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Infliximab composition containing histidine buffer system

A buffer system and composition technology, applied in the field of pharmacy, can solve problems such as easy structural change, biopharmaceutical safety impact, patient death, etc.

Inactive Publication Date: 2018-10-23
HISUN BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, infliximab is not stable enough and will undergo various chemical and physical degradations, especially the higher order structure is very fragile and prone to structural changes such as denaturation, aggregation and precipitation
These degradation or unstable products will have a great impact on the safety of biopharmaceuticals
In particular, some protein aggregates can stimulate the body's immune response, which can reduce the efficacy of biological drugs in mild cases, and even cause the death of patients in severe cases

Method used

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  • Infliximab composition containing histidine buffer system
  • Infliximab composition containing histidine buffer system
  • Infliximab composition containing histidine buffer system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] This example compares the influence of the current commercially available prescription (preparation 1) and the use of histidine buffer instead of phosphate buffer (preparation 2) on the stability of the infliximab pharmaceutical composition (Table 2).

[0073] Table 2. Composition of the pharmaceutical composition

[0074]

[0075] Formulation 1 and Formulation 2 in Table 1 were lyophilized.

[0076] The appearance and visible foreign matter of the preparation 1-2 were detected, and the polymer content was detected by SEC-HPLC. The results are shown in Table 3.

[0077] Table 3. Appearance / Visible Foreign Matter and Multimer Content of Preparation 1 and Preparation 2 After High Temperature and Light

[0078]

[0079] *Experimental data are mean ± standard deviation, repeated 3 times, the same below.

[0080] The polymer content is often used to indicate the stability of the formulation, the higher the polymer content, the worse the stability of the formulation. ...

Embodiment 2

[0082] This embodiment compares the impact of the type of buffer on the stability of the infliximab pharmaceutical composition. Formulation formulations 3-4 of the pharmaceutical composition are shown in Table 4.

[0083] Table 4. Composition of the pharmaceutical composition

[0084]

[0085] Comparison of particle size of infliximab in aqueous solution

[0086] The monoclonal antibody particle size of the two formulations in aqueous solution was studied using dynamic light scattering technique (Malvern Zetasizer Nano-ZS ZEN3600) (Table 5). The average particle size of preparation 3 containing phosphate was larger than that of preparation 4 containing histidine, which indicated that the monoclonal antibody interaction was weaker in histidine solution, and it was less likely to collide to form polymers, and the stability was better.

[0087] Table 5. Particle Sizes of Formulations 3-4 in Aqueous Solutions

[0088] serial number

Particle size (nm)

Fo...

Embodiment 3

[0094] In this example, each infliximab pharmaceutical composition (formulation 5-8) was prepared according to Table 7, wherein the pH was adjusted with hydrochloric acid. Formulations 5-8 were lyophilized using the lyophilization process in Table 1. After lyophilization, high temperature (40±2°C) and light (5°C±3°C, 4500Lx±500Lx, 10 days) tests were carried out.

[0095] Table 7. Composition of the pharmaceutical composition

[0096]

[0097] After being subjected to high temperature or light, the lyophilized preparation is a white blocky solid in appearance, and becomes a colorless clear liquid after dissolution, without visible foreign matter. After the test, the polymer content of preparations 5-8 was detected by SEC-HPLC, and the results are shown in Table 8.

[0098] Table 8. Preparation 5-8 polymer content (%) after high temperature and light

[0099] serial number

[0100]It can be seen from Table 8 that after a high temperature of 40°C, the higher the ...

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Abstract

The invention relates to a pharmaceutical composition. The pharmaceutical composition comprises infliximab, a histidine buffer system, a structural protection agent and a surfactant, wherein the concentration of histidine in the histidine buffer system is about 1 to 200 mM, preferably about 5 to 75 mM, more preferably about 25 to 45 mM.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to an infliximab composition comprising a histidine buffer system. Background technique [0002] Infliximab (infliximab, CAS#170277-31-3) is a human-mouse chimeric monoclonal antibody that specifically binds to TNF-α in the human body and prevents TNF-α from binding to its cell surface receptors, thereby preventing TNF-α from binding to its cell surface receptors. The biological activity of TNF-α is interrupted, ultimately reducing the inflammatory response and reducing the activation of osteoclasts, so as to achieve the purpose of controlling and relieving symptoms. Infliximab can be used to treat rheumatoid arthritis, psoriasis, ankylosing spondylitis, ulcerative colitis, and Crohn's disease, among others. [0003] However, infliximab is not stable enough and undergoes various chemical and physical degradations, especially the higher-order structure is very fragile and prone t...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K9/19A61K47/18A61K47/26A61P37/02A61P1/00A61P1/04A61P17/06A61P19/02A61P19/08A61P29/00
CPCA61K9/0019A61K9/19A61K39/3955A61K47/183A61K47/26A61K39/395A61K47/00A61K47/18A61P1/00A61P1/04A61P17/06A61P19/02A61P19/08A61P29/00A61P37/00A61P37/02C07K16/241
Inventor 方伟杰钱慈王海彬郑洪健高栋白骅
Owner HISUN BIOPHARMACEUTICAL CO LTD
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