Stable liquid formula comprising anti-TNFa antibody, acetate buffer, and glycine
Inventors
LEE, Joon Won • SHIN, Yeon Kyeong • Kang, Hye Young • Kim, Kwang Woo • Kim, So Young • KIM, Su Jung • OH, Jun Seok • HAN, Won Yong
Assignees
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Publication Number
US-11986523-B2
Publication Date
2024-05-21
Expiration Date
Abstract
Disclosed is a stable liquid formulation, comprising an antibody or antigen-binding portion thereof, an acetate buffer, glycine, and a surfactant, wherein the stable liquid formulation does not comprise at least one of sugar, a sugar alcohol and a metal salt, and the stable liquid formulation is still stable even upon high antibody content, and is superior in osmolality and viscosity, and subcutaneous administration thereof is possible.
Core Innovation
The invention relates to a stable liquid pharmaceutical formulation comprising an anti-TNFα antibody or an antigen-binding portion in an acetate buffer with glycine and a surfactant. The formulation excludes sucrose, trehalose, mannitol, sorbitol, NaCl, histidine, citrate, phosphate, maleate, tartrate, succinate, preservatives, and chelators. The anti-TNFα antibodies include adalimumab, infliximab, certolizumab pegol, and golimumab.
The formulation is characterized by an antibody concentration of 50 to 150 mg/mL, a glycine concentration of 210 to 300 mM, an osmolality ranging from 200 to 400 mmol/kg, a pH range of about 4.5 to 5.5, and a viscosity in the range of about 0.5 to 5.0 cP. The surfactant includes polysorbate.
The document states that the resulting liquid formulation provides improved stability compared with formulations that use NaCl or sugar alcohols/sugars and other buffer systems. Comparative evaluation results indicate better appearance and turbidity, lower aggregation markers including reduced high-molecular-weight species, higher monomer and intact IgG content, and fewer sub-visible particles.
The formulation is described as having favorable osmolality and viscosity suitable for subcutaneous use and compatible with container products such as pre-filled syringe and auto-injector.
Claims Coverage
The independent claim defines a liquid formulation with core quantitative composition limits and explicit excipient exclusions. Across the claim set provided, the key inventive elements include defined component concentrations, osmolality range, exclusion of specific excipients, absence of preservatives and chelating agents, definition of antibody CDR domain sequences, and subcutaneous administration.
Liquid formulation with acetate buffer, glycine, and surfactant meeting concentration and osmolality limits
A liquid formulation comprising an antibody or antigen-binding portion, an acetate buffer, glycine, and a surfactant, wherein the antibody has a concentration of 50 to 150 mg/mL, the glycine has a concentration of 210 to 300 mM, and the liquid formulation has an osmolality ranging from 200 to 400 mmol/kg.
Exclusion of sucrose, trehalose, mannitol, sorbitol, and NaCl
The liquid formulation does not comprise sucrose, trehalose, mannitol, sorbitol, or NaCl.
Absence of preservative and chelating agent
The liquid formulation is characterized by the absence of any preservative and any chelating agent, including mixtures.
Specific CDR domain sequence content of the antibody
A liquid formulation is provided in which the antibody includes specified light-chain and heavy-chain variable regions containing CDR1, CDR2, and CDR3 domains with amino acid sequences SEQ ID NO:1 to SEQ ID NO:6.
Exclusion of histidine, citrate, phosphate, maleate, tartrate, and succinate
A liquid formulation is defined as lacking at least one specified excipient selected from histidine, citrate, phosphate, maleate, tartrate, and succinate.
Formulated for subcutaneous administration
The liquid formulation is formulated for subcutaneous administration.
Claim coverage is anchored in a defined stable liquid formulation using an acetate buffer with glycine and a surfactant, constrained by antibody concentration, glycine concentration, and osmolality range, and characterized by explicit excipient exclusions. Dependent claims further add exclusions of preservatives and chelating agents, specify antibody CDR domain sequences, exclude certain buffering or acidifying excipients, and limit the formulation to subcutaneous administration.
Stated Advantages
Improved stability compared with formulations using NaCl or sugar alcohols/sugars and other buffer systems.
Better appearance and turbidity.
Lower aggregation markers, including reduced high-molecular-weight species.
Higher monomer and intact IgG content.
Fewer sub-visible particles.
Favorable osmolality and viscosity suitable for subcutaneous use.
Documented Applications
Subcutaneous administration of the liquid formulation, including compatibility with container products such as a pre-filled syringe and an auto-injector.
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