Pharmaceutical combination formulation comprising Lobeglitazone, Empagliflozin and Metformin as active ingredient

Abstract

The present invention discloses a pharmaceutical combination formulation comprising lobeglitazone, empagliflozin, and metformin as active ingredients.

Description

Technology Field

[0001] The present invention relates to a pharmaceutical combination formulation comprising lobeglitazone, empagliflozin, and metformin as active ingredients. Specifically, the present invention relates to a pharmaceutical combination formulation comprising a sustained-release layer containing metformin and an immediate-release layer containing lobeglitazone and empagliflozin, which improves stability under harsh / accelerated storage conditions and has in-vitro dissolution results similar to those of a single agent administered in combination. Background Technology

[0002] Diabetes is a disease characterized by persistent metabolic abnormalities, including hyperglycemia, due to insufficient insulin action, and a high likelihood of developing chronic vascular complications; it can be broadly classified into Type 1 and Type 2 diabetes. Among these, Type 2 diabetes is a disease involving both insulin resistance (i.e., a condition in which the responsiveness of cells or tissues to insulin at a given insulin concentration is lower than normal) and impaired insulin secretion caused by the decline in pancreatic β-cell function. More than 85% of diabetes patients have adult-onset Type 2 diabetes, and the prevalence of Type 2 diabetes is continuously increasing due to the Westernization of modern lifestyles and the rise in obesity.

[0003] According to diabetes management guidelines in Korea and other countries, reducing the risk of microvascular complications (retinopathy, nephropathy, neuropathy) and macrovascular complications is set as the primary treatment goal, and strict blood glucose control is recommended as the most effective method to achieve this. Since it is difficult for most patients to reach and maintain target HbA1c levels over the long term through lifestyle modifications alone, the use of oral hypoglycemic agents is necessary. Furthermore, as there is a correlation between the duration of exposure to hyperglycemia and the occurrence of diabetes complications, aggressive treatment involving early drug administration is required to shorten this period of exposure (Korean Diabetes Association, Diabetes Treatment Guidelines, 2015). However, among Korean diabetes patients, the proportion of those whose blood glucose is controlled below the target level (e.g., HbA1c < 6.5%) is only 23.3% (Diabetes Fact Sheet in Korea 2016, Korean Diabetes Association); therefore, continuous use of hypoglycemic agents is necessary to enhance treatment efficacy.

[0004] Oral hypoglycemic agents used for the treatment of diabetes can be classified according to their mechanism of action into: 1) insulin secretagogues (sulfonylureas, non-sulfonylureas), 2) biguanide-class drugs, 3) alpha-glucosidase inhibitors, 4) glitazone-class drugs, 5) DPPIV inhibitor-class drugs, and 6) SGLT-2 inhibitor-class drugs.

[0005] The structural formula of metformin, one of the biguanide class drugs, is as shown in Chemical Formula 1 below.

[0006] [Chemical Formula 1]

[0007]

[0008] Metformin is used as a treatment for non-insulin-dependent diabetes mellitus (NIDDM). Its mechanism of blood glucose regulation is known to act independently of insulin secretion and to activate glucose transporters in the liver. Metformin induces weight loss in diabetic patients and exhibits effects of decreasing blood triglycerides and low-density lipoproteins while increasing high-density lipoproteins. Therefore, metformin can be used as a first-line treatment for patients with insulin-independent diabetes mellitus who exhibit insulin resistance.

[0009] Side effects associated with the use of metformin include decreased appetite, abdominal distension, nausea, and diarrhea, which occur in 20 to 30 percent of patients. Most side effects are transient and often disappear after 2 to 3 weeks of use; however, if symptoms such as diarrhea or severe abdominal distension do not subside, it is advisable to discontinue use. These side effects can be improved by using sustained-release formulations that allow for a reduction in the minimum and / or sustained dose or a decrease in the frequency of administration.

[0010] However, sustained-release formulations generally have a higher excipient content compared to standard formulations, which results in larger tablet sizes. This can cause swallowing difficulties in elderly and pediatric patients, potentially leading to low medication adherence.

[0011] Meanwhile, glitazone-class drugs are PPARγ agonists (Peroxisome Proliferator Activated Receptor gamma agonists) that stimulate PPARγ, which is expressed in adipocytes and promotes adipogenesis and glucose uptake, thereby improving the body's sensitivity to insulin.

[0012] Glitazone drugs are known to be beneficial for protecting pancreatic β-cells because they do not work by a mechanism that promotes insulin secretion, and they are particularly effective for diabetic patients with insulin resistance as they improve insulin resistance, maintain blood glucose levels for a long time, slow the progression of type 2 diabetes, and show a more potent therapeutic effect in early-stage diabetes. Among these glitazone drugs, those with a thiazolidinedione (TZD) structure currently form the mainstream of the market.

[0013] The structural formula of lobeglitazone, one of these glitazone class drugs, is as shown in Chemical Formula 2 below.

[0014] [Chemical Formula 2]

[0015]

[0016] Lobeglitazone not only has a stable molecular dynamic energy structure but also possesses structural features that best match the active site pocket of PPARγ, thereby having high pharmacological activity and enhancing the weak blood lipid-lowering effect that was identified as a disadvantage of existing glitazone-class drugs.

[0017] Glitazone class drugs are known to be effective when administered in combination with drugs of different mechanisms of action. In particular, they can be administered in combination with metformin when blood glucose control is insufficient. As combination formulations of glitazone class drugs and metformin, European Patent Publication No. 0749751 discloses a combination formulation of pioglitazone and metformin, and International Patent Publication No. 98 / 57634 discloses a combination formulation of rosiglitazone and metformin.

[0018] Meanwhile, SGLT-2 (Sodium Glucose Co-Transporter 2) inhibitor drugs are drugs that inhibit the reabsorption of glucose in the blood to lower blood sugar and suppress the secretion of inflammatory cytokines, and are used in the treatment of cardiovascular diseases such as type 2 diabetes and heart failure. Known SGLT-2 inhibitors developed to date include dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, luseogliflozin, and tofogliflozin.

[0019] Among these SGLT-2 inhibitor drugs, empagliflozin is known to regulate blood sugar by inhibiting the Na-Glucose transporter that delivers glucose into the kidneys, and its structural formula is as shown in Chemical Formula 3 below.

[0020] [Chemical Formula 3]

[0021]

[0022] However, while empagliflozin carries a low risk of hypoglycemia when used alone, it is being developed in combination forms due to concerns regarding urinary tract infections and genital infections.

[0023] Since the etiology of diabetes is very complex and each diabetes treatment has distinct advantages and disadvantages, combination therapy using antidiabetic agents with different mechanisms of action is frequently prescribed in clinical practice to act on multiple targets simultaneously. By combining lobeglitazone (improving insulin resistance) and empagliflozin (reducing glucose reabsorption in the kidneys), which have different mechanisms of action, a synergistic effect in lowering blood glucose can be expected. Furthermore, the weight-loss effect of SGLT-2 inhibitors can be expected to offset the adverse effect of weight gain associated with Duvie Tab. Since the glucose-regulating mechanism of metformin acts independently of insulin action, its mechanism of action differs from that of the two active ingredients mentioned above, allowing for the expectation of a synergistic effect in lowering blood glucose. However, when formulating a pharmaceutical composition in a single-dose form containing three active ingredients, it is necessary to manufacture it by dividing it into an immediate-release layer and a sustained-release layer due to the characteristics of the active ingredients and the granular properties of each layer, and there are issues such as deterioration in quality, including layer separation and content uniformity problems, which may occur during the manufacturing or storage process. Prior art literature

[0024] European Patent Publication No. 0749751 and International Patent Publication No. 98 / 57634

[0025] The Korean Diabetes Association, Diabetes Clinical Guidelines, 2015 Diabetes Fact Sheet in Korea 2016, The Korean Diabetes Association The problem to be solved

[0026] The objective of the present invention is to provide a triple combination drug for the treatment of type 2 diabetes, and to solve the problem of increasing patient convenience by providing a pharmaceutical combination drug comprising lobeglitazone, empagliflozin, and metformin as active ingredients.

[0027] To achieve the above objective, the active ingredients of lobeglitazone and empagliflozin are mixed, wet-granulated, and then mixed to form a double tablet with a metformin sustained-release layer, or to improve content stability in formulations containing 0.25 mg, the immediate-release layers of lobeglitazone and empagliflozin are wet-granulated individually and then mixed to form a double tablet with a metformin sustained-release layer, or the immediate-release layers of lobeglitazone and empagliflozin are separated and then manufactured into a triple tablet with a metformin sustained-release layer, and an optimal solvent is selected when manufacturing the lobeglitazone wet-granulated product.

[0028] Through the means described above, it is possible to provide a pharmaceutical combination formulation with in-vitro dissolution results similar to those obtained when a single agent is administered in combination. means of solving the problem

[0029] In order to solve the above problem, the present invention discloses the following means.

[0030] In one embodiment, the present invention discloses a pharmaceutical compound comprising: a sustained-release layer comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient; and a rapid-release layer comprising lobeglitazone or a pharmaceutically acceptable salt thereof and empagliflozin or a pharmaceutically acceptable salt thereof as active ingredients. Effects of the invention

[0031] The pharmaceutical combination formulation according to the present invention is a combination product comprising lobeglitazone, empagliflozin, and metformin as active ingredients, and has the advantage of improving convenience of administration by using three drugs as a treatment for type 2 diabetes.

[0032] The pharmaceutical combination formulation according to the present invention has the advantage of being able to improve the safety of the content of the active ingredient and provide a pharmaceutical combination formulation with guaranteed safety and efficacy by securing bioequivalence through comparative dissolution experiments with a reference drug.

[0033] The effects of the present invention are not limited to those mentioned above, and various effects may be included within the scope obvious to a person skilled in the art from the contents described below. Brief explanation of the drawing

[0034] FIGS. 1 to 3 are schematic diagrams of a pharmaceutical complex formulation according to the present invention. (In FIG. 1 above, Lobe+Empa IR granules are immediate-release granules prepared as wet granules by mixing lobeglitazone and empagliflozin. In FIGS. 2 and 3, Lobe IR granules refer to lobeglitazone immediate-release granules, Empa IR granules refer to empagliflozin immediate-release granules, and Met XR granules refer to metformin sustained-release granules.) Specific details for implementing the invention

[0035] The present specification will be described in more detail below.

[0036] This is explained in detail as follows. The terms used in this specification have been selected to be as widely used as possible, taking into account their functions in the present invention; however, these terms may vary depending on the intent of those skilled in the art, case law, the emergence of new technologies, etc. Additionally, in specific cases, terms have been arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the relevant description of the invention. Therefore, the terms used in this invention should be defined not merely by their names, but based on their meanings and the overall content of the invention.

[0037] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by those skilled in the art to which the present invention pertains. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and should not be interpreted in an ideal or overly formal sense unless explicitly defined in this application.

[0038] Numerical ranges include the values ​​defined in the above ranges. All maximum numerical limits given throughout this specification include all lower numerical limits as clearly written. All minimum numerical limits given throughout this specification include all higher numerical limits as clearly written. All numerical limits given throughout this specification will include all better numerical ranges within a wider numerical range, as clearly written.

[0039] Hereinafter, each description and embodiment disclosed in the present invention may be applied to other descriptions and embodiments thereof. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific descriptions described below.

[0040] Expressions such as “comprising” as used in this specification should be understood as open-ended terms implying the possibility of including other embodiments, unless specifically otherwise stated in the phrase or sentence containing such expression.

[0041] While conducting research and development to develop a pharmaceutical combination formulation with lobeglitazone, empagliflozin, and metformin as active ingredients, the inventors of the present invention formed a double tablet containing 0.25 mg of lobeglitazone by configuring lobeglitazone and empagliflozin as immediate-release layers and metformin as a sustained-release layer. However, a decrease in content was observed in a formulation containing 0.25 mg of lobeglitazone under stability conditions. To improve this, the active ingredients of lobeglitazone and empagliflozin were mixed, wet-granulated, and then mixed to form a double tablet with a metformin sustained-release layer. Alternatively, to improve the content stability in a formulation containing 0.25 mg, the active ingredients were each prepared as individual wet granules, the lobeglitazone granules and empagliflozin granules were mixed, and then compressed into a double tablet with a metformin sustained-release layer. Additionally, a method was implemented in which the immediate-release layers of the active ingredients, lobeglitazone and empagliflozin, were separated and compressed into a triple tablet. The present invention was completed by confirming that the content stability of the pharmaceutical combination formulation in the form of a double tablet or triple tablet implemented through these methods was improved and that bioequivalence was demonstrated through comparative dissolution with a reference drug.

[0042] The present invention will be described in detail below.

[0043] In this specification, the term lobeglitazone may refer to lobeglitazone or a pharmaceutically acceptable salt thereof. Accordingly, in this specification, a granular / immediate-release layer containing lobeglitazone may mean a granular / immediate-release layer containing lobeglitazone or a pharmaceutically acceptable salt thereof.

[0044] In this specification, the term "empagliflozin" may refer to empagliflozin or a pharmaceutically acceptable salt thereof. Accordingly, in this specification, a granular / immediate-release layer containing empagliflozin may mean a granular / immediate-release layer containing empagliflozin or a pharmaceutically acceptable salt thereof.

[0045] In this specification, the term metformin may refer to metformin or a pharmaceutically acceptable salt thereof. Accordingly, in this specification, a granule / sustained-release layer containing metformin may mean a granule / sustained-release layer containing metformin or a pharmaceutically acceptable salt thereof.

[0046] Pharmaceutical combination preparations

[0047] In order to solve the above problem, the present invention discloses the following means.

[0048] In one embodiment, the present invention provides a pharmaceutical compound formulation comprising: a sustained-release layer comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient; and a rapid-release layer comprising lobeglitazone or a pharmaceutically acceptable salt thereof and empagliflozin or a pharmaceutically acceptable salt thereof as active ingredients.

[0049] In the present invention, the term "metformin" refers to a drug used to treat diabetes represented by the following chemical formula 1, which prevents glucose production in the liver, reduces glucose absorption in the intestines, and improves sensitivity to insulin.

[0050] [Chemical Formula 1]

[0051]

[0052] The above metformin can be easily manufactured and used by a person skilled in the art by chemically synthesizing it using a known synthesis method, or a commercially manufactured product can be purchased and used.

[0053] In the present invention, the term "lobeglitazone" refers to a compound represented by the following chemical formula 2, which is a thiazolidinedione-class diabetes drug that increases insulin sensitivity and controls blood sugar.

[0054] [Chemical Formula 2]

[0055]

[0056] The above lobeglitazone can be easily manufactured and used by a person skilled in the art by chemically synthesizing it using a known synthesis method, or a commercially manufactured product can be purchased and used.

[0057] In the present invention, the term “empagliflozin” refers to a compound represented by the following chemical formula 3, which plays a role in regulating blood sugar by inhibiting the Na-Glucose transporter that delivers glucose into the kidney.

[0058] [Chemical Formula 3]

[0059]

[0060] The above empagliflozin can be easily manufactured and used by a person skilled in the art by chemically synthesizing it using a known synthesis method, or a commercially manufactured product can be purchased and used.

[0061] In the present invention, the term "pharmaceuticalally acceptable salt" includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. In the present invention, a pharmaceutically acceptable salt refers to any organic or inorganic adduct salt at a concentration that has a relatively non-toxic and harmless active effect on the patient, wherein side effects caused by the salt do not impair the beneficial efficacy of the pharmacologically active ingredient.

[0062] In the present invention, pharmaceutically acceptable salts of metformin may be used in the form of hydrochloride, but are not limited thereto.

[0063] The above metformin hydrochloride can be easily manufactured and used by a person skilled in the art by chemically synthesizing it using a known synthesis method, or a commercially manufactured product can be purchased and used.

[0064] In the present invention, pharmaceutically acceptable salts of lobeglitazone may be used in the form of lobeglitazone sulfate, but are not limited thereto.

[0065] The above lobeglitazone sulfate can be easily manufactured and used by a person skilled in the art by chemically synthesizing it using a known synthesis method, or a commercially manufactured product can be purchased and used.

[0066] In the present invention, pharmaceutically acceptable salts of empagliflozin may be used in the form of empagliflozin L-proline, but are not limited thereto.

[0067] The above empagliflozin L-proline can be easily manufactured and used by a person skilled in the art by chemically synthesizing it using known synthesis methods, or a commercially manufactured product can be purchased and used.

[0068] In the present invention, the pharmaceutical complex formulation may be formulated as a solid oral formulation, specifically, it may be either a tablet or a film-coated tablet, specifically, it may be a film-coated tablet, but is not limited thereto.

[0069] In particular, in the case of film-coated tablets, a polyvinyl alcohol-based coating agent may be used, but is not limited thereto.

[0070] In the present invention, the metformin or its pharmaceutically acceptable salt included in the sustained-release release layer may be included in an amount of 750 mg to 1000 mg based on a unit formulation, specifically 750 mg or 1000 mg as metformin hydrochloride, but is not limited thereto.

[0071] In the present invention, lobeglitazone or its pharmaceutically acceptable salt included in the immediate-release layer may be included in an amount of 0.25 mg to 0.5 mg based on a unit formulation, specifically 0.25 mg or 0.5 mg as lobeglitazone sulfate, but is not limited thereto.

[0072] In the present invention, the empagliflozin or pharmaceutically acceptable salt thereof included in the immediate-release layer may be included in an amount of 5 mg to 50 mg based on a unit formulation, specifically, the empagliflozin or pharmaceutically acceptable salt thereof may be included in an amount of 10 mg to 25 mg based on a unit formulation as empagliflozin, more specifically, may be included in an amount of 10 mg, 12.5 mg, or 25 mg as empagliflozin, but is not limited thereto.

[0073] In the present invention, the sustained-release layer comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient is prepared by a wet granulation method, but is not limited thereto.

[0074] In the present invention, when wet granulating a sustained-release release layer comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, the solvent for wet granulation may be purified water, but is not limited thereto.

[0075] In the present invention, the immediate-release layer comprising lobeglitazone or its pharmaceutically acceptable salt and empagliflozin or its pharmaceutically acceptable salt as active ingredients is prepared by a wet granulation method, specifically by a wet granulation method using a high-speed mixer, but is not limited thereto.

[0076] In the present invention, when wet granulating an immediate-release layer comprising lobeglitazone or its pharmaceutically acceptable salt and empagliflozin or its pharmaceutically acceptable salt as active ingredients, the solvent for wet granulation may be 20% (w / w) to 100% (w / w) ethanol, specifically 60% (w / w) to 100% (w / w) ethanol, but is not limited thereto.

[0077] In the present invention, the formulation of the pharmaceutical complex preparation may be a double tablet or a triple tablet, but is not limited thereto.

[0078] In the present invention, when the pharmaceutical complex formulation is a double tablet, it means that a sustained-release layer and an immediate-release layer are prepared separately and then compressed into a tablet to form the formulation.

[0079] In the present invention, when the pharmaceutical compound is a double tablet, the immediate-release layer may be in the form of lobeglitazone or a pharmaceutically acceptable salt thereof and empagliflozin or a pharmaceutically acceptable salt thereof mixed in wet granules, but is not limited thereto (see FIG. 1).

[0080] Specifically, when the above pharmaceutical combination formulation is in the form of a double tablet as shown in FIG. 1, the immediate-release layer comprises, based on the immediate-release layer, 0.05 to 0.5 wt% lobeglitazone or its pharmaceutically acceptable salt, 1 to 15 wt% empagliflozin or its pharmaceutically acceptable salt, 0.5 to 5 wt% low-substituted hydroxypropylcellulose, 70 to 90 wt% D-mannitol, 1 to 5 wt% croscarmellose sodium, 0.5 to 2 wt% colloidal silicon dioxide, 0.5 to 2 wt% sodium stearyl fumarate, and 0.5 to 2 wt% magnesium stearate, and specifically, 0.1 to 0.2 wt% lobeglitazone or its pharmaceutically acceptable salt, 3 to 10 wt% empagliflozin or its pharmaceutically acceptable salt, and low-substituted hydroxypropylcellulose It contains 1.5~3 wt%, D-mannitol 80~90 wt%, croscarmellose sodium 2.5~4.5 wt%, colloidal silicon dioxide 0.5~2 wt%, sodium stearyl fumarate 0.5~2 wt%, and magnesium stearate 0.5~2 wt%.

[0081] And, based on the sustained-release release layer, the sustained-release release layer comprises 70-85 wt% metformin hydrochloride, 1-10 wt% polyvinylpyrrolidone, 10-20 wt% hydroxypropylmethylcellulose, 0.5-2 wt% colloidal silicon dioxide, and 0.5-2 wt% magnesium stearate, specifically comprising 72-80 wt% metformin hydrochloride, 3-8 wt% polyvinylpyrrolidone, 12-18 wt% hydroxypropylmethylcellulose, 0.5-2 wt% colloidal silicon dioxide, and 0.5-2 wt% magnesium stearate.

[0082] In addition, when the pharmaceutical complex formulation in the form of a double tablet shown in Fig. 1 is a coated tablet, it contains 1 to 5 weight percent of a coating agent based on the total weight of the pharmaceutical complex formulation.

[0083] In the present invention, when the pharmaceutical complex formulation is a double tablet, the immediate-release layer may be in the form of a mixture of wet granules containing lobeglitazone or its pharmaceutically acceptable salt as an active ingredient and wet granules containing empagliflozin or its pharmaceutically acceptable salt as an active ingredient; specifically, this means that wet granules containing lobeglitazone or its pharmaceutically acceptable salt as an active ingredient and wet granules containing empagliflozin or its pharmaceutically acceptable salt as an active ingredient are granulated individually and then mixed (see FIG. 2).

[0084] Specifically, when the above pharmaceutical complex formulation is in the form of a double tablet as shown in FIG. 2, the wet granules containing lobeglitazone or its pharmaceutically acceptable salt as an active ingredient comprise lobeglitazone or its pharmaceutically acceptable salt, polyvinylpyrrolidone, D-mannitol, and croscarmellose sodium, and the wet granules containing empagliflozin or its pharmaceutically acceptable salt as an active ingredient comprise empagliflozin or its pharmaceutically acceptable salt, low-substituted hydroxypropylcellulose, microcrystalline cellulose, D-mannitol, and croscarmellose sodium, and the immediate-release layer comprises the wet granules containing lobeglitazone or its pharmaceutically acceptable salt as an active ingredient and the wet granules containing empagliflozin or its pharmaceutically acceptable salt as an active ingredient, and subsequently mixed D-mannitol, croscarmellose sodium, and colloidal silicon dioxide. It contains sodium stearyl fumarate and magnesium stearate.

[0085] At this time, the wet granules containing lobeglitazone or its pharmaceutically acceptable salt as an active ingredient comprise 0.1 to 1 wt% of lobeglitazone or its pharmaceutically acceptable salt, 1 to 15 wt% of polyvinylpyrrolidone, 45 to 75 wt% of D-mannitol, and 15 to 45 wt% of croscarmellose sodium based on the wet granules, and specifically comprises 0.1 to 0.5 wt% of lobeglitazone or its pharmaceutically acceptable salt, 5 to 10 wt% of polyvinylpyrrolidone, 50 to 70 wt% of D-mannitol, and 20 to 40 wt% of croscarmellose sodium.

[0086] And, wet granules containing empagliflozin or its pharmaceutically acceptable salt as an active ingredient contain 5 to 15 wt% of empagliflozin or its pharmaceutically acceptable salt, 1 to 5 wt% of low-substituted hydroxypropylcellulose, 20 to 35 wt% of microcrystalline cellulose, 40 to 65 wt% of D-mannitol, and 1 to 10 wt% of croscarmellose sodium based on the wet granules, and specifically, wet granules containing empagliflozin or its pharmaceutically acceptable salt as an active ingredient contain 7 to 12 wt% of empagliflozin or its pharmaceutically acceptable salt, 1.5 to 3.5 wt% of low-substituted hydroxypropylcellulose, 20 to 30 wt% of microcrystalline cellulose, 50 to 60 wt% of D-mannitol, and 2 to 8 wt% of croscarmellose sodium based on the wet granules.

[0087] In addition, the above pharmaceutical additives added during post-mixing comprise 10-20% by weight of D-mannitol, 1-10% by weight of sodium croscarmellose, 0.5-2% by weight of colloidal silicon dioxide, 0.5-2% by weight of sodium stearyl fumarate, and 0.5-2% by weight of magnesium stearate, based on the total weight of the immediate-release layer.

[0088] And, based on the sustained-release release layer, the sustained-release release layer comprises 70-85 wt% metformin hydrochloride, 1-10 wt% polyvinylpyrrolidone, 10-20 wt% hydroxypropylmethylcellulose, 0.5-2 wt% colloidal silicon dioxide, and 0.5-2 wt% magnesium stearate, specifically comprising 72-80 wt% metformin hydrochloride, 3-8 wt% polyvinylpyrrolidone, 12-18 wt% hydroxypropylmethylcellulose, 0.5-2 wt% colloidal silicon dioxide, and 0.5-2 wt% magnesium stearate.

[0089] In addition, when the pharmaceutical complex formulation in the form of a double tablet shown in Fig. 2 is a coated tablet, it contains 1 to 5 weight percent of a coating agent based on the total weight of the pharmaceutical complex formulation.

[0090] In the present invention, when the pharmaceutical complex formulation is a triple tablet, the immediate-release layer may be in a form where the lobeglitazone immediate-release layer and the empagliflozin immediate-release layer are separated. Here, separation means configuring the immediate-release layer containing lobeglitazone or its pharmaceutically acceptable salt as an active ingredient and the immediate-release layer containing empagliflozin or its pharmaceutically acceptable salt as an active ingredient separately rather than as a single layer. Specifically, it means preparing a sustained-release layer containing metformin or its pharmaceutically acceptable salt as an active ingredient, an immediate-release layer containing lobeglitazone or its pharmaceutically acceptable salt as an active ingredient, and an immediate-release layer containing empagliflozin or its pharmaceutically acceptable salt as an active ingredient, respectively, and then compressing them into a tablet to form a formulation (see FIG. 3).

[0091] Specifically, when the above pharmaceutical complex formulation is in the form of a triple tablet shown in FIG. 3, the lobeglitazone immediate-release layer comprises, based on the lobeglitazone immediate-release layer, 0.05 to 1 wt% of lobeglitazone or its pharmaceutically acceptable salt, 1 to 10 wt% of polyvinylpyrrolidone, 15 to 45 wt% of microcrystalline cellulose, 5 to 20 wt% of croscarmellose sodium, 0.1 to 2 wt% of colloidal silicon dioxide, 35 to 55 wt% of D-mannitol, and 0.5 to 3 wt% of magnesium stearate, and specifically, 0.05 to 0.5 wt% of lobeglitazone or its pharmaceutically acceptable salt, 2 to 5 wt% of polyvinylpyrrolidone, 30 to 40 wt% of microcrystalline cellulose, 8 to 15 wt% of croscarmellose sodium, and 0.1 to 1 wt% of colloidal silicon dioxide. It contains 40-50% by weight of D-mannitol and 0.5-2% by weight of magnesium stearate.

[0092] And, based on the empagliflozin immediate-release layer, the empagliflozin immediate-release layer comprises 1 to 15 wt% empagliflozin or its pharmaceutically acceptable salt, 0.5 to 5 wt% low-substituted hydroxypropylcellulose, 25 to 55 wt% D-mannitol, 25 to 55 wt% microcrystalline cellulose, 1 to 25 wt% sodium croscarmellose, 0.5 to 5 wt% sodium stearyl fumarate, and 0.5 to 5 wt% magnesium stearate, and specifically, 5 to 10 wt% empagliflozin or its pharmaceutically acceptable salt, 1 to 3 wt% low-substituted hydroxypropylcellulose, 30 to 45 wt% D-mannitol, 30 to 45 wt% microcrystalline cellulose, 3 to 15 wt% sodium croscarmellose, and 1 to 3 wt% sodium stearyl fumarate. It contains 0.5 to 2 weight percent of magnesium stearate.

[0093] And, based on the metformin sustained-release release layer, the metformin sustained-release release layer comprises 55-80 wt% metformin hydrochloride, 1-10 wt% polyvinylpyrrolidone, 10-40 wt% hydroxypropylmethylcellulose, 0.1-2 wt% colloidal silicon dioxide, and 0.1-2 wt% magnesium stearate, specifically comprising 65-75 wt% metformin hydrochloride, 2-5 wt% polyvinylpyrrolidone, 20-30 wt% hydroxypropylmethylcellulose, 0.5-1.5 wt% colloidal silicon dioxide, and 0.5-1.5 wt% magnesium stearate.

[0094] In addition, when the pharmaceutical complex formulation in the form of a triple tablet shown in Fig. 3 is a coated tablet, it contains 1 to 5 weight percent of a coating agent based on the total weight of the pharmaceutical complex formulation.

[0095] In the present invention, the pharmaceutical complex formulation may be a pharmaceutical complex formulation for the treatment or prevention of diabetes, but is not limited thereto.

[0096] The present invention will be described in detail below based on examples and experimental examples. However, the following examples and experimental examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.

[0097] Examples and Comparative Examples.

[0098] Examples 1–2 and Comparative Example 1. Preparation of a double tablet comprising a metformin sustained-release layer / empagliflozin and lobeglitazone wet granule immediate-release layer.

[0099] 1. Manufacture of metformin sustained-release layer

[0100] a. Alliance and Formation

[0101] Metformin hydrochloride (Metformin HCl) and hydroxypropylmethylcellulose (HPMC, Hypromellose 2208) were placed in a high-speed mixer and mixed, then a binding solution in which polyvinylpyrrolidone (PVP K-30) was dissolved in purified water was added to carry out the binding process, and then a granulation process was carried out to produce granules (granules).

[0102] B. Drying and Establishment

[0103] The above granulated material was placed in a fluidized bed granulator and dryer and the drying process was carried out. Afterwards, the above dried material was placed in a granulator and the granulation process was carried out.

[0104] C. Final mixing (post-mixing)

[0105] Colloidal silicon dioxide and magnesium stearate were added to the above granules and mixed to prepare a metformin sustained-release layer.

[0106] 2. Preparation of an immediate-release layer by mixing lobeglitazone and empagliflozin after preparing individual wet granules.

[0107] a. Preparation of an immediate-release layer by mixing lobeglitazone and empagliflozin and then using a wet granulation process

[0108] Empagliflozin L-proline and D-mannitol were mixed, and Lobeglitazone Sulfate and D-mannitol were mixed. Then, D-mannitol and low-substituted hydroxypropylcellulose (HPC-L) were placed in a high-speed mixer and mixed. After that, a binding solution in which low-substituted hydroxypropylcellulose (HPC-L) was dissolved in ethanol was added to carry out the binding process, and then a granulation process was carried out to produce granules (granules).

[0109] B. Granule Drying and Formulation

[0110] The above granulated material was placed in a flat tray dryer and the drying process was carried out at 50 ± 5℃. Afterwards, the dried material was placed in a granulator and the granulation process was carried out.

[0111] C. Final mixing (post-mixing)

[0112] The above-mentioned formulation and D-mannitol, croscarmellose sodium (Ac-Di-Sol ® Empagliflozin and lobeglitazone immediate-release layers were prepared by adding and mixing sodium stearyl fumarate (SSF) and magnesium stearate.

[0113] 3. Tableting and Coating

[0114] a. Tablets

[0115] A tablet was prepared by compressing the layers in the order of metformin sustained-release layer, empagliflozin, and lobeglitazone immediate-release layer using a multilayer tablet press.

[0116] B. Coating and Light Testing

[0117] After coating the tablets up to 3% by weight of the total weight of the tablets using a polyvinyl alcohol-based coating agent (AMB II), a photolithography process was performed using carnauba wax.

[0118] Lobeglitazone and Empagliflozin Immediate-Release Layer Example 1 Example 2 Comparative Example 1 process Ingredient name mg / 1T Combined solution preparation Low-substituted hydroxypropyl cellulose (HPC-L) 6.00 3.00 6.00 Combined solution preparation Ethanol Anhydrous 36.00 18.00 36.00 Mix (LOBE) Lobeglitazone Sulfate 0.50 0.50 0.25 D-Mannitol 34.00 34.00 34.00 Mix (EMPA) Empagliflozin L-proline (as empagliflozin) 31.38(25.00) 12.54(10.00) 15.69(12.50) D-Mannitol 100.00 90.96 81.00 federation D-Mannitol 45.12 70.00 80.06 federation Low-substituted hydroxypropyl cellulose (HPC-L) - 6.00 - Lobeglitazone and empagliflozin internal granular mass 217.00 217.00 217.00 Post-mixing D-Mannitol 81.00 81.00 81.00 Post-mixing Croscarmellose sodium (Ac-Di-Sol) ® ) 12.00 12.00 12.00 Post-mixing Colloidal silicon dioxide 3.00 3.00 3.00 Post-mixing Sodium stearyl fumarate 3.50 3.50 3.50 Post-mixing Magnesium stearate 3.50 3.50 3.50 Total mass of lobeglitazone and empagliflozin immediate-release layers 320.00 320.000 320.000 Metformin sustained-release layer mg / 1T Preparation of combined solution Polyvinylpyrrolidone (PVP K-30) 90.00 38.00 Preparation of combined solution purified water 250.00 140.00 Main component alliance Metformin hydrochloride (Metformin HCl) 1000.00 750.00 Main component alliance Hydroxypropylmethylcellulose (Hypromellose 2208) 210.00 244.00 Metformin internal granular mass 1300.00 1032.00 Post-mixing Colloidal silicon dioxide 12.00 9.00 Post-mixing Magnesium stearate 12.00 9.00 Total mass of the metformin sustained-release layer 1324.00 1050.00 Najeong total mass 1644.00 1370.00 Coating agent Polyvinyl alcohol-based coating agent (AMB II) 49.00 41.00 Coating solvent purified water 250.00 250.00 Polish Carnauba 0.10 0.10 Total mass of coated tablets 1693.10 1411.10

[0119] Experimental Example 1. Stability Test

[0120] 1. Purpose of stability test

[0121] A test was conducted to determine whether a decrease in content of lobeglitazone included in pharmaceutical combination formulations occurs under stability conditions (harsh / open conditions). The test conditions are as follows, and the test results are shown in Table 2.

[0122] 2. Stability Test Conditions

[0123] A. Harsh Storage Test Conditions

[0124] Temperature: 60±2℃

[0125] Packaging: Bottle packaging (Container: High-density polyethylene (HDPE), Lid: Polypropylene (PP))

[0126] Period : 0, 1, 2 weeks

[0127] B. Accelerated Storage (Open) Test Conditions (Accelerated Open)

[0128] Temperature: 40±2℃

[0129] Humidity: RH 75±5%

[0130] Packaging: Bottle packaging (Container: High-density polyethylene (HDPE), open)

[0131] Period : 0, 1, 2 weeks

[0132] Check the effects of humidity under open conditions

[0133] 3. Stability Test Results

[0134] When compared to the pharmaceutical combination preparation containing 0.5 mg of lobeglitazone (prescriptions of Examples 1 and 2), it was confirmed that the content decreased in the pharmaceutical combination preparation containing 0.25 mg of lobeglitazone (prescription of Comparative Example 1) (see Table 2).

[0135] volume Prescription Information First edition Acceleration Open(40±2℃, 75±5%) Harsh (60±2℃) 1 week 2 weeks 1 week 2 weeks 0.5 / 25 / 1000 Example 1 100.6% 97.8%(-2.8%) 97.1%(-3.5%) 98.3%(-2.3%) 98.6%(-2.0%) 0.5 / 10 / 1000 Example 2 100.3% 99.6%(-0.7%) 100.5%(0.2%) 98.7%(-0.2%) 96.3%(-2.6%) 0.25 / 12.5 / 1000 Comparative Example 1 96.2% 89.9%(-6.3%) 87.2%(-9.0) 85.2%(-11.0%) 79.3%(-16.9%)

[0136] Examples 3–7. Preparation of a double tablet comprising a metformin sustained-release layer and an empagliflozin and lobeglitazone individual wet granule immediate-release layer.

[0137] 1. Manufacture of metformin sustained-release layer

[0138] a. Alliance and Formation

[0139] Metformin hydrochloride (Metformin HCl) and hydroxypropylmethylcellulose (HPMC, Hypromellose 2208) were placed in a high-speed mixer and mixed, then a binding solution in which polyvinylpyrrolidone (PVP K-30) was dissolved in purified water was added to carry out the binding process, and then a granulation process was carried out to produce granules (granules).

[0140] B. Drying and Establishment

[0141] The above granulated material was placed in a fluidized bed granulator and dryer and the drying process was carried out. Afterwards, the above dried material was placed in a granulator and the granulation process was carried out.

[0142] C. Final mixing (post-mixing)

[0143] Colloidal silicon dioxide and magnesium stearate were added to the above granules and mixed to prepare a metformin sustained-release layer.

[0144] 2. Preparation of an immediate-release layer by mixing lobeglitazone and empagliflozin prepared via an individual wet granulation process.

[0145] a. Empagliflozin mixing, combination, and formulation

[0146] After mixing Empagliflozin L-proline and D-mannitol, D-mannitol, microcrystalline cellulose (MCC), and croscarmellose sodium (Ac-Di-Sol ® After placing the mixture into a High Speed ​​Mixer and mixing it, a binding solution in which low-substituted hydroxypropylcellulose (HPC-L) was dissolved in ethanol was added to carry out a binding process, and then a granulation process was carried out to produce granules (granulated material).

[0147] B. Drying and Formulation of Empagliflozin Granules

[0148] The above granulated material was placed in a flat tray dryer and the drying process was carried out at 50 ± 5℃. Afterwards, the dried material was placed in a granulator and the granulation process was carried out.

[0149] C. Preparation and combination of lobeglitazone dissolution and binding solution, and granulation (ethanol solvent ratios Example 3: 20% (w / w), Example 4: 40% (w / w), Example 5: 60% (w / w), Example 6: 80% (w / w), Example 7: 100% (w / w))

[0150] Lobeglitazone sulfate is dissolved in 20–100% (w / w) ethanol, and polyvinylpyrrolidone (Povidone K-30) is dissolved to prepare a binder, after which D-mannitol and croscarmellose sodium (Ac-Di-Sol ®) was placed in a High Speed ​​Mixer and mixed, and then a binding process was carried out with the binding solution in which the above-mentioned lobeglitazone sulfate was dissolved, followed by a granulation process to produce granules (granulated material).

[0151] D. Drying and Formulation of Lobeglitazone Granules

[0152] The above granulated material was placed in a flat tray dryer and the drying process was carried out at 50 ± 5℃. Afterwards, the dried material was placed in a granulator and the granulation process was carried out.

[0153] E. Final mixing (post-mixing)

[0154] The above empagliflozin formulations and lobeglitazone formulations, D-mannitol, croscarmellose sodium (Ac-Di-Sol ® Lobeglitazone and empagliflozin immediate-release layers were prepared by adding and mixing colloidal silicon dioxide, sodium stearyl fumarate (SSF), and magnesium stearate.

[0155] 3. Tableting and Coating

[0156] a. Tablets

[0157] A tablet was prepared by compressing the layers in the order of metformin sustained-release layer, empagliflozin, and lobeglitazone immediate-release layer using a multilayer tablet press.

[0158] B. Coating and Light Testing

[0159] After coating the tablets up to 3% by weight of the total weight of the tablets using a polyvinyl alcohol-based coating agent (AMB II), a photolithography process was performed using carnauba wax.

[0160] Preparation of Lobeglitazone and Empagliflozin Immediate-Release Layers Example 3 Example 4 Example 5 Example 6 Example 7 process Ingredient name mg / 1T Combined solution preparation Polyvinylpyrrolidone (PVP K-30) 7.50 7.50 7.50 7.50 7.50 Combined solution preparation purified water 24.00 18.00 12.00 6.00 - Combined solution preparation Ethanol 6.00 12.00 18.00 24.00 30.00 Combined solution preparation Lobeglitazone Sulfate 0.25 0.25 0.25 0.25 0.25 federation D-Mannitol 62.25 62.25 62.25 62.25 62.25 federation Croscarmellose sodium (Ac-Di-Sol) ® ) 30.00 30.00 30.00 30.00 30.00 Lobeglitazone internal granular mass 100.00 100.00 100.00 100.00 100.00 Combined solution preparation Low-substituted hydroxypropyl cellulose (HPC-L) 4.00 4.00 4.00 4.00 4.00 Combined solution preparation Ethanol Anhydrous 24.00 24.00 24.00 24.00 24.00 federation Empagliflozin L-proline (as empagliflozin) 15.69(12.5) 15.69(12.5) 15.69(12.5) 15.69(12.5) 15.69(12.5) federation Microcrystalline cellulose (MCC) 40.00 40.00 40.00 40.00 40.00 federation D-Mannitol 81.31 81.31 81.31 81.31 81.31 federation Croscarmellose sodium (Ac-Di-Sol) ® ) 6.00 6.00 6.00 6.00 6.00 Empagliflozin internal granular mass 147.00 147.00 147.00 147.00 147.00 Post-mixing D-Mannitol 44.00 44.00 44.00 44.00 44.00 Post-mixing Croscarmellose sodium (Ac-Di-Sol) ® ) 20.00 20.00 20.00 20.00 20.00 Post-mixing Colloidal silicon dioxide 3.00 3.00 3.00 3.00 3.00 Post-mixing Sodium stearyl fumarate 3.00 3.00 3.00 3.00 3.00 Post-mixing Magnesium stearate 3.00 3.00 3.00 3.00 3.00 Total mass of lobeglitazone and empagliflozin immediate-release layers 320.000 320.000 320.000 320.000 320.000 Manufacture of metformin sustained-release layer mg / 1T Preparation of combined solution Polyvinylpyrrolidone (PVP K-30) 90.00 Preparation of combined solution purified water 250.00 Main component alliance Metformin hydrochloride (Metformin HCl) 1000.00 Main component alliance Hydroxypropylmethylcellulose (Hypromellose 2208) 210.00 Metformin internal granular mass 1300.00 Post-mixing Colloidal silicon dioxide 12.00 Post-mixing Magnesium stearate 12.00 Total mass of the metformin sustained-release layer 1324.00 Najeong total mass 1644.00 Coating agent Polyvinyl alcohol-based coating agent (AMB II) 49.00 Coating solvent purified water 245.00 Polish Carnauba 0.10 Total mass of coated tablets 1693.10

[0161] Examples 8–10. Preparation of a triple tablet comprising a metformin sustained-release layer / empagliflozin immediate-release layer / lobeglitazone immediate-release layer

[0162] 1. Manufacture of metformin sustained-release layer

[0163] a. Alliance and Formation

[0164] Metformin hydrochloride (Metformin HCl) and hydroxypropylmethylcellulose (HPMC, Hypromellose 2208) were placed in a high-speed mixer and mixed, then a binding solution in which polyvinylpyrrolidone (PVP K-30) was dissolved in purified water was added to carry out a binding process, and then a granulation process was carried out to produce granules (granules).

[0165] B. Drying and Establishment

[0166] The above granulated material was placed in a fluidized bed granulator and dryer and the drying process was carried out. Afterwards, the above dried material was placed in a granulator and the granulation process was carried out.

[0167] C. Final mixing (post-mixing)

[0168] Colloidal silicon dioxide and magnesium stearate were added to the above granules and mixed to prepare a metformin sustained-release layer.

[0169] 2. Preparation of Empagliflozin Immediate-Release Layer

[0170] a. Empagliflozin mixing, combination, and formulation

[0171] After mixing Empagliflozin L-proline and D-mannitol, D-mannitol, microcrystalline cellulose (MCC), and croscarmellose sodium (Ac-Di-Sol ® After placing the mixture into a High Speed ​​Mixer and mixing it, a binding solution in which low-substituted hydroxypropylcellulose (HPC-L) was dissolved in ethanol was added to carry out a binding process, and then a granulation process was carried out to produce granules (granulated material).

[0172] B. Drying and Establishment

[0173] The above granulated material was placed in a flat tray dryer and the drying process was carried out at 50 ± 5℃. Afterwards, the dried material was placed in a granulator and the granulation process was carried out.

[0174] C. Final mixing (post-mixing)

[0175] In the above-mentioned formulation, croscarmellose sodium (Ac-Di-Sol ® An empagliflozin immediate-release layer was prepared by adding and mixing microcrystalline cellulose (MCC), sodium stearyl fumarate (SSF), and magnesium stearate.

[0176] 3. Preparation of Lobeglitazone Immediate-Release Layer - Ethanol Solvent 60%(w / w), 80%(w / w), 100%(w / w) (Ethanol Solvent Example 8: 60%(w / w), Example 9: 80%(w / w), Example 10: 100%(w / w))

[0177] a. Preparation and combination of lobeglitazone dissolving and binding solution, and granulation

[0178] Lobeglitazone sulfate is dissolved in 60–100% (w / w) ethanol, and polyvinylpyrrolidone (Povidone K-30) is dissolved to prepare a binder, after which D-mannitol and croscarmellose sodium (Ac-Di-Sol ® ) was placed in a High Speed ​​Mixer and mixed, and then a binding process was carried out with the binding solution in which the above-mentioned lobeglitazone sulfate was dissolved, followed by a granulation process to produce granules (granulated material).

[0179] B. Drying and Establishment

[0180] The above granulated material was placed in a flat tray dryer and the drying process was carried out at 50 ± 5℃. Afterwards, the dried material was placed in a granulator and the granulation process was carried out.

[0181] C. Final mixing (post-mixing)

[0182] Colloidal silicon dioxide and croscarmellose sodium (Ac-Di-Sol) are included in the above formulation ®), D-mannitol, and magnesium stearate were added and mixed.

[0183] 4. Tableting and Coating

[0184] a. Tablets

[0185] A tablet was manufactured by compressing the layers in the order of metformin sustained-release layer, empagliflozin immediate-release layer, and lobeglitazone immediate-release layer using a multilayer tablet press.

[0186] B. Coating and Light Testing

[0187] After coating the tablets up to 3% by weight of the total weight of the tablets using a polyvinyl alcohol-based coating agent (AMB II), a photolithography process was performed using carnauba wax.

[0188] Lobeglitazone immediate-release layer (trilayer tablet) Example 8 Example 9 Example 10 process Ingredient name mg / 1T Preparation of combined solution Polyvinylpyrrolidone (Povidone K-30) 7.50 7.50 7.50 Preparation of combined solution purified water 12.00 8.00 - Preparation of combined solution Ethanol 24.00 32.00 40.00 Preparation of combined solution Lobeglitazone Sulfate 0.25 0.25 0.25 federation Microcrystalline cellulose (MCC) 73.50 73.50 73.50 federation Croscarmellose sodium (Ac-Di-Sol) ® ) 2.25 2.25 2.25 Lobeglitazone internal granular mass 83.50 83.50 83.50 Post-mixing Colloidal silicon dioxide 1.00 1.00 1.00 Post-mixing Croscarmellose sodium (Ac-Di-Sol) ® ) 22.75 22.75 22.75 Post-mixing D-Mannitol 90.75 90.75 90.75 Post-mixing Magnesium stearate 2.00 2.00 2.00 Total mass of the lobeglitazone immediate-release layer 200.00 200.00 200.00 Empagliflozin immediate-release layer (trilayer tablet) mg / 1T Preparation of combined solution Low-substituted hydroxypropyl cellulose (HPC-L) 5.00 Preparation of combined solution Ethanol Anhydrous 24.00 Mix (EMPA) Empagliflozin L-proline (as empagliflozin) 15.69(12.5) D-Mannitol 47.00 federation D-Mannitol 33.31 federation Microcrystalline cellulose (MCC) 40.00 federation Croscarmellose sodium (Ac-Di-Sol) ® ) 6.00 Empagliflozin internal granular mass 147.00 Post-mixing Croscarmellose sodium (Ac-Di-Sol) ® ) 6.00 Post-mixing Microcrystalline cellulose (MCC) 41.00 Post-mixing Sodium stearyl fumarate 4.00 Post-mixing Magnesium stearate 2.00 Total mass of the empagliflozin immediate-release layer 200.00 Manufacture of metformin sustained-release layer mg / 1T Preparation of combined solution Polyvinylpyrrolidone (PVP K-30) 38.00 Preparation of combined solution purified water 140.00 Main component alliance Metformin hydrochloride (Metformin HCl) 750.00 Main component alliance Hydroxypropylmethylcellulose (Hypromellose 2208) 244.00 Metformin internal granular mass 1032.00 Post-mixing Colloidal silicon dioxide 9.00 Post-mixing Magnesium stearate 9.00 Total mass of the metformin sustained-release layer 1050.00 Najeong total mass 1450.00 Coating agent Polyvinyl alcohol-based coating agent (AMB II) 43.50 Coating solvent purified water 245.00 Polish Carnauba 0.10 Total mass of coated tablets 1493.60

[0189] Experimental Example 2. Stability Test

[0190] 1. Purpose of stability test

[0191] Considering that a decrease in content occurred in a pharmaceutical combination preparation containing 0.25 mg of lobeglitazone according to Experimental Example 1 above, a test was conducted to determine whether stability could be improved by (1) preparing each active ingredient as individual wet granules, mixing them, and then compressing them into a double tablet, and (2) separating the active ingredients and compressing them into a triple tablet. The test conditions were as follows, and the test results are shown in Table 5.

[0192] 2. Stability Test Conditions

[0193] A. Harsh Storage Test Conditions

[0194] Temperature: 60±2℃

[0195] Packaging: Bottle packaging (Container: High-density polyethylene (HDPE), Lid: Polypropylene (PP))

[0196] Period : 0, 1, 2 weeks

[0197] B. Accelerated Storage (Open) Test Conditions (Accelerated Open)

[0198] Temperature: 40±2℃

[0199] Humidity: RH 75±5%

[0200] Packaging: Bottle packaging (Container: High-density polyethylene (HDPE), open)

[0201] Period : 0, 1, 2 weeks

[0202] Check the effects of humidity under open conditions

[0203] 3. Stability Test Results

[0204] Referring to Table 5, a greater decrease in content was observed under harsh conditions than under accelerated (open) conditions. It was confirmed that the stability conditions were best when lobeglitazone was dissolved in 60% (w / w) ethanol to prepare the binder.

[0205] volume Prescription Information First edition Acceleration Open(40±2℃, 75±5%) Harsh (60±2℃) Initial 1w 2w 1w 2w 0.25 / 12.5 / 1000 double layer Example 3 EtOH 20% 97.0% 92.9%(-4.1%) 89.5%(-7.5%) 86.8%(-10.2%) 86.0%(-11.0%) Example 4 EtOH 40% 95.5% 90.8%(-4.7%) 89.4%(-6.1%) 92.9%(-2.6%) 88.5%(-7.0%) Example 5 EtOH 60% 96.1% 95.4%(-0.7%) 93.7%(-2.4%) 94.1%(-2.0%) 95.8%(-0.3%) Example 6 EtOH 80% 97.2% 94.8%(-2.4%) 90.6%(-6.6%) 91.7%(-5.5%) 89.7%(-7.5%) Example 7 EtOH 100% 97.4% 93.7%(-3.7%) 93.0%(-4.4%) 93.8%(-3.6%) 87.9%(-9.5%) 0.25 / 12.5 / 750 Triple Reaction Example 8 EtOH 60% 96.4% 95.2%(-1.2%) 96.3%(-0.1%) 97.9%(1.5%) 92.9%(-3.5%) Example 9 EtOH 80% 97.7% 93.6%(-4.1%) 94.6%(-3.1%) 92.8%(-4.9% 86.0%(-11.7%) Example 10 EtOH 100% 97.4% 92.3%(-5.1%) 92.5%(-4.9%) 88.6%(-8.8%) 84.4%(-13.0%)

[0206] Experimental Example 3. Comparative dissolution test

[0207] 1. Purpose of the test

[0208] Tests were conducted to determine whether the formulations of Example 1 (containing 0.5 mg of lobeglitazone), Example 5, and Example 8 (containing 0.25 mg of lobeglitazone), which confirmed the stability of the lobeglitazone content through Experimental Examples 1 and 2 above, were equivalent to the control drug in terms of dissolution.

[0209] 2. Reference drug and test drug information

[0210] Group investigational drugs Great Treaty Duvie Tablet 0.5 mg (Lobeglitazone Sulfate 0.5 mg) Jardiance Tablet 25 mg (Empagliflozin 25 mg) Jardiance Tablet 10 mg (Empagliflozin 10 mg) Glucophage XR Extended-Release Tablet 1000 mg (Metformin Hydrochloride 1000 mg) Test drug (Example 1) Lobeglitazone sulfate 0.5 mg, Empagliflozin L-proline 31.38 mg (25.0 mg as Empagliflozin), Metformin hydrochloride 1000 mg Test drug (Example 2) Lobeglitazone sulfate 0.5 mg, Empagliflozin L-proline 12.54 mg (10.0 mg as Empagliflozin), Metformin hydrochloride 1000 mg Test drug (Example 5) Lobeglitazone sulfate 0.25 mg, Empagliflozin L-proline 15.69 mg (12.5 mg as Empagliflozin), Metformin hydrochloride 1000 mg Test drug (Example 8) Lobeglitazone sulfate 0.25 mg, Empagliflozin L-proline 15.69 mg (12.5 mg as Empagliflozin), Metformin hydrochloride 750 mg

[0211] 3. Dissolution Test Conditions

[0212] a) Dissolution method: Korean Pharmacopoeia Method II (Paddle method)

[0213] b) Eluent: pH 1.2, 6.8 buffer 900 mL

[0214] c) Dissolution temperature: 37 ± 0.5 ℃

[0215] D) Rotation speed: 50 rpm

[0216] 3. Device Operating Conditions

[0217] a) Lobeglitazone sulfate, empagliflozin

[0218] - Detector: Ultraviolet absorption spectrophotometer (Measurement wavelength: Lobeglitazone-250 nm, Empagliflozin-220 nm)

[0219] - Column: Hypersil BDS (4.6 x 250 mm, 5 μm) or equivalent column

[0220] - Injection volume: 50 μL

[0221] - Flow rate: 1.0 mL / min

[0222] - Column temperature: A constant temperature around 40℃

[0223] - Sample temperature: A constant temperature around 25℃

[0224] - Analysis time: 15 minutes

[0225] - This phase: Mixture of 50 mM ammonium acetate solution and methanol (40:60)

[0226] b) Metformin hydrochloride

[0227] - Detector: Ultraviolet absorption spectrophotometer (Measurement wavelength: 255 nm)

[0228] - Column: Hypersil BDS (4.6 x 250 mm, 5 μm) or equivalent column

[0229] - Injection volume: 5 μL

[0230] - Flow rate: 1.0 mL / min

[0231] - Column temperature: A constant temperature around 40℃

[0232] - Sample temperature: A constant temperature around 25℃

[0233] - Analysis time: 5 minutes

[0234] - This image: Mixture of 50 mM ammonium acetate solution and methanol (50:50)

[0235] 4. Comparative dissolution test results

[0236] Examples 1, 2, and 5 are double tablets composed of an immediate-release layer with lobeglitazone / empagliflozin as the main ingredient and a sustained-release layer with metformin as the main ingredient. As shown in the results of Tables 7 and 8, the dissolution rate of the lobeglitazone and empagliflozin main ingredients was 85% or more at 15 minutes, showing an immediate-release drug release pattern identical to that of the reference drug. As shown in the results of Table 10, the dissolution rate of the metformin main ingredient was 50 or more, showing a sustained-release drug pattern identical to that of the reference drug.

[0237] In addition, Example 8 is a triple tablet composed of an immediate-release layer with lobeglitazone as the main ingredient, an immediate-release layer with empagliflozin as the main ingredient, and a sustained-release layer with metformin as the main ingredient. As shown in the results of Tables 10 and 11, the dissolution rates of the lobeglitazone and empagliflozin main ingredients were over 85% at 15 minutes, showing an immediate-release drug release pattern identical to that of the reference drug. As shown in the results of Table 12, the dissolution rate of the metformin main ingredient was over 50, showing a sustained-release drug pattern identical to that of the reference drug.

[0238] Lobeglitazone pH 1.2 Dissolution rate (%) at each time point (time) Time (min) 5 10 15 30 45 60 Over 85% dissolution in 15 minutes Great Treaty 70.9±1.5 97.1±2.2 98.8±0.6 99.2±0.8 99.7±0.8 101.3±1.6 Example 1 65.2±14.8 93.7±6 97.6±4.2 99±4.4 99.9±3.8 100.6±4.8 Example 2 61.8±6.5 92.7±3.2 94.8±3.4 96.5±3.5 97.1±4 98±4 Example 5 70.7±30.2 94±2 95.4±2.4 96.9±2.2 97.7±2.6 98.1±2.6 pH 6.8 Dissolution rate (%) at each time point (time) Time (min) 5 10 15 30 45 60 Over 85% dissolution in 15 minutes Great Treaty 46.4±3.3 98.4±2.4 102.6±2.2 102.6±2 102.5±2.2 102.1±2.2 Example 1 57.1±7.8 84.4±4.1 88.5±2.9 91.2±3.5 92.2±3.9 92.4±3.9 Example 2 63.9±4.6 90.4±2.1 94±2.5 97.8±1.6 100±1.6 100.8±1.7 Example 5 47.6±16 91.3±3.4 93.7±3.2 96.4±3 97.4±3.2 97.8±3.2

[0239] Empagliflozin pH 1.2 Dissolution rate (%) at each time point (time) Time (min) 5 10 15 30 45 60 15 minutes, 85% or more dissolution Jardiance 25mg 64±2.9 83±5 88.8±2.9 95±2.7 96.5±2.6 97.3±2.7 Jardiance 10mg 75.3±1.1 89.1±1.6 93.1±1.8 95.1±1.6 96.3±1.8 96.3±1.9 Example 1 38.4±9.8 76.9±5.8 89.3±4.4 97.2±4.1 98.5±4.4 99.1±4.7 Example 2 60.1±6.5 94.8±3.1 97.1±3.4 97.8±3.1 98.3±3.5 98.8±3.6 Example 5 61.1±22.3 89.2±2.9 93.4±1.8 95.1±1.7 96±1.8 96.4±1.9 pH 6.8 Dissolution rate (%) at each time point (time) Time (min) 5 10 15 30 45 60 15 minutes, 85% or more dissolution Jardiance 25mg 73.8±2.4 87.2±2.3 91.1±2.5 93.2±2.5 94.1±2.6 94.7±2.7 Jardiance 10mg 76.2±4.9 89.7±4 93.1±3.7 94.4±3 95.9±3.1 96.1±3 Example 1 45.7±4.9 79.6±5.4 88.7±5.3 94.5±5.5 95.6±5.6 95.9±5.8 Example 2 47.7±14.5 87.7±9.4 92.9±6.3 95.2±5.5 96.4±5.6 96.8±5.7 Example 5 47.4±11.3 87.6±2.7 92.2±1.9 94.5±1.8 95.6±2.1 96±2.4

[0240] Metformin pH 1.2 Dissolution rate (%) at each time point (time) Time (min) 15 30 45 60 90 120 180 360 720 f2 Great Treaty 10.8±0.3 17.7±0.3 22.8±1.2 26.2±1.6 34.3±1 40.8±1.1 51.1±1.2 73.5±1.8 98.2±2.5 - Example 1 12.1±0.8 20.9±0.9 25.7±0.8 32.9±1.4 41.2±2 47.9±2.2 59.3±2.9 83.8±3.9 105±2.8 58.0 Example 2 12.3±1.2 20.9±1.6 24.6±1.4 32.8±2.5 41.5±3.4 48±3.5 58.8±4.6 82.1±4.7 102.4±0.9 62.1 Example 5 12.3±1 20.1±1.4 24.8±1 31.2±1.7 39.5±1.9 45.5±2 55.7±2 78.3±2.3 100.1±2 68.1 pH 6.8 Dissolution rate (%) at each time point (time) Time (min) 15 30 45 60 90 120 180 360 720 f2 Great Treaty 10±0.3 15.5±0.4 20.4±0.7 24.9±0.8 32.5±1.2 38.3±1.4 47.8±1.6 70.2±2.5 94±3.5 - Example 1 10.7±1 18.3±1 24.5±1.4 29.7±1.5 37.9±1.6 43.9±1.6 55.1±2 77.2±2.4 98.2±1.1 64.0 Example 2 9.4±1.3 16.6±1.6 22.3±1.9 27.3±2 35.4±2.2 41.9±2.1 52.4±2.6 73.7±3 95.8±0.7 76.0 Example 5 9.8±1.3 16.7±2 22.1±2.4 27±2.7 34.9±3 41.2±3.3 51.4±3.7 72.7±4.1 96.1±3.8 80.2

[0241] Lobeglitazone pH 1.2 Dissolution rate (%) at each time point (time) Time (min) 5 10 15 30 45 60 15 minutes, 85% or more dissolution Great Treaty 32.2±13.2 79.1±18.8 96.4±3.5 101.1±2.5 102.8±1.7 102.8±2.9 Example 8 82.7±11.4 90.2±10.2 92.3±8.9 95.6±6.3 97.7±5 98.7±3.9 pH 6.8 Dissolution rate (%) at each time point (time) Time (min) 5 10 15 30 45 60 15 minutes, 85% or more dissolution Great Treaty 36.5±1.5 85.9±8.8 93.8±9.7 95.4±8.6 97.6±8.5 97±7.3 Example 8 65.7±12.4 81.3±11.2 85.3±7.4 85.8±9.2 88.8±7.4 89.7±7.5

[0242] Empagliflozin pH 1.2 Dissolution rate (%) at each time point (time) Time (min) 5 10 15 30 45 60 15 minutes, 85% or more dissolution Great Treaty 60.6±5 79.6±3.6 87.7±1.9 97.1±1 100.2±1.5 101.7±1.5 Example 8 54.7±4 78.4±2.6 86.5±1.6 93.7±0.6 92.9±0.5 95.9±0.4 pH 6.8 Dissolution rate (%) at each time point (time) Time (min) 5 10 15 30 45 60 15 minutes, 85% or more dissolution Great Treaty 66.7±10.2 86.2±6.4 93.9±4.2 100.7±2.2 102.1±1.5 101.8±0.8 Example 8 47.5±23.5 77.8±7.1 89.7±1.8 94±4.3 94.3±4 95.3±2.5

[0243] Metformin pH 1.2 Dissolution rate (%) at each time point (time) Time (min) 15 30 45 60 90 120 180 360 720 f2 Great Treaty 11.7±0.3 18.5±0.4 24.1±0.5 29.1±0.4 37.1±0.5 43.9±0.5 55.1±0.6 77.1±0.6 96.5±0.8 70.2 Example 8 10.2±0.7 18.5±0.9 25.4±1 31.2±1.3 40.3±1.2 48.1±1.3 60.8±1.8 84.1±1.9 98.5±1.9 pH 6.8 Dissolution rate (%) at each time point (time) Time (min) 15 30 45 60 90 120 180 360 720 f2 Great Treaty 11.7±0.2 18.7±0.3 24.6±0.3 29.6±0.4 37.8±0.3 44.9±0.3 56.5±0.4 79.6±0.7 100.1±0.9 74.7 Example 8 10±0.1 18.2±0.3 24.9±0.5 30.5±0.5 39.9±0.6 47.8±0.6 60.9±0.7 85.8±1.8 102.1±2.7

[0244] Specific parts of the present invention have been described in detail above. It is evident to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. Accordingly, the actual scope of the invention will be defined by the appended claims and their equivalents.

Claims

Claim 1 A pharmaceutical combination formulation comprising: a sustained-release layer comprising metformin or its pharmaceutically acceptable salt as an active ingredient; and an immediate-release layer comprising lobeglitazone or its pharmaceutically acceptable salt and empagliflozin or its pharmaceutically acceptable salt as active ingredients. Claim 2 A pharmaceutical compound formulation according to claim 1, wherein the immediate-release layer is manufactured by the wet granulation method. Claim 3 A pharmaceutical compound formulation according to paragraph 2, wherein the solvent used in the preparation of wet granules comprising lobeglitazone or a pharmaceutically acceptable salt thereof as an active ingredient is 20% (w / w) to 100% (w / w) ethanol. Claim 4 In claim 1, the pharmaceutical complex formulation is a pharmaceutical complex formulation in the form of a double tablet or a triple tablet. Claim 5 A pharmaceutical combination formulation according to claim 4, wherein, in the case where the above pharmaceutical combination formulation is a double tablet, the immediate-release layer is in the form of a mixture of wet granules containing lobeglitazone or a pharmaceutically acceptable salt thereof as an active ingredient and wet granules containing empagliflozin or a pharmaceutically acceptable salt thereof as an active ingredient. Claim 6 A pharmaceutical combination formulation according to claim 4, wherein, in the case where the above pharmaceutical combination formulation is a double tablet, the immediate-release layer is in the form of lobeglitazone or its pharmaceutically acceptable salt and empagliflozin or its pharmaceutically acceptable salt mixed in wet granules. Claim 7 A pharmaceutical combination formulation according to claim 4, wherein, in the case where the above pharmaceutical combination formulation is a triple tablet, the immediate-release layer is in a form in which the immediate-release layer of lobeglitazone and the immediate-release layer of empagliflozin are separated.

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