CN1931179A - Medicine composition and its prepn process - Google Patents

Abstract

The present invention relates to one kind of medicine composition for treating cardiac and cerebral vascular diseases and its preparation process, and belongs to the field of medicine technology. The medicine composition of the present invention consists of breviscapine and penoniflorin, and may be prepared into injection, orally taken preparation and other pharmaceutically acceptable preparation forms. The preparation process of the present invention is reasonable and feasible, and the medicine composition has stable quality, determined curative effect and no toxic side effect.

Description

A kind of pharmaceutical composition and preparation method thereof

Technical field

The present invention relates to a kind of pharmaceutical composition that is used for the treatment of cardiovascular and cerebrovascular disease, the preparation method of said composition is provided simultaneously, belong to technical field of medicaments.

Technical background

Cardiovascular and cerebrovascular disease is one of maximum disease of world today's harm, and sickness rate still has continuous growth trend, in, young patient is also in continuous increase, although medicine emerges in an endless stream at present, Chinese medicine and western medicine respectively occupies half the sky, but compare Chinese medicine with Western medicine and have following advantage: toxic and side effects is less relatively, is suitable for prolonged application; A medicine can act on a plurality of pathology links; Improve symptom that the patient follows as breathe hard, weak, spirit depressing and sexual hypofunction etc. be comparatively obvious; Some middle pharmaceutically active ingredients of preventing and treating cardiovascular and cerebrovascular vessel have demonstrated good prospects for application, as breviscapine, puerarin, TANSHINONES, hirudin etc.Clinical and experimentation proves that all the Chinese traditional treatment cardiovascular and cerebrovascular vessel have coronary artery dilator, improve myocardial ischemia, suppress platelet aggregation, improve effects such as patient moving ability and quality of life.From market sale, the cardiovascular and cerebrovascular vessel medication has become the first quasi drugs of world's medical market, according to estimates, 2003, China's cardiovascular and cerebrovascular vessel medication is number two at drug market, be only second to the infection medication, the market share is 14.36%, wherein the retail total scale in Chinese patent medicine market is about 82.10 hundred million yuan, account for 25.41% of cardiovascular and cerebrovascular vessel medication (comprising Chinese patent medicine and chemical medicine) overall market, account for 3.64% of China's drug market, but studies show that, hospital market is still the leading market of cardiovascular and cerebrovascular vessel Chinese patent medicine, accounts for 78.3% of overall market.As seen Chinese patent medicine has occupied considerable position on China cardiovascular and cerebrovascular vessel medication market.Chinese medicine extract is the new medicine product that merges the modern pharmaceutical new technique, it is a kind of new product form on the international natural medicaments health-product market, it is the carrier of modern plants medicine advanced technology, be used as medicine with Chinese medicine extract, have exploitation less input, with high content of technology, advantage and characteristics such as added value of product is big, the international market is extensive.Chinese medicine extract is compared with Chinese patent medicine and is had following characteristics simultaneously: 1. know a kind of at least or an effective constituents, although this composition may be more essential composition.Chinese patent medicine usually only is concerned about effectiveness, is indifferent to or does not know effective ingredient; 2. use modern detecting, the definite quantitative index is arranged.Even it is can not be quantitative, at least also quantitative to marker ingredients to effective ingredient.And the Chinese patent medicine majority is not set up quantitative approach, or has only coarse quantitative approach; 3. adopt the modern industry isolation technics, make effective ingredient certain high-load that concentrated, form by crude drug or based on the extraction and the bulk processing fabrication techniques of water alcohol method or pure water law and Chinese patent medicine is many; 4. the harmful components major part is removed, thereby improves greatly than Chinese patent medicine in safety; 5. influence the impurity of preparation, be removed, thereby can make the preparation of high crude drug amount-preparation ratio, promoted product specification, overcome the shortcoming of " thick, big, black " of Chinese patent medicine as strong hygroscopicity composition; 6. pharmacology, drug effect, safety evaluatio etc. are modern system, and are international.So the present invention bases oneself upon Chinese medicine extract, develop the newtype drug of treatment cardiovascular and cerebrovascular disease.

Summary of the invention

The object of the present invention is to provide a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease, adopt the preparation that breviscapine and peoniflorin prescription are made to be needed; At prior art, breviscapine can significantly increase coronary flow, promote blood capillary open, microcirculation improvement, whole blood viscosity, plasma viscosity, erythrocyte electrophoresis and platelet electrophoresis all recover to some extent, have anticoagulation, antithrombotic formation and promote the fibrinolytic effect, improve the brain vessel blood state of several animal models.Clinical cerebral thrombosis, paralysis, coronary heart disease and the retinal vein occlusion etc. of being mainly used in.Peoniflorin has anti-platelet aggregation; inhibiting erythrocyte aggregation; antithrombotic forms; change hemorheology index; strengthen acute radiation injury mouse bone marrow adhesion function; atherosclerosis, dilating coronary blood vessel; thereby coronary blood flow increasing increases the myocardial nutrition blood flow; the protection ischemic myocardium; improve cardiac muscle to anoxybiotic toleration, reduce pulmonary vascular resistance, alleviate afterload; anti-experimental character myocardial ischemia, microcirculation improvement and the effect of reduction portal hypertension, damage has effects such as significant protection to rat neurocyte cerebral ischemia sample.The clinical premonitory apoplexy, cerebral infarction, acute cerebral thrombosis of being used for the treatment of forms.Results of pharmacodynamic test shows: prescription of the present invention can obviously improve the hemiplegia body card of rat due to the cerebral embolism, dwindles infarct size in the brain, the secondary lesion that alleviates cerebral edema and neurocyte; Anticoagulant has the obvious suppression effect to rat blood thrombosis, and tangible thrombolytic effect is arranged; Obviously prolong clotting time and prolong rats, prothrombin time and the partial thromboplastin time of mouse blood, reduce the rat serum fibrinogen concentration, have tangible function of promoting blood circulation to disperse blood clots.The results of pharmacodynamic test of prescription proportioning shows that peoniflorin and breviscapine two medicines share, and have stronger physiologically active.Another object of the present invention is to disclose the preparation of drug combination method of this treatment cardiovascular and cerebrovascular disease, comprise multiple injection type and peroral dosage form, effectively avoided the single inconvenience that brings of dosage form of present doctors and patients' medication, enriched the medication of clinician and extensive patients to a greater degree and selected.

The present invention constitutes like this: calculate according to components by weight percent, it is to be made for 99～1 parts by 1～99 part of breviscapine and peoniflorin; Specifically: calculate according to components by weight percent, it is to be made for 80～20 parts by 20～80 parts of breviscapines and peoniflorin; Say accurately, calculate that it is to be made for 70～40 parts by 30～60 parts of breviscapines and peoniflorin according to components by weight percent.

Described preparation is injection and oral formulations, and injection comprises: be directly used in drug administration by injection injection, need to be used for the concentrated solution for injection of intravenous drip after the dilution, directly for the infusion solution of intravenous drip and injectable sterile powder and the aseptic block that makes with freeze-drying or spray drying method; Oral formulations comprises: all acceptable dosage forms on tablet, dispersible tablet, effervescent tablet, oral cavity disintegration tablet, capsule, soft capsule, microcapsule, granule, pill, powder, drop pill, slow releasing preparation, controlled release preparation, oral liquid, soft extract, extractum, gel, membrane and other pharmaceuticss; Preferred preparation is the injection that is directly used in drug administration by injection, need to be used for the concentrated solution for injection of intravenous drip after the dilution, directly for the venous transfusion of intravenous drip and injectable sterile powder and aseptic block, drop pill, capsule, soft capsule, oral cavity disintegration tablet, tablet, pellet, dispersible tablet or the granule that makes with freeze-drying or spray drying method.

The preparation of drug combination method of described treatment cardiovascular and cerebrovascular disease is: breviscapine and peoniflorin are mixed, add different auxiliary material and make various preparations.The adjuvant that is adopted in the preparation comprises one or more in mannitol, galactose, glycine, glucose, sodium chloride, dextran, glycerol, ethanol, propylene glycol, Polyethylene Glycol, sorbitol, tween, poloxamer, dextrin, starch, polyvinylpolypyrrolidone PVPP, CMC-Na, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, Radix Glycyrrhizae charcoal, stevioside, soybean oil, sorbitol, Pulvis Talci, Cera Flava, modified starch, magnesium stearate, dimethicone, the liquid paraffin.

Injection is preparation like this: take by weighing breviscapine and join in a certain amount of water for injection, regulate pH value and be 7.0～7.5 and make dissolving, get peoniflorin again, add injection and blunge and make it dissolving, join in the above-mentioned breviscapine solution, mix homogeneously, regulating pH value is 6.5～8.0, adds 0.1～2% needle-use activated carbon, boil absorption, carbon removal, fine straining, filtrate adds different auxiliary material and makes various preparations.

The aseptic block of lyophilizing is preparation like this: take by weighing breviscapine and join in a certain amount of water for injection, adding sodium citrate, to regulate pH value be 7～7.5 to make dissolving, gets peoniflorin again, adds injection and blunge and make it dissolving, join in the above-mentioned breviscapine solution, mix homogeneously, regulating pH value is 6.5～8.0, adds 0.2% activated needle-use activated carbon, boil absorption, carbon removal, fine straining, filtrate for later use; Injection mannitol is added the injection water be mixed with 120mg/ml solution,, add the injection water to ormal weight with above-mentioned filtrate mixing, coarse filtration, fine straining, packing, temperature-45 ℃, pre-freeze time 10h, the beginning evacuation, and in 12～72 hours differential gradient increased temperature to 10 ℃ progressively, keep 2h, be warming up to 20 ℃, keep 2h, promptly.

Concentrated solution for injection or the injection with small volume that is directly used in drug administration by injection are preparations like this: take by weighing breviscapine and join in a certain amount of water for injection, adding sodium citrate, to regulate pH value be 7～7.5 to make dissolving, get peoniflorin again, add the injection blunge make it the dissolving, join in the above-mentioned breviscapine solution, mix homogeneously, regulating pH value is 6.5～7.5, add 0.2% activated needle-use activated carbon, boil absorption, carbon removal, fine straining, filtrate adds the injection water to ormal weight, spend the night coarse filtration 4 ℃ of cold preservations, fine straining divides to install in the ampoule bottle, in vapor (steam) temperature is 105 ℃, and actual pressure is at 110kN/m ³Pressure sterilizing is 40 minutes under the condition, promptly.

Compared with prior art, the present invention compares with Chinese patent medicine and has following characteristics with the be used as medicine preparation made of breviscapine and peoniflorin prescription: 1. know a kind of at least or an effective constituents, although this composition may be more essential composition.Chinese patent medicine usually only is concerned about effectiveness, is indifferent to or does not know effective ingredient; 2. use modern detecting, the definite quantitative index is arranged.Even it is can not be quantitative, at least also quantitative to marker ingredients to effective ingredient.And the Chinese patent medicine majority is not set up quantitative approach, or has only coarse quantitative approach; 3. adopt the modern industry isolation technics, make effective ingredient certain high-load that concentrated, form by crude drug or based on the extraction and the bulk processing fabrication techniques of water alcohol method or pure water law and Chinese patent medicine is many; 4. the harmful components major part is removed, thereby improves greatly than Chinese patent medicine in safety; 5. influence the impurity of preparation, be removed, thereby can make the preparation of high crude drug amount-preparation ratio, promoted product specification, overcome the shortcoming of " thick, big, black " of Chinese patent medicine as strong hygroscopicity composition; 6. pharmacology, drug effect, safety evaluatio etc. are modern system, and are international.Through pharmacological effect studies show that prescription of the present invention has that anticoagulation, antithrombotic form, transfer fat, vessel softening, bring high blood pressure down, the effects such as protection of blood vessel dilating, microcirculation improvement, neurocyte ischemic injuries; these effects all help the recovery of human body body function; the development test of prescription compatibility shows that both share and the comparison of breviscapine single preparations of ephedrine; has stronger blood circulation promoting and blood stasis dispelling, the effect of dredge the meridian passage.In addition, also can be used for treating the nephrotic syndrome, diseases such as viral myocarditis, diabetes sexually transmitted disease (STD) change on every side.

The applicant has carried out following a series of experiments, proves the effectiveness of medicine of the present invention.

Experimental example 1: medicament composing prescription experimental study

1, stasis syndrome rat model hemorheological property is influenced:

Wistar kind rat, male and female half and half about body weight 300g, are divided into 5 groups at random, and are 10 every group, as follows respectively: the blank group: every day, normal saline was irritated stomach, continuous 7 days.Stopped eating in the 7th day, detect inferior morning; Model group: every day, normal saline was irritated stomach, and continuous 7 days, in the 7th day subcutaneous injection epinephrine 0.8ml/kg totally 2 times, two minor ticks 4 hours, (front and back each 2 hours at interval) were immersed rat in the frozen water 5 minutes between the biphasic injection epinephrine.Stop eating after the disposal, detect inferior morning; Experimental group: be divided into three groups, one group of breviscapine group, one group of peoniflorin group, one group of the present invention group, every day, each 15mg/kg irritated stomach, continuous 7 days.Duplicated blood stasis model as stated above in the 7th day, the back of stopping eating is detected time morning.Carotid artery is got blood, and the heparin sodium anticoagulant detects each index of hemorheology.

Table 1 pair rat acute blood stasis model hemorheological property influence

Group	Whole blood contrast viscosity		The serum specific viscosity	Plasma viscosity	The Fibrinogen specific viscosity	Packed cell volume (HCT %)
							Low shear rate	High shear rate
	Of the present invention group of blank group blood stasis model group Breviscapinun group Paeoniflorin group	7.64± 1.22 14.88± 5.85 9.68± 1.80 10.21± 2.21 8.33± 1.25							4.54±0.65 5.75±1.11 5.22±0.33 5.46±0.72 5.02±0.45	1.53±0.25 1.58±0.12 1.55±0.12 1.67±0.07 1.61±0.09	1.65± 0.09 2.09± 0.11 1.92± 0.14 2.04± 0.18 1.90± 0.13	0.09± 0.14 0.51± 0.11 0.37± 0.13 0.37± 0.13 0.29± 0.11	42.1± 2.95 46.3± 1.98 43.2± 1.98 45.1± 1.88 42.1± 2.12

As shown in Table 1, breviscapine group, peoniflorin group all can make blood stasis model sticking, dense, alleviate with fixed attention, illustrate that two medicines are all invigorated blood circulation, depolymerisation, have the obvious synergistic effect after the two medicines associatings, make the blood stasis model group sticking, dense, obviously alleviate with fixed attention, more obvious than single drug effect.

2, to arachidonic acid-induction acute cerebral ischemia in rats therapeutical effect

Rat, male and female half and half, body weight 220～320g, CDL-581 anesthesia (20mg/100g), surgical incision partes occipitotemporalis skin, brain electrode is settled in boring, prepares the record electrocorticogram and uses.Operation separates internal carotid artery, external carotid artery and common carotid artery.Ligation external carotid artery and Carotid proximal part insert anticoagulant heparin pipe and fixing to distal end.Treat the in stable condition back of animal slowly inject in the internal carotid artery intubate sodium arachidonate (0.25～0.30mg/kg), observe brain wave frequency and oscillation amplitude change.Treat that brain wave frequency slows down, this invention preparation of lumbar injection, aspirin, matched group gives normal saline.The results are shown in Table 2～3.

The influence of table 2 pair experimental cerebral ischemia rat platelet aggregation

Group	Platelet aggregation
			Maximum agglutination rate (PagTmax%)	Maximum aggregation velocity (PagVmax%)
	At once 1h 2h 4h at once behind of the present invention group of ischemic of 1h 2h 4h at once behind the 1h 2h 4h aspirin group ischemic behind the physiological saline group ischemic	60.7±2.5 63.8±2.5 64.5±2.8 64.7±3.1 61.5±3.7 55.0±4.4 51.5±4.3 47.5±4.2 61.2±3.2 54.3±3.7 45.6±5.6 41.9±4.7			78.7±4.6 81.1±4.8 80.1±3.7 79.1±3.5 78.2±4.0 54.5±3.3 48.6±3.5 45.6±2.8 80.1±5.0 56.5±5.7 49.7±3.7 45.8±3.6

The influence of table 3 pair experimental cerebral ischemia rat index

Group	TXB 2 (nmol/L)	6-Keto-PGF 1a (pmol/L)	TXB 2/6-Keto-PGF 1a
				At once 1h 2h 4h at once behind of the present invention group of ischemic of 1h 2h 4h at once behind the 1h 2h 4h aspirin group ischemic behind the physiological saline group ischemic	388.3±26.5 413.9±34.0 477.4±22.3 516.7±37.9 388.6±33.8 220.0±27.1 193.6±20.1 165.5±15.8 300.6±31.7 212.0±22.7 156.4±16.4 124.1±8.6	100.5±5.9 94.1±4.8 86.8±4.3 81.9±3.5 94.0±7.4 87.4±7.9 83.6±5.8 72.0±4.6 92.7±5.3 102.3±4.0 109.6±3.8 115.2±4.7	3.95±0.23 4.41±0.45 5.53±0.41 6.32±0.54 4.16±0.53 2.54±0.41 2.23±0.35 2.18±0.26 3.27±0.52 2.08±0.30 1.43±0.20 1.08±0.12

Experimental example 2: injection technical study

(1) pH value of solution is investigated

For adapting to the Human Physiology needs, consider the character of each constituents in the medicinal liquid simultaneously, the applicant has investigated the pH value of medicinal liquid.Select solution appearance, paeoniflorin content and clarity as evaluation index.

Test method and result: after feeding intake and handle by recipe quantity,, filter with the concentrated solution mix homogeneously by above-mentioned condition, add water to 1000ml, adjust pH is when the different pH value that reaches shown in the following table, boil the back standing over night, observe the variation of appearance character under different pH condition.Experimental result sees Table 4.

The investigation of table 4 dosing pH value (is to investigate index with the solution appearance)

Sequence number	1	2	3	4	5	6	7	H
									Dosing pH boils pH	5.5 5.1	6.0 5.6	6.5 6.2	7.0 6.7	7.5 7.3	8.0 7.7	8.5 8.2	9.0 8.5
Outward appearance	Precipitation appears		No significant change				Color burn

Table 4 is the result show, medicinal liquid boils the back pH value and occur to precipitate at the sample 6.5 below, and pH value is obviously deepened in the color sample more than 8.0, and pH value is that 6.5～8.0 medicinal liquid is relatively stable, and outward appearance does not have significant change.Estimate from Radix Paeoniae former times content down.The results are shown in Table 5

The investigation of table 5 dosing pH value (is to investigate index with the peoniflorin)

Sequence number	Dosing pH	Paeoniflorin content (%)	Boil back pH	Paeoniflorin content (%)
					1 2 3 4 5 6 7	5.5 6.0 6.5 7.0 7.5 8.0 8.5	40.5 42.6 43.8 44.2 43.8 42.9 40.1	5.2 5.8 6.3 6.4 7.2 7.8 8.0	38.5 40.2 42.1 42.4 41.7 41.0 38.2

As shown in Table 5, medicinal liquid is between pH value 5.5-8.5, and before and after boiling, the index components paeoniflorin content does not have too big variation.Verify from the clarity aspect that below the applicant has investigated 30 ℃ of stability of placing 3 months of injection of different pH value, the results are shown in Table 6.

The investigation of table 6 dosing pH value (is to investigate index with the clarity)

	0 month		March
					pH 5.5 6.0 6.5 7.0 7.5 8.0 8.5	Clarity is slightly good slightly good clear and bright slightly good	Lamp inspection rate % 68.60 73.58 80.21 90.21 98.35 82.36 70.24	The slightly good clear and bright slightly good job of clarity difference difference	Lamp inspection rate % 58.25 65.32 70.85 88.29 95.62 74.25 60.21

As shown in Table 6, medicinal liquid is between pH6.5～8.0, and clarity is better, and the appearance character of comprehensive above-mentioned medicinal liquid and content of paeoniflorin change, and the pH value of medicinal liquid is transferred between 6.5～8.0 when determining dosing.

(2) screening of freeze-dried powder caffolding agent kind

The caffolding agent kind influences the molding of freeze-dried powder, so at first this is screened.The results are shown in Table 7.

The screening of table 7 caffolding agent kind

The caffolding agent kind	Caffolding agent: medicinal liquid (V: V)	Solubility	The finished product outward appearance
				Glucose galactose mannitol glycine dextran mannitol, the propylene glycol glycine, the Polyethylene Glycol dextran, sorbitol, the blank medicinal liquid of tween	2∶1 2∶1 2∶1 2∶1 2∶1 2∶1 2∶1 2∶1 3ml	Good generally carefully generally carefully general	Moulding; The moulding of subsiding of the moulding moulded part of part atrophy is moulding moulded, partial crushing moulding atrophy

As shown in Table 7, 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, use the effect of mannitol to be better than other several adjuvants separately from the solubility angle integrated survey of yield rate, molding situation, adjuvant addition and sample.

(3) lyophilization conditional filtering

Lyophilization is a veryer long dry run, needs to consume a large amount of energy.An ideal lyophilisation condition not only can be saved a large amount of energy, can also shorten man-hour simultaneously, so we are optimized screening to doing condition.The actual conditions screening sees Table 8.

Table 8 lyophilization conditional filtering

Time (h) temperature (℃)	Condition I	Condition II	Condition III	Cold-trap
					-45 (pre-freeze)-40 (pre-freeze)-40 (vacuumizing)-35 (vacuumizing)-30 (vacuumizing)-25 (vacuumizing)-20 (vacuumizing)-15 (vacuumizing)-10 (vacuumizing) 0 (vacuumizing) 10 (vacuumizing) 20 (vacuumizing)	8 - 8 - 8 - 8 - 5 5 2 2	- 8 - 8 - 8 - 8 - 5 4 4	8 - 10 - 10 - 10 - 5 5 3 3	Keep-70 ℃

Experimental result shows: finished product appearance character that condition I, II and III make and the equal conformance with standard of moisture.But comparatively speaking, condition II yield rate is low slightly, and condition III power consumption is bigger, considers the practical situation of production, short condition I of finally selected overall time spent, i.e. and lyophilization condition is: pre-freeze temperature-45 ℃, pre-freeze time 10h;-40 ℃ of evacuation keep 8h; Be warming up to-30 ℃ again, keep 8h; Be warming up to-20 ℃, keep 8h; Be warming up to-10 ℃, keep 5h; Be warming up to 0 ℃, keep 5h; Be warming up to 10 ℃, keep 2h; Be warming up to 20 ℃, keep 2h, get product.

Experimental example 3: pharmacological toxicology research

1, Pharmacodynamic test of active extract research

(1) coronary heart disease and myocardial infarction model result of the test show: preparation of the present invention can reduce myocardial infarction model dog left ventricle infarction size due to the coronary artery ligation method, reduces animal pattern Serum LDH, CPK, HR, ST displacement, MVO ₂And LVEDP, elevation model animal MAP, CO and LV+dp/dt, LVSP.Each group of the side of tearing open all can be improved LAD ligation dog part index number, but the trend that has effect to increase behind the compatibility.

(2) dog heart and hemodynamics test: preparation of the present invention can significantly increase the cardiac output and the coronary flow of anesthetized dog.To anesthetized dog electrocardio, heart rate and average femoral artery pressure, heart contraction and diastolic function, myocardial oxygen consumption index etc. do not have obviously influence.

(3) blood circulation promoting and blood stasis dispelling test: preparation of the present invention has the mice of improvement microcirculation; The effect of the blood stasis model of improvement rat blood rheological characteristic is arranged; Remarkable or utmost point significant prolongation PT and aPPT effect are arranged; Can suppress the inductive mouse tail thrombosis of carrageenin; Can shorten the rabbit fibrin dissolution time, reduce fiber protein content in the blood plasma; Externally can reduce platelet aggregation rate.More than the side of tearing open of every blood circulation promoting and blood stasis dispelling test studies show that prescription function of promoting blood circulation to disperse blood clots of the present invention use effect enhancing more separately.

2, animal acute toxicity test

Result of the test shows that preparation safety dosage range of the present invention is bigger.

3, the animal general pharmacology is learned test

This experimental observation to the influence of each system of intact animal, the result is as follows:

(1) to neural influence: do not cause tangible untoward reaction.

(2) to the influence of dog body temperature: do not cause tangible untoward reaction.

(3) cardiovascular system: 1. to Electrocardiographic influence: do not cause tangible untoward reaction.2. to hemodynamic influence: can be obviously or significantly increase anesthetized dog coronary flow and cardiac output.All the other indexs are not seen difference, do not cause tangible untoward reaction.

(4) to the influence of respiratory system: do not cause tangible untoward reaction.

The result shows: preparation general pharmacology experimental study of the present invention shows that this product mainly increases coronary flow and cardiac output, and blood pressure lowering is relevant with its drug effect.All the other nervous system to animal, muscle coordination exercise, body temperature and respiratory system do not have obvious effect.

4, long-term toxicity test for animals conclusion

(1) rat long term toxicity test

The result shows: preparation long term administration of the present invention causes that mainly rat HGB and RBC reduce, but still in the normal physiologic values scope, can recover no retardance toxicity after the drug withdrawal.The safe dose scope is big.

(2) Beagle dog long term toxicity test

The result shows: the more heavy dose of administration of preparation of the present invention may have certain influence to Beagl dog routine blood test, heart rate in 90 days, but specifically changed numerical value all within normal range, no retardance toxic reaction.The safe dose scope is big.

Concrete embodiment

(part is a unit of weight, as ton, kilogram, gram)

Embodiment 1: 99 parts of 1 part of peoniflorins of breviscapine

Getting breviscapine joins in a certain amount of water for injection, adding sodium citrate or sodium bicarbonate or sodium carbonate, to regulate pH value be 7～7.5 to make dissolving, gets peoniflorin again, adds injection and blunge and make it dissolving, join in the above-mentioned breviscapine solution, mix homogeneously, regulating pH value is 6.5～8.0, adds 0.2% activated needle-use activated carbon, boil absorption, carbon removal, fine straining, filtrate for later use; Injection mannitol is added the injection water be mixed with 120mg/ml solution,, add the injection water to ormal weight with above-mentioned filtrate mixing, coarse filtration, fine straining, packing, lyophilization, lyophilisation condition is: pre-freeze temperature-45 ℃, pre-freeze time 10h;-40 ℃ of evacuation keep 8h; Be warming up to-30 ℃ again, keep 8h; Be warming up to-20 ℃, keep 8h; Be warming up to-10 ℃, keep 5h; Be warming up to 0 ℃, keep 5h; Be warming up to 10 ℃, keep 2h; Be warming up to 20 ℃, keep 2h, promptly get the aseptic block of lyophilizing.

Embodiment 2: 1 part of 99 parts of peoniflorin of breviscapine

Getting breviscapine joins in a certain amount of water for injection, adding sodium citrate or sodium bicarbonate or sodium carbonate, to regulate pH value be 7～7.5 to make dissolving, get peoniflorin again, add the injection blunge make it the dissolving, join in the above-mentioned breviscapine solution mix homogeneously, regulating pH value is 6.5～8.0, add 0.2% activated needle-use activated carbon, boil absorption, carbon removal, fine straining, filtrate adds the injection water to ormal weight, spends the night coarse filtration 4 ℃ of cold preservations, fine straining, divide and install in the ampoule bottle, in vapor (steam) temperature is 105 ℃, and actual pressure pressure sterilizing 40 minutes under the 110kN/m3 condition promptly gets the injection with small volume or the concentrated solution for injection that are directly used in drug administration by injection.

Embodiment 3: 40 parts of 60 parts of peoniflorins of breviscapine

Getting breviscapine joins in a certain amount of water for injection, adding sodium citrate or sodium bicarbonate or sodium carbonate, to regulate pH value be 7～7.5 to make dissolving, get peoniflorin again, add the injection blunge make it the dissolving, join in the above-mentioned breviscapine solution mix homogeneously, the glucose of adding ormal weight, regulating pH value is 6.5～7.5, add 0.3% activated needle-use activated carbon, boil absorption, carbon removal, 5 ℃ of placements are spent the night, fine straining, filtrate add the injection water to ormal weight, packing, 110 ℃ of sterilizations 40 minutes, promptly get the glucose infusion liquid agent.

Embodiment 4: 70 parts of 30 parts of peoniflorins of breviscapine

Getting breviscapine joins in a certain amount of water for injection, adding sodium citrate or sodium bicarbonate or sodium carbonate, to regulate pH value be 7～7.5 to make dissolving, get peoniflorin again, add the injection blunge make it the dissolving, join in the above-mentioned breviscapine solution mix homogeneously, the glucose of adding ormal weight, regulating pH value is 6.5～8.0, add 0.3% activated needle-use activated carbon, boil absorption, carbon removal, 5 ℃ of placements are spent the night, fine straining, filtrate add the injection water to ormal weight, packing, 110 ℃ of sterilizations 40 minutes, promptly get the glucose infusion liquid agent.

Embodiment 5: 80 parts of 20 parts of peoniflorins of breviscapine

Getting breviscapine joins in a certain amount of water for injection, adding sodium citrate or sodium bicarbonate or sodium carbonate, to regulate pH value be 7～7.5 to make dissolving, get peoniflorin again, add the injection blunge make it the dissolving, join in the above-mentioned breviscapine solution mix homogeneously, the sodium chloride of adding ormal weight, regulating pH value is 6.5～8.0, add 0.3% activated needle-use activated carbon, boil absorption, carbon removal, 5 ℃ of placements are spent the night, fine straining, filtrate add the injection water to ormal weight, packing, 110 ℃ of sterilizations 40 minutes, promptly get the sodium chloride infusion solution.

Embodiment 6: 85 parts of 15 parts of peoniflorins of breviscapine

Get breviscapine and starch and manually mix mixedly, put again and mix mixedly in the high speed disintegrator strongly, add the dextrin that sieves through 80 orders then, put in the V-type mixing machine and mixed about 2 hours; Get peoniflorin, use 90% alcohol granulation, drying; Behind two medicated powder mixings, add 30% ethanol and make soft material, granulate through 20 order nylon mesh with oscillating granulator.Through 60-70 ℃ of drying, back to be dried adds the magnesium stearate mixing with 16 mesh sieve granulate then, with scrobicula ￠ 5.5mm drift tabletting, promptly gets tablet.

Embodiment 7: 65 parts of 35 parts of peoniflorins of breviscapine

Get breviscapine, peoniflorin and manually mix mixedly, put again and mix mixedly in the high speed disintegrator strongly, use 90% alcohol granulation, drying, it is an amount of to add dextrin, mixes thoroughly, makes granule, vacuum drying, packing promptly gets granule.

Embodiment 8: 45 parts of 55 parts of peoniflorins of breviscapine

Get breviscapine and peoniflorin and manually mix mixedly, put and mix mixedly in the high speed disintegrator strongly, medicated powder behind the mixing adds 2 times of amount Macrogol 4000s or 6000, mix homogeneously, 80-90 ℃ of heating and melting stirs, being transferred to the drop pill machine, is coolant with the liquid paraffin, drips system, the water dropper internal diameter is 3mm, external diameter 4.5mm drips apart from 4mm, collects drop pill, remove the liquid paraffin on surface, promptly get drop pill.

Embodiment 9: 42 parts of 38 parts of peoniflorins of breviscapine

Get breviscapine and peoniflorin and manually mix mixedly, put and mix mixedly in the high speed disintegrator strongly, the medicated powder behind the mixing adds starch, magnesium stearate is an amount of, is ground into fine powder, sieves, and mixing incapsulates, and promptly gets capsule.

Embodiment 10: 1 part of 1 part of peoniflorin of breviscapine

Getting breviscapine and peoniflorin and manually mix mixedly, put and mix mixedly in the high speed disintegrator strongly, is suspending agent with the Cera Flava, and vegetable oil is a diluent, and the dropping preparation method pill promptly gets soft capsule.

Embodiment 11: 99 parts of 99 parts of peoniflorins of breviscapine

Get breviscapine and peoniflorin and manually mix mixedly, add starch, add microcrystalline Cellulose and the ratio of low-substituted hydroxypropyl cellulose and be 4: 1 mix disintegrating agent and stevioside is an amount of, put in the high speed disintegrator again and mix thoroughly strongly, compacting is in blocks, promptly gets oral cavity disintegration tablet.

Embodiment 12: 99 parts of 1 part of peoniflorins of breviscapine

Get breviscapine and peoniflorin and manually mix mixedly, medicated powder behind the mixing adds starch, puts to mix mixedly in the high speed disintegrator strongly again, and the spheronization pill with Radix Glycyrrhizae charcoal coating, promptly gets pellet.

Embodiment 13: 1 part of 99 parts of peoniflorin of breviscapine

Get breviscapine and peoniflorin and manually mix mixedly, put and mix mixedly in the high speed disintegrator strongly, medicated powder behind the mixing adds microcrystalline Cellulose, adds an amount of mixing of polyvinylpolypyrrolidone PVPP, CMC-Na again, and it is moistening to add 70% ethanol, granulates, granulate, and tabletting promptly gets dispersible tablet.

Claims (10)

1, a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease is characterized in that: calculate according to components by weight percent, it is to be made for 99～1 parts by 1～99 part of breviscapine and peoniflorin.

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 components by weight percent, it is to be made for 80～20 parts by 20～80 parts of breviscapines and peoniflorin.

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 components by weight percent, it is to be made for 70～40 parts by 30～60 parts of breviscapines and peoniflorin.

4, according to the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease of claim 1-3, it is characterized in that: preparation of the present invention is injection and oral formulations, and injection comprises: be directly used in drug administration by injection injection, need to be used for the concentrated solution for injection of intravenous drip after the dilution, directly for the infusion solution of intravenous drip and injectable sterile powder and the aseptic block that makes with freeze-drying or spray drying method; Oral formulations comprises: all acceptable dosage forms on tablet, dispersible tablet, effervescent tablet, oral cavity disintegration tablet, capsule, soft capsule, microcapsule, granule, pill, powder, drop pill, slow releasing preparation, controlled release preparation, oral liquid, soft extract, extractum, gel, membrane and other pharmaceuticss.

5, according to the pharmaceutical composition of the described treatment cardiovascular and cerebrovascular disease of claim 4, it is characterized in that: preparation of the present invention is the injection that is directly used in drug administration by injection, need to be used for the concentrated solution for injection of intravenous drip after the dilution, directly for the venous transfusion of intravenous drip and injectable sterile powder and aseptic block, drop pill, capsule, soft capsule, oral cavity disintegration tablet, tablet, pellet, dispersible tablet or the granule that makes with freeze-drying or spray drying method.

6, according to the preparation of drug combination method of claim 4 or 5 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: breviscapine and peoniflorin are mixed, add different auxiliary material and make various preparations.

7, according to the preparation of drug combination method of the described treatment cardiovascular and cerebrovascular disease of claim 6, it is characterized in that: the adjuvant that is adopted in the preparation comprises mannitol, galactose, glycine, glucose, sodium chloride, dextran, glycerol, ethanol, propylene glycol, Polyethylene Glycol, sorbitol, tween, poloxamer, dextrin, starch, polyvinylpolypyrrolidone PVPP, CMC-Na, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, the Radix Glycyrrhizae charcoal, stevioside, vegetable oil, soybean oil, sorbitol, Pulvis Talci, Cera Flava, modified starch, magnesium stearate, dimethicone, in the liquid paraffin one or more.

8, according to the preparation of drug combination method of the described treatment cardiovascular and cerebrovascular disease of claim 6, it is characterized in that: injection is preparation like this: take by weighing breviscapine and join in a certain amount of water for injection, regulate pH value and be 7.0～7.5 and make dissolving, get peoniflorin again, add the injection blunge make it the dissolving, join in the above-mentioned breviscapine solution, mix homogeneously, regulating pH value is 6.5～8.0, add 0.1～2% needle-use activated carbon, boil absorption, carbon removal, fine straining, filtrate add different auxiliary material and make various preparations.

9, according to the preparation of drug combination method of the described treatment cardiovascular and cerebrovascular disease of claim 8, it is characterized in that: take by weighing breviscapine and join in a certain amount of water for injection, adding sodium citrate, to regulate pH value be 7～7.5 to make dissolving, get peoniflorin again, add the injection blunge make it the dissolving, join in the above-mentioned breviscapine solution mix homogeneously, regulating pH value is 6.5～8.0, add 0.2% activated needle-use activated carbon, boil absorption, carbon removal, fine straining, filtrate for later use; Injection mannitol is added the injection water be mixed with 120mg/ml solution,, add the injection water to ormal weight with above-mentioned filtrate mixing, coarse filtration, fine straining, packing, temperature-45 ℃, pre-freeze time 10h, the beginning evacuation, and in 12～72 hours differential gradient increased temperature to 10 ℃ progressively, keep 2h, be warming up to 20 ℃, keep 2h, promptly get the aseptic block of lyophilizing.

10, preparation of drug combination method according to the described treatment cardiovascular and cerebrovascular disease of claim 8, it is characterized in that: take by weighing breviscapine and join in a certain amount of water for injection, adding sodium citrate, to regulate pH value be 7～7.5 to make dissolving, get peoniflorin again, add the injection blunge make it the dissolving, join in the above-mentioned breviscapine solution, mix homogeneously, regulating pH value is 6.5～8.0, adds 0.2% 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 divides to install in the ampoule bottle, is 105 ℃ in vapor (steam) temperature, actual pressure pressure sterilizing 40 minutes under the 110kN/m3 condition promptly gets concentrated solution for injection or is directly used in the injection with small volume of drug administration by injection.