EP3740195A1 - Compositions sous forme d'une solution aqueuse injectable comprenant de l'amyline, un agoniste au recepteur de l'amyline ou un analogue d'amyline et un co-polyaminoacide - Google Patents
Compositions sous forme d'une solution aqueuse injectable comprenant de l'amyline, un agoniste au recepteur de l'amyline ou un analogue d'amyline et un co-polyaminoacideInfo
- Publication number
- EP3740195A1 EP3740195A1 EP18811583.6A EP18811583A EP3740195A1 EP 3740195 A1 EP3740195 A1 EP 3740195A1 EP 18811583 A EP18811583 A EP 18811583A EP 3740195 A1 EP3740195 A1 EP 3740195A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- radical
- formula
- polyamino acid
- hydrophobic
- amylin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002253 acid Substances 0.000 title claims abstract description 462
- 239000000203 mixture Substances 0.000 title claims abstract description 447
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 title claims abstract description 250
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 title claims abstract description 250
- 229940124035 Amylin receptor agonist Drugs 0.000 title claims abstract description 75
- 239000007864 aqueous solution Substances 0.000 title claims abstract description 49
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 340
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims abstract description 280
- 102000004877 Insulin Human genes 0.000 claims abstract description 151
- 108090001061 Insulin Proteins 0.000 claims abstract description 151
- 229940125396 insulin Drugs 0.000 claims abstract description 140
- 150000007942 carboxylates Chemical class 0.000 claims abstract description 51
- 108010029667 pramlintide Proteins 0.000 claims description 115
- NRKVKVQDUCJPIZ-MKAGXXMWSA-N pramlintide acetate Chemical group C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NRKVKVQDUCJPIZ-MKAGXXMWSA-N 0.000 claims description 115
- 229960003611 pramlintide Drugs 0.000 claims description 113
- 125000004432 carbon atom Chemical group C* 0.000 claims description 79
- 239000002243 precursor Substances 0.000 claims description 76
- -1 Fx = -CO- Chemical group 0.000 claims description 65
- 229920001308 poly(aminoacid) Polymers 0.000 claims description 60
- 238000006243 chemical reaction Methods 0.000 claims description 47
- 238000003756 stirring Methods 0.000 claims description 40
- 239000000556 agonist Substances 0.000 claims description 33
- 229910052708 sodium Inorganic materials 0.000 claims description 33
- 108091005466 amylin receptors Proteins 0.000 claims description 30
- 238000006116 polymerization reaction Methods 0.000 claims description 26
- 229920006395 saturated elastomer Polymers 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 150000001412 amines Chemical group 0.000 claims description 22
- 150000001408 amides Chemical group 0.000 claims description 21
- 125000006850 spacer group Chemical group 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 19
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 17
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 17
- 229920000570 polyether Polymers 0.000 claims description 17
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- 150000001768 cations Chemical class 0.000 claims description 13
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 12
- 150000007513 acids Chemical class 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- KFYRPLNVJVHZGT-UHFFFAOYSA-N Amitriptyline hydrochloride Chemical class Cl.C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KFYRPLNVJVHZGT-UHFFFAOYSA-N 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 150000001450 anions Chemical class 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 150000002170 ethers Chemical class 0.000 claims description 8
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 7
- 229940043131 pyroglutamate Drugs 0.000 claims description 7
- 125000002091 cationic group Chemical group 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 238000012544 monitoring process Methods 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical class Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 description 580
- 239000000243 solution Substances 0.000 description 260
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 174
- 241000894007 species Species 0.000 description 157
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 109
- 238000000034 method Methods 0.000 description 100
- 238000002360 preparation method Methods 0.000 description 91
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- 235000002639 sodium chloride Nutrition 0.000 description 87
- 238000005481 NMR spectroscopy Methods 0.000 description 79
- 239000000047 product Substances 0.000 description 66
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 64
- 230000008569 process Effects 0.000 description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- 230000002829 reductive effect Effects 0.000 description 55
- 239000007787 solid Substances 0.000 description 54
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 52
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 52
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- 239000011780 sodium chloride Substances 0.000 description 51
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 50
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 50
- 239000011734 sodium Substances 0.000 description 48
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 43
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- 150000003839 salts Chemical class 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
- 235000011187 glycerol Nutrition 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 29
- 229940024606 amino acid Drugs 0.000 description 29
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 29
- 235000001014 amino acid Nutrition 0.000 description 28
- 229920002643 polyglutamic acid Polymers 0.000 description 27
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 26
- 239000011592 zinc chloride Substances 0.000 description 26
- 235000005074 zinc chloride Nutrition 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 24
- 150000001413 amino acids Chemical class 0.000 description 24
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 23
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 23
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 22
- 239000012429 reaction media Substances 0.000 description 20
- 239000011347 resin Substances 0.000 description 19
- 229920005989 resin Polymers 0.000 description 19
- 239000000546 pharmaceutical excipient Substances 0.000 description 18
- 239000002244 precipitate Substances 0.000 description 18
- 238000001914 filtration Methods 0.000 description 16
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 15
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 15
- 102100040918 Pro-glucagon Human genes 0.000 description 15
- 150000002148 esters Chemical class 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 15
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 14
- 108090000765 processed proteins & peptides Proteins 0.000 description 14
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 13
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 13
- 238000001035 drying Methods 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- 239000008194 pharmaceutical composition Substances 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- BGGHCRNCRWQABU-SNVBAGLBSA-N (2r)-2-azaniumyl-5-oxo-5-phenylmethoxypentanoate Chemical compound [O-]C(=O)[C@H]([NH3+])CCC(=O)OCC1=CC=CC=C1 BGGHCRNCRWQABU-SNVBAGLBSA-N 0.000 description 12
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- 239000008103 glucose Substances 0.000 description 12
- 238000005259 measurement Methods 0.000 description 12
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical class N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 11
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 11
- 108010011459 Exenatide Proteins 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 10
- 230000008878 coupling Effects 0.000 description 10
- 238000010168 coupling process Methods 0.000 description 10
- 238000005859 coupling reaction Methods 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 239000004026 insulin derivative Substances 0.000 description 10
- 108010004367 lixisenatide Proteins 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- 229960002429 proline Drugs 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 230000000007 visual effect Effects 0.000 description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 9
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2/00—Peptides of undefined number of amino acids; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
Definitions
- the invention relates to amylin injection therapies, amylin receptor agonist or amylin analogue to treat diabetes.
- the invention relates to a composition in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least amylin, an amylin receptor agonist or a amylin analogue and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals according to the invention and compositions further comprising insulin (excluding basal insulins whose isoelectric point pi is between 5.8 and 8 , 5).
- the invention also relates to pharmaceutical formulations comprising the compositions according to the invention.
- the invention also relates to a use of the co-polyamino acids bearing carboxylate charges and hydrophobic radicals according to the invention for stabilizing amylin, agonist or amylin receptor agonist compositions.
- amylin as well as amylin, amylin receptor agonist or amylin analogue compositions further comprising insulin.
- the composition according to the invention does not include basal insulin whose isoelectric point pi is between 5.8 and 8.5, and in particular no insulin glargine.
- basal insulin whose isoelectric weight is between 5.8 and 8.5 insoluble insulin at pH 7 and whose duration of action is between 8 and 24 hours or greater than 24 hours in the standard models of diabetes.
- Type 1 diabetes is an autoimmune disease leading to the destruction of beta cells in the pancreas. These cells are known to produce insulin whose main role is to regulate glucose utilization in peripheral tissues (Gerich 1993 Control of glycaemia). As a result, patients with type 1 diabetes have chronic hyperglycaemia and must use exogenous insulin to reduce this hyperglycemia. Insulin therapy has drastically changed the life expectancy of these patients. However, control of glucose levels by exogenous insulin is not optimal, especially after a meal. This is due to the fact that these patients produce glucagon after a meal, which leads to the destocking of some of the glucose stored in the liver, which is not the case at home. the healthy person. This glucagon-mediated glucagon production aggravates the problem of regulating blood sugar in these patients.
- amylin another hormone produced by beta cells of the pancreas and therefore deficient in type 1 diabetic patients, plays a key role in the regulation of postprandial blood glucose.
- Amylin also known as "amyloid polypeptide islet" or IAPP, is a 37 amino acid peptide that is co-stored and co-secreted with insulin (Schmitz 2004 Amylin Agonists). This peptide is described to block the production of glucagon by alpha cells of the pancreas.
- insulin and amylin have complementary and synergistic roles, since insulin can reduce blood glucose concentration while amylin can reduce endogenous glucose entry into the blood by inhibiting blood glucose levels. production (secretion) of endogenous glucagon.
- Human amylin has properties that are not compatible with pharmaceutical requirements in terms of solubility and stability (Goldsbury CS, Cooper GJ, Goldie KN, Muller SA, Saafi EL, WT Gruijters, Misur MP, Engel A , Aebi U, Kistler 3: Polymorphic Fibrillar Assembly of Human Amylin J Struct Biol 119: 17-27, 1997).
- Amylin is known to form amyloid fibers which lead to the formation of plaques that are insoluble in water. Although being the natural hormone, it has been necessary to develop an analogue to solve these solubility problems.
- amylin is stable for about fifteen minutes at acidic pH, and less than one minute at neutral pH.
- the Amylin company has developed an analog of amylin, pramlintide, to overcome the lack of stability of human amylin.
- This product marketed as Symlin, was approved in 2005 by the FDA for the treatment of type 1 and type 2 diabetics. It must be administered subcutaneously three times a day, in the hour before the meal. to improve postprandial glucose control.
- This peptide is formulated at acidic pH and is described to fibrillate when the pH of the solution is greater than 5.5. Analog variants are described in US Patent 5,686,411.
- amylin an amylin analogue, or an amylin receptor agonist
- a prandial insulin since these two products are to be administered before the meal.
- the patent application WO2007104786 of NOVO NORDISK discloses a method for stabilizing a solution of pramlintide, which is an analogue of amylin, and insulin by the addition of a phospholipid, derived from glycerophosphoglycerol, in particular dimyristoyl glycerophosphoglycerol (DMPG).
- DMPG dimyristoyl glycerophosphoglycerol
- this solution requires the use of large quantities of DMPG which can pose a local tolerance problem.
- the DMPG leads to compositions having physical stabilities at 0-4 ° C quite low as described in the application WO2018122278.
- an amylin receptor agonist or an amylin analogue in order to can be administered with conventional devices.
- the pH of acid formulation and rapid fibrillation are brakes to obtain a pharmaceutical formulation at neutral pH based on amylin and pramlintide, but also a brake to combine amylin or pramlintide with other pharmaceutical ingredients.
- active agents in particular peptides or proteins.
- the co-polyamino acids according to the invention stabilize amylin, agonist or amylin receptor agonist compositions at a pH between
- compositions comprising amylin, an amylin receptor agonist or an amylin analogue in combination with a co-polyamino acid according to the invention have an increased stability over time, which is of great interest for pharmaceutical development.
- the co-polyamino acids according to the invention also make it possible to obtain a composition comprising prandial insulin and amylin, an amylin receptor agonist or a d-type analogue. amylin, said composition being clear and having improved fibrillation stability.
- a conventional method for measuring the stabilities of proteins or peptides is to measure the formation of fibrils using Thioflavin T, also called ThT. This method makes it possible to measure, under temperature and agitation conditions that allow an acceleration of the phenomenon, the latency time before the formation of fibrils by measuring the increase in fluorescence.
- the compositions according to the invention have a lag time before the formation of fibrils significantly greater than that of amylin, an agonist at the amylin receptor or an amylin analogue at the pH of interest. .
- compositions according to the invention have a physical stability, and possibly chemical, satisfactory at the desired pH.
- the invention relates to a composition in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least:
- said co-polyamino acid of formula I bearing at least one hydrophobic radical -Hy, of carboxylate charges and consisting of at least two chains of glutamic or aspartic units PLG linked together by a radical or spacer Q [- *] i ⁇ linear or branched divalent at least consisting of an alkyl chain comprising one or more heteroatoms selected from the group consisting of nitrogen and oxygen atoms and / or bearing one or more heteroatoms consisting of nitrogen atoms and oxygen and / or radicals bearing one or more heteroatoms consisting of nitrogen and oxygen atoms and / or carboxyl functions.
- radical or spacer Q [- *] k being bonded to at least two PLG glutamic or aspartic unit chains by an amide function and
- said amide bonds linking said radical or spacer Q [- *] k bonded to at least two chains of glutamic or aspartic units result from the reaction between an amine function and an acid function respectively carried either by the precursor Q 'of the radical or spacer Q [- *] k either by a glutamic or aspartic unit,
- hydrophobic radical -Hy being linked either to a terminal "amino acid” unit and then to a carboxyl function carried by one of the glutamic or aspartic unit chains PLG and then I ' is the average number of monomeric units carrying a hydrophobic radical -Hy.
- k is 2, 3, 4, 5 or 6.
- k 2.
- k 3.
- k 6.
- j is 1, 2, 3, 4, 5 or 6.
- j 1.
- j 2.
- j 3.
- j 4.
- j 5.
- j 6.
- co-polyamino acids bearing carboxylate charges and hydrophobic radicals of formula X are soluble in distilled water at a pH of between 6 and 8, at a temperature of 25 ° C. and at a concentration of less than 100 mg / ml. ml.
- alkyl radical means a carbon chain, linear or branched, which does not include a heteroatom.
- the co-polyamino acid is a random co-polyamino acid in the sequence of glutamic and / or aspartic units.
- the invention also relates to the precursors of said hydrophobic radicals of formula X.
- the invention further relates to a method for preparing stable injectable compositions.
- soluble capable of allowing to prepare a clear solution and free of particles at a concentration of less than 100 mg / ml in distilled water at 25 ° C.
- solution a liquid composition devoid of visible particles, using the procedure according to pharmacopeia EP 8.0, point 2.9.20, and US ⁇ 790>.
- compositions which after a certain storage period at a certain temperature satisfy the criteria of the visual inspection described in the European, American and international pharmacopoeia, that is to say compositions which are clear and which do not contain visible particles, but also colorless.
- chemically stable composition is meant compositions which, after storage for a certain time and at a certain temperature, exhibit a minimum recovery of the active ingredients and are in accordance with the specifications applicable to the pharmaceutical products.
- aqueous injectable solution water-based solutions that meet the requirements of EP and US pharmacopoeia, and which are sufficiently liquid to be injected.
- co-polyamino acid consisting of glutamic or aspartic units means non-cyclic linear sequences of glutamic acid or aspartic acid units linked together by peptide bonds, said sequences having a corresponding C-terminal portion. to the carboxylic acid of one end, and an N-terminal part, corresponding to the amine of the other end of the sequence.
- alkyl radical means a linear or branched carbon chain, which does not include a heteroatom.
- the co-polyamino acid is a random co-polyamino acid or block.
- the co-polyamino acid is a random co-polyamino acid in the sequence of glutamic and / or aspartic units.
- compositions in the form of an aqueous solution for injection according to the invention are clear solutions.
- the term "clear solution” means compositions which satisfy the criteria described in the US and European pharmacopoeias concerning injectable solutions.
- the solutions are defined in the ⁇ 1151> part referring to the injection ⁇ 1> (referring to ⁇ 788> according to USP 35 and specified in ⁇ 788> according to USP 35 and in ⁇ 787>, ⁇ 788> and ⁇ 790> USP 38 (from 1 August 2014), according to USP 38).
- injectable solutions must meet the criteria given in sections 2.9.19 and 2.9.20.
- composition according to the invention is characterized in that Hy comprises between 15 and 100 carbon atoms.
- composition according to the invention is characterized in that Hy comprises between 30 and 70 carbon atoms.
- composition according to the invention is characterized in that Hy comprises between 40 and 60 carbon atoms.
- the composition according to the invention is characterized in that Hy comprises between 20 and 30 carbon atoms. In one embodiment, Hy comprises more than 15 carbon atoms.
- Hy comprises more than 30 carbon atoms.
- the composition is characterized in that the pH is between 6.0 and 8.0.
- the composition is characterized in that the pH is between 6.6 and 7.8.
- the composition is characterized in that the pH is between 7.0 and 7.8.
- the composition is characterized in that the pH is between 6.8 and 7.4.
- radical or spacer Q [- *] i ⁇ is represented by a radical of formula II:
- radicals Q ' being identical or different and selected from the group consisting of the following radicals of formulas III to VI', to form
- At least one of u "i or u" 2 is different from 0.
- u'i and u'2 are identical or different and,
- v, v 'and v "identical or different are integers 3 0, and v + v' + v" ⁇ 15, with a radical of formula VI:
- F c , Fc- and Fc- are 2 -NH- and 1 -CO-, then at least one of the - (CH 2) - carrying a nitrogen is different from 0.
- F c , F C ' and F C " are 1 -NH- and 2 -CO- then no conditions.
- Fd and Fd- are -NH-, wi and w'i> 2 and / or w ⁇ and w'2> 2. In one embodiment, if Fd and Fd- are -CO-, wi and w'i> 1 and / or W2 and w'2> 1.
- the at least two chains of glutamic or aspartic units P LG being bound to Q [- *] k by a function F x or F y by a covalent bond to form an amide bond with a function -NH- or - CO- PLG.
- At least one of Q ' is a radical of formula III
- the precursor of the radical of formula III is a diamine selected from the group consisting of ethylenediamine, butylenediamine, hexylenediamine, 1,3-diaminopropane and 1,5-diaminopentane.
- t 2 and the precursor of the radical of formula III is ethylenediamine.
- t 4 and the precursor of the radical of formula III is butylenediamine.
- t 6 and the precursor of the radical of formula III is hexylenediamine.
- t 3 and the precursor of the radical of formula III is 1,3-diaminopropane.
- t 5 and the precursor of the radical of formula III is 1,5-diaminopentane.
- the precursor of the radical of formula III is an amino acid. In one embodiment, the precursor of the radical of formula III is an amino acid selected from the group consisting of aminobutanoic acid, aminohexanoic acid and beta-alanine.
- t 2 and and the precursor of the radical of formula III is beta-alanine.
- t 6 and and the precursor of the radical of formula III is aminohexanoic acid.
- t 4 and the precursor of the radical of formula III is aminobutanoic acid.
- the precursor of the radical of formula III is a diacid.
- the precursor of the radical of formula III is a diacid selected from the group consisting of succinic acid, glutaric acid and adipic acid.
- t 2 and and the precursor of the radical of formula III is succinic acid.
- t 3 and the precursor of the radical of formula III is glutaric acid.
- t 4 and the precursor of the radical of formula III is adipic acid.
- At least one of Q ' is a radical of formula IV, Formula IV whose precursor is a diamine.
- the precursor of the radical of formula IV is a diamine selected from the group consisting of diethylene glycol diamine, triethylene glycol diamine, 4,9-dioxa-1,12-dodecanediamine and 1-amino -4,7,10-trioxa-13-tridecanamine.
- At least one of Q ' is a radical of formula V
- Formula V whose precursor is selected from the group consisting of amino acids.
- the precursor of the radical of formula V is an amino acid selected from the group consisting of lysine, ornithine and 2,3-diaminopropionic acid.
- At least one of Q ' is a radical of formula V
- Formula V whose precursor is selected from the group consisting of triacids.
- the precursor of the radical of formula V is a triacid selected from the group consisting of tricarballylic acid.
- at least one of Q ' is a radical of formula V,
- the precursor of the radical of formula V is a triamine selected from the group consisting of (2- (aminomethyl) propane-1,3-diamine).
- At least one of Q ' is a radical of formula
- w " 2 0 and the precursor of the radical of formula
- VI is a triamine selected from the group consisting of spermidine, norspermidine, and diethylenetriamine and bis (hexamethylene) triamine.
- w "z 0 and the precursor of the radical of formula VI is spermidine.
- VI is norspermidine.
- w " 2 0 and the precursor of the radical of formula VI is diethylenetriamine.
- w " 2 0 and the precursor of the radical of formula VI is bis (hexamethylene) triamine.
- At least one of Q ' is a radical of formula VI
- w "2 1 and the precursor of the radical of formula VI is a tetramine.
- w "2 1 and the precursor of the radical of formula VI is a tetramine selected from the group consisting of spermine and triethylenetetramine.
- w "2 1 and the precursor of the radical of formula VI is spermine.
- w "2 1 and the precursor of the radical of formula VI is triethylenetetramine.
- the precursor of the radical or spacer Q [- *] k has 4 reactive functions, chosen from the group of amine functions and carboxylic acid functions.
- the precursor of the radical or spacer Q [- *] k has 4 reactive functions and the precursor of the radical or spacer Q [- *] k is 1,2,3,4-butanetrathoic acid. .
- At least one of Q ' is a radical of formula VI'
- w ' 2 0 and the precursor of the radical of formula VI' is a triamine selected from the group consisting of spermidine, norspermidine, and diethylenetriamine and bis (hexamethylene) triamine .
- w "2 0 and the precursor of the radical of formula VI 'is spermidine.
- At least one of Q ' is a radical of formula
- w "2 1 and the precursor of the radical of formula VI 'is a tetramine.
- w "2 1 and the precursor of the radical of formula VI 'is spermine.
- all are related to P Fx LG or other Fx or Fy.
- one or more Fx are free, that is to say are not related to the PLG, or another Fx or F y .
- an Fx is free, that is to say is not linked to the PLG, or to another Fx, or to an F y .
- the (s) F x of -CO- type is free, it is in the form of a carboxylic acid salt.
- the free -CO- type F x is carried by a radical Q 'of Formula V.
- the -NH- type F-(s) is free, it is in the form of amine or ammonium.
- composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa below:
- Ra and R 'a which are identical or different, are either a hydrophobic radical -Hy or a radical chosen from the group consisting of an H, a linear acyl group of C 2 to Cio, a branched acyl group of Ca to Cio, a benzyl, a terminal "amino acid” unit and a pyroglutamate,
- Ra and R'a being a hydrophobic radical -Hy
- n + m has the same definition as given above.
- the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and from at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXa in which R a and R ' a , identical are a hydrophobic radical -Hy.
- the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXa in which R a and R ' a , different are hydrophobic radicals -Hy.
- the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXa in which R a is a hydrophobic radical -Hy and R'a is not a hydrophobic radical -Hy.
- the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXa in which R ' a is a hydrophobic radical -Hy, and R a is not a hydrophobic radical -Hy.
- composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'below :
- ni + mi represents the number of glutamic units or aspartic units of the P LG chains of the co-polyamino acid bearing a radical -Hy,
- n '+ m' represents the degree of DP polymerization 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.
- the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'in which Ra and R 'a, identical are a hydrophobic radical -Hy.
- the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'in which Ra and R'a, different are hydrophobic radicals -Hy.
- the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'in which Ra is a hydrophobic radical -Hy and R'a is not a hydrophobic radical -Hy.
- the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'in which R'a is a hydrophobic radical -Hy, and Ra is not a hydrophobic radical -Hy.
- composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula
- Rb and R'b which are identical or different, are either a hydrophobic radical -Hy or a radical chosen from the group consisting of -OH, an amine group, a terminal "amino acid” unit and a pyroglutamate, at least one of Rb and R'b is a hydrophobic radical -Hy,
- the composition according to the invention is characterized in that the co-polyam inoacid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb in which Rb and R'b, identical are a hydrophobic radical -Hy.
- the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb in which Rb and R'b, different are hydrophobic radicals -Hy.
- the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb in which Rb is a hydrophobic radical -Hy and R'b is not a hydrophobic radical -Hy.
- the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb in which R'b is a hydrophobic radical -Hy, and Rb is not a hydrophobic radical -Hy.
- composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula
- Rb and R'b which are identical or different, are either a hydrophobic radical -Hy or a radical chosen from the group consisting of -OH, an amine group, a terminal "amino acid” unit and a pyroglutamate, at least one of Rb and R'b is a hydrophobic radical -Hy,
- Nl + ml represents the number of glutamic units or aspartic units of the P LG chains of the co-polyamino acid bearing a -Hy radical
- N2 + m2 represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid not carrying a -Hy radical
- n '+ m' represents the degree of DP polymerization 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.
- the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb 'in which Rb and R'b, identical are a hydrophobic radical -Hy.
- the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb 'in which Rb and R'b are different hydrophobic radicals -Hy. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb 'in which Rb is a hydrophobic radical -Hy and R'b is not a hydrophobic radical -Hy.
- the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb 'in which R'b is a hydrophobic radical -Hy, and Rb is not a hydrophobic radical -Hy.
- co-polyamino acid comprises one or more aspartic unit (s), that (s) can (s) undergo structural rearrangements.
- the composition according to the invention is characterized in that when the co-polyamino acid comprises aspartate units, then the co-polyamino acid may further comprise monomeric units of formula XXXX and / or XXXX ' :
- the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas XXXa, XXXa ', XXXb or XXXb' wherein the co-polyamino acid is selected from co-polyamino acids in which the group D is a -CH 2 - (aspartic unit) group.
- the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from co-polyamino acids of formulas, XXXa, XXXa, XXXb or XXXb. wherein the co-polyamino acid is selected from co-polyamino acids in which the group D is -CH2-CH2- (glutamic unit).
- the composition according to the invention is characterized in that n + m is between 10 and 250.
- composition according to the invention is characterized in that n + m is between 10 and 200.
- the composition according to the invention is characterized in that n + m is between 15 and 150.
- composition according to the invention is characterized in that n + m is between 15 and 100.
- composition according to the invention is characterized in that n + m is between 15 and 80.
- composition according to the invention is characterized in that n + m is between 15 and 65.
- composition according to the invention is characterized in that n + m is between 20 and 60.
- composition according to the invention is characterized in that n + m is between 20 and 50.
- the composition according to the invention is characterized in that n + m is between 20 and 40.
- the invention also relates to said co-polyamino acids bearing carboxylate charges and hydrophobic radicals of formula X and the precursors of said hydrophobic radicals.
- said at least one hydrophobic radical-Hy is chosen from radicals of formula X: Formula X in which
- GpR is chosen from the radicals of formulas VII, VU 'or VU ": ; Identical or different GpG and GpH are chosen from the radicals of formulas XI or XI ': * - NH- G- NH- *
- GpA is chosen from the radicals of formula VIII
- GpC is a radical of formula IX:
- b is an integer equal to 0 or 1;
- c is an integer equal to 0 or 1, and if c is 0 then d is 1 or 2; d is an integer of 0, 1 or 2;
- e is an integer equal to 0 or 1;
- A, A 1, A 2 and A 3, which may be identical or different, are linear or branched alkyl radicals comprising from 1 to 8 carbon atoms, and optionally substituted with a radical resulting from a saturated, unsaturated or aromatic ring;
- B is a radical selected from the group consisting of an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, optionally comprising an aromatic nucleus, comprising 1 to 9 carbon atoms;
- C x is a radical selected from the group consisting of a linear or branched monovalent alkyl radical, optionally comprising a cyclic part, in which x indicates the number of carbon atoms and 6 ⁇ x ⁇ 25:
- hydrophobic radical -Hy bears at least 5 -GpC then, 6 ⁇ x ⁇ 11;
- G is a divalent linear or branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),
- R is a radical chosen from the group consisting of a linear or branched divalent alkyl radical comprising from 1 to 12 carbon atoms, a linear or branched divalent alkyl radical comprising from 1 to 12 carbon atoms bearing one or more -CONH 2 functions or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 12 carbon atoms; at 5 oxygen atoms, the hydrophobic radical (s) -Hy of formula X being bonded to PLG:
- the degree of DP polymerization in glutamic or aspartic units for the PLG chains is between 5 and 250;
- the free acid functions being in the form of an alkaline cation salt selected from the group consisting of Na + and K + .
- the group GpR linked to P LG is chosen from GpR of formula VII.
- the GpR group bonded to PLG is chosen from GpR of formula VII and the second GpR is chosen from GpR of formula VII ".
- Formula Xc wherein GpR, GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, I, a' and V have the definitions given above.
- said at least one hydrophobic radical-Hy is chosen from radicals of formula Xc as defined below: Formula Xc in which GpR is a radical of formula VIF.
- GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, let G have the definitions given above.
- said at least one hydrophobic radical-Hy is chosen from radicals of formula Xc as defined below: Formula Xc wherein GpR is a radical of formula VII ". Form VII "
- GpR, GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, I and G have the definitions given above.
- said at least one hydrophobic radical - Hy is chosen from radicals of formula Xq as defined below:
- said at least one hydrophobic radical-Hy is chosen from radicals of formula Xr as defined below: Formula Xr in which GpR, GpA, GpL, GpH, GpC, r, a, a ', I, h and V have the definitions given above.
- GpR, GpA, GpC, r, a 'and a have the definitions given above.
- GpR, GpA, GpC and r have the definitions given above.
- GpA is a radical chosen from radicals of formula VIIId and GpR, GpC, r are as defined above.
- said at least one hydrophobic radical-Hy is chosen from radicals of formula X in which r, g, a, I, h are equal to 0, of formula Xo as defined below:
- said at least one hydrophobic radical-Hy is chosen from radicals of formula X in which r, g, a, I, h are equal to 0, of formula Xo as defined below:
- said at least one hydrophobic radical-Hy is chosen from radicals of formula Xs as defined below: Formula Xs
- GpR, GpG, GpL, GpH, GpC, r, g, I, h and G have the definitions given above.
- GpR, GpG, GpL, GpH, GpC, r, g, h, I and G have the definitions given above.
- Formula Xb in which GpA, GpR, GpG, GpL, GpH, GpC, r, g, h, I and G have the definitions given above.
- GpR, GpG, GpL, GpH, GpC, Al, ki, r, g, h, I and G have the definitions given above.
- GpR, GpG, GpL, GpH, GpC, Al, A2, A3, r, g, h, I and G have the definitions given above.
- said at least one hydrophobic radical - Hy is chosen from radicals of formula X in which GpR, GpG, GpA, GpH, GpC, r, g, a, h and a 'have the definitions given above.
- said at least one hydrophobic radical - Hy is chosen from radicals of formula X in which
- GpR, GpA, GpL and GpC have the definitions given above.
- said at least one hydrophobic radical-Hy is chosen from radicals of formulas X, Xa to Xu:
- said at least one hydrophobic radical - Hy is chosen from radicals of formula X in which
- said at least one hydrophobic radical-Hy is chosen from radicals of formula X in which
- the * indicate the sites of attachment of the hydrophobic radicals to the PLG or between the different groups GpR, GpG, GpA, GpL, GpH and GpC to form amide functions.
- radicals -Hy are attached to the PLG via amide functions.
- radicals -Hy, GpR, GpG, GpA, GpL, GpH and GpC are each independently identical or different from one residue to another.
- the GpCs are directly or indirectly related to N "i and" 2 and the PLG is directly or indirectly linked via- GpR to Nri, or GpC are directly or indirectly related to IV and Nri, and LG P is directly or indirectly linked via - GpRà IV; or
- GpCs are directly or indirectly related to IV and Npi, and PLG is linked directly or indirectly via - GpRà IV.
- the GpCs are directly or indirectly related to IV and IV and the PLG is directly or indirectly related to Npi; or
- GpCs are directly or indirectly related to IV and Npi, and PLG is directly or indirectly related to IV.
- PLG is directly or indirectly related to IV.
- GpCs are directly or indirectly related to IV, IV and Npi and PLG is directly or indirectly linked via -GpR to I; or
- GpCs are directly or indirectly related to IV, IV and I and the PLG is directly or indirectly linked via GpR to Nri; or
- GpCs are directly or indirectly linked to IV, Npi and I and PLG is linked directly or indirectly via -GpR- to IV; or
- the GpCs are directly or indirectly related to N ", Npi and V and the PLG is directly or indirectly linked via GpR to IV.
- GpCs are directly or indirectly related to IV, IV and Npi and the PLG is directly or indirectly related to V; or
- - GpC are directly or indirectly related to IV, N and IV and the PLG is directly or indirectly related to Npi;
- GpCs are directly or indirectly related to IV, Npi and Npi and PLG is directly or indirectly linked to IV; or
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent linear alkyl radical comprising from 2 to 12 carbon atoms.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising from 2 to 6 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent linear alkyl radical comprising from 2 to 6 carbon atoms.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising from 2 to 4 carbon atoms.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent linear alkyl radical comprising from 2 to 4 carbon atoms.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising 2 carbon atoms.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent linear alkyl radical comprising from 1 to 11 carbon atoms.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising from 1 to 6 carbon atoms.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising from 2 to 5 carbon atoms and bearing one or more amide functional groups ( -CONH2).
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent linear alkyl radical comprising from 2 to 5 carbon atoms and carrying one or more amide functions. (-CONH2).
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical chosen from the group consisting of the radicals represented by the formulas below:
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical of formula
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical of formula X2.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is bonded to the co-polyamino acid via an amide function carried by the carbon in the delta or epsilon position (or position 4 or 5) relative to the amide function (-COIMH2).
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a linear ether or unsubstituted polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 carbon atoms. oxygen atoms.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical ether.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is an ether radical comprising from 4 to 6 carbon atoms.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising 6 carbon atoms.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is an ether radical represented by the formula
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a polyether radical.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a linear polyether radical comprising from 6 to 10 carbon atoms and from 2 to 3 oxygen atoms. .
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a polyether radical chosen from the group consisting of the radicals represented by the formulas below:
- its composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical of formula X3.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical of formula X4.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a polyether radical chosen from the group consisting of the radicals represented by formulas X5 and X6 below. :
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a polyether radical of formula X5.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a polyether radical of formula X6.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpG and / or GpH is of formula CG in which G is an alkyl radical comprising 6 carbon atoms represented by the formula Z below:
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpG and / or GpH is of formula XI in which G is an alkyl radical comprising 4 carbon atoms represented by the formula Z 'below:
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpG and / or GpH is of formula XI in which G is an alkyl radical comprising 4 carbon atoms represented by - (CH2) 2-CH (COOH) -.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpG and / or GpH is of formula XI in which G is an alkyl radical comprising 4 carbon atoms represented by -CH ((CH2) 2COOH) -.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpG and / or GpH is of formula XI in which G is an alkyl radical comprising 3 carbon atoms represented by -CH 2 -CH- (COOH).
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpG and / or GpH is of formula XI in which G is an alkyl radical comprising 3 carbon atoms represented by -CH (CH2) (COOH) -.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpA is of formula VIII and in which Ai is chosen from the group consisting of the radicals represented by the formulas below :
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which the GpC radical of formula IX is chosen from the group consisting of the radicals of formulas IXe, IXf or IXg ci- after represented:
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which the GpC radical of formula IX is chosen from the group consisting of radicals of formulas IXe, IXf or IXg in which b is equal to 0, respectively corresponding to formulas IXh, IXi, and IXj hereinafter represented:
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which C x is chosen from the group consisting of linear alkyl radicals. In one embodiment, the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of branched alkyl radicals.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 9 and 14 carbon atoms.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of the radicals represented by the formulas below:
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 15 and 16 carbon atoms.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of the radicals represented by the formula below: ## STR2 ##
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which C x is chosen from the group consisting of the radicals represented by the formula below:
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which C x is chosen from the group consisting of alkyl radicals comprising between 17 and 25 carbon atoms.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 17 and 18 carbon atoms.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of the alkyl radicals represented by the formula below: ## STR5 ## [000304] In one embodiment, the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 18 and 25 carbon atoms.
- the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of the alkyl radicals represented by the formulas below: ## STR5 ##
- the composition is characterized in that the hydrophobic radical is a radical of formula X in which the GpC radical of formula IX is chosen from the group consisting of radicals in which C x is chosen from the group consisting of alkyl radicals comprising 14 or 15 carbon atoms.
- the composition is characterized in that the hydrophobic radical is a radical of formula X in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by the radicals represented by the formula below:
- the composition is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0.3.
- the composition is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3.
- the composition is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.2.
- the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspheric units is between 0.007 and 0. , 15.
- the composition is characterized in that the hydrophobic radical corresponds to formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0, 1.
- the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.08.
- the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical C x comprises between 9 and 10 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspheric units is between 0.03 and 0.15.
- the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio M between the number of hydrophobic radicals and the the number of glutamic or aspheric units is between 0.015 and 0.1.
- the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical C x comprises between 11 and 12 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.08. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical C x comprises between 13 and 15 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0, 1.
- the composition is characterized in that the hydrophobic radical corresponds to formula X in which the radical C x comprises between 13 and 15 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.06.
- the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0, 3.
- the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3.
- the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspheric units is between 0.015 and 0. 2.
- the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 11 and 14 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.2.
- the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 15 and 16 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.04 and 0.15.
- the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 17 and 18 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.02 and 0.06.
- the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspheric units is between 0.01 and 0.06. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical C x comprises between 19 and 25 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.05.
- the invention also relates to said co-polyamino acids I, carrying carboxylate charges and hydrophobic radicals of formula X and the precursors of said hydrophobic radicals.
- the invention also relates to a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical of formula X, said copolyamino acid being chosen from the copolyamino acids of formula I:
- said co-polyamino acid of formula I bearing at least one hydrophobic radical -Hy, of carboxylate charges and consisting of at least two chains of glutamic or aspartic units PLG bonded together by a radical or spacer Q [- *] k linear or ra m
- a radical or spacer Q [- *] k linear or ra m castord silica
- radical or spacer Q [- *] k being bonded to at least two PLG glutamic or aspartic unit chains by an amide function and
- said amide bonds linking said radical or spacer Q [- *] k bonded to at least two chains of glutamic or aspartic units result from the reaction between an amine function and an acid function respectively carried either by the precursor Q 'of the radical or spacer Q [- *] k either by a glutamic or aspartic unit,
- hydrophobic radical -Hy being linked either to a terminal "amino acid” unit and then to a carboxyl function carried by one of the glutamic or aspartic unit chains PLG and then I ' is the average number of monomeric units carrying a hydrophobic radical -Hy.
- the invention also relates to the precursors Hy 'of said hydrophobic radicals of formula X' as defined below: Formula X 'in which
- GpR is chosen from the radicals of formulas VII, VII 'or VU ": ;
- GpG and GpH identical or different are chosen from the radicals of formulas XI or XI ': * - NH- G- NH- *
- GpA is chosen from the radicals of formula VIII
- GpC is a radical of formula IX: Form IX; the * indicate the sites of attachment of the different groups linked by amide functions;
- b is an integer equal to 0 or 1;
- c is an integer equal to 0 or 1, and if c is 0 then d is 1 or 2;
- s' is an integer equal to 0 or 1;
- A, A 1, A 2 and A 3, which may be identical or different, are linear or branched alkyl radicals comprising from 1 to 8 carbon atoms, and optionally substituted with a radical resulting from a saturated, unsaturated or aromatic ring;
- B is a radical selected from the group consisting of an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, optionally comprising an aromatic nucleus, comprising 1 to 9 carbon atoms;
- C x is a radical selected from the group consisting of a linear or branched monovalent alkyl radical, optionally comprising a cyclic part, in which x indicates the number of carbon atoms and 6 ⁇ x ⁇ 25:
- G is a divalent linear or branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),
- R is a radical chosen from the group consisting of a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more functions; CONH 2 or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms
- the degree of DP polymerization in glutamic or aspartic units for P LG chains is between 5 and 250;
- the free acid functions being in the form of an alkaline cation salt selected from the group consisting of Na + and K + .
- Amylin or islet amyloid polypeptide (IAPP), is a peptide hormone with 37 residues. It is co-secreted with insulin from pancreatic beta cells in the ratio of about 100: 1. Amylin plays a role in glycemic regulation by stopping the secretion of endogenous glucagon and slowing down gastric emptying and by promoting satiety, thereby reducing postprandial glucose excursions in blood glucose levels.
- IAPP islet amyloid polypeptide
- IAPP is processed from a coding sequence of 89 residues.
- the Proislet amyloid polypeptide (proIAPP, proamyline, proislet protein) is produced in pancreatic beta cells (beta cells) in the form of a pro-peptide of SR0 67 amino acids, 7404 Dalton, and undergoes post-translational modifications including protease cleavage to produce amylin.
- amylin as mentioned refers to the compounds described in US Pat. Nos. 5,124,314 and 5,234,906.
- analogue when used with reference to a peptide or a protein, a peptide or a protein, in which one or more constituent amino acid residues of the primary sequence have been substituted with other amino acid residues and / or wherein one or more constituent amino acid residues have been deleted and / or wherein one or more constituent amino acid residues have been added.
- the percentage of homology allowed for the present definition of an analogue is 50%.
- an analogue may for example be derived from the primary amino acid sequence of amylin by substituting one or more natural or unnatural amino acids or peptidomimetics.
- derivative when used with reference to a peptide or a protein, a peptide or a protein or a chemically modified analogue with a substituent that is not present in the peptide or the protein or the reference analogue, i.e., a peptide or protein that has been modified by creation of covalent bonds, to introduce non-amino acid substituents.
- amylin receptor agonist refers to a compound that mimics one or more characteristics of amylin activity.
- Amylin derivatives are described in the article Yan et al. , PNAS, vol. 103, No. 7, p 2046-2051, 2006.
- the substituent is selected from the group consisting of fatty chains.
- Amyline analogues are described in US Pat. No. 5,686,411, US Pat. No. 6,114,304 or US Pat. No. 6,410,511.
- the composition is characterized in that the amylin analogue is pramlintide (Symlin ® ) marketed by the company ASTRAZENECA AB.
- the amylin analogue is pramlintide (Symlin ® ) marketed by the company ASTRAZENECA AB.
- the composition is characterized in that it comprises amylin, the amylin receptor agonist or the amylin analogue in a concentration ranging from 0.1 to 5 mg. / ml.
- the composition is characterized in that it comprises amylin, the amylin receptor agonist or the amylin analogue in a concentration ranging from 0.2 to 4 mg. / ml. In one embodiment, the composition is characterized in that it comprises amylin, the amylin receptor agonist or the amylin analogue in a concentration ranging from 0.3 to 3 mg. / ml.
- the composition is characterized in that it comprises amylin, the amylin receptor agonist or the amylin analogue in a concentration ranging from 0.4 to 2 mg. / ml.
- the composition is characterized in that it comprises amylin, the amylin receptor agonist or the amylin analogue in a concentration ranging from 0.5 to 1, 5 mg / ml.
- the composition is characterized in that it comprises amylin, the amylin receptor agonist or the amylin analogue in a concentration ranging from 0.5 to 1 mg. / ml.
- the composition is characterized in that it comprises amylin, the amylin receptor agonist or the amylin analogue at a concentration of 0.6 mg / ml. .
- the composition is characterized in that it comprises amylin, the amylin receptor agonist or the amylin analogue in a concentration of 0.9 mg / ml.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist, or amylin analog is greater than or equal to 1.
- the co-polyamino acid / amylin molar ratios, agonist at the amylin receptor or amylin analogue are between 1.5 and 75.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 1.8 and 50.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 2 and 35.
- the co-polyamino acid / amylin molar ratios, agonist at the amylin receptor or amylin analogue are between 2.5 and 30. In one embodiment, the co-polyamino acid / amylin molar ratios, agonist at the amylin receptor or amylin analogue are between 3 and 30.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 3.5 and 30.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 4 and 30.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 5 and 30.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 7 and 30.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 9 and 30.
- the polyamino acid / amylin co molar ratios are between 3 and 75.
- the polyamino acid / amylin co molar ratios are between 7 and 50.
- the polyamino acid / amylin co molar ratios are between 10 and 30.
- the polyamino acid / amylin co molar ratios are between 15 and 30.
- the co-polyamino acid / pramlintide molar ratios are between 1.5 and 75.
- the co-polyamino acid / pramlintide molar ratios are between 2 and 50.
- the co-polyamino acid / pramlintide molar ratios are between 3 and 30.
- the co-polyamino acid / pramlintide molar ratios are between 4 and 30. In one embodiment, the polyamino acid / pramlintide co molar ratios are between 5 and 30.
- the polyamino acid / pramlintide co molar ratios are between 8 and 30.
- the co-polyamino acid / pramlintide molar ratios are between 10 and 30.
- the hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between 1.5 and 150.
- the hydrophobic radical Hy / amylin, amylin receptor agonist or amyli analogue molar ratios are between 1.8 and 100.
- the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 2 and 70.
- the hydrophobic radical Hy / amylin, agonist at amylin receptor or amylin analogue molar ratios are between 2.5 and 60.
- the hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between 3 and 60.
- the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 3.5 and 60.
- the hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between 4 and 60.
- the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 5 and 60.
- the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 7 and 60. In one embodiment, the hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between 9 and 60.
- the hydrophobic radical Hy / amylin molar ratios are between 5 and 60.
- the hydrophobic radical Hy / amylin molar ratios are between 10 and 60.
- the hydrophobic radical Hy / amylin molar ratios are between 15 and 60.
- Hy / pramlintide are between 1, 5 and 60.
- the hydrophobic radical Hy / pramlintide molar ratios are between 2 and 60.
- the hydrophobic radical Hy / pramlintide molar ratios are between 3 and 60.
- the hydrophobic radical Hy / pramlintide molar ratios are between 4 and 60.
- the hydrophobic radical Hy / pramlintide molar ratios are between 5 and 60.
- the hydrophobic radical molar ratios [000392] In one embodiment, the hydrophobic radical molar ratios
- Hy / pramlintide are between 8 and 60.
- the hydrophobic radical Hy / pramlintide molar ratios are between 10 and 60.
- the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 1.0 and 70.
- the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 1.2 and 45.
- the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 1.3 and 30. In one embodiment, the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 1.7 and 27.
- the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 2.0 and 27.
- the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 2.3 and 27.
- the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 2.7 and 27.
- the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 3.3 and 27.
- the mass ratios of co-polyaminoacid / amyllne, agonist at the amylin receptor or amylin analogue are between 4.7 and 27.
- the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 6.0 and 27.
- the co-polyamino acid / amylin mass ratios are between 2.0 and 67.
- the co-polyamino acid / amylin mass ratios are between 4.7 and 27.
- the co-polyamino acid / amylin mass ratios are between 6.7 and 27.
- the co-polyamino acid / amylin mass ratios are between 10 and 27.
- the co-polyamino acid / pramlintide mass ratios are between 1.0 and 67.
- the co-polyamino acid / pramlintide mass ratios are between 1.3 and 45. In one embodiment, the polyamino acid / pramlintide mass ratios are between 2.7 and 27.
- the polyamino acid / pramlintide mass ratios are between 3.3 and 27.
- the polyamino acid / pramlintide mass ratios are between 5.3 and 27.
- the co-polyamino acid / pramlintide mass ratios are between 6.7 and 27.
- the composition is characterized in that it further comprises insulin.
- the composition is characterized in that the insulin is a mealtime insulin. Prandial insulins are soluble at pH 7.
- Meal insulin means a so-called fast or "regular" insulin.
- fast prandial insulins are insulins which must respond to the needs caused by the ingestion of proteins and carbohydrates during a meal, they must act in less than 30 minutes.
- the so-called "regular” meal insulin is human insulin.
- the prandial insulin is a recombinant human insulin as described in the European Pharmacopoeia and the American Pharmacopoeia.
- Human insulin is for example marketed under the trademarks Humulin ® (ELI LILLY) and Novolin ® (NOVO NORDISK).
- Fast-acting prandial insulins are insulins which are obtained by recombination and whose primary sequence has been modified to reduce their action time.
- the prandial insulins called fast are selected from the group consisting of insulin lispro (Humalog ®), insulin glulisine (Apidra ®) and insulin aspart (NovoLog ®) .
- the prandial insulin is insulin lispro.
- the mealtime insulin is insulin glulisine.
- the mealtime insulin is insulin aspart.
- the insulin concentration is between 240 and 3000 mM (40 to 500 U / mL).
- the insulin concentration is between 600 and 3000 mM (100 to 500 U / mL).
- the insulin concentration is between 600 and 2400 ⁇ M (100 to 400 U / mL).
- the insulin concentration is between 600 and 1800 ⁇ M (100 to 300 U / mL).
- the insulin concentration is between 600 and 1200 ⁇ M (100 to 200 U / mL).
- the insulin concentration is 600 ⁇ M (100 U / mL).
- the insulin concentration is 1200 ⁇ M (200 U / mL).
- it relates to a pharmaceutical formulation characterized in that the insulin concentration is 1800 ⁇ M (300 U / mL). In one embodiment, it relates to a pharmaceutical formulation characterized in that the insulin concentration is 2400 ⁇ M (400 U / mL).
- the insulin concentration is 3000 mM (500 U / mL).
- the co-polyamino acid / insulin molar ratio is greater than or equal to 1.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 1.5 and 75.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 1.8 and 50.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 2 and 35.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 2.5 and 30.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 3 and 30.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 3.5 and 30.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 4 and 30.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 5 and 30.
- the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 7 and 30. In one embodiment comprising prandial insulin, the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 9 and 30.
- the co-polyamino acid / amylin molar ratios are between 5 and 75.
- the co-polyamino acid / amylin molar ratios are between 10 and 50.
- the co-polyamino acid / amylin molar ratios are between 15 and 30.
- the co-polyamino acid / pramlintide molar ratios are between 1.5 and 75.
- the co-polyamino acid / pramlintide molar ratios are between 2 and 50.
- the co-polyamino acid / pramlintide molar ratios are between 3 and 30.
- the co-polyamino acid / pramlintide molar ratios are between 4 and 30.
- the co-polyamino acid / pramlintide molar ratios are between 5 and 30.
- the co-polyamino acid / pramlintide molar ratios are between 8 and 30.
- the co-polyamino acid / pramlintide molar ratios are between 10 and 30.
- the hydrophobic radical -Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 1.5 and 150.
- the hydrophobic radical molar ratios -Hy / amylin, amylin receptor agonist or amylin analogue are between 1.8 and 100.
- the hydrophobic radical -Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 2 and 70. In one embodiment comprising prandial insulin, the hydrophobic radical -Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 2.5 and 60.
- the hydrophobic radical -Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 3 and 60.
- the hydrophobic radical -Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 3.5 and 60.
- the hydrophobic radical molar ratios -Hy / amylin, amylin receptor agonist or amylin analogue are between 4 and 60.
- the hydrophobic radical -Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 5 and 60.
- the hydrophobic radical -Hy / amylin radical ratios, amylin receptor agonist or amylin analogue are between 7 and 60.
- the hydrophobic radical -Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 9 and 60.
- the hydrophobic radical -Hy / amyline molar ratios are between 5 and 60.
- the hydrophobic radical -Hy / amyline molar ratios are between 10 and 60.
- the hydrophobic radical -Hy / amyline molar ratios are between 15 and 60.
- the hydrophobic radical -Hy / pramlintide molar ratios are between 1.5 and 60.
- the hydrophobic radical -Hy / pramlintide molar ratios are between 2 and 60.
- the hydrophobic radical -Hy / pramlintide molar ratios are between 3 and 60.
- the hydrophobic radical -Hy / pramlintide molar ratios are between 4 and 60. In one embodiment comprising prandial insulin, the hydrophobic radical -Hy / pramlintide molar ratios are between 5 and 60.
- the hydrophobic radical -Hy / pramlintide molar ratios are between 8 and 60.
- the hydrophobic radical -Hy / pramlintide molar ratios are between 10 and 60.
- the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 1.0 and 70.
- the mass ratios co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 1.2 and 45.
- the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 1.3 and 30.
- the mass ratios co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 1.7 and 27.
- the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 2.0 and 27.
- the mass ratios co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 2.3 and 27.
- the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 2.7 and 27.
- the mass ratios co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 3.3 and 27.
- the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 4.7 and 27. In one embodiment comprising prandial insulin, the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 6.0 and 27.
- the co-polyamino acid / amylin mass ratios are between 3.3 and 67.
- the co-polyamino acid / amylin mass ratios are between 6.6 and 27.
- the co-polyamino acid / amylin mass ratios are between 10 and 27.
- the co-polyamino acid / pramlintide mass ratios are between 1.0 and 67.
- the co-polyamino acid / pramlintide mass ratios are between 1.2 and 45.
- the co-polyamino acid / pramlintide mass ratios are between 1.3 and 27.
- the co-polyamino acid / pramlintide mass ratios are between 1.7 and 27.
- the co-polyamino acid / pramlintide mass ratios are between 2.0 and 27.
- the co-polyamino acid / pramlintide mass ratios are between 2.3 and 27.
- the co-polyamino acid / pramlintide mass ratios are between 2.7 and 27.
- the co-polyamino acid / pramlintide mass ratios are between 3.3 and 27.
- the co-polyamino acid / pramlintide mass ratios are between 4.7 and 27.
- the co-polyamino acid / pramlintide mass ratios are between 6.0 and 27.
- GLP-1 RA GLP-1 receptor agonist
- GLP-1, GLP-1 analogs, or GLP-1 RA are said to be "fast”.
- Rapid is understood to mean GLP-1, GLP-1 analogs, or GLP-1 RA, whose apparent half-life of elimination after subcutaneous injection in humans is less than 8 hours, particularly inferior at 5 hours, preferably less than 4 hours or even less than 3 hours, such as exenatide and lixisenatide.
- GLP-1, GLP-1 analogs, or GLP-1 RA are selected from the group consisting of exenatide or Byetta ® (Astra-Zeneca), or the lixisenatide Lyxumia ® (SANOFI), their analogues or derivatives and their pharmaceutically acceptable salts.
- GLP-1, GLP-1 or GLP-1 RA is exenatide or Byetta ®, analogs or derivatives and their pharmaceutically acceptable salts.
- GLP-1, GLP-1 or GLP-1 RA is lixisenatide or Lyxumia ®, analogs or derivatives and their pharmaceutically acceptable salts.
- the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is in a range of 0.01 to 1.0 mg per 100 U of insulin.
- the concentration of exenatide, its analogues or derivatives and their pharmaceutically acceptable salts is from 0.01 to 0.5 mg per 100 U of insulin.
- the concentration of exenatide, its analogues or derivatives and their pharmaceutically acceptable salts is 0.02 to 0.4 mg per 100 U of insulin.
- the concentration of exenatide, its analogues or derivatives and their pharmaceutically acceptable salts is 0.03 to 0.3 mg per 100 U of insulin.
- the concentration of exenatide, its analogues or derivatives and their pharmaceutically acceptable salts is 0.04 to 0.2 mg per 100 U of insulin. In one embodiment, the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is from 0.04 to 0.15 mg per 100 U of insulin.
- the concentration of lixisenatide, its analogues or derivatives and their pharmaceutically acceptable salts is in a range of 0.01 to 1 mg per 100 U of insulin.
- the concentration of lixisenatide, its analogues or derivatives and their pharmaceutically acceptable salts is from 0.01 to 0.5 mg per 100 U of insulin.
- the concentration of lixisenatide, its analogues or derivatives and their pharmaceutically acceptable salts is 0.02 to 0.4 mg per 100 U of insulin.
- the concentration of lixisenatide, its analogues or derivatives and their pharmaceutically acceptable salts is 0.03 to 0.3 mg per 100 U of insulin.
- the concentration of lixisenatide, its analogues or derivatives and their pharmaceutically acceptable salts is 0.04 to 0.2 mg for
- the concentration of lixisenatide, its analogues or derivatives and their pharmaceutically acceptable salts is from 0.04 to 0.15 mg per 100 U of insulin.
- compositions according to the invention are produced by mixing solutions of amylin and commercial solutions of GLP-1, GLP-1 analogue or GLP-1 receptor agonist. 1 RA in volume ratios ranging from 10/90 to 90/10 in the presence of a co-polyamino acid.
- the invention also relates to compositions which further comprise ionic species, said ionic species making it possible to improve the stability of the compositions.
- the invention also relates to the use of ionic species selected from the group of anions, cations and / or zwitterions to improve the physicochemical stability of the compositions.
- the ionic species comprise less than 10 carbon atoms.
- Said ionic species are chosen from the group of anions, cations and / or zwitterions.
- Zwitterion means a species carrying at least one positive charge and at least one negative charge on two non-adjacent atoms.
- Said ionic species are used alone or in a mixture and preferably in a mixture.
- the anions are chosen from organic anions.
- the organic anions comprise less than 10 carbon atoms.
- the organic anions are chosen from the group consisting of acetate, citrate and succinate.
- the anions are chosen from anions of mineral origin.
- the anions of mineral origin are chosen from the group consisting of sulphates, phosphates and halides, especially chlorides.
- the cations are chosen from organic cations.
- the organic cations comprise less than 10 carbon atoms.
- the organic cations are chosen from the group consisting of ammoniums, for example 2-amino-2- (hydroxymethyl) propane-1,3-diol, where the amine is in the form of amines. ammonium.
- the cations are chosen from cations of mineral origin.
- the cations of mineral origin are chosen from the group consisting of zinc, in particular Zn2 + and alkali metals, in particular Na + and K +.
- the zwitterions are chosen from zwitterions of organic origin.
- the zwitterions of organic origin are chosen from amino acids.
- the amino acids are chosen from aliphatic amino acids in the group consisting of glycine, alanine, valine, isoleucine and leucine.
- the amino acids are chosen from cyclic amino acids in the group consisting of proline.
- the amino acids are chosen from hydroxylated or sulfur-containing amino acids in the group consisting of cysteine, serine, threonine, and methionine.
- the amino acids are chosen from aromatic amino acids in the group consisting of phenylalanine, tyrosine and tryptophan.
- the amino acids are chosen from amino acids whose carboxyl function of the side chain is amidated in the group consisting of asparagine and glutamine.
- the zwitterions of organic origin are selected from the group consisting of amino acids having an uncharged side chain.
- the zwitterions of organic origin are chosen from the group consisting of aminodiacides or acidic amino acids.
- aminodiacides are chosen from the group consisting of glutamic acid and aspartic acid, optionally in the form of salts.
- the zwitterions of organic origin are chosen from the group consisting of basic or so-called "cationic" amino acids.
- the so-called "cationic" amino acids are chosen from arginine, histidine and lysine, in particular arginine and lysine.
- the zwitterions comprise as many negative charges as positive charges and therefore a zero overall charge at the isoelectric point and / or at a pH between 6 and 8.
- the ionic species are introduced into the compositions in the form of salts.
- the introduction of these can be in solid form before dissolution in the compositions, or in the form of a solution, in particular of concentrated solution.
- the cations of mineral origin are provided in the form of salts selected from sodium chloride, zinc chloride, sodium phosphate, sodium sulfate, and the like.
- anions of organic origin are provided in the form of salts selected from sodium or potassium citrate, sodium acetate.
- amino acids are added in the form of salts chosen from arginine hydrochloride, histidine hydrochloride or in non-salified form, for example histidine or arginine.
- the total molar concentration of ionic species in the composition is greater than or equal to 10 mM.
- the total molar concentration of ionic species in the composition is greater than or equal to 20 mM.
- the total molar concentration of ionic species in the composition is greater than or equal to 30 mM.
- the total molar concentration of ionic species in the composition is greater than or equal to 50 mM.
- the total molar concentration of ionic species in the composition is greater than or equal to 75 mM.
- the total molar concentration of ionic species in the composition is greater than or equal to 100 mM.
- the total molar concentration of ionic species in the composition is greater than or equal to 200 mM.
- the total molar concentration of ionic species in the composition is greater than or equal to 300 mM.
- the total molar concentration of ionic species in the composition is greater than or equal to 500 mM.
- the total molar concentration of ionic species in the composition is greater than or equal to 600 mM.
- the total molar concentration of ionic species in the composition is greater than or equal to 700 mM.
- the total molar concentration of ionic species in the composition is greater than or equal to 800 mM.
- the total molar concentration of ionic species in the composition is greater than or equal to 900 mM.
- the total molar concentration of ionic species in the composition is less than or equal to 1000 mM.
- the total molar concentration of ionic species in the composition is less than or equal to 1500 mM.
- the total molar concentration of ionic species in the composition is less than or equal to 1200 mM.
- the total molar concentration of ionic species in the composition is less than or equal to 1000 mM.
- the total molar concentration of ionic species in the composition is less than or equal to 900 mM.
- the total molar concentration of ionic species in the composition is less than or equal to 800 mM.
- the total molar concentration of ionic species in the composition is less than or equal to 700 mM.
- the total molar concentration of ionic species in the composition is less than or equal to 600 mM.
- the total molar concentration of ionic species in the composition is less than or equal to 500 mM.
- the total molar concentration of ionic species in the composition is less than or equal to 400 mM.
- the total molar concentration of ionic species in the composition is less than or equal to 300 mM.
- the total molar concentration of ionic species in the composition is less than or equal to 200 mM.
- the total molar concentration of ionic species in the composition is less than or equal to 100 mM.
- the total molar concentration of ionic species in the composition is between 10 and 1000 mM.
- the total molar concentration of ionic species in the composition is between 20 and 1000 mM.
- the total molar concentration of ionic species in the composition is between 30 and 1000 mM.
- the total molar concentration of ionic species in the composition is between 50 and 1000 mM.
- the total molar concentration of ionic species in the composition is between 75 and 1000 mM.
- the total molar concentration of ionic species in the composition is between 100 and 1000 mM.
- the total molar concentration of ionic species in the composition is between 200 and 1000 mM.
- the total molar concentration of ionic species in the composition is between 300 and 1000 mM.
- the total molar concentration of ionic species in the composition is between 400 and 1000 mM.
- the total molar concentration of ionic species in the composition is between 500 and 1000 mM.
- the total molar concentration of ionic species in the composition is between 600 and 1000 mM.
- the total molar concentration of ionic species in the composition is between 10 and 900 mM.
- the total molar concentration of ionic species in the composition is between 20 and 900 mM.
- the total molar concentration of ionic species in the composition is between 30 and 900 mM.
- the total molar concentration of ionic species in the composition is between 50 and 900 mM.
- the total molar concentration of ionic species in the composition is between 75 and 900 mM.
- the total molar concentration of ionic species in the composition is between 100 and 900 mM.
- the total molar concentration of ionic species in the composition is between 200 and 900 mM.
- the total molar concentration of ionic species in the composition is between 300 and 900 mM.
- the total molar concentration of ionic species in the composition is between 400 and 900 mM. [000601] In one embodiment, the total molar concentration of ionic species in the composition is between 500 and 900 mM.
- the total molar concentration of ionic species in the composition is between 600 and 900 mM.
- the total molar concentration of ionic species in the composition is between 10 and 800 mM.
- the total molar concentration of ionic species in the composition is between 20 and 800 mM.
- the total molar concentration of ionic species in the composition is between 30 and 800 mM.
- the total molar concentration of ionic species in the composition is between 50 and 800 mM.
- the total molar concentration of ionic species in the composition is between 75 and 800 mM.
- the total molar concentration of ionic species in the composition is between 100 and 800 mM.
- the total molar concentration of ionic species in the composition is between 200 and 800 mM.
- the total molar concentration of ionic species in the composition is between 300 and 800 mM.
- the total molar concentration of ionic species in the composition is between 400 and 800 mM.
- the total molar concentration of ionic species in the composition is between 500 and 800 mM.
- the total molar concentration of ionic species in the composition is between 600 and 800 mM.
- the total molar concentration of ionic species in the composition is between 10 and 700 mM.
- the total molar concentration of ionic species in the composition is between 20 and 700 mM.
- the total molar concentration of ionic species in the composition is between 30 and 700 mM.
- the total molar concentration of ionic species in the composition is between 50 and 700 mM.
- the total molar concentration of ionic species in the composition is between 75 and 700 mM.
- the total molar concentration of ionic species in the composition is between 100 and 700 mM.
- the total molar concentration of ionic species in the composition is between 200 and 700 mM.
- the total molar concentration of ionic species in the composition is between 300 and 700 mM.
- the total molar concentration of ionic species in the composition is between 400 and 700 mM.
- the total molar concentration of ionic species in the composition is between 500 and 700 mM.
- the total molar concentration of ionic species in the composition is between 600 and 700 mM.
- the total molar concentration of ionic species in the composition is between 10 and 600 mM.
- the total molar concentration of ionic species in the composition is between 20 and 600 mM.
- the total molar concentration of ionic species in the composition is between 30 and 600 mM.
- the total molar concentration of ionic species in the composition is between 50 and 600 mM.
- the total molar concentration of ionic species in the composition is between 75 and 600 mM.
- the total molar concentration of ionic species in the composition is between 100 and 600 mM.
- the total molar concentration of ionic species in the composition is between 200 and 600 mM.
- the total molar concentration of ionic species in the composition is between 300 and 600 mM.
- the total molar concentration of ionic species in the composition is between 400 and 600 mM.
- the total molar concentration of ionic species in the composition is between 500 and 600 mM.
- the total molar concentration of ionic species in the composition is between 10 and 500 mM.
- the total molar concentration of ionic species in the composition is between 20 and 500 mM.
- the total molar concentration of ionic species in the composition is between 30 and 500 mM.
- the total molar concentration of ionic species in the composition is between 50 and 500 mM.
- the total molar concentration of ionic species in the composition is between 75 and 500 mM.
- the total molar concentration of ionic species in the composition is between 100 and 500 mM.
- the total molar concentration of ionic species in the composition is between 200 and 500 mM.
- the total molar concentration of ionic species in the composition is between 300 and 500 mM.
- the total molar concentration of ionic species in the composition is between 400 and 500 mM.
- the total molar concentration of ionic species in the composition is between 10 and 400 mM.
- the total molar concentration of ionic species in the composition is between 20 and 400 mM.
- the total molar concentration of ionic species in the composition is between 30 and 400 mM.
- the total molar concentration of ionic species in the composition is between 50 and 400 mM.
- the total molar concentration of ionic species in the composition is between 75 and 400 mM.
- the total molar concentration of ionic species in the composition is between 100 and 400 mM.
- the total molar concentration of ionic species in the composition is between 200 and 400 mM.
- the total molar concentration of ionic species in the composition is between 300 and 400 mM. In one embodiment, the total molar concentration of ionic species in the composition is between 10 and 300 mM.
- the total molar concentration of ionic species in the composition is between 20 and 300 mM.
- the total molar concentration of ionic species in the composition is between 30 and 300 mM.
- the total molar concentration of ionic species in the composition is between 50 and 300 mM.
- the total molar concentration of ionic species in the composition is between 75 and 300 mM.
- the total molar concentration of ionic species in the composition is between 100 and 300 mM.
- the total molar concentration of ionic species in the composition is between 200 and 300 mM.
- the total molar concentration of ionic species in the composition is between 10 and 200 mM.
- the total molar concentration of ionic species in the composition is between 20 and 200 mM.
- the total molar concentration of ionic species in the composition is between 30 and 200 mM.
- the total molar concentration of ionic species in the composition is between 50 and 200 mM.
- the total molar concentration of ionic species in the composition is between 75 and 200 mM.
- the total molar concentration of ionic species in the composition is between 100 and 200 mM.
- the total molar concentration of ionic species in the composition is between 10 and 100 mM.
- the total molar concentration of ionic species in the composition is between 20 and 100 mM.
- the total molar concentration of ionic species in the composition is between 30 and 100 mM.
- the total molar concentration of ionic species in the composition is between 50 and 100 mM. In one embodiment, the total molar concentration of ionic species in the composition is between 75 and 100 mM.
- the total molar concentration of ionic species in the composition is between 10 and 75 mM.
- the total molar concentration of ionic species in the composition is between 20 and 75 mM.
- the total molar concentration of ionic species in the composition is between 30 and 75 mM.
- the total molar concentration of ionic species in the composition is between 50 and 75 mM.
- the total molar concentration of ionic species in the composition is between 10 and 50 mM.
- the total molar concentration of ionic species in the composition is between 20 and 50 mM.
- the total molar concentration of ionic species in the composition is between 30 and 50 mM.
- said ionic species are present in a concentration ranging from 5 to 400 mM.
- said ionic species are present in a concentration ranging from 5 to 300 mM.
- said ionic species are present in a concentration ranging from 5 to 200 mM.
- said ionic species are present in a concentration ranging from 5 to 100 mM.
- said ionic species are present in a concentration ranging from 5 to 75 mM.
- said ionic species are present in a concentration ranging from 5 to 50 mM.
- said ionic species are present in a concentration ranging from 5 to 25 mM.
- said ionic species are present in a concentration ranging from 5 to 20 mM.
- said ionic species are present in a concentration ranging from 5 to 10 mM. In one embodiment, said ionic species are present in a concentration ranging from 10 to 400 mM.
- said ionic species are present in a concentration ranging from 10 to 300 mM.
- said ionic species are present in a concentration ranging from 10 to 200 mM.
- said ionic species are present in a concentration ranging from 10 to 100 mM.
- said ionic species are present in a concentration ranging from 10 to 75 mM.
- said ionic species are present in a concentration ranging from 10 to 50 mM.
- said ionic species are present in a concentration ranging from 10 to 25 mM.
- said ionic species are present in a concentration ranging from 10 to 20 mM.
- said ionic species are present in a concentration ranging from 20 to 300 mM.
- said ionic species are present in a concentration ranging from 20 to 200 mM.
- said ionic species are present in a concentration ranging from 20 to 100 mM.
- said ionic species are present in a concentration ranging from 20 to 75 mM.
- said ionic species are present in a concentration ranging from 20 to 50 mM.
- said ionic species are present in a concentration ranging from 20 to 25 mM.
- said ionic species are present in a concentration ranging from 50 to 300 mM.
- said ionic species are present in a concentration ranging from 50 to 200 mM.
- said ionic species are present in a concentration ranging from 50 to 100 mM. In one embodiment, said ionic species are present in a concentration ranging from 50 to 75 mM.
- its molar concentration within the composition may be between 0.25 and 20 mM, in particular between 0.25 and 10 mM or between 0.25 and 5 mM.
- the composition comprises zinc.
- the composition comprises from 0.2 to 2 mM of zinc.
- the composition comprises NaCl.
- the composition comprises from 10 to 250 mM of
- the composition comprises from 15 to 200 mM NaCl.
- the composition comprises from 20 to 150 mM NaCl.
- the composition comprises from 25 to 100 mM NaCl.
- compositions according to the invention also comprise zinc salts at a concentration of between 0 and 500 mM per 100 U of insulin.
- compositions according to the invention also comprise zinc salts at a concentration of between 0 and 400 ⁇ M per 100 U of insulin.
- compositions according to the invention also comprise zinc salts at a concentration of between 0 and 300 ⁇ M per 100 U of insulin.
- compositions according to the invention also comprise zinc salts at a concentration of between 0 and 200 ⁇ M per 100 U of insulin.
- compositions according to the invention also comprise zinc salts at a concentration of between 0 and 100 ⁇ M per 100 U of insulin.
- compositions according to the invention also comprise buffers.
- compositions according to the invention comprise buffers at concentrations of between 0 and 100 mM. In one embodiment, the compositions according to the invention comprise buffers at concentrations of between 15 and 50 mM.
- compositions according to the invention comprise a buffer selected from the group consisting of a phosphate buffer, Tris (trishydroxymethylaminomethane) and sodium citrate.
- the buffer is sodium phosphate.
- the buffer is Tris
- the buffer is sodium citrate.
- compositions according to the invention further comprise preservatives.
- the preservatives are selected from the group consisting of m-cresol and phenol, alone or in admixture.
- the concentration of the preservatives is between 10 and 50 mM.
- the concentration of the preservatives is between 10 and 40 mM.
- compositions according to the invention also comprise a surfactant.
- the surfactant is selected from the group consisting of propylene glycol and polysorbate.
- compositions according to the invention may further comprise additives such as tonicity agents.
- the tonicity agents are selected from the group consisting of glycerine, sodium chloride, mannitol and glycine.
- compositions according to the invention may furthermore comprise all the excipients compatible with the pharmacopoeia and compatible with the insulins used at the concentrations of use.
- the invention also relates to a pharmaceutical formulation according to the invention, characterized in that it is obtained by drying and / or lyophilization.
- the modes of administration envisaged are intravenous, subcutaneous, intradermal or intramuscular.
- the transdermal, oral, nasal, vaginal, ocular, oral, and pulmonary routes of administration are also contemplated.
- the invention also relates to a pump, implantable or transportable, comprising a composition according to the invention.
- the invention further relates to the use of a composition according to the invention intended to be placed in a pump, implantable or transportable.
- the invention also relates to single-dose formulations at pH between 6.0 and 8.0 comprising amylin, an amylin receptor agonist or an amylin analogue and a co-polyamino acid according to the invention. invention.
- the invention also relates to single-dose formulations having a pH of between 6.0 and 8.0, comprising amylin, an amylin receptor agonist or amylin analogue, a co-polyamino acid according to the invention. and a GLP-1, a GLP-1 analogue or a GLP-1 RA, as defined above.
- the invention also relates to single-dose formulations at a pH of between 6.6 and 7.8 comprising amylin, an amylin receptor agonist or an amylin analogue and a co-polyamino acid according to the invention. invention.
- the invention also relates to single-dose formulations at a pH of between 6.6 and 7.8 comprising amylin, an amylin receptor agonist or an amylin analogue, a co-polyamino acid according to the invention. invention and a mealtime insulin as defined above.
- the invention also relates to single-dose formulations having a pH of between 6.6 and 7.6 comprising amylin, an amylin receptor agonist or an amylin analogue and a co-polyamino acid according to the invention. invention.
- the invention also relates to single-dose formulations having a pH of between 6.6 and 7.6, comprising amylin, an amylin receptor agonist or an amylin analogue, a co-polyamino acid according to the invention. invention and a mealtime insulin as defined above.
- the single-dose formulations further comprise a co-polyamino acid as defined above.
- the formulations are in the form of an injectable solution.
- the preparation of a composition according to the invention has the advantage of being able to be carried out by simple mixing of an aqueous solution of amylin, a amylin receptor agonist or an amylin analogue, and a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical according to the invention, in aqueous solution or in freeze-dried form. If necessary, the pH of the preparation is adjusted to pH between 6 and 8.
- the preparation of a composition according to the invention has the advantage of being able to be carried out by simple mixing of an aqueous solution of amylin, of an agonist with the amylin receptor or of a d-type analogue.
- amylin, prandial insulin, and a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical according to the invention, in aqueous solution or in freeze-dried form. If necessary, the pH of the preparation is adjusted to pH between 6 and 8.
- the mixture of prandial insulin and co-polyamino acid is concentrated by ultrafiltration.
- composition of the mixture is adjusted by excipients such as glycerin, m-cresol, zinc chloride, and polysorbate (Tween ®) by addition of concentrated solutions of these excipients in the mixture.
- excipients such as glycerin, m-cresol, zinc chloride, and polysorbate (Tween ®)
- pH of the preparation is adjusted to pH between 6 and 8.
- compositions are characterized in that said compositions have a stability measured by ThT greater than that of a reference composition comprising amylin, an amylin receptor agonist or the like. of amylin but not comprising a co-polyamino acid bearing carboxylate charges and hydrophobic radicals -Hy.
- compositions are characterized in that said compositions have a stability measured by ThT greater than that of a reference composition comprising amylin, an amylin receptor agonist or the like. of amylin in combination with insulin but not comprising a co-polyamino acid bearing carboxylate charges and hydrophobic radicals -Hy.
- compositions are characterized in that said compositions have a stability measured by ThT greater than that of a reference composition comprising amylin, an amylin receptor agonist or the like. amylin in combination with GLP-1, GLP-1 analog or GLP-1 receptor agonist, but not comprising a co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy.
- compositions are characterized in that said compositions have a stability measured by ThT greater than that of a reference composition comprising amylin, an amylin receptor agonist or the like.
- amylin in combination with insulin and GLP-1, a GLP-1 analogue or a GLP-1 receptor agonist, but not comprising a co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy.
- the invention also relates to a use of a co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy for stabilizing a composition comprising amylin, an amylin receptor agonist or an amylin analogue.
- the invention also relates to a use of a co-polyamino acid bearing carboxylate charges and Hy hydrophobic radicals for stabilizing a composition comprising amylin, an amylin receptor agonist or an amylin analogue. and a mealtime insulin, and optionally a GLP-1, GLP-1 analogue, or GLP-1 receptor agonist.
- the present invention relates to a composition stabilization method comprising amylin, an amylin receptor agonist or an amylin analogue or a composition stabilizing method comprising amylin, an agonist at the receptor.
- amylin or an amylin analogue and a mealtime insulin and optionally a GLP-1, GLP-1 analogue or GLP-1 receptor agonist.
- Molecule 1 i Product obtained by the reaction between decanoyl chloride and L-proline.
- the reaction medium is filtered and introduced into a solution of L-lysine hydrochloride (30.51 g, 167.05 mmol) and / V, / V-diisopropylethylamine (DIPEA, 97, 16 g, 751.71 mmol) in water (66 mL) and the mixture is stirred for 48 h at 20 ° C. After concentration under reduced pressure, water (360 ml) is added and the mixture obtained is treated by successive addition of ethyl acetate (AcOEt, 500 ml) and then a 5% aqueous solution of Na2CO3 (1 L).
- DIPEA / V, / V-diisopropylethylamine
- the aqueous phase is then washed once more with AcOEt (200 mL), acidified by addition of a 6N aqueous HCl solution and the product is extracted with dichloromethane (DCM, 3 ⁇ 250 mL).
- DCM dichloromethane
- the organic phase is dried over NaiSC, filtered and concentrated in vacuo.
- the white solid obtained after crystallization in AcOEt is solubilized in DCM (400 mL), the organic phase is washed with an aqueous solution of 1N HCl (200 mL) and then a saturated aqueous solution of NaCl (200 mL), dried on a 2 S0 4 , filtered and concentrated under vacuum.
- a white solid of the A2 molecule is obtained after crystallization in AcOEt.
- Molecule 2 Product obtained by the reaction between lauroyl chloride and L-proline.
- Molecule 3 i Product obtained by the reaction between Fmoc-Lys (Fmoc) -OH and 2-Cl-trityl chloride resin.
- Molecule 4 Product obtained by reaction between the molecule 3 and a mixture of DMF / piperidine 80: 20.
- the molecule 3 previously washed with DMF, is treated with a mixture of DMF / piperidine 80: 20 (60 mL). After 30 minutes stirring at room temperature, the resin is filtered, washed successively with DMF (3 x 60 mL), isopropanol (1 x 60 mL) and DCM (3 x 60 mL).
- Molecule 5 Product obtained by reaction between the molecule 4 and 8- (9-Fluorenylmethyloxycarbonylamino) -3,6-dioxaoctanoic acid (Fmoc-020c-OH).
- Molecule 6 Product obtained by reaction between the molecule 5 and a mixture
- the molecule 6 is obtained.
- Molecule 7 i Product obtained by reaction between molecule 6 and lauric acid.
- Molecule 8 Product obtained by reaction between the molecule 7 and a mixture of dichloromethane / 1,1,3,3,3-hexafluoro-2-propanol (HFIP) 80: 20.
- the molecule 7 is treated with a mixture of dichloromethane / 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) 80: 20 (60 mL). After stirring for 20 minutes at room temperature, the resin is filtered and washed with dichloromethane (2 ⁇ 60 mL). The solvents are evaporated under reduced pressure. Two coevaporations are then carried out on the residue with dichloromethane (60 ml) and then diisopropyl ether (60 ml). A white solid of molecule 8 is obtained after recrystallization in acetonitrile. Yield: 2.63 g (66% over 6 steps)
- Molecule 9 Product obtained by the reaction between molecule 8 and N-Boc ethylenediamine. To a solution of the molecule 8 (2.63 g, 3.29 mmol) in chloroform (20 ml) at room temperature are successively added N-hydroxybenzotriazole (HOBt, 654 mg, 4.27 mmol) and N-Boc ethylenediamine (BocEDA, 580 mg, 3.62 mmol). The mixture is cooled to 0 ° C and then (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC, 819 mg, 4.27 mmol) is added. The reaction medium is stirred for 15 min at 0 ° C.
- Molecule 10 Product obtained by hydrogenation of retinoic acid.
- a solution of retinoic acid (19.0 g, 63.24 mmol) in methanol (450 mL) in the presence of 10% palladium on carbon (1.9 g) is placed under a hydrogen atmosphere (1). atm) at room temperature. After a night, the middle The reaction mixture is sintered and the filtrate is concentrated under reduced pressure. A colorless oil of molecule 10 is obtained.
- Molecule 11 Product obtained by coupling between Boc-1-amino-4,7,10-trioxa-13-tridecane amine (BocTOTA) and molecule 10.
- Molecule 12 i Product obtained by the reaction between molecule 4 and Fmoc-Glu (OtBu) -OH.
- the molecule 12 previously washed with DMF, is treated with a DMF / morpholine mixture 50:50 (60 mL). After stirring for 1 h at room temperature, the resin is filtered, washed successively with DMF (3 x 60 mL), isopropanol (1 x 60 mL) and dichloromethane (3 x 60 mL).
- Molecule 14 Product obtained by the reaction between its molecule Al and the molecule 13.
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Abstract
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US201762606139P | 2017-12-07 | 2017-12-07 | |
EP18181028 | 2018-06-29 | ||
PCT/EP2018/083964 WO2019110797A1 (fr) | 2017-12-07 | 2018-12-07 | Compositions sous forme d'une solution aqueuse injectable comprenant de l'amyline, un agoniste au recepteur de l'amyline ou un analogue d'amyline et un co-polyaminoacide |
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EP3740195A1 true EP3740195A1 (fr) | 2020-11-25 |
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EP18811583.6A Pending EP3740195A1 (fr) | 2017-12-07 | 2018-12-07 | Compositions sous forme d'une solution aqueuse injectable comprenant de l'amyline, un agoniste au recepteur de l'amyline ou un analogue d'amyline et un co-polyaminoacide |
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US (2) | US11173109B2 (fr) |
EP (1) | EP3740195A1 (fr) |
CN (1) | CN111565710A (fr) |
WO (1) | WO2019110797A1 (fr) |
Families Citing this family (8)
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EP3740229A1 (fr) | 2017-12-07 | 2020-11-25 | Adocia | Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes |
JP2021505605A (ja) | 2017-12-07 | 2021-02-18 | アドシア | 5.8〜8.5のpIを有する少なくとも1つの基礎インスリン、および、カルボキシレート電荷および疎水性ラジカルを有するコポリアミノ酸を含むpH7を有する注射溶液 |
EP3858373A1 (fr) | 2020-01-31 | 2021-08-04 | Adocia | Compositions comprenant au moins un agoniste au récepteur de l'amyline et un agoniste du récepteur glp-1 |
EP4091625A1 (fr) | 2021-05-22 | 2022-11-23 | Adocia | Compositions comprenant des hormones à brève durée d'action pour traiter ou prévenir l'obésité et pompes comprenant ladite composition |
WO2022248419A2 (fr) | 2021-05-22 | 2022-12-01 | Adocia | Compositions comprenant des hormones à action courte pour le traitement ou la prévention de l'obésité et pompes comprenant ladite composition |
EP4144362A1 (fr) | 2021-09-06 | 2023-03-08 | Adocia | Compositions comprenant des hormones à brève durée d'action pour traiter ou prévenir l'obésité et pompes comprenant ladite composition |
EP4129324A1 (fr) | 2021-08-02 | 2023-02-08 | Adocia | Compositions comprenant au moins un agoniste au récepteur de l'amyline et un agoniste du récepteur glp-1 |
EP4342486A1 (fr) | 2022-09-20 | 2024-03-27 | Adocia | Compositions comprenant au moins une insuline et un agoniste du récepteur de l'amyline pour le traitement du diabète |
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GB8720115D0 (en) | 1987-08-26 | 1987-09-30 | Cooper G J S | Treatment of diabetes mellitus |
IT1219712B (it) * | 1988-06-14 | 1990-05-24 | Ausimont Spa | Perossiacidi eterociclici con eteroatomo "n" ammidico |
US5234906A (en) | 1991-01-10 | 1993-08-10 | Amylin Pharmaceuticals, Inc. | Hyperglycemic compositions |
FR2672598A1 (fr) * | 1991-02-11 | 1992-08-14 | Adir | Nouveaux inhibiteurs de n-myristoyltransferase, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
HU222249B1 (hu) | 1991-03-08 | 2003-05-28 | Amylin Pharmaceuticals Inc. | Eljárás amilin agonista peptidszármazékok és ezeket tartalmazó gyógyszerkészítmények előállítására |
CA2171207C (fr) | 1993-09-07 | 2010-03-30 | Orville G. Kolterman | Methodes pour la regulation de la motilite gastro-intestinale |
US6410511B2 (en) | 1997-01-08 | 2002-06-25 | Amylin Pharmaceuticals, Inc. | Formulations for amylin agonist peptides |
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FR2801226B1 (fr) | 1999-11-23 | 2002-01-25 | Flamel Tech Sa | Suspension colloidale de particules submicroniques de vectorisation de principes actifs et son mode de preparation |
FR2840614B1 (fr) | 2002-06-07 | 2004-08-27 | Flamel Tech Sa | Polyaminoacides fonctionnalises par de l'alpha-tocopherol et leurs applications notamment therapeutiques |
FR2843117B1 (fr) * | 2002-07-30 | 2004-10-15 | Flamel Tech Sa | Polyaminoacides fonctionnalises par au moins un groupement hydrophobe et leurs applications notamment therapeutiques |
FR2855521B1 (fr) | 2003-05-28 | 2005-08-05 | Flamel Tech Sa | Polyaminoacides fonctionnalises par au moins un groupement h ydrophobe et leurs applications notamment therapeutiques. |
FR2860516B1 (fr) * | 2003-10-03 | 2006-01-13 | Flamel Tech Sa | Homopolyaminoacides telecheliques fonctionnalises par des groupements hydrophobes et leurs applications notamment therapeutiques |
FR2873704B1 (fr) * | 2004-07-30 | 2006-12-08 | Flamel Technologies Sa | Polyaminoacides fonctionnalises par des greffons hydrophobes portant une charge anionique et leurs applications notamment therapeutiques |
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JP5312054B2 (ja) | 2006-03-15 | 2013-10-09 | ノボ・ノルデイスク・エー/エス | アミリンとインスリンの混合物 |
FR2910318B1 (fr) | 2006-12-20 | 2009-07-03 | Flamel Technologies Sa | Dispersion de polyaminoacides dans une phase lipidique continue. |
ES2785056T3 (es) | 2007-07-02 | 2020-10-05 | Hoffmann La Roche | Un dispositivo para la administración de fármacos |
US20110082080A1 (en) * | 2007-10-12 | 2011-04-07 | Curedm Group Holdings, Llc | Compositions and methods of using the human proislet peptide receptor |
EP2078713A1 (fr) | 2007-12-28 | 2009-07-15 | QuoNova GmbH | Inhibiteurs de formation de biofilm de bactérie gram-positive et gram-négative |
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CN107029212A (zh) * | 2010-05-10 | 2017-08-11 | 诺沃—诺迪斯克有限公司 | 用于制备胰岛素‑锌复合物的方法 |
TWI480070B (zh) * | 2011-04-21 | 2015-04-11 | Univ Kaohsiung Medical | 具礦質親和能力之多歧狀胜肽構型 |
ES2574761T3 (es) | 2011-10-31 | 2016-06-21 | Xeris Pharmaceuticals, Inc. | Formulaciones para el tratamiento de la diabetes |
FR2985428B1 (fr) | 2012-01-09 | 2016-05-27 | Adocia | Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un polyaminoacide substitue |
FR2985429B1 (fr) * | 2012-01-09 | 2016-07-29 | Adocia | Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un polyaminoacide substitue obtenu par un procede de polymerisation controle |
CN107583039A (zh) | 2012-01-09 | 2018-01-16 | 阿道恰公司 | Ph为7且至少含pi为5.8至8.5之基础胰岛素和取代共聚(氨基酸)的可注射溶液 |
EP3424537B1 (fr) * | 2014-02-03 | 2021-01-13 | Eidgenössiche Technische Hochschule Zürich | Conjugués de médicaments à petites molécules |
FR3052072A1 (fr) | 2016-06-07 | 2017-12-08 | Adocia | Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes |
CN109562064A (zh) | 2016-06-07 | 2019-04-02 | 阿道恰公司 | 包含人胰高血糖素和统计共聚氨基酸的可注射水溶液形式的组合物 |
EP3562500B1 (fr) | 2016-12-27 | 2023-07-19 | Adocia | Compositions sous forme de solution aqueuse injectable comprenant de l'amyline, un agoniste au récepteur de l'amyline ou un analogue d'amyline et un co-polyaminoacide |
-
2018
- 2018-12-07 EP EP18811583.6A patent/EP3740195A1/fr active Pending
- 2018-12-07 WO PCT/EP2018/083964 patent/WO2019110797A1/fr unknown
- 2018-12-07 CN CN201880085885.6A patent/CN111565710A/zh active Pending
- 2018-12-07 US US16/213,776 patent/US11173109B2/en active Active
-
2021
- 2021-08-12 US US17/400,617 patent/US20220409523A1/en active Pending
Also Published As
Publication number | Publication date |
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WO2019110797A8 (fr) | 2019-09-19 |
US20220409523A1 (en) | 2022-12-29 |
US20190274954A1 (en) | 2019-09-12 |
WO2019110797A1 (fr) | 2019-06-13 |
CN111565710A (zh) | 2020-08-21 |
US11173109B2 (en) | 2021-11-16 |
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