CN1969899A - 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 several of Chinese angelica polysaccharides, Chinese angelica organic acids and Chinese angelica volatile oil 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, apoplexy, thrombotic phlebitis and capillary vessel hemorrhage.

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, cardiovascular and cerebrovascular disease has become the topmost disease that influences the residents ' health level, becomes the No.1 killer of harm humans health, is worldwide distribution.In China, annual nearly 2,600,000 people, every day, nearly 7000 people died from cardiovascular and cerebrovascular disease.Modern society is from the pressure of aspects such as work, society, life, add not science and do not get enough athletic exercise etc. of irregular, the diet of life, impel the sickness rate of cardiovascular and cerebrovascular disease in 30 years old to 40 years old young and middle-aged people also constantly to rise, the morbidity crowd has the trend of continuous rejuvenation, and the age span of morbidity is in continuous expansion.And hypertension, hypercholesterolemia, diabetes, obesity and smoking etc. these influence the most important risk factor of cardiovascular and cerebrovascular disease will long-term existence and progressively increase the weight of, still be continuous growth trend.Prevent and treat purpose in order to reach, a large amount of research has been done by many inventors and medicine enterprise, the product of some treatments also is provided, but the continuous variation and the arrival at aging age along with spectrum of disease, medicine constantly demonstrates its limitation at present, 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.

Modern study shows, Radix Angelicae Sinensis has stronger anticoagulation and anti thrombotic action, antioxidation, anti-aging effects are arranged, the protective effect of pair brain, renal ischaemia damage is arranged, study of anti-atherogenic effect, obviously anticoagulant has antitumor, anti-damage, pulmonary fibrosis resistant, hepatoprotective effect has sleep effect due to analgesia, anticonvulsant action, the prolongation pentobarbital, alleviates effect such as amnesia the central nervous system, suppresses the smooth muscle effect, effect such as antiinflammatory and enhance immunity, but how to be used as medicine with medical material at present, to cause bioavailability low, the curative effect undulatory property is big; Troxerutin has the erythrocyte of inhibition, platelet aggregation, prevent thrombosis, increase blood oxygen saturation, microcirculation improvement promotes neovascularity to generate the cerebral blood flow increasing amount, improve effects such as hemodynamic index, but owing to aspect cardiovascular and cerebrovascular disease, do not have absolute advantages, and certain side effect is arranged, so limited in clinical use; In view of above situation, the inventor adopt Radix Angelicae Sinensis effective site Radix Angelicae Sinensis polysaccharide, Radix Angelicae Sinensis organic acid, Radix Angelicae Sinensis volatile oil one or more 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 Radix Angelicae Sinensis 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 more and troxerutin prescription of Radix Angelicae Sinensis polysaccharide, Radix Angelicae Sinensis organic acid, Radix Angelicae Sinensis volatile oil.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 angelica sinensis preparations, 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 mainly is made one or more in X=Radix Angelicae Sinensis polysaccharide, Radix Angelicae Sinensis organic acid, the Radix Angelicae Sinensis volatile oil by troxerutin 1～99% with X 99～1%.Say that exactly calculate according to percentage by weight, it mainly is made one or more in X=Radix Angelicae Sinensis polysaccharide, Radix Angelicae Sinensis organic acid, the Radix Angelicae Sinensis volatile oil by 10～90% parts of troxerutins and X 90～10%.Preferably, calculate according to percentage by weight, it mainly is made one or more in X=Radix Angelicae Sinensis polysaccharide, Radix Angelicae Sinensis organic acid, the Radix Angelicae Sinensis volatile oil for 80～20% parts by 20～80% parts of troxerutins and X.

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 Radix Angelicae Sinensis polysaccharide, Radix Angelicae Sinensis organic acid, Radix Angelicae Sinensis volatile oil, the troxerutin one or more is prepared into liposome or pro-liposome.

Radix Angelicae Sinensis effective site is commercially available or adopts following method to prepare: get the Radix Angelicae Sinensis medical material, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Radix Angelicae Sinensis 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, Radix Angelicae Sinensis polysaccharide effective site; Get the Radix Angelicae Sinensis medical material, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Radix Angelicae Sinensis 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, Radix Angelicae Sinensis organic acid effective site; Get the Radix Angelicae Sinensis medical material, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Radix Angelicae Sinensis 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, Radix Angelicae Sinensis volatile oil.

The preparation of described treatment cardiovascular and cerebrovascular disease: calculate by weight percentage, the content of Radix Angelicae Sinensis 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 Radix Angelicae Sinensis 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 more that get troxerutin and Radix Angelicae Sinensis polysaccharide, Radix Angelicae Sinensis organic acid, Radix Angelicae Sinensis volatile oil clathrate add injection and blunge and make dissolving, filter, filtrate is boiled the active carbon that the back adds 0.6% (W/V), keeping little boiled 30 minutes, cold slightly filtration, boil filtrate adjust pH to 4.5～6.0, coarse filtration, fine straining are spent the night in cold preservation (4 ℃); Mannitol is added the injection water be mixed with 120mg/ml solution,, 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 compositions is mainly used in diseases such as treatment coronary heart disease, angina pectoris, arrhythmia, cerebral thrombosis, apoplexy, pulmonary heart disease, thrombophlebitis, capillary hemorrhage, arteriosclerosis.

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 being characterized as master, Radix Angelicae Sinensis organic acid composition characteristics, Radix Angelicae Sinensis volatile oil constituents based on the Radix Angelicae Sinensis polysaccharide constituents is characterized as in the main finger printing one or more;

(2) all or part of differential test method in Radix Angelicae Sinensis medical material, fructose, sucrose, ligustilide, ferulic acid, the troxerutin;

(3) content test method of all or part of composition in fructose, sucrose, ligustilide, ferulic acid, total polysaccharides, volatile oil, organic acid, the troxerutin.

In the prior art, Radix Angelicae Sinensis and troxerutin all are active drugs of treatment cardiovascular and cerebrovascular disease, but the preparation that is used as medicine with the Radix Angelicae Sinensis 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 Radix Angelicae Sinensis 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 in angina pectoris, arrhythmia, cerebral thrombosis, apoplexy etc.Simultaneously, can system further investigate Radix Angelicae Sinensis effective site and the safety of troxerutin compatibility and the controllability of quality, for data for clinical drug use is given security.By myocardial infarction and ischemia model test and PAgT, these two kinds of medicines have been carried out the prescription screening test of system, found that Radix Angelicae Sinensis effective site: troxerutin=20～80%: 80～20% 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 guarantee the stable and drug safety of clinical efficacy, with respect to the preparation of Radix Angelicae Sinensis, 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, the multiple different ejection preparation and the preparation method of 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

180 of healthy male mices; body weight 25～35g; be divided into 9 groups; grouping sees the following form, and 20 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 (%)
				10: 90 Radix Angelicae Sinensis active components of 20: 80 Radix Angelicae Sinensis active components of 80: 20 Radix Angelicae Sinensis active components of 90: 10 Radix Angelicae Sinensis active components of 99: 1 Radix Angelicae Sinensis active components of physiological saline group troxerutin injection group Radix Angelicae Sinensis active component group Radix Angelicae Sinensis active component-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group 1: 99	20 20 20 20 20 20 20 20 20	0 11 10 13 14 16 17 15 12	0 55 50 65 70 80 85 75 60

As shown in Table 1, the medicine of Radix Angelicae Sinensis 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 Radix Angelicae Sinensis effective site: troxerutin=20～80%: 80～20% 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
	10: 90 Radix Angelicae Sinensis active components of 20: 80 Radix Angelicae Sinensis active components of 80: 20 Radix Angelicae Sinensis active components of 90: 10 Radix Angelicae Sinensis active components of 99: 1 Radix Angelicae Sinensis active components of physiological saline group troxerutin injection group Radix Angelicae Sinensis active component group Radix Angelicae Sinensis active component-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group 1: 99	76.2± 2.51 73.8± 3.26 74.5± 4.67 72.9± 3.55 70.1± 4.28 71.5± 5.36 72.9± 4.22 69.5± 3.61 73.8± 4.87	79.2± 3.11 81.2± 4.21 79.3± 3.58 81.6± 5.23 83.1± 4.75 88.1± 6.38 90.8± 4.27 83.7± 6.14 82.3± 3.33	23.8± 2.51 26.2± 3.26 25.5± 4.67 27.1± 3.55 29.9± 4.28 28.5± 5.36 27.1± 4.22 30.5± 3.61 26.2± 4.87	20.8± 3.11 18.8± 4.21 20.7± 3.58 18.4± 5.23 16.9± 4.75 11.9± 6.38 9.2± 4.27 16.3± 6.14 17.7± 3.33	64.2± 3.47 63.4± 4.21 62.8± 3.69 61.5± 4.28 60.8± 5.26 63.4± 6.11 62.6± 4.32 62.3± 3.45 61.8± 4.26							61.8± 4.11 53.8± 5.26 54.7± 2.68 48.9± 3.51 46.2± 6.29 43.6± 7.21 41.0± 7.13 48.2± 5.24 51.2± 5.27

As shown in Table 2, the medicine of Radix Angelicae Sinensis 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: Radix Angelicae Sinensis effective site compatibility troxerutin can produce synergistic function, drug effect all is significantly improved than singly using with dosage troxerutin or Radix Angelicae Sinensis effective site, the medicine of troxerutin and the different proportionings of Radix Angelicae Sinensis 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 Radix Angelicae Sinensis effective site and troxerutin is: troxerutin: Radix Angelicae Sinensis effective site=20～80%: 80～20%.

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, 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	Ferulic acid (mg/ml)	Clarity	Ferulic acid (mg/ml)
	4.5 5.0 5.5 6.0 6.5 7.0	Clear and bright poor slightly	0.1 0.1 0.1 0.1 0.1 0.1	Clear and bright poor slightly					0.86 0.92 0.95 0.98 0.81 0.75

The result shows that the rational pH value scope of the present invention is 4.5～6.0.

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 ferulic acid rate of transform (%)	Outward appearance
			0.1 0.6 1.0	80.2 75.7 70.6	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 1.0% proper; Judge that from the rate of transform 0.1% 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%.

2.3 lyophilizing caffolding agent screening

The screening of caffolding agent kind

The caffolding agent kind	Caffolding agent: medicinal liquid (V: V)	Solubility	The finished product outward appearance
				The blank medicinal liquid of dextran glucosylmannitol glycine	2∶1 2∶1 2∶1 2∶1 3ml	General good general	Molding, part atrophy molding, the moulding moulded atrophy of partly subsiding

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.

2.4 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 (%)
				145 155 165	65 75 80	14 16 18	4.23 2.06 3.29

From above-mentioned result of the test as can be seen, three kinds of conditions all can obtain material preferably, but are 155 ℃ with inlet temperature by contrast, and outlet temperature is 75 ℃, and air velocity is 16ms ^-1Condition be best.

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 medicated powder ratio	Calcium hydrogen phosphate: medicated powder	Disintegration time (second)
				Crospolyvinylpyrrolidone low-substituted hydroxypropyl cellulose polyvinylpolypyrrolidone sodium carboxymethyl cellulose crospolyvinylpyrrolidone, the low-substituted hydroxypropyl cellulose low-substituted hydroxypropyl cellulose, the sodium carboxymethyl cellulose crospolyvinylpyrrolidone, microcrystalline Cellulose	1∶2 1∶2 1∶2 1∶2 1∶2 1∶2 1∶2	1∶1 1∶1 1∶1 1∶1 1∶1 1∶1 1∶1	130 145 140 163 80 110 95

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

The inventor is by a large amount of tests, troxerutin and Radix Angelicae Sinensis effective site mixed powder are prepared into the required substrate of drop pill to be investigated, different etc. with fusion situation, the ball method of double differences of drop pill outward appearance, principal agent and substrate serves as to investigate index, optimize and screened the substrate that influences the drop pill quality, result of the test is as table.

Method: substrate is put in the small beaker, be heated to 70～80 ℃, after treating whole fusions, the mixed material that adds troxerutin and Radix Angelicae Sinensis effective site, investigate the fusion situation of substrate and material, (drip the system condition: expect 75 ℃ of temperature, coolant is a liquid paraffin to the system of dripping to select the fusion situation to write out a prescription preferably, drip apart from 3～7cm, drip 30～40 droplets/minute of speed).

The substrate screening test

Sequence number	1	2	3	4	5	6
							It is different that heavy (g) PEG4000 PEG6000 polyoxyl 40 stearate poloxamer matrix of material and material merge the situation dripping pill outward appearance ball method of double differences	10 20---slightly poor smooth, roundness slightly differs from 7.1%	10 15-5-good smooth, roundness 6.3%	10 15--5 relatively poor roundness differ from 7.6%	10-20--slightly poor smooth, roundness 8.1%	10-15 5-better is smooth, roundness 8.5%	10-15-5 relatively poor roundness differ from 9.0%

By table as can be seen, most of substrate can satisfy the needs of preparations shaping, but take all factors into consideration, and with 3: 1 combination condition optimums, 1: 2 ratio of principal agent and substrate was preferable condition with PEG4000 and polyoxyethylene monostearate.

Experimental example 5: micropill substrate screening

The kind of adjuvant and quantity are bigger to the influence of the mouldability of micropill in the micropill, so we screen adjuvant medical starch, dextrin commonly used in the test, serve as to investigate index with the roundness of micropill.

The screening of table adjuvant

Supplementary product kind and consumption	Medical starch (30%)	Dextrin (30%)
			The micropill outward appearance	Rounding is even	Ball shape part is not round

As seen from table, starch and dextrin all can satisfy the micropill requirement, but the pill effect of starch is better than dextrin, and therefore selecting medical starch for use is the adjuvant of making micropill.

Concrete embodiment

Embodiments of the invention 1: troxerutin 20g Radix Angelicae Sinensis organic acid 80g

Get troxerutin, Radix Angelicae Sinensis organic acid and add injection and blunge and make dissolving, filter, filtrate is boiled the active carbon that the back adds 0.6% (W/V), and keep little and boiled 30 minutes, cold slightly filtration, boil filtrate adjust pH to 4.5～6.0, 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.

Embodiments of the invention 2: troxerutin 80g Radix Angelicae Sinensis polysaccharide 20g

Get troxerutin, Radix Angelicae Sinensis polysaccharide adds injection blunges and makes dissolving, filters, it is 4.5～6.0 that filtrate is regulated pH value, adds 0.5% activated needle-use activated carbon, boils absorption, carbon removal, fine straining, filtrate adds the injection water to ormal weight, spend the night 4 ℃ of cold preservations, coarse filtration, fine straining divide to install in the ampoule bottle sterilization, packing promptly gets injection with small volume or concentrated solution for injection.

Embodiments of the invention 3: troxerutin 50g Radix Angelicae Sinensis volatile oil 50g

Get troxerutin, Radix Angelicae Sinensis volatile oil, in volatile oil: beta-schardinger dextrin-: water is the ratio of 1ml: 7g: 70ml, volatile oil is joined in the beta-schardinger dextrin-saturated aqueous solution, the ethanol solution that adds volatile oil under stirring state stirred 4 hours at 45 ℃, and cold preservation is spent the night, sucking filtration, drying adds an amount of water for injection dissolving, and medicinal liquid is standby; Above-mentioned two medicinal liquids are merged, add 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 adds the injection water to an amount of, and boil adjust pH to 4.5～6.0,4 ℃ of cold preservations are spent the night, coarse filtration, fine straining add to the full amount of water for injection, packing, sterilization promptly gets glucose or sodium chloride intravenous infusion.

Embodiments of the invention 4: troxerutin 10g Radix Angelicae Sinensis total polysaccharides 90g

Get troxerutin, Radix Angelicae Sinensis effective site, add an amount of water for injection, stir and make dissolving, filter, filtrate adjust pH to 4.5～6.0 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, and divide to install in the enamel tray lyophilization, 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: troxerutin 90g Radix Angelicae Sinensis volatile oil 10g

Get troxerutin, Radix Angelicae Sinensis volatile oil, in volatile oil: beta-schardinger dextrin-: water is the ratio of 1ml: 10g: 70ml, volatile oil is joined in the beta-schardinger dextrin-saturated aqueous solution, the ethanol solution that adds volatile oil under stirring state stirred 4 hours at 45 ℃, and cold preservation is spent the night, sucking filtration, drying adds an amount of water for injection dissolving, and 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 4.5～6.0, and 4 ℃ of cold preservations are spent the night, add to the full amount of water for injection, coarse filtration, fine straining are 150 ℃ in inlet temperature, inlet temperature is 155 ℃, and outlet temperature is 75 ℃, and air velocity is a spray drying under the 16ms-1, packing gets the spray drying sterilized powder.

Embodiments of the invention 6: troxerutin 1g Radix Angelicae Sinensis organic acid, total polysaccharides 99g

With troxerutin and Radix Angelicae Sinensis effective site mix homogeneously, add 7% polyvinylpyrrolidone, 2% polyvinylpolypyrrolidone, an amount of steviosin, micropowder silica gel, compacting promptly get the oral cavity disintegration tablet that contains 1 part of troxerutin and 0.8 part of Radix Angelicae Sinensis organic acid, total polysaccharides in flakes.

Embodiments of the invention 7: troxerutin 99g Radix Angelicae Sinensis organic acid, volatile oil 1g

Get Radix Angelicae Sinensis volatile oil, in volatile oil: beta-schardinger dextrin-: water is the ratio of 1ml: 10g: 50ml, volatile oil is joined in the beta-schardinger dextrin-saturated aqueous solution, the ethanol solution that under stirring state, adds volatile oil, stirred 4 hours at 45 ℃, cold preservation is spent the night, sucking filtration, exsiccant volatile oil clathrate compound; Troxerutin, Radix Angelicae Sinensis organic acid, volatile oil clathrate compound are mixed, and adding with the spice ratio is 2: 1 PEG4000 and polyoxyethylene monostearate (2: 1) mix homogeneously, puts in the rustless steel container, mixing, be heated to whole fusions after, the insulation 30min, mechanical high-speed stirs 15min to even, being transferred to the drop pill machine, is coolant with dimethicone or liquid paraffin, drips system, collect drop pill, remove the dimethicone or the liquid paraffin on surface, packing promptly gets drop pill.

Embodiments of the invention 8: troxerutin 10g Radix Angelicae Sinensis organic acid, total polysaccharides, volatile oil 10g

With troxerutin and Radix Angelicae Sinensis organic acid, total polysaccharides mix homogeneously, in principal agent: the ratio of adjuvant=1: 1 adds calcium hydrogen phosphate, by principal agent: the ratio adding crospolyvinylpyrrolidone and the low-substituted hydroxypropyl cellulose composite auxiliary material mix homogeneously of adjuvant=2: 1,70% ethanol system soft material, granulate, drying, granulate sprays into volatile oil, add an amount of Pulvis Talci, micropowder silica gel, evenly mixed, tabletting gets dispersible tablet.

Embodiments of the invention 9: troxerutin 30g Radix Angelicae Sinensis total polysaccharides, organic acid 70g

With troxerutin and Radix Angelicae Sinensis total polysaccharides, organic acid 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 40g Radix Angelicae Sinensis total polysaccharides 60g

With troxerutin and Radix Angelicae Sinensis total polysaccharides mix homogeneously, add equivalent starch and equivalent dextrin, mix homogeneously is granulated, drying, granulate, encapsulated, promptly get capsule.

Embodiments of the invention 11: troxerutin 10g Radix Angelicae Sinensis organic acid 90g

With troxerutin and Radix Angelicae Sinensis organic acid mix homogeneously, press medication amount: substrate amount=1: 1.2 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: troxerutin 60g Radix Angelicae Sinensis volatile oil, organic acid 40g

With troxerutin, Radix Angelicae Sinensis organic acid mixing, add equivalent starch, equivalent dextrin mixing, spray into volatile oil, to granulate, packing promptly gets granule.

Embodiments of the invention 13: troxerutin 20g Radix Angelicae Sinensis polysaccharide, organic acid 80g

With Radix Angelicae Sinensis polysaccharide, organic acid, the troxerutin mix homogeneously, be dissolved in the phosphate buffer (0.1M) standbyly, 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, get liposome turbid liquor, phosphate buffer standardize solution, filtration sterilization, aseptic subpackaged, promptly get lipidosome injection.

Embodiments of the invention 14: troxerutin 80g Radix Angelicae Sinensis polysaccharide, organic acid, volatile oil 20g

With Radix Angelicae Sinensis polysaccharide, organic acid, volatile oil, the troxerutin mix homogeneously, be dissolved in the phosphate buffer (0.1M) standbyly, 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, get 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, Radix Angelicae Sinensis volatile oil, organic acid, polysaccharide can be with commercially available or angelol 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 Radix Angelicae Sinensis effective site is not less than 50%, and the content of the Radix Angelicae Sinensis 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, it is characterized in that: calculate according to percentage by weight, it is mainly to be made one or more in X=Radix Angelicae Sinensis polysaccharide, Radix Angelicae Sinensis organic acid, the Radix Angelicae Sinensis volatile oil 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 more in X=Radix Angelicae Sinensis polysaccharide, Radix Angelicae Sinensis organic acid, the Radix Angelicae Sinensis volatile oil by 10～90% parts of troxerutins and X 90～10%.

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 more in X=Radix Angelicae Sinensis polysaccharide, Radix Angelicae Sinensis organic acid, the Radix Angelicae Sinensis volatile oil for 80～20% parts by 20～80% parts of troxerutins and X.

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 Radix Angelicae Sinensis polysaccharide, Radix Angelicae Sinensis organic acid, Radix Angelicae Sinensis volatile oil, 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: Radix Angelicae Sinensis effective site is commercially available or adopts following method to prepare: get the Radix Angelicae Sinensis medical material, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Radix Angelicae Sinensis 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, Radix Angelicae Sinensis polysaccharide effective site; Get the Radix Angelicae Sinensis medical material, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Radix Angelicae Sinensis 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, Radix Angelicae Sinensis organic acid effective site; Get the Radix Angelicae Sinensis medical material, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Radix Angelicae Sinensis 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, Radix Angelicae Sinensis volatile oil.

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 Radix Angelicae Sinensis 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 Radix Angelicae Sinensis 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 more that get troxerutin and Radix Angelicae Sinensis polysaccharide, Radix Angelicae Sinensis organic acid, Radix Angelicae Sinensis volatile oil clathrate 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 4.5～6.0, 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.

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, arrhythmia, cerebral thrombosis, apoplexy, pulmonary heart disease, thrombophlebitis, capillary hemorrhage, arteriosclerosis.

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 being characterized as master, Radix Angelicae Sinensis organic acid composition characteristics, Radix Angelicae Sinensis volatile oil constituents based on the Radix Angelicae Sinensis polysaccharide constituents is characterized as in the main finger printing one or more;

(2) all or part of differential test method in Radix Angelicae Sinensis medical material, fructose, sucrose, ligustilide, ferulic acid, the troxerutin;

(3) content test method of all or part of composition in fructose, sucrose, ligustilide, ferulic acid, total polysaccharides, volatile oil, organic acid, the troxerutin.