CN104706609A - Dabigatran etexilate self-emulsifying dispersible tablets and preparation method thereof - Google Patents
Dabigatran etexilate self-emulsifying dispersible tablets and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Abstract
The invention relates to the technical field of medicament preparations, and discloses dabigatran etexilate self-emulsifying dispersible tablets and a preparation method thereof. The preparation method comprises the following steps: combining a certain proportion of dabigatran etexilate, an emulsifier and an assistant emulsifier into a dabigatran etexilate self-emulsifying solution; adsorbing by using a solid adsorbent to further obtain a solid self-emulsifying composition; and preparing the dabigatran etexilate self-emulsifying dispersible tablets by adopting a powder direct tabletting method. The dabigatran etexilate self-emulsifying solution and the self-emulsifying dispersible tablets prepared by the method disclosed by the invention can be self-emulsified in vivo after being orally taken to form a micro emulsion of which the particle size is about 200nm, so that the in vitro dissolution rate and in vivo intestinal absorption of dabigatran etexilate are significantly improved, and the in vivo bioavailability is improved.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of dabigatran ester self-emulsifying liquid and self emulsifying dispersible tablet and preparation method thereof.
Background technology
Atrial fibrillation, be called for short atrial fibrillation, be a kind of modal Fast convergence, its incidence rate constantly increases with age, and within more than 75 years old, prevalence can reach 10%.Anticoagulant therapy is a most important principle of atrial fibrillation therapy.The atrial fibrillation administration guide height that American Heart Association in 2014, ACC and rhythm of the heart association of the U.S. issue (AHA/ACC/HRS) highlights the importance of anticoagulant therapy to atrial fibrillation.
Clinical conventional anticoagulant warfarin (vitamin K antagon) is the oral drugs being applied to atrial fibrillation anticoagulant for a long time.But because it easily interacts with multi-medicament or food, treatment window is narrow, and individual difference greatly, needs to adjust the deficiencies such as dosage by frequently monitoring international normalized ratio (INR), cause that its clinical practice is inconvenient and patient compliance is poor.
Dabigatran etcxilate capsule is developed by German Boehringer Ingelheim company, take the lead in going on the market in April, 2008 in Germany and Britain, obtain FDA approval in October, 2010, in February, 2013 is granted in China, for preventing apoplexy and the systemic embolism (SEE) of adult's nonvalvular atrial fibrillation patient, (trade name:
).Structural formula is such as formula shown in I.Dabigatran etcxilate is the direct anticoagulation medicine of brand-new non-peptide class of first listing over more than 50 year after warfarin, have can oral, potent, without the need to features such as special Medication monitor, drug interaction are few.After dabigatran etcxilate oral medication rapidly and be converted into dabigatran completely, the latter is the active component of capsule in blood plasma.
The dissolubility of dabigatran etcxilate and Determination of oil-water partition coefficient all have significant pH value dependency, and dissolubility reduces with the rising of pH value, and Determination of oil-water partition coefficient is then just in time contrary, increases with the rising of pH value.Therefore, in gastric environment, dabigatran etcxilate dissolubility is better, but permeable membrane is very poor; In intestinal juice, permeable membrane is better, but dissolubility is very low, and medicine may be made to separate out in intestinal juice, causes bioavailability very low.Listing capsule preparations, for improving dissolubility, adopts two kinds of solution routes, the first simultaneously, is made into salt, i.e. dabigatran etcxilate mesylate; The second, the outer bread of pastille element ball is by one deck sealing coat, and its outer bag is again contained acid layer (tartaric acid) by one deck.The microenvironment of this relatively low pH that tartaric acid provides, can promote the stripping of medicine to a certain extent.But nonetheless, after this product oral administration, the absolute bioavailability of active component dabigatran is still only 6.5%.About the patent of dabigatran ester formulation in Chinese patent, no matter be prepare micropill fill capsule, or multilayer tablet and dispersible tablet, also be all the thinking following commercial preparation, namely add a kind of organic acid, utilize organic acid produce the environment of relatively low pH, promote the stripping of medicine.Although all carried out the investigation of dissolution, nearly all do not carry out pharmacokinetics investigation, cannot judge whether its bioavailability improves.
This patent, for the purpose of the bioavailability improving dabigatran etcxilate, is made into self-emulsified drug delivery system.Self-emulsified drug delivery system (Self-Emulsifying Drug Delivery System, SEDDS): the solid be made up of oil phase, non-ionic surface active agent and cosurfactant or liquid preparation, its basic feature is can in gastrointestinal tract or under the condition of ambient temperature suitable (being often referred to body temperature 37 DEG C) and gentle agitation, and spontaneous emulsification forms the Emulsion of particle diameter at about 100-500nm.Self-emulsifying drug delivery system has following characteristics: (1) medicine relies on the huge surface area of fine oil droplets to improve the dissolution of water-insoluble drug and bioavailability, and the hydrolysis of water-insoluble drug and medicine can be avoided gastrointestinal pessimal stimulation simultaneously; (2) self-emulsifiable preparation oral after, rapid emulsifying in gastrointestinal tract, medicine directly enters small bowel lymphatics, the transhipment of rear arrival thymic lymphoma pipe, instead of enters hepatic portal vein.Therefore, through lymphatic transport after microemulsion absorbs, avoid or reduce the first pass effect through liver, the bioavailability of medicine can be improved; (3) medicine dissolution is in oil phase, oral formation Emulsion, avoids Emulsion to deposit lamination problem in process, is conducive to drug storage and transport preparation technology is simple, stable in properties, taking convenience.
Traditional self-emulsifiable preparation is generally sealed in soft capsule in liquid form, and form is single and easily have medicine to separate out.Adopt suitable solid adjuvant material and preparation technique effectively above-mentioned single liquid preparation can be converted into solid preparation.This novel solid self-emulsifying preparation not only can improve dissolubility and increases the advantage of bioavailability by liquid hold-up self-emulsifiable preparation, the plurality of advantages such as also have that stability is high, zest is little and patient's compliance is high.Dispersible tablet is put into after water can disintegrate rapidly, forms finely dispersed suspension, has easy to use, the feature that bioavailability is high.The preparation method of dispersible tablet, working condition and production technology are simple, and instructions of taking is convenient, can swallow as conventional tablet, also can be distributed to wet suit and use.
Given this, dabigatran etcxilate is designed to self emulsifying dispersible tablet by the present invention, self emulsifying liquid is first formed by a certain proportion of medicine, oil phase, emulsifying agent and co-emulsifier, solid self-emulsifying composition can be obtained further through solid absorbent absorption, adopt direct powder compression to prepare dabigatran ester self-emulsifying dispersible tablet.The dabigatran ester self-emulsifying dispersible tablet that the present invention obtains, can form the microemulsion of particle diameter at about 200nm by self emulsifying in vivo after oral, and it carried out to the research of pharmacokinetics in In Vitro Dissolution and body.Result shows, said preparation meets the requirements of simultaneously meeting In Vitro Dissolution, significantly increases intestinal absorption in dabigatran etcxilate body, improves bioavailability in body.
Summary of the invention
For the deficiency of existing preparation, the object of the invention is to, self emulsifying dispersible tablet that a kind of dabigatran etcxilate is provided and preparation method thereof, solve the technical problem that dabigatran etcxilate oral administration biaavailability is low.In addition, it is simple that the present invention also has production technology, the feature being convenient for carrying and storing.
The present invention takes technical scheme to be that a kind of preparation method of self emulsifying dispersible tablet of dabigatran etcxilate, is characterized in that containing the following step:
(1) preparation method of self emulsifying liquid: take emulsifying agent and co-emulsifier by prescription precision, mix homogeneously, adds oil phase and dabigatran etcxilate, ultrasonic, makes complete drug dissolution;
(2) preparation of self emulsifying dispersible tablet: get above-mentioned self emulsifying emulsions, with solid adsorption material absorption, forms solid absorption mixture; In solid absorption mixture, add filler, disintegrating agent, dry adhesives, combine mixing by a certain percentage, then add lubricant and fluidizer, adopt direct powder compression to prepare dabigatran ester self-emulsifying dispersible tablet.
Inventor is in experimentation, first attempt using dabigatran etcxilate mesylate as principal agent, screened the compatibility of a large amount of oil phases, emulsifying agent and co-emulsifier, finding all can not under the condition simulating gastro-intestinal Fluid environment and gentle agitation, and spontaneous emulsification forms microemulsion.Therefore, principal agent is changed into dabigatran etcxilate.
Dabigatran ester self-emulsifying liquid of the present invention, homogeneous, the transparent solution be made up of medicine, oil phase, surfactant and cosurfactant.Its weight ratio is as follows: dabigatran etcxilate 1% ~ 10%, oil phase 25% ~ 50%, emulsifying agent 30% ~ 50%, co-emulsifier 5% ~ 20%.
Oil phase of the present invention is selected from the one in glyceryl monooleate, Masine 35-1, isopropyl myristate, ethyl oleate and oleic acid, preferred Masine 35-1, form with medium chain triglyceride and mix oil phase, ratio is 2: 1 ~ 1: 2, preferably 1: 1; Surfactant be selected from Labraso, lauric acid Polyethylene Glycol-32 glyceride, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, Tweens and HS15 one or more, preferred lauric acid Polyethylene Glycol-32 glyceride; Cosurfactant selects one or more in propylene glycol, ethylene glycol monomethyl ether, Liquid Macrogol ~ 600 and isopropyl alcohol, preferred ethylene glycol monomethyl ether.
Dabigatran ester self-emulsifying dispersible tablet of the present invention, solid absorbent is one or more that commodity are called in the microcrystalline Cellulose (PH and KG rank) of CEOLUS, micropowder silica gel, calcium carbonate, hypromellose, starch, polyvinylpolypyrrolidone, lactose, mannitol, sodium carbonate, sodium chloride and Macrogol 4000/6000, preferably microcrystalline cellulose and micropowder silica gel, obtain solid self-emulsifying composition after absorption.
Dabigatran ester self-emulsifying dispersible tablet of the present invention, its weight consists of: solid self-emulsifying composition 5% ~ 30%, disintegrating agent 5% ~ 30%, dry adhesives 5% ~ 15%, fluidizer 2% ~ 6%, lubricant 0.5% ~ 3%, and all the other are filler.
Dabigatran ester self-emulsifying dispersible tablet of the present invention, filler is selected from one or more in microcrystalline Cellulose, pregelatinized Starch, vertical compression mannitol and spray-dried lactose, preferably microcrystalline cellulose and spray-dried lactose; Disintegrating agent is one or more in cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone and carboxymethylstach sodium, preferred polyvinylpolypyrrolidone; Dry adhesives is selected from one or both the combination in pregelatinized Starch and hydroxypropyl cellulose; Fluidizer is selected from one or both the combination in Pulvis Talci and micropowder silica gel; Lubricant is selected from one or more in magnesium stearate, sodium stearyl fumarate, sodium laurylsulfate and Macrogol 4000/6000, preferred magnesium stearate and sodium stearyl fumarate.
Dabigatran ester self-emulsifying dispersible tablet of the present invention, various adjuvants wherein used, all wanted 100 mesh sieves in advance.
Dabigatran ester self-emulsifying dispersible tablet of the present invention, after adding lubricant and fluidizer by above-mentioned steps, mixture wanted 80 mesh sieve 3 times, mixing.By mixed pressed powder, make hardness at 4 ~ 7kg/mm
2tablet machine is regulated, tabletting in scope.
According to the ordinary skill in the art, dabigatran ester self-emulsifying liquid of the present invention can be made outside dispersible tablet, can also make the various suitable solid dosage form such as the tablet of micropill, soft capsule, granule or other types.
Detailed description of the invention
For better the present invention being described, below in conjunction with specific embodiment, the present invention is further elaborated, but protection content of the present invention is not defined in embodiment.
Embodiment 1 dabigatran ester self-emulsifying dispersible tablet
Specification 1000
Preparation method:
1. precision takes lauric acid Polyethylene Glycol-32 glyceride, ethylene glycol monomethyl ether, Masine 35-1 and medium chain triglyceride by weight ratio, and vortex mixed is even, adds dabigatran etcxilate, ultrasonic, makes complete drug dissolution.
2. get above-mentioned self emulsifying emulsions, adsorb with microcrystalline Cellulose PH 102, form solid self-emulsifying composition.
3. all solids adjuvant is all crossed 100 mesh sieves in advance, the spray-dried lactose of weight proportion, polyvinylpolypyrrolidone and pregelatinized Starch is added in above-mentioned solid absorption mixture, combine mixing by a certain percentage, add micropowder silica gel, Pulvis Talci and Macrogol 4000 again, mixture crosses 80 mesh sieve 3 times, mixing.Mixed powder is adopted direct powder compression compacting dispersible tablet, make hardness at 4 ~ 7kg/mm
2tablet machine is regulated, the heavy 0.5g of sheet in scope.
Embodiment 2 dabigatran ester self-emulsifying dispersible tablet
Specification 1000
Preparation method:
1. precision takes lauric acid Polyethylene Glycol-32 glyceride, ethylene glycol monomethyl ether, Masine 35-1 and medium chain triglyceride by weight ratio, and vortex mixed is even, adds dabigatran etcxilate, ultrasonic, makes complete drug dissolution.
2. get above-mentioned self emulsifying emulsions, adsorb with microcrystalline Cellulose KG 802, form solid self-emulsifying composition.
3. all solids adjuvant is all crossed 100 mesh sieves in advance, in above-mentioned solid absorption mixture, add micro-product cellulose of weight proportion, polyvinylpolypyrrolidone and hydroxypropyl cellulose, combine mixing by a certain percentage, then add micropowder silica gel and magnesium stearate, mixture crosses 80 mesh sieve 3 times, mixing.Mixed powder is adopted direct powder compression compacting dispersible tablet, make hardness at 4 ~ 7kg/mm
2tablet machine is regulated, the heavy 0.5g of sheet in scope.
Embodiment 3 dabigatran ester self-emulsifying dispersible tablet
Specification 1000
Preparation method:
1. precision takes lauric acid Polyethylene Glycol-32 glyceride, ethylene glycol monomethyl ether, Masine 35-1 and medium chain triglyceride by weight ratio, and vortex mixed is even, adds dabigatran etcxilate, ultrasonic, makes complete drug dissolution.
2. get above-mentioned self emulsifying emulsions, with micropowder silica gel absorption, form solid self-emulsifying composition.
3. all solids adjuvant is all crossed 100 mesh sieves in advance, the pregelatinized Starch of weight proportion, polyvinylpolypyrrolidone, microcrystalline Cellulose is added in above-mentioned solid absorption mixture, combine mixing by a certain percentage, add Pulvis Talci, sodium stearyl fumarate and Macrogol 4000 again, mixture crosses 80 mesh sieve 3 times, mixing.Mixed powder is adopted direct powder compression compacting dispersible tablet, make hardness at 4 ~ 7kg/mm
2tablet machine is regulated, the heavy 0.5g of sheet in scope.
Embodiment 4 dilution stability is tested
Dabigatran ester self-emulsifying liquid 0.5g in Example 1 ~ 3, at 37 DEG C, add the simulated gastric fluid of 37 DEG C 100,200,300,500 and 1000 times, slight wobble, be diluted to the microemulsion of different multiples, with the change of ZetaPALS Zeta potential analysis-e/or determining particle diameter.
Accompanying drawing 1 is shown in the impact of extension rate on particle diameter.Result shows, when diluting 100 ~ 1000 times, the particle diameter after the outer emulsifying of dabigatran etcxilate self-emulsifiable liquid is between 170 ~ 220nm, and the impact of extension rate on particle diameter is little.
The test of embodiment 5 dispersible tablet
1. the weight differential of the dabigatran ester self-emulsifying dispersible tablet of embodiment 1 ~ 3 preparation is little, and unilateral bright and clean, hardness is moderate, and friability meets the requirements.
2. dispersing uniformity inspection
According to the inspection technique of dispersing uniformity in the version Pharmacopoeia of the People's Republic of China in 2010 two annex IA tablets, each 6 of Example 1 ~ 3, put in 250mL beaker, add the water 100mL of 15 ~ 25 DEG C, jolting 3min, embodiment 1 ~ 3 all whole disintegrate also can pass through No. two sieves in jolting 3min, and in fact just all disintegrates when 1min, meet dispersing uniformity requirement.
3. drug dissolution test
Dabigatran ester self-emulsifying liquid in embodiment 1 is about 0.5g and is filled into No. 1 capsule, according to the version Pharmacopoeia of the People's Republic of China in 2010 two annex X C dissolution method second method (paddle method), with the acetate buffer of the simulated gastric fluid of 900mL and pH4.0 for dissolution medium, respectively at 3min, 5min, 10min, 15min, 30min and 45min samples, the simulated gastric fluid of 0.5mL is supplemented after every sub-sampling 0.5mL, measure the release concentration of medicine in different time points, draw the cumulative percentage release curve of preparation.
According to same method, measure the release concentration of the dabigatran ester self-emulsifying dispersible tablet in embodiment 1 in different time points, draw the cumulative percentage release curve of preparation.Reference substance is commercially available dabigatran etcxilate capsule (dosage is 150mg).The cumulative release percentage curve of preparation in two media is shown in accompanying drawing 2 and accompanying drawing 3.Stripping result shows, in simulated gastric fluid, although three kinds of preparations can realize the stripping close to 100% in 15min, compared with commercially available capsule, the dissolution rate of dabigatran ester self-emulsifying liquid and self emulsifying dispersible tablet is faster; In the acetate buffer of pH 4.0, there is precipitate in commercially available capsule, the accumulation stripping quantity in 45min is less than 5%, and the accumulation stripping quantity in dabigatran ester self-emulsifying liquid and self emulsifying dispersible tablet 45min is all close to 100%, and at front 5min, the dissolution rate of dispersible tablet is faster.
Experimental example 7 pharmacokinetic trial
Get healthy male Sprague-Dawley rat 180 ~ 220g 18, random point three groups, often organize 6.Before administration, fasting 12h, freely drinks water.All take Oral administration, give commercially available dabigatran etcxilate capsule (dosage 30mg/kg), the dabigatran ester self-emulsifying liquid (dosage 30mg/kg) according to embodiment 2 preparation and dabigatran ester self-emulsifying dispersible tablet a slice according to embodiment 2 preparation (every sheet is containing principal agent 5.868mg) respectively.By rat eyeground vein clump, after administration 0.25,0.5,0.75,1,1.5,2,2.5,3,4,6,8,10h gets blood about 300 μ L, is placed in the centrifuge tube of heparinization, after process, HPLC sample detection blood drug level.Result shows, and the bioavailability of dabigatran ester self-emulsifying liquid of the present invention and self emulsifying dispersible tablet is apparently higher than commercially available capsule (accompanying drawing 4).
Accompanying drawing explanation
Fig. 1, extension rate is on the impact of particle diameter;
When Fig. 2, pH=1, the cumulative release percentage curve of three kinds of preparations compares;
When Fig. 3, pH=4, the cumulative release percentage curve of three kinds of preparations compares;
Fig. 4, the dabigatran ester self-emulsifying liquid of commercially available dabigatran etcxilate capsule, embodiment 2 preparation and the blood concentration-time curve of self emulsifying dispersible tablet compare.
Claims (8)
1. a self emulsifying dispersible tablet for dabigatran etcxilate, is characterized in that containing the following step:
(1) preparation method of self emulsifying liquid: take emulsifying agent and co-emulsifier by prescription precision, mix homogeneously, adds oil phase and dabigatran etcxilate, ultrasonic, makes complete drug dissolution;
(2) preparation of self emulsifying dispersible tablet: get above-mentioned self emulsifying emulsions, with solid adsorption material absorption, forms solid absorption mixture; In solid absorption mixture, add filler, disintegrating agent, dry adhesives, combine mixing by a certain percentage, then add lubricant and fluidizer, adopt direct powder compression to prepare dabigatran ester self-emulsifying dispersible tablet.
2. dabigatran ester self-emulsifying liquid according to claim 1, is characterized in that: homogeneous, the transparent solution that it is made up of medicine, oil phase, surfactant and cosurfactant.Its weight ratio is as follows:
。
3. as right wants dabigatran ester self-emulsifying liquid according to claim 1, it is characterized in that, described oil phase is selected from the one in glyceryl monooleate, Masine 35-1, isopropyl myristate, ethyl oleate and oleic acid, preferred Masine 35-1, form with medium chain triglyceride and mix oil phase, ratio is 2: 1 ~ 1: 2, preferably 1: 1; Surfactant be selected from Labraso, lauric acid Polyethylene Glycol-32 glyceride, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, Tweens and HS15 one or more, preferred lauric acid Polyethylene Glycol-32 glyceride; Cosurfactant selects one or more in propylene glycol, ethylene glycol monomethyl ether, Liquid Macrogol ~ 600 and isopropyl alcohol, preferred ethylene glycol monomethyl ether.
4. dabigatran ester self-emulsifying dispersible tablet according to claim 1, it is characterized in that, described solid absorbent is one or more that commodity are called in the microcrystalline Cellulose (PH and KG rank) of CEOLUS, micropowder silica gel, calcium carbonate, hypromellose, starch, polyvinylpolypyrrolidone, lactose, mannitol, sodium carbonate, sodium chloride and Macrogol 4000/6000, preferably microcrystalline cellulose and micropowder silica gel, obtain solid self-emulsifying composition after absorption.
5. dabigatran ester self-emulsifying dispersible tablet according to claim 1, is characterized in that, the weight of dabigatran ester self-emulsifying dispersible tablet consists of:
。
6. dabigatran ester self-emulsifying dispersible tablet according to claim 1, filler is selected from one or more in microcrystalline Cellulose, pregelatinized Starch, vertical compression mannitol and spray-dried lactose, preferably microcrystalline cellulose and spray-dried lactose; Disintegrating agent is one or more in cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone and carboxymethylstach sodium, preferred polyvinylpolypyrrolidone; Dry adhesives is selected from one or both the combination in pregelatinized Starch and hydroxypropyl cellulose; Fluidizer is selected from one or both the combination in Pulvis Talci and micropowder silica gel; Lubricant is selected from one or more in magnesium stearate, sodium stearyl fumarate, sodium laurylsulfate and Macrogol 4000/6000, preferred magnesium stearate and sodium stearyl fumarate.
7. dabigatran ester self-emulsifying dispersible tablet according to claim 1, various adjuvants wherein used, all wanted 100 mesh sieves in advance.
8. a dabigatran ester self-emulsifying dispersible tablet according to claim 1, after adding lubricant and fluidizer by above-mentioned steps, mixture wanted 80 mesh sieve 3 times, mixing.By mixed pressed powder, make hardness at 4 ~ 7kg/mm
2tablet machine is regulated, tabletting in scope.
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| CN107970225A (en) * | 2017-12-22 | 2018-05-01 | 重庆植恩药业有限公司 | A kind of dabigatran etcxilate solid lipid nano granule and preparation method thereof |
| CN107970225B (en) * | 2017-12-22 | 2022-06-03 | 植恩生物技术股份有限公司 | Dabigatran etexilate solid lipid nanoparticle and preparation method thereof |
| CN111920767A (en) * | 2020-09-10 | 2020-11-13 | 湖南慧泽生物医药科技有限公司 | Dabigatran etexilate self-microemulsion composition, capsule and preparation method thereof |
| CN111920767B (en) * | 2020-09-10 | 2022-02-22 | 湖南慧泽生物医药科技有限公司 | Dabigatran etexilate self-microemulsion composition, capsule and preparation method thereof |
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