Monoclonal antibody drug oral nanogel and preparation method thereof

A nanogel and anti-drug technology, which is applied in nanotechnology, nanotechnology, nanomedicine, etc., can solve the problems of unseen research reports, large molecular weight of drugs, and loss of biological activity, so as to improve encapsulation efficiency and increase compliance sex, guaranteed active effect

Active Publication Date: 2021-06-04
THE FIRST AFFILIATED HOSPITAL ZHEJIANG UNIV COLLEGE OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the main problems faced by oral protein pharmaceutical preparations are that they are easily degraded by the acid-base environment and various proteolytic enzymes in the digestive tract and lose their biological activity; absorb
[0008] At present, there is no oral nano drug preparation of anti-TNF-α monoclonal antibody in the market, and there are no research reports on similar pharmaceutical preparations. Therefore, the development of such drugs not only has important clinical significance, but also has broad market prospects.

Method used

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  • Monoclonal antibody drug oral nanogel and preparation method thereof
  • Monoclonal antibody drug oral nanogel and preparation method thereof
  • Monoclonal antibody drug oral nanogel and preparation method thereof

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0031] This example is to adopt the method provided by the present invention to prepare adalimumab oral nanogel.

[0032] Preparation steps:

[0033] 1. Synthesis of cross-linking agent

[0034] Weigh an appropriate amount of 2-hydroxyethyl disulfide and bis(p-nitrophenyl)carbonate (the ratio of the amount of substances is 1:2.4), put them in a round bottom flask, add 10mL of anhydrous acetonitrile, stir to dissolve, and then Anhydrous triethylamine was added dropwise (the amount of the substance was twice that of 2-hydroxyethyl disulfide), and the reaction was stirred at room temperature for 24 hours. After the reaction, the reaction solution was rotatably evaporated under reduced pressure at 45°C, the solvent was completely spin-dried, an appropriate amount of dichloromethane was added, washed 3 times with pure water, dried over anhydrous sodium sulfate, concentrated, ethyl acetate:petroleum ether=1 :3 Precipitate and wash to no impurity, obtain pale yellow solid, after dr...

Embodiment 2

[0044] This example is the preparation of adalimumab oral nano-preparation by adopting the method provided by the present invention.

[0045] Preparation steps:

[0046] 1. Synthesis of cross-linking agent

[0047] With embodiment 1.

[0048] 2. Preparation of Nanogels

[0049] Weigh 1 mg of cross-linking agent and dissolve it in 1 mL of DMSO. Take 1 mL of adalimumab solution in PBS with a concentration of 0.08 μmol / mL, and adjust the pH value to 7.4. The DMSO solution of the cross-linking agent was slowly added dropwise to the antibody solution, and reacted at 25°C for 30 minutes. Take 1 mL of a PBS solution of hyaluronic acid with a concentration of 0.16 μmol / mL, add it dropwise to the above reaction solution, and continue the reaction at 25° C. for 30 minutes. The unreacted impurities were removed by dialysis, and finally the impurities were removed by using a Sephadex G100 Sephadex G100 column to obtain the adalimumab nanogel with a drug loading of 56.6% and an encaps...

Embodiment 3

[0051] This example is the preparation of adalimumab oral nano-preparation by adopting the method provided by the present invention.

[0052] Preparation steps:

[0053] 1. Synthesis of cross-linking agent

[0054] With embodiment 1.

[0055] 2. Preparation of Nanogels

[0056] Weigh 1 mg of cross-linking agent and dissolve it in 1 mL of DMSO. Take 1 mL of adalimumab solution in PBS with a concentration of 0.13 μmol / mL, and adjust the pH value to 7.4. The DMSO solution of the cross-linking agent was slowly added dropwise to the antibody solution, and reacted at 25°C for 30 minutes. Take 1 mL of a PBS solution of hyaluronic acid with a concentration of 0.26 μmol / mL, add it dropwise to the above reaction solution, and continue the reaction at 25° C. for 30 minutes. The unreacted impurities were removed by dialysis, and finally the impurities were removed by using a Sephadex G100 Sephadex G100 column to obtain the adalimumab nanogel with a drug loading capacity of 53.8% and ...

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Abstract

The invention discloses a monoclonal antibody drug oral nanogel preparation and a preparation method thereof. The monoclonal antibody drug oral nanogel is prepared by cross-linking a monoclonal antibody drug by using a disulfide bond cross-linking agent (2-[(2-{[(4-nitrophenoxy)carbonyl]oxy}ethyl)disulfide]ethyl 4-nitrobenzene carbonate) or a homologue thereof to form a nano cross-linked substance, and then connecting hyaluronic acid to the surface of the nano cross-linked substance through chemical synthesis. The monoclonal antibody drug oral nanogel can adopt an oral administration means to directly transfer an antibody drug to an inflammation site, so that adverse reaction caused by systemic administration of the drug can be avoided, and the compliance of a patient is improved. The nanogel prepared by the method disclosed by the invention can be gathered at the intestinal inflammation part through a targeting effect, and meanwhile, the antibody cross-linked S-S bonds can be responsively degraded in the intestinal environment to release the drug, so that the targeted positioning release of the drug at the intestinal inflammation part is realized.

Description

[0001] (1) Technical field [0002] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an oral nanogel of monoclonal antibody drugs and a preparation method thereof. [0003] (2) Background technology [0004] Inflammatory bowel disease (IBD) is a chronic non-specific intestinal inflammatory disease of unknown etiology, mainly including Crohn's disease and ulcerative colitis, both of which affect the intestinal mucosa and lead to intestinal inflammation , erosion, ulcer and hemorrhage seriously affected the quality of life of patients. Anti-TNF-α monoclonal antibodies (such as infliximab, adalimumab, certolizumab, etc.) have been tried clinically to treat IBD, and good curative effects have been achieved. However, anti-TNF-α monoclonal antibodies are usually administered by injection. This systemic administration method leads to the inhibition of TNF-α throughout the body due to the lack of selective action of the drug on ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K39/395A61K45/00A61K47/54A61K47/61A61P1/00A61P29/00B82Y5/00B82Y30/00B82Y40/00
CPCA61K47/61A61K9/0053A61P1/00A61P29/00A61K47/6903A61K47/54A61K39/3955A61K45/00B82Y5/00B82Y30/00B82Y40/00
Inventor 李鑫卢晓阳虞朝辉洪东升
Owner THE FIRST AFFILIATED HOSPITAL ZHEJIANG UNIV COLLEGE OF MEDICINE
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