CN1969950A - Pharmaceutical composition for treating cardiovascular and cerebrovascular diseases, preparation process and quality control method thereof - Google Patents

Abstract

The invention provides a pharmaceutical composition for treating cardiovascular and cerebrovascular diseases, its preparing process and quality control method, wherein Dipyridamole and total 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, cerebral infarction, apoplexy after-effect, 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; Dipyridamole has the effect of stronger antiplatelet aggregation, is 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, the Radix Salviae Miltiorrhizae total phenolic acids effective site that employing is closed the United Nations General Assembly in treatment cardiovascular and cerebrovascular disease curative effect is used as medicine, the compatibility dipyridamole, the proportion compatibility of research screening Radix Salviae Miltiorrhizae total phenolic acids effective site and dipyridamole 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 dipyridamole 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 quality control method of this pharmaceutical composition different dosage form; At prior art, according to cardiovascular and cerebrovascular disease such as coronary heart disease, cerebral thrombosis, alzheimer disease etc. all contract because of blood vessel is narrow, reason such as blood flow minimizing, blood stasis causes the diseases induced principle of blood supply insufficiency, on the basis of experiment screening, adopt dipyridamole and Radix Salviae Miltiorrhizae total phenolic acids compatibility to make preparation, optimize best prescription and technology, the product that obtains, show through pharmacodynamics test, Synergistic, more independent red sage formulation, the dipyridamole formulation 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 0.1～60 part 1 part of dipyridamole and Radix Salviae Miltiorrhizae total phenolic acids.Say accurately, calculate that it is mainly to be made up of for 0.5～50 part 1 part of dipyridamole 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 1～20 part 1 part of dipyridamole 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 dipyridamole 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 in the present composition: 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 dipyridamole 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 dipyridamole amount, pharmaceutical adjunct amount and the water quantities in the ejection preparation; Dipyridamole content should be 90.0%～110.0% of preparation labelled amount.

The Injectable sterile block of the present composition prepares like this: get dipyridamole, add the injection water, tartarize or citric acid stir and make it dissolving, and medicinal liquid is standby; Get Radix Salviae Miltiorrhizae total phenolic acids and add injection and blunge and make dissolving, filter filtrate for later use; Above-mentioned two medicinal liquids are merged, boil the active carbon that the back adds 0.5% (W/V), keep little and boiled 30 minutes, cold slightly filtration, boil filtrate adjust pH to 5.0～6.5, 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.

The present composition is mainly used in diseases such as treatment angina pectoris, myocardial infarction, pulmonary heart disease, myocardial ischemia, arteriosclerosis, cerebral thrombosis, cerebral infarction, apoplexy and apoplexy sequela, 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 dipyridamole;

(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 dipyridamole.

Compared with prior art, pharmaceutical composition of the present invention is by dipyridamole 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 dipyridamole anticoagulant has effects such as antithrombotic formation; 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 dipyridamole treating both the principal and secondary aspects of a disease, the Synergistic attenuation all is significantly improved with red sage formulation or dipyridamole formulation 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, myocardial infarction and ischemia model test due to the medicine method

90 of healthy SD rats, body weight 200～250g, the male and female dual-purpose, be divided into 9 groups, grouping sees the following form, every group 10, male and female half and half, give relative medicine shown in the according to the form below, continuous 7 days, after the last administration 1 hour, through with sodium pentobarbital 30mg/kg intravenous anesthesia, one section normal II ECG that leads was write down with the safe BL-420 of alliance type biological function signaling system in fixing back, back of the body position, iv pituitrin 1ug/kg then, 15s after administration, 30s, 1min, 2min, 3min, 4min, 5min, 10min, 15min, 20min writes down the II ECG that leads respectively, and with the T ripple of any time wherein or ST section rising 0.1mv or decline 0.05mv as the positive number of animals of myocardial ischemia, the results are shown in Table 1.

Table 1 pair rat pituitary pituitrin brings out the influence of acute myocardial ischemia

Group	Mus number (only)	The positive number of animals (only) of myocardial ischemia
			0.5: 1 salvianolic acid of 1: 1 salvianolic acid of 20: 1 salvianolic acids of 50: 1 salvianolic acids of 60: 1 salvianolic acids of physiological saline group dipyridamole injection liquid group danshen injections group salvianolic acid-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group 0.1: 1	10 10 10 10 10 10 10 10 10	10 6 7 5 4 2 1 4 3

As shown in Table 1, the medicine of Radix Salviae Miltiorrhizae total phenolic acids and the different proportionings of dipyridamole all can obviously resist the myocardial ischemia due to the pituitrin, and wherein with Radix Salviae Miltiorrhizae total phenolic acids: dipyridamole=1～20: 1 prescription pharmacological action is strong and consumption is lower.

2, to the influence of rabbit platelet aggregation

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

The influence of table 2 pair platelet aggregation

Group	Circle tree type (%)		Expansion type (%)		Aggregation number (individual)
							Before the administration	After the administration	Before the administration	After the administration	Before the administration	After the administration
	0.5: 1 salvianolic acid of 1: 1 salvianolic acid of 20: 1 salvianolic acids of 50: 1 salvianolic acids of 60: 1 salvianolic acids of physiological saline group dipyridamole injection liquid group danshen injections group salvianolic acid-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group 0.1: 1	72.3± 4.67 73.8± 5.06 70.1± 6.01 69.4± 4.95 68.5± 5.12 69.3± 5.63 71.2± 6.38 70.9± 6.24 68.7± 4.15	75.2± 3.28 79.2± 5.62 75.1± 5.13 77.6± 3.58 81.6± 4.15 88.4± 4.36 87.5± 4.92 78.2± 5.24 75.6± 4.75	27.7± 4.67 26.2± 5.06 29.9± 6.01 30.6± 4.95 31.5± 5.12 30.7± 5.63 39.8± 6.38 29.1± 6.24 31.3± 4.15	24.8± 3.28 20.8± 5.62 24.9± 5.13 22.4± 3.58 18.4± 4.15 12.6± 4.36 12.5± 4.92 21.8± 5.24 24.4± 4.75	63.1± 3.21 65.2± 5.87 60.3± 5.96 61.2± 4.28 62.5± 3.49 63.7± 6.05 60.4± 4.36 62.4± 4.68 61.8± 4.26							61.1± 2.58 55.4± 5.14 52.8± 6.14 48.5± 5.27 46.2± 5.63 38.5± 6.17 40.2± 6.34 45.2± 5.13 47.8± 6.07

As shown in Table 2, the medicine of Radix Salviae Miltiorrhizae total phenolic acids and the different proportionings of dipyridamole can significantly reduce surface activity of blood platelet or aggregation effect, and the strong and weak degree of this effect is relevant with the proportioning of medicine.

Table 1, table 2 show: Radix Salviae Miltiorrhizae total phenolic acids compatibility dipyridamole can produce synergistic function, drug effect all is significantly improved than singly using with dosage dipyridamole or Radix Salviae Miltiorrhizae total phenolic acids, the medicine of dipyridamole 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 dipyridamole is: 1 part of dipyridamole, 1～20 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)
	5.0 5.5 6.0 6.5 7.0 7.5 8.0	Clear and bright clear and bright poor slightly	1.56 1.56 1.56 1.56 1.56 1.56 1.56	Clear and bright clear and bright poor					1.51 1.52 1.53 1.54 1.53 1.47 1.45

The result shows that the rational pH value scope of the present invention is 5.0～7.0.

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 (%)	Total phenolic acid rate of transform (%)	Outward appearance
			0.1 0.5 1.0	70.5 68.2 63.7	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 dextran, the glucose poloxamer, mannitol glycine dextran 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	Carefully generally carefully general carefully general	The moulding moulded molding of part atrophy, a small amount of atrophy is moulding moulded, the molding of partly subsiding is moulding moulded, 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.

Experimental example 3: dispersible tablet disintegrating agent screening

The kind of disintegrating agent, quantity directly have influence on the dispersing uniformity of preparation in the dispersible tablet, are the leading indicators of weighing the dispersible tablet quality, thus we to select disintegration time for use be that performance assessment criteria is investigated different disintegrating agents, the results are shown in following table.

The disintegrating agent table of merit rating

Disintegrating agent	With the ointment ratio	Disintegration time (minute)
			Crospolyvinylpyrrolidone low-substituted hydroxypropyl cellulose carboxymethyl starch sodium crospolyvinylpyrrolidone, the low-substituted hydroxypropyl cellulose low-substituted hydroxypropyl cellulose, the microcrystalline Cellulose crospolyvinylpyrrolidone, microcrystalline Cellulose	1∶2.5 1∶2.5 1∶2.5 1∶2.5 1∶2.5 1∶2.5	2.4 2.6 2.8 2.1 2.5 2.3

From the result of above-mentioned test as can be seen, most of disintegrating agent can improve the disintegration time of dispersible tablet, all can reach the requirement of dispersible tablet.But by contrast, after employing crospolyvinylpyrrolidone and the low-substituted hydroxypropyl cellulose combination, the disintegrate best results.

Test example 4: 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 dipyridamole 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 6.5%	15 20-10--better smooth, roundness 5.8%	15--10-20 relatively poor roundness differ from 7.8%	15-20-10-better matter is soft, roundness 7.1%	15-15--15 better matter are soft, roundness 6.7%

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.

Concrete embodiment

Embodiments of the invention 1: dipyridamole 10g Radix Salviae Miltiorrhizae total phenolic acids 200g

Get dipyridamole, add the injection water, add the stirring of 0.6% citric acid and make it dissolving, medicinal liquid is standby; Get Radix Salviae Miltiorrhizae total phenolic acids and add injection and blunge and make dissolving, filter filtrate for later use; Above-mentioned two medicinal liquids are merged, boil the active carbon that the back adds 0.5% (W/V), keep little and boiled 30 minutes, cold slightly filtration, boil filtrate adjust pH to 5.0～6.5, 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 dipyridamole and 20 parts of Radix Salviae Miltiorrhizae total phenolic acidss.

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

Get dipyridamole, add the injection water, add the stirring of 0.5% tartaric acid and make it dissolving, medicinal liquid is standby; Get Radix Salviae Miltiorrhizae total phenolic acids 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 5.0～7.0, adds 0.5% activated needle-use activated carbon, boil absorption, carbon removal, fine straining, filtrate adds the injection water to ormal weight, spend the night 4 ℃ of cold preservations, coarse filtration, fine straining divide to install in the ampoule bottle sterilization, packing promptly gets the injection with small volume or the concentrated solution for injection that contain 1 part of dipyridamole and 1 part of Radix Salviae Miltiorrhizae total phenolic acids.

Embodiments of the invention 3: dipyridamole 10g Radix Salviae Miltiorrhizae total phenolic acids 600g

Get dipyridamole and add the injection water, add the stirring of 0.65% tartaric acid and make it dissolving, medicinal liquid is standby; Get Radix Salviae Miltiorrhizae total phenolic acids, add an amount of water for injection dissolving, medicinal liquid is standby; Above-mentioned two medicinal liquids are merged, add the glucose or the sodium chloride of ormal weight, by volume add 0.3% needle-use activated carbon behind the mixed dissolution, boil, keep little 30min that boils, cold slightly filtration, filtrate adds the injection water to an amount of, and boil adjust pH to 5.5～7.0,4 ℃ of cold preservations are spent the night, coarse filtration, fine straining add to the full amount of water for injection, packing, sterilization promptly gets the glucose or the sodium chloride intravenous infusion that contain 1 part of dipyridamole and 60 parts of Radix Salviae Miltiorrhizae total phenolic acidss.

Embodiments of the invention 4: dipyridamole 12g Radix Salviae Miltiorrhizae total phenolic acids 6g

Get dipyridamole and add the injection water, add the stirring of 0.2% citric acid and make it dissolving, medicinal liquid is standby; Get Radix Salviae Miltiorrhizae total phenolic acids, add an amount of water for injection, stir and make dissolving, medicinal liquid is standby; Above-mentioned two medicinal liquids are merged, adjust pH to 5.5～7.0 add the injection water to ormal weight, mixing, the needle-use activated carbon of adding 0.5%, boiled 30 minutes, coarse filtration, reuse 0.45 μ m and 0.22 μ m microporous filter membrane filter, divide and install in the enamel tray, lyophilization, the equilibration time when the balance solidification point of phase I is 0 ℃ is 1.5 hours, i.e. the time of shelf temperature and product temperature basically identical; The second stage solidification point is from 0 ℃ during to minimum eutectic temperature-16 ℃, and shelf temperature and product temperature equilibration time are 2 hours; Phase III continues to be cooled to-40 ℃, need 2 hours approximately, kept this temperature 2 hours, freeze the jail fully until product, promptly begin evacuation, enter drying program, under-40 ℃ of constant temperature-evacuation, slowly heat up, 2～4 ℃/h, to the lowest total of the melting point temperature, time is about 12 hours, after sublimation drying is finished, continue under the low pressure condition, it is dry to remove residual moisture to heat up, time is about 14～16 hours, kept more than 35 ℃ dry 1.5 hours, and under aseptic condition, divided to install in the cillin bottle, promptly get the lyophilizing injectable sterile powder that contains 1 part of dipyridamole and 0.5 part of Radix Salviae Miltiorrhizae total phenolic acids.

Embodiments of the invention 5: dipyridamole 1g Radix Salviae Miltiorrhizae total phenolic acids 50g

Getting dipyridamole, to add injection water and citric acid an amount of, stirs and make it dissolving, and medicinal liquid is standby; Get Radix Salviae Miltiorrhizae total phenolic acids, add an amount of water for injection dissolving, medicinal liquid is standby; Above-mentioned two medicinal liquids are merged, by volume add 0.5% active carbon, boil, keep little 30min that boils, cold slightly filtration, filtrate adds the injection water to an amount of, boil adjust pH to 5.5～7.0, and 4 ℃ of cold preservations are spent the night, add to the full amount of water for injection, coarse filtration, fine straining are 180 ℃ in inlet temperature, leaving air temp is 50 ℃, air velocity is a spray drying under the condition of 18ms-1, and packing promptly gets and contains 1 part of dipyridamole and 50 parts of Radix Salviae Miltiorrhizae total phenolic acids spray drying sterilized powders.

Embodiments of the invention 6: dipyridamole 10g Radix Salviae Miltiorrhizae total phenolic acids 1g

With dipyridamole and Radix Salviae Miltiorrhizae total phenolic acids mix homogeneously, polyvinylpyrrolidone, the stevioside of adding 5% are an amount of, and compacting promptly gets the oral cavity disintegration tablet that contains 1 part of dipyridamole and 0.1 part of Radix Salviae Miltiorrhizae total phenolic acids in flakes.

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

With dipyridamole 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 dipyridamole and 3 parts of Radix Salviae Miltiorrhizae total phenolic acidss.

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

With dipyridamole and Radix Salviae Miltiorrhizae total phenolic acids mix homogeneously, in principal agent: the ratio of adjuvant=2.5: 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 dipyridamole and 5 parts of Radix Salviae Miltiorrhizae total phenolic acids dispersible tablets.

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

With dipyridamole 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 dipyridamole and 7 parts of Radix Salviae Miltiorrhizae total phenolic acidss.

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

With dipyridamole 3g and Radix Salviae Miltiorrhizae total phenolic acids 24g mix homogeneously, add 3 times of amount starch and 1 times of amount dextrin, mix homogeneously is granulated, drying, granulate, encapsulated, promptly get the capsule that contains 1 part of dipyridamole and 1 part of Radix Salviae Miltiorrhizae total phenolic acids.

Embodiments of the invention 11: dipyridamole 3g Radix Salviae Miltiorrhizae total phenolic acids 30g

With dipyridamole and Radix Salviae Miltiorrhizae total phenolic acids mix homogeneously, add the vegetable oil of 0.7 times of weight and 1.0% Cera Flava, the dropping preparation method pill, compacting promptly gets and contains 1 part of dipyridamole and 10 parts of Radix Salviae Miltiorrhizae total phenolic acids soft capsules.

Embodiments of the invention 12: dipyridamole 4g Radix Salviae Miltiorrhizae total phenolic acids 60g

With dipyridamole, 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 dipyridamole and 15 parts of Radix Salviae Miltiorrhizae total phenolic acidss.

Embodiments of the invention 13: dipyridamole 2g Radix Salviae Miltiorrhizae total phenolic acids 8g

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 8g 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 8min, gets liposome turbid liquor, behind the frozen drying, cross 180 mesh sieves, aseptic subpackaged, promptly get the pro-liposome injectable powder.

Dipyridamole 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 0.1～60 part 1 part of dipyridamole 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 0.5～50 part 1 part of dipyridamole 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 1～20 part 1 part of dipyridamole 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 dipyridamole one or both is prepared into liposome or pro-liposome.

7, according to the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease in the claim 1～6, it is characterized in that: 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 dipyridamole 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 dipyridamole amount, pharmaceutical adjunct amount and the water quantities in the ejection preparation; Dipyridamole content should be 90.0%～110.0% of preparation labelled amount.

9, according to the 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 dipyridamole, add the injection water, tartarize or citric acid stir and make it dissolving, and medicinal liquid is standby; Get Radix Salviae Miltiorrhizae total phenolic acids and add injection and blunge and make dissolving, filter filtrate for later use; Above-mentioned two medicinal liquids are merged, boil the active carbon that the back adds 0.5% (W/V), keep little and boiled 30 minutes, cold slightly filtration, boil filtrate adjust pH to 5.0～6.5, 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.

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, 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 dipyridamole;

(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 dipyridamole.