CN102558153A - Novel pharmaceutical salt of dabigatran etexilate and preparation method thereof - Google Patents
Novel pharmaceutical salt of dabigatran etexilate and preparation method thereof Download PDFInfo
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- CN102558153A CN102558153A CN2012100276277A CN201210027627A CN102558153A CN 102558153 A CN102558153 A CN 102558153A CN 2012100276277 A CN2012100276277 A CN 2012100276277A CN 201210027627 A CN201210027627 A CN 201210027627A CN 102558153 A CN102558153 A CN 102558153A
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Abstract
The invention relates to a novel pharmaceutical salt of dabigatran etexilate. The novel pharmaceutical salt comprises benzenesulphonate, maleate, benzoate, oxalate, lactate, fumarate, tartrate, and the like. Combined with auxiliary materials, the novel pharmaceutical salt can be prepared into oral preparations including granules, common tablets, dispersible tablets, oral disintegrating tablets, sustained-release tablets, capsules, sustained-release capsules, and the like. The operations can be used in clinical anticoagulation treatments.
Description
Technical field
The present invention is pharmaceutical salts of dabigatran ester and preparation method thereof, belongs to medical technical field.
Background technology
Thrombus is a big killer of human health, but compares with other more noticeable diseases, and general public is but known little about it to the harm that thrombus causes.The annual life that just seizes area 500,000 people of European Union of venous thromboembolism (VTE) only is that the twice of total death toll of causing of this area's AIDS, mammary cancer, prostate cancer and traffic hazard is many.
The dabigatran ester is the direct thrombin inhibitors of a kind of novel synthetic, is the prodrug of dabigatran, belongs to the thrombin inhibitors of non-peptide class.Oral after stomach and intestine absorb, be converted into dabigatran in vivo with direct anticoagulant active.Dabigatran is incorporated into the scleroproein specific combination site of zymoplasm, stops Fibrinogen to be cracked into scleroproein, thereby has blocked the final step and the thrombosis of blood coagulation waterfall network.Dabigatran can dissociate from scleroproein one zymoplasm combination, performance reversible anticoagulation.
Summary of the invention
The present invention is the pharmaceutical salts of dabigatran ester, and its pharmaceutical salts comprises hydrochloride, vitriol, phosphoric acid salt, acetate, hydrobromate, malate, citrate, benzene sulfonate, PHENRAMINE MALEATE, benzoate, oxalate, lactic acid salt, fumarate, tartrate, SUMATRIPTAN SUCCINATE, gluconate, hydroxyl mesylate, isethionate, esilate etc.Its preparation method sees embodiment for details.
Described pharmaceutical salts can be processed oral prepns with the auxiliary material combination, comprises granule, ordinary tablet, chewable tablet, dispersible tablet, oral cavity disintegration tablet, buccal tablet, capsule, soft capsule, pill, slow releasing tablet, slow releasing capsule etc.Its unit consumption is (in the dabigatran ester) 25-450mg, preferred 75-150mg;
The present invention also comprises the purposes of described pharmaceutical salts in the preparation anticoagulant.
Embodiment
Embodiment 1: the dabigatran ester is phosphatic synthetic
The dabigatran ester (1.0g adds N in 1.59mmol), dinethylformamide (2mL) and 85% phosphoric acid solution (183mg, 1.59mmol) after, in 65 ℃ of stirring in water bath, question response liquid slowly is cooled to stirring at room 2h after clarifying.Then reaction solution is placed 4 ℃ of refrigerator hold over night, filter the crystal of separating out, use N, dinethylformamide and acetonitrile are washed, and obtain product 1.1g (73.8%) after the vacuum-drying.
Embodiment 2: dabigatran ester vitriol synthetic
Dabigatran ester (1.2g; 1.91mmol) be suspended in ethanol (1.2mL) and the ETHYLE ACETATE (10mL), Dropwise 5 0% sulphuric acid soln (0.38g, 1.94mmol); Be placed on 4 ℃ of refrigerator hold over night after the clarification of stirring at room question response liquid; The crystal that filtration is separated out is with ETHYLE ACETATE and alcohol mixeding liquid (v: v=10: 1) wash, obtain product 1.0g (72.2%) after the vacuum-drying.
Embodiment 3: dabigatran ester hydrochloride synthetic
Dabigatran ester (1.0g; 1.59mmol) be suspended in ethanol (20mL) and the ETHYLE ACETATE (10mL), the ethanolic soln of the hydrogenchloride of dropping 30w/w% (193mg, 1.59mmol); Being placed on 4 ℃ of refrigerators after the clarification of 40 ℃ of stirrings of water-bath temperature control question response liquid left standstill two days; The crystal that filtration is separated out is washed with small amount of ethanol, obtains product 0.4g (37.7%) after the vacuum-drying.
Embodiment 4: dabigatran ester tosilate synthetic
Dabigatran ester (1.5g; 2.39mmol) be suspended in the toluene (30mL), adding solid tosic acid (0.45g, 2.36mmol); The water-bath temperature control stirs for 60 ℃ and moves to the stirring at room crystallization after question response liquid is clarified; The crystal that the 5h after-filtration is separated out is washed with toluene and small amount of ethanol, obtains product 1.4g (71.4%) after the vacuum-drying.
Embodiment 5: dabigatran ester benzene sulfonate synthetic
Dabigatran ester (1.5g; 2.39mmol) be suspended in the acetonitrile (30mL), adding solid Phenylsulfonic acid (0.38g, 2.40mmol); The water-bath temperature control stirs for 60 ℃ and moves to 1 day crystallization of stirring at room after question response liquid is clarified; The crystal that filtration is separated out is washed with minor amounts of acetonitrile, obtains product 1.2g (65.6%) after the vacuum-drying.
Embodiment 6: dabigatran ester PHENRAMINE MALEATE synthetic
(1.9g 3.03mmol) is suspended in N to the dabigatran ester, in the dinethylformamide (30ml); (0.35g 2.97mmol), is placed on-20 ℃ of C refrigerator hold over night after the clarification of 50 ℃ of stirrings of water-bath temperature control question response liquid to add toxilic acid; The crystal that filtration is separated out; Use little amount of N, dinethylformamide and acetonitrile are washed, and obtain product 1.0g (44.6%) after the vacuum-drying.
Embodiment 7: dabigatran ester SUMATRIPTAN SUCCINATE (succinate) synthetic
Dabigatran ester (1.5g; 2.39mmol) be suspended in ethanol (20ml) and the ETHYLE ACETATE (10ml), the adding succsinic acid (0.29g, 2.46mmol); The water-bath temperature control stirs for 60 ℃ and is placed on-20 ℃ of refrigerator hold over night after question response liquid is clarified; The crystal that filtration is separated out is with amount of ethyl acetate and alcohol mixeding liquid (v: v=10: 1) wash, obtain product 0.95g (53.4%) after the vacuum-drying.
Embodiment 8: dabigatran ester tartrate synthetic
Dabigatran ester (1.5g; 2.39mmol) be suspended in ethanol (20ml) and the ETHYLE ACETATE (10ml), adding L-tartrate (0.36g, 2.40mmol); The water-bath temperature control stirs for 50 ℃ and is placed on-20 ℃ of refrigerator hold over night after question response liquid is clarified; The crystal that filtration is separated out is with amount of ethyl acetate and alcohol mixeding liquid (v: v=10: 1) wash, obtain product 1.1g (59.1%) after the vacuum-drying.
Embodiment 9 coating tablets
The preparation method:
1. recipe quantity propanesulfonic acid dabigatran and Zeparox, Microcrystalline Cellulose, PVPP is crossed 80 orders according to the equivalent incremental method and is mixed, and adds Magnesium Stearate, mixing, compressing tablet: No. 8 punch dies;
2. hand over coating powder to be dispersed in the suitable quantity of water, process coating liquid;
3. the gained coating liquid is passed through the coating pan bag to made label, the dressing temperature is the 20-30 degree, wraps to 1-2 hour, and 30 degree are dry, promptly get.
Embodiment 10 conventional tablets
The preparation method:
1. Phenylsulfonic acid dabigatran and W-Gum, lactose, pvp are crossed 100 orders and are mixed
2. add Magnesium Stearate, mixing outward;
3.12 number punch die compressing tablet promptly gets.
Embodiment 11 capsules
The preparation method:
1. Phenylsulfonic acid dabigatran and dried corn starch, the powder lactose is crossed 100 orders and is mixed, and adds Magnesium Stearate and mixes;
2. the hard gelatin capsule shell of packing into No. 2 promptly gets.
The influence in various salt pair mouse bleeding times of embodiment 12 dabigatran esters and clotting time
Experimental technique:
Influence to mouse bleeding time (BT)
Get 60 of Kunming kind healthy mices, male and female half and half, body weight (20 scholar 2) g is divided into 6 groups: the normal control group at random: give isometric(al) saline water; Positive controls: methylsulfonic acid dabigatran ester (30.8mg/kg); Treatment group: other pharmaceutical salts of dabigatran ester (30.8mg/kg is in the dabigatran ester).Each group is gastric infusion according to dosage respectively, irritates the stomach volume and be 0.2ml/10g. every day 2 times, successive administration 10d.Behind the last 1d administration 1h mouse is fixed, measure mouse tail length and mark, with operating scissors mouse tail 5mm place is cut off then with milimeter scale; Treating that blood overflows voluntarily picks up counting; Every inhaled to dehematize with filter paper at a distance from 30 seconds drip 1 time, stop (till not having blood during the filter paper suction) naturally until blood, be the bleeding time (BT); The longest 60min that observes of BT surpasses the still hemorrhage 60min that presses of 60min and calculates.
Influence to clotting time of mice (CT)
Mice group and medication are the same, last 1d gastric infusion 1h, and the eyeball of mouse blood sampling, measure CT with slide method: each one is bled in the slide glass two ends, and the drop of blood diameter is about 5mm, uses manual time-keeping immediately.Whenever provoked once gently inwards with cleaning pin autoblood edge at a distance from 30 seconds, and observation has or not the trace of blood to provoke.End to provoking the trace of blood from the blood sampling beginning, elapsed-time standards is the clotting time (CT).The longest 30min that observes of CT surpasses the noncondensing 30min that presses of 30min and calculates.
Experimental result:
Compare with the normal control group; Each dose groups all has the clotting time of mice of prolongation and the effect in bleeding time; And tool significant difference (P＜0.01); The medicine class salt of dabigatran ester according to the invention is slightly better than the action effect of methylsulfonic acid dabigatran ester, so complete alternative methylsulfonic acid dabigatran ester is used for anticoagulant therapy.The result sees table 1
The influence in table 1 pair mouse bleeding time (BT) and clotting time (CT) (
N=10)
Claims (4)
1. the pharmaceutical salts of dabigatran ester; It is characterized in that pharmaceutical salts comprises hydrochloride, vitriol, phosphoric acid salt, acetate, hydrobromate, malate, citrate, benzene sulfonate, PHENRAMINE MALEATE, benzoate, oxalate, lactic acid salt, fumarate, tartrate, SUMATRIPTAN SUCCINATE, gluconate, hydroxyl mesylate, isethionate, esilate etc.
2. the described pharmaceutical salts of claim 1 can be processed oral prepns with the auxiliary material combination, comprises granule, ordinary tablet, chewable tablet, dispersible tablet, oral cavity disintegration tablet, buccal tablet, capsule, soft capsule, pill, slow releasing tablet, slow releasing capsule etc.
3. the described pharmaceutical salts of claim 2 is characterized in that, its unit consumption is (in the dabigatran ester) 25-450mg, preferred 75-150mg.
4. the described pharmaceutical salts of claim 1 is in the purposes of preparation in the anticoagulant.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288800A (en) * | 2013-06-03 | 2013-09-11 | 华仁药业股份有限公司 | Dabigatran etexilate benzene sulfonate as well as preparation method and application thereof |
| CN103539779A (en) * | 2012-07-13 | 2014-01-29 | 四川海思科制药有限公司 | Hydroxyl substituted benzene sulfonate of dabigatran etexilate and preparation method and usage thereof |
| WO2014049586A3 (en) * | 2012-09-28 | 2014-05-15 | Ranbaxy Laboratories Limited | Process for the preparation of dabigatran etexilate or pharmaceutically acceptable salt thereof |
| CN104592380A (en) * | 2013-03-15 | 2015-05-06 | 深圳君圣泰生物技术有限公司 | Polypeptide, derivative of polypeptide, pharmaceutical salt of polypeptide, pharmaceutical composition and application of polypeptide or derivative of polypeptide |
| WO2015071841A1 (en) | 2013-11-12 | 2015-05-21 | Druggability Technologies Holdings Limited | Complexes of dabigatran and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
| CN104650212A (en) * | 2013-03-15 | 2015-05-27 | 深圳君圣泰生物技术有限公司 | Peptide, peptide derivatives, medicinal salts of peptide, medicine composition and application of peptide and peptide derivatives |
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| CN102123707A (en) * | 2008-08-19 | 2011-07-13 | 贝林格尔.英格海姆国际有限公司 | Dabigatran for percutaneous interventional cardiac catheterisation |
| WO2011110876A1 (en) * | 2010-02-02 | 2011-09-15 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | Novel salts for the manufacture of pharmaceutical compositions |
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| WO2008043759A1 (en) * | 2006-10-10 | 2008-04-17 | Boehringer Ingelheim International Gmbh | Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester |
| CN102123707A (en) * | 2008-08-19 | 2011-07-13 | 贝林格尔.英格海姆国际有限公司 | Dabigatran for percutaneous interventional cardiac catheterisation |
| WO2011110876A1 (en) * | 2010-02-02 | 2011-09-15 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | Novel salts for the manufacture of pharmaceutical compositions |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103539779A (en) * | 2012-07-13 | 2014-01-29 | 四川海思科制药有限公司 | Hydroxyl substituted benzene sulfonate of dabigatran etexilate and preparation method and usage thereof |
| CN103539779B (en) * | 2012-07-13 | 2016-12-21 | 四川海思科制药有限公司 | A kind of hydroxyl-substituted sulfonate of dabigatran etcxilate and its production and use |
| WO2014049586A3 (en) * | 2012-09-28 | 2014-05-15 | Ranbaxy Laboratories Limited | Process for the preparation of dabigatran etexilate or pharmaceutically acceptable salt thereof |
| CN104592380A (en) * | 2013-03-15 | 2015-05-06 | 深圳君圣泰生物技术有限公司 | Polypeptide, derivative of polypeptide, pharmaceutical salt of polypeptide, pharmaceutical composition and application of polypeptide or derivative of polypeptide |
| CN104650212A (en) * | 2013-03-15 | 2015-05-27 | 深圳君圣泰生物技术有限公司 | Peptide, peptide derivatives, medicinal salts of peptide, medicine composition and application of peptide and peptide derivatives |
| CN103288800A (en) * | 2013-06-03 | 2013-09-11 | 华仁药业股份有限公司 | Dabigatran etexilate benzene sulfonate as well as preparation method and application thereof |
| CN103288800B (en) * | 2013-06-03 | 2016-03-30 | 华仁药业股份有限公司 | Dabigatran etcxilate benzene sulfonate and its preparation method and application |
| WO2015071841A1 (en) | 2013-11-12 | 2015-05-21 | Druggability Technologies Holdings Limited | Complexes of dabigatran and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
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Application publication date: 20120711 |