CN105663127A - Famotidine composition prepared by freeze-drying method for injection - Google Patents
Famotidine composition prepared by freeze-drying method for injection Download PDFInfo
- Publication number
- CN105663127A CN105663127A CN201610180285.0A CN201610180285A CN105663127A CN 105663127 A CN105663127 A CN 105663127A CN 201610180285 A CN201610180285 A CN 201610180285A CN 105663127 A CN105663127 A CN 105663127A
- Authority
- CN
- China
- Prior art keywords
- famotidine
- weight portion
- acid
- injection
- mannitol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 title claims abstract description 94
- 229960001596 famotidine Drugs 0.000 title claims abstract description 94
- 238000004108 freeze drying Methods 0.000 title claims abstract description 74
- 238000000034 method Methods 0.000 title claims abstract description 61
- 239000000203 mixture Substances 0.000 title claims abstract description 48
- 238000002347 injection Methods 0.000 title abstract description 20
- 239000007924 injection Substances 0.000 title abstract description 20
- 238000001914 filtration Methods 0.000 claims abstract description 73
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 70
- 239000007788 liquid Substances 0.000 claims abstract description 67
- 238000003756 stirring Methods 0.000 claims abstract description 53
- 239000000243 solution Substances 0.000 claims abstract description 52
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 50
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 44
- 239000008215 water for injection Substances 0.000 claims abstract description 43
- 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 abstract description 41
- 229930195725 Mannitol Natural products 0.000 claims abstract description 37
- 239000000594 mannitol Substances 0.000 claims abstract description 37
- 235000010355 mannitol Nutrition 0.000 claims abstract description 37
- 239000000843 powder Substances 0.000 claims description 92
- 235000003704 aspartic acid Nutrition 0.000 claims description 42
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 41
- 239000003607 modifier Substances 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 239000004695 Polyether sulfone Substances 0.000 claims description 26
- 229920006393 polyether sulfone Polymers 0.000 claims description 26
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims description 19
- 238000005262 decarbonization Methods 0.000 claims description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 12
- 238000005261 decarburization Methods 0.000 claims description 12
- 239000012467 final product Substances 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 4
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 4
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 4
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 4
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000001117 sulphuric acid Substances 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- 239000003814 drug Substances 0.000 abstract description 22
- 238000011049 filling Methods 0.000 abstract description 2
- 230000001954 sterilising effect Effects 0.000 abstract description 2
- 229940009098 aspartate Drugs 0.000 abstract 2
- 229960001855 mannitol Drugs 0.000 abstract 2
- 229930182555 Penicillin Natural products 0.000 abstract 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 229940049954 penicillin Drugs 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 238000005303 weighing Methods 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 16
- 239000012535 impurity Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 229940083646 famotidine 20 mg Drugs 0.000 description 9
- 230000027119 gastric acid secretion Effects 0.000 description 9
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 208000008469 Peptic Ulcer Diseases 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 208000000718 duodenal ulcer Diseases 0.000 description 7
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 7
- 208000011906 peptic ulcer disease Diseases 0.000 description 6
- 208000025865 Ulcer Diseases 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000003002 pH adjusting agent Substances 0.000 description 5
- 231100000397 ulcer Toxicity 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 206010042220 Stress ulcer Diseases 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 229960001380 cimetidine Drugs 0.000 description 4
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 4
- 229960001340 histamine Drugs 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000008176 lyophilized powder Substances 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- 206010017866 Gastritis haemorrhagic Diseases 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 101150056637 Hrh2 gene Proteins 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 108010079943 Pentagastrin Proteins 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 206010046274 Upper gastrointestinal haemorrhage Diseases 0.000 description 2
- 230000037328 acute stress Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 229950002342 bisfentidine Drugs 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000002301 combined effect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940005526 famotidine injection Drugs 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 150000002240 furans Chemical class 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- FXJAOWANXXJWGJ-UHFFFAOYSA-N n-[4-(2-methyl-1h-imidazol-5-yl)phenyl]-n'-propan-2-ylmethanimidamide Chemical group C1=CC(NC=NC(C)C)=CC=C1C1=CN=C(C)N1 FXJAOWANXXJWGJ-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 210000001711 oxyntic cell Anatomy 0.000 description 2
- ANRIQLNBZQLTFV-DZUOILHNSA-N pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1[C]2C=CC=CC2=NC=1)NC(=O)CCNC(=O)OC(C)(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ANRIQLNBZQLTFV-DZUOILHNSA-N 0.000 description 2
- 229960000444 pentagastrin Drugs 0.000 description 2
- 208000000689 peptic esophagitis Diseases 0.000 description 2
- 235000011118 potassium hydroxide Nutrition 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 2
- 229960000620 ranitidine Drugs 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- YOMUTADJTWWJNM-UHFFFAOYSA-N 2-[4-[2-(3-amino-1,1-dioxo-1,2,4-thiadiazetidin-3-yl)ethylsulfanylmethyl]-1,3-thiazol-2-yl]guanidine Chemical compound S1C(N=C(N)N)=NC(CSCCC2(N)NS(=O)(=O)N2)=C1 YOMUTADJTWWJNM-UHFFFAOYSA-N 0.000 description 1
- BLXXXPVCYVHTQA-UHFFFAOYSA-N 3-[[2-(diaminomethylideneamino)-1,3-thiazol-4-yl]methylsulfanyl]propanamide Chemical compound NC(=O)CCSCC1=CSC(NC(N)=N)=N1 BLXXXPVCYVHTQA-UHFFFAOYSA-N 0.000 description 1
- 208000012895 Gastric disease Diseases 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000006477 desulfuration reaction Methods 0.000 description 1
- 230000023556 desulfurization Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 229940105082 medicinal charcoal Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000018556 stomach disease Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a famotidine composition prepared by a freeze-drying method for injection. The famotidine composition comprises famotidine, mannitol and aspartate; water content of the composition is lower than 5%; the composition is dissolved into solution with concentration 1mg/ml by water for injection and pH value of the solution ranges from 4.5 to 6.0. The composition is prepared by the steps of weighing a certain dosage of famotidine, mannitol and aspartate according to a formula, adding in an appropriate amount of water for injection, stirring to dissolve the components, adding in activated carbon with stirring and then removing the carbon by filtering, replenishing water for injection to full dose of the formula, stirring uniformly to obtain a solution, measuring/regulating pH value of the solution to 4.5-6.0, sterilizing and filtering the solution to obtain liquid medicine, filling the liquid medicine in penicillin bottles, and finally removing water content by the freeze drying method and plugging the bottles. The famotidine composition prepared by the freeze-drying method for injection has excellent pharmaceutical property.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to a kind of medicine treating gastropathy, particularly relate to a kind of famotidine for injection lyophilized powder injection drug compositions with excellent properties. The preparation method that the invention still further relates to this famotidine for injection lyophilized powder injection drug compositions. This famotidine for injection lyophilized powder injection drug compositions can be used for the treatment for gastric and duodenal ulcers, reflux esophagitis, upper gastrointestinal hemorrhage (peptic ulcer, acute stress ulcer, hemorrhagic gastritis are caused), Zhuo Ai syndrome etc. disease. The famotidine for injection injectable powder that the present invention prepares has the physicochemical property of excellence.
Background technology
Famotidine (Famotidine), famotidine chemical name is: [1-amino-3-[[[2-[(diamino methylene) amino]-4-thiazolyl] methyl] sulfenyl] propylidene] sulphamide, molecular formula: C8H15N7O2S3, molecular weight: 337.45.
Peptic ulcer includes gastric duodenal ulcer, is a kind of commonly encountered diseases, the sickness rate average out to 8～10% in crowd. Treatment for peptic ulcer, should excessively not emphasize to eliminate gastric acid and pepsic attack function, and should focus on that adjustment causes ulcer factor and antiulcer factor balance between the two, pay attention to the resistant function of mucosa, but gastric acid secretion inhibiting and neutralization gastric acid remain the major measure for the treatment of Peptic Ulcers. Famotidine is that the third generation has specific H2 receptor antagonist, suitable in gastric and duodenal ulcers, reflux esophagitis, upper gastrointestinal hemorrhage (peptic ulcer, acute stress ulcer, hemorrhagic gastritis are caused), Zhuo Ai syndromes etc., have determined curative effect, and untoward reaction is little, cheap, social required quantity is high relatively.
Famotidine is bisfentidine, it it is a kind of derivant narrowing thiazole, its chemical constitution is different from the cimetidine of imidazole ring-containing and the ranitidine containing furan nucleus, its Acidinhibitor has dosage correlation. and various H2 receptor antagonist Acidinhibitor intensity are different, comparing with cimetidine, famotidine is its 20～37 times. Famotidine is as H2 receptor antagonist, except being used for treating peptic ulcer, apply also for prevention and the treatment ulcer that causes of non-steroidal anti-inflammatory drugs, it is prevented that critical patient generation stress ulcer and hemorrhage, treatment Zhuo-Emhorn syndrome, gastroesophageal reflux disease etc. and acid-related disease.Generally speaking each medicine rate of side effects is low, and about 5% or lower, serious side reaction is rare, and reversible after drug withdrawal. Combined effect mechanism is that the H2 receptor on blocking histamine and parietal cell combines, thus gastric acid secretion inhibiting. H2 receptor antagonist has great gastric acid secretion inhibiting effect, basal gastric acid secretion and the gastric acid secretion stimulated by food, pentagastrin, histamine, insulin, caffeine can be suppressed, but the latter acts on not exclusively, it is taken as that its treatment ulcer effect is important with the former acting as. The main dosage form of existing market famotidine has tablet, capsule, injection etc.
Famotidine poor stability, the dosage form of many employings freeze-dried powder during Clinical practice. Such as, two famotidines recorded of 2015 editions Chinese Pharmacopoeias of latest edition and preparation thereof, wherein when carrying out Related substances separation, relate to two kinds of typical impurity, the i.e. impurity I of 1-amino group form, and impurity I continues the impurity II of desulfurization amide group, and these impurity generally are intended to monitoring especially. Three's chemical structural formula is as follows:
Famotidine
Impurity I[N'-[3-[[[2-(diamino methylene) amino]-4-thiazolyl] methyl] sulfenyl] propiono] sulphamide;
Impurity II3-[[[2-[(diamino methylene) amino]-4-thiazolyl] methyl] sulfenyl] propionic acid amide..
Prior art, when preparing the various preparation such as injectable powder of famotidine, uses to Aspartic Acid as pharmaceutic adjuvant to improve the stability of medicine more.
Such as, the preparation method that CN200910172752.5 discloses a kind of famotidine injection, in the injection of 1000ml, containing the famotidine of 20.0g, the Aspartic Acid of 3.5g, the disodium edetate of 0.2g, 0.5g medicinal charcoal, surplus is water for injection.
Such as, the preparation method that CN201310245628.3 discloses a kind of famotidine injection of famotidine, it is characterised in that, it comprises the following steps: step one, dense preparing tank adds the water for injection of amount of preparation 50%, adds Aspartic Acid, disodiumedetate, stirring and dissolving; Step 2, adds famotidine in the above-mentioned solution of step one, adds water for injection, stirring and dissolving; Step 3, adds water for injection to full dose, stirs 15 minutes so that it is uniformly; Step 4, returns filter with Suzhou sand rod, 0.45 μm of collapsible filter of polyether sulfone; Step 5, visible foreign matters inspection is done in sampling, and sampling censorship measured center surveys intermediates content and pH value simultaneously, every all qualified after, medicinal liquid is filtered into receiver, passes into nitrogen; Step 6, the medicinal liquid in receiver is through 0.22 μm of collapsible frit of polyether sulfone, and after visible foreign matters passed examination is done in sampling, input seat bottle is for embedding; Step 7, logical nitrogen embedding; Step 8, temperature be 100 DEG C, the time carry out sterilizing when being 30 minutes.
But, in maintaining medicament excellent properties such as its stability, necessity that prior art is still improved. Therefore, those skilled in the art still expect the preparation method that there is the famotidine lyophilization injectable powder possessing excellent pharmaceutical property.
Summary of the invention
A kind of method that it is an object of the invention to provide famotidine lyophilization injectable powder prepared and possess excellent pharmaceutical property, and expect that this injectable powder has excellent pharmaceutical properties and such as possesses the stability etc. of excellence. Present inventors have surprisingly discovered that, the injectable powder prepared by the inventive method is capable of the above-mentioned purpose of at least one aspect, and obtained freeze-drying powder needle set has the physicochemical property of excellence. The present invention finds based on this and is accomplished.
For this, first aspect present invention provides the compositions of a kind of famotidine lyophilization injectable powder, wherein comprises famotidine, mannitol and Aspartic Acid.
The compositions of any embodiment according to a first aspect of the present invention, wherein comprises famotidine 20 weight portion, mannitol 15～45 weight portion and Aspartic Acid 5～15 weight portion.
The compositions of any embodiment according to a first aspect of the present invention, wherein comprises famotidine 20 weight portion, mannitol 20～40 weight portion and Aspartic Acid 6～12 weight portion.
The compositions of any embodiment according to a first aspect of the present invention, wherein comprises famotidine 20 weight portion, mannitol 25～35 weight portion and Aspartic Acid 7～10 weight portion.
The compositions of any embodiment according to a first aspect of the present invention, wherein comprises famotidine 20 weight portion, mannitol 30 weight portion and Aspartic Acid 8 weight portion.
The compositions of any embodiment according to a first aspect of the present invention, it is packed by cillin bottle.
The compositions of any embodiment according to a first aspect of the present invention, wherein moisture is lower than 10%, it is preferable that lower than 8%, it is preferable that lower than 7%, more preferably less than 5%.
The compositions of any embodiment according to a first aspect of the present invention, wherein also includes acid-base modifier. In one embodiment, described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination. In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, for instance 1M hydrochloric acid solution or 1M sodium hydroxide solution.
It is known that, the lyophilization injectable powder (being often referred to simply as lyophilized injectable powder or freeze-dried powder) obtained through freezing-vacuum drying, it is that first each material solvent dissolves (being typically with water dissolution), it is configured to a solution, then this solution is made to carry out freezing, carrying out evacuation, distillation, dry and that obtain one again, substantially anhydrous (typically water content is lower than 8%, particularly be usually less than 7%, be particularly usually less than 5%) Powdered thing or block. Therefore, the pH value that the acid-base value of this solid lyophilized products regulates solution usually by process for preparation controls; Or can be adjusted so that the pH value that the solid lyophilized products that obtains controls this dissolving/diluent under the dissolving/dilute strength of regulation controls (acid-base value referred to herein as controlling solid lyophilized products) by prescription; Latter means generally more commonly uses, such as, in pharmacopeia contained many lyophilized injectable powders control the acid-base value of goods all in this way, and this mode control the acid-base value of product generally can not the recipe quantity of concrete regulation acid-base modifier, and only specify the acid-base value of finished product. What be equally applicable to the present invention is, lyophilized injectable powder described in any embodiment according to a first aspect of the present invention, the amount of wherein said optional acid-base modifier is, make the pH value of this solution amount in 4.5～6.0 scopes during the solution that described lyophilized injectable powder water for injection is dissolved into containing famotidine 1mg/ml concentration, for instance the pH value of this solution amount in 5.0～5.5 scopes.
The compositions of any embodiment according to a first aspect of the present invention, it is substantially by including prepared by the steps:
A () weighs the famotidine of recipe quantity, mannitol, Aspartic Acid, add appropriate water for injection, be stirred to dissolve;
B () rapid gained medicinal liquid one step up adds activated carbon, stir 5～15 hours at 0～5 DEG C of temperature, then stir 0.5～1.5 hour at 35～45 DEG C of temperature, filtering decarbonization;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) regulate to pH4.5～6.0 with acid-base modifier, it is preferable that pH5.0～5.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removes moisture, tamponade, to obtain final product.
The compositions of any embodiment according to a first aspect of the present invention, wherein appropriate water for injection described in step (a) is the water for injection of 20～40% amounts (such as 25～35% amount) of prescription full dose.
The compositions of any embodiment according to a first aspect of the present invention, wherein the addition of activated carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05～0.15% in medicinal liquid. Oneself is through surprisingly it has been found that first process a long period at low temperature place by the medicinal liquid adding activated carbon in this step, and then short period ground processes at relatively high temperatures, and the injectable powder obtained has beat all more excellent stability.
The compositions of any embodiment according to a first aspect of the present invention, wherein stirs 8～12 hours in step (b) at 0～5 DEG C of temperature.
The compositions of any embodiment according to a first aspect of the present invention, wherein stirs 1 hour in step (b) at 35～45 DEG C of temperature.
The compositions of any embodiment according to a first aspect of the present invention, wherein the mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then with the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration.
The compositions of any embodiment according to a first aspect of the present invention, wherein mends described in step (c) and injects water to prescription full dose and refer to and add water for injection until amount that activity component concentration is 15～25mg/ml (such as 20mg/ml).
The compositions of any embodiment according to a first aspect of the present invention, wherein aseptic filtration described in step (d) is that the polyether sulfone filter element using 0.22um carries out aseptic filtration.
Further, second aspect present invention provides the method for the lyophilization injectable powder such as lyophilization injectable powder described in first aspect present invention any embodiment preparing famotidine, and it consists essentially of following steps:
A () weighs the famotidine of recipe quantity, mannitol, Aspartic Acid, add appropriate water for injection, be stirred to dissolve;
B () rapid gained medicinal liquid one step up adds activated carbon, stir 5～15 hours at 0～5 DEG C of temperature, then stir 0.5～1.5 hour at 35～45 DEG C of temperature, filtering decarbonization;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) regulate to pH4.5～6.0 with acid-base modifier, it is preferable that pH5.0～5.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removes moisture, tamponade, to obtain final product.
The method of any embodiment according to a second aspect of the present invention, the compositions of wherein said famotidine lyophilization injectable powder comprises famotidine, mannitol and Aspartic Acid.
The method of any embodiment according to a second aspect of the present invention, the compositions of wherein said famotidine lyophilization injectable powder comprises famotidine 20 weight portion, mannitol 15～45 weight portion and Aspartic Acid 5～15 weight portion.
The method of any embodiment according to a second aspect of the present invention, the compositions of wherein said famotidine lyophilization injectable powder comprises famotidine 20 weight portion, mannitol 20～40 weight portion and Aspartic Acid 6～12 weight portion.
The method of any embodiment according to a second aspect of the present invention, the compositions of wherein said famotidine lyophilization injectable powder comprises famotidine 20 weight portion, mannitol 25～35 weight portion and Aspartic Acid 7～10 weight portion.
The method of any embodiment according to a second aspect of the present invention, the compositions of wherein said famotidine lyophilization injectable powder comprises famotidine 20 weight portion, mannitol 30 weight portion and Aspartic Acid 8 weight portion.
The method of any embodiment according to a second aspect of the present invention, wherein also includes acid-base modifier in gained lyophilization injectable powder. In one embodiment, described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination. In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, for instance 1M hydrochloric acid solution or 1M sodium hydroxide solution.
The method of any embodiment according to a second aspect of the present invention, wherein appropriate water for injection described in step (a) is the water for injection of 20～40% amounts (such as 25～35% amount) of prescription full dose.
The method of any embodiment according to a second aspect of the present invention, wherein the addition of activated carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05～0.15% in medicinal liquid. Oneself is through surprisingly it has been found that first process a long period at low temperature place by the medicinal liquid adding activated carbon in this step, and then short period ground processes at relatively high temperatures, and the injectable powder obtained has beat all more excellent stability.
The method of any embodiment according to a second aspect of the present invention, wherein stirs 8～12 hours in step (b) at 0～5 DEG C of temperature.
The method of any embodiment according to a second aspect of the present invention, wherein stirs 1 hour in step (b) at 35～45 DEG C of temperature.
The method of any embodiment according to a second aspect of the present invention, wherein the mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then with the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration.
The method of any embodiment according to a second aspect of the present invention, wherein mends described in step (c) and injects water to prescription full dose and refer to and add water for injection until amount that activity component concentration is 15～25mg/ml (such as 20mg/ml).
The method of any embodiment according to a second aspect of the present invention, wherein aseptic filtration described in step (d) is that the polyether sulfone filter element using 0.22um carries out aseptic filtration.
Method described in any embodiment according to a second aspect of the present invention, wherein removes after moisture in gained lyophilization material moisture in step (e) lower than 10%, it is preferable that lower than 8%, it is preferable that lower than 7%, more preferably less than 5%.
In the step of the above-mentioned preparation method of the present invention, although the concrete steps of its description in some details or language to describe the step described in preparation example of up and down literary composition detailed description of the invention part otherwise varied, but, those skilled in the art can summarize approach described above step completely according to the detailed disclosure of present invention full text.
Any embodiment of the either side of the present invention, it is possible to be combined with other embodiment, as long as they do not have contradiction. Additionally, in any embodiment of either side of the present invention, any technology feature goes for this technical characteristic in other embodiment, as long as they do not have contradiction.
The invention will be further described below.
All documents that the present invention is recited, their full content is incorporated herein by, and if when implication expressed by these documents is inconsistent with the present invention, it is as the criterion with the statement of the present invention. In addition, various terms and phrase that the present invention uses have and well known to a person skilled in the art general sense, nonetheless, the present invention remains desirable at this, these terms and phrase are described in more detail and explained, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
Have been found that the famotidine for injection lyophilization injectable powder that the inventive method prepares has beat all advantage. Such as it is embodied in following stability test aspect:
Stability test: whole injectable powder that Examples below 1 to embodiment 11 prepares, is placed in 42 DEG C of places and places May to carry out high-temperature treatment test; For each injectable powder, when using [HPLC method] to measure this injectable powder when 0 month and in May, there is related substance (relative to main constituent) content, particularly follow the tracks of and calculate the content of impurity I; The content being calculated as follows impurity I increases percent (% may be simply referred to as " impurity I increment "):
Above-mentioned whole injectable powder use and prepare with a collection of famotidine raw material medicine, and whole injectable powder impurity I content when 0 month is substantially suitable, all in 0.27～0.33% scope. But, after above-mentioned high-temperature treatment, different samples present visibly different impurity I situation of change; Specifically, impurity I increment (%) of the whole injectable powder of embodiment 9～11 gained is all in 186～233% scopes, and impurity I increment (%) of the whole injectable powder of embodiment 1-8 gained is all in 33～57% scopes. This shows, the famotidine powder pin using same materials to prepare through distinct methods, is substantially free of difference in an initial condition, but distinct methods products obtained therefrom but exists significant difference in the stability particularly impurity I stability characterized.
For above-mentioned 42 DEG C of test specimens disposing May, measure they famotidine content when 0 month and May respectively, for each sample, relative amount time when calculating its May relative to 0 month, this relative amount is powder pin in the residual content of active component after high-temperature treatment May. Result shows, the residual content of the whole injectable powder of embodiment 9～11 gained is all in 92～95% scopes, the whole injectable powder of embodiment 1-8 gained residual content all in 97～99% scopes, this shows, although embodiment 9～11 powder pin substantially meets requirement after high-temperature treatment still above 90%, but its stability is significantly not as good as embodiment 1-8 injectable powder.
In the present invention, it is preferred to lyophilized injectable powder of the present invention making with water in every 1ml after containing the solution of active component 1mg, measure the acid-base value of this freeze-dried powder further according to the method under Chinese Pharmacopoeia two annex VIH items of version in 2010 and pH value algoscopy.
The preparation process of lyophilization injectable powder is to well known to a person skilled in the art pharmaceutical technology, for instance following two kinds of schematic freeze-drying curves shown in freeze-drying curve A and freeze-drying curve B:
Preparing in the instantiation in lyophilization injectable powder below, if not otherwise specified, freeze-drying curve used is freeze-drying curve A.
Water content in lyophilization injectable powder is to be typically in less than 8%, it is preferable that lower than 7%, more preferably less than 5%.Moisture Control can control by suitably adjusting lyophilization program. Moisture in this lyophilization injectable powder can measure according to many known methods, for instance dry weight-loss method.
In the present invention, in order to regulate the pH value of medicinal liquid when necessary, it is possible to add suitable pH adjusting agent in compositions. Although the present inventor is only adjusted with the strong acid or strong base solution such as sodium hydrate aqueous solution and aqueous hydrochloric acid solution that do not have buffer capacity, but, skilled artisan understands that, if processing, by this pH adjusting agent not having buffer capacity, the pH requirement that system can be met, the pH adjusting agent then with buffer capacity will be better able to realize the object of the invention, therefore these buffer agents are not only able to regulate pH value, and can stablize pH value. Therefore arbitrary pH adjusting agent listed by the present invention or its combination are included in spirit and scope of the invention.
When preparing lyophilized injectable powder of the present invention, in the medicinal liquid prepared, solid content is for 1～20% (w/v), it is preferable that 2～15% (w/v), even more preferably 3～10%, even more preferably 4～8%. obtain owing to lyophilized injectable powder usually carries out lyophilization in tubulose cillin bottle, skilled artisan understands that this product is obtaining finished product even at before for doctor, typically each present a round pie, although lecture's fewer than the volume of original aqueous solution (slightly reducing) in the volume theory of this cake, but generally this reducing typically not narrows down to former aqueous solution volume 50%, would generally between the 80-120% of former aqueous solution volume, it is more typically between the 90-100% of former aqueous solution volume, and former aqueous solution liquid level vestige be can be observed in finished product cillin bottle, and (main body cake remains in the liquid level vestige bottle wall because of lyophilizing after reducing, even if the dried frozen aquatic products in cillin bottle is Powdered because of reasons such as a variety of causes such as collisions, generally still can retain original liquid level vestige), vestige also can estimate this freeze-dried composition aqueous solution volume before lyophilization accordingly. therefore, although the present invention is to provide a kind of substantially anhydrous lyophilization injectable powder, but still can substantially estimate it according to this injectable powder when preparation, the at least medicine liquid volume before lyophilization starts, weight according to the dry end-product in this volume estimated and cillin bottle, also can calculate when preparing lyophilized injectable powder of the present invention, the content of the solid content in the medicinal liquid prepared. therefore, lyophilized injectable powder according to a first aspect of the present invention, its solid content of medicinal liquid when preparation is 1～20% (w/v), it is preferable that 2～15% (w/v), even more preferably 3～10%, even more preferably 4～8%.
In the present invention, symbol %, according to its linguistic context used, it is possible to have the implication that skilled addressee readily understands that. Such as when mentioning solid content, this symbol represents the percent (w/v, for instance g/100ml) of weight/volume; Again during such as " water content " in mentioning lyophilization injectable powder, for instance water content is below 8%, and now this symbol % represents the percent (w/w, g/100g) of w/w. It is said that in general, when solid disperses in a liquid, % represents weight/volume percent; In solid dispersion, in solids or during liquid dispersion (such as the water content of powder pin) in solids, % represents w/w percent. In other cases, unless otherwise noted, symbol % represents w/w percent.
When preparing the medicinal liquid of the present invention, as well known to those skilled in the art, the microporous filter membrane of such as about 0.45um can be used to carry out coarse filtration filtration, by before in liquid medicine filling to cillin bottle, the microporous filter membrane that can use such as about 0.22um carries out fine straining and filters with degerming, it may be necessary to filter repeatedly.
Lyophilized injectable powder according to the present invention, it is lyophilization injectable powder. In one embodiment, this lyophilization injectable powder is single-dose preparations (injectable powder that such as XiLin is bottled), and in per unit dosage, the amount of reactive compound can such as but not limited to about 10mg, about 20mg, about 40mg, about 50mg.
Lyophilized injectable powder according to the present invention, it redissolves with water for injection, and the time of typically redissolving is in 30 seconds, it is preferable that in 20 seconds, more preferably in 15 seconds.
Lyophilized injectable powder according to the present invention, it is made containing the solution of reactive compound 1mg and according to the method mensuration under Chinese Pharmacopoeia two annex VIH items of version in 2010 in every 1ml with water, and the pH value of this solution is 4.5～6.0. In one embodiment, pH value is 5.0～5.5.
Lyophilized injectable powder provided by the invention can preserve at least 24 months at place dry below 25 DEG C, it is possible to meets the Storage Requirement of general lyophilization injectable powder.
Obtained freeze-drying injectable powder of the present invention particularly lyophilization injectable powder is generally white or the lyophilizing block of off-white color or its fragment or its powder, and odorless, bitter in the mouth are soluble in water.
Famotidine is bisfentidine, is a kind of derivant narrowing thiazole, and its chemical constitution is different from the cimetidine of imidazole ring-containing and the ranitidine containing furan nucleus, and its Acidinhibitor has dosage correlation. Various H2 receptor antagonist Acidinhibitor intensity are different, compare with cimetidine, and famotidine is its 20～37 times. Famotidine is as H2 receptor antagonist, except being used for treating peptic ulcer, apply also for prevention and the treatment ulcer that causes of non-steroidal anti-inflammatory drugs, it is prevented that critical patient generation stress ulcer and hemorrhage, treatment Zhuo-Emhorn syndrome, gastroesophageal reflux disease etc. and acid-related disease. Generally speaking each medicine rate of side effects is low, and about 5% or lower, serious side reaction is rare, and reversible after drug withdrawal. Combined effect mechanism is that the H2 receptor on blocking histamine and parietal cell combines, thus gastric acid secretion inhibiting. H2 receptor antagonist has great gastric acid secretion inhibiting effect, basal gastric acid secretion and the gastric acid secretion stimulated by food, pentagastrin, histamine, insulin, caffeine can be suppressed, but the latter acts on not exclusively, it is taken as that its treatment ulcer effect is important with the former acting as.
Detailed description of the invention
The present invention can be conducted further description by the following examples, but, the scope of the present invention is not limited to following embodiment. One of skill in the art is it is understood that under the premise without departing substantially from the spirit and scope of the present invention, it is possible to the present invention carries out various change and modification. The material that used and test method in test are carried out generality and/or concrete description by the present invention. Although for realize many materials that the object of the invention uses and operational approach is to it is known in the art that but the present invention remains in this to be described in detail as far as possible. Following example further illustrate the present invention rather than the restriction present invention. Any foundation pro forma but not substantial equivalent transformation that is only done by present inventive concept is regarded as technical scheme category.
In examples below, if not otherwise indicated, it is the famotidine raw material medicine (it meets the quality standard of Chinese Pharmacopoeia two famotidines recorded of version in 2015) of same batch of use when preparing injectable powder.
In examples below, the pH adjusting agent (in the present invention that is acid-base modifier) used, unless otherwise noted, it is 1M sodium hydroxide solution or 1M hydrochloric acid solution, when its consumption is to make to prepare injectable powder, the pH value of the solution prepared before making lyophilization regulates to a certain setting or scope, and this setting or scope are value or the scopes that lyophilization gained dry powder water for injection is diluted to the pH value that the solution containing active component 1mg/ml measures. The hereafter preparation process purpose in order to illustrate, and making some specific description based on the comparability of each citing, those skilled in the art can therefrom summarize completely according to existing knowledge and obtain the method that the present invention prepares lyophilized injectable powder. Dosing is prepared in various compositions below, and if not otherwise indicated, total dosing amount of every batch is 10000ml, but when listing formula, all illustrates containing the amount of famotidine 20mg in every bottle.
Assay method:
Assay that various samples (include injectable powder of the present invention) adopts the method described in [assay] in " famotidine for injection " kind that Chinese Pharmacopoeia version two in 2015 is recorded to carry out; The method described in " having related substance " in " famotidine for injection " kind that what various samples (included injectable powder of the present invention) have related substance adopts Chinese Pharmacopoeia version two in 2015 is recorded carries out.
Embodiment 1: prepare famotidine lyophilization injectable powder
Formula:
Famotidine 20mg,
Mannitol 30mg,
Aspartic Acid 8mg,
Acid-base modifier: appropriate, regulates the setting in pH extremely following method for making,
Water for injection: add to 1ml
Method for making:
A () weighs the famotidine of recipe quantity, mannitol, Aspartic Acid, add recipe quantity 30% water for injection, be stirred to dissolve;
B () rapid gained medicinal liquid one step up adds activated carbon (in medicine liquid volume 0.1%), stir 10 hours at 0～5 DEG C of temperature, then stir 1 hour at 40 DEG C of temperature, filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then with the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) regulate to pH5.2 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removes moisture (moisture is lower than 5%), tamponade, to obtain final product.
Embodiment 2: prepare famotidine lyophilization injectable powder
Formula:
Famotidine 20mg,
Mannitol 25mg,
Aspartic Acid 10mg,
Acid-base modifier: appropriate, regulates the setting in pH extremely following method for making,
Water for injection: add to 0.8ml
Method for making:
A () weighs the famotidine of recipe quantity, mannitol, Aspartic Acid, add recipe quantity 35% water for injection, be stirred to dissolve;
B () rapid gained medicinal liquid one step up adds activated carbon (in medicine liquid volume 0.15%), stir 5 hours at 0～5 DEG C of temperature, then stir 1.5 hours at 45 DEG C of temperature, filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then with the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) regulate to pH5.3 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removes moisture (moisture is lower than 5%), tamponade, to obtain final product.
This example uses freeze-drying curve B to carry out lyophilization.
Embodiment 3: prepare famotidine lyophilization injectable powder
Formula:
Famotidine 20mg,
Mannitol 35mg,
Aspartic Acid 7mg,
Acid-base modifier: appropriate, regulates the setting in pH extremely following method for making,
Water for injection: add to 1.33ml
Method for making:
A () weighs the famotidine of recipe quantity, mannitol, Aspartic Acid, add recipe quantity 25% water for injection, be stirred to dissolve;
B () rapid gained medicinal liquid one step up adds activated carbon (in medicine liquid volume 0.05%), stir 15 hours at 0～5 DEG C of temperature, then stir 0.5 hour at 35 DEG C of temperature, filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then with the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) regulate to pH4.5 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removes moisture (moisture is lower than 5%), tamponade, to obtain final product.
Embodiment 4: prepare famotidine lyophilization injectable powder
Formula:
Famotidine 20mg,
Mannitol 40mg,
Aspartic Acid 6mg,
Acid-base modifier: appropriate, regulates the setting in pH extremely following method for making,
Water for injection: add to 1ml
Method for making:
A () weighs the famotidine of recipe quantity, mannitol, Aspartic Acid, add recipe quantity 40% water for injection, be stirred to dissolve;
B () rapid gained medicinal liquid one step up adds activated carbon (in medicine liquid volume 0.1%), stir 10 hours at 0～5 DEG C of temperature, then stir 1 hour at 38 DEG C of temperature, filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then with the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) regulate to pH5.5 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removes moisture (moisture is lower than 5%), tamponade, to obtain final product.
Embodiment 5: prepare famotidine lyophilization injectable powder
Formula:
Famotidine 20mg,
Mannitol 20mg,
Aspartic Acid 12mg,
Acid-base modifier: appropriate, regulates the setting in pH extremely following method for making,
Water for injection: add to 1ml
Method for making:
A () weighs the famotidine of recipe quantity, mannitol, Aspartic Acid, add recipe quantity 20% water for injection, be stirred to dissolve;
B () rapid gained medicinal liquid one step up adds activated carbon (in medicine liquid volume 0.1%), stir 8 hours at 0～5 DEG C of temperature, then stir 0.8 hour at 42 DEG C of temperature, filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then with the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) regulate to pH5.0 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removes moisture (moisture is lower than 5%), tamponade, to obtain final product.
Embodiment 6: prepare famotidine lyophilization injectable powder
Formula:
Famotidine 20mg,
Mannitol 30mg,
Aspartic Acid 10mg,
Acid-base modifier: appropriate, regulates the setting in pH extremely following method for making,
Water for injection: add to 1ml
Method for making:
A () weighs the famotidine of recipe quantity, mannitol, Aspartic Acid, add recipe quantity 35% water for injection, be stirred to dissolve;
B () rapid gained medicinal liquid one step up adds activated carbon (in medicine liquid volume 0.12%), stir 12 hours at 0～5 DEG C of temperature, then stir 1 hour at 40 DEG C of temperature, filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then with the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) regulate to pH5.2 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removes moisture (moisture is lower than 5%), tamponade, to obtain final product.
Embodiment 7: prepare famotidine lyophilization injectable powder
Formula:
Famotidine 20mg,
Mannitol 20mg,
Aspartic Acid 5mg,
Acid-base modifier: appropriate, regulates the setting in pH extremely following method for making,
Water for injection: add to 1ml
Method for making:
A () weighs the famotidine of recipe quantity, mannitol, Aspartic Acid, add recipe quantity 25% water for injection, be stirred to dissolve;
B () rapid gained medicinal liquid one step up adds activated carbon (in medicine liquid volume 0.1%), stir 10 hours at 0～5 DEG C of temperature, then stir 1 hour at 45 DEG C of temperature, filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then with the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) regulate to pH5.5 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removes moisture (moisture is lower than 5%), tamponade, to obtain final product.
Embodiment 8: prepare famotidine lyophilization injectable powder
Formula:
Famotidine 20mg,
Mannitol 25mg,
Aspartic Acid 5mg,
Acid-base modifier: appropriate, regulates the setting in pH extremely following method for making,
Water for injection: add to 1ml
Method for making:
A () weighs the famotidine of recipe quantity, mannitol, Aspartic Acid, add recipe quantity 35% water for injection, be stirred to dissolve;
B () rapid gained medicinal liquid one step up adds activated carbon (in medicine liquid volume 0.1%), stir 10 hours at 0～5 DEG C of temperature, then stir 1 hour at 40 DEG C of temperature, filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then with the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) regulate to pH5.3 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removes moisture (moisture is lower than 5%), tamponade, to obtain final product.
Embodiment 9: prepare famotidine lyophilization injectable powder
Respectively refer to embodiment 1-8, the process that different is only does not carry out in step (b) " stirring at 0～5 DEG C of temperature ", but it is made directly at 35～45 DEG C of temperature the process of stir process, prepare 8 batches of powder pins.
Embodiment 10: prepare famotidine lyophilization injectable powder
Respectively referring to embodiment 1-8, different is only step (b) changed into: add activated carbon in rapid gained medicinal liquid one step up, at room temperature stirring 2 hours, and filtering decarbonization prepares 8 batches of powder pins.
Embodiment 11: prepare famotidine lyophilization injectable powder
Prescription and compound method carry out with reference to the embodiment 3 of China Patent No. 201010500571.3 (CN101972248B), obtain injectable powder.
Industrial applicability
The invention provides a kind of famotidine for injection lyophilization injectable powder with excellent properties and the preparation method of this famotidine for injection lyophilization injectable powder. Famotidine for injection lyophilization injectable powder of the present invention can be used for gastric associated diseases. The famotidine for injection lyophilization injectable powder that the present invention prepares has the physicochemical property of excellence.
Claims (10)
1. a compositions for famotidine lyophilization injectable powder, wherein comprises famotidine, mannitol and Aspartic Acid.
2. compositions according to claim 1, it is characterised in that:
Wherein comprise famotidine 20 weight portion, mannitol 15～45 weight portion and Aspartic Acid 5～15 weight portion;
Wherein comprise famotidine 20 weight portion, mannitol 20～40 weight portion and Aspartic Acid 6～12 weight portion;
Wherein comprise famotidine 20 weight portion, mannitol 25～35 weight portion and Aspartic Acid 7～10 weight portion; And/or
Wherein comprise famotidine 20 weight portion, mannitol 30 weight portion and Aspartic Acid 8 weight portion.
3. compositions according to claim 1, it is characterised in that:
Packed by cillin bottle;
Wherein moisture is lower than 10%, it is preferable that lower than 8%, it is preferable that lower than 7%, more preferably less than 5%;
Wherein also include acid-base modifier;
Described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination;
Described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, for instance 1M hydrochloric acid solution or 1M sodium hydroxide solution; And/or
The amount of wherein said optional acid-base modifier is, make the pH value of this solution amount in 4.5～6.0 scopes during the solution that described lyophilized injectable powder water for injection is dissolved into containing famotidine 1mg/ml concentration, for instance the pH value of this solution amount in 5.0～5.5 scopes.
4. compositions according to claim 1, it is substantially by including prepared by the steps:
A () weighs the famotidine of recipe quantity, mannitol, Aspartic Acid, add appropriate water for injection, be stirred to dissolve;
B () rapid gained medicinal liquid one step up adds activated carbon, stir 5～15 hours at 0～5 DEG C of temperature, then stir 0.5～1.5 hour at 35～45 DEG C of temperature, filtering decarbonization;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) regulate to pH4.5～6.0 with acid-base modifier, it is preferable that pH5.0～5.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removes moisture, tamponade, to obtain final product.
5. compositions according to claim 1, it is characterised in that:
Appropriate water for injection described in step (a) is the water for injection of 20～40% amounts (such as 25～35% amount) of prescription full dose;
The addition of activated carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05～0.15% in medicinal liquid;
Wherein step (b) stirs 8～12 hours at 0～5 DEG C of temperature;
Step (b) stirs 1 hour at 35～45 DEG C of temperature; And/or
The mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then with the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration.
6. compositions according to claim 1, it is characterised in that:
Mend described in step (c) and inject water to prescription full dose and refer to and add water for injection until amount that activity component concentration is 15～25mg/ml (such as 20mg/ml); And/or
Aseptic filtration described in step (d) is that the polyether sulfone filter element using 0.22um carries out aseptic filtration.
7. the method preparing the lyophilization injectable powder compositions of famotidine such as compositions described in any one of claim 1-6, it consists essentially of following steps:
A () weighs the famotidine of recipe quantity, mannitol, Aspartic Acid, add appropriate water for injection, be stirred to dissolve;
B () rapid gained medicinal liquid one step up adds activated carbon, stir 5～15 hours at 0～5 DEG C of temperature, then stir 0.5～1.5 hour at 35～45 DEG C of temperature, filtering decarbonization;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) regulate to pH4.5～6.0 with acid-base modifier, it is preferable that pH5.0～5.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removes moisture, tamponade, to obtain final product.
8. method according to claim 7, it is characterised in that:
Wherein said compositions comprises famotidine 20 weight portion, mannitol 15～45 weight portion and Aspartic Acid 5～15 weight portion;
Wherein said compositions comprises famotidine 20 weight portion, mannitol 20～40 weight portion and Aspartic Acid 6～12 weight portion;
Wherein said compositions comprises famotidine 20 weight portion, mannitol 25～35 weight portion and Aspartic Acid 7～10 weight portion;
Wherein said compositions comprises famotidine 20 weight portion, mannitol 30 weight portion and Aspartic Acid 8 weight portion;
Gained lyophilization injectable powder also includes acid-base modifier;
Described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination; And/or
Described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, for instance 1M hydrochloric acid solution or 1M sodium hydroxide solution.
9. method according to claim 7, it is characterised in that:
Appropriate water for injection described in step (a) is the water for injection of 20～40% amounts (such as 25～35% amount) of prescription full dose;
The addition of activated carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05～0.15% in medicinal liquid;
Step (b) stirs 8～12 hours at 0～5 DEG C of temperature;
Step (b) stirs 1 hour at 35～45 DEG C of temperature; And/or
The mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then with the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration.
10. method according to claim 7, it is characterised in that:
Mend described in step (c) and inject water to prescription full dose and refer to and add water for injection until amount that activity component concentration is 15～25mg/ml (such as 20mg/ml);
Aseptic filtration described in step (d) is that the polyether sulfone filter element using 0.22um carries out aseptic filtration; And/or
Step (e) removes after moisture in gained lyophilization material moisture lower than 10%, it is preferable that lower than 8%, it is preferable that lower than 7%, more preferably less than 5%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610180285.0A CN105663127B (en) | 2016-03-24 | 2016-03-24 | Injection is freeze-dried famotidine composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610180285.0A CN105663127B (en) | 2016-03-24 | 2016-03-24 | Injection is freeze-dried famotidine composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105663127A true CN105663127A (en) | 2016-06-15 |
| CN105663127B CN105663127B (en) | 2018-06-22 |
Family
ID=56225419
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610180285.0A Active CN105663127B (en) | 2016-03-24 | 2016-03-24 | Injection is freeze-dried famotidine composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105663127B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111904936A (en) * | 2020-08-28 | 2020-11-10 | 开封康诺药业有限公司 | Famotidine freeze-dried powder injection |
| CN113197869A (en) * | 2021-04-13 | 2021-08-03 | 河北智同生物制药股份有限公司 | Famotidine freeze-dried powder injection for injection and preparation method thereof |
| CN114681409A (en) * | 2021-10-20 | 2022-07-01 | 海南倍特药业有限公司 | Famotidine for injection and preparation method thereof |
| CN115737548A (en) * | 2022-11-21 | 2023-03-07 | 四川汇宇制药股份有限公司 | Preparation method of famotidine injection |
| WO2024062287A1 (en) * | 2022-09-21 | 2024-03-28 | Maiva Pharma Private Limited | A premixed room temperature stable composition of famotidine for intravenous bolus injection and method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101972248A (en) * | 2010-10-09 | 2011-02-16 | 江苏奥赛康药业有限公司 | Famotidine composition for injection and preparation method thereof |
-
2016
- 2016-03-24 CN CN201610180285.0A patent/CN105663127B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101972248A (en) * | 2010-10-09 | 2011-02-16 | 江苏奥赛康药业有限公司 | Famotidine composition for injection and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 唐小波等: "提高注射用法莫替丁澄清度的探讨", 《中南药学》 * |
| 屠锡德等: "《药剂学》", 31 March 2004 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111904936A (en) * | 2020-08-28 | 2020-11-10 | 开封康诺药业有限公司 | Famotidine freeze-dried powder injection |
| CN113197869A (en) * | 2021-04-13 | 2021-08-03 | 河北智同生物制药股份有限公司 | Famotidine freeze-dried powder injection for injection and preparation method thereof |
| CN114681409A (en) * | 2021-10-20 | 2022-07-01 | 海南倍特药业有限公司 | Famotidine for injection and preparation method thereof |
| WO2024062287A1 (en) * | 2022-09-21 | 2024-03-28 | Maiva Pharma Private Limited | A premixed room temperature stable composition of famotidine for intravenous bolus injection and method thereof |
| CN115737548A (en) * | 2022-11-21 | 2023-03-07 | 四川汇宇制药股份有限公司 | Preparation method of famotidine injection |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105663127B (en) | 2018-06-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105663127B (en) | Injection is freeze-dried famotidine composition | |
| KR102140982B1 (en) | Manufacture of degarelix | |
| CN103222963B (en) | Somatostatin freeze-dried powder injection | |
| CN113521018B (en) | Freeze-dried composition containing anti-HER 2-drug conjugate, freeze-dried preparation, preparation method and application thereof | |
| CN103202816B (en) | Pantoprazole sodium freeze-dried powder injection | |
| CN103330688B (en) | Ranitidine freeze-dried powder injection for curing gastropathy | |
| TWI696469B (en) | Formulation | |
| TWI660729B (en) | Formulation | |
| CN104666255A (en) | Pharmaceutical composition of omeprazole sodium freeze-dried powder for injection | |
| CN111214446A (en) | Peruvir L-arginine salt freeze-dried preparation for injection | |
| CN103860483A (en) | Compound glycyrrhizin lyophilized powder injection and preparation method thereof | |
| JP2022501440A (en) | Carbetocin drug and its manufacturing process | |
| CN103040767A (en) | Stable kalii dehydrographolidi succinas freeze-dried powder injection for injection | |
| Gopinath et al. | Pharmaceutical preformulation studies–current review | |
| WO2016045530A1 (en) | Chlorogenic acid lyophilised powder for injection having high resolubility and high stability | |
| CN103169674A (en) | Omeprazole sodium freeze-dried powder injection for injection | |
| CN103845295A (en) | Palonosetron preparation for injection and preparation method thereof | |
| CN104800172B (en) | Injection Carbazochrome Sodium Sulfonate powder-injection and preparation method | |
| CN101249078A (en) | Rabeprazole sodium freeze-dried powder injection | |
| CN103142513B (en) | A kind of injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder and preparation method thereof | |
| JP2019506377A (en) | Drug inclusion compound, preparation thereof, and production method therefor | |
| CN102440967A (en) | Sodium rabeprazole for injection and preparation method and detection method thereof | |
| CN103536567B (en) | Thymopentin (TP-5) powder injection | |
| CN109044980A (en) | Growth hormone release inhibiting hormone freeze drying powder injection pharmaceutical composition and preparation method thereof | |
| CN104721153B (en) | Aminomethylbenzoic acid freeze-dried powder injection pharmaceutical composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province Patentee after: Chengdu Tiantaishan Pharmaceutical Co.,Ltd. Address before: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province Patentee before: CHENGDU TIANTAISHAN PHARMACEUTICAL Co.,Ltd. |