Aflibercept formulations containing a lysine salt as tonicifying agent and uses thereof
Inventors
Gillespie, Alison J. • Floyd, Julee A. • Kerwin, Bruce A. • Siska, Christine C.
Assignees
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Publication Number
US-12178874-B2
Publication Date
2024-12-31
Expiration Date
Abstract
Ophthalmic formulations comprising aflibercept and a lysine salt tonicifying agent are disclosed that are suitable for a method of treatment of an eye disorder or disease by intravitreal or topical administration.
Core Innovation
The invention relates to aflibercept ophthalmic formulations comprising aflibercept, a phosphate or acetate buffer, a non-ionic surfactant, and a lysine salt as a tonicifying agent. The formulations have a final osmolality of 300+50 mOsm/kg and a pH about pH 5.0 to about pH 6.5, with lysine salt present at 2-3% (w/v). The formulations are described for ophthalmic administration, including intravitreal injection and topical administration.
The described approach addresses formulation stability by controlling tonicifying agents, buffer systems, and non-ionic surfactants to manage aggregation and high-molecular-weight (HMW) formation. The patent text describes reduced HMW aggregation/formation compared to a sucrose-based commercial comparator while maintaining acceptable osmolality and potency retention. It further associates the formulation design with quality-relevant metrics such as sub-visible particles and volume light obscuration.
Exemplary formulation embodiments and stability study results are presented using analytical stability and quality concepts including SE-HPLC and mass spectrometry multi-attribute method (MAM). The patent text also includes stress and storage-type evaluations, and reports that the lysine salt-based formulations show reduced HMW formation versus the comparator under the described conditions. In addition, tolerability is documented in rabbits following intravitreal injection of placebo lysine-based formulations.
Claims Coverage
The provided material includes four independent claims, each directed to an ophthalmic formulation comprising aflibercept, a buffer, a non-ionic surfactant, and a lysine salt tonicifying agent, constrained by final osmolality and pH. Dependent claims further restrict buffer identity, surfactant identity and/or concentrations, lysine salt form, and may add intravitreal administration for selected eye disorders.
Aflibercept ophthalmic formulation with phosphate or acetate buffer and lysine salt tonicifying agent
An ophthalmic formulation comprising aflibercept, a phosphate or acetate buffer, a non-ionic surfactant, and a lysine salt tonicifying agent, wherein the ophthalmic formulation has a final osmolality of 300+50 mOsm/kg and a pH about pH 5.0 to about pH 6.5.
Aflibercept ophthalmic formulation with specified surfactant group and lysine salt tonicifying agent
An ophthalmic formulation comprising aflibercept, a phosphate or acetate buffer, a non-ionic surfactant selected from the group consisting of a polysorbate and a poloxamer, and a lysine salt tonicifying agent, wherein the ophthalmic formulation has a final osmolality of 300+50 mOsm/kg and a pH about pH 5.0 to about pH 6.5.
Aflibercept ophthalmic formulation with phosphate buffer and constrained non-ionic surfactant levels at pH 6.0-6.5
An ophthalmic formulation comprising aflibercept, a phosphate buffer, a non-ionic surfactant selected from the group consisting of a polysorbate and a poloxamer, and a lysine salt tonicifying agent, wherein the ophthalmic formulation has a final osmolality of 300+50 mOsm/kg and a pH about pH 6.0 to about pH 6.5.
Aflibercept ophthalmic formulation with acetate buffer and constrained pH 5.0-5.5
An ophthalmic formulation comprising aflibercept, an acetate buffer, a non-ionic surfactant selected from the group consisting of a polysorbate and a poloxamer, and a lysine salt tonicifying agent, wherein the ophthalmic formulation has a final osmolality of 300+50 mOsm/kg and a pH about pH 5.0 to about pH 5.5.
Across the independent claims, the core claim coverage is an ophthalmic formulation that couples aflibercept with a phosphate or acetate buffer, a non-ionic surfactant, and a lysine salt tonicifying agent, while meeting final osmolality and specified pH windows. Additional coverage is provided in dependent claims for particular buffer and pH sub-ranges, specified surfactants and concentrations, particular lysine salt forms, and treatment-related dependent claim context via intravitreal injection for selected eye disorders.
Stated Advantages
Reduced high-molecular-weight (HMW) aggregation/formation versus a sucrose-based commercial comparator.
Acceptable osmolality and potency retention.
Reduction associated with volume light obscuration/HIAC and sub-visible particles (as quality-related outcomes described in the provided text).
Documented Applications
Intravitreal injection administration of the described lysine salt-based aflibercept ophthalmic formulations, including tolerability evaluation in rabbits using placebo lysine-based formulations.
Treatment of a selected eye disorder or disease by administering a therapeutically effective amount of the ophthalmic formulation via intravitreal injection for macular edema following Retinal Vein Occlusion (RVO), Central Retinal Vein Occlusion (CRVO), Branch Retinal Vein Occlusion (BRVO), Neovascular (Wet) Age-Related Macular Degeneration (AMD), impaired vision due to Myopic Choroidal Neovascularisation, Diabetic Macular Edema (DME), Diabetic Retinopathy (DR) in patients with DME, and neovascular Age-Related Macular Degeneration (AMD).
Topical administration of the described ophthalmic formulations.
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