EP2828297A1 - Oligosaccharides fonctionnalisés - Google Patents
Oligosaccharides fonctionnalisésInfo
- Publication number
- EP2828297A1 EP2828297A1 EP12726819.1A EP12726819A EP2828297A1 EP 2828297 A1 EP2828297 A1 EP 2828297A1 EP 12726819 A EP12726819 A EP 12726819A EP 2828297 A1 EP2828297 A1 EP 2828297A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- sodium
- functionalized
- acid
- oligosaccharide
- aspartate
- 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.)
- Withdrawn
Links
- 229920001542 oligosaccharide Polymers 0.000 title claims abstract description 110
- 150000002482 oligosaccharides Chemical class 0.000 title claims abstract description 108
- 229920002307 Dextran Polymers 0.000 claims abstract description 40
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 6
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 6
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 6
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 4
- 102000003886 Glycoproteins Human genes 0.000 claims abstract description 3
- 108090000288 Glycoproteins Proteins 0.000 claims abstract description 3
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 3
- 239000011734 sodium Substances 0.000 claims description 56
- 229910052708 sodium Inorganic materials 0.000 claims description 55
- 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 claims description 53
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 51
- 238000006467 substitution reaction Methods 0.000 claims description 44
- 239000002253 acid Substances 0.000 claims description 36
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 32
- 229940009098 aspartate Drugs 0.000 claims description 29
- 238000006116 polymerization reaction Methods 0.000 claims description 22
- 125000000539 amino acid group Chemical group 0.000 claims description 21
- -1 dioctyl aspartate Chemical compound 0.000 claims description 20
- 230000002209 hydrophobic effect Effects 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 229960005190 phenylalanine Drugs 0.000 claims description 17
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 16
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 15
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 14
- VGALFAWDSNRXJK-VIFPVBQESA-N L-aspartic acid beta-benzyl ester Chemical compound OC(=O)[C@@H](N)CC(=O)OCC1=CC=CC=C1 VGALFAWDSNRXJK-VIFPVBQESA-N 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 229940024606 amino acid Drugs 0.000 claims description 8
- 235000001014 amino acid Nutrition 0.000 claims description 8
- 150000001413 amino acids Chemical class 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- 150000001371 alpha-amino acids Chemical class 0.000 claims description 6
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 6
- 235000003704 aspartic acid Nutrition 0.000 claims description 6
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 6
- 150000001768 cations Chemical class 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- CBFCDTFDPHXCNY-UHFFFAOYSA-N octyldodecane Natural products CCCCCCCCCCCCCCCCCCCC CBFCDTFDPHXCNY-UHFFFAOYSA-N 0.000 claims description 6
- ZJBSYAFNSOWCMY-INIZCTEOSA-N octyl (2s)-2-amino-3-phenylpropanoate Chemical compound CCCCCCCCOC(=O)[C@@H](N)CC1=CC=CC=C1 ZJBSYAFNSOWCMY-INIZCTEOSA-N 0.000 claims description 5
- 235000018102 proteins Nutrition 0.000 claims description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical group 0.000 claims description 4
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 3
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 3
- RSDAUPFJPLUQDZ-RPLWDSOUSA-M [Na+].NC(O)=O.OC(=O)[C@@H](N)CC(O)=O.[O-]C(=O)[C@@H](N)CC1=CC=CC=C1 Chemical group [Na+].NC(O)=O.OC(=O)[C@@H](N)CC(O)=O.[O-]C(=O)[C@@H](N)CC1=CC=CC=C1 RSDAUPFJPLUQDZ-RPLWDSOUSA-M 0.000 claims description 3
- 235000005772 leucine Nutrition 0.000 claims description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 2
- 235000004279 alanine Nutrition 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 235000014705 isoleucine Nutrition 0.000 claims description 2
- 229960000310 isoleucine Drugs 0.000 claims description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 2
- 235000018977 lysine Nutrition 0.000 claims description 2
- 235000004400 serine Nutrition 0.000 claims description 2
- 239000004474 valine Substances 0.000 claims description 2
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 44
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 230000008569 process Effects 0.000 description 19
- 150000003254 radicals Chemical class 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 13
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- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 12
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- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 6
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- CJGXMNONHNZEQQ-JTQLQIEISA-N ethyl (2s)-2-amino-3-phenylpropanoate Chemical compound CCOC(=O)[C@@H](N)CC1=CC=CC=C1 CJGXMNONHNZEQQ-JTQLQIEISA-N 0.000 description 5
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- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
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- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- GYSCBCSGKXNZRH-UHFFFAOYSA-N 1-benzothiophene-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=CC2=C1 GYSCBCSGKXNZRH-UHFFFAOYSA-N 0.000 description 1
- SOHLZANWVLCPHK-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxo-4-phenylmethoxybutanoic acid Chemical compound CC(C)(C)OC(=O)NC(C(O)=O)CC(=O)OCC1=CC=CC=C1 SOHLZANWVLCPHK-UHFFFAOYSA-N 0.000 description 1
- TZYRSLHNPKPEFV-UHFFFAOYSA-N 2-ethyl-1-butanol Chemical compound CCC(CC)CO TZYRSLHNPKPEFV-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- OHXPGWPVLFPUSM-KLRNGDHRSA-N 3,7,12-trioxo-5beta-cholanic acid Chemical compound C1CC(=O)C[C@H]2CC(=O)[C@H]3[C@@H]4CC[C@H]([C@@H](CCC(O)=O)C)[C@@]4(C)C(=O)C[C@@H]3[C@]21C OHXPGWPVLFPUSM-KLRNGDHRSA-N 0.000 description 1
- 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 compound 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 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- YWWVWXASSLXJHU-UHFFFAOYSA-N 9E-tetradecenoic acid Natural products CCCCC=CCCCCCCCC(O)=O YWWVWXASSLXJHU-UHFFFAOYSA-N 0.000 description 1
- 235000021357 Behenic acid Nutrition 0.000 description 1
- DPUOLQHDNGRHBS-UHFFFAOYSA-N Brassidinsaeure Natural products CCCCCCCCC=CCCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-UHFFFAOYSA-N 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- URXZXNYJPAJJOQ-UHFFFAOYSA-N Erucic acid Natural products CCCCCCC=CCCCCCCCCCCCC(O)=O URXZXNYJPAJJOQ-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 235000021353 Lignoceric acid Nutrition 0.000 description 1
- CQXMAMUUWHYSIY-UHFFFAOYSA-N Lignoceric acid Natural products CCCCCCCCCCCCCCCCCCCCCCCC(=O)OCCC1=CC=C(O)C=C1 CQXMAMUUWHYSIY-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 235000021319 Palmitoleic acid Nutrition 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 229940116226 behenic acid Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 1
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- SECPZKHBENQXJG-UHFFFAOYSA-N cis-palmitoleic acid Natural products CCCCCCC=CCCCCCCCC(O)=O SECPZKHBENQXJG-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960002997 dehydrocholic acid Drugs 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 1
- 229940090949 docosahexaenoic acid Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 1
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 1
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- DPUOLQHDNGRHBS-KTKRTIGZSA-N erucic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-KTKRTIGZSA-N 0.000 description 1
- FPFQPLFYTKMCHN-PPHPATTJSA-N ethyl (2s)-2-amino-3-phenylpropanoate;hydron;chloride Chemical compound Cl.CCOC(=O)[C@@H](N)CC1=CC=CC=C1 FPFQPLFYTKMCHN-PPHPATTJSA-N 0.000 description 1
- FARYTWBWLZAXNK-WAYWQWQTSA-N ethyl (z)-3-(methylamino)but-2-enoate Chemical compound CCOC(=O)\C=C(\C)NC FARYTWBWLZAXNK-WAYWQWQTSA-N 0.000 description 1
- DUVOZUPPHBRJJO-UHFFFAOYSA-N ethyl 2-isocyanatoacetate Chemical compound CCOC(=O)CN=C=O DUVOZUPPHBRJJO-UHFFFAOYSA-N 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-M phenylalaninate Chemical compound [O-]C(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-M 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- ZRVUAXXSASAVFG-QRPNPIFTSA-M sodium;(2s)-2-amino-3-phenylpropanoate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CC1=CC=CC=C1 ZRVUAXXSASAVFG-QRPNPIFTSA-M 0.000 description 1
- KFDFYCRDUBAKHD-UHFFFAOYSA-M sodium;carbamate Chemical compound [Na+].NC([O-])=O KFDFYCRDUBAKHD-UHFFFAOYSA-M 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000002640 tocopherol group Chemical class 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
Definitions
- the present invention relates to anionic oligosaccharides for therapeutic and / or prophylactic use, for the administration of active principle (s) to humans or animals.
- oligosaccharides according to the invention having carboxyl groups have, because of their structure and their biocompatibility, a certain interest for the pharmaceutical industry, especially for the stabilization of active principles, for example protein,
- the oligosaccharides according to the invention retain the property of creating interactions with active principles, for example proteins.
- the present invention aims to provide oligosaccharides for stabilization, administration and delivery of active ingredients, which can be prepared by relatively simple methods to implement.
- the present invention is thus intended to provide oligosaccharides capable of allowing the stabilization, administration and delivery of active ingredients of great diversity.
- the present invention also aims to obtain oligosaccharides with a degree of functionalization in anionic groups that can go beyond two carboxylate groups per saccharide unit.
- the invention also aims at obtaining oligosaccharides which may have a biodegradability sufficiently fast and appropriate for their use in the preparation of a broad category of pharmaceutical formulations, including for medicaments intended for chronic administration and / or of high frequency,
- the invention aims to provide oligosaccharides meeting the constraints established by the pharmaceutical industry, particularly in terms of stability under normal conditions of storage and storage including in solution.
- the present invention relates to an oligodextran, chosen from dextrans whose average degree of polymerization is less than 10, modified by:
- radical - [AA] - denotes an amino acid residue attached to the backbone of dextran via a linker -Ri, and optionally carrying a radical - [R 2 ] n
- the linker -Ri is a C1-C15 carbon chain, optionally substituted and / or comprising at least one heteroatom (such as O, N and S) and optionally a carboxylic acid function; it forms with the amino acid residue [AA] an amide bond, and is directly attached to the dextran backbone by an ester, carbamate or ether bond
- radical -R 2 is an optionally substituted C1-C18 carbon chain
- n 0, 1 or 2
- -RI is a C1 to C15 carbon chain, optionally substituted and / or comprising at least one heteroatom (such as O, N and S) and at least one carboxylic acid function
- the oSigodextran is chosen from dextrans modified with:
- radical - [AA] - denotes an amino acid residue attached to the backbone of the dextran via a linker -Ri, and optionally carrying a radical - [R2] n
- the linker -Ri is a C1-C15 carbon chain, optionally substituted and / or comprising at least one heteroatom (such as O, N and S) and optionally a carboxylic acid function; it forms with the amino acid residue [AA] an amide bond, and is directly attached to the dextran backbone by an ester, carbamate or ether bond
- the radical -R 2 is a carbon chain C1 to C18, optionally substituted
- n 0, 1 or 2
- One or more substituents -R'I- which is a C1-C15 carbon chain, optionally substituted and / or comprising at least one heteroatom (such as O, N and S) and at least one acid function in the form of a salt of alkaline cations and is directly attached to the dextran backbone by an ester, carbamate or ether bond
- hetero atoms is meant an oxygen, nitrogen or sulfur atom.
- the linker -R1 forms with the amino acid residue [AA] an amide bond, and is directly attached to the dextran backbone through an ether linkage.
- the linker -R1 forms with the amino acid residue [AA] an amide linkage, and is directly attached to the dextran backbone via a carbamate linkage.
- the link arms -RI- and -R'I- are identical.
- the link arms -RI- and -R'I- are different.
- the linking arms -RI- and -R'I- are chosen from among the radicals
- O and p are the same or different, greater than or equal to 1 and less than or equal to 12, and
- R 3 and R 4 which are identical or different, are chosen from the group consisting of a hydrogen atom, a saturated or unsaturated, linear, branched or cyclic C1 to C6 alkyl, a benzyl or an alkyl-aryl and optionally containing heteroatoms selected from the group consisting of O, N and / or S, or functions selected from the group consisting of carboxylic acid, amine, alcohol or thiol functions,
- R ' 3 and R' 4 which are identical or different are chosen from the group consisting of a hydrogen atom, a saturated or unsaturated, linear, branched or cyclic C1 to C6 alkyl, a benzyl, an alkyl-aryl and optionally containing heteroatoms selected from the group consisting of O, N and / or S, or functions selected from the group consisting of carboxylic acid, amine, alcohol or thiol functions.
- the oligosaccharide is characterized in that the radical -R'I- is -CH2-. In one embodiment, the oligosaccharide is characterized in that Se radical -RI- is -CH2-.
- the polysaccharide is characterized in that the radical -R'1- is chosen from the group consisting of the following radicals:
- the polysaccharide is characterized in that the radical -RI - is chosen from the group consisting of the following radicals:
- the oligosaccharide is chosen from oligodextrans.
- the oligodextran has a number average molecular weight of less than 2000 g / me.
- At least 50% of the oligosaccharide population has a degree of polymerization of less than 10.
- the cations are chosen from alkaline cations, such as Na + or K + .
- the amino acids are selected from alpha amino acids. In one embodiment, the alpha amino acids are chosen from alpha natural amino acids.
- the natural alpha amino acids are chosen from hydrophobic amino acids chosen from the group comprising tryptophan, leucine, alanine, iso-leucine, glycine, phenylalanine and valine. .
- its natural alpha amino acids are selected from polar amino acids selected from the group consisting of aspartic acid, glutamic acid, lysine, serine.
- the oligosaccharide is characterized in that the radical R 2 is a benzyl radical.
- the oligosaccharide is characterized in that the radical -R 2 is derived from a hydrophobic alcohol.
- the hydrophobic alcohol is chosen from alcohols consisting of an unsaturated and / or saturated, branched or unbranched alkyl chain comprising from 4 to 18 carbons.
- the hydrophobic alcohol is chosen from alcohols consisting of an unsaturated and / or saturated, branched or unbranched alkyl chain comprising from 6 to 18 carbons.
- the hydrophobic alcohol is chosen from alcohols consisting of an unsaturated and / or saturated, branched or unbranched alkyl chain comprising from 8 to 16 carbons.
- the hydrophobic alcohol is octanol.
- the hydrophobic alcohol is 2-ethylbutanol.
- the fatty alcohol is selected from meristyl, ie cetyl, stearyl, cetearyl, butyl, oleyl, lanolin.
- the hydrophobic alcohol is selected from the group consisting of cholesterol and its derivatives.
- the hydrophobic alcohol is cholesterol
- the hydrophobic alcohol is chosen from menthol derivatives.
- the hydrophobic alcohol is menthol in its racemic form.
- the hydrophobic alcohol is the D-isomer of menthol.
- the hydrophobic alcohol is the L-isomer of menthol.
- the hydrophobic alcohol is chosen from tocopherols.
- the tocopherol is S'aipha tocopherol.
- alpha tocopherol is the racemic of alpha-tocopherol.
- tocopherol is the D isomer of alpha tocopherol.
- tocopherol is the L isomer of alpha tocopherol.
- the hydrophobic alcohol is chosen from alcohols bearing an aryl group.
- the aryl group-bearing alcohol is selected from the group consisting of benzyl alcohol and phenethyl alcohol.
- the ofigosaccharide is characterized in that the radical - 2 is derived from a hydrophobic acid.
- the hydrophobic acid is selected from fatty acids.
- the fatty acids are chosen from the group consisting of acids consisting of an unsaturated or saturated, branched or unbranched alkyl chain comprising from 6 to 50 carbons.
- the fatty acids are chosen from the group consisting of linear fatty acids.
- the linear fatty acids are selected from the group consisting of caproic acid, oenanthic acid, caprylic acid, capric acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, tricosanoic acid, lignoceric acid, heptacosanoic acid, octacosanoic acid and melissic acid.
- the fatty acids are selected from the group consisting of unsaturated fatty acids.
- the unsaturated fatty acids are selected from the group consisting of myristoleic acid, palmitoleic acid, oleic acid, elaidic acid, linoleic acid, alpha linoleic, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid.
- the fatty acids are chosen from the group consisting of ile acids and their derivatives,
- the bile acids and their derivatives are selected from the group consisting of cholic acid, dehydrocholic acid, deoxycholic acid, and chenodeoxycholic acid. In one embodiment, 0.1 ⁇ i ⁇ , 3
- the igosaccha wrinkle according to the invention has a mean degree of polymerization of between 2 and 10.
- it has a mean degree of polymerization of between 2 and 8.
- it has a mean degree of polymerization of between 3 and 6.
- anionic is meant an oligosaccharide which contains unfunctionalized and salt-forming carboxyl functional groups.
- polymerization degree DP is meant the average number of repeating units (monomers) per polymer chain. It is calculated by dividing the number average molar mass by the average mass of the repeating unit.
- M n number average molar mass
- the polymers can also be characterized by the chain length distribution, also called polydispersity index (Ip), and is equal to M w divided by M n .
- Ip polydispersity index
- the invention relates to an oligosaccharide chosen from the group consisting of the following oligosaccharides:
- the invention also relates to the use of functionalized oligosaccharides according to the invention for the preparation of pharmaceutical compositions.
- the invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising one of the oligosaccharides according to the invention as described above and at least one active ingredient.
- the invention also relates to a pharmaceutical composition characterized in that the active ingredient is selected from the group consisting of proteins, glycoproteins, peptides and non-peptide therapeutic molecules.
- active principle is meant a product in the form of a single chemical entity and / or in the form of a combination having a physiological activity.
- Said active ingredient may be exogenous, that is to say that it is provided by the composition according to the invention. It may also be endogenous, for example the growth factors that will be secreted in a wound during the first healing phase and that may be retained on said wound by the composition according to the invention.
- the modes of administration envisaged are intravenous, subcutaneous, intradermal, transdermal, intramuscular, oral, nasal, vaginal, ocular, oral, pulmonary and so on.
- compositions according to the invention are either in liquid form, in aqueous solution, or in powder, implant or film form. They further comprise conventional pharmaceutical excipients well known to those skilled in the art.
- compositions may advantageously comprise, in addition, excipients for formulating them in the form of gel, sponge, injectable solution, oral solution, lyoc, etc.
- the invention also relates to a pharmaceutical composition, characterized in that it is administrable in stent form, film or "coating" of implantable biomaterials, implant.
- Oligosaccharide 1 Sodium phenylalaninate functionalized dextranmethylcarboxylate [1DMC (1.03) PheOC 8 (0.2)]
- Octyl phenylalaninate, para-toluenesulfonic acid salt is prepared from octanol and phenylalanine according to the process described in US Patent 4,826,818 (Kenji M., et al.).
- [oligosaccharide] 31.5 mg / g
- the degree of substitution of methyicarboxyate is 1.03 per glucosidic unit.
- This sodium dextranethylcarboxylate is lyophilized for 18 hours.
- the sodium dextranmethylcarboxylate solution is acidified on a Purolite resin (anionic) to obtain the acid dextranemethylcarboxylic acid which is then lyophilized for 18 hours.
- the solution of phenylalaninate is added.
- octyl is added and the mixture is stirred at 10 ° C.
- the mixture is then heated to 50 ° C.
- 70 ml of an aqueous solution of imidazole (150 g / l) and 120 ml of water are added.
- the solution thus obtained is purified by ultrafiltration on PES membrane of 1 kDa against 0.9% NaCl, 0.01N NaOH, 0.9% NaCl and water.
- the oligosaccharide concentration of the final solution is determined by dry extract.
- a sample of solution is lyophilized and analyzed by RM NMR in D 2 0 to determine the degree of substitution of octyl phenylalaninate-grafted methyl carboxylates.
- Oligosaccharide 2 sodium dextranmethylcarboxylate functionalized with dilaurylate aspartate [lDMC (1.03) Asp (OC 12 ) 2 (0.07) 3
- the dilauryl aspartate, para-toluenesulfonic acid salt is prepared from dodecane and aspartic acid according to the process described in US Patent 4,826,818 (Kenji M., et al.).
- Oligosaccharide 3 Sodium dextranemethylcarboxylate functionalized with dilauryl aspartate [lDMC (1.65) Asp (OC 12 ) 2 (0.07)]
- the degree of substitution in methylcarboxylate is 1.65 per glucosidic unit.
- the sodium dextranemethylcarboxylate solution is passed through a Puroiite (anionic) resin to obtain the acid dextran-methylcarboxylic acid which is then lyophilized for 18 hours.
- Oligosaccharide 3 is a sodium dextranemethylcarboxylate functionalized with dilauryl aspartate prepared according to a process similar to that described for Oligosaccharide 2.
- Oligosaccharide 4 Sodium dextranemethylcarboxylate functionalized with dilauryl aspartate [lDMC (1.65) Asp (OCi 2 ) 2 (0.15)] 10 g of dextranethyl carboxylic acid characterized by a degree of substitution of methylcarboxylate of 1.65 per glucosidic unit are synthesized from a dextran with a weight average molecular mass of 1 kg / mol (Pharmacosmos, degree of polymerization of 3 9), according to a method similar to that described for Oligosaccharide 3, and then lyophilized.
- Oligosaccharide 5 Dextranmethyl sodium carboxylate functionalized with didecyl aspartate [1D C (1.03) Asp (OCi 0 ) 2 (0.05)]
- Didecyl aspartate, para-toluenesulfonic acid salt is prepared from decanol and aspartic acid according to the process described in US Pat. No. 4,826,818 (Kenji M., et al.).
- Oligosaccharide 5 is a sodium dextranmethylcarboxylate functionalized with didecyl aspartate, prepared according to a process similar to that described for Oligosaccharide 2.
- N 1 the degree of substitution in methylcarboxylates functionalized aspartate didecyl is 0.05.
- Oligosaccharide 6 Dioctylated aspartate functionalized sodium dextranmethylcarboxylate [1DMC (1.03) Asp (OC 3 ) 2 (0.07)]
- the dioctyl aspartate, para-toluenesulfonic acid salt is prepared from octanol and aspartic acid according to the process described in US Patent 4,826,818 (Kenji M., et al.).
- Oligosaccharide 6 is a sodium dextranethylcarboxylate functionalized with dioctyl aspartate, prepared according to a process similar to that described for Oligosaccharide 2.
- Oligosaccharide 7 Sodium dextranmethylcarboxylate functionalized with ⁇ -benzyl aspartate [lDMC (1.65) Asp (OBzl) OH (0.6)]
- Oligosaccharide 7 is a sodium dextranethylcarboxylate functionalized with ⁇ -benzyl aspartate, prepared according to a process similar to that described for Oligosaccharide 2 using aspartic acid of ⁇ -benzyl (Bachem).
- Oligosaccharide 8 Tryptophan Functionalized Dextranmethylcarboxylate [lDMC (1.65) Trp (1.0)]
- Oligosaccharide 9 Sodium dextranmethylcarboxyate functionalized with tryptophan [lDMC (2.1) Trp (1.3)]
- the concentration of oligosaccharides of the final solution is determined by dry extract, then an acid / base assay in a water / acetone 50/50 (V / V) mixture is carried out to determine the degree of substitution in methylcarboxylate.
- the degree of substitution in methylcarboxylate is 2.1 per glucosidic unit.
- Oligosaccharide 9 is a tryptophan functionalised sodium dextranmethylcarboxylate, prepared according to a process similar to that described for Oligosaccharide 8.
- Oligosaccharide 10 Sodium Dextranmethylcarboxylate Functionalized With Phenylalanine [lDMC (1.65) Phe (0.65)]
- the ethyl phenylalaninate solution is added and the mixture is stirred at 10 ° C.
- An aqueous solution of imidazole (340 g / l) is added.
- the solution is then heated to 30 ° C., 70 ml of water are added and the solution obtained is purified by ultrafiltration on a PES membrane of 1 kDa against 7 volumes of IMaOH ⁇ , ⁇ ⁇ , 7 volu mes of NaCl 0, 9% and 3 volumes of water.
- the concentration of oligosaccharides of the final solution is determined by dry extract.
- a sample solution is lyophilized and analyzed by NMR in D 2 0 s to determine the mole fraction of grafted methylcarboxylate by phenylalanine.
- Oligosaccharide 11 Sodium dextranmethylcarboxylate functionalized with phenylalanine [lDMC (2.1) Phe (1.0)]
- Oligosaccharide 11 is a phenylalanine functionalized dextranmethylcarboxylate, prepared according to a process similar to that described for Oligosaccharide 10.
- Oligosaccharide 12 sodium N-methylcarboxylate dextran carbamate modified with L-Phenylaianin [lDUGIy (1.65) Phe (0.65)]
- the degree of substitution of the hydroxyl functions by N-methylcarboxylate carbamate functions is 1.65 per saccharide unit.
- the solution of sodium N-methylcarboxylate dextran carbamate is acidified on a Purolite resin (anionic) to obtain the IM-methylcarboxylic acid dextran which is then lyophilized for 18 hours.
- Oligosaccharide 12 is a sodium N-methylcarboxylate dextran carbamate functionalized with phenylalanine, prepared according to a process similar to that described for Oligosaccharide 10.
- [Oligosaccharide 12] 23.8 mg / g
- N-methylcarboxylic acid dextran characterized by a degree of substitution of N-methylcarboxylate of 1.65 per glucosidic unit are synthesized from a dextran with a weight average molar mass of 1 kg / mol (Pharmacosmos, degree of polymerization of 3.9), according to a method similar to that described for Oligosaccharide 12, and then lyophilized.
- Oligosaccharide 13 is a sodium N-methylcarboxylate dextran carbamate functionalized with tryptophan, prepared according to a process similar to that described for Oligosaccharide 9.
- Oligosaccharide 14 Sodium dextranmethylcarboxylate functionalized with cholesteryl leucinate [lDMC (1.65) LeuChol (0.05)]
- Cholesteryl leucinate, paratoluenesulfonic acid salt is prepared from cholesterol and leucine according to the process described in US Pat. No. 4,826,818 (Kenji M., et al.).
- Oligosaccharide 14 is a sodium dextranmethylcarboxylate functionalized with cholesteryl leucinate, prepared according to a process similar to that described for Oligosaccharide 1.
- the degree of substitution with methylcarboxylates functionalized with cholesteryl leucinate is 0.05.
- the isocyanate of the ⁇ -benzyl-L-aspartate dipeptide of ethyl L-phenylalaninate is obtained according to the method described in the publication (Tsai, JH et al., Organic Synthesis 2004, 10, 544-545) from ethyl L-phenylalaninate ⁇ -benzyl-L-aspartate hydrochloride and triphosgene (Sigma).
- Toluene is added to the mixture and the medium is dehydrated by heteroazeotropic distillation.
- 80 ° C. 15.81 g (0.04 mol) of isocyanate of the ⁇ -benzyl-L-aspartate dipeptide of ethyl L-phenylalaninate are progressively introduced.
- the medium is diluted with water and purified by diafiltration on a 5 kD PES membrane against 0.1N NaOH, 0.9% NaCl and water.
- the final solution is assayed by dry extract to determine the polymer concentration, assayed by acid / base assay in water / acetone 50/50 (V / V) and then analyzed by 1 H NMR to determine the degree of hydroxyl functionalisation.
- 10DMC (II) Phe (0.45) is synthesized according to the same process as the oligosaccharide 10 from the dextran of average molar mass by weight of 10 kg / mol (Pharmacosmos, degree of polymerization of 19).
- Literature establishes, on the basis of dextran, a correlation between molecular weight and renal clearance of macromolecules (Caulfield, J. et al., The Journal of Cell Biology 1974, 63, 883-903; Chang RLS Kidney International 1975, 8, 212-218). These results establish that macromolecules with a molecular weight greater than 30 kDa are hardly eliminated by the kidney.
- a solution of 250 ml of oligosaccharide 10 at 20 g / l is ultrafiltered on PES membrane of 30 kDa against 20 volumes of water.
- the oligosaccharide concentration of the final solution is determined by dry extract and indicates a recovery of less than 10%.
- a solution of 250 ml of 10DMC (l.l) Phe (0.65) at 20 g / L is ultrafiltered on PES membrane of 30 kDa against 20 volumes of water.
- the polymer concentration of the final solution is determined by dry extract.
- BMP-7 Bone Morphogenetic Protein 7
- the oligosaccharides described in this application are implemented in this test.
- the test consists in using a solution of BMP-7 at acidic pH, for example a 10 mM lactate buffer at pH 3.
- BMP-7 is at an initial concentration of 2.47 mg / ml.
- 2.02 ml of this BMP-7 solution are mixed with 2.7 ml of a 18.5 mg / ml polymer solution containing 18 mM phosphate buffer at pH 7.4.
- After mixing the final pH is adjusted to physiological pH by adding a mixture of IN sodium hydroxide and water to obtain a final formulation volume of 5 mL.
- the formulations are analyzed by visual observation, turbidity and dynamic scattering of light to detect the presence of aggregates.
- oligosaccharides according to the invention thus make it possible to form complexes with a protein despite a very small number of saccharide units,
Abstract
Description
Claims
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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US201161484461P | 2011-05-10 | 2011-05-10 | |
FR1154039A FR2975099A1 (fr) | 2011-05-10 | 2011-05-10 | Polysaccharides a degre de fonctionnalisation modulable |
US201161541606P | 2011-09-30 | 2011-09-30 | |
FR1158885A FR2980796B1 (fr) | 2011-09-30 | 2011-09-30 | Oligosaccharides fonctionnalises |
US13/287,793 US20120094902A1 (en) | 2009-03-27 | 2011-11-02 | Fast-acting insulin formulation |
PCT/FR2012/051039 WO2012153070A1 (fr) | 2011-05-10 | 2012-05-10 | Oligosaccharides fonctionnalisés |
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EP2828297A1 true EP2828297A1 (fr) | 2015-01-28 |
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EP12726819.1A Withdrawn EP2828297A1 (fr) | 2011-05-10 | 2012-05-10 | Oligosaccharides fonctionnalisés |
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WO (1) | WO2012153070A1 (fr) |
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CA2843586A1 (fr) | 2011-08-10 | 2013-02-14 | Adocia | Solution injectable d'au moins une insuline basale |
US20130231281A1 (en) | 2011-11-02 | 2013-09-05 | Adocia | Rapid acting insulin formulation comprising an oligosaccharide |
CN104114155B (zh) | 2012-01-09 | 2019-02-15 | 阿道恰公司 | Ph为7并且至少包含pi为5.8至8.5之基础胰岛素和经取代共聚(氨基酸)的可注射溶液 |
US20150314003A2 (en) | 2012-08-09 | 2015-11-05 | Adocia | Injectable solution at ph 7 comprising at least one basal insulin the isoelectric point of which is between 5.8 and 8.5 and a hydrophobized anionic polymer |
FR3001896B1 (fr) | 2013-02-12 | 2015-07-03 | Adocia | Solution injectable a ph 7 comprenant au moins une insuline basale dont le point isolectrique est compris entre 5,8 et 8,5 et un polymere anionique hydrophobise |
MX360107B (es) | 2012-11-13 | 2018-10-23 | Adocia | Formulación de acción rápida de insulina que comprende un compuesto aniónico sustituido. |
CA2889345A1 (fr) | 2012-11-13 | 2014-05-22 | Adocia | Composes anioniques substitues constitues d'un squelette forme d'un nombre discret d'unites saccharidiques |
FR2997952B1 (fr) * | 2012-11-13 | 2014-11-21 | Adocia | Composes anioniques substitues constitues d'un squelette forme d'un nombre discret d'unites saccharidiques |
US9795678B2 (en) | 2014-05-14 | 2017-10-24 | Adocia | Fast-acting insulin composition comprising a substituted anionic compound and a polyanionic compound |
FR3020947B1 (fr) | 2014-05-14 | 2018-08-31 | Adocia | Composition aqueuse comprenant au moins une proteine et un agent solubilisant, sa preparation et ses utilisations |
FR3025428A1 (fr) | 2014-09-08 | 2016-03-11 | Adocia | Composition pharmaceutique stable comprenant du pdgf |
FR3043557B1 (fr) | 2015-11-16 | 2019-05-31 | Adocia | Composition a action rapide d'insuline comprenant un citrate substitue |
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FR2914305B1 (fr) * | 2007-03-29 | 2009-07-03 | Proteins & Peptides Man | Dextran fonctionnalise par des amino-acides hydrophobes. |
CN102065882A (zh) * | 2008-04-14 | 2011-05-18 | 阿道恰公司 | 包含生长因子/两亲性聚合物复合物、阳离子的可溶性盐和有机支持物的成骨组合物 |
FR2948573B1 (fr) * | 2009-07-31 | 2011-11-18 | Adocia | Nouvelle forme d'administration de complexes de proteines osteogeniques |
WO2011098962A2 (fr) * | 2010-02-09 | 2011-08-18 | Adocia | Polysaccharides anioniques fonctionnalisés par au moins deux groupements hydrophobes portés par un spacer au moins trivalent |
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- 2012-05-10 WO PCT/FR2012/051039 patent/WO2012153070A1/fr active Application Filing
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