The invention relates to novel insulin analogs having a basal time-action profile, which are characterized by the addition and/or substitution of negatively and positively charged amino acid residues and by an amidation of the C-terminal carboxy group of the B chain and histidine in position 8 of the insulin A chain. The invention also relates to the production and use thereof.

Claims

27 · 1 independent · depth 5

27 granted claims

›1.independentAn insulin analogue of the formula I:+26

›2.↳ 1The insulin analogue as claimed in claim 1, wherein A-1 corresponds to Arg.d2

›3.↳ 1The insulin analogue as claimed in claim 1, wherein A0 corresponds to Arg.d2

›4.↳ 1The insulin analogue as claimed in claim 1, wherein A5 corresponds to Glu.d2

›5.↳ 1The insulin analogue as claimed in claim 1, wherein A15 corresponds to Glu.d2

›6.↳ 1The insulin analogue as claimed in claim 1, wherein A18 corresponds to Asp.d2

›7.↳ 1The insulin analogue as claimed in claim 1, wherein A8 corresponds to His.d2

›8.↳ 1The insulin analogue as claimed in claim 1, wherein A21 corresponds to Gly.d2

›9.↳ 1The insulin analogue as claimed in claim 1, wherein B0 corresponds to Glu.d2

›10.↳ 1The insulin analogue as claimed in claim 1, wherein B3 corresponds to Asp.d2

›11.↳ 1The insulin analogue as claimed in claim 1, wherein B4 corresponds to Glu.d2

›12.↳ 1The insulin analogue as claimed in claim 1, wherein B30 corresponds to Arg.d2

›13.↳ 1The insulin analogue as claimed in claim 1, wherein B30 corresponds to Lys.d2

›14.↳ 1The insulin analogue as claimed in claim 1, which isnArg (A0), His (A8), Gly (A21), Arg (B31), Arg (B32) NH2 human insulin.d2

›15.↳ 1A pharmaceutical composition comprising an insulin analogue as claimed in claim 1 or a physiologically acceptable salt thereof.d2

›16.↳ 1A formulation of the insulin analogue as claimed in claim 1, wherein the formulation is in aqueous form comprising the dissolved insulin analogue.d2+7

›17.↳ 16The formulation as claimed in claim 16, which additionally comprises a glucagon-like peptide-1 (GLP 1) or an analogue thereof, or exendin-3 or -4 or a…d3+6

›18.↳ 17The formulation as claimed in claim 17, which additionally comprises exendin-4.d4+5

›19.↳ 18The formulation as claimed in claim 18, wherein an analogue of exendin-4 is selected from a group comprisingnH-desPro36-exendin-4-Lys6-NH2,H-des(Pro36…d5

›20.↳ 18The formulation as claimed in claim 18, wherein an analogue of exendin-4 is selected from a group comprisingndesPro36 [Asp28]exendin-4 (1-39),desPro36…d5

›21.↳ 18The formulation as claimed in claim 18, wherein the peptide -Lys6-NH2 is attached to the C termini of the analogues of exendin-4.d5

›22.↳ 18The formulation as claimed in claim 18, wherein an analogue of exendin-4 is selected from a group consisting of:nH-(Lys)6-des Pro36 [Asp28]exendin-4(1…d5

The formulation as claimed in claim 18, wherein an analogue of exendin-4 is selected from a group consisting of:nH-(Lys)6-des Pro36 [Asp28]exendin-4(1-39)-Lys6-NH2 des Asp28Pro36, Pro37, Pro38 exendin-4(1-39)-NH2,H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28]exendin-4(1-39)-NH2,H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Asp28]exendin-4(1-39)-NH2,des Pro36, Pro37, Pro38 [Asp28]exendin-4(1-39)-(Lys)6-NH2,H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28]exendin-4(1-39)-(Lys)6-NH2,H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28]exendin-4(1-39)-(Lys)6-NH2,H-(Lys)6-des Pro36 [Trp(O2)25, Asp28]exendin-4(1-39)-Lys6-NH2,H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25]exendin-4(1-39)-NH2,H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]exendin-4(1-39)-NH2,H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]exendin-4(1-39)-NH2,des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]exendin-4(1-39)-(Lys)6-NH2,H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]exendin-4(1-39)-(Lys)6-NH2,H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]exendin-4(1-39)-(Lys)6-NH2,H-(Lys)6-des Pro36 [Met(O)14, Asp28]exendin-4(1-39)-Lys6-NH2,des Met(O)14 Asp28 Pro36, Pro37, Pro38 exendin-4(1-39)-NH2,H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]exendin-4(1-39)-NH2,H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] exendin-4(1-39)-NH2,des Pro36, Pro37, Pro38 [Met(O)14, Asp28]exendin-4(1-39)-(Lys)6-NH2,H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]exendin-4(1-39)-Lys6-NH2,H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] exendin-4(1-39)-(Lys)6-NH2,H-(Lys)6-des Pro36 [Met(O)14, Trp(O2)25, Asp28]exendin-4(1-39)-Lys6-NH2,des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25]exendin-4(1-39)-NH2,H-(Lys)6-des Pro36⬲ Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]exendin-4(1-39)-NH2,H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(0)14, Asp28] exendin-4(1-39)-NH2,des Pro36, Pro37, Pro38 [Met(0)14, Trp(O2)25, Asp28]exendin-4(1-39)-(Lys)6-NH2,H-(Lys)6-des Pro36⬲ Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]exendin-4(1-39)-(Lys)6-NH2,H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] exendin-4(1-39)-(Lys)6-NH2,or a pharmacologically tolerable salt thereof.

›23.↳ 18The formulation as claimed in claim 18, which additionally comprises Arg34, Lys26 (Nε(γ-glutamyl(Nα-hexadecanoyl))) GLP-1 (7-37) [liraglutide].d5

›24.↳ 1A formulation of the insulin analogue as claimed in claim 1, wherein the formulation is in the form of a powder.d2

›25.↳ 1multiple · 1, 24The formulation as claimed in claim 24, wherein the insulin analogue as claimed in claim 1 is present in crystalline or amorphous form.d2

›26.↳ 1A formulation of the insulin analogue as claimed in claim 1, wherein the formulation is in the form of a suspension.d2

›27.↳ 1A formulation of the insulin analogue as claimed in claim 1, wherein the formulation additionally comprises a chemical chaperone.d2

Classifications

6 codes

IPC · International Patent Classification

Section A — Human necessities

A61K38/28
A61K38/26

USPC · US Patent Classification

514/5.9514/6.2514/7.2514/6.3

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Gyan Chandra

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Citations: 43 back · 2 forward

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2 priority documents

Priority

14 Apr 2008

earliest claimed

›Priority documents — 2

Type	Document	Date
provisional	US 61044662	14 Apr 2008
related publication	US 20110173722 A1	14 Jul 2011

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