Partially crystalline composition comprising poorly soluble drug or pharmaceutically acceptable salt thereof, and method for preparing same

Abstract

Provided are a partially crystalline composition comprising a drug having a low solubility or a pharmaceutically acceptable salt thereof, and a method for preparing same. The present invention relates to a partially crystalline composition comprising a poorly soluble drug or a pharmaceutically acceptable salt thereof, and a method for preparing same.

Description

Incomplete crystalline composition comprising a poorly soluble drug or a pharmaceutically acceptable salt thereof and a method for producing the same

[0001] The present invention relates to an incompletely curable composition comprising a poorly soluble drug or a pharmaceutically acceptable salt thereof and a method for producing the same.

[0002] Poorly soluble drugs play a crucial role in pharmacology, but their low solubility in water limits their absorption and therapeutic efficacy. For example, poorly soluble drugs such as niclosamide, docetaxel, paclitaxel, and cabazitaxel face limitations in achieving sufficient bioavailability when administered orally due to their low solubility in water. This problem frequently presents challenges in drug development, necessitating novel technological approaches to maximize drug efficacy and minimize side effects. Oral medications offer the advantage of superior convenience compared to other drug administration methods currently under development and marketed.

[0003] However, most drugs with excellent efficacy are difficult to develop for oral administration. Their structural characteristics, which make them poorly soluble, limit their absorption in the body. In particular, drugs such as niclosamide and taxane compounds, listed above, exhibit excellent anticancer, anti-inflammatory, and antiviral effects, but their clinical efficacy is severely limited due to low solubility, poor selective distribution, and rapid in vivo clearance. To overcome this, the pharmaceutical industry is using injectable formulations for drug administration. For example, taxotere is formulated for intravenous use, but the inclusion of Tween80 and ethanol in its formulation can cause adverse effects such as hemolysis and irritation in patients after administration.

[0004] In the past, various methods have been proposed to improve the solubility of poorly soluble drugs. Representative methods include nanoparticles, complex formation, the use of surfactants, and solid dispersion techniques. However, these methods have been plagued by complex manufacturing processes, insufficient physical and chemical stability, and limited solubility-enhancing effects.

[0005] Accordingly, the present applicant has designed a composition having an imperfect crystal structure that can be stably manufactured, improves in vivo utilization, and minimizes side effects.

[0006]

[0007] The present invention provides an invention that can improve the bioavailability of a poorly soluble drug or a pharmaceutically acceptable salt thereof and stably improve the drug effect in the body without side effects.

[0008]

[0009] The present invention provides an invention that can improve the bioavailability of a poorly soluble drug or a pharmaceutically acceptable salt thereof and stably improve the drug effect in the body without side effects by forming an incomplete crystalline composition by enabling the poorly soluble drug to form hydrogen bonds with a polymer.

[0010]

[0011] The present invention has the effect of improving the bioavailability of a poorly soluble drug or a pharmaceutically acceptable salt thereof and stably improving the drug effect in the body without side effects by forming an incomplete crystalline composition by enabling a poorly soluble drug to form hydrogen bonds with a polymer.

[0012] In addition, when forming an incomplete crystalline composition, unlike a general solid dispersion, hydrogen bonds can be formed, so that the polymer can more stably surround the insoluble drug, preventing recrystallization, and has the advantage of maintaining quality even during long-term storage.

[0013] Additionally, due to its low solubility, side effects such as gastrointestinal irritation and increased toxicity in the body can be reduced, and the dosage can be adjusted to a low dose to obtain effective efficacy.

[0014]

[0015] Figure 1 is a graph showing the plasma concentration measurement results for Examples 1 and 2 and Comparative Examples 1 and 2.

[0016] Figure 2 is a graph showing the total exposure amount of drug in plasma with AUClast results for Examples 1 and 2 and Comparative Examples 1 and 2, and showing how long and at what concentration the drug remained in the blood.

[0017] Figures 3 and 4 are graphs of AUC measurement results for Examples 3 to 20 and Comparative Examples 3 and 4.

[0018] Figure 5 is a graph showing the total exposure of the drug in the plasma with AUClast results for Examples 68 to 82, and showing how long and at what concentration the drug remained in the blood.

[0019] Figure 6 is a graph showing the results of plasma concentration by oral administration of Example 83 and Comparative Example 6.

[0020] Figure 7 is a graph showing the total exposure amount of the drug in the plasma as AUClast results by oral administration of Example 83 and Comparative Example 6, and showing how long and at what concentration the drug remained in the blood.

[0021] Figures 8 to 14 are graphs showing the results for the dissolution rate according to the dissolution conditions of Examples 84 to 88 and Comparative Examples 7 and 8.

[0022] Figures 15 to 18 are diagrams of the pharmacokinetic (PK) profiles of Niclosamide PO of Examples 134 to 139 and Reference Examples 1 to 3.

[0023] Figures 19 to 23 are graphs of XRD patterns of Examples 140 to 150 and Comparative Examples 10 to 12.

[0024] Figures 24 to 36 are graphs for XRD patterns of Examples 151 to 158 and 161 to 164. The composition of a specific example corresponding to each drawing is indicated above the drawing, and among the two XRD patterns, the upper XRD pattern is the XRD pattern for each example, and the lower XRD pattern means the pattern for niclosamide.

[0025] Figure 37 is a graph of the XRD pattern of Comparative Example 13.

[0026] Figure 38 is a graph showing the results of plasma concentration measurement for formulated oral docetaxel and docetaxel raw material.

[0027] Figure 39 is a graph showing the results of plasma concentration measurement for formulated oral paclitaxel and paclitaxel raw material.

[0028] Figure 40 is a graph showing changes in weight loss due to differences in the number of administrations when Example 177 was administered orally.

[0029] Figure 41 is a graph showing changes in tumor size depending on the number of administrations when Example 177 was administered orally.

[0030] Figures 42a to 42e are photographs of experimental results showing tumor treatment effects and metastasis analysis using the LL / 2 xenograft model.

[0031] Figure 43 is a graph of the plasma concentration profile of Paclitaxel PO 100 mg / kg.

[0032] Figure 44 is a graph of the log-transformed plasma concentration profile of Paclitaxel PO 100 mg / kg.

[0033] Figure 45 is a graph showing the total exposure of the drug in the plasma as an AUClast result value, and showing how long and at what concentration the drug remained in the blood.

[0034] Figure 46 is a graph of the dissolution rates of Examples 147 to 150 and Comparative Examples 11 and 12.

[0035] Figure 47 is an FT-IR graph for Niclosamide, Example 146, and HMPC.

[0036]

[0037] The present invention provides an incompletely crystalline composition comprising niclosamide or a pharmaceutically acceptable salt thereof; and a polymer, wherein the composition comprises niclosamide or a pharmaceutically acceptable salt thereof; and a polymer, and in XRD, includes peaks at 2 (θ) = 13.01°±0.5°, 13.74°±0.5°, and 25.68°±0.5°, and wherein the 2 (θ) = 26.87°±0.5° peak in the XRD of the niclosamide or the pharmaceutically acceptable salt thereof shifts in the direction of 2 (θ) by 25° or a change in the intensity of the 2 (θ) = 26.87°±0.5° peak occurs. The present inventors have confirmed that when a drug interacts with a polymer, a specific crystal plane can selectively increase its amorphous characteristics, thereby changing the existing 25-30° region diffraction line. In general, when the lattice parameter changes, the peak position (2θ value) may shift according to Bragg's Law (nλ=2dsinθ). In addition, when the lattice spacing (d-spacing) increases, the 2θ value may shift to lower angles, and when hydrogen bonding is reduced on the surface of a specific particle plane (hkl), the diffraction intensity of that plane becomes relatively low, which may result in a decrease in peak intensity. In addition, peak broadening may be observed, and the peak may broaden if the grain size changes or the internal stress increases.

[0038] In the present invention, it was confirmed that when niclosamide forms hydrogen bonds (OH···O, C=O···HO, etc.) through binding with a polymer, the π-π stacking structure changes, and a specific crystal plane can have an amorphous characteristic. The change in intermolecular spacing reflects a crystal plane with a shorter intermolecular distance for a diffraction line with a 2θ value of 25 to 30° according to Bragg's Law. Through this, it was confirmed that the niclosamide-polymer complex can form a new, modified crystal structure while partially maintaining crystallinity without changing to a completely amorphous state, thereby completing the present invention.

[0039] In the present invention, the incompletely crystalline composition may have a change value of 1.5 to 10% in the shift of the 2(θ)=26.87°±0.5° peak in the 25° direction in XRD, and the change in intensity of the 2(θ)=26.87°±0.5° peak may be changed in the range of 10 to 80%. This means that the peak of the XRD value of the included niclosamide or a pharmaceutically acceptable salt thereof changes due to the bonding process with the polymer. The present invention is characterized by obtaining an incompletely crystalline form rather than one having high amorphousness. When the peak value is in the above-mentioned range, there is an advantage in that the problem of very low solubility of crystalline niclosamide or a pharmaceutically acceptable salt thereof can be solved while improving bioavailability. In particular, the shift or change in the peak value of the present invention is different from that of a conventional solid dispersion form. The shift or change in the peak value of the present invention means that the polymer and niclosamide or a pharmaceutically acceptable salt thereof may be dispersed by forming hydrogen bonds between them due to the excessive use of a mixed solvent of ethanol and water during the manufacturing process. This bonding form has the advantage of achieving higher solubility and bioavailability.

[0040] In addition, the present invention provides an incomplete crystalline composition comprising a taxane compound or a pharmaceutically acceptable salt thereof; and a polymer. The above-described taxane compound may be at least one selected from docetaxel, paclitaxel, and cabazitaxel.

[0041] In the present invention, the polymer may be at least one compound selected from among polyvinylpyrrolidone compounds, cellulose compounds, poloxamer compounds, polyethylene glycol compounds, alginic acid compounds, dextrin compounds, sugar alcohol compounds, copolymer compounds containing acrylic acid or methacrylic acid, and poly-gamma glutamic acid.

[0042] In the present invention, the polyvinyl pyrrolidone compounds are polyvinylpyrrolidone K10 (MW 8000-10,000), polyvinylpyrrolidone K12 (MW 11,000-12,000), polyvinylpyrrolidone K15 (MW 14,000-18,000), polyvinylpyrrolidone K17 (MW 14,000-18,000), polyvinylpyrrolidone K18 (MW 14,000-18,000), polyvinylpyrrolidone K25 (MW 20,00-25,000), polyvinylpyrrolidone K30 (MW 30,00-40,000), polyvinylpyrrolidone K60 (MW 50,00-60,000) and polyvinylpyrrolidone. It may be at least one selected from the group consisting of K90 (MW 80,000 to 90,000). In the above, MW refers to molecular weight and weight average molecular weight.

[0043] In the present invention, the cellulose-based compound may be at least one selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), ethylcellulose (EC), methylcellulose (MC), cellulose acetate (CA), and calcium carboxymethylcellulose (Ca-CMC). The weight average molecular weight of the above-described cellulose-based compound may be 5,000 to 500,000.

[0044] In addition, the poloxamer compounds include poloxamer 101, poloxamer 105, poloxamer 105 benzoate, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 182 dibenzoate, 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 The poloxamer compound may be at least one selected from the group consisting of 288, poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403, and poloxamer 407, and poloxamer 407 may be more preferred. The weight average molecular weight of the above-described poloxamer compound may be 5,000 to 500,000.

[0045] In the present invention, the polyethylene glycol compound may be at least one selected from the group consisting of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 500, polyethylene glycol 1000, polyethylene glycol 1400, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 8000, polyethylene glycol 10000, and methoxy polyethylene glycol 550. The weight average molecular weight of the above-described polyethylene glycol compound may be 5,000 to 500,000.

[0046] In the present invention, the alginic acid compound may be alginate, alginic acid, and alginic acid ester, and the alginate may be sodium alginate, ammonium alginate, calcium alginate lactate, and potassium alginate.

[0047] In the present invention, the dextrin-based compound may be sodium dextrin sulfate, matodextrin, icodextrin, amylodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dextran, dextran40, dextran70, etc.

[0048] The above sugar alcohol compound may be a compound of HOCH2(CHOH)nCH2OH, where n is an integer from 1 to 30, and more specifically, may be ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fusitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotritol, maltotetraitol, and polyglycitol.

[0049] In the present invention, the copolymer compound containing acrylic acid or methacrylic acid may be an enteric coating agent, and may be a substance called Eudragit. Specifically, it may be a methacrylic acid-ethyl acrylate copolymer (Eudragit L 100, Eudragit S 100, Eudragit L 30D-55), a methacrylic acid-acrylate copolymer (Eudragit RS 100, Eudragit RL 100, Eudragit RS 30 D, Eudragit RL 30), a methacrylic acid-ethyl acrylate copolymer (Eudragit E 100, Eudragit E PO), and an acrylic acid ester copolymer (Eudragit NE 30 D).

[0050] The incompletely crystalline composition of the present invention is characterized in that it is prepared by stirring a water and ethanol mixed solvent when mixing a poorly soluble drug or a pharmaceutically acceptable salt thereof and a polymer. Specifically, the water and ethanol mixed solvent may be one in which water and ethanol are mixed at a ratio of 1:9 to 9:1. By using a water and ethanol mixed solvent, hydrogen bonding can be induced during the mixing reaction between the poorly soluble drug and the polymer compound. The mixed solvent may be used in a range of 1:10 to 1:100 with respect to niclosamide or a pharmaceutically acceptable salt thereof.

[0051]

[0052] The incomplete crystalline composition of the present invention may further comprise a mineral compound. The mineral in the mineral compound may be at least one selected from calcium, iron, potassium, sodium, zinc, magnesium, copper, manganese, chromium, cobalt, selenium, and molybdenum. More specifically, the mineral compounds are calcium carbonate, calcium bicarbonate, iron carbonate, potassium bicarbonate, sodium bicarbonate, zinc carbonate, magnesium carbonate, magnesium bicarbonate, copper carbonate, manganese carbonate, chromium carbonate, cobalt carbonate, selenium carbonate, calcium chloride, calcium sulfate, calcium nitrate, calcium oxide, calcium hydroxide, calcium silicate, iron chloride, iron nitrate, iron sulfate, iron hydroxide, potassium chloride, potassium nitrate, potassium hydroxide, sodium chloride, sodium nitrate, sodium hydroxide, zinc chloride, zinc nitrate, zinc sulfate, zinc oxide, zinc hydroxide, magnesium chloride, magnesium nitrate, magnesium sulfate, magnesium oxide, magnesium hydroxide, magnesium silicate, copper chloride, copper nitrate, copper sulfate, copper oxide, copper hydroxide, manganese chloride, manganese nitrate, manganese sulfate, manganese oxide, manganese hydroxide, chromium chloride, chromium nitrate, It may be at least one selected from chromium sulfate, chromium oxide, chromium hydroxide, cobalt chloride, cobalt nitrate, cobalt sulfate, cobalt oxide, cobalt hydroxide, selenium chloride, selenium nitrate, selenium sulfate, selenium oxide, selenium hydroxide, molybdenum chloride, molybdenum oxychloride, molybdenum oxide, molybdenum nitrate bromide, molybdenum nitrate, molybdenum sulfide, molybdenum hydroxide, and molybdenum oxalate.

[0053] In particular, the carbonate metal of the present invention plays a major role in the absorption of poorly soluble drugs. By coating the carbonate metal with a polymer, the decomposition of basic carbonate metal by gastric juice with a pH of 1.5 to 3.5 can be prevented, thereby helping the absorption of the drug. In particular, in the case of a substance with a strong sustained-release property, it can adhere to the digestive organs and gradually increase the pH of the adhered area, thereby helping the absorption of the drug. This is preferable in that the carbonate metal coated with the polymer is not lost by gastric acid, thereby increasing sustained-release in the digestive organs, thereby delaying the half-life of the drug concentration in the blood and maximizing the efficacy of the drug by maintaining the exposure time corresponding to the therapeutic window.

[0054] Specifically, the poorly soluble drugs or pharmaceutically acceptable salts thereof include, but are not limited to, niclosamide, tilorone, cyclosporine, perhexiline maleate, loperamide, mefloquine, proscillaridin, digitoxin, penfluridol, digoxin, clomiphene, hydroxyprogesterone, amodiaquine, phenazopyridine, toremifene, hexachlorophene, thioridazine, salinomycin, quinacrine, eltrombopag, Cepharanthine, oxyclozanide, ciclesonide, ceritinib (LDK378), dihydrogambogic acid, osimertinib (AZD-9291), isopomiferin, osajin, anidulafungin (LY303366), lustrombopag, gilteritinib, tetrandrine, berbamine, isosajin, ebastine, abemaciclib (USAN), ivacaftor, bazedoxifene, meequitazine, Triparanol, droloxifene, dronedarone, chloroquine, hydroxychloroquine,It can be a drug that can be used as an antiviral agent, antibiotic, antimalarial, analgesic, or more than one cardiovascular treatment selected from lopinavir, favipiravir, and atazanavir. In addition, docetaxel, paclitaxel, cabazitaxel, etoposide, topotecan, idarubicin, fluorouracil, abiraterone, cabozantinib, axitinib, ceritinib, bosutinib, dabrafenib, erlotinib, lapatinib, midostaurin, One or more anticancer drugs such as neratinib, nilotinib, pazopanib, sonidegib, nintedanib, trametinib, or anti-inflammatory or antioxidant drugs such as ascorbic acid, vitamin A, lipoic acid, pramipexole, allopurinol, pentoxifylline, quercetin, acetylcysteine, melatonin, probucol, transcrocetinate, nicaraven, lodoxamide, ferulic acid, idebenone, or Adalimumab, Pembrolizumab, Dulaglutide, Aflibercept, Denosumab, Ustekinumab, Secukinumab, Nivolumab, Vedolizumab, Dolutegravir,Liraglutide, and one or more drugs selected from Fimasartan. More preferably, the poorly soluble drug is a poorly soluble drug containing one or more hydroxyl groups, such as niclosamide or a taxane compound.

[0055] The present invention provides a method for preparing an incompletely crystalline composition, comprising the steps of: preparing a first solution by stirring niclosamide or a pharmaceutically acceptable salt thereof and a polymer in a mixed solvent of water and ethanol; and drying the first solvent to obtain a first product. In addition, the method for preparing an incompletely crystalline composition may further include the step of preparing a second solution by stirring the first product and a mineral salt in anhydrous ethanol. During preparation, the mixed solvent of water and ethanol may be mixed at a ratio of water to ethanol of 1:9 to 9:1, and the ratio of niclosamide or a pharmaceutically acceptable salt thereof and the mixed solvent in the first solution preparation step may be 1:10 to 1:100.

[0056] In addition, the present invention can provide a method for preparing an incompletely crystalline composition, comprising the steps of: stirring a poorly soluble drug or a pharmaceutically acceptable salt thereof with a polymer compound under anhydrous conditions to form a mixture of a poorly soluble drug and a polymer compound; and mixing a mineral compound into the mixture of the poorly soluble drug and the polymer compound.

[0057] The present invention provides a pharmaceutical composition comprising the above-described incomplete crystalline composition.

[0058] The pharmaceutical composition of the present invention may be anti-inflammatory, antiviral, and / or anticancer. In the present invention, anti-inflammatory means having an effect of alleviating an inflammatory response due to infectious, traumatic, endogenous, inflammatory, degenerative, or autoimmune causes. Specifically, the inflammatory disease includes inflammatory diseases including vascular restenosis; autoimmune diseases, pancreatitis, glomerulonephritis, myocardial infarction, and psoriasis; atopic diseases including allergic asthma, atopic dermatitis (eczema), and allergic rhinitis; It may be a disease such as cell-mediated hypersensitivity disease including allergic contact dermatitis and hypersensitivity pneumonitis, rheumatic disease including systemic lupus erythematosus (SLE), rheumatoid arthritis, juvenile arthritis, Sjogren's syndrome, scleroderma, polymyositis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, inflammatory disease and psoriatic arthritis, diabetes, autoimmune thyroid disease, brain disease including dementia, Parkinson's disease, Alzheimer's disease, other autoimmune diseases and degenerative diseases including arthritis.

[0059] In the present invention, the term "antiviral" means having an antiviral effect against DNA and / or RNA viruses, and more specifically, it means having an antiviral effect and an antibiotic function against viruses such as malaria infection causing viral diseases or coronaviruses such as Epstein-Barr Virus (EBV), hepatitis B virus, hepatitis C virus, HIV, HTLV 1, Varicella-Zoster Virus (VZV), Human Papilloma Virus (HPV), SARS-CoV and / or SARS-CoV2, rhinovirus causing colds or respiratory diseases, adenovirus, RS virus, parainfluenza virus, RS virus, etc., and other retroviruses.

[0060] In addition, the meaning of anticancer in the present invention means that it has anticancer activity by acting directly on DNA to block DNA replication, transcription, and translation processes, or by interfering with the synthesis of nucleic acid precursors in metabolic pathways and inhibiting cell division. Specifically, it is used to treat fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, and chordoma.

[0061] 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, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, Cysadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma,It means having a therapeutic effect on cancers including craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma, and carcinomas arising from breast, prostate, kidney, bladder, or colon tissue; and tumors appearing in adipose tissue such as adipose cell tumors such as lipoma, fibrolipoma, lipoblastoma, lipomatosis, hibemoma, hemangioma, and / or liposarcoma. More specifically, it can be breast cancer, bile duct cancer, gallbladder cancer, pancreatic cancer, colon cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, blood cancer, and liver cancer.

[0062] The pharmaceutical composition of the present invention may additionally contain a component that does not increase the efficacy but is commonly used in pharmaceutical compositions to improve odor, taste, sight, etc. In addition, the pharmaceutical composition of the present invention may additionally contain a pharmaceutically acceptable additive. Pharmaceutically acceptable additives include, but are not limited to, starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, lactose, mannitol, maltose, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, carnauba wax, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, sucrose, dextrose, sorbitol, and talc.

[0063] The incompletely crystalline composition of the present invention may further comprise a pharmaceutically acceptable carrier and be formulated for human or veterinary use, either oral or parenteral. When formulating the pharmaceutical composition of the present invention, in addition to the components listed above, diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants may be used. Solid preparations for oral administration include tablets, pills, powders, granules, and capsules, and these solid preparations may be prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose or lactose, and gelatin mannitol, with a pharmaceutical composition comprising the compound of the present invention. In addition to simple excipients, lubricants such as magnesium stearate and talc may be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives are used. The pharmaceutical composition of the present invention can be administered orally or parenterally depending on the intended method, and in case of parenteral administration, it is preferable to select a method of external application to the skin or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

[0064] The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" as used herein means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment. The effective dosage level may be determined based on factors including the patient's weight, sex, age, health status, severity, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment duration, concurrently used drugs, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. It may be administered singly or in multiple doses. It is important to administer an amount that achieves the maximum effect with the minimum amount without causing side effects by taking all of the above factors into consideration, and this can be easily determined by those skilled in the art.

[0065] For example, the incomplete crystalline composition according to the present invention may be administered at a dosage of 0.0001 to 500 mg / kg, preferably 0.001 to 500 mg / kg, and the administration may be administered once a day to five times a day. Additionally, the administration may be administered once every two days to once every ten days, depending on the purpose.

[0066] Example 1. In a round-bottom flask, 20 g of niclosamide is dissolved in 200 mL of 70% ethanol. 65 g of HPMC is added to the solution, stirred for 1 hour, and the solvent is completely removed through a rotary evaporator to obtain 25 g of niclosamide-HPMC6 powder. 5 g of the niclosamide-HPMC6 powder is mixed with 20 mL of anhydrous ethanol and 2.8 g of MgO, and the mixture is dried in a vacuum oven to obtain a yellow powder.

[0067] Example 2. In a round-bottom flask, 20 g of niclosamide is dissolved in 200 mL of 70% ethanol. 65 g of HPMC is added to the solution, stirred for 1 hour, and the solvent is completely removed through a rotary evaporator to obtain 25 g of niclosamide-HPMC6 powder. 2.8 g of MgO is added to 5 g of the niclosamide-HPMC6 powder, mixed, and a yellow powder is obtained.

[0068] Example 3. In a round-bottom flask, 20 g of niclosamide is dissolved in 200 mL of 70% ethanol. 65 g of HPMC is added to the solution, stirred for 1 hour, and the solvent is completely removed through a rotary evaporator to obtain 25 g of niclosamide-HPMC6 powder. 2.8 g of MgO is added to 5 g of the niclosamide-HPMC6 powder, mixed, and a yellow powder is obtained.

[0069] Example 4. In a round-bottom flask, 20 g of niclosamide was dissolved in 200 mL of 70% ethanol. 1005 g of HPMC was added to the solution, stirred for 1 hour, and the solvent was completely removed through a rotary evaporator to obtain 25 g of niclosamide-HPMC6 powder. 2.8 g of MgO was added to 5 g of the niclosamide-HPMC6 powder, mixed, and a yellow powder was obtained.

[0070] Example 5. In a round-bottom flask, 20 g of niclosamide is dissolved in 200 mL of 70% ethanol. 0.5 g of xanthan gum is added to the solution. After stirring for 1 hour, the solution is completely removed from the solvent through a rotary evaporator to obtain 20.5 g of niclosamide-Xantan gum powder. 2.8 g of MgO is added to 5 g of the niclosamide-Xantan gum powder, mixed, and a yellow powder is obtained.

[0071] Example 6. In a round-bottom flask, 20 g of niclosamide is dissolved in 500 mL of 70% ethanol. 10 g of polyvinylpyrrolidone (PVP K10) is added to the solution. After stirring for 1 hour, the solution is completely removed from the solution using a rotary evaporator to obtain 30 g of niclosamide-PVP powder. 2.8 g of MgO is added to 6 g of the niclosamide-PVP powder, mixed, and a yellow powder is obtained.

[0072] Example 7. In a round-bottom flask, 20 g of niclosamide is dissolved in 500 mL of 70% ethanol. 10 g of polyvinylpyrrolidone (PVP K30) is added to the solution. After stirring for 1 hour, the solution is completely removed from the solution using a rotary evaporator to obtain 30 g of niclosamide-PVP powder. 2.8 g of MgO is added to 6 g of the niclosamide-PVP powder, mixed, and a yellow powder is obtained.

[0073] Example 8. In a round-bottom flask, 20 g of niclosamide is dissolved in 500 mL of 70% ethanol. 80 g of polyvinylpyrrolidone (PVP K30) is added to the solution. After stirring for 1 hour, the solution is completely removed from the solution using a rotary evaporator to obtain 100 g of niclosamide-PVP powder. 2.8 g of MgO is added to 5 g of the niclosamide-PVP powder, mixed, and a yellow powder is obtained.

[0074] Example 9. In a round-bottom flask, 20 g of poloxamer (407) is added to a solution of 20 g of niclosamide dissolved in 100 mL of 70% ethanol, and the solution is stirred for 1 hour. After the solvent is completely removed through a rotary evaporator, 40 g of niclosamide-poloxamer powder is obtained. 2.8 g of MgO is added to 8 g of the niclosamide-poloxamer powder, and mixed to obtain a yellow powder.

[0075] Example 10. In a round-bottom flask, 20 g of polyethylene glycol (PEG400) is added to a solution of 20 g of niclosamide dissolved in 100 mL of 70% ethanol, stirred for 1 hour, and the solvent is completely removed through a rotary evaporator to obtain 40 g of niclosamide-PEG. 2.8 g of MgO is added to 8 g of the niclosamide-PEG, mixed, and a yellow powder is obtained.

[0076] Example 11. In a round-bottom flask, 20 g of polyethylene glycol (PEG4000) is added to a solution of 20 g of niclosamide dissolved in 100 mL of 70% ethanol, stirred for 1 hour, and the solvent is completely removed through a rotary evaporator to obtain 40 g of niclosamide-PVP powder. 2.8 g of MgO is added to 8 g of the niclosamide-PEG, mixed, and a yellow powder is obtained.

[0077] Example 12. In a round-bottom flask, 20 g of dextrin is added to a solution of 20 g of niclosamide dissolved in 100 mL of 70% ethanol, and the solution is stirred for 1 hour. After the solvent is completely removed through a rotary evaporator, 30 g of niclosamide-DEXTRAN powder is obtained. 2.8 g of MgO is added to 8 g of the niclosamide-DEXTRAN, and mixed to obtain a yellow powder.

[0078] Example 13. In a round-bottom flask, 80 g of dextrin is added to a solution of 20 g of niclosamide dissolved in 100 mL of 70% ethanol, stirred for 1 hour, and the solvent is completely removed through a rotary evaporator to obtain 30 g of niclosamide-DEXTRAN powder. 2.8 g of MgO is added to 5 g of the niclosamide-DEXTRAN, mixed, and a yellow powder is obtained.

[0079] Example 14. In a round-bottom flask, 20 g of niclosamide is dissolved in 100 mL of 70% ethanol. 80 g of alginic acid is added to the solution. After stirring for 1 hour, the solution is completely removed from the solvent through a rotary evaporator to obtain 30 g of niclosamide-arginic acid powder. 2.8 g of MgO is added to 5 g of the niclosamide-arginic acid, mixed, and a yellow powder is obtained.

[0080] Example 15. In a round-bottom flask, 20 g of poly-gamma glutamic acid is added to a solution of 20 g of niclosamide dissolved in 100 mL of 70% ethanol, stirred for 1 hour, and the solvent is completely removed through a rotary evaporator to obtain 30 g of niclosamide PGA powder. 2.8 g of MgO is added to 8 g of the niclosamide-PGA, mixed, and a yellow powder is obtained.

[0081] Example 16. In a round-bottom flask, 20 g of mannitol is added to a solution of 20 g of niclosamide dissolved in 100 mL of 70% ethanol, and the solution is stirred for 1 hour. After the solvent is completely removed through a rotary evaporator, 40 g of niclosamide-mannitol powder is obtained. 2.8 g of MgO is added to 8 g of the niclosamide-mannitol, and mixed to obtain a yellow powder.

[0082] Example 17. In a round-bottom flask, 80 g of sorbitol is added to a solution of 20 g of niclosamide dissolved in 100 mL of 70% ethanol, stirred for 1 hour, and the solvent is completely removed through a rotary evaporator to obtain 100 g of niclosamide-sorbitol powder. 2.8 g of MgO is added to 20 g of the niclosamide-sorbitol, mixed, and a yellow powder is obtained.

[0083] Example 18. In a round-bottom flask, 20 g of niclosamide is dissolved in 100 mL of 70% ethanol. 80 g of xylitol is added to the solution. After stirring for 1 hour, the solution is completely removed from the solvent through a rotary evaporator to obtain 100 g of niclosamide-xylitol powder. 2.8 g of MgO is added to 20 g of the niclosamide-xylitol, mixed, and a yellow powder is obtained.

[0084] Example 19. In a round-bottom flask, 20 g of niclosamide is dissolved in 200 mL of 70% ethanol. 5 g of carboxymethyl cellulose (CMC) is added to the solution. After stirring for 1 hour, the solution is completely removed from the solvent using a rotary evaporator to obtain 25 g of niclosamide-CMC powder. 2.8 g of MgO is added to the 5 g of niclosamide-CMC powder, mixed, and a yellow powder is obtained.

[0085] Example 20. In a round-bottom flask, 20 g of niclosamide is dissolved in 200 mL of 70% ethanol. 0.5 g of Eudragit is added to the solution. After stirring for 1 hour, the solution is completely removed from the solvent using a rotary evaporator to obtain 20.5 g of niclosamide-Eudragit powder. 2.8 g of MgO is added to 5 g of the niclosamide-Eudragit powder, and the mixture is mixed to obtain a yellow powder.

[0086] Example 21. 20 g of niclosamide was dissolved in 2 L of 70% ethanol in a round-bottomed flask. 3.5 g of HPMC (6) was added to the solution, stirred with a homogenizer for 1 hour, and the solution was spray-dried at 60°C to obtain 23.5 g of niclosamide-HPMC6 powder. 20 g of MgO (light) and 2.08 g of HPMC (15) were dissolved in anhydrous ethanol and spray-dried to obtain MgO-HPMC (15). 4.7 g of the niclosamide-HPMC (6) powder was mixed with 2.16 g of MgO (H) and 0.265 g of MgO (L)-HPMC (15) to obtain a yellow powder.

[0087] Example 22. 20 g of niclosamide was dissolved in 2 L of 70% ethanol in a round-bottomed flask. 3.5 g of HPMC (6) was added to the solution, stirred with a homogenizer for 1 hour, and the solution was spray-dried at 70°C to obtain 23.5 g of niclosamide-HPMC6 powder. 20 g of MgO (light) and 1.25 g of HPMC (15) were dissolved in anhydrous ethanol and spray-dried to obtain MgO HPMC (15). 4.7 g of the niclosamide-HPMC (6) powder was mixed with 1.6 g of MgO (H) and 0.425 g of MgO (L)-HPMC (15) to obtain a yellow powder.

[0088] Example 23. 20 g of niclosamide was dissolved in 2 L of 70% ethanol in a round-bottomed flask. 3.5 g of HPMC (6) was added to the solution, which was stirred with a homogenizer for 1 hour, and the solution was spray-dried at 80°C to obtain 23.5 g of niclosamide HPMC6 powder. 20 g of MgO (light) and 6.25 g of HPMC (6) were dissolved in anhydrous ethanol and spray-dried to obtain MgO-HPMC (6). 4.7 g of the niclosamide-HPMC (6) powder was mixed with 2.16 g of MgO (H) and 0.315 g of MgO (L) HPMC (6) to obtain a yellow powder.

[0089] Example 24. 20 g of niclosamide was dissolved in 2 L of 70% ethanol in a round-bottomed flask. 3.5 g of HPMC (6) was added to the solution, which was stirred with a homogenizer for 1 hour. The solution was spray-dried at 90°C to obtain 23.5 g of niclosamide HPMC6 powder. 20 g of MgO (light) and 8.33 g of HPMC (6) were dissolved in anhydrous ethanol and spray-dried to obtain MgO-HPMC (6). 4.7 g of the niclosamide-HPMC (6) powder was mixed with 2.16 g of MgO (H) and 0.34 g of MgO (L) HPMC (6) to obtain a yellow powder.

[0090] Example 25. 20 g of niclosamide was dissolved in 2 L of 70% ethanol in a round-bottomed flask. 3.5 g of HPMC (6) was added to the solution, which was stirred with a homogenizer for 1 hour. The solution was spray-dried at 99°C to obtain 23.5 g of niclosamide HPMC6 powder. 20 g of MgO (light) and 5 g of HPMC (6) were dissolved in anhydrous ethanol and spray-dried to obtain MgO-HPMC (6). 1.6 g of MgO (H) and 0.5 g of MgO (L)-HPMC (6) were mixed with 4.7 g of the niclosamide-HPMC (6) powder to obtain a yellow powder.

[0091] Example 26. 20 g of niclosamide was dissolved in 2 L of 70% ethanol in a round-bottomed flask. 5 g of HPMC6 was added to the solution, stirred with a homogenizer for 1 hour, and the solution was spray-dried at 80°C to obtain 25 g of niclosamide-HPMC6 powder. 20 g of MgO (light) and 7.14 g of polyvinylpyrrolidone (PVP-K30) were dissolved in anhydrous ethanol and spray-dried to obtain MgO-PVP. 2.52 g of MgO and 0.28 g of MgO-PVP were mixed with 5 g of the niclosamide-HPMC6 powder to obtain a yellow powder.

[0092] Example 27. 20 g of niclosamide was dissolved in 2 L of 70% ethanol in a round-bottomed flask. 5 g of HPMC6 was added to the solution, stirred with a homogenizer for 1 hour, and the solution was spray-dried at 80°C to obtain 25 g of niclosamide-HPMC6 powder. 20 g of MgO (light) and 8 g of polyvinylpyrrolidone (PVP-K30) were dissolved in anhydrous ethanol and spray-dried to obtain MgO (L)-PVP. 5 g of the niclosamide-HPMC6 powder was mixed with 2.25 g of MgO (H) and 0.25 g of MgO (L)-PVP to obtain a yellow powder.

[0093] Example 28. 20 g of niclosamide was dissolved in 2 L of 70% ethanol in a round-bottomed flask. 5 g of HPMC6 was added to the solution, stirred with a homogenizer for 1 hour, and the solution was spray-dried at 80°C to obtain 25 g of niclosamide-HPMC6 powder. 20 g of MgO (light) and 5 g of polyvinylpyrrolidone (PVP-K30) were dissolved in anhydrous ethanol and spray-dried to obtain MgO (L)-PVP. 1.6 g of MgO (H) and 0.4 g of MgO (L)-PVP were mixed with 5 g of the niclosamide-HPMC6 powder to obtain a yellow powder.

[0094] Example 29. 20 g of niclosamide was dissolved in 2 L of 70% ethanol in a round-bottomed flask. 5 g of HPMC6 was added to the solution, stirred with a homogenizer for 1 hour, and the solution was spray-dried at 80°C to obtain 25 g of niclosamide-HPMC6 powder. 20 g of MgO (light) and 14.28 g of polyvinylpyrrolidone (PVP-K30) were dissolved in anhydrous ethanol and spray-dried to obtain MgO-PVP. 2.52 g of MgO and 0.28 g of MgO-PVP were mixed with 5 g of the niclosamide-HPMC6 powder to obtain a yellow powder.

[0095] Example 30. 20 g of niclosamide was dissolved in 2 L of 70% ethanol in a round-bottomed flask. 5 g of HPMC6 was added to the solution, stirred with a homogenizer for 1 hour, and the solution was spray-dried at 80°C to obtain 25 g of niclosamide HPMC6 powder. 20 g of MgO (light) and 16 g of polyvinylpyrrolidone (PVP-K30) were dissolved in anhydrous ethanol and spray-dried to obtain MgO (L) PVP. 5 g of the niclosamide-HPMC6 powder was mixed with 2.25 g of MgO (H) and 0.25 g of MgO (L)-PVP to obtain a yellow powder.

[0096] Example 31. 20 g of niclosamide was dissolved in 2 L of 70% ethanol in a round-bottomed flask. 5 g of HPMC6 was added to the solution, stirred with a homogenizer for 1 hour, and the solution was spray-dried at 80°C to obtain 25 g of niclosamide-HPMC6 powder. 20 g of MgO (light) and 10 g of polyvinylpyrrolidone (PVP-K30) were dissolved in anhydrous ethanol and spray-dried to obtain MgO (L)-PVP. 1.6 g of MgO (H) and 0.4 g of MgO (L)-PVP were mixed with 5 g of the niclosamide-HPMC6 powder to obtain a yellow powder.

[0097] Example 32. In a round-bottom flask, dissolve 4 g of PVP in 50 mL of absolute ethanol, add 1 g of Docetaxel, and stir for 1 hour. Add 2 g of MgO, and stir for 1 hour. After completely removing the solvent from the solution using a rotary evaporator, obtain a white powder. Example 33. In a round-bottom flask, dissolve 4 g of PVP in 50 mL of absolute ethanol, add 1 g of Docetaxel, and stir for 1 hour. Add 2 g of MgO, and stir for 1 hour. After completely removing the solvent from the solution using a rotary evaporator, obtain a white powder.

[0098] Examples 34 to 43 were manufactured in the same manner as Example 33, except that each component was included in the ratios shown in Table 1 below.

[0099] [Table 1]

[0100]

[0101] Examples 44 to 54 were manufactured in the same manner as Example 33, except that each component was included in the ratios shown in Table 2 below.

[0102] [Table 2]

[0103]

[0104] Examples 56 to 67 were manufactured in the same manner as Example 33, except that each component was included in the ratios shown in Table 3 below.

[0105] [Table 3]

[0106]

[0107] Example 68. In a round-bottom flask, 4 g of PVP was dissolved in 50 mL of absolute ethanol. 1 g of Docetaxel was added. The solution was stirred for 1 hour. 0.875 g of HPMC (6 mPas) and 0.875 g of poloxamer 407 were added. After stirring for 1 hour, the solution was completely removed from the solvent using a rotary evaporator. 2 g of MgO was added to the entire powder obtained, mixed well, and a white powder was obtained.

[0108] Example 69. In a round-bottom flask, 4 g of PVP was dissolved in 50 mL of absolute ethanol. 1 g of Docetaxel was added. The solution was stirred for 1 hour. 0.875 g of HPMC (6 mPas) and 0.875 g of poloxamer 407 were added. After stirring for 1 hour, the solution was completely removed from the solvent using a rotary evaporator. 2.5 g of MgO was added to the entire powder obtained, mixed well, and a white powder was obtained.

[0109] Example 70. In a round-bottom flask, 1 g of Docetaxel is added to a solution of 4 g of PVP dissolved in 50 mL of absolute ethanol. The solution is stirred for 1 hour. 1 g of HPMC (6 mPas) and 1 g of poloxamer 407 are added, the solution is stirred for 1 hour, and the solvent is completely removed from the solution using a rotary evaporator. 3 g of MgO is added to the entire powder obtained, mixed well, and a white powder is obtained.

[0110] Example 71: In a round-bottom flask, 4 g of PVP was dissolved in 50 mL of absolute ethanol. 1 g of Docetaxel was added. The solution was stirred for 1 hour. 0.368 g of PGA (Poly gamma glutamic acid) was added. After stirring for 1 hour, the solution was completely removed from the solvent using a rotary evaporator. 2 g of MgO was added to the entire powder obtained, mixed well, and a white powder was obtained.

[0111] Example 72 In a round-bottom flask, 1 g of Docetaxel is added to a solution of 4 g of PVP dissolved in 50 mL of absolute ethanol. The solution is stirred for 1 hour, then 0.823 g of HPMC (6 mPas) and 0.412 g of PGA (Poly gamma glutamic acid) are added, and the solution is stirred for 1 hour. The solvent is completely removed from the solution using a rotary evaporator. 2 g of MgO is added to the entire powder obtained, mixed well, and a white powder is obtained.

[0112] Example 73 In a round-bottom flask, 1 g of Docetaxel was added to a solution of 4 g of PVP dissolved in 50 mL of absolute ethanol. The solution was stirred for 1 hour. Then, 0.933 g of HPMC (6 mPas), 0.933 g of poloxamer 407, and 0.4467 g of PGA (Poly gamma glutamic acid) were added and stirred for 1 hour. The solution was then subjected to a rotary evaporator to completely remove the solvent. 2 g of MgO was added to the entire powder obtained, mixed well, and a white powder was obtained.

[0113] Example 74: In a round-bottom flask, 4 g of PVP was dissolved in 50 mL of absolute ethanol. 1 g of Docetaxel was added. The solution was stirred for 1 hour. 0.778 g of HPMC (100 mPas) was added. After stirring for 1 hour, the solution was completely removed from the solvent using a rotary evaporator. 2 g of MgO was added to the entire powder obtained, mixed well, and a white powder was obtained.

[0114] Example 75: In a round-bottom flask, 4 g of PVP was dissolved in 50 mL of absolute ethanol. 1 g of Docetaxel was added to the solution. Stirred for 1 hour, 0.875 g of HPMC (100 mPas) and 0.875 g of poloxamer 407 were added, and stirred for 1 hour. The solution was then subjected to a rotary evaporator to completely remove the solvent. 2 g of MgO was added to the entire powder obtained, mixed well, and a white powder was obtained.

[0115] Example 76: In a round-bottom flask, 4 g of PVP was dissolved in 50 mL of absolute ethanol. 1 g of Docetaxel was added to the solution. Stirred for 1 hour, 0.368 g of SDS (sodium dodecyl sulfate) was added, and the solution was stirred for 1 hour. The solvent was completely removed from the solution using a rotary evaporator. 2 g of MgO was added to the entire powder obtained, mixed well, and a white powder was obtained.

[0116] Example 77 In a round-bottom flask, 1 g of Docetaxel is added to a solution of 4 g of PVP dissolved in 50 mL of absolute ethanol. The solution is stirred for 1 hour, 0.823 g of HPMC (6 mPas) and 0.412 g of SDS (sodium dodecyl sulfate) are added, and the solution is stirred for 1 hour. The solvent is completely removed from the solution using a rotary evaporator. 2 g of MgO is added to the entire powder obtained, mixed well, and a white powder is obtained.

[0117] Example 78 In a round-bottom flask, 1 g of Docetaxel is added to a solution of 4 g of PVP dissolved in 50 mL of absolute ethanol. After stirring the solution for 1 hour, 0.933 g of HPMC (6 mPas), 0.933 g of poloxamer 407, and 0.467 g of SDS (sodium dodecyl sulfate) are added, and after stirring for 1 hour, the solution is completely removed from the solvent through a rotary evaporator. 2 g of MgO is added to the entire powder obtained, mixed well, and a white powder is obtained.

[0118] Example 79 In a round-bottom flask, 4 g of PVP was dissolved in 50 mL of absolute ethanol. 1 g of Docetaxel was added. The solution was stirred for 1 hour. 1 g of HPMC (6 mPas), 1 g of poloxamer 407, and 0.5 g of SDS (sodium dodecyl sulfate) were added. After stirring for 1 hour, the solution was completely removed from the solvent using a rotary evaporator. 2.5 g of MgO was added to the entire powder obtained, mixed well, and a white powder was obtained.

[0119] Example 80: In a round-bottom flask, 4 g of PVP was dissolved in 50 mL of absolute ethanol. 1 g of Docetaxel was added to the solution. Stirred for 1 hour, 0.179 g of MMT was added, and the solution was stirred for 1 hour. The solvent was completely removed from the solution using a rotary evaporator. 2 g of MgO was added to the entire powder obtained, mixed well, and a white powder was obtained.

[0120] Example 81. In a round-bottom flask, 4 g of PVP is dissolved in 50 mL of absolute ethanol. 1 g of Docetaxel is added to the solution. Stirred for 1 hour, 0.368 g of MMT is added, and the solution is stirred for 1 hour. The solvent is completely removed from the solution using a rotary evaporator. 2 g of MgO is added to the entire powder obtained, mixed well, and a white powder is obtained.

[0121] Example 82 In a round-bottom flask, 1 g of Docetaxel is added to a solution of 4 g of PVP dissolved in 50 mL of absolute ethanol. After stirring for 1 hour, 0.903 g of HPMC (6 mPas), 0.903 g of poloxamer 407, and 0.226 g of MMT are added, and after stirring for 1 hour, the solution is completely removed from the solvent through a rotary evaporator. 2 g of MgO is added to the entire powder obtained, and after mixing well, a white powder is obtained.

[0122] Example 83. In a round-bottom flask, 1 g of Docetaxel is added to a solution of 4 g of PVP dissolved in 50 mL of absolute ethanol. The solution is stirred for 1 hour, 0.9 g of HPMC (6 mPas) and 0.9 g of poloxamer 407 are added, and the solution is stirred for 1 hour. The solvent is completely removed from the solution using a rotary evaporator to obtain 6.8 g of Docetaxel-PVP-HPMC powder. 2 g of MgO is added to the Docetaxel-PVP-HPMC powder, mixed well, and a white powder is obtained.

[0123] Example 84. In a round-bottom flask, 8 g of niclosamide is dissolved in 100 mL of 70% ethanol. 2 g of HPMC6 is added to the solution, stirred for 3 minutes, and the solvent is completely removed from the solution through a vacuum oven to obtain 11 g of niclosamide-HPMC6 powder. 5 g of the niclosamide-HPMC6 powder and 2.8 g of MgO are added and mixed to obtain a yellow powder.

[0124] Example 85. 12 g of niclosamide is dissolved in 100 mL of 70% ethanol in a round-bottomed flask. 3 g of HPMC6 is added to the solution. After stirring for 3 minutes, the solution is placed in a vacuum oven to completely remove the solvent, thereby obtaining 15 g of niclosamide-HPMC6 powder. 5 g of the niclosamide-HPMC6 powder and 2.8 g of MgO are added and mixed to obtain a yellow powder.

[0125] Example 86. 1.25 g of HPMC6 is added to a solution of 5 g of niclosamide dissolved in 1000 mL of 70% ethanol in a round-bottom flask, stirred for 30 minutes, and the solution is spray dried to obtain 6.25 g of niclosamide-HPMC6 powder. 5 g of the niclosamide HPMC6 powder and 2.8 g of MgO are added and mixed to obtain a yellow powder.

[0126] Example 87. 10 g of niclosamide is dissolved in 1000 mL of 70% ethanol in a round-bottom flask. 2.5 g of HPMC6 is added to the solution. After stirring for 30 minutes, the solution is spray-dried to obtain 12.5 g of niclosamide-HPMC6 powder. 5 g of the niclosamide HPMC6 powder and 2.8 g of MgO are added and mixed to obtain a yellow powder.

[0127] Example 88. 20 g of niclosamide is dissolved in 1000 mL of 70% ethanol in a round-bottomed flask. 5 g of HPMC6 is added to the solution. After stirring for 30 minutes, the solution is spray-dried to obtain 25 g of niclosamide-HPMC6 powder. 5 g of the niclosamide HPMC6 powder and 2.8 g of MgO are added and mixed to obtain a yellow powder.

[0128] Example 90. In a round-bottom flask, 4 g of niclosamide is dissolved in 2 L of 70% ethanol. 3.5 g of HPMC (6) is added to the solution, stirred with a homogenizer for 1 hour, and the solution is spray-dried at 80°C to obtain 23.5 g of niclosamide HPMC6 powder. 2.8 g of MgO (H) is simply dry-mixed with 5 g of the niclosamide-HPMC (6) powder to obtain a yellow powder.

[0129] Example 91 20 g of niclosamide was dissolved in 2 L of 70% ethanol in a round-bottom flask. 3.5 g of HPMC (6) was added to the solution, stirred with a homogenizer for 1 hour, and the solution was spray-dried at 80°C to obtain 23.5 g of niclosamide HPMC6 powder. 2.8 g of MgO (H) was simply dry-mixed with 5 g of the niclosamide-HPMC (6) powder to obtain a yellow powder.

[0130] Example 92 20 g of niclosamide was dissolved in 2 L of 70% ethanol in a round-bottomed flask. 3.5 g of HPMC (6) was added to the solution, stirred with a homogenizer for 1 hour, and the solution was spray-dried at 80°C to obtain 23.5 g of niclosamide HPMC6 powder. 5 g of the niclosamide-HPMC (6) powder was wet-mixed with 2.52 g of MgO (H) and 0.28 g of MgO (L) in anhydrous ethanol to obtain a yellow powder.

[0131] Example 93 7 g of HPMC (6) is added to a solution of 20 g of niclosamide dissolved in 2 L of 70% ethanol in a round-bottomed flask, stirred with a homogenizer for 1 hour, and the solution is spray-dried at 80°C to obtain 27 g of niclosamide-HPMC6 powder. 2.8 g of MgO (H) is simply dry-mixed with 5 g of the niclosamide-HPMC (6) powder to obtain a yellow powder.

[0132] Example 94 7 g of HPMC (6) was added to a solution of 20 g of niclosamide dissolved in 2 L of 70% ethanol in a round-bottomed flask, stirred with a homogenizer for 1 hour, and then the solution was spray-dried at 80°C to obtain 27 g of niclosamide-HPMC6 powder. 2.7 g of MgO (H) and 0.28 g of MgO (L) were wet-mixed with 5 g of the niclosamide-HPMC (6) powder and anhydrous ethanol to obtain a yellow powder.

[0133] Example 95 20 g of niclosamide and 2.5 g of PVP (K30) were dissolved in 2 L of 70% ethanol in a round-bottomed flask. 3.5 g of HPMC (6) was added to the solution, stirred with a homogenizer for 1 hour, and the solution was spray-dried at 80°C to obtain 27 g of niclosamide-HPMC6 powder. 2.8 g of MgO (H) was simply dry-mixed with 5 g of the niclosamide-HPMC (6) powder to obtain a yellow powder.

[0134] Example 96 7 g of HPMC (6) was added to a solution of 20 g of niclosamide and 2.5 g of PVP (K30) dissolved in 2 L of 70% ethanol in a round-bottomed flask, stirred with a homogenizer for 1 hour, and then the solution was spray-dried at 80°C to obtain 29.5 g of niclosamide HPMC6 powder. 5 g of the niclosamide-HPMC (6) powder was wet-mixed with 2.7 g of MgO (H) and 0.28 g of MgO (L) in anhydrous ethanol to obtain a yellow powder.

[0135] Example 97 7 g of HPMC (6) was added to a solution of 20 g of niclosamide and 2.5 g of PVP (K30) dissolved in 2 L of 70% ethanol in a round-bottomed flask, stirred with a homogenizer for 1 hour, and then the solution was spray-dried at 80°C to obtain 29.5 g of niclosamide HPMC6 powder. 2.8 g of MgO (H) was wet-mixed with 5 g of the niclosamide-HPMC (6) powder and anhydrous ethanol to obtain a yellow powder.

[0136] Example 98 4 g of niclosamide is added to a solution of 0.27 g of HPMC (6) and 200 mL of 80% ethanol in a beaker, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.014 g of Eudragit (EPO) are dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-Eudragit. 4.27 g of the niclosamide-HPMC (6) powder and MgO-Eudragit are mixed to obtain a yellow powder.

[0137] Example 99 4 g of niclosamide is added to a solution of 0.27 g of HPMC (6) and 200 mL of 80% ethanol in a beaker, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.027 g of Eudragit (EPO) are dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-Eudragit. 4.27 g of the niclosamide-HPMC (6) powder and MgO-Eudragit are mixed to obtain a yellow powder.

[0138] Example 100 In a beaker, 0.27 g of HPMC (6) and 200 mL of 80% ethanol are dissolved. 4 g of niclosamide is added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.068 g of HPMC (6) are dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-HPMC (6). 4.27 g of the niclosamide-HPMC (6) powder is mixed with MgO-HPMC (6) to obtain a yellow powder.

[0139] Example 101 In a beaker, 0.27 g of HPMC (6) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.135 g of HPMC (6) were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-HPMC (6). 4.27 g of the niclosamide-HPMC (6) powder and MgO-HPMC (6) were mixed to obtain a yellow powder.

[0140] Example 102 In a beaker, 0.27 g of HPMC (6) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.014 g of MCT oil were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-MCT. 4.27 g of the niclosamide-HPMC (6) powder and MgO-MCT were mixed to obtain a yellow powder.

[0141] Example 103 In a beaker, 0.27 g of HPMC (6) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.027 g of MCT oil were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-MCT. 4.27 g of the niclosamide-HPMC (6) powder and MgO-MCT were mixed to obtain a yellow powder.

[0142] Example 104 In a beaker, 0.27 g of HPMC (6) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.014 g of HPC (Hydroxypropylcellulose) were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-HPC. 4.27 g of the niclosamide-HPMC (6) powder and MgO-HPC were mixed to obtain a yellow powder.

[0143] Example 105 In a beaker, 0.27 g of HPMC (6) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC6 powder. 2.8 g of MgO and 0.027 g of HPC (Hydroxypropylcellulose) were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-HPC. 4.27 g of the niclosamide-HPC powder and MgO-HPC were mixed to obtain a yellow powder.

[0144] Example 106 In a beaker, 0.27 g of HPMC (6) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.014 g of caster oil were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-Caster. 4.27 g of the niclosamide HPMC (6) powder and MgO-Caster were mixed to obtain a yellow powder.

[0145] Example 107 In a beaker, 0.27 g of HPMC (6) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.027 g of caster oil were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-Caster. 4.27 g of the niclosamide-HPMC (6) powder and MgO-Caster were mixed to obtain a yellow powder.

[0146] Example 108 In a beaker, 0.27 g of HPMC (6) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.014 g of TPGS (Tocopeherol polyethylene glycol sucunate) were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-TPGS. 4.27 g of the niclosamide-HPMC (6) powder and MgO-TPGS were mixed to obtain a yellow powder.

[0147] Example 109 In a beaker, 0.27 g of HPMC (6) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.027 g of TPGS (Tocopeherol polyethylene glycol sucunate) were dissolved in anhydrous ethanol, and vacuum-dried to obtain MgO-TPGS. 4.27 g of the niclosamide-HPMC (6) powder and MgO-TPGS were mixed to obtain a yellow powder.

[0148] Example 110 In a beaker, 0.27 g of HPMC (6) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.014 g of PVP (Polyvinylpyrrolidone) were dissolved in anhydrous ethanol, and then vacuum-dried to obtain MgO-PVP. 4.27 g of the niclosamide-HPMC (6) powder and MgO-PVP were mixed to obtain a yellow powder.

[0149] Example 111 In a beaker, 0.27 g of HPMC (6) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC6 powder. 2.8 g of MgO and 0.027 g of PVP (Polyvinylpyrrolidone) were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-PVP. 4.27 g of the niclosamide-HPMC (6) powder and MgO-PVP were mixed to obtain a yellow powder.

[0150] Example 112 In a beaker, 4 g of niclosamide is added to a solution of 0.27 g of HPMC (6) and 200 mL of 80% ethanol, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.014 g of soybean oil are dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-soy. 4.27 g of the niclosamide HPMC (6) powder and MgO-soy are mixed to obtain a yellow powder.

[0151] Example 113 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.027 g of soybean oil were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-soy. 4.27 g of the niclosamide HPMC (6) powder and MgO-soy were mixed to obtain a yellow powder.

[0152] Example 114 In a beaker, 0.27 g of HPMC (6) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.014 g of lecithin were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-lecithin. 4.27 g of the niclosamide-HPMC (6) powder and MgO-lecithin were mixed to obtain a yellow powder.

[0153] Example 115 In a beaker, 0.27 g of HPMC (6) and 200 mL of 80% ethanol are dissolved. 4 g of niclosamide is added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (6) powder. 2.8 g of MgO and 0.027 g of lecithin are dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-lecithin. 4.27 g of the niclosamide-HPMC (6) powder and MgO-lecithin are mixed to obtain a yellow powder.

[0154] Example 116 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.014 g of Eudragit (EPO) were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-Eudragit. 4.27 g of the niclosamide-HPMC (3) powder and MgO-Eudragit were mixed to obtain a yellow powder.

[0155] Example 117 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.027 g of Eudragit (EPO) were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-Eudragit. 4.27 g of the niclosamide-HPMC (3) powder and MgO-Eudragit were mixed to obtain a yellow powder.

[0156] Example 118 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol are dissolved. 4 g of niclosamide is added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.068 g of HPMC (3) are dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-HPMC (6). 4.27 g of the niclosamide-HPMC (3) powder is mixed with MgO-HPMC (3) to obtain a yellow powder.

[0157] Example 119 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol are dissolved. 4 g of niclosamide is added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.135 g of HPMC (3) are dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-HPMC (6). 4.27 g of the niclosamide-HPMC (3) powder and MgO-HPMC (3) are mixed to obtain a yellow powder.

[0158] Example 120 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol are dissolved. 4 g of niclosamide is added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.014 g of MCT oil are dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-MCT. 4.27 g of the niclosamide-HPMC (3) powder and MgO-MCT are mixed to obtain a yellow powder.

[0159] Example 121 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.027 g of MCT oil were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-MCT. 4.27 g of the niclosamide-HPMC (3) powder and MgO-MCT were mixed to obtain a yellow powder.

[0160] Example 122 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.014 g of HPC (Hydroxypropylcellulose) were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-HPC. 4.27 g of the niclosamide-HPMC (3) powder and MgO-HPC were mixed to obtain a yellow powder.

[0161] Example 123 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.027 g of HPC (Hydroxypropylcellulose) were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-HPC. 4.27 g of the niclosamide-HPMC (3) powder and MgO-HPC were mixed to obtain a yellow powder.

[0162] Example 124 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.014 g of caster oil were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-Caster. 4.27 g of the niclosamide HPMC (3) powder and MgO-Caster were mixed to obtain a yellow powder.

[0163] Example 125 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.027 g of caster oil were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-Caster. 4.27 g of the niclosamide-HPMC (3) powder and MgO-Caster were mixed to obtain a yellow powder.

[0164] Example 126 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.014 g of TPGS (Tocopeherol polyethylene glycol sucunate) were dissolved in anhydrous ethanol, and then vacuum-dried to obtain MgO-TPGS. 4.27 g of the niclosamide-HPMC (3) powder and MgO-TPGS were mixed to obtain a yellow powder.

[0165] Example 127 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.027 g of TPGS (Tocopeherol polyethylene glycol sucunate) were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-TPGS. 4.27 g of the niclosamide-HPMC (3) powder and MgO-TPGS were mixed to obtain a yellow powder.

[0166] Example 128 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.014 g of PVP (Polyvinylpyrrolidone) were dissolved in anhydrous ethanol, and then vacuum-dried to obtain MgO-PVP. 4.27 g of the niclosamide-HPMC (3) powder and MgO-PVP were mixed to obtain a yellow powder.

[0167] Example 129 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol are dissolved. 4 g of niclosamide is added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.027 g of PVP (Polyvinylpyrrolidone) are dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-PVP. 4.27 g of the niclosamide-HPMC (3) powder and MgO-PVP are mixed to obtain a yellow powder.

[0168] Example 130 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.014 g of soybean oil were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-soy. 4.27 g of the niclosamide HPMC (3) powder and MgO-soy were mixed to obtain a yellow powder.

[0169] Example 131 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol were dissolved. 4 g of niclosamide was added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.027 g of soybean oil were dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-soy. 4.27 g of the niclosamide HPMC (3) powder and MgO-soy were mixed to obtain a yellow powder.

[0170] Example 132 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol are dissolved. 4 g of niclosamide is added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.014 g of lecithin are dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-lecithin. 4.27 g of the niclosamide-HPMC (3) powder and MgO-lecithin are mixed to obtain a yellow powder.

[0171] Example 133 In a beaker, 0.27 g of HPMC (3) and 200 mL of 80% ethanol are dissolved. 4 g of niclosamide is added to the solution, stirred for 2 minutes, and vacuum-dried to obtain 4.27 g of niclosamide HPMC (3) powder. 2.8 g of MgO and 0.027 g of lecithin are dissolved in anhydrous ethanol and vacuum-dried to obtain MgO-lecithin. 4.27 g of the niclosamide-HPMC (3) powder and MgO-lecithin are mixed to obtain a yellow powder.

[0172] Example 134 In a beaker, 1 g of HPMC6 is added to a solution of 4 g of niclosamide dissolved in 200 mL of 80% ethanol, and the solution is stirred for 1 hour. The solution is dried in a vacuum oven to completely remove the solvent, and 5.8 g of niclosamide-HPMC6 powder is obtained. 9.3 g of MgO is added to the 5.8 g of niclosamide HPMC6 powder, and mixed to obtain a yellow powder.

[0173] Example 135 In a beaker, 1 g of HPMC6 is added to a solution of 4 g of niclosamide dissolved in 200 mL of 80% ethanol, and the solution is stirred for 1 hour. The solution is dried in a vacuum oven to completely remove the solvent, and 5.8 g of niclosamide-HPMC6 powder is obtained. (LOD 1.4%) 9.3 g of MgO is added to 5.8 g of the niclosamide-HPMC6 powder, and mixed to obtain a yellow powder.

[0174] Example 136 In a beaker, 1 g of HPMC6 is added to a solution of 4 g of niclosamide dissolved in 200 mL of 80% ethanol, and stirred for 1 hour. The solution is dried in a vacuum oven to completely remove the solvent, and 5.8 g of niclosamide-HPMC6 powder is obtained. (LOD 1.8%) 9.3 g of MgO is added to 5.8 g of the niclosamide-HPMC6 powder, and mixed to obtain a yellow powder.

[0175] Example 137 In a beaker, 0.36 g of HPMC6 is added to a solution of 4 g of niclosamide dissolved in 200 mL of 80% ethanol, and the solution is stirred for 1 hour. The solution is dried in a vacuum oven to completely remove the solvent, thereby obtaining 4.36 g of niclosamide-HPMC6 powder. 1.87 g of MgO is added to 5.8 g of the niclosamide-HPMC6 powder, and mixed to obtain a yellow powder.

[0176] Example 138 In a round-bottom flask, 4 g of niclosamide is dissolved in 200 mL of 80% ethanol. 0.36 g of HPMC6 is added to the solution, stirred for 1 hour, and the solution is dried in a vacuum oven to completely remove the solvent, yielding 4.36 g of niclosamide-HPMC6 powder. 1.87 g of MgO is added to 5.8 g of the niclosamide-HPMC6 powder, mixed, and a yellow powder is obtained.

[0177] Example 139 In a round-bottom flask, 4 g of niclosamide is dissolved in 200 mL of 80% ethanol. 0.36 g of HPMC2000 is added to the solution, stirred for 1 hour, and the solution is dried in a vacuum oven to completely remove the solvent, yielding 4.36 g of niclosamide-HPMC2000 powder. 1.87 g of MgO is added to 5.8 g of the niclosamide-HPMC2000 powder, mixed, and a yellow powder is obtained.

[0178] Example 140. 4 g of niclosamide and 0.2 g of hpmc6 are added to 100 ml of 70% ethanol, stirred for 3 minutes, and then dried in a vacuum oven. The dried niclosamide-hpmc6 mixture is mixed with 1.86 g of CaO and then dried.

[0179] Example 141. 4 g of niclosamide and 0.2 g of hpmc6 are added to 100 ml of 70% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried niclosamide-hpmc6 mixture is mixed with 1.86 g of magnesium silicate and then dried.

[0180] Example 142. 4 g of niclosamide and 0.2 g of hpmc6 are added to 100 ml of 70% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried niclosamide-hpmc6 mixture is mixed with 1.86 g of Ca-silicate, and then dried.

[0181] Example 143 Preparation: 4 g of niclosamide and 0.1 g of hpmc6 are added to 100 ml of 50% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0182] Example 144 Preparation: 4 g of niclosamide and 0.4 g of hpmc6 are added to 100 ml of 50% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0183] Example 145 Preparation: Add 4 g of niclosamide and 0.4 g of hpmc6 to 10 ml of 90% ethanol solution, stir for 3 minutes, and dry.

[0184] Example 146 Preparation: Add 4 g of niclosamide and 0.4 g of hpmc6 to 100 ml of 90% ethanol solution, stir for 3 minutes, and dry.

[0185] Example 147 Preparation: 4 g of niclosamide and 0.4 g of hpmc6 are added to 100 ml of 20% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0186] Example 148 Preparation: 4 g of niclosamide and 0.4 g of hpmc6 are added to 100 ml of 50% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0187] Example 149 Preparation: 4 g of niclosamide and 0.4 g of hpmc6 are added to 100 ml of 80% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0188] Example 150 Preparation: 4 g of niclosamide and 0.4 g of hpmc6 are added to 100 ml of 90% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0189] Example 151 Preparation: 4 g of niclosamide and 0.1 g of hpmc50 are added to 100 ml of 50% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0190] Example 152 Preparation: 4 g of niclosamide and 0.4 g of CMC are added to 100 ml of 50% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0191] Example 153 Preparation: 4 g of niclosamide and 0.36 g of hpmc100 are added to 100 ml of 50% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0192] Example 154 Preparation: 4 g of niclosamide and 0.27 g of hpmc3 are added to 100 ml of 50% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0193] Example 155 Preparation: 4 g of niclosamide and 0.36 g of SMCC are added to 100 ml of 50% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0194] Example 156 Preparation: 4 g of niclosamide and 0.36 g of hpmc15 are added to 100 ml of 50% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0195] Example 157 Preparation: 4 g of niclosamide and 0.53 g of hpmc6 are added to 100 ml of 50% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of Ca-sililcate in anhydrous ethanol, and then dried to obtain a compound.

[0196] Example 158 Preparation: 4 g of niclosamide and 0.27 g of hpmc6 are added to 100 ml of 50% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of Mg-sililcate in anhydrous ethanol, and then dried to obtain a compound.

[0197] Example 159 Preparation: 4 g of niclosamide and 0.1 g of hpmc3 are added to 100 ml of 50% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of MgCO3 in anhydrous ethanol, and then dried to obtain a compound.

[0198] Example 160 Preparation: 4 g of niclosamide and 0.2 g of hpmc3 are added to 100 ml of 50% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaCO3 in anhydrous ethanol, and then dried to obtain a compound.

[0199] Example 161 Preparation: 4 g of niclosamide and 0.1 g of Eudragit EPO are added to 100 ml of 80% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.3 g of magnesium silicate in anhydrous ethanol, and then dried to obtain a compound.

[0200] Example 162 Preparation: 4 g of niclosamide and 0.1 g of Eudragit L100 are added to 100 ml of 80% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.3 g of Mg-silicate in anhydrous ethanol, and then dried to obtain the product.

[0201] Example 163 Preparation: 4 g of niclosamide and 0.1 g of Eudragit L100-55 are added to 100 ml of 80% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.3 g of Mg-silicate in anhydrous ethanol, and then dried to obtain the product.

[0202] Example 164 Preparation: 4 g of niclosamide and 0.1 g of Eudragit S100 are added to 100 ml of 80% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of Mg-sililcate in anhydrous ethanol, and then dried to obtain the product.

[0203] Example 165 Manufacturing: Dissolve 4 g of polyvinylpyrrolidone (PVP-K30), 0.1 g of hydroxypropyl cellulose (HPC), 0.875 g of poloxamer (poloxamer 407), and 0.2 g of hypromellose (HPMC6) in 100 ml of absolute ethanol by stirring. Then, add 1 g of paclitaxel to dissolve and dry in a vacuum oven. Mix 2 g of magnesium oxide (MgO) with the dried mixture and dry.

[0204] Example 166 Manufacturing: Dissolve 4 g of polyvinylpyrrolidone (PVP-K30), 0.1 g of hydroxypropyl cellulose (HPC), 0.875 g of poloxamer (poloxamer 407), 0.2 g of hypromellose (HPMC6), and 0.01 g of tocopherol polyethylene glycol succinate (TPGS) in 100 ml of absolute ethanol by stirring. Then, add 1 g of paclitaxel to dissolve and dry in a vacuum oven. Mix 2 g of magnesium oxide (MgO) with the dried mixture and dry.

[0205] Example 167 Preparation: 4 g of polyvinylpyrrolidone (PVP-K30), 0.1 g of hydroxypropyl cellulose (HPC), 0.4 g of poloxamer (poloxamer 407), 0.2 g of hypromellose (HPMC6), and 0.4 g of poloxamer (poloxamer 188) are stirred to dissolve in 100 ml of absolute ethanol, then 1 g of paclitaxel is added to dissolve and dried in a vacuum oven. 1.5 g of magnesium oxide (MgO) is mixed with the dried mixture and then dried.

[0206] Example 168 Manufacturing: Dissolve 4 g of polyvinylpyrrolidone (PVP-K30), 0.1 g of hydroxypropyl cellulose (HPC), 0.2 g of hypromellose (HPMC6), and 0.4 g of poloxamer (poloxamer 188) in 100 ml of absolute ethanol by stirring. Then, add 1 g of paclitaxel to dissolve and dry in a vacuum oven. Mix 1.5 g of magnesium oxide (MgO) with the dried mixture and dry.

[0207] Example 169 Manufacturing: Dissolve 4 g of polyvinylpyrrolidone (PVP-K30), 0.2 g of hydroxypropyl cellulose (HPC), and 0.875 g of poloxamer (poloxamer 407) in 100 ml of absolute ethanol by stirring, then add 1 g of paclitaxel to dissolve, and dry in a vacuum oven. Mix 2 g of magnesium oxide (MgO) with the dried mixture, and dry.

[0208] Example 170 Manufacturing: Dissolve 4 g of polyvinylpyrrolidone (PVP-K30), 0.2 g of hydroxypropyl cellulose (HPC), 0.875 g of poloxamer (poloxamer 407), and 0.01 g of tocopherol polyethylene glycol succinate (TPGS) in 100 ml of absolute ethanol by stirring. Then, add 1 g of paclitaxel to dissolve and dry in a vacuum oven. Mix 2 g of magnesium oxide (MgO) with the dried mixture and dry.

[0209] Example 171 Manufacturing: 4 g of polyvinylpyrrolidone (PVP-K30), 0.2 g of hydroxypropyl cellulose (HPC), 0.4 g of poloxamer (poloxamer 407), and 0.4 g of poloxamer (poloxamer 188) are stirred to dissolve in 100 ml of absolute ethanol, then 1 g of paclitaxel is added to dissolve and dried in a vacuum oven. 1.5 g of magnesium oxide (MgO) is mixed with the dried mixture and then dried.

[0210] Example 172 Manufacturing: Dissolve 4 g of polyvinylpyrrolidone (PVP-K30), 0.2 g of hydroxypropyl cellulose (HPC), and 0.4 g of poloxamer (poloxamer 188) in 100 ml of absolute ethanol by stirring, then add 1 g of paclitaxel to dissolve, and dry in a vacuum oven. Mix 1.5 g of magnesium oxide (MgO) with the dried mixture, and dry.

[0211] Example 173 Preparation: 1 g of paclitaxel and 0.1 g of hpmc6 are added to 100 ml of 90% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0212] Example 174 Manufacturing: 1 g of paclitaxel and 0.1 g of hpmc100 are added to 100 ml of 90% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0213] Example 175 Preparation: 1 g of paclitaxel and 60.1 g of hpmc are added to 100 ml of 90% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of Ca-silicate in anhydrous ethanol, and then dried to obtain a compound.

[0214] Example 176 Preparation: 1 g of paclitaxel and 0.1 g of hpmc6 are added to 100 ml of 90% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of Mg-silicate in anhydrous ethanol, and then dried to obtain a compound.

[0215] Example 177 (OAD) Preparation: Dissolve 4 g of polyvinylpyrrolidone (PVP-K30), 0.1 g of hydroxypropyl cellulose (HPC), 0.875 g of poloxamer (poloxamer 407), and 0.2 g of hypromellose (HPMC6) in 100 ml of absolute ethanol by stirring. Then, add 1 g of docetaxel, dissolve, and dry in a vacuum oven. Mix 2 g of magnesium oxide (MgO) with the dried mixture, and dry.

[0216] Example 178 Manufacturing: Add 1 g of docetaxel and 0.1 g of hpmc6 to 100 ml of 90% ethanol, stir for 3 minutes, and dry in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0217] Example 179 Manufacturing: Add 1 g of docetaxel and 0.1 g of hpmc100 to 100 ml of 90% ethanol, stir for 3 minutes, and dry in a vacuum oven. The dried mixture is mixed with 1.86 g of CaO in anhydrous ethanol, and then dried to obtain a compound.

[0218] Example 180 Preparation: Add 1 g of docetaxel and 60.1 g of hpmc to 100 ml of 90% ethanol, stir for 3 minutes, and dry in a vacuum oven. The dried mixture is mixed with 1.86 g of Ca-silicate in anhydrous ethanol, and then dried to obtain a compound.

[0219] Example 181 Preparation: Add 1 g of docetaxel and 0.1 g of hpmc6 to 100 ml of 90% ethanol, stir for 3 minutes, and dry in a vacuum oven. The dried mixture is mixed with 1.86 g of Mg-silicate in anhydrous ethanol, and then dried to obtain a compound.

[0220] Reference Example 1 In a beaker, 1 g of HPMC6 and 2.8 g of MgO are added to a solution of 4 g of niclosamide dissolved in 200 mL of 80% ethanol, stirred to mix, and dried in a vacuum oven to obtain a powder.

[0221] Reference Example 2 In a round-bottom flask, 4 g of niclosamide is dissolved in 200 mL of 80% ethanol. 1 g of HPMC6 and 1.9 g of MgO are added to the solution, stirred, mixed, and dried in a vacuum oven to obtain a powder.

[0222] Reference Example 3: In a speed mixer, add 0.5 g of HPMC6 and 2.8 g of MgO to a solution of 4 g of niclosamide dissolved in 200 mL of 70% ethanol, mix, and dry in a vacuum oven to obtain a powder.

[0223] Comparative Example 1. In a round-bottom flask, 20 g of niclosamide was dissolved in 200 mL of 70% ethanol. 5 g of HPMC6 and 2.8 g of MgO were added to the solution, mixed, and dried in a vacuum oven to obtain a powder.

[0224] Comparative Example 2. In a speed mixer, add 5 g of HPMC6 and 2.8 g of MgO to a solution of 20 g of niclosamide dissolved in 500 mL of 70% ethanol, mix, and dry in a vacuum oven to obtain a powder.

[0225] Comparative Example 3. In a round-bottom flask, add 65 g of HPMC and 2.8 g of MgO to a solution of 20 g of niclosamide dissolved in 200 mL of 70% ethanol, mix, and dry in a vacuum oven to obtain a powder.

[0226] Comparative Example 4. In a round-bottom flask, 20 g of niclosamide is dissolved in 500 mL of 70% ethanol. 10 g of PVP and 12 g of MgO are added to the solution, mixed, and dried in a vacuum oven to obtain a powder.

[0227] Comparative Example 5. In a round-bottom flask, 20 g of niclosamide was dissolved in 500 mL of 70% ethanol. 10 g of dextrin and 12 g of MgO were added to the solution, mixed, and dried in a vacuum oven to obtain a powder.

[0228] Comparative Example 6 Doxetaxel 100 wt%

[0229] Comparative Example 7. Add 8g of niclosamide, 2g of HPMC6, 5.6g of MgO, and 100ml of 70% ethanol solution to a beaker, stir for 10 minutes, and then completely remove the solvent through a vacuum oven to obtain a powder.

[0230] Comparative Example 8. Add zirconium balls, 40 g of niclosamide, 10 g of HPMC6, and 28 g of MgO to a reactor and ball mill at 250 rpm for 10 minutes. Add a 10 ml solution of 70% ethanol and ball mill for 15 minutes. Then, completely remove the solvent from the reactant through a vacuum oven to obtain a powder.

[0231] Comparative Example 9: 20 g of niclosamide jet-milled in a speed mixer is dissolved in 7 mL of ethanol and 3 mL of distilled water. 5 g of HPMC6 and 2.8 g of MgO are added to the solution, mixed, and dried in a vacuum oven to obtain a powder.

[0232] Comparative Example 10 Preparation: Add 4 g of niclosamide and 1.86 g of CaO to 100 ml of a 50% ethanol solution (ethanol 5:water 5), stir for 3 minutes, and dry. Wet mix 0.2 g of hpmc6 into the dried niclosamide-CaO mixture, and then dry.

[0233] Comparative Example 11 Manufacturing: Add 4 g of niclosamide, 0.4 g of hpmc6, and 1.86 g of CaO to 100 ml of a 50% ethanol solution (ethanol 5:water 5), stir for 3 minutes, and then dry.

[0234] Comparative Example 12 Manufacturing: 4 g of niclosamide and 0.4 g of hpmc6 are ball milled for 10 minutes. Add to 0.8 ml of a 50% ethanol solution (ethanol 5:water 5), ball milled for 5 minutes, and then dried.

[0235] Comparative Example 13 Preparation: 4 g of niclosamide and 0.1 g of hpmc50 are added to 10 ml of 50% ethanol, stirred for 3 minutes, and dried in a vacuum oven. The dried mixture is mixed with 1.86 g of CaCO3 in anhydrous ethanol, and then dried to obtain a solution.

[0236] Comparative Example 14: Paclitaxel raw material.

[0237] Experimental Example 1: In-vivo pharmacokinetic analysis of the compositions of the examples and comparative examples (hamster or rat)

[0238] In vivo pharmacokinetic analysis was performed using the compositions of Examples 1 and 2 and Comparative Examples 1 and 2. The compositions of Examples 1 and 2 and Comparative Examples 1 and 2 were administered orally to rats as a single dose, and plasma drug concentration information was obtained after the administration. In addition, the compositions of Examples 1 and 2 and the compositions of Comparative Examples 1 and 2 were each administered orally at a dose of 100 mg / kg, and the results are shown in Tables 4 and 5 and Figures 1 and 2.

[0239] [Table 4]

[0240]

[0241] [Table 5]

[0242]

[0243] Comparative examples 1 and 2 were performed by putting niclosamide, HPMC6, and MgO all into a solvent at the same time, and examples 1 and 2 were performed by dissolving niclosamide and HPMC6 in a solvent, drying them, and then mixing them with MgO. As a result, cmax increased by up to 7 times and AUC increased by up to 9 times.

[0244] Experimental Example 2: In-vivo pharmacokinetic analysis of the compositions of Examples 3 to 11 and Comparative Examples 3 and 4 (rat)

[0245] In vivo pharmacokinetic analysis was performed using the compositions of Examples 3 to 11 and Comparative Examples 3 and 4. The compositions of Examples 3 to 11 and Comparative Examples 3 and 4 were administered orally to rats as a single dose, and plasma drug concentration information was obtained after the administration in this manner.

[0246] In addition, experiments were conducted by orally administering the compositions of Examples 3 to 11 and Comparative Examples 3 and 4 at a dose of 100 mg / kg, respectively, and the results are shown in Table 6 and Figure 3.

[0247] [Table 6]

[0248]

[0249] * AUC: ng·h / mL, Cmax: ng / mL, Tmax& t1 / 2: h

[0250] Experimental Example 3: In-vivo pharmacokinetic analysis of the compositions of Examples 12 to 20 and Comparative Example 5 (rat)

[0251] In vivo pharmacokinetic analysis was performed using the compositions of Examples 12 to 20 and Comparative Example 5. The compositions of Examples 12 to 20 and Comparative Example 5 were administered orally to rats as a single dose, and plasma drug concentration information was obtained after administration in this manner.

[0252] In addition, experiments were conducted by administering the compositions of Examples 12 to 20 and Comparative Example 5 at a dose of 100 mg / kg, and the results are shown in Table 7 and Figure 4.

[0253] [Table 7]

[0254]

[0255] * AUC: ng·h / mL, Cmax: ng / mL, Tmax& t1 / 2: h

[0256] Experimental Example 5: In-vivo pharmacokinetic analysis of the compositions of Examples 34 to 82 and Comparative Example 6 (rat)

[0257] In vivo pharmacokinetic analysis was performed using the compositions of Examples 34 to 82 and Comparative Example 6. The compositions of Examples 34 to 82 and Comparative Example 6 were administered orally to rats as a single dose to obtain plasma drug concentration information. The results are shown in Tables 8 to 12 and Fig. 5.

[0258] In addition, experiments were conducted by administering the drugs of Examples 34 to 82 and Comparative Example 6 at a dose of 50 mg / kg each.

[0259] The graphs in Figures 9 and 10 show the concentration of docetaxel in plasma over time in rats, measured by collecting blood at intervals of 0 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, and 12 hr. Specific pharmacokinetic parameters are described in Tables 5 and 7 to 9 below, and the relationship between the tested composition and AUC is shown in Figure 11.

[0260] As a result of the experiment, it was confirmed that when docetaxel is formulated using PVP, HPMC, poloxamer, alginate, poly-gamma glutamic acid, sodium dodecyl sulfate, and PEG1400, the pharmacokinetic effect is improved by at least 2 times compared to the effect when docetaxel is administered orally. In addition, when used together with MgO or MMT, the AUC value is improved by at least 10 times, and the Cmax value can also be improved by more than 10 times. This can be confirmed immediately by numerically comparing the result values ​​of Comparative Example 6 with the result values ​​of the Examples.

[0261] The above experiment clearly confirmed that docetaxel, which has anticancer properties, can also exhibit drug efficacy in oral formulation. Specifically, docetaxel is currently the most widely used second-generation taxoid anticancer agent for breast, stomach, and lung cancers. The currently commercially available product using docetaxel is Taxotere® (Sanofi-Aventis Korea), an injection containing docetaxel and Tween 80, which is typically dissolved in distilled water for injection containing ethanol. However, this product exhibits serious side effects due to the drug itself and the solvent, and in particular, fatal side effects such as hypersensitivity and fluid retention due to the solvent. To overcome this, oral anticancer agents are being developed. However, the low blood concentration of docetaxel after oral administration is due to the drug's very poor solubility and body permeability. Consequently, most anticancer agents, especially taxoids (paclitaxel and docetaxel) with excellent anticancer properties, are very difficult to oral bioavailable. More specifically, anticancer drugs of the taxoid series have little absorption / interaction in the gastrointestinal (GI) tract. In the case of the present invention, it was experimentally confirmed that by increasing the blood concentration of the drug after oral administration of the above-mentioned poorly soluble substance, the exposure of the drug to the body is increased, thereby enabling anticancer / antiviral / anti-inflammatory treatment.

[0262] Therefore, the present invention not only improves convenience and ease of use by formulating poorly soluble drugs for oral administration, but also reduces drug costs. Furthermore, while injectable drugs require administration under the supervision of a physician or nurse, oral administration improves their utility by enabling outpatient or at-home administration.

[0263]

[0264] [Table 8]

[0265]

[0266] * AUC: ng·h / mL, Cmax: ng / mL,Tmax& t1 / 2: h ** NC: Not Calculated

[0267] [Table 9]

[0268]

[0269] * AUC: ng·h / mL, Cmax: ng / mL,Tmax& t1 / 2: h ** NC: Not Calculated

[0270] [Table 10]

[0271]

[0272] * AUC: ng·h / mL, Cmax: ng / mL,Tmax& t1 / 2: h ** NC: Not Calculated

[0273] [Table 11]

[0274]

[0275] * AUC: ng·h / mL, Cmax: ng / mL,Tmax& t1 / 2: h ** NC: Not Calculated

[0276] [Table 12]

[0277]

[0278] *Data are represented as the mean concentration (n=3)

[0279] *Plasma concentration: ng / mL

[0280] *ND: not detected, BQL: below quantitative limit (< 0.05 ng / mL)

[0281] Experimental Example 5: In-vivo pharmacokinetics of the compositions of Example 83 and Comparative Example 6

[0282] (pharmacokinetic) analysis (beagle)

[0283] In vivo pharmacokinetic analyses were performed using the compositions of Example 83 and Comparative Example 6. The compositions of Example 83 and Comparative Example 6 were administered orally to beagles as a single dose, and plasma drug concentration information was obtained. The results are presented in Tables 13, 14, and Figures 12 and 13 below.

[0284] In addition, the composition of Example 83 and the drug of Comparative Example 6 were administered at a dose of 50 mg / kg each to conduct the experiment.

[0285] The graph in Fig. 6 shows the concentration of docetaxel in the plasma over time in beagles, which was determined by collecting blood at intervals of 0 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, and 8 hr. Specific pharmacokinetic parameters are listed in Table 12 and Fig. 6 below, and the relationship between the tested composition and AUC is shown in Table 13 and Fig. 7. As a result of the experiment, it was confirmed that when docetaxel is formulated using compounds such as PVP, HPMC, and MgO, the pharmacokinetic effect is improved by at least 100 times compared to the effect when docetaxel is administered orally. This can be confirmed immediately by numerically comparing the results of Comparative Example 6 and Example 83. From the above experiment, it was confirmed that docetaxel, which has an anticancer effect, can exhibit drug efficacy even in an oral formulation. In particular, it was confirmed that the pharmacokinetic effect of the formulated docetaxel was significantly improved even in oral form in animals that were relatively large compared to rats, such as beagles, and had excessive gastric acid secretion.

[0286] Therefore, the present invention not only improves convenience and ease of use by formulating poorly soluble drugs for oral administration, but also reduces drug costs. Furthermore, while injectable drugs require the supervision of a physician or nurse, the oral form improves their utility by allowing them to be administered in outpatient settings or at home.

[0287] [Table 13]

[0288]

[0289] [Table 14]

[0290]

[0291] Experimental Example 6: Dissolution Experiment

[0292] The dissolution rates according to the dissolution conditions of Examples 84 to 88 and Comparative Examples 7 and 8 were confirmed.

[0293] [Table 15]

[0294]

[0295] [Table 16]

[0296]

[0297] [Table 17]

[0298]

[0299] [Table 18]

[0300]

[0301] The dissolution rates of Examples 84 and 85 and Comparative Examples 7 and 8 were analyzed under the conditions of Table 15, and the results are described in Figures 8 to 10.

[0302] [Table 19]

[0303]

[0304] [Table 20]

[0305]

[0306] [Table 21]

[0307]

[0308] The dissolution rates of Examples 84 and 85 and Comparative Example 8 were analyzed under the conditions of Table 19, and the results are shown in Figures 11 and 12 and Tables 20 and 21.

[0309] [Table 22]

[0310]

[0311] [Table 23]

[0312]

[0313] The dissolution rates of Example 85 and Comparative Example 8 were analyzed under the conditions of Table 22, and the results are shown in Table 23 and Figure 13.

[0314] [Table 24]

[0315]

[0316] Table 24 shows the conditions for comparing the dissolution rates of Examples 86 to 88 and Comparative Example 7, and the results are shown in Fig. 14.

[0317] Experimental Example 7: In-vivo pharmacokinetic analysis of the compositions of Examples 89 to 9 and Comparative Example 9 (rat)

[0318] In vivo pharmacokinetic analysis was performed using the compositions of Examples 91 to 97, Examples 134 to 139, Reference Examples 1 to 3, and Comparative Example 9. The compositions of Examples 91 to 97 and Comparative Example 9 were administered orally to rats at a single dose of 100 mg / kg to obtain plasma drug concentration information. The results are shown in Table 24 and FIG. 21 below.

[0319] Tables 25 to 29 show the concentration of docetaxel in the plasma of rats over time, measured by collecting blood at intervals of 0 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, and 8 hr or at 0 hr, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, and 8 hr. Specific pharmacokinetic graphs are shown in Figures 15 to 18.

[0320] [Table 25]

[0321]

[0322] * Data are represented as the mean concentration (n=2 or 3)

[0323] *ND: not detected, BQL: below quantitative limit (< 5 ng / mL)

[0324] *ND: not detected

[0325] [Table 26]

[0326]

[0327] [Table 27]

[0328]

[0329] [Table 28]

[0330]

[0331] [Table 29]

[0332]

[0333] When examining Figures 15 to 18, it was confirmed that the Examples (e.g., Examples 135, 137, 134) showed better PK profiles compared to the Reference Examples. It was confirmed that Examples 137, 135, and 134 showed relatively high C_max and AUC, indicating a better drug delivery method. As a result, it was confirmed that the Examples were better absorbed than the Reference Examples and were more likely to be maintained in the body for a longer period of time.

[0334] Experimental Example 8: Measurement of XRD peaks

[0335] The XRD graph values ​​of Examples 140 to 163 and Comparative Examples 10 to 13 described above are shown in Figs. 19 to 37. As can be seen in Figs. 19 to 37, it can be confirmed through the XRD graph that incomplete crystallinity is enhanced in the composition in which the poorly soluble drug and the polymer are first stirred and then the mineral compound is mixed. In particular, as shown in Fig. 4, when the peaks for P1 and P2 do not exist, and the 2θ value shifts by 1.3 to 10% at (2θ) 26.71 ± 0.5°, which is the V2 peak of niclosamide, or when the intensity changes, such as decreasing or increasing by 10 to 70% at 2θ = 26.71 ± 0.5°, it was confirmed that the bioavailability is significantly improved. Examples 143 and 144 used a method of mixing NIC and a polymer first and then mixing the mineral compound, and Comparative Example 10 used a method of mixing NIC and CaO first and then adding the polymer.

[0336] On the other hand, it was confirmed that the % theta and % intensity values ​​of Comparative Examples 10 and 11 did not change significantly compared to niclosamide. The change in intensity has specificity when it is +10% or more, and the change in theta value has specificity when it is +1.5% or more. The ratios such as 8:2 5:5 2:8 1:9 in the Xrd graph represent the ratio of ethanol and water when manufacturing the formulation.

[0337] The theta and intensity related tables of Figs. 19 to 37 are the results showing theta values ​​and intensity values ​​of peaks measured by XRD. The % value in the Theta table is a converted value when Niclosamide is viewed as 100, and the intensity change amount is a converted value when 0 in the table is the standard. The change in the Theta value or intensity is a result of changes in the diffraction pattern due to a decrease in crystallite size, an increase in lattice strain, and amorphization. As the amorphous region increases and the crystallinity decreases, broadening increases, and there is a high possibility that the sharp peak in the existing 25-30° region will change to broad or the intensity will decrease.

[0338] The XRD peak change values ​​for Fig. 20 are specifically described in Tables 30 and 31, the XRD peak change values ​​for Fig. 21 are specifically described in Tables 32 and 33, and the XRD peak change values ​​for Fig. 23 are specifically described in Tables 34 and 35.

[0339] [Table 30]

[0340]

[0341] [Table 31]

[0342]

[0343] [Table 32]

[0344]

[0345] [Table 33]

[0346]

[0347] [Table 34]

[0348]

[0349] [Table 35]

[0350]

[0351] Experimental Example 9

[0352] Experimental model: SD rat

[0353] Experimental process: Oral docetaxel and oral paclitaxel were administered orally at 50 mg / kg and 100 mg / kg, respectively, using a sonde, and blood was collected at regular intervals to analyze the drug concentration in the blood (as a control group, docetaxel and paclitaxel were administered orally at 50 mg / kg and 100 mg / kg, respectively). The experimental results are shown in Figures 38 and 39.

[0354] As can be seen in Figures 38 and 39, the PKa values ​​of orally formulated docetaxel and paclitaxel were found to be significantly higher.

[0355] Experimental Example 10

[0356] Experimental type: Antitumor model test using mice transplanted with cancer cell lines

[0357] Cancer cell line: PANC-1 (human pancreatic cancer cell line)

[0358] Model species and strains: BALB / c nude mice, BALB / cAJcl-nu / nu

[0359] Gender: Female

[0360] Age: 6 weeks old

[0361] Test method: Administer the formulated oral docetaxel continuously until the end of the test as follows and measure the tumor size.

[0362] The administration method and route are as shown in Table 36.

[0363] [Table 36]

[0364]

[0365] OAD is an oral dosage form of docetaxel of Example 177.

[0366] As a result of the test, the groups that received 10 mg / kg twice a day and three times a day showed a 50.2% and 61.4% reduction in tumor size, respectively, compared to the control group. The group that received 20 mg / kg once a day showed an 82.8% reduction in tumor size compared to the control group, and the group that received 40 mg / kg four times a week showed a 92.8% reduction in tumor size compared to the control group.

[0367] The anticancer effect was the greatest in the group administered 40 mg / kg four times a week, but by day 18, the group had lost 14.3% of its initial body weight. Conversely, no significant weight loss was observed in the groups administered 10 mg / kg twice or three times a day or the 20 mg / kg once a day. In terms of anticancer efficacy relative to side effects, the group administered 20 mg / kg once a day showed no weight loss and superior anticancer efficacy. The experimental results are shown in Figures 40 and 41.

[0368] Experimental Example 11

[0369] The experimental model was the LL2 syngeneic mouse model. Lung cancer was induced in mice using a lung cancer cell line. The targeted therapy used in the experiment was bevacizumab, administered twice weekly at a dose of 5 mg / kg (BIW). In humans, bevacizumab is administered once every two or three weeks at a dose of 10 mg / kg.

[0370] The niclosamide formulation was administered three times a day at doses of 50, 100, and 150 mg / kg per dose in combination with bevacizumab. When the mouse model was administered as described above for 18 days and the organs (lungs) were observed by dissecting the mouse, metastases were observed in 5 out of 6 mice in the untreated group (vehicle) and 4 out of 6 mice in the bevacizumab monotherapy group, whereas in the group administered in combination with the niclosamide formulation, metastases occurred in 2 out of 6 mice in the 50 mg / kg group, 0 out of 6 mice in the 100 mg / kg group, and 0 out of 6 mice in the 150 mg / kg group (1 death). Therefore, it was confirmed that niclosamide formulated by the method of the present invention did not induce resistance when administered in combination with a cancer treatment agent. The results are specifically shown in Fig. 42.

[0371] Experimental Example 12

[0372] To confirm the bioavailability of orally formulated paclitaxel, it was administered in the manner shown in Table 37 below.

[0373] [Table 37]

[0374]

[0375] The administration results are described in Figures 43 to 45.

[0376] Experimental Example 13

[0377] The dissolution graph shows the dissolution results of formulations prepared in different alcohol-to-water ratios. Niclosamide did not dissolve, so it appears as 0.

[0378] In contrast to nilosamide, the formulations of Examples 147 to 150 using a mixed solvent of alcohol and water were confirmed to have superior dissolution compared to Comparative Examples 11 and 12, which were prepared using different methods.

[0379] Experimental Example 14

[0380] In order to confirm the bioavailability, Balb / mouse administration was performed in the manner of Tables 38 to 41 for Examples 143 to 160 and Comparative Examples 10 to 13, and the administration results are described in Tables 42 to 49. As can be confirmed in Tables 42 to 49, when the peak shift or intensity change value having the characteristic of incomplete crystallinity as in Examples 143 to 160 was present, it was confirmed that the bioavailability was improved more excellently than that of Comparative Examples 10 to 13 containing the same composition.

[0381] [Table 38]

[0382]

[0383] [Table 39]

[0384]

[0385] [Table 40]

[0386]

[0387] [Table 41]

[0388]

[0389] [Table 42]

[0390]

[0391] [Table 43]

[0392]

[0393] * AUC: ng·h / mL, C max : ng / mL, T max & t 1 / 2 : h

[0394] [Table 44]

[0395]

[0396] * Data are represented as the mean concentration (n=3)

[0397] * Plasma concentration: ng / mL

[0398] *ND: not detected, BQL: below quantitative limit (<ng / mL)

[0399] [표 45]

[0400]

[0401] * AUC: ng·h / mL, C max : ng / mL, T max & t 1 / 2 : h

[0402] [표 46]

[0403]

[0404] * Data are represented as the mean concentration(n=3)

[0405] * Plasma concentration: ng / mL

[0406] *ND: not detected, BQL: below quantitative limit (<ng / mL)

[0407] [표 47]

[0408]

[0409] [표 48]

[0410]

[0411] * Data are represented as the mean concentration(n=3)

[0412] * Plasma concentration: ng / mL

[0413] *ND: not detected, BQL: below quantitative limit (<ng / mL)

[0414] [표 49]

[0415]

[0416] * AUC: ng·h / mL, C max : ng / mL, T max & t 1 / 2 : h

[0417] Experimental Example 15

[0418] FT-IR was measured for niclosamide, Example 146, and HPCM, and is shown in Fig. 47. As can be confirmed in Fig. 47, the absorption band 3460 cm-1 appearing in the w1 peak of HPMC is the stretching frequency of the -OH group, 2928 cm-1 of the w2 peak represents the C?H stretching vibration, 1378 cm-1 of the w3 peak represents the -OH bending vibration, and 1052 cm-1 of the w4 peak represents the -OH bending vibration. In comparison, in Example 146, it was observed that the peak position related to the -OH group, which is one of the functional groups, disappeared or the intensity was greatly reduced due to the hydrogen bonding between niclosamide and HPMC.

Claims

1. As an imperfect crystalline composition, Niclosamide or a pharmaceutically acceptable salt thereof; and a polymer, In XRD, it contains peaks at 2 (θ) = 13.01°± 0.5°, 13.74°± 0.5° and 25.68°± 0.5°, In the XRD of the above niclosamide or a pharmaceutically acceptable salt thereof, the 2(θ)=26.87°±0.5° peak shifts in the 25° direction from 2(θ) or a change in the intensity of the 2(θ)=26.87°±0.5° peak occurs. Incomplete crystalline composition.

2. In claim 1, An imperfectly crystalline composition, wherein the 2(θ)=26.87° ± 0.5° peak in the XRD has a change value of 1.5 to 10% in the 25° direction from 2(θ), and the intensity change of the 2(θ)=26.87° ± 0.5° peak varies in the range of 10 to 80%.

3. In claim 1, An incompletely crystalline composition, wherein the polymer is at least one compound selected from among polyvinylpyrrolidone compounds, cellulose compounds, poloxamer compounds, polyethylene glycol compounds, alginic acid compounds, dextrin compounds, sugar alcohol compounds, copolymer compounds containing acrylic acid or methacrylic acid, and poly-gamma glutamic acid.

4. In claim 1, The above incomplete crystalline composition is characterized in that it is prepared by stirring niclosamide or a pharmaceutically acceptable salt thereof and a polymer in a mixed solvent of water and ethanol.

5. In claim 4, the water and ethanol mixed solvent is an incomplete crystalline composition in which water and ethanol are mixed in a ratio of 1:9 to 9:

1.

6. In claim 4, An incomplete crystalline composition, wherein the above mixed solvent is used in a range of 1:10 to 1:100 with respect to niclosamide or a pharmaceutically acceptable salt thereof.

7. In claim 2, An imperfectly crystalline composition, wherein the mineral in the above mineral compound is at least one selected from calcium, iron, potassium, sodium, zinc, magnesium, copper, manganese, chromium, cobalt, selenium and molybdenum.

8. In claim 2, The above mineral compounds are calcium chloride, calcium sulfate, calcium nitrate, calcium oxide, calcium hydroxide, calcium silicate, iron chloride, iron nitrate, iron sulfate, iron hydroxide, potassium chloride, potassium nitrate, potassium hydroxide, sodium chloride, sodium nitrate, sodium hydroxide, zinc chloride, zinc nitrate, zinc sulfate, zinc oxide, zinc hydroxide, magnesium chloride, magnesium nitrate, magnesium sulfate, magnesium oxide, magnesium hydroxide, magnesium silicate, copper chloride, copper nitrate, copper sulfate, copper oxide, copper hydroxide, manganese chloride, manganese nitrate, manganese sulfate, manganese oxide, manganese hydroxide, chromium chloride, chromium nitrate, chromium sulfate, chromium oxide, chromium hydroxide, cobalt chloride, cobalt nitrate, cobalt sulfate, cobalt oxide, cobalt hydroxide, selenium chloride, selenium nitrate, selenium sulfate, An incompletely crystalline composition comprising at least one selected from selenium oxide, selenium hydroxide, molybdenum chloride, molybdenum oxychloride, molybdenum oxide, molybdenum bromide nitrate, molybdenum nitrate, molybdenum sulfide, molybdenum hydroxide, and molybdenum oxalate.

9. A step of preparing a first solution by stirring niclosamide or a pharmaceutically acceptable salt thereof and a polymer in a mixed solvent of water and ethanol; A method for producing an incompletely crystalline composition, comprising the step of drying the first solvent to obtain a first product.

10. In claim 9, A method for producing the above incompletely crystalline composition, further comprising the step of preparing a second solution by stirring the first product and the mineral salt in anhydrous ethanol.

11. In claim 9, A method for producing an incompletely crystalline composition, wherein the above mixed solvent of water and ethanol is mixed in a ratio of water and ethanol of 1:9 to 9:

1.

12. In claim 9, A method for producing an incomplete crystalline composition, wherein the ratio of niclosamide or a pharmaceutically acceptable salt thereof and a mixed solvent in the first solution production step is 1:10 to 1:

100.

13. A method for producing an incompletely crystalline composition according to claim 9, wherein the polymer is at least one compound selected from among polyvinylpyrrolidone compounds, cellulose compounds, poloxamer compounds, polyethylene glycol compounds, alginic acid compounds, dextrin compounds, sugar alcohol compounds, copolymer compounds containing acrylic acid or methacrylic acid, and poly-gamma glutamic acid.

14. As an imperfect crystalline composition, A taxane compound or a pharmaceutically acceptable salt thereof; and a polymer, Incomplete crystalline composition.

15. In claim 14, The above taxane compound is at least one selected from docetaxel, paclitaxel, and cabazitaxel. Incomplete crystalline composition.

16. In claim 14, An incomplete crystalline composition, wherein the polymer is at least one compound selected from among polyvinylpyrrolidone compounds, cellulose compounds, poloxamer compounds, polyethylene glycol compounds, alginic acid compounds, dextrin compounds, sugar alcohol compounds, and poly-gamma glutamic acid.

17. In claim 14, The above incomplete crystalline composition is prepared by stirring a taxane compound or a pharmaceutically acceptable salt thereof and a polymer in a mixed solvent of water and ethanol. The above water and ethanol mixed solvent is an incomplete crystalline composition in which water and ethanol are mixed in a ratio of 1:9 to 9:

1.

18. In claim 14, An incomplete crystalline composition, wherein the above mixed solvent is used in a range of 1:10 to 1:100 with respect to niclosamide or a pharmaceutically acceptable salt thereof.

19. In claim 14, The above imperfect crystalline composition further comprises a mineral compound, An imperfectly crystalline composition, wherein the mineral in the above mineral compound is at least one selected from calcium, iron, potassium, sodium, zinc, magnesium, copper, manganese, chromium, cobalt, selenium and molybdenum.

20. In claim 19, The above mineral compounds are calcium chloride, calcium sulfate, calcium nitrate, calcium oxide, calcium hydroxide, calcium silicate, iron chloride, iron nitrate, iron sulfate, iron hydroxide, potassium chloride, potassium nitrate, potassium hydroxide, sodium chloride, sodium nitrate, sodium hydroxide, zinc chloride, zinc nitrate, zinc sulfate, zinc oxide, zinc hydroxide, magnesium chloride, magnesium nitrate, magnesium sulfate, magnesium oxide, magnesium hydroxide, magnesium silicate, copper chloride, copper nitrate, copper sulfate, copper oxide, copper hydroxide, manganese chloride, manganese nitrate, manganese sulfate, manganese oxide, manganese hydroxide, chromium chloride, chromium nitrate, chromium sulfate, chromium oxide, chromium hydroxide, cobalt chloride, cobalt nitrate, cobalt sulfate, cobalt oxide, cobalt hydroxide, selenium chloride, selenium nitrate, selenium sulfate, An incompletely crystalline composition comprising at least one selected from selenium oxide, selenium hydroxide, molybdenum chloride, molybdenum oxychloride, molybdenum oxide, molybdenum bromide nitrate, molybdenum nitrate, molybdenum sulfide, molybdenum hydroxide, and molybdenum oxalate.

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