Injectable pH 7 solution comprising at least one basal insulin having a pI from 5.8 to 8.5 and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals
Inventors
Chan, You-Ping • GEISSLER, Alexandre • Noel, Romain • Charvet, Richard • LAURENT, Nicolas
Assignees
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Publication Number
US-11883496-B2
Publication Date
2024-01-30
Expiration Date
Abstract
A physically stable compositions in the form of an injectable aqueous solution with a pH from 6.0 to 8.0, include a basal insulin whose isoelectric point (pI) is from 5.8 to 8.5, and a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical.
Core Innovation
The invention relates to an aqueous injectable solution whose pH is comprised from 6.0 to 8.0, comprising a basal insulin whose isoelectric point pI is comprised from 5.8 to 8.5, in combination with a co-polyamino acid bearing carboxylate charges and hydrophobic radicals -Hy. The co-polyamino acid includes units selected from glutamic units, aspartic units, and units according to formula XXXa, and the hydrophobic radicals -Hy are according to formula X.
The hydrophobic radicals -Hy are bonded to the co-polyamino acid via an amide function formed by covalent bonding between a carbonyl of the hydrophobic radical and a nitrogen atom borne by the co-polyamino acid, or between a nitrogen atom of the hydrophobic radical and a carbonyl borne by the co-polyamino acid. The co-polyamino acid has a ratio M between the number of hydrophobic radicals and the number of glutamic and aspartic units from 0<M0.5, a degree of polymerization DP in glutamic or aspartic units from 5 to 250, and free carboxylic acid functions in the form of an alkali metal salt chosen from Na+ and K+.
The structural selections include GpR, GpG or GpH, GpA and A selections, GpL, and GpC, together with integer parameters and carbon-count and branching rules for the hydrophobic radicals. The partial claim set also includes insulin glargine, insulin lispro, basal insulin concentration and co-polyamino acid concentration limits, and a stability-improving addition of ionic species.
Claims Coverage
The consolidated claim coverage reflects one independent claim centered on an aqueous injectable solution with defined pH and basal insulin pI, combined with a carboxylate-charged co-polyamino acid bearing hydrophobic radicals -Hy linked through an amide function. Dependent features refine insulin identity, concentration limits, co-polyamino-acid unit selection, and addition of ionic species.
Aqueous injectable solution with specified pH and basal insulin pI
An aqueous injectable solution having a pH comprised from 6.0 to 8.0, comprising a basal insulin whose isoelectric point pI is comprised from 5.8 to 8.5.
Co-polyamino acid with carboxylate charges and hydrophobic radicals -Hy
A co-polyamino acid bearing carboxylate charges and hydrophobic radicals -Hy, wherein the co-polyamino acid includes units selected from glutamic units, aspartic units, and units according to formula XXXa.
Hydrophobic radicals defined by selected radicals and constrained integer parameters
The hydrophobic radicals -Hy are according to formula X with specific selections for GpR, GpG and GpH, GpA, GpL and GpC, and with integer parameters a, a, b, c, d, e, g, h, l, l, r and s obeying the stated relationships.
Amide function bonding between -Hy and the co-polyamino acid
The hydrophobic radical(s) -Hy are bonded to the co-polyamino acid via covalent bond formation that forms an amide function, either between a carbonyl of -Hy and a nitrogen atom borne by the co-polyamino acid, or between a nitrogen atom of -Hy and a carbonyl borne by the co-polyamino acid.
Constrained hydrophobic/glutamate-aspartate ratio, DP range, and alkali metal salt carboxylates
The ratio M between the number of hydrophobic radicals and the number of glutamic and aspartic units is from 0<M0.5, the degree of polymerization DP in glutamic or aspartic units is comprised from 5 to 250, and free carboxylic acid functions are in the form of an alkali metal salt chosen from Na+ and K+.
The inventive scope is centered on an aqueous injectable solution matching a specified pH window and basal insulin pI window, combined with a co-polyamino acid whose carboxylate/hydrophobic-radical structure, amide-function covalent bonding, and parameter limits for substitution, hydrophobic radical/glutamate-aspartate ratio, and degree of polymerization are explicitly defined.
Stated Advantages
Improve the physical and chemical stability of a composition by adding ionic species.
Improved insulin solubilization/stability.
Resistance of the copolyamino acids to hydrolysis.
Resistance of the copolyamino acids to oxidation.
Documented Applications
Insulin formulations using insulin glargine and/or insulin lispro at neutral pH and with co-polyamino acid components, including accelerated physical stability results comprising precipitation behavior.
A representative formulation evaluated with pharmacokinetic parameters in dogs, including precipitation behavior and pharmacokinetic parameters.
Diabetes treatment using physically stable injectable aqueous compositions comprising basal insulin.
Basal insulin compositions usable in the context of possible co-administration with prandial insulin and/or gastrointestinal hormones (GLP-1 RA).
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