Stable liquid pharmaceutical preparation
Inventors
LEE, Joon Won • HAN, Won Yong • KIM, Su Jung • OH, Jun Seok • Kim, So Young • Hong, Su Hyeon • SHIN, Yeon Kyeong
Assignees
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Publication Number
US-11951207-B2
Publication Date
2024-04-09
Expiration Date
Abstract
The present invention provides a stable liquid pharmaceutical formulation containing: an antibody or its antigen-binding fragment; a surfactant; a sugar or its derivative; and a buffer. The stable liquid pharmaceutical formulation according to the present invention has low viscosity while containing a high content of the antibody, has excellent long-term storage stability based on excellent stability under accelerated conditions and severe conditions, and may be administered subcutaneously.
Core Innovation
The invention relates to a stable liquid pharmaceutical formulation comprising an antibody comprising infliximab, or an antigen-binding fragment, wherein the formulation includes a surfactant comprising polysorbate 80, a sugar comprising sorbitol, and a buffer comprising sodium acetate. The formulation provides low viscosity and high antibody concentration while remaining stable during storage.
The formulation is defined by infliximab at 90 to 145 mg/ml, polysorbate 80 at 0.02 to 0.1% (w/v), sorbitol at 1 to 10% (w/v), and sodium acetate buffer at 1 to 50 mM. The disclosed formulation is associated with a pH in the range of 4.0 to 5.5 and stability under accelerated or severe conditions, with maintenance of product quality attributes after storage.
The disclosure states that replacing buffers and salts with a sorbitol plus acetate or histidine buffer approach, while using polysorbate 80 at defined levels, reduces precipitation and gelation and improves turbidity and aggregation behavior. Stability is evaluated using analytical assays for viscosity after storage, sub-visible particles, SEC-HPLC, intact IgG/HC+LC retention, oxidation of heavy-chain Met255, charge variants, and TNF-alpha binding affinity.
Claims Coverage
The partial claims set includes one independent claim that defines a stable liquid pharmaceutical formulation with four quantitative formulation components, and dependent claims that refine composition ranges and add product-quality and packaging or device constraints. The independent claim is centered on the combination of infliximab, polysorbate 80, sorbitol, and sodium acetate buffer to achieve stability in a defined liquid formulation.
Stable liquid formulation with infliximab at defined concentration
A stable liquid pharmaceutical formulation comprising 90 to 145 mg/ml of infliximab.
Polysorbate 80 surfactant at defined level
A stable liquid pharmaceutical formulation comprising 0.02 to 0.1% (w/v) of a surfactant comprising polysorbate 80.
Sorbitol sugar at defined level
A stable liquid pharmaceutical formulation comprising 1 to 10% (w/v) of a sugar comprising sorbitol.
Sodium acetate buffer at defined level
A stable liquid pharmaceutical formulation comprising 1 to 50 mM of a buffer comprising sodium acetate.
Viscosity targets after storage at defined conditions
The formulation has a viscosity in the range of approximately 8 cP after 1 month of storage at 40°C ± 2°C or approximately 4 cP after 6 months of storage at 5°C ± 3°C.
Freedom from specific amino acids
The stable liquid pharmaceutical formulation is free of aspartic acid, lysine, arginine, or mixtures thereof.
Freedom from specified inorganic salts
The formulation is free of NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4, or mixtures thereof.
Narrowed infliximab concentration range
The formulation comprises 100 to 125 mg/ml of infliximab.
Delivery device filled with the formulation
A pre-filled syringe is filled with the stable liquid pharmaceutical formulation of claim 1.
Across the independent and dependent claims provided, the coverage is directed to a stable liquid pharmaceutical formulation that combines infliximab with polysorbate 80, sorbitol, and sodium acetate buffer in specified ranges, and further includes constraints related to viscosity after storage, exclusion of certain amino acids and specified inorganic salts, a narrower infliximab concentration range, and a delivery configuration using a pre-filled syringe.
Stated Advantages
Provides low viscosity and high antibody concentration in a stable liquid pharmaceutical formulation.
Reduces precipitation and gelation.
Improves turbidity.
Improves aggregation behavior as assessed by SEC-HPLC and other product-quality measures.
Maintains intact IgG/HC+LC retention and preserves TNF-alpha binding affinity after storage.
Maintains stability with respect to oxidation of heavy-chain Met255 and charge variants.
Maintains sub-visible particle counts at specified low levels after storage.
Documented Applications
Subcutaneous administration using the stable liquid pharmaceutical formulation, including use in a pre-filled syringe and an auto-injector (mentioned).
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