CN1915293A - 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 red sage 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 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, cerebral thrombosis, alzheimer disease etc. have become the No.1 killer of human health, have become human mortality's one of the main reasons in many countries; According to investigations, sickness rate in recent years has and increases trend year by year, 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 medicine mainly concentrates on pure Chinese medicinal preparation and Western medicine two aspects at present, Western medicine is rapid-action, but mostly big Chinese medicine and western medicine coupling of toxic and side effects is the clinician and selects suitable Chinese medicine preparation to cooperate the Western medicine diagnosis and treatment of corresponding function according to the disease situation, and the prescription of Western medicine is fairly simple and side effect is bigger; Though the pure Chinese medicinal preparation toxic and side effects is little, their onset is slow, influences therapeutic effect; So searching better, compatibility is simple, therapeutic effect is desirable, 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 Radix Salviae Miltiorrhizae or Radix Salviae Miltiorrhizae extract and ozagrel compatibility are made to be needed, Radix Salviae Miltiorrhizae has coronary blood flow increasing, reduces myocardial excitability and conductivity, microcirculation improvement, antiplatelet aggregation and thrombosis, effects such as blood viscosity lowering, ozagrel are used for the acute thrombotic cerebral infarction disease of waiting indefinitely; The two share, and has synergism.The present invention is for treatment cardiovascular and cerebrovascular disease such as coronary heart disease, angina pectoris, cerebral thrombosis, apoplexy, the acute thrombotic cerebral infarction curative effect preferably of having waited indefinitely; 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 1～20 part of 10～10000 parts of Radix Salviae Miltiorrhizaes and ozagrel through extracting refining forming; Or the Radix Salviae Miltiorrhizae 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 1～15 part of 100～5000 parts of Radix Salviae Miltiorrhizaes and ozagrel through extracting refining forming; Or the Radix Salviae Miltiorrhizae 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 1～10 part of 100～2000 parts of Radix Salviae Miltiorrhizaes and ozagrel through extracting refining forming; Or the Radix Salviae Miltiorrhizae extract and the corresponding weight portion ozagrel that are obtained after extracting by corresponding weight portion medical material are made.

The described preparation of the pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease 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; 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 content of phenols component 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 red rooted salvia 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 should be 90.0%～110.0% of labelled amount.

The preparation of drug combination method of described treatment cardiovascular and cerebrovascular disease is: get Radix Salviae Miltiorrhizae, add entry or ethanol extraction, the extracting solution concentrate drying gets the Radix Salviae Miltiorrhizae crude extract, one or more that also can further adopt precipitate with ethanol, organic solvent extraction, alkali extraction and acid precipitation, column chromatography carry out suitably refining, get the Radix Salviae Miltiorrhizae extract, with Radix Salviae Miltiorrhizae crude extract or Radix Salviae Miltiorrhizae extract and ozagrel mixing, be prepared into the preparation that needs with diverse ways.

Radix Salviae Miltiorrhizae 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, antithrombotic, blood vessel dilating, reduction myocardial oxygen consumption, microcirculation improvement, increases the functions such as blood supply of ischemic region; Be used for the treatment of the dyskinesia that cardiovascular and cerebrovascular diseases such as coronary heart disease, angina pectoris, acute thrombotic cerebral infarction, apoplexy and cerebral infarction are followed.

Assay is to adopt in high performance liquid chromatography, spectrophotography, thin layer chromatography scanning, 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, Radix Salviae Miltiorrhizae or Radix Salviae Miltiorrhizae 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.Arbitrarily with both combinations, though can obtain potentiation, its preparation stability and peace safety can't guarantee clinically.The applicant plans Radix Salviae Miltiorrhizae extract and ozagrel and is combined into novel formulation and develops research, brings into play both cooperative compensating effects in angina pectoris, cerebral thrombosis, apoplexy by compatibility, is that the treatment of cardiovascular and cerebrovascular disease increases a new medication and selects.Simultaneously, can system further investigate Radix Salviae Miltiorrhizae or the safety of Radix Salviae Miltiorrhizae 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 Salviae Miltiorrhizae extract: ozagrel) carried out the prescription screening test of system, found that with Radix Salviae Miltiorrhizae extract: 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 arranged aspect blood circulation promoting and 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 Radix Salviae Miltiorrhizae, 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 effective effect of medicine provided by the invention.

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

We have carried out the prescription screening test of system in varing proportions to Radix Salviae Miltiorrhizae extract and ozagrel by antiplatelet aggregation test, inhibition mouse tail thrombotest, found that strong and consumption is lower with the pharmacological action of Radix Salviae Miltiorrhizae extract and ozagrel combination (3: 1) prescription, so determine that this ratio prescription is best prescription.

Table prescription research conclusion

Formula number	Prescription proportion of composing Radix Salviae Miltiorrhizae extract: ozagrel	The screening and assessment index
				Platelet suppression ratio (%)	Thrombosis suppression ratio (%)
		1 2 3 4 5 6 7	1∶3 1∶2 1∶1 3∶1 5∶1 8∶1 10∶1			81.3％ 79.6％ 80.1％ 78.3％ 66.2％ 64.4％ 60.8％	63.1％ 60.4％ 65.0％ 59.3％ 55.5％ 50.4％ 46.7％

From above-mentioned prescription screening result as can be seen, the Radix Salviae Miltiorrhizae extract of different purity and ozagrel compatibility all can produce certain curative effect, but through system thinking, determine to reach the effect of efficacy enhancing and toxicity reducing with Radix Salviae Miltiorrhizae extract and ozagrel by force and consumption is lower, preparations shaping and having good stability with 3: 1 ratio compatibility pharmacological action.

(2) Radix Salviae Miltiorrhizae 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 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 Radix Salviae Miltiorrhizae extract group	The ozagrel group
				Myocardial infarction model test improves mouse microcirculation test rat ICA injection thrombus local cerebral ischemia model test platelet aggregation-against and tests the test promoting blood circulation and removing blood stasis of anti-mouse tail thrombotest due to the dog CAL method	Effect is remarkable, the effect reinforced effects is remarkable, effect reinforced effects remarkable result is remarkable, the effect reinforced effects is remarkable, and the effect reinforced effects is remarkable	The general successful successful of successful successful effect successful	The general successful successful of successful effect successful successful

Concrete embodiment

Embodiment 1: the preparation Radix Salviae Miltiorrhizae extract: get 10 parts of Radix Salviae Miltiorrhizaes (kilogram or gram)

Get Radix Salviae Miltiorrhizae, pulverize the back and add 70% ethanol, soaked 12 hours, heating and refluxing extraction 3 times, each 1 hour, merge extractive liquid,, decompression recycling ethanol and when being condensed into 60 ℃ relative density be 1.08～1.15 extractum, add 3 times of water gaging stirring and dissolving, filter, filtrate is crossed the D-101 macroporous adsorptive resins, with 6 times of resinite hydrops and 4 times of resin volume 10% ethanol elution impurity, reuse 50% ethanol is resolved earlier, collects stripping liquid, reclaim the ethanol concentrate drying, pulverize and promptly get Radix Salviae Miltiorrhizae extract.

Embodiment 2: the preparation Radix Salviae Miltiorrhizae extract: 10000 parts of Radix Salviae Miltiorrhizaes (kilogram or gram)

Get Radix Salviae Miltiorrhizae, add 12 times of decoctings and boil 3 times, 2 hours for the first time, second and third time 1.5 hours, merge extractive liquid,, relative density is 1.05～1.15 thick paste when being concentrated into 50～80 ℃, adds ethanol and makes and contain pure flow control and once reach 50～70%, for the second time reach 85%, cold preservation is spent the night, and filters filtrate recycling ethanol, drying under reduced pressure gets Radix Salviae Miltiorrhizae extract.

Embodiment 3: the preparation Radix Salviae Miltiorrhizae extract: 8000 parts of Radix Salviae Miltiorrhizaes (kilogram or gram)

Extract: get Radix Salviae Miltiorrhizae, 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 Radix Salviae Miltiorrhizae extract.

Embodiment 4: the preparation Radix Salviae Miltiorrhizae extract: 20 parts of Radix Salviae Miltiorrhizaes (kilogram or gram)

Extract: get Radix Salviae Miltiorrhizae, add 10 times of decoctings and boil 3 times, 2 hours for the first time, second and third time 1.5 hours, merge extractive liquid,, relative density is about 1.05 clear paste when being concentrated into 70 ℃, 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 Radix Salviae Miltiorrhizae extract.

Embodiment 5: the preparation Radix Salviae Miltiorrhizae extract: 5000 parts of Radix Salviae Miltiorrhizaes (kilogram or gram)

Get Radix Salviae Miltiorrhizae, add 8 times of decoctings and boil 3 times, each 1.5 hours, merge extractive liquid,, relative density is 1.10～1.15 thick paste when being concentrated into 80 ℃, with the sodium carbonate liquor stirring and dissolving of equal-volume 20%, 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 promptly gets Radix Salviae Miltiorrhizae extract.

Embodiment 6: the preparation Radix Salviae Miltiorrhizae extract: 50 parts of Radix Salviae Miltiorrhizaes (kilogram or gram)

Get Radix Salviae Miltiorrhizae, pulverize the back and 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 Radix Salviae Miltiorrhizae extract.

Embodiment 7: 10 parts of 5000 parts of ozagrels of Radix Salviae Miltiorrhizae (part is: kilogram or gram)

Get Radix Salviae Miltiorrhizae, pulverize the back and 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 gagings heating, filter, filtrate is crossed the ZTC-1 macroporous resin column, with 20% ethanol elution impurity, and reuse 60% alcohol desorption, collect stripping liquid, reclaim the ethanol concentrate drying,, add the water for injection stirring and make it dissolving with the ozagrel mixing, 4 ℃ of cold preservations are spent the night, coarse filtration, fine straining, three grades of microporous filter membrane: be sequentially: 0.8um-0.45um-0.22um filters, embedding is sealed sterilization and is promptly got hydro-acupuncture preparation in the 10ml ampoule.

Embodiment 8: 20 parts of 10000 parts of ozagrels of Radix Salviae Miltiorrhizae (part is: kilogram or gram)

Get Radix Salviae Miltiorrhizae, pulverize the back and add 70% ethanol, soaked heating and refluxing extraction 3 times, each 1 hour 12 hours, merge extractive liquid,, decompression recycling ethanol and when being condensed into 60 ℃ relative density be 1.08～1.15 extractum, add 3 times of water gaging stirring and dissolving, filter, filtrate is crossed the D-101 macroporous adsorptive resins, with 6 times of resinite hydrops and 4 times of resin volume 10% ethanol elution impurity, reuse 50% ethanol is resolved earlier, collects stripping liquid, reclaim the ethanol concentrate drying, pulverize, join in an amount of water for injection and stir, add an amount of 10% sodium citrate solution, be stirred to solution and dissolve fully, standby; Taking by weighing ozagrel joins and is stirred to fully dissolving in the water for injection, add standby Radix Salviae Miltiorrhizae extract solution mix homogeneously, regulate pH value 4.2～5.5, stir and make it to dissolve fully the PEG400 of adding 30ml, the mannitol of 130g, stirring makes it to dissolve fully, adds the active carbon of 0.05% (g/ml), and 60 ℃ of static absorption are after 20 minutes, filter carbon removal, benefit adds to the full amount of water for injection, and regulates pH value 4.5～5.5, fine straining, the intermediate sampling, to be detected qualified after, quantitative filling 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 lyophilized injectable powder.

Embodiment 9: 20 parts of 3000 parts of ozagrels of Radix Salviae Miltiorrhizae (part is: kilogram or gram)

Get Radix Salviae Miltiorrhizae, be ground into the coarse powder of 10 mesh sieves, add 8 times of volume 70% alcohol reflux 2 times, each 1 hour, merge extractive liquid,, measuring relative density during decompression recycling ethanol to 60 ℃ is 1.05～1.15, the water dissolution that adds 3 times of medical material volumes filters, and filtrate is crossed D-101 type macroporous adsorbent resin, with 6 times of resinite hydrops 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, dry, pulverize,, add water for injection with the ozagrel mix homogeneously, 4 ℃ of cold preservations are spent the night, coarse filtration adds in an amount of glucose solution, adds 0.2% active carbon and boils 15 minutes, coarse filtration, fine straining promptly gets the glucose infusion liquid agent with the water for injection dilution.

Embodiment 10: 18 parts of 100 parts of ozagrels of Radix Salviae Miltiorrhizae (part is: kilogram or gram)

Get Radix Salviae Miltiorrhizae, add 12 times of decoctings and boil 3 times, 2 hours for the first time, second and third time 1.5 hours, merge extractive liquid,, relative density is 1.05～1.15 thick paste when being concentrated into 50～80 ℃, adds ethanol and makes and contain pure flow control and once reach 50～70%, reaches 85% for the second time, cold preservation is spent the night, filter filtrate recycling ethanol, drying under reduced pressure, with the ozagrel mix homogeneously, add water for injection, coarse filtration is spent the night in 4 ℃ of cold preservations, add in the proper amount of sodium chloride solution, add 0.2% active carbon and boiled 15 minutes, coarse filtration, fine straining promptly get the sodium chloride infusion solution with the water for injection dilution.

Embodiment 11: 10 parts of 300 parts of ozagrels of Radix Salviae Miltiorrhizae extract (part is: kilogram or gram)

Get Radix Salviae Miltiorrhizae extract,, add the water for injection stirring and make it dissolving with the ozagrel mixing, 4 ℃ of cold preservations are spent the night, coarse filtration, fine straining, three grades of microporous filter membrane: be sequentially: 0.8um-0.45um-0.22um, filter, embedding is sealed sterilization and is promptly got hydro-acupuncture preparation in the 10ml ampoule.The content of salviol constituents account in the preparation deduction adjuvant amount, water quantities and ozagrel amount total solid 52%, the component content sum that derives from red rooted salvia that all can be surveyed be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 78%.

Embodiment 12: 1 part of 3 parts of ozagrel of Radix Salviae Miltiorrhizae extract (part is: kilogram or gram)

Get Radix Salviae Miltiorrhizae extract, join in an amount of water for injection and stir, add an amount of 10% sodium citrate solution, be stirred to solution and dissolve fully, standby; Take by weighing ozagrel and join and be stirred to fully dissolving in the water for injection, adds standby Radix Salviae Miltiorrhizae extract solution mix homogeneously, adjusting pH value 4.2～5.5, stirring makes it to dissolve fully, adds the PEG400 of 30ml, the mannitol of 130g, stirring makes it to dissolve fully, adds the active carbon of 0.05% (g/ml), and 60 ℃ of static absorption are after 20 minutes, filter carbon removal, benefit adds to the full amount of water for injection, and regulates pH value 4.5～5.5, fine straining, intermediate sampling, to be detected qualified after, quantitatively; About 3ml fill 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 lyophilized injectable powder.The content of salviol constituents account in the preparation deduction adjuvant amount, water quantities and ozagrel amount total solid 15%, the component content sum that derives from red rooted salvia that all can be surveyed be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 21%.

Embodiment 13: 15 parts of 4000 parts of ozagrels of Radix Salviae Miltiorrhizae extract (part is: kilogram or gram)

Get 500ml water for injection earlier and put in the liquid dispenser, add Radix Salviae Miltiorrhizae extract 500mg, stirring at room makes it dissolving, adds 1.2g sodium citrate and 50ml 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 800mg tartaric acid, add ozagrel 400mg again, be stirred to and form clear and bright solution, under stirring this solution is added in the above-mentioned Radix Salviae Miltiorrhizae extract solution, add the injection water again to 1000ml.Measure pH value, tartaric acid with 1% or 0.1M sodium hydroxide solution are transferred pH to 4.8～5.7, add the 50g glucose, stirring and dissolving, adding 0.05% active carbon boils, stir insulation 20 minutes, filtered while hot, three grades of microporous filter membrane: be sequentially: 0.8um-0.45um-0.22um, filter, add an amount of water for injection dilution, embedding, 105 ℃ of sterilizations promptly got the glucose infusion liquid agent in 1 hour.The content of salviol constituents account in the preparation deduction adjuvant amount, water quantities and ozagrel amount total solid 87%, the component content sum that derives from red rooted salvia that all can be surveyed be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 94%.

Embodiment 14: 18 parts of 1000 parts of ozagrels of Radix Salviae Miltiorrhizae extract (part is: kilogram or gram)

Get Radix Salviae Miltiorrhizae extract, with the ozagrel mix homogeneously, add water for injection, 4 ℃ of cold preservations are spent the night, and coarse filtration adds in the proper amount of sodium chloride solution, add 0.2% active carbon and boil 15 minutes, and coarse filtration, fine straining promptly get the sodium chloride infusion solution with the water for injection dilution.Ozagrel content is 99.4% of preparation labelled amount.

Embodiment 15: 20 parts of 10000 parts of ozagrels of Radix Salviae Miltiorrhizae (part is: kilogram or gram)

Get Radix Salviae Miltiorrhizae, add 12 times of water gagings and decoct 2 times, 2h for the first time, 1.5h merges decoction liquor for the second time, filters, and filtrate is concentrated into 1000ml.Add the ethanol precipitation secondary, for the first time the teacher contains the alcohol amount and reaches 50%, makes for the second time to contain the alcohol amount and reach 60%, all cold preservation is placed the back and is filtered filtrate recycling ethanol, the dry Radix Salviae Miltiorrhizae extract that gets at every turn, add ozagrel, mixing adds PEG4000 and polyoxyethylene monostearate S-40 portion, mix homogeneously, water-bath is melted, and stirs evenly, drip and in dimethicone, to become ball, drip apart from 5cm bore 2.5mm, 70 ℃ of hybrid medicine temperature, liquid coolant height 60cm promptly gets drop pill.

Embodiment 16: 10 parts of 100 parts of ozagrels of Radix Salviae Miltiorrhizae extract (part is: kilogram or gram)

Get Radix Salviae Miltiorrhizae 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 60 ~ 70 ℃ gradually after 30 minutes, stir 5 hours third whiles evacuation and remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; The debugging pellet press, 65 ℃ of gelatin box temperature controls, film 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, rolled qualitative dry 2 hours, and 22 ℃ of baking temperatures, dry relative humidity should be lower than 65%, and promptly got soft capsule at 24～48 hours drying time.

Embodiment 17: 1 part of 200 parts of ozagrel of Radix Salviae Miltiorrhizae extract (part is: kilogram or gram)

Get Radix Salviae Miltiorrhizae extract, ozagrel mix homogeneously, add 7% polyvinylpolypyrrolidone PVPP and 2% mannitol, compacting promptly gets oral cavity disintegration tablet in flakes.The content of ozagrel is 96.0% of labelled amount.

Embodiment 18: 2 parts of 10 parts of ozagrels of Radix Salviae Miltiorrhizae (part is: kilogram or gram)

Get Radix Salviae Miltiorrhizae, add 70～95% alcohol reflux 1～8 hour, filter, filtrate recycling ethanol, medicinal residues decoct with water 1～5 hour, filter; Merge above-mentioned filtrate, being concentrated into relative density is the clear paste of 1.00～1.45 (60～95 ℃), adds ozagrel, starch is an amount of, mixing, drying is granulated, compacting in flakes, coating, promptly.Promptly get tablet.

Embodiment 19: 18 parts of 5000 parts of ozagrels of Radix Salviae Miltiorrhizae (part is: kilogram or gram)

Get Radix Salviae Miltiorrhizae and extract three times, add 95% alcohol reflux 1.5 hours for the first time, filter, filtrate is concentrated into the thick paste that relative density is 1.30 (55～60 ℃); Add for the second time 50% alcohol reflux 1.5 hours, filter; Add the water reflux, extract, for the third time 2 hours, and filtered, merge two, three times filtrate, filtrate is concentrated into the thick paste that relative density is 1.40 (55～60 ℃), adds concentrated solution for the first time, mixing, making relative density is 1.35～1.39 (55～60 ℃), adds ozagrel, 4% carboxymethyl starch sodium, mix, drying is granulated granulate, incapsulate, promptly get capsule.The content that records Radix Salviae Miltiorrhizae total phenols in the preparation with spectrophotography is 1.5%; The content of ozagrel is 107.0% of labelled amount.

Embodiment 20: 20 parts of 60 parts of ozagrels of Radix Salviae Miltiorrhizae extract (part is: kilogram or gram)

Get Radix Salviae Miltiorrhizae extract, the ozagrel mix homogeneously, get polyvinylpolypyrrolidone PVPP3.35g and CMC-Na1.05g, add the lemon yellow mixing, get half and medicated powder mixing, K30 anhydrous alcohol solution with 1.5% is made binding agent, 40 order system material, granulate remain half polyvinylpolypyrrolidone PVPP3.35g and CMC-Na1.05g, and the mixed powder that adds the lemon yellow mixing is added in the particle that makes, tabletting promptly gets dispersible tablet.

Embodiment 21: 15 parts of 100 parts of ozagrels of Radix Salviae Miltiorrhizae (part is: kilogram or gram)

Get Radix Salviae Miltiorrhizae, add 10 times of water gagings and decoct 4 times, 2 hours for the first time, 1.5h for the second time, third and fourth time 1h, decoction liquor merges, and filters, and filtrate is concentrated into 100ml, adds ozagrel, 15% lactose mixing, granulates, and sieves, and promptly gets granule.

Embodiment 22: 10 parts of 500 parts of ozagrels of Radix Salviae Miltiorrhizae extract (part is: kilogram or gram)

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

Embodiment 23: 20 parts of 100 parts of ozagrels of Radix Salviae Miltiorrhizae extract (part is: the public Room 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.

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 1～20 part of 10～10000 parts of Radix Salviae Miltiorrhizaes and ozagrel through extracting refining forming; Or the Radix Salviae Miltiorrhizae 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 1～15 part of 100～5000 parts of Radix Salviae Miltiorrhizaes and ozagrel through extracting refining forming; Or the Radix Salviae Miltiorrhizae 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 1～10 part of 100～2000 parts of Radix Salviae Miltiorrhizaes and ozagrel through extracting refining forming; Or the Radix Salviae Miltiorrhizae 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 phenols component 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 red rooted salvia 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 Salviae Miltiorrhizae, add entry or ethanol extraction, the extracting solution concentrate drying gets the Radix Salviae Miltiorrhizae crude extract, one or more that also can further adopt precipitate with ethanol, organic solvent extraction, alkali extraction and acid precipitation, column chromatography carry out suitably refining, get the Radix Salviae Miltiorrhizae extract,, be prepared into the preparation that needs with conventional method Radix Salviae Miltiorrhizae crude extract or Radix Salviae Miltiorrhizae extract and ozagrel mixing.

8, according to the preparation of drug combination method of the described treatment cardiovascular and cerebrovascular disease of claim 7, it is levied and is: Radix Salviae Miltiorrhizae 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, antithrombotic, blood vessel dilating, reduction myocardial oxygen consumption, microcirculation improvement, increases the functions such as blood supply of ischemic region.

10, as the application in the dyskinesia medicine that cardiovascular and cerebrovascular disease such as the acute thrombotic cerebral infarction of preparation treatment, coronary heart disease, angina pectoris, apoplexy 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: its assay is to adopt in high performance liquid chromatography, spectrophotography, thin layer chromatography scanning, the titrimetry one or more to record.