CN1969917A - 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 total flavones of safflower are employed in combination to obtain various dose forms of injections and oral administration preparations. The composite preparation is mainly used for treating cerebral hemorrhage, cerebral infarction, angina pectoris caused by coronary disease, vasculitis, arrhythmia, pulmonary heart disease, hyperlipemia, diabetic peripheral neuropathy, various cervical vertebra diseases, sclerema neonatorum, fatty liver, and idiopathic edema. The preparation of the invention has the advantages of high purity, ensured constituents, controllable quality, improved curative 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 medicine mainly concentrates on pure Chinese medicinal preparation and Western medicine two aspects at present, and the Western medicine side effect is bigger; Though the pure Chinese medicinal preparation toxic and side effects is little, their onset is slow, influences therapeutic effect; 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.

Lot of documents report, Flos Carthami have antithrombotic and form as Chinese medicine, anticoagulant, and cardiovascular and cerebrovascular disease can be treated or prevent to the effect that resists myocardial ischemia, and all is subjected to medicine circle personage's extensive favor all the time; But owing to all be used as medicine with medical material in the past, not only difficult quality guarantee, dose are big, and the hygiology index is difficult to control; Dipyridamole has the effect of stronger antiplatelet aggregation, is mainly used in the treatment of cardiovascular and cerebrovascular disease, but because Western medicine does not have the such absolute advantages of antibiotic aspect cardiovascular and cerebrovascular disease, so limited in clinical use; For this reason, the inventor adopts the safflower effective part total flavones directly to be used as medicine, the compatibility dipyridamole is examined or check its moulding process and drug action, further investigate the compatibility optimal proportion scope of Flos Carthami total flavone and dipyridamole simultaneously, for the extensive use more of Flos Carthami preparation and dipyridamole formulation provides possibility, for the patient provides a kind of more safe and effective, the curative effect fluctuation range is little, the pharmaceutical preparation that toxic and side effects is little simultaneously.

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 preparation method thereof and method of quality control are provided, this pharmaceutical composition is mainly by dipyridamole and Flos Carthami total flavones 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 Flos Carthami total flavone compatibility to make preparation, optimize best prescription and technology, the product that obtains, show through pharmacodynamics test, Synergistic, more independent Flos Carthami preparation such as Flos Carthami injection, dipyridamole formulation such as dipyridamole injection liquid, 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 0.1～100 part by 1 part of and Flos Carthami total flavones of dipyridamole.Specifically, calculate according to parts by weight, it is mainly to be made for 0.5～50 part by 1 part of and Flos Carthami total flavones of dipyridamole.Preferably, calculate according to parts by weight, it is mainly to be made for 1～10 part by 1 part of and Flos Carthami total flavones of dipyridamole.

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 Flos Carthami total flavone and the dipyridamole one or both is prepared into liposome or pro-liposome.

Flos Carthami total flavone effective site is commercially available or adopts following method to prepare: get flos carthami, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Flos Carthami 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, Flos Carthami total flavone 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 injection water, tartarize or citric acid stir and make it dissolving, and medicinal liquid is standby; Get Flos Carthami total flavone and add injection and blunge and make dissolving, filter filtrate for later use; Above-mentioned two medicinal liquids are merged, boil the active carbon that the back adds 0.5% (W/V), keep little and boiled 30 minutes, cold slightly filtration, boil filtrate adjust pH to 5.5～7.0, and 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; And in 12～72 hours differential gradient increased temperature to 10 ℃ progressively, keep 2h, be warming up to 20 ℃, keep 2h, be warming up to 30 ℃, keep 2h, promptly.

Compositions of the present invention is mainly used in diseases such as treatment cerebral hemorrhage, cerebral infarction, angina pectoris, vasculitis, arrhythmia, pulmonary heart disease, hyperlipidemia, diabetic peripheral neuropathy, each myelopathy, neonatal scleredema, sudden deafness, Meniere, fatty liver, idiopathic edema.

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

(1) finger printing test comprises with safflower flavonoids being characterized as main finger printing;

(2) all or part of differential test method in flos carthami, Carthamus yellow, HONGHUAMINGGAN A, the dipyridamole;

(3) content test method of all or part of composition in Carthamus yellow, HONGHUAMINGGAN A, total flavones, the dipyridamole.

Compared with prior art, Flos Carthami single preparations of ephedrine such as Flos Carthami injection and dipyridamole formulation such as dipyridamole injection liquid are widely used at the treatment treating cardiac and cerebral vascular diseases, but clinical practice is found, Flos Carthami injection is owing to be used as medicine with flos carthami, clinical use curative effect undulatory property is bigger, and dipyridamole is owing to there is certain toxic and side effects, and clinical frequency of utilization is limited, up to now, do not find the preparation and the relevant report of the two prescription.The applicant is with dipyridamole and Flos Carthami total flavones prescription, further investigate discovery, the two compatibility energy Synergistic attenuation, be used as medicine with total flavones owing to Flos Carthami simultaneously, the purity height, definite ingredients, technology is rationally feasible, stable and controllable for quality, 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 be guaranteed the stable and drug safety of clinical efficacy, Flos Carthami total flavone compatibility dipyridamole treating both the principal and secondary aspects of a disease, the Synergistic attenuation, with respect to Flos Carthami, the independent preparation of dipyridamole not only safety effectiveness aspect has very big raising, and uses and to carry all easily, and the preparation method of multiple different dosage form is provided, be suitable for different crowd and use, avoided dosage form single to hospitalized patients bring unfavorable.

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
			0.5: 1 safflower total flavone of 1: 1 safflower total flavone of 10: 1 safflower total flavones of 50: 1 safflower total flavones of 100: 1 safflower total flavones of physiological saline group dipyridamole injection liquid group Sofflower injection group safflower total flavone-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group 0.1: 1	10 10 10 10 10 10 10 10 10	10 8 7 5 3 1 1 3 2

As shown in Table 1, the medicine of Flos Carthami total flavone and the different proportionings of dipyridamole all can obviously resist the myocardial ischemia due to the pituitrin, and wherein with Flos Carthami total flavone: dipyridamole=1～10: 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
	0.5: 1 safflower total flavone of 1: 1 safflower total flavone of 10: 1 safflower total flavones of 50: 1 safflower total flavones of 100: 1 safflower total flavones of physiological saline group dipyridamole injection liquid group Sofflower injection group safflower total flavone-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group 0.1: 1	75.1± 3.07 69.4± 2.58 70.1± 2.36 67.2± 4.12 68.5± 3.69 69.3± 4.62 68.8± 4.32 68.1± 3.69 67.1± 4.21	79.3± 2.89 77.5± 3.22 75.3± 4.67 78.3± 3.82 81.2± 5.16 90.3± 7.56 87.5± 8.34 83.6± 6.48 82.9± 6.37	24.9± 3.07 30.6± 2.58 29.9± 2.36 32.8± 4.12 31.5± 3.69 30.7± 4.62 31.2± 4.32 31.9± 3.69 32.9± 4.21	20.7± 2.89 22.5± 3.22 24.7± 4.67 21.7± 3.82 18.8± 5.16 9.7± 7.56 12.5± 8.34 16.4± 6.48 17.1± 6.37	62.5± 5.36 65.1± 4.68 64.7± 5.67 63.7± 5.36 65.5± 6.32 63.7± 7.11 62.5± 6.58 61.4± 5.36 60.2± 4.98							55.7± 6.91 56.2± 7.28 56.1± 8.21 53.7± 7.54 46.1± 8.64 39.5± 8.74 41.8± 8.25 43.7± 6.97 45.1± 7.28

As shown in Table 2, the medicine of Flos Carthami total flavone 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: Flos Carthami total flavone compatibility dipyridamole can produce synergistic function, drug effect all is significantly improved than singly using with dosage dipyridamole or Flos Carthami total flavone, the medicine of the different proportionings of dipyridamole and Flos Carthami 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 Flos Carthami total flavone and dipyridamole is: 1 part of dipyridamole, 1～10 part of Flos Carthami total flavone.

Experimental example 2: injection Study on Forming

2.1pH value is to the influence of injection

The applicant finds that in development suitable acid-base value is the stable key factor of medicine, and in order to improve the quality of this injection, the applicant placed 3 months for 40 ℃ the injection of 6 kinds of different pH value, investigated its stability respectively.

PH value	0 month		March
					Clarity	Total flavones (mg/ml)	Clarity	Total flavones (mg/ml)
	5.0 5.5 6.0 6.5 7.0 7.5 8.0	Poor slightly clear and bright poor slightly	15.8 15.8 15.8 15.8 15.8 15.8 15.8	Difference is clear and bright poor					10.1 13.5 14.0 14.5 15.1 11.5 10.4

The result shows that the rational pH value scope of the present invention is 5.5～7.0.

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
			0.2 0.6 1.2	86.7 80.1 74.5	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 0.6% and 1.2% proper; Judge that from the rate of transform 0.2% consumption and 0.6% consumption are slightly better, take all factors into consideration above factor, so that be good with the activated carbon decolorizing of medicine liquid volume 0.6%.

2.3pH value is to the influence of freeze-dried powder

Numbering	1	2	3	4	5	6	7	8
									PH value of solution after the lyophilizing of pH value of solution mouldability color and luster before the lyophilizing	5.0 difference yellowish 4.6	5.5 good yellowish 5.3	6.0 good yellowish 5.7	6.5 good yellowish 6.3	7.0 slightly good yellowish 6.8	7.5 difference yellowish 7.0	8.0 difference yellowish-brown 7.4	8.5 difference yellowish-brown 8.0

The result shows that the rational pH value scope of the present invention is 5.5～7.0.

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 2.5 2.7 2.1 2.4 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.

Experimental example 4: drop pill substrate screening

Drip distance, drip selection fast, temperature: drip footpath 2.5m/2mm.Evaluation index: the heavy qualification rate of ball is by mass discrepancy requirement of Pharmacopoeia of the People's Republic of China version in 2000: meet ± 7.5% within.

Drip distance, drip selection fast, temperature

Group	Temperature/℃	Drip distance/cm	Liquid coolant height/cm	Heavy qualification rate/the % of ball
					1 2 3 4 5 6 7 8 9	90 90 90 80 80 80 70 70 70	4 5 8 4 5 8 4 5 8	60 70 80 70 80 60 80 60 70	70.2 66.8 76.1 85.3 90.7 89.2 75.3 94.3 71.2

The result shows, the optimum condition of preparation drop pill of the present invention: drip apart from 5cm, water dropper bore 2.5mm/2mm mixes 70 ℃ of ointment temperature, liquid coolant height 60cm.

Embodiment 5: soft capsule technology is investigated

Soft capsule disintegrate in gastrointestinal tract is fast, and after softgel shell broke, medicine disperseed rapidly, so the drug release stripping is fast, produce effects is rapid, the bioavailability height; Semi-transparent soft capsule can protect medicine not to be subjected to the effect of oxygen, light in dampness and the air with packaging material preferably, thereby improves the stability of labile element; So capsular stability and moulding process are very crucial technology.

5.1 disperse medium (or claiming substrate) is selected

At fill material and substrate energy mix homogeneously, and under the prerequisite of unobstructed defeated material of energy and pelleting, reduce substrates quantity as far as possible.By test of many times, determine medication amount (g): substrate amount (g)=be advisable at 1: 1.5, experimental result sees Table.

Substrates quantity is investigated

Medication amount (g): substrate amount (g) 1: 11: 1.5 1: 2

Big, the mobile difference viscosity of quality of liquid medicine viscosity, all good differences in viscosity of flowability are mobile big

5.2 opacifier is selected

The transparent adhesive tape softgel shell easily causes instability, so need to add a certain amount of opacifier.Select titanium dioxide (titanium dioxide) to make opacifier through investigation and can reach effective shaded effect, and steady quality, not with rubber cement and fill material generation chemical change.Its consumption is through investigating with gelatin: glycerol: water: titanium dioxide=100g: 40g: 100g: 1g is advisable, and little to the rubber quality influence, the results are shown in Table.

The opacifier consumption is selected

Usage ratio	The rubber transparency	Rubber cement viscosity (Mpas)	Overall merit
				Gelatin 100g: glycerol 40g: water 100g: titanium dioxide 0.5g gelatin 100g: glycerol 40g: water 100g: titanium dioxide 1g gelatin 100g: glycerol 40g: water 100g: titanium dioxide 2g gelatin 100g: glycerol 40g: water 100g: titanium dioxide 3g	Translucent opaque	3.25 3.45 3.60 3.75	The big viscosity of the good inadequately viscosity of consumption is bigger

Quality is more stable after adding opacifier in the soft capsule prescription.

5.3 batchingization glue is investigated

By aforementioned preferred prescription is gelatin: glycerol: water: titanium dioxide=100g: 40g: 100g: the 1g weigh batching with different temperatures glue, the results are shown in Table.

Changing the glue temperature investigates

Temperature (℃)	Change the glue time (H)	The rubber quality
			50 60 70 80 90	6 5 5 5 4	Good have bubble than the ebonite skin carefully, hard

By the table prompting, it is the most suitable with 60～70 ℃ to change the glue temperature.So batchingization adhesive tape part is: weigh batching, in the inputizations glue jar, merceration is warming up to 65 ± 5 ℃ gradually after 30 minutes, stirs 5 hours also the while evacuation except that bubble, treat sizing material even after blowing, incapsulate after the filtration in the sizing material bucket of machine.

Concrete embodiment

Embodiments of the invention 1: dipyridamole 5g Flos Carthami total flavone 50g

Get dipyridamole, add the injection water, add the stirring of 5% citric acid and make it dissolving, medicinal liquid is standby; Get Flos Carthami total flavone and add injection and blunge and make dissolving, filter filtrate for later use; Above-mentioned two medicinal liquids are merged, boil the active carbon that the back adds 0.6% (W/V), keep little and boiled 30 minutes, cold slightly filtration, boil filtrate adjust pH to 5.5～7.0, and 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; And in 12～72 hours differential gradient increased temperature to 10 ℃ progressively, keep 2h, be warming up to 20 ℃, keep 2h, be warming up to 30 ℃, keep 2h, promptly get the Injectable sterile block that contains 10 parts of Flos Carthami total flavones and 1 part of dipyridamole.

Embodiments of the invention 2: dipyridamole 10g Flos Carthami total flavone 500g

Get dipyridamole, add the injection water, add the stirring of 0.5% tartaric acid and make it dissolving, medicinal liquid is standby; Get Flos Carthami total flavone and add injection and blunge and make dissolving, filter filtrate for later use; Above-mentioned two medicinal liquids are merged, and regulating pH value is 5.5～7.0, adds 0.6% activated needle-use activated carbon, boil 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 50 parts of Flos Carthami total flavones and 1 part of dipyridamole.

Embodiments of the invention 3: dipyridamole 1g Flos Carthami total flavone 100g

Get dipyridamole and add the injection water, add the stirring of 0.4% tartaric acid and make it dissolving, medicinal liquid is standby; Get Flos Carthami total flavone, 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 5.5～7.0,4 ℃ 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 100 parts of Flos Carthami total flavones.

Embodiments of the invention 4: dipyridamole 25g Flos Carthami total flavone 25g

Get dipyridamole and add the injection water, add the stirring of 0.2% citric acid and make it dissolving, medicinal liquid is standby; Get Flos Carthami total flavone, 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 5.5～7.0 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 1 part of and Flos Carthami total flavones of dipyridamole.

Embodiments of the invention 5: dipyridamole 16g Flos Carthami total flavone 8g

Getting dipyridamole, to add injection water and citric acid an amount of, stirs and make it dissolving, and medicinal liquid is standby; Get Flos Carthami total flavone, 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 5.5～7.0, 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 0.5 part of Flos Carthami total flavone spray drying sterilized powder.

Embodiments of the invention 6: dipyridamole 50g Flos Carthami total flavone 5g

With dipyridamole and Flos Carthami total flavone mix homogeneously, polyvinylpyrrolidone, 3% polyvinylpolypyrrolidone, the lemon yellow of adding 5% are an amount of, and compacting promptly gets the oral cavity disintegration tablet that contains 1 part of dipyridamole and 0.1 part of Flos Carthami total flavone in flakes.

Embodiments of the invention 7: dipyridamole 10g Flos Carthami total flavone 20g

With dipyridamole 10g, Flos Carthami total flavone 20g, PEG4000 and polyoxyethylene monostearate (3: 1) 60g mix homogeneously, put in the rustless steel container, mixing, after being heated to whole fusions, insulation 30min, mechanical high-speed stirs 10min to even, drip and in dimethicone or liquid paraffin, to become ball, drip apart from 5cm drip footpath 2.5mm/2mm, mix 70 ℃ of ointment temperature, liquid coolant height 60cm collects drop pill, removes the dimethicone or the liquid paraffin on surface, packing promptly gets the drop pill that contains 1 part of dipyridamole and 2 parts of Flos Carthami total flavones.

Embodiments of the invention 8: dipyridamole 2g Flos Carthami total flavone 12g

With dipyridamole and Flos Carthami total flavone mix homogeneously, in principal agent: the ratio of adjuvant=1: 1 adds calcium carbonate, in principal agent: the ratio of adjuvant=3: 1 adds crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose composite auxiliary material mix homogeneously, and the system soft material is granulated, dry, granulate adds an amount of Pulvis Talci, micropowder silica gel, and is evenly mixed, tabletting promptly gets and contains 1 part of dipyridamole and 6 parts of Flos Carthami total flavone dispersible tablets.

Embodiments of the invention 9: dipyridamole 3g Flos Carthami total flavone 21g

With dipyridamole and Flos Carthami total flavone mix homogeneously, add appropriate amount of starch, dextrin and an amount of Celluloasun Microcrystallisatum, to granulate, drying adds 3% magnesium stearate, and sugar coating or film-coat promptly get the tablet that contains 1 part of dipyridamole and 7 parts of Flos Carthami total flavones.

Embodiments of the invention 10: dipyridamole 7g Flos Carthami total flavone 21g

With dipyridamole 3g and Flos Carthami total flavone 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 3 parts of Flos Carthami total flavones.

Embodiments of the invention 11: dipyridamole 2g Flos Carthami total flavone 12g

With dipyridamole and Flos Carthami total flavone mix homogeneously, press medication amount: substrate amount=1: 1.5 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 65 ± 5 ℃ gradually after 30 minutes, stirred 5 hours and simultaneously evacuation remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; The debugging pellet press, pelleting, drying promptly gets and contains 1 part of dipyridamole and 6 parts of Flos Carthami total flavone soft capsules.

Embodiments of the invention 12: dipyridamole 15g Flos Carthami total flavone 30g

With dipyridamole, Flos Carthami total flavone mixing, add 5 times of amount dextrin, 2 times of amount magnesium stearate, 1 times of amount microcrystalline Cellulose, mixing is granulated, and packing promptly gets the granule that contains 1 part of dipyridamole and 2 parts of Flos Carthami total flavones.

Embodiments of the invention 13: dipyridamole 1g Flos Carthami total flavone 6g

With dipyridamole, Flos Carthami total flavone mixing, drying adds appropriate amount of starch, ethanol with 65% and 1.8% soybean oil system soft material, and extruding-round as a ball pill selects ball, and drying promptly gets the pellet that contains 1 part of dipyridamole and 6 parts of Flos Carthami total flavones.

Embodiments of the invention 14: dipyridamole 1g Flos Carthami total flavone 10g

With Flos Carthami total flavone, 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 15: dipyridamole 10g Flos Carthami total flavone 10g

With Flos Carthami total flavone, 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.

Embodiments of the invention 16: dipyridamole 1g Carthamus yellow 10g

Get dipyridamole, add the injection water, add the stirring of 5% citric acid and make it dissolving, medicinal liquid is standby; Get Carthamus yellow and add injection and blunge and make dissolving, filter filtrate for later use; Above-mentioned two medicinal liquids are merged, boil the active carbon that the back adds 0.6% (W/V), keep little and boiled 30 minutes, cold slightly filtration, boil filtrate adjust pH to 5.5～7.0, and 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 to ormal weight with above-mentioned filtrate mixing, packing, lyophilization promptly gets the Injectable sterile block.

Embodiments of the invention 2: dipyridamole 1g Carthamus yellow 20g

Get dipyridamole, add the injection water, add the stirring of 0.5% tartaric acid and make it dissolving, medicinal liquid is standby; Get Flos Carthami total flavone and add injection and blunge and make dissolving, filter filtrate for later use; Above-mentioned two medicinal liquids are merged, and regulating pH value is 5.5～7.0, adds 0.6% activated needle-use activated carbon, boil 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 injection with small volume or concentrated solution for injection.

Dipyridamole among the above embodiment is the commercial goods that can directly buy, Flos Carthami total flavone can be with commercially available or Flos Carthami 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 Flos Carthami total flavone is not less than 50%, and the content of flavones ingredient is not less than 70% in the Flos Carthami total flavone 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 0.1～100 part by 1 part of and Flos Carthami total flavones of dipyridamole.

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 0.5～50 part by 1 part of and Flos Carthami total flavones of dipyridamole.

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 1～10 part by 1 part of and Flos Carthami total flavones of dipyridamole.

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 Flos Carthami total flavone 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: Flos Carthami total flavone effective site is commercially available or adopts following method to prepare: get flos carthami, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Flos Carthami 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, Flos Carthami total flavone 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 pharmaceutical composition 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 injection water, tartarize or citric acid stir and make it dissolving, and medicinal liquid is standby; Get Flos Carthami total flavone and add injection and blunge and make dissolving, filter filtrate for later use; Above-mentioned two medicinal liquids are merged, boil the active carbon that the back adds 0.6% (W/V), keep little and boiled 30 minutes, cold slightly filtration, boil filtrate adjust pH to 5.5～7.0, and 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; And in 12～72 hours differential gradient increased temperature to 10 ℃ progressively, 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 disease medicaments such as preparation treatment cerebral hemorrhage, cerebral infarction, angina pectoris, vasculitis, arrhythmia, pulmonary heart disease, hyperlipidemia, diabetic peripheral neuropathy, each myelopathy, neonatal scleredema, sudden deafness, Meniere, fatty liver, idiopathic edema.

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 safflower flavonoids being characterized as main finger printing;

(2) all or part of differential test method in flos carthami, Carthamus yellow, HONGHUAMINGGAN A, the dipyridamole;

(3) content test method of all or part of composition in Carthamus yellow, HONGHUAMINGGAN A, total flavones, the dipyridamole.