CN117045612B - Ezetimibe tablet and preparation method thereof - Google Patents

Ezetimibe tablet and preparation method thereof Download PDF

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Publication number
CN117045612B
CN117045612B CN202311313968.5A CN202311313968A CN117045612B CN 117045612 B CN117045612 B CN 117045612B CN 202311313968 A CN202311313968 A CN 202311313968A CN 117045612 B CN117045612 B CN 117045612B
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ezetimibe
parts
tablet
sucrose
fatty acid
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CN117045612A (en
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吕小娜
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Beijing Fuyuan Pharmaceutical Co ltd
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Beijing Fuyuan Pharmaceutical Co ltd
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    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Abstract

The invention provides ezetimibe tablet and a preparation method thereof, belonging to the technical field of medicinal preparations, wherein the tablet comprises ezetimibe, isopropyl myristate, sucrose fatty acid ester, a diluent, a disintegrating agent, an adhesive and a lubricant; wherein the particle diameter d0.9 of ezetimibe is not more than 10 μm. According to the ezetimibe tablet disclosed by the invention, the particle size d0.9 of ezetimibe is not more than 10 mu m, and isopropyl myristate and sucrose fatty acid ester are matched, so that the problems of poor solubility, poor fluidity and easiness in moisture absorption of ezetimibe can be overcome, the prepared tablet has good dissolution property, and the process smoothness of the preparation in the preparation process is ensured.

Description

Ezetimibe tablet and preparation method thereof
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to ezetimibe tablets and a preparation method of the tablets.
Background
Ezetimibe (Ezetimibe) was developed by Moesadong (MSD), approved by FDA in 10 th 2002, approved by the european union in 3 rd next year, and approved by the japan medical and instrument complex (PMDA) in 4 th 2007, and marketed by moesadong. Ezetimibe is a cholesterol absorption inhibitor that inhibits the absorption of cholesterol in the small intestine, reduces the cholesterol level in liver cells, and promotes the increase of cholesterol absorption in the circulation, thereby reducing the cholesterol level in the blood. Is mainly used for treating primary hyperlipidemia, mixed hyperlipidemia, homozygous familial hypercholesterolemia and homozygous sitosterol (phytosteremia) by assisting diet.
Ezetimibe is known by the chemical name 1- (4-fluorophenyl) - (3R) - [3- (4-fluorophenyl) - (3S) -hydroxypropyl ] - (4S) - (4-hydroxyphenyl) -2-azetidine (azetidine) one and has the structural formula:
。
ezetimibe is insoluble in water and the bioavailability of a compressed solid oral dosage form, such as a tablet, is often limited by its dissolution rate, thereby affecting the therapeutic efficacy of the drug. The reduction of particle size is one of the methods of increasing solubility commonly used in the art, and in fact, the method of reducing particle size to improve solubility has been used for ezetimibe. However, merely reducing the particle size does not effectively increase the dissolution rate of ezetimibe to a satisfactory extent. In addition, ezetimibe micronization has the defect of easy agglomeration, namely, the agglomeration is easy to occur due to electrostatic effect in the mixing process, even though the ezetimibe is processed in a sieving mode and the like, the ezetimibe cannot be improved, and the actual preparation is inconvenient after the agglomeration. Meanwhile, ezetimibe has poor fluidity and is easy to absorb moisture, so that the agglomeration phenomenon of ezetimibe after micronization is more serious, and difficulty is brought to preparation of ezetimibe tablets.
The solid dispersion technology can improve the dissolution rate and bioavailability of ezetimibe, but the preparation method is unsatisfactory, because the solid dispersion is easy to age after being placed for a long time, the dissolution rate of the prepared tablet is greatly improved, but the dispersion is too viscous, difficult to take out and difficult to industrialize. And a large amount of carriers and other pharmaceutical excipients are needed, so that the volume of the tablet is overlarge and is not easy to be accepted by patients.
The patent CN101394837A adopts a co-grinding method, so that the particle diameter d (0.5) is smaller than 5 mu m, d (0.9) is smaller than 20 mu m, and the solubility and dissolution rate of ezetimibe tablets are improved. However, the direct micronization medicine is easy to agglomerate, so that the superiority of micronization cannot be fully reflected.
Patent CN103655453a prepares ezetimibe into a uniform suspension, and then adopts a high-pressure homogenization method or a high-speed stirring ball mill to control the granularity of ezetimibe, so that the final product exists in micron order, thereby improving the dissolution rate. However, the method requires high-pressure ball milling equipment and is difficult to industrialize.
The ezetimibe is dissolved in polyethylene glycol and copovidone melting medium in the patent CN104825407A, so that the obtained preparation has high dissolution speed, does not need to add a surfactant and does not need micronization treatment. However, the method can lead to the ezetimibe tablet to have larger absorption fluctuation in vivo, can not be released continuously and stably, and is unstable in dissolution.
Therefore, the research and development focus of the invention is to overcome the defects of poor solubility, poor fluidity and easy moisture absorption of ezetimibe and ensure the stable quality of ezetimibe tablets.
Disclosure of Invention
The invention aims to solve the technical problems of poor solubility, poor fluidity and easy moisture absorption of ezetimibe, thereby realizing the technical effects of good dissolution and smooth preparation process of ezetimibe tablets.
The invention adopts the method of reducing the particle size of ezetimibe to increase the dissolution rate, but the ezetimibe is easy to agglomerate due to the increased viscosity after the particle size of ezetimibe is reduced, which is unfavorable for mixing and tabletting, and the phenomenon of the ezetimibe agglomeration is further aggravated after micronization due to the poor fluidity and easy moisture absorption of ezetimibe, and a series of problems of unsmooth preparation process such as serious sticking and punching, obvious dent on a sheet surface and the like occur in the tabletting process. The inventor finds that the problem of unsmooth preparation process can be overcome by adding isopropyl myristate and sucrose fatty acid ester, and the ezetimibe dissolution effect can be further improved. The ezetimibe tablet comprises ezetimibe, isopropyl myristate, sucrose fatty acid ester, a diluent, a disintegrating agent, a binder and a lubricant; wherein the particle diameter d0.9 of ezetimibe is not more than 10 μm. The particle diameter d0.9 of ezetimibe is preferably 3-8 μm. The invention can increase the dissolution rate of ezetimibe, overcome the problems of high viscosity, poor fluidity and easy moisture absorption after the particle size of ezetimibe is reduced, and the problems of sticky flushing and obvious dent on one surface in the preparation process, ensure the process smoothness of the preparation in the preparation process, and ensure the medicine quality and curative effect.
In the ezetimibe tablet, the sucrose fatty acid ester is one or more of sucrose behenate, sucrose oleate, sucrose palmitate and sucrose laurate.
In the ezetimibe tablet, the diluent comprises one or more of sorbitol, calcium hydrophosphate, microcrystalline cellulose, lactose, mannitol and pregelatinized starch.
In the ezetimibe tablet, the disintegrating agent comprises one or more of low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch and croscarmellose sodium.
In the ezetimibe tablet, the binder includes, but is not limited to, one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, and sodium carboxymethylcellulose.
In the ezetimibe tablet, the lubricant comprises one or more of silica gel micropowder, magnesium stearate, stearic acid, calcium stearate, talcum powder and hard sodium fumarate.
In the ezetimibe tablet, the dosage of each component is as follows in parts by weight: 10 parts of ezetimibe, 3-10 parts of isopropyl myristate, 15-30 parts of sucrose fatty acid ester, 60-110 parts of diluent, 2-10 parts of disintegrant, 2-8 parts of adhesive and 1-3 parts of lubricant.
The invention also provides a preparation method of the ezetimibe tablet, which comprises the following steps:
(1) Micronizing ezetimibe raw material;
(2) Uniformly mixing micronized ezetimibe, isopropyl myristate and sucrose fatty acid ester, adding a diluent, a disintegrating agent and a binder, and uniformly mixing to obtain a mixture;
(3) Granulating the mixture obtained in the step (2) by a dry method, and finishing to obtain drug particles;
(4) Uniformly mixing the drug particles with a lubricant, and tabletting;
wherein the particle size d0.9 of the micronized ezetimibe is not more than 10 μm.
In the preparation method of ezetimibe tablets, the particle size d0.9 of the micronized ezetimibe is 3-8 microns.
According to the ezetimibe tablet provided by the invention, the particle size d0.9 of ezetimibe is controlled to be not more than 10 mu m, and isopropyl myristate and sucrose fatty acid ester are matched, so that the problems of poor solubility, poor fluidity and easiness in moisture absorption of ezetimibe can be overcome, the prepared tablet has good dissolution property, and the process smoothness of the preparation in the preparation process is ensured.
Detailed Description
Example 1
The preparation method comprises the following steps:
(1) Micronizing ezetimibe raw material to obtain ezetimibe with a particle size d0.9 of 8 μm;
(2) Uniformly mixing micronized ezetimibe, isopropyl myristate and sucrose behenate, and then adding microcrystalline cellulose, lactose, povidone and crospovidone to uniformly mix to prepare a mixture;
(3) Granulating the mixture obtained in the step (2) by a dry method, and finishing to obtain drug particles;
(4) Mixing the medicinal particles with silica gel micropowder, and tabletting.
Example 2
The preparation method comprises the following steps:
(1) Micronizing ezetimibe raw material to obtain ezetimibe with a particle size d0.9 of 10 μm;
(2) Uniformly mixing micronized ezetimibe, isopropyl myristate and sucrose oleate, and then adding microcrystalline cellulose, lactose, sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose to uniformly mix to prepare a mixture;
(3) Granulating the mixture obtained in the step (2) by a dry method, and finishing to obtain drug particles;
(4) Mixing the medicinal particles with hard sodium fumarate, and tabletting.
Example 3
The preparation method comprises the following steps:
(1) Micronizing ezetimibe raw material to obtain ezetimibe with a particle size d0.9 of 7 μm;
(2) Uniformly mixing micronized ezetimibe with isopropyl myristate, sucrose palmitate and sucrose behenate, adding pregelatinized starch, hydroxypropyl methylcellulose and crospovidone, and uniformly mixing to obtain a mixture;
(3) Granulating the mixture obtained in the step (2) by a dry method, and finishing to obtain drug particles;
(4) Mixing the medicinal granule with pulvis Talci and magnesium stearate, and tabletting.
Example 4
The preparation method comprises the following steps:
(1) Micronizing ezetimibe raw material to obtain ezetimibe with a particle size d0.9 of 4 μm;
(2) Uniformly mixing micronized ezetimibe, isopropyl myristate and sucrose laurate, and then adding calcium hydrophosphate, mannitol, hydroxypropyl cellulose, sodium carboxymethyl starch and crosslinked sodium carboxymethyl cellulose to uniformly mix to prepare a mixture;
(3) Granulating the mixture obtained in the step (2) by a dry method, and finishing to obtain drug particles;
(4) Mixing the medicinal granule with stearic acid, and tabletting.
Example 5
The preparation method comprises the following steps:
(1) Micronizing ezetimibe raw material to obtain ezetimibe with a particle size d0.9 of 3 μm;
(2) Uniformly mixing micronized ezetimibe, isopropyl myristate and sucrose behenate, and then adding microcrystalline cellulose, sorbitol, hydroxypropyl cellulose, povidone and croscarmellose sodium to uniformly mix to prepare a mixture;
(3) Granulating the mixture obtained in the step (2) by a dry method, and finishing to obtain drug particles;
(4) Mixing the medicinal particles with silica gel micropowder, and tabletting.
Example 6
The preparation method comprises the following steps:
(1) Micronizing ezetimibe raw material to obtain ezetimibe with a particle size d0.9 of 8 μm;
(2) Uniformly mixing micronized ezetimibe, isopropyl myristate and sucrose palmitate, and then adding microcrystalline cellulose, starch, povidone and sodium carboxymethyl starch to uniformly mix to obtain a mixture;
(3) Granulating the mixture obtained in the step (2) by a dry method, and finishing to obtain drug particles;
(4) Mixing the medicinal granule with calcium stearate, and tabletting.
Example 7
The preparation method comprises the following steps:
(1) Micronizing ezetimibe raw material to obtain ezetimibe with a particle size d0.9 of 5 μm;
(2) Uniformly mixing micronized ezetimibe, isopropyl myristate and sucrose palmitate, adding microcrystalline cellulose, povidone and sodium carboxymethyl starch, and uniformly mixing to obtain a mixture;
(3) Granulating the mixture obtained in the step (2) by a dry method, and finishing to obtain drug particles;
(4) Mixing the medicinal granule with hard sodium fumarate, pulvis Talci, and tabletting.
Comparative example
The preparation method is the same as in example 1.
Repose angle test
The angle of repose of the mixtures prepared in examples 1-7 and comparative examples 1-5 was measured using a powder particle flowability analyzer (model FT-104 BA) and the results were as follows:
from the above data, examples 1 to 7 have a small angle of repose, and are excellent in powder flowability, and suitable for industrial mass production. In comparative examples 2 to 5, isopropyl myristate and sucrose behenate were not added at the same time, and the mixture had a large angle of repose and poor powder flowability, and was not suitable for industrial production.
Smoothness of process
The phenomenon of whether or not sticking occurs during the preparation of examples 1 to 7 and comparative examples 1 to 5, and whether or not there is a concave surface on the tablet surface was examined. The method comprises the following steps:
from the above data, it is clear that in comparative example 4, in which isopropyl myristate and sucrose behenate were not added, the micronized material was viscous, and the sticking and the concave surface on the tablet surface were observed during the preparation process. Comparative examples 2, 3 and 5 did not add isopropyl myristate and sucrose behenate at the same time, and also had the sticking phenomenon as well as less dishing.
Dissolution measurement
Samples prepared in examples 1 to 7 and comparative examples 1 to 5 were taken, phosphate buffer (pH 6.8) containing 0.2% sodium dodecyl sulfate was used as a dissolution medium, and dissolution (%) was measured by HPLC using a dissolution rate measurement method (chinese pharmacopoeia 2020 edition four 0931 dissolution rate and dissolution rate measurement method (second method)) at 50 rpm, and dissolution rates (%) were obtained at 5, 10, 15, 20, 30, 45min, as follows:
from the above data, it is clear that ezetimibe tablets prepared in examples 1 to 7 of the present invention had a starting dissolution rate of 45% or more in 5 minutes and a cumulative dissolution rate of 92% or more in 15 minutes, and were eluted in all 45 minutes, and the dissolution was excellent. In contrast, the particle size of comparative example 1 was more than 10. Mu.m, and sucrose behenate was not added in comparative examples 3 to 5, and the ezetimibe tablet obtained was not good in dissolution effect and had a problem of slow dissolution.

Claims (6)

1. An ezetimibe tablet, which is characterized by comprising ezetimibe, isopropyl myristate, sucrose fatty acid ester, a diluent, a disintegrating agent, a binder and a lubricant; wherein the grain diameter d0.9 of ezetimibe is 3-8 mu m; the sucrose fatty acid ester is one or more of sucrose behenate, sucrose oleate, sucrose palmitate and sucrose laurate; the dosage of each component is as follows in parts by mass: 10 parts of ezetimibe, 3-10 parts of isopropyl myristate, 15-30 parts of sucrose fatty acid ester, 60-110 parts of diluent, 2-10 parts of disintegrant, 2-8 parts of adhesive and 1-3 parts of lubricant.
2. Ezetimibe tablet according to claim 1, wherein the diluent is one or more of sorbitol, dibasic calcium phosphate, microcrystalline cellulose, lactose, mannitol, pregelatinized starch.
3. Ezetimibe tablet according to claim 1, wherein the disintegrant is one or more of low substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, and croscarmellose sodium.
4. Ezetimibe tablet according to claim 1, wherein the binder is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, sodium carboxymethylcellulose.
5. The ezetimibe tablet of claim 1, wherein the lubricant is one or more of colloidal silica, magnesium stearate, stearic acid, calcium stearate, talc, and hard sodium fumarate.
6. A method of preparing the ezetimibe tablet of claim 1, comprising the steps of:
(1) Micronizing ezetimibe raw material;
(2) Uniformly mixing micronized ezetimibe, isopropyl myristate and sucrose fatty acid ester, adding a diluent, a disintegrating agent and a binder, and uniformly mixing to obtain a mixture;
(3) Granulating the mixture obtained in the step (2) by a dry method, and finishing to obtain drug particles;
(4) Uniformly mixing the drug particles with a lubricant, and tabletting;
wherein the particle diameter d0.9 of the micronized ezetimibe is 3-8 mu m.
CN202311313968.5A 2023-10-11 2023-10-11 Ezetimibe tablet and preparation method thereof Active CN117045612B (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2540281A1 (en) * 2011-06-30 2013-01-02 LEK Pharmaceuticals d.d. Solid self-microemulsifying systems
CN104490833A (en) * 2014-12-11 2015-04-08 武汉武药科技有限公司 Ezetimibe orally disintegrating tablet and preparation method thereof
CN111803458A (en) * 2020-08-10 2020-10-23 北京福元医药股份有限公司 Ezetimibe pharmaceutical preparation
CN115087665A (en) * 2019-12-17 2022-09-20 Jpv01有限公司 Engineered platelets for targeted delivery of therapeutic agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2540281A1 (en) * 2011-06-30 2013-01-02 LEK Pharmaceuticals d.d. Solid self-microemulsifying systems
CN104490833A (en) * 2014-12-11 2015-04-08 武汉武药科技有限公司 Ezetimibe orally disintegrating tablet and preparation method thereof
CN115087665A (en) * 2019-12-17 2022-09-20 Jpv01有限公司 Engineered platelets for targeted delivery of therapeutic agents
CN111803458A (en) * 2020-08-10 2020-10-23 北京福元医药股份有限公司 Ezetimibe pharmaceutical preparation

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