CN102266549A - Injection preparation containing argatroban - Google Patents
Injection preparation containing argatroban Download PDFInfo
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- CN102266549A CN102266549A CN2010101910449A CN201010191044A CN102266549A CN 102266549 A CN102266549 A CN 102266549A CN 2010101910449 A CN2010101910449 A CN 2010101910449A CN 201010191044 A CN201010191044 A CN 201010191044A CN 102266549 A CN102266549 A CN 102266549A
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Abstract
The invention relates to an injection preparation using argatroban as an active component. The preparation for intravenous injection is prepared and developed from a medicinal active component of a single optical isomer of argatroban or a salt, a hydrate thereof, by adding specific varieties of accessories in a certain proportion according to a technical means in an instruction of the invention. Dosage forms comprise a powder injection, a low-capacity injection or a high-capacity injection.
Description
Technical field
The present invention relates to a kind of single optical isomer or its salt, purified hydrate with argatroban is the injection preparation of active component, comprises injectable powder, injection with small volume or high-capacity injection.Belong to medical technical field.
Background technology
Apoplexy (Stroke) is the apoplexy formal name used at school, is a kind of cerebral blood circulation obstacle disease of sudden onset.Clinical manifestation is with suddenly stupor, syncope or take place suddenly that facial hemiparalysis, hemiplegia, stiff tongue speech are not smoothgoing, dysnoesia is a principal character.Apoplexy comprises cerebral infarction (transient ischemic attack, Atherosclerosis and thrombosis and cerebral infarction, lacunar infarction, cerebral embolism), hemorrhagic apoplexy (cerebral hemorrhage, subarachnoid hemorrhage), hypertensive encephalopathy and vascular dementia four big classes.Reach 2,000,000 according to statistics China annual generation apoplexy patient.Sickness rate is up to 1,20/,100,000.The stroke patient 7,000,000 of now surviving, wherein 4,500,000 patients disability and can't take care of oneself in various degree.Disability rate is up to 75%.Leave over language, sensation or dyskinesia as the common patient that causes, need long-term be in hospital and the household looks after, give social and family brings serious economic problems, but even more serious patient threat to life then.Apoplexy takes place in annual nearly 3,000,000 people in China, and is also in rising trend in recent years, and lacks the acute stages treated medicine.Therefore, fully realize the seriousness of apoplexy, improve the treatment and the prevention level of apoplexy, the sickness rate, disability rate and the mortality rate that reduce apoplexy are medical worker's the task of top priority.
Argatroban (Argatroban) is the unique synthetic drug of ratifying in the world so far that is used for the acute ischemic cerebral apoplexy treatment, have following advantage: (1) is thrombin inhibitor directly, the affinity that thrombin is had height, selective inhibition of coagulation enzyme (2) molecular weight is little, the thrombin of free state in the deactivation blood not only, and can also enter into thrombosis inside, directly deactivation is very fast with bonded blood coagulation bolt of fibrin (3) and the bonded speed of thrombin, and is a kind of process of completely reversibility.Rapid-action, even the characteristics of very fast recovery make the effect of the excessive also very fast recovery coagulation function (4) naturally of argatroban not rely on intravital antithrombase after the drug withdrawal, can suppress during extremely low concentration to form and platelet aggregation by the fibrin due to the thrombin.Therefore it has better anticoagulant and anti thrombotic action than heparin, can be at 48 hours innerlich anwendens of morbidity, and treatment effective percentage height, rate of side effects is low.
Its optical isomer involved in the present invention, chemical name is: (2R, 4R)-l-[(2S)-5-(amino formamino) amino-1-oxo-2-[(3-methyl isophthalic acid, 2,3,4 tetrahydrochysenes-(3S)-methyl-8-quinoline) sulfoamido] penta institute]-4-methyl-2 piperidine carboxylic acid.
Chemical structural formula is:
Argatroban is at first synthetic by Mitsubishi chemistry institute (Mitsubishi Pharmaceutical Corp) in 1970. earlier by Japan's approval treatment periphery thrombotic disease and acute apoplexy.Permission, thrombocytopenia and the thrombosis syndrome that is brought out in order to heparin by drugs approved by FDA are successively bought by drugmaker of a few family of the U.S., France and Britain in the back.Argatroban is maintaining the leading position in antithrombotic aspect doing well,improving and the total effective rate, and its safety and high efficiency are that vast patients with cerebral apoplexy has brought hope.The appearance of argatroban provides a new departure for the treatment of acute ischemic cerebral apoplexy.
FDA Food and Drug Administration (FDA) has ratified the injection antithrombotic small-molecule drug argatroban (Argatroban of Smithkline Beecham (SmithKline Beecham) and Taxas Biotechnology Corp. (Texas Biotechnology) in 2000, Novastan) be applied to treat and prevent thrombosis and heparin-induced immune disease---thrombocytopenia (HIT), and the treatment that is used for needs are carried out percutaneous arteria coronaria interventional procedure (PCI) patient.The multicenter phase ii clinical trial result that on March 5th, 2003 announced in the 28th international apoplexy conference of U.S. apoplexy association shows, argatroban evident in efficacy, safe in the acute ischemic stroke treatment.
2005, a kind of new drug of Tianjin Medicine Research Academy Pharmaceutical Co., Ltd's treatment acute cerebral thrombosis " reaches the shellfish argatroban ", and oneself obtains State Food and Drug Administration's approval listing, this medicine is present domestic two kind new medicines of producing listing without competition, and is put into " 15 " national 863 projects and has issued state key new product certificate by the Ministry of Science and Technology.
The pharmacodynamics activity of argatroban formulation of the present invention is better than the argatroban racemic modification, and pharmacology's toxicity is then low than argatroban racemic modification, and steady quality, controlled, and is safe and effective.
Summary of the invention
Having the purpose of this invention is to provide a kind of is the injection preparation of active component with higher bioactive thrombolytic medicine argatroban or its salt or its hydrate.It is to be active component with the single optical isomer of argatroban or its salt, hydrate, but the pharmaceutical formulation of the stable injection made from acceptable accessories.The active component of this preparation is argatroban optical isomer but not its racemic modification.This dosage form can be injectable powder, injection.
Its specification of described injectable powder is 50mg-500mg, and the injection specification is 0.05mg/ml-200mg/ml.It is characterized in that described pharmaceutically acceptable pharmaceutic adjuvant comprises one or more in pharmaceutical carrier, isoosmotic adjusting agent, pH regulator, antioxidant, the intercalating agent.
Above-mentioned a kind of be the injectable powder of active component with the argatroban, it is characterized in that described pharmaceutical carrier can be one or more in mannitol, glucose, sorbitol, sodium chloride, dextran, sucrose, lactose, gelatin hydrolysate, trehalose, nicotiamide, citric acid, citrate, pantothenic acid and salt thereof, agedoite, aminoacid and amino acid salts, cholate, cyclodextrin and the derivant thereof.
Above-mentioned a kind of be the injection preparation of active component with the argatroban, it is characterized in that, described pH regulator is the water solublity regulator, can be in hydrochloric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, potassium acetate, sodium acetate, boric acid, Borax, citric acid, disodium citrate, citric acid trisodium, sodium citrate, citric acid monohydrate, Monopotassium citrate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, phosphate, dihydric phosphate, hydrophosphate, tartaric acid, biatrate, aminoacid and the salt thereof one or more.
Above-mentioned a kind of be the injection preparation of active component with the argatroban, it is characterized in that, described isoosmotic adjusting agent can be a sodium chloride, one or more in glucose, glycerol, propylene glycol, mannitol, glucose, sorbitol, dextran, nicotiamide, citric acid, citrate, pantothenic acid and salt thereof, agedoite, aminoacid and the amino acid salts.
Above-mentioned a kind of be the injection preparation of active component with the argatroban, it is characterized in that described antioxidant can be one or more in sulfurous acid, sulphite, bisulfites, pyrosulfite, thiosulfate, thioglycerin, gallic acid and salt cysteine, ascorbic acid and the salt thereof.
Above-mentioned a kind of be bulk capacity injection (more than the 50ml), the small-volume injection (20ml is following) of active component with the argatroban, it is characterized in that, its preparation technology is for getting part water for injection, add the argatroban stirring and dissolving, if necessary, can add an amount of antioxidant and chelating agen, transfer the pH value with the pH regulator agent, add an amount of needle-use activated carbon, medicinal liquid is heated to 50 ℃-70 ℃, stir, behind the filtering decarbonization, add the injection water, adopt 0.22 μ m microporous filter membrane fine straining again to total amount, fill is in ampoule bottle, and sterilization gets final product.
The specific embodiment
Come the present invention done further specifying by following example, comprise but be not restricted to following example.
Embodiment 1: the argatroban liquid drugs injection
Prescription:
| Component | Consumption |
| Argatroban | 100ｇ |
| Dehydrated alcohol | 400g |
| The D-sorbitol | 300g |
| Water for injection | q.s.1000ml |
| Make altogether | 1000ml |
Preparation method:
Get dehydrated alcohol 400g, add D-sorbitol stirring and dissolving, add argatroban, stirring and dissolving adds 0.1% needle-use activated carbon by amount of preparation, and medicinal liquid is heated to about 60 ℃, stirs 20min, behind the filtering decarbonization, adds the injection water to total amount, and intermediate detects.After the intermediate detection is qualified, adopt 0.22 μ m microporous filter membrane fine straining again, fill is in cillin bottle, and every bottle of 2.5ml jumps a queue, and rolls lid.Moist heat sterilization gets final product.
Embodiment 2: the argatroban liquid drugs injection
Prescription:
| Component | Consumption |
| Argatroban | 50ｇ |
| Dehydrated alcohol | 400g |
| The D-sorbitol | 300g |
| Water for injection | q.s.1000ml |
| Make altogether | 1000ml |
Preparation method:
Get dehydrated alcohol 400g, add D-sorbitol stirring and dissolving, add argatroban, stirring and dissolving adds 0.1% needle-use activated carbon by amount of preparation, and medicinal liquid is heated to about 60 ℃, stirs 20min, behind the filtering decarbonization, adds the injection water to total amount, and intermediate detects.After the intermediate detection is qualified, adopt 0.22 μ m microporous filter membrane fine straining again, fill is in cillin bottle, and every bottle of 2.5ml jumps a queue, and rolls lid.Moist heat sterilization gets final product.
Embodiment 3: the argatroban liquid drugs injection
Prescription:
| Component | Consumption |
| Argatroban | 200ｇ |
| Dehydrated alcohol | 400g |
| The D-sorbitol | 300g |
| Water for injection | q.s.1000ml |
| Make altogether | 1000ml |
Preparation method:
Get dehydrated alcohol 400g, add D-sorbitol stirring and dissolving, add argatroban, stirring and dissolving adds 0.1% needle-use activated carbon by amount of preparation, and medicinal liquid is heated to about 60 ℃, stirs 20min, behind the filtering decarbonization, adds the injection water to total amount, and intermediate detects.After the intermediate detection is qualified, adopt 0.22 μ m microporous filter membrane fine straining again, fill is in cillin bottle, and every bottle of 2.5ml jumps a queue, and rolls lid.Moist heat sterilization gets final product.
Embodiment 4: the argatroban aseptic powder injection
Prescription:
| First bottle of component | Consumption |
| Argatroban | 100ｇ |
| Second bottle of component | Consumption |
| Dehydrated alcohol | 400g |
| The D-sorbitol | 300g |
| Make altogether | 250 bottles |
Preparation method:
1. first bottle of preparation: get the argatroban aseptic powder, quantitative filling is in cillin bottle, and every bottle of 0.25g jumps a queue, and rolls lid and gets final product.
2. second bottle of preparation: get dehydrated alcohol 400g, add D-sorbitol stirring and dissolving, be solution.
3. when using,, dissolve first bottle of gained aseptic powder with second bottle of gained solution, and with the 0.9%NaCl injection, perhaps 5% glucose injection, perhaps lactated ringer's inj is diluted to 1mg/ml concentration, if there is the argatroban crystallization to separate out, still jolting can make its dissolving repeatedly during dilution.
Embodiment 5: the argatroban transfusion
Prescription:
| Component | Consumption |
| Argatroban | 50ｇ |
| Acetic acid | 5.46g |
| Sodium chloride | 59g |
| Water for injection | q.s.50000ml |
| Make altogether | 50000ml |
Preparation method:
Get 80% water for injection, add argatroban, stirring and dissolving, the acetic acid and the sodium chloride of adding recipe quantity, stirring and dissolving adds 0.05% needle-use activated carbon by amount of preparation, and medicinal liquid is heated to about 60 ℃, stirs 20min, behind the filtering decarbonization, add the injection water to total amount, intermediate detects.After the intermediate detection is qualified, adopt 0.22 μ m microporous filter membrane fine straining again, fill is jumped a queue in infusion bottle, rolls lid.Moist heat sterilization gets final product.
Embodiment 6: the argatroban transfusion
Prescription:
| Component | Consumption |
| Argatroban | 10ｇ |
| Tartaric acid | 123g |
| Sodium chloride | 59g |
| Water for injection | q.s.10000ml |
| Make altogether | 10000ml |
Preparation method:
Get 80% water for injection, add argatroban, stirring and dissolving, the tartaric acid and the sodium chloride of adding recipe quantity, stirring and dissolving adds 0.05% needle-use activated carbon by amount of preparation, and medicinal liquid is heated to about 60 ℃, stirs 20min, behind the filtering decarbonization, add the injection water to total amount, intermediate detects.After the intermediate detection is qualified, adopt 0.22 μ m microporous filter membrane fine straining again, fill is jumped a queue in infusion bottle, rolls lid.Moist heat sterilization gets final product.
Claims (7)
1. an injection preparation that contains argatroban is characterized in that, contains active component argatroban or its salt, purified hydrate and pharmaceutically acceptable pharmaceutic adjuvant, and wherein argatroban is a single optical isomer, and its structure is as follows:
Chemical name is: (2R, 4R)-l-[(2S)-5-(amino formamino) amino-1-oxo-2-[(3-methyl isophthalic acid, 2,3,4 tetrahydrochysenes-(3S)-and methyl-8-quinoline) sulfoamido] penta institute]-4-methyl-2 piperidine carboxylic acid.
2. according to the described injection preparation of claim 1, it is characterized in that its dosage form comprises injectable powder, bulk capacity injection (more than the 50ml), small-volume injection (20ml is following).
3. according to the described injection preparation of claim 2, it is characterized in that, described injectable powder, its specification is 50mg-500mg, injection (more than the 50ml) specification is 0.05mg/ml-200mg/ml.
4. according to the described injection preparation of claim 2, it is characterized in that described injection with small volume needs to add stabilizing agent and an amount of solvent in the injection.
5. stabilizing agent according to claim 4 is characterized in that, preferred sorbitol.
6. solvent according to claim 4 is characterized in that, preferred alcohol, propylene glycol, glycerol.
7. argatroban as claimed in claim 1 is the injection preparation of active component, can be used for prevention and treat various forms of thrombosis diseases related.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101910449A CN102266549A (en) | 2010-06-04 | 2010-06-04 | Injection preparation containing argatroban |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101910449A CN102266549A (en) | 2010-06-04 | 2010-06-04 | Injection preparation containing argatroban |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102266549A true CN102266549A (en) | 2011-12-07 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010101910449A Pending CN102266549A (en) | 2010-06-04 | 2010-06-04 | Injection preparation containing argatroban |
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| Country | Link |
|---|---|
| CN (1) | CN102266549A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102784382A (en) * | 2012-09-05 | 2012-11-21 | 江苏奥赛康药业股份有限公司 | Argatroban drug composition and preparation method and application of argatroban drug composition |
| CN103463614A (en) * | 2013-09-16 | 2013-12-25 | 浙江天瑞药业有限公司 | Argatroban injection and preparation method thereof |
| CN105816424A (en) * | 2016-04-12 | 2016-08-03 | 北京先通国际医药科技股份有限公司 | Argatroban composition and preparation method thereof |
| CN111544398A (en) * | 2020-06-24 | 2020-08-18 | 李书剑 | Argatroban freeze-dried powder and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101032485A (en) * | 2007-04-13 | 2007-09-12 | 天津市炜杰科技有限公司 | Application of 21(S) argatroban |
-
2010
- 2010-06-04 CN CN2010101910449A patent/CN102266549A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101032485A (en) * | 2007-04-13 | 2007-09-12 | 天津市炜杰科技有限公司 | Application of 21(S) argatroban |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102784382A (en) * | 2012-09-05 | 2012-11-21 | 江苏奥赛康药业股份有限公司 | Argatroban drug composition and preparation method and application of argatroban drug composition |
| CN102784382B (en) * | 2012-09-05 | 2014-02-19 | 江苏奥赛康药业股份有限公司 | Argatroban drug composition and preparation method and application of argatroban drug composition |
| CN103463614A (en) * | 2013-09-16 | 2013-12-25 | 浙江天瑞药业有限公司 | Argatroban injection and preparation method thereof |
| CN105816424A (en) * | 2016-04-12 | 2016-08-03 | 北京先通国际医药科技股份有限公司 | Argatroban composition and preparation method thereof |
| CN105816424B (en) * | 2016-04-12 | 2018-08-28 | 北京先通国际医药科技股份有限公司 | A kind of argatroban composition and preparation method thereof |
| CN111544398A (en) * | 2020-06-24 | 2020-08-18 | 李书剑 | Argatroban freeze-dried powder and preparation method thereof |
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Application publication date: 20111207 |