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Aqueous drug preparation of anti-TNF (tumor necrosis factor)-alpha human monoclonal antibody for strengthening stability

A technology for human monoclonal antibodies and pharmaceutical preparations, which is applied in the fields of antibodies, drug combinations, and drug delivery. It can solve the problems that mannitol cannot play a stabilizing effect, the finished product should not be placed for a longer period of time, and affect the stability of antibodies.

Active Publication Date: 2013-03-27
GENOR BIOPHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the preparation has stability, it is still not enough to stabilize the antibody for a long time, and it is expected that the finished product should not be placed for a longer period of time
This may be due to the fact that the antioxidant and osmotic pressure regulator used in the preparation - mannitol can not play a good stabilizing effect
In addition, the surfactant used in the existing adalimumab is Tween-80, although it can inhibit and / or prevent undesirable results such as polymerization and adsorption of protein molecules at the interface between water and air and the contact surface of the inner packaging material, thereby stabilizing Antibodies, but to a certain extent, they also undergo unsaturated bond oxidation and ester bond hydrolysis to produce acids, aldehydes, and hydrogen peroxide, which affects the stability of antibodies
At the same time, the composition of its prescription buffer solution is redundant and complicated, which not only increases the product cost, but also makes the preparation operation of the preparation cumbersome

Method used

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  • Aqueous drug preparation of anti-TNF (tumor necrosis factor)-alpha human monoclonal antibody for strengthening stability
  • Aqueous drug preparation of anti-TNF (tumor necrosis factor)-alpha human monoclonal antibody for strengthening stability
  • Aqueous drug preparation of anti-TNF (tumor necrosis factor)-alpha human monoclonal antibody for strengthening stability

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1. Preparation of buffer solution

[0051] 1.1 Prepare 8L disodium hydrogen phosphate / citric acid monohydrate ultrafiltration buffer solution (ultrafiltration buffer solution A)

[0052] Weigh 16g of disodium hydrogen phosphate, 12.32g of citric acid monohydrate, 120g of sorbitol, and 49.28g of sodium chloride, and add them to 7.9L with water for injection. After completely dissolving and mixing, adjust the pH to 5.2 with 1M sodium hydroxide. Set the volume to 8.0L for later use.

[0053] 1.2 Prepare 8L disodium hydrogen phosphate / sodium dihydrogen phosphate and sodium citrate / citric acid ultrafiltration buffer solution (ultrafiltration buffer solution B)

[0054] Weigh 6.88g sodium dihydrogen phosphate dihydrate, 12.24g disodium hydrogen phosphate dihydrate, 2.4g sodium citrate, 10.4g citric acid monohydrate, 96g mannitol, 49.28g sodium chloride, add water for injection to 7.9 L, after being completely dissolved and mixed evenly, adjust the pH to 5.2 with ...

Embodiment 2

[0057] Embodiment 2. antibody concentration is the preparation of the ultrafiltration concentrate of 51g / L

[0058] 2.1 The buffer solution is the preparation of the ultrafiltration concentrate of disodium hydrogen phosphate / citric acid monohydrate solution (ultrafiltration concentrate A)

[0059] Ultrafiltration instrument VIVA Flow 200 (manufacturer Sartorius) was cleaned with 0.2M sodium hydroxide according to the manufacturer's recommended steps, including cleaning the ultrafiltration membrane, ultrafiltration cup, pipeline, outlet, etc., and then using 0.5L of the ultrafiltration buffer solution in Example 1.1 A wash to remove sodium hydroxide. Add 0.48L of anti-TNF-α human monoclonal antibody solution (antibody concentration 25g / L, total antibody 12g) into the ultrafiltration cup, start equal volume replacement with ultrafiltration buffer solution A, the replacement volume is 4.8L. After changing the liquid, the antibody solution was concentrated from 0.48L to about 0.2...

Embodiment 3

[0064] Embodiment 3. the preparation of stoste

[0065] 3.1 Prepare 0.9mL / vial stock solution A (buffer solution is disodium hydrogen phosphate / citric acid monohydrate, preparation without Tween)

[0066] Under sterile conditions, take 50mL of the ultrafiltration concentrate A of Example 2.1, add 1mL of the ultrafiltration buffer solution A of Example 1.1 filtered through a sterile 0.22μm sterile filtration membrane without pyrogens, and mix well to obtain the stock solution a. Under aseptic conditions, it is divided into 2mL sterile pyrogen-free liquid injection vials, the filling volume is 0.9mL / bottle, divided into 54 tubes, and then sealed and stored at 2-8°C in the dark until use.

[0067] Description of each bottle: each bottle contains 0.9mL, and the labeled volume is 0.8mL. Its composition is as follows:

[0068]

[0069] 3.2 Prepare 0.9mL / vial stock solution B (buffer solution is disodium hydrogen phosphate / sodium dihydrogen phosphate and sodium citrate / citric ac...

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Abstract

The invention provides a new liquid aqueous drug preparation of an anti-TNF (tumor necrosis factor)-alpha human monoclonal antibody for strengthening the stability, wherein antibody solution is stabilized and osmotic pressure is regulated by sorbitol; disodium hydrogen phosphate / citric acid monohydrate or sodium acetate / acetic acid is taken as a buffer agent, and preferably, the disodium hydrogen phosphate / citric acid monohydrate is taken as the buffer agent; and tween-20 is taken as a surfactant, so that antibody preparation is stable, and long in retention time, meanwhile, preparation components are simplified, and the preparation is prepared simply and conveniently.

Description

technical field [0001] The invention belongs to the field of biotechnology, and relates to a liquid aqueous pharmaceutical preparation of a fully human monoclonal antibody drug with enhanced stability; it relates to the application of the liquid aqueous pharmaceutical preparation of the invention to treat related diseases. Background technique [0002] Human tumor necrosis factor alpha (TNF-α) has been confirmed to be associated with various diseases, such as autoimmune diseases such as rheumatoid arthritis and psoriasis. A number of anti-TNF-α drugs have been approved by the US FDA for the treatment of TNF-α-related autoimmune diseases, such as Adalimumab (Adalimumab, trade name Humira, Abbott). [0003] Adalimumab used in clinical treatment is a liquid injection preparation, and the inner packaging material is a prefilled syringe. Its preparation prescription contains sodium chloride, disodium hydrogen phosphate, sodium dihydrogen phosphate, citric acid, sodium citrate, m...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K9/08A61K47/34A61P37/02A61P17/06A61P19/02
Inventor 周新华李晓辉尚玉栓
Owner GENOR BIOPHARMA
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