CN1969927A - 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 glycosides of codonopsis pilosula 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, pulmonary heart disease, cerebral ischemia, nervous prostration, climacteric metancholia, The preparation of the invention has the advantages of high purity, ensured constituents, controllable quality, improved curative 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

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

Radix Codonopsis, has invigorating the spleen and replenishing QI, the effect of spleen invigorating lung benefiting, be used for deficiency of the spleen and lung, the cardiopalmus of breathing hard, anorexia and loose stool, dyspnea due to deficiency cough, interior-heat symptom such as quench one's thirst studies show that the glycoside composition is that main effective site has effects such as QI invigorating heart tonifying, alleviate myocardial ischemia, blood circulation promoting and blood stasis dispelling in the Radix Codonopsis, pharmacodynamics and modern clinical demonstration, Radix Codonopsis has good curative effect for diseases such as the deficiency of vital energy, the insufficiency of the spleen cardiac disorder that causes, shocks; Dipyridamole is antiplatelet aggregation and coronary artery expansion medicine, is being widely used aspect the treatment of cardiovascular and cerebrovascular disease, but clinical discovery, asiabell preparation mostly is pure Chinese medicinal preparation, and onset is slow, and the course of treatment is long, and bioavailability is not high, and the curative effect undulatory property is big; And dipyridamole has certain toxic and side effects, is not suitable for for a long time to take, and clinical practice also is subjected to certain limitation.Searching document and patent database find no the preparation of Radix Codonopsis effective site and dipyridamole composition of prescription.For this reason, the inventor adopts Radix Codonopsis effective site Radix Codonopsis Pilosulae total glucosides and dipyridamole composition of prescription, examine or check its moulding process and drug action, further investigate the optimal proportion scope of Radix Codonopsis Pilosulae total glucosides and dipyridamole compatibility simultaneously, and then provide a kind of more safe and effective for the patient, the curative effect fluctuation range is little, the pharmaceutical preparation that toxic and side effects is little.

Summary of the invention

In view of above situation, the inventor develops a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease, by Radix Codonopsis Pilosulae total glucosides and dipyridamole prescription.Radix Codonopsis Pilosulae total glucosides has alleviate myocardial ischemia, anticoagulant, functions such as blood flow increasing, dipyridamole has antiplatelet aggregation, coronary artery dilator increases its blood flow, improve functions such as myocardium blood supply and oxygen supply, preparation has been widely used in the treatment of cardiovascular and cerebrovascular disease separately, but up to now, does not have the technology of both compatibility agents.For this reason, the objective of the invention is to disclose this main pharmaceutical composition by dipyridamole and Radix Codonopsis Pilosulae total glucosides's prescription, 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 prescription and the technology of the best of the two, the product that obtains shows through pharmacodynamics test, Synergistic, more independent asiabell preparation, 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 0.1～50 part 1 part of dipyridamole and Radix Codonopsis Pilosulae total glucosides.Say exactly, calculate that it is mainly to be made up of for 0.5～20 part 1 part of dipyridamole and Radix Codonopsis Pilosulae total glucosides according to parts by weight.Preferred prescription is to calculate according to parts by weight, and it is mainly to be made up of for 1～15 part 1 part of dipyridamole and Radix Codonopsis Pilosulae total glucosides.

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 Codonopsis Pilosulae total glucosides and the dipyridamole one or both is prepared into liposome or pro-liposome.

Radix Codonopsis Pilosulae total glucosides's effective site is commercially available or adopts following method to prepare: get codonopsis pilosula, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Radix Codonopsis 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 Codonopsis Pilosulae total glucosides's effective site.

Calculate by weight percentage, the content of glycoside composition 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 glycoside composition 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 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 Codonopsis Pilosulae total glucosides 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 5.5～7.0, and coarse filtration, fine straining are spent the night in cold preservation (4 ℃); Mannitol is added the injection water be mixed with 120mg/ml solution,, 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 the coronary heart disease, pulmonary heart disease, cerebral ischemia, neurasthenia, climacteric syndrome of treatment spleen-deficient, qi-deficiency type.

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 with tangshenoside's constituents being characterized as main finger printing;

(2) all or part of differential test method in codonopsis pilosula, lobetyolin, the I of tangshenoside, atractylenoide, the dipyridamole;

(3) content test method of all or part of composition in lobetyolin, the I of tangshenoside, atractylenoide, total glycosides, the dipyridamole.

In the prior art, Radix Codonopsis and dipyridamole all are active drugs of treatment cardiovascular and cerebrovascular disease, but the preparation that is used as medicine with Radix Codonopsis, drawbacks such as exist onset slower, bioavailability is low, and the curative effect fluctuation is big, though and the onset of dipyridamole intravenously administrable is very fast, untoward reaction is arranged, be unsuitable for taking for a long time; So, the applicant is combined into novel formulation with Radix Codonopsis Pilosulae total glucosides and dipyridamole and develops research, bring into play both cooperative compensating effects by compatibility, for new medication of treatment increase of cardiovascular and cerebrovascular disease is selected at angina pectoris, arrhythmia, pulmonary heart disease, cerebral thrombosis etc.Simultaneously, can system further investigate Radix Codonopsis Pilosulae total glucosides and the safety of dipyridamole 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 Codonopsis Pilosulae total glucosides: dipyridamole=1～15: 1 prescription pharmacological action is strong and consumption is lower, preparations shaping and having good stability, and both compatibilities can reach the effect of efficacy enhancing and toxicity reducing.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 independent preparation of Radix Codonopsis, dipyridamole 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, myocardial infarction and ischemia model test due to the medicine method

162 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 18, 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 1 μ g/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 Radix Codonopsis Pilosulae total glucosides of 1: 1 Radix Codonopsis Pilosulae total glucosides of 15: 1 Radix Codonopsis Pilosulae total glucosides of 20: 1 Radix Codonopsis Pilosulae total glucosides of 50: 1 Radix Codonopsis Pilosulae total glucosides of group Radix Codonopsis Pilosulae total glucosides of physiological saline group dipyridamole injection liquid group Radix Codonopsis Pilosulae total glucosides-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group 0.1: 1	18 18 18 18 18 18 18 18 18	18 13 15 11 9 3 4 6 8

As shown in Table 1, the medicine of Radix Codonopsis Pilosulae total glucosides and the different proportionings of dipyridamole all can obviously resist the myocardial ischemia due to the pituitrin, and wherein with Radix Codonopsis Pilosulae total glucosides: dipyridamole=1～15: 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 Radix Codonopsis Pilosulae total glucosides of 1: 1 Radix Codonopsis Pilosulae total glucosides of 15: 1 Radix Codonopsis Pilosulae total glucosides of 20: 1 Radix Codonopsis Pilosulae total glucosides of 50: 1 Radix Codonopsis Pilosulae total glucosides of group Radix Codonopsis Pilosulae total glucosides of physiological saline group dipyridamole injection liquid group Radix Codonopsis Pilosulae total glucosides-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group-Dipyridamole group 0.1: 1	76.2± 2.34 73.8± 3.47 72.5± 3.56 74.3± 2.89 75.1± 3.06 72.5± 3.89 70.1± 4.23 71.5± 5.16 72.2± 4.11	79.5± 2.36 80.3± 3.42 77.2± 4.12 84.2± 3.68 85.1± 5.12 90.5± 7.23 89.4± 7.16 87.3± 6.95 85.1± 2.34	23.8± 2.34 26.2± 3.47 27.5± 3.56 25.7± 2.89 24.9± 3.06 27.5± 3.89 29.9± 4.23 28.5± 5.16 27.8± 4.11	20.5± 2.36 19.7± 3.42 22.8± 4.12 15.8± 3.68 14.9± 5.12 9.5± 7.23 10.6± 7.16 12.7± 6.95 14.9± 2.34	70.5± 5.12 68.3± 4.38 67.2± 5.78 71.8± 6.58 69.5± 8.14 68.4± 6.98 66.5± 6.43 67.2± 4.58 66.9± 8.36							67.6± 6.21 57.2± 5.78 59.7± 7.36 58.6± 7.15 49.3± 6.24 43.7± 7.36 46.2± 7.25 49.5± 5.69 53.2± 6.42

As shown in Table 2, the medicine of Radix Codonopsis Pilosulae total glucosides 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 Codonopsis Pilosulae total glucosides's compatibility dipyridamole can produce synergistic function, drug effect all is significantly improved than singly using with dosage dipyridamole or Radix Codonopsis Pilosulae total glucosides, dipyridamole all can significantly increase curative effect with the medicine of the different proportionings of Radix Codonopsis Pilosulae total glucosides, but the strong and weak degree of effect is relevant with the proportioning of medicine; From interpretation, the best proportioning of Radix Codonopsis Pilosulae total glucosides and dipyridamole is: 1 part of dipyridamole, 1～15 part of Radix Codonopsis Pilosulae total glucosides.

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 40 ℃ the injection of different pH value, investigated its stability respectively.

PH value	0 month		March
					Clarity	Total glycosides (mg/ml)	Clarity	Total glycosides (mg/ml)
	4.5 5.0 5.5 6.0 6.5 7.0 7.5	Difference is slightly poor clear and bright poor	3.58 3.58 3.58 3.58 3.58 3.58 3.58	Difference is poor slightly clear and bright poor					3.12 3.25 3.37 3.42 3.48 3.52 3.27

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

2.2 activated carbon dosage influences injection

Injection has the pyrogen material owing to solvent, raw material, container etc. in process of production, and the safety of injection is reduced, and therefore needs to remove the pyrogen material in the process of preparation injection.The applicant adopts active carbon adsorption, and heat of adsorption originality composition helps filter and decolouring simultaneously on the one hand, also can improve the appearance character of preparation, because of active carbon is investigated its consumption.

The activated carbon dosage investigation table

Activated carbon dosage (%)	The total glycosides rate of transform (%)	Outward appearance
			0.1 0.5 1.0	86.1 80.6 74.5	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 freeze-dry process examination

2.3.1 the screening of caffolding agent kind

The screening of caffolding agent kind

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

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

2.3.2 caffolding agent consumption screening

The mannitol solution (60mg/ml, 120mg/ml and 150mg/ml) of variable concentrations is mixed in varing proportions with medicinal liquid, filter, every cillin bottle loading amount is 3ml, lyophilization.Lyophilisation condition :-45 ℃, behind the pre-freeze 8h, the beginning evacuation, and be warming up to-40 ℃, keep 10h; Be warming up to-30 ℃, keep 10h; Be warming up to-20 ℃, keep 10h; Be warming up to-10 ℃, keep 5h; Be warming up to 0 ℃, keep 5h; Be warming up to 15 ℃, keep 2h; Be warming up to 30 ℃, keep 2h, the result is as table.

The screening of mannitol consumption

Numbering	Mannitol concentration (mg/ml)	Mannitol: medicinal liquid (v: v)	Profile	Solubility	Clarity
						1 2 3	60 120 150	2∶1 2∶1 2∶1	Part is subsided intact	Well carefully	Up to specification up to specification

As seen from table, when the ratio of caffolding agent consumption and medicinal liquid is 2: 1, the sample character is that the sample of 120mg/ml and 150mg/ml is relatively good with the mannitol concentration, the sample of 60mg/ml has part to subside, but major part still is molding, but take all factors into consideration the consumption and the clinical dose of adjuvant, the optimum selection mannitol concentration is 120mg/ml, and the volume ratio of mannitol solution and medicinal liquid is 2: 1.

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 (%)
				150 160 170	55 60 75	15 16 17	3.68 2.15 3.17

From above-mentioned result of the test as can be seen, three kinds of conditions all can obtain material preferably, but are 160 ℃ with inlet temperature by contrast, and outlet temperature is 60 ℃, and air velocity is that the condition of 16ms-1 is the 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 ointment ratio	Disintegration time (minute)
			Crospolyvinylpyrrolidone low-substituted hydroxypropyl cellulose polyvinylpolypyrrolidone crospolyvinylpyrrolidone, the low-substituted hydroxypropyl cellulose low-substituted hydroxypropyl cellulose, the sodium carboxymethyl cellulose crospolyvinylpyrrolidone, microcrystalline Cellulose	1∶1.5 1∶1.5 1∶1.5 1∶1.5 1∶1.5 1∶1.5	2.1 2.4 2.2 1.8 2.3 2.0

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, dipyridamole and Radix Codonopsis Pilosulae total glucosides's 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, 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 70～80 ℃, after treating whole fusions, the mixed material that adds dipyridamole and Radix Codonopsis Pilosulae total glucosides, investigate the fusion situation of substrate and material, (drip the system condition: expect 80 ℃ 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 5cm, 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 matrix of material and material merge the situation dripping pill outward appearance ball method of double differences	15 30--poor slightly smooth, roundness differs from 7.6% slightly	15 20-10 is good smooth, roundness 6.2%	15--30 relatively poor roundness differ from 9.0%	15-30-slightly is poor smooth, roundness 8.0%	15-20 10 is better smooth, roundness 7.1%	15 20 10-better is smooth, roundness 7.3%

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

Concrete embodiment

Embodiments of the invention 1: the dipyridamole 1g 50g of Radix Codonopsis Pilosulae total glucosides

Get dipyridamole, add the injection water, tartarize or citric acid stir and make it dissolving, and medicinal liquid is standby; Get Radix Codonopsis Pilosulae total glucosides 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 5.5～7.0, and coarse filtration, fine straining are spent the night in cold preservation (4 ℃); Mannitol is added the injection water be mixed with 120mg/ml solution,, 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 that contains 50 parts of Radix Codonopsis Pilosulae total glucosides and 1 part of dipyridamole.

Embodiments of the invention 2: the dipyridamole 2g 30g of Radix Codonopsis Pilosulae total glucosides

Get dipyridamole, add the injection water, tartarize or citric acid stir and make it dissolving, and medicinal liquid is standby; Get Radix Codonopsis Pilosulae total glucosides and add injection and blunge and make dissolving, filter filtrate for later use; Above-mentioned two medicinal liquids are merged, and regulating pH value is 5.5～7.0, adds 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 and contains 15 parts of Radix Codonopsis Pilosulae total glucosides and 1 part of dipyridamole injection with small volume or concentrated solution for injection.

Embodiments of the invention 3: the dipyridamole 5g 5g of Radix Codonopsis Pilosulae total glucosides

Get dipyridamole and add the injection water, tartarize stirs and makes it dissolving, and medicinal liquid is standby; Get Radix Codonopsis Pilosulae total glucosides, 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 0.6% 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 1 part of Radix Codonopsis Pilosulae total glucosides.

Embodiments of the invention 4: the dipyridamole 1g 20g of Radix Codonopsis Pilosulae total glucosides

Get dipyridamole and add the injection water, add the citric acid stirring and make it dissolving, medicinal liquid is standby; Get Radix Codonopsis Pilosulae total glucosides, add an amount of water for injection, stir and make dissolving, medicinal liquid is standby; Above-mentioned two medicinal liquids are merged, adjust pH to 5.5～7.0 add the injection water to ormal weight, mixing, the needle-use activated carbon of adding 0.6%, boiled 30 minutes, coarse filtration, reuse 0.45 μ m and 0.22 μ m microporous filter membrane filter, divide and install in the enamel tray, lyophilization, the equilibration time when the balance solidification point of phase I is 0 ℃ is 1.5 hours, i.e. the time of shelf temperature and product temperature basically identical; The second stage solidification point is from 0 ℃ during to minimum eutectic temperature-16 ℃, and shelf temperature and product temperature equilibration time are 2 hours; Phase III continues to be cooled to-40 ℃, need 2 hours approximately, kept this temperature 2 hours, freeze the jail fully until product, promptly begin evacuation, enter drying program, under-40 ℃ of constant temperature-evacuation, slowly heat up, 2～4 ℃/h, to the lowest total of the melting point temperature, time is about 12 hours, after sublimation drying is finished, continue under the low pressure condition, it is dry to remove residual moisture to heat up, time is about 14～16 hours, kept more than 35 ℃ dry 1.5 hours, and under aseptic condition, divided to install in the cillin bottle, promptly get the lyophilizing injectable sterile powder that contains 1 part of dipyridamole and 20 parts of Radix Codonopsis Pilosulae total glucosides.

Embodiments of the invention 5: the dipyridamole 10g 5g of Radix Codonopsis Pilosulae total glucosides

Getting dipyridamole, to add injection water and citric acid an amount of, stirs and make it dissolving, and medicinal liquid is standby; Get Radix Codonopsis Pilosulae total glucosides, 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 160 ℃ in inlet temperature, outlet temperature is 60 ℃, air velocity is a spray drying under the condition of 16ms-1, and packing promptly gets and contains 1 part of dipyridamole and 0.5 part of Radix Codonopsis Pilosulae total glucosides's spray drying sterilized powder.

Embodiments of the invention 6: the dipyridamole 10g 20g of Radix Codonopsis Pilosulae total glucosides

With dipyridamole and Radix Codonopsis Pilosulae total glucosides's mix homogeneously, add 8% polyvinylpyrrolidone, 3% polyvinylpolypyrrolidone, an amount of lemon yellow, micropowder silica gel, compacting promptly gets the oral cavity disintegration tablet that contains 1 part of dipyridamole and 2 parts of Radix Codonopsis Pilosulae total glucosides in flakes.

Embodiments of the invention 7: the dipyridamole 10g 1g of Radix Codonopsis Pilosulae total glucosides

With dipyridamole, Radix Codonopsis Pilosulae total glucosides, PEG4000 and polyoxyethylene monostearate (2: 1) mix homogeneously, put in the rustless steel container mixing, after being heated to whole fusions, insulation 30min, mechanical high-speed stirs 15min to evenly, is transferred to the drop pill machine, with dimethicone or liquid paraffin is coolant, drip system, collect drop pill, remove the dimethicone or the liquid paraffin on surface, packing promptly gets the drop pill that contains 1 part of dipyridamole and 0.1 part of Radix Codonopsis Pilosulae total glucosides.

Embodiments of the invention 8: the dipyridamole 4g 20g of Radix Codonopsis Pilosulae total glucosides

With dipyridamole and Radix Codonopsis Pilosulae total glucosides's mix homogeneously, in principal agent: the ratio of adjuvant=1: 1.5 adds calcium bicarbonate, in principal agent: the ratio of adjuvant=1.5: 1 adds crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose composite auxiliary material mix homogeneously, 70% ethanol system soft material, granulation, dry, granulate adds an amount of Pulvis Talci, micropowder silica gel, and is evenly mixed, tabletting promptly gets and contains 1 part of dipyridamole and 5 parts of Radix Codonopsis Pilosulae total glucosides's dispersible tablets.

Embodiments of the invention 9: the dipyridamole 3g 21g of Radix Codonopsis Pilosulae total glucosides

With dipyridamole and Radix Codonopsis Pilosulae total glucosides's 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 Codonopsis Pilosulae total glucosides.

Embodiments of the invention 10: the dipyridamole 7g 21g of Radix Codonopsis Pilosulae total glucosides

With dipyridamole and Radix Codonopsis Pilosulae total glucosides's mix homogeneously, add equivalent starch and equivalent dextrin, mix homogeneously is granulated, drying, granulate, encapsulated, promptly get the capsule that contains 1 part of dipyridamole and 3 parts of Radix Codonopsis Pilosulae total glucosides.

Embodiments of the invention 11: the dipyridamole 2g 40g of Radix Codonopsis Pilosulae total glucosides

With dipyridamole and Radix Codonopsis Pilosulae total glucosides's mix homogeneously, press medication amount: substrate amount=1: 1.8 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100g: 40g: 60g: 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 and contains 1 part of dipyridamole and 20 parts of Radix Codonopsis Pilosulae total glucosides's soft capsules.

Embodiments of the invention 12: the dipyridamole 15g 30g of Radix Codonopsis Pilosulae total glucosides

With dipyridamole, Radix Codonopsis Pilosulae total glucosides's mixing, add equivalent starch, equivalent dextrin mixing, to granulate, packing promptly gets the granule that contains 1 part of dipyridamole and 2 parts of Radix Codonopsis Pilosulae total glucosides.

Embodiments of the invention 13: the dipyridamole 2g 8g of Radix Codonopsis Pilosulae total glucosides

With dipyridamole, Radix Codonopsis Pilosulae total glucosides's mixing, drying adds appropriate amount of starch, ethanol with 65% and 1.8% soybean oil system soft material, and extruding-round as a ball pill selects ball, and drying promptly gets the pellet that contains 1 part of dipyridamole and 4 parts of Radix Codonopsis Pilosulae total glucosides.

Embodiments of the invention 14: the dipyridamole 1g 15g of Radix Codonopsis Pilosulae total glucosides

With Radix Codonopsis Pilosulae total glucosides, 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 15: the dipyridamole 8g 8g of Radix Codonopsis Pilosulae total glucosides

With Radix Codonopsis Pilosulae total glucosides, 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 Codonopsis Pilosulae total glucosides can be with commercially available or Radix Codonopsis alcohol extract provided by the invention, water extract, water extract-alcohol precipitation extract, semi-bionic extraction thing, supercritical extract or the like, but: the content for glycoside composition in the oral Radix Codonopsis Pilosulae total glucosides is not less than 50%, and the content of glycoside composition is not less than 70% in the Radix Codonopsis Pilosulae total glucosides of injection.

Claims (11)

1, a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease is characterized in that: calculate according to parts by weight, it mainly is to be made for 0.1～50 part by 1 part of dipyridamole and Radix Codonopsis Pilosulae total glucosides.

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 contains 1 part of dipyridamole and Radix Codonopsis Pilosulae total glucosides is made for 0.5～20 part.

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 contains 1 part of dipyridamole and Radix Codonopsis Pilosulae total glucosides is made for 1～15 part.

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 Codonopsis Pilosulae total glucosides 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 Codonopsis Pilosulae total glucosides's effective site is commercially available or adopts following method to prepare: get codonopsis pilosula, adding entry or alcoholic solution extracts, merge extractive liquid,, filter, filtrate concentrate the Radix Codonopsis 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, the total villous themeda effective site of Radix Codonopsis.

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 glycoside composition 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 glycoside composition 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 pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease in the claim 1～5, it is characterized in that: the Injectable sterile block prepares like this: get dipyridamole, add the injection water, tartarize or citric acid stir and make it dissolving, and medicinal liquid is standby; Get Radix Codonopsis Pilosulae total glucosides 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 5.5～7.0, and coarse filtration, fine straining are spent the night in cold preservation (4 ℃); Mannitol is added the injection water be mixed with 120mg/ml solution,, 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 the application at disease medicaments such as the coronary heart disease of preparation treatment spleen-deficient, qi-deficiency type, pulmonary heart disease, cerebral ischemia, neurasthenia, climacteric syndromes.

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 with tangshenoside's constituents being characterized as main finger printing;

(2) all or part of differential test method in codonopsis pilosula, lobetyolin, the I of tangshenoside, atractylenoide, the dipyridamole;

(3) content test method of all or part of composition in lobetyolin, the I of tangshenoside, atractylenoide, total glycosides, the dipyridamole.