JP2001506272A - 肺用組成物において使用するための亜鉛非含有のインスリン結晶 - Google Patents
肺用組成物において使用するための亜鉛非含有のインスリン結晶Info
- Publication number
- JP2001506272A JP2001506272A JP54474798A JP54474798A JP2001506272A JP 2001506272 A JP2001506272 A JP 2001506272A JP 54474798 A JP54474798 A JP 54474798A JP 54474798 A JP54474798 A JP 54474798A JP 2001506272 A JP2001506272 A JP 2001506272A
- Authority
- JP
- Japan
- Prior art keywords
- insulin
- human
- zinc
- human insulin
- crystal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims abstract description 188
- 102000004877 Insulin Human genes 0.000 title claims abstract description 91
- 108090001061 Insulin Proteins 0.000 title claims abstract description 90
- 229940125396 insulin Drugs 0.000 title claims abstract description 89
- 239000013078 crystal Substances 0.000 title claims abstract description 75
- 230000002685 pulmonary effect Effects 0.000 title claims abstract description 16
- 239000000203 mixture Substances 0.000 title claims description 34
- 239000000843 powder Substances 0.000 claims abstract description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 59
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 37
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 claims description 35
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 29
- 239000001632 sodium acetate Substances 0.000 claims description 29
- 235000017281 sodium acetate Nutrition 0.000 claims description 29
- 238000009472 formulation Methods 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 25
- 239000003623 enhancer Substances 0.000 claims description 13
- 230000001225 therapeutic effect Effects 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 238000010521 absorption reaction Methods 0.000 claims description 9
- -1 phenol compound Chemical class 0.000 claims description 9
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 claims description 9
- 206010012601 diabetes mellitus Diseases 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 150000003863 ammonium salts Chemical class 0.000 claims description 6
- 239000003833 bile salt Substances 0.000 claims description 5
- 229940093761 bile salts Drugs 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 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 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 108010005991 Pork Regular Insulin Proteins 0.000 claims description 4
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 4
- 239000000194 fatty acid Substances 0.000 claims description 4
- 229930195729 fatty acid Natural products 0.000 claims description 4
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 229960001855 mannitol Drugs 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- 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 3
- 101001011741 Bos taurus Insulin Proteins 0.000 claims description 3
- 241000282412 Homo Species 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose 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)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 claims description 3
- 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 3
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 claims description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 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 3
- IXIBAKNTJSCKJM-BUBXBXGNSA-N bovine insulin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 IXIBAKNTJSCKJM-BUBXBXGNSA-N 0.000 claims description 3
- 150000001720 carbohydrates Chemical class 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 239000004026 insulin derivative Substances 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 3
- 150000003904 phospholipids Chemical class 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 239000003755 preservative agent Substances 0.000 claims description 3
- 230000002335 preservative effect Effects 0.000 claims description 3
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose 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)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
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- 239000011734 sodium Substances 0.000 claims description 3
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
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- 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
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- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 2
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- 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
- 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
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- 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
- 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
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- ZSLUVFAKFWKJRC-IGMARMGPSA-N 232Th Chemical compound [232Th] ZSLUVFAKFWKJRC-IGMARMGPSA-N 0.000 claims 1
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- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
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- 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 description 1
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- 108010026951 Short-Acting Insulin Proteins 0.000 description 1
- WBWWGRHZICKQGZ-UHFFFAOYSA-N Taurocholic acid Chemical class OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)C(O)C2 WBWWGRHZICKQGZ-UHFFFAOYSA-N 0.000 description 1
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- 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 description 1
- 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 1
- 230000004071 biological effect Effects 0.000 description 1
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- 238000004587 chromatography analysis Methods 0.000 description 1
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- 238000004925 denaturation Methods 0.000 description 1
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- 201000010064 diabetes insipidus Diseases 0.000 description 1
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- 150000002016 disaccharides Chemical class 0.000 description 1
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- 150000004665 fatty acids Chemical class 0.000 description 1
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- 229930182830 galactose Natural products 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical class C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 description 1
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- 238000002664 inhalation therapy Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 229940045845 sodium myristate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- FIWQZURFGYXCEO-UHFFFAOYSA-M sodium;decanoate Chemical compound [Na+].CCCCCCCCCC([O-])=O FIWQZURFGYXCEO-UHFFFAOYSA-M 0.000 description 1
- JUQGWKYSEXPRGL-UHFFFAOYSA-M sodium;tetradecanoate Chemical compound [Na+].CCCCCCCCCCCCCC([O-])=O JUQGWKYSEXPRGL-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
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- 238000009827 uniform distribution Methods 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical class C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 229960001661 ursodiol Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- 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
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/62—Insulins
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Endocrinology (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Molecular Biology (AREA)
- Toxicology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.10μm以下の直径を有する亜鉛非含有インスリン結晶。 2.立方結晶系に属する結晶構造を有する請求項1に記載の亜鉛非含有インスリ ン結晶。 3.18面体又は12面体結晶形態にある請求項2に記載の亜鉛非含有インスリ ン結晶。 4.0.2から5μmの範囲、好ましくは0.2から2μmの範囲、より好まし くは0.5から1μmの範囲の直径を有する請求項1から3の何れか1項に記載 の亜鉛非含有インスリン結晶。 5.請求項1から4の何れか1項に記載の亜鉛非含有インスリン結晶であって、 該インスリンがヒトインスリン、ウシインスリン又はブタインスリンからなる群 より選択されるインスリン結晶。 6.請求項5に記載の亜鉛非含有インスリン結晶であって、前記インスリンがヒ トインスリンであるインスリン結晶。 7.請求項1から4の何れか1項に記載の亜鉛非含有インスリン結晶であって、 前記インスリンが速効活性インスリン、好ましくはdes(B30)ヒトインス リン、AspB28ヒトインスリン、又はLysB28ProB29ヒトインスリンであ るインスリン結晶。 8.請求項1から4の何れか1項に記載の亜鉛非含有インスリン結晶であって、 前記インスリンがインスリン誘導体であり、好ましくは、B29−Nε−ミリス トイル−des(B30)ヒトインスリン、B29−Nε−パルミトイル−de s(B30)ヒトインスリン、B29−Nε−ミリストイルヒトインスリン、B 29−Nε−パルミトイルヒトインスリン、B28−Nε−ミリストイルLysB28 ProB28ヒトインスリン、B28−Nε−バルミトイルLysB28ProB28 ヒトインスリン、B30−Nε−ミリストイルThyB29LysB30ヒトインスリ ン、B30−Nε−バルミトイル−ThrB29LysB30ヒトインスリン、B29 −Nε−(N−パルミトイル−γ−グルタミル)−des(B30)−ヒトイン スリン、B29−Nε−(N−リトコール−γ−グルタミル)−des(B30 )ヒトインスリン、B29−Nε−(ω−カルボキシヘブタデカノイル)−de s(B30)ヒ トインスリン、及びB29−Nε−(ω−カルボキシヘブタデカノイル)ヒトイ ンスリンからなる群より選択されれインスリン結晶。 9.請求項8に記載の亜鉛非含有インスリン結晶であって、前記インスリンがL ysB29(N−εアシル化)des(B30)ヒトインスリンであるインスリン 結晶 10.更にフェノール化合物を安定化量で含有する請求項1から9の何れか1項 に記載の亜鉛非含有インスリン結晶。 11.請求項10に記載の亜鉛非含有インスリン結晶であって、m−クレゾール 若しくはフェノール、又はその混合物を含有するインスリン結晶。 12.請求項1から11の何れか1項に記載の亜鉛非含有結晶を含有する肺投与 用に適した治療用粉末調合物。 13.請求項12に記載の治療用粉末調合物であって、更に、より低い気道にお けるインスリンの吸収を増強する増強剤を含有する調合物。 14.請求項13に記載の治療用粉末調合物であって、前記増強剤が界面活性剤 である調合物。 15.請求項14に記載の治療用粉末調合物であって、前記界面活性剤が脂肪酸 塩、胆汁酸塩又はリン脂質、好ましくは胆汁酸塩である調合物。 16.請求項15に記載の治療用粉末調合物であって、前記界面活性剤がタウロ コール酸塩、好ましくはタウロコール酸ナトリウムである調合物。 17.請求項12から16の何れか1項に記載の治療用粉末調合物であつて、更 に、担体、好ましくはトレハロース、ラフィノース、マンニトール、ソルビトー ル、キシリトール、イノシトール、スクロース、塩化ナトリウム及びクエン酸ナ トリウムからなる群より選択される担体を含有する調合物。 18.以下の工程を具備する請求項1から11の何れか1項に記載の亜鉛非含有 インスリン結晶の製造方法; a)pH7.0から9.5を有するインスリン溶液を調製することと; b)前記溶液を、アルカリ金属の塩又はアンモニウム塩の溶液と混合するこ とと;及び c)形成した結晶を回収すること。 19.請求項18に記載の方法であって、前記アルカリ金属又はアンモニウムの 塩が、ナトリウム、カリウム、リチウム若しくはアンモニアの塩酸塩又は酢酸塩 からなる群より選択され、或いはその混合物であり、好ましくは酢酸ナトリウム である方法。 20.請求項18又は19に記載の方法であって、前記インスリン溶液及び/又 はアルカリ金属の塩若しくはアンモニウム塩の溶液が、混合して得られる溶液中 の5から25%(v/v)に相当する量で水相溶性有機溶媒を含有する方法。 21.請求項20に記載の方法であって、前記水相溶性有機溶媒が、エタノール 、メタノール、アセトン及び2−プロパノールからなる群より選択され、好まし くはエタノールである方法。 22.請求項18から21の何れか1項に記載の方法であって、前記2つの溶液 が、2時間未満、好ましくは1時間未満、より好ましくは15分間未満、更によ り好ましくは5分間未満の期間内で混合される方法。 23.請求項18から22の何れか1項に記載の方法であって、混合後のインス リンの濃度が、0.5%から10%の間、好ましくは0.5%から5%の間、よ り好ましくは0.5%から2%の間の濃度である方法。 24.請求項18から23の何れか1項に記載の方法であって、混合後の前記塩 の濃度が、0.2Mから2Mの間、好ましくは約1Mである方法。 25.請求項18から24の何れか1項に記載の方法であって、更に、洗浄工程 [ここで、得られた結晶は、最終乾燥粉末に含まれるべき補助物質、好ましくは 増強剤及び/又は炭水化物を含有し、且つ任意に5−25%のアルコール、好ま しくはエタノール、5−50mMの保存剤、好ましくはフェノール、及び0.1 −2Mの塩、例えば酢酸ナトリウム等を含有する溶液で洗浄される]を具備する 方法。 26.真性糖尿病の治療における肺投与に適切な治療用粉末調合物を製造するた めの請求項1から11の何れか1項に記載の亜鉛非含有結晶の使用。 27.そのような治療が必要なヒトに対して請求項12から17の何れか1項に 記戟の治療用粉末調合物の有効量を投与することを具備する真性糖尿病の治療方 法。 28.そのような治療が必要なヒトに対して、活性開始が延期されたインスリン 誘導体、好ましくは、B29−Nε−ミリストイル−des(B30)ヒトイン スリン、B29−Nε−パルミトイル−des(B30)ヒトインスリン、B2 9−Nε−ミリストイルヒトインスリン、B29−Nε−パルミトイルヒトイン スリン、B28−Nε−ミリストイルLysB28ProB28ヒトインスリン、B2 8−Nε−パルミトイルLysB28ProB28ヒトインスリン、B30−Nε−ミ リストイルThyB29LysB30ヒトインスリン、B30−Nε−バルミトイル− ThrB29LysB30ヒトインスリン、B29−Nε−(N−パルミトイル−γ− グルタミル)−des(B30)−ヒトインスリン、B29−Nε−(N−リト コール−γ−グルタミル)−des(B30)ヒトインスリン、B29−Nε− (ω−カルボキシヘプタデカノイル)−des(B30)ヒトインスリン、及び B29−Nε−(ω−カルボキシヘプタデカノイル)ヒトインスリンからなろ群 より選択されるインスリン誘導体の有効量を肺送達により投与することを具備す る真性糖尿病の治療方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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DK31797 | 1997-03-20 | ||
DK0317/97 | 1997-03-20 | ||
PCT/DK1998/000109 WO1998042749A1 (en) | 1997-03-20 | 1998-03-20 | Zinc free insulin crystals for use in pulmonary compositions |
Publications (2)
Publication Number | Publication Date |
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JP2001506272A true JP2001506272A (ja) | 2001-05-15 |
JP3764174B2 JP3764174B2 (ja) | 2006-04-05 |
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JP54474798A Expired - Fee Related JP3764174B2 (ja) | 1997-03-20 | 1998-03-20 | 肺用組成物において使用するための亜鉛非含有のインスリン結晶 |
Country Status (17)
Country | Link |
---|---|
US (2) | US20070093411A1 (ja) |
EP (2) | EP1005490B1 (ja) |
JP (1) | JP3764174B2 (ja) |
KR (1) | KR20000076419A (ja) |
CN (1) | CN1259142A (ja) |
AT (1) | ATE321783T1 (ja) |
AU (1) | AU742591B2 (ja) |
BR (1) | BR9808285A (ja) |
CA (1) | CA2283705A1 (ja) |
DE (1) | DE69834028T2 (ja) |
ES (1) | ES2260832T3 (ja) |
HU (1) | HUP0000547A3 (ja) |
IL (1) | IL131796A0 (ja) |
NO (1) | NO994520D0 (ja) |
PL (1) | PL335777A1 (ja) |
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JP2013501773A (ja) * | 2009-08-11 | 2013-01-17 | バイオコン・リミテッド | クロマトグラフィーの方法およびその精製化合物 |
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US7193035B2 (en) | 2002-10-29 | 2007-03-20 | Sanofi-Aventis Deutschland Gmbh | Crystals of insulin analogs and processes for their preparation |
DE10250297A1 (de) * | 2002-10-29 | 2004-05-19 | Aventis Pharma Deutschland Gmbh | Kristalle von Insulinanaloga und Verfahren zu ihrer Herstellung |
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KR100798333B1 (ko) * | 2005-08-03 | 2008-01-28 | 고려대학교 산학협력단 | 락토오스 운반체와 혼합건조된 폐 전달용 인슐린미세결정분말 |
HUE037449T2 (hu) | 2008-10-17 | 2018-08-28 | Sanofi Aventis Deutschland | Egy inzulin és egy GLP-1 agonista kombinációja |
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RU2537239C2 (ru) | 2009-11-13 | 2014-12-27 | Санофи-Авентис Дойчланд Гмбх | Фармацевтическая композиция, включающая агонист glp-1, инсулин и метионин |
PT2611458T (pt) | 2010-08-30 | 2016-12-16 | Sanofi Aventis Deutschland | Utilização de ave0010 para o fabrico de um medicamento para o tratamento da diabetes mellitus tipo 2 |
US9821032B2 (en) | 2011-05-13 | 2017-11-21 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin |
PT2750699E (pt) | 2011-08-29 | 2015-11-03 | Sanofi Aventis Deutschland | Acelerómetro pendular |
TWI559929B (en) | 2011-09-01 | 2016-12-01 | Sanofi Aventis Deutschland | Pharmaceutical composition for use in the treatment of a neurodegenerative disease |
AR099569A1 (es) | 2014-02-28 | 2016-08-03 | Novo Nordisk As | Derivados de insulina y los usos médicos de estos |
EP3166595B1 (en) * | 2014-07-08 | 2019-05-15 | Amphastar Pharmaceuticals, Inc. | Micronized insulin, micronized insulin analogues, and methods of manufacturing the same |
CA2970200A1 (en) | 2014-12-12 | 2016-06-16 | Sanofi-Aventis Deutschland Gmbh | Insulin glargine/lixisenatide fixed ratio formulation |
TWI748945B (zh) | 2015-03-13 | 2021-12-11 | 德商賽諾菲阿凡提斯德意志有限公司 | 第2型糖尿病病患治療 |
TW201705975A (zh) | 2015-03-18 | 2017-02-16 | 賽諾菲阿凡提斯德意志有限公司 | 第2型糖尿病病患之治療 |
CN104761632A (zh) * | 2015-04-14 | 2015-07-08 | 珠海联邦制药股份有限公司 | 一种地特胰岛素结晶的制备方法及应用 |
CN106117345B (zh) * | 2015-05-05 | 2020-11-24 | 宜昌东阳光长江药业股份有限公司 | 一种制备甘精胰岛素结晶的方法 |
JP2018531900A (ja) | 2015-08-25 | 2018-11-01 | ノヴォ ノルディスク アー/エス | 新規インスリン誘導体及びその医学的使用 |
US20180244743A1 (en) | 2015-08-25 | 2018-08-30 | Novo Nordisk A/S | Novel Insulin Derivatives and the Medical Uses Hereof |
JP2018531901A (ja) | 2015-08-25 | 2018-11-01 | ノヴォ ノルディスク アー/エス | 新規インスリン誘導体及びその医学的使用 |
US10322168B2 (en) | 2016-01-07 | 2019-06-18 | Amphastar Pharmaceuticals, Inc. | High-purity inhalable particles of insulin and insulin analogues, and high-efficiency methods of manufacturing the same |
CN106749616B (zh) * | 2016-12-19 | 2021-09-03 | 华润昂德生物药业有限公司 | B30位苏氨酸缺失人胰岛素晶体的制备方法 |
CN109957001B (zh) * | 2017-12-26 | 2022-11-18 | 甘李药业股份有限公司 | 甘赖脯胰岛素结晶的制备方法 |
PL238016B1 (pl) * | 2018-07-06 | 2021-06-28 | Bioton Spolka Akcyjna | Krystaliczna, bezcynkowa postać insuliny glargine i sposób jej otrzymywania |
AU2020402135A1 (en) | 2019-12-11 | 2022-06-02 | Novo Nordisk A/S | Novel insulin analogues and uses thereof |
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US6310038B1 (en) * | 1997-03-20 | 2001-10-30 | Novo Nordisk A/S | Pulmonary insulin crystals |
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1998
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- 1998-03-20 JP JP54474798A patent/JP3764174B2/ja not_active Expired - Fee Related
- 1998-03-20 CA CA002283705A patent/CA2283705A1/en not_active Abandoned
- 1998-03-20 BR BR9808285-0A patent/BR9808285A/pt not_active IP Right Cessation
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- 1998-03-20 KR KR1019997008523A patent/KR20000076419A/ko not_active Application Discontinuation
- 1998-03-20 DE DE69834028T patent/DE69834028T2/de not_active Expired - Lifetime
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- 1998-03-20 WO PCT/DK1998/000109 patent/WO1998042749A1/en active IP Right Grant
- 1998-03-20 EP EP05109987A patent/EP1627642A3/en not_active Withdrawn
- 1998-03-20 AT AT98907916T patent/ATE321783T1/de not_active IP Right Cessation
- 1998-03-20 CN CN98805938A patent/CN1259142A/zh active Pending
- 1998-03-20 HU HU0000547A patent/HUP0000547A3/hu unknown
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- 1999-09-17 NO NO994520A patent/NO994520D0/no unknown
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2006
- 2006-01-23 US US11/337,855 patent/US20070093411A1/en not_active Abandoned
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013501773A (ja) * | 2009-08-11 | 2013-01-17 | バイオコン・リミテッド | クロマトグラフィーの方法およびその精製化合物 |
Also Published As
Publication number | Publication date |
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US20070093411A1 (en) | 2007-04-26 |
AU742591B2 (en) | 2002-01-10 |
US20070292520A1 (en) | 2007-12-20 |
HUP0000547A3 (en) | 2002-11-28 |
DE69834028T2 (de) | 2006-12-07 |
CN1259142A (zh) | 2000-07-05 |
KR20000076419A (ko) | 2000-12-26 |
EP1005490B1 (en) | 2006-03-29 |
ATE321783T1 (de) | 2006-04-15 |
ES2260832T3 (es) | 2006-11-01 |
NO994520L (no) | 1999-09-17 |
WO1998042749A1 (en) | 1998-10-01 |
US20090311326A9 (en) | 2009-12-17 |
EP1627642A2 (en) | 2006-02-22 |
DE69834028D1 (de) | 2006-05-18 |
EP1627642A3 (en) | 2006-04-19 |
AU6612098A (en) | 1998-10-20 |
JP3764174B2 (ja) | 2006-04-05 |
IL131796A0 (en) | 2001-03-19 |
NO994520D0 (no) | 1999-09-17 |
CA2283705A1 (en) | 1998-10-01 |
PL335777A1 (en) | 2000-05-22 |
HUP0000547A2 (hu) | 2000-08-28 |
BR9808285A (pt) | 2000-05-16 |
RU2198181C2 (ru) | 2003-02-10 |
EP1005490A1 (en) | 2000-06-07 |
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