CN115452813A - Method for detecting bacterial endotoxin of medicament containing quinoline ring structure - Google Patents
Method for detecting bacterial endotoxin of medicament containing quinoline ring structure Download PDFInfo
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Abstract
The invention provides a method for detecting bacterial endotoxin of a medicament containing a quinoline ring structure, and relates to the technical field of bacterial endotoxin detection. The method specifically comprises the following steps: dissolving a medicament containing a quinoline ring structure by using a solvent to obtain a test sample stock solution so as to release bacterial endotoxin in the medicament; the stock solution is diluted again to reduce the interference of the self property of the drug to the bacterial endotoxin; and finally, detecting bacterial endotoxin by a dynamic colorimetric method. Wherein the solvent is N, N-dimethylformamide with the volume fraction of 60-70%; the medicament containing the quinoline ring structure comprises imiquimod; the concentration of the stock solution of the test sample is 0.1-10mg/ml, and the dilution multiple of the stock solution is 10-1000 times. The technical scheme provided by the invention solves the problem that the medicament containing the quinoline ring structure is difficult to dissolve in water in the prior art, and effectively improves the accuracy of detecting the content of the bacterial endotoxin of the medicament containing the quinoline ring structure. Moreover, the conventional gel method is avoided, so that the problem of false negative of the result of the gel method detection of the supernatant is solved.
Description
Technical Field
The invention belongs to the technical field of bacterial endotoxin detection, and particularly relates to a method for detecting bacterial endotoxin of a medicament containing a quinoline ring structure.
Background
Bacterial endotoxins are characteristic structures on the cell wall of gram-negative bacteria, and their main chemical substance is lipopolysaccharide. Endotoxin is an exogenous pyrogen which can activate neutrophils and the like to release an endogenous pyrogen which acts on a thermoregulation center to cause fever, and severe patients can cause hypotension, toxic shock, disseminated intravascular coagulation, acute respiratory distress syndrome, multiple organ failure and even death. Therefore, drugs such as biological products, injection drugs, chemical drugs, radiopharmaceuticals, antibiotics, vaccines and the like can be used only after being qualified through bacterial endotoxin detection tests.
The current method for detecting bacterial endotoxin comprises the following steps: gel methods and photometric methods. Wherein the gel method is to qualitatively detect or semi-quantitatively detect endotoxin by using the principle that limulus reagent and bacterial endotoxin produce agglutination reaction. The photometric method includes a turbidity method and a chromogenic substrate (colorimetric) method, which quantitatively determine endotoxin by using the turbidity change during the reaction of a limulus reagent with endotoxin and the amount of a chromogen released from a specific substrate by the produced clotting enzyme, respectively. The colorimetric method can be further classified into an end-point colorimetric method and a dynamic colorimetric method. The method has high sensitivity and precision. However, the two methods included in the pharmacopoeia only provide a basis for detecting bacterial endotoxin, and a certain medicine is not specified. In practical application, some medicines cannot adopt a gel method or a photometric method due to the restriction of self specificity, and only can adopt a rabbit heat source test method; some drugs cannot be used in the gel method due to their specificity and sensitivity to limulus reagents, but can be used in a highly sensitive and highly accurate photometric quantitative test.
Drugs containing quinoline ring structures are generally insoluble in water, and have great interference on detection of bacterial endotoxin. Such as imiquimod, which is a small molecule immunomodulator of formula C 14 H 16 N 4 CAS registry number 99011-02-6. The imiquimod preparation is mainly externally applied ointment at present, bacterial endotoxin control is not needed, and with continuous and intensive research on imiquimod, the possibility of preparing imiquimod injection in the future is very high, so that the detection method for researching the bacterial endotoxin of the imiquimod has foresight characteristics. When the inventor tries to take the imiquimod supernatant for gel test detection, a false negative result appears, and the detection result deviates from a true value, so that the accurate detection of the bacterial endotoxin is not facilitated.
Therefore, the technical problem to be solved by those skilled in the art is to design a method capable of accurately and truly detecting bacterial endotoxin containing a quinoline ring structure.
Disclosure of Invention
The invention aims to provide a method for detecting bacterial endotoxin of a medicament containing a quinoline ring structure, which solves the problems that the medicament containing the quinoline ring structure is difficult to dissolve in water and is easy to generate interference to cause false negative in the prior art, and effectively improves the accuracy of detecting the content of bacterial endotoxin of the medicament containing the quinoline ring structure.
In order to achieve the above object, the present invention provides a method for detecting bacterial endotoxin containing quinoline ring structure, comprising the following steps: dissolving a medicament containing a quinoline ring structure by using a solvent to obtain a test sample stock solution so as to release bacterial endotoxin in the medicament; the stock solution is diluted again to reduce the interference of the self property of the drug to the bacterial endotoxin; and finally, detecting bacterial endotoxin by a dynamic colorimetric method.
In a preferred embodiment, the solvent is N, N-dimethylformamide in a volume fraction of 60 to 70%. In the search for a method for improving the accuracy of detecting the content of endotoxin in a bacterial drug containing a quinoline ring structure, the inventors of the present invention tried various reagents, including strong acids (such as hydrochloric acid and sulfuric acid), weak acids (such as glacial acetic acid and phosphoric acid), dimethyl sulfoxide, and the like. However, these reagents also destroy inactivated bacterial endotoxin while dissolving the drug containing the quinoline ring structure, resulting in false negative in the test result and failure to accurately measure the content of bacterial endotoxin in the drug. A large number of creative experimental researches show that when the N, N-dimethylformamide with the volume fraction of 60% -70% is used, a certain amount of medicine can be completely dissolved, bacterial endotoxin in the medicine can not be destroyed and inactivated, the bacterial endotoxin in the medicine can be completely released, and the detection result is more real and accurate.
The amount of N, N-dimethylformamide less than 60% for dissolving the medicine is limited, the concentration of the prepared solution is lower and is lower than the minimum effective dilution concentration, so that the detection result is invalid; more than 70% of N, N-dimethylformamide, the presence of dilution to the maximum effective dilution factor does not exclude the interference of the solvent on the detection of endotoxin, resulting in a recovery rate of endotoxin of less than 50%.
In a preferred embodiment, the drug comprising a quinoline ring structure comprises imiquimod.
In a preferred embodiment, the concentration of the sample stock solution is 0.1-10mg/ml, and the dilution factor of the stock solution is 10-1000 times, preferably, the concentration of the sample stock solution is 0.2mg/ml, 0.5mg/ml, 0.8mg/ml, 1mg/ml, 1.2mg/ml, 1.5mg/ml, 1.8mg/ml, 2mg/ml, 5mg/ml, 6mg/ml, 8mg/ml, and the dilution factor of the stock solution is 20 times, 50 times, 80 times, 100 times, 200 times, 400 times, 500 times, 600 times, 800 times. More preferably, when the endotoxin of imiquimod is detected, the concentration of the original test sample solution is 1mg/ml, and the dilution factor of the original solution is 200 times.
In a preferred embodiment, the method specifically comprises the following steps:
s1, preparing a standard curve reliability test solution, namely re-dissolving a bacterial endotoxin working standard substance into bacterial endotoxin standard substance solutions of 0.005EU/ml, 0.05EU/ml and 0.5 EU/ml;
s2, diluting N, N-dimethylformamide as a solvent;
s3, preparing a test solution: dissolving the medicament containing the quinoline ring structure by using the solvent obtained in the step S2 to obtain a test sample stock solution with the concentration of 0.1-10mg/ml, and diluting the stock solution to obtain a test sample solution;
s4, preparing a positive solution of the test sample: diluting the bacterial endotoxin standard solution by using the test solution obtained in the step S3 to prepare a test positive solution with the point concentration of 0.05EU/ml bacterial endotoxin in the standard curve;
s5, preparing a negative control solution, namely diluting the solvent obtained in the step S2;
s6, detecting bacterial endotoxin by a dynamic colorimetric method: redissolving a limulus reagent by a dynamic color development method; taking a 96-well plate, sequentially adding a negative control solution, a standard curve reliability test solution, a test sample solution and a test sample positive solution, and adding a limulus reagent solution with the same volume at a corresponding hole site; placing the 96-well plate after sample addition in an endotoxin detector for color reaction; the content of the endotoxin in the drug bacteria containing the quinoline ring structure is read by an endotoxin detector.
In a preferred embodiment, in step S2, the solvent is prepared to have a volume fraction of 60 to 70%;
in a preferred embodiment, in step S3, the dissolving condition is heating in water bath at 60-80 ℃ for 2-8min. Below this temperature the drug dissolves slowly, over a prolonged period of time, with the risk of destroying the inactivated endotoxin. The dissolution speed above this temperature cannot be greatly increased, but the energy consumption is increased, so the dissolution temperature is set to 60-80 ℃.
In a preferred embodiment, the specific operation steps of step S5 are: and (3) placing the solvent obtained in the step (S2) in a water bath at the temperature of 60-80 ℃ for 2-8min, standing to room temperature, and diluting by 100-200 times. The purpose of the step is as follows: the negative solution is used as a blank control solution, and the content of endotoxin in the medicine can be detected more truly only if the preparation process of the negative solution is consistent with that of the stock solution of the test sample.
In a preferred embodiment, in step S6, the sensitivity of the limulus reagent by the kinetic color development method is 0.005 to 50EU/ml. The sensitivity of the limulus reagent is commercially available, and can be selected according to the detection drug. More preferably, the limulus reagent sensitivity by the kinetic color method is 0.005EU/ml when detecting the endotoxin of imiquimod.
In a preferred embodiment, in step S6, the color reaction is carried out at 36-38 ℃ for 30-60min. More preferably, in step S6, the color reaction is carried out at 37 ℃ for 45-60min.
In a preferred embodiment, in order to avoid the influence of the external environment on the detection result, before step S1, all used vessels may be pretreated, and the exogenous endotoxin is removed.
In a preferred embodiment, in order to reduce the influence of the operation steps on the detection result, the bacterial endotoxin working standard is reconstituted or diluted in step S1, N-dimethylformamide is diluted in step S2, the solvent obtained in step S2 is diluted in step S5, and the limulus reagent is reconstituted or diluted in the bacterial endotoxin test water in step S6.
Compared with the prior art, the technical scheme of the invention has the following advantages:
the method provided by the invention has the advantages that the specific solvent is selected, the reaction conditions are optimized, so that the medicament containing the quinoline ring structure is fully dissolved, the bacterial endotoxin in the medicament containing the quinoline ring structure which is insoluble in water is completely released, and the content of the bacterial endotoxin can be quantified by a dynamic color development method.
The integral detection method is simple and convenient, has low requirements on reaction conditions and reaction equipment, and effectively solves the problem of insolubility of the medicament containing the quinoline ring structure; the gel method is avoided, so that the problem of false negative of the result of the traditional gel method for taking the supernatant is solved.
Detailed Description
The present invention will be described in further detail below with reference to specific embodiments for better understanding of the present invention by those skilled in the art, but it should be understood that the scope of the present invention is not limited to the specific embodiments.
The embodiment of the invention provides a method for detecting bacterial endotoxin of a medicament containing a quinoline ring structure, which solves the problems of difficult solubility of the medicament containing the quinoline ring structure and false negative of the result of the detection of the medicament by taking supernate as a test solution by a gel method in the prior art.
The apparatus, reagents and methods used in the method of the present invention are described as follows:
1. main instrument
Endotoxin detector, model 357, manufacturer: zhanjiang Andu biology Ltd, clean bench: SW-CJ-IFD type, manufacturer: manufactured by Sujing group Antai corporation, thermal resistance furnace, model SRJX, manufacturer: shanghai Pudong Rongfeng scientific instruments Co.
2. Reagent
Bacterial endotoxin working standard, potency: 10 EU/California, zhanjiang Amidoz Bio Inc.; limulus reagent, specification: 0.005EU/ml, zhanjiang Amidose Bio Inc.; water for bacterial endotoxin test, specification: 50 ml/bottle, zhanjiang Amidos Bio Inc.
The remaining raw materials, reagents, instruments, equipment and the like which are not specifically mentioned are commercially available or can be prepared by existing methods.
The technical scheme of the application is explained in detail by the following specific embodiments:
example 1 detection of the endotoxin content of imiquimod bacteria
(1) Effect of solvent on bacterial endotoxin test:
s1, preparing a standard curve reliability test solution, namely taking a bacterial endotoxin working standard substance, redissolving the bacterial endotoxin working standard substance by using water for checking bacterial endotoxin, oscillating the bacterial endotoxin in a vortex oscillator for 15min, and then preparing the bacterial endotoxin into a standard curve endotoxin solution of 0.005EU/ml, 0.05EU/ml and 0.5 EU/ml.
S2, diluting N, N-dimethylformamide with water for detecting bacterial endotoxin to obtain N, N-dimethylformamide solution with volume fraction of 65% as solvent,
s3, preparing a test solution: putting the solvent obtained in the step S2 for dissolving imiquimod in a water bath at 70 ℃ for 5min until the sample is completely dissolved, and preparing a 1mg/ml stock solution of the test sample; diluting the stock solution of the test sample by 200 times with water for detecting bacterial endotoxin to obtain a test sample solution;
s4, preparing a positive solution of the test sample: diluting the bacterial endotoxin standard solution obtained in the step S1 by using the test solution obtained in the step S3 to prepare a test positive solution containing 0.05EU/ml bacterial endotoxin at the midpoint concentration of a standard curve;
s5, preparing a negative control solution, namely putting the solvent obtained in the step S2 in a water bath at 70 ℃ for 5min, standing to room temperature, and diluting 200 times with bacterial endotoxin detection water to be used as the negative control solution;
s6, detecting bacterial endotoxin by a dynamic colorimetric method: redissolving a limulus reagent (sensitivity of 0.005 EU/ml) by dynamic chromogenic method; taking a 96-well plate, sequentially adding a negative control solution, a standard curve reliability test solution, a test sample solution and a test sample positive solution, and adding a limulus reagent solution with the same volume at a corresponding hole site; placing the 96-well plate after sample application in an endotoxin detector, and performing color reaction for 60min at 37.0 ℃; the content of the endotoxin in the drug bacteria containing the quinoline ring structure is read by an endotoxin detector.
Three parallel experiments were performed, the results of which are shown in table 1:
TABLE 1
As can be seen from Table 1, the correlation coefficients of the three samples, the reaction time of the negative control and the recovery rate all meet the requirements, so the detection values are effective and real.
Comparative example 1
Using the same three batches of imiquimod, the bacterial endotoxin test was carried out using water, the supernatant was taken as a test solution, and the bacterial endotoxin was detected by a gel method using limulus reagent sensitivity of 0.25EU/ML, 0.125EU/ML, 0.06EU/ML, 0.03EU/ML, respectively,
the gel method comprises the following specific steps:
minimum effective concentration
(lambda is limulus reagent sensitivity, L is bacterial endotoxin limit, imiquimod bacterial endotoxin limit is 1.0 EU/mg)
1, preparing a test article: weighing 50mg of imiquimod, adding 50ml of water for detecting bacterial endotoxin, shaking and shaking for 5min, standing, and taking supernatant as a stock solution of the test sample, wherein the concentration of the stock solution of the test sample is 1mg/ml. The test sample stock solutions were diluted to 0.25mg/ml, 0.125mg/ml, 0.06mg/ml, and 0.03mg/ml, respectively, as test sample solutions at different sensitivities.
2, preparing a positive control solution of a bacterial endotoxin working standard: taking a bacterial endotoxin working standard substance, redissolving the bacterial endotoxin working standard substance by using bacterial endotoxin detection water, shaking the bacterial endotoxin working standard substance in a vortex shaker for 15min, and then preparing a standard substance positive control solution of 2 lambda (0.5 EU/ML, 0.25EU/ML, 0.12EU/ML and 0.06 EU/ML) by using the bacterial endotoxin detection water respectively.
3, preparing a positive solution of the test sample: taking a bacterial endotoxin working standard substance, redissolving the bacterial endotoxin working standard substance with water for bacterial endotoxin detection, shaking the bacterial endotoxin working standard substance in a vortex shaker for 15min, and then respectively preparing a test substance positive control solution of 2 lambda (0.5 EU/ML, 0.25EU/ML, 0.12EU/ML and 0.06 EU/ML) by using a test substance solution.
4, negative control solution: water for bacterial endotoxin examination was taken as a negative control.
5, sample adding: taking 8 limulus reagents (0.1 ml), respectively adding 0.1ml of bacterial endotoxin detection water for redissolving, adding 0.1ml of test sample solution diluted according to the maximum effective dilution multiple or the minimum effective dilution concentration into 2 limulus reagents as test sample tubes, adding 0.1ml of bacterial endotoxin detection water into 2 limulus reagents to prepare endotoxin solution with the concentration of 2.0 lambda from bacterial endotoxin working standard products as positive control tubes, adding 0.1ml of bacterial endotoxin detection water into 2 limulus reagents to prepare endotoxin solution with the concentration of 2.0 lambda from the same bacterial endotoxin working standard products as negative control tubes, adding 0.1ml of test sample solution into 2 limulus reagents to prepare endotoxin solution with the concentration of 2.0 lambda as positive control tubes of the test samples, slightly mixing the solution in the test tubes, sealing the tube openings by using a sealing membrane, vertically placing the tubes into a constant-temperature incubator at 37 +/-1 ℃, and preserving the temperature for 60 +/-2 minutes.
6, judging the result: gently taking out the test tube from the thermostat, slowly reversing for 180 degrees, forming gel in the tube, wherein the gel is not deformed and positive if the gel does not slip from the tube wall, and recording (+); negative for no gel formation or for a gel formed that is not firm, deformed and slipped off the vessel wall, record (-). The positive control tube is (+) and the positive tube is (+) and the negative control tube is (-) and the test is effective.
2 test sample tubes are all (-) and the test sample is judged to be in accordance with the regulation; if 2 pieces are (+), judging that the pieces do not accord with the regulation; if 1 of the 2 tubes is (+) and 1 is (-), the test article is retested by 4 parallel tubes according to the method, and if all the parallel tubes are negative, the test article is judged to be in accordance with the specification; otherwise, the test article is judged not to be in accordance with the specification.
The results are shown in table 2:
TABLE 2
As can be seen from Table 2, the results of three batches of samples obtained by taking the supernatant and detecting the supernatant by using the gel method are unstable, the positive control of the test sample is not established, and false negative phenomena exist. Compared with a gel method, the technical scheme of the invention has stable results, solves the problems of the dissolution of imiquimod (neither destroying bacterial endotoxin in a sample nor introducing exogenous endotoxin), and the interference of a test sample on a test, can accurately check the content of the bacterial endotoxin, and overcomes the false negative phenomenon of the gel method.
The foregoing description of specific exemplary embodiments of the invention has been presented for the purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.
Claims (8)
1. A method for detecting bacterial endotoxin of a medicament containing a quinoline ring structure is characterized by comprising the following steps: dissolving a medicament containing a quinoline ring structure by using a solvent to obtain a test sample stock solution so as to release bacterial endotoxin in the medicament; the stock solution is diluted again to reduce the interference of the self property of the drug to the bacterial endotoxin; and finally, detecting bacterial endotoxin by a dynamic colorimetric method.
2. The method for detecting bacterial endotoxin of a drug containing a quinoline ring structure as claimed in claim 1, wherein the solvent is N, N-dimethylformamide having a volume fraction of 60 to 70%.
3. The method for detecting bacterial endotoxin of a drug containing a quinoline ring structure as claimed in claim 1, wherein said drug containing a quinoline ring structure comprises imiquimod.
4. The method for detecting bacterial endotoxin of a drug containing a quinoline ring structure as claimed in claim 1, wherein the concentration of the sample stock solution is 0.1 to 10mg/ml, and the dilution factor of the stock solution is 10 to 1000 times.
5. The method for detecting bacterial endotoxin of any one of claims 1 to 4, which is a drug containing a quinoline ring structure, comprising the steps of:
s1, preparing a standard curve reliability test solution, namely re-dissolving a bacterial endotoxin working standard substance to prepare a bacterial endotoxin standard substance solution of 0.005EU/ml, 0.05EU/ml and 0.5 EU/ml;
s2, diluting N, N-dimethylformamide as a solvent;
s3, preparing a test solution: dissolving the medicament containing the quinoline ring structure by using the solvent obtained in the step S2 to obtain a test sample stock solution with the concentration of 0.1-10mg/ml, and diluting the stock solution to obtain a test sample solution;
s4, preparing a positive solution of the test sample: diluting the bacterial endotoxin standard solution by using the test solution obtained in the step S3 to prepare a test positive solution with the point concentration of 0.05EU/ml bacterial endotoxin in the standard curve;
s5, preparing a negative control solution, namely diluting the solvent obtained in the step S2;
s6, detecting bacterial endotoxin by a dynamic colorimetric method: redissolving a limulus reagent by a dynamic chromogenic method; taking a 96-well plate, sequentially adding a negative control solution, a standard curve reliability test solution, a test sample solution and a test sample positive solution, and adding a limulus reagent solution with the same volume at a corresponding hole site; placing the 96-pore plate after sample addition in an endotoxin detector for color reaction; the content of the endotoxin in the drug bacteria containing the quinoline ring structure is read by an endotoxin detector.
6. The method for detecting bacterial endotoxin of a drug having a quinoline ring structure as claimed in claim 5, wherein the dissolving condition in step S3 is heating in water bath at 60-80 ℃ for 2-8min.
7. The method for detecting bacterial endotoxin of a pharmaceutical bacterium having a quinoline ring structure as claimed in claim 5, wherein the sensitivity of the limulus reagent in the dynamic color development method in step S6 is 0.005 to 50EU/ml.
8. The method for detecting bacterial endotoxin of a drug having a quinoline ring structure as claimed in claim 5, wherein in the step S6, the chromogenic reaction is carried out at 36 to 38 ℃ for 30 to 60min.
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