CN106880598B

CN106880598B - Ezetimibe tablet

Info

Publication number: CN106880598B
Application number: CN201510924329.1A
Authority: CN
Inventors: 张贵民; 郝贵周; 陈小伟
Original assignee: Shandong New Time Pharmaceutical Co Ltd
Current assignee: Shandong New Time Pharmaceutical Co Ltd
Priority date: 2015-12-14
Filing date: 2015-12-14
Publication date: 2021-08-31
Anticipated expiration: 2035-12-14
Also published as: CN106880598A

Abstract

An ezetimibe tablet is prepared by dissolving ezetimibe, hydroxypropyl betacyclodextrin, and polyvidone in anhydrous alcohol, granulating with pharmaceutically acceptable adjuvants, drying, and making into capsule. Compared with the prior art, the invention has the advantages of simple preparation process, uniform drug dispersion, no need of a large amount of surfactant, smooth production process and rapid drug dissolution.

Description

Ezetimibe tablet

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an ezetimibe tablet.

Background

Ezetimibe is a white crystalline powder, readily soluble in ethanol, methanol and acetone, practically insoluble in water, stable at room temperature with a melting point of about 163 ℃. Ezetimibe is mainly used for primary hypercholesterolemia in clinic, and can be used for treating hypercholesterolemia alone or in combination with HMG-CoA reductase inhibitors such as statins as adjuvant therapy besides diet control, and can be used for reducing Total Cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB), or used as adjuvant therapy for other lipid-lowering therapy (such as LDL-C plasmapheresis), and can also be used for reducing TC and LDL-C levels of HoFH patients when other lipid-lowering therapy is ineffective.

Ezetimibe is insoluble in water, and when a solid dosage form of ezetimibe is orally administered, the drug must be dissolved in gastric juice before it can be absorbed to exert its therapeutic effect. Conventional formulations of compressed solid oral dosage forms, such as tablets, often affect the therapeutic efficacy of the drug because their dissolution rate limits their bioavailability. Particle size reduction is one of the methods commonly used in the art to increase solubility, and in fact, particle size reduction has been used for ezetimibe to improve solubility. However, reducing the particle size is not effective in increasing the dissolution rate of ezetimibe to a satisfactory range. Therefore, how to further improve the particle size, thereby improving the solubility of the preparation and increasing the bioavailability becomes an urgent need in ezetimibe research.

CN103655481A provides a preparation method of an ezetimibe oral preparation. The ezetimibe and pharmaceutically acceptable auxiliary materials are prepared into a solid oral preparation by adopting a ball milling solid dispersion technology, so that the dissolution rate of the preparation is improved. However, the drug is ground with the ball milling material, and the ball milling material may be brought into the drug ball milling fine powder, which brings safety concerns for patients. This is also a recognized potential hazard with ball milling technology.

CN102292072A discloses a method for coating a carrier with drug microparticles. Coated carriers can be obtained in a single step process which requires evaporation of the solvent from microdroplets of the solution comprising the API to obtain dry microparticles which are then coated onto the carrier. However, it requires special production equipment, is difficult to industrialize, and cannot be dissolved out quickly and completely.

Disclosure of Invention

In view of the defects of the prior art, the inventor intends to provide an ezetimibe tablet which is fast in dissolution, uniform in dispersion and free of adding a surfactant.

The inventors first considered that the solid dispersion was prepared with the aim of becoming amorphous due to the crystalline structure of the ezetimibe starting material. If ezetimibe is prepared in an amorphous form by formulation techniques, the same effect is achieved without the aging phenomenon of solid dispersions.

The inventor tries to dissolve ezetimibe in ethanol, uses the solution as a bonding agent, and granulates on auxiliary materials to obtain the same quick-dissolving ezetimibe, but the ethanol solution of the ezetimibe is low in viscosity, the prepared granules are poor in flowability, and the filling amount difference is large; on the basis of the above, the inventors added various binders to the above solution, and although the solution could be prepared into better granules, the dissolution of the drug during storage became significantly slow, probably due to the slow transformation of the high-energy amorphous drug into the crystalline drug.

Surprisingly, the inventors considered whether or not a cyclodextrin inclusion technique could be used in combination, and added hydroxypropyl-beta-cyclodextrin to the above solution to prepare an amorphous ezetimibe inclusion compound by simple granulation and drying, and used hydroxypropyl-beta-cyclodextrin dissolved in ethanol to have a certain viscosity as a binder, and the resulting granules had good flowability. However, the clathrate also has a problem of ezetimibe crystal precipitation even after being left for a long time, resulting in a slow drug dissolution.

Furthermore, the inventor considers that if a material is added in the preparation process of the inclusion compound to inhibit crystallization, the effect can be obtained, and through a large number of experiments, the inventor selects deoxycholic acid as a carrier, so that not only the crystallization of the medicine is inhibited, but also the dissolution rate can be improved.

Specifically, the invention is realized by the following technical scheme:

according to the ezetimibe tablet, ezetimibe, hydroxypropyl betacyclodextrin and deoxycholic acid are dissolved in absolute ethyl alcohol, and then the solution is granulated on pharmaceutically acceptable auxiliary materials, dried and filled into capsules.

The weight ratio of the ezetimibe to the hydroxypropyl betacyclodextrin of the ezetimibe tablet is 1: 3-7.

Preferably, the weight ratio of ezetimibe to hydroxypropyl betacyclodextrin is 1: 5.

The weight ratio of the ezetimibe to the deoxycholic acid of the ezetimibe tablet is 1: 2-4.

Preferably, the weight ratio of ezetimibe to deoxycholic acid is 1: 3.

The ezetimibe tablet comprises pharmaceutically acceptable auxiliary materials including a filler, a disintegrant and a lubricant.

The filler is one or more of lactose, mannitol, starch, dextrin and microcrystalline cellulose.

The disintegrant is one or more of sodium carboxymethyl starch, crospovidone deoxycholic acid and croscarmellose sodium.

The lubricant is one or more of magnesium stearate, sodium fumarate stearate and talcum powder.

Compared with the prior art, the invention has the advantages of high drug dissolution speed, simple process, no need of adding a surfactant and no need of micronization treatment. The accelerated test result shows that the ezetimibe tablet prepared by the invention has good stability.

Detailed Description

The following examples further illustrate the benefits of the present invention, and the examples are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications apparent to those of ordinary skill in the art in light of the present disclosure are intended to be included within the scope of the present invention.

Example 1

The preparation process comprises the following steps:

dissolving ezetimibe, hydroxypropyl betacyclodextrin and deoxycholic acid in absolute ethyl alcohol, then granulating the solution on mixed powder of lactose, microcrystalline cellulose and sodium carboxymethyl starch, drying at 60 ℃, granulating by using a 18-mesh sieve, adding magnesium stearate into the dried granules, uniformly mixing and tabletting to obtain the compound powder.

Example 2

The preparation process comprises the following steps:

dissolving ezetimibe, hydroxypropyl betacyclodextrin and deoxycholic acid in absolute ethyl alcohol, then granulating the solution on mixed powder of lactose, microcrystalline cellulose and crospovidone, drying at 60 ℃, granulating by using a 18-mesh sieve, adding magnesium stearate into the dried granules, uniformly mixing and tabletting to obtain the ezetimibe tablet.

Example 3

The preparation process comprises the following steps:

Comparative example 1

The preparation process comprises the following steps:

the ezetimibe is pulverized by airflow, D90 is 15.1 microns, and then is uniformly mixed with microcrystalline cellulose, crospovidone and magnesium stearate, and the mixture is pressed by a direct tabletting process.

Comparative example 2

The preparation process comprises the following steps:

dissolving ezetimibe and hydroxypropyl betacyclodextrin in anhydrous ethanol, granulating the solution on mixed powder of lactose, microcrystalline cellulose and crospovidone, drying at 60 deg.C, grading with 18 mesh sieve, adding magnesium stearate into the dried granules, mixing, and tabletting.

Comparative example 3

The preparation process comprises the following steps:

dissolving ezetimibe, hydroxypropyl betacyclodextrin and povidone in absolute ethyl alcohol, then granulating the solution in lactose, drying at 60 ℃, grading by using a 18-mesh sieve, adding magnesium stearate into the dried granules, uniformly mixing and tabletting to obtain the ezetimibe tablet.

Comparative example 4

The preparation process comprises the following steps:

dissolving Ezetimibe, hydroxypropyl betacyclodextrin and poloxamer in anhydrous ethanol, granulating with lactose, drying at 60 deg.C, sieving with 18 mesh sieve, adding magnesium stearate into the dried granules, mixing, and tabletting.

Comparative example 5

The preparation process comprises the following steps:

heating polyethylene glycol 4000 and copovidone at 80 ℃ for melting, adding ezetimibe in a prescription amount, stirring for dissolving, granulating the molten liquid on mixed powder of mannitol and sodium carboxymethyl starch, granulating through a 20-mesh sieve, adding magnesium stearate in the prescription amount, uniformly mixing, and tabletting.

Verification examples

And (3) dissolution rate determination: the content of the sodium dodecyl sulfate is measured according to the item of the appendix of the second part of the 2010 version of the Chinese pharmacopoeia by a paddle method, the rotating speed is 50 revolutions per minute, the dissolution medium is 900ml of acetate buffer solution containing 0.45 percent of sodium dodecyl sulfate, the detection is carried out by a UV detector at 234nm, and the 5min dissolution limit is 80 percent.

Results of measurement in each example

Examples	Day 0 results (%)	Results after 6 months acceleration at 40 ℃ and 75% RH (%)
			Example 1	99.9	99.7
Example 2	99.9	99.6
			Example 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 can be seen from the table, the dissolution of examples 1 to 3 of the present invention was rapid, and the dissolution was almost unchanged after acceleration; in comparative example 1, the raw material is micronized and the dissolution is slower than that of the invention; in comparative example 2, deoxycholic acid was not added to the solvent, and after acceleration, dissolution slowed; comparative example 3 was less effective with povidone as the present invention; comparative example 4 was not as effective as the present invention with poloxamer; comparative example 5, melt granulation, dissolution rate was inferior to the present invention.

Claims

1. An ezetimibe tablet is characterized in that ezetimibe, hydroxypropyl betacyclodextrin and deoxycholic acid are dissolved in absolute ethyl alcohol, and then the solution is granulated, dried and tableted on pharmaceutically acceptable auxiliary materials; wherein the weight ratio of ezetimibe to hydroxypropyl betacyclodextrin is 1:3-7, and the weight ratio of ezetimibe to deoxycholic acid is 1: 2-4; the pharmaceutically acceptable auxiliary materials comprise a filling agent, a disintegrating agent and a lubricating agent, wherein the filling agent is one or more of lactose, mannitol, starch, dextrin and microcrystalline cellulose, the disintegrating agent is one or more of sodium carboxymethyl starch, crospovidone and croscarmellose sodium, and the lubricating agent is one or more of magnesium stearate, sodium fumarate stearate and talcum powder.

2. Ezetimibe tablet according to claim 1, wherein the weight ratio of ezetimibe to hydroxypropyl betacyclodextrin is 1: 5.

3. Ezetimibe tablet according to claim 1, wherein the weight ratio of ezetimibe to deoxycholic acid is 1: 3.