CN113209287B - Water-in-oil type nano vaccine adjuvant, preparation method and application thereof - Google Patents
Water-in-oil type nano vaccine adjuvant, preparation method and application thereof Download PDFInfo
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- CN113209287B CN113209287B CN202110153128.1A CN202110153128A CN113209287B CN 113209287 B CN113209287 B CN 113209287B CN 202110153128 A CN202110153128 A CN 202110153128A CN 113209287 B CN113209287 B CN 113209287B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
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- C12N2760/16011—Orthomyxoviridae
- C12N2760/16111—Influenzavirus A, i.e. influenza A virus
- C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a water-in-oil type nano vaccine adjuvant, a preparation method and application thereof, wherein the vaccine adjuvant comprises the following components in percentage by weight: 30-60% of surfactant, 30-70% of oil phase and 0.5-2% of stabilizer. The oil phase is a mixture of mineral oil and squalane; wherein the mass ratio of the mineral oil to the squalane is 10: 1-1: 10, and preferably, the mass ratio of the mineral oil to the squalane is 10: 1-5: 1. The water-in-oil type vaccine nanoemulsion is clear and transparent, has low viscosity, high immunocompetence, low residue and toxic and side effects, has stable product performance, and is beneficial to obviously improving the production efficiency of animals and the quality safety of products.
Description
Technical Field
The invention relates to the field of vaccine preparation, in particular to a water-in-oil type nano vaccine adjuvant, a preparation method and application thereof.
Background
The emulsifiable concentrate adjuvant is a wide adjuvant used in inactivated vaccines for animals. It can enhance the specific immune response of the body to the antigen or change the type of immune response. The emulsifiable concentrate adjuvant is mainly composed of low-viscosity mineral oil and emulsifier. Can be divided into three types according to the dosage form: oil-in-water, water-in-oil, and two-way.
The form of a water-in-oil adjuvant is such that water is dispersed in the oil in the form of small droplets. The aqueous phase is the internal or dispersed phase and the oil is the external or dispersion medium. The vaccine prepared by the water-in-oil adjuvant can protect antigen molecules from being damaged by organisms or external environments, and has a certain slow release effect. At present, the water-in-oil adjuvant sold in the market is mainly the water-in-oil adjuvant sold by French Saibek company, the price of the water-in-oil adjuvant is higher, and a plurality of livestock and poultry farmers can bear the water-in-oil adjuvant. However, the vaccine emulsion prepared by the existing water-in-oil adjuvant has high viscosity and large particle size (more than 1 mu m), which causes difficult injection, difficult absorption and metabolism in animal bodies, red swelling and ulceration at injection sites and strong stress response of animals.
In recent years, the development of nanotechnology and materials provides a new idea for the processing of veterinary drug formulations. In particular to the preparation of the nanometer adjuvant veterinary vaccine, which can overcome the defects of thick emulsion drop, high viscosity and low utilization rate of effective components of the traditional vaccine. The nano vaccine prepared by the nano adjuvant can enable antigen molecules to be dispersed in an oil phase in a particle size of less than 100 nm, improves the specific surface area of the antigen molecules, is more beneficial to being absorbed by an animal body, and fully exerts the advantages of a nano drug delivery system. Furthermore, the method is simple. The vaccine prepared by the nano adjuvant has low viscosity and good fluidity, is convenient to inject, reduces the pain of animals in immunization, greatly relieves stress reaction, and avoids red swelling and ulceration of injection parts.
Disclosure of Invention
The invention aims to provide a water-in-oil type nano vaccine adjuvant, a preparation method and application thereof, and aims to solve the technical problems that the existing vaccine is high in viscosity, difficult to inject, poor in stability, slow in effect taking, short in duration, multiple in side effects, difficult to absorb and metabolize when entering an animal body, red and swollen and ulcerated injection parts, strong in stress reaction of the animal and the like.
In order to achieve the purpose, the invention adopts the following technical scheme: the water-in-oil type nano vaccine adjuvant comprises the following components in percentage by weight: 30-60% of surfactant, 30-70% of oil phase and 0.5-2% of stabilizer.
Further, the oil phase is a mixture of mineral oil and squalane; the volume ratio of the mineral oil to the squalane is 10: 1-1: 10, and the mass ratio of the mineral oil to the squalane is preferably 10: 1-5: 1.
Further, the water-in-oil type nano vaccine adjuvant and the antigen extracting solution are emulsified to form a clear and transparent appearance, and the average particle size of the nano vaccine emulsion is less than 50 nm; the dispersion coefficient is less than 0.1.
Further, the surfactant comprises castor oil polyoxyethylene ether and span 80; the mass ratio of the castor oil polyoxyethylene ether to the span 80 is 10: 1-1: 10, and the mass ratio of the castor oil polyoxyethylene ether to the span 80 is preferably 1: 2.5-1: 5.
Further, the stabilizer is one selected from poloxamer, propylene glycol and glycerin.
The invention also provides a preparation method of the water-in-oil type nano vaccine adjuvant, which comprises the following steps:
step one, uniformly mixing mineral oil and squalane by magnetic stirring for 5min at the rotating speed of 600-1000 rpm to obtain an oil phase;
and step two, rapidly adding the castor oil polyoxyethylene ether and the span 80 into the oil phase obtained in the step one at the rotating speed of 600-1000 rpm, stirring for 5min, and standing to obtain the water-in-oil type nano vaccine adjuvant.
The invention also provides an application of the water-in-oil type nano vaccine adjuvant as a vaccine adjuvant in vaccines.
The invention also provides an application of the water-in-oil type nano vaccine adjuvant as a vaccine adjuvant in avian influenza H9N2 inactivated vaccine nano emulsion.
The invention has the following beneficial effects:
the water-in-oil type nano vaccine adjuvant, the preparation method and the application thereof provided by the invention can be used for producing a transparent nano emulsion system consisting of an inner water phase and an outer oil phase, the average particle size of droplets of the inner water phase is less than 50 nm, and the dispersion coefficient is less than 0.1, so that the fine emulsion size of a nano drug targeted delivery system can be achieved.
The water-in-oil type nano vaccine adjuvant, the preparation method and the application thereof provided by the invention have the advantages that the water-in-oil type vaccine nano emulsion is clear and transparent, has low viscosity, high immunocompetence, low residue and toxic and side effects, has stable product performance, and is beneficial to obviously improving the production efficiency of animals and the quality safety of products.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the invention. The primary objects and other advantages of the invention may be realized and attained by the structure particularly pointed out in the written description and claims hereof.
Reference numerals are as follows:
FIG. 1 is a photograph of products of avian influenza H9N2 inactivated vaccine nanoemulsion 1-3 and avian influenza H9N2 inactivated vaccine common emulsion.
FIG. 2-1, FIG. 2-2, and FIG. 2-3 are particle size distribution diagrams of avian influenza H9N2 inactivated vaccine nanoemulsion 1-3, respectively.
FIG. 3 is a diagram of: photograph of avian influenza H9N2 inactivated vaccine nanoemulsion 1-3 when stored at 4 ℃.
FIG. 4 is a photograph of the inactivated vaccine nanoemulsion 1-3 for avian influenza H9N2 in FIG. 3 stored for one year at 4 ℃.
Fig. 5 is an anatomical diagram of chickens vaccinated with avian influenza H9N2 inactivated vaccine nanoemulsion 1.
Fig. 6 is an anatomical image of chickens vaccinated with avian influenza H9N2 inactivated vaccine nanoemulsion 2.
Fig. 7 is an anatomical image of chickens vaccinated with avian influenza H9N2 inactivated vaccine nanoemulsion 3.
Detailed Description
The technical solutions of the present invention are described in detail below by examples, and the following examples are only exemplary and can be used only for explaining and explaining the technical solutions of the present invention, but not construed as limiting the technical solutions of the present invention.
The water-in-oil type nano vaccine adjuvant comprises the following components in percentage by weight:
30-60% of a surfactant, wherein the surfactant comprises castor oil polyoxyethylene ether and span 80; the mass ratio of the castor oil polyoxyethylene ether to the span 80 is 10: 1-1: 10, and preferably, the mass ratio of the castor oil polyoxyethylene ether to the span 80 is 1: 2.5-1: 5.
30-70% of an oil phase, wherein the oil phase is a mixture of mineral oil and squalane;
0.5-2% of a stabilizer. The stabilizer is one selected from poloxamer, propylene glycol and glycerol.
Wherein the mass ratio of the mineral oil to the squalane is 10: 1-1: 10, and preferably, the mass ratio of the mineral oil to the squalane is 10: 1-5: 1. The water-in-oil type nano vaccine adjuvant and the antigen solution are emulsified to form a clear and transparent appearance, and the average particle size of the nano vaccine emulsion is less than 50 nm; the dispersion coefficient is less than 0.1.
The preparation method of the water-in-oil type nano vaccine adjuvant is characterized by comprising the following steps:
step one, uniformly mixing mineral oil and squalane by magnetic stirring for 5min at the rotating speed of 600-1000 rpm to obtain an oil phase;
and step two, rapidly adding castor oil polyoxyethylene ether and span 80 into the oil phase obtained in the step one at the rotating speed of 600-1000 rpm, stirring for 5min, and standing to obtain the water-in-oil type nano vaccine adjuvant.
The invention also provides application of the vaccine taking the water-in-oil type nano vaccine adjuvant as a vaccine adjuvant.
The examples and comparative examples were prepared using the method provided by the present invention, and in particular, the ingredients of examples 1-3 are detailed in table 1 below:
table 1 shows the ingredients of examples 1 to 3
The water-in-oil type nano vaccine adjuvant prepared in examples 1-3 and the commercially available france sibiran montaini DETM ISA 71VG water-in-oil adjuvant were emulsified, and an emulsion comparison experiment was performed with avian influenza H9N2 inactivated antigen as follows:
1, material: nano adjuvant, french seebeck water-in-oil adjuvant (MONTANI DETM ISA 71VG), avian influenza H9N2 antigen solution prepared in examples 1-3;
2, an instrument: a german IKA T15 type emulsion machine;
3, the method:
1) mixing the adjuvant prepared in the embodiment 1-3 and the avian influenza H9N2 antigen according to the proportion of 5:5, adjusting the speed of a shearing machine to 5000 rpm/min, timing and emulsifying for 5min, standing for 10 min, and storing in a refrigerator at 4 ℃ to prepare the avian influenza H9N2 inactivated vaccine nanoemulsion 1-3.
2) Mixing the French seebeck water-in-oil adjuvant and the avian influenza H9N2 antigen according to the proportion of 7:3, adjusting the speed of a shearing machine to 1000 rpm/min, emulsifying for 10 minutes in a timing manner, standing for 10 minutes, and storing in a refrigerator at 4 ℃ to prepare the avian influenza H9N2 inactivated vaccine common emulsion.
3) The vaccine emulsion is respectively tested for appearance, granularity, viscosity, centrifugal stability, storage stability at 4 ℃, animal safety and immunocompetence.
4, comparison of inactivated vaccine nanoemulsion and Normal emulsion
1) Appearance: the vaccine emulsion prepared by the water-in-oil type nano adjuvant is transparent emulsion, the vaccine emulsion prepared by the French Saibek water-in-oil adjuvant is milky emulsion, and further, the picture of the product of the avian influenza H9N2 inactivated vaccine nano emulsion in the embodiment 1-3 and the avian influenza H9N2 inactivated vaccine common emulsion is shown in figure 1;
2) granularity: the average particle size of the avian influenza H9N2 inactivated vaccine nanoemulsion 1-3 is 42 nm, 31nm and 37nm through a Malvern particle size analyzer test, and is shown in figures 2-1, 2-2 and 2-3. The average particle size of the common emulsion of the avian influenza H9N2 inactivated vaccine is 4.5 mu m.
3) Viscosity: at room temperature of 25 deg.C, 1mL of the emulsion was aspirated with a 1mL glass pipette (bottom orifice inner diameter of 1.2mm, top orifice inner diameter of 2.7 mm), allowed to flow out naturally in a vertical direction, the time required for 0.4mL of the flow out was recorded, and the average value was determined three times. The results show that the average time required by the avian influenza H9N2 inactivated vaccine nanoemulsion 1-3 is 3.9 s, 3.4 s and 3.7s, and the average time required by the avian influenza H9N2 inactivated vaccine normal emulsion is 4.0 s.
4) Stability: and (3) centrifuging a proper amount of the emulsion for 30min at 6000rpm/min by using a centrifuge, and observing whether the emulsion is layered and demulsified. The result shows that neither avian influenza H9N2 inactivated vaccine nanoemulsion 1-3 nor common emulsion has the demixing phenomenon. Another 5 bottles of each emulsion (fig. 3) were placed at 4 ℃ for one year to observe whether the emulsions were stratified or broken. The results show that all the nano emulsions 1-3 of the avian influenza H9N2 inactivated vaccine are layered or demulsified (figure 4), and 1 bottle of the common emulsion of the avian influenza H9N2 inactivated vaccine is layered when stored for 8 months.
5) Animal safety: 21 SPF chickens of 28 days old were divided into 3 groups of 7 chickens each. 1-3 groups of chickens were injected with 1mL of avian influenza H9N2 inactivated vaccine nanoemulsion 1-3 per chicken to observe whether adverse reactions occurred at the injection site or on the whole body. The results show that no injection site or systemic adverse reaction occurs in the three groups of chickens. In addition, the 3 groups of chickens were dissected 28 days later and observed for the presence of vaccine residues. The results showed that the nano-vaccine emulsion was absorbed by the animal body and no residue appeared (fig. 5-7).
6) Immunological activity: 35 SPF chickens of 28 days old were divided into 5 groups of 7 chickens. 1-3 groups of chickens were injected with 1mL of avian influenza H9N2 water-in-oil nano vaccine emulsion 1-3, 4 groups of chickens were injected with 1.33 mL of water-in-oil ordinary vaccine emulsion, and 5 groups of chickens were injected with 1mL of physiological saline. 7\14\21\28\35\42 days after inoculation, 5 groups of SPF chickens are subjected to winged vein blood collection respectively, 1ml of blood is collected for each chicken, serum is separated, and HI antibodies are measured by using standard antigens. The results are shown in table 2 below:
TABLE 2 results of the immunological activity assay
From the above results, it can be seen that compared with france mosaic water-in-oil adjuvant (montaini DETM ISA 71VG), the water-in-oil type nano vaccine adjuvant of the present invention has the following advantages:
1) the average particle size of the emulsion drops is less than 50 nm, the emulsion drops are uniformly distributed, and the fine emulsion size of the nano drug targeted delivery system is achieved. Antigen molecules can be fully dispersed in the mobile phase, so that the contact area of the antigen is increased, the antigen is easier to be absorbed by organisms, and the bioavailability is improved.
2) The stability is good, the common emulsion (the particle size is more than 1 mu m) belongs to a thermodynamically unstable system, the nano emulsion (the particle size is less than 100 nm) belongs to a thermodynamically stable system, the particle size of the nano emulsion prepared by the invention is less than 50 nm, and compared with the common emulsion, the nano emulsion does not generate the phenomenon of layering and demulsification after being stored for one year at 4 ℃.
3) The viscosity is low, the particle size of the nano emulsion is small, so that the nano emulsion has better fluidity and is easier to inject when animals are immunized.
4) The immunity has quick effect and long lasting period.
In conclusion, the water-in-oil type nano vaccine adjuvant, the preparation method and the application thereof provided by the invention overcome the defects of the oil-in-water type nano vaccine adjuvant at the present stage, provide new components with strong practicability, low viscosity, good stability, quick response, long duration and low toxic and side effects, and the prepared nano emulsion for animals is easy to be absorbed and metabolized by animal organisms, thereby greatly reducing the toxic and side effects of the adjuvant and having good popularization effect.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that may be made by those skilled in the art within the technical scope of the present invention will be covered by the scope of the present invention.
Claims (2)
1. The water-in-oil type nano vaccine adjuvant is characterized in that: the vaccine adjuvant comprises the following components in percentage by weight: mineral oil 52%, squalane 7.5%, castor oil polyoxyethylene ether 10%, span 8030% and glycerol 0.5%.
2. The application of the water-in-oil type nano vaccine adjuvant as a vaccine adjuvant in preparation of avian influenza H9N2 inactivated vaccine nanoemulsion.
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