TWI700100B - Composite formulation for oral administration comprising ezetimibe and rosuvastatin and a process for the preparation thereof - Google Patents

Abstract

Provided is a solid composite formulation for oral administration that includes: an ezetimibe-wet granule portion including ezetimibe that is wet-granulated using a fluid-bed granulator; and a rosuvastatin mixture portion including rosuvastatin or a pharmaceutically acceptable salt thereof.

Description

Compound formulation containing ezetimibe (EZETIMIBE) and rosuvastatin (ROSUVASTATIN) for oral administration and preparation method thereof Invention field

The present disclosure relates to a compound formulation for oral administration, which has improved pharmaceutical characteristics, including improved dissolution rate and dissolution rate of active ingredients, improved content uniformity and improved productivity. The formulation includes ezetimibe and rosuvastatin (or a pharmaceutically acceptable salt thereof), and a method for preparing the solid composite formulation.

Background of the invention

Rosuvastatin or its pharmaceutically acceptable salt is one of HMG-CoA reductase inhibitors, which inhibits the synthesis of cholesterol to treat dyslipidemia. Crestor tablets (that is, rosuvastatin calcium salt available from AstraZeneca), which contain rosuvastatin as the main ingredient, have been widely used in China and Used internationally to treat dyslipidemia and disorders related to dyslipidemia. especially In fact, studies have reported that rosuvastatin is effective in reducing the level of LDL cholesterol in the blood and increasing the level of beneficial HDL cholesterol in the body. It uses the same mechanism as rosuvastatin, the commercially available drug Ato Compared with the efficacy of atorvastatin or simvastatin, there is a better efficacy. Therefore, interest in rosuvastatin formulations is increasing.

HMG-CoA reductase inhibitors are generally used in combination with therapeutic agents for dyslipidemia, which have a different mechanism from HMG-CoA reductase inhibitors to increase the efficacy of the treatment. Among these combinations, due to the good drug interaction between HMG-CoA reductase inhibitor and ezetimibe, ezetimibe is a drug that inhibits the reabsorption of cholesterol in the small intestine. Compound formulations composed of these two components are being actively studied. For example, a compound formulation of simvastatin and ezetimibe, Vytorin ^TM , has demonstrated its good pharmaceutical efficacy and stability, and is currently available in Obtained in the market and has notable sales performance.

Through many studies, the combination therapy of ezetimibe and rosuvastatin has also been reported to have excellent pharmaceutical efficacy. However, composite formulations are not yet available on the market (Brandon Ason et al., J Lipid Res. Apr 2011; 52(4): 679-687; Torimoto et al., Lipids in Health and Disease 2013, 12: 137). Therefore, there is a need to develop a compound formulation with improved pharmacological characteristics, which contains a combination of ezetimibe and rosuvastatin, whose pharmacological effects are permitted.

Summary of the invention

The present disclosure provides a solid composite formulation of rosuvastatin and ezetimibe for oral administration, in terms of the dissolution rate, dissolution rate and content uniformity of the active ingredient In other words, it can have improved pharmaceutical characteristics, and it can be economically prepared with high productivity.

The present disclosure provides a method for preparing the composite formulation of rosuvastatin and ezetimibe for oral administration.

According to one aspect of the present invention, there is provided a solid composite formulation for oral administration, which comprises: a wet granular part of ezetimibe containing ezetimibe, which utilizes a fluid bed The granulator performs wet granulation; and rosuvastatin (rosuvastatin) mixture part, which contains rosuvastatin or a pharmaceutically acceptable salt thereof.

According to another aspect of the present invention, there is provided a method for preparing a solid composite formulation for oral administration, the method comprising: preparing ezetimibe (ezetimibe) by using a fluid bed granulator The ezetimibe wet granule part; and the ezetimibe wet granule part and the rosuvastatin (rosuvastatin) mixture part are blended together, and the rosuvastatin mixture part contains rosuvastatin or Its pharmaceutically acceptable salts.

As described above, according to one or more specific examples of the present disclosure, a solid composite formulation of ezetimibe and rosuvastatin for oral administration can have sufficiently improved dissolution rate and dissolution rate of active ingredients , Without using an excessive amount of disintegrant, which can ensure a high bioavailability, and there is no decrease in the stability of the active ingredient due to excessive disintegrant. The solid composite formulation for oral administration can also have good content uniformity. The solid composite formulation for oral administration can have good tableting characteristics, and can be prepared at the low internal temperature of a fluid bed granulator, resulting in high productivity.

Detailed description of the preferred embodiment Invention Mode

Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning generally understood by those skilled in the art to which the present invention belongs. Even though the exemplified methods or materials are listed herein, other similar or equivalent methods or materials are also within the scope of the present invention. All publications disclosed in this article as reference materials are incorporated as reference materials in their entirety.

The inventor has researched and developed a solid composite formulation for oral administration, which has sufficient active ingredient dissolution rate to ensure good pharmaceutical efficacy, and can also be economically prepared with high productivity. and so, They found a solid composite formulation prepared as a mixture of ezetimibe wet granules and rosuvastatin or a pharmaceutically acceptable salt thereof. The ezetimibe wet granules utilize a fluid bed granulator The separated wet granulation has high productivity and significantly improved pharmaceutical characteristics in terms of the dissolution rate, dissolution rate and content uniformity of the active ingredients.

According to an aspect of the present disclosure, a solid composite formulation for oral administration is provided, which includes: a wet granular portion of ezetimibe containing ezetimibe, which utilizes a fluid bed The granulator performs wet granulation; and rosuvastatin (rosuvastatin) mixture part, which contains rosuvastatin or a pharmaceutically acceptable salt thereof.

As used herein, the term "wet particle fraction" refers to mixed particles prepared by wet granulation, and the term "mixture fraction" refers to a non-granulated mixture.

When the ezetimibe wet granule part is prepared using a fluid bed granulator, it can have a sufficiently high dissolution rate of ezatiostat, and in the tablet pressing method, due to the good fluidity of the wet granules, it can have a high Productivity. Therefore, a solid composite formulation as in any specific example can have high bioavailability and productivity. However, when other wet granulation methods available in the pharmaceutical field are used to prepare the ezetimibe wet granule part, it may not be easy to ensure both the high dissolution rate and productivity of the solid composite formulation (see Experimental Example 1).

When a high-speed mixer is used to prepare wet granules of ezetimibe, the high-speed mixer is widely used in the art because of the short process time and simple process It is used for wet granulation. When evaluated according to the dissolution method II of the Korean Pharmacopoeia (10th edition), the resulting solid composite formulation showed a very low dissolution rate of less than about 50% in 10 minutes. Although a reduced amount of solvent can be used to increase the dissolution rate, the 10-minute dissolution rate of ezetimibe may still be less than about 60%. In addition, the smaller the amount of solvent, the lower the productivity will become. When using an advanced mechanical method, Consigma to prepare ezetimibe wet granules, although a reduced amount of solvent can be used to increase the dissolution rate, the 10-minute dissolution rate of ezatiostat is still possible Less than about 70%. In addition, the smaller the amount of solvent, the lower the productivity will become. In order to improve the use of a high-speed mixer, Consigm or the like to prepare wet granules, the dissolution rate decreases, the amount of disintegrant in the granulation method can be increased. However, excessive use of disintegrants may affect the stability of the active ingredients and negatively affect the quality of the drug.

When ezetimibe wet granules are prepared using a fluid bed granulator, the dissolution rate will decrease as the amount of solvent used in the preparation method increases. However, the 10-minute dissolution rate of ezetimibe can be as high as about 80% or more, even when the amount of solvent exceeds about 1 part by weight, based on 1 part by weight of the wet granules of ezetimibe. Even if the amount of solvent is reduced, the productivity can be as high as 100,000 lozenges per hour (Experimental Example 1). For general wet granulation using solvents, when the amount of solvent used exceeds about 0.5 parts by weight or more based on 1 part by weight of the wet granules of ezetimibe, the early dissolution rate may be Will decrease because the particles harden and their density increases. However, in a solid composite formulation as in the specific example of the present disclosure, when the amount of the solvent is as high as about 0.5 parts by weight or more For a long time, a high dissolution rate can be ensured. To be more precise, productivity can be increased due to the improved fluidity of the pellets in the compacting method. Therefore, when the fluid bed granulator is used to prepare the wet granular fraction of ezetimibe as in the present disclosure, without using an excessive amount of disintegrant, both high dissolution rate and productivity can be ensured, and the result can be Get quality-improved medicines. This is an unexpected effect in the art. In view of the fact that compared with wet granulation using a high-speed mixer, wet granulation and tablet pressing methods using a fluid bed granulator are traditionally known to be due to the fluidity of wet granules. Poor, and reduce productivity.

The solvent may be any available solvent that can dissolve the adhesive to prepare a wet granulated adhesive solution. For example, the solvent may include distilled water, ethanol, or any combination thereof, but is not limited to these.

The solid composite formulation of any specific example of the present disclosure is compared with a solid composite formulation containing wet particles prepared by any other granulation method that does not use a fluid bed granulator (see Experimental Example 2) , Can significantly improve content uniformity (content uniformity). This is also an unexpected effect in the art. In view of the fact that wet granulation using a fluid bed granulator is traditionally known to reduce content uniformity compared to wet granulation using a high-speed mixer .

The solid composite formulation of any specific example of the present disclosure can achieve saturated solubility at a significantly high speed compared with any other granulation method that does not use a fluid bed granulator. It is known that ezetimibe is a poorly soluble drug that has a low saturated solubility of about 1 ppm or less under acidic or weakly alkaline conditions like body fluids. The saturation solubility and dissolution rate from the starting point of dissolution to saturation are the bioavailability of poorly soluble drugs Assess important indexes. As a result of experiments, the solid composite formulation of the specific example of this disclosure is compared with any solid composite formulation containing wet particles prepared by any other granulation method that does not use a fluid bed granulator, and is different from any other solid composite formulation containing wet particles. Compared with the granulation method using the fluid bed granulator, it was found that the saturation solubility was achieved at a significantly high speed, and thus the bioavailability of ezatiostat, such as a poorly soluble drug, was improved (see Experimental Example 3 ).

In some specific examples, based on the total weight of 1 part by weight of the wet granular part of ezetimibe, about 0.1 to about 2 parts by weight of the solvent can be used, and in some specific examples, about 0.2 Part by weight to about 1 part by weight of the solvent to prepare the ezetimibe wet particle portion of the solid composite formulation. As used herein, the expression "total weight of ingredients of the wet granule portion of ezetimibe" refers to the total weight of any active ingredients and additives used to prepare the wet granule portion of ezetimibe except for the solvent.

When the amount of the solvent is lower than the lower limit of these ranges, sufficient wet particles cannot be obtained, and thus productivity may decrease. When the amount of the solvent exceeds the upper limit of these ranges, the granulation time and thus the total preparation time may increase, which is inefficient.

In some specific examples, based on the total weight of 1 part by weight of the wet granular part of ezetimibe, the wet granular part of ezetimibe may contain about 0.1 to about 2 parts by weight of distilled water, And in some specific examples, about 0.2 parts by weight to about 1 part by weight of distilled water.

In some specific examples, the amount of ezetimibe as the first pharmaceutically active ingredient in the solid composite formulation is in a unit dosage form, It can be in the range of about 5 mg to about 20 mg, and in some specific examples, about 5 mg to about 10 mg in a unit dosage form.

The solid composite formulation according to any specific example contains rosuvastatin as the second pharmaceutically active ingredient. Rosuvastatin may be in free base form or a pharmaceutically acceptable salt thereof. Non-limiting examples of pharmaceutically acceptable salts include calcium, magnesium, and strontium salts. For example, rosuvastatin may be in the form of calcium salt. However, it is not limited to these specific examples.

Rosuvastatin or its pharmaceutically acceptable salts can inhibit HMG-CoA reductase, which is necessary for cholesterol synthesis to reduce the level of LDL-cholesterol in the blood and increase the level of HDL-cholesterol in the blood To promote the treatment of dyslipidemia.

In some embodiments, in the unit dosage form of the solid composite formulation, the amount of rosuvastatin or a pharmaceutically acceptable salt thereof may range from about 2.5 mg to about 40 mg, and in some embodiments , The range of about 5mg to about 20mg.

In some embodiments, in addition to the pharmaceutically active ingredients, the solid composite formulation may further include at least one pharmaceutically acceptable additive. For example, the wet granular part of ezetimibe or the mixture part of rosuvastatin may contain at least one additive selected from the group consisting of diluents, binders, and disintegrants. , And lubricants.

In some specific examples, based on 1 part by weight of ezetimibe, the ezetimibe wet granule part and the rosuvastatin mixture part may each further comprise about 0.5 part to about 50 parts of dilution. Agent, approximately 0.1 to about 20 parts of binder, about 0.1 to about 10 parts by weight of disintegrant, and about 0.1 to about 3 parts by weight of lubricant.

In this art, the type and quantity of these additives can be appropriately selected depending on the type of the target solid composite formulation. For example, the diluent may be selected from the group consisting of lactose, starch, mannitol, microcrystalline cellulose, carboxymethyl cellulose, and any combination thereof. The binder may be selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, copovidone, and any combination thereof. The disintegrant can be selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxy Propyl cellulose, and any combination thereof. The lubricant can be selected from the group consisting of magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and any combination thereof. However, it is not limited to these specific examples.

As used herein, the term "solid composite formulation for oral administration" refers to a formulation that is formed into a predetermined shape by molding or encapsulating the drug. The solid composite formulation for oral administration can be formulated into, but is not limited to, a pill, capsule, lozenge (including single-layer lozenges, double-layer lozenges, and pressed core tablets) , Powder, or granules. For example, the solid composite formulation for oral administration may be in the form of a capsule, a single-layer lozenge or a double-layer lozenge. When the solid composite formulation is in the form of a capsule, the capsule may contain powder, granules, lozenges, syrup, or pills in The inner form.

In some specific examples, the wet granular part of ezetimibe may contain lactose, microcrystalline cellulose, sodium laurel sulfate, povidone, and croscarmellose sodium, And the rosuvastatin mixture part may include microcrystalline cellulose, lactose, mannitol, crospovidone, and magnesium stearate.

In some specific examples, the solid composite formulation was evaluated in a buffer solution containing about 0.45% sodium lauryl sulfate at pH 4.5 at a paddle speed of about 50 rpm according to the Korean Pharmacopoeia Dissolution Method II (10th Edition) The dissolution rate of ezetimibe can be about 85% or more in 10 minutes. Therefore, the solid composite formulation can have a high bioavailability due to the increased dissolution rate (see Experimental Example 1).

According to another aspect of the present disclosure, there is provided a method for preparing a solid composite formulation for oral administration. The method includes: preparing ezetimibe (ezetimibe) by using a fluid bed granulator The ezetimibe wet granule part; and the ezetimibe wet granule part and the rosuvastatin (rosuvastatin) mixture part are blended together, and the rosuvastatin mixture part contains rosuvastatin or Its pharmaceutically acceptable salts.

The detailed description of the solid composite formulation of the specific example of the present disclosure can be applied to the detailed description of the preparation method of the solid composite formulation of the specific example of the present disclosure.

In some specific cases, in the part of the ezetimibe wet granules During preparation, the internal temperature of the fluid bed granulator can be from about 20°C to about 40°C.

As used herein, the term "internal temperature of the fluid bed granulator" refers to the use of electrons equipped in the vessel of the fluid bed granulator when the temperature is maintained due to the stable operation of the fluid bed granulator. Thermometer, which measures the internal temperature of the fluid bed granulator.

Generally speaking, if the granulation is performed while maintaining the internal temperature of the fluid bed granulator at a low temperature of about 30°C or lower, the early dissolution rate of the active ingredient will tend to decrease due to the increase in the size and density of the particles. However, according to the present disclosure, when the ezetimibe wet granule part is prepared at a low internal temperature of a fluid bed granulator of about 20°C to about 30°C, the dissolution rate can hardly decrease. Thus, a solid composite formulation with sufficiently high dissolution rate can be prepared at low temperature. Therefore, according to the specific example of the present disclosure, the wet granular portion of ezetimibe can be prepared at a low internal temperature of a fluid bed granulator of about 20°C to about 30°C. Thus, the source component solution can be transported to the fluid bed granulator more quickly, so that the process time can be reduced and the productivity of the solid composite formulation can be increased.

In some specific examples, a method for preparing a solid composite formulation for oral administration as in any of the specific examples described above may include: i) preparing a solid composite formulation containing ezetidine by using a fluid bed granulator Ezetimibe wet granules part of ezetimibe; ii) preparation of rosuvastatin (rosuvastatin) mixture part comprising rosuvastatin or a pharmaceutically acceptable salt thereof; and iii) step i) the ezetimibe wet granule part and the rosuvastatin (rosuvastatin) mixture part of step ii) are mixed together to obtain a mixture Compound, and a single-layer lozenge of the compound by using a general tableting method.

In some exemplary embodiments, a method for preparing a solid composite formulation for oral administration as in any of the above-mentioned specific embodiments may include: i) preparing a solid composite formulation by using a fluid bed granulator Ezetimibe wet granular part of ezetimibe, and tableting the wet granular part of ezetimibe to obtain a lozenge; ii) preparing a mixture part of rosuvastatin , Which includes rosuvastatin or a pharmaceutically acceptable salt thereof; and iii) a double-layer tablet is formed by using a general double-layer tablet forming method plus a double-layer tablet press to form a double-layer tablet. The layered lozenge includes the lozenge prepared in step i) as the first layer, and the rosuvastatin mixture portion of step ii) as the second layer.

In some other specific examples, a method for preparing a solid composite formulation for oral administration as in any one of the specific examples described above may include: i) preparing a solid composite formulation by using a fluid bed granulator The ezetimibe wet granule part of ezetimibe; ii) the preparation of a rosuvastatin mixture part, which includes rosuvastatin or a pharmaceutically acceptable salt thereof; and iii) The ezetimibe wet granule part prepared in step i) and the rosuvastatin mixture part prepared in step ii) are mixed together to obtain a mixture, and iv) according to general encapsulation ( encapsulating) method to encapsulate the mixture to form a capsule.

Invention Mode

One or more specific examples of the present disclosure will now be described in more detail with reference to the following examples. However, these examples are for illustrative purposes only. And it is not intended to limit the scope of one or more specific examples of this disclosure.

Comparative Examples 1 to 6: Preparation of composite formulations by using a high-speed mixer

The composite formulations were prepared according to the compositions listed in Table 1 below. Table 1 shows the ingredients and quantities used. Povidone was dissolved in distilled water to prepare a binder solution. Ezetimibe, lactose monohydrate, microcrystalline cellulose, sodium lauryl sulfate, and croscarmellose sodium were mixed, and the mixture was placed in a high-speed mixer (P/VAC60, (Available from Diosna), and then inject the aforementioned adhesive solution into the chamber while operating the high-speed mixer at a stirrer speed of about 100 rpm and a chopper speed of about 3000 rpm for a total of about 3 minutes. The mixture is granulated, and the resulting granules are then dried in a fluid bed dryer. The dried granules are then passed through a sieve with a mesh size of 20. The sieved granules and the rosuvastatin mixture part of the ingredient mixture in the quantities listed in Table 1 were mixed together, and then a rotary tablet press (MRC-45N, available from Sejong Pharmatech Co., Ltd. ., Korea) to compress the mixture into tablets with a hardness of 10kp.

Examples 1 to 6: Preparation of composite formulations by using a fluid bed granulator

The composite formulations were prepared according to the compositions listed in Table 1 below. Table 1 shows the ingredients and quantities used. Povidone was dissolved in distilled water to prepare a binder solution. Ezetimibe, lactose monohydrate, microcrystalline cellulose, sodium lauryl sulfate, and croscarmellose sodium are mixed, and the mixture is placed in a fluid bed granulator (GRETC- 30. It can be obtained from GR-ENG) in a container, and then the aforementioned adhesive solution is injected into the container by spraying, and at the same time The internal temperature of about 30℃, the spraying pressure of about 1.2 bar and the spraying speed of about 10rpm are used to operate the fluid bed granulator to granulate the mixture until all the binder solution is injected, and then make the generated particles in the fluid bed dryer Dry inside. The dried granules are then passed through a sieve with a mesh size of 20. The sieved granules and the rosuvastatin mixture part of the ingredient mixture in the quantities listed in Table 1 were mixed together, and then a rotary tablet press (MRC-45N, available from Sejong Pharmatech Co., Ltd. .) to compress the mixture into tablets with a hardness of 10kp.

Comparative Examples 7 to 12: Preparation of composite formulations by using ConsiGma

The composite formulations were prepared according to the compositions listed in Table 1 below. Table 1 shows the ingredients and quantities used. Povidone was dissolved in distilled water to prepare a binder solution. Ezetimibe, lactose monohydrate, microcrystalline cellulose, sodium lauryl sulfate, and croscarmellose sodium were mixed, and the mixture was placed in ConsiGma (ConsiGma) ( Consigma-1 (available from GEA) in the feeder, while operating at a spiral speed of about 700rpm for a total of about 3 minutes to granulate the mixture, The resulting particles are then dried in a fluid bed dryer. The dried granules are then passed through a sieve with a mesh size of 20. The sieved granules and the rosuvastatin mixture part of the ingredient mixture in the quantities listed in Table 1 were mixed together, and then a rotary tablet press (MRC-45N, available from Sejong Pharmatech Co., Ltd. .) to compress the mixture into tablets with a hardness of 10kp.

Experimental Example 1: Evaluation of dissolution rate and productivity

The dissolution rate and productivity of the composite formulations of Examples 1 to 6 and Comparative Examples 1 to 12 were evaluated. The results are shown in Table 2.

Using the tablets of Examples 1 to 6 and Comparative Examples 1 to 12, the dissolution rate evaluation was performed under the conditions described below.

The productivity of each compound formulation is evaluated as the total number of tablets produced per hour, which is shown as the total weight (g)/a rotary tablet press (MRC-45N, available from Sejong Pharmatech Co., Ltd., can compress 45 tablets per revolution and produce 108,000 tablets per hour at 40 rpm. The average weight of tablets (g/tablet) is adjusted to be about 10 or Larger hardness but no pressing defects such as capping, adhesion, laminating or the like, at the maximum speed of a good tablet.

<Dissolution test conditions>

1) Dissolution method: According to the dissolution method II (paddle method) of the Korean Pharmacopoeia (10th Edition)

2) Dissolving medium: 0.45% sodium laurel sulfate solution in 0.025M sodium dihydrogen phosphate (NaH ₂ PO ₄ ‧ 2H ₂ O) buffer (pH 4.5) (by dissolving 3.9 g of sodium dihydrogen phosphate in 900 mL of water , Use 50% (w/w) sodium hydroxide solution or phosphoric acid to adjust the pH to 4.5, fill with water to a total volume of 1,000 mL, and then thoroughly mix the solution)

3) The amount of dissolving medium: 500mL

4) The temperature of the dissolving instrument: 37.5℃

5) Paddle speed: 50rpm

6) The number of test samples in each experimental group: 6

7) Sampling time: 10 minutes

In Comparative Examples 5, 6, and 12, the density of the particles increased with the increase in the amount of distilled water, so that excessively hard particles were obtained, which may cause mechanical overload and thus interrupt smooth production.

It is found that the dissolution rate and productivity of the composite formulations of Comparative Examples 1 to 4 prepared using a high-speed mixer are not satisfactory compared with the dissolution rate and productivity of the solid composite formulations prepared by any other method .

The composite formulations of Comparative Examples 7 to 11 prepared by using ConsiGma have improved dissolution rates compared with those of Comparative Examples 1 to 4. However, the dissolution rate did not significantly reach 85% or higher to ensure a high bioavailability. The solid composite formulation of Comparative Example 11 has high productivity, but the dissolution rate is too low.

The solid composite formulations of Examples 1 to 6 prepared using a fluid bed granulator have an improved dissolution rate compared to those prepared using any other method. In particular, it was found that the composite formulations of Examples 1 to 5 had a dissolution rate of about 85% or higher after 10 minutes. The solid composite formulations of Examples 1 to 6 have improved productivity due to good particle flowabiliity. In particular, the solid composite formulations of Examples 1 to 5 have a significantly higher rate of approximately 100,000 tablets per hour. productive forces.

Experimental Example 2: Content uniformity test

The content uniformity test was performed in the composite formulations of Examples 1 to 6 and Comparative Examples 1 to 12, according to the content uniformity test method in the general test method of the Korean Pharmacopoeia (10th edition). The resulting test values (a smaller value is desired; quality is usually guaranteed at 15 or less) is shown in Table 3.

Refer to Table 3. The amount of distilled water used is more or less than the appropriate level, and the content uniformity test value tends to increase because the diameter of the wet particles may become irregular. Example 1 prepared by using a fluid bed granulator For the solid composite formulations up to 6, the content uniformity test value is absolutely low, accompanied by a small difference from the change in the amount of distilled water. Therefore, it is found that the solid composite formulations of Examples 1 to 6 have improved content uniformity under any preparation conditions.

Experimental Example 3: Evaluation of saturated solubility and dissolution rate

The saturated solubility and dissolution rate of the solid composite formulations of Comparative Examples 1 to 7 and Example 1 (obtained using the same amount of distilled water) were evaluated as the bioavailability index of poorly soluble drugs. The results are shown in Table 4.

This evaluation is performed under the following conditions. The concentration of ezetimibe at each sampling time is expressed in ppm, and whenever the difference between a certain concentration and the concentration measured at the subsequent sampling time is 0.05 ppm or less, the concentration measured at that sampling time The concentration considered to be saturated. The sampling time for ezetimibe saturation is expressed in terms of dissolution rate (time), and the concentration of ezetimibe at the sampling time is expressed in saturated solubility (ppm).

<Test conditions>

1) Test method: According to the dissolution method II (paddle method) of the Korean Pharmacopoeia (10th Edition)

2) Dissolution medium: Sodium acetate-acetic acid buffer (pH 4.0) used in the general test method of the Korean Pharmacopoeia (10th Edition)

3) The amount of dissolving medium: 1000mL

4) The temperature of the dissolving instrument: 37.5℃

5) Paddle speed: 50rpm

6) The number of test samples in each experimental group: 6

7) Sampling time: 0 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 45 minutes

Referring to Table 4, it is found that compared with the solid composite formulations of Comparative Examples 1 to 7 prepared by using the same amount of distilled water as in Example 1 but with different wet granulation methods, the examples prepared by using a fluid bed granulator The solid composite formulation of 1 has an improved saturated solubility and a dissolution rate approximately 3 to 6 times higher, which is defined as the time to reach the saturated solubility. Therefore, due to the increased saturation solubility and dissolution rate of ezetimibe, the bioavailability of the solid composite formulation of Example 1 is also improved.

Examples 7 to 11

The composite formulation was prepared according to the composition listed in Table 5 below. Table 5 shows the ingredients and quantities used. Povidone was dissolved in distilled water to prepare a binder solution. Ezetimibe, lactose monohydrate, microcrystalline cellulose, sodium lauryl sulfate, and croscarmellose sodium are mixed, and the mixture is placed in a fluid bed granulator (GRETC- 30. The internal temperature of the container and fluid bed granulator available from GR-ENG is set as shown in Table 5. Then, at a spraying pressure of about 1.2 bar and a spraying speed of about 10 rpm, the binder solution is injected into the container through spraying, and the fluid bed is operated at the same time The granulator is used to granulate the mixture, and then the resulting granules are dried in a fluid bed dryer. The dried granules are then passed through a sieve with a mesh size of 20. The sieved particles and the rosuvastatin mixture part of the ingredient mixture as listed in Table 5 were mixed together, and then a rotary tablet press (MRC-45N, available from Sejong Pharmateeh Co., Ltd. .) to compress the mixture into tablets with a hardness of 10kp.

Experimental Example 4: Dissolution rate, productivity, and content uniformity test at different internal temperatures

In the same manner as in Experimental Examples 1 to 3, the solubility rate, productivity, and content uniformity tests of the solid composite formulations of Example 3 and Examples 7 to 11 were performed. The results are shown in Table 6.

According to the results in Table 6, it is found that the dissolution rate, productivity, and content uniformity test of all solid composite formulations of Example 3 and Examples 7 to 11 are improved, especially when the fluid bed granulator The internal temperature is in the range of about 20°C to about 40°C.

It should be understood that the exemplified specific examples described herein should be regarded as descriptive only, rather than limiting. The description of the features or aspects in each specific example should typically be regarded as available for other similar features or aspects of other specific examples. Although one or more specific examples of the present invention have been described with reference to the drawings, it should be understood that those skilled in the art can make various changes and changes to the present invention in various forms and details without departing from the scope defined by the following patent applications The spirit and scope of the invention.

Claims (12)

A method for preparing a solid composite formulation for oral administration, the method comprising: preparing ezetimibe containing ezetimibe by using a fluid-bed granulator (fluid-bed granulator) Granule part; and the ezetimibe wet granule part and rosuvastatin (rosuvastatin) mixture part is formulated together, the rosuvastatin mixture part contains rosuvastatin or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein based on the total weight of the wet granular part of ezetimibe, the wet granular part of ezetimibe uses 0.2 parts by weight to 1 part by weight of a solvent and is made from the fluid bed Granules are prepared. The method of claim 2, wherein the solvent is distilled water, ethanol, or any combination thereof. According to the method of claim 1, wherein based on the total weight of the wet granular part of ezetimibe, the wet granular part of ezetimibe uses 0.2 parts by weight to 1 part by weight of distilled water, prepared from the fluid bed Granules are prepared. The method of claim 1, wherein the ezetimibe wet granule part or the rosuvastatin mixture part further comprises at least one pharmaceutically acceptable additive selected from the group consisting of: diluent, adhesive Agent, disintegrant, and lubricant. The method of claim 5, 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, hydroxypropyl cellulose, copovidone ( copovidone), and any combination thereof, the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, starch glycolate Sodium (sodium starch glycolate), low-substituted hydroxypropyl cellulose, and any combination thereof, and the lubricant is selected from the group consisting of magnesium stearate, talc, light anhydrous silicic acid , Sodium stearyl fumarate, and any combination thereof. The method of claim 1, wherein the wet granular part of ezetimibe comprises lactose, microcrystalline cellulose, sodium laurel sulfate, povidone and croscarmellose sodium, and the mixture part of rosuvastatin Contains microcrystalline cellulose, lactose, mannitol, crospovidone and magnesium stearate. The method of claim 1, wherein the amount of ezetimibe is in the range of 5 mg to 20 mg in a unit dosage form. The method of claim 1, wherein the amount of rosuvastatin or a pharmaceutically acceptable salt thereof is in the range of 2.5 mg to 40 mg in a unit dosage form. The method of claim 1, wherein the composite formulation is in the form of pills, capsules, single-layer lozenges, double-layer lozenges, press-coated tablets, powder, or granules. Such as the method of claim 1, which should be based on the dissolution method in the Korean Pharmacopoeia II When measured with a buffer solution containing about 0.45% sodium lauryl sulfate and a pH of about 4.5 at a paddle speed of about 50 rpm, the dissolution rate of ezetimibe was about 85% or higher in about 10 minutes. The method of claim 1, wherein the preparation of the wet granular portion of ezetimibe is carried out when the internal temperature of the fluid bed granulator is 20°C to 40°C.