阅读说明：本技术 包含至少一种pi在5.8与8.5之间的基础胰岛素和带有羧酸根电荷及疏水基的共聚氨基酸的ph 7为7的可注射溶液 (Injectable solution at pH 7 comprising at least one basal insulin with a PI between 5.8 and 8.5 and a polyamino acid with carboxylate charge and hydrophobic group ) 是由 陈友平 罗曼·诺埃尔 亚历山大·盖斯勒 沃尔特·罗格 里夏尔·沙尔韦 尼古拉斯·劳伦特 于 2018-12-07 设计创作，主要内容包括：在一个实施方案中,根据本发明的组合物的特征在于,带有羧酸根电荷及至少一个疏水基-Hy的共聚氨基酸选自根据下文式XXXb的共聚氨基酸：<Image he="317" wi="700" file="DDA0002561495820000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,●D独立地表示基团-CH<Sub>2</Sub>-(天冬氨酸)或基团-CH<Sub>2</Sub>-CH<Sub>2</Sub>-(谷氨酸),●X表示在包括碱阳离子的组中选择的阳离子实体,●R<Sub>b</Sub>和R<Sub>b</Sub>’相同或不同,为疏水基-Hy或在由H、C2至C10直链酰基、C3至C10支链酰基、苄基、末端“氨基酸”单元和焦谷氨酸根组成的组中选择的基团,Rb和R’b中的至少一者是疏水基-Hy,●Q和Hy如上所定义。●n+m表示共聚氨基酸的聚合度DP,即每个共聚氨基酸链的单体单元的平均数,且5≤n+m≤250。(In one embodiment, the composition according to the invention is characterized in that the copolymerized amino acids bearing a carboxylate charge and at least one hydrophobe-Hy are selected from the group consisting of the copolymerized amino acids according to formula XXXb below: wherein ● D independently represents a group-CH 2 - (aspartic acid) or radicals-CH 2 ‑CH 2 - (glutamic acid), ● X represents a cationic entity chosen in the group comprising the alkali cations, ● R b And R b 'same or different, is a hydrophobic group-Hy or a group selected in the group consisting of H, C2 to C10 straight acyl, C3 to C10 branched acyl, benzyl, a terminal "amino acid" unit, and pyroglutamate, at least one of Rb and R' b being a hydrophobic group-Hy, ● Q and Hy being as defined above. ● n + m represents the degree of polymerization DP of the copolymerized amino acid, i.e., the average number of monomer units per copolymerized amino acid chain, and 5. ltoreq. n + m. ltoreq.250.)

1. A composition in the form of an injectable aqueous solution, wherein the pH comprises from 6.0 to 8.0, comprising at least:

-the isoelectric point pI comprises between 5.8 and 8.5 basal insulin;

-a polyamino acid consisting of glutamic acid or aspartic acid units, selected from polyamino acids according to formula I as defined below:

[Q(PLG)_k][Hy]_j[Hy]_j’

Formula I

-wherein:

-j≥1；0≤j’≤n’1；k≥2

-said polyamino acids according to formula I carry at least one hydrophobic group-Hy, carboxylate charge and are composed of at least two linear or branched groups or spacers Q [ - ] passing through at least two valencies]_kComposed of a chain of glutamic or aspartic acid units PLG bonded together, Q [ - ]]_kConsisting of an alkyl chain comprising one or more heteroatoms chosen from the group consisting of nitrogen and oxygen atoms, and/or a group carrying one or more heteroatoms consisting of nitrogen and oxygen groups, and/or carrying one or more heteroatoms consisting of nitrogen and oxygen atoms, and/or a carboxyl function.

-said group or spacer Q [ - ]]_kBound to at least two chains of glutamic acid or aspartic acid units PLG via an amide function, and

-binding of said group or spacer Q [ - ]]_kThe amide function of (a) is linked to the at least two glutamic or aspartic acid unit chains by the group or spacer Q [ - ] respectively]_kResulting from the reaction between the amine function and the acid function carried by the glutamic or aspartic acid unit,

-said hydrophobe-Hy is either bound to a terminal "amino acid" unit, and when j is > 1, or to a carboxyl function carried by one of said chains PLG of glutamic or aspartic acid units, and when j ' ═ n ' 1, and n ' 1 is the average number of monomeric units carrying a hydrophobe-Hy.

2. The composition according to claim 1, wherein said group or spacer Q [ - ]]_kSelected from the group according to formula II:

Q[-*]_k＝([Q’]_q)[-*]_k

formula II

Wherein q is more than or equal to 1 and less than or equal to 5

3. Composition according to any one of the preceding claims, characterized in that the groups Q', which are identical or different, are chosen in the group consisting of the groups according to formulae III to VII below, so as to form Q [ - ] k by

A radical according to formula III

Wherein t is more than or equal to 1 and less than or equal to 8

A group according to formula IV:

wherein:

u₁"or u₂At least one of "is different from 0.

If u is₁"≠ 0, then u₁' ≠ 0, and if u₂"≠ 0, then u₂’≠0，

u₁' and u₂Are' the same or different, and

2≤u≤4，

0≤u₁’≤4，

0≤u₁”≤4，

0≤u₂’≤4

0≤u₂”≤4，

a group according to formula V:

wherein:

v, v 'and v' are the same or different,

v+v’+v”≤15，

a group according to formula VI:

wherein:

w₁' a different value from 0 is used for the,

0≤w₂”≤1，

w₁w is not more than 6₁' < 6, and/or w₂W is not more than 6₂’≤6

Wherein Fx ═ Fa, Fb, Fc, Fd, Fa ', Fb ', Fc ", and Fd ', which are the same or different, represent a functional group-NH-or-CO-, and Fy represents a trivalent nitrogen atom-N ═ N,

the two radicals Q' are joined together via a covalent bond between the carbonyl function Fx ═ -CO-and the amine function Fx ═ -NH-or Fy ═ N ═ to form an amide bond,

4. composition according to any one of the preceding claims, characterized in that the hydrophobic group-Hy is chosen from groups according to formula X as defined below:

Wherein

-GpR is selected from a group according to formula VII, VII' or VII ":

-GpG and GpH, equal or different, are selected from groups according to formula XI or XI':

-NH-G-NH-of formula XI'

-GpA is selected from the group according to formula VIII

Wherein A 'is selected from a group according to VIII', VIII 'or VIII'

- - -GpL is selected from the group according to formula XII

-GpC is a group according to formula IX:

-;

-a is an integer equal to 0 or equal to 1, and if a is 0, then a 'is 1, and if a is 1, then a' is 1, 2 or 3;

a' is an integer equal to 1, equal to 2 or equal to 3

-b is an integer equal to 0 or equal to 1;

-c is an integer equal to 0 or equal to 1, and if c is equal to 0, d is equal to 1 or equal to 2;

-d is an integer equal to 0, equal to 1 or equal to 2;

-e is an integer equal to 0 or equal to 1;

-g is an integer equal to 0, equal to 1, equal to 2, equal to 3 equal to 4 equal to 5 or equal to 6;

-h is an integer equal to 0, equal to 1, equal to 2, equal to 3 equal to 4 equal to 5 or equal to 6;

-l is an integer equal to 0 or 1, and if l is 0, then l 'is 1, and if l is 1, then l' is 2;

-r is an integer equal to 0, equal to 1 or equal to 2, and

-s' is an integer equal to 0 or 1;

-A、A₁、A₂and A₃Identical or different, is a linear or branched alkyl group comprising from 1 to 8 carbon atoms and optionally substituted by a group derived from a saturated, unsaturated or aromatic ring;

-B is a group selected in the group consisting of: an unsubstituted ether or polyether group containing from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms, or a linear or branched alkyl group containing from 1 to 9 carbon atoms optionally containing an aromatic core;

-C_xis a linear or branched monovalent alkyl group optionally containing cyclic moieties, wherein x indicates the number of carbon atoms, and 6 < x < 25:

■ when the hydrophobic group-Hy has 1-GpC, then x is more than or equal to 9 and less than or equal to 25,

■ when the hydrophobic group-Hy has 2-GpCs, then x is more than or equal to 9 and less than or equal to 15,

■ when the hydrophobic group-Hy has 3-GpCs, then x is more than or equal to 7 and less than or equal to 13,

■ when the hydrophobic group-Hy has 4-GpCs, then x is more than or equal to 7 and less than or equal to 11,

■ when the hydrophobic group-Hy carries at least 5-GpC, then x is 6-11,

-G is a branched alkyl group of 1 to 8 carbon atoms bearing one or more free carboxylic acid functions.

-R is a group selected in the group consisting of: divalent alkyl radicals, straight or branched, containing from 1 to 12 carbon atoms, carrying one or more functional groups-CONH₂A linear or branched divalent alkyl group containing 1 to 12 carbon atoms or an unsubstituted ether or polyether group containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms:

-one or more hydrophobic groups according to formula X-Hy are bound to said PLG in the following manner:

o via a covalent bond between the carbonyl group of the hydrophobic group-Hy and the nitrogen atom borne by the PLG, thereby forming an amide function resulting from the reaction of the amine function borne by the PLG and the acid function borne by the precursor-Hy' of the hydrophobic group-Hy, and

o via a covalent bond between the nitrogen atom of the hydrophobic group-Hy and the carbonyl group borne by the PLG, thereby forming an amide function resulting from the reaction of the amine function of the precursor-Hy' of the hydrophobic group-Hy and the acid function borne by the PLG,

-the ratio M between the number of hydrophobic groups and the number of glutamic or aspartic acid units is between 0 < M.ltoreq.0.5;

when several hydrophobic groups are carried by a polyamino acid, they are identical or different,

-the degree of polymerization DP of the glutamic or aspartic acid units of the PLG chain is from 5 to 250;

-the free carboxylic acid function is represented by Na⁺And K⁺In the form of a salt of an alkali cation selected from the group consisting of.

5. Composition according to any one of the preceding claims, characterized in that the copolymerized amino acids bearing a carboxylate charge and at least one hydrophobe-Hy are chosen from those according to formula XXXb below:

Wherein the content of the first and second substances,

● D independently represents a group-CH₂- (aspartic acid) or radicals-CH₂-CH₂- (glutamic acid),

● X represents a cationic entity selected in the group comprising alkali cations,

●R_band R_b' same or different, is a hydrophobic group-Hy or a group selected from the group consisting of H, C2 to C10 straight acyl, C3 to C10 branched acyl, benzyl, a terminal "amino acid" unit, and pyroglutamate,

● Q and Hy are as defined above.

● n + m represents the degree of polymerization DP of the copolymerized amino acid, i.e., the average number of monomer units per copolymerized amino acid chain, and 5. ltoreq. n + m. ltoreq.250.

6. Composition according to any one of the preceding claims, characterized in that the copolymerized amino acids bearing a carboxylate charge and at least one hydrophobe-Hy are chosen from those according to formula XXXa below:

wherein the content of the first and second substances,

● D independently represents a group-CH₂- (aspartic acid)) Or a group-CH₂-CH₂- (glutamic acid),

● X represents a cationic entity selected in the group comprising alkali cations,

●R_aand R'_aIdentical or different, is a hydrophobic group-Hy or a group selected from the group consisting of H, C2 to C10 straight acyl, C3 to C10 branched acyl, benzyl, a terminal "amino acid" unit and pyroglutamate,

At least one of Ra and R' a is a hydrophobic group-Hy,

● Q and-Hy are as defined above.

● n + m represents the degree of polymerization DP of the copolymerized amino acid, i.e., the average number of monomer units per copolymerized amino acid chain, and 5. ltoreq. n + m. ltoreq.250.

7. Composition according to any one of the preceding claims, characterized in that the copolymerized amino acids bearing a carboxylate charge and at least one hydrophobe-Hy are chosen from those according to formula XXXb' below:

wherein:

d and X are as defined above,

-Q and Hy are as defined above.

-Rb and Rb', which are identical or different, are a hydrophobic group-Hy or a group chosen from the group consisting of-OH, amine group, terminal "amino acid" unit and pyroglutamate,

at least one of-Rb and R' b is a hydrophobic group-Hy,

n1+ m1 represents the number of glutamic acid units or aspartic acid units of the PLG chain of the polyamino acid bearing the group-Hy,

n2+ m2 represents the number of glutamic acid units or aspartic acid units of the PLG chain without the copolymeric amino acid of the group-Hy,

-n1+ n2 ═ n ', and m1+ m2 ═ m',

-n '+ m' represents the degree of polymerization DP of the copolymeric amino acid, i.e. the average number of monomer units per copolymeric amino acid chain, and 5. ltoreq. n '+ m' 250.

8. Composition according to any one of the preceding claims, characterized in that the copolymerized amino acids bearing a carboxylate charge and at least one hydrophobe-Hy are chosen from those according to formula XXXa' below:

wherein:

-D, X, Ra and R' a are as defined above,

-Q and Hy are as defined above,

-n₁+m₁represents the number of glutamic acid units or aspartic acid units of the PLG chain of a polyamino acid having a group-Hy,

-n₂+m₂represents the number of glutamic acid units or aspartic acid units of the PLG chain without the copolymerized amino acid of the group-Hy,

-n₁+n₂n', and m₁+m₂＝m’

9. Composition according to any one of claims 4 to 8, characterized in that the copolymerized amino acid bearing a carboxylate charge and a hydrophobic group is selected from copolymerized amino acids according to formula XXXA, XXXA ', XXXB or XXXB', wherein the copolymerized amino acid is selected from wherein the group D is a group-CH₂A copolymerized amino acid of- (aspartic acid unit).

10. Composition according to any one of claims 4 to 8, characterized in that the copolymerized amino acid bearing a carboxylate charge and a hydrophobic group is selected from copolymerized amino acids according to formula XXXA, XXXA ', XXXB or XXXB', wherein the copolymerized amino acid is selected from wherein the group D is a group-CH ₂-CH₂(glutamic acid unit).

11. The composition according to any one of the preceding claims, wherein the basal insulin whose isoelectric point comprises 5.8 to 8.5 is insulin glargine.

12. Composition according to any one of the preceding claims, characterized in that it comprises basal insulin with an isoelectric point comprised between 5.8 and 8.5 between 40 and 500U/mL.

13. Composition according to any one of the preceding claims, characterized in that the concentration of copolymerized amino acids carrying carboxylate charges and hydrophobes does not exceed 60 mg/mL.

14. Composition according to any one of the preceding claims, characterized in that the concentration of copolymerized amino acids carrying carboxylate charges and hydrophobes does not exceed 40 mg/mL.

15. Composition according to any one of the preceding claims, characterized in that the concentration of copolymerized amino acids carrying carboxylate charges and hydrophobes does not exceed 20 mg/mL.

16. Composition according to any one of the preceding claims, characterized in that the concentration of copolymerized amino acids carrying carboxylate charges and hydrophobes does not exceed 10 mg/mL.

17. A co-amino acid bearing a carboxylate charge and at least one hydrophobic group according to formula X, selected from co-amino acids according to formula I:

[Q(PLG)_k][Hy]_j[Hy]_j’

Formula I

Wherein:

-j is equal to or greater than 1; j ' is more than or equal to 0 and less than or equal to n ' 1, j + j ' is more than or equal to 1, and k is more than or equal to 2

-said polyamino acids according to formula I carry at least one hydrophobic group-Hy, carboxylate charge and are composed of at least two linear or branched groups or spacers Q [ - ] passing through at least two valencies]_kBound glutamic acid or aspartic acid monoComposition of the Meta-chain PLG, Q [ - ]]_kConsisting of an alkyl chain comprising one or more heteroatoms selected from the group consisting of nitrogen and oxygen atoms, and/or a group carrying one or more heteroatoms consisting of nitrogen and oxygen groups and/or carrying one or more heteroatoms consisting of nitrogen and oxygen atoms and/or a carboxyl function,

-said group or spacer Q [ - ]]_kBound to at least two chains of glutamic acid or aspartic acid units PLG via an amide function, and

-binding of said group or spacer Q [ - ]]_kThe amide function of (a) is linked to the at least two glutamic or aspartic acid unit chains by the group or spacer Q [ - ] respectively]_kResulting from the reaction between the amine function and the acid function carried by the glutamic or aspartic acid unit,

-said hydrophobe-Hy is either bound to a terminal "amino acid" unit, and when j is > 1, or to a carboxyl function carried by one of said chains PLG of glutamic or aspartic acid units, and when j ' ═ n ' 1, and n ' 1 is the average number of monomeric units carrying a hydrophobe-Hy.

18. A hydrophobic base precursor Hy 'selected from compounds according to formula X' as defined below:

wherein the content of the first and second substances,

GpR is selected from a group according to formula VII, VII' or VII ":

GpG and GpH, equal or different, are selected from groups according to formula XI or XI':

GpA is selected from the group according to formula VIII

Wherein A 'is selected from a group according to VIII', VIII 'or VIII'

-GpL is selected from the group according to formula XII

GpC is a group according to formula IX:

indicates the binding sites of the different groups bound by the amide functional groups;

a is an integer equal to 0 or equal to 1, and if a is 0, then a 'is 1, and if a is 1, then a' is 1, 2, or 3;

a' is an integer equal to 1, equal to 2 or equal to 3

-b is an integer equal to 0 or equal to 1;

-c is an integer equal to 0 or equal to 1, and if c is equal to 0, d is equal to 1 or equal to 2;

d is an integer equal to 0, equal to 1 or equal to 2;

e is an integer equal to 0 or equal to 1;

g is an integer equal to 0, equal to 1, equal to 2, equal to 3, equal to 4, equal to 5 or equal to 6;

h is an integer equal to 0, equal to 1, equal to 2, equal to 3, equal to 4, equal to 5 or equal to 6;

-l is an integer equal to 0 or 1, and if l is 0, then l 'is 1, and if l is 1, then l' is 2;

-l' is an integer equal to 1 or equal to 2;

-r is an integer equal to 0, 1 or equal to 2, and

-s' is an integer equal to 0 or 1;

-A、A₁、A₂and A₃Identical or different, is a linear or branched alkyl group comprising from 1 to 8 carbon atoms and optionally substituted by a group derived from a saturated, unsaturated or aromatic ring;

-B is a group selected in the group consisting of: an unsubstituted ether or polyether group containing from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms, or a linear or branched alkyl group containing from 1 to 9 carbon atoms optionally containing an aromatic core;

-C_xis a group selected from the group consisting of linear or branched monovalent alkyl groups optionally containing cyclic moieties, wherein x indicates the number of carbon atoms, and 6. ltoreq. x.ltoreq.25:

■ when the hydrophobic group-Hy carries 1-GpC, then 9 ≦ x ≦ 25,

■ when the hydrophobic group-Hy carries 2-GpCs, then 9 ≦ x ≦ 15,

■ when the hydrophobic group-Hy carries 3-GpCs, then x is less than or equal to 7 and less than or equal to 13,

■ when the hydrophobic group-Hy carries 4-GpCs, then x is less than or equal to 7 and less than or equal to 11,

■ when the hydrophobic group-Hy carries at least 5-GpC, then 6. ltoreq. x.ltoreq.11,

g is a linear or branched divalent alkyl radical containing from 1 to 8 carbon atoms bearing one or more free carboxylic acid functional groups.

R is a group selected in the group consisting of: divalent alkyl radicals, straight or branched, containing from 1 to 12 carbon atoms, carrying one or more functional groups-CONH₂A linear or branched divalent alkyl group containing 1 to 12 carbon atoms or an unsubstituted ether or polyether group containing 4 to 14 carbon atoms and 1 to 5 oxygen atoms:

one or more hydrophobic groups according to formula X-Hy are bound to the PLG in the following manner:

via a covalent bond between the carbonyl group of the hydrophobic group-Hy and the nitrogen atom borne by the PLG, thereby forming an amide function resulting from the reaction of the amine function borne by the PLG and the acid function borne by the precursor-Hy' of the hydrophobic group-Hy, and

via a covalent bond between the nitrogen atom of the hydrophobic group-Hy and the carbonyl group borne by the PLG, thereby forming an amide function resulting from the reaction of the amine function of the precursor-Hy' of the hydrophobic group-Hy and the acid function borne by the PLG,

-the ratio M between the number of hydrophobic groups and the number of glutamic or aspartic acid units is between 0 < M.ltoreq.0.5;

when several hydrophobic groups are carried by a polyamino acid, they are identical or different,

-the degree of polymerization DP of the glutamic or aspartic acid units of the PLG chain is from 5 to 250;

-the free carboxylic acid function is represented by Na⁺And K⁺In the form of a salt of an alkali cation selected from the group consisting of.

19. Use of ionic substances selected in the group of anions, cations and/or zwitterions for increasing the physicochemical stability of the composition according to any one of claims 1 to 16.

Examples

Part a-synthesis of the hydrophobic intermediate compound Hyd to obtain the group-Hy.