CN115300613A - Pharmaceutical preparation composition containing insulin glargine and preparation method thereof - Google Patents
Pharmaceutical preparation composition containing insulin glargine and preparation method thereof Download PDFInfo
- Publication number
- CN115300613A CN115300613A CN202110492555.2A CN202110492555A CN115300613A CN 115300613 A CN115300613 A CN 115300613A CN 202110492555 A CN202110492555 A CN 202110492555A CN 115300613 A CN115300613 A CN 115300613A
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- Prior art keywords
- insulin glargine
- composition according
- pharmaceutical preparation
- injection
- pharmaceutical formulation
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- COCFEDIXXNGUNL-RFKWWTKHSA-N Insulin glargine 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)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)NCC(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 COCFEDIXXNGUNL-RFKWWTKHSA-N 0.000 title claims abstract description 48
- 229960002869 insulin glargine Drugs 0.000 title claims abstract description 48
- 108010057186 Insulin Glargine Proteins 0.000 title claims abstract description 47
- 239000000203 mixture Substances 0.000 title claims abstract description 40
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title abstract description 25
- 239000007924 injection Substances 0.000 claims abstract description 39
- 238000002347 injection Methods 0.000 claims abstract description 39
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 239000003755 preservative agent Substances 0.000 claims abstract description 7
- 230000002335 preservative effect Effects 0.000 claims abstract description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 16
- 239000000706 filtrate Substances 0.000 claims description 14
- 238000005303 weighing Methods 0.000 claims description 14
- 238000011049 filling Methods 0.000 claims description 11
- 238000005070 sampling Methods 0.000 claims description 10
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 230000001954 sterilising effect Effects 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- 102000008186 Collagen Human genes 0.000 claims description 5
- 108010035532 Collagen Proteins 0.000 claims description 5
- 239000000872 buffer Substances 0.000 claims description 5
- 239000008215 water for injection Substances 0.000 claims description 5
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 239000007853 buffer solution Substances 0.000 claims description 4
- 229920001436 collagen Polymers 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229920002674 hyaluronan Polymers 0.000 claims description 4
- 229960003160 hyaluronic acid Drugs 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical class [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical class [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000003002 pH adjusting agent Substances 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 150000002327 glycerophospholipids Chemical class 0.000 claims description 2
- 239000008176 lyophilized powder Substances 0.000 claims description 2
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 7
- 239000000843 powder Substances 0.000 abstract description 4
- 229940090044 injection Drugs 0.000 description 36
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 30
- 238000012360 testing method Methods 0.000 description 24
- 239000011592 zinc chloride Substances 0.000 description 15
- 235000005074 zinc chloride Nutrition 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 235000011187 glycerol Nutrition 0.000 description 13
- 239000003814 drug Substances 0.000 description 12
- 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 10
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 206010020751 Hypersensitivity Diseases 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 7
- 238000009472 formulation Methods 0.000 description 6
- 230000007774 longterm Effects 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 206010002198 Anaphylactic reaction Diseases 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 5
- 208000026935 allergic disease Diseases 0.000 description 5
- 230000007815 allergy Effects 0.000 description 5
- 208000003455 anaphylaxis Diseases 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 230000007794 irritation Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000001509 sodium citrate Substances 0.000 description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 206010018910 Haemolysis Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000008588 hemolysis Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229920000136 polysorbate Polymers 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 238000011895 specific detection Methods 0.000 description 3
- 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 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 206010070834 Sensitisation Diseases 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229930003836 cresol Natural products 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical group 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 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 238000012797 qualification Methods 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 230000008313 sensitization Effects 0.000 description 2
- 239000008354 sodium chloride injection Substances 0.000 description 2
- 239000008227 sterile water for injection Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 1
- 206010020565 Hyperaemia Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 206010024769 Local reaction Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 150000001484 arginines Chemical class 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000002608 insulinlike Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
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- 230000007935 neutral effect Effects 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
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- 229920001184 polypeptide Polymers 0.000 description 1
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- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000012383 pulmonary drug delivery Methods 0.000 description 1
- 238000011076 safety test Methods 0.000 description 1
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- 230000008961 swelling Effects 0.000 description 1
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- 208000001072 type 2 diabetes mellitus Diseases 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Obesity (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Emergency Medicine (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to the field of pharmaceutical formulation, and discloses a pharmaceutical formulation composition containing insulin glargine and a preparation method thereof. The pharmaceutical preparation composition does not contain a preservative, and has good stability. In addition, the invention also discloses a method for preparing the pharmaceutical preparation composition and a freeze-dried powder injection containing the insulin glargine with a therapeutically effective dose, which is prepared from the pharmaceutical preparation composition.
Description
Technical Field
The invention belongs to the field of pharmaceutic preparation, and particularly relates to a pharmaceutical preparation composition containing insulin glargine, a preparation method thereof, and a freeze-dried powder injection containing insulin glargine with a therapeutically effective dose, which is prepared from the pharmaceutical preparation composition.
Background
The insulin glargine uses glycine to replace aspartic acid at A21 position of human insulin, and two arginines are added at the carboxyl terminal of a B chain, so that the isoelectric point of the polypeptide is changed, and the pH value is increased from 5.4 to 6.7. The insulin glargine is modified by an amino acid sequence on the basis of human insulin, so that physiological insulin secretion can be better simulated, a stable hexamer can be formed after subcutaneous injection, the intermolecular binding force is increased, the dissolution and absorption time is delayed, and a small amount of insulin glargine is continuously released. Therefore, the medicine has predictable, long-acting, stable and non-peak blood concentration, and is clinically used for the I type diabetes of adults and children and the II type diabetes of adults. Due to its long-acting properties, insulin glargine needs to be administered to a patient by subcutaneous injection only once a day for a fixed period of time. Patients with type I diabetes and patients with type II diabetes who have failed to take oral hypoglycemic drugs need to use insulin-like products for life to control blood sugar, so that on the effective premise, the stability of the drugs is improved, and the security of the drugs is especially important.
Chinese patent CN1498113A discloses a stable insulin preparation without zinc or with low zinc ion prepared by adding surfactant (emulsifier) etc. As is well known, tween surfactants are used for injection, which is easy to cause adverse reactions such as allergy, hemolysis and the like, and the safety of Tween surfactants is always controversial.
Chinese patent CN101573133A discloses pegylated extended insulin, which mentions that after being pegylated in a specific manner, insulin can change its solubility, is soluble at neutral pH, is expected to improve bioavailability, extend action time, achieve the effect of pulmonary drug delivery, and also has a certain improvement in its stability. However, the stability effect of PEG and insulin on an insulin preparation without covalent bond combination is not mentioned, and the PEG preparation step is too complex, the requirement on equipment condition is high, the production cost is high, and the large-scale production is difficult to realize.
Chinese patent CN104688678B discloses a glargine insulin injection, which mentions that the stability of the injection is improved by using preservative, and the dosage is improper, causing body injury due to corrosive action on human tissues.
The inventor finds in experiments that the appearance of the insulin glargine injection is changed from colorless clear liquid into light blue liquid with floccule under the condition of 60 ℃ influencing factors, and the insulin glargine injection is filled by a pre-filling and sealing injector, but the pre-filling and sealing injector has high material packaging cost, long production period and high requirements on filling and plugging of equipment, and meanwhile, the liquid medicine is in contact with a rubber plug for a long time, so that the risk of the product is greatly increased.
Because the stability of insulin glargine in a peracid and over-alkali environment is greatly reduced, the tendency of the insulin glargine to agglomerate under thermal and physical mechanical stress is increased, and physical means such as stirring and the like are inevitably used in the preparation process of the injection, so that undesirable impurities are brought to the preparation. When a surfactant is added to an injection, allergic reactions can easily occur, especially in the case of long-term uninterrupted administration. The insulin glargine injection in the current market is added with preservatives of phenol, cresol, m-cresol and the like, and has corrosive effect on human tissues when the dosage is large, and can cause human poisoning.
Therefore, there is a need to improve the prior art to obtain a safe and good pharmaceutical formulation of insulin glargine with high stability and few process impurities.
Disclosure of Invention
In view of the above problems, an object of the present invention is to provide a pharmaceutical preparation composition containing insulin glargine, which comprises a therapeutically effective amount of insulin glargine and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises a pH adjusting agent, a buffer and an excipient for increasing stability, and the pharmaceutical preparation composition does not contain a preservative, has good stability, reduces the occurrence of allergic reactions, and achieves the purposes of improving the quality of insulin glargine pharmaceutical preparations and ensuring the medication safety of patients.
In a preferred embodiment of the invention, the concentration of insulin glargine in the pharmaceutical formulation is 40-500IU/mL, preferably 200-400IU/mL, more preferably 100IU/mL.
In a preferred embodiment of the present invention, the buffer is selected from one or more of sodium phosphate salts, sodium acetate salts and sodium citrate salts, preferably sodium phosphate salts.
The concentration of the buffer in the pharmaceutical preparation is preferably 0.1mg/ml to 5.0mg/ml, preferably 0.5mg/ml to 3.0mg/ml, more preferably 1.0mg/ml to 2.0mg/ml.
In a preferred embodiment of the invention, the pH adjusting agent is sodium hydroxide or hydrochloric acid, and the pH is preferably adjusted to 3.0 to 4.5, preferably 3.1 to 4.2, more preferably 3.1 to 4.0.
In a preferred embodiment of the invention, the stability-enhancing excipient is selected from one or more of butylene glycol, gelatin, mannitol, hyaluronic acid, glycerol, glycerophospholipids, poloxamers, collagen, glucose; one or more of butanediol, mannitol, glycerol, and hyaluronic acid is preferred.
In a preferred embodiment of the invention, the concentration of the stability-enhancing excipient is from 0.5% to 20%, preferably from 1% to 10%, more preferably 5% in weight/volume ratio.
In a preferred embodiment of the invention, the pharmaceutical formulation composition further comprises zinc in the range of 5 μ g to 200 μ g/mL, preferably 10 to 100 μ g/mL, more preferably 15 to 30 μ g/mL.
1) In another aspect, the present invention provides a method for preparing the pharmaceutical preparation composition of the present invention, which comprises the steps of: weighing buffer solution and excipient according to the prescription amount, dissolving in proper amount of injection water, and performing rough filtration;
2) Collecting filtrate, pouring into a container weighed with insulin glargine, adding certain water for injection, stirring and dissolving;
3) Adjusting pH value to proper value with pH regulator, diluting to constant volume, stirring, mixing, coarse filtering, and ultrafiltering;
4) Sampling and measuring parameters required, filling after the parameters are qualified, and sterilizing.
The last aspect of the invention also provides a freeze-dried powder injection containing the insulin glargine with a therapeutically effective dose, which is prepared from the pharmaceutical preparation composition. The lyophilized preparation is dissolved in 1ml of sterilized water for injection or 0.9% sodium chloride injection or 5% glucose solution for injection.
In the pharmaceutical preparation composition containing insulin glargine of the present invention, the buffer solution can provide a suitable environment to avoid degradation associated with pH for good stability; the excipient adopts common components which are easy to accept by human bodies, has the functions of an antioxidant, an isotonic regulator, a solubilizer, a preservative and the like, can effectively reduce the increase of related substances and high molecular protein content, and improves the stability of the medicine. Meanwhile, in the pharmaceutical preparation composition, preservatives such as cresol and the like are not contained, but the added glycerin and butanediol have bacteriostatic and preservative effects; does not contain Tween surfactants, thereby avoiding adverse reactions such as allergy, hemolysis and the like. Therefore, the pharmaceutical preparation composition is stable and safe, is convenient for patients, can be stored at normal temperature, and is suitable for practical clinical use.
Detailed Description
The present invention is further illustrated by the following examples, which are intended to be illustrative, but not limiting, of the present invention. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall into the protection scope of the present invention.
EXAMPLE 1 preparation of pharmaceutical preparation composition containing insulin glargine
1. Formulation formula (in 1000 mL)
| # | Components | Amount of prescription |
| 1 | Insulin glargine | 50IU |
| 2 | Citric acid sodium salt | 1g |
| 3 | Disodium hydrogen phosphate | 0.5g |
| 4 | Sodium hydroxide or hydrochloric acid | Adjusting the pH to 3.1 |
| 5 | Collagen protein | 3g |
| 6 | Zinc chloride | 15μg |
| 7 | Water for injection to | 1000mL |
2. Preparation process
Weighing 1g of sodium citrate, 0.5g of disodium hydrogen phosphate, 3g of collagen and 15 mu g of zinc chloride according to the formula amount, dissolving the sodium citrate, the disodium hydrogen phosphate, the collagen and the zinc chloride with 200mL of injection water, roughly filtering, collecting filtrate, pouring the filtrate into a container weighing 1.8189mg (converted according to 100IU = 3.6378mg) of insulin glargine, adding the injection water to the volume close to the solution preparation amount (the amount of reserved pH value adjustment) of 900mL, stirring and dissolving, adjusting the pH value of the solution to 3.1 by using sodium hydroxide or hydrochloric acid, fixing the volume to 1000mL by using the injection water, stirring and uniformly mixing, roughly filtering, ultrafiltering, sampling and measuring parameters required to be obtained, filling after qualification, and sterilizing.
Example 2
1. Formulation formula (in 1000 mL)
2. Preparation process
Weighing 1g of disodium hydrogen phosphate, 3g of butanediol, 5g of glycerol and 16 mu g of zinc chloride according to the prescription amount, dissolving the disodium hydrogen phosphate, 3g of butanediol, 5g of glycerol and 16 mu g of zinc chloride by using 300mL of injection water, roughly filtering, collecting filtrate, pouring the filtrate into a container weighing 3.6378mg of insulin glargine, adding the injection water to the volume close to the solution preparation amount (the amount reserved for adjusting the pH value) of 900mL, stirring for dissolving, adjusting the pH value of the solution to 3.2 by using sodium hydroxide or hydrochloric acid, fixing the volume to 1000mL by using the injection water, uniformly stirring, roughly filtering, ultrafiltering, sampling and measuring parameters required to be obtained, filling after qualification, and sterilizing.
Example 3
1. Formulation (in 1000 mL)
| # | Components | Amount of prescription |
| 1 | Insulin glargine | 100IU |
| 2 | Citric acid sodium salt | 1g |
| 3 | Glycerol | 5g |
| 4 | Sodium hydroxide or hydrochloric acid | Adjusting the pH to 3.2 |
| 5 | Zinc chloride | 15μg |
| 6 | Water for injection to | 1000mL |
2. Preparation process
Weighing 1g of sodium citrate, 5g of glycerol and 15 mu g of zinc chloride according to the prescription amount, dissolving the sodium citrate, the glycerol and the zinc chloride by using 300mL of injection water, roughly filtering, collecting filtrate, pouring the filtrate into a container weighing 3.6378mg of insulin glargine, adding the injection water to the volume close to the solution preparation amount (the amount for adjusting the pH value is reserved) of 900mL, stirring and dissolving, adjusting the pH value of the solution to be 3.2 by using sodium hydroxide or hydrochloric acid, fixing the volume to 1000mL by using the injection water, uniformly stirring, roughly filtering, ultrafiltering, sampling, measuring parameters required to be obtained, filling after the parameters are qualified, and sterilizing.
Example 4
1. Formulation formula (in 1000 mL)
2. Preparation process
Weighing 1g of disodium hydrogen phosphate, 5g of butanediol and 15 mu g of zinc chloride according to the prescription amount, dissolving the disodium hydrogen phosphate, the butanediol and the zinc chloride by using 300mL of injection water, roughly filtering, collecting filtrate, pouring the filtrate into a container weighing 3.6378mg of insulin glargine, adding the injection water to the volume close to the solution preparation amount (the amount for regulating the pH value) of 900mL, stirring and dissolving, regulating the pH value of the solution to be 3.2 by using sodium hydroxide or hydrochloric acid, fixing the volume to 1000mL by using the injection water, uniformly stirring, roughly filtering, ultrafiltering, sampling, measuring parameters required to be obtained, filling after the parameters are qualified, and sterilizing.
Example 5
1. Formulation formula (in 1000 mL)
| # | Components | Amount of prescription |
| 1 | Insulin glargine | 200IU |
| 2 | Sodium acetate (NaCI) | 2g |
| 3 | Glycerol | 15g |
| 4 | Sodium hydroxide or hydrochloric acid | Adjusting the pH to 3.5 |
| 5 | Zinc chloride | 16μg |
| 6 | Water for injection to | 1000mL |
2. Preparation process
Weighing 2g of sodium acetate, 15g of glycerol and 16 mu g of zinc chloride according to the prescription amount, dissolving the sodium acetate, 15g of glycerol and 16 mu g of zinc chloride by using 300mL of injection water, roughly filtering, collecting filtrate, pouring the filtrate into a container weighing 7.2756mg of insulin glargine, adding the injection water to the volume close to the solution preparation amount (the amount for regulating the pH value) 900mL, stirring and dissolving, regulating the pH value of the solution to 3.5 by using sodium hydroxide or hydrochloric acid, fixing the volume to 1000mL by using the injection water, uniformly stirring, roughly filtering, ultrafiltering, sampling and measuring parameters required to be obtained, filling after the parameters are qualified, and sterilizing.
Example 6
1. Formulation formula (in 1000 mL)
2. Preparation process
Weighing 1g of disodium hydrogen phosphate, 5g of glycerol, 3g of butanediol and 17 mu g of zinc chloride according to the prescription amount, dissolving the disodium hydrogen phosphate, 5g of glycerol, 3g of butanediol and 17 mu g of zinc chloride by using 300mL of injection water, roughly filtering, collecting filtrate, pouring the filtrate into a container weighing 7.2756mg of insulin glargine, adding the injection water until the volume is close to the solution dosage (the volume for regulating the pH value) of 900mL, stirring and dissolving, regulating the pH value of the solution to be 3.2 by using sodium hydroxide or hydrochloric acid, fixing the volume to 1000mL by using the injection water, uniformly stirring, roughly filtering, ultrafiltering, sampling and measuring parameters required to be obtained, filling after the solution is qualified, and sterilizing.
Example 7: preparation of freeze-dried powder injection
The pharmaceutical preparation composition containing insulin glargine prepared in examples 1 to 6 was prepared into lyophilized powder for injection by a conventional method. After freeze-drying, the mixture is dissolved by 1ml of sterilized water for injection or 0.9% sodium chloride injection or 5% glucose injection, and the injection is performed once a day and one injection is performed each time.
Example 8: stability test of pharmaceutical preparation composition containing insulin glargine
In order to examine the stability of the pharmaceutical preparation composition containing insulin glargine prepared according to the present invention, an accelerated test, a long-term test and a strong light irradiation test were performed in example 8.
1. Accelerated test
An accelerated test is carried out according to the 2010 version Chinese pharmacopoeia XIXC bulk drug and pharmaceutical preparation stability test guiding principle (II) to research the stability of the drug. Taking appropriate amount of samples of the three batches of examples 2, 4 and 6, taking appropriate amount of insulin glargine injection samples purchased in the market, accelerating for 6 months under the conditions of 25 +/-2 ℃ and 55 +/-5% of relative humidity, sampling once for detection at the time points of 0 th month, 1 st month, 2 th month, 3 th month and 6 th month end during the test period, and mainly investigating items according to stability, wherein the specific detection results are shown in table 1.
TABLE 1 accelerated test results
2. Long term test
And (3) carrying out long-term test according to the 2010 version Chinese pharmacopoeia XIXC bulk drug and pharmaceutical preparation stability test guiding principle (II), and detecting the validity period of the drug. Taking a proper amount of samples of the three batches of the samples of the examples 2, 4 and 6, taking a proper amount of samples purchased in the market, respectively placing the samples for 30 months under the conditions of the temperature of 22 +/-5 ℃ and the relative humidity of 55 +/-5%, respectively sampling at the time points of 0, 3, 6, 9, 12, 18, 24 and 30 months for one-time detection, and detecting according to the stability key items, wherein the specific detection results are shown in the table 2.
TABLE 2 Long term test results
3. Test by intense light irradiation
Performing a strong light irradiation test according to the 2010 version of China pharmacopoeia XIXC bulk drug and pharmaceutical preparation stability test guiding principle (II), taking a proper amount of samples in the examples 2, 4 and 6, taking a proper amount of samples purchased in the market, equally dividing a packaging group and a naked group for each batch, placing the samples for 0, 5 and 10 days under the condition that the illumination is 4500lx +/-500 lx, and comparing detection results of the samples, wherein the specific detection results are shown in Table 3.
TABLE 3 Strong light irradiation experiment
4. Results and conclusions
It can be obtained from the data of the accelerated test, the long-term test and the strong light irradiation test, and the data of the samples prepared in the embodiments 2, 4 and 6 of the invention have no obvious change in each investigation index under each condition compared with the data of 0, which indicates that the samples of the invention are more stable. The content of related substances and high molecular proteins of the samples in the market is obviously increased compared with the samples prepared by the invention, which indicates that the samples prepared by the invention are more stable than the samples in the market under various conditions.
Example 9: safety test of pharmaceutical preparation composition containing insulin glargine
In order to show that the insulin glargine medicinal preparation composition prepared by the invention is safer, irritation and allergy researches are carried out according to a method of technical guidance principles of irritation, allergy and hemolysis research of chemical medicines.
1. Irritation test at the site of administration
The irritation test is to observe whether the skin, mucous membrane and other parts of the animal contact with the test substance to cause local reactions such as red swelling, hyperemia and necrosis.
1) And (3) testing a product to be tested: insulin glargine samples prepared in example 2 and commercially available samples.
2) Experimental animals: the male and female half rabbits weigh 1.8-2.5kg, and are randomly divided into 3 groups of 3 rabbits each.
3) The administration method comprises the following steps: the continuous administration is carried out for 7 days, a left-side self-contrast method and a right-side self-contrast method are adopted, and the specific operation is as follows:
4) And (4) evaluating the results: the sample of the invention has no local stimulation to rabbits and is safer than the samples sold in the market.
2. Allergy test
1) And (3) a to-be-detected product: insulin glargine samples prepared in example 2.
2) Experimental animals: male guinea pigs with the weight of 200-300 g, 32 animals, were selected and were obtained from Shanghai Biochemical research institute.
3) And (4) observation: during sensitization, symptoms were observed daily for each animal.
TABLE 4 symptoms of anaphylaxis
4) And (4) evaluating the results: the extent of the allergic reaction can be judged according to Table 5. And calculating the incidence rate of anaphylactic reaction. And comprehensively judging according to the incidence rate and the incidence degree of the anaphylactic reaction.
TABLE 5 evaluation criteria for systemic sensitization
| 0 | - | Negative of |
| 1-4 symptoms | + | Weak positive |
| 5-10 symptoms | ++ | Positive for |
| 11-19 symptoms | +++ | Strong positive |
| 20 | ++++ | Very strong positive |
After the injection, if the anaphylactic reaction symptom is found, 2 healthy non-sensitized guinea pigs are taken, and the test substance with the exciting dose is injected intravenously to observe whether the similar anaphylactic reaction symptom caused by the action of the test substance exists or not, so as to be used as reference for judging the result.
5) And (4) test conclusion: the test result shows that the insulin glargine sample prepared by the invention has no anaphylactic effect when being administrated subcutaneously.
Claims (10)
1. A pharmaceutical preparation composition containing insulin glargine comprises insulin glargine and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises a buffer solution, a pH regulator and a stability-increasing excipient, and the pharmaceutical preparation composition does not contain a preservative and has good stability.
2. The pharmaceutical formulation composition according to claim 1, wherein the concentration of insulin glargine is 40-500IU/mL, preferably 200-400IU/mL, more preferably 100IU/mL.
3. The pharmaceutical preparation composition according to claim 1 or 2, wherein the buffer is one or more selected from the group consisting of sodium phosphate salts, sodium acetate salts and sodium citrate salts, preferably sodium phosphate salts.
4. The pharmaceutical preparation composition according to claim 1 or 2, wherein the pH adjusting agent is sodium hydroxide or hydrochloric acid, and the pH is adjusted to 3.0 to 4.5, preferably 3.1 to 4.2, more preferably 3.1 to 4.0.
5. The pharmaceutical formulation composition according to claim 1 or 2, wherein the stability-enhancing excipient is selected from one or more of butylene glycol, gelatin, mannitol, hyaluronic acid, glycerol, glycerophospholipids, poloxamers, collagen, glucose; one or more of butanediol, mannitol, glycerol, and hyaluronic acid is preferred.
6. The pharmaceutical formulation composition according to claim 1 or 2, further comprising zinc 5-200 μ g/mL, preferably 10-100 μ g/mL, more preferably 15-30 μ g/mL.
7. The pharmaceutical formulation composition according to claim 3, wherein the buffer is present in the pharmaceutical formulation in a concentration of 0.1mg/ml to 5.0mg/ml, preferably 0.5mg/ml to 3.0mg/ml, more preferably 1.0mg/ml to 2.0mg/ml.
8. The pharmaceutical formulation composition according to claim 5, wherein the concentration of the stability-enhancing excipient is 0.5% -20%, preferably 1% -10%, more preferably 5% on a weight/volume basis.
9. A process for preparing a pharmaceutical formulation composition according to any one of claims 1 to 8, comprising the steps of:
1) Weighing a buffer solution and an excipient with a prescription amount, dissolving in a proper amount of injection water, and performing rough filtration;
2) Collecting filtrate, pouring into a container weighed with insulin glargine, adding a certain amount of water for injection, stirring and dissolving;
3) Adjusting pH to appropriate value with pH regulator, diluting to desired volume, stirring, coarse filtering, and ultrafiltering;
4) Sampling and measuring parameters required, filling after the parameters are qualified, and sterilizing.
10. Lyophilized powder for injection containing insulin glargine prepared from the pharmaceutical preparation composition of claims 1-8.
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