Injectable solution at pH 7 comprising at least one basal insulin the pi of which is between 5.8 and 8.5 and a substituted co-polyamino acid
Inventors
Assignees
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Publication Number
US-10335489-B2
Publication Date
2019-07-02
Expiration Date
Abstract
A composition in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, including at least (a) a basal insulin, the isoelectric point pI of which is between 5.8 and 8.5; and (b) a co-polyamino acid bearing carboxylate charges and substituted with hydrophobic radicals. In one embodiment, the compositions also include a prandial insulin and/or a gut hormone.
Core Innovation
The invention relates to an injectable aqueous solution with a pH between 6.0 and 8.0, comprising a basal insulin having an isoelectric point pI between 5.8 and 8.5, a prandial insulin, and a co-polyamino acid bearing carboxylate charges and substituted with hydrophobic groups. The co-polyamino acid is selected from co-polyamino acids of formula I and is formed from aspartic units and/or glutamic units, with defined radicals R1, R2, R3, R4, and R5, and with hydrophobic grafting parameters.
The disclosed formulation addresses the acidic pH requirement of conventional insulin-glargine-type formulations by enabling solubilization at neutral-to-near-neutral pH. It allows mixing with prandial insulins or GLP-1 analogs in the same injectable aqueous solution while preserving the fast action of the prandial insulin described as soluble at pH 6–8 and unstable at acidic pH.
The substituted co-polyamino acids are described with hydrophobic groups selected as saturated or unsaturated, linear or branched C8 to C30 radicals, or as radicals of formula III or III’, and are characterized by molar degree of grafting and degree of polymerization. The document also reports formulation behavior showing solubilization and precipitation tendencies of insulin glargine with substituted sodium co-polyamino acids, and ternary combinations including GLP-1 analogs or derivatives.
Claims Coverage
The consolidated independent claim coverage centers on one independent claim directed to a pH-controlled injectable aqueous composition combining basal and prandial insulin with a specifically defined carboxylate-charged, hydrophobically substituted co-polyamino acid of formula I. The claim includes three inventive features: the pH-bounded injectable formulation, the basal/prandial insulin co-formulation, and the structural and polymerization constraints on the co-polyamino acid.
Neutral-to-near-neutral injectable aqueous insulin solution
An injectable aqueous solution with pH between 6.0 and 8.0.
Basal insulin with controlled isoelectric point
A basal insulin having an isoelectric point pI between 5.8 and 8.5.
Basal and prandial insulin co-formulation
The composition comprises a prandial insulin in addition to the basal insulin.
Carboxylate-charged hydrophobically substituted co-polyamino acid of formula I
A co-polyamino acid bearing carboxylate charges and substituted with hydrophobic groups, chosen from the co-polyamino acids of formula I with aspartic and glutamic units and defined radicals R1, R2, R3, R4, and R5.
Grafting and polymerization constraints for the co-polyamino acid
The co-polyamino acid has a molar degree of grafting n/(n+m) between 1 and 50 mol% and a degree of polymerization n+m between 5 and 100.
The independent claim coverage focuses on a neutral-to-near-neutral injectable aqueous composition that combines basal and prandial insulin with a defined family of carboxylate-charged co-polyamino acids substituted with hydrophobic groups. The co-polyamino acid is constrained by formula I structural definitions and by grafting and polymerization parameters, and the basal insulin is restricted by its isoelectric point range.
Stated Advantages
Enables solubilization of basal insulin at neutral-to-near-neutral pH.
Preserves basal insulin slow action via precipitation in subcutaneous tissue triggered by medium composition rather than pH.
Preserves fast action of co-formulated prandial insulin that is described as soluble at pH 6–8.
Allows mixing with prandial insulins or GLP-1 analogs by avoiding the acidic pH requirement of conventional insulin-glargine-type formulations.
Documented Applications
Injectable aqueous insulin use as a composition containing basal insulin and prandial insulin together in a single formulation at pH 6.0–8.0.
Injectable aqueous insulin use as a formulation optionally including gut hormones or GLP-1 analogs such as exenatide, liraglutide, and lixisenatide.
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