CN116270443A - Fu Nuola raw fumaric acid injection and preparation method thereof - Google Patents
Fu Nuola raw fumaric acid injection and preparation method thereof Download PDFInfo
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- 238000002347 injection Methods 0.000 title claims abstract description 121
- 239000007924 injection Substances 0.000 title claims abstract description 121
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims abstract description 86
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 239000001530 fumaric acid Substances 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title abstract description 29
- 239000000243 solution Substances 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 9
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 8
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 5
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 5
- 239000008139 complexing agent Substances 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 239000006172 buffering agent Substances 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 81
- 239000008215 water for injection Substances 0.000 claims description 44
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 37
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 30
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 30
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 30
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 25
- 239000001632 sodium acetate Substances 0.000 claims description 25
- 235000017281 sodium acetate Nutrition 0.000 claims description 25
- 239000001509 sodium citrate Substances 0.000 claims description 24
- 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 24
- 239000004289 sodium hydrogen sulphite Substances 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 238000011049 filling Methods 0.000 claims description 16
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 claims description 13
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 claims description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 238000001802 infusion Methods 0.000 claims description 6
- 235000011083 sodium citrates Nutrition 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 238000002474 experimental method Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 description 14
- 239000003814 drug Substances 0.000 description 13
- 229940124274 edetate disodium Drugs 0.000 description 13
- 238000007789 sealing Methods 0.000 description 13
- 239000003708 ampul Substances 0.000 description 12
- 229910001873 dinitrogen Inorganic materials 0.000 description 12
- 239000011521 glass Substances 0.000 description 12
- 230000003204 osmotic effect Effects 0.000 description 12
- 239000011148 porous material Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 229940079593 drug Drugs 0.000 description 9
- 230000000694 effects Effects 0.000 description 7
- 239000012535 impurity Substances 0.000 description 6
- 229920000858 Cyclodextrin Polymers 0.000 description 4
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 4
- 239000001116 FEMA 4028 Substances 0.000 description 4
- 208000007107 Stomach Ulcer Diseases 0.000 description 4
- 241000289690 Xenarthra Species 0.000 description 4
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 4
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 4
- 229960004853 betadex Drugs 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 230000027119 gastric acid secretion Effects 0.000 description 4
- 201000005917 gastric ulcer Diseases 0.000 description 4
- ROGSHYHKHPCCJW-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-n-methylmethanamine Chemical compound OC(=O)\C=C\C(O)=O.C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F ROGSHYHKHPCCJW-WLHGVMLRSA-N 0.000 description 3
- 206010063655 Erosive oesophagitis Diseases 0.000 description 3
- 208000007882 Gastritis Diseases 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 208000000718 duodenal ulcer Diseases 0.000 description 3
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- -1 organic acid salts Chemical class 0.000 description 3
- 208000000689 peptic esophagitis Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000019505 Deglutition disease Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000003978 infusion fluid Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000011146 sterile filtration Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 229950003825 vonoprazan Drugs 0.000 description 2
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- 102000019057 Cytochrome P-450 CYP2C19 Human genes 0.000 description 1
- 108010026925 Cytochrome P-450 CYP2C19 Proteins 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 239000003008 fumonisin Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940126535 potassium competitive acid blocker Drugs 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Classifications
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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
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a voronoi fumarate injection and a preparation method thereof. The injection comprises Fu Nuola raw fumaric acid, a metal ion complexing agent, a buffering agent, an antioxidant, a pH regulator and a solvent, wherein the metal ion complexing agent can enhance the stability of the fumaric acid Vonolamine injection to metal ions in the compatibility process, the buffering agent can effectively stabilize the pH value of the solution, the antioxidant can enhance the stability of the injection to oxygen, and the stability experiment shows that the injection is good in stability. Meanwhile, the invention also provides a method for preparing the Fu Nuola raw fumaric acid injection, which is simple to operate and suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a voronoi fumarate injection and a preparation method thereof.
Background
Fu Nuola (Vonoprazan Fumarate, TAK-438, chemical name: 5- (2-fluorophenyl) -N-methyl-1- (3-pyridinesulfonyl) -1H-pyrrole-3-methanamine fumarate, formula 1) is a novel potassium ion (K) + ) Competitive acid blockers (P-CAB) capable of inhibiting K in the last loop of gastric acid secretion by parietal cells + For H + ―K + The binding action of ATPase (proton pump) can stop gastric acid secretion in advance, and has strong and durable gastric acid secretion inhibiting action. The original manufacturer of the medicine is Japanese Wuta-tsai pharmaceutical Co., ltd, and the medicine is mainly used for treating reflux esophagitis, erosive esophagitis, gastric ulcer, duodenal ulcer, eradication of helicobacter pylori, and the like. Compared to the currently marketed mainstream gastric acid secretion inhibitor, the prazoles "proton pump inhibitors" (PPIs), show similar efficacy and safety among individuals in clinical trials due to the absence of CYP2C19 metabolism by vonolamine.
The current marketed formulation of vonolamine fumarate is a tablet, and no other formulation has been disclosed. Because the tablet belongs to an oral preparation, the compliance of dysphagia patients, children and old people is poor when the tablet is used for medicine; and for patients with acute gastritis and gastric ulcer needing quick effect, the tablet can not meet the clinical requirement of quick effect, so that the development of a new fumaraca drug dosage form, such as an injection, has important significance for providing treatment options for more patients with the requirement of drug administration and difficult administration of the tablet or curative effect.
Fumaric acid Fu Nuola is a substance which is slightly soluble in water, and is difficult to meet the requirement of injection on the solubility of medicines due to poor water solubility. Thus, there are great challenges in developing injectable dosage forms.
The prior art Chinese patent ZL201410154778.8 discloses novel water-soluble organic acid salts of voronoi (voronoi pyroglutamate and Fu Nuola pyrolactate) and injection of the novel water-soluble organic acid salts and a preparation method thereof, but compared with the voronoi fumarate which is an active ingredient on the market, the novel water-soluble organic acid salts have no treatment effect and safety supported by clinical experiments and medicinal practices, and have no technical means and effect for increasing the water solubility of the voronoi fumarate.
The Chinese patent ZL201610714831.4 reports an injection adopting substituted beta-cyclodextrin as a solubilizing auxiliary material, and the principle is that the beta-cyclodextrin inclusion technology is adopted: namely, the vonolamine fumarate molecules enter the beta-cyclodextrin cavity to increase the solubility of the bulk drug in the aqueous solution. However, researches in recent years find that the injection prepared by adopting the beta-cyclodextrin inclusion technology has great difference in bioavailability and effectiveness compared with the true solution (the crude drug is not included) injection, mainly because the crude drug can not be released from an inclusion state, and the human body can not effectively absorb the crude drug molecules in the inclusion state. Therefore, by adopting a non-inclusion method to improve the water solubility of the voronoi fumarate and improve the stability of an aqueous solution for injection, the development of the Fu Nuola fumaric acid composition and the injection suitable for injection and the preparation method thereof have great significance.
Disclosure of Invention
The invention aims to provide the futures injection and the preparation method thereof, which make up the blank that the futures tablet is mainly used and the injection is lacking in the current market, the injection has rapid drug effect, and can be directly injected into tissues, blood vessels or organs of human body in a liquid state during clinical application. Has strong practicability and is suitable for patients who are not suitable for oral administration. The injection is prepared by sealing liquid medicine or powder in a special container, isolating from external air, sterilizing or sterilizing during manufacture, and is more shelf stable than other liquid preparations. The Fu Nuola raw fumaric acid injection prepared by the method has stable and reliable quality, can maintain good physical and chemical stability in high-temperature and low-temperature environments, is simple and convenient to operate and convenient to implement, and has good industrial mass production prospect.
In a first aspect, the present invention provides a composition of voronoi fumarate comprising the metal ion complexing agent disodium edetate (disodium edentate), the buffering agent sodium acetate or sodium citrate and the antioxidant sodium bisulphite, the combination of disodium edetate (disodium edentate), sodium acetate or sodium citrate and sodium bisulphite being capable of increasing the solubility of voronoi fumarate in water.
The second aspect of the invention provides a Fu Nuola fumaric acid injection prepared from the composition of the first aspect, which has good storage stability, brings new medication options for special people who are not suitable for oral administration, and meets the clinical requirements of patients suffering from acute reflux esophagitis, gastritis, gastric ulcer, duodenal ulcer and erosive esophagitis for quick onset.
The third aspect of the invention provides a preparation method of the Fu Nuola fumaric acid injection according to the second aspect, which is simple and feasible, can be produced by adopting a sterile filtration technology, has good injection stability, less impurities and high safety, and is suitable for industrial production.
The fourth aspect of the invention also provides a solution for the voronoi fumarate infusion and a preparation method thereof.
Detailed Description
The invention provides a stable Fu Nuola raw fumaric acid injection which comprises raw material medicines of voronoi fumarate, metal ion complexing agent disodium ethylenediamine tetraacetate, buffer sodium acetate or sodium citrate, antioxidant sodium bisulphite, pH regulator dilute hydrochloric acid and solvent injection water, wherein the mass of the sodium acetate or the sodium citrate is 0.2-2.5 times of that of the voronoi fumarate, and the composition comprises the following components in mass-volume ratio, and the mass-volume ratio is in g/ml:
the mass ratio of the voronoi fumarate to the total volume of the injection is 0.40-1.50%;
the mass ratio of the disodium ethylenediamine tetraacetate relative to the total volume of the injection is 0.01-0.30%;
the mass ratio of sodium acetate or sodium citrate relative to the total volume of the injection is 0.10-3.00%;
the mass ratio of the sodium bisulfite relative to the total volume of the injection is 0.01-0.15%;
the pH regulator is dilute hydrochloric acid;
the solvent is water for injection;
the pH value of the injection is 3.5 to 4.0.
Further, the mass of sodium acetate or sodium citrate in the injection provided by the invention is 0.4-2.0 times of that of the voronoi fumarate, and the composition comprises the following components in mass-volume ratio, wherein the unit of mass-volume ratio is g/ml:
the mass ratio of the voronoi fumarate relative to the total volume of the injection is 0.60% -1.40%;
the mass ratio of the disodium ethylenediamine tetraacetate relative to the total volume of the injection is 0.03-0.25%;
the mass ratio of sodium acetate or sodium citrate relative to the total volume of the injection is 0.30-2.50%;
the mass ratio of the sodium bisulfite relative to the total volume of the injection is 0.01 to 0.13 percent;
a proper amount of dilute hydrochloric acid solution, and adjusting the pH value to 3.6-3.9;
the balance of water for injection.
The invention also provides a preparation method of the Fu Nuola fumaric acid injection, which comprises the following steps:
(A) Uniformly mixing vonolamine fumarate, disodium ethylenediamine tetraacetate, sodium acetate or sodium citrate and sodium bisulphite, and adding the mixture into a first part of injection water at 45-55 ℃ for dissolution and clarification, wherein the first part of injection water accounts for 50-95% of the total injection water;
(B) The pH value is regulated to 3.6 to 3.9 by adding 1mol/L dilute hydrochloric acid solution step by step;
(C) And adding a second part of water for injection into the mixture to reach the total volume, filtering the obtained solution by using a filter element with the aperture of 0.22um, filling, and filling nitrogen to obtain Fu Nuola raw fumaric acid injection, wherein the total amount of the water for injection in the second part and the water for injection in the first part is 100%.
In another aspect, the invention provides a solution for large infusion of voronoi fumarate. The large transfusion is prepared by directly adding the small-volume injection prepared by the invention into 0.9% sodium chloride solution or 5% glucose solution. The ratio of the mass of the voronoi fumarate to the total volume of the infusion is 0.02% -0.03% (W/V, g/mL).
The invention has the following beneficial technical effects:
(1) Based on the defects of the prior art, the invention discovers that the combination of disodium edetate (disodium edentate), sodium acetate or sodium citrate and sodium bisulphite can obviously increase the solubility of the fumonisin fumarate in water, and meanwhile, the solution has good stability and the effects of resisting metal ions, stabilizing the pH value of injection and resisting oxidization; the impurity content in the finished product can be effectively reduced;
(2) On one hand, the fumaric acid Fu Nuola raw injection prepared from the composition is a true solution (non-inclusion compound solution), has high bioavailability, quick response, good safety and good medication compliance for special people; on the other hand, the combination of disodium edetate (disodium edentate), sodium acetate or sodium citrate and sodium bisulphite and vonolamine fumarate is used in the preparation process of the injection, so that the solution stability is high, and the metal ion complexation phenomenon of large infusion solutions in the subsequent compatibility is avoided.
(3) The method has the advantages that the pH regulator 1mol/L dilute hydrochloric acid aqueous solution is added into the solution step by step in the preparation process of the injection, so that the impurity content in the finished product can be effectively reduced, the stability is good, the sample is placed at 60 ℃ for 3 days (72 hours), the impurity growth is little, and the method has good industrialized application prospect.
(4) The Fu Nuola raw fumaric acid injection composition provided by the invention can increase the solubility of the vonolamine fumarate in water, meets the requirement of preparing an injection, can be produced by adopting a sterile filtration technology, has few impurities and is high in safety; the Fu Nuola raw fumaric acid injection provided by the invention is a new dosage form, can meet the clinical requirements of patients with acute reflux esophagitis, gastritis, gastric ulcer, duodenal ulcer and erosive esophagitis on quick onset, can solve the administration difficulty of dysphagia patients, and has high safety and good stability. In addition, the preparation method of the voronoi fumarate infusion solution is simple and feasible, and is suitable for industrial production.
Detailed Description
The invention will be better understood by reference to the following examples, which are not intended to limit the scope of the invention:
example 1
TABLE 1 material ratios
The preparation method comprises the following steps:
(1) 2.672g of voronoi fumarate, 0.500g of edetate disodium, 5.00g of sodium acetate and 0.125g of sodium bisulphite are uniformly mixed, added into 200ml of water for injection at 45-55 ℃ and stirred, dissolved and clarified. Cooled to room temperature, ph=3.73 was adjusted by stepwise addition with 1mol/L hydrochloric acid under stirring, and the volume was fixed to 400ml with a second portion of water for injection.
(2) And then filtered by a filter element with the pore diameter of 0.22 um.
(3) Filling into 100 small water needle injection (4 ml/bottle) with glass ampoule, charging nitrogen gas, and sealing. The solution was allowed to stand at 25℃for 24 hours, and the solution was clarified.
The molar osmotic pressure concentration of the small water injection is measured as follows: 453 mOsmol/kg -1 。
Example 2
Table 2 material ratios
The preparation method comprises the following steps:
(1) 2.672g of voronoi fumarate, 0.500g of edetate disodium, 5.00g of sodium acetate and 0.125g of sodium bisulphite are uniformly mixed, added into 170ml of water for injection at 45-55 ℃, stirred, dissolved and clarified at 45-55 ℃. Cooled to room temperature, ph=3.74 was adjusted by stepwise addition with 1mol/L hydrochloric acid under stirring, and the volume was then fixed to 200ml with a second portion of water for injection.
(2) And then filtered by a filter element with the pore diameter of 0.22 um.
(3) Filling into 100 small water needle injection (2 ml/bottle) with glass ampoule bottle, charging nitrogen gas, and sealing. The solution was allowed to stand at 25℃for 24 hours, and the solution was clarified.
The molar osmotic pressure concentration of the small water injection is measured as follows: 792 mOsmol.kg -1 。
Example 3
Table 3 material proportions
The preparation method comprises the following steps:
(1) 2.672g of voronoi fumarate, 0.25g of edetate disodium, 2.50g of sodium acetate and 0.25g of sodium bisulphite are uniformly mixed, added into 200ml of water for injection at 45-55 ℃, stirred, dissolved and clarified at 45-55 ℃. Cooled to room temperature, ph=3.75 was adjusted by stepwise addition with 1mol/L hydrochloric acid under stirring, and the volume was then fixed to 400ml with a second portion of water for injection.
(2) And then filtered by a filter element with the pore diameter of 0.22 um.
(3) Filling into 100 small water needle injection (4 ml/bottle) with glass ampoule, charging nitrogen gas, and sealing. The solution was allowed to stand at 25℃for 24 hours, and the solution was clarified.
The molar osmotic pressure concentration of the small water injection is measured as follows: 239 mOsmol/kg -1 。
Example 4
Table 4 material proportions
The preparation method comprises the following steps:
(1) 2.672g of voronoi fumarate, 0.25g of edetate disodium, 2.50g of sodium acetate and 0.25g of sodium bisulphite are uniformly mixed, added into 170ml of water for injection at 45-55 ℃, stirred, dissolved and clarified at 45-55 ℃. Cooled to room temperature, the pH=3.74 was adjusted by stepwise addition with 1mol/L hydrochloric acid under stirring, and the volume was fixed to 200ml with a second portion of water for injection.
(2) And then filtered by a filter element with the pore diameter of 0.22 um.
(3) Filling into 100 small water needle injection (2 ml/bottle) with glass ampoule, charging nitrogen gas, and sealing. The solution was allowed to stand at 25℃for 24 hours, and the solution was clarified.
The molar osmotic pressure concentration of the small water injection is measured as follows: 451 mOsmol/kg -1 。
Example 5
Table 5 material ratios
The preparation method comprises the following steps:
(1) 2.672g of voronoi fumarate, 0.125g of edetate disodium, 1.250g of sodium acetate and 0.25g of sodium bisulphite are uniformly mixed, added into 200ml of water for injection at 45-55 ℃, stirred, dissolved and clarified at 45-55 ℃. Cooled to room temperature, ph=3.75 was adjusted by stepwise addition with 1mol/L hydrochloric acid under stirring, and the volume was fixed to 400ml with a second portion of water for injection.
(2) And then filtered by a filter element with the pore diameter of 0.22 um.
(3) Filling into 100 small water needle injection (4 ml/bottle) with glass ampoule, charging nitrogen gas, and sealing. The solution was allowed to stand at 25℃for 24 hours, and the solution was clarified.
The molar osmotic pressure concentration of the small water injection is measured as follows: 128 mOsmol.kg -1 。
Example 6
Table 6 material proportions
The preparation method comprises the following steps:
(1) 2.672g of voronoi fumarate, 0.125g of edetate disodium, 1.250g of sodium acetate and 0.25g of sodium bisulphite are uniformly mixed, added into 170ml of water for injection at 45-55 ℃, stirred, dissolved and clarified at 45-55 ℃. Cooled to room temperature, ph=3.75 was adjusted by stepwise addition with 1mol/L hydrochloric acid under stirring, and the volume was fixed to 200ml with a second portion of water for injection.
(2) And then filtered by a filter element with the pore diameter of 0.22 um.
(3) Filling into 100 small water needle injection (2 ml/bottle) with glass ampoule, charging nitrogen gas, and sealing. The solution was allowed to stand at 25℃for 24 hours, and the solution was clarified.
The molar osmotic pressure concentration of the small water injection is measured as follows: 246 mOsmol.kg -1 。
Example 7
TABLE 7 material ratios
The preparation method comprises the following steps:
(1) 2.672g of voronoi fumarate, 0.125g of edetate disodium, 1.250g of sodium acetate and 0.0625g of sodium bisulphite are uniformly mixed, added into 200ml of water for injection at 45-55 ℃, stirred, dissolved and clarified at 45-55 ℃. Cooled to room temperature, the ph=3.80 was adjusted by stepwise addition with 1mol/L hydrochloric acid under stirring, and the volume was fixed to 400ml with a second portion of water for injection.
(2) And then filtered by a filter element with the pore diameter of 0.22 um.
(3) Filling into 100 small water needle injection (4 ml/bottle) with glass ampoule, charging nitrogen gas, and sealing. The solution was allowed to stand at 25℃for 24 hours, and the solution was clarified.
The molar osmotic pressure concentration of the small water injection is measured as follows: 121mOsmol ]kg -1 。
Example 8
Table 8 material proportions
The preparation method comprises the following steps:
(1) 2.672g of voronoi fumarate, 0.500g of edetate disodium, 5.00g of sodium citrate and 0.125g of sodium bisulphite are uniformly mixed, added into 200ml of water for injection at 45-55 ℃ and stirred, dissolved and clarified. Cooled to room temperature, ph=3.76 was adjusted by stepwise addition with 1mol/L hydrochloric acid under stirring, and the volume was fixed to 400ml with a second portion of water for injection.
(2) And then filtered by a filter element with the pore diameter of 0.22 um.
(3) Filling into 100 small water needle injection (4 ml/bottle) with glass ampoule, charging nitrogen gas, and sealing. The solution was allowed to stand at 25℃for 24 hours, and the solution was clarified.
The molar osmotic pressure concentration of the small water injection is measured as follows: 264 mOsmol.kg -1 。
Example 9
Table 9 material proportions
The preparation method comprises the following steps:
(1) 2.672g of voronoi fumarate, 0.25g of edetate disodium, 2.50g of sodium citrate and 0.25g of sodium bisulphite are uniformly mixed, added into 350ml of water for injection at 45-55 ℃, stirred, dissolved and clarified at 45-55 ℃. Cooled to room temperature, ph=3.75 was adjusted by stepwise addition with 1mol/L hydrochloric acid under stirring, and the volume was then fixed to 400ml with a second portion of water for injection.
(2) And then filtered by a filter element with the pore diameter of 0.22 um.
(3) Filling into 100 small water needle injection (4 ml/bottle) with glass ampoule, charging nitrogen gas, and sealing. The solution was allowed to stand at 25℃for 24 hours, and the solution was clarified.
The molar osmotic pressure concentration of the small water injection is measured as follows: 157 mOsmol/kg -1 。
Example 10
Table 10 material proportions
The preparation method comprises the following steps:
(1) 2.672g of voronoi fumarate, 0.125g of edetate disodium, 1.250g of sodium citrate and 0.25g of sodium bisulphite are uniformly mixed, added into 370ml of water for injection at 45-55 ℃, stirred, dissolved and clarified at 45-55 ℃. Cooled to room temperature, ph=3.74 was adjusted by stepwise addition with 1mol/L hydrochloric acid under stirring, and the volume was fixed to 400ml with a second portion of water for injection.
(2) And then filtered by a filter element with the pore diameter of 0.22 um.
(3) Filling into 100 small water needle injection (4 ml/bottle) with glass ampoule, charging nitrogen gas, and sealing. The solution was allowed to stand at 25℃for 24 hours, and the solution was clarified.
The molar osmotic pressure concentration of the small water injection is measured as follows: 96 mOsmol.kg -1 。
Example 11
Table 11 material proportions
The preparation method comprises the following steps:
(1) 2.672g of voronoi fumarate, 0.125g of edetate disodium, 1.250g of sodium citrate and 0.0625g of sodium bisulphite are uniformly mixed, added into 350ml of water for injection at 45-55 ℃, stirred, dissolved and clarified at 45-55 ℃. Cooled to room temperature, ph=3.83 was adjusted by stepwise addition with 1mol/L hydrochloric acid under stirring, and the volume was fixed to 400ml with a second portion of water for injection.
(2) And then filtered by a filter element with the pore diameter of 0.22 um.
(3) Filling into 100 small water needle injection (4 ml/bottle) with glass ampoule, charging nitrogen gas, and sealing. The solution was allowed to stand at 25℃for 24 hours, and the solution was clarified.
The molar osmotic pressure concentration of the small water injection is measured as follows: 85 mOsmol.kg -1 。
Example 12
Table 12 material ratios
The preparation method comprises the following steps:
(1) 2.672g of voronoi fumarate, 0.125g of edetate disodium, 5.00g of sodium citrate and 0.0625g of sodium bisulphite are uniformly mixed, added into 170ml of water for injection at 45-55 ℃, stirred, dissolved and clarified at 45-55 ℃. Cooled to room temperature, and the pH=3.90 was adjusted by stepwise addition with 1mol/L hydrochloric acid under stirring, and the volume was fixed to 200ml with a second portion of water for injection.
(2) And then filtered by a filter element with the pore diameter of 0.22 um.
(3) Filling into 100 small water needle injection (2 ml/bottle) with glass ampoule, charging nitrogen gas, and sealing. The solution was clarified by standing at 25℃for 24 hours.
The molar osmotic pressure concentration of the small water injection is measured as follows: 480 mOsmol.kg -1 。
Comparative example 13
TABLE 13 material ratios
The preparation method comprises the following steps:
(1) 2.672g of voronoi fumarate, 0.125g of edetate disodium, 5.00g of disodium hydrogen phosphate and 0.0625g of sodium hydrogen sulfite are uniformly mixed, 200ml of water for injection at 45-55 ℃ is added, and the mixture is stirred for 2 hours at 45-55 ℃ without dissolution and clarification.
Example 14
Stability study conditions: the mixture was left at 60℃for 3 days (72 hours).
Stability study sample: example 1, example 3, example 5, example 7 injection samples.
TABLE 14 results of stability experiments
From the accelerated stability data, the water injection prepared by the method has good stability, the sample is placed at 60 ℃ for 3 days (72 hours), the impurity growth is little, and the water injection has good application prospect.
Example 15
Preparation of high-capacity infusion: a small volume injection (4 mL/branch) of the invention in example 1 was poured into 100mL of 0.9% (W/V, g/mL) sodium chloride solution, shaking up, and left at 25℃for 24 hours, the solution was clear.
High volume infusion osmolality measurement results: 303 mOsmol.kg -1 。
The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (10)
1. A stable Fu Nuola raw fumaric acid injection, which comprises Fu Nuola raw fumaric acid, disodium ethylenediamine tetraacetate serving as a metal ion complexing agent, sodium acetate or sodium citrate serving as a buffering agent, sodium bisulphite serving as an antioxidant, a pH regulator and a solvent, wherein the mass of sodium acetate or sodium citrate is 0.2-2.5 times that of voronoi fumarate, and the composition comprises the following components in mass-volume ratio, and the mass-volume ratio is in g/ml:
the mass ratio of the voronoi fumarate to the total volume of the injection is 0.40-1.50%;
the mass ratio of the disodium ethylenediamine tetraacetate relative to the total volume of the injection is 0.01-0.30%;
the mass ratio of sodium acetate or sodium citrate relative to the total volume of the injection is 0.10-3.00%;
the mass ratio of the sodium bisulfite relative to the total volume of the injection is 0.01-0.15%;
the pH regulator is dilute hydrochloric acid;
the solvent is water for injection;
the pH value of the injection is 3.5 to 4.0.
2. The injection according to claim 1, which is a small-volume injection, wherein the mass of sodium acetate or sodium citrate is 0.4-2.0 times the mass of voronoi fumarate, and the composition comprises the following components in g/ml by mass/volume ratio:
the mass ratio of the voronoi fumarate relative to the total volume of the injection is 0.60% -1.40%;
the mass ratio of the disodium ethylenediamine tetraacetate relative to the total volume of the injection is 0.03-0.25%;
the mass ratio of sodium acetate or sodium citrate relative to the total volume of the injection is 0.30-2.50%;
the mass ratio of the sodium bisulfite relative to the total volume of the injection is 0.01 to 0.13 percent;
a proper amount of dilute hydrochloric acid solution, and adjusting the pH value to 3.6-3.9;
the balance of water for injection.
3. Injection according to claim 1 or 2, consisting of the following components:
the ratio of the Vonoprazol fumarate mass to the total volume of the injection is 0.668%;
the mass ratio of the disodium ethylenediamine tetraacetate to the total volume of the injection is 0.0625%;
the proportion of the mass of sodium acetate relative to the total volume of the injection is 0.625%;
the proportion of the mass of the sodium bisulfite relative to the total volume of the injection is 0.0625 percent;
a proper amount of dilute hydrochloric acid solution, and adjusting the pH value to 3.6-3.9;
the balance of water for injection.
4. Injection according to claim 1 or 2, consisting of the following components:
the ratio of the Vonoprazol fumarate mass to the total volume of the injection is 0.668%;
the proportion of the mass of the disodium ethylenediamine tetraacetate relative to the total volume of the injection is 0.03125%;
the mass ratio of sodium acetate to the total volume of the injection is 0.3125%;
the proportion of the mass of the sodium bisulfite relative to the total volume of the injection is 0.0625 percent;
a proper amount of dilute hydrochloric acid solution, and adjusting the pH value to 3.6-3.9;
the balance of water for injection.
5. Injection according to claim 1 or 2, consisting of the following components:
the ratio of the Vonoprazol fumarate mass to the total volume of the injection is 0.668%;
the proportion of the mass of the disodium ethylenediamine tetraacetate relative to the total volume of the injection is 0.125%;
the proportion of the mass of sodium citrate relative to the total volume of the injection is 1.25%;
the proportion of the mass of the sodium bisulfite relative to the total volume of the injection is 0.03125%;
a proper amount of dilute hydrochloric acid solution, and adjusting the pH value to 3.6-3.9;
the balance of water for injection.
6. Injection according to claim 1 or 2, consisting of the following components:
the ratio of the Vonoprazol fumarate mass to the total volume of the injection is 0.668%;
the mass ratio of the disodium ethylenediamine tetraacetate to the total volume of the injection is 0.0625%;
the proportion of the mass of sodium citrate relative to the total volume of the injection is 0.625%;
the proportion of the mass of the sodium bisulfite relative to the total volume of the injection is 0.0625 percent;
a proper amount of dilute hydrochloric acid solution, and adjusting the pH value to 3.6-3.9;
the balance of water for injection.
7. Injection according to claim 1 or 2, consisting of the following components:
the ratio of the voronoi fumarate mass to the total volume of the injection is 1.336%;
the mass ratio of the disodium ethylenediamine tetraacetate to the total volume of the injection is 0.0625%;
the proportion of the mass of sodium citrate relative to the total volume of the injection is 2.5 percent;
the proportion of the mass of the sodium bisulfite relative to the total volume of the injection is 0.0313 percent;
a proper amount of dilute hydrochloric acid solution, and adjusting the pH value to 3.6-3.9;
the balance of water for injection.
8. The injection according to any one of claims 1 to 7, characterized in that it is a large volume infusion prepared by adding the small volume injection according to any one of claims 1 to 7 to a 0.9% sodium chloride solution or a 5% dextrose solution.
9. A method for preparing the Fu Nuola raw fumaric acid injection according to claims 1-7, which is characterized by comprising the following steps:
(A) Uniformly mixing vonolamine fumarate, disodium ethylenediamine tetraacetate, sodium acetate or sodium citrate and sodium bisulphite, adding the mixture into a first part of water for injection to dissolve and clarify, wherein the first part of water for injection accounts for 50% -95% of the total water for injection;
(B) The pH value is regulated to 3.6 to 3.9 by adding 1mol/L dilute hydrochloric acid solution step by step;
(C) And adding a second part of water for injection into the mixture to reach the total volume, filtering the obtained solution by using a filter element with the aperture of 0.22um, filling, and filling nitrogen to obtain Fu Nuola raw fumaric acid injection, wherein the total amount of the water for injection in the second part and the water for injection in the first part is 100 percent.
10. The method of preparing Fu Nuola green fumarate injection according to claim 9, wherein said first portion of water for injection has a temperature of 45 ℃ to 55 ℃.
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| WO2024027549A1 (en) * | 2022-08-04 | 2024-02-08 | 江苏柯菲平医药股份有限公司 | Pharmaceutical composition containing pyrrole gastric acid secretion inhibitor and preparation method therefor |
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| CN104582687A (en) * | 2012-06-27 | 2015-04-29 | 武田药品工业株式会社 | Liquid preparations of amines and organic acids stabilized by salts |
| CN106031710A (en) * | 2015-03-16 | 2016-10-19 | 南京优科制药有限公司 | Vonoprazan fumarate injection and preparation method thereof |
| CN106511344A (en) * | 2015-09-14 | 2017-03-22 | 王虹 | Novel application of gastric acid secretion inhibitor |
| US20180085361A1 (en) * | 2015-03-31 | 2018-03-29 | Takeda Pharmaceutical Company Limited | Novel pharmaceutical uses |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104582687A (en) * | 2012-06-27 | 2015-04-29 | 武田药品工业株式会社 | Liquid preparations of amines and organic acids stabilized by salts |
| CN106031710A (en) * | 2015-03-16 | 2016-10-19 | 南京优科制药有限公司 | Vonoprazan fumarate injection and preparation method thereof |
| US20180085361A1 (en) * | 2015-03-31 | 2018-03-29 | Takeda Pharmaceutical Company Limited | Novel pharmaceutical uses |
| CN106511344A (en) * | 2015-09-14 | 2017-03-22 | 王虹 | Novel application of gastric acid secretion inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2024027549A1 (en) * | 2022-08-04 | 2024-02-08 | 江苏柯菲平医药股份有限公司 | Pharmaceutical composition containing pyrrole gastric acid secretion inhibitor and preparation method therefor |
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