CN100389823C - Preparation method of hepatitis vaccine and its use - Google Patents
Preparation method of hepatitis vaccine and its use Download PDFInfo
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- CN100389823C CN100389823C CNB2005101351928A CN200510135192A CN100389823C CN 100389823 C CN100389823 C CN 100389823C CN B2005101351928 A CNB2005101351928 A CN B2005101351928A CN 200510135192 A CN200510135192 A CN 200510135192A CN 100389823 C CN100389823 C CN 100389823C
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Abstract
The present invention relates to a preparation method and a purpose of novel hepatitis B vaccine. The preparation method is basically characterized in that hepatitis B vaccine which is sold in a market and has no adjuvant is adsorbed on a nanometer aluminum adjuvant to generate the novel hepatitis B vaccine. The particle diameter of the nanometer aluminum adjuvant adopted by the novel hepatitis B vaccine is from 1 to 999 nanometers, and the components of the nanometer aluminum adjuvant is an aluminum hydroxide compound. The aluminum hydroxide compound whose particle diameter is from 1 to 999 nanometers has the advantages of good dispersion performance, no impurity, etc. Used equipment and technology are simple. The preparation method has favorable development prospects. 10 to 20 times of nanometer aluminum adjuvant is increased to adsorb the hepatitis B vaccine, and the novel hepatitis B vaccine of the present invention is formed. The novel hepatitis B vaccine of the present invention has an obvious waterfall release effect, and the novel hepatitis B vaccine can generate obvious antibody response within the former three weeks after immune. The novel hepatitis B vaccine is safe in use, and an injection part basically has no inflammation node, and even fundamentally has no inflammation node.
Description
Technical field
The present invention relates to a kind of human Hepatitis B virus vaccine and preparation method thereof, particularly contain Hepatitis B virus vaccine of nano-class aluminum adjuvant and preparation method thereof.
Technical background
The main component of Hepatitis B virus vaccine is HBsAg, and isoelectric point, IP is 4.5, and HBsAg contains a large amount of phosphate groups.Because the isoelectric point, IP (iep) of HBsAg and aluminum hydroxide adjuvant is respectively 4.5 and 11.4.Therefore, in the neutral environment of body pH=7.4, the former demonstrates negative charge, and the latter is a positive charge, and the two is because electrostatic force can well produce adsorption.
The main mechanism of aluminium adjuvant adsorption antigen comprises: electrostatic force, hydrophobic interaction and group exchange [Vogel FR, Hem SL.In:Plotkin SA, Orenstein MD, editors.Vaccines.4th ed.New York:Sanders].Absorption by hydrophobic interaction produces can be subjected to reducing the restriction that is exposed to hydrophobic region in the water environment because of protein folding.The hydroxyl of aluminium adjuvant and antigenic phosphate radical generation part exchange, and have produced adsorption [Bleam WF, Pfeffer PE, Goldberg S, et al.
31P solid-state nuclear magneticresonance study of phosphate adsorption at the boehmite/aqueous solution interface.Langmuir.1991,7:1702-1712.].Phosphate radical and aluminum have formed the endosphere surface under the inorganic equal value exchange effect of covalent bond.Phosphate radical is stronger than hydroxyl to the connection of aluminum atom, thereby replaced hydroxide ion [Hingston FJ, Atkinson RJ, Quirk JP.Specific adsorption of anions.Nature (London) .1967,215:1459-1461. with Liu J, Feldkamp JL, White JL, et al.Adsorption of phosphateby aluminum hydroxycarbonate.J Pharm Sci.1984,73:1355-1358.].[SeemaIyer such as Seema, Robin Robinett RS, Harm HogenEsch, et al.Mechanism of adsorption ofhepatitis B surface antigen by aluminum hydroxide adjuvant.Vaccine.2004,24:1475-1479] find that the adsorptivity of the two shows as high affine adsorption isotherm.Adsorbance through blue Mil's Equation for Calculating gained is the every microgram aluminum of 1.7 micrograms, and this is meant the HBsAg quantity in the monolayer scope, and the absorption affinity intensity index, adsorption coefficient is 6.0 milliliters of every micrograms.High adsorption strength shows that absorption is owing to strong absorption affinity, and the hydroxyl of antigenic phosphate radical of HBsAg and aluminum hydroxide adjuvant, the exchange between these two aglucons provides the strongest absorption mechanism.Can not influence adsoptivity by increasing ionic strength, the prompting charge attraction is not topmost absorption affinity.Can not influence adsoptivity by increasing ethylene glycol, the prompting hydrophobic interaction does not account for mastery reaction equally.Behind aluminium hydroxide absorption HBsAg, under 37 ℃ of conditions, be exposed in the interstitial fluid 12 hours, about 5% antigen desorption external.Commercial Hepatitis B virus vaccine only had only 1% antigen desorption after 48 hours.So the absorption of HBsAg and aluminium hydroxide is little with external variation in vivo, suffered desorption is extremely small.
Absorption just because of HBsAg and aluminium hydroxide is not by hydrophobic interaction, charge attraction, and mainly is the phosphate radical of HBsAg and the hydroxyl of aluminum hydroxide adjuvant, and the exchange between these two aglucons provides the strongest absorption mechanism.And little with external adsoptivity variation in the body, suffered desorption is extremely small.So when aluminum hydroxide adjuvant became nano-scale particle, because specific surface area sharply increases, nano-class aluminum adjuvant had excellent properties such as surface reaction activity increases, increase at the surface activity center, absorbability enhancing, adsorbable more HBsAg antigen.Formed hepatitis vaccine shows many advantages.
This moment, the particle diameter of aluminium adjuvant became the principal element that influences adsoptivity.
The present invention finds, is about 10-20 times of conventional aluminium adjuvant absorption with the Hepatitis B virus vaccine of nano-class aluminum adjuvant absorption of the present invention.
We are with the hepatitis vaccine immune animal of indication of the present invention, and in contrast with the common Hepatitis B virus vaccine of market sale, observe animal body fluid immunne response situation, 1st week, 2nd week of nano-class aluminum adjuvant behind the initial immunity Cavia porcellus just can produce anti--HBsAg antibody, its GMT is respectively 22.974 ± 1.3612 and 26.389 ± 1.4214, and the pairing numerical value of the common Hepatitis B virus vaccine of market sale (adding conventional aluminium adjuvant) is respectively 2.0 and 13.195 ± 1.1204.
Because the particle diameter of nano-particle is little, not only can adsorb more antigen protein, and be easy to by the antigen-presenting cell in the animal body (APC) picked-up the i.e. hepatitis vaccine performance burst release effect (burst-released) behind the animals received initial immunity of sening as an envoy to.People such as Raghuvanshi [Raghuvanshi RS, Katare YK, Komal Lalwani, et al.Improved immune response from biodegradable polymerparticles entraiepepng tetanus toxoid by use of different immunization protocol andadjuvants.International Journal of Pharmaceutics.2002,245:109-121] also observe this burst release effect.The burst release effect is the rapid release of " antigen storage vault " effect.The nanometer adjuvant more can be virus antigen fast and effectively passs APC cell [Guy B, Pascal N, Francon A, et al.Design, characterization and preclinical efficacy of a cationic liiepd adjuvant for influenzasplit vaccine.Vaccine.2001; 19 (13-14): 1794-1805].
The aluminium adjuvant of present commercial usefulness is mainly aluminium hydroxide and aluminum phosphate, but the aluminium adjuvant of indication mainly is an aluminium hydroxide usually, it is actually the inclined to one side aluminium hydroxide of fibrous crystal attitude product (aluminum oxyhydroxide) of Al (OH) 3 (aluminum hydroxide) intramolecular dehydration, and molecular formula is AlOOH.
Generally acknowledge that at present the Alhydrogel that Denmark produces is a standard, its micelle size is 3.07 microns.The isoelectric point, IP pI of aluminium adjuvant (isoelectric point)=11.4, positively charged in the interstitial fluid of body pH=7.4, the characteristics that can well adsorb acid proteantigen:
1. service time is long: bring into use from nineteen twenty-six; 2. safe and effective; 3. inexpensive; 4. extensive use; 5. assist a ruler in governing a country a little less than the effect to some vaccine or do not have adjuvanticity; 6. easily induce the expression of IgE; 7. the injection part digit pair occurs erythema, subcutaneous nodule, contact hypersensitivity and granulomatous inflammation etc., even the more serious local response of also appearance that has.
Summary of the invention
The invention provides a kind of novel human Hepatitis B virus vaccine, it is characterized in that, use the nano-class aluminum adjuvant material, make commercially available human Hepatitis B virus vaccine adsorbed by nano-class aluminum adjuvant more, effect is better than the adsorbed traditional human Hepatitis B virus vaccine of conventional aluminium adjuvant.
Novel human Hepatitis B virus vaccine of the present invention can produce apace after the immunity inoculation in the first time and reply, and is suitable for urgent prophylactic immunization.The novel human Hepatitis B virus vaccine also greatly reduces side effect, and the struvite tuberosity at vaccinate position obviously reduces even do not have at all.
The present invention is achieved by the following technical solutions, with the aluminium hydroxide raw material make nano_scale particle that particle diameter is the 1-999 nanometer, with the raw material of this aluminum hydroxide particle as aluminium adjuvant in the vaccine formulation, preferred aluminum hydroxide particles granularity is the 1-400 nanometer, be more preferably the 1-100 nanometer, most preferred is 72 nanometers.
The present invention measures hydroxide particle-size by the ultramicroscope method, to obtain qualified stay-in-grade nanoscale aluminum hydroxide particles.
Assay method is seen the embodiment of the invention.
Vaccine of the present invention contains the purified hepatitis B virus inactivated vaccine raw material that vaccine is used that can be used as, and through the nano-class aluminum adjuvant of the inventive method preparation, and vaccine protective agent human albumin.
Vaccine raw material of the present invention can adopt the known technology preparation, also can buy on market.
Vaccine of the present invention, each composition proportion is:
Hepatitis B virus recombiant vaccine raw material accounts for 20-80%; Nano-class aluminum adjuvant accounts for 20-80%
Hepatitis B virus inactivated vaccine raw material 50% preferably; Nano-class aluminum adjuvant 50%.
Hepatitis B virus vaccine of the present invention, described nano-class aluminum adjuvant consumption is every liter of a 0.1-5.0 mole, the dosage of described Hepatitis B virus vaccine is every of 5.0-60 microgram.Preferably the nano-class aluminum adjuvant consumption is 1.0 moles every liter.
Vaccine its preparation method of the present invention is that with the routine techniques of above composition according to the preparation bacterin preparation, through mixing, making can be for the pharmaceutical bacterin preparation of injection.
Nano-class aluminum adjuvant of the present invention can adopt two kinds of methods of chemical method and Mechanical Method.Chemical method can make nano level powder body.The mechanical crushing method cost is low, output is big, be the preparation ultrafine powder main means, now large-scale application in commercial production.Micronizing can be divided into dry pulverization process and waterproof pulverization: different according to the principle that produces crush force in the crushing process, dry pulverization process has several forms such as air-flowing type, dither formula, screw (rod) mill formula, paddle type mill and Self-milling; Waterproof pulverization mainly is colloid mill and homogenizer.The present invention can obtain the aluminium adjuvant product of particle diameter in the 1-999 nanometer by above arbitrary method, preferably uses chemical method.
As following method:
Get a certain amount of AlCl3, cyclohexane extraction and distilled water in beaker, add neutral ion protective agent, cosurfactant again, stir with the high speed dispersion homogenizer then, make its emulsifying become microemulsion.Pour the reaction bulb heated and stirred of lid into, slowly dropwise add excessive ammonia, cover lid reacted 3 hours, was Al (OH) 3 colloidal sols, adopted freeze-drying or boulton process, obtained dry powder.
Wherein cosurfactant is a mixed surfactant, is mixed with n-octyl alcohol by benzalkonium bromide, and mass ratio was with 1: 4; 1: 3; 1: 2; 8: 5; 1: 1; 2: 1; 3: 1; 4: 1 proportioning, best proportioning are 1: 1.Wherein mixed surfactant and cyclohexane extraction are 1: 9,1: 4,1: 3,4: 1,9: 1,3: 1,5: 0 according to mass ratio.The using dosage of ammonia is the 1-50 milliliter, and recommended dose is 10 milliliters, and the about 10-50 of speed that drips that adds ammonia drips per minute, recommend to drip about 30 per minutes of speed, the pH value that keeps system is more than 8, and recommending pH value is 10, response time is 0.5-5 hour, and Best Times is 2 hours; The water that uses is the pure water of laboratory purposes, recommends to use deionized water; Concentration of alcohol is 75-100%, and recommended density is 95%; The purpose that adds acetone in the reaction system is a breakdown of emulsion, and working concentration is 1.0 moles every liter, recommends operational analysis pure.
Preferable methods of the present invention is listed in the embodiment of the invention.
The present invention adopts a large amount of human Hepatitis B virus vaccine of nano-class aluminum adjuvant material absorption of the present invention, thereby has formed novel human Hepatitis B virus vaccine.Novel human Hepatitis B virus vaccine is on the basis that has possessed conventional Hepatitis B virus vaccine advantage, and immunne response that can also the quick active body causes the inflammatory reaction of injection site obviously to reduce, even do not have inflammatory reaction at all.
Beneficial effect of the present invention is listed in the embodiments of the invention.
The specific embodiment
Further specify the present invention by the following examples.
Embodiment 1, the preparation method of nano-class aluminum adjuvant involved in the present invention
Get a certain amount of AlCl3, cyclohexane extraction and distilled water in beaker, add again and add benzalkonium bromide-n-octyl alcohol-cyclohexane extraction-AlCl3 solution system again, stir with the high speed dispersion homogenizer then, make its emulsifying become microemulsion.Pour the reaction bulb heated and stirred of lid into, slowly dropwise add excessive ammonia, cover lid reacted 3 hours, was Al (OH) 3 colloidal sols, adopted freeze-drying or boulton process.Be dissolved in the water then, and use ultrasonic dispersing, in aqueous solution, be dispersity.The method that electron microscope observation is measured is measured the nanoparticle warp.
Embodiment 2, the preparation method of novel human Hepatitis B virus vaccine
The nano-class aluminum adjuvant of preparation is made into 0.1 milligram every milliliter (is solvent with water), ultrasonic dispersing nano-class aluminum adjuvant solution 20 minutes, adding commercially available no adjuvant human Hepatitis B virus vaccine dosage is every of 5.0 microgram, with human rabies vaccine and nano-class aluminum adjuvant volume mixture by 3: 1,4 ℃ of one weeks of absorption, with 15000 rpms centrifugal 30 minutes, adopt the ELISA double antibody sandwich method to detect rabies vaccine antigen concentration in the supernatant.According to the method for above introduction, the novel human Hepatitis B virus vaccine be attracted to the more conventional aluminium adjuvant of quantity on the nano-class aluminum adjuvant of unit mass raising 10-20 doubly.
Embodiment 3, the result of hepatitis vaccine immune mouse of the present invention
Main agents and preparation thereof
Wrap diluted liquid (0.05mol/L sodium carbonate-sodium bicarbonate buffer liquid, pH9.6) form:
Na2CO31.5g, NaHCO32.9g, Na2N30.2g adds distilled water to 1000ml, transfers to pH9.6.
Confining liquid (5% calf serum/PBS solution) is formed:
Calf serum 50ml adds PBS (pH7.4) 950ml.
Phosphate buffer (PB)
A liquid (0.2mol/L biphosphate sodium water solution) is formed: NaH2PO4H2O 27.6g is dissolved in ultra-pure water 1000ml.
B liquid (0.2mol/L sodium hydrogen phosphate aqueous solution) is formed: Na2HPO47H2O 53.6g (or Na2HPO412H2O 71.6g or Na2HPO42H2O 35.6g) is dissolved in ultra-pure water 1000ml.
Sample diluent (PBS, 0.01mol/L phosphate buffered saline) composition: PB A liquid 19ml; PB B liquid 81ml; NaCl 18.5g; Ultra-pure water 1000ml.
(PBST, pH7.4) form: PBS liquid 1000ml adds Tween 200.5ml to cleaning mixture, and thimerosal 0.1g transfers to pH7.4.
Substrate solution (OPD-H2O2) is formed and is originated: OPD (o-phenylenediamine＜hydrochlorate 〉).
A liquid (0.1mol/L citric acid solution) is formed: citric acid 19.2g, and adding distil water is to 1000ml;
B liquid (0.2mol/LNa2HPO4 solution) is formed: Na2HPO412H2O 71.7g, adding distil water is to 1000ml.
Stop buffer (2mol/L H2SO4 solution) is formed: distilled water 600ml, concentrated sulphuric acid 100ml (slowly drip and constantly stir) adds distilled water to 900ml.
The goat anti-mouse IgG of horseradish peroxidase-labeled.
Key instrument:
Microplate reader, electronic balance, pH analyzer, 96 hole polystyrene elisa plates, electric heating constant temperature hydro-thermal case, micro-bull cell harvestor.
Experimental technique: 20 of healthy Balb/c mices, female, in 6～8 ages in week, body weight 10～16 grams are divided into each 10 of experimental group, matched groups, at random by identical method and dosage immune mouse.ELISA measures antibody titer.
Indirect enzyme-linked immunosorbent (ELISA) method detects antibody, and the result is with the average OD value representation in two multiple holes, and specimen OD value to be measured/negative control OD value＞2.1 are judged to be the positive.
Embodiment 4, and nano-class aluminum adjuvant of the present invention is assisted a ruler in governing a country the experimental result of HBsAg vaccine immunity Cavia porcellus
The laboratory animal grouping: 10 of healthy guinea pigs, female, at 2 monthly ages, 100～150g is divided into each 50 of experimental group, matched groups at random, and two groups immunization method is identical with dosage.
The method of assay method and evaluation is with experimental example 3.
Embodiment 5, safety experiment
The reference literature reported method [Zhao Jing, Wang Lixin. the research of gelatine microsphere Hepatitis B virus vaccine animal immune effect. Chinese microbiology and Journal of Immunology .2000,20 (3): 236-239]
To above experimental guinea pig and mice, respectively observed 1 time in the 3rd day, the 7th day and the 14th day after immunity, and observe the mouse spleen variation.Hepatitis vaccine mice immunized of the present invention and Cavia porcellus all are good for and deposit, weight increase, and no whole body abnormal response, subcutaneous scleroma is significantly less than matched group.
Embodiment 6, the preparation method of novel human Hepatitis B virus vaccine
The nano-class aluminum adjuvant of preparation is made into 5.0 milligrams every milliliter (is solvent with water), ultrasonic dispersing nano-class aluminum adjuvant solution 20 minutes, adding commercially available no adjuvant human Hepatitis B virus vaccine dosage is every of 60 microgram, with human rabies vaccine and nano-class aluminum adjuvant volume mixture by 3: 1,4 ℃ of one weeks of absorption, with 15000 rpms centrifugal 30 minutes, adopt the ELISA double antibody sandwich method to detect rabies vaccine antigen concentration in the supernatant.According to the method for above introduction, the novel human Hepatitis B virus vaccine be attracted to the more conventional aluminium adjuvant of quantity on the nano-class aluminum adjuvant of unit mass raising 10-20 doubly.
Embodiment 7, the preparation method of novel human Hepatitis B virus vaccine
The nano-class aluminum adjuvant of preparation is made into 1.0 milligrams every milliliter (is solvent with water), ultrasonic dispersing nano-class aluminum adjuvant solution 20 minutes, adding commercially available no adjuvant human Hepatitis B virus vaccine dosage is every of 10 microgram, with human rabies vaccine and nano-class aluminum adjuvant volume mixture by 3: 1,4 ℃ of one weeks of absorption, with 15000 rpms centrifugal 30 minutes, adopt the ELISA double antibody sandwich method to detect rabies vaccine antigen concentration in the supernatant.According to the method for above introduction, the novel human Hepatitis B virus vaccine be attracted to the more conventional aluminium adjuvant of quantity on the nano-class aluminum adjuvant of unit mass raising 10-20 doubly.
Embodiment 8, the preparation method of novel human Hepatitis B virus vaccine
The nano-class aluminum adjuvant of preparation is made into 2.0 milligrams every milliliter (is solvent with water), ultrasonic dispersing nano-class aluminum adjuvant solution 20 minutes, adding commercially available no adjuvant human Hepatitis B virus vaccine dosage is every of 10 microgram, with human rabies vaccine and nano-class aluminum adjuvant volume mixture by 3: 1,4 ℃ of one weeks of absorption, with 15000 rpms centrifugal 30 minutes, adopt the ELISA double antibody sandwich method to detect rabies vaccine antigen concentration in the supernatant.According to the method for above introduction, the novel human Hepatitis B virus vaccine be attracted to the more conventional aluminium adjuvant of quantity on the nano-class aluminum adjuvant of unit mass raising 10-20 doubly.
Claims (1)
1. the preparation method of a human Hepatitis B virus vaccine, described human Hepatitis B virus vaccine contains hepatitis B virus recombiant vaccine raw material 20-80%; Nano-class aluminum adjuvant 20-80%, wherein the average particulate diameter of nano-class aluminum adjuvant is 72 nanometers, it is characterized in that, may further comprise the steps: hepatitis B virus recombiant vaccine raw material and nano-class aluminum adjuvant are mixed, the preparation process of wherein said nano-class aluminum adjuvant is as follows: get AlCl3, cyclohexane extraction and distilled water in beaker, add neutral ion protective agent, cosurfactant again, stir with the high speed dispersion homogenizer then, make its emulsifying become microemulsion; Pour the reaction bulb heated and stirred of lid into, slowly dropwise add excessive ammonia, cover lid, reacted 3 hours, be Al (OH) 3 colloidal sols, adopt freeze-drying or boulton process drying, wherein cosurfactant is a mixed surfactant, mixed with n-octyl alcohol by benzalkonium bromide, its mass ratio is 1: 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101991850A (en) * | 2010-11-05 | 2011-03-30 | 东南大学 | Preparation technology of nanometer aluminum hydroxide adjuvant |
| CN104208670B (en) * | 2014-09-09 | 2017-07-28 | 韩自勤 | A kind of pharmaceutical composition for treating hepatitis B |
| CN104940233B (en) * | 2015-06-29 | 2020-02-21 | 湖南科伦制药有限公司 | Preparation method of anti-hepatitis B immune ribonucleic acid freeze-dried powder injection |
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Non-Patent Citations (6)
| Title |
|---|
| 纳米铝佐剂吸附HBsAg及其免疫学效应的研究. 何萍等.高等学校化学学报，第26卷第5期. 2005 |
| 纳米铝佐剂吸附HBsAg及其免疫学效应的研究. 何萍等.高等学校化学学报，第26卷第5期. 2005 * |
| 纳米铝佐剂的制备及其辅佐HBsAg的免疫学效应研究. 何萍，第12,13,16,17,23,24,26,40页，第三军医大学. 2004 |
| 纳米铝佐剂的制备及其辅佐HBsAg的免疫学效应研究. 何萍，第12,13,16,17,23,24,26,40页，第三军医大学. 2004 * |
| 铝佐剂毫微粒的制备及其对小鼠TH2细胞亚群影响的研究. 何萍等.中华微生物学和免疫学杂志，第25卷第4期. 2005 |
| 铝佐剂毫微粒的制备及其对小鼠TH2细胞亚群影响的研究. 何萍等.中华微生物学和免疫学杂志，第25卷第4期. 2005 * |
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