Stable pharmaceutical formulation
Inventors
LEE, Joon Won • HAN, Won Yong • KIM, Su Jung • OH, Jun Seok • Kim, So Young • Kim, Kwang Woo • SHIN, Yeon Kyeong
Assignees
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Publication Number
US-11236146-B2
Publication Date
2022-02-01
Expiration Date
Abstract
Disclosed is a stable pharmaceutical formulation, comprising a fusion protein in which the extracellular ligand-binding domain of a human p75 tumor necrosis factor receptor is fused to the Fc domain of human IgG and a succinate buffering agent, without comprising a stabilizer. The stable pharmaceutical formulation enables the long-term storage of the TNFR-Fc fusion protein formulation and can exhibit superior storage stability without the need for demanding storage conditions, and is a simple formulation because no stabilizer is comprised therein and is thus more economical than other stabilizer-comprising formulations.
Core Innovation
The document describes a stable pharmaceutical formulation comprising a TNFR-Fc fusion protein formulation in which an extracellular ligand-binding domain of a human p75 tumor necrosis factor receptor is fused to an Fc domain of human IgG. The fusion protein is provided at a concentration of 50 mg/ml in a liquid formulation that contains 5-25 mM succinate, an isotonic agent, and no stabilizer, with sodium chloride at 120 to 160 mM defining isotonicity.
The formulation is characterized by storage stability defined by quantitative retention of main/aggregate contents measured by SE-HPLC and HI-HPLC. “Stable” is defined by measured main peak content and high-molecular-weight component content after storage at 40°C±2°C, optionally under relative humidity of 75%±5%, for 12 weeks, linking formulation composition to retention of defined chromatographic contents.
The document positions succinate as the buffering agent in a stabilizer-free composition and reports that stability is improved with higher succinate and the specified sodium chloride range. It compares the succinate formulation against phosphate, histidine, and citrate buffer formulations and against an Enbrel-like formulation containing sucrose and arginine, while noting reduced aggregation and oxidation, including oxidation of heavy-chain Met272.
The document further provides a formulation rationale based on osmotic pressure to minimize injection pain risk in the intended subcutaneous injection context, while avoiding the use of silicone oil-coated containers.
Claims Coverage
The partial set includes two independent claims. Independent claim clm-00001 covers a stable pharmaceutical formulation defined by composition ranges and an explicit exclusion of stabilizers, while independent claim clm-00012 covers a method of producing such a stable liquid pharmaceutical formulation with the same composition constraints and exclusions.
Stable pharmaceutical formulation with succinate buffering and isotonic sodium chloride
A stable pharmaceutical formulation comprising 50 mg/ml of a fusion protein in which an extracellular ligand-binding domain of a human p75 tumor necrosis factor receptor is fused to an Fc domain of human IgG; an isotonic agent; and 5-25 mM succinate, without comprising a stabilizer, wherein the isotonic agent is sodium chloride at a concentration of 120 to 160 mM.
Stabilizer-free production of succinate-buffered TNFR-Fc liquid formulation with defined ionic strength
A method of producing a stable liquid pharmaceutical formulation comprising preparing 5-25 mM succinate buffer having a pH 5.5 to 6.5; adding 50 mg/ml of a fusion protein in which an extracellular ligand-binding domain of a human p75 tumor necrosis factor receptor is fused to an Fc domain of human IgG to said buffer; and adding 120 to 160 mM sodium chloride to said buffer/protein mixture to form said stable liquid pharmaceutical formulation, wherein the formulation is free of a stabilizer, an amino acid, an ammonium salt, a saccharide, polysorbate, poloxamer, a polymer, or a mixture thereof.
Across the independent claims, the main inventive coverage is the same composition concept: a stabilizer-free liquid pharmaceutical formulation using succinate buffering agent (5-25 mM) at pH 5.5-6.5 together with isotonic sodium chloride (120-160 mM) for a TNFR-Fc fusion protein at 50 mg/ml, with the method claim restricting production to these composition ranges and explicit additive exclusions.
Stated Advantages
Reduced aggregation and oxidation relative to comparative phosphate, histidine, and citrate buffer formulations and to an Enbrel-like sucrose and arginine formulation, including oxidation of heavy-chain Met272.
Stability is improved with higher succinate within the specified range and with sodium chloride within the specified range.
Minimization of injection pain risk is addressed via an osmotic-pressure rationale for maintaining formulation osmotic pressure within an out-of-range risk boundary.
Documented Applications
Use in an intended subcutaneous injection context, including consideration of injection pain risk and the use of a container for a formulation intended for administration to a patient.
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