CN113521244A - Argatroban injection and preparation method thereof - Google Patents
Argatroban injection and preparation method thereof Download PDFInfo
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- CN113521244A CN113521244A CN202010304118.9A CN202010304118A CN113521244A CN 113521244 A CN113521244 A CN 113521244A CN 202010304118 A CN202010304118 A CN 202010304118A CN 113521244 A CN113521244 A CN 113521244A
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- China
- Prior art keywords
- argatroban
- injection
- acetic acid
- glacial acetic
- water
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- 229940033590 argatroban injection Drugs 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title abstract description 25
- AIEZTKLTLCMZIA-CZSXTPSTSA-N (2r,4r)-1-[(2s)-5-(diaminomethylideneamino)-2-[(3-methyl-1,2,3,4-tetrahydroquinolin-8-yl)sulfonylamino]pentanoyl]-4-methylpiperidine-2-carboxylic acid;hydrate Chemical compound O.OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NCC(C)C2 AIEZTKLTLCMZIA-CZSXTPSTSA-N 0.000 title 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 60
- 229960003856 argatroban Drugs 0.000 claims abstract description 60
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 claims abstract description 60
- KXNPVXPOPUZYGB-IOVMHBDKSA-N (2R,4R)-1-[(2S)-5-(diaminomethylideneamino)-2-[(3-methyl-1,2,3,4-tetrahydroquinolin-8-yl)sulfonylamino]-1-oxopentyl]-4-methyl-2-piperidinecarboxylic acid Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NCC(C)C2 KXNPVXPOPUZYGB-IOVMHBDKSA-N 0.000 claims abstract description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229960000583 acetic acid Drugs 0.000 claims abstract description 29
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 27
- 239000008215 water for injection Substances 0.000 claims abstract description 20
- 238000003756 stirring Methods 0.000 claims abstract description 19
- 230000001954 sterilising effect Effects 0.000 claims abstract description 18
- 239000004094 surface-active agent Substances 0.000 claims abstract description 17
- 238000001914 filtration Methods 0.000 claims abstract description 16
- 239000000243 solution Substances 0.000 claims description 26
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 12
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 12
- 229940068968 polysorbate 80 Drugs 0.000 claims description 12
- 229920000053 polysorbate 80 Polymers 0.000 claims description 12
- 101000656751 Haloarcula marismortui (strain ATCC 43049 / DSM 3752 / JCM 8966 / VKM B-1809) 30S ribosomal protein S24e Proteins 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- -1 polyoxyethylene Polymers 0.000 claims description 4
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims description 3
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- 229920001993 poloxamer 188 Polymers 0.000 claims description 3
- 229940044519 poloxamer 188 Drugs 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 abstract description 15
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 abstract description 15
- 239000000600 sorbitol Substances 0.000 abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 abstract description 12
- 238000002347 injection Methods 0.000 abstract description 9
- 239000007924 injection Substances 0.000 abstract description 9
- 229940090044 injection Drugs 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 238000011049 filling Methods 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000011259 mixed solution Substances 0.000 abstract 1
- 238000005352 clarification Methods 0.000 description 22
- 229960002920 sorbitol Drugs 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 12
- 239000012528 membrane Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 108090000190 Thrombin Proteins 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229960004072 thrombin Drugs 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010053942 Cerebral haematoma Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical group CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020565 Hyperaemia Diseases 0.000 description 1
- 206010021036 Hyponatraemia Diseases 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 239000004019 antithrombin Substances 0.000 description 1
- 108010072035 antithrombin III-protease complex Proteins 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011038 discontinuous diafiltration by volume reduction Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- QIWWZEXNQJWZCR-UHFFFAOYSA-M phosphoric acid tetrabutylazanium hydroxide Chemical compound P(O)(O)(O)=O.[OH-].C(CCC)[N+](CCCC)(CCCC)CCCC QIWWZEXNQJWZCR-UHFFFAOYSA-M 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- LCHWKMAWSZDQRD-UHFFFAOYSA-N silylformonitrile Chemical group [SiH3]C#N LCHWKMAWSZDQRD-UHFFFAOYSA-N 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 201000005665 thrombophilia Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- 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
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an argatroban injection and a preparation method thereof. The argatroban injection comprises argatroban, glacial acetic acid, a surfactant and water for injection, and is prepared by dissolving argatroban in glacial acetic acid, adding the mixed solution into the water for injection containing the surfactant, stirring, filtering, filling and sterilizing. The argatroban injection disclosed by the invention is not added with sorbitol, ethanol, glycerol and the like, so that the medication safety is ensured, and the solubility and the stability of the injection are improved by adding glacial acetic acid and a surfactant.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an argatroban injection and a preparation method thereof.
Background
Argatroban (Argatroban), chemical name (2R,4R) -4-methyl-1- [ N- [ (3-methyl-1, 2,3, 4-tetrahydro-8-quinolyl) sulfonyl]-L-arginyl]-2-piperidinecarboxylic acid of the formula C23H36N6O5S, molecular weight 508.6. Argatroban is a highly active, highly selective thrombin inhibitor, the anticoagulant effect of argatroban is independent of the antithrombin in vivo, but it directly binds to and inactivates thrombin free in blood; in addition, the argatroban with small molecular weight can directly enter the inside of the thrombus for inactivationThrombin, which has been bound to fibrin, indirectly inhibits thrombin generation, so that an extremely low concentration of argatroban inhibits platelet aggregation reaction induced by thrombin. The argatroban can greatly reduce the level of thrombin-antithrombin complex in blood plasma and effectively improve the hypercoagulable state of patients, so the argatroban has very good clinical effect in chronic thromboembolic diseases.
Poor water solubility is a major problem in the preparation of argatroban injections, and argatroban with a solubility of about 0.8-0.9mg/mL is considered as slightly to minimally soluble in water according to the classification of usp solutes, and is also sensitive to light and heat, which, unless stabilized, has a tendency to degrade. At present, the prescription of argatroban injection on the market in the United states comprises 250mg of argatroban, 750mg of D-sorbitol and 1000mg of absolute ethyl alcohol in each bottle, and the prescription on the market in Japan comprises 10mg of argatroban, 300mg of absolute ethyl alcohol and 900mg of glycerol in each bottle. The solubility of argatroban is increased by adding organic solvent into the two formulas, but the introduction of the organic solvent also increases the medication risk and the production difficulty, the production cost is high, and the product quality is difficult to control.
Sorbitol has solubilization effect on argatroban, 0.475-0.525g of argatroban and 50-60g of sorbitol are contained in each 1000ml of argatroban injection disclosed in CN103463614B, 0.5mg/ml of argatroban, 0.1-0.4mg/ml of nitroglycerin and 30-80mg/ml of D-sorbitol are contained in argatroban injection disclosed in CN102755289B, and a large amount of sorbitol is also contained in the injection disclosed in CN 103070822B. Sorbitol has tissue dehydration and diuresis effects, and can easily cause water and electrolyte disorder in vivo when used in large amount, resulting in heart failure, dilutive hyponatremia and hyperemia; meanwhile, patients suffering from acute cerebral hemorrhage and hematoma are not suitable for using a large amount of sorbitol, otherwise the symptoms are aggravated; for patients with osmotic nephropathy, after a large amount of sorbitol is used, the phenomenon of urine volume reduction is easy to appear clinically, and even acute renal failure is caused. Therefore, the addition of sorbitol in argatroban injection reduces the safety of the argatroban injection, and undoubtedly can significantly reduce the range of target patients. CN101516370A discloses an argatroban aqueous preparation, which is prepared into injection by adopting lactobionic acid and methionine as solubilizers and simultaneously assisting with stabilizers, and although the argatroban aqueous preparation does not contain organic solvents such as sorbitol, ethanol, glycerol and the like, the argatroban aqueous preparation has a complex preparation process and is not suitable for large-scale production in a workshop.
In view of this, an argatroban injection with simple preparation process, safe and reliable auxiliary materials and good stability is needed.
Disclosure of Invention
In view of the defects of the prior art, the invention provides an argatroban injection. The argatroban injection disclosed by the invention is free of sorbitol, ethanol, glycerol and the like, so that the medication safety is ensured, and the argatroban injection is good in solubility and high in stability.
In order to achieve the above object of the present invention, the inventors conducted a large number of experiments. As argatroban is almost insoluble in water, if no solubilizer is added, argatroban is difficult to dissolve, but the use of a large amount of solubilizer influences the safety of medication. The inventor dissolves argatroban in glacial acetic acid, and adds water for injection, so that precipitation is generated after the argatroban is placed for a period of time. On the basis, the inventor continues experiments, and finally finds that the stable argatroban injection can be obtained by compounding glacial acetic acid and a certain amount of surfactant.
The invention is realized by the following scheme:
an argatroban injection comprises argatroban, glacial acetic acid, surfactant and water for injection.
The surfactant is one of HS15, poloxamer 188, polysorbate 80, span 60 and polyoxyethylene 40 hydrogenated castor oil.
Preferably, the surfactant is HS15 or polysorbate 80.
The weight ratio of the argatroban to the surfactant is 1: 0.3-5.
Preferably, the weight ratio of argatroban to polysorbate 80 is 1: 0.6-3.
Further preferably, the weight ratio of argatroban to polysorbate 80 is 1: 0.8.
The weight ratio of argatroban to glacial acetic acid is 1: 1-10.
Preferably, the weight ratio of argatroban to glacial acetic acid is 1: 2-6.
Further preferably, the weight ratio of argatroban to glacial acetic acid is 1: 3.
The invention also provides a preparation method of the argatroban injection, which comprises the following specific steps: dissolving argatroban in glacial acetic acid, adding the solution into water for injection containing surfactant, stirring, filtering, bottling, and sterilizing.
Compared with the prior art, the invention has the following advantages: (1) the product does not contain sorbitol, ethanol and other solvents, and has high safety, good stability and high clarity; (2) the preparation process is simple and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are given for illustrative purposes only and are not intended to limit the present invention. Therefore, simple modifications of the present invention in the process of the present invention are within the scope of the claimed invention.
Example 1 Argatroban injection
1) Prescription
2) Preparation process
Dissolving argatroban in a prescription amount in glacial acetic acid, adding the solution into injection water containing polysorbate 80, stirring, filtering with 0.2 μm filter membrane, bottling, and sterilizing at 121 deg.C for 15 min.
Example 2 Argatroban injection
1) Prescription
2) Preparation process
Dissolving argatroban in a prescription amount in glacial acetic acid, adding the solution into water for injection containing HS15, stirring, filtering with 0.2 μm filter membrane, bottling, and sterilizing at 121 deg.C for 15 min.
Example 3 Argatroban injection
1) Prescription
2) Preparation process
Dissolving argatroban in a prescription amount in glacial acetic acid, adding the solution into water for injection containing poloxamer 188, stirring, filtering with 0.2 μm filter membrane, bottling, and sterilizing at 121 deg.C for 15 min.
Example 4 Argatroban injection
1) Prescription
2) Preparation process
Dissolving argatroban in glacial acetic acid, adding the solution into water for injection containing span 60, stirring, filtering with 0.2 μm filter membrane, bottling, and sterilizing at 121 deg.C for 15 min.
Example 5 Argatroban injection
1) Prescription
2) Preparation process
Dissolving argatroban in a prescription amount in glacial acetic acid, adding the solution into water for injection containing polyoxyethylene 40 hydrogenated castor oil, stirring, filtering with 0.2 μm filter membrane, bottling, and sterilizing at 121 deg.C for 15 min.
Example 6 Argatroban injection
1) Prescription
2) Preparation process
Dissolving argatroban in a prescription amount in glacial acetic acid, adding the solution into injection water containing polysorbate 80, stirring, filtering with 0.2 μm filter membrane, bottling, and sterilizing at 121 deg.C for 15 min.
Example 7 Argatroban injection
1) Prescription
2) Preparation process
Dissolving argatroban in a prescription amount in glacial acetic acid, adding the solution into injection water containing polysorbate 80, stirring, filtering with 0.2 μm filter membrane, bottling, and sterilizing at 121 deg.C for 15 min.
Example 8 Argatroban injection
1) Prescription
2) Preparation process
Dissolving argatroban in a prescription amount in glacial acetic acid, adding the solution into water for injection containing HS15, stirring, filtering with 0.2 μm filter membrane, bottling, and sterilizing at 121 deg.C for 15 min.
Example 9 Argatroban injection
1) Prescription
2) Preparation process
Dissolving argatroban in a prescription amount in glacial acetic acid, adding the solution into injection water containing polysorbate 80, stirring, filtering with 0.2 μm filter membrane, bottling, and sterilizing at 121 deg.C for 15 min.
Comparative example 1 Argatroban injection
Argatroban 10g
Glacial acetic acid 30g
Water for injection was added to 20L.
2) Preparation process
Dissolving argatroban in glacial acetic acid, adding the solution into water for injection, stirring, filtering with 0.2 μm filter membrane, bottling, and sterilizing at 121 deg.C for 15 min.
Comparative example 2 Argatroban injection
2) Preparation process
Dissolving argatroban in a prescription amount in 0.01mol/L dilute hydrochloric acid, adding the solution into water for injection containing polysorbate 80, stirring, filtering with 0.2 μm filter membrane, bottling, and sterilizing at 121 deg.C for 15 min.
Comparative example 3 Argatroban injection
1) Prescription
2) Preparation process
The equipment and glassware used for mixing, filtration and filling was thoroughly washed and depyrogenated. Sterilizing the filter assembly, fill tube assembly and other components and equipment; collecting cold injection water with 80% of the final volume in a scale mixing tank; adding sodium chloride to the tank, stirring the solution until the sodium chloride is dissolved, then adding sodium acetate trihydrate to the tank, stirring until all excipients are dissolved, adding water for injection to 90% of the final volume of the tank, and mixing. Adding acetic acid into 2L of water, and weighing argatroban into the 2L of acidified water to form a slurry solution; the slurry was then added to a mixing tank and the solution was mixed. Next, the solution was adjusted to pH 5.5 with sodium hydroxide or acetic acid, the solution was added with water for injection to the final volume, and mixed. Then putting the solution into 250ml non-PVC flexible bags, sealing the bags in aluminum foil bags, finally putting the product into an autoclave, and sterilizing at 121 ℃ for 20min to obtain the product.
Comparative example 4 Argatroban injection
1) Prescription
Argatroban 10g
20g of sorbitol
Water for injection was added to 20L.
2) Preparation process
Adding argatroban and sorbitol of a prescription amount into 40ml of methanol, stirring at 40 ℃ for dissolving, removing the methanol under reduced pressure to obtain an argatroban-sorbitol compound, adding water for injection of the prescription amount, stirring to obtain a clear solution, filling, and sterilizing at 115 ℃ for 30min to obtain the argatroban-sorbitol compound.
Verification examples stability test
1. Test materials: examples 1-9 and comparative examples 1-4.
2. The test method comprises the following steps:
and (3) placing the sample at 4 ℃ for 3 months, and observing the appearance of the sample.
And (3) accelerated test: the samples were placed in a constant temperature incubator at 60 ℃. + -. 2 ℃ and a relative humidity of 75%. + -. 10%, and the content of each sample and the content (%) of the substance were measured at 0 month and 6 months.
The content of argatroban in argatroban injection is detected by high performance liquid chromatography (2015 edition, fourth part 0512). Chromatographic conditions and system applicability test: using cyano silane bonded silica gel as filler (250X 4.6mm, 5 μm); methanol-water-10% tetrabutylammonium hydroxide-phosphoric acid (700:300:13:0.68) and ammonia solution (1 → 20) to adjust the pH value to 6.5 as a mobile phase; the detection wavelength is 257nm, and the column temperature is 40 ℃; and (3) injecting 20 mu l of argatroban reference substance solution into a liquid chromatograph, recording a chromatogram, adjusting the flow rate to ensure that the argatroban retention time is 6-10 min, and the theoretical plate number is not less than 2000 according to argatroban peak calculation.
The determination method comprises the following steps: precisely measuring 2ml of the solution, placing in a 10ml measuring flask, adding mobile phase to dilute to scale, shaking, precisely measuring 20 μ l, injecting into a liquid chromatograph, and recording chromatogram; taking a proper amount of reference substance, precisely weighing, adding mobile phase to obtain solution containing argatroban 0.1mg per 1ml, and measuring by the same method. Calculating according to the peak area by an external standard method to obtain the product.
3. And (3) test results: the test results are shown in tables 1 and 2.
TABLE 1 appearance of the samples
| Group of | Day 0 | 3 months old |
| Example 1 | Clarification | Clarification |
| Example 2 | Clarification | Clarification |
| Example 3 | Clarification | Clarification |
| Example 4 | Clarification | Clarification |
| Example 5 | Clarification | Clarification |
| Example 6 | Clarification | Clarification |
| Example 7 | Clarification | Clarification |
| Example 8 | Clarification | Clarification |
| Example 9 | Clarification | Clarification |
| Comparative example 1 | Turbidity | Turbidity |
| Comparative example 2 | Turbidity | Turbidity |
| Comparative example 3 | Clarification | Clarification |
| Comparative example 4 | Clarification | Clarification |
TABLE 2 accelerated test results
Through tests, after the argatroban injection of the examples 1-9 of the invention is placed at 4 ℃ for 3 months, the solution is clear, and after the argatroban injection is accelerated at 60 ℃ for 6 months, the increase of related substances is not obvious (see tables 1 and 2); in comparative example 1, no surfactant was added, and the drug precipitated and became turbid; comparative example 2 dilute hydrochloric acid was used instead of glacial acetic acid, and the solution likewise became cloudy; comparative examples 3 and 4, using the prior art, the increase in the relevant substances was evident after an acceleration of 6 months.
Claims (10)
1. An argatroban injection is characterized by comprising argatroban, glacial acetic acid, a surfactant and water for injection.
2. The argatroban injection according to claim 1, wherein the surfactant is one of HS15, poloxamer 188, polysorbate 80, span 60, polyoxyethylene 40 hydrogenated castor oil.
3. An argatroban injection as claimed in claim 1, wherein the weight ratio of argatroban to surfactant is 1: 0.3-5.
4. An argatroban injection according to claim 2, wherein the surfactant is HS 15.
5. An argatroban injection according to claim 2, wherein the surfactant is polysorbate 80.
6. An argatroban injection as claimed in claim 3, wherein the weight ratio of argatroban to polysorbate 80 is 1: 0.6-3.
7. An argatroban injection according to any one of claims 1 to 6, wherein the weight ratio of argatroban to glacial acetic acid is 1:1 to 10.
8. An argatroban injection according to claim 7, wherein the weight ratio of argatroban to glacial acetic acid is 1: 2-6.
9. A method for preparing argatroban injection as claimed in claim 7, comprising the steps of: dissolving argatroban in glacial acetic acid, adding the solution into water for injection containing surfactant, stirring, filtering, bottling, and sterilizing.
10. A method for preparing argatroban injection as claimed in any one of claims 1 to 6,8 and 9, comprising the steps of: dissolving argatroban in glacial acetic acid, adding the solution into water for injection containing surfactant, stirring, filtering, bottling, and sterilizing.
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| CN114306222A (en) * | 2021-12-09 | 2022-04-12 | 石家庄四药有限公司 | Argatroban injection and preparation method thereof |
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