CN109432418A - A kind of aluminum phosphate nanometer adjuvant and preparation method thereof that isoelectric point is controllable - Google Patents
A kind of aluminum phosphate nanometer adjuvant and preparation method thereof that isoelectric point is controllable Download PDFInfo
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Abstract
The invention belongs to pharmaceutical technology field, a kind of nano-aluminum phosphate adjuvant of the vaccine based on chemical precipitation principle, preparation method and its method of isoelectric point regulation are specifically disclosed.The partial size of above-mentioned adjuvant is between 10-40nm, between PDI monodispersity index 0.2-0.4, between isoelectric point 3-6.Aluminium phosphate adjuvant homogeneity of the present invention is good, property is stable, favorable dispersibility, and by the pH value in regulation reaction precipitation process, can be with the isoelectric point of accuracy controlling final product.The method of the present invention operating procedure is simple, easily controllable, is that the fields of biomedicine such as vaccine adjuvant have potential application prospect.
Description
Technical field
The present invention relates to the improvement of aluminum phosphate colloid production process, relates generally to a kind of aluminum phosphate that isoelectric point is controllable and receive
Rice adjuvant and preparation method thereof.
Background technique
In recent years, with to the continuous understanding of microorganism pathogenesis and deepening continuously for immunological investigation, live vector epidemic disease
The research of the new generation vaccines such as seedling and protein vaccine has been made significant headway.However, due to the immunogenicity of new generation vaccine
Limitation, the immune response that induction body generates is inadequate, therefore, the immune response effect of its antigen is guided and enhanced using adjuvant
It answers, gives human body more permanent effective preventive protection.
Although novel adjuvant develops rapidly, most of to be in the experimental study stage, Alum adjuvant is in vaccine adjuvant
In still occupy a big chunk ratio.In 80 kinds of vaccines of FDA approved, 36% vaccine has used different types of
Adjuvant, wherein the vaccine comprising Alum adjuvant accounts for 86% of the sum containing Adjuvanted vaccines, it is seen that carry out in-depth study to it and have both
Importance and necessity.As a kind of cationic Antigen adsorption agent important in Alum adjuvant, aluminum phosphate is all ground all the time
The characteristic of the hot spot studied carefully, immunological effect and adjuvant is closely bound up.Currently, the isoelectric point of commercialization Aluminium phosphate adjuvant is 5.0,
Exist in the solution of pH=7.4 in anionic form, is the good adsorption agent of cationic antigen.Studies have shown that aluminum phosphate
The immunological effect of adjuvant depends greatly on adjuvant itself to the adsorption capacity of antigen, thus by controlled material etc.
The adsorption capacity that material resistant original was put and then changed to electricity is the emphasis of Aluminium phosphate adjuvant research.Previous technical study shows phosphorus
The characteristic of sour aluminium adjuvant depends on the condition of preparation, and the concentration including reagent adds the sequence of reagent, addition and mix reagent
Rate, stirring rate, the pH etc. of precipitation process, therefore, it is difficult to maintain stable physicochemical characteristics, Wu Fabao in production
Demonstrate,prove the repeatability between batch.Therefore, there is still a need for more effective way at industrial scale, Lai Shixian aluminum phosphates for this field
The efficient preparation of adjuvant and its accuracy controlling of isoelectric point.
It, can be with by the present invention in that carry out homogeneous precipitation under condition of different pH to Al ion with phosphate anion precipitating reagent
The Aluminium phosphate adjuvant material of different isoelectric points is obtained, the application demand of vaccine in the formulation is met.
Summary of the invention
The purpose of the present invention is to provide a kind of improved methods that is simple, efficiently preparing aluminum phosphate nanometer adjuvant, pass through
Regulate and control the pH in its reaction process, obtains a series of controllable aluminum phosphate colloids of isoelectric point.The present invention is by changing reaction process
In pH carry out the isoelectric point of Aluminium phosphate adjuvant product obtained by accuracy controlling, principle is the rising with reaction pH, final to produce
Object Al (OH) x (PO4) y PO4/ OH ratio increases, and the content of phosphate radical substituted hydroxy increases, the point of zero electric charge decline of product,
That is the isoelectric point decline of product.Therefore, pH is higher in reaction process, and the isoelectric point of gained Aluminium phosphate adjuvant product is smaller, thus
Realize the accuracy controlling to Aluminium phosphate adjuvant isoelectric point.
The method that the present invention prepares vaccine aluminum phosphate nanometer adjuvant, specific steps are as follows:
1) it takes inorganic aluminate to be dissolved completely in deionized water and forms transparent clear aluminum salt solution (that is: precursor solution)；
Taking inorganic aluminate to be dissolved completely in the process of deionized water is to be stirred, dissolve at a certain temperature.
2) soluble alkali phosphate solution is added dropwise in above-mentioned aluminum salt solution as precipitating reagent, stirring is brought it about uniformly
Precipitating；The amount that sodium phosphate is added is controlled, reaction end pH is controlled, obtains a series of products of the pH from 3.0 to 6.0.
3) it sterilizes, cool down, be centrifuged, washing, is dried to obtain Aluminum phosphate powders solid.
For in the technical solution of preparation method described above, in preferred situation, the aluminium salt is mainly but unlimited
It, can be using such as aluminium chloride AlCl in Aluminium chloride hexahydrate3, aluminium hydroxide Al (OH)3, aluminum sulfate Al2(SO4)3Etc. common nothing
Or mixtures thereof one kind of machine aluminium salt.
For in the technical solution of preparation method described above, in preferred situation, the phosphate precipitating agent can be with
Using or mixtures thereof one of such as tertiary sodium phosphate, disodium hydrogen phosphate phosphate anion precipitating reagent.
For in the technical solution of preparation method described above, in preferred situation, predecessor concentration described in step 2)
For 0.01-0.5M.
For in the technical solution of preparation method described above, in preferred situation, precipitating reagent described in step 2) is with before
The molar ratio for driving object is (1-3): 1, it is preferential to select molar ratio ratio≤2.
For in the technical solution of preparation method described above, in preferred situation, speed of agitator described in step 2) is
200-1000rpm, preferably 500-600rpm；Mixing time is 10-60min, preferably 35-55min.
For in the technical solution of preparation method described above, in preferred situation, dropwise addition described in step 2) is preceding
Driving in object solution has under the existence condition of Al ion, controls the drop rate of phosphate precipitating agent, uses and is added dropwise dropwise or with one
The mode that fixed rate is added dropwise can make precipitating reagent and Al ion that homogeneous precipitation occur.
For in the technical solution of preparation method described above, in preferred situation, sterilization treatment temperature is in step 3)
121 DEG C, the preferred process time is 20-30min；It is preferred that 30min.Sterilizing bottle is placed in air or ice water after reaction
It is cooled down in bath, is cooled to room temperature to reactant.
For in the technical solution of preparation method described above, in preferred situation, sterilising conditions described in step 3) are
121 DEG C, 20-30min；In embodiment, the mixed liquor reaction total volume is 70mL-100L.
For in the technical solution of preparation method described above, in preferred situation, centrifugal rotational speed described in step 3) is
4000-9000rpm, centrifugation time 5-20min, washing times are 3-5 times；Final drying temperature is 50-100 DEG C, further
Freeze-day with constant temperature obtains white solid powder, most preferably 60 DEG C preferably at 40-60 DEG C.
Another aspect of the present invention is to protect the aluminum phosphate nanometer adjuvant of method as described above preparation.
In the present invention, using certain density aluminum salt solution as presoma, in room under the action of Al ion precipitation agent
Temperature is lower to obtain that isoelectric point is different with reaction pH and the aluminum phosphate nanometer adjuvant that changes, final product partial size between 10-40nm,
Between PDI monodispersity index 0.2-0.4, between isoelectric point 3-6.Method and process of the invention is simple, easily operated, repeatability
Good, applied widely, impurity in products is easy to remove by way of washing centrifugation, this method on the basis of chemical precipitation method,
By controlling the ingredient proportion of presoma and precipitating reagent, a series of different aluminum phosphate colloids of isoelectric point are obtained.
Detailed description of the invention
Fig. 1 is the transmission electron microscope picture for reacting aluminum phosphate colloid obtained by 30min in embodiment 1 under difference pH.Fig. 1 a-f difference
For the lower resulting aluminum phosphate colloidal materials of reaction in pH=3.38,4.0,4.5,5.0,5.5 and 6.0.Wherein, scale 100nm.
Fig. 2 is the X-ray diffraction characterization result for reacting aluminum phosphate colloid obtained by 30min in embodiment 1 under difference pH.
Fig. 3 is the hydration particle diameter distribution and Zeta electric potential for reacting aluminum phosphate colloid obtained by 30min in embodiment 1 under difference pH
Characterization result.
Fig. 4 is the line for reacting the isoelectric point of aluminum phosphate colloid obtained by 30min in embodiment 1 under difference pH and successively decreasing with system pH
Linearity curve.
Fig. 5 is the transmission electron microscope characterization result for reacting aluminum phosphate colloid obtained by 30min in the system of 450mL under difference pH.
Scale is 100nm in figure.
Specific embodiment
Following nonlimiting examples can with a person of ordinary skill in the art will more fully understand the present invention, but not with
Any mode limits the present invention.
Embodiment 1
It accurately weighs 4.237g Aluminium chloride hexahydrate and 6.947g sodium phosphate and it is dissolved into 50mL at room temperature respectively
It in deionized water solution, is stirred continuously during dissolution, stirring rate is controlled in 500-600rpm, to two reagents
It is dissolved completely in after deionized water forms transparent clear solution, sodium radio-phosphate,P-32 solution is taken to be added dropwise to Aluminium chloride hexahydrate solution dropwise
In, reaction end pH is controlled, time for adding controls within 10min.Solution becomes muddy with being continuously added for sodium phosphate,
It can be observed that there is white precipitate generation, the reaction time is controlled in 30min to 35min, and resulting mixed liquor is transferred to sterilizing
In bottle, being placed in high pressure sterilization case and carrying out heat treatment 30min post-processing temperature is 121 DEG C.Finally sterilizing bottle is taken out, to certainly
It is so cooled to room temperature, reaction product is taken out, using deionized water centrifuge washing two to three times, freeze-day with constant temperature at 60 DEG C is obtained
White powdery solids, as products therefrom aluminum phosphate nanometer adjuvant.
By characterization display, the Aluminium phosphate adjuvant dispersibility synthesized under pH=3.38 and pH=6.0 preferably, produces above-mentioned material
Object is undefined structure, and secondary particle size is each about 300nm, and the distribution of the partial size and Zeta electric potential of synthetic material is equal under each pH
Meet inverse relation, with the increase of reaction end pH, isoelectric point is from 5.5 linear decreases to 4.5, the result is shown in Figure 1, and 2,3,4.
Embodiment 2
The Aluminium chloride hexahydrate of 30g is accurately weighed, is dissolved in the deionized water of 450mL while stirring, it is accurate to claim
The Aluminium chloride hexahydrate of 46g is taken, is dissolved in the deionized water of 450mL while stirring, is constantly stirred to completely molten
Solution, solution are in clear state.It takes sodium phosphate as precipitating reagent, is dropwise added dropwise to sodium phosphate aqueous solution using syringe pump
In Aluminium chloride hexahydrate solution, control sodium phosphate aqueous solution drop rate is 30mL/min, is stirred during being added dropwise, and is controlled
Stirring rate processed is 500-600rpm, and control reaction end pH is 5.26.After completion of dropwise addition, above-mentioned solution is transferred to sterilizing
In bottle, it is placed at 121 DEG C the 30min that sterilizes, after subject to sterilization, product transfer is taken out and is placed in 50mL centrifuge tube, is carried out
Washing centrifugation, makes to be washed with deionized 3-5 times, and final product is placed in surface plate and dries, and 60 DEG C of drying temperature.Final institute
Obtain the aluminum phosphate nano material that product is white.Concrete outcome is shown in Fig. 5.
For any person skilled in the art, without departing from the scope of the technical proposal of the invention, all
Many possible changes and modifications are made to technical solution of the present invention using the technology contents of the disclosure above, or are revised as
With the equivalent embodiment of variation.Therefore, anything that does not depart from the technical scheme of the invention, according to the technical essence of the invention
Any simple modifications, equivalents, and modifications made to the above embodiment should all still fall within technical solution of the present invention protection
In range.
Claims (10)
1. a kind of preparation method for the aluminum phosphate nanometer adjuvant that isoelectric point is controllable, comprising the following steps:
1) it takes inorganic aluminate to be dissolved completely in deionized water and forms transparent clear aluminum salt solution；
2) alkaline phosphatase salting liquid is added dropwise in above-mentioned aluminum salt solution, stirring brings it about homogeneous precipitation；Sodium phosphate is controlled to be added
Amount, and then control reaction end pH, obtain a series of products of the pH from 3.0 to 6.0；
3) it sterilizes, cool down, be centrifuged, washing, is dried to obtain Aluminum phosphate powders solid.
2. a kind of preparation method of the controllable aluminum phosphate nanometer adjuvant of isoelectric point according to claim 1, it is characterised in that:
The aluminium salt is or mixtures thereof one of Aluminium chloride hexahydrate, aluminium chloride, aluminum sulfate or aluminium hydroxide.
3. a kind of preparation method of the controllable aluminum phosphate nanometer adjuvant of isoelectric point according to claim 1, it is characterised in that:
The phosphate precipitating agent is phosphate anion precipitating reagent.
4. a kind of preparation method of the controllable AlOOH nanometer adjuvant of crystallinity according to claim 3, it is characterised in that:
The phosphate precipitating agent is selected from or mixtures thereof one of sodium phosphate, disodium hydrogen phosphate.
5. a kind of preparation method of the controllable AlOOH nanometer adjuvant of crystallinity according to claim 1, it is characterised in that:
The predecessor concentration is 0.01-0.5M.
6. a kind of preparation method of the controllable aluminum phosphate nanometer adjuvant of isoelectric point according to claim 1, it is characterised in that:
The molar ratio of the precipitating reagent and aluminium salt is 1-3:1.
7. a kind of preparation method of the controllable AlOOH nanometer adjuvant of crystallinity according to claim 1, it is characterised in that:
Speed of agitator described in step 2) is 200-1000rpm, mixing time 10-60min.
8. a kind of preparation method of the controllable aluminum phosphate nanometer adjuvant of isoelectric point according to claim 1, it is characterised in that:
The sterilising conditions are 121 DEG C, 20-30min.
9. a kind of preparation method of the controllable aluminum phosphate nanometer adjuvant of isoelectric point according to claim 1, it is characterised in that:
The centrifugal rotational speed is 4000-9000rpm, and centrifugation time 5-20min, washing times are 3-5 times, drying temperature 50-
100℃。
10. utilizing the aluminum phosphate nanometer adjuvant of claim 1 the method preparation.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811297410.1A CN109432418A (en) | 2018-11-01 | 2018-11-01 | A kind of aluminum phosphate nanometer adjuvant and preparation method thereof that isoelectric point is controllable |
| PCT/CN2019/114245 WO2020088494A1 (en) | 2018-11-01 | 2019-10-30 | Aluminium phosphate nano adjuvant with controllable isoelectric point and preparation method therefor |
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| CN201811297410.1A CN109432418A (en) | 2018-11-01 | 2018-11-01 | A kind of aluminum phosphate nanometer adjuvant and preparation method thereof that isoelectric point is controllable |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020088494A1 (en) * | 2018-11-01 | 2020-05-07 | 大连理工大学 | Aluminium phosphate nano adjuvant with controllable isoelectric point and preparation method therefor |
| CN112138155A (en) * | 2019-06-28 | 2020-12-29 | 怡道生物科技(苏州)有限公司 | Compound adjuvant system and method for preparing adjuvant |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009136233A1 (en) * | 2008-05-08 | 2009-11-12 | Serum Institute Of India Ltd. | Aluminium phosphate nanoparticles |
| CN101730660A (en) * | 2007-07-10 | 2010-06-09 | 惠氏有限责任公司 | Process for producing aluminum phosphate |
| CN102188701A (en) * | 2010-03-12 | 2011-09-21 | 上海泽润生物科技有限公司 | Aluminium phosphate adjuvant and preparation method thereof. |
| CN106729702A (en) * | 2016-12-28 | 2017-05-31 | 北京民海生物科技有限公司 | A kind of Aluminium phosphate adjuvant and preparation method and application |
| CN107929729A (en) * | 2017-12-20 | 2018-04-20 | 北京民海生物科技有限公司 | A kind of preparation method of Aluminium phosphate adjuvant |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104055736A (en) * | 2014-07-08 | 2014-09-24 | 安徽医科大学 | Nano aluminum-encapsulating carrier and application thereof |
| CN109432418A (en) * | 2018-11-01 | 2019-03-08 | 大连理工大学 | A kind of aluminum phosphate nanometer adjuvant and preparation method thereof that isoelectric point is controllable |
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- 2018-11-01 CN CN201811297410.1A patent/CN109432418A/en active Pending
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- 2019-10-30 WO PCT/CN2019/114245 patent/WO2020088494A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101730660A (en) * | 2007-07-10 | 2010-06-09 | 惠氏有限责任公司 | Process for producing aluminum phosphate |
| WO2009136233A1 (en) * | 2008-05-08 | 2009-11-12 | Serum Institute Of India Ltd. | Aluminium phosphate nanoparticles |
| CN102188701A (en) * | 2010-03-12 | 2011-09-21 | 上海泽润生物科技有限公司 | Aluminium phosphate adjuvant and preparation method thereof. |
| CN106729702A (en) * | 2016-12-28 | 2017-05-31 | 北京民海生物科技有限公司 | A kind of Aluminium phosphate adjuvant and preparation method and application |
| CN107929729A (en) * | 2017-12-20 | 2018-04-20 | 北京民海生物科技有限公司 | A kind of preparation method of Aluminium phosphate adjuvant |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020088494A1 (en) * | 2018-11-01 | 2020-05-07 | 大连理工大学 | Aluminium phosphate nano adjuvant with controllable isoelectric point and preparation method therefor |
| CN112138155A (en) * | 2019-06-28 | 2020-12-29 | 怡道生物科技(苏州)有限公司 | Compound adjuvant system and method for preparing adjuvant |
| CN112138155B (en) * | 2019-06-28 | 2022-04-12 | 怡道生物科技(苏州)有限公司 | Compound adjuvant system and method for preparing adjuvant |
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