CN108066759A - A kind of aluminum hydroxide adjuvant and preparation method and application - Google Patents
A kind of aluminum hydroxide adjuvant and preparation method and application Download PDFInfo
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- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
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- A61K39/00—Medicinal preparations containing antigens or antibodies
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Abstract
The present invention provides a kind of aluminum hydroxide adjuvants and preparation method and application.The present invention is washed using 0.75% 0.95% sodium chloride solution and prepared by mixing aluminum salt solution and sodium hydroxide solution.The present invention is improved existing aluminum hydroxide adjuvant preparation process, aluminum hydroxide adjuvant surface charge can be realized using the method for the present invention and grain size tends towards stability and pH value is closer to human body fluid pH value, suitable for the absorption of one or more antigens, meet the application demand of a variety of vaccines in the formulation.
Description
Technical field
The invention belongs to bacterin preparation fields, and in particular to a kind of aluminum hydroxide adjuvant and preparation method and application.
Background technology
Immunologic adjuvant of the aluminium adjuvant as vaccine, using the history for having 90 years.Since it is with high absorption capacity
There is preferable adsorptivity better than other adjuvants with to some protide antigens, it is also uniquely by the people of U.S. FDA certification
Use vaccine adjuvant.Early in nineteen twenty-six, Glenny etc. has found that aluminium adjuvant is suspended with diphtheria toxin (DT), hence it is evident that increases diphtheria toxin
Immunogenicity.At present aluminium adjuvant mainly have aluminium hydroxide, aluminum phosphate, aluminium hydroxide-aluminum phosphate mixture.
Aluminum hydroxide adjuvant is widely used in vaccine preparation, and adsorption capacity is one of key index in prepared by vaccine.Hydrogen-oxygen
Change aluminium adjuvant particle is uniformly tiny, and large specific surface area just possesses high adsorption rate condition.In bacterin preparation, adsorption rate is higher, exempts from
Epidemic disease effect will be more apparent.
Method prepared by aluminum hydroxide adjuvant is typically that lye is added in into aluminum salt solution, the neutral uncharged Al of generation
(H2O3)(OH)3Mutually assemble and precipitate.Aluminium hydroxide is amphoteric compound, isoelectric point 11.4, therefore, in physiological ph feelings
It is positively charged when being used under condition, by electrostatic attraction, it is hydrophobic the effects that power and antigen binding.
The content of the invention
The present invention provides a kind of aluminum hydroxide adjuvant and preparation method and application, and the method for the present invention makes the hydrogen prepared
The physicochemical properties such as aluminum adjuvant particle size, adsorption capacity are consistent with commercialization.
Technical solution of the present invention is as follows：
A kind of preparation method of aluminum hydroxide adjuvant, includes the following steps：
1) 1-14% is added dropwise simultaneously into the sodium chloride solution of 0.85-0.95% (mass fraction) under conditions of stirring
The sodium hydroxide solution of the aluminum salt solution and 0.4-4% (mass fraction) of (mass fraction), by adjust the aluminum salt solution and
It is 5.5-6.4 that the rate of addition of the sodium hydroxide solution, which maintains pH value of reaction system scope,；Treat that aluminium ion is dense in reaction system
When degree reaches 2-10mg/mL, stop that the aluminum salt solution is added dropwise；Continue to be added dropwise the sodium hydroxide solution to pH value of reaction system
It is titration end-point for 6.4-7.2；
The aluminium salt is alum (KAl (SO4)·12H2O)；
2) stirring, after reaction system is static, supernatant discarding, using the chlorination of 0.75-0.95% (mass fraction) are stopped
Sodium solution carries out changing liquid, thoroughly the free potassium ion of removal, sulfate ion；
3) moist heat sterilization；
Official method can be used in the moist heat sterilization, general to use 121 DEG C, 30-60 minutes；
4) after moist heat sterilization, room temperature is cooled under conditions of stirring；It can be prepared by aluminum hydroxide adjuvant.
Room temperature of the present invention is generally 15-25 DEG C.
Further, the step 1) speed of agitator is 100-1000rpm, is preferably 300-700rpm.
Further, the concentration of the step 1) sodium chloride solution is 0.9% (mass fraction).
Further, the concentration of the step 1) aluminum salt solution is 8-10% (mass fraction).
Further, the concentration of the step 1) sodium hydroxide solution is 1-4% (mass fraction), is preferably 2%.
Further, step 1) maintains reactant by adjusting the rate of addition of the aluminum salt solution and sodium hydroxide solution
It is that pH value range is 5.9-6.2.
Further, step 1) continues to be added dropwise the sodium hydroxide solution to reaction after the aluminum salt solution drips
System pH is 6.5-6.8, is titration end-point.
Further, step 2) carries out changing liquid using the sodium chloride solution of 0.8-0.9% (mass fraction).General displacement 2-
6 times.
Further, the step 4) speed of agitator is 100-1000rpm, is preferably 300-700rpm.
On the basis of common knowledge of the art, above-mentioned each optimum condition can be mutually combined each preferably to get the present invention
Example.
A kind of preferable embodiment of the present invention is：A kind of preparation method of aluminum hydroxide adjuvant, includes the following steps：
1) 10% (matter is added dropwise simultaneously into the sodium chloride solution of 0.9% (mass fraction) under conditions of 500rpm stirrings
Measure fraction) aluminum salt solution and 2% (mass fraction) sodium hydroxide solution, by adjusting the aluminum salt solution and sodium hydroxide
It is 6.0 that the rate of addition of solution, which maintains pH value of reaction system scope,；Treat that aluminium ion concentration reaches 2-10mg/mL in reaction system
When, stop that the aluminum salt solution is added dropwise；
It is 6.8 to continue that the sodium hydroxide solution to pH value of reaction system is added dropwise, and is titration end-point；
The aluminium salt is alum；
2) stirring, after reaction system is static, supernatant discarding, using the sodium chloride solution of 0.9% (mass fraction) are stopped
It carries out changing liquid, thoroughly the free potassium ion of removal, sulfate ion；
3) moist heat sterilization：Using 121 DEG C, 30-60 minutes；
4) after moist heat sterilization, in 100-1000rpm stirring conditions down toward cooling room temperature, you can aluminum hydroxide adjuvant is made.
Present invention additionally comprises aluminum hydroxide adjuvants prepared by the above method.
Aluminum hydroxide adjuvant grain size prepared by the present invention is 1.4-12.6nm, is preferably 2.5-8.9nm.
A kind of preferable embodiment of the present invention is：A kind of aluminum hydroxide adjuvant, grain size 2.5-8.9nm, granularity point
Cloth is as shown in Figure of description 1, isoelectric point 10.2.
Present invention additionally comprises application of the above-mentioned aluminum hydroxide adjuvant in vaccine is prepared；The vaccine is preferably people's epidemic disease
Seedling includes but not limited to virus type adsorbed vaccine, protide adsorbed vaccine.
Preferably, the aluminum concentration of aluminum hydroxide adjuvant is 0.2-0.6mg/mL in the vaccine；The further preferred epidemic disease
The final adsorption concentration of aluminium is 0.3-0.5mg/mL in seedling.
The present invention is improved existing aluminum hydroxide adjuvant preparation process, and hydroxide can be realized using the method for the present invention
Aluminium adjuvant surface charge and grain size tend towards stability and pH value is closer to human body fluid pH value, suitable for one or more antigens
Absorption, meet the application demand of a variety of vaccines in the formulation.
Description of the drawings
Fig. 1 is the granule size figure of aluminum hydroxide adjuvant prepared by the present invention.
Specific embodiment
Following embodiment is not limited to the scope of the present invention for illustrating the present invention.It is not specified in embodiment specific
Technology or condition person carry out according to the described technology of document in the art or condition or according to product description.It is used
Production firm person is not specified in reagent or instrument, is the conventional products that can be commercially available by regular distributor.
The preparation of 1 aluminum hydroxide adjuvant of embodiment
(1) KAl (SO are weighed4)·12H2O is dissolved in water for injection, is configured to 10% aluminum salt solution；Weigh hydroxide
Sodium is dissolved in water for injection, is configured to 2% sodium hydroxide solution.
(2) 0.9% sodium chloride solution is added in into reactor, opens stirring 500rpm.
(3) above-mentioned aluminum salt solution and sodium hydroxide solution is added dropwise simultaneously into reactor, by adjusting wriggling pump speed, ties up
It is constant to hold pH value of reaction system 6.0, when aluminium ion concentration reaches 2-10mg/mL in reaction system, stops that the aluminium salt is added dropwise
Solution；Continue that above-mentioned sodium hydroxide solution is added dropwise, terminal to pH value 6.8 stops, and continues stirring 30 minutes.
(4) after static, remove supernatant, add in 0.9% sodium chloride solution, repeat replace 4 times, remove free potassium from
Son, sulfate ion；
(5) aluminum hydroxide adjuvant, 121 DEG C of moist heat sterilization, 30min are collected.After the completion of sterilizing, when temperature is down to 80 DEG C,
It is stirred, speed of agitator 500rpm, stirs to (20-25 DEG C) collection aluminum hydroxide adjuvant of room temperature.
The detection of 2 aluminum hydroxide adjuvant adsorption capacity of embodiment
Aluminum hydroxide adjuvant and Denmark's Alhydrogel adjuvants prepared by embodiment 1 according to《European Pharmacopoeia》Method detects
Adsorption capacity.
(1) experimental method
Aluminum hydroxide adjuvant (sample sets) and Denmark's Alhydrogel adjuvants (control group) prepared by embodiment 1 is dilute respectively
It is 5mg/mL to release to aluminium content, and it is 6.0 to adjust pH value.Secure ph is the BSA (bovine serum albumin(BSA)) that 6.0 contents are 10mg/mL
Solution is diluted to concentration as 1mg/mL, 2mg/mL, 3mg/mL, 5mg/mL, 8mg/mL, 10mg/mL respectively, and it is 6.0 to adjust pH value.
By aluminum hydroxide adjuvant and above-mentioned series BSA solution according to volume ratio 1:4 ratio mixing, final aluminium content are 1mg/mL.From
The heart collects supernatant, and Supernatant protein content is detected using lowry methods.
(2) experimental result
Testing result is as shown in table 1 (testing result is BSA content mg/mL in supernatant)
Table 1
The results show：Albumen is not detected in the BSA solution supernatants of three low concentration contents, and the albumen of three high concentrations presents
Increasing trend, sample sets are consistent with control group, meet criterion of acceptability.
3 aluminum hydroxide adjuvant particle size distribution measuring of embodiment
The aluminum hydroxide adjuvant and Denmark's Alhydrogel adjuvants prepared to embodiment 1 carries out physical and chemical parameter detection；
(1) using Malvern Zetaszer potentiometers and MPT-2 autotitrators detection sample aluminum hydroxide adjuvant etc.
Electric point；
(2) using the granular size of 3000 laser particle analyzers of Malvern Mastersier detection sample aluminum hydroxide adjuvant.
More than testing result see the table below 2 and Fig. 1：
Table 2：Aluminum hydroxide adjuvant physical and chemical parameter testing result
By aluminum hydroxide adjuvant prepared by the method for the present invention it can be seen from the result of table 2 and Fig. 1 and commercial product grain size point
Cloth is consistent.
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. a kind of preparation method of aluminum hydroxide adjuvant, which is characterized in that include the following steps：
1) aluminum salt solution and 0.4- of 1-14% is added dropwise in the sodium chloride solution under conditions of stirring to 0.85-0.95% simultaneously
4% sodium hydroxide solution maintains reactant by the rate of addition for adjusting the aluminum salt solution and the sodium hydroxide solution
It is that pH value range is 5.5-6.4；When aluminium ion concentration reaches 2-10mg/mL in reaction system, it is molten to stop the dropwise addition aluminium salt
Liquid；It is 6.4-7.2 to continue that the sodium hydroxide solution to pH value of reaction system is added dropwise, and is titration end-point；The aluminium salt is sulphur
Sour aluminium potassium；
2) stirring is stopped, after reaction system is static, supernatant discarding carries out changing liquid using the sodium chloride solution of 0.75-0.95%,
The thoroughly free potassium ion of removal, sulfate ion；
3) moist heat sterilization；
4) after moist heat sterilization, room temperature is cooled under conditions of stirring；It can be prepared by aluminum hydroxide adjuvant.
2. preparation method according to claim 1, which is characterized in that the concentration of the step 1) sodium chloride solution is
0.9%；And/or
The concentration of the step 1) aluminum salt solution is 8-10%；And/or
The concentration of the step 1) sodium hydroxide solution is 1-4%, is preferably 2%.
3. preparation method according to claim 1 or 2, which is characterized in that step 1) by adjust the aluminum salt solution and
It is 5.9-6.2 that the rate of addition of sodium hydroxide solution, which maintains pH value of reaction system scope,；And/or
For step 1) after the aluminum salt solution drips, it is 6.5- to continue that the sodium hydroxide solution to pH value of reaction system is added dropwise
6.8, it is titration end-point.
4. according to claim 1-3 any one of them preparation methods, which is characterized in that the step 1) speed of agitator is 100-
1000rpm is preferably 300-700rpm；And/or
Step 4) the speed of agitator is 100-1000rpm, is preferably 300-700rpm.
5. according to claim 1-4 any one of them preparation methods, which is characterized in that step 2) uses the chlorine of 0.8-0.9%
Change sodium solution to carry out changing liquid.
6. preparation method according to claim 1, which is characterized in that include the following steps：
1) 10% aluminum salt solution and 2% is added dropwise simultaneously in sodium chloride solution to 0.9% under conditions of 500rpm stirrings
Sodium hydroxide solution maintains pH value of reaction system scope by the rate of addition for adjusting the aluminum salt solution and sodium hydroxide solution
For 6.0；When aluminium ion concentration reaches 2-10mg/mL in reaction system, stop that the aluminum salt solution is added dropwise；Continue described in dropwise addition
Sodium hydroxide solution to pH value of reaction system is 6.8, is titration end-point；
2) stirring is stopped, after reaction system is static, supernatant discarding is carried out changing liquid, thoroughly gone using 0.9% sodium chloride solution
Except free potassium ion, sulfate ion；
3) moist heat sterilization：Using 121 DEG C, 30-60 minutes；
4) after moist heat sterilization, in 100-1000rpm stirring conditions down toward cooling room temperature, you can aluminum hydroxide adjuvant is made.
7. aluminum hydroxide adjuvant prepared by any one of claim 1-6 the method.
8. a kind of aluminum hydroxide adjuvant, grain size 1.4-12.6nm are preferably 2.5-8.9nm.
9. a kind of aluminum hydroxide adjuvant, grain size 2.5-8.9nm, size distribution is as shown in Figure of description 1；And/or its etc.
Electricity point is 10.2.
10. application of any one of the claim 7-9 aluminum hydroxide adjuvants in vaccine is prepared；The vaccine is preferably used for people
Vaccine includes but not limited to virus type adsorbed vaccine, protide adsorbed vaccine；
It is further preferred that the aluminum concentration of aluminum hydroxide adjuvant is 0.2-0.6mg/mL in the vaccine；The more preferable vaccine
The final adsorption concentration of middle aluminium is 0.3-0.5mg/mL.
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| CN201711403067.XA CN108066759B (en) | 2017-12-22 | 2017-12-22 | Aluminum hydroxide adjuvant and preparation method and application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111175348A (en) * | 2019-12-27 | 2020-05-19 | 深圳康泰生物制品股份有限公司 | Detection method of isoelectric point of aluminum hydroxide adjuvant and application of detection method in preparation of vaccine |
| CN111184860A (en) * | 2020-02-21 | 2020-05-22 | 中牧实业股份有限公司 | Improved aluminum hydroxide adjuvant and preparation method thereof |
| CN112569350A (en) * | 2019-09-30 | 2021-03-30 | 成都迈科康生物科技有限公司 | Aluminum hydroxide adjuvant and preparation method and application thereof |
| CN113666404A (en) * | 2021-09-23 | 2021-11-19 | 北京智飞绿竹生物制药有限公司 | Preparation method of high-concentration nano-scale aluminum hydroxide adjuvant suitable for large-scale production |
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| CN102167372A (en) * | 2010-11-30 | 2011-08-31 | 汪晋强 | Method for preparing aluminum hydroxide and iron hydroxide coproduced with potassium hydroxide and sodium sulfate by using vanadium slurry |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112569350A (en) * | 2019-09-30 | 2021-03-30 | 成都迈科康生物科技有限公司 | Aluminum hydroxide adjuvant and preparation method and application thereof |
| CN112569350B (en) * | 2019-09-30 | 2024-02-09 | 成都迈科康生物科技有限公司 | Aluminum hydroxide adjuvant and preparation method and application thereof |
| CN111175348A (en) * | 2019-12-27 | 2020-05-19 | 深圳康泰生物制品股份有限公司 | Detection method of isoelectric point of aluminum hydroxide adjuvant and application of detection method in preparation of vaccine |
| CN111184860A (en) * | 2020-02-21 | 2020-05-22 | 中牧实业股份有限公司 | Improved aluminum hydroxide adjuvant and preparation method thereof |
| CN111184860B (en) * | 2020-02-21 | 2022-05-06 | 中牧实业股份有限公司 | Improved aluminum hydroxide adjuvant and preparation method thereof |
| CN113666404A (en) * | 2021-09-23 | 2021-11-19 | 北京智飞绿竹生物制药有限公司 | Preparation method of high-concentration nano-scale aluminum hydroxide adjuvant suitable for large-scale production |
| CN113666404B (en) * | 2021-09-23 | 2023-07-28 | 北京智飞绿竹生物制药有限公司 | Preparation method of high-concentration nanoscale aluminum hydroxide adjuvant suitable for large-scale production |
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