Stabilized preparation of interferon beta variant
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Publication Number
US-11207411-B2
Publication Date
2021-12-28
Expiration Date
Abstract
The present invention relates to a stabilized pharmaceutical preparation of R27T, the preparation comprising a human interferon beta variant (R27T), an acetate buffer, arginine, trehalose, Poloxamer 188, and methionine. The stabilized R27T pharmaceutical preparation according to the present invention is obtained by the development of a preparation having a novel composition through the substitution of mannitol with trehalose in the composition of a preparation containing mannitol, which was previously studied by the present inventors. It was confirmed that the preparation can remedy a disadvantage of the protein aggregate increase due to the mixing and addition of mannitol and arginine HCl and can improve thermodynamic/structural stability and the resulting stability during the long-term storage, and thus it is expected that the preparation can be advantageously used in the prevention, alleviation, and treatment of multiple sclerosis, cancer, autoimmune diseases, viral infectious diseases, HIV infectious diseases, hepatitis C, rheumatoid arthritis, and the like.
Core Innovation
The patent discloses a stabilized pharmaceutical preparation of a human interferon beta variant (rhINF-β), identified as a variant with arginine substituted with threonine at amino acid 27. The preparation is formulated in an acetate buffer together with arginine, trehalose, Poloxamer 188, and methionine, and addresses formulation stability and aggregation behavior of the interferon beta variant in the stated composition.
The document describes a problem in which combining interferon beta variant formulations with mannitol is associated with aggregate formation, and motivates replacing mannitol with trehalose when combined with arginine HCl. The patent reports improved thermodynamic/structural stability and long-term storage stability in the trehalose-based formulation, together with reduced protein aggregation compared with mannitol-based formulations.
The patent states that the formulation achieves comparable anti-viral activity versus mannitol-based formulations. Experimental evidence is described using SEC, DSC, and CPE assays, including comparison of storage stability and aggregation outcomes, and the preparation is presented with multiple formulation variants involving trehalose and other excipients, with stated effects related to the presence or absence of arginine HCl.
Claims Coverage
The partial content provided includes one independent claim with two inventive features. The claim focuses on a stabilized pharmaceutical preparation defined by a specific human interferon beta variant, an acetate buffer condition, and a defined combination of stabilizing excipients at specified concentration ranges.
Stabilized pharmaceutical preparation with interferon beta R27T variant formulation
A stabilized pharmaceutical preparation comprising a human interferon beta variant, an acetate buffer having pH 3.6 to 4.0, arginine, trehalose, Poloxamer 188, and methionine, where the human interferon beta variant comprises substituting arginine which is amino acid 27 of the human interferon beta with threonine.
Specific composition ranges for acetate buffer, arginine, trehalose, Poloxamer 188, and methionine
The stabilized pharmaceutical preparation includes an acetate buffer at 10 to 20 mM, arginine at 50 mM, trehalose at 200 to 250 mM, Poloxamer 188 at 0.1 to 10 mg/mL, and methionine at 0.5 to 5 mM.
Overall, claim coverage centers on a rhINF-β R27T (arginine at amino acid 27 substituted with threonine) in a stabilized pharmaceutical preparation using an acetate buffer with defined pH and a defined combination of arginine, trehalose, Poloxamer 188, and methionine within specified concentration ranges.
Stated Advantages
Improved thermodynamic/structural stability.
Improved long-term storage stability.
Reduced protein aggregation compared with mannitol-based formulations.
Comparable anti-viral activity versus mannitol-based formulations.
Documented Applications
Multiple sclerosis.
Cancer.
Autoimmune diseases.
Viral infectious diseases, including HIV infectious diseases and hepatitis C.
Rheumatoid arthritis.
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