KR101977785B1 - Composite formulation for oral administration comprising ezetimibe and rosuvastatin and a process for the preparation thereof - Google Patents

Abstract

An aspect of the present invention provides a pharmaceutical composition comprising an ejtemhib wet granule comprising a wet granulation ejetimibe by a fluidized bed granulator; And
The present invention provides an oral combination preparation comprising a rosuvastatin mixed portion comprising rosuvastatin or a pharmaceutically acceptable salt thereof.

Description

TECHNICAL FIELD The present invention relates to a composition for oral administration comprising ezetimibe and rosuvastatin and a method for preparing the same,

The present invention relates to an oral combined preparation comprising ezetimibe and rosuvastatin or a pharmaceutically acceptable salt thereof and a preparation method thereof, and more particularly to a pharmaceutical composition for oral administration which comprises the active ingredient in terms of dissolution rate, dissolution rate, Productivity and the like, and a method for producing the same.

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 stability and is in commercial use with excellent sales.

In the case of rosuvastatin, the combination with ezetimibe has not yet been marketed, but the superiority of its pharmacological effect in combination with ezetimibe has been proved by many studies (Non-Patent Documents 1 and 2). Thus, there is a need for the development of combination formulations with good pharmaceutical properties for the combination of rosuvastatin and ezetimibe which have proven pharmacological effects as a combination.

1. Brandon Ason et al., J Lipid Res. Apr 2011; 52 (4): 679-687 2. Torimoto et al., Lipids in Health and Disease 2013, 12: 137

It is an object of the present invention to provide a pharmaceutical composition for oral administration of rosuvastatin and ezetimibe which is excellent in pharmaceutical properties such as dissolution rate, dissolution rate and content uniformity of active ingredient and can be produced economically with high productivity.

It is another object of the present invention to provide a process for the preparation of an oral combination preparation of rosuvastatin and ezetimibe.

One aspect of the present invention is

An ezetimibe wet granule comprising a wet granulated ezetimibe by a fluidized bed granulator; And

The present invention provides an oral combination preparation comprising a rosuvastatin mixed portion comprising rosuvastatin or a pharmaceutically acceptable salt thereof.

In another aspect of the present invention,

Preparing an ezetimibe wet granule containing ezetimibe by a fluidized bed granulator; And

Comprising the step of formulating a mixture of rosuvastatin comprising the above prepared ezetimibe wet granules and rosuvastatin or a pharmaceutically acceptable salt thereof.

The combined preparation comprising ezetimibe and rosuvastatin according to the present invention avoids the instability of the active ingredient due to the disintegration because it has a sufficiently good dissolution rate and dissolution rate of the active ingredient without containing excessive disintegrant At the same time, high bioavailability can be guaranteed. Further, the combination preparation according to the present invention is excellent in content uniformity. Moreover, the combined preparation according to the present invention can be produced with high productivity because it is well-formed and can be produced at a low internal product temperature of the fluidized bed granulator.

Hereinafter, the present invention will be described in more detail.

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.

The inventors of the present invention have made intensive studies on the development of a solid oral composition for oral administration, which can be produced economically by satisfactorily dissolving the active ingredient to ensure superior efficacy and productivity. As a result, it has been found that when ezetimibe is used as a separate wet granule and rosuvastatin or a pharmaceutically acceptable salt thereof is mixed with the above-mentioned ezetimibe wet granules, It has been found that a pharmaceutical preparation having a high productivity as well as excellent pharmaceutical properties such as an active ingredient dissolution rate, a dissolution rate, and a uniformity of content is obtained.

Accordingly, one aspect of the present invention is

An ejetimibe wet granule comprising a wet granulation ejetimibe by a fluidized bed granulator; And

The present invention provides an oral combination preparation comprising a rosuvastatin mixed portion comprising rosuvastatin or a pharmaceutically acceptable salt thereof.

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.

Since the wet granulation part of the ezetimibe has a sufficiently high ezetimibe dissolution rate in production using a fluidized bed granulator and has good flowability upon granulation, it has high productivity in tableting. Therefore, the combination preparation of the present invention has excellent bioavailability and productivity . On the other hand, when the wet granulation part of the ezetimibe is produced according to any other wet granulation method used in the field of pharmacy, neither high dissolution rate nor productivity can be secured (see Test Example 1).

Specifically, when preparing the wet granules of ezetimibe with a high-speed mixer which is most widely used in the related art in the production of wet granules because of short operation time and simple processes, As a result of the dissolution test according to the second method, it was found that the dissolution rate after 10 minutes had a very low dissolution rate of less than about 50% and the dissolution rate increased as the amount of the solvent used in the preparation was decreased , And the elution rate of the ezetimibe was less than about 60% after 10 minutes and the productivity tended to decrease as the amount of the solvent decreased. In addition, even when a high-tech mechanical process Consigma was used for the production of wet granules, the dissolution rate was increased as the amount of the solvent used in the preparation was decreased. However, the dissolution rate of the dissolution test was still less than about 70% And the productivity decreased as the amount of solvent decreased. Thus, in order to solve the problem of low dissolution rate when producing wet granules by a method such as a high-speed mixer and Consigma, it is necessary to increase the amount of disintegration upon assembly, but since the disintegrant may affect the stability of the active ingredient, Excessive use of release can severely affect the quality of the medicines.

On the other hand, when the ejetimibe wet granules were prepared using the fluidized bed granulator, the dissolution rate tended to decrease as the amount of the solvent of the binding solution used in the preparation increased. However, when the solvent was added to the wet granulation part The dissolution rate of the ezetimibe was found to be sufficiently high at about 80% or more after 10 minutes even when the amount was more than about 1 part by weight, and even when the amount of the solvent was reduced, Productivity (Test Example 1). If the amount of solvent is generally greater than about 0.5 part by weight per 1 part by weight of the total wet granulation in a wet granulation process involving the use of a solvent, the granules become hard, the density becomes high, and the initial dissolution rate is lowered. However, in the present invention, the use of more than 0.5 part by weight of the solvent does not cause any problem in the dissolution rate, and the flowability of the granules is improved, so that the productivity in the tabletting process is increased. Therefore, when the wet granulation part of the ezetimibe is produced by the fluidized bed granulator as in the present invention, a high dissolution rate and productivity can be secured without using an excessive amount of the disintegrant, and a medicine of excellent quality can be obtained . This is an epoch-making effect that is unpredictable in the related art in view of the conventional technology in which the wet granule by the fluidized bed granulator is generally less fluid than the wet granule by the high-speed mixer and is low in the productivity during the tabletting process.

The solvent refers to any solvent used in the preparation of the binding solution by dissolving the binder in the preparation of the wet granules, including, but not limited to, purified water, ethanol, or any combination thereof.

In addition, the combined preparation according to the present invention exhibited remarkably excellent content uniformity (see Test Example 2), as compared with the combined preparation containing wet granules by a different granulation method other than the fluidized bed granulator. Also, in general, the wet granulation by the fluidized bed granulator is an epoch-making effect unpredictable in the related art in view of the prior art which was known to have lower content uniformity than wet granulation by a high-speed mixer.

In addition, the combined preparation according to the present invention can attain saturation solubility at a significantly faster rate than the combined preparation containing wet granules by a different granulation method other than the fluidized bed granulator. Ezetimibe is an insoluble drug that exhibits low saturation solubility of about 1 ppm in both acidic to weakly basic conditions. The saturation solubility and the rate of dissolution from the start of dissolution to saturation are important indicators of the bioavailability of poorly soluble drugs. As a result of the test, the combined preparation according to the present invention can reach saturation solubility at a significantly faster rate than the combined preparation containing wet granules by a different granulation method other than the fluidized bed granulator, (See Test Example 3). ≪ tb > < TABLE >

In the combined preparation according to the present invention, the wet granulation part may be prepared by a fluidized bed granulator using 0.1 to 2 parts by weight of solvent per 1 part by weight of the total wet granulation raw material, preferably 0.2 to 1 Parts by weight of a solvent may be used. As used herein, the term " wet granulation part raw material " includes both the active ingredient and any additives used in the production of the wet granular part, excluding solvents.

If the content of the solvent is less than the above range, it is difficult to form sufficient wet granules and the productivity may be lowered. If the content of the solvent is too large, the granulation process takes a long time and the production time of the whole production process is increased It is inefficient.

In one embodiment of the invention, the wet granulation part comprises 0.1 to 2 parts by weight, more particularly 0.2 to 1 part by weight of purified water per 1 part by weight of the total wet granulation part raw material.

The first pharmacologically active ingredient, ezetimibe, in the combination preparation of the present invention may be used in an amount of about 5 mg to 20 mg, preferably about 5 mg to 10 mg, based on the unit dosage form of the combination preparation of the present invention have.

The combined preparation of the present invention comprises rosuvastatin as a second pharmacologically active ingredient, and rosuvastatin may be in the form of a free base or a pharmaceutically acceptable salt thereof. Examples of the pharmaceutically acceptable salts include calcium salts, magnesium salts, and strontium salts, and preferably rosuvastatin calcium salts, but are 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 from 2.5 mg to 40 mg, specifically from 5 mg to 20 mg, based on the unit dosage form of the combination preparation of the present invention.

The combined preparation of the present invention may further comprise at least one pharmaceutically acceptable additive necessary for formulation in addition to the above-mentioned pharmacologically active ingredient. Specifically, the mixture of the ezetimibe wet granules or the rosuvastatin may contain one or more pharmaceutically acceptable additives selected from the group consisting of excipients, binders, disintegrants, and glidants.

According to an embodiment of the present invention, the mixture of the ezetimibe granules and the rosuvastatin may contain 0.5 to 50 parts by weight of an excipient, 0.1 to 20 parts by weight of a binder, 0.1 to 20 parts by weight of a disintegrant, And 0.1 to 3 parts by weight of a lubricant.

The kind and content of such an additive can be appropriately selected according to the type of the specific formulation to be prepared by a person having ordinary skill in the art. For example, the excipient is selected from the group consisting of lactose, starch, mannitol, microcrystalline cellulose, carboxymethylcellulose, and combinations thereof, wherein the binder is selected from the group consisting of povidone, hypromellose, hydroxypropylcellulose, Wherein the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropylcellulose, and combinations thereof, wherein the lubricant is selected from the group consisting of But are not limited to, magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof.

The oral combination preparation of the present invention may be formulated into oral preparations such as, for example, pellets, capsules, tablets (including single-layer, double-layer, and inner-wall preparations), powders and granules, but is not limited thereto . More specifically, the oral combination preparation may be in the form of a capsule, monolayer or bilayer. When the complex preparation of the present invention is a capsule, the capsule may be in the form of powders, granules, tablets, syrups, pellets and the like.

According to an embodiment of the present invention, the ezetimibe granules include lactose, microcrystalline cellulose, sodium laurylsulfate, povidone, and croscarmellose sodium, and the rosuvastatin mixed portion includes microcrystalline cellulose, lactose, mannitol, Povidone, and magnesium stearate.

According to one embodiment of the present invention, the combination preparation of the present invention is prepared by dissolving pharmacopoeia in a pH of about 4.5 buffer containing about 0.45% sodium lauryl sulfate according to Method 2 at a paddle rotation rate of about 50 rpm , And elution rate of ezetimibe of about 85% or more at 10 minutes. Therefore, the combined preparation of the present invention can be expected to have a high bioavailability from securing a high dissolution rate (see Test Example 1).

In another aspect of the present invention,

Preparing an ezetimibe wet granule containing ezetimibe by a fluidized bed granulator; And

The present invention provides a method for producing an oral combination preparation comprising the step of formulating a mixture of the above-prepared ezetimibe wet granules and a rosuvastatin mixed portion comprising rosuvastatin or a pharmaceutically acceptable salt thereof.

The above description of the preparation method may be applied to the description of the combination preparation for oral administration according to one aspect of the present invention.

The production of the ezetimibe wet granules by the fluidized bed granulator can be carried out at an internal product temperature of the fluidized bed granulator of from 20 to 40 캜.

As used herein, the term " internal product temperature of the fluidized bed granulator " refers to the temperature at which the operation of the device is sufficiently stabilized and maintained at a constant temperature when the electronic thermometer is mounted on the container in the fluidized bed granulator.

When granules are produced by keeping the internal product temperature of the fluidized bed granulator at a low temperature of 30 ° C or lower, the particle size and density generally increase, and the initial active ingredient dissolution rate tends to decrease. However, according to the present invention, even when the internal product temperature of the fluidized bed granulator is set to a low temperature of 20 to 30 ° C to produce an agitated granule portion, the composite product having a sufficiently high dissolution rate is produced can do. Therefore, according to the present invention, it is possible to manufacture the wet granulation part by setting the internal temperature of the fluidized bed granulator to a low temperature of 20 - 30 ° C, thereby providing a faster fluid delivery amount to the fluidized bed granulator, , The productivity of the combined preparation can be increased.

One embodiment of the production process of the present invention comprises the steps of (i) preparing an ezetimibe wet granule part comprising ezetimibe by a fluidized bed granulator, (ii) incorporating suubistatin or a pharmaceutically acceptable salt thereof And (iii) mixing the wet granulation part prepared in step (i) and the mixing part prepared in step (ii), and then adding a single-layered tablet according to a conventional method for producing a tablet, And the like.

Another embodiment of the production method of the present invention comprises the steps of (i) preparing an ezetimibe wet granule part containing ezetimibe by a fluidized bed granulator, tableting it by tableting, (ii) (Iii) using the two-layer tablet machine to make the tablets prepared in step (i) as one layer, and mixing the mixture prepared in step (ii) And a step of preparing a two-layer tablet according to a conventional method for producing a tablet.

Another embodiment of the manufacturing method of the present invention includes the steps of (i) preparing an ezetimibe wet granule part containing ezetimibe by a fluidized bed granulator, (ii) preparing a wet granule part produced in step (i) (Ii) adding a mixture containing rosuvastatin or a pharmaceutically acceptable salt thereof to the mixture to prepare a mixture; and (iii) filling the capsule with the mixture according to a conventional method for preparing a capsule, .

[Example]

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

Comparative Example  1 to 6: To a high speed mixer  ≪ / RTI >

According to the ingredients and the contents shown in Table 1 below, povidone was dissolved in purified water separately, and ezetimibe, lactose hydrate, microcrystalline cellulose, sodium lauryl sulfate and croscarmellose sodium were mixed to prepare a high speed mixer P / VAC60, Diosna), and the machine was operated at a speed of 100 rpm of an agitator and 3000 rpm of a chopper, and the binding solution was injected. The granules were dried in a fluid bed dryer after being assembled under the above conditions for a total of 3 minutes. The dried granules were sieved through a No. 20 sieve and sieved. The components of this sizing composition and the components of the rosuvastatin mixed portion shown in Table 1 were mixed according to the indicated contents, and the mixture was kneaded with a rotary tablet machine (MRC-45N, Sejong Pharmatech) at a hardness of 10 kp.

Example  1 to 6: Manufacture of composite preparation by fluidized bed granulator

According to the ingredients and contents shown in Table 1 below, povidone was dissolved in purified water separately and a mixture of ezetimibe, lactose hydrate, microcrystalline cellulose, sodium laurylsulfate and croscarmellose sodium was mixed and fed into a fluidized bed granulator (GRETC- 30, GR-ENG), the machine was operated at an internal temperature of 30 ° C and a spray pressure of 1.2 bar, and sprayed at a speed of 10 rpm to inject the bonding solution. The granules were dried in a fluidized bed drier after being assembled under the above conditions for a period of time during which all the bonding liquid was injected. The dried granules were sieved through a No. 20 sieve and sieved. The ingredients of this sizing composition and the components of the rosuvastatin mixed portion shown in Table 1 were mixed according to the indicated contents, and the resulting mixture was tableted with a rotary tabletting machine to a hardness of 10 kp (MRC-45N, Sejong Pharmatech).

Comparative Example  7 to 12: Consigma ≪ / RTI >

According to the ingredients and contents shown in Table 1 below, povidone was dissolved in purified water separately, and ezetimibe, lactose hydrate, microcrystalline cellulose, sodium lauryl sulfate and croscarmellose sodium were mixed to prepare Consigma-1 , GEA), the machine was operated at a screw speed of 700 rpm, and a bonding liquid was injected. The granules were dried in a fluid bed dryer after being assembled under the above conditions for a total of 3 minutes. The dried granules were sieved through a No. 20 sieve and sieved. The lipid mixture and the rosuvastatin mixed portion shown in Table 1 were mixed according to the indicated contents, and the resulting mixture was compressed into 10 kp hardness with a rotary tablet machine (MRC-45N, Sejong Pharmatech).

Manufacture of compound preparation Wet granule
Manufacturing method Refining
(mg) Ezetimibe wet granulation part
Type and amount of additive (mg) After mixing with rosuvastatin,
Type and amount of additive (mg) Comparative Example 1
Hi
Speed mixer 15




Ezetimibe 10
Lactose Luggage 30
Microcrystalline cellulose 94
Sodium lauryl sulfate 2
Povidone 4
Croscarmellose sodium 10





Rosuvastatin 20
Microcrystalline cellulose 50
Lactose baggage 100
Mannitol 100
Crospovidone 3
Magnesium stearate 4 Comparative Example 2 30 Comparative Example 3 70 Comparative Example 4 100 Comparative Example 5 150 Comparative Example 6 200 Example 1
Fluidized bed
Assembly machine 15 Example 2 30 Example 3 70 Example 4 100 Example 5 150 Example 6 200 Comparative Example 7
Consigma 15 Comparative Example 8 30 Comparative Example 9 70 Comparative Example 10 100 Comparative Example 11 150 Comparative Example 12 200

Test Example  One: Dissolution rate  And productivity evaluation

The dissolution rate and productivity of the combination preparations prepared in Examples 1 to 6 and Comparative Examples 1 to 12 were evaluated, and the results are shown in Table 2 below.

The tablets prepared in Examples 1 to 6 and Comparative Examples 1 to 12 were evaluated for dissolution rate according to the following <dissolution test conditions>.

The productivity evaluation is usually carried out by adjusting the rotation speed of the tablet machine (MRC-45N, Sejong Pharmatech, 45 tablets per rotation, at a rotation speed of 40 rpm and 108,000 tablets per hour) used in the related art to perform capping, sticking, laminating The number of tablets produced per hour when the tablets were manipulated at the maximum speed capable of taking excellent tablets having a hardness of about 10 or more without ischemic injury was expressed by the gross weight (g) / average mass (g / tablet).

&Lt; Dissolution test conditions >

1) Dissolution method: Dissolution method 2 of Korea 10 pharmacopoeia (paddle method)

2) Eluent: A solution of 0.45% sodium lauryl sulfate (0.09M sodium dihydrogenphosphate (NaH2PO4.2H2O) buffer solution (pH 4.5) (dissolving 3.9g of sodium dihydrogenphosphate in 900 mL of water, Adjusted to pH 4.5 with sodium hydroxide solution or phosphoric acid, and then added with water to make the total volume to 1000 mL, followed by thorough mixing and mixing)

3) Amount of eluate: 500 mL

4) Elution temperature: 37.5 DEG C

5) Paddle speed: 50 rpm

6) Test number: 6

7) Sample collection time: 10 minutes

10 minutes Dissolution rate (%) Hourly output Average Standard Deviation Comparative Example 1 59.1 7.1 51,458.7 Comparative Example 2 52.7 6.6 66,157.6 Comparative Example 3 45.4 10.9 75,815.3 Comparative Example 4 25.1 9.8 99,542.5 Comparative Example 5 No production Comparative Example 6 No production Example 1 90.1 2.2 119,571.3 Example 2 88.9 1.7 112,414.7 Example 3 89.1 3.1 108.998.6 Example 4 90.2 1.6 105,621.4 Example 5 87.8 1.1 100,527.8 Example 6 83.5 5.4 91,711.7 Comparative Example 7 66.9 9.7 71,421.4 Comparative Example 8 62.5 5.4 79,994.5 Comparative Example 9 50.9 6.7 84,457.8 Comparative Example 10 43.7 12.5 90,515.5 Comparative Example 11 21.8 13.7 108,456.9 Comparative Example 12 No production

In the case of Comparative Examples 5 and 6 and Comparative Example 12, as the amount of purified water was increased, the density of the granules was increased and excessively hard granules were produced. As a result, mechanical overload was caused and production was not smooth.

In Comparative Examples 1 to 4 using a high-speed mixer, no sufficient dissolution rate was observed under any conditions, and productivity was significantly lower than in other production methods.

Comparative Examples 7 to 11 using Consigma showed improved dissolution rates compared to Comparative Examples 1 to 4, but not significantly over 85% of dissolution that could guarantee good bioavailability, and productivity was excellent in Comparative Example 11 The dissolution rate was excessively lowered.

On the other hand, Examples 1 to 6 using a fluidized bed granulator showed excellent dissolution rates compared with other production methods, and Examples 1 to 5 showed excellent elution by elution of 85% or more in 10 minutes. In addition, Examples 1 to 6 showed excellent productivity in terms of flowability of granules, and all of Examples 1 to 5 were found to have remarkably high productivity of over 100,000 tablets per hour.

Test Example  2: Content uniformity test

The content uniformity test was carried out on the combination preparations prepared in Examples 1 to 6 and Comparative Examples 1 to 12 according to the content uniformity term in the General Test Methods of the Korean Pharmacopoeia. The result is shown in Table 3 below (the smaller the value is, the better the product quality can be guaranteed, generally below 15).

Content uniformity test
Judgment Comparative Example 1 21.5 Comparative Example 2 16.6 Comparative Example 3 10.5 Comparative Example 4 12.2 Comparative Example 5 No production Comparative Example 6 No production Example 1 6.2 Example 2 6.0 Example 3 5.9 Example 4 5.8 Example 5 5.9 Example 6 5.7 Comparative Example 7 14.7 Comparative Example 8 11.3 Comparative Example 9 9.1 Comparative Example 10 8.8 Comparative Example 11 13.4 Comparative Example 12 No production

As can be seen from the results in Table 3, when the amount of the purified water used in the preparation of the wet granules is more or less than the proper amount, the particle size of the granules becomes irregular and the judgment of the content uniformity test increases. However, in Examples 1 to 6 prepared using a fluidized bed granulator, the absolute determination of the content uniformity test was not only low, but also showed a small variation in the judgment value according to the change in the amount of purified water. Therefore, the combination preparation according to the present invention was found to be excellent in content uniformity under any condition.

Test Example  3: Evaluation of saturation solubility and dissolution rate

The saturation solubility and dissolution rate, which are important indexes in evaluating the bioavailability of poorly water-soluble drugs, were evaluated for the combination preparations of Comparative Examples 1 and 7 and Example 1 (all using the same purified water), and the results are shown in Table 4 .

The evaluation was carried out using an elution machine according to the following <Test Conditions>. The concentration of ezetimibe detected in each sampling time was expressed in ppm, and it was assumed that the difference in concentration from the next sampling time was saturated at the sampling time of 0.05 ppm or less, and the corresponding time was set as the dissolution rate (time) Was expressed in terms of saturation solubility (ppm).

<Test Conditions>

1) Test method: Dissolution method 2 of the 10th Korean Pharmacopoeia (paddle method)

2) Test solution: 10 kcal of Korean Pharmacopoeia [Attached Table 5], Acetic acid in General Test Method, Sodium Acetate Buffer pH 4.0

3) Amount of eluate: 1000 mL

4) Elution temperature: 37.5 DEG C

5) Paddle speed: 50 rpm

6) Test number: 6

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

Saturated solubility (ppm) Dissolution rate (hours) Comparative Example 1 0.998 30 minutes Example 1 1.102 5 minutes Comparative Example 8 1.054 15 minutes

As shown in Table 4, in Example 1 using the fluidized bed granulator, the saturation solubility was higher than that of Comparative Examples 1 and 8 in which the wet granule was produced in the same amount of purified water and the time required for reaching the saturation solubility The dissolution rate is also about 3 to 6 times faster. Therefore, the combined preparation according to the present invention can obtain a significantly better bioavailability by increasing the saturation solubility and dissolution rate of ezetimibe.

Example  7 to 11

According to the ingredients and contents shown in Table 5 below, povidone was dissolved in purified water separately and a mixture of ezetimibe, lactose hydrate, microcrystalline cellulose, sodium lauryl sulfate, and croscarmellose sodium was mixed and fed into a fluidized bed granulator (GRETC- 30, GR-ENG), and the internal product temperature was set according to Table 5 below. The machine was operated at a spray pressure of 1.2 bar and the spray was sprayed at a speed of 10 rpm to inject the bonding solution. The granules were dried in a fluidized bed drier after being assembled under the above conditions for a period of time during which all the bonding liquid was injected. The dried granules were sieved through a No. 20 sieve and sieved. The components of this sizing composition and the components of the rosuvastatin mixed portion shown in Table 5 were mixed according to the indicated contents, and the resulting mixture was tableted with a rotary tabletting machine to a hardness of 10 kp (MRC-45N, Sejong Pharmatech).

Manufacture of wet granules by internal temperature of fluidized bed granulator Wet granule manufacturing method Refining (mg) *product
Temperature
(° C) Ezetimibe wet granulation part
Type and amount of additive (mg) After mixing with rosuvastatin,
Type and amount of additive (mg) Example 7

Fluidized bed

70
15 Ezetimibe 10
Lactose baggage 32
Microcrystalline cellulose 92
Sodium lauryl sulfate 2
Povidone 4
Croscarmellose sodium 10 Rosuvastatin 20
Microcrystalline cellulose 50
Lactose baggage 100
Mannitol 100
Crospovidone 3
Magnesium stearate 4 Example 8 20 Example 9 25 Example 10 40 Example 11 50

* Product temperature - The temperature when the machine is stable enough to maintain a constant temperature when the electronic thermometer is mounted on the container inside the fluidized bed granulator.

Test Example  4: By product temperature Dissolution rate , Productivity, and content uniformity test

The dissolution rate, productivity and content uniformity test were carried out in the same manner as in Test Example 1-3 with respect to Example 3 and Example 7-11, and the results are shown in Table 6 below.

Manufacture of wet granules by internal temperature of fluidized bed granulator Product temperature
(° C) 10 minutes Dissolution rate (%) Hourly output Formulation uniformity test
Judgment Average Standard Deviation Example 7 15 75.5 4.4 111.317.3 16.9 Example 8 20 86.7 2.2 108,664.5 7.2 Example 9 25 88.4 1.6 109.412.9 6.6 Example 3 30 89.1 3.1 108.998.6 5.9 Example 10 40 89.5 2.6 100,158.4 6.2 Example 11 50 No refining available

The above test results show excellent ezetimibe dissolution rate, productivity, and content uniformity throughout all the tested examples, but are particularly excellent when the internal product temperature of the fluidized bed granulator is from about 20 to 40 ° C It was confirmed that a combination product having dissolution rate of ezetimibe, productivity, and content uniformity was obtained.

Claims (13)

Preparing an ezetimibe wet granule containing ezetimibe by a fluidized bed granulator; And
Comprising the step of formulating a rosuvastatin mixed portion comprising the prepared ezetimibe wet granules and rosuvastatin or a pharmaceutically acceptable salt thereof, wherein the ezetimibe wetting agent Wherein the granules are manufactured at an internal product temperature of the fluidized-bed granulator at 20-40 DEG C. 2. The method of claim 1, wherein the wet granulation is produced by a fluidized bed granulator using 0.2 to 1 part by weight of solvent per 1 part by weight of the total wet granulation total raw material. 3. The method according to claim 2, wherein the solvent is purified water, ethanol, or a combination thereof. The method according to claim 1, wherein the wet granulation part is manufactured by a fluidized bed granulator using 0.2 to 1 part by weight of purified water per 1 part by weight of the total wet granulation part raw material. The oral composition of claim 1, wherein the mixture of ezetimibe wet granules or rosuvastatin further comprises at least one pharmaceutically acceptable additive selected from the group consisting of excipients, binders, disintegrants, and glidants. &Lt; / RTI &gt; 6. The method of claim 5,
The excipient is selected from the group consisting of lactose, starch, mannitol, microcrystalline cellulose, carboxymethylcellulose, and combinations thereof,
Wherein the binder is selected from the group consisting of povidone, hypromellose, hydroxypropylcellulose, copovidone, and combinations thereof,
Wherein the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropylcellulose, and combinations thereof,
Wherein the lubricant is selected from the group consisting of magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof. 3. The composition of claim 1, wherein the ezetimibe wet granulation comprises lactose, microcrystalline cellulose, sodium lauryl sulfate, povidone, and croscarmellose sodium, wherein the rosuvastatin mix comprises microcrystalline cellulose, lactose, mannitol, And magnesium stearate. 2. The method according to claim 1, wherein the ezetimibe is contained in an amount of 5 mg to 20 mg per unit dosage form. 2. The method 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 method according to claim 1, wherein the complex agent is in the form of a pellet, a capsule, a monolayer, a bilayer, an inner core, a powder or a granule. The pharmaceutical composition according to claim 1, wherein the combination preparation is eluted with a pH 4.5 buffer solution containing 0.45% sodium laurylsulfate according to Method 2 of the Pharmacopoeia in the elution test at a paddle rotation speed of 50 rpm. Wherein the dissolution rate of the oral composition is in the range of 1: 1 to 5: 1. delete delete