Compositions in the form of an injectable aqueous solution including at least human insulin A21G and a glucagon suppressor with prandial action
Inventors
Assignees
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Publication Number
US-10610572-B2
Publication Date
2020-04-07
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 disclosed injectable aqueous diabetes-treatment composition combines at least human insulin A21G, referred to as regular insulin, with at least one glucagon suppressor with prandial action. The composition is formulated as an injectable aqueous solution having an acidic pH of from 3.5 to 4.4.
The disclosure links the acidic pH of about 3.5 to 4.4 to physical and chemical stability of the combined injectable solution. The document reports fibrillation lag time behavior by Thioflavin T (ThT) and reports visible clarity and stability at 30°C, including the stated stability period and insulin/pramlintide chemical stability.
The disclosure further describes pharmacokinetic effects of combining insulin A21G with a prandial glucagon suppressor, including delayed prandial absorption of pramlintide, characterized by delayed tmax and reduced early AUC. The document associates these pharmacokinetic changes with improved post-prandial glycemia control and reduced adverse effects such as nausea.
The document also provides injectable aqueous formulation examples for the insulin A21G and prandial glucagon suppressor combination at acidic pH and describes an insulin A21G production approach involving carboxypeptidase B digestion of insulin glargine under specified conditions. The disclosure includes experimental pharmacokinetic/pharmacodynamic and glycemia results in dogs, pigs, and rats, including pramlintide absorption and food-consumption effects.
Claims Coverage
The independent claim is clm-00001. It sets out an injectable aqueous solution composition with two core inventive elements: a defined acidic pH range and the pairing of human insulin A21G (regular insulin) with at least one prandial-action glucagon suppressor; the dependent claims then add further constraints on pH, component concentration ranges, selected prandial glucagon suppressor types, specific formulation components, and bolus prior to meals administration.
Injectable aqueous solution at acidic pH range
An injectable aqueous solution having a pH from 3.5 to 4.4.
Regular insulin with prandial glucagon suppressor
The injectable aqueous solution comprises at least human insulin A21G referred to as regular and at least one glucagon suppressor with prandial action.
Tighter acidic pH sub-range
The injectable aqueous solution has a pH between 3.8 and 4.2.
Insulin A21G concentration range
The composition has a concentration of human insulin A21G in the range of 2 to 20 mg/mL.
Prandial glucagon suppressor concentration range
The composition has a prandial glucagon suppressor concentration ranging from 0.01 to 10 mg/mL.
Selected prandial glucagon suppressor types
The prandial-action glucagon suppressor is selected from an amylin analog, an amylin receptor agonist, a GLP-1 analog, or a GLP-1 receptor agonist (GLP-1 RA).
Bolus prior to meals diabetes treatment administration
A diabetes-treatment composition is administered as a bolus prior to meals.
Overall claim coverage centers on an injectable aqueous solution of regular human insulin A21G combined with a prandial-action glucagon suppressor, formulated at acidic pH 3.5 to 4.4, with dependent claim refinements specifying tighter pH and quantitative concentration ranges, selectable prandial glucagon suppressor classes (amylin/GLP-1 types), and a bolus-before-meals administration context.
Stated Advantages
Improved post-prandial glycemia control versus rapid prandial insulin analog combinations.
Physical/chemical stability of the injectable solution enabled by acidic pH.
Reduced early pramlintide absorption, evidenced by delayed tmax and reduced early AUC.
Reduction of adverse effects such as nausea.
Insulin/pramlintide chemical stability and reported visible clarity.
Documented Applications
Diabetes-treatment using the disclosed composition administered as a bolus prior to meals for effects on post-prandial glycemia and adverse effects related to pramlintide.
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