Compositions in the form of an injectable aqueous solution comprising amylin, an amylin agonist receptor or an amylin analogue 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-11129877-B2
Publication Date
2021-09-28
Expiration Date
Abstract
A composition in the form of an injectable aqueous solution, for which the pH is comprised from 6.0 to 8.0, includes at least: a) amylin, an amylin receptor agonist or an amylin analogue;b) a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, said co-polyamino acid being constituted of glutamic or aspartic units and said hydrophobic radicals Hy chosen according to formula X as defined below:c) characterized in that the composition does not include basal insulin for which the isoelectric point IP is comprised from 5.8 to 8.5. The composition also includes a prandial insulin.
Core Innovation
The invention relates to an injectable aqueous composition having a pH comprised from 6.0 to 8.0, comprising amylin or pramlintide 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 among radicals according to formula X, including selection among radicals according to formula VII, VII', VII'', XI, XI', VIII, VIII', VIII'', XII, IX, and specified selections of GpR, GpG/GpH, GpA/A', GpL, and GpC with associated attachment-site and carbon-count relationships.
The hydrophobic radicals -Hy are covalently bound to the PLG via covalent amide-forming bonds, including a covalent bond between a carbonyl of -Hy and a nitrogen atom borne by the PLG and a covalent bond between a nitrogen atom of -Hy and a carbonyl borne by the PLG. The radicals are further constrained by attachment-site notation and by integer variables that define the possible substitution and attachment patterns for the groups bound by amide functions.
The composition is additionally constrained by the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units, with 0<M≤0.5, and by the degree of polymerization DP in glutamic or aspartic units comprised from 5 to 250. Free carboxylic acids are in the form of an alkaline cation salt chosen from Na+ and K+, and when several hydrophobic radicals are borne by a co-polyamino acid they are identical or different.
Claims Coverage
The independent claims cover five inventive features: an injectable aqueous composition, a covalently modified co-polyamino acid, formula-based selection of hydrophobic radicals Hy, constrained hydrophobic radical loading and polymerization, and a hydrophobic radical precursor Hy'. Across the claims, the common limitations are formula-based hydrophobic radical selection, covalent amide-forming attachment to PLG, and the M and DP constraints.
Injectable aqueous composition with amylin or pramlintide and a glutamic/aspartic co-polyamino acid
An injectable aqueous solution having pH comprised from 6.0 to 8.0, comprising amylin or pramlintide and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, the co-polyamino acid being constituted of glutamic or aspartic units and the hydrophobic radicals Hy chosen among radicals according to formula X.
Covalent amide-forming binding of Hy to PLG
The hydrophobic radical(s) -Hy according to formula X being bound to the PLG via a covalent bond between a carbonyl of -Hy and a nitrogen atom borne by the PLG, thus forming an amide function, and via a covalent bond between a nitrogen atom of -Hy and a carbonyl borne by the PLG, thus forming an amide function.
Formula-based selection of hydrophobic radicals Hy
Hydrophobic radicals Hy selected among radicals according to formula X by choosing GpR among formulas VII, VII', or VII'', GpG and GpH among formulas XI or XI', GpA among formula VIII with A' among formulas VIII', VIII'', or VIII''', GpL among formula XII, and GpC according to formula IX with attachment-site integers and related structural constraints.
Constrained hydrophobic radical loading and polymerization
The ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0<M≤0.5, the degree of polymerization DP in glutamic or aspartic units 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' defined by formula X'
A hydrophobic radical precursor Hy' of the hydrophobic radical -Hy according to formula X', with the same selection sets for GpR, GpG/GpH, GpA/A', GpL, and GpC, and with the same covalent amide-forming connection requirements and composition constraints.
The claims define an injectable aqueous composition at pH 6.0–8.0 comprising amylin or pramlintide together with a glutamic or aspartic co-polyamino acid bearing carboxylate charges and formula-defined hydrophobic radicals Hy. The claims further require covalent amide-function attachment of -Hy to PLG and impose explicit constraints on M, DP, and the Na+ and K+ salt form of free carboxylic acids.
Stated Advantages
Improved latency times and stability depending on the co-polyamino acid and added NaCl/ZnCl2, as evaluated by Thioflavin T latency-time measurements and physical stability observations.
Increased Thioflavin T (ThT) latency and improved fibrillation/physical stability at the target pH.
Improvement of stability when measured by Thioflavin T (ThT) compared to a reference composition.
Improvement of physical-chemical stability by adding selected ionic species (anions, cations, and/or zwitterions).
Documented Applications
Formulations using these co-polyamino acids in pramlintide and human insulin contexts, including preparation and stability evaluation of pramlintide/insulin formulations in vial/cartridge.
Injectable aqueous formulations for amylin or pramlintide at a neutral pH comprising stabilized compositions that address amylin/pramlintide fibrillation and neutral-pH stability.
Injectable aqueous solutions comprising amylin or pramlintide, including combinations with prandial insulin and GLP-1/GLP-1 receptor agonist combinations as discussed in the partial content summary.
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