CN100546585C - Compound puerarin injection and preparation method thereof - Google Patents
Compound puerarin injection and preparation method thereof Download PDFInfo
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- CN100546585C CN100546585C CNB2006100353600A CN200610035360A CN100546585C CN 100546585 C CN100546585 C CN 100546585C CN B2006100353600 A CNB2006100353600 A CN B2006100353600A CN 200610035360 A CN200610035360 A CN 200610035360A CN 100546585 C CN100546585 C CN 100546585C
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Abstract
The present invention discloses a kind of compound puerarin injection and preparation method thereof, and described injection contains 1～50 weight portion taurine and 1～50 weight portion puerarin, also contains adjuvant 0～50 weight portion and water for injection 0～10000 weight portion.Compound puerarin injection of the present invention can be made into the dosage form of various clinical injection administrations such as injection, powder pin, transfusion, overcomes the caused sporadic hemolytic untoward reaction of injection puerarin effectively, improves the safety of puerarin injection administration.
Description
Technical field
The present invention relates to a kind of injection, be specifically related to a kind of puerarin injection.
Background technology
Puerarin (Puerarin) is to refine the effective ingredient that obtains from Radix Puerariae (Radix Puerariae), and chemistry is by name: 4 ', 7-dihydroxy-8-β-D glucone isoflavone is vasodilator.The modern pharmacological research result shows that puerarin has blood pressure lowering, coronary artery dilating and cerebrovascular, improves the brain microcirculation, protection ischemic myocardium and myocardial ischemia reperfusion injury, antithrombotic, decomposition plasma fibrinogen, blood viscosity lowering, prevent atherosclerosis, blood fat reducing, keep that blood glucose is normal, antioxidation, defying age, control bone resorption and promote bone growth, suppress natural death of cerebral cells, suppress effects such as growth of tumour cell.Puerarin preparation has injection, lyophilized injectable powder, eye drop, mainly is applied to clinically with drug administration by injection, and the oral administration new drug is not arranged as yet.Puerarin injection is used for auxiliary treatment coronary heart disease, angina pectoris, myocardial infarction, retina arteriovenous obstruction, sudden deafness etc. clinically.But puerarin injection can cause the situation of serious adverse reaction to cause the concern of administration section and research worker already, on January 1st, 2003, national drug untoward reaction monitoring center just can cause to puerarin injection that in the third phase " adverse drug reaction communication " security related problems such as acute intravascular hemolysis have carried out communication.In the same year, the prospective cohort study about " puerarin injection untoward reaction and correlative factor " has further confirmed the dependency of puerarin injection and acute intravascular hemolysis; In November, 2004, State Food and Drug Administration has issued " about the notice of revision puerarin injection description ", and December in 2005 issue on the 29th " about strengthening the notice of puerarin injection management " suspends the application for registration of puerarin injection.Puerarin injection can cause acute intravascular hemolysis, and morbidity is anxious, progress is fast, and the state of an illness is critical, as untimely discovery, treatment, and entail dangers to life.According to statistics, on January 1st, 2003, the untoward reaction case report of relevant puerarin injection was totally 1006 examples between 30 days June in 2005, wherein, and serious adverse reaction 30 examples, dead 11 examples.Serious adverse reaction is based on acute intravascular hemolysis, totally 18 examples, and dead 8 examples account for 73% of death.This shows that the untoward reaction that the hemolytic reaction that puerarin causes causes has caused the concern of the world of medicine.
Summary of the invention
Technical problem to be solved by this invention is to overcome puerarin injection to cause sporadic hemolytic untoward reaction.
The technical solution that solves the problems of the technologies described above of the present invention is:
A kind of compound puerarin injection contains following weight portion drug component: 1～50 part of taurine, 1～50 part of puerarin.
The invention described above compound puerarin injection is acceptable clinically powder pin, and this powder pin is made by taurine and puerarin mixing, sterilization.
Compound puerarin injection of the present invention, wherein drug component also has: 1～50 part of adjuvant, 1～10000 part of water for injection.
Compound puerarin injection of the present invention, wherein the preferable amount of each drug component is: 10 parts of taurines, 5 parts of puerarins, 9 parts of adjuvants, 2500 parts of waters for injection.
Compound puerarin injection of the present invention is acceptable clinically injection, powder pin or transfusion.
The preparation method of compound puerarin injection of the present invention; described powder pin is mixed by taurine, puerarin and sodium chloride, adds the dissolving of injection water, and the reuse sodium hydroxide solution is adjusted pH value to 3.0-9.0; filter, being potted in after the filtrate sterilization sterilizes in the powdery ampoule once more makes.
The preparation method of compound puerarin injection of the present invention, described injection is mixed by taurine, puerarin and sodium chloride, adds the dissolving of injection water; the reuse sodium hydroxide solution is adjusted pH value to 3.0-9.0; dissolving is filtered, and filtrate is potted in to sterilize in the ampoule and makes.
The preparation method of compound puerarin injection of the present invention; described transfusion is mixed by taurine, puerarin and sodium chloride, adds the dissolving of injection water, and the reuse sodium hydroxide solution is adjusted pH value to 6.5-7.5; filter, filtrate is potted in to sterilize in the saline vial and makes.
Injection consumption of the present invention calculates by adult 60Kg body weight, and per injection contains the injection of the present invention of puerarin 1～2400mg, taurine 2～2800mg.Directly intramuscular injection, intravenous injection during application also can be carried out intravenous injection with making injection and sodium chloride injection or glucose injection mixing, and 1～3 time on the one, 10～20 days is a course of treatment, can use 2～3 courses of treatment continuously.
Compound puerarin injection of the present invention is made by two flavor principal agent taurines, puerarin and an amount of medically acceptable excipient.Wherein, taurine, Radix Puerariae have the legal medicine standard and record, and coronary artery dilator and cerebrovascular are all arranged, and reduce myocardial oxygen consumption, the effect of microcirculation improvement and antiplatelet aggregation.Identical with the former indication of puerarin injection, two medicine mutual-assistance compatibilities have synergistic function preferably on drug effect, and the present invention finds taurine and the application of puerarin compatibility again, can overcome the untoward reaction that the sporadic haemolysis of former puerarin injection causes.
Advantage of the present invention is: taurine, puerarin two medicine mutual-assistance compatibilities, can overcome the untoward reaction that the sporadic haemolysis of former puerarin injection causes, and improve the safety of puerarin injection administration.
Test furthermore bright beneficial effect of the present invention below in conjunction with some:
Experiment one. the Study on Evaluation of puerarin injection haemolysis untoward reaction
Research puerarin injection agent medicine is to the erythrocytic influence of Beagle dog.Get the erythrocyte of 24 Beagle dogs, the puerarin injection, the propylene glycol liquid that add various dose respectively, observe erythrocytic state and incidence rate in 24 hours, analyze experimental result with the X2 inspection statistics, seek and cause the sporadic hemolytic reason of puerarin injection, set up the evaluation methodology of haemolysis untoward reaction.Now the result is reported as follows:
1. experiment material
1.1 be subjected to the reagent thing
Propylene glycol liquid provides lot number by Traditional Chinese Medicine University Of Guangzhou new drug development research center: 20060316, form by propylene glycol and normal saline (1: 1) configuration by volume, and include propylene glycol 0.5mL/mL.
Puerarin injection, available from the big day bio tech ltd in Guangzhou, lot number 01050801 includes puerarin 50mg/mL, propylene glycol 0.5mL/mL.
1.2 laboratory animal
24 of Beagle dogs (body weight 6～8Kg male and female half and half) are provided by Guangdong Province institute of Pharmaceutical Industry Beagle dog plant, the quality certification number: the moving word 0014298 of doctor.17～20 ℃ of room temperatures, raise under relative humidity 60%～68% condition.
1.3 reagent, instrument
Sodium chloride injection, lot number: 05112102, Anhui Huayuan Biological Pharmaceutical Industry Co., Ltd. produces; Water for injection, lot number: 200508011, railway central hospital in Guangzhou produces; 22XLJ-II type centrifugal precipitation mechanism, Shanghai medical apparatus factory; The biochemical incubator of SPX-150B, the magnificent biochemical instrument maker in last Haikang.
2. method
24 of Beagle dogs carry out hemolytic experiment respectively.Adopt dog forelimb venous blood 10ml, in the 50mL beaker, remove rapidly with toothpick and to defibrinate, place in the graduated centrifuge tube, add the proper amount of sodium chloride injection, with 2000 rev/mins centrifugal 10 minutes, discard liquid, add chlorination sodium injection mixing, centrifugal again, so cyclic washing is gone up liquid to centrifugal back and is till the water white transparency, and the gained erythrocyte is prepared into 50% red cell suspension with sodium chloride injection.Get 16 test tubes and add amount of liquid medicine by table 1, table 2, press table 3 preparation feminine gender and positive control, add the chlorination sodium injection again to total amount 5ml, mix with 50% red cell suspension 0.1ml, each pipe shakes up, be placed in the biochemical incubators of 37 ℃ of constant temperature, respectively at 15,30,60 minutes, 2,3,4,6 hours and observe each pipe next day and have or not haemolysis and hemagglutination.Add up 24 Beagle dog haemolysis incidence rates.
Be subjected to reagent thing adding method to see Table 1,2,3,4, the haemolysis determination methods sees Table 3.
Table 1 propylene glycol liquid group adding method and test solution proportioning
Table 2 puerarin injection adding method and test solution proportioning
Table 3 feminine gender and positive control adding method
Table 4 haemolysis determination methods
24 Begal dogs of table 5 hemolytic test outcome record
24 Begal dogs of table 6 hemolytic test is statistical table as a result
Annotate: compare * p＜0.05 ， $p＜0.01 with the negative group of normal saline; With the propylene glycol liquor ratio: #p＜0.05 ， ﹠amp; P＜0.01
3. result and discussion
This test is investigated variable concentrations puerarin injection, propylene glycol liquid altogether to 24 erythrocytic influences of Begal dog, and investigating the result all has itemized record, the equal photo record of hemolytic test, and 24 hours results of record hemolytic test see Table 5.Full haemolysis and part hemolytic experiment result are pressed the haemolysis counting, calculate puerarin injection and the haemolysis incidence rate of propylene glycol liquid under various concentration, analyze, the results are shown in Table 6 with the X2 inspection statistics.
The result shows: haemolysis does not appear in the normal saline group, and the whole haemolysis of water for injection group illustrate that this hemolytic experiment method is reliable and stable.Compare with the normal saline group, haemolysis does not all appear in propylene glycol liquid B1, B2, B4, B5 dosage group, one routine part haemolysis appears in B3 dosage, the negative group of propylene glycol liquid B1～B5 dosage haemolysis incidence rate and normal saline there are no significant difference (P＜0.05), 4 routine part haemolysis appear in propylene glycol liquid B6 dosage group, and there are significant difference (P＞0.05) in haemolysis incidence rate and normal saline group; The less generation of propylene glycol haemolysis of results suggest low concentration, the haemolysis probability of happening increases when concentration is increased to 10%.Compare with the normal saline group, haemolysis does not all appear in puerarin injection C1, C2 dosage group, one routine haemolysis all appears in C3, C4 dosage, 3 routine haemolysis appear in C5 dosage, puerarin injection C1～C5 dosage haemolysis incidence rate and normal saline group there are no significant difference (P＜0.05), when the puerarin injection agent concentration is increased to C6 dosage, 15 routine haemolysis appear, and there are utmost point significant difference (P＜0.01) in haemolysis incidence rate and normal saline group.Analyze according to the haemolysis incidence rate, (incidence rate is lower than 5.0% to puerarin injection 0.1～0.4mL/5mL) time at low concentration, incidence rate is 12.5% when intermediate concentration (0.5mL/5mL), incidence rate reaches 62.5% when high concentration (1mL/5mL), and puerarin injection haemolysis incidence rate and dosage are closely related.With the propylene glycol liquid group of same concentrations relatively, puerarin injection C1, C2, C3 dosage group haemolysis incidence rate are identical with propylene glycol liquid group; Along with increasing of puerarin dosage, C4, C5 dosage group haemolysis incidence rate are higher than propylene glycol liquid B4, B5 dosage group, though the trend that haemolysis increases appears in there was no significant difference (P＞0.05); When puerarin concentration was raised to 10mg/mL, C6 dosage group haemolysis incidence rate was significantly higher than propylene glycol liquid B6 dosage group, though both propylene glycol concentration are identical, the haemolysis incidence rate has utmost point significant difference (P＜0.01), obviously was because due to the puerarin of high concentration.
Propylene glycol is as adjuvant, wait cause under the condition of oozing that the hemolytic concentration of human blood is 30% about.But the puerarin injection haemolysis is that antibodies owing to puerarin and erythrocyte surface causes, and heavy dose of administration, and the puerarin injection untoward reaction is increased; The puerarin powder pin, puerarin sodium chloride injection, the puerarin glucose injection that do not contain propylene glycol all have untoward reaction to take place.Experiment finds that the sporadic hemolytic probability of happening of puerarin injection is significantly higher than propylene glycol liquid (P＜0.01), and closely related with the concentration of puerarin.This shows, puerarin injection, puerarin powder pin, puerarin sodium chloride injection, puerarin glucose injection etc. contain the intravenous administration formulation of puerarin, all the haemolysis untoward reaction might take place, especially heavy dose of administration will improve puerarin haemolysis incidence rate of adverse reaction.
This experiment adopts 24 Beagle dogs to carry out the external hemolytic test of compoundanimal, has overcome the single animal occasionality of pharmacopeia hemolytic test; Strengthen concentration, improve sporadic hemolytic incidence rate for reagent liquid.Because the untoward reaction probability of happening is generally lower, the laboratory animal number of elements should be no less than 24; It is excessive that untoward reaction generally occurs in dosage, and the drug level of hemolytic test also should be 2 times of maximum drug level of the conventional hemolytic test of pharmacopeia.For untoward reaction, 24 of Beagle dogs only are very little experiment sample numbers; (incidence rate is lower than 5.0% to puerarin injection 0.1～0.4mL/5mL) time, and incidence rate is 12.5% when intermediate concentration (0.5mL/5mL), though can find sporadic haemolysis, not statistically significant at low concentration.Prompting is used this experiment and is carried out sporadic haemolysis evaluation, when 24 Beagle dogs are found haemolysises first, under the situation of not statistically significant, should do the experiment of 24 Beagle dogs again, and carry out the experimental result statistical analysis of 48 Beagle dogs; Perhaps improve drug level, observe the hemolytic experiment result of 24 Beagle dogs again and carry out statistical analysis.
Repeated the external hemolytic test of puerarin injection high dose with this method, probability of happening is 79%, with the haemolysis probability of happening there was no significant difference of testing for the first time the puerarin injection high dose, and wherein most Beagle dog hemolytic test result all obtains reappearing, and illustration method can repeat.This method can be used for finding the potential accidental haemolysis of injection, is to carry out the injection new drug development to judge whether to exist sporadic hemolytic feasible test method, helps reducing the generation of untoward reaction, improves the safety of injection.
Experiment two. taurine is to the influence of puerarin injection haemolysis untoward reaction
Research taurine and puerarin share the erythrocytic influence of Beagle dog.Get the erythrocyte of 24 Beagle dogs; the taurine and the puerarin that add various dose respectively; observe erythrocytic state and incidence rate in 24 hours, analyze experimental result, seek taurine the sporadic hemolytic antagonism of puerarin injection with the X2 inspection statistics.Now the result is reported as follows:
1 experiment material
1.1 be subjected to the reagent thing
Compound puerarin injection of the present invention 6., every mL injection contains puerarin 10mg, taurine 5mg, sodium chloride 9mg, lot number: 20060329, provide by Traditional Chinese Medicine University Of Guangzhou new drug development research center.
Compound puerarin injection of the present invention 7., every mL injection contains puerarin 10mg, taurine 10mg, sodium chloride 9mg, lot number: 20060329, provide by Traditional Chinese Medicine University Of Guangzhou new drug development research center.
Compound puerarin injection of the present invention 8., every mL injection contains puerarin 10mg, taurine 20mg, sodium chloride 9mg, lot number: 20060329, provide by Traditional Chinese Medicine University Of Guangzhou new drug development research center.
Puerarin injection, available from the big day bio tech ltd in Guangzhou, lot number 01050801, every mL injection contains puerarin 50mg.Be made into every mL injection with normal saline during hemolytic test and contain puerarin 10mg as puerarin injection high dose matched group.
1.2 laboratory animal
24 of Beagle dogs (body weight 6～8Kg male and female half and half) are provided by Guangdong Province institute of Pharmaceutical Industry Beagle dog plant, the quality certification number: the moving word 0014298 of doctor.17～20 ℃ of room temperatures, raise under relative humidity 60%～68% condition.
1.3 reagent, instrument
Sodium chloride injection, lot number: 05112102, Anhui Huayuan Biological Pharmaceutical Industry Co., Ltd. produces; Water for injection, lot number: 200508011, railway central hospital in Guangzhou produces; 22XLJ-II type centrifugal precipitation mechanism, Shanghai medical apparatus factory; The biochemical incubator of SPX-150B, the magnificent biochemical instrument maker in last Haikang.
2. method
24 of Beagle dogs carry out hemolytic experiment respectively.Adopt Beagle dog forelimb venous blood 10ml, in the 50mL beaker, remove rapidly with toothpick and to defibrinate, place in the graduated centrifuge tube, add the proper amount of sodium chloride injection, with 2000 rev/mins centrifugal 10 minutes, discard liquid, add chlorination sodium injection mixing, centrifugal again, so cyclic washing is gone up liquid to centrifugal back and is till the water white transparency, and the gained erythrocyte is prepared into 50% red cell suspension with sodium chloride injection.Get 15 test tubes and add amount of liquid medicine by table 1, table 2, table 3, (puerarin injection 1mL is diluted to 5mL with normal saline by table 4 preparation feminine gender and positive control and the contrast of puerarin injection high dose, contain puerarin 10mg/mL), add the chlorination sodium injection again to total amount 5ml, mix with 50% red cell suspension 0.1ml, each pipe shakes up, and is placed in the biochemical incubator of 37 ℃ of constant temperature, respectively at 15,30,60 minutes, observed each pipe and have or not haemolysis and hemagglutination in 2,3,4,6,24 hours.
Be subjected to reagent thing adding method to see Table 7,8,9,10, the haemolysis determination methods sees Table 11.
3. result
This test is investigated when puerarin 10mg/mL concentration; different concentration of taurine is to 24 erythrocytic influences of Beagle dog; carry out simultaneously compound puerarin injection of the present invention 6., 7., the research of sporadic hemolytic experiment 8.; experimental result all has itemized record; the equal photo record of hemolytic test; 24 hours results of record hemolytic test see Table 12.Full haemolysis and part hemolytic experiment result are pressed the haemolysis counting, calculate the haemolysis incidence rate of respectively organizing test liquid, analyze, the results are shown in Table 13 with the X2 inspection statistics.
The result shows: haemolysis does not appear in the normal saline group, the whole haemolysis of water for injection group; Compare with the normal saline group, 19 routine haemolysis appear in the puerarin injection high dose group, and there are utmost point significant difference (P＜0.01) in haemolysis incidence rate and normal saline group; Compare with the haemolysis probability of happening of testing for the first time the puerarin injection high dose, there was no significant difference (P＞0.05) between twice test puerarin injection high dose group hemolysis rate, and wherein most Beagle dog hemolytic test result all obtains reappearing, illustrate that this hemolytic experiment method is reliable and stable, result of the test can repeat.Compare with the puerarin injection high dose group, 6., 7., 8. compound puerarin injection is respectively organized and haemolysis all do not occurred, and 6., 7., 8. compound puerarin injection is respectively organized the haemolysis incidence rate and all had utmost point significant difference (P＜0.01) with the puerarin injection high dose group; With the normal saline group relatively, compound puerarin injection 6., 7., 8. respectively organize the haemolysis incidence rate all with normal saline group zero difference (P=1.00); 6., 7., 8. compound puerarin injection is respectively organized identical with puerarin injection high dose group puerarin concentration; be 10mg/mL; but 6., 7., 8. compound puerarin injection is respectively organized and is contained 5mg/mL, 10mg/mL, 20mg/mL taurine respectively, and the puerarin injection high dose group does not contain taurine.Above results suggest: the taurine of variable concentrations and puerarin compatibility are used, but the haemolysis untoward reaction that equal antagonism is brought out by puerarin, and can make incidence rate be reduced to the normal saline level.
6. table 7 compound puerarin injection of the present invention adds method and test solution proportioning
7. table 8 compound puerarin injection of the present invention adds method and test solution proportioning
8. table 9 invention compound puerarin injection adds method and test solution proportioning
Table 10 feminine gender, positive and and puerarin injection high dose contrast adding method and test solution proportioning
Table 11 haemolysis determination methods
24 Begal dogs of table 12 hemolytic test outcome record
24 Begal dogs of table 13 hemolytic test is statistical table as a result
Annotate: compare * p＜0.05 ， $p＜0.01 with the negative group of normal saline; Compare with the puerarin injection high dose group: #p＜0.05 ， ﹠amp; P＜0.01
Experiment three, compound puerarin injection hemolytic test of the present invention
Puerarin injection is widely used in auxiliary treatment coronary heart disease, angina pectoris, myocardial infarction, retina arteriovenous obstruction, sudden deafness etc. clinically, is to use more Chinese medicine effective monomer injection clinically.But puerarin injection can cause untoward reaction such as acute intravascular hemolysis.Puerarin and taurine is compatible, make compound puerarin injection, be hopeful to reduce the haemolysis untoward reaction.Now adopt 24 Beagle dogs to carry out the haemolysis evaluation of compound puerarin injection, the result is reported as follows:
1. experiment material
1.1 be subjected to the reagent thing
Compound puerarin injection of the present invention 9., every mL injection contains puerarin 2mg, taurine 4mg, sodium chloride 9mg, lot number: 20060329, provide by Traditional Chinese Medicine University Of Guangzhou new drug development research center.
24 of Beagle dogs (body weight 6～8Kg male and female half and half) are provided by Guangdong Province institute of Pharmaceutical Industry Beagle dog plant, the quality certification number: the moving word 0014298 of doctor.17～20 ℃ of room temperatures, raise under relative humidity 60%～68% condition.
1.3 reagent, instrument
Sodium chloride injection, lot number: 05112102, Anhui Huayuan Biological Pharmaceutical Industry Co., Ltd. produces; Water for injection, lot number: 200508011, railway central hospital in Guangzhou produces; 22XLJ-II type centrifugal precipitation mechanism, Shanghai medical apparatus factory; The biochemical incubator of SPX-150B, the magnificent biochemical instrument maker in last Haikang.
2. method
24 of Beagle dogs carry out hemolytic experiment respectively.Adopt Beagle dog forelimb venous blood 10ml, in the 50mL beaker, remove rapidly with toothpick and to defibrinate, place in the graduated centrifuge tube, add the proper amount of sodium chloride injection, with 2000 rev/mins centrifugal 10 minutes, discard liquid, add chlorination sodium injection mixing, centrifugal again, so cyclic washing is gone up liquid to centrifugal back and is till the water white transparency, and the gained erythrocyte is prepared into 50% red cell suspension with sodium chloride injection.Get 15 test tubes and add amount of liquid medicine by table 1, press table 2 preparation feminine gender and positive control, add the chlorination sodium injection again to total amount 5ml, mix with 50% red cell suspension 0.1ml, each pipe shakes up, be placed in the biochemical incubator of 37 ℃ of constant temperature,, observed each pipe and have or not haemolysis and hemagglutination in 2,3,4,6,24 hours respectively at 15,30,60 minutes.
Be subjected to reagent thing adding method to see Table 14,15, the haemolysis determination methods sees Table 16.
3. result
This experiment adopts 24 Beagle dogs to carry out the hemolytic test of compound puerarin injection, and experimental result all has itemized record, the equal photo record of hemolytic test, and 24 hours results of record hemolytic test see Table 17.Full haemolysis and part hemolytic experiment result are pressed the haemolysis counting, calculate the haemolysis incidence rate of respectively organizing test liquid, analyze, the results are shown in Table 18 with the X2 inspection statistics.
The result shows: haemolysis does not appear in the normal saline group, and the whole haemolysis of water for injection group illustrate that this hemolytic experiment method is reliable and stable.Compare with the normal saline group, the result is all negative for 24 Beagle dogs of each dosage group of compound puerarin injection hemolytic experiment, each dosage group haemolysis incidence rate and normal saline zero difference.
9. table 14 compound puerarin injection of the present invention adds method and test solution proportioning
Table 15 feminine gender, positive control adding method
Table 16 haemolysis determination methods
24 Begal dogs of table 17 hemolytic test outcome record
24 Begal dogs of table 18 hemolytic test is statistical table as a result
Annotate: compare * p＜0.05 ， $p＜0.01 with the normal saline group;
Experiment four, contain the compound bovine bezoar injection hemolytic test of baicalin
The compound bovine bezoar injection is the Chinese medicine of new generation that comes from cow-bezoar bolus for resurrection, is formed by baicalin, puerarin, three kinds of effective ingredient compatibilities of taurine.But puerarin injection can cause untoward reaction such as acute intravascular hemolysis.In the compound bovine bezoar injection prescription that puerarin and taurine is compatible, be hopeful to reduce the haemolysis untoward reaction.Now adopt 24 Beagle dogs to carry out the haemolysis evaluation of compound bovine bezoar injection, the result is reported as follows:
1.1 experiment material
1.1 be subjected to reagent thing and animal
The compound bovine bezoar injection, every mL injection contains puerarin 5mg, taurine 25mg, baicalin 10mg, lot number: 20060316, provide by Traditional Chinese Medicine University Of Guangzhou new drug development research center.
24 of Beagle dogs (body weight 6～8Kg male and female half and half) are provided by Guangdong Province institute of Pharmaceutical Industry Beagle dog plant, the quality certification number: the moving word 0014298 of doctor.17～20 ℃ of room temperatures, raise under relative humidity 60%～68% condition.
1.3 reagent, instrument
Sodium chloride injection, lot number: 05112102, Anhui Huayuan Biological Pharmaceutical Industry Co., Ltd. produces; Water for injection, lot number: 200508011, railway central hospital in Guangzhou produces; 22XLJ-II type centrifugal precipitation mechanism, Shanghai medical apparatus factory; The biochemical incubator of SPX-150B, the magnificent biochemical instrument maker in last Haikang.
2. method
24 of Beagle dogs carry out hemolytic experiment respectively.Adopt Beagle dog forelimb venous blood 10ml, in the 50mL beaker, remove rapidly with toothpick and to defibrinate, place in the graduated centrifuge tube, add the proper amount of sodium chloride injection, with 2000 rev/mins centrifugal 10 minutes, discard liquid, add chlorination sodium injection mixing, centrifugal again, so cyclic washing is gone up liquid to centrifugal back and is till the water white transparency, and the gained erythrocyte is prepared into 50% red cell suspension with sodium chloride injection.Get 15 test tubes and add amount of liquid medicine by table 1, press table 2 preparation feminine gender and positive control, add the chlorination sodium injection again to total amount 5ml, mix with 50% red cell suspension 0.1ml, each pipe shakes up, be placed in the biochemical incubator of 37 ℃ of constant temperature,, observed each pipe and have or not haemolysis and hemagglutination in 2,3,4,6,24 hours respectively at 15,30,60 minutes.
Be subjected to reagent thing adding method to see Table 19,20, the haemolysis determination methods sees Table 21.
3. result
This experiment adopts 24 Beagle dogs to carry out the hemolytic test of compound bovine bezoar injection, and experimental result all has itemized record, the equal photo record of hemolytic test, and 24 hours results of record hemolytic test see Table 22.Full haemolysis and part hemolytic experiment result are pressed the haemolysis counting, calculate the haemolysis incidence rate of respectively organizing test liquid, analyze, the results are shown in Table 23 with the X2 inspection statistics.
The result shows: haemolysis does not appear in the normal saline group, and the whole haemolysis of water for injection group illustrate that this hemolytic experiment method is reliable and stable.Compare with the normal saline group, the result is all negative for 24 Beagle dogs of each dosage group of compound bovine bezoar injection hemolytic experiment, each dosage group haemolysis incidence rate and normal saline zero difference.
Table 19 compound bovine bezoar injection adding method and test solution proportioning
Table 20 feminine gender, positive control adding method
Table 21 haemolysis determination methods
24 Begal dogs of table 22 hemolytic test outcome record
24 Begal dogs of table 23 hemolytic test is statistical table as a result
Annotate: compare * p＜0.05 ， $p＜0.01 with the normal saline group;
The specific embodiment
The preparation of embodiment 1:(injection)
Get taurine 20g, puerarin 10g adds sodium chloride 9g, adds water to 1000ml, adjusts pH to 3.0-5.5 with the 1mol/l sodium hydroxide solution, filter, filtrate be potted in 2,5 or the ampoule of 10ml in, 100 ℃ of sterilization 30min obtain injection.But intravenous injection or intramuscular injection are used, each 1～500mL, and 1～3 time on the one, 10～20 days is a course of treatment, can use 2～3 courses of treatment continuously.
The preparation of embodiment 2:(injection)
Get taurine 10g, puerarin 10g adds sodium chloride 9g, adds water to 1000ml, adjusts pH to 6.5-9.0 with the 1mol/l sodium hydroxide solution, filter, filtrate be potted in 2,5 or the ampoule of 10ml in, 100 ℃ of sterilization 30min obtain injection.But intravenous injection or intramuscular injection are used, each 1～500mL, and 1～3 time on the one, 10～20 days is a course of treatment, can use 2～3 courses of treatment continuously.
The preparation of embodiment 3:(powder pin)
Get taurine 5g, puerarin 10g adds sodium chloride 4.5g, adds water to 500ml, adjusts pH to 5.5-7.5 with the 1mol/l sodium hydroxide solution, filters, and 100 ℃ of sterilizations of filtrate 30min is potted in the powder pin ampoule of 10ml, and 100 ℃ of sterilization 30min obtain the powder pin.Powder pin 1～5000mg and sodium chloride injection or normal saline solution mixing will be made during application, intravenous injection or intramuscular injection can be carried out, each 1～500mL, 1～3 time on the one, 10～20 days is a course of treatment, can use 2～3 courses of treatment continuously.
The preparation of embodiment 4:(powder pin)
Get taurine 50g, puerarin 1g is potted in the powder pin ampoule of 10ml, and 100 ℃ of sterilization 30min obtain the powder pin.Powder pin 1～5000mg and sodium chloride injection or normal saline solution mixing will be made during application, intravenous injection or intramuscular injection can be carried out, each 1～500mL, 1～3 time on the one, 10～20 days is a course of treatment, can use 2～3 courses of treatment continuously.
The preparation of embodiment 5:(powder pin)
Get taurine 4g, puerarin 2g is potted in the powder pin ampoule of 10ml, and 100 ℃ of sterilization 30min obtain the powder pin.Powder pin 1～5000mg and sodium chloride injection or normal saline solution mixing will be made during application, intravenous injection or intramuscular injection can be carried out, each 1～500mL, 1～3 time on the one, 10～20 days is a course of treatment, can use 2～3 courses of treatment continuously.
The preparation of embodiment 6:(powder pin)
Get taurine 50g, puerarin 25g is potted in the powder pin ampoule of 10ml, and 100 ℃ of sterilization 30min obtain the powder pin.Powder pin 1～5000mg and sodium chloride injection or normal saline solution mixing will be made during application, intravenous injection or intramuscular injection can be carried out, each 1～500mL, 1～3 time on the one, 10～20 days is a course of treatment, can use 2～3 courses of treatment continuously.
The preparation of embodiment 7:(powder pin)
Get taurine 1g, puerarin 50g adds sodium chloride 50g, is potted in the powder pin ampoule of 10ml, and 100 ℃ of sterilization 30min obtain the powder pin.Powder pin 1～5000mg and sodium chloride injection or normal saline solution mixing will be made during application, intravenous injection or intramuscular injection can be carried out, each 1～500mL, 1～3 time on the one, 10～20 days is a course of treatment, can use 2～3 courses of treatment continuously.
The preparation of embodiment 8:(transfusion)
Get taurine 2g, puerarin 2g, sodium chloride 9g adds water to 1000ml, adjusts pH to 6.5-7.5 with the 1mol/l sodium hydroxide solution, filters, and filtrate is potted in the saline vial of 250ml, and 100 ℃ of sterilization 30min obtain transfusion.Can directly carry out intravenous injection or intramuscular injection during application, each 1～500mL, 1～3 time on the one, 10～20 days is a course of treatment, can use 2～3 courses of treatment continuously.
The preparation of embodiment 9:(transfusion)
Get taurine 50g, puerarin 10g adds sodium chloride 9g, adds water to 1000ml, adjusts pH to 6.5-7.5 with the 1mol/l sodium hydroxide solution, filters, and filtrate is potted in the saline vial of 250ml, and 100 ℃ of sterilization 30min obtain transfusion.Can directly carry out intravenous injection or intramuscular injection during application, each 1～500mL, 1～3 time on the one, 10～20 days is a course of treatment, can use 2～3 courses of treatment continuously.
The preparation of embodiment 10:(transfusion)
Get taurine 4g, puerarin 2g adds sodium chloride 9g, adds water to 1000mL, adjusts pH to 6.8-7.3 with the 1mol/l sodium hydroxide solution, filters, and filtrate is potted in the saline vial of 100mL or 250mL, and 100 ℃ of sterilization 30min obtain transfusion.Can directly carry out intravenous injection or intramuscular injection during application, each 1～500mL, 1～3 time on the one, 10～20 days is a course of treatment, can use 2～3 courses of treatment continuously.
The preparation of embodiment 11:(transfusion)
Get taurine 25g, puerarin 5g adds sodium chloride 90g, adds water to 10000ml, adjusts pH to 6.5-7.5 with the 1mol/l sodium hydroxide solution, filters, and filtrate is potted in the saline vial of 100ml, and 100 ℃ of sterilization 30min obtain transfusion.Can directly carry out intravenous injection or intramuscular injection during application, each 1～500mL, 1～3 time on the one, 10～20 days is a course of treatment, can use 2～3 courses of treatment continuously.
The preparation of embodiment 12:(injection)
Get taurine 40g, puerarin 20g adds water to 1000ml, adjusts pH to 6.5-7.5 with the 1mol/l sodium hydroxide solution, filter, filtrate be potted in 2,5 or the ampoule of 10ml in, 100 ℃ of sterilization 30min obtain injection.Can directly carry out intravenous injection or intramuscular injection during application, each 1～500mL, 1～3 time on the one, 10～20 days is a course of treatment, can use 2～3 courses of treatment continuously.
Claims (7)
1, a kind of compound puerarin injection contains following weight portion drug component: 1～50 part of taurine, 1～50 part of puerarin; Not containing weight proportion is taurine: the drug component of puerarin=15: 1.
2, the described compound puerarin injection of claim 1 wherein also contains: 1～50 part of adjuvant, 1～10000 part of water for injection.
3, the described compound puerarin injection of claim 2, wherein each amounts of components is: 10 parts of taurines, 5 parts of puerarins, 9 parts of adjuvants, 2500 parts of waters for injection.
4, the described compound puerarin injection of claim 1, this injection are acceptable clinically powder pins.
5, the described compound puerarin injection of claim 4, described powder pin is made by taurine and puerarin mixing, sterilization.
6, the described compound puerarin injection of claim 1, this injection are acceptable clinically injection or powder pin.
7, the preparation method of the described compound puerarin injection of claim 6, described injection is mixed by taurine, puerarin and sodium chloride, adds the dissolving of injection water; the reuse sodium hydroxide solution is adjusted pH value to 3.0-9.0; dissolving is filtered, and filtrate is potted in to sterilize in the ampoule and makes.
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| CN104042602A (en) * | 2014-05-28 | 2014-09-17 | 西北农林科技大学 | Application of sodium glutamate in puerarin injection |
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Non-Patent Citations (2)
| Title |
|---|
| 葛根素注射液的不良反应口服制剂开发的探讨. 林吉，侯少贞，李耿，黄月纯，李卓明，吴燕红，苏子仁.世界科学与技术，第7卷第5期. 2005 |
| 葛根素注射液的不良反应口服制剂开发的探讨. 林吉，侯少贞，李耿，黄月纯，李卓明，吴燕红，苏子仁.世界科学与技术，第7卷第5期. 2005 * |
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