CN104876978A - Oligosaccharide ester and application thereof to preparation of vaccine adjuvant - Google Patents
Oligosaccharide ester and application thereof to preparation of vaccine adjuvant Download PDFInfo
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- CN104876978A CN104876978A CN201510281449.4A CN201510281449A CN104876978A CN 104876978 A CN104876978 A CN 104876978A CN 201510281449 A CN201510281449 A CN 201510281449A CN 104876978 A CN104876978 A CN 104876978A
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Abstract
The invention discloses oligosaccharide ester which is prepared by subjecting natural monosaccharide polymerization prior to esterification reaction with oleic acid, further discloses application of the oligosaccharide ester to preparation of a vaccine adjuvant, and particularly discloses the vaccine adjuvant comprising the oligosaccharide ester and a method for preparing vaccine with the vaccine adjuvant. The oligosaccharide ester serving as oleophilic surfactant can be used for preparing the safe and stable W/O/W vaccine adjuvant, and the finally prepared vaccine adjuvant can be used for preparing the animal vaccine high in stability, safety and valence of antibody. The problem of difficulty in preparation of the oleophilic surfactant is solved, and the monopoly of France in the technical field of W/O/W oil emulsion adjuvants is broken.
Description
Technical field
The present invention relates to preparation and the vaccine preparation field of vaccine adjuvant raw material, be specifically related to a kind of oligomeric sugar ester and preparing the application in vaccine adjuvant.
Background technology
Foot and mouth disease disease is classified as first transmissible disease in the category-A transmissible disease that its member states takes precautions against jointly by Food and Argriculture OrganizationFAO and International Office of Epizootics." livestock birds health cultivation and control and prevention of disease " is classified as the urgent need gordian technique in agriculture major fields by " national medium-term and long-term science and technology development planning outline ".Aftosa vaccine consumption pig for animals 84.15 hundred million parts are often only by China, cattle and sheep 22.02 hundred million parts, and every year with 10% speed increase.Therefore the market demand of vaccine is very large.
Vaccine adjuvant can improve the immunization effect of vaccine, its Main Function in immunity promotes body immune system to antigen or immunogenic immune response, strengthen the persistence of immune response intensity and reaction, thus improve body to resistibility that is viral or bacterium.Common adjuvants mainly comprises Alum adjuvant, oil emulsion adjuvant, surfactant-based adjuvant, bacterial micro-organism class adjuvant, propolis adjuvant, cytokine class adjuvant etc.
Current domestic W/O/W(water-in-oil-in-water) type oil emulsion adjuvant, all depend on 206 adjuvants that French SEPPIC company produces, import volume is up to 300,000,000 yuan/year.Because France carries out strict blockade on new techniques always, do not transfer the possession of uncooperative novel adjuvant technology, the new vaccine adjuvant that therefore China can be suitable with French 206 state of the art in the urgent need to research and development.
206 adjuvants are W/O/W type adjuvant, the technical bottleneck of domestic this type of adjuvant exploitation is at present, need in such adjuvant containing a kind of lipophilic surfactant, this tensio-active agent and other surfactant compounds use, a kind of stable self-emulsifying systems can be formed, preparation W/O/W emulsion, does not domesticly at present also find a kind of so suitable tensio-active agent.
In addition, from tensio-active agent Variety Development Trend in the world, tensio-active agent starts to tend to ecological safety, non-environmental-pollution, complete biodegradable, functional strong, chemical stability and Heat stability is good, future development that cost is low.
Glycosyl surfactant active, be the tensio-active agent made with carbohydrate, raw material is from natural reproducible resource, and Environmental compatibility is good, there are good skin compatibility and splendid biodegradability, have potential application prospect at pharmacy, biological chemistry and biomedical aspect.Therefore, glycosyl surfactant active meets the product of international tensio-active agent growth requirement just.
Glycosyl surfactant active can with other surfactant compound, not only can improve the performance of self, and the Application Areas or product that make new advances can be developed, widen the Application Areas of glycosyl surfactant active greatly.Therefore, utilize carbohydrate resource to prepare a kind of oil loving glycosyl surfactant active and be applied in preparation W/O/W type vaccine adjuvant, to substitute 206 adjuvants, and then utilizing W/O/W type vaccine adjuvant to make vaccine just to become and have a difficult problem to be solved.
Summary of the invention
For the above state of the art, the object of this invention is to provide a kind of preparation method of oligomeric sugar ester, and provide oligomeric sugar ester preparing safety, stable W/O/W type vaccine adjuvant to substitute 206 adjuvants and to be finally prepared into the application in animal vaccine as lipophilic surfactant.
For this reason, the technical solution used in the present invention is as follows:
A kind of oligomeric sugar ester, its preparation method is as follows:
(1) polyreaction: under the protection of nitrogen inert atmosphere, is heated to molten state by natural monosaccharide under stirring, and reaction 1-6 h, generates natural monosaccharide polymkeric substance;
(2) esterification: by respectively oleic acid and catalyzer dropwise being joined in natural monosaccharide polymkeric substance under stirring, reacting 1-6 h at 180 DEG C-280 DEG C, naturally cooling, generating oligomeric sugar ester crude product;
(3) by purified and dry for described oligomeric sugar ester crude product.
Preferably, described natural monosaccharide is any one in glucose, fructose, seminose, ribose or wood sugar; Described catalyzer is the mixture of one or more in phosphoric acid, phosphorous acid, sodium carbonate, potassium primary phosphate.
Particularly, in step (3), the concrete steps of purifying are: by described oligomeric sugar ester crude product methanol extraction, and the neutralization of extraction liquid NaOH solution, the washing unreacted phosphoric acid of removing and monose, finally with the oleic acid that normal hexane eccysis is residual, boil off solvent, drying for standby.
Preferably, the mass ratio of described oleic acid and natural monosaccharide is 1:0.5-10, and quality is than catalyzer: (monose+oleic acid)=1-10:1000.
Present invention also offers above-mentioned oligomeric sugar ester and prepare the application in vaccine adjuvant.
Present invention also offers the vaccine adjuvant comprising above-mentioned oligomeric sugar ester, it comprises the component of following mass percent: 50-90% injection stage light mineral oil for animals, the oligomeric sugar ester of 2.5-15%, 7-30% hydrophilic surfactant active, 0.5-5% auxiliary agent.
Wherein, described hydrophilic surfactant active be selected from polyoxyethylene sorbitan fatty acid ester (preferred polyoxyethylene sorbitan fatty acid ester T-20, T-40, T-60, T-80), polyoxyethylenated castor oil (preferred EL20, EL30, EL40), polyoxyethylene hydrogenated castor oil (preferred HEL20, HEL40), polyoxypropylene N.F,USP MANNITOL dioleate, polyoxyethylene sucrose fatty ester one or more; Described auxiliary agent is selected from polypropylene glycol PPG200, PPG400, PPG600, PPG800, vitamin-E, BHA (butylated hydroxy anisole), BHT (2,6 di tert butyl 4 methyl phenol), squalene, one or more in squalane.
The preparation method of above-mentioned vaccine adjuvant is: described injection stage light mineral oil for animals, oligomeric sugar ester, hydrophilic surfactant active and auxiliary agent are uniformly mixed under rotating speed 800rpm in proportion, namely obtains W/O/W type vaccine adjuvant.
The present invention still further provides the method being prepared vaccine by above-mentioned vaccine adjuvant, it is characterized in that its step is as follows: by described vaccine adjuvant in 121 DEG C of steam sterilizing 30 min, naturally cooling, puts into emulsion tank, and controlling temperature in emulsion tank is 30 ± 2 DEG C; Join in emulsion tank by aqueous phase antigen identical with temperature in emulsion tank for temperature, aqueous phase antigen addition is the 100-400% of described vaccine adjuvant quality; The mixture of described vaccine adjuvant and aqueous phase antigen is carried out emulsification under 400-1000rpm, and emulsifying temperature is 30 ± 2 DEG C, and emulsification times is 5-30 min, namely obtains vaccine after emulsification completes.
Particularly, described aqueous phase antigen is foot-and-mouth disease antigen, pig circular ring virus antigen or other virus antigens and bacterial antigens.
Oligomeric sugar ester prepared by the present invention can prepare safety, stable W/O/W type vaccine adjuvant as lipophilic surfactant, and the W/O/W type vaccine adjuvant finally prepared can be prepared into that stability is strong, security good, the animal vaccine that antibody titer is high.The invention solves a preparation difficult problem for lipophilic surfactant, break the monopolization of France in W/O/W type oil emulsion adjuvant technical field.
Accompanying drawing explanation
Fig. 1 is that in embodiment 9, each group pig circular ring virus vaccine ELISA antibody horizontal OD value moves towards figure.
Embodiment
In following examples, the various process do not described in detail and method are ordinary methods as known in the art.Raw material used or reagent except special instruction, all commercially.
One, the preparation embodiment of oligomeric sugar ester
Embodiment 1
(1) under nitrogen inert atmosphere protection, make wood sugar be in molten state in 120 DEG C of heating 450g wood sugar, stirring reaction 6h under 400rpm, generate wood sugar polymkeric substance;
(2) wood sugar polymkeric substance is warming up to 180 DEG C, dropwise adds 13.5 g phosphorous acid and 900 g oleic acid, stir at 180 DEG C, rotating speed 400rpm, stirring reaction 1h, cooling, generate the thick product of xylo-oligosaccharide ester;
(3) thick for xylo-oligosaccharide ester product is carried out methanol extraction, the extraction liquid NaOH solution obtained removes unreacted phosphorous acid and wood sugar, then with the oleic acid that n-hexane removing is residual, dry, obtains xylo-oligosaccharide ester.
Embodiment 2
(1) under nitrogen inert atmosphere protection, by 700g seminose in 200 DEG C of heating, make seminose be in molten state, under 400rpm, stir 1h, generate manose polymer;
(2) manose polymer is warming up to 280 DEG C, dropwise adds 1.2 g phosphorous acid, 0.6g sodium carbonate, 0.6g potassium primary phosphate and 700 g oleic acid, stir at 280 DEG C, rotating speed 400rpm, stirring reaction 2h, cooling, generate the thick product of Oligomeric manna sugar ester;
(3) thick for Oligomeric manna sugar ester product is carried out methanol extraction, the extraction liquid NaOH solution neutralization obtained, washing removing unreacted phosphorous acid, sodium carbonate, potassium primary phosphate and seminose, then residual oleic acid is removed with n-hexane, dry, obtain Oligomeric manna sugar ester.
Embodiment 3
(1) under nitrogen inert atmosphere protection, 1000 g fructose are heated to molten state in 160 DEG C, and 400rpm stirs 3h, generates fructose polymer;
(2) fructose polymer is warming up to 220 DEG C, dropwise adds 1.2 g phosphoric acid and 100 g oleic acid stir at 220 DEG C, rotating speed 400rpm, 6 h, cooling, generate the thick product of oligofructose ester;
(3) thick for oligofructose ester product is carried out methanol extraction, the extraction liquid NaOH solution neutralization obtained, the washing unreacted phosphoric acid of removing and fructose, then remove residual oleic acid with n-hexane, dry, obtains oligofructose ester.
Two, the embodiment prepared of vaccine adjuvant
Embodiment 4
By 80.42 g injection stage light mineral oil for animals, xylo-oligosaccharide ester prepared by 7.0 g embodiments 1,8 g T-80,4 g PPG400,0.04 g BHA, 0.04 g BHT, 0.5 g squalene is uniformly mixed, and rotating speed is that 800rpm stirs, and obtains W/O/W type vaccine adjuvant.
Embodiment 5
By 50 g injection stage light mineral oil for animals, Oligomeric manna sugar ester prepared by 15 g embodiments 2,30 g HEL, 4.5 g PPG400,0.5 g vitamin-E is uniformly mixed, and rotating speed is that 800rpm stirs, and obtains W/O/W type vaccine adjuvant.
Embodiment 6
By 90 g injection stage light mineral oil for animals, oligofructose ester prepared by 2.5 g embodiments 3,7 g T-80,0.5 g EL is uniformly mixed, and rotating speed is that 800rpm stirs, and obtains W/O/W type vaccine adjuvant.
Three, the embodiment prepared of vaccine
Embodiment 7
The vaccine adjuvant 500 g embodiments 4 prepared is in 121 DEG C of high pressure steam sterilization 30 min, and naturally cooling, puts into emulsion tank, and controlling temperature in emulsion tank is 30 ± 2 DEG C; Join in emulsion tank after 500 g foot-and-mouth disease antigens (deactivation, antigenic content 4.69 μ g/mL) are heated to 30 ± 2 DEG C; The mixture of vaccine adjuvant and aqueous phase antigen is carried out emulsification, and emulsification rotating speed is 400 rpm, and emulsifying temperature is 30 ± 2 DEG C, and emulsification times is 30 min, namely obtains aftosa vaccine after emulsification completes.
Aftosa vaccine physical behavior detects: aftosa vaccine is W/O/W type; Viscosity 1.9s; The centrifugal 15min of 3000rpm is not stratified without separating out; Place 12 months non-breakdowns of emulsion for 4 DEG C, place 1 month non-breakdown of emulsion for 25 DEG C, 37 DEG C of placements have no breakdown of emulsion in 10 days; Steriling test is qualified;
Aftosa vaccine effect evaluation: 30 18-22 g mouse (kunming mice, female, clean level) are divided into 3 groups at random: experimental group, control group, blank group.Vaccine group and control group often organize 10 mouse, blank group 10 mouse.Three groups of mouse are carried out subcutaneous injection, and scheme is as follows:
Experimental group: aftosa vaccine prepared by inoculation the present embodiment, dosage of inoculation 0.5 mL/ is only;
Control group: inoculate the aftosa vaccine that 206 adjuvants are prepared according to the method that the present embodiment is identical, dosage of inoculation 0.5 mL/ is only;
Blank group: not vaccination, simple injecting normal saline 0.5 mL/ only.
After vaccination or physiological saline, three groups of mouse reactions all without exception.Exempt from latter 21 days, three groups of mouse docking blood samplings, separation of serum, detects foot-and-mouth disease antibody in serum and tires.
The detected result of separate groups of mice serum antibody titer after table 1 vaccine immunity
Embodiment 8
By 300 g vaccine adjuvants in 121 DEG C of high pressure steam sterilization 30 min, naturally cooling, puts into emulsion tank, and controlling temperature in emulsion tank is 30 ± 2 DEG C; By 900 g pig circular ring virus antigens, (inactivation of viruses liquid tires 10
7.3tCID
50/ mL) be heated to 30 ± 2 DEG C after join in emulsion tank; The mixture of vaccine adjuvant and aqueous phase antigen is carried out emulsification, and emulsification rotating speed is 600 rpm, and emulsifying temperature is 30 ± 2 DEG C, and emulsification times is 15 min, namely obtains pig circular ring virus vaccine after emulsification completes.
Pig circular ring virus vaccine physical behavior detects: vaccine is W/O/W type; Viscosity 1.5s; 0.5% aqueous phase is separated out bottom the centrifugal 15min of 3000rpm; Place 12 months non-breakdowns of emulsion for 4 DEG C, place 1 month non-breakdown of emulsion for 25 DEG C, 37 DEG C of placements have no breakdown of emulsion in 10 days; Steriling test is qualified;
Pig circular ring virus vaccine potency is evaluated: 30 18-22 g mouse (kunming mice, female, clean level) are divided into 3 groups at random: experimental group, control group, blank group.Vaccine group and control group often organize 10 mouse, blank group 10 mouse.Three groups of mouse are carried out subcutaneous injection, and scheme is as follows:
Experimental group: pig circular ring virus epidemic disease vaccine prepared by inoculation the present embodiment, dosage of inoculation 0.5 mL/ is only;
Control group: inoculate the pig circular ring virus epidemic disease vaccine that 206 adjuvants are prepared according to the method that the present embodiment is identical, dosage of inoculation 0.5 mL/ is only;
Blank group: not vaccination, simple injecting normal saline 0.5 mL/ only.
After vaccination or physiological saline, three groups of mouse reactions all without exception.Exempt from latter 21 days, three groups of mouse docking blood samplings, separation of serum, detects pig circular ring virus epidemic disease antibody titer in serum.
Table 2: mouse antibodies bioactivity result
Embodiment 9
By 200 g vaccine adjuvants in 121 DEG C of high pressure steam sterilization 30 min, naturally cooling, puts into emulsion tank, and controlling temperature in emulsion tank is 30 ± 2 DEG C; By 800 g pig circular ring virus epidemic disease antigens, (inactivation of viruses liquid tires 10
7.3tCID
50/ mL) be heated to 30 ± 2 DEG C after join in emulsion tank; The mixture of vaccine adjuvant and aqueous phase antigen is carried out emulsification, and emulsification rotating speed is 1000 rpm, and emulsifying temperature is 30 ± 2 DEG C, and emulsification times is 5 min, namely obtains pig circular ring virus epidemic disease vaccine after emulsification completes.
Pig circular ring virus epidemic disease vaccine physical behavior detects: vaccine is W/O/W type; Viscosity 1.0s; 1% aqueous phase is separated out bottom the centrifugal 15min of 3000rpm; Place 12 months non-breakdowns of emulsion for 4 DEG C, place 1 month non-breakdown of emulsion for 25 DEG C, 37 DEG C of placements have no breakdown of emulsion in 10 days; Steriling test is qualified;
Pig circular ring virus epidemic disease vaccine potency is evaluated: 15 14-21 age in days sodium selenites (LPB-ELISA antibody titer≤1:8) are divided into 3 groups at random: experimental group, control group, blank group, often organizes 5.Three groups of piglets are carried out musculi colli injection, and scheme is as follows:
Experimental group: pig circular ring virus epidemic disease vaccine prepared by inoculation the present embodiment, dosage of inoculation 2 mL/ is only;
Control group: inoculate pig circular ring virus epidemic disease vaccine prepared by 206 adjuvants, dosage of inoculation 2 mL/ is only;
Blank group: not vaccination, simple injecting normal saline 2 mL/ only.
After vaccination or physiological saline, three groups of piglet reactions all without exception.Exempt from rear every 7d blood sampling, take a blood sample 10 weeks altogether, detect each all ELISA antibody horizontals, detected result is shown in Fig. 1 and table 3.
Table 3: piglet immunological each group vaccine ELISA antibody horizontal mean value
From pig circular ring virus vaccine piglet efficacy test result in Fig. 1 and table 3: (1) declines gradually along with blank group maternal antibody, and control group and experimental group antibody horizontal all present the trend of rising; (2) control group about 3 weeks antibody after exempting from rises rapidly, after exempting from, present weekly small size rising after 4 weeks, and antibody horizontal is comparatively steady, and individual difference is larger; (3) experimental group project adjuvant about 2 weeks antibody after exempt from has and significantly rises, and exempt to rise in rear 3-6 week comparatively steady, within two weeks afterwards, present the trend that straight line rises, by the 8th week, rear antibody presented small size rising again.
Claims (10)
1. an oligomeric sugar ester, is characterized in that it is adopted and prepares with the following method:
(1) polyreaction: under the protection of nitrogen inert atmosphere, natural monosaccharide is heated to molten state, in stirring lower reaction 1-6 h, generates natural monosaccharide polymkeric substance;
(2) esterification: dropwise join in natural monosaccharide polymkeric substance by after oleic acid and catalyst mix under stirring, react 1-6 h at 180 DEG C-280 DEG C, naturally cooling, generate oligomeric sugar ester crude product;
(3) by purified and dry for described oligomeric sugar ester crude product.
2. oligomeric sugar ester according to claim 1, is characterized in that, described natural polysaccharide is any one in glucose, fructose, seminose, ribose or wood sugar; Described catalyzer is the mixture of one or more in phosphoric acid, phosphorous acid, sodium carbonate, potassium primary phosphate.
3. oligomeric sugar ester according to claim 2, it is characterized in that the concrete steps of purifying in step (3) are: by described oligomeric sugar ester crude product methanol extraction, extraction liquid NaOH solution removes unreacted catalyzer and monose, the oleic acid remained finally is removed with normal hexane eccysis, boil off solvent, dry.
4. oligomeric sugar ester according to claim 3, is characterized in that: the mass ratio of described oleic acid and natural monosaccharide is 1:0.5-10, and quality is than catalyzer: (monose+oleic acid)=1-10:1000.
5. the oligomeric sugar ester described in any one of claim 1-4 is preparing the application in vaccine adjuvant.
6. comprise the vaccine adjuvant of the oligomeric sugar ester described in any one of claim 1-4, it is characterized in that it comprises the component of following mass percent: 50-90% injection stage light mineral oil for animals, the oligomeric sugar ester of 2.5-15%, 7-30% hydrophilic surfactant active, 0.5-5% auxiliary agent.
7. vaccine adjuvant according to claim 6, it is characterized in that described hydrophilic surfactant active is selected from polyoxyethylene sorbitan fatty acid ester, polyoxyethylenated castor oil, polyoxyethylene hydrogenated castor oil, polyoxypropylene N.F,USP MANNITOL dioleate, polyoxyethylene sucrose fatty ester one or more; Described auxiliary agent is selected from polypropylene glycol PPG200, PPG400, PPG600, PPG800, vitamin-E, BHA, BHT, squalene, one or more in squalane.
8. vaccine adjuvant according to claim 6, it is characterized in that, its preparation method is: described injection stage light mineral oil for animals, oligomeric sugar ester, hydrophilic surfactant active and auxiliary agent are uniformly mixed under rotating speed 800rpm in proportion, namely obtains W/O/W type vaccine adjuvant.
9. prepared the method for vaccine by vaccine adjuvant according to claim 6, it is characterized in that its step is as follows: by described vaccine adjuvant in 121 DEG C of steam sterilizing 30 min, naturally cooling, puts into emulsion tank, controlling temperature in emulsion tank is 30 ± 2 DEG C; Join in emulsion tank by aqueous phase antigen identical with temperature in emulsion tank for temperature, aqueous phase antigen addition is the 100-400% of described vaccine adjuvant quality; The mixture of described vaccine adjuvant and aqueous phase antigen is carried out emulsification under 400-1000rpm, and emulsifying temperature is 30 ± 2 DEG C, and emulsification times is 5-30 min, namely obtains vaccine after emulsification completes.
10. vaccine preparation method according to claim 9, is characterized in that, described aqueous phase antigen is virus antigen or bacterial antigens, preferred foot-and-mouth disease antigen or pig circular ring virus antigen.
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| CN112618710A (en) * | 2019-09-24 | 2021-04-09 | 华南理工大学 | Phytoglycogen pig oral vaccination nano adjuvant and preparation method and application thereof |
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| CN107596364A (en) * | 2017-09-19 | 2018-01-19 | 洛阳赛威生物科技有限公司 | A kind of w/o/w adjunvant compositions, the vaccine combination prepared and preparation method thereof |
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| CN112618710A (en) * | 2019-09-24 | 2021-04-09 | 华南理工大学 | Phytoglycogen pig oral vaccination nano adjuvant and preparation method and application thereof |
| CN112618710B (en) * | 2019-09-24 | 2023-09-29 | 华南理工大学 | Plant glycogen pig oral vaccination nanometer adjuvant and preparation method and application thereof |
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