CN1965923A - Pharmaceutical composition for treating cardiovascular and cerebrovascular diseases, preparation method and application thereof - Google Patents

Abstract

The invention provides a pharmaceutical composition for treating cardiovascular and cerebrovascular diseases, its preparing process and use thereof, wherein the composition is prepared from red peony root glycosides or white peony root glycosides and Breviscapine, various injection preparations and pharmacologically allowable dose forms such as oral administration preparations can be produced through charging auxiliary materials. The preparation of the composition is mainly used for treating ischemic cerebral apoplexy, angina pectoris caused by coronary disease, cardiac functional insufficiency, apoplexy after-effect, hepatorenal syndrome, coronary heart disease, diabetes and complications. The preparation has the advantages of definite constituents, fine external appearance, controllable quality, and appreciable curative effect.

Description

Pharmaceutical composition of treatment cardiovascular and cerebrovascular disease and its production and application

Technical field

The present invention relates to a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease and its production and application, belong to technical field of medicaments.

Technical background

According to national health department's investigation statistics, 2004, ten thousand people died from cardiovascular and cerebrovascular disease surplus China had 260, and people's death was just arranged in average per 12 seconds, cardiovascular and cerebrovascular disease patient sum nearly 1.5 hundred million, and annual control expenditure surpasses 100,000,000,000.And the cardiovascular and cerebrovascular disease patient generally has hyperlipemia, hypertension, high blood viscosity, thrombosis, sclerosis of blood vessels, angiostenosis etc.If the Therapeutic Method of " medicine one is controlled, treated the head when the head aches, foot cure foot bitterly " according at present, so the patient must eat every day surplus " lipid lowerers, the depressor, fall the sticking medicine of blood, Pimobendane, thrombolytic medicine " etc. five, six kind even ten in the kind, Western medicine.Better prevent and treat purpose in order to reach, a large amount of research has been done by many inventors and medicine enterprise, and some outstanding treatment products also are provided; As: number of patent application is: 200410040776.2, name is called the patent application of " compound recipe fleabane preparation of treatment cardiovascular and cerebrovascular disease and preparation method thereof ", and the disease that it is used for the treatment for the treatment of cardiac and cerebral vascular diseases has definite curative effect; But in further investigation, find, adopt the effective site compatibility can not only reduce patient's dose, remove the strong composition of some toxic and side effects in the medicinal substances extract, the safety of preparation and the controllability of quality have been improved, greatly improve curative effect, and more help the molding of preparation, reduced some unnecessary technologies in the forming process.

Summary of the invention

The objective of the invention is to: a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease and its production and application is provided; The present invention is directed to prior art, according to cardiovascular and cerebrovascular disease such as coronary heart disease, cerebral thrombosis, alzheimer disease etc. all contract because of blood vessel is narrow, reason such as blood flow minimizing causes the diseases induced principle of blood supply insufficiency, on the basis of experiment screening, adopt Radix Paeoniae Rubra total glycosides, breviscapine compatibility to make preparation, optimize best prescription and technology; The product that obtains, particularly ejection preparation product can play activating blood circulation to dissipate blood stasis, TONGMAI SHULUO, improve blood circulation and metabolism.For example coronary heart disease is that coronary atherosclerosis causes myocardial ischemia, anoxia and the heart disease that causes, and two medicines share, and can play to improve the myocardial metabolism effect, increase coronary flow, and the blood that improves cardiac muscle is provided with the effect of allevating angina pectoris.The present invention has curative effect preferably for treating cardiovascular and cerebrovascular disease such as coronary heart disease, angina pectoris, arrhythmia, cerebral thrombosis, alzheimer disease etc.But and the little patients life-time service of untoward reaction of the present invention.

The present invention constitutes like this: calculate according to percentage by weight, it is to be made by Radix Paeoniae Rubra total glycosides 1～99% and breviscapine 99～1% and suitable adjuvant.Be preferably: calculate according to percentage by weight, it is to be made by Radix Paeoniae Rubra total glycosides 95～50% and breviscapine 5～50% and suitable adjuvant.Say accurately: calculate according to percentage by weight, it is to be made by Radix Paeoniae Rubra total glycosides 90～50%, breviscapine 10～50% and suitable adjuvant.Radix Paeoniae Rubra total glycosides in the described prescription can be the highly finished product of Radix Paeoniae Rubra alcohol extract, Radix Paeoniae Rubra water extract, Radix Paeoniae Rubra water extract-alcohol precipitation extract, Radix Paeoniae Rubra semi-bionic extraction thing, Radix Paeoniae Rubra supercritical extract or above each extract; Breviscapine can be the Herba Erigerontis alcohol extract, the Herba Erigerontis water extract, Herba Erigerontis water extract-alcohol precipitation extract, Herba Erigerontis semi-bionic extraction thing, the described preparation of the highly finished product of Herba Erigerontis supercritical extract or above each extract is the injection that is directly used in drug administration by injection, directly supply the venous transfusion of intravenous drip, need to be used for the concentrated solution for injection of intravenous drip and injectable sterile powder and aseptic block and the tablet that makes with freeze-drying or spray drying method after the dilution, capsule, granule, drop pill, pill, soft capsule, oral liquid, oral cavity disintegration tablet or dispersible tablet.The preparation of described compositions can make on the basis that in Radix Paeoniae Rubra total glycosides, the breviscapine one or both is prepared into liposome or pro-liposome.Contain glycoside composition and breviscapine in the preparation, calculate by weight percentage, the glycoside composition contains 50% of the total solid that is not less than deduction breviscapine amount, adjuvant amount and water quantities in the preparation in the preparation.

In the pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease:

A, breviscapine are preparations like this: get the Herba Erigerontis medical material, adding entry or alcoholic solution after the pulverizing extracts, merge extractive liquid,, filter, concentrate the Herba Erigerontis crude extract, adopt in ethanol precipitation, column chromatography, extraction, the flocculent precipitation one or more to unite on this basis to use carry out suitably refining, breviscapine;

B, Radix Paeoniae Rubra total glycosides effective site are preparations like this: get the Radix Paeoniae Rubra medical material, adding entry or alcoholic solution after the pulverizing extracts, merge extractive liquid,, filter, concentrate the Radix Paeoniae Rubra crude extract, adopt in ethanol precipitation, column chromatography, extraction, the flocculent precipitation one or more to unite on this basis to use carry out suitably refining, Radix Paeoniae Rubra total glycosides effective site.

Described Injectable sterile block prepares like this: get Radix Paeoniae Rubra total glycosides, breviscapine and mannitol, add 1800ml water for injection, the mannitol consumption is 1.6g in wherein every 100ml medicinal liquid, stirring makes dissolving, with saturated sodium hydroxide solution adjust pH to 6.5～8.0, add the injection water to 2000ml, mixing, the needle-use activated carbon of adding 0.5%, boiled 30 minutes, coarse filtration, reuse 0.45 μ m and 0.22 μ m microporous filter membrane filter, the filtrate packing, every bottle of 2.0ml, lyophilization, the equilibration time when the balance solidification point of phase I is 0 ℃ is 2 hours, i.e. the time of shelf temperature and product temperature basically identical; The second stage solidification point is from 0 ℃ during to minimum eutectic temperature-19 ℃, and shelf temperature and product temperature equilibration time are 2.5 hours; Phase III continues to be cooled to-45 ℃, needs 2 hours approximately, keeps this temperature 2.5 hours, freeze the jail fully until product, promptly begin evacuation, enter drying program, evacuation under-45 ℃ of constant temperature slowly heats up 2～4 ℃/h, to the lowest total of the melting point temperature, the time is about 10 hours, after sublimation drying is finished, continuation is under the low pressure condition, and it is dry to remove residual moisture to heat up, and the time is about 9～11 hours, kept more than 35 ℃ dry 2 hours, gland, promptly.

Described pro-liposome prepares like this: gets Radix Paeoniae Rubra total glycosides, breviscapine, adds the phosphate buffer dissolving, add in the fused solution of fabaceous lecithin, cholesterol and 18-amine. mixing, stir, and supersound process, freezing, the dry powder that obtains sieves, promptly.

Described compositions is mainly used in diseases such as treatment ischemia apoplexy, angina pectoris, cardiac insufficiency, apoplexy sequela, hepatorenal syndrome, heart and lung diseases, diabetes and complication thereof.

Compared with prior art, the applicant carried out lot of experiments, and filtering out the prescription for the treatment of diseases such as angina pectoris is Radix Paeoniae Rubra total glycosides, breviscapine, and best compatibility scope is Radix Paeoniae Rubra total glycosides 90～50%, breviscapine 10%～50%.Adopt good, the steady quality of prepared product appearance of the present invention.

For proving that medicine provided by the invention has effective effect, the applicant has carried out a series of experiments.

Experimental example 1: to the comparative study of different proportioning pharmacodynamics

We by antiplatelet aggregation test, suppress the mouse tail thrombotest, the prescription of different proportion has been carried out the screening test of system, the result is as follows.

The prescription research conclusion

Formula number	Prescription is formed and the ratio breviscapine: Radix Paeoniae Rubra total glycosides	The screening and assessment index
				Platelet suppression ratio (%)	Thrombosis suppression ratio (%)
		1 2 3 4 5 6 7	1: 99 5: 95 10: 90 50: 50 99: 1 positive controls of model group			0.42％ 51.6％ 56.8％ 61.9％ 63.2％ 49.5％ 62.7％	-0.31％ 19.6％ 30.3％ 41.2％ 42.4％ 21.7％ 41.5％

By experimental result as can be known, Radix Paeoniae Rubra total glycosides, the best compatibility scope of breviscapine are Radix Paeoniae Rubra total glycosides 90～50% and breviscapine 10～50%.

Experimental example 2: injection Study on Forming

2.1 the selection of filler kind and consumption

2.1.1 the screening of filler kind

The applicant finds that in development suitable filler, filler loading are powder injection formulation molding and stable key factor, and in order to improve the quality of this powder injection formulation, at first, the applicant investigates the kind of filler.The results are shown in following table.

The screening of filler kind

Filler	Mannitol	Glucose	Lactose	Gelatin hydrolysate	Glycine sodium
						Mannitol consumption (g/100ml) mouldability	1.6 good	1.6 not molding	1.6 not molding	1.6 not molding	1.6 not molding

As seen, because the eutectic point height of mannitol, good water solubility be beneficial to the lyophilizing and the molding of this product, and other filler all is not suitable for this product, so selection mannitol is filler.

2.1.2 the screening of mannitol consumption

Then, the applicant investigates the weight ratio of mannitol and effective ingredient, the results are shown in following table.

The relation of mannitol addition and dried frozen aquatic products molding

Tested number	Mannitol addition (g/100ml)	Lyophilizing molding situation			Dissolubility
						1 2 3 4 5 6	0 0.4 0.8 1.2 1.6 2.0	The dark dark light color light color light color of surplus color is shallow	There is duricrust not have	There is atrophy not have	Rehydration difference rehydration difference is relatively poor carefully

Result of the test shows, the amount that adds mannitol in the 100ml medicinal liquid reaches 1.6g when above, can keep sample lyophilizing preceding volume and shape, no duricrust, and color and luster is good, not atrophy, sample is loose porous shape structure, and rehydration is good.So the mannitol that the present invention selects to add in the 100ml medicinal liquid is 1.6g.

Experimental example 3: preparation pharmacodynamic experiment

Protective effect to Acute Myocardial Ischemia in Rats: get the SD rat; body constitution amount 230～250g; male and female half and half; be divided into model group (giving the equivalent normal saline every day), dispersible tablet group of the present invention (administration every day 60mg/kg), injection group of the present invention (administration every day 60mg/kg), liposome group of the present invention (administration every day 60mg/kg) and Radix Paeoniae Rubra/Herba Erigerontis 50/50 medical material proportioning injection group at random and (be called for short medical material compatibility group; administration every day 60mg/kg); every group 10; continuous 7 days, 1h ligation rat coronary artery left anterior descending branch after the last administration.Ventricle is got blood 3ml behind coronary ligation 3h, and centrifugal 5min prepares serum with the speed of 3000 * g, gets serum, measures corresponding index in the serum respectively with superoxide dismutase (SOD), malonaldehyde (MDA) test kit.Win rat heart and discharge hematocele in the chambers of the heart, inhale the branch that anhydrates, reject non-cardiac muscular tissues such as fatty blood vessel, wipe out atrium and right ventricle, stay left ventricle and weigh, calculate infarcted region (weight in wet base) and account for left ventricle (weight in wet base) percentage ratio with normal saline flushing and with filter paper.The results are shown in following table.

Influence to SOD, MDA in myocardial infarct size and the serum behind the rat coronary ligation

Group	Heart infarction scope (%)	SOD(NU/ml)	MDA(nmol/ml)
				Model group injection group of the present invention dispersible tablet group of the present invention liposome medical material of the present invention compatibility group	15.2±1.3 10.5±1.5 11.4±2.2 9.8±0.9 12.0±1.4	163.7±25.3 324.8±26.8 309.6±24.9 332.4±31.2 286.5±36.7	7.16±1.02 4.59±2.34 4.91±0.62 3.86±0.71 5.24±0.97

By experimental result as can be known, pharmaceutical preparation of the present invention can obviously improve SOD activity in the coronary ligation rat blood serum, has significantly suppressed the generation of MDA, and obviously reduces myocardial infarction district area, and the effect of lipidosome injection group is stronger.

Concrete embodiment

Embodiments of the invention 1: Radix Paeoniae Rubra total glycosides 50g breviscapine 50g

Get Radix Paeoniae Rubra total glycosides, breviscapine and mannitol, add 1800ml water for injection, the mannitol consumption is 1.6g in wherein every 100ml medicinal liquid, stirring makes dissolving, with saturated sodium hydroxide solution adjust pH to 6.5～8.0, add the injection water to 2000ml, mixing, the needle-use activated carbon of adding 0.5%, boiled 30 minutes, coarse filtration, reuse 0.45 μ m and 0.22 μ m microporous filter membrane filter, the filtrate packing, every bottle of 2.0ml, lyophilization, the equilibration time when the balance solidification point of phase I is 0 ℃ is 2 hours, i.e. the time of shelf temperature and product temperature basically identical; The second stage solidification point is from 0 ℃ during to minimum eutectic temperature-19 ℃, and shelf temperature and product temperature equilibration time are 2.5 hours; Phase III continues to be cooled to-45 ℃, needs 2 hours approximately, keeps this temperature 2.5 hours, freeze the jail fully until product, promptly begin evacuation, enter drying program, evacuation under-45 ℃ of constant temperature, slowly heat up, 2～4 ℃/h, to the lowest total of the melting point temperature, the time is about 10 hours, after sublimation drying is finished, continuation is under the low pressure condition, and it is dry to remove residual moisture to heat up, and the time is about 9～11 hours, kept more than 35 ℃ dry 2 hours, gland promptly gets the Injectable sterile block, one time 2,1 time on the one, with using behind the 250ml0.9% physiological saline solution.Calculate by weight percentage, in the injection total glycosides constituents content, breviscapine content sum be deduction adjuvant amount and water quantities in the preparation total solid 83%.

Embodiments of the invention 2: Radix Paeoniae Rubra total glycosides 50g breviscapine 50g

Get Radix Paeoniae Rubra total glycosides, breviscapine, add an amount of water for injection dissolving, by volume add 0.5% active carbon, boil, keep little 30min that boils, cold slightly filtration, filtrate adds the injection water to ormal weight, with saturated sodium hydroxide solution adjust pH to 6.5～8.0, boils, 4 ℃ of cold preservations are spent the night, coarse filtration, fine straining add the injection water, divide to install to ampoule bottle, seal sterilization, promptly get injection with small volume or concentrated solution for injection.

Embodiments of the invention 3: Radix Paeoniae Rubra total glycosides 90g breviscapine 10g

Get Radix Paeoniae Rubra total glycosides, breviscapine, add an amount of water for injection dissolving, by volume add 0.5% active carbon, boil, keep little 30min that boils, cold slightly filtration, filtrate adds the injection water to ormal weight, with saturated sodium hydroxide solution adjust pH to 6.5～8.0, boils, 4 ℃ of cold preservations are spent the night, coarse filtration, fine straining add the injection water, divide to install to ampoule bottle, seal sterilization, promptly get injection with small volume or concentrated solution for injection.

Embodiments of the invention 4: Radix Paeoniae Rubra total glycosides 90g breviscapine 10g

Get Radix Paeoniae Rubra total glycosides, breviscapine and mannitol, add 1800ml water for injection, the mannitol consumption is 1.6g in wherein every 100ml medicinal liquid, stirring makes dissolving, with saturated sodium hydroxide solution adjust pH to 6.5～8.0, add the injection water to 2000ml, mixing, the needle-use activated carbon of adding 0.5%, boiled 30 minutes, coarse filtration, reuse 0.45 μ m and 0.22 μ m microporous filter membrane filter, the filtrate packing, every bottle of 2.0ml, lyophilization, the equilibration time when the balance solidification point of phase I is 0 ℃ is 2 hours, i.e. the time of shelf temperature and product temperature basically identical; The second stage solidification point is from 0 ℃ during to minimum eutectic temperature-19 ℃, and shelf temperature and product temperature equilibration time are 2.5 hours; Phase III continues to be cooled to-45 ℃, need 2 hours approximately, kept this temperature 2.5 hours, freeze the jail fully until product, promptly begin evacuation, enter drying program, evacuation under-45 ℃ of constant temperature, slowly heat up, 2～4 ℃/h, to the lowest total of the melting point temperature, time is about 10 hours, after sublimation drying is finished, continue under the low pressure condition, it is dry to remove residual moisture to heat up, time is about 9～11 hours, kept more than 35 ℃ dry 2 hours, and under aseptic condition, divided to install in the cillin bottle, promptly get injectable sterile powder.

Embodiments of the invention 5: Radix Paeoniae Rubra total glycosides 70g breviscapine 30g

Get Radix Paeoniae Rubra total glycosides, breviscapine, add an amount of water for injection dissolving, by volume add 0.5% active carbon, boil, keep little 30min that boils, cold slightly filtration, filtrate adds the injection water to ormal weight, with saturated sodium hydroxide solution adjust pH to 6.5～8.0, boils, 4 ℃ of cold preservations are spent the night, coarse filtration, fine straining add the injection water, divide to install to ampoule bottle, seal sterilization, promptly get injection with small volume or concentrated solution for injection.

Embodiments of the invention 6: Radix Paeoniae Rubra total glycosides 70g breviscapine 30g

Get Radix Paeoniae Rubra total glycosides, breviscapine and mannitol, add 1800ml water for injection, the mannitol consumption is 1.6g in wherein every 100ml medicinal liquid, stirring makes dissolving, with saturated sodium hydroxide solution adjust pH to 6.5～8.0, add the injection water to 2000ml, mixing, the needle-use activated carbon of adding 0.5%, boiled 30 minutes, coarse filtration, reuse 0.45 μ m and 0.22 μ m microporous filter membrane filter, the filtrate packing, every bottle of 2.0ml, lyophilization, the equilibration time when the balance solidification point of phase I is 0 ℃ is 2 hours, i.e. the time of shelf temperature and product temperature basically identical; The second stage solidification point is from 0 ℃ during to minimum eutectic temperature-19 ℃, and shelf temperature and product temperature equilibration time are 2.5 hours; Phase III continues to be cooled to-45 ℃, need 2 hours approximately, kept this temperature 2.5 hours, freeze the jail fully until product, promptly begin evacuation, enter drying program, evacuation under-45 ℃ of constant temperature, slowly heat up, 2～4 ℃/h, to the lowest total of the melting point temperature, time is about 10 hours, after sublimation drying is finished, continue under the low pressure condition, it is dry to remove residual moisture to heat up, time is about 9～11 hours, kept more than 35 ℃ dry 2 hours, and under aseptic condition, divided to install in the cillin bottle, promptly get injectable sterile powder.

Embodiments of the invention 7: Radix Paeoniae Rubra total glycosides 95g breviscapine 5g

Get Radix Paeoniae Rubra total glycosides, breviscapine, mixing adds an amount of water for injection dissolving, by volume add 0.5% active carbon, boil, keep little 30min that boils, cold slightly filtration, filtrate add the injection water to ormal weight, with saturated sodium hydroxide solution adjust pH to 6.5～8.0, boil, 4 ℃ of cold preservations are spent the night, and coarse filtration, fine straining are 120 ℃ in inlet temperature, leaving air temp is 55 ℃, and air velocity is 25ms ^-1Condition under spray drying get powder, packing promptly gets injectable sterile powder.

Embodiments of the invention 8: Radix Paeoniae Rubra total glycosides 80g breviscapine 20g

Get Radix Paeoniae Rubra total glycosides, breviscapine, add an amount of water for injection dissolving, add the glucose or the sodium chloride of ormal weight, by volume add 0.5% active carbon behind the mixed dissolution, boil, keep little 30min that boils, cold slightly filtration, filtrate add the injection water to ormal weight, the saturated sodium hydroxide solution of reuse adjust pH to 6.5～8.0, boil, 4 ℃ of cold preservations are spent the night, and coarse filtration, fine straining add the injection water, packing, sterilization promptly gets glucose or sodium chloride intravenous infusion.

Embodiments of the invention 9: Radix Paeoniae Rubra total glycosides 60g breviscapine 40g

With Radix Paeoniae Rubra total glycosides and Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total glycosides mix homogeneously, add 5% carboxymethyl starch sodium and 1.5% sorbitol, compacting promptly gets oral cavity disintegration tablet in flakes.

Embodiments of the invention 10: Radix Paeoniae Rubra total glycosides 65g breviscapine 35g

With Radix Paeoniae Rubra total glycosides and Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total glycosides mix homogeneously, to be that 1: 1.4 polyethylene glycol 6000 is put in the rustless steel container with the principal agent ratio, add extract, mix homogeneously, be heated to 80-85 ℃, treat whole fusions after, 70-75 ℃ of insulation, mechanical high-speed stirs 15min to even, be transferred in the reservoir, the dropping liquid valve is regulated in 70～75 ℃ of insulations, splash in 30～35 ℃ the kerosene, drip apart from 5～6cm, drip 40～45 droplets/minute of speed, to the greatest extent and wipe kerosene the drop pill drop that forms, packing promptly gets drop pill.

Embodiments of the invention 11: Radix Paeoniae Rubra total glycosides 99g breviscapine 1g

With Radix Paeoniae Rubra total glycosides and breviscapine mix homogeneously, in principal agent: the ratio of adjuvant=1: 1.2 adds calcium sulfate, by principal agent: the ratio adding pregelatinized starch of adjuvant=1.1: 1, and press principal agent: the calcium ammonium alginate of adjuvant=3: 1, evenly mixed, make soft material in right amount with 75% ethanol, cross 20 mesh sieve system granules, 50 ℃ of dryings are taken out, and cross 30 mesh sieve granulate, add an amount of Pulvis Talci, micropowder silica gel, evenly mixed, tabletting promptly gets dispersible tablet.

Embodiments of the invention 12: Radix Paeoniae Rubra total glycosides 1g breviscapine 99g

With Radix Paeoniae Rubra total glycosides and breviscapine mix homogeneously, add 2 times of amount starch, 0.5% lactose, 1.2% microcrystalline Cellulose with an amount of alcoholic solution system soft material, is granulated, and 75 ℃ of forced air dryings are granulated, and granulate promptly gets granule.

Embodiments of the invention 13: Radix Paeoniae Rubra total glycosides 75g breviscapine 25g

With Radix Paeoniae Rubra total glycosides and breviscapine mix homogeneously, add the starch of equivalent, mix homogeneously is granulated, and is encapsulated, promptly gets capsule.

Embodiments of the invention 14: Radix Paeoniae Rubra total glycosides 55g breviscapine 45g

With Radix Paeoniae Rubra total glycosides and breviscapine mix homogeneously, add distilled water, filter repeatedly, till the filtrate clarification., filter with absorbent cotton after the stirring and dissolving in filtrate with sucrose, it is an amount of to add distilled water on filter, shakes up, and promptly gets syrup.

Embodiments of the invention 15: Radix Paeoniae Rubra total glycosides 50g breviscapine 50g

With Radix Paeoniae Rubra total glycosides, breviscapine mix homogeneously, be dissolved in the phosphate buffer (0.1M) standby, a certain proportion of fabaceous lecithin, cholesterol are dissolved in the 18-amine. solution, add in the phosphate-buffered liquor of said medicine, the water-bath type Ultrasound Instrument is handled 10min, gets liposome turbid liquor, the phosphate buffer standardize solution, filtration sterilization, aseptic subpackaged, promptly get lipidosome injection.

Embodiments of the invention 16: Radix Paeoniae Rubra total glycosides 50g breviscapine 50g

With Radix Paeoniae Rubra total glycosides, breviscapine mix homogeneously, be dissolved in the phosphate buffer (0.1M) standby, a certain proportion of fabaceous lecithin, cholesterol are dissolved in the 18-amine. solution, add in the phosphate-buffered liquor of said medicine, the water-bath type Ultrasound Instrument is handled 8min, gets liposome turbid liquor, behind the frozen drying, cross 180 mesh sieves, aseptic subpackaged, promptly get the pro-liposome injectable powder.

Radix Paeoniae Rubra total glycosides among the above embodiment, breviscapine can be with Radix Paeoniae Rubra total glycosides, breviscapines commercially available or that make by the inventive method, no matter be alcohol extract, water extract, water extract-alcohol precipitation extract, semi-bionic extraction thing or supercritical extract etc., but, the content of glycoside composition can guarantee the therapeutic effect of product like this greater than 50% in the Radix Paeoniae Rubra total glycosides.

Claims (11)

1, a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease is characterized in that: calculate according to percentage by weight, it is to be made by Radix Paeoniae Rubra total glycosides 1～99% and breviscapine 99～1% and suitable adjuvant.

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 percentage by weight, it is to be made by Radix Paeoniae Rubra total glycosides 95～50% and breviscapine 5～50% and suitable adjuvant.

3, according to the pharmaceutical composition of claim 1 or 2 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: calculate according to percentage by weight, it is to be made by Radix Paeoniae Rubra total glycosides 90～50%, breviscapine 10～50% and suitable adjuvant.

4, according to the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease of claim 1～3, it is characterized in that: the Radix Paeoniae Rubra total glycosides in the described prescription can be the highly finished product of Radix Paeoniae Rubra alcohol extract, Radix Paeoniae Rubra water extract, Radix Paeoniae Rubra water extract-alcohol precipitation extract, Radix Paeoniae Rubra semi-bionic extraction thing, Radix Paeoniae Rubra supercritical extract or above each extract; Breviscapine can be the highly finished product of Herba Erigerontis alcohol extract, Herba Erigerontis water extract, Herba Erigerontis water extract-alcohol precipitation extract, Herba Erigerontis semi-bionic extraction thing, Herba Erigerontis supercritical extract or above each extract.

5, according to the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease of claim 1～4, it is characterized in that: described composite preparation be directly used in the injection of drug administration by injection, directly for the venous transfusion of intravenous drip, need be used for the concentrated solution for injection of intravenous drip and injectable sterile powder and aseptic block and tablet, capsule, granule, drop pill, pill, soft capsule, oral liquid, oral cavity disintegration tablet or the dispersible tablet that makes with freeze-drying or spray drying method after the dilution.

6, according to the pharmaceutical composition of the described treatment cardiovascular and cerebrovascular disease of claim 5, it is characterized in that: described composite preparation can make on the basis that in Radix Paeoniae Rubra total glycosides, the breviscapine one or both is prepared into liposome or pro-liposome.

7, according to the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease in the claim 1～6, it is characterized in that: contain glycoside composition and breviscapine in the preparation, calculate by weight percentage, in the preparation glycoside component content be not less than deduction breviscapine amount, adjuvant amount and water quantities in the preparation total solid 50%.

8, as the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease in the claim 1～6, it is characterized in that:

A, described breviscapine are preparations like this: get the Herba Erigerontis medical material, adding entry or alcoholic solution after the pulverizing extracts, merge extractive liquid,, filter, concentrate the Herba Erigerontis crude extract, adopt in ethanol precipitation, column chromatography, extraction, the flocculent precipitation one or more to unite on this basis to use carry out suitably refining, breviscapine;

B, described Radix Paeoniae Rubra total glycosides effective site are preparations like this: get the Radix Paeoniae Rubra medical material, adding entry or alcoholic solution after the pulverizing extracts, merge extractive liquid,, filter, concentrate the Radix Paeoniae Rubra crude extract, adopt in ethanol precipitation, column chromatography, extraction, the flocculent precipitation one or more to unite on this basis to use carry out suitably refining, Radix Paeoniae Rubra total glycosides effective site.

9, preparation of drug combination method according to any described treatment cardiovascular and cerebrovascular disease in the claim 1～6, it is characterized in that: the Injectable sterile block of described compositions prepares like this: get Radix Paeoniae Rubra total glycosides, breviscapine and mannitol, add 1800ml water for injection, the mannitol consumption is 1.6g in wherein every 100ml medicinal liquid, stirring makes dissolving, with saturated sodium hydroxide solution adjust pH to 6.5～8.0, add the injection water to 2000ml, mixing, the needle-use activated carbon of adding 0.5% boiled coarse filtration 30 minutes, reuse 0.45 μ m and 0.22 μ m microporous filter membrane filter, the filtrate packing, every bottle of 2.0ml, lyophilization, equilibration time when the balance solidification point of phase I is 0 ℃ is 2 hours, i.e. the time of shelf temperature and product temperature basically identical; The second stage solidification point is from 0 ℃ during to minimum eutectic temperature-19 ℃, and shelf temperature and product temperature equilibration time are 2.5 hours; Phase III continues to be cooled to-45 ℃, needs 2 hours approximately, keeps this temperature 2.5 hours, freeze the jail fully until product, promptly begin evacuation, enter drying program, evacuation under-45 ℃ of constant temperature slowly heats up 2～4 ℃/h, to the lowest total of the melting point temperature, the time is about 10 hours, after sublimation drying is finished, continuation is under the low pressure condition, and it is dry to remove residual moisture to heat up, and the time is about 9～11 hours, kept more than 35 ℃ dry 2 hours, gland, promptly.

10, according to the preparation of drug combination method of the described treatment cardiovascular and cerebrovascular disease of claim 6, it is characterized in that: the pro-liposome of described compositions prepares like this: get Radix Paeoniae Rubra total glycosides, breviscapine, add the phosphate buffer dissolving, add in the fused solution of fabaceous lecithin, cholesterol and 18-amine. mixing, stir supersound process, freezing, the dry powder that obtains sieves, promptly.

11, as the application of the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease in the claim 1～6, it is characterized in that: described compositions is mainly used in the application in disease medicaments such as preparation treatment ischemia apoplexy, angina pectoris, cardiac insufficiency, apoplexy sequela, hepatorenal syndrome, heart and lung diseases, diabetes and complication thereof.