Oral pharmaceutical formulations comprising sodium-glucose cotransporter 2 inhibitor and angiotensin II receptor blocker

Abstract

The invention relates to an oral pharmaceutical preparation containing a sodium-glucose cotransporter 2 inhibitor and an angiotensin II receptor blocker, and the sodium-glucose cotransporter 2 inhibitor and the angiotensin II receptor blocker which are independently taken before can be prepared into an oral single compound preparation. The present invention relates to a pharmaceutical composition, which can be implemented in a relatively small size, thereby improving ease of administration and patient compliance, and can be effectively used in patients requiring long-term administration, such as type 2 diabetes, hypertension, hypertension associated with diabetes, heart failure, and the like, since there is no drug interaction problem.

Description

Technical Field

[0001] The present invention relates to an oral pharmaceutical preparation comprising a sodium-glucose cotransporter 2 inhibitor and an angiotensin II receptor blocker.

[0002] The present invention was completed with the support of the National Research Foundation of Korea under the "Regional Innovation System (RIS) (Chungbuk Regional Innovation Platform, project identification number 1345370811, project number 2021RIS-001)" funded by the Ministry of Education in 2023.

[0003] The present invention was supported by the "Regional Innovation Strategy (RIS)" project (2021RIS-001) of the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE) of Korea. Background Art

[0004] Hypertensive vascular disease is one of the leading causes of death and is a multifactorial disease caused by the complex interaction of multiple chronic diseases with various risks such as smoking and obesity. In particular, it is reported that the prevalence of hypertension accompanied by diabetes in Korea is approximately 26% (Hypertension Fact Sheet 2020, Korean Society of Hypertension), and the number of hypertensive patients with diabetes continues to increase. It is well known that the incidence of hypertension in diabetic patients is approximately twice that of non-diabetic patients, and hypertension may occur or deteriorate due to microvascular and macrovascular complications caused by diabetes. In addition, hypertensive patients also have a high risk of developing diabetes, and it is reported that the mortality rate of diabetic patients due to cardiovascular disease is about 2 to 4 times higher than that of non-diabetic patients.

[0005] Therefore, hypertensive patients with diabetes are likely to exhibit pathophysiology different from that of hypertensive patients without diabetes or responses to drug treatment, and existing drug treatment methods may not be able to control blood pressure or may have poor effects. In addition, hypertensive patients with diabetes must take a large number of various drugs, so they often fail to achieve the desired therapeutic effect due to low medication convenience and drug compliance. Therefore, there is a need to develop combination therapies and combination preparations suitable for treating hypertensive patients with diabetes.

[0006] Sodium-glucose cotransporter-2 (SGLT-2) inhibitors inhibit the reabsorption of glucose in the blood, thereby reducing blood glucose and inhibiting the secretion of inflammatory cytokines. Therefore, they are used to treat cardiovascular diseases such as type 2 diabetes and heart failure. Known SGLT-2 inhibitors developed so far include dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, luseogliflozin, tofogliflozin, etc.

[0007] Different from angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers (ARBs) mainly act on smooth muscles and the adrenal gland, selectively interfering with the binding of angiotensin II to angiotensin II type 1 receptor (AT1R), thereby reducing blood pressure. Therefore, they are used as antihypertensive drugs. Known ARBs developed so far include valsartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, etc.

[0008] On the other hand, among ARBs, the solubility of telmisartan varies greatly according to the pH value, reaching more than 100 times. Not only is the solubility particularly low at the pH value of the in vivo absorption site, but when formulated into a compound preparation with an SGLT-2 inhibitor such as dapagliflozin, due to the low solubility of telmisartan, the dissolution rates of the two components slow down due to interference with the sink condition in the dissolution medium. In addition, telmisartan is prone to absorbing moisture, which may affect the stability of dapagliflozin, and dapagliflozin has a low melting point and low moisture stability. Therefore, it is difficult to develop a compound preparation of telmisartan and an SGLT-2 inhibitor. Therefore, since telmisartan and SGLT-2 inhibitors must be taken separately at present, for patients with type 2 diabetes, hypertension, hypertension accompanied by diabetes, or heart failure who must take the two drugs simultaneously, there are problems of low medication convenience and low drug compliance.

[0009] In view of this, the present inventors have completed the present invention by conducting research to develop an oral compound preparation of an SGLT-2 inhibitor and an ARB that can maintain a stable dosage form without drug interaction problems. Summary of the Invention

[0010] Technical problem

[0011] One object of the present invention is to provide an oral pharmaceutical preparation comprising: telmisartan or a pharmaceutically acceptable salt thereof as a first pharmacological component; a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a pharmaceutically acceptable salt thereof as a second pharmacological component; and an excipient.

[0012] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating type 2 diabetes, hypertension, hypertension with diabetes, or heart failure, which comprises the oral pharmaceutical preparation.

[0013] Another object of the present invention is to provide a method for preventing or treating type 2 diabetes, hypertension, hypertension with diabetes, or heart failure, which comprises the step of administering the oral pharmaceutical preparation to a subject.

[0014] Technical solution

[0015] One aspect of the present invention provides an oral pharmaceutical preparation comprising: telmisartan or a pharmaceutically acceptable salt thereof as a first pharmacological component; a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a pharmaceutically acceptable salt thereof as a second pharmacological component; and an excipient.

[0016] According to a specific example of the present invention, the sodium-glucose cotransporter-2 (SGLT-2) inhibitor may be dapagliflozin or empagliflozin.

[0017] According to a specific example of the present invention, the weight ratio of the first pharmacological component to the second pharmacological component may be 4:1 to 8:1.

[0018] According to a specific example of the present invention, the weight ratio of the total pharmacological components to the excipient may be 1:2 to 1:5.

[0019] According to a specific example of the present invention, the oral pharmaceutical preparation may be a tablet.

[0020] According to a specific example of the present invention, each tablet may comprise 40 mg to 80 mg of the first pharmacological component and 10 mg of the second pharmacological component.

[0021] According to a specific example of the present invention, when a dissolution test is performed at a paddle rotation speed of 50 rpm according to the dissolution test method 2 of the Korean Pharmacopoeia, the dissolution rate of the first pharmacological component of the tablet in a hydrochloric acid solution at pH 1.2 within 30 minutes can be 40% or more, and the dissolution rate within 90 minutes can be 85% or more. The dissolution rate of the second pharmacological component of the tablet in a hydrochloric acid solution at pH 1.2 within 5 minutes can be 60% or more, and the dissolution rate within 30 minutes can be 95% or more.

[0022] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating type 2 diabetes, hypertension, hypertension with diabetes, or heart failure, which comprises the oral pharmaceutical preparation.

[0023] Another aspect of the present invention provides a method for preventing or treating type 2 diabetes, hypertension, hypertension with diabetes, or heart failure, which comprises the step of administering the oral pharmaceutical preparation to a subject.

[0024] Effects of the Invention

[0025] The oral pharmaceutical preparation containing a sodium-glucose cotransporter 2 inhibitor and an angiotensin II receptor blocker according to the present invention can make the sodium-glucose cotransporter 2 inhibitor and the angiotensin II receptor blocker, which were previously taken separately, into an orally administrable single tablet combination preparation, and can be achieved in a relatively small size. Therefore, the convenience of taking the medicine and the compliance of patients can be improved. Moreover, since there is no problem of drug interaction, it can be effectively used for patients who need long-term medication, such as patients with type 2 diabetes, hypertension, hypertension with diabetes, and heart failure. Description of the Drawings

[0026] Figure 1 A bar graph showing the results of measuring the cell viability after treating A549 cells with telmisartan or olmesartan for 24 hours (A) and 48 hours (B).

[0027] Figure 2 A bar graph showing the results of measuring the cell viability after treating MDCK cells with telmisartan or olmesartan for 24 hours (A) and 48 hours (B).

[0028] Figure 3 A bar graph showing the results of evaluating the inhibitory activity of angiotensin converting enzyme (ACE) after treating the cardiomyocyte line H9c2, which was induced to be inflamed with lipopolysaccharide (LPS), with telmisartan or olmesartan.

[0029] Figure 4A figure showing the results of evaluating the inhibitory activity of ACE mRNA expression after treating the myocardial cell line H9c2 with LPS-induced inflammation with telmisartan or olmesartan for display.

[0030] Figure 5 A figure showing the evaluation of the inhibitory activity of ACE mRNA expression after treating the myocardial cell line H9c2 with LPS-induced inflammation with different sodium-glucose cotransporter 2 inhibitors and / or angiotensin II receptor blockers for display.

[0031] Figure 6 A bar graph showing the evaluation of the inhibitory activity of ACE mRNA expression after treating the myocardial cell line H9c2 with LPS-induced inflammation with different sodium-glucose cotransporter 2 inhibitors and / or angiotensin II receptor blockers for display.

[0032] Figure 7 A bar graph showing the evaluation of the inhibitory activity of ACE protein expression after treating the myocardial cell line H9c2 with LPS-induced inflammation with different sodium-glucose cotransporter 2 inhibitors and / or angiotensin II receptor blockers for display.

[0033] Figure 8 A graph showing the dissolution pattern of telmisartan in a mixed bilayer tablet of telmisartan and dapagliflozin according to a specific example of the present invention for display.

[0034] Figure 9 A graph showing the dissolution pattern of dapagliflozin in a mixed bilayer tablet of telmisartan and dapagliflozin according to a specific example of the present invention for display.

[0035] Figure 10 A graph showing the pharmacokinetics of dapagliflozin after single oral administration of a compound bilayer tablet of dapagliflozin and telmisartan according to a specific example of the present invention for display.

[0036] Figure 11 A graph showing the pharmacokinetics of telmisartan after single oral administration of a compound bilayer tablet of dapagliflozin and telmisartan according to a specific example of the present invention for display.

[0037] Figure 12 A figure showing the evaluation results of the body weight loss and heart weight reduction effects of the dapagliflozin and telmisartan combination preparation at 1 / 8 mg / kg / day (low-dose group, G2), 3 / 24 mg / kg / day (medium-dose group, G3), 9 / 72 mg / kg / day (high-dose group, G4) administration groups, the dapagliflozin single administration group at 9 mg / kg / day (G5), the telmisartan single administration group at 72 mg / kg / day (G6), and the control group (0.5% MC aqueous solution, G1) in male rats (A) and female rats (B) for display. Detailed implementation mode

[0038] One aspect of the present invention provides an oral pharmaceutical preparation, which comprises: telmisartan or a pharmaceutically acceptable salt thereof as a first pharmacological component; a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a pharmaceutically acceptable salt thereof as a second pharmacological component; and an excipient.

[0039] In the present invention, in order to prepare an orally administrable single tablet combination preparation of sodium-glucose cotransporter-2 (SGLT-2) and an angiotensin II receptor blocker (ARB) that were previously taken separately, the angiotensin-converting enzyme inhibitory activities of various SGLT-2s and ARBs were evaluated, and the optimal combination of SGLT-2 and ARB was obtained through a drug compatibility test and a preparation stability analysis. The toxicity, dissolution characteristics, and pharmacokinetics of the obtained combination were evaluated, thereby confirming that the oral pharmaceutical preparation according to a specific example of the present invention can be effectively applied to the prevention or treatment of type 2 diabetes, hypertension, hypertension accompanied by diabetes, or heart failure.

[0040] Specifically, in the present invention, it was confirmed that telmisartan has a more excellent angiotensin-converting enzyme inhibitory activity effect compared with olmesartan, and among ARBs, telmisartan has excellent compatibility and preparation stability with SGLT-2 inhibitors, especially with dapagliflozin and empagliflozin, compared with olmesartan and valsartan. Thus, an oral dosage form with excellent preparation stability, improved dissolution rate, and improved compatibility with drug additives was developed.

[0041] The SGLT-2 inhibitor contained in the oral pharmaceutical preparation of the present invention may be any one selected from the group consisting of dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, luseogliflozin, and tofogliflozin, but in terms of compatibility and preparation stability, dapagliflozin or empagliflozin is preferred.

[0042] The oral pharmaceutical preparation of the present invention may, for example, be in the form of a bilayer tablet or a Tab-in-Tab structure. Such a bilayer tablet comprises a first layer containing telmisartan as the first pharmacological ingredient and a second layer containing an SGLT-2 inhibitor as the second pharmacological ingredient. Such a Tab-in-Tab tablet comprises a core layer containing telmisartan as the first pharmacological ingredient and an outer layer containing an SGLT-2 inhibitor as the second pharmacological ingredient and surrounding the core layer, but is not limited thereto.

[0043] As previously reported, there is a problem that telmisartan interferes with the dissolution of SGLT-2 inhibitors, especially dapagliflozin. Specifically, telmisartan has a particularly low solubility at the pH values of the duodenum or small intestine, which is the absorption site in the body. Moreover, when preparing a compound preparation of the two ingredients, the dissolution rate is slowed down due to interference with the sink condition in the dissolution medium. In addition, for dapagliflozin, which is a component of an immediate-release preparation, the dissolution rate and dissolution rate are slowed down, which affects pharmacokinetics. For telmisartan, it is prone to absorb moisture, which affects the stability of dapagliflozin. In contrast, the oral pharmaceutical preparation of the present invention solves the problem of telmisartan dissolution interference. That is, the oral pharmaceutical preparation of the present invention comprises telmisartan as the first pharmacological ingredient and an SGLT-2 inhibitor as the second pharmacological ingredient. Since there are no interaction problems such as dissolution interference between the first pharmacological ingredient and the second pharmacological ingredient, the oral pharmaceutical preparation of the present invention only needs to take one tablet once a day to produce the same effect as taking one tablet once a day for a typical single telmisartan tablet and a single SGLT-2 inhibitor tablet respectively.

[0044] The term "oral pharmaceutical preparation" as used herein refers to a preparation obtained by molding or coating a pharmacological ingredient into a certain shape. For example, the oral pharmaceutical preparation may be formulated into a dry syrup, granules, tablets (single-layer tablets, bilayer tablets, Tab-in-Tab tablets, etc.), pills or capsules, etc., but is not limited thereto. The oral pharmaceutical preparation may be formulated into a dosage form in which wet granules are filled in the form of tablets, pills or capsules. The tablets, pills and capsules may be those commonly used in the art. The capsules may be hard capsules or soft capsules. When the oral pharmaceutical preparation is a capsule, the capsule may be made in a form containing granules or tablets.

[0045] The dosage of the oral pharmaceutical preparation according to a specific example of the present invention is as follows: For example, based on an adult, it can be in the range of about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, and it can be administered once a day, multiple times a day, or once a week, once every two weeks, once every three weeks, or once every four weeks to once a year. It can be administered in divided doses at regular time intervals according to the judgment of a doctor or a pharmacist, once to multiple times a day.

[0046] The oral pharmaceutical preparation of the present invention can be prepared by mixing telmisartan as the first pharmacological component, an SGLT-2 inhibitor as the second pharmacological component, and an excipient, and they can be mixed simultaneously or sequentially, and can be carried out by methods known in the art.

[0047] According to a specific example of the present invention, the sodium-glucose cotransporter-2 (SGLT-2) inhibitor can be dapagliflozin or empagliflozin.

[0048] As used herein, the term "dapagliflozin" refers to (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol, and the term "empagliflozin" refers to (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol, and 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.

[0049] The dapagliflozin, empagliflozin or telmisartan mentioned above may refer to those including their active metabolites and prodrugs. The "metabolite" is an active derivative that can be produced when dapagliflozin, empagliflozin or telmisartan is metabolized, and the "prodrug" refers to a compound that is metabolized into dapagliflozin, empagliflozin or telmisartan or into the same metabolite as dapagliflozin, empagliflozin or telmisartan. Moreover, dapagliflozin, empagliflozin or telmisartan may include all of their pharmaceutically acceptable salts, their crystal forms, hydrates, solvates, diastereoisomers or enantiomers.

[0050] For example, the term "Dapagliflozin propanediol hydrate" used in the present invention has the same meaning as "dapagliflozin propanediol hydrate".

[0051] According to a specific example of the present invention, the weight ratio of the first pharmacological component to the second pharmacological component may be from 4:1 to 8:1.

[0052] If, based on 1 weight of the second pharmacological component, less than 4 weights of the first pharmacological component are contained, an appropriate therapeutic effect cannot be expected due to a low blood drug concentration and the resulting low pharmacological effect. And if, based on 1 weight of the second pharmacological component, more than 8 weights of the first pharmacological component are contained, problems such as hypoglycemia and hypotension may occur due to a high blood drug concentration and the resulting side effects, toxicity, and excessive therapeutic effect, and an appropriate therapeutic effect cannot be expected.

[0053] According to a specific example of the present invention, the weight ratio of the total pharmacological components to the excipient may be from 1:2 to 1:5.

[0054] If, based on 1 weight of the total pharmacological components, less than 2 weights of the excipient are contained, the release pattern of each drug may change due to solubility interactions in the dissolution solution, and there is a possibility of toxicity problems due to excessive release. On the contrary, if, based on 1 weight of the total pharmacological components, more than 5 weights of the excipient are contained, the size of the oral drug may become too large, which may cause discomfort during administration, may reduce drug compliance, and may cause delayed release of each drug due to excessive use of the excipient, and thus problems of different release patterns may occur.

[0055] According to a specific example of the present invention, the oral pharmaceutical preparation may be a tablet.

[0056] For the convenience of patients taking medicine, when the tablet according to a specific example of the present invention is in the form of a double - tablet preparation, the first layer containing the first pharmacological component is preferably 500 mg or less, and the second layer containing the second pharmacological component is preferably 300 mg or less. When the tablet according to a specific example of the present invention is in the form of an Active Coating, the core layer containing the first pharmacological component is preferably 500 mg or less, and the outer layer containing the second pharmacological component is preferably 50 mg or less.

[0057] When the oral pharmaceutical preparation of the present invention is a tablet, the tablet may further comprise excipients, specifically selected from one or more pharmaceutically acceptable additives consisting of diluents, disintegrants, lubricants, binders, stabilizers, and coating substrates.

[0058] The excipient, specifically the diluent, for example, may be cellulose derivatives, including lactose or its hydrate, microcrystalline cellulose; sugar alcohols, including starch, gelled starch, granulated sugar, Ludipress mannitol, sorbitol, etc.; inorganic salts, including calcium phosphate, aluminum silicate, calcium sulfate, etc., but is not limited thereto.

[0059] The disintegrant, for example, may be selected from one or more components in the group consisting of polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, corn starch, crospovidone, low - substituted hydroxypropyl cellulose, and pre - gelatinized starch, but is not limited thereto.

[0060] The lubricant, for example, may be selected from one or more components in the group consisting of stearic acid, metal salts of stearic acid (such as calcium stearate, magnesium stearate, etc.), talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, wax, glycerol fatty acid esters, and glycerol distearate, but is not limited thereto. In a specific example, the lubricant may be magnesium stearate.

[0061] The binder refers to an "outer - phase - of - granule" binder added after the wet - granulation step. The outer - phase - of - granule binder, for example, may be selected from one or more components in the group consisting of hydroxypropyl cellulose (HPC), copovidone (a copolymer of vinylpyrrolidone and other vinyl derivatives), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (povidone), and polyethylene glycol, but is not limited thereto.

[0062] The stabilizer, for example, may be an antioxidant, an acidifying agent, or an alkalizing agent, but is not limited thereto.

[0063] The coating base material (coating agent) may be, for example, hydroxypropyl methylcellulose, polyvinyl alcohol, ethylcellulose, titanium oxide, polyethylene glycol, Opadry, but is not limited thereto. Relative to the total weight of the oral pharmaceutical preparation of the present invention, 0.1% by weight to 10% by weight, preferably 2% by weight to 7% by weight, and most preferably about 5% by weight of the coating base material may be included, but is not limited thereto.

[0064] According to a specific example of the present invention, each tablet may contain 40 mg to 80 mg of a first pharmacological component and 10 mg of a second pharmacological component.

[0065] If less than 40 mg of the first pharmacological component and / or less than 10 mg of the second pharmacological component are included, appropriate therapeutic effects for diabetes and hypertension cannot be expected due to low blood drug concentrations and the resulting low pharmacological effects. On the contrary, if more than 80 mg of the first pharmacological component and / or more than 10 mg of the second pharmacological component are included, problems such as hypoglycemia and hypotension may occur due to high blood drug concentrations and the resulting side effects, toxicity, and excessive therapeutic effects, and appropriate therapeutic effects cannot be expected. In a specific example, the tablet may contain 40 mg and 10 mg, or 80 mg and 10 mg of the first pharmacological component and the second pharmacological component, respectively.

[0066] On the other hand, when 12.3 mg of dapagliflozin propylene glycol hydrate is converted to dapagliflozin as a pharmacological component, it is equivalent to 10 mg.

[0067] According to a specific example of the present invention, when a dissolution test is performed at a paddle speed of 50 rpm according to the dissolution test method 2 of the Korean Pharmacopoeia, the dissolution rate of the first pharmacological component of the tablet in a hydrochloric acid solution at pH 1.2 within 30 minutes may be 40% or more, and the dissolution rate within 90 minutes may be 85% or more. The dissolution rate of the second pharmacological component of the tablet in a hydrochloric acid solution at pH 1.2 within 5 minutes may be 60% or more, and the dissolution rate within 30 minutes may be 95% or more.

[0068] When a dissolution test is performed, the dissolution rate of the first pharmacological component of the tablet within 30 minutes may be 40%, 45%, 50%, 55%, 60% or 70%, and the dissolution rate within 90 minutes may be 85%, 90%, 95 or 99%. Also, the dissolution rate of the second pharmacological component within 5 minutes may be 60%, 65% or 70%, and the dissolution rate within 30 minutes may be 95% or 99%.

[0069] The dissolution test may be carried out according to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia. The dissolution test may be carried out using simulated gastric fluid (SGF) with pH 1.2 or 0.1 N hydrochloric acid solution. The dissolution test may be carried out at 40 rpm to 60 rpm (revolution per minute), for example, 50 rpm. The dissolution test may be carried out at about 30°C to about 40°C, about 32°C to about 40°C, about 34°C to about 40°C, about 36°C to about 40°C, or about 37°C.

[0070] In a specific example, when the dissolution test is carried out at a paddle rotation speed of 50 rpm according to the dissolution test method 2 of the Korean Pharmacopoeia, the dissolution rate of telmisartan as the first pharmacological component of the tablet may be 40% or more within 30 minutes and 85% or more within 90 minutes in hydrochloric acid solution with pH 1.2, and the dissolution rate of dapagliflozin as the second pharmacological component of the tablet may be 60% or more within 5 minutes and 95% or more within 30 minutes in hydrochloric acid solution with pH 1.2.

[0071] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating type 2 diabetes, hypertension, hypertension with diabetes, or heart failure, which comprises the oral pharmaceutical preparation.

[0072] The composition of the present invention may comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier comprised in the composition of the present invention is a carrier commonly used in the preparation of pharmaceuticals, including lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil, etc., but is not limited thereto. In addition to the above components, the pharmaceutical composition of the present invention may further comprise lubricants, wetting agents, sweeteners, flavoring agents, emulsifying agents, suspending agents, preservatives, etc. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington: the science and practice of pharmacy 22nd edition (2013).

[0073] The pharmaceutical composition according to a specific example of the present invention may be administered together with one or more substances showing pharmacological activity against type 2 diabetes, hypertension, hypertension with diabetes, and / or heart failure.

[0074] In addition, the pharmaceutical composition according to a specific example of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug therapy, and / or biologic response modifiers to prevent or treat type 2 diabetes, hypertension, hypertension associated with diabetes, and / or heart failure.

[0075] The composition of the present invention may contain various bases and / or additives required and appropriate for the formulation of its dosage form, and can be prepared by further including known compounds within a range that does not impair its effectiveness, such as nonionic surfactants, silicone polymers, extender fillers, fragrances, preservatives, bactericides, oxidation stabilizers, organic solvents, ionic or nonionic thickeners, softeners, antioxidants, free radical scavengers, light blockers, stabilizers, emollients, silicones, α-hydroxy acids, defoamers, humectants, vitamins, insect repellents, fragrances, preservatives, surfactants, anti-inflammatory agents, substance P antagonists, fillers, polymers, propellants, alkalizing agents or acidifying agents, or colorants.

[0076] The appropriate dose of the composition of the present invention can be specified in various ways according to factors such as the formulation method, administration mode, patient's age, weight, gender, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity. Based on adults, the dose of the composition of the present invention can be 0.001 mg / kg to 1000 mg / kg.

[0077] The composition of the present invention can be administered orally. [[ID=II]]

[0078] When the composition of the present invention is administered orally, it can be administered in various dosage forms, such as tablets, pills, hard / soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, lozenges, etc., and can also contain various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc. Specifically, when the composition of the present invention is formulated into an oral dosage form, it can also contain suitable carriers, excipients, and diluents commonly used in its preparation. As the carriers, excipients, and diluents, for example, lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, and / or mineral oil can be used, but are not limited thereto. And it can be prepared to contain diluents or excipients commonly used in the formulation, including fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc., and in addition to the excipients, it can also contain lubricants, such as magnesium stearate or talc.

[0079] Another aspect of the present invention provides a method for preventing or treating type 2 diabetes, hypertension, hypertension with diabetes, or heart failure, which comprises the step of administering the oral pharmaceutical preparation to a subject.

[0080] Telmisartan or a pharmaceutically acceptable salt thereof, and an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof contained in the oral pharmaceutical preparation of the present invention can be administered orally in an amount effective for the treatment or prevention of an individual or patient according to the purpose. It should be understood that, when administering, the dose for a specific individual or patient should be determined according to various relevant factors, such as the patient's weight, age, race, gender, health status, diet, administration time, administration method, severity of the disease, etc., and can be appropriately increased or decreased by an expert. For example, a doctor can gradually increase the dose of the oral pharmaceutical preparation of the present invention starting from a level lower than that required to achieve the desired therapeutic effect until the desired effect is achieved, and this dose can be easily determined and specified as needed.

[0081] Embodiments of the invention

[0082] The present invention will be described in more detail below by one or more examples. However, these examples are only used to illustrate the present invention exemplarily, and the scope of the present invention is not limited to these examples.

[0083] Experimental Example 1. Screening of angiotensin II receptor blockers used in a compound preparation for treating heart failure

[0084] 1-1. Evaluation of cell viability

[0085] To screen for angiotensin II receptor blockers (ARBs) used in a compound preparation of an angiotensin II receptor blocker and a sodium-glucose cotransporter-2 (SGLT-2) inhibitor for treating heart failure, cell viability was evaluated.

[0086] Specifically, A549 cells were purchased from the Korean Cell Line Bank (KCLB) and passaged using RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% Penicillin, and MDCK cells were purchased from ATCC and passaged using DMEM medium supplemented with 10% FBS. The A549 cells and MDCK cells cultured in a 37 °C, 5% CO2 incubator were respectively seeded at 2×10 4Cells were dispensed into 96-well plates at 200 μl per well. Then, the control group was treated with 100 μl of culture medium, and the experimental groups were treated with 1.25, 25, 50, and 100 μM of telmisartan or olmesartan, respectively. After 24 hours and 48 hours, 50 μl of 2 mg / ml MTT reagent was added to each well and incubated in an incubator for 3 hours. Then, 500 μl of DMSO was added to each well, wrapped with foil paper, stirred at room temperature for 30 minutes, and the cell viability was obtained by measuring the absorbance at 570 nm.

[0087] Results confirmed that neither telmisartan nor olmesartan at a concentration of 25 μM had an effect on cell viability ( Figure 1 and Figure 2 ).

[0088] 1-2. Evaluation of angiotensin-converting enzyme inhibitory activity

[0089] To confirm the therapeutic effect of angiotensin II receptor blockers (ARBs) on heart failure, the angiotensin converting enzyme (ACE) inhibitory activity was evaluated.

[0090] Specifically, the human cardiac cell line H9c2 cells were purchased from the Korean Cell Line Bank (KCLB 40071, Korea) and cultured in DMEM medium supplemented with 10% FBS and 1% antibiotic-antimycotic (10 units / ml penicillin, 100 μg / ml streptomycin, 0.25 μg / ml amphotericin) at 37°C and 5% CO2 for later use.

[0091] To confirm the effect on ACE activity, the prepared H9c2 cells were treated with 2.5 μg / ml of lipopolysaccharide (LPS) to induce inflammation, and optimized conditions were set to confirm ACE expression, where the lipopolysaccharide was 2.5 times more than the amount used in existing inflammation-related experiments. The H9c2 cells induced with inflammation by LPS were treated with 10, 25, and 50 μM of telmisartan or olmesartan, respectively, and the H9c2 cells were harvested for ELISA assay. The harvested cells were treated with 1 ml of RIPA buffer and stirred at 4°C for 30 minutes to extract proteins. Then, after centrifugation at 4°C and 10,000 rpm for 20 minutes, the supernatant was transferred to a sterilized tube and stored at -80°C for ELISA assay.

[0092] For ELISA detection, 10000 pg / ml, 5000 pg / ml, 2500 pg / ml, 1250 pg / ml, 625 pg / ml, 312 pg / ml, and 156 pg / ml of human ACE standard solution and 0.1 ml of standard dilution buffer were added to each well of the antibody-coated 96-well plate. Then, 0.1 ml of ACE protein extracted from H9c2 cells was added to each well, and the plate was sealed with a lid and incubated at 37 °C for 90 minutes. In this experiment, the ACE protein was processed to a quantity of 20 μg in 0.1 ml of the treatment solution, and after treatment with 0.08 ml of sample dilution buffer, the final dilution ratio was set to 1:5. After incubation, the lid was removed, the contents of the plate were removed, and the residue was removed with a paper towel or other absorbent material while preventing the wells from drying out completely. After washing, 0.1 ml of the Biotinylated Anti-Human ACE antibody solution contained in the Human ACE ELISA kit was added to each well and incubated at 37 °C for 60 minutes. After incubation, the plate was washed 3 times with 0.01 M PBS, and the residual PBS solution was removed with a paper towel or other absorbent material. After washing, 0.1 ml of the ABC solution contained in the Human ACE ELISA kit was added to each well and incubated at 37 °C for 30 minutes, and then the plate was further washed 5 times with 0.01 M PBS. Then, 90 μl of the prepared TMB solution was added to each well and incubated in the dark at 37 °C for 20 to 25 minutes. To terminate the ACE ELISA reaction, 0.1 ml of the prepared TMB stop solution was added to each well, and the OD absorbance at 450 nm was read with a microplate reader within 30 minutes, and the relative OD450 was calculated using the following formula.

[0093] Relative OD450 = (OD450 of each well) - (OD450 of zero well) (The relative OD450=(theOD450 of each well)-(the OD450 of Zero well))

[0094] It was confirmed that at all treatment concentrations, the ACE expression inhibitory effect of telmisartan was better than that of olmesartan, and the ACE expression inhibitory effect of the 25 μM telmisartan treatment group was the best ( Figure 3 ).

[0095] 1-3. Evaluation of angiotensin-converting enzyme gene expression

[0096] To confirm the therapeutic effect of angiotensin II receptor blocker (ARB) on heart failure, it was confirmed whether the mRNA expression of angiotensin converting enzyme (ACE) was inhibited.

[0097] Specifically, H9c2 cells induced by LPS in Experimental Examples 1-2 were treated with 10 or 25 μM of telmisartan and 10 or 50 μM of olmesartan, and then treated with 1 ml of TRIZol (Sigma, USA) and 200 μl of chloroform, gently mixed, and after separating for 10 minutes, centrifuged at 4 °C and 10,000 rpm for 10 minutes. After centrifugation, only the supernatant in the tube was taken out, transferred to a new sterile tube, and the supernatant was treated with 500 μl of isopropanol to precipitate RNA. The precipitated RNA was centrifuged at 4 °C and 10,000 rpm for 10 minutes, then all the supernatant except the pellet in the tube was removed, and the RNA pellet was washed thoroughly by treating with 500 μl of 75% ethyl alcohol. The washed pellet was centrifuged at 4 °C and 10,000 rpm for 5 minutes, and then all the supernatant except the pellet was removed. After the supernatant was completely removed and the tube containing the pellet was treated with diethyl pyrocarbonate-water, it was stored at -80 °C for RT-PCR experiments.

[0098] cDNA was synthesized from mRNA using an RT-PCR kit containing DNA polymerase, buffer, dNTP, and tracking dye, and then RT-PCR was performed by cycling the ACE primers in Table 1 under the conditions in Table 2 35 times. The PCR products were electrophoresed on a 15% agarose gel and confirmed using a UV transilluminator, and were normalized to GAPDH for quantitative comparison.

[0099] Table 1

[0100]

[0101] Table 2

[0102] Distinguish Temperature Time Denaturation 94℃ 30 seconds Annealing 55℃-62℃ 30 seconds Elongation 72℃ 60 seconds

[0103] The results confirmed that, at all treatment concentrations, the inhibitory effect of telmisartan on mRNA expression was superior to that of olmesartan, and most mRNA expressions in the telmisartan 25 μM treatment group were inhibited ( Figure 4 ).

[0104] From these results, it was confirmed that telmisartan, as an angiotensin II receptor blocker used in a combination preparation of an angiotensin II receptor blocker and a sodium-glucose cotransporter-2 inhibitor for the treatment of heart failure, was more effective than olmesartan.

[0105] Experimental Example 2. Confirmation of angiotensin-converting enzyme inhibitory activity by inhibiting mRNA expression of a combination preparation of an ARB and an SGLT-2 inhibitor

[0106] To confirm the therapeutic effect of the combination preparation of the angiotensin II receptor blocker (ARB) and the sodium-glucose cotransporter-2 (SGLT-2) inhibitor of the present invention on heart failure, it was confirmed whether the mRNA expression of angiotensin-converting enzyme (ACE) was inhibited.

[0107] Specifically, the experimental samples are shown in Table 3.

[0108] Table 3

[0109]

[0110] To investigate the effect of each combination preparation or single substance on the mRNA expression of ACE, the H9c2 cells induced with inflammation by LPS in Experimental Examples 1-2 were treated with the experimental samples in Table 3, and the mRNA expression of ACE was evaluated in the same manner as in Experimental Examples 1-3.

[0111] The results confirmed that, for the single administration groups of telmisartan, empagliflozin, and dapagliflozin, in the low-concentration administration groups of 2.5 μM to 10 μM, the mRNA expression of ACE did not decrease to the normal level, while in the high-concentration administration groups of 15 μM (Comparative Example 8, Comparative Example 12, and Comparative Example 14), the mRNA expression of ACE decreased below the normal level. On the other hand, in the combination administration groups, the mRNA expression of ACE in Example 2 of the telmisartan 10 μM and dapagliflozin 5 μM treatment group was significantly inhibited compared with other combination administration groups ( Figure 5 and Figure 6 ).

[0112] From these results, it was confirmed that the combination of telmisartan and dapagliflozin is the most effective combination of an ARB and an SGLT-2 inhibitor for inhibiting ACE expression.

[0113] Experimental Example 3. Confirmation of angiotensin-converting enzyme inhibitory activity by inhibiting the protein expression of a compound preparation of an ARB and an SGLT-2 inhibitor

[0114] To confirm the therapeutic effect of the compound preparation of the angiotensin II receptor blocker (ARB) and the sodium-glucose cotransporter-2 (SGLT-2) inhibitor of the present invention on heart failure, it was confirmed whether the protein expression of angiotensin-converting enzyme (ACE) was inhibited.

[0115] Specifically, the H9c2 cells induced by LPS to be inflamed in Experimental Examples 1-2 were treated with the experimental samples in Table 3, and the H9c2 cells were harvested for ELISA detection. Then, the harvested cells were treated with 1 ml of RIPA buffer and stirred at 4°C for 30 minutes to extract proteins. Then, after centrifugation at 4°C and 10,000 rpm for 20 minutes, the supernatant was transferred to a sterilized tube and stored at -80°C for ELISA detection. ELISA detection was performed in the same manner as in Experimental Examples 1-2.

[0116] The results confirmed that in all the single-dose groups and the combined-dose groups, the expression of ACE protein in Example 2 of the group administered with 10 μM of telmisartan and 5 μM of dapagliflozin was significantly inhibited, followed by the significant inhibition of the expression of ACE protein in the group administered with 10 μM of telmisartan and 5 μM of empagliflozin ( Figure 7 ).

[0117] From these results, it was confirmed that the combination of telmisartan and dapagliflozin, or the combination of telmisartan and empagliflozin is the most effective combination of an ARB and an SGLT-2 inhibitor for inhibiting ACE expression, and is effectively applied to reduce the side effects caused by using high doses of an ARB or an SGLT-2 inhibitor.

[0118] Experimental Example 4. Toxicity evaluation of a compound preparation of an ARB and an SGLT-2 inhibitor

[0119] 4-1. Single-dose toxicity assessment

[0120] The single-dose toxicity of the combination of telmisartan and dapagliflozin, and the combination of telmisartan and empagliflozin, which were confirmed to be the most effective combination of a compound preparation of an ARB and an SGLT-2 inhibitor for inhibiting ACE expression, was evaluated.

[0121] Specifically, the grouping is as follows: the compound preparation of dapagliflozin (Dapagliflozin propanediol hydrate) and telmisartan at 3.1 / 20 mg / kg / day (low-dose group), 6.2 / 40 mg / kg / day (medium-dose group), 12.3 / 80 mg / kg / day (high-dose group) administration groups, the dapagliflozin single administration group at 12.3 mg / kg / day, the telmisartan single administration group at 80 mg / kg / day, the compound preparation of empagliflozin and telmisartan at 6.25 / 20 mg / kg / day (low-dose group), 12.5 / 40 mg / kg / day (medium-dose group), 25 / 80 mg / kg / day (high-dose group) administration groups, the empagliflozin single administration group at 25 mg / kg / day, the telmisartan single administration group at 80 mg / kg / day, and the control group (0.5% MC aqueous solution). Five male and five female 6-week-old Sprague-Dawley rats in each group were administered orally once. General symptoms were observed and body weights were measured 15 days after administration. After the observation period ended, they were euthanized and autopsied.

[0122] As a result, no animal deaths were observed in all the administration groups during the observation period. In addition, based on the observation of general symptoms, body weight measurement, and autopsy results, no results considered to be due to the effects of the ARB and SGLT-2 inhibitor compound preparations were confirmed in all the administration groups.

[0123] From these results, it was confirmed that after single oral administration of the compound preparation of dapagliflozin (Dapagliflozin propanediol monohydrate) and telmisartan, and the compound preparation of empagliflozin and telmisartan, the approximate lethal doses for male and female rats exceeded 12.3 / 80 mg / kg and 25 / 80 mg / kg, respectively.

[0124] 4-2. Toxicity assessment and determination of dosing regimen after 4 weeks of repeated oral administration

[0125] The toxicity after 4 weeks of repeated oral administration of the combinations of telmisartan and dapagliflozin, and telmisartan and empagliflozin, which were confirmed to be the most effective combinations of ARB and SGLT-2 inhibitor compound preparations for inhibiting ACE expression, was evaluated.

[0126] Specifically, the grouping was the same as in Experimental Example 4-1. Five male and five female 6-week-old Sprague-Dawley rats in each group were administered orally every day for 4 weeks. During the experiment, general symptoms, blood tests, and body weight measurements were performed. After the observation period ended, they were euthanized and autopsied.

[0127] Regarding the results of body weight measurement, an increase in body weight tended to be suppressed in the high-dose group and the group administered with telmisartan alone. Regarding the results of blood tests, it was confirmed that BUN increased according to the dose, GLU decreased in the group administered with dapagliflozin alone and all high-dose groups, and RBC, HGB, and HCT decreased in all high-dose groups. It was also confirmed that the absolute weight and relative weight of the kidneys increased in all low-, medium-, and high-dose groups, while the absolute weight and relative weight of the heart decreased in all medium- and high-dose groups. On the other hand, gastric gland lesions were confirmed in one male in the high-dose group and one female in the medium-dose group.

[0128] This trend was considered to be due to the excessive pharmacological action of dapagliflozin and the class effect caused by ARB drugs. Therefore, in the 13-week repeated-dose toxicity test, the high dose of dapagliflozin (dapagliflozin propanediol monohydrate) and telmisartan was set at 9.2 / 60 mg / kg / day (45-fold), with a ratio of 3.0, and the medium and low doses were set at 3.1 / 20 mg / kg / day and 1 / 6.7 mg / kg / day, respectively.

[0129] Experimental Example 5. Confirmation of the Optimal Combination and Dosage Form of an Angiotensin II Receptor Blocker and a Sodium-Glucose Cotransporter 2 Combination Preparation

[0130] 5-1. Identification of the optimal combination of an angiotensin II receptor blocker and sodium-glucose cotransporter 2 by pharmaceutical compatibility testing

[0131] The optimal combination of an angiotensin II receptor blocker (ARB) and a sodium-glucose cotransporter-2 (SGLT-2) inhibitor combination preparation with high stability that does not decompose even after long-term storage was confirmed by evaluating a drug-drug compatibility test.

[0132] Specifically, after storing the mixture of ARB and SGLT-2 inhibitor under the stability accelerated test conditions (40±2°C / 75±5% relative humidity) for 4 weeks, the content changes and property changes (color, caking, etc.) of each component and related substances were analyzed. Olmesartan, Valsartan, and Telmisartan were used as ARBs, and Empagliflozin, Dapagliflozin propanediolmonohydrate, and Canagliflozin were used as SGLT-2 inhibitors. The contents of each component are shown in Table 4.

[0133] Table 4

[0134]

[0135] To analyze the content of the main component and the generation degree of related substances, the mixtures of ARB and SGLT-2 inhibitor stored for 1 week, 2 weeks, 3 weeks, and 4 weeks were respectively placed into three 100 mL flasks and 10 T tablets were added. To extract the main component, a solution of 0.01 M hydrochloric acid aqueous solution and acetonitrile mixed in an appropriate ratio was added. After stirring, analysis was carried out by HPLC.

[0136] To observe the properties and viscosity of the main component, 10 g of the mixture of ARB and SGLT-2 inhibitor stored for 1 week, 2 weeks, 3 weeks, and 4 weeks was exposed to 100 ml of purified water at room temperature for 10 minutes, and then the performance and viscosity were confirmed.

[0137] The results confirmed that in the third week of acceleration, in the mixture of ARB and SGLT-2 inhibitor, all the indicators in Comparative Examples 22 to 26 did not meet the requirements, while the contents of Telmisartan and Empagliflozin (Example 3) and the mixture of Telmisartan and Dapagliflozin (Example 4) were 98.6% / 92.1% and 98.9 / 99.0% respectively, and the content changes were all within 10%. The total amount of related substances also met the requirements, so the drug compatibility was the best. However, it was confirmed that starting from the third week of acceleration, the properties did not meet the requirements, so a dosage form that can maintain the properties is needed (Table 5).

[0138] Table 5

[0139]

[0140]

[0141] 5-2. Preparation of an angiotensin II receptor blocker and sodium-glucose cotransporter 2 compound bilayer tablet by direct compression

[0142] The ARB particle layer of Table 6 was prepared by wet granulation. Granules were prepared by using the main component and mannitol, meglumine and sodium hydroxide solubilizer, and drying after preparation by the semi-aqueous method. All components in the composition of the ARB layer and the composition of the SGLT-2 inhibitor layer, except for sodium stearyl fumarate and magnesium stearate as lubricants, were sieved through a 20-mesh standard sieve, and then the compositions of each layer were premixed for the first time and mixed separately using a turbula mixer for at least 10 minutes. Then, the lubricant was added to each powder mixture and mixed again for 5 minutes. Finally, the mixtures forming each layer were injected into the hoppers of a double-layer tablet press, a compression force was applied, and then coated with a coating substrate to prepare double-layer tablets. Olmesartan, Valsartan, and Telmisartan were used as ARBs, and Empagliflozin, Dapagliflozin propanediol monohydrate, and Canagliflozin were used as SGLT-2 inhibitors. The combinations of each component are shown in Table 7.

[0143] Table 6

[0144]

[0145] Table 7

[0146]

[0147] 5-3. Preparation of an angiotensin II receptor blocker and sodium-glucose cotransporter 2 compound active-coated tablet by direct compression

[0148] The ARB granules of Table 8 were prepared by wet granulation. Granules were prepared by using the main component and mannitol, meglumine and sodium hydroxide solubilizer, and drying after preparation by the semi-aqueous method. The ARB granules and each component were sieved through a 20-mesh standard sieve and premixed for the first time, and then mixed using a turbula mixer for at least 10 minutes. Secondly, magnesium stearate as a lubricant was added to the powder mixture and mixed again for 5 minutes. The mixture was put into the hopper of a tablet press, and then a compression force was applied to prepare tablets. Finally, after mixing the SGLT-2 inhibitor with Aerosil and HPMC, the prepared tablets were coated using an automatic coating machine. First, the first main drug coating was carried out, and then the second bottom coating was carried out with a coating substrate to prepare active-coated tablets. Dapagliflozin and Telmisartan were used as SGLT-2 inhibitor and ARB components, respectively.

[0149] Table 8

[0150]

[0151] 5-4. Identification of the optimal combination of an angiotensin II receptor blocker and sodium-glucose cotransporter 2 by formulation stability analysis

[0152] By evaluating the stability of the formulation, the optimal combination of an angiotensin II receptor blocker (ARB) and a sodium-glucose cotransporter-2 (SGLT-2) inhibitor that does not decompose even after long-term storage and has high stability was confirmed.

[0153] Specifically, after storing the ARB and SGLT-2 inhibitor compound bilayer tablets prepared in Experimental Example 5-2 under stability accelerated test conditions (40 ± 2°C / 75 ± 5% relative humidity) or long-term stability test conditions (25 ± 2°C / 60 ± 5% relative humidity) for 6 months, the content changes of each component and related substances, the property changes (color, caking, etc.), and the dissolution changes (interference, dissolution changes, etc.) were analyzed.

[0154] The content changes and property changes (color, caking, etc.) of each component and related substances were analyzed in the same manner as in Experimental Example 5-1, and the dissolution changes of the ARB and SGLT-2 inhibitor compound bilayer tablets and active-coated tablets prepared in Experimental Examples 5-2 and 5-3 were analyzed using the method shown in Table 9.

[0155] Table 9

[0156]

[0157]

[0158] As a result, it was confirmed that at 6 months of acceleration and 6 months of long-term, in the ARB and SGLT-2 inhibitor compound bilayer tablets, most of the indicators in Comparative Examples 27 to 31 did not meet the requirements, while all the indicators of the telmisartan and empagliflozin compound bilayer tablets (Example 5) and the telmisartan and dapagliflozin (Dapagliflozin propanediol monohydrate) compound bilayer tablets (Example 6) met the requirements, so they had excellent formulation stability (Table 10). In particular, it was confirmed that the properties that showed non-compliance in the drug compatibility test showed compliance after being formulated into compound bilayer tablets. On the other hand, the dissolution patterns of the telmisartan and dapagliflozin dosage forms of Example 6 were respectively as Figure 8 and Figure 9 shown, and it was confirmed that the dissolution patterns of the compound bilayer tablets and the active-coated tablets were the same.

[0159] Table 10

[0160]

[0161]

[0162] Experimental Example 6. Pharmacokinetic Confirmation of Single Oral Administration of Compound Double-Layer Tablets of Dapagliflozin and Telmisartan

[0163] To confirm the pharmacokinetics of the compound double-layer tablets of dapagliflozin and telmisartan, a pharmacokinetic trial of single oral administration was conducted using beagle dogs.

[0164] Specifically, a total of 24 male beagle dogs (6 in each group) were administered Andatang 10 mg (dapagliflozin, control drug 1), Micardis 80 mg (telmisartan, control drug 2) alone or in combination, and the compound double-layer tablets of Example 6 (telmisartan 80 mg and dapagliflozin 10 mg (dapagliflozin propylene glycol hydrate 12.3 mg)) were administered as the test drug. Both the control drug and the test drug were administered as a single tablet by single oral administration and crossed four times at one-week intervals (4×4 cross over). Food was withheld from 17:00 to 18:00 on the day before dosing. After injecting the control drug and the test drug into the root of the tongue, about 15 ml of water was given, and feed was provided about 4 hours after dosing. Blood was collected at 0 (blank), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 hours (14 times) after administering the control drug and the test drug. After stopping the drug for 7 days, the AUC, C max , T max , t 1 / 2 etc. of dapagliflozin, telmisartan and the compound double-layer tablets of Example 6 were evaluated.

[0165] The results confirmed that, for dapagliflozin, the difference in AUC all between the single administration group and the combined administration group was 1.0-fold, so there was no drug-drug interaction (DDI) at all, the confidence interval equivalence was equal, and the judgment criteria (log 0.8 - 1.25) were met (Table 11 and Figure 10 ). For telmisartan, the group difference in AUC all between the single administration group and the combined administration group was 1.0-fold, so there was no drug-drug interaction (DDI) at all, the difference between the logarithmically transformed means was equal, and the judgment criteria of AUC all 1.01, C max 0.98 were met (Table 12 and Figure 11 ).

[0166] Table 11

[0167]

[0168] Table 12

[0169]

[0170] Experimental Example 7. Confirmation of Weight Loss and Heart Weight Loss Effects of ARB and SGLT-2 Inhibitor Combination Preparations

[0171] The weight loss and heart weight loss effects of the combination of telmisartan and dapagliflozin, which is the combination of ARB and SGLT-2 inhibitor combination preparations confirmed to be the most effective in inhibiting ACE expression, were evaluated.

[0172] Specifically, the grouping was as follows: groups administered with the combination preparation of dapagliflozin and telmisartan at 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), the group administered with dapagliflozin alone at 9 mg / kg / day (G5), the group administered with telmisartan alone at 72 mg / kg / day (G6), and the control group (0.5% MC aqueous solution, G1). Ten male and ten female 6-week-old Sprague-Dawley rats in each group were repeatedly orally administered for 13 weeks. After administration, general symptoms were observed and body weights were measured. After the observation period ended, they were euthanized and autopsied, and then heart weights were measured.

[0173] The results confirmed that the body weights and heart weights in the low-dose, medium-dose, and high-dose groups of the combination preparation of dapagliflozin and telmisartan were significantly reduced, especially the body weights and heart weights in the low-dose and medium-dose groups of the combination preparation of dapagliflozin and telmisartan in female rats( Figure 12 ).

[0174] From these results, it was confirmed that the combination preparation of dapagliflozin and telmisartan can reduce cardiac hypertrophy associated with heart failure.

[0175] Experimental Example 8. Summary of Phase 1 Clinical Trial (Clinical Research Information Service / CRIS: PRE20230908-003, Clinicaltrials.gov / NCT06063109)

[0176] 8-1. Research topic

[0177] A two-arm, open-label, single-sequence, repeated oral administration crossover design clinical trial for evaluating the safety and pharmacokinetic interactions when THP-00101 and THP-00102 are administered to healthy adult volunteers

[0178] 8-2. Research objective

[0179] After repeated oral administration of THP-00101 (telmisartan 80 mg) and THP-00102 (dapagliflozin 10 mg (dapagliflozin propylene glycol hydrate 12.3 mg)) alone or in combination to healthy adult volunteers, the pharmacokinetics and safety at steady state were compared and analyzed to explore the interaction between the two investigational medicinal products.

[0180] 8-3. Research type

[0181] An intervention study trial was conducted in a two-arm, open-label, single-sequence, repeated oral administration crossover design.

[0182] 8-4. Number of subjects

[0183] 50

[0184] 8-5. Results

[0185] From the results of the drug interaction test between telmisartan 80 mg (THP-00102) and dapagliflozin 10 mg (THP-00101) which are the main components of the drug, it was confirmed that in the presence of dapagliflozin, the Cmax of telmisartan was approximately 1.19-fold (T / R ratio 1.19, 90% confidence interval 0.99 - 1.43), the AUC was approximately 1.09-fold (T / R ratio 1.09, 90% confidence interval 1.01 - 1.18), and in the presence of telmisartan, the Cmax of dapagliflozin was approximately 1.02-fold (T / R ratio 1.02, 90% confidence interval 0.93 - 1.12), and the AUC was approximately 1.00-fold (T / R ratio 1.00, 90% confidence interval 0.97 - 1.03).

[0186] As described above, the present invention has been described by way of examples. Those skilled in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential features 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 defined by the claims rather than the foregoing description, and all differences within the equivalent scope should be construed as being included in the present invention.

Claims

1. An oral pharmaceutical preparation, characterized in that, Comprising: Telmisartan or a pharmaceutically acceptable salt thereof as a first pharmacological component; A sodium-glucose cotransporter 2 inhibitor or a pharmaceutically acceptable salt thereof as a second pharmacological component; and An excipient.

2. The oral pharmaceutical preparation according to claim 1, characterized in that, The sodium-glucose cotransporter 2 inhibitor is dapagliflozin or empagliflozin.

3. The oral pharmaceutical preparation according to claim 1, wherein The weight ratio of the first pharmacological component to the second pharmacological component is 4:1 to 8:

1.

4. The oral pharmaceutical preparation according to claim 1, wherein The weight ratio of the total pharmacological components to the excipient is 1:2 to 1:

5.

5. The oral pharmaceutical preparation according to claim 1, characterized in that, The oral pharmaceutical preparation is a tablet.

6. The oral pharmaceutical preparation according to claim 5, wherein Each tablet contains 40 mg to 80 mg of the first pharmacological component and 10 mg of the second pharmacological component.

7. The oral pharmaceutical preparation according to claim 5, characterized in that, When the dissolution test is carried out at a paddle speed of 50 rpm according to the dissolution test method 2 of the Korean Pharmacopoeia, the dissolution rate of the first pharmacological component of the tablet is more than 40% within 30 minutes and more than 85% within 90 minutes in a hydrochloric acid solution at pH 1.2, and the dissolution rate of the second pharmacological component of the tablet is more than 60% within 5 minutes and more than 95% within 30 minutes in a hydrochloric acid solution at pH 1.

2.

8. A pharmaceutical composition for preventing or treating type 2 diabetes, hypertension, hypertension with diabetes, or heart failure, characterized in that, Comprising the oral pharmaceutical preparation according to claim 1.

9. A method for preventing or treating type 2 diabetes, hypertension, hypertension with diabetes, or heart failure, characterized in that, Including the step of administering the oral pharmaceutical preparation according to claim 1 to a subject.

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