CN114767626A - Famotidine injection and preparation method thereof - Google Patents
Famotidine injection and preparation method thereof Download PDFInfo
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- CN114767626A CN114767626A CN202210342858.0A CN202210342858A CN114767626A CN 114767626 A CN114767626 A CN 114767626A CN 202210342858 A CN202210342858 A CN 202210342858A CN 114767626 A CN114767626 A CN 114767626A
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- famotidine
- injection
- chlorogenic acid
- water
- quaternary ammonium
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- 229940005526 famotidine injection Drugs 0.000 title claims abstract description 73
- 238000002360 preparation method Methods 0.000 title abstract description 26
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 51
- CWVRJTMFETXNAD-JUHZACGLSA-N chlorogenic acid Chemical compound O[C@@H]1[C@H](O)C[C@@](O)(C(O)=O)C[C@H]1OC(=O)\C=C\C1=CC=C(O)C(O)=C1 CWVRJTMFETXNAD-JUHZACGLSA-N 0.000 claims abstract description 48
- CWVRJTMFETXNAD-FWCWNIRPSA-N 3-O-Caffeoylquinic acid Natural products O[C@H]1[C@@H](O)C[C@@](O)(C(O)=O)C[C@H]1OC(=O)\C=C\C1=CC=C(O)C(O)=C1 CWVRJTMFETXNAD-FWCWNIRPSA-N 0.000 claims abstract description 45
- PZIRUHCJZBGLDY-UHFFFAOYSA-N Caffeoylquinic acid Natural products CC(CCC(=O)C(C)C1C(=O)CC2C3CC(O)C4CC(O)CCC4(C)C3CCC12C)C(=O)O PZIRUHCJZBGLDY-UHFFFAOYSA-N 0.000 claims abstract description 45
- CWVRJTMFETXNAD-KLZCAUPSSA-N Neochlorogenin-saeure Natural products O[C@H]1C[C@@](O)(C[C@@H](OC(=O)C=Cc2ccc(O)c(O)c2)[C@@H]1O)C(=O)O CWVRJTMFETXNAD-KLZCAUPSSA-N 0.000 claims abstract description 45
- 229940074393 chlorogenic acid Drugs 0.000 claims abstract description 45
- 235000001368 chlorogenic acid Nutrition 0.000 claims abstract description 45
- FFQSDFBBSXGVKF-KHSQJDLVSA-N chlorogenic acid Natural products O[C@@H]1C[C@](O)(C[C@@H](CC(=O)C=Cc2ccc(O)c(O)c2)[C@@H]1O)C(=O)O FFQSDFBBSXGVKF-KHSQJDLVSA-N 0.000 claims abstract description 45
- BMRSEYFENKXDIS-KLZCAUPSSA-N cis-3-O-p-coumaroylquinic acid Natural products O[C@H]1C[C@@](O)(C[C@@H](OC(=O)C=Cc2ccc(O)cc2)[C@@H]1O)C(=O)O BMRSEYFENKXDIS-KLZCAUPSSA-N 0.000 claims abstract description 45
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 claims abstract description 45
- 229960001596 famotidine Drugs 0.000 claims abstract description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 24
- 239000000243 solution Substances 0.000 claims abstract description 24
- 239000008215 water for injection Substances 0.000 claims abstract description 22
- 229920001661 Chitosan Polymers 0.000 claims abstract description 21
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 18
- 238000002347 injection Methods 0.000 claims abstract description 13
- 239000007924 injection Substances 0.000 claims abstract description 13
- 229940090044 injection Drugs 0.000 claims abstract description 12
- 229940045110 chitosan Drugs 0.000 claims abstract description 4
- 229960004063 propylene glycol Drugs 0.000 claims abstract description 4
- 239000011259 mixed solution Substances 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 18
- 230000001954 sterilising effect Effects 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000012528 membrane Substances 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 238000004659 sterilization and disinfection Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 11
- 239000012535 impurity Substances 0.000 abstract description 5
- 239000002510 pyrogen Substances 0.000 abstract description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 4
- 239000007853 buffer solution Substances 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- 230000003647 oxidation Effects 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 3
- 229910019142 PO4 Inorganic materials 0.000 abstract description 2
- 239000010452 phosphate Substances 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 7
- 238000009472 formulation Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 4
- 235000003704 aspartic acid Nutrition 0.000 description 4
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 208000008469 Peptic Ulcer Diseases 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 208000011906 peptic ulcer disease Diseases 0.000 description 3
- 235000013824 polyphenols Nutrition 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000001156 gastric mucosa Anatomy 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 description 2
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 1
- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 description 1
- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 1
- 101150056637 Hrh2 gene Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- AAWZDTNXLSGCEK-ZHQZDSKASA-N Quinic acid Natural products O[C@H]1CC(O)(C(O)=O)C[C@H](O)C1O AAWZDTNXLSGCEK-ZHQZDSKASA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010046274 Upper gastrointestinal haemorrhage Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 235000004883 caffeic acid Nutrition 0.000 description 1
- 229940074360 caffeic acid Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000001268 chyle Anatomy 0.000 description 1
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- YTJJRAWFHJBAMT-UHFFFAOYSA-N depside Natural products OC(=O)CC1=C(O)C=C(O)C=C1OC(=O)C1=CC=C(O)C(O)=C1 YTJJRAWFHJBAMT-UHFFFAOYSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- -1 diaminomethylene Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000002599 gastric fundus Anatomy 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
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- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Diabetes (AREA)
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a famotidine injection and a preparation method thereof. The famotidine injection comprises the following components: famotidine, chlorogenic acid, propylene glycol, chitosan quaternary ammonium salt and water for injection. The chlorogenic acid can greatly increase the solubility of famotidine in water, and the molecular structure of the chlorogenic acid contains a large amount of phenolic hydroxyl groups and has strong oxidation resistance, so that the famotidine injection is stable and is not degraded into other impurity substances; when sodium hydroxide or potassium hydroxide is added into the famotidine injection to adjust the pH value of the solution, as the molecular structure of chlorogenic acid contains carboxyl, the chlorogenic acid and the sodium hydroxide or the potassium hydroxide form a salt, the chlorogenic acid and the chlorogenic acid salt form a buffer system, the pH value of the solution can be kept stable for a long time, and the famotidine in the injection can be kept stable; the chitosan quaternary ammonium salt can adsorb phosphate radical and carboxylate radical on pyrogen molecules, and further remove pyrogen in famotidine injection.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to famotidine injection and a preparation method thereof.
Background
Famotidine (Famotidine), the third generation histamine H2 receptor antagonist of the family of peridothiazoles, was first discovered and synthesized in the 70's of the 20 th century by the central institute of pharmaceutical corporation, japan. The medicine has high affinity to H2 receptor, can reduce the stimulation of gastric acid to gastric mucosa, promote ulcer healing, increase blood flow of gastric mucosa to enhance defense factor, and has good therapeutic effect on peptic ulcer. Clinically, famotidine is mainly used for treating diseases such as upper gastrointestinal hemorrhage caused by peptic ulcer and gastric and duodenal chyle hemorrhage caused by tumor, esophagus or gastric fundus varicosis. Famotidine, chemically known as 3- [ [ [2- [ (diaminomethylene) -4-thiazolyl ] methyl ] thio ] -N-sulfamoylpropionamidine, is a white or off-white crystalline powder; slightly bitter in taste; the color becomes dark when meeting light; slightly soluble in methanol, very slightly soluble in acetone, hardly soluble in water or chloroform, and easily soluble in glacial acetic acid; the melting point is 160-165 ℃, and the materials are decomposed simultaneously during melting.
Because famotidine has poor solubility, the famotidine has extremely poor stability after being dissolved in water and is not dissolved in cold water, and the famotidine is dissolved by an acid solution which is used for assisting in dissolving, but the famotidine has poor stability in an acid environment and is more stable in a neutral solution. At present, common famotidine dosage forms are tablets, capsules, injections and the like. Chinese patent document CN 113143859A discloses a famotidine injection and a preparation method thereof, wherein the famotidine injection consists of famotidine, ethanol, glycerol, acid and mannitol, and the scheme adopts a compound system formed by ethanol-glycerol-acid to synergically and obviously increase the solubility, the tolerance to pH and the stability of the famotidine, so that the safety of the preparation is improved; chinese patent document CN 112006999A discloses a preparation method of famotidine preparation for injection, which greatly reduces the content of relevant substances of the prepared preparation and keeps the water content stable in the storage period by controlling the temperature of the prepared liquid at 20-30 ℃ and controlling the drying weight loss of a rubber plug to be below 0.15 percent, accelerates the dissolution speed of main medicine and obviously shortens the liquid preparation time by controlling the sequence of adding auxiliary materials, and all standards of the preparation accord with the regulations.
The prepared famotidine injection also has the problems of poor solubility, low stability, high impurity content and the like, and in view of the above, a famotidine injection is needed to be provided to solve the technical problems.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a famotidine injection and a preparation method thereof. Solves the problems of poor solubility, low stability, high impurity content and the like of the existing famotidine injection.
The invention aims to provide a famotidine injection.
A famotidine injection comprises the following components: famotidine, chlorogenic acid, propylene glycol, chitosan quaternary ammonium salt and water for injection.
Further, by mass percentage, the amount of famotidine is 1-1.5%, the amount of chlorogenic acid is 1-3%, the amount of propylene glycol is 5-8%, the amount of chitosan quaternary ammonium salt is 0.05-1%, and the balance is water for injection.
Further, the pH value of the famotidine injection is 5.2-6.0, and the pH value can be adjusted by adding sodium hydroxide or potassium hydroxide.
Furthermore, the pH value of the famotidine injection is 5.5-5.8.
The invention also aims to provide a preparation method of the famotidine injection.
The preparation method of the famotidine injection comprises the following steps:
s1, taking injection water with the amount of 80-90% of the prescription amount, heating and preserving heat;
s2, adding chlorogenic acid in a prescription amount into the water for injection in the step S1, fully stirring to dissolve the chlorogenic acid, adding famotidine in the prescription amount, and continuing stirring to fully dissolve the famotidine to obtain a first mixed solution;
s3, cooling the first mixed solution obtained in the step S2, then respectively adding the formula amount of propylene glycol, the formula amount of chitosan quaternary ammonium salt and the balance of water for injection, stirring uniformly, and adjusting the pH value of the solution to obtain a second mixed solution;
s4, filtering the second mixed solution obtained in the step S3 by a filter membrane, and then sterilizing to obtain the famotidine injection.
Further, in step S1, the heating temperature is 70-80 ℃.
Further, in step S3, the temperature of the temperature decrease is 30 ℃ or lower.
Further, in step S4, the filter size is 0.22 μm.
Further, in step S4, the sterilization parameters are as follows: sterilizing for 15-30 min at the temperature of 100-115 ℃.
Compared with the prior art, the invention has the following advantages:
the famotidine injection comprises the following components: famotidine, chlorogenic acid, propylene glycol, chitosan quaternary ammonium salt and water for injection. The chlorogenic acid is a depside acid formed by caffeic acid and quinic acid, the molecular structure of the chlorogenic acid has three partial structures of carboxyl, unsaturated double bond and polyphenol, the aqueous solution of the chlorogenic acid is acidic, the solubility of famotidine in water can be greatly increased, and the molecular structure of the chlorogenic acid contains a large amount of phenolic hydroxyl groups and has strong oxidation resistance, so that famotidine injection can be kept stable and is not degraded into other impurity substances; when sodium hydroxide or potassium hydroxide is added into the famotidine injection to adjust the pH value of the solution, as the molecular structure of chlorogenic acid contains carboxyl, the chlorogenic acid and the sodium hydroxide or the potassium hydroxide form a salt, the chlorogenic acid and the chlorogenic acid salt form a buffer system, the stability of the pH value of the solution can be kept for a long time, and the famotidine in the injection is kept stable; meanwhile, chlorogenic acid is also an antibacterial agent, and can obviously prolong the storage time of the famotidine injection; the propylene glycol is used as a dispersing agent, so that the famotidine injection is uniformly dispersed; the chitosan quaternary ammonium salt is a high molecular compound, has positive charges in the molecular structure, can adsorb phosphate radicals and carboxylate radicals on pyrogen molecules, further removes the pyrogen in the famotidine injection, has antibacterial performance, and has synergistic effect with chlorogenic acid, so that the storage time of the famotidine injection is greatly prolonged.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below. It is to be understood that the embodiments described are merely exemplary embodiments, rather than exemplary embodiments, and that all other embodiments may be devised by those skilled in the art without departing from the scope of the present invention.
The conventional reagents and equipment used in the present invention are commercially available unless otherwise specified.
Example 1
The famotidine injection comprises, by mass, 1% of famotidine, 1% of chlorogenic acid, 5% of propylene glycol, 0.05% of chitosan quaternary ammonium salt and the balance of water for injection.
The preparation method of the famotidine injection comprises the following steps:
s1, taking injection water with the amount of 80-90% of the prescription amount, heating to 70-80 ℃, and then preserving heat;
s2, adding chlorogenic acid in a prescription amount into the water for injection in the step S1, fully stirring to dissolve the chlorogenic acid, adding famotidine in the prescription amount, and continuing stirring to fully dissolve the famotidine to obtain a first mixed solution;
s3, cooling the first mixed solution obtained in the step S2 to a temperature below 30 ℃, then respectively adding the formula amount of propylene glycol, the formula amount of chitosan quaternary ammonium salt and the balance of water for injection, uniformly stirring, and adjusting the pH value of the solution to 5.8 to obtain a second mixed solution;
s4, filtering the second mixed solution obtained in the step S3 by a filter membrane with the specification of 0.22 mu m, and sterilizing for 15-30 min at the temperature of 100-115 ℃ to obtain the famotidine injection.
Example 2
The famotidine injection comprises, by mass, 1.2% of famotidine, 1.8% of chlorogenic acid, 6% of propylene glycol, 0.07% of chitosan quaternary ammonium salt and the balance of water for injection.
The preparation method of the famotidine injection comprises the following steps:
s1, taking injection water with the amount of 80-90% of the prescription amount, heating to 70-80 ℃, and then preserving heat;
s2, adding chlorogenic acid in a prescription amount into the water for injection in the step S1, fully stirring to dissolve the chlorogenic acid, adding famotidine in the prescription amount, and continuing stirring to fully dissolve the famotidine to obtain a first mixed solution;
s3, cooling the first mixed solution obtained in the step S2 to a temperature below 30 ℃, then respectively adding the propylene glycol, the chitosan quaternary ammonium salt and the rest of the water for injection according to the prescription amount, uniformly stirring, and adjusting the pH value of the solution to 5.7 to obtain a second mixed solution;
s4, filtering the second mixed solution obtained in the step S3 by a filter membrane with the specification of 0.22 μm, and sterilizing for 15-30 min at the temperature of 100-115 ℃ to obtain the famotidine injection.
Example 3
The famotidine injection comprises, by mass, 1.4% of famotidine, 2.5% of chlorogenic acid, 7% of propylene glycol, 0.09% of chitosan quaternary ammonium salt and the balance of water for injection.
The preparation method of the famotidine injection comprises the following steps:
s1, taking injection water with the amount of 80-90% of the prescription amount, heating to 70-80 ℃, and then preserving heat;
s2, adding chlorogenic acid in a prescription amount into the water for injection in the step S1, fully stirring to dissolve the chlorogenic acid, adding famotidine in the prescription amount, and continuing stirring to fully dissolve the famotidine to obtain a first mixed solution;
s3, cooling the first mixed solution obtained in the step S2 to a temperature below 30 ℃, then respectively adding the formula amount of propylene glycol, the formula amount of chitosan quaternary ammonium salt and the balance of water for injection, uniformly stirring, and adjusting the pH value of the solution to 5.6 to obtain a second mixed solution;
s4, filtering the second mixed solution obtained in the step S3 by a filter membrane with the specification of 0.22 mu m, and sterilizing for 15-30 min at the temperature of 100-115 ℃ to obtain the famotidine injection.
Example 4
The famotidine injection comprises, by mass, 1.5% of famotidine, 3% of chlorogenic acid, 8% of propylene glycol, 1% of chitosan quaternary ammonium salt and the balance of water for injection.
The preparation method of the famotidine injection comprises the following steps:
s1, taking injection water with the amount of 80-90% of the prescription amount, heating to 70-80 ℃, and then preserving heat;
s2, adding chlorogenic acid in a prescription amount into the water for injection in the step S1, fully stirring to dissolve the chlorogenic acid, adding famotidine in the prescription amount, and continuing stirring to fully dissolve the famotidine to obtain a first mixed solution;
s3, cooling the first mixed solution obtained in the step S2 to a temperature below 30 ℃, then respectively adding the propylene glycol, the chitosan quaternary ammonium salt and the rest of the water for injection according to the prescription amount, uniformly stirring, and adjusting the pH value of the solution to 5.5 to obtain a second mixed solution;
s4, filtering the second mixed solution obtained in the step S3 by a filter membrane with the specification of 0.22 μm, and sterilizing for 15-30 min at the temperature of 100-115 ℃ to obtain the famotidine injection.
Comparative example 1
The formula and preparation method of famotidine injection are basically the same as those in example 2, except that chlorogenic acid is not added into the famotidine injection, and hydrochloric acid is added during the preparation process.
Comparative example 2
The formulation and preparation method of famotidine injection are basically the same as those in example 2, except that chlorogenic acid in the famotidine injection is replaced by aspartic acid.
Comparative example 3
The formula and preparation method of famotidine injection are basically the same as those in example 2, except that chitosan quaternary ammonium salt is not added into famotidine injection.
Example 5
The famotidine injection solutions prepared in examples 1-4 and comparative examples 1-3 were tested for long-term stability, and samples were taken for 12 months under long-term conditions (25 + -2 deg.C, 60 + -10% RH), and then sampled at months 0, 6 and 12, respectively, to determine the contents, pH and related substances, and the results are shown in Table 1 below:
wherein, the content, the pH value and related substances are measured according to the regulations in famotidine injection in the second part of China pharmacopoeia 2020 edition.
TABLE 1 Long term stability test results
As can be seen from the results in the table, after the famotidine injection prepared in the examples 1-4 is placed for 12 months, the pH value of the solution is basically kept stable, the related substances are slightly increased, the content of famotidine is slightly reduced, the storage time of the whole injection is longer, and the solution is kept stable.
The formula and preparation method of the motidine injection in the comparative example 1 are basically the same as those in the example 2, except that chlorogenic acid is not added into the famotidine injection, and hydrochloric acid is added during the preparation process. As a result, after the prepared famotidine injection is placed for 12 months, the pH value of the solution is reduced, related substances are obviously increased, and the content of famotidine is obviously reduced. The water solution of the chlorogenic acid is acidic, so that the solubility of the famotidine in water can be greatly increased, and the molecular structure of the chlorogenic acid contains a large amount of phenolic hydroxyl groups and has strong oxidation resistance, so that the famotidine injection is stable and is not degraded into other impurity substances; when sodium hydroxide or potassium hydroxide is added into the famotidine injection to adjust the pH value of the solution, as the molecular structure of chlorogenic acid contains carboxyl, the chlorogenic acid and the sodium hydroxide or the potassium hydroxide form a salt, the chlorogenic acid and the chlorogenic acid salt form a buffer system, the pH value of the solution can be kept stable for a long time, and the famotidine in the injection can be kept stable.
The formulation and preparation method of famotidine injection in comparative example 2 are substantially the same as those in example 2, except that chlorogenic acid in the famotidine injection is replaced by aspartic acid. As a result, after the prepared famotidine injection is placed for 12 months, the pH value of the solution is reduced to a certain extent, related substances are increased, and the content of famotidine is reduced. Although the aqueous solution of the aspartic acid is acidic, the solubility of the famotidine in water can be greatly increased, but the aspartic acid lacks the anti-oxidation performance, so that the stability of the prepared famotidine injection is reduced.
The formulation and preparation method of famotidine injection in comparative example 3 are substantially the same as those in example 2, except that chitosan quaternary ammonium salt is not added to the famotidine injection. As a result, after the prepared famotidine injection is placed for 12 months, the pH value of the solution is reduced to a certain extent, related substances are increased, and the content of famotidine is reduced. This is because the pyrogen in the prepared famotidine injection cannot be removed without adding chitosan quaternary ammonium salt, which results in the increase of the content of other substances.
Example 6
10 patients with peptic ulcer and hemorrhagic symptoms were selected and treated with intravenous infusion using famotidine injection (2 mL: 24mg) prepared in example 2, and first, famotidine injection was diluted with 5% dextrose saline so that the concentration of the dilution was 0.08mg/mL, and then intravenous infusion was performed on each of the above 10 patients, and the presence or absence of side effects during the infusion was observed.
No side effect occurs in 10 cases of patients who are transfused during the transfusion process, and the result shows that the famotidine injection prepared by the invention is safe and has no obvious side effect.
Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will understand that: any person skilled in the art can modify or easily conceive the technical solutions described in the foregoing embodiments or equivalent substitutes for some technical features within the technical scope of the present disclosure; such modifications, changes or substitutions do not depart from the spirit and scope of the embodiments of the present invention, and they should be construed as being included therein.
Claims (9)
1. The famotidine injection is characterized by comprising the following components: famotidine, chlorogenic acid, propylene glycol, chitosan quaternary ammonium salt and water for injection.
2. The famotidine injection according to claim 1, wherein the famotidine is 1-1.5% by mass, the chlorogenic acid is 1-3% by mass, the propylene glycol is 5-8% by mass, the chitosan quaternary ammonium salt is 0.05-1% by mass, and the balance is water for injection.
3. The famotidine injection according to claim 1, wherein the famotidine injection has a pH value of 5.2-6.0, and the pH value can be adjusted by adding sodium hydroxide or potassium hydroxide.
4. The famotidine injection according to claim 3, wherein the famotidine injection has a pH of 5.5-5.8.
5. The method for preparing famotidine injection according to any one of claims 1 to 4, which comprises the following steps:
s1, taking 80-90% of injection water according to the prescription amount, heating and then preserving heat;
s2, adding chlorogenic acid with the prescription amount into the water for injection in the step S1, fully stirring to dissolve the chlorogenic acid, then adding famotidine with the prescription amount, and continuing stirring to fully dissolve the famotidine to obtain a first mixed solution;
s3, cooling the first mixed solution obtained in the step S2, then respectively adding the formula amount of propylene glycol, the formula amount of chitosan quaternary ammonium salt and the balance of water for injection, stirring uniformly, and adjusting the pH value of the solution to obtain a second mixed solution;
s4, filtering the second mixed solution obtained in the step S3 by a filter membrane, and then sterilizing to obtain the famotidine injection.
6. The method for preparing famotidine injection according to claim 5, wherein the heating temperature in step S1 is 70-80 ℃.
7. The method of claim 5, wherein the temperature of the solution is reduced to 30 ℃ or lower in step S3.
8. The method of claim 5, wherein the size of the filter membrane is 0.22 μm in step S4.
9. The method of claim 5, wherein the sterilization parameters in step S4 are as follows: sterilizing for 15-30 min at the temperature of 100-115 ℃.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11193233A (en) * | 1997-10-16 | 1999-07-21 | Yamanouchi Pharmaceut Co Ltd | Injection agent |
| CN1421204A (en) * | 2002-12-04 | 2003-06-04 | 黄振华 | Lafutidine injecta and its prepn |
| CN101716136A (en) * | 2009-11-27 | 2010-06-02 | 河南辅仁怀庆堂制药有限公司 | Famotidine injection and preparation method thereof |
| CN102225050A (en) * | 2011-06-28 | 2011-10-26 | 回音必集团(江西)东亚制药有限公司 | Method for preparing famotidine sodium chloride injection by inclusion method and product prepared by using the same |
| CN103550170A (en) * | 2013-10-15 | 2014-02-05 | 海南卫康制药(潜山)有限公司 | Lafutidine composition freeze-dried powder injection for injection |
-
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- 2022-03-31 CN CN202210342858.0A patent/CN114767626A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11193233A (en) * | 1997-10-16 | 1999-07-21 | Yamanouchi Pharmaceut Co Ltd | Injection agent |
| CN1421204A (en) * | 2002-12-04 | 2003-06-04 | 黄振华 | Lafutidine injecta and its prepn |
| CN101716136A (en) * | 2009-11-27 | 2010-06-02 | 河南辅仁怀庆堂制药有限公司 | Famotidine injection and preparation method thereof |
| CN102225050A (en) * | 2011-06-28 | 2011-10-26 | 回音必集团(江西)东亚制药有限公司 | Method for preparing famotidine sodium chloride injection by inclusion method and product prepared by using the same |
| CN103550170A (en) * | 2013-10-15 | 2014-02-05 | 海南卫康制药(潜山)有限公司 | Lafutidine composition freeze-dried powder injection for injection |
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