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Hepatitis B vaccine preparation method using aluminium phosphate adjuvant in-situ method

A technology of hepatitis B vaccine and disodium hydrogen phosphate, which is applied in the field of in-situ preparation of hepatitis B vaccine with aluminum phosphate adjuvant, can solve the problems of increased pain at the injection site of the vaccinators, local redness, increased chance of contamination, cumbersome process operations, etc., and achieves Improving the immune effect and seroconversion rate, reducing the degree of local redness and swelling, and the effect of high antigen adsorption rate

Active Publication Date: 2013-10-02
BEIJING MINHAI BIOTECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] At present, the hepatitis B vaccine prepared by the potassium aluminum sulfate in situ method has large adjuvant particles due to the presence of potassium ions and sulfate ions, which will increase the pain and local redness at the injection site of the vaccinators during the immunization injection.
In addition, during the preparation process, it is necessary to wash the precipitate many times, extract the supernatant, and open the reaction vessel many times, which increases the chance of pollution, cumbersome process operation, and relatively high cost

Method used

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  • Hepatitis B vaccine preparation method using aluminium phosphate adjuvant in-situ method
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  • Hepatitis B vaccine preparation method using aluminium phosphate adjuvant in-situ method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1 Preparation of Recombinant Hepatitis B Surface Antigen (Hansenula) Stock Solution

[0070] Cell fermentation: Inoculate 200 ml of YNB culture medium with recombinant Hansenula Hepatitis B vaccine working seed batch, and culture at 30°C for 20 hours for primary culture. The primary culture was transplanted into 2L of YNB medium, and cultured at 30°C for 20 hours for secondary culture. The secondary culture was transplanted into 12L of glycerol medium, cultured at 30°C for 88-95 hours, and 24L of Hansenula cell fermentation broth expressing hepatitis B surface antigen was collected.

[0071] Cell disruption: centrifuge the harvested culture at 4°C at 4500 rpm for 20 minutes, remove the supernatant, then add PB buffer to make the cell concentration 30%, and then add 1% of its volume Polysorbate 20 is used to break the cells with a high-pressure homogenizer, so that the breakage rate can reach more than 95%.

[0072] Preliminary purification: add 50% polyethylen...

Embodiment 2

[0078] Embodiment 2 Aluminum hydroxide in situ adsorption method prepares hepatitis B vaccine

[0079] The 5.0L reactor was started to stir at a speed of 200rpm. Add 1000ml of PBS solution, add hepatitis B surface antigen solution (the batch numbers of the antigen stock solution prepared in Example 1 are: B201101, B201102, and the final concentration of antigen is 20 μg / ml), then add 300ml of PBS solution, and then add 10% potassium sulfate dodecahydrate Aluminum solution 250ml, then add 0.85% sodium chloride solution to volume 2500ml. Add 0.5mol / L sodium hydroxide solution to the reaction tank at a flow rate of 50ml / min, and stop adding 0.5mol / L sodium hydroxide solution when the pH is 6.8±0.2. Add 0.85% sodium chloride solution to a volume of 3000ml, continue stirring for 30min, seal the reaction tank, and precipitate.

[0080] The first washing of the precipitate: after 24 hours of precipitation, the supernatant was discarded. Add 0.85% sodium chloride solution to a volu...

Embodiment 3

[0084] Embodiment 3 Aluminum phosphate in situ adsorption method prepares hepatitis B vaccine (the present invention)

[0085] Connect the sterile filtration system to the feed port of the 5.0L reactor, pass through the sterile filter, and filter 130.7ml of 10% aluminum chloride hexahydrate solution, 1000ml of sterile water for injection, and 4mol of chlorine at a flow rate of 100ml / min Add sodium chloride solution 51.9ml, hepatitis B surface antigen solution (the batch numbers of the antigen stock solution prepared in Example 1 are: B201101, B201102, B201103, B201104, and the final concentration of antigen is 20μg / ml), 500ml sterile water for injection into the reactor, and turn on Stir at 200rpm. After passing through the sterilizing filter, at a flow rate of 4.0ml / min, add a mixed solution of 5% disodium hydrogen phosphate dodecahydrate solution and 0.5mol / L sodium hydroxide solution to the reaction tank, and add the mixed solution until the pH of the suspension is 3. At 6...

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Abstract

The invention relates to a hepatitis B vaccine preparation method using an aluminium phosphate adjuvant in-situ method. The hepatitis B vaccine preparation method comprises the following steps: 1) sequentially adding an aluminum chloride solution, water, a sodium chloride solution and hepatitis B surface antigen stoste into a reactor for stirring and mixing; 2) adding a mixing solution of disodium hydrogen phosphate and sodium hydroxide for stirring. The vaccine prepared through the method is a polydispersity system with a grain diameter about 45 nm, the grains of the vaccine are uniform, fine and smooth, and the vaccine has excellent intracorporal and extracorporeal relative potencies and high stability. The hepatitis B vaccine preparation method is short in production cycle, simple in technological operation and low in manufacturing cost, and facilitates large-scale production.

Description

technical field [0001] The invention relates to a preparation method of a vaccine, in particular to a method for preparing a hepatitis B vaccine by an aluminum phosphate adjuvant in situ method. Background technique [0002] There are more than 300 million hepatitis B virus (HBV) carriers in the world, and about 600,000 people die from hepatitis B-related diseases every year, and it is estimated that 93% of them die from chronic hepatitis. my country is a "big hepatitis country", with more than 100 million people infected with hepatitis B virus, accounting for about 10% of the total population. Hepatitis B has seriously threatened the health and quality of life of people in my country and the world. In order to reduce and eliminate the threat of hepatitis B to human health, expanding immunization programs and producing safer and more effective vaccines has become the most urgent and sacred cause for current and future research and development, production and immunization of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/39A61K39/29A61P31/20
Inventor 陈鹏顾美荣张福春宋琳琳刘建凯
Owner BEIJING MINHAI BIOTECH
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