CN1969919A - 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 Troxerutin and barren wort flavones are employed in combination to obtain various dose forms of injections and oral administration preparations. The composite preparation is mainly used for treating coronary disease, angina pectoris, arrhythmia, cerebral thrombus, cerebral ischemia, hypertension, thrombotic phlebitis, capillary vessel hemorrhage, and decreased immune function.

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

At present, dead about 4,000,000 people of the annual cardiovascular and cerebrovascular disease of China account for more than 3/5 of death toll, have become the primary factor that threatens human health.Although a large amount of Chinese medicine and western medicine interviews are arranged at present, but the continuous variation and the arrival at aging age along with spectrum of disease, medicine constantly demonstrates its limitation at present, and for this reason, the medicine of this major disease of research and development treatment cardiovascular and cerebrovascular vessel just becomes focus and the focus that people pay close attention to all the time.

The lot of documents report, Herba Epimedii total flavones can suppress myocardial contraction, and can obviously reduce Peripheral resistance, and left chamber output is increased, reduce cardiac load, increase peripheral organ's perfusion, blood vessel dilating brings high blood pressure down, and improves cerebral ischemia and cerebral anoxia, in significantly reducing, the whole blood viscosity under the low shear rate, reduce adhering to the angle and reducing erythrocyte aggregation, blood fat reducing, blood sugar lowering promote bone growth, stop calcium loss, prevention of osteoporosis has gonadotropic Effect, defying age, antiinflammatory, antiviral, effects such as antitumor; But because marketed drug is used as medicine with medical material mostly, quality is difficult to guarantee that dose is big, the bad control of hygiology index, and the curative effect fluctuation is bigger; Troxerutin can anticoagulant, prevents thrombotic effect, and the blood vessel injury that can cause medmain, Kallidin I increases capillary resistance simultaneously, reduces capillary permeability, can prevent the edema that vascular permeability raises and causes; Be mainly used in ischemic cerebrovascular (as cerebral thrombosis, cerebral embolism), thrombophlebitis, central serous chorioretinopathy, vascular permeability increase due to disease such as edema; But because troxerutin has certain side effect, so limited in clinical use; For this reason, the inventor adopts Herba Epimedii total flavones effective site directly to be used as medicine, the compatibility troxerutin is examined or check its moulding process and drug action, further investigate the compatibility optimal proportion scope of Herba Epimedii total flavones and troxerutin simultaneously, for the extensive use more of Herba Epimedii preparation and troxerutin preparation 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

In view of above situation, the objective of the invention is to disclose a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease, adopt Herba Epimedii total flavones and troxerutin prescription, the applicant finds by further investigation, be used as medicine with the effective site Herba Epimedii total flavones, definite ingredients, quality controllable, the compatibility troxerutin, can anticoagulant, again can replenishing qi and promoting blood flow, treating both the principal and secondary aspects of a disease produces obvious Synergistic Attenuation; The present invention also aims to provide the preparation method and the quality control method of this pharmaceutical composition different dosage form; Comprise multiple injection type and peroral dosage form, effectively avoided the single inconvenience that brings of dosage form of present doctors and patients' medication, simultaneously stable and controllable for quality, satisfy the selection of clinician and extensive patients to a greater degree; A series of experiments have been carried out, to guarantee stability of formulation, safety and effectiveness.

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 mainly is made for 0.01～10 part by 1 part of troxerutin and Herba Epimedii total flavones.Say that exactly calculate according to parts by weight, it mainly is made for 0.05～5 part by 1 part of troxerutin and Herba Epimedii total flavones.Preferred prescription is: calculate according to parts by weight, it mainly is made for 0.1～2 part by 1 part of troxerutin and Herba Epimedii 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 Epimedii total flavones and the troxerutin one or both is prepared into liposome or pro-liposome.

Herba Epimedii total flavones effective site is commercially available preparing with the following method of employing: get epimedium herb, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Herba Epimedii 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 Epimedii 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 troxerutin 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 troxerutin amount, pharmaceutical adjunct amount and the water quantities in the ejection preparation; Troxerutin content should be 90.0%～110.0% of preparation labelled amount.

The Injectable sterile block prepares like this: get troxerutin, Herba Epimedii total flavones adds injection and blunges and make dissolving, filter, filtrate is boiled the active carbon that the back adds 0.6% (W/V), keeps little and boils 30 minutes, cold slightly filtration, filtrate adjust pH to 5.5～7.0, 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; 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.

Described pharmaceutical composition is mainly used in diseases such as coronary heart disease, angina pectoris, arrhythmia, cerebral thrombosis, cerebral ischemia, hypertension, thrombophlebitis, capillary hemorrhage, immunologic hypofunction.

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 the finger printing based on the Herba Epimedii total flavones composition characteristics;

(2) epimedium herb, icariin, icariside I, Herba Epimedii glycosides A, B, C, all or part of differential test method in Quercetin, the troxerutin;

(3) icariin, icariside I, Herba Epimedii glycosides A, B, C, the content test method of all or part of composition in Quercetin, total flavones, the troxerutin.

Compared with prior art, the preparation that great majority contain Herba Epimedii is used as medicine with medical material, cause the same preparation of different manufacturers that bigger difference is arranged, clinical use curative effect undulatory property is bigger, troxerutin is owing to there is certain side effect, clinical use is limited, up to now, does not find the preparation and the relevant report of the two prescription.The applicant is with troxerutin and Herba Epimedii total flavones prescription, by thrombotic model test and PAgT, these two kinds of medicines have been carried out the prescription screening test of system, found that Herba Epimedii total flavones: troxerutin=0.1～2: 1 prescription pharmacological action is strong and consumption is lower, preparations shaping and having good stability, and both compatibilities can reach the effect of efficacy enhancing and toxicity reducing.Be used as medicine with total flavones owing to Herba Epimedii 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 guarantee the stable and drug safety of clinical efficacy, Herba Epimedii total flavones compatibility troxerutin treating both the principal and secondary aspects of a disease, the Synergistic attenuation is with respect to Herba Epimedii, troxerutin preparation not only safety effectiveness aspect has very big raising, and use is carried all very convenient, the preparation method of multiple different dosage form is provided, has been suitable for different crowd and uses, 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, thrombotic model test due to the medicine method

144 of healthy male mices; body weight 25～35g; be divided into 9 groups; grouping sees the following form, and 16 every group, gives relative medicine shown in the according to the form below; the derivant that mixes of gastric infusion tail vein injection collagen protein after 1 hour (250 μ g/ only) and epinephrine (9 little μ g/); promptly observe dead mouse number within 5 minutes after the injection or the not recovery number of mice hemiplegia in 15 minutes, calculate the protective rate of medicine, the results are shown in Table 1 the mouse brain thrombosis.

The influence that the inductive mice thrombus in vivo of table 1 pair collagen protein-epinephrine forms

Group	Mus number (only)	Recover number (only) in the 15min	Recovery rate (%)
				0.05: 1 barren wort total chromocor of 0.1: 1 barren wort total chromocor of 2: 1 barren wort total chromocors of 5: 1 barren wort total chromocors of 10: 1 barren wort total chromocors of physiological saline group troxerutin injection group barren wort total chromocor group barren wort total chromocor-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group 0.01: 1	16 16 16 16 16 16 16 16 16	0 9 8 10 12 14 13 11 10	0 56.3 50.0 62.5 75.0 87.5 81.3 68.8 62.5

As shown in Table 1, the medicine of Herba Epimedii total flavones and the different proportionings of troxerutin has protective effect to the inductive mice thrombus in vivo of collagen protein-epinephrine, and the strong and weak degree of this effect is relevant with the proportioning of medicine.Wherein with Herba Epimedii total flavones: troxerutin=0.1～2: 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
	0.05: 1 barren wort total chromocor of 0.1: 1 barren wort total chromocor of 2: 1 barren wort total chromocors of 5: 1 barren wort total chromocors of 10: 1 barren wort total chromocors of physiological saline group troxerutin injection group barren wort total chromocor group barren wort total chromocor-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group 0.01: 1	76.1± 3.27 73.4± 2.61 72.8± 3.82 71.8± 5.13 72.3± 4.57 73.7± 3.62 70.6± 4.36 72.6± 3.36 73.2± 4.38	78.5± 4.03 82.1± 3.58 79.2± 4.26 83.6± 4.37 86.5± 5.87 92.1± 6.72 86.7± 5.82 87.1± 7.25 84.1± 5.33	23.9± 3.27 26.6± 2.61 27.2± 3.82 28.2± 5.13 27.7± 4.57 26.3± 3.62 29.4± 4.36 27.4± 3.36 26.8± 4.38	21.5± 4.03 17.9± 3.58 20.8± 4.26 16.4± 4.37 13.5± 5.87 8.9± 6.72 13.3± 5.82 12.9± 7.25 15.9± 5.33	68.3± 2.43 66.7± 3.26 63.4± 3.89 63.2± 5.63 60.5± 6.29 64.1± 6.23 61.4± 3.28 60.5± 5.11 64.3± 4.26							67.1± 3.26 58.3± 4.38 56.9± 4.72 51.4± 6.39 46.7± 5.36 45.3± 7.34 42.5± 5.16 44.2± 5.38 52.6± 3.59

As shown in Table 2, the medicine of Herba Epimedii total flavones and the different proportionings of troxerutin 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 Epimedii total flavones compatibility troxerutin can produce synergistic function, drug effect all is significantly improved than singly using with dosage troxerutin or Herba Epimedii total flavones, the medicine of troxerutin and the different proportionings of Herba Epimedii 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 Epimedii total flavones and troxerutin is: 1 part of troxerutin, 0.1～2 part of Herba Epimedii total flavones.

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	Poor slightly clear and bright poor slightly	30.1 30.1 30.1 30.1 30.1 7.53	Difference is clear and bright poor					27.5 28.9 29.4 29.7 29.9 7.05

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

2.2 active carbon influences injection

Activated carbon dosage is investigated:

Injection owing to solvent, raw material, container etc. have the pyrogen material, reduces the safety of injection in the process of producing, and therefore needs to remove the pyrogen material in the process of preparation injection.The method of depyrogenation mainly contains high temperature method, acid-base method, ultrafiltration and absorption method at present, active carbon adsorption not only can heat of adsorption originality composition, the effect that also has filter of helping and decolouring, when removing pyrogen, can improve the appearance character of preparation, therefore we select the active carbon adsorption depyrogenation for use, and its consumption investigated, the results are shown in following table.

The activated carbon dosage investigation table

Activated carbon dosage (%)	The total flavones rate of transform (%)	Outward appearance
			0.1 0.6 1.2	86.2 78.4 72.5	Reddish brown red

From the medicinal liquid outward appearance, select activated carbon dosage be 0.6% and 1.2% proper; But judge that from the rate of transform 0.1% consumption and 0.6% consumption are slightly better, the three all can satisfy the related request of injection, but takes all factors into consideration above factor, so that be the best with the activated carbon decolorizing of medicine liquid volume 0.6%.

The bleaching time investigation table

Time (minute)	The total flavones rate of transform (%)	Outward appearance
			10 30 60	81.25 75.32 71.24	Reddish brown red pale red

From top test as can be seen, along with the color of the prolongation medicinal liquid of time is thin out, but above-mentioned factor is taken all factors into consideration in the also corresponding minimizing of the rate of transform of effective ingredient, selects for use and boils 30 minutes for best.

2.3 caffolding agent consumption screening

The mannitol solution (60mg/ml, 120mg/ml and 180mg/ml) of variable concentrations is mixed in varing proportions with medicinal liquid, filter, every cillin bottle loading amount is 3ml, lyophilization.Lyophilisation condition :-45 ℃, behind the pre-freeze 8h, the beginning evacuation, and be warming up to-40 ℃, keep 10h; Be warming up to-30 ℃, keep 10h; Be warming up to-20 ℃, keep 10h; Be warming up to-10 ℃, keep 5h; Be warming up to 0 ℃, keep 5h; Be warming up to 15 ℃, keep 3h; Be warming up to 25 ℃, keep 3h, the result is as table.

The screening of mannitol consumption

Numbering	Mannitol concentration (mg/ml)	Mannitol: medicinal liquid (v: v)	Color and luster	Profile	Solubility	Clarity
							1 2 3	60 120 180	2∶1 2∶1 2∶1	Yellowish-brown Huang is yellowish	Part is subsided intact	Well carefully	Up to specification up to specification

As seen from table, when the ratio of caffolding agent consumption and medicinal liquid is 2: 1, the sample character is that the sample of 120mg/ml and 180mg/ml is relatively good with the mannitol concentration, the sample of 60mg/ml has part to subside, but major part still is molding, but take all factors into consideration the consumption and the clinical dose of adjuvant, the optimum selection mannitol concentration is 120mg/ml, and the volume ratio of mannitol solution and medicinal liquid is 2: 1.

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∶2.2 1∶2.2 1∶2.2 1∶2.2 1∶2.2 1∶2.2	2.0 2.3 2.6 1.7 2.1 1.9

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: dropping pill technique research

4.1 coolant is selected

Get the mixed powder 10g of Herba Epimedii total flavones and troxerutin, Macrogol 4000 20g, mix homogeneously, be heated to 80～90 ℃, treat whole fusions after, get an amount of, splashing into respectively in simethicone and the liquid paraffin coolant, is index with the molding situation of drop pill, the results are shown in Table.

The table coolant is selected

The cold agent kind of getting	Coolant temperature	Drip distance	Drip speed	The material temperature	Drop pill molding situation
						The dimethicone liquid paraffin	15℃ 15℃	6cm 6cm	30～40d/min 30～40d/min	70℃ 70℃	Roundness is good, and forming can molding, hangover on a small quantity

Last table shows, selects for use dimethicone, the liquid paraffin all can molding, but is coolant with the dimethicone, and drop pill roundness, mouldability are preferable.

4.2 coolant temperature is selected

Get three parts of the mixed powders of Herba Epimedii total flavones and troxerutin, each 10g, three parts of Macrogol 4000s, each 20g, mix homogeneously is heated to 80～90 ℃, treat whole fusions after, get an amount of, splash into respectively in the simethicone coolant of different temperatures, observe drop pill molding situation, the results are shown in Table.

The table coolant temperature is selected

Coolant temperature	Drip distance	Drip speed	The material temperature	Drop pill molding situation
					10 ℃ of 20 ℃ of gradients coolings	5cm 5cm 5cm	30～40d/min 30～40d/min 30～40d/min	80℃ 80℃ 80℃	Roundness is good, and the forming roundness is good, and the forming roundness is good, forming

Annotate: the gradient cooling means is: top is 10～20 ℃, and the bottom is 5～10 ℃.

Last table shows that under above-mentioned three kinds of chilling temperatures, the mouldability of this product is all good, is easy operation, and selecting coolant temperature is 10～20 ℃.

Embodiment 5: soft capsule disperse medium (or claiming substrate) is selected

Generally make soft capsule,, need to add disperse medium, make suspendible shape (or title " toothpaste-like "),, and under the prerequisite of unobstructed defeated material of energy and pelleting, reduce substrates quantity as far as possible at fill material and substrate mix homogeneously in order to be beneficial to the filling pelleting.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∶1.3	1∶1.4	1∶1.5	1∶1.6	1∶1.7
						Quality of liquid medicine	Viscosity is big, and is mobile poor	Viscosity, better mobile	Viscosity, good fluidity	Viscosity, better mobile	Differences in viscosity is mobile big

By table as seen, medication amount (g): soybean oil (g)=1: 1.3～1.7, quality of liquid medicine can satisfy condition substantially, but medication amount (g): soybean oil (g)=1: 1.5, quality of liquid medicine is better.

Concrete embodiment

Embodiments of the invention 1: troxerutin 10g Herba Epimedii total flavones 20g

Get troxerutin, Herba Epimedii total flavones and add injection and blunge and make dissolving, filter, filtrate is boiled the active carbon that the back adds 0.6% (W/V), keep little and boiled 30 minutes, cold slightly filtration, filtrate adjust pH to 5.5～7.0, 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 (volume ratio of mannitol solution and medicinal liquid is 2: 1),, filter, add and inject water, packing, lyophilization, pre-freeze temperature-45 ℃, pre-freeze time 10h to ormal weight with above-mentioned filtrate mixing;-40 ℃ of evacuation keep 8h; Be warming up to-30 ℃ again, keep 8h; Be warming up to-20 ℃, keep 8h; Be warming up to-10 ℃, keep 5h; Be warming up to 0 ℃, keep 5h; Be warming up to 10 ℃, keep 2h; Be warming up to 20 ℃, keep 2h, be warming up to 30 ℃, keep 2h, promptly get the Injectable sterile block that contains 1 part of Herba Epimedii total flavones and 2 parts of troxerutins.

Embodiments of the invention 2: troxerutin 10g Herba Epimedii total flavones 1g

Get troxerutin, Herba Epimedii total flavones and add injection and blunge and make dissolving, filter, it is 5.5～7.0 that filtrate is regulated pH value, add 0.6% activated needle-use activated carbon, boil absorption 30min, carbon removal, fine straining, filtrate adds the injection water to ormal weight, spends the night coarse filtration, fine straining 4 ℃ of cold preservations, divide and install in the ampoule bottle, sterilization, packing promptly gets the injection with small volume or the concentrated solution for injection that contain 0.1 part of Herba Epimedii total flavones and 1 part of troxerutin.

Embodiments of the invention 3: troxerutin 10g Herba Epimedii total flavones 50g

Get troxerutin, Herba Epimedii total flavones, add an amount of water for injection dissolving, filter, filtrate adds 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 troxerutin and 5 parts of Herba Epimedii total flavones.

Embodiments of the invention 4: troxerutin 5g Herba Epimedii total flavones 50g

Get troxerutin, Herba Epimedii total flavones, add an amount of water for injection, stir and make dissolving, filtrate adjust pH to 5.5～7.0 add the injection water to ormal weight, mixing, the needle-use activated carbon of adding 1.0%, 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 troxerutin and 10 parts of Herba Epimedii total flavones.

Embodiments of the invention 5: troxerutin 100g Herba Epimedii total flavones 5g

Get troxerutin, Herba Epimedii total flavones, add an amount of water for injection dissolving, filtrate by volume adds 0.5% active carbon, boil, keep little 30min that boils, cold slightly filtration, filtrate adds the injection water to an amount of, adjust pH to 5.5～7.0, boil, 4 ℃ of cold preservations are spent the night, and add to the full amount of water for injection, coarse filtration, fine straining, in inlet temperature is 180 ℃, and leaving air temp is 50 ℃, and air velocity is a spray drying under the condition of 18ms-1, packing promptly gets and contains 1 part of troxerutin and 0.05 part of Herba Epimedii total flavones spray drying sterilized powder.

Embodiments of the invention 6: troxerutin 200g Herba Epimedii total flavones 2g

With troxerutin and Herba Epimedii total flavones mix homogeneously, polyvinylpyrrolidone, 1% polyvinylpolypyrrolidone, the Fructus Citri Limoniae essence of adding 5% are an amount of, and compacting promptly gets the oral cavity disintegration tablet that contains 1 part of troxerutin and 0.01 part of Herba Epimedii total flavones in flakes.

Embodiments of the invention 7: troxerutin 10g Herba Epimedii total flavones 20g

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

Embodiments of the invention 8: troxerutin 2g Herba Epimedii total flavones 1g

With troxerutin and Herba Epimedii total flavones mix homogeneously, in principal agent: the ratio of adjuvant=1: 1.2 adds calcium bicarbonate, in principal agent: the ratio of adjuvant=2.2: 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 troxerutin and 0.5 part of Herba Epimedii total flavones dispersible tablet.

Embodiments of the invention 9: troxerutin 3g Herba Epimedii total flavones 6g

With troxerutin and Herba Epimedii total flavones 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 troxerutin and 2 parts of Herba Epimedii total flavones.

Embodiments of the invention 10: troxerutin 10g Herba Epimedii total flavones 4g

With troxerutin and Herba Epimedii total flavones mix homogeneously, add equivalent starch and equivalent dextrin, mix homogeneously is granulated, drying, granulate, encapsulated, promptly get the capsule that contains 1 part of troxerutin and 0.4 part of Herba Epimedii total flavones.

Embodiments of the invention 11: troxerutin 10g Herba Epimedii total flavones 10g

With troxerutin and Herba Epimedii total flavones mix homogeneously, by medication amount: soybean oil: Cera Flava=1: 1.5: 0.7 adds soybean oil, Cera Flava, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100g: 50g: 100g: 1g, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, insulation is at 65 ± 5 ℃, 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; Above-mentioned medicated powder is added in the spice bucket of capsule machine, the debugging pellet press, pelleting, drying promptly gets and contains 1 part of troxerutin and 1 part of Herba Epimedii total flavones soft capsule.

Embodiments of the invention 13: troxerutin 2g Herba Epimedii total flavones 4g

With Herba Epimedii total flavones, troxerutin 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: troxerutin 10g Herba Epimedii total flavones 1g

With Herba Epimedii total flavones, troxerutin 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.

Troxerutin among the above embodiment is the commercial goods that can directly buy, Herba Epimedii total flavones can be with commercially available or Herba Epimedii 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 Epimedii total flavones is not less than 50%, and the content of flavones ingredient is not less than 70% in the Herba Epimedii 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 mainly is made for 0.01～10 part by 1 part of troxerutin and Herba Epimedii 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 mainly is made for 0.05～5 part by 1 part of troxerutin and Herba Epimedii 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 mainly is made for 0.1～2 part by 1 part of troxerutin and Herba Epimedii 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 Epimedii total flavones and the troxerutin 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 Epimedii total flavones effective site is commercially available preparing with the following method of employing: get epimedium herb, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Herba Epimedii 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 Epimedii 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 troxerutin 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 troxerutin amount, pharmaceutical adjunct amount and the water quantities in the ejection preparation; Troxerutin 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 troxerutin, Herba Epimedii total flavones and add injection and blunge and make dissolving, filter, filtrate is boiled the active carbon that the back adds 0.6% (W/V), keeps little and boils 30 minutes, cold slightly filtration, filtrate adjust pH to 5.5～7.0, 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 (volume ratio of mannitol solution and medicinal liquid is 2: 1),, filter, add and inject water, packing, lyophilization, pre-freeze temperature-45 ℃, pre-freeze time 10h to ormal weight with above-mentioned filtrate mixing;-40 ℃ of evacuation keep 8h; Be warming up to-30 ℃ again, keep 8h; Be warming up to-20 ℃, keep 8h; Be warming up to-10 ℃, 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 1～3, it is characterized in that: described compositions is used for disease medicaments such as preparation treatment coronary heart disease, angina pectoris, arrhythmia, cerebral thrombosis, cerebral ischemia, hypertension, thrombophlebitis, capillary hemorrhage, immunologic hypofunction.

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 the finger printing based on the Herba Epimedii total flavones composition characteristics;

(2) epimedium herb, icariin, icariside I, Herba Epimedii glycosides A, B, C, all or part of differential test method in Quercetin, the troxerutin;

(3) icariin, icariside I, Herba Epimedii glycosides A, B, C, the content test method of all or part of composition in Quercetin, total flavones, the troxerutin.