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Buffered formulations of bevacizumab for use of treating diseases

A preparation and antibody technology, which can be applied to sensory diseases, medical preparations with inactive ingredients, and medical preparations containing active ingredients, etc., can solve problems such as the reduction of antibody efficacy

Pending Publication Date: 2021-03-23
前瞻疗法公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a result, the potency of the antibody decreases

Method used

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  • Buffered formulations of bevacizumab for use of treating diseases
  • Buffered formulations of bevacizumab for use of treating diseases
  • Buffered formulations of bevacizumab for use of treating diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0184] Reality Example 1 - Materials and methods

[0185] Introduction. The antibody ONS-5010 represents a biosimilar of bevacizumab and has been reformulated for enhanced storage stability. The buffered formulation is believed to reduce antibody aggregation, at least during long-term storage. It is believed that the buffer formulation can reduce non-covalent and covalent dimerization of the bevacizumab molecule. Bevacizumab, marketed as Atorvastatin® (Genentech, Inc.), was formulated in sodium phosphate buffer, which included trehalose as a stabilizer, and included a mild surfactant and an acidic pH of 6.2. The protocol described below included the development of reformulating bevacizumab for enhanced colloidal stability. Significant improvements in stability (especially in terms of reducing aggregation) were achieved by varying the buffer and pH.

[0186] Dynamic Light Scattering (DLS). DLS test method using Wyatt DynaPro TM Plate reader to provide information on prote...

Embodiment 2

[0197] Example 2 - Effect of Buffer, Stabilizer and pH on Bevacizumab Conformation and Colloidal Stability

[0198]Initial experiments evaluated the effect of buffer components on the conformation and colloidal stability of bevacizumab. Citrate, phosphate and acetate buffers were determined to be ideal for the stability of bevacizumab. Furthermore, these buffers alone showed protection against aggregation of bevacizumab induced by heat- or shaking-related stress. Further experiments evaluated whether combinations of these buffers (citrate, phosphate, and acetate) exhibited superior stabilization. Citrate phosphate buffer produced significantly lower aggregates (including covalent dimers) and lower charged species.

[0199] The effect of trehalose stabilizers in 50 mM sodium phosphate buffer was compared to alternative stabilizers including sucrose, sorbitol, mannitol and glycine. The conformational stability of the antibody in different stabilizing buffer compositions wa...

Embodiment 3

[0213] Example 3 - Storage Stability in Citrate Phosphate Buffered Trehalose and Acetate Sucrose Formulations

[0214] Four buffered formulations were selected to evaluate the long-term storage stability of the bevacizumab molecule over 18 months. These formulations were performed in parallel with the bevacizumab matching / reference formulation (Condition 1). Storage conditions were as follows: approximately 25 mg / ml (neat) or diluted antibody; storage at 5°C, 30°C, or 37°C; shaking at room temperature at 150 RPM; and freeze / thaw (20°C to room temperature for three cycle). The formulations tested are listed below:

[0215] Condition 1: Bevacizumab (Arvastatin®) matching

[0216] 50 mM sodium phosphate

[0217] 159 mM Trehalose

[0218] 0.04% Polysorbate 20

[0219] pH 6.20

[0220] Supplement to appropriate amount with sterile water for injection

[0221] Condition 2: Bevacizumab Citrate Phosphate, pH 5.8

[0222] 50 mM citrate phosphate

[0223] 159 mM Trehalos...

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Abstract

The invention provides buffered aqueous formulations of bevacizumab. The invention further provides methods of making buffered formulations of bevacizumab. The invention provides methods of treating eye disorders, particularly wet age-related macular degeneration and macular edema by administering the buffered antibody compositions of the disclosure.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 62 / 776,686, filed December 7, 2018, and U.S. Provisional Application No. 62 / 658,772, filed April 17, 2018, the contents of each of which are presented in their entirety and is incorporated herein by reference for all purposes. [0003] Incorporation of Sequence Listings [0004] The content of the text file named "ONBI-013_001WO_SeqListing_ST25.txt", which was created on April 16, 2019 and is 9 KB in size, is hereby incorporated by reference in its entirety. [0005] field of invention [0006] The present invention relates generally to the field of antibody formulation chemistry. More specifically, the present invention relates to buffered formulations of antibodies against vascular endothelial growth factor (VEGF), which enhance the thermal and colloidal stability of the antibodies, thereby enhancing the long-term storage of the antibodies. Such sta...

Claims

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Application Information

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IPC IPC(8): A61K39/395C07K16/22
CPCC07K16/22A61K39/395A61K2039/505A61K39/39591A61K9/0048A61K9/0019A61K47/12A61K47/02A61K47/26A61P27/02A61K47/08A61K47/30
Inventor C·尤南W·登达姆龙维特M·希利-弗里德
Owner 前瞻疗法公司
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