WO2025155160A1 - Pharmaceutical composition containing sodium-glucose cotransporter-2 inhibitor and angiotensin ii receptor blocker for prevention or treatment of obesity - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing a sodium-glucose cotransporter-2 inhibitor and an angiotensin II receptor blocker for the prevention or treatment of obesity. The pharmaceutical composition has no problem of interaction between drugs, shows a synergistic effect on weight loss, achieves rapid weight loss at the beginning of administration, and exhibits an effect of maintaining weight loss independent of dietary intake during long-term administration, and thus can be effectively applied to obese patients.

Description

Pharmaceutical composition for preventing or treating obesity containing a sodium glucose transporter-2 inhibitor and an angiotensin II receptor blocker

The present invention relates to a pharmaceutical composition for preventing or treating obesity containing a sodium glucose transporter-2 inhibitor and an angiotensin II receptor blocker.

The development of appetite-reducing drugs, the ultimate treatment for obesity, has been a difficult process that attempts to change thousands of years of human evolution in just a few decades. This difficult process of drug development has been fraught with trial and error. Obesity is classified as a disease, and is reported to be associated with type 2 diabetes, cardiovascular disease, osteoarthritis, some cancers, sleep apnea, asthma, and nonalcoholic fatty liver disease. The goal of anti-obesity drug treatment is not only weight loss, but also improvement of concomitant diseases such as hyperglycemia, dyslipidemia, and arteriosclerotic heart disease associated with obesity. After many twists and turns, anti-obesity drugs that have been newly approved by the U.S. Federal Drug Administration (FDA) in the past few years include lorcaserin, phentermine, topiramate, bupropion, naltrexone, and glucagon-like peptide-1 (GLP-1) receptor agonists.

However, the use of conventional anti-obesity agents may be associated with various side effects. For example, metformin may be associated with lactic acidosis or gastrointestinal side effects; sulfonylureas, glinides and insulin or insulin analogues may be associated with hypoglycemia and weight gain; thiazolidinediones may be associated with edema, fractures, weight gain and heart failure/cardiac effects; α-glucosidase inhibitors and GLP-1 or GLP-1 analogues may be associated with gastrointestinal side effects (e.g., indigestion, flatulence or diarrhea or nausea or vomiting) and, most seriously (but rarely), pancreatitis. Therefore, there is still a need in the art to provide effective, safe and acceptable therapies, particularly for obese or overweight patients.

In addition, the nature of metabolic diseases is multifactorial. Under certain circumstances, drugs with different mechanisms of action are combined. However, considering any combination of drugs with different modes of action, beneficial effects are not necessarily combined. Therefore, combination therapy that causes less harmful side effects is required.

Accordingly, the inventors of the present invention conducted research to develop a combination therapy that can be effectively applied to the treatment of obesity and completed the present invention.

One object of the present invention is to provide a pharmaceutical composition for preventing or treating obesity, comprising an angiotensin II receptor blocker or a pharmaceutically acceptable salt thereof as a first pharmacological ingredient; and a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a pharmaceutically acceptable salt thereof as a second pharmacological ingredient.

Another object of the present invention is to provide a method for preventing or treating obesity, comprising a step of administering the pharmaceutical composition to a subject.

One aspect of the present invention provides a pharmaceutical composition for preventing or treating obesity, comprising an angiotensin II receptor blocker or a pharmaceutically acceptable salt thereof as a first pharmacological ingredient; and a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a pharmaceutically acceptable salt thereof as a second pharmacological ingredient.

According to one specific example of the present invention, the sodium-glucose cotransporter-2 (SGLT-2) inhibitor may be dapagliflozin or empagliflozin.

According to one specific example of the present invention, the angiotensin Ⅱ receptor blocker may be Telmisartan.

According to one specific example of the present invention, the first pharmacological ingredient may be 40 mg to 80 mg, and the second pharmacological ingredient may be 10 mg.

According to a pharmaceutical composition for preventing or treating obesity containing a sodium glucose transporter-2 inhibitor and an angiotensin II receptor blocker, there is no problem of drug interaction, exhibits a synergistic effect on weight loss, and exhibits a rapid weight loss at the initial stage of administration and a weight loss maintenance effect independent of food intake during long-term administration, so it can be effectively applied to obese patients.

Figure 1 is a drawing showing the results of evaluating the effects of dapagliflozin and telmisartan combination drug administration groups of 1/8 mg/kg/day (low-dose group, G2), 3/24 mg/kg/day (medium-dose group, G3), and 9/72 mg/kg/day (high-dose group, G4) on body weight reduction and heart weight reduction in male (A) and female (B) normal SD rats, and in the single-dose groups of dapagliflozin 9 mg/kg/day (G5) and telmisartan 72 mg/kg/day (G6) and the control group (0.5% MC aqueous solution, G1).

Figure 2 is a drawing showing the body weight reduction effect in normal male SD rats after 13 weeks of nonclinical repeated administration of dapagliflozin and/or telmisartan.

Figure 3 is a graphic representation of the body weight reduction effect in normal female SD rats after 13 weeks of nonclinical repeated administration of dapagliflozin and/or telmisartan.

Figure 4 is a graphical representation of food intake in male rats following 13-week nonclinical repeated administration of dapagliflozin and/or telmisartan.

Figure 5 is a graph showing the weight loss effect in a nonclinical 13-week repeated-administration rat model of dapagliflozin and/or telmisartan.

Figure 6 is a graph showing the weight loss effect following administration of a combination of dapagliflozin and telmisartan in a high-fat diet-induced obese mouse model.

Figure 7 is a graph showing the effect of reducing food intake following administration of a combination of dapagliflozin and telmisartan in a high-fat diet-induced obese mouse model.

Figure 8 is a graph showing the improvement effect of AST and ALT, which are blood hepatitis indicators, and total glyceride (TG), which is a blood lipid indicator, following administration of a combination of dapagliflozin and telmisartan in a high-fat diet-induced obese mouse model.

Figure 9 is a graph showing the weight of white adipose tissue in epididymal adipose tissue (Epididymal-WAT weight) and white adipose tissue in retroperitoneal adipose tissue (Retro-WAT weight) according to administration of a combination of dapagliflozin and telmisartan in a high-fat diet-induced obese mouse model.

Figure 10 is a graph showing white adipose tissue weight and total adipose tissue weight according to administration of a combination of dapagliflozin and telmisartan in a high-fat diet-induced obese mouse model.

Figure 11 is a dexam image showing the effect of reducing abdominal fat in the high-dose combination group (T07) compared to the obese group (T02) following administration of a combination of dapagliflozin and telmisartan in a high-fat diet-induced obese mouse model.

One aspect of the present invention provides a pharmaceutical composition for preventing or treating obesity, comprising an angiotensin II receptor blocker or a pharmaceutically acceptable salt thereof as a first pharmacological ingredient; and a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a pharmaceutically acceptable salt thereof as a second pharmacological ingredient.

In the present invention, a combination of sodium-glucose cotransporter-2 (SGLT-2) and an angiotensin Ⅱ receptor blocker (ARB), which were previously administered separately, showed a synergistic effect in the treatment of obesity, and a drug compatibility test was performed to derive an optimal combination of SGLT-2 and ARB, thereby confirming that a pharmaceutical composition according to one specific example of the present invention can be effectively applied to the prevention or treatment of obesity.

As used herein, the term "overweight" may be defined as a condition in which an individual's body mass index (BMI) is greater than or equal to 25 kg/m2 and less than 30 kg/m2. "Overweight" and "pre-obese" are used interchangeably.

"Obesity" can be defined as a condition in which an individual's body mass index (BMI) is 30 kg/m2 or more. According to the WHO definition, "obesity" can be classified as follows: class I obesity is a condition in which the body mass index (BMI) is 30 kg/m2 or more but less than 35 kg/m2; class II obesity is a condition in which the body mass index (BMI) is 35 kg/m2 or more but less than 40 kg/m2; and class III obesity is a condition in which the body mass index (BMI) is 40 kg/m2 or more. Obesity can include, for example, visceral or abdominal obesity, and can include obese patients who do not have diabetes (especially type 1 or type 2 diabetes).

Visceral obesity can be defined as a condition in which the waist-to-hip ratio is measured as 1.0 or more in men and 0.8 or more in women. This defines the risk of developing insulin resistance and pre-diabetes.

Abdominal obesity is usually defined as a waist circumference greater than 40 inches or 102 cm in men and greater than 35 inches or 94 cm in women. For Japanese ethnicity or patients, abdominal obesity is defined as a waist circumference greater than 85 cm in men and greater than 90 cm in women (see, e.g., the Japanese Society for the Diagnosis of the Metabolic Syndrome).

The present invention relates to a method for reducing and maintaining body weight and/or body fat in a patient in need thereof, for example, an overweight or obese patient, comprising administering a sodium-glucose cotransporter-2 (SGLT-2) inhibitor and an angiotensin II receptor blocker.

The SGLT-2 inhibitor included in the pharmaceutical composition of the present invention may be any one substance selected from the group consisting of dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, luseogliflozin, and tofogliflozin, but dapagliflozin or empagliflozin is most preferable in terms of combination compatibility and synergistic effect.

The composition of the present invention may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier included in the composition of the present invention is one commonly used in the manufacture of drugs, and includes, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington: the science and practice of pharmacy 22nd edition (2013).

A pharmaceutical composition according to one specific embodiment of the present invention may be administered together with one or more substances exhibiting pharmacological activity in preventing or treating obesity.

In addition, the pharmaceutical composition according to one embodiment of the present invention can be used alone or in combination with methods using procedures, surgeries, hormone therapy, drug therapy, and/or biological response modifiers for the prevention or treatment of obesity.

The composition of the present invention may contain various bases and/or additives necessary and appropriate for the formulation of the dosage form, and may be manufactured by further including known compounds such as nonionic surfactants, silicone polymers, conditioners, fragrances, preservatives, bactericides, oxidation stabilizers, organic solvents, ionic or nonionic thickeners, softeners, antioxidants, free radical scavengers, opacifiers, stabilizers, emollients, silicones, α-hydroxy acids, antifoamers, moisturizers, vitamins, insect repellents, fragrances, preservatives, surfactants, anti-inflammatory agents, substance P antagonists, fillers, polymers, propellants, alkalizing or acidifying agents, or colorants, within a range that does not reduce the effectiveness.

The appropriate dosage of the composition of the present invention can be prescribed in various ways depending on factors such as the formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity. The dosage of the composition of the present invention can be 0.001 to 1000 mg/kg for adults.

The pharmaceutical composition of the present invention can be prepared by mixing an angiotensin II receptor blocker as a first pharmacological ingredient and an SGLT-2 inhibitor as a second pharmacological ingredient, and the mixing thereof can be performed simultaneously or sequentially, and can be performed using a method known in the art.

The composition of the present invention can be administered orally.

The composition of the present invention can be administered in various dosage forms when administered orally, such as tablets, pills, hard/soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc., and may further include various excipients, for example, wetting agents, sweeteners, flavoring agents, preservatives, etc. Specifically, when the composition of the present invention is formulated as an oral administration dosage form, it may further include appropriate carriers, excipients, and diluents commonly used in the manufacture thereof. Examples of the carrier, excipient and diluent may include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and/or mineral oil. In addition, the composition may be prepared by including diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants commonly used in formulations, and may further include a lubricant such as magnesium stearate or talc in addition to the excipients.

The composition of the present invention may be composed of about 0.1% to 90%, preferably about 1% to about 80%, of a pharmacological ingredient. Pharmaceutical preparations for oral use can be obtained by mixing the active ingredient with a solid excipient, preferably granulating the resulting mixture, and, if necessary or essential, adding suitable auxiliary substances, and then processing the mixture or granules into tablets or coated tablet cores.

The pharmaceutical composition of the present invention may be, for example, a double-layer tablet comprising an angiotensin II receptor blocker as a first pharmacological ingredient and an SGLT-2 inhibitor as a second pharmacological ingredient, or may be an inner core tablet structure comprising telmisartan as a first pharmacological ingredient and an SGLT-2 inhibitor as a second pharmacological ingredient and an outer layer surrounding an inner core layer, but is not limited thereto.

According to one specific example of the present invention, the sodium-glucose cotransporter-2 (SGLT-2) inhibitor may be dapagliflozin or empagliflozin.

As used herein, the term "dapagliflozin" refers to (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol, and "empagliflozin" refers to (1S)-1,5-Anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol.

According to one specific example of the present invention, the angiotensin Ⅱ receptor blocker may be Telmisartan.

As used herein, the term "telmisartan" refers to 4′-[(1,4′-dimethyl-2′-propyl[2,6′-bi-1H-benzimidazol]-1′-yl)methyl][1,1′-biphenyl]-2-carboxylic acid.

In the present invention, it was confirmed that telmisartan has superior combination compatibility and formulation stability with SGLT-2 inhibitors, particularly dapagliflozin and empagliflozin, compared to olmesartan and valsartan among ARBs.

The above dapagliflozin, empagliflozin or telmisartan may refer to both its active metabolites and prodrugs. The "metabolites" are each active derivatives that can be produced when dapagliflozin, empagliflozin or telmisartan is metabolized, and the "prodrugs" refer to compounds that are metabolized to dapagliflozin, empagliflozin or telmisartan, or to the same metabolite(s) as dapagliflozin, empagliflozin or telmisartan. In addition, dapagliflozin, empagliflozin or telmisartan may include all of its pharmaceutically acceptable salts, crystalline forms, hydrates, solvates, diastereomers or enantiomers.

According to one specific example of the present invention, the first pharmacological ingredient may be 40 mg to 80 mg, and the second pharmacological ingredient may be 10 mg.

When the first pharmacological ingredient is contained in an amount of less than 40 mg and/or the second pharmacological ingredient is contained in an amount of less than 10 mg, an appropriate therapeutic effect for diabetes and hypertension cannot be expected due to low drug blood concentration and low pharmacological effect resulting therefrom. On the other hand, when the first pharmacological ingredient is contained in an amount of more than 80 mg and/or the second pharmacological ingredient is contained in an amount of more than 10 mg, problems such as high drug blood concentration and side effects resulting therefrom, expression of toxicity, and induction of hypoglycemia and hypotension due to excessive therapeutic effect may occur, and an appropriate therapeutic effect cannot be expected. In one specific example, the tablet may contain 40 mg and 10 mg, or 80 mg and 10 mg, of the first pharmacological ingredient and the second pharmacological ingredient, respectively.

Another aspect of the present invention provides a method for preventing or treating obesity comprising administering the pharmaceutical composition to a subject.

The angiotensin II receptor blocker or a pharmaceutically acceptable salt thereof, and the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof, included in the pharmaceutical composition of the present invention, may be administered orally in an amount effective for the treatment or prevention of a subject or patient, depending on the intended purpose. It should be understood that the dosage for administration to a specific subject or patient should be determined based on various related factors such as the patient's weight, age, race, sex, health condition, diet, administration time, administration method, and severity of disease, and may be appropriately increased or decreased by a specialist. For example, a doctor may start the dosage of the pharmaceutical composition of the present invention at a level lower than that required to achieve the intended therapeutic effect, and gradually increase the dosage until the intended effect is achieved, and may easily determine and prescribe the dosage as needed.

Hereinafter, the present invention will be described in more detail through one or more examples. However, these examples are intended to exemplify the present invention and the scope of the present invention is not limited to these examples.

Experimental Example 1. Confirmation of the effects of ARB and SGLT-2 inhibitor combination on reducing heart weight and promoting urine excretion

1-1. Nonclinical 13-week repeated administration method

We evaluated the effects of the combination of telmisartan, an angiotensin II receptor blocker (ARB), and dapagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, on reducing heart weight and promoting urine excretion.

Specifically, the group composition was as shown in Table 1, and 6-week-old normal Sprague-Dawley (SD) rats (10 male and 10 female per group) were administered oral administration repeatedly every day for 13 weeks. During the test, general symptoms were observed, blood tests and urine excretion were measured, and after the observation period, the rats were euthanized and autopsied to measure the heart weight.

army Dosage
(mg/kg/day) Dosage
(mL/kg) Dapagliflozin Telmisartan G1 Normal control group 0 0 10 G2 Composite low dose group 1 8 10 G3 Composite medium capacity group 3 24 10 G4 Composite high capacity group 9 72 10 G5 Dapagliflozin monotherapy group 9 0 10 G6 Telmisartan monotherapy group 0 72 10

Dapagliflozin was used as dapagliflozin propanediol hydrate, and telmisartan was used as telmisartan powder (23.9%), and each was administered according to the dosage.

1-2. Confirmation of the effects of the combination of dapagliflozin and telmisartan on reducing heart weight and promoting urine excretion

In Experimental Example 1-1, when dapagliflozin and/or telmisartan alone/combined components were repeatedly orally administered to normal SD rats for 13 weeks, a significant decrease in heart weight was confirmed in the low-dose, medium-dose, and high-dose groups of the dapagliflozin and telmisartan combination drug. In particular, a significant decrease in heart weight was confirmed in the low-dose and medium-dose groups of the dapagliflozin and telmisartan combination drug in female rats (Fig. 1). In addition, it was confirmed that urinary excretion was promoted in the low-dose, medium-dose, and high-dose groups of the dapagliflozin and telmisartan combination drug.

Through these results, it was confirmed that cardiac hypertrophy due to obesity could be reduced by the combination of dapagliflozin and telmisartan.

Experimental Example 2. Confirmation of weight loss effect independent of food intake of ARB and SGLT-2 inhibitor combination

2-1. Confirmation of weight loss effect of combination of dapagliflozin and telmisartan

In the same manner as in Experimental Example 1-1, dapagliflozin and/or telmisartan alone/in combination was repeatedly orally administered to normal SD rats for 13 weeks and body weights were measured. As a result, a significant weight loss effect was confirmed in the low, medium, and high dose groups of dapagliflozin and telmisartan combination. On the other hand, in the telmisartan alone administration group, no weight loss effect was confirmed in females, and in the dapagliflozin alone administration group, no weight loss effect was confirmed in either females or males (Figs. 2 and 3).

Through these results, the synergistic effect of the combination of dapagliflozin and telmisartan on weight loss was confirmed.

2-2. Confirmation of weight loss effect independent of food intake of combination of dapagliflozin and telmisartan

In the same manner as Experimental Example 1-1, dapagliflozin and/or telmisartan alone/combined components were repeatedly orally administered to normal SD rats for 13 weeks, and food intake was measured and the relationship with body weight was analyzed. As a result, food intake was found to significantly increase in the low, medium, and high-dose groups of dapagliflozin and telmisartan combination components (Figure 4), and a 12.3% weight loss effect was confirmed in the medium-dose group of dapagliflozin and telmisartan combination components (Figure 5).

Through these results, it was confirmed that the combination of dapagliflozin and telmisartan can effectively reduce body weight independently of food intake, as it shows a weight-reducing effect even when food intake increases in normal rats that are not induced to become obese.

Experimental Example 3. Confirmation of the obesity-improving effect of ARB and SGLT-2 inhibitor combination in a high-fat diet-induced obese mouse model

3-1. Establishment of a high-fat diet-induced obesity mouse model and design of experimental groups

To evaluate the anti-obesity effect of the combination of telmisartan, an angiotensin II receptor blocker, and dapagliflozin, a sodium glucose transporter-2 inhibitor, a high-fat diet-induced obese mouse model was established and the experimental groups were designed.

Specifically, the experimental group for evaluating the obesity improvement effect was composed as shown in Table 2. The normal control group was prepared by feeding regular solid feed to male C57BL/6J mice for 4 weeks. The obese mouse model was prepared by feeding 60% Kcal high-fat diet (HFD) feed to male C57BL/6J mice for 4 weeks, and then dividing them into an obese group and an experimental group so that the average body weights were similar. After that, the test substance was administered to each group while feeding regular solid feed or HFD feed for 5 weeks.

army Test substance Dosage T01 Normal control group (n=8) Distilled water 10mL/kg T02 Obese group (n=8) Distilled water 10mL/kg T07 Composite high-dose group (n=8) Dapagliflozin 9 mg/kg/day + Telmisartan 72 mg/kg/day 10mL/kg

Dapagliflozin was used as dapagliflozin propanediol hydrate, and telmisartan was used as telmisartan powder (23.9%), and each was administered according to the dosage.

Body weight and food intake were measured twice a week during the 9-week experiment. After the 9-week experiment was completed, the whole body of the mice was photographed using Dexascan, and blood was collected and then dissected for use in subsequent experiments.

3-2. Check the weight loss effect

According to Experimental Example 3-1, the body weight of each experimental group was measured, and it was confirmed that the body weight of the obese group significantly increased compared to the normal control group, and the body weight of the combined high-dose group significantly decreased compared to the obese group. In particular, it was confirmed that the body weight of the combined high-dose group began to significantly decrease compared to the obese group just 4 days after the start of test substance administration. After 2 weeks from the start of test substance administration, the body weight of the combined high-dose group statistically significantly decreased to the level of the normal control group, and a weight loss effect of 28.2% was confirmed in the combined high-dose group compared to the obese group (Fig. 6).

In addition, as a result of measuring the food intake of each experimental group according to Experimental Example 3-1, the food intake of the complex high-dose group significantly decreased compared to the obese group, and it was confirmed that the food intake of the complex high-dose group decreased by 21.4% compared to the obese group at the end of the experiment (Figure 7).

Meanwhile, as a result of monitoring the body weight and food intake of each experimental group for three weeks after the end of the experiment, it was confirmed that the food intake of the complex high-dose group (2.90 g/day) recovered to a level similar to that of the obese group (3.08 g/day), while the body weight of the complex high-dose group was maintained at a 25.5% decrease compared to the obese group.

Through these results, it was confirmed that the combination of dapagliflozin and telmisartan can induce a decrease in food intake and body weight in the early stage of administration in obese mice, and can effectively maintain the reduced body weight despite a similar level of food intake before administration during long-term administration, and thus can exhibit a long-term weight loss maintenance effect independent of food intake in obese patients.

3-3. Confirmation of improvement in blood biochemical indicators

Using an SST tube (BD, USA), the blood obtained in Example 3-1 was centrifuged at 10,000 rpm for 15 minutes (LABOGENE, USA) to separate and dispense the serum, which was then stored at -80°C. After that, HITACHI (7180, Japan) was used to analyze the blood hepatitis indicators AST (Aspartate aminotransferase) and ALT (Alanine aminotransferase) and the blood lipid indicator total glyceride (TG) from the stored serum.

As a result, it was confirmed that both hepatitis indicators and blood lipid indicators significantly increased in the obese group compared to the normal control group. On the other hand, it was confirmed that AST, ALT, and TG were all statistically significantly decreased in the combined high-dose group compared to the obese group (Figure 8), and in particular, TG was confirmed to decrease by 51.8%.

Through these results, it was confirmed that the combination of dapagliflozin and telmisartan could improve blood hepatitis and lipid indices without adverse effects on the liver, kidneys, and muscles.

3-4. Check the fat reduction effect

In Experimental Example 3-1, the weights of white adipose tissue (WAT) and brown adipose tissue (BAT) in the epididymal adipose tissue and retroperitoneal adipose tissue of the mouse dissected were measured, and from this, the weight of white adipose tissue in the epididymal adipose tissue (Epididymal-WAT weight), the weight of white adipose tissue in the retroperitoneal adipose tissue (Retro-WAT weight), the weight of white adipose tissue, and the weight of total adipose tissue were derived.

As a result, it was confirmed that the weight of each adipose tissue significantly increased in the obese group compared to the normal control group. On the other hand, it was confirmed that the weight of each adipose tissue significantly decreased in the complex high-dose group compared to the obese group (Figs. 9 and 10), and it was confirmed that the weight of white adipose tissue of the epididymal adipose tissue, white adipose tissue weight of the retroperitoneal adipose tissue, white adipose tissue weight, and total adipose tissue weight in the complex high-dose group compared to the obese group decreased by 85.1%, 92.6%, 87.3%, and 85.2%, respectively.

In addition, as a result of comparing the dexams taken in Experimental Example 3-1, it was confirmed that the abdominal fat of the combined high-dose group was reduced to the level of the normal control group (Figure 11).

3-5. Statistical Analysis

The results of Experimental Example 3 were expressed as the mean + standard deviation (SD), and all experimental results were analyzed by an independent t-test. The significant differences by the independent t-test between the normal control group (T01) and the obese group (T02) were expressed as ^†† p<0.01 and ^† p<0.05, and the significant differences by the independent t-test between the obese group (T02) and the combined high-dose group (T07) were expressed as ^** p<0.01 and ^* p<0.05.

Experimental Example 4. Confirmation of the optimal combination of ARB and SGLT-2 inhibitors

The optimal combination of an angiotensin II receptor blocker (ARB) and a sodium-glucose cotransporter-2 (SGLT-2) inhibitor that does not decompose and has high stability even after long-term storage was identified through drug-drug compatibility test.

Specifically, after storing a mixture of ARB and SGLT-2 inhibitors for 2 weeks under accelerated stability test conditions (40±2℃/75±5% relative humidity), the changes in the content and appearance (color, lumping, etc.) of each component and flexible substance were analyzed. Olmesartan, valsartan, and telmisartan were used as ARBs, and empagliflozin, dapagliflozin propanediol monohydrate, and canagliflozin were used as SGLT-2 inhibitors, and the contents of each component are as shown in Table 3.

division ingredient ARB SGLT-2 inhibitors Example 1 Telmisartan 40mg Empagliflozin 40mg Example 2 Telmisartan 40mg Dapagliflozin 40mg Comparative Example 1 Telmisartan 80mg - Comparative Example 2 - Empagliflozin 80mg Comparative Example 3 - Dapagliflozin 80mg Comparative Example 4 Olmesartan 80mg - Comparative Example 5 Valsartan 80mg - Comparative Example 6 - Canagliflozin 80mg Comparative Example 7 Telmisartan 40mg Canagliflozin 40mg Comparative Example 8 Olmesartan 40mg Empagliflozin 40mg Comparative Example 9 Olmesartan 40mg Dapagliflozin 40mg Comparative Example 10 Valsartan 40mg Empagliflozin 40mg Comparative Example 11 Valsartan 40mg Dapagliflozin 40mg

To analyze the content of the main component and the degree of production of flexible substances, 10T tablets of the mixture of ARB and SGLT-2 inhibitor stored for 1 week and 2 weeks were placed in three 100 mL flasks, respectively, and a solution of 0.01 M hydrochloric acid aqueous solution and acetonitrile in an appropriate ratio was added to extract the main component, stirred, and then analyzed by HPLC.

To observe the properties and viscosity of the main components, 10 g of a mixture of ARB and SGLT-2 inhibitor stored for 1 week and 2 weeks was taken and exposed to 100 ml of purified water for 10 minutes at room temperature, and then the properties and viscosity were checked.

As a result, in the second week of acceleration, all indices were confirmed to be unsuitable in Comparative Examples 22 to 26 among the mixtures of ARB and SGLT-2 inhibitors, whereas the contents of telmisartan and empagliflozin (Example 1) and the mixture of telmisartan and dapagliflozin (Example 2) were 99.4%/95.1% and 99.2/99.2%, respectively, showing content changes of less than 10% in all, and the total amount of flexible substances was also found to be appropriate, confirming that the combination of drugs was the most appropriate (Table 4).

division Test items Initial Acceleration 1 week Acceleration 2 weeks Example 1 Content 99.9/100 99.5/97.6 99.4/95.1 flexible material 0.1 or less 1.0 or higher 1.0 or higher Constellation fitness fitness fitness Example 2 Content 99.9/100.1 99.4/99.9 99.2/99.2 flexible material 0.1 or less 0.1 or higher 0.1 or higher Constellation fitness fitness fitness Comparative Example 1 Content 100.1 100.1 100 flexible material 0.1 or less 0.1 or less 0.1 or less Constellation fitness fitness fitness Comparative Example 2 Content 99.9 97.3 95.1 flexible material 0.1 or less 1.0 or below 1.0 or higher Constellation fitness fitness fitness Comparative Example 3 Content 100.3 100.1 100.2 flexible material 0.1 or less 0.1 or less 0.1 or less Constellation fitness fitness fitness Comparative Example 4 Content 99.9 99.7 99.7 flexible material 0.1 or less 0.1 or higher 0.1 or higher Constellation fitness fitness fitness Comparative Example 5 Content 99.7 99.4 99.2 flexible material 0.1 or less 0.1 or higher 0.1 or higher Constellation fitness fitness fitness Comparative Example 6 Content 99.5 95.2 89.2 flexible material 0.1 or less 1.0 or below 5.0 or higher Constellation fitness Inappropriate Inappropriate Comparative Example 7 Content 99.5/92.1 99.1/89.1 98.9/82.3 flexible material 0.1 or less 5.0 or higher 5.0 or higher Constellation fitness Inappropriate Inappropriate Comparative Example 8 Content 100.1/99.9 99.1/90 95.4/84.6 flexible material 0.1 or less 5.0 or higher 5.0 or higher Constellation fitness fitness Inappropriate Comparative Example 9 Content 100.1/100 97.8/89.1 95/79.7 flexible material 0.1 or less 5.0 or higher 5.0 or higher Constellation fitness fitness Inappropriate Comparative Example 10 Content 100.2/99.9 95.5/95.4 93.3/90.1 flexible material 0.1 or less fitness 5.0 or higher Constellation fitness Inappropriate Inappropriate Comparative Example 11 Content 100.3/99.7 95.5/95.7 91.1/92.3 flexible material 0.1 or less 1.0 or higher 1.0 or higher Constellation fitness Inappropriate Inappropriate

The present invention has been described with reference to embodiments thereof. Those skilled in the art will appreciate that the present invention may be implemented in modified forms without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the present invention is set forth in the claims, not in the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.

Claims (4)

Angiotensin II receptor blocker or a pharmaceutically acceptable salt thereof as the first pharmacological ingredient; and As a second pharmacological ingredient, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a pharmaceutically acceptable salt thereof A pharmaceutical composition for preventing or treating obesity comprising: A pharmaceutical composition for preventing or treating obesity, wherein in claim 1, the sodium-glucose cotransporter-2 (SGLT-2) inhibitor is dapagliflozin or empagliflozin. A pharmaceutical composition for preventing or treating obesity, wherein in claim 1, the angiotensin Ⅱ receptor blocker is telmisartan. In paragraph 1, The above first pharmacological ingredient is 40 mg to 80 mg, The above second pharmacological ingredient is 10 mg A pharmaceutical composition for preventing or treating obesity.