Liquid formulation of Anti-tnf alpha antibody

A liquid preparation and antibody technology, applied in the direction of antibodies, antibody medical components, medical preparations with non-active ingredients, etc., can solve the problems of difficult drug application and viscosity production for patients, reduce aggregation and particle formation, and improve patient convenience. sex, pain relief

Pending Publication Date: 2019-12-27
LG CHEM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among these problems, excessive increase in viscosity makes production difficult and also makes administration to patients difficult due to increased injection pressure

Method used

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  • Liquid formulation of Anti-tnf alpha antibody
  • Liquid formulation of Anti-tnf alpha antibody
  • Liquid formulation of Anti-tnf alpha antibody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Confirmation of the effect and stability of reducing the viscosity of adalimumab solution by additives

[0072] To identify the additives to be used in the preparation of the liquid formulation of adalimumab, a pH 5.2 composition consisting of sucrose (55 mg / mL), methionine (5 mM), polysorbate 80 (1 mg / mL) and adalimumab was prepared Formulation 1 of mAb (100 mg / mL).

[0073] In addition, by further adding arginine hydrochloride, lysine hydrochloride, leucine, isoleucine, phenylalanine, glutamic acid, glycine, proline, alanine to the composition of formulation 1, Formulations 2 to 13 were prepared for each of sodium chloride, calcium chloride, and magnesium chloride, and the viscosity of each formulation was measured using an mVROC device (Rheosense Inc.). The types and concentrations of additives added to the formulations and the viscosity of each formulation are shown in Table 1 below and figure 1 middle.

[0074] [Table 1]

[0075] Preparation number ...

Embodiment 2

[0085] Stability assessment based on arginine hydrochloride content1

[0086] In order to evaluate the stability of adalimumab formulations according to the content of arginine hydrochloride, the following formulations were prepared.

[0087] Formulation 14 was prepared to contain sucrose (55 mg / mL), methionine (5 mM), polysorbate 80 (1 mg / mL) and adalimumab (100 mg / mL). Formulations 15 and 16 were prepared by adding arginine hydrochloride (20 mM) and arginine hydrochloride (40 mM) to the composition of formulation 14, respectively, and filling 0.4 mL into 1 mL glass syringes, respectively. Each syringe was stored at 40°C for 2 months and then subjected to SE-HPLC analysis for stability analysis. The composition of each formulation and the HMW contained therein before and after storage are shown in Table 4 below.

[0088] [Table 4]

[0089]

[0090] With reference to the SE-HPLC results in Table 4, when the content of arginine hydrochloride was increased from 0 mM (prepa...

Embodiment 3

[0092] Comparison of the formation of charged variants of antibodies according to arginine content

[0093] To compare the level of formation of charged variants of the antibody according to arginine content, formulations containing arginine and formulations without arginine were prepared, stored at 40°C for 1 month, and compared by CEX-HPLC. Characteristics of charged variants. The content of charged variants before and after each formulation and storage is shown in Table 5 below.

[0094] [table 5]

[0095]

[0096] Formulation A was prepared to contain sucrose (55mg / mL), methionine (5mM), polysorbate 80 (PS80: 1mg / mL) and adalimumab (100mg / mL), and formulation B was prepared to contain The composition of A also contained arginine hydrochloride (20 mM). The content of the acidic variant was similar for both formulations prior to storage at 40°C for 1 month. After comparing the two formulations after storage, it was confirmed that formulation B containing arginine hydr...

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Abstract

The present invention relates to a liquid formulation of an anti-TNF alpha antibody, particularly adalimumab.

Description

technical field [0001] The present invention relates to a liquid formulation of an anti-TNF-α antibody, and in particular, to a liquid formulation of adalimumab. Background technique [0002] Tumor necrosis factor alpha (TNF-α) is a cytokine produced by various cell types such as monocytes, macrophages, etc. under the stimulation of endotoxin and the like. TNF-α is an important mediator of important inflammatory, immune and pathophysiological responses, TNF-α activates TNF receptors and induces responses such as activation of T cells, proliferation of thymocytes, etc. (Grell, M. et al., (1995 ) Cell, 83:793 to 802). [0003] Adalimumab is a recombinant human immunoglobulin G1 monoclonal antibody that inhibits immune responses induced by TNF-α by selectively binding to TNF-α in vivo. Adalimumab was developed by BASP Bioresearch Corporation in 1993 and approved for sale by Abbott Laboratories for the treatment of rheumatoid arthritis. Adalimumab is currently sold under the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/08A61K47/10A61K47/18A61K47/26A61K39/395
CPCA61K9/08A61K39/395A61K47/10A61K47/18A61K47/26A61K47/183A61K39/3955A61K39/39558
Inventor 尹素罗高衍庆苏震彦
Owner LG CHEM LTD
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