CN113521244B - Argatroban injection and preparation method thereof - Google Patents
Argatroban injection and preparation method thereof Download PDFInfo
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- CN113521244B CN113521244B CN202010304118.9A CN202010304118A CN113521244B CN 113521244 B CN113521244 B CN 113521244B CN 202010304118 A CN202010304118 A CN 202010304118A CN 113521244 B CN113521244 B CN 113521244B
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- argatroban
- injection
- acetic acid
- glacial acetic
- prescription
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- 229940033590 argatroban injection Drugs 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 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 58
- 229960003856 argatroban Drugs 0.000 claims abstract description 54
- 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 52
- 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 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229960000583 acetic acid Drugs 0.000 claims abstract description 28
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 26
- 230000001954 sterilising effect Effects 0.000 claims abstract description 16
- 238000003756 stirring Methods 0.000 claims abstract description 16
- 238000001914 filtration Methods 0.000 claims abstract description 15
- 239000008215 water for injection Substances 0.000 claims abstract description 15
- 239000004094 surface-active agent Substances 0.000 claims abstract description 14
- 239000000243 solution Substances 0.000 claims description 25
- 238000004806 packaging method and process Methods 0.000 claims description 13
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 11
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 11
- 229940068968 polysorbate 80 Drugs 0.000 claims description 11
- 229920000053 polysorbate 80 Polymers 0.000 claims description 11
- -1 polyoxyethylene Polymers 0.000 claims description 7
- 101000656751 Haloarcula marismortui (strain ATCC 43049 / DSM 3752 / JCM 8966 / VKM B-1809) 30S ribosomal protein S24e Proteins 0.000 claims description 5
- 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
- 238000000034 method Methods 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 17
- 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 9
- 229940090044 injection Drugs 0.000 abstract description 8
- 238000002347 injection Methods 0.000 abstract description 8
- 239000007924 injection Substances 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 5
- 235000011187 glycerol Nutrition 0.000 abstract description 4
- 238000011049 filling Methods 0.000 abstract description 3
- 239000011259 mixed solution Substances 0.000 abstract 1
- 229960002920 sorbitol Drugs 0.000 description 16
- 235000010356 sorbitol Nutrition 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 12
- 239000012528 membrane Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 108090000190 Thrombin Proteins 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229960004072 thrombin Drugs 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000007788 liquid Substances 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
- 206010053942 Cerebral haematoma Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010014418 Electrolyte imbalance 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 compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia 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
- 238000003556 assay Methods 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
- 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
- 230000001882 diuretic effect Effects 0.000 description 1
- 230000000694 effects Effects 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
- 238000001727 in vivo Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 229940099563 lactobionic acid Drugs 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
- 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
- 238000011003 system suitability test Methods 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
Abstract
The invention belongs to the technical field of medicinal preparations, and in particular relates to an Argatroban injection and a preparation method thereof. The Argatroban injection comprises Argatroban, glacial acetic acid, a surfactant and water for injection, wherein the Argatroban is dissolved in the glacial acetic acid, then the mixed solution is added into the water for injection containing the surfactant, and the Argatroban injection is obtained after stirring, filtering, filling and sterilizing. The Argatroban injection of the invention is free from adding sorbitol, ethanol, glycerin and the like, ensures the medication safety, and improves the solubility and stability of the injection by adding glacial acetic acid and surfactant.
Description
Technical Field
The invention belongs to the technical field of medicinal preparations, and in particular 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-quinolinyl) sulfonyl]-L-arginyl]-2-piperidinecarboxylic acid of formula C 23 H 36 N 6 O 5 S, molecular weight 508.6. Argatroban is a highly active, highly selective thrombin inhibitor whose anticoagulant effect is independent of antithrombin in the body, but which binds directly to and inactivates free thrombin in the blood; in addition, the argatroban has smaller molecular weight, can directly enter the thrombus, inactivate thrombin combined with fibrin and indirectly inhibit the generation of thrombin, so that the argatroban with extremely low concentration can inhibit the platelet aggregation reaction induced by thrombin. Argatroban can greatly reduce the level of thrombin-antithrombin complex in blood plasma and effectively improve the hypercoagulability of patients, so that the argatroban has a very good clinical effect in chronic thromboembolic diseases.
Poor water solubility is a major challenge in the preparation of argatroban injection solutions, and argatroban having a solubility of about 0.8-0.9mg/mL is considered to be slightly to very slightly soluble in water, is also sensitive to light and heat, and has a tendency to degrade unless stabilized, depending on the classification of the solute in the united states pharmacopoeia. Argatroban injection on the market in the United states at present is prescribed to contain 250mg of Argatroban, 750mg of D-sorbitol and 1000mg of absolute ethyl alcohol per bottle, and Argatroban injection on the market in Japan is prescribed to contain 10mg of Argatroban, 300mg of absolute ethyl alcohol and 900mg of glycerin per bottle. Both prescriptions increase the solubility of Argatroban by adding an organic solvent, 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, wherein each 1000ml of Argatroban injection disclosed by CN103463614B contains Argatroban 0.475-0.525g, sorbitol 50-60g, argatroban injection disclosed by CN102755289B contains Argatroban 0.5mg/ml, nitroglycerin 0.1-0.4mg/ml and D-sorbitol 30-80mg/ml, and injection disclosed by CN103070822B also contains a large amount of sorbitol. Sorbitol has tissue dehydration and diuretic effects, and can easily cause in vivo water and electrolyte disturbance when used in large quantities, resulting in heart failure, dilutability hyponatremia and hyperlipidemia; at the same time, 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 kidney disease, the phenomenon of urine volume reduction is easy to occur clinically after a large amount of sorbitol is used, and even acute renal failure is caused. Therefore, the addition of sorbitol to Argatroban injection reduces its safety in administration, which clearly significantly reduces its target patient population. CN101516370a discloses an aqueous preparation of argatroban, which adopts lactobionic acid and methionine as solubilizer, and is prepared into injection by adding stabilizing agent, although not containing organic solvents such as sorbitol, ethanol, glycerol, etc., the preparation process is complex, and is not suitable for workshop mass production.
In view of the above, there is a need for an argatroban injection with simple preparation process, safe and reliable auxiliary materials and good stability.
Disclosure of Invention
In view of the defects in the prior art, the invention provides Argatroban injection. The argatroban injection of the invention is free from adding sorbitol, ethanol, glycerin and the like, ensures the medication safety, and has good solubility and high stability.
In order to achieve the above object of the present invention, the inventors have conducted a lot of experiments. Since argatroban is hardly soluble in water, it is difficult to dissolve without adding a solubilizing agent, but the use of a large amount of solubilizing agent affects the safety of medication. The inventors dissolved Argatroban in glacial acetic acid and added water for injection, and precipitated after leaving for a period of time. Based on the above, the inventor continues to test, and finally discovers that glacial acetic acid and a certain amount of surfactant are compounded, so that the stable Argatroban injection can be obtained.
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 the Argatroban to the 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 the Argatroban to the glacial acetic acid is 1:1-10.
Preferably, the weight ratio of the Argatroban to the 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, packaging, and sterilizing.
Compared with the prior art, the invention has the following advantages: (1) The medicine does not contain sorbitol, solvents such as ethanol and the like, and has high medicine safety, good stability and high clarity; (2) The preparation process is simple and is suitable for industrial mass production.
Detailed Description
The invention is further illustrated by the following examples. It should be correctly understood that: the examples of the present invention are given solely for the purpose of illustration and are not intended to be limiting. Therefore, simple modifications to the invention, which are within the scope of the claimed invention, are possible with the method of the invention.
Example 1 Argatroban injection
1) Prescription of prescription
2) Preparation process
Dissolving Argatroban with prescription amount in glacial acetic acid, adding the solution into injection water containing polysorbate 80, stirring, filtering with 0.2 μm filter membrane, packaging, and sterilizing at 121deg.C for 15 min.
Example 2 Argatroban injection
1) Prescription of prescription
2) Preparation process
Dissolving Argatroban with prescription amount in glacial acetic acid, adding the solution into water for injection containing HS15, stirring, filtering with 0.2 μm filter membrane, packaging, and sterilizing at 121deg.C for 15 min.
Example 3 Argatroban injection
1) Prescription of prescription
2) Preparation process
Dissolving Argatroban with prescription amount in glacial acetic acid, adding the solution into injectable water containing poloxamer 188, stirring, filtering with 0.2 μm filter membrane, packaging, and sterilizing at 121deg.C for 15 min.
Example 4 Argatroban injection
1) Prescription of prescription
2) Preparation process
Dissolving Argatroban with prescription amount in glacial acetic acid, adding the solution into injectable water containing span 60, stirring, filtering with 0.2 μm filter membrane, packaging, and sterilizing at 121deg.C for 15 min.
Example 5 Argatroban injection
1) Prescription of prescription
2) Preparation process
Dissolving Argatroban with prescription amount in glacial acetic acid, adding the solution into injectable water containing polyoxyethylene 40 hydrogenated castor oil, stirring, filtering with 0.2 μm filter membrane, packaging, and sterilizing at 121deg.C for 15 min.
Example 6 Argatroban injection
1) Prescription of prescription
2) Preparation process
Dissolving Argatroban with prescription amount in glacial acetic acid, adding the solution into injection water containing polysorbate 80, stirring, filtering with 0.2 μm filter membrane, packaging, and sterilizing at 121deg.C for 15 min.
Example 7 Argatroban injection
1) Prescription of prescription
2) Preparation process
Dissolving Argatroban with prescription amount in glacial acetic acid, adding the solution into injection water containing polysorbate 80, stirring, filtering with 0.2 μm filter membrane, packaging, and sterilizing at 121deg.C for 15 min.
Example 8 Argatroban injection
1) Prescription of prescription
2) Preparation process
Dissolving Argatroban with prescription amount in glacial acetic acid, adding the solution into water for injection containing HS15, stirring, filtering with 0.2 μm filter membrane, packaging, and sterilizing at 121deg.C for 15 min.
Example 9 Argatroban injection
1) Prescription of prescription
2) Preparation process
Dissolving Argatroban with prescription amount in glacial acetic acid, adding the solution into injection water containing polysorbate 80, stirring, filtering with 0.2 μm filter membrane, packaging, and sterilizing at 121deg.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 with prescription amount in glacial acetic acid with prescription amount, adding the solution into injectable water, stirring, filtering with 0.2 μm filter membrane, packaging, and sterilizing at 121deg.C for 15 min.
Comparative example 2 Argatroban injection
2) Preparation process
Dissolving Argatroban with prescription amount in 0.01mol/L diluted hydrochloric acid, adding the solution into injection water containing polysorbate 80, stirring, filtering with 0.2 μm filter membrane, packaging, and sterilizing at 121deg.C for 15 min.
Comparative example 3 Argatroban injection
1) Prescription of prescription
2) Preparation process
The equipment for mixing, filtration and filling and glassware are thoroughly washed and depyrogenated. Sterilizing the filter assembly, fill tube assembly and other components and equipment; collecting 80% of the final volume of cold water for injection in a graduated mixing tank; sodium chloride was added to the tank, the solution was stirred until sodium chloride dissolved, then sodium acetate trihydrate was added to the tank, stirred until all excipients dissolved, and water for injection was added to 90% of the final volume of the tank, and mixed. Adding acetic acid into 2L of water, and weighing Argatroban into the 2L of acidified water to form a slurry solution; the slurry is then added to a mixing tank and the solution is mixed. Next, the solution is adjusted to pH 5.5 with sodium hydroxide or acetic acid, the solution is added with water for injection to the final volume, and mixed. Then the solution is filled into 250ml non-PVC flexible bags, the bags are sealed in aluminum foil bags, finally the products are filled into an autoclave, and the products are sterilized for 20min at 121 ℃.
Comparative example 4 Argatroban injection
1) Prescription of prescription
Argatroban 10g
Sorbitol 20g
Water for injection was added to 20L.
2) Preparation process
Adding the Argatroban and sorbitol with the prescription amount into 40ml of methanol, stirring at 40 ℃ to dissolve, decompressing to remove the methanol to obtain Argatroban sorbitol compound, adding the water for injection with the prescription amount, stirring to obtain clear solution, filling, and sterilizing at 115 ℃ for 30min to obtain the Argatroban sorbitol compound.
Verification example stability test
1. Test materials: samples prepared in examples 1-9 and comparative examples 1-4.
2. The test method comprises the following steps:
the samples were placed at 4℃for 3 months and observed for appearance.
Acceleration 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 relevant substance (%) were measured at month 0 and month 6.
The argatroban content in the argatroban injection is detected by high performance liquid chromatography (2015 edition fourth part 0512). Chromatographic conditions and system suitability test: cyano silane bonded silica gel was used as filler (250X 4.6mm,5 μm); methanol-water-10% tetrabutylammonium hydroxide-phosphoric acid (700:300:13:0.68) and ammonia solution (1-20) are used for adjusting the pH value to 6.5 to obtain a mobile phase; the detection wavelength is 257nm, and the column temperature is 40 ℃; taking 20 μl of Argatroban reference substance solution, injecting into a liquid chromatograph, recording the chromatogram, adjusting the flow rate to make Argatroban retention time 6-10 min, and calculating theoretical plate number according to Arg Qu Banfeng to be not less than 2000.
Assay: precisely measuring 2ml of the solution, placing in a 10ml measuring flask, adding mobile phase to dilute to scale, shaking, precisely measuring 20 μl, injecting into a liquid chromatograph, and recording chromatogram; and taking a proper amount of reference substance, precisely weighing, adding a mobile phase to prepare a solution containing about 0.1mg of Argatroban in each 1ml, and determining by the same method. And calculating according to an external standard method and peak area to obtain the product.
3. Test results: the test results are shown in tables 1 and 2.
Table 1 sample appearance
| Group of | Day 0 | For 3 months |
| Example 1 | Clarifying | Clarifying |
| Example 2 | Clarifying | Clarifying |
| Example 3 | Clarifying | Clarifying |
| Example 4 | Clarifying | Clarifying |
| Example 5 | Clarifying | Clarifying |
| Implementation of the embodimentsExample 6 | Clarifying | Clarifying |
| Example 7 | Clarifying | Clarifying |
| Example 8 | Clarifying | Clarifying |
| Example 9 | Clarifying | Clarifying |
| Comparative example 1 | Cloudiness | Cloudiness |
| Comparative example 2 | Cloudiness | Cloudiness |
| Comparative example 3 | Clarifying | Clarifying |
| Comparative example 4 | Clarifying | Clarifying |
TABLE 2 accelerated test results
Experiments prove that the Argatroban injection in the examples 1-9 is clear after being placed for 3 months at 4 ℃, and related substances are not obviously increased after being accelerated for 6 months at 60 ℃; comparative example 1 without surfactant, the drug precipitated out becoming cloudy; comparative example 2 the solution was likewise cloudy with dilute hydrochloric acid instead of glacial acetic acid; comparative examples 3 and 4 use the prior art, and the increase of the related substances is remarkable after accelerating for 6 months.
Claims (4)
1. The Argatroban injection is characterized by comprising Argatroban, glacial acetic acid, a surfactant and water for injection; the surfactant is one of HS15, poloxamer 188, polysorbate 80, span 60 and polyoxyethylene 40 hydrogenated castor oil; the weight ratio of the argatroban to the surfactant is 1:0.3-3; the weight ratio of the Argatroban to the glacial acetic acid is 1:1-10.
2. The argatroban injection according to claim 1, characterized in that the weight ratio of argatroban to polysorbate 80 is 1:0.6-3.
3. The argatroban injection according to claim 1, characterized in that the weight ratio of argatroban to glacial acetic acid is 1:2-6.
4. A process for the preparation of an argatroban injection according to any of claims 1 to 3, comprising the steps of: dissolving Argatroban in glacial acetic acid, adding the solution into water for injection containing surfactant, stirring, filtering, packaging, and sterilizing.
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| KR20190142601A (en) * | 2018-06-18 | 2019-12-27 | 경성대학교 산학협력단 | Injection or eye drops in which indirubin is solubilized using glacial acetic acid and polyoxy-35-castor oil, and manufacturing method the same |
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| KR20190142601A (en) * | 2018-06-18 | 2019-12-27 | 경성대학교 산학협력단 | Injection or eye drops in which indirubin is solubilized using glacial acetic acid and polyoxy-35-castor oil, and manufacturing method the same |
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