CN104367998B - A kind of preparation method of aluminum hydroxide adjuvant - Google Patents
A kind of preparation method of aluminum hydroxide adjuvant Download PDFInfo
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- CN104367998B CN104367998B CN201410635636.3A CN201410635636A CN104367998B CN 104367998 B CN104367998 B CN 104367998B CN 201410635636 A CN201410635636 A CN 201410635636A CN 104367998 B CN104367998 B CN 104367998B
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- aluminum hydroxide
- hydroxide adjuvant
- added dropwise
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- 239000002671 adjuvant Substances 0.000 title claims abstract description 48
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 58
- 239000000243 solution Substances 0.000 claims abstract description 34
- 239000011780 sodium chloride Substances 0.000 claims abstract description 29
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000012266 salt solution Substances 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 17
- 230000001954 sterilising effect Effects 0.000 claims abstract description 5
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 3
- 238000012856 packing Methods 0.000 claims abstract description 3
- 239000011541 reaction mixture Substances 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 54
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 19
- 229910052782 aluminium Inorganic materials 0.000 claims description 19
- 239000004411 aluminium Substances 0.000 claims description 19
- 238000010438 heat treatment Methods 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000012528 membrane Substances 0.000 claims description 6
- 230000033228 biological regulation Effects 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 230000002572 peristaltic effect Effects 0.000 claims description 5
- 239000002244 precipitate Substances 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- 239000012670 alkaline solution Substances 0.000 claims description 2
- 239000000568 immunological adjuvant Substances 0.000 claims description 2
- 230000006641 stabilisation Effects 0.000 claims description 2
- 238000011105 stabilization Methods 0.000 claims description 2
- 238000004659 sterilization and disinfection Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000001556 precipitation Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 6
- 239000008215 water for injection Substances 0.000 description 6
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 241000694440 Colpidium aqueous Species 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 159000000013 aluminium salts Chemical class 0.000 description 3
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000009938 salting Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229940037003 alum Drugs 0.000 description 2
- 229910001593 boehmite Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- FAHBNUUHRFUEAI-UHFFFAOYSA-M hydroxidooxidoaluminium Chemical compound O[Al]=O FAHBNUUHRFUEAI-UHFFFAOYSA-M 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 241000208340 Araliaceae Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 1
- REDXJYDRNCIFBQ-UHFFFAOYSA-N aluminium(3+) Chemical compound [Al+3] REDXJYDRNCIFBQ-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960003983 diphtheria toxoid Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000011164 primary particle Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to a kind of compound method of aluminum hydroxide adjuvant, comprise the following steps:(1) aluminum salt solution, aqueous slkali are prepared;(2) aqueous slkali is added dropwise in aluminum salt solution;(3) step (2) reaction product is centrifuged, dissolved again with 0.1 0.5% NaCl solution;(4) reaction mixture washed is heated;(5) wash;(6) sterilizing and packing.
Description
Technical field
The invention belongs to bacterin preparation field, in particular to a kind of preparation method of aluminum hydroxide adjuvant.
Background technology
Aluminium adjuvant is used for long time as immunologic adjuvant, and its security is with immunological enhancement already by people
Confirmed.Glenny and its colleague have found aluminium salt (KAl (SO first in nineteen twenty-six4)2·12H2O) it is total to diphtheria toxoid
Precipitation, can significantly improve its potency.Present Alum adjuvant mainly has alum, aluminum phosphate, aluminium hydroxide.Wherein hydroxide
Aluminium adjuvant is employed the most extensive.
Aluminum hydroxide adjuvant is the boehmite (poorly-crystalline boehmite, PCB) of weak crystal formation, its chemistry
Formula AlO (OH), it is inclined aluminium hydroxide.X-ray diffraction show the aluminum hydroxide adjuvants of PCB crystal habits 12.6,27.5,
38.2nd, 48.4 and 64.4 ° of 2 θ has wider characteristic peak to occur.Isoelectric point is to describe a ginseng of aluminum hydroxide adjuvant feature
Number, its isoelectric point of the aluminium hydroxide of different commercializations is different,Isoelectric point be 9.5 or so, and
Rehydragel LV isoelectric point is 11.6.Aluminum hydroxide adjuvant is into size 1- by many fibrous primary particle agglomerations
10 μm of secondary, the size of this particle play an important role when playing adjuvant immunity effect, and the size of particle can influence
Intake of the BMDC to antigen, particle is bigger, and intake effect is poorer.In addition, it is different from《Chinese Pharmacopoeia》It is extensive
Professional etiquette is determined,《European Pharmacopoeia》(7.0 editions) are on also including attached ability, sedimentation situation etc. in aluminum hydroxide adjuvant quality control index
Parameter of physicochemical properties etc..
Existing 2 big aluminum hydroxide adjuvant manufacturer of the whole world (Brenntag Biosector and General Chemical,
That is trade nameWith Rehydragel LV aluminum hydroxide adjuvant) hydrogen-oxygen for meeting above-mentioned parameter can be produced
Change aluminium adjuvant, but due to being related to its know-how, do not there is the preparation of its aluminum hydroxide adjuvant of disclosed document and patent report
Method.It is therefore, domestic that there is an urgent need to a kind of commercialization aluminum hydroxide adjuvant for approving in the world of industrialized production of being capable of at present
Method.
The content of the invention
The present invention relates to a kind of compound method of aluminum hydroxide adjuvant, this method makes the crystalline substance of the aluminum hydroxide adjuvant made
The physicochemical property such as volume morphing, particle size, isoelectric point, adsorption capacity parameter is consistent with the commercialization adjuvant approved in the world.
The collocation method of aluminum hydroxide adjuvant of the present invention comprises the following steps:
(1) aluminum salt solution, aqueous slkali are prepared;
(2) aqueous slkali is added dropwise in aluminum salt solution, 50-70 DEG C of keeping temperature during dropwise addition, is added dropwise to certain pH
During value, invariable in the pH value by the way that alkaline solution and aluminum salt solution maintenance reaction system are added dropwise simultaneously, constant pH is added dropwise
Continue 30~60min, then stop that aluminum salt solution is added dropwise, continue that aqueous slkali is added dropwise to pH value of reaction system compared to constant dropwise addition
When pH value lifting 0.8~1.7 be reaction end;
(3) step (2) reaction product is centrifuged, washed with 0.1-0.5% NaCl solution, then with 0.1-0.5%'s
NaCl solution dissolves again;
(4) reaction mixture washed is heated to 60-100 DEG C of the first temperature, is stirred and is added dropwise in heating process
0.1-4% NaOH solution regulation pH value is untill 5.8-7.0 and stabilization, due to having aluminium hydroxide during pH is adjusted
Crystal structure change, so as to cause pH value to reduce always, therefore it is required that be added drop-wise to final pH not change (this again
When be that structure is basicly stable) untill, at such a temperature be heat-treated 1-5 hours, then raise temperature to 110~150 DEG C of heat of second temperature
Processing 1~43 hour;
(5) wash:Product after heat treatment is centrifuged, washed 1-3 times with the sodium chloride solution containing 0.1-0.5%,
And dissolved again with 0.1-0.5% sodium chloride;
(6) sterilizing and packing:Using moist heat sterilization, sterilized 30 minutes at 121 DEG C, then in an aseptic environment keep 60~
Dispensed after being filtered at 80 DEG C with 50-150 micron membrane filters.
In collocation method of the present invention,
Aluminium salt can be AlCl3 or Al2 (SO4) 3 in step (1), and alkali can be NaOH or ammoniacal liquor, preferably AlCl3 with
NaOH solution is reacted, and Al2 (SO4) 3 reacts with ammonia spirit;
The concentration of described aluminium salt is 0.01-1M, and the concentration of aqueous slkali is 0.01-1M;
Described aluminum salt solution is most preferably aluminium composition 0.25mol/L AlCl36H2O solution;
Described aqueous slkali is preferably 0.265mol/L NaOH solution;
Certain pH value scope described in step (2) is 2.5~4.5, preferably 3.0-4.0, after constant pH is added dropwise,
Continue be added dropwise aqueous slkali to pH value of reaction system compared to constant dropwise addition when pH value lifting 0.8 be reaction end;
Described solution is added dropwise and is preferably added dropwise by peristaltic pump, and the temperature of reaction system is preferably 60 DEG C;
Step (3) washing is to be washed 1~3 time using 0.3% (wt) NaCl solution, is less than to free aluminium content
Untill the 5% of total aluminium content, it is preferred that wash untill free aluminium content is less than the 1% of total aluminium content.
The first temperature described in step (4) is preferably 80 DEG C, and heat treatment time is preferably 3h at the first temperature, described
Second temperature is preferably 120 DEG C, and the time being heat-treated at the second temperature is preferably 4h, and described pH adjusting agent is preferably
0.4% NaOH solution;
Washing described in step (5) is preferably to be to sodium chloride concentration by washing of precipitate using 0.1% sodium chloride
Untill 0.1%-0.5%, the described sodium chloride that concentration is 0.25% that is dissolved as dissolves again.
Filtering described in step (6) is preferably at 70 DEG C, is filtered with 100 microns of worry film.
Technical scheme of the present invention has the beneficial effect that:Crystal type is PCB;Granular size is distributed in 1-10 μ mostly
M, and it is homogeneous, without visible lumpy precipitate;Adsorption capacity is high;Isoelectric point between 9-12, these features with it is general in the world
Commercialization aluminum hydroxide adjuvant is basically identical.
Brief description of the drawings
Fig. 1 is the x-ray diffraction pattern that aluminum hydroxide adjuvant is prepared in embodiment 1.
Fig. 2 is the granular size figure that aluminum hydroxide adjuvant is prepared in embodiment 1.
Embodiment
The present invention provides a kind of compound method of aluminum hydroxide adjuvant, and this method is last using a series of technical step
Obtained aluminum hydroxide adjuvant physicochemical property is consistent with the commercialization adjuvant approved in the world.
The preparation of the aluminum hydroxide adjuvant of embodiment 1.
(1) weigh AlCl36H2O to be dissolved in water for injection, be configured to aluminium composition 0.25mol/L aluminum salt solution.
Weigh NaOH to be dissolved with water for injection, be configured to the aqueous slkali that NaOH content is 0.265mol/L.
(2) first aluminum salt solution being added in reactor, adds 2 times of volume injection water, unlatching is uniformly mixed,
Temperature is raised to 60 DEG C.Aqueous slkali is added dropwise with peristaltic pump, when being added drop-wise to pH4.0, while aluminum salt solution is added dropwise, by adjusting aluminium
The rate of addition of salting liquid, pH is set to keep constant.Constant pH, which is added dropwise, lasts about 40min, stops that aluminum salt solution is added dropwise, continues to be added dropwise
Aqueous slkali is to pH4.8.
(3) will be washed 1 time with isometric 0.3% sodium chloride solution after above-mentioned solution centrifugal, and with 0.3% sodium chloride
Solution dissolves precipitation again.The NaCl and purpose dissolved is to remove free aluminium ion, and keep certain ion strong
Degree.
(4) adjust temperature to 80 DEG C, be added dropwise 0.4% NaOH regulation pH, until pH is kept between 5.8-7.0 stably,
80 DEG C of heat treatment 3h are kept, are changed to 120 DEG C of heat treatment 4h.
(5) cool down, centrifuge, washing precipitation 1 time with containing 0.1% sodium chloride solution, finally being entered with 0.25%NaCl solution
Row weight is molten.0.25%NaCl solution can provide the basic ionic strength of long-time storage.
(6) kept for 70 DEG C after sample of the weight after molten is sterilized, obtained in an aseptic environment by 100 microns of filter membrane sterile
Uniform aluminum hydroxide adjuvant.
The preparation of the aluminum hydroxide adjuvant of embodiment 2.
(1) weigh AlCl36H2O to be dissolved in water for injection, be configured to aluminium composition 0.25mol/L aluminum salt solution.
Weigh NaOH to be dissolved with water for injection, be configured to the aqueous slkali that NaOH content is 0.265mol/L.
(2) first aluminum salt solution being added in reactor, adds 2 times of volume injection water, unlatching is uniformly mixed,
Temperature is raised to 60 DEG C.Aqueous slkali is added dropwise with peristaltic pump, when being added drop-wise to pH3.5, while aluminum salt solution is added dropwise, by adjusting aluminium
The rate of addition of salting liquid, pH is set to keep constant.Constant pH, which is added dropwise, lasts about 35min, stops that aluminum salt solution is added dropwise, continues to be added dropwise
Aqueous slkali is to pH4.5.
(3) will be washed 1 time with the sodium chloride solution of 2 times of volumes 0.3% after above-mentioned solution centrifugal, and with 0.3% chlorination
Sodium solution dissolves precipitation again.
(4) adjust temperature to 80 DEG C, be added dropwise 0.4% NaOH regulation pH, until pH is kept between 5.8-7.0 stably,
80 DEG C of heat treatment 3h are kept, are changed to 120 DEG C of heat treatment 4h.
(5) cool down, centrifuge, washing precipitation 1 time with containing 0.1% sodium chloride solution, finally being entered with 0.25%NaCl solution
Row weight is molten.
(6) kept for 70 DEG C after sample of the weight after molten is sterilized, obtained in an aseptic environment by 100 microns of filter membrane sterile
Uniform aluminum hydroxide adjuvant.
The preparation of the aluminum hydroxide adjuvant of embodiment 3.
(1) weigh AlCl36H2O to be dissolved in water for injection, be configured to aluminium composition 0.25mol/L aluminum salt solution.
Weigh NaOH to be dissolved with water for injection, be configured to the aqueous slkali that NaOH content is 0.265mol/L.
(2) first aluminum salt solution being added in reactor, adds 2 times of volume injection water, unlatching is uniformly mixed,
Temperature is raised to 60 DEG C.Aqueous slkali is added dropwise with peristaltic pump, when being added drop-wise to pH3.5, while aluminum salt solution is added dropwise, by adjusting aluminium
The rate of addition of salting liquid, pH is set to keep constant.Constant pH, which is added dropwise, lasts about 40min, stops that aluminum salt solution is added dropwise, continues to be added dropwise
Aqueous slkali is to pH5.2.
(3) will be washed 1 time with the sodium chloride solution of 0.5 times of volume 0.3% after above-mentioned solution centrifugal, and with 0.3% chlorine
Change sodium solution and dissolve precipitation again.
(4) adjust temperature to 80 DEG C, be added dropwise 0.4% NaOH regulation pH, until pH is kept between 5.8-7.0 stably,
80 DEG C of heat treatment 3h are kept, are changed to 120 DEG C of heat treatment 4h.
(5) cool down, centrifuge, washing precipitation 1 time with containing 0.1% sodium chloride solution, finally being entered with 0.25%NaCl solution
Row weight is molten.
(6) kept for 70 DEG C after sample of the weight after molten is sterilized, obtained in an aseptic environment by 100 microns of filter membrane sterile
Uniform aluminum hydroxide adjuvant.
The aluminum hydroxide adjuvant physical and chemical parameter of embodiment 4. detects
The physical and chemical parameter of aluminum hydroxide adjuvant obtained by above-described embodiment 1-3 is detected,
(1) using the crystal habit of X-ray diffraction measure aluminum hydroxide adjuvant;
(2) surface charge of Zeta potential analysis-e/or determining sample is used, so as to calculate the isoelectric point of aluminium hydroxide;
(3) with Malvern laser particle size analyzer EPA2000 measure granular sizes;
(4) the measure reference of adsoptivity and sedimentation situation《European Pharmacopoeia》(7.0 editions)
Every physical and chemical parameter testing result of the aluminum hydroxide adjuvant of above-described embodiment 1~3 is as shown in table 1 below
1. each embodiment of table and commercially available import aluminum hydroxide adjuvant physical and chemical parameter
Note 1., unit:mgBSA/mgAl
Finally it should be noted that above example is only used for explaining the essence of the present invention, it is not intended as protecting the present invention
Protect the restriction of scope.
Claims (9)
1. a kind of collocation method of aluminum hydroxide adjuvant, it is characterised in that comprise the following steps:
(1) aluminium composition 0.25mol/L AlCl is prepared3·6H2O aluminum salt solution, 0.265mol/L NaOH aqueous slkalis;
(2) aqueous slkali is added dropwise in aluminum salt solution, 60 DEG C of keeping temperature during dropwise addition, when being added dropwise to certain pH value, institute
The certain pH value stated is any one point value between 3.0~4.0, remains anti-by the way that alkaline solution and aluminum salt solution are added dropwise simultaneously
Answer system invariable in the pH value, constant pH, which is added dropwise, continues 30~60min, then stops that aluminum salt solution is added dropwise, continues to drip
Add aqueous slkali to pH value of reaction system compared to constant dropwise addition when pH value lifting 0.8~1.7 be reaction end;
(3) step (2) reaction product is centrifuged, washed with 0.1-0.5% NaCl solution, then use 0.1-0.5% NaCl
Solution dissolves again;
(4) reaction mixture washed is heated to 60-100 DEG C of the first temperature, is stirred in heating process and 0.1- is added dropwise
4% NaOH solution regulation pH value is heat-treated 3 hours untill 5.8-7.0 and stabilization, then raises temperature to second at such a temperature
110~150 DEG C of temperature is heat-treated 4 hours;
(5) wash:Product after heat treatment is centrifuged, is washed 1-3 times, is used in combination with the sodium chloride solution containing 0.1-0.5%
0.1-0.5% sodium chloride dissolves again;
(6) sterilizing and packing:Using moist heat sterilization, sterilized 30 minutes at 121 DEG C, then keep 60~80 DEG C in an aseptic environment
It is lower filtered with 50-150 micron membrane filters after dispense.
2. the collocation method of aluminum hydroxide adjuvant according to claim 1, it is characterised in that in step (2), described is molten
Drop adds as being added dropwise by peristaltic pump.
3. the collocation method of aluminum hydroxide adjuvant according to claim 1, it is characterised in that in step (3), the washing
The NaCl solution for being 0.3% for use quality content is washed 1~3 time, and be less than total aluminium content to free aluminium content 5% is
Only.
4. the collocation method of aluminum hydroxide adjuvant according to claim 3, it is characterised in that washing to free aluminium content
Less than total aluminium content 1% untill.
5. the collocation method of aluminum hydroxide adjuvant according to claim 1, it is characterised in that in step (4), described
One temperature is 80 DEG C, and described second temperature is 120 DEG C, and described 0.1-4% NaOH solution is 0.4% NaOH solution.
6. the collocation method of aluminum hydroxide adjuvant according to claim 1, it is characterised in that in step (5), described washes
Wash for using 0.1% sodium chloride by washing of precipitate untill sodium chloride concentration is 0.1%-0.5%, described is dissolved as using
The sodium chloride that concentration is 0.25% dissolves again.
7. the collocation method of aluminum hydroxide adjuvant according to claim 1, it is characterised in that in step (6), described mistake
Filter at 70 DEG C, to be filtered with 100 microns of filter membrane.
8. the aluminum hydroxide adjuvant product prepared by any described methods of claim 1-7.
9. application of the aluminum hydroxide adjuvant as immunologic adjuvant described in claim 8.
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CN107998387A (en) * | 2017-12-06 | 2018-05-08 | 周柳青 | A kind of medical porous Al (OH)3The preparation method and applications of adjuvant |
CN108066759B (en) * | 2017-12-22 | 2023-01-13 | 北京民海生物科技有限公司 | Aluminum hydroxide adjuvant and preparation method and application thereof |
CN109395075A (en) * | 2018-11-01 | 2019-03-01 | 大连理工大学 | AlOOH nano adjuvant with controllable crystallinity and preparation method thereof |
CN109432417A (en) * | 2018-11-01 | 2019-03-08 | 大连理工大学 | AlOOH nano adjuvant with controllable length-diameter ratio and preparation method 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 |
CN111000996A (en) * | 2019-12-27 | 2020-04-14 | 深圳康泰生物制品股份有限公司 | 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 its application in vaccine preparation |
CN111643662A (en) * | 2020-07-01 | 2020-09-11 | 大连理工大学 | Hydroxyl alumina nano adjuvant synthesized based on fully mixed flow model and synthetic method thereof |
CN113559255B (en) * | 2021-07-30 | 2024-10-18 | 成都生物制品研究所有限责任公司 | Preparation method of aluminum hydroxide adjuvant |
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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