meter content 85.2%, Determination of Hyperoside 3.1%, Determination of Hypericin from Extraction 0.15%, moisture 4.1%, residue on ignition 1.50% resin residue quality testing are looked into and are met the content regulation;
Get extract of hypericum perforatum 152g, add carboxymethyl starch sodium 27g, microcrystalline Cellulose 10g, the starch slurry take 5% is the wetting agent wet granulation, drying, granulate adds magnesium stearate 1 weight portion, is pressed into 1000, and dissolution test is 78%.
Embodiment 5:
Get Herba Hyperici Monogyni medical material 100kg chopping, with 55% alcohol reflux 3 times: add 10 times of weight solvents for the first time, soak extraction after 12 hours, return time 2 hours; For the second time add 6 times of weight solvents, refluxed 1 hour; Add for the third time 6 times of weight solvents, refluxed 1 hour, merge behind three extracting solution concentrated, Recycled ethanol, 1.04 (without the alcohol flavors) when concentrated extracting solution to relative density is 30 ℃; Thin up is to 6 times of medical material weight, and mixing is centrifugal; Supernatant is crossed the macroporous adsorptive resins of the D-101 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 5 times of column volume, discards water lotion; Use again 50% ethanol elution, collect eluent, Recycled ethanol, when concentrate eluant to relative density is 30 ℃ 1.012, spray drying namely gets extract of hypericum perforatum 3.2kg.
Extract is in dry product, and total flavones is with hyperin (C
21H
20O
12) meter content 90.0%, Determination of Hyperoside 4.1%, Determination of Hypericin from Extraction 0.23%, moisture 4.6%, residue on ignition 1.78% resin residue quality testing are looked into and are met the content regulation;
Get extract of hypericum perforatum 152g, add carboxymethyl starch sodium 38g, dry-pressing is granulated, and granulate is dressed up 1000 capsules, and dissolution test is 85%.
Claims (16)
1. the medicine of a Cure of depression, it is characterized in that this medicine makes by the following method: get the chopping of Herba Hyperici Monogyni medical material, extract 2-3 time with 30-80% ethanol or 30-100% methanol eddy: add 8-12 times of weight solvent for the first time, direct reflux, extract, or immersion reflux, extract, after 2-16 hour, return time 2 hours; For the second time and/or add respectively for the third time 4-8 times of weight solvent, refluxed 1 hour at every turn; The extracting solution graded concentrated or merge after concentrate again, reclaim solvent, being concentrated into relative density is 1.00～1.05 in the time of 30 ℃; Add water and ethanol dilution to the 3-7 of medical material weight doubly, and transfer to and contain the alcohol amount and be 10-20%, mixing, centrifugal; Supernatant is crossed the D-101 macroporous adsorptive resins of handling well, stops loading after resin absorption is saturated; Wash with water, till the eluent clarification, discard water lotion; Use again the 50-90% ethanol elution, collect eluent, Recycled ethanol, concentrate eluant is 1.00～1.05 to relative density 30 ℃ the time, spray drying namely gets extract of hypericum perforatum; The extract that makes adds conventional adjuvant, makes clinical acceptable dosage form according to common process.
2. medicine as claimed in claim 1 is characterized in that this medicine makes by the following method: get the chopping of Herba Hyperici Monogyni medical material, with 55% alcohol reflux 3 times: add 10 times of weight solvents for the first time, soak extraction after 8 hours, return time 2 hours; For the second time add 6 times of weight solvents, refluxed 1 hour; Add for the third time 6 times of weight solvents, refluxed 1 hour, merge behind three extracting solution concentratedly, Recycled ethanol is when concentrated extracting solution to relative density is 30 ℃ 1.00～1.05; Add water and ethanol dilution to 5 times of medical material weight, and transfer to that to contain alcohol amount be 15%, mixing, centrifugal; Supernatant is crossed the macroporous adsorptive resins of the D-101 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 5 times of column volume, discards water lotion; Use again 70% ethanol elution, collect eluent, Recycled ethanol, when concentrate eluant to relative density is 30 ℃ 1.00～1.05, spray drying namely gets extract of hypericum perforatum; The extract that makes adds conventional adjuvant, makes clinical acceptable dosage form according to common process.
3. medicine as claimed in claim 1 is characterized in that this medicine makes by the following method: get the chopping of Herba Hyperici Monogyni medical material, with 55% alcohol reflux 3 times: add 10 times of weight solvents for the first time, soak extraction after 8 hours, return time 2 hours; For the second time add 6 times of weight solvents, refluxed 1 hour; Add for the third time 6 times of weight solvents, refluxed 1 hour, the extracting solution gradation is concentrated, Recycled ethanol, and merging three concentrated solution to concentrated solution cumulative volumes is 3 times of medical material weight, when relative density is 30 ℃ 1.00～1.05; Add water and ethanol dilution to 5 times of medical material weight, and transfer to that to contain alcohol amount be 15%, mixing, centrifugal; Supernatant is crossed the macroporous adsorptive resins of the D-101 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 3 times of column volume, discards water lotion; Use again 90% ethanol elution, collect eluent, Recycled ethanol, when concentrate eluant to relative density is 30 ℃ 1.00～1.05, spray drying namely gets extract of hypericum perforatum; The extract that makes adds conventional adjuvant, makes clinical acceptable dosage form according to common process.
4. such as the preparation method of the arbitrary described medicine of claim 1-3, it is characterized in that the method is: get the chopping of Herba Hyperici Monogyni medical material, extract 2-3 time with 30-80% ethanol or 30-100% methanol eddy: add 8-12 times of weight solvent for the first time, direct reflux, extract, or immersion reflux, extract, after 2-16 hour, return time 2 hours; For the second time and/or add respectively for the third time 4-8 times of weight solvent, refluxed 1 hour at every turn; The extracting solution graded concentrated or merge after concentrate again, reclaim solvent, when being concentrated into relative density and being 30 ℃ 1.00～1.05; Add water and ethanol dilution to the 3-7 of medical material weight doubly, and transfer to and contain the alcohol amount and be 10-20%, mixing, centrifugal; Supernatant is crossed the macroporous adsorptive resins of the D-101 that handles well, stops loading after resin absorption is saturated; Wash with water, till the eluent clarification, discard water lotion; Use again the 50-90% ethanol elution, collect eluent, Recycled ethanol, when concentrate eluant to relative density is 30 ℃ 1.00～1.05, spray drying namely gets extract of hypericum perforatum; The extract that makes adds conventional adjuvant, makes clinical acceptable dosage form according to common process.
5. the preparation method of medicine as claimed in claim 4 is characterized in that the method is: get the chopping of Herba Hyperici Monogyni medical material, with 55% alcohol reflux 3 times: add 10 times of weight solvents for the first time, soak extraction after 8 hours, return time 2 hours; For the second time add 6 times of weight solvents, refluxed 1 hour; Add for the third time 6 times of weight solvents, refluxed 1 hour, merge behind three extracting solution concentratedly, Recycled ethanol is when concentrated extracting solution to relative density is 30 ℃ 1.00～1.05; Add water and ethanol dilution to 5 times of medical material weight, and transfer to that to contain alcohol amount be 15%, mixing, centrifugal; Supernatant is crossed the macroporous adsorptive resins of the D-101 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 5 times of column volume, discards water lotion; Use again 70% ethanol elution, collect eluent, Recycled ethanol, when concentrate eluant to relative density is 30 ℃ 1.00～1.05, spray drying namely gets extract of hypericum perforatum; The extract that makes adds conventional adjuvant, makes clinical acceptable dosage form according to common process.
6. the preparation method of medicine as claimed in claim 4 is characterized in that the method is: get the chopping of Herba Hyperici Monogyni medical material, with 55% alcohol reflux 3 times: add 10 times of weight solvents for the first time, soak extraction after 8 hours, return time 2 hours; For the second time add 6 times of weight solvents, refluxed 1 hour; Add for the third time 6 times of weight solvents, refluxed 1 hour, the extracting solution gradation is concentrated, Recycled ethanol, and merging three concentrated solution to concentrated solution cumulative volumes is 3 times of medical material weight, when relative density is 30 ℃ 1.00～1.05; Add water and ethanol dilution to 5 times of medical material weight, and transfer to that to contain alcohol amount be 15%, mixing, centrifugal; Supernatant is crossed the macroporous adsorptive resins of the D-101 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 3 times of column volume, discards water lotion; Use again 90% ethanol elution, collect eluent, Recycled ethanol, when concentrate eluant to relative density is 30 ℃ 1.00～1.05, spray drying namely gets extract of hypericum perforatum; The extract that makes adds conventional adjuvant, makes clinical acceptable dosage form according to common process.
7. the medicine of a Cure of depression that is made by extract of hypericum perforatum, it is characterized in that this medicine makes by the following method: get raw material, extract of hypericum perforatum 140-160 weight portion adds one or more in carboxymethyl starch sodium 20-50 weight portion, microcrystalline Cellulose 1-20 weight portion, pregelatinized Starch 1-20 weight portion, the magnesium stearate 1-3 weight portion; Mixing, with the starch slurry wet granulation of dehydrated alcohol or 5-10%, dry or direct dry granulation, granulate, encapsulated or be pressed into tablet; Wherein said extract of hypericum perforatum is made by the following method: get the chopping of Herba Hyperici Monogyni medical material, extract 2-3 time with 30-80% ethanol or 30-100% methanol eddy: add 8-12 times of weight solvent for the first time, direct reflux, extract, or immersion reflux, extract, after 2-16 hour, return time 2 hours; For the second time and/or add respectively for the third time 4-8 times of weight solvent, refluxed 1 hour at every turn; The extracting solution graded concentrated or merge after concentrate again, reclaim solvent, when being concentrated into relative density and being 30 ℃ 1.00～1.05; Add water and ethanol dilution to the 3-7 of medical material weight doubly, and transfer to and contain the alcohol amount and be 10-20%, mixing, centrifugal; Supernatant is crossed the D-101 macroporous adsorptive resins of handling well, stops loading after resin absorption is saturated; Wash with water, till the eluent clarification, discard water lotion; Use again the 50-90% ethanol elution, collect eluent, Recycled ethanol, when concentrate eluant to relative density is 30 ℃ 1.00～1.05, spray drying namely gets extract of hypericum perforatum.
8. medicine as claimed in claim 7 is characterized in that extract of hypericum perforatum wherein makes by the following method:
Get Herba Hyperici Monogyni medical material chopping, with 55% alcohol reflux 3 times: add 10 times of weight solvents for the first time, soak extraction after 8 hours, return time 2 hours; For the second time add 6 times of weight solvents, refluxed 1 hour; Add for the third time 6 times of weight solvents, refluxed 1 hour, merge behind three extracting solution concentratedly, Recycled ethanol is when concentrated extracting solution to relative density is 30 ℃ 1.00～1.05; Add water and ethanol dilution to 5 times of medical material weight, and transfer to that to contain alcohol amount be 15%, mixing, centrifugal; Supernatant is crossed the macroporous adsorptive resins of the D-101 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 5 times of column volume, discards water lotion; Use again 70% ethanol elution, collect eluent, Recycled ethanol, concentrate eluant to relative density 30 ℃ the time 1.00～1.05, spray drying namely gets extract of hypericum perforatum.
9. by medicine claimed in claim 7, it is characterized in that wherein said extract of hypericum perforatum makes by the following method: get the chopping of Herba Hyperici Monogyni medical material, with 55% alcohol reflux 3 times: add 10 times of weight solvents for the first time, soaks extraction after 8 hours, return time 2 hours; For the second time add 6 times of weight solvents, refluxed 1 hour; Add for the third time 6 times of weight solvents, refluxed 1 hour, the extracting solution gradation is concentrated, Recycled ethanol, and merging three concentrated solution to concentrated solution cumulative volumes is 3 times of medical material weight, when relative density is 30 ℃ 1.00～1.05; Add water and ethanol dilution to 5 times of medical material weight, and transfer to that to contain alcohol amount be 15%, mixing, centrifugal; Supernatant is crossed the macroporous adsorptive resins of the D-101 type of handling well, stops loading after resin absorption is saturated; Wash with water, effluent volume is 3 times of column volume, discards water lotion; Use again 90% ethanol elution, collect eluent, Recycled ethanol, when concentrate eluant to relative density is 30 ℃ 1.00～1.05, spray drying namely gets extract of hypericum perforatum.
10. such as the arbitrary described medicine of claim 7-9, it is characterized in that its Raw consists of:
Extract of hypericum perforatum 152 weight portions add carboxymethyl starch sodium 38 weight portions.
11. such as the arbitrary described medicine of claim 7-9, it is characterized in that its Raw consists of:
Extract of hypericum perforatum 152 weight portions add carboxymethyl starch sodium 45 weight portions, microcrystalline Cellulose 10 weight portions, pregelatinized Starch 10 weight portions.
12. such as the arbitrary described medicine of claim 7-9, it is characterized in that its Raw consists of:
Extract of hypericum perforatum 152 weight portions add carboxymethyl starch sodium 27 weight portions, microcrystalline Cellulose 10 weight portions, magnesium stearate 1 weight portion.
13. such as the arbitrary described pharmaceutical preparation of claim 7-9, it is characterized in that the per unit preparation contains total flavones in hyperin with determined by ultraviolet spectrophotometry, should be 70.0mg～145.0mg, per unit preparation high effective liquid chromatography for measuring Determination of Hypericin from Extraction, should be 0.15mg～0.6mg, the per unit preparation should be 3.0mg～10.0mg with the high effective liquid chromatography for measuring Determination of Hyperoside.
14. pharmaceutical preparation as claimed in claim 10, it is characterized in that the per unit preparation contains total flavones in hyperin with determined by ultraviolet spectrophotometry, should be 70.0mg～145.0mg per unit preparation high effective liquid chromatography for measuring Determination of Hypericin from Extraction, should be 0.15mg～0.6mg per unit preparation and should be 3.0mg～10.0mg with the high effective liquid chromatography for measuring Determination of Hyperoside.
15. pharmaceutical preparation as claimed in claim 10, it is characterized in that the per unit preparation contains total flavones in hyperin with determined by ultraviolet spectrophotometry, should be 70.0mg～145.0mg per unit preparation high effective liquid chromatography for measuring Determination of Hypericin from Extraction, should be 0.15mg～0.6mg per unit preparation and should be 3.0mg～10.0mg with the high effective liquid chromatography for measuring Determination of Hyperoside.
16. pharmaceutical preparation as claimed in claim 10, it is characterized in that the per unit preparation contains total flavones in hyperin with determined by ultraviolet spectrophotometry, should be 70.0mg～145.0mg per unit preparation high effective liquid chromatography for measuring Determination of Hypericin from Extraction, should be 0.15mg～0.6mg per unit preparation and should be 3.0mg～10.0mg with the high effective liquid chromatography for measuring Determination of Hyperoside.
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| CN1562919A (en) * | 2004-03-24 | 2005-01-12 | 华东理工大学 | Technique for preparing general flavone from Guanyelianqiao |
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