CN103893110B - A kind of lixisenatide injection and preparation method thereof - Google Patents
A kind of lixisenatide injection and preparation method thereof Download PDFInfo
- Publication number
- CN103893110B CN103893110B CN201210572013.7A CN201210572013A CN103893110B CN 103893110 B CN103893110 B CN 103893110B CN 201210572013 A CN201210572013 A CN 201210572013A CN 103893110 B CN103893110 B CN 103893110B
- Authority
- CN
- China
- Prior art keywords
- injection
- lixisenatide
- solution
- stirring
- dissolving
- 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 - Fee Related
Links
- XVVOERDUTLJJHN-IAEQDCLQSA-N lixisenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 XVVOERDUTLJJHN-IAEQDCLQSA-N 0.000 title claims abstract description 179
- 229960001093 lixisenatide Drugs 0.000 title claims abstract description 178
- 108010004367 lixisenatide Proteins 0.000 title claims abstract description 178
- 238000002347 injection Methods 0.000 title claims abstract description 161
- 239000007924 injection Substances 0.000 title claims abstract description 161
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 239000003002 pH adjusting agent Substances 0.000 claims abstract description 35
- 230000003204 osmotic Effects 0.000 claims abstract description 32
- 239000000203 mixture Substances 0.000 claims abstract description 31
- 230000000844 anti-bacterial Effects 0.000 claims abstract description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 34
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 30
- 239000008215 water for injection Substances 0.000 claims description 29
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 27
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 claims description 26
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 26
- 238000001914 filtration Methods 0.000 claims description 26
- 239000000594 mannitol Substances 0.000 claims description 26
- 235000010355 mannitol Nutrition 0.000 claims description 26
- 230000001954 sterilising Effects 0.000 claims description 26
- 238000004659 sterilization and disinfection Methods 0.000 claims description 26
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 19
- RLSSMJSEOOYNOY-UHFFFAOYSA-N M-Cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 claims description 15
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 15
- 229940100630 metacresol Drugs 0.000 claims description 15
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 14
- IYNDLOXRXUOGIU-UHFFFAOYSA-M potassium;3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [K+].O=C1N2C(C([O-])=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 IYNDLOXRXUOGIU-UHFFFAOYSA-M 0.000 claims description 11
- 229960003742 phenol Drugs 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 229960004926 Chlorobutanol Drugs 0.000 claims description 8
- 229960000583 Acetic Acid Drugs 0.000 claims description 7
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- OQUFOZNPBIIJTN-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;sodium Chemical compound [Na].OC(=O)CC(O)(C(O)=O)CC(O)=O OQUFOZNPBIIJTN-UHFFFAOYSA-N 0.000 claims description 3
- -1 chlorobutanol Compound Chemical class 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 239000002068 microbial inoculum Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- QVLTXCYWHPZMCA-UHFFFAOYSA-K phosphoric acid;phosphate Chemical group OP(O)(O)=O.[O-]P([O-])([O-])=O QVLTXCYWHPZMCA-UHFFFAOYSA-K 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 22
- 238000006243 chemical reaction Methods 0.000 abstract description 18
- 230000002218 hypoglycaemic Effects 0.000 abstract description 18
- 230000002496 gastric Effects 0.000 abstract description 13
- 239000002671 adjuvant Substances 0.000 abstract description 3
- 230000000240 adjuvant Effects 0.000 abstract description 3
- 229940090044 Injection Drugs 0.000 description 149
- 239000000243 solution Substances 0.000 description 125
- 238000003756 stirring Methods 0.000 description 68
- 238000004140 cleaning Methods 0.000 description 25
- 238000005352 clarification Methods 0.000 description 19
- 238000005303 weighing Methods 0.000 description 18
- 241000700159 Rattus Species 0.000 description 14
- 210000004369 Blood Anatomy 0.000 description 12
- 239000008280 blood Substances 0.000 description 12
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- 238000011068 load Methods 0.000 description 10
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exendin-4 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 8
- 229920002892 amber Polymers 0.000 description 8
- 229960001519 exenatide Drugs 0.000 description 8
- OSASVXMJTNOKOY-UHFFFAOYSA-N Chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 7
- 108010011459 Exenatide Proteins 0.000 description 7
- 230000001580 bacterial Effects 0.000 description 7
- DTHNMHAUYICORS-KTKZVXAJSA-N 107444-51-9 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 6
- 206010012601 Diabetes mellitus Diseases 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 229920001184 polypeptide Polymers 0.000 description 5
- 206010047700 Vomiting Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229940047296 exenatide Injection Drugs 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 206010012735 Diarrhoea Diseases 0.000 description 3
- 102100003818 GCG Human genes 0.000 description 3
- 101710042131 GCG Proteins 0.000 description 3
- 210000000936 Intestines Anatomy 0.000 description 3
- 229960003105 Metformin Drugs 0.000 description 3
- 210000002784 Stomach Anatomy 0.000 description 3
- 229960001052 Streptozocin Drugs 0.000 description 3
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N Streptozotocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000004059 degradation Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 201000008286 diarrhea Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000003203 everyday Effects 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 101700062901 DPP Proteins 0.000 description 2
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- 206010018473 Glycosuria Diseases 0.000 description 2
- 206010019233 Headache Diseases 0.000 description 2
- 210000002381 Plasma Anatomy 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000002269 analeptic agent Substances 0.000 description 2
- 230000003816 axenic Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000007979 citrate buffer Substances 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 235000020828 fasting Nutrition 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 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 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006011 modification reaction Methods 0.000 description 2
- 230000001264 neutralization Effects 0.000 description 2
- 230000001151 other effect Effects 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 210000001015 Abdomen Anatomy 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 240000002268 Citrus limon Species 0.000 description 1
- 241000551547 Dione <red algae> Species 0.000 description 1
- 101700024131 EXE4 Proteins 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 229960004666 Glucagon Drugs 0.000 description 1
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 1
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N Glucagonum Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 210000000496 Pancreas Anatomy 0.000 description 1
- 230000035957 Urine Volume Effects 0.000 description 1
- 210000003462 Veins Anatomy 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 229940090129 blood glucose lowering drugs Thiazolidinediones Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000593 degrading Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- 230000037308 hair color Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 210000002571 pancreatic alpha cell Anatomy 0.000 description 1
- 230000000149 penetrating Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 230000004936 stimulating Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
Abstract
The present invention relates to pharmaceutical field, particularly relate to a kind of lixisenatide injection and preparation method thereof.The lixisenatide injection composition that the present invention provides, including lixisenatide, pH adjusting agent, antibacterial and osmotic pressure regulator.The lixisenatide injection steady quality that the present invention provides, the most degradable, hypoglycemic effect is obvious, and medicine frequency is low, and gastrointestinal reaction is less, can strengthen the compliance that patient takes medicine.Its required adjuvant of preparation is easily obtained, and the pH adjusting agent of selection can effectively adjust pH value to safeguard stablizing of lixisenatide in injection.
Description
Technical field
The present invention relates to pharmaceutical field, particularly relate to a kind of lixisenatide injection and preparation thereof.
Background technology
GLP-1 is a kind of natural peptide matters in human body, can be produced by small intestinal and release in several minutes after the meal
Put, pancreatic alpha cells can be suppressed to secrete glucagon, stimulating pancreas β cells secrete insulin, but important
, blood glucose normal or relatively low time, it is the most inactive.Due to, use GLP-1 receptor agonist treatment
Time, occur hypoglycemic risk relatively low, GLP-1 receptor stimulating agent has been widely deployed as II type glycosuria
Sick elements addition medicine (add-on therapy).
Lixisenatide (Lixisenatide) is glucagon-like-peptide-1 (GLP-1) receptor stimulating agent, is base
Synthesize in the modification of 6 lysine residues of C-terminal of GLP-1 analog Exendin-4 of tool hypoglycemic activity
Novel glp-1-1 analog, be resistant to the Degradation of internal dipeptidyl peptidase IV (DPP4).Lixisenatide
Structure shown in formula I:
Formulas I
As the one of GLP-1 analog, lixisenatide is applicable to take metformin, sulphanylureas, thiazole
II type glycosuria associated with alkane diones, metformin and sulphanylureas combination, metformin and thiazolidinediones
In patient, it is impossible to effectively control the auxiliary treatment of the patient of blood glucose, to improve the control to blood glucose.
Lixisenatide, as the medicine for the treatment of type ii diabetes, is carrying out clinical III phase conceptual phase at present, by
Being a kind of polypeptides matter in lixisenatide, character is unstable, and it easily decomposes in the intestines and stomach, and easily causes
Serious gastrointestinal reaction, the most not yet has the lixisenatide dosage form of applicable Clinical practice to list.
Summary of the invention
In view of this, the technical problem to be solved in the present invention be to provide a kind of lixisenatide injection and
Preparation method, the lixisenatide injection stable in properties that the present invention provides is not easily decomposed and is difficult to cause gastrointestinal
Road reacts.
The invention provides a kind of lixisenatide injection, including lixisenatide, pH adjusting agent, antibacterial,
Osmotic pressure regulator and water for injection.
In the lixisenatide injection that the present invention is supplied to, pH adjusting agent, antibacterial and osmotic pressure regulator
Ratio different because of its kind and the difference of consumption.
As preferably, in lixisenatide injection, lixisenatide, pH adjusting agent, antibacterial and osmotic pressure are adjusted
The mass ratio of joint agent is 0.5:(0.5 ~ 10.5): (0.5 ~ 8.5): (79.3 ~ 99.3).
It is highly preferred that it is lixisenatide in the lixisenatide injection that provides of the present invention, pH adjusting agent, antibacterial
The mass ratio of agent and osmotic pressure regulator is 0.5:(3 ~ 8): (2.5 ~ 6.5): (84.3 ~ 94.3).
Most preferably, lixisenatide in the lixisenatide injection that the present invention provides, pH adjusting agent, antibacterial
The mass ratio of agent and osmotic pressure regulator is 0.5:(5 ~ 6): (4 ~ 5): (88 ~ 89).
Preferably, the pH value of the lixisenatide injection that the present invention provides is 7 ~ 9.
Owing to lixisenatide is a kind of basic polypeptide class material, more stable under the conditions of neutral meta-alkali, and
It is 4 ~ 9 that human body can tolerate pH scope, therefore, uses pH in the lixisenatide injection that the present invention provides
The pH value of lixisenatide injection is adjusted to 7 ~ 9 to maintain stablizing of lixisenatide by regulator.
Preferably, in the lixisenatide injection that the present invention provides, pH adjusting agent is phosphoric acid, citric acid, ice
A kind of or both mixture above in acetic acid, dilute hydrochloric acid.
Preferably, in the lixisenatide injection that the present invention provides, pH adjusting agent also includes disodium hydrogen phosphate.
In the lixisenatide injection that the present invention provides, pH adjusting agent is phosphoric acid, citric acid, glacial acetic acid, dilute
A kind of in hydrochloric acid or both above and mixture of disodium hydrogen phosphate.
It is highly preferred that pH adjusting agent is phosphoric acid and phosphoric acid hydrogen two in the lixisenatide injection of present invention offer
The mixture of the mixture of sodium or citric acid and disodium hydrogen phosphate.
Most preferably, in the pH adjusting agent of the lixisenatide injection that the present invention provides, phosphoric acid and phosphoric acid hydrogen
The mass ratio of disodium is 48:53, and citric acid is 5:2 with the mass ratio of disodium hydrogen phosphate.
Injection should have identical with a blood plasma or slightly biased high osmotic pressure, otherwise due to osmolality disturbance or
Other effects, quickly can cause patient to have a headache and the untoward reaction such as vomiting.Regulate suitable osmotic pressure can drop
Intestines and stomach reaction after low patient medication.
Preferably, in the lixisenatide injection that the present invention provides, osmotic pressure regulator is mannitol.
It is highly preferred that the osmotic pressure molar density of lixisenatide injection that the present invention is supplied to is 285
MOsmol/kg～310mOsmol/kg.
Polypeptide easily by bacterial degradation, therefore application axenic purification water dissolution add antibacterial and prevent it from degrading.
Preferably, in the lixisenatide injection that the present invention provides, antibacterial is metacresol, phenol or trichlorine
A kind of or both mixture above in the tert-butyl alcohol.
It is highly preferred that antibacterial is metacresol in the lixisenatide injection of present invention offer.
The preparation method of the lixisenatide injection that the present invention provides is: take osmotic pressure regulator and antibacterial
It is dissolved in water, mixes with pH adjusting agent, lixisenatide, filtration sterilization, to obtain final product.
Preferably, the present invention provide lixisenatide injection preparation method in, osmotic pressure regulator and
After antibacterial is dissolved in water, first mix with pH adjusting agent, then mix with lixisenatide.
Preferably, the preparation of lixisenatide injection is aseptically carried out.
Preferably, the packaged form of lixisenatide injection is injection pen or cillin bottle.
The invention provides a kind of lixisenatide injection, comprising: lixisenatide, pH adjusting agent, press down
Microbial inoculum, osmotic pressure regulator and water.The lixisenatide injection steady quality that the present invention provides, is difficult to fall
Solving, gastrointestinal reaction is less, and hypoglycemic effect is obvious, and medicine frequency is low, and can strengthen that patient takes medicine complies with
Property.The required adjuvant of its preparation is easily obtained, and the pH adjusting agent of selection can effectively adjust pH to safeguard injection
In liquid, lixisenatide stablizes.Experiment shows, the lixisenatide injection providing the present invention carries out stable
Property the result investigated show, place after 10 days under high light hot conditions, solution clarification, without bacterial growth,
After routine preservation 12 months, solution is still clarified, and represents that content is basically unchanged, shows what the present invention provided
Lixisenatide injection has good stability the most degradable.In terms of gastrointestinal reaction after medication, injection profit
Gastrointestinal reaction after hila comes to be less than existing hypoglycemic medicine, shows that the present invention is by regulation injection
Osmotic pressure, further reduces the gastrointestinal reaction after patient medication.In the fall to diabetes rat
Sugar effect aspect, compared with existing hypoglycemic medicine, once-a-day injects the hypoglycemic effect and of lixisenatide
The hypoglycemic effect of the Exenatide of day double injection is suitable, and speed is slightly faster than Exenatide.
Detailed description of the invention
The invention provides a kind of lixisenatide injection and preparation method thereof, those skilled in the art are permissible
Use for reference present disclosure, be suitably modified technological parameter and realize.Special needs to be pointed out is, all similar replacing
Changing and change apparent to those skilled in the art, they are considered as being included in the present invention.
Method and the application of the present invention are described by preferred embodiment, and related personnel substantially can be not
In disengaging present invention, spirit and scope, method described herein and application it is modified or suitably becomes
More with combination, realize and apply the technology of the present invention.
The invention provides a kind of lixisenatide injection, including lixisenatide, pH adjusting agent, antibacterial,
Osmotic pressure regulator and water for injection.
Lixisenatide, pH adjusting agent, antibacterial and osmotic pressure in the lixisenatide injection that the present invention provides
The mass ratio of regulator is 0.5:(0.5 ~ 10.5): (0.5 ~ 8.5): (79.3 ~ 99.3).
Solution-stabilized for making, the present invention provide lixisenatide injection in lixisenatide, pH adjusting agent,
The mass ratio of antibacterial and osmotic pressure regulator is 0.5:(3 ~ 8): (2.5 ~ 6.5): (84.3 ~ 94.3).
For making solution more stable, the present invention provide lixisenatide injection in lixisenatide, pH adjusting agent,
The mass ratio of antibacterial and osmotic pressure regulator is 0.5:(5 ~ 6): (4 ~ 5): (88 ~ 89).
In the lixisenatide injection that the present invention provides, pH adjusting agent is phosphoric acid, citric acid, glacial acetic acid, dilute
A kind of or both mixture above in hydrochloric acid.
It addition, pH adjusting agent also includes disodium hydrogen phosphate in the lixisenatide injection of present invention offer.
In the lixisenatide injection that the present invention provides, pH adjusting agent is phosphoric acid, citric acid, glacial acetic acid, dilute
A kind of in hydrochloric acid or both above and mixture of disodium hydrogen phosphate.
In some embodiments of the invention, in lixisenatide injection composition each component in terms of mass parts
For:
In some embodiments of the invention, in lixisenatide injection composition each component in terms of mass parts
For:
In some embodiments of the invention, in lixisenatide injection composition each component in terms of mass parts
For:
In some embodiments of the invention, in lixisenatide injection composition each component in terms of mass parts
For:
In some embodiments of the invention, in lixisenatide injection composition each component in terms of mass parts
For:
In some embodiments of the invention, in lixisenatide injection composition each component in terms of mass parts
For:
In some embodiments of the invention, in lixisenatide injection composition each component in terms of mass parts
For:
In some embodiments of the invention, in lixisenatide injection composition each component in terms of mass parts
For:
In some embodiments of the invention, in lixisenatide injection composition each component in terms of mass parts
For:
Owing to lixisenatide is a kind of basic polypeptide class material, more stable under the conditions of neutral meta-alkali, and
It is 4 ~ 9 that human body can tolerate pH scope, therefore, uses pH in the lixisenatide injection that the present invention provides
The pH value of lixisenatide injection is adjusted to 7 ~ 9 to maintain stablizing of lixisenatide by regulator.
For maintaining pH stable, in the lixisenatide injection that the present invention provides, pH adjusting agent is phosphoric acid and phosphorus
The mixture of the acid mixture of disodium hydrogen or citric acid and disodium hydrogen phosphate.
For maintaining pH stable further, in the pH adjusting agent of the lixisenatide injection that the present invention provides,
The mass ratio of phosphoric acid and disodium hydrogen phosphate is 48:53, and citric acid is 5:2 with the mass ratio of disodium hydrogen phosphate.
Injection should have identical with a blood plasma or slightly biased high osmotic pressure, otherwise due to osmolality disturbance or
Other effects, quickly can cause patient to have a headache and the untoward reaction such as vomiting.
Regulating the intestines and stomach reaction after suitable osmotic pressure can reduce patient medication, therefore, the present invention provides
Lixisenatide injection in osmotic pressure regulator be mannitol.
It is highly preferred that, the osmotic pressure molar density of the lixisenatide injection that the present invention is supplied to is 285
MOsmol/kg～310mOsmol/kg.
Due to polypeptide easily by bacterial degradation, therefore application axenic purification water dissolution add antibacterial and prevent it
Degraded.
In the lixisenatide injection that the present invention provides, antibacterial is in metacresol, phenol or chlorobutanol
One or both mixing.
In order to preferably kill except antibacterial, in the lixisenatide injection that the present invention provides, antibacterial is metacresol.
In the lixisenatide injection that the present invention provides, water is water for injection.
The preparation method of the lixisenatide injection that the present invention provides is: take osmotic pressure regulator and antibacterial
It is dissolved in water, mixes with pH adjusting agent, lixisenatide, filtration sterilization, to obtain final product.
Owing to lixisenatide is the most stable, the lixisenatide injection that the present invention provides
In preparation method, after osmotic pressure regulator and antibacterial are dissolved in water, first mix with pH adjusting agent, then
Mix with lixisenatide.
For ensureing injection quality, the preparation of lixisenatide injection is aseptically carried out.
For convenience of using, the packaged form of lixisenatide injection is injection pen or cillin bottle.
The invention provides a kind of lixisenatide injection, comprising: lixisenatide, pH adjusting agent, press down
Microbial inoculum, osmotic pressure regulator and water, the lixisenatide injection steady quality that the present invention provides, it is difficult to fall
Solving, hypoglycemic effect is obvious, and medicine frequency is low, and gastrointestinal reaction is less, and can strengthen that patient takes medicine complies with
Property.The required adjuvant of its preparation is easily obtained, and the pH adjusting agent of selection can effectively adjust pH to safeguard Li Xi
Draw stablizing of lixisenatide in injection.Experiment shows, the lixisenatide injection providing the present invention
The result carrying out study on the stability shows, after placing 10 days under high light hot conditions, solution clarification, nothing are carefully
Bacteria growing, routine preservation is after 12 months, and solution is still clarified, and represents that content is basically unchanged, shows this
The lixisenatide injection of bright offer has good stability the most degradable.In terms of gastrointestinal reaction after medication,
Gastrointestinal reaction after injection lixisenatide to be less than existing hypoglycemic medicine, shows that the present invention is noted by regulation
Penetrate the osmotic pressure of liquid, further reduce the gastrointestinal reaction after patient medication.Big to diabetes
The hypoglycemic effect aspect of Mus, compared with existing hypoglycemic medicine, once-a-day injects the blood sugar lowering effect of lixisenatide
Fruit is suitable with the hypoglycemic effect of the Exenatide of double injection on the one, and speed is slightly faster than Exenatide.
The reagent that the present invention uses is all common commercially available product, all can buy in market.
Below in conjunction with embodiment, the present invention is expanded on further.
The preparation of embodiment 1 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 5160mg mannitol and 100mg chlorobutanol, add the stirring of 120mL water for injection
After dissolving, weighing 30mg lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds
96mg phosphoric acid and 106mg disodium hydrogen phosphate, stirring and dissolving to solution clarifies, and the pH value making solution is
7 ~ 9, filtration sterilization；The solution prepared is poured in amber 2mL cillin bottle, rolls lid, fill altogether
50.
The preparation of embodiment 2 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 5160g mannitol and 100g phenol, after adding 24L water for injection stirring and dissolving, weigh
6g lixisenatide, adds in solution, and stirring and dissolving to solution is clarified, and adds 19.2g phosphoric acid and 21.2
G disodium hydrogen phosphate, the clarification of stirring and dissolving to solution, the pH value making solution is 7 ~ 9, filtration sterilization；Will
The solution prepared pours in silication the 3mL clamped bottle jumped a queue, rolls lid, loads disposable injection pen
In, fill 10000 altogether.
The preparation of embodiment 3 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 5160mg mannitol and 100mg chlorobutanol, add the stirring of 120mL water for injection
After dissolving, weighing 30mg lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds
185mg glacial acetic acid, the clarification of stirring and dissolving to solution, the pH value making solution is 7 ~ 9, filtration sterilization；Will
The solution prepared pours in silication the 3mL clamped bottle jumped a queue, rolls lid, loads disposable injection pen
In, fill 50 altogether.
The preparation of embodiment 4 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 5160mg mannitol and 100mg chlorobutanol, add the stirring of 120mL water for injection
After dissolving, weighing 30mg lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds
180mg dilute hydrochloric acid, the clarification of stirring and dissolving to solution, the pH value making solution is 7 ~ 9, filtration sterilization；Will
The solution prepared pours in silication the 3mL clamped bottle jumped a queue, rolls lid, loads disposable injection pen
In, fill 50 altogether.
The preparation of embodiment 5 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 4758mg mannitol and 510mg metacresol, add 120mL water for injection stirring and dissolving
After, weighing 30mg lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds 30mg
Dilute hydrochloric acid, the clarification of stirring and dissolving to solution, the pH value making solution is 7 ~ 9, filtration sterilization；To prepare
Solution pour in silication the 3mL clamped bottle jumped a queue, roll lid, load
In disposable injection pen, fill 50 altogether.
The preparation of embodiment 6 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 5958mg mannitol and 30mg metacresol, after adding 120mL water for injection stirring and dissolving,
Weighing 30mg lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds 630mg dilute
Hydrochloric acid, the clarification of stirring and dissolving to solution, the pH value making solution is 7 ~ 9, filtration sterilization；To prepare
Solution pour in silication the 3mL clamped bottle jumped a queue, roll lid, load in disposable injection pen, altogether
Fill 50.
The preparation of embodiment 7 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 5058mg mannitol and 390mg metacresol, add 120mL water for injection stirring and dissolving
After, weighing 30mg lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds 180mg
Dilute hydrochloric acid, the clarification of stirring and dissolving to solution, the pH value making solution is 7 ~ 9, filtration sterilization；To prepare
Solution pour in silication the 3mL clamped bottle jumped a queue, roll lid, load in disposable injection pen, altogether
Fill 50.
The preparation of embodiment 8 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 5658mg mannitol and 150mg metacresol, add 120mL water for injection stirring and dissolving
After, weighing 30mg lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds 240mg
Dilute hydrochloric acid, the clarification of stirring and dissolving to solution, the pH value making solution is 7 ~ 9, filtration sterilization；To prepare
Solution pour in amber 2mL cillin bottle, roll lid, altogether fill 50.
The preparation of embodiment 9 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 5280mg mannitol and 300mg metacresol, add 120mL water for injection stirring and dissolving
After, weighing 30mg lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds 300mg
Dilute hydrochloric acid, the clarification of stirring and dissolving to solution, the pH value making solution is 7 ~ 9, filtration sterilization；To prepare
Solution pour in amber 2mL cillin bottle, roll lid, altogether fill 50.
The preparation of embodiment 10 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 5340mg mannitol and 240mg metacresol, add 120mL water for injection stirring and dissolving
After, weighing 30mg lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds 360mg
Dilute hydrochloric acid, the clarification of stirring and dissolving to solution, the pH value making solution is 7 ~ 9, filtration sterilization；To prepare
Solution pour in amber 2mL cillin bottle, roll lid, altogether fill 50.
The preparation of embodiment 11 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 5160mg mannitol and 100mg phenol, after adding 120mL water for injection stirring and dissolving,
Weighing 30mg lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds 80mg phosphorus
Acid, the clarification of stirring and dissolving to solution, the pH value making solution is 7 ~ 9, filtration sterilization；Molten by prepare
Liquid pours in amber 2mL cillin bottle, rolls lid, fill 50 altogether.
The preparation of embodiment 12 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 5160mg mannitol and 260mg metacresol, add 120mL water for injection stirring and dissolving
After, weighing 30mg lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds 80mg
Phosphoric acid, the clarification of stirring and dissolving to solution, the pH value making solution is 7 ~ 9, filtration sterilization；By prepare
Solution pours in silication the 3mL clamped bottle jumped a queue, rolls lid, loads in disposable injection pen, fills altogether
Fill 50.
The preparation of embodiment 13 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 1032g mannitol and 20g phenol, after adding 24L water for injection stirring and dissolving, weigh 6
G lixisenatide, adds in solution, and stirring and dissolving to solution is clarified, and adds 25g citric acid and 1g phosphorus
Acid dihydride sodium, the clarification of stirring and dissolving to solution, the pH value making solution is 7 ~ 9, filtration sterilization；Will preparation
Good solution pours in silication the 3mL clamped bottle jumped a queue, rolls lid, loads in disposable injection pen,
Fill 10000 altogether.
The preparation of embodiment 14 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 5160mg mannitol and 100mg phenol, after adding 120mL water for injection stirring and dissolving,
Weighing 30mg lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds 120mg lemon
Lemon acid, the clarification of stirring and dissolving to solution, the pH value making solution is 7 ~ 9, filtration sterilization；By prepare
Solution pours in amber 2mL cillin bottle, rolls lid, fill 50 altogether.
The preparation of embodiment 15 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 5160mg mannitol and 100mg phenol, after adding 120mL water for injection stirring and dissolving,
Weighing 30mg lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds 80mg phosphoric acid,
Stirring and dissolving is clarified to solution, and the pH value making solution is 7 ~ 9, filtration sterilization；The solution prepared is filled
Enter in amber 2mL cillin bottle, roll lid, fill 50 altogether.
The preparation of embodiment 16 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 1032g mannitol and 52g metacresol, after adding 24L water for injection stirring and dissolving, weigh
6g lixisenatide, adds in solution, and stirring and dissolving to solution is clarified, and adds 16g phosphoric acid, stirs molten
Solution is clarified to solution, and the pH value making solution is 7 ~ 9, filtration sterilization；The solution prepared is poured into silicon
In the 3mL clamped bottle changed and jump a queue, roll lid, load in disposable injection pen, fill 10000 altogether.
The preparation of embodiment 17 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 1032g mannitol and 52g metacresol, after adding 24L water for injection stirring and dissolving, weigh
6g lixisenatide, adds in solution, and stirring and dissolving to solution is clarified, and adds 36g dilute hydrochloric acid, stirring
Being dissolved to solution clarification, the pH value making solution is 7 ~ 9, filtration sterilization；The solution prepared is poured into
In silication the 3mL clamped bottle jumped a queue, roll lid, load in disposable injection pen, fill 10000 altogether.
The preparation of embodiment 18 profit hila injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 1160g mannitol and 20g chlorobutanol, after adding 24L water for injection stirring and dissolving,
Weighing 30g lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds 24g citric acid,
Stirring and dissolving is clarified to solution, and the pH value making solution is 7 ~ 9, filtration sterilization；The solution prepared is filled
Enter in silication the 3mL clamped bottle jumped a queue, roll lid, load in disposable injection pen, fill 10000 altogether
?.
The preparation of embodiment 19 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 1160g mannitol and 20g chlorobutanol, after adding 24L water for injection stirring and dissolving,
Weighing 6g lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds 40g dilute hydrochloric acid,
Stirring and dissolving is clarified to solution, and the pH value making solution is 7 ~ 9, filtration sterilization；The solution prepared is filled
Enter in silication the 3mL clamped bottle jumped a queue, roll lid, load in disposable injection pen, fill 10000 altogether
?.
The preparation of embodiment 20 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 5160mg mannitol and 260mg metacresol, add 120mL water for injection stirring and dissolving
After, weighing 30mg lixisenatide, stirring and dissolving to solution is clarified, and adds in solution, adds 180mg
Dilute hydrochloric acid, the clarification of stirring and dissolving to solution, the pH value making solution is 7 ~ 9, filtration sterilization；To prepare
Solution pour in silication the 3mL clamped bottle jumped a queue, roll lid, load in disposable injection pen, altogether
Fill 50.
The preparation of embodiment 21 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 1032g mannitol and 20g chlorobutanol, after adding 24L water for injection stirring and dissolving,
Weighing 30g lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds 37g glacial acetic acid,
Stirring and dissolving is clarified to solution, and the pH value making solution is 7 ~ 9, filtration sterilization；The solution prepared is filled
Enter in silication the 3mL clamped bottle jumped a queue, roll lid, load in disposable injection pen, fill 10000 altogether
?.
The preparation of embodiment 22 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 1032g mannitol and 20g phenol, after adding 24L water for injection stirring and dissolving, weigh 6
G lixisenatide, adds in solution, and stirring and dissolving to solution is clarified, and adds 40g dilute hydrochloric acid, stirring
Being dissolved to solution clarification, the pH value making solution is 7 ~ 9, filtration sterilization；The solution prepared is poured into
In silication the 3mL clamped bottle jumped a queue, roll lid, load in disposable injection pen, fill 10000 altogether.
The preparation of embodiment 23 lixisenatide injection
Hundred-grade super-clean workbench in ten thousand grades of toilets and in toilet is carried out, and takes each component:
Weigh 5160mg mannitol and 100mg phenol, after adding 120mL water for injection stirring and dissolving,
Weighing 30mg lixisenatide, add in solution, stirring and dissolving to solution is clarified, and adds 18mg dilute
Hydrochloric acid, the clarification of stirring and dissolving to solution, the pH value making solution is 7 ~ 9, filtration sterilization；By prepare
Solution pours in amber 2mL cillin bottle, rolls lid, fill 50 altogether.
The lixisenatide injection Detection of Stability that embodiment 24 present invention provides
The lixisenatide injection embodiment of the present invention 1 ~ 20 prepared is respectively under high light hot conditions
(60 DEG C, 40 DEG C), placement 5 days and 10 days, the most separately sampled, investigate its changes of contents, solution
Clarity and bacterial growth situation (see Table 1)
The lixisenatide injection Detection of Stability that table 1 present invention provides
The testing result of the lixisenatide injection that embodiment 5 ~ 10 and embodiment 16 ~ 23 provide and this phase
Seemingly.
As shown in Table 1, the lixisenatide note that the embodiment of the present invention 1, embodiment 2 and embodiment 13 provide
Penetrating lixisenatide in liquid and indicate the decrease speed of content the most slowly, the solution with buffer pH regulation system is more single
PH regulator is solution-stabilized, and the concentration of antibacterial reaches requirement, and each prescription is all without bacterial growth.
Take the lixisenatide injection of the embodiment of the present invention 1, embodiment 2 and embodiment 13 offer at 2 DEG C
~ 8 DEG C of temperature, relative humidity 60%, under holding conditions, investigate the lixisenatide that the present invention provides further
The long-time stability of injection, solution clarity change and bacterial growth situation, the results are shown in Table 2.
Table 2 lixisenatide injection study on the stability result
As shown in Table 2, the lixisenatide injection that the present invention provides after storage 12 months at content, clear
Lightness and bacterial growth situation are the most qualified, steady quality.
Comprehensive Tables 1 and 2 understands, and the lixisenatide injection that the present invention provides has good stability,
The pH of the lixisenatide injection making the present invention provide that buffer pH regulates system maintains between 7 ~ 9,
Under the conditions of ensureing that lixisenatide is saved in optimum pH；And the use of antibacterial makes antibacterial to grow, thus
Avoid the antibacterial degraded to lixisenatide；Show that the use of pH adjusting agent and antibacterial ensure that profit hila
The stability come.
The testing result of the lixisenatide injection that other embodiments of the invention provide is similarly.
The hypoglycemic effect of the lixisenatide injection that embodiment 25 present invention provides
Take the lixisenatide injection that the embodiment of the present invention 22 provides, carry out hypoglycemic effect detection, take commercially available
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] injection and Exenatide injection as comparison.
Take male and healthy SD rat 50, body weight 200g ~ 250g, cleaning grade.Randomly select wherein 10
Being only used as normal group, feeding normal feedstuff, by 1.5mL water for injection gavage.Remaining rat adaptability is fed
After supporting 5d, i.e. starting feeding high lipid food, coordinate normal diet, after 7 days, overnight fast, next day is just
Chang Zuyong normal saline replaces streptozotocin lumbar injection, and remaining uses streptozotocin with 50mg/kg abdomen
Chamber injection (with the aseptic citrate buffer solution preparation of 0.1mol/L, pH value is 4.5), cut tail after 72 hours
Surveying blood glucose, using fasting glucose > 11.1mmol/L is as the modeling Success Flag of diabetes rat.
After modeling success, it is divided into normal group A；Model control group B；Exenatide injection neck dorsal sc
It is administered every day twice administration group C, each 5 μ g Kg sooner or later-1；Lixisenatide injection neck dorsal sc is given
The each 20 μ g Kg of medicine administration group once a day D-1；Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] injection nape portion subcutaneous administration every day one
Secondary, each 0.6mg Kg-1, after administration the 0th week, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, within 6 weeks, receive
Collection tail vein, detects blood glucose value by blood glucose meter, at this experiment each data acquisition SPSS16.0 software
Reason is analyzed, and each group is compared employing t inspection, the results are shown in Table 3.
Table 3 experimental rat blood glucose value (mmol/L)
| Group | Number of animals | Before injection | Inject 1 week | Inject 2 weeks | Inject 3 weeks | Inject 4 weeks | Inject 5 weeks | Inject 6 weeks |
| A group | 10 | 5.1±1.0 | 5.2±1.1 | 5.3±1.5 | 5.3±1.3 | 5.5±2.0 | 5.6±2.5 | 5.4±1.4 |
| B group | 10 | 15.8±3.1 | 18.0±3.5 | 20.3±4.0 | 23.7±3.8 | 24.6±4.4 | 26.0±2.5 | 28.7±3.3 |
| C group | 10 | 17.3±2.2 | 13.8±1.3 | 10.0±1.2 | 9.3±2.3 | 8.3±1.5 | 7.1±1.2 | 6.0±2.1 |
| D group | 10 | 17.5±1.5 | 10.7±2.3 | 9.0±2.0 | 7.8±1.5 | 7.1±1.3 | 6.3±2.2 | 5.7±1.5 |
| E group | 10 | 18.0±2.0 | 11.9±1.2 | 10.2±1.5 | 9.0±2.1 | 7.8±1.7 | 6.2±1.3 | 6.0±1.9 |
As shown in Table 3, compared with A group, B group P < 0.01, there is significant difference, compared with B group,
C, D, E group P<0.01, there is significant difference, compared with C group, D, E group P>0.05, without notable
Sex differernce, total hypoglycemic effect is suitable, but finds out from upper table, and lixisenatide injection is injected with Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37]
Liquid hypoglycemic effect Exenatide to be slightly faster than injection.
Illustrate, the present invention provide lixisenatide injection compared with commercially available existing blood sugar lowering injection, blood sugar lowering
Effect is suitable, all has significant hypoglycemic effect, and blood sugar lowering speed to be slightly faster than commercially available Exenatide note
Penetrate liquid.
The testing result of the lixisenatide injection that other embodiments of the invention provide is similarly.
The lixisenatide injection untoward reaction that embodiment 23 present invention provides is identified
Owing to being often accompanied by gastrointestinal reaction when GLP-1 analog is administered, so in the embodiment of the present invention 22
Rat after medication is observed.Take male and healthy SD rat 50, body weight 200g ~ 250g, cleaning
Level.Randomly selecting and wherein 10 be only used as normal group, feeding normal feedstuff, by 1.5mL water for injection gavage.
After remaining rat adaptability feeds 5d, i.e. start feeding high lipid food, coordinate normal diet, after 7 days,
Overnight fast, next day, normal group normal saline replaced streptozotocin lumbar injection, and remaining is helped with chain urea
With 50mg/kg lumbar injection, (with the aseptic citrate buffer solution preparation of 0.1mol/L, pH value is rhzomorph
4.5), cut tail after 72 hours and survey blood glucose, using fasting glucose 11.1mmol/L is as the modeling of diabetes rat
Success Flag.After modeling success, it is divided into normal group A；Model control group B；Exenatide injection nape
Portion's subcutaneous administration every day twice administration group C, each 5 μ g Kg sooner or later-1；Lixisenatide injection nape portion
The each 20 μ g Kg of subcutaneous administration administration group once a day D-1；Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] injection nape portion subcutaneous administration
Once a day, each 0.6mg Kg-1, carry out state observation after administration, record its reaction after medication,
Result is as shown in table 4:
State observation after table 4 rat medication
As shown in Table 4, during non-administration, there is substantially " three-many-one-little " diabetic symptom in modeling rat,
After drug administration by injection 6 weeks, rat hair color, urine volume, amount of drinking water, the most normally, but C group injection Exenatide
Food-intake is less, and rat has vomiting and diarrhoea phenomenon, E group injection Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] to have 1% diarrhoea phenomenon, D
Group injection lixisenatide rat is without vomiting and diarrhoea phenomenon.
Illustrate this law prepare lixisenatide injection relatively with list Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] and Exenatide injection liquid phase
Ratio, gastrointestinal reaction significantly reduces.Illustrate that the lixisenatide injection that the present invention provides have employed reasonably
Osmotic pressure regulator has also adjusted suitable osmotic pressure.
The testing result of the lixisenatide injection that other embodiments of the invention provide is similarly.
The above is only the preferred embodiment of the present invention, it is noted that general for the art
For logical technical staff, under the premise without departing from the principles of the invention, it is also possible to make some improvement and profit
Decorations, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (4)
1. a lixisenatide injection, it is characterised in that by lixisenatide, pH adjusting agent, press down
Microbial inoculum, osmotic pressure regulator and water for injection composition；
The mass ratio of described lixisenatide, pH adjusting agent, antibacterial and osmotic pressure regulator is 0.5:
(0.5～10.5): (0.5～8.5): (79.3～99.3)；
The pH value of described lixisenatide injection is 7～9；
Described pH adjusting agent be the one in phosphoric acid, citric acid, glacial acetic acid, dilute hydrochloric acid or both with
On mixture；
Described osmotic pressure regulator is mannitol；
Described antibacterial is a kind of or both above the mixing in metacresol, phenol or chlorobutanol
Compound.
Lixisenatide injection the most according to claim 1, it is characterised in that described pH
Regulator also includes the mixture of disodium hydrogen phosphate；Described pH adjusting agent is phosphoric acid and disodium hydrogen phosphate
Mixture or the mixture of citric acid and disodium hydrogen phosphate.
Lixisenatide injection the most according to claim 1, it is characterised in that described Li Xi
The manner of packing drawing injection is injection pen or cillin bottle.
4. the preparation method of lixisenatide injection as claimed in claim 1, it is characterised in that
Take described osmotic pressure regulator and described antibacterial is dissolved in water, with described pH adjusting agent, profit hila
Mix, filtration sterilization, to obtain final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210572013.7A CN103893110B (en) | 2012-12-25 | A kind of lixisenatide injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210572013.7A CN103893110B (en) | 2012-12-25 | A kind of lixisenatide injection and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103893110A CN103893110A (en) | 2014-07-02 |
| CN103893110B true CN103893110B (en) | 2016-11-30 |
Family
ID=
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101444618A (en) * | 2007-11-26 | 2009-06-03 | 杭州九源基因工程有限公司 | Pharmaceutical preparation containing exenatide |
| WO2012028172A1 (en) * | 2010-08-30 | 2012-03-08 | Sanofi-Aventis Deutschland Gmbh | Use of ave0010 for the manufacture of a medicament for the treatment of diabetes mellitus type 2 |
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101444618A (en) * | 2007-11-26 | 2009-06-03 | 杭州九源基因工程有限公司 | Pharmaceutical preparation containing exenatide |
| WO2012028172A1 (en) * | 2010-08-30 | 2012-03-08 | Sanofi-Aventis Deutschland Gmbh | Use of ave0010 for the manufacture of a medicament for the treatment of diabetes mellitus type 2 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1273187C (en) | Insulin preparations, which donot contain any zinc or only small quantity of zinc of improved stability | |
| CN1501809B (en) | Chronic treatment regimen using glucagon-like insulinotropic peptides | |
| CN100349573C (en) | Formulation for lipophilic agents | |
| CN101163467B (en) | Pharmaceutical uses for trans-clomiphene | |
| CN100475267C (en) | Liquid formulations with a high concentration of human growth hormone (hgh) comprising glycin | |
| PL191022B1 (en) | Method of and composition for parenteral feeding | |
| CN101095942B (en) | Formulation of the Exendin injection medicine containing stabilizing agent | |
| US11771773B2 (en) | Pharmaceutical preparation containing polyethylene gylcol loxenatide and preparation method thereof | |
| US11590086B2 (en) | Compositions and methods for treatment of erectile disfunction | |
| CN105473155A (en) | Insulin glargine/lixisenatide fixed ratio formulation | |
| CN104840415A (en) | Long-acting controlled release liposome gel combination containing blood sugar reducing active component, and preparation method thereof | |
| CN107205920A (en) | Injectable buprenorphine formulation | |
| CN103349666A (en) | Pharmaceutical composition injection of compound liposoluble vitamin and preparation method thereof | |
| CN107865964A (en) | Hypo-osmoticity lipolysis composition and preparation method thereof | |
| CN103893110B (en) | A kind of lixisenatide injection and preparation method thereof | |
| CN102302462A (en) | Gemcitabine hydrochloride lyophilized preparation | |
| US20140249077A1 (en) | Gel compositions | |
| CN106581646A (en) | Oral insulin composition | |
| CN104548096A (en) | Pharmaceutical composition containing GLP-1 analogue and DPP-4 inhibitor and preparation method thereof | |
| WO2019170153A1 (en) | GLP-1 Composition for Treating Obesity and Weight Management | |
| CN101822822A (en) | Drug composition of pramlintide and preparation method thereof | |
| US9943560B2 (en) | Medical compositions containing liquorice extracts with synergistic effect | |
| CN104490902B (en) | A kind of composite vitamin for injection freeze drying powder injection composition and preparation method thereof | |
| CN103893110A (en) | Lixisenatide injection, and preparation method thereof | |
| CN111603439A (en) | Long-acting in-situ phase change gel injection of brexpiprazole and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20161130 Termination date: 20201225 |