Compositions in the form of an injectable aqueous solution comprising human glucagon and a co-polyamino acid
Inventors
Chan, You-Ping • GEISSLER, Alexandre • Noel, Romain • Charvet, Richard • LAURENT, Nicolas
Assignees
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Publication Number
US-11191812-B2
Publication Date
2021-12-07
Expiration Date
Abstract
Physically stable compositions in the form of an injectable aqueous solution, for which the pH is comprised from 6.0 to 8.0, having at least: human glucagon, and a co-polyamino acid bearing carboxylate charges and Hy hydrophobic radicals. In one embodiment, the compositions according to the invention also includes a gastro-intestinal hormone.
Core Innovation
The invention relates to an injectable aqueous solution having a pH comprised from 6.0 to 8.0, comprising human glucagon 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 chosen according to formula X with defined sub-radicals and structural constraints.
The hydrophobic radical(s) Hy are bound to the PLG via covalent bonds forming amide functions, including covalent bonds between carbonyl and nitrogen sites. The ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is 0<M≤0.5, the degree of polymerization DP in glutamic or aspartic units for the PLG chains is comprised from 5 to 250, and free carboxylic acids are in the form of an alkaline cation salt chosen from Na+ and K+.
The hydrophobic radical precursor Hy′ is also defined according to formula X′ with corresponding structural selection rules and is bound to PLG through covalent amide-function formation. The disclosed subject matter includes formula-based structures for hydrophobic co-polyamino acids and hydrophobic conjugates, with sodium carboxylates and hydrophobic radical Hy segments described in relation to the structural definition range.
Claims Coverage
The independent claims cover an injectable aqueous glucagon composition and a hydrophobic radical precursor Hy′. Across the claims, the inventive features center on the structural definition of Hy according to formula X, covalent amide linkage to PLG, and the quantitative constraints on M, DP, and Na+/K+ counterion form.
Injectable aqueous glucagon composition at pH 6.0 to 8.0
An injectable aqueous solution comprising human glucagon and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, with pH comprised from 6.0 to 8.0.
Hydrophobic radical Hy structural definition with formula X
A co-polyamino acid constituted of glutamic or aspartic units, with hydrophobic radicals Hy chosen according to formula X and selected among the referenced radical groups and integer constraints.
Covalent amide-function binding of hydrophobic radicals to PLG
Hydrophobic radical(s) Hy are bound to the PLG via covalent bonds forming amide functions between carbonyl and nitrogen atoms.
Hydrophobic-to-unit ratio and polymerization limits
The ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is 0<M≤0.5, the degree of polymerization DP is comprised from 5 to 250, and free carboxylic acids are in the form of an alkaline cation salt chosen from Na+ and K+.
Hydrophobic radical precursor Hy′
A hydrophobic radical precursor Hy′ according to formula X′ with corresponding structural selection rules and amide linkage to PLG under the same quantitative constraints.
The claims focus on an injectable aqueous glucagon composition at pH 6.0–8.0 containing a PLG-based co-polyamino acid with hydrophobic radicals Hy defined by formula X, together with a precursor Hy′ defined by formula X′. The claims further require covalent amide-forming binding to PLG and impose quantitative limits on M and DP, with free carboxylic acids present as Na+ or K+ salts.
Stated Advantages
Delayed fibril formation as indicated by Thioflavin T lag time.
Improved resistance to hydrolysis.
Improved resistance to oxidation.
Glucagon activity is preserved in the presence of the specified co-polyamino acid and optionally a gastro-intestinal hormone.
Increased stability/lag time versus glucagon at acidic pH alone, as assessed by Thioflavin T latency time.
Improved physical stability at 37°C in cartridges/vials.
Reported visual clarity of the glucagon formulations containing the specified co-polyamino acids.
Documented Applications
Injectable aqueous solutions containing human glucagon for use under pH 6.0 to 8.0 conditions.
Injectable pharmaceutical composition formulations combining human glucagon with GLP-1 receptor agonists (GLP-1 RAs) or analogues.
Glucagon formulations containing the disclosed co-polyamino acids, evaluated in cartridges/vials for visual clarity and physical stability at 37°C.
Fibrillation assessment of glucagon formulations using Thioflavin T latency time to evaluate amyloid fibrillation behavior.
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