Compositions in the form of an injectable aqueous solution comprising amylin, an amylin receptor agonist or an amylin analog, and a co-polyamino acid

Patent metadata

Field	Value
Publication number	US-2018193421-A1
Application number	US-201715855496-A
Country	US
Kind code	A1
Filing date	Dec 27, 2017
Priority date	Dec 27, 2016
Publication date	Jul 12, 2018
Grant 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:
GpR r GpA a GpC) p   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.

First claim

1 . A composition in the form of 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:
GpR r GpA a GpC) p   I

in which
GpR is a radical of formula II or

GpA is a radical of formula III or III′:

GpC is a radical of formula IV:

the * indicate the sites of attachment of the different groups;
a is a whole number equal to 0 or to 1;
b is a whole number equal to 0 or to 1;
p is a whole number equal to 1 or 2 and
if p is equal to 1 then a is equal to 0 or to 1 and GpA is a radical of formula III′, and
if p is equal to 2 then a is equal to 1, and GpA is a radical of formula III;

c is a whole number equal to 0 or to 1, and if c is equal to 0 then d is equal to 1 or to 2;
d is a whole number equal to 0, to 1 or to 2;
r is a whole number equal to 0 or to 1, and
if r is equal to 0 then the hydrophobic radical of formula I is attached to the co-polyamino acid via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in N-terminal position of the co-polyamino acid, thus forming an amide function originating from the reaction of an amine function in N-terminal position of the precursor of the co-polyamino acid and an acid function borne by the precursor of the hydrophobic radical, and
if r is equal to 1 then the hydrophobic radical of formula I is attached to the co-polyamino acid:
via a covalent bond between a nitrogen atom of the hydrophobic radial and a carbonyl of the copolyamino acid, thus forming an amide function originating from the reaction of an amine function of the precursor of the hydrophobic radical and an acid function borne by the precursor of the co-polyamino acid, or
via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in N-terminal position of the co-polyamino acid, thus forming an amide function originating from the reaction of an acid function of the precursor of the hydrophobic radical and an amine function in N-terminal position borne by the precursor of the co-polyamino acid;

R is a radical selected from the group consisting of:
a linear or branched divalent alkyl radical comprising 2 to 12 carbon atoms if GpR is a radical of formula II or 1 to 11 carbon atoms if GpR is a radical of formula II′ or II″;
a linear or branched divalent alkyl radical comprising 2 to 11 carbon atoms if GpR is a radical of formula II or 1 to 11 carbon atoms if GpR is a radical of formula II′ or II″, 1 to 11 carbon atoms, said alkyl radical bearing one or more —CONH 2 functions, and
an unsubstituted ether or polyether radical comprising 4 to 14 carbon atoms and 1 to 5 oxygen atoms;

A is a linear or branched alkyl radical comprising 1 to 6 carbon atoms;
B is a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising 1 to 9 carbon atoms;
Cx is a linear or branched monovalent alkyl radical, in which x indicates the number of carbon atoms and:
if p is equal to 1, x is from 11 to 25 (11≤x≤25):
if p is equal to 2, x is from 9 to 15 (9≤x≤15),

the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units being from° to 0.5 (0<i≤0.5);
when several hydrophobic radicals are borne by a co-polyamino acid, then they are identical or different,
the degree of polymerization DP of glutamic or aspartic units is from 5 to 250;
the free acid functions being in the form of a salt of an alkali cation selected from the group consisting of Na+ and K+;

wherein the composition does not comprise a basal insulin of which the isoelectric point pI is from 5.8 to 8.5.

2 . The composition according to claim 1 , wherein said hydrophobic radicals are selected from the hydrophobic radicals of formula I in which p=1, represented by the following formula V:
*GpR r GpA a GpC   formula V
wherein GpR, GpA, GpC, r and a have the definitions given above.

3 . The composition according to claim 1 , wherein said hydrophobic radicals are selected from the hydrophobic radicals of formula I in which a=1 and p=2, represented by the following formula VI:
*GpR r GpAGpC) 2   Formula VI

in which
GpR, GpA, GpC and r have the definitions given above.

4 . The composition according to claim 1 , wherein the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is selected from the co-polyamino acids having the following formula VII:

in which,
D represents, independently, either a —CH 2 — group (aspartic unit) or a —CH 2 —CH 2 — group (glutamic unit),
Hy is a hydrophobic radical selected from the hydrophobic radicals of formula I, V or VI in which r=1 and GpR is a radical of formula II,
R 1 is a hydrophobic radical selected from the hydrophobic radicals of formula I, V or VI in which r=0 or r=1 and GpR is a radical of formula II′, or a radical selected from the group consisting of an H, a linear C2 to C10 acyl group, a branched C3 to C10 acyl group, benzyl, a terminal “amino acid” unit, and a pyroglutamate,
R 2 is a hydrophobic radical selected from the hydrophobic radicals of formula I, V or VI in which r=1 and GpR is a radical of formula II, or a —NR′R″ radical, R′ and R″, which may be identical or different, being selected from the group consisting of H, the linear or branched or cyclic C2 to C10 alkyls, benzyl, and said alkyls R′ and R″ optionally forming together one or more saturated, unsaturated and/or aromatic carbon rings and/or optionally comprising heteroatoms selected from the group consisting of O, N and S,
X represents an H or a cationic entity selected from the group comprising the metal cations; and
n+m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomeric units per co-polyamino acid chain, and 5≤n+m≤250.

5 . The composition according to claim 4 , wherein the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is selected from the co-polyamino acids of formula VII in which R 1 =R′ 1 and R 2 =R′ 2 , having the following formula VIIa:

in which,
m, n, X, D and Hy have the definitions given above;
R′ 1 is a radical selected from the group consisting of an H, a linear C2 to C10 acyl group, a branched C3 to C10 acyl group, benzyl, a terminal “amino acid” unit, and a pyroglutamate;
R′ 2 is a —NR′R″ radical, R′ and R″, which may be identical or different, being selected from the group consisting of H, the linear or branched or cyclic C2 to C10 alkyls, benzyl, and said alkyls R′ and R″ optionally forming together one or more saturated, unsaturated and/or aromatic carbon rings and/or optionally comprising heteroatoms selected from the group consisting of O, N and S.

6 . The composition according to claim 4 , wherein the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is selected from the co-polyamino acids of

Assignees

• Adocia

Inventors

• Soula Remi

Classifications

• A61K47/34

  Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) · CPC title

• A61K9/08

  Solutions {(composition of solutions A61K47/00)} · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K38/28

  Insulins · CPC title