Chimeric cytokine formulations for ocular delivery
Inventors
Zarbis-Papastoitsis, Gregory • Lowden, Patricia • Chang, Byeong
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10799589-B2
Publication Date
2020-10-13
Expiration Date
Abstract
Featured herein are vehicle formulations and formulations containing a chimeric cytokine designed for e.g., ocular delivery.
Core Innovation
The core invention provides an aqueous formulation for delivering an IL-1β/IL-1Ra chimeric cytokine protein comprising an amino acid sequence selected from any one of SEQ ID NOs: 1-7. The formulation includes a buffering agent selected from sodium citrate and sodium phosphate, sorbitol at a concentration of 3.5-6.5% (w/v), and poloxamer 188 at a concentration of 0.07-0.13% (w/v) or 0.05-0.15% (w/v). The formulation further has a pH of 5.5 to 7.5 and protein concentration ranges of 1-50 mg/ml or 1-100 mg/ml.
The invention addresses an aqueous formulation challenge for IL-1 inhibition, including stability of an IL-1β/IL-1Ra chimeric cytokine protein in an ocular vehicle. The vehicle is described as maintaining purity and monomer content, providing low particulate counts meeting USP ophthalmic particulate criteria, and retaining stability after agitation/heat and after blow-fill-seal (BFS) processing and container storage, including multi-dose conditions.
The invention additionally describes formulation-related approaches to manage oxidation of the chimeric cytokine protein, including reduced oxidation when methionine is present in multidose/stress conditions. The described formulation is associated with biological and clinical evidence, including IL-1R/IL-1β activity modulation by the chimeric proteins, animal efficacy in dry eye with reduced corneal fluorescein staining, and human clinical trial improvements in OSDI, pain, and corneal fluorescein staining with therapeutic and vehicle formulations.
Claims Coverage
The independent claims are directed to aqueous formulations containing an IL-1β/IL-1Ra chimeric cytokine protein with amino acid sequence selected from SEQ ID NOs: 1-7. Across the independent claims, the key inventive formulation features include defined buffering agents, sorbitol, poloxamer 188, and a specified pH range, with concentration ranges for the chimeric cytokine protein differing between independent claims.
An aqueous formulation with defined chimeric cytokine concentration, sodium citrate/sodium phosphate buffer, sorbitol, poloxamer 188, and pH 5.5 to 7.5
The formulation comprises 1-50 mg/ml of an IL-1β/IL-1Ra chimeric cytokine protein comprising an amino acid sequence selected from any one of SEQ ID NOs: 1-7, a buffering agent selected from sodium citrate and sodium phosphate, sorbitol at 3.5-6.5% (w/v), and poloxamer 188 at 0.07-0.13% (w/v), wherein the formulation has a pH of 5.5 to 7.5.
An aqueous formulation with defined chimeric cytokine concentration, sodium citrate/sodium phosphate buffer, sorbitol, poloxamer 188 0.05-0.15% w/v, and pH 5.5 to 7.5
The formulation comprises 1-50 mg/ml of an IL-1β/IL-1Ra chimeric cytokine protein comprising an amino acid sequence selected from any one of SEQ ID NOs: 1-7, a buffering agent selected from sodium citrate and sodium phosphate, sorbitol at 3.5-6.5% (w/v), and poloxamer 188 at 0.05-0.15% (w/v), wherein the formulation has a pH of 5.5 to 7.5.
An aqueous formulation with higher defined chimeric cytokine concentration, sodium citrate/sodium phosphate buffer, sorbitol, poloxamer 188 0.05-0.15% w/v, and pH 5.5 to 7.5
The formulation comprises 1-100 mg/ml of an IL-1β/IL-1Ra chimeric cytokine protein comprising an amino acid sequence selected from any one of SEQ ID NOs: 1-7, a buffering agent selected from sodium citrate and sodium phosphate, sorbitol at 3.5-6.5% (w/v), and poloxamer 188 at 0.05-0.15% (w/v), wherein the formulation has a pH of 5.5 to 7.5.
Across the independent claims, the inventive coverage centers on aqueous ocular formulations containing an IL-1β/IL-1Ra chimeric cytokine protein (SEQ ID NOs: 1-7) in combination with specific buffering agents (sodium citrate or sodium phosphate), sorbitol (3.5-6.5% w/v), poloxamer 188 (either 0.07-0.13% w/v or 0.05-0.15% w/v), and a pH of 5.5 to 7.5, with IL-1β/IL-1Ra protein concentration ranges of 1-50 mg/ml or 1-100 mg/ml.
Stated Advantages
Maintains purity/monomer content.
Provides low particulate counts meeting USP ophthalmic particulate criteria.
Retains stability after agitation/heat and after blow-fill-seal (BFS) processing and container storage, including multi-dose.
Methionine reduces oxidation in multidose/stress conditions.
Improves in vitro IL-1R/IL-1β activity modulation.
Reduces corneal fluorescein staining in a dry eye animal efficacy model.
Improves clinical outcomes in humans, including OSDI, pain, and corneal fluorescein staining with therapeutic and vehicle formulations.
Documented Applications
Topical eye delivery for dry eye, with reduced corneal fluorescein staining in an animal efficacy model.
Human clinical use for dry eye symptoms, with improvements in OSDI, pain, and corneal fluorescein staining from therapeutic and vehicle formulations.
Interested in licensing this patent?