CN112516082A - Amino caproic acid injection and preparation method thereof - Google Patents

Amino caproic acid injection and preparation method thereof Download PDF

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Publication number
CN112516082A
CN112516082A CN202011636307.2A CN202011636307A CN112516082A CN 112516082 A CN112516082 A CN 112516082A CN 202011636307 A CN202011636307 A CN 202011636307A CN 112516082 A CN112516082 A CN 112516082A
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CN
China
Prior art keywords
injection
preparation
amino
aminocaproic acid
water
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Pending
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CN202011636307.2A
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Chinese (zh)
Inventor
刘玉华
尹文娟
顾赵芬
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Changzhou Lanling Pharmaceutical Co ltd
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Changzhou Lanling Pharmaceutical Co ltd
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Priority to CN202011636307.2A priority Critical patent/CN112516082A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Abstract

The invention discloses an amino caproic acid injection and a preparation method thereof, wherein the preparation method comprises the following steps: adding 50-80% of water for injection into a diluting preparation tank, adding aminocaproic acid, heating to 75-90 ℃, stirring until the mixture is completely dissolved, adding the water for injection to 90-98%, and filtering by using a 1.0-micrometer titanium rod; adjusting the pH value to 6.2-7.4, supplementing water for injection to the full amount, performing precise reflux through polyether sulfone filter elements of 0.45 mu m and 0.22 mu m in sequence, and filtering to a liquid storage tank; thirdly, performing terminal filtration through polyethersulfone filter elements of 0.22 mu m and 0.10 mu m in sequence, finally filling into ampoules, and sterilizing. The method does not adopt activated carbon to adsorb pyrogen, so that impurities introduced by the activated carbon can be effectively avoided, meanwhile, five-stage filtration is adopted, especially, a 0.10 mu m polyethersulfone filter element is finally adopted for terminal filtration, and the content of bacterial endotoxin can be effectively controlled.

Description

Amino caproic acid injection and preparation method thereof
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an amino caproic acid injection and a preparation method thereof.
Background
Aminocaproic acid (i.e., 6-aminocaproic acid) is one of the more important functional chemicals, and can be widely used in the medical field. The aminocaproic acid has the function of stopping bleeding, can be used for acute diseases such as surgical hemorrhage, gynecological hemorrhage, pulmonary hemorrhage, upper gastrointestinal hemorrhage and the like, and has high market value. The amino caproic acid injection developed by the method can also be suitable for preventing and treating various hemorrhages caused by hyperfibrinolysis.
Chinese patent document CN107115280A discloses an amino-adipic acid injection and a preparation method thereof, the document only reduces visible foreign matters by using secondary sterilization filtration, and the document does not mention about improving the color of the injection and the content of related substances.
Chinese patent document CN108685843A discloses an aminocaproic acid injection and a preparation method thereof, which comprises an aminocaproic acid bulk drug treatment stage and an aminocaproic acid injection preparation stage. The preparation method comprises the steps of firstly preparing in a concentrated manner and then preparing in a diluted manner, and adopting activated carbon adsorption treatment (mainly used for adsorbing bacterial endotoxin) in the concentrated preparation process. The document can obviously improve the solution color of the injection and reduce the content of related substances. However, the only relevant substances involved are caprolactam and aminocaproic acid dimer, and nothing is said about other relevant substances (e.g. aminocaproic acid trimer and other unknown impurities).
The activated carbon is the most common pyrogen adsorbent for injections, has been applied for many years, and plays an important role in improving the quality of the injections. But due to the source of the activated carbon and the diversity of production, the activated carbon can easily introduce impurities while adsorbing pyrogens. It has not been suggested to use activated carbon to control pyrogen levels in injections.
Disclosure of Invention
The invention aims to solve the problems and provides the amino caproic acid injection which can effectively control the pyrogen level (bacterial endotoxin content) and the related impurity content and the preparation method thereof.
The technical scheme for realizing the purpose of the invention is as follows: a preparation method of an amino caproic acid injection comprises the following steps:
adding 50-80% of injection water according to the prescription amount into a diluting preparation tank, then adding aminocaproic acid according to the prescription amount, heating to 75-90 ℃, stirring until the aminocaproic acid is completely dissolved, then adding the injection water to 90-98% of the prescription amount, and finally filtering by using a 1.0 mu m titanium rod;
secondly, adding a pH regulator into the filtrate obtained in the first step, regulating the pH to 6.2-7.4, supplementing water for injection to full amount, performing precision reflux on the intermediate after passing the inspection, sequentially passing through polyether sulfone filter elements of 0.45 mu m and 0.22 mu m, and filtering to a liquid storage tank;
and thirdly, filtering the filtrate in the liquid storage tank in sequence through 0.22 mu m and 0.10 mu m polyethersulfone filter cores for terminal filtration, finally filling into ampoules, and sterilizing to obtain the aminocaproic acid injection.
The aminocaproic acid in the step (i) is a purified aminocaproic acid product obtained by treatment in Chinese patent document CN 108685843A.
In the second step, the pH regulator is sodium hydroxide or hydrochloric acid.
In the third step, the ampoule is a pyrogen-free polypropylene ampoule or a neutral borosilicate glass ampoule.
And the sterilization temperature of the third step is 121-124 ℃, and the sterilization time is 10-30 min.
The invention has the following positive effects:
(1) according to the method, activated carbon is not used for adsorbing pyrogen, so that impurities introduced by the activated carbon can be effectively avoided, the content of related impurities in the amino caproic acid injection is effectively controlled, a concentration step can be omitted, a dilution step is directly adopted, the solution preparation time is saved, the cleanness and consumption of equipment are reduced, and the pollution risk is reduced.
(2) The method adopts five-stage filtration, particularly adopts a polyether sulfone filter element with the diameter of 0.10 mu m for terminal filtration, can effectively control the content of bacterial endotoxin, finally ensures that the prepared amino caproic acid injection not only has low impurity content, but also has the bacterial endotoxin content meeting the requirements, and ensures the effectiveness, safety and stability of the product.
Detailed Description
(example 1)
The formula of the amino caproic acid injection of the embodiment is as follows: 2000g of purified aminocaproic acid (obtained by the method of step S1 of example 1 of Chinese patent document CN 108685843A), and 10000mL of water for injection.
The preparation method of the aminocaproic acid injection of the embodiment comprises the following steps:
7000mL of water for injection is added to a dilution tank, 2000g of a refined aminocaproic acid is added thereto, the temperature is raised to 80 ℃ and the mixture is stirred until the mixture is completely dissolved, then water for injection is added to 9500mL, and finally the mixture is filtered by a 1.0 μm titanium rod.
Secondly, adding a pH regulator into the filtrate obtained in the step one, regulating the pH to 6.6, supplementing water for injection to 10000mL, performing precision reflux on the intermediate after passing the inspection (wherein the pH value is 6.6), sequentially passing through polyether sulfone filter cores of 0.45 mu m and 0.22 mu m, and filtering the filtrate to a liquid storage tank.
And thirdly, sequentially passing the filtrate in the liquid storage tank from the step two through a 0.22 mu m and 0.10 mu m polyethersulfone filter element for terminal filtration, finally filling into a neutral borosilicate glass ampoule, and sterilizing at 121 ℃ for 12min to obtain the aminocaproic acid injection.
(examples 2 to 3)
The preparation method of the amino caproic acid injection of each example is basically the same as that of example 1 except for the difference shown in table 1.
TABLE 1
Example 1 Example 2 Example 3
Step I stirring and dissolving temperature 80℃ 85℃ 77℃
Step II of pH value 6.6 6.8 6.7
Step III ampoule material Neutral borosilicate glass ampoule Polypropylene ampoule Neutral borosilicate glass ampoule
Step III Sterilization conditions 121℃×12min 121℃×15min 121℃×30min
(test example)
The amino-caproic acid injection prepared in example 1 to example 3 was examined at 60 ℃ for 0 day, 5 days, 10 days and 30 days, including properties, bacterial endotoxin and related substances, and the results are shown in tables 2 to 4.
Wherein the content of bacterial endotoxin is limited to 0.016EU/mg, and the content is lower than the content and meets the specification, otherwise, the content does not meet the specification.
TABLE 2
Day 0 5 days 10 days 30 days
Traits Colorless clear liquid Colorless clear liquid Colorless clear liquid Colorless clear liquid
Bacterial endotoxins Compliance with regulations Compliance with regulations Compliance with regulations Compliance with regulations
Caprolactam 0.005% 0.005% 0.005% 0.006%
Amino caproic acid dimer 0.008% 0.008% 0.009% 0.009%
Unknown impurity A Not detected out Not detected out Not detected out 0.008%
Aminohexanoic acid trimer Not detected out Not detected out Not detected out Not detected out
Total miscellaneous 0.013% 0.013% 0.014% 0.023%
TABLE 3
Day 0 5 days 10 days 30 days
Traits Colorless clear liquid Colorless clear liquid Colorless clear liquid Colorless clear liquid
Bacterial endotoxins Compliance with regulations Compliance with regulations Compliance with regulations Compliance with regulations
Caprolactam 0.006% 0.006% 0.007% 0.007%
Amino caproic acid dimer 0.009% 0.009% 0.010% 0.011%
Unknown impurity A Not detected out Not detected out Not detected out 0.009%
Aminohexanoic acid trimer Not detected out Not detected out Not detected out Not detected out
Total miscellaneous 0.015% 0.015% 0.017% 0.027%
TABLE 4
Day 0 5 days 10 days 30 days
Traits Colorless clear liquid Colorless clear liquid Colorless clear liquid Colorless clear liquid
Bacterial endotoxins Compliance with regulations Compliance with regulations Compliance with regulations Compliance with regulations
Caprolactam 0.007% 0.007% 0.007% 0.008%
Amino caproic acid dimer 0.008% 0.008% 0.009% 0.009%
Unknown impurity A Not detected out Not detected out Not detected out 0.009%
Aminohexanoic acid trimer Not detected out Not detected out Not detected out Not detected out
Total miscellaneous 0.015% 0.015% 0.016% 0.026%
Comparative example 1
See chinese patent CN108685843A for example 1 for the preparation of amino caproic acid injection.
Comparative example 2
The preparation method of the amino caproic acid injection of the comparative example 2 is basically the same as that of the example 1, except that the steps of (1): 7000mL of water for injection was added to a dilution tank, 2000g of a purified product of aminocaproic acid was then added, the temperature was raised to 80 ℃ and stirred until completely dissolved, then 0.5% (w/v) of activated carbon for injection was added, the mixture was heated to boiling for 30min, then water for injection was added to 9000mL, and finally, the mixture was filtered with a 1.0 μm titanium rod.
(comparative example 3)
The preparation method of the amino caproic acid injection of the comparative example 3 is basically the same as that of the example 1, except that the third step is to perform end filtration by a filter element of 0.22 mu m polyether sulfone.
Comparative example 4
The preparation method of the amino caproic acid injection of the comparative example 3 is basically the same as that of the example 1, except that the third step is to perform end filtration by using a 0.22 mu m polyethersulfone filter element for three times.
Comparative test example
The amino caproic acid injection prepared in comparative examples 1 to 4 is examined for 0 day, 5 days, 10 days and 30 days at the high temperature of 60 ℃, and the results including characters, bacterial endotoxin and related substances are respectively shown in tables 5 to 8.
TABLE 5
Day 0 5 days 10 days 30 days
Traits Colorless clear liquid Almost colorless clear liquid Almost colorless clear liquid Yellow clear liquid
Bacterial endotoxins Compliance with regulations Compliance with regulations Compliance with regulations Compliance with regulations
Caprolactam 0.007% 0.007% 0.007% 0.009%
Amino caproic acid dimer 0.010% 0.009% 0.009% 0.009%
Unknown impurity B 0.003% 0.003% 0.003% 0.004%
Unknown impurity A 0.011% 0.022% 0.034% 0.190%
Aminohexanoic acid trimer 0.004% 0.005% 0.008% 0.009%
Total miscellaneous 0.035% 0.046% 0.061% 0.221%
TABLE 6
Day 0 5 days 10 days 30 days
Traits Colorless clear liquid Almost colorless clear liquid Almost colorless clear liquid Yellow clear liquid
Bacterial endotoxins Compliance with regulations Compliance with regulations Compliance with regulations Compliance with regulations
Caprolactam 0.006% 0.007% 0.007% 0.009%
Amino caproic acid dimer 0.009% 0.008% 0.008% 0.009%
Unknown impurity A 0.012% 0.025% 0.030% 0.160%
Aminohexanoic acid trimer 0.003% 0.004% 0.006% 0.008%
Total miscellaneous 0.030% 0.044% 0.051% 0.186%
As can be seen from comparative examples 1 and 2: unknown impurities with certain colors can be introduced into the activated carbon, and after the activated carbon is treated at high temperature for multiple times, the content of the unknown impurities and other unstable impurities can be rapidly increased, so that the color of the injection solution is yellowed.
TABLE 7
Day 0 5 days 10 days 30 days
Traits Colorless clear liquid Colorless clear liquid Colorless clear liquid Colorless clear liquid
Bacterial endotoxins Out of compliance with the regulations Out of compliance with the regulations Out of compliance with the regulations Out of compliance with the regulations
Caprolactam 0.006% 0.005% 0.006% 0.007%
Amino caproic acid dimer 0.008% 0.008% 0.009% 0.009%
Unknown impurity A Not detected out Not detected out Not detected out 0.007%
Aminohexanoic acid trimer Not detected out Not detected out Not detected out Not detected out
Total miscellaneous 0.014% 0.013% 0.015% 0.023%
TABLE 8
Day 0 5 days 10 days 30 days
Traits Colorless clear liquid Colorless clear liquid Colorless clear liquid Colorless clear liquid
Bacterial endotoxins Out of compliance with the regulations Out of compliance with the regulations Out of compliance with the regulations Out of compliance with the regulations
Caprolactam 0.005% 0.005% 0.005% 0.006%
Amino caproic acid dimer 0.007% 0.007% 0.008% 0.008%
Unknown impurity A Not detected out Not detected out Not detected out 0.006%
Aminohexanoic acid trimer Not detected out Not detected out Not detected out Not detected out
Total miscellaneous 0.012% 0.012% 0.013% 0.020%
As can be seen from comparative examples 3 and 4: active carbon is not adopted, and the filtering mode of the application is not adopted, so that bacterial endotoxin is difficult to effectively remove.

Claims (6)

1. A preparation method of an amino caproic acid injection comprises the following steps:
adding 50-80% of injection water according to the prescription amount into a diluting preparation tank, then adding aminocaproic acid according to the prescription amount, heating to 75-90 ℃, stirring until the aminocaproic acid is completely dissolved, then adding the injection water to 90-98% of the prescription amount, and finally filtering by using a 1.0 mu m titanium rod;
secondly, adding a pH regulator into the filtrate obtained in the first step, regulating the pH to 6.2-7.4, supplementing water for injection to full amount, performing precision reflux on the intermediate after passing the inspection, sequentially passing through polyether sulfone filter elements of 0.45 mu m and 0.22 mu m, and filtering to a liquid storage tank;
and thirdly, filtering the filtrate in the liquid storage tank in sequence through 0.22 mu m and 0.10 mu m polyethersulfone filter cores for terminal filtration, finally filling into ampoules, and sterilizing to obtain the aminocaproic acid injection.
2. The preparation method of the amino-adipic acid injection as claimed in claim 1, wherein the preparation method comprises the following steps: the aminocaproic acid in the step I is an aminocaproic acid refined product obtained by dissolving an aminocaproic acid raw material with medicinal purified water, decoloring with medicinal active carbon, performing reduced pressure distillation and crystallization, recrystallizing with ethanol, and finally performing vacuum drying.
3. The method for preparing the amino-adipic acid injection according to claim 1 or 2, which is characterized in that: in the second step, the pH regulator is sodium hydroxide or hydrochloric acid.
4. The method for preparing the amino-adipic acid injection according to claim 1 or 2, which is characterized in that: in the third step, the ampoule is a pyrogen-free polypropylene ampoule or a neutral borosilicate glass ampoule.
5. The method for preparing the amino-adipic acid injection according to claim 1 or 2, which is characterized in that: and the sterilization temperature of the third step is 121-124 ℃, and the sterilization time is 10-30 min.
6. An amino caproic acid injection prepared by the method of any one of claims 1 to 5.
CN202011636307.2A 2020-12-31 2020-12-31 Amino caproic acid injection and preparation method thereof Pending CN112516082A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107115280A (en) * 2016-02-25 2017-09-01 上海信谊金朱药业有限公司 A kind of aminocaproic acid parenteral solution and preparation method thereof
CN108685843A (en) * 2018-05-31 2018-10-23 常州兰陵制药有限公司 aminocaproic acid injection and preparation method thereof
CN111388415A (en) * 2020-03-19 2020-07-10 石家庄四药有限公司 Moxifloxacin hydrochloride sodium chloride injection and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107115280A (en) * 2016-02-25 2017-09-01 上海信谊金朱药业有限公司 A kind of aminocaproic acid parenteral solution and preparation method thereof
CN108685843A (en) * 2018-05-31 2018-10-23 常州兰陵制药有限公司 aminocaproic acid injection and preparation method thereof
CN111388415A (en) * 2020-03-19 2020-07-10 石家庄四药有限公司 Moxifloxacin hydrochloride sodium chloride injection and preparation method thereof

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Application publication date: 20210319