Pharmaceutical composition comprising niclosamide or pharmaceutically acceptable salt thereof, or co-administration formulation using same

Abstract

The present invention relates to: a composition comprising niclosamide or a pharmaceutically acceptable salt thereof for preventing hair loss or promoting hair growth; a composition comprising niclosamide or a pharmaceutically acceptable salt thereof for preventing or treating prostate cancer; a composition comprising niclosamide or a pharmaceutically acceptable salt thereof for alleviating or treating malignant tumor diseases; a composition comprising niclosamide or a pharmaceutically acceptable salt thereof for alleviating or treating skin diseases; an anticancer adjuvant comprising niclosamide or a pharmaceutically acceptable salt thereof; an anticancer combination formulation; a Parkinson's disease treatment agent; and a treatment method.

Description

Pharmaceutical composition comprising niclosamide or a pharmaceutically acceptable salt thereof or a combination preparation using the same

[0001] The present invention relates to a pharmaceutical composition comprising niclosamide or a pharmaceutically acceptable salt thereof, or a combination administration preparation and combination administration method using the same.

[0002]

[0003] Scalp conditions can be caused by a variety of factors, including genetics, environmental aggravations, and immunological factors. Hair loss, in particular, is known to have diverse clinical presentations and varying degrees of severity due to its recurrence and difficulty in treatment. Furthermore, symptoms can improve and worsen repeatedly depending on factors such as lifestyle, behavioral habits, and climate change, making it difficult to completely cure. Ongoing management is necessary to prevent recurrence, and treatment regimens may be adjusted every 12 to 24 months to minimize medication side effects.

[0004] Alopecia is a condition in which hair falls out from parts of the body, especially the scalp. Hair loss occurs when the resting phase of the hair growth cycle is prolonged or the number of hair follicles in the resting phase increases due to genetic factors, endocrine disorders, medications, poor lifestyle habits, and psychological stress. This leads to excessive hair loss, resulting in hair loss in areas where hair should normally grow. In both men and women with a genetic predisposition, alopecia leads to the gradual miniaturization of hair follicles. The hair follicle growth cycle begins with the catagen phase, followed by the telogen phase, when hair growth ceases, and then a new cycle, the anagen phase, begins. In normal hair, approximately 90% of the hair is in the anagen phase, with less than 10% in the telogen phase. The anagen phase is known to last 3-6 years, and the length of this anagen phase determines the thickness and length of the hair.

[0005] Hair loss can be caused by a variety of factors. Among them, male pattern baldness is often genetic, with androgens, the male hormone, being identified as a key factor. Non-hereditary hair loss can occur regardless of gender and can be categorized into stress-induced alopecia, skin diseases like seborrheic dermatitis, and rarer forms like alopecia areata, alopecia universalis, or alopecia universalis, which are believed to be caused by autoimmune diseases.

[0006] The main causes of male pattern baldness are testosterone, dihydrotestosterone (DHT), and 5α-reductase (5AR). Testosterone is converted to DHT by 5AR, and DHT exhibits a stronger affinity for the androgen receptor than testosterone. Ultimately, hair loss occurs through the conversion of testosterone to DHT by 5AR, and through hair follicle cell signaling via the DHT-androgen receptor. Based on this mechanism, it can be seen that preventing hair loss requires inhibiting the role of 5AR in converting testosterone to DTH or suppressing cell signaling via DHT-androgen receptor binding (see Figure 20).

[0007] To date, three 5AR isoforms have been identified. Types 1 and 3 are distributed throughout the body, with type 1 being predominantly expressed in the pilosebaceous glands. Type 2 is primarily expressed in androgen-targeting tissues, including the prostate, epididymis, and hair follicles. In the skin, it is highly expressed primarily in the outer root sheath, inner root sheath, and dermal papilla. However, the causes of hair loss, including stress and environmental factors, are diverse, making it difficult to completely address these causes.

[0008] Despite the advancement of modern medicine, only three types of treatments have been developed to treat hair loss, and drugs to promote hair growth have not yet been significantly developed. In addition, hair loss treatments are related to hormones, so some hair loss treatments, such as Propecia, have side effects that can affect the fetus, which has led to the problem that women cannot use them. In particular, finasteride and dutasteride are 5α-reductase inhibitors that, when taken long-term, cause androgen deficiency in various tissues and organs in the body, which may increase the risk of metabolic disorders, insulin resistance, T2DM (Type 2 DM), non-alcoholic fatty liver disease, renal failure, and dry eye. In addition, Finjuve Spray (finasteride), a topical hair loss treatment, has adverse effects on children, the elderly, pregnant women, and the fetus, and has the problem of causing side effects such as skin rash when administered to areas other than the scalp. In other words, hair loss treatments developed to date have side effects including effects on the fetus. Because of concerns about its use, there is a great need to develop safer hair loss treatments.

[0009] Accordingly, the present applicant intends to expand the indications of niclosamide, a drug with proven safety that has been used as an anti-parasitic drug for over 50 years, and develop it as a hair loss treatment. The present applicant has discovered a new drug mechanism of niclosamide that can minimize side effects or skin rashes depending on age or gender, and alleviate or improve alopecia by blocking a specific signal transmission system caused by the expression of androgens. The present applicant has confirmed a completely new use of niclosamide that can be used on areas other than the scalp, and can maximize the drug treatment effect for symptoms such as hair loss in addition to male pattern baldness by alleviating seborrheic dermatitis.

[0010] In addition, the therapeutic effect on prostate cancer, a disease closely related to the androgen receptor, which plays an important role in the signaling system related to hair loss, was confirmed. Androgen-induced androgen receptor activation is essential for the growth of early-stage prostate cancer cells, and prostate cancer is also treated by blocking androgen synthesis or inhibiting androgen receptors through hormone therapy. The present applicant conducted an experiment to confirm the therapeutic effect on prostate cancer under the assumption that if niclosamide is involved in the androgen receptor-mediated signaling system involved in hair loss, it would also be effective on prostate cancer. As a result, the possibility that niclosamide can be applied to the treatment of prostate cancer was confirmed.

[0011] In addition, there have been studies showing that niclosamide affects mitochondrial uncoupling (Tao, H et. al. (2014). Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice. Nature medicine, 20(11), 1263-1269.), and that it is closely related to the apoptosis mechanism involving p53 and mitochondria (Marchenko ND et. al. Mitochondrial death functions of p53. Mol Cell Oncol. 2014 Oct 31;1(2):e955995.). p53, a tumor suppressor protein, is nicknamed the "guardian of the genome" because it plays a role in maintaining genome stability by preventing mutations. Despite the fact that the p53 gene is the most frequently mutated gene in the process of cancer development, no anticancer drug targeting p53 has yet been developed. Therefore, the present applicant hypothesized that niclosamide may have anticancer effects on cancer cells caused by p53 mutations and associated diseases. The applicant conducted experiments to determine whether niclosamide had an anticancer effect on tumors caused by p53 mutations and confirmed its efficacy. Specifically, some studies have shown that p53 gene activity plays a crucial role in the onset and progression of neurodegenerative diseases. p53 can induce apoptosis in response to cellular stress and damage. Excessive activation of this apoptotic function has been reported to promote neuronal loss, potentially contributing to the progression of diseases such as Parkinson's disease and being closely related to aging.Therefore, the present invention discloses that niclosamide can produce a synergistic effect with other therapeutic agents and can exhibit excellent effects as a combination agent, therapeutic adjuvant, or combination agent, and intends to apply for this.

[0012]

[0013] Prior art literature

[0014] Republic of Korea Patent Publication No. 10-2021-0086456

[0015] Niclosamide Exhibits Potent Anticancer Activity and Synergizes with Sorafenib in Human Renal Cell Cancer Cells (Xinyi Yu et al. Cell PhysiolBiochem. 2018;47(3):957-971. doi: 10.1159 / 000490140. Epub 2018 May 24)

[0016] Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice(Tao, H et. al. (2014); Nature medicine, 20(11), 1263-1269.)

[0017] Mitochondrial death functions of p53 (Marchenko ND et. al.; Mol Cell Oncol. 2014 Oct 31;1(2): e955995.)

[0018]

[0019]

[0020] The present invention is designed to solve the problems in the prior art described above, and provides various uses of a pharmaceutical composition containing niclosamide or a pharmaceutically acceptable salt thereof, and combination administration agents, therapeutic adjuvants and / or combination administration methods utilizing the same.

[0021] In addition, the present invention provides a composition for preventing hair loss or promoting hair growth, comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0022] In addition, the present invention provides a composition for preventing or treating prostate cancer comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0023] In addition, the present invention provides a composition for improving and / or treating malignant tumor diseases, comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0024] In addition, the present invention provides a composition for improving and / or treating skin diseases, comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0025] In addition, the present invention provides an anticancer adjuvant comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0026] Additionally, the present invention utilizes niclosamide or a pharmaceutically acceptable salt thereof for the treatment and / or improvement of Parkinson's disease.

[0027] In addition, the present invention uses niclosamide or a pharmaceutically acceptable salt thereof as a therapeutic adjuvant.

[0028] In addition, the present invention uses niclosamide or a pharmaceutically acceptable salt thereof as a combination therapy agent.

[0029]

[0030] The present invention provides a composition for preventing hair loss or promoting hair growth, comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0031] In addition, the present invention provides a composition for improving and / or treating malignant tumor diseases, comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0032] In addition, the present invention provides an anticancer agent comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0033] In addition, the present invention provides an anticancer adjuvant comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0034] In addition, the present invention provides a composition for treating seborrheic dermatitis comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0035] In addition, the present invention provides a composition for treating and / or improving Parkinson's disease, comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0036] In addition, the present invention provides a therapeutic adjuvant comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0037] In addition, the present invention provides a combination therapy comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0038]

[0039] The present invention provides a composition that can be effectively used for treating hair loss by preventing hair loss or promoting hair growth through a method of blocking the male hormone signaling system, i.e., inhibiting the androgen receptor, using niclosamide or a pharmaceutically acceptable salt thereof.

[0040] In addition, the present invention can provide an effect of maintaining a constant blood concentration of a drug in order to maximize the therapeutic efficacy of the drug and increase the convenience of taking the drug.

[0041] In addition, the present invention increases the bioavailability by increasing the solubility of niclosamide or a pharmaceutically acceptable salt thereof, thereby enabling efficient use of the autophagy mechanism-inducing effect that niclosamide or a pharmaceutically acceptable salt thereof can exert, thereby providing a composition capable of providing not only hair loss prevention or hair growth promotion effects, but also prostate cancer prevention and / or treatment effects, malignant tumor disease improvement and / or prevention effects, skin disease improvement and / or prevention effects, and Parkinson's disease prevention and / or treatment effects.

[0042] In addition, the present invention can provide an effect of enhancing the therapeutic effect by reducing the resistance of the anticancer agent to cancer cells when co-administered with an anticancer agent by utilizing niclosamide or a pharmaceutically acceptable salt thereof.

[0043] In addition, niclosamide has the effect of inhibiting the Wnt / β-catenin signaling pathway, inhibiting the mTOR pathway, inhibiting the NF-κB signaling pathway, inhibiting the oxidative phosphorylation process of mitochondria, and activating autophagy, which is a cellular autophagy. The present invention provides an effect of increasing the bioavailability of the effect of niclosamide or a pharmaceutically acceptable salt thereof, thereby enhancing the therapeutic effect of drugs by using it as a therapeutic adjuvant or combination agent for other drugs.

[0044]

[0045] Figure 1 is a graph showing the blood concentration of drugs when administered with Examples 1 and 4 and Yomesan.

[0046] Figure 2 is a graph showing the blood concentration of drugs when Examples 13 to 16 were administered.

[0047] Figure 3 is a graph of the blood concentration of the drug of the compositions of Examples 28 to 30.

[0048] Figure 4 is a graph of the AUC results of Examples 28 and 29.

[0049] Figure 5 is a graph showing the blood concentration of drugs of compositions 12 and 13 for reference.

[0050] Figure 6 is a graph of the blood concentration of the drug of the compositions of Reference Examples 9 to 11 and Examples 31 to 33.

[0051] Figure 7 is a graph of the AUC results of the compositions of Reference Examples 9 to 11 and Examples 31 to 33.

[0052] Figure 8 is a graph of the blood concentration of the drug of the compositions of Examples 34 to 37.

[0053] Figure 9 is a graph of the AUC results of the compositions of Examples 34 to 37.

[0054] Figure 10 is a graph of the blood concentration of the drugs of Examples 38 and 39 and yomesan.

[0055] Figure 11 is a graph of the AUC results of the compositions of Examples 38 and 39 and yomesan.

[0056] Figures 12 and 13 are photographs of the hair growth area of ​​mice administered the example and positive control groups.

[0057] Figure 14 is a graph of body weight for each group on day 26 in Experimental Example 6.

[0058] Figure 15 is a graph showing the change in tumor size for each group up to day 26 in Experimental Example 6.

[0059] Figure 16 is a graph of tumor weights for each group on day 26 in Experimental Example 6.

[0060] Figure 17 is a graph of tumor weight for each group in Experimental Example 7.

[0061] Figure 18 is a photograph showing the improvement effect of seborrheic dermatitis that occurred on the palm in Experimental Example 8.

[0062] Figure 19 is a photograph showing the improvement effect of seborrheic dermatitis that occurred on the shin in Experimental Example 8.

[0063] Figure 20 is a photograph showing the hair loss prevention and hair growth promotion effects in Experimental Example 9.

[0064] Figure 21 is a diagram explaining the hair loss induction mechanism.

[0065] Figure 22 is a drawing explaining the experimental method of Experimental Example 10.

[0066] Figure 23 is a graph of the pole test results (1) Values ​​are expressed as mean ± SD on total time for each group (n=5~10), 2) N, Normal; C, Control, MPTP induced mice; P, Positive control, madopar 100 mg / kg (administered once a day); SA, sample A (administered three times a day, 8-hour intervals); SB, sample B (administered twice a day, 12-hour intervals), 3) #, p<0.05 vs. C; a, p<0.05 vs. pole test (Before), 4) A: Before test substance administration, B: During test substance administration, C: After test substance administration, D: Total time in Pole test).

[0067] Figure 24 is a graph of the results of the open field test (1) Values ​​are expressed as mean ± SD on entrance in center for each group (n=5~10), 2) N, Normal; C, Control, MPTP induced mice; P, Positive control, madopar 100 mg / kg (administered once a day); SA, sample A (administered three times a day, 8-hour intervals); SB, sample B (administered twice a day, 12-hour intervals), 3) *, p<0.05 vs. N; a, p<0.05 vs. open field test (pre), 4) A: before test substance administration, B: during test substance administration, C: after test substance administration, D: Entrance in center of open field test).

[0068] Figure 25 is a graph of the results of the water maze test (1) Values ​​are expressed as mean ± SD on the number of escape latency for each group (n = 5~10), 2) N, Normal; C, Control, MPTP induced mice; P, Positive control, madopar 100 mg / kg (administered once a day); SA, sample A (administered three times a day, 8-hour intervals); SB, sample B (administered twice a day, 12-hour intervals), 3) *, p<0.05 vs. N; #, p<0.05 vs. C; a, p<0.05 vs. water maze test (Pre); b, p<0.05 vs. water maze test (Medi), 4) A: before test substance administration, B: during test substance administration, C: after test substance administration, D: Number of escape latency).

[0069] Figure 26 shows the analysis of dopamine content in brain tissue (1) Values ​​are expressed as mean ± SD on dopamine concentration for each group, 2) N, Normal; C, Control, MPTP-induced mice; P, Positive control, madopar 100 mg / kg (administered once a day); SA, sample A (administered three times a day, at 8-hour intervals); SB, sample B (administered twice a day, at 12-hour intervals), 3) *, p<0.05 vs. N; #, p<0.05 vs. C).

[0070] Figure 27 is a photograph confirming the expression of α-synuclein in brain tissue (1) Values ​​are expressed as mean ± SD on dopamine concentration for each group, 2) N, Normal; C, Control, MPTP induced mice; P, Positive control, madopar 100 mg / kg (administered once a day); SA, sample 210 mg / kg (administered three times a day, at 8-hour intervals); SB, sample 210 mg / kg (administered twice a day, at 12-hour intervals), 3) *, p<0.05 vs. N; #, p<0.05 vs. C).

[0071] Figure 28 is a photograph of the analysis for confirming Tyrosine hydroxylase expression in brain tissue (1) Values ​​are expressed as mean ± SD on dopamine concentration for each group, 2) N, Normal; C, Control, MPTP induced mice; P, Positive control, madopar 100 mg / kg (administered once a day); SA, sample 210 mg / kg (administered three times a day, at 8-hour intervals); SB, sample 210 mg / kg (administered twice a day, at 12-hour intervals), 3) *, p<0.05 vs. N; #, p<0.05 vs. C).

[0072] Figure 29 is a photograph illustrating the expression sites of α-synuclein and Tyrosine hydroxylase in the brain.

[0073]

[0074] The present invention is to discover a new drug efficacy of niclosamide or a pharmaceutically acceptable salt thereof, and to confirm that niclosamide or a pharmaceutically acceptable salt thereof is effective in preventing hair loss and / or promoting hair growth, and to use it as a composition for preventing hair loss and / or promoting hair growth.

[0075]

[0076] Specifically, the present invention provides a composition for preventing hair loss or promoting hair growth, comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0077]

[0078] In addition, the present invention has discovered a new drug effect of niclosamide or a pharmaceutically acceptable salt thereof, and has confirmed that niclosamide or a pharmaceutically acceptable salt thereof is effective in preventing and / or treating prostate cancer, thereby providing use thereof as a composition for preventing and / or treating prostate cancer.

[0079]

[0080] In addition, the present invention provides a composition for improving and / or treating malignant tumor disease, comprising niclosamide or a pharmaceutically acceptable salt thereof, and an enhancing effect when administered in combination with a malignant tumor disease agent.

[0081]

[0082] In addition, the present invention provides an anticancer agent involved in the inhibition mechanism of p 53, comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0083]

[0084] In addition, the present invention provides a composition for improving and / or treating skin diseases, comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0085]

[0086] In addition, the present invention provides an anticancer adjuvant and / or a combination thereof comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0087]

[0088] In addition, the present invention provides a composition for treating seborrheic dermatitis comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0089]

[0090] The present invention also provides a composition for treating a neurological brain disease, comprising niclosamide or a pharmaceutically acceptable salt thereof. In particular, when the composition of the present invention is used as a composition for treating a neurological brain disease, utilizing a specific administration method may be preferable in that it can have an excellent effect in treating the neurological brain disease. Specifically, the neurological brain disease may be Parkinson's disease, dementia, Alzheimer's disease, epilepsy, Lou Gehrig's disease, autism, schizophrenia, depression, attention deficit hyperactivity disorder, drug addiction, Tourette syndrome, Huntington's disease, etc.

[0091]

[0092] In addition, the present invention provides a therapeutic adjuvant comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0093]

[0094] In addition, the present invention provides a combination therapy comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0095]

[0096] At least one of the pharmaceutical compositions, therapeutic adjuvants and combination agents described above of the present invention may further include an inorganic substance, and the inorganic substance may be represented by at least one chemical formula selected from chemical formulas 1 to 4.

[0097] [Chemical Formula 1]

[0098] [(M 2+ (1-x) M 3+ x (OH)2)·((A n- ) z )]·yH2O

[0099] (In the above chemical formula 1,

[0100] M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0101] M 3+ is Al 3+ , Fe 3+ , V 3+ , Ti 3+ , Mn 3+ and Ga 3+ A trivalent metal cation selected from the group consisting of

[0102] x is a number with a range greater than 0 and less than or equal to 0.5,

[0103] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0104] n is the charge number of anion A, and is a number ranging from 0.5 to 2.

[0105] z is a number in the range of 0 to 2,

[0106] y is a number in the range of 0 to 20.)

[0107] [Chemical Formula 2]

[0108] [(M 2+ (OH) 2-x )·((A n- ) z )]·yH2O

[0109] (In the above chemical formula 2,

[0110] M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0111] x is a number in the range of 0 to 2,

[0112] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0113] n is the charge number of the anion A, and is a number ranging from 0 to 2.

[0114] z is a number in the range of 0 to 2,

[0115] y is a number in the range of 0 to 20.)

[0116] [Chemical Formula 3]

[0117] [(M 2+ (O) 2-x )·((A n- ) z )]·yH2O

[0118] (In the above chemical formula 3,

[0119] M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0120] x is a number in the range of 1 to 2,

[0121] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0122] n is the charge number of the anion A, and is a number ranging from 0 to 2.

[0123] z is a number with a range of 0 to 2,

[0124] y is a number in the range of 0 to 20.)

[0125] [Chemical Formula 4]

[0126] M(A n- ) z

[0127] (In the above chemical formula 4,

[0128] M 2+ Silver Mg 2+ , Ni 2+ , Fe 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

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

[0130] n is the charge number of the anion A, and is a number ranging from 0 to 2.

[0131] z is a number with a range of 0 to 2.)

[0132]

[0133] In the present invention, the composition for improving and / or treating malignant tumor disease further comprises an inorganic substance, and the inorganic substance may be represented by one or more chemical formulas selected from the chemical formulas 1 to 4 described above.

[0134]

[0135] When the composition of the present invention includes inorganic substances, due to their alkaline physical characteristics, they can act as a pH regulator in the stomach when administered orally, thereby increasing the absorption rate and sustained-release of the drug in the stomach. This absorption mechanism can have different effects depending on the pore size and surface area of ​​the inorganic substances. In particular, when modifications such as drying are performed, the specific surface area can be increased due to the formation of various pores, i.e., mesoporous pores. Therefore, when inorganic substances are included, the amount and absorption capacity of the drug in the stomach increase, resulting in the effect of increasing the persistence of the drug in the blood. More specifically, the inorganic material is calcium carbonate, calcium bicarbonate, iron carbonate, potassium bicarbonate, sodium bicarbonate, zinc carbonate, magnesium carbonate, magnesium bicarbonate, copper carbonate, manganese carbonate, chromium carbonate, cobalt carbonate, calcium chloride, calcium sulfate, calcium nitrate, calcium, calcium hydroxide, 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, 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, It may be at least one selected from cobalt nitrate, cobalt sulfate, cobalt oxide, and cobalt hydroxide.Specifically, the above-mentioned inorganic substances enhance the role of drug dispersants due to their physicochemical characteristics, which is manifested by electrostatic attraction or Lewis acid and base on the surface of the inorganic substance. In particular, when it contains one or more of calcium carbonate, magnesium oxide (MgO), and zinc oxide, the compound in which these substances are physically conjugated with niclosamide or a pharmaceutically acceptable salt thereof can form ionic bonds with the cell membrane and exhibit greater effects. In addition, the inorganic substances can also form physical bonds with specific functional groups of drugs such as niclosamide. When the drug is a poorly soluble drug having a hydroxyl group (-OH) or NH group, the absorption capacity can be greatly increased by hydrogen bonding with the inorganic substances.

[0136]

[0137] The present invention also provides a composition for improving or treating skin diseases, comprising niclosamide or a pharmaceutically acceptable salt thereof. The composition for improving or treating skin diseases may further comprise an inorganic substance. The composition for improving or treating skin diseases is provided, wherein the inorganic substance is represented by one or more chemical formulas selected from Chemical Formulas 1 to 4. The one or more chemical formulas selected from Chemical Formulas 1 to 4 are also the same as Chemical Formulas 1 to 4 described above.

[0138]

[0139] The present invention also provides an anticancer adjuvant comprising niclosamide or a pharmaceutically acceptable salt thereof and an inorganic substance. The anticancer adjuvant may be administered simultaneously or sequentially with an anticancer agent. More specifically, the anticancer adjuvant may exhibit a more superior anticancer effect when administered together with an anticancer agent.The above anticancer drugs include docetaxel, retinoic acid, gemcitabine, cisplatin, abiraterone, prednisone, quinacrine, sorafenib, entinostat, tanespimycin, vorinostat, pimitespib, belinostat, pimitespib, dichloroacetate, 8-quinolinol, atorvastatin, fluvastatin, lovastatin, camptothecin, U0126, Doxorubicin, Paclitaxel, Metformin, Domperidone, Imipramine, Amitriptyline, Desipramine, Clomipramine, Domperidone, Cyclodextrin, Temozolomide, 5-Fluorouracil (5-FU), Colistin, Enzalutamide, Bicalutamide, Erlotinib, Oxaliplatin, Dasatinib, Palladium(II) saccharinate complex of terpyridine It can be administered in combination with one or more of the following drugs: TRA-8, cytarabine, daunorubicin, and vincristine. It can also be administered in combination with radiation therapy.

[0140]

[0141] In addition, the present invention provides an anticancer combination preparation comprising an anticancer agent and the above-described anticancer adjuvant.

[0142] The present invention is to discover a new drug efficacy of niclosamide or a pharmaceutically acceptable salt thereof, and to confirm that niclosamide or a pharmaceutically acceptable salt thereof is effective in preventing hair loss and / or promoting hair growth, and to use it as a composition for preventing hair loss and / or promoting hair growth.

[0143]

[0144] Specifically, the present invention provides a composition for preventing hair loss or promoting hair growth, comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0145]

[0146] In addition, the present invention has discovered a new drug effect of niclosamide or a pharmaceutically acceptable salt thereof, and has confirmed that niclosamide or a pharmaceutically acceptable salt thereof is effective in preventing and / or treating prostate cancer, thereby providing use thereof as a composition for preventing and / or treating prostate cancer.

[0147]

[0148] In addition, the present invention provides a composition for improving and / or treating malignant tumor disease, comprising niclosamide or a pharmaceutically acceptable salt thereof, and an enhancing effect when administered in combination with a malignant tumor disease agent.

[0149]

[0150] In addition, the present invention provides an anticancer agent involved in the inhibition mechanism of p 53, comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0151]

[0152] In addition, the present invention provides a composition for improving and / or treating skin diseases, comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0153]

[0154] In addition, the present invention provides an anticancer adjuvant and / or a combination thereof comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0155]

[0156] In addition, the present invention provides a composition for treating seborrheic dermatitis comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0157]

[0158] The present invention also provides a composition for treating a neurological brain disease, comprising niclosamide or a pharmaceutically acceptable salt thereof. In particular, when the composition of the present invention is used as a composition for treating a neurological brain disease, utilizing a specific administration method may be preferable in that it can have an excellent effect in treating the neurological brain disease. Specifically, the neurological brain disease may be Parkinson's disease, dementia, Alzheimer's disease, epilepsy, Lou Gehrig's disease, autism, schizophrenia, depression, attention deficit hyperactivity disorder, drug addiction, Tourette syndrome, Huntington's disease, etc.

[0159]

[0160] In addition, the present invention provides a therapeutic adjuvant comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0161]

[0162] In addition, the present invention provides a combination therapy comprising niclosamide or a pharmaceutically acceptable salt thereof.

[0163]

[0164] At least one of the pharmaceutical compositions, therapeutic adjuvants and combination agents described above of the present invention may further include an inorganic substance, and the inorganic substance may be represented by at least one chemical formula selected from chemical formulas 1 to 4.

[0165] [Chemical Formula 1]

[0166] [(M 2+ (1-x) M 3+ x (OH)2)·((A n- ) z )]·yH2O

[0167] (In the above chemical formula 1,

[0168] M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0169] M 3+ is Al 3+ , Fe 3+ , V 3+ , Ti 3+ , Mn 3+ and Ga 3+ A trivalent metal cation selected from the group consisting of

[0170] x is a number with a range greater than 0 and less than or equal to 0.5,

[0171] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0172] n is the charge number of anion A, and is a number ranging from 0.5 to 2.

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

[0174] y is a number in the range of 0 to 20.)

[0175] [Chemical Formula 2]

[0176] [(M 2+ (OH) 2-x )·((A n- ) z )]·yH2O

[0177] (In the above chemical formula 2,

[0178] M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0179] x is a number in the range of 0 to 2,

[0180] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0181] n is the charge number of the anion A, and is a number ranging from 0 to 2.

[0182] z is a number in the range of 0 to 2,

[0183] y is a number in the range of 0 to 20.)

[0184] [Chemical Formula 3]

[0185] [(M 2+ (O) 2-x )·((A n- ) z )]·yH2O

[0186] (In the above chemical formula 3,

[0187] M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0188] x is a number in the range of 1 to 2,

[0189] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0190] n is the charge number of the anion A, and is a number ranging from 0 to 2.

[0191] z is a number with a range of 0 to 2,

[0192] y is a number in the range of 0 to 20.)

[0193] [Chemical Formula 4]

[0194] M(A n- ) z

[0195] (In the above chemical formula 4,

[0196] M 2+ Silver Mg 2+ , Ni 2+ , Fe 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of

[0197] A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of,

[0198] n is the charge number of the anion A, and is a number ranging from 0 to 2.

[0199] z is a number with a range of 0 to 2.)

[0200]

[0201] In the present invention, the composition for improving and / or treating malignant tumor disease further comprises an inorganic substance, and the inorganic substance may be represented by one or more chemical formulas selected from the chemical formulas 1 to 4 described above.

[0202]

[0203] When the composition of the present invention includes inorganic substances, due to their alkaline physical characteristics, they can act as a pH regulator in the stomach when administered orally, thereby increasing the absorption rate and sustained-release of the drug in the stomach. This absorption mechanism can have different effects depending on the pore size and surface area of ​​the inorganic substances. In particular, when modifications such as drying are performed, the specific surface area can be increased due to the formation of various pores, i.e., mesoporous pores. Therefore, when inorganic substances are included, the amount and absorption capacity of the drug in the stomach increase, resulting in the effect of increasing the persistence of the drug in the blood. More specifically, the inorganic material is calcium carbonate, calcium bicarbonate, iron carbonate, potassium bicarbonate, sodium bicarbonate, zinc carbonate, magnesium carbonate, magnesium bicarbonate, copper carbonate, manganese carbonate, chromium carbonate, cobalt carbonate, calcium chloride, calcium sulfate, calcium nitrate, calcium, calcium hydroxide, 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, 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, It may be at least one selected from cobalt nitrate, cobalt sulfate, cobalt oxide, and cobalt hydroxide.Specifically, the above-mentioned inorganic substances enhance the role of drug dispersants due to their physicochemical characteristics, which is manifested by electrostatic attraction or Lewis acid and base on the surface of the inorganic substance. In particular, when it contains one or more of calcium carbonate, magnesium oxide (MgO), and zinc oxide, the compound in which these substances are physically conjugated with niclosamide or a pharmaceutically acceptable salt thereof can form ionic bonds with the cell membrane and exhibit greater effects. In addition, the inorganic substances can also form physical bonds with specific functional groups of drugs such as niclosamide. When the drug is a poorly soluble drug having a hydroxyl group (-OH) or NH group, the absorption capacity can be greatly increased by hydrogen bonding with the inorganic substances.

[0204]

[0205] The present invention also provides a composition for improving or treating skin diseases, comprising niclosamide or a pharmaceutically acceptable salt thereof. The composition for improving or treating skin diseases may further comprise an inorganic substance. The composition for improving or treating skin diseases is provided, wherein the inorganic substance is represented by one or more chemical formulas selected from Chemical Formulas 1 to 4. The one or more chemical formulas selected from Chemical Formulas 1 to 4 are also the same as Chemical Formulas 1 to 4 described above.

[0206]

[0207] The present invention also provides an anticancer adjuvant comprising niclosamide or a pharmaceutically acceptable salt thereof and an inorganic substance. The anticancer adjuvant may be administered simultaneously or sequentially with an anticancer agent. More specifically, the anticancer adjuvant may exhibit a more superior anticancer effect when administered together with an anticancer agent.The above anticancer drugs include docetaxel, retinoic acid, gemcitabine, cisplatin, abiraterone, prednisone, quinacrine, sorafenib, entinostat, tanespimycin, vorinostat, pimitespib, belinostat, pimitespib, dichloroacetate, 8-quinolinol, atorvastatin, fluvastatin, lovastatin, camptothecin, U0126, Doxorubicin, Paclitaxel, Metformin, Domperidone, Imipramine, Amitriptyline, Desipramine, Clomipramine, Domperidone, Cyclodextrin, Temozolomide, 5-Fluorouracil (5-FU), Colistin, Enzalutamide, Bicalutamide, Erlotinib, Oxaliplatin, Dasatinib, Palladium(II) saccharinate complex of terpyridine It can be administered in combination with one or more of the following drugs: TRA-8, cytarabine, daunorubicin, and vincristine. It can also be administered in combination with radiation therapy.

[0208]

[0209] In addition, the present invention provides an anticancer combination preparation comprising an anticancer agent and the above-described anticancer adjuvant.

[0210]

[0211] Additionally, the compositions for the above-described uses of the present invention may further include a dispersant.

[0212]

[0213] The dispersant of the present invention may be used without limitation in the type thereof, such as a surfactant, a water-soluble acid salt, a water-soluble silicate thickener, and / or a protective colloid, as long as it is commonly used. However, a polymer-type dispersant may be more preferable in that it can exhibit the effect of increasing the absorption of drugs into the mucous membrane or skin when used as an oral or transdermal drug delivery system by enhancing the role of a dispersant for drugs due to its physical characteristics.

[0214]

[0215] In the present invention, the polymer-type dispersant may be at least one selected from a polyvinylpyrrolidone-based compound, a polyethylene glycol-based compound, a poloxamer-based compound, a polyoxyethylene sorbitan fatty acid ester-based compound, and a cellulose-based compound.

[0216]

[0217] Specifically, polyvinylpyrrolidone compounds include polyvinylpyrrolidone K10 (MW8000~10,000), polyvinylpyrrolidone K12 (MW11,000~12,000), polyvinylpyrrolidone K15 (MW14,000~18,000), polyvinylpyrrolidone, K17 (MW14,000~18,000), polyvinylpyrrolidone K18 (MW14,000~18,000), polyvinylpyrrolidone K25 (MW2,000~25,000), polyvinylpyrrolidone K30 (MW3,000~40,000), polyvinylpyrrolidone K60 (MW5,000~60,000), and polyvinylpyrrolidone. It may be at least one selected from the group consisting of K90 (MW8,000~90,000). In the above, MW means molecular weight.

[0218] The polyvinylpyrrolidone compound may be included in an amount of 5 to 70 wt% based on 100 wt% of the total composition of the present invention, and it may be preferable that niclosamide or a pharmaceutically acceptable salt thereof be included in an amount of 0.1 to 50 wt%.

[0219] In addition, the cellulose-based compound may be at least one selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxypropylcellulose (HPC), carboxymethyl cellulose (CMC), ethyl cellulose (EC), methylcellulose (MC), and cellulose acetate (CA). The weight average molecular weight of the above-described cellulose-based compound may be 5,000 to 500,000.

[0220] In the composition of the present invention, the cellulose compound may be included in an amount of 10 to 80 wt% based on 100 wt% of the total composition, and it is preferable that niclosamide or a pharmaceutically acceptable salt thereof be included in an amount of 0.1 to 50 wt%.

[0221] In addition, the above poloxamer compounds are 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.

[0222] With respect to the total 100% by weight of the composition of the present invention, the poloxamer compound may be included in an amount of 1 to 50% by weight, and it is preferable that niclosamide or a pharmaceutically acceptable salt thereof be included in an amount of 0.1 to 50% by weight.

[0223] In addition, the polyoxyethylene sorbitan fatty acid ester compound is polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monopalmitate (polyoxyethylenesorbitan monolaurate)

[0224] Polyoxyethylene sorbitan monopalmitate (Tween 40), polyoxyethylene glycol sorbitan monostearate (Tween 60), Tween 65, polyoxyethylene sorbitan monooleate (Tween 80), and polyoxyethylene sorbitan trioleate (Tween 85).

[0225]

[0226] The polyoxyethylene sorbitan fatty acid ester compound may be included in an amount of 1 to 60 wt% based on 100 wt% of the total composition of the present invention, and it is preferable that niclosamide or a pharmaceutically acceptable salt thereof be included in an amount of 0.1 to 50 wt%.

[0227]

[0228] In addition, 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 methoxypolyethylene glycol 550. The weight average molecular weight of the above-described polyethylene glycol compound may be 5,000 to 500,000.

[0229]

[0230] The polyethylene glycol compound may be included in an amount of 5 to 60 wt% based on 100 wt% of the total composition of the present invention, and in this case, it is preferable that niclosamide or a pharmaceutically acceptable salt thereof be included in an amount of 0.1 to 50 wt%.

[0231] In addition, the composition for preventing hair loss or promoting hair growth of the present invention may further include amino acids and / or peptides.

[0232] In addition, the composition for preventing or treating prostate cancer of the present invention may further include amino acids and / or peptides.

[0233] In addition, the composition for improving or treating a malignant tumor disease of the present invention may further include an amino acid and / or a peptide.

[0234] In addition, the composition for improving or treating skin diseases of the present invention may further include amino acids and / or peptides.

[0235] Additionally, the anticancer adjuvant of the present invention may further include amino acids and / or peptides.

[0236] Additionally, the composition for treating and / or preventing Parkinson's disease of the present invention may further comprise amino acids and / or peptides.

[0237]

[0238] The composition and / or anticancer adjuvant described in the present invention may be advantageous in that it may exhibit superior bioavailability compared to simply using niclosamide or a pharmaceutically acceptable salt thereof when further including amino acids and / or peptides. Specifically, the amino acids may be used without limitation as long as they are commonly used amino acids, but may include non-polar amino acids, polar amino acids, acidic amino acids, and basic amino acids.

[0239]

[0240] More specifically, the nonpolar amino acids include glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, etc., the polar amino acids include serine, threonine, cysteine, tyrosine, asparagine, glutamine, etc., the acidic amino acids include aspartic acid and glutamic acid, and the basic amino acids include lysine, arginine, histidine, etc. Among the amino acids, an amino acid having a side chain PKa value of 3 or more may be more preferable. This includes cysteine ​​(side chain pKa 8.33), tyrosine (side chain pKa 10.07), aspartic acid (side chain pKa 3.86), glutamic acid (side chain pKa 4.25), lysine (side chain pKa 10.79), arginine (side chain pKa 12.48), and histidine (side chain pKa 6.04) belong to this group. When these are used, the characteristic of niclosamide increasing its solubility in a weakly alkaline solution can be utilized.

[0241] The composition described in the present invention is characterized by discovering a new effect of niclosamide or a pharmaceutically acceptable salt thereof for preventing hair loss or promoting hair growth and / or a new effect of treating or preventing skin diseases (particularly seborrheic dermatitis, etc.), and further comprising a dispersing agent and / or an amino acid, etc. to increase the bioavailability of niclosamide or a pharmaceutically acceptable salt thereof, thereby enabling application to drug treatment excellent in improving hair loss and / or promoting hair growth, thereby exhibiting an effect of treating diseases and alleviating symptoms.

[0242] The composition of the present invention is characterized by the discovery of the possibility of a role as an anticancer adjuvant or combination agent that can enhance the effect of anticancer drugs when used in combination with niclosamide or a pharmaceutically acceptable salt thereof for the prevention or treatment of malignant tumors or with other anticancer drugs.

[0243] The effect of the present invention is characterized by improving the bioavailability of niclosamide, which has been judged to be capable of acting as an anticancer agent or an anti-inflammatory agent, or a pharmaceutically acceptable salt thereof, by using it in combination with a specific inorganic substance, etc., thereby improving the solubility in blood and thereby enabling sufficient medicinal effects.

[0244] In addition, the hair loss prevention or hair growth promotion composition of the present invention has the characteristic of not showing side effects caused by drugs such as existing hair loss treatment agents such as minoxidil, finasteride, and dutasteride, such as decreased libido, erectile dysfunction, breast tenderness, and orthostatic hypotension.

[0245]

[0246] In addition, the present invention can use any commonly used additive other than the above-described composition without limitation. In the present invention, the excipient is most preferably an excipient containing anionic, cationic, neutral polymers and surfactants, oils, fatty acids, etc., and the excipient may be lecithin, fatty acid, glycerol fatty acid esters, sorbitan fatty acid esters, sodium dodecyl sulfate, sodium stearyl fumarate, stearic acid, lauric acid, carrageenan, etc.

[0247] The above lecithin type is a substance for lecithin and its derivatives, and may be phospholipids, phosphatidyl choline, mixed phospholipids, sodium cholate, hydroxylated phospholipids, hydroxylated lecithin, etc. The above oil type may be soybean, MCT oil (Medium-Chain Triglyceride), caster oil, etc. The fatty acids include butyric acid, caproic acid, caprylic acid, capric acid, stearic acid, lauric acid, oleic acid, myristoleic acid, palmitoic acid, oleic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, gadoleic acid, eicosadienoic acid, eicosapentaenoic acid, arachidoic acid, erucic acid, docosadienoic acid, These may include docostrienoicacid, docosapentaenoic acid, docosahexaenoic acid, adrenic acid, and nervonic acid.The above glycerol fatty acid ester may be polyglycerol fatty acid esters, polyglycerol polyricinoleate, polyoxyethyleneglyceroltriricinoleate, cremophor EL, etc. The above sorbitan fatty acid ester may be sorbitan monoaurate (Span 20), sorbitan monooleate (Span 80), etc. When the above-described excipients are used, the solubility and dispersibility of a metal (hydr)oxide complex including a poorly soluble drug can be improved, which may be more preferable in that the bioavailability of the poorly soluble drug can be increased.

[0248] In addition, when the composition of the present invention is not formulated using a sustained-release agent, the cmax may be shown within 1 hour (or within 0.5 hours) due to absorption in the stomach or upper small intestine in the body behavior of the drug after oral administration.

[0249] In addition, the composition of the present invention may further include an enteric coating as needed, and specifically, may include an enteric material selected from the group consisting of hydroxypropyl-methyl cellulose phthalate, zein, shellac, Eudragit, and mixtures thereof as a coating base.

[0250] In addition, the composition of the present invention may further include a pharmaceutically acceptable carrier and may be formulated for human or veterinary use, either oral or parenteral. When formulating the composition for preventing hair loss or promoting hair growth of the present invention, in addition to the components listed above, diluents or excipients such as fillers, extenders, 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 the composition for preventing hair loss or promoting hair growth 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. In addition to the commonly used simple diluents water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases can include witepsol, macrogol, Tween 61, cacao butter, laurin butter, and glycerol.

[0251]

[0252] The composition of the present invention can be administered orally or parenterally depending on the intended method, and when administered parenterally, 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.

[0253]

[0254] The 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 at 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, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or, especially when used as an anticancer agent, may be administered 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.

[0255]

[0256] For example, the composition according to the present invention can be administered at a dosage of 0.0001 to 500 mg / kg, preferably 0.001 to 500 mg / kg, and the administration can be administered once a day to five times a day. In addition, the administration can be administered once every two days to once every ten days, depending on the purpose. Specifically, when the composition according to the present invention is administered for the treatment of Parkinson's disease, it can be administered at 100 mg to 2000 mg per day, and more preferably 210 mg to 1350 mg per day.

[0257]

[0258] The composition of the present invention may contain 0.1 to 60 wt% of niclosamide or a pharmaceutically acceptable salt thereof and 0.2 to 90 wt% of a dispersant, when the total weight of the composition is 100 wt%. The composition may further contain 0.1 to 80 wt% of an inorganic substance.

[0259]

[0260] The composition of the present invention may have one or more of the effects of improving and / or treating inflammatory diseases, antiviral effects, and improving and / or treating malignant tumor diseases.

[0261]

[0262] The inflammatory diseases include vascular restenosis; inflammatory diseases including autoimmune diseases, pancreatitis, glomerulonephritis, myocardial infarction, and psoriasis; atopic diseases including allergic asthma, atopic dermatitis (eczema), and allergic rhinitis; cell-mediated hypersensitivity diseases including allergic contact dermatitis and hypersensitivity pneumonitis; Rheumatic diseases including Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis, Juvenile Arthritis, Sjogren's Syndrome, Scleroderma, Polymyositis, Ankylosing Spondylitis, and Psoriatic Arthritis; Diabetes; Autoimmune Thyroid Disease; Brain Diseases including Epilepsy, Dementia, Parkinson's Disease, and Alzheimer's Disease; and other autoimmune diseases and degenerative diseases including arthritis.

[0263]

[0264] The above malignant tumor diseases are fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma. carcinoma), adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, testicular tumor, lung carcinoma,Cancers including small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma, and carcinomas arising from breast, prostate, kidney, bladder, or colon tissue; It may be a tumor disease that appears in adipose tissue, such as a lipoma, fibrolipoma, lipoblastoma, lipomatosis, hibemoma, hemangioma, and / or liposarcoma.

[0265]

[0266] The composition used for skin diseases in the present invention can be effective for seborrheic dermatitis, atopic dermatitis, psoriasis, erythema, fungal infection, keratosis pilaris, freckles, diaper dermatitis, basal cell carcinoma, impetigo, herpes simplex, shingles, eczema, tinea, urticaria, folliculitis, Behcet's disease, dandruff, warts, pubic lice, intraepithelial neoplasia, cellular nevus, fibroma, pruritus, Pseudomonas infection, Stevens-Johnson syndrome, melanoma, ichthyosis, scabies, bedsores, contact dermatitis, tinea onychomycosis, paronychia, skin tags, seborrheic dermatitis, pemphigus, keloid, cholinergic urticaria, anthrax, dermatomyositis, dermatofibrosarcoma, skin cancer, benign tumor, hidradenitis, pompholyx, etc., and in particular, the composition of the present invention can effectively improve and / or treat seborrheic dermatitis.

[0267]

[0268] The present invention also provides a composition for preventing hair loss or promoting hair growth, and also provides a composition for treating seborrheic dermatitis and a method for preparing the same. Specifically, when the composition of the present invention includes an inorganic substance, a method for preparing the composition is provided, including a step of reacting the inorganic substance with niclosamide or a pharmaceutically acceptable salt thereof in an anhydrous organic solvent.

[0269]

[0270] Another embodiment of the method for preparing a composition of the present invention provides a method for preparing a composition, comprising the steps of drying an inorganic material to prepare a dried inorganic material; and reacting the dried inorganic material with niclosamide or a pharmaceutically acceptable salt thereof in an anhydrous organic solvent.

[0271]

[0272] The temperature at which the inorganic material is dried in the above drying step may be 20-1000°C. As the above drying step progresses, the adsorption amount of the inorganic material and niclosamide or a pharmaceutically acceptable salt thereof may be improved, thereby increasing bioavailability.

[0273]

[0274] In addition, another embodiment of the manufacturing method of the present invention provides a method for manufacturing a composition, comprising a step of mechanochemically mixing an inorganic substance and niclosamide or a pharmaceutically acceptable salt thereof.

[0275]

[0276] In addition, another embodiment of the manufacturing method of the present invention provides a method for manufacturing a composition, comprising a step of simply mixing niclosamide or a pharmaceutically acceptable salt thereof with at least one of a dispersant, a metal hydroxide, and a metal oxide.

[0277]

[0278] In the present invention, the mechanochemical mixing step refers to a method of grinding or milling powder by applying physical force, and any method commonly used in the field can be used without limitation. More specifically, grinding and / or milling synthesis can be used as a synthesis method for solid-state reaction (mechanochemic synthesis). The milling synthesis methods include a grinding mill, wet or dry ball milling, a mortar grinder, a ball mill, a bead mill, a roller mill, a mix & heat, a super-fine grinding mill, an attrition mill, etc., and these methods can reduce the particle size of the powder material and achieve the effects of grinding, dispersion, and mixing. Including the mechanochemical mixing step as described above can have the advantages of low manufacturing costs and less waste generated after manufacturing. The mechanochemical mixing method, which corresponds to a solvent-free manufacturing method using a solid phase, can be preferable in that it can minimize the restoration of the inorganic material to its pre-drying state by the solvent when the inorganic material undergoes a drying step.

[0279] Manufacturing example

[0280] <STEP 1>

[0281] Take 3g of hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) powder and place it in each of three reaction vessels and dry it at 350℃ for 8 hours.

[0282] <STEP 2>

[0283] 50 ml of absolute ethanol was placed in each container and the powder was well dispersed by sonication for 10 minutes. The solution was stirred at 700 rpm or higher, 3 g of niclosamide was added, and the stirring was continued for 6 hours. For purification, the filtrate was removed through a filter membrane, washed 4-5 times with absolute ethanol, and then vacuum-dried to obtain a yellow powder. The final niclosamide content was 46%.

[0284] <STEP 3>

[0285] In addition to the DHT-NIC complex manufactured by Steps 1 and 2, an additional solution of niclosamide and HPMC dissolved in anhydrous ethanol and dichloromethane was added, stirred, and then evaporated (or spray dried) to manufacture a composition for preventing hair loss or promoting hair growth of Examples 1 to 6 below. Examples 1 to 6 are slightly different from the contents of STEP 3 described below, and other implementation methods are as described in the manufacturing examples.<STEP 1> and<STEP 2> It was manufactured using the method of .

[0286] Examples 1 to 6

[0287] Example 1 STEP 3

[0288] Dissolve 0.546 g of HPMC in a 1:1 ratio solution of absolute ethanol and dichloromethane in a main tank. Add 2.728 g of DHT-NIC prepared in the above manufacturing example to the main tank and stir rapidly for 30 minutes. Evaporate the solvent using a rotary evaporator, and dry the obtained hair loss prevention or hair growth promotion composition (yellow powder) to obtain a hair loss prevention or hair growth promotion composition.

[0289] Example 2 STEP 3

[0290] Dissolve 0.390 g of HPMC in a 1:1 ratio solution of absolute ethanol and dichloromethane in a main tank. Add 0.61 g of niclosamide to this solution and dissolve, then add 1.34 g of DHT-NIC to the main tank and stir rapidly for 30 minutes. Evaporate the solvent using a rotary evaporator, and dry the resulting hair loss prevention or hair growth promotion composition (yellow powder) to obtain a hair loss prevention or hair growth promotion composition.

[0291] Example 3 STEP 3

[0292] Dissolve 0.316 g of HPMC in a 1:1 ratio solution of absolute ethanol and dichloromethane in a main tank. Add 0.906 g of niclosamide to this solution and dissolve, then add 1.34 g of DHT-NIC to the main tank and stir rapidly for 30 minutes. Evaporate the solvent using a rotary evaporator, and dry the resulting hair loss prevention or hair growth promotion composition (yellow powder) to obtain a hair loss prevention or hair growth promotion composition.

[0293] Example 4 STEP 3

[0294] Dissolve 1.092 g of tween60 in anhydrous ethanol solution in a main tank. Add 2.728 g of DHT-NIC to the main tank and stir rapidly for 30 minutes. Evaporate the solvent using a rotary evaporator, and dry the resulting hair loss prevention or hair growth promotion composition (yellow powder) to obtain a hair loss prevention or hair growth promotion composition.

[0295] Example 5 STEP 3

[0296] Dissolve 0.78 g of tween60 in anhydrous ethanol solution in a main tank. Add 0.61 g of niclosamide to this solution and dissolve, then add 1.34 g of DHT-NIC to the main tank and stir rapidly for 30 minutes. Evaporate the solvent using a rotary evaporator, and dry the resulting hair loss prevention or hair growth promotion composition (yellow powder) to obtain a hair loss prevention or hair growth promotion composition.

[0297] Example 6 STEP 3

[0298] Dissolve 0.632 g of tween60 in anhydrous ethanol solution in a main tank. Add 0.906 g of niclosamide to this solution and dissolve, then add 1.34 g of DHT-NIC to the main tank and stir rapidly for 30 minutes. Evaporate the solvent using a rotary evaporator, and dry the resulting hair loss prevention or hair growth promotion composition (yellow powder) to obtain a hair loss prevention or hair growth promotion composition.

[0299] The specific contents of the hair loss prevention or hair growth promotion compositions of Examples 1 to 6 manufactured by the above-described method are as shown in Tables 1 and 2 below.

[0300] [Table 1]

[0301]

[0302] [Table 2]

[0303]

[0304] Examples 7-1 to 7-4

[0305] <step1>

[0306] Take 3g of Mg(OH)2 powder each and place it in two reaction vessels and perform calcination for 6 hours under conditions of 200℃(12-1) and 300℃(12-2).

[0307] <step2>

[0308] 50 ml of absolute ethanol was placed in each container and the powder was well dispersed by sonication for 10 minutes. The solution was stirred at 700 rpm or higher, 3 g of niclosamide was added, and the mixture was stirred for 4 hours. For purification, the filtrate was removed through a filter membrane, washed 4 to 5 times with absolute ethanol, and then vacuum-dried to obtain a yellow powder. The final niclosamide content was 35.2% for the composite calcined at 200°C (metal hydroxide-NIC complex of Example 7-1), and 14.5% for the composite calcined at 300°C (metal hydroxide-NIC complex of Example 7-2).

[0309] <step3>

[0310] 2 g of each metal hydroxide-NIC complex prepared by Steps 1 and 2 above was added to a 1:1 ratio solution of anhydrous ethanol and dichloromethane containing HPMC, stirred, and then evaporated (or spray dried) to prepare a composition for preventing hair loss or promoting hair growth.

[0311] The specific contents of the hair loss prevention or hair growth promotion compositions of Examples 7-3 and 7-4 manufactured by the above-described method are as shown in Table 3 below.

[0312] [Table 3]

[0313]

[0314] Examples 8-1 and 8-2

[0315] <step1>

[0316] Take 3g of MgO powder, place it in a reaction vessel, and perform calcination at 800℃ for 6 hours.

[0317] <STEP 2>

[0318] 50 ml of absolute ethanol was placed in each container and the powder was well dispersed by sonication for 10 minutes. The solution was stirred at 700 rpm or higher, 3 g of niclosamide was added, and the stirring was continued for 4 hours. For purification, the filtrate was removed through a filter membrane, washed 4-5 times with absolute ethanol, and then vacuum-dried to obtain a yellow powder. The final niclosamide content was 34.6% (Example 8-1).

[0319] <STEP 3>

[0320] 2 g of the MgO-NIC complex manufactured by the above Steps 1 and 2 was added to a 1:1 ratio solution of anhydrous ethanol and dichloromethane containing 0.306 g of HPMC, stirred, and then evaporated (or spray dried) to manufacture a composition for preventing hair loss or promoting hair growth of Example 8-2.

[0321] The specific content of the composition for preventing hair loss or promoting hair growth of Example 8-2 manufactured by the above-described method is as shown in Table 4 below.

[0322] [Table 4]

[0323]

[0324] Example 9

[0325] <STEP 1>

[0326] Take 3g of MgO powder and place it in a reaction vessel, add 50ml of absolute ethanol to the vessel, and sonicate to disperse the powder well for 10 minutes. Stir the solution at 700 rpm or higher, add 3g of niclosamide, and stir for 4 hours. For purification, remove the filtrate through a filter membrane, wash with absolute ethanol 4-5 times, and then vacuum dry to obtain a yellow powder.

[0327] <STEP 2>

[0328] 2 g of the MgO-NIC complex manufactured by Step 1 above was added to a 1:1 ratio solution of anhydrous ethanol and dichloromethane containing 0.306 g of HPMC, stirred, and then evaporated (or spray dried) to manufacture a composition for preventing hair loss or promoting hair growth.

[0329] Example 10

[0330] Add 3g of niclosamide, 3g of MgO, and 1.5g of HPMC to a mortar container and grind for 10 minutes using a grinder.

[0331] Example 11

[0332] Place zirconium balls, 3 g of niclosamide, 3 g of MgO, and 1.5 g of HPMC in a milling container and mill at 250 rpm for 10 minutes.

[0333] Example 12

[0334] <STEP 1>

[0335] Take 3g of each hydrotalcite (Sigma Aldrich or Kwoya Chemical Industry CO., LTD) powder and place it in each of three reaction vessels and dry it at 350℃ for 8 hours.

[0336] <STEP 2>

[0337] Add zirconium balls, 3 g of niclosamide, 3 g of dried hydrotalcite (DHT), HPMC, and 10 ml of anhydrous ethanol to a milling container and mill at 250 rpm for 10 minutes.

[0338] Example 13

[0339] Place zirconium balls, 4 g of niclosamide, 2.8 g of MgO, and 1 g of HPMC in a milling container and mill at 250 rpm for 10 minutes.

[0340] Example 14

[0341] Add zirconium balls, 4 g of niclosamide, 2.8 g of MgO, 1 g of HPMC, and 3 ml of anhydrous ethanol to a milling container and mill at 250 rpm for 10 minutes.

[0342] Example 15

[0343] Add 4g of niclosamide, 4g of MgO, and 2g of HPMC to the container and perform simple mixing.

[0344] Example 16

[0345] A composition was prepared by placing 4 g of niclosamide, 4 g of MgO, and 2 g of HPMC in a container and suspending it using 5% Tween 60.

[0346] Example 17

[0347] Add 3g of niclosamide and 3g of MgO to the container and mix by moving up and down or shaking.

[0348] Example 18

[0349] Add 3g of niclosamide and 3g of hydrotalcite to the container and mix by moving up and down or shaking.

[0350] Example 19

[0351] Add 3g of niclosamide and 3g of MgO to the container and mix by voltexing.

[0352] Example 20

[0353] Add 3g of niclosamide and 3g of hydrotalcite to the container and mix using voltexing.

[0354] Example 21

[0355] In a round-bottom flask, dissolve 4 g of PVP in 50 mL of absolute ethanol, add 1 g of Niclosamide, stir for about 1 hour, and dry. Dry mix 5 g of dried NIC-PVP and 2 g of MgO.

[0356] Example 22

[0357] In a round-bottom flask, dissolve 4 g of PVP in 50 mL of absolute ethanol, add 1 g of Niclosamide, stir for about 1 hour, and dry. Dry mix 5 g of dried NIC-PVP, 2 g of MgO, and 0.368 g of alginate-Na.

[0358] Example 23

[0359] In a round-bottom flask, dissolve 4 g of PVP in 50 mL of absolute ethanol, add 1 g of Niclosamide, stir for about 1 hour, and dry. Dry mix 5 g of dried NIC-PVP, 2 g of MgO, and 0.368 g of xanthan gum.

[0360] Example 24

[0361] In a round-bottom flask, dissolve 4 g of PVP in 50 mL of absolute ethanol, add 1 g of Niclosamide, stir for about 1 hour, and dry. Dry mix 5 g of dried NIC-PVP, 2 g of MgO, and 0.368 g of chitosan.

[0362] Example 25

[0363] In a round bottom flask, dissolve 4g of PVP and 1g of polyethylene glycol 400 in 50mL of absolute ethanol. Add 1g of Niclosamide to the solution and stir for about 1 hour to make a solution.

[0364] Example 26

[0365] Add 10 ml of purified water, 45 ml of ethanol, 45 ml of propylene glycol, and 21 ml of polyethylene glycol 400 to a beaker and mix until homogeneous. Heat to above 40 degrees to create a yellow solution.

[0366] Example 27

[0367] Add 10 ml of purified water, 45 ml of ethanol, 5 g of polysorbate 20, and 21 ml of sorbitol to a beaker and mix until homogeneous to create a yellow solution.

[0368] Example 28

[0369] In a round-bottom flask, 1 g of Niclosamide is added to a solution of 4 g of PVP dissolved in 50 mL of absolute ethanol, stirred for about 1 hour, 1 g of HPMC (6 mPas) is added, stirred for 1 hour, and the solvent is completely removed through a rotary evaporator to obtain a yellow powder.

[0370] Example 29

[0371] In a round-bottom flask, add 1 g of Niclosamide to a solution of 4 g of PVP dissolved in 50 mL of absolute ethanol and stir for about 1 hour. Then, add 1 g of poloxamer and 1 g of HPMC (6 mPas) and stir for 1 hour. Completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0372] Example 30

[0373] In a round-bottom flask, dissolve 4 g of PVP in 50 mL of absolute ethanol. Add 1 g of Niclosamide to the solution and stir for about 1 hour. Then, add 0.18 g of chitosan and 2 g of MgO and stir for 1 hour. Completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0374] Example 31

[0375] In a round-bottom flask, dissolve 4 g of PVP in 50 mL of absolute ethanol. Add 1 g of Niclosamide to the solution and stir for about 1 hour. Then, add 1 g of HPMC (6 mPas), 1 g of poloxamer, and 2 g of MgO and stir for 1 hour. Completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0376] Example 32

[0377] In a round-bottom flask, dissolve 8 g of PVP in 50 mL of absolute ethanol. Add 1 g of Niclosamide to the solution and stir for about 1 hour. Then, add 1 g of HPMC (6 mPas), 1 g of poloxamer, and 2 g of MgO and stir for 1 hour. Completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0378] Example 33

[0379] In a round-bottom flask, dissolve 8 g of PVP in 50 mL of absolute ethanol. Add 1 g of Niclosamide to the solution and stir for about 1 hour. Then, add 1 g of PEG1400 and stir for 1 hour. Completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0380] Example 34

[0381] In a round-bottom flask, dissolve 4 g of PVP in 20 mL of absolute ethanol, add 1 g of Niclosamide, and stir for 1 hour. Add 2 g of MgO and 0.53 g of arginine, stir for 1 hour, and then completely remove the solvent through a rotary evaporator to obtain a yellow powder.

[0382] Example 35

[0383] In a round-bottom flask, dissolve 4 g of PVP in 20 mL of absolute ethanol, add 1 g of Niclosamide, and stir for 1 hour. Add 2 g of MgO, 0.2 g of PGA (poly gamma glutamic acid), and 0.53 g of arginine, and stir for 1 hour. Then, completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0384] Example 36

[0385] In a round-bottom flask, add 1 g of Niclosamide to a solution of 4 g of PVP dissolved in 20 mL of absolute ethanol and stir for 1 hour. Add 2 g of MgO, 0.2 g of PGA (poly gamma glutamic acid), 0.5 g of SDS (sodium dodecyl sulfate), and 0.53 g of arginine and stir for 1 hour. Then, completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0386] Example 37

[0387] In a round-bottom flask, add 2 g of MgO, 0.2 g of PGA (poly gamma glutamic acid), 0.5 g of SDS (sodium dodecyl sulfate), and 0.53 g of arginine to a solution of 1 g of niclosamide dissolved in 20 mL of absolute ethanol, stir for 1 hour, and then completely remove the solvent through a rotary evaporator to obtain a yellow powder.

[0388] Example 38

[0389] In a round-bottom flask, add 1 g of MgO and 0.3 g of arginine to a solution of 1 g of niclosamide dissolved in 50 mL of absolute ethanol, stir for 1 hour, and then completely remove the solvent through a rotary evaporator to obtain a yellow powder (granules). Coat the granules with a composition of 10% coating ratio of HP-50, an enteric coating agent, using a fluidized bed coater.

[0390] Example 39

[0391] In a round-bottom flask, add 1 g of MgO to a solution of 1 g of niclosamide dissolved in 50 mL of absolute ethanol, stir for 1 hour, and then completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder (granules). After coating the granules with a composition of 5% of the enteric coating agent Eudragit L-100, the solvent from the solution is completely removed using a rotary evaporator to obtain a yellow powder.

[0392] Example 40

[0393] In a round-bottom flask, add 1 g of Niclosamide to a solution of 1 g of PVP dissolved in 50 mL of absolute ethanol, stir for about 1 hour, then add 1 g of MgO and stir for 1 hour. The solution is then used in a rotary evaporator to completely remove the solvent, obtaining a yellow powder.

[0394] Example 41

[0395] In a round-bottom flask, 1 g of Niclosamide is added to a solution of 2 g of PVP dissolved in 50 mL of absolute ethanol, stirred for about 1 hour, 1 g of MgO is added, stirred for 1 hour, and the solution is completely removed from the solvent through a rotary evaporator to obtain a yellow powder.

[0396] Example 42

[0397] In a round-bottom flask, 1 g of Niclosamide is added to a solution of 4 g of PVP dissolved in 50 mL of absolute ethanol, stirred for about 1 hour, 1 g of MgO is added, stirred for 1 hour, and the solution is completely removed from the solvent through a rotary evaporator to obtain a yellow powder.

[0398] Example 43

[0399] In a round bottom flask, 1 g of Niclosamide is added to a solution of 8 g of PVP dissolved in 50 mL of absolute ethanol, stirred for about 1 hour, 1 g of MgO is added, stirred for 1 hour, and the solution is completely removed from the solvent through a rotary evaporator to obtain a yellow powder.

[0400] Example 44

[0401] In a round-bottom flask, dissolve 1 g of PVP in 50 mL of absolute ethanol. Add 1 g of Niclosamide to the solution and stir for about 1 hour. Then, add 1 g of poloxamer and stir for 1 hour. Add 1 g of MgO and stir for 1 hour. Then, completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0402] Example 45

[0403] In a round-bottom flask, dissolve 2 g of PVP in 50 mL of absolute ethanol. Add 1 g of Niclosamide to the solution and stir for about 1 hour. Then, add 1 g of poloxamer and stir for 1 hour. Add 1 g of MgO and stir for 1 hour. Then, completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0404] Example 46

[0405] In a round-bottom flask, dissolve 4 g of PVP in 50 mL of absolute ethanol. Add 1 g of Niclosamide to the solution and stir for about 1 hour. Then, add 1 g of poloxamer and stir for 1 hour. Add 1 g of MgO and stir for 1 hour. Then, completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0406] Example 47

[0407] In a round-bottom flask, dissolve 8 g of PVP in 50 mL of absolute ethanol. Add 1 g of Niclosamide to the solution and stir for about 1 hour. Then, add 1 g of poloxamer and stir for 1 hour. Add 1 g of MgO and stir for 1 hour. Then, completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0408] Example 48

[0409] In a round-bottom flask, add 200 mL of 70% ethanol and 0.27 mL of hydroxypropylmethylcellulose 6 (HPMC6) and dissolve. Add 4 g of niclosamide to this solution, stir for 3 minutes, and dry in a vacuum oven. To the dried mixture, add 2.8 g of magnesium oxide (MgO) and 5 mL of absolute ethanol, mix, and dry in a vacuum oven to obtain the substance.

[0410] Reference Example 1

[0411] In a round-bottom flask, add 1 g of Niclosamide to a solution of 1 g of PVP dissolved in 50 mL of absolute ethanol and stir for about 1 hour. Completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0412] Reference Example 2

[0413] In a round-bottom flask, dissolve 2 g of PVP in 50 mL of absolute ethanol. Add 1 g of Niclosamide to the solution and stir for about 1 hour. Completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0414] Reference Example 3

[0415] In a round-bottom flask, dissolve 4 g of PVP in 50 mL of absolute ethanol. Add 1 g of Niclosamide to the solution and stir for about 1 hour. Completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0416] Reference Example 4

[0417] In a round-bottom flask, dissolve 8 g of PVP in 50 mL of absolute ethanol. Add 1 g of Niclosamide to the solution and stir for about 1 hour. Completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0418] Reference Example 5

[0419] In a round-bottom flask, 1 g of Niclosamide is added to a solution of 1 g of PVP dissolved in 50 mL of absolute ethanol, stirred for about 1 hour, then 1 g of poloxamer is added and stirred for 1 hour, and the solvent is completely removed through a rotary evaporator to obtain a yellow powder.

[0420] Reference Example 6

[0421] In a round bottom flask, 1 g of Niclosamide is added to a solution of 2 g of PVP dissolved in 50 mL of absolute ethanol, stirred for about 1 hour, then 1 g of poloxamer is added and stirred for 1 hour, and the solvent is completely removed through a rotary evaporator to obtain a yellow powder.

[0422] Reference Example 7

[0423] In a round-bottom flask, 1 g of Niclosamide is added to a solution of 4 g of PVP dissolved in 50 mL of absolute ethanol, stirred for about 1 hour, then 1 g of poloxamer is added and stirred for 1 hour, and the solvent is completely removed through a rotary evaporator to obtain a yellow powder.

[0424] Reference Example 8

[0425] In a round bottom flask, 8g of PVP is dissolved in 50mL of absolute ethanol. 1g of Niclosamide is added to the solution and stirred for about 1 hour. Then, 1g of poloxamer is added and stirred for 1 hour. The solution is completely removed from the solvent through a rotary evaporator to obtain a yellow powder.

[0426] Reference Example 9

[0427] In a round-bottom flask, dissolve 4 g of PVP in 50 mL of absolute ethanol. Add 1 g of Niclosamide to the solution and stir for about 1 hour. Then, add 1 g of HPMC (6 mPas) and stir for 1 hour. Completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0428] Reference Example 10

[0429] In a round-bottom flask, dissolve 4 g of PVP in 50 mL of absolute ethanol. Add 1 g of Niclosamide to the solution and stir for about 1 hour. Then, add 1 g of HPMC (6 mPas) and 1 g of poloxamer and stir for 1 hour. Completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0430] Reference Example 11

[0431] In a round-bottom flask, dissolve 8 g of PVP in 50 mL of absolute ethanol. Add 1 g of Niclosamide to the solution and stir for about 1 hour. Then, add 1 g of sodium dodecyl sulfate and stir for 1 hour. Completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0432] Reference Example 12

[0433] In a round-bottom flask, dissolve 1 g of Poloxamer407 in 15 mL of absolute ethanol. Add 1 g of Niclosamide and 0.5 g of HPMC (6 mPas) to the solution and stir for about 1 hour. Completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0434] Reference Example 13

[0435] In a round-bottom flask, dissolve 1 g of Poloxamer407 in 15 mL of absolute ethanol. Add 1 g of Niclosamide and 1 g of HPMC (6 mPas) to the solution and stir for about 1 hour. Completely remove the solvent from the solution using a rotary evaporator to obtain a yellow powder.

[0436]

[0437] Experimental Example 1: In-vivo pharmacokinetic analysis of compositions of examples and comparative examples (hamster or rat)

[0438] In vivo pharmacokinetic analysis was performed using the compositions of Examples 1, 4, Examples 13 to 16, Examples 28 to 30 and Reference Examples 12 and 13. Experimental Example 1: In vivo pharmacokinetic analysis of the compositions of Examples and Comparative Examples (hamster or rat)

[0439] In vivo pharmacokinetic analysis was performed using the compositions of Examples 1 and 4, Examples 13 to 16, Examples 28 to 30, and Reference Examples 12 and 13. The compositions of Examples 1 and 4, Examples 13 to 16, and Examples 28 to 30 were administered orally to hamsters, and then plasma drug concentration information was obtained. The compositions of Reference Examples 12 and 13 were administered orally to rats, and then plasma drug concentration information was obtained.

[0440] In addition, the composition of Example 1 was administered at a dose of 10, 33 or 100 mg / kg, respectively, the composition of Example 4 was administered at a dose of 100 mg / kg, and the compositions of Examples 13 to 16 and Examples 28 to 30 were administered at a dose of 50 mg / kg, respectively, to conduct the experiment.

[0441] In the above analysis, the results of administration of Example 1 or Example 4 are shown in FIG. 1 and Table 1, the results of administration of Examples 13 to 16 are shown in FIG. 2, and the results of administration of Examples 28 to 30 are shown in FIG. 3. The graphs in FIGS. 1 to 3 show the NIC concentration in plasma over time in hamsters. Specific pharmacokinetic parameters are described in Tables 1 to 3 below, and the relationship between the tested composition and AUC is shown in FIG. 4. As a result of the experiment, it was found that excipients such as PVP, HPMC, and poloxamer contributed to improving the bioavailability of the drug when formulated with niclosamide, and it was confirmed that the combination of PVP, HPMC, and poloxamer was more effective in improving the bioavailability of niclosamide than the combination of PVP and HPMC. In addition, the results of administration of Reference Examples 12 and 13 are shown in FIG. 5. The graph in FIG. 5 shows the NIC concentration in plasma over time in rats. Experiments also confirmed that the excipients HPMC and poloxamer could not only improve the bioavailability of niclosamide but also increase the duration of its blood concentration.

[0442] [Table 5]

[0443]

[0444] * AUC: ng·h / mL, C max : ng / mL, T max & t 1 / 2 : h

[0445] [Table 6]

[0446]

[0447] [Table 7]

[0448]

[0449] Experimental Example 2: In-vivo pharmacokinetic analysis of the compositions of the examples and reference examples (Beagle)

[0450] In vivo pharmacokinetic analysis was performed using the compositions of Examples 31 to 37 and Reference Examples 9 to 11. The compositions of Examples 31 to 37 and Reference Examples 9 to 11 were administered orally as a single dose to beagles to obtain plasma drug concentration information.

[0451] In addition, the compositions of Examples 31 to 37 and Reference Examples 9 to 11 were each administered once a day at a dose of 20 mg / kg.

[0452] In the above analysis, the administration results of Examples 31 to 37 and Reference Examples 9 to 11 are shown in FIGS. 6 to 9. The graphs in FIGS. 6 and 8 show the NIC concentration in the plasma of a beagle over time. Specific pharmacokinetic parameters are described in Tables 8 to 11 below. The relationship between the tested composition and AUC is shown in FIGS. 7 and 9.

[0453] [Table 8]

[0454]

[0455] [Table 9]

[0456]

[0457] [Table 10]

[0458]

[0459] [Table 11]

[0460]

[0461]

[0462] Experimental Example 3: In-vivo pharmacokinetic analysis of the compositions of the examples and reference examples (minipigs)

[0463] In vivo pharmacokinetic analysis was performed by single oral administration of the compositions of Examples 38 and 39 to minipigs to obtain plasma drug concentration information.

[0464] Additionally, the compositions of Examples 38 and 39 were each administered once a day at a dose of 500 mg / head.

[0465] The administration results of Examples 38 and 39 in the above analysis are shown in FIGS. 10 and 11. The graph in FIG. 8 shows the plasma NIC concentration of minipigs over time. Through the experiment, it was confirmed that enteric coating agents (HP-50, L-100) contributed to improving the bioavailability of niclosamide, and in particular, it was discovered that bioavailability could be maximized through the addition of arginine, a basic amino acid. Specific pharmacokinetic parameters are described in Tables 12 and 13 below. The relationship between the tested composition and AUC is shown in FIG. 9.

[0466]

[0467] [Table 12]

[0468]

[0469]

[0470] [Table 13]

[0471]

[0472] Experimental Example 4: Evaluation of the hair growth effect of a test substance in a C57BL / 6 mouse model of dihydrotestosterone (DHT) and testosterone-induced alopecia.

[0473] This experiment was designed to determine whether the test substance has a hair loss prevention or hair growth promotion effect and a preventive and / or therapeutic effect on prostate cancer. Dihydrotestosterone (hereinafter referred to as 'DHT'; TOKYO CHEMICAL INDUSTRY CO., LTD.) as hair loss inducer 1 was used in mice, or Testosterone (Testosterone propionate; TOKYO CHEMICAL INDUSTRY CO., LTD.) as hair loss inducer 2 was administered to mice, and the effect of administration of the test substance on hair growth promotion was evaluated in a C57BL / 6 mouse model of alopecia.

[0474] The composition of Example 14 of the present invention was administered, and Avodart (Dutasteride) was administered as positive control substance 1, and Propecia (Finasteride) was administered as positive control substance 2 to confirm the hair growth promotion effect and / or hair loss prevention effect.

[0475] Test system information

[0476]

[0477] [Table 14]

[0478]

[0479] The mice obtained as shown in Table 14 above were observed for general symptoms for 7 days (acclimatization period) after acquisition to confirm their health status, and healthy animals were used in the test.

[0480]

[0481] Test group composition

[0482] [Table 15]

[0483]

[0484] Setting the dosage and amount of administration

[0485] In accordance with the client's request, the composition of Example 14 and positive control substances 1 and 2 were administered orally, and the hair loss-inducing substance (Testosterone, DHT) was administered subcutaneously. For Testosterone, the dose was set at 5 mg / mL and 0.1 mL / head, and for DHT, the dose was set at 10 mg / kg and 10 mg / mL. The specific number of times and duration of administration of the hair loss-inducing substance are as follows.

[0486] Testosterone, DHT

[0487] : It was administered daily at intervals of 1 time / day. The start date of testosterone and DHT administration was set as Day 0.

[0488] G1

[0489] : Administered daily at 1-time / day intervals from Day 0.

[0490] G4, G5

[0491] : Administered daily at 1-time / day intervals from Day 0.

[0492] G6, G7

[0493] : Administered daily at 2-day intervals from Day 2.

[0494] In addition, the composition of Example 14 and positive control substances 1 and 2 were administered as indicated in Table 11 above.

[0495] Observation and inspection items

[0496] (1) Hair removal

[0497] Hair removal was performed on Day -1 without using hair removal cream. After hair removal, individuals with red backs were selected and grouped.

[0498]

[0499] (2) Photographing and analysis

[0500] On days 0, 7, 14, 21, 28, 35, and 42, animals were anesthetized, and the application sites were photographed with a digital camera and analyzed using ImageJ software (NIH, Bethesda, MD).

[0501]

[0502] (3) Weight measurement

[0503] Body weight was measured on days 0, 7, 14, 21, 28, 35, 42, and 49.

[0504]

[0505] (4) Autopsy

[0506] On day 49, the skin was removed and fixed in 10% neutral buffered formalin solution.

[0507]

[0508] (5) Histopathological examination

[0509] The fixed tissues underwent general tissue processing such as trimming, dehydration, paraffin embedding, and sectioning to prepare specimens for histopathological examination, and then hematoxylin & eosin (H&E) staining was performed. Hair follicle formation and hair growth efficacy were evaluated using an optical microscope (Olympus BX53, Japan), and skin thickness was measured. The histopathological examination was compared based on the number of hair follicles and dermal thickness based on the number of hair follicles in a typical mouse (11-12). The degree of decrease was assigned a score of mild; -1, moderate; -2, severe; -3, and the degree of increase was assigned a score of mild; +1, moderate; +2, severe; +3 (Lee et al, 2017; Lee et al, 2016).

[0510]

[0511] Statistical analysis

[0512] For the results of this study, parametric or non-parametric multiple comparison procedures were used. For parametric multiple comparisons, one-way ANOVA was applied, and if the ANOVA results were significant, Dunnett's multiple comparison test was performed as a post hoc test to examine the significance between the test groups. For non-parametric multiple comparisons, the Kruskal-Wallis' H-test was performed, and if the results were significant, the Mann Whitney test was used as a post hoc analysis to examine the significance between the test groups. Statistical analysis was performed using Prism 9.4.1 (GraphPad Software Inc., San Diego, CA, USA), and a p value less than 0.05 was considered statistically significant.

[0513] result

[0514] (1) Weight

[0515] Body weight changes are shown in Tables 16 and 17. From Day 0 to Day 49, the body weight levels of the DHT-induced NIC-A1 100 mg / kg administration group (G6) and the DHT-induced NIC-A1 200 mg / kg administration group (G7) were significantly lower than those of the vehicle control group 2 (G3) (p<0.001), and significantly lower than those of the normal control group (G1) on Day 0 (p<0.01 or p<0.05). On Day 7, the body weight levels of the vehicle control group 1 (G2), G3, and testosterone-induced NIC-A1 100 mg / kg administration group (G6) were significantly higher than those of G1 (p<0.001 or p<0.01), and on Day 14, the body weight levels of G2, G3, positive control group 1 (G4), and positive control group 2 (G5) were significantly higher than those of G1 (p<0.001 or p<0.05). From Day 21 to Day 49, the body weight levels of G2, G3, G4, and G5 were significantly higher than those of G1 (p<0.001 or p<0.01), and on Day 21 and Day 35, the body weight level of G4 was significantly lower than that of G2 (p<0.05).

[0516] [Table 16]

[0517]

[0518] Data are expressed as Mean±SD

[0519] The day of the first administration of the induced substance was designated as Day 0

[0520] G1: Normal control, G2: Vehicle control (Testosterone), G3: Vehicle control (DHT), G4: Testosterone + Dutasteride 0.5 mg / kg, G5: Testosterone + Finasteride 0.5 mg / kg, G6: Testosterone + NIC-A1 100 mg / kg, G7: Testosterone + NIC-A1 200 mg / kg, G8: DHT + NIC-A1 100 mg / kg, G9: DHT + NIC-A1 200 mg / kg

[0521] *** / ** / * A significant difference at p<0.001 / p<0.01 / p<0.05 level compared to G1

[0522]

[0523] [표 17]

[0524]

[0525] Data are expressed as Mean±S.D.

[0526] The day of the first administration of the induced substance was designated as Day 0

[0527] G1: Normal control, G2: Vehicle control (Testosterone), G3: Vehicle control (DHT), G4: Testosterone + Dutasteride 0.5 mg / kg, G5: Testosterone + Finasteride 0.5 mg / kg, G6: Testosterone + NIC-A1 100 mg / kg, G7: Testosterone + NIC-A1 200 mg / kg, G8: DHT + NIC-A1 100 mg / kg, G9: DHT + NIC-A1 200 mg / kg

[0528] *** / ** / * A significant difference at p<0.001 / p<0.01 / p<0.05 level compared to G1

[0529] ## / # A significant difference at p<0.01 / p<0.05 level compared to G2

[0530] $$$ A significant difference at p<0.001 level compared to G3

[0531] (3) Hair growth area

[0532] Specific data on hair growth area are shown in Tables 18 and 19 and Figs. 12 and 13. The analysis results showed that from Day 7 to Day 21, the hair growth area levels of all hair loss-induced groups (G2-G7) were significantly lower than those of G1 (p<0.001 or p<0.01), and from Day 28 to Day 35, the hair growth area levels of all hair loss-induced groups (G2-G7) except G5 were significantly lower than those of G1 (p<0.001 or p<0.05). On Day 42, the hair growth area levels of all hair loss-induced groups (G2-G7) except G2 and G5 were significantly lower than those of G1 (p<0.001). On Day 21, the hair growth area level of G5 was significantly higher than that of G2 (p<0.05), and from Day 35 to Day 42, the hair growth area level of G4 was significantly lower than that of G2 (p<0.05).

[0533] On day 42, the hair growth area levels of G6 and G7 were significantly higher than those of G3 (p<0.01 or p<0.05).

[0534] [Table 18]

[0535]

[0536] Data are expressed as Mean±SD

[0537] The day of the first administration of the induced substance was designated as Day 0

[0538] G1: Normal control, G2: Vehicle control (Testosterone), G3: Vehicle control (DHT), G4: Testosterone + Dutasteride 0.5 mg / kg, G5: Testosterone + Finasteride 0.5 mg / kg, G6: Testosterone + NIC-A1 100 mg / kg, G7: Testosterone + NIC-A1 200 mg / kg, G8: DHT + NIC-A1 100 mg / kg, G9: DHT + NIC-A1 200 mg / kg

[0539] *** / ** / * A significant difference at p<0.001 / p<0.01 / p<0.05 level compared to G1

[0540]

[0541] [표 19]

[0542]

[0543] Data are expressed as Mean±S.D.

[0544] The day of the first administration of the induced substance was designated as Day 0

[0545] G1: Normal control, G2: Vehicle control (Testosterone), G3: Vehicle control (DHT), G4: Testosterone + Dutasteride 0.5 mg / kg, G5: Testosterone + Finasteride 0.5 mg / kg, G6: Testosterone + NIC-A1 100 mg / kg, G7: Testosterone + NIC-A1 200 mg / kg, G8: DHT + NIC-A1 100 mg / kg, G9: DHT + NIC-A1 200 mg / kg

[0546] *** / ** A significant difference at p<0.001 / p<0.01 level compared to G1

[0547] ### / ## A significant difference at p<0.001 / p<0.01 level compared to G2

[0548] $$ / $ A significant difference at p<0.01 / p<0.05 level compared to G3

[0549]

[0550] As a result of examining the hair growth area confirmed above, it was confirmed that the composition of the present invention is remarkably effective in promoting hair growth and preventing hair loss in response to DHT. That is, it can be confirmed that it can inhibit cell signaling by DHT-androgen receptor binding or inhibit the role by 5AR. In other words, it was confirmed that not only the hair growth effect that can be confirmed with the naked eye from the hair growth promotion or hair loss prevention effect of niclosamide, but also the mechanism by androgen or 5AR that can affect prostate cancer can be inhibited, thereby confirming that it can be applied to the treatment of prostate cancer.

[0551]

[0552] (4) Histopathological examination

[0553] Specific results of the histopathological examination are detailed in Table 20. The analysis results showed that the dermal thickness level of G2 was significantly lower than that of G1 (p<0.05), and the dermal thickness levels of G5, G6, and G7 were significantly higher than that of G1 (p<0.001 or p<0.05). The dermal thickness levels of G4 and G5 were significantly higher than that of G2 (p<0.05), and the dermal thickness levels of G6 and G7 were significantly higher than that of G3 (p<0.05).

[0554] The follicle count levels of G4, G6, and G7 were significantly higher than those of G1 (p<0.05), and the follicle count level of G4 was significantly higher than those of G2 (p<0.05).

[0555] [Table 20]

[0556]

[0557] Data are expressed as Mean±SD

[0558] The day of the first administration of the induced substance was designated as Day 0

[0559] G1: Normal control, G2: Vehicle control (Testosterone), G3: Vehicle control (DHT), G4: Testosterone + Dutasteride 0.5 mg / kg, G5: Testosterone + Finasteride 0.5 mg / kg, G6: Testosterone + NIC-A1 100 mg / kg, G7: Testosterone + NIC-A1 200 mg / kg, G8: DHT + NIC-A1 100 mg / kg, G9: DHT + NIC-A1 200 mg / kg

[0560] *** / ** A significant difference at p<0.001 / p<0.01 level compared to G1

[0561] ### / ## A significant difference at p<0.001 / p<0.01 level compared to G2

[0562] $$ / $ A significant difference at p<0.01 / p<0.05 level compared to G3

[0563]

[0564] The experimental groups can be categorized as follows: G1: normal control group, G2: vehicle control group 1 (Testosterone-induced), G3: vehicle control group 2 (DHT-induced), G4: positive control group 1 (Testosterone-induced, Dutasteride-administered), G5: positive control group 2 (Testosterone-induced, Dutasteride-administered), G6: DHT-induced NIC-A1 100 mg / kg administration group, G7: DHT-induced NIC-A1 200 mg / kg administration group.

[0565]

[0566] As a result of body weight measurement, the body weight level of the DHT-induced NIC-A1 administration group (G6, G7) during the test period was significantly lower than that of the vehicle control group and was similar to that of the normal control group.

[0567] As a result of measuring the hair growth area, the hair growth area level of the test substance administration group (G6, G7) during the test period tended to be lower than that of the normal control group and vehicle control group, but on Day 42, the hair growth area level of the DHT-induced NIC-A1 administration group (G6, G7) was significantly higher than that of the vehicle control group.

[0568] Histopathological examination results showed that in general, individuals with a decreased number of hair follicles showed a tendency for dermal thickness to decrease, and individuals with an increased number of hair follicles showed a tendency for dermal thickness to increase. The dermal thickness and number of hair follicles in the DHT-induced NIC-A1 administration group (G6, G7) were significantly higher than those in the normal control group.

[0569] When the test substance was administered to a C57BL / 6 mouse model that had undergone hair removal under these test conditions, the DHT-induced NIC-A1 administration group showed a significantly higher hair growth area level than the vehicle control group on Day 42, and the histopathological examination results also showed a tendency for improvement compared to the vehicle control group.

[0570] Therefore, it is thought that administration of NIC-A1 in a C57BL / 6 mouse model of alopecia caused by DHT administration may help prevent hair loss, promote hair growth, and prevent and / or treat prostate cancer.

[0571]

[0572] Experimental Example 5: P53 expression rate confirmation test using a mice xenograft model

[0573] This test was performed to create a xenograft model by subcutaneously transplanting five types of cell lines into nude mice, and then administering test substances to confirm the P53 expression rate.

[0574] Place 1 vial of frozen human tumor cell lines (PANC-1 / A549 / H1975 / DU4475 / MDA-MA-231) in a cell culture flask with medium (PANC-1: DMEM; A549 / H1975 / DU4475 / MDA-MA-231: RPMI1640) containing heat-inactivated 10% FBS (fetal bovine serum, Gibco, 10082-147) and culture in a 5% CO2 incubator at 37°C. Wash with PBS, add 10-fold diluted 2.5% Trypsin-EDTA (Gibco, 15090), and detach the cells. Centrifuge (1,000 rpm, 5 min), discard the supernatant, and obtain a cell suspension with new medium. After checking viability using a microscope, prepare the cell line by diluting it in DPBS to a concentration of 2.0 x 107 cells / mL.

[0575] After the adaptation period in the breeding environment has ended, the day before cell line transplantation, the back of the mouse is shaved using an electric razor. The cell line is prepared according to the method described above. When preparing the cell line, resuspend it and homogenize it, and the prepared cell line is immediately administered to the animal. When transplanting the cell line, the back of the animal is disinfected with 70% alcohol, and then 2.0 X 106 cells / 0.1 mL / head is administered subcutaneously using a syringe equipped with a 26 gauge needle.

[0576] The test group composed is as shown in Table 21 below.

[0577] [Table 21]

[0578]

[0579] In the above Table 21, among the administered substances, CND means the composition of Example 14, and vehicle means

[0580] During the acclimatization period, healthy animals were selected and inoculated with cell lines. The tumor size at the site where the cell lines were transplanted was approximately 80 - 150 mm. 3 When reached, the tumor sizes of each group are distributed as evenly as possible according to the ranked tumor sizes. Administration was performed orally, and 28 times in total were administered twice a day (morning and evening) for 2 weeks. The start date of test substance administration was set as Day 0. After correcting the animals using the transdorsal skin correction method, the test substance was administered directly into the stomach using an oral administration sonde.

[0581] From the day of group separation (the start of test substance administration, Day 0) until the end of test substance administration, tumor development was confirmed and tumor size was measured twice a week. The length, width, and height of the tumors were measured using calipers, and the tumor size was calculated using the following formula. The results are presented in Table 22.

[0582] *Tumor size = ab 2 / 2 (a: long axis length, b: short axis length)

[0583] [Table 22]

[0584]

[0585] ( ): Number of remaining animals

[0586] Data are expressed as Mean±SD

[0587] The day of the first administration was designated as day 0

[0588] G1: Vehicle control (PANC-1), G2: Test article(PANC-1), G3: Vehicle control(A549), G4: Test article(A549), G5: Vehicle control(H1975), G6: Test article(H1975), G7: Vehicle control(DU4475), G8: Test article(DU4475)

[0589]

[0590] As can be confirmed from the results described in Table 18 above, in the G2, G4, G6 and G8 groups administered the composition of Example 14, the tumor size was confirmed to have decreased 18 days later compared to the control group (G1, G3, G5 and G7) administered the vehicle. That is, from this experiment, in terms of anticancer efficacy, it can be confirmed that the anticancer efficacy is against p53 mutant cells in addition to androgen receptors.

[0591]

[0592] Experimental Example 6: Confirmatory test for the anticancer or anticancer adjuvant effect of Example 14 (anticancer efficacy test using a Xenograft model using DU4475 (triple-negative breast cancer))

[0593] The test substances used in Experimental Example 6 are as follows.

[0594] (1) Test substance 1: OAD (Docetxel, MgO, PVP, poloxamer, SDS mixture)

[0595] (2) Test substance 2: CND (composition of Example 14)

[0596] (3) Control material: Taxotere (Notus Co., Ltd.)

[0597] (4) Excipients: Sterile water for injection (Daehan Sterile Distilled Water; Notus Co., Ltd.)

[0598] One vial of frozen human tumor cell line (DU4475) was placed in a cell culture flask with RPMI1640 medium (Gibco, 22400-089) containing heat-inactivated 10% FBS (fetal bovine serum, Gibco, 10082-147) and cultured in a 5% CO2 incubator at 37°C. The cells were washed with PBS, diluted 10-fold with 2.5% Trypsin-EDTA (Gibco, 15090), and then separated by adding it. The cells were centrifuged (1,000 rpm, 5 min), the supernatant was discarded, and a cell suspension was obtained with new medium. Viability was confirmed using a microscope, and 2.0 x 10 7 Cell lines were prepared by diluting in DPBS at a concentration of 10 cells / mL. After the adaptation period in the breeding environment, the day before cell line transplantation, the backs of the mice were shaved using an electric shaver. Cell lines were prepared according to the method described above. When preparing cell lines, resuspension was performed to homogenize them, and the prepared cell lines were immediately administered to the animals. When transplanting cell lines, the backs of the animals were disinfected with 70% alcohol, and then 2.0 X 10 6 It was administered subcutaneously at a dosage of 0.1 mL / head of cells.

[0599] The test groups used are as shown in Table 23 below.

[0600] [Table 23]

[0601]

[0602] During the acclimatization period, healthy animals were selected and inoculated with cell lines. The tumor size at the site where the cell lines were transplanted was approximately 80-150 mm. 3 When reached, the tumor sizes of each group were distributed as evenly as possible according to the ranked tumor sizes.

[0603] For G2, Taxotere was administered as a single dose (8:00).

[0604] For G3, Taxotere was administered once (8:00), and the test substance CND was administered twice / day for 2 weeks (8:00 and 18:00).

[0605] For G4, it was administered 3 times / day for 2 weeks (8:00, 13:00, and 18:00).

[0606] For G5, G7, and G9, the test substance OAD was administered once / day for 2 weeks (8:00), and the test substance CND was administered once / day for 2 weeks (18:00).

[0607] For G6, G8, and G10, the test substance OAD was administered twice a day for 2 weeks (8:00 and 18:00), and the test substance CND was administered once a day for 2 weeks (13:00).

[0608] For G11, the test substance OAD was administered on the day of test substance administration (Day 0) and then once / 2 days for 2 weeks (8:00), and the test substance CND was administered once / day for 2 weeks (18:00).

[0609] For OAD, a preparation was prepared using the test substance and sterile water for injection to match the concentration (11.42%), then dispensed into a single dose, stored frozen, and thawed and administered in the single dose amount when administering the test substance.

[0610] For CND, a preparation was prepared using the test substance and sterile water for injection to match the concentration (51.28%), then dispensed into a single dose, stored frozen, and thawed and administered in the single dose amount when administering the test substance.

[0611] For Taxotere, the animal was carefully placed in the compensator and then administered intravenously into the caudal vein using a syringe equipped with a 26-gauge needle.

[0612] For test substances CND and OAD, animals were fixed using the dorsal skin fixation method, and administered directly into the stomach using an oral administration sonde.

[0613] On Day 0, the day of group separation and initiation of test substance administration, tumor occurrence was confirmed and tumor size was measured twice a week for 4 weeks. The long and short axes of the tumors were measured using calipers, and the tumor size was calculated using the following formula.

[0614] Tumor size = ab 2 / 2 (a: long axis length, b: short axis length)

[0615] The results of this experiment were analyzed using parametric multiple comparison procedures, assuming data normality. If the parametric one-way ANOVA results were significant, a post hoc test was performed using Dunnett's multiple comparison test. Statistical analysis was performed using Prism 7.04 (GraphPad Software Inc., San Diego, CA, USA), and a p value less than 0.05 was considered statistically significant.

[0616] [result]

[0617] As a result of observation of general symptoms, 1 animal in the OAD 20 mg / kg + CND 300 mg / kg PO administration group (G9) and 3 animals in the OAD 40 mg / kg + CND 300 mg / kg PO administration group (G11) died on the 1st day after starting test substance administration, 1 animal in the Taxotere 2 mg / kg IV + CND 300 mg / kg PO administration group (G3) died on the 14th day after starting test substance administration, and 1 animal in the OAD 20 mg / kg + CND 200 mg / kg PO administration group (G10) died on the 21st day after starting test substance administration.

[0618] The results of body weight measurement on day 26 are shown in Figure 14. In terms of body weight change, no statistical significance was observed in any group throughout the entire test period.

[0619] The tumor size measurement results are shown in Fig. 15. From the 11th to the 21st day after the start of test substance administration, the tumor size level of the Taxotere 10 mg / kg IV administration group (G2) was significantly lower than that of the vehicle control group (G1) (p<0.01), and on the 18th day after the start of test substance administration, the tumor size levels of G3 and G10 were significantly lower than that of G1 (p<0.01 or p<0.05).

[0620] The tumor weight measurement results are shown in Figure 16, and no statistical significance was observed in any group.

[0621] This study was conducted to evaluate the anticancer effect by administering test substances after creating a xenograft model by subcutaneously transplanting human tumor cell line DU4475 cells into nude mice (G1: vehicle control group, G2: Taxotere 10 mg / kg IV administration group, G3: Taxotere 2 mg / kg IV + CND 300 mg / kg PO administration group, G4: CND 300 mg / kg PO administration group, G5: OAD 10 mg / kg + CND 300 mg / kg PO administration group, G6: OAD 10 mg / kg + CND 200 mg / kg PO administration group, G7: OAD 15 mg / kg + CND 300 mg / kg PO administration group, G8: OAD 15 mg / kg + CND 200 mg / kg PO administration group, G9: OAD 20 mg / kg + CND 300 mg / kg PO administration group, G10: OAD 20 mg / kg + CND 200 mg / kg PO administration group, G11: OAD 40 mg / kg + CND 300 mg / kg PO administration group).

[0622] As a result of body weight measurement, no statistical significance was observed throughout the entire test period.

[0623] As a result of tumor size measurement, the tumor size levels of the Taxotere 2 mg / kg IV + CND 300 mg / kg PO administration group and the OAD 20 mg / kg + CND 200 mg / kg PO administration group were significantly lower than those of the vehicle control group on the 18th day after the start of test substance administration. In the case of the OAD 20 mg / kg + CND 200 mg / kg PO administration group, no statistically significant difference was observed compared to the vehicle control group from the 21st day after the start of test substance administration until the end of the study. In the case of the Taxotere 2 mg / kg IV + CND 300 mg / kg PO administration group, not a single tumor was observed from the 18th day after the start of test substance administration, which is thought to have induced a complete response.

[0624] As a result of tumor weight measurement, no statistical significance was observed in any group.

[0625] Under these test conditions, when a xenograft model was created by subcutaneously transplanting human tumor cell line DU4475 cells into nude mice and then the test substance was administered, 18 days after the start of test substance administration, the tumor size level of some Taxotere and CND combination administration groups was significantly lower than that of the vehicle control group, and not a single tumor was observed.

[0626] Therefore, it is thought that the combined administration of Taxotere and CND, as control substances, to a xenograft model in which DU4475 cells were subcutaneously transplanted into nude mice induced a complete response to the tumor in one individual, and may help suppress tumor growth. In other words, from the above experiment, it can be confirmed that niclosamide or a pharmaceutically acceptable salt thereof can be used as an anticancer agent, and especially, since it is closely related to the control of p 53, it can have a preventive and / or therapeutic effect on not only general cancer but also prostate cancer in addition to its use for hair loss.

[0627] Experimental Example 7: Confirmatory test for the anticancer or anticancer adjuvant effect of Example 14 (anticancer efficacy test using a Xenograft model using DU4475 (triple-negative breast cancer))

[0628] The test substances used in Experimental Example 7 are as follows.

[0629] (1) Test substance 1: OAD (Docetxel, MgO, PVP, poloxamer, SDS mixture)

[0630] (2) Test substance 2: CND (composition of Example 14)

[0631] (3) Control substance: Taxotere (Notus Co., Ltd.)

[0632] (4) Excipients: Sterile water for injection (Daehan Sterile Distilled Water; Notus Co., Ltd.)

[0633] One vial of frozen human tumor cell line (DU4475) was placed in a cell culture flask with RPMI1640 medium (Gibco, 22400-089) containing heat-inactivated 10% FBS (fetal bovine serum, Gibco, 10082-147) and cultured in a 5% CO2 incubator at 37°C. The cells were washed with PBS, diluted 10-fold with 2.5% Trypsin-EDTA (Gibco, 15090), and then separated by adding it. The cells were centrifuged (1,000 rpm, 5 min), the supernatant was discarded, and a cell suspension was obtained with new medium. Viability was confirmed using a microscope, and 2.0 x 10 7 Cell lines were prepared by diluting in DPBS at a concentration of 10 cells / mL. After the adaptation period in the rearing environment, the day before cell line transplantation, the backs of the mice were shaved using an electric shaver. Cell lines were prepared according to the method described above. When preparing cell lines, resuspension was performed to homogenize them, and the prepared cell lines were immediately administered to the animals. When transplanting cell lines, the backs of the animals were disinfected with 70% alcohol, and then 2.0 X 10 6 It was administered subcutaneously at a dosage of 0.1 mL / head of cells.

[0634] The test groups used are as shown in Table 24 below.

[0635] [Table 24]

[0636]

[0637] During the acclimatization period, healthy animals were selected and inoculated with cell lines. The tumor size at the site where the cell lines were transplanted was approximately 80-150 mm. 3 When reached, the tumor sizes of each group were distributed as evenly as possible according to the ranked tumor sizes.

[0638] In Experimental Example 7, the administration method is as follows.

[0639] For G2, Taxotere is administered intravenously three times in total (Day 0, 4, 7, 8:00).

[0640] For G3, test substance CND is administered orally twice a day for 4 weeks (8:00 and 18:00).

[0641] For G4, Taxotere is administered intravenously three times a day (Day 0, 4, 7, 8:00), and the test substance CND is administered orally twice a day for 4 weeks (8:00 and 18:00).

[0642] For G5 and G8, the test substance OAD is administered orally twice a day for 4 weeks (8:00 and 18:00).

[0643] For G6 and G9, test substance OAD is administered orally twice a day for 4 weeks (8:00 and 18:00), and test substance CND is administered orally once a day for 4 weeks (13:00).

[0644] For G7 and G10, Taxotere is administered intravenously once (Day 0, 8:00), the test substance OAD is administered orally twice a day for 4 weeks (8:00 and 18:00), and the test substance CND is administered orally once a day for 4 weeks (13:00).

[0645] For OAD, prepare a preparation according to the concentration (11.42%) using the test substance and sterile water for injection, then dispense into single doses, store in the freezer, and thaw and administer the single dose when administering the test substance.

[0646] For CND, a preparation is prepared using the test substance and sterile water for injection at a concentration (51.28%), then dispensed into single-dose portions, stored frozen, and thawed for administration. For Taxotere, the animal is carefully placed in a compensator, and then administered intravenously via the tail vein using a syringe fitted with a 26-gauge needle.

[0647] For test substances CND and OAD, animals are fixed using the dorsal skin fixation method, and the substances are administered directly into the stomach using an oral administration sonde.

[0648] During the administration and observation period, the type, date of onset, and severity of general symptoms, including death, should be observed daily and recorded for each individual. Individuals with worsening general symptoms should be isolated, and moribund or dead animals should be treated as if undergoing a scheduled necropsy. Body weight should be measured on the day of group separation, then twice a week thereafter, and on the day of the necropsy.

[0649] Tumor size was measured on the first day of group separation and test substance administration (Day 0), and then twice weekly for 4 weeks to confirm tumor occurrence and determine tumor size. The long and short axes of the tumors were measured using calipers, and the tumor size was calculated using the following formula.

[0650] Tumor size = ab 2 / 2 (a: long axis length, b: short axis length)

[0651] On the day of the autopsy, all surviving animals are anesthetized, the abdominal aorta and posterior vena cava are cut to exsanguine / kill them, and the tumors are removed. The removed tumors are lightly washed with PBS, dried, photographed, and then weighed. The scheduled autopsy date may be changed at the request of the requesting party.

[0652] The results of this study were analyzed using parametric multiple comparison procedures. For parametric multiple comparisons, data normality was assumed and a parametric one-way ANOVA was used to test the results. If the results were significant, a post hoc Dunnett's multiple comparison test was used to analyze significant differences between groups.

[0653] Statistical analysis was performed using Prism 7.04 (GraphPad Software Inc., San Diego, CA, USA), and a p-value less than 0.05 was considered statistically significant.

[0654] Microsoft® Excel® was used to calculate the mean, standard deviation, and other data for this study. Data in the final report will be expressed as Mean±SD. The data format may be changed prior to the start of the study, subject to consultation with the sponsor.

[0655] The results for tumor size are shown in Table 25 below.

[0656] [Table 25]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667] The average values ​​for changes in tumor size are shown in Figure 17.

[0668] According to the experimental results for Fig. 17, a certain degree of anticancer efficacy was observed in the chemotherapy (Taxotere; G2 group) used as a treatment for triple-negative breast cancer, but no statistically significant difference was observed compared to the control group. In the group treated only with CND (G3), which is an example, no statistically significant anticancer efficacy was observed compared to the control group. However, in the group treated with a combination of chemotherapy (Taxotere) and CND (G4), statistically significant anticancer efficacy was observed compared to the control group. Therefore, it was confirmed that the composition of the present invention can exhibit remarkably excellent effects when administered in combination with an anticancer agent.

[0669] Information on weight changes is shown in Table 26 below.

[0670] [Table 26]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676] Experimental Example 8: Experiment to Prove the Effectiveness of Treating Seborrheic Dermatitis

[0677] In order to conduct the test, the complex prepared through Example 3 was mixed with distilled water to make an aqueous solution with a concentration of 0.1% compared to niclosamide, and NaOH was added to adjust the pH to 8 to 8.5 to complete the aqueous solution. The composition prepared using the above Reference Example 3 was applied evenly 2 to 3 times a day, about 1 cc per time, for a total of 2 to 3 cc per day, to a test subject with symptoms of seborrheic dermatitis on the hands. After using the composition for 10 days, the results were observed, and the initial symptoms and symptoms after 10 days are shown in Fig. 18.

[0678] As can be confirmed in Fig. 18, it was confirmed that the condition of the finger skin damaged by keratinization, etc., improved after 10 days of applying the composition of the present invention to a person with seborrheic dermatitis symptoms.

[0679]

[0680] In addition, the niclosamide complex prepared in Example 14 was applied evenly 2-3 times a day, about 3 cc per time, for a total of 6-9 cc per day, to a test subject with seborrheic dermatitis symptoms on the front part of the shins, and the results were observed after 15 days. The results before and 15 days after application of the composition are shown in Fig. 19.

[0681]

[0682] As can be seen in Fig. 19, it was confirmed that symptoms accompanied by erythema, keratinization, and itching were significantly alleviated after 15 days of applying the composition of the present invention to a person with seborrheic dermatitis symptoms.

[0683]

[0684] Experimental Example 9: Confirmation of hair loss prevention and hair growth promotion

[0685] The test subjects with hair loss symptoms were observed for 72 days while using the composition manufactured using Example 14 above, 2 cc at a time, 1 to 2 times a day in the morning and evening after washing their hair. The results were observed by applying 2 to 4 cc evenly to the specific scalp area of ​​the frontal region where hair loss had progressed and massaging the composition.

[0686] As can be seen in Fig. 20, the composition of the present invention was applied to a specific scalp area of ​​the frontal region of a patient with hair loss symptoms, and it was confirmed that after 72 days, hair was restored to a thick state in the area where hair had fallen out.

[0687]

[0688] Experimental Example 10: Confirmation of the effect of treating, preventing, and / or improving Parkinson's disease.

[0689] The composition prepared in Example 48 was used to conduct the test. The specific experimental method is described in Figure 22. The experiment was conducted in five groups, and the administered substances and administration methods for each group are as follows. The animal model used was a Parkinson's disease animal model, a brain or peripherally injected MPTP-induced PD model. This model can identify the progressive pathological processes of PD, including dopamine neuron loss, cerebral oxidative stress, and mitochondrial dysfunction.

[0690] - Normal(N): saline (10mL / kg)

[0691] - Control(C): saline (10mL / kg)

[0692] - Positive control (P): madopar 100 mg / kg (10 mL / kg) (administered once daily)

[0693] - Group A (SA) (Example 48 administered 3 times, 8-hour intervals): Example 48 was administered at 210 mg / kg (10.5 mL / kg per dose)

[0694] - Group B (SB) (Example 48, 2 doses, 12-hour interval): Example 48 was administered at 210 mg / kg (1 dose 10.5 mL / kg)

[0695] In this experiment, both sample A and sample B refer to the composition according to Example 48.

[0696] In the above group, MPTP 30 mg / kg ip administration was administered once a day for 2 weeks to all groups except the Normal group before the behavioral experiment.

[0697]

[0698] The results of the pole test in the above experiment are shown in Fig. 23. The pole test is a behavioral experiment to check the motor nerves of mice and check the time to reach the ground. Fig. 23A is the value before administration of Example 48, and there was no significant difference in the test substance administration group compared to group C. Fig. 23B is the value during administration of Example 48, and there was the result one week after administration of the test substance, and there was no significant difference in the test substance administration group compared to group C. Fig. 23C is the value after administration of Example 48, and there was the result two weeks after administration of the test substance, and it was confirmed that there was a significant increase in group C compared to group N, and a significant decrease in the test substance administration group compared to group C. Therefore, the results of the pole test confirmed that administration of the composition of Example 48 improved motor nerves.

[0699]

[0700] The results of the Open field test for the above experiment are shown in Fig. 24. Fig. 24 is a behavioral experiment to check the instability and cognitive ability of mice using the Open field test, and Entrance in center means the proportion (%) that stayed in the center. Fig. 24 A is the result before administration of Example 48, and a significant difference was shown in the test substance administration group compared to group C. Fig. 24 B is the result during administration of Example 48, and the result was 1 week after administration of the test substance, and a significant increase was shown in the positive control group compared to group C. Fig. 24 C is the result after administration of Example 48, and the result was 2 weeks after administration of the test substance, and a significant decrease was found in group C compared to group N, but only an increasing trend was confirmed in the positive control group and SB group compared to group C.

[0701] In the above experiment, the water maze test is described in Fig. 25. This is a behavioral experiment to check the cognitive ability of mice, and the number of escape latencies refers to the number of times they entered the escape platform. Fig. 25A shows the results before administration of Example 48, and the number of times they entered the escape platform was significantly reduced in group C compared to group N. Fig. 25 B shows the values ​​during administration of Example 48, and the results are for 1 week after administration of the test substance, and the number of times they entered the escape platform was significantly reduced in group C compared to group N, but no significant difference was confirmed in the sample administration group compared to group C. Fig. 25 C shows the values ​​after administration of Example 48, and the results are for 2 weeks after administration of the test substance, and the number of times they entered the escape platform was significantly reduced in group C compared to group N, and the number of times they entered the test substance administration group compared to group C was significantly increased. These results confirmed that administration of Experimental Example 48 improved the cognitive ability of mice.

[0702] Figure 26 shows the results of the analysis of dopamine content in brain tissue. Dopamine was measured using an ELISA method using brain tissue, and body weight, food intake, and water intake were measured once a week. Parkinson's disease is a movement disorder caused by dopamine deficiency, and this was analyzed to determine whether dopamine deficiency was recovered through the analysis of dopamine content in brain tissue. As a result of the analysis, as can be confirmed in Figure 26, it was confirmed that the dopamine content in the brain tissue of mice administered with Example 48 significantly increased compared to group C, which induced Parkinson's disease. Therefore, it was confirmed that the Example can be significantly effective in the treatment of Parkinson's disease when administered as a Parkinson's disease treatment agent or in combination with a Parkinson's disease treatment agent.

[0703] Figures 27 and 28 show the results of dopaminergic neuron index measurements, which were performed using immunochemical staining (tyrosine hydroxylase, α-synuclein) using brain tissue, with five mice per group as the standard. Figure 27 shows the results of α-synuclein expression analysis in brain tissue, which shows that as Parkinson's disease symptoms worsen, it coagulates and accumulates without being broken down. It was confirmed that α-synuclein accumulation increased with MPTP administration compared to the N group.

[0704] Figure 28 shows the results of an analysis of tyrosine hydroxylase (TH) expression in brain tissue. Tyrosine hydroxylase (TH) is a factor that regulates dopamine synthesis and is observed less frequently as Parkinson's disease symptoms worsen. Example 48 confirmed that tyrosine hydroxylase (TH) expression in the brain tissue of mice administered with the drug increased compared to the MPTP-induced C group. ​ ​

Claims

1. A composition for preventing hair loss or promoting hair growth, comprising niclosamide or a pharmaceutically acceptable salt thereof as an active ingredient.

2. A composition for preventing hair loss or promoting hair growth, wherein the composition further comprises an inorganic substance, and the inorganic substance is represented by at least one chemical formula selected from chemical formulas 1 to 4. [Chemical Formula 1] [(M 2+ (1-x) M 3+ x (OH)2)((A n- ) z )]yH2O (In the above chemical formula 1, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of M 3+ is Al 3+ , Fe 3+ , V 3+ , Ti 3+ , Mn 3+ and Ga 3+ A trivalent metal cation selected from the group consisting of x is a number with a range greater than 0 and less than or equal to 0.5, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of anion A, and is a number ranging from 0.5 to 2. z is a number in the range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 2] [(M 2+ (OH) 2-x )((A n- ) z )]yH2O (In the above chemical formula 2, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of x is a number in the range of 0 to 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number in the range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 3] [(M 2+ (About) 2-x )((A n- ) z )]yH2O (In the above chemical formula 3, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ , Mo 2+ and Zn 2+ A divalent metal cation selected from the group consisting of x is a number in the range of 1 to 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number with a range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 4] M(A n- ) z (In the above chemical formula 4, M 2+ Silver Mg 2+ , Ni 2+ , Fe 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number with a range of 0 to 2.) 3. In claim 2, The above inorganic substances 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, calcium chloride, calcium sulfate, calcium nitrate, calcium, calcium hydroxide, 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, 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, A composition for preventing hair loss or promoting hair growth, comprising at least one selected from cobalt sulfate, cobalt oxide, and cobalt hydroxide.

4. In claim 1, the composition further comprises a dispersant. A composition for preventing hair loss or promoting hair growth.

5. In claim 1, the composition further comprises at least one selected from amino acids and peptides. A composition for preventing hair loss or promoting hair growth.

6. In claim 4, The above dispersant comprises at least one selected from a polyvinylpyrrolidone compound, a polyethylene glycol compound, a poloxamer compound, a polyoxyethylene sorbitan fatty acid ester compound, and a cellulose compound. A composition for preventing hair loss or promoting hair growth.

7. A composition for improving or treating malignant tumor disease, comprising niclosamide or a pharmaceutically acceptable salt thereof.

8. In claim 7, A composition for improving or treating a malignant tumor disease, wherein the composition further comprises an inorganic substance, and the inorganic substance is represented by at least one chemical formula selected from chemical formulas 1 to 4. [Chemical Formula 1] [(M 2+ (1-x) M 3+ x (OH)2)((A n- ) z )]yH2O (In the above chemical formula 1, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of M 3+ is Al 3+ , Fe 3+ , V 3+ , Ti 3+ , Mn 3+ and Ga 3+ A trivalent metal cation selected from the group consisting of x is a number with a range greater than 0 and less than or equal to 0.5, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of anion A, and is a number ranging from 0.5 to 2. z is a number in the range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 2] [(M 2+ (OH) 2-x )((A n- ) z )]yH2O (In the above chemical formula 2, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of x is a number in the range of 0 to 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number in the range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 3] [(M 2+ (About) 2-x )((A n- ) z )]yH2O (In the above chemical formula 3, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of x is a number in the range of 1 to 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number with a range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 4] M(A n- ) z M(A n- ) z (In the above chemical formula 4, M 2+ Silver Mg 2+ , Ni 2+ , Fe 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number with a range of 0 to 2.) 9. In claim 8, The above inorganic substances 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, calcium chloride, calcium sulfate, calcium nitrate, calcium, calcium hydroxide, 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, 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, At least one selected from cobalt sulfate, cobalt oxide and cobalt hydroxide. A composition for preventing hair loss or promoting hair growth.

10. A composition for improving or treating skin diseases, comprising niclosamide or a pharmaceutically acceptable salt thereof and an inorganic substance, A composition for improving or treating skin diseases, wherein the inorganic substance is represented by at least one chemical formula selected from chemical formulas 1 to 4. [Chemical Formula 1] [(M 2+ (1-x) M 3+ x (OH)2)((A n- ) z )]yH2O (In the above chemical formula 1, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of M 3+ is Al 3+ , Fe 3+ , V 3+ , Ti 3+ , Mn 3+ and Ga 3+ A trivalent metal cation selected from the group consisting of x is a number with a range greater than 0 and less than or equal to 0.5, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of anion A, and is a number ranging from 0.5 to 2. z is a number in the range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 2] [(M 2+ (OH) 2-x )((A n- ) z )]yH2O (In the above chemical formula 2, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of x is a number in the range of 0 to 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number in the range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 3] [(M 2+ (About) 2-x )((A n- ) z )]yH2O (In the above chemical formula 3, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of x is a number in the range of 1 to 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number with a range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 4] M(A n- ) z (In the above chemical formula 4, M 2+ Silver Mg 2+ , Ni 2+ , Fe 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number with a range of 0 to 2.) 11. In claim 10, The above inorganic substances 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, calcium chloride, calcium sulfate, calcium nitrate, calcium, calcium hydroxide, 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, 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, A composition for improving or treating skin diseases, comprising at least one selected from cobalt sulfate, cobalt oxide, and cobalt hydroxide.

12. In claim 10, The above skin disease is seborrheic dermatitis, a composition for improving or treating skin disease.

13. An anticancer adjuvant comprising niclosamide or a pharmaceutically acceptable salt thereof and an inorganic substance.

14. In claim 13, An anticancer adjuvant, wherein the above-mentioned inorganic substance is represented by at least one chemical formula selected from chemical formulas 1 to 4. [Chemical Formula 1] [(M 2+ (1-x) M 3+ x (OH)2)((A n- ) z )]yH2O (In the above chemical formula 1, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of M 3+ is Al 3+ , Fe 3+ , V 3+ , Ti 3+ , Mn 3+ and Ga 3+ A trivalent metal cation selected from the group consisting of x is a number with a range greater than 0 and less than or equal to 0.5, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of anion A, and is a number ranging from 0.5 to 2. z is a number in the range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 2] [(M 2+ (OH) 2-x )((A n- ) z )]yH2O (In the above chemical formula 2, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of x is a number in the range of 0 to 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number in the range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 3] [(M 2+ (About) 2-x )((A n- ) z )]yH2O (In the above chemical formula 3, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of x is a number in the range of 1 to 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number with a range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 4] M(A n- ) z (In the above chemical formula 4, M 2+ Silver Mg 2+ , Ni 2+ , Fe 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number with a range of 0 to 2.) 15. In claim 14, The above inorganic substances 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, calcium chloride, calcium sulfate, calcium nitrate, calcium, calcium hydroxide, 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, 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, An anticancer adjuvant comprising at least one selected from cobalt sulfate, cobalt oxide, and cobalt hydroxide.

16. In claim 13, The above anticancer adjuvant can be administered simultaneously or sequentially with an anticancer drug.

17. In claim 14, The above anticancer drugs include docetaxel, retinoic acid, gemcitabine, cisplatin, abiraterone, prednisone, quinacrine, sorafenib, entinostat, tanespimycin, vorinostat, pimitespib, belinostat, pimitespib, dichloroacetate, 8-quinolinol, atorvastatin, fluvastatin, lovastatin, camptothecin, U0126, Doxorubicin, Paclitaxel, Metformin, Domperidone, Imipramine, Amitriptyline, Desipramine, Clomipramine, Domperidone, Cyclodextrin, Temozolomide, 5-Fluorouracil (5-FU), Colistin, Enzalutamide, Bicalutamide, Erlotinib, Oxaliplatin, Dasatinib, Palladium(II) saccharinate complex of terpyridine An anticancer adjuvant comprising at least one selected from TRA-8, cytarabine, daunorubicin, and vincristine.

18. An anticancer combination preparation comprising an anticancer agent and an anticancer adjuvant of claim 13.

19. A composition for preventing or treating prostate cancer, comprising niclosamide or a pharmaceutically acceptable salt thereof; and an inorganic substance.

20. In claim 19, A composition for preventing or treating prostate cancer, wherein the inorganic substance is represented by at least one chemical formula selected from chemical formulas 1 to 4. [Chemical Formula 1] [(M 2+ (1-x) M 3+ x (OH)2)((A n- ) z )]yH2O (In the above chemical formula 1, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of M 3+ is Al 3+ , Fe 3+ , V 3+ , Ti 3+ , Mn 3+ and Ga 3+ A trivalent metal cation selected from the group consisting of x is a number with a range greater than 0 and less than or equal to 0.5, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of anion A, and is a number ranging from 0.5 to 2. z is a number in the range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 2] [(M 2+ (OH) 2-x )((A n- ) z )]yH2O (In the above chemical formula 2, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of x is a number in the range of 0 to 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number in the range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 3] [(M 2+ (About) 2-x )((A n- ) z )]yH2O (In the above chemical formula 3, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of x is a number in the range of 1 to 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number with a range of 0 to 2, y is a number in the range of 0 to 20.) 21. In claim 20, The above inorganic substances 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, calcium chloride, calcium sulfate, calcium nitrate, calcium, calcium hydroxide, 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, 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, At least one selected from cobalt sulfate, cobalt oxide and cobalt hydroxide. A composition for preventing or treating prostate cancer.

22. A composition for treating a neurological brain disease, comprising niclosamide or a pharmaceutically acceptable salt thereof as an active ingredient.

23. In claim 22, the composition for treating a neurological brain disease promotes tyrosine hydroxylase activity.

24. In claim 22, The above composition further comprises an inorganic substance, A composition for treating a neurological brain disease, wherein the inorganic substance is represented by at least one chemical formula selected from chemical formulas 1 to 4. [Chemical Formula 1] [(M 2+ (1-x) M 3+ x (OH)2)((A n- ) z )]yH2O (In the above chemical formula 1, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of M 3+ is Al 3+ , Fe 3+ , V 3+ , Ti 3+ , Mn 3+ and Ga 3+ A trivalent metal cation selected from the group consisting of x is a number with a range greater than 0 and less than or equal to 0.5, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of anion A, and is a number ranging from 0.5 to 2. z is a number in the range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 2] [(M 2+ (OH) 2-x )((A n- ) z )]yH2O (In the above chemical formula 2, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of x is a number in the range of 0 to 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number in the range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 3] [(M 2+ (About) 2-x )((A n- ) z )]yH2O (In the above chemical formula 3, M 2+ Silver Mg 2+ , Ni 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ , Mo 2+ and Zn 2+ A divalent metal cation selected from the group consisting of x is a number in the range of 1 to 2, A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number with a range of 0 to 2, y is a number in the range of 0 to 20.) [Chemical Formula 4] M(A n- ) z (In the above chemical formula 4, M 2+ Silver Mg 2+ , Ni 2+ , Fe 2+ , Ca 2+ , Cu 2+ , Co 2+ , Cr 2+ , Mn 2+ and Zn 2+ A divalent metal cation selected from the group consisting of A is CO3 2- , NO3 - , Br - , Cl - , SO4 2- , HPO4 2- and F - is an anion selected from the group consisting of, n is the charge number of the anion A, and is a number ranging from 0 to 2. z is a number with a range of 0 to 2.) 25. In claim 24, The above inorganic substances 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, calcium chloride, calcium sulfate, calcium nitrate, calcium, calcium hydroxide, 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, 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, Containing at least one selected from cobalt sulfate, cobalt oxide and cobalt hydroxide, Composition for treating neurological brain diseases.

26. In claim 22, A composition for treating a neurological brain disease, wherein the neurological brain disease is at least one selected from Parkinson's disease, dementia, Alzheimer's disease, epilepsy, Lou Gehrig's disease, autism spectrum disorder, schizophrenia, depression, attention deficit hyperactivity disorder, drug addiction, Tourette syndrome, and Huntington's disease.

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