Injectable solution at pH 7 comprising at least one basal insulin for which the pI is from 5.8 to 8.5 and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals
Inventors
Assignees
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Publication Number
US-11576952-B2
Publication Date
2023-02-14
Expiration Date
Abstract
A composition in the form of an injectable aqueous solution, whose pH consists from 6.0 to 8.0, including at least: a basal insulin whose isoelectric point includes from 5.8 to 8.5; a co-polyamino-acid bearing carboxylate charges and hydrophobic radicals Hy, the co-polyamino-acid being constituted of glutamic or aspartic units and said hydrophobic radicals Hy according to the following formula I:
Core Innovation
The invention relates to an injectable aqueous solution with a pH comprised from 6.0 to 8.0, comprising a basal insulin whose isoelectric point is comprised from 5.8 to 8.5 and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy. The co-polyamino acid is constituted of glutamic or aspartic units, and the hydrophobic radicals Hy are defined according to formula I and are bound to the co-polyamino acid through specified covalent amide functions using binding-site notations.
The copolyamino acid architecture is defined by structural families using radicals GpR, GpA and GpC according to formulas II/II′, III/III′ and IV, with attachment and covalent-bond formation parameterized by integers b, p, c, d and r. The hydrophobic radical density ratio i is defined as the number of hydrophobic radicals versus the number of glutamic or aspartic units, and i is comprised from 0 to 0.5.
The composition is further constrained by the degree of polymerization DP of glutamic or aspartic units comprised from 5 to 250, and by free acid functions in the form of an alkaline cation salt chosen from Na+ and K+. The invention also addresses co-formulation with prandial insulin and gastrointestinal hormones, notably GLP-1 receptor agonists.
Claims Coverage
The claim set defines an injectable aqueous solution composition with multiple refinements to insulin identity, copolyamino-acid selection, and optional additional components. The inventive features primarily cover the basal insulin pI requirement, a charged co-polyamino acid with hydrophobic radicals Hy, specified Hy attachment through amide functions using defined structural radicals and binding sites, constrained structural and ratio parameters, and optional prandial insulin or gastrointestinal hormones.
Basal insulin with defined isoelectric point in an injectable aqueous solution
An injectable aqueous solution with pH 6.0 to 8.0 comprising a basal insulin whose isoelectric point is comprised from 5.8 to 8.5.
Charged co-polyamino acid bearing hydrophobic radicals Hy bound via amide functions
A co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, constituted of glutamic or aspartic units, wherein the hydrophobic radicals Hy are according to formula I and GpR, GpA and GpC radicals are bound by amide functions as indicated by binding sites (*), with covalent bonding defined by the integer r.
Defined hydrophobic radical density ratio i and degree of polymerization DP
The ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units is from 0 to 0.5, and the degree of polymerization DP of glutamic or aspartic units is comprised from 5 to 250.
Structural and integer-defined selection of radicals and free acid functions
Radicals R and the structural selections for A/A′/A″, B, Cx and related parameters, with constraints depending on p, together with integer parameters b, p, c, d and r and alkaline cation salt selection for free acid functions.
Optional formulation with specified prandial insulin or gastrointestinal hormones
The composition can further include prandial insulin and/or a gastrointestinal hormone, including GLP-1 receptor agonists and their analogues or derivatives.
Across the independent claim and its refinements, the composition is anchored by a basal insulin having a specified isoelectric point range and by a charged glutamic/aspartic co-polyamino acid carrying hydrophobic radicals Hy. The Hy attachment is defined by amide-function covalent bonding using specified radicals and binding sites, while the hydrophobic radical density ratio i and the copolyamino-acid degree of polymerization DP are constrained, with optional prandial insulin or gastrointestinal hormones.
Stated Advantages
Physical stability under accelerated dynamic conditions including assessment by visible particles/turbidity criteria.
Reduced precipitation behavior described using a PBS/BSA precipitation model.
Glucose-lowering activity described as biphasic and consistent with prandial and basal insulin effects in dog pharmacodynamic studies.
Improved physical stability under hydrolysis and oxidation stress.
Improved solubilization/stabilization of insulin glargine at lower excipient ratios.
Maintains precipitation propensity.
Provides improved physical stability while maintaining clear, particle-free injectable solutions.
Maintains performance when combined with prandial insulin.
Maintains performance when combined with gastrointestinal hormones, including GLP-1 receptor agonists.
Documented Applications
Injectable insulin compositions containing insulin glargine, optionally with insulin lispro, combined with hydrophobicly grafted copolyamino acids and evaluated for physical stability and precipitation behavior.
Dog pharmacodynamic evaluation comparing the co-polyamino acid/insulin glargine/lispro composition to separate Humalog/Lantus injections, with glucose monitoring over 24 h and described biphasic hypoglycemic activity.
Formulating injectable aqueous insulin compositions for use with prandial insulin.
Formulating injectable aqueous insulin compositions for combination with gastrointestinal hormones, including GLP-1 receptor agonists.
A physically stable injectable aqueous solution intended to address problems arising from acidic basal insulin formulations and prandial insulin incompatibility at acidic pH.
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