CN104825391A - Pradaxa-containing microemulsion preparation - Google Patents
Pradaxa-containing microemulsion preparation Download PDFInfo
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- CN104825391A CN104825391A CN201510190505.3A CN201510190505A CN104825391A CN 104825391 A CN104825391 A CN 104825391A CN 201510190505 A CN201510190505 A CN 201510190505A CN 104825391 A CN104825391 A CN 104825391A
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Abstract
The invention relates to the technical field of medicine preparations, and particularly relates to a pradaxa-containing microemulsion preparation and a preparation method thereof. The pradaxa-containing microemulsion preparation is prepared by combination of a certain proportion of a surfactant, a cosurfactant, an oil phase, a water phase and a moderate amount of a stabilizer, a suspension aid, a sweetener and a preservative, the prepared pradaxa-containing microemulsion preparation is oil-in-water type, the particle size is in the range of 200-400 nm, appearance is clear transparent uniform, and stability is good. The microemulsion preparation, compared with an oral solid preparation, has the advantages of low production cost, simple preparation process and the like, after oral administration, dissolution of pradaxa in the gastrointestinal tract is increased, the bioavailability is improved, and the pradaxa-containing microemulsion preparation has the good market prospect.
Description
Technical field
The present invention relates to a kind of microemulsion formulation containing dabigatran etcxilate (dabigatran etexilate) and its preparation method and application, belong to medical art.
Background technology
Thrombosis is a large killer of human health, but compared with other more noticeable diseases, general public is but known little about it to the harm that thrombosis causes.Due to bad diet and living habit, cause many people to become the High risk group of thrombotic disease, make the features such as the thrombotic disease field of China presents high morbidity, high death, height is disabled, height recurs.And in European Union area, only venous thromboembolism (VTE) just seizes the life of 500,000 people every year, be that this area's acquired immune deficiency syndrome (AIDS), breast carcinoma, carcinoma of prostate and vehicle accident cause the twice of total death toll many.
At present, oral antithrombotic reagent that go on the market through FDA approval, that be used for prevention Post operation VTE and atrial fibrillation only has warfarin.But warfarin is subject to many limitations in use, such as, when this medicine is taken together with many common drugs and food, interaction can be produced; In addition, the therapeutical effect of this medicine must utilize international normalized ratio (INR) blood testing method to monitor, to guarantee that patient uses appropriate and safe dosage by general practitioner (GPs).Therefore, exploitation should compare favourably with warfarin on efficacy and saferry, can not produce again the interaction between medicine, and does not preferably need the medicine of Treatment monitoring to be the vital task of pharmacy worker.
Involved in the present invention to the chemical constitution of active substance dabigatran etcxilate be 3-[(2-{ [4-(own oxygen carbonylamino-imino-methyl)-phenyl amino]-methyl }-1-methyl isophthalic acid H-benzimidazole-5-carbonyl)-pyridine-2-base-amino]-ethyl propionate, have following chemical structural formula, this active substance is by known in WO 98/37075.
Dabigatran etcxilate is a kind of direct thrombin inhibitor of novel synthesis, belong to the thrombin inhibitor of non-peptide class, can be used for (such as) postoperative prevention dvt to be formed and prevention of stroke, be used in particular for the apoplexy preventing to suffer from auricular fibrillation patient.Dabigatran etcxilate is a kind of prodrug, oral after gastrointestinal absorption, direct thrombin inhibitor dabigatran that is potent, reversible, competition can be converted to by esterase in blood plasma and liver, to suppress change fibrinogen for fibrin, thus the final step of blood coagulation waterfall and the formation of thrombosis are blocked.Dabigatran can dissociate from fibrin-thrombin coalition, plays reversible anticoagulation.The structural formula of dabigatran is as follows:
Dabigatran etcxilate (commodity are called Pradaxa) is developed by German Boehringer Ingelheim company, take the lead in going on the market in April, 2008 in Germany and Britain, within 2010, go on the market in the U.S., within 2011, go on the market in Japan, for the patient with rhythm abnormality (auricular fibrillation) with prevention of stroke and blood clotting, this is the oral anticoagulant thing of the first new classification of going on the market over 50 years after warfarin.The listing of this product, is a major progress in anticoagulation therapy field and potential lethal thrombus prevention field, has milestone significance.
The dissolubility of dabigatran etcxilate in pure water is only 1.8mg/ml, and the dissolubility of this active substance has the pH dependency of height, and dissolubility is higher in acid condition, and as pH > 4, dissolubility significantly reduces.Dabigatran etcxilate belongs to the II class in Biopharmaceutics Classification system (BCS), that is: low dissolving high osmosis.
Current listing containing the preparation of dabigatran etcxilate only have containing dabigatran etcxilate mesylate containing sour pellet capsule, namely at specific organic acid core material surface bag sealing coat and active material layer.Patent (publication number CN101632668A) discloses the salt of this dabigatran etcxilate or the pharmaceutical composition of hydrate, be bag sealing coat and active material layer in organic acid core material, wherein sour core material comprises the organic acidic material such as tartaric acid, fumaric acid, succinic acid, citric acid, glutamic acid or aspartic acid as dabigatran etcxilate dissolving and stripping promoter.Medicine ordinance is become suspension by this technique, then in the medicine-feeding of organic acid ball wicking surface fluidisation, but the method has medicine-feeding rate is low, uneven, the shortcoming such as complex operation, dosage form are complicated of adding medicine to; Simultaneously, although dabigatran etcxilate is good at gastric stripping property, but absorbability is poor, and after it proceeds to enteral, along with the rising of pH, the dissolubility of dabigatran etcxilate declines, stripping medicine can crystallization again, medicine can not be absorbed, cause its bioavailability lower, be only 6.5%, this limits its application clinically to a certain extent.
Patent (publication number CN103536535A) discloses a kind of dabigatran etexilate liposome, this liposome is made up of at least one phospholipid and lipophilic compound, and containing filler, disintegrating agent, binding agent, lubricant, sweeting agent, aromatic etc.But prepare liposome and need the organic solvents such as a large amount of acetone and dichloromethane, toxicity is larger; Meanwhile, the lecithin facile hydrolysis oxidation in liposome membrane composition makes the mobility of film reduce, and the bad stability of liposome, promotes drug leakage, and thus anelasticity is deteriorated, and easily produces and assembles and precipitate, and produce toxicity, cause its bioavailability lower.In addition, drug solution is carried out spraying dry to prepare liposome by this technique, and investment cost is high, preparation process is complicated; Meanwhile, spraying dry belongs to convective drying type, and the thermal efficiency is low, and heat loss is large.
Patent (publication number CN103638000A) discloses a kind of dispersible preparation containing dabigatran etcxilate, and this dispersible preparation mainly comprises dispersible tablet containing active substance dabigatran etcxilate and discrete particles capsule.This dispersible preparation can rapid disintegrate dispersed in water, the the same containing sour pellet capsule of dabigatran etcxilate mesylate is contained with commercially available, mainly solve the problem of dabigatran etcxilate stripping difference under one's belt, improve dabigatran etcxilate stripping under one's belt, but still the problem of dabigatran etcxilate poor solubility, easily precipitation, absorption difference in intestinal can not be changed, make the bioavailability of dabigatran etcxilate low.Meanwhile, in the production process of dispersible tablet and discrete particles capsule, need crude drug to carry out micronization processes, add production process, improve cost.
Above-mentioned effort provide only the lower dabigatran etexilate liposome of the loaded down with trivial details or complex process of preparation or poor stability or bioavailability or the solid dosage forms containing dabigatran etcxilate.Therefore preparation is needed to stablize, easily or conveniently prepare, provide a kind of novel form dabigatran etexilate liposome as an alternative of the bioavailability of expectation or the solid dosage forms containing dabigatran etcxilate.
For the problems referred to above, the present inventor is providing a kind of dabigatran etcxilate microemulsion formulation and preparation method thereof after tight experiment, dabigatran etcxilate is made microemulsion class preparation, the stripping of dabigatran etcxilate in gastrointestinal tract can be increased after oral, improve bioavailability, improve its shortcoming in clinical practice.
Microemulsion (microemulsion) is mixed by proper proportion by surfactant, cosurfactant, oil phase, aqueous phase, transparent or semitransparent, low viscosity, the isotropism of spontaneous formation and thermodynamically stable drug-loading system.Microemulsion is generally the colloidal dispersion system of particle diameter at 10-100nm, can be divided into oil/water (O/W), water/oil (W/O) and co-continuous structure.Dabigatran etcxilate is prepared into thermodynamically stable microemulsion class preparation, this system is less by the impact of extraneous pH, and insoluble drug is mainly directly dissolved in oil phase in fluid form, in the gastrointestinal tract in droplet shape after oral, do not need redispersion, medicine can directly contact with gastrointestinal wall from oil phase, thus promotes the absorption of medicine; Pass through oral administration, because surface tension is lower, can through lymphatic absorption, thus get around portal vein, overcome the first pass effect of liver and macromolecular drug by obstacle during gastrointestinal tract epithelial cell film, increase dabigatran etcxilate contact with gastrointestinal tract epithelial cell after affinity, improve curative effect and the bioavailability of medicine.Meanwhile, convenient oral, dosage is accurate, with sweeting agent with the use of more covering bitter taste of drug, improves the compliance and convenience taken, meets the needs of gerontal patient and child, make doctor have more selectivity when providing medicine for patient.
Summary of the invention
The object of the invention is to overcome the deficiency that prior art exists, provide that a kind of taking convenience, bioavailability are high, cost is low, technique is simple, the oral dabigatran etcxilate O/W microemulsion formulation of good stability and preparation method thereof.
The object of the invention is to be reached by following measure:
A kind of oral dabigatran etcxilate O/W microemulsion formulation, particle diameter, between 200-400nm, is characterized in that the component containing, for example lower mass percent:
Surplus is deionized water, and the mass percent sum of each raw material is 100%.
Component preferably containing following mass percent in dabigatran etcxilate microemulsion formulation:
Surplus is deionized water, and the mass percent sum of each raw material is 100%.
Oil phase of the present invention be selected from into middle carbochain triglyceride (Medium ChainTriglycerids, be called for short MCT, refer to saturated alkyl C
8~ C
12triglyceride), one or more mixture in Oleum Ricini, Ethyl linoleate.The preferred oil phase of the present invention is middle carbochain triglyceride, the one of Oleum Ricini or mixture.
Surfactant of the present invention is selected from the mixture of one or more in polyoxyethylene castor oil class, Ovum Gallus domesticus Flavus lecithin class, poloxamer class, Tweens; Described polyoxyethylene castor oil class surfactant comprises polyoxyethylene castor oil (Cremophor EL-40), polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH-40); Tweens comprises tween 20, tween 80 etc.The preferred surfactant of the present invention is one or more mixture of polyoxyethylene hydrogenated Oleum Ricini, PLURONICS F87, Ovum Gallus domesticus Flavus lecithin, tween 80.
Cosurfactant of the present invention is selected from one or more mixture in ethanol, propylene glycol, isopropyl alcohol.The preferred cosurfactant of the present invention is ethanol, the one of propylene glycol or mixture.
Additives of the present invention are selected from one or more mixture in stabilizing agent, suspending agent, sweeting agent, antiseptic.
Stabilizing agent of the present invention is selected from one or more mixture in oleic acid, cholic acid, deoxycholic acid and salt thereof.The preferred stabilizing agent of the present invention is oleic acid.
Suspending agent of the present invention is selected from one or more mixture in sodium carboxymethyl cellulose, sodium alginate, arabic gum, tragakanta, polyvidone.The preferred suspending agent of the present invention is polyvidone.
Sweeting agent of the present invention is selected from one or more mixture in steviosin, aspartame, sucrose, fructose.The preferred sweeting agent of the present invention is steviosin, the one of aspartame or mixture.
Antiseptic of the present invention is selected from one or more mixture in sorbic acid, sorbate, benzoic acid, benzoate.The preferred antiseptic of the present invention is sorbic acid, the one of potassium sorbate or mixture.
A preparation method for oral dabigatran etcxilate microemulsion formulation, comprises the steps:
A. dabigatran etcxilate, surfactant, cosurfactant, oil, antiseptic, sweeting agent, stabilizing agent, suspending agent and deionized water is taken in proportion, for subsequent use;
B. dabigatran etcxilate is dissolved in cosurfactant, then adds surfactant and the oil of slightly solubility, be uniformly mixed, prepare oil phase;
C. get the water miscible surfactant of metering, add deionized water and stirring mix homogeneously, prepare aqueous phase;
D. under magnetic stirring, oil phase is slowly joined in aqueous phase, until outward appearance forms liquid that is transparent, that clarify, have light blue opalescence.
In aforesaid liquid, add appropriate antiseptic again, deionized water standardize solution, be prepared into dabigatran etcxilate microemulsion oral liquid.
The preparation method of dabigatran etcxilate microemulsion formulation of the present invention can adopt following method one or more be combined and be prepared: stir newborn even method, high pressure homogenize breast even method, the even method of ultrasonic breast.The newborn even method of preferred stirring or the even method of ultrasonic breast contribute to the formation of microemulsion and the consumption reducing adjuvant.
(1) stir newborn even method: be dissolved in cosurfactant by proportioning by medicine dabigatran etcxilate, room temperature or be heated to 45 DEG C ~ 60 DEG C to accelerate medicine dissolution, after dabigatran etcxilate dissolves completely, add surfactant and oil, mixing, obtains oil phase; The oil phase of preparation is slowly added drop-wise in aqueous phase and mixes, high-speed stirred 8 ~ 10min, add appropriate additives, obtain dabigatran etcxilate microemulsion.
(2) the even method of high pressure homogenize breast: medicine dabigatran etcxilate is dissolved in cosurfactant by proportioning, room temperature or be heated to 45 DEG C ~ 60 DEG C to accelerate medicine dissolution, after dabigatran etcxilate dissolves completely, adds surfactant and oil, mixing, obtains oil phase; The oil phase of preparation is slowly added drop-wise in aqueous phase and mixes, with high pressure homogenizer homogenized milk even 4 ~ 6 times, add appropriate additives, obtain dabigatran etcxilate microemulsion.
(3) the even method of ultrasonic breast: medicine dabigatran etcxilate is dissolved in cosurfactant by proportioning, room temperature or be heated to 45 DEG C ~ 60 DEG C to accelerate medicine dissolution, after dabigatran etcxilate dissolves completely, adds surfactant and oil, and mixing, obtains oil phase; The oil phase of preparation is slowly added drop-wise in aqueous phase and mixes, under the power of 250W, with the even 4 ~ 8min of the ultrasonic breast of Probe Ultrasonic Searching instrument, add appropriate additives, obtain dabigatran etcxilate microemulsion.
The physicochemical property of microemulsion formulation and physical stability in this invention:
The physicochemical property testing 1 microemulsion detects
Outward appearance: the microemulsion of preparation is creamy white, has nattier blue opalescence, good fluidity.
Form: get microemulsion appropriate, operation transmission electron microscope observation routinely.Result shows, microemulsion great majority under Electronic Speculum are spheroidal.
Type: get appropriate dabigatran etcxilate microemulsion solution, adds oil-soluble dyes tonyred and water-soluble dye methylene blue respectively, observes the speed of the diffusion velocity of solution in microemulsion of two kinds of different colours.Measurement result shows, blue diffusion velocity in microemulsion is faster than redness, illustrates that this microemulsion is O/W type microemulsion.
Particle diameter: get microemulsion appropriate, measure with Malvern Particle Size Analyzer, measurement result shows, the mean diameter of the dabigatran etcxilate microemulsion of test preparation is 367.6 ± 13.9nm, polydispersity coefficient is 0.234 ± 0.043, and the particle size distribution of this microemulsion formulation is narrower and even as seen.Meet the Spreading requirements about particle diameter and granularity of microemulsion.
Test 2 centrifugal tests
Get appropriate microemulsion of the present invention in centrifuge tube, sealing orifice, is placed in high speed centrifuge, with the centrifugal 10min of 3000r/min, and observe phenomena.Measurement result shows, this microemulsion does not produce the phenomenons such as precipitation, layering, muddiness, and good fluidity, still keep original outward appearance.Illustrate that its physical stability is good.
In the present invention, adopt the newborn even method of stirring or the even method of ultrasonic breast to prepare dabigatran etcxilate microemulsion, medicine is wrapped in interior phase oil phase, has good stability.Microemulsion oral liquid prepared by the present invention, through test of many times, selects suitable, safe oil phase, surfactant and cosurfactant, selects proportionate relationship suitable between this three simultaneously, and the final microemulsion particle diameter formed remains between 200-400nm.
Accompanying drawing explanation
Fig. 1 is the transmission electron microscope picture (× 15000 times) of dabigatran etcxilate microemulsion formulation of the present invention
Fig. 2 is the grain size distribution of dabigatran etcxilate microemulsion formulation of the present invention
Detailed description of the invention:
Dabigatran etcxilate microemulsion formulation that a kind of technique is simple, evident in efficacy, untoward reaction is little and preparation method thereof is provided by following instance, the dabigatran etcxilate microemulsion that application the method obtains can improve the bioavailability of medicine significance, but is not limited in following instance.
Embodiment 1 one kinds of dabigatran etcxilate microemulsion formulations, each proportioning raw materials of this microemulsion formulation is as follows:
Specification: 100ml
Preparation technology: take dabigatran etcxilate 0.25g in prescription ratio precision, and be dissolved in propylene glycol, adds middle carbochain triglyceride, polyoxyethylene hydrogenated Oleum Ricini, oleic acid, and normal-temperature continuous is stirred to dissolves and mixes, and obtains dabigatran etcxilate pastille oil phase; Be dissolved in deionized water by PLURONICS F87, PVP K30, mix homogeneously, obtains aqueous phase; Oil phase and aqueous phase are heated to 60 DEG C respectively, under magnetic stirring, oil phase are instilled in aqueous phase lentamente, high-speed stirred 8min, continue to add sorbic acid, steviosin, aspartame, finally add deionized water and be settled to 100ml, obtain dabigatran etcxilate microemulsion.
Embodiment 2 one kinds of dabigatran etcxilate microemulsion formulations, each proportioning raw materials of this microemulsion formulation is as follows:
Specification: 100ml
Preparation technology: take dabigatran etcxilate 0.25g in prescription ratio precision, and be dissolved in propylene glycol, add middle carbochain triglyceride, Oleum Ricini, polyoxyethylene hydrogenated Oleum Ricini, oleic acid, normal-temperature continuous is stirred to dissolves and mixes, and obtains dabigatran etcxilate pastille oil phase; Be dissolved in deionized water by PLURONICS F87, PVP K30, mix homogeneously, obtains aqueous phase; Oil phase and aqueous phase are heated to 60 DEG C respectively, under magnetic stirring, oil phase are instilled in aqueous phase lentamente, high-speed stirred 8min, continue to add sorbic acid, steviosin, aspartame, finally add deionized water and be settled to 100ml, obtain dabigatran etcxilate microemulsion.
Embodiment 3 one kinds of dabigatran etcxilate microemulsion formulations, each proportioning raw materials of this microemulsion formulation is as follows:
Specification: 100ml
Preparation technology: take dabigatran etcxilate 0.25g in prescription ratio precision, and be dissolved in propylene glycol, adds middle carbochain triglyceride, Ovum Gallus domesticus Flavus lecithin, oleic acid, and normal-temperature continuous is stirred to dissolves and mixes, and obtains dabigatran etcxilate pastille oil phase; Be dissolved in deionized water by PLURONICS F87, PVP K30, mix homogeneously, obtains aqueous phase; Oil phase and aqueous phase are heated to 60 DEG C respectively, under magnetic stirring, oil phase are instilled in aqueous phase lentamente, high-speed stirred 8min, continue to add sorbic acid, steviosin, aspartame, finally add deionized water and be settled to 100ml, obtain dabigatran etcxilate microemulsion.
Embodiment 4 one kinds of dabigatran etcxilate microemulsion formulations, each proportioning raw materials of this microemulsion formulation is as follows:
Specification: 100ml
Preparation technology: take dabigatran etcxilate 0.25g in prescription ratio precision, and be dissolved in propylene glycol, adds middle carbochain triglyceride, polyoxyethylene hydrogenated Oleum Ricini, oleic acid, and normal-temperature continuous is stirred to dissolves and mixes, and obtains dabigatran etcxilate pastille oil phase; PVP K30 is dissolved in deionized water, mix homogeneously, obtains aqueous phase; Oil phase and aqueous phase are heated to 60 DEG C respectively, under magnetic stirring, oil phase are instilled in aqueous phase lentamente, high-speed stirred 8min, continue to add sorbic acid, steviosin, aspartame, finally add deionized water and be settled to 100ml, obtain dabigatran etcxilate microemulsion.
Embodiment 5 one kinds of dabigatran etcxilate microemulsion formulations, each proportioning raw materials of this microemulsion formulation is as follows:
Specification: 100ml
Preparation technology: take dabigatran etcxilate 0.25g in prescription ratio precision, and be dissolved in propylene glycol, adds middle carbochain triglyceride, polyoxyethylene hydrogenated Oleum Ricini, oleic acid, and normal-temperature continuous is stirred to dissolves and mixes, and obtains dabigatran etcxilate pastille oil phase; Be dissolved in deionized water by Tween 80, PVP K30, mix homogeneously, obtains aqueous phase; Oil phase and aqueous phase are heated to 60 DEG C respectively, under magnetic stirring, oil phase are instilled in aqueous phase lentamente, high-speed stirred 8min, continue to add sorbic acid, steviosin, aspartame, finally add deionized water and be settled to 100ml, obtain dabigatran etcxilate microemulsion.
Embodiment 6 one kinds of dabigatran etcxilate microemulsion formulations, each proportioning raw materials of this microemulsion formulation is as follows:
Specification: 100ml
Preparation technology: take dabigatran etcxilate 0.5g in prescription ratio precision, and be dissolved in propylene glycol, add middle carbochain triglyceride, Oleum Ricini, polyoxyethylene hydrogenated Oleum Ricini, oleic acid, normal-temperature continuous is stirred to dissolves and mixes, and obtains dabigatran etcxilate pastille oil phase; Be dissolved in deionized water by PLURONICS F87, PVP K30, mix homogeneously, obtains aqueous phase; Oil phase and aqueous phase are heated to 60 DEG C respectively, under magnetic stirring, oil phase are instilled in aqueous phase lentamente, mixing, under 250W, the even 8min of ultrasonic breast, continue to add potassium sorbate, steviosin, aspartame, finally add deionized water and be settled to 100ml, obtain dabigatran etcxilate microemulsion.
Embodiment 7 one kinds of dabigatran etcxilate microemulsion formulations, each proportioning raw materials of this microemulsion formulation is as follows:
Specification: 100ml
Preparation technology: take dabigatran etcxilate 0.5g in prescription ratio precision, and be dissolved in ethanol, propylene glycol, adds middle carbochain triglyceride, polyoxyethylene hydrogenated Oleum Ricini, oleic acid, and normal-temperature continuous is stirred to dissolves and mixes, and obtains dabigatran etcxilate pastille oil phase; Be dissolved in deionized water by Tween 80, PVP K30, mix homogeneously, obtains aqueous phase; Oil phase and aqueous phase are heated to 60 DEG C respectively, under magnetic stirring, oil phase are instilled in aqueous phase lentamente, high-speed stirred 8min, continue to add sorbic acid, steviosin, aspartame, finally add deionized water and be settled to 100ml, obtain dabigatran etcxilate microemulsion.
Embodiment 8 one kinds of dabigatran etcxilate microemulsion formulations, each proportioning raw materials of this microemulsion formulation is as follows:
Specification: 100ml
Preparation technology: take dabigatran etcxilate 0.5g in prescription ratio precision, and be dissolved in ethanol, propylene glycol, add middle carbochain triglyceride, Oleum Ricini, polyoxyethylene hydrogenated Oleum Ricini, oleic acid, normal-temperature continuous is stirred to dissolves and mixes, and obtains dabigatran etcxilate pastille oil phase; Be dissolved in deionized water by PLURONICS F87, PVP K30, mix homogeneously, obtains aqueous phase; Oil phase and aqueous phase are heated to 60 DEG C respectively, under magnetic stirring, oil phase are instilled in aqueous phase lentamente, mixing, under 250W, the even 8min of ultrasonic breast, continue to add potassium sorbate, steviosin, aspartame, finally add deionized water and be settled to 100ml, obtain dabigatran etcxilate microemulsion.
Claims (9)
1. have a dabigatran etcxilate microemulsion formulation for blood coagulation resisting function, being fed intake according to a certain ratio by each component forms, and it is characterized in that:
Surplus is deionized water, and the mass percent sum of each raw material is 100%.
2. dabigatran etcxilate microemulsion formulation as claimed in claim 1, it is characterized in that, described microemulsion formulation prescription is as follows:
Surplus is deionized water, and the mass percent sum of each raw material is 100%.
3. dabigatran etcxilate microemulsion formulation as claimed in claim 1 or 2, (Medium ChainTriglycerids is called for short MCT, refers to saturated alkyl C to it is characterized in that being selected from middle carbochain triglyceride by described oil-phase medium
8~ C
12triglyceride), one or more mixture in Oleum Ricini, Ethyl linoleate.
4. dabigatran etcxilate microemulsion formulation as claimed in claim 1 or 2, is characterized in that described surfactant is selected from the mixture of one or more in polyoxyethylene castor oil class, Ovum Gallus domesticus Flavus lecithin class, poloxamer class, Tweens; Described polyoxyethylene castor oil class surfactant comprises polyoxyethylene castor oil (Cremophor EL-40), polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH-40); Tweens comprises tween 20, tween 80 etc.
5. dabigatran etcxilate microemulsion formulation as claimed in claim 1 or 2, is characterized in that described cosurfactant is selected from one or more mixture in ethanol, propylene glycol, isopropyl alcohol.
6. dabigatran etcxilate microemulsion formulation as claimed in claim 1 or 2, is characterized in that described additives are selected from one or more mixture in stabilizing agent, suspending agent, sweeting agent, antiseptic.
7. dabigatran etcxilate microemulsion formulation as claimed in claim 6, is characterized in that described stabilizing agent is selected from one or more mixture in oleic acid, cholic acid, deoxycholic acid and salt thereof; Described suspending agent is selected from one or more mixture in sodium carboxymethyl cellulose, sodium alginate, arabic gum, tragakanta, polyvidone; Described sweeting agent is selected from one or more mixture in steviosin, aspartame, sucrose, fructose; Described antiseptic is selected from one or more mixture in sorbic acid, sorbate, benzoic acid, benzoate.
8. the preparation method of dabigatran etcxilate microemulsion formulation as claimed in claim 1 or 2, it is characterized in that getting dabigatran etcxilate is dissolved in cosurfactant, room temperature or be heated to 45 DEG C ~ 60 DEG C to accelerate medicine dissolution, after dabigatran etcxilate dissolves completely, add surfactant and oil, mix homogeneously, prepares oil phase; The oil phase of preparation is slowly added drop-wise in aqueous phase and mixes, make microemulsion by stirring, high pressure homogenize or ultrasonic dissolution, then add sweeting agent, antiseptic, suspending agent, stabilizing agent, be prepared into dabigatran etcxilate microemulsion oral liquid.Concrete preparation method is as follows:
Stir newborn even method: be dissolved in cosurfactant by proportioning by medicine dabigatran etcxilate, room temperature or be heated to 45 DEG C ~ 60 DEG C to accelerate medicine dissolution, after dabigatran etcxilate dissolves completely, add surfactant and oil, mix homogeneously, prepare oil phase; The oil phase of preparation is slowly added drop-wise in aqueous phase and mixes, high-speed stirred 8 ~ 10min, add appropriate additives, obtain dabigatran etcxilate microemulsion.
The even method of high pressure homogenize breast: by proportioning, medicine dabigatran etcxilate is dissolved in surfactant, room temperature or be heated to 45 DEG C ~ 60 DEG C to accelerate medicine dissolution, after dabigatran etcxilate dissolves completely, adds surfactant and oil, mix homogeneously, prepare oil phase; The oil phase of preparation is slowly added drop-wise in aqueous phase and mixes, with high pressure homogenizer homogenized milk even 4 ~ 6 times, add appropriate additives, obtain dabigatran etcxilate microemulsion.
The even method of ultrasonic breast: medicine dabigatran etcxilate is dissolved in surfactant by proportioning, room temperature or be heated to 45 DEG C ~ 60 DEG C to accelerate medicine dissolution, after dabigatran etcxilate dissolves completely, adds surfactant and oil, mix homogeneously, prepares oil phase; The oil phase of preparation is slowly added drop-wise in aqueous phase and mixes, under the power of 250W, with the even 4 ~ 8min of the ultrasonic breast of Probe Ultrasonic Searching instrument, add appropriate additives, obtain dabigatran etcxilate microemulsion.
9. the preparation method of dabigatran etcxilate microemulsion formulation as claimed in claim 8, is characterized in that the particle diameter of microemulsion formulation is 200-400nm.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105708798A (en) * | 2016-03-08 | 2016-06-29 | 中国药科大学 | Dabigatran etexilate and phospholipid compound nanoemulsion and preparation method thereof |
| CN108210454A (en) * | 2016-12-14 | 2018-06-29 | 深圳市华力康生物医药有限公司 | A kind of Orally taken emulsion of Pabuk former times profit cloth and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105708798A (en) * | 2016-03-08 | 2016-06-29 | 中国药科大学 | Dabigatran etexilate and phospholipid compound nanoemulsion and preparation method thereof |
| CN108210454A (en) * | 2016-12-14 | 2018-06-29 | 深圳市华力康生物医药有限公司 | A kind of Orally taken emulsion of Pabuk former times profit cloth 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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