CS208147B2 - Method of making the stabile low antigennous or the antigene of the plain insuline preparation of the protracted effect - Google Patents
Method of making the stabile low antigennous or the antigene of the plain insuline preparation of the protracted effect Download PDFInfo
- Publication number
- CS208147B2 CS208147B2 CS76270A CS27076A CS208147B2 CS 208147 B2 CS208147 B2 CS 208147B2 CS 76270 A CS76270 A CS 76270A CS 27076 A CS27076 A CS 27076A CS 208147 B2 CS208147 B2 CS 208147B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- insulin
- solution
- preparation
- bovine
- buffer
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 230000000694 effects Effects 0.000 title claims description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims abstract description 208
- 229940125396 insulin Drugs 0.000 claims abstract description 101
- 102000004877 Insulin Human genes 0.000 claims abstract description 97
- 108090001061 Insulin Proteins 0.000 claims abstract description 97
- 102000007327 Protamines Human genes 0.000 claims abstract description 14
- 108010007568 Protamines Proteins 0.000 claims abstract description 14
- 239000004202 carbamide Substances 0.000 claims abstract description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229920001184 polypeptide Polymers 0.000 claims abstract description 7
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 7
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 7
- 239000012062 aqueous buffer Substances 0.000 claims abstract 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 32
- 101001011741 Bos taurus Insulin Proteins 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 20
- 229940048914 protamine Drugs 0.000 claims description 12
- 239000012535 impurity Substances 0.000 claims description 8
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 7
- 239000003381 stabilizer Substances 0.000 claims description 6
- 238000005342 ion exchange Methods 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 102000018146 globin Human genes 0.000 claims description 2
- 108060003196 globin Proteins 0.000 claims description 2
- 230000000087 stabilizing effect Effects 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims 1
- 125000002091 cationic group Chemical group 0.000 claims 1
- 229910052804 chromium Inorganic materials 0.000 claims 1
- 239000011651 chromium Substances 0.000 claims 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 230000002473 insulinotropic effect Effects 0.000 claims 1
- 229940124272 protein stabilizer Drugs 0.000 claims 1
- 125000005493 quinolyl group Chemical group 0.000 claims 1
- 239000000243 solution Substances 0.000 abstract description 33
- 238000006243 chemical reaction Methods 0.000 abstract description 5
- 238000003776 cleavage reaction Methods 0.000 abstract description 3
- 150000002894 organic compounds Chemical class 0.000 abstract description 3
- 230000007017 scission Effects 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract 2
- 230000002378 acidificating effect Effects 0.000 abstract 1
- 230000002045 lasting effect Effects 0.000 abstract 1
- 229940070353 protamines Drugs 0.000 abstract 1
- 239000002244 precipitate Substances 0.000 description 23
- 239000000872 buffer Substances 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 13
- LEMUFSYUPGXXCM-JNEQYSBXSA-N caninsulin Chemical compound [Zn].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](CC3N=CN=C3)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)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)C1C=NC=N1 LEMUFSYUPGXXCM-JNEQYSBXSA-N 0.000 description 10
- 229920005654 Sephadex Polymers 0.000 description 9
- 239000012507 Sephadex™ Substances 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 238000002523 gelfiltration Methods 0.000 description 8
- 230000016784 immunoglobulin production Effects 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 108010005991 Pork Regular Insulin Proteins 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
- 239000002671 adjuvant Substances 0.000 description 5
- 230000000890 antigenic effect Effects 0.000 description 5
- 239000011701 zinc Substances 0.000 description 5
- 229910052725 zinc Inorganic materials 0.000 description 5
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- 101000993800 Sus scrofa Insulin Proteins 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000012064 sodium phosphate buffer Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229910021653 sulphate ion Inorganic materials 0.000 description 4
- 239000011592 zinc chloride Substances 0.000 description 4
- 206010053567 Coagulopathies Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 230000035602 clotting Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 229920002401 polyacrylamide Polymers 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 235000005074 zinc chloride Nutrition 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- PMDCZENCAXMSOU-UHFFFAOYSA-N N-ethylacetamide Chemical compound CCNC(C)=O PMDCZENCAXMSOU-UHFFFAOYSA-N 0.000 description 2
- 108010076181 Proinsulin Proteins 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000001502 gel electrophoresis Methods 0.000 description 2
- -1 hydroxymethylaminomethyl Chemical group 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000005185 salting out Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000004859 Copal Substances 0.000 description 1
- GUBGYTABKSRVRQ-WFVLMXAXSA-N DEAE-cellulose Chemical compound OC1C(O)C(O)C(CO)O[C@H]1O[C@@H]1C(CO)OC(O)C(O)C1O GUBGYTABKSRVRQ-WFVLMXAXSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 241000782205 Guibourtia conjugata Species 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021664 Increased insulin requirement Diseases 0.000 description 1
- 241001202975 Isophanes Species 0.000 description 1
- 241000208202 Linaceae Species 0.000 description 1
- 235000004431 Linum usitatissimum Nutrition 0.000 description 1
- 206010049287 Lipodystrophy acquired Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- 101000993774 Ovis aries Insulin Proteins 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- 241001311547 Patina Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- WKWQKPOJSGLGLI-UHFFFAOYSA-N [6-[(4-amino-2-methylquinolin-6-yl)carbamoylamino]-2-methylquinolin-4-yl]azanium;chloride Chemical compound [Cl-].N1=C(C)C=C([NH3+])C2=CC(NC(=O)NC3=CC4=C(N)C=C(N=C4C=C3)C)=CC=C21 WKWQKPOJSGLGLI-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000006286 aqueous extract 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
- 150000007514 bases Chemical class 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000002242 deionisation method Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000001516 effect on protein Effects 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- 239000006167 equilibration buffer Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000008076 immune mechanism Effects 0.000 description 1
- 239000004026 insulin derivative Substances 0.000 description 1
- 230000002608 insulinlike Effects 0.000 description 1
- 238000001155 isoelectric focusing Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 208000006132 lipodystrophy Diseases 0.000 description 1
- 229910052744 lithium Inorganic materials 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
- 238000005259 measurement Methods 0.000 description 1
- WDWDWGRYHDPSDS-UHFFFAOYSA-N methanimine Chemical compound N=C WDWDWGRYHDPSDS-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 108010011110 polyarginine Proteins 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 235000015277 pork Nutrition 0.000 description 1
- 229940119528 pork insulin Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000003307 slaughter Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008961 swelling Effects 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
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07K14/625—Extraction from natural sources
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biophysics (AREA)
- Endocrinology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Diabetes (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK8375AA DK140801B (da) | 1975-01-15 | 1975-01-15 | Fremgangsmåde til fremstilling af et stabilt langtidsvirkende insulinpræparat. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS208147B2 true CS208147B2 (en) | 1981-08-31 |
Family
ID=8089535
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS76270A CS208147B2 (en) | 1975-01-15 | 1976-01-15 | Method of making the stabile low antigennous or the antigene of the plain insuline preparation of the protracted effect |
Country Status (36)
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK374579A (da) * | 1979-09-07 | 1981-03-08 | Nordisk Insulinlab | Fremgangsmaade til fremstilling af et injucerbart insulinpraeparat |
| US4459226A (en) * | 1982-02-26 | 1984-07-10 | Eli Lilly And Company | Process for recovering insulin |
| US4801575A (en) * | 1986-07-30 | 1989-01-31 | The Regents Of The University Of California | Chimeric peptides for neuropeptide delivery through the blood-brain barrier |
| AU609769B2 (en) * | 1987-02-10 | 1991-05-09 | Drug Delivery Systems Inc. | Electrolytic transdermal delivery of proteins |
| US4878892A (en) * | 1987-02-10 | 1989-11-07 | Drug Delivery Systems Inc. | Electrolytic transdermal delivery of polypeptides |
| US6221367B1 (en) | 1992-06-15 | 2001-04-24 | Emisphere Technologies, Inc. | Active agent transport systems |
| US5629020A (en) | 1994-04-22 | 1997-05-13 | Emisphere Technologies, Inc. | Modified amino acids for drug delivery |
| US5714167A (en) | 1992-06-15 | 1998-02-03 | Emisphere Technologies, Inc. | Active agent transport systems |
| US5447728A (en) | 1992-06-15 | 1995-09-05 | Emisphere Technologies, Inc. | Desferrioxamine oral delivery system |
| US5643957A (en) | 1993-04-22 | 1997-07-01 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| US6051258A (en) | 1995-06-07 | 2000-04-18 | Emisphere Technologies, Inc. | Proteinoid emulsions and methods for preparation and use thereof |
| US5750147A (en) | 1995-06-07 | 1998-05-12 | Emisphere Technologies, Inc. | Method of solubilizing and encapsulating itraconazole |
| EP2077132A1 (en) | 2008-01-02 | 2009-07-08 | Boehringer Ingelheim Pharma GmbH & Co. KG | Dispensing device, storage device and method for dispensing a formulation |
| JP5670421B2 (ja) | 2009-03-31 | 2015-02-18 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | コンポーネント表面のコーティング方法 |
| US9265910B2 (en) | 2009-05-18 | 2016-02-23 | Boehringer Ingelheim International Gmbh | Adapter, inhalation device, and nebulizer |
| JP5715640B2 (ja) | 2009-11-25 | 2015-05-13 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ネブライザ |
| US10016568B2 (en) | 2009-11-25 | 2018-07-10 | Boehringer Ingelheim International Gmbh | Nebulizer |
| EP2504051B1 (en) | 2009-11-25 | 2019-09-04 | Boehringer Ingelheim International GmbH | Nebulizer |
| US9943654B2 (en) | 2010-06-24 | 2018-04-17 | Boehringer Ingelheim International Gmbh | Nebulizer |
| WO2012130757A1 (de) | 2011-04-01 | 2012-10-04 | Boehringer Ingelheim International Gmbh | Medizinisches gerät mit behälter |
| US9827384B2 (en) | 2011-05-23 | 2017-11-28 | Boehringer Ingelheim International Gmbh | Nebulizer |
| WO2013152894A1 (de) | 2012-04-13 | 2013-10-17 | Boehringer Ingelheim International Gmbh | Zerstäuber mit kodiermitteln |
| JP6643231B2 (ja) | 2013-08-09 | 2020-02-12 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ネブライザ |
| EP2835146B1 (en) | 2013-08-09 | 2020-09-30 | Boehringer Ingelheim International GmbH | Nebulizer |
| DK3139984T3 (da) | 2014-05-07 | 2021-07-19 | Boehringer Ingelheim Int | Forstøver |
| CN106255554B (zh) | 2014-05-07 | 2021-05-04 | 勃林格殷格翰国际有限公司 | 容器、喷雾器及用途 |
| PT3139982T (pt) | 2014-05-07 | 2022-04-05 | Boehringer Ingelheim Int | Nebulizador |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1285023A (en) * | 1968-08-09 | 1972-08-09 | Novo Terapeutisk Labor As | Improvements in or relating to injectable insulin preparations |
| US3758683A (en) * | 1971-04-30 | 1973-09-11 | R Jackson | Insulin product |
-
1975
- 1975-01-15 DK DK8375AA patent/DK140801B/da not_active IP Right Cessation
-
1976
- 1976-01-06 ZA ZA00760058A patent/ZA7658B/xx unknown
- 1976-01-07 GR GR49734A patent/GR58608B/el unknown
- 1976-01-07 IN IN41/CAL/76A patent/IN143279B/en unknown
- 1976-01-12 CA CA243,587A patent/CA1094549A/en not_active Expired
- 1976-01-12 FI FI760058A patent/FI66751C/fi not_active IP Right Cessation
- 1976-01-12 NZ NZ179733A patent/NZ179733A/xx unknown
- 1976-01-13 IT IT19221/76A patent/IT1054211B/it active
- 1976-01-13 IE IE62/76A patent/IE42395B1/en unknown
- 1976-01-13 LU LU74175A patent/LU74175A1/xx unknown
- 1976-01-13 DE DE2600971A patent/DE2600971C2/de not_active Expired
- 1976-01-13 SE SE7600284A patent/SE437219B/xx not_active IP Right Cessation
- 1976-01-14 RO RO7684491A patent/RO71576A/ro unknown
- 1976-01-14 AT AT21376A patent/AT362492B/de not_active IP Right Cessation
- 1976-01-14 GB GB1309/76A patent/GB1524431A/en not_active Expired
- 1976-01-14 NL NL7600338.A patent/NL166464C/xx not_active IP Right Cessation
- 1976-01-14 PT PT64696A patent/PT64696B/pt unknown
- 1976-01-14 DD DD190805A patent/DD124379A5/xx unknown
- 1976-01-14 FR FR7600854A patent/FR2297634A1/fr active Granted
- 1976-01-14 BR BR7600206A patent/BR7600206A/pt unknown
- 1976-01-14 NO NO760118A patent/NO146698C/no unknown
- 1976-01-14 OA OA55703A patent/OA05209A/xx unknown
- 1976-01-14 PL PL1976186526A patent/PL99927B1/pl unknown
- 1976-01-14 YU YU00083/76A patent/YU8376A/xx unknown
- 1976-01-14 MX MX764822U patent/MX4052E/es unknown
- 1976-01-15 BE BE163542A patent/BE837600A/xx not_active IP Right Cessation
- 1976-01-15 HU HU76NO198A patent/HU175142B/hu unknown
- 1976-01-15 CS CS76270A patent/CS208147B2/cs unknown
- 1976-01-15 ES ES444558A patent/ES444558A1/es not_active Expired
- 1976-01-15 IL IL48845A patent/IL48845A/xx unknown
- 1976-01-15 CH CH47076A patent/CH631625A5/de not_active IP Right Cessation
- 1976-01-16 JP JP51003293A patent/JPS5946939B2/ja not_active Expired
- 1976-01-17 EG EG16/76A patent/EG11988A/xx active
-
1978
- 1978-01-14 AR AR261924A patent/AR213088A1/es active
-
1979
- 1979-02-07 KE KE2919A patent/KE2919A/xx unknown
- 1979-12-30 MY MY169/79A patent/MY7900169A/xx unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CS208147B2 (en) | Method of making the stabile low antigennous or the antigene of the plain insuline preparation of the protracted effect | |
| US4183849A (en) | Therapeutic insulin preparation and a process for the production of a stable insulin preparation with protracted effect | |
| Striessnig et al. | Identification of a phenylalkylamine binding region within the alpha 1 subunit of skeletal muscle Ca2+ channels. | |
| US5561046A (en) | Methods for the detection of acid-labile subunit (ALS) of insulin-like growth factor binding protein complex | |
| AU627423B2 (en) | Human somatomedin carrier protein subunits and process for producing them | |
| Gold et al. | Biochemical and immunological characterization of three binding sites on human plasma fibronectin with different affinities for heparin | |
| EP0197901A1 (en) | Biologically active fragments of the human antihemophilic factor and method for their preparation and pharmaceutical preparations | |
| EP0424416B1 (en) | Acid-labile subunit (als) of insulin-like-growth factor (igf) binding protein complex | |
| Baseler et al. | Purification of haptoglobin and its effects on lymphocyte and alveolar macrophage responses | |
| JPH04503154A (ja) | 変型ヒト成長ホルモン | |
| JP2710645B2 (ja) | ｓｎＲＮＰ−Ａ抗原及びそのフラグメント | |
| Yue et al. | Antigenicity of “monocomponent” pork insulin in diabetic subjects | |
| Shemer et al. | Insulin receptors in lizard brain and liver: structural and functional studies of α and β subunits demonstrate evolutionary conservation | |
| Stevens et al. | Chick calretinin: purification, composition, and metal binding activity of native and recombinant forms | |
| JPH0723398B2 (ja) | 初乳由来ポリペプチド因子 | |
| US7485622B2 (en) | Paralytic peptide for use in neuromuscular therapy | |
| CZ389397A3 (cs) | Stimulační faktor kostí | |
| Lundwall et al. | Isolation of tryptic fragments of human C4 expressing Chido and Rodgers antigens | |
| CA1108535A (en) | Protein and process for isolating it | |
| Ingham et al. | Ligand-induced self-association of human chorionic gonadotropin. Positive cooperativity in the binding of 8-anilino-1-naphthalenesulfonate | |
| CS205040B2 (en) | Method of production of the water soluble,injected cross screened orgothein | |
| Weiler et al. | Synthesis and characterization of a bioactive 82-residue sphingolipid activator protein, saposin C | |
| Watkins et al. | The immunological properties of proteins treated with di-2-chloroethylmethylamine | |
| Kelso et al. | Induction of hyperglycemia with insulin antibodies to B-chain determinants | |
| Huang et al. | Modulation of allosteric interactions in neurophysin induced by succinylation of serine-56 or cleavage of residues 1-8 |