CN105769759B - Composition and preparation method of ondansetron hydrochloride injection - Google Patents
Composition and preparation method of ondansetron hydrochloride injection Download PDFInfo
- Publication number
- CN105769759B CN105769759B CN201610225573.3A CN201610225573A CN105769759B CN 105769759 B CN105769759 B CN 105769759B CN 201610225573 A CN201610225573 A CN 201610225573A CN 105769759 B CN105769759 B CN 105769759B
- Authority
- CN
- China
- Prior art keywords
- injection
- ondansetron hydrochloride
- ondansetron
- solution
- acid
- 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.)
- Active
Links
- MKBLHFILKIKSQM-UHFFFAOYSA-N 9-methyl-3-[(2-methyl-1h-imidazol-3-ium-3-yl)methyl]-2,3-dihydro-1h-carbazol-4-one;chloride Chemical compound Cl.CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 MKBLHFILKIKSQM-UHFFFAOYSA-N 0.000 title claims abstract description 133
- 229960000770 ondansetron hydrochloride Drugs 0.000 title claims abstract description 133
- 238000002347 injection Methods 0.000 title claims abstract description 126
- 239000007924 injection Substances 0.000 title claims abstract description 126
- 239000000203 mixture Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title abstract description 36
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 claims abstract description 52
- 229960005343 ondansetron Drugs 0.000 claims abstract description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 47
- 239000008215 water for injection Substances 0.000 claims abstract description 43
- 239000000243 solution Substances 0.000 claims description 116
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 46
- 239000003814 drug Substances 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 229940079593 drug Drugs 0.000 claims description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 22
- 239000004695 Polyether sulfone Substances 0.000 claims description 21
- 229920006393 polyether sulfone Polymers 0.000 claims description 21
- 239000011259 mixed solution Substances 0.000 claims description 16
- 239000007788 liquid Substances 0.000 claims description 12
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- 239000011521 glass Substances 0.000 claims description 11
- 239000011148 porous material Substances 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 8
- 238000011146 sterile filtration Methods 0.000 claims description 5
- 238000005262 decarbonization Methods 0.000 claims 2
- 238000002512 chemotherapy Methods 0.000 description 16
- 206010047700 Vomiting Diseases 0.000 description 15
- 238000001990 intravenous administration Methods 0.000 description 14
- 239000012535 impurity Substances 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 11
- 206010028980 Neoplasm Diseases 0.000 description 10
- 201000011510 cancer Diseases 0.000 description 10
- 238000001959 radiotherapy Methods 0.000 description 10
- 229940126409 proton pump inhibitor Drugs 0.000 description 8
- 239000000612 proton pump inhibitor Substances 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000001802 infusion Methods 0.000 description 7
- 230000009885 systemic effect Effects 0.000 description 7
- 230000008673 vomiting Effects 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000009826 distribution Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229940044683 chemotherapy drug Drugs 0.000 description 5
- 102000035037 5-HT3 receptors Human genes 0.000 description 4
- 108091005477 5-HT3 receptors Proteins 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000010255 intramuscular injection Methods 0.000 description 4
- 239000007927 intramuscular injection Substances 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 239000012085 test solution Substances 0.000 description 4
- 206010028817 Nausea and vomiting symptoms Diseases 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 230000000095 emetic effect Effects 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 210000001186 vagus nerve Anatomy 0.000 description 3
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 2
- 208000032755 Anticipatory Vomiting Diseases 0.000 description 2
- 229940121891 Dopamine receptor antagonist Drugs 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 208000031649 Postoperative Nausea and Vomiting Diseases 0.000 description 2
- 229920001131 Pulp (paper) Polymers 0.000 description 2
- 206010062237 Renal impairment Diseases 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 2
- 238000009513 drug distribution Methods 0.000 description 2
- 238000001631 haemodialysis Methods 0.000 description 2
- 230000000322 hemodialysis Effects 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 230000000474 nursing effect Effects 0.000 description 2
- 229960000381 omeprazole Drugs 0.000 description 2
- 229960004048 pantoprazole sodium Drugs 0.000 description 2
- YNWDKZIIWCEDEE-UHFFFAOYSA-N pantoprazole sodium Chemical compound [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-UHFFFAOYSA-N 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 230000011514 reflex Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 229940113081 5 Hydroxytryptamine 3 receptor antagonist Drugs 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- AGQJDIDJKSFVTC-UHFFFAOYSA-N 9-methyl-3-methylidene-1,2-dihydrocarbazol-4-one Chemical compound C12=CC=CC=C2N(C)C2=C1C(=O)C(=C)CC2 AGQJDIDJKSFVTC-UHFFFAOYSA-N 0.000 description 1
- 108010001237 Cytochrome P-450 CYP2D6 Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- UQOFGTXDASPNLL-XHNCKOQMSA-N Muscarine Chemical compound C[C@@H]1O[C@H](C[N+](C)(C)C)C[C@H]1O UQOFGTXDASPNLL-XHNCKOQMSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 230000009956 central mechanism Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000003737 chromaffin cell Anatomy 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229960002344 dexamethasone sodium phosphate Drugs 0.000 description 1
- PLCQGRYPOISRTQ-FCJDYXGNSA-L dexamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-FCJDYXGNSA-L 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 238000002283 elective surgery Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 210000004055 fourth ventricle Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960003727 granisetron Drugs 0.000 description 1
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000002780 ion channel assay Methods 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 1
- 229960003702 moxifloxacin Drugs 0.000 description 1
- 231100000219 mutagenic Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 231100000150 mutagenicity / genotoxicity testing Toxicity 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 231100001160 nonlethal Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940114636 ondansetron 16 mg Drugs 0.000 description 1
- 229940006351 ondansetron 24 mg Drugs 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 231100000857 poor renal function Toxicity 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000002336 repolarization Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- 229940121356 serotonin receptor antagonist Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- LCHWKMAWSZDQRD-UHFFFAOYSA-N silylformonitrile Chemical group [SiH3]C#N LCHWKMAWSZDQRD-UHFFFAOYSA-N 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 238000011003 system suitability test Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域technical field
本发明属于制药工程技术领域，具体地说，涉及一种盐酸昂丹司琼产品以及其制法，特别是涉及一种盐酸昂丹司琼注射液组合物，以及它的制备方法。The invention belongs to the technical field of pharmaceutical engineering, and in particular relates to an ondansetron hydrochloride product and a preparation method thereof, in particular to an ondansetron hydrochloride injection composition and a preparation method thereof.
背景技术Background technique
目前，治疗癌症多采用放疗、化疗，但接受放疗和化疗的癌症患者会出现不同程度的恶心、呕吐症状。化疗引起的恶心、呕吐，是指在化疗过程中，由化疗药物所导致的一种毒性反应。化疗病人中约60％出现恶心、呕吐症状，分为急性恶心呕吐、迟发性呕吐及预期性呕吐。化疗药物所致恶心、呕吐主要由几方面引起：①化疗药物刺激胃肠道粘膜，致黏膜上的嗜铬细胞释放5-HT3等神经递质，5-HT3与5-HT3受体结合产生的神经冲动由迷走神经和交感神经传入呕吐中枢而致呕吐；②化疗药物及其代谢产物直接刺激CTZ，然后通过多巴胺、组胺、毒蕈碱、5-HT3等一系列受体进而传递至呕吐中枢引发呕吐；③感觉、精神因子直接刺激大脑皮质通路导致呕吐，多见于预期性呕吐。At present, radiotherapy and chemotherapy are mostly used to treat cancer, but cancer patients who receive radiotherapy and chemotherapy will experience nausea and vomiting symptoms to varying degrees. Nausea and vomiting caused by chemotherapy refer to a toxic reaction caused by chemotherapy drugs during chemotherapy. Nausea and vomiting symptoms occur in about 60% of chemotherapy patients, which can be divided into acute nausea and vomiting, delayed vomiting and anticipatory vomiting. Nausea and vomiting caused by chemotherapy drugs are mainly caused by several aspects: ① Chemotherapy drugs stimulate the gastrointestinal mucosa, causing chromaffin cells on the mucosa to release 5-HT3 and other neurotransmitters, which are produced by the combination of 5-HT3 and 5-HT3 receptors. Nerve impulses are transmitted to the vomiting center by the vagus nerve and sympathetic nerve to cause vomiting; ② chemotherapy drugs and their metabolites directly stimulate CTZ, and then transmit to the vomiting center through a series of receptors such as dopamine, histamine, muscarine, and 5-HT3 Cause vomiting; ③ sensory and mental factors directly stimulate the cerebral cortex pathway to cause vomiting, which is more common in anticipatory vomiting.
临床常用的止吐药物主要有：5-HT3受体拮抗剂、多巴胺受体拮抗剂、类固醇等，以昂丹司琼、格拉司琼等5-HT3受体拮抗剂最为常用。Antiemetic drugs commonly used in clinical practice mainly include: 5-HT3 receptor antagonists, dopamine receptor antagonists, steroids, etc. 5-HT3 receptor antagonists such as ondansetron and granisetron are the most commonly used.
盐酸昂丹司琼(Ondansetron Hydrochloride，ODS)，2015年版《中国药典》已经收载，以其二水合物提供，其结构式、分子式、分子量如下：Ondansetron Hydrochloride (ODS), the 2015 edition of "Chinese Pharmacopoeia" has been recorded, and it is provided as its dihydrate. Its structural formula, molecular formula and molecular weight are as follows:
盐酸昂丹司琼是一种高选择性5-羟色胺受体拮抗剂。临床主要应用于癌症放疗和化疗以及外科手术引起的恶心、呕吐症状。Ondansetron hydrochloride is a highly selective serotonin receptor antagonist. It is mainly used clinically for nausea and vomiting symptoms caused by cancer radiotherapy and chemotherapy, as well as surgery.
2015年版《中国药典》已经收载的盐酸昂丹司琼制剂包括其片剂和小容量注射液。然而，已经发现，有诸多关于盐酸昂丹司琼小容量注射液在与质子泵抑制剂同时使用时引起配伍禁忌的问题的文献报道。例如刘春平等(刘春平等，护理实践与研究，2010年第7卷第22期下半月版第31页)发现注射用泮托拉唑钠与盐酸昂丹司琼存在配伍禁忌；邵萍(邵萍，山西医药杂志2012年1月第41卷第1期下半月第100页)亦发现泮托拉唑与盐酸昂丹司琼注射液存在配伍禁忌；刘燕(刘燕，护理实践与研究，2008年第5卷第4期上半月版第64页)发现盐酸昂丹司琼注射液与奥美拉唑存在配伍禁忌；Ondansetron hydrochloride preparations that have been recorded in the 2015 edition of "Chinese Pharmacopoeia" include its tablets and small-volume injections. However, it has been found that there are many literature reports on the problem of incompatibility of ondansetron hydrochloride small-volume injection when it is used simultaneously with proton pump inhibitors. For example Liu Chunping (Liu Chunping, Nursing Practice and Research, 2010 the 7th volume the 22nd second half month edition page 31) finds that injection pantoprazole sodium and ondansetron hydrochloride have incompatibility; Shaoping ( Shao Ping, Shanxi Medical Journal, Volume 41, Issue 1, Second Half of January, 2012, Page 100) also found that pantoprazole and ondansetron hydrochloride injection had incompatibility; Liu Yan (Liu Yan, Nursing Practice and Research , 2008, Volume 5, Issue 4, First Half Edition, Page 64) found that ondansetron hydrochloride injection and omeprazole were incompatible;
因此，提供一种具有优良药学性质的盐酸昂丹司琼注射液例如其具备高安全性例如可避免配伍禁忌，以及制备这种注射液的方法，仍是本领域技术人员非常期待的，这对于临床用药而言是非常有益的。Therefore, to provide a kind of ondansetron hydrochloride injection with excellent pharmaceutical properties, for example, it has high safety, such as avoiding incompatibility, and the method for preparing this injection, is still very much expected by those skilled in the art, which is very important for It is very beneficial for clinical medicine.
发明内容Contents of the invention
为此，本发明的目的在于提供一种新的方法来制备盐酸昂丹司琼注射液，并且期待这些方法制备的盐酸昂丹司琼注射液具有优异的药学性质例如其具备高安全性例如可避免配伍禁忌。本发明人出人意料地发现，使用本发明方法获得的盐酸昂丹司琼注射液具有一个或多个方面的优异性质。本发明基于此发现而得以完成。For this reason, the purpose of the present invention is to provide a kind of new method to prepare ondansetron hydrochloride injection, and expect the ondansetron hydrochloride injection prepared by these methods to have excellent pharmaceutical properties such as it possesses high safety such as can Avoid incompatibility. The present inventors unexpectedly found that the ondansetron hydrochloride injection obtained by using the method of the present invention has excellent properties in one or more aspects. The present invention has been accomplished based on this finding.
为此，本发明第一方面提供了一种盐酸昂丹司琼注射液，其中包含：盐酸昂丹司琼和注射用水。Therefore, the first aspect of the present invention provides an ondansetron hydrochloride injection, which comprises: ondansetron hydrochloride and water for injection.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其中盐酸昂丹司琼的浓度以昂丹司琼计为1～3mg/ml。The ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention, wherein the concentration of ondansetron hydrochloride is 1-3 mg/ml calculated as ondansetron.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其中盐酸昂丹司琼的浓度以昂丹司琼计为1.5～2.5mg/ml。The ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention, wherein the concentration of ondansetron hydrochloride is 1.5-2.5 mg/ml calculated as ondansetron.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其中盐酸昂丹司琼的浓度以昂丹司琼计为1.75～2.25mg/ml。The ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention, wherein the concentration of ondansetron hydrochloride is 1.75-2.25 mg/ml calculated as ondansetron.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其中盐酸昂丹司琼的浓度以昂丹司琼计为2mg/ml。The ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention, wherein the concentration of ondansetron hydrochloride is 2 mg/ml calculated as ondansetron.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其pH在3.0～4.0范围内，优选其pH在3.25～3.75范围内。The ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention has a pH in the range of 3.0-4.0, preferably a pH in the range of 3.25-3.75.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，为了调节pH值的需要，其中还可以包含酸碱调节剂。在一个实施方案中，所述的酸碱调节剂是盐酸或者氢氧化钠，例如1M盐酸溶液或1M氢氧化钠溶液。在一个实施方案中，所述酸碱调节剂的用量是使得所述注射液的pH在3.0～4.0范围内，优选其pH在3.25～3.75范围内。According to any embodiment of the first aspect of the present invention, the ondansetron hydrochloride injection may further contain an acid-base regulator in order to adjust the pH value. In one embodiment, the acid-base regulator is hydrochloric acid or sodium hydroxide, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution. In one embodiment, the acid-base regulator is used in an amount such that the pH of the injection is in the range of 3.0-4.0, preferably in the range of 3.25-3.75.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其是通过包括如下步骤的方法制备得到的：Ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention, which is prepared by a method comprising the following steps:
(1)取处方量的盐酸昂丹司琼原料药，加至适量的注射用水中，搅拌使药物溶解；(1) Get the ondansetron hydrochloride crude drug of prescription quantity, add in the appropriate amount of water for injection, stir to make medicine dissolve;
(2)向步骤(1)所得溶液中以药液体积计加入0.05～0.2％的针用活性炭，混合均匀，接着用酸碱调节剂调节药液的pH在6.5～7.5范围内，在室温处搅拌药液30～60分钟；(2) Add 0.05 to 0.2% activated carbon for needles in the solution obtained in step (1) based on the volume of the medicinal solution, mix well, then use an acid-base regulator to adjust the pH of the medicinal solution within the range of 6.5 to 7.5, Stir the liquid medicine for 30-60 minutes;
(3)将步骤(2)所得混合液过滤脱炭，用酸碱调节剂调节药液的pH在3.25～3.75范围内，补加注射用水至处方全量，任选的用酸碱调节剂调节药液的pH在3.25～3.75范围内；(3) Filter and decarbonize the mixed solution obtained in step (2), adjust the pH of the medicinal solution within the range of 3.25 to 3.75 with an acid-base regulator, add water for injection to the full amount of the prescription, and optionally use an acid-base regulator to adjust the drug The pH of the liquid is in the range of 3.25 to 3.75;
(4)将步骤(3)配制的药液除菌过滤，灌装入玻璃瓶中，封口，进行热压灭菌，即得。(4) The medicinal solution prepared in step (3) is sterilized and filtered, filled into a glass bottle, sealed, and sterilized by autoclaving to obtain the product.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其中步骤(1)中注射用水的用量是处方全量的50～90％，特别是60～80％。Ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention, wherein the amount of water for injection in step (1) is 50-90% of the full prescription, especially 60-80%.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其中所用的注射用水的水温在40℃以下。Ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention, wherein the water temperature of the water for injection used is below 40°C.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其中步骤(2)中针用活性炭的加入量为0.05～0.15％。Ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention, wherein the amount of activated carbon for needles added in step (2) is 0.05-0.15%.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其中步骤(2)中针用活性炭的加入量为0.1％。Ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention, wherein the amount of activated carbon for needles added in step (2) is 0.1%.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其中步骤(2)中用酸碱调节剂调节药液的pH在7.0～7.5范围内。The ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention, wherein in step (2), an acid-base regulator is used to adjust the pH of the medicinal solution within the range of 7.0-7.5.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其中步骤(2)中药液在室温处搅拌药液30～45分钟。Ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention, wherein the medicinal solution in step (2) is stirred at room temperature for 30-45 minutes.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其中步骤(3)中混合液过滤脱炭是照如下方式操作的：先用滤纸过滤，接着用孔径为1um的钛棒过滤，再用0.45um的聚醚砜滤芯将药液粗滤。According to the ondansetron hydrochloride injection of any embodiment of the first aspect of the present invention, wherein in the step (3), the mixed solution is filtered and decarbonized as follows: first filter with filter paper, and then use a titanium rod with a pore size of 1um Filter, and then use a 0.45um polyethersulfone filter element to coarsely filter the drug solution.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其中步骤(2)和步骤(3)中，所用的酸碱调节剂选自氢氧化钠、氢氧化钾、磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、磷酸氢二钾、盐酸、磷酸、硝酸、硫酸、或其组合。在一个实施方案中，所述的酸碱调节剂是盐酸溶液或者氢氧化钠溶液，特别是例如1M盐酸溶液或者1M氢氧化钠溶液。Ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention, wherein in step (2) and step (3), the acid-base regulator used is selected from sodium hydroxide, potassium hydroxide, dihydrogen phosphate Sodium, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combinations thereof. In one embodiment, the acid-base regulator is hydrochloric acid solution or sodium hydroxide solution, especially for example 1M hydrochloric acid solution or 1M sodium hydroxide solution.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其中步骤(3)中所述补加注射用水至处方全量是指补加注射用水直至活性成分浓度为1～3mg/ml(例如1.5～2.5mg/ml，例如1.75～2.25mg/ml，例如2mg/ml)的量。Ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention, wherein adding water for injection to the full amount of the prescription in step (3) refers to adding water for injection until the concentration of the active ingredient is 1-3 mg/ml (eg 1.5-2.5 mg/ml, eg 1.75-2.25 mg/ml, eg 2 mg/ml).
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其中步骤(4)中所述除菌过滤是使用0.22um的聚醚砜滤芯进行除菌过滤。The ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention, wherein the sterile filtration in step (4) is performed with a 0.22um polyethersulfone filter element.
根据本发明第一方面任一实施方案的盐酸昂丹司琼注射液，其中步骤(4)中热压灭菌处理是在121℃下灭菌处理30分钟。Ondansetron hydrochloride injection according to any embodiment of the first aspect of the present invention, wherein the autoclaving treatment in step (4) is sterilization at 121° C. for 30 minutes.
另外，本发明第二方面提供了制备盐酸昂丹司琼注射液例如本发明第一方面任一实施方案所述盐酸昂丹司琼注射液的方法，其包括如下步骤：In addition, the second aspect of the present invention provides a method for preparing ondansetron hydrochloride injection, such as the ondansetron hydrochloride injection described in any embodiment of the first aspect of the present invention, which includes the following steps:
(1)取处方量的盐酸昂丹司琼原料药，加至适量的注射用水中，搅拌使药物溶解；(1) Get the ondansetron hydrochloride crude drug of prescription quantity, add in the appropriate amount of water for injection, stir to make medicine dissolve;
(2)向步骤(1)所得溶液中以药液体积计加入0.05～0.2％的针用活性炭，混合均匀，接着用酸碱调节剂调节药液的pH在6.5～7.5范围内，在室温处搅拌药液30～60分钟；(2) Add 0.05 to 0.2% activated carbon for needles in the solution obtained in step (1) based on the volume of the medicinal solution, mix well, then use an acid-base regulator to adjust the pH of the medicinal solution within the range of 6.5 to 7.5, Stir the liquid medicine for 30-60 minutes;
(3)将步骤(2)所得混合液过滤脱炭，用酸碱调节剂调节药液的pH在3.25～3.75范围内，补加注射用水至处方全量，任选的用酸碱调节剂调节药液的pH在3.25～3.75范围内；(3) Filter and decarbonize the mixed solution obtained in step (2), adjust the pH of the medicinal solution within the range of 3.25 to 3.75 with an acid-base regulator, add water for injection to the full amount of the prescription, and optionally use an acid-base regulator to adjust the drug The pH of the liquid is in the range of 3.25 to 3.75;
(4)将步骤(3)配制的药液除菌过滤，灌装入玻璃瓶中，封口，进行热压灭菌，即得。(4) The medicinal solution prepared in step (3) is sterilized and filtered, filled into a glass bottle, sealed, and sterilized by autoclaving to obtain the product.
根据本发明第二方面任一实施方案的方法，其中步骤(1)中注射用水的用量是处方全量的50～90％，特别是60～80％。According to the method according to any embodiment of the second aspect of the present invention, the amount of water for injection in step (1) is 50-90% of the full prescription, especially 60-80%.
根据本发明第二方面任一实施方案的方法，其中所用的注射用水的水温在40℃以下。The method according to any embodiment of the second aspect of the present invention, wherein the water temperature of the water for injection used is below 40°C.
根据本发明第二方面任一实施方案的方法，其中步骤(2)中针用活性炭的加入量为0.05～0.15％。According to the method of any embodiment of the second aspect of the present invention, wherein in step (2), the amount of activated carbon for needles added is 0.05-0.15%.
根据本发明第二方面任一实施方案的方法，其中步骤(2)中针用活性炭的加入量为0.1％。According to the method of any embodiment of the second aspect of the present invention, wherein in step (2), the amount of activated carbon for needle use is 0.1%.
根据本发明第二方面任一实施方案的方法，其中步骤(2)中用酸碱调节剂调节药液的pH在7.0～7.5范围内。The method according to any embodiment of the second aspect of the present invention, wherein in step (2), an acid-base regulator is used to adjust the pH of the medicinal solution within the range of 7.0-7.5.
根据本发明第二方面任一实施方案的方法，其中步骤(2)中药液在室温处搅拌药液30～45分钟。The method according to any embodiment of the second aspect of the present invention, wherein in step (2), the medicinal solution is stirred at room temperature for 30-45 minutes.
根据本发明第二方面任一实施方案的方法，其中步骤(3)中混合液过滤脱炭是照如下方式操作的：先用滤纸过滤，接着用孔径为1um的钛棒过滤，再用0.45um的聚醚砜滤芯将药液粗滤。According to the method of any embodiment of the second aspect of the present invention, wherein in the step (3), the mixed solution is filtered and decarbonized as follows: first filter with filter paper, then filter with a titanium rod with a pore size of 1um, and then filter with a 0.45um The polyethersulfone filter element coarsely filters the liquid medicine.
根据本发明第二方面任一实施方案的方法，其中步骤(2)和步骤(3)中，所用的酸碱调节剂选自氢氧化钠、氢氧化钾、磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、磷酸氢二钾、盐酸、磷酸、硝酸、硫酸、或其组合。在一个实施方案中，所述的酸碱调节剂是盐酸溶液或者氢氧化钠溶液，特别是例如1M盐酸溶液或者1M氢氧化钠溶液。According to the method of any embodiment of the second aspect of the present invention, wherein in step (2) and step (3), the acid-base regulator used 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, sulfuric acid, or combinations thereof. In one embodiment, the acid-base regulator is hydrochloric acid solution or sodium hydroxide solution, especially for example 1M hydrochloric acid solution or 1M sodium hydroxide solution.
根据本发明第二方面任一实施方案的方法，其中步骤(3)中所述补加注射用水至处方全量是指补加注射用水直至活性成分浓度为1～3mg/ml(例如1.5～2.5mg/ml，例如1.75～2.25mg/ml，例如2mg/ml)的量。According to the method of any embodiment of the second aspect of the present invention, wherein adding water for injection to the full amount of the prescription in step (3) refers to adding water for injection until the concentration of the active ingredient is 1-3mg/ml (for example, 1.5-2.5mg /ml, such as 1.75～2.25mg/ml, such as 2mg/ml).
根据本发明第二方面任一实施方案的方法，其中步骤(4)中所述除菌过滤是使用0.22um的聚醚砜滤芯进行除菌过滤。According to the method of any embodiment of the second aspect of the present invention, wherein the sterile filtration in step (4) is to use a 0.22um polyethersulfone filter element for sterile filtration.
根据本发明第二方面任一实施方案的方法，其中步骤(4)中热压灭菌处理是在121℃下灭菌处理30分钟。The method according to any embodiment of the second aspect of the present invention, wherein the autoclaving treatment in step (4) is a sterilization treatment at 121° C. for 30 minutes.
根据本发明第二方面任一实施方案的方法，其所制得的盐酸昂丹司琼注射液中活性成分的浓度以昂丹司琼计为1～3mg/ml。According to the method of any embodiment of the second aspect of the present invention, the concentration of the active ingredient in the prepared ondansetron hydrochloride injection is 1-3 mg/ml calculated as ondansetron.
根据本发明第二方面任一实施方案的方法，其所制得的盐酸昂丹司琼注射液中活性成分的浓度以昂丹司琼计为1.5～2.5mg/ml。According to the method of any embodiment of the second aspect of the present invention, the concentration of the active ingredient in the prepared ondansetron hydrochloride injection is 1.5-2.5 mg/ml calculated as ondansetron.
根据本发明第二方面任一实施方案的方法，其所制得的盐酸昂丹司琼注射液中活性成分的浓度以昂丹司琼计为1.75～2.25mg/ml。According to the method of any embodiment of the second aspect of the present invention, the concentration of the active ingredient in the prepared ondansetron hydrochloride injection is 1.75-2.25 mg/ml calculated as ondansetron.
根据本发明第二方面任一实施方案的方法，其所制得的盐酸昂丹司琼注射液中活性成分的浓度以昂丹司琼计为2mg/ml。According to the method of any embodiment of the second aspect of the present invention, the concentration of the active ingredient in the prepared ondansetron hydrochloride injection is 2 mg/ml calculated as ondansetron.
根据本发明第二方面任一实施方案的方法，其所制得的盐酸昂丹司琼注射液pH在3.0～4.0范围内，优选其pH在3.25～3.75范围内。According to the method of any embodiment of the second aspect of the present invention, the prepared ondansetron hydrochloride injection has a pH in the range of 3.0-4.0, preferably a pH in the range of 3.25-3.75.
在本发明上述方法的步骤中，虽然其描述的具体步骤在某些细节上或者语言描述上与下文具体实施方式部分的实例中所描述的步骤有所区别，然而，本领域技术人员根据本发明全文的详细公开完全可以概括出以上所述方法步骤。In the steps of the above-mentioned methods of the present invention, although the specific steps described therein are different from the steps described in the examples of the specific embodiment section below in some details or language descriptions, those skilled in the art can according to the present invention The detailed disclosure of the full text can fully summarize the above-mentioned method steps.
本发明的任一方面的任一实施方案，可以与其它实施方案进行组合，只要它们不会出现矛盾。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们不会出现矛盾。下面对本发明作进一步的描述。Any embodiment of any aspect of the present invention may be combined with other embodiments as long as they do not contradict each other. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments, as long as there is no contradiction between them. The present invention will be further described below.
本发明所引述的所有文献，它们的全部内容通过引用并入本文，并且如果这些文献所表达的含义与本发明不一致时，以本发明的表述为准。此外，本发明使用的各种术语和短语具有本领域技术人员公知的一般含义，即便如此，本发明仍然希望在此对这些术语和短语作更详尽的说明和解释，提及的术语和短语如有与公知含义不一致的，以本发明所表述的含义为准。All the documents cited in the present invention are incorporated herein by reference in their entirety, and if the meaning expressed in these documents is inconsistent with the present invention, the expression of the present invention shall prevail. In addition, various terms and phrases used in the present invention have common meanings known to those skilled in the art. Even so, the present invention still hopes to make a more detailed description and explanation of these terms and phrases here. The terms and phrases mentioned are as follows: If there is any inconsistency with the known meaning, the meaning expressed in the present invention shall prevail.
在本发明中，如未另外说明，使用到的试剂和原料均是从市场上购得。In the present invention, unless otherwise stated, the reagents and raw materials used are purchased from the market.
根据本发明任一方面的一个实施方案，其中在制备所述盐酸昂丹司琼注射液时，在其中的步骤(2)中与活性炭一起还添加纸浆，纸浆添加量以纸的干重计为活性炭的40～60％。已经出人意料地发现，由此方式制得的盐酸昂丹司琼注射液在与多种质子泵抑制剂配伍时不会出现配伍禁忌。例如，分别照上文所述刘春平和刘燕文献方法考察述盐酸昂丹司琼注射液与注射用泮托拉唑钠和注射用奥美拉唑粉针配伍的方法，考察盐酸昂丹司琼注射液与质子泵抑制剂的配伍情况，结果显示，实施例1-7的7种注射液在与两类质子泵抑制剂配伍时均出现白色絮状物，显示这些注射液不能与质子泵抑制剂的配伍；但是实施例8所得7种注射液在与两类质子泵抑制剂配伍时均未出现上述配伍禁忌的情况。另外，从市场上购得不4批在售的盐酸昂丹司琼注射液(以产地和缩略国药准字号表示，分别为成都329、安徽842、山东029、江西340)，结果显示四种在售盐酸昂丹司琼注射液分别与两种质子泵抑制剂配伍时混合液中均出现白色絮状物。但是令人无法解释的是，对于实施例8的7种注射液，如果在制备它们的步骤中，在步骤(2)中不将药液调节到pH6.5～7.5范围内进行处理，而是直接调节到3.0～4.0范围内进行处理，则即使在制备过程中同样是活性炭与纸浆组合使用得到的7种注射液在分别与两种质子泵抑制剂配伍时混合液中均出现不同程度的白色絮状物，可见纸浆与pH的制备工艺条件对于获得具有优良性质的注射液是必不可少的。According to an embodiment of any aspect of the present invention, wherein when preparing said ondansetron hydrochloride injection, pulp is also added together with activated carbon in step (2) wherein, and the amount of pulp added is calculated by the dry weight of paper 40-60% of activated carbon. It has been unexpectedly found that the ondansetron hydrochloride injection prepared in this way does not have incompatibility when it is compatible with various proton pump inhibitors. For example, according to the methods of Liu Chunping and Liu Yan mentioned above, respectively, investigate the compatibility method of ondansetron hydrochloride injection with pantoprazole sodium for injection and omeprazole powder injection for injection, investigate the method of ondansetron hydrochloride Compatibility of Qiong injection with proton pump inhibitors, the results show that white flocs appear in the seven injections of Examples 1-7 when they are compatible with two types of proton pump inhibitors, showing that these injections cannot be combined with proton pump inhibitors. Compatibility of inhibitors; however, none of the above-mentioned incompatibility contraindications occurred when the 7 injections obtained in Example 8 were compatible with the two types of proton pump inhibitors. In addition, not four batches of ondansetron hydrochloride injection (indicated by place of origin and abbreviated national drug approval number, respectively Chengdu 329, Anhui 842, Shandong 029, and Jiangxi 340) were purchased from the market, and the results showed that four When ondansetron hydrochloride injection was mixed with two proton pump inhibitors respectively, white flocs appeared in the mixed solution. However, what is inexplicable is that, for the 7 kinds of injection solutions in Example 8, if in the step of preparing them, the medicinal solution is not adjusted to the pH range of 6.5-7.5 for processing in step (2), but If it is directly adjusted to the range of 3.0 to 4.0 for treatment, even if the seven kinds of injections obtained by using activated carbon and pulp in the preparation process are also compatible with the two proton pump inhibitors, the mixtures will appear white to varying degrees. The preparation process conditions of floc, visible pulp and pH are essential to obtain injections with excellent properties.
本发明盐酸昂丹司琼注射液用于控制癌症化疗和放射治疗引起的恶心和呕吐；亦适用于预防和手术后恶心呕吐。对于儿童患者而言，4岁以上儿童：控制癌症化疗和放疗引起的恶心和呕吐；4岁以下儿童：控制癌症化疗引起的恶心呕吐；2岁以上儿童：预防和治疗手术后的恶心呕吐。The ondansetron hydrochloride injection of the present invention is used for controlling nausea and vomiting caused by cancer chemotherapy and radiotherapy; it is also suitable for preventing and postoperative nausea and vomiting. For children, children over 4 years old: control nausea and vomiting caused by cancer chemotherapy and radiotherapy; children under 4 years old: control nausea and vomiting caused by cancer chemotherapy; children over 2 years old: prevent and treat nausea and vomiting after surgery.
本发明盐酸昂丹司琼注射液由化疗和放射治疗引起的恶心呕吐时，可肌肉注射和静脉注射。成人(由化疗和放射治疗引起的恶心呕吐)时，起始治疗，通常放疗和化疗前使用剂量为8mg,使用如下：注射溶液：治疗前立即缓慢静注或肌注本品8mg。某些病例(使用高致吐性细胞毒药和/或极高处方剂量；存在病人个体相关因素，如先前进行细胞毒药治疗时出现呕吐的年轻病人、女性病人，等等)需要更高的初始剂量。对于高致吐性化疗，盐酸昂丹司琼注射液最大起始剂量为16毫克，静脉输注时间15分钟。单次静脉给药剂量不应超过16毫克。对于高致吐性化疗，在化疗前静脉输注单剂地塞米松磷酸钠20毫克，可增强盐酸昂丹司琼注射液的疗效。盐酸昂丹司琼注射液剂量高于8毫克至16毫克时，静脉输注前使用0.9％生理盐水或5％葡萄糖溶液50-100毫升进行稀释，输注时间不少于15分钟。盐酸昂丹司琼注射液8毫克或以下剂量不需要稀释，可缓慢(不得少于30秒)肌肉或静脉注射。在盐酸昂丹司琼注射液首次给药之后间隔2至4小时，可以附加2次静脉或肌肉给药8毫克，或者恒速静脉输注1毫克/小时，持续24小时。继续治疗(预防迟发性或延迟性呕吐)时，次日每12小时口服本品8mg片剂等口服制剂2-3天，最长可能达5天。When the ondansetron hydrochloride injection of the present invention is caused by chemotherapy and radiotherapy, it can be injected intramuscularly or intravenously. For adults (nausea and vomiting caused by chemotherapy and radiotherapy), the initial treatment is usually 8 mg before radiotherapy and chemotherapy, as follows: injection solution: slow intravenous or intramuscular injection of 8 mg of this product immediately before treatment. Certain cases (use of highly emetogenic cytotoxics and/or very high prescribed doses; individual patient-related factors such as young patients who vomited on previous cytotoxic therapy, female patients, etc.) require higher initial doses . For highly emetogenic chemotherapy, the maximum initial dose of ondansetron hydrochloride injection is 16 mg, and the intravenous infusion time is 15 minutes. A single intravenous dose should not exceed 16 mg. For highly emetogenic chemotherapy, intravenous infusion of a single dose of dexamethasone sodium phosphate 20 mg before chemotherapy can enhance the efficacy of ondansetron hydrochloride injection. When the dose of ondansetron hydrochloride injection is higher than 8 mg to 16 mg, it should be diluted with 50-100 ml of 0.9% normal saline or 5% glucose solution before intravenous infusion, and the infusion time should not be less than 15 minutes. Ondansetron hydrochloride injection 8 mg or less does not need to be diluted, and can be injected slowly (not less than 30 seconds) intramuscularly or intravenously. Two additional intravenous or intramuscular doses of 8 mg, or a constant rate intravenous infusion of 1 mg/hour for 24 hours, may be given at intervals of 2 to 4 hours after the first dose of ondansetron hydrochloride injection. When continuing treatment (prevention of delayed or delayed vomiting), oral preparations such as 8 mg tablets of this product are taken orally every 12 hours the next day for 2-3 days, up to a maximum of 5 days.
药理作用方面，昂丹司琼是一种选择性5HT3受体拮抗剂，虽然昂丹司琼的作用机制还未完全研究清楚，但其不是多巴胺受体拮抗剂。化疗药物和放射治疗可造成小肠释放5-HT，经由5-HT受体激活迷走神经的传入支，触发呕吐反射。迷走神经传入支的激动也可引起位于第四脑室底部后区的5-HT释放，从而经过中枢机制而加强。昂丹司琼能阻断这一反射的触发，对化疗、放疗引起的恶心、呕吐，可能通过拮抗位于周围和中枢神经局部的神经元的5-HT3受体而发挥作用。In terms of pharmacological action, ondansetron is a selective 5HT3 receptor antagonist. Although the mechanism of action of ondansetron has not been fully studied, it is not a dopamine receptor antagonist. Chemotherapy drugs and radiation therapy can cause the small intestine to release 5-HT, which activates the afferent branch of the vagus nerve through 5-HT receptors and triggers the gag reflex. Activation of the afferent branches of the vagus nerve can also cause the release of 5-HT in the posterior region of the fourth ventricle floor, which can be enhanced through central mechanisms. Ondansetron can block the triggering of this reflex, and it may play a role in the nausea and vomiting caused by chemotherapy and radiotherapy by antagonizing the 5-HT3 receptors of neurons located in the peripheral and central nervous system.
毒理研究方面，急性毒性试验显示昂丹司琼未见明显的系统性和组织特异性毒性。大鼠研究中经口给药10mg/kg，未观察到任何作用，当剂量增加为80mg/kg时，出现中度的行为改变，但无动物死亡。大鼠静脉注射的最大非致死剂量为15mg/kg。大鼠连续经口给药昂丹司琼达18个月，仅在高血药浓度达1407ng/ml时出现行为改变。因此可以认为在药物治疗剂量下无毒性。In terms of toxicology studies, acute toxicity tests showed that ondansetron had no obvious systemic and tissue-specific toxicity. Oral administration of 10 mg/kg in the rat study did not observe any effect. When the dose was increased to 80 mg/kg, moderate behavioral changes occurred, but no animals died. The maximum non-lethal dose of intravenous injection in rats is 15mg/kg. Rats were continuously orally administered ondansetron for 18 months, and behavioral changes occurred only at high blood levels of 1407 ng/ml. It can therefore be considered non-toxic at therapeutic doses of the drug.
在常规致突变性试验中显示昂丹司琼无致突变性。雄性和雌性大鼠经口给药昂丹司琼达0.15mg/kg/天(约为推荐人体静脉注射剂量的3.8倍，按体表面积计)，显示对雄性和雌性大鼠生育力或一般生殖能力无影响。在受孕大鼠和家兔静脉注射给药昂丹司琼剂量高达4mg/kg/天，分别大约为推荐人体静脉注射剂量(0.15mg/kg，每天3次，以体表面积计)的1.4和2.9倍，显示昂丹司琼不会对胎仔造成损伤。在大鼠和小鼠的2年试验研究中，经口给药昂丹司琼的剂量高达10和30mg/kg/天，相当于推荐人体静脉注射剂量(0.15mg/kg，每天3次，按体表面积计)的3.6和5.4倍，结果显示无致癌作用。QT间期延长，在克隆的人体心脏离子通道试验中，临床使用剂量的昂丹司琼可阻断hERG钾通道从而影响心脏复极化的潜在作用。在健康志愿者的全面QT研究中，也观察到剂量依赖性的QT延长。在58名健康男女性受试者参加的双盲、随机、安慰剂和阳性药物(莫西沙星)对照、交叉研究中，评估了昂丹司琼单次给药对QTc间期的影响。昂丹司琼的给药剂量为8mg和32mg静脉输注15分钟。在给予最高研究剂量32mg后，基线校正后QTcF间期与安慰剂差异的最大平均值(95％CI的上限)为19.5(21.8)msec。在给予最低研究剂量8mg后，基线校正后QTcF间期与安慰剂差异的最大平均值(95％CI的上限)为5.6(7.4)ms。在这项研究中，没有出现QTcF值大于480ms，也没有出现QTcF延长大于60ms。昂丹司琼浓度和ΔΔQTcF之间存在确定的明显的暴露-效应关系。根据确立的暴露-效应关系，预测昂丹司琼24mg静脉输注15min，ΔΔQTcF平均值(95％CI的上限)为14.0(16.3)ms。反之，昂丹司琼16mg静脉输注15min，ΔΔQTcF平均值(95％CI的上限)为9.1(11.2)ms。Ondansetron was not shown to be mutagenic in conventional mutagenicity tests. Oral administration of ondansetron to male and female rats up to 0.15 mg/kg/day (approximately 3.8 times the recommended human intravenous dose, based on body surface area) showed no effect on male and female rat fertility or general reproduction Ability has no effect. Intravenous administration of ondansetron doses up to 4 mg/kg/day in pregnant rats and rabbits is approximately 1.4 and 2.9 of the recommended human intravenous dose (0.15 mg/kg, 3 times a day, based on body surface area), respectively. times, showing that ondansetron does not cause harm to the fetus. In a 2-year experimental study in rats and mice, ondansetron was administered orally at doses up to 10 and 30 mg/kg/day, equivalent to the recommended human intravenous dose (0.15 mg/kg, 3 times a day, as Body surface area) 3.6 and 5.4 times, the results showed no carcinogenic effect. QT interval prolongation, clinically used doses of ondansetron can block hERG potassium channels and thus affect cardiac repolarization potential in cloned human cardiac ion channel assays. In a comprehensive QT study in healthy volunteers, a dose-dependent QT prolongation was also observed. The effect of a single dose of ondansetron on the QTc interval was evaluated in a double-blind, randomized, placebo- and active drug (moxifloxacin)-controlled, crossover study involving 58 healthy male and female subjects. Ondansetron is administered in doses of 8 mg and 32 mg intravenously over 15 minutes. After the highest study dose of 32 mg, the maximum mean (upper limit of the 95% CI) difference in the baseline-adjusted QTcF interval from placebo was 19.5 (21.8) msec. After the lowest study dose of 8 mg, the maximum mean (upper limit of the 95% CI) difference in the baseline-adjusted QTcF interval from placebo was 5.6 (7.4) ms. In this study, there were no QTcF values greater than 480 ms and no QTcF prolongation greater than 60 ms. There was a well established and significant exposure-response relationship between ondansetron concentration and ΔΔQTcF. Based on the established exposure-response relationship, the predicted mean ΔΔQTcF (upper limit of 95% CI) of ondansetron 24 mg intravenous infusion over 15 minutes was 14.0 (16.3) ms. On the contrary, ondansetron 16mg intravenous infusion 15min, ΔΔQTcF mean (upper limit of 95% CI) was 9.1 (11.2) ms.
药代动力学方面，一次静脉给药4毫克，在5分钟内给药，达到的血浆峰浓度约为65纳克/毫升。4毫克肌肉注射给药后，在注射后10分钟内达血浆峰浓度(约为25纳克/毫升)。肌肉注射4毫克和静脉注射4毫克后，其系统暴露是等同的。昂丹司琼口服、肌肉注射或静脉注射后半衰期无明显差异，半衰期约为3小时，稳态分布容积约为140升。In terms of pharmacokinetics, once intravenous administration of 4 mg within 5 minutes, the peak plasma concentration reached is about 65 ng/ml. After intramuscular injection of 4 mg, the peak plasma concentration (approximately 25 ng/ml) was reached within 10 minutes after injection. Systemic exposures were equivalent after intramuscular injection of 4 mg and intravenous injection of 4 mg. There is no significant difference in the half-life of ondansetron after oral administration, intramuscular injection or intravenous injection, the half-life is about 3 hours, and the steady-state volume of distribution is about 140 liters.
昂丹司琼的蛋白结合率为70-76％。昂丹司琼通过不同的代谢途径，主要为肝脏代谢后从循环中清除。从尿中排出的原形药量小于摄入剂量的5％。缺乏酶CYP2D6(异喹胍多态性)不影响昂丹司琼的药代动力学。重复给药其药代动力学也无改变。The protein binding of ondansetron is 70-76%. Ondansetron is eliminated from circulation by different metabolic pathways, mainly after hepatic metabolism. The amount of unchanged drug excreted in urine is less than 5% of the ingested dose. The absence of the enzyme CYP2D6 (isoquineguanine polymorphism) did not affect the pharmacokinetics of ondansetron. The pharmacokinetics of repeated administration did not change.
健康老年人早期I期研究显示，有轻微的年龄相关性昂丹司琼清除率降低和半衰期延长。但广泛的受试者间变异导致年轻受试者(<65岁)与老年受试者(≥65岁)之间药代动力学参数有相当部分的重叠，在CINV临床试验纳入的年轻癌症患者与老年癌症患者之间没有观察到明显的安全性和有效性差异，没有支持老年癌症患者应用不同剂量的证据。An early phase I study in healthy older adults showed a slight age-related decrease in clearance and increased half-life of ondansetron. However, extensive inter-subject variability results in considerable overlap in pharmacokinetic parameters between young subjects (<65 years) and elderly subjects (≥65 years), and young cancer patients included in CINV clinical trials No significant differences in safety and efficacy were observed with elderly cancer patients, and there is no evidence to support different doses in elderly cancer patients.
根据近期昂丹司琼血浆浓度和暴露-效应模型，与年轻成人相比较，在≥75岁患者中预期有更大的QTcF效应。对65岁以上患者和75岁以上患者提供了特殊给药信息。Based on recent ondansetron plasma concentrations and exposure-effect modeling, a greater QTcF effect is expected in patients ≥75 years of age compared with young adults. Special dosing information is provided for patients over 65 years of age and for patients over 75 years of age.
可观察到昂丹司琼的利用度具有性别差异，女性口服后的吸收速率和程度较高，全身清除和容积分布较低(经体重调整)。Gender differences in the availability of ondansetron were observed, with females having a higher rate and extent of oral absorption and lower systemic clearance and volume distribution (weight-adjusted).
在一项试验中，月龄1-4个月的儿童(n＝19)接受外科手术后，经体重标准化的药物清除率，比在5-24个月的儿童(n＝22)慢月30％，但是与3-12岁的儿童相似。药物半衰期，在月龄1-4个月的儿童中平均为6.7小时，在5-24个月的儿童和3-12岁的儿童中为2.9小时。对于月龄在1-4个月的儿童的药代动力学参数出现的差异性，可能是因为在婴儿中水分占总体中的百分比更高，所以水溶性药物，如昂丹司琼的分布容积更大。In one trial, children 1-4 months of age (n=19) had a body weight-normalized drug clearance that was 30 months slower than children 5-24 months of age (n=22) following surgical procedures. %, but similar to children aged 3-12. The half-life of the drug averages 6.7 hours in children aged 1-4 months, and 2.9 hours in children aged 5-24 months and children aged 3-12 years. The differences in pharmacokinetic parameters for children aged 1-4 months may be due to the higher percentage of water in infants, so the volume of distribution of water-soluble drugs, such as ondansetron bigger.
进行性择期外科手术和全身麻醉的3-12岁儿童患者，其清除和分布容积的绝对值较成年人是下降的。两组数据随体重增加而呈线性增加，其数值12岁接近年轻成年人水平。当用体重将消除率和分布容积标准化后，其数值在不同年龄群是相似的。按体重给药可弥补年龄相关性的改变，有效的使儿童患者系统暴露标准化。Pediatric patients aged 3-12 years who underwent elective surgery and general anesthesia had decreased absolute values of clearance and volume of distribution compared with adults. The two groups of data increased linearly with weight gain, and the value was close to the level of young adults at 12 years old. When the elimination rate and volume of distribution were normalized by body weight, the values were similar across age groups. Weight-based dosing compensates for age-related changes and effectively normalizes systemic exposure in pediatric patients.
对428例受试者(包括癌症患者、手术患者以及健康志愿者)进行了群体药代动力学分析。受试者年龄为1个月到44岁，接受静脉注射昂丹司琼。分析结果显示，除了月龄为1-4个月的婴儿外，儿童和青少年口服或注射昂丹司琼的药物系统暴露量(AUC)与成人相当。本品的药物分布容积呈年龄相关性，成人的药物分布容积比婴儿和儿童低。除了月龄为1-4个月的婴儿外，本品的清除率与体重而非年龄呈相关性。由于进入1-4个月年龄组的受试者数量太少，不能肯定本品的清除率在婴儿中是否与年龄呈相关性降低，或仅是研究本身固有的变异。由于6个月以下的儿童进行手术后恶心呕吐的预防和治疗时只是单剂量给药，清除率的降低不具有临床相关性。A population pharmacokinetic analysis was performed on 428 subjects (including cancer patients, surgical patients and healthy volunteers). Participants, aged 1 month to 44 years, received intravenous ondansetron. The results of the analysis showed that, except for infants aged 1-4 months, the systemic exposure (AUC) of ondansetron to children and adolescents by oral or injection was comparable to that of adults. The drug distribution volume of this product is age-related, and the drug distribution volume of adults is lower than that of infants and children. Except for infants aged 1-4 months, the clearance of this product was related to body weight rather than age. Due to the small number of subjects entered into the 1-4 month age group, it cannot be determined whether the clearance of the product is reduced in relation to age in infants or is simply a variation inherent in the studies themselves. Since a single dose was administered for the prophylaxis and treatment of postoperative nausea and vomiting in children younger than 6 months, the reduction in clearance was not clinically relevant.
中度肾功能受损的患者(肌酐清除率15-60ml/min),其系统清除率及分布容积降低。可造成消除半衰期(T1/2 5.4小时)稍有增加，但无临床意义。对需定期血液透析的重症肾损害病人的研究显示，在血液透析间期测定的昂丹司琼的药代动力学基本无改变。在严重肝损害患者，昂丹司琼全身清除率明显降低，消除半衰期延长至15-32小时。In patients with moderately impaired renal function (creatinine clearance 15-60ml/min), systemic clearance and volume of distribution are reduced. It can cause a slight increase in the elimination half-life (T1/2 5.4 hours), but it has no clinical significance. Studies in patients with severe renal impairment requiring regular hemodialysis showed that the pharmacokinetics of ondansetron measured between hemodialysis were essentially unchanged. In patients with severe hepatic impairment, the systemic clearance of ondansetron was significantly reduced, and the elimination half-life was prolonged to 15-32 hours.
本发明的积极进步效果在于：本发明的方法可以有效的用于制备具有优异性能的盐酸昂丹司琼注射液，具有良好的市场应用前景。The positive progress effect of the present invention is that: the method of the present invention can be effectively used to prepare ondansetron hydrochloride injection with excellent performance, and has a good market application prospect.
具体实施方式Detailed ways
通过下面的实施例可以对本发明进行进一步的描述，然而，本发明的范围并不限于下述实施例。本领域的专业人员能够理解，在不背离本发明的精神和范围的前提下，可以对本发明进行各种变化和修饰。本发明对试验中所使用到的材料以及试验方法进行一般性和/或具体的描述。虽然为实现本发明目的所使用的许多材料和操作方法是本领域公知的，但是本发明仍然在此作尽可能详细描述。以下实施例进一步说明本发明，而不是限制本发明。The present invention can be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art can understand that various changes and modifications can be made in the present invention without departing from the spirit and scope of the present invention. The present invention provides general and/or specific descriptions of the materials and test methods used in the tests. While many of the materials and methods of manipulation which are employed for the purposes of the invention are well known in the art, the invention has been described here in as much detail as possible. The following examples further illustrate the invention without limiting it.
下文制备步骤为了举例的目的，并基于各举例的可比较性而作了某些具体描述，本领域技术人员根据已有知识完全可以从中概括得到本发明方案。下面在配制盐酸昂丹司琼注射液时使用同一批次的盐酸昂丹司琼原料药。在下面配制盐酸昂丹司琼注射液时，以每1ml的量列明处方，但是在实际投料时，每一批次物料量为5000ml的量。The following preparation steps are for the purpose of illustration and based on the comparability of each example, some specific descriptions are made, and those skilled in the art can fully obtain the scheme of the present invention based on the existing knowledge. The same batch of ondansetron hydrochloride crude drug is used below when preparing ondansetron hydrochloride injection. When preparing ondansetron hydrochloride injection below, the prescription is listed in the amount of 1ml, but in actual feeding, the amount of each batch of material is 5000ml.
在下面配制盐酸昂丹司琼注射液时，如未另外说明，使用到的酸碱调节剂是1M盐酸溶液或1M氢氧化钠溶液。When preparing ondansetron hydrochloride injection below, unless otherwise specified, the acid-base regulator used is 1M hydrochloric acid solution or 1M sodium hydroxide solution.
实施例1：配制盐酸昂丹司琼注射液Embodiment 1: preparation of ondansetron hydrochloride injection
配方：formula:
盐酸昂丹司琼(以昂丹司琼计)，2mg/ml；Ondansetron hydrochloride (calculated as ondansetron), 2mg/ml;
注射用水，适量，加至1ml。Water for injection, appropriate amount, added to 1ml.
制法：Preparation method:
(1)取处方量的盐酸昂丹司琼原料药，加至配制量75％的注射用水(40℃以下，下同)中，搅拌使药物溶解；(1) Take the ondansetron hydrochloride crude drug of the prescribed amount, add it to water for injection (below 40°C, the same below) with a preparation amount of 75%, and stir to dissolve the drug;
(2)向步骤(1)所得溶液中以药液体积计加入0.1％的针用活性炭，混合均匀，接着用酸碱调节剂调节药液的pH在7.0～7.5范围内，在室温处搅拌药液45分钟；(2) Add 0.1% activated carbon for needles in the solution obtained in step (1) based on the volume of the medicinal solution, mix uniformly, then adjust the pH of the medicinal solution with an acid-base regulator in the range of 7.0 to 7.5, and stir the medicinal solution at room temperature 45 minutes;
(3)将步骤(2)所得混合液过滤脱炭(操作法：先用滤纸过滤，接着用孔径为1um的钛棒过滤，再用0.45um的聚醚砜滤芯将药液粗滤)，用酸碱调节剂调节药液的pH在3.25～3.75范围内，补加注射用水至处方全量，任选的用酸碱调节剂调节药液的pH在3.25～3.75范围内；(3) Decarbonize the mixed solution obtained in step (2) by filtration (operation method: first filter with filter paper, then filter with a titanium rod with a pore size of 1um, and then use a 0.45um polyethersulfone filter element to coarsely filter the medicinal solution), use An acid-base regulator is used to adjust the pH of the medicinal solution within the range of 3.25 to 3.75, add water for injection to the full amount of the prescription, and optionally use an acid-base regulator to adjust the pH of the medicinal solution within the range of 3.25 to 3.75;
(4)将步骤(3)配制的药液用0.22um的聚醚砜滤芯除菌过滤，灌装入玻璃瓶中，封口，进行热压灭菌(121℃下灭菌处理30分钟)，即得。(4) The medicinal solution prepared in step (3) is sterilized and filtered with a 0.22um polyethersulfone filter element, filled into a glass bottle, sealed, and autoclaved (sterilized at 121°C for 30 minutes), namely have to.
实施例2：配制盐酸昂丹司琼注射液Embodiment 2: preparation of ondansetron hydrochloride injection
配方：formula:
盐酸昂丹司琼(以昂丹司琼计)，1mg/ml；Ondansetron hydrochloride (calculated as ondansetron), 1mg/ml;
注射用水，适量，加至1ml。Water for injection, appropriate amount, added to 1ml.
制法：Preparation method:
(1)取处方量的盐酸昂丹司琼原料药，加至配制量90％的注射用水(40℃以下，下同)中，搅拌使药物溶解；(1) Take the ondansetron hydrochloride crude drug of the prescribed amount, add it to water for injection (below 40°C, the same below) with a preparation amount of 90%, and stir to dissolve the drug;
(2)向步骤(1)所得溶液中以药液体积计加入0.05％的针用活性炭，混合均匀，接着用酸碱调节剂调节药液的pH在6.5～7.0范围内，在室温处搅拌药液30分钟；(2) Add 0.05% activated carbon for needles in the solution obtained in step (1) based on the volume of the medicinal solution, mix well, then use an acid-base regulator to adjust the pH of the medicinal solution within the range of 6.5 to 7.0, and stir the medicinal solution at room temperature solution for 30 minutes;
(3)将步骤(2)所得混合液过滤脱炭(操作法：先用滤纸过滤，接着用孔径为1um的钛棒过滤，再用0.45um的聚醚砜滤芯将药液粗滤)，用酸碱调节剂调节药液的pH在3.0～3.5范围内，补加注射用水至处方全量，任选的用酸碱调节剂调节药液的pH在3.0～3.5范围内；(3) Decarbonize the mixed solution obtained in step (2) by filtration (operation method: first filter with filter paper, then filter with a titanium rod with a pore size of 1um, and then use a 0.45um polyethersulfone filter element to coarsely filter the medicinal solution), use An acid-base regulator is used to adjust the pH of the medicinal solution within the range of 3.0 to 3.5, add water for injection to the full amount of the prescription, and optionally use an acid-base regulator to adjust the pH of the medicinal solution within the range of 3.0 to 3.5;
(4)将步骤(3)配制的药液用0.22um的聚醚砜滤芯除菌过滤，灌装入玻璃瓶中，封口，进行热压灭菌(121℃下灭菌处理30分钟)，即得。(4) The medicinal solution prepared in step (3) is sterilized and filtered with a 0.22um polyethersulfone filter element, filled into a glass bottle, sealed, and autoclaved (sterilized at 121°C for 30 minutes), namely have to.
实施例3：配制盐酸昂丹司琼注射液Embodiment 3: preparation of ondansetron hydrochloride injection
配方：formula:
盐酸昂丹司琼(以昂丹司琼计)，3mg/ml；Ondansetron hydrochloride (calculated as ondansetron), 3mg/ml;
注射用水，适量，加至1ml。Water for injection, appropriate amount, added to 1ml.
制法：Preparation method:
(1)取处方量的盐酸昂丹司琼原料药，加至配制量50％的注射用水(40℃以下，下同)中，搅拌使药物溶解；(1) Take the ondansetron hydrochloride crude drug of the prescribed amount, add it to water for injection (below 40°C, the same below) with a preparation amount of 50%, and stir to dissolve the drug;
(2)向步骤(1)所得溶液中以药液体积计加入0.2％的针用活性炭，混合均匀，接着用酸碱调节剂调节药液的pH在6.5～7.0范围内，在室温处搅拌药液60分钟；(2) Add 0.2% activated carbon for needles in the solution obtained in step (1) based on the volume of the medicinal solution, mix well, then use an acid-base regulator to adjust the pH of the medicinal solution within the range of 6.5 to 7.0, and stir the medicinal solution at room temperature 60 minutes;
(3)将步骤(2)所得混合液过滤脱炭(操作法：先用滤纸过滤，接着用孔径为1um的钛棒过滤，再用0.45um的聚醚砜滤芯将药液粗滤)，用酸碱调节剂调节药液的pH在3.5～4.0范围内，补加注射用水至处方全量，任选的用酸碱调节剂调节药液的pH在3.5～4.0范围内；(3) Decarbonize the mixed solution obtained in step (2) by filtration (operation method: first filter with filter paper, then filter with a titanium rod with a pore size of 1um, and then use a 0.45um polyethersulfone filter element to coarsely filter the medicinal solution), use An acid-base regulator is used to adjust the pH of the medicinal solution within the range of 3.5-4.0, add water for injection to the full amount of the prescription, and optionally use an acid-base regulator to adjust the pH of the medicinal solution within the range of 3.5-4.0;
(4)将步骤(3)配制的药液用0.22um的聚醚砜滤芯除菌过滤，灌装入玻璃瓶中，封口，进行热压灭菌(121℃下灭菌处理30分钟)，即得。(4) The medicinal solution prepared in step (3) is sterilized and filtered with a 0.22um polyethersulfone filter element, filled into a glass bottle, sealed, and autoclaved (sterilized at 121°C for 30 minutes), namely have to.
实施例4：配制盐酸昂丹司琼注射液Embodiment 4: preparation of ondansetron hydrochloride injection
配方：formula:
盐酸昂丹司琼(以昂丹司琼计)，1.5mg/ml；Ondansetron hydrochloride (calculated as ondansetron), 1.5mg/ml;
注射用水，适量，加至1ml。Water for injection, appropriate amount, added to 1ml.
制法：Preparation method:
(1)取处方量的盐酸昂丹司琼原料药，加至配制量60％的注射用水(40℃以下，下同)中，搅拌使药物溶解；(1) Take the ondansetron hydrochloride crude drug of the prescribed amount, add it to water for injection (below 40°C, the same below) with a preparation amount of 60%, and stir to dissolve the drug;
(2)向步骤(1)所得溶液中以药液体积计加入0.15％的针用活性炭，混合均匀，接着用酸碱调节剂调节药液的pH在6.7～7.2范围内，在室温处搅拌药液40分钟；(2) In the solution gained in step (1), add 0.15% activated carbon for needles by the volume of the medicinal solution, mix well, then adjust the pH of the medicinal solution with an acid-base regulator in the range of 6.7 to 7.2, and stir the medicinal solution at room temperature solution for 40 minutes;
(3)将步骤(2)所得混合液过滤脱炭(操作法：先用滤纸过滤，接着用孔径为1um的钛棒过滤，再用0.45um的聚醚砜滤芯将药液粗滤)，用酸碱调节剂调节药液的pH在3.3～3.7范围内，补加注射用水至处方全量，任选的用酸碱调节剂调节药液的pH在3.3～3.7范围内；(3) Decarbonize the mixed solution obtained in step (2) by filtration (operation method: first filter with filter paper, then filter with a titanium rod with a pore size of 1um, and then use a 0.45um polyethersulfone filter element to coarsely filter the medicinal solution), use An acid-base regulator is used to adjust the pH of the medicinal solution within the range of 3.3 to 3.7, add water for injection to the full amount of the prescription, and optionally use an acid-base regulator to adjust the pH of the medicinal solution within the range of 3.3 to 3.7;
(4)将步骤(3)配制的药液用0.22um的聚醚砜滤芯除菌过滤，灌装入玻璃瓶中，封口，进行热压灭菌(121℃下灭菌处理30分钟)，即得。(4) The medicinal solution prepared in step (3) is sterilized and filtered with a 0.22um polyethersulfone filter element, filled into a glass bottle, sealed, and autoclaved (sterilized at 121°C for 30 minutes), namely have to.
实施例5：配制盐酸昂丹司琼注射液Embodiment 5: preparation of ondansetron hydrochloride injection
配方：formula:
盐酸昂丹司琼(以昂丹司琼计)，2.5mg/ml；Ondansetron hydrochloride (calculated as ondansetron), 2.5mg/ml;
注射用水，适量，加至1ml。Water for injection, appropriate amount, added to 1ml.
制法：Preparation method:
(1)取处方量的盐酸昂丹司琼原料药，加至配制量80％的注射用水(40℃以下，下同)中，搅拌使药物溶解；(1) Take the ondansetron hydrochloride crude drug of the prescribed amount, add it to water for injection (below 40°C, the same below) with a preparation amount of 80%, and stir to dissolve the drug;
(2)向步骤(1)所得溶液中以药液体积计加入0.1％的针用活性炭，混合均匀，接着用酸碱调节剂调节药液的pH在6.7～7.2范围内，在室温处搅拌药液35分钟；(2) Add 0.1% activated carbon for needles in the solution obtained in step (1) based on the volume of the medicinal solution, mix uniformly, then use an acid-base regulator to adjust the pH of the medicinal solution within the range of 6.7 to 7.2, and stir the medicinal solution at room temperature solution for 35 minutes;
(3)将步骤(2)所得混合液过滤脱炭(操作法：先用滤纸过滤，接着用孔径为1um的钛棒过滤，再用0.45um的聚醚砜滤芯将药液粗滤)，用酸碱调节剂调节药液的pH在3.5～3.8范围内，补加注射用水至处方全量，任选的用酸碱调节剂调节药液的pH在3.5～3.8范围内；(3) Decarbonize the mixed solution obtained in step (2) by filtration (operation method: first filter with filter paper, then filter with a titanium rod with a pore size of 1um, and then use a 0.45um polyethersulfone filter element to coarsely filter the medicinal solution), use An acid-base regulator is used to adjust the pH of the medicinal solution within the range of 3.5 to 3.8, add water for injection to the full amount of the prescription, and optionally use an acid-base regulator to adjust the pH of the medicinal solution within the range of 3.5 to 3.8;
(4)将步骤(3)配制的药液用0.22um的聚醚砜滤芯除菌过滤，灌装入玻璃瓶中，封口，进行热压灭菌(121℃下灭菌处理30分钟)，即得。(4) The medicinal solution prepared in step (3) is sterilized and filtered with a 0.22um polyethersulfone filter element, filled into a glass bottle, sealed, and autoclaved (sterilized at 121°C for 30 minutes), namely have to.
实施例6：配制盐酸昂丹司琼注射液Embodiment 6: preparation of ondansetron hydrochloride injection
配方：formula:
盐酸昂丹司琼(以昂丹司琼计)，1.75mg/ml；Ondansetron hydrochloride (calculated as ondansetron), 1.75mg/ml;
注射用水，适量，加至1ml。Water for injection, appropriate amount, added to 1ml.
制法：Preparation method:
(1)取处方量的盐酸昂丹司琼原料药，加至配制量70％的注射用水(40℃以下，下同)中，搅拌使药物溶解；(1) Take the ondansetron hydrochloride crude drug of the prescribed amount, add it to water for injection (below 40°C, the same below) with a preparation amount of 70%, and stir to dissolve the drug;
(2)向步骤(1)所得溶液中以药液体积计加入0.15％的针用活性炭，混合均匀，接着用酸碱调节剂调节药液的pH在6.7～7.2范围内，在室温处搅拌药液55分钟；(2) In the solution gained in step (1), add 0.15% activated carbon for needles by the volume of the medicinal solution, mix well, then adjust the pH of the medicinal solution with an acid-base regulator in the range of 6.7 to 7.2, and stir the medicinal solution at room temperature 55 minutes;
(3)将步骤(2)所得混合液过滤脱炭(操作法：先用滤纸过滤，接着用孔径为1um的钛棒过滤，再用0.45um的聚醚砜滤芯将药液粗滤)，用酸碱调节剂调节药液的pH在3.3～3.7范围内，补加注射用水至处方全量，任选的用酸碱调节剂调节药液的pH在3.3～3.7范围内；(3) Decarbonize the mixed solution obtained in step (2) by filtration (operation method: first filter with filter paper, then filter with a titanium rod with a pore size of 1um, and then use a 0.45um polyethersulfone filter element to coarsely filter the medicinal solution), use An acid-base regulator is used to adjust the pH of the medicinal solution within the range of 3.3 to 3.7, add water for injection to the full amount of the prescription, and optionally use an acid-base regulator to adjust the pH of the medicinal solution within the range of 3.3 to 3.7;
(4)将步骤(3)配制的药液用0.22um的聚醚砜滤芯除菌过滤，灌装入玻璃瓶中，封口，进行热压灭菌(121℃下灭菌处理30分钟)，即得。(4) The medicinal solution prepared in step (3) is sterilized and filtered with a 0.22um polyethersulfone filter element, filled into a glass bottle, sealed, and autoclaved (sterilized at 121°C for 30 minutes), namely have to.
实施例7：配制盐酸昂丹司琼注射液Embodiment 7: preparation of ondansetron hydrochloride injection
配方：formula:
盐酸昂丹司琼(以昂丹司琼计)，2.25mg/ml；Ondansetron hydrochloride (calculated as ondansetron), 2.25mg/ml;
注射用水，适量，加至1ml。Water for injection, appropriate amount, added to 1ml.
制法：Preparation method:
(1)取处方量的盐酸昂丹司琼原料药，加至配制量75％的注射用水(40℃以下，下同)中，搅拌使药物溶解；(1) Take the ondansetron hydrochloride crude drug of the prescribed amount, add it to water for injection (below 40°C, the same below) with a preparation amount of 75%, and stir to dissolve the drug;
(2)向步骤(1)所得溶液中以药液体积计加入0.1％的针用活性炭，混合均匀，接着用酸碱调节剂调节药液的pH在7.0～7.5范围内，在室温处搅拌药液40分钟；(2) Add 0.1% activated carbon for needles in the solution obtained in step (1) based on the volume of the medicinal solution, mix uniformly, then adjust the pH of the medicinal solution with an acid-base regulator in the range of 7.0 to 7.5, and stir the medicinal solution at room temperature solution for 40 minutes;
(3)将步骤(2)所得混合液过滤脱炭(操作法：先用滤纸过滤，接着用孔径为1um的钛棒过滤，再用0.45um的聚醚砜滤芯将药液粗滤)，用酸碱调节剂调节药液的pH在3.3～3.7范围内，补加注射用水至处方全量，任选的用酸碱调节剂调节药液的pH在3.3～3.7范围内；(3) Decarbonize the mixed solution obtained in step (2) by filtration (operation method: first filter with filter paper, then filter with a titanium rod with a pore size of 1um, and then use a 0.45um polyethersulfone filter element to coarsely filter the medicinal solution), use An acid-base regulator is used to adjust the pH of the medicinal solution within the range of 3.3 to 3.7, add water for injection to the full amount of the prescription, and optionally use an acid-base regulator to adjust the pH of the medicinal solution within the range of 3.3 to 3.7;
(4)将步骤(3)配制的药液用0.22um的聚醚砜滤芯除菌过滤，灌装入玻璃瓶中，封口，进行热压灭菌(121℃下灭菌处理30分钟)，即得。(4) The medicinal solution prepared in step (3) is sterilized and filtered with a 0.22um polyethersulfone filter element, filled into a glass bottle, sealed, and autoclaved (sterilized at 121°C for 30 minutes), namely have to.
实施例8：配制盐酸昂丹司琼注射液Embodiment 8: preparation of ondansetron hydrochloride injection
配方和制法分别参照实施例1-7，不同的仅是在步骤(2)中与活性炭一起还添加纸浆，纸浆以纸的干重计为活性炭的40％(实施例1、2)、50％(实施例3、4)、60％(实施例5、6、7)，得到7批注射液，分别计为#81、#82、等依此类推。Recipe and preparation method are respectively with reference to embodiment 1-7, and difference is only also to add paper pulp together with active carbon in step (2), and paper pulp is 40% (embodiment 1,2), 50% of active carbon by the dry weight of paper. % (embodiment 3,4), 60% (embodiment 5,6,7), obtain 7 batches of injections, respectively count as #81, #82, etc. and so on.
试验例1：注射液中有关物质检查、活性成分的含量测定、pH值检查的试验及方法Test Example 1: Tests and methods for inspection of related substances in injections, content determination of active ingredients, and pH value inspection
【含量测定】【Content Determination】
照高效液相色谱法(2015年版中国药典四部通则0512)测定。Determine according to high-performance liquid chromatography (2015 edition Chinese Pharmacopoeia IV general rule 0512).
色谱条件与系统适用性试验：用氰基硅烷键合硅胶为填充剂(Kromasil CN柱，4.6mmX250mm，5um或效能相当的色谱柱)；以0.02mol/L磷酸二氢钠溶液(用氢氧化钠试液调节pH值至5.4)-乙腈(50:50)为流动相；检测波长为310nm。昂丹司琼峰保留时间约为11分钟；理论板数按昂丹司琼峰计算不低于2000。Chromatographic conditions and system suitability test: use cyanosilane bonded silica gel as filler (Kromasil CN column, 4.6mmX250mm, 5um or equivalent chromatographic column); use 0.02mol/L sodium dihydrogen phosphate solution (with sodium hydroxide Adjust the pH value of the test solution to 5.4)-acetonitrile (50:50) as the mobile phase; the detection wavelength is 310nm. The retention time of the ondansetron peak is about 11 minutes; the number of theoretical plates is not less than 2000 based on the ondansetron peak.
测定法：精密量取盐酸昂丹司琼注射液适量，用流动相定量稀释制成每1ml中约含昂丹司琼80ug的溶液，作为供试品溶液，精密量取10ul注入液相色谱仪，记录色谱图；另取盐酸昂丹司琼对照品，同法测定。按外标法以峰面积计算，并将结果乘以0.8895，即得。Assay method: accurately measure an appropriate amount of ondansetron hydrochloride injection, quantitatively dilute with mobile phase to make a solution containing about 80ug of ondansetron per 1ml, as the test solution, accurately measure 10ul and inject into the liquid chromatograph , record the chromatogram; take another ondansetron hydrochloride reference substance, and determine with the same method. According to the external standard method to calculate the peak area, and multiply the result by 0.8895, that is.
药典通常要求，盐酸昂丹司琼注射液含盐酸昂丹司琼按昂丹司琼(C18H19N3O)计算，应为标示量的93.0％～107.0％。The Pharmacopoeia generally requires that ondansetron hydrochloride injection contains ondansetron hydrochloride calculated as ondansetron (C18H19N3O), which should be 93.0% to 107.0% of the labeled amount.
经测定，上文实施例1-8中全部14种注射液活性成分含量均在其标示量的98.0％～102.0％范围内，且在步骤(2)中加或不加纸浆均无差异，例如实施例1注射液与#81注射液的含量无差异。It has been determined that the contents of active ingredients in all 14 injections in the above Examples 1-8 are within the range of 98.0% to 102.0% of their labeled amounts, and there is no difference whether pulp is added or not in step (2), for example There is no difference in content between Example 1 injection and #81 injection.
【有关物质】【relative substance】
取盐酸昂丹司琼注射液适量，加流动相制成每1ml中约含昂丹司琼0.5mg的溶液，作为供试品溶液；精密量取1ml，置100ml量瓶中，用流动相稀释至刻度，摇匀，作为对照溶液。Take an appropriate amount of ondansetron hydrochloride injection, add mobile phase to make a solution containing about 0.5 mg of ondansetron per 1 ml, as the test solution; accurately measure 1 ml, put in a 100 ml measuring bottle, and dilute with mobile phase To the mark, shake well, as a control solution.
除检测波长为216mn和328mn外，照含量测定项下的色谱条件，精密量取供试品溶液与对照溶液各10ul，分别注入液相色谱仪，记录色谱图至主成分峰保留时间的5倍。Except that the detection wavelength is 216mn and 328mn, according to the chromatographic conditions under the content determination item, accurately measure 10ul each of the test solution and the control solution, inject them into the liquid chromatograph respectively, and record the chromatogram to 5 times of the retention time of the main component peak .
药典通常要求，在216nm波长下，盐酸昂丹司琼注射液供试品溶液的色谱图中如有杂质峰，单个杂质峰面积不得大于对照溶液主峰面积的0.2倍(0.2％)，各杂质峰面积的和不得大于对照溶液主峰面积的0.5倍(0.5％)。在328nm波长下，盐酸昂丹司琼杂质I(相对保留时间约为0.6)的峰面积不得大于对照溶液主峰面积的1.5倍(1.5％)。其中盐酸昂丹司琼杂质I为9-甲基-3-亚甲基-2,3-二氢-1H-咔唑-4(9H)-酮。Pharmacopoeia generally requires, at 216nm wavelength, if there are impurity peaks in the chromatogram of ondansetron hydrochloride injection need testing solution, single impurity peak area must not be greater than 0.2 times (0.2%) of contrast solution main peak area, each impurity peak The sum of the areas shall not be greater than 0.5 times (0.5%) of the main peak area of the control solution. At 328nm wavelength, the peak area of ondansetron hydrochloride impurity I (relative retention time is about 0.6) must not be greater than 1.5 times (1.5%) of the main peak area of the control solution. Wherein the ondansetron hydrochloride impurity I is 9-methyl-3-methylene-2,3-dihydro-1H-carbazol-4(9H)-one.
经测定，上文实施例1-8中全部14种注射液的有关物质均满足上述药典常规的要求，例如，在216nm波长下，盐酸昂丹司琼注射液供试品溶液的色谱图中的杂质峰，单个杂质峰面积均小于0.08％，各杂质峰面积的和均小于0.26％；在328nm波长下，盐酸昂丹司琼杂质I均小于0.43％；且在步骤(2)中加或不加纸浆均无差异，例如实施例1注射液与#81注射液的有关物质无差异。After determination, the related substances of all 14 kinds of injections in the above embodiments 1-8 all meet the requirements of the above-mentioned pharmacopoeia routine, for example, at 216nm wavelength, the chromatogram of ondansetron hydrochloride injection need testing solution Impurity peak, single impurity peak area is all less than 0.08%, and the sum of each impurity peak area is all less than 0.26%; At 328nm wavelength, ondansetron hydrochloride impurity I is all less than 0.43%; And add or not in step (2) There is no difference when adding pulp, for example, there is no difference in related substances between the injection of Example 1 and the injection of #81.
【pH值检查】直接测定注射液的pH值。[pH value check] directly measure the pH value of the injection.
经测定，上文实施例1-8中全部14种注射液的pH值均与其制备工艺中设定的pH值相同；且在步骤(2)中加或不加纸浆均无差异，例如实施例1注射液与#81注射液的pH值无差异。It has been determined that the pH values of all 14 injections in the above examples 1-8 are the same as the pH values set in their preparation process; and there is no difference in step (2) with or without pulp, for example 1 injection and #81 injection had no difference in pH.
试验例2：注射液的稳定性试验及方法Test example 2: Stability test and method of injection
取注射液，置40℃暗处放置6个月，测定注射液在0月以及6月时的活性成分含量、有关物质、pH值。对于活性成分含量变化，每个注射液计算其在6月时含量相对于其0月时含量的百分数，即为残余百分含量，通常而言药物的残余百分含量应大于90％才是认为合格的。Take the injection, put it in a dark place at 40°C for 6 months, and measure the active ingredient content, related substances, and pH value of the injection at 0 and 6 months. For the content change of the active ingredient, the percentage of the content at 6 months relative to the content at 0 month is calculated for each injection, which is the residual percentage content. Generally speaking, the residual percentage content of the drug should be greater than 90% to be considered qualified.
上文实施例1-8中全部14种注射液，经测定，它们在6月时的有关物质和pH值均在药典规定的范围内；例如216nm波长下，盐酸昂丹司琼注射液单个杂质均小于0.13％，各杂质峰面积的和均小于0.41％；在328nm波长下，盐酸昂丹司琼杂质I均小于0.65％；它们在6月时的pH值均在3.0-4.0范围内。All 14 kinds of injections in the above examples 1-8, after determination, their related substances and pH value in 6 months are all within the scope specified in the Pharmacopoeia; for example, at 216nm wavelength, the single impurity of ondansetron hydrochloride injection All less than 0.13%, the sum of the peak areas of each impurity is less than 0.41%; at a wavelength of 328nm, the ondansetron hydrochloride impurity I is less than 0.65%; their pH values in June are all within the range of 3.0-4.0.
上文实施例1-8中全部14种注射液，经测定，它们在6月时的活性成分残余百分含量均在96～98％范围内，显示全部注射液均具有优异的稳定性。All 14 kinds of injections in Examples 1-8 above have been determined to have residual percentages of active ingredients in the range of 96-98% at 6 months, showing that all injections have excellent stability.
产业适用性Industry Applicability
本发明属于药品制造技术领域，涉及一种盐酸昂丹司琼产品以及其制法，特别是涉及一种盐酸昂丹司琼注射液，以及它的制备方法。根据本发明的盐酸昂丹司琼注射液，其还任选地呈现其它方面的优异效果。The invention belongs to the technical field of medicine manufacture, and relates to an ondansetron hydrochloride product and a preparation method thereof, in particular to an ondansetron hydrochloride injection and a preparation method thereof. According to the ondansetron hydrochloride injection of the present invention, it also optionally exhibits other excellent effects.
Claims (16)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610225573.3A CN105769759B (en) | 2016-04-13 | 2016-04-13 | Composition and preparation method of ondansetron hydrochloride injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610225573.3A CN105769759B (en) | 2016-04-13 | 2016-04-13 | Composition and preparation method of ondansetron hydrochloride injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105769759A CN105769759A (en) | 2016-07-20 |
| CN105769759B true CN105769759B (en) | 2018-06-29 |
Family
ID=56396338
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610225573.3A Active CN105769759B (en) | 2016-04-13 | 2016-04-13 | Composition and preparation method of ondansetron hydrochloride injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105769759B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20190358249A1 (en) * | 2018-05-22 | 2019-11-28 | Navinta Iii Inc | Injectable Combination Products Of Fosaprepitant And 5-HT3 Blocker |
| CN109464385A (en) * | 2018-12-20 | 2019-03-15 | 江西润泽药业有限公司 | Ondansetron hydrochloride and the composition of dexamethasone and preparation method thereof |
| CN109464386A (en) * | 2018-12-20 | 2019-03-15 | 江西润泽药业有限公司 | Ondansetron hydrochloride injection and preparation method thereof |
| CN114209648A (en) * | 2021-12-31 | 2022-03-22 | 贵州景峰注射剂有限公司 | Ondansetron hydrochloride injection and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1555795A (en) * | 2004-01-08 | 2004-12-22 | 陈庆财 | Ondansijiong hydrochleride freeze dried powder ampoule for injection and its preparation method |
| CN102125550A (en) * | 2010-12-30 | 2011-07-20 | 江苏奥赛康药业有限公司 | Ondansetron hydrochloride composition for injection and preparation method thereof |
| CN103432070A (en) * | 2013-09-13 | 2013-12-11 | 四川鼎诺泰宸科技有限公司 | Levetiracetam injection and preparation method thereof |
| CN103536910A (en) * | 2013-10-31 | 2014-01-29 | 成都天台山制药有限公司 | Cytochrome c injection |
| CN104274395A (en) * | 2014-09-19 | 2015-01-14 | 威海爱威制药有限公司 | Ondansetron hydrochloride sodium chloride injection and preparation method thereof |
-
2016
- 2016-04-13 CN CN201610225573.3A patent/CN105769759B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1555795A (en) * | 2004-01-08 | 2004-12-22 | 陈庆财 | Ondansijiong hydrochleride freeze dried powder ampoule for injection and its preparation method |
| CN102125550A (en) * | 2010-12-30 | 2011-07-20 | 江苏奥赛康药业有限公司 | Ondansetron hydrochloride composition for injection and preparation method thereof |
| CN103432070A (en) * | 2013-09-13 | 2013-12-11 | 四川鼎诺泰宸科技有限公司 | Levetiracetam injection and preparation method thereof |
| CN103536910A (en) * | 2013-10-31 | 2014-01-29 | 成都天台山制药有限公司 | Cytochrome c injection |
| CN104274395A (en) * | 2014-09-19 | 2015-01-14 | 威海爱威制药有限公司 | Ondansetron hydrochloride sodium chloride injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 盐酸昂丹司琼氯化钠注射液处方工艺控制研究;李洁等;《齐鲁药事》;20110531;第30卷(第5期);第254页-256页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105769759A (en) | 2016-07-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105769759B (en) | Composition and preparation method of ondansetron hydrochloride injection | |
| TWI355936B (en) | Uses of palonosetron hydrochloride | |
| CN114126596A (en) | Ketamine formulations for subcutaneous injection | |
| CN103370066B (en) | Combination therapy comprising vemurafenib and interferon for the treatment of cancer | |
| CN103070871A (en) | Pharmaceutical composition of fulvestrant | |
| CN106727278A (en) | A kind of Timoptic-XE agent and preparation method thereof | |
| JP2020500915A (en) | Phenytoin for local action for use in treating peripheral neuropathic pain | |
| CN115969778B (en) | Sulpiride injection for treating mental diseases and preparation method and application thereof | |
| CN118401241A (en) | Aldosterone synthase inhibitors for the treatment of chronic kidney disease | |
| CN109862895A (en) | Treatment of prurigo nodularis | |
| CN109310656A (en) | Treatment of uremic pruritus | |
| Barcia et al. | Compatibility of haloperidol and hyoscine-N-butyl bromide in mixtures for subcutaneous infusion to cancer patients in palliative care | |
| CN117180189B (en) | Shubianli injection and preparation method and application thereof | |
| WO2022120745A1 (en) | Medicine for relieving or eliminating protracted opioid abstinence syndrome and preparation method therefor | |
| EP4185291B1 (en) | Low dose regimen and formulation of a 5-methyl-1,2,4-oxadiazol-3-yl compound | |
| CN114828889B (en) | Ganaxolone for the treatment of tuberous sclerosis complex | |
| CN104721154B (en) | Pharmaceutical composition of norfloxacin glutamic acid freeze-dried powder for injection | |
| CN116157119A (en) | Pharmaceutical composition of ARNi and calcium ion antagonist and application thereof | |
| CN102302495A (en) | Tropisetron hydrochloride medicament composition for injection | |
| TWI857310B (en) | Ketorolac tromethamine liquid composition, preparation method and use thereof | |
| CN114053282B (en) | Application of Velingic Acid and Anisodamine Capsules in the Preparation of Medicines for Treating Diabetes | |
| CN114848650B (en) | A stable estazolam preparation composition and its preparation method | |
| RU2345775C1 (en) | Nonsteroid antiinflammatory medicinal agent | |
| TW201806599A (en) | Dosing regimens for fast onset of antidepressant effect | |
| CN107823130A (en) | A kind of preparation method of tetrandrine injection agent medicine 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 |