Compositions in the form of an injectable aqueous solution including at least human insulin A21G and a glucagon suppressor with prandial action
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Publication Number
US-11065305-B2
Publication Date
2021-07-20
Expiration Date
Abstract
A composition in the form of an injectable aqueous solution, with pH from 3.5 to 4.4, including at least human insulin A21G and at least one glucagon suppressor with prandial action. In an embodiment, the glucagon suppressor with prandial action is selected from an amylin analog or an amylin receptor agonist or a GLP-1 analog or a GLP-1 receptor agonist (GLP-1 RA). In an embodiment, the glucagon suppressor with prandial action is an amylin analog or an amylin receptor agonist. In an embodiment, the glucagon suppressor peptide with prandial action is pramlintide. Also, a method for obtaining human insulin A21G, includes at least one step of reacting human insulin A21G, B31R, B32R (insulin glargine) with rat carboxypeptidase B at an insulin/carboxypeptidase ratio from 500 to 2000, at a pH from 7.5 to 8.5 and a temperature from 20 to 30° C. for 10 to 20 hours.
Core Innovation
The invention provides an injectable aqueous composition for diabetes therapy that combines human insulin A21G (“regular”) with pramlintide. The injectable aqueous solution has a pH from 3.5 to 4.4 and is formulated with human insulin A21G in a range of 100 to 300 U/ml and pramlintide at 0.4 to 3.0 mg/ml.
The co-formulation is used to enable compatibility between the insulin component and prandial glucagon suppressors, particularly pramlintide. The disclosed formulation targets post-meal glucagon and prandial action by providing a co-formulation that supports meal-time use.
At the specified acidic pH, the formulation is described as showing physical and chemical stability, including fibrillation lag time measured by Thioflavin T (ThT), clear solution behavior, and stability that meets requirements over time and storage conditions. The document also describes mechanistic and preclinical evidence that co-formulation slows pramlintide absorption, reflected in delayed tmax and reduced early AUC0–30min, which is associated with improved PK/PD profiles compatible with prandial, post-meal use.
Claims Coverage
The provided claim set contains three independent claims directed to an injectable aqueous insulin A21G/pramlintide composition with acidic pH and defined concentration ranges, a solid composition with a specified insulin-to-pramlintide ratio, and a method for treating a diabetic patient using the defined injected co-formulation. Across these independent claims, there are three main inventive features: specific co-formulation composition constraints, a solid insulin-to-pramlintide ratio, and injection-based treatment of diabetes.
Acidic injectable aqueous co-formulation of regular insulin A21G and pramlintide
An injectable aqueous solution having a pH of 3.5 to 4.4, including human insulin A21G (regular) in a range from 100 to 300 U/ml and pramlintide at a concentration of between 0.4 to 3.0 mg/ml.
Solid composition with insulin A21G to pramlintide ratio
A solid composition comprising at least human insulin A21G (regular) and pramlintide in a ratio from 33 to 167 U insulin /mg of pramlintide.
Injected treatment of a diabetic patient using an acidic insulin A21G/pramlintide composition
A method for treating a diabetic patient in need of an insulin formulation by administering by injection a composition comprising human insulin A21G (regular) at a concentration range from 100 to 300 U/ml and pramlintide at a concentration range from 0.4 to 3 mg/ml, wherein the pH of the composition is in a range from 3.5 to 4.4.
The independent claims focus on defined co-formulations of human insulin A21G (“regular”) and pramlintide, with critical formulation constraints for the injectable aqueous form, a defined insulin-to-pramlintide ratio for the solid form, and an injection-based method for treating a diabetic patient using the specified injectable composition.
Stated Advantages
Improved post-prandial hyperglycemia control using insulin therapy together with pramlintide prandial action.
Reduced early pramlintide exposure and delayed tmax associated with improved PK/PD profiles compatible with meal-time use.
Reduced pramlintide-related adverse effects, including nausea, as supported by delayed absorption and improved PK/PD profiles.
Physical and chemical stability of the injectable aqueous co-formulation at pH 3.5–4.4, including fibrillation lag time and clear solution behavior.
Documented Applications
Treating a diabetic patient in need of an insulin formulation by administering an injectable aqueous co-formulation containing human insulin A21G (regular) and pramlintide with pH 3.5–4.4.
Post-meal glycemic control using an insulin therapy co-formulated with pramlintide for prandial action.
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