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Aqueous pharmaceutical composition of recombinant monoclonal antibody to TNF[alpha]

A monoclonal antibody and composition technology, which is applied in drug combination, antibody, drug delivery, etc., can solve problems such as low aggregation temperature, insufficient colloidal stability of high-concentration antibodies, and instability of freezing and thawing

Pending Publication Date: 2019-12-03
BIOCAD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above formulations have a number of disadvantages: 1) insufficient colloidal stability of antibodies at high concentrations, 2) insufficient stability under heat stress conditions, and 3) aggregation during long-term storage
The above formulations have a number of disadvantages: 1) significant freeze and thaw instability, and 2) low aggregation temperature

Method used

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  • Aqueous pharmaceutical composition of recombinant monoclonal antibody to TNF[alpha]
  • Aqueous pharmaceutical composition of recombinant monoclonal antibody to TNF[alpha]
  • Aqueous pharmaceutical composition of recombinant monoclonal antibody to TNF[alpha]

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0176] Preparation of PEG 6000 solution

[0177] A solution of PEG 6000 with a mass concentration of 20-25% in the research additive formulation was prepared. The resulting solution was filtered through a 0.45 μm Durapore filter.

[0178] Transfer calculated amounts of sample, additive solution, and 20-25% PEG 6000 solution into a 96-well UV spectrophotometric plate such that the PEG 6000 concentration per well is 0-18%, and the protein concentration per well is 1 mg / mL . All resulting well solutions were mixed thoroughly by pipetting.

[0179] Next, the degree of turbidity of the solution was visually evaluated, and the optical density of the solution was measured at a wavelength of 400 nm. The more unstable the sample, the lower the PEG 6000 concentration will form visible aggregates (opalescent). The degree of turbidity of the solution was also assessed one or more days after the solution was prepared.

[0180] 4. Determination of Protein Homogeneity and Aggregation Si...

Embodiment 1

[0236] Embodiment 1. Selection of buffer solution properties.

[0237] research formulation

[0238] Four buffer solutions were chosen for this study, and the initial Humira formulations (for formulations with protein content of 50 mg / mL and 100 mg / mL) were used as controls.

[0239]

[0240]

[0241] 1.1. Determination of colloidal stability by PEG aggregation.

[0242] For each sample, the "PEG aggregation" test was performed in triplicate. Analyze according to procedure 3. Data on the average optical density of the solutions are shown in Table 1. The result is also like figure 1 shown.

[0243] Table 1. Average optical density of solutions after preparation

[0244]

[0245] Visible aggregation was present.

[0246] 1.2. Thermal stability was determined by protein aggregation points using dynamic light scattering (DLS) technique.

[0247] Analyze according to Procedure 4. The results are shown in Table 2 and Figure 4-8 shown.

[0248] 1.3. Thermal sta...

Embodiment 2

[0259] Example 2. Composition pH and buffer capacity optimization.

[0260]Based on the results of the first part of the study, adalimumab showed the best stability in acetate buffer solution at pH 5.0. According to the prior art, most patents and patent applications for pharmaceutical compositions comprising adalimumab protect solutions with a pH of 4.0-8.0. Therefore, the purpose of this section was to investigate the possibility of obtaining a stable composition comprising acetate ions at a pH below 4.

[0261] research formulation

[0262] abbreviation Concentration, mM рН Acet 5mM pH 6 5 6.0 Acet 5mM pH 5.5 5 5.5 Acet 5mM pH 5 5 5.0 Acet 5mM pH 4 5 4.0 Acet 5mM pH 3.75 5 3.75 Acet 5mM pH 3.5 5 3.5 Acet 10mM pH 6 10 6.0 Acet 10mM pH 5.5 10 5.5 Acet 10mM pH 5 10 5.0 Acet 10mM pH 4 10 4.0 Acet 10mM pH 3.75 10 3.75 Acet 10mM pH 3.5 10 3.5 Acet 20mM pH 6 20 6.0 Acet 2...

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Abstract

The invention relates to improved aqueous pharmaceutical compositions of a recombinant monoclonal antibody to TNF[alpha], and to a method for producing same. The present invention also relates to theuse of improved aqueous pharmaceutical compositions of a recombinant monoclonal antibody to TNF[alpha] to treat TNF[alpha]-mediated diseases. The proposed invention allows prevention of physical-chemical instability expressed in the formation of aggregates and fragments of proteins or in the modification of proteins in a solution, and also prevents instability during freezing / thawing, agitating and shaking.

Description

[0001] technical field of invention [0002] The present invention relates to medical pharmacology, and in particular to aqueous pharmaceutical compositions of human antibodies that specifically bind or neutralize TNF[alpha] and uses thereof. [0003] Background of the invention [0004] Tumor necrosis factor alpha (TNFα) is a naturally occurring mammalian cytokine produced by various types of cells, including monocytes and macrophages, in response to endotoxins or other stimuli. TNFα is a major mediator of inflammatory, immune and pathophysiological responses (Grell, M., et al. (1995) Cell, 83:793-802). [0005] Soluble TNFα is formed by cleavage of a precursor transmembrane protein (Kriegler, et al. (1988) Cell 53:45-53), and the 17 kilodalton (kDa) secreted polypeptide aggregates to form a soluble homotrimeric complex (Smith, et al. (1987), J. Biol. Chem. 262:6951-6954; Butler, et al. (1986), Nature 320:584; Old (1986), Science 230:630). These complexes then bind to recept...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61P37/00
CPCA61P37/00C07K16/241A61K39/39591A61K9/0019A61K47/183A61K47/26A61K47/34A61K39/395A61K9/08
Inventor E.A.隆科娃A.O.艾克弗勒夫V.O.希缇科娃A.M.莱科弗斯卡亚D.V.莫洛佐夫
Owner BIOCAD