WO2020060183A1 - Formation de liquide pour stabiliser un anticorps de trastuzumab - Google Patents
Formation de liquide pour stabiliser un anticorps de trastuzumab Download PDFInfo
- Publication number
- WO2020060183A1 WO2020060183A1 PCT/KR2019/012056 KR2019012056W WO2020060183A1 WO 2020060183 A1 WO2020060183 A1 WO 2020060183A1 KR 2019012056 W KR2019012056 W KR 2019012056W WO 2020060183 A1 WO2020060183 A1 WO 2020060183A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- liquid formulation
- trastuzumab
- stabilizer
- acid
- antigen
- Prior art date
Links
- 229960000575 trastuzumab Drugs 0.000 title claims abstract description 52
- 239000007788 liquid Substances 0.000 title description 6
- 230000000087 stabilizing effect Effects 0.000 title description 3
- 230000015572 biosynthetic process Effects 0.000 title description 2
- 239000012669 liquid formulation Substances 0.000 claims abstract description 61
- 239000003381 stabilizer Substances 0.000 claims abstract description 39
- 239000000427 antigen Substances 0.000 claims abstract description 36
- 102000036639 antigens Human genes 0.000 claims abstract description 36
- 108091007433 antigens Proteins 0.000 claims abstract description 36
- 239000012634 fragment Substances 0.000 claims abstract description 34
- 239000006172 buffering agent Substances 0.000 claims abstract description 30
- 239000004094 surface-active agent Substances 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 19
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 30
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 29
- 229930182817 methionine Natural products 0.000 claims description 29
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 27
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 27
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 24
- -1 met oligosaccharide Chemical class 0.000 claims description 16
- 229920000136 polysorbate Polymers 0.000 claims description 10
- 150000005846 sugar alcohols Chemical class 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 8
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 8
- 150000001413 amino acids Chemical class 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 8
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 8
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 8
- 229940068977 polysorbate 20 Drugs 0.000 claims description 8
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 6
- 229950008882 polysorbate Drugs 0.000 claims description 6
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 5
- 229920000053 polysorbate 80 Polymers 0.000 claims description 5
- 229940068968 polysorbate 80 Drugs 0.000 claims description 5
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims description 4
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims description 4
- 238000010253 intravenous injection Methods 0.000 claims description 4
- 229920005862 polyol Polymers 0.000 claims description 4
- 150000003077 polyols Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000010254 subcutaneous injection Methods 0.000 claims description 4
- 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 3
- 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 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 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 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 claims description 3
- 235000011187 glycerol Nutrition 0.000 claims description 3
- 229920001542 oligosaccharide Polymers 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- LUAHEUHBAZYUOI-KVXMBEGHSA-N (2s,3r,4r,5r)-4-[(2r,3r,4r,5s,6r)-5-[(2r,3r,4r,5s,6r)-3,4-dihydroxy-6-(hydroxymethyl)-5-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyhexane-1,2,3,5,6-pentol Chemical compound O[C@@H]1[C@@H](O)[C@@H](O[C@@H]([C@H](O)[C@@H](O)CO)[C@H](O)CO)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@@H](CO)O1 LUAHEUHBAZYUOI-KVXMBEGHSA-N 0.000 claims description 2
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 229920002101 Chitin Polymers 0.000 claims description 2
- 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 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-ZXXMMSQZSA-N D-iditol Chemical compound OC[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-ZXXMMSQZSA-N 0.000 claims description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 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
- 229930091371 Fructose Natural products 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- 229920002527 Glycogen Polymers 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
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- XJCCHWKNFMUJFE-CGQAXDJHSA-N Maltotriitol Chemical compound O[C@@H]1[C@@H](O)[C@@H](O[C@@H]([C@H](O)[C@@H](O)CO)[C@H](O)CO)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 XJCCHWKNFMUJFE-CGQAXDJHSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 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
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 2
- UQZIYBXSHAGNOE-USOSMYMVSA-N Stachyose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](CO[C@@H]2[C@@H](O)[C@@H](O)[C@@H](O)[C@H](CO)O2)O1 UQZIYBXSHAGNOE-USOSMYMVSA-N 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 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
- 235000019414 erythritol Nutrition 0.000 claims description 2
- 229940009714 erythritol Drugs 0.000 claims description 2
- FTSSQIKWUOOEGC-RULYVFMPSA-N fructooligosaccharide Chemical compound OC[C@H]1O[C@@](CO)(OC[C@@]2(OC[C@@]3(OC[C@@]4(OC[C@@]5(OC[C@@]6(OC[C@@]7(OC[C@@]8(OC[C@@]9(OC[C@@]%10(OC[C@@]%11(O[C@H]%12O[C@H](CO)[C@@H](O)[C@H](O)[C@H]%12O)O[C@H](CO)[C@@H](O)[C@@H]%11O)O[C@H](CO)[C@@H](O)[C@@H]%10O)O[C@H](CO)[C@@H](O)[C@@H]9O)O[C@H](CO)[C@@H](O)[C@@H]8O)O[C@H](CO)[C@@H](O)[C@@H]7O)O[C@H](CO)[C@@H](O)[C@@H]6O)O[C@H](CO)[C@@H](O)[C@@H]5O)O[C@H](CO)[C@@H](O)[C@@H]4O)O[C@H](CO)[C@@H](O)[C@@H]3O)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@@H](O)[C@@H]1O FTSSQIKWUOOEGC-RULYVFMPSA-N 0.000 claims description 2
- 229940107187 fructooligosaccharide 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
- 229930182830 galactose Natural products 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 229940096919 glycogen Drugs 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
- 239000000905 isomalt Substances 0.000 claims description 2
- 235000010439 isomalt Nutrition 0.000 claims description 2
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 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
- 239000008101 lactose Substances 0.000 claims description 2
- 239000000845 maltitol Substances 0.000 claims description 2
- 235000010449 maltitol Nutrition 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
- 229940035436 maltitol Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 235000010987 pectin Nutrition 0.000 claims description 2
- 239000001814 pectin Substances 0.000 claims description 2
- 229920001277 pectin Polymers 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
- UQZIYBXSHAGNOE-XNSRJBNMSA-N stachyose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)O2)O)O1 UQZIYBXSHAGNOE-XNSRJBNMSA-N 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 239000000203 mixture Substances 0.000 description 52
- 238000009472 formulation Methods 0.000 description 48
- 108010003272 Hyaluronate lyase Proteins 0.000 description 20
- 230000000052 comparative effect Effects 0.000 description 16
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 12
- 230000004071 biological effect Effects 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 239000000178 monomer Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 102000003886 Glycoproteins Human genes 0.000 description 5
- 108090000288 Glycoproteins Proteins 0.000 description 5
- 102000001974 Hyaluronidases Human genes 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 5
- 230000002776 aggregation Effects 0.000 description 5
- 229960002773 hyaluronidase Drugs 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000003642 reactive oxygen metabolite Substances 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000000872 buffer Substances 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000008177 pharmaceutical agent Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 239000004743 Polypropylene Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000008365 aqueous carrier Substances 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
- 238000000502 dialysis Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940022353 herceptin Drugs 0.000 description 3
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-MNSSHETKSA-N 0.000 description 3
- 229920002674 hyaluronan Polymers 0.000 description 3
- 229940099552 hyaluronan Drugs 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229920001155 polypropylene Polymers 0.000 description 3
- 229940068965 polysorbates Drugs 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- QZNNVYOVQUKYSC-JEDNCBNOSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid;hydron;chloride Chemical compound Cl.OC(=O)[C@@H](N)CC1=CN=CN1 QZNNVYOVQUKYSC-JEDNCBNOSA-N 0.000 description 2
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 150000005215 alkyl ethers Chemical class 0.000 description 2
- 239000008228 bacteriostatic water for injection Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 238000012506 imaged capillary isoelectric focusing Methods 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004792 oxidative damage Effects 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 238000001525 receptor binding assay Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000008227 sterile water for injection Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- 229940043375 1,5-pentanediol Drugs 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical group OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 description 1
- 101000585728 Homo sapiens Protein O-GlcNAcase Proteins 0.000 description 1
- 101100178973 Homo sapiens SPAM1 gene Proteins 0.000 description 1
- 102100021102 Hyaluronidase PH-20 Human genes 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical group CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 101150055528 SPAM1 gene Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940042450 amphadase Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000013368 capillary electrophoresis sodium dodecyl sulfate analysis Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 230000001687 destabilization Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
- 229940113120 dipropylene glycol Drugs 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 229940051250 hexylene glycol Drugs 0.000 description 1
- 239000013628 high molecular weight specie Substances 0.000 description 1
- 102000046319 human OGA Human genes 0.000 description 1
- 229940048921 humira Drugs 0.000 description 1
- 229940044734 hydase Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 108010023571 hylase Proteins 0.000 description 1
- 229940044700 hylenex Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000000050 ionisation spectroscopy Methods 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000013627 low molecular weight specie Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- WCVRQHFDJLLWFE-UHFFFAOYSA-N pentane-1,2-diol Chemical compound CCCC(O)CO WCVRQHFDJLLWFE-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 230000004845 protein aggregation Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229940068638 simponi Drugs 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000001269 time-of-flight mass spectrometry Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229940054953 vitrase Drugs 0.000 description 1
- 229940099073 xolair Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
-
- 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
Definitions
- the present invention relates to a stable liquid formulation comprising trastuzumab or an antigen-binding fragment thereof, and more specifically, a liquid formulation capable of stabilizing trastuzumab or an antigen-binding fragment thereof that does not contain a surfactant, and its preparation It's about how.
- Antibody pharmaceuticals may be exposed to various environments during manufacture, transportation, storage and administration or undergo phase changes such as air-liquid, solid-liquid, or liquid-liquid. In particular, when the antibody contacts the hydrophobic interface, problems such as protein aggregation or particle formation may occur.
- surfactants such as polysorbate 20 or polysorbate 80 are mainly used.
- Antibody formulations comprising polysorbate 20 are known to reduce protein uptake or aggregation.
- polysorbates are known to degrade through oxidation and hydrolysis, which in turn produces reactive oxygen species (ROS), resulting in oxidative damage to antibody proteins.
- ROS reactive oxygen species
- One aspect of the present invention is to provide a liquid formulation capable of maintaining stability without inducing aggregation of the antibody without including a surfactant capable of decomposing by oxidation and hydrolysis to generate ROS.
- Another aspect of the present invention adding a stabilizer and a buffering agent to the solvent to prepare a mixed solution; And adding trastuzumab to the mixed solution.
- One aspect of the invention (a) Trastuzumab or an antigen-binding fragment thereof; (b) stabilizer; And (c) a buffering agent and no surfactant.
- Another aspect of the present invention adding a stabilizer and a buffering agent to the solvent to prepare a mixed solution; And adding trastuzumab to the mixed solution.
- liquid formulation according to one aspect of the present invention can maintain the stability of the antibody without including polysorbate, which may cause ROS under stress conditions.
- Example 1 is a change in the percent high molecular weight material (percent high molecular weight,% HMW) of Example 1 and Comparative Example 1 under temperature stress conditions by size exclusion-high performance liquid chromatography (Size-Exclusion HPLC, SE-HPLC) It is a graph showing one result.
- Example 1 The formulations of Example 1 and Comparative Example 1 were prepared.
- trastuzumab (5 mM histidine buffer (pH 6.0), 40 mg / mL, Samsung Bioepis) and a buffering agent and a stabilizer, except for the surfactant, are made of polycarbonate material of 5L baotainer (biotainer) ) 5L buffer solution was prepared by adding to sterile distilled water in a container.
- trastuzumab solution in 5 mM histidine buffer at pH 6.0 was placed in a dialysis cassette (MWCO 10 kDa) (Slide-A-Lyzer cassette, Thermo Fisher Scientific), and then a cassette containing this trastuzumab solution was placed in a 2L beaker containing 1,600 mL of the buffer solution to make dialysis, and the 5 mM histidine buffer at pH 6.0 was exchanged with the buffer solution. Thereafter, trastuzumab was concentrated to 120 mg / mL or more.
- MWCO 10 kDa Slide-A-Lyzer cassette, Thermo Fisher Scientific
- Example 1 Concentration was achieved by passing the dialysis trastuzumab containing solution through an Amicon Filter with a cutoff molecular weight of 30 kDa. Finally, to the concentrated trastuzumab solution, a surfactant prepared at a concentration of 20x, that is, 0.8 w / v%, in the buffer solution prepared above was added to a concentration of 1x.
- the composition of Comparative Example 1 is also listed in Table 1. The formulation of Example 1 had a pH of about 5.5.
- Comparative Example 1 was prepared in the same manner as in Example 1, except that polysorbate 20 was added as a surfactant.
- the pH of the formulation obtained after adding the surfactant in Comparative Example 1 was about 5.5.
- Table 1 shows the composition of the formulations of Example 1 and Comparative Example 1.
- Example 1 Comparative Example 1 Trastuzumab (mg / mL) 120 120 Buffering agent Histidine (mM) 20 20 Stabilizer Methionine (mM) 10 10 Trehalose (w / v%) 8 8 Surfactants Polysorbate 20 (w / v%) - 0.04
- Test Example 1 Check the stability of the surfactant-free formulation
- Example 1 Although the preparation of Example 1 prepared does not contain a surfactant, it was confirmed by SE-HPLC whether it can maintain stability under temperature stress and freeze-thaw stress.
- Example 1 and Comparative Example 1 For the temperature stress, 1 mL of each of the formulations of Example 1 and Comparative Example 1 was placed in a 1.5 mL microtube made of polypropylene (Axygen), and the tube was heated to 40 ° C. in a stability thermostat (JEIO TECH). They were exposed to temperature stress conditions for 4 weeks. Specifically, the tube was placed in the stability thermostat and placed for 4 weeks under conditions of temperature 40 ⁇ 2 ° C. and relative humidity 75 ⁇ 5%. % HMW,% monomer and% LMW were measured using SE-HPLC for formulations stored for 4 weeks.
- a stability thermostat JEIO TECH
- HMW high molecular weight
- LMW low molecular weight
- Example 1 1 mL of each of the formulations of Example 1 and Comparative Example 1 was placed in a 1.5 mL microtube (Axygen) made of polypropylene, and the tube was maintained at -70 ⁇ 10 ° C. After placing it in a deep freezer (Thermo scientific) and maintaining it for 18 hours in a frozen and frozen state, the tube was taken out and left at room temperature for 1 hour to keep it in a thawed and thawed state. This process was repeated 5 times. If the antibody in the formulation loses stability, aggregation will be observed to increase the proportion of high molecular weight (HMW) material.
- HMW high molecular weight
- Example 1 showed better stability than Comparative Example 1 in freeze-thaw stress. Specifically, the formulation of Example 1 reduced ⁇ % HMW by 33% compared to the formulation of Comparative Example 1 in freeze-thaw stress.
- the surfactant-free formulations identified by this example were more stable than the surfactant-containing formulations, which is a remarkable remarkable effect by those skilled in the art.
- One aspect of the invention (a) Trastuzumab or an antigen-binding fragment thereof; (b) stabilizer; And (c) a buffering agent and no surfactant.
- antigen binding fragment is a fragment of a portion capable of binding to an antigen in a Trastuzumab antibody, including, but not limited to, Fab, F (ab ′) 2 and Fv, for example.
- the antigen can be a HER2 receptor.
- Trastuzumab is a monoclonal antibody used to treat cancer, including breast cancer, and is marketed under the name Herceptin TM under one of several trade names. Trastuzumab is used for breast cancer that is positive for HER2 receptors. In addition, trastuzumab can be used alone or in combination with other chemotherapeutic agents. Trastuzumab is administered by intravenous injection and subcutaneous injection. Trastuzumab works by binding to the HER2 receptor and slows cell replication. Trastuzumab is a recombinant IgG1 kappa humanized from mice that binds to the extracellular domain of human epidermal growth factor receptor protein (HER2), a whole antibody.
- HER2 human epidermal growth factor receptor protein
- the concentration of trastuzumab or an antigen-binding fragment thereof in the liquid formulation may be 2 to 300 mg / mL.
- the concentration of the antibody can be freely adjusted within a range that does not substantially affect the stability, viscosity and desired pH of the liquid formulation of the present invention.
- the concentration of the trastuzumab or antigen binding fragment thereof is, for example, 10 to 300 mg / mL, 20 to 300 mg / mL, 30 to 300 mg / mL, 50 to 300 mg / mL, 80 To 300 mg / mL, 100 to 300 mg / mL, 80 to 250 mg / mL, 80 to 200 mg / mL, 80 to 180 mg / mL, 80 to 150 mg / mL, 100 to 150 mg / mL, 100 to 140 mg / mL, 105-135 mg / mL, 110-130 mg / mL, 115-125 mg / mL, 100-250 mg / mL, 100-200 mg / mL, 100-180 mg / mL, 100-150 mg / mL, 100-140 mg / mL, 150-300 mg / mL, 200-300 mg / mL, 220-300 mg / m
- the liquid formulation of the present invention does not contain a surfactant.
- the liquid formulations of the present invention may or may not contain surfactant at all. When substantially free of surfactant, it can mean, for example, that the surfactant comprises less than 0.04 w / v%, less than 0.02 w / v%, or less than 0.01 w / v%.
- surfactants not included in the liquid formulation of the present invention include polyoxyethylene sorbitan fatty acid ester (Tween), polyethylene-polypropylene glycol, polyoxyethylene stearate, polyoxyethylene alkyl ether, polyoxyethylene- Polyoxypropylene copolymer (poloxamer), or sodium dodecyl sulfate.
- the polyoxyethylene alkyl ether may be, for example, polyoxyethylene monolauryl ether, alkylphenylpolyoxyethylene 30 ether (Triton-X).
- the polysorbate is a polyoxyethylene sorbitan fatty acid ester or a derivative thereof. Polysorbates are known to degrade through oxidation and hydrolysis, which in turn produces ROS, which is known to cause oxidative damage to antibody proteins.
- the liquid formulation of the present invention can maintain the stability of the antibody and antigen-binding fragment thereof without containing a surfactant such as polysorbate. Further, in one embodiment, the surfactant that is not included in the liquid formulation of the present invention may be polysorbate.
- the polysorbate may mean polysorbate 20 or polysorbate 80.
- the liquid formulation of the present invention may be one that does not include polysorbate 20 and polysorbate 80.
- the stabilizer may be one or more selected from the group consisting of sugar, sugar alcohol, sugar acid, polyol, metal salt and amino acid.
- the sugar may be selected from monosaccharides, disaccharides, oligosaccharides, polysaccharides, or derivatives thereof.
- the sugar derivative may mean sugar alcohol or sugar acid.
- the sugar, sugar alcohol or sugar acid is glucose, fructose, galactose, sucrose, lactose, maltose, trehalose, fructooligosaccharide, galactoligosaccharide, mango-oligosaccharide, starch, glycogen, cellulose, chitin, pectin , Glycerol, erythritol, thritol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fusitol, iditol, inositol, boletitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol ,
- the concentration of the sugar, sugar alcohol or sugar acid may be 1 to 20w / v%. In another embodiment, the concentration of the sugar, sugar alcohol or sugar acid is 2 to 20w / v%, 4 to 20w / v%, 6 to 20w / v%, 6 to 12w / v%, 4 to 14w / v%, respectively.
- the concentration of sugar, sugar alcohol or sugar acid can be freely adjusted within a desired range to maintain the stability of the trastuzumab or antigen-binding fragment thereof in the liquid formulation of the present invention and the viscosity of the liquid formulation, and each specific sugar, sugar alcohol or It can vary individually depending on the sugar acid.
- polyol can mean an organic compound having two or more hydroxyl groups (-OH) in its molecule.
- the polyol is any one selected from the group consisting of propanediol, glycerin, butylene glycol, propylene glycol, dipropylene glycol, pentylene glycol, hexylene glycol, polyethylene glycol, and sorbitol You can.
- the metal salt may be NaCl, KCl, NaF, KBr, NaBr, Na 2 SO 4 , NaSCN, or K 2 SO 4 , but is not limited thereto. In one embodiment, the metal salt may be NaCl. The concentration of the metal salt may be 0.1 to 10w / v%.
- the concentration of the metal salt is 0.1 to 8w / v%, 0.1 to 6w / v%, 0.1 to 5w / v%, 0.1 to 3w / v%, 0.1 to 1w / v%, 0.3 to 10w / v %, 0.3 to 8 w / v%, 0.3 to 6 w / v%, 0.3 to 5 w / v%, 0.3 to 3 w / v% or 0.3 to 1 w / v%, 0.5 to 10 w / v%, 0.5 to 8 w / v% , 0.5 to 6w / v%, 0.5 to 5w / v%, 0.5 to 3w / v% or 0.5 to 1w / v%.
- the concentration of the metal salt can be freely adjusted within a range in which the stability of trastuzumab or an antigen-binding fragment thereof in the liquid formulation of the present invention is not precipitated, and
- the amino acid is glycine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, histidine, glutamine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine It may be one or more selected from the group consisting of.
- the concentration of amino acids can be freely adjusted within a range that does not affect the desired pH of the liquid formulation of the present invention, and does not affect the stability of trastuzumab or antigen-binding fragments thereof, and can be individually adjusted for each specific amino acid. It may vary.
- the amino acid may be methionine.
- the stabilizer may include two or more stabilizers.
- the stabilizer may be one or more selected from the group consisting of trehalose and methionine.
- the stabilizer may be one or more selected from the group consisting of 1 to 15w / v% trehalose and 1 to 50 mM methionine.
- the stabilizer may be at least one selected from the group consisting of 2 to 14w / v% trehalose and 1 to 30 mM methionine.
- the stabilizer may be at least one selected from the group consisting of 3 to 13w / v% trehalose and 1 to 20 mM methionine.
- the stabilizer may be at least one selected from the group consisting of 4 to 12w / v% trehalose and 1 to 20 mM methionine.
- the stabilizer may be at least one selected from the group consisting of 5 to 11w / v% trehalose and 2 to 18 mM methionine.
- the stabilizer may be at least one selected from the group consisting of 6 to 10w / v% trehalose and 2 to 18 mM methionine.
- the stabilizer may be at least one selected from the group consisting of 6 to 10w / v% trehalose and 4 to 16 mM methionine.
- the stabilizer may be at least one selected from the group consisting of 6 to 10w / v% trehalose and 6 to 14 mM methionine.
- the stabilizer may be at least one selected from the group consisting of 7 to 9w / v% trehalose and 8 to 12 mM methionine.
- the stabilizer may be at least one selected from the group consisting of 2 to 8w / v% trehalose and 1 to 20 mM methionine.
- the buffering agent may be to provide a pH of 4.0 to 7.0.
- the liquid formulation may have a pH of 4.0 to 7.0.
- the pH of the liquid formulation may be 4.5 to 6.5, 5.0 to 6.0 or 5.5 ⁇ 0.2.
- the pH of the liquid formulation can be freely adjusted within a range suitable for preventing aggregation of the antibody and maintaining activity.
- the liquid formulation of the present invention may contain a buffering agent to maintain the desired pH for stabilizing trastuzumab or an antigen-binding fragment thereof.
- buffer refers to a neutralizing material that minimizes the change in pH by acid or alkali, and in one embodiment, the buffering agent is histidine, phosphoric acid, citric acid, maleic acid, tartaric acid, succinic acid, citrate, acetate , Carbonate and salts thereof, but are not limited thereto.
- the buffering agent is histidine. In one embodiment, the buffering agent is 1 to 100 mM histidine. The concentration of histidine is, for example, 1 to 80 mM, 1 to 70 mM, 1 to 60 mM, 1 to 50 mM, 1 to 40 mM, 1 to 30 mM, 2 to 80 mM, 2 to 70 mM, 2 To 60 mM, 2 to 50 mM, 2 to 40 mM, 2 to 30 mM, 2 to 25 mM, 3 to 80 mM, 3 to 70 mM, 3 to 60 mM, 3 to 50 mM, 3 to 40 mM, 3 To 30 mM, 3 to 25 mM, 4 to 80 mM, 4 to 70 mM, 4 to 60 mM, 4 to 50 mM, 4 to 40 mM, 4 to 30 mM, 4 to 25 mM, 5 to 80 mM, 5 To 70 mM, 5 to 60 mM, 5 to 60 m
- the histidine may be in the form of histidine and its conjugate acid.
- the conjugate acid may be histidine HCl.
- the ratio of histidine and its conjugate acid may vary depending on the pH of the selected agent. For example, when the pH of the formulation is 5.5 ⁇ 0.2, the concentration ratio of histidine and histidine HCl monohydrate may be about 1: 6.
- the stabilizer, buffering agent, and surfactant may be different.
- the trastuzumab or antigen-binding fragment thereof may be stabilized.
- the liquid formulation may be a stable liquid pharmaceutical formulation.
- stabilization means that trastuzumab or an antigen-binding fragment thereof substantially retains its physical stability, chemical stability and / or biological activity before and after administration, during further manufacturing processes, storage or storage. Physical stability, chemical stability and / or biological activity can be assessed by commonly known methods.
- Stability can be measured for a selected period of time at a selected temperature.
- a stable formulation is one in which no significant change is observed at 2-8 ° C. for 12 months or longer.
- a stable formulation is one that does not exhibit significant changes at 2-8 ° C. for 18 months or longer.
- a stable formulation is one where no significant change is observed for 3 months or longer at 23-27 ° C.
- a stable formulation is one where no significant changes are observed for 6 months or longer at 23-27 ° C.
- a stable formulation is one where no significant change is observed at 23-27 ° C. for 12 months or longer.
- a stable formulation is one where no significant change is observed at 23-27 ° C.
- Stability criteria for antibody formulations are as follows.
- the antibody monomer is 10% or less, for example, 5% or less, or 2.5% or less relative to the initial monomer amount.
- the antibody potency is within 60 to 140%, or 80 to 120%, of the control or standard antibody.
- LMW low molecular weight
- the change in the amount of the low molecular weight species is less than 10%, less than 5%, or less than 2.5% relative to its initial amount. It may have.
- the change in the amount of the high molecular weight species is 10% or less, 5% or less, or 2.5% or less relative to its initial amount. It may have.
- the concentration of the formulation, and the pH may have a change of 0% or less, ⁇ 5% or less, or ⁇ 2.5% or less relative to the initial value.
- the initial pH is 10% or less, 5% or less, or 2.5% or less
- the pH changes within the range.
- the formulation is placed in a freezer maintained at -70 ⁇ 10 ° C and maintained for 18 hours to maintain a frozen state, and then the process of removing the tube and leaving it at room temperature for 1 hour to maintain it in a thawed state is repeated 5 times.
- the pH changes within the range of 10% or less, 5% or less, or 2.5% or less of the initial pH.
- the preparation is when 1 mL is placed in a 1.5 mL microtube (Axygen) made of polypropylene, and the tube is mounted on a stirrer (Heidolph) and stirred at 400 rpm for 72 hours at room temperature.
- PH is changed within the range of 10% or less, 5% or less, or 2.5% or less with respect to the initial pH.
- the trastuzumab or antigen-binding fragment thereof retains chemical stability within the pharmaceutical agent when it is chemically stable at a predetermined time that appears to still retain biological activity.
- Chemical stability can be assessed by detecting and quantifying a chemically modified form of the antibody.
- Chemical modification includes size modification or charge change.
- the charge change can be, for example, a charge change that occurs as a result of deamidation.
- the size modification is size exclusion chromatography (SE-HPLC), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), capillary electrophoresis-sodium dodecyl sulfate, CE-SDS ) Analysis, and substrate-assisted laser desorption / ionization / time-of-flight mass spectrometry (MALDI / TOF MS).
- charge changes can be evaluated by ion exchange chromatography (IEC), and imaged capillary isoelectric focusing (icIEF).
- Activity can be determined through HER2 receptor binding assay.
- the HER2 receptor binding assay can be performed by Enzyme-linked immuonsorbent assay (ELISA).
- ELISA analysis measures the ratio (%) of trastuzumab binding to the HER2 receptor.
- ELISA can be performed using the Her2 ELISA kit (R & D system). After reacting with the trastuzumab sample and the HER2 receptor on the ELISA substrate, the binding degree can be determined by measuring the absorbance at 450 nm to obtain a relative binding rate (%).
- the trastuzumab or antigen-binding fragment thereof retains biological activity in the pharmaceutical agent when the trastuzumab or antigen-binding fragment thereof is biologically active for its intended purpose.
- the biological activity is, for example, about 30%, about 20%, within about 10%, about 5% of the biological activity at which the biological activity of the trastuzumab or antigen-binding fragment thereof in the pharmaceutical agent is indicated at the time of manufacture of the pharmaceutical agent.
- Biological activity is retained within or within analytical error.
- the biological activity can be determined, for example, in antigen binding assays.
- Stabilization is temperature stress, e.g., 1 to 4 weeks at 40 ° C, freeze-thaw stress, e.g., 5 repetitions of cycles at -70 ° C freeze and thaw at room temperature, or stirring stress, e.g. , Can be evaluated by measuring% HMW,% monomer and / or% LMW using SE-HPLC, by applying 400 rpm rotational force for 72 hours in a stirrer.
- the liquid formulations of the present invention may have less ⁇ % HMW, ⁇ % monomer and / or ⁇ % LMW values compared to Herceptin®.
- the liquid formulation provided herein has a change in% HMW measured when stored at 40 ° C for 4 weeks at 40 ° C when the antibody content is 120 mg / ml (pH 5.5), that is,% HMW at week 4 of storage- Week 0% HMW value is about 5% or less, about 3% or less, about 2.5% or less, about 2.3% or less, about 2.0% or less, about 0.5 to about 5%, about 0.8 to about 3%, about 0.1 to About 2.25%, about 1.00 to about 2.23%, about 1.15% ⁇ 0.08%, and also about 1.15% ⁇ 0.04%.
- the "week 0" indicates the initial time of storage.
- the liquid formulation provided herein is thawed by maintaining the liquid composition at -70 ⁇ 10 ° C for 18 hours, and then standing at room temperature for 1 hour when the antibody content is 120 mg / ml (pH 5.5).
- the change amount of% HMW measured by conventional SEC is about 2% or less, about 1.5% or less, about 1.0% or less, about 0.5% or less, about 0.1% or less, about 0.05% or less, or about 0.01% or less, about 0.001% or less, about 0.1 to about 1%, about -0.05 to about 0.05%, about -0.03 to about 0.03%, about -0.02% ⁇ 0.02%, or about -0.02% ⁇ 0.01% have.
- the liquid formulation may be for subcutaneous or intravenous injection.
- the liquid formulation may further include an aqueous carrier suitable for injection.
- the aqueous carrier may be a safe and non-toxic pharmaceutically acceptable drug when administered to humans.
- the aqueous carrier includes, but is not limited to, sterile alcohol, for example, sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), sterile saline solution, Ringer's solution, and dextrose.
- the liquid formulation of the present invention may have an appropriate range of osmolality upon subcutaneous or intravenous injection.
- Osmolarity may be, for example, 200 to 400 mOsm / kg, 250 to 380 mOsm / kg, or 270 to 360 mOsm / kg.
- the osmolarity concentration can be appropriately adjusted to minimize pain that may occur during administration.
- the liquid formulation of the present invention may have an appropriate range of viscosity when subcutaneously or intravenously injected.
- the viscosity for example, 0.5 to 50 cp, can be appropriately adjusted to minimize pain that may occur upon administration.
- the liquid formulation of the present invention may include a hyaluronidase enzyme.
- the amount of the hyaluronidase enzyme may vary depending on the hyaluronidase enzyme used.
- the amount of hyaluronidase enzyme can be an amount sufficient to increase the dispersion and absorption of an anti-HER2 antibody, e.g., trastuzumab or an antigen binding fragment thereof, administered together.
- the amount of hyaluronidase enzyme can be 150 U / ml or more.
- An effective amount of hyaluronidase enzyme is, for example, about 1,000 to 16,000 U / ml, where the amount corresponds to about 0.01 mg to 0.16 mg based on 100,000 U / mg of estimated specific activity.
- the concentration of the hyaluronidase enzyme may be about 1,500 to 12,000 U / ml, or about 2,000 to 12,000 U / ml. This amount corresponds to the amount of hyaluronidase enzyme added to the formulation.
- the amount of hyaluronidase enzyme measured in the final formulation can vary within a specific range.
- the ratio (w / w) of hyaluronidase enzyme to anti-HER2 antibody is 1: 5,00 to 1: 100,000, 1: 1,000 to 1: 50,000, 1: 1,000 to 1: 30,000, 1: 1,000 to 1: 20,000, 1: 1,000 to 1: 15,000, 1: 1,000 to 1: 13,000, 1: 1,000 to 1: 12,000, 1: 1,000 to 1: 10,000, 1: 1,000 to 1: 8,000, 1: 4,000 to 1: 5,000, Or about 1: 6,000.
- the hyaluronidase enzyme may be derived from an animal, bacterial, or human sample or prepared by recombinant DNA technology.
- the hyaluronidase enzyme may be soluble hyaluronidase glycoproteins (sHASEGPs). These soluble hyaluronidase glycoproteins can be administered together with the agent or separately. The addition of the soluble hyaluronidase glycoprotein can facilitate the subcutaneous administration of the therapeutic drug.
- soluble hyaluronidase glycoprotein By rapidly depolymerizing hyaluronan (HA) in the extracellular space, the soluble hyaluronidase glycoprotein lowers the viscosity of the interstitium, increasing hydraulic conductance, making it easier for large volumes to subcutaneous tissue. Make it administered comfortably.
- the increased hydraulic conductivity induced by soluble hyaluronidase glycoproteins through reduced interstitial viscosity can result in better dispersion, thereby increasing the systemic bioavailability of the subcutaneously administered therapeutic drug.
- the hyaluronidase enzyme may be licensed for use in humans in any one or more countries.
- the hyaluronidase enzyme may be, for example, Hylase TM , Dessau, Hyalase TM , EU approved, Vitrase TM , Hydase TM , Amphadase TM , or Hylenex TM , licensed in the United States.
- the hyaluronidase enzyme may be a human hyaluronidase enzyme such as PH20 or rHuPH20. Recombinant human PH20 (rHuPH20) is a member of the neutral and acid-active ⁇ -1,4 glycosyl hydrolase family.
- rHuPH20 depolymerizes hyaluronan by hydrolysis of a ⁇ -1,4 bond between the C1 position of N-acetyl glucosamine and the C4 position of glucuronic acid.
- rHuPH20 may be a truncated deletion variant without amino acid at the carboxy terminal required for lipid attachment developed by Halozyme.
- Another aspect of the present invention provides a liquid formulation, wherein the trastuzumab or antigen-binding fragment thereof is 2 to 300 mg / mL, the stabilizer is a combination of trehalose and methionine, and the buffering agent is histidine. .
- the stabilizer is a combination of 1 to 20 w / v% trehalose and 1 to 20 mM methionine, and the buffering agent is 10 to 50 mM histidine.
- the concentration of the trehalose is 2 to 20w / v%, 4 to 20w / v%, 6 to 20w / v%, 1 to 18w / v%, 1 to 15w / v%, 1 to 12w / v%, 1 to 10w / v%, 2 to 18w / v%, 2 to 15w / v%, 2 to 12w / v%, 2 to 10w / v%, 4 to 18w / v%, 4 to 15w / v%, 4 to 12w / v% or 4 to 10 w / v%.
- the concentration of the methionine is 1 to 20 mM, 2 to 20 mM, 5 to 20 mM, 8 to 20 mM, 1 to 18 mM, 2 to 18 mM, 5 to 18 mM, 1 to 15 mM, 2 to 15 mM, 5 to 15 mM, 8 to 15 mM, 1 to 12 mM, 2 to 12 mM, 5 to 12 mM, or 8 to 12 mM.
- the histidine may be 10 to 45 mM, 10 to 40 mM, 10 to 35 mM, 10 to 30 mM, 15 to 25 mM, or 18 to 22 mM.
- the formulation may be pH 5.5 ⁇ 0.2.
- One embodiment of the present invention (a) Trastuzumab or an antigen-binding fragment 80 to 160 mg / ml thereof; (b) 1 to 20 mM methionine and 1 to 15 (w / v)% of trehalose as stabilizers; And (c) 1-50 mM histidine as a buffering agent.
- the formulation may be pH 5.5 ⁇ 0.2.
- One embodiment of the present invention is (a) Trastuzumab or an antigen-binding fragment 80 to 160 mg / ml thereof; (b) 1 to 20 mM methionine and 1 to 15 (w / v)% trehalose as stabilizers; And (c) 1 to 40 mM histidine as a buffering agent.
- the formulation may be pH 5.5 ⁇ 0.2.
- One embodiment of the present invention is (a) Trastuzumab or an antigen-binding fragment 100 to 140 mg / ml thereof; (b) 3 to 18 mM of methionine and 2 to 13 (w / v)% of trehalose as stabilizers; And (c) 10-30 mM histidine as a buffering agent.
- the formulation may be pH 5.5 ⁇ 0.2.
- One embodiment of the present invention (a) Trastuzumab or an antigen-binding fragment 110 to 130 mg / ml thereof; (b) 5 to 15 mM methionine as stabilizer and 4 to 12 (w / v)% trehalose; And (c) 15 to 25 mM histidine as a buffering agent.
- the formulation may be pH 5.5 ⁇ 0.2.
- One embodiment of the present invention (a) Trastuzumab or an antigen-binding fragment 110 to 130 mg / ml thereof; (b) 8 to 12 mM methionine and 6 to 10 (w / v)% threonyl as stabilizers; And (c) 16 to 24 mM histidine as a buffering agent.
- the formulation may be pH 5.5 ⁇ 0.2.
- One embodiment of the present invention (a) Trastuzumab or an antigen-binding fragment thereof 120 mg / ml ⁇ 5%; (b) 10 mM ⁇ 5% methionine as stabilizer and 8% (w / v)% ⁇ 5% trehalose; And (c) 20 mM ⁇ 5% histidine as a buffering agent.
- ⁇ 5% indicates that there is a variation of “ ⁇ 5%” with respect to the basic amount.
- the liquid formulation may be pH 5.5 ⁇ 0.2.
- the histidine may include histidine and its conjugate acid, for example, histidine HCl.
- the buffering agent may include only histidine and its conjugate acid.
- the formulation may be one that does not contain a surfactant, for example, a nonionic surfactant.
- the formulation may not contain polysorbate 20 or 80.
- Another aspect of the present invention adding a stabilizer and a buffering agent to the solvent to prepare a mixed solution; And adding trastuzumab to the mixed solution.
Abstract
La présente invention concerne une formulation liquide comprenant : un trastuzumab ou un fragment de liaison d'antigène de celui-ci ; un stabilisant ; et un agent tampon, la formulation liquide étant exempte d'un tensioactif, ainsi que son procédé de préparation.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR20180111666 | 2018-09-18 | ||
KR10-2018-0111666 | 2018-09-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020060183A1 true WO2020060183A1 (fr) | 2020-03-26 |
Family
ID=69888559
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2019/012056 WO2020060183A1 (fr) | 2018-09-18 | 2019-09-18 | Formation de liquide pour stabiliser un anticorps de trastuzumab |
PCT/KR2019/012077 WO2020060192A1 (fr) | 2018-09-18 | 2019-09-18 | Formulation liquide stabilisante de trastuzumab contenant une concentration élevée de tensioactif |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2019/012077 WO2020060192A1 (fr) | 2018-09-18 | 2019-09-18 | Formulation liquide stabilisante de trastuzumab contenant une concentration élevée de tensioactif |
Country Status (1)
Country | Link |
---|---|
WO (2) | WO2020060183A1 (fr) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113855798A (zh) * | 2021-09-30 | 2021-12-31 | 佛山汉腾生物科技有限公司 | 抗cd20的抗体制剂 |
WO2023100095A1 (fr) * | 2021-11-30 | 2023-06-08 | Enzene Biosciences Limited | Composition comprenant un anticorps her2, formulation et son procédé de préparation |
WO2024022414A1 (fr) * | 2022-07-29 | 2024-02-01 | 舒泰神(北京)生物制药股份有限公司 | Préparation d'anticorps monoclonal à haute concentration et son utilisation |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004066957A2 (fr) * | 2003-01-30 | 2004-08-12 | Medimmune, Inc. | Preparation d'anticorps anti-integrine $g(a)v$g(b)3 et utilisations associees |
JP2006511448A (ja) * | 2002-06-14 | 2006-04-06 | メディミューン,インコーポレイテッド | 安定化された抗呼吸器合胞体ウイルス(rsv)抗体製剤 |
US7132100B2 (en) * | 2002-06-14 | 2006-11-07 | Medimmune, Inc. | Stabilized liquid anti-RSV antibody formulations |
KR20130041374A (ko) * | 2009-07-31 | 2013-04-24 | 에프. 호프만-라 로슈 아게 | 피하용 항-에이치이알2 항체 제형 |
KR20180003452A (ko) * | 2016-06-30 | 2018-01-09 | (주)셀트리온 | 안정한 액체 약제학적 제제 |
KR20180085801A (ko) * | 2015-12-07 | 2018-07-27 | 메르크 파텐트 게엠베하 | 항-pd-1 항체 아벨루맙을 포함하는 수성 약학 제형 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009006301A2 (fr) * | 2007-06-29 | 2009-01-08 | Battelle Memorial Institute | Stabilisation de protéines |
MX345226B (es) * | 2008-10-29 | 2017-01-20 | Ablynx Nv | Formulaciones de moleculas de union a antigeno de dominio sencillo. |
EP3402470A4 (fr) * | 2016-01-12 | 2019-11-13 | Dr. Reddy's Laboratories Limited | Composition pharmaceutique stable |
-
2019
- 2019-09-18 WO PCT/KR2019/012056 patent/WO2020060183A1/fr active Application Filing
- 2019-09-18 WO PCT/KR2019/012077 patent/WO2020060192A1/fr active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006511448A (ja) * | 2002-06-14 | 2006-04-06 | メディミューン,インコーポレイテッド | 安定化された抗呼吸器合胞体ウイルス(rsv)抗体製剤 |
US7132100B2 (en) * | 2002-06-14 | 2006-11-07 | Medimmune, Inc. | Stabilized liquid anti-RSV antibody formulations |
WO2004066957A2 (fr) * | 2003-01-30 | 2004-08-12 | Medimmune, Inc. | Preparation d'anticorps anti-integrine $g(a)v$g(b)3 et utilisations associees |
KR20130041374A (ko) * | 2009-07-31 | 2013-04-24 | 에프. 호프만-라 로슈 아게 | 피하용 항-에이치이알2 항체 제형 |
KR20180085801A (ko) * | 2015-12-07 | 2018-07-27 | 메르크 파텐트 게엠베하 | 항-pd-1 항체 아벨루맙을 포함하는 수성 약학 제형 |
KR20180003452A (ko) * | 2016-06-30 | 2018-01-09 | (주)셀트리온 | 안정한 액체 약제학적 제제 |
Also Published As
Publication number | Publication date |
---|---|
WO2020060192A1 (fr) | 2020-03-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2020060183A1 (fr) | Formation de liquide pour stabiliser un anticorps de trastuzumab | |
AU2016283557B9 (en) | A stable liquid formulation of fusion protein with IgG Fc domain | |
WO2011090305A2 (fr) | Formulations liquides pour un conjugué de g-csf à action prolongée | |
WO2012008779A2 (fr) | Formulation liquide d'un conjugué d'hormone de croissance humaine à action prolongée | |
WO2012165917A1 (fr) | Formulation liquide stable d'étanercept | |
EP2328559B1 (fr) | Formulation comprenant un anticorps contre p-selectin | |
EP2399604A1 (fr) | Nouvelle formulation d'anticorps | |
US20110158987A1 (en) | Novel antibody formulation | |
HU220256B (hu) | Granulocita-kolónia stimuláló faktort (G-CSF) tartalmazó, stabilan eltartható, liofilizált gyógyszerkészítmények és eljárás az előállításukra | |
US20090068196A1 (en) | Pharmaceutical formulation of an antibody against IL13Ralpha1 | |
WO2013117969A1 (fr) | Procédé pour préparer des compositions pharmaceutiques stables de composés sensibles à l'hydrolyse | |
US20160120946A1 (en) | Compositions comprising gc-macrophage activating factor and uses thereof | |
WO2021118321A1 (fr) | Préparation pharmaceutique d'anticorps anti-pd-1 stable | |
WO2013147559A1 (fr) | Formulation liquide de conjugué d'hormone de croissance humaine à action prolongée hautement concentrée | |
EA020069B1 (ru) | Жидкая лекарственная форма конъюгата | |
KR101699677B1 (ko) | 고나도트로핀을 위한 제제 | |
US20170112903A1 (en) | Lyophilized pharmaceutical composition of fc-peptide fusion protein | |
WO2020060179A1 (fr) | Formulation de stabilisation d'anticorps trastuzumab exempte d'agent tampon | |
US20210188941A1 (en) | Stable fusion protein formulation | |
WO2021125852A1 (fr) | Nouvelle formulation injectable | |
US10052361B2 (en) | Liquid pharmaceutical composition of conjugated erythropoietin | |
EP0508435B1 (fr) | Composition pharmaceutique de [Leu 13]-motiline-Hse stabilisée | |
WO2021071326A1 (fr) | Composition liquide stable, procédé pour sa préparation, et formulation la comprenant | |
WO2021154027A1 (fr) | Préparation pharmaceutique d'anticorps anti-pd-1 stable |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 19863212 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 19863212 Country of ref document: EP Kind code of ref document: A1 |