A method for preparing aluminum hydroxide dry powder and its sol and its application.

Abstract

A method for preparing aluminum hydroxide dry powder and its sol, and its application, relates to the field of vaccine adjuvant preparation. The method includes: preparing an ammonia solution or sodium hydroxide solution; preparing an aluminum chloride solution; neutralizing the ammonia solution or sodium hydroxide solution with the aluminum chloride solution at 15-20°C to generate a milky white, translucent colloidal suspension; filtering; freeze-drying followed by aging to obtain aluminum hydroxide dry powder; adding the dry powder to a sodium chloride electrolyte solution, processing it in a high-speed shear disperser, redispersing the dry powder into a sol at a certain temperature, and homogenizing it cyclically in a high-pressure homogenizer to obtain aluminum hydroxide sol; removing electrolytes from the aluminum hydroxide sol using electrodialysis, followed by high-pressure sterilization and packaging. This invention solves the problems of clumping and sedimentation during sterilization and storage, poor stability, inconvenience in transportation and use, and limited concentration in existing aluminum hydroxide adjuvant preparation methods.

Description

Technical Field

[0001] This invention relates to the field of vaccine adjuvant preparation technology, specifically to a method for preparing aluminum hydroxide dry powder and its sol and its application. Background Technology

[0002] Aluminum hydroxide adjuvant is currently the most widely used vaccine adjuvant. It adsorbs antigens through various physical and chemical interactions, including electrostatic interactions, hydrophobic interactions, and ligand exchange between surface hydroxyl groups and phosphate groups; the mechanisms involved are complex. The properties and structure of the antigen, as well as the properties of the adjuvant, all significantly influence the adsorption and immunization effects.

[0003] Aluminum hydroxide sol has been widely used and developed due to its high chemical stability, thixotropy, and strong adsorption properties. As a drug sustained-release agent, aluminum hydroxide sol can achieve a large drug loading capacity and stable drug delivery performance due to its fine particle size, stable gel properties, and intact fibrous structure.

[0004] The current traditional method for preparing aluminum hydroxide adjuvants involves reacting ammonia solution (or sodium hydroxide solution) with aluminum chloride solution via titration. This method has the following technical problems:

[0005] (1) Aluminum hydroxide adjuvant that has been prepared in one go is prone to clumping and precipitation during the subsequent sterilization and storage process. The aluminum hydroxide adjuvant solution is unstable and needs to be prepared again.

[0006] (2) Liquid aluminum hydroxide adjuvant is not conducive to transportation and use.

[0007] (3) The concentration of adjuvants used is limited. Summary of the Invention

[0008] To address the problems of clumping and sedimentation during sterilization and storage, poor stability, difficulty in transportation and use, and limited concentration in existing aluminum hydroxide adjuvant preparation methods, this invention provides a method for preparing aluminum hydroxide dry powder and its sol, as well as their applications.

[0009] The technical solution adopted by this invention to solve the technical problem is as follows:

[0010] The present invention provides a method for preparing aluminum hydroxide dry powder and its sol, comprising the following steps:

[0011] Step 1: Prepare an ammonia solution or a sodium hydroxide solution;

[0012] Step 2: Prepare aluminum chloride solution;

[0013] Step 3: Neutralize the ammonia solution or sodium hydroxide solution with the aluminum chloride solution at 15-20℃ for 10-15 minutes to produce a milky white, translucent colloidal suspension.

[0014] Step 4: Filtering;

[0015] Step 5: Freeze-dry first, then age to obtain aluminum hydroxide dry powder;

[0016] Step 6: Add the dry powder to the sodium chloride electrolyte solution, then process it in a high-speed shear disperser. At a certain temperature, redisperse the dry powder into a sol, and then homogenize it in a high-pressure homogenizer to obtain aluminum hydroxide sol.

[0017] Step 7: Use electrodialysis to remove electrolytes from the aluminum hydroxide sol, then perform autoclaving and repackaging.

[0018] In a preferred embodiment, in step one, concentrated ammonia water is diluted at a ratio of 1:3 (w / v) to prepare an ammonia solution; the concentration of the sodium hydroxide solution is 0.1-0.5 mol / L.

[0019] In a preferred embodiment, in step two, an aluminum chloride solution is prepared at a ratio of 1:24 (w / v).

[0020] In a preferred embodiment, the temperature in step three is 15°C.

[0021] In a preferred embodiment, the neutralization reaction time in step three is 15 minutes.

[0022] As a preferred embodiment, in step five, during freeze drying, a freeze dryer is used to freeze dry at a temperature of -80 to -40°C for 6-12 hours.

[0023] In a preferred embodiment, in step six, the dry powder is added to a sodium chloride electrolyte solution to make the final concentration of sodium chloride 0.5M; then it is added to a high-speed shear disperser for 1 minute, followed by a 10-minute interval.

[0024] In a preferred embodiment, in step six, the dry powder is redispersed into a sol at a temperature of 70-80°C, and then homogenized twice by a high-pressure homogenizer at a pressure of 200-300 MPa to obtain aluminum hydroxide sol.

[0025] In a preferred embodiment, in step seven, the autoclaving conditions are 121°C for 30-60 minutes.

[0026] This invention provides the application of aluminum hydroxide dry powder and its sol in the preparation of vaccine adjuvants.

[0027] The beneficial effects of this invention are:

[0028] This invention controls the problem of poor gelation caused by crystallization of aluminum hydroxide sol due to excessively high temperatures by setting low-temperature sol generation conditions, thus achieving a high concentration of aluminum hydroxide sol. Aluminum hydroxide powder is prepared by freeze-drying, preventing particle aggregation during the drying process, improving product quality, and facilitating transportation and use. A mechanical processing method combining high-speed shear dispersion and high-pressure homogenization effectively controls the uniformity and size of the sol particles. Simultaneously, electrodialysis is used to remove excess electrolytes from the aluminum hydroxide sol.

[0029] This invention provides a method for preparing aluminum hydroxide dry powder and its sol, which features high preparation efficiency and the ability to store it in dry powder form for immediate use. Depending on different application needs, aluminum hydroxide sol of varying concentrations can be prepared using the dry powder. Detailed Implementation

[0030] The present invention provides a method for preparing aluminum hydroxide dry powder and its sol, which specifically includes the following steps:

[0031] Step 1: Prepare an ammonia solution by diluting concentrated ammonia water at a ratio of 1:3 (w / v); or prepare a 0.1-0.5 mol / L sodium hydroxide solution.

[0032] Step 2: Prepare an aluminum chloride solution (AlCl3·6H2O) at a ratio of 1:24 (w / v).

[0033] Step 3: Neutralize the ammonia solution or sodium hydroxide solution with the aluminum chloride solution at 15-20℃ for 10-15 minutes to generate a milky white, translucent colloidal suspension. By setting low-temperature sol formation conditions, the problem of poor gelation caused by aluminum hydroxide sol crystallization due to excessively high temperatures is controlled, thus enabling the acquisition of a higher concentration of aluminum hydroxide sol.

[0034] Step 4: Filtering.

[0035] Step 5: First freeze-dry, then age to obtain aluminum hydroxide dry powder; during freeze-drying, use a freeze dryer at a temperature of -80 to -40℃ for 6-12 hours; freeze-drying facilitates transportation and use, and the precipitated and aged powder is less prone to colloidal reaction. The freeze-drying method was used to prepare aluminum hydroxide dry powder, thereby preventing particle aggregation during the drying process, improving product quality, and facilitating transportation and use.

[0036] Step Six: Add the dry powder to the sodium chloride electrolyte solution to achieve a final sodium chloride concentration of 0.5M; process it in a high-speed shear disperser for 1 minute, followed by a 10-minute interval; redisperse the dry powder into a sol at 70-80℃, and then homogenize it twice using a high-pressure homogenizer at 200 MPa to obtain aluminum hydroxide sol. This combined high-speed shear dispersion and high-pressure homogenization mechanical processing method effectively controls the particle size and uniformity of the sol.

[0037] Step 7: Use electrodialysis to remove excess electrolytes from the aluminum hydroxide sol, then autoclave and repackage it; the autoclave conditions are 121℃ for 30-60 minutes.

[0038] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0039] Example 1: Preparation of aluminum hydroxide dry powder and its sol

[0040] Prepare an ammonia solution by diluting concentrated ammonia water at a ratio of 1:3 (w / v); prepare an aluminum chloride solution (AlCl3·6H2O) at a ratio of 1:24 (w / v); neutralize the ammonia solution and aluminum chloride solution at 15℃ for 10 min to generate a milky white, translucent colloidal suspension; filter; freeze-dry first, then age to obtain aluminum hydroxide powder; freeze-drying is performed at -80℃ for 6 h using a freeze dryer; freeze-drying facilitates transportation and use, and prevents peptization after precipitation and aging; add the powder to a sodium chloride electrolyte solution to achieve a final sodium chloride concentration of 0.5M; process in a high-speed shear disperser for 1 min, followed by a 10 min interval; redisperse the powder into a sol at 70℃, and homogenize twice using a high-pressure homogenizer at 300 MPa to obtain aluminum hydroxide sol; remove excess electrolytes from the aluminum hydroxide sol using electrodialysis, then autoclave and dispense; autoclave conditions are 121℃ for 30 min.

[0041] Example 2: Preparation of aluminum hydroxide dry powder and its sol

[0042] Prepare a 0.1-0.5 mol / L sodium hydroxide solution; prepare an aluminum chloride solution (AlCl3·6H2O) at a ratio of 1:24 (w / v); neutralize the sodium hydroxide solution and aluminum chloride solution at 20℃ for 15 min to produce a milky white, translucent colloidal suspension; filter; freeze-dry first, then age to obtain aluminum hydroxide powder; freeze-dry at -40℃ for 12 h using a freeze dryer; freeze-drying facilitates transportation and use, and the precipitated powder is less prone to gelation after aging. The process involved adding the dry powder to a sodium chloride electrolyte solution to achieve a final sodium chloride concentration of 0.5 M; then processing it in a high-speed shear disperser for 1 min, followed by a 10 min interval; redispersing the dry powder into a sol at 80 °C; and then homogenizing it twice in a high-pressure homogenizer at 200 MPa to obtain aluminum hydroxide sol; removing excess electrolytes from the aluminum hydroxide sol using electrodialysis; followed by autoclaving and packaging; and autoclaving at 121 °C for 60 min.

[0043] Example 3: Preparation of aluminum hydroxide dry powder and its sol

[0044] Prepare an ammonia solution by diluting concentrated ammonia water at a ratio of 1:3 (w / v); prepare an aluminum chloride solution (AlCl3·6H2O) at a ratio of 1:24 (w / v); neutralize the ammonia solution and aluminum chloride solution at 18°C ​​for 13 min to produce a milky white, translucent colloidal suspension; filter; freeze-dry first, then age to obtain aluminum hydroxide powder; freeze-drying was performed at -70°C for 7 h; freeze-drying facilitates transportation and use, and prevents peptization after precipitation and aging; add the powder to a sodium chloride electrolyte solution to achieve a final sodium chloride concentration of 0.5 M; process in a high-speed shear disperser for 1 min, followed by a 10 min interval; redisperse the powder into a sol at 80°C, and homogenize twice under high pressure at 300 MPa to obtain aluminum hydroxide sol; remove excess electrolyte from the aluminum hydroxide sol using electrodialysis, then autoclave and dispense; autoclave conditions were 121°C for 45 min.

[0045] Example 4: Preparation of aluminum hydroxide dry powder and its sol

[0046] Prepare a 0.1-0.5 mol / L sodium hydroxide solution; prepare an aluminum chloride solution (AlCl3·6H2O) at a ratio of 1:24 (w / v); neutralize the sodium hydroxide solution and aluminum chloride solution at 16℃ for 14 min to produce a milky white, translucent colloidal suspension; filter; freeze-dry first, then age to obtain aluminum hydroxide powder; freeze-dry at -60℃ for 10 h using a freeze dryer; freeze-drying facilitates transportation and use, and the precipitated powder is less prone to gelation after aging. The process involved adding the dry powder to a sodium chloride electrolyte solution to achieve a final sodium chloride concentration of 0.5 M; then processing it in a high-speed shear disperser for 1 min, followed by a 10 min interval; redispersing the dry powder into a sol at 75 °C; and then homogenizing it twice in a high-pressure homogenizer at 200 MPa to obtain aluminum hydroxide sol; removing excess electrolytes from the aluminum hydroxide sol using electrodialysis; followed by autoclaving and packaging; and autoclaving at 121 °C for 50 min.

[0047] This invention discloses a method for preparing aluminum hydroxide dry powder and its sol, as well as its applications. Those skilled in the art can refer to the content of this document and appropriately modify the process parameters to achieve the desired results. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The product of this invention has been described through preferred embodiments, and those skilled in the art can clearly modify or appropriately change and combine the product described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

Claims

1. A method for producing an aluminum hydroxide dry powder and a sol thereof, characterized by, Includes the following steps: Step 1: Prepare an ammonia solution or a sodium hydroxide solution; Step 2: Prepare aluminum chloride solution; Step 3: Neutralize the ammonia solution or sodium hydroxide solution with the aluminum chloride solution at 15-20℃ for 10-15 minutes to produce a milky white, translucent colloidal suspension. Step 4: Filtering; Step 5: Freeze-dry first, then age to obtain aluminum hydroxide dry powder; Step 6: Add the dry powder to the sodium chloride electrolyte solution, then process it in a high-speed shear disperser. At a certain temperature, redisperse the dry powder into a sol, and then homogenize it in a high-pressure homogenizer to obtain aluminum hydroxide sol. Step 7: Use electrodialysis to remove electrolytes from the aluminum hydroxide sol, then perform autoclaving and repackaging.

2. The method for preparing aluminum hydroxide dry powder and its sol according to claim 1, characterized in that, In step one, an ammonia solution is prepared by diluting concentrated ammonia water at a ratio of 1:3 (w / v); the concentration of the sodium hydroxide solution is 0.1-0.5 mol / L.

3. The method for preparing aluminum hydroxide dry powder and its sol according to claim 1, characterized in that, In step two, an aluminum chloride solution is prepared at a ratio of 1:24 (w / v).

4. The method for preparing aluminum hydroxide dry powder and its sol according to claim 1, characterized in that, In step three, the temperature is 15°C.

5. The method for preparing aluminum hydroxide dry powder and its sol according to claim 1, characterized in that, In step three, the neutralization reaction time is 15 minutes.

6. The method for preparing aluminum hydroxide dry powder and its sol according to claim 1, characterized in that, In step five, during freeze drying, a freeze dryer is used to freeze dry the food at a temperature of -80 to -40°C for 6-12 hours.

7. The method for preparing aluminum hydroxide dry powder and its sol according to claim 1, characterized in that, In step six, the dry powder is added to the sodium chloride electrolyte solution to make the final concentration of sodium chloride 0.5M; it is then added to a high-speed shear disperser for 1 minute, followed by a 10-minute interval.

8. The method for preparing aluminum hydroxide dry powder and its sol according to claim 1, characterized in that, In step six, the dry powder is redispersed into a sol at a temperature of 70-80℃, and then homogenized twice by a high-pressure homogenizer at a pressure of 200-300 MPa to obtain aluminum hydroxide sol.

9. The method for preparing aluminum hydroxide dry powder and its sol according to claim 1, characterized in that, In step seven, the conditions for high-pressure sterilization are 121°C for 30-60 minutes.

10. The use of aluminum hydroxide dry powder and its sol as described in any one of claims 1 to 9 in the preparation of vaccine adjuvants.