CN1969912A - Pharmaceutical composition for treating cardiovascular and cerebrovascular diseases, preparation process and quality control method thereof - Google Patents

Abstract

The invention provides a pharmaceutical composition for treating cardiovascular and cerebrovascular diseases, its preparing process and quality control method, wherein Dipyridamole and significant parts of herba erigerontis flavones are employed in combination to obtain various dose forms of injections and oral administration preparations. The composite preparation is mainly used for treating cerebral thrombus, cerebral infarction, cerebral hemorrhage, hemiplegia, senile dementia, angina pectoris caused by coronary disease, myocardial infarction, auricular fibrillation, viral myocarditis, pulmonary heart disease, retina venous clogging, hepatorenal syndrome, diabetes and complications. The preparation of the invention has the advantages of high purity, ensured constituents, controllable quality, improved treatment effect, wider range of safely, and less fluctuation of treatment effects.

Description

Pharmaceutical composition of treatment cardiovascular and cerebrovascular disease and preparation method thereof and quality control method

Technical field

The present invention relates to a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease and preparation method thereof and quality control method, belong to technical field of medicaments.

Technical background

Cardiovascular and cerebrovascular disease such as coronary heart disease, angina pectoris, arrhythmia, cerebral thrombosis, apoplexy etc. have become one of key factor that threatens human health.According to investigations, sickness rate constantly increases in recent years, and continuous rejuvenation trend is arranged, in, young patient constantly increases, cardiovascular and cerebrovascular disease has become commonly encountered diseases, the frequently-occurring disease of harm China people ' s health.And at present medicine mainly concentrates on pure Chinese medicinal preparation and Western medicine two aspects, although the prescription of Western medicine is fairly simple, can very fast relief of symptoms, and owing to have certain toxic and side effects, be not suitable for long term administration, it is relatively poor to consolidate curative effect simultaneously; Though the pure Chinese medicinal preparation toxic and side effects is little, but their onset is slow, although some ejection preparations are widely used in the treatment of urgency, serious symptom, also obtain simultaneously certain curative effect, but because quality of the pharmaceutical preparations problem often influences therapeutic effect, though and oral preparation of Chinese traditional medicinal is various in style, indication is also more complete, but because bioavailability is not high, makes troubles for the part patient; Therefore in conjunction with the organic conception of Chinese medicine with consolidate principle and disease characteristics, carry out Chinese medicine and western medicine and be combined into the direction that people begin one's study.Lot of documents report, Herba Erigerontis total flavones have antithrombotic and form, and anticoagulant resists myocardial ischemia, and is mainly used in obliterated cerebral vascular disease clinically, the treatment of cardiovascular and cerebrovascular disease such as paralyse after coronary heart disease, angina pectoris, vasculitis, the apoplexy; Dipyridamole has anticoagulant, effects such as antithrombotic formation, be widely used in the treatment of cardiovascular and cerebrovascular diseases such as myocardial ischemia, angina pectoris, cerebral thrombosis, clinical discovery, fleabane preparation such as Herba Erigerontis injection determined curative effect, but existing preparation common oral preparation bioavailability is low, and day clothes number of times is more, the normal injection preparation administration half-life is short, eliminate in the body rapidly, curative effect has certain undulatory property simultaneously, and dipyridamole is unsuitable for taking for a long time because untoward reaction is arranged; 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 objective of the invention is to: a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease is provided, this pharmaceutical composition is by dipyridamole and Herba Erigerontis total flavones effective site prescription, definite ingredients, quality controllable, can anticoagulant, again can replenishing qi and promoting blood flow, treating both the principal and secondary aspects of a disease, produce obvious synergism, curative effect obviously improves; The present invention also aims to provide the preparation method and the quality control method of this pharmaceutical composition different dosage form; At 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, blood stasis causes the diseases induced principle of blood supply insufficiency, on the basis of experiment screening, adopt dipyridamole and Herba Erigerontis total flavones compatibility to make preparation, optimize best prescription and technology, the product that obtains, show through pharmacodynamics test, Synergistic, more independent fleabane preparation, the dipyridamole formulation curative effect all is significantly increased.

The technical solution adopted in the present invention is:

A kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease calculates according to parts by weight, and it is mainly to be made for 0.01～50 part by 1 part of dipyridamole and Herba Erigerontis total flavones.Specifically, calculate according to parts by weight, it is mainly to be made for 0.1～10 part by 1 part of dipyridamole and Herba Erigerontis total flavones.Preferred prescription is: calculate according to parts by weight, it is mainly to be made for 1～5 part by 1 part of dipyridamole and Herba Erigerontis total flavones.

Described combination dosage form be directly used in the injection of drug administration by injection, directly for the venous transfusion of intravenous drip, need to be used for after the dilution all acceptable dosage forms on the pharmaceuticss such as the concentrated solution for injection of intravenous drip and the injectable sterile powder that makes with freeze-drying or spray drying method and aseptic block and tablet, capsule, granule, drop pill, pellet, pill, soft capsule, oral liquid, oral cavity disintegration tablet, dispersible tablet, membrane, sublingual lozenge.Preferred dosage form comprise the injection that is directly used in drug administration by injection, directly for the venous transfusion of intravenous drip, need to be used for after the dilution concentrated solution for injection of intravenous drip and the injectable sterile powder that makes with freeze-drying or spray drying method and aseptic block and drop pill, pellet, oral liquid, oral cavity disintegration tablet, dispersible tablet, sublingual lozenge.

Described composite preparation can make on the basis that in Herba Erigerontis total flavones and the dipyridamole one or both is prepared into liposome or pro-liposome.

Herba Erigerontis total flavones effective site is commercially available or adopts following method to prepare in the present composition: get the Herba Erigerontis medical material, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Herba Erigerontis crude extract, adopt on this basis ethanol precipitation, water return in molten method, column chromatography, extraction, the flocculent precipitation one or more unite use carry out suitably refining, Herba Erigerontis total flavones effective site.

Calculate by weight percentage, the content of flavones ingredient is not less than in the preparation 50% of total solid after deduction dipyridamole amount, pharmaceutical adjunct amount and the water quantities in the oral formulations, and the content of flavones ingredient is not less than 70% of total solid after deduction dipyridamole amount, pharmaceutical adjunct amount and the water quantities in the ejection preparation; Dipyridamole content should be 90.0%～110.0% of preparation labelled amount.

The Injectable sterile block prepares like this: get dipyridamole, add the stirring of 0.5% tartaric acid or citric acid and make it dissolving; Get Herba Erigerontis total flavones and add injection and blunge and make dissolving, two solution are mixed shaking up, filter, filtrate is boiled the active carbon that the back adds 0.5% (W/V), keep little and boiled 30 minutes, cold slightly filtration, filtrate adjust pH to 6.5～8.0, boil, coarse filtration, fine straining are spent the night in cold preservation (4 ℃); Mannitol is added the injection water be mixed with 120mg/ml solution,, filter, add the injection water, packing, lyophilization, pre-freeze temperature-45 ℃, pre-freeze time 10h to ormal weight with above-mentioned filtrate mixing; 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.

The present composition is mainly used in treatment cerebral thrombosis, cerebral infarction, cerebral hemorrhage, post-stroke hemiplegia, diseases such as alzheimer disease, angina pectoris, myocardial infarction, atrial fibrillation, viral myocarditis, pulmonary heart disease, the retinal vein occlusion, hepatorenal syndrome, diabetes and complication thereof.

The method of quality control of the pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease comprises following all or part of content:

(1) finger printing test comprises with the Herba Erigerontis flavones ingredient being characterized as main finger printing;

(2) all or part of differential test method in Herba Erigerontis medical material, scutellarin, the dipyridamole etc.;

(3) content test method of all or part of composition in scutellarin, total flavones, the dipyridamole etc.

Compared with prior art, pharmaceutical composition of the present invention is by dipyridamole and Herba Erigerontis total flavones effective site prescription, the Herba Erigerontis flavones ingredient has tangible antithrombotic and forms, and anticoagulant resists myocardial ischemia, effects such as blood vessel dilating, blood viscosity lowering, microcirculation improvement; But dipyridamole anticoagulant, have effects such as antithrombotic formation, the two all is widely used in the treatment of cardiovascular and cerebrovascular disease, Herba Erigerontis total flavones and dipyridamole prescription, purity height, definite ingredients, quality controllable, it is big to have overcome the fluctuation of pure Chinese medicinal preparation curative effect simultaneously, the shortcoming that the Western medicine untoward reaction is many, can guarantee the stable and drug safety of clinical efficacy, Integrative Chinese-Western, treating both the principal and secondary aspects of a disease, the Synergistic attenuation all is significantly improved with fleabane preparation or dipyridamole formulation curative effect than single.

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

1, myocardial infarction and ischemia model test due to the medicine method

90 of healthy SD rats, body weight 200～250g, the male and female dual-purpose, be divided into 9 groups, grouping sees the following form, every group 10, male and female half and half, give relative medicine shown in the according to the form below, continuous 7 days, after the last administration 1 hour, through with sodium pentobarbital 30mg/kg intravenous anesthesia, one section normal II ECG that leads was write down with the safe BL-420 of alliance type biological function signaling system in fixing back, back of the body position, iv pituitrin 1ug/kg then, 15s after administration, 30s, 1min, 2min, 3min, 4min, 5min, 10min, 15min, 20min writes down the II ECG that leads respectively, and with the T ripple of any time wherein or ST section rising 0.1mv or decline 0.05mv as the positive number of animals of myocardial ischemia, the results are shown in Table 1.

Table 1 pair rat pituitary pituitrin brings out the influence of acute myocardial ischemia

Group	Mus number (only)	The positive number of animals (only) of myocardial ischemia
			0.1: 1 Herba Erigerontis total flavones of 1: 1 Herba Erigerontis total flavones of 5: 1 Herba Erigerontis total flavones of 10: 1 Herba Erigerontis total flavones of 50: 1 Herba Erigerontis total flavones of physiological saline group dipyridamole injection liquid group Erigeron Breviscapus Injection group Herba Erigerontis total flavones-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group 0.01: 1	10 10 10 10 10 10 10 10 10	10 7 6 5 5 2 1 4 3

As shown in Table 1, the medicine of Herba Erigerontis total flavones and the different proportionings of dipyridamole can obviously resist the myocardial ischemia due to the pituitrin, the strong and weak degree of this effect is relevant with the proportioning of medicine, and wherein with Herba Erigerontis total flavones: dipyridamole is that 1～5: 1 prescription pharmacological action is strong and consumption is lower.

2, to the influence of rabbit platelet aggregation

Get 45 of rabbit, body weight 3～5kg, male, be divided into 9 groups, grouping sees the following form, 5 every group, give relative medicine shown in the according to the form below, measure surface activity of blood platelet and aggregation from heart extracting blood before the administration, in auricular vein injection relative medicine or equivalent normal saline, check surface activity of blood platelet or aggregation after 1 hour.The results are shown in Table 2.

The influence of table 2 pair platelet aggregation

Group	Circle tree type (%)		Expansion type (%)		Aggregation number (individual)
							Before the administration	After the administration	Before the administration	After the administration	Before the administration	After the administration
	0.1: 1 Herba Erigerontis total flavones of 1: 1 Herba Erigerontis total flavones of 5: 1 Herba Erigerontis total flavones of 10: 1 Herba Erigerontis total flavones of 50: 1 Herba Erigerontis total flavones of physiological saline group dipyridamole injection liquid group Erigeron Breviscapus Injection group Herba Erigerontis total flavones-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group 0.01: 1	71.5± 2.15 72.3± 5.17 71.6± 5.92 70.8± 5.68 69.8± 5.38 71.6± 6.05 70.4± 5.28 69.5± 6.15 68.7± 5.28	73.6± 2.57 79.8± 5.31 76.4± 5.27 79.5± 5.89 83.1± 5.42 89.5± 7.58 88.2± 5.63 83.6± 5.78 76.9± 6.29	28.5± 2.15 27.7± 5.17 28.4± 5.92 29.2± 5.68 30.2± 5.38 28.4± 6.05 29.6± 5.28 30.5± 6.15 31.3± 5.28	26.4± 2.57 20.2± 5.31 23.6± 5.27 20.5± 5.89 16.9± 5.42 10.5± 7.58 11.8± 5.63 21.8± 5.24 24.4± 4.75	65.8± 2.36 66.1± 4.89 64.2± 6.24 63.7± 5.17 64.8± 4.25 62.9± 5.23 60.4± 5.12 63.7± 3.58 60.5± 4.26							62.5± 2.78 57.6± 4.23 56.8± 4.35 50.4± 5.38 48.2± 4.57 43.5± 8.26 40.2± 7.48 47.2± 6.05 47.8± 5.22

As shown in Table 2, the medicine of Herba Erigerontis total flavones and the different proportionings of dipyridamole can significantly reduce surface activity of blood platelet or aggregation effect, and the strong and weak degree of this effect is relevant with the proportioning of medicine.

Table 1, table 2 show: Herba Erigerontis total flavones compatibility dipyridamole can produce synergistic function, drug effect all is significantly improved than singly using with dosage dipyridamole or Herba Erigerontis total flavones, the medicine of dipyridamole and the different proportionings of Herba Erigerontis total flavones all can significantly increase curative effect, but the strong and weak degree of effect is relevant with the proportioning of medicine; From interpretation, the best proportioning of Herba Erigerontis total flavones and dipyridamole is: 1 part of dipyridamole, 1～5 part of Herba Erigerontis total flavones.

Experimental example 2: injection Study on Forming

2.1pH value is to the influence of injection

For adapting to the Human Physiology needs, consider the character of each constituents in the medicinal liquid simultaneously, the applicant placed 3 months for 40 ℃ the injection of 8 kinds of different pH value, investigated its stability respectively.The results are shown in following table.

PH value	0 month		March
					Clarity	Total flavones (mg/ml)	Clarity	Total phenolic acid (mg/ml)
	5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5	The difference difference is clear and bright clear and bright slightly poor	0.85 0.85 0.85 0.85 0.85 0.85 0.85 0.85	The difference difference is clear and bright clear and bright poor					0.70 0.73 0.78 0.81 0.82 0.83 0.83 0.75

The result shows that the rational pH value scope of the present invention is 6.0～8.0.

2.2 activated carbon dosage influences injection

Injection has the pyrogen material owing to solvent, raw material, container etc. in process of production, and the safety of injection is reduced, and therefore needs to remove the pyrogen material in the process of preparation injection.The applicant adopts active carbon adsorption, and heat of adsorption originality composition helps filter and decolouring simultaneously on the one hand, also can improve the appearance character of preparation, because of active carbon is investigated its consumption.

The activated carbon dosage investigation table

Activated carbon dosage (%)	The total flavones rate of transform (%)	Outward appearance
			0.1 0.5 1.0	70.5 68.2 63.7	Reddish brown red

As seen from table, the three all can satisfy the related request of injection, but from the medicinal liquid outward appearance, select activated carbon dosage be 0.5% and 1.0% proper; Judge that from the rate of transform 0.1% consumption and 0.5% consumption are slightly better, take all factors into consideration above factor, so that be good with the activated carbon decolorizing of medicine liquid volume 0.5%.

2.3 lyophilization conditional filtering

Lyophilization is a veryer long dry run, also is the process of a power consumption simultaneously.An ideal lyophilisation condition not only can make the samples met standard, simultaneously also can save the energy and man-hour, so we are optimized screening to lyophilisation condition, sees Table.

Table lyophilization conditional filtering

Time-temperature (℃)	Condition I	Condition II	Condition III	Cold-trap
					-45 (pre-freeze)-40 (pre-freeze)-40 (vacuumizing)-35 (vacuumizing)-25 (vacuumizing)-15 (vacuumizing) 0 (vacuumizing) 10 (vacuumizing), 20 (vacuumizing) 30 (vacuumizing)	10 - 8 8 8 5 5 2 2 2	- 8 - 8 8 8 5 4 4 4	10 - 10 10 10 5 5 9 2 2	Keep-70 ℃

Experimental result shows: spray bottle, atrophy phenomenon, the finished product appearance character that condition I and condition III make and the equal conformance with standard of moisture appear in condition II gained sample.Consider the practical situation of production, the condition I that the finally selected overall time spent is short, i.e. lyophilization condition is: 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, get finished product.

Experimental example 3: dispersible tablet disintegrating agent screening

The kind of disintegrating agent, quantity directly have influence on the dispersing uniformity of preparation in the dispersible tablet, are the leading indicators of weighing the dispersible tablet quality, thus we to select disintegration time for use be that performance assessment criteria is investigated different disintegrating agents, the results are shown in following table.

The disintegrating agent table of merit rating

Disintegrating agent	With the ointment ratio	Disintegration time (minute)
			Crospolyvinylpyrrolidone low-substituted hydroxypropyl cellulose carboxymethyl starch sodium crospolyvinylpyrrolidone, the low-substituted hydroxypropyl cellulose low-substituted hydroxypropyl cellulose, the microcrystalline Cellulose crospolyvinylpyrrolidone, microcrystalline Cellulose	1∶3 1∶3 1∶3 1∶3 1∶3 1∶3	2.4 2.6 2.8 2.1 2.5 2.3

From the result of above-mentioned test as can be seen, most of disintegrating agent can improve the disintegration time of dispersible tablet, all can reach the requirement of dispersible tablet.But by contrast, after employing crospolyvinylpyrrolidone and the low-substituted hydroxypropyl cellulose combination, the disintegrate best results.

Test example 4: drop pill substrate screening

The inventor is prepared into the required substrate of drop pill to extract and investigates by a large amount of tests, and different etc. with fusion situation, the ball method of double differences of drop pill outward appearance, principal agent and substrate serves as to investigate index, optimizes and has screened the substrate that influence the drop pill quality, and result of the test is as showing.

Method: substrate is put in the small beaker, be heated to 80～90 ℃, after treating whole fusions, the mixed material that adds dipyridamole and Herba Erigerontis total flavones, investigate the fusion situation of substrate and material, (drip the system condition: expect 75 ℃ of temperature, coolant is a dimethicone to the system of dripping to select the fusion situation to write out a prescription preferably, drip apart from 3～7cm, drip 30～45 droplets/minute of speed).

Table substrate screening test

Sequence number	1	2	3	4	5
						It is different that heavy (g) PEG4000 PEG6000 polyoxyl 40 stearate polyethers poloxamer matrix of material and material merge the situation dripping pill outward appearance ball method of double differences	20 40----better smooth, roundness slightly differs from 7.0%	20 30-10--better smooth, roundness 6.5%	20--10-30 relatively poor roundness differ from 8.2%	20-30-10-better matter is soft, roundness 8.6%	20-20--20 better matter are soft, roundness 7.2%

From above table as can be seen, most of substrate can satisfy the needs of preparations shaping, but with the combination condition optimum of PEG4000 and polyoxyethylene monostearate.

Concrete embodiment

Embodiments of the invention 1: dipyridamole 10g Herba Erigerontis total flavones 50g

Get dipyridamole, add the stirring of 0.5% tartaric acid or citric acid and make it dissolving; Get Herba Erigerontis total flavones and add injection and blunge and make dissolving, two solution are mixed shaking up, filter, filtrate is boiled the needle-use activated carbon that the back adds 0.5% (W/V), keep little and boiled 30 minutes, cold slightly filtration, filtrate adjust pH to 6.5～8.0, boil, coarse filtration, fine straining are spent the night in cold preservation (4 ℃); Mannitol is added the injection water be mixed with 120mg/ml solution,, filter, add the injection water, packing, lyophilization, pre-freeze temperature-45 ℃, pre-freeze time 10h to ormal weight with above-mentioned filtrate mixing; 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 to get finished product.Promptly get the aseptic block of lyophilizing that contains 1 part of dipyridamole and 5 parts of Herba Erigerontis total flavones.

Embodiments of the invention 2: dipyridamole 1g Herba Erigerontis total flavones 1g

Get dipyridamole, add the stirring of 0.5% tartaric acid or citric acid and make it dissolving; Get Herba Erigerontis total flavones, add an amount of stirring of injection water and make it dissolving, two medicinal liquid mixings, adding 5mol/L sodium hydroxide solution adjusting pH value is 6.0～8.0, adds the activated needle-use activated carbon of 0.5% (W/V), boils absorption, carbon removal, fine straining, filtrate adds the injection water to ormal weight, spend the night 4 ℃ of cold preservations, coarse filtration, fine straining divide to install in the ampoule bottle sterilization, packing promptly gets the injection with small volume or the concentrated solution for injection that contain 1 part of dipyridamole and 1 part of Herba Erigerontis total flavones.

Embodiments of the invention 3: dipyridamole 10g Herba Erigerontis total flavones 500g

Get dipyridamole and add the injection water, add the stirring of 0.5% tartaric acid and make it dissolving, medicinal liquid is standby; Get Herba Erigerontis total flavones, add an amount of water for injection dissolving, medicinal liquid is standby; Above-mentioned two medicinal liquids are merged, add the glucose or the sodium chloride of ormal weight, by volume add 0.5% needle-use activated carbon behind the mixed dissolution, boil, keep little 30min that boils, cold slightly filtration, filtrate adds the injection water to an amount of, and boil adjust pH to 6.0～8.0,4 ℃ of cold preservations are spent the night, coarse filtration, fine straining add to the full amount of water for injection, packing, sterilization promptly gets the glucose or the sodium chloride intravenous infusion that contain 1 part of dipyridamole and 50 parts of Herba Erigerontis total flavones.

Embodiments of the invention 4: dipyridamole 5g Herba Erigerontis total flavones 50g

Get dipyridamole and add the injection water, add the stirring of 0.2% citric acid and make it dissolving, medicinal liquid is standby; Get Herba Erigerontis total flavones, add an amount of water for injection, stir and make dissolving, medicinal liquid is standby; Above-mentioned two medicinal liquids are merged, adjust pH to 6.5～8.0 add the injection water to ormal weight, 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, divide and install in the enamel tray, lyophilization, the equilibration time when the balance solidification point of phase I is 0 ℃ is 1.5 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-16 ℃, and shelf temperature and product temperature equilibration time are 2 hours; Phase III continues to be cooled to-40 ℃, need 2 hours approximately, kept this temperature 2 hours, freeze the jail fully until product, promptly begin evacuation, enter drying program, under-40 ℃ of constant temperature-evacuation, slowly heat up, 2～4 ℃/h, to the lowest total of the melting point temperature, time is about 12 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 14～16 hours, kept more than 35 ℃ dry 1.5 hours, and under aseptic condition, divided to install in the cillin bottle, promptly get the lyophilizing injectable sterile powder that contains 1 part of dipyridamole and 10 parts of Herba Erigerontis total flavones.

Embodiments of the invention 5: dipyridamole 100g Herba Erigerontis total flavones 1g

Getting dipyridamole, to add injection water and citric acid an amount of, stirs and make it dissolving, and medicinal liquid is standby; Get Herba Erigerontis total flavones, add an amount of water for injection dissolving, medicinal liquid is standby; Above-mentioned two medicinal liquids are merged, by volume add 0.5% active carbon, boil, keep little 30min that boils, cold slightly filtration, filtrate adds the injection water to an amount of, boil adjust pH to 6.5～8.0, and 4 ℃ of cold preservations are spent the night, add to the full amount of water for injection, coarse filtration, fine straining are 180 ℃ in inlet temperature, leaving air temp is 50 ℃, air velocity is a spray drying under the condition of 18ms-1, and packing promptly gets and contains 1 part of dipyridamole and 0.01 part of Herba Erigerontis total flavones spray drying sterilized powder.

Embodiments of the invention 6: dipyridamole 10g Herba Erigerontis total flavones 1g

With dipyridamole and Herba Erigerontis total flavones mix homogeneously, polyvinylpyrrolidone, the stevioside of adding 8% are an amount of, and compacting promptly gets the oral cavity disintegration tablet that contains 1 part of dipyridamole and 0.1 part of Herba Erigerontis total flavones in flakes.

Embodiments of the invention 7: dipyridamole 10g Herba Erigerontis total flavones 30g

With dipyridamole 10g, Herba Erigerontis total flavones 30g, PEG4000 and polyoxyethylene monostearate (3: 1) 80g mix homogeneously, put in the rustless steel container mixing, after being heated to whole fusions, insulation 30min, mechanical high-speed stirs 10min to evenly, is transferred to the drop pill machine, with dimethicone or liquid paraffin is coolant, drip system, collect drop pill, remove the dimethicone or the liquid paraffin on surface, packing promptly gets the drop pill that contains 1 part of dipyridamole and 3 parts of Herba Erigerontis total flavones.

Embodiments of the invention 8: dipyridamole 6g Herba Erigerontis total flavones 30g

With dipyridamole and Herba Erigerontis total flavones mix homogeneously, in principal agent: the ratio of adjuvant=3: 1 adds crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose composite auxiliary material mix homogeneously, the system soft material, granulate, dry, granulate, tabletting promptly gets and contains 1 part of dipyridamole and 5 parts of Herba Erigerontis total flavones dispersible tablets.

Embodiments of the invention 9: dipyridamole 3g Herba Erigerontis total flavones 21g

With dipyridamole and Herba Erigerontis total flavones mix homogeneously, add appropriate amount of starch, dextrin, to granulate, drying adds magnesium stearate, and coating promptly gets the tablet that contains 1 part of dipyridamole and 7 parts of Herba Erigerontis total flavones.

Embodiments of the invention 10: dipyridamole 50g Herba Erigerontis total flavones 0.5g

With dipyridamole 3g and Herba Erigerontis total flavones 24g mix homogeneously, add 3 times of amount starch and 1 times of amount dextrin, mix homogeneously is granulated, drying, granulate, encapsulated, promptly get the capsule that contains 1 part of dipyridamole and 0.01 part of Herba Erigerontis total flavones.

Embodiments of the invention 11: dipyridamole 2.5g Herba Erigerontis total flavones 5g

With dipyridamole and Herba Erigerontis total flavones mix homogeneously, add the vegetable oil of 0.5 times of weight and 1.2% Cera Flava, the dropping preparation method pill, compacting promptly gets and contains 1 part of dipyridamole and 0.5 part of Herba Erigerontis total flavones soft capsule.

Embodiments of the invention 12: dipyridamole 4g Herba Erigerontis total flavones 16g

With dipyridamole, Herba Erigerontis total flavones mixing, add medicinal starch, Celluloasun Microcrystallisatum is an amount of, mixing, the spheronization pill, packing promptly gets the pellet that contains 1 part of dipyridamole and 4 parts of Herba Erigerontis total flavones.

Embodiments of the invention 13: dipyridamole 2g Herba Erigerontis total flavones 8g

With Herba Erigerontis total flavones, dipyridamole 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 14: dipyridamole 8g Herba Erigerontis total flavones 2g

With Herba Erigerontis total flavones, dipyridamole 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.

Dipyridamole among the above embodiment is the commercial goods that can directly buy, Herba Erigerontis total flavones can be with commercially available or Herba Erigerontis alcohol extract provided by the invention, water extract, water extract-alcohol precipitation extract, semi-bionic extraction thing, supercritical extract or the like, but: the content for flavones ingredient in the oral Herba Erigerontis total flavones is not less than 50%, and the content of flavones ingredient is not less than 70% in the Herba Erigerontis total flavones of injection.

Claims (11)

1, a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease is characterized in that: calculate according to parts by weight, it is mainly to be made for 0.01～50 part by 1 part of dipyridamole and Herba Erigerontis total flavones.

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 parts by weight, it is mainly to be made for 0.1～10 part by 1 part of dipyridamole and Herba Erigerontis total flavones.

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 parts by weight, it is mainly to be made for 1～5 part by 1 part of dipyridamole and Herba Erigerontis total flavones.

4, pharmaceutical composition according to any described treatment cardiovascular and cerebrovascular disease of claim 1～3 is characterized in that: described combination dosage form 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, pellet, pill, soft capsule, oral liquid, oral cavity disintegration tablet, dispersible tablet, membrane, all acceptable dosage forms on the pharmaceuticss such as sublingual lozenge.

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

6, according to the pharmaceutical composition of the described treatment cardiovascular and cerebrovascular disease of claim 4～5, it is characterized in that: described composite preparation can make on the basis that in Herba Erigerontis total flavones and the dipyridamole 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: Herba Erigerontis total flavones effective site is commercially available or adopts following method to prepare: get the Herba Erigerontis medical material, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Herba Erigerontis crude extract, adopt on this basis ethanol precipitation, water return in molten method, column chromatography, extraction, the flocculent precipitation one or more unite use carry out suitably refining, Herba Erigerontis total flavones effective site.

8, according to the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease in the claim 4～6, it is characterized in that: calculate by weight percentage, the content of flavones ingredient is not less than in the preparation 50% of total solid after deduction dipyridamole amount, pharmaceutical adjunct amount and the water quantities in the oral formulations, and the content of flavones ingredient is not less than 70% of total solid after deduction dipyridamole amount, pharmaceutical adjunct amount and the water quantities in the ejection preparation; Dipyridamole content should be 90.0%～110.0% of preparation labelled amount.

9, according to the preparation of drug combination method of any described treatment cardiovascular and cerebrovascular disease in the claim 1～5, it is characterized in that: the Injectable sterile block prepares like this: get dipyridamole, add the stirring of 0.5% tartaric acid or citric acid and make it dissolving; Get Herba Erigerontis total flavones and add injection and blunge and make dissolving, two solution are mixed shaking up, filter, filtrate is boiled the needle-use activated carbon that the back adds 0.5% (W/V), keep little and boiled 30 minutes, cold slightly filtration, filtrate adjust pH to 6.5～8.0, boil, coarse filtration, fine straining are spent the night in cold preservation (4 ℃); Mannitol is added the injection water be mixed with 120mg/ml solution,, filter, add the injection water, packing, lyophilization, pre-freeze temperature-45 ℃, pre-freeze time 10h to ormal weight with above-mentioned filtrate mixing; 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.

10, according to 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 used for preparation treatment cerebral thrombosis, cerebral infarction, cerebral hemorrhage, post-stroke hemiplegia, disease medicaments such as alzheimer disease, angina pectoris, myocardial infarction, atrial fibrillation, viral myocarditis, pulmonary heart disease, the retinal vein occlusion, hepatorenal syndrome, diabetes and complication thereof.

11, according to the method for quality control of the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease in the claim 4～6, it is characterized in that: this method comprises following all or part of content:

(1) finger printing test comprises with the Herba Erigerontis flavones ingredient being characterized as main finger printing;

(2) all or part of differential test method in Herba Erigerontis medical material, scutellarin, the dipyridamole etc.;

(3) content test method of all or part of composition in scutellarin, total flavones, the dipyridamole etc.