Protein formulations with increased stability

Inventors

Jezek, Jan • Derham, Barry Kingston

Assignees

Arecor Ltd

Abstract

The invention relates to the discovery that the addition of aromatic carboxylate ions inhibit protein instability caused by aromatic preservatives. Thus, the invention relates to compositions, preferably aqueous compositions, comprising a protein, an aromatic preservative and aromatic carboxylate ions. The proteins remain stable and suitable for storage at ambient temperatures or lower, even in aqueous form. Preferably, the aqueous composition comprises a protein, a phenolic preservative and benzoate ions, wherein the pH of the composition is at least 1 unit greater than the pKa of benzoic acid. The invention also provides methods of reducing protein degradation by aromatic preservatives in an aqueous formulation of a protein susceptible to such degradation, comprising the step of adding aromatic carboxylate ions to the formulation wherein the formulation is maintained at a pH that is at least 1 unit greater than the pKa of the corresponding aromatic carboxylic acid.

Core Innovation

The disclosed invention concerns an aqueous pharmaceutical composition that includes a protein, an aromatic preservative selected from phenol, m-cresol, and benzyl alcohol, and aromatic carboxylate ions selected from specified aromatic carboxylic acids. The aromatic preservative is present at a molar concentration of 10–60 mM, and the aromatic carboxylate ions are present at a molar concentration of 30–100 mM. The composition is defined to improve protein stability upon storage at room temperature for at least 1 month compared to an aqueous composition without the aromatic carboxylate ions.

A further defining aspect is that the pH of the composition is at least one unit higher than the pKa of the carboxylate group of the aromatic carboxylate ions. Maintaining this pH relationship keeps the carboxylate largely ionized, so the aromatic carboxylate ions act to inhibit protein instability that is driven by aromatic preservatives such as phenol, m-cresol, and benzyl alcohol. The aromatic carboxylate ions are drawn from a list that includes benzoic acid and multiple hydroxybenzoic acids, trihydroxybenzoic acid (gallic acid), methoxybenzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acids, indole-3-acetic acid, phenylacetic acid, 3-phenylpropionic acid, cinnamic acids, and mandelic acid.

The document further describes that the choice of aromatic carboxylate ions can reduce formation of high molecular weight species and aggregation associated with preservative-driven degradation. In contrast, at least one non-aromatic carboxylate can worsen stability in the presence of aromatic preservatives. The specification additionally indicates that the compositions may use conventional formulation additives and considers storage stability at ambient or refrigerated conditions, including preservation-problem mitigation for proteins used in multi-dose contexts.

Claims Coverage

The document provides one independent claim. The independent claim defines an aqueous pharmaceutical composition with three main inventive feature groups: selection and concentration of the aromatic preservative, selection and concentration of aromatic carboxylate ions, and a pH condition relative to pKa, with an explicitly stated stability outcome at room temperature for at least 1 month versus a composition lacking aromatic carboxylate ions.

Overall, the independent claim requires a protein aqueous formulation combining a specified aromatic preservative concentration range with specified aromatic carboxylate ion identities and concentrations, while enforcing a pH condition relative to the aromatic carboxylate pKa and requiring improved protein stability at room temperature for at least 1 month versus an otherwise similar composition lacking aromatic carboxylate ions.

Stated Advantages

Documented Applications