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Publication Number
US-12551529-B2
Publication Date
2026-02-17
Expiration Date
Abstract
The present invention relates to liquid pharmaceutical compositions of a VEGF antagonist for intravitreal administration comprising a histidine buffer, an inorganic salt, a carbohydrate and a polysorbate.
Core Innovation
The invention relates to liquid pharmaceutical compositions for intravitreal administration that contain a histidine containing buffer composed of L-histidine/histidine hydrochloride, a non-ionic surfactant, an inorganic salt, a carbohydrate, and a VEGF antagonist. The liquid compositions are characterized by low particle/aggregate content and stability, including stability without lyophilisation, and are described with near-physiological pH values of 6.0–6.5, with preferred pH 6.2 or 6.5.
The VEGF antagonist is preferably aflibercept or ranibizumab, formulated with polysorbate 20 as the non-ionic surfactant, NaCl as the inorganic salt, and sucrose as the carbohydrate. The document provides composition examples defined in terms of histidine hydrochloride/L-histidine, polysorbate 20, NaCl, sucrose, and aflibercept or ranibizumab concentrations, including a more specific formulation example consisting of these components.
A stability package is reported for aflibercept in the described liquid histidine-based formulations, including physical, chemical, and biological stability assessments. The testing includes low HMWS and comparable stability across multiple stress and storage conditions, with analytical characterization referenced such as SEC, AF4, SDS-PAGE, isoelectric focusing, reduced peptide mapping, FTIR, relative potency ELISA, and FcRn binding. The formulation approach is linked to suitability for treating intraocular neovascular disease.
Claims Coverage
The provided excerpt includes two independent claims that both claim methods of treating intraocular neovascular disease by administering specific liquid pharmaceutical compositions. Across the independent claims, the claims consistently require a histidine-containing buffer with L-histidine/histidine hydrochloride, a non-ionic surfactant, a VEGF antagonist, an inorganic salt, and a carbohydrate, with pH specified in each claim.
Histidine-containing buffer with specified L-histidine/histidine hydrochloride concentration
Administering a liquid pharmaceutical composition comprising a histidine containing buffer at a concentration of from 8 mM to 15 mM, wherein the histidine-containing buffer is L-histidine/histidine hydrochloride.
Non-ionic surfactant at specified concentration
Administering a liquid pharmaceutical composition comprising a non-ionic surfactant at a concentration of 0.02% to 0.04% (w/v).
VEGF antagonist as aflibercept at specified concentration
Administering a liquid pharmaceutical composition comprising a VEGF antagonist, wherein said VEGF antagonist is aflibercept at a concentration of from 6 mg/mL to 45 mg/mL.
Inorganic salt at specified concentration range
Administering a liquid pharmaceutical composition comprising an inorganic salt at a concentration of from 35 to 45 mM.
Carbohydrate at specified concentration range
Administering a liquid pharmaceutical composition comprising a carbohydrate at a concentration of from 3% to 20% (w/v).
Defined “consisting of” formulation with pH of 6.2 or 6.5
Administering a liquid pharmaceutical composition consisting of histidine hydrochloride/L-histidine, polysorbate 20, NaCl, aflibercept, sucrose and water and having a pH of 6.2 or 6.5.
Overall, the independent claims cover methods of treating intraocular neovascular disease by administering liquid compositions that combine a L-histidine/histidine hydrochloride buffer with non-ionic surfactant, inorganic salt, and carbohydrate excipients, together with aflibercept as a VEGF antagonist. One independent claim is defined by component concentration ranges, while the other is defined by a “consisting of” component list and specific pH values.
Stated Advantages
Low particle/aggregate content and stability without lyophilisation.
Near-physiological pH (pH 6.0–6.5; preferred pH 6.2 or 6.5).
Stability characterized as low HMWS and comparable physical/chemical/biological stability across tested histidine-based formulations.
Documented Applications
Intraocular neovascular diseases including AMD, DME-related visual impairment (diabetic macular oedema), macular oedema secondary to branch or central retinal vein occlusion (RVO), and CNV secondary to pathologic myopia.
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