Injectable solution at ph 7 comprising at least one basal insulin the isoelectric point of which is comprised in 5.8 and 8.5 and an anionic compound bearing carboxylate charges and hydrophobic radicals

A composition in the form of an injectable aqueous solution, the pH of which is between 6.6 and 7.8, comprising at least:

• a) a basal insulin, the isoelectric point pI of which is between 5.8 and 8.5;
• b) an anionic compound bearing carboxylate charges and hydrophobic radicals, of formula I:
• in which:
• 1) a=0 or 1;
• 2) b=0 or 1;
• 3) —X— is either a —C═O— radical, or a —CH2— radical;
• 4) —Z— is either a —C═O— radical, or a —CH2— radical;
• 5) —R1 is chosen from the group consisting of the radicals:
• i. —OH;
• ii. -ƒ-[A]-COOH, then —X—═—CH2—;
• in which,
• -A- is an at least divalent radical comprising from 1 to 15 carbon atoms comprising at least one heteroatom chosen from O, N and S, optionally bearing carboxyl or amine functions and/or -ƒ-[A]-COOH, comprising from 2 to 16 carbon atoms, is derived from an amino acid, from a diacid or from an alcohol acid and is bonded to the backbone of the molecule via a function ƒ;
• ƒ is chosen from the group consisting of ether, ester, carbamate, amide or carbonate functions;
• iii. -g-[B]-(k-[D])p, then —X—═—CH2—;
• in which,
• —B— is an at least divalent radical comprising from 1 to 15 carbon atoms comprising at least one heteroatom chosen from O, N and S, optionally bearing carboxyl or amine functions and/or -g-[B]-(k-)p, comprising from 2 to 16 carbon atoms, is derived from an amino acid, from a diacid, from a dialcohol, from an alcohol acid, from a diamine or from an amine alcohol and is bonded to the backbone of the molecule via a function g and is bonded to at least one radical -D via a function k;
• g is chosen from the group consisting of ether, ester, carbamate, amide and carbonate functions;
• k is chosen from the group consisting of ester, amide, carbamate and carbonate functions;
• p is a positive integer equal to 1 or 2;
• said radical -D being a radical -[Hy] if p=2 or -[E]-(o-[Hy])t if p=1;
• in which,
• -E- is an at least divalent radical comprising from 1 to 15 carbon atoms comprising at least one heteroatom chosen from O, N and S, optionally bearing carboxyl or amine functions and/or k-[E]-(o-)t, comprising from 2 to 16 carbon atoms, is derived from an amino acid, from a dialcohol, from a diamine, from a diacid or from an amine alcohol;
• -Hy is a C8 to C30 linear or cyclic alkyl group or a C8 to C30 alkylaryl or arylalkyl, optionally substituted with one or more C1 to C3 alkyl groups, derived from a hydrophobic compound;
• o is an ester, amide, carbamate or carbonate function;
• t is a positive integer equal to 1 or 2;
• k and o are identical or different;
• iv. —NH-[E]-(o-[Hy])t if —R′, —R2, —R3, —R4, —R5 and —R6 are different from
• -g-[B]-k-[D], —NH-[D] and —O-[D], in which
• -E-, -Hy, o and t have the definitions given above;
• v. —N(L)z-[E]-(o-[Hy])t if —R′, —R2, —R3, —R4, —R5 and —R6 are different from
• -g-[B]-k-[D], —NH-[D] and —O-[D], and if —X—═—CH2—, in which,
• -D-, -Hy, -E-, o and t have the definitions given above;
• z is equal to 1 or 2;
• -L is chosen from the group consisting of:
• —H and z is equal to 1, and/or
• -[A]-COOH if ƒ is an ether function,
• —CO-[A]-COOH and z is equal to 1, if ƒ is an ester function, and
• —CO—NH-[A]-COOH and z is equal to 1 if ƒ is a carbamate function;
• A has the meaning given above;
• and
• viii. -A-, —B— or -E- which may be identical or different,
• 6) —R″ is chosen from the group consisting of the radicals:
• i. —H, hydrogen atom, if b=1;
• and
• ii. -k-[Hy] or -k-[E]-(o-[Hy])t if b=0, a=0 and —R1, —R2, —R3 different from -g-[B]-(k-[D])p and —NH-[D];
• -E- and t have the definitions given above;
• -Hy is a C12 to C30 linear or cyclic alkyl group or a C12 to C30 alkylaryl or arylalkyl, optionally substituted with one or more C1 to C3 alkyl groups, derived from a hydrophobic compound;
• 7) —R5 is chosen from the group consisting of the radicals:
• i. —OH;
• ii. -ƒ-[A]-COOH;
• and
• iii. -g-[B]-(k-[D])p;
• in which:
• -A-, —B—, -D- and p are defined as above,
• ƒ, g and k, which may be identical or different, are defined as above;
• 8) —R3 or —R4, which may be identical or different, are chosen from the group consisting of the radicals:
• i. —OH;
• ii. -ƒ-[A]-COOH;
• and
• iii. -g-[B]-(k-[D])p;
• -A-, —B—, -D-, p, ƒ, g and k being defined as above;
• and/or
• —R6 is chosen from the group consisting of the radicals:
• i. —OH;
• ii. -ƒ-[A]-COOH if —Z—═—CH2—;
• iii. -g-[B]-(k-[D])p if —Z—═—CH2—;
• iv. —O-[D] if —Z—═—C═O—;
• and
• v. —NH-[D] if —Z—═—C═O—;
• -A-, —B—, -D-, p, ƒ, g and k being defined as above;
• and/or
• —R2 is chosen from the group consisting of the radicals:
• i. —OH;
• ii. -ƒ-[A]-COOH;
• iii. -g-[B]-(k-[D])p;
• iv. —NH—COCH3;
• v. —NH2;
• and
• vi. —NH-[D];
• -A-, —B—, -D-, p, ƒ, g and k being defined as above;
• and/or
• at most one of —R2, —R3, —R4 and —R6 is a backbone formed from a discrete number u of between 1 and 7 (1≦u≦7) of identical or different saccharide units linked via identical or different glycosidic linkages, said saccharide units being chosen from the group consisting of:
• i. hexoses in cyclic form or in open reduced form,
• ii. uronic acids in cyclic form or in open oxidized form,
• iii. hexosamines in cyclic form, in open reduced form or in open oxidized form, and
• iv. N-acetylhexosamines in cyclic form or in open reduced form, and
• at least one of said saccharide units is substituted with at least one substituent —R′ chosen from:
• -ƒ-[A]-COOH and/or
• -k-[D] or g-[B]-(k-[D])p, in which
• -A-, —B—, -D-, p, ƒ, g and k are defined as above;
• and
• when —R1 is —NH-[E]-(o-[Hy])t or —N(L)z[E]-(o-[Hy])t then —R2, —R3, —R4, —R5 and —R6 are different from -g-[B]-(k-[D])p, —O-[D] or
• —NH-[D] and —R′ is different from -k-[D] or -g-[B]-(k-[D])p;
• and
• 9) the asymmetric carbon atoms are of absolute configuration R or S;
• the free acid functions being in the form of salts of alkali metal cations chosen from the group consisting of Na+ and K+.