A combination formulation containing sacubitril-valsartan and an SGLT-2 inhibitor, ensuring improved stability and dissolution rate.

Abstract

The present invention relates to a pharmaceutical compound formulation that contains sacubitril-valsartan and an SGLT-2 inhibitor as active ingredients, thereby having a synergistic effect in the treatment of heart failure, while minimizing the effects of drug dissolution between each drug to ensure bioequivalence, suppressing the generation of related substances, and exhibiting excellent stability of the active ingredients.

Description

[Technical Field]

[0001] This invention relates to a compound formulation containing sacubitril-valsartan and an SGLT-2 inhibitor as active ingredients, which exhibits excellent stability and dissolution rate. [Background technology]

[0002] Heart failure is a condition in which the heart's ability to receive blood (relaxation) and pump out blood (contraction) is reduced due to structural or functional abnormalities of the heart, resulting in the heart being unable to properly supply the body's tissues with the necessary blood. When heart failure occurs, regardless of the cause, it can lead to a decrease in myocardial function, remodeling of the left ventricle, hemodynamic changes, activation of the neurohormonal system, cytokine expression, and dysfunction of vascular endothelial cells, which can result in various types of arrhythmias, atrial fibrillation, stroke, acute pulmonary edema, renal impairment, and sudden death.

[0003] With the number of heart failure patients, particularly those with heart failure with preserved ejection fraction (HFpEF), increasing globally, there are no approved treatments, and there is great expectation for the development of related drugs. Entresto is a newly introduced treatment for heart failure. TM (The active ingredient, sacubitril-valsartan complex), is attracting attention as the first therapeutic agent to bypass existing ACE inhibitors.

[0004] Entrance TM The active ingredient is sacubitril-valsartan sodium 2.5 hydrate, the contents of which are publicly known in International Patent Publication WO2007 / 056546A1 (Patent Document 1) (therefore, the entire contents of the said patent document are incorporated together as prior art in this specification). TM While it has been reported to reduce the risk factors for death and heart failure due to cardiovascular disease, it has poor stability and water solubility, making it very difficult to formulate.

[0005] Meanwhile, recent large-scale clinical trials both in Korea and abroad have confirmed that SGLT-2 inhibitors, formerly marketed as diabetes medications, are effective in treating heart failure regardless of whether or not diabetes is present. The revised 2022 guidelines for heart failure treatment, recently published by the Korean Heart Failure Society, also include the use of entrepreneurial agents. TM In addition, Fosiga Jardiance TM Sodium-glucose cotransporter 2 (SGLT2) drugs such as [specific drug name] were recommended as the first-line standard treatment (Class I, with a rationale of Grade A).

[0006] Therefore, the inventors sought to develop a combination formulation containing sacubitril-valsartan and an SGLT2 inhibitor to enhance the therapeutic effect of heart failure and ischemic heart disease. Consequently, considering the site of action of these drugs, they developed the combination formulation of the present invention, which allows for rapid release of both components while possessing excellent stability, thus completing the present invention. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication Patent No. 2007 / 056546 [Patent Document 2] U.S. Registered Patent No. 6515117 [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] One objective of the present invention is to provide an oral compound formulation that contains sacubitril-valsartan and an SGLT-2 inhibitor as active ingredients, thereby having a synergistic effect in the treatment of heart failure, while ensuring a dissolution profile equivalent to that of these drugs administered individually as single agents, and also exhibiting excellent stability. Another object of the present invention is to provide a method for efficiently producing the oral compound formulations provided in the present invention.

[0009] However, the technical problems that this invention aims to solve are not limited to those mentioned above, and other problems not mentioned will be clearly understood by those with ordinary skill in the art from the following description. [Means for solving the problem]

[0010] One embodiment of the present invention relates to a pharmaceutical compound formulation comprising (1) a first release portion containing sacubitril-valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, and (2) a second release portion containing an SGLT-2 (Sodium-Glucose Cotransporter 2) inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0011] In the present invention, the first discharge section and the second discharge section may exist in a physically separate manner.

[0012] In the present invention, the pharmaceutical compound formulation may be a multilayer tablet or a drug-coated tablet.

[0013] 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.

[0014] In the present invention, the first release portion or the second release portion may contain one or more pharmaceutically acceptable additives selected from the group consisting of excipients, disintegrants, and lubricants.

[0015] In the present invention, the excipient can 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 monohydrate, lactose anhydrous, calcium hydrogen phosphate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, dextrin, mannitol, sorbitol, starch, calcium phosphate monohydrate, calcium carbonate, sugars, and mixtures thereof.

[0016] In the present invention, the disintegrant can be selected from the group consisting of crospovidone, methylcellulose, cross-linked carboxymethylcellulose sodium (C.CMC Na, or croscamerose sodium), carboxymethylcellulose calcium, sodium starch glycolate, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose, starch, pre-gelatinized starch, corn starch, potato starch, alginic acid or its sodium salt, and combinations thereof.

[0017] In the present invention, the lubricant can be selected from the group consisting of calcium stearate, colloidal silicon dioxide (fumed 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 combinations thereof.

[0018] In the present invention, the second release portion may contain a coating base.

[0019] In the present invention, the coating base may be one or more selected from the group consisting of hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, polymers of acrylic acid and its salts, polymethacrylate, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer, carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethyl hydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone (PVP), vinyl pyrrolidone-vinyl acetate copolymer, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, and mixtures thereof.

[0020] In the present invention, the first release part can contain, based on the total weight of the first release part, 10 to 80% by weight of an 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.

[0021] In the present invention, the second release part can contain, based on the total weight of the second release part, 0.5 to 50% by weight of an 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.

[0022] In the present invention, the second release part can contain, based on the total weight of the second release part, 10 to 70% by weight of an active ingredient, and 30 to 90% by weight of a coating base.

[0023] In the present invention, the first release portion may contain, 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 hydroxypropyl cellulose, 5 to 30% by weight of at least one of sodium starch glycolate and croscamerose 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.

[0024] In the present invention, the second release portion may contain, 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 monohydrate, 10 to 50% by weight of mannitol, 0.1 to 20% by weight of hydroxypropyl cellulose, 0.5 to 20% by weight of croscamerose sodium, and 0.5 to 20% by weight of stearyl fumarate sodium.

[0025] In the present invention, the pharmaceutical compound formulation may be a two-layer tablet comprising a first layer containing a first release portion containing the sacubitril-valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, and a second layer containing a second release portion containing the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0026] In the present invention, the pharmaceutical compound formulation may be a drug-coated tablet comprising a core having a first release portion containing the sacubitril-valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, and a coating layer having a second release portion located on at least a portion of the surface of the core, containing the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0027] In the present invention, the first release portion comprises granules containing the active ingredient of sacubitril-valsartan or a pharmaceutically acceptable salt thereof, excipients, disintegrants and lubricants, and a post-mixing portion containing disintegrants and lubricants. The second release portion may include granules containing the active ingredient, excipients, disintegrants, and lubricants of the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof, and a post-mixing portion containing disintegrants and lubricants.

[0028] Another embodiment of the present invention relates to a method for producing a pharmaceutical compound formulation, comprising the steps of: (a) producing a first release portion containing sacubitril-valsartan or a pharmaceutically acceptable salt thereof as an active ingredient; (b) producing a second release portion containing 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 dosage form.

[0029] In the present invention, step (a) includes the steps of producing granules containing sacubitril-valsartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, and mixing the granules with a post-mixing portion containing a disintegrant and a lubricant; step (b) includes the steps of producing granules containing an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, and mixing the granules with a post-mixing portion containing a disintegrant and a lubricant; and step (c) may include the step of compressing the mixed powder from step (a) and the mixed powder from step (b) into tablets to produce a two-layer tablet.

[0030] In the present invention, step (a) includes the steps of: producing granules containing sacubitril-valsartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; mixing the granules with a post-mixing portion containing a disintegrant and a lubricant; and compressing the mixed powder into tablets to produce uncoated tablets; step (b) includes the steps of: mixing an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof with a coating base to produce a coating solution; and step (c) may include the steps of: coating the surface of the uncoated tablets produced in step (a) with the coating solution produced in step (b) to produce drug-coated tablets. [Effects of the Invention]

[0031] The oral compound formulation provided by the present invention contains sacubitril-valsartan and an SGLT-2 inhibitor as active ingredients, thereby providing a pharmacochemical compound formulation that has a synergistic effect in the treatment of heart failure while minimizing the effects of drug dissolution between each drug and ensuring bioequivalence. Furthermore, the oral compound formulation of the present invention also exhibits excellent stability of the active ingredients due to the suppression of the generation of related substances. [Brief explanation of the drawing]

[0032] [Figure 1] This figure shows the experimental results for Experimental Example 1, comparing the dissolution rate of dapagliflozin under pH 1.2 conditions for the combined formulations of Examples 1-3 and Comparative Examples 1-5 with the control drug. [Figure 2] This figure shows the experimental results for Experimental Example 1, comparing the dissolution rate of sacubitril under pH 1.2 conditions for the combined formulations of Examples 1-3 and Comparative Examples 1-5 with the control drug. [Figure 3] This figure shows the experimental results for Experimental Example 1, comparing the dissolution rate of valsartan under pH 1.2 conditions for the combined formulations of Examples 1-3 and Comparative Examples 1-5 with the control drug. [Figure 4] This figure shows the experimental results for Experimental Example 1, comparing the dissolution rate of dapagliflozin under pH 6.8 conditions for the combined formulations of Examples 1-3 and Comparative Examples 1-5 with the control drug. [Figure 5] This figure shows the experimental results for Experimental Example 1, comparing the dissolution rate of sacubitril under pH 6.8 conditions for the combined formulations of Examples 1-3 and Comparative Examples 1-5 with the control drug. [Figure 6] This figure shows the experimental results for Experimental Example 1, comparing the dissolution rate of valsartan under pH 6.8 conditions for the combined formulations of Examples 1-3 and Comparative Examples 1-5 with the control drug. [Figure 7] This figure shows the experimental results for Experimental Example 2, comparing the amount of dapagliflozin RRT0.38 analogues generated under initial, accelerated, or harsh conditions for the combined formulations of Examples 1-3 and Comparative Examples 1-5 with the control drug. [Figure 8]This figure shows the experimental results for Experimental Example 2, comparing the amount of dapagliflozin RRT0.74 analogues generated under initial, accelerated, or harsh conditions for the combined formulations of Examples 1-3 and Comparative Examples 1-5 with the control drug. [Figure 9] This figure shows the experimental results for Experimental Example 2, comparing the amount of dapagliflozin RRT1.59 analogues generated under initial, accelerated, or harsh conditions for the combined formulations of Examples 1-3 and Comparative Examples 1-5 with the control drug. [Modes for carrying out the invention]

[0033] One embodiment of the present invention relates to a pharmaceutical compound formulation comprising (1) a first release portion containing sacubitril-valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, and (2) a second release portion containing an SGLT-2 (Sodium-Glucose Cotransporter 2) inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0034] In the compound formulation according to the present invention, the first release portion and the second release portion may exist in a state where they are physically separated from each other.

[0035] In the present invention, the compound formulation may be in the form of a two-layer tablet or a multi-layer tablet, or it may be in the form of a drug-coated tablet with a core-shell structure.

[0036] In the present invention, in the two-layer or multi-layer tablet, the first layer includes a first dispensing section or a second dispensing section, and the second layer may include a second dispensing section or a first dispensing section.

[0037] In the present invention, the drug-coated tablet may have a structure comprising a core and a coating layer covering at least a portion of the surface of the core. In the present invention, the core may include a first release portion or a second release portion, and the coating layer may include a second release portion or a first release portion.

[0038] In one example, the first layer may contain an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof, and the second layer may contain sacubitril-valsartan or a pharmaceutically acceptable salt thereof.

[0039] In other examples, the compound formulation may be a two-layer tablet comprising a first layer containing sacubitril-valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, and a second layer containing an SGLT-2 inhibitor, such as dapagliflozin or a pharmaceutically acceptable salt thereof as an active ingredient.

[0040] In the present invention, the drug-coated tablet may consist of a core comprising a first release portion and a drug coating layer comprising a second release portion.

[0041] In one example, the core may contain sacubitril-valsartan or a pharmaceutically acceptable salt thereof, and the coating layer may contain an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0042] In the present invention, the first and second release portions may additionally contain pharmaceutically acceptable additives such as excipients (diluents), disintegrants, lubricants, or coating bases, depending on the form of the composite formulation.

[0043] In the present invention, the compound formulation is a two-layer tablet or a multi-layer tablet, and the first or second dispensing portion may contain one or more pharmaceutically acceptable additives selected from the group consisting of excipients (diluents), disintegrants, and lubricants.

[0044] In one example, the compound formulation is a two-layer tablet or a multi-layer tablet, and the first release portion contains an active ingredient as well as an excipient (diluent), a disintegrant, and a lubricant, and the second release portion may also contain an active ingredient as well as an excipient (diluent), a disintegrant, and a lubricant.

[0045] Furthermore, in the present invention, the compound formulation is a drug-coated tablet, and the first or second dispensing portion may contain a coating base.

[0046] In one example, the compound formulation is a drug-coated tablet, the first release portion contains, in addition to the active ingredient, one or more pharmaceutically acceptable additives selected from the group consisting of excipients (diluents), disintegrants, and lubricants, and the second release portion may contain the active ingredient and a coating base.

[0047] In other examples, the compound formulation is a drug-coated tablet, the second release portion contains, in addition to the active ingredient, one or more pharmaceutically acceptable additives selected from the group consisting of excipients (diluents), disintegrants, and lubricants, and the first release portion may contain the active ingredient and a coating base. [Examples]

[0048] One embodiment of the present invention relates to a pharmaceutical compound formulation comprising (1) a first release portion containing sacubitril-valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, and (2) a second release portion containing an SGLT-2 (Sodium-Glucose Cotransporter 2) inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0049] In the present invention, "sacubitril" is a compound of 4-{[(2S,4R)-1-(4-biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid, represented by the following chemical formula 1. Sacubitril is a neprilysin (NEP) inhibitor and is activated to sacubitrilat by deethylation of esterase, and is known to degrade atrial and cerebral natriuretic peptides, which are blood pressure-lowering peptides that reduce blood flow.

[0050] [ka] In the present invention, "valsartan" is a compound of (S)-N-(1-carboxy-2-methyl-prop-1-pyru)-N-pentanoyl-N-[2'-(1H-tetrazole-5-yl)biphenyl-4-yl-methyl]amine, represented by the following chemical formula 2. Valsartan is an angiotensin-II receptor blocker and, by blocking the action of angiotensin-II, not only functions to relax blood vessels and lower blood pressure, but is also used in the treatment of heart failure, ischemic heart disease, and other conditions.

[0051] [ka] In the present invention, the term "pharmaceutically acceptable salt" means a salt commonly used in the art, and includes not only salts produced from inorganic ions, inorganic acids, or organic acids, but also hydrates or solvates of such salts. Suitable sacubitril-valsartan or its pharmaceutically acceptable salts for the present invention include free acids, or inorganic ion salts such as sodium, calcium, potassium, and magnesium (1 to 3 atoms), or monohydrates to trihydrates thereof.

[0052] In the first release portion of the present invention, the 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 in a molar ratio of 1:1, but is not limited thereto.

[0053] In the pharmaceutical complex formulation of the present invention, "sacubitril-valsartan" as the active ingredient may be included in the form of a supramolecular complex of sacubitril and valsartan, or in the form of a physical mixture of the free acids or salts of each component, or may include all of these drugs as coprecipitations, cocrystals, co-amorphous compounds, or single compounds formed by ionic bonding, nonionic bonding, covalent bonding, non-covalent bonding or hydrogen bonding. Here, the "supramolecular complex" is intended to describe the interaction between two pharmaceutical agents, a cation, and any existing entities such as a solvent, particularly water, through non-covalent or intermolecular bonding. The interaction results in the association of species present in the supramolecular complex, which distinguishes the complex from a physical mixture of species.

[0054] In one example, the sacubitril-valsartan may be provided in the form of a compound represented by the following chemical formula 3, but is not limited thereto.

[0055] [ka] In the aforementioned chemical formula 3, A1 is valsartan in its anionic form; A2 is a sacbitryl in an anionic form; Na + It is a sodium ion; x may be a rational number between 0.5 and 7, preferably between 2.5 and 3.5, and more preferably 2.5 or 3, but is not limited to these values.

[0056] In other examples, the sacubitril-valsartan may be, but is not limited to, a supramolecular complex of sacubitril-valsartan trisodium salt trihydrate.

[0057] In other examples, the sacubitril-valsartan may be, but is not limited to, the crystalline type II sacubitril-valsartan trisodium salt trihydrate represented by the following chemical formula 4: [ka] In other examples, the sacubitril-valsartan may be, but is not limited to, a supramolecular complex of sacubitril-valsartan trisodium hemipentahydrate, conventionally referred to as "LCZ696" (see Korean Patent No. 10-1589317).

[0058] In the present invention, not only sacubitril or N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoate ethyl ester or pharmaceutically acceptable salts thereof, but also (2R,4S)-5-biphenyl-4-yl-4(3-carboxy-propionylamino)-2-methylpentanoic acid can be produced by known methods such as the method described in U.S. Patent No. 5,217,996, which is incorporated herein by reference.

[0059] In the present invention, valsartan or (S)-N-valeryl-N-{[2'-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}valine or a pharmaceutically acceptable salt thereof can be purchased from a commercial source or produced by known methods such as those described in U.S. Patent No. 5,399,578 and European Patent No. 0443983, the teachings of which are included by reference in this application. Valsartan can be used in specific embodiments of the present invention not only in its free acid form but also in any preferred salt form. Depending on the circumstances, carboxyl-grouped esters or other derivatives may be used, as well as tetrazole-grouped salts and derivatives.

[0060] In the present invention, sacubitril-valsartan is administered as an initial dose of 50 mg twice daily (24.3 / 25.7 mg as sacubitril-valsartan), and the dose can be increased to 200 mg twice daily (97.2 / 102.8 mg as sacubitril-valsartan) if necessary.

[0061] In the pharmaceutical compound formulation of the present invention, the second release portion contains an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0062] In the present invention, the SGLT-2 inhibitor is a benzene derivative compound substituted with glucopyranosyl that has the ability to inhibit the sodium glucose cotransporter. 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, but is not limited thereto.

[0063] In one example, the SGLT-2 inhibitor may be dapagliflozin, but is not limited thereto.

[0064] In other examples, the SGLT-2 inhibitor may be, but is not limited to, empagliflozin.

[0065] In other examples, the SGLT-2 inhibitor may be, but is not limited to, canagliflozin.

[0066] In other examples, the SGLT-2 inhibitor may be, but is not limited to, ertugliflozin.

[0067] In other examples, the SGLT-2 inhibitor may be, but is not limited to, sotagliflozin.

[0068] In other examples, the SGLT-2 inhibitor may be, but is not limited to, ipragliflozin.

[0069] In other examples, the SGLT-2 inhibitor may be, but is not limited to, tofogliflozin.

[0070] In other examples, the SGLT-2 inhibitor may be, but is not limited to, luseogliflozin.

[0071] In other examples, the SGLT-2 inhibitor may be, but is not limited to, bexagliflozin.

[0072] In other examples, the SGLT-2 inhibitor may be, but is not limited to, remogliflozin.

[0073] In the present invention, the SGLT-2 inhibitor can be manufactured by methods known in the art, for example, as shown in International Publication No. 2006 / 120208, International Publication No. 2007 / 031548, or International Publication No. 2008 / 002824.

[0074] In the present invention, dapagliflozin is (1S)-1,5-anhydro-1-C-4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl-D-glucitol, represented by the following chemical formula 5. Dapagliflozin inhibits SGLT-2 in the renal tubules, thereby suppressing the reabsorption process of glucose and reducing blood glucose levels by causing glucose to be excreted in the urine.

[0075] [ka] In the present invention, the SGLT-2 inhibitor, for example, dapagliflozin, may include all pharmaceutically acceptable forms of its salts, esters, or solvates.

[0076] In the present invention, the dapagliflozin or a pharmaceutically acceptable salt thereof may be in a continuous and / or discontinuous amorphous form or in a cocrystalline form.

[0077] In the present invention, the dapagliflozin may include its prodrug ester. Here, the pharmaceutically acceptable ester can be cleaved in the body of a human or animal to produce a parent acid (e.g., if the ester is methoxymethyl) or a hydroxyl group (e.g., if the ester is an acetyl ester).

[0078] In the present invention, the solvate of dapagliflozin may include or consist of a propylene glycol solvate of dapagliflozin, such as dapagliflozin propylene glycol (1:1). In one example, the solvate of dapagliflozin may be in the form of its propylene glycol solvate hydrate (1:1:1). Here, the propylene glycol may be in the (S) form, the (R) form, or a mixture thereof, and is preferably in the (S) form, but is not limited thereto.

[0079] Furthermore, in the present invention, the solvate of dapagliflozin may be in the form of a solvate comprising dapagliflozin and a 1,2-alkanediol or its hydrate. Here, the 1,2-alkanediol may be 1,2-propanediol, 1,2-butanediol, 1,2-pentanediol, 1,2-hexanediol, and 1,2-heptanediol, or their hydrates or mixtures. For example, the solvate of dapagliflozin may be dapagliflozinpropanediol monohydrate, or dapagliflozin compounded with (2S)-1,2-propanediol hydrate in a ratio of about 1:1:1, but is not limited thereto.

[0080] The second release portion of the present invention may contain one or more amino acids together with dapagliflozin. Here, the amino acid can 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. In addition, in the present invention, the dapagliflozin and the amino acid may be in the form of a cocrystal. In one example, the second release portion may contain dapagliflozin and proline (e.g., L-proline or D-proline), but is not limited thereto.

[0081] The combined formulation of the present invention may contain, per unit dosage form, 50 to 200 mg of sacubitril-valsartan as sacubitril-valsartan free base and 5 to 10 mg of dapagliflozin as free base. For example, the combined formulation may contain 100 mg or 200 mg of sacubitril-valsartan as free base and 10 mg of dapagliflozin per unit dosage form.

[0082] In this specification, when sacubitril, valsartan, SGLT-2 inhibitors, or dapagliflozin are mentioned, it should be understood that this includes all of the salts, solvates, and isomers of each of the aforementioned substances.

[0083] In the compound formulation according to the present invention, the first release portion and the second release portion may exist in a state where they are physically separated from each other.

[0084] In the present invention, the compound formulation may be in the form of a two-layer tablet or a multi-layer tablet, or it may be in the form of a drug-coated tablet with a core-shell structure.

[0085] In the present invention, in the two-layer or multi-layer tablet, the first layer includes a first dispensing section or a second dispensing section, and the second layer may include a second dispensing section or a first dispensing section.

[0086] In the present invention, in the two-layer or multi-layer tablet, the first layer may consist of a first dispensing section, and the second layer may consist of a second dispensing section.

[0087] In one example, the first layer may contain sacubitril-valsartan or a pharmaceutically acceptable salt thereof, and the second layer may contain an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0088] In other examples, the first layer may contain an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof, and the second layer may contain sacubitril-valsartan or a pharmaceutically acceptable salt thereof.

[0089] In further examples, the compound formulation may be a two-layer tablet comprising a first layer containing sacubitril-valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, and a second layer containing an SGLT-2 inhibitor, such as dapagliflozin or a pharmaceutically acceptable salt thereof as an active ingredient. Here, the terms "first layer" and "second layer" are used to distinguish between different layers (i.e., the first layer is any single layer of the two-layer tablet, and the second layer is any other layer), and the first layer may be located on top or on the bottom, and the second layer may be located on the bottom or on the top. In such a two-layer tablet, sacubitril, valsartan, and the SGLT-2 inhibitor are each contained in different layers.

[0090] In the present invention, the drug-coated tablet may have a structure comprising a core and a coating layer covering at least a portion of the surface of the core. In the present invention, the core may include a first release portion or a second release portion, and the coating layer may include a second release portion or a first release portion.

[0091] In the present invention, the drug-coated tablet may consist of a core comprising a first release portion and a drug coating layer comprising a second release portion.

[0092] In one example, the core may contain sacubitril-valsartan or a pharmaceutically acceptable salt thereof, and the coating layer may contain an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0093] In other examples, the core may contain an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof, and the coating layer may contain sacubitril-valsartan or a pharmaceutically acceptable salt thereof.

[0094] In yet another example, the compound formulation may be a drug-coated tablet comprising a core containing sacubitril-valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, and a coating layer containing an SGLT-2 inhibitor, such as dapagliflozin or a pharmaceutically acceptable salt thereof as an active ingredient.

[0095] In the present invention, the first and second release portions may additionally contain pharmaceutically acceptable additives such as excipients (diluents), disintegrants, lubricants, or coating bases, depending on the form of the composite formulation.

[0096] In the present invention, the compound formulation is a two-layer tablet or a multi-layer tablet, and the first or second dispensing portion may contain one or more pharmaceutically acceptable additives selected from the group consisting of excipients (diluents), disintegrants, and lubricants.

[0097] Furthermore, in the present invention, the compound formulation is a drug-coated tablet, and the first or second dispensing portion may contain a coating base.

[0098] In one example, the first release portion may contain, in addition to the active ingredient, one or more pharmaceutically acceptable additives selected from the group consisting of excipients (diluents), disintegrants, and lubricants, and the second release portion may contain the active ingredient and a coating base.

[0099] In other examples, the second release portion may contain, in addition to the active ingredient, one or more pharmaceutically acceptable additives selected from the group consisting of excipients (diluents), disintegrants, and lubricants, and the first release portion may contain the active ingredient and a coating base.

[0100] In the present invention, sacubitril-valsartan, which is included as an active ingredient in the first release portion, may be present in an amount of 10-80% by weight, 20-80% by weight, or 30-80% by weight, based on the total weight of the first release portion, but is not limited thereto.

[0101] In the present invention, the SGLT-2 inhibitor contained in the second layer as an active ingredient, 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, but is not limited thereto.

[0102] In the present invention, the excipient contained 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, but is not limited thereto.

[0103] In the present invention, the excipient may be included in an amount of 20-95% by weight, 30-90% by weight, 40-90% by weight, 50-80% by weight, or 60-80% by weight, based on the total weight of the second release portion, but is not limited thereto.

[0104] In the present invention, the disintegrant may be included in an amount of 5-50% by weight, 10-50% by weight, 10-40% by weight, or 15-30% by weight, based on the total weight of the first release section, but is not limited thereto.

[0105] In the present invention, the disintegrant may be present in 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 section, but is not limited thereto.

[0106] In the present invention, the lubricant may be included 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 discharge portion, but is not limited thereto.

[0107] In the present invention, the lubricant may be present in an amount of 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 discharge portion, but is not limited thereto.

[0108] In the present invention, the coating base may be included in an amount of 30-90% by weight, 40-90% by weight, 40-80% by weight, or 50-80% by weight, based on the total weight of the first or second discharge portion, but is not limited thereto.

[0109] In one example, the first discharge portion may contain, but is not limited to, 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, based on the total weight of the first discharge portion.

[0110] In one example, the second discharge portion may contain, but is not limited to, 0.5 to 50% by weight of an 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, based on the total weight of the second discharge portion.

[0111] In one example, the first or second discharge section may contain, but is not limited to, 10 to 70% by weight of the active ingredient and 30 to 90% by weight of the coating base, based on the total weight.

[0112] In the present invention, the excipient (diluent) can be selected from the group consisting of, for example, microcrystalline cellulose, silicified microcrystalline cellulose, magnesium aluminometasilicate, magnesium aluminosilicate, aluminum silicate, sodium silicate, potassium silicate, magnesium silicate, calcium silicate, lactose, lactose monohydrate, lactose anhydrous, calcium hydrogen phosphate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, dextrin, mannitol, sorbitol, starch, calcium phosphate monohydrate, calcium carbonate, sugars, and any mixture thereof, but is not limited thereto. However, in the present invention, anhydrous calcium phosphate is not included as an excipient because its compatibility with dapagliflozin and sacubitril-valsartan is poor.

[0113] In the present invention, the disintegrant can be selected from, but is not limited to, the group consisting of, for example, crospovidone, methylcellulose, cross-linked carboxymethylcellulose sodium (C.CMC Na, or croscamerose sodium), carboxymethylcellulose calcium, sodium starch glycolate, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose, starch, pre-gelatinized starch, corn starch, potato starch, alginic acid or its sodium salt, and any combination thereof.

[0114] In the present invention, the lubricant can be selected from, but is not limited to, the group consisting of, for example, calcium stearate, colloidal silicon dioxide (fumed 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 combination thereof.

[0115] In the present invention, the coating base may be one or more hydrophilic polymers selected from the group consisting of, for example, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, polymers of acrylic acid and its salts, polymethacrylate, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer (e.g., Eudragit® E, Evonik), carboxymethylcellulose (sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone (povidone; PVP), vinylpyrrolidone-vinyl acetate copolymer (e.g., Kollidon® VA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan gum, and mixtures thereof. Preferably, the coating base may be hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, or poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer (e.g., Eudragit® E, Evonik).

[0116] In the present invention, the first release portion may contain additives selected from microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose (L-HPC), croscamerose sodium, sodium starch glycolate, colloidal silicon dioxide (fumed silica, Aerosil), talc, magnesium stearate, and any combination thereof.

[0117] In one example, the first release portion may include additives comprising at least one of microcrystalline cellulose and mannitol; low-substituted hydroxypropyl cellulose (L-HPC); at least one of croscamerose sodium and sodium starch glycolate; colloidal silicon dioxide (fumed silica, Aerosil); talc; and magnesium stearate.

[0118] In other examples, the first release portion may include additives such as microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose (L-HPC), croscamerose sodium, colloidal silicon dioxide (fumed silica, Aerosil), talc, and magnesium stearate.

[0119] In further examples, the first release portion may include additives such as microcrystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC), sodium starch glycolate, colloidal silicon dioxide (fumed silica, Aerosil), talc, and magnesium stearate.

[0120] In the present invention, the first release portion may contain at least one of microcrystalline cellulose and mannitol in amounts 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 contain microcrystalline cellulose. In another example, the first release portion may contain mannitol. In yet another example, the first release portion may contain both microcrystalline cellulose and mannitol. In yet another example, the first release portion may contain, but is not limited to, microcrystalline cellulose in amounts of 1 to 30% by weight, 1 to 20% by weight, or 1 to 10% by weight. In yet another example, the first release portion may contain, but is not limited to, mannitol in amounts of 1 to 30% by weight, 1 to 20% by weight, or 1 to 10% by weight.

[0121] In the present invention, the first release portion may contain low-substituted hydroxypropyl cellulose in an amount of 5-30% by weight, 5-20% by weight, 5-15% by weight, or 10-20% by weight, based on the total weight of the first release portion.

[0122] In the present invention, the first release portion may contain at least one of sodium starch glycolate and croscamerose sodium in amounts 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 contain sodium starch glycolate. In another example, the first release portion may contain croscamerose sodium. In yet another example, the first release portion may contain both sodium starch glycolate and croscamerose sodium. In yet another example, the first release portion may contain, but is not limited to, sodium starch glycolate in amounts of 1 to 30% by weight, 5 to 30% by weight, 5 to 20% by weight, or 5 to 15% by weight. In yet another example, the first release portion may contain, but is not limited to, croscamerose sodium in amounts of 1 to 30% by weight, 5 to 30% by weight, 5 to 20% by weight, or 5 to 15% by weight.

[0123] In the present invention, the first release portion may contain 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.

[0124] In the present invention, the first discharge section may contain 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 discharge section.

[0125] In the present invention, the first discharge portion may contain 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 discharge portion.

[0126] In one example, the first release portion may, but is not limited to, contain 10-80% by weight of the active ingredient, 5-50% by weight of at least one of microcrystalline cellulose and mannitol, 5-30% by weight of low-substituted hydroxypropyl cellulose, 5-30% by weight of at least one of sodium starch glycolate and croscamerose sodium, 0.1-10% by weight of colloidal silicon dioxide, 0.1-10% by weight of talc, and 0.1-10% by weight of magnesium stearate, based on the total weight of the first release portion.

[0127] In other examples, the first release portion may, but is not limited to, contain 10-80% by weight of the active ingredient, 5-50% by weight of microcrystalline cellulose, 5-30% by weight of low-substituted hydroxypropyl cellulose, 5-30% by weight of sodium starch glycolate, 0.1-10% by weight of colloidal silicon dioxide, 0.1-10% by weight of talc, and 0.1-10% by weight of magnesium stearate, based on the total weight of the first release portion.

[0128] In further examples, the first release portion may, but is not limited to, contain 10-80% by weight of the active ingredient, 1-30% by weight of microcrystalline cellulose, 1-20% by weight of mannitol, 5-30% by weight of low-substituted hydroxypropyl cellulose, 5-30% by weight of croscamerose sodium, 0.1-10% by weight of colloidal silicon dioxide, 0.1-10% by weight of talc, and 0.1-10% by weight of magnesium stearate, based on the total weight of the first release portion.

[0129] In further examples, the first release portion may, but is not limited to, contain 10-80% by weight of the active ingredient, 1-10% by weight of microcrystalline cellulose, 1-10% by weight of mannitol, 5-20% by weight of low-substituted hydroxypropyl cellulose, 5-20% by weight of croscamerose sodium, 0.1-10% by weight of colloidal silicon dioxide, 0.1-10% by weight of talc, and 0.1-10% by weight of magnesium stearate, based on the total weight of the first release portion.

[0130] In the present invention, the second release portion may contain additives selected from microcrystalline cellulose, lactose monohydrate, mannitol, hydroxypropyl cellulose, sodium stearyl fumarate, sodium crocamellose, and any combination thereof.

[0131] In one example, the second release portion may contain additives comprising at least one of microcrystalline cellulose and lactose monohydrate; mannitol; hydroxypropyl cellulose; sodium stearyl fumarate; and sodium crocamellose.

[0132] In other examples, the second release portion may include additives comprising microcrystalline cellulose, mannitol, hydroxypropyl cellulose, sodium stearyl fumarate, and sodium crocamellose.

[0133] In further examples, the second release portion may include additives comprising lactose monohydrate, mannitol, hydroxypropyl cellulose, sodium stearyl fumarate, and sodium crocamellose.

[0134] In the present invention, the second release portion may contain at least one of microcrystalline cellulose and lactose monohydrate in amounts of 10-50% by weight, 20-50% by weight, 10-40% by weight, 15-40% by weight, 10-30% by weight, or 15-30% by weight, based on the total weight of the second release portion. In one example, the second release portion may contain microcrystalline cellulose. In another example, the second release portion may contain lactose monohydrate. In yet another example, the second release portion may contain both microcrystalline cellulose and lactose monohydrate. In yet another example, the second release portion may contain microcrystalline cellulose in amounts of 10-50% by weight, 10-40% by weight, or 15-30% by weight. In yet another example, the second release portion may contain lactose monohydrate in amounts of 10-50% by weight, 20-50% by weight, 10-40% by weight, or 15-40% by weight, but is not limited thereto.

[0135] In the present invention, the second release portion may contain mannitol in amounts of 10-70% by weight, 20-70% by weight, 30-70% by weight, 40-70% by weight, 10-60% by weight, 20-60% by weight, 30-60% by weight, 40-60% by weight, 10-50% by weight, 20-50% by weight, or 30-50% by weight, based on the total weight of the second release portion.

[0136] In the present invention, the second release portion may contain hydroxypropyl cellulose in an amount of 0.1 to 20% by weight, 0.5 to 20% by weight, 0.1 to 10% 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.

[0137] In the present invention, the second discharge portion may contain croscamerose 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 discharge portion.

[0138] In the present invention, the second release portion may contain 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.

[0139] In one example, the second release portion may, but is not limited to, contain 0.5 to 50% by weight of the active ingredient, 10 to 50% by weight of at least one of microcrystalline cellulose and lactose monohydrate, 10 to 50% by weight of mannitol, 0.1 to 20% by weight of hydroxypropyl cellulose, 0.5 to 20% by weight of croscamerose sodium, and 0.5 to 20% by weight of stearyl fumarate sodium, based on the total weight of the second release portion.

[0140] In other examples, the second release portion may, but is not limited to, contain 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 hydroxypropyl cellulose, 0.5 to 20% by weight of croscamerose sodium, and 0.5 to 20% by weight of stearyl fumarate sodium, based on the total weight of the second release portion.

[0141] In further examples, the second release portion may, but is not limited to, contain 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 hydroxypropyl cellulose, 0.5 to 20% by weight of croscamerose sodium, and 0.1 to 20% by weight of stearyl fumarate sodium, based on the total weight of the second release portion.

[0142] In further examples, the second release portion may, but is not limited to, contain 0.5 to 50% by weight of the active ingredient, 10 to 50% by weight of lactose monohydrate, 10 to 50% by weight of mannitol, 0.1 to 20% by weight of hydroxypropyl cellulose, 0.5 to 20% by weight of croscamerose sodium, and 0.5 to 20% by weight of stearyl fumarate sodium, based on the total weight of the second release portion.

[0143] Furthermore, in the present invention, the first release portion may contain, in addition to the active ingredient, polyvinylpyrrolidone (povidone; PVP) and a macrogol-polyvinyl alcohol copolymer.

[0144] In the present invention, the first discharge portion may contain 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 discharge portion.

[0145] In the present invention, the first discharge portion may contain macrogol-polyvinyl alcohol copolymer in an amount of 30-80% by weight, 40-80% by weight, 30-70% by weight, or 40-70% by weight, based on the total weight of the first discharge portion.

[0146] In one example, the first release portion may contain, but is not limited to, 10-70% by weight of the active ingredient, 5-20% by weight of povidone (PVP), and 30-80% by weight of the macrogol-polyvinyl alcohol copolymer, based on the total weight of the first release portion.

[0147] In the present invention, the second release portion may contain, in addition to the active ingredient, polyvinylpyrrolidone (povidone; PVP) and a macrogol-polyvinyl alcohol copolymer.

[0148] In the present invention, the second discharge portion may contain 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 second discharge portion.

[0149] In the present invention, the second discharge portion may contain macrogol-polyvinyl alcohol copolymer in an amount of 30-80% by weight, 40-80% by weight, 30-70% by weight, or 40-70% by weight, based on the total weight of the second discharge portion.

[0150] In one example, the second release portion may contain, but is not limited to, 10-70% by weight of the active ingredient, 5-20% by weight of povidone (PVP), and 30-80% by weight of the macrogol-polyvinyl alcohol copolymer, based on the total weight of the second release portion.

[0151] In the present invention, when the compound formulation is manufactured in the form of a drug-coated tablet, the coating layer may additionally contain a variety of bioinert components for additional purposes such as coating efficiency, drug stability, appearance, color, protection, maintenance, binding, performance improvement, and manufacturing process improvement. The bioinert components additionally contained in the coating layer may be one or more selected from the group consisting of plasticizers, lubricants, colorants, flavoring agents, surfactants, stabilizers, antioxidants, foaming agents, defoaming agents, paraffin, and waxes, but are not limited thereto.

[0152] In addition, in the present invention, various additives may be further mixed into the first release section and / or the second release section to improve the physical properties, manufacturability, compressibility, appearance, palatability, and / or drug stability of the final composite formulation. Examples of such additives include stabilizers, solubilizers, sweeteners, flavoring agents, pigments, wetting agents, fillers, stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, adsorbents, flavoring agents, binders, suspending agents, curing agents, antioxidants, glossing agents, flavoring agents, pigments, coating agents, wetting agents, wetting modifiers, defoaming agents, cooling agents, chewing agents, antistatic agents, colorants, sugar coating agents, isotonic agents, softeners, emulsifiers, adhesives, thickeners, foaming agents, pH adjusters, excipients, dispersants, disintegrants, waterproofing agents, preservatives, solubilizers, solvents, and fluidizing agents, but are not limited to these; any pharmaceutically acceptable additive can be used.

[0153] In the present invention, as described above, in a two-layer tablet compound formulation, the layers of the tablet containing the first release portion and the second release portion may contain granules containing the active ingredient and a post-mixing portion.

[0154] In the present invention, the layer containing the first release portion (first layer) may contain granules containing an active ingredient and a post-mixing portion. In this case, the granules may additionally contain pharmaceutically acceptable additives such as excipients, disintegrants, or lubricants. The post-mixing portion may additionally contain at least one pharmaceutically acceptable additive, such as a disintegrant and a lubricant.

[0155] In one example, the layer including the first release portion may include, but is not limited to, granules containing an active ingredient, an excipient, a disintegrant, and a lubricant, and a post-mixing portion containing a disintegrant and a lubricant.

[0156] In the present invention, the granules in the layer containing the first release portion may contain the active ingredient in an amount of 10-80% by weight, 20-80% by weight, or 30-80% by weight, based on the total weight of the first release portion.

[0157] In the present invention, the granules in the layer containing 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.

[0158] In the present invention, the granules in the layer containing 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.

[0159] In the present invention, the granules in the layer containing 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.

[0160] In the present invention, the post-mixing portion within the layer containing the first discharge portion may contain 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 discharge portion.

[0161] In the present invention, the post-mixing portion within the layer containing the first discharge portion may contain 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 of the first discharge portion.

[0162] In one example, the granules in the layer containing the first release portion contain, based on the total weight of the first release portion, 10-80% by weight of the active ingredient, 5-50% by weight of the excipient, 1-30% by weight of the disintegrant, and 0.1-10% by weight of the lubricant, and the post-mixing portion may contain, but is not limited to, 1-20% by weight of the disintegrant and 0.1-10% by weight of the lubricant, based on the total weight of the first release portion.

[0163] In other examples, the granules in the layer containing the first release portion may contain, 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 the excipient, 1 to 30% by weight of the disintegrant, and 0.1 to 10% by weight of the lubricant, and the post-mixing portion may contain, but is not limited to, 1 to 20% by weight of the disintegrant and 0.1 to 10% by weight of the lubricant, based on the total weight of the first release portion.

[0164] In further examples, the granules in the layer containing the first release portion may contain, 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 the excipient, 10 to 30% by weight of the disintegrant, and 0.1 to 10% by weight of the lubricant, and the post-mixing portion may contain, but is not limited to, 1 to 20% by weight of the disintegrant and 0.1 to 10% by weight of the lubricant, based on the total weight of the first release portion.

[0165] In the present invention, the granules in the layer containing the first release portion may contain at least one of microcrystalline cellulose and mannitol in amounts 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 granules in the layer containing the first release portion may contain microcrystalline cellulose. In another example, the granules in the layer may contain mannitol. In yet another example, the granules in the layer may contain both microcrystalline cellulose and mannitol. In yet another example, the granules in the layer may contain, but are not limited to, 1 to 30% by weight, 1 to 20% by weight, or 1 to 10% by weight of microcrystalline cellulose. In yet another example, the granules in the layer may contain, but are not limited to, 1 to 30% by weight, 1 to 20% by weight, or 1 to 10% by weight of mannitol.

[0166] In the present invention, the granules in the layer containing the first release portion may contain low-substituted hydroxypropyl cellulose in an amount of 5-30% by weight, 5-20% by weight, 5-15% by weight, or 10-20% by weight.

[0167] In the present invention, the granules in the layer containing the first release portion may contain at least one of sodium starch glycolate and croscamerose 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 containing the first release portion may contain sodium starch glycolate. In another example, the granules in the layer may contain croscamerose sodium. In yet another example, the granules in the layer may contain both sodium starch glycolate and croscamerose sodium. In yet another example, the granules in the layer may contain, but are not limited to, 1 to 15% by weight, 1 to 10% by weight, or 2 to 8% by weight of sodium starch glycolate. In yet another example, the granules in the layer may contain, but are not limited to, 1 to 15% by weight, 1 to 10% by weight, or 2 to 8% by weight of croscamerose sodium.

[0168] In the present invention, the granules in the layer containing the first release portion may contain 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.

[0169] In the present invention, the granules in the layer containing the first release portion may contain talc in an amount of 0.1 to 10% by weight, 0.1 to 5% by weight, or 1 to 5% by weight.

[0170] In the present invention, the granules in the layer containing the first release portion may contain magnesium stearate in an amount of 0.1 to 5% by weight, 0.5 to 5% by weight, or 1 to 5% by weight.

[0171] In one example, the granules in the layer containing the first release portion may contain, based on the total weight of the first release portion, 10-80% by weight of the active ingredient, 1-50% by weight of at least one of microcrystalline cellulose and mannitol, 5-30% by weight of low-substituted hydroxypropyl cellulose, 1-15% by weight of at least one of sodium starch glycolate and croscamerose sodium, 0.1-5% by weight of colloidal silicon dioxide, 0.1-10% by weight of talc, and 0.1-5% by weight of magnesium stearate. The post-mixing portion may contain, but is not limited to, 1-15% by weight of sodium starch glycolate, 0.1-5% by weight of colloidal silicon dioxide, and 0.1-5% by weight of magnesium stearate, based on the total weight of the first release portion.

[0172] In other examples, the granules in the layer containing the first release portion may contain, based on the total weight of the first release portion, 10-80% by weight of the active ingredient, 5-50% by weight of microcrystalline cellulose, 5-30% by weight of low-substituted hydroxypropyl cellulose, 1-15% by weight of sodium starch glycolate, 0.1-5% by weight of colloidal silicon dioxide, 0.1-10% by weight of talc, and 0.1-5% by weight of magnesium stearate. The post-mixing portion may contain, but is not limited to, 1-15% by weight of sodium starch glycolate, 0.1-5% by weight of colloidal silicon dioxide, and 0.1-5% by weight of magnesium stearate, based on the total weight of the first release portion.

[0173] In further examples, the granules in the layer containing the first release portion may, based on the total weight of the first release portion, contain 10-80% by weight of the active ingredient, 1-30% by weight of microcrystalline cellulose, 1-20% by weight of mannitol, 5-30% by weight of low-substituted hydroxypropyl cellulose, 1-15% by weight of croscamerose sodium, 0.1-5% by weight of colloidal silicon dioxide, 0.1-10% by weight of talc, and 0.1-5% by weight of magnesium stearate, and the post-mixing portion may, but is not limited to, contain 1-15% by weight of croscamerose sodium, 0.1-5% by weight of colloidal silicon dioxide, and 0.1-5% by weight of magnesium stearate, based on the total weight of the first layer.

[0174] In further examples, the granules in the layer containing the first release portion may, based on the total weight of the first release portion, contain 10-80% by weight of the active ingredient, 1-20% by weight of microcrystalline cellulose, 1-20% by weight of mannitol, 5-20% by weight of low-substituted hydroxypropyl cellulose, 1-10% by weight of croscamerose sodium, 0.1-5% by weight of colloidal silicon dioxide, 0.1-5% by weight of talc, and 0.1-5% by weight of magnesium stearate, and the post-mixing portion may, but is not limited to, contain 1-10% by weight of croscamerose sodium, 0.1-5% by weight of colloidal silicon dioxide, and 0.1-5% by weight of magnesium stearate, based on the total weight of the first layer.

[0175] In the present invention, the layer containing the second release portion (second layer) may contain granules containing the active ingredient and a post-mixing portion. In this case, the granules may additionally contain pharmaceutically acceptable additives such as excipients, disintegrants, or lubricants. The post-mixing portion may additionally contain at least one pharmaceutically acceptable additive, such as a disintegrant and a lubricant.

[0176] In one example, the layer including the second release portion may include, but is not limited to, granules containing an active ingredient, an excipient, a disintegrant, and a lubricant, and a post-mixing portion containing a disintegrant and a lubricant.

[0177] In the present invention, the granules in the layer containing the second release portion may contain 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.

[0178] In the present invention, the granules in the layer containing the second release portion may contain an excipient in an amount of 20-95% by weight, 30-90% by weight, 40-90% by weight, 50-80% by weight, or 60-80% by weight, based on the total weight of the second release portion.

[0179] In the present invention, the granules in the layer containing the second release portion may contain 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.

[0180] In the present invention, the granules in the layer containing the second release portion may contain 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.

[0181] In the present invention, the post-mixing portion within the layer containing the second discharge portion may contain 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 discharge portion.

[0182] In the present invention, the post-mixing portion within the layer containing the second discharge portion may contain 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 discharge portion.

[0183] In one example, the granules in the layer containing the second release portion may contain, 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 10% by weight of the lubricant, and the post-mixing portion may contain, but is not limited to, 1 to 30% by weight of the disintegrant and 0.1 to 10% by weight of the lubricant, based on the total weight of the second release portion.

[0184] In other examples, the granules in the layer containing the second release portion may contain, 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 the excipient, 1 to 10% by weight of the disintegrant, and 1 to 10% by weight of the lubricant, and the post-mixing portion may contain, but is not limited to, 5 to 20% by weight of the disintegrant and 0.1 to 10% by weight of the lubricant, based on the total weight of the second release portion.

[0185] In further examples, the granules in the layer containing the second release portion may contain, 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 monohydrate, 10 to 50% by weight of mannitol, 0.1 to 20% by weight of hydroxypropyl cellulose, and 0.1 to 10% by weight of sodium stearyl fumarate, and the post-mixing portion may contain, but is not limited to, 0.5 to 20% by weight of croscamerose sodium and 0.1 to 10% by weight of sodium stearyl fumarate, based on the total weight of the second release portion.

[0186] In further examples, the granules in the layer containing the second release portion may contain, 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 hydroxypropyl cellulose, and 0.1 to 10% by weight of sodium stearyl fumarate, and the post-mixing portion may contain, but is not limited to, 0.5 to 20% by weight of croscamerose sodium and 0.1 to 10% by weight of sodium stearyl fumarate, based on the total weight of the second layer.

[0187] The combined formulation according to the present invention, as described above, contains both sacubitril-valsartan and an SGLT-2 inhibitor, such as dapagliflozin, as two pharmacologically active ingredients in a single formulation. This makes it potentially useful for the treatment or prevention of heart failure, particularly heart failure that is not adequately controlled by a single drug alone, and significantly improves the convenience of medication for patients by eliminating the inconvenience of having to take two separate formulations. Depending on the amount of the main ingredients contained, the combined formulation can be administered once, twice, three times, or four times a day.

[0188] Furthermore, the compound formulation of the present invention has the advantage of being in the form of a two-layer tablet or a drug-coated tablet in which a first release portion containing sacubitril-valsartan and a second release portion containing an SGLT-2 inhibitor are physically separated, so that the SGLT-2 inhibitor is dissolved at a faster rate than sacubitril-valsartan, and sacubitril-valsartan, which has low solubility in low pH environments such as stomach acid, does not inhibit the dissolution of the SGLT-2 inhibitor, so that all of these components have an immediate-release dissolution pattern, thereby ensuring the rapid and sufficient pharmacological effects of each component within the administration period.

[0189] Furthermore, the combined formulation according to the present invention has a synergistic effect of treatment through the combined use of sacubitril-valsartan and an SGLT-2 inhibitor, and has high stability by suppressing the generation of related substances.

[0190] In one example, the compound formulation according to the present invention is characterized in that, during an dissolution test (pH 1.2 solution, 37°C, 900 mL, 50 rpm), the dissolution rate (by weight) of the SGLT-2 inhibitor (e.g., dapagliflozin) is 50% or more, 60% or more, 70% or more, or 80% or more within 10 minutes, 80% or more, 85% or more, or 90% or more within 15 minutes, and 85% or more, 90% or more, or 95% or more within 30 minutes.

[0191] In other examples, the compound formulation according to the present invention shows that, in dissolution tests (pH 1.2 solution, 37°C, 900 mL, 50 rpm), sacubitril dissolves at a rate of 10-40% after 30 minutes and within 50% after 2 hours, but is not limited to this.

[0192] In other examples, the compound formulation according to the present invention can dissolve valsartan at a rate of 10-40% after 30 minutes and within 50% after 2 hours in an dissolution test (pH 1.2 solution, 37°C, 900 mL, 50 rpm), but is not limited to this.

[0193] In further examples, the compound formulation according to the present invention is characterized in that, during an dissolution test (pH 6.8 solution, 37°C, 900 mL, 50 rpm), the dissolution rate (by weight) of the SGLT-2 inhibitor (e.g., dapagliflozin) is 50-95% or 60-90% within 10 minutes, 80% or more, 85% or more, or 90% or more within 15 minutes, and 90% or more, or 95% or more within 30 minutes.

[0194] In other examples, the compound formulation according to the present invention may have a dissolution rate of 80% or more, 90% or more, or 95% or more of sacubitril within 30 minutes during a dissolution test (pH 6.8 solution, 37°C, 900 mL, 50 rpm), but is not limited thereto.

[0195] In other examples, the compound formulation according to the present invention may, but is not limited to, an valsartan dissolution rate of 80% or more, 90% or more, or 95% or more within 30 minutes during a dissolution test (pH 6.8 solution, 37°C, 900 mL, 50 rpm).

[0196] Another embodiment of the present invention relates to a method for producing a compound formulation according to the present invention, comprising the following steps: (a) A step of manufacturing a first release section containing sacubitril-valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, (b) A step of manufacturing a second release section containing an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient, (c) The step of compounding the first release unit and the second release unit into a single solid dosage form may be included.

[0197] In the present invention, the compound formulation at step (c) may be formulated in the form of a two-layer tablet, a multi-layer tablet, or a drug-coated tablet with a core-shell structure.

[0198] In the present invention, steps (a) and (b) do not necessarily have to be performed sequentially. Step (b) can be performed after step (a), or step (a) can be performed after step (b), or steps (a) and (b) can be performed simultaneously.

[0199] In the present invention, the step of (a) manufacturing the first release portion may include (a-1) mixing sacubitril-valsartan or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive; (a-2) manufacturing granules; and (a-3) mixing the granules with the post-mixing portion.

[0200] In the present invention, in step (a-1) above, the sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof in the first release portion of the present invention may be contained in a molar ratio of 1:5 to 5:1, preferably in a molar ratio of 1:1, but is not limited thereto.

[0201] In the present invention, the pharmaceutically acceptable additive in step (a-1) or the post-mixing portion in step (a-3) may each contain one or more selected from the group consisting of excipients, disintegrants, and lubricants.

[0202] In the present invention, the excipient (diluent) can be selected from the group consisting of, for example, microcrystalline cellulose, silicified microcrystalline cellulose, magnesium aluminometasilicate, magnesium aluminosilicate, aluminum silicate, sodium silicate, potassium silicate, magnesium silicate, calcium silicate, lactose, lactose monohydrate, lactose anhydrous, calcium hydrogen phosphate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, dextrin, mannitol, sorbitol, starch, calcium phosphate monohydrate, calcium carbonate, sugars, and any mixture thereof, but is not limited thereto. However, in the present invention, anhydrous calcium phosphate is not included as an excipient (diluent) because its compatibility with dapagliflozin and sacubitril-valsartan is poor.

[0203] In the present invention, the disintegrant can be selected from, but is not limited to, the group consisting of, for example, crospovidone, methylcellulose, cross-linked carboxymethylcellulose sodium (C.CMC Na, or croscamerose sodium), carboxymethylcellulose calcium, sodium starch glycolate, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose, starch, pre-gelatinized starch, corn starch, potato starch, alginic acid or its sodium salt, and any combination thereof.

[0204] In the present invention, the lubricant can be selected from, but is not limited to, the group consisting of, for example, calcium stearate, colloidal silicon dioxide (fumed 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 combination thereof.

[0205] In one example, in step (a-1) above, granules can be produced by adjusting and mixing sacubitril and valsartan or pharmaceutically acceptable salts thereof as active ingredients and pharmaceutically acceptable additives selected from microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose (L-HPC), crocamellose sodium, sodium starch glycolate, colloidal silicon dioxide (fumed silica, Aerosil), talc, magnesium stearate, and any combination thereof, in appropriate amounts.

[0206] In other examples, step (a-1) above may include sacubitril and valsartan or pharmaceutically acceptable salts thereof as active ingredients, and pharmaceutically acceptable additives selected from microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose (L-HPC), crocamellose sodium, colloidal silicon dioxide (fumed silica, Aerosil), talc, magnesium stearate, and any combination thereof.

[0207] In further examples, step (a-1) may include sacubitril and valsartan or pharmaceutically acceptable salts thereof as active ingredients, and pharmaceutically acceptable additives selected from microcrystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC), sodium starch glycolate, colloidal silicon dioxide (fumed silica, Aerosil), talc, magnesium stearate, and any combination thereof.

[0208] In the present invention, step (a-2) granule production can be carried out by any granule production method known in the art, for example, by a dry granulation method. Specifically, a mixture of sacubitril and valsartan or a pharmaceutically acceptable salt thereof as active ingredients and a pharmaceutically acceptable additive such as an excipient, disintegrant or lubricant can be granulated using roller compacting or slugging. Here, roller compacting refers to a method of producing granules by pressing powder between two rollers at a constant pressure while passing it through them. The roller compacting method can be carried out using a roller compactor. The roller-compacted mixture can then be further processed by grinding and refining using a fitzmill, oscillator, etc., as needed, to obtain granules of an appropriate size.

[0209] In the present invention, in step (a-3), the post-mixing portion may include a disintegrant, a lubricant, or a mixture thereof, and may additionally include excipients (diluents) or binders as needed.

[0210] In one example, in step (a-3), the granules obtained in step (a-2) and a post-mixing portion containing sodium starch glycolate, colloidal silicon dioxide (fumed silica, Aerosil), and magnesium stearate can be adjusted and mixed in appropriate proportions.

[0211] In the present invention, depending on the dosage form of the compound formulation to be ultimately produced, the step of tableting (a-4) may be further included after step (a-3).

[0212] In the present invention, step (a-4) above may be performed using a commonly used tablet press, such as a rotary tablet press, for the purpose of tableting granules.

[0213] In the present invention, in step (a-4) above, the tablets obtained after tableting can be manufactured in a variety of shapes, for example, elliptical, rectangular, egg-shaped, triangular, almond-shaped, peanut-shaped, parallelogram-shaped, circular, pentagonal, hexagonal, or trapezoidal, preferably circular, egg-shaped, or parallelogram-shaped.

[0214] In the present invention, the content of each component mixed during the manufacture of the first release portion overlaps with that described in the first layer of the composite formulation according to the present invention, and in order to avoid excessive complexity in the specification, a detailed description thereof is omitted below.

[0215] In the present invention, the step of (b) manufacturing the second release portion may include the step of (b-1) mixing an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive.

[0216] In the present invention, the pharmaceutically acceptable additive in step (b-1) above may be one or more selected from the group consisting of excipients, disintegrants, and lubricants.

[0217] In the present invention, the excipient (diluent) can be selected from the group consisting of, for example, microcrystalline cellulose, silicified microcrystalline cellulose, magnesium aluminometasilicate, magnesium aluminosilicate, aluminum silicate, sodium silicate, potassium silicate, magnesium silicate, calcium silicate, lactose, lactose monohydrate, lactose anhydrous, calcium hydrogen phosphate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, dextrin, mannitol, sorbitol, starch, calcium phosphate monohydrate, calcium carbonate, sugars, and any mixture thereof, but is not limited thereto. However, in the present invention, anhydrous calcium phosphate is not included as an excipient (diluent) because its compatibility with dapagliflozin and sacubitril-valsartan is poor.

[0218] In the present invention, the disintegrant can be selected from, but is not limited to, the group consisting of, for example, crospovidone, methylcellulose, cross-linked carboxymethylcellulose sodium (C.CMC Na, or croscamerose sodium), carboxymethylcellulose calcium, sodium starch glycolate, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose, starch, pre-gelatinized starch, corn starch, potato starch, alginic acid or its sodium salt, and any combination thereof.

[0219] In the present invention, the lubricant can be selected from, but is not limited to, the group consisting of, for example, calcium stearate, colloidal silicon dioxide (fumed 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 combination thereof.

[0220] In one example, if the dosage form of the compound formulation ultimately manufactured is a two-layer tablet, then in step (b-1), an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof can be adjusted and mixed in appropriate amounts as the active ingredient, and pharmaceutically acceptable excipients selected from microcrystalline cellulose, lactose monohydrate, mannitol, hydroxypropyl cellulose, sodium stearyl fumarate, crocamellose sodium, and any combination thereof.

[0221] In one example, if the dosage form of the compound formulation ultimately manufactured is a two-layer tablet, in step (b-1) above, an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof can be adjusted and mixed in appropriate amounts as the active ingredient, and pharmaceutically acceptable excipients selected from microcrystalline cellulose, mannitol, hydroxypropyl cellulose, sodium stearyl fumarate, crocamellose sodium, and any combination thereof.

[0222] Furthermore, in the present invention, if the dosage form of the compound formulation finally manufactured is a two-layer tablet, the invention may include, after step (b-1), a step of (b-2) manufacturing granules and a step of (b-3) mixing the granules with the post-mixing portion.

[0223] In the present invention, the post-mixing portion of step (b-3) may include a disintegrant, a lubricant, or a mixture thereof, and may additionally include an excipient (diluent) or a binder as needed.

[0224] In one example, in step (b-3), the granules obtained in step (b-2) and a post-mixing portion containing sodium stearyl fumarate and sodium crocamellose can be adjusted and mixed in appropriate amounts.

[0225] In the present invention, in step (c), in order to manufacture a composite formulation in the form of a two-layer tablet, the mixed powder of the first release portion (a mixture of granules and post-mixing portion) obtained in step (a-3) and the mixed powder of the second release portion (b-3) obtained in step (b-3) can be used as the upper layer mixed powder and lower layer mixed powder of the two-layer tablet, or conversely, the lower layer mixed powder and upper layer mixed powder, and pressure can be applied in a tablet press to manufacture a two-layer tablet.

[0226] On the other hand, in the present invention, if the dosage form of the compound formulation to be finally manufactured is a drug-coated tablet, a coating solution can be manufactured in step (b-1) above by adjusting and mixing an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof with a coating base in appropriate amounts.

[0227] In the present invention, the coating base may be one or more hydrophilic polymers selected from the group consisting of, for example, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, polymers of acrylic acid and its salts, polymethacrylate, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer (e.g., Eudragit® E, Evonik), carboxymethylcellulose (sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone (povidone; PVP), vinylpyrrolidone-vinyl acetate copolymer (e.g., Kollidon® VA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan gum, and mixtures thereof. Preferably, the coating base may be hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, or poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer (e.g., Eudragit® E, Evonik).

[0228] Furthermore, in the present invention, the coating solvent used in the production of the coating solution can be ethanol, methanol, acetone, acetonitrile, tetrahydrofuran, hexane, methylene chloride, isopropyl alcohol, water, or mixtures thereof. Preferably, ethanol, water, or mixtures thereof can be used.

[0229] In the present invention, for additional purposes such as improving the efficiency of coating during the production of the coating solution, improving drug stability, appearance, color, protection, maintenance, bonding, performance improvement, and improving the manufacturing process, one or more substances selected from the group consisting of plasticizers, lubricants, colorants, fragrances, surfactants, stabilizers, antioxidants, foaming agents, defoaming agents, paraffin, and waxes may be added and mixed in.

[0230] In step (c) of the present invention, in order to produce a compound formulation in the form of a drug-coated tablet, a core containing sacubitril-valsartan or a pharmaceutically acceptable salt thereof obtained in step (a) as an active ingredient, preferably a tablet-shaped core obtained in step (a-4), can be coated with the coating solution of the second release portion obtained in step (b-1) to produce a drug-coated tablet in which the sacubitril-valsartan core is coated with an SGLT-2 inhibitor drug. Herein, the coating may be carried out using conventional methods used in the art for coating drugs, for example, a coating method using a pan coating machine can be used, but is not limited thereto.

[0231] In one example of a manufacturing method, a method for manufacturing a compound formulation in the form of a two-layer tablet may include the steps of: (a-1) mixing sacubitril and valsartan or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive; (a-2) manufacturing granules; (a-3) mixing the post-mixing portion to manufacture a mixed powder for the first release portion; (b-1) mixing an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive; (b-2) manufacturing granules; (b-3) mixing the post-mixing portion to manufacture a mixed powder for the second release portion; and (c) compressing the mixed powder for the first release portion and the mixed powder for the second release portion into tablets to manufacture a two-layer 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 limited.

[0232] In another example of a manufacturing method, a method for manufacturing a compound formulation in the form of a drug-coated tablet may include the steps of: (a-1) mixing sacubitril and valsartan or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive; (a-2) manufacturing granules; (a-3) mixing a post-mixing portion to manufacture a mixed powder of a first release portion; (a-4) compressing the mixed powder of the first release portion to manufacture an uncoated tablet; (b-1) mixing an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof with a coating base to manufacture a coating solution; and (c) coating the surface of an uncoated tablet containing the first release portion with the coating solution to manufacture a drug-coated tablet. However, the order in which steps (a-1), (a-2), (a-3), (a-4) and (b-1) are performed is not particularly limited.

[0233] The manufacturing method of the present invention may further include a step of coating the obtained compound formulation, particularly the compound formulation in the form of a two-layer tablet, with a pharmaceutically active film coating base that is normally available in the art, in a conventional manner. For example, a moisture-proof film coating of about 3% with Opadry II coating solution can be performed based on the total weight of the uncoated two-layer tablet, but is not limited thereto.

[0234] The present invention will be described in more detail below through the examples. These examples are merely for the purpose of illustrating the present invention in more detail, and it will be obvious to those with ordinary skill in the art that the scope of the present invention is not limited by these examples, given the gist of the invention.

[0235] Examples [Comparative Examples 1-2] Manufacturing of single-layer tablets containing sacubitril-valsartan and dapagliflozin To manufacture a single compound tablet in which sacubitril-valsartan and dapagliflozin are physically mixed, sacubitril-valsartan, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium starch glycolate, colloidal silicon dioxide, talc, and magnesium stearate are mixed according to the composition shown in Table 1 below, and the mixture is carried out using a roller compressor (TFC-LAB, Freund vector) with a hydraulic pressure of 5 MPa, a roller speed of 1 rpm, and a screw speed of 5 rpm. After forming dry granules by compression under the condition of speed, the granules were refined using a sieve with a mesh size of 20 mesh (0.86 mm), and then sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate were added and mixed to produce the final mixed powder. In addition, dapagliflozin, microcrystalline cellulose, D-mannitol, hydroxypropyl cellulose, croscamerose sodium, and sodium stearyl fumarate were added during the process of producing the dry granules (Comparative Example 1) or during the post-mixing process (Comparative Example 2) to produce the final mixed powder. Subsequently, single-layer tablets with a hardness of approximately 15 KP were produced using a tablet press (AUTOTAB-200TR, Ichihashi Seiki) at a tableting pressure of 10 KN.

[0236] [Table 1]

[0237] [Examples 1-2] Preparation of two-layer tablets containing sacubitril-valsartan and dapagliflozin Sacubitryl-valsartan, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium starch glycolate, colloidal silicon dioxide, talc, and magnesium stearate were mixed according to the composition shown in Table 2 below. Dry granules were formed by compression using a roller compressor (TFC-LAB, Freund vector) under conditions of 5 MPa hydraulic pressure, 1 rpm roller speed, and 5 rpm screw speed, and then refined using a sieve with a mesh size of 20 mesh (0.86 mm). Sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate were then added and mixed to produce the final scubitryl-valsartan mixed powder. Then, dapagliflozin, microcrystalline cellulose, lactose monohydrate, D-mannitol, hydroxypropyl cellulose, croscamerose sodium, and stearyl fumarate sodium were mixed and compressed using a roller compressor (TFC-LAB, Freund vector) under conditions of 5 MPa hydraulic pressure, 1 rpm roller speed, and 5 rpm screw speed to form dry granules, which were then refined using a sieve with a mesh size of 20 mesh (0.86 mm). Stearyl fumarate sodium was then added to produce the final dapagliflozin mixture powder. The sacubitril-valsartan final mixture powder was used as the lower layer and the dapagliflozin final mixture powder as the upper layer, and two-layer tablets (hardness approximately 15 KP) were produced by compressing them with a tablet press (Autotab-200TR, Ichihashi Seiki) using an oval punch with dimensions of 17.5 mm horizontally and 9 mm vertically at a compression pressure of 10 KN.

[0238] [Table 2]

[0239] [Example 3] Manufacture of drug-coated tablets containing sacubitril-valsartan and dapagliflozin After preparing the sacubitril-valsartan final mixed powder in the same manner as in Example 1, uncoated tablets were produced by compressing them in a tablet press. To prepare the drug coating solution, a coating solution containing dapagliflozin, povidone, and a macrogol-polyvinyl alcohol copolymer was prepared per 1T in 200 mg of purified water and 200 mg of ethanol, according to the composition shown in Table 3 below. Subsequently, using a high-speed mixing machine (XENA-IV, Raon), with an air supply temperature of 55°C, an exhaust temperature of 45°C, a pan speed of 6 rpm, and an air pressure gauge of 2-4 kgf / cm², the mixture was prepared. 2 Under these conditions, the coating solution was coated onto the surface of the uncoated tablet.

[0240] [Table 3]

[0241] [Comparative Example 3] Manufacturing of nuclear tablets containing sacubitril-valsartan and dapagliflozin Using the same composition as in Example 1, a sacubitril-valsartan final mixed powder for the core tablet and a dapagliflozin final mixed powder for the outer core tablet were prepared. The sacubitril-valsartan final mixed powder was compressed in a tablet press to produce core tablets. Half of the dapagliflozin final mixed powder and the core tablet were sequentially filled, and then the remaining dapagliflozin final mixed powder was filled, and pressure was applied to produce core tablets. At this time, the compression pressure was adjusted to 7-10 kN and no prepress was applied.

[0242] [Comparative Example 4] Production of polycaps containing sacubitril-valsartan tablets and dapagliflozin tablets Sacubitril-valsartan final mixed powder and dapagliflozin final mixed powder were prepared using the same composition as in Example 1. Two single-layer tablets were produced by compressing each of the sacubitril-valsartan final mixed powder and dapagliflozin final mixed powder using a tablet press. Capsules were produced using a polycap filling machine (GKF2500, Bosch) under conditions of an air pressure of 5-7 bar and a filling speed of 30-150 C / min, such that each capsule contained both of these tablets. HPMC capsules with a moisture content of approximately 3-7%, gelatin of approximately 13-16%, and gelatin-PEG of approximately 10-14% were used as the capsule base.

[0243] [Comparative Example 5] Modification of excipient components in a two-layer tablet containing sacubitril-valsartan and dapagliflozin. To confirm the changes in the dissolution pattern and stability of the compound tablets due to the components of the excipients, two-layer tablets were prepared using the same manufacturing method as in Example 1, and the microcrystalline cellulose used as an excipient in the production of the final mixed powder of dapagliflozin was replaced with anhydrous calcium phosphate to produce the two-layer tablets as shown in Table 4 below.

[0244] [Table 4]

[0245] [Experimental Example 1] Dissolution evaluation of different compound formulations Both sacubitril-valsartan and dapagliflozin are fast-absorbing drugs, with a time to reach peak blood concentration (Tmax) of less than 2 hours after administration, and have high bioavailability of approximately 80% or more. In the case of dapagliflozin, solubility is high at all pH levels, but in the case of sacubitril-valsartan, solubility decreases as the pH decreases. Considering these characteristics, the following experiment was conducted to ensure that both components exhibited immediate release and had a dissolution profile similar to the control drug in solutions at pH 1.2 and pH 6.8.

[0246] Specifically, dissolution evaluations of dapagliflozin, saxagliptin, and valsartan in the combination preparations containing 10 mg of dapagliflozin and 200 mg of saxagliptin-valsartan manufactured in Examples 1 to 3 and Comparative Examples 1 to 5 were performed. Considering the absorption position and rate of the drug, comparison of drug release at low pH and high pH was carried out under the following test and analysis conditions. The dissolution rates of each component in the combination preparation in pH 1.2 solution and pH 6.8 solution were compared with those of the single-agent control drugs, Fosiga tablets TM (dapagliflozin propanediol hydrate) 10 mg, Enrest tablets TM (saxagliptin / valsartan) 200 mg, and the results are shown in Tables 5 to 10 and Figures 1 to 6.

[0247] <Dissolution test conditions> Dissolution test solution: pH 1.2 buffer (900 mL), pH 6.8 buffer (900 mL) Dissolution apparatus: Paddle Rotation speed: 50 rpm Temperature: 37 °C

[0248] <Analysis conditions - LC> Column: Inertsil C8 (4.6 × 150 mm, 5 μm) or a column equivalent thereto Flow rate: 1.5 ml / min Column temperature: 40 °C Injection volume: 20 μL Mobile phase: pH 2.0 buffer: ACN = 60:40 pH 2.0 buffer: Dissolve 3.48 g of potassium dihydrogen phosphate in 1000 mL, and adjust the pH to 2.0 with phosphoric acid.

[0249]

Table 5

[0250]

Table 6

[0251]

Table 7

[0252]

Table 8

[0253]

Table 9

[0254]

Table 10

[0255] As shown in Tables 5 to 10 above, in Comparative Examples 1 and 2 which are single-layer tablets containing saxagliptin-valsartan and dapagliflozin physically mixed, saxagliptin-valsartan and dapagliflozin are released simultaneously. However, in the process of the two components dissolving simultaneously in the pH 1.2 solution and the pH 6.8 solution, it was confirmed that a sticky property change occurred, suppressing each other's dissolution and delaying the elution. In particular, in the pH 1.2 solution, the elution rate of both components was confirmed to be 10% or less at 45 minutes.

[0256] In the case of the nucleated tablets of Comparative Example 3 designed such that saxagliptin-valsartan is distributed in the inner core layer and dapagliflozin is distributed in the outer core layer, after the disintegration of the outer core layer progresses, the disintegration of the inner core layer is initiated. Therefore, in the case of the elution rate of dapagliflozin present in the outer core layer, a rapid elution profile similar to the control was confirmed. However, in the case of saxagliptin-valsartan present in the inner core layer, a relatively slow elution profile compared to the control drug was confirmed.

[0257] In the case of the polycap in Comparative Example 4, in which a single tablet of sacubitril-valsartan and a single tablet of dapagliflozin were filled into one capsule, the disintegration of the tablets began after the capsule dissolved. As a result, the initial dissolution rate at 5 or 10 minutes was relatively slower than that of the control drug, and the dissolution rate gradually increased after 15 minutes. However, even after 45 minutes, the dissolution rate of dapagliflozin remained extremely low compared to the control drug in both the pH 1.2 and pH 6.8 solutions.

[0258] On the other hand, in the case of the two-layer tablets of Examples 1 and 2, in which sacubitril-valsartan and dapagliflozin were positioned in separate layers, similar dissolution profiles to the control drug were observed for all components of sacubitril, valsartan, and dapagliflozin in pH 1.2 and pH 6.8 solutions. However, in the case of the two-layer tablet of Comparative Example 5, which used anhydrous calcium phosphate as an excipient, unlike the microcrystalline cellulose in Example 1 and lactose monohydrate in Example 2, anhydrous calcium phosphate is insoluble in water, and due to its high density, a dissolution profile was observed in which the disintegration of the dapagliflozin tablet portion was relatively slower than that of the control drug.

[0259] In the case of the drug-coated tablets of Example 3, in which the sacubitril-valsartan core was drug-coated with dapagliflozin, the initial dissolution rate at 5 or 10 minutes tended to be slightly faster than the control drug because dapagliflozin encountered the dissolution test solution the fastest. However, similar dissolution profiles were observed at subsequent time points, and sacubitril and valsartan showed similar dissolution profiles to the control drug under all conditions, including pH 1.2 and pH 6.8 solutions.

[0260] [Experimental Example 2] Evaluation of related stability for different compound formulations While sacubitril-valsartan exhibits relatively stable properties against heat and moisture, and has good compatibility with commonly used excipients, dapagliflozin is highly susceptible to structural deformation due to external factors, given that there are over 80 known related substances. Therefore, confirming the stability of dapagliflozin's related substances is essential during dosage form development.

[0261] Therefore, analogous stability evaluations were performed on the compound formulations produced in Examples 1-3 and Comparative Examples 1-5. The increasing trend of dapagliflozin analogs in samples prepared according to dosage form and excipient type was evaluated by exposure to accelerated conditions (40°C, 75%RH) and harsh conditions (60°C) for two weeks. The results are shown in Figures 7-10. The analytical conditions for analogs are as follows. For a control example, Farxiga tablets were used. TM The analysis results for related substances of 10 mg of (dapagliflozin propanediol hydrate) are shown.

[0262] <Analysis conditions-LC> Column: Waters X-Bridge C18 (4.6 × 150 mm, 3.5 μm) or equivalent column Flow rate: 1.0ml / min Column temperature: 50℃ Injection volume: 10μL Mobile phase: A-ACN:pH2.5 buffer=10:90, B-MeOH:pH2.5 buffer=90:10 pH 2.5 buffer: Dissolve 3.12 g of monosodium phosphate dihydrate in 1000 mL, then adjust the pH to 2.5 with phosphoric acid.

[0263] [Table 11]

[0264] As shown in Figures 7-10, in Comparative Examples 1 and 2, which are mixed single tablets, sacubitril-valsartan and dapagliflozin are not separated but exist while influencing each other. However, sacubitril-valsartan, which has a high property of absorbing moisture during accelerated exposure, absorbs moisture and affects dapagliflozin, and it was confirmed that the level of the unknown related substance (RRT1.59) generated by moisture under accelerated exposure conditions increased.

[0265] In the case of the core-containing tablet in Comparative Example 3, dapagliflozin was compressed as the outer core layer, surrounding the inner core layer. At this time, high compression pressure was transmitted in all directions in order to maintain the morphology, resulting in the detection of an unknown related substance (RRT0.38), which shows an increase due to heat, at a high level from the beginning, and it showed an increase further during acceleration and severe exposure.

[0266] On the other hand, in the case of the two-layer tablets of Examples 1 and 2, it was confirmed that the stability of related substances was generally good. However, in the case of the two-layer tablet of Comparative Example 5, which used anhydrous calcium phosphate as an excipient, the compatibility of the formulation between dapagliflozin and anhydrous calcium phosphate was poor, and as a result, the unknown related substance (RRT0.74) increased significantly when exposed to moisture and heat, and it was confirmed that the increase due to heat was even greater.

[0267] In the case of the drug-coated tablet of Example 3, dapagliflozin is partially exposed to heat during the drug coating process, so the detection level of the unknown related substance (RRT0.74) tends to be slightly higher. However, it can be confirmed that the amount detected is extremely low compared to the core tablet of Comparative Example 3.

[0268] [Example 4] Preparation of a two-layer tablet containing sacubitril-valsartan and dapagliflozin Saxagliptin - valsartan, microcrystalline cellulose, D - mannitol, low - substituted hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, talc, and magnesium stearate were mixed according to the composition shown in Table 12 below, and then charged into a roller compactor to produce dry granules. Croscarmellose sodium and colloidal silicon dioxide were mixed to produce a secondary mixed powder, and then magnesium stearate was post - mixed to produce the saxagliptin - valsartan final mixed powder (the first mixed powder). Then, dapagliflozin propanediol, microcrystalline cellulose, D - mannitol, hydroxypropyl cellulose, croscarmellose sodium, and sodium stearyl fumarate were mixed and charged into a roller compactor to produce dry granules. Subsequently, croscarmellose sodium was mixed with the granules to produce a secondary mixed powder, and then sodium stearyl fumarate was post - mixed to produce the dapagliflozin final mixed powder (the second mixed powder). Using the saxagliptin - valsartan final mixed powder as the lower layer and the dapagliflozin final mixed powder as the upper layer, tablets were compressed with a tableting pressure of 10 KN using a tableting machine (Autotab - 200TR, ichihashi seiki) and an elliptical punch with a width of 17.5 mm and a length of 9 mm to produce bilayer tablets (hardness approximately 15 KP).

[0269] [Table 12]

[0270] [Experimental Example 3] Dissolution Evaluation of Bilayer Tablets To evaluate the dissolution ability of each active ingredient in the bilayer tablets of saxagliptin - valsartan and dapagliflozin produced in Example 4 above, the dissolution profiles in pH 1.2 solution were confirmed by the same method as in Experimental Example 1, and the results are shown in Tables 13 - 15 below.

[0271] [Table 13]

[0272] [Table 14]

[0273] [Table 15]

[0274] As shown in Tables 13-15 above, in the case of the two-layer tablet of Example 4, in which sacubitril-valsartan and dapagliflozin were positioned in separate layers, all components of sacubitril, valsartan, and dapagliflozin showed excellent dissolution profiles in a pH 1.2 solution.

[0275] [Examples 5 and 6] Preparation of two-layer tablets containing sacubitril-valsartan and dapagliflozin Sacubitryl-valsartan, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium starch glycolate, colloidal silicon dioxide, talc, and magnesium stearate were mixed according to the composition shown in Table 16 below. Dry granules were formed by compression using a roller compressor (TFC-LAB, Freund vector) under conditions of 5 MPa hydraulic pressure, 1 rpm roller speed, and 5 rpm screw speed, and then refined using a sieve with a mesh size of 20 mesh (0.86 mm). Sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate were then added and mixed to produce the final scubitryl-valsartan mixed powder. Then, dapagliflozin, microcrystalline cellulose, lactose monohydrate, D-mannitol, hydroxypropyl cellulose, croscamerose sodium, and stearyl fumarate sodium were mixed and compressed using a roller compressor (TFC-LAB, Freund vector) under conditions of 5 MPa hydraulic pressure, 1 rpm roller speed, and 5 rpm screw speed to form dry granules, which were then refined using a sieve with a mesh size of 20 mesh (0.86 mm). Stearyl fumarate sodium was then added to produce the final dapagliflozin mixture powder. The sacubitril-valsartan final mixture powder was used as the lower layer and the dapagliflozin final mixture powder as the upper layer, and two-layer tablets (hardness approximately 15 KP) were produced by compressing them with a tablet press (Autotab-200TR, Ichihashi Seiki) using an oval punch with dimensions of 17.5 mm horizontally and 9 mm vertically at a compression pressure of 10 KN.

[0276] [Table 16]

[0277] [Example 7] Manufacture of drug-coated tablets containing sacubitril-valsartan and dapagliflozin After preparing the sacubitril-valsartan final mixed powder in the same manner as in Example 5, uncoated tablets were produced by compressing them in a tablet press. To prepare the drug coating solution, a coating solution containing dapagliflozin, povidone, and a macrogol-polyvinyl alcohol copolymer was prepared per 1T in 200 mg of purified water and 200 mg of ethanol, according to the composition shown in Table 17 below. Subsequently, using a high-speed mixing machine (XENA-IV, Raon), the mixture was prepared with an air supply temperature of 55°C, an exhaust temperature of 45°C, a pan speed of 6 rpm, and an air pressure gauge of 2-4 kgf / cm². 2 Under these conditions, the coating solution was coated onto the surface of the uncoated tablet.

[0278] [Table 17]

[0279] [Example 8] Preparation of a two-layer tablet containing sacubitril-valsartan and dapagliflozin Sacubitryl-valsartan, microcrystalline cellulose, D-mannitol, low-substituted hydroxypropyl cellulose, croscamerose sodium, colloidal silicon dioxide, talc, and magnesium stearate were mixed according to the composition shown in Table 18 below, and fed into a roller compactor to produce dry granules. After mixing croscamerose sodium and colloidal silicon dioxide to produce a secondary mixed powder, magnesium stearate was added to produce the final scubitryl-valsartan mixed powder (first mixed powder). Then, dapagliflozin propanediol, microcrystalline cellulose, D-mannitol, hydroxypropyl cellulose, croscamerose sodium, and stearyl fumarate sodium were mixed and fed into a roller compactor to produce dry granules. Subsequently, croscamerose sodium was mixed with the granules to produce a secondary mixed powder, and then sodium stearyl fumarate was added to produce the final mixed powder (second mixed powder) of dapagliflozin. The sacubitril-valsartan final mixed powder was used as the lower layer, and the dapagliflozin final mixed powder as the upper layer. Two-layer tablets (hardness approximately 15KP) were produced by compressing them with a tablet press (Autotab-200TR, Ichihashi Seiki) and an oval punch measuring 17.5 mm horizontally and 9 mm vertically at a compression pressure of 10KN.

[0280] [Table 18]

[0281] Although specific parts of the present invention have been described in detail above, it will be clear to those with ordinary skill in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. Accordingly, the substantial scope of the invention is defined by the appended claims and their equivalents. [Industrial applicability]

[0282] This invention relates to a pharmaceutical combination formulation containing sacubitril-valsartan and an SGLT-2 inhibitor, which can be used to treat heart failure and ischemic heart disease. The pharmaceutical combination formulation provided in this invention exhibits excellent stability and dissolution rate.

Claims

1. (1) A first release section containing sacubitril-valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, (2) A pharmaceutical compound comprising a second release portion containing an SGLT-2 (Sodium-Glucose Cotransporter 2) inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

2. The pharmaceutical compound formulation according to claim 1, wherein the first release portion and the second release portion exist in a physically separate manner.

3. The pharmaceutical compound formulation according to claim 1, wherein the pharmaceutical compound formulation is a multilayer tablet or a drug-coated tablet.

4. The SGLT-2 inhibitor is selected from the group consisting of dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, sotagliflozin, ipragliflozin, tofogliflozin, luseogliflozin, bexagliflozin, and remogliflozin, as described in claim 1.

5. The pharmaceutical compound formulation according to claim 1, wherein the first or second release portion contains one or more pharmaceutically acceptable additives selected from the group consisting of excipients, disintegrants, and lubricants.

6. The excipient is 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 monohydrate, lactose anhydrous, calcium hydrogen phosphate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, dextrin, mannitol, sorbitol, starch, calcium phosphate monohydrate, calcium carbonate, sugars, and mixtures thereof, as described in claim 5.

7. The pharmaceutical compound formulation according to claim 5, wherein the disintegrant is selected from the group consisting of crospovidone, methylcellulose, cross-linked carboxymethylcellulose sodium (Cross-linked CMC Na, C.CMC Na, or croscamerose sodium), carboxymethylcellulose calcium, starch glycolate sodium, hydroxypropylcellulose, low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose, starch, pre-gelatinized starch, corn starch, potato starch, alginic acid or its sodium salt, and combinations thereof.

8. The pharmaceutically complex formulation according to claim 5, wherein the lubricant is selected from the group consisting of calcium stearate, fused silicon dioxide, 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. The pharmaceutical compound formulation according to claim 1, wherein the second release portion comprises a coating base.

10. The pharmaceutically complex formulation according to claim 9, wherein the coating base is one or more selected from the group consisting of hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, polymer of acrylic acid and its salts, polymethacrylate, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer, carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymer, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan gum, and mixtures thereof.

11. The pharmaceutical compound formulation according to claim 1, wherein the first release portion contains, based on the total weight, 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.

12. The pharmaceutical compound formulation according to claim 1, wherein the second release portion contains, based on the total weight, 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.

13. The pharmaceutical compound formulation according to claim 1, wherein the second release portion contains 10 to 70% by weight of the active ingredient and 30 to 90% by weight of the coating base, based on the total weight.

14. The pharmaceutical compound formulation according to claim 1, wherein 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 hydroxypropyl cellulose, 5 to 30% by weight of at least one of sodium starch glycolate and croscamerose 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. The pharmaceutical compound formulation according to claim 1, wherein the second release portion contains, 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 monohydrate, 10 to 50% by weight of mannitol, 0.1 to 20% by weight of hydroxypropyl cellulose, 0.5 to 20% by weight of croscamerose sodium, and 0.5 to 20% by weight of stearyl fumarate sodium.

16. The pharmaceutical compound formulation comprises a first layer including a first release section containing sacubitril-valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, The pharmaceutical compound formulation according to claim 1, comprising a two-layer tablet and a second layer comprising a second release portion containing the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

17. The aforementioned pharmaceutical compound formulation comprises a core including a first release section containing sacubitril-valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, A pharmaceutical compound formulation according to claim 1, comprising a coating layer having a second release portion located on at least a portion of the surface of the core, the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

18. The first release portion comprises granules containing the active ingredient of sacubitril-valsartan or a pharmaceutically acceptable salt thereof, excipients, disintegrants and lubricants, and a post-mixing portion containing disintegrants and lubricants. The pharmaceutical compound formulation according to claim 1, wherein the second release portion comprises granules containing the active ingredient of the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof, an excipient, a disintegrant, and a lubricant, and a post-mixing portion containing a disintegrant and a lubricant.

19. (a) A step of manufacturing a first release section containing sacubitril-valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, (b) A step of manufacturing a second release section containing an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient, (c) A method for producing a pharmaceutical compound formulation, comprising the step of formulating the first release portion and the second release portion into a single solid dosage form.

20. The method for producing a pharmaceutical compound formulation according to claim 19, wherein the step of producing the first release portion (a) comprises (a-1) mixing sacubitril-valsartan or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive; (a-2) producing granules; and (a-3) mixing the granules with a post-mixing portion.

21. A method for producing a pharmaceutical compound formulation according to claim 20, further comprising the step of (a-4) compressing tablets after step (a-3) above.

22. The method for producing a pharmaceutical compound formulation according to claim 20, wherein the step of producing the second release portion comprises (b-1) mixing an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive; (b-2) producing granules; and (b-3) mixing the granules with a post-mixing portion.

23. The method for producing a pharmaceutical compound preparation according to claim 22, wherein the step of (c) formulation into a solid preparation includes the step of compressing the mixed powder of the first release portion obtained in step (a-3) and the mixed powder of the second release portion obtained in step (b-3) into tablets to produce a two-layer tablet.

24. The step of (b) manufacturing the second release section includes (b-1) mixing an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof with a coating base to manufacture a coating solution, The method for producing a pharmaceutical compound formulation according to claim 21, wherein the step of (c) formulation into a solid dosage form includes coating the tablet-shaped core obtained in step (a-4) with the coating solution of the second release portion obtained in step (b-1).

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