CN101670103A - Compound panax ginseng total saponin and levamisole nano emulsion adjuvant and preparation method thereof - Google Patents
Compound panax ginseng total saponin and levamisole nano emulsion adjuvant and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a compound panax ginseng saponin and levamisole nano emulsion adjuvant. The adjuvant has the particle diameter of 1-100 nm and comprises panax ginseng saponin, levamisole, a surface active agent, a cosurfactant, oil and distilled water. The product is transparent faint yellow liquid in appearance, and the particle parameter is smaller than 100 nm; the viscosity is lower, and the viscosity requirement of emulsion as a vaccine adjuvant is met; the stability is higher, and the product can be preserved at room temperature or 4 DEG C for a long time; the special emulsification is not needed during seedling preparation, the requirement to equipment is low, and the quality of the product is easy to control. Egg white albumin (OVA) as mode antigen indicates that the compound panax ginseng saponin and levamisole nano emulsion adjuvant can induce better immune reaction than an aluminum adjuvant in a certain dosage, generate higher antibody titer, reduce the dosage of theadjuvant or the antigen, simulate Th1 and Th2 reaction, reinforce the body fluid and cell immunization of an organism and play a role of complete immune protection.
Description
Technical field
The present invention relates to the vaccine adjuvant field, be specifically related to a kind of compound ginseng Saponin and levamisole oil-in-water nanometer breast adjuvant that can form compositions, have the immune effect of enhancement antigen, be used for the prevention and the treatment of Animal diseases with antigen.
Background technology
In recent years, along with the generation of some Animal diseases or infecting both domestic animals and human disease, new vaccine development work is very poverty-stricken.Science and technology development makes production of vaccine turn to subunit seedling or the artificial synthesis peptide's Seedling that only contains microorganism specificity component from complete microorganism Seedling, but the latter's immunogenicity is weak relatively, is difficult to induce body to produce efficient immune.For strengthening the immunogenicity of vaccine, add immunological adjuvant in the development of the viral vaccine of being everlasting, dna vaccination and polypeptide vaccine.Immunological adjuvant is a kind of immunomodulator, can mix prior to antigen or with antigen or inject simultaneously in the animal body, and the immunogenicity of energy non-specific ground enhancement antigen improves immune effect.
China's live vaccine adjuvant mainly contains oily adjuvant and aluminium glue.Though both can effectively be used to strengthen the immunization of vaccine clinically, they in use still come with some shortcomings.Aluminium adjuvant mainly promotes humoral immunization; stimulate and produce the reaction of Th2 type; the antibody that produces is based on IgG1; and cellular immune responses does not almost have effect; make that the immunoprotection of vaccine is not comprehensive, not lasting, and some side effect are also arranged; form granuloma as slight local response, even local aseptic abscess takes place.The oil adjuvant is to use animal at present to use wider adjuvant in the inactivated vaccine, but this class adjuvant is generally water in oil emulsion, unstable, than thickness, need exert oneself during injection, and mineral oil is difficult for disperseing and metabolism in body, is easy to generate local side reactions such as erythema, pustule, influences the quality of animal shape and meat.China adopts the oily adjuvant that is of inactivated vaccine at present, mainly is the oily adjuvant of homemade mineral oil and import.Though homemade mineral oil low price (0.01～0.02 yuan/milliliter), quality instability, side effect are bigger, cause allergy and cause animal dead; Though the side effect of import oil adjuvant is less, price height (about 0.15～0.2 yuan/milliliter) causes vaccine price higher.Oil adjuvant developing direction from now on is to replace nonmetabolizable mineral oil with vegetable oil or animal oil, and sifting property surface of good activating agent adopts more advanced emulsifying process, and it is low to prepare viscosity, the novel adjuvant Seedling that poison is secondary little, easy to use.W/O/W Emulsion has not only reduced viscosity but also good immunogenicity is arranged, but the less stable of this system, difficulty is bigger on technology of preparing.
Summary of the invention
At above-mentioned problems of the prior art and defective, the purpose that the present invention sends out is to provide a kind of compound panax ginseng total saponin and levamisole nano emulsion adjuvant, and this nano emulsion adjuvant production technology is simple, viscosity is suitable, good stability, the efficient and little oil-in-water adjuvant of side effect.
Realize that foregoing invention purpose technical scheme is, a kind of compound ginseng Saponin and levamisole nano emulsion adjuvant, the particle diameter of this nano emulsion adjuvant is between 1～100nm, be made up of following weight percentages: ginsenoside 0.10%～2.00%, levamisole 0.10%～9.00%, surfactant 15.00%～40.00%, cosurfactant 1.00%～20.00%, oil 1.64%～12.40% and distilled water 42.00%～82.16%, the gross weight of above-mentioned raw materials is 100%.
The optimum ratio of compound ginseng Saponin of the present invention and levamisole nano emulsion adjuvant is: ginsenoside 1.00%～1.50%, levamisole 2.00%～5.00%, surfactant 17.50%～25.00%, cosurfactant 10.70%～17.50%, oil 5.00%～8.80% and distilled water 50.00%～60.00%, the gross weight of above-mentioned raw materials is 100%.
Ginsenoside of the present invention is Radix Ginseng total saponins or panaxoside monomer;
Levamisole of the present invention is the levamisole salt;
Surfactant of the present invention is the non-ionic surface active agent of HLB＞8, preferentially selects one or more the mixture in polyoxyethylene ether castor oil hydrogenated, polyoxyethylene ether Oleum Ricini, tween 80 and the Tween-60 for use.
Cosurfactant of the present invention is preferentially selected one or more mixture of Macrogol 200, PEG400, glycerol, propylene glycol for use.
Grease separation of the present invention is from mineral oil and vegetable oil, as Oleum Arachidis hypogaeae semen, olive oil, isopropyl myristate, vitamin E oil, liquid paraffin and Fructus Hordei Germinatus wet goods.
Another object of the present invention provides the preparation method of above-mentioned compound ginseng Saponin and levamisole oil-in-water type nano emulsion adjuvant, may further comprise the steps:
1) take by weighing ginsenoside, levamisole, surfactant, cosurfactant, oil and distilled water, standby;
2) at 37 ℃ the ginsenoside is dissolved in surfactant, cosurfactant and the oily formed oil phase, stirring is dissolved the ginsenoside fully, and gained is oil phase;
3) under the room temperature, levamisole is dissolved in the distilled water, stirring is dissolved it fully, filters, and gained is water;
4) under the room temperature, water slowly is added drop-wise in the oil phase, constantly stirs in the time of dropping,, filter, promptly until forming transparent system.
The theory of constitution of compound ginseng Saponin of the present invention and levamisole oil-in-water type nano emulsion adjuvant:
1. after the QuilA Saponin is used as vaccine adjuvant, it is found that many Saponins have the activity of adjuvant.Studies show that the adjuvant of ginsenoside as vaccine both at home and abroad, have the advantage of aluminium adjuvant and QuilA concurrently, its safety obviously is better than QuilA, and being is worth exploitation to be used for the Chinese medicine adjuvant of people or poultry.Patent No. ZL02110578.2 has announced that Radix Ginseng total saponins or monomer ginsenoside Rb1 are used to prepare the purposes of vaccine immunity adjuvant, and it is compared with traditional immunological adjuvant aluminum hydroxide adjuvant, has many advantages, is well suited for as immunological adjuvant.
2, levamisole is a kind of wide spectrum nematicide, is again a kind of immunomodulator simultaneously, can improve cellular immune function, has advantages such as efficient, medicine source abundance, stable in properties, also is widely used in the immunocompetence that strengthens animal.
3. Radix Ginseng total saponins is rich in 18 kinds of ginseng monomer Saponins, is dissolved in 80 ℃ water, easily is dissolved in ethanol.Studies show that when pH value of solution 6.03, Radix Ginseng total saponins solution is the most stable under the room temperature.Levamisole hydrochloride is very easily dissolving in water, and is more stable in acid solution.Nano-emulsion of the present invention can be realized the two kind medicament solubilization effects different to dissolubility, and the nano-emulsion system is faintly acid, has satisfied both requirements to sour environment.
4. ginsenoside and levamisole all are immunomodulators preferably.The ginsenoside is the main component of Radix Ginseng, can strengthen humoral immunization and cellular immunization simultaneously, and is higher to the safety of body; Levamisole is a chemical medicine, can improve cellular immune function.The compound recipe of levamisole and some Chinese medicine also can be obtained good immune effect.Liu Ruisheng etc. combine herbal polysaccharide with levamisole, the compound slow-releasing immunostimulant of making, the advantage separately of performance Chinese medicine and western medicine immunostimulant, it is convenient to throw clothes, slowly stable release in the chicken body, long action time can strengthen chicken humoral immune function and cellular immune function.At present the research of share about ginsenoside and levamisole is rare.But the astragalin injection for animals that long-range biotechnology company produces just contains ginsenoside and levamisole, is mainly used in the animal virosis control.
Compared with prior art, compound ginseng Saponin of the present invention and the following advantage of levamisole oil-in-water type nano emulsion adjuvant tool:
1) ginsenoside has different dissolubilities with levamisole, and it is acid that levamisole solution is, and the ginsenoside is had a considerable influence in nano-emulsion, by nano-emulsion carrier of the present invention, can realize that both are dissolved in same system simultaneously.In addition, nano-emulsion inner phase oil phase can dissolve liposoluble constituent, and the foreign minister can be dissolved water soluble ingredient, can realize multiple monomeric dissolving simultaneously equally, and not have medicine and separate out.
2) levamisole is a kind of chemical medicine, and its using dosage has only its immune effect of competence exertion within the specific limits, and levamisole mainly regulates cellular immunization, acts on singlely, and dosage is crossed conference animal is had side effects; And the ginsenoside can strengthen body fluid and cellular immunization; ginsenoside and levamisole is composite, can bring into play the complementary advantage of Chinese medicine and western medicine to a certain extent, stimulate Th1 and Th2 reaction; the body fluid of enhancing body and immunization of cell play comprehensive immanoprotection action.
3) preparation method of the present invention simply, does not need special installation; Made compound nanometer emulsion adjuvant viscosity is low, convenient injection, deposits the maintenance clear state in 4～8 ℃ or room temperature, phenomenons such as medicine is separated out, layering can not occur.
4) raw material of the present invention easily obtains, and has better biocompatibility; Compound nanometer emulsion adjuvant can reduce the use amount of medicine under the condition that does not lessen the curative effect, perhaps antigenic use amount has reduced immune cost to a certain extent.
Need not special emulsifying when 5) compound nanometer emulsion adjuvant of the present invention is joined Seedling, only need simple the mixing, low for equipment requirements, simple to operate, product quality is controlled easily.
Description of drawings
Fig. 1 is the transmission electron microscope photo (* 100000) of nano emulsion adjuvant.
Fig. 2 is the particle size distribution figure of nano emulsion adjuvant.
The specific embodiment
Further introduce product of the present invention and preparation method below by embodiment.
1) accurately take by weighing component polyoxyethylene ether (40) castor oil hydrogenated 40.00g, glycerol 1.00g, isopropyl myristate 1.64g, Radix Ginseng total saponins 1.00g, levamisole hydrochloride 0.10g and distilled water 56.26g, standby;
2) 37 ℃ with polyoxyethylene ether (40) castor oil hydrogenated, glycerol and isopropyl myristate stirring and evenly mixing, then the ginsenoside is added wherein, make its dissolving, gained is oil phase;
3) under the room temperature condition, levamisole is dissolved in the distilled water fully, leaves standstill 1h, filter, gained is water.
4) under the room temperature, water slowly is added drop-wise in the oil phase, constantly stirs in the time of dropping, until forming transparent system, filter, promptly getting outward appearance of the present invention is flaxen nano emulsion adjuvant.
Embodiment 2
Constituent content
Radix Ginseng total saponins 1.50%
Leoamisole phosphate 5.00%
Polyoxyethylene ether (40) castor oil hydrogenated 17.50%
Glycerol 17.50%
Isopropyl myristate 5.00%
Distilled water 53.50%
Embodiment 3
Constituent content
The ginsenoside Rb1 1.00%
Levamisole hydrochloride 2.00%
Polyoxyethylene ether (40) castor oil hydrogenated 15.00%
Glycerol 15.00%
Oleum Arachidis hypogaeae semen 8.80%
Distilled water 58.20%
Embodiment 4
Constituent content
Ginsenoside Rg1 0.10%
Levamisole hydrochloride 0.10%
Polyoxyethylene ether (40) castor oil hydrogenated 25.00%
Macrogol 200 20.00%
Isopropyl myristate 12.40%
Distilled water 42.40%
Embodiment 5
Constituent content
Ginsenoside Rg1 0.10%
Leoamisole phosphate 0.10%
Polyoxyethylene ether (40) castor oil hydrogenated 15.00%
PEG400 1.00%
Olive oil 1.64%
Distilled water 82.16%
Embodiment 6
Constituent content
The ginsenoside Rb1 2.00%
Leoamisole phosphate 9.00%
Polyoxyethylene ether (35) castor oil hydrogenated 31.30%
PEG400 10.70%
Liquid paraffin 5.00%
Distilled water 42.00%
Embodiment 7
Constituent content
Radix Ginseng total saponins 2.00%
Levamisole hydrochloride 4.00%
Propylene glycol 10.70%
Wheat germ oil 5.00%
Distilled water 50.00%
Embodiment 8
Constituent content
The ginsenoside Rb1 2.00%
Levamisole hydrochloride 3.00%
Polyoxyethylene ether (40) castor oil hydrogenated 22.30%
Macrogol 200 10.70%
Wheat germ oil 2.00%
Distilled water 60.00%
Embodiment 9
Constituent content
Ginsenoside Rg1 1.00%
Levamisole hydrochloride 1.00%
Polyoxyethylene ether (40) Oleum Ricini 22.30%
Glycerol 10.70%
Vitamin E 2.00%
Distilled water 63.00%
Constituent content
Radix Ginseng total saponins 2.00%
Leoamisole phosphate 2.00%
Polysorbate60 28.00%
Glycerol 10.00%
Isopropyl myristate 5.00%
Distilled water 53.00%
The physicochemical property of test example 1 nano emulsion adjuvant
1.1 outward appearance and pH value nano emulsion adjuvant of the present invention is a light yellow transparent liquid, good fluidity, pH are 6.02.
1.2 viscosity conveying end internal diameter is the 1.2mm glass pipette, draws the 1mL sample, room temperature condition record down flows out the 0.4mL needed time of sample (s), is its viscosity.Nano emulsion adjuvant viscosity of the present invention is 4.20s.
1.3 the morphologic observation nano emulsion adjuvant drops on the copper mesh that is covered with supporting film after suitably diluting with distilled water, leaves standstill 10min, drips Salkowski's solution negative staining 5min on copper mesh of 3% again, volatilizes naturally, nano-emulsion is spheroidal under the transmitted electron mirror, sees accompanying drawing 1.
1.4 particle diameter and distribution Zetasizer Nano ZS nano particle size instrument thereof record the particle size distribution of nano emulsion adjuvant, see accompanying drawing 2.Its mean diameter is 72.2nm, and polydispersity index is (PDI) 0.052.Particle diameter accounts for 97.7% at the particle of 43.8～78.8nm, only accounts for 2.3% greater than the particle of 78.8nm.The particle size distribution range of nano emulsion adjuvant of the present invention is narrow, and size ratio is more even.
1.5 study on the stability
Nano emulsion adjuvant still keeps the outward appearance of transparent homogeneous in the centrifugal 10min of 10000rpm speed, layering and medicine do not occur and phenomenon such as separates out.
Nano emulsion adjuvant is sub-packed in the cillin bottle, after packing, places,, measure each index such as pH value, emulsion droplet particle diameter and content, see Table 1 in the 15th day and sampling in the 30th day respectively under 4,25,37,40,60 ℃ and high light (4500 ± 500) the lx condition.Nano emulsion adjuvant is placed 30d under 4,25,37,40 ℃ and illumination condition, liquid keeps the clear state, does not see layering, flocculation and breakdown of emulsion, and pH value, emulsion droplet particle diameter and medicament contg are not seen significant change.But under 60 ℃ of conditions, it is muddy that nano emulsion adjuvant becomes, and puts and recover the clear attitude under the room temperature again.Show that nano emulsion adjuvant of the present invention is comparatively stable room temperature or 4 ℃.
The stability of table 1 nano emulsion adjuvant
The immunological adjuvant effect test of test example 2 nano emulsion adjuvants
The ICR female mice is divided into 9 groups at random, 5 every group.Wherein use normal saline and OVA antigen (100 μ g/ only) to come immune mouse respectively for two groups.All the other each groups are on OVA antigen (100 μ g/ only) basis, add aluminium glue (Alum 50 μ g/ only) respectively, ginsenoside (GS) and levamisole (LMS) normal saline solution (GS 10 μ g+LMS 250 μ g/ only, GS 50 μ g+LMS 250 μ g/ only, GS 250 μ g+LMS 250 μ g/ only) and ginsenoside (GS) and levamisole (LMS) nano-emulsion (GS-NE 10 μ g+LMS 250 μ g/, GS-NE 50 μ g+LMS 250 μ g/, GS-NE 250 μ g+LMS 250 μ g/).Little mouse's head is exempted from back 21d and is carried out secondary immunity, and two exempt from back 2 week blood sampling, and separation of serum, ELISA detect serum OVA inducing specific antibody horizontal, and experimental data is represented with X ± S, with minimum variation square law in the SAS8.02 software, checks the diversity between each group.Observe immunity front and back mice behavior and body weight change.
Respectively organize for the first time mice after the immunity and occur being afraid of cold outside stress and body weight descend to some extent, but the very fast disappearance of stress, body weight recovers just to be weightening finish trend gradually; Two respectively organize the mice body weight after exempting from, and significant change does not take place, and mice is all no abnormal variation at aspects such as appetite and ability to acts.Each is organized the influence that OVA exempted from the mice serum specific antibody level and sees Table 2.
Each group of table 2 is exempted from influence (n=5, the x ± S) of mice serum OVA inducing specific antibody horizontal
Annotate: compare with the OVA antigen group,
1)P＜0.05; Compare with Alum adjuvant group,
2)P＜0.05; Compare with GS 250 μ g+LMS 250 μ g,
3)P＜0.05.
Behind the mice secondary immunity, GS-NE+LMS 250 each experimental group of μ g (10,50 and 250 μ g) serum OVA specific IgG, IgG1 and IgG2a antibody horizontal all are significantly higher than OVA antigen control group and GS+LMS 250 each experimental group of μ g (10,50 and 250 μ g) (P＜0.05); The IgG of GS-NE+LMS 250 each experimental group of μ g and IgG1 antibody horizontal and Alum adjuvant group be there was no significant difference on statistics, but the IgG and the IgG1 antibody horizontal of GS-NE 50 μ g+LMS 250 μ g group are higher than Alum adjuvant group, and GS-NE+LMS 250 each experimental group of μ g (10,50 and 250 μ g) IgG2a antibody horizontal all is significantly higher than Alum adjuvant group (P＜0.05); GS-NE+LMS 250 each experimental group of μ g (10,50 and 250 μ g) interior IgG, IgG1 and IgG2a antibody horizontal there was no significant difference, wherein three kinds of antibody horizontals of GS-NE 50 μ g+LMS 250 μ g are the highest.
The ginsenoside can promote Th1 type and Th2 type antibody response.Th1 type immunne response mainly produces antibody such as IgG2a, and the Th2 type mainly produces antibody such as IgG1.People such as Rivera report that the ginsenoside does not have adjuvant effect when dosage 160 μ g, have adjuvant effect when 830 μ g.This experiment finds that nano emulsion adjuvant produces the suitable of specific antibody level and aluminium glue when 10～250 μ g, obviously is better than ginsenoside's normal saline solution.Nano-emulsion can strengthen ginsenoside's immunocompetence, promotes Th1 and Th2 immunne response, reduces ginsenoside's dosage, and possibility nano-emulsion particle diameter is little on the one hand, and the ginsenoside is enriched in the emulsion droplet; On the other hand, may play the effect of adsorption antigen, thereby increase the surface area of medicine and antigenic action, can finely act on, stimulate production of antibodies with antigen presenting cell and antibody forming cell.
Claims (3)
1. compound ginseng Saponin and levamisole nano emulsion adjuvant is characterized in that the particle diameter of this nano emulsion adjuvant is made by following weight percentages between 1～100nm:
The ginsenoside 0.10%～2.00%
Levamisole 0.10%～9.00%
Surfactant 15.00%～40.00%
Cosurfactant 1.00%～20.00%
Oil 1.64%～12.40%
Distilled water 42.00%～82.16%
The gross weight of above-mentioned raw materials is 100%;
Described ginsenoside is Radix Ginseng total saponins or panaxoside monomer;
Described levamisole is the levamisole salt;
Described surfactant is one or more in polyoxyethylene ether castor oil hydrogenated, polyoxyethylene ether Oleum Ricini, tween 80 and the Tween-60;
Described cosurfactant is selected from: Macrogol 200, PEG400, glycerol and propylene glycol one or more;
Described grease separation one or more in Oleum Arachidis hypogaeae semen, olive oil, isopropyl myristate, vitamin E oil, liquid paraffin and wheat germ oil.
2. compound ginseng Saponin according to claim 1 and levamisole nano emulsion adjuvant is characterized in that, are made by following weight percentages:
The ginsenoside 1.00%～1.50%
Levamisole 2.00%～5.00%
Surfactant 17.50%～25.00%
Cosurfactant 10.70%～17.50%
Oil 5.00%～8.80%
Distilled water 50.00%～60.00%
The gross weight of above-mentioned raw materials is 100%.
3. the preparation method of described compound ginseng Saponin of claim 1 and levamisole nano emulsion adjuvant is characterized in that, comprises the following steps:
1) take by weighing ginsenoside, levamisole, surfactant, cosurfactant, oil and distilled water, standby;
2) at 37 ℃ the ginsenoside is dissolved in surfactant, cosurfactant and the oily formed oil phase, stirring is dissolved the ginsenoside fully, and gained is oil phase;
3) under the room temperature, levamisole is dissolved in the distilled water, stirring is dissolved it fully, filters, and gained is water;
4) under the room temperature, water slowly is added drop-wise in the oil phase, constantly stirs in the time of dropping,, filter, promptly until forming transparent system.
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| CN104857511A (en) * | 2015-02-13 | 2015-08-26 | 浙江大学 | Ginsenoside-containing vaccine diluent |
| CN105963343A (en) * | 2016-05-14 | 2016-09-28 | 运城学院 | Compound radix codonopsis total saponins and immunopolysaccharides nano emulsion composition and preparation method thereof |
| CN106924730A (en) * | 2017-02-14 | 2017-07-07 | 商丘美兰生物工程有限公司 | PRV Aloe Vera Gel nano emulsion adjuvant inactivated vaccine and preparation method thereof |
| CN108578688A (en) * | 2018-04-03 | 2018-09-28 | 武汉轻工大学 | The preparation method of multiple nano-emulsion vaccine adjuvant |
| CN108853493A (en) * | 2018-07-26 | 2018-11-23 | 中国人民解放军陆军军医大学 | Ophiopogonin D and its nano-emulsion are preparing the application in vaccine adjuvant |
| CN110507606A (en) * | 2012-12-18 | 2019-11-29 | 唐纳吉有限公司 | Transdermal antiparasitic preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110507606A (en) * | 2012-12-18 | 2019-11-29 | 唐纳吉有限公司 | Transdermal antiparasitic preparation |
| CN104857511A (en) * | 2015-02-13 | 2015-08-26 | 浙江大学 | Ginsenoside-containing vaccine diluent |
| CN105963343A (en) * | 2016-05-14 | 2016-09-28 | 运城学院 | Compound radix codonopsis total saponins and immunopolysaccharides nano emulsion composition and preparation method thereof |
| CN106924730A (en) * | 2017-02-14 | 2017-07-07 | 商丘美兰生物工程有限公司 | PRV Aloe Vera Gel nano emulsion adjuvant inactivated vaccine and preparation method thereof |
| CN106924730B (en) * | 2017-02-14 | 2019-11-08 | 商丘美兰生物工程有限公司 | Porcine pseudorabies virus Aloe Vera Gel nano emulsion adjuvant inactivated vaccine and preparation method thereof |
| CN108578688A (en) * | 2018-04-03 | 2018-09-28 | 武汉轻工大学 | The preparation method of multiple nano-emulsion vaccine adjuvant |
| CN108578688B (en) * | 2018-04-03 | 2022-02-11 | 武汉轻工大学 | Preparation method of multiple nanoemulsion vaccine adjuvant |
| CN108853493A (en) * | 2018-07-26 | 2018-11-23 | 中国人民解放军陆军军医大学 | Ophiopogonin D and its nano-emulsion are preparing the application in vaccine adjuvant |
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Application publication date: 20100317 |