CN104127410A - Ornidazole injection liquid - Google Patents
Ornidazole injection liquid Download PDFInfo
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- CN104127410A CN104127410A CN201410261673.2A CN201410261673A CN104127410A CN 104127410 A CN104127410 A CN 104127410A CN 201410261673 A CN201410261673 A CN 201410261673A CN 104127410 A CN104127410 A CN 104127410A
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Abstract
The invention provides a preparation method of an ornidazole injection liquid. The preparation method comprises the steps: evenly mixing ornidazole and a solvent, wherein the solvent is a mixture of propylene glycol and at least a part of injection water, or the solvent is a mixture of propylene glycol, ethanol and at least a part of injection water; adjusting the pH value of the obtained mixture to 3-6 with acetic acid; and then carrying out at least two times of heating cooling circulation on the material after the pH value is adjusted. The invention also provides the ornidazole injection liquid, wherein the ornidazole injection liquid is prepared according to the above method. Through the technical scheme, the storage stability of the ornidazole injection liquid under a condition of relatively low temperatures (-10 DEG C to 20 DEG C) is significantly improved, and irritation is relatively small after injection.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of preparation method of ornidazole injection and the ornidazole injection that this preparation method prepares.
Background technology
Ornidazole injection is antibacterials, the mechanism of action is by the nitro in its molecule, in oxygen-free environment, be reduced into amino or by the formation of free radical, interact with Cell Component, thereby cause the death of microorganism, the disease therefore anaerobe, infusorian, ameba worm etc. being caused has stronger therapeutical effect.
Ornidazole injection is extensive in clinical practice, it is the choice drug for the treatment of anaerobic infection, can be used for prevention infection and the operation treatment of anaerobic infection afterwards before performing the operation, also can treat the serious ameba parasitosis of digestive system, as amebic dysentery, amebic liver abscess.But ornidazole water solublity is bad, existing process adjustments pH value to 1.8～2.3, make ornidazole injection basicly stable in preparation and storage process, and (single mixing do not surpass 0.5% to the not super quality standard limit of related substance, total mixing do not surpass 1.0%), but the ornidazole injection making is stronger to blood vessel irritation, the tolerance limit that has exceeded human body, infusion pain and phlebitic incidence rate have been increased simultaneously, show according to statistics, ornidazole injection causes that pain and various phlebitic patient are in various degree about 59% (Wang Bo, Chinese medical forward position, 2009, 4 (24): 69).
Existing document (CN201310000708.2) discloses a kind of ornidazole injection, and the pH value of this ornidazole injection reaches 4.0-7.0, and can keep the good storage stability of 6 months under the condition of 40 ± 2 ℃ of temperature and humidity 75 ± 5%.
But, research discovery, above-mentioned ornidazole injection storage stability under (10 ℃ to 20 ℃) under lower temperature conditions is poor, easily occurs the defect that visible particulate matter exceeds standard.
Summary of the invention
Poor in order to overcome ornidazole injection storage stability under (10 ℃ to 20 ℃) under lower temperature conditions, easily there is the defect that particulate matter exceeds standard, the invention provides a kind of preparation method of ornidazole injection.The present inventor finds unexpectedly, by least twice heating cool cycles, can improve significantly the storage stability of ornidazole injection, has obtained thus the present invention.
The invention provides a kind of preparation method of ornidazole injection, this preparation method comprises: ornidazole and solvent is even, described solvent is the mixture of propylene glycol and at least part of water for injection, or described solvent is the mixture of propylene glycol, ethanol and at least part of water for injection, and with acetic acid adjustment pH value, be 3-6 by gained mixture; Then the material of adjusting after pH value is carried out at least twice heating cool cycles; Wherein, described heating cool cycles comprises: first from the temperature of 10-30 ℃, be heated to the temperature of 75-85 ℃, then from the temperature of 75-85 ℃, be cooled to the temperature of 10-30 ℃.
The present invention also provides a kind of ornidazole injection, and this ornidazole injection prepares according to method as above.
Pass through technique scheme, the present invention has improved ornidazole injection storage stability under (10 ℃ to 20 ℃) under lower temperature conditions significantly, and owing to can improving the pH value of ornidazole and reducing the consumption of organic solvent, after injection, zest is less.
Other features and advantages of the present invention partly in detail are described the specific embodiment subsequently.
The specific embodiment
Below the specific embodiment of the present invention is elaborated.Should be understood that, the specific embodiment described herein only, for description and interpretation the present invention, is not limited to the present invention.
Herein, in the situation that not doing contrary explanation, the gas of use and liquid volume numerical value are 20 ℃, the numerical value under 101 kPas.In the present invention, ethanol used is dehydrated alcohol.
The invention provides a kind of preparation method of ornidazole injection, this preparation method comprises: ornidazole and solvent is even, described solvent is the mixture of propylene glycol and at least part of water for injection, or described solvent is the mixture of propylene glycol, ethanol and at least part of water for injection, and with acetic acid adjustment pH value, be 3-6 by gained mixture; Then the material of adjusting after pH value is carried out at least twice heating cool cycles; Wherein, described heating cool cycles comprises: first from the temperature of 10-30 ℃, be heated to the temperature of 75-85 ℃, then from the temperature of 75-85 ℃, be cooled to the temperature of 10-30 ℃.
Wherein, ornidazole refers to the material of chemistry 1-(the chloro-2-hydroxypropyl of 3-)-2-5-nitro imidazole by name.
Wherein, in the situation that described solvent is the mixture of propylene glycol and at least part of water for injection, the consumption of ornidazole, propylene glycol and water for injection can be consumption conventional in ornidazole injection preparation field, for example, with respect to the ornidazole of 1g, the use amount of propylene glycol can be 0.9-4.5g, and the consumption of water for injection can be 8-22mL; Preferably, for the ornidazole of 1g, the use amount of propylene glycol is 1.2-1.4g, and the consumption of water for injection is 10-20mL.
Wherein, in the situation that described solvent is the mixture of propylene glycol, ethanol and at least part of water for injection, the consumption of ornidazole, propylene glycol, ethanol and water for injection can be consumption conventional in ornidazole injection preparation field, for example, with respect to the ornidazole of 1g, the use amount of propylene glycol can be 0.5-4.5g, the use amount of ethanol can be 1-3.5g, and the consumption of water for injection can be 8-22mL; Preferably, with respect to the ornidazole of 1g, the use amount of propylene glycol is 0.9-1.5g, and ethanol use amount is 1.8-3g, and the consumption of water for injection is 11-21mL; More preferably, with respect to the ornidazole of 1g, the use amount of propylene glycol is 1.2-1.4g, and the use amount of ethanol is 2.4-2.9g, and the consumption of water for injection is 10-20mL.
Wherein, the material of adjusting after pH value is carried out at least twice heating cool cycles; The material of adjusting after pH value can be carried out twice, three times, four times, five times or six heating cool cycles; Preferably the material of adjusting after pH value is carried out to heating cool cycles twice.Wherein, heat temperature used in cool cycles can be identical or different at every turn.
Wherein, the condition of ornidazole, propylene glycol and water for injection mix homogeneously is not had to special requirement, for example, can at 10-85 ℃, be uniformly mixed.Can ornidazole, propylene glycol and water for injection be added in container simultaneously and at 10-30 ℃, be mixed to evenly.For speed production speed, shorten mix homogeneously required time, preferably, first propylene glycol is heated to 75-85 ℃, under stirring, add ornidazole, ornidazole is dissolved completely, then mix homogeneously with water for injection.
Wherein, the condition of ornidazole, propylene glycol, ethanol and water for injection mix homogeneously is not had to special requirement, for example, can at 10-85 ℃, be uniformly mixed.Can ornidazole, propylene glycol, ethanol and water for injection be added in container simultaneously and at 10-30 ℃, be mixed to evenly.For speed production speed, shorten mix homogeneously required time, preferably, first, by propylene glycol and ethanol mix homogeneously, be then heated to 75-85 ℃, under stirring, add ornidazole, ornidazole is dissolved completely, then mix homogeneously with water for injection.
Wherein, the temperature of the material after adjustment pH value before heating cool cycles can be 10-30 ℃.
Wherein, preferably, once heat in cool cycles, from the temperature of 10-30 ℃, being heated to the time that the temperature of 75-85 ℃ experiences is 15-30 minute.
Wherein, preferably, once heat in cool cycles, from the temperature of 75-85 ℃, being cooled to the time that the temperature of 10-30 ℃ experiences is 30-45 minute.
Wherein, in described heating cool cycles, can after being heated to 75-85 ℃, lower the temperature immediately, also can after being heated to 75-85 ℃, at 75-85 ℃, keep 1-2000s, preferably, in described heating cool cycles, at the temperature of 75-85 ℃, keep 180-1800s.
Wherein, described water for injection can be the water for injection through the saturated processing of carbon dioxide.
Wherein, described method can also comprise: the material having carried out after at least twice heating cool cycles can be mixed with active carbon, then remove by filter active carbon.With respect to the carrying out of 100mL the material after at least twice heating cool cycles, the consumption of active carbon can be 0.1-0.5g; The time of mixing can be 300-1200s.
Wherein, the operation of ornidazole, propylene glycol, ethanol and at least part of water for injection mix homogeneously is comprised by the embodiment of ornidazole, propylene glycol, ethanol and whole water for injection mix homogeneously and by the embodiment of ornidazole, propylene glycol, ethanol and part water for injection mix homogeneously.In order to adjust more accurately the concentration of ornidazole injection, preferably, by ornidazole, propylene glycol, ethanol and part water for injection mix homogeneously, described method also comprises: to the water for injection that fills into remainder in the material removing by filter after active carbon.The amount of the water for injection filling into does not have special requirement, can adjust according to required concentration.Wherein, in order to meet the hygienic requirements of injection, can carry out filtration sterilization or high pressure degerming.Filtration sterilization filter membrane used can be for below 0.22 μ m.The temperature of high pressure degerming can be 120-122 ℃.
Wherein, the operation of ornidazole, propylene glycol and at least part of water for injection mix homogeneously is comprised by the embodiment of ornidazole, propylene glycol and whole water for injection mix homogeneously and by the embodiment of ornidazole, propylene glycol and part water for injection mix homogeneously.In order to adjust more accurately the concentration of ornidazole injection, preferably, by ornidazole, propylene glycol and part water for injection mix homogeneously, described method also comprises: to the water for injection that fills into remainder in the material removing by filter after active carbon.The amount of the water for injection filling into does not have special requirement, can adjust according to required concentration.Wherein, in order to meet the hygienic requirements of injection, can carry out filtration sterilization or high pressure degerming.Filtration sterilization filter membrane used can be for below 0.22 μ m.The temperature of high pressure degerming can be 120-122 ℃.
The present invention also provides a kind of ornidazole injection, and this ornidazole injection prepares according to method as above.
Further describe by the following examples the present invention.In following examples, water for injection all by being filled with carbon dioxide until saturated processing.
Embodiment 1
1.3g propylene glycol is heated to 80 ℃, adds 1g ornidazole under stirring, ornidazole is dissolved completely, then mix homogeneously with 15mL water for injection, and adjust pH value to 4.5 with acetic acid, the temperature of having adjusted the material of pH value is 20 ℃.The material of having adjusted pH value was heated to 80 ℃ through 20 minutes, at 80 ℃, maintains 300s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the first time cool cycles.By having completed the material that heats for the first time cool cycles, through 20 minutes, be heated to 80 ℃, at 80 ℃, maintain 300s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the second time cool cycles.
By having carried out material and the 0.06g active carbon after heating cool cycles twice, mix 900s, then remove by filter active carbon.Then filling into water for injection to volume is 20mL filtration sterilization, prepares the ornidazole injection of the 0.05g/mL of the present embodiment.
Embodiment 2
1.2g propylene glycol is heated to 76 ℃, adds 1g ornidazole under stirring, ornidazole is dissolved completely, then mix homogeneously with 19.5mL water for injection, and adjust pH value to 4.9 with acetic acid, the temperature of having adjusted the material of pH value is 15 ℃.The material of having adjusted pH value was heated to 76 ℃ through 15 minutes, at 76 ℃, maintains 600s, then through 30 minutes, be cooled to 11 ℃, complete and heat for the first time cool cycles.By having completed the material that heats for the first time cool cycles, through 15 minutes, be heated to 83 ℃, at 83 ℃, maintain 600s, then through 30 minutes, be cooled to 28 ℃, complete and heat for the second time cool cycles.
By having carried out the material and 0.03g active carbon mixing 600s after heating cool cycles twice, then remove by filter active carbon.Then filling into water for injection to volume is 25mL filtration sterilization, prepares the ornidazole injection of the 0.04g/mL of the present embodiment.
Embodiment 3
1.4g propylene glycol is heated to 84 ℃, adds 1g ornidazole under stirring, ornidazole is dissolved completely, then mix homogeneously with 10.5mL water for injection, and adjust pH value to 4.1 with acetic acid, the temperature of having adjusted the material of pH value is 25 ℃.By having adjusted the heating material to 84 ℃ of pH value, at 84 ℃, maintain 300s, be then cooled to 28 ℃, complete and heat for the first time cool cycles.By having completed the heating material to 79 ℃ that heats for the first time cool cycles, at 79 ℃, maintain 1200s, be then cooled to 13 ℃, complete and heat for the second time cool cycles.
By having carried out the material and 0.015g active carbon mixing 660s after heating cool cycles twice, then remove by filter active carbon.Then filling into water for injection to volume is 20mL filtration sterilization, prepares the ornidazole injection of the 0.05g/mL of the present embodiment.
Embodiment 4
0.9g propylene glycol is heated to 80 ℃, adds 1g ornidazole under stirring, ornidazole is dissolved completely, then mix homogeneously with 21mL water for injection, and adjust pH value to 4.5 with acetic acid, the temperature of having adjusted the material of pH value is 20 ℃.The material of having adjusted pH value was heated to 80 ℃ through 20 minutes, at 80 ℃, maintains 300s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the first time cool cycles.By having completed the material that heats for the first time cool cycles, through 20 minutes, be heated to 80 ℃, at 80 ℃, maintain 300s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the second time cool cycles.
By having carried out material and the 0.06g active carbon after heating cool cycles twice, mix 900s, then remove by filter active carbon.Then filling into water for injection to volume is 25mL filtration sterilization, prepares the ornidazole injection of the 0.04g/mL of the present embodiment.
Embodiment 5
4.3g propylene glycol is heated to 80 ℃, adds 1g ornidazole under stirring, ornidazole is dissolved completely, then mix homogeneously with 18mL water for injection, and adjust pH value to 4.5 with acetic acid, the temperature of having adjusted the material of pH value is 20 ℃.The material of having adjusted pH value was heated to 80 ℃ through 20 minutes, at 80 ℃, maintains 300s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the first time cool cycles.By having completed the material that heats for the first time cool cycles, through 20 minutes, be heated to 80 ℃, at 80 ℃, maintain 300s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the second time cool cycles.
By having carried out material and the 0.06g active carbon after heating cool cycles twice, mix 900s, then remove by filter active carbon.Then filling into water for injection to volume is 25mL filtration sterilization, prepares the ornidazole injection of the 0.04g/mL of the present embodiment.
Embodiment 6
By 1.3g propylene glycol and 2.7g ethanol mix homogeneously, be then heated to 80 ℃, under stirring, add 1g ornidazole, ornidazole is dissolved completely, then mix homogeneously with 15mL water for injection, and adjust pH value to 4.5 with acetic acid, the temperature of having adjusted the material of pH value is 20 ℃.The material of having adjusted pH value was heated to 80 ℃ in 20 minutes, at 80 ℃, maintains 290s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the first time cool cycles.By having completed the material that heats for the first time cool cycles, in 18 minutes, be heated to 80 ℃, at 80 ℃, maintain 280s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the second time cool cycles.
By having carried out the material and 0.06g active carbon mixing 850s after heating cool cycles twice, then remove by filter active carbon.Then filling into water for injection to volume is 20mL filtration sterilization, prepares the ornidazole injection of the 0.05g/mL of the present embodiment.
Embodiment 7
By 1.2g propylene glycol and 2.85g ethanol mix homogeneously, be then heated to 76 ℃, under stirring, add 1g ornidazole, ornidazole is dissolved completely, then mix homogeneously with 19.5mL water for injection, and adjust pH value to 4.9 with acetic acid, the temperature of having adjusted the material of pH value is 15 ℃.The material of having adjusted pH value was heated to 76 ℃ through 15 minutes, at 76 ℃, maintains 600s, then through 32 minutes, be cooled to 11 ℃, complete and heat for the first time cool cycles.By having completed the material that heats for the first time cool cycles, through 28 minutes, be heated to 83 ℃, at 83 ℃, maintain 600s, then through 40 minutes, be cooled to 28 ℃, complete and heat for the second time cool cycles.
By having carried out the material and 0.03g active carbon mixing 600s after heating cool cycles twice, then remove by filter active carbon.Then filling into water for injection to volume is 25mL filtration sterilization, prepares the ornidazole injection of the 0.04g/mL of the present embodiment.
Embodiment 8
By 1.4g propylene glycol and 2.4g ethanol mix homogeneously, be then heated to 84 ℃, under stirring, add 1g ornidazole, ornidazole is dissolved completely, then mix homogeneously with 10.5mL water for injection, and adjust pH value to 4.1 with acetic acid, the temperature of having adjusted the material of pH value is 25 ℃.The material of having adjusted pH value was heated to 84 ℃ through 12 minutes, at 84 ℃, maintains 300s, then through 42 minutes, be cooled to 28 ℃, complete and heat for the first time cool cycles.By having completed the material that heats for the first time cool cycles, through 20 minutes, be heated to 79 ℃, at 79 ℃, maintain 1200s, then through 40 minutes, be cooled to 13 ℃, complete and heat for the second time cool cycles.
By having carried out material and the 0.02g active carbon after heating cool cycles twice, mix 660s, then remove by filter active carbon.Then filling into water for injection to volume is 20mL filtration sterilization, prepares the ornidazole injection of the 0.05g/mL of the present embodiment.
Embodiment 9
By 0.95g propylene glycol and 2.95g ethanol mix homogeneously, be then heated to 80 ℃, under stirring, add 1g ornidazole, ornidazole is dissolved completely, then mix homogeneously with 21mL water for injection, and adjust pH value to 4.5 with acetic acid, the temperature of having adjusted the material of pH value is 20 ℃.The material of having adjusted pH value was heated to 80 ℃ through 20 minutes, at 80 ℃, maintains 1800s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the first time cool cycles.By having completed the material that heats for the first time cool cycles, through 20 minutes, be heated to 80 ℃, at 80 ℃, maintain 1800s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the second time cool cycles.
By having carried out the material and 0.03g active carbon mixing 1200s after heating cool cycles twice, then remove by filter active carbon.Then filling into water for injection to volume is 25mL filtration sterilization, prepares the ornidazole injection of the 0.04g/mL of the present embodiment.
Embodiment 10
By 1.5g propylene glycol and 1g ethanol mix homogeneously, be then heated to 80 ℃, under stirring, add 1g ornidazole, ornidazole is dissolved completely, then to mix homogeneously with 8mL water for injection, and adjust pH value to 4.5 with acetic acid, the temperature of having adjusted the material of pH value is 20 ℃.The material of having adjusted pH value was heated to 80 ℃ through 20 minutes, at 80 ℃, maintains 1200s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the first time cool cycles.By having completed the material that heats for the first time cool cycles, through 20 minutes, be heated to 80 ℃, at 80 ℃, maintain 1200s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the second time cool cycles.
By having carried out the material and 0.1g active carbon mixing 600s after heating cool cycles twice, then remove by filter active carbon.Then filling into water for injection to volume is 20mL filtration sterilization, prepares the ornidazole injection of the 0.05g/mL of the present embodiment.
Embodiment 11
By 1.3g propylene glycol, 2.7g ethanol, 1g ornidazole and 15mL water for injection mix homogeneously at 25 ℃, and adjust pH value to 4.5 with acetic acid, the temperature of having adjusted the material of pH value is 20 ℃.The material of having adjusted pH value was heated to 80 ℃ through 20 minutes, at 80 ℃, maintains 600s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the first time cool cycles.By having completed the material that heats for the first time cool cycles, through 20 minutes, be heated to 80 ℃, at 80 ℃, maintain 600s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the second time cool cycles.
By having carried out the material and 0.02g active carbon mixing 600s after heating cool cycles twice, then remove by filter active carbon.Then filling into water for injection to volume is 20mL filtration sterilization, prepares the ornidazole injection of the 0.05g/mL of the present embodiment.
Embodiment 12
By 1.3g propylene glycol and 2.7g ethanol mix homogeneously, be then heated to 80 ℃, under stirring, add 1g ornidazole, ornidazole is dissolved completely, then mix homogeneously with 15mL water for injection, and adjust pH value to 4.5 with acetic acid, the temperature of having adjusted the material of pH value is 20 ℃.The material of having adjusted pH value was heated to 80 ℃ through 20 minutes, then through 40 minutes, is cooled to 20 ℃, complete and heat for the first time cool cycles.By having completed the material that heats for the first time cool cycles, through 20 minutes, be heated to 80 ℃, then through 40 minutes, be cooled to 20 ℃, complete and heat for the second time cool cycles.
By having carried out the material and 0.04g active carbon mixing 900s after heating cool cycles twice, then remove by filter active carbon.Then filling into water for injection to volume is 20mL filtration sterilization, prepares the ornidazole injection of the 0.05g/mL of the present embodiment.
Comparative example 1
By 1.3g propylene glycol and 2.7g ethanol mix homogeneously, be then heated to 80 ℃, under stirring, add 1g ornidazole, ornidazole is dissolved completely, then mix homogeneously with 15mL water for injection, and adjust pH value to 4.5 with acetic acid, the temperature of having adjusted the material of pH value is 20 ℃.The material of having adjusted pH value was heated to 70 ℃ through 20 minutes, at 70 ℃, maintains 600s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the first time cool cycles.By having completed the material that heats for the first time cool cycles, through 20 minutes, be heated to 70 ℃, at 70 ℃, maintain 600s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the second time cool cycles.
By having carried out the material and 0.02g active carbon mixing 900s after heating cool cycles twice, then remove by filter active carbon.Then filling into water for injection to volume is 20mL, prepares the ornidazole injection of the 0.05g/mL of this comparative example.
Comparative example 2
1.3g propylene glycol is heated to 80 ℃, adds 1g ornidazole under stirring, ornidazole is dissolved completely, then mix homogeneously with 15mL water for injection, and adjust pH value to 4.5 with acetic acid, the temperature of having adjusted the material of pH value is 20 ℃.The material of having adjusted pH value was heated to 80 ℃ through 20 minutes, at 80 ℃, maintains 600s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the first time cool cycles.
Material and 0.02g active carbon mixing 600s by having carried out once heating after cool cycles, then remove by filter active carbon.Then filling into water for injection to volume is 20mL filtration sterilization, prepares the ornidazole injection of the 0.05g/mL of this comparative example.
Comparative example 3
1.3g propylene glycol is heated to 80 ℃, adds 1g ornidazole under stirring, ornidazole is dissolved completely, then mix homogeneously with 15mL water for injection, and adjust pH value to 4.5 with acetic acid, the temperature of having adjusted the material of pH value is 20 ℃.By having adjusted the material and 0.02g active carbon mixing 900s of pH value, then remove by filter active carbon.Then filling into water for injection to volume is 20mL filtration sterilization, prepares the ornidazole injection of the 0.05g/mL of this comparative example.
Comparative example 4
By 1.3g propylene glycol and 2.7g ethanol mix homogeneously, be then heated to 80 ℃, under stirring, add 1g ornidazole, ornidazole is dissolved completely, then mix homogeneously with 15mL water for injection, and adjust pH value to 4.5 with acetic acid, the temperature of having adjusted the material of pH value is 20 ℃.The material of having adjusted pH value was heated to 70 ℃ through 20 minutes, at 70 ℃, maintains 600s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the first time cool cycles.By having completed the material that heats for the first time cool cycles, through 20 minutes, be heated to 70 ℃, at 70 ℃, maintain 600s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the second time cool cycles.
By having carried out the material and 0.02g active carbon mixing 900s after heating cool cycles twice, then remove by filter active carbon.Then filling into water for injection to volume is 20mL, prepares the ornidazole injection of the 0.05g/mL of this comparative example.
Comparative example 5
By 1.3g propylene glycol and 2.7g ethanol mix homogeneously, be then heated to 80 ℃, under stirring, add 1g ornidazole, ornidazole is dissolved completely, then mix homogeneously with 15mL water for injection, and adjust pH value to 4.5 with acetic acid, the temperature of having adjusted the material of pH value is 20 ℃.The material of having adjusted pH value was heated to 80 ℃ through 20 minutes, at 80 ℃, maintains 600s, then through 40 minutes, be cooled to 20 ℃, complete and heat for the first time cool cycles.
Material and 0.02g active carbon mixing 600s by having carried out once heating after cool cycles, then remove by filter active carbon.Then filling into water for injection to volume is 20mL filtration sterilization, prepares the ornidazole injection of the 0.05g/mL of this comparative example.
Comparative example 6
By 1.3g propylene glycol and 2.7g ethanol mix homogeneously, be then heated to 80 ℃, under stirring, add 1g ornidazole, ornidazole is dissolved completely, then mix homogeneously with 15mL water for injection, and adjust pH value to 4.5 with acetic acid, the temperature of having adjusted the material of pH value is 20 ℃.By having adjusted the material and 0.02g active carbon mixing 900s of pH value, then remove by filter active carbon.Then filling into water for injection to volume is 20mL filtration sterilization, prepares the ornidazole injection of the 0.05g/mL of this comparative example.
Test implementation example 1
According to the method for the regulation in document (< < Pharmacopoeia of People's Republic of China > > 2010 editions), the color of the ornidazole injection of embodiment 1-12 and comparative example 1-6, related substance, bacterial endotoxin, aseptic and osmotic pressure are detected, and testing result all meets the regulation of < < Pharmacopoeia of People's Republic of China > > 2010 editions.
According to the method for the regulation in document (< < Pharmacopoeia of People's Republic of China > > 2010 editions), the high temperature of the ornidazole injection of embodiment 1-12 and comparative example 1-6 (40 ℃) storage stability, room temperature (20 ℃) storage stability, low temperature (4 ℃) storage stability and ice temperature (10 ℃) storage stability are measured.Concrete grammar comprises: by the ornidazole injection of embodiment 1-12 and comparative example 1-6, under 75 ± 5% humidity, at 40 ℃, 20 ℃, 4 ℃ and-10 ℃, store 200 days, then carry out the inspection of particulate matter inspection Check method (carrying out with reference to 2010 editions appendix IX R of < < Pharmacopoeia of People's Republic of China > >), result is as shown in table 1.
Table 1
Visible according to the data of table 1, the prepared ornidazole injection of method of the present invention can keep good storage stability under lower temperature conditions under (10 ℃ to 20 ℃), significantly reduced the generation of particulate matter.Its possible reason is, at least twice heating cool cycles of the present invention can promote the formation of the solvate of ornidazole effectively, improved the storage stability of ornidazole injection.
More than describe the preferred embodiment of the present invention in detail; but the present invention is not limited to the detail in above-mentioned embodiment, within the scope of technical conceive of the present invention; can carry out multiple simple variant to technical scheme of the present invention, these simple variant all belong to protection scope of the present invention.
It should be noted that in addition, each concrete technical characterictic described in the above-mentioned specific embodiment, in reconcilable situation, can combine by any suitable mode, for fear of unnecessary repetition, the present invention is to the explanation no longer separately of various possible compound modes.
In addition, between various embodiment of the present invention, also can carry out combination in any, as long as it is without prejudice to thought of the present invention, it should be considered as content disclosed in this invention equally.
Claims (10)
1. the preparation method of an ornidazole injection, it is characterized in that: this preparation method comprises: ornidazole and solvent is even, described solvent is the mixture of propylene glycol and at least part of water for injection, or described solvent is the mixture of propylene glycol, ethanol and at least part of water for injection, and with acetic acid adjustment pH value, be 3-6 by gained mixture; Then the material of adjusting after pH value is carried out at least twice heating cool cycles; Wherein, described heating cool cycles comprises: first from the temperature of 10-30 ℃, be heated to the temperature of 75-85 ℃, then from the temperature of 75-85 ℃, be cooled to the temperature of 10-30 ℃.
2. preparation method according to claim 1, is characterized in that: described solvent is the mixture of propylene glycol and at least part of water for injection, and with respect to the ornidazole of 1g, the use amount of propylene glycol is 0.9-4.5g, and the consumption of water for injection is 8-22mL.
3. preparation method according to claim 2, is characterized in that: with respect to the ornidazole of 1g, the use amount of propylene glycol is 1.2-1.4g, and the consumption of water for injection is 10-20mL.
4. preparation method according to claim 1, it is characterized in that: described solvent is the mixture of propylene glycol, ethanol and at least part of water for injection, and with respect to the ornidazole of 1g, the use amount of propylene glycol is 0.5-4.5g, the use amount of ethanol is 1-3.5g, and the consumption of water for injection is 8-22mL.
5. preparation method according to claim 4, is characterized in that: with respect to the ornidazole of 1g, the use amount of propylene glycol is 1.2-1.4g, and the use amount of ethanol is 1.8-3g, and the consumption of water for injection is 10-20mL.
6. according to the preparation method described in any one in claim 1-5, it is characterized in that: in described heating cool cycles, at the temperature of 75-85 ℃, keep 180-1800s.
7. according to the preparation method described in any one in claim 1-5, it is characterized in that: once heat in cool cycles, from the temperature of 10-30 ℃, being heated to the time that the temperature of 75-85 ℃ experiences is 15-30 minute, and from the temperature of 75-85 ℃, being cooled to the time that the temperature of 10-30 ℃ experiences is 30-45 minute.
8. according to the preparation method described in any one in claim 1-5, it is characterized in that: gained mixture is adjusted to pH value to 4-5 with acetic acid.
9. according to the preparation method described in any one in claim 1-5, it is characterized in that: described method also comprises: the material having carried out after at least twice heating cool cycles is mixed with active carbon, then remove by filter active carbon.
10. an ornidazole injection, is characterized in that, this ornidazole injection is to prepare according to the method described in any one in claim 1-9.
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| CN106309359A (en) * | 2016-08-31 | 2017-01-11 | 北京京科泰来科技有限公司 | Omidazole injection |
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| CN107041868A (en) * | 2016-02-05 | 2017-08-15 | 南京卡文迪许生物工程技术有限公司 | Ornidazole injection and S- ornidazole injections of a kind of stabilization and preparation method thereof |
| CN110538142A (en) * | 2018-05-29 | 2019-12-06 | 牛涛涛 | Anti-infective drug injection composition |
| CN112220747A (en) * | 2020-10-21 | 2021-01-15 | 山西普德药业有限公司 | Ornidazole injection convenient to store and preparation method thereof |
| WO2021058014A1 (en) * | 2019-09-29 | 2021-04-01 | 扬子江药业集团南京海陵药业有限公司 | Ornidazole pharmaceutical composition and preparation method and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107041868A (en) * | 2016-02-05 | 2017-08-15 | 南京卡文迪许生物工程技术有限公司 | Ornidazole injection and S- ornidazole injections of a kind of stabilization and preparation method thereof |
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| CN110507605B (en) * | 2016-02-05 | 2022-06-24 | 南京卡文迪许生物工程技术有限公司 | Stable ornidazole injection and S-ornidazole injection and preparation method thereof |
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| CN110538142A (en) * | 2018-05-29 | 2019-12-06 | 牛涛涛 | Anti-infective drug injection composition |
| WO2021058014A1 (en) * | 2019-09-29 | 2021-04-01 | 扬子江药业集团南京海陵药业有限公司 | Ornidazole pharmaceutical composition and preparation method and use thereof |
| CN112220747A (en) * | 2020-10-21 | 2021-01-15 | 山西普德药业有限公司 | Ornidazole injection convenient to store and preparation method thereof |
| CN114432237A (en) * | 2020-10-30 | 2022-05-06 | 康普药业股份有限公司 | Ornidazole injection |
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| CN104127410B (en) | 2016-04-27 |
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