CN1969897A - 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 one or two of ligustilides and Ligusticum wallichii alkaloids 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, cerebrovascular disease, pulmonary heart disease, thrombotic phlebitis, capillary vessel hemorrhage and hypertension.

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

In the human cause of death, annual nearly 1,700 ten thousand people in the whole world die from cardiovascular and cerebrovascular disease, account for more than 50% of total death toll, rank first place; In human diseases, the relapse rate of cardiovascular and cerebrovascular disease ranks first place up to 87%; In human diseases, the disability rate of cardiovascular and cerebrovascular disease is up to 50%, rank first place, this severe fact has been subjected to various circles of society and has highly watched attentively, the at present clinical Chinese medicine and western medicine that is used for the treatment of cardiovascular and cerebrovascular disease is a lot, and chemicals is used for symptom control, determined curative effect, but attend to one thing and lose sight of another, and side effect and untoward reaction are seen more; Though pure Chinese medicinal preparation blood circulation promoting and blood stasis dispelling, qi and blood tonifying, treating both the principal and secondary aspects of a disease are various in style, available property is bigger, and bioavailability is low, and curative effect is longer, and curative effect fluctuation simultaneously is bigger.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 hot fragrant row of Rhizoma Chuanxiong looses, the temperature promoting blood circulation, last wardrobe top, under walk the sea of blood, the function blood-activating and qi-promoting, wind-expelling pain-stopping is described as gas medicine in the blood by forefathers, modern study shows: the total lactone of Rhizoma Chuanxiong, Rhizoma Chuanxiong total alkaloids, Rhizoma Chuanxiong volatile oil is its major physiological active component, has spasmolytic, reduce the effect of vascular resistance and strong inhibition platelet aggregation, accumulative platelet is had depolymerisation, can obviously reduce whole blood viscosity, increase coronary flow, improve myocardial oxygen delivery, reduce effects such as myocardial oxygen consumption, but how to be used as medicine at present with medical material, cause bioavailability low, the curative effect undulatory property is big; Troxerutin has anticoagulant, prevents effects such as thrombosis, but owing to there is side effect, should not take for a long time.In view of above situation, the inventor adopt the total lactone of Rhizoma Chuanxiong effective site Rhizoma Chuanxiong, Rhizoma Chuanxiong total alkaloids one or both directly be used as medicine, the compatibility troxerutin is examined or check its moulding process and drug action, further investigate the optimal proportion scope of Rhizoma Chuanxiong effective site and troxerutin compatibility simultaneously, 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.

Summary of the invention

The inventor's purpose is to disclose a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease, by one or both and troxerutin prescription of the total lactone of Rhizoma Chuanxiong, Rhizoma Chuanxiong total alkaloids.This pharmaceutical composition definite ingredients, quality controllable, treating both the principal and secondary aspects of a disease, 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; On the basis of experiment screening, optimize the proportion compatibility scope and the preparation technology of the best of the two, the product that obtains shows through pharmacodynamics test, Synergistic, than the Rhizoma Chuanxiong preparation, the troxerutin preparation, 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 percentage by weight, and it is mainly to be made one or both of the total lactone of X=Rhizoma Chuanxiong, Rhizoma Chuanxiong total alkaloids by troxerutin 1～99% with X 99～1%.Say accurately, calculate that it is mainly part to be made one or both of the total lactone of X=Rhizoma Chuanxiong, Rhizoma Chuanxiong total alkaloids by troxerutin 20～80% and X80～20% according to percentage by weight.Preferably, calculate according to percentage by weight, it is mainly to be made one or both of the total lactone of X=Rhizoma Chuanxiong, Rhizoma Chuanxiong total alkaloids by troxerutin 30～70% with X 70～30%.

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 Rhizoma Chuanxiong total alkaloids, the total lactone of Rhizoma Chuanxiong, the troxerutin one or more is prepared into liposome or pro-liposome.

The total lactone effective site of Rhizoma Chuanxiong is commercially available or adopts following method to prepare: get the Rhizoma Chuanxiong medical material, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Rhizoma Chuanxiong crude extract, adopt on this basis ethanol precipitation, water return in molten method, column chromatography, extraction, flocculent precipitation, salting out method, the recrystallization method one or more unite use carry out suitably refining, the total lactone effective site of Rhizoma Chuanxiong; Get the Rhizoma Chuanxiong medical material, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Rhizoma Chuanxiong crude extract, adopt on this basis ethanol precipitation, water return in molten method, column chromatography, extraction, flocculent precipitation, salting out method, the recrystallization method one or more unite use carry out suitably refining, Rhizoma Chuanxiong total alkaloids effective site.

The preparation of described treatment cardiovascular and cerebrovascular disease: calculate by weight percentage, the content of Rhizoma Chuanxiong effective site 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 Rhizoma Chuanxiong effective site 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: one or both that get the total lactone of troxerutin and Rhizoma Chuanxiong, Rhizoma Chuanxiong total alkaloids add injection and blunge and make dissolving, filter, filtrate is boiled the active carbon that the back adds 1.0% (W/V), keeping little boiled 30 minutes, cold slightly filtration, boil filtrate adjust pH to 5.5～7.0, 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; 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 compositions is mainly used in diseases such as treatment coronary heart disease, angina pectoris, apoplexy, hyperlipidemia, pulmonary heart disease, thrombophlebitis, capillary hemorrhage, hypertension.

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 that with Rhizoma Chuanxiong alkaloids composition characteristics be in the finger printing of the total lactone composition characteristics of Rhizoma Chuanxiong one or both of advocating peace;

(2) all or part of differential test method in Rhizoma Chuanxiong medical material, ligustrazine, ferulic acid, the troxerutin;

(3) content test method of all or part of composition in Rhizoma Chuanxiong total alkaloids, the total lactone of Rhizoma Chuanxiong, ligustrazine, ferulic acid, the troxerutin.

In the prior art, Rhizoma Chuanxiong and troxerutin all are active drugs of treatment cardiovascular and cerebrovascular disease, but the preparation that is used as medicine with the Rhizoma Chuanxiong medical material, exist onset slower, drawbacks such as bioavailability is low, and curative effect fluctuation is big, though and the onset of troxerutin intravenously administrable is very fast, but untoward reaction is arranged, be unsuitable for taking for a long time; So, the applicant is combined into novel formulation with Rhizoma Chuanxiong effective site and troxerutin and develops research, bring into play both cooperative compensating effects by compatibility, for new medication of treatment increase of cardiovascular and cerebrovascular disease is selected at angina pectoris, arrhythmia, pulmonary heart disease, cerebral thrombosis etc.Simultaneously, can system further investigate Rhizoma Chuanxiong effective site and the safety of troxerutin compatibility and the controllability of quality, for data for clinical drug use is given security.By cardiac thrombosis model test and PAgT, these two kinds of medicines have been carried out the prescription screening test of system, found that Rhizoma Chuanxiong effective site: troxerutin=30～70%: 70～30% 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.Pharmaceutical preparation of the present invention, 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 be guaranteed the stable and drug safety of clinical efficacy, with respect to the preparation of Rhizoma Chuanxiong, troxerutin better efficacy not only, treating both the principal and secondary aspects of a disease, the Synergistic attenuation, and use and to carry all easily, multiple different ejection preparation and oral formulations are 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, thrombotic model test due to the medicine method

108 of healthy male mices; body weight 25～35g; be divided into 9 groups; grouping sees the following form, and 12 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 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 (%)
				20: 80 extract of Ligusticum chuanxiong Horts of 30: 70 extract of Ligusticum chuanxiong Horts of 70: 30 extract of Ligusticum chuanxiong Horts of 80: 20 extract of Ligusticum chuanxiong Horts of 99: 1 extract of Ligusticum chuanxiong Horts of physiological saline group troxerutin injection group extract of Ligusticum chuanxiong Hort group extract of Ligusticum chuanxiong Hort-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group 1: 99	12 12 12 12 12 12 12 12 12	0 7 5 9 8 10 11 7 9	0 58.3 41.7 75 66.7 83.3 91.7 58.3 75.0

As shown in Table 1, the medicine of Rhizoma Chuanxiong effective site and the different proportionings of troxerutin all can have 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 Rhizoma Chuanxiong effective site: troxerutin=30～70%: 70～30% 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
	20: 80 extract of Ligusticum chuanxiong Horts of 30: 70 extract of Ligusticum chuanxiong Horts of 70: 30 extract of Ligusticum chuanxiong Horts of 80: 20 extract of Ligusticum chuanxiong Horts of 99: 1 extract of Ligusticum chuanxiong Horts of physiological saline group troxerutin injection group extract of Ligusticum chuanxiong Hort group extract of Ligusticum chuanxiong Hort-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group 1: 99	76.5± 2.13 75.3± 3.18 73.5± 4.17 74.8± 2.69 70.6± 3.45 69.8± 3.95 71.2± 4.32 70.6± 3.82 68.5± 2.73	78.9± 3.28 84.3± 5.13 79.3± 3.64 86.1± 3.28 84.2± 4.35 89.6± 5.41 88.2± 4.69 84.6± 5.28 79.2± 3.48	23.5± 2.13 24.7± 3.18 26.5± 4.17 25.2± 2.69 29.4± 3.45 30.2± 3.95 28.8± 4.32 29.4± 3.82 31.5± 2.73	21.1± 3.28 15.7± 5.13 20.7± 3.64 13.9± 3.28 15.8± 4.35 10.4± 5.41 10.8± 4.69 15.4± 5.28 20.8± 3.48	64.5± 3.02 63.1± 4.68 62.8± 5.72 61.9± 6.58 60.8± 4.39 63.4± 5.27 61.4± 3.59 60.5± 6.19 61.5± 2.53							61.3± 4.06 54.6± 7.31 54.3± 7.23 48.6± 5.11 45.2± 6.57 45.1± 4.68 43.8± 7.22 46.2± 7.48 50.6± 3.28

As shown in Table 2, the medicine of Rhizoma Chuanxiong effective site 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: Rhizoma Chuanxiong effective site compatibility troxerutin can produce synergistic function, drug effect all is significantly improved than singly using with dosage troxerutin or Rhizoma Chuanxiong effective site, the medicine of troxerutin and the different proportionings of Rhizoma Chuanxiong effective site 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 Rhizoma Chuanxiong effective site and troxerutin is: troxerutin: Rhizoma Chuanxiong effective site is 30～70%: 70～30%.

Experimental example 2: injection Study on Forming

2.1pH value is to the influence of injection

This Shen clear people find in development, and suitable acid-base value is the stable key factor of medicine, for adapting to the Human Physiology needs, also will consider the character of each constituents in the medicinal liquid simultaneously, need suitably adjust the pH value of medicinal liquid when dosing.The applicant placed 3 months for 35 ℃ the injection of different pH value, investigated its stability respectively.

PH value	0 month		March
					Clarity	Total alkaloids (mg/ml)	Clarity	Total alkaloids (mg/ml)
	4.5 5.0 5.5 6.0 6.5 7.0 7.5	Difference is slightly poor clear and bright poor	1.35 1.35 1.35 1.35 1.35 1.35 1.35	Difference is poor slightly clear and bright poor					1.02 1.18 1.23 1.29 1.32 1.34 1.09

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 alkaloids rate of transform (%)	Outward appearance
			0.5 1.0 1.5	75.6 70.5 64.8	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 1.0% and 1.5% proper; Judge that from the rate of transform 0.5% consumption and 1.0% consumption are slightly better, take all factors into consideration above factor, so that be good with the activated carbon decolorizing of medicine liquid volume 1.0%.

2.3 freeze-dry process examination

2.3.1 the screening of caffolding agent kind

The screening of caffolding agent kind

The caffolding agent kind	Caffolding agent: medicinal liquid (V: V)	Solubility	The finished product outward appearance
				Galactolipin dextran glucan sweet mellow wine glycine sweet mellow wine, propane diols glycine, the blank soup of polyethylene glycol	2∶1 2∶1 2∶1 2∶1 2∶1 2∶1 2∶1 3m1	Generally well generally well generally carefully	Molding, the part molding of subsiding, part atrophy molding, the part moulding moulded molding of molding of subsiding, frangible atrophy

As seen from table, in the adjuvant that is screened, under the identical situation of other conditions, most of adjuvant all can be made into freeze-dried powder, but solubility angle integrated survey from yield rate, molding situation and sample, use the effect of mannitol to be better than other several adjuvants separately, can satisfy the every requirement of injection, reduce simultaneously as far as possible and add too much adjuvant.

2.3.2 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: pre-freeze temperature-45 ℃, pre-freeze time 8h;-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.

The screening of mannitol consumption

Numbering	Mannitol concentration (mg/ml)	Mannitol: medicinal liquid (v: v)	Profile	Solubility	Clarity
						1 2 3 4 5 6 7 8 9	60 60 60 120 120 120 180 180 180	2∶1 1∶1 1∶2 2∶1 1∶1 1∶2 2∶1 1∶1 1∶2	The part atrophy minute quantity atrophy minute quantity atrophy of well subsiding on a small quantity of well subsiding on a small quantity of subsiding of the inhomogeneous part of part	Carefully well carefully	Up to specification up to specification

As seen from table, variable concentrations and different proportion, major part can molding, but when the ratio of caffolding agent consumption and medicinal liquid be 2: during l, the sample character is better than other two ratios, so the ratio of mannitol solution and medicinal liquid is defined as 2: 1; And for the sample of same ratio, be that the sample of 120mg/ml and 180mg/ml is relatively good with the mannitol concentration, take all factors into consideration the consumption and the clinical dose of adjuvant, finally selecting mannitol concentration is 120mg/ml, the volume ratio of mannitol solution and medicinal liquid is 2: 1.

2.4 spray drying conditional filtering

Spray drying technology can make sample dry rapidly under the situation of atomizing, and the protection effective ingredient can make the water content of sample reduce simultaneously, helps stability of formulation.It is bigger that but the air temperature and current speed that spray-dired effect is imported and exported influences, so we are that evaluation index is investigated these three factors with the loss of active ingredients rate.

Spray drying condition investigation table

Inlet temperature (℃)	Outlet temperature (℃)	Air velocity (ms -1)	Loss rate (%)
				130 140 150	50 60 70	18 19 20	5.12 2.86 4.23

From above-mentioned result of the test as can be seen, three kinds of conditions all can obtain material preferably, but are 140 ℃ with inlet temperature by contrast, and outlet temperature is 60 ℃, and air velocity is that the condition of 19ms-1 is the best.

Concrete embodiment

Embodiments of the invention 1: the total lactone 70g of troxerutin 30g Rhizoma Chuanxiong

Get the total lactone of troxerutin and Rhizoma Chuanxiong and add injection and blunge and make dissolving, filter, filtrate is boiled the active carbon that the back adds 1.0% (W/V), and 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 (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; 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.

Embodiments of the invention 2: troxerutin 70g Rhizoma Chuanxiong total alkaloids 30g

Get troxerutin, add the injection water, stir and make it dissolving, medicinal liquid is standby; Get Rhizoma Chuanxiong total alkaloids 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 1.0% 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.

Embodiments of the invention 3: troxerutin 1g Rhizoma Chuanxiong total alkaloids 99g

Get troxerutin, Rhizoma Chuanxiong total alkaloids and add an amount of water for injection dissolving, filter, filtrate adds the glucose or the sodium chloride of ormal weight, by volume add 1.0% needle-use activated carbon behind the mixed dissolution, boil, keep little 30min that boils, cold slightly filtration, filtrate add the injection water to an amount of, adjust pH to 5.5～7.0, boil, 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 glucose or sodium chloride intravenous infusion.

Embodiments of the invention 4: troxerutin 99g Rhizoma Chuanxiong total alkaloids and total lactone 1g

Get troxerutin and add the injection water, stir and make it dissolving, medicinal liquid is standby; Get Rhizoma Chuanxiong total alkaloids and total lactone, 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 0.6%, 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.

Embodiments of the invention 5: the total lactone 90g of troxerutin 10g Rhizoma Chuanxiong

Get troxerutin, the total lactone of Rhizoma Chuanxiong, add an amount of water for injection dissolving, filter, filtrate by volume adds 0.5% active carbon, boils, and keeps little 30min that boils, cold slightly filtration, filtrate add 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 are 140 ℃ in inlet temperature, and outlet temperature is 60 ℃, air velocity is a spray drying under the condition of 19ms-1, and packing promptly gets the spray drying sterilized powder.

Embodiments of the invention 6: troxerutin 80g Rhizoma Chuanxiong total alkaloids 20g

With troxerutin and Rhizoma Chuanxiong total alkaloids mix homogeneously, add 6% polyvinylpyrrolidone, 3% polyvinylpolypyrrolidone, an amount of steviosin, micropowder silica gel, compacting promptly gets oral cavity disintegration tablet in flakes.

Embodiments of the invention 7: troxerutin 20g Rhizoma Chuanxiong total alkaloids and total lactone 80g

With troxerutin, Rhizoma Chuanxiong effective site, PEG4000 and polyoxyethylene monostearate (2: 1) mix homogeneously, put in the rustless steel container mixing, after being heated to whole fusions, insulation 30min, mechanical high-speed stirs 15min 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 drop pill.

Embodiments of the invention 8: the total lactone 50g of troxerutin 50g Rhizoma Chuanxiong

With troxerutin and the total lactone mix homogeneously of Rhizoma Chuanxiong, in principal agent: the ratio of adjuvant=1: 1.2 adds calcium carbonate, in principal agent: the ratio of adjuvant=1.8: 1 adds crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose composite auxiliary material mix homogeneously, 65% ethanol system soft material is granulated drying, granulate, add an amount of Pulvis Talci, evenly mixed, tabletting promptly gets dispersible tablet.

Embodiments of the invention 9: troxerutin 10g Rhizoma Chuanxiong total alkaloids, total lactone 90g

With troxerutin and Rhizoma Chuanxiong total alkaloids, total lactone mix homogeneously, add appropriate amount of starch, dextrin, to granulate, drying adds magnesium stearate, and coating promptly gets tablet.

Embodiments of the invention 10: troxerutin 1g Rhizoma Chuanxiong total alkaloids 1g

With troxerutin and Rhizoma Chuanxiong total alkaloids mix homogeneously, add equivalent starch and equivalent dextrin, mix homogeneously is granulated, drying, granulate, encapsulated, promptly get capsule.

Embodiments of the invention 11: troxerutin 99g Rhizoma Chuanxiong total alkaloids and total lactone 99g

With troxerutin and Rhizoma Chuanxiong total alkaloids and total lactone 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: 50g: 100g: 1g, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, insulation is at 60～70 ℃, stirred 5 hours and the while vacuumize degassing, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine, insulation incapsulates above-mentioned material in the spice bucket of machine about 65 ℃; The debugging pellet press, pelleting; Drying promptly gets soft capsule.

Embodiments of the invention 12: the total lactone 70g of troxerutin 30g Rhizoma Chuanxiong

With troxerutin, the total lactone mixing of Rhizoma Chuanxiong, add equivalent starch, equivalent dextrin mixing, to granulate, packing promptly gets granule.

Embodiments of the invention 13: total lactone of troxerutin 70g Rhizoma Chuanxiong and total alkaloids 30g

With the total lactone of Rhizoma Chuanxiong and total alkaloids, 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: the total lactone 30g of troxerutin 70g Rhizoma Chuanxiong

With the total lactone of Rhizoma Chuanxiong, 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 15: troxerutin 30g Rhizoma Chuanxiong total alkaloids 70g

With Rhizoma Chuanxiong total alkaloids, 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, Rhizoma Chuanxiong total alkaloids, the total lactone of Rhizoma Chuanxiong, Rhizoma Chuanxiong total alkaloids and total lactone effective site can be with commercially available or Rhizoma Chuanxiong alcohol extract provided by the invention, water extract, water extract-alcohol precipitation extract, semi-bionic extraction thing, supercritical extracts or the like, but: the content for oral Rhizoma Chuanxiong effective site is not less than 50%, and the content of the Rhizoma Chuanxiong effective site of injection is not less than 70%.

Claims (11)

1, a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease is characterized in that: calculate according to percentage by weight, it is mainly to be made one or both of the total lactone of X=Rhizoma Chuanxiong, Rhizoma Chuanxiong total alkaloids by troxerutin 1～99% with X 99～1%.

2, according to the pharmaceutical composition of the described treatment cardiovascular and cerebrovascular disease of claim 1, it is characterized in that: calculate according to percentage by weight, it is mainly to be made one or both of the total lactone of X=Rhizoma Chuanxiong, Rhizoma Chuanxiong total alkaloids by troxerutin 20～80% for 80～20% parts with X.

3, according to the pharmaceutical composition of claim 1 or 2 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: calculate according to percentage by weight, it is mainly to be made one or both of the total lactone of X=Rhizoma Chuanxiong, Rhizoma Chuanxiong total alkaloids by troxerutin 30～70% with X 70～30%.

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 Rhizoma Chuanxiong total alkaloids, the total lactone of Rhizoma Chuanxiong, the troxerutin one or more is prepared into liposome or pro-liposome.

7, according to the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease of claim 1～6, it is characterized in that: Rhizoma Chuanxiong effective site is commercially available or adopts following method to prepare: get the Rhizoma Chuanxiong medical material, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Rhizoma Chuanxiong crude extract, adopt on this basis ethanol precipitation, water return in molten method, column chromatography, extraction, flocculent precipitation, salting out method, the recrystallization method one or more unite use carry out suitably refining, the total lactone effective site of Rhizoma Chuanxiong; Get the Rhizoma Chuanxiong medical material, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Rhizoma Chuanxiong crude extract, adopt on this basis ethanol precipitation, water return in molten method, column chromatography, extraction, flocculent precipitation, salting out method, the recrystallization method one or more unite use carry out suitably refining, Rhizoma Chuanxiong total alkaloids effective site.

8, according to the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease of claim 4～6, it is characterized in that: calculate by weight percentage, the content of Rhizoma Chuanxiong effective site 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 Rhizoma Chuanxiong effective site 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 the described treatment cardiovascular and cerebrovascular disease of claim 1～5, it is characterized in that: the Injectable sterile block prepares like this: one or both that get the total lactone of troxerutin and Rhizoma Chuanxiong, Rhizoma Chuanxiong total alkaloids add injection and blunge and make dissolving, filter, filtrate is boiled the active carbon that the back adds 1.0% (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; 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 coronary heart disease, angina pectoris, apoplexy, hyperlipidemia, pulmonary heart disease, thrombophlebitis, capillary hemorrhage, hypertension.

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 that with Rhizoma Chuanxiong alkaloids composition characteristics be one or both of finger printing of the total lactone composition characteristics of Rhizoma Chuanxiong of advocating peace;

(2) all or part of differential test method in Rhizoma Chuanxiong medical material, ferulic acid, ligustrazine, the troxerutin;

(3) content test method of all or part of composition in Rhizoma Chuanxiong total alkaloids, the total lactone of Rhizoma Chuanxiong, ferulic acid, ligustrazine, the troxerutin.