CN1915283A - 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 pueraria root 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 compound preparation 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 is a big persistent ailment that threatens world's healthy population as coronary heart disease, myocardial infarction, rhomboembolia type cerebrovascular, and the trend that progressively rises is arranged in recent years.The height of cardiovascular and cerebrovascular disease mortality rate is to weigh a country, resident's quality of life, the important indicator of sanitary health career, along with the arriving of fairly comfortable life, and the change of meals spectrum, resident's longevity, healthy existence desire improve constantly.In order to prevent, control the generation of cardiovascular and cerebrovascular disease, develop cardiovascular and cerebrovascular disease class medicine and become a main trend.So far existing a large amount of Chinese medicine and western medicine emerge.But the side effect of Western medicine is big, and Chinese medicine is long the course of treatment.Therefore, it is low to seek a kind of cost, determined curative effect, and the natural Chinese medicines preparation that has no side effect is very urgent, contrast after deliberation, we develop a kind of compound preparation for the treatment of cardiovascular and cerebrovascular disease, are made up of Radix Puerariae or Radix Puerariae extract and ozagrel.In the prior art, kudzu vine root preparation such as puerarin injection and ozagrel sheet, ozagrel injection have been widely used in the treatment cardiovascular and cerebrovascular disease, but the puerarin injection widely used while clinically, untoward reaction such as dermoreaction, haemolysis, drug fever, the report of angioedema etc. is also increasing day by day, ozagrel has gastrointestinal reaction and anaphylaxis, and contraindication is also more.So the inventor is also arranged by comparative study, finds that both prescriptions can Synergistic and energy attenuation.

Summary of the invention

The objective of the invention is to disclose a kind of compound preparation for the treatment of cardiovascular and cerebrovascular disease, adopt the preparation that Radix Puerariae or Radix Puerariae extract and ozagrel 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, cerebral thrombosis, arteriosclerosis 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 method of the compound preparation 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 Radix Puerariaes and ozagrel through extracting refining forming; Or the Radix Puerariae extract and the corresponding weight portion ozagrel that are obtained after extracting by corresponding weight portion medical material are made; Specifically, 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 Radix Puerariaes and ozagrel through extracting refining forming; Or the Radix Puerariae 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 Radix Puerariaes and ozagrel through extracting refining forming; Or the Radix Puerariae extract and the corresponding weight portion ozagrel 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 content of flavones ingredient be not less than in the preparation deduction adjuvant amount, water quantities and ozagrel amount total solid 1%; The component content sum that derives from the Radix Puerariae 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 Radix Puerariae, add entry or ethanol or limewater extraction, the extracting solution concentrate drying gets the Radix Puerariae 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 Radix Puerariae extract, with Radix Puerariae crude extract or Radix Puerariae extract and ozagrel mixing, be prepared into the preparation that needs with conventional method.

Radix Puerariae 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, anticoagulation, antithrombotic, protection ischemic myocardium, increases coronary blood flow, reduces myocardial oxygen consumption, changes functions such as microcirculation, blood vessel dilating, blood sugar lowering, blood fat reducing, blood pressure lowering; Be used for the treatment of coronary heart disease, angina pectoris, arteriosclerosis, the acute thrombotic cerebral infarction dyskinesia that cardiovascular and cerebrovascular disease and cerebral infarction follow of waiting indefinitely.

The method of quality control of the pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease is characterized in that: its assay is to adopt in high performance liquid chromatography, spectrophotography, TLC scanning method, the titrimetry one or more to record.

In the prior art, Radix Puerariae or Radix Puerariae extract and ozagrel all demonstrate certain advantage in the treatment cardiovascular and cerebrovascular disease, because its effective ingredient purity is higher, the application of injection in the emergency and severe disease treatment of single medicinal material are all arranged at present.The inventor finds clinically both to be made up, and can obtain potentiation, but up to now, does not have the preparation report of the two prescription.So, the applicant is combined into novel formulation with Radix Puerariae extract and ozagrel and develops research, bringing into play both in coronary heart disease, angina pectoris, arteriosclerosis, the acute thrombotic cerebral infarction cooperative compensating effect aspect waiting indefinitely by compatibility, is that the treatment of cardiovascular and cerebrovascular disease increases a new medication and selects.Simultaneously, can system further investigate Radix Puerariae or the safety of Radix Puerariae 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 (Radix Puerariae extract: ozagrel) carried out the prescription screening test of system, found that with Radix Puerariae extract (flavones ingredient content is 90%): the prescription pharmacological action of ozagrel-8: 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.

Synergistic between the pharmaceutical composition of the present invention, aspect the drug effect of treatment cardiovascular and cerebrovascular disease, the folk prescription medicine that is better than Radix Puerariae and ozagrel respectively indicates that medicine of the present invention can obviously improve the effective percentage of clinical treatment and further improve patient's life quality; Alleviate the drug-induced untoward reaction of folk prescription simultaneously, because the adding of the Radix Astragali or Radix Astragali extract has reduced the ozagrel amount of drug, thereby gastrointestinal reaction and anaphylaxis that independent use ozagrel causes have been alleviated or have reduced, as serial untoward reaction such as nauseating, vomiting, urticaria, erythra; The 3rd, pharmaceutical preparation bioavailability height of the present invention complements each other on the mechanism of action, has overcome the low shortcoming of bioavailability that independent medication exists.

The applicant has also carried out following experiment, to prove effective 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 Radix Puerariae extract and the ozagrel of different content carried out system in varing proportions, found that the curative effect after Radix Puerariae or Radix Puerariae extract and ozagrel compatibility use has remarkable potentiation with ozagrel more separately, it with flavones ingredient content 90% Radix Puerariae extract: ozagrel=combination in 8: 1, the prescription pharmacological action is strong and consumption is lower, is best prescription so determine this ratio prescription.

Table 1 prescription research conclusion

Formula number	Prescription is formed and ratio	The screening and assessment index
				Radix Puerariae extract: ozagrel	Platelet suppression ratio (%)	Thrombosis suppression ratio (%)
	1 2 3 4 5 6 7	1∶10 1∶5 1∶1 6∶1 8∶1 15∶1 20∶1	82.2％ 80.5％ 78.9％ 79.8％ 80.4％ 74.3％ 67.9％				56.4％ 57.8％ 54.5％ 58.7％ 52.5％ 47.5％ 52.1％

Annotate: the content of flavones ingredient is 90% in the Radix Puerariae extract.

Table 2: prescription research conclusion

Formula number	Prescription is formed and ratio	The screening and assessment index
				Radix Puerariae extract: ozagrel	Platelet suppression ratio (%)	Thrombosis suppression ratio (%)
	1 2 3 4 5 6 7	2∶1 4∶1 8∶1 10∶1 15∶1 50∶1 80∶1	73.2％ 71.5％ 69.9％ 64.8％ 58.4％ 53.3％ 45.9％				46.4％ 42.8％ 35.5％ 40.4％ 34.5％ 32.5％ 28.1％

Annotate: the content of flavones ingredient is 60% in the Radix Puerariae extract.

Table 3: prescription research conclusion

Formula number	Prescription is formed and ratio	The screening and assessment index
				Radix Puerariae extract: ozagrel	Platelet suppression ratio (%)	Thrombosis suppression ratio (%)
	1 2 3 4 5 6 7	4∶1 8∶1 20∶1 80∶1 200∶1 400∶1 600∶1	52.1％ 45.4％ 40.2％ 38.4％ 34.3％ 30.7％ 25.4％				28.4％ 29.9％ 24.9％ 29.2％ 23.5％ 19.2％ 17.3％

Annotate: the content of flavones ingredient is 30% in the Radix Puerariae extract.

Table 4: prescription research conclusion

Formula number	Prescription is formed and ratio	The screening and assessment index
				Radix Puerariae extract: ozagrel	Platelet suppression ratio (%)	Thrombosis suppression ratio (%)
	1 2 3 4 5 6 7	8∶1 15∶1 50∶1 200∶1 500∶1 800∶1 1000∶1	46.2％ 38.2％ 29.7％ 25.1％ 15.2％ 18.6％ 8.7％				31.5％ 20.9％ 15.2％ 19.3％ 10.2％ 11.3％ 7.2％

Annotate: the content of flavones ingredient is 5% in the Radix Puerariae extract.

From above-mentioned prescription screening result as can be seen, the Radix Puerariae extract of different purity and ozagrel compatibility all can produce certain curative effect, but through system thinking, determine with flavones ingredient content be 90% Radix Puerariae extract with ozagrel with 8: 1 ratio compatibility pharmacological action by force and consumption is lower, preparations shaping and having good stability, can reach the effect of efficacy enhancing and toxicity reducing.

(2) Radix Puerariae extract: affirmation and the side's of tearing open research conclusion of ozagrel=8: 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 coronary heart disease, angina pectoris, cerebral thrombosiss the obvious synergistic effect is arranged also; simultaneously; can obviously increase blood flow, reduction Ischemic Heart load, the antagonism myocardial oxygen consumption of arteria coronaria, thus the better protection ischemic myocardium.

The prescription research conclusion

Pilot project	Prescription of the present invention	The Radix Puerariae extract group	The ozagrel group
				Myocardial infarction model test rat ICA injection thrombus local cerebral ischemia model test is improved blood stasis model rat blood rheology test platelet aggregation-against and is tested anti-mouse tail thrombotest rabbit fibrin solubility test due to the dog CAL method	Effect is remarkable, effect reinforced effects remarkable result is remarkable, the effect reinforced effects is remarkable, the effect reinforced effects is remarkable, the effect reinforced effects is obvious, and effect strengthens	The general effect of the general successful successful of the general effect of effect effect is general	The general successful successful of the general successful effect of effect effect is general

Concrete embodiment

Embodiment 1: the preparation Radix Puerariae extract: get 10 parts of Radix Puerariaes (part is: kilogram or gram)

The Radix Puerariae coarse powder adds 70% alcohol reflux 3 times, and each 1.5 hours, leave standstill, sucking filtration, merging filtrate, ethanol liquid decompression recycling ethanol is concentrated into 1: 2, adds hydrochloric acid, adjust pH 1-2 acid solution; By the resin column of macroporous resin is housed, water is cooked cleanout fluid, is that eluent carries out eluting with 50% ethanol of pH value 1-2, TCL check and inspection eluent; Add NaOH liquid adjust pH to 5-6, concentrate, it is even to add kieselguhr, drying, porphyrize powder; Put in the apparatus,Soxhlet's and extract 8h, get acetic acid ethyl fluid with the ethyl acetate continuous backflow; Add 2% active carbon backflow 30min, decolorization filtering, filtrate concentrating promptly gets Radix Puerariae extract.

Embodiment 2: the preparation Radix Puerariae extract: 1000 parts of Radix Puerariaes (kilogram or gram)

The material coarse powder of getting it filled places the reflux, extract, device, is solvent thermal backflow 30min with 80% ethanol, and extracting solution is ultrasonic extraction 30min in ultrasonic cleaner, filters and discards filtering residue, and concentrated filtrate gets Radix Puerariae extract.

Embodiment 3: the preparation Radix Puerariae extract: 3000 parts of Radix Puerariaes (kilogram or gram)

Get Radix Puerariae, add 10 times of water gagings and soak 30min, decoct 25min, centrifugal filtration adds 6 times of amounts of water in the medicinal residues, decoct 2 times, decoct 30min at every turn, filter merging filtrate, n-butyl alcohol with 3 times of amount extracting solution divides 3 extractions, merges butanol extraction liquid, and the pressure reducing and steaming n-butyl alcohol promptly gets Radix Puerariae extract.

Embodiment 4: the preparation Radix Puerariae extract: 5000 parts of Radix Puerariaes (kilogram or gram)

Radix Puerariae cold water soak 12h adds 8 times of water gagings and decocts, and decocting liquid is concentrated into 1: 1, adds the Ca (OH) of 1 times of amount of crude drug while hot ₂Emulsion filters to get filtrate and precipitates, and precipitation is suspended in 70% ethanol, adds concentrated sulphuric acid and transfers pH4, and decalcification filters to get filtrate and precipitates, and precipitation is with 80% alcohol reflux of 10 times of amounts 2 hours, filtration; Merge above filtrate, add ammonia and transfer pH about 7, leave standstill, filter, filtrate decompression concentrates, and concentrated solution adds 95% ethanol, leaves standstill, and filters, and reclaims ethanol, Radix Puerariae extract.

Embodiment 5: the preparation Radix Puerariae extract: 100 parts of Radix Puerariaes (kilogram or gram)

Radix Puerariae is measured 70% alcohol heat reflux with 10 times, and extracting solution was evaporated to 1: 7, reclaims ethanol, returns the neutral lead acetate of half amount of crude drug, stir, leave standstill, filter, filtrate adds 3/10 Lead monosubacetate of crude drug amount, stir, leave standstill, filter, precipitation is suspended in 70% ethanol, 9/2.5 the sodium sulfate that adds the crude drug amount stirs, and leaves standstill deleading, precipitation adds 70% alcohol heat reflux 2h, filters, and merges above filtrate, concentrating under reduced pressure, drying promptly gets Radix Puerariae extract.

Embodiment 6: the preparation Radix Puerariae extract: 10000 parts of Radix Puerariaes (kilogram or gram)

Get Radix Puerariae crude drug in whole powder, adopt 3 leachings of saturated limewater (8,6,6 times), lixiviating solution is transferred pH 5, adds ethanol and makes and contain the alcohol amount and reach 65%, leaves standstill, and spends the night, filter, filtrate concentrate Radix Puerariae extract.

Embodiment 7: 10 parts of Radix Puerariaes, 50 parts of ozagrels (part is: kilogram or gram)

Get the Radix Puerariae coarse powder, add 70% alcohol reflux 3 times, each 1.5 hours, leave standstill, sucking filtration, merging filtrate, ethanol liquid decompression recycling ethanol is concentrated into 1: 2, adds hydrochloric acid, adjust pH 1-2 acid solution; By the resin column of macroporous resin is housed, water is cooked cleanout fluid, is that eluent carries out eluting with 50% ethanol of pH value 1-2, TCL check and inspection eluent; Add NaOH liquid adjust pH to 5-6, concentrate, it is even to add kieselguhr, drying, porphyrize powder; Put in the apparatus,Soxhlet's and extract 8h, get acetic acid ethyl fluid with the ethyl acetate continuous backflow; Add 2% active carbon backflow 30min, decolorization filtering, filtrate is concentrated into a little, leaves standstill, and separates out crystallization, adds a small amount of water for injection and makes it dissolving, and medicinal liquid is standby; Get ozagrel, add the injection blunge make it the dissolving, with above-mentioned medicinal liquid mixing, add 0.5% active carbon and boil 15min, filter, filtrate adds injection and is diluted with water to full dose, adjust pH to 5.2～5.8 are divided to install to ampoule bottle, seal sterilization and promptly get injection with small volume or concentrated solution for injection.The content of ozagrel is 107.1% of labelled amount.

Embodiment 8: 500 parts of ozagrels of Radix Puerariae: 20 parts (part is: kilogram or gram)

Radix Puerariae is measured 70% alcohol heat reflux with 10 times, and extracting solution was evaporated to 1: 7, reclaims ethanol, the neutral lead acetate that adds half amount of crude drug stirs, and leaves standstill, filter, filtrate adds 3/10 Lead monosubacetate of crude drug amount, stirs, and leaves standstill, filter, precipitation is suspended in 70% ethanol, and 9/25 the sodium sulfate that adds the crude drug amount stirs, and leaves standstill, deleading, precipitation adds 70% alcohol heat reflux 2h, filters, and merges above filtrate, concentrating under reduced pressure, drying adds the injection water, adds an amount of Macrogol 4000 and an amount of mannitol, stirring makes it to dissolve fully, standby: as to get ozagrel, join in an amount of water for injection, make it dissolving, add standby medicinal liquid mix homogeneously, regulate pH value 5.2～5.8, stir and make it dissolving, add an amount of Macrogol 4000 and an amount of mannitol, stirring makes it to dissolve fully, add 0.2% active carbon according to mass volume ratio, behind the static absorption of the room temperature 20min, filter carbon removal, benefit adds to the full amount of water for injection, regulate pH to 5.2～5.8, fine straining, intermediate sampling, to be detected qualified after, quantitatively be sub-packed in the 10ml 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.

Embodiment 9: 1000 parts of ozagrels of Radix Puerariae: 30 parts (part is: kilogram or gram)

Radix Puerariae is measured 70% alcohol heat reflux with 10 times, and extracting solution was evaporated to 1: 7, reclaims ethanol, the neutral lead acetate that adds half amount of crude drug stirs, and leaves standstill, filter, 3/10 the Lead monosubacetate that filtrate adds the crude drug amount stirs, leave standstill, filter, precipitation is suspended in 70% ethanol, 9/2.5 the sodium sulfate that adds the crude drug amount stirs, and leaves standstill deleading, precipitation adds 70% alcohol heat reflux 2h, filters, and merges above filtrate, concentrating under reduced pressure, drying adds the injection water, stirring at room makes it dissolving, adds an amount of sodium citrate and minor amounts of propylene glycol again, stirs evenly, make it into settled solution, get 200ml water for injection again and put in the liquid dispenser, add ozagrel, stir to clarify, under stirring this solution is joined in the above-mentioned Radix Puerariae extract solution, measure pH value, tartaric acid with 1% or the sodium hydroxide solution of 0.1mol/L are regulated PH to 5.2～5.8, filter, ultrafiltration, add in an amount of process glucose solution that boils, be diluted to full dose with water for injection, embedding, sterilization promptly gets glucose injection.

Embodiment 10: 10000 parts of ozagrels of Radix Puerariae: 10 parts (part is: kilogram or gram)

Radix Puerariae cold water soak 12h adds 8 times of water gagings and decocts, and decocting liquid is concentrated into 1: 1, adds the Ca (OH) of 1 times of amount of crude drug while hot ₂Emulsion filters to get filtrate and precipitates, and precipitation is suspended in 70% ethanol, adds concentrated sulphuric acid and transfers pH about 4, and decalcification filters to get filtrate and precipitates, and precipitation is with 80% alcohol reflux of 10 times of amounts 2 hours, filtration; Merge above filtrate, add ammonia and transfer pH about 7, leave standstill, filter, filtrate decompression concentrates, and concentrated solution 95% ethyl alcohol recrystallization filters, and reclaims ethanol, adds water for injection, adds polysorbate 40 again and stirs and make it to dissolve, and is standby; Get ozagrel, add an amount of water for injection stirring and make it dissolving, above-mentioned two parts of solution and mannitol are mixed, add 0.3% active carbon, heated and boiled keeps little and boiled 15 minutes, fine straining, cooling, coarse filtration, fine straining, add in an amount of process sodium chloride solution that boils, be diluted to full dose with water for injection, embedding, sterilization promptly gets sodium chloride injection.

Embodiment 11: Radix Puerariae extract: 1000 parts, and ozagrel: 28 parts (part is: kilogram or gram)

Get the stirring of Radix Puerariae extract adding water for injection and make it dissolving, standby; Get ozagrel, join in an amount of water for injection, stirring makes it dissolving, adds standby medicinal liquid mix homogeneously, regulates pH value 5.2～5.8, stirring makes it dissolving, add an amount of Macrogol 4000 and an amount of mannitol, stirring makes it to dissolve fully, adds 0.2% active carbon according to mass volume ratio, behind the static absorption of the room temperature 20min, filter carbon removal, benefit adds to the full amount of water for injection, and regulates pH to 5.2～5.8, fine straining, intermediate sampling, to be detected qualified after, quantitatively be sub-packed in the 10ml 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 flavones ingredient be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 53%.

Embodiment 12: Radix Puerariae extract: 50 parts of ozagrels: 2 parts (part is: kilogram or gram)

Getting 500ml water for injection puts in the liquid dispenser, add Radix Puerariae extract, stirring at room makes it dissolving, add an amount of sodium citrate and minor amounts of propylene glycol again, stir evenly, make it into settled solution, getting 200ml water for injection again puts in the liquid dispenser, add ozagrel, stir to clarify, under stirring this solution is joined in the above-mentioned Radix Puerariae extract solution, measure pH value, tartaric acid with 1% or the sodium hydroxide solution of 0.1mol/L are regulated PH to 5.2～5.8, filter, ultrafiltration adds an amount of through in the glucose solution that boils, be diluted to full dose with water for injection, embedding, sterilization promptly gets glucose injection.The content of flavones ingredient be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 89%.

Embodiment 13: Radix Puerariae extract: 1000 parts of ozagrels: 20 parts (part is: kilogram or gram)

Get Radix Puerariae extract, add water for injection, add the Polysorbate stirring again and make it dissolving, standby; Other gets ozagrel, adds an amount of water for injection stirring and makes it dissolving, and above-mentioned two parts of solution and mannitol are mixed, add 0.3% active carbon, heated and boiled keeps little and boiled 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.The component content sum that derives from the Radix Puerariae medical material that all can be surveyed be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 22%.

Embodiment 14: Radix Puerariae extract: 10 parts of ozagrels: 1 part (part is: kilogram or gram)

Get Radix Puerariae extract, add the injection water and make it dissolving, medicinal liquid is standby; Get ozagrel, add the injection water, stir and make it dissolving, with above-mentioned medicinal liquid mixing, add 0.5% active carbon and boil 15min, filter, filtrate adds injection and is diluted with water to full dose, and adjust pH to 5.2～5.8 are divided to install to ampoule bottle, seal sterilization and promptly get injection with small volume.The component content sum that derives from the Radix Puerariae medical material that all can be surveyed be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 91%, ozagrel content should be 101.3% of preparation labelled amount.

Embodiment 15: 100 parts of Radix Puerariaes, 15 parts of ozagrels (part is: kilogram or gram)

Radix Puerariae is measured 70% alcohol heat reflux with 10 times, and extracting solution was evaporated to 1: 7, reclaims ethanol, adds the neutral lead acetate of half amount of crude drug, stir, leave standstill, filter, filtrate adds 3/10 Lead monosubacetate of crude drug amount, stir, leave standstill, filter, precipitation is suspended in 70% ethanol, 9/25 the sodium sulfate that adds the crude drug amount stirs, and leaves standstill deleading, precipitation adds 70% alcohol heat reflux 2h, filters, and merges above filtrate, concentrating under reduced pressure, drying, pulverize, add ozagrel, mixing, add polyethylene glycol 6000, mix homogeneously, heating and melting, stir, be transferred to the drop pill machine, drip system, collect drop pill, remove the liquid paraffin on surface, promptly get drop pill.

Embodiment 16: 100 parts of Radix Puerariae extracts, 10 parts of ozagrels (part is: kilogram or gram)

The prescription of gelatin solution is a gelatin: glycerol: water=5: 1: 6, and get gelatin and add 4 parts of water and make its abundant swelling, other gets glycerol and remains 2 parts of water and puts and be heated to 70～80 ℃ in the evaporating dish, mix homogeneously adds expansible gelatin and stirs fusion, be made into the suitable gelatin solution of viscosity, be incubated 1～2 hour, leave standstill, make the foam come-up, scrape off the foam of come-up, filter with clean calico,, be incubated standby except that behind the bubble; Get Radix Puerariae extract, ozagrel facing-up method mix homogeneously, press medication amount: substrate amount=1: 1.2 adding hydrogenated vegetable oil, mixing; Get gelatin solution and put in the drop pill machine storage tank, 60 ℃ of insulations are put into liquor tank with above-mentioned medicinal liquid in addition; Regulate water dropper temperature and the rubber weight and the thickness uniformity, splash in the coolant fluid paraffin body, the earlier even stall with goods spread out on the ground for sale of the soft gelatin capsule that oozes is on gauze, at the blowing of low temperature below 10 ℃ 5h, wipe again and show liquid paraffin, blow more than 20 hours at low temperature below 10 ℃ then and take out, behind the oil reservoir of petroleum ether flush away surface, drying up cleaning mixture, about 50 ℃ dry 24 hours then, take out exsiccant soft gelatin capsule, quality inspection, packing promptly gets soft capsule.

Embodiment 17: 10 parts of Radix Puerariae extracts, 5 parts of ozagrels (part is: kilogram or gram)

Get Radix Puerariae extract, ozagrel mix homogeneously, it is an amount of to add starch slurry, and the system soft material is crossed sieve series granule on the 14th, and oven dry after 16 mesh sieve granulate, adds 1% Pulvis Talci, 8% dried starch is mixed thoroughly, and compacting promptly gets oral cavity disintegration tablet in flakes.

Embodiment 18: 10000 parts of Radix Puerariaes, 50 parts of ozagrels (part is: kilogram or gram)

The material coarse powder of getting it filled is wrapped with filter paper, places hot diafiltration reflux, extract, device, with 80% ethanol is solvent thermal backflow 30min, and extracting solution is ultrasonic extraction 30min in ultrasonic cleaner, filters to discard filtering residue, concentrated filtrate gets Radix Puerariae extract,, with the ozagrel mixing, adding starch is an amount of, oven dry, granulate, compacting promptly gets tablet in flakes.

Embodiment 19: 500 parts of Radix Puerariae extracts, 25 parts of ozagrels (part is: kilogram or gram)

Get Radix Puerariae extract, add ozagrel, mixing is pulverized, and adds right amount of auxiliary materials,, to mix, drying is granulated, and granulate incapsulates, and promptly gets capsule.

Embodiment 20: 100 parts of Radix Puerariae extracts, 35 parts of ozagrels (part is: kilogram or gram)

Get Radix Puerariae extract, the ozagrel mix homogeneously adds 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.In the preparation content of flavones ingredient be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 3%.

Embodiment 21: 10 parts of Radix Puerariaes, 20 parts of ozagrels (part is: kilogram or gram)

Get Radix Puerariae crude drug in whole powder, adopt saturated limewater (8,6,6 times) 3 leachings, lixiviating solution is transferred pH5, adds ethanol and makes and contain the alcohol amount and reach 65%, leave standstill, spend the night, filter, filtrate concentrate Radix Puerariae extract,, add ozagrel, mixing, drying adds hydroxypropyl cellulose, steviosin is an amount of, tabletting promptly gets buccal tablet.

Embodiment 22: 300 parts of Radix Puerariae extracts, 18 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 Radix Puerariae extract and ozagrel 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 23: 120 parts of Radix Puerariaes, 20 parts of ozagrels (part is: kilogram or gram)

The material coarse powder of getting it filled is wrapped with filter paper, places hot diafiltration reflux, extract, device, with 80% ethanol is solvent thermal backflow 30min, and extracting solution is ultrasonic extraction 30min in ultrasonic cleaner, filters to discard filtering residue, the concentrated filtrate drying, pulverize, with soluble starch, spray drying, add ozagrel, mixing, granulate, sieve, promptly get granule.

Claims (11)

1, a kind of compound preparation 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 Radix Puerariaes and ozagrel through extracting refining forming; Or the Radix Puerariae extract and the corresponding weight portion ozagrel that are obtained after extracting by corresponding weight portion medical material are made.

2, according to the compound preparation 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 Radix Puerariaes and ozagrel through extracting refining forming; Or the Radix Puerariae extract and the corresponding weight portion ozagrel that are obtained after extracting by corresponding weight portion medical material are made.

3, according to the compound preparation 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 Radix Puerariaes and ozagrel through extracting refining forming; Or the Radix Puerariae 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: little liquid drugs injection, powder pin or infusion solutions; Oral formulations comprises: all acceptable dosage forms on 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 and other pharmaceutics.

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 content of flavones ingredient be not less than in the preparation deduction adjuvant amount, water quantities and ozagrel amount total solid 1%; The component content sum that derives from the Radix Puerariae 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 Radix Puerariae, add entry or ethanol or limewater extraction, the extracting solution concentrate drying gets the Radix Puerariae 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 Radix Puerariae extract, with Radix Puerariae crude extract or Radix Puerariae 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: Radix Puerariae 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: pharmaceutical composition of the present invention has anticoagulant, anticoagulation, antithrombotic, protection ischemic myocardium, increases coronary blood flow, reduces myocardial oxygen consumption, changes functions such as microcirculation, blood vessel dilating, blood sugar lowering, blood fat reducing, blood pressure lowering.

10, according to the application in preparation treatment coronary heart disease, angina pectoris, arteriosclerosis, 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: its assay is to adopt in high performance liquid chromatography, spectrophotography, TLC scanning method, the titrimetry one or more to record.