CN104983730A - Ezetimibe solid orally-taken preparation for degrading cholesterol and preparing method of ezetimibe solid orally-taken preparation for degrading cholesterol - Google Patents
Ezetimibe solid orally-taken preparation for degrading cholesterol and preparing method of ezetimibe solid orally-taken preparation for degrading cholesterol Download PDFInfo
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- CN104983730A CN104983730A CN201510332515.6A CN201510332515A CN104983730A CN 104983730 A CN104983730 A CN 104983730A CN 201510332515 A CN201510332515 A CN 201510332515A CN 104983730 A CN104983730 A CN 104983730A
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- ezetimibe
- solid orally
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- orally ingestible
- trometamol
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Abstract
The invention discloses an ezetimibe solid orally-taken preparation for degrading cholesterol and a preparing method of the ezetimibe solid orally-taken preparation for degrading cholesterol. The preparation is prepared through a medicine-contained compound and acceptable auxiliary materials on pharmacy; preferentially, the direct compression method is adopted for making a tablet; and the medicine-contained compound is an ezetimibe-tromethamine compound. The preparation is rapid in medicine dissolution and simple in preparing method, raw materials do not need to be specially smashed, complex preparation devices are not needed, and industrialization large-scale production of the ezetimibe solid orally-taken preparation is easy to achieve.
Description
Technical field
The invention belongs to technical field of medicine, in particular to a kind of solid orally ingestible, Ezetimibe solid orally ingestible particularly relating to a kind of cholesterol reducing and preparation method thereof.
Background technology
Ezetimibe is white crystalline powder, easily molten in ethanol, methanol and acetone, almost insoluble in water, Ezetimibe fusing point about 163 DEG C, and at room temperature stablize, structural formula is as follows:
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, but, reduce granularity and can not effectively make the raising of the dissolution rate of Ezetimibe reach gratifying scope.So how granularity to be further improved, thus improve the dissolubility of preparation, increase bioavailability, become the demand that in Ezetimibe preparation research one is urgent.
CN103655481A discloses a kind of oral formulations preparation method of Ezetimibe, and it adopts ball milling solid dispersion technology, Ezetimibe and pharmaceutically acceptable adjuvant is prepared into solid orally ingestible, improves 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.
CN102292072A discloses the method with drug microparticles coating carrier, and its coating carrier can obtain in one-step method, and the method to 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.
CN103877051A discloses a kind of preparation method of Ezetimibe sheet, and hydroxypropyl cellulose and Ezetimibe are dissolved in ethanol, carrier material mannitol dissolves in aqueous.Supercritical carbon dioxide fluid and above-mentioned two kinds of solution are passed into a coaxial three-channel nozzle respectively; utilize the solvent resistant effect of supercritical carbon dioxide fluid; the ultra-fine grain obtained containing Ezetimibe, hydroxypropyl cellulose and mannitol mixes powder, ultra-fine grain is mixed powder and pharmaceutically acceptable adjuvant direct compression forms.The method needs to use supercritical equipment, expensive, and operation with high pressure, is not suitable for suitability for industrialized production.
CN104666260A discloses a kind of preparation method of Ezetimibe sheet, and Ezetimibe, hydroxypropyl cellulose are dissolved in TC by it, and add aerosil absorption, then with pharmaceutically acceptable adjuvant mix homogeneously, tabletting forms.But TC does not have medicinal certification at present, and in the long-time storage process of tablet, likely react with packaging material PVC, PVDC etc., plasticiser is wherein adsorbed onto in tablet, affects Drug safety.
Summary of the invention
For the problem of Ezetimibe poorly water-soluble, inventor attempts Ezetimibe to be dispersed in water, then adds solubilizing agent and promote that it dissolves, but various solubilizing agent effect is all general.
Surprisingly, when adding trometamol in the suspension of inventor at Ezetimibe, drug solubility increases, even if but add the trometamol of Ezetimibe 20 times amount, Ezetimibe can not dissolve completely.And then inventor attempts using ethanol instead, Ezetimibe, trometamol are dissolved in ethanol, by this solution evaporate to dryness, obtain Ezetimibe-trometamol complex, this pastille complex dissolubility in water greatly improves, thus solves the slow difficult problem of Ezetimibe solid orally ingestible dissolution.
Based on above-mentioned achievement in research, the object of the present invention is to provide that a kind of preparation technology is simple, drug-eluting Ezetimibe solid orally ingestible and preparation method thereof rapidly.Specifically, the object of the invention is to be achieved through the following technical solutions:
An Ezetimibe solid orally ingestible for cholesterol reducing, said preparation is prepared from pastille complex and pharmaceutically acceptable adjuvant, and described pastille complex is Ezetimibe-trometamol complex.
Preferably, Ezetimibe solid orally ingestible as above, pastille complex wherein obtains as follows: trometamol, Ezetimibe are added in alcoholic solvent successively and make dissolving, and dry removing ethanol, obtains pastille complex.
Preferably, Ezetimibe solid orally ingestible as above, Ezetimibe wherein and the weight ratio of trometamol are 1:(5-15).
Further preferably, Ezetimibe solid orally ingestible as above, Ezetimibe wherein and the weight ratio of trometamol are 1:(7-10).
It should be noted that, in Ezetimibe solid orally ingestible of the present invention, described pharmaceutically acceptable adjuvant comprises disintegrating agent, filler and lubricant.Described disintegrating agent is one or more in polyvinylpolypyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose and cross-linking sodium carboxymethyl cellulose.Described filler is one or more in microcrystalline Cellulose, lactose and mannitol.Described lubricant is one or both in magnesium stearate and zinc stearate.
Present invention also offers a kind of preparation method of Ezetimibe tablet, the method comprises the steps: trometamol to be dissolved in alcoholic solvent, add Ezetimibe, be stirred to dissolve, 50-58 DEG C of dry removing ethanol, obtain pastille complex, this pastille complex is mixed homogeneously with pharmaceutically acceptable adjuvant, direct compression.
Preferably, the preparation method of Ezetimibe tablet as above, alcoholic solvent is wherein ethanol.
Compared with prior art, the Ezetimibe solid orally ingestible that the present invention relates to and preparation method thereof tool has the following advantages and marked improvement: (1) drug-eluting is rapid; (2) preparation method is simple, and raw material does not need special pulverizing, does not need complicated preparation equipment, is easy to industrialized great production.
Detailed description of the invention
Preparation process and the implementation result of invention formulation is now further described by following examples, person skilled in the art obviously easily can make various amendment to these embodiments, and General Principle described herein is applied in other embodiments and need not through performing creative labour.Therefore, the invention is not restricted to embodiment here, those skilled in the art, according to announcement of the present invention, do not depart from improvement that scope makes and amendment all should within protection scope of the present invention.
Embodiment 1
Preparation technology:
Recipe quantity takes trometamol and dissolves in ethanol, adds the Ezetimibe of recipe quantity, is stirred to dissolve, 50 DEG C of dry removing ethanol, obtain mixture, this mixture are crossed 60 mesh sieves, then mix homogeneously with the microcrystalline Cellulose of recipe quantity, carboxymethyl starch sodium, magnesium stearate, tabletting.
Embodiment 2
Preparation technology:
Recipe quantity takes trometamol and dissolves in ethanol, adds the Ezetimibe of recipe quantity, is stirred to dissolve, 55 DEG C of dry removing ethanol, obtain mixture, this mixture are crossed 80 mesh sieves, then mix homogeneously with the microcrystalline Cellulose of recipe quantity, lactose, polyvinylpolypyrrolidone, magnesium stearate, tabletting.
Embodiment 3
Preparation technology:
Recipe quantity takes trometamol and dissolves in ethanol, adds the Ezetimibe of recipe quantity, is stirred to dissolve, 50 DEG C of dry removing ethanol, obtain mixture, this mixture are crossed 65 mesh sieves, then mix homogeneously with the microcrystalline Cellulose of recipe quantity, carboxymethyl starch sodium, magnesium stearate, tabletting.
Comparative example 1
Preparation technology:
Trometamol, Ezetimibe, microcrystalline Cellulose, carboxymethyl starch sodium are all crossed 100 mesh sieves, and recipe quantity takes, and adds the magnesium stearate mix homogeneously of recipe quantity, tabletting.
Comparative example 2
Ezetimibe 10g
Trometamol 20g/50g/100g/200g
Water 1000ml
Preparation technology:
Take trometamol by the recipe quantity of 20g, 50g, 100g, 200g, be dissolved in respectively in 1000ml 50 DEG C of water, add the Ezetimibe of recipe quantity, stir 10min, result medicinal liquid is all in muddy shape, and Ezetimibe cannot dissolve after measured.
Embodiment 4: the quality testing test of Ezetimibe sheet
Dissolution determination: measure according under Chinese Pharmacopoeia version in 2010 two annex items, paddle method, rotating speed is with 50 revs/min, and dissolution medium volume is 900ml, and medium is the acetate buffer solution of pH4.5, detects under 234nm with UV detector, and 15min stripping limit is 80%.
Table 1: each embodiment prepares the dissolution determination results contrast of Ezetimibe sheet
Known from the result of the test of table 1, preparation stripping prepared by the embodiment of the present invention is rapid, is not adding in the dissolution medium of surfactant, the basic stripping completely of 5min; Ezetimibe is only simply mixed rear tabletting with trometamol by comparative example 1, and do not form the complex of Ezetimibe and trometamol, therefore drug solubility is poor, and stripping is slow.
Claims (10)
1. an Ezetimibe solid orally ingestible for cholesterol reducing, is characterized in that, said preparation is prepared from pastille complex and pharmaceutically acceptable adjuvant, and described pastille complex is Ezetimibe-trometamol complex.
2. Ezetimibe solid orally ingestible according to claim 1, is characterized in that, described pastille complex obtains as follows: trometamol, Ezetimibe are added in alcoholic solvent successively and make dissolving, and dry removing ethanol, obtains pastille complex.
3. Ezetimibe solid orally ingestible according to claim 1, is characterized in that, the weight ratio of Ezetimibe and trometamol is 1:(5-15).
4. Ezetimibe solid orally ingestible according to claim 3, is characterized in that, the weight ratio of Ezetimibe and trometamol is 1:(7-10).
5. according to the Ezetimibe solid orally ingestible of any one of claim 1-4, it is characterized in that, described pharmaceutically acceptable adjuvant comprises disintegrating agent, filler and lubricant.
6. Ezetimibe solid orally ingestible according to claim 5, is characterized in that, described disintegrating agent is one or more in polyvinylpolypyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose and cross-linking sodium carboxymethyl cellulose.
7. Ezetimibe solid orally ingestible according to claim 5, is characterized in that, described filler is one or more in microcrystalline Cellulose, lactose and mannitol.
8. Ezetimibe solid orally ingestible according to claim 5, is characterized in that, described lubricant is one or both in magnesium stearate and zinc stearate.
9. the preparation method according to the Ezetimibe tablet of any one of claim 1-4, it is characterized in that, the method comprises the steps: trometamol to be dissolved in alcoholic solvent, add Ezetimibe, be stirred to dissolve, 50-58 DEG C of dry removing ethanol, obtains pastille complex, this pastille complex is mixed homogeneously with pharmaceutically acceptable adjuvant, direct compression.
10. the preparation method of Ezetimibe tablet according to claim 9, is characterized in that, described alcoholic solvent is ethanol.
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| CN201510332515.6A CN104983730A (en) | 2015-06-16 | 2015-06-16 | Ezetimibe solid orally-taken preparation for degrading cholesterol and preparing method of ezetimibe solid orally-taken preparation for degrading cholesterol |
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| CN201510332515.6A CN104983730A (en) | 2015-06-16 | 2015-06-16 | Ezetimibe solid orally-taken preparation for degrading cholesterol and preparing method of ezetimibe solid orally-taken preparation for degrading cholesterol |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114831951A (en) * | 2022-04-25 | 2022-08-02 | 扬子江药业集团广州海瑞药业有限公司 | Ezetimibe tablets and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103690955A (en) * | 2013-12-27 | 2014-04-02 | 福州乾正药业有限公司 | Ticagrelor-containing drug composition as well as preparation method and application thereof |
| CN103877051A (en) * | 2014-04-19 | 2014-06-25 | 青岛科技大学 | Preparation method of ezetimibe tablet |
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2015
- 2015-06-16 CN CN201510332515.6A patent/CN104983730A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103690955A (en) * | 2013-12-27 | 2014-04-02 | 福州乾正药业有限公司 | Ticagrelor-containing drug composition as well as preparation method and application thereof |
| CN103877051A (en) * | 2014-04-19 | 2014-06-25 | 青岛科技大学 | Preparation method of ezetimibe tablet |
Non-Patent Citations (1)
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| 李安良等: "《生物利用度控制-药物化学原理、方法和应用》", 30 June 2004 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114831951A (en) * | 2022-04-25 | 2022-08-02 | 扬子江药业集团广州海瑞药业有限公司 | Ezetimibe tablets and preparation method thereof |
| CN114831951B (en) * | 2022-04-25 | 2023-10-03 | 扬子江药业集团广州海瑞药业有限公司 | Ezetimibe tablet and preparation method thereof |
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Application publication date: 20151021 |