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Publication Number
US-10576128-B2
Publication Date
2020-03-03
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 a liquid pharmaceutical composition for treating an intraocular neovascular disease by administering a liquid formulation of an aflibercept-containing VEGF antagonist. The composition consists of histidine hydrochloride/L-histidine, polysorbate 20, NaCl, aflibercept, sucrose, and water, and is formulated to have a pH from 6.2 to 6.5.
The background and rationale address the need for intravitreal injections to reduce insoluble particles and to maintain stability of the VEGF antagonist. The formulation approach targets reduced high-molecular-weight species and aggregates and reduced fragments by selecting a histidine-containing buffer system at the specified pH range and including polysorbate 20, NaCl, and sucrose.
The document further describes characterizing formulation stability using multiple analytical methods, including SEC, SDS-PAGE (reduced and non-reduced), IEF, reduced peptide mapping (methionine oxidation and deamidation), FTIR secondary-structure assessment, relative potency assays, and FcRn binding by biolayer interferometry. Stability data are described for formulations stored under stress/freezing and various temperature and humidity conditions.
Claims Coverage
The independent claim describes one method of treating an intraocular neovascular disease using a specific liquid composition with histidine hydrochloride/L-histidine, polysorbate 20, NaCl, aflibercept, sucrose, and water at a pH from 6.2 to 6.5. Dependent claims refine the composition with additional quantitative excipient and drug constraints and narrow the administration route and specific disease etiologies.
Liquid pharmaceutical composition at pH 6.2 to 6.5 for intravitreal treatment
A method of treating an intraocular neovascular disease comprising administering a liquid pharmaceutical composition consisting of histidine hydrochloride/L-histidine, polysorbate 20, NaCl, aflibercept, sucrose and water and having a pH from 6.2 to 6.5.
Specific histidine hydrochloride/L-histidine concentration
The method further includes histidine hydrochloride/L-histidine at a concentration between 1 mM and 40 mM.
Specific polysorbate 20 concentration
The method includes polysorbate 20 present at a concentration of 0.03% (w/v).
Specific aflibercept concentration range
The method includes aflibercept present at a concentration ranging from 6 to 45 mg/ml.
Specific sucrose concentration
The method includes sucrose at a concentration of 5% (w/v).
Intravitreal injection administration route
The method further specifies that the pharmaceutical composition is administered by intravitreal injection.
Across the independent claim and refinements, the main inventive coverage is the administration of a liquid aflibercept-containing formulation for intraocular neovascular disease, constrained to a pH of 6.2–6.5 and to specific excipient and drug concentration selections (histidine hydrochloride/L-histidine, polysorbate 20, NaCl, aflibercept, sucrose), with intravitreal injection as the administration route.
Stated Advantages
Reduce insoluble particles and maintain stability of the formulation for intravitreal injection.
Target reduced high-molecular-weight species (HMWS)/aggregates and reduced fragments.
Provide stability supported by analytical characterization including SEC, SDS-PAGE, IEF, reduced peptide mapping, FTIR, relative potency assays, and FcRn binding.
Documented Applications
Treatment of intraocular neovascular diseases including AMD.
Treatment of intraocular neovascular diseases including DME (diabetic macular oedema).
Treatment of intraocular neovascular diseases including RVO-related macular edema.
Treatment of intraocular neovascular diseases including CNV secondary to pathologic myopia.
Administration as a liquid pharmaceutical composition using prefilled syringes/ready-to-use containers.
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