CN105012244A - Medicine ezetimibe composition granules for treating hyperlipidemia - Google Patents
Medicine ezetimibe composition granules for treating hyperlipidemia Download PDFInfo
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- CN105012244A CN105012244A CN201510478954.8A CN201510478954A CN105012244A CN 105012244 A CN105012244 A CN 105012244A CN 201510478954 A CN201510478954 A CN 201510478954A CN 105012244 A CN105012244 A CN 105012244A
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Abstract
The invention discloses medicine ezetimibe composition granules for treating hyperlipidemia and belongs to the technical field of medicines. The medicine ezetimibe composition granules are prepared by ezetimibe, cane sugar, calcium edetate, flavoring orange essence and purified water. The ezetimibe is a novel crystal-form compound and is different from the ezetimibe disclosed in the prior art, and the X-ray powder diffraction diagram obtained through Cu-K alpha ray measurement is as shown in the figure 1. A test shows that the ezetimibe composition of the medicine ezetimibe composition granules is good in fluidity, solubility is greatly improved, and the prepared granules are simple in ingredients, low in impurity content and good in stability, and a preparation method is simple.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine Ezetimibe composition granule for the treatment of hyperlipidemia.
Background technology
Ezetimibe is white crystalline powder, easily molten in ethanol, methanol 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 auxiliary treatment beyond diet control, can separately or with HMG-CoA reductase inhibitor as Statins be united and applied in treatment hypercholesterolemia, T-CHOL (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) can be reduced, or as the complementary 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 forms 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 rate of dissolution, thus have impact on the curative effect of medicine.Reducing granularity is one of method of the increase dissolubility 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 formulations preparation method of Ezetimibe.Adopt ball milling solid dispersion technology, Ezetimibe and pharmaceutically acceptable adjuvant are prepared into solid orally ingestible, improve the dissolution 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 diluent of pharmaceutical composition suspension solution, and drying is prepared into granule and the powder of ezetimibe medicine composition; 3) become with powder preparation by granule 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 diluent, 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, the method need from the solution droplets comprising API evaporating solvent to obtain dry microgranule, then by its coating on carrier.But need special production equipment, 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 dissolubility 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 pharmaceutic adjuvants, 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 initial processing to Ezetimibe sheet, directly add adjuvant afterwards and carry out tabletting 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, long term test impurity 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, and dissolubility improves greatly, and the granule component made is simple, impurity content is low, good stability and preparation method is simple.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of medicine Ezetimibe composition granule for the treatment of hyperlipidemia.In order to complete object of the present invention, the technical scheme of employing is:
The present invention relates to a kind of medicine Ezetimibe composition granule for the treatment of hyperlipidemia, it is characterized in that, described compositions is made up of Ezetimibe, sucrose, Ca-EDTA, flavoring orange essence, purified water; Described Ezetimibe is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
As preferably, with parts by weight, described compositions is made up of the Ezetimibe of 1 weight portion, the sucrose of 34-35 weight portion, the Ca-EDTA of 1.5-1.9 weight portion, the flavoring orange essence of 0.2-0.3 weight portion, the purified water of 3-5 weight portion.
As preferably, with parts by weight, described compositions is made up of the Ezetimibe of 1 weight portion, the sucrose of 34.3 weight portions, the Ca-EDTA of 1.7 weight portions, the flavoring orange essence of 0.25 weight portion, the purified water of 4 weight portions.
As preferably, the preparation method of described compositions comprises the following steps:
1) supplementary material process: Ezetimibe was pulverized 120 mesh sieves with shaking screen;
2) weigh: weigh each supplementary material according to technology preparation amount;
3) binding agent preparation: the flavoring orange essence of recipe quantity is joined in the purified water of recipe quantity, stirring and dissolving;
4) granulate: the Ezetimibe of recipe quantity, sucrose, Ca-EDTA are added in high-speed mixing granulating machine, open stirring motor low speed (I speed) mixing 10 minutes, add the binding agent prepared, low speed (I speed) wet mixing 90-110 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
5) drying and screening: boiling drier inlet temperature is controlled at 55 DEG C-60 DEG C, wet granular is placed in boiling drier, note checking exsiccator upper-lower seal situation and granule boiling situation time dry and double granule, reach uniform drying, be dried to < 4%, granule shaking screen after drying sieved the granule got between 16 order-32 orders;
6) always mix: the dry granule after granulate is joined in mixer, mixing velocity 12r/min, open mixer and mix 5 minutes;
7) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
The preparation method of the Ezetimibe compound crystal in the present composition comprises the following steps:
Get Ezetimibe crude drug, the volume adding 35 DEG C is that in the mixed solvent A of the acetone of Ezetimibe weight 6 times, 2,4-lutidines, acetone, 2,4-lutidines volume ratios are 3:1, obtain solution; Then in the horizontal direction of the liquid level of gained solution, apply the stationary magnetic field that magnetic field intensity is 1.0T, and under the condition of this stationary magnetic field, drip the mixed solvent B that volume is Ezetimibe weight 8 times of water, methyl ether in solution, the volume ratio of water, methyl ether is 4:1; After being added dropwise to complete, be cooled to-5 DEG C, leave standstill 5 hours, filter, washing, vacuum drying, obtains described Ezetimibe crystal.
Below technical scheme of the present invention is made further explanation:
The present invention is by the precise controlling to crystallization condition, and prepared a kind of Ezetimibe novel crystal forms unlike the prior art, the X-ray powder diffraction pattern of this Ezetimibe crystal unlike the prior art.Simultaneously due to the ins and outs of this crystal formation, find through test, Ezetimibe compound flow provided by the invention is good, and dissolubility improves greatly, and the granule component made is simple, and impurity content is low, good stability and preparation method is simple.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction of Ezetimibe crystal prepared by the embodiment of the present invention 1.
Detailed description of the invention
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
embodiment 1:the preparation of Ezetimibe crystal
Get Ezetimibe crude drug, the volume adding 35 DEG C is that in the mixed solvent A of the acetone of Ezetimibe weight 6 times, 2,4-lutidines, acetone, 2,4-lutidines volume ratios are 3:1, obtain solution; Then in the horizontal direction of the liquid level of gained solution, apply the stationary magnetic field that magnetic field intensity is 1.0T, and under the condition of this stationary magnetic field, drip the mixed solvent B that volume is Ezetimibe weight 8 times of water, methyl ether in solution, the volume ratio of water, methyl ether is 4:1; After being added dropwise to complete, be cooled to-5 DEG C, leave standstill 5 hours, filter, washing, vacuum drying, obtains described Ezetimibe crystal.
The X-ray powder diffraction pattern that the Ezetimibe crystal prepared uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1.
embodiment 2:the preparation of Ezetimibe granule:
Prescription: with parts by weight as table 1
Table 1 Ezetimibe composition prescription
Preparation method:
1) supplementary material process: Ezetimibe was pulverized 120 mesh sieves with shaking screen;
2) weigh: weigh each supplementary material according to technology preparation amount;
3) binding agent preparation: the flavoring orange essence of recipe quantity is joined in the purified water of recipe quantity, stirring and dissolving;
4) granulate: the Ezetimibe of recipe quantity, sucrose, Ca-EDTA are added in high-speed mixing granulating machine, open stirring motor low speed (I speed) mixing 10 minutes, add the binding agent prepared, low speed (I speed) wet mixing 90-110 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
5) drying and screening: boiling drier inlet temperature is controlled at 55 DEG C-60 DEG C, wet granular is placed in boiling drier, note checking exsiccator upper-lower seal situation and granule boiling situation time dry and double granule, reach uniform drying, be dried to < 4%, granule shaking screen after drying sieved the granule got between 16 order-32 orders;
6) always mix: the dry granule after granulate is joined in mixer, mixing velocity 12r/min, open mixer and mix 5 minutes;
7) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
embodiment 3:the preparation of Ezetimibe granule:
Prescription: with parts by weight as table 2
Table 2 Ezetimibe composition prescription
Preparation method:
1) supplementary material process: Ezetimibe was pulverized 120 mesh sieves with shaking screen;
2) weigh: weigh each supplementary material according to technology preparation amount;
3) binding agent preparation: the flavoring orange essence of recipe quantity is joined in the purified water of recipe quantity, stirring and dissolving;
4) granulate: the Ezetimibe of recipe quantity, sucrose, Ca-EDTA are added in high-speed mixing granulating machine, open stirring motor low speed (I speed) mixing 10 minutes, add the binding agent prepared, low speed (I speed) wet mixing 90-110 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
5) drying and screening: boiling drier inlet temperature is controlled at 55 DEG C-60 DEG C, wet granular is placed in boiling drier, note checking exsiccator upper-lower seal situation and granule boiling situation time dry and double granule, reach uniform drying, be dried to < 4%, granule shaking screen after drying sieved the granule got between 16 order-32 orders;
6) always mix: the dry granule after granulate is joined in mixer, mixing velocity 12r/min, open mixer and mix 5 minutes;
7) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
embodiment 4:the preparation of Ezetimibe granule:
Prescription: with parts by weight as table 3
Table 3 Ezetimibe composition prescription
Preparation method:
1) supplementary material process: Ezetimibe was pulverized 120 mesh sieves with shaking screen;
2) weigh: weigh each supplementary material according to technology preparation amount;
3) binding agent preparation: the flavoring orange essence of recipe quantity is joined in the purified water of recipe quantity, stirring and dissolving;
4) granulate: the Ezetimibe of recipe quantity, sucrose, Ca-EDTA are added in high-speed mixing granulating machine, open stirring motor low speed (I speed) mixing 10 minutes, add the binding agent prepared, low speed (I speed) wet mixing 90-110 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
5) drying and screening: boiling drier inlet temperature is controlled at 55 DEG C-60 DEG C, wet granular is placed in boiling drier, note checking exsiccator upper-lower seal situation and granule boiling situation time dry and double granule, reach uniform drying, be dried to < 4%, granule shaking screen after drying sieved the granule got between 16 order-32 orders;
6) always mix: the dry granule after granulate is joined in mixer, mixing velocity 12r/min, open mixer and mix 5 minutes;
7) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
test example 1:fluidity test
This experimental example has investigated the mobility of Ezetimibe compound crystal provided by the invention.
With reference to obtained 3 batch samples of experimental example 1 by working sample angle of repose assess sample mobility, concrete grammar is as follows: sample thief granule, flow into from fixing little funnel in circular surface plate, know and obtain the highest cone, measure cone height H and radius R, calculate α angle of repose by tan α=H/R, the results are shown in Table 4, angle of repose is larger, and mobility is poorer.
Table 4 fluidity test result
As seen from Table 4, Ezetimibe compound crystal of the present invention has excellent mobility, is conducive to the accuracy improving subpackage, and is easy to mix homogeneously when mixing with other compositions.
test example 2: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 granule, 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, and filtered, as need testing solution.Precision measures reference substance solution and each 30 μ L of need testing solution, respectively injection liquid chromatography, and record chromatogram is to 2 times of main 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 5.
Table 5 related substance investigates result
Wherein, sample 1 is first sample of Ezetimibe granule that the embodiment of the present invention 2 obtains;
Sample 2 is Ezetimibe granule second batch samples that the embodiment of the present invention 2 obtains;
Sample 3 is with reference to the obtained Ezetimibe sheet of the method for patent CN103877051A embodiment 1;
Sample 4 is with reference to the obtained Ezetimibe sheet of patent CN103655481A embodiment 7;
Sample 5 is import clothing Ezetimibe sheet (manufacturers: MSD Pharma (Singapore) Pte. Ltd. trade name benefit is suitable pure)
As shown in Table 5, the Ezetimibe granule its related substances that the present invention obtains obviously reduces.
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 6.
Table 6 accelerated test result
Wherein, sample 1 is first sample of Ezetimibe granule that the embodiment of the present invention 2 obtains;
Sample 2 is Ezetimibe granule second batch samples that the embodiment of the present invention 2 obtains;
Sample 3 is with reference to the obtained Ezetimibe sheet of the method for patent CN103877051A embodiment 1;
Sample 4 is with reference to the obtained Ezetimibe sheet of patent CN103655481A embodiment 7;
Sample 5 is import clothing Ezetimibe sheet (manufacturers: MSD Pharma (Singapore) Pte. Ltd. trade name benefit is suitable pure)
As can be seen from Table 6, the embodiment of the present invention 2 product is after temperature 40 ± 2 DEG C, relative humidity 75 ± 5% carry out accelerated test, and impurity index is obviously better than imported product and prior art products, and stability is better.
Identical test is carried out to other embodiments, has obtained similar test result.
Claims (5)
1. treat a medicine Ezetimibe composition granule for hyperlipidemia, it is characterized in that, described compositions is made up of Ezetimibe, sucrose, Ca-EDTA, flavoring orange essence, purified water; Described Ezetimibe is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
2. Ezetimibe composition granule according to claim 1, it is characterized in that, with parts by weight, described compositions is made up of the Ezetimibe of 1 weight portion, the sucrose of 34-35 weight portion, the Ca-EDTA of 1.5-1.9 weight portion, the flavoring orange essence of 0.2-0.3 weight portion, the purified water of 3-5 weight portion.
3. Ezetimibe composition granule according to claim 1, it is characterized in that, with parts by weight, described compositions is made up of the Ezetimibe of 1 weight portion, the sucrose of 34.3 weight portions, the Ca-EDTA of 1.7 weight portions, the flavoring orange essence of 0.25 weight portion, the purified water of 4 weight portions.
4. Ezetimibe composition granule according to claim 1, is characterized in that, the preparation method of described compositions comprises the following steps:
1) supplementary material process: Ezetimibe was pulverized 120 mesh sieves with shaking screen;
2) weigh: weigh each supplementary material according to technology preparation amount;
3) binding agent preparation: the flavoring orange essence of recipe quantity is joined recipe quantity purified water in, stirring and dissolving;
4) granulate: the Ezetimibe of recipe quantity, sucrose, Ca-EDTA are added in high-speed mixing granulating machine, open stirring motor I speed mixing 10 minutes, add the binding agent prepared, stirring motor I speed wet mixing 90-110 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
5) drying and screening: boiling drier inlet temperature is controlled at 55 DEG C-60 DEG C, wet granular is placed in boiling drier, note checking exsiccator upper-lower seal situation and granule boiling situation time dry and double granule, reach uniform drying, be dried to < 4%, granule shaking screen after drying sieved the granule got between 16 order-32 orders;
6) always mix: the dry granule after granulate is joined in mixer, mixing velocity 12r/min, open mixer and mix 5 minutes;
7) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
5. Ezetimibe composition granule according to claim 1, is characterized in that, the preparation method of the crystal of described Ezetimibe comprises the following steps:
Get Ezetimibe crude drug, the volume adding 35 DEG C is that in the mixed solvent A of the acetone of Ezetimibe weight 6 times, 2,4-lutidines, acetone, 2,4-lutidines volume ratios are 3:1, obtain solution; Then in the horizontal direction of the liquid level of gained solution, apply the stationary magnetic field that magnetic field intensity is 1.0T, and under the condition of this stationary magnetic field, drip the mixed solvent B that volume is Ezetimibe weight 8 times of water, methyl ether in solution, the volume ratio of water, methyl ether is 4:1; After being added dropwise to complete, be cooled to-5 DEG C, leave standstill 5 hours, filter, washing, vacuum drying, obtains described Ezetimibe crystal.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060234996A1 (en) * | 2005-04-14 | 2006-10-19 | Itai Adin | Novel crystalline form of ezetimibe and processes for the preparation thereof |
| WO2009067960A2 (en) * | 2007-11-30 | 2009-06-04 | Zentiva, A.S. | A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates |
| CN104644587A (en) * | 2015-03-20 | 2015-05-27 | 王雪雁 | Preparation method of medicine composition for treating cardiovascular disease |
| CN104644597A (en) * | 2015-03-20 | 2015-05-27 | 王雪雁 | Pharmaceutical composition for treating hyperlipidemia |
| CN104784146A (en) * | 2015-05-15 | 2015-07-22 | 苗怡文 | Pharmaceutical Ilaprazole sodium composition for treating peptic ulcer |
| CN104800221A (en) * | 2015-05-15 | 2015-07-29 | 苗怡文 | Medicinal cefetamet pivoxil hydrochloride composition for treating sensitive bacteria infectious diseases |
-
2015
- 2015-08-03 CN CN201510478954.8A patent/CN105012244A/en not_active Withdrawn
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060234996A1 (en) * | 2005-04-14 | 2006-10-19 | Itai Adin | Novel crystalline form of ezetimibe and processes for the preparation thereof |
| WO2009067960A2 (en) * | 2007-11-30 | 2009-06-04 | Zentiva, A.S. | A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates |
| CN104644587A (en) * | 2015-03-20 | 2015-05-27 | 王雪雁 | Preparation method of medicine composition for treating cardiovascular disease |
| CN104644597A (en) * | 2015-03-20 | 2015-05-27 | 王雪雁 | Pharmaceutical composition for treating hyperlipidemia |
| CN104784146A (en) * | 2015-05-15 | 2015-07-22 | 苗怡文 | Pharmaceutical Ilaprazole sodium composition for treating peptic ulcer |
| CN104800221A (en) * | 2015-05-15 | 2015-07-29 | 苗怡文 | Medicinal cefetamet pivoxil hydrochloride composition for treating sensitive bacteria infectious diseases |
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