Metal (HYDRO) oxide composite comprising poorly soluble drug, preparation method thereof, and pharmaceutical composition comprising same

Abstract

To provide a metal (water) oxide complex containing a hardly soluble drug or its prodrug having excellent bioavailability by improving low dispersibility and blood concentration maintenance effect which are problems of the hardly soluble drug.SOLUTION: A pharmaceutical composition comprising a metal (hydrogen) oxide, a compound comprising at least one hydroxy group in the compound or a salt thereof, and a cellulose-based surfactant. The compound having at least one hydroxy group in the compound is one or more compounds selected from compounds represented by the following chemical formula, and the metal (water) oxide is one or more compounds selected from compounds represented by a specific chemical formula.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention provides a method for improving the dispersibility of poorly soluble drugs and improving their bioavailability. Metal (hydr)oxide complex containing a drug, its preparation method, and pharmaceutical composition containing the same do. [Background technology]

[0002] Technological advances have extended human lifespans, leading to a worsening aging population in countries around the world. As the situation worsens, the number of patients suffering from viral and cancer-related diseases is also increasing. Furthermore, there is also a tendency for illnesses caused by living environment, eating habits, and stress to increase. Therefore, many drugs have been developed that are effective as antiviral agents, anti-inflammatory agents, anti-cancer agents, etc. However, the application of these drugs is limited due to their poor solubility. Improvement of the bioavailability and bioavailability of drugs have become major challenges in drug development. Furthermore, the recent spread of the new coronavirus has led to an urgent need for the development of therapeutic agents. However, since the development of new drugs takes a huge amount of time, it is difficult to provide the appropriate treatment at the time it is needed. Therefore, we have been trying to develop new drugs that can be used as antivirals. Research has been conducted to recreate it as a drug. In addition, they are using a method called "genetic regeneration." In the past, niclosamine was considered a candidate substance for the novel coronavirus. Drugs such as benzodiazepine and ciclesonide have been studied as treatments for COVID-19. Docetaxel is being studied as a promising anti-cancer drug. amide and ciclesonide are used as a treatment for parasitic infections, an anti-inflammatory agent, and an antimalarial agent, respectively. It is a drug that has been approved for development and is already on the market, and in the case of docetaxel, it is an anticancer drug. These drugs have been approved for development and are already on the market. It has the advantage of being mass-produced, but it is a poorly soluble drug and has a low dissolution rate in the body. As a result, the number of drugs currently on the market for COVID-19 treatment and anti-cancer drugs has dropped significantly. However, there was a problem in that it was difficult to achieve the appropriate effect. In the case of poorly soluble drugs such as those mentioned above, the effects of antiviral and / or anticancer drugs in the body are To maximize this, dispersibility should be improved and a high concentration should be maintained in the blood. Unless this problem is solved, bioavailability cannot be increased. I can't. However, to date, research into recreating these drugs has not been able to effectively increase their bioavailability. Furthermore, in the conventional method of increasing the dispersibility of poorly soluble drugs, As shown in Patent Document 1, there is a method of using a dispersant such as a water-soluble polymer carrier. The method of simply using a dispersant, such as the method of solubility-in-water method, does not allow the dispersibility of poorly soluble drugs to be utilized in vivo. There was a problem in that the solubility and dispersibility could not be increased to the maximum extent possible. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Korean Patent No. 10-1897995 Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention addresses the problems of poor dispersibility of poorly soluble drugs and poor blood concentration maintenance. The present invention provides a metal (hydroxide) complex containing a poorly soluble drug with excellent bioavailability. The purpose is to provide a union. Another object of the present invention is to provide a method for producing the above-mentioned metal (hydr)oxide composite. The present invention also provides a pharmaceutical composition containing the above-mentioned metal (hydroxide) complex, which has superior bioavailability. The present invention aims to provide a pharmaceutical composition. [Means for solving the problem]

[0005] This metal (hydroxide) and a compound containing at least one hydroxyl group in the compound or includes its salts, The metal (hydroxide) is at least one selected from the compounds represented by the following formulas 3 to 5: That is, A metal (hydr)oxide complex is provided.

[0006] [ka]

[0007] (In the above Chemical Formula 3, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ , and Zn 2+ Selected from the group consisting of is a divalent metal cation that M 3+ Al 3+ , Fe 3+ , V 3+ , Ti 3+ , Mn 3+ , and Ga 3+ A group consisting of is a trivalent metal cation selected from the group consisting of x is a number ranging from 0 to 0.5, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- , and F - from an anion selected from the group consisting of: n is the charge number of the anion A, n is a number ranging from 0.5 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.)

[0008] [ka]

[0009] (In the above Chemical Formula 4, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ , and Zn 2+ Selected from the group consisting of is a divalent metal cation that x is a number ranging from 0 to 0.4, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- , and F - from an anion selected from the group consisting of: n is the charge number of the anion A, n is a number ranging from 0 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.)

[0010] [ka]

[0011] (In the above Chemical Formula 5, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ , or Zn 2+ and x is a number greater than or equal to 1 and less than 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- , and F - from an anion selected from the group consisting of: n is the charge number of the anion A, n is a number ranging from 0 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.) The present invention also provides a compound containing at least one hydroxy group in a metal (hydr)oxide. The compound or its salt containing the compound includes an additive, The metal (hydr)oxide is one or more compounds represented by the following chemical formulas 3 to 5: Pharmaceutical compositions are provided.

[0012] [ka]

[0013] (In the above Chemical Formula 3, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ , and Zn 2+ Selected from the group consisting of is a divalent metal cation that M 3+ Al 3+ , Fe 3+ , V 3+ , Ti3+ , Mn 3+ , and Ga 3+ A group consisting of is a trivalent metal cation selected from the group consisting of x is a number ranging from 0 to 0.5, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- , and F - from an anion selected from the group consisting of: n is the charge number of the anion A, n is a number ranging from 0.5 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.)

[0014] [ka]

[0015] (In the above Chemical Formula 4, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ , and Zn 2+ Selected from the group consisting of is a divalent metal cation that x is a number ranging from 0 to 0.4, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- , and F - from an anion selected from the group consisting of: n is the charge number of the anion A, n is a number ranging from 0 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.)

[0016] [ka]

[0017] (In the above Chemical Formula 5, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ , or Zn 2+ and x is a number greater than or equal to 1 and less than 2, A is a cation, n is the charge number of the anion A, n is a number ranging from 0 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.) [Effects of the Invention]

[0018] The present invention utilizes a metal (hydroxide) complex to overcome the problems of poorly soluble drugs, such as poor dispersibility and blood solubility. Poorly soluble drugs or their prodrugs with improved medium concentration maintenance effect and excellent bioavailability The present invention has the effect of providing a metal (hydr)oxide complex containing the compound. The present invention is a metal (hydr)oxide that improves the poor dispersibility and low dissolution effect of poorly soluble drugs in blood. The present invention has the effect of providing a method for producing a substance composite. In addition, when the calcined metal (hydr)oxide complex of the present invention is used, not only poorly soluble drugs but also It also has the effect of protecting drugs that are easily decomposed in the body and increasing their bioavailability. [Brief explanation of the drawings]

[0019] [Figure 1] Schematic diagram of the antiviral mechanism of niclosamide against SARS-CoV-2 virus. [Figure 2](a) is a schematic diagram of a method for producing a DHT-NIC complex, and (b) is a schematic diagram of a method for producing a surfactant-treated composition of a DHT-NIC complex. [Figure 3] (a) XRD graph for NIC, (b) for HT, (c) for DHT, and (d) for the DHT-NIC composite. [Figure 4] 1 shows XRD graphs for Example 1-1, Example 1-2, Reference Example 3, Reference Example 4, and NIC. [Figure 5] 1 is an XRD graph for MgO, Al2O3, MgO+Al2O3 grinding, and Reference Example 4. [Figure 6] 1 shows XRD graphs for Example 1-1, Example 4, Reference Example 5, Reference Example 7, Reference Example 8, and NIC. [Figure 7] 1 shows XRD graphs for Example 1-1, Example 1-2, Reference Example, Reference Example 5, Reference Example 6, and NIC. [Figure 8] 1 is an XRD graph for Example 1-1, Example 3, Reference Example 4, Reference Example 9, and NIC. [Figure 9] 1 is an XRD graph for Example 1-1, Example 1-3, Example 1-4, Example 1-5, Reference Example 4, and NIC. [Figure 10] 1 is an XRD graph for Reference Example 3 (HT), Reference Example 10 (DHT 250° C.), and Reference Example 4 (DHT 350° C.). [Figure 11] 1 shows XRD graphs for Reference Example 12, Reference Example 14, Reference Example 4, Reference Example 10, and Reference Example 3 (HT). [Figure 12] 1 shows XRD graphs for Reference Example 11, Reference Example 12, Example 1-1, Reference Example 4, and NIC. [Figure 13] 1 is an XRD graph for Example 12-1, Example 12-2, NIC, and Mg(OH) 2 . [Figure 14] 1 is an XRD graph for Example 13-1, NIC, and MgO. [Figure 15] 1 is an XRD graph for Example 14-1, DTX, Reference Example 4, and Reference Example 3. [Figure 16] 1 is an XRD graph for Example 16-1, DTX, MgO (MgO calcined at 800° C.), and MgO (uncalcined MgO). [Figure 17] A is a field emission scanning electron microscope (FE-SEM) image, B is a TEM image, and C is a TEM cross-sectional image, where (a) is the image for Reference Example 3, (b) is the image for Reference Example 4, and (c) is the image for Example 1-1. [Figure 18] 1 shows Fourier transform infrared (FT-IR) spectrum graphs of NIC, HT (Reference Example 3), DHT (Reference Example 4), and a DHT-NIC composite (Example 1-1). [Figure 19] 1 is a Fourier transform infrared (FT-IR) spectrum of HT (Reference Example 3) and DHT (Reference Example 4). [Figure 20] 1 is a Fourier transform infrared (FT-IR) spectrum graph obtained by repeated measurements of NIC and Examples 1-4. [Figure 21] 1 is a DSC-TGA graph of Example 1-1. [Figure 22] 1 is a graph showing nitrogen adsorption-desorption isotherms of HT (Reference Example 3), DHT (Reference Example 4), and DHT-NIC composite (Example 1-1). [Figure 23] 1 shows field emission scanning electron microscope (FE-SEM) images of HT (Reference Example 3), DHT (Reference Example 4), and DHT-NIC composite (Example 1-1). [Figure 24] 1 shows the results of dynamic light scattering analysis, where (a) is a graph of the average particle size distribution of HT (Reference Example 3), (b) is a graph of the average particle size distribution of DHT (Reference Example 4), and (c) is a graph of the average particle size distribution of the DHT-NIC complex (Example 1-1). [Figure 25] 1 is a graph of plasma NIC concentration over time. [Figure 26] 1 is a graph of plasma NIC concentration over time. [Figure 27] 1 is a graph of plasma NIC concentration over time. [Figure 28] 1 is a graph of plasma NIC concentration over time. [Figure 29] 1 is a graph of plasma NIC concentration over time. [Figure 30] 1 is a graph of plasma NIC concentration over time. [Figure 31] 1 is a graph of plasma NIC concentration over time. [Figure 32] 1 is a graph of plasma NIC concentration over time. [Figure 33] 1 is a graph of plasma NIC concentration over time. [Figure 34] 1 is a graph of plasma NIC concentration over time. [Figure 35] 1 is a graph of plasma NIC concentration over time. [Figure 36] 1 is a graph of the AUC results for docetaxel, Example 14, and Example 16. [Figure 37] 1 is a graph showing the results of the release rate of Example 6 (D56H), Example 12-3 (Mg(OH)2), Example 13-2 (MgO), Comparative Example 4 (HT), and Comparative Example 1 (Yomesan). [Figure 38] 1 is a graph showing the virus killing results for the infected control group, Yomesan, and Example 11. [Figure 39] 1 is a graph showing the plasma NIC concentration over time for Example 20 (NIC:MgO:HPMC6:poloxamer (1:0.5:1:1)), Example 21 (NIC:MgO:HPMC6:poloxamer (1:1:1:1)), Example 22 (NIC:MgO:HPMC6:poloxamer (1:2:1:1)), and Comparative Example 5 (NIC:HPMC6:poloxamer (1:1:1)). [Figure 40] 1 is a graph showing the trend of AUC with increasing MgO content for Examples 23-1, 23-2, and 23-3, respectively. [Figure 41]1 is a graph showing plasma drug concentrations over time for the control group (plain 5-FU) and Comparative Example 2 (5-FU:MgO:HPMC). [Figure 42] 1 is a graph showing the plasma drug concentration over time for the control group (simple lipoic acid) and Comparative Example 3 (lipoic acid:MgO:HPMC). [Figure 43] 1 is a graph showing the plasma drug concentration over time for the control group (plain artesunate) and Comparative Example 4 (artesunate:MgO:HPMC). [Figure 44] 1 is a graph showing the results of the improvement rate of macroscopic pneumonia lesions for a non-virus-infected control group (NC), a virus-infected control group (VC), and virus-infected hamsters administered the pharmaceutical composition of Example 24 at 20 mg / kg, 40 mg / kg, and 80 mg / kg, respectively, and the composition of Comparative Example 5 at 80 mg / kg. [Figure 45] 1 is a graph showing the results of lung tissue pathology findings for a non-virus-infected control group (NC), a virus-infected control group (VC), and virus-infected hamsters administered the pharmaceutical composition of Example 24 at 20 mg / kg, 40 mg / kg, and 80 mg / kg, respectively, and the composition of Comparative Example 5 at 80 mg / kg. [Figure 46] 1 is a graph showing the results of viral load in lung samples for a virus-infected control group (VC), virus-infected hamsters administered the pharmaceutical composition of Example 24 at 20 mg / kg, 40 mg / kg, and 80 mg / kg, and the composition of Comparative Example 5 at 80 mg / kg. [Figure 47] 1 shows cell photographs that provide evidence for lung histopathological findings for a non-virus-infected control group (NC), a virus-infected control group (VC), and virus-infected hamsters administered the pharmaceutical composition of Example 24 at 20 mg / kg, 40 mg / kg, and 80 mg / kg, respectively, and the composition of Comparative Example 5 at 80 mg / kg. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention will be explained in more detail below. The present invention provides metal (hydro)conjugates containing poorly soluble drugs with significantly improved dispersibility, solubility, and bioavailability. In the present invention, the poorly soluble drug is an oxide complex having a very low solubility in water. It means a compound containing at least one hydroxy group in the compound. The compound has extremely low solubility in water if its solubility in water is less than 0.001 mM. It means it is full. The present invention relates to a compound or a compound containing one or more hydroxy groups in a metal (hydr)oxide. and its salts, The metal (hydroxide) is at least one selected from the compounds represented by the following formulas 3 to 5: The present invention provides a metal (hydr)oxide complex,

[0021] [ka]

[0022] (In the above Chemical Formula 3, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ , and Zn 2+ Selected from the group consisting of is a divalent metal cation that M 3+ Al 3+ , Fe 3+ , V 3+ , Ti 3+ , Mn 3+ , and Ga 3+ A group consisting of is a trivalent metal cation selected from the group consisting of x is a number ranging from 0 to 0.5, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2-, HPO4 2- , and F - from an anion selected from the group consisting of: n is the charge number of the anion A, n is a number ranging from 0.5 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.)

[0023] [ka]

[0024] (In the above Chemical Formula 4, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ , and Zn 2+ Selected from the group consisting of is a divalent metal cation that x is a number ranging from 0 to 0.4, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- , and F - from an anion selected from the group consisting of: n is the charge number of the anion A, n is a number ranging from 0 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.)

[0025] [ka]

[0026] (In the above Chemical Formula 5, M 2+ is Mg 2+ , Ni2+ , Cu 2+ , or Zn 2+ and x is a number greater than or equal to 1 and less than 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- , and F - from an anion selected from the group consisting of: n is the charge number of the anion A, n is a number ranging from 0 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.) In the present invention, the metal (hydr)oxide refers to both metal oxides and metal hydroxides. In addition, in the chemical formulas 3 to 5, y, which represents the number of water molecules, is 0. A positive number in the range of 0 to 20. The metal (hydr)oxide complexes of the present invention are represented by the following chemical formulas 6 to 8.

[0027] [ka]

[0028] (In the above Chemical Formula 6, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ , and Zn 2+ Selected from the group consisting of is a divalent metal cation that x is a number ranging from 1 to 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- , and F- from an anion selected from the group consisting of: Q is a compound or a salt thereof containing at least one hydroxy group, n is the charge number of the anion A, n is a number ranging from 0 to 2; z is a number ranging from 0 to 1; y is a positive number greater than 0.)

[0029] [ka]

[0030] (In the above Chemical Formula 7, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ , and Zn 2+ Selected from the group consisting of is a divalent metal cation that Q is a compound or a salt thereof containing at least one hydroxy group, x is a number ranging from 0 to 2, y is a number ranging from 0 to 1, x+y does not exceed 3, x and y do not simultaneously have the value 0, z is a number ranging from 0 to 10.

[0031] [ka]

[0032] (In the above Chemical Formula 8, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ , and Zn 2+ Selected from the group consisting of is a divalent metal cation that x is a number ranging from 0 to 0.4, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- , and F - from an anion selected from the group consisting of: Q is a compound or a salt thereof containing at least one hydroxy group, n is the charge number of the anion A, n is a number ranging from 0 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.) In Formulas 6 to 8, y represents the number of water molecules and is a positive number greater than 0; Preferably, it is a positive number in the range of more than 0 and 20 or less. In the present invention, a compound containing at least one hydroxy group and soluble in water is For compounds with concentrations less than 0.01 mM, see niclosamide. , loperamide, penfluridol , ciclesonide, oxyclozanide de), dihydrogambogic acid, Osaji Osajin, lusutrombopag, isoosajin (isoosajin), ivacaftor, triparanol riparanol), droloxifene, lopinavir opinavir, docetaxel, vitamin A n A), idebenone, paclitaxel ), Fulvestrant, probucol , doxorubicin, gemcitabine ), quercetin, cyanidin, delphi Delphinidin, malvidin, pelargonidin (pelargonidin), petunidin, curcumin rcumin), epigallocatechin gallate (epigallocatechin-3- gallate), genistein, resveratrol eratrol), estradiol, camptothecin ptothecin), podophyllotoxin, Laro Raloxifene, topotecan, bortezomib Bortezomib, netilmicin, branapram branaplam, and spiramycin. . The compound containing at least one hydroxy group has a low solubility in water. More specifically, the compound has at least one hydroxyl group. Among compounds containing a silyl group, compounds with a water solubility of less than 0.01 are niclosamide, Peramide, penfluridol, ciclesonide, oxyclozanide, dihydrogambogic acid , Osajin, Lusutrombopag, Isoosajin, Ivacaftor, Triparanol, Doro Roxifene, lopinavir, docetaxel, vitamin A, idebenone, paclitaxel, Examples include fulvestrant and probucol. The compound having a solubility in water of less than 0.01 mM and containing one or more hydroxy groups More specifically, the compound or its salt is selected from compounds represented by the following chemical formula 1 or 2: There are more than one type to be selected.

[0033] [ka]

[0034] (In the above Chemical Formula 1, R1 to R6 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, or a hydroxy group. a silyl group, an ester group, an acyl group, an aromatic ring, or a nitro group; At least one of R1 to R6 is a hydroxy group.

[0035] [ka]

[0036] (In the above Chemical Formula 2, A is a nitrogen atom or an oxygen atom, When A is a nitrogen atom, R1 is a hydrogen atom, a halogen atom, a hydroxyl group, or an alkyl group. and if A is an oxygen atom, it has no substituent; R2 to R11 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, or a hydroxy group. an oxy group, an ester group, an acyl group, an aromatic ring, or a nitro group; At least one of R1 to R11 is a hydroxy group. In the substituent of the above-mentioned Chemical Formula 1 or Chemical Formula 2, the halogen atom is a fluorine atom (F), a chlorine atom (C), It means an atom (Cl), a bromine atom (Br), or an iodine atom (I). In the case of a group, it is a saturated hydrocarbon having 1 to 10 carbon atoms or an unsaturated hydrocarbon having 1 to 10 carbon atoms. The saturated hydrocarbons having 1 to 10 carbon atoms include methyl, ethyl, propyl, and isopropyl groups. The substituents of the formula 1 or 2 include a propyl group, a butyl group, etc. The alkoxy group includes a methoxy group, an ethoxy group, a propoxy group, a butoxy group, etc. The aryl group is a formyl group, an acetyl group (ethanoyl group), a benzoyl group, etc., and aromatic The ring is an aromatic ring having 3 to 20 carbon atoms. The compound represented by Chemical Formula 1 is more particularly selected from docetaxel and paclitaxel. The compound is one or more compounds selected from the group consisting of: The compound represented by Chemical Formula 2 is, more specifically, niclosamide. In the present invention, the bioavailability is increased by forming a complex with a metal oxide or metal hydroxide. The drug has a solubility in water of less than 0.01 and contains at least one hydrogen atom in the compound structure. Compounds that contain a hydroxyl group (OH) are highly soluble in water. The formation of complexes using chlorides or hydroxides does not improve the bioavailability of the compounds. Even if the solubility in water is low, metal oxides that do not contain hydroxyl groups may be used. or reaction with metal oxide and / or metal hydroxide in the process of forming a complex with metal hydroxide It is difficult to affect the solubility of drugs due to the low responsiveness, and it also has the effect of increasing bioavailability. It was confirmed that no results were achieved. Bioavailability of compounds, salts thereof, and / or drugs among the metal oxides and metal hydroxides of the present invention The most effective is most preferably a complex with magnesium oxide (MgO) form. be. The present invention also provides a compound containing at least one hydroxy group in a metal (hydr)oxide. The compound or its salt containing the compound includes an additive, The metal (hydroxide) is one or more of the compounds represented by the above-mentioned chemical formulas 3 to 5. The present invention provides a pharmaceutical composition comprising: The present invention also provides a metal (hydr)oxide powder and a poorly soluble drug powder mechanochemically synthesized to obtain a metal (hydr)oxide powder. A method of manufacturing is provided that includes the step of forming a (hydr)oxide complex. In addition, the present invention provides a method for mechanochemically synthesizing metal (hydr)oxide powders and poorly soluble drug powders. The mechanochemical synthesis step includes applying a physical force. It means a method of drawing or milling powder, and is commonly used in the field. In particular, a method for reaction in a solid state ( Mechanochemical synthesis methods for solid-state reactions Nochemical synthesis includes grinding, and / or milling synthesis. More specifically, the milling synthesis method is Grinding mills, mortar grinders, ball mills, bead mills, rollers Mill, Mix and Heat, Ultra-Precision Grinding Mill, Attrition Mill, etc. These methods reduce the particle size of powder materials and allow them to be crushed, dispersed, and mixed. When the step of mechanochemical synthesis is included as described above, low production costs can be achieved. It has the advantage of generating less cost and waste after production, and is produced without solvents. The calcined metal (hydr)oxide is further restored to its pre-calcined state by minimizing This is preferable in that it can be made into a The present invention also provides a method for physically mixing a metal (hydr)oxide powder, a poorly soluble drug powder, and a surfactant powder. The present invention provides a pharmaceutical composition prepared by grinding the In the present invention, when calcining metal (hydr)oxide, the temperature condition is in the range of 200 to 850°C. More specifically, if the material to be calcined is hydrotalcite, the temperature is 200 to 800°C. If the material being calcined is a metal hydroxide, e.g., Mg(OH)2, then It is preferred to carry out the calcination at a temperature in the range of 00 to 300°C. On the other hand, in the case of metal oxides, for example, MgO, there is a small amount of cation in the compound even without the calcination process. It can also form complexes with compounds and / or drugs containing one or more hydroxyl groups to effectively dissolve them. This can increase the dissolution rate or bioavailability. One embodiment of the present invention involves incorporating a poorly soluble drug in the form of a calcined metal (hydr)oxide. The calcined metal (hydr)oxide structure (e.g., DHT) is not calcined. It may contain niclosamide, a drug that is less soluble than metal (hydr)oxide (e.g., HT) structures. The increased surface area provided by the particles further improves the solubility and dispersibility of poorly soluble drugs. In the present invention, the anhydrous organic solvent can be used without limitation as long as it is an organic solvent that does not contain water. More specifically, absolute alcohol, acetone, acetonitrile, dichloromethene, tetrahydrofuran, chloroform, etc. The absolute alcohol is anhydrous. These include ethanol, anhydrous methanol, and anhydrous butanol. The present invention also provides a method for producing a metal (hydroxide) by calcining the metal (hydroxide). on) to produce a calcined metal (hydroxide); ) reacting the oxide and the poorly soluble drug or its prodrug in an anhydrous organic solvent; and a metal (hydr)oxide complex containing a poorly soluble drug or a prodrug thereof. In the reacting step, hydration reactions are minimized to obtain a calcined form of metal (hydr)oxide. The object is characterized by minimizing further recovery of the object to its pre-calcination shape. When prepared by the above method, the metal (hydr)oxide complex is a calcined form of the metal (hydr)oxide. Specifically, the poorly soluble drug is contained in the calcined form of the metal (hydr)oxide. In rare cases, the poorly soluble drug reacts with the calcined form of the metal (hydr)oxide to form the metal (hydr)oxide. The formation of a compound complex can significantly increase the dispersibility and solubility of poorly soluble drugs. This is preferable in that it has the effect of increasing the bioavailability of poorly soluble drugs. The present invention also provides a method for physically mixing a metal (hydr)oxide powder, a poorly soluble drug powder, and a surfactant powder. The present invention provides a pharmaceutical composition prepared by grinding the In the present invention, the anhydrous organic solvent can be used without limitation as long as it is an organic solvent that does not contain water. More specifically, absolute alcohol, acetone, acetonitrile, dichloromethene, tetrahydrofuran, chloroform, etc. The absolute alcohol is anhydrous. These include ethanol, anhydrous methanol, and anhydrous butanol. The present invention also relates to a metal (hydroxide) and a poorly soluble drug or its prodrug, which are produced by the above-mentioned method. A method for preparing a poorly soluble drug or a prodrug thereof, comprising the step of reacting a poorly soluble drug or a prodrug thereof with an anhydrous organic solvent. The present invention provides a metal (hydr)oxide composite containing a hydroxy group. In the reacting step, hydration reactions are minimized to obtain a calcined form of metal (hydr)oxide. The object is characterized by minimizing further recovery of the object to its pre-calcination shape. When prepared by the above method, the metal (hydr)oxide complex is a calcined form of the metal (hydr)oxide. Specifically, the poorly soluble drug is contained in the calcined form of the metal (hydr)oxide. In rare cases, the poorly soluble drug reacts with the calcined form of the metal (hydr)oxide to form the metal (hydr)oxide. The formation of a compound complex can significantly increase the dispersibility and solubility of poorly soluble drugs. This is preferable in that it has the effect of increasing the bioavailability of poorly soluble drugs. The present invention also provides metal (hydr)oxides and compounds containing at least one hydroxy group. A pharmaceutical composition comprising a metal (hydr)oxide complex containing a compound or a salt thereof and an additive. to provide. The pharmaceutical composition contains 10 or more metal (hydr)oxides relative to 100% by weight of the total pharmaceutical composition. 0.1 to 60% by weight of the compound or its salt, and 10 to 85% by weight of the additive. % by weight, more specifically, 10 to 40% by weight of the compound or its salt, metal (water) It contains 10 to 45% by weight of oxide and 10 to 80% by weight of additive. In addition to the above, in the pharmaceutical composition, metal (hydr)oxides and compounds may contain a small amount of Compounds containing at least one hydroxy group and their salts in a ratio of 1:0.1 to 10 Included. The metal (hydr)oxide complex contained in the pharmaceutical composition is selected from the following chemical formulas 6 to 8: It is represented by one or more of the following:

[0037] [ka]

[0038] (In the above Chemical Formula 6, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ , and Zn 2+ Selected from the group consisting of is a divalent metal cation that x is a number ranging from 1 to 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- , and F - from an anion selected from the group consisting of: Q is a compound containing at least one hydroxy group, n is the charge number of the anion A, n is a number ranging from 0 to 2; z is a number ranging from 0 to 1; y is a positive number greater than 0.)

[0039] [ka]

[0040] (In the above Chemical Formula 7, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ , and Zn 2+ Selected from the group consisting of is a divalent metal cation that Q is a compound containing at least one hydroxy group, x is a number ranging from 0 to 2, y is a number ranging from 0 to 1, x+y does not exceed 3, x and y do not simultaneously have the value 0, z is a number ranging from 0 to 10.

[0041] [ka]

[0042] (In the above Chemical Formula 8, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ , and Zn 2+ Selected from the group consisting of is a divalent metal cation that x is a number ranging from 0 to 0.4, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- , and F - from an anion selected from the group consisting of: Q is a compound containing at least one hydroxy group, n is the charge number of the anion A, n is a number ranging from 0 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.) The pharmaceutical composition is administered at 0.1 to 500 mg / Kg. In the present invention, the additive is most preferably a surfactant, and the surfactant is preferably a ce cellulose, polyoxyethylene sorbitan fatty acid ester ( polyoxyethylene sorbitan fatty acid este rs), poloxamer, lecithin, Glycerol fatty acid esters ), sorbitan fatty acid esters rs), PEG system, thickener (Long chain of sugar), stabilizer system (G um), gelling agent, thickening polysaccharide, and dodecyl sulfate Sodium etc. In detail, cellulose-based Hydroxypropyl methylcellulose (HPMC), Hydroxyethyl cellulose, hydroxyethyl cellulose Hydroxypropylcellulose (HPC), Carboxymethylcellulose (CMC) , ethylcellulose (EC), and cellulose acetate (c Although cellulose acetate (CA) and the like may be used, HPMC is most preferred. In the case of the polyoxyethylene sorbitan fatty acid ester, commercially available Tween series The most common surfactant is a fatty acid and ethylene oxide ester bonded. The polyoxyethylene sorbitan fatty acid ester system is polyoxyethylene monolaurate. Ethylene sorbitan (Polyoxyethylene sorbitan monol aurate; Tween 20), polyoxyethylene sorbitan monopalmitate ( polyoxyethylene sorbitan monopalmitate;T Ween 40), polyethylene glycol sorbitan monostearate (polyet hylene glycol sorbitan monostearate; Twe en 60), Tween 65, polyoxyethylene sorbitan monooleate (pol yoxyethylene sorbitan monooleate;Tween80 ), and polyoxyethylene sorbitan trioleate sorbitan monooleate; Tween 80), etc. The phospholipids are substances similar to lecithin and its derivatives. ipids), phosphatidyl choline , mixed phospholipids, sodium cholate (s sodium cholate), hydroxylated phospholipids phospholipids, hydroxylated lecithin The glycerol fatty acid ester is a polyglycerol. Fatty acid esters (polyglycerol fatty acid esters), Polyglycerol polyricinoleate leate), triricinoleic acid polyoxyethylene glycerol (polyglyce rol polyricinoleate), Cremophor EL (Cremophor The sorbitan fatty acid ester is sorbitan monolaurate (s EL). Sorbitan monolaurate (Span 20), sorbitan monooleate sorbitan monooleate (Span 80), etc. PEG200, PEG300, PEG400, PEG500, PEG1000, PE G1500, mPEG550, etc. Poloxamer-based compounds include Poloxamer 101, Poloxamer Poloxamer 105, Poloxamer 108, Poloxamer 122, Poloxamer 123, Poloxamer Poloxamer 124, Poloxamer 181, Poloxamer 182, Poloxamer 183, Poloxamer Poloxamer 184, Poloxamer 185, Poloxamer 188, Poloxamer 212, Poloxamer Poloxamer 215, Poloxamer 217, Poloxamer 231, Poloxamer 234, Poloxamer Poloxamer 235, Poloxamer 237, Poloxamer 238, Poloxamer 282, Poloxamer Poloxamer 284, Poloxamer 288, Poloxamer 331, Poloxamer 333, Poloxamer Poloxamer 334, Poloxamer 335, Poloxamer 338, Poloxamer 401, Poloxamer Poloxamer 402, Poloxamer 403, and Poloxamer 407. For details on stabilizers, gelling agents, and thickening polysaccharides, see Microfiber Cellulose ( Microfibrous cellulose), CMC (Carboxy Meth) yl Cellulose, Nitrocellulose, Hydroxypropyl guar, modified starch (Mo dified starches), xanthan gum, gelatin, guar gum, gum arabic, cellulose Sugar gum, locust bean gum, tamarind gum, tara gum, glucomannan, polyquaternium-10 Polyquat, Carbopol Pregel, Hycell, Polystearic acid, Al Acid, Carrageenan, Agar, Furcellar an), Gum tracanth, Karaya gum gum, Gellan gum, Rhamsan gum m), Welan gum, Quince seed gum ed Gum), dextran, hyaluronic acid, Carbopol 941 , Carbopol 934, and Carbopol 940, cationic polymers (Polyqua ternium-10), polyvinyl alcohol ), medium-chain fatty acids, stearyl fumarate. By using the surfactants mentioned above, it is possible to The solubility and dispersibility of the metal (hydr)oxide complex can be improved, thereby This is more preferable in that it can increase the bioavailability of soluble drugs. In addition to the above-mentioned additives, the pharmaceutical composition of the present invention may contain any of the additives commonly used in the art. Any additive may be further contained without any limitation, and the type thereof is not limited. Additives are plasticizers added to resins to give them flexibility and workability. r) and a pH for adjusting the acidity of the pharmaceutical composition to a level suitable for use as a formulation. Modifiers, excipients, and solubilizers (s) for increasing the solubility of substances in semi-solid and solid phases. olubilizing agent and sweetener agent ) and a gelling agent, which provides adsorption, solidification, and consistency to the mixture. A bonding agent for high temperature moisture absorption and a hard capsule A hardener and a cellulose-based or Tween-based agent other than the above. surfactants, used to absorb moisture or prevent solidification Anticaking agents and brighteners r) Brightening agents and flavoring agents to maximize or adjust the original taste and aroma enhancer and a base for inactive ingredients used as a vehicle for the active drug. e) and a porosifying agent that forms a structure with many small gaps by rapid evaporation due to rapid heating. , sugar coating agents, and bulking agents agent for freeze-drying and isotonic agent agent), a liner, a hair softener, a light-reducing agent, a soothing agent, and adhesive tape adhesive. A semi-permeable membrane acts as a paper to protect the surface and allow for easy removal during use, and a foaming agent (effervescent agent), preservative, radioprotectant, waterproofing agent (d esiccant and release-modifying agent ), culture medium, denaturants, and preservatives. obial preservative and anti-adherent ) and a propellant that is a liquefied gas with a vapor pressure greater than 14.7 lb / sq at 40.6°C ( aerosol propellant and dispersing agent t), an opacifying agent, a disintegrant, and an electron-removing agent. Acidifying agents, which are substances that cause oxidation, and oxidizing agents, which are substances that cause oxidation. zer), and osmotic pressure regulators (osmo) that use the principle of osmotic pressure to adjust the drug release rate. tic regulator and sustained release deodorizing agent, cleaner, and antifoaming agent Foaming Agent, Humectant, and Stabilizer bilizing agent and alkalizing agent ) and a mattress that stores the drug storage layer drug, a soft capsule base, and a softener that softens the skin. The emollient is a cream-like substance that has a high pH. A buffering agent that prevents the material from changing rapidly and a solvent vent, an emulsifying agent, and an active pharmaceutical ingredient Transporting agents, softeners, and emulsifiers used to bind or melt the product (emulsifier) ​​and anticoagulant (blood coagulation inhibitor) inhibitor, anit-allergenic, and enteric coating (enteric coating agent) and viscosity-increasing agent increasing agent), adhesive (complexing agent) , adhesive support, release film, support, and shielding UV protectors and screening agents that can eliminate unpleasant tastes or odors in medicines Masking agents, colors, and flavors and perfumes) and medicines that are placed in the container to aid in drug administration. Available accessories and solvents to help solutes go into solution and to be used when administering drugs. , refreshing agents and to increase volume or weight Fillers added to other materials (air displacement) and chemical solution penetration a penetration enhancer used to make the material smooth; Coating agents and chelating agents Agent, discolorant, degreaser, and labeling agent ing agent), coating, antioxidant, and suspending agent ( suspending agent) and added to the product in the same volume as the diluent or softener. The purpose of the ingredients is to prevent the pills from sticking together, mold growth, and moisture evaporation. and a pill-like coating, which is a powder that is applied to the skin but has a coating that reduces friction to make it easier to swallow. A glidant agent and a volatile res trainer), a volatilization promoter, an absorbent that absorbs gas and liquid, and a surface absorbent that absorbs gas and liquid. or an adsorbent for adsorbing a solute, a humectant liquid phase agent, and a temperature Warming agents, which are substances that give a feeling of warmth, and pH-dependent, swelling behavior-adjusting agents such as Eudragit Examples include enteric coating agents that have a beneficial effect. In the present invention, the pharmaceutical composition is used to treat bacterial or viral infectious diseases, inflammatory diseases, and and malignant tumor diseases. The pharmaceutical composition of the present invention is for the prevention or treatment of novel coronavirus and for anti-cancer purposes. be. The bacterial or viral infectious disease may be a malaria infection or an Epstein-Barr virus infection. Epstein-Barr Virus (EBV), Hepatitis B virus, Hepatitis C Viruses, HIV, HTLV-1, Varicella-Zoster virus (Varicella-Zoster) er Virus (VZV), and Human Papillomavirus (Human Papillomavirus) viral diseases, including HPV), SARS-CoV and / or S Viral infection caused by coronaviruses such as ARS-CoV2 These include infectious diseases and other retrovirus infections. The inflammatory diseases include vascular restenosis and autoimmune diseases. Infectious diseases, pancreatitis, glomerulonephritis, myocardial infarction (m Inflammatory diseases, including eosinophilic cardiac infarction and psoriasis, and allergic Allergic conditions include allergic asthma, atopic dermatitis (eczema), and allergic rhinitis (rhinitis). Atopic dermatitis (Atopy) and allergic contact dermatitis (Allergic C Contact Dermatitis and Hypersensitivity Pneumonitis Cell Mediated Hypersensitivity (Cell Mediated Hypersensitivity) including Hypersensitivity) and Systemic Lupus Erythematosus Lupus Erythematosus (SLE), rheumatoid arthritis, juvenile arthritis (Juvenile Arthritis), Sjogren's Syndrome Syndrome, Scleroderma, Polymyositis ositis), ankylosing spondylitis, and Rheumatic diseases, including psoriatic arthritis, Including diabetes, autoimmune thyroid disease, dementia, Parkinson's disease, and Alzheimer's disease These include brain diseases and other autoimmune and degenerative diseases, including arthritis. The malignant tumor diseases include fibrosarcoma, myxosarcoma, sarcoma, liposarcoma, chondrosarcoma coma), osteosarcoma (osteogenic sarcoma), osteosarcoma (chordo ma), angiosarcoma, endotheliosarcoma Lymphangiosarcoma, lymphangiosarcoma, intralymphatic sarcoma tumor (lymphangioendotheliosarcoma), synovial tumor (synov) ioma, mesothelioma, Ewing's sarcoma tumor), leiomyosarcoma, rhabdomyosarcoma omyosarcoma, colon carcinoma, pancreatic cancer (pancreatic cancer), breast cancer, eggs ovarian cancer, prostate cancer r), squamous cell carcinoma, basal cell Basal cell carcinoma, adenocarcinoma inoma, sweat gland carcinoma, sebaceous gland carcinoma sebaceous gland carcinoma, papillary carcinoma lary carcinoma), papillary adenoca cystadenocarcinoma, medullary carcinoma medullary carcinoma, bronchogenic carcinoma enic carcinoma), renal cell carcinoma oma), hepatoma, bile duct cancer noma, choriocarcinoma, seminoma ma), embryonal carcinoma, Wilms' tumor ( Wilms tumor, cervical cancer, testicular cancer (testicular tumor), lung carcinoma, small cell lung carcinoma, bladder cancer (bladder carcinoma), epithelial carcinoma rcinoma), glioma, astrocytoma , medulloblastoma, craniopharyn gioma, ependymoma, pinealoma, Hemangioblastoma, acoustic neuroma uroma), oligodendroglioma, meningioma melanoma, neuroblastoma ma, and cancers including retinoblastoma, and breast, anterior Carcinomas arising from prostate, kidney, bladder, or colon tissue, and carcinomas arising from the bladder Fat cell tumors, e.g., lipoma, fibrolipoma , lipoblastoma, lipomatosis, brown Lipoma, hemangioma, and / or liposarcoma These include neoplastic diseases that manifest in adipose tissue, such as liposarcoma. The pharmaceutical composition according to the present invention can be administered orally, injectably, mucosally, inhaled, topically, or transdermally. (ointments, creams, etc.), but oral forms are preferred. . In the present invention, the pH adjuster is one that is commonly used in the art, but is preferably Citric acid, malic acid, lactic acid, fumaric acid, glycolic acid, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid Use an acid etc. As used herein, the excipients include polyvinylpyrrolidone, glucose, phosphatides, Polyhydric alcohols, sucrose, trehalose Monosaccharides including dextrose, mannitol, lactose, citric acid, mannitol, and dextrose Use one or more of the sugars that can be used in medicines, such as sugars, disaccharides, and trisaccharides. The present invention includes a step of calcining a metal (hydr)oxide to produce a calcined metal (hydr)oxide. and the calcined metal (hydr)oxide and the poorly soluble drug or its prodrug are dissolved in an anhydrous organic solvent. and reacting a poorly soluble drug or its prodrug with a metal (water) ) A method for producing an oxide composite is provided. In the step of reacting in an anhydrous solvent, no hydration reaction occurs. More specifically, the calcination in the step of producing the calcined metal (hydr)oxide is 25 It is carried out at temperatures between 0°C and 2000°C. In addition, the present invention provides a method for producing a metal (hydroxide) complex by treating the metal (hydroxide) complex with a surfactant. The method for producing the pharmaceutical composition further comprises the step of coating the compound conjugate. provide. The surfactant treatment step may include dissolving a surfactant in an organic solvent to form a surfactant solution. preparing a surfactant solvent by mixing the metal (hydr)oxide complex with the surfactant solvent. and stirring to form a mixture; and evaporating the solvent from the mixture. , including. Reference Example 1: Synthesis of uncalcined metal (hydr)oxide-niclosamide complexes (HT) Hydrotalcite (Sigma Aldrich or Kwoya Che) was prepared under austere conditions. (Mical Industry CO., LTD.) 6.9g suspended in 700ml of purified water After turbidity, the mixture was stirred for 30 minutes. solution) were mixed to prepare an aqueous solution of niclosamide sodium salt substituted with the sodium salt. Then, the aqueous sodium salt solution is slowly added dropwise to the hydrotalcite suspension for 30 minutes. During titration, the pH of the solution is maintained at 8.5 using NaOH. After titration, the solution is heated in a nitrogen atmosphere at room temperature. After stirring for 18 hours, the suspension was filtered through a membrane filter. After filtering using a pH-adjusted aqueous solution, the mixture is washed three times. Finally, after washing twice more with ethanol, the mixture was dried in a vacuum oven (1 mbar, 40 The final white complex was obtained in a yield of 70% (drug base). was obtained. Reference Example 2: Synthesis of uncalcined metal (hydr)oxide-niclosamide complexes (HT) Niclosamide is converted to carbonate ions (CO3 2- ) was dissolved in triple distilled water from which the The solution was converted from Zn(NO3)2·H2O to carbonate ions (CO3 2- ) was removed 3 After dissolving it in distilled water, adjust the pH to about 6-7 using 0.2M NaOH. The titrated solution was separated by a centrifuge and washed. The unreacted salt was removed through a washing process. Then, the produced zinc basic salt precipitate was obtained and further After centrifugation and washing, the mixture was dried in a vacuum to obtain a yellow powder. Reference Example 3: HT(MgAl(OH) 16 CO 3. 4H2O) Reference Example 4: DHT (350℃) Hydrotalcite (Sigma Aldrich or Kwoya Che) was prepared under nitrogen atmosphere. (Mical Industry CO., LTD.) powder (3g each) The mixture is placed in each reactor and calcined at 350°C for 8 hours to obtain DHT. Reference Example 5: DHT (350°C): NIC = 1: 0.4-grinding The DHT and niclosamide of Reference Example 4 were mixed in a weight ratio of 0.6:0.4, and 0.6 g of DHT and 0.6 g of niclosamide were mixed. Reference Example 5 was obtained by grinding 0.4 g of samid. Reference Example 6: DHT (350°C): NIC = 0.8: 0.2-grinding The DHT and niclosamide of Reference Example 4 were mixed in a weight ratio of 0.8:0.2, and 0.8 g of DHT and 0.8 g of niclosamide were mixed. Reference Example 6 was obtained by grinding 0.2 g of samid. Reference Example 7: MgO:Al2O3 = 2:1-grinding The MgO and Al2O3 samples were mixed in a weight ratio of 2:1, with 2g of MgO powder and 1g of Al2O3 powder. 1g was ground to obtain Reference Example 7. Reference Example 8: MgO:Al2O3:NIC=2:1:1-grinding The MgO, Al2O3, and niclosamide samples were mixed in a weight ratio of 2:2:1. Reference Example 8 was obtained by grinding 1 g of l2O3 powder and 1 g of NIC. Reference example 9: HT-NIC(36%) / EtOH Add hydrotalcite (Sigma Aldrich or Kwoya Chem) to a flask. ical Industry CO., LTD.) 3g powder and 50ml absolute ethanol Add the powder and disperse it thoroughly by ultrasonication for 10 minutes. Stir the solution at 700 rpm or more. Add 3g of niclosamide and stir for 6 hours. Remove the remaining liquid through an envelope, wash with absolute ethanol 4-5 times, and then vacuum dry. After drying, a yellow powder of DHT-NIC compound was obtained (content 36%). Dissolve 0.356 g of PMC in a 1:1 solution of absolute ethanol and dichloromethane. 2.0 g of HT-NIC is added to each of the two main tanks and rapidly stirred for 30 minutes. After evaporating the solvent using a rotary evaporator, the resulting pharmaceutical composition (yellow powder) was dried. After drying, the pharmaceutical composition shown in Figure 8 (blue) was obtained. Reference Example 10: DHT (250℃) Hydrotalcite (Sigma Aldrich or Kwoya Che) was prepared under nitrogen atmosphere. (Mical Industry CO., LTD.) powder (3g each) The mixture was placed in each reaction vessel and calcined at 250°C for 8 hours to obtain DHT of Reference Example 10. do. Reference Example 11: DHT (350°C)-NIC / EtOH+H2O Dehydrotalcite and niclosamide calcined at 350°C after synthesis in absolute ethanol (NIC content 44%), DHT-NIC and absolute ethanol solution were mixed with water (4%), and 4 The mixture was stirred for 8 hours. Reference Example 12: DHT (350°C) / EtOH+H2O Dehydrotalcite calcined at 350°C was dissolved in anhydrous ethanol and water (4%) was added. Then, the mixture was stirred for 48 hours. Reference example 13: HT-NIC / HPMC Hydrotalcite (Sigma Aldrich or Kwoya Chemical Niclosamide was synthesized and purified with absolute ethanol by the Japan Atomic Energy Agency (JAC). After filtering and washing, the collected HT-NIC (NIC content 35%) was mixed with HPMC. It was obtained by reacting with anhydrous ethanol and dichloromethane solution. Reference Example 14: DHT (350°C) / EtOH Dehydrotalcite calcined at 350°C was stirred in anhydrous ethanol solution for 48 hours. Synthesis of Examples 1-1 and 1-2: Calcined Metal (Hydroxy)oxide-Niclosamide Composites Body synthesis (DHT-NIC complex) <Step 1> Hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD.) powder, and place 3g of each powder in each reaction vessel. The mixture is then calcined at 350°C for 8 hours. <Step 2> Add 200 ml of anhydrous methanol to each container and thoroughly disperse the powder by ultrasonication for 10 minutes. While stirring each solution at 700 rpm or more, add 3 g of niclosamide (Example 1-1), 1. Add 5g (Example 1-2) and stir for 6 hours. Remove the remaining liquid through a purifier, wash with anhydrous methanol 4-5 times, and the yellow color will appear. The final niclosamide content was 44% for 1-1 and 22% for 1-2. The quantity was shown. Synthesis of Examples 1-3 and 1-5: Calcined Metal (Hydroxy)oxide-Niclosamide Composites Body synthesis (DHT-NIC complex) <Step 1> Hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD.) powder was taken from each of the three reactions. The container (Example 1-3, Example 1-4, Example 1-5) was placed under 350°C for 8 hours. Calcination is carried out. <Step 2> Put 100ml, 50ml and 25ml of absolute ethanol into each container and sonicate for 1 minute. Disperse the powder thoroughly for 3 minutes. Add niclosamide 3 to each solution while stirring at 700 rpm or more. After adding 1000g, the mixture was stirred for 6 hours. Remove the remaining liquid, wash with absolute ethanol 4-5 times, and vacuum dry to obtain a yellow powder. The final niclosamide content was 32% for 1-3, 46% for 1-4, and 3% for 1-5. The content was 1%. Example 2. Synthesis of calcined metal (hydr)oxide-niclosamide complex (DHT-NIC complex) Combined) Commercially available hydrotalcite (Sigma Aldrich or Kwoya Chemical al Industry CO., LTD.) under the condition of 250℃ to 800℃ At 50°C intervals, 3g of powder was taken and placed in each reaction vessel and calcined for 8 hours. Add 50 ml of absolute ethanol to a container and disperse the powder thoroughly by ultrasonication for 30 minutes. Add 50 ml of absolute ethanol and 3 g of niclosamide while stirring at 700 rpm or more. Stir for 24 hours. Remove the remaining liquid through a filter membrane for purification. Then, it was washed with absolute ethanol 4-5 times and dried in vacuum to obtain a yellow powder. . Example 3. Synthesis of calcined metal (hydr)oxide-niclosamide complex (DHT-NIC complex) Combined) In a nitrogen environment, 6.9 g of pristine ZnAl-LDH was suspended in 700 ml of purified water. After that, the suspension was stirred for 30 minutes. After mixing the above solutions to prepare an aqueous solution of niclosamide sodium salt substituted with sodium salt, The sodium salt solution is slowly added dropwise to the LDH pristine suspension for 30 minutes. In this case, the pH of the solution is maintained at 8.5 using NaOH. After titration, the solution is heated under nitrogen atmosphere at room temperature. The suspension was stirred for 18 hours under reduced pressure, and then filtered through a filtered glass (membrane After filtering using a filter, the solution is washed three times with a pH-adjusted solution. Finally, the mixture was washed twice more with ethanol and then dried in a vacuum oven (1 mbar The final white complex was obtained in 70% yield (drug ba Next, the temperature was measured at 50°C intervals under the conditions of 250°C to 800°C. 3g of powder was taken and placed in each reaction vessel and calcined for 8 hours. Add 0 ml of each solution and disperse the powder thoroughly by ultrasonication for 30 minutes. Add 50 ml of absolute ethanol and 3 g of niclosamide while stirring, then stir for 24 hours. For purification, remove the remaining liquid through a filter membrane and acetonitrile 4 to 5 times. The mixture was washed with toluene and absolute ethanol and then vacuum dried to obtain a yellow powder. Examples 4 and 5. Pharmaceutical compositions containing calcined metal (hydr)oxide-niclosamide complexes Manufacturing <Step 1> Hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD.) powder, put it in an alumina container, and heat it in a furnace. Calcination is carried out at 350°C for 8 hours. <Step 2> Each powder was placed in a flask, 50 ml of absolute ethanol was added, and the powder was sonicated for 10 minutes. Disperse well. Add 3 g of niclosamide while stirring each solution at 700 rpm or more. After that, stir for 6 hours. Remove the remaining liquid through a filter membrane for purification. Then, it was washed 4-5 times with anhydrous methanol and dried in vacuum to synthesize yellow DHT-NIC. The resulting powder contained 43.3% of niclosamide. The IR graph is shown in FIG. <Step 3> Two main tanks, each containing 0.270g of HPMC or 0.540g of Tween 60 Dissolve in a 1:1 solution of absolute ethanol and dichloromethane, or in absolute ethanol. 1.350 g of the DHT-NIC was added to each of the two main tanks and rapidly heated for 30 minutes. After evaporating the solvent using a rotary evaporator, the resulting pharmaceutical composition (yellow Powder) are dried to obtain the pharmaceutical compositions of Examples 4 and 5, respectively. Examples 6 and 11. Pharmaceutical compositions containing calcined metal (hydr)oxide-niclosamide complexes Manufacturing <Step 1> Hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD.) powder was taken from each of the three reactions. The mixture is placed in a container and calcined at 350°C for 8 hours. <Step 2> Add 50 ml of absolute ethanol to each container and disperse the powder thoroughly by ultrasonication for 10 minutes. The solution was stirred at 700 rpm or more, and 3 g of niclosamide was added, and then the mixture was stirred for 6 hours. For purification, remove the remaining liquid through a filter membrane and stir for 4- After washing five times with absolute ethanol and drying in vacuum, a yellow powder was obtained. The closamide content was 46%. <Step 3> The DHT-NIC complex prepared by steps 1 and 2 was further treated with niclosamide and H Add an additional solution of PMC dissolved in absolute ethanol and dichloromethane, stir, and evaporate. (or spray-dried) to produce the pharmaceutical compositions of Examples 6 to 11. The method for carrying out step 3 in each of Examples 6 to 11 is as follows. Step 3 of Example 6 In the main tank, add 0.546g of HPMC to a solution of absolute ethanol and dichloromethane in a 1:1 ratio. Dissolve 2.728g of DHT-NIC in the main tank and stir rapidly for 30 minutes. After evaporating the solvent using a rotary evaporator, the resulting pharmaceutical composition (yellow powder) was Drying provides the pharmaceutical composition. Step 3 of Example 7 Add 0.390g of HPMC to a 1:1 solution of absolute ethanol and dichloromethane in the main tank. Dissolve 0.61g of niclosamide in this solution, then dissolve it in DHT-NIC1.3 Add 4g of the solution to the main tank and stir quickly for 30 minutes. After evaporation, the resulting pharmaceutical composition (yellow powder) is dried to obtain the pharmaceutical composition. Step 3 of Example 8 In the main tank, add 0.316 g of HPMC to a solution of absolute ethanol and dichloromethane in a 1:1 ratio. Dissolve 0.906 g of niclosamide in this solution and dissolve it. Add 34g of the solvent to the main tank and stir quickly for 30 minutes. After evaporation, the resulting pharmaceutical composition (yellow powder) is dried to obtain the pharmaceutical composition. In step 3 above, the DHT-NIC was further treated with niclosamide and Tween 60. The pharmaceutical compositions of Examples 9 to 11 were prepared in the same manner as described above, except that the The specific preparation method of Step 3 in Examples 9 to 11 is as follows. Step 3 of Example 9 Dissolve 1.092g of Tween 60 in absolute ethanol in the main tank. Add 0.728g of the solution to the main tank and stir rapidly for 30 minutes. After evaporating the solvent, the resulting pharmaceutical composition (yellow powder) was dried to obtain the pharmaceutical composition. do. Step 3 of Example 10 Dissolve 0.78g of Tween 60 in absolute ethanol in the main tank. Add 0.61g of mido and dissolve it, then add 1.34g of DHT-NIC to the main tank. Stir rapidly for 30 minutes. After evaporating the solvent using a rotary evaporator, the resulting pharmaceutical The target composition (yellow powder) is dried to obtain the pharmaceutical composition. Step 3 of Example 11 Dissolve 0.632g of Tween 60 in absolute ethanol in the main tank. Add 0.906g of Samid and dissolve it, then add 1.34g of DHT-NIC to the main tank. The mixture was stirred rapidly for 30 minutes. After evaporating the solvent using a rotary evaporator, the resulting The pharmaceutical composition (yellow powder) is dried to obtain the pharmaceutical composition. The specific contents of the pharmaceutical compositions of Examples 6 to 11 prepared by the above-mentioned methods are as follows: As shown in Tables 1 and 2.

[0043] [Table 1]

[0044] [Table 2]

[0045] Examples 12-1 and 12-4: Calcined metal (hydr)oxide-niclosamide complexes and Preparation of pharmaceutical compositions containing the same <Step 1> 3g of Mg(OH)2 powder was taken and placed in two reaction vessels, and heated to 200℃ (12-1) and and calcination at 300°C (12-2) for 6 hours. <Step 2> Add 50 ml of absolute ethanol to each container and disperse the powder thoroughly by ultrasonication for 10 minutes. The solution was stirred at 700 rpm or more, and 3 g of niclosamide was added, and then the mixture was stirred for 4 hours. For purification, remove the remaining liquid through a filter membrane and stir for 4- After washing five times with absolute ethanol and drying in vacuum, a yellow powder was obtained. The content of closamide in the composite calcined at 200°C was 35.2% (metal in Example 12-1). The composite calcined at 300°C was 14.5% (Example 12-2 The content of metal hydroxide-NIC complex was shown. <Step 3> 2 g of each of the metal hydroxide-NIC composites prepared in steps 1 and 2 was added to the Add HPMC to a 1:1 solution of absolute ethanol and dichloromethane and stir. After stirring, the mixture was evaporated (or spray dried) to produce a pharmaceutical composition. Specific examples of the pharmaceutical compositions of Examples 12-3 and 12-4 prepared by the above-mentioned methods The contents are as shown in Table 3 below.

[0046] [Table 3]

[0047] Examples 13-1 and 13-2: Calcined metal oxide-niclosamide complexes and their Manufacture of a pharmaceutical composition comprising <Step 1> 3 g of MgO powder is taken and placed in a reaction vessel, and calcined at 800° C. for 6 hours. <Step 2> Add 50 ml of absolute ethanol to each container and disperse the powder thoroughly by ultrasonication for 10 minutes. The solution was stirred at 700 rpm or more, and 3 g of niclosamide was added, and then the mixture was stirred for 4 hours. For purification, remove the remaining liquid through a filter membrane and stir for 4- After washing five times with absolute ethanol and drying in vacuum, a yellow powder was obtained. The closamide content was 34.6% (Example 13-1). <Step 3> 2 g of the DHT-NIC complex prepared in steps 1 and 2 was added to 0.3 g of HPMC. Add 6g of the compound to a 1:1 solution of absolute ethanol and dichloromethane and stir. After that, evaporation (or spray drying) was performed to prepare the pharmaceutical composition of Example 13-2. The specific contents of the pharmaceutical composition of Example 13-2 prepared by the above method are shown in the following table. It seems to be 4.

[0048] [Table 4]

[0049] Examples 14-1 and 14-2: Calcined metal (hydr)oxide-docetaxel complexes and Preparation of pharmaceutical compositions containing the same <Step 1> Hydrotalcite (Sigma Aldrich or Kwoya Chemical 3g of the powder was placed in a reaction vessel and heated to 350℃. Calcination is carried out under conditions for 8 hours. <Step 2> Add 50 ml of anhydrous acetonitrile to each container and thoroughly disperse the powder by ultrasonication for 10 minutes. While stirring the solution at 700 rpm or more, 3 g of docetaxel is added, and then The mixture was stirred at 0°C for 1 hour. The mixture was dried in vacuo to give a white powder (DHT-DTX complex). Example 14-1) was obtained. <Step 3> 1 g of the DHT-DTX complex prepared in steps 1 and 2 was added to 0.22 mL of HPMC. Add 1g of the compound to a 1:1 solution of absolute ethanol and dichloromethane and stir. After that, evaporation (or spray drying) was performed to prepare the pharmaceutical composition of Example 14-2. Examples 15-1 and 15-2: Calcined metal (hydr)oxide-docetaxel complexes and Preparation of pharmaceutical compositions containing the same <Step 1> Hydrotalcite (Sigma Aldrich or Kwoya Chemical 3g of the powder was placed in a reaction vessel and heated to 350℃. Calcination is carried out under conditions for 8 hours. <Step 2> Add 50 ml of anhydrous acetonitrile to each container and thoroughly disperse the powder by ultrasonication for 10 minutes. While stirring the solution at 700 rpm or more, 3 g of docetaxel is added, and then Stir at room temperature for 1 hour. Remove the remaining liquid through a filter membrane for purification. Then, the mixture was washed 4-5 times with absolute ethanol and vacuum dried to obtain a white powder (DHT -DTX complex (Example 15-1) was obtained. <Step 3> DHT-DTX Complex 1 of Example 15-1 prepared by Steps 1 and 2 0.221g of HPMC is dissolved in absolute ethanol and dichloromethane in a 1:1 ratio. and then evaporated (or spray dried) to obtain the pharmaceutical composition of Example 15-2. was manufactured. Examples 16-1 and 16-2: Calcined metal oxide-docetaxel complexes and their Manufacture of a pharmaceutical composition comprising <Step 1> 3 g of MgO powder is taken and placed in a reaction vessel, and calcined at 800° C. for 6 hours. <Step 2> Add 50 ml of anhydrous acetonitrile to each container and thoroughly disperse the powder by ultrasonication for 10 minutes. While stirring the solution at 700 rpm or more, 3 g of docetaxel is added, and then The mixture was stirred at 0°C for 1 hour. The mixture was dried in vacuum to obtain a white powder (MgO-DTX complex). Example 16-1) was obtained. <Step 3> MgO-DTX composite 1 of Example 16-1 prepared by steps 1 and 2 0.221g of HPMC is dissolved in absolute ethanol and dichloromethane in a 1:1 ratio. and then evaporated (or spray dried) to obtain the pharmaceutical composition of Example 16-2. was manufactured. Examples 17-1 and 17-2: Calcined metal oxide-docetaxel complexes and their Manufacture of a pharmaceutical composition comprising <Step 1> 3 g of MgO powder is taken and placed in a reaction vessel, and calcined at 800° C. for 6 hours. <Step 2> Add 50 ml of anhydrous acetonitrile to each container and thoroughly disperse the powder by ultrasonication for 10 minutes. While stirring the solution at 700 rpm or more, 3 g of docetaxel is added, and then Stir at room temperature for 1 hour. Remove the remaining liquid through a filter membrane for purification. The mixture was then washed 4-5 times with absolute ethanol and vacuum dried to obtain a white powder (MgO -DTX complex (Example 17-1) was obtained. <Step 3> MgO-DTX composite 1 of Example 17-1 prepared by steps 1 and 2 0.221g of HPMC is dissolved in absolute ethanol and dichloromethane in a 1:1 ratio. The mixture was stirred in a solution of 100% ethanol and then evaporated (or spray dried) to prepare a pharmaceutical composition. Example 18: Preparation of a pharmaceutical composition containing a calcined metal (hydr)oxide-niclosamide complex Manufacturing (Physical grinding method) In this example, the powder was prepared without solvent by the simple method of physical grinding or milling. The components are mixed and the homogeneity and dispersity are measured. Pharmaceutical compositions containing calcined metal (hydr)oxide complexes with increasing concentrations of HCl were prepared. <Step 1> Hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD.) and place 3g of powder in a reaction vessel. The mixture is calcined at 350°C for 8 hours. <Step 2> DH in the container of the mortar grinder or bead mill equipment respectively After adding 0.5g of T, 0.5g of niclosamide, and 0.255g of HPMC and mixing A yellow powder was obtained, which was the pharmaceutical composition of Example 18. The final niclosamide content was The content was 40%. The specific contents of the pharmaceutical composition of Example 18 prepared by the above method are shown in Table 5 below. It seems.

[0050] [Table 5]

[0051] Example 19: Preparation of a pharmaceutical composition containing a calcined metal (hydr)oxide-niclosamide complex Construction <Step 1> Hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD.) and place 3g of powder in a reaction vessel. The mixture is calcined at 350°C for 8 hours. <Step 2> Add 50 ml of absolute ethanol to each container and disperse the powder thoroughly by ultrasonication for 10 minutes. While stirring the solution at 700 rpm or more, 3 g of niclosamide was added and stirred for 6 hours. After stirring and drying in vacuum, a yellow powder was obtained. The final niclosamide content was 49%. The contents are shown. <Step 3> In the main tank, add 0.394g of HPMC to a solution of absolute ethanol and dichloromethane in a 1:1 ratio. Dissolve 2.025g of DHT-NIC in the main tank and stir rapidly for 30 minutes. After evaporating the solvent using a rotary evaporator, the resulting pharmaceutical composition of Example 19 ( The resulting yellow powder is dried to obtain the pharmaceutical composition. Example 20: Preparation of a pharmaceutical composition containing a metal oxide-niclosamide complex (NIC-Mg O-HPMC-Poloxamer: 1:0.5:1:1) Add 0.5 g of niclosamide and 0.5 g of Mg to the container of a mortar grinder or bead mill. Add 0.225g of O (room temperature), 0.5g of HPMC, and 0.5g of poloxamer and mix. The above procedure was carried out to obtain a powder of the pharmaceutical composition of Example 20. Example 21: Preparation of a pharmaceutical composition containing a metal oxide-niclosamide complex (NIC-Mg O-HPMC-Poloxamer: 1:1:1:1) Add 0.5 g of niclosamide and 0.5 g of Mg to the container of a mortar grinder or bead mill. An experiment was carried out in which 0.5g of O, 0.5g of HPMC, and 0.5g of poloxamer were added and mixed. A powder of the pharmaceutical composition of Example 20 was obtained. Example 22: Preparation of a pharmaceutical composition containing a metal oxide-niclosamide complex (NIC-Mg O-HPMC-Poloxamer: 1:2:1:1) Add 0.5 g of niclosamide and 0.5 g of Mg to the container of a mortar grinder or bead mill. Example 2: 1 g of O, 0.5 g of HPMC, and 0.5 g of poloxamer were added and mixed. A powder of pharmaceutical composition No. 0 was obtained. Examples 23-1 and 23-3: Preparation of pharmaceutical compositions containing metal oxide-niclosamide complexes Structure (NIC-MgO-HPMC-Poloxamer: 1:2:1:1) Add niclosamide, MgO, and HP to the containers of a mortar grinder or bead mill. MC and poloxamer were added in the amounts shown in Table 6 and mixed. A powder of pharmaceutical composition 23-3 was obtained.

[0052] [Table 6]

[0053] Example 24: Preparation of a pharmaceutical composition containing a metal oxide-niclosamide complex Mix niclosamide, MgO (room temperature), HPMC, and poloxamer in a 1:2 ratio in a container. The mixture was added in a 1:1 weight ratio and dispersed evenly in ethanol, after which the ethanol was vacuum dried. As a result, a powder of the pharmaceutical composition of Example 24 was obtained. Example 25: Preparation of a pharmaceutical composition containing a metal oxide-niclosamide complex 400 mg of niclosamide was mixed with 280 mg of MgO (at room temperature) and stirred in EtOH for 6 hours. After stirring, the EtOH was removed using a vacuum dryer to obtain a powder. (6maps) 100mg and then ground to obtain a powder. Comparative example 1: Yomesan Yomesan, a commercially available drug containing niclosamide, was used as a comparative example with only the adjusted content. Ta. Comparative Example 2: Metal ( (Hydroxy)oxide Complexes and Pharmaceutical Compositions Thereof - Patent application Add 0.5 g of MgO and 5-FU ( Add 0.5g of HPMC (solubility in water 12.2mg / mL) and mix. After mixing, a powder of the pharmaceutical composition of Comparative Example 2 was obtained. Comparative Example 3: Metal ( (Hydroxy)oxide Complexes and Pharmaceutical Compositions Thereof - Patent application Add 0.5 g of MgO and 0.5 g of lipoic acid (water) to the container of a mortar grinder or bead mill. Add 0.5g of 0.24mg / mL of soluble cellulose and 0.255g of HPMC and mix. After carrying out the above steps, a powder of the pharmaceutical composition of Comparative Example 3 was obtained. Comparative Example 4: Metal ( (Hydroxy)oxide Complexes and Pharmaceutical Compositions Thereof - Patent application Add 0.5g of MgO and Artesuna to the container of a mortar grinder or bead mill. 0.255 g of cellulose acetate (solubility in water: 0.5 mL) and HPMC were added and mixed. After that, a powder of the pharmaceutical composition of Comparative Example 4 was obtained. Comparative Example 5: Preparation of a pharmaceutical composition of niclosamide Add 0.5 g of niclosamide and HP to the container of a mortar grinder or bead mill. 0.5 g of MC and 0.5 g of poloxamer were added and mixed, and then the pharmaceutical composition of Example 5 was added. A powder of the composition was obtained. Experimental Example 1: HPLC analysis <Experimental methods and conditions> HPLC analysis method for niclosamide -Final update: 2021.04.14 -wavelength:UV 330nm -column:Poroshell120 C18 2.7um(21×100mm) -Mobile Phase->A:10mM Ammonium acetate(0 0.1% Formic acid), B:ACN -Gradient method JPEG2026035763000024.jpg39170

[0054] -Column temperature: 40℃ -injection: 5μl -Runtime: 15 min -Bar(pressure):280-300 bar 1) Standard curve sample pretreatment method Niclosamide powder was weighed and dissolved in MeOH (0.25% TFA). Prepare a solution with a concentration of 70-75 ppm and sonicate it for 10 minutes, then prepare diluted solutions. (minimum 7 points), stir for 10 minutes, and then analyze. (Niclosamide concentration measurement (Standard curve available from 1 to 70 ppm). 2) Sampling of analytical powder The weight of the niclosamide dosage form sample (granule) was measured and then the weight of the niclosamide dosage form sample (granule) was measured and ... A) A solution was prepared in MeOH at a concentration of 100 ppm and sonicated for 10 minutes. Stir for 1 minute, then filter through a 0.2µm PTFE filter and analyze. (Sample concentration measurement) (Measured at 30-50 ppm). 3) Measurement and comparative analysis of raw material content After HPLC analysis (15 min analysis), the integration and other RTs were detected. Check the Report area and compare it with the conventional standard curve. Substitute into to find the content. Experimental Example 2: Powder X-ray Diffraction (PXRD) analysis Equipment: Powder X-ray Diffraction (PXRD) X-ray diffractometer(D / MAXPRINT 2200-Ult ima, Rigaku, Japan) Cu-Kα radiation(λ=1.5418Å) Tube voltage: 40kV, current: 30mA The X-ray diffractometer is a D / M manufactured by Rigaku (Japan). Measurements were taken using an AXPRINT 2200-Ultima. The negative electrode that generates X-rays is C The negative electrode is used, and the measurement range measured with Kα rays (λ=1.5418Å) is 2θ=3 ~70°, scanning speed:0.02° / 0.2sec, diverge nce slit, scattering slit, and receiving sl It was measured at 0.1, 1, and 1 mm, respectively. The tube voltage was 40 kV, the current was 3 0mA was applied. -Evaluation criteria One-dimensional (1D) electron density along the z-axis ty is calculated by the following formula:

[0055]

number

[0056] The powder obtained by synthesis is comparatively analyzed through XRD diffraction patterns, and the layers are The distance between the two beams is calculated using Bragg's equation (see below). In the case of the peak located at the front, the layer of the synthesized metal compound and anions are present. This indicates the interlayer distance including the distance to the layer in question, and can be said to be an important interlayer distance.

[0057]

number

[0058] (λ = wavelength of X-rays, d = lattice spacing of crystal, θ = angle of incidence) The measured XRD patterns are shown in FIGS. In Figure 3, (a) is NIC, (b) is HT, (c) is DHT, and (d) is DHT-NI. XRD graph for C-complex (* indicates impurity, ▼ indicates periclas) In detail, in Fig. 3, peaks with two-dimensional characteristics of HT are The (001) planes were expressed at 11.6° (003) and 23.3° (006), respectively. After calcination at about 300 °C, the characteristic peaks are broadened to include pseudo-3D peaks. This conversion is called Al 3+ Non-stoichiometric MgO containing ions (nonstoichiometric) periclase formation After hybridizing DHT and NIC, XRD of the DHT-NIC complex When the peaks were observed, it was confirmed that they exhibited the characteristic XRD peak values ​​of DHT and NIC. Obvious changes such as amorphous and pseudo-3D structures are mentioned above. This was clearly confirmed by PXRD analysis, but the change in XRD values ​​suggests that the NIC molecule is efficiently accommodated and protected by DHT to provide better solubility. These results can be confirmed in future in-vitro / in-vivo studies. It is useful for improving antiviral efficacy in vo. In addition, FIG. 11 analyzes the changes in the XRD graphs of Reference Examples 3, 4, 12, and 14. did. In FIG. 11, Reference Examples 12 and 5 and Reference Example 3, DHT and HT calcined at 350° C. were fused. It can be seen that the crystal structure is completely different. Excellent crystallinity and HT performance at 11°, 23°, 35°, 38°, 46°, 60°, and 62°. In the case of Reference Example 4, MgO crystals were formed during calcination at 350°C. is generated and Al is present in the structure as it is mixed. , 43°, 62°. This means that the crystallinity is very low, which means that the crystallographic c-axis This means that the crystallinity in the direction has decreased, and the HT layer structure has decreased, increasing the specific surface area. This can be confirmed from the results of Experimental Example 4. When water is added to the DHT (Reference Example 4) calcined at 350°C in FIG. ) The crystal structure reconstruction process is carried out in the structure of Reference Example 12, which was reacted with water. As confirmed, the structural identity of DHT with broad peaks at 35°, 43°, and 62° The characteristics change and phase changes appear around 11°, 35°, and 65°. This phenomenon can be confirmed by Reference Example 11 in which water is added to Example 1-1 in FIG. However, when the peaks of Example 1-1 in Figure 12 are examined, it is clear that niclosamide is present in the DHT structure. In order to take the form of a complex formed by the reaction of The characteristic peak of DHT and niclosamide, which is an olive-green graph, has a peak in the range When water was added to the DHT-NIC complex of Reference Example 4, the HT The crystal structure reconstruction process is carried out, and the niclosamide and DH contained in the raw material of Example 1-1 are The T peak reflects the reconstruction process of the crystal structure to HT due to the phase transition. The layer changes around 11°, 35°, and 65° in Comparative Example 2 and the peak at 20-30° are seen. The peaks change in a wide range. Experimental Example 3: TEM analysis TEM analysis reveals that the structures of metal (hydroxides) and calcined metal (hydroxides) are different. TEM analysis also confirmed that poorly soluble drugs were effective on calcined metal (hydroxide) compounds. We confirmed that the files were loaded automatically. In detail, A in FIG. 17 shows an FE-SEM image, and B and C show TEM images. (a) and (a) of B are HT of Reference Example 3, and the structure of the hydrotalcite before calcination is confirmed. The HT of Reference Example 3 has a hexagonal single crystal diffraction pattern (selective uniform d-area electron diffraction (SAED) In Fig. 17C(a), the HT structure has a lamellar structure. is 7.6 Å, and (001) (where (001) is the crystallographically high It can be seen that the planes have a regular lattice pattern (indicating crystallinity). Such a structure is shown in Figure 11. This corresponds to the results of XRD data analysis of Reference Example 3. On the other hand, in the case of DHT in Reference Example 4, instead of having an ordered thin layer structure like HT, , chain-like or channel-like This is because HT such as in Reference Example 3 has magnesium and aluminum oxides after calcination. As can be seen in Figure 17, B(b) and C(c), DH The surface of T has a discrete structure with reduced order compared to HT. This is attributed to the partial disappearance of carbonate and water molecules from the HT phase after calcination. The DHT of Reference Example 4 has blocks and transitions formed by alternation along the crystallographic c-axis. The structure is formed through the tunnel structure, as can be seen from the red box in Figure 17B(b). As shown in Fig. 1, intracrystalline spots are formed. The SAED pattern shows a porous channel-like structure. This shows a topotactic transformation upon calcination. ectic transformation). Compared with the DHT structure of Reference Example 4, a TEM image of the DHT-NIC complex (Example 1-1) was obtained. As a result, the surface is softer than the DHT structure, as shown in Figure 17B(c) and C(c). It can be seen that the ring structure is more dispersed than in the SAED pattern. This indicates the presence of atypical atoms arranged in a short range. The TEM image in Figure 17 shows that niclosamide at the molecular level successfully formed the porous channel structure of DHT. It can be seen that the particles are packed tightly together and uniformly deposited on the surface of the DHT. Experimental Example 4: Fourier Transform Infrared (FT-IR) analysis To obtain FT-IR spectra, a Jasco FT / IR-6100 spectrometer was used. The transmission meter (Ja-325 pan) equipment is used. n mode(spectral range 4000-400cm -1 , 326 r Solution 1cm -1 , 40 scans per spectrum) The Br disk method was used. The FT-IR spectra were recorded with a J asco FT / IR-6100 spectrometer(Ja- 325 pan ) by the standard KBr disk method in tra nsmission mode(spectral range 4000-400cm -1 , 326 resolution 1cm -1 , 40 scans per spe ctrum) FIG. 18 shows the results for NIC, HT (Reference Example 3), DHT (Reference Example 4), and DHT-NI, respectively. This is the Fourier transform infrared (FR-IR) spectrum of the N C complex (Example 1-1). The characteristic peak of IC is 3577 cm -1 , 3490cm -1 , 1650cm -1 , 15 17cm -1 , and 570 cm -1 are represented by -OH, -NH, and -C=O, respectively. , -NO2, and C-Cl groups. For HT, 3400 cm -1 Wide range of peaks The peaks are shown at 1630 and 1545 cm -1 The peak can be confirmed (see Figure 19). The peaks are due to the vibration of the (OH) groups caused by the hydroxyl groups and the water between the layers. On the other hand, not only -OH but also -CO3 2-The band with the characteristic This phenomenon can be confirmed by TGA and DTA analysis. In detail, the TGA and DTA results in Figure 21 show that calcination at 350°C for 8 hours The weight change of the substance can be confirmed when the temperature is raised to 256.49°C. There was a weight loss of 12.72% and a weight loss of 7.143% while heating to 342.95°C. The weight loss is then measured during calcination at 350°C for 8 hours. A total weight loss of 37.61% was recorded. It was confirmed that a physical change occurred, but most of the water molecules remained until the first inflection point (256.49°C). is eliminated, and when it proceeds to the second inflection point (342.95℃), -OH is gradually eliminated and -O The temperature (350℃) is maintained and the -CO3 2- is reduced (See Figure 21). In HT, the carbonate 1360cm -1 The peak at is seen to be divided into two peaks at DHT (Fig. 19), this phenomenon is due to the conversion of HT to DHT as mentioned above. In addition, a notable phenomenon in this experiment is that the bands corresponding to -OH and -NH are in the DHT-NIC complex. This phenomenon is reduced in the combined structure, but this is because the NIC is successfully loaded into the DHT. It is possible to confirm this. FIG. 13 shows the results of Example 12-1 (blue), Example 12-2 (red), and NIC (olive). , and Mg(OH)2 (gray). FIG. 14 shows the results for Example 13-1 (blue), NIC (olive), and MgO (gray), respectively. 10 is a corresponding XRD graph. FIG. 15 shows the results of Example 14-1 (pink), DTX (green), Reference Example 4 (gray), and 1 is an XRD graph for Reference Example 3 (black). FIG. 16 shows the results of Example 16-1 (blue), DTX (green), and MgO (calcined at 800°C), respectively. XRD graphs for MgO (calcined MgO) (gray), and MgO (uncalcined MgO) (black) It is Fu. Experimental Example 5: Surface Area and Porosity Analysis 322 BELSORP II mini instrument for analyzing surface area and porosity The experiment was conducted at 77K (Kelvin temperature) using equipment from the Institute of Materials Science (Japan). Ta. For the measurement, HT and DHT were subjected to a degassing process at 100°C for 6 hours, and NIC-D The HT composite was allowed to degas for 12 hours at room temperature. FIG. 22 shows the results of HT (Reference Example 3), DHT (Reference Example 4), and the DHT-NIC complex (Example 1). -1) nitrogen adsorption-desorption isotherm A graph showing the results is shown. Each surface area (S BET ) and total pore volume (V p ) values ​​using the BET method, as shown in Figure 2 The adsorption isotherms of DHT and DHT-2 were calculated and are shown in Table 7. DHT in Reference Example 4 is in the calcined form. Therefore, it was confirmed that the HT had a significantly higher surface area value than the uncalcined HT of Reference Example 3. This is because the surface area becomes uneven (concave-convex) by calcination. Therefore, the total pore volume changes from 0.0061 to 0.0061 when it changes from HT to DHT. The surface area and total porosity of the DHT-NIC composite increased from 0.0099 to 0.0099. The product value was lower than that of DHT, which is due to the D This is thought to be because it was attached to the surface of HT.

[0059] [Table 7]

[0060] In Table 7, S BET is calculated by correcting with the BET equation is the specific surface area value, V p was calculated from the adsorption amount at P / P0 = 0.99 is the total pore volume. Experimental Example 5: FE-SEM analysis For the observation of HT, DHT, and NIC-DHT using FE-SEM, a Sigma 3 00(Carl 328 Zeiss, Germany) field-emissio A scanning electron microscope was used. FIG. 23 shows the results of HT (Reference Example 3), DHT (Reference Example 4), and the DHT-NIC complex (Example 1). The field emission scanning electron microscope (FE-SEM) image of HT-1 is shown. The plate-like structure has a diameter of about 300 nm. The structure described above is the most typical form of layered materials. When the form of DHT, which is a calcined form of HT, is examined, the average of the HT forms is The particle size was almost the same, but the surface of the DHT was more rough than the smooth surface of the HT. This change in surface condition is due to the dehydration of HT that occurs during the calcination step. Dehydration and carbon dioxide removal reactions On the other hand, the morphology of the DHT-NIC complex was almost the same as that of DHT. However, it was confirmed that the surface of the NIC particles was uneven compared to the morphology of DHT and HT. This is thought to be due to surface adsorption of Experimental Example 6: Particle Size Analysis To analyze particle size, a particle size analyzer (ELSZ) was used. - 330 2000ZS; Otsuka, Japan) is used, and 99.9% efficiency HT, DHT, and NIC-DHT were dispersed in ethanol and measured. Measurements were performed three times. Ta. Dynamic light scattering analysis results The results are shown in Figure 24. HT (Reference Example 3), DHT (Reference Example 4), and DHT-NIC complex ( The average particle sizes of Example 1-1) were 279.9±35.6 and 268.5±23, respectively. 8 and 292.7 ± 28.3, which were similar in size to each other. This is consistent with the results of the FE-SEM analysis in Experimental Example 5. The average particle size was in the range of <300 nm (by DLS and FE-SEM analysis). Therefore, these results suggest that all of these molecules could be ideally used as antiviral therapeutic agents. This is because the SARS-CoV-2 virus has a small particle size. However, the DHT-NIC complex that the inventors aimed to achieve was also The virus must penetrate into the infected cells and exert an antiviral effect. This is because the following should be expressed. The researchers identified potential endocytic mechanisms related to hydrotalcite from previous studies. A potential endocytosis mechanism was established. Therefore, if a drug is administered orally or parenterally, it is easy to It was confirmed that it is very important to protect the drug candidate population from elimination. In all cases, NIC was confirmed to have very low plasma concentrations after oral administration. Therefore, in oral or parenteral administration, NIC can be used as a calcined metal (hydr)oxide. Protecting the NIC using an ideal nanocarrier is a promising solution. It helps to improve the therapeutic effect. Experimental Example 8: In vivo (in-) evaluation of pharmaceutical compositions containing metal (hydr)oxide-niclosamide complexes (vivo) pharmacokinetic analysis In vivo pharmacokinetic analysis was performed using DHT-NIC or MgO-NIC complexes. Pharmaceutical compositions using the DHT-NIC complex or MgO-NIC complex (Examples 5 to 11, or Examples 20 to 22, and 23-1 to 23-3) It is administered orally to hamsters or rats. After the procedure, plasma drug concentration information was obtained. The composition of Example 5 was administered at doses of 50 mg / kg and 200 mg / kg, respectively. In the case of a higher dose of 200 mg / kg, it is possible to use it in vivo. The appropriateness of the dosage form was confirmed in Examples 20 to 22, and 23-1 to 23-3. The above compositions were each administered to rats at a dose of 30 mg / kg in the experiment. In the above analysis, the administration results of Example 5 are shown in FIG. 25, and the administration results of Examples 20 to 22 are shown in FIG. The results of administration of Examples 23-1 and 23-3 are shown in Figure 39, and the results of administration of Examples 23-1 and 23-3 are shown in Figure 40. The figure shows the plasma NIC concentration over time in rats. The meters are listed in Table 8 below.

[0061] [Table 8]

[0062] The AUC value of the DHT-NIC complex / Tween 60 formulation was 1823.83±305.3n gh / mL, which is approximately 1.8 times higher than the commercially available NIC drug Yomesan It was confirmed that the C value of the DHT-NIC complex / Tween 60 preparation was m ax The value was approximately 1350.4±614.0ng.h / mL, and 0.25 hours after oral administration Therefore, the T of the DHT-NIC complex / Tween 60 formulation max value is about 16 times shorter than Yomesan, and in the case of Yomesan, T max C at 4h max The value was approximately 155.3±39.9ng.h / mL. The PK profile in Table 8 was obtained by varying the ratio of NIC to DHT and the administration of the NIC-DHT complex. This suggests that sequential optimization can be achieved by varying the amount of C. max The value is 50m It was confirmed that the effect was significantly improved when the concentration was increased from 100 mg / Kg to 200 mg / Kg. It was confirmed that the AUC value increased approximately 4-fold with increasing dose. 50 The time required to maintain plasma concentrations above this value remained unchanged and was maintained for approximately 8 hours. It was confirmed that The results are shown in FIG. 26 in comparison with Yomesan. In addition, the effect values ​​of the different surfactant types in the above analysis are shown in Figure 27. A composition was prepared by replacing the surfactant from een60 (Example 9) with HPMC (Example 6). When building, C max It was confirmed that the value was improved by 3.9 times and the AUC value by 4.7 times. Figure 28 shows the results of an interspecies comparison between hamsters and rats. It was confirmed that the patterns of changes in blood drug concentrations differ depending on the animal species. The 11 compositions were administered in different weight amounts to hamsters and rats, respectively. The rats were given 200 mg / Kg of body weight, and the hamsters were given 100 mg / Kg of body weight. In rats, the blood drug concentration remained at 100 ng / mL for more than 12 hours, but in hamsters It was confirmed that the blood drug concentration remained at 100 ng / mL for only about 6 hours. Figure 29 is a graph showing the results of changes in blood drug concentration depending on the number of administrations. The composition was administered to hamsters twice at 12-hour intervals, and ten times at 12-hour intervals. In this study, blood drug concentration patterns were measured regardless of the number of doses. It was confirmed that similar rings were formed. FIG. 30 is a graph showing the results of the drug concentration pattern in the blood depending on the amount of the composition. The composition of Example 11 was administered in doses of 25 mg / Kg, 50 mg / Kg, and 100 mg / Kg, respectively. The results in Figure 30 show that C max and AUC values ​​are It was confirmed that the amount of the product increased or decreased in proportion to the volume of the product. FIG. 31 shows the blood drug concentration pattern according to the dose when the composition of Example 6 of the present invention was administered to rats. 26 is a graph showing the results for the composition of Example 6 of the present invention. At a dose 1 / 10 smaller than that of esan, the AUC value was similar to that of Yomesan. , C max The value was about twice as high, and the AUC was about five times higher at the same dose. max The value is about 10 times higher In addition, in the case of Example 6, the AUC and C max It was confirmed that the value increased. FIG. 32 shows the results of administering Yomesan (NIC), the compositions of Reference Example 13, and the compositions of Example 12 to rats. Consequences of single oral administration of 100 mg / kg on blood drug concentration patterns According to FIG. 32, the composition of Example 12 is C max Value and A It was confirmed that the UC value was significantly higher, but the composition of Example 12 had a higher UC value than Yomesan. m ax 9.3-fold and 5.8-fold higher AUC than simple HT-NIC complex coated with HPMC AUC 2.1 times higher than Reference Example 13, and C max It was confirmed that it was 5.4 times higher. Figure 33 shows the results of calcined metal (hydr)oxides and metal oxide-NIC complexes other than DHT. The blood drug concentration pattern after a single oral administration of 100 mg / kg to rats was The results are shown in the graphs of the calcined Mg(OH) of Examples 12-1 and 13. The bioavailability of 2 and the MgO-NIC complex was also significantly increased by the calcination process. In the case of Example 12, the AUC increase rate was about 11 times that of Yomesan, and and approximately 20.5 times C max In Example 13, the increase rate was about 1% compared to Yomesan. A 6.8-fold increase in AUC and approximately 25-fold increase in C max It was confirmed that the rate of increase was observed. FIG. 34 shows the pharmaceutical composition containing the DHT-NIC complex of Example 19 prepared by an anhydrous organic solvent synthesis method. The DHT-NIC complex prepared by the step of mechanochemical synthesis and The blood drug concentration pattern after single oral administration of a pharmaceutical composition containing 100 mg / kg As can be seen in Figure 34, the anhydrous organic solvent mixture It was confirmed that the pharmaceutical compositions prepared by synthetic and mechanochemical synthesis methods have similar effects. FIG. 39 shows the use of a compound formed into a metal (hydr)oxide complex in the preparation of a pharmaceutical composition. Regarding the change in bioavailability when the compound itself is formulated using surfactants, etc. As can be seen from FIG. 39, in the case of Comparative Example 5 in which MgO was not used, It was confirmed that the bioavailability decreased sharply, and the bioavailability decreased slightly as the MgO content decreased. In detail, we confirmed that niclosamide, MgO, and surfactants (HPMC6 and It was confirmed that Example 22, in which the ratio of poloxamer was (1:2:2), had the highest bioavailability. did. The rapid systemic circulation of NIC with improved bioavailability, as confirmed by the above results, may be a key factor in preventing SARS. -It will be an effective treatment strategy against the CoV-2 virus, especially in the early symptomatic and asymptomatic stages. This suggests that The present inventors have found that administration of a composition comprising a metal (hydr)oxide-NIC complex / surfactant can improve the cytotoxicity of cytotoxicity. Improves biochemical function by avoiding or altering rapid intestinal or hepatic metabolism by chromium-P450 enzymes It is hypothesized that this could improve the utilization rate. NIC is rapidly decomposed in the liver (fast metabolism). When NIC is orally administered, most of the NIC is converted to NIC-glucuronic acid. It has already been reported that the hydroxyl group is removed while being transformed into the hydroxyl group. Therefore, in this study, we performed a rational method to form a complex by attaching NIC to a metal (hydroxide). Molecular engineering strategies may further improve mucosal adhesion and help maintain NIC in the lymphatic system. This allowed high plasma concentrations to be achieved after a single oral dose. The results should be emphasized. To the best of our knowledge, the current study was conducted using 8-hour NIC. IC 50 of an orally available formulation of NIC capable of maintaining plasma concentrations exceeding 100mg / kg / day. This is the first study to explain this. The present invention also provides a method for producing a NIC composite comprising the above-mentioned calcined metal (hydr)oxide-NIC complex / surfactant. Considering the medical applications of the compositions, most drugs administered orally are transmitted to the systemic circulation. Assuming that the composition enters IC 100 Exceeding The maximum therapeutic NIC concentration was also achieved. Interestingly, the (hydr)oxide-NIC complex / surfactant composition showed no significant effect on plasma up to 8 hours. It was confirmed that therapeutic concentrations were maintained at 1000 mg / kg / day (see Figures 25, 39, and 40). Experimental Example 9: Bioavailability of pharmaceutical compositions containing niclosamide complexes depending on the content of metal (hydr)oxides Intravenous pharmacokinetic analysis To confirm the influence of metal (hydr)oxide content on in vivo pharmacokinetics, the MgO content was An experiment was designed to confirm the change in AUC value due to the addition of MgO-NIC complex. The pharmaceutical composition using the MgO-NIC complex (Example 5) The MgO content was varied while forming the following examples (Examples 11 to 20). Examples were prepared (see Examples 23-1 to 23-3). After this procedure, plasma drug concentration information was obtained. Ta. The compositions of Examples 23-1 to 23-3 were administered at a dose of 30 mg / kg. carried out. The analysis results are shown in Figure 40. The AUC effect increased proportionally with the increase in MgO content. This indicates that MgO plays an important role in improving bioavailability. The results confirmed this. Experimental Example 10: In vivo pharmacokinetics of pharmaceutical compositions containing metal (hydr)oxide-docetaxel complexes state analysis In vivo pharmacokinetic analysis was performed using pharmaceutical compositions containing DHT-docetaxel complexes. The pharmaceutical composition containing the DHT-docetaxel complex was administered orally to rats. After the procedure was completed, plasma drug concentration information was obtained. The morphological study was carried out by coating a pharmaceutical composition containing the DHT-docetaxel complex with HPMC. Docetaxel (DTX) was prepared as an orally administrable composition (Examples 14 and 16). It was said. In addition, the compositions of Examples 14 and 16 were each diluted to 100 mL / kg at a volume of 40 mg / kg. The solution was dissolved in 5% Tween solution in an amount of 1 kg and administered orally in a single dose. The results are shown in Figure 35 and 36, and the specific data values ​​are listed in Table 9 below.

[0063] [Table 9]

[0064] The control group received only docetaxel at a dose of 40 mg / kg without any additional formulation. The pharmacological effects of Examples 14 and 16 of the present invention were significantly greater than those of the simple administration of docetaxel. When the composition was administered, the bioavailability was 10 times higher than that of the control group. As can be seen from the results in Table 9, docetaxel was administered orally In oral administration studies using rats, the AUC of docetaxel was 47.46, C max The value was 5.25, but as in Examples 14 and 16, the organic-inorganic hybrid After applying the bulleting technique, the AUC increased by 12 and 14 times, respectively, and C max Each Therefore, it was confirmed that the bioavailability of the drug was low and that it was developed as an oral dosage form. Docetaxel, which was previously difficult to utilize, has been made bioavailable by applying organic-inorganic hybrid technology. We have seen a dramatic increase in rates. Experimental Example 11: Compounds with a solubility in water of 0.01 or more and / or that do not contain a hydroxy group In vivo pharmacokinetic analysis of pharmaceutical compositions of metal (hydr)oxides containing In vivo pharmacokinetic analysis was performed using the compound itself and its metal (hydr)oxide complex. The experiments were carried out using the same pharmaceutical compositions (Comparative Examples 2 to 4). 5-FU, lipoic acid, and artesunate, respectively, and Comparative Examples 2, 3, and 4 The pharmaceutical composition is administered orally to hamsters or rats in a single dose. After the procedure, plasma drug concentration information was obtained. In addition, the compound and the pharmaceutical compositions of Comparative Examples 2 to 4 were each administered at a dose of 40 mg / kg. The results of the experiment are shown in Figures 41 to 43. The control group received 40 ml of 5-FU, lipoic acid, and artesunate without any additional formulation. The 5-FU, lipoic acid, and artesunate were administered at a dose of 1000 mg / kg. In the case of compounds, MgO is used due to its chemical structure or its water solubility characteristics. Although these compounds were prepared as metal (hydroxide) complexes, their bioavailability was poor. I confirmed that it had not improved. Experimental Example 12: Drug release experiment Drug release experiments were performed using 500 mL of artificial intestinal fluid (pH 6.8) supplemented with 2% Tween 60. The experiment was carried out at 37°C using the same method as in Example 6 (D56H) and Example 12-1 (Mg(OH) 2), Example 13 (MgO), Reference Example 13 (HT), and Comparative Example 1 (Yomesan). It was used to conduct experiments. Referring to FIG. 37, the NIC loaded on metal (hydr)oxides was compared with Yomesan. The release rate of the metal hydroxides was found to be higher than that of the reference example 13. It was confirmed that the release rate of the coated NIC further increased. From the drug release results, it is clear that the use of the metal (hydr)oxide complex of the present invention can effectively release poorly soluble drugs in vivo. It was confirmed that the utilization rate would be even higher. Experimental Example 13: Antiviral efficacy test Test model: golden Syrian hamster Administered drug: D24T (CP-COV03) Drug dosage: 25mg / Kg Volume administered: 20 mL / kg The composition of Example 11 was administered to hamsters infected with the novel coronavirus (SARS-CoV2). The hamsters were orally administered the drug at 4-hour intervals starting the day after infection. Blood samples taken from hamsters were analyzed by RT-qPCR. The viral RNA concentration in the blood was significantly higher than that in the control group. It was confirmed that the taste was reduced (ANOVA, P<0.05) (see Figure 38). In Comparative Example 1, the group administered 25 mg / kg of Yomesan had low bioavailability and the blood It was confirmed that the virus concentration was not reduced (see Figure 38). Experimental Example 14: Antiviral efficacy test Test model: golden Syrian hamster Administered drug: Example 24 Drug dosage: 20, 40, and 80 mg / Kg Volume administered: 20 mL / kg In the case of the composition of Example 24, the respective drug contents are based on the above-mentioned values, and in the case of the composition of Comparative Example 5, the values ​​are based on the above-mentioned values. In the case of SARS-CoV2 infection, a dose of 80mg / Kg After that, drugs were administered at 12-hour intervals starting 6 hours after infection, and the model was dissected on the 4th day after infection. After dissection of the hamsters, the lungs were examined with the naked eye, the degree of lung tissue lesions was observed, and the virus The amount of gas was measured, and the results are shown in Figures 44 to 48. If SARS-CoV2 infection progresses to pneumonia, lung lesions will occur, but if not infected, A control group of healthy hamsters (NC; negative control) and infected hamsters were A control group (VC; vehicle control) was compared with the uninfected hamsters. The lung lesion score for the infected hamster was calculated as 100, and the lung lesion score for the infected hamster was calculated as 1. In case 5, the incidence of pulmonary lesions was only 4.1% despite the administration of 80 mg / kg. On the other hand, in Example 24, the incidence of lung lesions increased as the dose of CP-COV03 increased. The improvement rate increased, and lung lesions improved by 31.6% at 80 mg / kg. (See Figure 44). In addition, the lung tissues extracted at autopsy were fixed and stained, and detailed observations and pathological findings were used to determine the degree of damage ( The injury score was calculated and is shown in Figure 45. In the case of Comparative Example 5, the degree of lung damage was 1.13, and in the case of Comparative Example 6, even when 80 mg / Kg was administered, The damage level did not improve significantly (it did not decrease) (damage level: 1.05). In Example 24, the damage level was reduced by increasing the dose, especially at 80 mg / Kg. When administered, the damage score was reduced to 0.86, demonstrating a significantly improved effect. (See Figure 45.) Finally, the virus count (viral load) in the lung tissue was quantified using RT-qPCR. The results are shown in Figure 46. The virus counts in the group administered with Comparative Example 5 showed a large deviation. Therefore, it was unclear whether the virus counts were lower than in the control group (VC). In Example 24, a significant antiviral activity was observed, and the number of viruses increased with increasing dose. The results showed that the values ​​were lower (see Figure 46).

Claims

1. The composition includes a metal (hydr)oxide, a compound containing at least one hydroxy group or a salt thereof, and a cellulose surfactant. The cellulose surfactant includes at least one of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; The compound having at least one hydroxy group is one or more compounds selected from compounds represented by Chemical Formula 1, 【Chemistry 1】 (In the above Chemical Formula 1, R １ ~R ６ are each independently a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group, an ester group, an acyl group, an aromatic ring, or a nitro group, The R １ ~R ６ At least one of them is a hydroxy group.) The metal (hydr)oxide is at least one selected from compounds represented by the following chemical formulas 3 to 5: Pharmaceutical compositions. 【Chemistry 2】 (In the above Chemical Formula 3, M ２＋ is Mg ２＋ , Ni ２＋ , Cu ２＋ , Co ２＋ , and Zn ２＋ is a divalent metal cation selected from the group consisting of M ３＋ is Al ３＋ , Fe ３＋ , V ３＋ , Ti ３＋ , Mn ３＋ , and Ga ３＋ is a trivalent metal cation selected from the group consisting of x is a number having a range of more than 0 and less than or equal to 0.5; A is CO ３ ２－ , NO ３ － ,Br － , Cl － , S.O. ４ ２－ , H.P.O. ４ ２－ , and F － an anion selected from the group consisting of n is the charge number of the anion A, n is a number ranging from 0.5 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.) 【Transformation 3】 (In the above Chemical Formula 4, M ２＋ is Mg ２＋ , Ni ２＋ , Cu ２＋ , Co ２＋ , and Zn ２＋ is a divalent metal cation selected from the group consisting of x is a number ranging from 0 to 0.4, A is CO ３ ２－ , NO ３ － ,Br － , Cl － , S.O. ４ ２－ , H.P.O. ４ ２－ , and F － an anion selected from the group consisting of n is the charge number of the anion A, n is a number ranging from 0 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.) 【Chemistry 4】 (In the above Chemical Formula 5, M ２＋ is Mg ２＋ , Ni ２＋ , Cu ２＋ , or Zn ２＋ and x is a number greater than or equal to 1 and less than 2, A is CO ３ ２－ , NO ３ － ,Br － , Cl － , S.O. ４ ２－ , H.P.O. ４ ２－ , and F － an anion selected from the group consisting of n is the charge number of the anion A, n is a number ranging from 0 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.)

2. The compound having at least one hydroxy group or a salt thereof includes one or more selected from the group consisting of docetaxel and paclitaxel. The pharmaceutical composition of claim 1.

3. The pharmaceutical composition of claim 1 further comprising an additive.

4. the additive comprises a surfactant; The surfactant is at least one selected from polyoxyethylene sorbitan fatty acid ester surfactants, poloxamer surfactants, lecithin surfactants, glycerol fatty acid ester surfactants, sorbitan fatty acid ester surfactants, PEG surfactants, thickeners, stabilizer surfactants, gelling agent surfactants, thickening polysaccharide surfactants, and sodium dodecyl sulfate. The pharmaceutical composition of claim 3.

5. The metal (hydr)oxides include MgO and Mg(OH). ２ , ZnO and hydrotalcite compounds, The pharmaceutical composition of claim 1.

6. The pharmaceutical composition is for preventing or treating any one or more of a viral infection disease, an inflammatory disease, and a malignant tumor disease. The pharmaceutical composition according to any one of claims 1 to 5.

7. It includes a metal (hydr)oxide and a compound or a salt thereof containing at least one hydroxy group in the compound, The compound having at least one hydroxy group is one or more compounds selected from compounds represented by Chemical Formula 2, 【Transformation 5】 (In the above Chemical Formula 2, A is a nitrogen atom or an oxygen atom, R １ is a hydrogen atom, a halogen atom, a hydroxy group, or an alkyl group when A is a nitrogen atom, and has no substituent when A is an oxygen atom, R ２ ~R １１ are each independently a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, an ester group, an acyl group, or a nitro group, The R １ ~R １１ At least one of them is a hydroxy group.) The metal (hydr)oxide is at least one selected from compounds represented by the following chemical formulas 3 to 5: Pharmaceutical compositions. 【Transformation 6】 (In the above Chemical Formula 3, M ２＋ is Mg ２＋ , Ni ２＋ , Cu ２＋ , Co ２＋ , and Zn ２＋ is a divalent metal cation selected from the group consisting of M ３＋ is Al ３＋ , Fe ３＋ , V ３＋ , Ti ３＋ , Mn ３＋ , and Ga ３＋ is a trivalent metal cation selected from the group consisting of x is a number having a range of more than 0 and less than or equal to 0.5; A is CO ３ ２－ , NO ３ － ,Br － , Cl － , S.O. ４ ２－ , H.P.O. ４ ２－ , and F － an anion selected from the group consisting of n is the charge number of the anion A, n is a number ranging from 0.5 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.) 【Transformation 7】 (In the above Chemical Formula 4, M ２＋ is Mg ２＋ , Ni ２＋ , Cu ２＋ , Co ２＋ , and Zn ２＋ is a divalent metal cation selected from the group consisting of x is a number ranging from 0 to 0.4, A is CO ３ ２－ , NO ３ － ,Br － , Cl － , S.O. ４ ２－ , H.P.O. ４ ２－ , and F － an anion selected from the group consisting of n is the charge number of the anion A, n is a number ranging from 0 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.) 【Transformation 8】 (In the above Chemical Formula 5, M ２＋ is Mg ２＋ , Ni ２＋ , Cu ２＋ , or Zn ２＋ and x is a number greater than or equal to 1 and less than 2, n is the charge number of the anion A, n is in the range of 0 to 2. A is CO ３ ２－ , NO ３ － ,Br － , Cl － , S.O. ４ ２－ , H.P.O. ４ ２－ , and F － an anion selected from the group consisting of is the number of z is a number ranging from 0 to 1, y is a positive number greater than 0.)

8. The pharmaceutical composition of claim 7 further comprising an additive.

9. the additive comprises a surfactant; The surfactant is at least one selected from polyoxyethylene sorbitan fatty acid ester surfactants, poloxamer surfactants, lecithin surfactants, glycerol fatty acid ester surfactants, sorbitan fatty acid ester surfactants, PEG surfactants, thickeners, stabilizer surfactants, gelling agent surfactants, thickening polysaccharide surfactants, and sodium dodecyl sulfate. The pharmaceutical composition of claim 8.

10. The compound having at least one hydroxy group or a salt thereof includes one or more selected from niclosamide and oxyclozanide. The pharmaceutical composition of claim 7.

11. The metal (hydr)oxides include MgO and Mg(OH). ２ , ZnO and hydrotalcite compounds, The pharmaceutical composition of claim 7.

12. The pharmaceutical composition is for preventing or treating any one or more of a viral infection disease, an inflammatory disease, and a malignant tumor disease. The pharmaceutical composition according to any one of claims 7 to 11.

13. The present invention includes a calcined metal (hydr)oxide, a compound containing at least one hydroxy group or a salt thereof, and a cellulose-based surfactant. The cellulose surfactant includes at least one of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; The calcined metal (hydr)oxide is at least one selected from compounds represented by the following formulas 3 to 5: The calcined metal (hydr)oxide is calcined at 200 to 850°C; The compound having at least one hydroxy group therein is one or more compounds selected from the compounds represented by Chemical Formula 1 or Chemical Formula 2, Pharmaceutical compositions. 【Chemistry 9】 (In the above Chemical Formula 1, R １ ~R ６ are each independently a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group, an ester group, an acyl group, an aromatic ring, or a nitro group, The R １ ~R ６ At least one of them is a hydroxy group.) 【Chemistry 10】 (In the above Chemical Formula 2, A is a nitrogen atom or an oxygen atom, R １ is a hydrogen atom, a halogen atom, a hydroxy group, or an alkyl group when A is a nitrogen atom, and has no substituent when A is an oxygen atom, R ２ ~R １１ are each independently a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, an ester group, an acyl group, or a nitro group, The R １ ~R １１ At least one of them is a hydroxy group.) The metal (hydr)oxide is at least one selected from compounds represented by the following chemical formulas 3 to 5: 【Chemistry 11】 (In the above Chemical Formula 3, M ２＋ is Mg ２＋ , Ni ２＋ , Cu ２＋ , Co ２＋ , and Zn ２＋ is a divalent metal cation selected from the group consisting of M ３＋ is Al ３＋ , Fe ３＋ , V ３＋ , Ti ３＋ , Mn ３＋ , and Ga ３＋ is a trivalent metal cation selected from the group consisting of x is a number having a range of more than 0 and less than or equal to 0.5; A is CO ３ ２－ , NO ３ － ,Br － , Cl － , S.O. ４ ２－ , H.P.O. ４ ２－ , and F － an anion selected from the group consisting of n is the charge number of the anion A, n is a number ranging from 0.5 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.) 【Chemistry 12】 (In the above Chemical Formula 4, M ２＋ is Mg ２＋ , Ni ２＋ , Cu ２＋ , Co ２＋ , and Zn ２＋ is a divalent metal cation selected from the group consisting of x is a number ranging from 0 to 0.4, A is CO ３ ２－ , NO ３ － ,Br － , Cl － , S.O. ４ ２－ , H.P.O. ４ ２－ , and F － an anion selected from the group consisting of n is the charge number of the anion A, n is a number ranging from 0 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.) 【Chemistry 13】 (In the above Chemical Formula 5, M ２＋ is Mg ２＋ , Ni ２＋ , Cu ２＋ , or Zn ２＋ and x is a number greater than or equal to 1 and less than 2, A is CO ３ ２－ , NO ３ － ,Br － , Cl － , S.O. ４ ２－ , H.P.O. ４ ２－ , and F － an anion selected from the group consisting of n is the charge number of the anion A, n is a number ranging from 0 to 2, z is a number ranging from 0 to 1, y is a positive number greater than 0.)

14. Further containing additives, the additive comprises a surfactant; The surfactant is at least one selected from polyoxyethylene sorbitan fatty acid ester surfactants, poloxamer surfactants, lecithin surfactants, glycerol fatty acid ester surfactants, sorbitan fatty acid ester surfactants, PEG surfactants, thickeners, stabilizer surfactants, gelling agent surfactants, thickening polysaccharide surfactants, and sodium dodecyl sulfate.

14. The pharmaceutical composition of claim 13.

15. The metal (hydr)oxides include MgO and Mg(OH). ２ , ZnO and hydrotalcite compounds, 14. The pharmaceutical composition of claim 13.

16. The pharmaceutical composition is for preventing or treating any one or more of a viral infection disease, an inflammatory disease, and a malignant tumor disease. The pharmaceutical composition according to any one of claims 13 to 15.

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