CN106880598A - A kind of Ezetimibe tablet - Google Patents
A kind of Ezetimibe tablet Download PDFInfo
- Publication number
- CN106880598A CN106880598A CN201510924329.1A CN201510924329A CN106880598A CN 106880598 A CN106880598 A CN 106880598A CN 201510924329 A CN201510924329 A CN 201510924329A CN 106880598 A CN106880598 A CN 106880598A
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- CN
- China
- Prior art keywords
- ezetimibe
- tablet according
- cyclodextrin
- hydroxypropyl beta
- tablet
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A kind of Ezetimibe tablet, Ezetimibe, HYDROXYPROPYL BETA-CYCLODEXTRIN, PVP are dissolved in absolute ethyl alcohol, then will be pelletized on this solution pharmaceutically acceptable auxiliary material, are dried, and capsule charge is formed.Compared with prior art, preparation process is simple of the present invention, dispersion of medicine, without exhibiting high surface activating agent, smoothly, drug-eluting is rapid for production process.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of Ezetimibe tablet.
Background technology
Ezetimibe is white crystalline powder, readily soluble in ethanol, methyl alcohol and acetone, almost insoluble in water, Ezetimibe
About 163 DEG C of fusing point, stablizes at room temperature.Ezetimibe clinic is mainly used in primary hypercholesterolemia, and this product is used as drink
Auxiliary treatment beyond food control, can be united and applied in treatment courage high individually or with HMG-CoA reductase inhibitor such as Statins
Sterol mass formed by blood stasis, it is possible to decrease T-CHOL (TC), LDL-C (LDL-C), apolipoprotein B (ApoB), or
As the complementary therapy (such as LDL-C Apheresises) of other lipid-lowering therapies, can also be when other lipid-lowering therapies be invalid
TC and LDL-C levels for reducing HoFH patient.
Ezetimibe is water insoluble, and when the solid dosage forms of Ezetimibe is used by oral administration, the medicine must dissolve in gastric juice,
Curative effect could be played by absorbing.The common preparation of the solid oral dosage form of compacting, such as tablet is usually because its rate of dissolution is limited
Its bioavilability is made, so as to have impact on the curative effect of medicine.Reduce the side that granularity is increase solubility commonly used in the art
One of method, in fact reduces the granularity deliquescent method of improvement and has been used for Ezetimibe.However, reduce granularity can not
Effectively improve the dissolution rate of Ezetimibe and reach gratifying scope.So how to be further improved granularity,
So as to improve the solubility of preparation, increase bioavilability, as a urgent demand in being studied in Ezetimibe.
CN103655481A provides a kind of oral formulations preparation method of Ezetimibe.Using ball milling solid dispersion technology,
Ezetimibe is prepared into solid orally ingestible with pharmaceutically acceptable auxiliary material, the dissolution rate of preparation is improve.But by medicine
Thing is ground with milling material, and milling material may be brought into medicine ball milling fine powder, and safety concerns are brought during patient medication.
This is also a generally acknowledged potential risk of ball grinding technique.
CN102292072A is disclosed with the method for drug microparticles coating carrier.Coating carrier can be obtained in one-step method,
The method needs the evaporation solvent from the solution droplets comprising API to obtain dry particulate, is then coated on carrier.But
Need special production equipment, industrialization is more difficult, and can not be quick and complete dissolution.
The content of the invention
In view of the deficiencies in the prior art, inventor intend providing a kind of Fast Stripping, be uniformly dispersed, without surfactant
Ezetimibe tablet.
Inventor considers that the purpose for preparing solid dispersions is exactly become because Ezetimibe raw material is crystalline structure first
For amorphous.If Ezetimibe is prepared into by preparation technique amorphous, reach effect same, and in the absence of solid
The aging phenomenon of dispersion.
Inventor attempts Ezetimibe dissolving in ethanol, this solution as adhesive being pelletized on auxiliary material, obtains
The Ezetimibe of same Fast Stripping, but the ethanol solution of Ezetimibe viscosity is smaller, and the mobility of particle of preparation is poor, dress
Amount difference is big；On this basis, inventor adds various adhesives in above-mentioned solution, although can be prepared into preferable
Grain, but in storage process, drug-eluting is substantially slack-off, it may be possible to and the amorphous drug of high-energy is slowly transformed into crystalline state medicine
Thing causes.
Unexpectedly, whether inventor is considered to combine and uses cyclodextrin inclusion technique, and hydroxypropyl is added in above-mentioned solution
By his cyclodextrin, unbodied Ezetimibe inclusion compound is prepared by simple granulation, drying, and using hydroxypropyl again he
Cyclodextrin has certain viscosity in ethanol, is used as adhesive, and the mobility of particle for obtaining is good.But,
Inclusion compound also occurs the problem that Ezetimibe crystallization is separated out in long-time is placed, and causes drug-eluting slack-off.
Further, if inventor is considered in inclusion compound preparation process, a kind of material is added, is separated out with suppressing crystallization,
Effect is might have, by many experiments, inventor, as carrier, not only suppresses drug crystallization from deoxycholic acid, and
Dissolution rate can be improved.
Specifically, the present invention is achieved through the following technical solutions：
Ezetimibe tablet of the present invention, Ezetimibe, HYDROXYPROPYL BETA-CYCLODEXTRIN, deoxycholic acid is dissolved in anhydrous
In ethanol, then will be pelletized on this solution pharmaceutically acceptable auxiliary material, dried, capsule charge is formed.
Described Ezetimibe tablet, Ezetimibe is 1 with the weight ratio of HYDROXYPROPYL BETA-CYCLODEXTRIN:3-7.
Preferably, Ezetimibe and the weight ratio of HYDROXYPROPYL BETA-CYCLODEXTRIN are 1:5.
Described Ezetimibe tablet, Ezetimibe is 1 with the weight ratio of deoxycholic acid:2-4.
Preferably, Ezetimibe and the weight ratio of deoxycholic acid are 1:3.
Described Ezetimibe tablet, pharmaceutically acceptable auxiliary material is filler, disintegrant and lubricant.
Described filler is one or more in lactose, mannitol, starch, dextrin and microcrystalline cellulose.
Described disintegrant is the one kind in sodium carboxymethyl starch, PVPP deoxycholic acid and Ac-Di-Sol
Or it is various.
Described lubricant is one or more in magnesium stearate, sodium stearyl fumarate and talcum powder.
Compared with prior art, drug-eluting speed is fast, process is simple, it is not necessary to add surfactant, also not for the present invention
Need micronization processes.Accelerated test result shows that Ezetimibe tablet stability prepared by the present invention is good.
Specific embodiment
Following examples further describe beneficial effects of the present invention, and embodiment is only used for the purpose of illustration, does not limit the present invention
Scope, while those of ordinary skill in the art are also contained in this hair according to the obvious change made of the present invention and modification
Within the scope of bright.
Embodiment 1
Preparation technology：
Ezetimibe, HYDROXYPROPYL BETA-CYCLODEXTRIN, deoxycholic acid are dissolved in absolute ethyl alcohol, then by this solution lactose,
Pelletized on microcrystalline cellulose, the mixed powder of sodium carboxymethyl starch, 60 DEG C of dryings, 18 mesh sieve whole grains add stearic acid in dry particl
Magnesium, is well mixed, and compressing tablet is formed.
Embodiment 2
Preparation technology：
Ezetimibe, HYDROXYPROPYL BETA-CYCLODEXTRIN, deoxycholic acid are dissolved in absolute ethyl alcohol, then by this solution lactose,
Pelletized on microcrystalline cellulose, the mixed powder of PVPP, 60 DEG C of dryings, 18 mesh sieve whole grains add magnesium stearate in dry particl,
Well mixed, compressing tablet is formed.
Embodiment 3
Preparation technology：
Ezetimibe, HYDROXYPROPYL BETA-CYCLODEXTRIN, deoxycholic acid are dissolved in absolute ethyl alcohol, then by this solution lactose,
Pelletized on microcrystalline cellulose, the mixed powder of PVPP, 60 DEG C of dryings, 18 mesh sieve whole grains add magnesium stearate in dry particl,
Well mixed, compressing tablet is formed.
Comparative example 1
Preparation technology：
Ezetimibe air-flow crushing, then mixes with microcrystalline cellulose, PVPP, magnesium stearate by D90=15.1 microns
Uniformly, formed using the compacting of direct tablet compressing technique.
Comparative example 2
Preparation technology：
Ezetimibe, HYDROXYPROPYL BETA-CYCLODEXTRIN are dissolved in absolute ethyl alcohol, then by this solution in lactose, microcrystalline cellulose
Pelletized on element, the mixed powder of PVPP, 60 DEG C of dryings, 18 mesh sieve whole grains add magnesium stearate in dry particl, mixing is equal
Even, compressing tablet is formed.
Comparative example 3
Preparation technology：
Ezetimibe, HYDROXYPROPYL BETA-CYCLODEXTRIN, PVP are dissolved in absolute ethyl alcohol, then by this solution in lactose system
Grain, 60 DEG C of dryings, 18 mesh sieve whole grains add magnesium stearate in dry particl, be well mixed, and compressing tablet is formed.
Comparative example 4
Preparation technology：
Ezetimibe, HYDROXYPROPYL BETA-CYCLODEXTRIN, poloxamer are dissolved in absolute ethyl alcohol, then by this solution in lactose
Granulation, 60 DEG C of dryings, 18 mesh sieve whole grains add magnesium stearate in dry particl, be well mixed, and compressing tablet is formed.
Comparative example 5
Preparation technology：
Macrogol 4000,80 DEG C of heating meltings of copolyvidone, are subsequently adding recipe quantity Ezetimibe, are stirred to dissolve, so
This fused solution is pelletized on the mixed powder of mannitol and sodium carboxymethyl starch afterwards, 20 mesh sieve whole grains add recipe quantity magnesium stearate,
Well mixed, compressing tablet is formed.
Checking embodiment
Dissolution determination：Determined according to Chinese Pharmacopoeia version in 2010 two annex are lower, paddle method, rotating speed be with 50 revs/min,
Dissolution medium contains in the acetate buffer of 0.45% lauryl sodium sulfate for 900ml, with UV detectors in 234nm
Lower detection, 5min dissolutions limit is 80%.
Each embodiment measurement result
| Embodiment | 0 day result (%) | 40 DEG C, 75%RH accelerate 6 months after result (%) |
| Embodiment 1 | 99.9 | 99.7 |
| Embodiment 2 | 99.9 | 99.6 |
| Embodiment 3 | 99.9 | 99.9 |
| Comparative example 1 | 50.2 | 48.9 |
| Comparative example 2 | 96.6 | 61.2 |
| Comparative example 3 | 90.2 | 88.4 |
| Comparative example 4 | 88.1 | 86.7 |
| Comparative example 5 | 90.4 | 88.8 |
As seen from the table, embodiment of the present invention 1-3 dissolutions are rapid, and dissolution is substantially unchanged after acceleration；Comparative example 1,
Raw material micronization processes, dissolution is more of the invention slow；Comparative example 2, and deoxycholic acid is not added in solvent, molten after acceleration
Go out slack-off；Comparative example 3 is using PVP effect not as the present invention；Comparative example 4 is not so good as using poloxamer effect
The present invention；Comparative example 5, melt granulation, and dissolution rate is not as the present invention.
Claims (8)
1. a kind of Ezetimibe tablet, it is characterised in that by Ezetimibe, HYDROXYPROPYL BETA-CYCLODEXTRIN, deoxycholic acid dissolving
In absolute ethyl alcohol, then will be pelletized on this solution pharmaceutically acceptable auxiliary material, dried, filling piece is formed.
2. Ezetimibe tablet according to claim 1, it is characterised in that Ezetimibe and HYDROXYPROPYL BETA-CYCLODEXTRIN
Weight ratio be 1:3-7.
3. Ezetimibe tablet according to claim 1, it is characterised in that Ezetimibe and HYDROXYPROPYL BETA-CYCLODEXTRIN
Weight ratio be 1:5.
4. Ezetimibe tablet according to claim 1, it is characterised in that the weight ratio of Ezetimibe and deoxycholic acid
It is 1:2-4, preferably 1:3.
5. Ezetimibe tablet according to claim 1, it is characterised in that pharmaceutically acceptable auxiliary material be filler,
Disintegrant and lubricant.
6. Ezetimibe tablet according to claim 5, it is characterised in that described filler be lactose, mannitol,
One or more in starch, dextrin and microcrystalline cellulose.
7. Ezetimibe tablet according to claim 5, it is characterised in that described disintegrant be sodium carboxymethyl starch,
One or more in PVPP and Ac-Di-Sol.
8. Ezetimibe tablet according to claim 5, it is characterised in that described lubricant is magnesium stearate, hard
One or more in resin acid fumaric acid sodium and talcum powder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510924329.1A CN106880598B (en) | 2015-12-14 | 2015-12-14 | Ezetimibe tablet |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510924329.1A CN106880598B (en) | 2015-12-14 | 2015-12-14 | Ezetimibe tablet |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106880598A true CN106880598A (en) | 2017-06-23 |
| CN106880598B CN106880598B (en) | 2021-08-31 |
Family
ID=59173173
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510924329.1A Active CN106880598B (en) | 2015-12-14 | 2015-12-14 | Ezetimibe tablet |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106880598B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114652725A (en) * | 2022-04-20 | 2022-06-24 | 北京丰科睿泰医药科技有限公司 | Alvatripopa maleate cyclodextrin inclusion compound and pharmaceutical preparation thereof |
| 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 (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1230123A (en) * | 1996-07-11 | 1999-09-29 | 荷兰发马克有限公司 | Inclusion complex containing indole selective serotonin agonist |
| CN101115758A (en) * | 2005-02-04 | 2008-01-30 | 韩美药品株式会社 | Amorphous taclolimus solid dispersion having an enhanced solubility and pharmaceutical composition comprising same |
| WO2008074723A1 (en) * | 2006-12-21 | 2008-06-26 | Lek Pharmaceuticals D.D. | Inclusion complex of ezetimibe and a cyclodextrin and processes in the preparation thereof |
| US20120041068A1 (en) * | 2010-08-11 | 2012-02-16 | Aptapharma, Inc. | Extended Release Pharmaceutical Preparations for Active Pharmaceutical Ingredients with pH Dependent Solubility |
| CN104825407A (en) * | 2015-04-20 | 2015-08-12 | 山东新时代药业有限公司 | Ezetimibe tablet |
-
2015
- 2015-12-14 CN CN201510924329.1A patent/CN106880598B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1230123A (en) * | 1996-07-11 | 1999-09-29 | 荷兰发马克有限公司 | Inclusion complex containing indole selective serotonin agonist |
| CN101115758A (en) * | 2005-02-04 | 2008-01-30 | 韩美药品株式会社 | Amorphous taclolimus solid dispersion having an enhanced solubility and pharmaceutical composition comprising same |
| WO2008074723A1 (en) * | 2006-12-21 | 2008-06-26 | Lek Pharmaceuticals D.D. | Inclusion complex of ezetimibe and a cyclodextrin and processes in the preparation thereof |
| US20120041068A1 (en) * | 2010-08-11 | 2012-02-16 | Aptapharma, Inc. | Extended Release Pharmaceutical Preparations for Active Pharmaceutical Ingredients with pH Dependent Solubility |
| CN104825407A (en) * | 2015-04-20 | 2015-08-12 | 山东新时代药业有限公司 | Ezetimibe tablet |
| CN104825407B (en) * | 2015-04-20 | 2018-05-18 | 山东新时代药业有限公司 | A kind of Ezetimibe tablet |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114652725A (en) * | 2022-04-20 | 2022-06-24 | 北京丰科睿泰医药科技有限公司 | Alvatripopa maleate cyclodextrin inclusion compound and pharmaceutical preparation thereof |
| 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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| Publication number | Publication date |
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| CN106880598B (en) | 2021-08-31 |
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