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Publication Number
US-11278624-B2
Publication Date
2022-03-22
Expiration Date
Abstract
According to the invention there is provided inter alia an aqueous liquid pharmaceutical formulation comprising insulin or an insulin analogue, ionic zinc, a chelating agent and polysorbate 80.
Core Innovation
The invention relates to a rapid-acting aqueous liquid pharmaceutical formulation comprising an insulin analogue together with ionic zinc, citrate as a chelating agent, and polysorbate 80. The formulation is described with defined concentration ranges for the insulin analogue, ionic zinc, citrate, and polysorbate 80, and is characterized by the requirement that fewer than 20 particles are detectable after 8 weeks at 30°C using the method described in the 2.9.20 European Pharmacopoeia Monograph.
The described problem is that zinc chelators, particularly in formulations associated with citrate/histidine/pyrophosphate, can cause adverse effects including precipitation and loss of intact insulin peaks, which are associated with visible particles and decreased performance in the formulation. The invention addresses the stability and particle-formation issues by including polysorbate 80 in an aqueous liquid pharmaceutical formulation containing ionic zinc and citrate.
The document further discloses that the formulation can be assessed using stability and particle-formation related-parameter assessment methods, including size-exclusion chromatography (SEC) and reverse-phase HPLC (RP-HPLC), and that example results show that adding polysorbate 80 mitigates the adverse effects caused by zinc chelators compared with formulations lacking polysorbate 80 or using alternative surfactants. The formulation is also described for treating diabetes mellitus, including optional delivery formats and a dry solid reconstitution variant.
Claims Coverage
The partial content includes one independent claim. The independent claim is directed to a specific aqueous liquid formulation defined by ingredient identities and quantitative concentration ranges, and further limited by a particle-count stability criterion after storage. The dependent claims refine by specifying particular insulin analogues and narrowing additional quantitative ranges and conditions, and by defining therapeutic use for diabetes mellitus and delivery and container aspects.
Aqueous liquid insulin formulation with ionic zinc and citrate chelation plus polysorbate 80
An aqueous liquid pharmaceutical formulation comprising an insulin analogue at 100-1000 U/ml, ionic zinc at 0.25-1% by weight of zinc based on the weight of the insulin analogue, citrate at 10-50 mM, and polysorbate 80 at 0.05-0.5 mg/ml, wherein fewer than 20 particles are detectable after 8 weeks at 30°C using the method described in the 2.9.20 European Pharmacopoeia Monograph.
Specific insulin analogues as the insulin analogue
The formulation includes insulin lispro as the insulin analogue, and other dependents refine to particular named insulin analogues as stated in the partial content.
Narrowed ionic zinc concentration based on insulin analogue weight
The formulation includes ionic zinc at 0.35-0.75% by weight of zinc based on the weight of the insulin analogue in the formulation.
Narrowed citrate concentration
The formulation further specifies that the citrate is present at a concentration of 30-50 mM.
Narrowed formulation pH range
The formulation is characterized by a pH between 7.0 and 7.5.
Diabetes mellitus treatment by administration
Treating diabetes mellitus by administering an effective amount of the formulation as defined in claim 1 to a subject in need.
Across the available independent claim and refinements described in the partial content, the inventive coverage centers on an aqueous liquid insulin formulation combining ionic zinc, citrate chelation, and polysorbate 80, with a defined particle-count criterion after storage, and further refinements specify particular insulin analogues, tighter quantitative ranges for ionic zinc and citrate, formulation pH, and therapeutic use for diabetes mellitus.
Stated Advantages
Fewer than 20 particles are detectable after 8 weeks at 30°C using the method described in the 2.9.20 European Pharmacopoeia Monograph.
Mitigation of adverse effects, including precipitation and loss of intact insulin peaks, caused by zinc chelators, particularly in formulations associated with citrate/histidine/pyrophosphate.
Documented Applications
Treating diabetes mellitus by administering an effective amount of the aqueous liquid formulation to a subject in need.
Optional packaging and delivery formats are described, including a container and injection device and a medical device with pump, and a dry solid pharmaceutical composition for reconstitution is also disclosed.
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