CN101152233B - Pharmaceutical composition of snakegourd fruit and folium ginkgo - Google Patents
Pharmaceutical composition of snakegourd fruit and folium ginkgo Download PDFInfo
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- CN101152233B CN101152233B CN200610159484XA CN200610159484A CN101152233B CN 101152233 B CN101152233 B CN 101152233B CN 200610159484X A CN200610159484X A CN 200610159484XA CN 200610159484 A CN200610159484 A CN 200610159484A CN 101152233 B CN101152233 B CN 101152233B
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Abstract
The invention belongs to the medical technical field and discloses a drug combination for the cardiovascular disease and the preparation method and purpose of the drug combination. The drug combination contains the pharmacodynamic components of the raw materials of drugs of 100 to 2000 portion of snakegourd fruits or 2 to 160 portion of the extract of the snakegourd fruits and 100 to 1000 portion of ginkgo biloba leaves or the extract of the ginkgo biloba leaves. The drug combination can be made into any preparation type which is acceptable in the pharmacy, and the injection preparation and the oral preparation are preferential. The drug combination has significant curative effect towards the cardiovascular diseases of the coronary heart disease, the hyperlipidemia etc.
Description
1, technical field
The present invention relates to a kind of new pharmaceutical composition, and the application in preparation treatment cardiovascular disease medicine, and the preparation that contains this pharmaceutical composition, medical technical field belonged to.
2, background technology
Cardiovascular disease is meant that sclerosis takes place for heart and arteries and the heart ischemia that causes or hemorrhage disease comprise coronary heart disease, angina pectoris, hyperlipidemia, arrhythmia, myocardial infarction etc., and China has 2,000,000 above patients to die from cardiovascular disease every year; This disease sickness rate is the trend that rises year by year, and there is patients with hypertension more than 100,000,000 in the whole nation, annual newly-increased patient 3,500,000 people, and prevalence increased by 50% in per ten years; Remove foreign genetic element, excessive, spiritual high-pressure of youngster operating pressure or overanxiexty, life style are bad, thereby cause cardiovascular and cerebrovascular disease to present rejuvenation trend; Among the China old people, cardiovascular diseases's sickness rate is up to 30%, and cardiovascular disease occupies cause of the death first place, is much higher than the ratio of other disease.Yet at present, therefore press for the effectively medicine of treatment cardiovascular disease of exploitation at the development rate of Chinese cardiovascular drug high incidence not as good as the cardiovascular diseases.
Fructus Trichosanthis is the dry fruit of calabash plant Fructus Trichosanthis Trichosanthes kirilowii Maxim or trichosanthes rosthornii Harms Trichosanthes rosthorniiHarms, and the beginning is stated from Shennong's Herbal.Mainly contain number of chemical compositions such as oils and fats, organic acid, sterol, triterpene and glycoside thereof, protein, amino acids and trace element, water soluble polysaccharide.Modern study shows, Fructus Trichosanthis energy coronary artery dilator, and coronary blood flow increasing increases myocardial contraction, the expansion blood capillary, antiplatelet aggregation improves hypoxia-bearing capability, can blood fat reducing, reduce effects such as serum cholesterol, angina pectoris, coronary heart disease there are better curative effect.
Folium Ginkgo is the dried leaves of Ginkgoaceae plant Ginkgo biloba (Ginkgo biloba L.).In recent years, the medical value of Folium Ginkgo medical material and extract thereof has caused extensive concern both domestic and external, and relevant its active component and Study of Clinical Application report are more.Folium Ginkgo extract (Extract of Ginkgo bilola leaves, EGb) be a kind of action range, the less natural drug of untoward reaction, its effective ingredient is mainly flavonoid and terpenoid, and EGb has antioxidation, remove free radical (FR), antiplatelet activity factor (PAF) effect.EGb prevents and treats atherosclerosis by blood lipid regulation, ischemia resisting, ischemical reperfusion injury, and arrhythmia reaches the effect of protection cardiac function.
Folium Ginkgo extract has national standard, sees the 6th page of Chinese Pharmacopoeia version in 2000 enlarged edition in 2002, or one one the 281st page of Chinese Pharmacopoeia version in 2005.Standard code, this product contain total flavonoids by dry product, must not be less than 24.0%; Contain terpene lactone with bilobalide (C
15H
18O
8), ginkalide A (C
20H
24O
9), ginkalide B (C
20H
24O
10) and ginkalide C (C
20H
24O
11) the total amount meter, must not be less than 6.0%; This product contains total ginkgolic acids must not cross 10/1000000ths; Preparation is a Folium Ginkgo.Domestic listing also have SHUXUENING ZHUSHEYE, can blood vessel dilating, microcirculation improvement, be used for ischemic cardiovascular, coronary heart disease, angina pectoris, cerebral embolism, cerebral vasospasm etc.
At present, utilize the interaction of Fructus Trichosanthis or Fructus Trichosanthis extract and Folium Ginkgo or Folium Ginkgo extract, composition of prescription, the medicine of preparation treatment cardiovascular disease etc. does not appear in the newspapers as yet.
3, summary of the invention
In order to meet clinical needs, better treat cardiovascular disease, improve the people's health level, the invention provides new pharmaceutical composition, and Preparation Method And The Use is provided, and the preparation that contains said composition.It is to be made by Fructus Trichosanthis or its extract and Folium Ginkgo or its extract, and is evident in efficacy aspect the treatment cardiovascular disease.
Pharmaceutical composition of the present invention is mainly made by Fructus Trichosanthis and Folium Ginkgo, and its parts by weight are: 100～2000 parts of Fructus Trichosanthis, 100～1000 parts of Folium Ginkgos; Preferred umber is: 500～1500 parts of Fructus Trichosanthis, 150～400 parts of Folium Ginkgos; Best umber is: 1000 parts of Fructus Trichosanthis, 200 parts of Folium Ginkgos.
More than form to be by weight as proportioning, when producing, can or reduce according to the corresponding proportion increase, as large-scale production can be unit with the kilogram, or be unit with the ton, small-scale production can be unit with the gram also, weight can increase or reduce, but the weight proportion between each composition is constant.
Fructus Trichosanthis in the aforementioned pharmaceutical compositions and Folium Ginkgo can obtain extract by singly carrying or mixing to obtain through refining fully with The suitable solvent and method, and total extract is made arbitrary preparation with mixing acceptable accessories again.The suitable solvent is meant solvent, preferred water or the alcohol that Chinese medicine extraction is commonly used.Extracting method can adopt the conventional method of Chinese medicine extraction, as infusion process, percolation, decocting method, reflux extraction or continuous extraction.
The invention provides the extraction process of Fructus Trichosanthis, specific as follows:
Technology one: get the Fructus Trichosanthis medical material, oven dry is ground into coarse powder, add the entry reflux, extract, 2 times, add 10 times of water gagings at every turn, reflux, extract, 2 hours, filter, merging filtrate, being concentrated into relative density is the concentrated solution of 1.10～1.15 (60 ℃), add ethanol and reach 80% to containing the alcohol amount, placement is spent the night, and gets supernatant, reclaim ethanol to there not being the alcohol flavor, be decompressed to the thick paste shape, vacuum drying promptly gets Fructus Trichosanthis crude extract (but pro ore).
Fructus Trichosanthis extract yield by this prepared is 6～8%, and wherein steroidal saponins total content is not less than 20%.
Technology two: with obtaining the Fructus Trichosanthis crude extract in the technology one with after the suitable quantity of water dissolving, extract 2 times with the jolting of equivalent petroleum ether, water liquid extracts 3 times with the jolting of equivalent water-saturated n-butanol, merge n-butanol extracting liquid, be concentrated into driedly, residue adds low amounts of water makes dissolving, last macroporous resin column, difference water, 15% ethanol, 70% ethanol elution, collect 70% ethanol elution, decompression recycling ethanol is concentrated into the thick paste shape, spray drying promptly gets the Fructus Trichosanthis essence extract.(but injection)
Fructus Trichosanthis extract yield by this prepared is 2～4%, and wherein steroidal saponins total content is not less than 30%.
The invention provides the extraction process of Folium Ginkgo, specific as follows:
Technology one: get Folium Ginkgo, pulverize, add twice of 75% alcohol reflux, add for the first time 10 times of amounts of alcohol, extracted 3 hours, add 8 times of amounts of alcohol for the second time, extracted 2 hours, merging filtrate, filtrate being concentrated into contains alcohol about 5%～10%, the water that adds equivalent, stir evenly, 1～4 ℃ of cold preservation 24～48 hours, centrifugal, get the supernatant upper prop, with 3～4 times of amount volume water, 15% ethanol, 75% washing with alcohol, collect 75% ethanol liquid respectively, be evaporated to 1/3 volume number of medical material amount, leave standstill, filter, filtrate decompression concentrates, vacuum drying, pulverize, promptly.
Folium Ginkgo extract yield by above-mentioned prepared is 1～4%, contains total flavonoids and is not less than 24.0%, and terpene lactone is not less than 6.0%.
Technology two: get Folium Ginkgo, pulverize, add 60% aqueous acetone solution, 57～59 ℃ of vigorous stirring 30min filter, and repeat above-mentioned steps, extract again one time, merging filtrate, filtrate decompression is concentrated into and contains about 30%～40% (content about 5% of acetone at this moment) of solids.Thin up is to 2 times of original volume, be cooled to about 12 ℃ under stirring, be incubated 1 hour, centrifugal, discard precipitation, supernatant adds ammonium sulfate by 30%, stir evenly, make molten entirely, with butanone-acetone mixed solution (6: 4) extraction 2 times, each is 0.5 times of amount of aqueous solution, butanone-acetone mixed solution is evaporated to and contains solids 50%～70%, adds entry and makes that to contain solids about 10%, with the water-saturated n-butanol extraction of 1/2 volume 3 times, n-butyl alcohol liquid is evaporated to and contains solids more than at least 50%, add suitable quantity of water then and continue again to concentrate, in the gained concentrated solution, add entry and ethanol, make solid contents reach 10%, determining alcohol reaches 30%, add n-hexane extraction 3 times, each 1/3 amount, water concentrates, and drying under reduced pressure (60～80 ℃), promptly.
Folium Ginkgo extract yield by above-mentioned prepared is 1～3%, contains total flavonoids and is not less than 24.0%, and terpene lactone is not less than 6.0%.
Technology three: get Folium Ginkgo, pulverize, earlier with 12 times of amount 60% alcoholic solution reflux secondaries, each 3 hours, filter, merge ethanol extract, be condensed into thick paste, become every 1ml to be equivalent to the solution of 0.5g crude drug with the hot water dissolving, leave standstill cooling, filter macroporous resin on the filtrate (DA201) post, use 18% respectively, 30%, and the ethanol elution of 50% concentration, 18%, 30% ethanol takes off liquid and is concentrated into nothing alcohol flavor, and last polyamide column is with 95% ethanol elution, 50% ethanol elution of macroporous resin and the eluent of polyamide column are merged, be concentrated into no ethanol flavor,, discard the cyclohexane extraction extract with the cyclohexane extraction extraction, the concentrated solution spray drying, promptly.
Folium Ginkgo extract yield by above-mentioned prepared is 1～3%, contains total flavonoids and is not less than 24.0%, and terpene lactone is not less than 6.0%.
Technology four: get Folium Ginkgo, pulverize, add 60 ℃ of warm macerating of 70% ethanol and extract twice, add 15 times of amounts of alcohol, warm macerating is 2 hours under stirring, merge extractive liquid, at every turn, filter, filtrate recycling ethanol to relative density is 1.03～1.09 (50 ℃), adds the water of 4 times of amounts, stir evenly, 1～4 ℃ of cold preservation is spent the night, and filters, the filtrate upper prop is respectively with 3～4 times of amount volume water, 15% ethanol, 70 washing with alcohol are collected 70% ethanol liquid, concentrating under reduced pressure, vacuum drying, extractum add 5 times of amount ethanol extraction secondaries, each 15 minutes, merging filtrate, concentrating under reduced pressure, vacuum drying, extractum add 8 times of water gagings, are heated to boiling, little boiling 5 minutes placed room temperature, and 1～4 ℃ of cold preservation is spent the night, filter, filtrate adds the polyamide of 25% crude extract, stirs 5 minutes, filter, concentrating under reduced pressure, vacuum drying, promptly.
Folium Ginkgo extract yield by above-mentioned prepared is 1～3%, contains total flavonoids and is not less than 24.0%, and terpene lactone is not less than 6.0%.
In the aforementioned pharmaceutical compositions, Folium Ginkgo extract can also can be made with extra care commercial or commercial back by above-mentioned prepared, can also pass through other prepared.
Pharmaceutical composition of the present invention also can be made by Fructus Trichosanthis extract and Folium Ginkgo extract, calculate with respect to the yield of medical material according to extract, be that the Fructus Trichosanthis extract yield is 2～8%, the Folium Ginkgo extract yield is 1～4%, the corresponding parts by weight of its extract are: 2～160 parts of Fructus Trichosanthis extracts, 1～40 part of Folium Ginkgo extract, preferred umber is: 10～120 parts of Fructus Trichosanthis extracts, 1.5～16 parts of Folium Ginkgo extract, optimum umber is: 20～80 parts of Fructus Trichosanthis extracts, 2～8 parts of Folium Ginkgo extract.
In the aforementioned pharmaceutical compositions, steroidal saponins content is not less than 20% in the Fructus Trichosanthis extract, preferably is not less than 30%; Total flavonoids content is not less than 24.0% in the Folium Ginkgo extract, terpene lactone contents is not less than 6.0%, total ginkgolic acids is no more than 10/1000000ths, preferably be no more than 1,000,000/.
Another object of the present invention is to provide a kind of pharmaceutical composition that is used for cardiovascular disease, this pharmaceutical composition for coronary heart disease, hyperlipidemia, etc. better curative effect arranged.
Pharmaceutical composition of the present invention can be made clinically any or pharmaceutically acceptable dosage form, optimizing injection or oral formulations with acceptable accessories; Can parenteral or mode such as oral administration be applied to the patient who needs this treatment.
When being used for parenteral, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or concentrated solution that injection can be divided into injection, injectable sterile powder and concentrated solution for injection.Injection means that the confession that medicine is made is injected into sterile solution type injection, emulsion-type injection or the suspension type injection of using in the body, can be used for intramuscular injection, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection of using for intravenous drip also claims venous transfusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available venous transfusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray drying method or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic concentrated solution of using for intravenous drip with preceding dilution.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has buccal tablet, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coatel tablets etc.Capsule means medicine or is added with the adjuvant filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (soft gelatin capsule), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable adjuvant uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises drop pill, sugar pill, piller etc.Granule means that medicine and suitable adjuvant make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as granule), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral supernatant liquid preparation in suitable solvent.Oral suspensions means the slightly solubility solid drugs, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspension or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making injection, can adopt the conventional method production in the existing pharmaceutical field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solutions; Non-aqueous solvent commonly used is a vegetable oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, Polyethylene Glycol etc.During the preparation injection, can add suitable additives according to the character of medicine, as osmotic pressure regulator, pH value regulator, solubilizing agent, filler, antioxidant, antibacterial, emulsifying agent, suspending agent etc.Osmotic pressure regulator commonly used comprises sodium chloride, glucose, potassium chloride, magnesium chloride, calcium chloride, sorbitol etc., preferred sodium chloride or glucose; PH value regulator commonly used comprises acetic acid-sodium acetate, lactic acid, citric acid-sodium citrate, sodium bicarbonate-sodium carbonate etc.; Solubilizing agent commonly used comprises polyoxyethylene sorbitan monoleate, propylene glycol, lecithin, polyoxyethylene castor oil etc.; Filler commonly used comprises lactose, mannitol, sorbitol, dextran etc.; Antioxidant commonly used has sodium sulfite, sodium sulfite, sodium pyrosulfite etc.; Antibacterial commonly used is phenol, cresol, chlorobutanol etc.Injection container commonly used has glass ampule, vial, plastic ampoule, plastic bottle etc.
When making oral formulations, can add suitable filler, binding agent, disintegrating agent, lubricant etc.Filler commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol etc.; Typical binders comprises sodium carboxymethyl cellulose, PVP-K30, hydroxypropyl cellulose, starch slurry, methylcellulose, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dried starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises magnesium stearate, Pulvis Talci, sodium lauryl sulphate, micropowder silica gel etc.
The invention has the advantages that:
(1) provides first by what Fructus Trichosanthis or Fructus Trichosanthis extract and Folium Ginkgo or Folium Ginkgo extract were made and be used to prepare the pharmaceutical composition for the treatment of cardiovascular disease, and confirmed the effect that the two has Synergistic, be better than the two independent medication by pharmacological evaluation.
(2) proportioning of pharmaceutical composition Chinese medicine component of the present invention has been carried out groping in a large number research, the influence of the rat platelet agglutination that adenosine diphosphate (ADP) is caused by research pharmaceutical composition of the present invention and to the influence of anoxia enduring time-to-live of mice normal pressure filters out the weight proportion scope with significant curative effect.
(3) pharmacological effect studies show that; pharmaceutical composition of the present invention has synergistic function; can significantly suppress the rat platelet coagulation that adenosine diphosphate (ADP) causes; significantly strengthen mice normal pressure hypoxia-bearing capability; significantly reduce the serum cholesterol and the triglyceride levels of diet hyperlipemia rat; the myocardial ischemia-reperfusion rat being had remarkable protective effect, aspect the treatment cardiovascular disease remarkable result is being arranged, is that those of ordinary skills institute is beyond thought.
(4) present composition can directly be fed intake by Fructus Trichosanthis extract and Folium Ginkgo extract and be processed into preparation, preparation technology is easy, avoided because the shortcoming that the quality of the pharmaceutical preparations that the crude drug mass discrepancy causes differs greatly, the quality of the pharmaceutical preparations improves a lot, impurity content significantly reduces, and safety is higher.
(5) effective ingredient of pharmaceutical composition of the present invention is clear and definite, content is high, confirms that by stability experiment better stability of preparation is convenient to control product quality, can guarantee clinical drug safety.
Below routine by experiment beneficial effect of further setting forth medicine of the present invention, these experimental examples comprise the pharmacological effect experiment of pharmaceutical composition of the present invention.Fructus Trichosanthis extract used in the following experimental example is all with reference to the preparation of the Fructus Trichosanthis extract preparation method among the embodiment 1, and Folium Ginkgo extract all prepares with reference to the Folium Ginkgo extract preparation method among the embodiment 2.
Experimental example 1 pharmaceutical composition of the present invention is to the influence of the inductive platelet aggregation effect of external anti-ADP
Animal subject: 140 of male rats, body weight 200～220g is divided into 14 groups at random, 10 every group.
Test sample: sodium chloride injection: 250ml:2.25g, Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd.;
The Fructus Trichosanthis injection: with the Fructus Trichosanthis extract is the crude drug self-control;
The YINXINGYE ZHUSHEYE group: with the Folium Ginkgo extract is the crude drug self-control;
Melon silver injection: with Fructus Trichosanthis extract and Folium Ginkgo extract is the crude drug self-control, and different proportionings see Table 1.
Experimental technique: rat is divided into 14 groups at random, is respectively matched group, YINXINGYE ZHUSHEYE group, Fructus Trichosanthis injection group, the different proportioning groups of melon silver injection.Each administration treated animal is pressed table 1 intraperitoneal injection, and matched group is given and sodium chloride injection, every day 1 time, and successive administration 7 days, the last administration is after 1 hour, and from abdominal aortic blood, anticoagulant adopts 3.28% sodium citrate after the Animal Anesthesia, mixes with 1: 9 with blood.The centrifugal 5min of anticoagulated whole blood 1500rpm under 20 ℃ of conditions is obtained platelet rich plasma (PPR).After leaving and taking quantitative PPR, will remain PPR, obtain own control platelet poor plasma (PPP) once more with the centrifugal 10min of 3000rpm.Regulate PPR concentration with PPP, make each PPR concentration identical.PPR after the preheating, is added adenosine diphosphate (ADP) (ADP, final concentration are 3 μ molL-1) and causes platelet aggregation in 37 ℃ constant temperature hole, the record maximum agglutination rate.
Experimental result: experimental result sees Table 1.
1) compare with matched group, Fructus Trichosanthis injection group, YINXINGYE ZHUSHEYE group all significantly suppress platelet aggregation (p＜0.05), and each proportioning group of melon silver injection all suppresses platelet aggregation (p＜0.05, p＜0.01) significantly.
2) compare with Fructus Trichosanthis injection group, each proportioning group of melon silver injection all suppresses platelet aggregation (p＜0.05, p＜0.01) significantly.
3) compare with the YINXINGYE ZHUSHEYE group, each proportioning group of melon silver injection all suppresses platelet aggregation (p＜0.05, p＜0.01) significantly.
Table 1 pharmaceutical composition of the present invention to the influence of rat platelet agglutination (X ± S, n=10)
Annotate:
*P＜0.05,
*Compare with matched group in p＜0.01;
#P＜0.05,
##Compare with the YINXINGYE ZHUSHEYE group p＜0.01;
﹠amp;P＜0.05,
﹠amp; ﹠amp;Compare with Fructus Trichosanthis injection group p＜0.01.
Conclusion: by experimental result as can be known, with individually dosed group of comparison, the effect of each proportioning group of melon silver injection is all more remarkable.Wherein, when melon silver proportioning 100～2000 parts of Fructus Trichosanthis, in the time of in 100～1000 parts of scopes of Folium Ginkgo, it is obvious to suppress the platelet aggregation effect, particularly works as melon silver proportioning 500～1500 parts of Fructus Trichosanthis, in the time of in 150～400 parts of scopes of Folium Ginkgo, platelet aggregation rate reduces more remarkable, with melon silver proportioning is 1000: 200 o'clock best results, and prompting Fructus Trichosanthis extract and Folium Ginkgo extract have synergistic function, and pharmaceutical composition of the present invention is suppressing aspect the platelet aggregation significant curative effect is arranged.
Experimental example 2 pharmaceutical compositions of the present invention are to the influence of mice normal pressure anoxia enduring
Animal subject: Kunming mouse, 150, body weight 18～22g, the male and female dual-purpose is divided into 15 groups at random.
Test sample: sodium chloride injection: 250ml:2.25g, Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd.;
The Fructus Trichosanthis sheet: with the Fructus Trichosanthis is the crude drug self-control;
Folium Ginkgo: with the Folium Ginkgo is the crude drug self-control;
Melon silver strip group: with Fructus Trichosanthis and Folium Ginkgo is crude drug, by different proportioning self-controls, sees Table 2;
Isoproterenol hydrochloride inj (Iso), Shanghai Hefeng Pharmaceutical Co., Ltd.;
Experimental technique: 150 of mices, divide equally 15 groups, be respectively matched group, model control group, Folium Ginkgo group, Fructus Trichosanthis sheet group, the different proportioning groups of melon silver strip.All irritate the stomach normal saline for the 1st, 2 group, all the other administration groups are irritated the stomach relative medicine respectively, before each drug administration all with distilled water diluting to suitable concentration.Behind the administration 30min, equal subcutaneous injection Iso 20mg/kg except that first group behind the 15min, puts into the sealing of 250ml ground wide mouthed bottle respectively, puts 1 of white mice for every bottle, is index with last breathing then, the time-to-live of record white mice, and carry out the t check.
The experimental result conclusion: experimental result sees Table 2.
1) compare with blank, the model group mice time-to-live obviously shortens (p＜0.05), shows the modeling success.
2) compare with model group, Folium Ginkgo group, Fructus Trichosanthis sheet group mice time-to-live significant prolongation (p＜0.05) show that the two all has oxygen lack resistant function.But the different proportioning groups of melon silver strip are the significant prolongation mice time-to-live (p＜0.05, p＜0.01) all.Illustrate that Fructus Trichosanthis and Folium Ginkgo share raising mice hypoxia-bearing capability.
3) with the Folium Ginkgo group relatively, the different proportioning assembly of melon silver strip are than 500～1500 parts of Fructus Trichosanthis, in the time of in 150～400 parts of scopes of Folium Ginkgo, mice time-to-live significant prolongation (p＜0.05, p＜0.01), proportioning is 1000: 200 o'clock, best results.
4) with Fructus Trichosanthis sheet group relatively, the different proportioning assembly of melon silver strip are than 500～1500 parts of Fructus Trichosanthis, in the time of in 150～400 parts of scopes of Folium Ginkgo, mice time-to-live significant prolongation (p＜0.05, p＜0.01), proportioning is 1000: 200 o'clock, best results.
Conclusion: by experimental result as can be known, with individually dosed group of comparison, the effect of each proportioning group of melon silver injection is all more remarkable.Wherein, when melon silver proportioning 100～2000 parts of Fructus Trichosanthis, in the time of in 100～1000 parts of scopes of Folium Ginkgo, it is obvious to suppress the platelet aggregation effect, particularly works as melon silver proportioning 500～1500 parts of Fructus Trichosanthis, in the time of in 150～400 parts of scopes of Folium Ginkgo, the mice prolonged survival period is more remarkable, with melon silver proportioning is 1000: 200 o'clock best results, and prompting Fructus Trichosanthis extract and Folium Ginkgo extract have synergistic function, and pharmaceutical composition of the present invention is having significant curative effect aspect the mice normal pressure anoxia enduring.
Table 2 pharmaceutical composition of the present invention to the influence of mice normal pressure anoxia enduring (X ± S, n=10)
Annotate:
#Compare with the blank group p＜0.05;
*P＜0.05,
*Compare with model control group in p＜0.01;
ΔP＜0.05,
The Δ ΔCompare with the Folium Ginkgo group p＜0.01;
﹠amp;P＜0.05,
﹠amp; ﹠amp;Compare with Fructus Trichosanthis sheet group p＜0.01.
Experimental example 3 pharmaceutical compositions of the present invention are to the influence of rat experiment hyperlipidemia
Animal subject: rat, 50, body weight 220～240g is divided into 5 groups at random, 10 every group.
Test sample: sodium chloride injection: 250ml:2.25g, Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd.;
The Fructus Trichosanthis sheet: with the Fructus Trichosanthis extract is the crude drug self-control;
Folium Ginkgo: with the Folium Ginkgo extract is the crude drug self-control;
The melon silver strip: with Fructus Trichosanthis extract and Folium Ginkgo extract is the crude drug self-control.
Dosage: dosage group 250mg crude drug/kg, melon silver strip high dose group 300mg crude drug/kg in Fructus Trichosanthis sheet 1g crude drug/kg, Folium Ginkgo 250mg crude drug/kg, melon silver strip low dose group 200mg crude drug/kg, the melon silver strip.Before each administration group drug administration all with distilled water diluting to suitable concentration.
Experimental technique: rat is built hyperlipidemia model after surveying preceding cholesterol of medicine and triglyceride levels.Except that the blank group gives the normal diet, all the other each groups all give high lipid food (prescription is normal diet 86.8%, cholesterol 3%, Adeps Sus domestica 10%, the phonetic shallow lake 0.2% of rosickyite oxygen), feed was surveyed serum cholesterol and triglyceride levels after 10 days continuously, determined that hyperlipidemia model builds up.Continue to raise high lipid food after model builds up, the administration group is the gastric infusion relative medicine respectively, and difference gastric infusion every day 1 time, successive administration were got blood again and surveyed cholesterol and triglyceride levels after 20 days.
Table 3 pharmaceutical composition of the present invention to the influence of diet hyperlipemia rat serum cholesterol (X ± S, n=10)
Annotate:
##Compare with the blank group p＜0.01;
*P＜0.05,
*Compare with the hyperlipidemia model group in p＜0.01;
ΔP＜0.05,
The Δ ΔCompare with the Folium Ginkgo group p＜0.01;
﹠amp;P＜0.05,
﹠amp; ﹠amp;Compare with Fructus Trichosanthis sheet group p＜0.01.
Table 4 pharmaceutical composition of the present invention to the influence of diet hyperlipemia rat serum triglycerides (X ± S, n=10)
Annotate:
##Compare with the blank group p＜0.01;
*P＜0.05,
*Compare with the hyperlipidemia model group in p＜0.01;
Experimental result: experimental result sees Table 3 and table 4.
1) compare with the blank group, high blood lipid model group rat blood serum cholesterol and triglyceride all extremely significantly raise (p＜0.01), and the modeling success is described.
2) compare with the hyperlipidemia model group, Fructus Trichosanthis sheet group, Folium Ginkgo group, melon silver strip low dose group can significantly reduce the serum cholesterol and the triglyceride levels (p＜0.05) of diet hyperlipemia rat, middle dosage group and high dose group can extremely significantly reduce the serum cholesterol level (p＜0.01) of diet hyperlipemia rat, substantial reduction in triglycerides level (p＜0.05).
3) compare with the Folium Ginkgo group, the middle and high dosage group of melon silver strip obviously reduces the serum cholesterol level (p＜0.05) of rat.
4) compare with Fructus Trichosanthis sheet group, the middle and high dosage group of melon silver strip significantly reduces the serum cholesterol level (p＜0.05) of rat.
Conclusion: as can be known by the result, when giving separately with animal subject Folium Ginkgo or Fructus Trichosanthis sheet, rat hyperlipidemia level obviously reduces, after giving the melon silver strip of making by Fructus Trichosanthis extract and Folium Ginkgo extract with rat, serum cholesterol and triglyceride levels reduce more remarkable, and the effect that the two has Synergistic is described, point out pharmaceutical composition of the present invention that significant hypolipemic function is arranged, and dose-effect relationship is obvious, for the treatment hyperlipidemia good curative effect will be arranged.
Experimental example 4 pharmaceutical compositions of the present invention are to the influence of experimental rat myocardial ischemia reperfusion injury
Animal subject: Wistar rat, 60, body weight 180～220g.
Test sample: the Fructus Trichosanthis granule is the crude drug self-control with the Fructus Trichosanthis extract;
The Folium Ginkgo granule is the crude drug self-control with the Folium Ginkgo extract;
Melon silver granule is the crude drug self-control with Fructus Trichosanthis extract and Folium Ginkgo extract;
Sodium chloride injection: 250ml:2.25g, Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd.;
Dosage: dosage group 250mg crude drug/kg, melon silver granule high dose group 300mg crude drug/kg in Fructus Trichosanthis granule group 1g crude drug/kg, Folium Ginkgo granule group 250mg crude drug/kg, melon silver granule low dose group 200mg crude drug/kg, the melon silver granule.
Experimental technique: rat fasting 12h, divide equally 6 groups: dosage group, melon silver granule high dose group in Fructus Trichosanthis granule group, Folium Ginkgo granule group, melon silver granule low dose group, the melon silver granule.Irritate the relative medicine of stomach various dose respectively, matched group is given the isometric(al) normal saline.Behind the 1h, lumbar injection pentobarbital sodium 35mg/kg anesthesia.Open breast knot under the artificial respiration and prick LCA 7min, pour into 15min subsequently again.Trace II disloyalty electrograph.Observe again perfusion back arrhythmia time of occurrence and hold time (above 15min, in 15min), and recording room quivers (VF), number and ventricular premature contraction number (VPB) take place ventricular tachycardia (VT).The results are shown in Table 5
Table 5 pharmaceutical composition of the present invention is to the influence of experimental rat myocardial ischemia reperfusion injury
Annotate:
*P＜0.05,
*Compare with the normal saline matched group p＜0.01;
ΔP＜0.05,
The Δ ΔCompare with Folium Ginkgo granule group p＜0.01;
﹠amp;P＜0.05,
﹠amp; ﹠amp;Compare with Fructus Trichosanthis granule group p＜0.01.
Experimental result: experimental result sees Table 5.
1) with the normal saline matched group relatively, Folium Ginkgo granule group, Fructus Trichosanthis granule group all can significantly make rat pour into back arrhythmia time of occurrence again and lag behind (p＜0.05), significantly shorten arrhythmia hold time (p＜0.05); Melon silver granule low dose group can significantly make rat pour into back arrhythmia time of occurrence again and lag behind (p＜0.05), significantly shortens arrhythmia hold time (p＜0.05); The middle and high dosage group of melon silver granule can extremely significantly make rat pour into back arrhythmia time of occurrence again and lag behind (p＜0.01), extremely significantly shortens arrhythmia hold time (p＜0.01).
2) with Folium Ginkgo granule group relatively, the middle and high dosage group of melon silver granule can significantly make rat pour into back arrhythmia time of occurrence again and lag behind (p＜0.05), significantly shortens arrhythmia hold time (p＜0.05).
3) with Fructus Trichosanthis granule group relatively, the middle and high dosage group of melon silver granule can significantly make rat pour into back arrhythmia time of occurrence again and lag behind (p＜0.05), significantly shortens arrhythmia hold time (p＜0.05).
Conclusion: each administration group all can make rat pour into back arrhythmia time of occurrence again and lag behind; significantly shortening arrhythmia holds time; all can the chamber of making quiver (VF), number takes place and reduces in ventricular tachycardia (VT) ventricular premature contraction ripple (VPB); the middle and high dosage group of melon silver granule effect is best, shows that damage obviously has protective effect to this name pharmaceutical composition to Ischemia and Reperfusion in vivo in Rats.
Experimental example 5 composite injection stability experiments
Sample: composite injection, self-control, (prescription and preparation method are referring to the preparation of embodiment 3 aqueous injection).
Investigation project: character, pH value, clarity, related substance, sign content; And at accelerated tests 6 months and the aseptic and pyrogen test of long-term experiment end of term increase.
1, influence factor's experiment
The strong illumination experiment: get test sample, putting illumination is interior the placement 10 days of lighting box of 4500Lx.
High temperature experiment: get test sample, place respectively under 40 ℃, the 60 ℃ conditions and placed 10 days.
Low temperature test: get test sample, in 4 ℃ of refrigerators, placed 10 days.
Above-mentioned experiment was respectively at the 5th, 10 day sampling and measuring.Relatively test every index after the character, and with result and comparison in 0 day.
The result: placed 10 days under the illumination 4500Lx condition, except that related substance slightly raise, all other indexs had no significant change.Placed 10 days under 60 ℃ of conditions of high temperature, every index does not have significant change.Placed 10 days under 40 ℃ of high temperature, 4 ℃ of conditions of low temperature, every index does not have significant change.
2, accelerated tests
Method: put under the condition of 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% and placed 6 months.Respectively at taking a sample 1st month, 2 months, 3 months, 6 the end of month, relatively after the outward appearance, test every index at experimental session, with result and comparison in 0 month; And at 6 aseptic and pyrogen tests of increase at the end of month.
Result: placed 6 months under the condition of 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%, removing related substance slightly increases, and outside sign content slightly descended, all other indexs had no significant change, at 6 the end of month of accelerated tests, pyrogen, sterility test are all up to specification.
3, long-term experiment
Long-time stability experimental technique and result: this product is put under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% and placed 6 months, 12 months, every index has no significant change, experimental result show composite injection long-term place basicly stable.
Conclusion: reached a conclusion by above-mentioned investigation result, in every experiment, the injection of Fructus Trichosanthis and compositions extracted from gingko biloba leaves is all more stable.Can be used for amplifying and produce.
4, the specific embodiment
The specific embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.In following examples in the preparation of each dosage form the preparation method of used Fructus Trichosanthis extract, Folium Ginkgo extract see embodiment 1, embodiment 2 respectively, adjuvant can be replaced with acceptable accessories, perhaps reduces, increases.
The preparation of embodiment 1 Fructus Trichosanthis extract and discriminating and assay
The preparation of Fructus Trichosanthis extract
1) get the Fructus Trichosanthis medical material, oven dry is ground into coarse powder, add the entry reflux, extract, 2 times, add 10 times of water gagings at every turn, reflux, extract, 2 hours, filter, merging filtrate, being concentrated into relative density is the concentrated solution of 1.10～1.15 (60 ℃), add ethanol to content and reach 80%, placement is spent the night, and gets supernatant, reclaim ethanol to there not being the alcohol flavor, be decompressed to the thick paste shape, vacuum drying promptly gets Fructus Trichosanthis crude extract (but pro ore).
2) with 1) in obtain the Fructus Trichosanthis crude extract with after the suitable quantity of water dissolving, extract 2 times with the jolting of equivalent petroleum ether, water liquid extracts 3 times with the jolting of equivalent water-saturated n-butanol, merge n-butanol extracting liquid, be concentrated into driedly, residue adds low amounts of water makes dissolving, last macroporous resin column, difference water, 15% ethanol, 70% ethanol elution, collect 70% ethanol elution, decompression recycling ethanol is concentrated into the thick paste shape, spray drying promptly gets the Fructus Trichosanthis essence extract.(but injection)
The Fructus Trichosanthis extract assay
The assay of steroidal saponins
Reference substance solution preparation: get the about 20mg of ginsenoside Rg1 reference substance, through 60 ℃ of vacuum dryings 2 hours, the accurate title, put in the 10ml measuring bottle calmly, with anhydrous alcohol solution and be diluted to scale, shakes up, and makes the solution that every 1ml contains Rg1 reference substance 2mg, promptly.
Standard curve preparation: accurately pipette ginsenoside's standard substance Rg1 (concentration is 2mg/ml) 5 respectively, 10,30,50,70,90,110 make series standard solution in 10ml tool plug test tube, water-bath volatilizes methanol, add 0.7ml8% vanillin glacial acetic acid solution, add people 5ml perchloric acid again, shake up, in 60 ℃ of water-bath 15min, take out at once and dash to room temperature with tap water, do blank to add the parallel sample of sample, measure absorbance in 560nm, with absorbance to content of ginsenoside (M, unit: μ g) make regression curve, get regression equation: M=213.13A+4.7576, R=0.997.
Algoscopy: accurately pipette sample solution 30 μ l, place 10ml tool plug test tube, water-bath volatilizes methanol, add 0.5mL 8% vanillin glacial acetic acid solution, add people 5ml perchloric acid again, shake up, in 60 ℃ of water-bath 15min, take out at once and dash to room temperature, make blank, measure absorbance in 560nm to add the parallel sample of sample with tap water, with absorbance to content of ginsenoside (M, unit: μ g) make regression curve, get regression equation: M=213.13A+4.7576, R=0.997.
By above-mentioned prepared Fructus Trichosanthis crude extract, yield is 7.5%, and steroidal saponins assay is 24.96%, the Fructus Trichosanthis essence extract, and yield is 3.40%, steroidal saponins assay is 33.61%, the results are shown in Table 6.
The assay result and the yield of table 6 Fructus Trichosanthis extract
The preparation of embodiment 2 Folium Ginkgo extract and discriminating and assay
The preparation of Folium Ginkgo extract
Get Folium Ginkgo 5kg, pulverize, add 60 ℃ of warm macerating of 70% ethanol and extract twice, add 15 times of amounts of alcohol, warm macerating is 2 hours under stirring, merge extractive liquid, at every turn, filter, filtrate recycling ethanol to relative density is 1.03～1.09 (50 ℃), adds the water of 4 times of amounts, stir evenly, 1～4 ℃ of cold preservation is spent the night, and filters, the filtrate upper prop is respectively with 3～4 times of amount volume water, 15% ethanol, 70 washing with alcohol are collected 70% ethanol liquid, concentrating under reduced pressure, vacuum drying, extractum add 5 times of amount ethanol extraction secondaries, each 15 minutes, merging filtrate, concentrating under reduced pressure, vacuum drying, extractum add 8 times of water gagings, are heated to boiling, little boiling 5 minutes placed room temperature, and 1～4 ℃ of cold preservation is spent the night, filter, filtrate adds the polyamide of 25% crude extract, stirs 5 minutes, filter, concentrating under reduced pressure, vacuum drying, promptly.
Prepare three batches of Folium Ginkgo extract respectively, yield sees Table 7.
The discriminating of Folium Ginkgo extract
(1) get Folium Ginkgo extract 0.2g, add n-butyl alcohol 15ml, put in the water-bath warm macerating 15 minutes and jolting constantly, put coldly, filter the filtrate evaporate to dryness, residue adds ethanol 2ml makes dissolving, as need testing solution.Other gets Folium Ginkgo reference extract 0.2g, shines extract solution in pairs with legal system.Test according to thin layer chromatography, draw each 3 μ l of above-mentioned two kinds of solution, put respectively in same be on the silica gel g thin-layer plate of adhesive with the carboxymethylcellulose sodium solution that contains 0.4% sodium acetate, with ethyl acetate-butanone-methanol-water (5: 3: 1: 1) be developing solvent, launch, take out, dry, spray is put under the ultra-violet lamp (365nm) and is inspected with 3% aluminum chloride alcoholic solution.In the test sample chromatograph, with the corresponding position of reference extract chromatograph on, show the fluorescence speckle of same color.
(2) according to the thin layer chromatography experiment, terpene lactone need testing solution under the assay item of absorption terpene lactone and each 15 μ l of reference substance solution, put respectively in same be on the silica gel g thin-layer plate of adhesive with the carboxymethylcellulose sodium solution that contains 0.4% sodium acetate, with toluene-ethyl acetate-acetone-methanol (10: 5: 5: 0.6) be developing solvent, launching below 15 ℃, take out, dry, smoked 15 minutes with the acetic anhydride steam, 140～160 ℃ of heating 30 minutes, put coldly, put under the ultra-violet lamp (365nm) and inspect.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the fluorescence speckle of same color.
Three batches of Folium Ginkgo extract to above-mentioned preparation carry out identification experiment, all meet the requirements.
The assay of Folium Ginkgo extract
The assay of total pyrite alcohol glycosides
High performance liquid chromatography
Chromatographic condition and system suitability experiment are filler with the octadecylsilane chemically bonded silica; With methanol-0.4% phosphoric acid solution (50: 50) is mobile phase; The detection wavelength is 360nm.Number of theoretical plate calculates by the Quercetin peak should be not less than 2500.
The preparation of reference substance solution precision respectively takes by weighing Quercetin reference substance, kaempferide reference substance, isorhamnetin reference substance, adds methanol and makes the mixed solution that every 1ml contains 30 μ g, 30 μ g, 20 μ g respectively, product solution in contrast.
The about 35mg of Folium Ginkgo extract is got in the preparation of need testing solution, the accurate title, decide, the mixed solution 25ml that adds methanol-25% hydrochloric acid solution (4: 1) put in the water-bath reflux 30 minutes, was cooled to room temperature rapidly, be transferred in the 50ml measuring bottle, be diluted to scale with methanol, shake up, filter, get subsequent filtrate, promptly.
Accurate respectively reference substance solution and each the 10 μ l of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, and calculate the content of Quercetin, kaempferide and isorhamnetin respectively, are converted into the content of total pyrite alcohol glycosides by following formula.
Total pyrite alcohol glycosides=(quercetin content+kaempferide content+isorhamnetin content) * 2.51
The assay of terpene lactone
High performance liquid chromatography
Chromatographic condition and system suitability experiment are filler with the octadecylsilane chemically bonded silica; With normal propyl alcohol-oxolane-water (1: 15: 84) is mobile phase; Detect with evaporative light scattering detector.Number of theoretical plate calculates by the bilobalide peak should be not less than 2500.
The preparation of reference substance solution respectively precision to take by weighing bilobalide reference substance, ginkalide A reference substance, ginkalide B reference substance and ginkalide C reference substance an amount of, add methanol and make the mixed solution that every 1ml contains 2mg, 1mg, 1mg, 1mg, in contrast product solution.
The about 0.15g of Folium Ginkgo extract is got in the preparation of need testing solution, and accurate the title decides, and adds water 10ml, puts to heat in the water-bath to make molten loosing, add 2 of 2% hydrochloric acid solutions, extract 4 (15ml, 10ml, 10ml with the ethyl acetate jolting, 10ml), merge extractive liquid, washs with 5% sodium acetate solution 20ml.Combined ethyl acetate extracting solution and washing liquid wash with water 2 times, and each 20ml divides water intaking liquid, with ethyl acetate 10ml washing, combined ethyl acetate liquid, reclaim solvent to doing, residue is with dissolve with methanol and be transferred in the 5ml measuring bottle, add methanol to scale, shake up, get subsequent filtrate, promptly.
Respectively accurate reference substance solution and need testing solution 5 μ l, the 10 μ l of drawing of algoscopy inject chromatograph of liquid, and mensuration is calculated the content of bilobalide, ginkalide A, ginkalide B and ginkalide C respectively with external standard two-point method logarithmic equation, promptly.Three batches of Folium Ginkgo extract to above-mentioned preparation carry out assay respectively, and measurement result sees Table 7.
The assay result and the yield of table 7 Folium Ginkgo extract
The preparation of embodiment 3 pharmaceutical composition aqueous injection of the present invention
Prescription:
Fructus Trichosanthis extract 339g (being equivalent to Fructus Trichosanthis crude drug 10kg)
Folium Ginkgo extract 42.8g (being equivalent to Folium Ginkgo crude drug 2kg)
Water for injection adds to 10000ml
Prepare 2000 altogether
Preparation technology:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) get the water for injection of dosing amount 80%, add the Fructus Trichosanthis extract and the Folium Ginkgo extract of recipe quantity, the heated and stirred dissolving fully.
3) benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) with the solution sealing by fusing in glass ampule.
9) 100 ℃ of flowing steam sterilizations are 30 minutes.
10) while hot sample being put into 0.01% methylene blue solution hunts leak.
11) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 4 pharmaceutical composition injectable powder of the present invention
Prescription:
Fructus Trichosanthis extract 339g (being equivalent to Fructus Trichosanthis crude drug 10kg)
Folium Ginkgo extract 42.8g (being equivalent to Folium Ginkgo crude drug 2kg)
Mannitol 500g
Sterile water for injection adds to 10000ml
Prepare 1000 altogether
Preparation technology:
1) vessel of at first dosing being used and antibiotic glass bottle, plug etc. carry out aseptic process.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) get the sterile water for injection of dosing amount 80%, Fructus Trichosanthis extract and Folium Ginkgo extract are added the heated and stirred dissolving fully.Add the dissolving of mannitol heated and stirred more fully, add sterile water for injection to full dose.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.22um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) be sub-packed in the antibiotic glass bottle half tamponade.Sample is put into the freeze dryer lyophilization.Pre-freeze-45 ℃ 5 hours, low-temperature vacuum drying-45 ℃～0 ℃ 20 hours was warming up to 25 ℃ of vacuum dryings 3 hours then.
9) lyophilizing finishes, and lid is rolled in tamponade.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 5 pharmaceutical composition sodium chloride transfusions of the present invention
Prescription:
Fructus Trichosanthis extract 339g (being equivalent to Fructus Trichosanthis crude drug 10kg)
Folium Ginkgo extract 42.8g (being equivalent to Folium Ginkgo crude drug 2kg)
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Preparation technology:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) water for injection of getting dosing amount 20% adds the heated and stirred dissolving fully with Fructus Trichosanthis extract and Folium Ginkgo extract.Sodium chloride is complete with the water for injection dissolving of dosing amount 40%.
3) merge two solution, benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) fill is in the infusion bottle of 100ml.
9) 115 ℃ of pressure sterilizings are 30 minutes.
10) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6 pharmaceutical composition glucose infusion liquids of the present invention
Prescription:
Fructus Trichosanthis extract 339g (being equivalent to Fructus Trichosanthis crude drug 10kg)
Folium Ginkgo extract 42.8g (being equivalent to Folium Ginkgo crude drug 2kg)
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Preparation technology:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) water for injection of getting dosing amount 20% adds the heated and stirred dissolving fully with Fructus Trichosanthis extract and Folium Ginkgo extract.Glucose is complete with the water for injection dissolving of dosing amount 40%.
3) merge two solution, benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) fill is in the infusion bottle of 100ml.
9) 115 ℃ of pressure sterilizings are 30 minutes.
10) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 7 pharmaceutical composition tablets of the present invention
Prescription:
Fructus Trichosanthis extract 339g (being equivalent to Fructus Trichosanthis crude drug 10kg)
Folium Ginkgo extract 42.8g (being equivalent to Folium Ginkgo crude drug 2kg)
Starch 120.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 2.0g
Carboxymethylstach sodium 4.0g
Prepare 2000 altogether
Preparation technology:
1) it is standby Fructus Trichosanthis crude extract and Folium Ginkgo extract to be pulverized 100 mesh sieves.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) with Fructus Trichosanthis extract, Folium Ginkgo extract, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material.
5) cross 20 mesh sieve system granules.
6) granule is dried under 60 ℃ condition.
7) dry good granule adds magnesium stearate and carboxymethylstach sodium, crosses 18 mesh sieve granulate, mix homogeneously.
8) sampling, the semi-finished product chemical examination.
9) the sheet weight sheet of determining according to chemical examination.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 8 medicament composition capsule agent of the present invention
Prescription:
Fructus Trichosanthis extract 339g (being equivalent to Fructus Trichosanthis crude drug 10kg)
Folium Ginkgo extract 42.8g (being equivalent to Folium Ginkgo crude drug 2kg)
Starch 60g
Microcrystalline Cellulose 20g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 1g
Prepare 2000 altogether
Preparation technology:
1) it is standby Fructus Trichosanthis extract and Folium Ginkgo extract to be pulverized 100 mesh sieves.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) with Fructus Trichosanthis extract, Folium Ginkgo extract, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material.
5) cross 20 mesh sieve system granules.
6) granule is dried under 60 ℃ condition.
7) dry good granule adds magnesium stearate, crosses 18 mesh sieve granulate, mix homogeneously.
8) sampling, the semi-finished product chemical examination.
9) loading amount of determining according to chemical examination incapsulates.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 9 medicament composition granule agent of the present invention
Prescription:
Fructus Trichosanthis extract 339g (being equivalent to Fructus Trichosanthis crude drug 10kg)
Folium Ginkgo extract 42.8g (being equivalent to Folium Ginkgo crude drug 2kg)
Icing Sugar 1500g
2%HPMC50% ethanol is molten an amount of
Liquid
Prepare 1000 bags altogether
Preparation technology:
1) it is standby that sucrose was pulverized 100 mesh sieves.It is standby that Fructus Trichosanthis extract and Folium Ginkgo extract were pulverized 100 mesh sieves.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) the method mix homogeneously that Fructus Trichosanthis extract, Folium Ginkgo extract and Icing Sugar are progressively increased with equivalent, it is an amount of to add the 2%HPMC50% alcoholic solution, stirs, and makes suitable soft material.
4) cross 20 mesh sieve system granules.
5) granule is dried under 60 ℃ condition.
6) dried granule is crossed 18 mesh sieve granulate.
7) sampling, the content of principal agent is determined loading amount in the semi-finished product chemical examination granule.
8) packing, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 10 drug composition oral liquid of the present invention
Prescription:
Fructus Trichosanthis extract 339g (being equivalent to Fructus Trichosanthis crude drug 10kg)
Folium Ginkgo extract 42.8g (being equivalent to Folium Ginkgo crude drug 2kg)
Sodium benzoate 15g
Cyclamate 10g
Water adds to 10000ml
Prepare 1000 altogether
Preparation technology:
1) earlier that EDTA-2NA is complete with the water dissolution of dosing amount 60%, again Fructus Trichosanthis extract and Folium Ginkgo extract are added the heated and stirred dissolving fully.
2) sodium benzoate and cyclamate is complete with the water dissolution of dosing amount 20%.
3) merge above-mentioned two solution, mend and add water to full dose.
4) filtering with microporous membrane of mistake 0.8um.
5) semi-finished product chemical examination.
8) fill.Finished product is examined entirely, the packing warehouse-in.
Claims (6)
1. a pharmaceutical composition that is used for cardiovascular disease is characterized in that, the parts by weight composition of making the crude drug of the contained active ingredient of this pharmaceutical composition is: 2～160 parts of Fructus Trichosanthis extracts, 1～40 part of Folium Ginkgo extract,
Wherein the preparation method of Fructus Trichosanthis extract is: (1) gets the Fructus Trichosanthis medical material, and oven dry is ground into coarse powder, add the entry reflux, extract, 2 times, add 10 times of water gagings at every turn, reflux, extract, 2 hours, filter, merging filtrate is concentrated into relative density and is 1.10～1.15 concentrated solution under 60 ℃ of conditions, add ethanol to content and reach 80%, placement is spent the night, and gets supernatant, reclaim ethanol to there not being the alcohol flavor, be decompressed to the thick paste shape, vacuum drying, promptly get the Fructus Trichosanthis crude extract, but pro ore; (2) with obtaining the Fructus Trichosanthis crude extract in (1) with after the suitable quantity of water dissolving, extract 2 times with the jolting of equivalent petroleum ether, water liquid extracts 3 times with the jolting of equivalent water-saturated n-butanol, merge n-butanol extracting liquid, be concentrated into driedly, residue adds low amounts of water makes dissolving, last macroporous resin column, water, 15% ethanol, 70% ethanol elution are collected 70% ethanol elution, decompression recycling ethanol respectively, be concentrated into the thick paste shape, spray drying promptly gets the Fructus Trichosanthis essence extract, but injection;
Wherein the preparation method of Folium Ginkgo extract is: get Folium Ginkgo, pulverize, add 60 ℃ of warm macerating of 70% ethanol and extract twice, add 15 times of amounts of alcohol, warm macerating is 2 hours under stirring, merge extractive liquid, at every turn, filter, filtrate recycling ethanol to relative density is 1.03～1.09 under 50 ℃ of conditions, adds the water of 4 times of amounts, stir evenly, 1～4 ℃ of cold preservation is spent the night, and filters, the filtrate upper prop is respectively with 3～4 times of amount volume water, 15% ethanol, 70% washing with alcohol is collected 70% ethanol liquid, concentrating under reduced pressure, vacuum drying, extractum add 5 times of amount ethanol extraction secondaries, each 15 minutes, merging filtrate, concentrating under reduced pressure, vacuum drying, extractum add 8 times of water gagings, are heated to boiling, little boiling 5 minutes placed room temperature, and 1～4 ℃ of cold preservation is spent the night, filter, filtrate adds the polyamide of 25% crude extract, stirs 5 minutes, filter, concentrating under reduced pressure, vacuum drying, promptly.
2. pharmaceutical composition as claimed in claim 1 is characterized in that, the parts by weight of this pharmaceutical composition crude drug consist of: 10～120 parts of Fructus Trichosanthis extracts, 1.5～16 parts of Folium Ginkgo extract.
3. pharmaceutical composition as claimed in claim 2 is characterized in that, the parts by weight of this pharmaceutical composition crude drug consist of: 20～80 parts of Fructus Trichosanthis extracts, 2～8 parts of Folium Ginkgo extract.
4. as the described pharmaceutical composition of the arbitrary claim of claim 1～3, it is characterized in that, the content of steroidal saponins is not less than 20% in the Fructus Trichosanthis extract, and the content of total flavonoids is not less than 24.0% in the Folium Ginkgo extract, the content of terpene lactone is not less than 6.0%, total ginkgolic acids is no more than 10/1000000ths.
5. as the described pharmaceutical composition of the arbitrary claim of claim 1～3, it is characterized in that this pharmaceutical composition can be made clinically any or pharmaceutically acceptable dosage form.
6. pharmaceutical composition as claimed in claim 5 is characterized in that this pharmaceutical composition can be made injection or oral formulations.
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| CN103304490B (en) * | 2013-06-18 | 2015-02-18 | 山东中医药大学 | Method for separating and purifying five purine and pyrimidine bases from trichosanthes bark |
| CN104706778A (en) * | 2015-02-13 | 2015-06-17 | 淄博夸克医药技术有限公司 | Medicine for treating herpes zoster |
| CN107375356B (en) * | 2017-05-31 | 2020-06-16 | 神威药业集团有限公司 | Method for simultaneously preparing high-purity total flavonol glycosides and ginkgolides |
| CN108152437A (en) * | 2017-12-06 | 2018-06-12 | 广州卡马生物科技有限公司 | American Ginseng reference extract and its preparation method and application |
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