Combined formulation comprising sacubitril-valsartan and SGLT-2 inhibitor having improved stability and dissolution rate.

Description

1 / 75 Combined formulation comprising sacubitril-valsartan and SGLT-2 inhibitor having improved stability and dissolution rate. TECHNICAL FIELD

[0001] The present invention relates to a combined formulation containing sacubitril-valsartan and an SGLT2 inhibitor as active ingredients and having excellent stability and dissolution rate. BACKGROUND OF THE INVENTION

[0002] Heart failure refers to a condition in which the filling function (diastolic function) of the heart to receive blood or the pumping function (systolic function) of the heart to compress blood is reduced due to a structural or functional abnormality of the heart and, as a result, the heart does not adequately supply the necessary blood to the body's tissues. When heart failure occurs, regardless of the cause, decreased myocardial function, left ventricular remodeling, hemodynamic changes, activation of the neurohormonal system, cytokine expression, vascular endothelial cell dysfunction, etc., may occur, leading to various types of complications such as arrhythmia, atrial fibrillation, stroke, acute pulmonary edema, impaired renal function, and sudden death.

[0003] Although the number of patients with heart failure, especially heart failure with preserved ejection fraction (HFpEF), is increasing worldwide, there is no approved therapeutic agent, and therefore expectations are high for the development of related drugs. Recently, Entresto™ (ingredient name: sacubitril-valsartan combination formulation), a newly introduced therapeutic agent for heart failure, has attracted attention as the first therapeutic agent that surpasses Petition 870250090236, dated 03 / 10 / 2025, pages 185 / 265 2 / 75 of the existing ACE inhibitors.

[0004] The active ingredient in Entresto™ is sacubitrilvalsartan sodium hemipentahydrate, the content of which is disclosed in International Patent Publication No. WO 2007 / 056546 A1 (Patent Document 1) (the entire content of the patent document is incorporated herein as prior art in this descriptive report). Entresto™ has been reported to be effective in reducing deaths from cardiovascular disease and risk factors due to heart failure, but it has low stability and solubility in water, and the efficiency of its preparation is very low.

[0005] Meanwhile, recent large-scale clinical trials conducted in Korea and other countries have indicated that SGLT-2 inhibitors, previously launched as antidiabetic drugs, are effective in treating heart failure, regardless of the presence or absence of diabetes. In the revised 2022 treatment guidelines for heart failure, recently published by the Korean Heart Failure Society, sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as Farxiga™ and Jardiance™, as well as Entresto™, were recommended as first-line standard treatment (Class I, level of evidence A).

[0006] Consequently, the present inventors sought to develop a combined formulation containing sacubitrilvalsartan and an SGLT2 inhibitor so that its effect in the treatment of heart failure and ischemic heart disease could be increased and, as a result, they developed a combined form of the present invention, which allows the immediate release of the two ingredients, considering the sites of action of these drugs, while exhibiting excellent stability, thus completing the present invention. Petition 870250090236, dated 03 / 10 / 2025, pages 186 / 265 3 / 75

[0007] (Patent Document 1) International Patent Publication No. WO2007 / 056546

[0008] (Patent Document 2) US Patent No. 6515117 DISCLOSURE Technical Problem

[0009] One objective of the present invention is to provide a combined formulation for oral administration that has a synergistic effect in the treatment of heart failure, containing sacubitril-valsartan and an SGLT-2 inhibitor as active ingredients and, at the same time, can exhibit dissolution profiles equivalent to those of the individual administration of these drugs alone, in addition to exhibiting excellent stability.

[00010] Another objective of the present invention is to provide a method for efficiently preparing the combined formulation for oral administration provided by the present invention.

[00011] However, the objectives to be achieved by the present invention are not limited to the objectives mentioned above, and other objectives not mentioned above can be clearly understood by those skilled in the art from the following description. Technical Solution

[00012] According to one embodiment of the present invention, the present invention relates to a combined pharmaceutical formulation comprising: (1) a first release portion comprising sacubitril-valsartan or pharmaceutically acceptable salts thereof as an active ingredient; and (2) a second release portion comprising a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[00013] In the present invention, the first release portion and the second release portion may be present in a state in which they are physically separated from each other.

[00014] In the present invention, the combined formulation Petition 870250090236, dated 03 / 10 / 2025, pp. 187 / 265 4 / 75 pharmaceutical can be a multilayer tablet or a drug-coated tablet.

[00015] In the present invention, the SGLT-2 inhibitor can be selected from the group consisting of dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, sotagliflozin, ipragliflozin, tofogliflozin, luseogliflozin, bexagliflozin and remogliflozin.

[00016] In the present invention, the first or second release portion may comprise at least one pharmaceutically acceptable additive selected from the group consisting of an excipient, a disintegrant and a lubricant.

[00017] In the present invention, the excipient may be selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, magnesium aluminometasilicate, magnesium aluminosilicate, aluminum silicate, sodium silicate, potassium silicate, magnesium silicate, calcium silicate, lactose, lactose hydrate, anhydrous lactose, calcium hydrogen phosphate, hydroxypropylcellulose, hydroxypropylmethylcellulose, dextrin, mannitol, sorbitol, starch, hydrated calcium phosphate, calcium carbonate, sugars and mixtures thereof.

[00018] In the present invention, the disintegrant may be selected from the group consisting of crospovidone, methylcellulose, cross-linked sodium carboxymethylcellulose (CMC Na cross-linked, C.CMC Na or croscarmellose sodium), calcium carboxymethylcellulose, sodium starch glycolate, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose, starch, pregelatinized starch, corn starch, potato starch, alginic acid or its sodium salt and combinations thereof.

[00019] In the present invention, the lubricant can be selected from the group consisting of calcium stearate, colloidal silicon dioxide (pyrogenic silica, Aerosil), monostearate Petition 870250090236, dated 03 / 10 / 2025, pp. 188 / 265 5 / 75 glyceryl, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc and combinations thereof.

[00020] In the present invention, the second release portion may comprise a coating agent.

[00021] In the present invention, the coating agent can be at least one selected from the group consisting of hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyvinyl alcohol-macrogol graft copolymers, acrylic acid polymers and their salts, polymethacrylate, copolymers of poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate), carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymers, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan gum, and mixtures thereof.

[00022] In the present invention, the first release portion may comprise, based on the total weight of the first release portion, 10 to 80% by weight of the active ingredient, 1 to 50% by weight of an excipient, 5 to 50% by weight of a disintegrant, and 0.1 to 20% by weight of a lubricant.

[00023] In the present invention, the second release portion may comprise, based on the total weight of the second release portion, 0.5 to 50% by weight of the active ingredient, 20 to 95% by weight of an excipient, 0.1 to 20% by weight of a disintegrant, and 0.1 to 20% by weight of a lubricant.

[00024] In the present invention, the second release portion may comprise, based on the total weight of the second release portion, 10 to 70% by weight of the active ingredient and 30 to 90% in Petition 870250090236, dated 03 / 10 / 2025, pp. 189 / 265 6 / 75 the weight of a coating agent.

[00025] In the present invention, the first release portion may comprise, based on the total weight of the first release portion, 10 to 80% by weight of the active ingredient, 5 to 50% by weight of at least one of microcrystalline cellulose and mannitol, 5 to 30% by weight of low-substituted hydroxypropylcellulose, 5 to 30% by weight of at least one of sodium starch glycolate and croscarmellose sodium, 0.1 to 10% by weight of colloidal silicon dioxide, 0.1 to 10% by weight of talc, and 0.1 to 10% by weight of magnesium stearate.

[00026] In the present invention, the second release portion may comprise, based on the total weight of the second release portion, 0.5 to 50% by weight of the active ingredient, 10 to 50% by weight of at least one of microcrystalline cellulose and lactose hydrate, 10 to 50% by weight of mannitol, 0.1 to 20% by weight of hydroxypropylcellulose, 0.5 to 20% by weight of croscarmellose sodium and 0.5 to 20% by weight of sodium stearyl fumarate.

[00027] In the present invention, the combined pharmaceutical formulation may be a bilayer tablet comprising: a first layer comprising a first-release moiety comprising sacubitril-valsartan or pharmaceutically acceptable salts thereof as an active ingredient; and a second layer comprising a second-release moiety comprising an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[00028] In the present invention, the combined pharmaceutical formulation may be a drug-coated tablet comprising: a core comprising a first release portion comprising sacubitril-valsartan or pharmaceutically acceptable salts thereof as an active ingredient; and a coating layer located on at least a portion of the surface of the core and comprising a second release portion comprising an SGLT-2 inhibitor or a salt Petition 870250090236, dated 03 / 10 / 2025, pp. 190 / 265 7 / 75 pharmaceutically acceptable of the same as an active ingredient.

[00029] In the present invention, the first release portion may comprise granules comprising sacubitril-valsartan or pharmaceutically acceptable salts thereof as an active ingredient, an excipient, a disintegrant and a lubricant, and a post-mixing portion comprising a disintegrant and a lubricant, and the second release portion may comprise granules comprising an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient, an excipient, a disintegrant and a lubricant, and a post-mixing portion comprising a disintegrant and a lubricant.

[00030] According to another embodiment of the present invention, the present invention is directed to a method for preparing a combined pharmaceutical formulation, the method comprising the steps of: (a) preparing a first release portion comprising sacubitril-valsartan or pharmaceutically acceptable salts thereof as an active ingredient; (b) preparing a second release portion comprising an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient; and (c) formulating the first release portion and the second release portion into a single solid formulation.

[00031] In the present invention, step (a) may comprise the steps of: preparing granules comprising sacubitril-valsartan or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable additive; and mixing the granules with a post-mixing portion comprising a disintegrant and a lubricant; step (b) may comprise the steps of: preparing granules comprising the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and mixing the granules with a post-mixing portion comprising a disintegrant and a lubricant; and step (c) may comprise compressing the mixture of step (a) and the mixture of step (b) into Petition 870250090236, dated 03 / 10 / 2025, pp. 191 / 265 8 / 75 one bilayer tablet.

[00032] In the present invention, step (a) may comprise the steps of: preparing granules comprising sacubitrilvalsartan or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable additive; mixing the granules with a post-mixture portion comprising a disintegrant and a lubricant; and compressing the mixture into an uncoated tablet; step (b) may comprise the step of preparing a coating solution by mixing the SGLT-2 inhibitor or pharmaceutically acceptable salt thereof with a coating agent; and step (c) may comprise the step of preparing a drug-coated tablet by coating the surface of the uncoated tablet of step (a) with the coating solution of step (b). Advantageous Effects

[00033] The oral combination formulation provided by the present invention can provide a pharmaceutical combination formulation that has a synergistic effect in the treatment of heart failure, comprising sacubitril-valsartan and an SGLT-2 inhibitor as active ingredients, while ensuring bioequivalence, as the effect of one drug on the dissolution of the other is minimized. Furthermore, the oral combination formulation of the present invention suppresses the generation of impurities and therefore exhibits excellent stability of the active ingredients. BRIEF DESCRIPTION OF THE DRAWINGS

[00034] FIG. 1 shows the results of an experiment comparing the dissolution rate of dapagliflozin in pH 1.2 buffer between the combined formulations of Examples 1 to 3 and Comparative Examples 1 to 5 and a reference drug, in Experimental Example 1.

[00035] FIG. 2 shows the results of an experiment comparing the dissolution rate of sacubitril in pH 1.2 buffer between the combined formulations of Examples 1 to 3 and Examples Petition 870250090236, dated 03 / 10 / 2025, pp. 192 / 265 9 / 75 Comparisons 1 to 5 and a reference drug, in Experimental Example 1.

[00036] FIG. 3 shows the results of an experiment comparing the dissolution rate of valsartan in pH 1.2 buffer between the combined formulations of Examples 1 to 3 and Comparative Examples 1 to 5 and a reference drug, in Experimental Example 1.

[00037] FIG. 4 shows the results of an experiment comparing the dissolution rate of dapagliflozin in pH 6.8 buffer for the combined formulations of Examples 1 to 3 and Comparative Examples 1 to 5 and a reference drug, in Experimental Example 1.

[00038] FIG. 5 shows the results of an experiment comparing the dissolution rate of sacubitril in pH 6.8 buffer between combined formulations of Examples 1 to 3 and Comparative Examples 1 to 5 and a reference drug, in Experimental Example 1.

[00039] FIG. 6 shows the results of an experiment comparing the dissolution rate of valsartan in pH 6.8 buffer between combined formulations of Examples 1 to 3 and Comparative Examples 1 to 5 and a reference drug, in Experimental Example 1.

[00040] FIG. 7 shows the results of an experiment comparing the amount of dapagliflozin impurity (at RRT 0.38) generated under initial, accelerated, or stress conditions between combined formulations of Examples 1 to 3 and Comparative Examples 1 to 5 and a reference drug, in Experimental Example 2.

[00041] FIG. 8 shows the results of an experiment comparing the amount of dapagliflozin impurity (at RRT 0.74) generated under initial, accelerated, or stress conditions between combined formulations of Examples 1 to 3 and Comparative Examples 1 to 5 and a reference drug, in Example Petition 870250090236, dated 03 / 10 / 2025, pp. 193 / 265 10 / 75 Experiment 2.

[00042] FIG. 9 shows the results of an experiment comparing the amount of dapagliflozin impurity (with an RRT of 1.59) generated under initial, accelerated, or stress conditions between the combined formulations of Examples 1 to 3 and Comparative Examples 1 to 5 and a reference drug, in Experimental Example 2. DETAILED DESCRIPTION

[00043] According to one embodiment of the present invention, the present invention relates to a combined pharmaceutical formulation comprising: (1) a first release portion comprising sacubitril-valsartan or pharmaceutically acceptable salts thereof as an active ingredient; and (2) a second release portion comprising a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[00044] In the combined formulation according to the present invention, the first release portion and the second release portion may be present in a state in which they are physically separated from each other.

[00045] In the present invention, the combined formulation may be in the form of a bilayer or multilayer tablet, or it may be in the form of a drug-coated tablet with a core-shell structure.

[00046] In the bilayer or multilayer tablet of the present invention, the first layer may comprise the first release portion or the second release portion, and the second layer may comprise the second release portion or the first release portion.

[00047] In the present invention, the drug-coated tablet may be composed of a structure comprising: a core; and a coating layer with which at least a portion of the surface of the core is coated. In the present invention, Petition 870250090236, dated 03 / 10 / 2025, pp. 194 / 265 11 / 75 The core may comprise the first release portion or the second release portion, and the coating layer may comprise the second release portion or the first release portion.

[00048] In one example, the first layer may comprise an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof, and the second layer may comprise sacubitril-valsartan or pharmaceutically acceptable salts thereof.

[00049] In another example, the combined formulation may be a bilayer tablet comprising: a first layer comprising sacubitril-valsartan or pharmaceutically acceptable salts thereof; and a second layer comprising an SGLT-2 inhibitor, such as dapagliflozin, or a pharmaceutically acceptable salt thereof.

[00050] In the drug-coated tablet of the present invention, the core may consist of the first release moiety, and the drug coating layer may consist of the second release moiety.

[00051] In one example, the core may comprise sacubitrilvalsartan or pharmaceutically acceptable salts thereof, and the coating layer may comprise an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[00052] In the present invention, the first release portion and the second release portion may additionally comprise pharmaceutically acceptable additives, such as an excipient (diluent), a disintegrant, a lubricant or a coating agent, depending on the form of the combined formulation.

[00053] In the present invention, the combined formulation may be a bilayer tablet or a multilayer tablet, and the first or second release portion may comprise at least one pharmaceutically acceptable additive selected from the group consisting of an excipient (diluent), a disintegrant and a lubricant. Petition 870250090236, dated 03 / 10 / 2025, pages 195 / 265 12 / 75

[00054] In one example, the combined formulation may be a bilayer tablet or a multilayer tablet, the first release portion may comprise an excipient (diluent), a disintegrant and a lubricant, in addition to the active ingredient, and the second release portion may also comprise an excipient (diluent), a disintegrant and a lubricant, in addition to the active ingredient.

[00055] Furthermore, in the present invention, the combined formulation may be a drug-coated tablet, and the first-release portion or the second-release portion may comprise a coating agent.

[00056] In one example, the combined formulation may be a drug-coated tablet, the first release portion may comprise, in addition to the active ingredient, at least one pharmaceutically acceptable additive selected from the group consisting of an excipient (diluent), a disintegrant and a lubricant, and the second release portion may comprise the active ingredient and a coating agent.

[00057] In another example, the combined formulation may be a drug-coated tablet, the second release portion may comprise, in addition to the active ingredient, at least one pharmaceutically acceptable additive selected from the group consisting of an excipient (diluent), a disintegrant and a lubricant, and the first release portion may comprise the active ingredient and a coating agent. Invention Mode

[00058] According to one embodiment of the present invention, the present invention relates to a combined pharmaceutical formulation comprising: (1) a first release portion comprising sacubitril-valsartan or pharmaceutically acceptable salts thereof as an active ingredient; and (2) a second release portion comprising a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a pharmaceutically acceptable salt thereof. Petition 870250090236, dated 03 / 10 / 2025, pp. 196 / 265 13 / 75 acceptable of the same as an active ingredient.

[00059] In the present invention, sacubitril is a 4-{[(2S,4R)-1-(4-biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid compound represented by Formula 1 below. Sacubitril is a neprilysin (NEP) inhibitor, which is known to be activated to sacubitrilate by deethylation via esterases and to act on the degradation of atrial and cerebral natriuretic peptides, which are hypotensive peptides that reduce blood flow. [Formula 1]

[00060] In the present invention, valsartan is a (S)—N—(1-carboxy-2-methyl-prop-1-1)-N-pentanoyl-N-[2'-(1H-tetrazol-5-1)biphenyl-4-yl-methyl]amine compound represented by Formula 2 below. Valsartan is an angiotensin II receptor blocker, which not only blocks the action of angiotensin II and relaxes blood vessels, thus reducing blood pressure, but is also used to treat heart failure, ischemic heart disease, etc. [Formula 2] Petition 870250090236, dated 03 / 10 / 2025, pp. 197 / 265 14 / 75

[00061] In the present invention, "pharmaceutically acceptable salt" refers to salts commonly used in the art and includes salts formed with inorganic ions, inorganic acids or organic acids, as well as hydrates or solvates of the salts. Examples of sacubitril-valsartan or pharmaceutically acceptable salts thereof suitable for the present invention include free acid forms or salts of 1 to 3 inorganic ions, such as sodium, calcium, potassium or magnesium ions, or monohydrates to trihydrates thereof.

[00062] In the first release portion of the present invention, sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof may be contained in a molar ratio of 1:5 to 5:1, preferably 1:1, without being limited to the same.

[00063] “Sacubitril-valsartan, which is contained as an active ingredient in the combined pharmaceutical formulation of the present invention, may be contained in the form of a supramolecular complex of sacubitril and valsartan, or may be contained in the form of a physical mixture of the free acids or salts of sacubitril and valsartan, or the forms of these drugs include all coprecipitation compounds, cocrystals or coamorphs, or single compounds linked by ionic bonds, non-ionic bonds, covalent bonds, non-covalent bonds or hydrogen bonds. In this document, the “supramolecular complex” is intended to describe an interaction between the two pharmaceutically active agents, the cations and any other entity present, such as a solvent, in particular water, by means of non-covalent intermolecular bonding between them. This interaction leads to an association of the species present in the supramolecular complex, distinguishing this complex from a physical mixture of the species.

[00064] In one example, sacubitril-valsartan may be supplied in the form of a compound represented by Formula 3 Petition 870250090236, dated 03 / 10 / 2025, pp. 198 / 265 15 / 75 below, without being limited to the same. [Formula 3] [(A>)(A2)|(Na*)j · x HjO where Ai is valsartana in the dianionic form; A2 is sacubitril in its anionic form; Na+ is a sodium ion; ex can be a rational number ranging from 0.5 to 7, preferably a rational number from 2.5 to 3.5, more preferably 2.5 or 3, without being limited to the same.

[00065] In another example, sacubitril-valsartan may be a supramolecular complex of sacubitril and valsartan as a trisodium trihydrate salt, without being limited to the same.

[00066] In another example, sacubitril-valsartan may be the crystalline form II of trisodium sacubitril-valsartan trihydrate, represented by Formula 4 below, without limitation: [Formula 4]

[00067] In another example, sacubitril-valsartan may be a supramolecular complex of sacubitril and valsartan as trisodium hemipentahydrate (see Korean Patent No. 101589317), conventionally designated LCZ696, without being limited to the same.

[00068] In the present invention, sacubitril or ethyl ester of N—(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4 Petition 870250090236, dated 03 / 10 / 2025, pp. 199 / 265 16 / 75 amino-2R-methylbutanoic acid or a pharmaceutically acceptable salt thereof, as well as (2R,4S)-5-biphenyl-4-yl-4(3-carboxypropionyl amino)-2-methylpentanoic acid, can be prepared by known methods, such as the method described in U.S. Patent No. 5,217,996, which is incorporated herein by reference.

[00069] In the present invention, valsartan or (S)-N-valerylN-{[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]-methyl}-valine) or a pharmaceutically acceptable salt thereof may be obtained from commercial sources or may be prepared according to known methods, such as the methods described in U.S. Patent No. 5,399,578 and European Patent No. 0443983, the preparation teachings of which are incorporated herein by reference. Valsartan may be used in certain embodiments of the invention in its free acid form as well as in any suitable salt form. Depending on the circumstances, esters or other carboxylic group derivatives may be used, as well as salts and tetrazole group derivatives.

[00070] In the present invention, treatment with sacubitrilvalsartan can be initiated with an initial dose of 50 mg (24.3 / 25.7 mg as sacubitril-valsartan) twice daily and, if necessary, the dose can be increased to 200 mg (97.2 / 102.8 mg as sacubitril-valsartan) twice daily.

[00071] In the combined pharmaceutical formulation of the present invention, the second release moiety comprises an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[00072] In the present invention, the SGLT-2 inhibitor is a glucopyranosyl-substituted benzene derivative having the ability to inhibit sodium-glucose cotransporters. In the present invention, the SGLT-2 inhibitor can be selected from the group consisting of dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, sotagliflozin, ipragliflozin, tofogliflozin, luseogliflozin, bexagliflozin and Petition 870250090236, dated 03 / 10 / 2025, pages 200 / 265 17 / 75 remogliflozin, without being limited to them.

[00073] In one example, the SGLT-2 inhibitor may be dapagliflozin, without being limited to it.

[00074] In another example, the SGLT-2 inhibitor may be empagliflozin, without being limited to it.

[00075] In another example, the SGLT-2 inhibitor may be canagliflozin, without being limited to it.

[00076] In another example, the SGLT-2 inhibitor may be ertugliflozin, without being limited to it.

[00077] In another example, the SGLT-2 inhibitor may be sotagliflozin, without being limited to it.

[00078] In another example, the SGLT-2 inhibitor could be ipragliflozin, without being limited to it.

[00079] In another example, the SGLT-2 inhibitor may be tofogliflozin, without being limited to it.

[00080] In another example, the SGLT-2 inhibitor could be luseogliflozin, without being limited to it.

[00081] In another example, the SGLT-2 inhibitor could be bexagliflozin, without being limited to it.

[00082] In another example, the SGLT-2 inhibitor could be remogliflozin, without being limited to it.

[00083] In the present invention, the SGLT-2 inhibitor can be prepared according to methods known in the art, such as those presented in International Patent Publication No. WO 2006 / 120208, International Patent Publication No. WO 2007 / 031548 or International Patent Publication No. WO 2008 / 002824.

[00084] In the present invention, dapagliflozin is (1S)-1,5-andhydro-1-C-4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl-D-glucitol, represented by Formula 5 below. Dapagliflozin is able to inhibit SGLT-2 in the renal tubules and inhibit the process of glucose reabsorption to excrete glucose in the urine, thus suppressing the increase in blood glucose levels. Petition 870250090236, dated 03 / 10 / 2025, pp. 201 / 265 18 / 75

[00085] In the present invention, the SGLT-2 inhibitor, such as dapagliflozin, may include any pharmaceutically acceptable form of the salt, ester or solvate thereof.

[00086] In the present invention, dapagliflozin or a pharmaceutically acceptable salt thereof may be in continuous and / or discontinuous amorphous form or in the form of a cocrystal.

[00087] In the present invention, dapagliflozin may include a prodrug ester thereof. In this document, the pharmaceutically acceptable ester may be cleaved in the human or animal body to produce the parent acid (e.g., where said ester is methoxymethyl) or hydroxy group (e.g., where said ester is an acetyl ester).

[00088] In the present invention, dapagliflozin solvate may comprise or consist of a dapagliflozin propylene glycol solvate, such as dapagliflozin propylene glycol (1:1). In one example, the dapagliflozin solvate may be in the form of its propylene glycol solvate hydrate (1:1:1). In this document, the propylene glycol may be in form (S), form (R), or a mixture thereof. Preferably, the propylene glycol may be in form (S), without being limited to the same.

[00089] Furthermore, in the present invention, the dapagliflozin solvate may be in the form of a solvate comprising dapagliflozin and 1,2-alkanediol or a hydrate thereof. In this document, the 1,2-alkanediol may be 1,2-propanediol, 1,2-butanediol, 1,2-pentanediol, 1,2-hexanediol and 1,2-heptanediol or Petition 870250090236, dated 03 / 10 / 2025, pages 202 / 265 19 / 75 a hydrate or a mixture thereof. For example, dapagliflozin solvate may be dapagliflozin propanediol monohydrate, or dapagliflozin compound with (2S)-1,2-propanediol and hydrate in a ratio of about 1:1:1, without being limited to the same.

[00090] The second release moiety of the present invention may comprise at least one amino acid together with dapagliflozin. In this document, the amino acid may be selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan, serine, cysteine, threonine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, histidine, and lysine. Furthermore, in the present invention, dapagliflozin and the amino acid may be in the form of a cocrystal. In one example, the second release moiety may comprise dapagliflozin and proline (e.g., L-proline or D-proline), without being limited to the same.

[00091] The combined formulation of the present invention may contain, per dosage unit, 50 to 200 mg of sacubitril-valsartan as a free base of sacubitril-valsartan and 5 to 10 mg of dapagliflozin as a free base. For example, the combined formulation may contain, per dosage unit, 100 mg or 200 mg of sacubitril-valsartan as a free base and 10 mg of dapagliflozin.

[00092] In this descriptive report, it should be understood that, even if sacubitril, valsartan, the SGLT-2 inhibitor or dapagliflozin is mentioned, it is understood that all include the aforementioned salts, solvates and isomers thereof.

[00093] In the combined formulation according to the present invention, the first release portion and the second release portion may be present in a state in which they are physically separated from each other.

[00094] In the present invention, the combined formulation may be in the form of a bilayer tablet or a tablet in Petition 870250090236, dated 03 / 10 / 2025, pages 203 / 265 20 / 75 multilayer, or it may be in the form of a drug-coated tablet having a core-shell structure.

[00095] In the bilayer or multilayer tablet of the present invention, the first layer may comprise the first release portion or the second release portion, and the second layer may comprise the second release portion or the first release portion.

[00096] In the bilayer or multilayer tablet of the present invention, the first layer may consist of the first release portion, and the second layer may consist of the second release portion.

[00097] In one example, the first layer may comprise sacubitril-valsartan or pharmaceutically acceptable salts thereof, and the second layer may comprise an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof.

[00098] In another example, the first layer may comprise an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof, and the second layer may comprise sacubitril-valsartan or a pharmaceutically acceptable salt thereof.

[00099] In another example, the combined formulation may be a bilayer tablet comprising: a first layer comprising sacubitril-valsartan or pharmaceutically acceptable salts thereof; and a second layer comprising an SGLT-2 inhibitor, such as dapagliflozin, or a pharmaceutically acceptable salt thereof. In this document, the terms “first layer” and “second layer” are used to distinguish between different layers (i.e., the term “first layer” refers to any layer of the bilayer tablet, and the term “second layer” refers to a different layer that is not any layer), and the first layer may be an upper layer or a lower layer, and the second layer may be a lower layer or an upper layer. These terms mean that sacubitril-valsartan and the SGLT-2 inhibitor are contained Petition 870250090236, dated 03 / 10 / 2025, pages 204 / 265 21 / 75 in different layers of this bilayer tablet. [000100] In the present invention, the drug-coated tablet may consist of a structure comprising: a core; and a coating layer with which at least a portion of the surface of the core is coated. In the present invention, the core may comprise the first-release portion or the second-release portion, and the coating layer may comprise the second-release portion or the first-release portion. [000101] In the drug-coated tablet of the present invention, the core may consist of the first release moiety, and the drug coating layer may consist of the second release moiety. [000102] In one example, the core may comprise sacubitril-valsartan or pharmaceutically acceptable salts thereof, and the coating layer may comprise an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof. [000103] In another example, the core may comprise an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof, and the coating layer may comprise sacubitrilvalsartan or pharmaceutically acceptable salts thereof. [000104] In another example, the combined formulation may be a drug-coated tablet comprising: a core comprising sacubitril-valsartan or pharmaceutically acceptable salts thereof; and a coating layer comprising an SGLT-2 inhibitor, such as dapagliflozin, or a pharmaceutically acceptable salt thereof. [000105] In the present invention, the first release portion and the second release portion may additionally comprise pharmaceutically acceptable additives, such as an excipient (diluent), a disintegrant, a lubricant or a coating agent, depending on the form of the combined formulation. Petition 870250090236, dated 03 / 10 / 2025, pages 205 / 265 22 / 75 [000106] In the present invention, the combined formulation may be a bilayer tablet or a multilayer tablet, and the first or second release portion may comprise at least one pharmaceutically acceptable additive selected from the group consisting of an excipient (diluent), a disintegrant and a lubricant. [000107] Furthermore, in the present invention, the combined formulation may be a drug-coated tablet, and the first-release portion or the second-release portion may comprise a coating agent. [000108] In one example, the first release portion may comprise, in addition to the active ingredient, at least one pharmaceutically acceptable additive selected from the group consisting of an excipient (diluent), a disintegrant and a lubricant, and the second release portion may comprise the active ingredient and a coating agent. [000109] In another example, the second release portion may comprise, in addition to the active ingredient, at least one pharmaceutically acceptable additive selected from the group consisting of an excipient (diluent), a disintegrant and a lubricant, and the first release portion may comprise the active ingredient and a coating agent. [000110] In the present invention, sacubitril-valsartan, understood as an active ingredient in the first-release portion, may be contained in an amount of 10 to 80% by weight, 20 to 80% by weight, or 30 to 80% by weight, based on the total weight of the first-release portion, without being limited to the same. [000111] In the present invention, the SGLT-2 inhibitor comprised as an active ingredient in the second layer, preferably dapagliflozin, may be present in an amount of 0.5 to 50% by weight, 0.5 to 30% by weight or 0.5 to 10% by weight, based on the total weight of the second layer, without being Petition 870250090236, dated 03 / 10 / 2025, pages 206 / 265 23 / 75 limited to the same. [000112] In the present invention, the excipient comprised in the first release portion may be present in an amount of 1 to 50% by weight, 5 to 50% by weight, 5 to 30% by weight, 10 to 30% by weight, 5 to 20% by weight, 10 to 20% by weight or 5 to 15% by weight, based on the total weight of the first release portion, without being limited to the same. [000113] In the present invention, the excipient comprised in the second release portion may comprise an amount of 20 to 95% by weight, 30 to 90% by weight, 40 to 90% by weight, 50 to 80% by weight or 60 to 80% by weight, based on the total weight of the second release portion, without being limited to the same. [000114] In the present invention, the disintegrant comprised in the first release portion may comprise an amount of 5 to 50% by weight, 10 to 50% by weight, 10 to 40% by weight or 15 to 30% by weight, based on the total weight of the first release portion, without being limited to the same. [000115] In the present invention, the disintegrant comprised in the second release portion may comprise an amount of 0.1 to 40% by weight, 0.1 to 20% by weight, 0.5 to 40% by weight, 0.5 to 20% by weight, 1 to 40% by weight, 5 to 40% by weight, 5 to 30% by weight, 10 to 30% by weight, 1 to 10% by weight or 1 to 5% by weight, based on the total weight of the second release portion, without being limited to the same. [000116] In the present invention, the lubricant contained in the first release portion may be contained in an amount of 0.1 to 20% by weight, 0.5 to 20% by weight, 1 to 10% by weight or 2 to 8% by weight, based on the total weight of the first release portion, without being limited to the same. [000117] In the present invention, the lubricant contained in the second release portion may be contained in an amount Petition 870250090236, dated 03 / 10 / 2025, pages 207 / 265 24 / 75 from 0.1 to 20% by weight, 0.5 to 20% by weight, 1 to 15% by weight, 5 to 15% by weight, 1 to 10% by weight, 5 to 10% by weight, 2 to 8% by weight or 5 to 8% by weight, based on the total weight of the second release portion, without being limited to the same. [000118] In the present invention, the coating agent may comprise an amount of 30 to 90% by weight, 40 to 90% by weight, 40 to 80% by weight, or 50 to 80% by weight, based on the total weight of the first release portion or the second release portion, without being limited to the same. [000119] In one example, the first release portion may comprise, based on the total weight of the first release portion, 10 to 80% by weight of the active ingredient, 1 to 50% by weight of the excipient, 5 to 50% by weight of the disintegrant and 0.1 to 20% by weight of the lubricant, without being limited to the same. [000120] In one example, the second release portion may comprise, based on the total weight of the second release portion, 0.5 to 50% by weight of the active ingredient, 20 to 95% by weight of the excipient, 0.1 to 20% by weight of the disintegrant and 0.1 to 20% by weight of the lubricant, without being limited to the same. [000121] In one example, the first release portion or the second release portion may comprise, based on the total weight of the second release portion thereof, 10 to 70% by weight of the active ingredient and 30 to 90% by weight of the coating agent, without being limited to the same. [000122] In the present invention, the excipient (diluent) may, for example, be selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, magnesium aluminometasilicate, magnesium aluminate silicate, aluminum silicate, sodium silicate, potassium silicate, magnesium silicate, calcium silicate, lactose, lactose hydrate, lactose anhydride, calcium hydrogen phosphate, hydroxypropylcellulose, hydroxypropylmethylcellulose, dextrin, mannitol, sorbitol, starch, Petition 870250090236, dated 03 / 10 / 2025, pages 208 / 265 25 / 75 calcium phosphate monohydrate, calcium carbonate, sugars and any mixtures thereof, without being limited to the same. However, in the present invention, anhydrous calcium phosphate has low compatibility with dapagliflozin and sacubitrilvalsartan and is therefore not included as an excipient. [000123] In the present invention, the disintegrant may, for example, be selected from the group consisting of crospovidone, methylcellulose, cross-linked sodium carboxymethylcellulose (CMC Na cross-linked, C.CMC Na or croscarmellose sodium), calcium carboxymethylcellulose, sodium starch glycolate, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose, starch, pregelatinized starch, corn starch, potato starch, alginic acid or its sodium salt, and any combinations thereof, without being limited to the same. [000124] In the present invention, the lubricant may, for example, be selected from the group consisting of calcium stearate, colloidal silicon dioxide (pyrogenic silica, Aerosil), glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc and any combinations thereof, without being limited to the same. [000125] In the present invention, the coating agent is a hydrophilic polymer and may be, for example, at least one selected from the group consisting of hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyvinyl alcohol-macrogol graft copolymers, acrylic acid polymers and their salts, polymethacrylate copolymers, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) (for example, Eudragit® E, Evonik), carboxymethylcellulose (sodium salt and calcium salt), Petition 870250090236, dated 03 / 10 / 2025, pp. 209 / 265 26 / 75 ethylcellulose, methylcellulose, hydroxyethylcellulose, ethyl hydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone (povidone; PVP), vinylpyrrolidone-vinylacetate copolymers (e.g., Kollidon® VA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan gum, and mixtures thereof, without being limited to the same. Preferably, the coating agent may be hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), a copolymer grafted with polyvinyl alcohol and macrogol, or a copolymer of poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) (e.g., Eudragit® E, Evonik). [000126] In the present invention, the first release portion may comprise an additive selected from microcrystalline cellulose, mannitol, low-substituted hydroxypropylcellulose (L-HPC), croscarmellose sodium, sodium starch glycolate, colloidal silicon dioxide (pyrogenic silica, Aerosil), talc, magnesium stearate, and any combinations thereof. [000127] In one example, the first release portion may comprise additives including: at least one of microcrystalline cellulose and mannitol; low-substituted hydroxypropylcellulose (L-HPC); at least one of croscarmellose sodium and sodium starch glycolate; colloidal silicon dioxide (pyrogenic silica, Aerosil); talc; and magnesium stearate. [000128] In another example, the first release portion may comprise additives including microcrystalline cellulose, mannitol, low-substituted hydroxypropylcellulose (L-HPC), croscarmellose sodium, colloidal silicon dioxide (pyrogenic silica, Aerosil), talc, and magnesium stearate. [000129] In another example, the first release portion may comprise additives including microcrystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC), sodium starch glycolate, colloidal silicon dioxide (silica). Petition 870250090236, dated 03 / 10 / 2025, pages 210 / 265 27 / 75 pyrogenic, Aerosil), talc and magnesium stearate. [000130] In the present invention, the first release portion may comprise at least one of microcrystalline cellulose and mannitol in an amount of 1 to 50% by weight, 5 to 50% by weight, 1 to 30% by weight, 5 to 30% by weight, 1 to 20% by weight, or 5 to 20% by weight, based on the total weight of the first release portion. In one example, the first release portion may comprise microcrystalline cellulose. In another example, the first release portion may comprise mannitol. In another example, the first release portion may comprise microcrystalline cellulose and mannitol. In another example, the first release portion may comprise microcrystalline cellulose in an amount of 1 to 30% by weight, 1 to 20% by weight, or 1 to 10% by weight, without being limited to the same. In another example, the first release portion may comprise mannitol in an amount of 1 to 30% by weight, 1 to 20% by weight, or 1 to 10% by weight, without being limited to these amounts. [000131] In the present invention, the first release portion may comprise low-substitution hydroxypropylcellulose in an amount of 5 to 30% by weight, 5 to 20% by weight, 5 to 15% by weight, or 10 to 20% by weight, based on the total weight of the first release portion. [000132] In the present invention, the first release portion may comprise at least one of sodium starch glycolate and croscarmellose sodium in an amount of 1 to 30% by weight, 5 to 30% by weight, 5 to 20% by weight, or 5 to 15% by weight, based on the total weight of the first release portion. In one example, the first release portion may comprise sodium starch glycolate. In another example, the first release portion may comprise croscarmellose sodium. In another example, the first release portion may comprise sodium starch glycolate and croscarmellose sodium. In another example, the first release portion may comprise sodium starch glycolate. Petition 870250090236, dated 03 / 10 / 2025, pages 211 / 265 28 / 75 sodium in an amount of 1 to 30% by weight, 5 to 30% by weight, 5 to 20% by weight or 5 to 15% by weight, without being limited to the same. In another example, the first release portion may comprise croscarmellose sodium in an amount of 1 to 30% by weight, 5 to 30% by weight, 5 to 20% by weight or 5 to 15% by weight, without being limited to the same. [000133] In the present invention, the first release portion may comprise colloidal silicon dioxide in an amount of 0.1 to 10% by weight, 0.1 to 5% by weight, 0.1 to 3% by weight, or 0.1 to 2% by weight, based on the total weight of the first release portion. [000134] In the present invention, the first release portion may comprise talc in an amount of 0.1 to 10% by weight, 0.1 to 5% by weight, 0.1 to 3% by weight or 0.1 to 2% by weight, based on the total weight of the first release portion. [000135] In the present invention, the first release portion may comprise magnesium stearate in an amount of 0.1 to 10% by weight, 0.1 to 5% by weight, 1 to 5% by weight or 1 to 3% by weight, based on the total weight of the first release portion. [000136] In one example, the first release portion may comprise, based on the total weight of the first release portion, 10 to 80% by weight of the active ingredient, 5 to 50% by weight of at least one of microcrystalline cellulose and mannitol, 5 to 30% by weight of low-substituted hydroxypropylcellulose, 5 to 30% by weight of at least one of sodium starch glycolate and croscarmellose sodium, 0.1 to 10% by weight of colloidal silicon dioxide, 0.1 to 10% by weight of talc and 0.1 to 10% by weight of magnesium stearate, without being limited to the same. [000137] In another example, the first release portion may comprise, based on the total weight of the first release portion, 10 to 80% by weight of active ingredient, 5 to 50% by weight of microcrystalline cellulose, 5 to 30% by weight of Petition 870250090236, dated 03 / 10 / 2025, pages 212 / 265 29 / 75 hydroxypropylcellulose with low substitution, 5 to 30% by weight of sodium starch glycolate, 0.1 to 10% by weight of colloidal silicon dioxide, 0.1 to 10% by weight of talc and 0.1 to 10% by weight of magnesium stearate, without being limited to the same. [000138] In another example, the first release portion may comprise, based on the total weight of the first release portion, 10 to 80% by weight of active ingredient, 1 to 30% by weight of microcrystalline cellulose, 1 to 20% by weight of mannitol, 5 to 30% by weight of low-substituted hydroxypropylcellulose, 5 to 30% by weight of croscarmellose sodium, 0.1 to 10% by weight of colloidal silicon dioxide, 0.1 to 10% by weight of talc and 0.1 to 10% by weight of magnesium stearate, without being limited to the same. [000139] In another example, the first release portion may comprise, based on the total weight of the first release portion, 10 to 80% by weight of active ingredient, 1 to 10% by weight of microcrystalline cellulose, 1 to 10% by weight of mannitol, 5 to 20% by weight of low-substituted hydroxypropylcellulose, 5 to 20% by weight of croscarmellose sodium, 0.1 to 10% by weight of colloidal silicon dioxide, 0.1 to 10% by weight of talc and 0.1 to 10% by weight of magnesium stearate, without being limited to the same. [000140] In the present invention, the second release portion may comprise an additive selected from microcrystalline cellulose, lactose hydrate, mannitol, hydroxypropylcellulose, sodium stearyl fumarate, croscarmellose sodium, and any combinations thereof. [000141] In one example, the second release portion may comprise additives including: at least one of microcrystalline cellulose and lactose hydrate; mannitol; hydroxypropylcellulose; sodium stearyl fumarate; and croscarmellose sodium. [000142] In another example, the second release portion Petition 870250090236, dated 03 / 10 / 2025, pp. 213 / 265 30 / 75 may contain additives including microcrystalline cellulose, mannitol, hydroxypropylcellulose, sodium stearyl fumarate and croscarmellose sodium. [000143] In another example, the second release portion may comprise additives including lactose hydrate, mannitol, hydroxypropylcellulose, sodium stearyl fumarate, and croscarmellose sodium. [000144] In the present invention, the second release portion may comprise at least one of microcrystalline cellulose and lactose hydrate in an amount of 10 to 50% by weight, 20 to 50% by weight, 10 to 40% by weight, 15 to 40% by weight, 10 to 30% by weight, or 15 to 30% by weight, based on the total weight of the second release portion. In one example, the second release portion may comprise microcrystalline cellulose. In another example, the second release portion may comprise lactose hydrate. In another example, the second release portion may comprise microcrystalline cellulose and lactose hydrate. In another example, the second release portion may comprise microcrystalline cellulose in an amount of 10 to 50% by weight, 10 to 40% by weight, or 15 to 30% by weight. In another example, the second release portion may comprise lactose hydrate in an amount of 10 to 50% by weight, 20 to 50% by weight, 10 to 40% by weight, or 15 to 40% by weight, without being limited to the same. [000145] In the present invention, the second release portion may comprise mannitol in an amount of 10 to 70% by weight, 20 to 70% by weight, 30 to 70% by weight, 40 to 70% by weight, 10 to 60% by weight, 20 to 60% by weight, 30 to 60% by weight, 40 to 60% by weight, 10 to 50% by weight, 20 to 50% by weight or 30 to 50% by weight, based on the total weight of the second release portion. [000146] In the present invention, the second release portion may comprise hydroxypropylcellulose in an amount of 0.1 to 20% by weight, 0.5 to 20% by weight, 0.1 to 10% by weight. Petition 870250090236, dated 03 / 10 / 2025, pp. 214 / 265 31 / 75 by weight, 0.5 to 10% by weight, 1 to 10% by weight, or 2 to 8% by weight, based on the total weight of the second release portion. [000147] In the present invention, the second release portion may comprise croscarmellose sodium in an amount of 0.5 to 20% by weight, 1 to 20% by weight, 5 to 20% by weight or 5 to 15% by weight, based on the total weight of the second release portion. [000148] In the present invention, the second release portion may comprise sodium stearyl fumarate in an amount of 0.5 to 20% by weight, 1 to 20% by weight, 5 to 20% by weight or 5 to 15% by weight, based on the total weight of the second release portion. [000149] In one example, the second release portion may comprise, based on the total weight of the second release portion, 0.5 to 50% by weight of the active ingredient, 10 to 50% by weight of at least one of microcrystalline cellulose and lactose hydrate, 10 to 50% by weight of mannitol, 0.1 to 20% by weight of hydroxypropylcellulose, 0.5 to 20% by weight of croscarmellose sodium and 0.5 to 20% by weight of sodium stearyl fumarate, without being limited to the same. [000150] In another example, the second release portion may comprise, based on the total weight of the second release portion, 0.5 to 50% by weight of the active ingredient, 10 to 50% by weight of microcrystalline cellulose, 10 to 50% by weight of mannitol, 0.1 to 20% by weight of hydroxypropylcellulose, 0.5 to 20% by weight of croscarmellose sodium and 0.5 to 20% by weight of sodium stearyl fumarate, without being limited to the same. [000151] In another example, the second release portion may comprise, based on the total weight of the second release portion, 0.5 to 50% by weight of the active ingredient, 10 to 30% by weight of microcrystalline cellulose, 20 to 70% by weight of mannitol, 0.5 to 20% by weight of hydroxypropylcellulose, 0.5 to 20% by weight of croscarmellose sodium, and 0.1 to 20% by weight of stearyl fumarate. Petition 870250090236, dated 03 / 10 / 2025, pages 215 / 265 32 / 75 sodium, without being limited to the same. [000152] In another example, the second release portion may comprise, based on the total weight of the second release portion, 0.5 to 50% by weight of the active ingredient, 10 to 50% by weight of lactose hydrate, 10 to 50% by weight of mannitol, 0.1 to 20% by weight of hydroxypropylcellulose, 0.5 to 20% by weight of croscarmellose sodium and 0.5 to 20% by weight of sodium stearyl fumarate, without being limited to the same. [000153] Furthermore, in the present invention, the first release moiety may comprise polyvinylpyrrolidone (povidone; PVP) and a macrogol-polyvinyl alcohol copolymer, in addition to the active ingredient. [000154] In the present invention, the first release portion may comprise polyvinylpyrrolidone (povidone; PVP) in an amount of 1 to 20% by weight, 5 to 20% by weight, 5 to 15% by weight, or 5 to 10% by weight, based on the total weight of the first release portion. [000155] In the present invention, the first release portion may comprise a macrogol-polyvinyl alcohol copolymer in an amount of 30 to 80% by weight, 40 to 80% by weight, 30 to 70% by weight, or 40 to 70% by weight, based on the total weight of the first release portion. [000156] In one example, the first release portion may comprise, based on the total weight of the first release portion, 10 to 70% by weight of the active ingredient, 5 to 20% by weight of povidone (PVP), and 30 to 80% by weight of a macrogol-polyvinyl alcohol copolymer, without being limited to the same. [000157] In the present invention, the second release moiety may comprise polyvinylpyrrolidone (povidone; PVP) and a macrogol-polyvinyl alcohol copolymer, in addition to the active ingredient. [000158] In the present invention, the second releasing moiety may comprise polyvinylpyrrolidone (povidone; PVP) Petition 870250090236, dated 03 / 10 / 2025, pages 216 / 265 33 / 75 in an amount of 1 to 20% by weight, 5 to 20% by weight, 5 to 15% by weight, or 5 to 10% by weight, based on the total weight of the second release portion. [000159] In the present invention, the second release portion may comprise a macrogol-polyvinyl alcohol copolymer in an amount of 30 to 80% by weight, 40 to 80% by weight, 30 to 70% by weight, or 40 to 70% by weight, based on the total weight of the second release portion. [000160] In one example, the second release portion may comprise, based on the total weight of the second release portion, 10 to 70% by weight of the active ingredient, 5 to 20% by weight of povidone (PVP), and 30 to 80% by weight of a macrogol-polyvinyl alcohol copolymer, without being limited to the same. [000161] In the present invention, when the combined formulation is prepared in the form of a drug-coated tablet, the coating layer may additionally comprise various biologically inactive ingredients for additional purposes, such as coating efficiency, drug stability, appearance, color, protection, maintenance, binding, performance enhancement, and preparation process improvement. The biologically inactive ingredients that may additionally be contained in the coating layer may be one or more selected from the group consisting of plasticizers, lubricants, colorants, fragrances, surfactants, stabilizers, antioxidants, foaming agents, antifoaming agents, paraffin, and waxes, without being limited to the same. [000162] Furthermore, in the present invention, the first release portion and / or the second release portion may additionally contain various additives to improve the physical properties, manufacturability, compressibility, appearance, taste, and / or stability of the drug in the final combined formulation. These additives include, Petition 870250090236, dated 03 / 10 / 2025, pp. 217 / 265 34 / 75 for example, stabilizers, solubilizers, sweeteners, flavor enhancers, pigments, humectants, fillers, stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, adsorbents, flavor enhancers, binders, suspending agents, curing agents, antioxidants, pharmaceutical whiteners, fragrances, flavoring agents, pigments, coating agents, humectants, wetting regulators, antifoaming agents, refreshing agents, chewing agents, antistatic agents, coloring agents, sugar coating agents, isotonic agents, softeners, emulsifiers, adhesives, thickeners, foaming agents, pH regulators, excipients, dispersants, disintegrants, waterproofing agents, preservatives, preservatives, dissolving aids, solvents and fluidizing agents, but are not limited to them and any pharmaceutically acceptable additives may be Used. [000163] In the present invention, in the combined formulation in the form of a bilayer tablet, as described above, the tablet-shaped layer comprising each of the first and second release portions may comprise granules containing the active ingredient and a postmix portion. [000164] In the present invention, the layer comprising the first release portion (first layer) may comprise granules containing the active ingredient and a post-mixing portion. In this document, the granules may additionally contain pharmaceutically acceptable additives, such as an excipient, a disintegrant, or a lubricant. Additionally, the post-mixing portion may further comprise at least one pharmaceutically acceptable additive selected from a disintegrant and a lubricant. [000165] In one example, the layer comprising the first Petition 870250090236, dated 03 / 10 / 2025, pages 218 / 265 35 / 75 The release portion may comprise granules containing the active ingredient, an excipient, a disintegrant and a lubricant, and a post-mixture portion comprising a disintegrant and a lubricant, but not limited to the same. [000166] In the present invention, the granules in the layer comprising the first release portion may contain the active ingredient in an amount of 10 to 80% by weight, 20 to 80% by weight, or 30 to 80% by weight, based on the total weight of the first release portion. [000167] In the present invention, the granules in the layer comprising the first release portion may contain an excipient in an amount of 5 to 50% by weight, 5 to 30% by weight, or 5 to 20% by weight, based on the total weight of the first release portion. [000168] In the present invention, the granules in the layer comprising the first release portion may contain a disintegrant in an amount of 1 to 30% by weight, 10 to 30% by weight, or 10 to 20% by weight, based on the total weight of the first release portion. [000169] In the present invention, the granules in the layer comprising the first release portion may contain a lubricant in an amount of 0.1 to 10% by weight, 1 to 10% by weight, or 1 to 5% by weight, based on the total weight of the first release portion. [000170] In the present invention, the post-mixing portion in the layer comprising the first release portion may comprise a disintegrant in an amount of 1 to 20% by weight, 1 to 10% by weight, or 2 to 8% by weight, based on the total weight of the first release portion. [000171] In the present invention, the post-mix portion in the layer comprising the first release portion may comprise a lubricant in an amount of 0.1 to 10% by weight, 0.1 to 5% by weight, or 1 to 5% by weight, based on the total weight. Petition 870250090236, dated 03 / 10 / 2025, pp. 219 / 265 36 / 75 of the first release portion. [000172] In one example, the granules in the layer comprising the first release portion may comprise, based on the total weight of the first release portion, 10 to 80% by weight of the active ingredient, 5 to 50% by weight of an excipient, 1 to 30% by weight of a disintegrant and 0.1 to 10% by weight of a lubricant, and the post-mixing portion may comprise, based on the total weight of the first release portion, 1 to 20% by weight of a disintegrant and 0.1 to 10% by weight of a lubricant, without being limited to the same. [000173] In another example, the granules in the layer comprising the first release portion may comprise, based on the total weight of the first release portion, 10 to 80% by weight of the active ingredient, 5 to 50% by weight of an excipient, 1 to 30% by weight of a disintegrant and 0.1 to 10% by weight of a lubricant, and the post-mix portion may comprise, based on the total weight of the first release portion, 1 to 20% by weight of a disintegrant and 0.1 to 10% by weight of a lubricant, without being limited to the same. [000174] In another example, the granules in the layer comprising the first release portion may comprise, based on the total weight of the first release portion, 10 to 80% by weight of the active ingredient, 5 to 20% by weight of an excipient, 10 to 30% by weight of a disintegrant and 0.1 to 10% by weight of a lubricant, and the post-mixing portion may comprise, based on the total weight of the first release portion, 1 to 20% by weight of a disintegrant and 0.1 to 10% by weight of a lubricant, without being limited to the same. [000175] In the present invention, the granules in the layer comprising the first release portion may comprise at least one of microcrystalline cellulose and mannitol in an amount of 1 to 50% by weight, 5 to 50% by weight, 1 to 30% by weight, 5 to 30% by weight, 1 to 20% by weight, or 5 to 20% by weight. In one example, the Petition 870250090236, dated 03 / 10 / 2025, pages 220 / 265 37 / 75 granules in the layer comprising the first release portion may comprise microcrystalline cellulose. In another example, the granules in the layer may comprise mannitol. In another example, the granules in the layer may comprise microcrystalline cellulose and mannitol. In another example, the granules in the layer may comprise microcrystalline cellulose in an amount of 1 to 30% by weight, 1 to 20% by weight, or 1 to 10% by weight, without limitation. In another example, the granules in the layer may comprise mannitol in an amount of 1 to 30% by weight, 1 to 20% by weight, or 1 to 10% by weight, without being limited thereto. [000176] In the present invention, the granules in the layer comprising the first release portion may comprise low-substituted hydroxypropylcellulose in an amount of 5 to 30% by weight, 5 to 20% by weight, 5 to 15% by weight, or 10 to 20% by weight. [000177] In the present invention, the granules in the layer comprising the first release portion may comprise at least one of sodium starch glycolate and croscarmellose sodium in an amount of 1 to 15% by weight, 1 to 10% by weight, or 2 to 8% by weight. In one example, the granules in the layer comprising the first release portion may comprise sodium starch glycolate. In another example, the granules in the layer may comprise croscarmellose sodium. In another example, the granules in the layer may comprise sodium starch glycolate and croscarmellose sodium. In another example, the granules in the layer may comprise sodium starch glycolate in an amount of 1 to 15% by weight, 1 to 10% by weight, or 2 to 8% by weight, without being limited to the same. In another example, the granules in the coating may comprise croscarmellose sodium in an amount of 1 to 15% by weight, 1 to 10% by weight, or 2 to 8% by weight, without being limited to the same. [000178] In the present invention, the granules in the layer comprising the first release portion may comprise Petition 870250090236, dated 03 / 10 / 2025, pages 221 / 265 38 / 75 colloidal silicon dioxide in an amount of 0.1 to 5% by weight, 0.1 to 3% by weight or 0.1 to 2% by weight. [000179] In the present invention, the granules in the layer comprising the first release portion may comprise talc in an amount of 0.1 to 10% by weight, 0.1 to 5% by weight or 1 to 5% by weight. [000180] In the present invention, the granules in the layer comprising the first release portion may comprise magnesium stearate in an amount of 0.1 to 5% by weight, 0.5 to 5% by weight or 1 to 5% by weight. [000181] In one example, the granules in the layer comprising the first release portion may comprise, based on the total weight of the first release portion, 10 to 80% by weight of the active ingredient, 1 to 50% by weight of at least one of microcrystalline cellulose and mannitol, 5 to 30% by weight of low-substituted hydroxypropylcellulose, 1 to 15% by weight of at least one of sodium starch glycolate and croscarmellose sodium, 0.1 to 5% by weight of colloidal silicon dioxide, 0.1 to 10% by weight of talc, and 0.1 to 5% by weight of magnesium stearate, and the post-mixing portion may comprise, based on the total weight of the first release portion, 1 to 15% by weight of sodium starch glycolate, 0.1 to 5% by weight of colloidal silicon dioxide, and 0.1 to 5% by weight of stearate magnesium, but not limited to it. [000182] In another example, the granules in the layer comprising the first release portion may comprise, based on the total weight of the first release portion, 10 to 80% by weight of the active ingredient, 5 to 50% by weight of microcrystalline cellulose, 5 to 30% by weight of low-substituted hydroxypropylcellulose, 1 to 15% by weight of sodium starch glycolate, 0.1 to 5% by weight of colloidal silicon dioxide, 0.1 to 10% by weight of talc, and 0.1 to 5% by weight of magnesium stearate, and the post-mixing portion may comprise, based on the total weight of Petition 870250090236, dated 03 / 10 / 2025, pages 222 / 265 39 / 75 first release portion, 1 to 15% by weight of sodium starch glycolate, 0.1 to 5% by weight of colloidal silicon dioxide and 0.1 to 5% by weight of magnesium stearate, without being limited to the same. [000183] In another embodiment, the granules in the layer comprising the first release portion may comprise, based on the total weight of the first release portion, 10 to 80% by weight of the active ingredient, 1 to 30% by weight of microcrystalline cellulose, 1 to 20% by weight of mannitol, 5 to 30% by weight of low-substituted hydroxypropylcellulose, 1 to 15% by weight of croscarmellose sodium, 0.1 to 5% by weight of colloidal silicon dioxide, 0.1 to 10% by weight of talc, and 0.1 to 5% by weight of magnesium stearate, and the post-mixing portion may comprise, based on the total weight of the first layer, 1 to 15% by weight of croscarmellose sodium, 0.1 to 5% by weight of colloidal silicon dioxide, and 0.1 to 5% by weight of magnesium stearate, without being limited to same. [000184] In another embodiment, the granules in the layer comprising the first release portion may comprise, based on the total weight of the first release portion, 10 to 80% by weight of the active ingredient, 1 to 20% by weight of microcrystalline cellulose, 1 to 20% by weight of mannitol, 5 to 20% by weight of low-substituted hydroxypropylcellulose, 1 to 10% by weight of croscarmellose sodium, 0.1 to 5% by weight of colloidal silicon dioxide, 0.1 to 5% by weight of talc and 0.1 to 5% by weight of magnesium stearate, and the post-mixing portion may comprise, based on the total weight of the first layer, 1 to 10% by weight of croscarmellose sodium, 0.1 to 5% by weight of colloidal silicon dioxide and 0.1 to 5% by weight of magnesium stearate, without being limited to the same. [000185] In the present invention, the layer (second layer) comprising the second release portion may comprise granules, which comprise the active ingredient, and a portion of Petition 870250090236, dated 03 / 10 / 2025, pages 223 / 265 40 / 75 post-mixing. In this document, the granules may additionally comprise pharmaceutically acceptable additives, such as an excipient, a disintegrant, or a lubricant. Furthermore, the post-mixing portion may additionally include at least one pharmaceutically acceptable additive selected from a disintegrant and a lubricant. [000186] In one example, the layer comprising the second release portion may comprise granules comprising the active ingredient, an excipient, a disintegrant and a lubricant, and a post-mixture portion comprising a disintegrant and a lubricant, but not limited to the same. [000187] In the present invention, the granules in the layer comprising the second release portion may comprise the active ingredient in an amount of 0.5 to 50% by weight, 0.5 to 30% by weight, or 0.5 to 10% by weight, based on the total weight of the second release portion. [000188] In the present invention, the granules in the layer comprising the second release portion may comprise an excipient in an amount of 20 to 95% by weight, 30 to 90% by weight, 40 to 90% by weight, 50 to 80% by weight or 60 to 80% by weight, based on the total weight of the second release portion. [000189] In the present invention, the granules in the layer comprising the second release portion may comprise a disintegrant in an amount of 0.1 to 20% by weight, 1 to 10% by weight, or 2 to 8% by weight, based on the total weight of the second release portion. [000190] In the present invention, the granules in the layer comprising the second release portion may comprise a lubricant in an amount of 0.1 to 20% by weight, 1 to 10% by weight, or 2 to 8% by weight, based on the total weight of the second release portion. [000191] In the present invention, the post-mixing portion in the layer comprising the second release portion can Petition 870250090236, dated 03 / 10 / 2025, pages 224 / 265 41 / 75 comprise a disintegrant in an amount of 1 to 30% by weight, 1 to 20% by weight, 5 to 20% by weight or 5 to 10% by weight, based on the total weight of the second release portion. [000192] In the present invention, the post-mix portion in the layer comprising the second release portion may comprise a lubricant in an amount of 0.1 to 20% by weight, 1 to 10% by weight, or 2 to 8% by weight, based on the total weight of the second release portion. [000193] In one example, the granules in the layer comprising the second release portion may comprise, based on the total weight of the second release portion, 0.5 to 50% by weight of the active ingredient, 20 to 95% by weight of an excipient, 0.1 to 20% by weight of a disintegrant and 0.1 to 10% by weight of a lubricant, and the post-mix portion may comprise, based on the total weight of the second release portion, 1 to 30% by weight of a disintegrant and 0.1 to 10% by weight of a lubricant, without being limited to the same. [000194] In another example, the granules in the layer comprising the second release portion may comprise, based on the total weight of the second release portion, 0.5 to 50% by weight of the active ingredient, 50 to 90% by weight of an excipient, 1 to 10% by weight of a disintegrant and 1 to 10% by weight of a lubricant, and the post-mixing portion may comprise, based on the total weight of the second release portion, 5 to 20% by weight of a disintegrant and 0.1 to 10% by weight of a lubricant, without being limited to the same. [000195] In another example, the granules in the layer comprising the second release portion may comprise, based on the total weight of the second release portion, 0.5 to 50% by weight of the active ingredient, 10 to 50% by weight of at least one of microcrystalline cellulose and lactose hydrate, 10 to 50% by weight of mannitol, 0.1 to 20% by weight of hydroxypropylcellulose and 0.1 to 10% by weight of sodium stearyl fumarate, and the post-mixing portion Petition 870250090236, dated 03 / 10 / 2025, pages 225 / 265 42 / 75 may comprise, based on the total weight of the second-release portion, 0.5 to 20% by weight of croscarmellose sodium and 0.1 to 10% by weight of sodium stearyl fumarate, but is not limited to these. [000196] In another example, the granules in the layer comprising the second release portion may comprise, based on the total weight of the second release portion, 0.5 to 50% by weight of the active ingredient, 10 to 30% by weight of microcrystalline cellulose, 20 to 70% by weight of mannitol, 0.5 to 20% by weight of hydroxypropylcellulose and 0.1 to 10% by weight of sodium stearyl fumarate, and the post-mixing portion may comprise, based on the total weight of the second layer, 0.5 to 20% by weight of croscarmellose sodium and 0.1 to 10% by weight of sodium stearyl fumarate, without being limited to the same. [000197] As the combined formulation according to the present invention, as described above, contains two pharmacologically active ingredients, namely sacubitrilvalsartan and an SGLT-2 inhibitor, such as dapagliflozin, in a single dosage unit, it can be useful in the treatment or prevention of heart failure, especially heart failure that is not sufficiently controlled with a single medication, alleviates the inconvenience of having to take two medications separately, and significantly improves patient adherence to medication. The combined formulation can be administered once daily, twice daily, three times daily, or four times daily, depending on the content of the active ingredients contained therein. [000198] Furthermore, as the combined formulation of the present invention is in the form of a double-layer tablet or drug-coated tablet, in which the first release portion comprising sacubitril-valsartan and the second release portion comprising the SGLT-2 inhibitor are physically separated from each other, it allows the inhibitor Petition 870250090236, dated 03 / 10 / 2025, pages 226 / 265 43 / 75 of SGLT-2 dissolves at a faster rate than sacubitrilvalsartan, so sacubitril-valsartan, which has low solubility in a low pH environment such as stomach acid, does not inhibit the dissolution of the SGLT-2 inhibitor, so all these ingredients have an immediate-release dissolution pattern. Thus, the combined formulation has the advantage that each of these ingredients can exhibit a rapid and sufficient pharmacological effect within the administration period. [000199] Additionally, the combined formulation according to the present invention has a synergistic therapeutic effect due to the combined use of sacubitril-valsartan and the SGLT-2 inhibitor, and exhibits high safety by suppressing the generation of impurities. [000200] In one example, in the combined formulation according to the present invention, the dissolution rate (by weight) of the SGLT-2 inhibitor (e.g., dapagliflozin) during a dissolution test (pH 1.2 buffer, 37 °C, 900 mL, 50 rpm) may be 50% or more, 60% or more, 70% or more, or 80% or more in 10 minutes, 80% or more, 85% or more, or 90% or more in 15 minutes, and 85% or more, 90% or more, or 95% or more in 30 minutes. [000201] In another example, in the combined formulation according to the present invention, the dissolution rate of sacubitril during a dissolution test (pH 1.2 buffer, 37 °C, 900 mL, 50 rpm) can be 10 to 40% after 30 minutes and 50% or less after 2 hours, without being limited to the same. [000202] In another example, in the compound preparation according to the present invention, the dissolution rate of valsartan during a dissolution test (pH 1.2 buffer, 37 °C, 900 mL, 50 rpm) can be 10 to 40% after 30 minutes and 50% or less after 2 hours, without being limited to the same. [000203] In another example, in the combined formulation according to the present invention, the dissolution rate (by weight) Petition 870250090236, dated 03 / 10 / 2025, pages 227 / 265 The 44 / 75 concentration of the SGLT-2 inhibitor (e.g., dapagliflozin) during a dissolution test (pH 6.8 buffer, 37 °C, 900 mL, 50 rpm) can be 50 to 95%, or 60 to 90% in 10 minutes, 80% or more, 85% or more, or 90% or more in 15 minutes, and 90% or more, or 95% or more in 30 minutes. [000204] In another example, in the combined formulation according to the present invention, the dissolution rate of sacubitril during a dissolution test (pH 6.8 buffer, 37 °C, 900 mL, 50 rpm) may be 80% or more, 90% or more, or 95% or more in 30 minutes, without being limited to the same. [000205] In another example, in the compound preparation according to the present invention, the dissolution rate of valsartan during a dissolution test (pH 6.8 buffer, 37 °C, 900 mL, 50 rpm) may be 80% or more, 90% or more, or 95% or more in 30 minutes, without being limited to the same. [000206] According to another embodiment of the present invention, the present invention relates to a method for preparing the combined formulation according to the present invention, the method comprising the steps of: (a) prepare a first-release moiety comprising sacubitril-valsartan or pharmaceutically acceptable salts thereof as an active ingredient; (b) prepare a second release portion comprising an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient; and (c) formulate the first release portion and the second release portion into a single solid formulation. [000207] In the present invention, in step (c), the combined formulation can be formulated in the form of a bilayer or multilayer tablet, or in the form of a drug-coated tablet with a core-shell structure. [000208] In the present invention, steps (a) and (b) do not necessarily need to be performed sequentially, and the Petition 870250090236, dated 03 / 10 / 2025, pages 228 / 265 45 / 75 step (b) can be performed after step (a) has been performed, or step (a) can be performed after step (b) has been performed, or steps (a) and (b) can be performed simultaneously. [000209] In the present invention, step (a) of preparing the first release portion may comprise the steps of: (a-1) mixing sacubitril-valsartan or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable additive; (a-2) preparing the granules; and (a-3) mixing the granules and a post-mixing portion. [000210] In the present invention, in step (a-1), sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof may be contained in the first release portion of the present invention in a molar ratio of 1:5 to 5:1, preferably 1:1, without being limited to the same. [000211] In the present invention, the pharmaceutically acceptable additive in step (a-1) or the post-mixing portion in step (a-3) may each comprise at least one selected from the group consisting of an excipient, a disintegrant and a lubricant. [000212]

[00223] In the present invention, the excipient (diluent) may, for example, be selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, magnesium aluminometasilicate, magnesium aluminate silicate, aluminum silicate, sodium silicate, potassium silicate, magnesium silicate, calcium silicate, lactose, lactose hydrate, lactose anhydride, calcium hydrogen phosphate, hydroxypropylcellulose, hydroxypropylmethylcellulose, dextrin, mannitol, sorbitol, starch, calcium phosphate monohydrate, calcium carbonate, sugars and any mixtures thereof, without being limited to the same. However, in the present invention, anhydrous calcium phosphate exhibits low compatibility with dapagliflozin and sacubitril. Petition 870250090236, dated 03 / 10 / 2025, pages 229 / 265 46 / 75 valsartan and is therefore not included as an excipient (diluent). [000213] In the present invention, the disintegrant may, for example, be selected from the group consisting of crospovidone, methylcellulose, cross-linked sodium carboxymethylcellulose (CMC Na cross-linked, C.CMC Na or croscarmellose sodium), calcium carboxymethylcellulose, sodium starch glycolate, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose, starch, pregelatinized starch, corn starch, potato starch, alginic acid or its sodium salt and any combinations thereof, without being limited to the same. [000214] In the present invention, the lubricant may, for example, be selected from the group consisting of calcium stearate, colloidal silicon dioxide (pyrogenic silica, Aerosil), glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc and any combinations thereof, without being limited to the same. [000215] In one example, in step (a-1), sacubitrilvalsartan or pharmaceutically acceptable salts thereof as an active ingredient, and a pharmaceutically acceptable additive selected from microcrystalline cellulose, mannitol, low-substituted hydroxypropylcellulose (L-HPC), croscarmellose sodium, sodium starch glycolate, colloidal silicon dioxide (pyrogenic silica, Aerosil), talc, magnesium stearate and any combinations thereof may be adjusted to appropriate levels and mixed to prepare granules. [000216] In another example, the mixture obtained in step (a1) may comprise sacubitril-valsartan or salts Petition 870250090236, dated 03 / 10 / 2025, pages 230 / 265 47 / 75 pharmaceutically acceptable compounds thereof as an active ingredient, and a pharmaceutically acceptable additive selected from microcrystalline cellulose, mannitol, low-substituted hydroxypropylcellulose (L-HPC), croscarmellose sodium, colloidal silicon dioxide (pyrogenic silica, Aerosil), talc, magnesium stearate and any combinations thereof. [000217] In another example, the mixture obtained in step (a1) may comprise sacubitril-valsartan or pharmaceutically acceptable salts thereof as an active ingredient, and a pharmaceutically acceptable additive selected from microcrystalline cellulose, low-substituted hydroxypropylcellulose (LHPC), sodium starch glycolate, colloidal silicon dioxide (pyrogenic silica, Aerosil), talc, magnesium stearate and any combinations thereof. [000218] In the present invention, the granule preparation step (a-2) can be carried out according to any granule preparation method known in the art, for example, by a dry granulation method. Specifically, a mixture of sacubitril-valsartan or pharmaceutically acceptable salts thereof as an active ingredient, and pharmaceutically acceptable additives, such as an excipient, a disintegrant or a lubricant, can be granulated using a roller compaction method or an agglomeration method. In this document, roller compaction refers to a granule preparation method by compacting the powder at a constant pressure while the powder passes between two rollers. The roller compaction method can be carried out using a roller compactor. The roller-compacted mixture can then be subjected to grinding and sieving processes using a Fitz mill, an oscillator, etc.as needed to obtain granules of the appropriate size. [000219] In the present invention, the post-mix portion in step (a-3) may comprise a disintegrant, a lubricant Petition 870250090236, dated 03 / 10 / 2025, pages 231 / 265 48 / 75 or a mixture thereof and, if necessary, may further comprise an excipient (diluent) or a binder. [000220] In one example, in step (a-3), the granules obtained in step (a-2) and a post-mixture portion comprising sodium starch glycolate, colloidal silicon dioxide (pyrogenic silica, Aerosil) and magnesium stearate can be adjusted to the appropriate proportions and mixed. [000221] In the present invention, the method may further comprise step (a-4) of compressing the mixture into tablets after step (a-3), depending on the formulation of the final combination. [000222] In the present invention, step (a-4) can be performed using a tablet press commonly used for pressing granules into tablets, for example, a rotary tablet press. [000223] In the present invention, the tablet obtained after compression of the mixture in step (a-4) can have various shapes. For example, the tablet can have an elliptical, rectangular, oval, triangular, almond-shaped, peanut-shaped, parallelogram, circular, pentagonal, hexagonal or trapezoidal shape, preferably a circular, oval or parallelogram shape. [000224] In the present invention, the content of the ingredients mixed during the preparation of the first release portion overlaps with those described above in relation to the first layer of the combined formulation according to the present invention and, therefore, its detailed description will be omitted below to avoid excessive complexity of the descriptive report. [000225] In the present invention, step (b) of preparing the second release portion may comprise step (b-1) of mixing an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive. [000226] In the present invention, the pharmaceutically acceptable additive in step (b-1) can be at least one selected from Petition 870250090236, dated 03 / 10 / 2025, pages 232 / 265 49 / 75 group consisting of an excipient, a disintegrant and a lubricant. [000227] In the present invention, the excipient (diluent) may, for example, be selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, magnesium aluminometasilicate, magnesium aluminate silicate, aluminum silicate, sodium silicate, potassium silicate, magnesium silicate, calcium silicate, lactose, lactose hydrate, lactose anhydride, calcium hydrogen phosphate, hydroxypropylcellulose, hydroxypropylmethylcellulose, dextrin, mannitol, sorbitol, starch, calcium phosphate monohydrate, calcium carbonate, sugars and any mixtures thereof, without being limited to the same. However, in the present invention, anhydrous calcium phosphate has low compatibility with dapagliflozin and sacubitrilvalsartan and, therefore, is not included as the excipient (diluent). [000228] In the present invention, the disintegrant may, for example, be selected from the group consisting of crospovidone, methylcellulose, cross-linked sodium carboxymethylcellulose (CMC Na cross-linked, C.CMC Na or croscarmellose sodium), calcium carboxymethylcellulose, sodium starch glycolate, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose, starch, pregelatinized starch, corn starch, potato starch, alginic acid or its sodium salt and any combinations thereof, without being limited to the same. [000229] In the present invention, the lubricant may, for example, be selected from the group consisting of calcium stearate, colloidal silicon dioxide (pyrogenic silica, Aerosil), glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, Petition 870250090236, dated 03 / 10 / 2025, pages 233 / 265 50 / 75 hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc and any combinations thereof, without being limited to the same. [000230] In one example, when the formulation of the combined formulation to be finally prepared is a bilayer tablet, in step (b-1), an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable additive selected from microcrystalline cellulose, lactose hydrate, mannitol, hydroxypropylcellulose, sodium stearyl fumarate, croscarmellose sodium and any combinations thereof may be adjusted to appropriate levels and mixed. [000231] In one example, when the formulation of the combined formulation to be finally prepared is a bilayer tablet, in step (b-1), an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable additive selected from microcrystalline cellulose, mannitol, hydroxypropylcellulose, sodium stearyl fumarate, croscarmellose sodium and any combinations thereof may be adjusted to appropriate levels and mixed. [000232] Furthermore, in the present invention, when the formulation of the combined formulation to be finally prepared is a bilayer tablet, the method may comprise, after step (b-1), the steps of: (b-2) preparing the granules; and (b3) mixing the granules with a post-mixing portion. [000233] In the present invention, the post-mixing portion in step (b-3) may comprise a disintegrant, a lubricant or a mixture thereof and, if necessary, may further comprise an excipient (diluent) or a binder, etc. [000234] In one example, in step (b-3), the granules obtained in step (b-2) and the post-mixture portion containing sodium stearyl fumarate and croscarmellose sodium can be Petition 870250090236, dated 03 / 10 / 2025, pages 234 / 265 51 / 75 adjusted for appropriate proportions and blended. [000235] In the present invention, in step (c), in order to prepare a combined formulation in the form of a bilayer tablet, the mixture (mixture of granules and post-mixing portion) for the first release portion, obtained in step (a-3), and the mixture (mixture of granules and post-mixing portion) for the second release portion, obtained in step (b-3), can be used as a mixture for the top layer of the bilayer tablet and a mixture for the bottom layer, respectively, or, conversely, as a mixture for the bottom layer and a mixture for the top layer, respectively, and can be compressed with a tablet press, thus preparing a bilayer tablet. [000236] Meanwhile, in the present invention, when the combined formulation to be finally prepared is a drug-coated tablet, in step (b-1), an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient and a coating agent may be adjusted to appropriate levels and mixed, thus preparing a coating solution. [000237] In the present invention, the coating agent is a hydrophilic polymer and may be, for example, at least one selected from the group consisting of hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyvinyl alcohol-macrogol graft copolymers, acrylic acid polymers and their salts, polymethacrylate, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymers (e.g., Eudragit® E, Evonik), carboxymethylcellulose (sodium salt and calcium salt), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethyl hydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone (povidone; PVP), vinylpyrrolidone-vinyl acetate copolymers (e.g., Petition 870250090236, dated 03 / 10 / 2025, pages 235 / 265 52 / 75 Kollidon® VA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan gum and mixtures thereof, without being limited to the same. Preferably, the coating agent may be hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), a copolymer grafted with polyvinyl alcohol and macrogol or a copolymer of poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) (for example, Eudragit® E, Evonik). [000238] Furthermore, in the present invention, the coating solvent used to prepare the coating solution may be ethanol, methanol, acetone, acetonitrile, tetrahydrofuran, hexane, methylene chloride, isopropyl alcohol, water, etc., or a mixture thereof. Preferably, ethanol, water, or a mixture thereof may be used as the coating solvent. [000239] In the present invention, to prepare the coating solution, at least one selected from the group consisting of plasticizers, lubricants, colorants, fragrances, surfactants, stabilizers, antioxidants, foaming agents, antifoaming agents, paraffin and waxes can be used as an additional additive for additional purposes such as coating efficiency, drug stability, appearance, color, protection, maintenance, agglutination, performance improvement and preparation process improvement. [000240] In step (c) of the present invention, in order to prepare a combined formulation in the form of a drug-coated tablet, the core containing sacubitril-valsartan or pharmaceutically acceptable salts thereof, obtained in step (a), preferably the tablet-shaped core obtained in step (a-4), can be coated with the coating solution for the second release portion, obtained in step (b-1), thus preparing a drug-coated tablet in which the core containing sacubitril-valsartan is coated with the drug. Petition 870250090236, dated 03 / 10 / 2025, pages 236 / 265 53 / 75 SGLT-2 inhibitor. In this document, coating can be performed using a conventional method that is used for drug coating in the art and, for example, a coating method using a rotary vessel coating machine can be used, without being limited to the same. [000241] In one example, the method for preparing the combined formulation in the form of a bilayer tablet may comprise the steps of: (a-1) mixing sacubitril-valsartan or pharmaceutically acceptable salts thereof with a pharmaceutically acceptable additive; (a-2) preparing granules; (a-3) preparing a mixture for the first release portion by mixing the granules with a post-mixing portion; (b-1) mixing an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive; (b-2) preparing granules; (b-3) preparing a mixture for the second release portion by mixing the granules with a post-mixing portion; and (c) compressing the mixture for the first release portion and the mixture for the second release portion into a bilayer tablet. However, the order in which steps (a-1), (a-2), (a-3), (b-1), (b-2) and (b-3) are performed is not particularly restricted. [000242] In another example, the method for preparing the combined formulation in the form of a drug-coated tablet may comprise the steps of: (a-1) mixing sacubitril-valsartan or pharmaceutically acceptable salts thereof with a pharmaceutically acceptable additive; (a-2) preparing granules; (a-3) preparing a mixture for the first-release portion by mixing the granules with a post-mixing portion; (a-4) compressing the mixture for the first-release portion into an uncoated tablet; (b-1) preparing a coating solution by mixing an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof with a coating agent; and (c) preparing a drug-coated tablet. Petition 870250090236, dated 03 / 10 / 2025, pages 237 / 265 54 / 75 coating the surface of the uncoated tablet comprising the first release portion with the coating solution. However, the order in which steps (a-1), (a2), (a-3), (a-4) and (b-1) are performed is not particularly restricted. [000243] The preparation method according to the present invention may further comprise a step of coating the resulting combined formulation, especially the combined formulation in the form of a bilayer tablet, with a pharmaceutical immediate-release film coating agent, which may be commonly used in the art according to a conventional method. In one example, based on the total weight of the uncoated bilayer tablet, a moisture-proof film coating of about 3% may be achieved with, but not limited to, the Opadry II coating solution. [000244] The present invention will now be described in more detail by means of examples. These examples are intended only to illustrate the present invention in more detail, and it will be evident to those skilled in the art that the scope of the present invention, according to the object of the present invention, is not limited by these examples. EXAMPLES (Comparative Examples 1 and 2) Preparation of Single-Layer Tablets Containing Sacubitril-Valsartan and Dapagliflozin [000245] To prepare single-combination tablets by physical mixing of sacubitril-valsartan and dapagliflozin, sacubitril-valsartan, microcrystalline cellulose, low-substituted hydroxypropylcellulose, sodium starch glycolate, colloidal silicon dioxide, talc, and magnesium stearate were mixed according to the composition shown in Table 1 below, and the mixture was compacted using a roller compactor (TFC-LAB, Freund Vector) under conditions of hydraulic pressure of 5 MPa, roller speed of 1 rpm, and speed of Petition 870250090236, dated 03 / 10 / 2025, pages 238 / 265 A 55 / 75 screw mill at 5 rpm was used to form dry granules. The granules were sieved through a sieve with a 20 mesh (0.86 mm) mesh size and then post-mixed with sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate, thus preparing the final mixture. During the preparation of the dry granules (Comparative Example 1) or during post-mixing (Comparative Example 1), dapagliflozin, microcrystalline cellulose, D-mannitol, hydroxypropylcellulose, croscarmellose sodium, and sodium stearyl fumarate were added, thus preparing the final mixture. The final mixture was then compressed using a tablet press (AUTOTAB-200TR, Ichihashi Seiki) at a pressure of 10 kN, thus preparing single-layer tablets with a hardness of approximately 15 kP. (Table 1) Process Ingredients Concentrations (mg / tablet) Comparative Example 1 Comparative Example 2 Mixed tablet (during simultaneous granulation) Mixed tablet (during post-mixing) Compaction Sacubitril-valsartan trisodium trihydrate 228.34 228.34 Dapagliflozin propanediol 12.30 Microcrystalline cellulose 53.66 53.66 Low-substituted hydroxypropyl cellulose 50.00 50.00 Sodium starch glycolate 20.00 20.00 Colloidal silicon dioxide 1.60 1.60 Talc 4.00 4.00 Magnesium stearate 6.00 6.00 Final mixture Dapagliflozin propanediol 12.30 Sodium starch glycolate 20.00 20.00 Colloidal silicon dioxide 2.40 2.40 Magnesium stearate 4.00 4.00 (Examples 1 and 2) Preparation of Bilayer Tablets Containing Sacubitril-Valsartan and Dapagliflozin [000246] Sacubitril-valsartan, microcrystalline cellulose, Petition 870250090236, dated 03 / 10 / 2025, pages 239 / 265 56 / 75 low-substituted hydroxypropylcellulose, sodium starch glycolate, colloidal silicon dioxide, talc, and magnesium stearate were mixed according to the composition shown in Table 2 below, and the mixture was compacted using a roller compactor (TFC-LAB, Freund Vector) under conditions of 5 MPa hydraulic pressure, 1 rpm roller speed, and 5 rpm screw speed to form dry granules that were then sieved through a 20 mesh (0.86 mm) sieve. The sieved granules were subsequently mixed with sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate, thus preparing the final mixture containing sacubitril-valsartan.Meanwhile, dapagliflozin, microcrystalline cellulose, lactose hydrate, D-mannitol, hydroxypropylcellulose, croscarmellose sodium, and sodium stearyl fumarate were mixed, and the mixture was compacted using a roller compactor (TFC-LAB, Freund Vector) under conditions of 5 MPa hydraulic pressure, 1 rpm roller speed, and 5 rpm screw speed to form dry granules that were then sieved through a 20 mesh (0.86 mm) sieve. The sieved granules were subsequently mixed with sodium stearyl fumarate, thus preparing the final mixture containing dapagliflozin.The final mixture containing sacubitrilvalsartan, which constitutes a lower layer, and the final mixture containing dapagliflozin, which constitutes an upper layer, were compressed using a tablet press (AUTOTAB200TR, Ichihashi Seiki) and an oval punch (17.5 mm wide x 9 mm long) at a pressure of 10 kN, thus preparing bilayer tablets (hardness: approximately 15 kP). (Table 2) Processes Ingredients Contents (mg / tablet) Example 1 Example 2 Bilayer tablet (Cellulose) Bilayer tablet (Hydrated Petition 870250090236, dated 03 / 10 / 2025, pages 240 / 265 57 / 75 Microcrystalline cellulose (a) lactose) Sacubitril-valsartan Compaction Sacubitril-valsartan trisodium trihydrate 228.34 228.34 Microcrystalline cellulose 53.66 53.66 Low-substituted hydroxypropyl cellulose 50.00 50.00 Sodium starch glycolate 20.00 20.00 Colloidal silicon dioxide 1.60 1.60 Talc 4.00 4.00 Magnesium stearate 6.00 6.00 Final mixture Sodium starch glycolate 20.00 20.00 Colloidal silicon dioxide 2.40 2.40 Magnesium stearate 4.00 4.00 Total quantity 390 390 Dapagliflozin Compaction Dapagliflozin propanediol 12.30 12.30 Microcrystalline cellulose 99.10 _ Lactose hydrate _ 99.10 Anhydrous calcium phosphate _ _ D-mannitol 90.00 90.00 Hydroxypropylcellulose 10.00 10.00 Sodium stearyl fumarate 12.00 12.00 Final mixture Croscarmellose sodium 20.00 20.00 Sodium stearyl fumarate 8.00 8.00 Total quantity 251.4 251.4 (Example 3) Preparation of a Coated Tablet Containing Sacubitril-Valsartan and Dapagliflozin [000247] The final mixture containing sacubitril-valsartan was prepared in the same manner as in Example 1 and then compressed using a tablet press, thus obtaining uncoated tablets. To prepare a coating solution for the drug, a coating solution containing dapagliflozin, povidone, and a polyvinyl macrogol alcohol copolymer in 200 mg of purified water and 200 mg of ethanol per tablet was prepared according to the composition shown in Table 3 below. The surface of the uncoated tablet was then coated with the coating solution using a high-speed coating system (XENA-IV, Raon) under the temperature conditions of Petition 870250090236, dated 03 / 10 / 2025, pages 241 / 265 58 / 75 air supply temperature of 55 °C, air discharge temperature of 45 °C, rotating vessel speed of 6 rpm and gauge air pressure of 2 to 4 kgf / cm2. (Table 3) Processes Ingredients Concentrations (mg / tablet) Example 3 Drug-coated tablet Sacubitrilvalsartan Compaction Sacubitril-valsartan trisodium trihydrate 228.34 Microcrystalline cellulose 53.66 Low-substituted hydroxypropyl cellulose 50.00 Sodium starch glycolate 20.00 Colloidal silicon dioxide 1.60 Talc 4.00 Magnesium stearate 6.00 Final mixture Sodium starch glycolate 20.00 Colloidal silicon dioxide 2.40 Magnesium stearate 4.00 Total quantity 390 Dapagliflozin Drug coating Dapagliflozin propanediol 12.30 Povidone 2.80 Macrogol-polyvinyl alcohol copolymer 20.00 Total quantity 35.1 (Comparative Example 3) Preparation of a Core-Containing Sacubitril-Valsartan and Dapagliflozin Tablet [000248] The final mixture containing sacubitril-valsartan for an inner-core tablet and the final mixture containing dapagliflozin for an outer-core tablet were prepared using the same compositions as in Example 1. The final mixture containing sacubitril-valsartan was compressed using a tablet press, thus preparing the tablets with Petition 870250090236, dated 03 / 10 / 2025, pages 242 / 265 59 / 75 inner core. Half of the final mixture containing dapagliflozin and the tablets with an inner core were filled sequentially, and then the remaining final mixture containing dapagliflozin was filled and pressure was applied to it, thus preparing the tablets with a core. At this point, the compression pressure was adjusted between 7 and 10 kN, and no pre-compression was applied. (Comparative Example 4) Preparation of a Polycap containing one sacubitril-valsartan tablet and one dapagliflozin tablet. [000249] The final mixture containing sacubitril-valsartan and the final mixture containing dapagliflozin were prepared using the same compositions as in Example 1. The final sacubitril-valsartan mixture and the final dapagliflozin mixture were compressed separately using a tablet press, thus preparing two single-layer tablets. These two tablets were packaged in a capsule using a capsule filling machine (GKF2500, Bosch) under air pressure conditions of 5 to 7 bar (500 to 700 kPa) and a filling speed of 30 to 150 °C / min, thus preparing a capsule. As base material for the capsule, an HPMC capsule with a water content of about 3 to 7%, gelatin with a water content of about 13 to 16%, and PEG-gelatin with a water content of about 10 to 14% were used. (Comparative Example 5) Change in Excipient Ingredients in Bilayer Tablets Containing Sacubitril-Valsartan and Dapagliflozin [000250] In order to examine changes in the dissolution patterns or stability of combined tablets, depending on the excipient ingredients, a bilayer tablet was prepared according to the same preparation method as in Example 1, except that microcrystalline cellulose was used as Petition 870250090236, dated 03 / 10 / 2025, pages 243 / 265 60 / 75 an excipient in the preparation of the final mixture containing dapagliflozin was changed to anhydrous calcium phosphate, as shown in Table 4 below. (Table 4) Process Ingredients Concentrations (mg / tablet) Example Comparative 5 Bilayer tablet (anhydrous calcium phosphate) Sacubitril-valsartan Compaction Sacubitril-valsartan trisodium trihydrate 228.34 Microcrystalline cellulose 53.66 Low-substituted hydroxypropyl cellulose 50.00 Sodium starch glycolate 20.00 Colloidal silicon dioxide 1.60 Talc 4.00 Magnesium stearate 6.00 Final mixture Sodium starch glycolate 20.00 Colloidal silicon dioxide 2.40 Magnesium stearate 4.00 Total quantity 390 Dapagliflozin Compaction Dapagliflozin propanediol 12.30 Microcrystalline cellulose _ Lactose hydrate _ Anhydrous calcium phosphate 99.10 D-mannitol 90.00 Hydroxypropylcellulose 10.00 Sodium stearyl fumarate 12.00 Final mixture Croscarmellose sodium 20.00 Sodium stearyl fumarate 8.00 Total quantity 251.4 (Experimental Example 1) Evaluation of Dissolution for Each Combined Formulation [000251] The ingredients sacubitril-valsartan and dapagliflozin are drugs that exhibit a rapid absorption rate, with a time to peak blood concentration (Tmax) of 2 hours or less after drug administration, and high bioavailability, of approximately 80% or more. Dapagliflozin is Petition 870250090236, dated 03 / 10 / 2025, pp. 244 / 265 61 / 75 is characterized by high solubility at all pH levels, but sacubitril-valsartan is characterized by its solubility decreasing as the pH decreases. Considering these characteristics, the following experiment was conducted to confirm whether both ingredients would exhibit immediate release in buffers of pH 1.2 and pH 6.8 and, thus, present dissolution profiles similar to those of the reference drugs. [000252] Specifically, for the combined formulations containing 10 mg of dapagliflozin and 200 mg of sacubitril / valsartan, prepared in Examples 1 to 3 and Comparative Examples 1 to 5, the dissolution of dapagliflozin, sacubitril, and valsartan was evaluated. Considering the site and rate of absorption of each drug, the comparison of drug release at low pH and high pH was performed under the following test and analysis conditions. The dissolution rates of each ingredient in the combined formulation in pH 1.2 buffer and pH 6.8 buffer were compared with those of the single reference drugs, Forxiga Tab™ (dapagliflozin propanediol hydrate) 10 mg and Entresto™ tablet (sacubitril / valsartan) 200 mg, and the results are shown in Tables 5 to 10 below and FIGS. 1 to 6. [000253]<Condições do teste de dissolução> Dissolution test solutions: pH 1.2 buffer (900 mL) and pH 6.8 buffer (900 mL) Dissolution device: Paddle Rotation speed: 50 rpm Temperature: 37 °C [000254]

[00277] <Condições de análise - LC> Column: Inertsil C8 (4.6 x 150 mm, 5 μm) or equivalent column. Flow rate: 1.5 ml / min. Column temperature: 40 °C. Injection volume: 20 μE. Mobile phase: pH 2.0 buffer; ACN = 60:40 Petition 870250090236, dated 03 / 10 / 2025, pages 245 / 265 62 / 75 pH 2.0 buffer: Dissolve 3.48 g of monopotassium phosphate in 1000 mL of water and adjust the pH to 2.0 with phosphoric acid. (Table 5) Time-dependent dissolution rate (%) of dapagliflozin in pH 1.2 buffer Dissolution rate (%) Example Comp. 1 Example Comp. 2 Example Comp. 3 Example Comp. 4 Example Comp. Example 1 Example 2 Example 3 Example of Ref. 0 min 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 5 min 0.0 1.1 58.2 20.0 21.1 65.2 60.1 73.5 66.8 10 min 0.5 2.5 73.2 35.2 39.2 90.5 87.2 96.2 94.6 15 min 1.2 3.8 86.5 48.2 53.2 95.1 92.1 98.1 98.2 30 min 1.9 5.2 88.1 68.2 72.7 98. 1 95, 3 99, 0 98, 5 45 min 3.7 7.2 91.2 78, 1 85, 7 98, 9 96, 1 ​​99.2 99, 1 f2 (similarity factor) 4 5 46 20 20 81 64 76 - (Table 6) Time-dependent dissolution rate (%) of sacubitril in pH 1.2 buffer Dissolution rate (%) Example Comp. 1 Example Comp. 2 Example Comp. 3 Example Comp. 4 Example Comp. Example 1 Example 2 Example 3 Example of Ref. 0 min 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 5 min 1.1 2.1 0.5 1.5 1.0 2.3 0.8 0.7 0.6 10 min 1.5 3.2 4.0 4.2 9.3 7.4 5.2 6.0 6.3 15 min 2.5 4.5 8.0 10.0 21.3 13.6 10.0 11.0 12.0 30 min 3.7 6.7 13.3 21.3 38.8 30.1 22.3 26.0 25.3 45 min 5.4 8.9 18.2 27.1 42.9 38.0 28.7 32.0 33.8 f2 (similarity factor) 41 44 54 73 55 76 78 94 - (Table 7) Time-dependent dissolution rate (%) of valsartan in pH 1.2 buffer Dissolution rate (%) Example Comp. 1 Example Comp. 2 Example Comp. 3 Example Comp. 4 Example Comp. Example 1 Example 2 Example 3 Example of Ref. 0 min 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 5 min 1.0 2.2 0.1 1.8 2.4 2.5 0.7 0.3 0.6 10 min 1.9 3.3 1.1 5.2 8.8 7.9 4.8 5.0 5.5 15 min 2.7 4.2 1.5 11.8 19.6 14.5 11.0 9.2 10.5 30 min 3.8 6.6 1.3 22.5 36.1 31.1 23.0 26.1 22.6 45 min 5, 3 8, 8 2,1 29,2 41,0 38, 4 29, 1 33, 0 30, 3 f2 (factor 44 47 41 94 54 64 96 83 _ Petition 870250090236, dated 03 / 10 / 2025, pages 246 / 265 63 / 75 of similarity) (Table 8) Time-dependent dissolution rate (%) of dapagliflozin in pH 6.8 buffer Dissolution rate (%) Example Comp. 1 Example Comp. 2 Example Comp. 3 Example Comp. 4 Example Comp. Example 1 Example 2 Example 3 Example of Ref. 0 min 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 5 min 26.8 30.2 40.0 25.1 24.2 47.1 40.5 71.2 48.0 10 min 47.0 51.0 75.3 35.1 38.4 82.1 79.1 88.9 81.6 15 min 60.3 63.2 82.3 47.5 48.5 93.0 90.4 95.2 92.0 30 min 71.5 74.8 86.1 65.2 67.5 97.1 94.2 98.0 98.2 45 min 74.0 78.0 90.1 67.1 69.7 99.0 96.7 99.0 98.6 f2 (similarity factor) 29 32 54 24 25 95 70 50 - (Table 9) Time-dependent dissolution rate (%) of sacubitril in pH 6.8 buffer Dissolution rate (%) Example Comp. 1 Example Comp. 2 Example Comp. 3 Example Comp. 4 Example Comp. Example 1 Example 2 Example 3 Example of Ref. 0 min 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 5 min 32.8 28.1 13.2 16.7 15.2 20.1 15.1 18.1 19.8 10 min 53.6 48.5 30.5 43.2 40.1 50.3 43.2 46.2 49.1 15 min 76.4 63.2 47.2 68.2 65.0 72.1 66.0 67.0 71.0 30 min 82.7 72.1 91.9 87.2 81.2 98.1 95.2 96.0 97.9 45 min 87.4 75.9 95.7 91.3 86.0 99.2 97.1 97.2 98.9 f2 (similarity factor) 50 41 44 60 50 96 70 79 _ (Table 10) Time-dependent dissolution rate (%) of valsartan in pH 6.8 buffer Dissolution rate (%) Example Comp. 1 Example Comp. 2 Example Comp. 3 Example Comp. 4 Example Comp. Example 1 Example 2 Example 3 Example of Ref. 0 min 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 5 min 32.6 27.1 14.5 17.1 16.1 17.1 14.1 19.1 20.4 10 min 54.0 49.2 32.2 44.1 42.1 44.1 44.2 47.3 49.7 15 min 69.8 64.2 49.5 69.6 67.1 69.6 65.0 68.2 71.7 30 min 82.8 73.1 92.3 88.3 83.5 88.3 96.1 96.5 98.7 45 min 87.9 77.2 96.1 93.2 89.2 93.2 98.1 96.9 99.7 f2 (factor 51 42 46 62 53 62 67 83 _ Petition 870250090236, dated 03 / 10 / 2025, pages 247 / 265 64 / 75 of similarity) [000255] As demonstrated in Tables 5 to 10 above, it was confirmed that, in Comparative Examples 1 and 2, which are single-layer tablets containing physically mixed sacubitril-valsartan and dapagliflozin, sacubitril-valsartan and dapagliflozin were released simultaneously, and in the process in which the two ingredients were dissolved simultaneously in pH 1.2 buffer and pH 6.8 buffer, the two components transformed into a sticky state and inhibited each other's dissolution, thus delaying dissolution. In particular, in pH 1.2 buffer, the dissolution rates of both ingredients at 45 minutes were 10% or less. [000256] In the case of the core tablet of Comparative Example 3, designed so that sacubitril-valsartan was distributed in the inner core tablet layer and dapagliflozin was distributed in the outer tablet layer, it was confirmed that the disintegration of the inner core tablet layer began after the disintegration of the outer tablet layer had progressed and, therefore, the dapagliflozin present in the outer tablet layer showed a rapid dissolution profile similar to that of the reference drug, but the sacubitril-valsartan present in the inner core tablet layer showed a relatively slow dissolution profile compared to the reference drug. [000257] In the case of the polymeric capsule of Comparative Example 4, where the single sacubitrilvalsartan tablet and the single dapagliflozin tablet were placed in a capsule, tablet disintegration begins after the capsule dissolves, and the dissolution rate in the initial stage (5 or 10 minutes) was relatively low compared to that of the reference drug, and the dissolution rate gradually increased after 15 minutes, but the dissolution rate of Petition 870250090236, dated 03 / 10 / 2025, pages 248 / 265 The 65 / 75 concentration of dapagliflozin was significantly lower than that of the reference drug, even after 45 minutes in pH 1.2 and pH 6.8 buffers. [000258] Meanwhile, in the case of the bilayer tablets of Examples 1 and 2, in which sacubitril-valsartan and dapagliflozin were placed in separate layers, the bilayer tablets showed dissolution profiles similar to those of the reference drugs in pH 1.2 and pH 6.8 buffers with respect to all ingredients (sacubitril, valsartan and dapagliflozin). However, in the case of the bilayer tablet of Comparative Example 5, which contained anhydrous calcium phosphate as an excipient instead of microcrystalline cellulose of Example 1 or lactose hydrate of Example 2, it was shown that the dissolution profile of the dapagliflozin tablet portion was relatively slow compared to that of the reference drug, because anhydrous calcium phosphate is insoluble in water and has a high density. [000259] In the case of the drug-coated tablet from Example 3, where the core containing sacubitril-valsartan was coated with the drug dapagliflozin, it was confirmed that, since the moment when dapagliflozin encountered the dissolution test solution was the fastest, the initial dissolution rate of dapagliflozin at 5 or 10 minutes tended to be slightly faster than that of the reference drug, but the dissolution profile of dapagliflozin at a later time was similar to that of the reference drug, and sacubitril and valsartan showed dissolution profiles similar to those of the reference drug under all conditions (pH 1.2 and pH 6.8 buffers). (Experimental Example 2) Evaluation of the Stability of Each Combined Formulation against Impurity Generation [000260] Sacubitril-valsartan is relatively stable to heat and water and exhibits good compatibility with commonly used excipients. However, dapagliflozin has greater Petition 870250090236, dated 03 / 10 / 2025, pages 249 / 265 66 / 75 probability of being structurally modified by external factors, such that there are more than 80 known types of impurities. Thus, in the development of dapagliflozin formulations, it is essential to evaluate the stability of dapagliflozin against the generation of impurities. [000261] Consequently, stability against impurity generation was assessed on the combined formulations prepared in Examples 1 to 3 and Comparative Examples 1 to 5. The tendency for increased dapagliflozin impurities in samples prepared according to formulation and excipient types was evaluated by exposure to accelerated conditions (40 °C and 75% RH) and stress conditions (60 °C) for 2 weeks, and the results are shown in FIGS. 7 to 4-0. The analysis conditions for impurities are as follows. As a reference example, the results of the impurity analysis for Forxiga Tab™ (propanediol dapagliflozin hydrate) 10 mg are shown. [000262]<Condições de análise - LC> Column: Waters X-Bridge C18 (4.6 x 150 mm, 3.5 pm) or equivalent column. Flow rate: 1.0 ml / min Column temperature: 50 °C Injection volume: 10 pL Mobile phase: A - ACN: buffer pH 2.5 = 10:90, B - MeOH: buffer pH 2.5 = 90:10 pH 2.5 buffer: Dissolve 3.12 g of monosodium phosphate dihydrate in 1000 mL of water and adjust the pH to 2.5 with phosphoric acid. (Table 11) Time (min) A (%) B (%) 0 60 40 5 60 40 40 40 60 50 25 75 58 25 75 60 60 40 Petition 870250090236, dated 03 / 10 / 2025, pages 250 / 265 67 / 75 70 60 40 [000263] As shown in FIGS. 7 to 4-0¼ it can be confirmed that, in Comparative Examples 1 and 2, which are individual combined tablets in which sacubitrilvalsartan and dapagliflozin are not separated from each other but exist while influencing each other, sacubitrilvalsartan, which has a high moisture absorption property, absorbed moisture during accelerated exposure and affected dapagliflozin, and therefore the level of unknown impurities (at RRT 1.59) generated by moisture under accelerated exposure conditions tended to increase. [000264] In the case of the core tablet of Comparative Example 3, tablet formation was performed using dapagliflozin as the outer tablet layer surrounding the inner core tablet layer, and during tablet formation, high compression pressure was applied in all directions to maintain the shape. For this reason, unknown impurities (with an RRT of 0.38), which tended to increase with heat, were detected at high levels from the initial stage and tended to increase further during exposure to accelerated and stress conditions. [000265] However, it can be confirmed that, in the case of the bilayer tablets of Examples 1 and 2, stability against the generation of impurities was generally good. However, it can be confirmed that, in the case of the bilayer tablet of Comparative Example 5, which contains anhydrous calcium phosphate as an excipient, the compatibility between dapagliflozin and anhydrous calcium phosphate was not good and, for this reason, the unknown impurity (with an RRT of 0.74) increased significantly when exposed to moisture and heat, and the increase in the unknown impurity due to heat was greater. [000266] It can be confirmed that, in the case of the drug-coated tablet of Example 3, since the Petition 870250090236, dated 03 / 10 / 2025, pages 251 / 265 68 / 75 dapagliflozin was partially exposed to heat during the drug coating process, the detection level of unknown impurities (at RRT 0.74) tended to be slightly high, but the amount detected was much lower than that in the core tablet of Comparative Example 3. (Example 4) Preparation of a bilayer tablet containing sacubitril-valsartan and dapagliflozin [000267] Sacubitril-valsartan, microcrystalline cellulose, D-mannitol, low-substituted hydroxypropylcellulose, croscarmellose sodium, colloidal silicon dioxide, talc, and magnesium stearate were mixed according to the composition shown in Table 12 below, and the mixture was fed into a roller compactor, thus preparing dry granules. The granules were subsequently mixed with croscarmellose sodium and colloidal silicon dioxide, and the resulting mixture was then post-mixed with magnesium stearate, thus preparing a final mixture containing sacubitril-valsartan (first mixture). Meanwhile, dapagliflozin propanediol, microcrystalline cellulose, D-mannitol, hydroxypropylcellulose, croscarmellose sodium, and sodium stearyl fumarate were mixed and fed into a roller compactor, preparing dry granules.Next, the granules were mixed with croscarmellose sodium, and the resulting mixture was subsequently mixed with sodium stearyl fumarate, thus preparing a final mixture containing dapagliflozin (second mixture). The final mixture containing sacubitril-valsartan, which constitutes a lower layer, and the final mixture containing dapagliflozin, which constitutes an upper layer, were compressed using a tablet press (AUTOTAB-200TR, Ichihashi Seiki) and an oval punch (17.5 mm wide x 9 mm long) at a pressure of 10 kN, thus preparing bilayer tablets. Petition 870250090236, dated 03 / 10 / 2025, pages 252 / 265 69 / 75 (hardness: about 15 kP). (Table 12) Processes Ingredients Concentrations (mg / tablet) Example 4 Bilayer tablet (Microcrystalline cellulose) Sacubitrilvalsartan (portion of the bottom layer) Dry granulation Sacubitril-valsartan trisodium trihydrate 228.3 Microcrystalline cellulose 25.0 D-mannitol 19.7 Low-substituted hydroxypropyl cellulose 59.0 Croscarmellose sodium 20.0 Colloidal silicon dioxide 1.5 Talc 4.0 Magnesium stearate 6.0 Second mixture Croscarmellose sodium 20.0 Colloidal silicon dioxide 2.5 Final mixture Magnesium stearate 4.0 Total quantity 390 Dapagliflozin (portion of the top layer) Compaction Dapagliflozin propanediol 12.3 Microcrystalline cellulose 39.4 D-mannitol 113. 6 Hydroxypropylcellulose 10.0 Sodium stearyl fumarate 8.4 Second mixture Croscarmellose sodium 20.0 Final mixture Sodium stearyl fumarate 6.3 Total quantity 210 (Experimental Example 3) Evaluation of Tablet Dissolution in a Bilayer [000268] In order to evaluate the dissolution of each active ingredient in the bilayer tablet containing sacubitrilvalsartan and dapagliflozin, prepared in Example 4, the dissolution profile of each active ingredient in pH 1.2 buffer was analyzed in the same way as in Experimental Example 1, and the results are presented in Tables 13 to 15 below. (Table 13) Dapagliflozin in pH 1.2 buffer Example 4 5 min Dissolution rate (%) 44.0 Petition 870250090236, dated 03 / 10 / 2025, pages 253 / 265 70 / 75 (min to max) (38.8 to 50.8) Deviation (%) 5.0 10 min Dissolution rate (%) (min to max) 74.8 (71.2 to 80.9) Deviation (%) 4.2 15 min Dissolution rate (%) (min to max) 84.8 (80.2 to 92.6) Deviation (%) 5.4 30 min Dissolution rate (%) (min to max) 96.5 (94.2 to 98.5) Deviation (%) 1.8 45 min Dissolution rate (%) (min to max) 97.5 (95.3 to 99.1) Deviation (%) 1.7 (Table 14) Sacubitril in pH 1.2 buffer Example 4 5 min Dissolution rate (%) (min to max) 3.8 (2.1 to 4.7) Deviation (%) 1.2 10 min Dissolution rate (%) (min to max) 10.1 (7.4 to 11.6) Deviation (%) 1.9 15 min Dissolution rate (%) (min to max) 16.4 (14.0 to 19.1) Deviation (%) 2.1 30 min Dissolution rate (%) (min to max) 27.6 (26.2 to 29.7) Deviation (%) 1.7 45 min Dissolution rate (%) (min to max) 33.5 (32.0 to 34.4) Deviation (%) 1.1 (Table 15) Valsartan in pH 1.2 buffer Example 4 5 min Dissolution rate (%) (min to max) 4.1 (1.8 to 4.5) Deviation (%) 1.1 10 min Dissolution rate (%) (min to max) 9.8 (7.3 to 11.4) Deviation (%) 1.8 15 min Dissolution rate (%) (min to max) 15.3 (13.8 to 18.7) Deviation (%) 2.0 30 min Dissolution rate (%) (min to max) 28.2 (27.1 to 30.2) Deviation (%) 1.8 45 min Dissolution rate (%) (min to max) 34.1 (33.1 to 34.5) Petition 870250090236, dated 03 / 10 / 2025, pages 254 / 265 71 / 75 Deviation (%) 1.3 [000269] As shown in Tables 13 to 15, in the case of the bilayer tablet of Example 4, in which sacubitril-valsartan and dapagliflozin were located in separate layers, the bilayer tablet showed excellent dissolution profiles in pH 1.2 buffer with respect to all ingredients (sacubitril, valsartan and dapagliflozin). (Examples 5 and 6) Preparation of a Bilayer Tablet Containing Sacubitril-Valsartan and Dapagliflozin [000270] Sacubitril-valsartan, microcrystalline cellulose, low-substituted hydroxypropylcellulose, sodium starch glycolate, colloidal silicon dioxide, talc, and magnesium stearate were mixed according to the composition shown in Table 16 below, and the mixture was compacted using a roller compactor (TFC-LAB, Freund Vector) under conditions of 5 MPa hydraulic pressure, 1 rpm roller speed, and 5 rpm screw speed to form dry granules. The granules were sieved through a sieve having a 20 mesh (0.86 mm) mesh size. The sieved granules were subsequently mixed with sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate, thus preparing a final mixture containing sacubitril-valsartan.Meanwhile, dapagliflozin, microcrystalline cellulose, lactose hydrate, D-mannitol, hydroxypropylcellulose, croscarmellose sodium, and sodium stearyl fumarate were mixed and compacted using a roller compactor (TFC-LAB, Freund Vector) under hydraulic pressure conditions of 5 MPa, roller speed of 1 rpm, and screw speed of 5 rpm to form dry granules that were then sieved through a sieve having a mesh size of 20 mesh (0.86 mm). The sieved granules were subsequently mixed with sodium stearyl fumarate, thus preparing a final mixture containing dapagliflozin. The final mixture containing sacubitril-valsartan, which constitutes a bottom layer, and a. Petition 870250090236, dated 03 / 10 / 2025, pages 255 / 265 72 / 75 final mixture containing dapagliflozin, which constitutes an upper layer, were compressed using a tablet press (AUTOTAB-200TR, Ichihashi Seiki) and an oval punch (17.5 mm wide x 9 mm long) at a pressure of 10 kN, thus preparing bilayer tablets (hardness: approximately 15 kP). (Table 16) Process Ingredients Concentrations (mg / tablet) Example 5 Example 6 Sacubitril-valsartan Compaction Sacubitril-valsartan trisodium hemipentahydrate 226.2 226.2 Microcrystalline cellulose 55.8 55.8 Low-substituted hydroxypropyl cellulose 50.00 50.00 Sodium starch glycolate 20.00 20.00 Colloidal silicon dioxide 1.60 1.60 Talc 4.00 4.00 Magnesium stearate 6.00 6.00 Final mixture Sodium starch glycolate 20.00 20.00 Colloidal silicon dioxide 2.40 2.40 Magnesium stearate 4.00 4.00 Total quantity 390 390 Dapagliflozin Compaction Dapagliflozin Propanediol 12.30 12.30 Microcrystalline cellulose 99.10 Lactose hydrate 99.10 Anhydrous calcium phosphate D-mannitol 90.00 90.00 Hydroxypropylcellulose 10.00 10.00 Sodium stearyl fumarate 12.00 12.00 Final mixture Croscarmellose sodium 20.00 20.00 Sodium stearyl fumarate 8.00 8.00 Total quantity 251.4 251.4 (Example 7) Preparation of a Coated Tablet Containing Sacubitril-Valsartan and Dapagliflozin [000271] A final mixture containing sacubitril-valsartan was prepared in the same manner as in Example 5 and then compressed using a tablet press, obtaining Petition 870250090236, dated 03 / 10 / 2025, pages 256 / 265 73 / 75 uncoated tablets. To prepare a coating solution for the drug, a coating solution containing dapagliflozin, povidone, and a polyvinyl alcohol macrogol copolymer in 200 mg of purified water and 200 mg of ethanol per tablet was prepared according to the composition shown in Table 17 below. Then, the surface of the uncoated tablet was coated with the coating solution using a high-speed coating system (XENA-IV, Raon) under conditions of an air supply temperature of 55 °C, an air discharge temperature of 45 °C, a rotating vessel speed of 6 rpm, and a gauge air pressure of 2 to 4 kgf / cm². (Table 17) Process Ingredients Concentrations (mg / tablet) Example 7 Sacubitril-valsartan Compaction Sacubitril-valsartan trisodium hemipentahydrate 226.2 Microcrystalline cellulose 55.8 Low-substituted hydroxypropyl cellulose 50.00 Sodium starch glycolate 20.00 Colloidal silicon dioxide 1.60 Talc 4.00 Magnesium stearate 6.00 Final mixture Sodium starch glycolate 20.00 Colloidal silicon dioxide 2.40 Magnesium stearate 4.00 Total quantity 390 Dapagliflozin Drug coating Dapagliflozin propanediol 12.30 Povidone 2.80 Macrogol-polyvinyl alcohol copolymer 20.00 Total quantity 35.1 (Example 8) Preparation of a bilayer tablet containing Sacubitril-Valsartan and Dapagliflozin [000272] Sacubitril-valsartan, microcrystalline cellulose, D-mannitol, low-substituted hydroxypropylcellulose, Petition 870250090236, dated 03 / 10 / 2025, pages 257 / 265 74 / 76 Croscarmellose sodium, colloidal silicon dioxide, talc, and magnesium stearate were mixed according to the composition shown in Table 18 below, and the mixture was fed into a roller compactor, thus preparing dry granules. The granules were subsequently mixed with croscarmellose sodium and colloidal silicon dioxide, and the resulting mixture was then post-mixed with magnesium stearate, thus preparing a final mixture containing sacubitril-valsartan (first mixture). Meanwhile, dapagliflozin propanediol, microcrystalline cellulose, D-mannitol, hydroxypropylcellulose, croscarmellose sodium, and sodium stearyl fumarate were mixed and fed into a roller compactor, preparing dry granules. The granules were then mixed with croscarmellose sodium, and the resulting mixture was subsequently mixed with sodium stearyl fumarate, thus preparing a final mixture containing dapagliflozin (second mixture).The final mixture containing sacubitril-valsartan, which constitutes a lower layer, and the final mixture containing dapagliflozin, which constitutes an upper layer, were compressed using a tablet press (AUTOTAB-200TR, Ichihashi Seiki) and an oval punch (17.5 mm wide x 9 mm long) at a pressure of 10 kN, thus preparing bilayer tablets (hardness: approximately 15 kP). (Table 18) Processes Ingredients Contents (mg / tablet) Example 8 Sacubitrilvalsartan (portion of the lower layer) Dry granulation Sacubitril-valsartan trisodium hemipentahydrate 226.2 Microcrystalline cellulose 27.1 D-mannitol 19.7 Low-substituted hydroxypropyl cellulose 59.0 Croscarmellose sodium 20.0 Colloidal silicon dioxide 1.5 Petition 870250090236, dated 03 / 10 / 2025, pages 258 / 265 75 / 75 Talc 4.0 Magnesium stearate 6.0 Second mixture Croscarmellose sodium 20.0 Colloidal silicon dioxide 2.5 Final mixture Magnesium stearate 4.0 Total quantity 390 Dapagliflozin (portion of the top layer) Compaction Dapagliflozin propanediol 12.3 Microcrystalline cellulose 39.4 D-mannitol 113.6 Hydroxypropylcellulose 10.0 Sodium stearyl fumarate 8.4 Second mixture Croscarmellose sodium 20.0 Final mixture Sodium stearyl fumarate 6.3 Total quantity 210 [000273] Although the present invention has been described in detail with reference to its specific features, it will be evident to those skilled in the art that this description refers only to a preferred embodiment thereof and does not limit the scope of the present invention. Thus, the substantial scope of the present invention will be defined by the appended and equivalent claims thereof. INDUSTRIAL APPLICABILITY [000274] The present invention relates to a pharmaceutical combination formulation containing sacubitril-valsartan and an SGLT-2 inhibitor, which can be used for the treatment of heart failure and ischemic heart disease. The pharmaceutical combination formulation provided by the present invention exhibits excellent stability and dissolution rate. Petition 870250090236, dated 03 / 10 / 2025, pages 259 / 265

Claims

1 / 6 CLAIMS 1. Pharmaceutical combination formulation, characterized in that it comprises: (1) a first release portion comprising sacubitril-valsartan or pharmaceutically acceptable salts thereof as an active ingredient; and (2) a second release portion comprising a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

2. A combined pharmaceutical formulation, according to claim 1, characterized in that the first release portion and the second release portion are present in a state in which they are physically separated from each other.

3. Pharmaceutical combination formulation, according to claim 1, characterized in that the pharmaceutical combination formulation is a multilayer tablet or a drug-coated tablet.

4. Pharmaceutical combination formulation, according to claim 1, characterized in that the SGLT-2 inhibitor is selected from the group consisting of dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, sotagliflozin, ipragliflozin, tofogliflozin, luseogliflozin, bexagliflozin and remogliflozin.

5. Pharmaceutical combination formulation, according to claim 1, characterized in that the first or second release portion comprises at least one pharmaceutically acceptable additive selected from the group consisting of an excipient, a disintegrant and a lubricant.

6. Pharmaceutical combination formulation, according to claim 5, characterized in that the excipient is selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, magnesium aluminometasilicate, magnesium aluminosilicate, aluminum silicate, Petition 870250090236, dated 03 / 10 / 2025, page 260 / 265 2 / 6 sodium silicate, potassium silicate, magnesium silicate, calcium silicate, lactose, lactose hydrate, anhydrous lactose, calcium hydrogen phosphate, hydroxypropylcellulose, hydroxypropylmethylcellulose, dextrin, mannitol, sorbitol, starch, hydrated calcium phosphate, calcium carbonate, sugars and mixtures thereof.

7. Pharmaceutical combination formulation, according to claim 5, characterized in that the disintegrant is selected from the group consisting of crospovidone, methylcellulose, cross-linked sodium carboxymethylcellulose (CMC Na cross-linked, C.CMC Na or croscarmellose sodium), calcium carboxymethylcellulose, sodium starch glycolate, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose, starch, pregelatinized starch, corn starch, potato starch, alginic acid or its sodium salt and combinations thereof.

8. Pharmaceutical combination formulation, according to claim 5, characterized in that the lubricant is selected from the group consisting of calcium stearate, colloidal silicon dioxide (pyrogenic silica), glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc and combinations thereof.

9. Combined pharmaceutical formulation, according to claim 1, characterized in that the second release portion comprises a coating agent.

10. Pharmaceutical combination formulation, according to claim 9, characterized in that the coating agent is at least one selected from the group consisting of hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyvinyl alcohol graft copolymers and macrogol, Petition 870250090236, dated 03 / 10 / 2025, p. 261 / 265 3 / 6 Acrylic acid polymers and their salts, polymethacrylate, copolymers of poly(butylmethacrylate, 2-dimethylaminoethyl methacrylate, methylmethacrylate), carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymers, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan gum and mixtures thereof.

11. Combined pharmaceutical formulation, according to claim 1, characterized in that the first release portion comprises, based on the total weight of the first release portion, 10 to 80% by weight of the active ingredient, 1 to 50% by weight of an excipient, 5 to 50% by weight of a disintegrant and 0.1 to 20% by weight of a lubricant.

12. Pharmaceutical combination formulation, according to claim 1, characterized in that the second release portion comprises, based on the total weight of the second release portion, 0.5 to 50% by weight of the active ingredient, 20 to 95% by weight of an excipient, 0.1 to 20% by weight of a disintegrant and 0.1 to 20% by weight of a lubricant.

13. Pharmaceutical combination formulation, according to claim 1, characterized in that the second release portion comprises, based on the total weight of the second release portion, 10 to 70% by weight of the active ingredient and 30 to 90% by weight of a coating agent.

14. Pharmaceutical combination formulation, according to claim 1, characterized in that the first release portion comprises, based on the total weight of the first release portion, 10 to 80% by weight of the active ingredient, 5 to 50% by weight of at least one of microcrystalline cellulose and mannitol, 5 to 30% by weight of low-substituted hydroxypropylcellulose, 5 to 30% by weight of at least one of sodium starch glycolate and croscarmellose sodium, 0.1 to 10% by weight of colloidal silicon dioxide, 0.1 to 10% by weight of talc and 0.1 to 10% by weight of magnesium stearate.

15. Pharmaceutical combination formulation, according to claim 1, characterized in that the second release portion comprises, based on the total weight of the second release portion, 0.5 to 50% by weight of the active ingredient, 10 to 50% by weight of at least one of microcrystalline cellulose and lactose hydrate, 10 to 50% by weight of mannitol, 0.1 to 20% by weight of hydroxypropylcellulose, 0.5 to 20% by weight of croscarmellose sodium and 0.5 to 20% by weight of sodium stearyl fumarate.

16. Pharmaceutical combination formulation, according to claim 1, characterized in that the pharmaceutical combination formulation is a bilayer tablet comprising: a first layer comprising the first release portion comprising sacubitril-valsartan or pharmaceutically acceptable salts thereof as an active ingredient; and a second layer comprising the second release portion comprising the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

17. Pharmaceutical combination formulation, according to claim 1, characterized in that the pharmaceutical combination formulation is a drug-coated tablet comprising: a core comprising the first release portion containing sacubitril-valsartan or pharmaceutically acceptable salts thereof as an active ingredient; and a coating layer located on at least one portion of the surface of the core and comprising the second release portion comprising the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

18. Pharmaceutical combination formulation, according to Petition 870250090236, dated 10 / 03 / 2025, page 263 / 265 5 / 6 claim 1, characterized in that the first release portion comprises granules containing sacubitril-valsartan or pharmaceutically acceptable salts thereof as an active ingredient, an excipient, a disintegrant and a lubricant, and a post-mixing portion comprising a disintegrant and a lubricant, and the second release portion comprises granules comprising the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient, an excipient, a disintegrant and a lubricant, and a post-mixing portion containing a disintegrant and a lubricant.

19. Method for preparing a combined pharmaceutical formulation, the method characterized in that it comprises the steps of: (a) preparing a first release portion comprising sacubitril-valsartan or pharmaceutically acceptable salts thereof as an active ingredient; (b) preparing a second release portion comprising an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient; and (c) formulating the first release portion and the second release portion into a solid formulation.

20. Method according to claim 19, characterized in that step (a) of preparing the first release portion comprises the steps of: (a-1) mixing sacubitrilvalsartan or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable additive; (a-2) preparing the granules; and (a-3) mixing the granules and a post-mixture portion.

21. Method according to claim 20, characterized in that it further comprises, after step (a-3), step (a-4) of compressing the mixture into tablets.

22. Method according to claim 20, characterized in that step (b) of preparing the second release portion comprises the steps of: (b-1) mixing an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive; (b-2) preparing the granules; and (b-3) mixing the granules and a post-mixture portion.

23. Method according to claim 22, characterized in that step (c) of formulating the first release portion and the second release portion in the single solid formulation comprises a compression step of the mixture for the first release portion, obtained in step (a-3), and of the mixture for the second release portion, obtained in step (b-3), thus preparing a bilayer tablet.

24. Method according to claim 21, characterized in that step (b) of preparing the second release portion comprises step (b-1) of preparing a coating solution by mixing the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof and a coating agent, and step (c) of formulating the first release portion and the second release portion in the solid formulation comprises a step of coating a tablet-shaped core, obtained in step (a-4), with the coating solution for the second release portion, obtained in step (b-1). Petition 870250090236, dated 03 / 10 / 2025, pp. 265 / 265

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