CN103467484B - Compound and medicine composition containing micronized prasugrel and salts of prasugrel - Google Patents
Compound and medicine composition containing micronized prasugrel and salts of prasugrel Download PDFInfo
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- CN103467484B CN103467484B CN201310388714.XA CN201310388714A CN103467484B CN 103467484 B CN103467484 B CN 103467484B CN 201310388714 A CN201310388714 A CN 201310388714A CN 103467484 B CN103467484 B CN 103467484B
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- prasugrel
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Abstract
The invention relates to a compound and medicine composition containing micronized prasugrel and salts of prasugrel. Prasugrel and the salts of prasugrel are micronized by adopting a superfine grinding technology till the particle sizes of the prasugrel and the prasugrel salts are in the range from 3micrometers to 10 micrometers, thus the micronized compound is obtained. The medicine composition is prepared from the micronized compound of prasugrel and the salts of prasugrel and appropriate auxiliary materials, wherein the weight of prasugrel and the salts of prasugrel accounts for 0.1%-10% of the total weight of the medicine composition. The superfine grinding technology is used for preparing the compound of the prasugrel and salts of the prasugrel and the particle size of the compound is 3 to 10 micrometers, so that the water solubility of the prasugrel and the prasugrel salts is increased, the biological availability is improved, and the clinical effect of the medicinal preparation is improved.
Description
Technical field
The present invention relates to a kind of micronized prasugrel that superfine communication technique makes and product of salt and preparation thereof of adopting, belong to medical technical field.
Background technology
Prasugrel (prasugrel) is a novel antiplatelet drug, in Europe and U.S.'s listing.(clopidogrel) is similar for same clopidogrel, and prasugrel passes through to suppress adenosine diphosphate (ADP) (adenosine diphosphate, ADP) thereby the platelet aggregation performance antiplatelet effects of induction.But the antiplatelet effects of prasugrel is stronger than clopidogrel, and onset is faster.Prasugrel is thiophene chloropyridine, chlorine pyrrole thunder lattice analogue, 1993 by Japan three altogether, the P2Y12 purinoceptor antagonist with oral property of Ube Industries, Lilly joint development, 2009 in European Union and successively approval listing of FDA, it is the lead compound in a series of tetrahydrothieno pyridines analog derivatives, as platelet aggregation inhibitor, to prevent and to treat thrombosis.
The preparation that prasugrel goes on the market abroad is at present tablet, and prasugrel sheet is mainly used in hospital clinical abroad.Clinical studies show, prasugrel has than the better blood coagulation resisting function of current main flow medicine clopidogrel, simultaneously to heart attack, apoplexy, because the integrated risk of deaths from heart disease is low by 20%, and instant effect, good effect, have good resistance and bioavailability.This kind is the good efficacy in market abroad, will excite its use scale in market at home.
The solvability of prasugrel and salt thereof is poor, causes bioavailability lower, utilizes existing preparation technique to improve its water-soluble, improves bioavailability, becomes a present popular problem.
Micronizing is nearly new and high technology developing rapidly for 20 years, starting material can be processed into the even nano level micro mist of micron, is widely used in every profession and trade.Air-flow superfine communication technique is the one of superfine communication technique, it utilizes material under the effect of high velocity air, obtain huge kinetic energy, in crushiing chamber, cause high velocity impact, acutely friction between material particles, high velocity air produces shearing action to material simultaneously, thereby reach the object of comminuting matter, it can become Raw material processing superfine powder, and (< 10 μ m).But at present, superfine communication technique is applied to Chinese medicine by the technician of pharmaceutical field, up to now, almost superfine communication technique is not applied to pharmaceutical chemicals Western medicine aspect, to improve the application of the existing defect in preparation aspect of pharmaceutical chemicals.
Prior art CN102675338A discloses a kind of micronization prasugrel and the pharmaceutical composition for activeconstituents thereof, wherein micronization prasugrel, and the particle diameter at its 90% cumulative volume place is below 25 μ m.
Generally speaking, by to medical compounds crystallization pulverize to there is less particle diameter, contribute to improve the stripping property of medicament, but for containing the solid preparation of prasugrel, predict that how the drug microparticles of particle diameter is difficult to control stripping property for the professional and technical personnel of this field.
Only by measuring the dissolution rate of pharmaceutical preparation in the hydrochloric acid medium of simulation normal human gastric acid environment, be not enough to predict medicine dissolving out capability and bioavailability in vivo, only make pharmaceutical preparation under the multiple pH condition that may exist, all there is good dissolution characteristic and could in different people colony, can bring into play respective action by effective guarantee medicine.
In fact, the size distribution of drug microparticles and the bioavailability of medicament are not linear variation.Although prior art has been instructed the existence of the micronization technology of prasugrel, but its bioavailability not makes patient satisfaction, is unsuitable for clinical use.Therefore, find the pharmaceutical formulations of the micronization prasugrel with gratifying biological utilisation that is suitable for clinical use become when preclinical therapy in the urgent need to.
Summary of the invention
For the problems referred to above of prasugrel and salt existence thereof, the inventor is through long-term conscientious research, find that prasugrel and salt compound grain diameter thereof are not directly proportional little to its pharmacokinetics effect, superfine communication technique is applied in the preparation of prasugrel and salt compound thereof, obtain micronization prasugrel in specified particle diameter and the particle of salt compound thereof, can significantly improve the solvability in its water, produce beyond thought effect, greatly improve bioavailability, thereby completed the present invention.
The object of the present invention is to provide the compound of a kind of micronized prasugrel and salt thereof, its particle diameter is 3-10 μ m.Prasugrel molecular formula C
20h
20fNO
3s, molecular weight 373.44, structural formula is:
Described prasugrel and salt thereof comprise prasugrel, hydrochloric acid prasugrel, prasugrel hydrobromide, fumaric acid prasugrel, Phenylsulfonic acid prasugrel, prasugrel hydrobromide acetic acid compound, hydrochloric acid prasugrel acetic acid compound, fumaric acid prasugrel acetic acid compound, Phenylsulfonic acid prasugrel acetic acid compound.
The present invention also provides the method for the compound of a kind of micronization prasugrel and salt thereof, carries out precomminution by prasugrel and salt thereof, and making particle diameter is 70-150 μ m particle, then adopts superfine communication technique to carry out micronization, and making particle diameter is 3-10 μ m fine powder.
As the present invention's one preferred embodiment, precomminution adopts the conventional crushing technology in this area to carry out, and described technology comprises, but be not limited to grind, push, collide, cut, shredding unit used includes, but are not limited to mortar, ball mill, fluid energy mill, preferably adopts the fluid energy mill of impacting technology.
As the present invention's one preferred embodiment, superfine communication technique is selected from mechanical disintegration, vibrant pulverization, comminution by gas stream, ultrasonication, high pressure grinding, preferably airflow pulverization.Superfine communication technique equipment therefor is selected from QWJ-5 air-flow vortex pulverizer, QWJ-15 air-flow vortex pulverizer, CWM-80 super vortex mill, CWM-120 super vortex mill, CWJ-30 supper micron mill, CWJ-45 supper micron mill, preferably CWJ-30 type supper micron mill.
Preferred, the concrete operation step that described airflow pulverization adopts is as follows: be that coarse grained prasugrel and salt thereof and the rare gas element after lyophilize inject supper micron mill jointly by precomminution, adopt high velocity air to pulverize, preferably, rare gas element after lyophilize, preferably air or nitrogen, temperature is 0-15 DEG C, preferably 5 DEG C-10 DEG C, water content≤1%, when air Injection supper micron mill, pressure is 0.8-1.5MPa, preferably 1.1-1.2MPa, the operating pressure of supper micron mill is 0.8-1.5MPa, preferably 1.1-1.2MPa, internal work temperature is 0-8 DEG C, preferably 2 DEG C-6 DEG C, grinding time is 30-200min, preferably 50-150min.
Another object of the present invention is to provide a kind of pharmaceutical composition that contains micronized prasugrel and salt thereof, and it can be tablet, capsule and granule.This pharmaceutical composition comprises prasugrel and salt and suitable auxiliary material, and wherein prasugrel and salt thereof account for the 0.1%-10% of pharmaceutical composition gross weight.
The auxiliary material of the pharmaceutical composition of prasugrel of the present invention and salt thereof, include but not limited to disintegrating agent, weighting agent, tackiness agent, wetting agent, lubricant, sweeting agent etc., wherein disintegrating agent is selected from one or more in carboxymethylstach sodium, croscarmellose sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose; Weighting agent is selected from one or more in lactose, Microcrystalline Cellulose, starch, sucrose, pregelatinized Starch, dicalcium phosphate dihydrate, N.F,USP MANNITOL, sorbyl alcohol; Tackiness agent is selected from one or more in hypromellose, PVP K30, Xylo-Mucine, starch slurry; Wetting agent is selected from second alcohol and water; Lubricant is selected from one or more in Magnesium Stearate, silicon-dioxide, talcum powder, sodium lauryl sulphate, sodium stearyl fumarate, PEG6000; Sweeting agent is selected from one or more in aspartame, Steviosin, Sucralose, soluble saccharin.
The pharmaceutical composition of prasugrel of the present invention and salt thereof, its preparation method comprises the steps:
(1) be that the prasugrel of 3-10 μ m and salt thereof and disintegrating agent, weighting agent philosophy are crossed 100 mesh sieves by micronized particle diameter, then mix;
(2) in the supplementary material powder mixing, add binder solution or wetting agent, prepare softwood, cross 20-30 mesh sieve wet granular processed, 50-70 DEG C of forced air drying 30-90 minute;
(3) dry particle is crossed the whole grain of 18 mesh sieves, adds always mixed 5-15 minute of lubricant, mixes;
(4) compressing tablet, filled capsules or pack, to obtain final product.
The present invention adopts superfine communication technique to prepare prasugrel that particle diameter is 3-10 μ m and the compound of salt thereof, has improved the water-soluble of prasugrel and salt thereof, has improved bioavailability, has increased the clinical efficacy of pharmaceutical preparation.
Brief description of the drawings
Fig. 1 has illustrated the extremely salt of prasugrel with specified particle diameter, makes supersaturated solution, calculates prasugrel and the solubleness of salt in water thereof by detection level.
embodiment
Provide as follows the specific embodiment of the present invention, be to be understood that the present invention is not limited to these concrete embodiments, those skilled in the art can not deviate under the spirit and scope of the present invention, can carry out various modifications and change to the present invention, but such improvement is considered to be all included in the scope of the application's claims.
The micronization of embodiment 1 prasugrel
(1) prasugrel is adopted the fluid energy mill of impacting technology carry out precomminution, making particle diameter is 150 μ m particles;
(2) adopt CWJ-30 type supper micron mill to carry out micronizing to above-mentioned coarse particles, be ground into 3-10 μ m fine powder;
Pulverization conditions: the air themperature after lyophilize is 6 DEG C, water content 0.5%, while injecting supper micron mill, pressure is 0.8MPa, and the operating pressure of supper micron mill is 0.8MPa, and internal work temperature is 6 DEG C, and grinding time is 50min.
The micronization of embodiment 2 hydrochloric acid prasugrels
(1) adopt the fluid energy mill of impacting technology to carry out precomminution hydrochloric acid prasugrel, making particle diameter is 250 μ m particles;
(2) adopt CWJ-30 type supper micron mill to carry out micronizing to above-mentioned coarse particles, be ground into 3-10 μ m fine powder;
Pulverization conditions: the air themperature after lyophilize is 10 DEG C, water content 0.4%, while injecting supper micron mill, pressure is 1.2MPa, and the operating pressure of supper micron mill is 1.1MPa, and internal work temperature is 2 DEG C, and grinding time is 100min.
The micronization of embodiment 3 prasugrel hydrobromides
(1) prasugrel hydrobromide is adopted the fluid energy mill of impacting technology carry out precomminution, making particle diameter is 200 μ m particles;
(2) adopt CWJ-30 type supper micron mill to carry out micronizing to above-mentioned coarse particles, be ground into 3-10 μ m fine powder;
Pulverization conditions: the air themperature after lyophilize is 8 DEG C, water content 0.7%, while injecting supper micron mill, pressure is 1.5MPa, and the operating pressure of supper micron mill is 1.2MPa, and internal work temperature is 4 DEG C, and grinding time is 150min.
The micronization of embodiment 4 prasugrel hydrobromide acetic acid compounds
(1) adopt the fluid energy mill of impacting technology to carry out precomminution prasugrel hydrobromide acetic acid compound, making particle diameter is 200 μ m particles;
(2) adopt CWJ-30 type supper micron mill to carry out micronizing to above-mentioned coarse particles, be ground into 3-10 μ m fine powder;
Pulverization conditions: the air themperature after lyophilize is 8 DEG C, water content 0.6%, while injecting supper micron mill, pressure is 1.0MPa, and the operating pressure of supper micron mill is 1.1MPa, and internal work temperature is 5 DEG C, and grinding time is 130min.
The preparation of embodiment 5 prasugrel sheets
(1) be that the prasugrel 10g of 3-10 μ m and croscarmellose sodium 20g, N.F,USP MANNITOL 50g, Microcrystalline Cellulose 120g cross respectively 100 mesh sieves by micronized particle diameter, then mix;
(2) in the supplementary material powder mixing, add 2% hypromellose 50% ethanolic soln to prepare softwood, cross 20 mesh sieve wet granular processed, 50 DEG C of forced air dryings 90 minutes;
(3) dry particle is crossed the whole grain of 18 mesh sieves, adds lubricant always mixed 5 minutes, mixes;
(4) compressing tablet, to obtain final product.
The preparation of embodiment 6 hydrochloric acid prasugrel sheets
(1) be that the hydrochloric acid prasugrel 5g of 3-10 μ m and croscarmellose sodium 8g, N.F,USP MANNITOL 30g, Microcrystalline Cellulose 57g cross respectively 100 mesh sieves by micronized particle diameter, then mix;
(2) in the supplementary material powder mixing, add 20% ethanolic soln of 5% PVP K30 to prepare softwood, cross 30 mesh sieve wet granular processed, 70 DEG C of forced air dryings 30 minutes;
(3) dry particle is crossed the whole grain of 18 mesh sieves, adds lubricant always mixed 15 minutes, mixes;
(4) compressing tablet, to obtain final product.
The preparation of embodiment 7 prasugrel hydrobromide particles
(1) be that the prasugrel hydrobromide 5g of 3-10 μ m and carboxymethylstach sodium 40g, sucrose 700g, N.F,USP MANNITOL 150g, Microcrystalline Cellulose 80g, aspartame 30g cross respectively 100 mesh sieves by micronized particle diameter, then mix;
(2) in the supplementary material powder mixing, add 2% hypromellose 50% ethanolic soln to prepare softwood, cross 20 mesh sieve wet granular processed, 60 DEG C of forced air dryings 70 minutes;
(3) dry particle is crossed the whole grain of 18 mesh sieves, adds lubricant always mixed 10 minutes, mixes;
(4) pack, to obtain final product.
The preparation of embodiment 8 prasugrel hydrobromide acetic acid compound capsules
(1) be that the prasugrel hydrobromide acetic acid compound 10g of 3-10 μ m and croscarmellose sodium 30g, N.F,USP MANNITOL 60g, Microcrystalline Cellulose 100g cross respectively 100 mesh sieves by micronized particle diameter, then mix;
(2) in the supplementary material powder mixing, add 50% ethanolic soln of 5% PVP K30 to prepare softwood, cross 24 mesh sieve wet granular processed, 60 DEG C of forced air dryings 60 minutes;
(3) dry particle is crossed the whole grain of 18 mesh sieves, adds lubricant always mixed 8 minutes, mixes;
(4) filled capsules, to obtain final product.
Embodiment 9 solubility tests
Prasugrel and salt thereof prepared by embodiment 1-4 are soluble in water, make supersaturated solution, calculate prasugrel and the solubleness of salt in water thereof by detection level, and and contrast without micronized raw material, result is as follows:
| Material | Without micronization | After micronization |
| Prasugrel | 0.71μg/ml | 1.33μg/ml |
| Hydrochloric acid prasugrel | 0.78μg/ml | 1.45μg/ml |
| Prasugrel hydrobromide | 0.65μg/ml | 1.29μg/ml |
| Prasugrel hydrobromide acetic acid compound | 0.82μg/ml | 1.63μg/ml |
Comparative example 1 adopts prescription and the technique identical with embodiment 5, and difference is to select without micronized prasugrel raw material.
Comparative example 2 adopts prescription and the technique identical with embodiment 6, and difference is to select without micronized hydrochloric acid prasugrel raw material.
Comparative example 3 adopts prescription and the technique identical with embodiment 7, and difference is to select without micronized prasugrel hydrobromide raw material.
Comparative example 4 adopts prescription and the technique identical with embodiment 8, and difference is to select without micronized prasugrel hydrobromide acetic acid compound raw material.
Embodiment 10 dissolution in vitro tests
Prasugrel prepared by embodiment 5-8 and comparative example 1-4 and the preparation of salt thereof carry out dissolution in vitro detection, concrete grammar is: get this product, according to dissolution method (Chinese Pharmacopoeia version annex X C the second method in 2010), taking pH4.0 Citric Acid phosphate buffered saline buffer 900ml as solvent, rotating speed is that per minute 75 turns, operation in accordance with the law, sampling in the time of 45 minutes, adopt high-efficient liquid phase technique to detect, result is as follows:
| Sample | Dissolution rate (%) |
| Embodiment 5 | 95.6 |
| Embodiment 6 | 98.8 |
| Embodiment 7 | 93.2 |
| Embodiment 8 | 99.7 |
| Comparative example 1 | 66.7 |
| Comparative example 2 | 71.3 |
| Comparative example 3 | 60.5 |
| Comparative example 4 | 76.4 |
Conclusion: can be found out by above test-results, the sample dissolution rate of embodiment 5-8 prepared by the micronized prasugrel of process and salt thereof is apparently higher than the sample of preparing without micronized comparative example 1-4, illustrate that prasugrel and salt thereof are after micronizing reduces particle diameter, the dissolution rate of related preparations improves greatly, and in body, bioavailability also improves thereupon.
The prasugrel of embodiment 11 different-grain diameters and the dissolubility test of salt thereof
According to the preparation technology of embodiment 1-4, preparation has the extremely salt of prasugrel of specified particle diameter, makes supersaturated solution, calculates prasugrel and the solubleness of salt in water thereof by detection level, and result is as follows:
| Product | Particle diameter < 3 μ m | Particle diameter 3-10 μ m | Particle diameter 10-25 μ m | Particle diameter > 25 μ m |
| Prasugrel | 1.44μg/ml | 1.33μg/ml | 1.04μg/ml | 0.82μg/ml |
| Hydrochloric acid prasugrel | 1.57μg/ml | 1.45μg/ml | 1.07μg/ml | 0.86μg/ml |
| Prasugrel hydrobromide | 1.43μg/ml | 1.29μg/ml | 1.00μg/ml | 0.79μg/ml |
| Prasugrel hydrobromide acetic acid compound | 1.71μg/ml | 1.63μg/ml | 1.12μg/ml | 0.91μg/ml |
According to above data, the prasugrel of different-grain diameter and the solubility curve of salt thereof are illustrated in fig. 1 shown below.Conclusion: from above testing data and curve, the solubleness of prasugrel and salt thereof reduces along with the increase of particle diameter.
The prasugrel of embodiment 12 different-grain diameters and the test of the bioavailability of salt thereof
According to the preparation technology of embodiment 5-8, adopt respectively the prasugrel of specified particle diameter and salt thereof to prepare corresponding preparation, then oral rear by detecting Plasma Concentration, judge its bioavailability, result:
Conclusion: known by above-mentioned data, preparation bioavailability the best prepared by the prasugrel of particle diameter 3-10 μ m and salt thereof, be the prasugrel of particle diameter <3 μ m and preparation bioavailability prepared by salt thereof and then, and be much higher than particle diameter and be greater than the prasugrel of 10 μ m and preparation prepared by salt thereof; So select prasugrel and the salt thereof of particle diameter 3-10 μ m both to ensure bioavailability, make again production technique feasible, absolutely prove benefit of the present invention and innovation.
Claims (3)
1. a compound for micronized prasugrel and salt thereof, is characterized in that prasugrel and salt thereof to carry out precomminution, and making particle diameter is 70-150 μ m particle, then adopts superfine communication technique to carry out micronization, and making particle diameter is 3-10 μ m fine powder.
2. the compound of micronized prasugrel according to claim 1 and salt thereof, is characterized in that the salt of described prasugrel is selected from hydrochloric acid prasugrel, prasugrel hydrobromide, fumaric acid prasugrel, Phenylsulfonic acid prasugrel, prasugrel hydrobromide acetic acid compound, hydrochloric acid prasugrel acetic acid compound, fumaric acid prasugrel acetic acid compound, Phenylsulfonic acid prasugrel acetic acid compound, naphthalene disulfonic acid prasugrel and acetic acid compound thereof.
3. contain a pharmaceutical composition for the compound of micronized prasugrel claimed in claim 1 and salt thereof, it is characterized in that described pharmaceutical composition is selected from tablet, capsule and granule, wherein prasugrel and salt thereof account for the 0.1%-10% of gross weight.
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| CN105435237B (en) * | 2015-12-17 | 2018-12-28 | 河南润弘制药股份有限公司 | A kind of prasugrel hydrochloride pharmaceutical composition, tablet and preparation method thereof |
| CN106913549A (en) * | 2015-12-25 | 2017-07-04 | 山东新时代药业有限公司 | A kind of prasugrel tablets and preparation method thereof |
| CN106913542B (en) * | 2015-12-28 | 2021-06-04 | 山东新时代药业有限公司 | Prasugrel tablet and preparation method thereof |
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| US20090281136A1 (en) * | 2008-05-08 | 2009-11-12 | Sandeep Mhetre | Prasugrel pharmaceutical formulations |
| CN102232949A (en) * | 2010-04-27 | 2011-11-09 | 孙远 | Drug dissolution increasing composition and preparation method thereof |
| CN102675338A (en) * | 2011-03-11 | 2012-09-19 | 上海现代制药股份有限公司 | Micronization prasugrel and medicinal composition of prasugrel |
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