CN110964776A - Analysis method for content of microorganisms in pemetrexed disodium raw material medicine - Google Patents
Analysis method for content of microorganisms in pemetrexed disodium raw material medicine Download PDFInfo
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- CN110964776A CN110964776A CN201911347624.XA CN201911347624A CN110964776A CN 110964776 A CN110964776 A CN 110964776A CN 201911347624 A CN201911347624 A CN 201911347624A CN 110964776 A CN110964776 A CN 110964776A
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
- C12Q1/04—Determining presence or kind of microorganism; Use of selective media for testing antibiotics or bacteriocides; Compositions containing a chemical indicator therefor
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/195—Assays involving biological materials from specific organisms or of a specific nature from bacteria
- G01N2333/21—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Pseudomonadaceae (F)
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/195—Assays involving biological materials from specific organisms or of a specific nature from bacteria
- G01N2333/305—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Micrococcaceae (F)
- G01N2333/31—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Micrococcaceae (F) from Staphylococcus (G)
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- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/195—Assays involving biological materials from specific organisms or of a specific nature from bacteria
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/37—Assays involving biological materials from specific organisms or of a specific nature from fungi
- G01N2333/38—Assays involving biological materials from specific organisms or of a specific nature from fungi from Aspergillus
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/37—Assays involving biological materials from specific organisms or of a specific nature from fungi
- G01N2333/39—Assays involving biological materials from specific organisms or of a specific nature from fungi from yeasts
- G01N2333/40—Assays involving biological materials from specific organisms or of a specific nature from fungi from yeasts from Candida
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Abstract
The invention provides an analysis method of the content of microorganisms in a pemetrexed disodium raw material medicine, which comprises the steps of utilizing membrane filtration, microorganism culture and counting to obtain the content of the microorganisms in the pemetrexed disodium raw material medicine. The analysis method provided by the invention can realize the analysis of the content of microorganisms in the pemetrexed disodium raw material medicine, and has higher accuracy and precision.
Description
Technical Field
The invention belongs to the technical field of analysis, and relates to a method for analyzing the content of microorganisms in a pemetrexed disodium raw material medicine.
Background
Pemetrexed disodium is an active ingredient contained in a special drug (pharmaceutical specificity) alimata, a novel folic acid-based antitumor compound, widely used for the treatment of non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma, and is under investigation for the treatment of other tumor pathologies. The Alimta mainly acts on a DNA base synthetase system, blocks the DNA synthesis of tumor cells by preparing a plurality of DNA base synthetases so as to achieve the aim of inhibiting and eliminating the tumor cells, effectively solves the problem that the anti-tumor drugs of tumors generate drug resistance in clinical treatment, and is a representative novel drug in the research of the current anti-tumor drugs. Pemetrexed disodium belongs to the group of multi-targeted antifolates, i.e. those antineoplastic active ingredients that act at the level of some folate-dependent enzyme systems involved in the biosynthesis of purines and pyrimidines, which are the starting points for the biosynthesis of DNA and RNA.
CN104119346A discloses a preparation method of pemetrexed disodium, which does not need to form a salt with p-toluenesulfonic acid and/or purify a product by adopting a crystallization method in the preparation process, but directly hydrolyzes the product to form a salt after removing an organic solvent, thereby omitting the step of forming a salt with p-toluenesulfonic acid and/or crystallizing by adopting ethanol in the prior art; in the preparation process, the peptide condensing agent is prepared, so that the peptide condensing agent and the pemetrexed acid fully react in an organic solvent to form a transition acid ester, and then the pemetrexed disodium is prepared.
At present, although the preparation method of pemetrexed disodium is increasingly improved, the pemetrexed disodium serving as a raw material medicine of an anti-tumor preparation medicine needs to effectively control the number (load) of microorganisms in the pemetrexed disodium raw material medicine in order to ensure the sterility of the preparation, so that the product quality of a subsequently produced preparation can be more effectively controlled; however, no better analysis method exists at present.
Therefore, a method for analyzing the content of microorganisms in the pemetrexed disodium raw material drug is needed to realize the quality control of the subsequently produced preparation product.
Disclosure of Invention
The invention aims to provide an analysis method for the content of microorganisms in a pemetrexed disodium raw material medicine. The analysis method provided by the invention can realize the analysis of the content of microorganisms in the pemetrexed disodium raw material medicine, and has higher accuracy and precision.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides an analysis method for the content of microorganisms in a pemetrexed disodium raw material drug, wherein the analysis method comprises the steps of membrane filtration, microorganism culture and counting to obtain the content of the microorganisms in the pemetrexed disodium raw material drug.
According to the invention, by utilizing membrane filtration, if microorganisms exist in the pemetrexed disodium raw material drug, the microorganisms can remain on the membrane, then the microorganisms are cultured and counted, and the content of the microorganisms in the pemetrexed disodium raw material drug can be obtained through certain calculation.
The pemetrexed disodium raw material medicine refers to pemetrexed disodium, and when the pemetrexed disodium raw material medicine is applied, the pemetrexed disodium raw material medicine is used as a raw material of an anti-tumor preparation medicine, and certain impurities are inevitably contained in the pemetrexed disodium raw material medicine, so that the pemetrexed disodium raw material medicine is distinguished from a specific impurity-free substance, namely the pemetrexed disodium raw material medicine.
In the present invention, the microorganism includes any one of aerobic bacteria, mold or yeast or a combination of at least two thereof.
Preferably, the aerobic bacteria comprise any one of pseudomonas aeruginosa, staphylococcus aureus, bacillus subtilis, candida albicans or aspergillus brasiliensis or a combination of at least two of the same.
The content of certain bacteria can be analyzed, for example, the content of pseudomonas aeruginosa, staphylococcus aureus and the like can be analyzed, and the total content of certain bacteria such as aerobic bacteria and the like can be analyzed.
The specific implementation mode is as follows, and the analysis method comprises the following steps:
(1) dissolving pemetrexed disodium raw material medicine in a buffer solution to obtain a test solution;
(2) filtering the test solution by using a film;
(3) and (3) attaching the filtered filter membrane to a culture medium for culture, and then counting and calculating to obtain the microbial content in the pemetrexed disodium raw material medicine.
Dissolving the raw materials in a buffer solution, filtering, remaining microorganisms contained in the raw materials on a film, culturing, growing the microorganisms, counting by the method, and calculating to obtain the content of the microorganisms in the raw materials.
In the present invention, the buffer in step (1) is a sterile sodium chloride peptone buffer at pH 7.0.
Preferably, in the test solution, the concentration of the pemetrexed disodium drug substance is 0.01-0.1g/mL, such as 0.02g/mL, 0.03g/mL, 0.04g/mL, 0.05g/mL, 0.06g/mL, 0.07g/mL, 0.08g/mL, 0.09g/mL, and the like, more preferably 0.05-0.1g/mL, still more preferably 0.06-0.1 g/mL.
When the concentration of the raw material medicine is in the range of 0.01-0.1g/mL, the analysis of the content of microorganisms in the raw material medicine can be realized, most preferably 0.06-0.1g/mL, in the concentration range, the analysis data of the content of the raw material medicine is most accurate, if the concentration is too high, the raw material medicine can be separated out due to supersaturation, the analysis of a result is influenced, and if the concentration of the raw material medicine is too low, the sampling amount is lower in the subsequent sampling and filtering process, so that a larger error is caused.
Preferably, the pore diameter of the membrane in the step (2) is 0.45 μm.
Preferably, in step (2), 1mL of the sample solution is filtered through a membrane.
Preferably, the filtration surface of the filter membrane of step (3) is remote from the culture medium.
In the invention, the bacteria face is required to face the air, and then different bacteria are cultured by utilizing the culture medium.
Preferably, the medium is selected from trypticase soy agar medium or Sabouraud dextrose agar medium.
Preferably, the microorganism is an aerobic bacterium and the medium is trypticase soy peptone agar medium.
Preferably, the microorganism is an aerobic bacterium, and the temperature of the culture is 30-35 ℃, such as 31 ℃, 32 ℃, 33 ℃, 34 ℃ and the like, for 5-6 days, such as 5.5 days.
Preferably, the microorganism is a mold and/or a yeast, and the culture medium is a Sasa glucose agar culture medium.
Preferably, the microorganism is a mold and/or yeast, and the culturing is carried out at a temperature of 20-25 deg.C, such as 21 deg.C, 22 deg.C, 23 deg.C, 24 deg.C, etc., for a period of 7-8 days, such as 7.5 days.
Preferably, the content of microorganisms in the pemetrexed disodium bulk drug is K times of the counting result obtained in the step (3); wherein the K value is the volume ratio of the buffer solution to the filtered test solution.
In order to ensure the accuracy of the analysis result, preferably, for the analysis method of the content of the microorganisms in the pemetrexed disodium drug substance, two parallel tests are carried out, and the average value of the results of the two parallel tests is the content of the microorganisms.
Compared with the prior art, the invention has the following beneficial effects:
(1) according to the invention, by utilizing membrane filtration, if the pemetrexed disodium raw material drug contains microorganisms, the microorganisms can remain on the membrane, then the microorganisms are cultured and counted, and the content of the microorganisms in the pemetrexed disodium raw material drug can be obtained through certain calculation;
(2) the analysis method provided by the invention is simple and accurate, and has higher accuracy and precision.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Example 1
A method for analyzing the content of microorganisms in a pemetrexed disodium raw material medicine, wherein the microorganisms to be analyzed are aerobic bacteria, and the method comprises the following steps:
(1) weighing 10.0g of pemetrexed disodium as a raw material drug, and placing the pemetrexed disodium in 200mL of sterile NaCI peptone buffer solution with the pH value of 7.0 to prepare a test solution with the ratio of 1: 20;
(2) and (3) filtering 1mL of test solution by using a film, sticking the filtered bacteria surface of the filter film to a trypticase soy agar culture medium in the air direction, culturing for 5 days at the temperature of 30 ℃, counting, and multiplying by 200 to obtain the content of aerobic bacteria in the pemetrexed disodium raw material medicine.
(3) Repeating the step (2) once, and then taking the average value of the two calculated results.
Example 2
A method for analyzing the content of microorganisms in a pemetrexed disodium raw material medicine, wherein the microorganisms to be analyzed are moulds, and the method comprises the following steps:
(1) weighing 10.0g of pemetrexed disodium as a raw material drug, and placing the pemetrexed disodium in 200mL of sterile NaCI peptone buffer solution with the pH value of 7.0 to prepare a test solution with the ratio of 1: 20;
(2) and (3) filtering 1mL of test solution by using a film, sticking the filtered filter membrane fungus surface to a Sabouraud glucose agar culture medium in the air direction, culturing for 7 days at the temperature of 20 ℃, counting, and multiplying by 200 to obtain the content of the fungus in the pemetrexed disodium raw material medicine.
(3) Repeating the step (2) once, and then taking the average value of the two calculated results.
Example 3
A method for analyzing the content of microorganisms in a pemetrexed disodium raw material medicine is disclosed, wherein the microorganisms to be analyzed are yeasts, and the method comprises the following steps:
(1) weighing 10.0g of pemetrexed disodium as a raw material drug, and placing the pemetrexed disodium in 200mL of sterile NaCI peptone buffer solution with the pH value of 7.0 to prepare a test solution with the ratio of 1:20, wherein the concentration of the test solution is 0.05 g/mL;
(2) and (3) filtering 1mL of test solution by using a film, sticking the filtered filter membrane bacteria face to the air direction to a Sabouraud's dextrose agar culture medium, culturing for 7 days at the temperature of 20 ℃, counting, and multiplying by 200 to obtain the content of the microzyme in the pemetrexed disodium raw material medicine.
(3) Repeating the step (2) once, and then taking the average value of the two calculated results.
Examples 4 to 7
The differences from example 1 are that the concentrations of the test solutions were 0.06g/mL (example 4), 0.08g/mL (example 5), 0.04g/mL (example 6), and 0.1 (example 7).
Comparative example 1
The test solution prepared in example 1 was tested by the direct pour-on dish method, as follows:
1.0ml of a 1:20 sample solution was put into a 90mm sterile empty plate, 4 portions in total were prepared, and TSA and SDA media were poured, and TSA was cultured at 30 ℃ for 5 days and SDA was cultured at 20 days.
Due to the growth characteristics of the bacteria, the growth forms of the bacteria are irregular and uneven, the bacteria are not clear during counting, and the influence of other impurities on the inhibition effect of the bacteria cannot be eliminated.
The film filtering method of the invention can ensure that the growth forms of the bacteria on the film are relatively neat and uniform, the counting is clearer, and the influence of other impurities on the inhibition of the bacteria can be eliminated.
Performance testing
The analytical methods provided in examples 1 to 7 and comparative example 1 were examined as follows:
(1) and (3) recovery rate:
(A) experimental group
The test solution prepared in example 1 was added with 80cfu of test bacteria (staphylococcus aureus, bacillus subtilis, pseudomonas aeruginosa, candida albicans, and aspergillus brasiliensis, respectively), and then the microbial content was counted according to the method provided in example 1;
(B) control group
The difference from the experimental group is that the control group is free of test bacteria.
(C) Bacterial liquid set
The difference from the experimental group is that the test solution prepared in example 1 was replaced with sterile sodium chloride peptone buffer at pH 7.0.
Wherein the recovery rate is (A)1-A2)/A0×100％；
Wherein A is1Mean colony number for experimental group; a. the2Average number of colonies for control group, A0The average colony number of the bacterial liquid group is shown.
The total recovery rates of the aerobic bacteria are respectively 0.73 (pseudomonas aeruginosa), 0.83 (staphylococcus aureus), 0.76 (bacillus subtilis), 0.82 (candida albicans) and 0.87 (aspergillus brazilian); the total recovery rates of the mold and the yeast are 0.86 (Candida albicans) and 0.91 (Aspergillus brazilian), respectively;
the recovery rate is in the range of 0.5-2, and meets the acceptable standard of the scheme, so that the analysis method provided by the invention can successfully analyze and identify the content of microorganisms in the pemetrexed disodium raw material medicine.
The applicant states that the present invention is illustrated by the above examples to describe the method of analysis of the microbial content of the pemetrexed disodium drug substance of the present invention, but the present invention is not limited to the above detailed method, i.e. it does not mean that the present invention must rely on the above detailed method to be practiced. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. The analysis method for the content of the microorganisms in the pemetrexed disodium raw material medicine is characterized by comprising the steps of membrane filtration, microorganism culture and counting to obtain the content of the microorganisms in the pemetrexed disodium raw material medicine.
2. The assay of claim 1, wherein the microorganism comprises any one or a combination of at least two of an aerobic bacterium, a mold, or a yeast;
preferably, the aerobic bacteria comprise any one of pseudomonas aeruginosa, staphylococcus aureus, bacillus subtilis, candida albicans or aspergillus brasiliensis or a combination of at least two of the same.
3. The analytical method according to claim 1 or 2, characterized in that it comprises the following steps:
(1) dissolving pemetrexed disodium raw material medicine in a buffer solution to obtain a test solution;
(2) filtering the test solution by using a film;
(3) and (3) attaching the filtered filter membrane to a culture medium for culture, and then counting and calculating to obtain the microbial content in the pemetrexed disodium raw material medicine.
4. The assay method according to claim 3, wherein the buffer in step (1) is a sterile sodium chloride peptone buffer at pH 7.0;
preferably, in the test solution, the concentration of the pemetrexed disodium raw material drug is 0.04-0.1g/mL, more preferably 0.05-0.08g/mL, and still more preferably 0.05-0.06 g/mL.
5. The analytical method according to claim 3 or 4, wherein the pore size of the membrane of step (2) is 0.45 μm;
preferably, in step (2), 1mL of the sample solution is filtered through a membrane.
6. The assay of any one of claims 3-5, wherein the filtration surface of the filter of step (3) is distal to the culture medium;
preferably, the medium is selected from trypticase soy agar medium or Sabouraud dextrose agar medium.
7. The assay of claim 6, wherein the microorganism is an aerobic bacterium and the medium is trypticase Soy agar;
preferably, the microorganism is an aerobic bacterium, and the temperature of the culture is 30 to 35 ℃ for 5 to 6 days.
8. The assay of claim 6, wherein the microorganism is a mold and/or yeast, and the culture medium is a Sabouraud dextrose agar medium;
preferably, the microorganism is mould and/or yeast, and the culture temperature is 20-25 deg.C and the culture time is 7-8 days.
9. The assay of any one of claims 3-8, wherein the content of microorganisms in the pemetrexed disodium drug substance is K times the count obtained in step (3);
wherein the K value is the volume ratio of the buffer solution to the filtered test solution.
10. The assay of any one of claims 3-9, wherein for the assay of the microbial content of the pemetrexed disodium drug substance, two parallel tests are performed, the average of the results of the two parallel tests being the microbial content.
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| CN110093397A (en) * | 2019-06-10 | 2019-08-06 | 甘肃省药品检验研究院 | A kind of microbial limit method applicability inspection method, system and equipment |
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| CN110093397A (en) * | 2019-06-10 | 2019-08-06 | 甘肃省药品检验研究院 | A kind of microbial limit method applicability inspection method, system and equipment |
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| Title |
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| 国家药典委员会: "《中华人民共和国药典 2015年版 四部》", 30 June 2015, 中国医药科技出版社 * |
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