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Granular type adjuvant as well as preparation method and application thereof

A granular and adjuvant technology, applied in the biological field, can solve the problems of ATRA light instability, reduced bioavailability, poor water solubility, etc., and achieve the effects of protecting from hydrolysis, promoting interaction, and delaying the release rate

Active Publication Date: 2018-07-27
INST OF PROCESS ENG CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since ATRA is dissolved in PEG400 for delivery and is not co-loaded with the antigen, long-acting administration cannot be achieved, resulting in reduced bioavailability, resulting in weaker systemic immunity
And because of frequent administration, it cannot be widely used
[0009] In order to achieve the goal of eliciting both systemic immunity and mucosal immune response through the method of injection vaccination, the adjuvant dosage form still needs to face the following challenges: 1) ATRA has light and heat instability, and is easy to denature; 2) due to ATRA 3) ATRA needs to interact with the antigen to achieve the effect; 3) The activation of intracellular RAR and RXR receptors requires the production of IL-6 and IL at the injection site The synergistic effect of inflammatory factors such as -24; 4) Whether it is the immune activation or immunosuppression of ATRA, it is necessary to precisely control the amount of ATRA embedding
However, there are no relevant preparation reports in the known literature or patents, and the known particle adjuvant dosage forms have not been designed and optimized according to the goal of simultaneously triggering systemic immunity and mucosal immune response.

Method used

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  • Granular type adjuvant as well as preparation method and application thereof
  • Granular type adjuvant as well as preparation method and application thereof
  • Granular type adjuvant as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] In this example, ATRA-embedded biocompatible oil and biocompatible polymer material composite particle adjuvant was prepared by the following method

[0132] Accurately weigh 2.0 g of PLGA (molecular weight: 130,000 Daltons), 1.0 g of squalene, 0.3 g of dimethyl dioctadecyl ammonium bromide and 1 mg of all-trans retinoic acid with an electronic balance, and dissolve them in 30 mL In the mixed solution of ethanol, acetone and dichloromethane (1:1:9), the solution was quickly poured into 250mL aqueous solution (containing 1wt.% of PVA (alcoholysis degree is 99%, viscosity is 5.0mPa·s), Disperse under ultrasonic conditions (100W, 2min, interval time 4s). Stir overnight at 25°C (magnetic stirring, speed 500rpm) to remove the organic solvent in the system and achieve the curing effect. Centrifuge at 25000g for 10min, discard the supernatant , add 10 mL of deionized water to the precipitate, ultrasonically disperse, centrifuge at 25,000g for 10 min, discard the supernatant, f...

Embodiment 2

[0141] In this example, an ATRA-embedded particle adjuvant that triggers both intestinal mucosal and systemic immune responses as an EV71 recombinant vaccine adjuvant was prepared by the following method:

[0142]Adopt electronic balance to accurately weigh 1.0g of PLGA (molecular weight is 130,000 Daltons), 1.0g squalene, 0.2g dimethyl dioctadecyl ammonium bromide and 0.1mg all-trans retinoic acid, dissolve in 30mL of a mixed solution of ethanol and dichloromethane (1:9), quickly pour the solution into 200mL aqueous solution (containing 2wt.% of PVA (alcoholysis degree of 99%, viscosity of 8.0 mPa s), in the fast membrane Emulsification (the membrane pore size is 1.4 μm, the membrane pressure is 3MPa, and the membrane is passed 5 times). Stir overnight at 25°C (magnetic stirring, the rotation speed is 500rpm), and use the normal temperature solvent evaporation method to solidify the hard emulsion particles. Centrifuge at 15000g for 5min, discard Remove the supernatant, add 10...

Embodiment 3

[0151] In this example, ATRA-embedded particle adjuvants were prepared as HIV nucleic acid vaccine adjuvants to trigger a dual response of reproductive mucosa and systemic immunity:

[0152] Accurately weigh 2.0g of PLGA (molecular weight: 130,000 Daltons), 1.0g of ethyl linoleate / miglitol (1:1), and 0.2g of brominated dimethyl dioctadecyl using an electronic balance Ammonium and 0.1 mg of all-trans retinoic acid were dissolved in 20 mL of ethanol, a mixed solution of acetone and dichloromethane (1:2:7), and the solution was quickly poured into 100 mL of aqueous solution (containing 2wt.% of PVA (alcoholysis) degree of 99%, viscosity is 5.0mPa s), high-pressure homogeneous (10000rpm, 5.0MPa, 5min). Stir overnight at 25°C (magnetic stirring, rotating speed is 500rpm), thereby solidifying the particles. Centrifuge at 15000g for 10min, Discard the supernatant, add 10 mL of deionized water to the precipitate, ultrasonically disperse, and centrifuge at 15,000 g for 10 min. After di...

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Abstract

The invention provides a granular type adjuvant as well as a preparation method and application thereof. The granular type adjuvant is prepared from a biocompatible wall material, biocompatible greaseand all-trans retinoic acid, wherein an inner core formed by the biocompatible grease is covered in a shell formed by the biocompatible wall material; the all-trans retinoic acid is coated in the inner core. According to the granular type adjuvant provided by the invention, compared with single activation of an existing method, systemic immunization and mucosal immunization are activated throughan injection immunization method, and a dual activation effect of the systemic immunization and the mucosal immunization is realized; antigens and hydrophobic immunoregulation substances ATRA are commonly loaded, delivered and released at the same time.

Description

technical field [0001] The invention belongs to the field of biotechnology, and relates to a granular adjuvant and its preparation method and application. Background technique [0002] The mucosal immune system, including gut-associated mucosal tissue, nasal cavity mucosal tissue, lung mucosal tissue, and reproductive mucosal tissue, is the first physiological barrier of the human body. Most pathogens, such as influenza virus, AIDS virus, hand, foot and mouth virus, Helicobacter pylori, and HPV cancer-causing virus, enter the human body through mucous membranes. Therefore, the mucosal immune response is as important as the systemic immunity (humoral and cellular). [0003] However, it has been proved repeatedly that the activation of mucosal immunity cannot be achieved through traditional injection immunization. The most direct way to elicit a mucosal immune response is through mucosal administration. However, there is a self-clearing effect in the mucosa, and the strong ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/39A61K9/127A61K45/06A61K9/50A61K47/34A61P37/04
CPCA61K9/127A61K9/5031A61K39/39A61K45/06A61K2039/55511A61K2039/57A61K2300/00Y02A50/30
Inventor 马光辉吴颉夏宇飞苗春宇杜逸群周炜清
Owner INST OF PROCESS ENG CHINESE ACAD OF SCI
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