CN1475266A - Production method of injection agent used for treating cardio and cerebro vascular diseases and its product - Google Patents
Production method of injection agent used for treating cardio and cerebro vascular diseases and its product Download PDFInfo
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- CN1475266A CN1475266A CNA031482813A CN03148281A CN1475266A CN 1475266 A CN1475266 A CN 1475266A CN A031482813 A CNA031482813 A CN A031482813A CN 03148281 A CN03148281 A CN 03148281A CN 1475266 A CN1475266 A CN 1475266A
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- injection
- normal saline
- pheretima
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- hirudo
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Abstract
An injection for treating cardiovascular and cerebrovascular diseases is prepared from leech and earthworm through extracting in physiological saline and proportionally mixing. Its advantages are high curative effect and quickly taking its effect.
Description
Technical field
The present invention relates to pure technical field of Chinese medicines, manufacture method of particularly a kind of injection for the treatment of cardiovascular disease (commodity by name dredge blood logical) and products thereof.
Background technology
As everyone knows, cardiovascular and cerebrovascular disease is one of three higher big diseases of the generally acknowledged fatality rate of World Health Organization (WHO), be the frequently-occurring disease and the commonly encountered diseases of global range, belong to big disease, serious symptom, danger disease, emergency case, being positioned at first of the tcm internal medicine four disaster diseases, is the highest a kind of disease of middle-aged and elderly people sickness rate and case fatality rate.Wherein, cardiovascular disease is high and occupy first of many diseases with hurried, the overworked dead rate height of its onset and sequela incidence rate.The cardiovascular disease clinical manifestation is that apoplexy holds down, obnubilation, hemiplegia, facial hemiparalysis, slurred speech and whole body numbness etc.Because onset is hurried, change rapidly and sb.'s sickness becomes critical, must determination of treatment based on pathogenesis obtained through differentiation of symptoms and signs, race against time, rescue timely, could among critically ill, save life; Rescuing in time can be out of danger, but the incidence rate of sequela is very high.
Though the Chinese and western drugs of treatment cardiovascular disease is a lot of at present, efficient, quick-acting, safe specific drug is rare, causes the mortality rate of cardiovascular disease and the incidence rate of sequela to remain high.For this reason, develop a kind of efficient, quick-acting, safe drugs, reduce the main direction that case fatality rate and sequela incidence rate just become the world of medicine.
Summary of the invention
Main purpose of the present invention provides manufacture method of a kind of injection for the treatment of cardiovascular and cerebrovascular disease and products thereof, by the normal saline extraction liquid of Hirudo and Pheretima is formed according to certain proportioning, adopt the direct administration of injection vein, make the active substance of Chinese medicine Hirudo and Pheretima directly enter blood circulation, through focus, thus the case fatality rate and the sequela incidence rate of cardiovascular and cerebrovascular disease effectively reduced.This injection has anticoagulant, thromboembolism preventing, thrombolytic, improves blood circulation, promotes the mechanisms of action such as tissue repair, protective tissue cell, has overcome the drawback of prior art, reaches the case fatality rate of reduction cardiovascular and cerebrovascular disease and the purpose of sequela incidence rate.
The object of the present invention is achieved like this: a kind of manufacture method for the treatment of the injection of cardiovascular and cerebrovascular disease, it is characterized in that: it comprises the steps:
(1) material choice and low temperature dipping: at ambient temperature, Hirudo and Pheretima are soaked with normal saline respectively, its surface is fully launched, clean to clean with normal saline repeatedly again, place 2～4 times normal saline respectively with cleaning to clean water trematodiasis and Pheretima, flooded 15～30 hours for 0～4 ℃ in low temperature, filter, filtrate and medicinal residues preserve separately is standby;
(2) smash grinding to pieces: adopt high-speed tissue mashing machine will organize cutting and crushing medicinal residues, then mix with above-mentioned filtrate again and use homogenizer to be milled to the homogenate of diameter less than 0.5 μ m;
(3) freezing and separate and melt: as homogenate to be taken out after below-15 ℃ freezing 15～30 hours, under 0～4 ℃ of condition of low temperature, separate and melt, melt at least 2 times repeatedly by the freezing reconciliation of above-mentioned condition again;
(4) separate and purification: liquid being melted in above-mentioned freezing reconciliation place the centrifuge centrifugalize, is that 50,000 filter post carries out coarse filtration with supernatant by molecular weight again, and filtrate was through 105～136 ℃ of hot pressing 10～30 minutes; Be that 10,000 ultrafiltration post further filters purification by molecular weight again;
(5) dosing: Hirudo solution that will extract respectively and Pheretima solution comprise and make the injection that 1-20ml/ props up with the certain proportion mix homogeneously, or the injection of 50-200ml/ bottle, or dehydrate becomes injectable powder, back after testing packing.
This Hirudo and/or Pheretima raw material comprise dry product and/or bright product.Freezing and the Xie Rongzhong of this step (3), its homogenate are freezing 20 hours at-20 ℃.
The present invention also provides a kind of injection for the treatment of cardiovascular disease, it is characterized in that: it includes Hirudo normal saline extraction liquid 33%～84% and Pheretima normal saline extraction liquid 16%～67%.
The significance of treatment cardiovascular and cerebrovascular disease injection of the present invention is the precious legacy of further excavating and inheriting in motherland's medicine and pharmacology; Secondly the characteristics hurried at the cardiovascular and cerebrovascular disease onset, that variation is rapid, sb.'s sickness becomes critical, excavate out a kind of efficient, quick-acting, safe injection medicine, start the beginning of animal tcm compound injection, reduced the case fatality rate and the apoplexy sequela of cardiovascular and cerebrovascular disease to greatest extent; By to the omnibearing research of animal kind medicine thing, on the Chinese medicine basis, adopt modern biochemical technology to be improved, give full play to the advantage of animal tcm, it is brought benefit to the mankind better.
Further specify below in conjunction with preferred embodiment and accompanying drawing.
Description of drawings
Fig. 1 is the process flow diagram that manufacturing 1-20ml/ of the present invention props up injection.
Fig. 2 is the process flow diagram of manufacturing 50-500ml/ bottle injection of the present invention.
Fig. 3 is the process flow diagram of manufacturing powder needle injection of the present invention.
The specific embodiment
Embodiment 1
Consult shown in Figure 1, embodiments of the invention 1 be the preparation a kind of method that is used for the treatment of the injection of cardiovascular and cerebrovascular disease, comprise the steps:
1, material choice and low temperature dipping: the main Chinese medicinal materials raw material is Hirudo and Pheretima, select materials by following proportioning: Hirudo 355g (dry product) and Pheretima 645g (dry product), at ambient temperature, soaked about 3 hours with normal saline respectively, make its surface fully launch (to need dry basis as adopting bright product, and omit this step, following examples together), clean to clean with normal saline repeatedly again, place 2 times normal saline respectively with cleaning to clean water trematodiasis and Pheretima, flooded 30 hours in low temperature (0～4 ℃), filter, filtrate and medicinal residues preserve separately is standby;
2, smash grinding to pieces: medicinal residues are adopted high-speed tissue mashing machine (1000rpm), utilize the blade of high speed rotating will organize cutting and crushing, then mix with above-mentioned filtrate again, use homogenizer to utilize two frosting phase mutual friction, tissue is milled to the homogenate of diameter less than 0.5 μ m;
3, freezing and separate and melt: as homogenate to be taken out after freezing 18 hours at-18 ℃, under 0～4 ℃ of condition of low temperature, separate and melt, melt 3 times repeatedly by the freezing reconciliation of above-mentioned condition again;
4, separation and purification: liquid being melted in above-mentioned freezing reconciliation place centrifuge (5000r/min) centrifugalize, is that 50,000 filter post carries out coarse filtration with supernatant by molecular weight again, and filtrate was through 115 ℃ of hot pressing 30 minutes; Be that 10,000 ultrafiltration post further filters purification by molecular weight again;
5, dosing, embedding are to finished product: the Hirudo that will extract respectively and Pheretima solution are evenly mixed, add normal saline to 2000ml, embedding, every 2ml, sterilization, detect, packing.
6, testing result: total amino acids 5.90mg/ props up; Total sugar 15.20mg/ props up; Hypoxanthine 0.136mg/ props up; Total solid 25.16mg/ props up; Controlled index accounts for total solid 84.40%.
Need to prove: when dosing, the normal saline of adding can be 2000-5000ml, makes the injection of serial variable concentrations, to satisfy different patients' demand.
Embodiment 2
Consult shown in Figure 2, the treatment cardiovascular and cerebrovascular disease of the embodiment of the invention 2 the bottle injection manufacture method comprise the steps:
1, material choice and low temperature dipping: the main Chinese medicinal materials raw material is Hirudo and Pheretima, Hirudo 655g (dry product) and Pheretima 345g (dry product), at ambient temperature, soaked about 2.5 hours with normal saline respectively, its surface is fully launched, clean to clean with normal saline repeatedly again, place 4 times normal saline respectively with cleaning to clean water trematodiasis and Pheretima, flooded 15 hours in low temperature (0～4 ℃), filter, filtrate and medicinal residues preserve separately is standby;
2, smash grinding to pieces: medicinal residues are adopted high-speed tissue mashing machine (1000rpm), utilize the blade of high speed rotating will organize cutting and crushing, then mix with above-mentioned filtrate again, use homogenizer to utilize two frosting phase mutual friction, tissue is milled to the homogenate of diameter less than 0.5 μ m;
3, freezing and separate and melt: as homogenate to be taken out after below-15 ℃ freezing 25 hours, under 0～4 ℃ of condition of low temperature, separate and melt, melt 4 times repeatedly by the freezing reconciliation of above-mentioned condition again;
4, separation and purification: liquid being melted in above-mentioned freezing reconciliation place centrifuge (5000r/min) centrifugalize, is that 50,000 filter post carries out coarse filtration with supernatant by molecular weight again, and filtrate was through 121 ℃ of hot pressing 20 minutes; Be that 10,000 ultrafiltration post further filters purification by molecular weight again;
5, dosing, branch are filled to finished product: the Hirudo that will extract respectively and Pheretima solution mix homogeneously add normal saline to 50000ml, packing, every bottle of 100ml, sterilization, check, packing
6, testing result: total amino acids 9.00mg/ bottle; Total sugar 29.0mg/ bottle; Hypoxanthine 0.331mg/ bottle; Total solid 45.52mg/ bottle; Controlled index accounts for total solid 84.21%.
Embodiment 3
Consult shown in Figure 3ly, the manufacture method of the lyophilized injectable powder of the treatment cardiovascular and cerebrovascular disease of the embodiment of the invention 3 comprises the steps:
1, material choice and low temperature dipping: the main Chinese medicinal materials raw material is Hirudo and Pheretima, Hirudo 715g (dry product) and Pheretima 285g (dry product), at ambient temperature, soaked about 2 hours with normal saline respectively, its surface is fully launched, clean to clean with normal saline repeatedly again, place 3 times normal saline respectively with cleaning to clean water trematodiasis and Pheretima, flooded 25 hours in low temperature (0～4 ℃), filter, filtrate and medicinal residues preserve separately is standby;
2, smash grinding to pieces: medicinal residues are adopted high-speed tissue mashing machine (1000rpm), utilize the blade of high speed rotating will organize cutting and crushing, then mix with above-mentioned filtrate again, use homogenizer to utilize two frosting phase mutual friction, tissue is milled to the homogenate of diameter less than 0.5 μ m;
3, freezing and separate and melt: as homogenate to be taken out after freezing 15 hours at-20 ℃, under 0～4 ℃ of condition of low temperature, separate and melt, melt 5 times repeatedly by the freezing reconciliation of above-mentioned condition again;
4, separation and purification: liquid being melted in above-mentioned freezing reconciliation place centrifuge (5000r/min) centrifugalize, is that 50,000 filter post carries out coarse filtration with supernatant by molecular weight again, and filtrate was through 130 ℃ of hot pressing 10 minutes; Be that 10,000 ultrafiltration post further filters purification by molecular weight again;
5, dosing, packing, lyophilizing: the Hirudo that will extract respectively and Pheretima solution mix homogeneously, add 5% mannitol, add normal saline to 2000ml, be that 10,000 ultrafiltration post filters earlier, through 0.22 μ m microporous filter membrane terminal aseptic filtration, be sub-packed in cillin bottle or the ampoule again through molecular weight,-40 ℃ to-60 ℃ pre-freezes 3～4 hours, evacuation (vacuum is lower than 15pa), promptly can be made into lyophilized injectable powder at linear temperature increase, drying time 20～36 hours subsequently.
6, testing result: total amino acids 8.44mg/ props up; Total sugar 28.8mg/ props up; Hypoxanthine 0.344mg/ props up; Total solid 44.56mg/ props up; Controlled index accounts for total solid 84.34%.
Further specify as follows about manufacture method of the present invention creationary:
1, about the selection of raw material and dosage form:
Hirudo is as blood-activating and stasis-removing commonly used simply, and its indication treatment emphasis also by in the past gynecological diseases, is transferred on the present cardiovascular and cerebrovascular disease.Traditional Hirudo is used for the treatment of on the cardiovascular and cerebrovascular disease, have with the compound recipe determination of treatment based on pathogenesis obtained through differentiation of symptoms and signs, more then be that the throwing of single medicinal material is controlled, all received better effects, owing to be oral administration all, the bioavailability of its active substance is lower, causes its curative effect comparatively slow, the demand of incompatibility acute cardio cerebral angiopathy.
The medical value of Pheretima is usually used in cough with asthma, apoplexy sequela, chronic glomerulonephritis, parotitis, traumatic injury etc., no matter is the compound recipe combination, or folk prescription executes and control, and clinical efficacy is preferably all arranged.But owing to be oral administration all, the bioavailability of its active substance is lower, causes its curative effect comparatively slow, the demand of incompatibility acute cardio cerebral angiopathy.
The present invention with above the two share, reach the meaning that has promoting blood circulation to remove obstruction in the collateral among the removing blood stasis, softening the hard mass is invigorated blood circulation and is helped collateral dredging, is to bring out the best in each other, because that injection has an onset is reliable rapidly, be applicable to critical patient unsuitable or can not oral administration, and cardiovascular and cerebrovascular disease, especially acute cardiovascular and cerebrovascular disease, it is characteristics that how hurried with onset, variation reaches the state of an illness critical rapidly, therefore, injection is the first-selected route of administration of treatment cardiovascular and cerebrovascular disease.By with Hirudo and Pheretima compatibility, make low capacity injection, bulk capacity injection or injectable powder, reach the efficient quick-acting blood circulation promoting and blood stasis dispelling of playing altogether, the effect of dredge the meridian passage, and the purpose of treatment cardiovascular disease.
2, about the method for the pre-treatment of raw material:
For the ease of storage and transport, Chinese crude drug adopts dry product mostly, raw material of Chinese medicine Hirudo and Pheretima pre-treating method that the present invention uses are: at ambient temperature, soaked about 3 hours with normal saline respectively, its surface is fully launched, clean to clean with normal saline repeatedly again, its soak is through " paper chromatography " (the appendix VI A of Chinese Pharmacopoeia-portion in 2000) test, do not find wherein to have aminoacid, this processing method promptly reaches dry medical material is launched, the removal of contamination dirt does not make the purpose of loss of effective components again.
3, about extracting the process of Effective Components of Chinese Herb:
For the traditional method of extracting Effective Components of Chinese Herb is to adopt alcohol extraction to follow the example of or the decocting cooking method, the inventor follows the example of the extracting solution for preparing same concentrations respectively with decocting cooking method and method of the present invention with alcohol extraction and is applied to rat, measure clotting time, the results are shown in Table shown in 1.
Table 1
| Group | The example number | Concentration (g/kg) | Full clotting time (min) | |
| Alcohol extraction | Matched group | ????7 | ??0 | ????3.7±0.54 |
| Experimental group | ????7 | ??2 | ????8.6±3.01 | |
| Decocting boils | Matched group | ????8 | ??0 | ????2.8±0.41 |
| Experimental group | ????8 | ??2 | ????7.4±2.16 | |
| The inventive method | Matched group | ????10 | ??0 | ????3.4±0.87 |
| Experimental group | ????10 | ??2 | ????28.2±15.42 | |
Three kinds of extracting solution illustrate method the best of the present invention to the influence of the full clotting time of rat (CTg) as seen from Table 1.
4, about the breaking method of cell:
Hirudo used in the present invention and Pheretima be dry product normally, soak again through after cleaning, though tissue deliquescing directly grinds to form homogenate, still quite time-consuming difficulty again, therefore, the present invention adopts high-speed tissue mashing machine (1000rpm) earlier, utilizes the sharp blade of high speed rotating will organize cutting and crushing, then mixes with above-mentioned filtrate again, use homogenizer to utilize two frosting phase mutual friction, tissue is milled to the homogenate of diameter less than 0.5 μ m;
On the basis of Mechanical Crushing, further adopt the physics crush method, i.e. freezing method repeatedly, promptly make it to freeze solid, and then separate lentamente and melt operation so repeatedly in low temperature (15～-20 ℃), most of cell and cell endoparticle are destroyed, and its principle is: because the variation of osmotic pressure is freezed bound water, produce the distortion of tissue, Borneolum Syntheticum is dissolved in the solution, protein-based soluble component simultaneously the cell membrane fragmentation, can make the lipoprotein freezing denaturation, be beneficial to remove.
5, about the selection of filtration condition and hot pressing condition:
Product of the present invention is an intravenous injection, is again the preparation of driven Object Extraction, therefore, macromolecular substances such as protein can not be arranged, otherwise its consequence is hardly imaginable.The method applied in the present invention is: at first select the filter post about 50,000 molecular weight to carry out coarse filtration, the material that is lower than 50,000 molecular weight is passed through, remove the macromolecule materials such as protein more than 50,000; Second step selected for use the ultrafiltration post of molecular weight below 10,000 to filter, and made the micromolecule polypeptide that keeps below 10,000, removed than the macromole peptide.
Because the character and the amino acid similarity of oligopeptide, it was both water-soluble, also was dissolved in alcohol, and was heated and does not solidify, and was difficult to remove, and no matter it uses high concentration alcohol, or adopted and boil cold preservation or activated carbon adsorption etc. and all can not be removed.The present invention creates the filtrate of sening as an envoy to and handled in 10～45 minutes through 105～136 ℃ of hot pressing through a large amount of experimentatioies, can make the part oligopeptide further resolve into aminoacid on the one hand, is dissolved in the extracting solution; The part oligopeptide is solidified separate out precipitation, so that remove.
It below is the experimental study of pharmacodynamics, pharmacology, quality standard, stability of drug products and the clinical trial etc. of injection (the commodity blood of dredging by name leads to) about the treatment cardiovascular disease of method manufacturing of the present invention.
Entrust institute of Materia Medica,Chinese Academy of Medical Sciences, Nat'l Pharmaceutical ﹠ Biological Products Control Institute, Inst. of Physics, CAS further according to the requirement of " Chinese medicine development guideline (trying) ", has carried out comprehensive and systematic experimental study to pharmacodynamics, pharmacology, quality standard and stability of drug products etc.Now the experimental study result is summarized as follows:
(1) experimental study of pharmacodynamics and general pharmacology
1, to the influence of clotting time of mice:
After giving mouse tail iv injection 2.5 and 5.0g/kg (crude drug amount, as follows) injection of the present invention respectively, measure its clotting time, the result shows: the equal significant prolongation of clotting time;
2, to the influence of rat platelet:
(1) to the influence of rat platelet: after giving rat tail iv injection 1.0,2.5 and 5.0g/kg injection of the present invention respectively, measure its platelet count, the result shows: all have slight reduction platelet count, significantly reduce hematoblastic adherent effect, help reducing the formation of thrombosis;
(2) to the influence of rat platelet aggregation: after giving rat tail iv injection 0.5,1.0 and 2.5g/kg injection of the present invention respectively, measure its platelet aggregation, the result shows: the platelet aggregation of ADP, arachidonic acid and thrombin induction is reduced, and demonstrate certain dose-effect relationship;
3, to the influence of thrombosis:
(1) to preventing thrombotic influence: after giving rat tail iv injection 0.5,1.0 and 2.5g/kg injection of the present invention respectively, carry out the test of its external thrombus and body angular vein thrombosis, the result shows: formed thrombus weight all has alleviating in various degree, illustrates to have the thrombotic effect of inhibition;
To the preventative thrombotic influence of rat artery: after giving rat tongue intravenous injection 0.5,1.0 and 2.5g/kg injection of the present invention respectively, carry out its thrombosis test, the result shows: all make thrombotic time lengthening;
(2) effect of thrombus dissolving
1. to the influence of the blood flow volume of femoral artery thrombosis Canis familiaris L.: after 30 minutes, measure its blood flow to Canis familiaris L. injection 30g/kg injection of the present invention, the result shows: blood flow obviously increases;
2. the injection of the present invention and the UK of various dose, to fibrinogenic influence: to Canis familiaris L. injection 30g/kg injection of the present invention after 30 minutes, measure its fibrinogenic content, the result shows: all do not have obvious variation, show that injection of the present invention does not have influence to Fibrinogen;
3. to the influence of the blood plasma euglobulin lysis time of femoral artery thrombosis Canis familiaris L.: give femoral artery thrombosis Canis familiaris L. injection 15g/kg and 30g/kg injection of the present invention after 30 minutes, measure the dissolved time of its euglobulin, the result shows: all significantly shortens, and remarkable with comparing difference before the administration;
4. to the influence of Canis familiaris L. thigh arteries and veins thrombus weight: give femoral artery thrombosis Canis familiaris L. injection 30g/kg injection of the present invention after 30 minutes, measure its femoral artery thrombus weight, the result shows: the femoral artery thrombus weight obviously alleviates, and left and right sides femoral artery thrombus weight reduces 35.8% and 34.9% respectively;
Give femoral artery thrombosis Canis familiaris L. injection 15g/kg injection of the present invention after 30 minutes, left and right sides femoral artery thrombus weight reduces 17.8% and 32.6% respectively.Show that injection of the present invention has thrombolytic effect;
4, ligation causes the influence of ischemia to intraluminal middle cerebral artery occlusion in rats: injection of the present invention is according to 1.0,2.5 and the 5.0g/kg administration, the ischemia behavior disorder that ligation rat brain tremulous pulse is caused alleviates, the cerebral ischemia area reduces 28.4%, 35.8% and 71.7% respectively, shows that injection of the present invention has the good curing effect to ischemic cerebrovascular and apoplexy.
5, to the test of normal anesthetized dog: inject injection of the present invention for the dog iv of normal anesthesia,, measure BP and HR and all do not have obvious change according to 0.75 and the 1.5g/kg administration, but according to the 3.0g/kg administration, measure BP and HR, the HR that then obviously slows down, and BP is not had obvious influence.Point out injection antagonism cerebral ischemia diseases of the present invention and thrombosis not to realize by expansion of cerebral vascular.
6, general pharmacology experiment: according to 1.0,2.5 with after 5.0g/kg gives Kunming mouse tail iv injection, discovery activity and outward appearance dystropy do not show that this medicine does not have obvious influence to nervous system and outward appearance behavior with injection of the present invention; And the mice autonomic activities there is not obvious shadow.
In addition with injection of the present invention with 0.5 and 2.0g/kg give dog iv injection, to respiratory depth, frequency, the blood pressure of dog, heart rate and II conductive pattern all do not have tangible influence.
(2) toxicological test research:
1, acute toxicity test: show by a large amount of animal experiments: the LD of mice is given in intravenous injection
50Be 112.5g/kg (calculating), the LD of lumbar injection according to the crude drug amount
50Be 173.83g/kg, the maximum tolerated dose of gastric infusion is 390g/kg.4345 times of the quite clinical people's dosage of abdominal cavity medication; (computational methods about this point are 2800 times of the quiet quite clinical people's dosage of dosage: the LD of mice
50Be 112.5g/kg, clinical is 0.5g/ml (crude drug) with injection; The adult uses 4ml every day, the quite quiet 2g crude drug that splashes into, and by body weight 50kg estimation, everyone every day, the quiet 0.04g/kg that splashes into counted, and gave the LD of the quiet notes of mice
50Value is 112.5g/kg, is equivalent to 2800 times of people's clinical application), show that the toxicity of injection of the present invention is lower, clinical application belongs to safety.
2, long term toxicity test:
1. with injection of the present invention according to 0.4,2.5 and three dosage of 15.0g/kg give rat intravenous injection, continuous 30 days result and convalescent result, show: the general behavior performance of each administration group, food ration, body weight gain rate, hematology, serum biochemistry are learned indexs such as inspection, organ coefficient and histopathological examination, compare with the blank group, equal no significant difference, illustrate that injection of the present invention 0, in 4～15.0g/kg (10～375 times of quite clinical plan consumptions) dosage range, does not have obvious toxic-side effects to rat.
2. with injection of the present invention according to 0.5,1.0 and three dosage of 3.0g/kg give the intravenous injection of Beagla dog, continuous 30 days result and convalescent result, overview, no abnormality seen;
Carry out hematology, blood biochemical inspection, internal organs system and electrocardiogram in 2～4 weeks of administration and convalescent period, there is no unusual;
The equal no significant difference of histopathological examination and internal organs illustrates that injection of the present invention 0, in 5～3.0g/kg (75 times of the quite clinical plan consumptions of heavy dose of group) dosage range, does not have obvious toxic-side effects to dog.Visual injection of the present invention is safe drugs.
(3) safety testing:
1, irritation test:
1. local irritation test: injection of the present invention to four quadriceps femoris injections of two rabbit, is and does not see depletion of blood or downright bad phenomenon, is 0 according to the score value of irritant reaction level, is no significant change; Pathologic finding does not have obvious inflammatory reaction.Show no local irritation reaction.
2. blood vessel irritation test: injection of the present invention is injected according to the dosage ear of 1.0g/kg rabbit, continuous 3 times, 24 hours execution rabbit after the last administration, be and do not see depletion of blood or downright bad phenomenon, getting the auricle of injection site fixes, the routine pathology histological examination at microscopically, is not observed blood vessel irritating reaction such as degeneration or necrosis in a organized way of injection site.
2, sensitivity test: according to the one sensitivity test requirement of " Chinese medicine guideline (trying) " adnexa, Cavia porcellus injected there is no reacting phenomenons such as perpendicular hair, dyspnea, sneeze, cough, retch, tic, collapse, death behind the injection of the present invention in 15 minutes, show that injection of the present invention does not have anaphylaxis to Cavia porcellus.
3, hemolytic test: injection of the present invention and concentrated solution all find no haemolysis, and also not seeing has erythroagglutination.
(4) quality standard of injection of the present invention:
According to the requirement of working out about quality standard in " Chinese medicine guideline (the trying) " of Ministry of Public Health promulgation, the discriminating of having set up ultraviolet absorption maximum, hole C and gel electrophoresis;
Inspection item has been worked out the inspection of heavy metal, arsenic salt, protein, Ph, relative density, residue on ignition, potassium ion etc. according to pertinent regulations, all meets the requirement of quality standard;
Assay is taked high effective liquid chromatography for measuring total amino acids, polypeptide amino acid and hypoxanthine; With iodometric determination total sugar and polysaccharide; Measure total solids content with seasoning; Make the index of controllable part reach more than 60% of total solid.
(5) stability of drug products test:
Take the accelerated test equistability test method in reserved sample observing method, luminescence method, the 40 ℃ of climatic chambers, carried out continuous trimestral observation, every with quality standard as investigating index, test on schedule, result and comparison in 0 month, its physicochemical property is stablized no change, and the steady quality of injection of the present invention is described.
It below is the clinical experimental study of injection of the present invention.
The injection of treatment cardiovascular disease of the present invention is through a large amount of clinical practice experimental studies, proves specially good effect that it has the treatment cardiovascular disease and quick-acting, and do not have toxic side effect and have the effect that reduces sequela.Below illustrate.
1, clinical trial 1:
By to 10 healthy people volunteers tests, injection of the present invention to be to be equivalent to quiet of crude drug amount 2 gram consumptions every day 21, no matter from clinical manifestation, or blood, routine urinalysis, liver, kidney, cardiac inspection are not all found toxic and side effects.
Then improve 1.5 times of dosage, injection promptly of the present invention was equivalent to quiet of crude drug amount 3 gram consumptions every day 21, no matter from clinical manifestation, or blood, routine urinalysis, liver, kidney, cardiac inspection are not all found toxic and side effects.Think that quiet of the consumption of the suitable crude drug amount of injection of the present invention administration every day 3 grams was safe on 21st.
2, clinical trial 2:
Use injection of the present invention that 50 routine cerebral infarction patients have been carried out the treatment clinical trial of a course of treatment (10 days) by a definite date, the result shows: total effective rate reaches 84%, curative effect obviously is better than matched group, and it only is 36% that matched group uses the total effective rate of " troxerutin ";
The CT examination result is before and after above-mentioned two groups of treatments: treatment group improvement rate reaches 96%, and the matched group improvement rate is 54%;
After treating for two weeks, wherein the volume Nie Shi low density area of 20 examples on average dwindles 64%, and the blood supply of expression middle cerebral artery improves; Wherein the volume top low density area of 10 examples has occupying lesion, and through continuing treatment, its low density area on average dwindles 20%, and occupying lesion disappears.
Wherein the former left basal ganglia region of 10 routine cerebral infarction is ovum garden low density area edge clear, and center line moves to right, and on average dwindles 70% through the treatment low-density, the center line disappearance that moves to right.
3, clinical trial 3:
Use injection of the present invention that 30 routine cardiovascular disease patients are carried out clinical trial, matched group is for using the Svate test, and the result shows: the effective percentage of injection of the present invention reaches 90%, and matched group is 86%; Find simultaneously injection of the present invention treatment patient thromboxane B2 and fiber egg day is former and the platelet number average has the minimizing of highly significant before than treatment; Whole blood contrast viscosity, plasma viscosity and whole blood reduced viscosity are all than obviously reducing before the treatment, illustrate that injection of the present invention can effectively reduce blood viscosity, improve the hemocyte electrophoretic mobility, reduce platelet adhesion, the blood supply and the cerebrocellular edema in cerebral infarction district are improved, make impaired neurocyte recover its function.
In sum, through experimental study comprehensive to injection of the present invention, system, show that every research contents all meets " Chinese medicine development guideline (trying) " and the requirement of provisions for new drugs approval " about the revision and the supplementary provisions of Chinese medicine part " of Ministry of Public Health issue.
Detailed content about the clinical practice experimental study of the injection of treatment cardiovascular disease of the present invention sees also following adnexa 1～8:
1, adnexa 1 testing datas of totally 8 pages of general pharmacologies research;
2, adnexa 2 totally 22 pages of main pharmacodynamics researchs that thin blood is logical;
3, adnexa 3 totally 21 pages of long-term toxicity test for animals data;
4, adnexa 4 totally 21 pages of blood circulation promoting injections treatment apoplexy II phase clinical summaries;
5, adnexa 5 totally 15 pages of blood circulation promoting injection IV phase clinical summaries;
6, sum up by the design of totally 7 pages of blood circulation promoting injection I clinical trial phases and I clinical trial phase for adnexa 6.
7, adnexa 7 clinical observation and the evaluation of totally 8 pages of thin blood extensively treating treatment ischemic cerebrovasculars.
8, adnexa 8 totally 4 pages of thin blood extensively treating treat the clinical efficacy of cerebral infarction and to hemorheological influence.
Claims (6)
1, a kind of manufacture method for the treatment of the injection of cardiovascular and cerebrovascular disease, it is characterized in that: it comprises the steps:
(1) material choice and low temperature dipping:
At ambient temperature, Hirudo and Pheretima are soaked with normal saline respectively, its surface is fully launched, clean to clean with normal saline repeatedly again, place 2～4 times normal saline respectively with cleaning to clean water trematodiasis and Pheretima, flooded 15～30 hours for 0～4 ℃ in low temperature, filter, filtrate and medicinal residues preserve separately is standby;
(2) smash grinding to pieces:
Adopt high-speed tissue mashing machine will organize cutting and crushing medicinal residues, then mix with above-mentioned filtrate again and use homogenizer to be milled to the homogenate of diameter less than 0.5 μ m;
(3) freezing and separate and melt:
Homogenate was taken out after below-15 ℃ freezing 15～30 hours, under 0～4 ℃ of condition of low temperature, separate and melt, melt at least 2 times repeatedly by the freezing reconciliation of above-mentioned condition again;
(4) separation and purification:
Liquid being melted in above-mentioned freezing reconciliation place the centrifuge centrifugalize, is that 50,000 filter post carries out coarse filtration with supernatant by molecular weight again, and filtrate was through 105～136 ℃ of hot pressing 10～45 minutes; Be that 10,000 ultrafiltration post further filters purification by molecular weight again;
(5) dosing:
Above two kinds of filtrates that make are even according to the mixed of Hirudo normal saline extraction liquid 33%～84% and Pheretima normal saline extraction liquid 16%～67%, make the injection that 1-20ml/ props up, or the injection of 50-200ml/ bottle, or dehydrate becomes injectable powder.
2, the manufacture method of the injection of treatment cardiovascular and cerebrovascular disease according to claim 1 is characterized in that: this Hirudo and/or Pheretima raw material comprise dry product and/or bright product.
3, the manufacture method of the injection of treatment cardiovascular disease according to claim 1 is characterized in that: the freezing and Xie Rongzhong of this step (3), its homogenate are freezing 20 hours at-20 ℃.
4, the manufacture method of the injection of treatment cardiovascular disease according to claim 1, it is characterized in that: the dehydrate in the dosing of this step (4) becomes injectable powder to comprise, with Hirudo and the Pheretima solution mix homogeneously that extracts respectively, add 5% mannitol, add normal saline to 2000ml, elder generation is 10,000 ultrafiltration post filtration through molecular weight, again through 0.22 μ m microporous filter membrane terminal aseptic filtration, be sub-packed in cillin bottle or the ampoule,-40 ℃ to-60 ℃ pre-freezes 3～4 hours, evacuation (vacuum is lower than 15pa) subsequently, linear temperature increase, 20～36 hours drying times, promptly make lyophilized injectable powder.
5, a kind of injection for the treatment of cardiovascular disease is characterized in that: it includes Hirudo normal saline extraction liquid 33%～84% and Pheretima normal saline extraction liquid 16%～67%.
6, the injection of treatment cardiovascular disease according to claim 5 is characterized in that: the content of the total amino acids in this injection, polypeptide amino acid, hypoxanthine, total sugar and polysaccharide is more than 60% of total solid.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101340921B (en) * | 2006-06-28 | 2011-09-28 | 李振国 | Extract for preventing and treating embolus disease |
| CN102389442A (en) * | 2011-11-23 | 2012-03-28 | 南京中医药大学 | Lumbricus extract possessing antithrombotic effect |
| CN102389441A (en) * | 2011-11-17 | 2012-03-28 | 牡丹江友搏药业有限责任公司 | Application of Shuxuetong composition in preparation of medicaments for treating myocardial ischemia |
| CN103592303A (en) * | 2013-11-25 | 2014-02-19 | 牡丹江友搏药业股份有限公司 | Antithrombin activity assay method of injection for promoting blood circulation to remove blood stasis |
| CN105923213A (en) * | 2016-05-03 | 2016-09-07 | 重庆多普泰制药股份有限公司 | Electron irradiation sterilization device and sterilization method for medical hirudo |
| CN113813291A (en) * | 2021-11-10 | 2021-12-21 | 山东新时代药业有限公司 | Preparation method of animal medicinal material freeze-dried powder |
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2003
- 2003-07-01 CN CNB031482813A patent/CN1192782C/en not_active Expired - Lifetime
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101340921B (en) * | 2006-06-28 | 2011-09-28 | 李振国 | Extract for preventing and treating embolus disease |
| US8252340B2 (en) | 2006-06-28 | 2012-08-28 | Mudanjiang Youbo Pharmaceutical Co., Ltd | Extract for treating thrombotic diseases |
| CN102389441A (en) * | 2011-11-17 | 2012-03-28 | 牡丹江友搏药业有限责任公司 | Application of Shuxuetong composition in preparation of medicaments for treating myocardial ischemia |
| CN102389442A (en) * | 2011-11-23 | 2012-03-28 | 南京中医药大学 | Lumbricus extract possessing antithrombotic effect |
| CN102389442B (en) * | 2011-11-23 | 2013-03-13 | 南京中医药大学 | Lumbricus extract possessing antithrombotic effect |
| CN103592303A (en) * | 2013-11-25 | 2014-02-19 | 牡丹江友搏药业股份有限公司 | Antithrombin activity assay method of injection for promoting blood circulation to remove blood stasis |
| CN105628702A (en) * | 2013-11-25 | 2016-06-01 | 牡丹江友搏药业股份有限公司 | Method for determining antithrombin activity of Shuxuetong injection |
| CN105923213A (en) * | 2016-05-03 | 2016-09-07 | 重庆多普泰制药股份有限公司 | Electron irradiation sterilization device and sterilization method for medical hirudo |
| CN113813291A (en) * | 2021-11-10 | 2021-12-21 | 山东新时代药业有限公司 | Preparation method of animal medicinal material freeze-dried powder |
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