CN102144965A - More-stable carbetocin acetate injection - Google Patents
More-stable carbetocin acetate injection Download PDFInfo
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- CN102144965A CN102144965A CN 201010526006 CN201010526006A CN102144965A CN 102144965 A CN102144965 A CN 102144965A CN 201010526006 CN201010526006 CN 201010526006 CN 201010526006 A CN201010526006 A CN 201010526006A CN 102144965 A CN102144965 A CN 102144965A
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- China
- Prior art keywords
- acetic acid
- injection
- carbetocin
- sodium
- 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.)
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Links
- 108700021293 carbetocin Proteins 0.000 title claims abstract description 85
- NSTRIRCPWQHTIA-DTRKZRJBSA-N carbetocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSCCCC(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(OC)C=C1 NSTRIRCPWQHTIA-DTRKZRJBSA-N 0.000 title claims abstract description 85
- 229960001118 carbetocin Drugs 0.000 title claims abstract description 85
- 238000002347 injection Methods 0.000 title abstract description 130
- 239000007924 injection Substances 0.000 title abstract description 130
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 title abstract 3
- 238000002360 preparation method Methods 0.000 claims abstract description 26
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 15
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 8
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 8
- 230000001105 regulatory effect Effects 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 208
- 229960000583 acetic acid Drugs 0.000 claims description 75
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 36
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 18
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 17
- 239000012362 glacial acetic acid Substances 0.000 claims description 17
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 16
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical group [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000008103 glucose Substances 0.000 claims description 13
- 239000011780 sodium chloride Substances 0.000 claims description 10
- 229960004926 chlorobutanol Drugs 0.000 claims description 9
- 235000010323 ascorbic acid Nutrition 0.000 claims description 8
- 239000011668 ascorbic acid Substances 0.000 claims description 8
- 229960005070 ascorbic acid Drugs 0.000 claims description 8
- 235000010265 sodium sulphite Nutrition 0.000 claims description 8
- 239000008215 water for injection Substances 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 230000036592 analgesia Effects 0.000 claims description 6
- 235000006708 antioxidants Nutrition 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical group O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 6
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 6
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 6
- 229940001482 sodium sulfite Drugs 0.000 claims description 6
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000010253 intravenous injection Methods 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- 229930003427 Vitamin E Natural products 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 2
- 235000003969 glutathione Nutrition 0.000 claims description 2
- 229960003180 glutathione Drugs 0.000 claims description 2
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- -1 pH value regulator Substances 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 229960001309 procaine hydrochloride Drugs 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 2
- 229940001474 sodium thiosulfate Drugs 0.000 claims description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 235000019165 vitamin E Nutrition 0.000 claims description 2
- 229940046009 vitamin E Drugs 0.000 claims description 2
- 239000011709 vitamin E Substances 0.000 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 12
- 238000001914 filtration Methods 0.000 abstract description 11
- 210000004291 uterus Anatomy 0.000 abstract description 10
- 238000005303 weighing Methods 0.000 abstract description 6
- 208000018525 Postpartum Hemorrhage Diseases 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 208000002193 Pain Diseases 0.000 abstract description 3
- 230000036407 pain Effects 0.000 abstract description 3
- 230000000202 analgesic effect Effects 0.000 abstract 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000007789 sealing Methods 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 120
- 238000012360 testing method Methods 0.000 description 52
- 230000007794 irritation Effects 0.000 description 36
- 210000004204 blood vessel Anatomy 0.000 description 32
- 241000283973 Oryctolagus cuniculus Species 0.000 description 28
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- 238000006243 chemical reaction Methods 0.000 description 24
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- 206010002198 Anaphylactic reaction Diseases 0.000 description 16
- 206010030113 Oedema Diseases 0.000 description 16
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- 208000003455 anaphylaxis Diseases 0.000 description 16
- 230000002949 hemolytic effect Effects 0.000 description 16
- 241000700199 Cavia porcellus Species 0.000 description 12
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- 206010020565 Hyperaemia Diseases 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 12
- 230000004520 agglutination Effects 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical group OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- 101800000989 Oxytocin Proteins 0.000 description 9
- 102400000050 Oxytocin Human genes 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
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- 210000003314 quadriceps muscle Anatomy 0.000 description 8
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 7
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 7
- 229960001723 oxytocin Drugs 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 6
- 238000010255 intramuscular injection Methods 0.000 description 6
- 239000007927 intramuscular injection Substances 0.000 description 6
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 5
- 239000003708 ampul Substances 0.000 description 5
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- 239000003643 water by type Substances 0.000 description 4
- 229960004217 benzyl alcohol Drugs 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- WVVSZNPYNCNODU-CJBNDPTMSA-N Ergometrine Natural products C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@@H](CO)C)C2)=C3C2=CNC3=C1 WVVSZNPYNCNODU-CJBNDPTMSA-N 0.000 description 2
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- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 208000036029 Uterine contractions during pregnancy Diseases 0.000 description 2
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a more-stable carbetocin acetate injection. The preparation consists of carbetocin acetate, an isoosmotic adjusting agent, a pH value regulating agent, an antioxidant, a local analgetic and a solvent, wherein the addition of the antioxidant can improve the stability of the preparation, and the addition of the local analgetic can relieve pains of a patient but does not affect the basic remedy. The process for preparing the preparation mainly comprises the following steps: weighing, dissolving, adsorbing a heat source by activated carbon, filtering, filtering by a terminal, subpackaging and sealing. The preparation is used for preventing and treating insufficient uterus tension and postpartum hemorrhage. The preparation has stable quality and an exact curative effect, and can be accepted by patients.
Description
Technical field:
The present invention relates to formulation art, specifically is a kind of more stable acetic acid carbetocin injection.
Background technology:
Carbetocin (Carbetocin) is a kind of synthetic long-acting oxytocin nonapeptide analog with agonist character.Single dose intravenously administrable immediately behind the cesarotomy under epidural or the lumbar anesthesia is with prevention uterus tension force deficiency and postpartum hemorrhage.
Clinical and the pharmacological property of carbetocin and the oxytocin of natural generation are similar.As oxytocin, carbetocin combines with the ocytocin receptor of uterine smooth muscle, causes that the rhythmicity in uterus is shunk, and on original contraction basis, increases its frequency and increases uterus tension force.Under non pregnant state, the ocytocin receptor content in uterus is very low, increases at pregnancy duration, reaches the peak during childbirth.Therefore carbetocin still has effective uterine contraction effect to the uterus of gestation and the uterus of harsh product to the not effect of nogestational uterus.
No matter after being intravenous injection or intramuscular injection carbetocin, shrink rapidly in the uterus, can in 2 minutes, reach a clear and definite intensity.Therefore single dose intravenous injection carbetocin sustainable about 1 hour to the active function in uterus is enough to prevent the postpartum hemorrhage in harsh puerperal.After giving carbetocin puerperal, all long aspect amplitude in contraction frequency than oxytocin, and to bleeding tendency being arranged, need the extra oxytocin person of use, the carbetocin better tolerance is the same with oxytocin effective even more effective.
Present clinical promotion uterine contraction medicine ergometrine commonly used can cause feeling sick, vomiting, hypertension and coronary spasm etc.Carbetocin is a kind of long lasting class oxytocin medicine.Compare with ergometrine, use carbetocin effective equally aspect the postpartum hemorrhage of prevention vaginal delivery, and feel sick, vomiting, hypertensive generation ratio significantly reduce.
Therefore carbetocin has good application prospects clinically, has very high exploitation and is worth.
The prescription of the carbetocin injection that has gone on the market includes 100 μ g/ml acetic acid carbetocins, 9.0mg/ml sodium chloride, 50nl/ml glacial acetic acid.Its poor stability, only in 2 ℃～8 ℃ preservations of refrigerator temperature, can not be frozen; It is during to patient's intravenous injection or intramuscular injection, and the injection site produces pain, is unfavorable for that the patient accepts.The present invention is directed to these problems and propose, add antioxidant to improve stability of formulation, adding the local analgesia agent does not have influence with the pain that alleviates the patient to principal agent.The said preparation steady quality, determined curative effect is beneficial to the patient and accepts.
Summary of the invention:
The objective of the invention is to prepare a kind of is the injection of active component with the acetic acid carbetocin, has steady quality, and determined curative effect is beneficial to the patient by advantage such as being subjected to.
The present invention has prepared a kind of injection that contains acetic acid carbetocin medicine, and it comprises acetic acid carbetocin, isoosmotic adjusting agent, pH value regulator, antioxidant, local analgesia agent and solvent.
The present invention has prepared a kind of injection that contains acetic acid carbetocin medicine, and its isoosmotic adjusting agent is selected from sodium chloride, glucose, fructose, magnesium chloride, phosphate, sodium citrate etc.; Its pH value regulator is selected from glacial acetic acid, hydrochloric acid, sulphuric acid, lactic acid, malic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydrogen phosphate etc.; Its antioxidant is selected from sodium sulfite, sodium pyrosulfite, sodium thiosulfate, ascorbic acid, sodium sulfite, propyl gallate, glutathion, thiourea, TGA, vitamin E etc.; Its local analgesia agent is selected from benzyl alcohol, chlorobutanol and procaine hydrochloride etc.; Its solvent is a water for injection.
Through a large amount of optimization experiment, the present invention has found that most preferably prescription is formed.Wherein, its isoosmotic adjusting agent is sodium chloride and glucose most preferably, and the pH value regulator is glacial acetic acid most preferably, and antioxidant is sodium sulfite and sodium pyrosulfite most preferably, and the local analgesia agent is benzyl alcohol and chlorobutanol most preferably, and pH value is 3.0-5.5 most preferably.
In addition, the present invention also provides preparation to contain the method for the injection of acetic acid carbetocin medicine.Its technology is as follows:
1 precision takes by weighing the above-mentioned material of recipe quantity to container;
2 add an amount of water for injection dissolves fully;
3 usefulness glacial acetic acid are regulated pH value to 3.0 between 5.5;
4 water for injection standardize solution;
5 activated carbon adsorption pyrogens;
60.22 μ m titanium rod filter filters;
70.22 μ m filtering with microporous membrane;
Fill is sealed to sterilized ampoule after 8 passed examinations;
Labeling packing after 9 passed examinations.
The specific embodiment:
The present invention is including but not limited to following examples.
Embodiment 1:
Acetic acid carbetocin (in carbetocin 100 μ g/ml), 9.0mg/ml sodium chloride, the 0.1%w/v sodium sulfite, the 2%w/v benzyl alcohol, regulating pH with glacial acetic acid is 3.8, its preparation technology is as follows:
Weighing acetic acid carbetocin (in carbetocin 100mg), 9.0g sodium chloride, the 1.0g sodium sulfite, the 20.0g benzyl alcohol dissolves fully with recipe quantity 80% water for injection, transfers pH to 3.8 with glacial acetic acid, adds the injection water to 1000ml.Before filtration, add the 5g activated carbon in the injection, under agitation adsorbed pyrogen 30 minutes, decarburization is filtered.Filtrate is filtered through 0.22 μ m titanium rod filter, and again through 0.22 μ m microporous filter membrane aseptic filtration, fill is sealed in 1ml sterilization ampoule.Make every to be equivalent to 100 μ g carbetocins.
Make 1000 of acetic acid carbetocin injections (containing carbetocin 100 μ g) by present embodiment,, its stability and clinical drug safety are investigated by accelerated test and animal blood vessels zest, muscle irritation, haemolysis and anaphylaxis experiment.
Accelerated test:
The a collection of test sample that will go on the market respectively and to put into temperature by a batch sample of commercially available back be that 40 ± 2 ℃, relative humidity are that 75% ± 45% climatic chamber is investigated, 0,1,2,3 and sampling and measuring 6 months the time, the results are shown in Table 1-1 and table 1-2 respectively.
Table 1-1 test sample accelerated test result
Table 1-2 sample accelerated test result
By showing 1-1 and table 1-2 as can be seen, investigate 6 months through accelerated test, the acetic acid carbetocin injection of the present invention's preparation compares with the acetic acid carbetocin injection that has gone on the market, appearance luster, acidity, clarity of solution index are suitable, the impurity of the test sample of listing increases, content descends, show that the acetic acid carbetocin injection that the present invention prepares can preserve under room temperature, stability increases.
Blood vessel irritation, muscle irritation, haemolysis and anaphylaxis experiment:
Blood vessel irritation:
Choose 6 of the undamaged healthy rabbits of ears, left side auricular vein injection embodiment 1 injection 1ml, capacity 5% glucose injections such as auris dextra injection, were injected 7 days continuously at every day 1 time.
During the injection, regularly observe the irritative response of auricular vein every day.Put to death rabbit on the 8th day, get bilateral auricular vein and surrounding tissue, use formaldehyde fixed, be respectively 110,215 in the distance injection site, the proximal part of 315cm does the conventional organization section, light microscopic observation down has or not pathological change.Observation index and criterion see Table 1-3.
Table 1-3 blood vessel irritation scoring and criterion
The result shows that the zest of rabbit auricular vein injection embodiment 1 injection compares no significant difference with 5% glucose injection.Inflammatory reactions such as the congestion of blood vessel, surrounding tissue edema are not seen in perusal.Tissue slice checks, do not see that blood vessel structure is unusual, endothelial injury, thrombosis and other pathological change.The blood vessel of its naked eyes and om observation, the cumulative score of surrounding tissue show nonirritant all less than 0.5.
Muscle irritation:
Get 6 of healthy rabbits, injection embodiment 1 injection 1ml in every rabbit left side quadriceps femoris, inject with the volume normal saline on the right side.The injection back is observed injection site muscle and is had or not reactions such as hyperemia, edema, and (the 3rd day) sacrificed by exsanguination behind the half animal 48h is vertically cut skin, and injection site, perusal both sides has or not reactions such as hyperemia, edema, and gets its tissue and do pathologic finding.Then by the irritant reaction of showing this medicine of standard evaluation among the 1-4.Remaining animal continues to observe 14d, repeats aforesaid operations in the 18th day after the sacrificed by exsanguination, and evaluation criterion sees Table 1-4.
Table 1-4 muscular irritation reaction evaluating standard
The result shows, after injecting embodiment 1 injection in the quadriceps femoris of rabbit left side, perusal injection site muscle does not have reactions such as hyperemia, edema, and explicitly irritant reaction such as tissue degeneratiaon or necrosis are not also seen in the pathological tissue inspection, compare no significant difference with the normal saline side.
Sensitization to Cavia porcellus:
Choose 6 of healthy guinea pigs, every lumbar injection embodiment 1 injection 0.5ml, the next day, inject 1 time, injects altogether 3 times.Be divided into 2 groups then at random, after the 1st administration 14 or 21 days respectively, quiet notes embodiment 1 injection 1ml.Observe Cavia porcellus and have or not allergic symptoms such as excited uneasiness, dyspnea.
Two groups of Cavia porcelluss of result are all movable normal, do not see adnormal respiration etc.
External hemolytic test:
Prepare 2% rabbit red cell suspension.Get 7 in test tube, 1-5 adds various liquid by table.Each test tube is shaken up gently, put in 37 ℃ of waters bath with thermostatic control and hatch, observe 0.5,1,2,3,6 hour result.Erythrocyte agglutination in vitro and hemolytic criterion see Table 1-6.
The outer hemolytic test application of sample table of table 1-5 acetic acid carbetocin injecting fluid
Outer haemolysis of table 1-6 red cell body and agglutination test criterion
As a result, the distilled water control tube was complete hemolysis in 0.5 hour.Normal saline and each acetic acid carbetocin injection did not all have haemolysis in 6 hours.Jolting gently, the erythrocyte of normal saline and each concentration acetic acid carbetocin liquid injection pipe bottom sediments all can disperse fully, shows that acetic acid carbetocin injection does not have red cell agglutination.
Blood vessel irritation, muscle irritation, external hemolytic and anaphylaxis experiment show that embodiment 1 injection does not have tangible zest, anaphylaxis, can not cause hemolytic reaction yet.Show that the acetic acid carbetocin injection safety that the present invention prepares is good, can use for clinical vein injection and intramuscular injection.
Embodiment 2:
Acetic acid carbetocin (in carbetocin 100 μ g/ml), 9.0mg/ml sodium chloride, the 0.1%w/v sodium pyrosulfite, the 0.4%w/v chlorobutanol, regulating pH with glacial acetic acid is 3.8, its preparation technology is as follows:
Weighing acetic acid carbetocin (in carbetocin 100mg), 9.0g sodium chloride, the 1.0g sodium pyrosulfite, the 4.0g chlorobutanol dissolves fully with recipe quantity 80% water for injection, transfers pH to 3.8 with glacial acetic acid, adds the injection water to 1000ml.Before filtration, add the 5g activated carbon in the injection, under agitation adsorbed pyrogen 30 minutes, decarburization is filtered.Filtrate is filtered through 0.22 μ m titanium rod filter, and again through 0.22 μ m microporous filter membrane aseptic filtration, fill is sealed in 1ml sterilization ampoule.Make every to be equivalent to 100 μ g carbetocins.
Make 1000 of acetic acid carbetocin injections (containing carbetocin 100 μ g) by present embodiment,, its stability and clinical drug safety are investigated by accelerated test and animal blood vessels zest, muscle irritation, haemolysis and anaphylaxis experiment.
Accelerated test:
The a collection of test sample that will go on the market respectively and to put into temperature by a batch sample of commercially available back be that 40 ± 2 ℃, relative humidity are that 75% ± 5% climatic chamber is investigated 0,1,2,3 and sampling and measuring 6 months the time, the results are shown in Table 2-1 and table 2-2 respectively.
Table 2-1 test sample accelerated test result
Table 2-2 sample accelerated test result
By showing 2-1 and table 2-2 as can be seen, investigate 6 months through accelerated test, the acetic acid carbetocin injection of the present invention's preparation compares with the acetic acid carbetocin injection that has gone on the market, appearance luster, acidity, clarity of solution index are suitable, the impurity of the test sample of listing increases, content descends, show that the acetic acid carbetocin injection that the present invention prepares can preserve under room temperature, stability increases.
Blood vessel irritation, muscle irritation, haemolysis and anaphylaxis experiment:
Blood vessel irritation:
Choose 6 of the undamaged healthy rabbits of ears, left side auricular vein injection embodiment 2 injection 1ml, capacity 5% glucose injections such as auris dextra injection, were injected 7 days continuously at every day 1 time.
During the injection, regularly observe the irritative response of auricular vein every day.Put to death rabbit on the 8th day, get bilateral auricular vein and surrounding tissue, use formaldehyde fixed, be respectively 110,215 in the distance injection site, the proximal part of 315cm does the conventional organization section, light microscopic observation down has or not pathological change.Observation index and criterion see Table 2-3.
Table 2-3 blood vessel irritation scoring and criterion
The result shows that the zest of rabbit auricular vein injection embodiment 2 injection compares no significant difference with 5% glucose injection.Inflammatory reactions such as the congestion of blood vessel, surrounding tissue edema are not seen in perusal.Tissue slice checks, do not see that blood vessel structure is unusual, endothelial injury, thrombosis and other pathological change.The blood vessel of its naked eyes and om observation, the cumulative score of surrounding tissue show nonirritant all less than 0.5.
Muscle irritation:
Get 6 of healthy rabbits, injection embodiment 2 injection 1ml in every rabbit left side quadriceps femoris, inject with the volume normal saline on the right side.The injection back is observed injection site muscle and is had or not reactions such as hyperemia, edema, and (the 3rd day) sacrificed by exsanguination behind the half animal 48h is vertically cut skin, and injection site, perusal both sides has or not reactions such as hyperemia, edema, and gets its tissue and do pathologic finding.Then by the irritant reaction of showing this medicine of standard evaluation among the 2-4.Remaining animal continues to observe 14d, repeats aforesaid operations in the 18th day after the sacrificed by exsanguination, and evaluation criterion sees Table 2-4.
Table 2-4 muscular irritation reaction evaluating standard
The result shows, after injecting embodiment 2 injection in the quadriceps femoris of rabbit left side, perusal injection site muscle does not have reactions such as hyperemia, edema, and explicitly irritant reaction such as tissue degeneratiaon or necrosis are not also seen in the pathological tissue inspection, compare no significant difference with the normal saline side.
Sensitization to Cavia porcellus:
Choose 6 of healthy guinea pigs, every lumbar injection embodiment 2 injection 0.5ml, the next day, inject 1 time, injects altogether 3 times.Be divided into 2 groups then at random, after the 1st administration 14 or 21 days respectively, quiet notes embodiment 2 injection 1ml.Observe Cavia porcellus and have or not allergic symptoms such as excited uneasiness, dyspnea.
Two groups of Cavia porcelluss of result are all movable normal, do not see adnormal respiration etc.
External hemolytic test:
Prepare 2% rabbit red cell suspension.Get 7 in test tube, 2-5 adds various liquid by table.Each test tube is shaken up gently, put in 37 ℃ of waters bath with thermostatic control and hatch, observe 0.5,1,2,3,6 hour result.Erythrocyte agglutination in vitro and hemolytic criterion see Table 2-6.
The outer hemolytic test application of sample table of table 2-5 acetic acid carbetocin injecting fluid
Outer haemolysis of table 2-6 red cell body and agglutination test criterion
As a result, the distilled water control tube was complete hemolysis in 0.5 hour.Normal saline and each acetic acid carbetocin injection did not all have haemolysis in 6 hours.Jolting gently, the erythrocyte of normal saline and each concentration acetic acid carbetocin liquid injection pipe bottom sediments all can disperse fully, shows that acetic acid carbetocin injection does not have red cell agglutination.
Blood vessel irritation, muscle irritation, external hemolytic and anaphylaxis experiment show that embodiment 2 injection do not have tangible zest, anaphylaxis, can not cause hemolytic reaction yet.Show that the acetic acid carbetocin injection safety that the present invention prepares is good, can use for clinical vein injection and intramuscular injection.
Embodiment 3:
Acetic acid carbetocin (in carbetocin 100 μ g/ml), the 5%w/v glucose, the 0.1%w/v ascorbic acid, the 2%w/v benzyl alcohol, regulating pH with glacial acetic acid is 3.8, its preparation technology is as follows:
Weighing acetic acid carbetocin (in carbetocin 100mg), the 50.0g glucose, the 1.0g ascorbic acid, the 20.0g benzyl alcohol dissolves fully with recipe quantity 80% water for injection, transfers pH to 3.8 with glacial acetic acid, adds the injection water to 1000ml.Before filtration, add the 5g activated carbon in the injection, under agitation adsorbed pyrogen 30 minutes, decarburization is filtered.Filtrate is filtered through 0.22 μ m titanium rod filter, and again through 0.22 μ m microporous filter membrane aseptic filtration, fill is sealed in 1ml sterilization ampoule.Make every to be equivalent to 100 μ g carbetocins.
Make 1000 of acetic acid carbetocin injections (containing carbetocin 100 μ g) by present embodiment,, its stability and clinical drug safety are investigated by accelerated test and animal blood vessels zest, muscle irritation, haemolysis and anaphylaxis experiment.
Accelerated test:
The a collection of test sample that will go on the market respectively and to put into temperature by a batch sample of commercially available back be that 40 ± 2 ℃, relative humidity are that 75% ± 5% climatic chamber is investigated 0,1,2,3 and sampling and measuring 6 months the time, the results are shown in Table 3-1 and table 3-2 respectively.
Table 3-1 test sample accelerated test result
Table 3-2 sample accelerated test result
By showing 3-1 and table 3-2 as can be seen, investigate 6 months through accelerated test, the acetic acid carbetocin injection of the present invention's preparation compares with the acetic acid carbetocin injection that has gone on the market, appearance luster, acidity, clarity of solution index are suitable, the impurity of the test sample of listing increases, content descends, show that the acetic acid carbetocin injection that the present invention prepares can preserve under room temperature, stability increases.
Blood vessel irritation, muscle irritation, haemolysis and anaphylaxis experiment:
Blood vessel irritation:
Choose 6 of the undamaged healthy rabbits of ears, left side auricular vein injection embodiment 3 injection 1ml, capacity 5% glucose injections such as auris dextra injection, were injected 7 days continuously at every day 1 time.
During the injection, regularly observe the irritative response of auricular vein every day.Put to death rabbit on the 8th day, get bilateral auricular vein and surrounding tissue, use formaldehyde fixed, be respectively 110,215 in the distance injection site, the proximal part of 315cm does the conventional organization section, light microscopic observation down has or not pathological change.Observation index and criterion see Table 3-3.
Table 3-3 blood vessel irritation scoring and criterion
The result shows that the zest of rabbit auricular vein injection example 3 injection compares no significant difference with 5% glucose injection.Inflammatory reactions such as the congestion of blood vessel, surrounding tissue edema are not seen in perusal.Tissue slice checks, do not see that blood vessel structure is unusual, endothelial injury, thrombosis and other pathological change.The blood vessel of its naked eyes and om observation, the cumulative score of surrounding tissue show nonirritant all less than 0.5.
Muscle irritation:
Get 6 of healthy rabbits, injection embodiment 3 injection 1ml in every rabbit left side quadriceps femoris, inject with the volume normal saline on the right side.The injection back is observed injection site muscle and is had or not reactions such as hyperemia, edema, and (the 3rd day) sacrificed by exsanguination behind the half animal 48h is vertically cut skin, and injection site, perusal both sides has or not reactions such as hyperemia, edema, and gets its tissue and do pathologic finding.Then by the irritant reaction of showing this medicine of standard evaluation among the 3-4.Remaining animal continues to observe 14d, repeats aforesaid operations in the 18th day after the sacrificed by exsanguination, and evaluation criterion sees Table 3-4.
Table 3-4 muscular irritation reaction evaluating standard
The result shows, after injecting embodiment 3 injection in the quadriceps femoris of rabbit left side, perusal injection site muscle does not have reactions such as hyperemia, edema, and explicitly irritant reaction such as tissue degeneratiaon or necrosis are not also seen in the pathological tissue inspection, compare no significant difference with the normal saline side.
Sensitization to Cavia porcellus:
Choose 6 of healthy guinea pigs, every lumbar injection embodiment 3 injection 0.5ml, the next day, inject 1 time, injects altogether 3 times.Be divided into 2 groups then at random, after the 1st administration 14 or 21 days respectively, quiet notes embodiment 3 injection 1ml.Observe Cavia porcellus and have or not allergic symptoms such as excited uneasiness, dyspnea.
Two groups of Cavia porcelluss of result are all movable normal, do not see adnormal respiration etc.
External hemolytic test:
Prepare 2% rabbit red cell suspension.Get 7 in test tube, 3-5 adds various liquid by table.Each test tube is shaken up gently, put in 37 ℃ of waters bath with thermostatic control and hatch, observe 0.5,1,2,3,6 hour result.Erythrocyte agglutination in vitro and hemolytic criterion see Table 3-6.
The outer hemolytic test application of sample table of table 3-5 acetic acid carbetocin injecting fluid
Outer haemolysis of table 3-6 red cell body and agglutination test criterion
As a result, the distilled water control tube was complete hemolysis in 0.5 hour.Normal saline and each acetic acid carbetocin injection did not all have haemolysis in 6 hours.Jolting gently, the erythrocyte of normal saline and each concentration acetic acid carbetocin liquid injection pipe bottom sediments all can disperse fully, shows that acetic acid carbetocin injection does not have red cell agglutination.
Blood vessel irritation, muscle irritation, external hemolytic and anaphylaxis experiment show that embodiment 3 injection do not have tangible zest, anaphylaxis, can not cause hemolytic reaction yet.Show that each acetic acid carbetocin injection safety of system of the present invention is good, can use for clinical vein injection and intramuscular injection.
Embodiment 4:
Acetic acid carbetocin (in carbetocin 100 μ g/ml), the 5%w/v glucose, the 0.1%w/v ascorbic acid, the 0.4%w/v chlorobutanol, regulating pH with glacial acetic acid is 3.8, its preparation technology is as follows:
Weighing acetic acid carbetocin (in carbetocin 100mg), the 50.0g glucose, the 1.0g ascorbic acid, the 4.0g chlorobutanol dissolves fully with recipe quantity 80% water for injection, transfers pH to 3.8 with glacial acetic acid, adds the injection water to 1000ml.Before filtration, add the 5g activated carbon in the injection, under agitation adsorbed pyrogen 30 minutes, decarburization is filtered.Filtrate is filtered through 0.22 μ m titanium rod filter, and again through 0.22 μ m microporous filter membrane aseptic filtration, fill is sealed in 1ml sterilization ampoule.Make every to be equivalent to 100 μ g carbetocins.
Make 1000 of acetic acid carbetocin injections (containing carbetocin 100 μ g) by present embodiment,, its stability and clinical drug safety are investigated by accelerated test and animal blood vessels zest, muscle irritation, haemolysis and anaphylaxis experiment.
Accelerated test:
The a collection of test sample that will go on the market respectively and to put into temperature by a batch sample of commercially available back be that 40 ± 2 ℃, relative humidity are that 75% ± 5% climatic chamber is investigated 0,1,2,3 and sampling and measuring 6 months the time, the results are shown in Table 4-1 and table 4-2 respectively.
Table 4-1 test sample accelerated test result
Table 4-2 sample accelerated test result
By showing 4-1 and table 4-2 as can be seen, investigate 6 months through accelerated test, the acetic acid carbetocin injection of the present invention's preparation compares with the acetic acid carbetocin injection that has gone on the market, appearance luster, acidity, clarity of solution index are suitable, the impurity of the test sample of listing increases, content descends, show that the acetic acid carbetocin injection that the present invention prepares can preserve under room temperature, stability increases.
Blood vessel irritation, muscle irritation, haemolysis and anaphylaxis experiment:
Blood vessel irritation:
Choose 6 of the undamaged healthy rabbits of ears, left side auricular vein injection embodiment 4 injection 1ml, capacity 5% glucose injections such as auris dextra injection, were injected 7 days continuously at every day 1 time.
During the injection, regularly observe the irritative response of auricular vein every day.Put to death rabbit on the 8th day, get bilateral auricular vein and surrounding tissue, use formaldehyde fixed, be respectively 110,215 in the distance injection site, the proximal part of 315cm does the conventional organization section, light microscopic observation down has or not pathological change.Observation index and criterion see Table 4-3.
Table 4-3 blood vessel irritation scoring and criterion
The result shows that the zest of rabbit auricular vein injection embodiment 4 injection compares no significant difference with 5% glucose injection.Inflammatory reactions such as the congestion of blood vessel, surrounding tissue edema are not seen in perusal.Tissue slice checks, do not see that blood vessel structure is unusual, endothelial injury, thrombosis and other pathological change.The blood vessel of its naked eyes and om observation, the cumulative score of surrounding tissue show nonirritant all less than 0.5.
Muscle irritation:
Get 6 of healthy rabbits, injection embodiment 4 injection 1ml in every rabbit left side quadriceps femoris, inject with the volume normal saline on the right side.The injection back is observed injection site muscle and is had or not reactions such as hyperemia, edema, and (the 3rd day) sacrificed by exsanguination behind the half animal 48h is vertically cut skin, and injection site, perusal both sides has or not reactions such as hyperemia, edema, and gets its tissue and do pathologic finding.Press the irritant reaction of this medicine of standard evaluation in the table 4 then.Remaining animal continues to observe 14d, repeats aforesaid operations in the 18th day after the sacrificed by exsanguination, and evaluation criterion sees Table 4-4.
Table 4-4 muscular irritation reaction evaluating standard
The result shows, after injecting embodiment 4 injection in the quadriceps femoris of rabbit left side, perusal injection site muscle does not have reactions such as hyperemia, edema, and explicitly irritant reaction such as tissue degeneratiaon or necrosis are not also seen in the pathological tissue inspection, compare no significant difference with the normal saline side.
Sensitization to Cavia porcellus:
Choose 6 of healthy guinea pigs, every lumbar injection embodiment 4 injection 0.5ml, the next day, inject 1 time, injects altogether 3 times.Be divided into 2 groups then at random, after the 1st administration 14 or 21 days respectively, quiet notes embodiment 4 injection 1ml.Observe Cavia porcellus and have or not allergic symptoms such as excited uneasiness, dyspnea.
Two groups of Cavia porcelluss of result are all movable normal, do not see adnormal respiration etc.
External hemolytic test:
Prepare 2% rabbit red cell suspension.Get 7 in test tube, 4-5 adds various liquid by table.Each test tube is shaken up gently, put in 37 ℃ of waters bath with thermostatic control and hatch, observe 0.5,1,2,3,6 hour result.Erythrocyte agglutination in vitro and hemolytic criterion see Table 4-6.
The outer hemolytic test application of sample table of table 4-5 acetic acid carbetocin injecting fluid
Outer haemolysis of table 4-6 red cell body and agglutination test criterion
As a result, the distilled water control tube was complete hemolysis in 0.5 hour.Normal saline and each acetic acid carbetocin injection did not all have haemolysis in 6 hours.Jolting gently, the erythrocyte of normal saline and each concentration acetic acid carbetocin liquid injection pipe bottom sediments all can disperse fully, shows that acetic acid carbetocin injection does not have red cell agglutination.
Blood vessel irritation, muscle irritation, external hemolytic and anaphylaxis experiment show that embodiment 4 injection do not have tangible zest, anaphylaxis, can not cause hemolytic reaction yet.Show that the acetic acid carbetocin injection safety that the present invention prepares is good, can use for clinical vein injection and intramuscular injection.
Claims (10)
1. more stable acetic acid carbetocin intravenous injection and administered intramuscular preparation is characterized in that described preparation is by principal agent acetic acid carbetocin and isoosmotic adjusting agent, pH value regulator, antioxidant, local analgesia agent and solvent composition.
2. the described preparation of claim 1, its isoosmotic adjusting agent selects white sodium chloride, glucose, fructose, magnesium chloride, phosphate, sodium citrate etc.
3. the described preparation of claim 1, its pH value regulator is selected from glacial acetic acid, hydrochloric acid, sulphuric acid, lactic acid, malic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydrogen phosphate etc., and regulating pH is between 2.5 to 6.0.
4. the described preparation of claim 1, its antioxidant is selected from sodium sulfite, sodium pyrosulfite, ascorbic acid, sodium thiosulfate, sodium sulfite, glutathion, thiourea, TGA, vitamin E etc.
5. the described preparation of claim 1, its local analgesia agent is selected from benzyl alcohol, chlorobutanol and procaine hydrochloride etc.
6. the described preparation of claim 1, its solvent is a water for injection.
7. the described preparation of claim 1-6, its prescription consists of: 5-500 μ g/ml acetic acid carbetocin, 0.1-50.0mg/ml sodium chloride, the 0.01-2%w/v sodium sulfite, the 0.1-5%w/v benzyl alcohol, transferring pH with glacial acetic acid is 3.0-5.5.
8. the described preparation of claim 1-6, its prescription consists of: 5-500 μ g/ml acetic acid carbetocin, 0.1-50.0mg/ml sodium chloride, the 0.01-2%w/v sodium pyrosulfite, the 0.03-2%w/v chlorobutanol, transferring pH with glacial acetic acid is 3.0-5.5.
9. the described preparation of claim 1-6, its prescription consists of: 5-500 μ g/ml acetic acid carbetocin, the 1%-50%w/v glucose, the 0.005-2%w/v ascorbic acid, the 0.1-5%w/v benzyl alcohol, transferring pH with glacial acetic acid is 3.0-5.5.
10. the described preparation of claim 1-6, its prescription consists of: 5-500 μ g/ml acetic acid carbetocin, the 1%-50%w/v glucose, the 0.005-2%w/v ascorbic acid, the 0.03-2%w/v chlorobutanol, transferring pH with glacial acetic acid is 3.0-5.5.
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| US11844764B2 (en) | 2018-09-20 | 2023-12-19 | Acadia Pharmaceuticals, Inc. | Agitation process for preparing a carbetocin drug product |
| CN109010796A (en) * | 2018-10-22 | 2018-12-18 | 成都市海通药业有限公司 | A kind of preparation method of oxytocin injection |
| CN110404050A (en) * | 2019-07-26 | 2019-11-05 | 翔宇药业股份有限公司 | The preparation process of carbetocin injection |
| CN110279658A (en) * | 2019-08-06 | 2019-09-27 | 苏州素仕生物科技有限公司 | A kind of oxytocin injection and preparation method thereof |
| CN110339340A (en) * | 2019-08-27 | 2019-10-18 | 成都市海通药业有限公司 | A kind of preparation method of oxytocin injection |
| CN111012739A (en) * | 2019-12-04 | 2020-04-17 | 长春圣金诺生物制药有限公司 | Injection containing carbetocin and stabilizer and capable of being stored at normal temperature |
| CN115531517A (en) * | 2022-10-26 | 2022-12-30 | 海南皇隆制药股份有限公司 | Carbetocin injection and preparation method thereof |
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Address after: 518057, room 2, building ten, Shenzhen biological incubation center, No. 412, Nanshan District hi tech, Shenzhen, Guangdong Applicant after: Shenzhen City Jianyuan Pharmaceutical Technology Co., Ltd. Address before: 518000, overseas student Pioneer Building, 29 South Ring Road, Nanshan hi tech Zone, Guangdong, Shenzhen 1702 Applicant before: Shenzhen City Jianyuan Pharmaceutical Technology Co., Ltd. |
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Application publication date: 20110810 |