CN102145162B - Injection of medicine for treating premature delivery - Google Patents
Injection of medicine for treating premature delivery Download PDFInfo
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- CN102145162B CN102145162B CN2010105444265A CN201010544426A CN102145162B CN 102145162 B CN102145162 B CN 102145162B CN 2010105444265 A CN2010105444265 A CN 2010105444265A CN 201010544426 A CN201010544426 A CN 201010544426A CN 102145162 B CN102145162 B CN 102145162B
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Abstract
The invention relates to injection of a medicine for treating premature delivery. The preparation consists of atosiban acetate, isoosmotic adjustment agent. pH value adjusting agent, antioxidant, local painkiller and solvent, wherein the antioxidant is added to enhance the stability of the preparation and the local painkiller is added to mitigate the pain of patient without impacting basic remedy. The preparation process of the preparation mainly comprises weighing, dissolution, pyrogen adsorption by activated carbon, filtration, end filtration, subpackage and piston injection and capping. The preparation is used for inhibiting uterine contraction in order to achieve the therapeutic effect of resisting premature delivery. The preparation is stable in quality, accurate in therapeutic effect and favorable for being accepted by patients.
Description
Technical field:
The present invention relates to formulation art, specifically a kind of injection for the treatment of the premature labor medicine.
Background technology:
Atosiban is a kind of Oxitocin analogues, is the ring type polypeptide of synthetic, is the oxytocin competitive antagonist of receptor on intrauterine and decidua, the fetal membrane, uses clinically its acetate treatment premature labor.But atosiban dosage correlation ground suppresses uterine contraction, and the prostaglandin secretion of oxytocin mediation is reduced, and reaches the purpose of preventing miscarriage.
Premature labor is a most important reason of enclosing living youngster's mortality rate and sickness rate.The reason of ND childhood period that it being 75% perinatal death and 50%.Best tocolytic agent should be, is safe to mother and fetus, can prolong gestation so that there is time enough to reduce significantly premature labor, makes Fetal Maturation, encloses living youngster's mortality rate and sickness rate thereby reduce.Yet tocolytic agent does not meet these requirements at present.They have been proved to be can postpone significantly to give a birth and have reached 48 hours, help the lung glucocorticoid inducible ripe, and productive rate significance ground reduces but they do not make early.In addition, they have common side effect, cause the sickness rate of mother and fetus and to withdraw from rate very high, especially beta-2-agonists (present First Line medicine).
Atosiban is a kind of breakthrough product in the department of obstetrics and gynecology medicine, and it is a kind of specific oxytocin receptor antagonists, is used for postponing not term labor.In the past several years, its efficacy and saferry has been assessed in many clinical trials.Atosiban can suppress uterine contraction rapidly, prolong gestation, and to mother, fetus and baby does not have harmful effect.Therefore atosiban has good application prospect clinically, has very high exploitation and is worth.
The prescription of the atosiban injection that has gone on the market includes the 7.5mg/ml atosiban acetate, 50.0mg/ml mannitol, 1mol/L hydrochloric acid adjust pH to 4.5.Its poor stability is only in 2 ℃～8 ℃ preservations of refrigerator temperature; It is during to patient's intravenous injection or intramuscular injection, and the injection site produces pain, is unfavorable for that the patient accepts.The present invention is directed to these problems and propose, add antioxidant to improve the stability of preparation, adding the local analgesia agent does not have impact with the pain that alleviates the patient to principal agent.The said preparation steady quality, determined curative effect is beneficial to the patient and accepts.
Summary of the invention:
The objective of the invention is to prepare a kind of injection take atosiban acetate as active component, have steady quality, determined curative effect is beneficial to the advantages such as patient's acceptance.
The present invention has prepared a kind of injection that contains the atosiban acetate medicine, and it comprises atosiban acetate, isoosmotic adjusting agent, pH value regulator, antioxidant, local analgesia agent and solvent.
The present invention has prepared a kind of injection that contains the atosiban acetate medicine, and its isoosmotic adjusting agent is selected from mannitol, glucose, sodium chloride, fructose, magnesium chloride, phosphate, sodium citrate etc.; Its pH value regulator is selected from hydrochloric acid, glacial acetic acid, sulphuric acid, lactic acid, malic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydrogen phosphate etc.; Its antioxidant is selected from sodium sulfite, sodium pyrosulfite, ascorbic acid, sodium thiosulfate, sodium sulfite, propyl gallate, glutathion, thiourea, TGA, vitamin E etc.; Its local analgesia agent is selected from benzyl alcohol, chlorobutanol and procaine hydrochloride etc.; Its solvent is water for injection.
Through a large amount of optimization experiment, the present invention has found that most preferably prescription forms.Wherein, its isoosmotic adjusting agent is the manna alcohol and glucose most preferably, and the pH value regulator is hydrochloric acid most preferably, and antioxidant is sodium sulfite and sodium pyrosulfite most preferably, and the local analgesia agent is benzyl alcohol and chlorobutanol most preferably, and pH value is 3.5-5.5 most preferably.
In addition, the present invention also provides preparation to contain the method for the injection of atosiban acetate medicine.Its technique is as follows:
1 precision takes by weighing the above-mentioned material of recipe quantity to container;
2 add an amount of water for injection dissolves fully;
3 usefulness glacial acetic acid are regulated pH value to 3.5 between 5.5;
4 water for injection standardize solution;
5 activated carbon adsorption pyrogens;
60.22 μ m titanium rod filter filters;
70.22 μ m filtering with microporous membrane;
Fill is to the sterilized cillin bottle after 8 passed examinations, tamponade Zha Gai;
Labeling packing after 9 passed examinations.
The specific embodiment:
The present invention is including but not limited to following examples.
Embodiment 1:
Atosiban acetate (in atosiban 7.5mg/ml), 50.0mg/ml mannitol, the 0.1%w/v sodium sulfite, the 2%w/v benzyl alcohol is 4.5 with 1mol/L salt acid for adjusting pH, its preparation technology is as follows:
Weighing atosiban acetate (in atosiban 37.5g), 250.0g mannitol, the 5.0g sodium sulfite, the 100.0g benzyl alcohol dissolves fully with recipe quantity 80% water for injection, transfers pH to 4.5 with hydrochloric acid, injects water to 5000ml.Before filtration, add the 5g activated carbon in the injection, under agitation adsorbed pyrogen 30 minutes, decarburization is filtered.Filtrate is filtered through 0.22 μ m titanium rod filter, again through 0.22 μ m microporous filter membrane aseptic filtration, fill in 7ml sterilization cillin bottle (5ml/ bottle), tamponade Zha Gai.Make every to be equivalent to the 37.5mg atosiban.
Make 1000 of atosiban acetate injections (containing atosiban 37.5mg) by present embodiment, by accelerated test and animal blood vessels zest, muscle irritation, haemolysis and anaphylaxis experiment, its stability and clinical drug safety are investigated.
Accelerated test:
The a collection of test sample that will go on the market respectively and to put into temperature by a batch sample of commercially available back be that 40 ± 2 ℃, relative humidity are that 75% ± 5% climatic chamber is investigated 0,1,2,3 and sampling and measuring 6 months the time, the results are shown in Table 1-1 and table 1-2 respectively.
Table 1-1 listing reference substance accelerated test result
Table 1-2 self-control sample accelerated test result
Can find out by table 1-1 and table 1-2, investigate 6 months through accelerated test, the atosiban acetate injection of the present invention's preparation compares with the atosiban acetate injection that has gone on the market, appearance luster, acidity, clarity of solution index are suitable, the impurity of the test sample of listing increases, content decrease, show that the atosiban acetate injection that the present invention prepares can preserve under room temperature, stability increases.
Blood vessel irritation, muscle irritation, haemolysis and anaphylaxis experiment:
Blood vessel irritation:
Choose 6 of the undamaged healthy rabbits of ears, left side auricular vein injection embodiment 1 injection 1ml, capacity 5% glucose injections such as auris dextra injection, were injected 7 days continuously at every day 1 time.
During the injection, regularly observe the irritative response of auricular vein every day.Put to death rabbit on the 8th day, get bilateral auricular vein and surrounding tissue, fix with formaldehyde, be respectively 110,215 in the distance injection site, the proximal part of 315cm does the conventional organization section, observe under the light microscopic to have or not pathological change.Observation index and criterion see Table 1-3.
Table 1-3 blood vessel irritation scoring and criterion
The result shows that the zest of rabbit auricular vein injection embodiment 1 injection compares no significant difference with 5% glucose injection.Perusal has no the inflammatory reactions such as the congestion of blood vessel, surrounding tissue edema.Tissue slice checks, has no that blood vessel structure is unusual, endothelial injury, thrombosis and other pathological change.The blood vessel of its naked eyes and om observation, the cumulative score of surrounding tissue show nonirritant all less than 0.5.
Muscle irritation:
Get 6 of healthy rabbits, injection embodiment 1 injection 1ml in every rabbit left side quadriceps femoris, inject with the volume normal saline on the right side.Observe injection site muscle after the injection and have or not the reactions such as hyperemia, edema, (the 3rd day) sacrificed by exsanguination behind the half animal 48h is vertically cut skin, and injection site, perusal both sides has or not the reactions such as hyperemia, edema, and gets its tissue and do pathologic finding.Then by the irritant reaction of showing this medicine of standard evaluation among the 1-4.Remaining animal continues to observe 14d, repeats aforesaid operations in the 18th day after the sacrificed by exsanguination, and evaluation criterion sees Table 1-4.
Table 1-4 muscular irritation reaction evaluating standard
The result shows, after injecting embodiment 1 injection in the quadriceps femoris of rabbit left side, perusal injection site muscle is without reactions such as hyperemia, edema, and pathologic diagnosis also has no the explicitly irritant reaction such as tissue degeneratiaon or necrosis, compares without significant difference with the normal saline side.
Sensitization to Cavia porcellus:
Choose 6 of healthy guinea pigs, every lumbar injection embodiment 1 injection 0.5ml, the next day, inject 1 time, injects altogether 3 times.Then be divided at random 2 groups, after the 1st administration 14 or 21 days respectively, quiet notes embodiment 1 injection 1ml.Observe Cavia porcellus and have or not the allergic symptoms such as excited uneasiness, dyspnea.
Two groups of Cavia porcelluss of result are all movable normal, have no adnormal respiration etc.
External hemolytic test:
Prepare 2% rabbit red cell suspension.Get 7 in test tube, 1-5 adds various liquid by table.Each test tube is shaken up gently, put in 37 ℃ of waters bath with thermostatic control and hatch, observe 0.5,1,2,3,6 hour result.The criterion of erythrocyte agglutination in vitro and haemolysis sees Table 1-6.
The outer hemolytic test application of sample table of table 1-5 atosiban acetate injecting fluid
The outer haemolysis of table 1-6 red cell body and agglutination test criterion
As a result, the distilled water control tube was complete hemolysis in 0.5 hour.Normal saline and each atosiban acetate injection in 6 hours all without haemolysis.Gently jolting, the erythrocyte of normal saline and each concentration atosiban acetate liquid injection pipe bottom sediments all can disperse fully, shows that the atosiban acetate injection is without red cell agglutination.
Blood vessel irritation, muscle irritation, external hemolytic and anaphylaxis experiment show that embodiment 1 injection can not cause hemolytic reaction without obvious zest, anaphylaxis yet.Show that the atosiban acetate injection safety that the present invention prepares is good, can use for clinical vein injection and intramuscular injection.
Embodiment 2:
Atosiban acetate (in atosiban 7.5mg/ml), 50.0mg/ml mannitol, the 0.1%w/v sodium pyrosulfite, the 0.4%w/v chlorobutanol is 4.5 with 1mol/L salt acid for adjusting pH, its preparation technology is as follows:
Weighing atosiban acetate (in atosiban 37.5g), 250.0g mannitol, the 5.0g sodium pyrosulfite, the 20.0g chlorobutanol dissolves fully with recipe quantity 80% water for injection, transfers pH to 4.5 with hydrochloric acid, injects water to 5000ml.Before filtration, add the 5g activated carbon in the injection, under agitation adsorbed pyrogen 30 minutes, decarburization is filtered.Filtrate is filtered through 0.22 μ m titanium rod filter, again through 0.22 μ m microporous filter membrane aseptic filtration, fill in 7ml sterilization cillin bottle (5ml/ bottle), tamponade Zha Gai.Make every to be equivalent to the 37.5mg atosiban.
Make 1000 of atosiban acetate injections (containing atosiban 37.5mg) by present embodiment, by accelerated test and animal blood vessels zest, muscle irritation, haemolysis and anaphylaxis experiment, its stability and clinical drug safety are investigated.
Accelerated test:
The a collection of test sample that will go on the market respectively and to put into temperature by a batch sample of commercially available back be that 40 ± 2 ℃, relative humidity are that 75% ± 5% climatic chamber is investigated 0,1,2,3 and sampling and measuring 6 months the time, the results are shown in Table 2-1 and table 2-2 respectively.
Table 2-1 listing reference substance accelerated test result
Table 2-2 self-control sample accelerated test result
Can find out by table 2-1 and table 2-2, investigate 6 months through accelerated test, the atosiban acetate injection of the present invention's preparation compares with the atosiban acetate injection that has gone on the market, appearance luster, acidity, clarity of solution index are suitable, the impurity of the test sample of listing increases, content decrease, show that the atosiban acetate injection that the present invention prepares can preserve under room temperature, stability increases.
Blood vessel irritation, muscle irritation, haemolysis and anaphylaxis experiment:
Blood vessel irritation:
Choose 6 of the undamaged healthy rabbits of ears, left side auricular vein injection embodiment 2 injection 1ml, capacity 5% glucose injections such as auris dextra injection, were injected 7 days continuously at every day 1 time.
During the injection, regularly observe the irritative response of auricular vein every day.Put to death rabbit on the 8th day, get bilateral auricular vein and surrounding tissue, fix with formaldehyde, be respectively 110,215 in the distance injection site, the proximal part of 315cm does the conventional organization section, observe under the light microscopic to have or not pathological change.Observation index and criterion see Table 2-3.
Table 2-3 blood vessel irritation scoring and criterion
The result shows that the zest of rabbit auricular vein injection embodiment 2 injection compares no significant difference with 5% glucose injection.Perusal has no the inflammatory reactions such as the congestion of blood vessel, surrounding tissue edema.Tissue slice checks, has no that blood vessel structure is unusual, endothelial injury, thrombosis and other pathological change.The blood vessel of its naked eyes and om observation, the cumulative score of surrounding tissue show nonirritant all less than 0.5.
Muscle irritation:
Get 6 of healthy rabbits, injection embodiment 2 injection 1ml in every rabbit left side quadriceps femoris, inject with the volume normal saline on the right side.Observe injection site muscle after the injection and have or not the reactions such as hyperemia, edema, (the 3rd day) sacrificed by exsanguination behind the half animal 48h is vertically cut skin, and injection site, perusal both sides has or not the reactions such as hyperemia, edema, and gets its tissue and do pathologic finding.Then by the irritant reaction of showing this medicine of standard evaluation among the 2-4.Remaining animal continues to observe 14d, repeats aforesaid operations in the 18th day after the sacrificed by exsanguination, and evaluation criterion sees Table 2-4.
Table 2-4 muscular irritation reaction evaluating standard
The result shows, after injecting embodiment 2 injection in the quadriceps femoris of rabbit left side, perusal injection site muscle is without reactions such as hyperemia, edema, and pathologic diagnosis also has no the explicitly irritant reaction such as tissue degeneratiaon or necrosis, compares without significant difference with the normal saline side.
Sensitization to Cavia porcellus:
Choose 6 of healthy guinea pigs, every lumbar injection embodiment 2 injection 0.5ml, the next day, inject 1 time, injects altogether 3 times.Then be divided at random 2 groups, after the 1st administration 14 or 21 days respectively, quiet notes embodiment 2 injection 1ml.Observe Cavia porcellus and have or not the allergic symptoms such as excited uneasiness, dyspnea.
Two groups of Cavia porcelluss of result are all movable normal, have no adnormal respiration etc.
External hemolytic test:
Prepare 2% rabbit red cell suspension.Get 7 in test tube, 2-5 adds various liquid by table.Each test tube is shaken up gently, put in 37 ℃ of waters bath with thermostatic control and hatch, observe 0.5,1,2,3,6 hour result.The criterion of erythrocyte agglutination in vitro and haemolysis sees Table 2-6.
The outer hemolytic test application of sample table of table 2-5 atosiban acetate injecting fluid
The outer haemolysis of table 2-6 red cell body and agglutination test criterion
As a result, the distilled water control tube was complete hemolysis in 0.5 hour.Normal saline and each atosiban acetate injection in 6 hours all without haemolysis.Gently jolting, the erythrocyte of normal saline and each concentration atosiban acetate liquid injection pipe bottom sediments all can disperse fully, shows that the atosiban acetate injection is without red cell agglutination.
Blood vessel irritation, muscle irritation, external hemolytic and anaphylaxis experiment show that embodiment 2 injection can not cause hemolytic reaction without obvious zest, anaphylaxis yet.Show that the atosiban acetate injection safety that the present invention prepares is good, can use for clinical vein injection and intramuscular injection.
Embodiment 3:
Atosiban acetate (in atosiban 7.5mg/ml), the 5%w/v glucose, the 0.1%w/v ascorbic acid, the 2%w/v benzyl alcohol is 4.5 with 1mol/L salt acid for adjusting pH, its preparation technology is as follows:
Weighing atosiban acetate (in atosiban 37.5g), the 250.0g glucose, the 5.0g ascorbic acid, the 100.0g benzyl alcohol dissolves fully with recipe quantity 80% water for injection, transfers pH to 4.5 with hydrochloric acid, injects water to 5000ml.Before filtration, add the 5g activated carbon in the injection, under agitation adsorbed pyrogen 30 minutes, decarburization is filtered.Filtrate is filtered through 0.22 μ m titanium rod filter, again through 0.22 μ m microporous filter membrane aseptic filtration, fill in 7ml sterilization cillin bottle (5ml/ bottle), tamponade Zha Gai.Make every to be equivalent to the 37.5mg atosiban.
Make 1000 of atosiban acetate injections (containing atosiban 37.5mg) by present embodiment, by accelerated test and animal blood vessels zest, muscle irritation, haemolysis and anaphylaxis experiment, its stability and clinical drug safety are investigated.
Accelerated test:
The a collection of test sample that will go on the market respectively and to put into temperature by a batch sample of commercially available back be that 40 ± 2 ℃, relative humidity are that 75% ± 5% climatic chamber is investigated 0,1,2,3 and sampling and measuring 6 months the time, the results are shown in Table 3-1 and table 3-2 respectively.
Table 3-1 listing reference substance accelerated test result
Table 3-2 self-control sample accelerated test result
Can find out by table 3-1 and table 3-2, investigate 6 months through accelerated test, the atosiban acetate injection of the present invention's preparation compares with the atosiban acetate injection that has gone on the market, appearance luster, acidity, clarity of solution index are suitable, the impurity of the test sample of listing increases, content decrease, show that the atosiban acetate injection that the present invention prepares can preserve under room temperature, stability increases.
Blood vessel irritation, muscle irritation, haemolysis and anaphylaxis experiment:
Blood vessel irritation:
Choose 6 of the undamaged healthy rabbits of ears, left side auricular vein injection embodiment 3 injection 1ml, capacity 5% glucose injections such as auris dextra injection, were injected 7 days continuously at every day 1 time.
During the injection, regularly observe the irritative response of auricular vein every day.Put to death rabbit on the 8th day, get bilateral auricular vein and surrounding tissue, fix with formaldehyde, be respectively 110,215 in the distance injection site, the proximal part of 315cm does the conventional organization section, observe under the light microscopic to have or not pathological change.Observation index and criterion see Table 3-3.
Table 3-3 blood vessel irritation scoring and criterion
The result shows that the zest of rabbit auricular vein injection example 3 injection compares no significant difference with 5% glucose injection.Perusal has no the inflammatory reactions such as the congestion of blood vessel, surrounding tissue edema.Tissue slice checks, has no that blood vessel structure is unusual, endothelial injury, thrombosis and other pathological change.The blood vessel of its naked eyes and om observation, the cumulative score of surrounding tissue show nonirritant all less than 0.5.
Muscle irritation:
Get 6 of healthy rabbits, injection embodiment 3 injection 1ml in every rabbit left side quadriceps femoris, inject with the volume normal saline on the right side.Observe injection site muscle after the injection and have or not the reactions such as hyperemia, edema, (the 3rd day) sacrificed by exsanguination behind the half animal 48h is vertically cut skin, and injection site, perusal both sides has or not the reactions such as hyperemia, edema, and gets its tissue and do pathologic finding.Then by the irritant reaction of showing this medicine of standard evaluation among the 3-4.Remaining animal continues to observe 14d, repeats aforesaid operations in the 18th day after the sacrificed by exsanguination, and evaluation criterion sees Table 3-4.
Table 3-4 muscular irritation reaction evaluating standard
The result shows, after injecting embodiment 3 injection in the quadriceps femoris of rabbit left side, perusal injection site muscle is without reactions such as hyperemia, edema, and pathologic diagnosis also has no the explicitly irritant reaction such as tissue degeneratiaon or necrosis, compares without significant difference with the normal saline side.
Sensitization to Cavia porcellus:
Choose 6 of healthy guinea pigs, every lumbar injection embodiment 3 injection 0.5ml, the next day, inject 1 time, injects altogether 3 times.Then be divided at random 2 groups, after the 1st administration 14 or 21 days respectively, quiet notes embodiment 3 injection 1ml.Observe Cavia porcellus and have or not the allergic symptoms such as excited uneasiness, dyspnea.
Two groups of Cavia porcelluss of result are all movable normal, have no adnormal respiration etc.
External hemolytic test:
Prepare 2% rabbit red cell suspension.Get 7 in test tube, 3-5 adds various liquid by table.Each test tube is shaken up gently, put in 37 ℃ of waters bath with thermostatic control and hatch, observe 0.5,1,2,3,6 hour result.The criterion of erythrocyte agglutination in vitro and haemolysis sees Table 3-6.
The outer hemolytic test application of sample table of table 3-5 atosiban acetate injecting fluid
The outer haemolysis of table 3-6 red cell body and agglutination test criterion
As a result, the distilled water control tube was complete hemolysis in 0.5 hour.Normal saline and each atosiban acetate injection in 6 hours all without haemolysis.Gently jolting, the erythrocyte of normal saline and each concentration atosiban acetate liquid injection pipe bottom sediments all can disperse fully, shows that the atosiban acetate injection is without red cell agglutination.
Blood vessel irritation, muscle irritation, external hemolytic and anaphylaxis experiment show that embodiment 3 injection can not cause hemolytic reaction without obvious zest, anaphylaxis yet.Show that the atosiban acetate injection safety that the present invention prepares is good, can use for clinical vein injection and intramuscular injection.
Embodiment 4:
Atosiban acetate (in atosiban 7.5mg/ml), the 5%w/v glucose, the 0.1%w/v ascorbic acid, the 0.4%w/v chlorobutanol is 4.5 with 1mol/L salt acid for adjusting pH, its preparation technology is as follows:
Weighing atosiban acetate (in atosiban 37.5g), the 250.0g glucose, the 5.0g ascorbic acid, the 20.0g chlorobutanol dissolves fully with recipe quantity 80% water for injection, transfers pH to 4.5 with hydrochloric acid, injects water to 5000ml.Before filtration, add the 5g activated carbon in the injection, under agitation adsorbed pyrogen 30 minutes, decarburization is filtered.Filtrate is filtered through 0.22 μ m titanium rod filter, again through 0.22 μ m microporous filter membrane aseptic filtration, fill in 7ml sterilization cillin bottle (5ml/ bottle), tamponade Zha Gai.Make every to be equivalent to the 37.5mg atosiban.
Make 1000 of atosiban acetate injections (containing atosiban 37.5mg) by present embodiment, by accelerated test and animal blood vessels zest, muscle irritation, haemolysis and anaphylaxis experiment, its stability and clinical drug safety are investigated.
Accelerated test:
The a collection of test sample that will go on the market respectively and to put into temperature by a batch sample of commercially available back be that 40 ± 2 ℃, relative humidity are that 75% ± 5% climatic chamber is investigated 0,1,2,3 and sampling and measuring 6 months the time, the results are shown in Table 4-1 and table 4-2 respectively.
Table 4-1 listing reference substance accelerated test result
Table 4-2 self-control sample accelerated test result
Can find out by table 4-1 and table 4-2, investigate 6 months through accelerated test, the atosiban acetate injection of the present invention's preparation compares with the atosiban acetate injection that has gone on the market, appearance luster, acidity, clarity of solution index are suitable, the impurity of the test sample of listing increases, content decrease, show that the atosiban acetate injection that the present invention prepares can preserve under room temperature, stability increases.
Blood vessel irritation, muscle irritation, haemolysis and anaphylaxis experiment:
Blood vessel irritation:
Choose 6 of the undamaged healthy rabbits of ears, left side auricular vein injection embodiment 4 injection 1ml, capacity 5% glucose injections such as auris dextra injection, were injected 7 days continuously at every day 1 time.
During the injection, regularly observe the irritative response of auricular vein every day.Put to death rabbit on the 8th day, get bilateral auricular vein and surrounding tissue, fix with formaldehyde, be respectively 110,215 in the distance injection site, the proximal part of 315cm does the conventional organization section, observe under the light microscopic to have or not pathological change.Observation index and criterion see Table 4-3.
Table 4-3 blood vessel irritation scoring and criterion
The result shows that the zest of rabbit auricular vein injection embodiment 4 injection compares no significant difference with 5% glucose injection.Perusal has no the inflammatory reactions such as the congestion of blood vessel, surrounding tissue edema.Tissue slice checks, has no that blood vessel structure is unusual, endothelial injury, thrombosis and other pathological change.The blood vessel of its naked eyes and om observation, the cumulative score of surrounding tissue show nonirritant all less than 0.5.
Muscle irritation:
Get 6 of healthy rabbits, injection embodiment 4 injection 1ml in every rabbit left side quadriceps femoris, inject with the volume normal saline on the right side.Observe injection site muscle after the injection and have or not the reactions such as hyperemia, edema, (the 3rd day) sacrificed by exsanguination behind the half animal 48h is vertically cut skin, and injection site, perusal both sides has or not the reactions such as hyperemia, edema, and gets its tissue and do pathologic finding.Then by the irritant reaction of showing this medicine of standard evaluation among the 4-4.Remaining animal continues to observe 14d, repeats aforesaid operations in the 18th day after the sacrificed by exsanguination, and evaluation criterion sees Table 4-4.
Table 4-4 muscular irritation reaction evaluating standard
The result shows, after injecting embodiment 4 injection in the quadriceps femoris of rabbit left side, perusal injection site muscle is without reactions such as hyperemia, edema, and pathologic diagnosis also has no the explicitly irritant reaction such as tissue degeneratiaon or necrosis, compares without significant difference with the normal saline side.
Sensitization to Cavia porcellus:
Choose 6 of healthy guinea pigs, every lumbar injection embodiment 4 injection 0.5ml, the next day, inject 1 time, injects altogether 3 times.Then be divided at random 2 groups, after the 1st administration 14 or 21 days respectively, quiet notes embodiment 4 injection 1ml.Observe Cavia porcellus and have or not the allergic symptoms such as excited uneasiness, dyspnea.
Two groups of Cavia porcelluss of result are all movable normal, have no adnormal respiration etc.
External hemolytic test:
Prepare 2% rabbit red cell suspension.Get 7 in test tube, 4-5 adds various liquid by table.Each test tube is shaken up gently, put in 37 ℃ of waters bath with thermostatic control and hatch, observe 0.5,1,2,3,6 hour result.The criterion of erythrocyte agglutination in vitro and haemolysis sees Table 4-6.
The outer hemolytic test application of sample table of table 4-5 atosiban acetate injecting fluid
The outer haemolysis of table 4-6 red cell body and agglutination test criterion
As a result, the distilled water control tube was complete hemolysis in 0.5 hour.Normal saline and each atosiban acetate injection in 6 hours all without haemolysis.Gently jolting, the erythrocyte of normal saline and each concentration atosiban acetate liquid injection pipe bottom sediments all can disperse fully, shows that the atosiban acetate injection is without red cell agglutination.
Blood vessel irritation, muscle irritation, external hemolytic and anaphylaxis experiment show that embodiment 4 injection can not cause hemolytic reaction without obvious zest, anaphylaxis yet.Show that the atosiban acetate injection safety that the present invention prepares is good, can use for clinical vein injection and intramuscular injection.
Claims (4)
1. medicine for the treatment of premature labor is characterized in that: contain the 0.1-100mg/mL atosiban acetate in the solution, and 1-100.0mg/ml mannitol, the 0.01-2%w/v sodium sulfite, the 0.1-5%w/v benzyl alcohol, transferring pH with 1mol/L hydrochloric acid is 3.5-5.5; Its preparation technology is: weighing atosiban acetate (in atosiban 37.5g), 250.0g mannitol, 5.0g sodium sulfite, the 100.0g benzyl alcohol dissolves fully with recipe quantity 80% water for injection, transfer pH to 4.5 with hydrochloric acid, inject water to 5000ml, before filtration, add the 5g activated carbon in the injection, under agitation adsorbed pyrogen 30 minutes, decarburization is filtered.Filtrate is filtered through 0.22 μ m titanium rod filter, and again through 0.22 μ m microporous filter membrane aseptic filtration, fill is in 7ml sterilization cillin bottle (5ml/ bottle), and tamponade Zha Gai makes every to be equivalent to the 37.5mg atosiban.
2. medicine for the treatment of premature labor is characterized in that: contain the 0.1-100mg/ml atosiban acetate in the solution, and 1-100.0mg/ml mannitol, the 0.01-2%w/v sodium pyrosulfite, the 0.03-2%w/v chlorobutanol, transferring pH with 1mol/L hydrochloric acid is 3.5-5.5; Its preparation technology is: weighing atosiban acetate (in atosiban 37.5g), 250.0g mannitol, 5.0g sodium pyrosulfite, 20.0g chlorobutanol, dissolve fully with recipe quantity 80% water for injection, transfer pH to 4.5 with hydrochloric acid, inject water to 5000ml, before filtration, add the 5g activated carbon in the injection, under agitation adsorbed pyrogen 30 minutes, decarburization is filtered, and filtrate is filtered through 0.22 μ m titanium rod filter, again through 0.22 μ m microporous filter membrane aseptic filtration, fill is in 7ml sterilization cillin bottle (5ml/ bottle), and tamponade Zha Gai makes every to be equivalent to the 37.5mg atosiban.
3. medicine for the treatment of premature labor is characterized in that: contain the 0.1-100mg/ml atosiban acetate in the solution, and the 1%-50%w/v glucose, the 0.005-2%w/v ascorbic acid, the 0.1-5%w/v benzyl alcohol, transferring pH with 1mol/L hydrochloric acid is 3.5-5.5; Its preparation technology is: weighing atosiban acetate (in atosiban 37.5g), 250.0g glucose, 5.0g ascorbic acid, 100.0g benzyl alcohol, dissolve fully with recipe quantity 80% water for injection, transfer pH to 4.5 with hydrochloric acid, inject water to 5000ml, before filtration, add the 5g activated carbon in the injection, under agitation adsorbed pyrogen 30 minutes, decarburization is filtered, and filtrate is filtered through 0.22 μ m titanium rod filter, again through 0.22 μ m microporous filter membrane aseptic filtration, fill is in 7ml sterilization cillin bottle (5ml/ bottle), and tamponade Zha Gai makes every to be equivalent to the 37.5mg atosiban.
4. medicine for the treatment of premature labor is characterized in that: contain the 0.1-100mg/ml atosiban acetate in the solution, and the 1%-50%w/v glucose, the 0.005-2%w/v ascorbic acid, the 0.03-2%w/v chlorobutanol, transferring pH with 1mol/L hydrochloric acid is 3.5-5.5; Its preparation technology is: weighing atosiban acetate (in atosiban 37.5g), 250.0g glucose, 5.0g ascorbic acid, 20.0g chlorobutanol, dissolve fully with recipe quantity 80% water for injection, transfer pH to 4.5 with hydrochloric acid, inject water to 5000ml, before filtration, add the 5g activated carbon in the injection, under agitation adsorbed pyrogen 30 minutes, decarburization is filtered, and filtrate is filtered through 0.22 μ m titanium rod filter, again through 0.22 μ m microporous filter membrane aseptic filtration, fill is in 7ml sterilization cillin bottle (5ml/ bottle), and tamponade Zha Gai makes every to be equivalent to the 37.5mg atosiban.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010105444265A CN102145162B (en) | 2010-11-12 | 2010-11-12 | Injection of medicine for treating premature delivery |
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| CN2010105444265A CN102145162B (en) | 2010-11-12 | 2010-11-12 | Injection of medicine for treating premature delivery |
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| CN102145162B true CN102145162B (en) | 2013-02-27 |
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| CN103417475B (en) * | 2013-06-27 | 2015-06-17 | 深圳翰宇药业股份有限公司 | Barusiban injection and preparation method thereof |
| CN105920581A (en) * | 2016-05-27 | 2016-09-07 | 扬子江药业集团广州海瑞药业有限公司 | Atosiban acetate composition |
| CN106267148A (en) * | 2016-08-15 | 2017-01-04 | 海南合瑞制药股份有限公司 | A kind of atosiban acetate compositions and preparation method thereof |
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| EP1555029A1 (en) * | 2004-01-19 | 2005-07-20 | Ferring B.V. | Use of substances having oxytocin antagonistic properties for the preparation of a medicament for treating hypertension |
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| Title |
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| 林宁主编.《药剂学》.《药剂学》.湖北科学技术出版社,2007,27页，48页. * |
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Address after: 518057 Nanshan District, Guangdong Province, a high tech in the middle of the road No. ten Shenzhen biological incubation base, building 412, room 2, No. Patentee after: Shenzhen City Jianyuan Pharmaceutical Technology Co., Ltd. Address before: 518000, overseas student Pioneer Building, 29 South Ring Road, Nanshan hi tech Zone, Guangdong, Shenzhen 1702 Patentee before: Shenzhen City Jianyuan Pharmaceutical Technology Co., Ltd. |
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Application publication date: 20110810 Assignee: Shenzhen Kin yuan biological pharmaceutical Co., Ltd. Assignor: Shenzhen City Jianyuan Pharmaceutical Technology Co., Ltd. Contract record no.: 2015440020004 Denomination of invention: Injection of medicine for treating premature delivery Granted publication date: 20130227 License type: Exclusive License Record date: 20150108 |
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Effective date of registration: 20181227 Address after: 518118 No. 14 Jinhui Road, Kengzi Street, Pingshan New District, Shenzhen City, Guangdong Province, No. 7 Building, Shenzhen Biomedical Innovation Industrial Park Patentee after: Shenzhen Jianxiang Biological Pharmaceutical Co Ltd Address before: 518057 Room 412, Building 2, Shenzhen Biological Incubation Base, No. 10 Zhongxin Road, Nanshan District, Shenzhen City, Guangdong Province Patentee before: Shenzhen City Jianyuan Pharmaceutical Technology Co., Ltd. |