Compositions in the form of an injectable aqueous solution comprising amylin, an amylin receptor agonist or an amylin analog, and a co-polyamino acid
Inventors
DURACHER, DAVID • MEIFFREN, GREGORY • Soula, Remi
Assignees
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Publication Number
US-11707507-B2
Publication Date
2023-07-25
Expiration Date
Abstract
An injectable aqueous solution, of which the pH is from 6.0 to 8.0, comprising at least: a) amylin, an amylin receptor agonist or an amylin analog; b) a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, said co-polyamino acid consisting of glutamic or aspartic units and said hydrophobic radicals Hy having the following formula I:wherein the composition does not comprise a basal insulin of which the isoelectric point pI is from 5.8 to 8.5. It also relates to a composition wherein it moreover comprises a prandial insulin.
Core Innovation
The invention relates to hydrophobic-molecule substituted co-polyamino acids defined by Formula VII, Formula VIIa, or Formula VIIb, including hydrochloride-salt derivatives and sodium salt forms. The described structures include carboxylate charges and hydrophobic radicals, with hydrophobic radicals selected from hydrophobic radical formulas I, V, or VI, and examples include sodium poly(glutamate)-based co-polymers modified with hydrophobic moieties.
The co-polyamino acid structures include R1 as H or pyroglutamate, and the hydrophobic radicals are described with linear, branched, and long-chain alkyl substituents, including alkyl/alkenyl radicals and alkylated aromatic or cyclic amide-containing hydrophobes. The document also reports representative structures and variants, together with polymer-related parameters including i and degree of polymerization (DP), and the relationship between m and n in the illustrated polymer-structure variants.
The invention also relates to a hydrophobic molecule having formula VI, in which the molecular structure is defined by groups GpR, GpA, and GpC of respective formulas II, III, and IV, with attachment sites indicated by an asterisk and parameter constraints including b=0, c equal to 0 or 1, a conditional limitation on d when c is 0, d equal to 0, 1 or 2, and r equal to 1. The disclosed hydrophobic molecule further specifies that R is selected from a linear or branched divalent alkyl group with defined carbon ranges, or a linear or branched divalent alkyl group with a separate carbon range, or an unsubstituted ether or polyether group comprising 4 to 14 carbon atoms and 1 to 5 oxygen atoms.
The invention also relates to injectable aqueous diabetes therapies containing amylin, an amylin receptor agonist, or an amylin analog. The therapies include a co-polyamino acid bearing carboxylate charges and hydrophobic radicals as defined by hydrophobic radical formulas, including formula I, to stabilize the amylin, amylin receptor agonist, or amylin analog at neutral pH in the range of 6.0 to 8.0, and the compositions are described as being combinable with prandial insulin while excluding basal insulin.
Claims Coverage
The provided claim coverage centers on one independent claim for a hydrophobic molecule defined by formula VI, with substituent groups GpR, GpA, and GpC defined by formulas II, III, and IV. The claim is limited by constrained integer parameters and specified substituent choices for R, A, B, and Cx, and the supplied content does not explicitly map Formula VII, VIIa, or VIIb to the claim.
Hydrophobic molecule defined by formula VI with constrained GpR, GpA, and GpC
A hydrophobic molecule having formula VI, where GpR is a group of formula II, GpA is a group of formula III, and GpC is a group of formula IV.
Integer parameter constraints linking attachment sites and substitution counts
The formula VI is constrained by attachment sites marked by * and integer parameters including b=0; c=0 or c=1 with a condition that if c=0 then d=1 or 2; d=0, 1, or 2; and r=1.
Selected substituent group R with carbon and ether/polyether limits
R is selected from a linear or branched divalent alkyl group comprising 2 to 12 carbon atoms; a linear or branched divalent alkyl group comprising 2 to 11 carbon atoms; or an unsubstituted ether or polyether group comprising 4 to 14 carbon atoms and 1 to 5 oxygen atoms.
Auxiliary substituent A and B alkyl carbon limits and optional aromatic ring
A is a linear or branched alkyl group comprising 1 to 6 carbon atoms, and B is a linear or branched alkyl group optionally comprising an aromatic ring comprising 1 to 9 carbon atoms.
Terminal group Cx limited by monovalent alkyl carbon count
C is a linear or branched monovalent alkyl group where x indicates the number of carbon atoms and x is from 9 to 15 (9≤x≤15).
The claim coverage is limited to a hydrophobic molecule defined by formula VI with GpR/GpA/GpC defined by formulas II/III/IV, together with constrained integer parameters and specified choices for R, A, B, and Cx.
Stated Advantages
Solubility.
Stability, including physical and chemical stability.
Stabilizes amylin, amylin receptor agonist, or amylin analog at neutral pH (6.0 to 8.0).
Increases fibril latency (using Thioflavin T (ThT) latency).
Yields clear solutions.
Allows combination with prandial insulin while excluding basal insulin.
Documented Applications
Compositions combined with amylin and amylin receptor agonists or analogs such as pramlintide.
Compositions combined with insulin and prandial insulin.
Optionally combined with GLP-1 or GLP-1 receptor agonists including exenatide and lixisenatide.
Injectable aqueous diabetes therapies comprising amylin, an amylin receptor agonist, or an amylin analog with the defined co-polyamino acid/hydrophobic radical stabilization system.
Injectable compositions combined with prandial insulin, with basal insulin excluded.
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