CN105287513A - Ezetimibe medicine composition and preparation method thereof - Google Patents
Ezetimibe medicine composition and preparation method thereof Download PDFInfo
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- CN105287513A CN105287513A CN201510700243.0A CN201510700243A CN105287513A CN 105287513 A CN105287513 A CN 105287513A CN 201510700243 A CN201510700243 A CN 201510700243A CN 105287513 A CN105287513 A CN 105287513A
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Abstract
The invention belongs to the technical field of medicines and particularly relates to an Ezetimibe medicine composition. The Ezetimibe medicine composition is used for achieving rapid dissolution of Ezetimibe hard to dissolve and ensuring the stability of the dissolution rate. The Ezetimibe medicine composition comprises Ezetimibe, a filling agent, an adhesive, a disintegrating agent, a surface active agent and a lubricating agent. The adhesive is hydroxy propyl cellulose. The invention further provides a preparation method of the Ezetimibe medicine composition. The Ezetimibe, the filling agent, the disintegrating agent, the adhesive and the surface active agent are mixed to be even, granulation is performed, the remaining filling agent and the lubricant are added and mixed to be even, and pressing is performed to obtain tablets. The Ezetimibe medicine composition achieves rapid dissolution of the Ezetimibe hard to dissolve through the preparation technology and ensures the stability of the dissolution rate.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of ezetimibe medicine composition, for realizing the Fast Stripping of insoluble drug Ezetimibe and ensureing the stable of dissolution.
Background technology
Ezetimibe is a kind of Cholesterol Inhibitor, and energy Selective depression small intestinal cholesterol transporter, effectively reduces intestinal inner cholesterol and absorb, reduce blood plasma cholesterol level and hepatic cholesterol reserves.Ezetimibe water solublity is little, and dissolution velocity is slow, and stripping is slow and incomplete.State Food and Drug Administration's import drugs registered standard, standard No. JX20030223, following provisions are done to the dissolution of Ezetimibe sheet: with sodium lauryl sulphate-sodium-acetate buffer (pH=4.5) for dissolution medium, rotating speed is 50 turns per minute, measure trap at the wavelength place of 233nm, require that 30 minutes stripping limits are 85% of mark amount.
Mention in US Patent No. RE37721E, advocate by Ezetimibe and the pharmaceutical composition that forms as the lactose monohydrate (filler) of excipient, microcrystalline Cellulose (filler), polyvidone (binding agent), cross-linking sodium carboxymethyl cellulose (disintegrating agent), sodium lauryl sulphate (surfactant) and magnesium stearate (lubricant).One section " preparation method of Ezetimibe compositions " by name, patent No. US20120135976A1, this patent relates to " the Free drug particle form " of Ezetimibe, be specially " wherein the granularity of grain graininess 1 to 30 micron of at least 90% ", the preferably grain graininess 5 to 30 microns of at least 90%, the more preferably grain graininess 8 to 25 microns of at least 90%.
We find medicine and drug excipient to be prepared with reference to above-mentioned disclosed patent technique by research, wherein the uniformity of dosage units of tablet is qualified, but the homogeneity of tablet dissolution rate at the appointed time and dissolution cannot well be reappeared, in table 1, consider because the low aqueous solubility of Ezetimibe and hypotonicity can be incompatible with common drug excipient, the therefore problem of existence and stability.
In conjunction with lot of experimental data, we find that the simple reduction Ezetimibe particle diameter that passes through can not reach its tablet Fast Stripping (stripping quantity was greater than 70% in 10 minutes) and meet the technical goal of dissolution homogeneity, refer to table 2, need to utilize preparation technique to improve.
Table 1: Ezetimibe sheet content and dissolution data
Table 2: Ezetimibe particle diameter is on the impact of tablet stripping
Summary of the invention
In order to overcome above-mentioned the deficiencies in the prior art, the invention provides a kind of novel ezetimibe medicine composition, for realizing the Fast Stripping of insoluble drug Ezetimibe and ensureing the stable of dissolution.
The technical solution adopted in the present invention is: mixed homogeneously with filler, disintegrating agent, binding agent and surfactant (drug excipient is totally 900 weight portions) by 100 weight portion Ezetimibes, granulate, add surplus filler and mix lubricant even, be pressed into tablet.Make Ezetimibe sheet 10 minutes stripping quantities in 0.45% sodium lauryl sulphate-sodium-acetate buffer (pH=4.5) be greater than 70%, 30 minutes stripping quantities and be greater than 90%, and dissolution homogeneity is good.
A kind of ezetimibe medicine composition, include Ezetimibe, filler, binding agent, disintegrating agent, surfactant and lubricant, described binding agent is hydroxypropyl cellulose, and the content of described binding agent is 10-100 weight portion, is preferably 40 weight portions.
Preferably, Ezetimibe exists with primary particles form, for improving dissolution rate, ensure the physical stability of Ezetimibe simultaneously and reduce the aggregation tendency of medicine, the grain graininess of Ezetimibe primary particles at least 90% is 1 to 40 micron, preferably the grain graininess of at least 90% is 5 to 30 microns, and more preferably the grain graininess of at least 90% is 8 to 15 microns, particularly the granularity of about 9 microns.
Preferably, filler is the compositions of one or more in lactose, microcrystalline Cellulose, pregelatinized Starch, preferred lactose and microcrystalline Cellulose.The consumption of filler is 500-900 weight portion, wherein adding ratio in filler is that 40%-60% is (in all adjuvants, lactose and microcrystalline Cellulose are all filleies, wherein add in lactose, microcrystalline Cellulose is additional, and overall consumption is 500-900 weight portion, adding ratio is wherein 40%-60%), be preferably lactose 550 weight portion, microcrystalline Cellulose 200 weight portion.
Preferably, disintegrating agent is the compositions of one or more in cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, preferred carboxymethyl starch sodium.The content of described disintegrating agent is 30-200 weight portion, is preferably 80 weight portions.
Preferably, surfactant is the compositions of one or more in sodium lauryl sulphate, tween 80, cetab, preferably sodium dodecyl sulfate.The content of described surfactant is 10-100 weight portion, is preferably 20 weight portions.
Preferably, lubricant is the compositions of one or more in magnesium stearate, silicon dioxide, Pulvis Talci, preferred magnesium stearate.Described lubricant total amount is 2-50 weight portion, is preferably 10 weight portions.
The preparation method of ezetimibe medicine composition, by Ezetimibe, filler, disintegrating agent, binding agent and surfactant mix homogeneously, granulation, adds surplus filler and mix lubricant is even, is pressed into tablet; Add water or the waterborne liquid of maximum 15wt.% during granulation, or the non-aqueous liquid adding maximum 25wt.% is granulated.Preferred 10wt.% water is granulated.
Ezetimibe medicine composition provided by the invention realizes the Fast Stripping of insoluble drug Ezetimibe by preparation technique and ensures the stable of dissolution.
Detailed description of the invention
Illustrate the present invention below in conjunction with embodiment, the embodiment in the present invention is only for illustration of technical scheme of the present invention, and non-limiting essence of the present invention.Every variation or equivalent alternative all within protection scope of the present invention not deviating from the present invention's design.
Dissolution of Tablet assay method: get this product, according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex XC second methods), (sodium lauryl sulphate 4.5g is got with sodium lauryl sulphate-sodium-acetate buffer (pH=4.5), anhydrous sodium acetate 4.1g, the 1000ml that adds water makes dissolving, pH to 4.5 ± 0.1 is regulated with 1mol/L hydrochloric acid solution or 50% sodium hydroxide solution) 500ml is dissolution medium, rotating speed is 50 turns per minute, operate in accordance with the law, when different time, get solution respectively appropriate, filter, precision measures subsequent filtrate 5ml, put in 10ml measuring bottle, add sodium lauryl sulphate-sodium-acetate buffer (pH=4.5) and be diluted to scale, shake up, according to ultraviolet visible spectrophotometry (Chinese Pharmacopoeia version in 2010 two annex IV A), absorbance is measured at the wavelength place of 233nm, separately get Ezetimibe reference substance and be about 10mg, accurately weighed, put in 500ml measuring bottle, add methanol 5ml and make dissolving, add sodium lauryl sulphate-sodium-acetate buffer (pH=4.5) and be diluted to scale, shake up, in contrast product solution, be measured in the same method absorbance, calculate the stripping quantity of every sheet and calculate RSD value.
Embodiment 1
Preparation method: by Ezetimibe (D90=12.5 μm), lactose, carboxymethyl starch sodium and sodium lauryl sulphate mix homogeneously, hydroxypropyl cellulose is soluble in water, the solution being configured to moderate concentration adds, make suitable soft material, cross 30 mesh sieves to granulate, dry granule at 60-65 degree, after crossing 30 order granulate, after adding microcrystalline Cellulose, magnesium stearate mixing 10min, be pressed into tablet.
Embodiment 2
Preparation method: by Ezetimibe (D90=9.6 μm), lactose, carboxymethyl starch sodium and sodium lauryl sulphate mix homogeneously, hydroxypropyl cellulose is soluble in water, the solution being configured to moderate concentration adds, make suitable soft material, cross 30 mesh sieves to granulate, dry granule at 60-65 degree, after crossing 30 order granulate, after adding microcrystalline Cellulose, magnesium stearate mixing 10min, be pressed into tablet.
Embodiment 3
Preparation method: by Ezetimibe (D90=8.3 μm), lactose, hydroxypropyl cellulose, carboxymethyl starch sodium and sodium lauryl sulphate mix homogeneously, add purified water, make suitable soft material, cross 30 mesh sieves to granulate, granule is dried at 60-65 degree, after crossing 30 order granulate, after adding microcrystalline Cellulose, magnesium stearate mixing 10min, be pressed into tablet.
Embodiment 4
Preparation method: by the cross-linking sodium carboxymethyl cellulose of Ezetimibe (D90=14.8 μm), 50% recipe quantity, sodium lauryl sulphate and lactose mix homogeneously, hydroxypropyl cellulose is soluble in water, the solution being configured to moderate concentration adds, make suitable soft material, cross 30 mesh sieves to granulate, dry granule at 60-65 degree, after crossing 30 order granulate, after adding residue cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose and magnesium stearate mixing 10min, be pressed into tablet.
Embodiment 5
Preparation method: by Ezetimibe (D90=11.5 μm), cross-linking sodium carboxymethyl cellulose, sodium lauryl sulphate and lactose mix homogeneously, hydroxypropyl cellulose is soluble in water, the solution being configured to moderate concentration adds, make suitable soft material, cross 30 mesh sieves to granulate, dry granule at 60-65 degree, after crossing 30 order granulate, after adding microcrystalline Cellulose and magnesium stearate mixing 10min, be pressed into tablet.
Stripping curve test is carried out to above-mentioned 5 case study on implementation, the results are shown in Table 3:
Table 3: case study on implementation stripping curve data summarization
Known by the stripping curve data of above-mentioned 5 case study on implementation, ezetimibe medicine composition provided by the invention achieves the object of tablet Fast Stripping.
Comparative example 1
Preparation method: by Ezetimibe (D90=12.5 μm), lactose, carboxymethyl starch sodium and sodium lauryl sulphate mix homogeneously, polyvidone is soluble in water, the solution being configured to moderate concentration adds, make suitable soft material, cross 30 mesh sieves to granulate, dry granule at 60-65 degree, after crossing 30 order granulate, after adding microcrystalline Cellulose and magnesium stearate mixing 10min, be pressed into tablet.
Comparative example 2
Preparation method: by the cross-linking sodium carboxymethyl cellulose of Ezetimibe (D90=9.6 μm), 50% recipe quantity, sodium lauryl sulphate and lactose mix homogeneously, polyvidone is soluble in water, the solution being configured to moderate concentration adds, make suitable soft material, cross 30 mesh sieves to granulate, dry granule at 60-65 degree, after crossing 30 order granulate, after adding residue cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose and magnesium stearate mixing 10min, be pressed into tablet.
Comparative example 3
Preparation method: by Ezetimibe (D90=8.3 μm), lactose, anhydrous calcium phosphate, carboxymethyl starch sodium and sodium lauryl sulphate mix homogeneously, hydroxypropyl cellulose is soluble in water, the solution being configured to moderate concentration adds, make suitable soft material, cross 30 mesh sieves to granulate, dry granule at 60-65 degree, after crossing 30 order granulate, after adding magnesium stearate mixing 10min, be pressed into tablet.
Comparative example 4
Preparation method: by Ezetimibe (D90=14.8 μm), lactose, carboxymethyl starch sodium and sodium lauryl sulphate mix homogeneously, hydroxypropyl cellulose is soluble in water, the solution being configured to moderate concentration adds, make suitable soft material, cross 30 mesh sieves to granulate, dry granule at 60-65 degree, after crossing 30 order granulate, after adding magnesium stearate mixing 10min, be pressed into tablet.
Comparative example 5
Preparation method: by Ezetimibe (D90=11.5 μm), lactose, microcrystalline Cellulose, carboxymethyl starch sodium and sodium lauryl sulphate mix homogeneously, hydroxypropyl cellulose is soluble in water, the solution being configured to moderate concentration adds, make suitable soft material, cross 30 mesh sieves to granulate, dry granule at 60-65 degree, after crossing 30 order granulate, after adding magnesium stearate mixing 10min, be pressed into tablet.
Dissolution Rate Testing is carried out to above-mentioned case study on implementation and contrast case study on implementation, the results are shown in Table 4:
Table 4: case study on implementation gathers with contrast case study on implementation dissolution data
Known by above-mentioned case study on implementation 1-5 and contrast case study on implementation 1-5, hydroxypropyl cellulose can significantly improve the dissolution homogeneity of insoluble drug Ezetimibe sheet as binding agent, the compositions of the preferred lactose of filler and microcrystalline Cellulose, adds the preferred 40%-60% of ratio in filler.Known by above-mentioned case study on implementation, ezetimibe medicine composition provided by the invention achieves the dissolution homogeneity of tablet.
Claims (10)
1. an ezetimibe medicine composition, is characterized in that, includes Ezetimibe, filler, binding agent, disintegrating agent, surfactant and lubricant, and described binding agent is hydroxypropyl cellulose.
2. ezetimibe medicine composition according to claim 1, is characterized in that, described filler is the compositions of one or more in lactose, microcrystalline Cellulose, pregelatinized Starch.
3. ezetimibe medicine composition according to claim 2, is characterized in that, described filler is the compositions of lactose and microcrystalline Cellulose.
4. ezetimibe medicine composition according to claim 1, is characterized in that, the grain graininess of Ezetimibe primary particles at least 90% is 1 to 40 micron.
5., according to the arbitrary described ezetimibe medicine composition of claim 1-4, it is characterized in that,
Disintegrating agent is the compositions of one or more in cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium;
Surfactant is the compositions of one or more in sodium lauryl sulphate, tween 80, cetab;
Lubricant is the compositions of one or more in magnesium stearate, silicon dioxide, Pulvis Talci.
6. ezetimibe medicine composition according to claim 5, is characterized in that, the ratio of each component is:
7. ezetimibe medicine composition according to claim 6, it is characterized in that, the weight ratio of Ezetimibe and drug excipient is 1:9.
8. ezetimibe medicine composition according to claim 7, it is characterized in that, the consumption of filler is 500-900 weight portion, and wherein adding ratio in filler is 40%-60%.
9. ezetimibe medicine composition according to claim 8, is characterized in that, the ratio of each component is:
10. according to the preparation method of the arbitrary described ezetimibe medicine composition of claim 1-9, it is characterized in that, by Ezetimibe, filler, disintegrating agent, binding agent and surfactant mix homogeneously, granulate, add surplus filler and mix lubricant even, be pressed into tablet; Add water or the waterborne liquid of maximum 15wt.% during granulation, or the non-aqueous liquid adding maximum 25wt.% is granulated.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114848633A (en) * | 2022-04-28 | 2022-08-05 | 云南省第一人民医院 | Medicine for treating alpha-amatoxin poisoning and application thereof |
| CN116270508A (en) * | 2023-03-20 | 2023-06-23 | 江苏亚邦强生药业有限公司 | Ezetimibe tablet with powerful lipid-lowering effect and preparation method thereof |
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| CN1131416A (en) * | 1993-09-21 | 1996-09-18 | 先灵公司 | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
| WO2006134604A1 (en) * | 2005-06-15 | 2006-12-21 | Hetero Drugs Limited | Combination composition of cholesterol absorption inhibitor and 3-hydroxy-3-methylglutaryl-coenzyme a (hmg-coa) reductase inhibitor |
| WO2008101723A2 (en) * | 2007-02-23 | 2008-08-28 | Krka | Pharmaceutical composition containing a cholesterol absorption inhibitor |
| CN103655453A (en) * | 2013-12-27 | 2014-03-26 | 华润赛科药业有限责任公司 | Preparation method of ezetimibe medicine composition |
| CN103784436A (en) * | 2014-02-27 | 2014-05-14 | 安徽联创药物化学有限公司 | Lipid-lowering compound preparation and preparation method thereof |
| CN103877051A (en) * | 2014-04-19 | 2014-06-25 | 青岛科技大学 | Preparation method of ezetimibe tablet |
| CN104825407A (en) * | 2015-04-20 | 2015-08-12 | 山东新时代药业有限公司 | Ezetimibe tablet |
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2015
- 2015-10-23 CN CN201510700243.0A patent/CN105287513A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1131416A (en) * | 1993-09-21 | 1996-09-18 | 先灵公司 | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
| WO2006134604A1 (en) * | 2005-06-15 | 2006-12-21 | Hetero Drugs Limited | Combination composition of cholesterol absorption inhibitor and 3-hydroxy-3-methylglutaryl-coenzyme a (hmg-coa) reductase inhibitor |
| WO2008101723A2 (en) * | 2007-02-23 | 2008-08-28 | Krka | Pharmaceutical composition containing a cholesterol absorption inhibitor |
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| CN103877051A (en) * | 2014-04-19 | 2014-06-25 | 青岛科技大学 | Preparation method of ezetimibe tablet |
| CN104825407A (en) * | 2015-04-20 | 2015-08-12 | 山东新时代药业有限公司 | Ezetimibe tablet |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114848633A (en) * | 2022-04-28 | 2022-08-05 | 云南省第一人民医院 | Medicine for treating alpha-amatoxin poisoning and application thereof |
| CN116270508A (en) * | 2023-03-20 | 2023-06-23 | 江苏亚邦强生药业有限公司 | Ezetimibe tablet with powerful lipid-lowering effect and preparation method thereof |
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