Combination preparation containing ezetimibe, rosuvastatin and empagliflozin, with improved drug compliance

Abstract

The present invention relates to a pharmaceutical combination preparation, which comprises all of ezetimibe, rosuvastatin and empagliflozin as active ingredients, and thus can be administered as a single drug, and not through co-administration, in the simultaneous treatment of dyslipidemia and diabetes, thereby increasing patient dosing convenience, minimally affecting dissolution between drugs, ensuring biological equivalence, and providing excellent stability of the active ingredients.

Description

A combination formulation containing ezetimibe, rosuvastatin, and empagliflozin with improved medication adherence

[0001] Cross-citation with related application(s)

[0002] This application claims the benefit of priority from Korean Patent Application No. 10-2024-0060726, filed May 8, 2024, the entire contents of which are incorporated herein by reference.

[0003] The present invention relates to a combination preparation comprising ezetimibe, rosuvastatin, and empagliflozin with improved medication compliance.

[0004] Diabetics are two to four times more likely to die from cardiovascular disease. Cardiovascular disease accounts for 60 to 80% of all deaths among diabetic patients, making it a significant risk factor. For every 39 mg / dL increase in LDL cholesterol, the risk of developing coronary artery disease increases by approximately 60%. Therefore, active treatment is necessary when dyslipidemia is present.

[0005] According to the Dyslipidemia Fact Sheet, patients with diabetes are at a significantly higher risk of dyslipidemia than those without diabetes, with approximately 90% of people with diabetes aged 20 years and older having dyslipidemia. Approximately 48% of people with diabetes have LDL cholesterol levels above 100 mg / dL, highlighting the need for active concurrent management.

[0006] Based on this high rate of disease comorbidity, currently, specific drugs for the treatment of dyslipidemia and diabetes are on the market.

[0007] In practice, the combination of diabetes and dyslipidemia medications is recommended. For example, Jardiance, a single tablet of empagliflozin, is recommended for the treatment of diabetes. TM (Boehringer Ingelheim, once daily administration) and Rosjet tablets, a combination preparation of ezetimibe / rosuvastatin calcium for the treatment of dyslipidemia TM(Hanmi Pharmaceutical, once-daily administration) is being administered in combination. Active and regular medication use is highly correlated with successful treatment outcomes. Therefore, formulating the two drugs currently administered in combination into a single formulation offers the advantage of allowing simultaneous risk factor management for patients.

[0008] The combination preparation of ezetimibe / rosuvastatin is known as a combination preparation of drugs related to cardiovascular diseases such as amlodipine and / or losartan, as in patent document 1, but has not yet been suggested for a combination with empagliflozin, a diabetes treatment drug.

[0009] Meanwhile, Patent Document 2 proposes a combination formulation comprising ezetimibe, pitavastatin, and the DPP-4 inhibitor linagliptin, as a treatment for metabolic diseases such as dyslipidemia or diabetes. Empagliflozin is an SGLT-2 inhibitor and belongs to a different class of drugs than the aforementioned DPP-4 inhibitors, and a combination formulation containing ezetimibe, rosuvastatin, and empagliflozin has not yet been proposed.

[0010] Empagliflozin causes problems with tablet consistency when formulated into tablets due to its sticky nature, and it affects the dissolution rate and stability of other active ingredients used together, so caution is required when manufacturing combination preparations.

[0011] The present inventors sought to develop a combination formulation containing both dyslipidemia and diabetes treatment agents, and furthermore, by considering the sites of action of these drugs, developed a combination formulation form of the present invention that can secure a high dissolution rate of all three components while also having excellent stability, thereby completing the present invention.

[0012] [Prior Art Literature]

[0013] [Patent Document]

[0014] (Patent Document 1) KR Registered Patent No. 10-2569271

[0015] (Patent Document 2) KR Registered Patent No. 10-2289381

[0016] One object of the present invention is to provide an oral combination formulation that contains ezetimibe, rosuvastatin, and empagliflozin as active ingredients, thereby having a synergistic effect in the concomitant treatment of dyslipidemia and diabetes, while also having a dissolution profile equivalent to that of single administration of these drugs individually, and also having excellent stability.

[0017] Another object of the present invention is to provide a method for efficiently manufacturing the oral administration compound preparation provided in the present invention.

[0018] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0019] According to one embodiment of the present invention, the present invention relates to a pharmaceutical combination preparation comprising (1) ezetimibe or a pharmaceutically acceptable salt thereof, (2) rosuvastatin or a pharmaceutically acceptable salt thereof, and (3) empagliflozin or a pharmaceutically acceptable salt thereof as active ingredients.

[0020] The above empagliflozin may be included in an amount of 1.5 to 8 wt% based on the total weight of the pharmaceutical combination preparation.

[0021] The above pharmaceutical combination preparation may contain ezetimibe in an amount of 5 to 20 mg per unit dosage form, rosuvastatin in an amount of 2 to 20 mg, and empagliflozin in an amount of 5 to 40 mg.

[0022] The above pharmaceutical combination preparation may contain ezetimibe in an amount of 5 to 20 mg per unit dosage form, rosuvastatin in an amount of 2.5 to 20 mg, and empagliflozin in an amount of 10 to 25 mg.

[0023] The pharmaceutical combination formulation may contain ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin in an amount of 2.5 to 10 mg, and empagliflozin in an amount of 10 or 25 mg.

[0024] The above pharmaceutical combination preparation may contain a disintegrant in an amount of 1 to 15 wt% based on the total weight of the pharmaceutical combination preparation.

[0025] The disintegrant may be selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate methylcellulose, cross-linked carboxymethylcellulose sodium (Cross-linked CMC Na, C.CMC Na, or croscarmellose sodium), carboxymethylcellulose calcium, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose, starch, pregelatinized starch, corn starch, potato starch, pregelatinized starch, alginic acid or its sodium salt, and combinations thereof.

[0026] The above pharmaceutical combination preparation may contain excipients in an amount of 60 to 95 wt% based on the total weight of the pharmaceutical combination preparation.

[0027] The above excipient may include at least one selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, magnesium aluminosilicate, magnesium aluminosilicate, aluminum silicate, sodium silicate, potassium silicate, magnesium silicate, calcium silicate, lactose, lactose hydrate, lactose anhydrous, calcium hydrogen phosphate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, dextrin, mannitol, sorbitol, starch, calcium phosphate hydrate, calcium carbonate, and sugars.

[0028] The above pharmaceutical combination preparation may further include an active agent in an amount of 0.1 to 10 wt% based on the total weight of the pharmaceutical preparation, and a binder in an amount of 0.1 to 5 wt%.

[0029] In the above pharmaceutical combination preparation, the ezetimibe or a pharmaceutically acceptable salt thereof may be physically separated from the rosuvastatin or a pharmaceutically acceptable salt thereof and the empagliflozin or a pharmaceutically acceptable salt thereof.

[0030] The above pharmaceutical combination preparation may include a granular portion comprising ezetimibe or a pharmaceutically acceptable salt thereof; and a postmixed portion comprising rosuvastatin or a pharmaceutically acceptable salt thereof and empagliflozin or a pharmaceutically acceptable salt thereof.

[0031] Empagliflozin in the above post-mixing unit may be included in an amount of 0.5 to 11 wt% based on the total weight of the above post-mixing unit.

[0032] The above post-mixing unit may contain excipients in an amount of 60 to 97 wt% based on the total weight of the post-mixing unit.

[0033] The above post-mixing portion may contain excipients in an amount of 60 to 90 wt% based on the total weight of the pharmaceutical combination preparation.

[0034] The above post-mixing unit may contain a disintegrant in an amount of 0.1 to 15 wt% based on the total weight of the pharmaceutical combination preparation.

[0035] The above granular portion may contain a disintegrant in an amount of 0.5 to 5 wt% based on the total weight of the pharmaceutical combination preparation.

[0036] The above pharmaceutical combination preparation may have a dissolution rate of rosuvastatin of 70% or more within 5 minutes, 85% or more within 15 minutes, and 90% or more within 30 minutes in a dissolution test (pH 1.2 solution, 37°C, 900 mL, 50 rpm).

[0037] The above pharmaceutical combination preparation may have a dissolution rate (based on weight) of empagliflozin of 50% or more within 5 minutes, 80% or more within 15 minutes, and 85% or more within 30 minutes in a dissolution test (pH 1.2 solution, 37°C, 900 mL, 50 rpm).

[0038] According to another embodiment of the present invention, there is provided a method for preparing a pharmaceutical combination preparation, comprising the steps of: (a) preparing a granular portion comprising ezetimibe or a pharmaceutically acceptable salt thereof as an active ingredient; (b) preparing a postmixed portion comprising rosuvastatin or a pharmaceutically acceptable salt thereof and empagliflozin or a pharmaceutically acceptable salt thereof as active ingredients; and (c) mixing the granular portion and the postmixed portion to prepare a solid preparation.

[0039] The above empagliflozin can be mixed in an amount of 1.5 to 8 wt% based on the total weight of the pharmaceutical combination preparation.

[0040] A disintegrant may be added during at least one of the steps of (a) preparing the granule portion; and (b) preparing the post-mixing portion.

[0041] The above disintegrant may be added in an amount of 1 to 15 wt% based on the total weight of the pharmaceutical combination preparation.

[0042] The combination formulation provided by the present invention contains ezetimibe, rosuvastatin, and empagliflozin as active ingredients, thereby having a synergistic effect in the concomitant treatment of dyslipidemia and diabetes, while also securing a dissolution profile equivalent to that of single administration of these drugs individually, and providing an oral combination formulation with excellent stability. In addition, the oral combination formulation of the present invention can administer two drugs that are conventionally administered in combination in a single formulation, thereby enabling simultaneous management of risk factors in patients and improving medication compliance. In addition, the oral combination formulation of the present invention has excellent friability, thereby enhancing tabletability and moisture stability, thereby preventing a decrease in productivity.

[0043] Figure 1 is a drawing showing the results of an experiment comparing the dissolution rates of empagliflozin under the conditions of a pH 1.2 solution, targeting Examples 1 to 3 and Comparative Examples 1 and 2 in Experimental Example 1 and the control drug, Control Example 2.

[0044] Figure 2 is a drawing showing the results of an experiment comparing the dissolution rates of rosuvastatin under conditions of a pH 1.2 solution, targeting Examples 1 to 3 and Comparative Examples 1 and 2 in Experimental Example 1 and the control drug, Control Example 1.

[0045] Figure 3 is a drawing showing the results of an experiment comparing the dissolution rates of empagliflozin under the conditions of a pH 1.2 solution for the tablets of Examples 2 and 4 to 8 in Experimental Example 2.

[0046] Figure 4 is a drawing showing the results of an experiment comparing the dissolution rates of rosuvastatin under the conditions of a pH 1.2 solution, targeting the tablets of Examples 2 and 4 to 8 in Experimental Example 2.

[0047] Figure 5 is a drawing showing the results of an experiment comparing the dissolution rates of ezetimibe in the tablets of Example 2 and Examples 4 to 8 under the condition of a pH 6.8 solution in Experimental Example 2.

[0048] Figure 6 is a drawing showing the results of an experiment comparing the dissolution rates of empagliflozin under pH 1.2 solution conditions, targeting the tablets of Examples 2, 9 to 11, and Comparative Example 3 in Experimental Example 3 and the control drug, Control Example 2.

[0049] Figure 7 is a drawing showing the results of an experiment comparing the dissolution rates of rosuvastatin under conditions of a pH 1.2 solution, targeting the tablets of Examples 2, 9 to 11, and Comparative Example 3 in Experimental Example 3 and the control drug, Control Example 1.

[0050] Figure 8 is a graph showing the change in plasma concentration (ng / mL) of ezetimibe over time as a result of evaluating the pharmacokinetic parameters of ezetimibe after administering the tablet of Example 2 to a beagle dog in Experimental Example 5 or administering the tablets of Control Examples 1 and 2 together.

[0051] Figure 9 is a graph showing the change in the plasma concentration (ng / mL) of rosuvastatin over time as a result of evaluating the pharmacokinetic parameters of rosuvastatin after administering the tablet of Example 2 to a beagle dog in Experimental Example 5 or administering the tablets of Control Examples 1 and 2 together.

[0052] Figure 10 is a graph showing the change in the plasma concentration (ng / mL) of empagliflozin over time as a result of the evaluation of the pharmacokinetic parameters of empagliflozin after administering the tablet of Example 2 to a beagle dog in Experimental Example 5 or administering the tablets of Control Examples 1 and 2 together.

[0053] According to one embodiment of the present invention, a pharmaceutical combination preparation is provided comprising (1) ezetimibe or a pharmaceutically acceptable salt thereof, (2) rosuvastatin or a pharmaceutically acceptable salt thereof, and (3) empagliflozin or a pharmaceutically acceptable salt thereof as active ingredients.

[0054] According to another embodiment of the present invention, a method for preparing a pharmaceutical combination preparation is provided, comprising the steps of: (a) preparing a granular portion comprising ezetimibe or a pharmaceutically acceptable salt thereof as an active ingredient; (b) preparing a postmixed portion comprising rosuvastatin or a pharmaceutically acceptable salt thereof and empagliflozin or a pharmaceutically acceptable salt thereof as active ingredients; and (c) mixing the granular portion and the postmixed portion to prepare a solid preparation.

[0055] Patients with metabolic diseases such as diabetes or dyslipidemia typically take a large number of medications, often with multiple types and durations, increasing the burden of medication. Furthermore, diabetes and dyslipidemia have a high co-morbidity, meaning patients with both conditions face the burden of having to take medications for each condition separately.

[0056] In the present invention, the active ingredients of ezetimibe and rosuvastatin, which are effective in treating dyslipidemia, and empagliflozin, which is effective in treating diabetes, are included in a single formulation, thereby enabling concurrent treatment of dyslipidemia and diabetes with only one formulation, and the number of medications that a patient must take is reduced, thereby improving convenience of taking the medication and compliance with medication.

[0057] According to one embodiment of the present invention, the present invention relates to a pharmaceutical combination preparation comprising (1) ezetimibe or a pharmaceutically acceptable salt thereof, (2) rosuvastatin or a pharmaceutically acceptable salt thereof, and (3) empagliflozin or a pharmaceutically acceptable salt thereof as active ingredients.

[0058] In the present specification, the "ezetimibe" is a compound of (3R,4S)-1-(4-fluorophenyl)-3-[(S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one represented by the following chemical formula 1. The ezetimibe is known to lower blood lipid-related levels by preventing cholesterol ingested through food from being reabsorbed into the body in the small intestine.

[0059] [Chemical Formula 1]

[0060]

[0061] In the present specification, the "rosuvastatin" is a compound of (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid) represented by the following chemical formula 2. The rosuvastatin is known to inhibit HMG-CoA reductase, which is essential for the cholesterol synthesis process, thereby lowering blood LDL-cholesterol levels and, conversely, increasing HDL-cholesterol levels, thereby contributing to the treatment of dyslipidemia.

[0062] [Chemical Formula 2]

[0063]

[0064] In this specification, "empagliflozin" is a compound of (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol) represented by the following chemical formula 3. The empagliflozin inhibits SGLT-2 in the renal tubules, thereby inhibiting the reabsorption process of glucose and excreting glucose in the urine, thereby suppressing an increase in blood sugar levels.

[0065] [Chemical Formula 3]

[0066]

[0067] The term "pharmaceutically acceptable salt" as used herein refers to a salt commonly used in the relevant technical field, and includes not only salts prepared with inorganic ions, inorganic acids or organic acids, but also hydrates or solvates of the salts. In the present invention, pharmaceutically acceptable salts of ezetimibe, rosuvastatin or empagliflozin include acetate, adipate, L-ascorbate, L-aspartate, caprate, carbonate, citrate, fumarate, mucosal salt, D-glucoheptone, D-gluconate, D-glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hippurate, hydrochloride, DL-lactate, laurate, maleate, (-)-L-malic acid, palmitate, phosphate, sebacate, stearate, succinate, sulfate, (+)-L-tartrate, thiocyanate, alginic acid, benzenesulfonate, benzoate, (+)-camphorate, caprylate, cyclamate, dodecylsulfate, ethane-1,2-disulfonate, Examples thereof include, but are not limited to, 2-hydroxyethanesulfonate, ethanesulfonate, gentisate, 2-oxo-glutarate, isobutyrate, lactobionic acid salt, malonate, methanesulfonate, naphthalene-1,5-disulfonate, naphthalene-2-sulfonate, 1-hydroxy-2-naphthoate, nicotinate, oleate, orotate, oxalate, pamoate, propionate, (-)-L-pyroglutamate, and p-toluenesulfonate.

[0068] In the present invention, pharmaceutically acceptable salts of rosuvastatin include calcium salts, magnesium salts, zinc salts, strontium salts, etc., and are preferably rosuvastatin calcium salts, but are not limited thereto.

[0069] In addition, in the present invention, the empagliflozin may be used together with one or more amino acids. Here, the amino acid may be selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan, serine, cysteine, threonine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, histidine, and lysine. In addition, in the present invention, the empagliflozin and the amino acid may be in the form of a co-crystal. In one example, the active ingredient may include, but is not limited to, empagliflozin and proline (e.g., L-proline or D-proline).

[0070] Any reference in this specification to “ezetimibe,” “rosuvastatin,” and “empagliflozin” should be understood to include all salts, solvates, and isomers of each of the above-mentioned compounds.

[0071] Generally, when manufacturing a combination preparation containing two or more active ingredients, there is a possibility that the active ingredients may react with each other, and the dissolution or disintegration of some ingredients may be problematic due to other ingredients, making it difficult to formulate them for application to the human body. As a result of extensive efforts, the inventors of the present invention have discovered an optimal combination of active ingredients in the contents that includes ezetimibe, rosuvastatin or a pharmaceutically acceptable salt thereof, and empagliflozin while ensuring excellent dissolution stability of each ingredient, thereby leading to the present invention.

[0072] The combination formulation of the present invention may contain ezetimibe in an amount of 5 mg to 20 mg per unit dosage form, and preferably in an amount of 5 mg to 15 mg. As an example, the pharmaceutical formulation of the present invention may contain ezetimibe as an active ingredient in an amount of 10 mg, but is not limited thereto. Here, the content refers to the amount contained as ezetimibe in a free state, i.e., not in the form of an inorganic or organic salt, ester, hydrate, or solvate.

[0073] The combination preparation of the present invention may contain rosuvastatin in an amount of 2 mg to 40 mg or 2 to 20 mg per unit dosage form, and preferably 2.5 mg to 40 mg or 2.5 mg to 20 mg. As an example, the pharmaceutical preparation of the present invention may contain rosuvastatin as an active ingredient in an amount of, but not limited to, 2.5 mg, 5 mg, 10 mg, or 20 mg. Here, the content refers to the amount contained as rosuvastatin in a free state, i.e., not in the form of an inorganic or organic salt, ester, hydrate, or solvate. As another example, the pharmaceutical preparation of the present invention may contain rosuvastatin calcium salt as an active ingredient in an amount of, but not limited to, 2.6 mg, 5.2 mg, 10.4 mg, or 20.8 mg. The content at this time refers to the amount contained as rosuvastatin calcium salt.

[0074] The combination preparation of the present invention may contain empagliflozin in an amount of 5 mg to 40 mg or 10 to 40 mg per unit dosage form, and preferably 5 mg to 25 mg or 10 mg to 25 mg. As an example, the pharmaceutical preparation of the present invention may contain empagliflozin as an active ingredient in an amount of, but not limited to, 10 mg, 12.5 mg, 15 mg, 20 mg or 25 mg. Here, the content refers to the amount contained as empagliflozin in a free state, i.e., not in the form of an inorganic or organic salt, ester, hydrate or solvate.

[0075] As an example, the combination formulation of the present invention may include, but is not limited to, ezetimibe in an amount of 5 mg to 20 mg, rosuvastatin in an amount of 2 mg to 40 mg, and empagliflozin in an amount of 5 mg to 40 mg per unit dosage form.

[0076] As another example, the combination formulation of the present invention may contain, but is not limited to, ezetimibe in an amount of 5 mg to 15 mg, rosuvastatin in an amount of 2 mg to 20 mg, and empagliflozin in an amount of 5 mg to 40 mg per unit dosage form.

[0077] As another example, the combination formulation of the present invention may include, but is not limited to, ezetimibe in an amount of 5 mg to 20 mg, rosuvastatin in an amount of 2.5 mg to 20 mg, and empagliflozin in an amount of 10 mg to 25 mg per unit dosage form.

[0078] As another example, the combination formulation of the present invention may include, but is not limited to, ezetimibe in an amount of 5 mg to 15 mg, rosuvastatin in an amount of 2.5 mg to 20 mg, and empagliflozin in an amount of 10 mg to 25 mg per unit dosage form.

[0079] As another example, the combination formulation of the present invention may include, but is not limited to, ezetimibe in an amount of 10 mg, rosuvastatin in an amount of 2.5 mg to 20 mg, and empagliflozin in an amount of 10 mg or 25 mg per unit dosage form.

[0080] As another example, the combination formulation of the present invention may comprise ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin in an amount of 2.5 mg, 5 mg, 10 mg, or 20 mg, and empagliflozin in an amount of 10 mg, 12.5 mg, 15 mg, 20 mg, or 25 mg, but is not limited thereto.

[0081] As another example, the combination formulation of the present invention may comprise ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin in an amount of 2.5 mg, 5 mg or 10 mg, and empagliflozin in an amount of 10 mg, 12.5 mg, 15 mg, 20 mg or 25 mg, but is not limited thereto.

[0082] As another example, the combination formulation of the present invention may comprise, but is not limited to, ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin in an amount of 2.5 mg, 5 mg, 10 mg or 20 mg, and empagliflozin in an amount of 10 mg or 25 mg.

[0083] As another example, the combination formulation of the present invention may comprise, but is not limited to, ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin in an amount of 2.5 mg, 5 mg or 10 mg, and empagliflozin in an amount of 10 mg or 25 mg.

[0084] As another example, the combination formulation of the present invention may comprise ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin in an amount of 2.5 mg, and empagliflozin in an amount of, but not limited to, 10 mg, 12.5 mg, 15 mg, 20 mg, or 25 mg.

[0085] As another example, the combination formulation of the present invention may comprise ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin in an amount of 5 mg, and empagliflozin in an amount of, but not limited to, 10 mg, 12.5 mg, 15 mg, 20 mg, or 25 mg.

[0086] As another example, the combination formulation of the present invention may comprise ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin in an amount of 10 mg, and empagliflozin in an amount of 10 mg, 12.5 mg, 15 mg, 20 mg, or 25 mg, but is not limited thereto.

[0087] As another example, the combination formulation of the present invention may include, but is not limited to, ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin in an amount of 2.5 mg, and empagliflozin in an amount of 10 mg or 25 mg.

[0088] As another example, the combination formulation of the present invention may include, but is not limited to, ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin in an amount of 5 mg, and empagliflozin in an amount of 10 mg or 25 mg.

[0089] As another example, the combination formulation of the present invention may include, but is not limited to, ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin in an amount of 10 mg, and empagliflozin in an amount of 10 mg or 25 mg.

[0090] As another example, the combination formulation of the present invention may include, but is not limited to, ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin in an amount of 2.5 mg, 5 mg or 10 mg, and empagliflozin in an amount of 10 mg.

[0091] As another example, the combination formulation of the present invention may include, but is not limited to, ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin in an amount of 2.5 mg, 5 mg or 10 mg, and empagliflozin in an amount of 25 mg.

[0092] As another example, the combination formulation of the present invention may include, but is not limited to, 10 mg of ezetimibe, 2.5 mg of rosuvastatin, and 10 mg of empagliflozin per unit dosage form.

[0093] As another example, the combination formulation of the present invention may include, but is not limited to, 10 mg of ezetimibe, 5 mg of rosuvastatin, and 10 mg of empagliflozin per unit dosage form.

[0094] As another example, the combination formulation of the present invention may include, but is not limited to, 10 mg of ezetimibe, 10 mg of rosuvastatin, and 10 mg of empagliflozin per unit dosage form.

[0095] As another example, the combination formulation of the present invention may include, but is not limited to, 10 mg of ezetimibe, 2.5 mg of rosuvastatin, and 25 mg of empagliflozin per unit dosage form.

[0096] As another example, the combination formulation of the present invention may include, but is not limited to, 10 mg of ezetimibe, 5 mg of rosuvastatin, and 25 mg of empagliflozin per unit dosage form.

[0097] As another example, the combination formulation of the present invention may include, but is not limited to, 10 mg of ezetimibe, 10 mg of rosuvastatin, and 25 mg of empagliflozin per unit dosage form.

[0098] As another example, the combination formulation of the present invention may contain, but is not limited to, ezetimibe in an amount of 5 mg to 15 mg, rosuvastatin calcium salt in an amount of 2.6 mg to 20.8 mg, and empagliflozin in an amount of 10 mg to 25 mg per unit dosage form.

[0099] As another example, the combination formulation of the present invention may contain, but is not limited to, 10 mg of ezetimibe, 2.6 mg to 20.8 mg of rosuvastatin calcium salt, and 10 mg or 25 mg of empagliflozin per unit dosage form.

[0100] As another example, the combination formulation of the present invention may contain, but is not limited to, ezetimibe in an amount of 5 mg to 20 mg, rosuvastatin calcium salt in an amount of 2.6 mg to 20.8 mg, and empagliflozin in an amount of 5 mg to 25 mg per unit dosage form.

[0101] As another example, the combination formulation of the present invention may contain, but is not limited to, ezetimibe in an amount of 5 mg to 15 mg per unit dosage form, rosuvastatin in an amount of 2.6 mg to 10.4 mg as a calcium salt, and empagliflozin in an amount of 10 mg to 25 mg.

[0102] As another example, the combination formulation of the present invention may comprise ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin calcium salt in an amount of 2.6 mg, 5.2 mg, 10.4 mg, or 20.8 mg, and empagliflozin in an amount of, but not limited to, 10 mg, 12.5 mg, 15 mg, 20 mg, or 25 mg.

[0103] As another example, the combination formulation of the present invention may comprise ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin calcium salt in an amount of 2.6 mg, 5.2 mg or 10.4 mg, and empagliflozin in an amount of 10 mg, 12.5 mg, 15 mg, 20 mg or 25 mg, but is not limited thereto.

[0104] As another example, the combination formulation of the present invention may comprise ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin calcium salt in an amount of 2.6 mg, 5.2 mg, 10.4 mg or 20.8 mg, and empagliflozin in an amount of 10 mg or 25 mg, but is not limited thereto.

[0105] As another example, the combination formulation of the present invention may comprise ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin calcium salt in an amount of 2.6 mg, 5.2 mg or 10.4 mg, and empagliflozin in an amount of 10 mg or 25 mg, but is not limited thereto.

[0106] As another example, the combination formulation of the present invention may comprise ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin calcium salt in an amount of 2.6 mg, and empagliflozin in an amount of, but not limited to, 10 mg, 12.5 mg, 15 mg, 20 mg, or 25 mg.

[0107] As another example, the combination formulation of the present invention may comprise ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin calcium salt in an amount of 5.2 mg, and empagliflozin in an amount of, but not limited to, 10 mg, 12.5 mg, 15 mg, 20 mg, or 25 mg.

[0108] As another example, the combination formulation of the present invention may comprise ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin calcium salt in an amount of 10.4 mg, and empagliflozin in an amount of, but not limited to, 10 mg, 12.5 mg, 15 mg, 20 mg, or 25 mg.

[0109] As another example, the combination formulation of the present invention may include, but is not limited to, ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin calcium salt in an amount of 2.6 mg, and empagliflozin in an amount of 10 mg or 25 mg.

[0110] As another example, the combination formulation of the present invention may include, but is not limited to, ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin calcium salt in an amount of 5.2 mg, and empagliflozin in an amount of 10 mg or 25 mg.

[0111] As another example, the combination formulation of the present invention may include, but is not limited to, ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin calcium salt in an amount of 10.4 mg, and empagliflozin in an amount of 10 mg or 25 mg.

[0112] As another example, the combination formulation of the present invention may comprise ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin calcium salt in an amount of 2.6 mg, 5.2 mg or 10.4 mg, and empagliflozin in an amount of 10 mg, but is not limited thereto.

[0113] As another example, the combination formulation of the present invention may comprise, but is not limited to, ezetimibe in an amount of 10 mg per unit dosage form, rosuvastatin calcium salt in an amount of 2.6 mg, 5.2 mg, or 10.4 mg, and empagliflozin in an amount of 25 mg.

[0114] As another example, the combination formulation of the present invention may include, but is not limited to, 10 mg of ezetimibe, 2.6 mg of rosuvastatin calcium salt, and 10 mg of empagliflozin per unit dosage form.

[0115] As another example, the combination formulation of the present invention may include, but is not limited to, 10 mg of ezetimibe, 5.2 mg of rosuvastatin calcium salt, and 10 mg of empagliflozin per unit dosage form.

[0116] As another example, the combination formulation of the present invention may include, but is not limited to, 10 mg of ezetimibe, 10.4 mg of rosuvastatin calcium salt, and 10 mg of empagliflozin per unit dosage form.

[0117] As another example, the combination formulation of the present invention may include, but is not limited to, 10 mg of ezetimibe, 2.6 mg of rosuvastatin calcium salt, and 25 mg of empagliflozin per unit dosage form.

[0118] As another example, the combination formulation of the present invention may include, but is not limited to, 10 mg of ezetimibe, 5.2 mg of rosuvastatin calcium salt, and 25 mg of empagliflozin per unit dosage form.

[0119] As another example, the combination formulation of the present invention may include, but is not limited to, 10 mg of ezetimibe, 10.4 mg of rosuvastatin calcium salt, and 25 mg of empagliflozin per unit dosage form.

[0120] The combination preparation of the present invention may contain ezetimibe in an amount of 1 to 3 wt%, 1 to 2.5 wt%, 1 to 2 wt%, 1.5 to 3 wt%, 1.5 to 2.5 wt%, or 1.5 to 2 wt% based on the total weight of the combination preparation.

[0121] In addition, the combination preparation of the present invention may contain rosuvastatin or a pharmaceutically acceptable salt thereof, preferably rosuvastatin calcium salt, in an amount of 0.1 to 3 wt%, 0.1 to 2.5 wt%, 0.1 to 2.2 wt%, 0.5 to 3 wt%, 0.5 to 2.5 wt%, or 0.5 to 2.2 wt% based on the total weight of the combination preparation.

[0122] In addition, the combination preparation of the present invention may contain empagliflozin in an amount of 1.5 to 8 wt%, 1.5 to 7.5 wt%, 1.5 to 7 wt%, 1.5 to 6 wt%, or 1.5 to 5 wt% based on the total weight of the combination preparation.

[0123] In the combination preparation of the present invention, if the content of ezetimibe, rosuvastatin or a pharmaceutically acceptable salt thereof, or empagliflozin is outside the above-mentioned range, particularly if the content of empagliflozin is outside the above-mentioned range, the dissolution stability may be reduced, and it may be difficult to expect the target dissolution rate, that is, the same level as the dissolution rate obtained when each component is administered as a single drug.

[0124] In addition, the combination preparation of the present invention can increase the dissolution stability of the active ingredients and also improve the physical stability of the preparation itself by including a disintegrant together with the above-mentioned active ingredients in an amount of 1 to 15 wt%, 1 to 12 wt%, 1 to 10 wt%, 1 to 5 wt%, 2 to 15 wt%, 2 to 12 wt%, 2 to 10 wt%, or 2 to 5 wt% based on the total weight of the pharmaceutical combination preparation. When the content of the disintegrant is less than 1 wt%, the dissolution rate of the active ingredient may decrease, and when the content exceeds 15 wt%, the physical stability of the preparation may decrease.

[0125] In the present invention, the disintegrant may be selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, carboxymethylcellulose calcium, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose, starch, pregelatinized starch, corn starch, potato starch, alginic acid or a sodium salt thereof, and any combination thereof, and preferably may include at least one of crospovidone, croscarmellose sodium, and sodium starch glycolate, but is not limited thereto.

[0126] The complex preparation of the present invention may additionally include one or more pharmaceutically acceptable additives selected from the group consisting of excipients (diluents), lubricants, and binders.

[0127] The combined preparation of the present invention may contain an excipient (diluent) in an amount of 60 to 95 wt%, 60 to 90 wt%, 65 to 95 wt%, 65 to 90 wt%, 70 to 95 wt%, 70 to 90 wt%, 75 to 95 wt%, 75 to 90 wt%, 78 to 95 wt%, or 78 to 90 wt% based on the total weight of the pharmaceutical preparation, but is not limited thereto.

[0128] In the present invention, the excipient (diluent) may include a substance selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, magnesium aluminosilicate metasilicate, magnesium aluminosilicate, aluminum silicate, sodium silicate, potassium silicate, magnesium silicate, calcium silicate, lactose, lactose hydrate, lactose anhydrous, calcium hydrogen phosphate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, dextrin, mannitol, sorbitol, starch, calcium phosphate hydrate, calcium carbonate, sugars, and any mixture thereof, but is not limited thereto. Any substance used as an excipient (diluent) in the art may be included without limitation.

[0129] The combined preparation of the present invention may contain the lubricant in an amount of 0.1 to 10 wt%, 0.1 to 5 wt%, 0.1 to 3 wt%, 0.1 to 2 wt%, 0.1 to 1.5 wt%, 0.5 to 10 wt%, 0.5 to 5 wt%, 0.5 to 3 wt%, 0.5 to 2 wt%, or 0.5 to 1.5 wt% based on the total weight of the pharmaceutical preparation, but is not limited thereto.

[0130] In the present invention, the lubricant may be selected from the group consisting of calcium stearate, colloidal silicon dioxide (fumed silica, Aerosil), glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hardened vegetable oil, polyethylene glycol, sodium benzoate, talc, and any combination thereof, but is not limited thereto, and any substance used as a lubricant in the art may be included without limitation.

[0131] The combination preparation of the present invention may contain a binder in an amount of 0.1 to 5 wt%, 0.1 to 3 wt%, 0.1 to 2 wt%, 0.1 to 1 wt%, or 0.1 to 0.6 wt% based on the total weight of the pharmaceutical preparation, but is not limited thereto. However, in the present invention, when only a solvent is used in the wet granulation of the granule portion, the binder may not be included.

[0132] The composite preparation of the present invention may include a granular portion and a post-mixed portion, and in this case, the granular portion and the post-mixed portion may be mixed and present in the composite preparation.

[0133] In the present invention, the granular portion means a state in which a plurality of components are mixed to form a plurality of granules, and may include both dry granules and wet granules, but may preferably be wet granules.

[0134] In order to suppress problems such as differences in physicochemical properties between the active ingredients in the composite preparation of the present invention or interference due to mutual reactions, one of the three active ingredients and the other two active ingredients can be physically separated.

[0135] Specifically, in the combination preparation according to the present invention, the ezetimibe may exist in a physically separated state from rosuvastatin and empagliflozin. In the combination preparation, the active ingredients, ezetimibe and rosuvastatin / empagliflozin, may have problems with the stability of the active ingredients, such as an increase in related substances of ezetimibe and rosuvastatin / empagliflozin, due to differences in their stable pH conditions when formulated as a combination preparation. Accordingly, it may be preferable for the ezetimibe and rosuvastatin / empagliflozin to exist in a physically separated state. Here, the term "physically separated state" refers to a processing step for separating a reference active ingredient from other active ingredients, and a state in which the reference active ingredient is maintained in a state distinguishable from other active ingredients in the final combination preparation obtained through such a processing step. This does not apply to a case in which the components themselves are mixed in a mixing process in advance without such a processing step. A physically separated state can be formed through, for example, physical separation using granule manufacturing, physical separation by dividing the layers and pressing them into tablets, physical separation by pressing them into separate tablets, and physical separation using a core-shell structure.

[0136] As an example, in the present invention, the granular portion may include ezetimibe or a pharmaceutically acceptable salt thereof, and the post-mixed portion may include rosuvastatin or a pharmaceutically acceptable salt thereof and empagliflozin or a pharmaceutically acceptable salt thereof.

[0137] As another example, in the present invention, the granular portion may include rosuvastatin or a pharmaceutically acceptable salt thereof and empagliflozin or a pharmaceutically acceptable salt thereof, and the post-mixed portion may include ezetimibe or a pharmaceutically acceptable salt thereof.

[0138] In the composite preparation of the present invention, the granular portion or the post-mixing portion may additionally include one or more pharmaceutically acceptable additives selected from the group consisting of excipients (diluents), disintegrants, binders, and lubricants.

[0139] In the present invention, at least one of the granular portion and the post-mixing portion may include a disintegrant. In one example, the granular portion may include a disintegrant, in another example, the post-mixing portion may include a disintegrant, and in yet another example, both the granular portion and the post-mixing portion may include a disintegrant.

[0140] In the present invention, the granular portion contains ezetimibe or a pharmaceutically acceptable salt thereof as an active ingredient, and may additionally contain one or more pharmaceutically acceptable additives selected from the group consisting of excipients (diluents), disintegrants, lubricants, and binders.

[0141] In the present invention, ezetimibe, which is included as an active ingredient in the granular portion, may be included in an amount of 10 to 30 wt%, 10 to 20 wt%, or 10 to 15 wt% based on the total weight of the granular portion, but is not limited thereto.

[0142] In the present invention, the granular portion may further include a disintegrant. At this time, the content of the disintegrant included in the granular portion may be included in an amount of 0.5 to 5 wt%, 0.5 to 4 wt%, 0.5 to 3 wt%, 0.5 to 2 wt%, 1 to 5 wt%, 1 to 4 wt%, 1 to 3 wt%, or 1 to 2 wt% based on the total weight of the pharmaceutical combination preparation. When the content is less than 0.5 wt%, the dissolution rate of the active ingredient may decrease, and when the content exceeds 5 wt%, the friability of the preparation may decrease, which may significantly deteriorate the tableting properties or the stability of the drug due to moisture.

[0143] In addition, the content of the disintegrant included in the granular portion may be included in an amount of 3 to 20 wt%, 3 to 15 wt%, 3 to 10 wt%, 5 to 15 wt%, or 5 to 10 wt% based on the total weight of the granular portion. If the content of the disintegrant in the granular portion is less than 3 wt%, the dissolution rate of the active ingredient may decrease, and if the content exceeds 20 wt%, the friability of the formulation may decrease, resulting in a significant decrease in tableting properties or drug stability due to moisture.

[0144] In the present invention, the disintegrant included in the granular portion may be selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, carboxymethylcellulose calcium, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose, starch, pregelatinized starch, corn starch, potato starch, alginic acid or a sodium salt thereof, and any combination thereof, and preferably may include at least one of crospovidone, croscarmellose sodium, and sodium starch glycolate, but is not limited thereto.

[0145] In the present invention, the granular portion may further include an excipient (diluent). The content of the excipient (diluent) in the granular portion may be included in an amount of 5 to 20 wt%, 5 to 15 wt%, 10 to 25 wt%, 10 to 20 wt%, or 10 to 15 wt% based on the total weight of the pharmaceutical combination preparation, but is not limited thereto.

[0146] In addition, in the present invention, the granular portion may contain an excipient (diluent) in an amount of 50 to 80 wt%, 60 to 80 wt%, or 70 to 80 wt% based on the total weight of the granular portion, but is not limited thereto.

[0147] In the present invention, the excipient (diluent) included in the granular portion may include a substance selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, magnesium aluminometasilicate, magnesium aluminosilicate, aluminum silicate, sodium silicate, potassium silicate, magnesium silicate, calcium silicate, lactose, lactose monohydrate, lactose anhydrous, calcium hydrogen phosphate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, dextrin, mannitol, sorbitol, starch, calcium phosphate monohydrate, calcium carbonate, sugars, and any mixture thereof, but is not limited thereto. Any substance used as an excipient (diluent) in the art may be included without limitation.

[0148] In the present invention, the granular portion may further include a lubricant. The lubricant included in the granular portion may be included in an amount of 0.05 to 5 wt%, 0.05 to 3 wt%, 0.05 to 2 wt%, 0.05 to 1 wt%, 0.05 to 0.5 wt%, 0.1 to 5 wt%, 0.1 to 2 wt%, 0.1 to 3 wt%, 0.1 to 1 wt%, or 0.1 to 0.5 wt% based on the total weight of the pharmaceutical combination preparation, but is not limited thereto.

[0149] In addition, the lubricant included in the granular portion in the present invention may be included in an amount of 0.1 to 10 wt%, 0.1 to 5 wt%, 0.1 to 3 wt%, 0.1 to 2 wt%, 0.5 to 10 wt%, 0.5 to 5 wt%, 0.5 to 3 wt%, or 0.5 to 2 wt% based on the total weight of the granular portion, but is not limited thereto.

[0150] In the present invention, the lubricant included in the granular portion may be selected from the group consisting of calcium stearate, colloidal silicon dioxide (fumed silica, Aerosil), glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hardened vegetable oil, polyethylene glycol, sodium benzoate, talc, and any combination thereof, but is not limited thereto, and any material used as a lubricant in the art may be included without limitation.

[0151] In the present invention, the granular portion may further include a binder for producing wet granules. The binder included in the granular portion may be included in an amount of 0.1 to 5 wt%, 0.1 to 3 wt%, 0.1 to 2 wt%, 0.1 to 1 wt%, or 0.1 to 0.6 wt% based on the total weight of the pharmaceutical combination preparation, but is not limited thereto.

[0152] In addition, the binder included in the granular portion in the present invention may be included in an amount of 0.5 to 10 wt%, 0.5 to 5 wt%, 0.5 to 3 wt%, 1 to 10 wt%, 1 to 5 wt%, or 1 to 3 wt% based on the total weight of the granular portion, but is not limited thereto.

[0153] However, in the present invention, when only a solvent is used for binding when manufacturing wet granules using the granule portion, a binder may not be included.

[0154] In the present invention, the binder included in the granular portion may be selected from the group consisting of povidone, hypromellose, hydroxypropylcellulose, copovidone, and any combination thereof, but is not limited thereto, and any material used as a binder in the art may be included without limitation.

[0155] In the present invention, the granular portion may further include, in addition to the active ingredient, an additive selected from among microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, povidone, sodium lauryl sulfate, and any combination thereof, as a pharmaceutically acceptable additive.

[0156] In the present invention, the post-mixing portion includes, as active ingredients, rosuvastatin or a pharmaceutically acceptable salt thereof and empagliflozin or a pharmaceutically acceptable salt thereof, and may further include one or more pharmaceutically acceptable additives selected from the group consisting of a disintegrant, an excipient (diluent), and a lubricant.

[0157] In the present invention, rosuvastatin included as an active ingredient in the post-mixing portion may be included in an amount of 0.1 to 10 wt%, 0.1 to 8 wt%, 0.1 to 6 wt%, 0.1 to 3 wt%, 0.5 to 10 wt%, 0.5 to 8 wt%, 0.5 to 6 wt%, 0.5 to 3 wt%, 1 to 10 wt%, 1 to 8 wt%, 1 to 6 wt%, or 1 to 3 wt%, based on the total weight of the post-mixing portion, but is not limited thereto.

[0158] In addition, in the present invention, when rosuvastatin is included in the post-mixing portion in the form of a calcium salt, the rosuvastatin calcium salt may be included in an amount of 0.1 to 10 wt%, 0.1 to 8 wt%, 0.1 to 6 wt%, 0.1 to 3 wt%, 0.5 to 10 wt%, 0.5 to 8 wt%, 0.5 to 6 wt%, 0.5 to 3 wt%, 1 to 10 wt%, 1 to 8 wt%, 1 to 6 wt%, or 1 to 3 wt% based on the total weight of the post-mixing portion, but is not limited thereto.

[0159] In the present invention, empagliflozin included as an active ingredient in the post-mixing portion may be included in an amount of 0.5 to 11 wt%, 0.5 to 10 wt%, 0.5 to 8 wt%, 0.5 to 6 wt%, 1 to 11 wt%, 1 to 10 wt%, 1 to 8 wt%, 1 to 6 wt%, 1.5 to 11 wt%, 1.5 to 10 wt%, 1.5 to 8 wt%, or 1.5 to 6 wt%, based on the total weight of the post-mixing portion, but is not limited thereto. Empagliflozin itself has sticky properties as a raw material. Therefore, it is important to control the content range when manufacturing a formulation. In the present invention, if the content of empagliflozin exceeds 11 wt%, not only will the sticky nature of empagliflozin prevent an appropriate dissolution rate, but it may also reduce the initial dissolution rate of rostatin, which is added together. If too little is used, the effects of the active ingredient cannot be fully exerted.

[0160] In the present invention, the post-mixing unit may further include a disintegrant. At this time, the content of the disintegrant included in the post-mixing unit may be included in an amount of 0.1 to 15 wt%, 0.1 to 10 wt%, 0.1 to 8 wt%, 0.1 to 5 wt%, 0.1 to 3 wt%, 1 to 10 wt%, 1 to 8 wt%, 1 to 5 wt%, or 1 to 3 wt% based on the total weight of the pharmaceutical combination preparation. When the content of the disintegrant is less than 0.5 wt%, the dissolution rate of the active ingredient may decrease, and when the content exceeds 15 wt%, the friability of the preparation may decrease, which may significantly deteriorate the tableting properties or the stability of the drug due to moisture.

[0161] In addition, in the present invention, the disintegrant included in the post-mixing section may be included in an amount of 0.1 to 18 wt%, 0.1 to 15 wt%, 0.1 to 12 wt%, 0.1 to 7 wt%, 0.1 to 5 wt%, 0.5 to 18 wt%, 0.5 to 15 wt%, 0.5 to 12 wt%, 0.5 to 7 wt%, 0.5 to 5 wt%, 1 to 18 wt%, 1 to 15 wt%, 1 to 12 wt%, 1 to 7 wt%, or 1 to 5 wt% based on the total weight of the post-mixing section, but is not limited thereto. If the content of the disintegrant is less than 0.1 wt%, the dissolution rate of the active ingredient may decrease, and if the content exceeds 18 wt%, the friability of the formulation may decrease, resulting in a significant decrease in tableting properties or drug stability due to moisture.

[0162] In the present invention, the disintegrant included in the post-mixing portion may be selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, carboxymethylcellulose calcium, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose, starch, pregelatinized starch, corn starch, potato starch, alginic acid or a sodium salt thereof, and any combination thereof, and preferably may include at least one of crospovidone, croscarmellose sodium, and sodium starch glycolate, but is not limited thereto.

[0163] In the present invention, the post-mixing unit may further include an excipient (diluent). The content of the excipient (diluent) in the post-mixing unit may be included in an amount of 50 to 90 wt%, 50 to 85 wt%, 50 to 80 wt%, 60 to 90 wt%, 60 to 85 wt%, 60 to 80 wt%, 70 to 90 wt%, 70 to 85 wt%, or 70 to 80 wt% based on the total weight of the pharmaceutical preparation, but is not limited thereto.

[0164] In addition, in the present invention, the excipient (diluent) included in the post-mixing unit may be included in an amount of 60 to 97 wt%, 60 to 95 wt%, 70 to 97 wt%, 70 to 95 wt%, 75 to 97 wt%, 75 to 95 wt%, 80 to 97 wt%, or 80 to 95 wt%, based on the total weight of the post-mixing unit, but is not limited thereto. In particular, the content of the excipient (diluent) in the post-mixing unit is related to the dissolution rate of empagliflozin. When the content of the excipient (diluent) is less than 60 wt%, the dissolution is delayed due to the sticky and easily aggregated nature of empagliflozin, and the dissolution of rosuvastatin mixed together may be inhibited. On the other hand, if the content of excipients (diluents) exceeds 97 wt%, it may increase the generation of flexible substances or rather suppress the release of the drug.

[0165] In the present invention, the excipient (diluent) included in the post-mixing section may include, but is not limited to, a material selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, magnesium aluminosilicate metasilicate, magnesium aluminosilicate, aluminum silicate, sodium silicate, potassium silicate, magnesium silicate, calcium silicate, lactose, lactose monohydrate, lactose anhydrous, calcium hydrogen phosphate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, dextrin, mannitol, sorbitol, starch, calcium phosphate monohydrate, calcium carbonate, sugars, and any mixture thereof. Any material used as an excipient (diluent) in the art may be included without limitation.

[0166] In the present invention, the post-mixing unit may further include a lubricant. The lubricant included in the post-mixing unit may be included in an amount of 0.1 to 5 wt%, 0.1 to 3 wt%, 0.1 to 2 wt%, 0.1 to 1 wt%, 0.5 to 5 wt%, 0.5 to 3 wt%, 0.5 to 2 wt%, or 0.5 to 1 wt% based on the total weight of the pharmaceutical combination preparation, but is not limited thereto.

[0167] In the present invention, the lubricant included in the post-mixing section may be included in an amount of 0.1 to 20 wt%, 0.1 to 15 wt%, 0.1 to 10 wt%, 0.1 to 5 wt%, 0.1 to 2 wt%, 0.5 to 20 wt%, 0.5 to 15 wt%, 0.5 to 10 wt%, 0.5 to 5 wt%, or 0.5 to 2 wt% based on the total weight of the post-mixing section, but is not limited thereto.

[0168] In the present invention, the post-mixing unit may include an additive selected from microcrystalline cellulose, lactose monohydrate, mannitol, crospovidone, magnesium stearate, and any combination thereof.

[0169] In order to improve the physical properties, manufacturability, compressibility, appearance, preference and / or drug stability of the composite preparation of the present invention, various additives may be additionally mixed into the granular portion and / or post-mixing portion, if necessary. Such additives include, but are not limited to, stabilizers, solubilizers, sweeteners, flavoring agents, pigments, humectants, fillers, stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, adsorbents, flavoring agents, binders, suspending agents, curing agents, antioxidants, brighteners, flavoring agents, flavoring agents, pigments, coating agents, humectants, moisture regulators, fillers, antifoaming agents, refreshing agents, chewing agents, antistatic agents, coloring agents, sugar coating agents, isotonic agents, softeners, emulsifiers, adhesives, thickeners, foaming agents, pH regulators, excipients, dispersants, disintegrants, waterproofing agents, preservatives, preservatives, solubilizing agents, solvents, and fluidizing agents, and any pharmaceutically acceptable agent may be used.

[0170] In addition, the present invention may further include an outer coating layer on at least one surface of the composite formulation, if necessary. In this case, the outer coating layer may include a coating agent.

[0171] In the present invention, the coating agent may use a polymer commonly used in the art, and non-limiting examples thereof include methylcellulose, ethylcellulose, polyvinylacetic acid, polyvinyl alcohol, polyvinylacetic acid, polyvinylpyrrolidone, povidone, methacrylic acid-ethyl acrylate copolymer, triacetin, propylene glycol, hydroxyethylcellulose, hydroxypropyl methylcellulose, etc., or OpadryTM sold by Colorcon may be used as the coating agent.

[0172] The outer coating layer of the present invention may additionally include various biologically inactive ingredients for additional purposes such as coating efficiency, drug stability, appearance, color, protection, maintenance, binding, performance improvement, and manufacturing process improvement. The biologically inactive ingredients that may be additionally included in the outer coating layer may be at least one selected from the group consisting of plasticizers, lubricants, colorants, flavoring agents, surfactants, stabilizers, antioxidants, foaming agents, anti-foaming agents, paraffin, and wax, but are not limited thereto.

[0173] In the present invention, the amount of the outer coating layer or the coating agent used is preferably kept to a minimum to provide an optimal formulation size and ensure effective manufacturing. For example, the coating agent may be included in an amount ranging from 0.1 to 20 wt%, preferably from 1 to 5 wt%, based on the total weight of the pharmaceutical combination formulation, but is not limited thereto.

[0174] The combination formulation according to the present invention, as described above, contains all three pharmacologically active ingredients, ezetimibe, rosuvastatin, and empagliflozin, in a single formulation, thereby alleviating the inconvenience of having to take two separate formulations for the treatment of dyslipidemia and diabetes and significantly improving patient convenience in taking the medication. The combination formulation may be administered once daily, twice daily, three times daily, or four times daily, depending on the content of the main ingredients contained.

[0175] The combination preparation of the present invention may be a preparation for oral administration.

[0176] The combination preparation of the present invention may be in the form of a single preparation, a pellet, a capsule, a single-layer tablet, a double-layer tablet, a multi-layer tablet, an inner-core tablet, a drug-coated tablet, a powder, or a granule, and the capsule may be a polycap or a drug-coated capsule. Preferably, the combination preparation of the present invention may be in the form of a single-layer tablet, but is not limited thereto.

[0177] The total weight of the combination preparation of the present invention may be, but is not limited to, 400 to 1,000 mg, 450 to 1,000 mg, 500 to 1,000 mg, 400 to 900 mg, 450 to 900 mg, 500 to 900 mg, 400 to 800 mg, 450 to 800 mg, 500 to 800 mg, 400 to 700 mg, 450 to 700 mg, 500 to 700 mg, 400 to 600 mg, 450 to 600 mg or 500 to 600 mg.

[0178] Furthermore, the combination preparation according to the present invention has a therapeutic synergy effect according to the combined use of ezetimibe, rosuvastatin, and empagliflozin, and can prevent delay in drug release and reach the target dissolution rate.

[0179] The combination preparation according to the present invention is characterized in that, in a dissolution test (pH 6.8 solution + 0.1% polysorbate, 37°C, 900 mL, 75 rpm), the dissolution rate of ezetimibe is 40% or more, 45% or more, or 50% or more within 10 minutes, 50% or more, 55% or more, or 60% or more within 15 minutes, 65% or more, 70% or more, or 75% or more within 30 minutes, 70% or more, 75% or more, or 80% or more within 45 minutes, and 80% or more, 85% or more, or 90% or more within 1 hour.

[0180] The compound preparation according to the present invention is characterized in that, in a dissolution test (pH 1.2 solution, 37°C, 900 mL, 50 rpm), the dissolution rate of rosuvastatin is 60% or more, 70% or more, 75% or more, or 80% or more within 5 minutes, 75% or more, 80% or more, 85% or more, or 90% or more within 10 minutes, 80% or more, 85% or more, or 90% or more within 15 minutes, 85% or more, 90% or more, or 95% or more within 30 minutes, and 90% or more or 95% or more within 45 minutes.

[0181] The compound preparation according to the present invention is characterized in that, in a dissolution test (pH 1.2 solution, 37°C, 900 mL, 50 rpm), the dissolution rate (based on weight) of empagliflozin is 45% or more, 50% or more, 60% or more, 70% or more, or 80% or more within 5 minutes, 65% or more, 70% or more, 75% or more, or 80% or more within 10 minutes, 75% or more, 80% or more, 85% or more, or 90% or more within 15 minutes, 85% or more, 90% or more, or 95% or more within 30 minutes, and 85% or more, 90% or more, or 95% or more within 45 minutes.

[0182]

[0183] According to another embodiment of the present invention, there is provided a method for preparing a compound preparation according to the present invention, comprising the following steps:

[0184] (a) a step of preparing a granule portion comprising ezetimibe or a pharmaceutically acceptable salt thereof as an active ingredient;

[0185] (b) a step of preparing a post-mixed portion comprising rosuvastatin or a pharmaceutically acceptable salt thereof as an active ingredient and empagliflozin or a pharmaceutically acceptable salt thereof; and

[0186] (c) It may include a step of mixing the granular portion and the post-mixed portion to prepare a solid preparation.

[0187] In the present invention, steps (a) and (b) do not necessarily have to be performed sequentially, and step (b) may be performed after step (a), or step (a) may be performed after step (b), or steps (a) and (b) may be performed simultaneously.

[0188] In the present invention, the step of preparing the granule portion (a) may include the step of preparing a mixture for preparing granules by mixing ezetimibe or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and the step of preparing granules (a-2).

[0189] In the present invention, the pharmaceutically acceptable additive mixed with the active ingredient in the step (a-1) may include at least one selected from the group consisting of a disintegrant, an excipient (diluent), a lubricant, and a binder, but preferably includes an excipient (diluent), a disintegrant, and a lubricant.

[0190] In the present invention, the granule manufacturing step (a-2) can be performed according to any granule manufacturing method known in the art, and can be performed, for example, by a wet granulation method. Ezetimibe is a poorly soluble drug that exhibits a low saturation solubility of about 1 ppm in both acidic and weakly alkaline body fluid conditions. Saturated solubility and the dissolution rate from the start of dissolution to saturation can be important indicators for evaluating the bioavailability of poorly soluble drugs. In the present invention, by manufacturing the granules containing the ezetimibe as wet granules, ezetimibe can reach saturation solubility at a faster rate, ultimately increasing the bioavailability of ezetimibe.

[0191] In the present invention, the wet granulation method may be performed using a fluid bed granulator, or may be performed using a high speed mixer, etc.

[0192] In the present invention, when wet granulation is performed using a fluidized bed granulator, the wet granulation can be performed by specifically suspending the granule-making mixture in the fluidized bed granulator and spraying a binding coating solution thereon. If necessary, an additional drying process can be performed.

[0193] The binding coating solution used in the wet granulation process of the present invention can be prepared by dissolving a binding agent in a solvent. The type of solvent used is not particularly limited, but may include, for example, water, ethanol, isopropanol, acetone, or a combination thereof.

[0194] In the present invention, in order to obtain granules of an appropriate size in the step (a-2), a step of crushing or sizing the granules using a crusher (fitzmill), an oscillator, etc. may be additionally included, if necessary.

[0195] In the present invention, the step of preparing the post-mixing portion (b) may be performed by mixing rosuvastatin / empagliflozin or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable additive.

[0196] In the present invention, the pharmaceutically acceptable additive mixed with the active ingredient in step (b) may be at least one selected from the group consisting of a disintegrant, an excipient (diluent), and a lubricant, and preferably may include an excipient (diluent) and a disintegrant, and may further include a lubricant.

[0197] As an example, in the present invention, step (b) may be performed by first mixing the active ingredient, excipients, and disintegrant, and then second mixing the lubricant, but is not limited thereto.

[0198] As another example, in the present invention, step (b) may be performed by mixing the active ingredient, disintegrant, excipient (diluent), and lubricant together, but is not limited thereto.

[0199] In addition, in the present invention, the disintegrant may be added during the preparation of the mixed powder for preparing granules (a-1) and / or during the preparation of the post-mixing section (b). As an example, the disintegrant may be added during the preparation of the mixed powder for preparing granules (a-1), and as another example, the disintegrant may be added during the preparation of the post-mixing section (b), and as yet another example, the disintegrant may be added during the preparation of the mixed powder for preparing granules (a-1), and also during the preparation of the post-mixing section (b).

[0200] In the present invention, the step of formulating into a solid formulation (c) may be performed by a tableting process, but is not limited thereto, and may be appropriately adjusted depending on the desired formulation.

[0201] In the present invention, the tableting machine used in the tableting process is not particularly limited as long as it is a device that typically manufactures pharmaceutically compressed products, and a known tableting machine such as a rotary tableting machine or a single-shot tableting machine can be used. In the present invention, the appropriate hardness of the tablets manufactured by the tableting process before forming the film coating layer can be, for example, 1 to 30 kp.

[0202] In the present invention, the tablet obtained after the pressing in the step (c) can be manufactured in various shapes, for example, oval, rectangular, egg-shaped, triangular, almond-shaped, peanut-shaped, parallelogram-shaped, circular, pentagonal, hexagonal or trapezoidal, preferably circular, egg-shaped or parallelogram-shaped.

[0203] In the present invention, a step of coating the outer surface of the tablet obtained after the tableting process in step (c) may be additionally included using a coating solution containing a coating agent.

[0204] In the present invention, the coating solution can be prepared by dissolving the coating agent in a solvent. Examples of solvents that can be used include, but are not limited to, ethanol, methanol, acetone, acetonitrile, tetrahydrofuran, hexane, methylene chloride, isopropyl alcohol, water, and mixtures thereof.

[0205] In addition, in the present invention, when preparing the coating solution, for additional purposes such as improving coating efficiency, drug stability, appearance, color, protection, maintenance, binding, performance, and manufacturing process, one or more selected from the group consisting of plasticizers, lubricants, colorants, flavoring agents, surfactants, stabilizers, antioxidants, foaming agents, antifoaming agents, paraffin, and waxes may be additionally mixed and used.

[0206] In the present invention, the coating can be performed using a conventional method used in the art for coating drugs, for example, a coating method using a pan coater can be used, but is not limited thereto.

[0207] In the manufacturing method of the present invention, the types and contents of each component added during the manufacture of the granule portion, post-mix portion, and coating solution are described in detail in the previous pharmaceutical preparation, and thus, to avoid excessive complexity of the specification, the description thereof has been omitted.

[0208]

[0209] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0210]

[0211] Example

[0212] [Examples 1 to 3] Preparation of a combination formulation of ezetimibe, rosuvastatin, and empagliflozin

[0213] According to the ingredients and contents shown in Table 1 below, a binding coating solution (a solution of 4 mg of povidone dissolved in 90 mg of water) was prepared separately by dissolving povidone in purified water, and the granule mixture, ezetimibe, sodium lauryl sulfate, croscarmellose sodium, lactose monohydrate, and microcrystalline cellulose, was prepared by mixing them. The granule mixture was fed into a fluidized bed granulator and fluidized. The machine was operated at an inlet temperature of 65 ℃ and a spray pressure of 1500 mbar, and a spray rate of 750 g / min was used to inject the povidone binding coating solution. While the binding coating solution was being injected, the granules were assembled under the same initial conditions, and then the inlet temperature was increased to 75 ℃ during drying, and then drying was performed. After drying, the granules were sieved through a sieve with a mesh size of 30 (0.6 mm) to produce ezetimibe wet granules (wet granulation section).

[0214] The manufactured ezetimibe wet granules were post-mixed with rosuvastatin calcium salt, empagliflozin, microcrystalline cellulose, D-mannitol, lactose monohydrate, and crospovidone, and then sodium stearyl fumarate was mixed therewith to prepare a final mixed mixture (post-mixing section).

[0215] The resulting final mixture was compressed into tablets using a tablet press (AUTOTAB-200TR, Ichihashi Seiki) to produce single-layer tablets (uncoated tablets) having a hardness of approximately 20 KP.

[0216] Process ingredient content (mg / T) Example 1 Example 2 Example 3 Wet granulation Granulation mixed powder Zetimibe 10.0 10.0 10.0 Sodium lauryl sulfate 1.0 1.0 1.0 Croscarmellose sodium 6.5 6.5 6.5 Lactose monohydrate 16.0 16.0 16.0 Microcrystalline cellulose 44.5 44.5 44.5 Binder solution Povidone 2.0 2.0 2.0 Post-mixed post-mixed powder Rosuvastatin calcium (as rosuvastatin) 10.4 (1 0.0)10.4(10.0)10.4(10.0)Empagliflozin10.025.025.0Microcrystalline cellulose130.0130.0130.0D-mannitol210.0125.040.0Lactose monohydrate210.0125.040.0Crospovidone10.210.210.2Magnesium stearate4.44.44.41Tablet Total weight (mg / T)665.0510.0340.0

[0217] [Comparative Examples 1 and 2] Preparation of a combination formulation of ezetimibe, rosuvastatin, and empagliflozin

[0218] A triple-combination single tablet of ezetimibe, rosuvastatin, and empagliflozin was manufactured by performing the same procedure as in Examples 1 to 3 above, but adjusting the content of empagliflozin and excipients as shown in Table 2 below.

[0219] Process ingredient content (mg / T) Comparative example 1 Comparative example 2 Wet granulation Granulation mixed powder Zetimibe 10.0 10.0 Sodium lauryl sulfate 1.0 1.0 Croscarmellose sodium 6.5 6.5 Lactose monohydrate 16.0 16.0 Microcrystalline cellulose 44.5 44.5 Binding solution Povidone 2.0 2.0 Post-mixed powder Post-mixed powder Rosuvastatin calcium 10.4 10.4 Empagliflozin 25.0 25.0 Microcrystalline cellulose 130.0 80.0 D-mannitol 20.0 20.0 Lactose monohydrate 20.0 20.0 Crospovidone 10.2 10.2 Magnesium stearate 4.4 4.4 1 Tablet Total weight (mg / T) 300.0 250.0

[0220] [Experimental Example 1] Evaluation of dissolution rate according to the content of empagliflozin and excipients

[0221] In order to confirm the change in the dissolution rate of the active ingredients in the post-mixing section according to the content of empagliflozin and excipients based on the total weight of the formulation, the dissolution evaluation of empagliflozin and rosuvastatin was performed in a pH 1.2 solution for the combination formulations of Examples 1 to 3 and Comparative Examples 1 and 2. The specific dissolution test conditions are as follows, and the dissolution test solution samples were collected at 0, 5, 10, 15, 30 and 45 minutes after the start of the test, and the change in the dissolution rate was measured by performing liquid chromatography, and the results are shown in Tables 3 and 4 below and Figures 1 and 2. However, the control drug was Rosuzet tablets, which are a combination control drug. TM (Ezetimibe / Rosuvastatin calcium, 10 / 10 mg, control example 1) and Jardiance tablets as a single-agent control drug TM (Empagliflozin, 25 mg, Control Example 2) was evaluated for dissolution.

[0222] <Dissolution test conditions>

[0223] Dissolution test solution: Rosuvastatin calcium and empagliflozin (pH 1.2 buffer, 900 mL)

[0224] Dispensing device: Paddle

[0225] Rotation speed: Rosuvastatin calcium and empagliflozin (50 rpm)

[0226] Temperature: 37℃±0.5℃

[0227] <Analysis Conditions - High-Performance Liquid Chromatography>

[0228] Column: ZORBAX SB- C8, (4.6Х100mm, 3.5μm)) or equivalent column

[0229] Mobile phase: 0.05mol / L KH2PO4 Buffer:ACN:THF(=60:30:10)

[0230] Flow rate: 1.2 ml / min

[0231] Column temperature: 30 ℃

[0232] Injection volume: 20 μL

[0233] Analysis time: 12 minutes

[0234] * For rosuvastatin, calculated by adding the main peak and decomposition peak.

[0235] Dissolution rate of empagliflozin by time in pH 1.2 solution (%)Dissolution rate (%)0 min 5 min 10 min 15 min 30 min 45 minExample 1064.978.586.293.696.5Example 2060.875.985.092.692.8Example 3056.774.582.991.591.7Comparative example 1038.865.776.180.182.2Comparative example 2020.857.069.372.375.1Control example 2055.374.481.087.088.2

[0236] Dissolution rate of rosuvastatin by time in pH 1.2 solution (%)Dissolution rate (%)0 min5 min10 min15 min30 min45 minExample 1082.092.39394.295.0Example 2080.292.594.997.397.5Example 3076.889.095.295.795.9Comparative example 1070.584.291.894.295.6Comparative example 2065.480.189.897.397.5Control example 1074.589.994.897.298.6

[0237] As shown in Table 3 and FIG. 1, the tablets of Examples 1 to 3, in which empagliflozin was included in the post-mixing portion in an amount of 1.5 to 8 wt% based on the total weight of the tablet, and the excipient (diluent) was included in the post-mixing portion in an amount of 60 to 90 wt% based on the total weight of the tablet, exhibited a dissolution rate of empagliflozin equivalent to that of the control drug containing only empagliflozin (Control Example 2). However, the tablets of Comparative Examples 1 and 2, in which empagliflozin was included in a high content and the excipient (diluent) was included in a relatively small content in the post-mixing portion, exhibited a very low dissolution rate of empagliflozin not only in the initial stage but also throughout the experimental period compared to the control drug. This is because empagliflozin itself is sticky and has the property of easily agglomerating, and in the tablets of Comparative Examples 1 and 2, the content of empagliflozin in the post-mixing section was high and the content of excipients was relatively low, so it is interpreted that empagliflozin was tightly agglomerated in the dissolution port, resulting in a low dissolution rate.

[0238] In addition, looking at the results in Table 4 and Fig. 2, it could be seen that the dissolution rate of rosuvastatin calcium salt included in the post-mixing section together with the above-mentioned active ingredients was affected depending on the content of empagliflozin and excipients (diluents) in the post-mixing section. Specifically, in the tablets of Examples 1 to 3, the dissolution rate of rosuvastatin was equivalent to that of the control drug (Control Example 1), whereas in the tablets of Comparative Examples 1 and 2, the initial dissolution rate of rosuvastatin was confirmed to be low. This means that in the tablets of Comparative Examples 1 and 2, the content of empagliflozin in the post-mixing section was high and the content of excipients (diluents) was relatively low, which inhibited the dissolution of rosuvastatin mixed together in the post-mixing section due to the aggregation of empagliflozin.

[0239] [Examples 4 to 8] Preparation of a combination formulation of ezetimibe, rosuvastatin, and empagliflozin

[0240] The same procedure as in Examples 1 to 3 was followed, but the contents of ezetimibe, rosuvastatin, and empagliflozin were varied as shown in Table 5 below to manufacture a single tablet of a triple combination preparation of ezetimibe, rosuvastatin, and empagliflozin.

[0241] Process ingredient content (mg / T) Example 4 Example 5 Example 6 Example 7 Example 8 Wet granulation Granulation mixed powder Zetimibe 10.0 10.0 10.0 10.0 10.0 10.0 Sodium lauryl sulfate 1.0 1.0 1.0 1.0 1.0 Croscarmellose sodium 6.5 6.5 6.5 6.5 6.5 6.5 Lactose monohydrate 16.0 16.0 16.0 16.0 16.0 Microcrystalline cellulose 44.5 44.5 44.5 44.5 4.5 Povidone binding solution 2.0 2.0 2.0 2.0 2.0 Post-mixed post-mixed powder Rosuvastatin calcium (as rosuvastatin) 5.2 (5.0) 2.6 (2.5) 10 .4(10.0)5.2(5.0)2.6(2.5)Empagliflozin25.025.010.010.010.0Microcrystalline cellulose130.0130.0130.0130.0130.0D-mannitol125.0125.0125.0125.0125.0125.0Lactose monohydrate125.0125.0125.0125.0125.0125.0Crospovidone10.210.210.210.210.2Magnesium stearate4.44.44.44.44.41Tablet Total weight (mg / T)504.8502.2495.0489.8487.2

[0242] [Experimental Example 2] Evaluation of dissolution rate according to the content of each active ingredient and excipient

[0243] In order to confirm the change in dissolution rate according to the content of the active ingredients of ezetimibe, rosuvastatin, and empagliflozin based on the total weight of the formulation, the dissolution evaluation of rosuvastatin and empagliflozin was performed in a pH 1.2 solution for the combination formulations of Examples 4 to 8, and the dissolution evaluation of ezetimibe was performed in a pH 6.8 solution. In addition, the dissolution evaluation was also performed for the combination formulation of Example 2 to confirm the change in dissolution rate according to the content of the excipient. The dissolution test conditions of rosuvastatin and empagliflozin were the same as those described in Experimental Example 1, and the dissolution test conditions of ezetimibe were as follows. Dissolution test liquid samples were collected at 0, 5, 10, 15, 30, and 45 minutes after the start of the test, and the change in dissolution rate was measured by liquid chromatography, and the results are shown in Tables 6 to 8 and Figures 3 to 5 below.

[0244] <Dissolution test conditions>

[0245] Dissolution test solution: Ezetimibe (pH 6.8 phosphate buffer + 0.1% polysorbate 80, 900 mL)

[0246] Dispensing device: Paddle

[0247] Rotation speed: Ezetimibe (75 rpm)

[0248] Temperature: 37℃±0.5℃

[0249] <Analysis Conditions - High-Performance Liquid Chromatography>

[0250] Column: ZORBAX SB- C8, (4.6Х100mm, 3.5μm) or equivalent column

[0251] Mobile phase: 0.05mol / L KH2PO4 Buffer:ACN:THF(=60:30:10)

[0252] Flow rate: 1.2 ml / min

[0253] Column temperature: 30 ℃

[0254] Injection volume: 20 μL

[0255] Analysis time: 12 minutes

[0256] Dissolution rate of empagliflozin over time in pH 1.2 solution (%)Dissolution rate (%)0 min 5 min 10 min 15 min 30 min 45 minExample 2060.875.985.092.692.8Example 4061.876.386.293.194.1Example 5063.576.586.793.894.0Example 6069.883.087.892.694.6Example 7070.282.188.393.794.6Example 8071.485.689.994.595.9

[0257] Dissolution rate of rosuvastatin over time in pH 1.2 solution (%)Dissolution rate (%)0 min 5 min 10 min 15 min 30 min 45 minExample 2080.292.594.997.397.5Example 4082.393.295.296.296.7Example 5082.191.895.296.296.7Example 6086.594.897.297.697.1Example 7086.895.297.297.697.1Example 8087.295.798.598.198.4

[0258] Dissolution rate of ezetimibe over time in pH 6.8 solution (%)Dissolution rate (%)0 min 5 min 10 min 15 min 30 min 45 min 60 minExample 2025.650.563.279.886.690.3Example 4026.852.564.181.288.690.9Example 5023.448.963.077.284.689.4Example 6021.047.862.475.884.388.5Example 7021.546.861.876.783.287.6Example 8021.245.861.777.184.586.9

[0259] As can be seen in Tables 6 to 8 and Figures 3 to 5, in all six prescriptions of Examples 2 and 4 to 8, the dissolution rates of ezetimibe, rosuvastatin, and empagliflozin were similar, proving the dissolution equivalence between them.

[0260] [Examples 9 to 11] Preparation of a combination formulation of ezetimibe, rosuvastatin, and empagliflozin

[0261] Triple-combination single tablets of ezetimibe, rosuvastatin, and empagliflozin were manufactured in the same manner as in Examples 1 to 3 above, but the content of the disintegrant was adjusted as shown in Table 10 below. Since a change in the total weight of the formulation would change the ratio of the main ingredients, which would rather have a greater effect on the soluble substances or dissolution, in this experiment, the amounts of excipients (D-mannitol, lactose monohydrate) added were varied, and the total tablet weight was maintained at 510 mg / T.

[0262] Process ingredient content (mg / T) Example 9 Example 10 Example 11 Wet granulation Granulation mixed powder Zetimibe 10.0 10.0 10.0 Sodium lauryl sulfate 1.0 1.0 1.0 Croscarmellose sodium 6.5 6.5 6.5 Lactose monohydrate 16.0 16.0 16.0 Microcrystalline cellulose 44.5 44.5 44.5 Binder solution Povidone 2.0 2.0 2.0 Post-mixed post-mixed powder Rosuvastatin calcium (as rosuvastatin) 10.4 (1 0.0)10.4(10.0)10.4(10.0)Empagliflozin25.025.025.0Microcrystalline cellulose130.0130.0130.0D-mannitol129.5120.0105.0Lactose monohydrate129.5120.0105.0Crospovidone1.220.250.2Magnesium stearate4.44.44.41Tablet Total weight (mg / T)510.0510.0510.0

[0263] [Comparative Examples 3 and 4] Preparation of a combination formulation of ezetimibe, rosuvastatin, and empagliflozin

[0264] Triple-combination single tablets of ezetimibe, rosuvastatin, and empagliflozin were manufactured in the same manner as in Examples 1 to 3 above, but the content of the disintegrant was adjusted as shown in Table 10 below. Since a change in the total weight of the formulation would change the ratio of the main ingredients, which would rather have a greater effect on the soluble substances or dissolution, in this experiment, the amounts of excipients (D-mannitol, lactose monohydrate) added were varied, and the total tablet weight was maintained at 510 mg / T.

[0265] Process ingredient content (mg / T) Comparative example 3 Comparative example 4 Wet granulation Granulation mixed powder Zetimibe 10.0 10.0 Sodium lauryl sulfate 1.0 1.0 Croscarmellose sodium 1.5 6.5 Lactose monohydrate 16.0 16.0 Microcrystalline cellulose 44.5 44.5 Binder solution Povidone 2.0 2.0 Post-mixed powder Post-mixed powder Rosuvastatin calcium 10.4 10.4 Empagliflozin 25.0 25.0 Microcrystalline cellulose 130.0 130.0 D-mannitol 132.0 90.0 Lactose monohydrate 132.0 90.0 Crospovidone 1.2 8 0.2 Magnesium stearate 4.4 4.4 1 Tablet Total weight (mg / T) 510.0 510.0

[0266] [Experimental Example 3] Evaluation of dissolution rate according to disintegrant content

[0267] In order to confirm the change in dissolution rate according to the content of the disintegrant based on the total weight of the formulation, the dissolution evaluation of rosuvastatin and empagliflozin was performed in a pH 1.2 solution for the combination formulations of Examples 2 and 9 to 11 and Comparative Example 3. The dissolution test conditions for rosuvastatin and empagliflozin were the same as those described in Experimental Example 1, and the dissolution test liquid samples were collected at 0, 5, 10, 15, 30, and 45 minutes after the start of the test, and the change in dissolution rate was measured by performing liquid chromatography, and the results are shown in Tables 11 and 12 below and Figures 6 and 7. The control drug was Rosuzet tablet, a combination control drug. TM (Ezetimibe / Rosuvastatin calcium, 10 / 10 mg, control example 1) and Jardiance tablets as a single-agent control drug TM (Empagliflozin, 25 mg, Comparative Example 2) was evaluated for dissolution. The tablet of Comparative Example 4 was not evaluated for dissolution due to severe wear after tableting.

[0268] Dissolution rate of empagliflozin by time in pH 1.2 solution (%)Dissolution rate (%)0 min 5 min 10 min 15 min 30 min 45 minExample 2060.875.985.092.692.8Example 9057.876.385.093.194.1Example 10068.38387.892.694.6Example 11075.885.288.393.794.6Comparative Example 3044.868.778.585.590.1Control Example 2055.374.481.087.088.2

[0269] Dissolution rate of rosuvastatin by time in pH 1.2 solution (%)Dissolution rate (%)0 min 5 min 10 min 15 min 30 min 45 minExample 2080.292.594.997.397.5Example 9073.290.494.999.696.5Example 10082.393.797.297.897.6Example 11085.295.197.197.997.8Comparative Example 3064.882.588.796.897.0Control Example 1074.589.994.897.298.6

[0270] As shown in Tables 11 and 12 above and FIGS. 6 and 7, the tablets of Examples 2 and 9 to 11 showed dissolution profiles comparable to those of the control drug for both empagliflozin and rosuvastatin. In comparison, the tablet of Comparative Example 3, which used a small amount of disintegrant in the granule portion and post-mix portion, showed very low initial dissolution rates for empagliflozin and rosuvastatin.

[0271] [Experimental Example 4] Evaluation of Friability According to Disintegrant Content

[0272] Friability evaluation was conducted on the tablets manufactured in Examples 2, 10, and 11 and Comparative Example 4, and the results are shown in Table 13 below. In general, 100-time friability is used as an evaluation item to check for tableting problems in the tableting process, and 400-time friability is used as an evaluation item to ensure tablet stability in the coating machine. The evaluation standard for 100-time friability is within 0.2%, and the evaluation standard for 400-time friability is within 1%.

[0273] Example 2 Example 10 Example 11 Comparative Example 4 Disintegrant content (granular part / post-mixed part) 8.13 wt% / 2.37 wt% 8.13 wt% / 4.70 wt% 8.13 wt% / 11.67 wt% 8.13 wt% / 18.65 wt% 100-cycle wear (within 0.2%) 0.01 0.07 0.18 0.56 400-cycle wear (within 1.0%) 0.08 0.20 0.80 1.52

[0274] As shown in Table 13 above, when an excessive amount of disintegrant was used, as in Comparative Example 4, the friability of the tablets was significantly reduced. This reduction in friability ultimately leads to a decrease in tableting properties and moisture stability of the drug, which can ultimately lead to productivity issues.

[0275] [Experimental Example 4] Pharmacokinetic study using beagle dogs

[0276] A pharmacokinetic study was conducted on beagle dogs using the tablets manufactured in Example 2 and the control drugs of Control Examples 1 and 2. The specific experimental method is as follows:

[0277] (1) Test animals

[0278] Twelve beagle dogs were used as test animals, and pentagastrin 6 ug / kg IM was administered 30 minutes before drug administration.

[0279] (2) Experimental method

[0280] A 2x2 crossover test was conducted on six beagle dogs divided into two groups. After oral administration of the tablets of Example 2 (10 / 10 / 25 mg) and Control Example 1 (10 / 10 mg) + Control Example 2 (25 mg) once each, blood samples were collected to measure the blood concentrations of ezetimibe / rosuvastatin / empagliflozin.

[0281] (3) Test results

[0282] The blood concentration profiles and pharmacokinetic parameters obtained from beagle dogs after each purified administration are shown in Tables 14 to 16 and Figures 8 to 10.

[0283] Pharmacokinetic evaluation parameters of ezetimibe Example 2 (T) Control Example 1+2 (R) T / RAUC 0-10 (ng.hr / mL) 9.24±3.7 8.94±4.2 1.03 4 Cmax (ng / mL) 0.89±0.4 0.90±0.5 0.99 4 Tmax (hr) 3.5±1.6 4.1±1.7 0.875

[0284] Pharmacokinetic evaluation parameters of rosuvastatin Example 2 (T) Control Example 1+2 (R) T / RAUC 0-10 (ng.hr / mL) 186.3±44.9 19 1.0±47.1 0.975 Cmax (ng / mL) 51.7±20.0 5 3.9±19.2 0.95 9 Tmax (hr) 0.7±0.5 0.9±0.6 0.745

[0285] Pharmacokinetic evaluation parameters of empagliflozin Example 2 (T) Control Example 1+2 (R) T / RAUC 0-10 (ng.hr / mL) 16457.1±2280.5 16548.5±2235.0 0.99 4 Cmax (ng / mL) 2794.4±350 2786.4±476.8 1.00 3 Tmax (hr) 0.8±0.2 0.8±0.3 0.919

[0286] As shown in Tables 14 to 16 and Figures 8 to 10, when Example 2, a triple combination single tablet of ezetimibe, rosuvastatin, and empagliflozin, was administered, the commercially available combination preparation of ezetimibe / rosuvastatin calcium (Rosujet tablet) TM ; Control example 1) and empagliflozin single tablet (Jardiance tablet) TM ; In the case of combined administration of control example 2), it was confirmed that the AUC, Cmax and Tmax parameters were statistically bioequivalent.

[0287] Through these results, the triple combination preparation of ezetimibe, rosuvastatin, and empagliflozin according to the present invention can be used instead of single administration of these drugs as separate preparations, thereby significantly improving the convenience of taking the drug for patients.

[0288]

[0289] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions are merely preferred implementation examples and do not limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents.

[0290] The present invention is applicable to a combination preparation comprising ezetimibe, rosuvastatin, and empagliflozin.

Claims

(1) Ezetimibe or a pharmaceutically acceptable salt thereof; (2) Rosuvastatin or a pharmaceutically acceptable salt thereof, and (3) A pharmaceutical combination preparation containing empagliflozin or a pharmaceutically acceptable salt thereof as an active ingredient. In the first paragraph, A pharmaceutical combination preparation wherein the empagliflozin is included in an amount of 1.5 to 8 wt% based on the total weight of the pharmaceutical combination preparation. In the first paragraph, A pharmaceutical combination preparation comprising ezetimibe in an amount of 5 to 20 mg per unit dosage form of the pharmaceutical combination preparation, rosuvastatin in an amount of 2 to 20 mg, and empagliflozin in an amount of 5 to 40 mg. In the first paragraph, A pharmaceutical combination preparation comprising ezetimibe in an amount of 5 to 20 mg per unit dosage form of the pharmaceutical combination preparation, rosuvastatin in an amount of 2.5 to 20 mg, and empagliflozin in an amount of 10 to 25 mg. In the first paragraph, A pharmaceutical combination preparation comprising ezetimibe in an amount of 10 mg per unit dosage form of the pharmaceutical combination preparation, rosuvastatin in an amount of 2.5 to 10 mg, and empagliflozin in an amount of 10 or 25 mg. In the first paragraph, The pharmaceutical combination preparation above comprises a disintegrant in an amount of 1 to 15 wt% based on the total weight of the pharmaceutical combination preparation. In paragraph 6, A pharmaceutical combination preparation wherein the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate methylcellulose, cross-linked carboxymethylcellulose sodium (Cross-linked CMC Na, C.CMC Na, or croscarmellose sodium), carboxymethylcellulose calcium, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose, starch, pregelatinized starch, corn starch, potato starch, pregelatinized starch, alginic acid or its sodium salt, and combinations thereof. In the first paragraph, The above pharmaceutical combination preparation is a pharmaceutical combination preparation containing excipients in an amount of 60 to 95 wt% based on the total weight of the pharmaceutical combination preparation. In paragraph 8, A pharmaceutical combination preparation comprising at least one excipient selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, magnesium aluminosilicate metasilicate, magnesium aluminosilicate, aluminum silicate, sodium silicate, potassium silicate, magnesium silicate, calcium silicate, lactose, lactose monohydrate, lactose anhydrous, calcium hydrogen phosphate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, dextrin, mannitol, sorbitol, starch, calcium phosphate monohydrate, calcium carbonate, and sugars. In the first paragraph, A pharmaceutical combination preparation comprising an active agent in an amount of 0.1 to 10 wt% based on the total weight of the pharmaceutical combination preparation, and further comprising a binder in an amount of 0.1 to 5 wt%. In the first paragraph, In the above pharmaceutical combination preparation, A pharmaceutical combination preparation wherein the ezetimibe or a pharmaceutically acceptable salt thereof is physically separated from rosuvastatin or a pharmaceutically acceptable salt thereof and empagliflozin or a pharmaceutically acceptable salt thereof. In the first paragraph, The above pharmaceutical combination preparation is, A granular portion comprising ezetimibe or a pharmaceutically acceptable salt thereof; and A pharmaceutical combination preparation comprising a postmixed portion comprising rosuvastatin or a pharmaceutically acceptable salt thereof and empagliflozin or a pharmaceutically acceptable salt thereof. In Article 12, A pharmaceutical combination preparation, wherein empagliflozin in the post-mixing portion is included in an amount of 0.5 to 11 wt% based on the total weight of the post-mixing portion. In Article 13, A pharmaceutical combination preparation, wherein the post-mixing portion contains excipients in an amount of 60 to 97 wt% based on the total weight of the post-mixing portion. In Article 13, A pharmaceutical combination preparation, wherein the above-mentioned post-mixing portion contains excipients in an amount of 60 to 90 wt% based on the total weight of the pharmaceutical combination preparation. In Article 12, A pharmaceutical combination preparation, wherein the above-mentioned post-mixing unit contains a disintegrant in an amount of 0.1 to 15 wt% based on the total weight of the pharmaceutical combination preparation. In Article 12, A pharmaceutical combination formulation, wherein the granular portion comprises a disintegrant in an amount of 0.5 to 5 wt% based on the total weight of the pharmaceutical combination formulation. In the first paragraph, The above pharmaceutical combination preparation is a pharmaceutical combination preparation in which, in a dissolution test (pH 1.2 solution, 37℃, 900mL, 50rpm), the dissolution rate of rosuvastatin is 70% or more within 5 minutes, 85% or more within 15 minutes, and 90% or more within 30 minutes. In the first paragraph, The above pharmaceutical combination preparation is a pharmaceutical combination preparation in which the dissolution rate (based on weight) of empagliflozin is 50% or more within 5 minutes, 80% or more within 15 minutes, and 85% or more within 30 minutes in a dissolution test (pH 1.2 solution, 37℃, 900mL, 50rpm). (a) a step of preparing a granule portion comprising ezetimibe or a pharmaceutically acceptable salt thereof as an active ingredient; (b) a step of preparing a post-mixture comprising rosuvastatin or a pharmaceutically acceptable salt thereof as an active ingredient and empagliflozin or a pharmaceutically acceptable salt thereof; and (c) A method for manufacturing a pharmaceutical combination preparation, comprising a step of mixing the granular portion and the post-mixed portion to prepare a solid preparation. In Article 20, A method for manufacturing a pharmaceutical combination preparation, wherein the empagliflozin is mixed in an amount of 1.5 to 8 wt% based on the total weight of the pharmaceutical combination preparation. In Article 20, When performing at least one of the steps (a) of manufacturing the granule portion; and (b) of manufacturing the post-mixing portion; a disintegrant is added, A method for producing a pharmaceutical combination preparation, wherein the disintegrant is added in an amount of 1 to 15 wt% based on the total weight of the pharmaceutical combination preparation.

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