CN112213438A - Method for testing white oil of inactivated vaccine adjuvant - Google Patents
Method for testing white oil of inactivated vaccine adjuvant Download PDFInfo
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- CN112213438A CN112213438A CN202011082196.5A CN202011082196A CN112213438A CN 112213438 A CN112213438 A CN 112213438A CN 202011082196 A CN202011082196 A CN 202011082196A CN 112213438 A CN112213438 A CN 112213438A
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- 238000000034 method Methods 0.000 title claims abstract description 22
- 239000012646 vaccine adjuvant Substances 0.000 title claims abstract description 12
- 229940031551 inactivated vaccine Drugs 0.000 title abstract description 9
- 238000012360 testing method Methods 0.000 title description 11
- 239000012188 paraffin wax Substances 0.000 claims abstract description 16
- 238000001514 detection method Methods 0.000 claims abstract description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 238000004458 analytical method Methods 0.000 claims abstract description 4
- 238000007405 data analysis Methods 0.000 claims abstract description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 17
- 229960005486 vaccine Drugs 0.000 claims description 14
- 239000002671 adjuvant Substances 0.000 claims description 10
- 238000002347 injection Methods 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- 230000001965 increasing effect Effects 0.000 claims description 6
- 229940124931 vaccine adjuvant Drugs 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- -1 polysiloxane Polymers 0.000 claims description 3
- 229920001296 polysiloxane Polymers 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 2
- 239000003921 oil Substances 0.000 description 62
- 239000000427 antigen Substances 0.000 description 8
- 102000036639 antigens Human genes 0.000 description 8
- 108091007433 antigens Proteins 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000005457 optimization Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000012086 standard solution Substances 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000002979 Influenza in Birds Diseases 0.000 description 1
- 108010008038 Synthetic Vaccines Proteins 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 206010064097 avian influenza Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000000091 immunopotentiator Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 229940023041 peptide vaccine Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940031626 subunit vaccine Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Sampling And Sample Adjustment (AREA)
Abstract
The invention provides a method for inspecting white oil as an inactivated vaccine adjuvant, wherein the standard for determining whether a white oil sample is qualified is that the sum of carbon chain normal paraffins C15-C20 and the value standard is 46.28-58.36%. The detection method provided by the invention is characterized in that a white oil sample to be detected is diluted by using an organic solvent to be used as an oil sample to be detected; and then, the oil sample is put into a gas chromatograph for detection, the results are sorted and analyzed through a data analysis system of the gas chromatograph, the content of the C15-C20 normal paraffin is subjected to sum value analysis, and whether the white oil is in a standard specified range or not is determined. The detection method and the detection standard established by the invention can accurately analyze the intrinsic difference of various manufacturers and white oil types, analyze the peak-out time and content of the C14-C24 n-isoparaffin, have obvious effect on the research of white oil components, and provide a foundation for the detection of the white oil of the inactivated vaccine adjuvant.
Description
Technical Field
The invention belongs to the technical field of vaccine adjuvant detection, and particularly relates to a method for detecting white oil serving as an inactivated vaccine adjuvant.
Background
An oil emulsion adjuvant for animal vaccine is a substance which is used before or together with an antigen, can enhance the nonspecific immunity of the body and the immunogenicity of the antigen, and does not have the characteristics of the antigen. The oil emulsion adjuvant vaccine is a vaccine using mineral oil and an emulsifier as immunopotentiators, and the adjuvant can enable antigens to be continuously and stably released at an injection site, provides a carrier for the transfer of the antigens in a lymphatic system, increases the formation and aggregation of mononuclear cells, improves the immune efficacy of the vaccine, and is one of the most products in the vaccine markets at home and abroad at present. Along with the prevalence of epidemic diseases such as avian influenza and the like in the global scope, the demand for producing inactivated vaccines with good immune effect is increasingly urgent. With the increasing purity of antigens, subunit vaccines, synthetic peptide vaccines and the like are widely applied, and the function of the adjuvant in enhancing the immunogenicity of the antigens is particularly important.
The oil emulsion adjuvant can enable various antigens to generate high-titer antibodies, and is one of the most widely applied adjuvants in animal vaccines. As the main raw material of the oil emulsion adjuvant, the components of the white oil and the emulsion stability thereof have important influence on the activity of the vaccine.
The white oil is hydrocarbon, contains two elements of carbon and hydrogen except for extremely tiny impurities, and the carbon chain of the white oil used in the production of general animal vaccines is maintained at about 19 carbon.
The quality of the white oil has certain influence on the immune effect of the vaccine, and a good white oil not only needs to be inspected for the physicochemical indexes, but also has the intrinsic components which are the most important, so that the development of a method for inspecting the components of the white oil is very important for the application of the white oil in the aspect of the vaccine.
Disclosure of Invention
The invention aims to provide a method for testing white oil of an inactivated vaccine adjuvant, which can effectively test the quality of the white oil for adjuvant injection, thereby making up for the defects of the prior art.
The invention firstly provides a standard for determining the quality of adjuvant white oil for vaccine injection, wherein the standard is that the sum of carbon chain normal alkanes C15-C20 is 46.28-58.36%;
the invention also provides a method for detecting the vaccine adjuvant white oil, which comprises the following steps:
1) diluting a white oil sample to be detected by using an organic solvent to serve as an oil sample to be detected;
the organic solvent is specifically described as n-hexane in one embodiment;
the volume ratio of the n-hexane to the white oil sample to be detected is preferably 100: 1;
2) placing the oil sample obtained in the step 1) into a gas chromatograph for detection, wherein a chromatographic column is a 5% phenyl-methyl polysiloxane capillary column chromatographic column; the chromatographic conditions were as follows: the initial temperature is 50 ℃, the sample injection amount is 0.1 mu l, the temperature is increased to 100 ℃ at the rate of 10 ℃ per minute, and then is increased to 320 ℃ at the rate of 5 ℃ per minute, and the temperature is maintained for 9 minutes; the temperature of a sample inlet is 350 ℃; the temperature of the detector is 350 ℃;
the standards for the columns are as follows: 0.32 mm. times.30 mm, film thickness 0.25 μm;
3) the results are sorted and analyzed by a data analysis system of a gas chromatograph, the peak-out time and the content of the C8-C40 normal isoparaffin are analyzed, the content of the C15-C20 normal paraffin is subjected to sum value analysis, and whether the white oil is in a standard specified range is determined; and if the value standard of the C15-C20 normal paraffin is 46.28-58.36%, the white oil to be detected is qualified white oil.
The detection method and the detection standard established by the invention can accurately analyze the intrinsic difference of various manufacturers and white oil types, analyze the peak-out time and content of the C14-C24 n-isoparaffin, have obvious effect on the research of white oil components, and provide a foundation for the detection of the white oil of the inactivated vaccine adjuvant.
Drawings
FIG. 1: data graphs of the peak-out time and the content of 23 normal paraffin mixed standard C8-C40;
FIG. 2: marcol52 (VG6100923P) chromatogram and data map;
FIG. 3: a white oil 1# chromatogram and a data chart;
FIG. 4: a white oil 2# chromatogram and a data map;
FIG. 5: white oil # 3 chromatogram and data sheet.
Detailed Description
The apparatus, reagents and methods used in the method of the invention are first explained as follows:
1. main instrument
Gas chromatograph (GC7890B, Agilent, USA)
2. Reagent
N-hexane: chromatographic grade, SIGMA company; 23 normal paraffins, C8-C40, available from Shanghai' an spectral company.
The procedures and physical and chemical properties of the white oil testing method of the present invention will be described in detail with reference to the following examples.
Example 1: establishing a detection method
1) Preparation of Standard solutions
Accurately transferring 10ul of 23 normal paraffin mixed standard C8-C40 standard products (table 1), and metering the volume to 1ml by using normal hexane to obtain 23 normal paraffin mixed standard C8-C40 standard stock solutions with the concentration of 10 mu g/ml.
Table 1: name and content table of 23 normal paraffin mixed standard C8-C40
2) Sample preparation
10 mul of sample was accurately transferred and the volume was made up to 1ml with n-hexane, 10 mug/ml.
3) Measurement of
An accurate detection method is established by optimizing chromatographic conditions, a temperature rise program and detecting a standard substance.
The specific optimization process is as follows:
optimization of chromatography columns
The best performing quartz capillary column was chosen as the column for the (5% phenyl) -methyl polysiloxane capillary column (0.32mm x 30mm, film thickness 0.25 μm).
Column temperature optimization
Too high column temperature will cause the peak broadening to be increased, while too low column temperature will cause the system pressure to be too high, and the initial temperature is selected to be 50 ℃ and the sample amount is 0.1 mul through the selection of different column temperatures and the test. Heating to 100 deg.C at a rate of 10 deg.C per minute, heating to 320 deg.C at a rate of 5 deg.C per minute, and maintaining for 9 min; the temperature of a sample inlet is 350 ℃; the detector temperature was 350 ℃.
Extraction solvent optimization
The extraction solvent is tested, different solvents are considered, and the test compares solvents with better solubility, such as petroleum ether, normal hexane, methanol and the like. The experimental results show that: the n-hexane has low toxicity, lower polarity than petroleum ether and high recovery rate, and is used as an effective solvent for extracting white oil.
3) And (3) confirmation: according to the optimized conditions, 23 normal paraffin mixed standard samples are analyzed, and the peak-out time and the content of the obtained standard product are shown in figure 1.
As can be seen from FIG. 1, the retention time intervals of the n-alkanes analyzed by the method are all about 1-2 minutes, the peak heights are above 200pa, and the peak emergence time and the content of the n-alkanes can be accurately identified. The method has the advantages of high sensitivity, low detection limit, high stability and high identifiability, and can accurately perform qualitative and quantitative analysis on the normal paraffin in the white oil.
Example 2: determination of a test standard
1) Preparation of Standard solutions
Accurately transferring 10ul of 23 normal paraffin mixed standard C8-C40 standard products, and metering the volume to 1ml by using normal hexane to obtain 23 normal paraffin mixed standard C8-C40 standard stock solutions with the concentration of 10 mu g/ml.
2) Sample preparation
Accurately transferring 10ul of a known Marcol52 white oil sample, and fixing the volume to 1ml by using normal hexane, wherein the concentration is 10 mu g/ml.
3) Measurement of
The Marcol52 white oil was tested by the optimized chromatographic conditions and the data are shown in Table 2 and FIG. 2.
Table 2: marcol52 (VG6100923P) chromatography data sheet
4) Standards were established for data accumulation on a known qualified Marcol52 white oil, with results as shown in table 3.
Table 3: known qualified Marcol52 white oil data accumulation table
Since the white oil normal paraffin chains mainly determine the safety problem of vaccines, and the C15-C20 chains have correlation on the efficacy and safety of the vaccines, the sum of the values of the normal paraffins C15-C20 is summarized, and the white oil carbon chain normal paraffins C15-C20 for injection are formulated according to the formula AVERAGE +/-2 STDEV, and the standard of the value is 46.28-58.36%.
Example 3: determination of unknown liquid samples
1) Preparation of Standard solutions
Accurately transferring 10 mu l of 23 normal paraffin mixed standard C8-C40 standard substances, and metering the volume to 1ml by using normal hexane to obtain 23 normal paraffin mixed standard C8-C40 standard stock solutions with the concentration of 10 mu g/ml.
2) Sample preparation
Accurately transferring 10 mul of white oil sample to be detected, wherein the white oil type comprises white oil No. 1, and the white oil No. 2 and white oil No. 3 are constant volume to 1ml by normal hexane, and the concentration is 10 mug/ml.
3) Measurement of
The white oil of each manufacturer was tested according to the chromatographic conditions established in the examples, the normal paraffins C14-C20 were calibrated according to the standard peak time, and the test data determined by the method for testing the carbon chain component content of the white oil are shown in the following tables 4-6 and FIGS. 3-5. .
Table 4: white oil 1# chromatogram data sheet
Table 5: white oil 2# chromatogram data sheet
TABLE 6 white oil 3# chromatogram data sheet
The testing method can accurately analyze the peak-out time and the content of the normal isoparaffin and accurately analyze each normal isoparaffin by utilizing white oil of different manufacturers and models, and has sufficient quantitative analysis on the internal components of the white oil.
The results show that the white oil 1# n-alkane has the sum of C15-C20 of 49.11 percent and meets the sum of the n-alkane of C15-C20 standard of 46.28-58.36 percent, and the white oil 2# and 3# are regarded as qualified white oil, while the white oil is regarded as unqualified white oil because the sum of the n-alkane of C15-C20 is not in the standard range.
According to the method, a specific temperature rise program is used for sampling, mixing and sampling through a gas chromatograph, and a data analysis system, the internal differences and the disordered internal components of the white oil of various manufacturers and types of the white oil can be analyzed remarkably, the spectrum can preliminarily show the differences of the types of the white oil and the peak concentration of the manufacturers, the peak output time and the content of the n-isoparaffin can be analyzed accurately, the same type of the white oil has inspection stability, the white oil component is researched and has remarkable effect, and the method is simple, high in sensitivity, high in stability and high in accuracy, and is suitable for the actual inspection and analysis of the inactivated vaccine adjuvant white oil.
Claims (7)
1. The standard for determining the quality of the adjuvant white oil for vaccine injection is characterized in that the standard is carbon chain n-alkanes C15-C20 and the value of 46.28-58.36% of qualified white oil.
2. Use of the criteria of claim 1 for determining the quality of white oil.
3. A method for detecting vaccine adjuvant white oil, which is characterized in that whether a white oil sample meets the use requirements of a vaccine adjuvant is judged according to the standard of claim 1.
4. A method as claimed in claim 3, characterized in that the method comprises the following steps:
1) diluting a white oil sample to be detected by using an organic solvent to serve as an oil sample to be detected;
2) placing the oil sample obtained in the step 1) into a gas chromatograph for detection, wherein a chromatographic column is a 5% phenyl-methyl polysiloxane capillary column chromatographic column; the chromatographic conditions were as follows: the initial temperature is 50 ℃, the sample injection amount is 0.1 mu l, the temperature is increased to 100 ℃ at the rate of 10 ℃ per minute, and then is increased to 320 ℃ at the rate of 5 ℃ per minute, and the temperature is maintained for 9 minutes; the temperature of a sample inlet is 350 ℃; the temperature of the detector is 350 ℃;
3) the results are sorted and analyzed by a data analysis system of a gas chromatograph, the peak-out time and the content of the C8-C40 normal isoparaffin are analyzed, the content of the C15-C20 normal paraffin is subjected to sum value analysis, and whether the white oil is in a standard specified range is determined; and if the value standard of the C15-C20 normal paraffin is 46.28-58.36%, the white oil to be detected is qualified white oil.
5. The method according to claim 4, wherein the organic solvent in 1) is n-hexane.
6. The method according to claim 4, wherein the volume ratio of the organic solvent in 1) to the white oil sample to be detected is 100: 1.
7. The method of claim 4, wherein the standard of the chromatography column in 2) is as follows: 0.32 mm. times.30 mm, film thickness 0.25. mu.m.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09268130A (en) * | 1995-11-30 | 1997-10-14 | Chemo Sero Therapeut Res Inst | Oil adjuvant vaccine and its preparation |
| US20090291103A1 (en) * | 2006-11-08 | 2009-11-26 | Novartis Ag | Quality control methods for oil-in-water emulsions containing squalene |
| CN105396132A (en) * | 2015-12-29 | 2016-03-16 | 天津佐沐生物科技有限公司 | White oil which is special for animal vaccine adjuvant and capable of reducing side reaction of inactivated vaccine |
| CN105497892A (en) * | 2015-12-29 | 2016-04-20 | 天津佐沐生物科技有限公司 | Low-pour-point white oil special for inactivated vaccine adjuvant |
| WO2020169903A1 (en) * | 2019-02-18 | 2020-08-27 | Total Marketing Services | Adjuvant composition for a vaccine |
-
2020
- 2020-10-12 CN CN202011082196.5A patent/CN112213438A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09268130A (en) * | 1995-11-30 | 1997-10-14 | Chemo Sero Therapeut Res Inst | Oil adjuvant vaccine and its preparation |
| US20090291103A1 (en) * | 2006-11-08 | 2009-11-26 | Novartis Ag | Quality control methods for oil-in-water emulsions containing squalene |
| CN105396132A (en) * | 2015-12-29 | 2016-03-16 | 天津佐沐生物科技有限公司 | White oil which is special for animal vaccine adjuvant and capable of reducing side reaction of inactivated vaccine |
| CN105497892A (en) * | 2015-12-29 | 2016-04-20 | 天津佐沐生物科技有限公司 | Low-pour-point white oil special for inactivated vaccine adjuvant |
| WO2020169903A1 (en) * | 2019-02-18 | 2020-08-27 | Total Marketing Services | Adjuvant composition for a vaccine |
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Application publication date: 20210112 |