KR102206535B1 - Oral composite tablet comprising ezetimibe and rosuvastatin - Google Patents

Abstract

One aspect of the present invention is ezetimibe wet granulation portion including ezetimibe; And
As a combination tablet for oral administration comprising a rosuvastatin mixture containing rosuvastatin or a pharmaceutically acceptable salt thereof,
The ezetimibe wet granulation part contains povidone having a weight average molecular weight of 30,000 to 50,000 as a binder,
The rosuvastatin mixing part includes a water-soluble diluent and a water-insoluble diluent as a diluent, and the water-insoluble diluent has a particle size (d90) of 98 to 229 μm corresponding to 90% of the maximum particle size in the cumulative particle size distribution. , And a method of manufacturing the same.

Description

Oral compound tablet containing ezetimibe and rosuvastatin {ORAL COMPOSITE TABLET COMPRISING EZETIMIBE AND ROSUVASTATIN}

The present invention relates to an oral complex tablet having an initial dissolution rate and productivity of ezetimibe, and excellent ezetimibe including rosuvastatin or a pharmaceutically acceptable salt thereof, and a method for preparing the same.

Rosuvastatin or a pharmaceutically acceptable salt thereof is one of HMG-CoA reductase inhibitors that treat dyslipidemia by inhibiting the synthesis of cholesterol. Cresto tablets (Rosuvastatin Calcium Salt, AstraZeneca Co., Ltd.) containing rosuvastatin as a main component are widely used in the treatment of dyslipidemia and related diseases at home and abroad. In particular, studies have shown that rosuvastatin is not only superior in lowering blood LDL cholesterol levels than other commercially available HMG-CoA reductase inhibitor drugs, atorvastatin or simvastatin, but also increasing the level of beneficial HDL cholesterol in the body. As it is emerging, interest in formulations containing rosuvastatin is increasing.

HMG-CoA reductase inhibitors are generally administered in combination with other mechanisms of dyslipidemia treatment to increase the therapeutic effect. Of these, it has an excellent interaction with Ezetimibe, a drug that inhibits cholesterol reuptake in the small intestine. Research on combination formulations containing two ingredients is active. For example, Vitorin ^® , a combination formulation of simvastatin and ezetimibe, has already proven its pharmacological efficacy and stability, showing excellent sales volume, and is commercially available.

When rosuvastatin is also administered in combination with ezetimibe, its excellent efficacy has been proven by many studies (Non-Patent Documents 1 and 2). Accordingly, studies on a combination formulation of rosuvastatin and ezetimibe excellent in efficacy and productivity are being conducted.

Since ezetimibe has a quick T _max of less than 1 hour, it must be rapidly disintegrated and eluted after being administered in a tablet form to be absorbed into the body to obtain the desired therapeutic effect. However, since ezetimibe is a material that is practically insoluble in water, it is difficult to obtain a high dissolution rate, and thus, it is not easy to secure sufficient bioavailability. Therefore, it is necessary to develop a combination formulation that can secure a high dissolution rate of ezetimibe and is excellent in pharmaceutical aspects such as productivity and stability.

Brandon Ason et al., J Lipid Res. Apr 2011; 52(4): 679-687 Torimoto et al., Lipids in Health and Disease 2013, 12:137

One aspect of the present invention is to provide an oral combination tablet of rosuvastatin and ezetimibe having high productivity while exhibiting a high dissolution rate of ezetimibe.

Another aspect of the present invention is to provide a method for preparing an oral combination tablet of rosuvastatin and ezetimibe.

One aspect of the present invention

Ezetimibe wet granulation portion including ezetimibe; And

As a combination tablet for oral administration comprising a rosuvastatin mixture containing rosuvastatin or a pharmaceutically acceptable salt thereof,

The ezetimibe wet granulation part contains povidone having a weight average molecular weight of 30,000 to 50,000 as a binder,

The rosuvastatin mixing part includes a water-soluble diluent and a water-insoluble diluent as a diluent, and the water-insoluble diluent has a particle size (d90) of 98 to 229 μm corresponding to 90% of the maximum particle size in the cumulative particle size distribution. Provides.

Another aspect of the present invention

Preparing an ezetimibe wet granulation part by wet granulating ezetimibe with a pharmaceutical additive containing povidone having a weight average molecular weight of 30,000 to 50,000 as a binder; And

Comprising the step of tabletting a rosuvastatin or a rosuvastatin mixture comprising a pharmaceutically acceptable salt thereof and a pharmaceutical additive together with the ezetimibe wet granulation part, and the pharmaceutical additive is a water-soluble diluent and water as a diluent. Including an insoluble diluent, wherein the water-insoluble diluent has a particle size (d90) of 98-229 μm corresponding to 90% of the maximum particle size in the cumulative particle size distribution,

It provides a method of manufacturing the oral composite tablet according to an aspect of the present invention.

The oral composite tablet containing the ezetimibe wet granule part and the rosuvastatin mixture part according to one aspect of the present invention contains povidone having a weight average molecular weight of 30,000 to 50,000 as a binder in the ezetimibe wet granule part, while the initial dissolution rate is high. It can also have granules having an angle of repose excellent in productivity.

In addition, by including an insoluble diluent with an average particle size (d90) of 98 to 229 μm in the rosuvastatin mixture, the initial dissolution rate of ezetimibe increases compared to the case of using an insoluble diluent with a larger particle size. , It is possible to ensure proper flowability of the mixture of the wet granulation part of ezetimibe and the rosuvastatin mixing part. In addition, the accumulation of insoluble diluents in the dissolution port during the dissolution test of the composite tablet is alleviated, so that the dissolution deviation of ezetimibe can be significantly reduced, so that an appropriate quality evaluation of the composite tablet can be made.

Therefore, the oral composite tablet according to an aspect of the present invention can secure a high initial dissolution rate of ezetimibe, and can have an appropriate quality evaluation for the dissolution rate of ezetimibe, while having excellent productivity. It can be said that it is a very desirable combination tablet of ezetimibe and rosuvastatin from the side.

All technical terms used in the present invention, unless otherwise defined, are used in the same sense as those of ordinary skill in the art generally understand in the related field of the present invention. In addition, although preferred methods or samples are described in the present specification, those similar or equivalent are included in the scope of the present invention. In addition, the numerical values described herein are considered to include the meaning of "about" even if not specified. The contents of all publications referred to herein by reference are incorporated herein by reference in their entirety.

One aspect of the present invention

Ezetimibe wet granulation portion including ezetimibe; And

As a combination tablet for oral administration comprising a rosuvastatin mixture containing rosuvastatin or a pharmaceutically acceptable salt thereof,

The ezetimibe wet granulation part contains povidone having a weight average molecular weight of 30,000 to 50,000 as a binder,

The rosuvastatin mixing part includes a water-soluble diluent and a water-insoluble diluent as a diluent, and the water-insoluble diluent has a particle size (d90) of 98 to 229 μm corresponding to 90% of the maximum particle size in the cumulative particle size distribution. Provides.

In the present specification, "d90" means a particle size corresponding to 90% of the maximum particle size in the cumulative particle size distribution, and has the same meaning as commonly understood in the industry. For example, “d90 is 100 μm” means that 90% or more of the active ingredient particles have an equivalent spherical volume diameter of 100 μm or less. Such equivalent spherical volume diameter may be measured using, for example, Mastersizer (Malvern Instruments), HELOS Particle Size Analysis (Sympatec), etc., but the present invention is not limited to such a particle size measuring device.

From the point of view of pharmacokinetics, ezetimibe's Tmax is fast within 1 hour, so it must be rapidly disintegrated and eluted after being administered in tablet form and absorbed into the body to obtain the desired therapeutic effect. In order to obtain rapid initial dissolution, the granules containing the active ingredient must be prepared to be bulky (lower density), but the bulky granules cause tableting disorders such as capping or a large mass deviation of the prepared tablets during tableting. On the contrary, if granules without problems during tableting are prepared, the disintegration time is slow in the case of tablets produced therefrom, and a fast initial dissolution rate cannot be expected. As such, it is not easy to manufacture a tablet that has excellent productivity and secures a high initial dissolution rate.

The oral composite tablet according to an aspect of the present invention includes povidone having a weight average molecular weight of 30,000 to 50,000 as a binder in the wet granule part of ezetimibe, so that a high initial dissolution rate of ezetimibe of the composite tablet can be secured. At the same time, it is possible to have a repose angle range (35-40) of the granules to ensure proper flowability of the ezetimibe wet granules. As a result of the test, when the composite tablet according to one embodiment contains povidone having a weight average molecular weight of 30,000 to 50,000 as a binder in the ezetimibe wet granule, the composite tablet is paddle rotation speed of 75 rpm according to the second elution method of the Korean Pharmacopoeia. During the furnace dissolution test, it was confirmed that the dissolution rate of ezetimibe was 90% or more in 30 minutes in a sodium acetate buffer containing 37.5°C, pH 4.5, and 0.45% sodium lauryl sulfate (Test Example 2, Table 7), and ezetimibe When measuring the physical properties of wet granules, it was found that they were within the 35-40 angle of repose required to secure productivity during tableting (Test Example 1, Table 5). Therefore, the oral complex tablet has a very excellent pharmaceutical advantage in that it can secure high productivity while having a high initial dissolution rate of ezetimibe.

In one embodiment, the ezetimibe wet granulation part may contain povidone having a weight average molecular weight of 30,000 to 50,000 as a binder in a range of about 0.2 to 0.6 parts by weight based on 1 part by weight of ezetimibe.

In addition, the rosuvastatin mixing part of the oral complex tablet contains a water-soluble diluent and a water-insoluble diluent as a diluent, and a water-insoluble diluent having a d90 of 98 to 229 μm is contained, so that the high initial stage of ezetimibe of the combination tablet The dissolution rate can be secured. At the same time, it is possible to have an angle of repose of the final mixture (35-40) to ensure proper flowability when the final mixture of the ezetimibe wet granulation part and the rosuvastatin mixing part is tableted. As a result of the test, when the composite tablet according to one embodiment contains a water-insoluble diluent of the rosuvastatin mixture portion and a d90 of 98 to 229 μm, the composite tablet is subjected to a paddle rotation speed of 75 rpm according to the second elution method of the Korean Pharmacopoeia. During the dissolution test, while showing the dissolution rate of ezetimibe of 90% or more in 30 minutes in a sodium acetate buffer solution containing 37.5° C., pH 4.5, and 0.45% sodium lauryl sulfate (Test Example 2, Table 7), ezetimibe wet granules and It was found that the angle of repose of the final mixture of the rosuvastatin mixture was 35-40 (Test Example 1, Table 4). Therefore, the oral composite tablet has a high initial dissolution rate of ezetimibe by containing a water-insoluble diluent in a specific particle size range in the rosuvastatin mixture part, and high productivity can be secured during tableting for the manufacture of the composite tablet. .

In addition, the oral composite tablet may exhibit the effect of reducing the dissolution deviation of ezetimibe remarkably by reducing the accumulation of insoluble diluent in the dissolution vessel of the dissolution test device during the dissolution test of the composite tablet. Therefore, an appropriate quality evaluation of the combined tablet can be made. The complex tablet includes both an insoluble diluent and a water-insoluble diluent as a diluent in the rosuvastatin mixing part, and the insoluble diluent does not dissolve during the dissolution test of the complex tablet and may accumulate at the outlet. The accumulation of water-insoluble diluents at the elution port may result in delays in the dissolution of ezetimibe, which is hardly soluble in water, into the eluate, which delays dissolution in the dissolution test for the quality evaluation of complex tablets and reduces dissolution rate deviation. It can be a cause of enlargement. The rosuvastatin mixing part of the oral composite tablet contains a water-soluble diluent and a water-insoluble diluent as a diluent, and contains a water-insoluble diluent having a d90 of 98-229 μm, so that the accumulation of the water-insoluble diluent is significantly reduced. It can be, through this, it is possible to increase the dissolution rate of ezetimibe and reduce the dissolution deviation (see Test Example 2, Table 6, and Test Example 3, Table 8). Therefore, the oral composite tablet can not only have a high initial dissolution rate of ezetimibe by containing a water-insoluble diluent of a specific particle size in the rosuvastatin mixture part, but also have a remarkably small dissolution deviation during ezetimibe dissolution test. It is effective so that an appropriate quality evaluation can be made in relation to the dissolution rate of ezetimibe of the combined tablet.

The water-insoluble diluent with a d90 of 98 to 229 μm contained in the rosuvastatin mixing portion may be any diluent known in the art, for example, microcrystalline cellulose, starch, pregelatinized starch, and dicalcium phosphate. (DCP), low-substituted hydroxypropyl cellulose, or any combination thereof, but is not limited thereto. In one embodiment, the water-insoluble diluent is microcrystalline cellulose.

In one embodiment, the water-insoluble diluent having a d90 of 98-229 μm is an insoluble diluent having a d90 of 98-229 μm and a particle size (d50) of 44-108 μm corresponding to 50% of the maximum particle size in the cumulative particle size distribution. . In one embodiment, the water-insoluble diluent having a d90 of 98-229 μm is a microcrystalline cellulose having a d90 of 98-229 μm and a d50 of 44-108 μm.

The water-insoluble diluent may be present in about 2 to 10 parts by weight, based on 1 part by weight of rosuvastatin.

The water-soluble diluent may be present in about 2 to 10 parts by weight, based on 1 part by weight of rosuvastatin.

In the present specification, "wet granulation part" refers to a mixed granule manufactured in a wet state, and "mixing part" refers to a simple mixture that is only mixed without granulation or a mixed granule manufactured by any method Means.

In one embodiment, the rosuvastatin mixing unit has the form of a simple mixture or dry granules. As a result of the test, compared to the case of manufacturing the mixed portion of rosuvastatin in the form of wet granules using moisture and then manufacturing the complex tablet, when manufacturing the complex tablet after manufacturing the simple mixture or dry granules without using any moisture It was found that the amount of lactone-related substances of rosuvastatin was remarkably low when the composite tablet was stored under severe conditions, and it was confirmed that it could be reduced to less than 1.5% (see Test Example 4 and Table 9). Accordingly, the complex tablet can be prepared as a complex formulation having significantly improved stability for rosuvastatin through a production process that minimizes moisture exposed to rosuvastatin.

In the composite tablet according to the above aspect, the ezetimibe wet granulation part and the rosuvastatin mixing part may further include a diluent, a binder, a disintegrant, and a lubricant, and a pharmaceutical additive selected from any combination thereof. .

The diluent, binder, disintegrant, and lubricant may be any additive known to be commonly used in the art. 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 hydroxypropyl cellulose, 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.

Ezetimibe, the first active ingredient contained in the combination tablet, may 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 tablet.

The combined tablet contains rosuvastatin or a pharmaceutically acceptable salt thereof as the second active ingredient. That is, the rosuvastatin may be in a free base state or a pharmaceutically acceptable salt thereof. Examples of the pharmaceutically acceptable salts include calcium salts, magnesium salts, and strontium salts. In one embodiment, rosuvastatin calcium salts may be used, but the present invention is not limited thereto.

The rosuvastatin or a pharmaceutically acceptable salt thereof is used in an amount of about 2.5 mg to about 40 mg, specifically about 5 mg to about 20 mg, as a free base, based on the unit dosage form of the combination tablet of the present invention. I can.

The oral composite tablet may have any tablet form including an ezetimibe wet granule part and a rosuvastatin mixture part, and may be, for example, a single-layer tablet, a double-layer tablet, or an inner core tablet, but is limited thereto. It does not become.

In one embodiment, the oral composite tablet is a dissolution test at a paddle rotation speed of 75 rpm according to the dissolution method of the Korean Pharmacopoeia, at 37.5°C, pH 4.5, in a sodium acetate buffer containing 0.45% sodium lauryl sulfate at 90 for 30 minutes. It is an oral composite tablet that shows the dissolution rate of ezetimibe of% or more.

In one embodiment, the oral composite tablet is a dissolution rate of 20% or more ezetimibe in 30 minutes in 37.5°C pH 1.2 artificial gastric juice (SGF) when a dissolution test is performed at a paddle rotation speed of 50 rpm according to the dissolution method of the Korean Pharmacopoeia It is an oral composite tablet that represents.

In one embodiment, the oral composite tablet is an oral composite tablet wherein the total content of rosuvastatin lactone related substances is less than 1.5% when subjected to a severe test for 2 weeks under conditions of 60°C.

Another aspect of the present invention

Preparing an ezetimibe wet granulation part by wet granulating ezetimibe with a pharmaceutical additive containing povidone having a weight average molecular weight of 30,000 to 50,000 as a binder; And

Comprising the step of tabletting a rosuvastatin or a rosuvastatin mixture comprising a pharmaceutically acceptable salt thereof and a pharmaceutical additive together with the ezetimibe wet granulation part, and the pharmaceutical additive is a water-soluble diluent and water as a diluent. It includes an insoluble diluent, and the water-insoluble diluent has a d90 of 98-229 μm,

It provides a method of manufacturing the oral composite tablet according to an aspect of the present invention.

Details of the preparation method may be applied as it is to the description of the oral composite tablet according to an aspect of the present invention.

In one embodiment, wet granulation for the manufacture of the ezetimibe wet granulation part may be performed by a fluidized bed assembly method, a spray drying method, or a high speed mixer.

The mixture of rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutical additive may be a simple mixture formed only by mixing, or a dry granule prepared by a dry granulation method.

The ezetimibe wet granulation part may be prepared to include povidone having a weight average molecular weight of 30,000 to 50,000 as a binder in a range of about 0.2 to 0.6 parts by weight based on 1 part by weight of ezetimibe.

In the above manufacturing method, the ezetimibe granular part and the rosuvastatin mixing part, respectively, based on 1 part by weight of ezetimibe, about 0.5-about 50 parts by weight of a diluent, about 0.1-about 20 parts by weight of a binder, about 0.1-about a disintegrant 40 parts by weight, about 0.1 to about 3 parts by weight of a lubricant, or any combination thereof.

One specific example of the manufacturing method is the step of (i) wet granulating ezetimibe as a binder with a pharmaceutical additive containing povidone having a weight average molecular weight of 30,000 to 50,000 to prepare an ezetimibe wet granule, (ii) Rosuvastatin or a simple mixture comprising a pharmaceutically acceptable salt and pharmaceutical additives thereof, or a rosuvastatin mixing unit for preparing dry granules, and (iii) the wet granulation unit prepared in step (i) And the final mixture including the mixing part prepared in step (ii) may include the step of preparing a single-layer tablet according to a conventional tablet manufacturing method.

Another embodiment of the manufacturing method is (i) wet granulation of ezetimibe as a binder with a pharmaceutical additive containing povidone having a weight average molecular weight of 30,000 to 50,000 to prepare an ezetimibe wet granule, and tableting it Step of tabletting, (ii) preparing a rosuvastatin mixture for preparing a simple mixture or dry granules containing rosuvastatin or a pharmaceutically acceptable salt and pharmaceutical additives thereof, and (iii) a double-layer tablet press By using the tablet prepared in step (i) as one layer, and the mixing portion prepared in step (ii) as two layers, a step of preparing a two-layer tablet according to a conventional method for preparing a tablet may be included.

The preparation of the dry granules can be carried out by any method known in the art, and in one embodiment, a simple mixture of rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutical additive is dried using a roller compactor. After granulation, the process of sizing with an oscillator can be performed.

[Example]

Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples are for illustrative purposes only, and the scope of the present invention is not limited thereby.

Manufacturing example One : Rosuvastatin Mixed Preparation of complex tablets according to the manufacturing method

[ Ezetimibe Preparation of wet granules]

As shown in Table 1 below, ezetimibe was mixed with lactose hydrate, microcrystalline cellulose, sodium lauryl sulfate, and croscarmellose sodium at the components and contents described in the wet granulation part. The resulting mixture was introduced into a fluidized bed granulator and flowed, and the machine was operated at an inlet temperature of 50 degrees Celsius (℃) and a spray pressure of 1.0 bar, and a spray was sprayed at a speed of 10 rpm. ) Was injected. While the binder solution was injected, the initial assembly was performed under the same conditions, and then the inlet temperature was lowered to 45 degrees during drying, followed by drying. After drying, it was sieved through a 20 mesh sieve to prepare ezetimibe wet granules.

Example One: Rosuvastatin Preparation of simple mixing and complex tablets

The prepared ezetimibe wet granules were used as the ezetimibe wet granules and mixed with a simple mixture of the components described in the rosuvastatin mixing unit shown in Table 1 below. The resulting final mixture was tableted with a tablet press to prepare a composite tablet.

Example 2: Rosuvastatin Preparation of dry granules and preparation of complex tablets

The mixture of the components described in the rosuvastatin mixing unit shown in Table 1 was sieved and mixed, and then dry granulated using a roller compactor, and then sized with an oscillator to prepare dry granules. The obtained rosuvastatin dry granules were mixed with the prepared ezetimibe wet granules, and the obtained mixture was tableted with a tablet press to prepare a composite tablet.

Comparative example One: Rosuvastatin High speed Preparation of mixer wet granules and preparation of complex tablets

The mixture of components other than the water listed in the rosuvastatin mixing section shown in Table 1 below was combined with 50 mg of water using a high speed mixer (combination conditions: Agitator speed: 150 rpm, Agitator pressure: 1.6 A, Chopper Speed: 3000rpm), dried, and then sieved through a sieve of about 20 meshes to prepare rosuvastatin wet granules. The obtained rosuvastatin wet granules were mixed with the prepared ezetimibe wet granules, and the obtained mixture was tableted with a tablet press to prepare a composite tablet.

Comparative example 2: Rosuvastatin Manufacture of fluidized bed granulated wet granules and composite tablets

As shown in Table 1 below, a mixture of components other than water described in the wet granulator was introduced into a fluid bed granulator to flow, and then the machine was operated at an inlet temperature of 50 degrees and a spray pressure of 1.0 bar, and a speed of 10 rpm. Water was injected by spraying with a spray. While water was injected, the inlet temperature was lowered to 45 degrees during drying after assembling under the same initial conditions, followed by drying. After drying, it was sieved through a 20 mesh sieve to prepare rosuvastatin wet granules. The obtained rosuvastatin wet granules were mixed with the prepared ezetimibe wet granules, and the obtained mixture was tableted with a tablet press to prepare a composite tablet.

[Table 1]

Manufacturing example 2: Rosuvastatin Mixed diluent On the granularity Preparation of composite tablets according to

As shown in Table 2 below, ezetimibe wet granules were prepared in the same manner as in Example 1 except that the microcrystalline cellulose used in the rosuvastatin mixing portion was used in the microcrystalline cellulose of various particle sizes. Then, a final mixture was prepared by mixing with a simple mixture of rosuvastatin, and then tableted to prepare a complex tablet.

[Table 2]

Manufacturing example 3: Ezetimibe Wet granular Povidone Preparation of composite tablets according to weight average molecular weight

As shown in Table 3 below, ezetimibe wet granules were used in the same manner as in Example 1, except that the binder used in the preparation of ezetimibe wet granules was only using povidone of various weight average molecular weights. Then, a complex tablet with a simple mixture of rosuvastatin was prepared.

[Table 3]

Test example One: Ezetimibe Included Wet granulation Physical property measurement

The density and angle of repose were measured for the final mixture obtained by mixing ezetimibe wet granules and a simple mixture of rosuvastatin obtained in Preparation Example 2, and the Hausner ratio (tap density/bulk density) was calculated. The results are shown in Table 4 below. The range of the angle of repose to ensure productivity during tableting is 35-40.

[Table 4]

In addition, the density and angle of repose of the ezetimibe wet granules according to the povidone weight average molecular weight obtained in Preparation Example 3 were measured. The results are shown in Table 5 below.

[Table 5]

Test example 2: dissolution test (1)

The dissolution test was performed on the composite tablets of Examples 1, 3 and 4 and Comparative Examples 3 and 4 obtained in Preparation Example 2 under the following conditions. In addition, the dissolution test was performed on the composite tablets of Examples 1 and 5 and Comparative Examples 5, 6 and 7 obtained in Preparation Example 3 under the following conditions.

<Dissolution test conditions>

1) Method of dissolution: Method 2 of dissolution of the Korean Pharmacopoeia (paddle method)

2) Eluent: pH 4.5 sodiμm acetate buffer + 0.45% SLS

3) Amount of eluate: 500 mL

4) Eluent temperature: 37.5℃

5) Paddle speed: 75rpm

6) Number of test groups: 6

7) Sample collection time: 5 minutes and 30 minutes

<Sample analysis conditions>

Detector: Ultraviolet absorption photometer (measurement wavelength: 250nm)

Column: ODS-2 C18 150mm column

Flow rate: 1.5ml/min

Column temperature: 40℃

Analysis time: 20 minutes

<Test result>

[Table 6]

[Table 7]

Test example 3: dissolution test (2)

The dissolution test was performed on the composite tablets of Examples 1, 3 and 4 and Comparative Examples 3 and 4 obtained in Preparation Example 2 under the following conditions.

<Dissolution test conditions>

1) Method of dissolution: Method 2 of dissolution of the Korean Pharmacopoeia (paddle method)

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

3) Amount of eluate: 900 mL

4) Eluent temperature: 37.5℃

5) Paddle speed: 50 rpm

6) Number of test groups: 6

7) Sample collection time: 5 minutes and 30 minutes

<Sample analysis conditions>

Detector: Ultraviolet absorption photometer (measurement wavelength: 250nm)

Column: ODS-2 C18 150mm column

Flow rate: 1.5ml/min

Column temperature: 40℃

Analysis time: 20 minutes

<Test result>

[Table 8]

According to the results of Tables 4 and 6, in the case of Comparative Example 3 having a small particle size of the insoluble diluent in the rosuvastatin mixing portion, the dissolution rate is improved, but the repose angle is high and the flowability is not good. The flowability affects the tabletability of the tablet, and the low flowability causes a large variation in the mass of the tablet, and it is not suitable for mass production since it lowers the production efficiency. In the case of Comparative Example 4 having a large particle size of the insoluble diluent in the rosuvastatin mixing portion, excellent flowability was shown, but the elution deviation was very large. This is believed to be due to the fact that the large particle size insoluble diluent contained in the rosuvastatin mixing part was accumulated in the dissolution vessel during the dissolution test, preventing the release of the active ingredient ezetimibe. According to the U.S. Pharmacopoeia (USP), the appropriate deviation range in the dissolution test is within 20% of the dissolution rate within 10 minutes and within 10% of the dissolution rate after 10 minutes (see USP <1092>). Complex tablets have a problem that proper product quality evaluation cannot be made due to large standard deviations during the dissolution test.

In addition, according to Tables 4 and 8, the composite tablet of Comparative Example 4 exhibits a delayed dissolution compared to the composite tablets of other examples in the artificial gastric juice. Ezetimibe is a component within 1 hour of Tmax, and its dissolution in gastric juice, which is the initial dissolution rate, greatly affects the bioavailability. Therefore, the composite tablet of Comparative Example 4 is expected to actually have a low bioavailability due to a low initial dissolution rate.

According to the results of Tables 5 and 7, it was found that the ezetimibe wet granules of Comparative Examples 6 and 7 having a large weight average molecular weight of povidone, which is a binder used in the preparation of ezetimibe wet granules, were excellent in flowability. The composite tablets of Comparative Examples 6 and 7 showed that the dissolution of ezetimibe was delayed in the dissolution test, and thus the initial dissolution rate was lower than that of the control formulation. Since the initial dissolution rate of ezetimibe is important for bioavailability, it was found that the use of povidone having a high weight average molecular weight when preparing ezetimibe wet granules as in Comparative Examples 6 and 7 was not preferable in terms of dissolution rate. On the contrary, in the case of Comparative Example 5 having a low weight average molecular weight, the initial ezetimibe dissolution rate of the composite tablet was improved, but the flowability of the ezetimibe wet granules was poor, which deteriorated the tablet productivity. .

Test example 4: Related substances exam

After the composite tablets obtained in Example 1-2 and Comparative Example 1-2 were packaged in aluminum-aluminum blister, exposed for 2 weeks under severe conditions (about 60° C.), a test was performed to measure lactone-related substances under the following conditions. I did. The results are shown in Table 9 below.

<Test conditions>

Detector: Ultraviolet absorption photometer (measurement wavelength: 250nm)

Column: ODS-2 C18 250 mm column

Flow rate: 1.0 ml/min

Column temperature: 45℃

Analysis time: 70 minutes

[Table 9]

According to the test results, the combined tablets of Comparative Examples 1 and 2 in which the mixed portion of rosuvastatin was prepared by wet granulation showed a remarkable increase in lactone-related substances after leaving for 2 weeks under severe conditions. Therefore, when the rosuvastatin mixture is prepared by simple mixing or dry granulation without the use of water, a complex tablet having high stability of rosuvastatin can be prepared.

So far, the present invention has been looked at around its preferred embodiments. Those of ordinary skill in the art to which the present invention pertains will be able to understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative point of view rather than a limiting point of view. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.

Claims (13)

Ezetimibe wet granulation portion including ezetimibe; And
As a combination tablet for oral administration comprising a rosuvastatin mixture containing rosuvastatin or a pharmaceutically acceptable salt thereof,
The ezetimibe wet granulation part contains povidone having a weight average molecular weight of 30,000 to 50,000 Da as a binder,
The rosuvastatin mixing part includes a water-soluble diluent and a water-insoluble diluent as a diluent, and the water-insoluble diluent has a particle size (d90) of 98 to 229 μm corresponding to 90% of the maximum particle size in the cumulative particle size distribution. Is,
The water-insoluble diluent is present in 2 to 10 parts by weight based on 1 part by weight of rosuvastatin,
The water-insoluble diluent is microcrystalline cellulose,
The ezetimibe is included in an amount of 5 mg to 20 mg per unit dosage form, and the rosuvastatin or a pharmaceutically acceptable salt thereof is contained in an amount of 2.5 mg to 40 mg as a free base per unit dosage form,
The rosuvastatin mixing part is a simple mixture or a combined oral tablet in the form of dry granules. delete The composite tablet for oral administration of claim 1, wherein the ezetimibe wet granulation part and the rosuvastatin mixing part contain a pharmaceutical additive selected from a diluent, a binder, a disintegrant, a lubricant, and any combination thereof. The method according to claim 3, wherein the diluent is selected from the group consisting of lactose, starch, mannitol, microcrystalline cellulose, carboxymethyl cellulose, and any combination thereof,
The binder is selected from the group consisting of povidone, hypromellose, hydroxypropylcellulose, copovidone, and any combination thereof,
The disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and any combination thereof,
The lubricant is selected from the group consisting of magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof. delete delete The oral composite tablet of claim 1, wherein the oral composite tablet is in the form of a single layer tablet, a double layer tablet, or an inner core tablet. The method of claim 1, wherein the oral complex tablet is dissolution tested at a paddle rotation speed of 75 rpm according to the dissolution method of the Korean Pharmacopoeia, 37.5°C, pH 4.5, 0.45% (w/v) sodium lauryl sulfate-containing sodium acetate buffer. The composite tablet for oral use that shows the dissolution rate of ezetimibe of 90% or more in 30 minutes. The method according to claim 1, wherein the dissolution test of the composite tablet at a paddle rotation speed of 50 rpm according to the dissolution method of the Korean Pharmacopoeia shows a dissolution rate of ezetimibe of 20% or more in 30 minutes in 37.5°C pH 1.2 artificial gastric juice (SGF). It is an oral combination tablet. The oral combination tablet according to claim 1, wherein the total content of rosuvastatin lactone related substances is less than 1.5% when the combination tablet is subjected to a severe test for 2 weeks under conditions of 60°C. delete delete Preparing ezetimibe wet granulation part by wet granulating ezetimibe with a pharmaceutical additive containing povidone having a weight average molecular weight of 30,000 to 50,000 Da as a binder; And
Comprising the step of tabletting a rosuvastatin or a rosuvastatin mixture comprising a pharmaceutically acceptable salt thereof and a pharmaceutical additive together with the ezetimibe wet granulation part, the pharmaceutical additive is a water-soluble diluent and water Including an insoluble diluent, wherein the water-insoluble diluent has a particle size (d90) of 98-229 μm corresponding to 90% of the maximum particle size in the cumulative particle size distribution,
A method for preparing the oral composite tablet according to any one of claims 1, 3 to 4 and 7 to 10.