CN1915270A - 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 safflower 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, 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, Flos Carthami 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 is through scientific appraisal, adopt the preparation that Flos Carthami or Flos Carthami extract and ozagrel compatibility are made to be needed, reduced the clinical consumption of ozagrel, effectively avoided gastrointestinal reaction due to the ozagrel and anaphylaxis as feel sick, untoward reaction such as vomiting, measles, erythra; Brought into play the rapid-action advantage of Western medicine simultaneously, the onset of having avoided Flos Carthami single preparation to be occurred is slower, the drawback that can not finely play a role in urgency, serious symptom treatment.The pharmacological effect result shows that the two share, and has obvious synergism at aspects such as treating cardiovascular and cerebrovascular disease such as thrombosis cerebrovascular, coronary heart disease, vasculitis, and is evident in efficacy; Another object of the present invention is the formulation method 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 1～30 part of 10～10000 parts on Flos Carthami and ozagrel through extracting refining forming; Or the Flos Carthami 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 5～30 parts of 10～5000 parts on Flos Carthami and ozagrels through extracting refining forming; Or the Flos Carthami 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 10～30 parts of 100～3000 parts on Flos Carthami and ozagrels through extracting refining forming; Or the Flos Carthami 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 acceptable dosage form on the pharmaceuticss such as injection and oral formulations.Injection comprises: 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, buccal 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.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 accounts in injection or the oral formulations and always to be not less than 5% with the scale of construction after deduction ozagrel and adjuvant amount and the water quantities in the preparation; The component content sum that derives from flos carthami 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 labelled amount in the preparation.

The preparation of drug combination method of described treatment cardiovascular and cerebrovascular disease is: get Flos Carthami, add entry or ethanol extraction, the extracting solution concentrate drying gets the Flos Carthami crude extract, one or more that also can further adopt precipitate with ethanol, organic solvent extractionprocess, column chromatography unite use carry out suitably refining, get the Flos Carthami extract, with Flos Carthami crude extract or Flos Carthami extract and ozagrel mixing, add different adjuvants and be prepared into the preparation that needs with conventional method.

Flos Carthami 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 antiplatelet aggregation, blood vessel dilating, and coronary blood flow increasing, reduction myocardial excitability and conductivity resist myocardial ischemia functions such as microcirculation improvement; Be used for the treatment of the dyskinesia that cardiovascular and cerebrovascular diseases such as thrombosis cerebral infarction, coronary heart disease, angina pectoris, vasculitis and cerebral infarction are followed.

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.

Compared with prior art, the independent preparation of existing at present clinically Flos Carthami or Flos Carthami extract and ozagrel, simple combination, though can obtain potentiation, its preparation stability and safety can't guarantee.The applicant is combined into novel formulation with Flos Carthami extract and ozagrel and develops research, by compatibility bring into play both in thrombosis cerebrovascular, coronary heart disease, angina pectoris, vasculitis, improve the cooperative compensating effect of the dyskinesia that cerebral infarction follows etc., be that the treatment of cardiovascular and cerebrovascular disease increases a new medication and selects.Simultaneously, can system further investigate Flos Carthami or the safety of Flos Carthami 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 (Flos Carthami extract: ozagrel) carried out the prescription screening test of system, found that with Flos Carthami extract (Flos Carthami total flavone content is 90%): the prescription pharmacological action of ozagrel=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 thrombosis obvious synergistic effect is being arranged also; can obviously increase simultaneously the increase of blood flow coronarius, antagonism myocardial oxygen consumption, thus the better protection ischemic myocardium.

Pharmaceutical preparation of the present invention, with respect to the independent preparation of Flos Carthami, ozagrel better efficacy not only, and use and carry all easily, the preparation method of multiple different oral formulations is provided, be suitable for different crowd and use, 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 Flos Carthami extract and the ozagrel of different content carried out system in varing proportions, found that with Flos Carthami total flavone content be 90% Flos Carthami extract and the pharmacological action of ozagrel=6: 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 Flos Carthami 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％ 81.6％ 80.1％ 82.1％ 82.2％ 83.4％ 73.8％	59.3％ 52.4％ 55.8％ 57.4％ 56.5％ 50.9％ 46.2％

Annotate: the content of Flos Carthami total flavone is 90% in the Flos Carthami extract.

Table 2: prescription research conclusion

Formula number	Prescription is formed and the ratio Flos Carthami 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			71.6％ 63.1％ 59.1％ 60.3％ 53.8％ 54.2％ 47.7％	62.4％ 55.8％ 55.4％ 40.5％ 38.2％ 36.9％ 30.2％

Annotate: the content of Flos Carthami total flavone is 60% in the Flos Carthami extract.

Table 3: prescription research conclusion

Formula number	Prescription is formed and the ratio Flos Carthami 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			63.1％ 60.1％ 56.3％ 52.8％ 49.4％ 40.3％ 32.7％	47.5％ 50.1％ 40.7％ 36.1％ 25.2％ 23.5％ 16.2％

Annotate: the content of Flos Carthami total flavone is 30% in the Flos Carthami extract.

Table 4: prescription research conclusion

Formula number	Prescription is formed and the ratio Flos Carthami extract: ozagrel	The screening and assessment index
				Platelet suppression ratio (%)	Thrombosis suppression ratio (%)
		1 2 3 4 5 6 7	2∶1 4∶1 6∶1 15∶1 50∶1 100∶1 150∶1			53.1％ 48.4％ 41.2％ 37.7％ 30.3％ 22.7％ 15.7％	35.4％ 31.9％ 27.6％ 23.2％ 23.1％ 16.2％ 8.2％

Annotate: the content of Flos Carthami total flavone is 5% in the Flos Carthami extract.

From above-mentioned prescription screening result as can be seen, the Flos Carthami extract of different purity and ozagrel compatibility all can produce certain curative effect, but through system thinking, determine with Flos Carthami total flavone content be 90% Flos Carthami extract with ozagrel with 6: 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) Flos Carthami extract: affirmation and the side's of tearing open research conclusion of ozagrel=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 blood flow of arteria coronaria, the increase of 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 Flos Carthami extract group	The ozagrel group
				Myocardial infarction model test improves blood stasis model rat blood rheology test platelet aggregation-against and tests anti-mouse tail thrombotest test rat ICA injection promoting blood circulation and removing blood stasis thrombus local cerebral ischemia model 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, and effect reinforced effects remarkable result is remarkable	The general successful effect of successful successful successful effect is general	The general successful successful of effect successful successful successful

Concrete embodiment

Embodiment 1: the preparation Flos Carthami extract: get 10 parts on Flos Carthami (part is: kilogram or gram)

Get Flos Carthami, be ground into coarse powder, add 70 ℃ of warm macerating of 8 times of volume water and extract 2 times, each 1 hour, merge extractive liquid, filters, and filtrate is crossed D-101 type macroporous adsorbent resin, with 4 times of resinite hydrops and 2 times of resin volume 5% alcohol flushing impurity, use 40% alcohol desorption of 3 times of resin volumes then, collect stripping liquid, measuring relative density during decompression recycling ethanol to 60 ℃ is 1.05～1.15, get thick paste, concentrate drying promptly gets Flos Carthami extract.

Embodiment 2: the preparation Flos Carthami extract: 5000 parts on Flos Carthami (part is: kilogram or gram)

Get Flos Carthami, add the water of 10 times of medical material amounts, extract each 0.5h 3 times in 80 ℃, merge extractive liquid, filters, and saffron aqueous solution separates with the macroporous adsorbent resin eluting, collect eluent and be fluid extract, under constantly stirring, add 8 times of amounts of fluid extract volume of ethanol in 60 ℃ of concentrating under reduced pressure, fully mix and stir, leave standstill cold preservation then, to be crystallized separating out, filter, precipitation is with behind the water dissolution, with ethanol repurity once, precipitation is dry, pulverizes, and promptly gets Flos Carthami extract.

Embodiment 3: the preparation Flos Carthami extract: 3000 parts on Flos Carthami (part is: kilogram or gram)

Get Flos Carthami, be ground into coarse powder, decoct with water three times, first and second time 1 hour, 40 minutes for the third time, collecting decoction filters, and filtrate is concentrated into thick paste, adds ethanol and makes and contain the alcohol amount and reach 70%, cold preservation, standing over night filters filtrate recycling ethanol, the simmer down to thick paste adds ethanol and makes and contain alcohol amount and reach 80%, cold preservation, standing over night, filter, filtrate recycling ethanol also is concentrated into thick paste, aqueous precipitation again, cold preservation, left standstill 16～24 hours, and filtered, filtrate concentrates, and promptly gets Flos Carthami extract.

Embodiment 4: the preparation Flos Carthami extract: 100 parts on Flos Carthami (part is: kilogram or gram)

Get Flos Carthami, be ground into coarse powder, add 80 ℃ of warm macerating of 10 times of volume water and extract each 1 hour 3 times, merge extractive liquid,, filter, filtrate is crossed D-101 type macroporous adsorbent resin, with 5 times of resinite hydrops and 3 times of resin volume 5% alcohol flushing impurity, use 30% alcohol desorption of 4 times of resin volumes then, collect stripping liquid, measuring relative density during decompression recycling ethanol to 60 ℃ is 1.05～1.15, promptly gets Flos Carthami extract.

Embodiment 5: the preparation Flos Carthami extract: 10000 parts on Flos Carthami (part is: kilogram or gram)

Get Flos Carthami, be ground into coarse powder, add and get Flos Carthami, the water that adds 10 times of medical material amounts extracts each 0.5h 3 times in 80 ℃, merge extractive liquid, filters silica gel column chromatography on the saffron aqueous solution, silica gel is with chloroform wet method dress post, and sample on suitable quantity of water extract and the silica gel mixing dry method is an eluent system with chloroform, ethanol, water, carry out gradient elution, collect eluent, reclaim solvent, concentrate drying promptly gets Flos Carthami extract.

Embodiment 6: 5000 parts of ozagrels of Flos Carthami: 20 parts (part is: kilogram or gram)

Get Flos Carthami, add the water of 10 times of medical material amounts, extract 3 times in 80 ℃, each 0.5h, merge extractive liquid, filters, saffron aqueous solution separates with the macroporous adsorbent resin eluting, collects eluent and is fluid extract in 60 ℃ of concentrating under reduced pressure, under constantly stirring, add 8 times of amounts of fluid extract volume of ethanol, fully mix and stir, leave standstill cold preservation then, to be crystallized separating out, filter, precipitation is with behind the water dissolution, with ethyl alcohol recrystallization once.The precipitation drying, pulverizing gets Flos Carthami extract, adds the dissolving of injection water, adds 8.0 stirrings of 5% sodium hydroxide solution adjusting pH value and makes dissolving, and is standby; Get ozagrel, add the water for injection dissolving, it is standby to stir; With above-mentioned two parts of solution mix homogeneously, regulating pH value is 7.0～7.8, filters, and embedding is in ampoule, and 100 ℃ of flowing steam sterilization 45min promptly get hydro-acupuncture preparation.

Embodiment 7: 60 parts of ozagrels of Flos Carthami: 1 part (part is: kilogram or gram)

Get Flos Carthami, be ground into coarse powder, add 80 ℃ of warm macerating of 10 times of volume water and extract 3 times, each 1 hour, merge extractive liquid, filtered, filtrate is crossed D-101 type macroporous adsorbent resin, with 5 times of resinite hydrops and 3 times of resin volume 5% alcohol flushing impurity, use 30% alcohol desorption of 4 times of resin volumes then, collect stripping liquid, measuring relative density during decompression recycling ethanol to 60 ℃ is 1.05～1.15, add an amount of water for injection, add 5% sodium hydroxide solution and regulate pH value, as standby medicinal liquid; With ozagrel, mannitol and above-mentioned medicinal liquid mixing, add water for injection, with the pH value of 1% hydrochloric acid solution regulator solution, add 0.3% active carbon, heated and boiled keeps little and boiled 15 minutes, and cooling is filtered, filtrate adds to the full amount of water for injection, packing, pre-freeze temperature-45 ℃, pre-freeze time 10h; The beginning evacuation, and be warming up to-40 ℃, keep 8h; Be warming up to-35 ℃ again, keep 8h; Be warming up to-25 ℃, keep 8h; Be warming up to-15 ℃, keep 5h; Be warming up to 0 ℃, keep 5h; Be warming up to 10 ℃, keep 2h; Be warming up to 20 ℃, keep 2h; Be warming up to 30 ℃, keep 2h, promptly get freeze-dried powder injection.

Embodiment 8: Flos Carthami: 100 parts of ozagrels: 26 parts (part is: kilogram or gram)

Get Flos Carthami, add the water of 10 times of medical material amounts, extract 3 times in 80 ℃, each 0.5h, merge extractive liquid, filters, and saffron aqueous solution separates with the macroporous adsorbent resin eluting, collect eluent and be fluid extract in 60 ℃ of concentrating under reduced pressure, under constantly stirring, add 8 times of amounts of fluid extract volume of ethanol, fully mix and stir, leave standstill cold preservation then, to be crystallized separating out filters, and precipitation is with behind the water dissolution, with ethanol repurity once, precipitation is dry, pulverizes, and adds water for injection, add 20% sodium hydroxide solution again and make dissolving, it is standby to stir; Other gets ozagrel, adds the water for injection dissolving, and it is standby to stir; Above-mentioned two parts of solution are mixed and the mannitol mix homogeneously, add 0.3% active carbon, heated and boiled keeps little and boiled 15 minutes, cooling, coarse filtration, fine straining add in an amount of process glucose solution that boils, and are diluted to full dose with water for injection, embedding, sterilization promptly gets the glucose infusion liquid agent.

Embodiment 9: Flos Carthami: 10000 parts of ozagrels: 30 parts (part is: kilogram or gram)

Get Flos Carthami, be ground into coarse powder, add 80 ℃ of warm macerating of 10 times of volume water and extract 3 times, each 1 hour, merge extractive liquid, filters, and filtrate is crossed D-101 type macroporous adsorbent resin, with 5 times of resinite hydrops and 3 times of resin volume 5% alcohol flushing impurity, use 30% alcohol desorption of 4 times of resin volumes then, collect stripping liquid, measuring relative density during decompression recycling ethanol to 60 ℃ is 1.05～1.15, add an amount of water for injection, transfer pH value to exist with 0.5% sodium hydroxide; Other gets ozagrel, adds the water for injection dissolving, and is standby; With above-mentioned two parts of solution and mannitol mix homogeneously, add 0.3% active carbon again, 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 10: Flos Carthami extract: 100 parts of ozagrels: 15 parts (part is: kilogram or gram)

Get Flos Carthami extract, add the dissolving of injection water, add 8.0 stirrings of 5% sodium hydroxide solution adjusting pH value and make dissolving, standby; Get ozagrel, add the water for injection dissolving, it is standby to stir; With above-mentioned two parts of solution mix homogeneously, regulating pH value is 7.0～7.8, filters, and embedding is in ampoule, and 100 ℃ of flowing steam sterilization 45min promptly get hydro-acupuncture preparation.The content that records Flos Carthami total flavone in the said preparation with spectrophotography is 19%.The component content sum that derives from flos carthami that all can be surveyed in the preparation be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 21%.

Embodiment 11: Flos Carthami extract: 30 parts of ozagrels: 5 parts (part is: kilogram or gram)

Get Flos Carthami extract, add water for injection, add 20% sodium hydroxide solution again and make dissolving, it is standby to stir; Other gets ozagrel, adds the water for injection dissolving, and it is standby to stir; Above-mentioned two parts of solution are mixed and the mannitol mix homogeneously, add 0.3% active carbon, heated and boiled keeps little and boiled 15 minutes, cooling, coarse filtration, fine straining add in an amount of process glucose solution that boils, and are diluted to full dose with water for injection, embedding, sterilization promptly gets the glucose infusion liquid agent.The content that records Flos Carthami total flavone in the said preparation with spectrophotography is 84%.

Embodiment 12: Flos Carthami extract: 60 parts of ozagrels: 10 parts (part is: kilogram or gram)

Get Flos Carthami extract, add an amount of water for injection, add 5% sodium hydroxide solution and regulate pH value, as standby medicinal liquid; With ozagrel, mannitol and above-mentioned medicinal liquid mixing, add water for injection, with the pH value of 1% hydrochloric acid solution regulator solution, add 0.3% active carbon, heated and boiled keeps little and boiled 15 minutes, and cooling is filtered, filtrate adds to the full amount of water for injection, packing, pre-freeze temperature-45 ℃, pre-freeze time 10h; The beginning evacuation, and be warming up to-40 ℃, keep 8h; Be warming up to-35 ℃ again, keep 8h; Be warming up to-25 ℃, keep 8h; Be warming up to-15 ℃, keep 5h; Be warming up to 0 ℃, keep 5h; Be warming up to 10 ℃, keep 2h; Be warming up to 20 ℃, keep 2h; Be warming up to 30 ℃, keep 2h, promptly get freeze-dried powder injection.The content that records Flos Carthami total flavone in the said preparation with spectrophotography is 47%.

Embodiment 13: Flos Carthami extract: 200 parts of ozagrels: 16 parts (part is: kilogram or gram)

Get Flos Carthami extract, add an amount of water for injection, transfer pH value to exist with 0.5% sodium hydroxide; Other gets ozagrel, adds the water for injection dissolving, and is standby; With above-mentioned two parts of solution and mannitol mix homogeneously, add 0.3% active carbon again, 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.The component content sum that derives from flos carthami that all can be surveyed in the preparation be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 93%.

Embodiment 14: 8000 parts of Flos Carthami extracts, 20 parts of ozagrels (part is: kilogram or gram)

Get PEG6000, in oil bath, be heated to 140 ℃, add Flos Carthami extract fine powder, ozagrel, constantly stir and make whole fusions, filtered while hot is transferred to reservoir, airtight and insulation is regulated the dropping liquid quantitative valve at 140 ℃, splashes in the dimethicone about 10 ℃, drip apart from 5cm bore 2.5mm, 70 ℃ of hybrid medicine temperature, liquid coolant height 60cm, with the drop pill drop that is shaped to the greatest extent and wipe liquid Paraffin, drying promptly gets drop pill.The component content sum that derives from flos carthami that all can be surveyed in the preparation be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 22%.

Embodiment 15: 3000 parts on Flos Carthami, 30 parts of ozagrels (part is: kilogram or gram)

Get Flos Carthami, be ground into coarse powder, decoct with water three times, first and second time 1 hour, 40 minutes for the third time, collecting decoction, filter, filtrate is concentrated into thick paste, adds ethanol and makes and contain the alcohol amount and reach 70%, cold preservation, standing over night filters, filtrate recycling ethanol, the simmer down to thick paste adds ethanol and makes and contain alcohol amount and reach 80%, cold preservation, standing over night filters, filtrate recycling ethanol also is concentrated into thick paste, aqueous precipitation again, cold preservation, left standstill 16～24 hours, and filtered, filtrate concentrates, get Flos Carthami extract, with the ozagrel mix homogeneously, press medication amount: substrate amount=1: 1.2 adding PEG400, mixing; Other gets glycerol and water is heated to 70～80 ℃, adds gelatin, stirs and melts, and is incubated 1～3 hour, and evacuation removes bubble simultaneously, filters (holding temperature), treats evenly back blowing of sizing material, incapsulates after the filtration in the sizing material bucket of machine; The debugging pellet press, pelleting, drying adopts the typing drying of rolling to combine with two steps of tray dried, promptly gets soft capsule.

Embodiment 16: 150 parts of Flos Carthami extracts, 25 parts of ozagrels (part is: kilogram or gram)

Get Flos Carthami extract, ozagrel mix homogeneously, add 3% low-substituted hydroxypropyl cellulose and 1% mannitol, mixing, drying is granulated, and compacting promptly gets oral cavity disintegration tablet in flakes.

Embodiment 17: 500 parts on Flos Carthami, 10 parts of ozagrels (part is: kilogram or gram)

Get Flos Carthami, add the water of 10 times of medical material amounts, extract 3 times in 80 ℃, each 0.5h, merge extractive liquid, filters, saffron aqueous solution separates with the macroporous adsorbent resin eluting, collect eluent and be fluid extract, add ozagrel, 0.2% hydroxypropyl cellulose is an amount of, mixing in 60 ℃ of concentrating under reduced pressure, dry, granulate, compacting promptly gets tablet in flakes.

Embodiment 18: 300 parts of Flos Carthami extracts, 30 parts of ozagrels (part is: kilogram or gram)

Get Flos Carthami extract, pulverize, add ozagrel, mixing adds modified starch and 0.3% magnesium stearate, mix, and drying, granulation, granulate incapsulates, and promptly gets capsule.The content that records Flos Carthami total flavone in the said preparation with spectrophotography is 5%.

Embodiment 19: 5000 parts on Flos Carthami, 20 parts of ozagrels (part is: kilogram or gram)

Get Flos Carthami, add the water of 10 times of medical material amounts, extract 3 times in 80 ℃, each 0.5h, merge extractive liquid, filters, saffron aqueous solution separates with the macroporous adsorbent resin eluting, collects eluent and is fluid extract in 60 ℃ of concentrating under reduced pressure, under constantly stirring, add 8 times of amounts of fluid extract volume of ethanol, fully mix and stir, leave standstill cold preservation then, to be crystallized separating out, filter, precipitation is with behind the water dissolution, with ethyl alcohol recrystallization once.Precipitation is dry, pulverize, with the ozagrel mix homogeneously, get polyvinylpolypyrrolidone PVPP2.35g and CMC-Na0.5g mixing, get half and medicated powder mixing, make binding agent with 1.5% K30 anhydrous alcohol solution, system material, granulate, the mixed powder that remains half polyvinylpolypyrrolidone PVPP2.35g and CMC-Na0.5g mixing is added in the particle that makes, and tabletting promptly gets dispersible tablet.

Embodiment 20: 100 parts of Flos Carthami extracts, 18 parts of ozagrels (part is: kilogram or gram)

Get Flos Carthami extract, add ozagrel, add 12% lactose mixing, granulate, drying, granulate, packing promptly get granule.

Embodiment 21: 600 parts of Flos Carthami extracts, 10 parts of ozagrels (part is: kilogram or gram)

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

Embodiment 22: 2000 parts of Flos Carthami extracts, 26 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 Flos Carthami 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.The content of ozagrel is 103.5% of labelled amount in the preparation.

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 1～30 part of 10～10000 parts on Flos Carthami and ozagrel through extracting refining forming; Or the Flos Carthami 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 5～30 parts of 10～5000 parts on Flos Carthami and ozagrels through extracting refining forming; Or the Flos Carthami 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 1-2, it is characterized in that: calculate according to parts by weight, it by 10～30 parts of 100～3000 parts on Flos Carthami and ozagrels through extracting refining forming; Or the Flos Carthami 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 total solid that the content of flavones ingredient accounts in injection or the oral formulations 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 flos carthami 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 labelled amount in the preparation.

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 Flos Carthami, add entry or ethanol extraction, the extracting solution concentrate drying gets the Flos Carthami crude extract, one or more that also can further adopt precipitate with ethanol, organic solvent extractionprocess, column chromatography unite use carry out suitably refining, get the Flos Carthami extract, with Flos Carthami crude extract or Flos Carthami extract and ozagrel mixing, add different adjuvants and 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: Flos Carthami 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, blood vessel dilating, coronary blood flow increasing, reduction myocardial excitability and conductivity, resist myocardial ischemia functions such as microcirculation improvement.

10, according to the application in the dyskinesia medicine that cardiovascular and cerebrovascular disease such as preparation treatment thrombosis cerebral infarction, coronary heart disease, angina pectoris, vasculitis and cerebral infarction are followed 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, TLC scanning method, spectrophotography, the titrimetry one or more to record.