Metal (HYDR)oxide composite comprising poorly soluble drug, method for manufacturing same, and pharmaceutical composition comprising same

Abstract

The present invention relates to a metal (hydr)oxide composite comprising a poorly soluble drug, a method for manufacturing same, and a pharmaceutical composition comprising same.

Description

Metal (hydride) oxide complex containing a poorly soluble drug, method for preparing the same, and pharmaceutical composition containing the same

[0001] The present invention relates to a metal (hydride) oxide complex containing a poorly soluble drug, which has the effect of improving the dispersibility of the poorly soluble drug and thereby improving bioavailability, a method for producing the same, and a pharmaceutical composition containing the same.

[0002] Technological advancements have extended human lifespans, leading to a global aging population. This aging trend has led to a rise in the number of patients suffering from viral and cancerous diseases, as well as a rise in diseases caused by lifestyle factors, dietary habits, and stress. While numerous effective antiviral, anti-inflammatory, and anticancer drugs have been developed, their poor solubility limits their application. Therefore, improving the solubility and bioavailability of these drugs has become a major challenge in drug development.

[0003] Furthermore, the recent COVID-19 pandemic has created an urgent need for therapeutic development. However, because new drug development takes a significant amount of time, it is difficult to develop appropriate treatments when needed. Therefore, research is underway to repurpose existing drugs as antiviral agents, using a method known as "drug repurposing." Furthermore, drugs with anticancer properties are also being repurposed. Drugs such as niclosamide and ciclesonide have been studied as potential COVID-19 treatments, while docetaxel is being studied as a promising anticancer agent. Niclosamide and ciclesonide are already approved for development as antiparasitic, anti-inflammatory, and antimalarial agents, respectively, and are already commercially available. Docetaxel, on the other hand, is already approved for development as an anticancer agent and is already commercially available. These drugs have already been proven safe and have the advantage of being mass-produced. However, as poorly soluble drugs, their solubility in the body is significantly low, making it difficult for them to be effective as COVID-19 treatments and anticancer agents in their commercially available form.

[0004] In the case of poorly soluble drugs as described above, in order to maximize their action as antiviral and / or anticancer agents in the body, dispersibility must be improved, and the problem of maintaining high concentrations in the blood must be resolved to increase bioavailability.

[0005] However, up to now, research to recreate the above drugs has had the problem of not being able to effectively increase bioavailability. In addition, in the case of a method to increase the dispersibility of a poorly soluble drug, there is a method using a dispersing agent such as a water-soluble polymer carrier, as described in Korean Patent No. 10-1897995. However, there has been a problem that the method described above simply using a dispersing agent cannot increase the solubility and dispersibility of a poorly soluble drug to a level that can be utilized in the body.

[0006] [Patent Document]

[0007] Korean Patent No. 10-1897995

[0008] The present invention aims to provide a metal (hydroxide) complex containing a poorly soluble drug having an excellent bioavailability effect by improving the problems of poor dispersibility and poor blood concentration maintenance of the poorly soluble drug.

[0009] In addition, it is an object of the present invention to provide a method for producing the above-described metal (hydride) oxide complex.

[0010] In addition, the present invention aims to provide a pharmaceutical composition comprising the above-described metal (hydride) oxide complex having superior bioavailability.

[0011] Comprising a metal (hydroxide) and a compound or salt thereof containing at least one hydroxyl group in the compound,

[0012] The above metal (hydride) oxide is at least one selected from compounds represented by the following chemical formulas 3 to 5.

[0013] Provides a metal (hydride) oxide complex.

[0014] [Chemical Formula 3]

[0015] [(M 2+ (1-x) M 3+ x (OH)2)((A n- )z )]yH2O

[0016] (In the above chemical formula 3,

[0017] M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0018] M 3+ is Al 3+ , Fe 3+ , V 3+ , Ti 3+ , Mn 3+ and Ga 3+ A trivalent metal cation selected from the group consisting of

[0019] x is a number with a range greater than 0 and less than or equal to 0.5,

[0020] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0021] n is the charge of the anion A,

[0022] n is a number in the range of 0.5 to 2,

[0023] z is a number with a range of 0 to 1,

[0024] y is a positive number greater than 0.)

[0025] [Chemical Formula 4]

[0026] [(M 2+ (OH) 2-x )((A n- ) z )]yH2O

[0027] (In the above chemical formula 4,

[0028] M 2+ Silver Mg2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0029] x is a number in the range of 0 to 0.4,

[0030] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0031] n is the charge of the anion A,

[0032] n is a number in the range of 0 to 2,

[0033] z is a number with a range of 0 to 1,

[0034] y is a positive number greater than 0.)

[0035] [Chemical Formula 5]

[0036] [(M 2+ (O) 2-x )((A n- ) z )]yH2O

[0037] (In the above chemical formula 5,

[0038] M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ or Zn 2+ and,

[0039] x is a number greater than or equal to 1 and less than or equal to 2,

[0040] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F -is an anion selected from the group consisting of,

[0041] n is the charge of the anion A,

[0042] n is a number in the range of 0 to 2,

[0043] z is a number with a range of 0 to 1,

[0044] y is a positive number greater than 0.)

[0045] The present invention also comprises a metal (hydride) oxide; a compound or a salt thereof containing at least one hydroxyl group in the compound; and an additive,

[0046] A pharmaceutical composition is provided, wherein the metal (hydride) oxide is at least one compound represented by the following chemical formulas 3 to 5.

[0047] [Chemical Formula 3]

[0048] [(M 2+ (1-x) M 3+ x (OH)2)((A n- ) z )]yH2O

[0049] (In the above chemical formula 3,

[0050] M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0051] M 3+ is Al 3+ , Fe 3+ , V 3+ , Ti 3+ , Mn 3+ and Ga 3+ A trivalent metal cation selected from the group consisting of

[0052] x is a number with a range greater than 0 and less than or equal to 0.5,

[0053] A is CO32- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0054] n is the charge of the anion A,

[0055] n is a number in the range of 0.5 to 2,

[0056] z is a number with a range of 0 to 1,

[0057] y is a positive number greater than 0.)

[0058] [Chemical Formula 4]

[0059] [(M 2+ (OH) 2-x )((A n- ) z )]yH2O

[0060] (In the above chemical formula 4,

[0061] M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0062] x is a number in the range of 0 to 0.4,

[0063] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0064] n is the charge of the anion A,

[0065] n is a number in the range of 0 to 2,

[0066] z is a number with a range of 0 to 1,

[0067] y is a positive number greater than 0.)

[0068] [Chemical Formula 5]

[0069] [(M 2+ (O) 2-x )((A n- ) z )]yH2O

[0070] (In the above chemical formula 5,

[0071] M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ or Zn 2+ and,

[0072] x is a number greater than or equal to 1 and less than or equal to 2,

[0073] A is an anion,

[0074] n is the charge of the anion A,

[0075] n is a number in the range of 0 to 2,

[0076] z is a number with a range of 0 to 1,

[0077] y is a positive number greater than 0.)

[0078]

[0079] The present invention has the effect of providing a metal (hydr)oxide complex containing a poorly soluble drug or a prodrug thereof with excellent bioavailability by improving the low dispersibility and blood concentration maintenance effect, which are problems of poorly soluble drugs, using a metal (hydr)oxide complex.

[0080] The present invention has the effect of providing a method for producing a metal (hydride) oxide complex capable of improving the low dispersibility and low blood dissolution effect of a poorly soluble drug.

[0081] In addition, when the calcined metal (hydride) oxide complex of the present invention is used, it can have the effect of protecting not only poorly soluble drugs but also drugs that are easily decomposed in the body, thereby increasing bioavailability.

[0082] Figure 1 is a schematic diagram of the antiviral mechanism of niclosamide against the SARS-CoV-2 virus.

[0083] Figure 2 (a) is a schematic diagram of a method for manufacturing a DHT-NIC complex, and (b) is a schematic diagram of a method for manufacturing a composition in which the DHT-NIC complex is treated with a surfactant.

[0084] Figure 3 shows XRD graphs for (a) NIC, (b) HT, (c) DHT, and (d) DHT-NIC complex.

[0085] Figure 4 is an XRD graph for Example 1-1, Example 1-2, Reference Example 3, Reference Example 4, and NIC.

[0086] Figure 5 is an XRD graph for MgO, Al2O3, MgO+ Al2O3grinding and Reference Example 4.

[0087] Figure 6 is an XRD graph for Example 1-1, Reference Example 4, Reference Example 5, Reference Example 7, Reference Example 8, and NIC.

[0088] Figure 7 is an XRD graph for Example 1-1, Example 1-2, Reference Example, Reference Example 5, Reference Example 6, and NIC.

[0089] Figure 8 is an XRD graph for Example 1-1, Reference Example 3, Reference Example 4, Reference Example 9, and NIC.

[0090] Figure 9 is an XRD graph for Example 1-1, Example 1-3, Example 1-4, Example 1-5, Reference Example 4, and NIC.

[0091] Figure 10 is an XRD graph for Reference Example 3 (HT), Reference Example 10 (DHT 250°C), and Reference Example 4 (DHT 350°C).

[0092] Figure 11 is an XRD graph for Reference Example 12, Reference Example 14, Reference Example 4, Reference Example 10, and Reference Example 3 (HT).

[0093] Figure 12 is an XRD graph for Reference Example 11, Reference Example 12, Example 1-1, Reference Example 4, and NIC.

[0094] Figure 13 is an XRD graph for Example 12-1, Example 12-2, NIC, and Mg(OH)2.

[0095] Figure 14 is an XRD graph for Example 13-1, NIC, MgO.

[0096] Figure 15 is an XRD graph for Example 14-1, DTX, Reference Example 4, and Reference Example 3.

[0097] Figure 16 is an XRD graph for Example 16-1, DTX, MgO (MgO calcined at 800°C) and MgO (uncalcined MgO).

[0098] In Fig. 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 an image for Reference Example 3, (b) is an image for Reference Example 4, and (c) is an image for Example 1-1.

[0099] Figure 18 is a Fourier transform infrared (FT-IR) spectrum graph of NIC, HT (Reference Example 3), DHT (Reference Example 4), and DHT-NIC complex (Example 1-1).

[0100] Figure 19 is a Fourier transform infrared (FT-IR) spectrum graph of HT (Reference Example 3) and DHT (Reference Example 4).

[0101] Figure 20 is a Fourier transform infrared (FT-IR) spectrum graph obtained by repeated measurements of NIC and Examples 1-4.

[0102] Figure 21 is a DSC-TGA graph of Example 1-1.

[0103] Figure 22 is a graph of nitrogen adsorption-desorption isotherms of HT (Reference Example 3), DHT (Reference Example 4), and DHT-NIC complex (Example 1-1).

[0104] Figure 23 is a field emission scanning electron microscope (FE-SEM) image of HT (Reference Example 3), DHT (Reference Example 4), and DHT-NIC complex (Example 1-1).

[0105] Figure 24 is a graph showing the results of dynamic light scattering analysis, with (a) showing the average particle size distribution of HT (Reference Example 3), (b) showing DHT (Reference Example 4), and (c) showing the average particle size distribution of the DHT-NIC complex (Example 1-1).

[0106] Figures 25 to 35 are graphs of plasma NIC concentration over time.

[0107] Figure 36 is a graph of AUC results for docetaxel, Examples 14 and 16.

[0108] Figure 37 is a graph showing the results of the release rates of Example 6 (D56H), Example 12-3 (Mg(OH)2), Example 13-2 (MgO), Comparative Example 4 (HT), and Comparative Example 1 (Yomesan).

[0109] Figure 38 is a graph showing the results of virus killing for the infection control group, Yomesan, and Example 11.

[0110] Figure 39 is a graph of the plasma NIC concentration over time in Example 20 (NIC:MgO:HPMC6:poloxamer(1:0.5:1:1)), 21 (NIC:MgO:HPMC6:poloxamer(1:1:1:1)), 22 (NIC:MgO:HPMC6:poloxamer(1:2:1:1)) and Comparative Example 5 (NIC:HPMC6:poloxamer(1:1:1)).

[0111] Figure 40 is a graph showing the AUC trend according to the increase in MgO content in Examples 23-1, 23-2, and 23-3, respectively.

[0112] Figure 41 is a graph of the drug concentration in plasma over time for the control group (simple 5-FU) and comparative example 2 (5-FU:MgO:HPMC).

[0113] Figure 42 is a graph of the drug concentration in plasma over time for the control group (simple lipoic acid) and comparative example 3 (lipoic acid:MgO:HPMC).

[0114] Figure 43 is a graph of the drug concentration in plasma over time for the control group (simple artesunate) and comparative example 4 (artesunate:MgO:HPMC).

[0115] Figure 44 is a graph showing the results of the macroscopic pneumonia lesion improvement rate for groups administered 20 mg / Kg, 40 mg / Kg, and 80 mg / Kg of the pharmaceutical composition of Example 24 and 80 mg / Kg of the composition of Comparative Example 5 to a virus-free control group (NC), a virus-infected control group (VC), and virus-infected hamsters, respectively.

[0116] Figure 45 is a graph showing the results of lung tissue pathology findings for groups administered 20 mg / Kg, 40 mg / Kg, and 80 mg / Kg of the pharmaceutical composition of Example 24 to virus-free control (NC), virus-infected control (VC), and virus-infected hamsters, respectively, and 80 mg / Kg of the composition of Comparative Example 5.

[0117] Figure 46 is a graph showing the results for viral load in lung samples for the virus-infected control group (VC), the groups administered 20 mg / Kg, 40 mg / Kg, and 80 mg / Kg of the pharmaceutical composition of Example 24 to virus-infected hamsters, and 80 mg / Kg of the composition of Comparative Example 5.

[0118] Figure 47 is a cell photograph that serves as the basis for the lung tissue pathology findings for the groups administered 20 mg / Kg, 40 mg / Kg, and 80 mg / Kg of the pharmaceutical composition of Example 24 to the virus-free control group (NC), the virus-infected control group (VC), and the virus-infected hamsters, respectively, and 80 mg / Kg of the composition of Comparative Example 5.

[0119] Hereinafter, the present invention will be described in more detail.

[0120] The present invention provides a metal (hydroxide) complex comprising a poorly soluble drug with significantly improved dispersibility, solubility, and bioavailability. In the present invention, a poorly soluble drug refers to a drug with significantly low water solubility, and includes at least one hydroxyl group. Significantly low water solubility may mean that the compound has a water solubility of less than 0.01 mM.

[0121] The present invention comprises a metal (hydride) oxide; and a compound or a salt thereof containing at least one hydroxyl group in the compound,

[0122] The above metal (hydr)oxide provides a metal (hydr)oxide complex, wherein the metal (hydr)oxide is at least one selected from compounds represented by the following chemical formulas 3 to 5.

[0123] [Chemical Formula 3]

[0124] [(M 2+ (1-x) M 3+ x (OH)2)·((A n- ) z)]·yH2O

[0125] (In the above chemical formula 3,

[0126] M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0127] M 3+ is Al 3+ , Fe 3+ , V 3+ , Ti 3+ , Mn 3+ and Ga 3+ A trivalent metal cation selected from the group consisting of

[0128] x is a number with a range greater than 0 and less than or equal to 0.5,

[0129] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0130] n is the charge of the anion A,

[0131] n is a number in the range of 0.5 to 2,

[0132] z is a number with a range of 0 to 1,

[0133] y is a positive number greater than 0.)

[0134] [Chemical Formula 4]

[0135] [(M 2+ (OH) 2-x )·((A n- ) z )]·yH2O

[0136] (In the above chemical formula 4,

[0137] M 2+ Silver Mg2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0138] x is a number in the range of 0 to 0.4,

[0139] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0140] n is the charge of the anion A,

[0141] n is a number in the range of 0 to 2,

[0142] z is a number with a range of 0 to 1,

[0143] y is a positive number greater than 0.)

[0144] [Chemical Formula 5]

[0145] [(M 2+ (O) 2-x )·((A n- ) z )]·yH2O

[0146] (In the above chemical formula 5,

[0147] M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ or Zn 2+ and,

[0148] x is a number greater than or equal to 1 and less than or equal to 2,

[0149] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F -is an anion selected from the group consisting of,

[0150] n is the charge of the anion A,

[0151] n is a number in the range of 0 to 2,

[0152] z is a number with a range of 0 to 1,

[0153] y is a positive number greater than 0.)

[0154] In the present invention, the metal (hydroxide) refers to both metal oxide and metal hydroxide. In addition, in the chemical formulas 3 to 5, y, which represents the number of water molecules, is a positive number exceeding 0, and may be in the range of 0 to 20.

[0155] The metal (hydride) oxide complex of the present invention may be represented by the following chemical formulas 6 to 8.

[0156] [Chemical Formula 6]

[0157] [(M 2+ (O) 2-x )·((A n- ) z )]·[Q]·yH2O

[0158] (In the above chemical formula 6,

[0159] M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0160] x is a number in the range of 1 to 2,

[0161] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0162] Q is a compound or a salt thereof containing at least one hydroxyl group in the compound,

[0163] n is the charge of the anion A,

[0164] n is a number ranging from 0 to 2,

[0165] z is a number ranging from 0 to 1,

[0166] y is a positive number greater than 0.)

[0167]

[0168] [Chemical Formula 7]

[0169] [(M 2+ (OH) x · (O) y )]·[Q]·zH2O

[0170] (In the above chemical formula 7,

[0171] M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0172] Q is a compound or a salt thereof containing at least one hydroxyl group in the compound,

[0173] x is a number in the range of 0 to 2,

[0174] y is a number in the range of 0 to 1,

[0175] x+y does not exceed 3,

[0176] x and y do not have the value 0 at the same time,

[0177] z is a number in the range of 0 to 10.)

[0178] [Chemical Formula 8]

[0179] [(M 2+ (OH) 2-x )· ((A n- ) z )]· [Q]· yH2O

[0180] (In the above chemical formula 8,

[0181] M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0182] x is a number in the range of 0 to 0.4,

[0183] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0184] Q is a compound or a salt thereof containing at least one hydroxyl group in the compound,

[0185] n is the charge of the anion A,

[0186] n is a number in the range of 0 to 2,

[0187] z is a number with a range of 0 to 1,

[0188] y is a positive number greater than 0.)

[0189] In the above chemical formulas 6 to 8, y represents the number of water molecules and is a positive number exceeding 0, preferably a positive number in the range of 0 to 20.

[0190] In the present invention, compounds containing at least one hydroxyl group and having a solubility in water of less than 0.01 mM are specifically niclosamide, loperamide, penfluridol, ciclesonide, oxyclozanide, dihydrogambogic acid, osajin, lusutrombopag, isosajin, ivacaftor, triparanol, droloxifene, lopinavir, docetaxel, vitamin A, idebenone, paclitaxel, fulvestrant, probucol, These may include doxorubicin, gemcitabine, quercetin, cyanidin, delphinidin, malvidin, pelargonidin, petunidin, curcumin, epigallocatechin-3-gallate, genistein, resveratrol, estradiol, camptothecin, podophyllotoxin, raloxifene, topotecan, bortezomib, netilmicin, branaplam, and spiramycin.

[0191] The compound containing at least one hydroxyl group in the above compound may have a solubility in water of less than 0.01 mM. Specifically, among the compounds containing at least one hydroxyl group in the compound, the compounds having a solubility in water of less than 0.01 may be niclosamide, loperamide, penfluridol, ciclesonide, oxyclozanide, dihydrogambogic acid, osajin, lusutrombopag, isosajin, ivacaftor, triparanol, droloxifene, lopinavir, docetaxel, vitamin A, idebenone, paclitaxel, fulvestrant, and probucol.

[0192] The compound or salt thereof having a solubility in water of less than 0.01 mM and containing at least one hydroxyl group may more preferably be at least one selected from compounds represented by the following chemical formula 1 or chemical formula 2.

[0193] [Chemical Formula 1]

[0194]

[0195] (In the above chemical formula 1,

[0196] R1 to R6 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,

[0197] At least one of the above R1 to R6 is a hydroxy group.)

[0198] [Chemical Formula 2]

[0199]

[0200] (In the above chemical formula 2,

[0201] A is a nitrogen atom or an oxygen atom,

[0202] R1 may be a hydrogen atom, a halogen atom, a hydroxyl group, or an alkyl group when A is a nitrogen atom, and may not have a substituent when A is an oxygen atom.

[0203] R2 to R11 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,

[0204] At least one of the above R1 to R11 is a hydroxy group.)

[0205] In the substituent of the above chemical formula 1 or 2, the halogen atom means a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br), or an iodine atom (I). In addition, in the case of an alkyl group, it may be a saturated hydrocarbon having 1 to 10 carbon atoms or an unsaturated hydrocarbon having 1 to 10 carbon atoms, and the saturated hydrocarbon having 1 to 10 carbon atoms may include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, or the like. In the substituent of the above chemical formula 1 or 2, the alkoxy group may be a methoxy group, an ethoxy group, a propoxy group, a butoxy group, or the like, the acyl group may be a formyl group or an acetyl group (ethanoyl group), a benzoyl group, or the like, and the aromatic ring may be an aromatic ring having 3 to 20 carbon atoms.

[0206] The compound represented by the above chemical formula 1 may be, more specifically, one or more compounds selected from docetaxel and paclitaxel.

[0207] The compound represented by the above chemical formula 2 may be, more specifically, niclosamide.

[0208] In the present invention, a drug capable of increasing bioavailability by forming a complex with a metal oxide or metal hydroxide may be a compound having a solubility in water of less than 0.01 and containing at least one hydroxyl group (OH) in the compound structure. In the case of a compound having high solubility in water, even if a complex is formed using a metal oxide or hydroxide, the effect of improving the bioavailability of the compound may not be exhibited. In addition, even if the solubility in water is low, if a hydroxyl group is not included, the reactivity with the metal oxide and / or metal hydroxide is low during the complex formation process with the metal oxide or metal hydroxide, making it difficult to affect the solubility enhancement of the drug and also not exhibiting the effect of increasing bioavailability.

[0209] Among the metal oxides and metal hydroxides of the present invention, the compound that most preferably increases the bioavailability of the salt and / or drug may be a complex with magnesium oxide (MgO).

[0210] The present invention also comprises a metal (hydride) oxide; a compound or a salt thereof containing at least one hydroxyl group in the compound; and an additive,

[0211] A pharmaceutical composition can be provided in which the metal (hydride) oxide is at least one of the compounds represented by the chemical formulas 3 to 5 described above.

[0212] In addition, the present invention provides a manufacturing method including a step of mechanochemically synthesizing a metal (hydr)oxide powder and a poorly soluble drug powder to form a metal (hydr)oxide complex.

[0213] In addition, the present invention provides a manufacturing method including a step of mechanochemically synthesizing a metal (hydr)oxide powder and a poorly soluble drug powder. The mechanochemically synthesizing step refers to a method of grinding or milling a powder by applying physical force, and any method commonly used in the field can be used without limitation. More specifically, grinding and / or milling synthesis can be used for mechanochemical synthesis for solid-state reaction. More specifically, the milling synthesis method includes a grinding mill, a mortar grinder, a ball mill, a bead mill, a roller mill, a mix&heat, a super-fine grinding mill, an attrition mill, etc., and through these methods, the particle size of the powder material can be reduced and the effects of grinding, dispersion, and mixing can be obtained. Including a mechanistically chemically synthesized step as described above not only has the advantage of low manufacturing cost and less waste generated after manufacturing, but is also desirable in that it can minimize the reversion of the metal (hydr)oxide calcined by the solvent-free manufacturing method to the metal (hydr)oxide state before calcination.

[0214] In addition, the present invention can provide a pharmaceutical composition manufactured by physically grinding a metal (hydride) oxide powder, a poorly soluble drug powder, and a surfactant powder.

[0215] In the present invention, when calcining a metal (hydr)oxide, the temperature conditions may be in the range of 200 to 850°C. More specifically, when the material to be calcined is hydrotalcite, calcination may be performed in the range of 200 to 800°C, and when the material to be calcined is a metal hydroxide, for example, Mg(OH)2, it may be preferable to perform calcination in the temperature range of 200 to 300°C.

[0216] Meanwhile, in the case of metal oxides, for example, MgO, the solubility or bioavailability can be effectively increased by forming a complex with a compound and / or drug containing at least one hydroxyl group in the compound without a calcination process.

[0217] One embodiment of the present invention is characterized by including a poorly soluble drug in the form of a calcined metal (hydr)oxide. Since the structure of the calcined metal (hydr)oxide (e.g., DHT) has a larger surface area for including the poorly soluble drug, niclosamide, compared to the structure of an uncalcined metal (hydr)oxide (e.g., HT), the solubility and dispersibility of the poorly soluble drug can be further improved.

[0218] In the present invention, the anhydrous organic solvent may be used without limitation as long as it is an organic solvent that does not contain water, but more specifically, it may be anhydrous alcohol, acetone, acetonitrile, dichloromethane, tetrahydrofuran, chloroform, etc. In addition, the anhydrous alcohol may be anhydrous ethanol, anhydrous methanol, anhydrous butanol, etc.

[0219] In addition, the present invention provides a metal (hydroxide) complex including a poorly soluble drug or a prodrug thereof, which comprises the steps of: calcining a metal (hydroxide) as described above to produce a calcined metal (hydroxide); and reacting the calcined metal (hydroxide) and a poorly soluble drug or a prodrug thereof in an anhydrous organic solvent.

[0220] The above reaction step is characterized in that the hydration reaction is minimized, thereby minimizing the recovery of the calcined metal (hydr)oxide back to its pre-calcination form.

[0221] When manufactured by the above-described method, the metal (hydr)oxide complex may include a metal (hydr)oxide in a calcined form. Specifically, when a poorly soluble drug is included in the metal (hydr)oxide in the calcined form, and the poorly soluble drug subsequently reacts with the metal (hydr)oxide in the calcined form to form a metal (hydr)oxide complex, the dispersibility and solubility of the poorly soluble drug can be significantly increased, which is preferable in that it can have the effect of increasing the bioavailability of the poorly soluble drug.

[0222] In addition, the present invention can provide a pharmaceutical composition manufactured by physically grinding a metal (hydride) oxide powder, a poorly soluble drug powder, and a surfactant powder.

[0223] In the present invention, the anhydrous organic solvent may be used without limitation as long as it is an organic solvent that does not contain water, but more specifically, it may be anhydrous alcohol, acetone, acetonitrile, dichloromethane, tetrahydrofuran, chloroform, etc. In addition, the anhydrous alcohol may be anhydrous ethanol, anhydrous methanol, anhydrous butanol, etc.

[0224] In addition, the present invention provides a metal (hydr)oxide complex containing a poorly soluble drug or a prodrug thereof, which comprises the step of reacting the metal (hydr)oxide and the poorly soluble drug or a prodrug thereof in an anhydrous organic solvent, which is the manufacturing method described above.

[0225] The above reaction step is characterized in that the hydration reaction is minimized, thereby minimizing the recovery of the calcined metal (hydr)oxide back to its pre-calcination form.

[0226] When manufactured by the above-described method, the metal (hydr)oxide complex may include a metal (hydr)oxide in a calcined form. Specifically, when a poorly soluble drug is included in the metal (hydr)oxide in the calcined form, and the poorly soluble drug subsequently reacts with the metal (hydr)oxide in the calcined form to form a metal (hydr)oxide complex, the dispersibility and solubility of the poorly soluble drug can be significantly increased, which is preferable in that it can have the effect of increasing the bioavailability of the poorly soluble drug.

[0227] The present invention also provides a pharmaceutical composition comprising a metal (hydr)oxide complex comprising a metal (hydr)oxide and a compound or a salt thereof containing at least one hydroxyl group in the compound; and an additive.

[0228] The pharmaceutical composition may contain 10 to 60 wt% of the metal (hydr)oxide, 0.1 to 60 wt% of the compound or its salt, and 10 to 85 wt% of the additive, based on 100 wt% of the total pharmaceutical composition, and more preferably 10 to 40 wt% of the compound or its salt, 10 to 45 wt% of the metal (hydr)oxide, and 10 to 80 wt% of the additive.

[0229] In addition to the above, in the pharmaceutical composition, the metal (hydr)oxide and the compound or salt thereof containing at least one hydroxyl group in the compound may be included in a ratio of 1:0.1 to 10.

[0230] The metal (hydride) oxide complex included in the above pharmaceutical composition may be represented by one or more selected from the following chemical formulas 6 to 8.

[0231] [Chemical Formula 6]

[0232] [(M 2+ (O) 2-x )((A n- ) z )][Q]yH2O

[0233] (In the above chemical formula 6,

[0234] M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0235] x is a number in the range of 1 to 2,

[0236] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0237] Q is a compound containing at least one hydroxyl group in the compound,

[0238] n is the charge of the anion A,

[0239] n is a number ranging from 0 to 2,

[0240] z is a number ranging from 0 to 1,

[0241] y is a positive number greater than 0.)

[0242] [Chemical Formula 7]

[0243] [(M 2+ (OH) x (O) y )][Q]zH2O

[0244] (In the above chemical formula 7,

[0245] M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0246] Q is a compound containing at least one hydroxyl group in the compound,

[0247] x is a number in the range of 0 to 2,

[0248] y is a number in the range of 0 to 1,

[0249] x+y does not exceed 3,

[0250] x and y do not have the value 0 at the same time,

[0251] z is a number in the range of 0 to 10.)

[0252] [Chemical Formula 8]

[0253] [(M 2+ (OH) 2-x )((A n- ) z )][Q]yH2O

[0254] (In the above chemical formula 8,

[0255] M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0256] x is a number in the range of 0 to 0.4,

[0257] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0258] Q is a compound containing at least one hydroxyl group in the compound,

[0259] n is the charge of the anion A,

[0260] n is a number in the range of 0 to 2,

[0261] z is a number with a range of 0 to 1,

[0262] y is a positive number greater than 0.)

[0263] Additionally, the pharmaceutical composition may be administered at 0.1 to 500 mg / Kg.

[0264] In the present invention, the additive may be most preferably a surfactant, and the surfactant may be a cellulose-based, polyoxyethylene sorbitan fatty acid ester-based, poloxamer-based, lecithin-based, glycerol fatty acid ester-based, sorbitan fatty acid ester-based, PEG-based, thickener (long chain of sugar), stabilizer-based (gum), gelling agent-based, thickening polysaccharide-based, and sodium dodecyl sulfate. Specifically, the cellulose-based may be hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), ethyl It can be cellulose (ethylcellulose; EC) and cellulose acetate (cellulose acetate; CA), but HPMC may be most preferred. In the case of the polyoxyethylene sorbitan fatty acid ester type, the most representative commercially available Tween type surfactant is one in which fatty acid and ethylene oxide are bonded in an ester form.The above polyoxyethylene sorbitan fatty acid ester may be polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monopalmitate (Tween 40), polyoxyethylene glycol sorbitan monostearate (Tween 60), Tween 65, polyoxyethylene sorbitan monooleate (Tween 80), and polyoxyethylene sorbitan trioleate (Tween 85). The lecithin-based substances include lecithin and its derivatives, such as phospholipids, phosphatidyl choline, mixed phospholipids, sodium cholate, hydroxylated phospholipids, and hydroxylated lecithin. The glycerol fatty acid esters include polyglycerol fatty acid esters, polyglycerol polyricinoleate, polyoxyethyleneglycerol triricinoleate, and cremophor EL. The above sorbitan fatty acid ester may be sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), etc.PEG series can be PEG 200, PEG 300, PEG 400, PEG 500, PEG 1000, PEG 1500, mPEG 550, etc. Poloxamer series includes poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403, and poloxamer 407.The above thickener (long chain of sugar), stabilizer (gum), gelling agent, and thickening polysaccharide are specifically microfibrous cellulose, CMC (Carboxy Methyl Cellulose), nitrocellulose, hydroxypropyl guar, modified starches, xanthan gum, gelatin, guar gum, arabic gum, cellulose gum, locust bean gum, tamarind gum, tara gum, glucomannan, polyquater, carbopol free gel, highcel, polystearate, alginate, carrageenan, agar, agar, furcellaran, gum tracanth, karaya gum, gellan gum, rhamsan gum, welan gum, Quince seed gum, dextran, hyaluronic acid, carbopol 941, carbopol 934 and carbopol 940, cationic polymer (polyquaternium-10), polyvinyl alcohol, medium chain fatty acid, stearyl fumaric acid. When the above-mentioned surfactants are used, the solubility and dispersibility of the metal (hydroxide) complex containing the poorly soluble drug can be improved, and thus, the bioavailability of the poorly soluble drug can be increased, which is more preferable.

[0265] In addition, the pharmaceutical composition according to the present invention may further include, without limitation, any additives commonly used in the art other than the above-described additives, and the types thereof are not limited. More specifically, the additives include a plasticizer added to the resin to impart flexibility and workability; a pH regulator to adjust the acidity of the pharmaceutical composition to an appropriate level for use as a preparation; an excipient; Solubilizing agent for increasing the solubility of a substance in a semi-solid and solid state; sweetener agent; gelling agent; bonding agent for adsorption, solidification, and consistency (absorbing moisture at high temperature) to a mixture; hard capsule base; hardener; surfactant other than the above-mentioned cellulosic and Tween-based agents; anticaking agent used for absorbing moisture or preventing solidification; brightener; flavors enhancer for maximizing or adjusting the original taste and aroma; base of inert ingredients that can be used as a vehicle for active pharmaceutical ingredients; porous agent that forms a structure with many small voids by rapid evaporation due to rapid heating; sugar coating agent; bulking agent for freeze-drying; isotonic agent; liner; hair softener; matting agent; A pain-free agent; a paper that protects the adhesive surface of an adhesive tape and allows for easy peeling when used; a semipermeable membrane; an effervescent agent; an antiseptic; a radioprotector; a desiccant; a release-modifying agent; a culture medium; a denaturant; an antimicrobial preservative; an anti-adherent;Aerosol propellant, a liquefied gas with a vapor pressure higher than 14.7 lb / sq at 40.6°C; dispersing agent; opacifying agent; disintegrant; acidifying agent, a substance that removes electrons; oxidizer; osmotic regulator, which controls the release rate of a drug by using the principle of osmosis; sustained release modifying agent; cleanser; antifoaming agent; humectant; stabilizing agent; alkalizing agent; drug storage layer, a mattress that stores drugs; soft capsule base; emollient, a cream-like substance that softens the skin; buffering agent, which prevents a large change in the hydrogen ion index; solvent; Solubilizing agent (emulsifying agent; carrier used in connection with binding or application of active pharmaceutical ingredients; fluidizing agent; softener; emulsifier; blood coagulation inhibitor; anit-allergenic; enteric coating agent; viscosity-increasing agent; complexing agent; adhesive support; adhesive / support; removal film; support; UV protector; masking agent capable of removing unpleasant taste or odor of pharmaceutical ingredients; color; flavors and perfumes; accessories contained in pharmaceutical containers and usable as an auxiliary during drug administration;An auxiliary solvent used to help dissolve solutes into a solution and to administer drugs; a refreshing agent; an air displacement agent added to other substances to increase the capacity or weight; a penetration enhancer used to facilitate the penetration of the drug solution; a coating agent; a chelating agent; a discolorant; a degreasing agent; a labeling agent; a covering agent; an antioxidant; a suspending agent; an expanding agent to be added to a product in the same capacity as a diluent or emollient; a reducing agent; a pilling agent, which is a powder used to prevent mutual adhesion, mold growth, and moisture transpiration of pills; a glidant agent to reduce friction for application to the skin or ease of swallowing; a volatile restrainer; a volatile accelerator; an absorbent that absorbs gases and liquids; an adsorbent for adsorbing gases, liquids, or solutes on a surface; a diluent (humectant) liquid agent; A warming agent, which is a substance that provides a sense of warmth; an enteric coating agent capable of controlling pH-dependent and swelling behavior, such as Eudragit;

[0266] In the present invention, the pharmaceutical composition may be used for the prevention or treatment of one or more of bacterial or viral infectious diseases, inflammatory diseases, and malignant tumors. More specifically, the pharmaceutical composition of the present invention may be used for the prevention or treatment of coronaviruses, and may also be used for anticancer purposes.

[0267] The bacterial or viral infectious disease may be a malaria infection or a viral disease including Epstein-Barr Virus (EBV), Hepatitis B Virus, Hepatitis C Virus, HIV, HTLV 1, Varicella-Zoster Virus (VZV), and Human Papilloma Virus (HPV), a viral infection caused by a coronavirus such as SARS-CoV and / or SARS-CoV2, or other retrovirus infections.

[0268] The inflammatory diseases include vascular restenosis; inflammatory diseases including autoimmune diseases, pancreatitis, glomerulonephritis, myocardial infarction, and psoriasis; atopic diseases including allergic asthma, atopic dermatitis (eczema), and allergic rhinitis; cell-mediated hypersensitivity diseases including allergic contact dermatitis and hypersensitivity pneumonitis; Rheumatic diseases including Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis, Juvenile Arthritis, Sjogren's Syndrome, Scleroderma, Polymyositis, Ankylosing Spondylitis, and Psoriatic Arthritis; Diabetes; Autoimmune Thyroid Disease; Brain Diseases including Dementia, Parkinson's Disease, and Alzheimer's Disease; and other autoimmune diseases and degenerative diseases including arthritis.

[0269] The above malignant tumor diseases are fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma. carcinoma), adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, testicular tumor, lung carcinoma,Cancers including small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma, and carcinomas arising from breast, prostate, kidney, bladder, or colon tissue; It may be a tumor disease that appears in adipose tissue, such as a lipoma, fibrolipoma, lipoblastoma, lipomatosis, hibemoma, hemangioma, and / or liposarcoma.

[0270] The pharmaceutical composition according to the present invention may be in the form of an oral preparation, an injection, a mucosal preparation, an inhalation preparation, an external preparation, a transdermal absorption preparation (ointment, cream, etc.), but is not limited thereto, and an oral preparation form may be preferred.

[0271] In the present invention, the pH regulator can be one commonly used in the art, and preferably, citric acid, malic acid, lactic acid, fumaric acid, glycolic acid, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, etc. can be used.

[0272] In the present invention, the excipient may be one or more of those usable in pharmaceuticals, such as monosaccharides, disaccharides, and trisaccharides, including polyvinylpyrrolidone, glucose, phosphatide, polyhydric alcohol, and sucrose, trehalose, mannitol, lactose, citric acid, mannitol, and dextrose.

[0273] The present invention provides a method for producing a metal (hydr)oxide complex containing a poorly soluble drug or a prodrug thereof, comprising the steps of: calcining a metal (hydr)oxide to produce a calcined metal (hydr)oxide; and reacting the calcined metal (hydr)oxide and a poorly soluble drug or a prodrug thereof in an anhydrous organic solvent.

[0274] In the step of reacting in the above anhydrous organic solvent, a hydration reaction may not occur.

[0275] More specifically, the calcination in the step of manufacturing the above-mentioned calcined metal (hydr)oxide may be performed at a temperature of 250°C or higher and 2000°C or lower.

[0276] In addition, the present invention can provide a method for preparing a pharmaceutical composition, further comprising a step of coating the metal (hydroxide) complex described above by treating the metal (hydroxide) complex described above with a surfactant.

[0277] The step of performing the surfactant treatment may include a step of preparing a surfactant solvent by dissolving a surfactant in an organic solvent; a step of mixing and stirring the metal (hydride) oxide complex described above with the surfactant solvent to form a mixture; and a step of evaporating the solvent from the mixture.

[0278] Reference Example 1. Synthesis of non-calcined metal (hydride) oxide-niclosamide complex (HT)

[0279] In a nitrogen atmosphere, 6.9 g of hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) is suspended in 700 ml of purified water and stirred for 30 minutes. 3.4 g of niclosamide is mixed with NaOH (0.1 M aqueous solution) to prepare an aqueous solution of niclosamide sodium salt substituted with a sodium salt. This sodium salt aqueous solution is then slowly added dropwise to the hydrotalcite suspension over 30 minutes. The pH of the solution is maintained at 8.5 using NaOH. After titration, the solution is stirred for 18 hours under a nitrogen atmosphere at room temperature, the suspension is filtered using a filtered glass (membrane filter), and then washed three times using the pH-adjusted aqueous solution. Finally, after washing twice with ethanol, the product was dried for one day using a vacuum dryer (1 mbar, 40°C) to obtain a white final complex with a yield of 70% (drug base).

[0280] Reference Example 2. Synthesis of uncalcined metal (hydride) oxide-niclosamide complex (HT)

[0281] Niclosamide is dissolved in carbonate ion (CO3 2- ) was dissolved in the 3rd distilled water, and the solution was dissolved in Zn(NO3)2ㆍH2O and carbonate ion (CO3 2- ) was dissolved in a solution dissolved in triple distilled water from which the salt was removed, and then the pH was adjusted to about 6 to 7 using 0.2 M NaOH to obtain a zinc basic salt precipitate. The titrated solution was separated using a centrifuge and the unreacted salt was removed through a washing process. After that, the manufactured zinc basic salt precipitate was obtained, and then centrifuged and washed again, and then vacuum dried to obtain a yellow powder.

[0282] Reference Example 3: HT(Mg6Al2(OH) 16 CO3·4H2O)

[0283] Reference Example 4: DHT (350℃)

[0284] In a nitrogen environment, 3 g of hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) powder is placed in each reaction vessel and calcination is performed for 8 hours under conditions of 350°C to obtain DHT.

[0285] Reference Example 5: DHT (350℃): NIC = 1: 0.4 - grinding

[0286] Reference Example 5 was obtained by grinding DHT and Niclosamide of Reference Example 4 at a weight ratio of 0.6:0.4, 0.6 g of DHT and 0.4 g of Niclosamide.

[0287] Reference Example 6: DHT(350℃):NIC=0.8:0.2 - grinding

[0288] DHT and Niclosamide of Reference Example 4 were ground at a weight ratio of 0.8:0.2, and 0.8 g of DHT and 0.2 g of Niclosamide were ground to obtain Reference Example 6.

[0289] Reference Example 7: MgO:Al2O3=2:1 - grinding

[0290] Reference Example 7 was obtained by grinding MgO and Al2O3 samples at a weight ratio of 2:1, 2 g of MgO powder and 1 g of Al2O3 powder.

[0291] Reference Example 8: MgO:Al2O3:NIC=2:1:1 - grinding

[0292] Reference Example 8 was obtained by grinding MgO, Al2O3, and Niclosamide samples in a weight ratio of 2:1:1, 2 g of MgO powder, 1 g of Al2O3 powder, and 1 g of NIC.

[0293] Reference Example 9: HT-NIC (36%) / EtOH

[0294] A flask was charged with 3 g of hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) powder and 50 ml of absolute ethanol, and the powder was well dispersed by sonication for 10 minutes. The solution was stirred at 700 rpm or higher, and 3 g of niclosamide was added and stirred for 6 hours. For purification, the filtrate was removed through a filter membrane, washed 4 to 5 times with absolute ethanol, and then vacuum-dried to obtain a yellow DHT-NIC compound powder (content 36%). 0.356 g of HPMC was dissolved in a 1:1 ratio solution of absolute ethanol and dichloromethane in a flask. 2.0 g of the HT-NIC was placed in each of the two main tanks and rapidly stirred for 30 minutes. After evaporating the solvent using a rotary evaporator, the obtained pharmaceutical composition (yellow powder) was dried to obtain the pharmaceutical composition of Fig. 8 (blue).

[0295] Reference Example 10: DHT (250℃)

[0296] In a nitrogen environment, 3 g of each hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) powder is placed in each reaction vessel and calcination is performed for 8 hours under conditions of 250°C to obtain DHT of Reference Example 10.

[0297] Reference Example 11: DHT (350°C)-NIC / EtOH+H2O

[0298] After dehydrotalcite and Niclosamide calcined at 350℃ were synthesized in anhydrous ethanol (NIC content 44%), water (4%) was added to the DHT-NIC and anhydrous ethanol solution, and stirred for 48 hours.

[0299] Reference Example 12: DHT (350°C) / EtOH+H2O

[0300] Dehydrotalcite calcined at 350℃ was added to anhydrous ethanol solution and stirred for 48 hours after adding water (4%).

[0301] Reference Example 13: HT-NIC / HMPC

[0302] HT-NIC, which was obtained by synthesizing hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) and Niclosamide in anhydrous ethanol, filtering, and washing (NIC content 35%), was reacted with HPMC in anhydrous ethanol and dichloromethane solution to obtain HT-NIC.

[0303] Reference Example 14: DHT (350°C) / EtOH

[0304] Dehydrotalcite calcined at 350℃ was stirred in anhydrous ethanol solution for 48 hours.

[0305] Synthesis of Examples 1-1 and 1-2: Synthesis of calcined metal (hydride) oxide-niclosamide complex (DHT-NIC complex)

[0306] <STEP 1>

[0307] Take 3g of hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) powder and place it in each reaction vessel, and perform calcination at 350℃ for 8 hours.

[0308] <STEP 2>

[0309] 200 ml of anhydrous methanol was placed in each container and the powder was well dispersed by sonication for 10 minutes. Each solution was stirred at 700 rpm or higher, and 3 g (Example 1-1) and 1.5 g (Example 1-2) of niclosamide were added and stirred for 6 hours. For purification, the filtrate was removed through a filter membrane, washed 4-5 times with anhydrous methanol, and then vacuum-dried to obtain a yellow powder. The final niclosamide content was 44% for 1-1 and 22% for 1-2.

[0310] Synthesis of Examples 1-3 to 1-5: Synthesis of calcined metal (hydride) oxide-niclosamide complex (DHT-NIC complex)

[0311] <STEP 1>

[0312] Take 3 g of powder of hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) and place it in each of three reaction vessels (Example 1-3, Example 1-4, Example 1-5) and perform calcination at 350°C for 8 hours.

[0313] <STEP 2>

[0314] 100ml, 50ml, and 25ml of absolute ethanol were placed in containers, respectively, and the powders were well dispersed by sonication for 10 minutes. Each solution was stirred at 700 rpm or higher, and 3g of niclosamide was added and stirred for 6 hours. For purification, the filtrate was removed through a filter membrane, washed 4-5 times with absolute ethanol, and then vacuum-dried to obtain a yellow powder. The final niclosamide contents were 32% for 1-3, 46% for 1-4, and 31% for 1-5.

[0315]

[0316] Example 2. Synthesis of calcined metal (hydride) oxide-niclosamide complex (DHT-NIC complex)

[0317] Take 3g of commercially available hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) powder at 50℃ intervals under conditions of 250℃ to 800℃, place it in each reaction vessel, and calcinate for 8 hours. Add 50ml of absolute ethanol to each vessel and sonicate for 30 minutes to disperse the powder well. Stir each solution at 700 rpm or higher, add 50ml of absolute ethanol and 3g of niclosamide, and stir for 24 hours. For purification, remove the filtrate through a filter membrane, wash with absolute ethanol 4 to 5 times, and then dry in a vacuum to obtain a yellow powder.

[0318] Example 3. Synthesis of calcined metal (hydride) oxide-niclosamide complex (DHT-NIC complex)

[0319] Under a nitrogen atmosphere, 6.9 g of pristine ZnAl-LDH was suspended in 700 ml of purified water and stirred for 30 minutes. 3.4 g of niclosamide was mixed with NaOH (0.1 M aqueous solution) to prepare an aqueous solution of niclosamide sodium salt substituted with a sodium salt. This sodium salt aqueous solution was then slowly added dropwise to the LDH pristine suspension over 30 minutes. The pH of the solution was maintained at 8.5 using NaOH. After titration, the solution was stirred for 18 hours under a nitrogen atmosphere at room temperature, the suspension was filtered using a filtered glass (membrane filter), and washed three times with the pH-adjusted aqueous solution. Finally, after two additional washes with ethanol, the solution was dried in a vacuum desiccator (1 mbar, 40°C) for one day to obtain the final white complex in a yield of 70% (drug base). Next, 3g of powder is taken at intervals of 50℃ under conditions of 250℃ or higher and 800℃ or lower, placed in each reaction vessel, and calcination is performed for 8 hours. 50ml of anhydrous ethanol is placed in each vessel and the powder is well dispersed by sonication for 30 minutes. Each solution is stirred at 700 rpm or higher, and 50ml of anhydrous ethanol and 3g of niclosamide are added and stirred for 24 hours. For purification, the filtrate is removed through a filter membrane, and the solution is washed 4-5 times with acetone and anhydrous ethanol, and then vacuum dried to obtain a yellow powder.

[0320] Examples 4 and 5. Preparation of pharmaceutical compositions comprising calcined metal (hydride)oxide-niclosamide complexes

[0321] <step1>

[0322] Take 3g of hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) powder, place it in an alumina container, and calcinate it in a furnace at 350℃ for 8 hours.

[0323] <step2>

[0324] Each powder was placed in a flask, 50 ml of anhydrous ethanol was added, and the powder was well dispersed by sonication for 10 minutes. Each solution was stirred at 700 rpm or higher, 3 g of niclosamide was added, and stirred for 6 hours. For purification, the filtrate was removed through a filter membrane, washed 4-5 times with anhydrous methanol, and then vacuum-dried to obtain a yellow DHT-NIC complex powder, which showed a niclosamide content of 43.3%. The FT-IR graph of the complex is shown in Fig. 19.

[0325] <step3>

[0326] Dissolve 0.270 g of HPMC or 0.540 g of tween60 in a 1:1 ratio solution of absolute ethanol and dichloromethane or absolute ethanol in two main tanks, respectively. Add 1.350 g of the above DHT-NIC to each of the two main tanks and stir rapidly for 30 minutes. Evaporate the solvent using a rotary evaporator, and dry the obtained pharmaceutical composition (yellow powder) to obtain the pharmaceutical compositions of Examples 4 and 5, respectively.

[0327] Examples 6 to 11. Preparation of pharmaceutical compositions comprising calcined metal (hydride)oxide-niclosamide complexes

[0328] <STEP 1>

[0329] Take 3g of hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) powder each and place it in three reaction vessels and calcinate it at 350℃ for 8 hours.

[0330] <STEP 2>

[0331] 50 ml of absolute ethanol was placed in each container and the powder was well dispersed by sonication for 10 minutes. The solution was stirred at 700 rpm or higher, 3 g of niclosamide was added, and the stirring was continued for 6 hours. For purification, the filtrate was removed through a filter membrane, washed 4-5 times with absolute ethanol, and then vacuum-dried to obtain a yellow powder. The final niclosamide content was 46%.

[0332] <STEP 3>

[0333] In addition to the DHT-NIC complex prepared by Steps 1 and 2, an additional solution of niclosamide and HPMC dissolved in anhydrous ethanol and dichloromethane was added, stirred, and then evaporated (or spray dried) to prepare pharmaceutical compositions of Examples 6 to 11.

[0334] The method of implementing STEP 3 of each of Examples 6 to 11 is as follows.

[0335] Example 6 STEP 3

[0336] Dissolve 0.546 g of HPMC in a 1:1 ratio solution of absolute ethanol and dichloromethane in a main tank. Add 2.728 g of DHT-NIC to the main tank and stir rapidly for 30 minutes. Evaporate the solvent using a rotary evaporator, and dry the resulting pharmaceutical composition (yellow powder) to obtain a pharmaceutical composition.

[0337] Example 7 STEP 3

[0338] Dissolve 0.390 g of HPMC in a 1:1 ratio solution of absolute ethanol and dichloromethane in a main tank. Add 0.61 g of niclosamide to this solution and dissolve, then add 1.34 g of DHT-NIC to the main tank and stir rapidly for 30 minutes. Evaporate the solvent using a rotary evaporator, and dry the resulting pharmaceutical composition (yellow powder) to obtain a pharmaceutical composition.

[0339] Example 8 STEP 3

[0340] Dissolve 0.316 g of HPMC in a 1:1 ratio solution of absolute ethanol and dichloromethane in a main tank. Add 0.906 g of niclosamide to this solution and dissolve, then add 1.34 g of DHT-NIC to the main tank and stir rapidly for 30 minutes. Evaporate the solvent using a rotary evaporator, and dry the resulting pharmaceutical composition (yellow powder) to obtain a pharmaceutical composition.

[0341] In STEP 3 described above, the pharmaceutical compositions of Examples 9 to 11 were prepared in the same manner as described above, except that niclosamide and Tween 60 were additionally dissolved in the DHT-NIC. The specific manufacturing methods of STEP 3 of Examples 9 to 11 are as follows, respectively.

[0342] Example 9 STEP 3

[0343] Dissolve 1.092 g of tween60 in anhydrous ethanol solution in a main tank. Add 2.728 g of DHT-NIC to the main tank and stir rapidly for 30 minutes. Evaporate the solvent using a rotary evaporator, and dry the resulting pharmaceutical composition (yellow powder) to obtain a pharmaceutical composition.

[0344] Example 10 STEP 3

[0345] Dissolve 0.78 g of tween60 in anhydrous ethanol solution in a main tank. Add 0.61 g of niclosamide to this solution and dissolve. Then, add 1.34 g of DHT-NIC to the main tank and stir rapidly for 30 minutes. Evaporate the solvent using a rotary evaporator, and dry the resulting pharmaceutical composition (yellow powder) to obtain a pharmaceutical composition.

[0346] Example 11 STEP 3

[0347] Dissolve 0.632 g of tween60 in anhydrous ethanol solution in a main tank. Add 0.906 g of niclosamide to this solution and dissolve. Then, add 1.34 g of DHT-NIC to the main tank and stir rapidly for 30 minutes. Evaporate the solvent using a rotary evaporator, and dry the resulting pharmaceutical composition (yellow powder) to obtain a pharmaceutical composition.

[0348] The specific contents of the pharmaceutical compositions of Examples 6 to 11 manufactured by the above-described method are as shown in Tables 1 and 2 below.

[0349] Distinctive ingredient ratio Manufacturing ingredient DHT / (DHT+NIC) (%) HPMC (%) NIC / DHT (mg) Additional NIC (mg) HPMC (6mPas) (mg) Example 6 DHT-D56H56 16.727280546 Example 7 DHT-D38H38 16.71340610546 Example 8 DHT-D24H24 16.7668906546

[0350] Distinctive Composition Ratio Manufacturing Ingredients DHT / (DHT+NIC) (%) Tween 60 (%) NIC / DHT (mg) Additional NIC (mg) Tween 60 (mg) Example 9 DHT-D56T5633.4272801092 Example 10 DHT-D38T3833.413406101092 Example 11 DHT-D24T2433.46689061092

[0351] Examples 12-1 to 12-4: Preparation of calcined metal (hydride)oxide-niclosamide complex and pharmaceutical composition containing the same

[0352] <step1>

[0353] Take 3g of Mg(OH)2 powder each and place it in two reaction vessels and perform calcination for 6 hours under conditions of 200℃(12-1) and 300℃(12-2).

[0354] <step2>

[0355] 50 ml of absolute ethanol was placed in each container and the powder was well dispersed by sonication for 10 minutes. The solution was stirred at 700 rpm or higher, 3 g of niclosamide was added, and the stirring was continued for 4 hours. For purification, the filtrate was removed through a filter membrane, washed 4 to 5 times with absolute ethanol, and then vacuum-dried to obtain a yellow powder. The final niclosamide content was 35.2% for the composite calcined at 200°C (metal hydroxide-NIC complex of Example 12-1), and 14.5% for the composite calcined at 300°C (metal hydroxide-NIC complex of Example 12-2).

[0356] <step3>

[0357] 2 g of each metal hydroxide-NIC complex prepared by Steps 1 and 2 above was added to a 1:1 ratio solution of anhydrous ethanol and dichloromethane containing HPMC, stirred, and then evaporated (or spray dried) to prepare a pharmaceutical composition.

[0358] The specific contents of the pharmaceutical compositions of Examples 12-3 and 12-4 manufactured by the above-described method are as shown in Table 3 below.

[0359] Distinctive Composition Ratio Manufacturing Composition Mg(OH)2 / (Mg(OH)2+NIC) (%) HPMC (%) NIC / Mg(OH)2(mg) Additional NIC (mg) HPMC(mg) Example 12-3 Mg(OH)2 200℃ 65 13.6 20000 314 Example 12-4 Mg(OH)2 300℃ 85.5 13.6 13400 131

[0360]

[0361] Examples 13-1 and 13-2: Preparation of calcined metal oxide-niclosamide complex and pharmaceutical composition containing the same

[0362] <step1>

[0363] Take 3g of MgO powder, place it in a reaction vessel, and perform calcination at 800℃ for 6 hours.

[0364] <STEP 2>

[0365] 50 ml of absolute ethanol was placed in each container and the powder was well dispersed by sonication for 10 minutes. The solution was stirred at 700 rpm or higher, 3 g of niclosamide was added, and the stirring was continued for 4 hours. For purification, the filtrate was removed through a filter membrane, washed 4 to 5 times with absolute ethanol, and then vacuum-dried to obtain a yellow powder. The final niclosamide content was 34.6% (Example 13-1).

[0366] <STEP 3>

[0367] 2 g of the DHT-NIC complex prepared by the above Steps 1 and 2 was added to a 1:1 ratio solution of anhydrous ethanol and dichloromethane containing 0.306 g of HPMC, stirred, and then evaporated (or spray dried) to prepare a pharmaceutical composition of Example 13-2.

[0368] The specific contents of the pharmaceutical composition of Example 13-2 manufactured by the above-described method are as shown in Table 4 below.

[0369] Distinctive ingredient ratio Manufacturing ingredient MgO / (MgO+NIC) (%)HPMC (%)NIC / MgO (mg)Additional NIC (mg)HPMC (mg)Example 13-2MgO 800℃65.413.620000306

[0370]

[0371] Examples 14-1 and 14-2: Preparation of calcined metal (hydride)oxide-docetaxel complex and pharmaceutical composition containing the same

[0372] <STEP 1>

[0373] Take 3 g of hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) powder, place it in a reaction vessel, and calcinate it at 350°C for 8 hours.

[0374] <STEP 2>

[0375] Each container was filled with 50 ml of anhydrous acetonitrile and the powder was well dispersed by sonication for 10 minutes. The solution was stirred at 700 rpm or higher, 3 g of docetaxel was added, and the mixture was stirred at 0°C for 1 hour. The composite was vacuum-dried to obtain a white powder (DHT-DTX complex; Example 14-1).

[0376] <STEP 3>

[0377] 1 g of the DHT-DTX complex prepared by the above Steps 1 and 2 was added to a 1:1 ratio solution of anhydrous ethanol and dichloromethane containing 0.221 g of HPMC, stirred, and then evaporated (or spray dried) to prepare a pharmaceutical composition of Example 14-2.

[0378] Examples 15-1 and 15-2: Preparation of calcined metal (hydride)oxide-docetaxel complex and pharmaceutical composition containing the same

[0379] <STEP 1>

[0380] Take 3 g of hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) powder, place it in a reaction vessel, and calcinate it at 350°C for 8 hours.

[0381] <STEP 2>

[0382] 50 ml of anhydrous acetonitrile was placed in each container and the powder was well dispersed by sonication for 10 minutes. The solution was stirred at 700 rpm or higher, 3 g of docetaxel was added, and the mixture was stirred at room temperature for 1 hour. For purification, the filtrate was removed through a filter membrane, washed 4 to 5 times with anhydrous ethanol, and then vacuum-dried to obtain a white powder (DHT-DTX complex; Example 15-1).

[0383] <STEP 3>

[0384] 1 g of the DHT-DTX complex of Example 15-1 prepared by the above Steps 1 and 2 was added to a 1:1 ratio solution of anhydrous ethanol and dichloromethane containing 0.221 g of HPMC, stirred, and then evaporated (or spray dried) to prepare a pharmaceutical composition of Example 15-2.

[0385] Examples 16-1 and 16-2: Preparation of calcined metal oxide-docetaxel complex and pharmaceutical composition containing the same

[0386] <STEP 1>

[0387] Take 3g of MgO powder, place it in a reaction vessel, and calcinate it at 800℃ for 6 hours.

[0388] <STEP 2>

[0389] Each container was filled with 50 ml of anhydrous acetonitrile and the powder was well dispersed by sonication for 10 minutes. The solution was stirred at 700 rpm or higher, 3 g of docetaxel was added, and the mixture was stirred at 0°C for 1 hour. The composite was vacuum-dried to obtain a white powder (MgO-DTX complex; Example 16-1).

[0390] <STEP 3>

[0391] 1 g of the MgO-DTX complex of Example 16-1 prepared by the above Steps 1 and 2 was added to a 1:1 ratio solution of anhydrous ethanol and dichloromethane containing 0.221 g of HPMC, stirred, and then evaporated (or spray dried) to prepare a pharmaceutical composition of Example 16-2.

[0392] Examples 17-1 and 17-2: Preparation of calcined metal oxide-docetaxel complex and pharmaceutical composition containing the same

[0393] <STEP 1>

[0394] Take 3g of MgO powder, place it in a reaction vessel, and calcinate it at 800℃ for 6 hours.

[0395] <STEP 2>

[0396] Each container was filled with 50 ml of anhydrous acetonitrile and the powder was well dispersed by sonication for 10 minutes. The solution was stirred at 700 rpm or higher, 3 g of docetaxel was added, and the mixture was stirred at room temperature for 1 hour. For purification, the filtrate was removed through a filter membrane, washed 4 to 5 times with anhydrous ethanol, and then vacuum-dried to obtain a white powder (MgO-DTX complex; Example 17-1).

[0397] <STEP 3>

[0398] 1 g of the MgO-DTX complex of Example 17-1 prepared by the above Steps 1 and 2 was added to a 1:1 ratio solution of anhydrous ethanol and dichloromethane containing 0.221 g of HPMC, stirred, and then evaporated (or spray dried) to prepare a pharmaceutical composition.

[0399] Example 18: Preparation of a pharmaceutical composition comprising a calcined metal (hydride) oxide-niclosamide complex (preparation by physical grinding method)

[0400] In this example, a pharmaceutical composition including a calcined metal (hydride) oxide complex was prepared by mixing the components through a simple method of physical grinding or milling without a solvent to increase the homogeneity and dispersion.

[0401] <STEP 1>

[0402] Take 3g of each hydrotalcite powder (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) and place it in a reaction vessel and calcinate at 350℃ for 8 hours.

[0403] <STEP 2>

[0404] 0.5 g of DHT, 0.5 g of niclosamide, and 0.225 g of HPMC were each added to the container of a mortar grinder or bead mill and mixed to obtain a yellow powder, which is the pharmaceutical composition of Example 18. The final niclosamide content was 40%.

[0405] The specific contents of the pharmaceutical composition of Example 18 manufactured by the above-described method are as shown in Table 5 below.

[0406] Distinctive ingredient ratio Manufacturing ingredient DHT / (DHT+NIC) (%) HPMC (%) NIC / DHT (mg) Additional NIC (mg) HPMC (mg) Example 18 (AB40hg) 5018.3710000225

[0407]

[0408] Example 19: Preparation of a pharmaceutical composition comprising a calcined metal (hydride) oxide-niclosamide complex

[0409] <STEP 1>

[0410] Take 3g of each hydrotalcite powder (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) and place it in a reaction vessel, then calcinate it at 350℃ for 8 hours.

[0411] <STEP 2>

[0412] 50 ml of absolute ethanol was placed in each container and the powder was well dispersed by sonication for 10 minutes. The solution was stirred at 700 rpm or higher, 3 g of niclosamide was added, stirred for 6 hours, and vacuum-dried to obtain a yellow powder. The final niclosamide content was 49%.

[0413] <STEP 3>

[0414] Dissolve 0.394 g of HPMC in a 1:1 ratio solution of absolute ethanol and dichloromethane in a main tank. Add 2.025 g of DHT-NIC to the main tank and stir rapidly for 30 minutes. Evaporate the solvent using a rotary evaporator, and dry the resulting pharmaceutical composition of Example 19 (yellow powder) to obtain a pharmaceutical composition.

[0415] Example 20: Preparation of a pharmaceutical composition comprising a metal oxide-niclosamide complex (NIC-MgO-HPMC-Poloxamer: 1:0.5:1:1)

[0416] A powder pharmaceutical composition of Example 20 was obtained by mixing 0.5 g of niclosamide, 0.225 g of MgO (room temperature), 0.5 g of HPMC, and 0.5 g of poloxamer in a container of a mortar grinder or bead mill, respectively.

[0417] Example 21: Preparation of a pharmaceutical composition comprising a metal oxide-niclosamide complex (NIC-MgO-HPMC-Poloxamer: 1:1:1:1)

[0418] A powder pharmaceutical composition of Example 20 was obtained by mixing 0.5 g of niclosamide, 0.5 g of MgO, 0.5 g of HPMC, and 0.5 g of poloxamer in a container of a mortar grinder or bead mill, respectively.

[0419] Example 22: Preparation of a pharmaceutical composition comprising a metal oxide-niclosamide complex (NIC-MgO-HPMC-Poloxamer: 1:2:1:1)

[0420] A powder pharmaceutical composition of Example 20 was obtained by mixing 0.5 g of niclosamide, 1 g of MgO, 0.5 g of HPMC, and 0.5 g of poloxamer in a container of a mortar grinder or bead mill, respectively.

[0421] Examples 23-1 to 23-3: Preparation of pharmaceutical compositions comprising metal oxide-niclosamide complex (NIC-MgO-HPMC-Poloxamer: 1:2:1:1)

[0422] Niclosamide, MgO, HPMC, and poloxamer were each added to the container of a mortar grinder or bead mill in the amounts shown in Table 6 and mixed to obtain powders of the pharmaceutical compositions of Examples 23-1 to 23-3.

[0423] Content (g)NiclosamideMgOMgO content in surfactant composition (%)HPMCpoloxamerExample 23-110.51115Example 23-2111125Example 23-3121140

[0424] Example 24: Manufacturing of a pharmaceutical composition containing a metal oxide-niclosamide complex Niclosamide, MgO (room temperature), HPMC, and poloxamer were each added to a container at a weight ratio of 1:2:1:1, dispersed evenly in ethanol, and then the ethanol was vacuum-dried to obtain a powder, which is the pharmaceutical composition of Example 24.

[0425] Example 25: Preparation of a pharmaceutical composition comprising a metal oxide-niclosamide complex

[0426] 400 mg of niclosamide was mixed with 280 mg of MgO (room temperature), stirred in an EtOH solvent for 6 hours, and the EtOH was removed using a vacuum desiccator to obtain a powder. This was mixed with 100 mg of HPMC (6 maps) and then ground to obtain a powder.

[0427]

[0428] Comparative Example 1: Yomesan

[0429] Yomesan, a commercially available niclosamide drug, was used as a comparative example by adjusting only the content.

[0430] Comparative Example 2: Preparation of a metal (hydride) oxide complex and a pharmaceutical composition thereof having a solubility in water of 0.01 or more and / or a compound not containing an OH group

[0431] 0.5 g of MgO, 0.5 g of 5-FU (solubility in water: 12.2 mg / mL), and 0.225 g of HPMC were each added to the container of a mortar grinder or bead mill, and mixing was performed to obtain a powder, which is the pharmaceutical composition of Comparative Example 2.

[0432] Comparative Example 3: Preparation of a metal (hydride) oxide complex and a pharmaceutical composition thereof having a solubility in water of 0.01 or more and / or a compound not containing an OH group

[0433] 0.5 g of MgO, 0.5 g of lipoic acid (solubility in water 0.24 mg / mL), and 0.225 g of HPMC were each added to the container of a mortar grinder or bead mill, and mixing was performed to obtain a powder pharmaceutical composition of Comparative Example 3.

[0434] Comparative Example 4: Preparation of a metal (hydride) oxide complex and a pharmaceutical composition thereof having a solubility in water of 0.01 or more and / or a compound not containing an OH group

[0435] 0.5 g of MgO, 0.5 g of artesunate (solubility in water 0.5 / mL), and 0.225 g of HPMC were each added to the container of a mortar grinder or bead mill device, and mixing was performed to obtain a powder, which is the pharmaceutical composition of Comparative Example 4.

[0436] Comparative Example 5: Preparation of a pharmaceutical composition of niclosamide

[0437] 0.5 g of niclosamide, 0.5 g of HPMC, and 0.5 g of poloxamer were each added to the container of a mortar grinder or bead mill, and mixing was performed to obtain a powder pharmaceutical composition of Comparative Example 5.

[0438]

[0439] Experimental Example 1: HPLC Analysis

[0440] <Experimental methods and conditions>

[0441] □ Niclosamide HPLC analysis method

[0442] -Final update: 2021.04.14

[0443] -wavelength: UV 330nm

[0444] -column: Poroshell 120 C18 2.7um (21 x 100mm)

[0445] -Mobile Phase -> A: 10mM Ammonium acetate (0.1% Formic acid), B: ACN

[0446] - Gradient method

[0447]

[0448] -column temperature: 40℃

[0449] -injection: 5㎕

[0450] -Runtime: 15 min

[0451] -Bar(pressure): 280-300 bar

[0452] 1) Standard curve sample preprocessing method

[0453] After measuring the weight of niclosamide (powder), make a solution with a concentration of 70-75 ppm in (0.25% TFA) MeOH, sonicate for 10 minutes, make diluted solutions in sequence (at least 7 points), stir for 10 minutes, and then analyze. (Niclosamide concentration can be measured from 1 to 70 ppm using a standard curve).

[0454] 2) Analysis powder sampling

[0455] Measure the weight of the niclosamide formulation sample (granule) and make a solution with a concentration of 100 ppm in (0.25% TFA) MeOH. After 10 minutes of sonication and 10 minutes of stirring, analyze it using a 0.2 um PTFE filter. (The sample concentration is measured at 30-50 ppm).

[0456] 3) Measurement and comparative analysis of raw material content

[0457] After HPLC analysis (15 min analysis), check for integration and other peaks detected near RT. Check the area of ​​the report and substitute it into the existing standard curve to obtain the content.

[0458] Experimental Example 2: Powder X-ray Diffraction (PXRD) Analysis

[0459] Device: Powder X-ray Diffraction (PXRD)

[0460] X-ray diffractometer (D / MAXPRINT 2200-Ultima, Rigaku, Japan)

[0461] Cu-Kα radiation (λ= 1.5418Å)

[0462] Tube voltage 40kV, current 30mA

[0463] The X-ray diffractometer used was a D / MAXPRINT 2200-Ultima from Rigaku (Japan). The cathode that generated X-rays used Cu metal, and the measurement range was 2θ=3~70° with Kα rays (λ = 1.5418Å). The scanning speed was 0.02° / 0.2 sec. The divergence slit, scattering slit, and receiving slit were 0.1, 1, and 1 mm, respectively. The tube voltage was 40 kV, and the current was 30 mA.

[0464] -metewand

[0465] The one-dimensional (1D) electron density along the z-axis is calculated by the following equation:

[0466] [Equation 1]

[0467]

[0468] The powder obtained through synthesis was comparatively analyzed through XRD diffraction patterns, and the interlayer distance was calculated using Bragg's equation (Equation 2 below). The peak located at the frontmost position represents the interlayer distance including the distance between the layer of the synthesized metal compound and the layer containing the anion, and can be considered the main interlayer distance.

[0469] [Equation 2]

[0470]

[0471] (λ=wavelength of X-ray, d=lattice spacing of crystal, θ=angle of incidence)

[0472] The measured XRD patterns are described in Figs. 3 to 12.

[0473] In Fig. 3, (a) is an XRD graph for NIC, (b) is an XRD graph for HT, (c) is an XRD graph for DHT, and (d) is an XRD graph for the DHT-NIC composite (* indicates impurity, ▼ indicates periclase (MgO)). Specifically, in Fig. 3, peaks (001) having two-dimensional characteristics of HT appeared at 11.6 ° (003) and 23.3 ° (006), respectively. These characteristic peaks were converted into broad peaks, which are pseudo-3D peaks, after calcination at about 300 °C. This conversion was performed by Al 3+ It is shown by the nonstoichiometric periclase formation of MgO containing ions. After hybridizing DHT and NIC, the XRD peaks of the DHT-NIC complex were observed to show the characteristic XRD peak values ​​of DHT and NIC.

[0474] Obvious changes, such as amorphous and pseudo-3D structures, were clearly identified from the PXRD analysis as described above. These changes in XRD values ​​confirm that NIC molecules can be efficiently accommodated and protected by DHT to provide better solubility. These results may be useful for improving antiviral efficacy in vitro and in vivo in future studies.

[0475] In addition, in Fig. 11, the changes in the XRD graphs of Reference Examples 3 and 4, and Reference Examples 12 and 14 were analyzed.

[0476] It can be confirmed that the crystal structures of DHT and HT calcined at 350°C through Reference Examples 12 and 5 and Reference Example 3 in FIG. 11 are completely different. That is, the HT of Reference Example 3 has very high crystallinity, and the peaks at 11°, 23°, 35°, 38°, 46°, 60°, and 62°, which represent HT, are very well displayed, but in the case of Reference Example 4, when calcined at 350°C, MgO crystals are created, and Al exists as if mixed between these structures, resulting in a characteristic of broad peaks at 35°, 43°, and 62° (see FIG. 10). This means that the crystallinity is very low, which means that the crystallinity in the c-axis direction is reduced in terms of crystallography, and the stacked structure of HT is reduced, resulting in an increase in the specific surface area, which can be confirmed from the results of Experimental Example 4.

[0477] When water is added to the 350°C calcined DHT (Reference Example 4) of Fig. 11, the crystal structure is reconstructed back into the HT (Reference Example 3) structure. As can be seen in Reference Example 12, which reacted by adding water, the structural characteristics of DHT, which has broad peaks at 35°, 43°, and 62°, change, resulting in phase changes around 11°, 35°, and 65°.

[0478] This phenomenon can be confirmed through Reference Example 11, which added water from Example 1-1 of FIG. 12. Looking at the peaks of Example 1-1 of FIG. 12, since it takes the form of a complex in which niclosamide is reacted with a DHT structure, the characteristic peaks of DHT with broad peaks of 35°, 43°, and 62° as in Reference Example 4 and niclosamide in the olive-colored graph appear together. When water is added to the DHT-NIC complex of Reference Example 4, the crystal structure reconstruction process into HT occurs again, and the crystal structure reconstruction process into HT due to the phase transition in the peaks of niclosamide and DHT of the raw material of Example 1-1 is reflected in the peaks, and as a result, it has the characteristic of changing into a broad peak, such as the phase change around 11°, 35°, and 65° of Comparative Example 2 and the peak at 20-30°.

[0479] Experimental Example 3: TEM Analysis

[0480] TEM analysis confirmed that the structures of the metal (hydr)oxide and the calcined metal (hydr)oxide were different. Furthermore, TEM analysis confirmed that the poorly soluble drug was effectively loaded into the calcined metal (hydr)oxide.

[0481] Specifically, A. of Fig. 17 represents an FE-SEM image, and B and C represent TEM images. (a) of A and (a) of B of Fig. 17 represent HT of Reference Example 3, which confirms the structure of hydrotalcite before calcination. HT of Reference Example 3 has a uniform lamellar structure with a hexagonal single-crystal diffraction pattern (selected-area electron diffraction; SAED). In Fig. 17 C.(a), it can be confirmed that the HT structure has a regular lattice pattern with an interlayer distance of 7.6 Å and a (00l) plane (where (00l) indicates high crystallinity in the crystallographic c-axis direction). This structure corresponds to the results of XRD data analysis of Reference Example 3 of Fig. 11.

[0482] On the other hand, in the case of DHT of Reference Example 4, it takes a chain-like or channel-like structure rather than an ordered thin layer structure like HT. This shows that HT, like Reference Example 3, was converted into magnesium and aluminum oxides after calcination. As can be seen in (b) of Fig. 17B and (c) of C, the surface of DHT has a discrete structure with reduced regularity compared to HT. This is believed to be due to the partial loss of carbonate and water molecules in the HT layer after calcination. DHT of Reference Example 4 is structurally formed through block and tunnel structures formed by substitution along the crystallographic c-axis, and shows a SAED pattern with intracrystalline spotty-rings as can be seen in the red box of Fig. 17B(b), indicating a porous channel-like structure. This is thought to be a topotactic transformation due to calcination.

[0483] Compared to the DHT structure of Reference Example 4, the TEM image of the DHT-NIC complex (Example 1-1) shows that it has a smoother surface than the DHT structure, as shown in B.(c) and C(c) of Fig. 17, and that the SAED pattern shows a more dispersed ring structure. This indicates the presence of amorphous atoms arranged in a short range.

[0484] From the TEM image in Figure 17, it can be confirmed that molecular-level niclosamide was successfully filled into the porous channel structure of DHT and evenly deposited on the surface of DHT.

[0485] Experimental Example 4: Fourier Transform Infrared (FT-IR) Analysis

[0486] To obtain FT-IR spectra, a Jasco FT / IR-6100 spectrometer (Ja- 325 pan) was used, operating in transmission mode (spectral range 4000-400 cm -1 , 326 resolution 1 cm -1 , 40 scans per spectrum) using the KBr disk method.

[0487] The FT-IR spectra were recorded with a Jasco FT / IR-6100 spectrometer (Ja- 325 pan) by the standard KBr disk method in transmission mode (spectral range 4000-400 cm -1 , 326 resolution 1 cm -1 , 40 scans per spectrum)

[0488] Figure 18 shows the Fourier transform infrared (FT-IR) spectra of NIC, HT (Reference Example 3), DHT (Reference Example 4), and DHT-NIC complex (Example 1-1), respectively. The characteristic peak of NIC is 3577 cm -1 , 3490cm -1 , 1650cm -1 , 1517cm -1 and 570cm -1 , which correspond to -OH, -NH, -C=O, -NO2, and C-Cl groups, respectively. In the case of HT, 3400 cm -1 Broad peaks appear at 1630 and 1545 cm -1 Peaks can be confirmed in (see Fig. 19). The above peaks may be caused by the vibration of (OH) groups by water in the hydroxide layer and the interlayer. Meanwhile, -OH as well as -CO3 2- The bands with the characteristic of are noticeably reduced after the calcination step, and this phenomenon can be confirmed by TGA and DTA analyses. Specifically, looking at the TGA and DTA results of Fig. 21, the weight change of the material can be confirmed when calcination is performed at 350℃ for 8 hours. As the temperature increases to 256.49℃, a weight loss of 12.72% occurs, and as the temperature increases to 342.95℃, an additional weight loss of 7.143% occurs. After that, as calcination is performed at 350℃ for 8 hours, the weight loss is further increased, recording a total weight loss of 37.61%. It can be seen that physical changes in HT occur as inflection points occur at each temperature increase section, and up to the first inflection point (256.49℃), most of the water molecules are eliminated, and as the second inflection point (342.95℃) progresses, -OH is gradually eliminated and changes into the form of -O, and as the temperature (350℃) is maintained, it gradually changes into -CO3. 2- It can be seen that the decrease occurs (see Fig. 21). 1360 cm corresponding to carbonate in HT -1 It can be seen that the peak in is split into two peaks in DHT (see Fig. 19), which is due to the conversion from HT to DHT described above. In addition, a notable phenomenon in this experiment is that the bands corresponding to -OH and -NH are reduced in the DHT-NIC complex structure, which confirms that NIC was successfully loaded into DHT.

[0489] Figure 13 is an XRD graph for Example 12-1 (blue), Example 12-2 (red), NIC (olive), and Mg(OH)2 (gray), respectively.

[0490] Figure 14 is an XRD graph for Example 13-1 (blue), NIC (olive), and MgO (gray), respectively.

[0491] Figure 15 is an XRD graph for Example 14-1 (pink), DTX (green), Reference Example 4 (gray), and Reference Example 3 (black), respectively.

[0492] Figure 16 is an XRD graph for Example 16-1 (blue), DTX (green), MgO (MgO calcined at 800°C) (gray), and MgO (uncalcined MgO (black)), respectively.

[0493] Experimental Example 5: Surface Area and Porosity Analysis

[0494] For surface area and porosity analysis, a 332 BELSORP II mini instrument (Japan) was used, and the experiment was performed at 77 K (Kelvin temperature).

[0495] For measurements, HT and DHT were degassing at 100 °C for 6 h, and the NIC-DHT complex was degassing at room temperature for 12 h.

[0496] Figure 22 shows graphs of nitrogen adsorption-desorption isotherms of HT (Reference Example 3), DHT (Reference Example 4), and DHT-NIC complex (Example 1-1).

[0497] The surface area of ​​each (S BET ) and total pore volume (V p ) values ​​were calculated from the adsorption isotherm of Fig. 22 using the BET method and are listed in Table 7. Since the DHT of Reference Example 4 corresponds to a calcined form, it was confirmed that it had a very large surface area value compared to the HT of Reference Example 3 that was not calcined. This is because the surface area takes on a concave-convex structure due to calcination. Accordingly, the total pore volume increased from 0.0061 to 0.0099 as HT changed to DHT. On the other hand, the surface area value and total pore volume value of the DHT-NIC complex were lowered compared to DHT, which is thought to be because the NIC molecules were attached to the surface of DHT with an uneven surface pattern.

[0498] Classification S BET (m 2 / g)Vp(cm 3 / g)Reference Example 3 (HT) 9.05 0.0061Reference Example 4 (DHT) 62.18 0.0099Example 1-1 (DHT-NIC complex) 6.85 0.0035

[0499]

[0500] S in Table 7 above BET is the specific surface area value calculated by correction using the BET equation, and Vp is the total pore volume calculated from the adsorption amount at P / P0=0.99.

[0501] Experimental Example 5: FE-SEM Analysis

[0502] For observation of HT, DHT, and NIC-DHT using FE-SEM, a Sigma 300 (Carl 328 Zeiss, Germany) field-emission scanning electron microscope was used.

[0503] FIG. 23 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). HT has a plate-like shape with a smooth surface and a diameter of ~300 nm. The above-described structure represents the most typical shape of a layered material. When examining the morphology of DHT, which is a calcined form of HT, the average particle size of the HT form was almost maintained, but compared to the smooth surface state of HT, the surface of DHT had a rougher shape. It is thought that this change in the surface state is due to the dehydration and decarbonation reactions of HT that occur during the calcination step. Meanwhile, the morphology of the DHT-NIC composite almost maintained the morphology of DHT, but it was confirmed that it had an uneven surface compared to the DHT and HT forms. It is thought that this is due to the surface adsorption of NIC particles.

[0504] Experimental Example 6: Particle Size Analysis

[0505] For particle size analysis, a particle size analyzer (ELSZ-330 2000ZS; Otsuka, Japan) was used, and HT, DHT, and NIC-DHT were dispersed in 99.9% ethanol and measured. The measurements were repeated three times.

[0506] The results of dynamic light scattering analysis are shown in Fig. 24. The average particle sizes of HT (Reference Example 3), DHT (Reference Example 4), and DHT-NIC complex (Example 1-1) were 279.9 ± 35.6, 268.5 ± 23.8, and 292.7 ± 28.3, respectively, showing similar sizes. These results are also consistent with the FE-SEM analysis results of Experimental Example 5.

[0507] Since the average particle size is in the range of <300 nm (based on DLS and FE-SEM analyses), these results confirmed that all of the above molecules can be ideally used as antiviral therapeutics. This is because the SARS-CoV-2 virus has a small particle size (50-150 nm), and therefore, the DHT-NIC complex we aim for should also be able to penetrate into virus-infected cells and exert its antiviral effect by penetrating into the cells.

[0508] Based on previous studies, our research team has established a potential endocytosis mechanism involving hydrotalcite. Therefore, we have confirmed that protecting readily eliminated drug candidates, such as NIC, is crucial when administered orally or parenterally. In most reported cases, NIC has been shown to have very low plasma concentrations after oral administration. Therefore, protecting NIC using an ideal nanocarrier, such as calcined metal (hydr)oxide, in oral or parenteral administration may help enhance the therapeutic efficacy of NIC.

[0509] Experimental Example 8: In-vivo pharmacokinetic analysis of a pharmaceutical composition containing a metal (hydride)oxide-niclosamide complex

[0510] In vivo pharmacokinetic analysis was performed using a DHT-NIC complex or a MgO-NIC complex. Pharmaceutical compositions using the DHT-NIC complex or the MgO-NIC complex (in the form of Examples 5 to 11 or Examples 20 to 22 and 23-1 to 23-3) were administered orally to hamsters or rats, and plasma drug concentration information was obtained after the administration in this manner.

[0511] The compositions of Example 5 were administered at doses of 50 mg / kg and 200 mg / kg, respectively, and experiments were conducted. In the case of the higher dose of 200 mg / kg, the validity of the formulation was confirmed so that it could be used in vivo, and the compositions of Examples 20 to 22 and Examples 23-1 to 23-3 were administered to rats at doses of 30 mg / kg, respectively, and experiments were conducted.

[0512] In the above analysis, the administration results of Example 5 are shown in Figure 25, the administration results of Examples 20 to 22 are shown in Figure 39, and the administration results of Examples 23-1 to 23-3 are shown in Figure 40. The graph in Figure 25 shows the plasma NIC concentration in rats over time. The most important pharmacokinetic parameters are listed in Table 8 below.

[0513] [Table 8]

[0514]

[0515] The AUC value of the DHT-NIC complex / Tween 60 preparation was 1823.83±305.3ng·h / mL, which was approximately 1.8 times higher than that of the commercially available NIC drug, Yomesan. In addition, the C of the DHT-NIC complex / Tween 60 preparation max The value was approximately 1350.4±614.0 ng·h / mL, which appeared 0.25 h after oral administration. Therefore, the T of the DHT-NIC complex / Tween 60 preparation max The value was about 16 times shorter than that of Yomesan, and in the case of Yomesan, T max C at value 4h max The value was approximately 155.3±39.9ng·h / mL.

[0516] The PK profiles in Table 8 above suggest that sequential optimization is possible by varying the ratio of NIC to DHT and the dosage of the NIC-DHT complex. C max The values ​​were confirmed to be significantly improved when the dosage was increased from 50 mg / kg to 200 mg / kg. In addition, it was confirmed that the value of AUC increased approximately fourfold due to the increase in dosage. However, the NIC was lower than the IC 50 The time required to maintain plasma concentration above the value did not change, and it was confirmed that it was maintained for approximately 8 hours.

[0517] In the above results, the comparison values ​​with Yomesan are shown in Fig. 26.

[0518] In addition, in the above analysis, the effect values ​​for changes in the type of surfactant are shown in Figure 27. When a composition was prepared by replacing the surfactant from Tween 60 (Example 9) to HPMC (Example 6), it was confirmed that the Cmax value was improved by 3.9 times and the AUC value was improved by 4.7 times.

[0519] Figure 28 shows the results of an interspecies comparison between hamsters and rats. It was confirmed that even when the same drug was administered, the pattern of changes in blood drug concentrations varied depending on the animal species. The composition of Example 11 was administered to hamsters and rats in different weights. 200 mg / kg of weight was administered to rats, and 100 mg / kg of weight was administered to hamsters. It was confirmed that the blood drug concentration of 100 ng / mL was maintained for more than 12 hours in rats, but the blood drug concentration of 100 ng / mL was maintained for only about 6 hours in hamsters.

[0520] Figure 29 is a graph showing the results of changes in blood drug concentration according to the number of administrations. Hamsters were divided into two groups: one group administered the composition of Example 11 twice at 12-hour intervals, and the other group administered ten times at 12-hour intervals. This study confirmed that blood drug concentration patterns were similar regardless of the number of administrations.

[0521] Figure 30 is a graph showing the results of blood drug concentration patterns according to the dosage of the composition. In Example 11, the composition was administered to hamsters at dosages of 25 mg / kg, 50 mg / kg, and 100 mg / kg, respectively. According to the results of Figure 30, it was confirmed that the Cmax and AUC values ​​increased or decreased in proportion to the dosage of the composition.

[0522] Figure 31 is a graph showing the results of blood drug concentration patterns according to the dosage when the composition of Example 6 of the present invention was administered to rats. According to Figure 26, the composition of Example 6 of the present invention showed an AUC value similar to that of Yomesan at a dosage 1 / 10 lower than that of Yomesan, but the Cmax value was about twice as high, and it was confirmed that the composition had an effect of about 5 times higher in AUC and about 10 times higher in Cmax at the same dosage. In addition, in the case of Example 6, it was confirmed that as the dosage increased, the AUC and Cmax values ​​increased.

[0523] Figure 32 is a graph showing the results of blood drug concentration patterns after a single oral administration of 100 mg / kg of the compositions of Yomesan (NIC), Reference Example 13, and Example 12 to rats. According to Figure 32, it can be confirmed that the composition of Example 12 has significantly higher Cmax and AUC values, and the composition of Example 12 has Cmax 9.3 times higher and AUC 5.8 times higher than Yomesan, and has AUC 2.1 times higher and Cmax 5.4 times higher than Reference Example 13, which is a simple HT-NIC complex coated with HPMC.

[0524] Figure 33 is a graph showing the results of blood drug concentration patterns after a single oral administration of 100 mg / kg of calcined metal (hydr)oxides and metal oxide and NIC complexes to rats, other than DHT. It was also confirmed that the calcined Mg(OH)2 and MgO and NIC complexes of Examples 12-1 and 13 significantly increased bioavailability due to the calcination process. In the case of Example 12, it was confirmed that the AUC increased by about 11 times and the Cmax increased by about 20.5 times compared to Yomesan, and in the case of Example 13, it was confirmed that the AUC increased by about 16.8 times and the Cmax increased by about 25 times compared to Yomesan.

[0525] Figure 34 is a graph showing the blood drug concentration patterns after a single oral administration of 100 mg / kg of a pharmaceutical composition comprising the DHT-NIC complex of Example 19 using an anhydrous organic solvent synthesis method and a pharmaceutical composition comprising the DHT-NIC complex prepared by a mechanochemical synthesis step. As can be seen in Figure 34, it was confirmed that the pharmaceutical compositions prepared by the anhydrous organic solvent synthesis method and the mechanochemical synthesis method had similar effects.

[0526] Figure 39 is a graph related to the results of changes in bioavailability when a compound is formed into a metal (hydride) complex and used when manufacturing a pharmaceutical composition, or when the compound itself is formulated using a surfactant, etc. As can be seen in Figure 39, in the case of Comparative Example 5 where MgO was not used, it was confirmed that the bioavailability decreased rapidly, and it was confirmed that the bioavailability decreased somewhat as the MgO content decreased. Specifically, it was confirmed that the bioavailability of Example 22, in which the ratio of niclosamide, MgO, and surfactant (HPMC6 and poloxamer) was (1:2:2), was the best.

[0527] The rapid systemic circulation of NIC with enhanced bioavailability, as confirmed by the above results, suggests that it may be a particularly effective therapeutic strategy against the SARS-CoV-2 virus in the early symptomatic and asymptomatic stages.

[0528] We hypothesize that administration of a composition comprising a metal (hydr)oxide-NIC complex / surfactant could enhance bioavailability by avoiding or altering rapid intestinal or hepatic metabolism by cytochrome P450 enzymes. It has been previously reported that NIC undergoes rapid metabolism in the liver, and that most NIC is eliminated orally as NIC-glucuronic acid.

[0529] Therefore, the rational molecular engineering strategy of attaching NIC to metal (hydr)oxide to form a complex performed in this study could further improve mucosal adhesion, helping NIC to be maintained in the lymphatic system, and thus achieving high plasma concentrations even after a single oral administration, and these results should be emphasized. To the best of our knowledge, the present study is the first to demonstrate the effect of IC administration of NIC for 8 hours. 50 This is the first study to describe the pharmacokinetics of an orally administrable formulation of NIC that can maintain plasma concentrations exceeding 100 mg / kg.

[0530] In addition, considering the medical application of the composition comprising the above-described calcined metal(hydr)oxide-NIC complex / surfactant of the present invention, assuming that most drugs administered orally enter the systemic circulation, the composition is IC 100 It was also possible to achieve a maximum therapeutic NIC concentration exceeding . Interestingly, it was confirmed that the composition comprising the above-described calcined metal(hydr)oxide-NIC complex / surfactant was able to maintain therapeutic concentrations in plasma for up to 8 hours (see FIGS. 25, 39, and 40).

[0531] Experimental Example 9: In-vivo pharmacokinetic analysis of pharmaceutical compositions containing niclosamide complexes according to the content of metal (hydr)oxide

[0532] In order to confirm the influence of the content of metal (hydr)oxide on the in vivo pharmacokinetics, an experiment was designed to confirm the change in AUC value according to the content of MgO. The in vivo pharmacokinetic analysis was performed using MgO-NIC complexes. Examples in which the MgO content was varied while forming pharmaceutical compositions (in the form of Examples 5 to 11 or Examples 20 to 24) using the above MgO-NIC complexes were prepared (see Examples 23-1 to 23-3). These were administered orally as a single dose to hamsters or rats, and plasma drug concentration information was obtained after the procedure.

[0533] The experiment was conducted by administering the compositions of Examples 23-1 to 23-3 at a dose of 30 mg / kg each.

[0534] The results of the above analysis are shown in Figure 40. It was confirmed that the AUC effect increased proportionally as the MgO content increased. This result confirmed that MgO plays a significant role in improving bioavailability.

[0535] Experimental Example 10: In-vivo pharmacokinetic analysis of a pharmaceutical composition containing a metal (hydride)oxide-docetaxel complex

[0536] In vivo pharmacokinetic analysis was performed using a pharmaceutical composition comprising a DHT-docetaxel complex. The pharmaceutical composition comprising the DHT-docetaxel complex was administered orally to rats as a single dose, and plasma drug concentration information was obtained after the study. The in vivo pharmacokinetic study was conducted by coating the pharmaceutical composition comprising the DHT-docetaxel complex with HPMC to form an orally administrable composition of docetaxel (DTX) (Examples 14 and 16).

[0537] In addition, each of the compositions of Examples 14 and 16 was dissolved in a 5% tween solution at a dose of 40 mg / kg in an amount of 10 mL / kg and administered orally once. The results are shown in Figures 35 and 36, and the specific data values ​​are described in [Table 9] below.

[0538] [Table 9]

[0539]

[0540] The control group was administered only docetaxel without additional formulation at a dose of 40 mg / kg, and it was confirmed that the bioavailability increased by more than 10 times compared to the control group when the pharmaceutical compositions of Examples 14 and 16 of the present invention were administered rather than simply administering docetaxel. As can be seen in the results in Table 9 above, docetaxel has low bioavailability when administered orally. In an oral administration experiment using rats, the AUC of docetaxel was 47.46 and the Cmax was 5.25, but when the organic-inorganic hybrid technology was applied as in Examples 14 and 16, the AUC increased by 12-fold and 14-fold, respectively, and the Cmax increased by 51-fold and 74-fold, respectively. Therefore, it was confirmed that the bioavailability of docetaxel, which had been difficult to develop into an oral dosage form due to its low bioavailability, can be dramatically increased by applying the organic-inorganic hybrid technology.

[0541] Experimental Example 11: In-vivo pharmacokinetic analysis of a pharmaceutical composition of a metal (hydride) having a solubility in water of 0.01 or more and / or a compound not containing a hydroxyl group.

[0542] In vivo pharmacokinetic analysis was performed using the compound itself and pharmaceutical compositions prepared by forming a metal (hydr)oxide complex with it (Comparative Examples 2 to 4).

[0543] Each of 5-FU, lipoic acid and artesunate, and the pharmaceutical compositions of Comparative Examples 2, 3 and 4 were administered orally to hamsters or rats, and plasma drug concentration information was obtained after the experiment.

[0544] In addition, experiments were conducted by administering the compound and pharmaceutical compositions of Comparative Examples 2 to 4 at a dose of 40 mg / kg, respectively, and the results are shown in Figures 41 to 43.

[0545] The control group was administered 40 mg / kg of 5-FU, lipoic acid, and artesunate, respectively, without additional formulation. It was confirmed that the bioavailability of the compounds of 5-FU, lipoic acid, and artesunate was not improved even though they were prepared as metal (hydr)oxide complexes using MgO due to their chemical structures or their water solubility characteristics.

[0546] Experimental Example 12: Drug Release Experiment

[0547] Drug release experiments were conducted at 37°C using 500 mL of artificial intestinal fluid (pH 6.8) supplemented with 2% Tween 60. Experiments were conducted using Example 6 (D56H), Example 12-1 (Mg(OH)2), Example 13 (MgO), Reference Example 13 (HT), and Comparative Example 1 (Yomesan).

[0548] Referring to Figure 37, it can be seen that the release rate of NIC loaded on the metal (hydr)oxide is higher than that of Yomesan, and it can be confirmed that the release rate of NIC loaded on the calcined metal (hydr)oxide is further increased compared to Reference Example 13.

[0549] From the drug release results, it can be confirmed that the bioavailability of poorly soluble drugs is higher when the metal (hydride) oxide complex of the present invention is used.

[0550] Experimental Example 13: Antiviral Efficacy Test

[0551] Test model: golden Syrian hamster

[0552] Drug administered: D24T (CP-COV03)

[0553] Drug dosage: 25 mg / kg

[0554] Dosage: 20mL / kg

[0555] The composition of Example 11 was orally administered to hamsters infected with the COVID-19 virus (SARS-CoV2) at 4-hour intervals starting the day after infection. On the second day after hamster infection (one day after administration), blood collected from the hamsters was analyzed by RT-qPCR. The results showed that the viral RNA concentration in the blood was significantly (ANOVA, P<0.05) reduced compared to the infected control group (untreated group) (see Figure 38). Meanwhile, the group administered 25 mg / kg of Yomesan of Comparative Example 1 showed no decrease in the viral concentration in the blood due to low bioavailability (see Figure 38).

[0556] Experimental Example 14: Antiviral Efficacy Test

[0557] Test model: golden Syrian hamster

[0558] Drug administration: Example 24

[0559] Drug dosage: 20, 40, and 80 mg / kg

[0560] Dosage: 20mL / kg

[0561] For the composition of Example 24, it was based on the respective drug dosages above, and for the composition of Comparative Example 5, after infection with the coronavirus (SARS-CoV2) at a dosage of 80 mg / kg, the drug was administered at 12-hour intervals starting 6 hours after infection, and the model was dissected on the 4th day after infection. After dissecting the hamster, macroscopic observation of the lungs, observation of lung tissue lesions, and measurement of viral load were performed, and the results are shown in Figures 44 to 48.

[0562] When pneumonia progresses due to SARS-CoV-2 infection, lung lesions occur. By comparing the uninfected hamster control group (NC; negative control) and the infected hamster control group (VC; vehicle control), the lung lesion score of the uninfected hamster was calculated as 100, and the lung lesion score of the infected hamster was calculated as 1. In Comparative Example 5, even though 80 mg / kg was administered, the lung lesion improvement rate was only 4.1%. On the other hand, in Example 24, as the CP-COV03 dose increased, the lung lesion improvement rate increased, and it was confirmed that the lung lesion improved by 31.6% at 80 mg / kg (see Figure 44).

[0563] In addition, the tissue of the lungs extracted through dissection was fixed and stained, and the injury score (degree of damage) was calculated based on detailed observation and pathological findings, and is shown in Fig. 45. In the case of the infected hamster (VC), the lung damage degree was 1.13, and in the case of Comparative Example 5, even when 80 mg / kg was administered, the injury score was not significantly improved (decreased) (injury score: 1.05). On the other hand, in the case of Example 24, the injury score decreased as the dose increased, and in particular, when 80 mg / kg was administered, the injury score was lowered to 0.86, showing a significantly improved effect (see Fig. 45).

[0564] Finally, the viral load in lung tissue was quantified using RT-qPCR, and the results are shown in Fig. 46. The viral load in the administration group administered Comparative Example 5 showed a large deviation, and it was unclear whether the viral load was lowered compared to the control group (VC). On the other hand, Example 24 showed a clear antiviral activity, and the viral load was lowered by increasing the dose (see Fig. 46).

Claims

1. A metal (hydride) oxide; and a compound or a salt thereof containing at least one hydroxyl group in the compound, The above metal (hydride) oxide is at least one selected from compounds represented by the following chemical formulas 3 to 5. Metal (hydride) oxide complex. [Chemical Formula 3] [(M 2+ (1-x) M 3+ x (OH) 2 )·((HAS n- ) z )]·yH 2 O (In the above chemical formula 3, M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ 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+ A trivalent metal cation selected from the group consisting of: x is a number with a range greater than 0 and less than or equal to 0.5, A is CO 3 2- , NO 3 - , Br - , Cl - , SO 4 2- , HPO 4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, n is a number in the range of 0.5 to 2, z is a number with a range of 0 to 1, y is a positive number greater than 0.) [Chemical Formula 4] [(M 2+ (OH) 2-x )·((A n- , z )] yH 2 O (In the above chemical formula 4, M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ A divalent metal cation selected from the group consisting of: x is a number with a range of 0 to 0.4, A is CO 3 2- , NO 3 - , Br - , Cl - , SO 4 2- , HPO 4 2- and F - is an anion selected from the group consisting of n is the charge number of the anion A, n is a number in the range of 0 to 2, z is a number with a range of 0 to 1, y is a positive number greater than 0.) [Chemical Formula 5] [(M 2+ (O) 2-x )·((A n- , z )] yH 2 O (In the above chemical formula 5, M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ or Zn 2+ And, x is a number greater than or equal to 1 and less than or equal to 2, A is CO 3 2- , NO 3 - , Br - , Cl - , SO 4 2- , HPO 4 2- and F - is an anion selected from the group consisting of n is the charge number of the anion A, n is a number in the range of 0 to 2, z is a number with a range of 0 to 1, y is a positive number greater than 0.) 2. In claim 1, A compound having at least one hydroxyl group in the above compound or a salt thereof has a solubility in water of less than 0.01 mM. Metal (hydride) oxide complex.

3. In claim 1, Compounds containing one or more hydroxy groups in the compound or salts thereof are selected from the group consisting of niclosamide, loperamide, penfluridol, ciclesonide, oxyclozanide, dihydrogambogic acid, osajin, lusutrombopag, isosajin, ivacaftor, triparanol, droloxifene, lopinavir, docetaxel, vitamin A, idebenone, paclitaxel, fulvestrant, probucol, doxorubicin, gemcitabine, Comprising at least one selected from quercetin, cyanidin, delphinidin, malvidin, pelargonidin, petunidin, curcumin, epigallocatechin-3-gallate, genistein, resveratrol, estradiol, camptothecin, podophyllotoxin, raloxifene, topotecan, bortezomib, netilmicin, branaplam, and spiramycin. Metal (hydride) oxide complex.

4. In claim 1, The compound having at least one hydroxyl group in the above compound is at least one compound selected from compounds represented by Chemical Formula 1 or Chemical Formula 2. Metal (hydride) oxide complex. [Chemical Formula 1] (In the above chemical formula 1, R 1 Inland R 6 are, each independently, a hydrogen atom, a halogen atom, a hydroxyl group, a methoxy group, an ester group or a nitro group, Above R 1 Inland R 6 At least one of them is a hydroxyl group.) [Chemical formula 2] (In the above chemical formula 2, A is a nitrogen atom or an oxygen atom, R 1 If A is a nitrogen atom, it can be a hydrogen atom, a halogen atom, a hydroxyl group, or an alkyl group, and if A is an oxygen atom, it does not have a substituent. R 2 Inland R 11 are, each independently, a hydrogen atom, a halogen atom, a hydroxyl group, a methoxy group, an ester group, an acyl group, or a nitro group, Above R 1 Inland R 11 At least one of them is a hydroxyl group.) 5. In claim 1, The above metal (hydride) oxide complex is for the prevention or treatment of one or more diseases among viral infectious diseases, inflammatory diseases, and malignant tumor diseases. Metal (hydride) oxide complex.

6. A metal (hydroxide); a compound or a salt thereof containing at least one hydroxyl group in the compound; and an additive, The above metal (hydride) oxide is at least one selected from compounds represented by the following chemical formulas 3 to 5. Pharmaceutical composition. [Chemical Formula 3] [(M 2+ (1-x) M 3+ x (OH) 2 )·((HAS n- ) z )]·yH 2 O (In the above chemical formula 3, M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ 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+ A trivalent metal cation selected from the group consisting of: x is a number with a range greater than 0 and less than or equal to 0.5, A is CO 3 2- , NO 3 - , Br - , Cl - , SO 4 2- , HPO 4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, n is a number in the range of 0.5 to 2, z is a number with a range of 0 to 1, y is a positive number greater than 0.) [Chemical Formula 4] [(M 2+ (OH) 2-x )·((A n- , z )] yH 2 O (In the above chemical formula 4, M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ A divalent metal cation selected from the group consisting of: x is a number with a range of 0 to 0.4, A is CO 3 2- , NO 3 - , Br - , Cl - , SO 4 2- , HPO 4 2- and F - is an anion selected from the group consisting of n is the charge number of the anion A, n is a number in the range of 0 to 2, z is a number with a range of 0 to 1, y is a positive number greater than 0.) [Chemical Formula 5] [(M 2+ (O) 2-x )·((A n- , z )] yH 2 O (In the above chemical formula 5, M 2+ Silver Mg 2+ , Ni 2+ , Cu 2+ or Zn 2+ And, x is a number greater than or equal to 1 and less than or equal to 2, A is CO 3 2- , NO 3 - , Br - , Cl - , SO 4 2- , HPO 4 2- and F - is an anion selected from the group consisting of n is the charge number of the anion A, n is a number in the range of 0 to 2, z is a number with a range of 0 to 1, y is a positive number greater than 0.) 7. In claim 6, Compounds containing at least one hydroxy group in the above compound or salts thereof are selected from the group consisting of niclosamide, loperamide, penfluridol, ciclesonide, oxyclozanide, dihydrogambogic acid, osajin, lusutrombopag, isosajin, ivacaftor, triparanol, droloxifene, lopinavir, docetaxel, vitamin A, idebenone, paclitaxel, fulvestrant, probucol, doxorubicin, gemcitabine, Comprising at least one selected from quercetin, cyanidin, delphinidin, malvidin, pelargonidin, petunidin, curcumin, epigallocatechin-3-gallate, genistein, resveratrol, estradiol, camptothecin, podophyllotoxin, raloxifene, topotecan, bortezomib, netilmicin, branaplam, and spiramycin. Pharmaceutical composition.

8. In claim 6, The compound or salt thereof containing at least one hydroxyl group in the compound is at least one compound selected from compounds represented by chemical formula 1 or 2. Pharmaceutical composition. [Chemical Formula 1] (In the above chemical formula 1, R1 to R6 are each independently a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, an ester group or a nitro group, At least one of the above R1 to R6 is a hydroxy group.) [Chemical formula 2] (In the above chemical formula 2, A is a nitrogen atom or an oxygen atom, R1 may be a hydrogen atom, a halogen atom, a hydroxyl group, or an alkyl group when A is a nitrogen atom, and has no substituent when A is an oxygen atom. R2 to R11 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, At least one of the above R1 to R11 is a hydroxy group.) 9. In claim 6, With respect to the total 100 wt% of the pharmaceutical composition, it comprises 10 to 60 wt% of metal (hydr)oxide, 0.1 to 60 wt% of compound or salt thereof, and 10 to 85 wt% of additives. Pharmaceutical composition.

10. In claim 6, The above additive is a surfactant, Pharmaceutical composition.

11. In claim 6, The metal (hydride) oxide and the compound or salt thereof containing at least one hydroxyl group in the compound are included in a ratio of 1:0.1 to 10. Pharmaceutical composition.

12. In claim 6, The above pharmaceutical composition is for the prevention or treatment of one or more diseases among viral infectious diseases, inflammatory diseases, and malignant tumor diseases. Pharmaceutical composition.

13. In claim 6, The above surfactant is at least one selected from polyoxyethylene sorbitan fatty acid esters, poloxamer, lecithin, glycerol fatty acid esters, sorbitan fatty acid esters, PEG, thickeners (long chain of sugar), stabilizers (gum), gelling agents, thickening polysaccharides, and sodium dodecyl sulfate. Pharmaceutical composition.