CN1915269A - Medicinal composition, preparation method and quality control method - Google Patents

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 shortscape fleabane herb or its extract and ozagrel. Its preparing process and quality control method are also disclosed.

Description

A kind of pharmaceutical composition and preparation method thereof and method of quality control

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

Cardiovascular and cerebrovascular disease such as coronary heart disease, angina pectoris, arrhythmia, cerebral thrombosis, apoplexy etc. have become one of key factor that threatens human health.According to investigations, sickness rate constantly increases in recent years, and continuous rejuvenation trend is arranged, in, young patient constantly increases, cardiovascular and cerebrovascular disease has become commonly encountered diseases, the frequently-occurring disease of harm China people ' s health.And at present medicine mainly concentrates on pure Chinese medicinal preparation and Western medicine two aspects, although the prescription of Western medicine is fairly simple, can very fast relief of symptoms, and owing to have certain toxic and side effects, be not suitable for long term administration, it is relatively poor to consolidate curative effect simultaneously; Though the pure Chinese medicinal preparation toxic and side effects is little, but their onset is slow, although some ejection preparations are widely used in the treatment of urgency, serious symptom, also obtains certain curative effect simultaneously, but because quality of the pharmaceutical preparations problem, often influence therapeutic effect, occur the situation of attending to one thing and lose sight of another simultaneously, though and oral preparation of Chinese traditional medicinal is various in style, indication is also more complete, but because bioavailability is not high, can not be applicable to urgency, serious symptom administration, make troubles for the part patient; Therefore in conjunction with the organic conception of Chinese medicine with consolidate principle, carry out Chinese medicine and western medicine and be combined into the direction that people begin one's study.In the prior art, lot of documents report, Herba Erigerontis have antithrombotic and form, and anticoagulant resists myocardial ischemia, and is mainly used in obliterated cerebral vascular disease, the treatment of cardiovascular and cerebrovascular diseases such as coronary heart disease, angina pectoris, vasculitis; Ozagrel is a thromboxane synthetase inhibitor, can suppress TXA2 generates, have antiplatelet and build up and the blood vessel dilating effect, be widely used in the treatment of cardiovascular and cerebrovascular diseases such as cerebral thrombosis, acute cerebral infarction, transient ischemic attack, coronary heart disease, angina pectoris, acute ischemic cerebrovascular disease.In view of such circumstances, searching better, compatibility is simple, therapeutic effect is desirable, and effective medicine that toxic and side effects is little has just become people's urgent problem.

Summary of the invention

The object of the present invention is to provide a kind of pharmaceutical composition for the treatment of cardiovascular disease and preparation method thereof and method of quality control; At prior art, the present invention adopts the preparation that Herba Erigerontis or Herba Erigerontis extract and ozagrel compatibility are made to be needed, Herba Erigerontis has coronary blood flow increasing, reduce myocardial excitability and conductivity, microcirculation improvement, antiplatelet aggregation and thrombosis, and blood viscosity is descended, ozagrel is a thromboxane synthetase inhibitor, can suppress TXA2 generates, effect with antiplatelet accumulation and expansion blood vessel etc., discover that through pharmacology pharmacodynamic the preparation that the two compatibility is made is in treatment cardiovascular and cerebrovascular disease such as coronary heart disease, angina pectoris, aspects such as obliterated cerebral vascular disease have good efficacy; Another object of the present invention is the method for Chinese medicinal of these treatment cardiovascular and cerebrovascular diseases of open preparation; The present invention also aims to provide its method of quality control; To overcome the problem that prior art exists.

Preparation of the present invention is to constitute like this: it by 1～50 part of 10～10000 parts of Herba Erigerontiss and ozagrel through extracting refining forming; Or the Herba Erigerontis extract and the corresponding weight portion ozagrel 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 Herba Erigerontiss and ozagrel through extracting refining forming; Or the Herba Erigerontis extract and the corresponding weight portion ozagrel 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 100～3000 parts of Herba Erigerontiss and ozagrel through extracting refining forming; Or the Herba Erigerontis extract and the corresponding weight portion ozagrel that are obtained after extracting by corresponding weight portion medical material are made.

The pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease, dosage form are injection and oral formulations; 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, capsule, soft capsule, microcapsule, granule, pill, powder, drop pill, slow releasing preparation, controlled release preparation, oral liquid, soft extract, extractum, gel, membrane.Preferred preparation 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.

The pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease: count by weight percentage: the total solid that the content of flavones ingredient accounts in the preparation after deduction ozagrel and adjuvant amount and the water quantities in the preparation is not less than 5%; The component content sum that derives from the Herba Erigerontis medical material that all can be surveyed in the injection be not less than in the preparation deduction adjuvant amount, water quantities and ozagrel amount total solid 20%; Ozagrel content should be 90.0%～110.0% of preparation labelled amount.The preparation of drug combination method of described treatment cardiovascular and cerebrovascular disease is: get Herba Erigerontis, add entry or ethanol extraction, the extracting solution concentrate drying gets the Herba Erigerontis crude extract, one or more that also can further adopt precipitate with ethanol, organic solvent extraction, flocculent precipitation, column chromatography unite use carry out suitably refining, get the Herba Erigerontis extract, with Herba Erigerontis crude extract or Herba Erigerontis extract and ozagrel mixing, be prepared into the preparation that needs with conventional method.

Described Herba Erigerontis extract can also be commercially available or adopt other preparation methoies to prepare.

The pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease has antiplatelet aggregation, the cerebral blood flow increasing amount, reduce cerebral vascular resistance, improve cardiac hemodynamic, promote coronary flow, reduce myocardial oxygen consumption, functions such as blood vessel dilating, and the application in preparation treatment coronary heart disease, angina pectoris, apoplexy, cerebral infarction, acute thrombotic cerebral infarction are waited indefinitely the dyskinesia medicine that cardiovascular and cerebrovascular disease and cerebral infarction follow.

Its assay is to adopt in high performance liquid chromatography, spectrophotography, thin layer chromatography scanning or the titrimetry one or more to record in the method for quality control of the pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease.

Compared with prior art, Herba Erigerontis or Herba Erigerontis extract and ozagrel all are active drugs of cardiovascular and cerebrovascular diseases, because its effective ingredient purity is higher, and the intravenous administrations that adopt in the acute disease treatment more.With both combinations, though can obtain potentiation, its preparation stability and safety can't guarantee clinically.The applicant is combined into novel formulation with Herba Erigerontis extract and ozagrel and develops research, bringing into play both in the wait indefinitely cooperative compensating effect of cardiovascular and cerebrovascular disease of treatment angina pectoris, apoplexy, cerebral infarction, acute thrombotic cerebral infarction by compatibility, is that the treatment of cardiovascular and cerebrovascular disease increases a new medication and selects.Simultaneously, can system further investigate Herba Erigerontis or the safety of Herba Erigerontis extract and ozagrel compatibility and the controllability of quality, for data for clinical drug use is given security.By antiplatelet aggregation test, inhibition mouse tail thrombotest, to these two kinds of medicines (Herba Erigerontis extract: ozagrel) carried out the prescription screening test of system, found that with Herba Erigerontis extract (flavones ingredient content is 90%): the prescription pharmacological action of ozagrel=3: 1 is strong and consumption is lower, preparations shaping and having good stability, and both compatibilities can reach potentiation antidotal effect.The result shows; after two medication combined application; the obvious synergistic effect is being arranged aspect the chemical blood stasis dispelling; aspect the treatment cerebral ischemia obvious synergistic effect is being arranged also; the increase that can obviously increase blood flow coronarius simultaneously, reduce the Ischemic Heart load, resist myocardial oxygen consumption, thereby better protection ischemic myocardium.

Pharmaceutical preparation of the present invention, with respect to the independent preparation of Herba Erigerontis, ozagrel better efficacy not only, and use is carried all very convenient, the preparation method of multiple different oral formulations is 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

(1) the prescription screening experimental study conclusion of drug regimen compatibility

We are by antiplatelet aggregation test, inhibition mouse tail thrombotest, the prescription screening test that the Herba Erigerontis extract and the ozagrel of different content carried out system in varing proportions, found that with flavones ingredient content be 90% Herba Erigerontis extract and the pharmacological action of ozagrel=3: 1 combination prescription is strong and consumption is lower, so determine that this ratio prescription is best prescription.

Table 1 prescription research conclusion

Formula number	Prescription proportion of composing Herba Erigerontis extract: ozagrel	The screening and assessment index
				Platelet suppression ratio (%)	Thrombosis suppression ratio (%)
		1 2 3 4 5 6 7	1∶10 1∶5 1∶1 2∶1 3∶1 6∶1 12∶1			85.7％ 88.6％ 83.1％ 79.1％ 80.2％ 73.4％ 66.8％	70.3％ 65.4％ 65.4％ 53.4％ 65.5％ 50.9％ 56.2％

Annotate: the content of flavones ingredient is 90% in the Herba Erigerontis extract.

Table 2: prescription research conclusion

Formula number	Prescription is formed and the ratio Herba Erigerontis extract: ozagrel	The screening and assessment index
				Platelet suppression ratio (%)	Thrombosis suppression ratio (%)
		1 2 3 4 5 6 7	1∶2 1∶1 2∶1 6∶1 10∶1 15∶1 18∶1			77.6％ 73.1％ 69.1％ 70.3％ 63.8％ 54.2％ 47.7％	32.4％ 35.2％ 35.4％ 40.1％ 38.2％ 36.9％ 20.2％

Annotate: the content of Herba Erigerontis total flavones is 50% in the Herba Erigerontis extract.

Table 3: prescription research conclusion

Formula number	Prescription is formed and the ratio Herba Erigerontis extract: ozagrel	The screening and assessment index
				Platelet suppression ratio (%)	Thrombosis suppression ratio (%)
		1 2 3 4 5 6 7	1∶1 2∶1 4∶1 6∶1 10∶1 20∶1 30∶1			73.1％ 60.1％ 57.3％ 50.8％ 49.4％ 40.3％ 32.7％	52.8％ 45.4％ 38.5％ 36.2％ 25.7％ 23.5％ 16.0％

Annotate: the content of flavones ingredient is 20% in the Herba Erigerontis extract.

Table 4: prescription research conclusion

Formula number	Prescription is formed and the ratio Herba Erigerontis extract: ozagrel	The screening and assessment index
				Platelet suppression ratio (%)	Thrombosis suppression ratio (%)
		1 2 3 4 5 6 7	2∶1 6∶1 20∶1 40∶1 60∶1 90∶1 150∶1			45.2％ 38.2％ 34.7％ 25.6％ 28.4％ 19.6％ 12.7％	25.5％ 19.9％ 18.0％ 24.5％ 17.2％ 17.3％ 10.2％

Annotate: the content of flavones ingredient is 3% in the Herba Erigerontis extract.

From above-mentioned prescription screening result as can be seen, the Herba Erigerontis extract of different purity and ozagrel compatibility all can produce certain curative effect, but through system thinking, determine with flavones ingredient content be 90% Herba Erigerontis extract with ozagrel with 3: 1 ratio compatibility pharmacological action by force and consumption is lower, preparations shaping and having good stability, can reach potentiation antidotal effect.

(2) Herba Erigerontis extract: affirmation and the side's of tearing open research conclusion of ozagrel=3: 1 combination prescription effectiveness

Drug efficacy study through system shows; after two medication combined application; 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 affirmation of prescription effectiveness and the side's of tearing open research conclusion

Pilot project	Prescription of the present invention	The Herba Erigerontis extract group	The ozagrel group
				The test of global brain ischemia model test rabbit fibrin solubility test blood circulation promoting and blood stasis dispelling	Effect is remarkable, the effect reinforced effects is remarkable, and the effect reinforced effects is remarkable	The general effect of effect positive effect is obvious	The general effect of effect positive effect is obvious

Concrete embodiment

Embodiment 1: the preparation Herba Erigerontis extract: get 10 parts of Herba Erigerontiss (kilogram or gram)

Get Herba Erigerontis, pulverize the back and add 80% ethanol, soaked 12 hours, percolation extracts, merge extractive liquid,, decompression recycling ethanol and to measure relative density when being condensed into 60 ℃ of extractum be 1.05～1.15 adds 3 times of water gagings and heats 50 ℃ of stirring and dissolving, filter, filtrate is crossed ZTC-1 type macroporous resin column, with 20% ethanol elution impurity, and reuse 60% alcohol desorption, collect stripping liquid, reclaim the ethanol concentrate drying, pulverize the back, filter with 2 times of amount dissolve with ethanols, filtrate adds the silica gel oven dry, silicagel column on the dry method is used eluent ethyl acetate, collects eluent, reclaim solvent, concentrate drying promptly gets Herba Erigerontis extract.

Embodiment 2: the preparation Herba Erigerontis extract: 10000 parts of Herba Erigerontiss (kilogram or gram)

Get Herba Erigerontis, add 10 times of water gagings and decoct 3 times, each 1.5 hours, merge extractive liquid,, relative density is 1.05～1.15 thick paste when being concentrated into 80 ℃, adds ethanol and makes that to contain the alcohol amount be 50%, and cold preservation is spent the night, and filters, filtrate recycling ethanol, drying under reduced pressure gets Herba Erigerontis extract.

Embodiment 3: the preparation Herba Erigerontis extract: 8000 parts of Herba Erigerontiss (kilogram or gram)

Get Herba Erigerontis, add 6 times of amount 50% alcohol reflux 3 times, each 1 hour, merge extractive liquid,, decompression recycling ethanol, relative density is 1.05～1.15 thick paste when being concentrated into 80 ℃, adds 3 times of water gagings, heats 60 ℃ of stirring and dissolving, filter, filtrate is condensed into thick paste, and vacuum drying gets Herba Erigerontis extract.

Embodiment 4: the preparation Herba Erigerontis extract: 20 parts of Herba Erigerontiss (kilogram or gram)

Get Herba Erigerontis, add 80 ℃ of warm macerating of 10 times of volume water and extract 3 times, each 1 hour, merge extractive liquid,, relative density is 1.05～1.15 thick paste when being concentrated into 80 ℃, adding 20% sulfuric acid solution adjustment pH value is 2～3, stirs, and adds the equal-volume ethyl acetate extraction 4 times, isolate ethyl acetate layer, reclaim solvent, concentrate, drying under reduced pressure gets Herba Erigerontis extract.

Embodiment 5: the preparation Herba Erigerontis extract: 5000 parts of Herba Erigerontiss (kilogram or gram)

Get Herba Erigerontis, add 8 times of volume decoctings and boil each 1.5 hours 3 times, merge extractive liquid,, relative density is 1.05～1.15 thick paste when being concentrated into 80 ℃, adds 20% sodium carbonate liquor stirring and dissolving, filter, filtrate adds 20% sulfuric acid solution, and regulating pH value is 2～3, stir, cold preservation 24 hours is filtered, the precipitation water wash to pH value be 5～6, drying under reduced pressure, that is, and Herba Erigerontis extract.Add the equal-volume ethyl acetate extraction 4 times, isolate ethyl acetate layer, reclaim solvent, concentrate, drying under reduced pressure gets Herba Erigerontis extract.

Embodiment 6: 500 parts of Herba Erigerontiss, 10 parts of ozagrels (part is: kilogram or gram)

Get Herba Erigerontis, add 80% ethanol, soaked 12 hours, percolation extracts, merge extractive liquid,, decompression recycling ethanol and when being condensed into 80 ℃ relative density be 1.05～1.15 extractum, add 50 ℃ of stirring and dissolving of 3 times of water gaging heating, filter, filtrate is crossed the ZTC-1 macroporous resin column, with 20% ethanol elution impurity, reuse 60% alcohol desorption, collect stripping liquid, reclaim the ethanol concentrate drying, get Herba Erigerontis extract.

Embodiment 7: 1000 parts of ozagrels of Herba Erigerontis: 50 parts (part is: kilogram or gram)

Get Herba Erigerontis 1000g, pulverize the back and add 80% ethanol, soaked 12 hours, percolation extracts, merge extractive liquid,, decompression recycling ethanol and to measure relative density when being condensed into 60 ℃ of extractum be 1.05～1.15, add 50 ℃ of stirring and dissolving of 3 times of water gaging heating, filter, filtrate is crossed ZTC-1 type macroporous resin column, with 20% ethanol elution impurity, reuse 60% alcohol desorption, collect stripping liquid, reclaim the ethanol concentrate drying, pulverize the back and measure dissolve with ethanols with 2 times, filter, filtrate adds the silica gel oven dry, and silicagel column on the dry method is used eluent ethyl acetate, collect eluent, reclaim solvent, concentrate drying promptly gets Herba Erigerontis extract, adds water for injection, stir, add an amount of sodium citrate and propylene glycol again, stir evenly, make it to form clear and bright solution.Get water for injection again and put in the liquid dispenser, add ozagrel, be stirred to and form clear and bright solution, under stirring this solution is added in the above-mentioned Herba Erigerontis extract solution, add the injection water again to ormal weight.Measure pH value, (0.8um--0.45um--0.22um filters sequentially), and potting is in the 10ml ampoule, and 100 ℃ of flowing steam sterilization 30min promptly get aqueous injection for tartaric acid with 1% or 0.1M NaOH solution accent pH to 7.5～8.0, three grade microporous filter membrane.

Embodiment 8: Herba Erigerontis: 3000 parts, and ozagrel: 20 parts (part is: kilogram or gram)

Get Herba Erigerontis, add 8 times of volume decoctings and boil each 1.5 hours 3 times, merge extractive liquid,, relative density is 1.05～1.15 thick paste when being concentrated into 80 ℃, adds 20% sodium carbonate liquor stirring and dissolving, filter, filtrate adds 20% sulfuric acid solution, and regulating pH value is 2～3, stir, cold preservation 24 hours is filtered, the precipitation water wash to pH value be 5～6, drying under reduced pressure, that is, and Herba Erigerontis extract.Add the equal-volume ethyl acetate extraction 4 times, isolate ethyl acetate layer, reclaim solvent, concentrate, drying under reduced pressure gets Herba Erigerontis extract, joins in the 1000ml water for injection to stir, add an amount of 10% sodium citrate solution, be stirred to solution and dissolve fully, standby: as to take by weighing ozagrel and join and be stirred to solution in the water for injection and dissolve fully, add standby Herba Erigerontis extract solution mix homogeneously, regulate pH value 7.5-8.0, stirring makes it to dissolve fully, adds an amount of PEG400 and mannitol, stirs to make it to dissolve fully, the active carbon that adds 0.05% (g/ml), 60 ℃ of static absorption were filtered carbon removal after 20 minutes, and benefit adds to the full amount of water for injection, regulate pH value 7.5-8.0, fine straining, intermediate sampling, to be detected qualified after, quantitatively (about 3ml) fill is in cillin bottle, half moulding plug, the freeze dryer of packing into, lyophilization.After the end to be dried, the intrinsic pressure plug of case, outlet lock aluminium lid, packing promptly gets freeze-dried powder.

Embodiment 9: Herba Erigerontis: 1000 parts of ozagrels: 50 parts (part is: kilogram or gram)

Get Herba Erigerontis,, add 80 ℃ of warm macerating of 10 times of volume water and extract 3 times, each 1 hour, merge extractive liquid,, relative density is 1.05～1.15 thick paste when being concentrated into 80 ℃, adding 20% sulfuric acid solution adjustment pH value is 2～3, stir, add the equal-volume ethyl acetate extraction 4 times, isolate ethyl acetate layer, reclaim solvent, concentrate, drying under reduced pressure gets Herba Erigerontis extract; Get an amount of water for injection and put in the liquid dispenser, add the Herba Erigerontis extract stirring at room and make it dissolving, add an amount of sodium citrate and propylene glycol again, stir evenly, make it to form clear and bright solution.Get water for injection again and put in the liquid dispenser, add ozagrel, be stirred to and form clear and bright solution, under stirring this solution is added in the above-mentioned Herba Erigerontis extract solution, add the injection water again to ormal weight.Measure pH value, tartaric acid with 1% or 0.1M NaOH solution are transferred pH to 7.5～8.0, add in an amount of process glucose solution that boils, stirring and dissolving adds 0.05% active carbon and boils, stir insulation 20 minutes, filtered while hot, (0.8um--0.45um--0.22um filters three grades of microporous filter membrane sequentially), embedding, 105 ℃ of sterilizations promptly got the glucose infusion liquid agent in 1 hour.

Embodiment 10: Herba Erigerontis: 10000 parts of ozagrels: 50 parts (part is: kilogram or gram)

Get Herba Erigerontis, add 80% ethanol, soaked 12 hours, percolation extracts, merge extractive liquid,, decompression recycling ethanol and when being condensed into 80 ℃ relative density be 1.05～1.15 extractum, add 50 ℃ of stirring and dissolving of 3 times of water gaging heating, filter, filtrate is crossed the ZTC-1 macroporous resin column, with 20% ethanol elution impurity, reuse 60% alcohol desorption, collect stripping liquid, reclaim the ethanol concentrate drying, Herba Erigerontis extract, add an amount of water for injection, with 25% sodium hydroxide adjust pH 7.5～8.0; Other gets ozagrel, adds the water for injection dissolving, and is standby; With above-mentioned two parts of solution mix homogeneously, add 0.3% active carbon, heated and boiled keeps little and boiled fine straining 15 minutes, cooling, coarse filtration, fine straining adds an amount of through in the sodium chloride solution that boils, be diluted to full dose with water for injection, embedding, sterilization promptly gets sodium chloride injection.

Embodiment 11: Herba Erigerontis extract: 5000 parts of ozagrels: 20 parts (part is: kilogram or gram)

Get an amount of water for injection earlier and put in the liquid dispenser, add Herba Erigerontis extract, stirring at room makes it dissolving, adds an amount of sodium citrate and an amount of propylene glycol again, stirs evenly, and makes it to form clear and bright solution.Get water for injection again and put in the liquid dispenser, add ozagrel, be stirred to and form clear and bright solution, under stirring this solution is added in the above-mentioned Herba Erigerontis extract solution, add the injection water again to 1000ml.Measure pH value, (0.8um--0.45um--0.22um filters sequentially), and potting is in the 10ml ampoule, and 100 ℃ of flowing steam sterilization 30min promptly get aqueous injection for tartaric acid with 1% or 0.1M NaOH solution accent pH to 4.8～5.7, three grade microporous filter membrane.To account in the preparation total solid after deduction ozagrel and adjuvant amount and the water quantities be 95% to the content of scutellarin in the preparation, all the content sums that can survey composition account for that the total solid behind the deduction ozagrel and adjuvant amount and water quantities is 98% in the preparation in the injection, and ozagrel content is 97.6% of preparation labelled amount.

Embodiment 12: 3000 parts of Herba Erigerontis extracts, 20 parts of ozagrels (part is: kilogram or gram)

Get Herba Erigerontis extract, join in the ormal weight water for injection and stir, add an amount of 10% sodium citrate solution, be stirred to solution and dissolve fully, standby: as to take by weighing ozagrel and join and be stirred to solution in the water for injection and dissolve fully, add standby Herba Erigerontis extract solution mix homogeneously, regulate pH value 7.5～8.0, stirring makes it to dissolve fully, adds an amount of PEG400 and mannitol, stirs dissolving fully just, the active carbon that adds 0.05% (g/ml), 60 ℃ of static absorption were filtered carbon removal after 20 minutes, and benefit adds to the full amount of water for injection, regulate pH value 4.5-5.5, fine straining, intermediate sampling, to be detected qualified after, quantitative filling is in cillin bottle, half moulding plug, the freeze dryer of packing into, lyophilization.After the end to be dried, the intrinsic pressure plug of case, outlet lock aluminium lid, packing promptly gets freeze-dried powder.To account in the preparation total solid after deduction ozagrel and adjuvant amount and the water quantities be 53% to the content of flavones ingredient in the preparation.

Embodiment 13: 500 parts of Herba Erigerontis extracts, 10 parts of ozagrels (part is: kilogram or gram)

Get 600ml water for injection earlier and put in the liquid dispenser, add Herba Erigerontis extract 500mg, stirring at room makes it dissolving, adds an amount of sodium citrate and propylene glycol again, stirs evenly, and makes it to form clear and bright solution.Get 300ml water for injection again and put in the liquid dispenser, add ozagrel 10mg, be stirred to and form clear and bright solution, under stirring this solution is added in the above-mentioned Herba Erigerontis extract solution, add to the full amount of water for injection again.Measure pH value, tartaric acid with 1% or 0.1M NaOH solution are transferred pH to 7.5 ~ 8.0, add the 100g glucose, stirring and dissolving adds 0.05% active carbon and boils, stir insulation 20 minutes, filtered while hot, (0.8um-0.45um--0.22um filters three grades of microporous filter membrane sequentially), embedding, 105 ℃ of sterilizations promptly got glucose injection in 1 hour.All the content sums that can survey composition account for that the total solid behind the deduction ozagrel and adjuvant amount and water quantities is 46% in the preparation in the injection.

Embodiment 14: 3 parts of Herba Erigerontis extracts, 1 part of ozagrel (part is: kilogram or gram)

Get 600ml water for injection earlier and put in the liquid dispenser, add Herba Erigerontis extract, stirring at room makes it dissolving, adds an amount of sodium citrate and propylene glycol again, stirs evenly, and makes it to form clear and bright solution.Get 300ml water for injection again and put in the liquid dispenser, add ozagrel, be stirred to and form clear and bright solution, under stirring this solution is added in the above-mentioned Herba Erigerontis extract solution, add the injection water again to 1000ml.Measure pH value, tartaric acid with 1% or 0.1M NaOH solution are transferred pH to 7.5～8.0, three grade microporous filter membrane, and (0.8um--0.45um--0.22um filters sequentially), add an amount of process and boil in the sodium chloride solution of depyrogenation, promptly get the sodium chloride infusion solution with the water for injection dilution.All the content sums that can survey composition account for that the total solid behind the deduction ozagrel and adjuvant amount and water quantities is 22% in the preparation in the injection

Embodiment 15: 10000 parts of Herba Erigerontiss, 50 parts of ozagrels (part is: kilogram or gram)

Get Herba Erigerontis, add 8 times of volume decoctings and boil each 1.5 hours 3 times, merge extractive liquid,, relative density is 1.05～1.15 thick paste when being concentrated into 80 ℃, adds 20% sodium carbonate liquor stirring and dissolving, filter, filtrate adds 20% sulfuric acid solution, and regulating pH value is 2～3, stir, cold preservation 24 hours is filtered, the precipitation water wash to pH value be 5～6, drying under reduced pressure, that is, and Herba Erigerontis extract.Add the equal-volume ethyl acetate extraction 4 times, isolate ethyl acetate layer, reclaim solvent, concentrate, drying under reduced pressure gets Herba Erigerontis extract; Get Herba Erigerontis extract, dipyridamole mix homogeneously, get 2 parts of mixed powders, two parts of PEG4000 and polyoxyethylene monostearate S-40 portion, mix homogeneously fuses in the water-bath, stir evenly, drip and in dimethicone, to become ball, drip apart from 5cm drip footpath 2.5mm/2mm, 70 ℃ of hybrid medicine temperature, liquid coolant height 60cm promptly gets drop pill.

Embodiment 16: 300 parts of Herba Erigerontis extracts, 10 parts of ozagrels (part is: kilogram or gram)

Get Herba Erigerontis extract, ozagrel mix homogeneously, press medication amount: substrate amount=1: 1.2 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100g: 40g: 100g: 1g, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, merceration is warming up to 65 ± 5 ℃ gradually after 30 minutes, stirred 5 hours and simultaneously evacuation remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; The debugging pellet press, 65 ℃ of gelatin box temperature controls, mould rotating speed 2.0 is rolled in 45 ℃ of sprinkler body temperature controls, rubber thickness 0.8mm, 18～25 ℃ of indoor temperatures, relative humidity＜40%, pelleting; The dry typing drying of rolling that adopts combined with two steps of tray dried, dry 2 hours of the typing of rolling, and 22 ℃ of baking temperatures, dry relative humidity should be lower than 65%, and promptly got soft capsule at 24～48 hours drying time.To account in the preparation total solid after deduction ozagrel and adjuvant amount and the water quantities be 19% to the content of flavones ingredient in the preparation.

Embodiment 17: 81 parts of Herba Erigerontis extracts, 27 parts of ozagrels (part is: kilogram or gram)

Get Herba Erigerontis extract, ozagrel mix homogeneously, add 7% polyvinylpolypyrrolidone PVPP and 2% mannitol, compacting promptly gets oral cavity disintegration tablet in flakes., tabletting promptly gets oral cavity disintegration tablet.To account in the preparation total solid after deduction ozagrel and adjuvant amount and the water quantities be 6% to the content of flavones ingredient in the preparation.

Embodiment 18: 5000 parts of Herba Erigerontiss, 40 parts of ozagrels (part is: kilogram or gram)

Get Herba Erigerontis, add 10 times of water gagings and decoct 3 times, each 1.5 hours, merge extractive liquid,, relative density is 1.05～1.15 thick paste when being concentrated into 80 ℃, adds ethanol and makes that to contain the alcohol amount be 50%, and cold preservation is spent the night, and filters, filtrate recycling ethanol, drying under reduced pressure gets Herba Erigerontis extract; Get Herba Erigerontis extract, ozagrel mix homogeneously, granulate tabletting, coating, 3%80W type Opadry is a coating material, and the coating solution speed of spraying into is 230～250g/min, and inlet temperature is for being controlled between 85～88 ℃, pot body rotating speed is controlled at 8～9r/min, promptly gets tablet.

Embodiment 19: 24 parts of Herba Erigerontis extracts, 8 parts of ozagrels (part is: kilogram or gram)

Get Herba Erigerontis extract, add ozagrel, mixing adds the magnesium stearate of 4% carboxymethyl starch sodium and 0.3%, mix, and drying, granulation, granulate incapsulates, and promptly gets capsule.To account in the preparation total solid after deduction ozagrel and adjuvant amount and the water quantities be 56% to the content of scutellarin in the preparation.

Embodiment 20: 2000 parts of Herba Erigerontiss, 35 parts of ozagrels (part is: kilogram or gram)

Get Herba Erigerontis, pulverize the back and add 80% ethanol, soaked 12 hours, percolation extracts, merge extractive liquid,, decompression recycling ethanol and to measure relative density when being condensed into 60 ℃ of extractum be 1.05～1.15 adds 3 times of water gagings and heats 50 ℃ of stirring and dissolving, filter, filtrate is crossed ZTC-1 type macroporous resin column, with 20% ethanol elution impurity, and reuse 60% alcohol desorption, collect stripping liquid, reclaim the ethanol concentrate drying, pulverize the back, filter with 2 times of amount dissolve with ethanols, filtrate adds the silica gel oven dry, silicagel column on the dry method is used eluent ethyl acetate, collects eluent, reclaim solvent, concentrate drying promptly gets Herba Erigerontis extract; Get Herba Erigerontis extract, ozagrel mix homogeneously, get PPVP3.35g and CMC-Na1.05g and add the lemon yellow mixing, get 3/5 with the medicated powder mix homogeneously, K30 anhydrous alcohol solution with 1.5% is made binding agent, 40 order system material, granulate, the mixed powder that residue 2/5PPVP3.25g and CMC-Na1.05g add the lemon yellow mixing is added in the particle that makes, and tabletting promptly gets dispersible tablet.

Embodiment 21: 100 parts of Herba Erigerontis extracts, 15 parts of ozagrels (part is: kilogram or gram)

Get Herba Erigerontis extract, ozagrel mix homogeneously, add 5% poloxamer, 12% lactose, 30% low-substituted hydroxypropyl cellulose sodium, mixing is granulated, and promptly gets granule.

Embodiment 22: 500 parts of Herba Erigerontis extracts, 10 parts of ozagrels (part is: kilogram or gram)

Get Herba Erigerontis extract, add ozagrel, mixing, drying adds 2% magnesium stearate, stevioside is an amount of, and tabletting promptly gets buccal tablet.

Embodiment 23: 100 parts of Herba Erigerontis extracts, 28 parts of ozagrels (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 Herba Erigerontis extract and ozagrel mixing, add slowly in the colloid solution, mix; Other gets sucrose, citric acid 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.

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 weight combinations, it by 1～50 part of 10～10000 parts of Herba Erigerontiss and ozagrel through extracting refining forming; Or the Herba Erigerontis extract and the corresponding weight portion ozagrel 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 Herba Erigerontiss and ozagrel through extracting refining forming; Or the Herba Erigerontis extract and the corresponding weight portion ozagrel 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 Herba Erigerontiss and ozagrel through extracting refining forming; Or the Herba Erigerontis extract and the corresponding weight portion ozagrel 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: 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 any described treatment cardiovascular and cerebrovascular disease among the claim 1-3, it is characterized in that: count by weight percentage: the total solid that the content of flavones ingredient accounts in the preparation after deduction ozagrel and adjuvant amount and the water quantities in the preparation is not less than 5%; The component content sum that derives from the Herba Erigerontis medical material that all can be surveyed in the injection be not less than in the preparation deduction adjuvant amount, water quantities and ozagrel amount total solid 20%; Ozagrel content should be 90.0%～110.0% of preparation 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 Herba Erigerontis, add entry or ethanol extraction, the extracting solution concentrate drying gets the Herba Erigerontis crude extract, one or more that also can further adopt precipitate with ethanol, organic solvent extraction, flocculent precipitation, column chromatography unite use carry out suitably refining, get the Herba Erigerontis extract, with Herba Erigerontis crude extract or Herba Erigerontis extract and ozagrel mixing, be prepared into the preparation that needs with conventional method.

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: Herba Erigerontis 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 antiplatelet aggregation, the cerebral blood flow increasing amount, reduce cerebral vascular resistance, improve cardiac hemodynamic, promote coronary flow, reduce myocardial oxygen consumption, functions such as blood vessel dilating.

10, according to the application in preparation treatment coronary heart disease, angina pectoris, apoplexy, cerebral infarction, acute thrombotic cerebral infarction are waited indefinitely the dyskinesia medicine that cardiovascular and cerebrovascular disease and cerebral infarction follow 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, thin layer chromatography scanning, the titrimetry one or more to record.