CN1969949A - 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 total savianolic acid significant parts 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, myocardial infarction, myocardial ischemia, pulmonary heart disease, arteriosclerosis, cerebral thrombus, myocardial and cerebral infarction, apoplexy after-effect, thrombotic phlebitis, capillary vessel hemorrhage, liver and kidney syndrome. The preparation of the invention has the advantages of high purity, ensured constituents, controllable quality, improved treatment effect, wider range of safely, and less fluctuation of treatment effects.

Description

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

Technical field

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

Technical background

Cardiovascular and cerebrovascular disease such as coronary heart disease, cerebral thrombosis, alzheimer disease etc. have become the No.1 killer of human health, have become human mortality's one of the main reasons in many countries; According to investigations, sickness rate in recent years has and increases trend year by year, and continuous rejuvenation trend is arranged, in, young patient constantly increases, cardiovascular and cerebrovascular disease has become commonly encountered diseases, the frequently-occurring disease of harm China people ' s health.And medicine mainly concentrates on pure Chinese medicinal preparation and Western medicine two aspects at present, mostly the Chinese medicine and western medicine coupling is that the clinician selects suitable Chinese medicine preparation to cooperate the Western medicine diagnosis and treatment of corresponding function according to the disease situation, and the side effect of Western medicine is bigger, be unsuitable for taking for a long time of this chronic disease, pure Chinese medicinal preparation is used as medicine with crude drug in whole or the extractum after simple the extraction mostly, cause dose bigger, simultaneously because all multifactor impacts make the clinical efficacy fluctuation bigger.In view of such circumstances, searching better, compatibility is simple, therapeutic effect is desirable, and effective medicine that toxic and side effects is little has just become people's urgent problem.

Radix Salviae Miltiorrhizae is as conventional Chinese medicine, is used for the treatment of or prevents cardiovascular and cerebrovascular disease with a long history, is subjected to people in the industry's favor in recent years especially; Troxerutin has and suppresses erythrocyte, platelet aggregation, prevents thrombosis, increases blood oxygen saturation, and microcirculation improvement promotes neovascularity to generate, and promotes side Zhi Xunhuan, and effects such as cerebral blood flow increasing amount are mainly used in the treatment of cardiovascular and cerebrovascular disease.Single red sage formulation such as Radix Salviae Miltiorrhizae Injection are getting the nod aspect the treatment cardiovascular and cerebrovascular disease at present, but because preparation technology is relatively more traditional, dna purity is not high, quality controllability is relatively poor relatively, make red sage formulation application clinically be subjected to restriction significantly, for this reason, the applicant furthers investigate, employing the treatment cardiovascular and cerebrovascular disease aspect curative effect preferably Radix Salviae Miltiorrhizae total phenolic acids effective site be used as medicine, the compatibility troxerutin, the proportion compatibility of research screening Radix Salviae Miltiorrhizae total phenolic acids effective site and troxerutin optimum is further studied preparations shaping and stability problem, and then selects for the patient provides a new medication.

Summary of the invention

The objective of the invention is to: a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease is provided, this pharmaceutical composition is by troxerutin and Radix Salviae Miltiorrhizae total phenolic acids prescription, definite ingredients, quality controllable, can anticoagulant, again can replenishing qi and promoting blood flow, treating both the principal and secondary aspects of a disease, produce obvious synergism, curative effect obviously improves; The present invention also aims to provide the preparation method and the method for quality control of this pharmaceutical composition different dosage form.The key of acute ischemic cerebral apoplexy treatment is to dwindle ischemia half blanking bar, troxerutin be rutin through hydroxyethylation obtain with 7,3, the 4-troxerutin is main mixture.Troxerutin can suppress erythrocyte, platelet aggregation, prevent thrombosis, simultaneously can increase blood oxygen saturation, microcirculation improvement promotes neovascularity to generate, and promotes side Zhi Xunhuan, thereby cerebral blood flow increasing amount, increase the blood supply in half blanking bar zone, improve hemodynamic every index, improve clinical symptoms and sign.Radix Salviae Miltiorrhizae total phenolic acids is the main active in the red rooted salvia, modern study shows, degree of association maximum in Radix Salviae Miltiorrhizae total phenolic acids and the cardiovascular and cerebrovascular diseases medicament, the curative effect of Radix Salviae Miltiorrhizae Injection aspect cardiovascular and cerebrovascular disease gets the nod, for this reason, the present invention is on the basis of experiment screening, adopt troxerutin and Radix Salviae Miltiorrhizae total phenolic acids compatibility to make preparation, optimize best prescription and technology, the product that obtains shows through pharmacodynamics test, Synergistic, more independent red sage formulation, 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 parts by weight, and it is mainly to be made up of for 0.05～15 part 1 part of troxerutin and Radix Salviae Miltiorrhizae total phenolic acids.Say accurately, calculate that it is mainly to be made up of for 0.1～10 part 1 part of troxerutin and Radix Salviae Miltiorrhizae total phenolic acids according to parts by weight.Preferred prescription is that according to parts by weight calculating, it is mainly to be made up of for 0.2～5 part 1 part of troxerutin and Radix Salviae Miltiorrhizae total phenolic acids.

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 Salviae Miltiorrhizae total phenolic acids and the troxerutin one or both is prepared into liposome or pro-liposome.

Radix Salviae Miltiorrhizae total phenolic acids effective site is commercially available or adopts following method to prepare: get red rooted salvia, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Radix Salviae Miltiorrhizae 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, Radix Salviae Miltiorrhizae total phenolic acids effective site.

Calculate by weight percentage, the content of liposoluble 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 liposoluble 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, Radix Salviae Miltiorrhizae total phenolic acids and add injection and blunge and make dissolving, filter, filtrate is boiled the active carbon that the back adds 0.5% (W/V), keeping little boiled 30 minutes, cold slightly filtration, boil filtrate adjust pH to 5.0～6.5, 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 angina pectoris, myocardial infarction, myocardial ischemia, pulmonary heart disease, arteriosclerosis, cerebral thrombosis, cerebral infarction, apoplexy and apoplexy sequela, thrombophlebitis, capillary hemorrhage, hepatorenal syndrome.

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 salvianolic acid composition characteristics;

(2) all or part of differential test method in red rooted salvia, danshensu or its sodium salt, protocatechualdehyde, salvianolic acid B or its magnesium salt, the troxerutin;

(3) content test method of all or part of composition in danshensu or its sodium salt, protocatechualdehyde, salvianolic acid B or its magnesium salt, total phenolic acid, the troxerutin.

Compared with prior art, pharmaceutical composition of the present invention is by troxerutin and Radix Salviae Miltiorrhizae total phenolic acids effective site prescription, the salvianolic acid constituents has the effect of obvious suppression platelet aggregation, anticoagulant, molten fibre and anti peroxidation of lipid, is the active component of Radix Salviae Miltiorrhizae blood circulation promoting and blood stasis dispelling; But the troxerutin anticoagulant prevents effects such as thrombosis; The two prescription, purity height, definite ingredients, quality controllable, it is big to have overcome the fluctuation of pure Chinese medicinal preparation curative effect simultaneously, the shortcoming that the Western medicine untoward reaction is many can be guaranteed the stable and drug safety of clinical efficacy, Radix Salviae Miltiorrhizae total phenolic acids compatibility troxerutin treating both the principal and secondary aspects of a disease, the Synergistic attenuation all is significantly improved with red sage formulation or troxerutin preparation curative effect than single.

For proving that medicine provided by the invention has effective effect, the applicant has carried out a series of experiments.

Experimental example 1: to the comparative study of different proportioning pharmacodynamics

1, 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 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 (%)
				0.1: 1 salvianolic acid of 0.2: 1 salvianolic acid of 5: 1 salvianolic acids of 10: 1 salvianolic acids of 15: 1 salvianolic acids of physiological saline group troxerutin injection group danshen injections group salvianolic acid-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group 0.05: 1	16 16 16 16 16 16 16 16 16	0 10 8 10 11 14 13 12 11	0 62.5 50.0 62.5 68.8 87.5 81.3 75.0 68.8

As shown in Table 1; the medicine of Radix Salviae Miltiorrhizae total phenolic acids and the different proportionings of troxerutin has protective effect to the inductive mice thrombus in vivo of collagen protein-epinephrine; the strong and weak degree of this effect is relevant with the proportioning of medicine, and wherein with Radix Salviae Miltiorrhizae total phenolic acids: dipyridamole=0.2～5: 1 prescription pharmacological action is strong and consumption is lower.

2, to the influence of rabbit platelet aggregation

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

The influence of table 2 pair platelet aggregation

Group	Circle tree type (%)		Expansion type (%)		Aggregation number (individual)
							Before the administration	After the administration	Before the administration	After the administration	Before the administration	After the administration
	0.1: 1 salvianolic acid of 0.2: 1 salvianolic acid of 5: 1 salvianolic acids of 10: 1 salvianolic acids of 15: 1 salvianolic acids of physiological saline group troxerutin injection group danshen injections group salvianolic acid-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group 0.05: 1	74.1± 3.47 71.1± 4.28 70.4± 5.11 72.3± 5.28 70.3± 3.21 69.8± 4.25 71.5± 4.59 70.2± 5.36 69.4± 3.65	76.8± 4.25 80.5± 3.82 77.5± 4.35 84.6± 4.21 85.2± 4.15 89.5± 5.13 88.1± 5.46 84.7± 6.32 81.4± 5.12	25.9± 3.47 28.9± 4.28 29.6± 5.11 27.7± 5.28 29.7± 3.21 30.2± 4.25 28.5± 4.59 29.8± 5.36 30.6± 3.65	23.2± 4.25 19.5± 3.82 22.5± 4.35 15.4± 4.21 14.8± 4.15 10.5± 5.13 11.9± 5.46 15.3± 6.32 18.6± 5.12	67.2± 4.43 66.3± 4.27 65.1± 6.32 66.8± 3.54 64.7± 5.82 63.2± 4.34 62.4± 5.18 59.4± 6.17 60.8± 5.26							65.1± 5.68 56.2± 6.78 57.2± 5.33 53.5± 4.81 48.2± 7.14 44.8± 5.62 45.2± 7.27 45.2± 7.52 47.8± 7.04

As shown in Table 2, the medicine of Radix Salviae Miltiorrhizae total phenolic acids 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 Salviae Miltiorrhizae total phenolic acids compatibility troxerutin can produce synergistic function, drug effect all is significantly improved than singly using with dosage troxerutin or Radix Salviae Miltiorrhizae total phenolic acids, the medicine of troxerutin and the different proportionings of Radix Salviae Miltiorrhizae total phenolic acids 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 Salviae Miltiorrhizae total phenolic acids and troxerutin is: 1 part of troxerutin, 0.2～5 part of Radix Salviae Miltiorrhizae total phenolic acids.

Experimental example 2: injection Study on Forming

2.1pH value is to the influence of injection

For adapting to the Human Physiology needs, consider the character of each constituents in the medicinal liquid simultaneously, the applicant placed 3 months for 40 ℃ the injection of 6 kinds of different pH value, investigated its stability respectively.The results are shown in following table.

PH value	0 month		March
					Clarity	Total phenolic acid (mg/ml)	Clarity	Total phenolic acid (mg/ml)
	4.5 5.0 5.5 6.0 6.5 7.0 7.5	Slightly poor clear and bright slightly poor	80.2 80.2 80.2 80.2 80.2 80.2 80.2	Difference is clear and bright poor slightly					74.3 78.6 79.1 79.5 79.8 76.2 74.1

The result shows that the rational pH value scope of the present invention is 5.0～6.5.

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 (%)	Total phenolic acid rate of transform (%)	Outward appearance
			0.1 0.5 1.0	87.2 84.1 78.2	Reddish brown red

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

2.3 the screening of lyophilizing 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
				Glucosylmannitol glucosan glycine dextran dextran, the glucose poloxamer, mannitol mannitol, the propylene glycol glycine, the blank medicinal liquid of Polyethylene Glycol	2∶1 2∶1 2∶1 2∶1 2∶1 2∶1 2∶1 2∶1 2∶1 3ml	Generally well carefully generally carefully	The part atrophy is moulding moulded, frangible molding, part is subsided moulding moulded, a small amount of moulding moulded molding of atrophy, a small amount of broken atrophy

As seen from table, 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.

Test example 3: drop pill substrate screening

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

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

Table substrate screening test

Sequence number	1	2	3	4	5
						It is different that heavy (g) PEG4000 PEG6000 polyoxyl 40 stearate polyethers poloxamer matrix of material and material merge the situation dripping pill outward appearance ball method of double differences	15 30----better smooth, roundness slightly differs from 6.3%	15 20-10--better smooth, roundness 5.7%	15--10-20 relatively poor roundness differ from 7.5%	15-20-10-better matter is soft, roundness 6.9%	15-15--15 better matter are soft, roundness 6.5%

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

Experimental example 4: micropill technology is investigated

The micropill diameter is less than 2.5mm, and class is in particle properties, the bioavailability height, and the applicant is when development product micropill of the present invention, and maximum difficulty is exactly that hygroscopicity is strong and mobile poor, and poor plasticity is difficult to molding.The micropill manufacturing technology and the adjuvant that adopt the applicant's screening to obtain make product be easy to disintegrate, and the bioavailability height is well-behaved.

The wettability test result

Sample-product		Pure medicated powder	Medicated powder+starch
				The weighing bottle numbering		1	2
Weight of material (g)		0.9905 1.15 2.45 4.28 6.38 8.47 10.68 13.65 16.28 19.28 23.46 31.62 37.45 43.62 46.57	0.9918 1.02 2.13 4.04 6.08 7.11 8.21 10.32 12.07 14.52 17.41 22.47 25.15 26.42 28.13
				Moisture absorption blanking time percentage (%)	1h 2h 3h 4h 6h 8h 10h 12h 24h 36h 48h 72h 84h 96h

The result shows that it is rationally feasible to adopt starch to make adjuvant.

Concrete embodiment

Embodiments of the invention 1: troxerutin 10g Radix Salviae Miltiorrhizae total phenolic acids 100g

Get troxerutin, Radix Salviae Miltiorrhizae total phenolic acids and add injection and blunge and make dissolving, filter, filtrate is boiled the active carbon that the back adds 0.5% (W/V), and keep little and boiled 30 minutes, cold slightly filtration, boil filtrate adjust pH to 5.0～6.5, 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 aseptic block of lyophilizing that contains 1 part of troxerutin and 10 parts of Radix Salviae Miltiorrhizae total phenolic acidss.

Embodiments of the invention 2: troxerutin 10g Radix Salviae Miltiorrhizae total phenolic acids 1g

Get troxerutin, Radix Salviae Miltiorrhizae total phenolic acids adds injection blunges and makes dissolving, filters, it is 5.0～7.0 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 the injection with small volume or the concentrated solution for injection that contain 1 part of troxerutin and 0.1 part of Radix Salviae Miltiorrhizae total phenolic acids.

Embodiments of the invention 3: troxerutin 10g Radix Salviae Miltiorrhizae total phenolic acids 50g

Get troxerutin, Radix Salviae Miltiorrhizae total phenolic acids, add an amount of water for injection dissolving, filter, filtrate adds the glucose or the sodium chloride of ormal weight, by volume adds 0.4% needle-use activated carbon behind the mixed dissolution, boils, keep little 30min that boils, cold slightly filtration, filtrate adds the injection water to an amount of, boil adjust pH to 5.5～7.0, and 4 ℃ of cold preservations are spent the night, 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 Radix Salviae Miltiorrhizae total phenolic acidss.

Embodiments of the invention 4: troxerutin 15g Radix Salviae Miltiorrhizae total phenolic acids 3g

Get troxerutin, Radix Salviae Miltiorrhizae total phenolic acids, 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 0.5%, boiled 30 minutes, coarse filtration, reuse 0.45 μ m and 0.22 μ m microporous filter membrane filter, divide and install in the enamel tray, lyophilization, the equilibration time when the balance solidification point of phase I is 0 ℃ is 1.5 hours, i.e. the time of shelf temperature and product temperature basically identical; The second stage solidification point is from 0 ℃ during to minimum eutectic temperature-16 ℃, and shelf temperature and product temperature equilibration time are 2 hours; Phase III continues to be cooled to-40 ℃, need 2 hours approximately, kept this temperature 2 hours, freeze the jail fully until product, promptly begin evacuation, enter drying program, under-40 ℃ of constant temperature-evacuation, slowly heat up, 2～4 ℃/h, to the lowest total of the melting point temperature, time is about 12 hours, after sublimation drying is finished, continue under the low pressure condition, it is dry to remove residual moisture to heat up, time is about 14～16 hours, kept more than 35 ℃ dry 1.5 hours, and under aseptic condition, divided to install in the cillin bottle, promptly get the lyophilizing injectable sterile powder that contains 1 part of troxerutin and 0.2 part of Radix Salviae Miltiorrhizae total phenolic acids.

Embodiments of the invention 5: troxerutin 1g Radix Salviae Miltiorrhizae total phenolic acids 15g

Get troxerutin, Radix Salviae Miltiorrhizae total phenolic acids, 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 the spray drying sterilized powder that contains 1 part of troxerutin and 15 parts of Radix Salviae Miltiorrhizae total phenolic acidss.

Embodiments of the invention 6: troxerutin 100g Radix Salviae Miltiorrhizae total phenolic acids 5g

With troxerutin and Radix Salviae Miltiorrhizae total phenolic acids mix homogeneously, polyvinylpyrrolidone, 3% microcrystalline Cellulose, the mannitol of adding 7% are an amount of, and compacting promptly gets the oral cavity disintegration tablet that contains 1 part of troxerutin and 0.05 part of Radix Salviae Miltiorrhizae total phenolic acids in flakes.

Embodiments of the invention 7: troxerutin 10g Radix Salviae Miltiorrhizae total phenolic acids 30g

With troxerutin 10g, Radix Salviae Miltiorrhizae total phenolic acids 30g, PEG4000 and polyoxyethylene monostearate (2: 1) 80g mix homogeneously, put in the rustless steel container mixing, after being heated to whole fusions, insulation 30min, mechanical high-speed stirs 10min to evenly, is transferred to the drop pill machine, with dimethicone or liquid paraffin is coolant, drip system, collect drop pill, remove the dimethicone or the liquid paraffin on surface, packing promptly gets the drop pill that contains 1 part of troxerutin and 3 parts of Radix Salviae Miltiorrhizae total phenolic acidss.

Embodiments of the invention 8: troxerutin 6g Radix Salviae Miltiorrhizae total phenolic acids 30g

With troxerutin and Radix Salviae Miltiorrhizae total phenolic acids mix homogeneously, in principal agent: the ratio of adjuvant=2.4: 1 adds crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose composite auxiliary material mix homogeneously, the system soft material, granulate, dry, granulate, tabletting promptly gets and contains 1 part of troxerutin and 5 parts of Radix Salviae Miltiorrhizae total phenolic acids dispersible tablets.

Embodiments of the invention 9: troxerutin 3g Radix Salviae Miltiorrhizae total phenolic acids 21g

With troxerutin and Radix Salviae Miltiorrhizae total phenolic acids mix homogeneously, add appropriate amount of starch, dextrin, to granulate, drying adds magnesium stearate, and coating promptly gets the tablet that contains 1 part of troxerutin and 7 parts of Radix Salviae Miltiorrhizae total phenolic acidss.

Embodiments of the invention 10: troxerutin 5g Radix Salviae Miltiorrhizae total phenolic acids 5g

With troxerutin and Radix Salviae Miltiorrhizae total phenolic acids mix homogeneously, add 2 times of amount starch and 2 times of amount dextrin and an amount of Pulvis Talci, mix homogeneously is granulated, drying, granulate, encapsulated, promptly get the capsule that contains 1 part of troxerutin and 1 part of Radix Salviae Miltiorrhizae total phenolic acids.

Embodiments of the invention 11: troxerutin 5g Radix Salviae Miltiorrhizae total phenolic acids 30g

With troxerutin and Radix Salviae Miltiorrhizae total phenolic acids mix homogeneously, press medication amount: substrate amount=1: 2 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100g: 70g: 100g: 1g, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, merceration is warming up to 65 ± 5 ℃ gradually after 30 minutes, stirred 5 hours and simultaneously evacuation remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; Spice incapsulates in the material barrel of machine, the debugging pellet press, and the pelleting drying promptly gets and contains 1 part of troxerutin and 6 parts of Radix Salviae Miltiorrhizae total phenolic acids soft capsules.

Embodiments of the invention 12: troxerutin 4g Radix Salviae Miltiorrhizae total phenolic acids 8g

With troxerutin, Radix Salviae Miltiorrhizae total phenolic acids mixing, add medicinal starch, Celluloasun Microcrystallisatum is an amount of, mixing, the spheronization pill, packing promptly gets the pellet that contains 1 part of troxerutin and 2 parts of Radix Salviae Miltiorrhizae total phenolic acidss.

Embodiments of the invention 13: dipyridamole 10g Radix Salviae Miltiorrhizae total phenolic acids 2g

With Radix Salviae Miltiorrhizae total phenolic acids, dipyridamole mix homogeneously, be dissolved in the phosphate buffer (0.1M) standby, a certain proportion of fabaceous lecithin, cholesterol are dissolved in the 18-amine. solution, add in the phosphate-buffered liquor of said medicine, the water-bath type Ultrasound Instrument is handled 10min, gets liposome turbid liquor, the phosphate buffer standardize solution, filtration sterilization, aseptic subpackaged, promptly get lipidosome injection.

Embodiments of the invention 14: dipyridamole 4g Radix Salviae Miltiorrhizae total phenolic acids 20g

With Radix Salviae Miltiorrhizae total phenolic acids, dipyridamole mix homogeneously, be dissolved in the phosphate buffer (0.1M) standby, a certain proportion of fabaceous lecithin, cholesterol are dissolved in the 18-amine. solution, add in the phosphate-buffered liquor of said medicine, the water-bath type Ultrasound Instrument is handled 8min, gets liposome turbid liquor, behind the frozen drying, cross 180 mesh sieves, aseptic subpackaged, promptly get the pro-liposome injectable powder.

Troxerutin among the above embodiment is the commercial goods that can directly buy, Radix Salviae Miltiorrhizae total phenolic acids can be with commercially available or tanshinol 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 liposoluble ingredient in the oral Radix Salviae Miltiorrhizae total phenolic acids is not less than 50%, and the content of liposoluble ingredient is not less than 70% in the Radix Salviae Miltiorrhizae total phenolic acids of injection.

Claims (11)

1, a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease is characterized in that: calculate according to parts by weight, it is mainly to be made up of for 0.05～15 part 1 part of troxerutin and Radix Salviae Miltiorrhizae total phenolic acids.

2, according to the pharmaceutical composition of the described treatment cardiovascular and cerebrovascular disease of claim 1, it is characterized in that: calculate according to parts by weight, it is mainly to be made up of for 0.1～10 part 1 part of troxerutin and Radix Salviae Miltiorrhizae total phenolic acids.

3, according to the pharmaceutical composition of claim 1 or 2 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: calculate according to parts by weight, it is mainly to be made up of for 0.2～5 part 1 part of troxerutin and Radix Salviae Miltiorrhizae total phenolic acids.

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 Salviae Miltiorrhizae total phenolic acids 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: Radix Salviae Miltiorrhizae total phenolic acids effective site is commercially available or adopts following method to prepare: get red rooted salvia, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Radix Salviae Miltiorrhizae 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, Radix Salviae Miltiorrhizae total phenolic acids 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 liposoluble 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 liposoluble 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 preparation of drug combination method of any described treatment cardiovascular and cerebrovascular disease in the claim 1～5, it is characterized in that: the Injectable sterile block prepares like this: get troxerutin, Radix Salviae Miltiorrhizae total phenolic acids and add injection and blunge and make dissolving, filter, filtrate is boiled the active carbon that the back adds 0.5% (W/V), keeps little and boils 30 minutes, cold slightly filtration, filtrate adjust pH to 5.0～6.5, 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 angina pectoris, myocardial infarction, myocardial ischemia, pulmonary heart disease, arteriosclerosis, cerebral thrombosis, cerebral infarction, apoplexy and apoplexy sequela, thrombophlebitis, capillary hemorrhage, hepatorenal syndrome.

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 salvianolic acid composition characteristics;

(2) all or part of differential test method in red rooted salvia, danshensu or its sodium salt, protocatechualdehyde, salvianolic acid B or its magnesium salt, the troxerutin;

(3) content test method of all or part of composition in danshensu or its sodium salt, protocatechualdehyde, salvianolic acid B or its magnesium salt, total phenolic acid, the troxerutin.