Cocrystal containing camostat and niclosamide, pharmaceutical composition containing same, and method for producing same

Abstract

The present invention relates to a novel cocrystal, a pharmaceutical composition containing the same, and a method for producing the same. The cocrystal of the present invention can be used to effectively prevent and / or treat cancer, inflammatory diseases, or viral infections.

Description

[Technical field]

[0001] The present invention relates to a cocrystal comprising camostat or a pharma- ceutically acceptable salt thereof and niclosamide; or a cocrystal comprising camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a coformer; a pharmaceutical composition comprising the same, and a method for preparing the same. [Background technology]

[0002] A cocrystal is a form in which two or more different molecules form a crystal structure in a single crystal lattice with a certain stoichiometric ratio. In a cocrystal, the molecules that are different from each other, two or more drugs, or a drug and a co-former, can form a crystal structure in a single crystal lattice and are bonded by hydrogen bonds, van der Waals interactions, or π-π stacking interactions, etc., and are different from the bond forms of salts and mixtures. Although cocrystals are already known, the overall research into them is insufficient, accounting for less than 1% of the research into common organic compounds. Camostat is a drug represented by Chemical Formula 1 below, and its salt, camostat mesylate, is a drug represented by Chemical Formula 2 below. These are anticoagulants that are not only used as a pancreatitis treatment, but are also known to have potential antiviral and anticancer effects. Recently, it has been reported that camostat is a useful compound for treating and preventing, for example, Coronavirus disease 2019 (COVID-19), which requires S protein priming of TMPRSS2, by suppressing the activity of TMPRSS2 on the cell surface. <C1> JPEG2024504532000002.jpg60154<2> JPEG2024504532000003.jpg69163Niclosamide is a drug represented by the following formula 3. <3> JPEG2024504532000004.jpg6495Niclosamide has very low water solubility and intestinal permeability, and its bioavailability is extremely low, so it is prescribed by orally administering an excessive amount of niclosamide, but due to the characteristics of niclosamide itself, it is fundamentally difficult to expect any efficacy from systemic exposure of the drug. In particular, due to its low solubility, there is a limit to the extent to which these therapeutic or ameliorative effects can be obtained. [Prior art document] (Non-Patent Document 0001) Ko, M., Jeon, S., Ryu, WS, & Kim, S. (2020.08.07). Comparative analysis of antiviral efficacy of FDA-approved drugs against SARS-CoV-2 in human lung cells. Journal of medical virology. Summary of the Invention [Problem to be solved by the invention]

[0003] The present invention provides a cocrystal comprising camostat or a pharma- ceutically acceptable salt thereof and niclosamide; a pharmaceutical composition comprising the same; and a method for preparing the same. The present invention provides a pharmaceutical composition for the prevention or treatment of cancer, an inflammatory disease, or a viral infection, comprising camostat or a pharma- ceutical acceptable salt thereof, and a cocrystal containing niclosamide. The present invention provides a method for preventing or treating cancer, an inflammatory disease, or a viral infection, comprising administering to an individual a cocrystal comprising camostat or a pharma- ceutical acceptable salt thereof, and niclosamide. The present invention provides a use of a cocrystal comprising camostat or a pharma- ceutically acceptable salt thereof and niclosamide for the prevention or treatment of cancer, an inflammatory disease, or a viral infection disease. The present invention provides use of a cocrystal comprising camostat or a pharma- ceutically acceptable salt thereof and niclosamide for the manufacture of a medicament for the prophylaxis or treatment of cancer, an inflammatory disease, or a viral infection disease. The present invention provides a co-crystal comprising camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a co-former; a pharmaceutical composition comprising the same; and a method for preparing the same. The present invention provides a method for preventing or treating cancer, an inflammatory disease, or a viral infection, comprising administering to an individual a co-crystal comprising camostat or a pharma- ceutical acceptable salt thereof, niclosamide, and a co-former. The present invention provides a use of camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a cocrystal including a coformer for the prophylaxis or treatment of cancer, an inflammatory disease, or a viral infection disease. The present invention provides a use of camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a cocrystal including a coformer for the manufacture of a medicament for the prophylaxis or treatment of cancer, an inflammatory disease, or a viral infection disease. [Means for solving the problem]

[0004] The inventors attempted to maximize the efficacy of niclosamide, which acts primarily inside cells, and camostat, which inhibits viral entry into cells from outside the cells, simultaneously. As a result, the inventors have produced cocrystals containing camostat or a pharma- ceutically acceptable salt thereof and niclosamide; or cocrystals containing camostat or a pharma-ceutically acceptable salt thereof, niclosamide, and a coformer, thereby producing cocrystals in which the solubility and permeability of individual drugs are improved, and have confirmed the excellent efficacy of these, thereby completing the invention. The present invention will be described in more detail below. Meanwhile, each description and embodiment disclosed in the present invention can be applied to other descriptions and embodiments. That is, all combinations of various elements disclosed in the present invention belong to the scope of the present invention. In addition, the scope of the present invention is not limited to the specific description described below. Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the art to which the present invention pertains. Terms as defined in commonly used dictionaries should be interpreted to have a meaning consistent with the meaning they have in the context of the relevant art, and should not be interpreted in an idealized or overly formal sense unless expressly defined in this application.

[0005] Cocrystals The present invention provides a cocrystal comprising camostat or a pharma- ceutically acceptable salt thereof and niclosamide. The cocrystal is a fused crystal comprising camostat or a pharma- ceutically acceptable salt thereof and niclosamide, and may refer to a cocrystal of camostat or a pharma- ceutically acceptable salt thereof and niclosamide. The cocrystal containing camostat or a pharma- ceutically acceptable salt thereof and niclosamide has improved solubility, bioavailability, and biomembrane permeability, and can be usefully used for cancer, inflammatory diseases, and viral infections. In addition, the cocrystal is a substance with significantly increased solubility and bioavailability compared to the existing single substances of niclosamide or camostat, and has improved solubility and biomembrane permeability, and can be effectively used for the prevention and / or treatment of cancer, inflammatory bowel disease, or viral infections such as coronavirus. In addition, the cocrystal is economical because it is safe and easy to store, and can be easily produced and mass-produced. In one embodiment of the present invention, the cocrystal containing camostat or a pharma- ceutically acceptable salt thereof and niclosamide may exhibit an endothermic peak in differential scanning calorimetry (DSC) at 144.38±3°C when the heating rate is 10°C / min. The co-crystal may have a powder X-ray diffraction (XRD) pattern including diffraction peaks at diffraction angle 2θ (±0.2°) values ​​of 5.37715°, 15.1122°, 18.2258°, 18.7579°, 20.3344°, 25.596°, and 26.069°. In addition, the cocrystal may further include a diffraction peak in a powder X-ray diffraction (XRD) pattern at at least one of the diffraction angle 2θ (±0.2°) values ​​of 10.6979°, 13.1612°, 17.7134°, 26.4434°, and 27.882°. In one embodiment of the present invention, the cocrystal containing camostat or a pharma- ceutically acceptable salt thereof and niclosamide may exhibit an endothermic peak in differential scanning calorimetry (DSC) at 126.35±3°C when the heating rate is 10°C / min. The co-crystal may have a powder X-ray diffraction (XRD) pattern including diffraction peaks at diffraction angle 2θ (±0.2°) values ​​of 6.55954°, 10.7176°, 18.147°, 19.5855°, 21.3591°, and 26.8178°. In addition, the cocrystal may further include a diffraction peak in a powder X-ray diffraction (XRD) pattern at at least one of the diffraction angle 2θ (±0.2°) values ​​of 13.8509°, 15.2501°, 16.6296°, 20.9059°, 22.3642°, 24.3151°, 24.8866°, and 27.7637°. In one embodiment of the present invention, the cocrystal containing camostat or a pharma- ceutically acceptable salt thereof and niclosamide may exhibit an endothermic peak in differential scanning calorimetry (DSC) at 182.74±3°C when the heating rate is 10°C / min. The co-crystal may have a powder X-ray diffraction (XRD) pattern including diffraction peaks at diffraction angle 2θ (±0.2°) values ​​of 11.3876°, 16.0975°, 16.6493°, 18.679°, 23.0539°, 23.9013°, 24.4333°, and 29.7344°. In addition, the cocrystal may further include a diffraction peak at at least one of the diffraction angle 2θ (±0.2°) values ​​of 7.82075°, 18.679°, 19.0929°, 22.6992°, 25.4975°, 26.9755°, and 30.365° in a powder X-ray diffraction (XRD) pattern. In one embodiment of the present invention, the cocrystal containing camostat or a pharma- ceutically acceptable salt thereof and niclosamide may exhibit an endothermic peak in differential scanning calorimetry (DSC) at 151.69±3°C when the heating rate is 10°C / min. The co-crystal may have a powder X-ray diffraction (XRD) pattern including diffraction peaks at diffraction angle 2θ (±0.2°) values ​​of 6.81572°, 7.46604°, 9.87023°, 12.3532°, 13.24°, and 18.6396°. In addition, the cocrystal may further include a diffraction peak in a powder X-ray diffraction (XRD) pattern at at least one of the diffraction angle 2θ (±0.2°) values ​​of 12.8262°, 22.6795°, 23.259°, 24.7881°, 25.6946°, and 27.5667°. The present invention also provides a co-crystal comprising camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a co-former. The co-crystal is a fused crystal comprising camostat or a pharma-ceutically acceptable salt thereof, niclosamide, and a co-former, and may refer to a co-crystal consisting of camostat or a pharma-ceutically acceptable salt thereof, niclosamide, and a co-former. The cocrystal containing camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a coformer has improved solubility, bioavailability, and biomembrane permeability, and can be usefully used for cancer, inflammatory diseases, and viral infections. In addition, the cocrystal is a substance with significantly increased solubility and bioavailability compared to the existing single substances of niclosamide or camostat, and has improved solubility and permeability, and can be effectively used for the prevention and / or treatment of cancer, inflammatory bowel disease, or viral infections such as coronavirus. In addition, the cocrystal is economical because it is safe and easy to store, and can be easily produced and mass-produced. In one embodiment of the present invention, the cocrystal comprising camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a coformer may exhibit an endothermic peak at 126.03°C in differential scanning calorimetry (DSC) when the heating rate is 10°C / min. The co-crystal may have a powder X-ray diffraction (XRD) pattern including diffraction peaks at diffraction angle 2θ (±0.2°) values ​​of 7.0522°, 7.6239°, 9.06226°, 12.4912°, 18.009°, and 21.9897°. In addition, the cocrystal may further include a diffraction peak at at least one of the diffraction angles 2θ (±0.2°) of 24.2166° and 27.1134° in a powder X-ray diffraction (XRD) pattern. The cocrystal of the present invention can have a molar ratio of camostat or a pharma- ceutically acceptable salt thereof to niclosamide of about 1:4 to 4:1, more specifically, about 1:1. When the cocrystal of the present invention includes a coformer, it can contain about 1 to 6 moles of the coformer per mole of camostat or a pharma- ceutically acceptable salt thereof, or niclosamide, and more specifically, it can contain about 5 moles. The coformer is not particularly limited as long as it is pharma- ceutically acceptable, and may be one or more selected from meglumine, histidine, arginine, nicotinamide, benzoate, formic acid, sorbic acid, citroic acid (citric acid), malic acid, caffeine, theophylline, urea, etc. In one embodiment of the present invention, the coformer may be meglumine, nicotinamide, caffeine, arginine, or citroic acid (citric acid). In the present invention, the term "cocrystal" refers to a form in which two or more different molecules form a crystal structure in a single crystal lattice at a certain stoichiometric ratio, and the intermolecular bonding form in a cocrystal is distinguished from that of a salt or a mixture. In the present invention, the "cocrystal of the present invention", the "cocrystal of the present invention", or a cocrystal that can be interpreted as referring to the cocrystal of the present invention refers to all of the cocrystals of the present invention that contain camostat or a pharma- ceutically acceptable salt thereof, and niclosamide; and all of the cocrystals of the present invention that contain camostat or a pharma-ceutically acceptable salt thereof, niclosamide, and a co-former. In the present invention, the "pharmaceutically acceptable salt" is not particularly limited as long as it is a salt prepared by a conventional method known to those skilled in the art. For example, the pharmaceutically acceptable salt of camostat may be a sulfonate prepared from one or more acids selected from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid. In one embodiment of the present invention, the pharmaceutically acceptable salt may be a methanesulfonate, i.e., a mesylate. In one embodiment of the present invention, the pharmaceutically acceptable salt of camostat in the cocrystal may be camostat mesylate. In the present invention, the term "co-former" refers to a pharmacologically inactive molecule that changes the crystalline form of a solid drug through the formation of a co-crystal, an inclusion compound, or other crystalline solid form, and may refer to an inactive molecule among the molecules that constitute the crystal of a co-crystal. The cocrystal of the present invention may have a structure in which one molecule of niclosamide is bound to one molecule of camostat or a pharma- ceutically acceptable salt of camostat. It may also have a structure in which one molecule of niclosamide is bound to one molecule of camostat or a pharma- ceutically acceptable salt of camostat and one or more molecules of coformer. In addition, it may include cocrystals having various binding ratios.

[0006] Method for producing cocrystals The present invention provides a method for preparing a cocrystal containing camostat or a pharma- ceutically acceptable salt thereof and niclosamide, the method comprising the steps of mixing and fusing camostat or a pharma- ceutically acceptable salt thereof and niclosamide to form a cocrystal. In one embodiment of the present invention, the co-crystallization step may include mixing camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a solvent. Specifically, the co-crystallization step may include mixing camostat or a pharma- ceutically acceptable salt thereof, and niclosamide with a solvent to prepare a mixed solution; and obtaining a co-crystal from the mixed solution. For example, camostat or a pharma- ceutically acceptable salt thereof and niclosamide may be crystallized in the mixed solution to obtain a co-crystal, and the co-crystal synthesized in the mixed solution may be separated in the form of a dry powder. The solvent may be at least one selected from water, a linear or branched alcohol having 1 to 5 carbon atoms, acetone, acetonitrile, dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), ethyl acetate, toluene, hexane, tetrahydrofuran, etc. Examples of the alcohol may be at least one selected from methanol, ethanol, 2-propanol, n-propanol, etc., but are not limited thereto. In one embodiment of the present invention, camostat or a pharma- ceutically acceptable salt thereof and niclosamide may be mixed and fused in a molar ratio of about 1:4 to 4:1, more specifically, about 1:1, or may be mixed and fused in various other ratios. The step of removing the solvent to obtain the co-crystal may include a step of removing the solvent by filtering the mixed solution, and then drying the mixed solution under reduced pressure. Through the drying process, a solid phase co-crystal powder can finally be obtained. In one embodiment of the present invention, camostat mesylate may be used as the salt of camostat. The present invention provides a method for preparing a co-crystal comprising camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a co-former, the method comprising the steps of mixing and fusing camostat or a pharma-ceutically acceptable salt thereof, niclosamide, and a co-former to allow crystallization. In one embodiment of the present invention, the co-crystallization step may include mixing camostat or a pharma- ceutically acceptable salt thereof, niclosamide, a co-former, and a solvent. Specifically, the co-crystallization step may include mixing camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a co-former with a solvent to prepare a mixed solution; and obtaining a co-crystal from the mixed solution. For example, camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a co-former may be crystallized in the mixed solution to obtain a co-crystal, and the co-crystal synthesized in the mixed solution may be separated in the form of a dry powder. In one embodiment of the present invention, camostat or a pharma- ceutically acceptable salt thereof and niclosamide may be mixed and fused in a molar ratio of about 1:4 to 4:1, more specifically, about 1:1, or may be mixed and fused in various other ratios. The coformer may be included in an amount of about 1 mole to 6 moles, more specifically, about 5 moles, per mole of camostat or a pharma- ceutically acceptable salt thereof, or niclosamide. Specifically, the molar ratio of camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and the coformer may be 1:1:1 to 1:1:6. The matters mentioned in the method for producing a cocrystal containing camostat or a pharma- ceutical acceptable salt thereof, niclosamide, and a coformer, which relate to the solvent and the step of removing the solvent to obtain a cocrystal, can be similarly applied to the contents of the method for producing a cocrystal containing camostat or a pharma-ceutical acceptable salt thereof, and niclosamide. In addition to the above-mentioned preparation method, the cocrystal of the present invention can be prepared in various combinations depending on the ratio of the drug composition, the type of the alkalizing agent, the type and ratio of the solvent, etc. The cocrystal of the present application can be a crystal in which camostat or a pharma- ceutically acceptable salt thereof, and niclosamide are all present in one crystal lattice, or a crystal in which camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and the coformer are all present in one crystal lattice. The cocrystal of the present invention and its manufacturing method are as follows: 1. A cocrystal comprising camostat, or a pharma- ceutically acceptable salt thereof, and niclosamide. 2. The cocrystal according to item 1 above, which consists of camostat or a pharma- ceutically acceptable salt thereof and niclosamide. 3. The cocrystal according to items 1 and 2 above, wherein the molar ratio of camostat or a pharma- ceutical acceptable salt thereof to niclosamide is 1:4 to 4:1. 4. The cocrystal according to items 1 and 2 above, wherein the molar ratio of camostat or a pharma- ceutical acceptable salt thereof to niclosamide is 1:1. 5. A cocrystal according to any one of items 1 to 4 above, wherein the powder X-ray diffraction (XRD) pattern includes diffraction peaks at diffraction angles 2θ (±0.2°) of 5.37715°, 15.1122°, 18.2258°, 18.7579°, 20.3344°, 25.596°, and 26.069°. 6. A cocrystal according to any one of 1 to 4 above, which exhibits an endothermic peak in differential scanning calorimetry (DSC) at 144.38±3°C when the heating rate is 10°C / min. 7. A cocrystal according to any one of items 1 to 4 above, wherein the powder X-ray diffraction (XRD) pattern includes diffraction peaks at diffraction angles 2θ (±0.2°) of 6.55954°, 10.7176°, 18.147°, 19.5855°, 21.3591°, and 26.8178°. 8. A cocrystal according to any one of 1 to 4 above, which shows an endothermic peak in differential scanning calorimetry (DSC) at 126.35±3°C when the heating rate is 10°C / min. 9. A cocrystal according to any one of items 1 to 4 above, wherein the powder X-ray diffraction (XRD) pattern includes diffraction peaks at diffraction angles 2θ (±0.2°) of 11.3876°, 16.0975°, 16.6493°, 18.679°, 23.0539°, 23.9013°, 24.4333°, and 29.7344°. 10. A cocrystal according to any one of 1 to 4 above, which exhibits an endothermic peak in differential scanning calorimetry (DSC) at 182.74±3°C when the heating rate is 10°C / min. 11. A cocrystal according to any one of items 1 to 4 above, wherein the powder X-ray diffraction (XRD) pattern includes diffraction peaks at diffraction angles 2θ (±0.2°) of 6.81572°, 7.46604°, 9.87023°, 12.3532°, 13.24°, and 18.6396°. 12. A cocrystal according to any one of 1 to 4 above, which exhibits an endothermic peak in differential scanning calorimetry (DSC) at 151.69±3°C when the heating rate is 10°C / min. 13. A cocrystal comprising camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a coformer. 14. The cocrystal according to item 13 above, which comprises camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a coformer. 15. The cocrystal according to items 13 and 14, wherein the molar ratio of camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and the coformer is 1:1:1 to 1:1:6. 16. The cocrystal according to any one of items 13 to 14, wherein the coformer is one or more selected from meglumine, histidine, arginine, nicotinamide, benzoate, formic acid, sorbic acid, citroic acid, malic acid, caffeine, theophylline, and urea. 17. The cocrystal according to any one of items 13 to 14 above, wherein the powder X-ray diffraction (XRD) pattern includes diffraction peaks at diffraction angles 2θ (±0.2°) of 7.0522°, 7.6239°, 9.06226°, 12.4912°, 18.009°, and 21.9897°. 18. A cocrystal according to any one of items 13 to 16, which exhibits an endothermic peak in differential scanning calorimetry (DSC) at 126.03°C when the heating rate is 10°C / min. 19. A method for producing a cocrystal according to any one of items 1 to 12, comprising mixing camostat or a pharma- ceutically acceptable salt thereof and niclosamide and co-crystallizing them. 20. The method for producing a cocrystal according to any one of items 1 to 12, wherein in item 19, the cocrystallizing step includes mixing camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a solvent, and the solvent is one or more selected from water, a linear or branched alcohol having 1 to 5 carbon atoms, acetone, acetonitrile, dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), ethyl acetate, toluene, hexane, and tetrahydrofuran. 21. The method for producing a cocrystal according to any one of items 1 to 12, wherein in the cocrystallization step, camostat or a pharma- ceutical acceptable salt thereof and niclosamide are fused in a molar ratio of 1:4 to 4:1. 22. The method for producing a cocrystal according to any one of items 1 to 12, wherein in the cocrystallization step, camostat or a pharma- ceutically acceptable salt thereof and niclosamide are fused in a molar ratio of 1:1. 23. A method for producing a cocrystal according to any one of items 13 to 18, comprising fusing camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a coformer to form a cocrystal. 24. A pharmaceutical composition for preventing or treating cancer, inflammatory diseases, or viral infections, comprising a cocrystal according to any one of items 1 to 18 as an active ingredient. 25. The pharmaceutical composition according to item 24 above, wherein the cancer is one or more selected from pancreatic cancer, breast cancer, liver cancer and lung cancer. 26. The pharmaceutical composition according to item 24, wherein the viral infection disease is one or more selected from the group consisting of coronavirus infection disease, SARS virus infection disease, influenza virus infection disease, and killer tick-borne infection disease. 27. The pharmaceutical composition according to item 24, wherein the inflammatory disease is one or more selected from allergies, dermatitis, atopy, conjunctivitis, periodontitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, ankylosing spondylitis, fibromyalgia, psoriatic arthritis, osteoarthritis, tendonitis, tendonitis, peritendinitis, myositis, hepatitis, cystitis, nephritis, Sjogren's syndrome, multiple sclerosis, acute inflammatory diseases, and chronic inflammatory diseases. 28. A method for preventing or treating cancer, an inflammatory disease, or a viral infection, comprising administering to an individual a cocrystal according to any one of items 1 to 18. 29. Use of a cocrystal according to any one of items 1 to 18 for the prevention or treatment of cancer, inflammatory diseases or viral infections. 30. Use of a cocrystal according to any one of items 1 to 18 for the manufacture of a medicament for the prevention or treatment of cancer, inflammatory diseases and viral infections.

[0007] Pharmaceutical composition, therapeutic method using same and its use The present invention provides a pharmaceutical composition comprising, as active ingredients, camostat or a pharma- ceutical acceptable salt thereof and a cocrystal containing niclosamide. The present invention provides a pharmaceutical composition for the prevention or treatment of cancer, an inflammatory disease, or a viral infection, comprising camostat or a pharma- ceutical acceptable salt thereof, and a cocrystal containing niclosamide as active ingredients. The present invention provides a pharmaceutical composition comprising as active ingredients camostat or a pharma- ceutical acceptable salt thereof, niclosamide, and a co-crystal including a co-former. The present invention provides a pharmaceutical composition for the prevention or treatment of cancer, an inflammatory disease, or a viral infection, comprising camostat or a pharma- ceutical acceptable salt thereof, niclosamide, and a cocrystal including a co-former as active ingredients. A pharmaceutical composition containing the cocrystal of the present invention as an active ingredient can be useful for preventing or treating cancer, inflammatory diseases, and viral infections. Pharmaceutical compositions containing the cocrystal of the present invention as an active ingredient can be prepared into tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments, patches, etc. using commonly used pharma- ceutical acceptable carriers, excipients, and other additives, and can be administered orally or parenterally. The pharma- ceutically acceptable carrier may be, but is not limited to, one or more selected from lactose, dextrose, sucrose, sorbitol, mannitol, sugar, fructose, pregelatinized starch, starch, gum arabic, calcium phosphate, carrageenan, sodium carboxymethylcellulose, calcium carboxymethylcellulose, alginate, gelatin, calcium silicate, light anhydrous silicic acid or its derivatives, silicon dioxide, polyacrylate or its copolymer, microcrystalline cellulose, polyvinylpyrrolidine, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, minerals, and oils. The preparation may be prepared by a conventional method used in the art for preparation, and may be formulated into various preparations depending on each disease or ingredient. Liquid compositions for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs, and may contain commonly used inert diluents, such as purified water, dimethyl sulfoxide (DMSO), polysorbate 20, polysorbate 80, or ethyl alcohol. The pharmaceutical compositions may contain, in addition to inert diluents, auxiliary agents such as solubilizers, dissolution aids, wetting agents, and suspending agents, sweeteners, flavors, aromatics, or preservatives. Injections for parenteral administration may include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Diluents for aqueous solutions and suspensions include, for example, distilled water for injections, physiological saline, etc. Diluents for non-aqueous solutions and suspensions include, for example, glycols such as propylene glycol, polyethylene glycol, etc.; vegetable oils such as olive oil, corn oil, etc.; alcohols such as ethyl alcohol; lipophilic surfactants such as Span 80, etc.; hydrophilic surfactants such as polysorbate 80, etc. The pharmaceutical composition of the present invention may contain additives such as isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers, or dissolution aids. These may be sterilized by filtration through a bacteria-retaining filter, mixing with a bactericide, or exposure to ultraviolet light. In addition, in the present invention, a sterile solid composition may be prepared and dissolved in a sterilized injectable solvent before use. The dose (therapeutically effective amount) of the cocrystal according to the present invention to an individual may be appropriately determined in consideration of the indication, severity of the disease, body weight, age, sex, etc., and the administration dose and method of use may be appropriately varied depending on various conditions. The pharma- ceutical effective amount and effective dosage of the pharmaceutical composition of the present invention may vary depending on the formulation method, mode of administration, administration time and / or administration route of the pharmaceutical composition, and on many factors including the type and degree of reaction to be achieved by administration of the pharmaceutical composition, the type, age, weight, general health condition, symptoms and degree of disease, sex, diet, excretion, drugs used simultaneously or at different times with the individual, other components of the composition, and similar factors well known in the medical field, and a person having ordinary skill in the art may easily determine and prescribe an effective dosage for the intended treatment. The present invention provides a method for preventing or treating cancer, an inflammatory disease, or a viral infection, comprising administering to an individual a cocrystal comprising camostat or a pharma- ceutical acceptable salt thereof, and niclosamide; or a pharmaceutical composition comprising the same. The present invention provides a method for preventing or treating cancer, an inflammatory disease, or a viral infection, comprising administering to an individual a cocrystal comprising camostat or a pharma- ceutical acceptable salt thereof, niclosamide, and a co-former; or a pharmaceutical composition comprising the same. The method for preventing or treating cancer, an inflammatory disease, or a viral infection of the present invention can involve administering a therapeutically effective amount of the cocrystal of the present invention. The cocrystal of the present invention can be usefully used in the prevention or treatment of cancer, inflammatory diseases, or viral infections. The cocrystals of the present invention can be administered to an individual suffering from cancer, an inflammatory disease, or a viral infection. In the present invention, "administration" means the introduction of a given substance into an individual by a suitable method. In the present invention, the term "individual" refers to all animals, including rats, mice, livestock, etc., including humans, and specifically may be mammals, including humans, but is not limited thereto. In the present invention, "prevention" refers to any action that inhibits or delays the onset of a disease by administering the cocrystal of the present invention. In the present invention, "treatment" refers to any action that improves or alters the symptoms of a disease suspected or affected individual by administration of the cocrystal of the present invention. In the present invention, the term "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not to cause side effects, which can be determined by a person skilled in the art based on factors including the patient's sex, age, weight, health condition, type and severity of the disease, drug activity, drug sensitivity, administration method, administration time, administration route, excretion rate, treatment period, drugs used in combination or simultaneously, and other factors well known in the medical field. It is preferable that a specific therapeutically effective amount for a particular patient is applied depending on various factors including the type and degree of response to be achieved, the specific composition including whether or not other preparations are used, the patient's age, weight, general health condition, sex and diet, administration time, administration route and excretion rate of the composition, treatment period, drugs used together with the specific composition or used simultaneously, and similar factors well known in the medical field. In the present invention, the term "cancer" refers to lung cancer, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia including acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML), adrenal cancer, anal cancer, basal squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, Ewing's series tumors, eye cancer, gallbladder cancer, gastrointestinal carcinomas, gastrointestinal stromal tumors, and the like. The cancer may be one or more selected from the group consisting of pulmonary carcinoma, gestational trophoblastic disease, glioma, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, hypopharyngeal cancer, liver cancer, lung carcinoids, lymphoma including cutaneous T-cell lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, testicular cancer, thymic cancer, thyroid cancer including anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor. In the present invention, the "inflammatory disease" may be one or more selected from allergies, dermatitis, atopy, conjunctivitis, periodontitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, ankylosing spondylitis, fibromyalgia, psoriatic arthritis, osteoarthritis, tendonitis, tendonitis, peritendinitis, myositis, hepatitis, cystitis, nephritis, Sjogren's syndrome, multiple sclerosis, acute inflammatory diseases, and chronic inflammatory diseases. In the present invention, the "viral infection disease" may be one or more selected from a coronavirus infection disease induced by a coronavirus infection, an influenza virus infection (influenza virus infection) induced by an influenza virus infection, a SARS virus infection induced by a SARS virus infection, and a killer tick-borne infection induced by a killer tick infection. The coronavirus may be one or more selected from Alphacoronavirus, Betacoronavirus, Gammacoronavirus, Deltacoronavirus, and Mutant coronavirus. The coronavirus infection disease may be Severe Acute Respiratory Syndrome (SARS), specifically, a disease caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), more specifically, coronavirus disease-19. The cocrystal of the present invention has been confirmed to have excellent antiviral activity against SARS-CoV-2. That is, the cocrystal of the present invention can inhibit cell invasion by SARS-CoV-2. The cocrystal of the present invention can prevent or treat coronavirus disease-19, which is a disease caused by SARS-CoV-2. Symptoms of SARS-CoV-2 infection can include fever, fatigue, cough, difficulty breathing, phlegm, sore throat, headache, hemoptysis, nausea, gastrointestinal symptoms, kidney disease, respiratory disease, and diarrhea. The present invention provides a use of a cocrystal comprising camostat or a pharma- ceutically acceptable salt thereof and niclosamide for the prevention or treatment of cancer, an inflammatory disease, or a viral infection disease. The present invention provides a use of a cocrystal comprising camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a co-former for the prevention or treatment of cancer, an inflammatory disease, or a viral infection disease. The present invention provides use of a cocrystal comprising camostat or a pharma- ceutically acceptable salt thereof and niclosamide for the manufacture of a medicament for the prophylaxis or treatment of cancer, an inflammatory disease, and a viral infection disease. The present invention provides a use of a cocrystal comprising camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a co-former for the manufacture of a medicament for the prophylaxis or treatment of cancer, an inflammatory disease, or a viral infection. The items mentioned in each section of the present invention, i.e., cocrystal, preparation method, pharmaceutical composition, treatment method and use, are equally applicable unless they are mutually inconsistent. Effect of the Invention

[0008] The cocrystal of the present invention has improved solubility, bioavailability and biomembrane permeability and can be usefully used for the treatment of cancer, inflammatory diseases and viral infections. The cocrystal of the present invention is a substance having significantly increased solubility and bioavailability compared to existing niclosamide or camostat, and has improved solubility and biological membrane permeability, and can be effectively used for the prevention and / or treatment of cancer, inflammatory diseases, or viral infectious diseases such as coronaviruses. The cocrystal of the present invention is economical because it is safe and easy to store, and can be easily produced and mass-produced. [Brief description of the drawings]

[0009] [Figure 1] PXRD results for niclosamide, camostat mesylate, camostat, and the cocrystals α, β, γ, δ, and ε of the present application. [Diagram 2] 1 shows the results of differential scanning calorimetry (DSC) analysis of niclosamide, camostat mesylate, camostat, and the cocrystals α, β, γ, δ, and ε of the present application. [Diagram 3] 1 shows the results of evaluating the anticancer efficacy of the cocrystals of Examples 1 and 17 and a positive control drug in a paclitaxel-resistant breast cancer cell line. [Figure 4] The results show the results of evaluating the antiviral efficacy of the cocrystals of Examples 1 and 17 and the positive control drug against SARS-CoV-2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The best mode for carrying out the present invention will now be described in detail. The inventors of the present invention have developed cocrystals comprising camostat or a pharma- ceutically acceptable salt thereof and niclosamide; and cocrystals comprising camostat or a pharma-ceutically acceptable salt thereof, niclosamide, and a coformer, and in order to confirm the cocrystal formation, the prepared cocrystals were analyzed by various experimental methods as follows: As described above, in the cocrystal of the present invention, a single cocrystal having a certain quality can be obtained with good reproducibility. In addition, the cocrystal of the present invention is a crystal of a drug substance (a raw material for a drug) used in the manufacture of a medicine, can be supplied stably, and has excellent storage safety. The difference in the crystal form between the simple mixture and the cocrystal is clear from the results of differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) analyses. Niclosamide and camostat mesylate are identified by the PXRD diffraction angles, relative intensities and DSC endothermic peaks shown in Tables 8, 10 and Figure 1. As the cocrystals of the present invention, cocrystal α, cocrystal β, cocrystal γ, cocrystal δ and cocrystal ε are identified by the PXRD diffraction angles, relative intensities and DSC endothermic peaks shown in Tables 9, 10 and Figure 1. In addition, due to the characteristics of the data, in determining the identity of crystals, the spacing of the crystal lattice and the overall pattern are important, and the results of heat flow measurements may vary slightly depending on the direction of crystal growth, particle size, and measurement conditions, so they should not be interpreted too strictly. The method for producing a cocrystal according to the present invention includes a step of mixing camostat or a pharma- ceutically acceptable salt thereof and niclosamide and co-crystallizing them, and the co-crystallization step can be carried out by various methods known as methods for producing cocrystals. For example, the cocrystals α, β, γ, δ, and ε according to the present invention can be prepared independently by using a crystallization method such as a liquid-assisted grinding method, a slurry method, or a solvent cooling method. When using the liquid-assisted grinding method, camostat or a pharma- ceutically acceptable salt thereof and an alkalizing agent are reacted by grinding together with a small amount of a solvent such as distilled water using a tool such as a mortar and pestle, and then a small amount of distilled water, an organic solvent such as acetone, acetonitrile, tetrahydrofuran, or alcohols, and niclosamide are added and continuously ground to produce the cocrystal according to the present invention. When using the slurry method, camostat or a pharma- ceutically acceptable salt thereof and an alkalizing agent are added to distilled water, acetone, acetonitrile, tetrahydrofuran, or an organic solvent such as methanol, ethanol, isopropyl alcohol, and niclosamide to prepare a supersaturated solution, which is then continuously stirred to prepare the cocrystal according to the present invention. In addition, a cocrystal having a different crystal form can be prepared by adding a dry cocrystal to a specific organic solvent and slurrying it. When using the solvent cooling method, camostat or a pharma- ceutically acceptable salt thereof and an alkalizing agent are stirred and reacted in a first solvent such as distilled water, and then a niclosamide solution completely dissolved by heating in a second solvent such as acetone or alcohol is added, and the solvent is cooled and stirred to synthesize the cocrystal according to the present invention. The volume ratio of the first solvent to the second solvent may be about 10:1 to 1:10. For example, the volume ratio of the first solvent to the second solvent may be about 4:1 to 5:1. In the anti-solvent method, camostat mesylate and an alkalizing agent are stirred and reacted in a first solvent such as distilled water, filtered and dried to obtain a dry powder of camostat, and then a solution of niclosamide completely dissolved by heating in a second solvent such as acetone or alcohol is mixed with the dry camostat and stirred. Then, distilled water is added as an anti-solvent to produce the cocrystal according to the present invention. The alkalizing agent used in the liquid-assisted grinding method, the slurry method, the solvent cooling method, or the antisolvent method may be one or more selected from basic substances such as sodium bicarbonate (NaHCO3), sodium carbonate (Na2CO3), sodium hydroxide (NaOH), potassium hydroxide (KOH), calcium hydroxide (Ca(OH)2), and magnesium hydroxide (Mg(OH)2), but is not limited thereto. The present invention will be specifically described below with reference to examples. That is, the cocrystal containing camostat or its pharma- ceutically acceptable salt and niclosamide of the present invention can be prepared by the method described below, but the examples provided in this application or the use of exemplary language are merely intended to more clearly illustrate the present invention and do not limit the scope of the claimed invention.

[0011] <Example> In the examples, niclosamide was purchased from Hengcheng Pharmaceutical Co., Ltd.; camostat mesylate was purchased from MFC Co., Ltd.; alkalizing agents such as sodium hydroxide, sodium carbonate, and sodium bicarbonate were purchased from Samchun Co., Ltd.; ethanol was purchased from Samchun Co., Ltd.; acetonitrile and acetone were purchased from Daejung Co., Ltd.; and coformers were purchased from Merck Co., Ltd. <Examples 1 to 8> Preparation of cocrystal α In one embodiment of the present invention, the cocrystal α according to the present invention was prepared by a slurry method. The contents of niclosamide and camostat mesylate, the type and content of the alkalizing agent, and the types and contents of the first and second solvents were as shown in Table 1 below. Example 1. 49.45 g of camostat mesylate was added to 2.5 kg of distilled water (first solvent) at 25°C and stirred at 100 rpm until completely dissolved. 8.4 g of sodium bicarbonate (alkalinizing agent) was added to 0.1 kg of distilled water (first solvent) at 25°C and stirred at 100 rpm until completely dissolved. Also, 32.71 g of niclosamide was added to 2.0 kg of absolute ethanol (second solvent) at 30°C and stirred at 100 rpm until completely dissolved. The camostat mesylate solution and the niclosamide solution were filtered using a 0.45 μm filter to remove any foreign matter that may have been present. The filtered camostat mesylate solution was mixed with the sodium bicarbonate solution and stirred at 100 rpm for 30 minutes. When the mixed solution became sufficiently opaque, the filtered niclosamide solution was added and stirred at 200 rpm for 3 hours. Thereafter, the reactants were filtered using a vacuum pump and a paper filter to remove the solvent, and then the reactants were dried at 30° C. for one day using a vacuum dryer to obtain cocrystal α in the form of a dry powder. Examples 2 to 8. Cocrystals α of Examples 2 to 8 were produced using substantially the same method as that of Example 1 above, but using the components and contents listed in Table 1 below. [Table 1] JPEG2024504532000005.jpg105147 <Examples 9 and 16> Preparation of cocrystal β In one embodiment of the present invention, the cocrystal β according to the present invention was prepared by a slurry method. The contents of niclosamide and camostat mesylate, the type and content of the alkalizing agent, and the types and contents of the first solvent, second solvent, and third solvent were as shown in Table 2 below. Example 9. 49.45 g of camostat mesylate was added to 2.5 kg of distilled water (first solvent) at 25°C and stirred at 100 rpm until completely dissolved. 8.4 g of sodium bicarbonate (alkalinizing agent) was added to 0.1 kg of distilled water (first solvent) at 25°C and stirred at 100 rpm until completely dissolved. Also, 32.71 g of niclosamide was added to 2.0 kg of ethanol (second solvent) at 30°C and stirred at 100 rpm until completely dissolved. The camostat mesylate solution and the niclosamide solution were filtered using a 0.45 μm filter to remove any foreign matter that may have been present. The filtered camostat mesylate solution was mixed with the sodium bicarbonate solution and stirred at 100 rpm for 30 minutes. When the mixed solution became sufficiently opaque, the filtered niclosamide solution was added and stirred at 100 rpm for 3 hours. After that, the solvent was removed by filtering the reactants using a vacuum pump and a paper filter, and then the reactants were dried at 30°C for one day using a vacuum dryer to obtain a cocrystal raw material in the form of a dry powder. The obtained cocrystal raw material was placed in 1.6 kg of anhydrous ethanol (third solvent) at 25°C and stirred at 100 rpm for three hours. After that, the solvent was removed by filtering the reactants using a vacuum pump and a paper filter, and then the reactants were dried at 25°C for one day using a vacuum dryer to obtain cocrystal β in the form of a dry powder. Examples 10 to 16. The cocrystal β of Examples 10 to 16 was produced using substantially the same method as that of Example 9 above, but using the components and contents listed in Table 2 below. [Table 2] JPEG2024504532000006.jpg105152 <Examples 17 to 20> Preparation of cocrystal β In one embodiment of the present invention, the cocrystal β according to the present invention was prepared by a slurry method. The contents of niclosamide and camostat mesylate, the type and content of the alkalizing agent, and the type and content of the first and second solvents were as shown in Table 3 below. Example 17. 49.45g of camostat mesylate was added to 2.5kg of distilled water (first solvent) at 25°C and stirred at 100 rpm to completely dissolve. 10.6g of sodium carbonate (alkalinizing agent) was added to 0.1kg of distilled water (first solvent) at 25°C and stirred at 100 rpm to completely dissolve. The camostat mesylate solution was filtered using a 0.45μm filter to remove any foreign matter that may be present. The filtered camostat mesylate solution was added to the sodium carbonate solution, mixed, and stirred at 100 rpm for 30 minutes. When the mixed solution became sufficiently opaque, the reactants were filtered using a vacuum pump and a paper filter to remove the solvent, and then dried in a vacuum dryer at 25°C for one day to obtain camostat in the form of a dry powder. Then, 32.71 g of niclosamide was added to 1.6 kg of anhydrous ethanol (second solvent) at 30°C, stirred at 100 rpm to completely dissolve, and then filtered using a 0.45 μm filter to remove any foreign matter that may have been present. The filtered niclosamide solution was added to the camostat and stirred at 100 rpm for 3 hours at 25°C. After that, the reaction mixture was filtered using a vacuum pump and a paper filter to remove the solvent, and then dried at 25°C for one day using a vacuum dryer to obtain cocrystal β in the form of a dry powder. Examples 18 to 20. The cocrystal β of Examples 18 to 20 was produced using substantially the same method as that of Example 17 above, but using the components and contents listed in Table 3 below. [Table 3] JPEG2024504532000007.jpg59147 <Examples 21 to 24> Preparation of cocrystal γ In one embodiment of the present invention, the cocrystal γ according to the present invention was prepared by a slurry method. The contents of niclosamide and camostat mesylate, the type and content of the alkalizing agent, and the type and content of the first and second solvents were as shown in Table 4 below. Example 21. 49.45g of camostat mesylate was added to 2.5kg of distilled water (first solvent) at 25°C and stirred at 100 rpm to completely dissolve. 8.4g of sodium bicarbonate was added to 0.1kg of distilled water (first solvent) at 25°C and stirred at 100 rpm to completely dissolve. The camostat mesylate solution was filtered using a 0.45μm filter to remove any foreign matter that may be present. The filtered camostat mesylate solution was added to the sodium bicarbonate solution, mixed, and stirred at 100 rpm for 30 minutes. When the mixed solution became sufficiently opaque, the reactants were filtered using a vacuum pump and a paper filter to remove the solvent, and then dried at 25°C for one day using a vacuum dryer to obtain camostat in the form of a dry powder. Then, 32.71 g of niclosamide was added to 1.6 kg of acetone (second solvent) at 30°C, stirred at 100 rpm to completely dissolve, and then filtered using a 0.45 μm filter to remove any foreign matter that may have been present. The filtered niclosamide solution was added to the camostat and stirred at 100 rpm for 3 hours at 25°C. After that, the reaction mixture was filtered using a vacuum pump and a paper filter to remove the solvent, and then dried at 25°C for one day using a vacuum dryer to obtain cocrystal γ in the form of a dry powder. Examples 22 to 24. The cocrystal γ of Examples 22 to 24 was produced using substantially the same method as that of Example 21, but using the components and contents shown in Table 4 below. [Table 4] JPEG2024504532000008.jpg59147 <Examples 25 to 28> Preparation of cocrystal δ In one embodiment of the present invention, the cocrystal δ according to the present invention was prepared by a slurry method. The contents of niclosamide and camostat mesylate, the type and content of the alkalizing agent, and the types and contents of the first solvent, second solvent, third solvent, and fourth solvent were as shown in Table 5 below. Example 25. 49.45 g of camostat mesylate was added to 2.5 kg of distilled water (first solvent) at 25°C and stirred at 100 rpm until completely dissolved. 8.4 g of sodium bicarbonate (alkalinizing agent) was added to 0.1 kg of distilled water (first solvent) at 25°C and stirred at 100 rpm until completely dissolved. Also, 32.71 g of niclosamide was added to 1.6 kg of acetone (second solvent) at 30°C and stirred at 100 rpm until completely dissolved. The camostat mesylate solution and the niclosamide solution were filtered using a 0.45 μm filter to remove any foreign matter that may be present. The filtered camostat mesylate solution was mixed with the sodium carbonate solution and stirred at 100 rpm for 30 minutes. When the mixed solution became sufficiently opaque, the filtered niclosamide solution was added and stirred at 100 rpm for 3 hours. After that, the reactants were filtered using a vacuum pump and a paper filter to remove the solvent, and then dried at 30°C for one day using a vacuum dryer to obtain a cocrystal raw material in the form of a dry powder. The obtained cocrystal raw material was placed in 1.6 kg of anhydrous ethanol (third solvent) at 25°C and stirred at 100 rpm for three hours. After that, the reactants were filtered using a vacuum pump and a paper filter to remove the solvent, and then dried at 25°C for one day using a vacuum dryer to obtain a cocrystal raw material in the form of a dry powder. The obtained cocrystal raw material was placed in 1.6 kg of acetonitrile (fourth solvent) at 25°C and stirred at 100 rpm for three hours. After that, the reactants were filtered using a vacuum pump and a paper filter to remove the solvent, and then dried at 25°C for one day using a vacuum dryer to obtain a cocrystal δ in the form of a dry powder. Examples 26 to 28. Cocrystal δ of Examples 26 to 28 were produced using substantially the same method as that of Example 25 above, but using the components and contents listed in Table 5 below. [Table 5] JPEG2024504532000009.jpg81152 <Examples 29 to 32> Preparation of cocrystal δ In one embodiment of the present invention, the cocrystal δ according to the present invention was prepared by a slurry method. The contents of niclosamide and camostat mesylate, the type and content of the alkalizing agent, and the type and content of the first and second solvents were as shown in Table 6 below. Example 29. 49.45g of camostat mesylate was added to 2.5kg of distilled water (first solvent) at 25°C and stirred at 100 rpm to completely dissolve. 8.4g of sodium carbonate (alkalinizing agent) was added to 0.1kg of distilled water (first solvent) at 25°C and stirred at 100 rpm to completely dissolve. The camostat mesylate solution was filtered using a 0.45μm filter to remove any foreign matter that may be present. The filtered camostat mesylate solution was added with sodium carbonate solution, mixed, and stirred at 100 rpm for 30 minutes. When the mixed solution became sufficiently opaque, the reactants were filtered using a vacuum pump and a paper filter to remove the solvent, and then dried at 25°C for one day using a vacuum dryer to obtain camostat in the form of a dry powder. Then, 32.71g of niclosamide was added to 1.6kg of acetonitrile (second solvent) at 30°C, and the obtained camostat was added and stirred at 100 rpm for 3 hours. Thereafter, the reactants were filtered using a vacuum pump and a paper filter to remove the solvent, and then the reactants were dried at 30° C. for one day using a vacuum dryer to obtain cocrystal δ in the form of a dry powder. Examples 30 to 32. Cocrystal δ of Examples 30 to 32 were produced using substantially the same method as that of Example 29 above, but using the components and contents listed in Table 6 below. [Table 6] JPEG2024504532000010.jpg59147 <Examples 33 to 40> Preparation of cocrystal ε In one embodiment of the present invention, the cocrystal δ according to the present invention was prepared by a slurry method. The contents of niclosamide, camostat mesylate, and meglumine, the type and content of the alkalizing agent, and the types and contents of the first solvent, second solvent, and third solvent were as shown in Table 7 below. Example 33. 49.45 g of camostat mesylate was added to 2.5 kg of distilled water (first solvent) at 25°C and stirred at 100 rpm until completely dissolved. 10.5 g of sodium carbonate was added to 0.1 kg of distilled water (first solvent) at 25°C and stirred at 100 rpm until completely dissolved. Also, 32.71 g of niclosamide was added to 2.0 kg of absolute ethanol (second solvent) at 30°C and stirred at 100 rpm until completely dissolved. The camostat mesylate solution and the niclosamide solution were filtered using a 0.45 μm filter to remove any foreign matter that may be present. The filtered camostat mesylate solution was mixed with the sodium carbonate solution and stirred at 100 rpm for 30 minutes. When the mixed solution became sufficiently opaque, the filtered niclosamide solution was added and stirred at 100 rpm for 3 hours. After that, the reactants were filtered using a vacuum pump and a paper filter to remove the solvent, and then dried at 30°C for one day using a vacuum dryer to obtain a cocrystal raw material in the form of a dry powder. The obtained cocrystal raw material was added to 1.6 kg of acetonitrile (third solvent) at 25°C together with 97.6 g of meglumine (coformer), and then stirred at 100 rpm for 3 hours. After that, the reactants were filtered using a vacuum pump and a paper filter to remove the solvent, and then dried at 20°C for one day using a vacuum dryer to obtain cocrystal ε in the form of a dry powder. Examples 34 to 40. Cocrystal ε of Examples 34 to 40 were prepared using substantially the same method as that of Example 33, but using the components and contents shown in Table 7 below. [Table 7] JPEG2024504532000011.jpg150152 The production yield of the cocrystal of the present invention produced in the above Examples 1 to 40 was all 70% or more, and the purity was at least 95% or more. Hereinafter, analytical experiments for the cocrystals α, β, γ, δ, and ε produced in Examples 1, 17, 21, 25, and 33 and the results thereof will be described in more detail. <Experimental Example> The cell lines used in the experiments were purchased from the American Type Culture Collection (ATCC) or the Korean Cell Line Bank (KCLB). Experimental Example 1. Powder X-ray Diffraction (PXRD) Analysis Powder X-ray diffraction (PXRD) analysis was carried out for each of the cocrystal samples according to Examples 1, 17, 21, 25, and 33 of the present invention and the comparative samples (niclosamide, camostat, camostat mesylate) under the following conditions using a D8 ADVANCE with Davinci (trade name, Bruker AXS Inc, GmbH, Germany) powder X-ray diffraction (PXRD) analyzer. Detector: High-speed LynxEye detector Tube:Cu Tube current: 40mA Tube voltage: 40kV Sampling width: 0.020° Scanning speed: 0.1sec / step Wavelength: 1.54056Å Measurement angle range (2θ): 2.5 to 40° The cocrystal samples of the present invention are the cocrystals in the form of dry powder obtained in Examples 1, 17, 21, 25 and 33, respectively, and the comparative samples are the raw materials niclosamide, camostat and camostat mesylate used to form the cocrystals. The diffraction angles (2θ) of the main X-ray diffraction patterns through the PXRD analysis of the cocrystal samples according to Examples 1, 17, 21, 25 and 33 of the present invention and the comparative samples are shown in Tables 8 and 9 below with their relative intensities. [Table 8] JPEG2024504532000012.jpg106147[Table 9] JPEG2024504532000013.jpg198147 In FIG. 1, the x-axis is 2θ (Bragg angle, unit: °), and the y-axis is X-ray intensity (cps). Referring to Tables 8 and 9 and Figure 1, it can be seen that the process of forming the cocrystal of the coformer has a non-stoichiometric hydrate, which causes a shift in the distance and a shift in the diffraction angle (20). In other words, when compared with niclosamide, camostat mesylate, and camostat in Figure 1, it can be seen that the cocrystal of the present invention is a new crystal form that shows a diffraction pattern different from that of the raw material. Experimental Example 2. Differential scanning calorimetry (DSC) analysis Differential scanning calorimetry (DSC) was performed on niclosamide, camostat mesylate, camostat, and the cocrystals prepared in Examples 1, 17, 21, 25, and 33. For the analysis by temperature differential scanning calorimetry, a DSC Q2000 System (trade name, TA Instrument, USA) was used as a DSC analyzer, and the temperature was raised from 0°C to the melting point at a heating rate of 10°C / min. N2 gas was supplied at a rate of 50mL / min, and the measurement was performed in an aluminum sample pan. The samples were analyzed using Universal Analysis 2000 software (trade name, TA instruments, USA). The maximum endothermic temperatures of the single components niclosamide, camostat, and their fused crystals obtained through differential scanning calorimetry (DSC) analysis are shown in Table 10 and Figure 2 below. [Table 10] JPEG2024504532000014.jpg78147In FIG. 2, the x-axis represents temperature (unit: °C) and the y-axis represents heat flow (unit: W / g). Referring to Table 10 above together with FIG. 2 , it can be seen that when the heating rate is 10° C. / min, cocrystal α shows an endothermic peak in differential scanning calorimetry (DSC) at 144.38° C., cocrystal β shows an endothermic peak in differential scanning calorimetry (DSC) at 126.35° C., cocrystal γ shows an endothermic peak in differential scanning calorimetry (DSC) at 182.74° C., cocrystal 5 shows an endothermic peak in differential scanning calorimetry (DSC) at 151.69° C., and cocrystal ε shows an endothermic peak in differential scanning calorimetry (DSC) at 126.03° C. In other words, when compared with each of niclosamide, camostat mesylate, and camostat, it can be confirmed that the cocrystal of the present invention is a new crystal that exhibits new thermodynamic properties different from those of the raw materials. Experimental Example 3. Evaluation of niclosamide solubility in the present cocrystals The solubility of niclosamide alone and that of niclosamide contained in the cocrystals prepared in Examples 17 and 33 of the present application were measured and compared in a pH 7 buffer solution. A pH 7 buffer solution was prepared by mixing 0.1N potassium phosphate and 0.1N sodium hydroxide to prepare a solution of pH 7. At room temperature, 5 mg of niclosamide alone, cocrystal β of Example 17, and cocrystal ε of Example 33 were added to 25 ml of the prepared pH solution and stirred at 600 rpm. After stirring for 1 hour, 5 ml of the supernatant was taken and filtered through a 0.45 μm PVDF filter, and the amount of dissolved niclosamide was evaluated as the sample. The HPLC instrument conditions were a flow rate of 1.5 ml / min, injection volume of 100 μl, detection wavelength of 287 nm, and column oven temperature of 25° C. Mobile phase A was a pH 6 buffer solution (potassium phosphate 2 g / L, disodium phosphate 1 g / L, tetrabutylammonium hydrogen sulfate 2 g / L, adjusted to pH 6.0±0.05 with IM NaOH), and mobile phase B was acetonitrile. The mobile phase conditions are as shown in Table 11 below. [Table 11] JPEG2024504532000015.jpg47147Referring to Table 12 below, niclosamide has low solubility at pH 7 and is difficult to detect, but in the cocrystal of Example 17, niclosamide was dissolved at 55.2 μg / ml, demonstrating a significant improvement in solubility of niclosamide compared to niclosamide alone.In addition, in the cocrystal of Example 33, niclosamide was dissolved at 0.4 μg / ml, demonstrating a significant improvement in solubility of niclosamide compared to niclosamide alone. [Table 12] JPEG2024504532000016.jpg21147 Experimental Example 4: Evaluation of the artificial membrane permeability of the present cocrystal Camostat The artificial membrane permeability of the camostat cocrystal prepared in Example 21 of the present application was evaluated using a side-by-side cell 1 system and compared with that of the single substance camostat. As the artificial membrane, 200 μl of GIT-0-Lipid solution was taken and instilled into the center of a 25 mm hydrophobic PVDF membrane. 5 ml of a pH 5.0 FeSSIF solution at 37°C was taken and placed in a donor cell, and 20 mg of the sample was weighed and administered to the donor cell 1. The test was started after 5 ml of ethyl alcohol: pH 7.4 PBS buffer (1:9, v / v) solution was placed in the acceptor cell, and the solution taken 5 times at 200 μl each in the acceptor cell at specified times was used as the test solution. Then, 1 ml of ethyl alcohol: pH 7.4 PBS buffer (1:9, v / v) solution was placed in the acceptor cell to maintain the total volume at 5 ml. [Table 13] JPEG2024504532000017.jpg21147 Referring to Table 13 above, the cumulative permeation amount of the single substance Camostat was 561.89, and the cumulative permeation amount of the cocrystal of Example 21 Camostat was 876.29, confirming that the cumulative permeation amount of Camostat was 1.56 times superior. In other words, it was confirmed that the cocrystal of the present invention has excellent membrane permeability and therefore has an excellent absorption rate in the living body. Experimental Example 5. Evaluation of artificial membrane permeability of the present cocrystal niclosamide The permeability of the cocrystal of Example 17 of the present application to niclosamide through an artificial membrane (PermeaPad barrier membrane, 25 mm) was evaluated using a side-by-side cell 1 system and compared with that of niclosamide alone. 5 ml of a pH 6.5 FeSSIF solution (37°C) containing 3% (w / w) Kolliphor ELP was taken and placed in a donor cell, and 20 mg of the sample was weighed and administered to donor cell 1. After placing 5 ml of a pH 7.4 PBS solution containing 20% ​​(w / w) HP-β-CD in acceptor cell 1, the test was started, and the liquid taken 5 times at 200 μl each in the acceptor cell at specified times was used as the test liquid. Then, 1 ml of a pH 7.4 PBS solution containing 20% ​​(w / w) HP-β-CD was placed in the acceptor cell to maintain the total volume at 5 ml. [Table 14] JPEG2024504532000018.jpg21147 Referring to Table 14 above, the cumulative permeation amount of niclosamide alone was 1.18, while the cumulative permeation amount of niclosamide of the cocrystal of Example 17 was 2.03, confirming that the cumulative permeation amount of niclosamide of the cocrystal of the present application was 1.72 times superior. In other words, it was confirmed that the cocrystal of the present invention has excellent membrane permeability and therefore has an excellent absorption rate in the living body. Experimental Example 6. Evaluation of cancer cell proliferation inhibitors The cocrystal of the present application was evaluated as a cytostatic agent to verify its anticancer efficacy in pancreatic cancer, breast cancer, non-small cell lung cancer, and liver cancer cell lines. The conditions for the anticancer in vitro efficacy test for evaluating the growth inhibitory properties of the cocrystal of the present application in each cancer cell line are as shown in Table 15 below. Hereinafter, cocrystal α is the cocrystal produced in Example 1. A total of eight cell lines, including two pancreatic cancer cell lines (PANC-1, MIAPACA-2), two breast cancer cell lines (MCF-7, MDA-MB-231), two non-small cell lung cancer cell lines (A-549, H-1299), and two liver cancer cell lines (Hep-3B, Huh-7), were used to culture 2 × 10 cells per well in a 96-well tissue culture plate. 3 ~4×10 3After culturing in cell culture medium for 24 hours, the cells were treated with each cocrystal drug at a total of six concentrations of 0.3, 3, 30, 300, 3000, and 30000ng / mL. After 48 hours of drug treatment, the CCK-8 assay kit was used to react the reagent for 1 to 4 hours to observe the color change, and the absorbance island was measured at 450nm wavelength using a microreader to measure cell viability. [Table 15] JPEG2024504532000019.jpg78147To verify the anticancer efficacy of the cocrystals against various types of cancer cells, cell viability was measured in pancreatic cancer, breast cancer, non-small cell lung cancer, and liver cancer cells to obtain IC 50 The results are shown in Table 16 below. IC of positive control group 50 The values ​​are based on the facts described in the following documents. Gemcitabine:HONGGANG WANG, BEVERLY R.WORD and BEVERLY D.LYN-COOK:Enhanced Efficacy of Gemcitabine by Indo1e-3-carbino1 in Pancreatic Cell Lines:The Role of Human Equi1ibrative Nucleoside Transporter 1.Anticancer research 31(10):3171-3180, 2011. Gefitinib: CHI PAN, HUIJIE DUAN, YINAN WU, CHUNPENG ZHU, CHENGHAO YI, YIN DUAN, DEMIN LU, CHENG GUO, DEQI WU, YANYAN WANG, XIANHUA FU, JING XU, YIDING CHEN, MENG LUO, WEI TIAN, TAO PAN, WENHONG XU, SUZHAN ZHANG and JIANJIN HUANG: Inhibition of DNA-PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC. International journal of oncology 57:939-955, 2020 Docetaxel: Aliakbar Taherian, 1Tahereh Mazoochi: Different Expression of Extracellular Signa1-Regu1ated Kinases(ERK) 1 / 2 and Phospho-Erk Proteins in MBA-MB-231 and MCF-7 Cells after Chemotherapy with Doxorubicin or Docetaxel. Iranian Journal of basic Medical sciences 15, 669-677, 2012 Sorafenib: Y-C Shen 1, D-L Ou, C Hsu, K-L Lin, C-Y Chang, C-Y Lin, S-H Liu, A-L Cheng: Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma. BJC 108, 72-81, 2013 [Table 16] JPEG2024504532000020.jpg66147 Referring to Table 16 above, the IC of the co-crystal of Example 1 according to the present invention 50was confirmed to be 99.30 nM in pancreatic cancer cell line PANC-1 cells and 729.32 nM in MIAPACA-2 cells; 427.86 nM in breast cancer cell line MCF-7 cells and 126.31 nM in MDA-MB-231 cells; 975.81 nM in non-small cell lung cancer cell line A-549 cells and 381.13 nM in H-1299 cells; 41.33 nM in liver cancer cell line Hep-3B cells and 134.45 nM in Huh-7 cells. This resulted in the IC of the cocrystal of Example 1. 50 The IC value was confirmed for a total of eight cell lines, two each of pancreatic cancer, breast cancer, non-small cell lung cancer, and liver cancer cell lines, and the IC value was low for pancreatic cancer cell lines, which are still classified as intractable cancers and have no therapeutic agent. 50 The IC value was confirmed and it was confirmed that it can be effectively applied as a growth inhibitor for pancreatic cancer cells. In addition, under the relevant test conditions, it showed low IC values ​​in breast cancer, non-small cell lung cancer, and liver cancer cell lines. 50 The values ​​were confirmed, thereby confirming the effect of the cocrystal of the present invention as an inhibitor of cancer cell growth. In addition, the IC of the positive control group and the cocrystal of Example 1 50 To compare the IC of gemcitabine, a drug used to treat pancreatic cancer patients, gefitinib, a drug used to treat non-small cell lung cancer patients, docetaxel, a drug used to treat breast cancer patients, and sorafenib, a drug used to treat liver cancer patients, 50 was confirmed through the literature. When compared to the positive control drug, the cocrystal of Example 1 of the present application had a significantly lower IC than the positive control drug in all cell lines. 50 It was confirmed that the IC value of the cocrystal of the present invention was higher than that of gemcitabine. 50 was 432-fold lower in PANC-1 cell line and 127-fold lower in MIAPACA-2 cells, 13-fold lower in A-549 cells and 45-fold lower in H-1299 cells compared to gefitinib, 1.7-fold lower in MCF-7 cells and 5-fold lower in MDA-MB-231 cells compared to docetaxel, and 297-fold lower in Hep-3B cells and 44-fold lower in Huh-7 cells compared to sorafenib. In other words, it was confirmed that the cocrystal of the present invention has superior efficacy as a cancer cell proliferation inhibitor compared to conventionally used cancer therapeutic agents. Experimental Example 7. Comparison and verification of anticancer efficacy between the cocrystal of the present invention and a positive control group in subtype-specific breast cancer cell lines The cocrystal of the present application was evaluated as a cytostatic agent in subtype-specific breast cancer cell lines, and the conditions for the anticancer in vitro efficacy evaluation test for the evaluation were as shown in Table 17 below. The cocrystals of the present application were verified for a total of 19 types of breast cancer cell lines. The drugs listed in Table 17 below were used as positive controls. The cocrystals prepared in Examples 1 and 17 were serially diluted at 1 / 2 times to eight different concentrations for each cell line, and a luminescent cell viability assay was performed using CellTiter glo. CellTiter-Glo Substrate and CellTiter-Glo Buffer were mixed to prepare CellTiter-Glo Reagent, and the same amount of CellTiter-Glo Reagent as the cell culture medium (40 μl volume) was added, and the cells were left at room temperature for 10 minutes, and then the cells were measured using a Luminometer (GloMax (registered trademark) Drug susceptibility was confirmed by measuring ATP using a Discover Microplate Reader. IC was calculated using nonlinear regression analysis with GraphPad Prism9 software. 50 The values ​​were calculated and compared. [Table 17] JPEG2024504532000021.jpg153147To verify the anticancer efficacy of the cocrystal of the present application against subtyped breast cancer cell lines, a dose-response curve study was conducted in a total of 19 types of breast cancer cells, and cell viability was measured to obtain IC 50 Representative results are shown in FIG. 3 and Tables 18 to 21 below. [Table 18] JPEG2024504532000022.jpg27147[Table 19] JPEG2024504532000023.jpg34150[Table 20] JPEG2024504532000024.jpg34150[Table 21] JPEG2024504532000025.jpg32150 Drug responses appeared differently for each cell line, but the IC of the drugs used in Examples 1 and 17 and as control drugs was observed in all cell lines. 50 I was able to secure the value. In the case of hormone-positive breast cancer cell lines, Examples 1 and 17 had lower IC than the positive controls Tamoxifen and Docetaxel. 50 In particular, in the case of ZR-75-1 cells, Example 1 had an IC value 1.7 times lower than that of Tamoxifen, and Example 17 had an IC value 1.4 times lower than that of Tamoxifen. 50 As a result, it was confirmed that the cocrystal of the present invention, that is, the cocrystal of Example 1 and Example 17, exhibits a more excellent anticancer effect than the positive control drug currently being used for hormone-positive breast cancer patients. In the case of HER2-positive breast cancer cell line HCC1419 cells, Example 1 had a significantly lower IC of 19 times and Example 17 had a significantly lower IC of 16 times compared to the positive control drug Herceptin. 50 It was confirmed that the cocrystal of the present invention also showed a significantly lower IC 50 In other words, it was confirmed that the effect of the cocrystal of the present invention on reducing cell viability in HER2-positive breast cancer cell lines was significantly superior to that of the positive control group. In the case of triple-negative breast cancer cell lines, the most widely known MDA-MB-231 cells, the IC20 was 14-fold and 11-fold lower than the positive control drug Cisplatin in both Examples 1 and 17. 50 The anticancer effect of the cocrystal of the present invention was confirmed to be far superior to that of existing therapeutic agents, even in triple-negative breast cancer cell lines, which are the most difficult to treat among breast cancers. Using drug-resistant breast cancer cell lines that were exposed to doxorubicin, paclitaxel, tamoxifen, or Herceptin for a long period of time and were resistant to the corresponding drugs, the IC 50 In drug-resistant breast cancer cell lines, the cocrystals of the examples of this application showed lower IC 50In particular, in a breast cancer cell line resistant to Paclitaxel, a representative drug used as a cytotoxic therapeutic agent, Example 1 and Example 17 had IC values ​​more than two times lower. 50 I was able to secure the value. Experimental Example 8. Evaluation of the antiviral efficacy of the present cocrystal against SARS-CoV-2 in comparison with a positive control drug An experiment was conducted to verify the antiviral efficacy of the cocrystal of the present application against SARS-CoV-2 using a SARS-CoV-2 cell infection model, and the experimental conditions are as shown in Table 22 below. Groups treated with the drugs chloroquine, lopinavir, or remdesivir were used as positive control groups. To test the antiviral efficacy of the cocrystals against SARS-CoV-2, 1.2 x 10 4 Vero cells were inoculated with 1000 μM of cocrystals or positive control drugs, which were diluted 2-fold in DMS0, and the highest concentration of the cocrystals or positive control drugs was 50 μM. Approximately 1 hour after the cocrystals or positive control drugs were treated, the cells were infected with SARS-CoV-2 (provided by the Korea Centers for Disease Control and Prevention (KCDC), 0.125 M0I) in a Biosafety level 3 (BSL3) facility and cultured at 37°C for 24 hours. The cells were then fixed with 4% paraformaldehyde (PFA) and permeabilized. The cells were then stained with anti-SARS-CoV-2 nucleocapsid (N) primary antibody, Alexa Fluor 488-conjugated goat anti-rabbit IgG secondary antibody and Hoechst 33342. Fluorescent images of the infected cells were obtained using Operetta (Perkin Elmer), a large-capacity image analysis device. [Table 22] JPEG2024504532000026.jpg129149 To verify the antiviral efficacy of the cocrystals against SARS-CoV-2, a dose-response curve study was conducted in a SARS-CoV-2 cell infection model, and the results are shown in Table 23 below. The selectivity index (SI) value was CC 50 / I C 50was calculated. [Table 23] JPEG2024504532000027.jpg40147 Referring to Table 23, the IC of the cocrystals of Example 1 and Example 17 50 is indicated by 0.16 μm, CC 50 The IC value was 50 μm or more, and the SI was 306 for the cocrystal of Example 1 and 313 for the cocrystal of Example 17. 50 is 3.48 μm, and the IC of the cocrystal is 50 In addition, the IC value of lopinavir, an AIDS drug that has been attracting attention as a coronavirus treatment, was about 21.75 times higher than that of 50 The IC of the cocrystal of the present application is 10.30 μm. 50 The IC value was approximately 64.38 times higher than that of the malaria drug chloroquine. 50 The IC of the cocrystal of the present application is 7.47 μm. 50 The value was approximately 46.69 times higher than that of Through this, the cocrystal of this application has a significantly lower IC compared to the drug remdesivir currently used as a COVID-19 treatment. 50 It was confirmed that the compound had excellent antiviral effects. In addition, the present cocrystal was confirmed to have a significantly higher selective index (SI) value against viruses compared to the positive control group. The selective index is an index that shows the ratio of antiviral activity to cytotoxicity, and the higher the value, the more effective and safe the compound is. Therefore, it was confirmed that the cocrystal can selectively inhibit the proliferation of the SARS-CoV-2 virus. Although the present invention has been described above with reference to an embodiment, it will be understood that those skilled in the art can make various modifications and changes to the present invention without departing from the spirit and scope of the present invention as set forth in the following claims. Accordingly, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. 1. A cocrystal comprising camostat, or a pharma- ceutically acceptable salt thereof, and niclosamide.

2. 2. The cocrystal of claim 1, which consists of camostat or a pharma- ceutically acceptable salt thereof and niclosamide.

3. The cocrystal of claim 1 or 2, wherein the molar ratio of camostat or a pharma- ceutically acceptable salt thereof to niclosamide is from 1:4 to 4:

1.

4. 3. The cocrystal of claim 1 or claim 2, wherein the molar ratio of camostat or a pharma- ceutically acceptable salt thereof to niclosamide is 1:

1.

5. 3. The co-crystal of claim 1 or 2, wherein the powder x-ray diffraction (XRD) pattern comprises diffraction peaks at diffraction angle 2θ (±0.2°) values ​​of 5.37715°, 15.1122°, 18.2258°, 18.7579°, 20.3344°, 25.596° and 26.069°.

6. 3. The cocrystal according to claim 1 or 2, which exhibits an endothermic peak in differential scanning calorimetry (DSC) at 144.38±3° C. when the heating rate is 10° C. / min.

7. 3. The co-crystal of claim 1 or 2, wherein the powder X-ray diffraction (XRD) pattern comprises diffraction peaks at diffraction angle 2θ (±0.2°) values ​​of 6.55954°, 10.7176°, 18.147°, 19.5855°, 21.3591° and 26.8178°.

8. 3. The cocrystal according to claim 1 or 2, which exhibits an endothermic peak in differential scanning calorimetry (DSC) at 126.35±3° C. when the heating rate is 10° C. / min.

9. 3. The cocrystal of claim 1 or 2, wherein the powder X-ray diffraction (XRD) pattern comprises diffraction peaks at diffraction angle 2θ (±0.2°) values ​​of 11.3876°, 16.0975°, 16.6493°, 18.679°, 23.0539°, 23.9013°, 24.4333° and 29.7344°.

10. 3. The cocrystal according to claim 1 or 2, which exhibits an endothermic peak in differential scanning calorimetry (DSC) at 182.74±3° C. when the heating rate is 10° C. / min.

11. 3. The co-crystal of claim 1 or 2, wherein the powder X-ray diffraction (XRD) pattern comprises diffraction peaks at diffraction angle 2θ (±0.2°) values ​​of 6.81572°, 7.46604°, 9.87023°, 12.3532°, 13.24° and 18.6396°.

12. 3. The cocrystal according to claim 1 or 2, which exhibits an endothermic peak in differential scanning calorimetry (DSC) at 151.69±3° C. when the heating rate is 10° C. / min.

13. A cocrystal comprising camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a coformer.

14. 14. The cocrystal of claim 13, which consists of camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a coformer.

15. 14. The cocrystal of claim 13, wherein the molar ratio of camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and the coformer is from 1:1:1 to 1:1:

6.

16. 14. The co-crystal of claim 13, wherein the coformer is one or more selected from meglumine, histidine, arginine, nicotinamide, benzoate, formic acid, sorbic acid, citroic acid, malic acid, caffeine, theophylline, and urea.

17. 15. The co-crystal of claim 13 or 14, wherein the powder X-ray diffraction (XRD) pattern comprises diffraction peaks at diffraction angle 2θ (±0.2°) values ​​of 7.0522°, 7.6239°, 9.06226°, 12.4912°, 18.009° and 21.9897°.

18. The cocrystal according to claim 13 or 14, which exhibits an endothermic peak in differential scanning calorimetry (DSC) at 126.03° C. when the heating rate is 10° C. / min.

19. A method for producing a cocrystal, comprising fusing and co-crystallizing camostat or a pharma- ceutically acceptable salt thereof and niclosamide.

20. The co-crystallizing step comprises mixing camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a solvent; The solvent is at least one selected from water, a linear or branched alcohol having 1 to 5 carbon atoms, acetone, acetonitrile, dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), ethyl acetate, toluene, hexane, and tetrahydrofuran; A method for producing the cocrystal described in claim 19.

21. The method for producing a cocrystal according to claim 19, wherein in the cocrystallization step, camostat or a pharma- ceutically acceptable salt thereof and niclosamide are fused in a molar ratio of 1:4 to 4:

1.

22. 20. The method for producing a cocrystal according to claim 19, wherein in the cocrystallizing step, camostat or a pharma- ceutically acceptable salt thereof and niclosamide are fused in a molar ratio of 1:

1.

23. The method includes the step of co-crystallizing camostat or a pharma- ceutically acceptable salt thereof, niclosamide, and a coformer. Method for producing cocrystals.

24. A composition comprising the cocrystal according to claim 1 or claim 13 as an active ingredient. A pharmaceutical composition for preventing or treating cancer, inflammatory diseases or viral infections.

25. The pharmaceutical composition according to claim 24, wherein the cancer is one or more selected from pancreatic cancer, breast cancer, liver cancer and lung cancer.

26. The pharmaceutical composition according to claim 24, wherein the viral infection disease is one or more selected from the group consisting of coronavirus infection disease, SARS virus infection disease, influenza virus infection disease, and killer tick-borne infection disease.

27. The pharmaceutical composition according to claim 24, wherein the inflammatory disease is one or more selected from allergies, dermatitis, atopy, conjunctivitis, periodontitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, ankylosing spondylitis, fibromyalgia, psoriatic arthritis, osteoarthritis, tendonitis, tendonitis, peritendinitis, myositis, hepatitis, cystitis, nephritis, Sjogren's syndrome, multiple sclerosis, acute inflammatory diseases, and chronic inflammatory diseases.

28. Use of the cocrystal of claim 1 or claim 13 for the prevention or treatment of cancer, inflammatory diseases or viral infections.

29. Use of the cocrystal according to claim 1 or claim 13 for the manufacture of a medicament for the prevention or treatment of cancer, inflammatory diseases and viral infections.

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