CA1246549A - Crystal suspensions of insulin derivatives, processes for their preparation and their use - Google Patents
Crystal suspensions of insulin derivatives, processes for their preparation and their useInfo
- Publication number
- CA1246549A CA1246549A CA000459844A CA459844A CA1246549A CA 1246549 A CA1246549 A CA 1246549A CA 000459844 A CA000459844 A CA 000459844A CA 459844 A CA459844 A CA 459844A CA 1246549 A CA1246549 A CA 1246549A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- insulin
- crystallization
- radical
- crystals
- 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.)
- Expired
Links
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical class 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 71
- 239000013078 crystal Substances 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 title claims abstract description 38
- 239000000725 suspension Substances 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000002425 crystallisation Methods 0.000 claims abstract description 21
- 230000008025 crystallization Effects 0.000 claims abstract description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- 239000012736 aqueous medium Substances 0.000 claims abstract description 3
- 125000000962 organic group Chemical group 0.000 claims abstract 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 30
- 229940125396 insulin Drugs 0.000 claims description 26
- 108090001061 Insulin Proteins 0.000 claims description 25
- 102000004877 Insulin Human genes 0.000 claims description 25
- 239000004026 insulin derivative Substances 0.000 claims description 14
- 150000001413 amino acids Chemical class 0.000 claims description 13
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002609 medium Substances 0.000 claims description 11
- 235000001014 amino acid Nutrition 0.000 claims description 10
- 108010076181 Proinsulin Proteins 0.000 claims description 9
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 9
- 239000011701 zinc Substances 0.000 claims description 9
- 229910052725 zinc Inorganic materials 0.000 claims description 9
- 239000002245 particle Substances 0.000 claims description 8
- 150000008575 L-amino acids Chemical class 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 claims description 3
- VOUAQYXWVJDEQY-QENPJCQMSA-N 33017-11-7 Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)NCC(=O)NCC(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)CCC1 VOUAQYXWVJDEQY-QENPJCQMSA-N 0.000 claims description 3
- 108010075254 C-Peptide Proteins 0.000 claims description 3
- 150000008574 D-amino acids Chemical class 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012928 buffer substance Substances 0.000 claims description 3
- 229930003836 cresol Natural products 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims 4
- 239000007924 injection Substances 0.000 claims 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 1
- -1 aromatic hydroxy compound Chemical class 0.000 abstract description 6
- 230000007935 neutral effect Effects 0.000 abstract description 6
- 150000002148 esters Chemical group 0.000 abstract description 3
- 150000002596 lactones Chemical class 0.000 abstract description 3
- 150000001408 amides Chemical group 0.000 abstract description 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 abstract 1
- 150000003254 radicals Chemical class 0.000 abstract 1
- 235000013350 formula milk Nutrition 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000003111 delayed effect Effects 0.000 description 8
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 108010066381 preproinsulin Proteins 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 4
- 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 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241001202975 Isophanes Species 0.000 description 3
- 229960001231 choline Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 2
- 108010005991 Pork Regular Insulin Proteins 0.000 description 2
- 102000007327 Protamines Human genes 0.000 description 2
- 108010007568 Protamines Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 235000009697 arginine Nutrition 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000010353 genetic engineering Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 229940048914 protamine Drugs 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- CSXHKOSAWQTJBT-YDYKLMMDSA-N (2z)-2-[(3r,4s,5s,8s,9s,10s,11r,13r,14s,16s)-16-acetyloxy-3,11-dihydroxy-4,8,10,14-tetramethyl-2,3,4,5,6,7,9,11,12,13,15,16-dodecahydro-1h-cyclopenta[a]phenanthren-17-ylidene]-6-methylhept-5-enoic acid;hydrate Chemical compound O.O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C.O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C CSXHKOSAWQTJBT-YDYKLMMDSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- QNRATNLHPGXHMA-XZHTYLCXSA-N (r)-(6-ethoxyquinolin-4-yl)-[(2s,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]methanol;hydrochloride Chemical compound Cl.C([C@H]([C@H](C1)CC)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OCC)C=C21 QNRATNLHPGXHMA-XZHTYLCXSA-N 0.000 description 1
- UFAABHKZLQFLSG-YFKPBYRVSA-N 2-[(4s)-4-amino-5-hydroxypentyl]guanidine Chemical compound OC[C@@H](N)CCCN=C(N)N UFAABHKZLQFLSG-YFKPBYRVSA-N 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000518994 Conta Species 0.000 description 1
- 102100026398 Cyclic AMP-responsive element-binding protein 3 Human genes 0.000 description 1
- 101710128029 Cyclic AMP-responsive element-binding protein 3 Proteins 0.000 description 1
- 102000005593 Endopeptidases Human genes 0.000 description 1
- 108010059378 Endopeptidases Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- QJPWUUJVYOJNMH-VKHMYHEASA-N L-homoserine lactone Chemical compound N[C@H]1CCOC1=O QJPWUUJVYOJNMH-VKHMYHEASA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000001484 arginines Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 102000018146 globin Human genes 0.000 description 1
- 108060003196 globin Proteins 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 235000015250 liver sausages Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- CKRORYDHXIRZCH-UHFFFAOYSA-N phosphoric acid;dihydrate Chemical compound O.O.OP(O)(O)=O CKRORYDHXIRZCH-UHFFFAOYSA-N 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000001810 trypsinlike Effects 0.000 description 1
- 238000012982 x-ray structure analysis Methods 0.000 description 1
Classifications
-
- 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
-
- 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
- C07K14/622—Insulins at least 1 amino acid in D-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
- A61K9/10—Dispersions; Emulsions
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
-
- 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)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Gastroenterology & Hepatology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Toxicology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- Materials Engineering (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Metallurgy (AREA)
- Animal Behavior & Ethology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3327709.5 | 1983-07-29 | ||
| DE19833327709 DE3327709A1 (de) | 1983-07-29 | 1983-07-29 | Insulin-derivat-kristallsuspensionen, verfahren zu deren herstellung und deren verwendung |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1246549A true CA1246549A (en) | 1988-12-13 |
Family
ID=6205461
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000459844A Expired CA1246549A (en) | 1983-07-29 | 1984-07-27 | Crystal suspensions of insulin derivatives, processes for their preparation and their use |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US4959351A (enExample) |
| EP (1) | EP0133285B1 (enExample) |
| JP (1) | JPH0764876B2 (enExample) |
| KR (1) | KR910009344B1 (enExample) |
| AT (1) | ATE32729T1 (enExample) |
| AU (1) | AU567360B2 (enExample) |
| CA (1) | CA1246549A (enExample) |
| DE (2) | DE3327709A1 (enExample) |
| DK (1) | DK172241B1 (enExample) |
| ES (1) | ES8601109A1 (enExample) |
| FI (1) | FI80277C (enExample) |
| GR (1) | GR82438B (enExample) |
| HU (1) | HU201096B (enExample) |
| IE (1) | IE57711B1 (enExample) |
| IL (1) | IL72512A (enExample) |
| NO (1) | NO167207C (enExample) |
| NZ (1) | NZ209041A (enExample) |
| PH (1) | PH22649A (enExample) |
| PT (1) | PT78980A (enExample) |
| ZA (1) | ZA845819B (enExample) |
Families Citing this family (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4946828A (en) * | 1985-03-12 | 1990-08-07 | Novo Nordisk A/S | Novel insulin peptides |
| DK347086D0 (da) * | 1986-07-21 | 1986-07-21 | Novo Industri As | Novel peptides |
| DK119785D0 (da) * | 1985-03-15 | 1985-03-15 | Nordisk Gentofte | Insulinpraeparat |
| DE3604868A1 (de) * | 1986-02-15 | 1987-08-20 | Behringwerke Ag | Insulinderivate, verfahren zu ihrer herstellung und ihre verwendung |
| DE3837825A1 (de) * | 1988-11-08 | 1990-05-10 | Hoechst Ag | Neue insulinderivate, ihre verwendung und eine sie enthaltende pharmazeutische zubereitung |
| DE3844211A1 (de) * | 1988-12-29 | 1990-07-05 | Hoechst Ag | Neue insulinderivate, verfahren zu deren herstellung, ihre verwendung und eine sie enthaltende pharmazeutische zubereitung |
| DK134189D0 (da) * | 1989-03-20 | 1989-03-20 | Nordisk Gentofte | Insulinforbindelser |
| WO1992010284A2 (en) | 1990-12-07 | 1992-06-25 | Cnc Development, Inc. | Catalytic chemical reactor |
| EP0705275B1 (en) * | 1993-06-21 | 1999-02-03 | Novo Nordisk A/S | Asp-b28 insulin crystals |
| DK72793D0 (da) * | 1993-06-21 | 1993-06-21 | Novo Nordisk As | Nyt produkt |
| US5504188A (en) * | 1994-06-16 | 1996-04-02 | Eli Lilly And Company | Preparation of stable zinc insulin analog crystals |
| US5461031A (en) * | 1994-06-16 | 1995-10-24 | Eli Lilly And Company | Monomeric insulin analog formulations |
| US5547929A (en) * | 1994-09-12 | 1996-08-20 | Eli Lilly And Company | Insulin analog formulations |
| US5597893A (en) * | 1994-10-31 | 1997-01-28 | Eli Lilly And Company | Preparation of stable insulin analog crystals |
| AR002976A1 (es) * | 1995-03-31 | 1998-05-27 | Lilly Co Eli | Formulaciones farmaceuticas parenterales de efecto prolongado de insulina; cristales de dichos analogos aplicables en dichas formulaciones yprocedimiento de las formulaciones mencionadas |
| PT840748E (pt) | 1995-07-25 | 2003-08-29 | Novartis Ag | Cristais de factor de crescimento transformante beta |
| PT821006E (pt) * | 1996-07-26 | 2004-09-30 | Aventis Pharma Gmbh | Derivados de insulina com ligacao a zinco aumentada |
| ATE294189T1 (de) * | 1997-02-07 | 2005-05-15 | Novo Nordisk As | Kristallisation von proteinen |
| US5898067A (en) * | 1997-02-07 | 1999-04-27 | Novo Nordisk A/S | Crystallization of proteins |
| HUP0004169A3 (en) | 1997-10-24 | 2001-06-28 | Lilly Co Eli | Insoluble insulin compositions and process for production thereof |
| CO4970787A1 (es) * | 1997-12-23 | 2000-11-07 | Lilly Co Eli | Composiciones insolubles de insulina y derivados de insulina que controlan la glucosa sanguinea |
| US6541606B2 (en) * | 1997-12-31 | 2003-04-01 | Altus Biologics Inc. | Stabilized protein crystals formulations containing them and methods of making them |
| DE19825447A1 (de) * | 1998-06-06 | 1999-12-09 | Hoechst Marion Roussel De Gmbh | Neue Insulinanaloga mit erhöhter Zinkbildung |
| EP1345968A2 (en) | 2000-12-28 | 2003-09-24 | Altus Biologics Inc. | Crystals of whole antibodies and fragments thereof and methods for making and using them |
| DE60217066T4 (de) * | 2001-02-09 | 2010-07-01 | Genentech, Inc., South San Francisco | Kristallisierung von igf-1 |
| DE10114178A1 (de) * | 2001-03-23 | 2002-10-10 | Aventis Pharma Gmbh | Zinkfreie und zinkarme Insulinzubereitungen mit verbesserter Stabilität |
| JP2005500304A (ja) * | 2001-06-21 | 2005-01-06 | アルタス バイオロジックス インコーポレイテッド | 球状タンパク質粒子およびそれらの作製方法および使用方法 |
| DE10227232A1 (de) * | 2002-06-18 | 2004-01-15 | Aventis Pharma Deutschland Gmbh | Saure Insulinzubereitungen mit verbesserter Stabilität |
| US7833513B2 (en) | 2004-12-03 | 2010-11-16 | Rhode Island Hospital | Treatment of Alzheimer's Disease |
| PL373543A1 (pl) * | 2005-03-10 | 2006-09-18 | Instytut Biotechnologii i Antybiotyków | Kompozycja farmaceutyczna zawierająca biosyntetyczny analog insuliny ludzkiej, oraz jej zastosowanie w terapii cukrzycy |
| WO2008065138A1 (en) * | 2006-11-29 | 2008-06-05 | Novo Nordisk A/S | Novel insulin crystal and method for preparing the crystal |
| PL219335B1 (pl) * | 2008-07-04 | 2015-04-30 | Inst Biotechnologii I Antybiotyków | Pochodna insuliny lub jej farmaceutycznie dopuszczalna sól, jej zastosowanie oraz zawierająca ją kompozycja farmaceutyczna |
| PT3228320T (pt) | 2008-10-17 | 2020-03-26 | Sanofi Aventis Deutschland | Combinação de uma insulina e de um agonista do glp-1 |
| PH12011502708B1 (en) | 2009-07-06 | 2017-11-10 | Sanofi Aventis Deutschland | Insulin preparations containing methionine |
| SG10201500871TA (en) | 2009-11-13 | 2015-04-29 | Sanofi Aventis Deutschland | Pharmaceutical composition comprising a glp-1 agonist and methionine |
| JP5832439B2 (ja) | 2009-11-13 | 2015-12-16 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Ｇｌｐ−１アゴニスト、インスリン及びメチオニンを含む薬学的組成物 |
| CN103179978A (zh) | 2010-08-30 | 2013-06-26 | 赛诺菲-安万特德国有限公司 | Ave0010用于制造供治疗2型糖尿病用的药物的用途 |
| CN102219851B (zh) * | 2011-05-09 | 2012-05-30 | 甘李药业有限公司 | 甘精胰岛素结晶的制备方法 |
| 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 |
| JP6367115B2 (ja) | 2011-08-29 | 2018-08-01 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | ２型糖尿病患者の血糖コントロールに使用する組合せ医薬 |
| TWI559929B (en) | 2011-09-01 | 2016-12-01 | Sanofi Aventis Deutschland | Pharmaceutical composition for use in the treatment of a neurodegenerative disease |
| AR095986A1 (es) * | 2013-04-03 | 2015-11-25 | Sanofi Sa | Proteínas modificadas que regulan glucosa en sangre con perfil alterado de actividad farmacológica y preparación de las mismas |
| WO2015084694A2 (en) | 2013-12-04 | 2015-06-11 | Merck Sharp & Dohme Corp. | Method for preparing crystalline insulin |
| CN107206058A (zh) | 2014-12-12 | 2017-09-26 | 赛诺菲-安万特德国有限公司 | 甘精胰岛素/利西拉来固定比率配制剂 |
| 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 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB729670A (en) * | 1951-11-15 | 1955-05-11 | Novo Terapeutisk Labor As | Improved process for the production of insulin in crystalline form and crystalline insulin produced thereby |
| DK78069C (da) * | 1952-06-23 | 1954-09-06 | Novo Terapeutisk Labor As | Fremgangsmåde til fremstilling af krystallinsk insulin. |
| US3719655A (en) * | 1969-12-05 | 1973-03-06 | Lilly Co Eli | Process for the crystallization of the ammonium and alkali metal salts in insulin |
| DE2459515C3 (de) * | 1974-12-17 | 1982-02-11 | Hoechst Ag, 6000 Frankfurt | Arzneimittelzubereitungen mit antidiabetischer Wirkung |
| DK319780A (da) * | 1980-07-24 | 1982-01-25 | Forenede Bryggerier As | Fremgangsmaade til enzymatisk udskiftning af b-30 aminosyren i insuliner |
| NL8201650A (nl) * | 1982-04-21 | 1983-11-16 | Akzo Nv | Semisynthetische bereiding van humane insuline. |
| DE3327928A1 (de) * | 1983-08-03 | 1985-02-21 | Hoechst Ag, 6230 Frankfurt | Verfahren zur herstellung von insulin-derivaten |
-
1983
- 1983-07-29 DE DE19833327709 patent/DE3327709A1/de not_active Withdrawn
-
1984
- 1984-07-23 HU HU842841A patent/HU201096B/hu not_active IP Right Cessation
- 1984-07-25 AT AT84108769T patent/ATE32729T1/de not_active IP Right Cessation
- 1984-07-25 DE DE8484108769T patent/DE3469535D1/de not_active Expired
- 1984-07-25 EP EP84108769A patent/EP0133285B1/de not_active Expired
- 1984-07-26 FI FI842981A patent/FI80277C/fi not_active IP Right Cessation
- 1984-07-26 PT PT78980A patent/PT78980A/pt not_active IP Right Cessation
- 1984-07-26 IL IL72512A patent/IL72512A/xx not_active IP Right Cessation
- 1984-07-27 IE IE1947/84A patent/IE57711B1/en not_active IP Right Cessation
- 1984-07-27 NZ NZ209041A patent/NZ209041A/xx unknown
- 1984-07-27 CA CA000459844A patent/CA1246549A/en not_active Expired
- 1984-07-27 NO NO843048A patent/NO167207C/no not_active IP Right Cessation
- 1984-07-27 GR GR75437A patent/GR82438B/el unknown
- 1984-07-27 AU AU31272/84A patent/AU567360B2/en not_active Ceased
- 1984-07-27 PH PH31042A patent/PH22649A/en unknown
- 1984-07-27 ES ES534684A patent/ES8601109A1/es not_active Expired
- 1984-07-27 ZA ZA845819A patent/ZA845819B/xx unknown
- 1984-07-27 US US06/635,257 patent/US4959351A/en not_active Expired - Fee Related
- 1984-07-27 DK DK368884A patent/DK172241B1/da not_active IP Right Cessation
- 1984-07-27 JP JP59155695A patent/JPH0764876B2/ja not_active Expired - Lifetime
- 1984-07-28 KR KR1019840004496A patent/KR910009344B1/ko not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ES534684A0 (es) | 1985-10-16 |
| DK172241B1 (da) | 1998-02-02 |
| DK368884A (da) | 1985-01-30 |
| NO167207C (no) | 1991-10-16 |
| FI80277C (fi) | 1990-05-10 |
| NO167207B (no) | 1991-07-08 |
| JPH0764876B2 (ja) | 1995-07-12 |
| AU3127284A (en) | 1985-01-31 |
| ZA845819B (en) | 1985-03-27 |
| US4959351A (en) | 1990-09-25 |
| DE3469535D1 (en) | 1988-04-07 |
| JPS6051118A (ja) | 1985-03-22 |
| FI842981A0 (fi) | 1984-07-26 |
| DK368884D0 (da) | 1984-07-27 |
| FI842981A7 (fi) | 1985-01-30 |
| EP0133285A1 (de) | 1985-02-20 |
| PH22649A (en) | 1988-10-28 |
| PT78980A (de) | 1984-08-01 |
| KR910009344B1 (ko) | 1991-11-12 |
| EP0133285B1 (de) | 1988-03-02 |
| IL72512A (en) | 1989-08-15 |
| ES8601109A1 (es) | 1985-10-16 |
| AU567360B2 (en) | 1987-11-19 |
| IE57711B1 (en) | 1993-03-10 |
| IE841947L (en) | 1985-01-29 |
| ATE32729T1 (de) | 1988-03-15 |
| IL72512A0 (en) | 1984-11-30 |
| HU201096B (en) | 1990-09-28 |
| NO843048L (no) | 1985-01-30 |
| KR850000981A (ko) | 1985-03-14 |
| NZ209041A (en) | 1989-02-24 |
| DE3327709A1 (de) | 1985-02-07 |
| HUT35001A (en) | 1985-05-28 |
| FI80277B (fi) | 1990-01-31 |
| GR82438B (enExample) | 1984-12-13 |
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Legal Events
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| MKEX | Expiry |