CN1915255A - Medicinal composition, preparation method and quality control method - Google Patents
Medicinal composition, preparation method and quality control method Download PDFInfo
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- CN1915255A CN1915255A CN 200510093129 CN200510093129A CN1915255A CN 1915255 A CN1915255 A CN 1915255A CN 200510093129 CN200510093129 CN 200510093129 CN 200510093129 A CN200510093129 A CN 200510093129A CN 1915255 A CN1915255 A CN 1915255A
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Abstract
A composite medicine in the form of injection or orally taken medicine for treating cardiovascular and cerebrovascular diseases, such as coronary heart disease, angina pectoris, apoplexy sequelae, cerebral thrombus, etc, is prepared from Chuan-xiong rhizonme or its extract and dipyridamole. Its preparing process and quality control method are also disclosed.
Description
Technical field
The invention provides a kind of pharmaceutical composition that is used for the treatment of cardiovascular and cerebrovascular disease, the preparation method and the method for quality control of said composition is provided simultaneously, belong to technical field of medicaments.
Technical background
In the human cause of death, annual nearly 1,700 ten thousand people in the whole world die from cardiovascular and cerebrovascular disease, account for more than 50% of total death toll, rank first place; In human diseases, the relapse rate of cardiovascular and cerebrovascular disease ranks first place up to 87%; In human diseases, the disability rate of cardiovascular and cerebrovascular disease is up to 50%, rank first place, this severe fact has been subjected to various circles of society and has highly watched attentively, the at present clinical Chinese medicine and western medicine that is used for the treatment of cardiovascular and cerebrovascular disease is a lot, and chemicals is used for symptom control, determined curative effect, but attend to one thing and lose sight of another, and side effect and untoward reaction are seen more; Though Chinese medicine demonstrates advantage to a certain extent, but because or quality controllability poor, consolidate a little less than the curative effect, or narrow application range, it is unfavorable to bring for clinician and part patient, though oral preparation of Chinese traditional medicinal blood circulation promoting and blood stasis dispelling, qi and blood tonifying, treating both the principal and secondary aspects of a disease, various in style, available property is bigger, but bioavailability is low, can not be from anxious, the serious symptom of fast treatment cardiovascular and cerebrovascular vessel, it is more apparent slowly to consolidate effect.In the prior art, the hot fragrant row of Rhizoma Chuanxiong looses, the temperature promoting blood circulation, last wardrobe top is walked the sea of blood, function blood-activating and qi-promoting down, wind-expelling pain-stopping, be described as gas medicine in the blood by forefathers, modern study shows: Rhizoma Chuanxiong extract has spasmolytic, reduce the effect of vascular resistance and strong inhibition platelet aggregation, accumulative platelet is had depolymerisation, can obviously reduce whole blood viscosity, increase coronary flow, improve myocardial oxygen delivery, reduce the effect of myocardial oxygen consumption, treatment ischemic cerebral vascular and coronary heart disease, angina pectoris is respond well, can also treat other cardiovascular and cerebrovascular diseases such as serious symptom pulmonary heart disease, the dipyridamole antithrombotic forms, anticoagulant, can be applicable to urgency so exploitation is a kind of, serious symptom is rescued, can be adapted to usual treatment again, treating both the principal and secondary aspects of a disease, bioavailability is high, and to be used to control and treat the medicine of cardiovascular and cerebrovascular disease just very urgent.
Summary of the invention
The objective of the invention is to disclose a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease, adopt the preparation that Rhizoma Chuanxiong or Rhizoma Chuanxiong extract and dipyridamole compatibility are made to be needed, test finds that this prescription compatibility does not have toxic and side effects through pharmacological effect, and given full play to the advantage of Chinese medicine and western medicine, rapid-action, curative effect affirms that the two share, and has the obvious synergistic synergistic function for treating cardiovascular and cerebrovascular disease such as coronary heart disease, angina pectoris, cerebrovascular, pulmonary heart disease etc.Effectively avoided using separately at present the drawback of Chinese medicine or Western medicine; Another object of the present invention is to disclose the preparation of drug combination method of this treatment cardiovascular and cerebrovascular disease, comprise multiple injection type and peroral dosage form, effectively avoid the single inconvenience that brings of dosage form of present doctors and patients' medication, satisfied the selection of clinician and extensive patients to a greater degree; The present invention also aims to provide its method of quality control,, and then overcome the variety of issue that prior art exists with assurance stability of formulation, safety and effectiveness.
Preparation of the present invention is to constitute like this: calculate according to components by weight percent, it by 1～50 part of 10～10000 parts of Rhizoma Chuanxiongs and dipyridamole through extracting refining forming; Or the Rhizoma Chuanxiong extract and the corresponding weight portion dipyridamole that are obtained after extracting by corresponding weight portion medical material are made.The pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease is characterized in that: calculate according to components by weight percent, it by 1～30 part of 100～5000 parts of Rhizoma Chuanxiongs and dipyridamole through extracting refining forming; Or the Rhizoma Chuanxiong extract and the corresponding weight portion dipyridamole that are obtained after extracting by corresponding weight portion medical material are made.Say exactly: calculate according to parts by weight, it by 1～20 part of 1000～3000 parts of Rhizoma Chuanxiongs and dipyridamole through extracting refining forming; Or the Rhizoma Chuanxiong extract and the corresponding weight portion dipyridamole that are obtained after extracting by corresponding weight portion medical material are made.
The pharmaceutical composition of treatment cardiovascular and cerebrovascular disease of the present invention, dosage form are injection and oral formulations.Wherein injection comprises: liquid drugs injection, powder pin or infusion solutions; Oral formulations comprises: all acceptable dosage forms on the pharmaceuticss such as tablet, dispersible tablet, effervescent tablet, oral cavity disintegration tablet, buccal tablet, capsule, soft capsule, microcapsule, granule, pill, powder, drop pill, slow releasing preparation, controlled release preparation, oral liquid, soft extract, extractum, gel, membrane.Particularly preferably be liquid drugs injection, powder pin, infusion solutions, oral liquid, drop pill, capsule, soft capsule, oral cavity disintegration tablet, tablet, capsule, dispersible tablet, buccal tablet, oral gel or granule.
The pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease: count by weight percentage: the component content sum that derives from the Rhizoma Chuanxiong medical material that all can be surveyed in the injection be not less than in the preparation deduction adjuvant amount, water quantities and dipyridamole amount total solid 20%; Dipyridamole should be 90.0%～110.0% of labelled amount.
The preparation of drug combination method of described treatment cardiovascular and cerebrovascular disease is: get Rhizoma Chuanxiong, add entry or ethanol extraction, the extracting solution concentrate drying gets the Rhizoma Chuanxiong crude extract, one or more that also can further adopt precipitate with ethanol, organic solvent extractionprocess, flocculent precipitation, column chromatography unite use carry out suitably refining, get the Rhizoma Chuanxiong extract, with Rhizoma Chuanxiong crude extract or Rhizoma Chuanxiong extract and dipyridamole mixing, be prepared into the preparation that needs with diverse ways.
Rhizoma Chuanxiong extract can also be commercially available or adopt other preparation methoies to prepare in the preparation of drug combination method of described treatment cardiovascular and cerebrovascular disease.
The pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease has anticoagulant, coronary artery dilator, increase coronary flow, improves myocardial oxygen delivery, reduces that myocardial oxygen consumption, anti-acute myocardial ischemia anoxia, antithrombotic form, significantly fibrinolytic, expansion lung blood vessel, reduces functions such as pulmonary vascular resistance; Be used for the treatment of cardiovascular and cerebrovascular diseases such as coronary heart disease, angina pectoris, cerebrovascular, pulmonary heart disease, hypertension.
Its assay is to adopt in high performance liquid chromatography, spectrophotography, TLC scanning method, the titrimetry one or more to record in the method for quality control of the pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease.
In the prior art, Rhizoma Chuanxiong or Rhizoma Chuanxiong extract and dipyridamole all are active drugs of treatment cardiovascular and cerebrovascular disease, because its effective ingredient purity is higher, and the intravenous administrations that adopt in the emergency and severe disease treatment more.The inventor finds arbitrarily both to be made up clinically, can obtain potentiation, but its preparation stability and safety can't guarantee.Up to now, the preparation report that does not have the two prescription.So, the applicant is combined into novel formulation with Rhizoma Chuanxiong extract and dipyridamole and develops research, bring into play both cooperative compensating effects by compatibility, for new medication of treatment increase of cardiovascular and cerebrovascular disease is selected at angina pectoris, arrhythmia, cerebral thrombosis etc.Simultaneously, can system further investigate Rhizoma Chuanxiong or the safety of Rhizoma Chuanxiong extract and dipyridamole compatibility and the controllability of quality, for data for clinical drug use is given security.By antiplatelet aggregation test, inhibition mouse tail thrombotest and the anti-protective effect test that lacks sugared anoxia to the In vitro culture myocardial cell injury; these two kinds of medicines (Rhizoma Chuanxiong extract and dipyridamole) have been carried out the prescription screening test of system; found that with Rhizoma Chuanxiong extract: the prescription pharmacological action of dipyridamole=6: 1 is strong and consumption is lower, preparations shaping and having good stability, and both compatibilities can reach the effect of efficacy enhancing and toxicity reducing.The result shows; after the two herbal medicine use in conjunction, the obvious synergistic effect is arranged aspect blood circulation promoting and blood stasis dispelling, aspect the treatment cerebral ischemia obvious synergistic effect is being arranged also; can obviously increase simultaneously blood flow coronarius, reduce myocardial oxygen consumption, thus the better protection ischemic myocardium.
Pharmaceutical preparation of the present invention, with respect to the independent preparation of Rhizoma Chuanxiong, dipyridamole better efficacy not only, and use is carried all very convenient, the multiple different ejection preparation and the preparation method of oral formulations are provided, being suitable for different crowd uses, heart disease and hyperpietic also can take for a long time, avoided dosage form single to hospitalized patients bring unfavorable.
The applicant has also carried out following experiment, to prove the beneficial effect of medicine provided by the invention.
The prescription screening experimental study of experimental example 1 drug regimen compatibility
We are by antiplatelet aggregation test, inhibition mouse tail thrombotest and the anti-protective effect test that lacks sugared anoxia to the In vitro culture myocardial cell injury; Rhizoma Chuanxiong extract and dipyridamole have been carried out the prescription screening test of system in varing proportions; found that the curative effect after Rhizoma Chuanxiong or Rhizoma Chuanxiong extract and dipyridamole compatibility use has remarkable potentiation with dipyridamole more separately; with Rhizoma Chuanxiong extract: dipyridamole=combination in 6: 1; the prescription pharmacological action is strong and consumption is lower, is best prescription so determine this ratio prescription.
Table prescription research conclusion
| Formula number | Prescription is formed and the ratio Rhizoma Chuanxiong extract: dipyridamole | The screening and assessment index | |||
| Platelet suppression ratio (%) | Thrombosis suppression ratio (%) | The test of cultivation myocardial cell injury | |||
| LDH reduces % | CK reduces % | ||||
| 1 2 3 4 5 6 7 | 1∶10 3∶5 1∶1 2∶1 6∶1 10∶1 15∶1 | 79.2％ 75.5％ 68.9％ 72.8％ 80.4％ 75.3％ 62.9％ | 45.4％ 40.8％ 35.5％ 38.5％ 52.5％ 42.5％ 35.1％ | 35.2％ 32.2％ 30.5％ 38.1％ 49.3％ 42.5％ 37.0％ | 47.5％ 38.8％ 33.7％ 35.5％ 50.2％ 42.1％ 37.5％ |
From above-mentioned prescription screening result as can be seen, Rhizoma Chuanxiong extract all can produce certain curative effect with the different compatibilities of dipyridamole, but through system thinking, determine to reach the effect of efficacy enhancing and toxicity reducing with Rhizoma Chuanxiong extract and dipyridamole by force and consumption is lower, preparations shaping and having good stability with 6: 1 ratio compatibility pharmacological action.
(2) Rhizoma Chuanxiong extract: affirmation and the side's of tearing open research conclusion of dipyridamole=6: 1 combination prescription effectiveness
Drug efficacy study through system shows; after the two herbal medicine use in conjunction; aspect blood circulation promoting and blood stasis dispelling, has the obvious synergistic effect; at aspects such as treatment cerebral thrombosis, apoplexy the obvious synergistic effect is arranged also; simultaneously; can obviously increase the increase of the blood flow of arteria coronaria, the afterload that reduces Ischemic Heart, antagonism myocardial oxygen consumption, thus the better protection ischemic myocardium.
The prescription research conclusion
| Pilot project | Prescription of the present invention | The Rhizoma Chuanxiong extract group | The dipyridamole group |
| Myocardial infarction model test improves blood stasis model rat blood rheology test platelet aggregation-against and tests anti-mouse tail thrombotest rabbit fibrin solubility test due to the dog CAL method | Effect is remarkable, the effect reinforced effects is remarkable, the effect reinforced effects is remarkable, the effect reinforced effects is remarkable, the effect reinforced effects is remarkable, and effect strengthens | The general successful successful of successful successful effect | The general successful successful of successful effect effect is general |
Concrete embodiment
Embodiment 1: the preparation Rhizoma Chuanxiong extract: get 10 parts of Rhizoma Chuanxiongs (part is: kilogram or gram)
Get Rhizoma Chuanxiong, be ground into coarse powder, with 80% soak with ethanol after 1 hour, reflux, extract, 2 times adds 8 times of amount ethanol for the first time, extracts 2 hours, add for the second time 6 times of amount ethanol, extracted merge extractive liquid, 1.5 hours, after extracting liquid filtering concentrated, the macroporous adsorptive resins of flowing through again washed with water earlier, reuse 30% ethanol elution, collect 30% ethanol elution, concentrating under reduced pressure promptly gets Rhizoma Chuanxiong extract.
Embodiment 2: the preparation Rhizoma Chuanxiong extract: 1000 parts of Rhizoma Chuanxiongs (part is: kilogram or gram)
Get Rhizoma Chuanxiong, be ground into coarse powder, extracting in water 3 times, each 10 times of water gagings, 1.5h, extracting solution filters, filtrate merging is condensed into thick paste, add suitable quantity of water, heating for dissolving, (ratio of dried cream and resin is 1: 15-20) to be added to the macroporous resin column of having handled well, wash with water earlier to the reaction of sugar (the 1ml eluent that is negative, add 5%a-naphthols ethanol liquid 2-3 and drip, shake up, slowly add the 0.5ml concentrated sulphuric acid along test tube wall, produce purplish red colour circle at test solution and vitriolic interface) extremely colourless with 30% ethanol elution, collect the eluent reclaim under reduced pressure, low temperature gets Rhizoma Chuanxiong extract I in dry (50 ℃), and residue adds 6 times of amount 80% alcohol reflux 3 times, each 0.5 hour, merge extractive liquid,, concentrate extract II, united extraction thing I, II promptly gets Rhizoma Chuanxiong extract.
Embodiment 3: the preparation Rhizoma Chuanxiong extract: 3000 parts of Rhizoma Chuanxiongs (part is: kilogram or gram)
Get Rhizoma Chuanxiong, be ground into coarse powder, use alcohol reflux, the extracting solution concentrating under reduced pressure, put coldly, remove desaccharide and oil, remove remaining ethanol in water-bath, add the hot water dissolving, ether extraction is used in the cooling back, ether extract hydrochloric acid extraction, and acid solution is transferred PH9-10 with saturated sodium carbonate, use chloroform extraction, the reclaim under reduced pressure chloroform gets chloroform extract.With the chloroform extract dissolving with hydrochloric acid, reuse ammonia transfers PH about about 10, and with chloroform extraction, the reclaim under reduced pressure chloroform gets Rhizoma Chuanxiong extract.
Embodiment 4: the preparation Rhizoma Chuanxiong extract: 5000 parts of Rhizoma Chuanxiongs (part is: kilogram or gram)
Get Rhizoma Chuanxiong, be ground into coarse powder, with 80% alcohol reflux 2 times, merge extractive liquid, and concentrating under reduced pressure, cooling, desaccharide and oil, remove remaining ethanol in water-bath, add the hot water dissolving, cooling back ether extraction, ether extract hydrochloric acid extraction, acid solution is transferred PH9-10 with saturated sodium carbonate, uses chloroform extraction, the reclaim under reduced pressure chloroform gets chloroform extract, and with the chloroform extract dissolving with hydrochloric acid, reuse ammonia is transferred PH about about 10, with chloroform extraction, the reclaim under reduced pressure chloroform gets total alkali.Total alkali is handled with petroleum ether (60～90 ℃), and the petroleum ether soluble fraction concentrates.Refrigerator place coarse-grain, after mother solution concentrates again through the alkali alumina column chromatography for separation, petroleum ether-chloroform (8: 2) eluting part also coarse-grain, merge coarse-grain and through distillation, the ligustrazine crude product.
Embodiment 5: the preparation Rhizoma Chuanxiong extract: 100 parts of Rhizoma Chuanxiongs (part is: kilogram or gram)
Get the Rhizoma Chuanxiong coarse powder, with 80 ℃ of hot water extraction 2 times, each 1.5 hours, cooling was filtered, and residue is used 30%, 50%, 70%, 80% ethanol precipitation successively, the filtrate concentrate drying, Rhizoma Chuanxiong extract.
Embodiment 6: the preparation Rhizoma Chuanxiong extract: 10000 parts of Rhizoma Chuanxiongs (part is: kilogram or gram)
Get the Rhizoma Chuanxiong medical material, be ground into coarse powder, add twice of 10 times of amount 70% alcohol reflux, each 1.5h merges medicinal liquid, reclaims ethanol, add water-cooled and soaked 8 hours, filter, be added to pre-treatment after filtrate concentrates and get the AB-8 resin column, flow velocity is 0.3ml/min, and after last sample finished, it was colourless to be washed till effluent with distilled water, reuse 40% ethanol elution is colourless to effluent, collect eluent, concentrate, promptly get Rhizoma Chuanxiong extract.
Embodiment 7: 10 parts of Rhizoma Chuanxiongs, 50 parts of dipyridamoles (part is: kilogram or gram)
Get Rhizoma Chuanxiong, be ground into coarse powder, with 80% alcohol reflux 2 times, merge extractive liquid, and concentrating under reduced pressure, cooling, desaccharide and oil remove remaining ethanol in water-bath, add the hot water dissolving, ether extraction is used in the cooling back, ether extract hydrochloric acid extraction, and acid solution is transferred PH9-10 with saturated sodium carbonate, use chloroform extraction, the reclaim under reduced pressure chloroform gets chloroform extract, and with the chloroform extract dissolving with hydrochloric acid, reuse ammonia is transferred pH about about 10, with chloroform extraction, the reclaim under reduced pressure chloroform gets extract, and extract is handled with petroleum ether (60～90 ℃), and the petroleum ether soluble fraction concentrates, refrigerator place coarse-grain, again through the alkali alumina column chromatography for separation, petroleum ether chloroform (8: 2) eluting partly got coarse-grain after mother solution concentrated, and filtered with water for injection dissolving back cold preservation, be concentrated into 1: 5, adjust pH to 6.8 adds 0.2% active carbon and boils 10min, filters, filtrate adds water for injection, and it is standby to stir; Get dipyridamole, add the injection water and be that an amount of 0.65% tartaric acid solution stirs and makes it dissolving; With above-mentioned two parts of solution and mannitol mix homogeneously, add 0.2% active carbon again, heated and boiled keeps little and boiled 15 minutes, fine straining, cooling is filtered, and filtrate adds to the full amount of water for injection, regulate pH 5.5～7.0, divide to install to ampoule bottle, seal sterilization and promptly get injection with small volume.
Embodiment 8: 180 parts of dipyridamoles of Rhizoma Chuanxiong: 30 parts (part is: kilogram or gram)
Get Rhizoma Chuanxiong, be ground into coarse powder, with 80% soak with ethanol after 1 hour, reflux, extract, 2 times adds 8 times of amount ethanol for the first time, extracts 2 hours, add for the second time 6 times of amount ethanol, extracted merge extractive liquid, 1.5 hours, after extracting liquid filtering concentrated, the macroporous adsorptive resins of flowing through again washed with water earlier, reuse 30% ethanol elution is collected 30% ethanol elution, concentrating under reduced pressure, drying, add the injection blunge make it the dissolving, standby; Dipyridamole adds the injection water, adds 0.65% tartaric acid solution again and makes it dissolving, and it is standby to stir; With above-mentioned medicinal liquid and mannitol mix homogeneously, add 0.2% active carbon again, heated and boiled, keep little and boiled 15 minutes, fine straining, cooling, filter, filtrate adds to the full amount of water for injection, and regulates pH 5.5～7.0, the intermediate sampling, to be detected qualified after, quantitatively be sub-packed in the cillin bottle lyophilization: pre-freeze temperature-45～-40 ℃, pre-freeze time 6～8h;-40～-35 ℃ of evacuation keep 6～8h; Be warming up to-30～-25 ℃ again, keep 6～8h; Be warming up to-20～-15 ℃, keep 6～8h; Be warming up to-10～-5 ℃, keep 3～5h; Be warming up to 0 ℃, keep 3～5h; Be warming up to 15～20 ℃, keep 1～3h; Be warming up to 25～30 ℃, keep 1～3h, be warming up to 35～40 ℃, keep 1～3h, packing promptly gets lyophilized injectable powder.The content of dipyridamole is 107.5% of labelled amount.
Embodiment 9: Rhizoma Chuanxiong: 1000 parts, and dipyridamole: 20 parts (part is: kilogram or gram)
Get the Rhizoma Chuanxiong medical material, be ground into coarse powder, add twice of 10 times of amount 70% alcohol reflux, each 1.5h merges medicinal liquid, reclaims ethanol, concentrated solution is added to pre-treatment and gets the AB-8 resin column, and flow velocity is 0.3ml/min, after last sample finishes, it is colourless to be washed till effluent with distilled water, and reuse 80% ethanol elution is colourless to effluent, collects eluent, concentrated, dry, pulverize, add injection and blunge and make it dissolving, standby; Get dipyridamole, add the injection water, add 0.65% tartaric acid solution again and make it dissolving, it is standby to stir; With above-mentioned medicinal liquid and mannitol mix homogeneously, add 0.2% active carbon again, heated and boiled keeps little and boiled 15 minutes, cooling, filtration, ultrafiltration add in an amount of process glucose solution that boils, and are diluted to full dose with water for injection, regulate pH 5.5～7.0, embedding, sterilization promptly gets glucose injection.The content of ligustrazine is 27% in the preparation
Embodiment 10: 60 parts of dipyridamoles of Rhizoma Chuanxiong extract: 8 parts (part is: kilogram or gram)
Get Rhizoma Chuanxiong extract, filter with water for injection dissolving back cold preservation, be concentrated into 1: 5, adjust pH to 6.8 adds 0.2% active carbon and boils 10min, filters, and filtrate adds water for injection, and it is standby to stir; Get dipyridamole, add the injection water and be that an amount of 0.65% tartaric acid solution stirs and makes it dissolving; With above-mentioned two parts of solution and mannitol mix homogeneously, add 0.2% active carbon again, heated and boiled keeps little and boiled 15 minutes, fine straining, cooling is filtered, and filtrate adds to the full amount of water for injection, regulate pH about 5.5～7.0, divide to install to ampoule bottle, seal sterilization and promptly get injection with small volume.The composition that derives from the Rhizoma Chuanxiong medical material that all can be surveyed in the preparation comprise alkaloids, lactone, phenols component content sum be deduction adjuvant amount, water quantities and dipyridamole amount in the preparation total solid 26%.
Embodiment 11: 6 parts of dipyridamoles of Rhizoma Chuanxiong extract: 1 part (part is: kilogram or gram)
Get Rhizoma Chuanxiong extract, add the injection blunge make it the dissolving, standby; Get dipyridamole, add the injection water, add 0.65% tartaric acid solution again and make it dissolving, it is standby to stir; With above-mentioned medicinal liquid and mannitol mix homogeneously, add 0.2% active carbon again, heated and boiled, keep little and boiled 15 minutes, fine straining, cooling, filter, filtrate adds to the full amount of water for injection, and regulates pH about 5.5～7.0, the intermediate sampling, to be detected qualified after, quantitatively be sub-packed in the cillin bottle lyophilization: pre-freeze temperature-45～-40 ℃, pre-freeze time 6～8h;-40～-35 ℃ of evacuation keep 6～8h; Be warming up to-30～-25 ℃ again, keep 6～8h; Be warming up to-20～-15 ℃, keep 6～8h; Be warming up to-10～-5 ℃, keep 3～5h; Be warming up to 0 ℃, keep 3～5h; Be warming up to 15～20 ℃, keep 1～3h; Be warming up to 25～30 ℃, keep 1～3h, be warming up to 35～40 ℃, keep 1～3h, packing promptly gets lyophilized injectable powder.The composition that derives from the Rhizoma Chuanxiong medical material that all can be surveyed in the preparation comprise alkaloids, lactone, phenols component content sum be deduction adjuvant amount, water quantities and dipyridamole amount in the preparation total solid 46%.
Embodiment 12: 100 parts of dipyridamoles of Rhizoma Chuanxiong extract: 6 parts (part is: kilogram or gram)
Get Rhizoma Chuanxiong extract, add the injection blunge make it the dissolving, standby; Get dipyridamole, add the injection water, add 0.65% tartaric acid solution again and make it dissolving, it is standby to stir; With above-mentioned medicinal liquid and mannitol mix homogeneously, add 0.2% active carbon again, heated and boiled keeps little and boiled 15 minutes, cooling, filtration, ultrafiltration add in an amount of process glucose solution that boils, and are diluted to full dose with water for injection, regulate pH 5.8～7.0, embedding, sterilization promptly gets glucose injection.The composition that derives from the Rhizoma Chuanxiong medical material that all can be surveyed in the preparation comprise alkaloids, lactone, phenols component content sum be deduction adjuvant amount, water quantities and dipyridamole amount in the preparation total solid 83%.
Embodiment 13: 10000 parts of Rhizoma Chuanxiongs, 50 parts of dipyridamoles (part is: kilogram or gram)
Get Rhizoma Chuanxiong, be ground into coarse powder, with 80% alcohol reflux 2 times, merge extractive liquid, and concentrating under reduced pressure, cooling, desaccharide and oil, remove remaining ethanol in water-bath, add the hot water dissolving, cooling back ether extraction, ether extract hydrochloric acid extraction, acid solution is transferred PH9-10 with saturated sodium carbonate, uses chloroform extraction, the reclaim under reduced pressure chloroform gets chloroform extract, and with the chloroform extract dissolving with hydrochloric acid, reuse ammonia is transferred PH about about 10, with chloroform extraction, the reclaim under reduced pressure chloroform gets total alkali.Total alkali is handled with petroleum ether (60～90 ℃), and the petroleum ether soluble fraction concentrates.Refrigerator place coarse-grain, after mother solution concentrates again through the alkali alumina column chromatography for separation, petroleum ether-chloroform (8: 2) eluting part also coarse-grain, merge coarse-grain and through distillation, the ligustrazine crude product.Pulverize, add dipyridamole, mixing adds polyethylene glycol 6000, mix homogeneously, and heating and melting stirs, and is transferred to the drop pill machine, drips system, collects drop pill, removes the dimethicone on surface, promptly gets drop pill.
Embodiment 14: 300 parts of Rhizoma Chuanxiong extracts, 18 parts of dipyridamoles (part is: kilogram or gram)
Get Rhizoma Chuanxiong extract, dipyridamole mix homogeneously, press medication amount: substrate amount=1: 1.2 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water=100: 40: 100, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, merceration is warming up to 60 ~ 70 ℃ gradually after 30 minutes, stir 5 hours whiles evacuation and remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; The debugging pellet press, pelleting; The dry typing drying of rolling that adopts combined with two steps of tray dried, and dry relative humidity should be lower than 65%, and promptly got soft capsule at 24～48 hours drying time.The content of dipyridamole is 95.5% of labelled amount.
Embodiment 15: 10 parts of Rhizoma Chuanxiong extracts, 4 parts of dipyridamoles (part is: kilogram or gram)
Get Rhizoma Chuanxiong extract, dipyridamole mix homogeneously, add small amount of mannitol, compacting promptly gets oral cavity disintegration tablet in flakes, and dipyridamole content is 103% of preparation labelled amount.
Embodiment 16: 3000 parts of Rhizoma Chuanxiongs, 30 parts of dipyridamoles (part is: kilogram or gram)
Get Rhizoma Chuanxiong, be ground into coarse powder, use alcohol reflux, the extracting solution concentrating under reduced pressure, put coldly, remove desaccharide and oil, remove remaining ethanol in water-bath, add the hot water dissolving, ether extraction is used in the cooling back, ether extract hydrochloric acid extraction, and acid solution is transferred PH9-10 with saturated sodium carbonate, use chloroform extraction, the reclaim under reduced pressure chloroform gets chloroform extract.With the chloroform extract dissolving with hydrochloric acid, reuse ammonia transfers PH about about 10, and with chloroform extraction, the reclaim under reduced pressure chloroform gets Rhizoma Chuanxiong extract.With the dipyridamole mixing, adding starch is an amount of, and oven dry is granulated, and compacting promptly gets tablet in flakes.The component content sum that derives from the Rhizoma Chuanxiong medical material that all can be surveyed be deduction adjuvant amount, water quantities and dipyridamole amount in the preparation total solid 24%.
Embodiment 17: 500 parts of Rhizoma Chuanxiongs, 25 parts of dipyridamoles (part is: kilogram or gram)
Get the Rhizoma Chuanxiong medical material, be ground into coarse powder, add twice of 10 times of amount 70% alcohol reflux, each 1.5h merges medicinal liquid, reclaims ethanol, add water-cooled and soaked 8 hours, filter, be added to pre-treatment after filtrate concentrates and get the AB-8 resin column, flow velocity is 0.3ml/min, and after last sample finished, it was colourless to be washed till effluent with distilled water, reuse 40% ethanol elution is colourless to effluent, collects eluent, concentrates, dry, add dipyridamole, pulverize 4% carboxymethyl starch sodium, mix, drying is granulated granulate, incapsulate, promptly get capsule.
Embodiment 18: 100 parts of Rhizoma Chuanxiong extracts, 30 parts of dipyridamoles (part is: kilogram or gram)
Get Rhizoma Chuanxiong extract, the dipyridamole mix homogeneously adds polyvinylpolypyrrolidone PVPP, CMC-Na, an amount of and lemon yellow mixing, makes binding agent with 1.5% K30 anhydrous alcohol solution, 40 order system material, granulate, and tabletting promptly gets dispersible tablet.
Embodiment 19: 100 parts of Rhizoma Chuanxiongs, 12 parts of dipyridamoles (part is: kilogram or gram)
Get the Rhizoma Chuanxiong coarse powder, with 80 ℃ of hot water extraction 2 times, each 1.5 hours, cooling is filtered, and residue is used 30%, 50%, 70%, 80% ethanol precipitation successively, the filtrate concentrate drying, get Rhizoma Chuanxiong extract, add dipyridamole, mixing, dry, add hydroxypropyl cellulose, Fructus Citri Limoniae essence is an amount of, tabletting promptly gets buccal tablet.
Embodiment 20: 300 parts of Rhizoma Chuanxiong extracts, 40 parts of dipyridamoles (part is: kilogram or gram)
Get an amount of K-carrageenan, locust bean gum makes swelling with low amounts of water, and slight fever makes dissolving, slowly adds fluid extract, mix homogeneously, and warm macerating is 2 hours under 40 ℃ temperature.With Rhizoma Chuanxiong extract and dipyridamole mixing, add slowly in the colloid solution, mix; Other gets lactose and potassium sorbate, with an amount of water dissolution, filters, and adds in the above-mentioned colloid solution, adds water to ormal weight, and mix homogeneously is crossed colloid mill, and packing promptly gets oral gel.
Embodiment 21: 1500 parts of Rhizoma Chuanxiongs, 35 parts of dipyridamoles (part is: kilogram or gram)
Get Rhizoma Chuanxiong, be ground into coarse powder, with 80% soak with ethanol after 1 hour, reflux, extract, 2 times, add for the first time 8 times of amount ethanol, extracted 2 hours, add 6 times of amount ethanol for the second time, extracted 1.5 hours, merge extractive liquid,, after extracting liquid filtering concentrated, the macroporous adsorptive resins of flowing through again washed with water earlier, reuse 30% ethanol elution is collected 30% ethanol elution, and concentrating under reduced pressure promptly gets the Rhizoma Chuanxiong total extract, with soluble starch, spray drying adds dipyridamole, mixing, granulate, sieve, promptly get granule.
Claims (11)
1, a kind of pharmaceutical composition that is used for the treatment of cardiovascular and cerebrovascular disease is characterized in that: calculate according to components by weight percent, it by 1～50 part of 10～10000 parts of Rhizoma Chuanxiongs and dipyridamole through extracting refining forming; Or the Rhizoma Chuanxiong extract and the corresponding weight portion dipyridamole that are obtained after extracting by corresponding weight portion medical material are made.
2, according to the pharmaceutical composition of the described treatment cardiovascular and cerebrovascular disease of claim 1, it is characterized in that: calculate according to components by weight percent, it by 1～30 part of 100～5000 parts of Rhizoma Chuanxiongs and dipyridamole through extracting refining forming; Or the Rhizoma Chuanxiong extract and the corresponding weight portion dipyridamole that are obtained after extracting by corresponding weight portion medical material are made.
3, according to the pharmaceutical composition of the described treatment cardiovascular and cerebrovascular disease of claim 2, it is characterized in that: calculate according to parts by weight, it by 1～20 part of 100～3000 parts of Rhizoma Chuanxiongs and dipyridamole through extracting refining forming; Or the Rhizoma Chuanxiong extract and the corresponding weight portion dipyridamole that are obtained after extracting by corresponding weight portion medical material are made.
4, according to the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease among the claim 1-3, it is characterized in that: preparation of the present invention is injection and oral formulations; Injection comprises: little liquid drugs injection, powder pin or infusion solutions; Oral formulations comprises: all acceptable dosage forms on the pharmaceuticss such as tablet, dispersible tablet, effervescent tablet, oral cavity disintegration tablet, capsule, soft capsule, microcapsule, granule, pill, powder, drop pill, slow releasing preparation, controlled release preparation, oral liquid, soft extract, extractum, gel, membrane.
5, according to the pharmaceutical composition of the described treatment cardiovascular and cerebrovascular disease of claim 4, it is characterized in that: preparation of the present invention is liquid drugs injection, powder pin, infusion solutions, oral liquid, drop pill, capsule, soft capsule, oral cavity disintegration tablet, tablet, capsule, dispersible tablet, buccal tablet, oral gel or granule.
6, according to the pharmaceutical composition of claim 4 or 5 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: count by weight percentage: the component content sum that derives from the Rhizoma Chuanxiong medical material that all can be surveyed in the injection be not less than in the preparation deduction adjuvant amount, water quantities and dipyridamole amount total solid 20%; Dipyridamole should be 90.0%～110.0% of labelled amount.
7, according to the preparation of drug combination method of claim 4 or 5 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: get Rhizoma Chuanxiong, add entry or ethanol extraction, the extracting solution concentrate drying gets the Rhizoma Chuanxiong crude extract, one or more that also can further adopt precipitate with ethanol, organic solvent extractionprocess, flocculent precipitation, column chromatography unite use carry out suitably refining, get the Rhizoma Chuanxiong extract,, be prepared into the preparation that needs with conventional method Rhizoma Chuanxiong crude extract or Rhizoma Chuanxiong extract and dipyridamole mixing.
8, according to the preparation of drug combination method of the described treatment cardiovascular and cerebrovascular disease of claim 7, it is characterized in that: Rhizoma Chuanxiong extract can also be commercially available or adopt other preparation methoies to prepare.
9, according to the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease among the claim 1-3, it is characterized in that: the present invention has anticoagulant, coronary artery dilator, increase coronary flow, improves myocardial oxygen delivery, reduces that myocardial oxygen consumption, anti-acute myocardial ischemia anoxia, antithrombotic form, significantly fibrinolytic, expansion lung blood vessel, reduces functions such as pulmonary vascular resistance.
10, according to the application in cardiovascular and cerebrovascular diseases medicaments such as preparation treatment coronary heart disease, angina pectoris, cerebrovascular, pulmonary heart disease, hypertension of the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease among the claim 1-3.
11, according to the method for quality control of the pharmaceutical composition of claim 4 or 5 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: assay is to adopt in high performance liquid chromatography, spectrophotography, TLC scanning method, the titrimetry one or more to record.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510093129 CN1915255A (en) | 2005-08-19 | 2005-08-19 | Medicinal composition, preparation method and quality control method |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200510093129 CN1915255A (en) | 2005-08-19 | 2005-08-19 | Medicinal composition, preparation method and quality control method |
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| CN1915255A true CN1915255A (en) | 2007-02-21 |
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| CN 200510093129 Pending CN1915255A (en) | 2005-08-19 | 2005-08-19 | Medicinal composition, preparation method and quality control method |
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| CN (1) | CN1915255A (en) |
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