CN105017119A - Lipid-lowering drug ezetimibe compound - Google Patents
Lipid-lowering drug ezetimibe compound Download PDFInfo
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- CN105017119A CN105017119A CN201510434722.2A CN201510434722A CN105017119A CN 105017119 A CN105017119 A CN 105017119A CN 201510434722 A CN201510434722 A CN 201510434722A CN 105017119 A CN105017119 A CN 105017119A
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- ezetimibe
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- acetonitrile
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention belongs to the technical field of drugs, and relates to a lipid-lowering drug ezetimibe compound. The lipid-lowering drug ezetimibe compound is measured by Cu-K alpha ray to obtain an X- ray powder diffraction pattern shown in Figure 1, the lipid-lowering drug ezetimibe compound has good liquidity, and a tablet prepared from the lipid-lowering drug ezetimibe compound has high dissolution, low impurity content, and good stability.
Description
Technical field
The invention belongs to medical art, relate to a kind of blood lipid-lowering medicine Ezetimibe compound.
Background technology
Ezetimibe is white crystalline powder, easily molten in ethanol, methyl alcohol and acetone, almost insoluble in water, and Ezetimibe fusing point about 163 DEG C, at room temperature stablizes.Ezetimibe is clinical is mainly used in primary hypercholesterolemia, this product is as the assisting therapy beyond dietary control, can separately or with HMG-CoA reductase inhibitor as Statins be united and applied in treatment hypercholesterolemia, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) can be reduced, or as the adjuvant therapy (as LDL-C Apheresis) of other lipid-lowering therapies, can also when other lipid-lowering therapies are invalid for reducing TC and the LDL-C level of HoFH patient.
Ezetimibe is water insoluble, and when oral administration uses the solid dosage of Ezetimibe, this medicine must be dissolved in gastric juice, could be played curative effect by absorption.The solid oral dosage form of compacting, as the common preparations such as tablet usually limit its bioavailability because of its dissolution rate, thus have impact on the curative effect of medicine.Reducing granularity is one of method of the increase solubleness that this area is commonly used, and in fact reduction granularity is improved deliquescent method and is used to Ezetimibe.
CN103655481A provides a kind of oral preparations preparation method of Ezetimibe.Adopt ball milling solid dispersion technology, Ezetimibe and pharmaceutically acceptable auxiliary material are prepared into solid orally ingestible, improve the dissolution rate of preparation.But medicine and milling material are ground, milling material may be brought in medicine ball milling fine powder, brings safety concerns during patient medication.This is also the potential risk that ball grinding technique is generally acknowledged, Dissolution of Tablet of the present invention also can further improve simultaneously, and its related substances also needs to be reduced further.
CN103655453A relates to a kind of preparation method of ezetimibe medicine composition.Comprise the following steps: 1) Ezetimibe is suspended in suitable solvent, be prepared into homogeneous Ezetimibe micron order suspension solution; 2) adopt the mode of spraying to join in the thinner of pharmaceutical composition suspension solution, and drying is prepared into particle and the powder of ezetimibe medicine composition; 3) become with powder preparation by particle the medicinal minimum dose unit of Ezetimibe first medicine to be prepared into micron order suspension solution, adopt the mode of one-step palletizing to granulate, medicine is joined in thinner, be finally prepared into minimum pharmaceutical dosage unit.Stripping only 95% in 15min, not yet stripping completely.
CN102292072A discloses the method with drug microparticles coating carrier.Coating carrier can obtain in one-step method, this method need from the solution droplets comprising API evaporating solvent to obtain dry particulate, then by its dressing on carrier.But need special production unit, industrialization is comparatively difficult, and stripping that can not be quick and complete.
Disclose in US Patent No. 2010234342A1 and to grind Ezetimibe and water soluble adjuvant altogether to reach that d (0.5) is less than 2 μm, d (0.9) is less than 4.5 μm, and the d (0.5) that disclosed in US Patent No. 2007/0275075A1, grinding is obtained is altogether less than 5 μm, d (0.9) is less than 20 μm; The micronization of insoluble drug has the lot of advantages such as solubleness raising, dissolution rate quickening.But direct micronized medicine has a common shortcoming: powder compounds is very easy to reunite, and usually makes it can not fully show micronized superiority.Solid dispersions technique can improve dissolution rate and the bioavailability of Ezetimibe, but this preparation method is not of great satisfaction, because solid dispersion is long placed in easily aging, and need to adopt a large amount of carriers and some other pharmaceutical excipients, cause the volume of preparation excessive, not easily by patient is accepted.
CN103877051A applies for that name is a kind of preparation method of Ezetimibe sheet, it adopts supercritical carbon dioxide fluid to carry out roughing to Ezetimibe sheet, directly add auxiliary material afterwards and carry out compressing tablet process, the tablet 15min obtained just energy stripping completely, but applicant finds that although the method can make even particle size distribution in enforcement the method process, but particle agglomeration phenomenon is also obvious, material dispersion is poor, also easy plug nozzle in preparation process, very be not suitable for large-scale industrial application, and the tablet its related substances that the present invention obtains is high, test of long duration foreign matter content increases obviously, considerably increase drug safety.
Given this, the present inventor starts with from the research of Ezetimibe solid chemical material existence, the new crystalline compounds of a kind of Ezetimibe has been prepared through a large amount of tests, surprisingly find through overtesting, Ezetimibe compound flow provided by the invention is good, the Dissolution of Tablet made is high, and foreign matter content is low, good stability.
Summary of the invention
Primary goal of the invention of the present invention is to propose a kind of Ezetimibe compound.
Second goal of the invention of the present invention is the preparation method proposing Ezetimibe compound.
In order to realize the first object of the present invention, the technical solution used in the present invention is:
A kind of blood lipid-lowering medicine Ezetimibe compound, the X-ray powder diffraction pattern that wherein said Ezetimibe compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
Polymorph in pharmaceuticals phenomenon is ubiquitous problem in present drug research.The polymorphism of medicine can affect its physico-chemical property, and then may have influence on the clinical efficacy of medicine.The present inventor obtains a kind of good fluidity by a large amount of tests, and the Dissolution of Tablet made is high, foreign matter content is low, the Ezetimibe compound of good stability.
In order to realize the second object of the present invention, the technical solution used in the present invention is:
A preparation method for Ezetimibe compound, the method comprises the steps:
(1) Ezetimibe crude product is ground, sieve, then join in the mixing solutions of acetonitrile, ethanol, acetone, stir 20 minutes;
(2) add acetonitrile under stirring, heat up simultaneously;
(3) after solution adds, leave standstill 2-3 hour, drip the deionized water of 0 DEG C-5 DEG C under the condition of stirring, at the uniform velocity dropwise in 2-3h;
(4) be added dropwise to complete rear cooling, continue to stir 2-3h, leave standstill 1-2h crystallize out, filter, vacuum-drying obtains Ezetimibe crystal.
As preferably, sieve described in step (1) and referred to 60-90 mesh sieve.
As preferably, the volume ratio of acetonitrile, ethanol and the acetone described in step (1) is 3:3:1, the volume of the mixing solutions of acetonitrile, ethanol, acetone be the 8-10 of Ezetimibe weight doubly.
As preferably, described in step (1), stirring velocity is 65-75 rev/min, described in step (2), stirring velocity is 110-120 rev/min, and described in step (3), stirring velocity is 80-90 rev/min, and described in step (4), stirring velocity is 40-50 rev/min.
As preferably, the volume of acetonitrile described in step (2) be the 5-7 of the Ezetimibe weight starting to add doubly.
As preferably, heating up described in step (2) refers to and is warming up to 30-35 DEG C.
As preferably, the volume of deionized water described in step (3) be the 10-12 of the Ezetimibe weight starting to add doubly.
As preferably, cooling described in step (4) refers to and is cooled to-10 DEG C--5 DEG C.
The present inventor is after having carried out large quantifier elimination to it, obtain above-mentioned preparation method, prepare a kind of Ezetimibe crystalline compounds being different from prior art, surprisingly find through overtesting, Ezetimibe compound flow provided by the invention is good, the Dissolution of Tablet made is high, and foreign matter content is low, good stability.
accompanying drawing illustrates:
Fig. 1 is the X-ray powder diffraction pattern of Ezetimibe compound prepared by embodiment 1.
Embodiment
The specific embodiment of the present invention is only limitted to explain further and the present invention is described, does not limit Composition of contents of the present invention.
embodiment 1:the preparation of Ezetimibe compound
(1) ground by Ezetimibe crude product, cross 60 mesh sieves, then join in the mixing solutions of acetonitrile that volume is 8 times of Ezetimibe weight, ethanol, acetone, the volume ratio of acetonitrile, ethanol and acetone is 3:3:1, and 65 revs/min are stirred 20 minutes;
Add the acetonitrile that volume is 5 times of Ezetimibe weight under (2) 110 revs/min of stirrings, be warming up to 30 DEG C simultaneously;
(3) after solution adds, leave standstill 2 hours, drip the deionized water of 0 DEG C under 80 revs/min of conditions stirred, the volume of deionized water is 10 times of Ezetimibe weight, at the uniform velocity dropwises in 2h;
(4) be cooled to-10 DEG C after being added dropwise to complete, continue to stir 2h under the stir speed (S.S.) of 40 revs/min, leave standstill 1h crystallize out, filter, vacuum-drying obtains Ezetimibe crystal.
The X-ray powder diffractogram using the measurement of Cu-K alpha-ray to obtain to prepared Ezetimibe compound as shown in Figure 1.
embodiment 2:the preparation of Ezetimibe compound
(1) ground by Ezetimibe crude product, cross 75 mesh sieves, then join in the mixing solutions of acetonitrile that volume is 9 times of Ezetimibe weight, ethanol, acetone, the volume ratio of acetonitrile, ethanol and acetone is 3:3:1, and 70 revs/min are stirred 20 minutes;
Add the acetonitrile that volume is 6 times of Ezetimibe weight under (2) 115 revs/min of stirrings, be warming up to 32.5 DEG C simultaneously;
(3) after solution adds, leave standstill 2.5 hours, drip the deionized water of 2.5 DEG C under 85 revs/min of conditions stirred, the volume of deionized water is 11 times of Ezetimibe weight, at the uniform velocity dropwises in 2.5h;
(4) be cooled to-7.5 DEG C after being added dropwise to complete, continue to stir 2.5h under the stir speed (S.S.) of 45 revs/min, leave standstill 1.5h crystallize out, filter, vacuum-drying obtains Ezetimibe crystal.
The X-ray powder diffractogram using the measurement of Cu-K alpha-ray to obtain to prepared Ezetimibe compound is similar to embodiment 1.
embodiment 3:the preparation of Ezetimibe compound
(1) ground by Ezetimibe crude product, cross 90 mesh sieves, then join in the mixing solutions of acetonitrile that volume is 10 times of Ezetimibe weight, ethanol, acetone, the volume ratio of acetonitrile, ethanol and acetone is 3:3:1, and 75 revs/min are stirred 20 minutes;
Add the acetonitrile that volume is 7 times of Ezetimibe weight under (2) 120 revs/min of stirrings, be warming up to 35 DEG C simultaneously;
(3) after solution adds, leave standstill 3 hours, drip the deionized water of 5 DEG C under 90 revs/min of conditions stirred, the volume of deionized water is 12 times of Ezetimibe weight, at the uniform velocity dropwises in 3h;
(4) be cooled to-5 DEG C after being added dropwise to complete, continue to stir 3h under the stir speed (S.S.) of 50 revs/min, leave standstill 2h crystallize out, filter, vacuum-drying obtains Ezetimibe crystal.
The X-ray powder diffractogram using the measurement of Cu-K alpha-ray to obtain to prepared Ezetimibe compound is similar to embodiment 1.
test example 1: fluidity test
This test example has investigated the mobility of the Ezetimibe compound crystal that embodiment of the present invention 1-3 provides.
This test example carrys out the mobility of assess sample by the slope of repose of working sample, concrete grammar is as follows: sample thief particle, flow into from fixing little funnel in circular watch-glass, until obtain the highest cone, measure cone height H and radius R, calculate slope of repose α by tan α=H/R, the results are shown in Table 1, slope of repose is larger, and mobility is poorer.
Table 1 fluidity test result
As seen from Table 1, Ezetimibe compound crystal of the present invention has excellent mobility, is conducive to the accuracy improving packing, and is easy to mix when mixing with other compositions.
test example 2: dissolution determination
Measure according to the second method in dissolution method (" Chinese Pharmacopoeia " 2010 editions two annex X C), each stripping fills the pH4.5 solution containing 0.15%SDS of 500mL, and heat and make water remain on 37 DEG C ± 0.5 DEG C, rotating speed of agitator is 50 revs/min.Get Ezetimibe sheet 6, drop in 6 stripping rotors respectively, to 45min sampling, every sub-sampling 10mL, through 0.45 μm of filtering with microporous membrane.Get clear filtrate, according to ultraviolet spectrophotometry (Chinese Pharmacopoeia 2005 editions two annex IV A), measure absorbancy at the wavelength place of 233nm, calculate the dissolution rate of every sheet by retinue standard meter, dissolution results is in table 2.
test example 3: related substance is investigated
Get Ezetimibe reference substance appropriate, accurately weighed, add Glacial acetic acid-acetonitrile-water (0.1:60:40) and dissolve and quantitatively dilute the solution made about containing 0.4 μ g in every 1mL, product solution in contrast.Get Ezetimibe orally disintegrating tablet 10, put in 500mL measuring bottle, add Glacial acetic acid-acetonitrile-water (0.1:60:40) appropriate, ultrasonic 30 minutes, jolting 45 minutes, added Glacial acetic acid-acetonitrile-water (0.1:60:40) and is diluted to scale, shake up, filter, as need testing solution.Precision measures reference substance solution and each 30 μ L of need testing solution, respectively injection liquid chromatography, and record color atlas is to 2 times of principal constituent peak retention time.Need testing solution is as aobvious impurity peaks, and by external standard method with calculated by peak area, list must not mix more than 0.2%, always must not mix more than 0.5%, and related substance is investigated and be the results are shown in Table 2.
Table 2 dissolution rate and related substance investigate result
Wherein, sample 1 is the Ezetimibe compound adopting the embodiment of the present invention 1, with reference to the Ezetimibe sheet that the method for patent CN103877051A embodiment 1 is obtained;
Sample 2 adopts common raw material, with reference to the Ezetimibe sheet that the method for patent CN103877051A embodiment 1 is obtained;
Sample 3 is the Ezetimibe compounds adopting the embodiment of the present invention 1, with reference to the Ezetimibe sheet that patent CN103655481A embodiment 7 is obtained;
Sample 4 adopts common raw material, with reference to the Ezetimibe sheet that patent CN103655481A embodiment 7 is obtained;
Sample 5 is import clothing Ezetimibe sheet (manufacturers: MSD Pharma (Singapore) Pte. Ltd. trade(brand)name benefit is suitable pure).
As shown in Table 2, the Ezetimibe dissolution rate adopting Ezetimibe compound of the present invention obtained is high, and its related substances obviously reduces, and illustrates that the compounds of this invention has the dissolution rate improving tablet, the advantage reducing its related substances.
Also carried out identical test to other embodiments, the result obtained is consistent with embodiment 1.
test example 4: accelerated test
Sample thief, by commercially available back, carries out accelerated test, investigates 6 months under the condition of temperature 40 DEG C ± 2 DEG C, relative humidity 75% ± 5%, respectively at 1,2,3, sampling in June, investigate by stability high spot reviews project, result is as following table 3.
Table 3 accelerated test result
Wherein, sample 1 is the Ezetimibe compound adopting the embodiment of the present invention 1, with reference to the Ezetimibe sheet that the method for patent CN103877051A embodiment 1 is obtained;
Sample 2 adopts common raw material, with reference to the Ezetimibe sheet that the method for patent CN103877051A embodiment 1 is obtained;
Sample 3 is the Ezetimibe compounds adopting the embodiment of the present invention 1, with reference to the Ezetimibe sheet that patent CN103655481A embodiment 7 is obtained;
Sample 4 adopts common raw material, with reference to the Ezetimibe sheet that patent CN103655481A embodiment 7 is obtained;
Sample 5 is import clothing Ezetimibe sheet (manufacturers: MSD Pharma (Singapore) Pte. Ltd. trade(brand)name benefit is suitable pure).
As can be seen from Table 3, the embodiment of the present invention 1 product is after temperature 40 ± 2 DEG C, relative humidity 75 ± 5% carry out accelerated test, and dissolution rate, impurity index are obviously better than imported product and prior art products, and stability is better.
Also carried out identical test to other embodiments, the result obtained is consistent with embodiment 1.
Claims (9)
1. a blood lipid-lowering medicine Ezetimibe compound, is characterized in that: the X-ray powder diffraction pattern that described Ezetimibe compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
2. prepare a method for blood lipid-lowering medicine Ezetimibe compound according to claim 1, it is characterized in that comprising the following steps:
(1) Ezetimibe crude product is ground, sieve, then join in the mixing solutions of acetonitrile, ethanol, acetone, stir 20 minutes;
(2) add acetonitrile under stirring, heat up simultaneously;
(3) after solution adds, leave standstill 2-3 hour, drip the deionized water of 0 DEG C-5 DEG C under the condition of stirring, at the uniform velocity dropwise in 2-3h;
(4) be added dropwise to complete rear cooling, continue to stir 2-3h, leave standstill 1-2h crystallize out, filter, vacuum-drying obtains Ezetimibe crystal.
3. the preparation method of blood lipid-lowering medicine Ezetimibe compound according to claim 2, is characterized in that, sieving described in step (1) referred to 60-90 mesh sieve.
4. the preparation method of Ezetimibe Ezetimibe compound according to claim 2, it is characterized in that, the volume ratio of acetonitrile, ethanol and the acetone described in step (1) is 3:3:1, and the volume of the mixing solutions of acetonitrile, ethanol, acetone is 8-10 times of Ezetimibe weight.
5. the preparation method of Ezetimibe Ezetimibe compound according to claim 2, it is characterized in that: described in step (1), stirring velocity is 65-75 rev/min, described in step (2), stirring velocity is 110-120 rev/min, described in step (3), stirring velocity is 80-90 rev/min, and described in step (4), stirring velocity is 40-50 rev/min.
6. the preparation method of Ezetimibe Ezetimibe compound according to claim 2, is characterized in that: the volume of acetonitrile described in step (2) is 5-7 times of the Ezetimibe weight starting to add.
7. the preparation method of Ezetimibe Ezetimibe compound according to claim 2, is characterized in that: intensification described in step (2) refers to and is warming up to 30-35 DEG C.
8. the preparation method of Ezetimibe Ezetimibe compound according to claim 2, is characterized in that: the volume of deionized water described in step (3) is 10-12 times of the Ezetimibe weight starting to add.
9. the preparation method of Ezetimibe Ezetimibe compound according to claim 2, is characterized in that: cooling described in step (4) refers to and is cooled to-10 DEG C--5 DEG C.
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| CN201510434722.2A CN105017119A (en) | 2015-07-23 | 2015-07-23 | Lipid-lowering drug ezetimibe compound |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106588737A (en) * | 2016-11-08 | 2017-04-26 | 山东裕欣药业有限公司 | New crystal form of ezetimibe and preparation method for new crystal form of ezetimibe |
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| US20060234996A1 (en) * | 2005-04-14 | 2006-10-19 | Itai Adin | Novel crystalline form of ezetimibe and processes for the preparation thereof |
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| CN104402790A (en) * | 2014-12-28 | 2015-03-11 | 严白双 | Improved method for preparing ezetimibe |
| CN104447473A (en) * | 2014-11-06 | 2015-03-25 | 成都森科制药有限公司 | Preparation method of Ezetimibe intermediate |
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2015
- 2015-07-23 CN CN201510434722.2A patent/CN105017119A/en active Pending
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| WO2005009955A1 (en) * | 2003-07-31 | 2005-02-03 | Hetero Drugs Limited | Ezetimibe polymorphs |
| US20060234996A1 (en) * | 2005-04-14 | 2006-10-19 | Itai Adin | Novel crystalline form of ezetimibe and processes for the preparation thereof |
| WO2011158052A1 (en) * | 2010-06-18 | 2011-12-22 | Nanoform Cardiovascular Therapeutics Ltd. | Nanostructured ezetimibe compositions, process for the preparation thereof and pharmaceutical compositions containing them |
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| CN104447473A (en) * | 2014-11-06 | 2015-03-25 | 成都森科制药有限公司 | Preparation method of Ezetimibe intermediate |
| CN104402790A (en) * | 2014-12-28 | 2015-03-11 | 严白双 | Improved method for preparing ezetimibe |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106588737A (en) * | 2016-11-08 | 2017-04-26 | 山东裕欣药业有限公司 | New crystal form of ezetimibe and preparation method for new crystal form of ezetimibe |
| CN106588737B (en) * | 2016-11-08 | 2019-06-18 | 山东裕欣药业有限公司 | Novel crystal forms of Ezetimibe and preparation method thereof |
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