PHARMACEUTICAL COMBINATION PREPARATION COMPRISING EZETIMIBE AND LOSARTAN

Abstract

The present invention relates to a pharmaceutical combination preparation comprising ezetimibe and losartan. When the pharmaceutical combination preparation is dissolved in a solution of pH 4.0 to 5.0 for 10 minutes, the amount of losartan dissolved is 5,700 µg or less, and the amount of ezetimibe dissolved is 270 µg or more. Dissolution in a solution of pH 4.0 to 5.0 is carried out under conditions of a temperature of 37°C and a paddle method of 50 rpm in 500 mL of acetate pH regulator in accordance with the United States Pharmacopeia for the preparation of a pharmaceutical combination comprising 20 mg of ezetimibe and 183 mg of losartan.

Description

PHARMACEUTICAL COMBINATION PREPARATION COMPRISING EZETIMIBE AND LOSARTAN Technical field The present invention relates to a pharmaceutical combination preparation comprising ezetimibe and losartan. More specifically, the present invention relates to a pharmaceutical combination preparation comprising ezetimibe and losartan, wherein the dissolution between each drug is minimally affected. This application claims the benefit of priority based on Korean Patent Application No. 102019-0045295 filed on April 18, 2019, all of the contents of which are incorporated herein by reference. Background of the invention Losartan is the generic name for 2-butyl-4-chloro-1[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-methanol and is described in U.S. Patents Nos. 5,608,075, 5,138,069, 5,153,197 and similar patents, and in particular, losartan calcium is currently available commercially under the trade name Cozaar®. Losartan is used to treat hypertension and heart failure, to treat ischemic peripheral circulatory disorder and myocardial ischemia (angina pectoris), and to prevent the progression of QQC7 Ln / Lznz / E / YILI heart failure after a myocardial infarction and to treat diabetic neuropathy, glaucoma and the like, by blocking the binding of angiotensin II, which is a vasoconstrictor substance, to its receptor. Ezetimibe is an azetidinone derivative, chemically known as 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. It is used as a cholesterol reabsorption inhibitor in the treatment and prevention of arteriosclerosis and is also used in combination with a statin to inhibit cholesterol synthesis in the liver. Ezetimibe is practically insoluble in water, resulting in low solubility in aqueous media such as gastric juice and, consequently, low bioavailability after oral administration. To effectively treat cardiovascular diseases, combination preparations using different mechanisms such as losartan and ezetimibe are increasingly required in the clinical field, but the dissolution rate and stability are likely to decrease due to the interaction between the drugs and the difficulty of development is high, so they are not marketed. To prepare an effective combination formulation, high bioavailability of the active ingredients must be ensured. The dissolution pattern of the active ingredients in solid oral preparations is closely related to the bioavailability of the formulation, and high bioavailability implies a high dissolution rate. In general, the smaller the particle size of the granules that make up the tablet, the better the dissolution rate tends to be. However, the smaller the particle size of the granules, the lower the granule flowability and, therefore, the lower the angle of repose. If the granule flowability is low, productivity decreases during the manufacture of tablets and capsules. Therefore, in the technical field, there is a need to develop a combination preparation that has excellent pharmaceutical properties even in a combination preparation comprising losartan and ezetimibe, and ongoing research is being conducted in this regard. Description Technical problem The inventors hereof seek to experimentally confirm the dissolution correlation of each drug in a pharmaceutical combination preparation comprising ezetimibe and losartan as active ingredients, and provide a pharmaceutical combination preparation in which the dissolution between each drug is minimally affected in the pharmaceutical combination preparation comprising ezetimibe and losartan, thus providing a pharmaceutical combination preparation that has a similar pharmacokinetic parameter compared to a single ezetimibe preparation. Technical solution According to a first aspect of the present invention, the present invention provides a pharmaceutical combination preparation comprising ezetimibe or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof, wherein when the pharmaceutical combination preparation is dissolved in a solution of pH 4.0 to 5.0 for 10 minutes, the dissolved amount of losartan is 5,700 pg or less, and the dissolved amount of ezetimibe is 270 pg or more. In one embodiment of the present invention, dissolution in a pH 4.0 to 5.0 solution is carried out under the conditions of a temperature of 37°C and a paddle method of 50 rpm in 500 mL of acetate pH regulator in accordance with the United States Pharmacopeia for the preparation of a pharmaceutical combination comprising 20 mg of ezetimibe and 183 mg of losartan. In one embodiment of the present invention, when the pharmaceutical combination preparation is dissolved in a pH 4.0 to 5.0 solution for 10 minutes, the dissolved amount of losartan is 5,200 pg or less, and the dissolved amount of ezetimibe is 300 pg or more. In one embodiment of the present invention, ezetimibe or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof are physically separated from each other. In one embodiment of the present invention, ezetimibe or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof are each present in granular form. In one embodiment of the present invention, the granule comprising ezetimibe or a pharmaceutically acceptable salt thereof has a content of 15% by weight or less of granule having a diameter of more than 250 pm. In one embodiment of the present invention, the granule comprising losartan or a pharmaceutically acceptable salt thereof has a content of 35 to 55% by weight of granule with a diameter greater than 250 µm and a content of 10 to 30% by weight of granule having a diameter greater than 500 µm. In one embodiment of the present invention, the pharmaceutical combination preparation includes 5 to 10 mg of ezetimibe or a pharmaceutically acceptable salt thereof converted into ezetimibe free acid form, and includes 40 to 100 mg of losartan or a pharmaceutically acceptable salt thereof converted into losartan free acid form. In one embodiment of the present invention, the granule comprising ezetimibe or a pharmaceutically acceptable salt thereof further comprises a solubilizing agent. In one embodiment of the present invention, the solubilizing agent is sodium lauryl sulfate. In one embodiment of the present invention, the solubilizing agent is included in the granule comprising ezetimibe or a pharmaceutically acceptable salt thereof, in an amount of 5 to 50 parts by weight, based on 100 parts by weight of ezetimibe. In one embodiment of the present invention, the granule comprising losartan or a pharmaceutically acceptable salt thereof further comprises 1 to 30 parts by weight of disintegrant, based on 100 parts by weight of losartan. In one embodiment of the present invention, the pharmaceutical combination preparation is present in the form of a bilayer tablet comprising: a first layer comprising ezetimibe or a pharmaceutically acceptable salt thereof; and a second layer comprising losartan or a pharmaceutically acceptable salt thereof. According to a second aspect of the present invention, the present invention provides a pharmaceutical combination preparation having the form of a bilayer tablet comprising: a first layer comprising ezetimibe or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof; and a second layer comprising losartan or a pharmaceutically acceptable salt thereof, wherein when the pharmaceutical combination preparation is dissolved in a solution of pH 4.0 to 5.0 for 10 minutes, the dissolved amount of losartan is 5,700 pg or less, and the dissolved amount of ezetimibe is 270 pg or more. In one embodiment of the present invention, ezetimibe or a pharmaceutically acceptable salt thereof is included in granular form in the first layer, and losartan or a pharmaceutically acceptable salt thereof is included in granular form in the second layer. Advantageous effects The present invention provides a pharmaceutical combination preparation comprising ezetimibe and losartan, wherein the ezetimibe or a pharmaceutically acceptable salt thereof is present in a physically separate state from the losartan or a pharmaceutically acceptable salt thereof, and the dissolution rate of the losartan is controlled, so as to provide a pharmaceutical combination preparation in which the dissolution between each drug is minimally affected and being able to provide a pharmaceutical combination preparation that ensures the QQC7 Ln / Lznz / Ε / ΥΙΛΙ biological equivalence. Furthermore, if a pharmaceutical combination preparation comprising amlodipine and rosuvastatin in addition to ezetimibe and losartan is provided, the ezetimibe is physically separated from amlodipine, losartan, and rosuvastatin, respectively, and the dissolution rate of losartan is controlled, thereby ensuring the biological equivalence of the pharmaceutical combination preparation. Description of the drawings Figure 1 is a graph showing the results of dissolving ezetimibe by pH (pH 1.2, 4.5 and 6.8) in the tablet according to Example 1. Figure 2 is a graph showing the results of dissolving ezetimibe at pH 4.5 in tablets according to Example 1 and Comparative Example 1 and capsules according to Example 3 and Comparative Example 2. Figure 3 is a graph showing the results of dissolving losartan at pH 4.5 in tablets according to Example 1 and Comparative Example 1 and capsules according to Example 3 and Comparative Example 2. Figure 4 is a graph showing the results of dissolved ezetimibe at pH 4.5 in tablets according to Examples 1 and 2 and tablets according to Comparative Examples 3 and 4. Figure 5 is a graph showing the results of dissolving losartan at pH 4.5 in tablets according to Examples 1 and 2 and tablets according to Comparative Examples 3 and 4. Figure 6 is a graph showing the results of dissolving ezetimibe at pH 4.5 in tablets according to Examples 1 and 4. Figure 7 is a graph showing the results of dissolving losartan at pH 4.5 in tablets according to Examples 1 and 4. Figure 8 is a graph showing the plasma concentration pattern of ezetimibe in tablets according to Example 1 and Comparative Examples 1 and 3. Best way The embodiments provided in accordance with the present invention can be achieved by the following description. It should be understood that the following description describes preferred embodiments of the present invention and the present invention is not necessarily limited to them. The present invention provides a pharmaceutical combination preparation comprising ezetimibe or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof. The pharmaceutical combination preparation according to the present invention comprises ezetimibe or a pharmaceutically acceptable salt thereof as the first active ingredient. Ezetimibe is primarily used to inhibit cholesterol absorption for the treatment and prevention of arteriosclerosis. The daily dose of ezetimibe or a pharmaceutically acceptable salt thereof is 5 mg to 15 mg. In one embodiment of the present invention, the pharmaceutical combination preparation includes 5 to 10 mg of ezetimibe or a pharmaceutically acceptable salt thereof converted into the free acid form of ezetimibe. The free acid form of the active ingredient means the active ingredient itself without any other compounds, such as a base, attached to it. The pharmaceutical combination preparation according to the present invention may comprise losartan or a pharmaceutically acceptable salt thereof as the second active ingredient. Examples of a pharmaceutically acceptable salt of losartan include, but are not necessarily limited to, losartan potassium salt. Losartan contributes to blocking the binding of angiotensin II, a vasoconstrictor, to its receptor to treat hypertension and heart failure, to treat ischemic peripheral circulatory disorder and myocardial ischemia (angina pectoris), to prevent the progression of heart failure after myocardial infarction, and to QQC7 Ln / Lznz / E / YILI treats diabetic neuropathy, glaucoma, and similar conditions. The daily dose of losartan or a pharmaceutically acceptable salt thereof is 40 mg to 100 mg. In one embodiment of the present invention, the pharmaceutical combination preparation includes 40 to 100 mg of losartan or a pharmaceutically acceptable salt thereof converted into the form of free losartan acid. In a pharmaceutical combination preparation comprising ezetimibe and losartan as active ingredients, the dissolution of losartan may affect the dissolution of ezetimibe. Since these effects are not equally apparent under all conditions, it may be more important to select specific conditions to identify them. The inventors hereof have confirmed that, through the following and similar examples, when the pharmaceutical combination preparation comprising ezetimibe and losartan is dissolved in a solution of pH 4.0 to 5.0, the amount of ezetimibe dissolved is highly dependent on the amount of losartan dissolved. A pharmaceutical combination preparation is then provided in which the dissolution of ezetimibe and losartan is minimally affected. When the pharmaceutical combination preparation comprising ezetimibe and losartan according to the present invention is dissolved in a solution of pH 4.0 to 5.0 for 10 minutes, the amount of losartan dissolved is 5,700 pg or less, preferably 5,450 pg or less, and most preferably 5,200 pg or less. When the pharmaceutical combination preparation is dissolved in a solution of pH 4.0 to 5.0 for 10 minutes, the amount of ezetimibe dissolved is 270 pg or more, preferably 285 pg or more, and most preferably 300 pg or more. The dissolution test is performed under conditions of a temperature of 37 °C and a paddle method of 50 rpm in 500 mL of acetate pH regulator in accordance with the United States Pharmacopeia for the preparation of a pharmaceutical combination comprising 20 mg of ezetimibe and 183 mg of losartan, and the amount dissolved is a measured average value 5 times or more, preferably 10 times or more.The amount dissolved can be controlled by various methods, such as the use of additives, the form of a granule or preparation, and the like. As described above, since losartan can affect the dissolution and saturation solubility of ezetimibe, it is preferable that ezetimibe and losartan be present in a physically separate state to control the dissolution rate of losartan. In this case, the physically separate state means that a processing step is performed to separate a reference active ingredient from other active ingredients, and the reference active ingredient is maintained in a state that is distinct from other active ingredients in the final combination preparation. QQC7 Ln / Lznz / E / YILI obtained through this processing step, but the case where the ingredients themselves are mixed in a pre-mixing process without this processing step does not correspond to this meaning. The physically separated state can be achieved, for example, by physical separation using granulation, physical separation by multi-layer tablet formation, physical separation by tablets each formed separately, physical separation using a core-shell structure, etc. According to one embodiment of the present invention, to physically separate ezetimibe and losartan, the production process of ezetimibe and losartan in a separate granular form can be carried out and then mixed.At this time, if the state in which the active ingredient (losartan), other than ezetimibe, is not substantially present in the granules is maintained as in the processing step even after the combination preparation is completed, and even if there is an interface where the ezetimibe is in contact with the losartan on the surface of each ezetimibe granule in the combination preparation, it can be said that the ezetimibe is present in a state physically separate from the losartan in the combination preparation as described in the present invention. Furthermore, in another embodiment, the combination preparation can be obtained by mixing rosuvastatin and amlodipine with the ezetimibe granule produced after processing. QQC7 Ln / Lznz / E / YILI ezetimibe granulation, in the event that the other active ingredients (rosuvastatin and amlodipine) are not substantially present in the ezetimibe granule, the ezetimibe may be considered to be present in a physically separate state from the rosuvastatin and amlodipine. In one embodiment of the present invention, the pharmaceutical combination preparation may be present in the form of a bilayer tablet consisting of: a first layer comprising ezetimibe or a pharmaceutically acceptable salt thereof; and a second layer comprising losartan or a pharmaceutically acceptable salt thereof. The method for producing an ezetimibe granule is not particularly limited, but producing granules in a wet state may be preferable. Ezetimibe is a poorly soluble drug with a low saturation solubility of approximately 1 ppm under acidic or weakly basic conditions, such as body fluids. Saturation solubility and the rate of dissolution from the onset of dissolution to the saturation point can be important indicators for assessing the bioavailability of a poorly soluble drug, and wet granules can reach saturation solubility more quickly, thus ensuring high bioavailability for the poorly soluble drug ezetimibe. The method for producing a losartan granule is not particularly limited, but producing granules in a wet state may be preferable. QQC7 Ln / Lznz / E / YILI produce granules by a compression granulation method. When the ezetimibe granules are sieved through a sieve opening size of 250 µm (size 60), the content of granules (residue) having a diameter of more than 250 µm may be 15% by weight or less, preferably 10% by weight or less. When losartan granules are sieved through a sieve opening size of 250 pm, the content of granules (residue) having a diameter of more than 250 pm can be 35 to 55% by weight, preferably 40 to 50% by weight, and when sieved through a sieve opening size of 500 pm (size 35), the content of granules (residue) having a diameter of more than 500 pm can be 10 to 30% by weight, preferably 15 to 25% by weight.If the ezetimibe and losartan granules are within the above ranges, the dissolved amounts of ezetimibe and losartan granules can be adjusted to an appropriate level. The combination preparation of the present invention may further comprise one or more pharmaceutically acceptable additives necessary for the preparation in addition to the aforementioned active ingredients. Specifically, the ezetimibe granule portion or the losartan granule portion may comprise one or more pharmaceutically acceptable additives selected from the group consisting of excipients, binders, and disintegrants. QQC7 Ln / Lznz / E / YILI in accordance with one embodiment of the present invention, the excipient may be included in the granulated portion of ezetimibe in an amount of 50 to 5,000 parts by weight, preferably 500 to 4,000 parts by weight, most preferably 1,000 to 3,000 parts by weight based on 100 parts by weight of ezetimibe. The binder may be included in the granulated portion of ezetimibe in an amount of 10 to 1,000 parts by weight, preferably 20 to 500 parts by weight, most preferably 30 to 100 parts by weight based on 100 parts by weight of ezetimibe. The disintegrant can be included in the granulated part of ezetimibe in an amount of 10 to 1,000 parts by weight, preferably 20 to 500 parts by weight, most preferably 30 to 300 parts by weight based on 100 parts by weight of ezetimibe.According to one embodiment of the present invention, the excipient may be included in the granulated portion of losartan in an amount of 50 to 1000 parts by weight, preferably 100 to 500 parts by weight, and most preferably 150 to 300 parts by weight, based on 100 parts by weight of losartan. Since the dissolution of losartan may affect the dissolution of ezetimibe, the disintegrant content in the granulated portion of losartan may be an important element in preparing the pharmaceutical combination according to the present invention. In one embodiment of the present invention, the disintegrant may be included in an amount of 1 to 30 parts by weight. QQC7 Ln / Lznz / E / YILI preferably 10 to 25 parts by weight based on 100 parts by weight of losartan. If the disintegrant is included in an amount of less than 1 part by weight, the dissolution of losartan may be reduced, and if the disintegrant is included in an amount of more than 30 parts by weight, the dissolution of ezetimibe may be reduced due to the dissolution of losartan. The granulated portion of ezetimibe or the granulated portion of losartan may be mixed with glides after the preparation of the granules. According to one embodiment of the present invention, the slip can be mixed with the granulated portion of ezetimibe in an amount of 5 to 300 parts by weight, preferably 10 to 200 parts by weight, most preferably 15 to 100 parts by weight based on 100 parts by weight of ezetimibe, and can be mixed with the granulated portion of losartan in an amount of 0.1 to 20 parts by weight, preferably 0.5 to 15 parts by weight, very preferably 1 to 10 parts by weight based on 100 parts by weight of losartan. The type and content of these additives can be appropriately selected by a person skilled in the art, according to the specific formulation to be prepared. For example, the excipient is selected from the group consisting of, but not limited to, lactose, starch, mannitol, microcrystalline cellulose, carboxymethylcellulose, and combinations thereof; the binder is selected from the group consisting of QQC7 Ln / Lznz / E / YILI in, but not limited to, povidone, hypromellose, hydroxypropylcellulose, copovidone and combinations thereof; the disintegrant is selected from the group consisting of, but not limited to, crospovidone, croscarmellose sodium, sodium starch glycolate, slightly substituted hydroxypropylcellulose and combinations thereof; and the slider is selected from the group consisting of, but not limited to, magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate and combinations thereof. Since ezetimibe is a poorly soluble drug, as described above, the granulated portion of ezetimibe may further comprise a solubilizing agent. In one embodiment of the present invention, the solubilizing agent may be included in the granulated portion of ezetimibe in an amount of 5 to 50 parts by weight, preferably 10 to 40 parts by weight, and most preferably 15 to 30 parts by weight, based on 100 parts by weight of ezetimibe. If the amount of solubilizing agent is less than 5 parts by weight, the dissolution rate of ezetimibe is markedly reduced, whereas if the amount of solubilizing agent is greater than 50 parts by weight, the improved dissolution rate effect of the solubilizing agent is negligible. Furthermore, if the solubilizing agent is used in an excessive amount, the stability of the ezetimibe granules may be reduced.Sodium lauryl sulfate (SLS) can preferably be used as a solubilizing agent. The pharmaceutical combination preparation according to the present invention may further comprise the ingredient selected from the group consisting of amlodipine or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and combinations thereof. The pharmaceutical combination preparation according to the present invention may comprise amlodipine or a pharmaceutically acceptable salt thereof as the third active ingredient. Examples of pharmaceutically acceptable salts of amlodipine include, but are not necessarily limited to, hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, fumarate, lactate, tartrate, citrate, gluconate, besylate, and camsylate salts, preferably amlodipine besylate and amlodipine camsylate. In addition, the amlodipine of the present invention includes racemates of amlodipine and (S)-amlodipine. Amlodipine is used in the treatment of cardiovascular diseases such as angina pectoris, hypertension, and congestive heart failure by blocking the calcium channel. The daily dose of amlodipine or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg. QQC7 Ln / Lznz / E / YILI The pharmaceutical combination preparation according to the present invention comprises rosuvastatin or a pharmaceutically acceptable salt thereof as the fourth active ingredient. Examples of pharmaceutically acceptable salts of rosuvastatin include, but are not limited to, calcium salt, magnesium salt, strontium salt, etc., and preferably rosuvastatin calcium salt. Rosuvastatin contributes to the treatment of dyslipidemia by inhibiting HMG-CoA reductase, which is essential for cholesterol synthesis, thereby reducing LDL cholesterol levels in the blood while increasing HDL cholesterol levels. The daily dose of rosuvastatin or a pharmaceutically acceptable salt thereof is 10 mg to 20 mg. Ezetimibe is present in a physically separate state from rosuvastatin, amlodipine, and losartan, respectively. The physically separate state follows the description above. If the pharmaceutical combination preparation comprises all of ezetimibe, rosuvastatin, amlodipine, and losartan as active ingredients, the pharmaceutical combination preparation may be present in the form of a bilayer tablet consisting of: a first layer comprising ezetimibe or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof; and a second layer comprising losartan or a pharmaceutically acceptable salt thereof.Ezetimibe or a pharmaceutically acceptable salt thereof in the first layer is present mixed with rosuvastatin or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof, in granular form. Losartan or a pharmaceutically acceptable salt thereof in the second layer is present in granular form. The first and second layers of the bilayer tablet may comprise one or more pharmaceutically acceptable additives selected from the group consisting of excipients, binders, disintegrants, and glidants. The present invention provides a method for preparing a pharmaceutical combination preparation comprising ezetimibe or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof. The method for preparing a pharmaceutical combination preparation according to the present invention comprises the steps of: i) producing an ezetimibe granule comprising ezetimibe or a pharmaceutically acceptable salt thereof; ii) producing a losartan granule comprising losartan or a pharmaceutically acceptable salt thereof; and iii) controlling the dissolved amount of ezetimibe or losartan. Step iii) is to control the dissolved amount of ezetimibe or losartan according to the aforementioned criteria, and the dissolved amount of ezetimibe or losartan may be controlled by the use of additives, the shape of a granule or preparation, and the like. The details of the preparation method are supplemented by the descriptions mentioned above and the following examples. The following are preferred examples to aid in understanding the present invention, but the following examples are given not to limit the present invention but to facilitate understanding of the present invention. Examples Example 1: Preparation of a bilayer tablet comprising ezetimibe and losartan A coated bilayer tablet comprising ezetimibe and losartan as active ingredients was prepared according to the composition shown in Table 1 below. Specifically, ezetimibe was placed in a fluidized bed granulator along with hydrated lactose, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate and mixed for 3 minutes. A binder solution, in which povidone was dissolved in water, was added, and the transfer pump was set to 2 rpm and combined to perform granulation for approximately 50 minutes. The resulting product was dried in a fluidized bed dryer at 45°C and then sieved through a 0.6 mm sieve. QQC7 LO / LZnZ / E / YILI opening to produce an ezetimibe granule. At this time, the ezetimibe granule had a content of 5% by weight of granule with a diameter of more than 250 pm. Potassium losartan was placed in a mixer along with hydrated lactose, microcrystalline cellulose, and crospovidone, and mixed for 20 minutes. The resulting product was pressed under conditions of an oil pressure of 2 MPa, a feed rate of 5 rpm, and a roller speed of 1 rpm using a roller compressor (TF-1-A60, Freund Vector) to form flakes, and then a losartan granule was produced by passing it through a 0.8 mm sieve opening. At this time, the losartan granules contained 45% by weight of granules with a diameter greater than 250 µm and 20% by weight of granules with a diameter greater than 500 µm. Magnesium stearate was added to the ezetimibe granules and further mixed in a mixer for 5 minutes to prepare the top layer mixture for the bilayer tablet. Magnesium stearate was also added to the losartan granules and further mixed in a mixer for 5 minutes to prepare the bottom layer mixture for the bilayer tablet. The top and bottom layer mixtures were then pressurized using a tablet press (Autotab200TR, Ichihashi Seiki) to produce a bilayer tablet with a hardness of approximately 12 kp. The bilayer tablet was coated using a coating machine (SFC-30F, Sejong) according to the coating layer prescription shown in Table 1 below. Example 2: Preparation of a bilayer tablet comprising ezetimibe and losartan A coated bilayer tablet comprising ezetimibe and losartan as active ingredients was prepared according to the composition shown in Table 1 below in the same manner as in Example 1. Example 3: Preparation of a capsule containing a minitablet containing ezetimibe and losartan A capsule was prepared containing a coated minitablet comprising each ezetimibe and losartan as the active ingredient according to the composition shown in Table 1 below. Specifically, an ezetimibe granule and a losartan granule were prepared in the same manner as in Example 1. A minitablet containing losartan (303 mg / 30T) and a minitablet containing ezetimibe (157 mg / 10T), each with a diameter of 2 mm and a hardness of approximately 1.5 kp, were prepared from each granule using a tablet press. QQC7 LO / LZnZ / E / YILI containing losartan and the minitablet containing ezetimibe were respectively coated using a fluidized bed coating machine according to the coating layer prescription shown in Table 1 and were introduced into size 0 hard capsules. Example 4: Preparation of a bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan A coated bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan as active ingredients was prepared according to the composition shown in Table 1 below. Specifically, a losartan granule was produced in the same manner as in Example 1, and magnesium stearate was mixed with the losartan granule to prepare a top-coat mixture. In addition, an ezetimibe granule was produced in the same manner as in Example 1, and then the ezetimibe granule was placed in a mixer along with a mixture having the composition described in the mixing section of Table 1 and mixed for 15 minutes. Magnesium stearate was then added, and the mixture was further mixed for 5 minutes to prepare a bottom-layer mixture. The top-layer and bottom-layer mixtures were pressurized using a tablet-making machine to prepare a bilayer tablet having a hardness of approximately 20 kp. The bilayer tablet was coated using a coating machine according to the 5-layer coating prescription shown in Table 1 below. The specific compositions of the pharmaceutical combination preparations according to Examples 1 to 4 are shown in Table 1 below. QQC7 Ln / Lznz / E / YILI Table 1 Classification Ingredient Example 1 (mg / T) Example 2 (mg / T) Example 3 (mg / C) Example 4 (mg / T) Losartan Granules Losartan Potassium (as losartan) 100.0 (91.5) 100.0 (91.5) 100.0 (91.5) - 100.0 (91.5) Microcrystalline Cellulose (Avicel PH101) 125.0 120.0 125.0 - 125.0 Hydrated Lactose (#200) 60.0 60.0 60.0 - 60.0 Crospovidone (XL-10) 15.0 20.0 15.0 - 15.0 Post-mix Magnesium Stearate 3.0 3.0 3.0 - 3.0 Total Mass 303.0 303.0 303.0 - 303.0 Ezetimibe Granules Ezetimibe 10.0 10.0 - 10.0 10.0 Microcrystalline Cellulose (Avicel PH101) 90.0 90.0 — 90.0 90.0 Hydrated Lactose (#200) 35.0 35.0 - 35.0 35.0 Croscarmellose Sodium 15.0 15.0 - 15.0 15.0 Sodium Lauryl Sulfate 2.0 2.0 - 2.0 2.0 Povidone (K-30) 5.0 5.0 - 5.0 5.0 Purified Water* (70.0) (70.0) - (70.0) (70.0) Postmix Magnesium Stearate 2.0 2.0 — 2.0 - Total mass 159.0 159.0 - 159.0 157.0 Part of the mixture Amlodipine besylate as amlodipine) — — — — 6.94 (5.0) Rosuvastatin - - - - 20.8 Calcium (as rosuvastatin) (20.0) Mannitol (SD200) - - - - 120.0 Hydrated lactose (supertab) — - — — 120.0 Microcrystalline cellulose (Avicel PH101) — — — — 30.0 Crospovidone (XL-10) - - - - 24.0 Magnesium stearate — - — — 4.0 Total mass of uncoated tablet 462.0 462.0 303.0 159.0 785.74 Coating layer Hydroxypropyl cellulose 6.4 6.4 4.3 10.9 2.1 Polyethylene glycol 0.9 0.9 0.6 1.6 0.3 Talc 0.2 0.2 0.2 0.4 0.1 Titanium dioxide 0.9 0.9 0.6 1.5 0.3 Red iron oxide 0.4 0.4 0.2 0.6 0.1 Purified water* (80.6) (80.6) (52.8) (137.0) (27.7) Total mass of coated tablet 470.8 470.8 308.9 161.9 470.8 * Purified water is removed during the process. Comparative Examples 1: Preparation of tablets containing ezetimibe A coated tablet comprising ezetimibe as the active ingredient was prepared according to the composition shown in Table 2 below. Specifically, a mixture comprising an ezetimibe granule was prepared in the same manner as in Example 1 and pressurized with a tablet-making machine to prepare a tablet having a hardness of approximately 7 kp. The tablet was coated using a coating machine according to the coating layer prescription shown in Table 2 below. QQC7 Ln / Lznz / E / YILI Comparative Examples 2: Preparation of a capsule comprising ezetimibe minitablet and losartan granule A coated minitablet (157 mg / IOT) comprising the losartan granule obtained in Example 1 and the ezetimibe obtained in Example 3 was introduced into a size 0 hard capsule. Comparative Examples 3 and 4: Preparation of bilayer tablets comprising ezetimibe and losartan A coated bilayer tablet comprising ezetimibe and losartan as active ingredients was prepared according to the composition shown in Table 2 below in the same manner as in Example 1. The specific compositions of the pharmaceutical combination preparations according to Comparative Examples 1, 3 and 4 are shown in Table 2 below. Table 2 Classification Ingredient Comparative Example 1 (mg / T) Comparative Example 3 (mg / T) Comparative Example 4 (mg / T) Losartan Granule Losartan Potassium (as losartan) — 100.0 (91.5) 100.0 (91.5) Microcrystalline Cellulose (Avicel PH101) — 110.0 95.0 Hydrated Lactose (#200) - 60.0 60.0 Crospovidone (XL-10) - 30.0 45.0 Post-mix Magnesium stearate - 3.0 3.0 Total mass - 303.0 303.0 Ezetimibe granule Ezetimibe 10.0 10.0 10.0 Microcrystalline cellulose (Avicel PH101) 90.0 90.0 90.0 Hydrated lactose (#200) 35.0 35.0 35.0 Croscarmellose sodium 15.0 15.0 15.0 Sodium lauryl sulfate 2.0 2.0 2.0 Povidone (k-30) 5.0 5.0 5.0 Purified water* (70.0) (70.0) (70.0) Post-mix Magnesium stearate 2.0 2.0 2.0 Total mass 159.0 159.0 159.0 Total mass of uncoated tablet 159.0 462.0 462.0 Coating layer Hydroxypropyl cellulose 2.2 6.4 6.4 Polyethylene glycol 0.3 0.9 0.9 Talc 0.1 0.2 0.2 Titanium dioxide 0.3 0.9 0.9 Red iron oxide 0.1 0.4 0.4 Purified water* (27.7) (80.6) (80.6) Total mass of coated tablet 162.0 470.8 470.8 The purified water is removed during the process. Test example Example test 1: Dissolution test Under the following dissolution and analytical conditions, the dissolution rates of ezetimibe and losartan in tablets or capsules were measured respectively according to Examples 1 to 4 and Comparative Examples 1 to 4, and the results are shown in Figures 1 to 7. Dissolution conditions Dissolution medium: Two tablets or two capsules (20 mg as ezetimibe, 183 mg as losartan) are taken and analyzed in 500 ml of the following solution. - pH 1.2: Simulated gastric fluid USP without enzyme - pH 4.5: Acetic Acid pH Regulator USP - pH 6.8: Simulated intestinal fluid USP without enzyme Device: paddle method, 50 ± 2 rpm Temperature: 37 + 0.5°C Dissolution time: 5, 10, 15, 30, 45, 60 minutes (After 45 minutes, the paddle speed was changed to 150 rpm and stirred for 15 minutes, and then the dissolution medium was taken at 60 minutes). Analytical conditions Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm was filled with 3 pm of silylated octadecyl silica gel for liquid chromatography. Mobile phase: * 9 mM sodium hexansulfonate / 0.13% (v / v) phosphoric acid: acetonitrile (52:48, v / v) (* g mjq ¿θ sodium hexansulfonate / 0.13% (v / v) phosphoric acid: 1.86 g of sodium hexansulfonate (1 sodium hexansulfonate monohydrate) are placed in a 1 1 flask and 1.3 ml of phosphoric acid are carefully added. QQC7 Ln / Lznz / E / YILI Purified water is added to it and it is dissolved, diluted and mixed well. Detector: ultraviolet absorption spectrophotometer (measurement wavelength 254 nmj) Flow rate: 1.3 ml / min Injection volume: 10 pL Column temperature: 45°C Figure 1 shows the results of ezetimibe dissolution by pH in the tablet according to Example 1. According to Figure 1, it was confirmed that the dissolved amount of the main ingredient is maintained when the tablet according to Example 1 is dissolved at pH 1.2 and pH 6.8, while when dissolved at pH 4.5, which is between pH 1.2 and pH 6.8, for approximately 10 minutes, the dissolved amount of the main ingredient gradually decreases after reaching the maximum value to remain below the maximum value. Figures 2 and 3 show the dissolution results of ezetimibe and losartan at pH 4.5 in tablets prepared according to Example 1 and Comparative Example 1, and in capsules prepared according to Example 3 and Comparative Example 2. First, the dissolution patterns of the tablet prepared according to Example 1, comprising ezetimibe and losartan, were compared with those of the capsule prepared according to Comparative Example 1, comprising only ezetimibe but without losartan. According to Figure 2, it was confirmed that in the case of the capsule prepared according to Comparative Example 1 without losartan, the amount of ezetimibe dissolved at pH 4.5 remained at the maximum value.Ezetimibe is a poorly soluble drug and is known to exhibit low solubility in a dissolution medium that does not contain a surfactant, but the deposition of ezetimibe again after dissolution is considered an unusual phenomenon and it is determined that this is because losartan affects the dissolution and saturation solubility of ezetimibe. Subsequently, although ezetimibe was prepared in the same manner, the capsule prepared according to Example 3, which had a controlled dissolution rate due to the inclusion of losartan in the form of a coated minitablet, was compared with the capsule prepared according to Comparative Example 2, which had rapid dissolution due to the inclusion of losartan in granular form. According to Figures 2 and 3, it was confirmed that the initial dissolution rate and saturation solubility of ezetimibe were low when the dissolution of losartan was rapid, as in the capsule prepared according to Comparative Example 2. These results indicate that losartan affects the dissolution pattern of ezetimibe, as in the previous comparison between the tablet prepared according to Example 1 and the tablet prepared according to Comparative Example 1. Figures 4 and 5 show the dissolution results of ezetimibe and losartan at pH 4.5 in tablets prepared according to Examples 1 and 2 and tablets prepared according to Comparative Examples 3 and 4. The tablets prepared according to Examples 1 and 2 and tablets prepared according to Comparative Examples 3 and 4 differ in the amount of disintegrant in the losartan layer, respectively. It was confirmed that if the disintegrant was included in the losartan layer in amounts of 15 mg and 20 mg, respectively, as in the tablets prepared according to Examples 1 and 2, the dissolution patterns of losartan and ezetimibe appeared similar.Conversely, it was confirmed that if the disintegrant was included in the losartan layer in an amount of 30 mg and 45 mg, respectively, as in the tablets according to Comparative Examples 3 and 4, compared to the tablets according to Examples 1 and 2, the dissolution rate of losartan was increased, but the maximum amount of ezetimibe dissolved was small. Figures 6 and 7 show the dissolution results of ezetimibe and losartan at pH 4.5 in the tablets according to Examples 1 and 4. According to Figures 6 and 7, it was confirmed that even when amlodipine and rosuvastatin were mixed with the ezetimibe granule as in the tablet according to Example 4, the maximum amount of ezetimibe dissolved was not significantly different compared to the tablet according to Example 1. Through these results, it is determined that the dissolution pattern of ezetimibe is directly affected by losartan rather than by amlodipine and rosuvastatin. Example test 2: Pharmacokinetic evaluation of ezetimibe For the compositions in Example 1, Comparative Example 1, and Comparative Example 3, the pharmacokinetic parameters of ezetimibe were evaluated in beagle dogs. Eighteen beagle dogs (male, 20 months of age, 12 ± 2 kg) were randomly assigned to three groups, and a 3-way crossover study was performed for six beagle dogs per group. Each group of beagle dogs, previously fasted for 14 hours the day before, was orally administered Example 1, Comparative Example 1, and Comparative Example 3, respectively, and then forced to drink 40 mL of water. Blood collection was performed by taking 2 mL of blood from the cephalic vein into a tube containing anticoagulant (1,000 IU / mL, heparin 5 pL) before oral administration (0 hour) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 24 hours after oral administration.Blood samples were centrifuged (12,000 rpm, 2 minutes, Eppendrof) to separate the plasma and were stored in a freezer at -20°C. For the analysis, 15 pL of β-glucuronidase (Helix pomatia) is added to 100 pL of plasma and mixed for 30 seconds. 100 μL of distilled water is added and mixed for another 30 seconds, then the mixture is incubated at 50°C for 1 hour. After 1 hour of enzymatic reaction, 15 pL of the internal standard solution (Ezetimibe-d4, 50 ppb) is added to the plasma and mixed for 30 seconds. 1 mL of methyl tert-butyl ether (MTBE) is added and the mixture is incubated for 10 minutes and then centrifuged (15,000 rpm, 3 minutes). The supernatant is collected and evaporated using a nitrogen evaporator at 45°C. The residue is redissolved in 1 mL of 50% ACN and then analyzed using liquid chromatography-mass spectrometry (LC-MS). Analytical conditions Device used: Xevo TQ-S (Waters) Ionization mode: [MH] + (negative) Column: CHS C18 (2.1 * 150 mm, 1.8 pm, Waters) Column temperature: 35°C Mobile phase: ACN / ammonium acetate 2 mM = 70 / 30 (v / v) Flow rate: 0.18 ml / min Injection volume: 5 pL The results are shown in Table 3 below and Figure 8 shows the arithmetic mean of the plasma concentration of ezetimibe (ng / ml) versus time (hr) on a linear scale. QQC7 LO / LZnZ / E / YILI Table 3 Pharmacokinetic evaluation of Ezetimibe Parameter Example 1 (TI) Comparative example 3 (T2) Comparative example 1 (R) T1 / R T2 / R AUCo-24 (ng-hr / mL) 347.01 ± 109.51 299.81 ± 115.12 360.62 ± 148.25 0.962 0.831 Cmax (ng / mL) 87.68 ± 47.29 78.74 ± 50.94 86.79 ± 44.15 1.010 0.907 As shown in Table 3 and Figure 8, it was confirmed that, compared to the tablet according to Comparative Example 1, the tablet according to Example 1 had the equivalent level within +10% of AUC and Cmax, but the tablet according to Comparative Example 3 had the unequal level close to the lower limit criteria. Taking the results from Test Examples 1 and 2 together, the dissolution pattern of ezetimibe was changed according to the dissolution rate of losartan, and in this way, the change in pharmacokinetic parameters was confirmed. Therefore, it was confirmed that the dissolution rate of losartan should be controlled at pH 4.5 when developing a combination pharmaceutical preparation comprising ezetimibe and losartan. It should be noted that all simple modifications and variations of the present invention are within the scope of the present invention, and the specific scope of the present invention to be protected will be defined by the appended claims.

Claims

1. A pharmaceutical combination preparation comprising ezetimibe or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof, wherein, when the pharmaceutical combination preparation is dissolved in a solution of pH 4.0 to 5.0 for 10 minutes, the dissolved amount of losartan is 5,700 pg or less, and the dissolved amount of ezetimibe is 270 pg or more.

2. The preparation of a pharmaceutical combination according to claim 1, wherein the dissolution in a pH 4.0 to 5.0 solution is carried out under the conditions of a temperature of 37 °C and a paddle method of 50 rpm in 500 mL of acetate pH regulator in accordance with the United States Pharmacopeia for the preparation of a pharmaceutical combination comprising 20 mg of ezetimibe and 183 mg of losartan.

3. The pharmaceutical combination preparation according to claim 1, wherein, when the pharmaceutical combination preparation is dissolved in a solution of pH 4.0 to 5.0 for 10 minutes, the dissolved amount of losartan is 5,200 pg or less, and the dissolved amount of ezetimibe is 300 pg or more.

4. The pharmaceutical combination preparation according to claim 1, wherein ezetimibe or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof are physically separated from each other.

5. The pharmaceutical combination preparation according to claim 4, wherein ezetimibe or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof are each present in granular form.

6. The pharmaceutical combination preparation according to claim 5, wherein the granule comprising ezetimibe or a pharmaceutically acceptable salt thereof has a content of 15% by weight or less of granule having a diameter of more than 250 pm.

7. The pharmaceutical combination preparation according to claim 5, wherein the granule comprising losartan or a pharmaceutically acceptable salt thereof has a content of 35 to 55% by weight of granule having a diameter of more than 250 pm, and has a content of 10 to 30% by weight of granules having a diameter greater than 500 pm.

8. The pharmaceutical combination preparation according to claim 1, wherein the pharmaceutical combination preparation includes 5 to 10 mg of ezetimibe or a pharmaceutically acceptable salt thereof converted into ezetimibe free acid, and includes 40 to 100 mg of losartan or a pharmaceutically acceptable salt thereof converted into losartan free acid.

9. The pharmaceutical combination preparation according to claim 5, wherein the granule comprising ezetimibe or a pharmaceutically acceptable salt thereof further comprises a solubilizing agent.

10. The preparation of a pharmaceutical combination according to claim 9, wherein the solubilizing agent is sodium lauryl sulfate.

11. The pharmaceutical combination preparation according to claim 9, wherein the solubilizing agent is included in the granule comprising ezetimibe or a pharmaceutically acceptable salt thereof, in an amount of 5 to 50 parts by weight, based on 100 parts by weight of ezetimibe.

12. The pharmaceutical combination preparation according to claim 5, wherein the granule comprising losartan or a pharmaceutically acceptable salt thereof further comprises 1 to 30 parts by weight of disintegrant, based on 100 parts by weight of losartan.

13. The pharmaceutical combination preparation according to claim 1, wherein the pharmaceutical combination preparation is present in the form of a bilayer tablet consisting of: QQC7 LO / LZnZ / E / YILI a first layer comprising ezetimibe or a pharmaceutically acceptable salt thereof; and a second layer comprising losartan or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical combination preparation having the form of a bilayer tablet consisting of: a first layer comprising ezetimibe or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof; and a second layer comprising losartan or a pharmaceutically acceptable salt thereof, wherein, when the pharmaceutical combination preparation is dissolved in a solution of pH 4.0 to 5.0 for 10 minutes, the dissolved amount of losartan is 5,700 pg or less, and the dissolved amount of ezetimibe is 270 pg or more.

15. The pharmaceutical combination preparation according to claim 14, wherein ezetimibe or a pharmaceutically acceptable salt thereof is included in granular form in the first layer, and losartan or a pharmaceutically acceptable salt thereof is included in granular form in the second layer. SUMMARY OF THE INVENTION QQC7 LO / LZnZ / E / YILI The present invention relates to a pharmaceutical combination preparation comprising ezetimibe and losartan. 5 When the pharmaceutical combination preparation is dissolved in a solution of pH 4.0 to 5.0 for 10 minutes, the dissolved amount of losartan is 5,700 pg or less, and the dissolved amount of ezetimibe is 270 pg or more. The dissolution in a solution of pH 4.0 to 5.0.0 is carried out under the conditions of a temperature of 37°C and a paddle method of 50 rpm in 500 mL of acetate pH regulator in accordance with the United States Pharmacopeia for the preparation of a pharmaceutical combination comprising 20 mg of ezetimibe and 183 mg of losartan.