KR20230068348A - Pharmaceutical composition containing methylcobalamin - Google Patents
Pharmaceutical composition containing methylcobalamin Download PDFInfo
- Publication number
- KR20230068348A KR20230068348A KR1020220149492A KR20220149492A KR20230068348A KR 20230068348 A KR20230068348 A KR 20230068348A KR 1020220149492 A KR1020220149492 A KR 1020220149492A KR 20220149492 A KR20220149492 A KR 20220149492A KR 20230068348 A KR20230068348 A KR 20230068348A
- Authority
- KR
- South Korea
- Prior art keywords
- methylcobalamin
- phosphate
- pharmaceutical composition
- composition according
- present
- Prior art date
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- 235000007672 methylcobalamin Nutrition 0.000 title claims abstract description 89
- 239000011585 methylcobalamin Substances 0.000 title claims abstract description 89
- JEWJRMKHSMTXPP-BYFNXCQMSA-M methylcobalamin Chemical compound C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O JEWJRMKHSMTXPP-BYFNXCQMSA-M 0.000 title claims abstract description 88
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 27
- 239000000203 mixture Substances 0.000 claims abstract description 63
- 150000005846 sugar alcohols Chemical class 0.000 claims abstract description 17
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 15
- 239000010452 phosphate Substances 0.000 claims abstract description 15
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 46
- 235000010355 mannitol Nutrition 0.000 claims description 28
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 20
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical group [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 20
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 17
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 17
- 239000000872 buffer Substances 0.000 claims description 14
- 230000003204 osmotic effect Effects 0.000 claims description 12
- 229930195725 Mannitol Natural products 0.000 claims description 10
- 239000000594 mannitol Substances 0.000 claims description 10
- 238000002347 injection Methods 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 7
- 238000007911 parenteral administration Methods 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 6
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
- 235000010447 xylitol Nutrition 0.000 claims description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 3
- 229960002675 xylitol Drugs 0.000 claims description 3
- 239000004254 Ammonium phosphate Substances 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- HEBKCHPVOIAQTA-QWWZWVQMSA-N D-arabinitol Chemical compound OC[C@@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-QWWZWVQMSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 239000005696 Diammonium phosphate Substances 0.000 claims description 2
- 239000004386 Erythritol Substances 0.000 claims description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 2
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims description 2
- JVWLUVNSQYXYBE-UHFFFAOYSA-N Ribitol Natural products OCC(C)C(O)C(O)CO JVWLUVNSQYXYBE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000148 ammonium phosphate Inorganic materials 0.000 claims description 2
- 235000019289 ammonium phosphates Nutrition 0.000 claims description 2
- 229910000388 diammonium phosphate Inorganic materials 0.000 claims description 2
- 235000019838 diammonium phosphate Nutrition 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 235000019414 erythritol Nutrition 0.000 claims description 2
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 2
- 229940009714 erythritol Drugs 0.000 claims description 2
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 claims description 2
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims description 2
- 229960000367 inositol Drugs 0.000 claims description 2
- 239000000832 lactitol Substances 0.000 claims description 2
- 235000010448 lactitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 claims description 2
- 229960003451 lactitol Drugs 0.000 claims description 2
- 239000000845 maltitol Substances 0.000 claims description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 2
- 235000010449 maltitol Nutrition 0.000 claims description 2
- 229940035436 maltitol Drugs 0.000 claims description 2
- -1 maltotritol Chemical compound 0.000 claims description 2
- 229960001855 mannitol Drugs 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- HEBKCHPVOIAQTA-ZXFHETKHSA-N ribitol Chemical compound OC[C@H](O)[C@H](O)[C@H](O)CO HEBKCHPVOIAQTA-ZXFHETKHSA-N 0.000 claims description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 229960002920 sorbitol Drugs 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019798 tripotassium phosphate Nutrition 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims description 2
- 235000019801 trisodium phosphate Nutrition 0.000 claims description 2
- YOZNUFWCRFCGIH-BYFNXCQMSA-L hydroxocobalamin Chemical compound O[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O YOZNUFWCRFCGIH-BYFNXCQMSA-L 0.000 abstract description 18
- 235000004867 hydroxocobalamin Nutrition 0.000 abstract description 9
- 239000011704 hydroxocobalamin Substances 0.000 abstract description 9
- 229960001103 hydroxocobalamin Drugs 0.000 abstract description 9
- 238000006243 chemical reaction Methods 0.000 abstract description 4
- 239000007791 liquid phase Substances 0.000 abstract description 3
- 239000007853 buffer solution Substances 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 27
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 23
- 238000002360 preparation method Methods 0.000 description 14
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 11
- 239000008363 phosphate buffer Substances 0.000 description 11
- 239000012669 liquid formulation Substances 0.000 description 9
- 238000005259 measurement Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 229930003779 Vitamin B12 Natural products 0.000 description 6
- 235000000639 cyanocobalamin Nutrition 0.000 description 6
- 239000011666 cyanocobalamin Substances 0.000 description 6
- 229960002104 cyanocobalamin Drugs 0.000 description 6
- 235000019163 vitamin B12 Nutrition 0.000 description 6
- 239000011715 vitamin B12 Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 235000006279 cobamamide Nutrition 0.000 description 5
- 239000011789 cobamamide Substances 0.000 description 5
- ZIHHMGTYZOSFRC-UWWAPWIJSA-M cobamamide Chemical compound C1(/[C@](C)(CCC(=O)NC[C@H](C)OP(O)(=O)OC2[C@H]([C@H](O[C@@H]2CO)N2C3=CC(C)=C(C)C=C3N=C2)O)[C@@H](CC(N)=O)[C@]2(N1[Co+]C[C@@H]1[C@H]([C@@H](O)[C@@H](O1)N1C3=NC=NC(N)=C3N=C1)O)[H])=C(C)\C([C@H](C/1(C)C)CCC(N)=O)=N\C\1=C/C([C@H]([C@@]\1(CC(N)=O)C)CCC(N)=O)=N/C/1=C(C)\C1=N[C@]2(C)[C@@](C)(CC(N)=O)[C@@H]1CCC(N)=O ZIHHMGTYZOSFRC-UWWAPWIJSA-M 0.000 description 5
- 229910000397 disodium phosphate Inorganic materials 0.000 description 5
- 235000019800 disodium phosphate Nutrition 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
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- 206010002065 Anaemia megaloblastic Diseases 0.000 description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 3
- 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 3
- 208000000682 Megaloblastic Anemia Diseases 0.000 description 3
- 206010029240 Neuritis Diseases 0.000 description 3
- 206010036105 Polyneuropathy Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
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- 235000002639 sodium chloride Nutrition 0.000 description 3
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000006820 DNA synthesis Effects 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
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- 239000007864 aqueous solution Substances 0.000 description 2
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
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- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical group [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
- 229910001429 cobalt ion Inorganic materials 0.000 description 2
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
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- QWSZRRAAFHGKCH-UHFFFAOYSA-M sodium;hexane-1-sulfonate Chemical compound [Na+].CCCCCCS([O-])(=O)=O QWSZRRAAFHGKCH-UHFFFAOYSA-M 0.000 description 2
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- LJUQGASMPRMWIW-UHFFFAOYSA-N 5,6-dimethylbenzimidazole Chemical group C1=C(C)C(C)=CC2=C1NC=N2 LJUQGASMPRMWIW-UHFFFAOYSA-N 0.000 description 1
- LLQHSBBZNDXTIV-UHFFFAOYSA-N 6-[5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-4,5-dihydro-1,2-oxazol-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC1CC(=NO1)C1=CC2=C(NC(O2)=O)C=C1 LLQHSBBZNDXTIV-UHFFFAOYSA-N 0.000 description 1
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- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
본 발명은 메틸코발라민을 포함하는 안정성이 개선된 약학 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition with improved stability comprising methylcobalamin.
코발라민 (cobalamin)이라고도 불리는 비타민 B12는 DNA 합성, 조혈, 뇌 발달 및 신경 기능에 역할을 하는 것으로 알려진 수용성 비타민이다. 비타민 B12는 일반적으로 인체의 모든 세포의 대사에 관여하며, 특히 DNA 합성에 영향을 미치고, 지방산 및 아미노산 대사에도 영향을 미친다.Vitamin B12, also called cobalamin, is a water-soluble vitamin known to play a role in DNA synthesis, hematopoiesis, brain development, and nerve function. Vitamin B12 is generally involved in the metabolism of all cells of the human body, particularly affecting DNA synthesis, and also affecting fatty acid and amino acid metabolism.
비타민 B12는 비타민 중 가장 복잡한 구조를 가지며, 기본적인 화학구조는 두 가지 성분으로 이루어져 있다. 하나는 포르피린 (porphyrin) 고리모양 구조이고, 다른 하나는 알파-글리코시드 (glycoside) 결합을 갖는 뉴클레오티드이다. 포르피린 고리모양 구조는 4개의 5, 6-디메틸벤즈이미다졸 (dimethylbenzimidazole) 고리로 이루어지고, 4개의 질소 원자가 코발트이온을 중심으로 배위하여 킬레이트화합물을 이루고 있다. 코발트 원자에 시안기가 결합한 것을 시아노코발라민 (cyanocobalamin)이라고 하며, 이 시안기를 제거한 구조가 영양학적으로나 생화학적으로 중요하다. 즉, 생체 내에서는 활성형이 되기 전에 시안기가 떨어져 나가고 코발라민은 생체 내에서 조효소 및 코발라민 효소로서 변환된다.Vitamin B12 has the most complex structure among vitamins, and its basic chemical structure consists of two components. One is a porphyrin ring-shaped structure, and the other is a nucleotide having an alpha-glycoside bond. The porphyrin ring-shaped structure consists of four 5,6-dimethylbenzimidazole rings, and four nitrogen atoms are coordinated with the cobalt ion as the center to form a chelate compound. A cyan group bonded to a cobalt atom is called cyanocobalamin, and the structure in which the cyan group is removed is nutritionally and biochemically important. That is, in vivo, the cyanide group is removed before becoming active, and cobalamin is converted into coenzyme and cobalamin enzyme in vivo.
비타민 B12의 주요 형태로는 시아노코발라민, 히드록소코발라민 (hydroxocobalamin), 메틸코발라민 (methylcobalamin) 및 아데노실코발라민 (adenosylcobalamin)이 있다. 기본적인 코발라민 분자는 미생물에 의해서만 합성되지만, 모든 포유동물의 세포는 코발라민을 코엔자임인 아데노실코발라민과 메틸코발라민으로 전환할 수 있다. 히드록소코발라민, 메틸코발라민 및 아데노실코발라민은 포유동물의 조직으로부터 가장 빈번하게 분리되는 코발라민의 세 가지 형태이다. 그러나, 메틸코발라민과 아데노실코발라민만이 인체 효소에서 보조 인자로서 기능을 가지고 있다. 아데노실코발라민은 세포의 조직을 구성하며 세포 내 미토콘드리아에 존재하고, 메틸코발라민은 주로 혈장과 대뇌 척수액과 같은 체액에 존재하며 세포에서는 세포질에서 발견된다.The major forms of vitamin B12 are cyanocobalamin, hydroxocobalamin, methylcobalamin and adenosylcobalamin. Although the basic cobalamin molecule is synthesized only by microorganisms, cells of all mammals can convert cobalamin into the coenzymes adenosylcobalamin and methylcobalamin. Hydroxocobalamin, methylcobalamin and adenosylcobalamin are the three forms of cobalamin most frequently isolated from mammalian tissues. However, only methylcobalamin and adenosylcobalamin have functions as cofactors in human enzymes. Adenosylcobalamin constitutes tissue of cells and is present in mitochondria within cells, and methylcobalamin is mainly present in body fluids such as plasma and cerebral spinal fluid, and is found in the cytoplasm of cells.
코발라민은 당뇨병성 신경장애, 다발성 신경염 등의 말초성 신경장애, 특히 저림, 통증 및 마비의 치료개선이나, 비타민 B12 결핍으로 인한 거대적아세포성 빈혈 등에 이용되고 있으며, 대부분의 상업용 비타민 B12 제제는 가장 안정한 형태로서 제제화하기에 용이한 시아노코발라민이 이용되고 있다. 시아노코발라민은 생산 시 가격이 저렴하며 안정성이 높아 보관이 용이하나, 다른 코발라민 형태와 비교하여 인체 내 흡수과정이 비효율적이고 효과가 떨어지는 단점이 있다.Cobalamin is used to treat peripheral neuropathy such as diabetic neuropathy and polyneuritis, especially numbness, pain and paralysis, or megaloblastic anemia due to vitamin B12 deficiency. Most commercial vitamin B12 preparations are the most stable. Cyanocobalamin, which is easy to formulate as a form, is used. Cyanocobalamin is inexpensive when produced and is easy to store due to its high stability. However, compared to other forms of cobalamin, the absorption process in the human body is inefficient and the effect is low.
메틸코발라민은 활성형 비타민 B12로 다른 코발라민 형태와 비교하여 흡수가 빠르고, 생체이용률 및 신경 조직으로의 이행성이 우수하여 최근 비타민 B12 결핍증에 효과적인 치료제로 주목받고 있다. 그러나, 메틸코발라민은 분리된 형태에서 빛에 불안정한 것으로 알려져 있으며, 수용액에서 히드록소코발라민으로 쉽게 변형되는 문제점을 갖고 있다.Methylcobalamin, an active form of vitamin B12, is rapidly absorbed compared to other forms of cobalamin, has excellent bioavailability and transferability to nerve tissue, and has recently attracted attention as an effective treatment for vitamin B12 deficiency. However, methylcobalamin is known to be unstable to light in an isolated form, and has a problem of being easily transformed into hydroxocobalamin in an aqueous solution.
이러한 배경 하에서, 본 발명자들은 메틸코발라민의 안정성을 개선하기 위한 방안을 찾고자 연구노력한 결과, 수용액에서 메틸코발라민이 히드록소코발라민으로 전환되는 원인을 분석하고, 인산계 완충액 및 당알코올을 포함시킴으로써 메틸코발라민의 안정성을 현저하게 향상시킬 수 있음을 발견하고 본 발명을 완성하였다.Under this background, the present inventors have made research efforts to find a way to improve the stability of methylcobalamin, and as a result, analyzed the cause of conversion of methylcobalamin to hydroxocobalamin in an aqueous solution, and included a phosphate-based buffer and sugar alcohol to improve the stability of methylcobalamin. It was found that the stability could be remarkably improved, and the present invention was completed.
본 발명의 목적은 메틸코발라민을 포함하는 안정성이 개선된 약학 조성물을 제공하는 것이다. 구체적으로 본 발명의 목적은 안정성이 개선된 메틸코발라민, 인산계 완충액 및 당알코올을 포함하는 약학 조성물을 제공하기 위한 것이다. An object of the present invention is to provide a pharmaceutical composition containing methylcobalamin with improved stability. Specifically, an object of the present invention is to provide a pharmaceutical composition comprising methylcobalamin, a phosphate-based buffer, and sugar alcohol with improved stability.
이를 구체적으로 설명하면 다음과 같다. 한편, 본 발명에서 개시된 각각의 설명 및 실시형태는 각각의 다른 설명 및 실시 형태에도 적용될 수 있다. 즉, 본 발명에서 개시된 다양한 요소들의 모든 조합이 본 발명의 범주에 속한다. 또한, 하기 기술된 구체적인 서술에 의하여 본 발명의 범주가 제한된다고 볼 수 없다.A detailed description of this is as follows. Meanwhile, each description and embodiment disclosed in the present invention may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be seen that the scope of the present invention is limited by the specific descriptions described below.
본 발명은 메틸코발라민, 인산계 완충액 및 당알코올을 포함하는 약학 조성물을 제공한다. The present invention provides a pharmaceutical composition comprising methylcobalamin, a phosphate-based buffer and a sugar alcohol.
본 발명의 조성물은 메틸코발라민과 함께 인산계 완충액 및 당알코올을 포함함으로써 메틸코발라민이 히드록소코발라민으로 전환되는 것을 억제 또는 지연시켜 우수한 보관 안정성을 나타낼 수 있다.The composition of the present invention can exhibit excellent storage stability by inhibiting or delaying the conversion of methylcobalamin to hydroxocobalamin by including a phosphate-based buffer and sugar alcohol together with methylcobalamin.
본 발명에 있어 메틸코발라민은 시아노코발라민의 코발트에 결합하고 있는 시아노기가 메틸기로 치환된 화합물로서, 하기 화학식 1로 표시되는 화합물일 수 있다.In the present invention, methylcobalamin is a compound in which a cyano group bonded to cobalt of cyanocobalamin is substituted with a methyl group, and may be a compound represented by Formula 1 below.
[화학식 1][Formula 1]
상기 메틸코발라민은 당뇨병성 신경장애, 다발성 신경염 등의 말초성 신경장애, 거대적아구성 빈혈 (megaloblastic anaemia), 근위축성 측색 경화증 (Amyotrophic lateral sclerosis, ALS) 등의 비타민 B12 결핍증의 치료를 위한 유효성분으로 사용될 수 있다. The methylcobalamin is used as an active ingredient for the treatment of vitamin B12 deficiency, such as peripheral neuropathy such as diabetic neuropathy and polyneuritis, megaloblastic anaemia, and amyotrophic lateral sclerosis (ALS). can
본 발명에 이용되는 메틸코발라민은 공지의 물질로서, 공지의 방법에 따라 제조할 수 있다. 예를 들어, 알칼리성 용액에서 수소화붕소나트륨 (sodium borohydride)으로 시아노코발라민을 환원시킨 후 요오드화메틸을 첨가하여 제조할 수 있다. 또한, 상기 메틸코발라민은 상업적으로 구입할 수 있다. Methylcobalamin used in the present invention is a known substance and can be prepared according to a known method. For example, it can be prepared by reducing cyanocobalamin with sodium borohydride in an alkaline solution and then adding methyl iodide. In addition, the methylcobalamin can be purchased commercially.
본 발명의 조성물에 포함된 메틸코발라민의 함량은 0.01 내지 10.0 mg/ml일 수 있다.바람직하게, 본 발명의 메틸코발라민의 함량은 0.5 mg/ml 일 수 있으나, 이에 제한되는 것은 아니다.The content of methylcobalamin included in the composition of the present invention may be 0.01 to 10.0 mg/ml. Preferably, the content of methylcobalamin of the present invention may be 0.5 mg/ml, but is not limited thereto.
본 발명에 있어, 인산(phosphate)계 완충액은 인산을 포함하는 완충용액으로 본 발명에서 인산염 완충액과 상호호환하여 사용될 수 있다. 상기 인산계 완충액은 조성물의 pH를 일정하게 유지하는데 도움을 주며 액상 제형에서의 메틸코발라민의 안정성을 향상시키는 역할을 수행할 수 있다. 구체적으로, 액상에서 메틸코발라민이 히드록소코발라민으로 전환됨에 따라 변화되는 pH를 인산계 완충액으로 억제함으로써 메틸코발라민의 안정성을 향상시킬 수 있다.In the present invention, a phosphate buffer is a buffer solution containing phosphoric acid and may be used interchangeably with a phosphate buffer in the present invention. The phosphate-based buffer helps to keep the pH of the composition constant and can serve to improve the stability of methylcobalamin in a liquid formulation. Specifically, the stability of methylcobalamin can be improved by suppressing the pH, which is changed as methylcobalamin is converted into hydroxocobalamin in a liquid phase, with a phosphate-based buffer.
본 발명의 인산계 완충액은 인산이수소나트륨(NaH2PO4), 인산수소이나트륨(Na2HPO4), 인산삼나트륨(Na3PO4), 인산이수소칼륨(KH2PO4), 인산수소이칼륨(K2HPO4), 인산삼칼륨(K3HPO4), 인산암모늄((NH4)H2PO4) 및 인산이암모늄((NH4)2HPO4)으로 이루어진 군으로부터 선택되는 하나 이상일 수 있으며, 바람직하게 인산수소이나트륨(Na2HPO4), 인산이수소나트륨(NaH2PO4) 또는 이들의 혼합물일 수 있다. The phosphate-based buffer of the present invention is sodium dihydrogen phosphate (NaH 2 PO 4 ), disodium hydrogen phosphate (Na 2 HPO 4 ), trisodium phosphate (Na 3 PO 4 ), potassium dihydrogen phosphate (KH 2 PO 4 ), phosphoric acid Dipotassium hydrogen (K 2 HPO 4 ), tripotassium phosphate (K 3 HPO 4 ), ammonium phosphate ((NH 4 )H 2 PO 4 ) and diammonium phosphate ((NH 4 ) 2 HPO 4 ) selected from the group consisting of It may be one or more, preferably disodium hydrogen phosphate (Na 2 HPO 4 ), sodium dihydrogen phosphate (NaH 2 PO 4 ), or a mixture thereof.
보다 바람직하게, 본 발명의 인산계 완충액은 인산수소이나트륨 및 인산이수소나트륨일 수 있다.More preferably, the phosphate-based buffer of the present invention may be disodium hydrogen phosphate and sodium dihydrogen phosphate.
본 발명의 일 실시양태에 따르면, 상기 인산수소이나트륨 및 인산이수소나트륨의 중량비는 0.1 : 1 내지 20 : 1, 구체적으로 0.3 : 1 내지 10 : 1일 수 있고 바람직하게 0.6 : 1 내지 7 :１ 일 수 있다. According to one embodiment of the present invention, the weight ratio of the disodium hydrogen phosphate and sodium dihydrogen phosphate may be 0.1: 1 to 20: 1, specifically 0.3: 1 to 10: 1, preferably 0.6: 1 to 7:1 can be
보다 바람직하게 본 발명 조성물의 인산수소이나트륨 및 인산이수소나트륨의 중량비는 0.64 :1 내지 6.52 :1일 수 있다. More preferably, the weight ratio of disodium hydrogen phosphate and sodium dihydrogen phosphate in the composition of the present invention may be 0.64:1 to 6.52:1.
본 발명의 일 실험예에 따르면, 인산수소이나트륨 및 인산이수소나트륨의 중량비가 0.6 : 1 내지 7 :１의 범위에 해당하는 실시예 2-4의 경우 가속조건(40 ℃, 75% 상대습도)에서 2개월 후 메틸코발라민의 함량이 거의 변화하지 않아 안정성이 매우 우수함을 확인하였고, 한편 인산수소이나트륨 및 인산이수소나트륨의 중량비가 0.6 : 1 내지 7 :１의 범위에서 벗어나는 실시예 1 및 11의 경우 가속조건(40 ℃, 75% 상대습도)에서 2개월 후 메틸코발라민의 함량이 떨어지는 것을 확인하였다. According to an experimental example of the present invention, in the case of Examples 2-4 in which the weight ratio of disodium hydrogen phosphate and sodium dihydrogen phosphate is in the range of 0.6: 1 to 7: 1, accelerated conditions (40 ° C., 75% relative humidity) After 2 months, it was confirmed that the content of methylcobalamin hardly changed and the stability was very excellent, while the weight ratio of disodium hydrogen phosphate and sodium dihydrogen phosphate was 0.6: 1 to 7: 1. In this case, it was confirmed that the content of methylcobalamin fell after 2 months under accelerated conditions (40 ℃, 75% relative humidity).
또한, 본 발명의 조성물은 6.0 내지 8.0의 pH를 나타낼 수 있으며, 구체적으로 6.2 내지 7.9, 6.3 내지 7.8, 또는 6.5 내지 7.8, 바람직하게 6.5 내지 7.5 일 수 있다. 본 발명 조성물의 pH는 상기 인산계 완충액의 종류 및 이의 비율을 통해 적절하게 조절될 수 있다. 상기 범위로 조성물의 pH를 조절함에 따라 조성물 내 메틸코발라민의 분해를 억제하고 조성물의 안정성을 향상시킬 수 있다. In addition, the composition of the present invention may exhibit a pH of 6.0 to 8.0, specifically may be 6.2 to 7.9, 6.3 to 7.8, or 6.5 to 7.8, preferably 6.5 to 7.5. The pH of the composition of the present invention can be appropriately adjusted through the type and ratio of the phosphate-based buffer. As the pH of the composition is adjusted within the above range, decomposition of methylcobalamin in the composition may be suppressed and stability of the composition may be improved.
본 발명의 당알코올은 만니톨, 솔비톨, 자일리톨, 에리스리톨, 아라비톨, 리비톨, 말티톨, 말토트리톨, 갈락티톨, 이노시톨 및 락티톨로 이루어진 군으로부터 선택되는 하나 이상일 수 있으며, 바람직하게 만니톨일 수 있다. The sugar alcohol of the present invention may be at least one selected from the group consisting of mannitol, sorbitol, xylitol, erythritol, arabitol, ribitol, maltitol, maltotritol, galactitol, inositol, and lactitol, and may be preferably mannitol. .
본 발명에 있어, 당알코올은 메틸코발라민의 코발트 이온과 착화합물을 이루어 메틸코발라민의 안정성을 더욱 개선할 수 있다.In the present invention, the sugar alcohol forms a complex with the cobalt ion of methylcobalamin to further improve the stability of methylcobalamin.
본 발명의 일 실시양태에 따르면, 상기 당알코올은 조성물 총 중량에 대하여 0.1 내지 10 중량%, 구체적으로 0.5 내지 9 중량%, 보다 구체적으로 1 내지 7 중량%로 포함될 수 있다.According to one embodiment of the present invention, the sugar alcohol may be included in 0.1 to 10% by weight, specifically 0.5 to 9% by weight, more specifically 1 to 7% by weight based on the total weight of the composition.
본 발명의 조성물 내 메틸코발라민 및 당알코올의 중량비는 1 : 5 내지 1 : 200, 구체적으로 1 : 7 내지 1 : 190 일 수 있으며, 보다 구체적으로 1 : 10 내지 1 : 180 일 수 있다.The weight ratio of methylcobalamin and sugar alcohol in the composition of the present invention may be 1:5 to 1:200, specifically 1:7 to 1:190, and more specifically 1:10 to 1:180.
또한, 바람직하게 본 발명의 조성물 내 메틸코발라민 및 만니톨의 중량비는 1 : 20 내지 1 : 140일 수 있다. Also, preferably, the weight ratio of methylcobalamin and mannitol in the composition of the present invention may be 1:20 to 1:140.
보다 바람직하게, 본 발명의 조성물 내 메틸코발라민 및 만니톨의 중량비는 1 : 60 내지 1 : 140일 수 있다. More preferably, the weight ratio of methylcobalamin and mannitol in the composition of the present invention may be 1:60 to 1:140.
본 발명의 일 실험예에 따르면, 메틸코발라민 조성물에 당알코올을 추가로 포함함으로써 메틸코발라민의 분해율을 더욱 낮추어 우수한 안정성을 나타냄을 확인하였다.According to an experimental example of the present invention, it was confirmed that the decomposition rate of methylcobalamin was further lowered by further including sugar alcohol in the methylcobalamin composition, thereby exhibiting excellent stability.
또한 본 발명의 일 실험예에 따르면, D-만니톨 및 메틸코발라민의 중량 비가 1 : 60 내지 1 : 180의 범위에 해당하는 실시예 조성물들은 가속조건(40 ℃, 75% 상대습도)에서 2개월 후 메틸코발라민의 함량이 거의 변화하지 않아 안정성이 매우 우수함을 확인하였으나, D-만니톨 및 메틸코발라민의 중량 비가 1 : 20의 범위에 해당하는 실시예의 경우 가속조건(40 ℃, 75% 상대습도)에서 2개월 후 메틸코발라민의 함량이 다소 떨어졌고, D-만니톨 및 메틸코발라민의 중량 비가 1 : 10의 범위에 해당하는 실시예의 경우 가속조건(40 ℃, 75% 상대습도)에서 2개월 후 메틸코발라민의 함량이 상당히 저하됨을 확인할 수 있었다. In addition, according to an experimental example of the present invention, the example compositions corresponding to the weight ratio of D-mannitol and methylcobalamin in the range of 1: 60 to 1: 180 are accelerated conditions (40 ℃, 75% relative humidity) after 2 months Although the content of methylcobalamin hardly changed, it was confirmed that the stability was very excellent. However, in the case of the example in which the weight ratio of D-mannitol and methylcobalamin was in the range of 1: 20, under accelerated conditions (40 ℃, 75% relative humidity) 2 After 2 months, the content of methylcobalamin fell slightly, and in the case of examples in which the weight ratio of D-mannitol and methylcobalamin was in the range of 1: 10, the content of methylcobalamin after 2 months under accelerated conditions (40 ° C., 75% relative humidity) It was found that this significantly decreased.
또한 본 발명의 조성물은 바람직하게 삼투압이 600 mOsmol/Kg 이하일 수 있다. In addition, the composition of the present invention may preferably have an osmotic pressure of 600 mOsmol/Kg or less.
본 발명의 일 실험예에 따르면 본 발명의 조성물에 포함된 당알코올, 예를 들어 만니톨의 함량이 늘어남에 따라 조성물 삼투압이 증가하는 경향을 나타내었는데, D-만니톨 및 메틸코발라민의 중량비가 1 : 140을 초과하는 경우 조성물의 삼투압이 600 mOsmol/Kg을 초과하였고, D-만니톨 및 메틸코발라민의 중량비가 1 : 140 이하인 경우, 주사 투여에 적합한 삼투압인 600 mOsmol/Kg 이하의 삼투압을 나타냄을 확인하였다.According to an experimental example of the present invention, the osmotic pressure of the composition tended to increase as the content of sugar alcohol, for example, mannitol, included in the composition of the present invention increased. The weight ratio of D-mannitol and methylcobalamin was 1:140. It was confirmed that the osmotic pressure of the composition exceeded 600 mOsmol/Kg when exceeding 600 mOsmol/Kg, and when the weight ratio of D-mannitol and methylcobalamin was 1:140 or less, the osmotic pressure suitable for injection administration was 600 mOsmol/Kg or less.
본 발명의 조성물은 40 ℃, 75% 상대습도 조건에서 2개월간 보관 후 조성물 내 메틸코발라민의 함량이 90% 이상, 구체적으로 94% 이상, 보다 구체적으로 98% 이상 유지될 수 있다.In the composition of the present invention, the content of methylcobalamin in the composition may be maintained at 90% or more, specifically 94% or more, and more specifically 98% or more after storage for 2 months at 40° C. and 75% relative humidity.
바람직하게 본 발명의 조성물은 40 ℃, 75% 상대습도 조건에서 2개월간 보관 후 조성물 내 메틸코발라민의 함량이 98.5% 이상, 보다 바람직하게는 99.0% 이상 유지될 수 있다. Preferably, the composition of the present invention can maintain a methylcobalamin content of 98.5% or more, more preferably 99.0% or more, after storage for 2 months at 40° C. and 75% relative humidity.
또한, 본 발명의 조성물은 약학적으로 허용가능한 첨가제 및/또는 담체를 더 포함할 수 있다. 상기 첨가제는 등장화제, 계면활성제, 안정화제, 보존제, 킬레이트제 및 항산화제로 이루어진 군으로부터 선택된 하나 이상일 수 있고, 상기 담체는 유기 용매 및 수성 용매로 이루어진 군으로부터 선택된 하나 이상일 수 있다. In addition, the composition of the present invention may further include a pharmaceutically acceptable additive and/or carrier. The additive may be one or more selected from the group consisting of an isotonic agent, a surfactant, a stabilizer, a preservative, a chelating agent, and an antioxidant, and the carrier may be one or more selected from the group consisting of an organic solvent and an aqueous solvent.
상기 등장화제는 당, 염류 등을 포함하며, 예를 들어 글루코오스, 글리세린, 염화나트륨, 염화칼슘, 황산나트륨, 글리세린, 프로필렌글리콜, 폴리에틸렌글리콜(예를 들어, 분자량 1000 이하의 폴리에틸렌글리콜), 덱스트로오스, 히드록시프로필 베타덱스, 염화칼륨, 덱스트란, 피콜, 젤라틴, 히드록시에칠 전분 등을 포함하나, 이에 제한되는 것은 아니다. 상기 등장화제는 생리학적으로 허용가능한 삼투압을 제공하기에 적합한 양으로 사용될 수 있다.The tonicity agent includes sugars, salts, etc., for example, glucose, glycerin, sodium chloride, calcium chloride, sodium sulfate, glycerin, propylene glycol, polyethylene glycol (eg, polyethylene glycol having a molecular weight of 1000 or less), dextrose, hydro hydroxypropyl betadex, potassium chloride, dextran, ficoll, gelatin, hydroxyethyl starch, and the like, but are not limited thereto. The tonicity agent may be used in an amount suitable to provide a physiologically acceptable osmotic pressure.
상기 보존제는 제제학 분야에서 통상적으로 사용되는 항균제를 포함한다. 상기 보존제는 벤질알코올, 글리세린, m-크레솔, 페놀, 염화 벤잘코늄, 염화 벤잘토늄, 아카시아, 알부민, 알코올, 알긴산, 아스코빌팔미테이트, 아스파탐, 붕산, 구연산, 펜테틱산, 아세트산 나트륨, 소르빈산, 클로로부탄올, o-크레솔, ρ-크레솔, 클로로크레솔, 페닐수은산 질산염, 티메로살, 벤조산, 콜레스테롤 등을 포함하나, 이에 제한되는 것은 아니다.The preservatives include antimicrobial agents commonly used in the field of pharmaceuticals. The preservative is benzyl alcohol, glycerin, m-cresol, phenol, benzalkonium chloride, benzaltonium chloride, acacia, albumin, alcohol, alginic acid, ascorbyl palmitate, aspartame, boric acid, citric acid, pentetic acid, sodium acetate, sorbic acid, chlorobutanol, o-cresol, ρ-cresol, chlorocresol, phenylmercuric acid nitrate, thimerosal, benzoic acid, cholesterol, and the like, but are not limited thereto.
상기 항산화제는 알파 토코페롤 (Alpha tocopherol), 부틸레이티드 하이드록시톨루엔 (Butylated hydroxytoluene), 부틸레이티드 하이드록시아니솔 (Butylated hydroxyanisole), 포타슘메타비술파이트 (Potassium metabisulfite), 소듐 비술파이트 (Sodium bisulfite), 시스테인 (Cysteine) 등을 포함하나, 이에 제한되는 것은 아니다.The antioxidant is alpha tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, potassium metabisulfite, sodium bisulfite , Cysteine and the like, but are not limited thereto.
상기 수성 용매는 주사용수, 멸균 증류수, 염수, 수성 덱스트로스 또는 수성 수크로오스 등을 포함하나, 이에 제한되는 것은 아니다.The aqueous solvent includes, but is not limited to, water for injection, sterile distilled water, saline, aqueous dextrose or aqueous sucrose, and the like.
본 발명에 따른 약학 조성물은 메틸코발라민을 유효성분으로 투여하여 치료되는 모든 질병, 장애 및/또는 증상의 의약 용도라면 제한되지 않고 사용될 수 있으며, 예를 들어, 당뇨병성 신경장애, 다발성 신경염 등의 말초성 신경장애, 거대적아구성 빈혈 (megaloblastic anaemia), 근위축성 측색 경화증 (Amyotrophic lateral sclerosis, ALS) 등의 비타민 B12 결핍증의 예방 및/또는 치료를 위해 사용될 수 있다.The pharmaceutical composition according to the present invention can be used without limitation as long as it is for medicinal purposes for all diseases, disorders and / or symptoms treated by administering methylcobalamin as an active ingredient, for example, peripheral neuropathy such as diabetic neuropathy and polyneuritis. It can be used for the prevention and/or treatment of vitamin B12 deficiency, such as neuropathy, megaloblastic anaemia, and amyotrophic lateral sclerosis (ALS).
바람직하게 본 발명의 조성물은 액상 조성물일 수 있다. Preferably, the composition of the present invention may be a liquid composition.
또한, 본 발명의 조성물은 비경구로 투여될 수 있으며, 구체적으로 비경구로 국소 투여될 수 있다. 상기 국소 투여는 눈 밑, 턱 밑, 팔 밑, 엉덩이, 종아리, 등, 넓적다리, 발목, 복부 부위 등에 국소로 적용되는 것을 포함한다. 예를 들어, 본 발명의 조성물은 비경구 투여용 제제(국소 투여 제제를 포함)로 제제화될 수 있으며, 구체적으로 상기 비경구 투여용 제제는 주사제일 수 있고, 보다 구체적으로 경피 투여용 제제, 피하 투여용 제제, 정맥내 투여용 제제, 근육내 투여용 제제 또는 복강내 투여용 제제일 수 있다.In addition, the composition of the present invention may be administered parenterally, and specifically, may be administered topically parenterally. The topical administration includes topical application under the eyes, under the chin, under the arms, buttocks, calves, back, thighs, ankles, abdomen, and the like. For example, the composition of the present invention may be formulated as a preparation for parenteral administration (including topical administration preparations), specifically, the preparation for parenteral administration may be an injection, more specifically, a preparation for transdermal administration, subcutaneous administration It may be a preparation for administration, a preparation for intravenous administration, a preparation for intramuscular administration, or a preparation for intraperitoneal administration.
상기 비경구 투여용 제제는 단회 또는 수회 투여될 수 있으며, 투여 형태는 조성물을 투여하는 목적에 따라 적절히 선택될 수 있다. 상기 비경구 투여용 제제의 투여량은 사용된 약리학적 활성물질의 공지된 투여량과 동일하나, 환자의 질환의 종류, 증상 정도, 연령, 체중, 성별 등에 따라 달라질 수 있다. 예를 들어, 상기 수회 투여용 제제는 메틸코발라민으로서 1일 1회 500 ㎍을 주 3회 근육, 정맥 또는 피하 주사될 수 있고, 증상 소실 후에는 1 ~ 3개월에 1회 500 ㎍을 근육, 정맥 또는 피하 주사될 수 있으며, 환자의 연령, 증상 등에 따라 적절히 증감할 수 있다. 또한, 필요에 따라 상기 비경구 투여용 제제는 0.5 내지 2.0 cm로 이격된 부위에 반복 투여될 수 있다.The preparation for parenteral administration may be administered once or several times, and the dosage form may be appropriately selected depending on the purpose of administering the composition. The dose of the preparation for parenteral administration is the same as the known dose of the pharmacologically active substance used, but may vary depending on the type of disease, degree of symptoms, age, weight, sex, etc. of the patient. For example, the formulation for multiple administration is methylcobalamin, which can be injected intramuscularly, intravenously or subcutaneously at 500 μg once a day three times a week, and after symptom disappearance, 500 μg intramuscularly or intravenously once every 1 to 3 months Alternatively, it may be injected subcutaneously, and may be appropriately increased or decreased according to the patient's age, symptoms, and the like. In addition, if necessary, the formulation for parenteral administration may be repeatedly administered to sites spaced apart from each other by 0.5 to 2.0 cm.
본 발명의 조성물이 피하, 피내 또는 근육 주사로 투여될 경우, 조성물의 삼투압은 600 mOsmol/kg 이하일 수 있다. When the composition of the present invention is administered by subcutaneous, intradermal or intramuscular injection, the osmotic pressure of the composition may be 600 mOsmol/kg or less.
상기 비경구 투여용 제제는 용액, 에멀젼, 현탄액, 동결건조 등의 형태를 포함하며, 구체적으로 용액 또는 에멀젼의 형태일 수 있다. 상기 액상 제제는 통상 밀봉, 멸균된 플라스틱 또는 유기 용기 내에 담겨져 있을 수 있다. 용기는 앰플, 바이알, 시린지 또는 카트리지와 같은 규정 용량의 형상으로 공급할 수 있거나 주사용 백 또는 병과 같은 대용량의 형상으로 공급할 수도 있다.The formulation for parenteral administration includes solutions, emulsions, suspensions, freeze-dried forms, and the like, and may be specifically in the form of solutions or emulsions. The liquid preparation may be contained in a sealed, sterilized plastic or organic container. The container may be supplied in the form of a prescribed volume such as an ampoule, vial, syringe or cartridge, or may be supplied in the form of a large volume such as a bag or bottle for injection.
본 발명의 인산계 완충액 및 당알코올을 포함하는 메틸코발라민 조성물은 액상에서 메틸코발라민의 히드록소코발라민으로의 전환을 억제 또는 지연시켜 우수한 안정성을 나타낼 수 있다.The methylcobalamin composition containing the phosphate-based buffer and sugar alcohol of the present invention can exhibit excellent stability by inhibiting or delaying the conversion of methylcobalamin to hydroxocobalamin in a liquid phase.
이하, 실시예를 통하여 본 발명의 구성 및 효과를 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들 실시예에 의해 제한되는 것은 아니다.Hereinafter, the configuration and effects of the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, but the scope of the present invention is not limited by these examples.
실시예 1 내지 11Examples 1 to 11
하기 표 1의 성분 및 함량을 사용하여 본 발명의 조성물을 액상 형태의 제제로 제조하였다. The composition of the present invention was prepared as a liquid formulation using the components and contents shown in Table 1 below.
구체적으로, 제조탱크 내 주사용수 9 kg을 채수하여 질소퍼지를 실시한 후 D-만니톨을 추가하여 350 rpm으로 20분 동안 교반하여 완전히 용해시켰다. 이 후, 인산수소이나트륨과 인산이수소나트륨을 첨가하여 완전히 용해될 때까지 교반하였다. 상기 제조탱크 내에 메틸코발라민을 첨가하고, 제조탱크의 최종 부피가 10 L가 될 때까지 채수한 후 350 rpm으로 20분 동안 최종 교반하였다. 상기의 모든 공정은 차광상태에서 나트륨등의 점등 하에 진행하였다.Specifically, 9 kg of water for injection in the production tank was collected and purged with nitrogen, and then D-mannitol was added and stirred at 350 rpm for 20 minutes to dissolve completely. Thereafter, disodium hydrogen phosphate and sodium dihydrogen phosphate were added and stirred until completely dissolved. Methylcobalamin was added to the production tank, and water was sampled until the final volume of the production tank was 10 L, followed by final stirring at 350 rpm for 20 minutes. All of the above processes were performed under the lighting of a sodium lamp in a shaded state.
비교예 1 내지 3Comparative Examples 1 to 3
하기 표 2의 성분 및 함량을 사용하여 비교예 1 내지 3의 조성물을 액상 형태의 제제로 제조하였으며, 구체적인 제조방법은 상기 실시예 1 내지 11의 제조방법과 동일하다.The compositions of Comparative Examples 1 to 3 were prepared as liquid formulations using the ingredients and contents of Table 2 below, and specific preparation methods are the same as those of Examples 1 to 11.
실험예 1: 약학 조성물의 pH 측정Experimental Example 1: pH measurement of pharmaceutical composition
각 실시예 및 비교예에서 제조된 액상 제제의 초기(0일) 및 가속(40 ℃, 75% 상대습도) 조건에서 2개월간 보관 후 pH를 측정하였다. 구체적으로, 실시예 1 내지 4와 비교예 1 및 2를 350 rpm으로 10분 간 교반하여 각 액의 pH를 25 ± 2 ℃에서, pH 미터(Mettler toledo, SevenCompact pH/Ion meter, USA)를 이용하여 측정하였으며, 측정 결과를 하기 표 3에 나타내었다.The pH of the liquid formulations prepared in each Example and Comparative Example was measured after storage for 2 months under initial (day 0) and accelerated (40 °C, 75% relative humidity) conditions. Specifically, Examples 1 to 4 and Comparative Examples 1 and 2 were stirred at 350 rpm for 10 minutes to measure the pH of each solution at 25 ± 2 ° C using a pH meter (Mettler toledo, SevenCompact pH / Ion meter, USA). was measured, and the measurement results are shown in Table 3 below.
상기 표 3에서 확인되는 바와 같이, 비교예 1 및 2는 가속조건에서 2개월 후 pH가 상승한 반면, 본 발명의 조성물은 가속조건 2개월 후에도 초기 pH를 유지함을 확인하였다.As confirmed in Table 3, while the pH of Comparative Examples 1 and 2 increased after 2 months under accelerated conditions, it was confirmed that the composition of the present invention maintained its initial pH even after 2 months under accelerated conditions.
실험예 2: 약학 조성물의 안정성 평가Experimental Example 2: Evaluation of stability of pharmaceutical composition
각 실시예 및 비교예에서 제조된 액상 제제를 40 ℃, 75% 상대습도 조건 하에서 2개월간 보관한 후 검체의 메틸코발라민 및 총 코발라민 함량을 측정하였으며, 상기 '총 코발라민 함량'은 메틸코발라민 및 히드록소코발라민 함량의 합을 의미한다.The liquid formulations prepared in each Example and Comparative Example were stored for 2 months at 40 ° C. and 75% relative humidity, and then the contents of methylcobalamin and total cobalamin of the sample were measured. Means the sum of cobalamin content.
구체적으로, 메틸코발라민의 함량을 하기 조건의 HPLC(Waters, E2695XC, USA)를 이용하여 측정하였다Specifically, the content of methylcobalamin was measured using HPLC (Waters, E2695XC, USA) under the following conditions.
<HPLC 분석 조건><HPLC analysis conditions>
검 출 기 : 자외부흡광광도계 (측정파장 : 266 nm)Detector: UV absorbance photometer (measurement wavelength: 266 nm)
칼 럼 : Zorbax SB-C18(4.6 Х 250 mm, 5 ㎛) 또는 이와 동등한 칼럼Column: Zorbax SB-C18 (4.6 Х 250 mm, 5 ㎛) or equivalent column
칼럼온도 : 40 ℃ 부근의 일정한 온도Column temperature: constant temperature around 40 ℃
샘플온도 : 25 ℃ 부근의 일정한 온도Sample temperature: constant temperature around 25 ℃
주 입 량 : 10 μLInjection volume: 10 μL
유 량 : 0.6 mL/분Flow rate: 0.6 mL/min
이 동 상 : 아세토니트릴 200 mL에 pH 3.5 인산염 완충액 800 mL를 넣고 1-헥산설폰산나트륨 3.76 g을 넣어 녹임 Transition phase: Add 800 mL of pH 3.5 phosphate buffer to 200 mL of acetonitrile and dissolve 3.76 g of sodium 1-hexanesulfonate.
또한, 검액에 시안화칼륨용액을 첨가한 액을 200 W의 형광등으로 30 cm의 거리에서 때때로 흔들어 섞으면서 90 분간 쪼인 액을 가지고 시안화칼륨용액(1 → 200)을 대조로 하여 자외가시부흡광도측정장비(JASCO, UV-750, JAPAN)를 이용하여 총 코발라민 함량 측정(368 nm)을 수행하였다.In addition, the solution in which the potassium cyanide solution was added to the test solution was incubated for 90 minutes while shaking occasionally at a distance of 30 cm with a 200 W fluorescent lamp, and the potassium cyanide solution (1 → 200) was used as a control. (JASCO, UV-750, JAPAN) was used to measure the total cobalamin content (368 nm).
메틸코발라민 및 총 코발라민 함량의 측정 결과를 하기 표 4에 나타내었다.The measurement results of methylcobalamin and total cobalamin content are shown in Table 4 below.
상기 표 4에서 확인되는 바와 같이, 비교예 2, 3 및 실시예 11은 총 코발라민 함량에서 비교적 높은 수치를 나타내었으나, 메틸코발라민 함량은 현저히 감소되었으며, 이는 메틸코발라민이 분해되거나 히드록소코발라민으로 전환된 것으로 해석된다. As confirmed in Table 4, Comparative Examples 2 and 3 and Example 11 showed relatively high values in total cobalamin content, but the methylcobalamin content was significantly reduced, indicating that methylcobalamin was decomposed or converted to hydroxocobalamin. interpreted as
이와 달리, 본 발명에 따른 실시예 1 내지 10의 조성물은 비교예 1 내지 3과 비교하여 총 코발라민 함량뿐만 아니라 메틸코발라민 함량 또한 높은 수준으로 유지되었다. 특히, 실시예 2 내지 4 및 6 내지 10의 조성물은 가속조건에서 98.0% 이상의 메틸코발라민 함량을 유지하여 더욱욱 우수한 안정성을 나타냄을 확인하였다.In contrast, the compositions of Examples 1 to 10 according to the present invention maintained high levels of methylcobalamin content as well as total cobalamin content compared to Comparative Examples 1 to 3. In particular, it was confirmed that the compositions of Examples 2 to 4 and 6 to 10 showed more excellent stability by maintaining the methylcobalamin content of 98.0% or more under accelerated conditions.
비교예 4 내지 7Comparative Examples 4 to 7
하기 표 5의 성분 및 함량을 사용하여 비교예 4 내지 6의 조성물을 액상 형태의 제제로 제조하였으며, 구체적인 제조방법은 상기 실시예 1 내지 11의 제조방법과 동일하다.The compositions of Comparative Examples 4 to 6 were prepared as liquid formulations using the components and contents shown in Table 5 below, and specific preparation methods are the same as those of Examples 1 to 11.
실험예 3: 약학 조성물의 pH 측정Experimental Example 3: pH measurement of pharmaceutical composition
각 실시예 및 비교예에서 제조된 액상 제제의 초기(0일) 및 가속(40 ℃, 75% 상대습도) 조건에서 2개월간 보관 후 pH를 측정하였다. 구체적으로, 실시예 11과 비교예 4 및 5를 350 rpm으로 10분 간 교반하여 각 액의 pH를 25 ± 2 ℃에서, pH 미터(Mettler toledo, SevenCompact pH/Ion meter, USA)를 이용하여 측정하였으며, 측정 결과를 하기 표 6에 나타내었다.The pH of the liquid formulations prepared in each Example and Comparative Example was measured after storage for 2 months under initial (day 0) and accelerated (40 °C, 75% relative humidity) conditions. Specifically, Example 11 and Comparative Examples 4 and 5 were stirred at 350 rpm for 10 minutes, and the pH of each solution was measured at 25 ± 2 ° C using a pH meter (Mettler toledo, SevenCompact pH / Ion meter, USA). And the measurement results are shown in Table 6 below.
상기 표 6에서 확인되는 바와 같이, 본 발명의 조성물은 가속조건 2개월 후에도 pH 변화가 거의 없었던 반면, 비교예 4 및 5는 가속조건에서 2개월 후 pH가 낮아짐을 확인하였다. 이를 통해 다른 pH 조정제를 사용한 경우 대비 인산염계 완충제를 사용할 경우 메틸코발라민 조성물의 안정성을 유지하는 데 더욱 효과적임을 알 수 있었다.As confirmed in Table 6, the composition of the present invention showed little change in pH even after 2 months under accelerated conditions, whereas Comparative Examples 4 and 5 confirmed that the pH decreased after 2 months under accelerated conditions. Through this, it was found that the use of a phosphate-based buffer was more effective in maintaining the stability of the methylcobalamin composition compared to the case of using other pH adjusting agents.
실험예 4: 약학 조성물의 삼투압 측정Experimental Example 4: Measurement of osmotic pressure of pharmaceutical composition
각 실시예에서 제조된 액상 제제의 삼투압을 빙점강하(어는점내림) 측정원리를 응용한 삼투압측정기(제조사: Gonotec (독일), 모델: Osmomat030D)를 이용하여 검체 50 μL를 이용하여 측정하였으며, 그 결과를 각 조성물 내 포함된 D-만니톨/메틸코발라민의 비율계수와 함께 하기 표 7에 나타내었다.The osmotic pressure of the liquid formulation prepared in each example was measured using 50 μL of the sample using an osmometer (manufacturer: Gonotec (Germany), model: Osmomat030D) applying the freezing point depression (freezing point depression) measurement principle, and the results It is shown in Table 7 below along with the ratio coefficient of D-mannitol/methylcobalamin included in each composition.
상기 표 7에서 확인되는 바와 같이, 본 발명의 조성물은 D-만니톨/메틸코발라민 중량 비율이 10 내지 180의 범위를 가진다. 삼투압 측정 결과, D-만니톨/메틸코발라민의 중량 비율이 140 이하인 경우 조성물의 삼투압이 600 mOsmol/kg을 초과하지 않아 근육 또는 정맥 주사로 사용하기에 적합함을 확인할 수 있었고, 한편, D-만니톨/메틸코발라민의 중량 비율이 140을 초과하는 180인 경우, 조성물의 삼투압이 702 mOsmol/kg로 600 mOsmol/kg을 초과하여 주사 투여에 적절하지 않음을 확인하였다.As confirmed in Table 7, the composition of the present invention has a D-mannitol/methylcobalamin weight ratio in the range of 10 to 180. As a result of the osmotic pressure measurement, it was confirmed that when the weight ratio of D-mannitol/methylcobalamin was 140 or less, the osmotic pressure of the composition did not exceed 600 mOsmol/kg, making it suitable for intramuscular or intravenous injection. When the weight ratio of methylcobalamin was greater than 140 to 180, the composition had an osmotic pressure of 702 mOsmol/kg and exceeded 600 mOsmol/kg, confirming that it was not suitable for injection administration.
실험예 5: 약학 조성물의 안정성 평가Experimental Example 5: Evaluation of stability of pharmaceutical composition
각 실시예 및 비교예에서 제조된 액상 제제를 40 ℃, 75% 상대습도 조건 하에서 2개월간 보관한 후 검체의 메틸코발라민 함량을 측정하였다.The liquid formulations prepared in each Example and Comparative Example were stored at 40 °C and 75% relative humidity for 2 months, and then the methylcobalamin content of the sample was measured.
구체적으로, 메틸코발라민의 함량을 하기 조건의 HPLC(Waters, E2695XC, USA)를 이용하여 측정하고 그 결과를 각 조성물 내 인산염 완충제의 비율계수(인산수소나트륨 중량/인산이수소나트륨 중량)과 함께 표 8에 나타내었다. Specifically, the content of methylcobalamin was measured using HPLC (Waters, E2695XC, USA) under the following conditions, and the results were tabulated together with the ratio coefficient (sodium hydrogen phosphate weight / sodium dihydrogen phosphate weight) of the phosphate buffer in each composition 8.
<HPLC 분석 조건><HPLC analysis conditions>
검 출 기 : 자외부흡광광도계 (측정파장 : 266 nm)Detector: UV absorbance photometer (measurement wavelength: 266 nm)
칼 럼 : Zorbax SB-C18(4.6 Х 250 mm, 5 ㎛) 또는 이와 동등한 칼럼Column: Zorbax SB-C18 (4.6 Х 250 mm, 5 ㎛) or equivalent column
칼럼온도 : 40 ℃ 부근의 일정한 온도Column temperature: constant temperature around 40 ℃
샘플온도 : 25 ℃ 부근의 일정한 온도Sample temperature: constant temperature around 25 ℃
주 입 량 : 10 μLInjection volume: 10 μL
유 량 : 0.6 mL/분Flow rate: 0.6 mL/min
이 동 상 : 아세토니트릴 200 mL에 pH 3.5 인산염 완충액 800 mL를 넣고 1-헥산설폰산나트륨 3.76 g을 넣어 녹임Transition phase: Add 800 mL of pH 3.5 phosphate buffer to 200 mL of acetonitrile and dissolve 3.76 g of sodium 1-hexanesulfonate.
(인산수소나트륨 중량/인산이수소나트륨 중량)Ratio factor of phosphate buffer
(weight of sodium hydrogen phosphate/weight of sodium dihydrogen phosphate)
상기 표 8에서 확인되는 바와 같이, pH 조정제로 인산염 완충제를 사용한 실시예 1 내지 4 및 11의 메틸코발라민 함량 안정성 결과 가속조건 2개월 후 각 실시예 별로 메틸코발라민의 함량이 상이하였다. 구체적으로 인산염 완충액 중량 비율계수(인산수소나트륨의 중량/인산이수소나트륨의 중량)가 11.36인 실시예 1과 0.30인 실시예 11의 가속조건 2개월 후 메틸코발라민 함량은 현저히 떨어졌으나, 인산염 완충액 비율계수(인산수소나트륨의 중량/인산이수소나트륨의 중량)가 6.52 내지 0.64인 실시예 2 내지 4의 조성물은 가속조건 2개월 후, 메틸코발라민의 함량이 안정적으로 유지됨을 확인할 수 있었다. As confirmed in Table 8, the methylcobalamin content stability results of Examples 1 to 4 and 11 using a phosphate buffer as a pH adjusting agent were different for each example after 2 months under accelerated conditions. Specifically, the phosphate buffer weight ratio coefficient (weight of sodium hydrogen phosphate / weight of sodium dihydrogen phosphate) was 11.36 in Example 1 and 0.30 in Example 11. After 2 months of accelerated conditions, the methylcobalamin content dropped significantly, but the phosphate buffer ratio It was confirmed that the compositions of Examples 2 to 4 having a coefficient (weight of sodium hydrogen phosphate/weight of sodium dihydrogen phosphate) of 6.52 to 0.64 maintained a stable content of methylcobalamin after 2 months under accelerated conditions.
또한, 동일한 인산염 완충액 비율계수(인산수소나트륨의 중량/인산이수소나트륨의 중량)의 인산염 완충액을 사용한 경우에도, D-만니톨/메틸코발라민의 중량 비율계수에 차이가 있는 실시예 5-10의 메틸코발라민 함량 안정성 결과가 상이하였다. 구체적으로, D-만니톨/메틸코발라민의 중량 비율계수가 10인 실시예 5의 조성물은 가속조건 2개월 후 메틸코발라민 함량은 상당히 떨어졌고, D-만니톨/메틸코발라민의 중량 비율계수가 20인 실시예 6의 조성물은 가속조건 2개월 후 메틸코발라민 함량은 다소 떨어졌다. 한편, D-만니톨/메틸코발라민의 중량 비율계수가 60 내지 180인 실시예 7-10의 조성물은 가속조건 2개월 후, 메틸코발라민의 함량이 안정적으로 유지됨을 확인할 수 있었다.In addition, even when using the same phosphate buffer ratio coefficient (weight of sodium hydrogen phosphate / weight of sodium dihydrogen phosphate), the methyl of Example 5-10 having a difference in the weight ratio coefficient of D-mannitol / methylcobalamin The cobalamin content stability results were different. Specifically, in the composition of Example 5 in which the weight ratio factor of D-mannitol/methylcobalamin was 10, the content of methylcobalamin dropped significantly after 2 months under accelerated conditions, and the weight ratio factor of D-mannitol/methylcobalamin was 20. In the composition of 6, the content of methylcobalamin dropped slightly after 2 months under accelerated conditions. On the other hand, in the compositions of Examples 7-10 having a weight ratio coefficient of D-mannitol/methylcobalamin of 60 to 180, it was confirmed that the content of methylcobalamin was stably maintained after 2 months under accelerated conditions.
다른 한편, 인산염 완충제 대신 다른 종류의 pH 조정제를 사용하는 비교예 3 및 4, 만니톨 대신 다른 당알콜을 사용한 비교예 6 및 7의 경우 가속조건 2개월 후 메틸코발라민 함량은 현저히 떨어짐을 확인할 수 있었다. On the other hand, in the case of Comparative Examples 3 and 4 using a different type of pH adjusting agent instead of the phosphate buffer and Comparative Examples 6 and 7 using another sugar alcohol instead of mannitol, it was confirmed that the methylcobalamin content significantly decreased after 2 months under accelerated conditions.
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