Stabilizer for protein preparation comprising meglumine and use thereof

A kind of meglumine, protein technology, applied in the stabilizer of protein preparation containing meglumine and its utilization field

Inactive Publication Date: 2008-08-06
CHUGAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, meglumine is used as X-ray contrast agent (diatrizoate meglumine), MRI contrast agent (gadopentetate meglumine), etc., and there is no report on its effect on protein stabilization

Method used

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  • Stabilizer for protein preparation comprising meglumine and use thereof
  • Stabilizer for protein preparation comprising meglumine and use thereof
  • Stabilizer for protein preparation comprising meglumine and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0184] [Example 1] Research on the stabilizing effect of meglumine on hVB22B

[0185] Using highly purified sc(Fv)2, hVB22B sc(Fv)2u2-wz4 (SEQ ID NO. 1, refer to the following reference example), the effect of meglumine on inhibiting the aggregation reaction was studied. The solvent conditions and hVB22B concentration in the stability test are as follows.

[0186]

[0187] Control: 20mM sodium citrate (pH 6.5)

[0188] Meglumine: 20mM sodium citrate, pH 6.5, 10% meglumine

[0189] hVB22B u2-wz4: 1.0mg / ml

[0190] Under the above conditions, after 55°C-3 days and 6 days, use SEC (Size Exclusion Chromatography) to measure the monomer residual rate (the monomer residual rate is the monomer peak area of ​​the thermal acceleration test sample relative to the initial state monomer % of peak area). The analysis conditions of SEC are as follows.

[0191]

[0192] Column: TSKgel Super2000sw (TOSOH)

[0193] Eluent: 50mM Sodium Phosphate, 300mM KCl, pH 7.0

[0194] Flow rate:...

Embodiment 2

[0198] [Example 2] Meglumine to other sc (Fv) 2 molecule, and the study of the stabilizing effect of full-length antibody

[0199] sc(Fv)2 other than hVB22B shown in [Example 1]: mVB22B shown below (SEQ ID NO. 2, refer to Reference Example below), 12E10 (SEQ ID NO. 3, WO02 / 33072), 2D7 (SEQ ID NO.4, refer to Reference Example below), the stabilization effect of meglumine was studied. Also for the stabilization of humanized anti-IL-6 receptor antibody (H chain-SEQ ID NO.5, L chain-SEQ ID NO.6, WO92 / 19759) that is not sc(Fv)2 but full-length antibody IgG1 The chemical effect was studied. The solvent conditions and the concentration of each antibody in the stability test are as follows.

[0200]

[0201] Control: 20mM citrate buffer, pH 6.5

[0202] Meglumine: 20mM citrate buffer, 10% meglumine, pH 6.5

[0203] mVB22B: 28μg / ml, measured after 40°C-1 week and 2 weeks later

[0204] 2D7: 59μg / ml, measured at 40°C after 1 week and 2 weeks

[0205] 12E10: 10μg / ml, measured at ...

Embodiment 3

[0220] [Example 3] Research on meglumine as an IgG solution stabilizer and an excipient for freeze-dried preparations

[0221] The stabilizing effect of meglumine as a stabilizer for IgG solution preparations or as an excipient for lyophilized preparations was studied. Comparison using normal sucrose as an IgG stabilizer (excipient). Sucrose has been reported to be very effective as a lyophilized formulation of the formulation. The specimens used for the tests and the stable experimental conditions are shown below.

[0222]

[0223] Sample 1: IgG 80mg / bottle, sucrose 100mg / bottle, polysorbate 80 1mg / bottle, sodium phosphate salt 30μmol / bottle, pH 6.0

[0224] Sample 2: IgG 80mg / bottle, sucrose 70mg / bottle, polysorbate 80 1mg / bottle, sodium phosphate salt 30μmol / bottle, pH 6.0

[0225] Sample 3: IgG 80mg / bottle, sucrose 50mg / bottle, polysorbate 80 1mg / bottle, sodium phosphate salt 30μmol / bottle, pH 6.0

[0226] Sample 4: IgG 80mg / bottle, meglumine 55mg / bottle, polysorbate...

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Abstract

An object of the present invention is to provide a method for stabilizing a protein or a method for inhibiting aggregation of a protein, these methods including the step of adding meglumine to the protein. The present invention also provides a drug containing meglumine, which stabilizes protein, or a drug which inhibits protein aggregation. Furthermore, the object of the present invention is to provide a pharmaceutical composition containing an antibody molecule stabilized by meglumine, a method for preparing the pharmaceutical composition, and a kit containing the pharmaceutical composition. In order to solve the above-mentioned problems, the present inventors studied the antibody stability effect of a kind of amino sugar, meglumine. It was found that meglumine can be used as a stabilizer for antibody molecules and also as an excipient for lyophilized formulations.

Description

technical field [0001] The present invention relates to a drug containing amino sugar - meglumine, which stabilizes protein and its application. More specifically, the present invention relates to a medicament for stabilizing antibody molecules containing meglumine, and a method for stabilizing antibody molecules comprising the step of adding meglumine. The present invention also relates to pharmaceutical compositions containing antibody molecules stabilized by meglumine and methods for their preparation. Background technique [0002] For formulation of biopharmaceuticals, formulations capable of stably storing proteins used as pharmaceuticals are required (Non-Patent Document 1). [0003] Common protein degradation pathways are known to include: formation of soluble polymers or degradation pathways accompanied by physical aggregation of protein molecules such as precipitation and insoluble formation (Non-Patent Document 2); and hydrolysis / deamidation reactions , methionin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/26A61K9/19A61K39/395
CPCA61K9/0019C07K16/2866C07K16/2833C07K2317/34C07K2317/622C07K16/00C07K2317/626A61K47/26A61K9/19A61K39/39591C07K2317/73C07K2317/24A61P37/02A61K39/395
Inventor 井川智之龟冈大介
Owner CHUGAI PHARMA CO LTD
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