CN114209648A - Ondansetron hydrochloride injection and preparation method thereof - Google Patents
Ondansetron hydrochloride injection and preparation method thereof Download PDFInfo
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- CN114209648A CN114209648A CN202111667338.9A CN202111667338A CN114209648A CN 114209648 A CN114209648 A CN 114209648A CN 202111667338 A CN202111667338 A CN 202111667338A CN 114209648 A CN114209648 A CN 114209648A
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- ondansetron hydrochloride
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- 238000002347 injection Methods 0.000 title claims abstract description 69
- 239000007924 injection Substances 0.000 title claims abstract description 69
- 229960000770 ondansetron hydrochloride Drugs 0.000 title claims abstract description 53
- 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 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 30
- 239000007788 liquid Substances 0.000 claims abstract description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 55
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 42
- 238000001914 filtration Methods 0.000 claims description 35
- 230000001954 sterilising effect Effects 0.000 claims description 31
- 238000004659 sterilization and disinfection Methods 0.000 claims description 29
- 238000002156 mixing Methods 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 28
- 238000004519 manufacturing process Methods 0.000 claims description 23
- 239000011780 sodium chloride Substances 0.000 claims description 21
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 claims description 20
- 229960002303 citric acid monohydrate Drugs 0.000 claims description 20
- 229960000999 sodium citrate dihydrate Drugs 0.000 claims description 20
- 239000002994 raw material Substances 0.000 claims description 17
- 230000008569 process Effects 0.000 claims description 15
- 239000008215 water for injection Substances 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
- 239000011521 glass Substances 0.000 claims description 10
- 239000002671 adjuvant Substances 0.000 claims description 6
- 238000003825 pressing Methods 0.000 claims description 6
- 229960002668 sodium chloride Drugs 0.000 claims description 6
- 238000011049 filling Methods 0.000 claims description 5
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 3
- 238000005096 rolling process Methods 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 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 12
- 229940090044 injection Drugs 0.000 description 52
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 22
- 239000000126 substance Substances 0.000 description 19
- FELGMEQIXOGIFQ-UHFFFAOYSA-N Ondansetron Chemical compound CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-UHFFFAOYSA-N 0.000 description 18
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 17
- 229940114430 ondansetron injection Drugs 0.000 description 15
- 239000012535 impurity Substances 0.000 description 14
- 238000011160 research Methods 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 10
- 239000000463 material Substances 0.000 description 9
- 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 description 7
- 239000002033 PVDF binder Substances 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 7
- 238000007731 hot pressing Methods 0.000 description 7
- 229960005343 ondansetron Drugs 0.000 description 7
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 7
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- 238000010438 heat treatment Methods 0.000 description 6
- 239000012528 membrane Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
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- 239000002904 solvent Substances 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- -1 compound ondansetron hydrochloride Chemical class 0.000 description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 3
- 229960003957 dexamethasone Drugs 0.000 description 3
- 238000005265 energy consumption Methods 0.000 description 3
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- 229940072018 zofran Drugs 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
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- 208000031649 Postoperative Nausea and Vomiting Diseases 0.000 description 2
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- 230000001105 regulatory effect Effects 0.000 description 2
- 238000012502 risk assessment Methods 0.000 description 2
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- 229940113081 5 Hydroxytryptamine 3 receptor antagonist Drugs 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010066962 Procedural nausea Diseases 0.000 description 1
- 206010066963 Procedural vomiting Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
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- 238000002512 chemotherapy Methods 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
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- 238000007918 intramuscular administration Methods 0.000 description 1
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- 230000007794 irritation Effects 0.000 description 1
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- 230000000813 microbial effect Effects 0.000 description 1
- CEYGNZMCCVVXQW-UHFFFAOYSA-N phosphoric acid;propane-1,2-diol Chemical compound CC(O)CO.OP(O)(O)=O CEYGNZMCCVVXQW-UHFFFAOYSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
- A61L2/0023—Heat
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
- A61L2202/20—Targets to be treated
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Abstract
The invention relates to an ondansetron hydrochloride injection and a preparation method thereof, the method is characterized in that liquid medicine is filtered in two stages, the pH value of the filtered liquid medicine is stabilized within a standard requirement range, hydrochloric acid or sodium hydroxide is not required to be used for adjustment, the liquid medicine is clear, the content is uniform and stable, and the preparation method is safe, effective, stable, simple and convenient and meets the requirements of excellent pharmaceutical properties.
Description
Technical Field
The invention belongs to the field of medicine injection, and particularly relates to ondansetron hydrochloride injection and a preparation method thereof.
Background
Ondansetron hydrochloride injection is a clear, colorless, pyrogen-free, sterile intravenous or intramuscular solution that is a 5-HT3 receptor antagonist useful for preventing nausea and vomiting associated with initial and repeated cancer chemotherapy and post-operative nausea and/or vomiting.
In the prior art, ondansetron hydrochloride injection is prepared by a plurality of methods, but certain problems exist, such as:
application number CN201811567020.1 in the prior art, invention name: the composition of ondansetron hydrochloride and dexamethasone and the preparation method thereof contain ondansetron hydrochloride, dexamethasone, propylene glycol, phosphate buffer solution and water for injection, and the composition is prepared by the following steps: (1) adding water for injection into a mixing tank, heating, adding ondansetron hydrochloride, dexamethasone, propylene glycol and a phosphate buffer solution, and stirring to dissolve; (2) adding a hydrochloric acid solution or a sodium hydroxide solution into the batching tank to adjust the pH value to be within the range of 6.5-7.5; (3) adding activated carbon for injection into a mixing tank, stirring, filtering again, and filtering with a titanium rod filter to obtain injection; (4) and sterilizing and filtering the injection, filling the injection into a glass bottle, sealing the glass bottle, and performing hot-pressing sterilization to obtain the ondansetron hydrochloride injection.
CN201811567020.1 has the following drawbacks: (1) the prescription contains propylene glycol, which may cause strong irritation to blood vessels; (2) the preparation method is complex: the method needs an acid-base regulator to regulate the pH value, and a hydrochloric acid solution or a sodium hydroxide solution is used for regulating the pH value in the preparation process, so that the pH value of the prepared injection can reach the range specified by pharmacopeia; the injection can be obtained only by adding activated carbon for filtration and then filtering the solution by a titanium rod, and the activated carbon is used as a common adsorbent in the injection to perform corresponding functions of impurity removal and pyrogen adsorption, but simultaneously, the diversity of the raw materials and the production process of the activated carbon, the uncertainty of the activation mechanism and the limitation of quality control, and the possibility of introducing impurities and insoluble particles caused by the diversity of the raw materials and the production process bring risks to the application of the activated carbon in the injection. In the technical requirements for evaluating the quality and the curative effect consistency of the imitation drugs of chemical injection issued by the State drug administration, the control on the original auxiliary package, the production process and the like needs to be strengthened in order to effectively control pyrogen (bacterial endotoxin), and active carbon is not used in the production of the injection; the injection after filling and sealing needs to be sterilized by hot pressing at 250 ℃ for 20-30min at 200 ℃ for obtaining the injection, and the sterilization temperature is high and the time is long.
Application number CN201610225573.3 in the prior art, invention name: ondansetron hydrochloride injection composition and preparation method, contain ondansetron hydrochloride and water for injection, it is prepared from the following steps: (1) taking ondansetron hydrochloride raw material medicine with the prescription amount, adding the raw material medicine into proper amount of water for injection, and stirring to dissolve the medicine; (2) adding 0.05-0.2% of needle activated carbon into the solution obtained in the step (1) by volume of the liquid medicine, and simultaneously adding paper pulp, wherein the adding amount of the paper pulp is 40-60% of the activated carbon by dry weight of the paper; uniformly mixing, then adjusting the pH of the liquid medicine to be within a range of 6.5-7.5 by using an acid-base regulator, and stirring the liquid medicine for 30-60 minutes at room temperature; (3) filtering and decarburizing the mixed solution obtained in the step (2), adjusting the pH of the liquid medicine to be within a range of 3.2-3.75 by using an acid-base regulator, adding water for injection to the full amount of the prescription, and adjusting the pH of the liquid medicine to be within a range of 3.25-3.75 by using the acid-base regulator; the mixed solution filtration and decarburization are carried out according to the following modes: filtering with filter paper, filtering with titanium rod with aperture of 1 μm, and coarse-filtering with 0.45 μm polyethersulfone filter core; (4) and (4) sterilizing and filtering the liquid medicine prepared in the step (3), filling the liquid medicine into a glass bottle, sealing the glass bottle, and performing hot-pressing sterilization to obtain the traditional Chinese medicine.
However, CN201610225573.3 has the following drawbacks: (1) the stirring time is longer: the stirring and dissolving process is carried out at room temperature, the temperature is low, the raw material dissolving difficulty is increased, the dissolving time is prolonged, and the uniformity of the product is difficult to ensure; (2) the method is more complex: a. the pH value needs to be adjusted by using an acid-base regulator: in the preparation process, pH value of the injection prepared by the method can reach the range specified by pharmacopeia only by adjusting pH value with an acid-base regulator twice; b. the filter decarburization is needed: firstly, filtering with filter paper, then filtering with a titanium rod with the aperture of 1 mu m, then roughly filtering the liquid medicine with a polyether sulfone filter element with the aperture of 0.45 mu m, and then performing sterilization filtration, wherein the production process is complex, the cost is high, and active carbon is not recommended to be used in the production of the injection; c. the injection filled and sealed needs to be sterilized by hot pressing at 121 ℃ for 30min, and the sterilization time is relatively long.
Application number CN201811561191.3 in the prior art, invention name: the compound ondansetron hydrochloride injection and the preparation method thereof contain ondansetron hydrochloride, mannitol and water for injection, and the compound ondansetron hydrochloride injection is prepared by the following steps: (1) adding ondansetron hydrochloride and mannitol into a mixing tank, and adding water for injection; (2) adding hydrochloric acid solution or sodium hydroxide solution to adjust pH to 4.4-4.5; (3) adding active carbon for injection, and sequentially carrying out primary heating and stirring and secondary heating and stirring to obtain a mixed solution; wherein, the conditions of the first heating and stirring comprise: the temperature is 30-45 deg.C, and the time is 10-20 min; the conditions of the second heating and stirring include: the temperature is 40-55 deg.C, and the time is 3-8 min; (4) and filtering the mixed solution through a microporous filter membrane into a sterile room, subpackaging, freeze-drying, and then carrying out hot-pressing sterilization to obtain the compound ondansetron hydrochloride injection.
However, CN201811561191.3 has the following drawbacks: (1) the pH value needs to be adjusted by using an acid-base regulator: in the preparation process, hydrochloric acid solution or sodium hydroxide solution is used for adjusting the pH value, so that the pH value of the prepared injection can reach the range specified by pharmacopeia; (2) this method is complex: a. the injection is obtained by freeze drying and hot-pressing sterilization, so that the process steps and key process parameters are increased, the risk is improved, and the production cost is increased; b. adding active carbon, heating and stirring twice; c. the hot-pressing sterilization temperature of 200 ℃ and 250 ℃ is too high, the energy consumption is large, and the production cost is too high.
In order to solve the defects of the prior art, the invention provides a safe, effective, stable, simple and convenient preparation method of ondansetron hydrochloride injection with excellent pharmaceutical properties.
Disclosure of Invention
The invention aims to provide a formula of ondansetron hydrochloride injection.
The invention also aims to provide a preparation method of the ondansetron hydrochloride injection.
The ondansetron hydrochloride injection comprises 1-3 mg of ondansetron hydrochloride, 8-10 mg of sodium chloride, 0.3-0.7 mg of citric acid monohydrate, 0.20-0.30 mg of sodium citrate dihydrate and 0.5-1.5 ml of water for injection.
Preferably, the ondansetron hydrochloride injection disclosed by the invention comprises 2.49mg of ondansetron hydrochloride, 9.0mg of sodium chloride, 0.5mg of citric acid monohydrate, 0.25mg of sodium citrate dihydrate and 1.0ml of water for injection.
The preparation method of the injection comprises the following steps:
1) adding injection water with the preparation amount of 5-20% into a pre-dissolving tank, adjusting the water temperature, adding sodium chloride, citric acid monohydrate and sodium citrate dihydrate with the prescription amount, and mixing until the sodium chloride, the citric acid monohydrate and the sodium citrate dihydrate are dissolved;
2) adding injection water with the preparation amount of 5-20% into a pre-dissolving tank, adjusting the water temperature, adding ondansetron hydrochloride with the prescription amount, and mixing until the ondansetron hydrochloride is dissolved;
3) mixing the dissolved adjuvants and raw materials in a mixing tank, adding injectable water to the full amount of the prescription, and stirring;
4) filtering the liquid medicine through a two-stage filter with the diameter of 0.22 mu m under the pressure of nitrogen gas of not less than 0.2mPa, filling the liquid medicine into a small glass bottle, pressing a stopper, rolling a cover, and performing moist heat sterilization at the temperature of 115-128 ℃ for 10-20min to obtain the liquid medicine.
Preferably, the water temperature in the step 1) is 40 to 80 ℃.
More preferably, the water temperature in the step 1) is 60 ℃.
Preferably, the water temperature in the step 2) is 40 to 80 ℃.
More preferably, the water temperature in the step 2) is 60 ℃.
The stirring time in the step 3) is 10 to 30 minutes.
Preferably, the stirring in the step 3) is carried out for 20 minutes.
And (3) performing moist heat sterilization at the temperature of 121 ℃ for 15min in the step 4).
In the invention, the preferable filter element is made of polyvinylidene fluoride, and the liquid medicine is subjected to secondary filtration.
Has the advantages that:
1. compared with the prior art, the invention has the following beneficial effects:
the liquid medicine is filtered in two stages, the pH value of the filtered liquid medicine is stabilized within the standard required range, hydrochloric acid or sodium hydroxide is not required to be used for adjusting, and the liquid medicine is clear and has uniform and stable content.
2. According to the research on the dissolution characteristic and granularity of the ondansetron hydrochloride bulk drug, the research on the influence of the solvent temperature on the dissolution time and the research on the influence of the charging sequence and retention time of the raw materials and the auxiliary materials, the production process is preferably selected after a large number of research experiments, the raw materials and the auxiliary materials are respectively pre-dissolved and then mixed, the water temperature is controlled to be 40-80 ℃, the solution uniformity can be realized after the stirring time is 10-30 minutes, and in addition, an acid-base regulator is not required to be additionally used in the prescription process for regulating the pH value to the standard requirement of pharmacopeia.
3. Through filtration research, a large number of experiments prove that the filter membrane of 0.22 mu m (PVDF) has no influence on the quality of the ondansetron hydrochloride injection after filtration, and two-stage filtration is adopted in production, so that the removal of impurities is ensured to a greater extent. The process does not need to add activated carbon for impurity removal and heat source removal, avoids the risk that the activated carbon cannot completely remove or introduce impurities or increase insoluble particles, reduces the production process steps and reduces the production cost.
4. Through the research on the sterilization conditions, a large number of experiments prove that F is obtained under the condition of autoclave sterilization at 121 ℃ for 15min0Not less than 12min, and the quality of the ondansetron hydrochloride injection is not changed. The sterilization condition not only improves the sterility guarantee and the stability of the product qualityQualitative, greatly reduced production energy consumption, and saved production cost.
5. The ondansetron hydrochloride injection is placed in a stability inspection box at 60 ℃, samples are taken at 0 month, 1 month, 2 months, 3 months and 6 months, and detection is carried out according to the specification of the character, content, chromatographic purity and related substances D, pH in the ondansetron injection in USP. The content of the ondansetron which is the active ingredient of the injection combined under different conditions is within the range of 95.0-105.0% of the marked amount, the content of related substances D is less than 0.12%, other single impurities are less than 0.2%, the total impurities are less than 0.5%, the pH value is within the range of 3.3-4.0, all detection results meet the standard requirement of USP, and no obvious difference exists among data accelerated for 6 months, which indicates that all injections have excellent stability.
Drawings
FIG. 1. ondansetron injection stability 0 month related substance D detection-diluent
FIG. 2 ondansetron injection stability 0 month related substance D detection-control solution
FIG. 3. ondansetron injection stability 0 month related substance D detection-resolution solution
FIG. 4 stability of ondansetron injection at 0 month related substance D detection-sample solution
FIG. 5 detection of the stability of ondansetron injection at 0 month and the chromatographic purity-Diluent
FIG. 6 detection of the content of ondansetron injection in stability for 0 month and the chromatographic purity-control solution
FIG. 7 stability of ondansetron injection at 0 month content and chromatographic purity test-resolution solution-1
FIG. 8 stability of ondansetron injection at 0 month content and chromatographic purity test-resolution solution-2
FIG. 9 detection of the Stable 0 month content and chromatographic purity of ondansetron injection-sample solution
Detailed Description
The technical solution of the present invention will be further specifically described below by way of specific examples.
Example 1
The formula is as follows: 2.49mg of ondansetron hydrochloride, 9.0mg of sodium chloride, 0.5mg of citric acid monohydrate, 0.25mg of sodium citrate dihydrate and 1.0ml of water for injection.
Example 2
The formula is as follows: 1mg of ondansetron hydrochloride, 8mg of sodium chloride, 0.3mg of citric acid monohydrate, 0.20mg of sodium citrate dihydrate and 0.5ml of water for injection.
Example 3
The formula is as follows: ondansetron 3mg, sodium chloride 10mg, citric acid monohydrate 0.7mg, sodium citrate dihydrate 0.30mg, and water for injection 1.5 ml.
Examples 1-3 were prepared according to any of the following methods
Example 4
1) Adding 10% of injection water into a pre-dissolving tank, adding sodium chloride, citric acid monohydrate and sodium citrate dihydrate according to the prescription amount at the water temperature of 60 ℃, and mixing until the sodium chloride, the citric acid monohydrate and the sodium citrate dihydrate are dissolved;
2) adding injection water with the preparation amount of 10% into a pre-dissolving tank, adding ondansetron hydrochloride with the prescription amount at the water temperature of 60 ℃, and mixing until the ondansetron hydrochloride is dissolved;
3) mixing the dissolved adjuvants and raw materials in a mixing tank, adding injectable water to the full amount of the prescription, and stirring for 20 min;
4) filtering the medicinal liquid with two 0.22 μm filters under nitrogen pressure of 0.2mPa or more, bottling into small glass bottle, pressing, capping, and performing moist heat sterilization at 121 deg.C for 15 min.
Example 5
1) Adding 5% of injection water into a pre-dissolving tank, keeping the water temperature at 80 ℃, adding the sodium chloride, citric acid monohydrate and sodium citrate dihydrate according to the prescription amount, and mixing until the sodium chloride, the citric acid monohydrate and the sodium citrate dihydrate are dissolved;
2) adding injection water with the preparation amount of 5% into a pre-dissolving tank, wherein the water temperature is 80 ℃, adding ondansetron hydrochloride with the prescription amount, and mixing until the ondansetron hydrochloride is dissolved;
3) mixing the dissolved adjuvants and raw materials in a mixing tank, adding injectable water to the full amount of the prescription, and stirring for 30 min;
4) filtering the medicinal liquid with two 0.22 μm filters under nitrogen pressure of 0.2mPa or more, bottling into small glass bottle, pressing, capping, and performing moist heat sterilization at 121 deg.C for 15 min.
Example 6
1) Adding 20% of injection water into a pre-dissolving tank, adding sodium chloride, citric acid monohydrate and sodium citrate dihydrate according to the prescription amount at the water temperature of 40 ℃, and mixing until the sodium chloride, the citric acid monohydrate and the sodium citrate dihydrate are dissolved;
2) adding injection water with the preparation amount of 20% into a pre-dissolving tank, adding ondansetron hydrochloride with the prescription amount at the water temperature of 40 ℃, and mixing until the ondansetron hydrochloride is dissolved;
3) mixing the dissolved adjuvants and raw materials in a mixing tank, adding injectable water to the full amount of the prescription, and stirring for 10 min;
4) filtering the medicinal liquid with two 0.22 μm filters under nitrogen pressure of 0.2mPa or more, bottling into small glass bottle, pressing, capping, and performing moist heat sterilization at 121 deg.C for 15 min.
To further verify the feasibility of the present invention, the inventors performed the following experiments, in particular:
experimental example 1: the formula and the preparation method have the following source descriptions:
ondansetron injection, the reference formulation for USP (RLD), is ZOFRAN, the time of initial U.S. approval: in 1991, but ZOFRAN has now stopped production or sale, the ZOFRAN specification explicitly describes the prescription composition containing 2mg of ondansetron anhydrous, 9mg of sodium chloride, 0.5mg of citric acid monohydrate and 0.25mg of sodium citrate dihydrate per 1mL of aqueous solution in a 2mL single dose bottle; the pH is 3.3-4.0. Applicants applied QbD the concept to develop a manufacturing process to ensure that ondansetron injection is safe, effective and of controlled quality.
During the entire development process, the risk assessment is used to determine potentially high risk variables in the recipe and process, and thus which studies need to be performed to increase our understanding of the recipe process. The corresponding risks decrease as our understanding and research on products and processes continues to improve. For each unit operation, a risk assessment is performed, and the identified high risk variables are studied to determine key material attributes (CMAs) and key process parameters (CPPs). Therefore, the preparation method of the ondansetron injection which meets the quality standard and has simple and easily-controlled process is preferably selected through a large number of tests, and specifically comprises the following steps:
1) the inventor researches the dissolution characteristics and granularity of the ondansetron hydrochloride raw material medicine, the influence of the solvent temperature on the dissolution time and the influence of the charging sequence and retention time of the raw materials and auxiliary materials, optimizes the production process after a large number of research experiments, mixes the raw materials and the auxiliary materials after respectively pre-dissolving, only needs to control the water temperature at 40-80 ℃, can realize the solution uniformity after stirring for 10-30 minutes, and does not need to additionally use an acid-base regulator to regulate the pH value to the standard requirement of pharmacopeia in the prescription process.
2) The inventor carries out filtration research, and a large number of experiments prove that the filter membrane of 0.22 mu m (PVDF) has no influence on the quality of the ondansetron hydrochloride injection after filtration, and two-stage filtration is adopted in production, so that the removal of impurities is ensured to a greater extent. The process does not need to add activated carbon for impurity removal and heat source removal, avoids the risk that the activated carbon cannot completely remove or introduce impurities or increase insoluble particles, reduces the production process steps and reduces the production cost.
3) The inventor conducts the research of the sterilization condition, and a large number of experiments prove that F is formed under the condition of autoclave sterilization at 121 ℃ for 15min0Not less than 12min, and the quality of the ondansetron hydrochloride injection is not changed. The sterilization condition not only improves the stability of sterility guarantee and product quality, but also greatly reduces the production energy consumption and saves the production cost.
Experimental example 2 Process screening test
1. Materials and methods are shown in tables 1 and 2
TABLE 1 instruments and manufacturers
| Instrument for measuring the position of a moving object | Manufacturer of the product | Model number |
| Electronic balance | Mettler Toledo | XPE205 |
| PH meter | Mettler Toledo | FE20 |
| HPLC | Waters | e2695 |
| HPLC | Agilent | 1260 |
TABLE 2 sources of raw and auxiliary materials
| Name of material | Manufacturer of the product |
| Ondansetron hydrochloride | Taiwan Shenlong GmbH, China |
| Sodium chloride | Merck KGaA |
| Citric acid | Merck KGaA |
| Citric acid sodium salt | Merck KGaA |
| Water for injection | Self-made |
| Nitrogen gas | Self-made |
2. Influence of solvent temperature on ondansetron dissolution time
The ondansetron hydrochloride is weighed according to the prescription amount and is subjected to dissolution test at different temperatures (40 ℃,60 ℃ and 80 ℃), the solution is placed for different times, the stability of the solution is inspected, and the properties, pH, content and related substances of the solution are measured, and the results are shown in table 3.
TABLE 3 Effect of solvent temperature on ondansetron dissolution time
From table 3, the solubility of ondansetron hydrochloride is shown: the higher the temperature, the faster the dissolution rate; the characters, pH, content and related substances have no obvious change at 40 ℃,60 ℃ and 80 ℃, the related substance D is slightly increased along with the time extension at 80 ℃, which shows that the raw material can be quickly dissolved at 40 ℃ to 60 ℃, the related substance D is not obviously increased, and the preferred temperature of the invention is 60 ℃.
3. Stirring time screening experiment
In order to determine the stirring uniformity of the ingredient liquid medicine, after the ingredient constant volume is finished, sampling is carried out for 15 minutes, 20 minutes and 25 minutes to detect the pH value and the content. The results are shown in Table 4.
TABLE 4 results of the stirring time screening experiment
The data statistics show that all detection indexes meet the requirements after stirring for 15 minutes, 20 minutes and 25 minutes, and the stirring time is preferably 20 minutes.
4. Filtration study
The stability of the drug solution was examined by filtering the drug solution with a 0.22 μm (PVDF) filter membrane, and the properties, pH, content and related substances before and after the filtration were measured, and the results are shown in Table 5.
TABLE 5 results of the filtration study
The properties, pH, content and related substances are unchanged. Shows that the material of polyvinylidene fluoride (0.22 mu m (PVDF)) filter membrane has no obvious influence on the ondansetron injection. The microbial load quality standard of the liquid medicine after the secondary filtration requires that aerobic bacteria, mould and microzyme are all less than 1cfu/100 ml. In the invention, the preferable filter element is made of polyvinylidene fluoride, and the liquid medicine is subjected to secondary filtration.
5. Study of Sterilization conditions
The invention researches the influence of terminal sterilization conditions on the stability of the ondansetron injection, and inspects the temperature at 121 ℃/15 min; 121 ℃/20 min; 121 ℃/30 min; 121 ℃/60 min; 125 ℃/20 min; 125 ℃/30 min; the properties, pH, contents and related substances of the liquid medicine under the sterilization condition of 125 ℃/60min are shown in Table 6.
TABLE 6 results of the study of the Sterilization conditions
From the above results, it can be seen that: related substance D, maximum unknown single impurity, and total impurity all increased with the increase of sterilization temperature and sterilization time. The related substance D already exceeds the quality standard requirement at 121 deg.C/30 min, and F at 121 deg.C/15 min0The value has reached 22.4 minutes, greater than the 12 minutes required by the standard. The preferred sterilization condition of the invention is 121 ℃/15 min.
Experimental example 3 stability
The injection of example 4 was placed in a stability test chamber at 60 ℃ and sampled at 0, 1, 2, 3 and 6 months, and tested as specified under D, pH items for properties, content, chromatographic purity and related substances in the ondansetron injection in USP. In the above examples, the content of ondansetron as an active ingredient of the injection combined under different conditions is within the range of 95.0% -105.0% of the marked amount, the content of related substances D is less than 0.12%, the content of other single impurities is less than 0.2%, the total impurities are less than 0.5%, the pH value is within the range of 3.3-4.0, all detection results meet the standard requirements of USP, and no obvious difference exists among data accelerated for 6 months, which indicates that all injections have excellent stability. The content and chromatographic purity of 0 month of stability, typical pattern of related substance D are shown in FIGS. 1 to 9, Table 7.
TABLE 7 stability data from accelerated testing
The experimental examples prove that the preferred process of the invention is as follows:
1) adding 10% of injection water into a pre-dissolving tank, adding sodium chloride, citric acid monohydrate and sodium citrate dihydrate according to the prescription amount at the water temperature of 60 ℃, and mixing until the sodium chloride, the citric acid monohydrate and the sodium citrate dihydrate are dissolved;
2) adding injection water with the preparation amount of 10% into a pre-dissolving tank, adding ondansetron hydrochloride with the prescription amount at the water temperature of 60 ℃, and mixing until the ondansetron hydrochloride is dissolved;
3) mixing the dissolved adjuvants and raw materials in a mixing tank, adding injectable water to the full amount of the prescription, and stirring for 20 min;
4) filtering the medicinal liquid with two 0.22 μm filters under nitrogen pressure of 0.2mPa or more, bottling into small glass bottle, pressing, capping, and performing moist heat sterilization at 121 deg.C for 15 min.
While the invention has been described in detail in the foregoing by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that certain changes and modifications may be made therein based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. The ondansetron hydrochloride injection is characterized by comprising 1-3 mg of ondansetron hydrochloride, 8-10 mg of sodium chloride, 0.3-0.7 mg of citric acid monohydrate, 0.20-0.30 mg of sodium citrate dihydrate and 0.5-1.5 ml of water for injection.
2. The ondansetron hydrochloride injection of claim 1 wherein the injection is formulated from 2.49mg ondansetron hydrochloride, 9.0mg sodium chloride, 0.5mg citric acid monohydrate, 0.25mg sodium citrate dihydrate and 1.0ml water for injection.
3. The process for the preparation of an injection according to any one of claims 1 to 2, characterized in that it comprises the following steps:
1) adding injection water with the preparation amount of 5-20% into a pre-dissolving tank, adjusting the water temperature, adding sodium chloride, citric acid monohydrate and sodium citrate dihydrate with the prescription amount, and mixing until the sodium chloride, the citric acid monohydrate and the sodium citrate dihydrate are dissolved;
2) adding injection water with the preparation amount of 5-20% into a pre-dissolving tank, adjusting the water temperature, adding ondansetron hydrochloride with the prescription amount, and mixing until the ondansetron hydrochloride is dissolved;
3) mixing the dissolved adjuvants and raw materials in a mixing tank, adding injectable water to the full amount of the prescription, and stirring;
4) filtering the liquid medicine through a two-stage filter with the diameter of 0.22 mu m under the pressure of nitrogen gas of not less than 0.2mPa, filling the liquid medicine into a small glass bottle, pressing a stopper, rolling a cover, and performing moist heat sterilization at the temperature of 115-128 ℃ for 10-20min to obtain the liquid medicine.
4. The method for preparing an injection according to claim 3, wherein the water temperature in step 1) is 40 to 80 ℃.
5. The method for preparing injection according to claim 4, wherein the water temperature in step 1) is 60 ℃.
6. The method for preparing an injection according to claim 3, wherein the water temperature in the step 2) is 40 to 80 ℃.
7. The method for preparing injection according to claim 6, wherein the water temperature in step 2) is 60 ℃.
8. The method for preparing an injection according to claim 3, wherein the stirring time in the step 3) is 10 to 30 minutes.
9. The process for preparing an injection according to claim 8, wherein the stirring time in step 3) is 20 minutes.
10. The method for preparing the injection according to claim 3, wherein the step 4) is performed by moist heat sterilization at 121 ℃ for 15 min.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105769759A (en) * | 2016-04-13 | 2016-07-20 | 山东北大高科华泰制药有限公司 | Ondansetron hydrochloride injection composition and preparing method |
| CN112842991A (en) * | 2021-03-11 | 2021-05-28 | 北京鑫开元医药科技有限公司 | Granisetron hydrochloride injection and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105769759A (en) * | 2016-04-13 | 2016-07-20 | 山东北大高科华泰制药有限公司 | Ondansetron hydrochloride injection composition and preparing method |
| CN112842991A (en) * | 2021-03-11 | 2021-05-28 | 北京鑫开元医药科技有限公司 | Granisetron hydrochloride injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 无: "ZOFRAN injection prescribing information", 《ZOFRAN INJECTION PRESCRIBING INFORMATION》 * |
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