CN1320924C - Self-emulsifying vaccine adjuvant and preparation thereof - Google Patents
Self-emulsifying vaccine adjuvant and preparation thereof Download PDFInfo
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- CN1320924C CN1320924C CNB2005100376398A CN200510037639A CN1320924C CN 1320924 C CN1320924 C CN 1320924C CN B2005100376398 A CNB2005100376398 A CN B2005100376398A CN 200510037639 A CN200510037639 A CN 200510037639A CN 1320924 C CN1320924 C CN 1320924C
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- 229940124931 vaccine adjuvant Drugs 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 239000002671 adjuvant Substances 0.000 claims abstract description 39
- 239000004094 surface-active agent Substances 0.000 claims abstract description 17
- 239000003921 oil Substances 0.000 claims description 27
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- -1 polyoxyethylene Polymers 0.000 claims description 16
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- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 11
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 11
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- 239000007957 coemulsifier Substances 0.000 claims description 11
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 11
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- 230000001804 emulsifying effect Effects 0.000 claims description 9
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 claims description 4
- 125000005456 glyceride group Chemical group 0.000 claims description 4
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- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical class CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 claims description 3
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 claims description 3
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 claims description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 2
- HVUMOYIDDBPOLL-UHFFFAOYSA-N 2-(3,4-Dihydroxyoxolan-2-yl)-2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)C1OCC(O)C1O HVUMOYIDDBPOLL-UHFFFAOYSA-N 0.000 claims description 2
- IJCWFDPJFXGQBN-UHFFFAOYSA-N 2-[4-Hydroxy-3-(octadecanoyloxy)oxolan-2-yl]-2-(octadecanoyloxy)ethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)C1OCC(O)C1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-UHFFFAOYSA-N 0.000 claims description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 2
- 229920001219 Polysorbate 40 Polymers 0.000 claims description 2
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 2
- 229920002651 Polysorbate 85 Polymers 0.000 claims description 2
- 229960002903 benzyl benzoate Drugs 0.000 claims description 2
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 claims description 2
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 2
- 229940093471 ethyl oleate Drugs 0.000 claims description 2
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 2
- 239000002480 mineral oil Substances 0.000 claims description 2
- 235000010446 mineral oil Nutrition 0.000 claims description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 2
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- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 claims description 2
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 claims description 2
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims description 2
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Abstract
The present invention relates to a field of a vaccine adjuvant, more specifically a novel self-emulsifying vaccine adjuvant and a preparation method thereof. The adjuvant of the present invention is composed of 15 to 98% of oil phase, 1 to 30% of hydrophilicity surface active agent, 1 to 30% of lipophilicity surface active agent and 0 to 20% of assisted emulsifying agent. Compared with a similar adjuvant supplied in the market at present, the vaccine adjuvant of the present invention not only has the same self-emulsifying effect as the similar adjuvant but also has the advantages of better stability and lower cost.
Description
Technical field
The present invention relates to the vaccine adjuvant field, be specifically related to vaccine adjuvant of a kind of new self emulsifying and preparation method thereof.
Background technology
Though antigenic specificity and hypotoxicity that highly purified new generation vaccine tool is good, immunogenicity is low, and need cooperating efficiently, adjuvant uses.Adjuvant is prior to antigen or is injected in simultaneously in the animal body, can change non-specificly or enhancing body to the material of antigenic specific immune response, also claim immunostimulant.
Because it is complicated that vaccine development becomes day by day, equally adjuvant also had higher requirement; Biological example chemistry expert finds: (effectively antigen typically refers to the ingredient of those energy immune response stimulatings in antibacterial or the virus earlier the effective antigen in the vaccine to be carried out purification, also claim main immunizing antigen), antigen behind the purification can improve immune effect, reduce or avoid part side effect (untoward reaction), this vaccine is called subunit vaccine.But, these less relatively less immunizing antigens will come enhance immunity reaction relying on vaccine adjuvant to a greater extent; Improvement innovation on other manufacturing technologies, as delay the antigen rate of release, can prolong the immune effect duration of vaccine, these all are the result who improves vaccine adjuvant usually.So research and develop new adjuvant technology, stimulate the immunity that produces and make vaccine (human and for animals) more effective safer thereby improve vaccine antigen, this is the major fields that global each big vaccine manufacturer researches and develops.
Oil emulsion vaccine is one of type that product is maximum on the at present domestic and international vaccine market, and oil emulsion vaccine has three types: 1) Water-In-Oil (W/O) type.This dosage form is used the most general, and remarkable advantage is to obtain high-level persistent immunoenhancement result.Shortcoming is than thickness, and injection is difficulty.2) oil-in-water (O/W) type.Set up this method for reducing in the Emulsion oil content, but widespread usage not.This dosage form advantage is that viscosity is low, is easy to injection, and shortcoming is a little less than the immunogenicity, only produces more weak immunne response in the induced animal body.3) W/O/W (W/O/W) type.The w/o type vaccine is prepared through being distributed to for the second time aqueous phase.Purpose is to reduce viscosity, not only has been convenient to inject but also have good immunogenicity, and this dosage form is with the advantage of w/o type and O/W type, and effect is fine.But difficulty is bigger on the technology of preparing, and vaccine stability is poor, if can overcome this shortcoming, and it is optimal emulsion vaccine.
The best import vaccine adjuvant commodity of generally acknowledging by name 206 (are called in the following text: the import adjuvant) prepared W/O/W type emulsion vaccine by the self emulsifying technology both at home and abroad, solved the difficult problem of W/O/W type emulsion vaccine preparation, and have certain stability, obtained extensive use in the world.Its weak point is that prepared W/O/W type emulsion vaccine stability is also not too satisfactory.Therefore, prepare stable W/O/W type Emulsion by the self emulsifying technology and have extremely important realistic meaning and market value.
The present invention also by the self emulsifying technological development a kind of new self-emulsifying vaccine adjuvant, solve W/O/W type emulsion vaccine and prepared problem of difficult, prepared emulsion vaccine not only is convenient to inject but also have good immunogenicity, and the stable W/O/W type emulsion vaccine more prepared than import adjuvant is better.
Summary of the invention
The invention discloses a kind of new self-emulsifying vaccine adjuvant and preparation method thereof, solved W/O/W type emulsion vaccine by the self emulsifying technology and prepared problem of difficult, the prepared W/O/W type emulsion vaccine stability W/O/W type emulsion vaccine more prepared than existing adjuvant is better.
Self-emulsifying vaccine adjuvant of the present invention, form by following component and percentage by weight:
Oil phase 15-98%
Hydrophilic surfactant active 1-30%
Lipophilic surfactant 1-30%
Co-emulsifier 0-20%
Each weight percentages of components is all in the adjuvant gross weight.
Preferred ingredients and percentage by weight are formed:
Oil phase 35-85%
Hydrophilic surfactant active 6-25%
Lipophilic surfactant 6-25%
Co-emulsifier 3-15%
Each weight percentages of components is all in the adjuvant gross weight.
Aforesaid vaccine adjuvant, wherein oil phase is one or more in mineral oil, vegetable oil, benzyl benzoate, the ethyl oleate etc.
Aforesaid vaccine adjuvant, wherein the hydrophilic surfactant active is HLB value one or more in the surfactant more than 8, as polyoxyethylene nonyl 2, 2-Oxydiphenol (polyoxyethylene nonylphenol ether), polyoxyethylene aliphatic alcohol ether (milky white clever A), sad certain herbaceous plants with big flowers acid polyethylene glycol glyceride (Labrasol), polysorbas20, polysorbate40, polysorbate60, Tween 80, sorbimacrogol oleate100, polysorbate85, polyoxyethylene hydrogenated Oleum Ricini, pluronic F-68, polyoxyethylene lauryl alcohol alcohol ether etc.
Aforesaid vaccine adjuvant, wherein lipophilic surfactant is one or more in the surfactant of HLB value between 3-8, as lecithin, fabaceous lecithin, sorbester p37, span 83, sorbester p17, sorbester p38, sorbester p18, glyceryl monostearate, glyceryl monooleate, the single oleic acid sorbitol ester etc. that contracts.
Aforesaid vaccine adjuvant, wherein co-emulsifier is selected from one or more in Macrogol 200, Liquid Macrogol, PEG400, ethanol, propylene glycol, oleic acid, 18-amine., the octadecanol etc.
The inventor finds that after test of many times preferred component of vaccine adjuvant and weight consist of:
White oil 60-73%
Sad certain herbaceous plants with big flowers acid polyethylene glycol glyceride and/or tween 5-12%
Single oleic acid contract sorbitol ester and/or span 10-20%
Oleic acid 3-9%
Each weight percentages of components is all in the adjuvant gross weight.Under this component and percentage by weight, the stability of vaccine adjuvant is better.
The preparation method of vaccine adjuvant of the present invention: take by weighing recipe quantity emulsifying agent, co-emulsifier and oil phase mix homogeneously, obtain adjuvant.
Vaccine adjuvant of the present invention is compared with the similar adjuvant of supply in the market, has not only had the self emulsifying effect same with it, and stability is better, and primary raw material is homemade, and it is nearly 40% that cost has reduced, and has economic worth and market potential.
Prepare oil emulsion vaccine with vaccine adjuvant of the present invention and import adjuvant (trade name 206) with same method, carry out stability test, immunoprotection test and field test respectively simultaneously.
1 oil emulsion vaccine stability test
The adjuvant 2000ml that will be preheated to 30 ℃ earlier is added in the mulser, stirs, and slowly adds to be preheated to 30 ℃ antigen liquid 2000ml (antigen: oily adjuvant=1: 1 in stirring, V/V), add the back and stirred 15 minutes, make its uniformity after, emulsifying is promptly finished in emulsifying 5 minutes.Under aseptic condition, open the mulser bottom valve then, pour in the serum bottle of the 10000ml through doing roasting sterilization, from serum bottle, divide again in the 100ml plastic bottle that is filled to after the sterilization, add the sterilization plug, the jewelling lid.Centrifugal, viscosity and outward appearance detect.And respectively at depositing under the room temperature condition to observe its stability.Experimental result sees Table 1,2,3.
Table 1 outward appearance, viscosity and centrifugal testing result
| Emulsion | Import adjuvant (206) | Self-control adjuvant (embodiment 4) | Self-control adjuvant (embodiment 3) |
| Appearance color viscosity is centrifugal | Homogeneous latex emulsion LightPink 4 ' 22 " uniformities | Homogeneous latex emulsion milky white 4 ' 23 " uniformities | Homogeneous latex emulsion milky white 4 ' 20 " uniformities |
Table 2 low temperature (0-4 ℃) stability test
| Standing time | Import adjuvant (206) | Self-control adjuvant (embodiment 4) | Self-control adjuvant (embodiment 3) |
| 0 day | The homogeneous powder redness | The homogeneous powder redness | The homogeneous powder redness |
| 5 days | The homogeneous powder redness | The homogeneous powder redness | The homogeneous powder redness |
| 10 days | The homogeneous powder redness | The homogeneous powder redness | The homogeneous powder redness |
| 1 month | The homogeneous powder redness | The homogeneous powder redness | The homogeneous powder redness |
| 2 months | The homogeneous powder redness | The homogeneous powder redness | The homogeneous powder redness |
| 3 months | The homogeneous powder redness | The homogeneous powder redness | The homogeneous powder redness |
| 6 months | The homogeneous powder redness | The homogeneous powder redness | The homogeneous powder redness |
| 10 months 6 days | See layering is arranged | The homogeneous powder redness | The homogeneous powder redness |
| 11 months 22 days | / | See layering is arranged | The homogeneous powder redness |
| 12 months 18 days | / | / | See layering is arranged |
Table 3 room temperature (20-25 ℃) stability test
| Standing time | Import adjuvant (206) | Self-control adjuvant (embodiment 4) | Self-control adjuvant (embodiment 3) |
| 0 day | The homogeneous powder redness | The homogeneous powder redness | The homogeneous powder redness |
| 5 days | The homogeneous powder redness | The homogeneous powder redness | The homogeneous powder redness |
| 8 days | See layering is arranged | The homogeneous powder redness | The homogeneous powder redness |
| 36 days | / | See layering is arranged | The homogeneous powder redness |
| 40 days | / | / | See layering is arranged |
Test of 2 oil emulsion vaccine immunoprotections and field test
2.1 immunoprotection test: make oil emulsion vaccine (method is with 1) with the self-control adjuvant, undertaken by " Schweineseuche O-shaped inactivated vaccine (II) check specification ".Experimental result sees Table 4.
Table 4 oil emulsion vaccine is to the immunoprotection test of pig
| Project | Import adjuvant (206) | Self-control adjuvant (embodiment 4) | Self-control adjuvant (embodiment 3) |
| Size of animal | 10 | 10 | 10 |
| Incidence | 0/10 | 0/10 | 0/10 |
| The protection situation | 10/10 | 10/10 | 10/10 |
2.2 field test: make oil emulsion vaccine (method is with 1) with the self-control adjuvant, carry out inoculation, observe its clinical response on two pig farms.Pig all has slight clinical response in the injection rear section: fervescence subtracts food.Recovered normal in 3-4 days.
The specific embodiment
Embodiment 1
Take by weighing recipe quantity emulsifying agent, co-emulsifier and oil phase mix homogeneously by the listed percentage by weight of table 5, obtain adjuvant.
Table 5
| Composition | Percentage by weight (%) |
| No. 7 white oils of polyoxyethylene hydrogenated Oleum Ricini Tween 80 sorbester p17 sorbester p37 Macrogol 200 | 5 6 6 4 6 73 |
Embodiment 2
Take by weighing recipe quantity emulsifying agent, co-emulsifier and oil phase mix homogeneously by the listed percentage by weight of table 6, obtain adjuvant.
Table 6
| Composition | Mass percent (%) |
| Tween 80 | 6 |
| No. 10 white oils of polyoxyethylene nonylphenol ether glyceryl monooleate span 83 oleic acid Oleum Arachidis hypogaeae semen | 4 5 4 6 5 70 |
Embodiment 3
Take by weighing recipe quantity emulsifying agent, co-emulsifier and oil phase mix homogeneously by the listed mass percent of table 7, obtain adjuvant.
Table 7
| Composition | Mass percent (%) |
| Single oleic acid No. 1 white oil of sorbitol ester Labrasol sorbester p17 sorbester p37 acetic acid that contracts | 5 6 4 6 6 73 |
Embodiment 4
Take by weighing recipe quantity emulsifying agent, co-emulsifier and oil phase mix homogeneously by the listed mass percent of table 8, obtain adjuvant.
Table 8
| Composition | Mass percent (%) |
| No. 1 white oil of Tween 80 Labrasol sorbester p17 sorbester p37 oleic acid | 5 6 4 7 7 71 |
Claims (7)
1, a kind of vaccine adjuvant of self emulsifying is characterized in that being made up of following component and percentage by weight:
Oil phase 35-85%
Hydrophilic surfactant active 6-25%
Lipophilic surfactant 6-25%
Co-emulsifier 3-15%
Each weight percentages of components is all in the adjuvant gross weight.
2, the described vaccine adjuvant of claim 1, wherein oil phase is one or more in mineral oil, vegetable oil, benzyl benzoate, the ethyl oleate.
3, the described vaccine adjuvant of claim 1, wherein the hydrophilic surfactant active is HLB value one or more in the surfactant more than 8, is selected from polyoxyethylene nonyl 2, 2-Oxydiphenol, polyoxyethylene aliphatic alcohol ether, sad certain herbaceous plants with big flowers acid polyethylene glycol glyceride, polysorbas20, polysorbate40, polysorbate60, Tween 80, sorbimacrogol oleate100, polysorbate85, polyoxyethylene hydrogenated Oleum Ricini, pluronic F-68 or polyoxyethylene lauryl alcohol alcohol ether.
4, the described vaccine adjuvant of claim 1, wherein lipophilic surfactant is one or more in the surfactant of HLB value between 3-8, is selected from lecithin, fabaceous lecithin, sorbester p37, sorbester p17, sorbester p38, sorbester p18, glyceryl monostearate, glyceryl monooleate or the single oleic acid sorbitol ester that contracts.
5, the described vaccine adjuvant of claim 1, wherein co-emulsifier is selected from one or more in Macrogol 200, Liquid Macrogol, PEG400, ethanol, propylene glycol, oleic acid, 18-amine., the octadecanol.
6, the described vaccine adjuvant of claim 1, form by following component and percentage by weight:
White oil 60-73%
Sad certain herbaceous plants with big flowers acid polyethylene glycol glyceride and/or tween 5-12%
Single oleic acid contract sorbitol ester and/or span 10-20%
Oleic acid 3-9%
Each weight percentages of components is all in the adjuvant gross weight.
7, the preparation method of each described vaccine adjuvant in the claim 1 to 6: take by weighing surfactant, co-emulsifier and oil phase mix homogeneously, promptly obtain adjuvant.
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Cited By (1)
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| RU2789546C2 (en) * | 2017-02-24 | 2023-02-06 | МЕРК ШАРП И ДОУМ ЭлЭлСи | Composition of pneumococcal conjugate vaccine |
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| CN102293743B (en) * | 2010-06-24 | 2013-09-18 | 辽宁成大生物股份有限公司 | Lipid microsphere composition |
| CN103610641B (en) * | 2013-11-29 | 2016-05-04 | 吴福文 | Two-phase oil emulsion adjuvant and preparation method thereof for live vaccine |
| CN103816537A (en) * | 2014-01-26 | 2014-05-28 | 乾元浩生物股份有限公司 | Nanometer adjuvant and preparation method for same |
| CN104398478B (en) * | 2014-11-03 | 2017-05-10 | 江苏省农业科学院 | Compound emulsion carrier of medicine used for animal and application thereof |
| CN105854014B (en) * | 2015-01-22 | 2019-07-26 | 中牧实业股份有限公司 | A kind of vaccine adjuvant and its animal vaccine without polyoxyethylene groups emulsifier |
| KR101743142B1 (en) | 2015-09-09 | 2017-06-02 | 강원대학교산학협력단 | Ready-to-use adjuvant composition for intranasal immunization based on microemulsion |
| CN106267184B (en) * | 2016-03-03 | 2020-01-21 | 彭建彪 | Water-in-oil-in-water emulsifier and application and using method thereof |
| CN107551268A (en) * | 2016-06-30 | 2018-01-09 | 国年实业有限公司 | Birds Newcastle Disease vaccine adjuvant and preparation method thereof |
| CN106511996B (en) * | 2016-11-04 | 2019-09-10 | 江苏省农业科学院 | Emulsion type adjuvant and preparation method thereof for aftosa vaccine |
| CA3049985A1 (en) * | 2017-02-24 | 2018-08-30 | Merck Sharp & Dohme Corp. | Pneumococcal polysaccharide-protein vaccine formulations comprising improved surfactant systems |
| CN110101661B (en) * | 2019-05-21 | 2022-01-21 | 肇庆大华农生物药品有限公司 | Formula and preparation method of oil emulsion inactivated vaccine capable of rapidly generating antibody |
| CN112641939B (en) * | 2020-12-28 | 2024-04-02 | 吉林冠界生物技术有限公司 | Water-in-oil type composite adjuvant, preparation method and application thereof, and preparation method of vaccine |
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