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

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 angiotensin II receptor blocker

[0001] 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.

[0002] The development of appetite-suppressing drugs, the ultimate treatment for obesity, has been a arduous process, attempting to change thousands of years of human evolution in a matter of decades. This challenging drug development process has been fraught with trial and error. Obesity is classified as a disease and has been linked to type 2 diabetes, cardiovascular disease, osteoarthritis, some cancers, sleep apnea, asthma, and non-alcoholic fatty liver disease. The goal of anti-obesity drug treatment is not only weight loss, but also, more importantly, the improvement of obesity-related comorbidities such as hyperglycemia, dyslipidemia, and atherosclerotic heart disease. After many twists and turns, new anti-obesity drugs approved by the U.S. Food and Drug Administration (FDA) in the past few years include lorcaserin, phentermine, topiramate, bupropion, naltrexone, and glucagon-like peptide-1 (GLP-1) receptor agonists.

[0003] However, the use of conventional anti-obesity agents can be associated with various side effects. For example, metformin can be associated with lactic acidosis or gastrointestinal side effects; sulfonylureas, glinides, and insulin or insulin analogues can be associated with hypoglycemia and weight gain; thiazolidinediones can be associated with edema, fractures, weight gain, and heart failure / cardiac effects; and α-glucosidase inhibitors and GLP-1 or GLP-1 analogues can be associated with gastrointestinal side effects (e.g., dyspepsia, flatulence, or diarrhea or nausea or vomiting) and, most seriously (but rarely), pancreatitis. Therefore, there remains a need in the art to provide effective, safe, and acceptable therapies, particularly for obese or overweight patients.

[0004] Furthermore, metabolic diseases are multifactorial in nature. 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 therapies with fewer harmful side effects are needed.

[0005] 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.

[0006] 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.

[0007] Another object of the present invention is to provide a method for preventing or treating obesity, comprising administering the pharmaceutical composition to a subject.

[0008] 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.

[0009] According to one specific example of the present invention, the sodium-glucose cotransporter-2 (SGLT-2) inhibitor may be dapagliflozin or empagliflozin.

[0010] According to one specific example of the present invention, the angiotensin II receptor blocker may be telmisartan.

[0011] 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.

[0012] 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, it exhibits a synergistic effect on weight loss, and it exhibits a rapid weight loss in the early 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.

[0013] Figure 1 is a drawing showing the results of evaluating the effects of body weight reduction and heart weight reduction in male (A) and female (B) normal SD rats administered a combination of dapagliflozin and telmisartan at doses 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), and in the single-dose group of dapagliflozin 9 mg / kg / day (G5) and telmisartan 72 mg / kg / day (G6) and the control group (0.5% MC aqueous solution, G1).

[0014] Figure 2 is a diagram showing the body weight reduction effect in male normal SD rats after 13 weeks of nonclinical repeated administration of dapagliflozin and / or telmisartan.

[0015] Figure 3 is a diagram showing the body weight reduction effect in female normal SD rats after 13 weeks of nonclinical repeated administration of dapagliflozin and / or telmisartan.

[0016] Figure 4 is a graph showing food intake in male rats after 13 weeks of nonclinical repeated administration of dapagliflozin and / or telmisartan.

[0017] Figure 5 is a graph showing the weight loss effect in a nonclinical 13-week repeated administration rat model of dapagliflozin and / or telmisartan.

[0018] 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 obesity mouse model.

[0019] 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 obesity mouse model.

[0020] 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 obesity mouse model.

[0021] 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 obesity mouse model.

[0022] 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 obesity mouse model.

[0023] Figure 11 is a dexamnography image showing the abdominal fat reduction effect of the combined high-dose 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.

[0024] 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.

[0025] 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-to-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.

[0026] 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.

[0027] "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 (particularly type 1 or type 2 diabetes).

[0028] Visceral obesity is defined as a waist-to-hip ratio (WHR) of 1.0 or greater in men and 0.8 or greater in women. This increases the risk of developing insulin resistance and prediabetes.

[0029] Abdominal obesity is typically 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 individuals 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 Metabolic Syndrome).

[0030] 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.

[0031] 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.

[0032] The composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers included in the composition of the present invention are those commonly used in the manufacture of pharmaceuticals, and include, but are 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 ingredients, the pharmaceutical composition of the present invention may further include lubricants, wetting agents, sweetening agents, flavoring agents, emulsifiers, suspending agents, preservatives, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington: the science and practice of pharmacy 22nd edition (2013).

[0033] A pharmaceutical composition according to one embodiment of the present invention may be administered together with one or more substances exhibiting pharmacological activity in the prevention or treatment of obesity.

[0034] 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.

[0035] The composition of the present invention may include 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, pigments, fragrances, preservatives, bactericides, oxidation stabilizers, organic solvents, ionic or nonionic thickeners, softeners, antioxidants, free radical scavengers, opacifiers, stabilizers, emollients, silicones, α-hydroxy acids, antifoaming agents, 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 thereof.

[0036] The appropriate dosage of the composition of the present invention may be prescribed in various ways depending on factors such as the formulation method, administration method, patient age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity. The dosage of the composition of the present invention may be 0.001 to 1000 mg / kg for adults.

[0037] 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.

[0038] The composition of the present invention can be administered orally.

[0039] 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, fragrances, preservatives, etc. Specifically, when the composition of the present invention is formulated into 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 formulation may be prepared by including diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants and surfactants commonly used in formulations, and in addition to the excipients, a lubricant such as magnesium stearate or talc may be further included.

[0040] The composition of the present invention may comprise about 0.1% to 90%, preferably about 1% to about 80%, of the active 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.

[0041] 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.

[0042] According to one specific example of the present invention, the sodium-glucose cotransporter-2 (SGLT-2) inhibitor may be dapagliflozin or empagliflozin.

[0043] 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.

[0044] According to one specific example of the present invention, the angiotensin II receptor blocker may be telmisartan.

[0045] 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.

[0046] 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.

[0047] The above dapagliflozin, empagliflozin or telmisartan may refer to both its active metabolites and prodrugs. The "metabolites" are each active derivative 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, crystal forms, hydrates, solvates, diastereomers or enantiomers.

[0048] 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.

[0049] If 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, if 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, occurrence 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.

[0050] Another aspect of the present invention provides a method for preventing or treating obesity, comprising administering the pharmaceutical composition to a subject.

[0051] 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 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 body weight, age, race, sex, health condition, diet, administration time, administration method, and severity of the disease, and may be appropriately increased or decreased by a specialist. For example, a physician may start the dosage of the pharmaceutical composition of the present invention at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved, and may easily determine and prescribe the dosage as needed.

[0052] The present invention will be described in more detail below 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.

[0053]

[0054] Experimental Example 1. Confirmation of the effects of ARB and SGLT-2 inhibitor combination on reducing heart weight and promoting urine excretion.

[0055] 1-1. Nonclinical 13-week repeated administration method

[0056] The effects of a 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 were evaluated.

[0057] Specifically, the group composition was as shown in Table 1, and 10 male and 10 female normal 6-week-old Sprague-Dawley (SD) rats per group were administered oral administration repeatedly daily 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.

[0058]

[0059] Group Dosage (mg / kg / day) Dosage (mL / kg) Dapagliflozin Telmisartan G1 Normal control group 00 10 G2 Low-dose combination group 18 10 G3 Medium-dose combination group 32 4 10 G4 High-dose combination group 97 2 10 G5 Dapagliflozin monotherapy group 90 10 G6 Telmisartan monotherapy group 07 2 10

[0060]

[0061] Dapagliflozin was administered in the form of dapagliflozin propanediol hydrate, and telmisartan was administered in the form of telmisartan powder (23.9%), each administered in the appropriate dosage.

[0062]

[0063] 1-2. Confirmation of the effects of the combination of dapagliflozin and telmisartan on reducing heart weight and promoting urine excretion.

[0064] 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. In particular, a significant decrease in heart weight was confirmed in the low-dose and medium-dose groups of the dapagliflozin and telmisartan combination 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.

[0065] Through these results, it was confirmed that cardiac hypertrophy due to obesity could be reduced by the combination of dapagliflozin and telmisartan.

[0066]

[0067] Experimental Example 2. Confirmation of the weight loss effect independent of food intake of ARB and SGLT-2 inhibitor combination.

[0068] 2-1. Confirmation of the weight loss effect of the combination of dapagliflozin and telmisartan.

[0069] In the same manner as in Experimental Example 1-1, dapagliflozin and / or telmisartan alone / combined components were repeatedly orally administered to normal SD rats for 13 weeks and body weights were measured. As a result, a significant body weight reduction effect was confirmed in the low, medium, and high dose groups of dapagliflozin and telmisartan combination components. On the other hand, in the telmisartan alone administration group, no body weight reduction effect was confirmed in females, and in the dapagliflozin alone administration group, no body weight reduction effect was confirmed in both males and females (Figs. 2 and 3).

[0070] Through these results, the synergistic effect of the combination of dapagliflozin and telmisartan on weight loss was confirmed.

[0071]

[0072] 2-2. Confirmation of the weight loss effect of the combination of dapagliflozin and telmisartan independent of food intake.

[0073] 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).

[0074] 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 loss effect even when food intake increases in normal rats that are not induced to become obese.

[0075]

[0076] Experimental Example 3. Confirmation of the obesity-improving effect of a combination of ARB and SGLT-2 inhibitors in a high-fat diet-induced obese mouse model.

[0077] 3-1. Establishment of a high-fat diet-induced obesity mouse model and design of experimental groups

[0078] To evaluate the anti-obesity effect of a 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 experimental groups were designed.

[0079] Specifically, the experimental groups for evaluating the obesity improvement effect were composed as shown in Table 2. The normal control group was prepared by feeding regular solid food to male C57BL / 6J mice for 4 weeks. The obese mouse model was prepared by feeding 60% Kcal high-fat diet (HFD) food 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 substances were administered to each group while feeding regular solid food or HFD food for 5 weeks.

[0080]

[0081] Group test substance administration amount T01 Normal control group (n=8) Distilled water 10 mL / kg T02 Obese group (n=8) Distilled water 10 mL / kg T07 High-dose combination group (n=8) Dapagliflozin 9 mg / kg / day + Telmisartan 72 mg / kg / day 10 mL / kg

[0082]

[0083] Dapagliflozin was administered in the form of dapagliflozin propanediol hydrate, and telmisartan was administered in the form of telmisartan powder (23.9%), each administered in the appropriate dosage.

[0084] Body weight and food intake were measured twice a week during the nine-week experiment. Upon completion of the nine-week experiment, the mice were photographed using a Dexascan scanner, and blood samples were collected. The mice were then dissected and used for subsequent experiments.

[0085]

[0086] 3-2. Check the weight loss effect

[0087] As a result of measuring the body weight of each experimental group according to Experimental Example 3-1, 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 decrease significantly 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 28.2% weight loss effect was confirmed in the combined high-dose group compared to the obese group (Fig. 6).

[0088] 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 was significantly reduced compared to the obese group, and it was confirmed that the food intake of the complex high-dose group was reduced by 21.4% compared to the obese group at the end of the experiment (Fig. 7).

[0089] 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 remained at a level reduced by 25.5% compared to the obese group.

[0090] Through these results, it was confirmed that the combination of dapagliflozin and telmisartan can induce a decrease in food intake and body weight in obese mice at the initial stage of administration, 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.

[0091]

[0092] 3-3. Confirmation of improved blood biochemical indicators

[0093] The blood obtained in Example 3-1 was centrifuged at 10,000 rpm for 15 minutes using an SST tube (BD, USA) to separate and aliquot the serum (LABOGENE, USA), and then stored at -80°C. Thereafter, 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.

[0094] As a result, both hepatitis indicators and blood lipid indicators were confirmed to be significantly increased in the obese group compared to the normal control group. In contrast, in the combined high-dose group compared to the obese group, AST, ALT, and TG were all confirmed to be statistically significantly reduced (Figure 8), and TG in particular was confirmed to be reduced by 51.8%.

[0095] These results confirmed that the combination of dapagliflozin and telmisartan could improve blood hepatitis and lipid indices without adverse effects on the liver, kidneys, and muscles.

[0096]

[0097] 3-4. Confirmation of fat reduction effect

[0098] 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 obtained by dissection 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 (white adipose tissue weight), and the weight of total adipose tissue (Total dipose tissue weight) were derived.

[0099] As a result, it was confirmed that the weight of each adipose tissue was 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 was significantly decreased in the combined high-dose group compared to the obese group (Figs. 9 and 10). It was confirmed that the weight of white adipose tissue of epididymal adipose tissue, white adipose tissue weight of retroperitoneal adipose tissue, white adipose tissue weight, and total adipose tissue weight in the combined high-dose group compared to the obese group decreased by 85.1%, 92.6%, 87.3%, and 85.2%, respectively.

[0100] 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 (Fig. 11).

[0101]

[0102] 3-5. Statistical Analysis

[0103] The results of Experimental Example 3 were expressed as mean + standard deviation (SD), and all experimental results were analyzed using an independent t-test. There was no significant difference between the normal control group (T01) and the obese group (T02) by an independent t-test. †† p<0.01 and †p<0.05, there was no significant difference by independent t-test between the obese group (T02) and the combined high-dose group (T07). ** p<0.01 and * p<0.05 was expressed.

[0104]

[0105] Experimental Example 4. Confirmation of the optimal combination of ARB and SGLT-2 inhibitors.

[0106] 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 by evaluating drug-drug compatibility test.

[0107] Specifically, after storing a mixture of ARB and SGLT-2 inhibitor for 2 weeks under accelerated stability test conditions (40±2℃ / 75±5% relative humidity), the changes in the content and appearance (color, clumping, etc.) of each component and related substances 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.

[0108]

[0109] Classification IngredientsARBSGLT-2 InhibitorExample 1 Telmisartan 40mgEmpagliflozin 40mgExample 2 Telmisartan 40mgDapagliflozin 40mgComparative Example 1 Telmisartan 80mg-Comparative Example 2-Empagliflozin 80mgComparative Example 3-Dapagliflozin 80mgComparative Example 4 Olmesartan 80mg-Comparative Example 5 Valsartan 80mg-Comparative Example 6-Canagliflozin 80mgComparative Example 7 Telmisartan 40mgCanagliflozin 40mgComparative Example 8 Olmesartan 40mgEmpagliflozin 40mgComparative Example 9 Olmesartan 40mgDapagliflozin 40mgComparative Example 10 Valsartan 40mgEmpagliflozin 40mgComparative Example 11 Valsartan 40 mg Dapagliflozin 40 mg

[0110]

[0111] In order to analyze the content of the main ingredient and the degree of formation 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, and a solution of 0.01 M hydrochloric acid aqueous solution and acetonitrile mixed in an appropriate ratio was added to extract the main ingredient, stirred, and then analyzed by HPLC.

[0112] In order to observe the properties and viscosity of the main ingredients, 10 g of the mixture of ARB and SGLT-2 inhibitor stored for 1 week and 2 weeks was taken and exposed to 100 ml of purified water at room temperature for 10 minutes, and then the properties and viscosity were checked.

[0113]

[0114] 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).

[0115]

[0116] Classification Test Item 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 more 1.0 or more Property Suitable Suitable Suitable Example 2 Content 99.9 / 100.1 99.4 / 99.99 9.2 / 99.2 Flexible material 0.1 or less 0.1 or more 0.1 or more Property Suitable Suitable Suitable Comparison Example 1 Content 100.1 100.1 100 Flexible material 0.1 or less 0.1 or less 0.1 or less Property Suitable Suitable Suitable Comparison Example 2 Content 99.99 7.3 95.1 Flexible material 0.1 or less 1.0 or less 1.0 or more Property Suitable Suitable Suitable Comparison Example 3 Content 100.3 100.1 100.2 Flexible material 0.1 Below 0.1 Below 0.1 Below Property Suitable Suitable Suitable Comparison Example 4 Content 99.999.799.7 Flexible material 0.1 Below 0.1 Above 0.1 Above Property Suitable Suitable Suitable Comparison Example 5 Content 99.799.499.2 Flexible material 0.1 Below 0.1 Above 0.1 Above Property Suitable Suitable Suitable Comparison Example 6 Content 99.595.289.2 Flexible material 0.1 Below 1.0 Below 5.0 Above Property Suitable Inappropriate Inappropriate Comparison Example 7 Content 99.5 / 92.199.1 / 89.198.9 / 82.3 Flexible material 0.1 Below 5.0 Above 5.0 Above Property Suitable Inappropriate Inappropriate Comparison Example 8 Content 100.1 / 99.999.1 / 9095.4 / 84.6 Flexible material 0.1 Below 5.0 Above 5.0 Above Property Suitable Suitable Unsuitable Comparison Example 9 Content 100.1 / 100 97.8 / 89.1 95 / 79.7 Flexible material 0.1 Below 5.0 Above 5.0 Above Property Suitable Suitable Unsuitable Comparison Example 10 Content 100.2 / 99.9 95.5 / 95.4 93.3 / 90.1 Flexible material 0.1 Below 5.0 Above Property Suitable Unsuitable Unsuitable Comparison Example 11 Content 100.3 / 99.7 95.5 / 95.7 91.1 / 92.3 Flexible material 0.1 Below 1.0 Above 1.0 Above Property Suitable Unsuitable Unsuitable

[0117]

[0118] The present invention has been described above, focusing on specific embodiments thereof. Those skilled in the art will appreciate that the present invention can be implemented in modified forms without departing from its essential characteristics. Therefore, the disclosed embodiments should be considered illustrative rather than limiting. The scope of the present invention is set forth in the claims, not the foregoing description, and all differences within the scope equivalent thereto should be construed as being encompassed by the present invention.

Claims

1. 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:

2. A pharmaceutical composition for preventing or treating obesity, wherein the sodium-glucose cotransporter-2 (SGLT-2) inhibitor in paragraph 1 is dapagliflozin or empagliflozin.

3. A pharmaceutical composition for preventing or treating obesity, wherein the angiotensin Ⅱ receptor blocker in paragraph 1 is telmisartan.

4. 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.

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