CN1969926A - 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 Codonopsis pilosula glycosides 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, thrombotic phlebitis, capillary vessel hemorrhage, nervous prostration and climacteric metancholia.

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 main effective site in the Radix Codonopsis, have effects such as QI invigorating heart tonifying, alleviate myocardial ischemia, blood circulation promoting and blood stasis dispelling, 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; Troxerutin has anticoagulant, prevents thrombosis, and the blood vessel injury that medmain, Kallidin I are caused increases capillary resistance simultaneously, reduces effects such as capillary permeability medicine, is widely used in 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 troxerutin has certain side effect, 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 troxerutin composition of prescription.For this reason, the inventor adopts Radix Codonopsis effective site Radix Codonopsis Pilosulae total glucosides and troxerutin 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 troxerutin 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, mainly by Radix Codonopsis Pilosulae total glucosides and troxerutin prescription.Radix Codonopsis Pilosulae total glucosides has effects such as QI invigorating heart tonifying, alleviate myocardial ischemia, blood circulation promoting and blood stasis dispelling, and troxerutin can suppress erythrocyte, platelet aggregation, prevents thrombosis, increase blood oxygen saturation, microcirculation improvement promotes neovascularity to generate, and promotes side Zhi Xunhuan, the cerebral blood flow increasing amount, increase the blood supply in half blanking bar zone, improve hemodynamic every index, promote the recovery of pathological changes function of peripheral nerves, improve clinical symptoms and sign, preparation has been widely used in the treatment of cardiovascular and cerebrovascular disease separately.Up to now, the preparation that does not have both compatibilities.For this reason, the objective of the invention is to disclose this main pharmaceutical composition by troxerutin 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, the troxerutin preparation, curative effect all is significantly increased.

The technical solution adopted in the present invention is:

A kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease calculates according to parts by weight, and it is mainly to be made up of for 0.01～10 part 1 part of troxerutin and Radix Codonopsis Pilosulae total glucosides.Say exactly, calculate that it is mainly to be made up of for 0.1～5 part 1 part of troxerutin 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 0.5～3 part 1 part of troxerutin 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 troxerutin 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 according to percentage by weight, the content of glycoside composition 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 glycoside composition 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, 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, thrombophlebitis, capillary hemorrhage, 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 troxerutin;

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

In the prior art, Radix Codonopsis and troxerutin 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 troxerutin 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 troxerutin and develops research, bring into play both cooperative compensating effects by compatibility, for new medication of treatment increase of cardiovascular and cerebrovascular disease is selected at angina pectoris, arrhythmia, pulmonary heart disease, cerebral thrombosis etc.Simultaneously, can system further investigate Radix Codonopsis Pilosulae total glucosides and the safety of troxerutin compatibility and the controllability of quality, for data for clinical drug use is given security.By thrombotic 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: troxerutin=0.5～3: 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, troxerutin better efficacy not only, treating both the principal and secondary aspects of a disease, the Synergistic attenuation, and use and to carry all easily, the multiple different ejection preparation and the preparation method of oral formulations are provided, be suitable for different crowd and use, avoided dosage form single to hospitalized patients bring unfavorable.

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

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

1, thrombotic model test due to the medicine method

135 of healthy male mices; body weight 25～35g; be divided into 9 groups; grouping sees the following form, and 15 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 Radix Codonopsis Pilosulae total glucosides of 0.5: 1 Radix Codonopsis Pilosulae total glucosides of 3: 1 Radix Codonopsis Pilosulae total glucosides of 5: 1 Radix Codonopsis Pilosulae total glucosides of 10: 1 Radix Codonopsis Pilosulae total glucosides of group Radix Codonopsis Pilosulae total glucosides of physiological saline group troxerutin injection group Radix Codonopsis Pilosulae total glucosides-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group 0.01: 1	15 15 15 15 15 15 15 15 15	0 10 8 11 12 13 14 11 10	0 66.7 53.3 73.3 80 86.7 93.3 73.3 66.7

As shown in Table 1, the medicine of Radix Codonopsis Pilosulae total glucosides and the different proportionings of troxerutin has protective effect to the inductive mice thrombus in vivo of collagen protein-epinephrine, and the strong and weak degree of this effect is relevant with the proportioning of medicine.Wherein with Radix Codonopsis Pilosulae total glucosides: troxerutin=0.5～3: 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 Radix Codonopsis Pilosulae total glucosides of 0.5: 1 Radix Codonopsis Pilosulae total glucosides of 3: 1 Radix Codonopsis Pilosulae total glucosides of 5: 1 Radix Codonopsis Pilosulae total glucosides of 10: 1 Radix Codonopsis Pilosulae total glucosides of group Radix Codonopsis Pilosulae total glucosides of physiological saline group troxerutin injection group Radix Codonopsis Pilosulae total glucosides-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group-Troxerutin group 0.01: 1	75.2± 3.38 74.1± 2.58 73.5± 3.11 72.1± 4.26 73.4± 2.89 70.2± 3.66 72.8± 3.24 71.5± 4.27 73.6± 3.42	77.1± 4.25 83.3± 3.17 80.2± 4.63 85.2± 5.14 88.1± 6.23 91.2± 5.43 88.1± 6.39 86.3± 5.92 81.1± 3.24	24.8± 3.38 25.9± 2.58 26.5± 3.11 27.9± 4.26 26.6± 2.89 29.8± 3.65 27.2± 3.24 18.5± 4.27 26.4± 3.42	22.9± 4.25 16.7± 3.17 19.8± 4.63 14.8± 5.14 11.9± 6.23 8.8± 5.43 11.9± 6.39 13.7± 5.92 18.9± 3.24	65.5± 4.36 65.2± 5.11 64.3± 3.95 63.4± 3.54 64.7± 5.13 63.4± 3.52 64.5± 5.38 63.2± 4.15 62.9± 2.65							63.6± 5.23 56.3± 6.23 57.7± 5.31 50.2± 6.27 49.2± 5.31 43.7± 6.71 45.2± 6.92 49.5± 3.24 53.2± 3.42

As shown in Table 2, the medicine of Radix Codonopsis Pilosulae total glucosides 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 Codonopsis Pilosulae total glucosides's compatibility troxerutin can produce synergistic function, drug effect all is significantly improved than singly using with dosage troxerutin or Radix Codonopsis Pilosulae total glucosides, troxerutin 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 troxerutin is: 1 part of troxerutin, 0.5～3 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	10.1 10.1 10.1 10.1 10.1 10.1 10.1	Difference is slightly poor clear and bright poor					9.76 9.85 9.92 9.96 9.98 10.0 9.81

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

2.2 freeze-dry process examination

2.2.1 the screening of caffolding agent kind

The screening of caffolding agent kind

The caffolding agent kind	Caffolding agent: medicinal liquid (V: V)	Solubility	The finished product outward appearance
				Galactolipin dextran glucan sweet mellow wine glycine sweet mellow wine, propane diols glycine, the blank soup of polyethylene glycol	2∶1 2∶1 2∶1 2∶1 2∶1 2∶1 2∶1 3ml	Well generally carefully 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.

2.2.2 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.

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 (second)
			Crospolyvinylpyrrolidone low-substituted hydroxypropyl cellulose polyvinylpolypyrrolidone crospolyvinylpyrrolidone, the low-substituted hydroxypropyl cellulose crospolyvinylpyrrolidone, microcrystalline Cellulose	1∶2 1∶2 1∶2 1∶2 1∶2	124 145 162 100 113

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.

Concrete embodiment

Embodiments of the invention 1: the troxerutin 10g 30g of Radix Codonopsis Pilosulae total glucosides

Get troxerutin, Radix Codonopsis Pilosulae total glucosides 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 5.5～7.0, 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 3 parts of Radix Codonopsis Pilosulae total glucosides and 1 part of troxerutin.

Embodiments of the invention 2: the troxerutin 10g 5g of Radix Codonopsis Pilosulae total glucosides

Get troxerutin, Radix Codonopsis Pilosulae total glucosides and add injection and blunge and make dissolving, filter, it is 5.5～7.0 that filtrate is regulated pH value, add 0.5% activated needle-use activated carbon, boil absorption, carbon removal, fine straining, filtrate adds the injection water to ormal weight, spends the night coarse filtration, fine straining 4 ℃ of cold preservations, divide and install in the ampoule bottle, sterilization, packing promptly gets and contains 0.5 part of Radix Codonopsis Pilosulae total glucosides and 1 part of troxerutin injection with small volume or concentrated solution for injection.

Embodiments of the invention 3: the troxerutin 3g 15g of Radix Codonopsis Pilosulae total glucosides

Get troxerutin, Radix Codonopsis Pilosulae total glucosides, add an amount of water for injection dissolving, filtrate adds the glucose or the sodium chloride of ormal weight, by volume add 0.5% needle-use activated carbon behind the mixed dissolution, boil, keep little 30min that boils, cold slightly filtration, filtrate add the injection water to an amount of, adjust pH to 5.5～7.0, boil, 4 ℃ of cold preservations are spent the night, coarse filtration, fine straining, add to the full amount of water for injection, packing, sterilization promptly gets the glucose or the sodium chloride intravenous infusion that contain 1 part of troxerutin and 5 parts of Radix Codonopsis Pilosulae total glucosides.

Embodiments of the invention 4: the troxerutin 20g 2g of Radix Codonopsis Pilosulae total glucosides

Get troxerutin and add the injection water, stir 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 troxerutin and 0.1 part of Radix Codonopsis Pilosulae total glucosides.

Embodiments of the invention 5: the troxerutin 10g 100g of Radix Codonopsis Pilosulae total glucosides

Get troxerutin add the injection blunge make it the dissolving, 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 troxerutin and 10 parts of Radix Codonopsis Pilosulae total glucosides's spray drying sterilized powders.

Embodiments of the invention 6: the troxerutin 100g 1g of Radix Codonopsis Pilosulae total glucosides

With troxerutin 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 troxerutin and 0.01 part of Radix Codonopsis Pilosulae total glucosides in flakes.

Embodiments of the invention 7: the troxerutin 3g 12g of Radix Codonopsis Pilosulae total glucosides

With troxerutin, Radix Codonopsis Pilosulae total glucosides, adding and material ratio are 2: 1 PEG4000 and polyoxyethylene monostearate (3: 1) mix homogeneously, put in the rustless steel container, mixing, be heated to whole fusions after, the insulation 30min, mechanical high-speed stirs 15min to even, being transferred to the drop pill machine, is coolant with dimethicone or liquid paraffin, drips system, collect drop pill, remove the dimethicone or the liquid paraffin on surface, packing promptly gets the drop pill that contains 1 part of troxerutin and 4 parts of Radix Codonopsis Pilosulae total glucosides.

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

With troxerutin and Radix Codonopsis Pilosulae total glucosides's mix homogeneously, in principal agent: the ratio of adjuvant=1: 1 adds calcium hydrogen phosphate, in principal agent: the ratio of adjuvant=2: 1 adds crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose composite auxiliary material mix homogeneously, and the system soft material is granulated, dry, granulate adds an amount of Pulvis Talci, micropowder silica gel, and is evenly mixed, tabletting promptly gets and contains 1 part of troxerutin and 5 parts of Radix Codonopsis Pilosulae total glucosides's dispersible tablets.

Embodiments of the invention 9: the troxerutin 3g 24g of Radix Codonopsis Pilosulae total glucosides

With troxerutin 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 troxerutin and 8 parts of Radix Codonopsis Pilosulae total glucosides.

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

With troxerutin 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 troxerutin and 3 parts of Radix Codonopsis Pilosulae total glucosides.

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

With troxerutin and Radix Codonopsis Pilosulae total glucosides's mix homogeneously, press medication amount: substrate amount=1: 0.8 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100g: 40g: 70g: 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 troxerutin and 1 part of Radix Codonopsis Pilosulae total glucosides's soft capsule.

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

With troxerutin, 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 troxerutin and 2 parts of Radix Codonopsis Pilosulae total glucosides.

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

With troxerutin, Radix Codonopsis Pilosulae total glucosides's mixing, drying adds appropriate amount of starch, ethanol with 75% and 1.5% 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 troxerutin and 4 parts of Radix Codonopsis Pilosulae total glucosides.

Embodiments of the invention 14: the troxerutin 5g 15g of Radix Codonopsis Pilosulae total glucosides

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

Embodiments of the invention 15: the troxerutin 10g 5g of Radix Codonopsis Pilosulae total glucosides

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

Troxerutin among the above embodiment is the commercial goods that can directly buy, 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 etc., 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 0.01～10 part by 1 part of troxerutin 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 troxerutin and Radix Codonopsis Pilosulae total glucosides is made for 0.1～5 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 troxerutin and Radix Codonopsis Pilosulae total glucosides is made for 0.5～3 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 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 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.

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 flavones 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 flavones 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 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 troxerutin, Radix Codonopsis Pilosulae total glucosides 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 5.5～7.0, boil, coarse filtration, fine straining are spent the night in cold preservation (4 ℃); Mannitol is added the injection water be mixed with 120mg/ml solution,, 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, thrombophlebitis, capillary hemorrhage, 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 troxerutin;

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