KR101834559B1 - Solid composite formulation for oral administration comprising ezetimibe and rosuvastatin - Google Patents

Abstract

The present invention relates to an ezetimibe wet granule comprising an ezetimibe amorphous form; And
And a rosuvastatin mixed portion comprising rosuvastatin or a pharmaceutically acceptable salt thereof,
Wherein the granules of the ezetimibe wet granules have a particle size of not less than 150 탆 of not less than 40% by weight, and a process for producing the same.

Description

SOLID COMPOSITE FORMULATION FOR ORAL ADMINISTRATION COMPRISING EZETIMIBE AND ROSUVASTATIN CONTAINING EZETIMIBE AND ROSUBASTATIN [0002]

The present invention relates to an oral solid combination preparation having improved dissolution rate and productivity of an active ingredient comprising ezetimibe and rosuvastatin or a pharmaceutically acceptable salt thereof and a preparation method thereof.

Rosuvastatin, or a pharmaceutically acceptable salt thereof, is one of the HMG-CoA reductase inhibitors that inhibit the synthesis of cholesterol to treat dyslipidemia. Crestor tablets (rosuvastatin calcium salt, AstraZeneca) containing rosuvastatin as a main ingredient are widely used in the treatment of dyslipidemia and related diseases at home and abroad. In particular, rosuvastatin is superior to atorvastatin or simvastatin, which is commonly used as a drug of the same mechanism, to lower the LDL cholesterol concentration in the blood as well as to increase the concentration of HDL cholesterol in the body. Interest in suvastatin formulation is increasing.

HMG-CoA reductase inhibitors generally increase therapeutic efficacy by co-administration with other dyslipidemic agents. The interaction with Ezetimibe, a drug that suppresses cholesterol reabsorption in the small intestine, is excellent, so that a complex formulation study between the two components is active. For example, vytorin, which is a combination of simvastatin and ezetimibe, has already proved its superior pharmacological efficacy and safety and is in commercial use with excellent sales.

Ezetimibe is a practically insoluble substance that exhibits low solubility in aqueous media such as gastric juices and thus exhibits low bioavailability when administered orally.

The high bioavailability of the active ingredients must be ensured in order to produce an effective combination formulation. The elution pattern of the active ingredient from the oral solid preparation is closely related to the bioavailability of the preparation, and the high bioavailability is based on a high dissolution rate. Generally, the dissolution rate tends to improve as the particle size of the granules constituting the tablet is lowered. However, when the particle size of the granule is lowered, the granule has lower fluidity and the angle of repose becomes smaller. If the fluidity of the granules is lowered, there is a problem that the productivity is lowered in the production of tablets and capsules.

Patent Document 1 discloses a formulation containing, in the form of a solid dispersion in which an ezetimibe is dispersed in a water-soluble polymer, in order to increase the dissolution rate of ezetimibe. In addition, a spray-drying method is used to produce the solid dispersion. It is disclosed that the agent can form or maintain an amorphous form in the solid dispersion, thereby increasing the dissolution rate of ezetimibe. However, since the preparation of the spray type requires complete dissolution of the ezetimibe in the organic solvent, the stability of the active ingredient of ezetimibe may be lowered. Further, since an organic solvent is used, it is difficult to control the residual amount of the organic solvent. In addition, due to the nature of being produced by spraying, there is a disadvantage that the yield of the active ingredient is poor and the reference content can not be obtained. In addition, the granules produced by the production of the spray type have a low particle size, and there is a possibility that the productivity is lowered when the tablets are tableted.

WO 2008-101723

It is an object of the present invention to provide a solid combination preparation for oral administration of rosuvastatin and ezetimibe which exhibits a high dissolution rate of the active ingredient but can maintain the stability of the active ingredient and does not cause any residual organic solvent .

Another object of the present invention is to provide a method for producing the solid combination preparation for oral administration of rosuvastatin and ezetimibe.

One aspect of the present invention is

An ezetimibe wet granule comprising an ezetimibe amorphous; And

And a rosuvastatin mixed portion comprising rosuvastatin or a pharmaceutically acceptable salt thereof,

Wherein the granules of the wet granulation part of the ezetimibe have a particle size of not less than 150 mu m of not less than 40 wt%.

In another aspect of the present invention,

Wet granulating a mixture comprising an ezetimibe amorphous to produce an ezetimibe wet granule; And

An oral solid composition according to one aspect of the present invention, comprising the step of formulating a mixture of rosuvastatin and a pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof, Of the present invention.

The solid combination preparation for oral use according to the present invention has high bioavailability due to high dissolution rate of ezetimibe, including amorphous ezetimibe, and high stability of ezetimibe. The particle size of the ezetimibe granules is such that particles having a granular particle size of not less than 150 탆 have a high value of not less than 40% by weight, and thus can be manufactured with high productivity due to reduction in angle of repose. In addition, since it can be produced by a high-speed mixer in the production of the ezetimibe granules contained in the solid combination preparation, there is no fear of residual organic solvent, and there is no need to dissolve the active ingredient in the organic solvent, And can be prepared with high yields for the active ingredient of ezetimibe.

Therefore, the oral solid combination preparation according to the present invention can be regarded as a combined preparation of ezetimibe and rosuvastatin, which is highly desirable in many aspects such as bioavailability, stability, increase in productivity, decrease in residual organic solvent, and the like.

All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety.

One aspect of the present invention is

An ezetimibe wet granule comprising an ezetimibe amorphous; And

And a rosuvastatin mixed portion comprising rosuvastatin or a pharmaceutically acceptable salt thereof,

Wherein the granules of the wet granulation part of the ezetimibe have a particle size of not less than 150 mu m of not less than 40 wt%.

The ezetimibe used as the first pharmacologically active ingredient is known to exist in the form of a polymorphic form and a method for preparing an ezetimibe amorphous form is also known in the art (see, for example, WO 2005 / 062897). Generally, it is known that amorphous form of drug has higher solubility and lower stability than crystalline form. Therefore, in the case of poorly soluble drugs, amorphous may be used to increase the bioavailability but is often not readily available due to the fear of reduced stability. The combined preparation according to the present invention showed stability similar to the case of using crystalline ezetimibe (see Test Example 3) despite the use of amorphous ezetimibe which is generally known to have low stability. In addition, while showing similar stability and using amorphous ezetimibe, the dissolution rate was remarkably increased 3 times or more (see Test Example 2, Tables 5 and 6) compared with the case of using crystalline ezetimibe. Therefore, the combined preparation has an advantage that the stability of the ejetimibe can be ensured while having a remarkably excellent bioavailability.

The composite preparation according to the present invention is characterized in that the granules of the granules of the ezetimibe wet granules have a particle size of not less than 150 탆 of not less than 40% by weight. The particle size of the granules can be measured according to any method known in the art, for example, measurements by sieve screening or air current classification can be used.

As a result of the test, when the granules of the granules of the ezetimibe wet granules have a particle size of 150 탆 or more of 40 wt% or more, the angle of repose of the granules was found to be about 35 째 to 40 째. It is generally known that the angle of repose for securing the productivity when preparing capsules by tableting tablets using granules or by filling granules into a capsule is about 35-40 degrees. Therefore, the combined preparation according to the present invention can be produced with high productivity.

On the other hand, as a result of the test, the combined preparation according to the present invention showed that the dissolution rate was lowered as the granule size of the granules of the ezetimibe wet granules was lowered. However, when the granules of the granules of the granules of ezetimibe were 150 m or more, In the case of more than 1% by weight (see Test Example 2, Tables 9 and 10), the 30-minute dissolution rate in artificial gastric juice and artificial intestinal fluid was found to have a sufficient dissolution rate of 20% or more. Therefore, the combined preparation according to the present invention has both amorphous use of ezetimibe and wet granules in a high particle size range, thus ensuring bioavailability, stability, and productivity.

The ezetimibe can be used in an amount of about 5 mg to about 20 mg, preferably about 5 mg to about 10 mg, based on the unit dosage form of the combination preparation of the present invention.

In the present invention, the term " wet granules "means mixed granules prepared in a wet state, and" mixed portion "means a mixture mixed in a non-granulated state.

The combination preparation of the present invention comprises rosuvastatin or a pharmaceutically acceptable salt thereof as the second pharmacologically active ingredient.

The rosuvastatin may be in the free base form or in the form of a pharmaceutically acceptable salt thereof. Examples of the pharmaceutically acceptable salt include calcium salt, magnesium salt, and strontium salt, and in one embodiment, rosuvastatin calcium salt may be used, but is not limited thereto.

The rosuvastatin or pharmaceutically acceptable salt thereof inhibits HMG-CoA reductase, which is essential for the synthesis of cholesterol, thereby lowering the blood LDL-cholesterol level and conversely increasing the HDL-cholesterol level, thereby contributing to the treatment of dyslipidemia.

The rosuvastatin or a pharmaceutically acceptable salt thereof may be used in an amount of about 2.5 mg to about 40 mg, specifically about 5 mg to about 20 mg, based on the unit dosage form of the combination preparation of the present invention.

The combination preparation of the present invention may further comprise at least one pharmaceutically acceptable additive in addition to the above-mentioned pharmacologically active ingredient. Specifically, the pharmaceutically acceptable additive may further include at least one substance selected from the group consisting of a diluent, a binder, a disintegrant, and a glidant.

In one embodiment, the wet granulation or rosuvastatin admixture comprises from about 0.5 to about 50 parts by weight of a diluent, from about 0.1 to about 20 parts by weight of a binder, from about 0.1 to about 40 parts by weight of a disintegrant, About 0.1 to about 3 parts by weight of a lubricant, or any combination thereof.

The diluent, binder, disintegrant, and lubricant may be any additives known to be commonly used in the art, but the stability and dissolution rate of the active ingredient may be further improved by the selection of specific additives . As the additive, the diluent may be selected from the group consisting of lactose, starch, mannitol, microcrystalline cellulose, carboxymethylcellulose, and any combination thereof, but is not limited thereto; The binder may be selected from the group consisting of povidone, hypromellose, hydroxypropylcellulose, copovidone, and any combination thereof, but is not limited thereto; The disintegrant may be selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropylcellulose, and any combination thereof, but is not limited thereto; The lubricant may be selected from the group consisting of magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and any combination thereof, but is not limited thereto.

In the present invention, the term " oral solid combination preparation " means a preparation made by molding or spraying a medicine into a certain shape. The solid oral complex preparation may be formulated into, for example, pellets, capsules, tablets (including single-layer, double-layer, and inner-wall), granules and the like, but is not limited thereto. More specifically, the oral solid combination preparation may be in the form of a capsule, a single-layer tablet or a two-layer tablet. When the oral solid preparation for oral use is a capsule, the capsule may be in the form of granules or tablets.

In one embodiment, the oral solid combination preparation of the present invention has a pH of 1.2 or a simulated gastric fluid (SGF) of 37 ° C or a pH of 6.8 in a dissolution test at a paddle rotation speed of 50 rpm according to Korean Pharmacopoeia Wherein the composition exhibits a dissolution rate of 20% or more of erythemic in 30 minutes in 900 ml of simulated intestinal fluid (SIF). As a result of the test, the dissolution test was carried out while varying the particle size of the crystalline form of ezetimibe and the wet granules of the ezetimibe in the solid combination preparation of the present invention. As a result, it was found that an emulsion of ezetimibe was used, When the particle size of 150 μm or more was made to be 40% by weight or more, the dissolution rate of artificial gastric fluid and / or artificial intestinal fluid was 20% or more within 30 minutes (see Test Example 2, Tables 5 and 6 and Tables 9 and 10).

In one embodiment, the combination preparation of the present invention is a solid combination preparation for oral use (see Test Example 3), wherein the total content of the ezetimibe suppository is less than about 3.0% when subjected to a severe test for 4 weeks at 60 캜.

Another aspect of the present invention is

Preparing a mixture containing an ezetimibe amorphous by wet granulation so that the particles having a particle size of 150 mu m or more account for not less than 40 wt% of the granules, thereby producing an ezetimibe wet granule; And

A method for preparing the solid combination preparation for oral use according to the present invention, comprising the step of formulating the mixture with the rosuvastatin mixed portion comprising the formed ezetimibe granule portion and rosuvastatin or a pharmaceutically acceptable salt thereof .

The above description of the preparation method can be applied to the oral solid combination preparation according to one aspect of the present invention as it is.

In one embodiment, the wet granulation can be performed by a high speed mixer.

The production of wet granules by a high-speed mixer is a method for preparing granules by adding together both the active ingredient and the pharmaceutical additive to be granulated and mixing them together, and does not require the dissolution of the drug in the organic solvent. The production of wet granules by a high-speed mixer is the most widely used method because of its short operation time and simple process. Generally, when the poorly soluble drug is wet granulated with a high-speed mixer, the dissolution rate is lowered due to the generation of hard granules having a high density, so that the bioavailability can not be guaranteed. Other methods for producing wet granules other than the high speed mixer include a spray-type manufacturing method such as fluidized bed granulation, spray drying and the like. However, since granules are produced by spraying, the production yield may be poor and the standard content may not be obtained There are disadvantages. In addition, it is necessary to dissolve and spray the active ingredient in the organic solvent. In this process, it is difficult to secure the stability of the active ingredient with respect to the organic solvent, and it is often difficult to remove the residual organic solvent in the final product.

However, the solid combination preparation for oral use according to the present invention can obtain a sufficiently high bioavailability of ezetimibe even when a high-speed mixer is used in the production of the ezetimibe wet granules. Therefore, the solid composite preparation according to the present invention can be produced by a high-speed mixer, and thus it is possible to produce the wet granule by the high-speed mixer, that is, to avoid the concern of instability of the active ingredient due to dissolution in the organic solvent, Avoiding the need to remove residual organic solvent in the final product, and the like.

In the wet granulation, the binding liquid is not particularly limited, but in one embodiment, the ratio of ethanol: water is at least 4: 1 in the binding liquid upon wet granulation.

The amount of the binding liquid to be used in the wet granulation is not particularly limited, but in one embodiment, the binding liquid is 6 to 15 parts by weight based on 1 part by weight of the ejetimibe in the wet granulation.

In one embodiment of the present invention, the wet granulation is wet granulation by a high speed mixer, and the wet granulation has a ratio of ethanol: water of at least 4: 1. In one embodiment of the present invention, when the wet granulation is performed by a high-speed mixer and the ratio of ethanol: water is 4: 1 or more when the wet granulation is performed, the complex preparation of the present invention, The dissolution rate of the thymidine was found to be about 20% or more for 30 minutes in the artificial gastric juice and the artificial intestinal fluid, and was remarkably superior to that in the case of not satisfying the binding liquid condition (see Test Example 2, Tables 7 and 8).

In one embodiment of the present invention, the wet granulation is wet granulation by a high speed mixer, and the wet granulation uses an amount of 6 to 15 parts by weight based on 1 part by weight of ejetimibe. In one embodiment of the present invention, when the wet granulation is performed by a high-speed mixer and the amount of the binding liquid when wet granulating is 6 to 15 parts by weight based on 1 part by weight of ezetimibe, the resulting ezetimibe wet granules Of particles having a particle size of 150 m or more was 40% by weight or more (see Test Example 1, Table 4). However, the dissolution rate of ejetimibe in the above range was found to be sufficiently high as the elution rate of 30 minutes in artificial gastric juice and artificial intestinal juice was about 20% or more in the above range Example 2, Tables 9 and 10).

In the preparation method, the mixture of the ezetimibe granules and the rosuvastatin may contain about 0.5 to about 50 parts by weight of a diluent, about 0.1 to about 20 parts by weight of a binder, about 0.1 to about 20 parts by weight of a disintegrant, From about 0.1 to about 3 parts by weight of a lubricant, or any combination thereof.

One embodiment of the production method of the present invention comprises (i) wet granulating a mixture containing an amorphous form of ezetimibe such that the particles having a granule size of not less than 150 mu m are not less than 40% by weight to prepare an ezetimibe wet granule (Ii) producing a rosuvastatin mixed portion comprising suvastatin or a pharmaceutically acceptable salt thereof, and (iii) mixing the wet granulation portion prepared in Step (i) and the wet granulation portion in step (ii) Preparing a single-layered tablet according to a conventional method for preparing a tablet after mixing the prepared mixed portion.

 Another embodiment of the production method of the present invention comprises (i) wet granulating a mixture containing (i) an ezetimibe amorphous so that the particles having a granule particle size of 150 m or more account for not less than 40% by weight to prepare an ezetimibe wet granule part (Ii) preparing a mixture by adding a mixed portion containing rosuvastatin or a pharmaceutically acceptable salt thereof, and (iii) adding a mixture containing rosuvastatin or a pharmaceutically acceptable salt thereof to the step ( preparing the two-layer tablet according to a conventional method for producing a tablet, wherein the tablet prepared in i) has one layer and the mixed portion prepared in the step (ii) has two layers.

Another embodiment of the production method of the present invention is a method for producing a granulated product comprising (i) wet granulation of a mixture containing an amorphous form of ezetimibe such that the particles having a granule size of not less than 150 m are not less than 40% (Ii) adding a mixed portion comprising rosuvastatin or a pharmaceutically acceptable salt thereof to the wet granule portion prepared in the step (i) to prepare a mixture, and (iii) And then filling the capsules with the mixture according to a conventional method for producing capsules to prepare capsules.

[Example]

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Production Example 1

A. Preparation of wet granules by high speed mixer

As shown in Table 1 below, ezetimibe was mixed with lactose hydrate, microcrystalline cellulose, sodium lauryl sulfate and croscarmellose sodium in the components and contents described in the wet granulation part. The resulting mixture was dried by coalescence (about 4 mg of povidone in 90 mg of ethanol) in a binding solution (associated conditions: Agitator speed: 150 rpm, Agitator pressure: 1.6 A, Chopper speed: 3000 rpm), and then sieved with about 20 mesh sieve to obtain an ezetimibe wet granule . The resulting ezetimibe wet granules were mixed with the mixture of components described in the mixture of rosuvastatin in Table 1 below as the ejetimibe wet granules. The resulting mixture was then tabletted using a tablet machine.

B. Preparation of wet granules by fluid bed system after tabletting

As shown in Table 1 below, ezetimibe was mixed with lactose hydrate, microcrystalline cellulose, sodium lauryl sulfate and croscarmellose sodium in the components and contents described in the wet granulation part. The mixture was poured into a fluidized bed pelletizer and flowed. The machine was operated at an inlet temperature of 50 ° C and a spray pressure of 1.0 bar. Spray was sprayed at 10 rpm to dissolve the binding solution (approximately 4 mg of povidone in 90 mg of ethanol) Respectively. During the injection of the binding solution, the granules were assembled under the same initial conditions, and the temperature was lowered to 45 ° C. during the drying. After drying, the granules were sieved with about 20 mesh sieve to prepare the ezetimibe wet granules. The resulting ezetimibe wet granules were mixed with the mixture of components described in the mixture of rosuvastatin in Table 1 below as the ejetimibe wet granules. The resulting mixture was then tabletted using a tablet machine.

[Table 1]

Production Example 2: Preparation of granules according to the ratio of ethanol in the binding solution

As shown in Table 2 below, ezetimibe was mixed with lactose hydrate, microcrystalline cellulose, sodium lauryl sulfate and croscarmellose sodium in the components and contents described in the wet granules. Approximately 4 mg of povidone was combined with 90 mg of the coupling solution of each preparation example (combined conditions: Agitator speed: 150 rpm, Agitator pressure: 1.6 A, Chopper speed: 3000 rpm) Wet granules were prepared. The obtained ezetimibe wet granules were mixed with the mixture of components described in the rosuvastatin mixed portion shown in Table 2 below as the ezetimibe wet granules. The resulting mixture was then tabletted using a tablet machine.

[Table 2]

Preparation Example 3 Preparation of granules according to the amount of binding solution

As shown in Table 3 below, ezetimibe was mixed with lactose hydrate, microcrystalline cellulose, sodium lauryl sulfate and croscarmellose sodium in the components and contents described in the wet granules. Approximately 4 mg of povidone was combined with the binding solution of each preparation example (combined conditions: Agitator speed: 150 rpm, Agitator pressure: 1.6 A, Chopper speed: 3000 rpm), and then the mixture was sieved with about 20 mesh sieve to obtain an ezetimibe wet granule . The resulting ezetimibe wet granules were used as wet granules and mixed with the mixture of components described in the rosuvastatin mixed portion shown in Table 3 below. The resulting mixture was then tabletted using a tablet machine.

[Table 3]

Test Example 1: Measurement of physical properties of wet granules containing ezetimibe

The particle size distribution, density and angle of repose of the granules to the wet granules of ezetimibe obtained in Preparation Example 3 were measured.

The results are shown in Table 4 below.

[Table 4]

According to the test results, density and particle size tend to increase as the amount of bonding liquid increases, and fluidity increases as the angle of repose is small. In general, the range of the angle of repose for securing the productivity during tableting is about 35-40 °, and therefore Examples 1, 4 and 5 having the angle of repose of 40 ° or less show excellent productivity, Weight% or more.

Test Example 2: Dissolution test

All of the combined preparations obtained in Examples 1 to 5 and Comparative Examples 1 to 7 were subjected to a dissolution test under the following conditions.

≪ Dissolution test conditions >

1) Elution method: Elution of Korean Pharmacopoeia Method 2 (paddle method)

2) Elution:

Artificial gastric juice - 2.0 g of sodium chloride (NaCl) and 3.2 g of purified pepsin are dissolved in 1000 ml of water containing 7.0 ml of hydrochloric acid (HCl).

After dissolving 6.8 g of artificial intestinal fluid-potassium dihydrogenphosphate (KH ₂ PO ₄ ) in 250 ml of water, add 77 ml of 0.2 N sodium hydroxide (NaOH) solution and 500 ml of water, and then add 10.0 g of pancreatin. After adjusting the pH to 6.8, add water to make 1000 ml.

3) Amount of eluate: 900 mL

4) Elution temperature: 37.5 DEG C

5) Paddle speed: 50 rpm

6) Test number: 6

7) Sample collection time: 5 minutes and 30 minutes

≪ Specimen analysis condition >

Detector: ultraviolet absorption spectrophotometer (measurement wavelength: 250 nm)

Column: ODS-2 C18 150 mm column

Flow rate: 1.5 ml / min

Column temperature: 40 ° C

Analysis time: 20 minutes

<Test Results>

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

According to the test results, the dissolution rate of ezetimibe was increased in the case of using amorphous ezetimibe as compared with granules prepared using crystalline ezetimibe in the production of granules (Tables 5 and 6, Example 1 vs. Comparative Example 1). In addition, the granules produced by a high-speed mixer during the production of granules using amorphous ezetimibe showed an increase in the dissolution rate of ezetimibe compared with the granules prepared by the fluidized bed granulation method, (Table 5 and 6, see Examples 1 and 2, Comparative Example 2). &Lt; tb &gt; &lt; TABLE &gt;

In addition, when the amorphous ezetimibe granules were produced by a high-speed mixer, the dissolution rate of the ezetimibe was increased as the ratio of ethanol in the binding solution was increased. Especially, when the ratio of ethanol: water was 4: 1 or more (See Tables 7 and 8).

In addition, when the amorphous ezetimibe granules were produced by a high-speed mixer, the dissolution rate was decreased as the amount of the binding solution was increased (see Tables 9 and 10), and as the amount of the binding solution increased, the density and the particle size It seems to be because of growing. However, the degree of decrease was not remarkable, and in the case of the granules prepared with 40 wt% or more of the granules having a particle size of 150 mu m or more, the dissolution rate in 30 minutes was maintained at 20% or more.

Test Example 3: Flexible material test

After the composite preparations obtained in Examples 1-3 and Comparative Examples 1, 4 and 5 were exposed for 1, 2, and 4 weeks at about 60 캜, a test was conducted to measure total flexible materials under the following conditions. The results are shown in Table 11 below.

 <Test Conditions>

Detector: ultraviolet absorption spectrophotometer (measurement wavelength: 250 nm)

Column: ODS-2 C18 250 mm column

Flow rate: 1.0 ml / min

Column temperature: 45 ° C

Analysis time: 70 minutes

[Table 11]

According to the test results, the amount of the flexible substance increased slightly in the preparation of the combined preparation of ezetimibe amorphous form compared to the crystalline form of ezetimibe, but no significant difference was found. In addition, as the ethanol ratio of the binding solution used in the preparation of the ezetimibe granules was increased, the amount of the flexible substance was remarkably decreased.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the above-described embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (13)

An ezetimibe wet granule comprising an ezetimibe amorphous; And
And a rosuvastatin mixed portion comprising rosuvastatin or a pharmaceutically acceptable salt thereof,
The ezetimibe wet granulation part is prepared by a high speed mixer,
Wherein the granules of the wet granulation part of the ezetimibe have a particle size of not less than 150 mu m of not less than 40 wt%. 2. The oral solid composition of claim 1, wherein the ezetimibe wet granulation or rosuvastatin admixture comprises a pharmaceutical additive selected from a diluent, a binder, a disintegrant, a glidant, and any combination thereof. Formulation. 3. The composition of claim 2 wherein the diluent is selected from the group consisting of lactose, starch, mannitol, microcrystalline cellulose, carboxymethylcellulose, and any combination thereof,
Wherein the binder is selected from the group consisting of povidone, hypromellose, hydroxypropylcellulose, copovidone, and any combination thereof,
Wherein said disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropylcellulose, and any combination thereof,
Wherein the lubricant is selected from the group consisting of magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof. 2. The oral solid combination preparation according to claim 1, wherein the ezetimibe is contained in an amount of 5 mg to 20 mg per unit dosage form. 2. The oral solid combination preparation according to claim 1, wherein the rosuvastatin or a pharmaceutically acceptable salt thereof is contained in an amount of 2.5 mg to 40 mg per unit dosage form. The solid combination preparation for oral administration according to claim 1, wherein the oral solid composition is in the form of a capsule, a monolayer, a bilayer, an inner core, or a granule. The method according to claim 1, wherein the combination preparation is subjected to a dissolution test at a paddle rotation speed of 50 rpm according to Method 2 of Pharmacopuncture 2 of the present invention. The dissolution test is carried out at 37 ° C in pH 1.2 artificial stomach fluid (SGF) or in 900 ml of artificial intestinal fluid (SIF) Wherein the dissolution rate of ezetimibe is 20% or more. 2. The oral solid combination preparation according to claim 1, wherein the total amount of the ezetimibe is less than 3.0% when the combination preparation is subjected to a severe test for 4 weeks under the condition of 60 占 폚. Preparing a mixture containing the ezetimibe amorphous by wet granulation with a high speed mixer such that the particles having a granule particle size of not less than 150 m are not less than 40% by weight; And
9. A pharmaceutical composition according to any one of claims 1 to 8, which comprises the step of formulating with the rosuvastatin mixed portion comprising the above prepared ezetimibe granule part and rosuvastatin or a pharmaceutically acceptable salt thereof &Lt; / RTI &gt; delete delete The production method according to claim 9, wherein the wetting granulation solution is 6 to 15 parts by weight based on 1 part by weight of ezetimibe. 10. The pharmaceutical composition according to claim 9, wherein the mixture of ezetimibe granules and rosuvastatin comprises 0.5 to 50 parts by weight of a diluent, 0.1 to 20 parts by weight of a binder, 0.1 to 40 parts by weight of a disintegrant, 0.1 to 3 parts by weight of a lubricant, or any combination thereof.