WO2023008719A1 - Compound for preventing or treating alzheimer's disease, comprising anticancer compound as active ingredient - Google Patents

Compound for preventing or treating alzheimer's disease, comprising anticancer compound as active ingredient Download PDF

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WO2023008719A1
WO2023008719A1 PCT/KR2022/007689 KR2022007689W WO2023008719A1 WO 2023008719 A1 WO2023008719 A1 WO 2023008719A1 KR 2022007689 W KR2022007689 W KR 2022007689W WO 2023008719 A1 WO2023008719 A1 WO 2023008719A1
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dementia
alzheimer
pharmaceutical composition
app
preventing
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김명옥
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주식회사 알츠코리아
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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  • the present invention relates to a composition for preventing or treating Alzheimer's disease, comprising an anticancer compound as an active ingredient.
  • Dementia one of the neurological diseases, is a disease accompanied by general disorders of systemic functions such as memory impairment and loss of judgment. It is a geriatric disease in which symptoms rarely appear before the age of 50, but the frequency of occurrence gradually increases after the age of 60. As the elderly population increases due to the development of medical technology and the improvement of quality of life, it is a disease that is prevalent not only in Korea but also worldwide. is a rapidly growing disease. The number of dementia patients aged 65 years or older registered in Korea in 2008 was 421,000, accounting for 8.4% of the total elderly population. According to the results of the 2008 Dementia Prevalence Survey by the Ministry of Health and Welfare, the onset of dementia is very diverse. About 70% of the dementia onset in Korea is of the Alzheimer type, and about 25% is of Vascular Dementia. type), other alcoholic dementia, and Parkinson's disease dementia are counted at less than 5%.
  • AD Alzheimer disease
  • Alzheimer disease the most common form of dementia, shows two characteristic lesions. One is caused by hyperphosphorylation and aggregation of tau protein in neurons in the cerebral cortex and hippocampus of the brain. Neurofibrillary tangle is formed in the cell, and the other is plaque formed outside the cell by aggregation of amyloid ⁇ -1/42.
  • Alzheimer's disease has not yet been clearly identified, but tangles, plaques, or precursors, which are aggregated forms of the two proteins involved in aggregation, are deposited in the areas of neurons responsible for memory and recognition in the brain, resulting in neuronal cell death. It is said that it causes the functional decline and death of Alzheimer's disease.
  • aggregated tau protein it is responsible for stabilizing microtubules. As tau protein reduced by aggregation does not perform its normal function, the binding force of microtubules is weakened and the dysfunction works over a long period of time, resulting in the deterioration of individual nerve cells. , and will lead to extinction.
  • Korean Patent No. 1755097 discloses a pharmaceutical composition for regenerating brain tissue for the treatment of Alzheimer's disease
  • Korean Patent No. 1631362 discloses Alzheimer's disease containing a leaf extract as an active ingredient.
  • a pharmaceutical composition for regenerating brain tissue for the treatment of sexual dementia has been disclosed
  • a composition for preventing or treating Alzheimer's dementia comprising the anticancer drug compound of the present invention as an active ingredient has not yet been disclosed.
  • the present invention has been derived from the above needs, and the present invention provides a composition for preventing or treating Alzheimer's disease comprising an anticancer compound as an active ingredient, and includes talazoparib, the active ingredient of the present invention; Olaparib, NU9056, thalazoparib + NU9056 and olaparib + NU9056 have the effect of reducing the expression of amyloid protein that causes plaque formation, which is the main cause of Alzheimer's dementia.
  • the present invention was completed by confirming that there is a significantly enhanced synergistic effect when two or more of them are combined rather than used alone.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of Alzheimer's dementia comprising any one or two or more selected from anticancer agents of Chemical Formulas 1 to 3 as active ingredients.
  • the present invention provides a method for preventing or treating Alzheimer's disease, comprising administering the pharmaceutical composition of the present invention to an animal other than human.
  • the present invention relates to a composition for the prevention or treatment of Alzheimer's dementia comprising an anticancer compound as an active ingredient, and the active ingredient of the present invention is Talazoparib, Olaparib, NU9056, Talazoparib + NU9056 And olaparib + NU9056 has the effect of reducing the expression of amyloid protein that causes the formation of plaque, which is the main cause of Alzheimer's dementia. There is a markedly enhanced synergistic effect when
  • Figure 1 shows cells identified by treatment with thalazoparib (A), olaparib (B), NU9056 (C), thalazoparib + NU9056 (D) and olazoparib + NU9056 (E) of the present invention in mouse hippocampal cell line HT22 survival rate result.
  • CTL is a control without any treatment
  • Tal is treated with 3.2 ⁇ M of thalazoparib
  • NU is treated with 10 ⁇ M of NU9056
  • Tal+NU is a mixture of 3.2 ⁇ M of thalazoparib + 10 ⁇ M of NU9056.
  • CTL is a control without any treatment
  • Ola is treated with 20 ⁇ M of parib up
  • NU is treated with 10 ⁇ M of NU9056
  • Ola + NU is a mixture of 20 ⁇ M of up parrib + 10 ⁇ M of NU9056.
  • Figure 2 is the result of confirming the change in the expression levels of amyloid precursor protein (APP), Bim and pAKT confirmed by treating the mouse hippocampal cell line HT22 with thalazoparib of the present invention.
  • CTL represents the expression levels of APP, Bim, and pAKT in the mouse hippocampal cell line that was not treated with anything
  • APP is the expression level of APP, Bim, and pAKT in the mouse hippocampal cell line HT22 in which overexpression of amyloid precursor protein (APP) was induced.
  • APP+Talazoparib 1.6 ⁇ M, APP+Talazoparib 3.2 ⁇ M indicates the expression levels of APP, Bim, and pAKT in mouse hippocampal cell line HT22 treated with APP+Talazoparib 1.6 ⁇ M or APP+Talazoparib 3.2 ⁇ M.
  • ## indicates a statistically significant decrease in the pAKT expression level in the APP group compared to the CTL group, p ⁇ 0.01.
  • Figure 3 is the result of confirming the expression level of APP, Bim and pAKT confirmed by processing the mouse hippocampal cell line HT22 up to parip of the present invention.
  • CTL represents the expression levels of APP, Bim, and pAKT in the mouse hippocampal cell line that was not treated with anything
  • APP is the expression level of APP, Bim, and pAKT in the mouse hippocampal cell line HT22 in which overexpression of amyloid precursor protein (APP) was induced.
  • APP amyloid precursor protein
  • APP + olaparib 10 ⁇ M, APP + olaparib 20 ⁇ M shows the expression levels of APP, Bim and pAKT in mouse hippocampal cell line HT22 treated with APP + olaparib 10 ⁇ M or APP + olaparib 20 ⁇ M.
  • Figure 4 shows the results of confirming the expression levels of APP, Bim, and pAKT confirmed by treating the mouse hippocampal cell line HT22 with NU9056 of the present invention.
  • CTL represents the expression levels of APP, Bim, and pAKT in the mouse hippocampal cell line that was not treated with anything
  • APP is the expression level of APP, Bim, and pAKT in the mouse hippocampal cell line HT22 in which overexpression of amyloid precursor protein (APP) was induced.
  • APP amyloid precursor protein
  • APP+NU9056 5 ⁇ M and APP+NU9056 20 ⁇ M show the expression levels of APP, Bim and pAKT in mouse hippocampal cell line HT22 treated with APP+NU9056 5 ⁇ M or APP+NU9056 20 ⁇ M.
  • Figure 5 is the result of confirming the expression level of amyloid precursor protein (APP) confirmed by treating the mouse hippocampal cell line HT22 with thalazoparib, NU9056 and thalazoparib + NU9056 of the present invention.
  • *, **, **** are the expression levels of amyloid precursor protein (APP) in the group treated with thalazoparib + NU9056;
  • Statistically significantly decreased than the amount * is p ⁇ 0.05, ** is p ⁇ 0.01, **** is 0.0001.
  • Figure 6 is the result of confirming the expression level of the amyloid precursor protein (APP) confirmed by processing the present invention up parip, NU9056 and up parip +NU9056 in the mouse hippocampal cell line HT22.
  • *, **, **** indicates that the expression level of amyloid precursor protein (APP) in the group treated with olaparib + NU9056 was higher than the expression level of amyloid precursor protein (APP) in the APP group, olaparib-treated group, and NU9056-treated group.
  • * is p ⁇ 0.05
  • ** is p ⁇ 0.01
  • **** is 0.0001.
  • the present invention relates to a pharmaceutical composition for the prevention or treatment of Alzheimer's dementia comprising any one or two or more selected from the following anticancer agents represented by Chemical Formulas 1 to 3 as active ingredients.
  • the anticancer drug of Chemical Formula 1 is called Talazoparib
  • the anticancer drug of Chemical Formula 2 is called Olaparib
  • the anticancer drug of Chemical Formula 3 is called NU9056.
  • Anticancer agents of Chemical Formulas 1 to 3 may decrease the expression level of amyloid precursor protein, decrease the expression level of Bim protein, and increase the expression level of pAKT protein, but are not limited thereto.
  • the composition Based on the total weight of the composition, it is preferable to include 0.1 to 100% by weight of the active ingredient.
  • pharmaceutically acceptable saline sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia Gum, calcium phosphate, alginates, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and minerals It may further contain one or more carriers selected from oils, and in addition to the above active ingredients, pharmaceutically acceptable antioxidants, buffers, bacteriostatic agents, diluents, surfactants, binders, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, and suspending agents And at least one adjuvant selected from preservatives
  • the pharmaceutical composition may be administered in an oral or parenteral formulation according to a conventional method, and when formulated, diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants are used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose, It is prepared by mixing gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, internal solutions, emulsions, syrups, etc.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories.
  • vegetable oils such as propylene glycol, polyethylene glycol, olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
  • a base for the suppository witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogeratin and the like may be used.
  • the present invention relates to a method for preventing or treating Alzheimer's disease, comprising administering the pharmaceutical composition of the present invention to an animal other than human.
  • Talazoparib, olaparib, and NU9056 were treated with mouse hippocampal cell line HT22, and MTT assay was performed to evaluate cell viability.
  • talazoparib, olaparib, and NU9056 did not have any effect on cell viability, and it was found that the combined treatment of thalazoparib and NU9056 and the combined treatment of olazoparib and NU9056 did not affect cell viability (Fig. One).
  • Alzheimer's disease neurodegeneration progresses due to cell death and decreased nerve cell metabolism due to abnormal protein aggregation. It was confirmed whether the expression level of proteins associated with abnormal protein aggregation or neuronal cell death was regulated by thalazoparib, olaparib, NU9056 and their combination treatment.
  • APP Swe/Ind plasmid was transfected into mouse hippocampal cell line HT22 for 48 hours to induce overexpression of amyloid precursor protein (APP), followed by thalazoparib, olaparib, NU9056 and these were co-treated.
  • APP amyloid precursor protein
  • APP overexpression was induced, and APP expression levels were reduced by thalazoparib, olaparib, NU9056, and their combined treatment.
  • Bim BCL2-like protein 11
  • AKT protein kinase B

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Abstract

The present invention relates to a composition for preventing or treating Alzheimer's disease, comprising an anticancer compound as an active ingredient. The active ingredients of the present invention, Talazoparib, Olaparib, NU9056, Talazoparib+NU9056, and Olaparib+NU9056, have an effect of reducing the expression of an amyloid protein that causes plaque formation, which is a main cause of Alzheimer's disease, and in particular, since there is a remarkably enhanced synergistic effect when two or more of the active ingredients are combined rather than using the anticancer compound alone, the present invention can be effectively used as a medicine for Alzheimer's disease.

Description

항암제 화합물을 유효성분으로 포함하는 알츠하이머성 치매의 예방 또는 치료용 조성물Composition for preventing or treating Alzheimer's disease comprising an anticancer compound as an active ingredient
본 발명은 항암제 화합물을 유효성분으로 포함하는 알츠하이머성 치매의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating Alzheimer's disease, comprising an anticancer compound as an active ingredient.
신경질환 중의 하나인 치매(dementia)는 기억력 장애, 판단력 상실 등 전신기능의 전반적인 장애를 동반하는 질환이다. 50세 이전에는 증상이 거의 나타나지 않지만 60세 이후로는 발생 빈도가 점진적으로 증가하는 노인성 질환으로서, 의학기술의 발전 및 삶의 질 향상으로 인한 노인 인구의 증가에 따라 국내뿐만 아니라 전 세계적으로 발병 인구가 급속히 증가하고 있는 질환이다. 2008년에 등록된 국내의 65세 이상 치매 환자 수는 421,000명으로 노인 전체 인구의 8.4%를 차지하고 있으며, 2030년에는 1,135,000명으로 전체 노인 인구의 9.6%를 넘어설 것으로 예측된바 있다. 2008년 보건복지부의 치매 유병률 조사 결과, 치매의 발병 형태는 매우 다양한데, 국내 발병하는 치매의 약 70% 정도는 알츠하이머형 치매(dementia of Alzheimer type)이며, 약 25% 정도는 혈관성 치매(dementia of Vascular type), 기타 알코올성 치매 및 파킨슨병 치매는 5% 이하로 집계되고 있다. Dementia, one of the neurological diseases, is a disease accompanied by general disorders of systemic functions such as memory impairment and loss of judgment. It is a geriatric disease in which symptoms rarely appear before the age of 50, but the frequency of occurrence gradually increases after the age of 60. As the elderly population increases due to the development of medical technology and the improvement of quality of life, it is a disease that is prevalent not only in Korea but also worldwide. is a rapidly growing disease. The number of dementia patients aged 65 years or older registered in Korea in 2008 was 421,000, accounting for 8.4% of the total elderly population. According to the results of the 2008 Dementia Prevalence Survey by the Ministry of Health and Welfare, the onset of dementia is very diverse. About 70% of the dementia onset in Korea is of the Alzheimer type, and about 25% is of Vascular Dementia. type), other alcoholic dementia, and Parkinson's disease dementia are counted at less than 5%.
치매의 가장 주요한 발병 형태인 알츠하이머병(Alzheimer disease, AD)은 두 가지 특징적인 병변을 보이게 되는데 하나는 뇌의 대뇌피질과 해마 부위의 신경세포에서 타우(tau) 단백질의 과인산화 및 응집에 의해 나타나는 세포 내의 신경섬유수초(Neurofibrillary tangle) 형성이고 다른 하나는 아밀로이드 β-1/42(amyloid β-1/42)의 응집에 의해 세포 외부에 형성되는 플라그(plague)이다.Alzheimer disease (AD), the most common form of dementia, shows two characteristic lesions. One is caused by hyperphosphorylation and aggregation of tau protein in neurons in the cerebral cortex and hippocampus of the brain. Neurofibrillary tangle is formed in the cell, and the other is plaque formed outside the cell by aggregation of amyloid β-1/42.
알츠하이머병의 원인은 아직 확실하게 규명되어 있지 않으나, 응집에 관여되는 두 단백질의 응집된 형태인 tangle이나 플라그(plague), 또는 전구체들이 뇌의 기억 및 인식을 담당하는 신경세포 부위에 침적되어 신경세포의 기능저하 및 사멸을 일으켜 알츠하이머를 일으킨다는 것이다. 응집된 tau 단백질의 경우 미세소관의 안정화를 담당하는데, 응집으로 감소된 tau 단백질이 정상적인 기능을 수행하지 못함에 따라 미세소관의 결합력이 약해지고 기능 이상이 긴 시간에 걸쳐 작용하여 개별 신경 세포의 기능저하, 나아가서 사멸에 이르게 된다는 것이다. The cause of Alzheimer's disease has not yet been clearly identified, but tangles, plaques, or precursors, which are aggregated forms of the two proteins involved in aggregation, are deposited in the areas of neurons responsible for memory and recognition in the brain, resulting in neuronal cell death. It is said that it causes the functional decline and death of Alzheimer's disease. In the case of aggregated tau protein, it is responsible for stabilizing microtubules. As tau protein reduced by aggregation does not perform its normal function, the binding force of microtubules is weakened and the dysfunction works over a long period of time, resulting in the deterioration of individual nerve cells. , and will lead to extinction.
한편, 알츠하이머성 치매 관련 기술로, 한국등록특허 제1755097호에 알츠하이머성 치매 치료를 위한 뇌 조직 재생용 약제학적 조성물이 개시되어 있고, 한국등록특허 제1631362호에 소엽 추출물을 유효성분으로 포함하는 알츠하이머성 치매 치료를 위한 뇌 조직 재생용 약제학적 조성물이 개시되어 있으나, 아직까지 본 발명의 항암제 화합물을 유효성분으로 포함하는 알츠하이머성 치매의 예방 또는 치료용 조성물에 대해 개시된 바 없다.On the other hand, as a technology related to Alzheimer's disease, Korean Patent No. 1755097 discloses a pharmaceutical composition for regenerating brain tissue for the treatment of Alzheimer's disease, and Korean Patent No. 1631362 discloses Alzheimer's disease containing a leaf extract as an active ingredient. Although a pharmaceutical composition for regenerating brain tissue for the treatment of sexual dementia has been disclosed, a composition for preventing or treating Alzheimer's dementia comprising the anticancer drug compound of the present invention as an active ingredient has not yet been disclosed.
본 발명은 상기와 같은 요구에 의해 도출된 것으로서, 본 발명은 항암제 화합물을 유효성분으로 포함하는 알츠하이머성 치매의 예방 또는 치료용 조성물을 제공하고, 본 발명의 유효성분인 탈라조파립(Talazoparib), 올라파립(Olaparib), NU9056, 탈라조파립+NU9056 및 올라파립+NU9056이 알츠하이머성 치매의 주요 원인인 플라그(plague) 형성을 일으키는 아밀로이드 단백질의 발현을 감소시키는 효과가 있으며, 특히, 상기 항암제 화합물을 단독으로 사용하는 것보다, 이들을 둘 이상으로 조합하였을 때 현저하게 증진된 시너지 효가가 있다는 것을 확인함으로써, 본 발명을 완성하였다.The present invention has been derived from the above needs, and the present invention provides a composition for preventing or treating Alzheimer's disease comprising an anticancer compound as an active ingredient, and includes talazoparib, the active ingredient of the present invention; Olaparib, NU9056, thalazoparib + NU9056 and olaparib + NU9056 have the effect of reducing the expression of amyloid protein that causes plaque formation, which is the main cause of Alzheimer's dementia. The present invention was completed by confirming that there is a significantly enhanced synergistic effect when two or more of them are combined rather than used alone.
상기 목적을 달성하기 위하여, 본 발명은 화학식 1 내지 3의 항암제 중에서 선택된 어느 하나 또는 둘 이상을 유효성분으로 포함하는 알츠하이머성 치매의 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for the prevention or treatment of Alzheimer's dementia comprising any one or two or more selected from anticancer agents of Chemical Formulas 1 to 3 as active ingredients.
또한, 본 발명은 인간을 제외한 동물에게 본 발명의 약학 조성물을 투여하는 단계;를 포함하는 것을 특징으로 하는 알츠하이머성 치매의 예방 또는 치료방법을 제공한다.In addition, the present invention provides a method for preventing or treating Alzheimer's disease, comprising administering the pharmaceutical composition of the present invention to an animal other than human.
본 발명은 항암제 화합물을 유효성분으로 포함하는 알츠하이머성 치매의 예방 또는 치료용 조성물에 관한 것으로, 본 발명의 유효성분인 탈라조파립(Talazoparib), 올라파립(Olaparib), NU9056, 탈라조파립+NU9056 및 올라파립+NU9056이 알츠하이머성 치매의 주요 원인인 플라그(plague) 형성을 일으키는 아밀로이드 단백질의 발현을 감소시키는 효과가 있으며, 특히, 상기 항암제 화합물을 단독으로 사용하는 것보다, 이들을 둘 이상으로 조합하였을 때 현저하게 증진된 시너지 효가가 있다.The present invention relates to a composition for the prevention or treatment of Alzheimer's dementia comprising an anticancer compound as an active ingredient, and the active ingredient of the present invention is Talazoparib, Olaparib, NU9056, Talazoparib + NU9056 And olaparib + NU9056 has the effect of reducing the expression of amyloid protein that causes the formation of plaque, which is the main cause of Alzheimer's dementia. There is a markedly enhanced synergistic effect when
도 1은 본 발명의 탈라조파립(A), 올라파립(B), NU9056(C), 탈라조파립+NU9056(D) 및 올라파립+NU9056(E)을 마우스 해마 세포주 HT22에 처리하여 확인한 세포생존율 결과이다. (D)에서 CTL은 아무것도 처리하지 않은 대조군이고, Tal은 탈라조파립 3.2μM을 처리한 것이고, NU는 NU9056 10μM을 처리한 것이며, Tal+NU는 탈라조파립 3.2μM+NU9056 10μM을 혼합한 것이다. (E)에서 CTL은 아무것도 처리하지 않은 대조군이고, Ola은 올라파립 20μM을 처리한 것이고, NU는 NU9056 10μM을 처리한 것이며, Ola+NU는 올라파립 20μM+NU9056 10μM을 혼합한 것이다. Figure 1 shows cells identified by treatment with thalazoparib (A), olaparib (B), NU9056 (C), thalazoparib + NU9056 (D) and olazoparib + NU9056 (E) of the present invention in mouse hippocampal cell line HT22 survival rate result. In (D), CTL is a control without any treatment, Tal is treated with 3.2 μM of thalazoparib, NU is treated with 10 μM of NU9056, and Tal+NU is a mixture of 3.2 μM of thalazoparib + 10 μM of NU9056. . In (E), CTL is a control without any treatment, Ola is treated with 20 μM of parib up, NU is treated with 10 μM of NU9056, and Ola + NU is a mixture of 20 μM of up parrib + 10 μM of NU9056.
도 2는 본 발명의 탈라조파립을 마우스 해마 세포주 HT22에 처리하여 확인한 아밀로이드 전구체 단백질(APP), Bim 및 pAKT의 발현량 변화를 확인한 결과이다. CTL은 아무것도 처리하지 않은 마우스 해마 세포주에서의 APP, Bim 및 pAKT의 발현량을 나타낸 것이고, APP는 아밀로이드 전구체 단백질(APP)의 과발현을 유도한 마우스 해마 세포주 HT22에서의 APP, Bim 및 pAKT의 발현량을 나타낸 것이며, APP+탈라조파립 1.6μM, APP+탈라조파립 3.2μM는 APP+Talazoparib 1.6μM 또는 APP+Talazoparib 3.2μM을 처리한 마우스 해마 세포주 HT22에서의 APP, Bim 및 pAKT의 발현량을 나타낸 것이다. ##은 CTL군 대비 APP 군에서의 pAKT 발현량이 통계적으로 유의미하게 감소하였다는 것으로 p<0.01이다. **, ***은 APP군 대비 APP+탈라조파립 1.6μM, APP+탈라조파립 3.2μM을 처리한 군에서의 APP, Bim 및 pAKT 발현량이 통계적으로 유의미하게 감소 또는 증가하였다는 것으로, **은 p<0.01이고, ***은 p<0.001이다.Figure 2 is the result of confirming the change in the expression levels of amyloid precursor protein (APP), Bim and pAKT confirmed by treating the mouse hippocampal cell line HT22 with thalazoparib of the present invention. CTL represents the expression levels of APP, Bim, and pAKT in the mouse hippocampal cell line that was not treated with anything, and APP is the expression level of APP, Bim, and pAKT in the mouse hippocampal cell line HT22 in which overexpression of amyloid precursor protein (APP) was induced. , APP+Talazoparib 1.6 μM, APP+Talazoparib 3.2 μM indicates the expression levels of APP, Bim, and pAKT in mouse hippocampal cell line HT22 treated with APP+Talazoparib 1.6 μM or APP+Talazoparib 3.2 μM. ## indicates a statistically significant decrease in the pAKT expression level in the APP group compared to the CTL group, p<0.01. **, *** indicate that APP, Bim, and pAKT expression levels were statistically significantly decreased or increased in the groups treated with APP+Talazoparib 1.6μM and APP+Talazoparib 3.2μM compared to the APP group, ** p<0.01, *** indicates p<0.001.
도 3은 본 발명의 올라파립을 마우스 해마 세포주 HT22에 처리하여 확인한 APP, Bim 및 pAKT의 발현량을 확인한 결과이다. CTL은 아무것도 처리하지 않은 마우스 해마 세포주에서의 APP, Bim 및 pAKT의 발현량을 나타낸 것이고, APP는 아밀로이드 전구체 단백질(APP)의 과발현을 유도한 마우스 해마 세포주 HT22에서의 APP, Bim 및 pAKT의 발현량을 나타낸 것이며, APP+올라파립 10μM, APP+올라파립 20μM은 APP+올라파립 10μM 또는 APP+올라파립 20μM을 처리한 마우스 해마 세포주 HT22에서의 APP, Bim 및 pAKT의 발현량을 나타낸 것이다. *, **은 APP군 대비 APP+올라파립 10μM, APP+올라파립 20μM을 처리한 군에서의 APP, Bim 및 pAKT 발현량이 통계적으로 유의미하게 감소 또는 증가하였다는 것으로, *은 p<0.05이고, **은 p<0.01이다.Figure 3 is the result of confirming the expression level of APP, Bim and pAKT confirmed by processing the mouse hippocampal cell line HT22 up to parip of the present invention. CTL represents the expression levels of APP, Bim, and pAKT in the mouse hippocampal cell line that was not treated with anything, and APP is the expression level of APP, Bim, and pAKT in the mouse hippocampal cell line HT22 in which overexpression of amyloid precursor protein (APP) was induced. , and APP + olaparib 10 μM, APP + olaparib 20 μM shows the expression levels of APP, Bim and pAKT in mouse hippocampal cell line HT22 treated with APP + olaparib 10 μM or APP + olaparib 20 μM. *, ** indicates that APP, Bim, and pAKT expression levels were statistically significantly decreased or increased in the groups treated with APP + olaparib 10 μM and APP + olaparib 20 μM compared to the APP group, * indicates p<0.05, and ** is p<0.01.
도 4는 본 발명의 NU9056을 마우스 해마 세포주 HT22에 처리하여 확인한 APP, Bim 및 pAKT의 발현량을 확인한 결과이다. CTL은 아무것도 처리하지 않은 마우스 해마 세포주에서의 APP, Bim 및 pAKT의 발현량을 나타낸 것이고, APP는 아밀로이드 전구체 단백질(APP)의 과발현을 유도한 마우스 해마 세포주 HT22에서의 APP, Bim 및 pAKT의 발현량을 나타낸 것이며, APP+NU9056 5μM, APP+NU9056 20μM는 APP+NU9056 5μM 또는 APP+NU9056 20μM을 처리한 마우스 해마 세포주 HT22에서의 APP, Bim 및 pAKT의 발현량을 나타낸 것이다. *, **은 APP군 대비 APP+NU9056 5μM, APP+NU9056 20μM을 처리한 군에서의 APP, Bim 및 pAKT 발현량이 통계적으로 유의미하게 감소 또는 증가하였다는 것으로, *은 p<0.05이고, **은 p<0.01이다.Figure 4 shows the results of confirming the expression levels of APP, Bim, and pAKT confirmed by treating the mouse hippocampal cell line HT22 with NU9056 of the present invention. CTL represents the expression levels of APP, Bim, and pAKT in the mouse hippocampal cell line that was not treated with anything, and APP is the expression level of APP, Bim, and pAKT in the mouse hippocampal cell line HT22 in which overexpression of amyloid precursor protein (APP) was induced. , and APP+NU9056 5 μM and APP+NU9056 20 μM show the expression levels of APP, Bim and pAKT in mouse hippocampal cell line HT22 treated with APP+NU9056 5 μM or APP+NU9056 20 μM. *, ** indicates that APP, Bim, and pAKT expression levels were statistically significantly decreased or increased in the groups treated with APP+NU9056 5 μM and APP+NU9056 20 μM compared to the APP group, * indicates p<0.05, and ** is p<0.01.
도 5는 본 발명의 탈라조파립, NU9056 및 탈라조파립+NU9056을 마우스 해마 세포주 HT22에 처리하여 확인한 아밀로이드 전구체 단백질(APP)의 발현량을 확인한 결과이다. *, **, ****은 탈라조파립+NU9056을 처리한 군에서의 아밀로이드 전구체 단백질(APP)의 발현량이 APP군, 탈라조파립 처리군 및 NU9056 처리군의 아밀로이드 전구체 단백질(APP) 발현량보다 통계적으로 유의미하게 감소하였다는 것으로, *은 p<0.05이고, **은 p<0.01이며, ****은 0.0001이다.Figure 5 is the result of confirming the expression level of amyloid precursor protein (APP) confirmed by treating the mouse hippocampal cell line HT22 with thalazoparib, NU9056 and thalazoparib + NU9056 of the present invention. *, **, **** are the expression levels of amyloid precursor protein (APP) in the group treated with thalazoparib + NU9056; Statistically significantly decreased than the amount, * is p <0.05, ** is p <0.01, **** is 0.0001.
도 6은 본 발명의 올라파립, NU9056 및 올라파립+NU9056을 마우스 해마 세포주 HT22에 처리하여 확인한 아밀로이드 전구체 단백질(APP)의 발현량을 확인한 결과이다. *, **, ****은 올라파립+NU9056을 처리한 군에서의 아밀로이드 전구체 단백질(APP)의 발현량이 APP군, 올라파립 처리군 및 NU9056 처리군의 아밀로이드 전구체 단백질(APP) 발현량보다 통계적으로 유의미하게 감소하였다는 것으로, *은 p<0.05이고, **은 p<0.01이며, ****은 0.0001이다.Figure 6 is the result of confirming the expression level of the amyloid precursor protein (APP) confirmed by processing the present invention up parip, NU9056 and up parip +NU9056 in the mouse hippocampal cell line HT22. *, **, **** indicates that the expression level of amyloid precursor protein (APP) in the group treated with olaparib + NU9056 was higher than the expression level of amyloid precursor protein (APP) in the APP group, olaparib-treated group, and NU9056-treated group. Statistically significant decrease, * is p <0.05, ** is p <0.01, **** is 0.0001.
본 발명은 하기 화학식 1 내지 3의 항암제 중에서 선택된 어느 하나 또는 둘 이상을 유효성분으로 포함하는 알츠하이머성 치매의 예방 또는 치료용 약학 조성물에 관한 것이다. 하기 화학식 1의 항암제는 탈라조파립(Talazoparib)이라고 하며, 화학식 2의 항암제는 올라파립(Olaparib)이라고 하고, 화학식 3의 항암제는 NU9056이라고 칭한다.The present invention relates to a pharmaceutical composition for the prevention or treatment of Alzheimer's dementia comprising any one or two or more selected from the following anticancer agents represented by Chemical Formulas 1 to 3 as active ingredients. The anticancer drug of Chemical Formula 1 is called Talazoparib, the anticancer drug of Chemical Formula 2 is called Olaparib, and the anticancer drug of Chemical Formula 3 is called NU9056.
Figure PCTKR2022007689-appb-img-000001
Figure PCTKR2022007689-appb-img-000001
Figure PCTKR2022007689-appb-img-000002
Figure PCTKR2022007689-appb-img-000002
Figure PCTKR2022007689-appb-img-000003
Figure PCTKR2022007689-appb-img-000003
상기 화학식 1~3의 항암제는 아밀로이드 전구체 단백질의 발현량을 감소시킬수 있고, Bim 단백질의 발현량을 감소시키며, pAKT 단백질의 발현량을 증가시킬 수 있지만 이에 제한하는 것은 아니다. Anticancer agents of Chemical Formulas 1 to 3 may decrease the expression level of amyloid precursor protein, decrease the expression level of Bim protein, and increase the expression level of pAKT protein, but are not limited thereto.
상기 조성물의 총 중량에 대하여, 0.1 내지 100 중량%의 유효성분을 포함하는 것이 바람직하다. Based on the total weight of the composition, it is preferable to include 0.1 to 100% by weight of the active ingredient.
상기 약학 조성물의 유효성분 이외에 약학적으로 허용가능한 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토덱스트린 용액, 글리세롤, 에탄올, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 중에서 선택된 1종 이상의 담체를 더 함유할 수 있으며, 상기 유효성분 이외에 약학적으로 허용 가능한 항산화제, 완충액, 정균제, 희석제, 계면활성제, 결합제, 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제 및 보존제 중에서 선택된 1종 이상의 보조제를 더 함유할 수 있다.In addition to the active ingredients of the pharmaceutical composition, pharmaceutically acceptable saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia Gum, calcium phosphate, alginates, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and minerals It may further contain one or more carriers selected from oils, and in addition to the above active ingredients, pharmaceutically acceptable antioxidants, buffers, bacteriostatic agents, diluents, surfactants, binders, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, and suspending agents And at least one adjuvant selected from preservatives may be further contained.
상기 약학 조성물은 통상의 방법에 따라 경구 또는 비경구의 제형으로 투여될 수 있으며, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 조성물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로오스, 락토오스, 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 또한, 비수성용제, 현탁제로는 프로필렌 글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The pharmaceutical composition may be administered in an oral or parenteral formulation according to a conventional method, and when formulated, diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants are used. . Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose, It is prepared by mixing gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, internal solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. there is. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. In addition, vegetable oils such as propylene glycol, polyethylene glycol, olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogeratin and the like may be used.
또한, 본 발명은 인간을 제외한 동물에게 본 발명의 약학 조성물을 투여하는 단계;를 포함하는 것을 특징으로 하는 알츠하이머성 치매의 예방 또는 치료방법에 관한 것이다.In addition, the present invention relates to a method for preventing or treating Alzheimer's disease, comprising administering the pharmaceutical composition of the present invention to an animal other than human.
이하, 실시예를 이용하여 본 발명을 더욱 상세하게 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로 본 발명의 범위가 이들에 의해 제한되지 않는다는 것은 당해 기술분야에서 통상의 지식을 가진 자에게 있어 자명한 것이다. Hereinafter, the present invention will be described in more detail using examples. These examples are only for explaining the present invention in more detail, and it is obvious to those skilled in the art that the scope of the present invention is not limited thereto.
실시예 1. 탈라조파립(Talazoparib), 올라파립(Olaparib) 및 NU9056의 처리에 따른 세포 생존율 확인Example 1. Talazoparib, Olaparib, and cell viability confirmed by treatment with NU9056
탈라조파립, 올라파립 및 NU9056을 마우스 해마 세포주 HT22에 처리하여 세포생존율에 대한 평가를 위해 MTT 어세이를 실시하였다. Talazoparib, olaparib, and NU9056 were treated with mouse hippocampal cell line HT22, and MTT assay was performed to evaluate cell viability.
그 결과, 탈라조파립, 올라파립 및 NU9056은 세포생존율에 아무런 영향을 미치지 않았고, 탈라조파립과 NU9056의 병용처리, 올라파립과 NU9056의 병용처리시에도 세포생존율에는 영향을 미치지 않는 것으로 나타났다(도 1).As a result, talazoparib, olaparib, and NU9056 did not have any effect on cell viability, and it was found that the combined treatment of thalazoparib and NU9056 and the combined treatment of olazoparib and NU9056 did not affect cell viability (Fig. One).
실시예 2. 탈라조파립(Talazoparib), 올라파립(Olaparib) 및 NU9056의 신경세포 보호 효과Example 2. Talazoparib, Olaparib and NU9056 Neuronal Cell Protection Effect
알츠하이머병은 비정상적 단백질 응집으로 인한 세포 사멸 및 신경 세포 대사 저하로 신경퇴행이 진행된다. 비정상적 단백질 응집 또는 이에 의한 신경세포 사멸과 관련이 있는 단백질질의 발현량이 탈라조파립, 올라파립, NU9056 및 이들의 병용처리에 의해 조절되는지를 확인하였다. In Alzheimer's disease, neurodegeneration progresses due to cell death and decreased nerve cell metabolism due to abnormal protein aggregation. It was confirmed whether the expression level of proteins associated with abnormal protein aggregation or neuronal cell death was regulated by thalazoparib, olaparib, NU9056 and their combination treatment.
구체적으로, 마우스 해마 세포주 HT22에 1㎍의 APPSwe/Ind 플라스미드를 48시간 동안 형질 주입하여 아밀로이드 전구체 단백질(amyloid precursor protein; APP)의 과발현을 유도한 후, 24시간 동안 탈라조파립, 올라파립, NU9056 및 이들을 병용처리하였다. Specifically, 1 μg of APP Swe/Ind plasmid was transfected into mouse hippocampal cell line HT22 for 48 hours to induce overexpression of amyloid precursor protein (APP), followed by thalazoparib, olaparib, NU9056 and these were co-treated.
이후, 웨스턴블랏을 실시하여 APP, Bim(BCL2-like protein 11) 또는 pAKT(protein kinase B)의 발현량 변화를 확인하였다. Then, Western blotting was performed to confirm changes in the expression levels of APP, Bim (BCL2-like protein 11) or pAKT (protein kinase B).
그 결과 APP 과발현 유도가 되었으며, 탈라조파립, 올라파립, NU9056 및 이들의 병용처리에 의하여 APP 발현 수준이 감소하였다. As a result, APP overexpression was induced, and APP expression levels were reduced by thalazoparib, olaparib, NU9056, and their combined treatment.
또한, 세포사멸시에 증가하는 단백질인 Bim(BCL2-like protein 11)의 발현이 탈라조파립, 올라파립, NU9056 및 이들의 병용처리에 의하여 감소하는 것을 확인하였다. 신경 세포 대사 활성 정도를 나타내는 단백질인 AKT(protein kinase B)의 인산화가 APP 과발현시 감소하였으나, 탈라조파립, 올라파립, NU9056 및 이들의 병용처리에 의하여 회복되는 것을 확인하였다(도 2 내지 도 6). In addition, it was confirmed that the expression of Bim (BCL2-like protein 11), a protein that increases during apoptosis, was decreased by thalazoparib, olaparib, NU9056 and their combination treatment. Phosphorylation of AKT (protein kinase B), a protein representing the degree of neuronal metabolic activity, was reduced when APP was overexpressed, but it was confirmed that it was restored by thalazoparib, olaparib, NU9056, and their combination treatment (Figs. 2 to 6 ).

Claims (7)

  1. 하기 화학식 1 내지 3의 항암제 중에서 선택된 어느 하나 또는 둘 이상을 유효성분으로 포함하는 알츠하이머성 치매의 예방 또는 치료용 약학 조성물.A pharmaceutical composition for the prevention or treatment of Alzheimer's dementia comprising any one or two or more selected from the following anticancer agents of Formulas 1 to 3 as active ingredients.
    [화학식 1][Formula 1]
    Figure PCTKR2022007689-appb-img-000004
    Figure PCTKR2022007689-appb-img-000004
    [화학식 2][Formula 2]
    Figure PCTKR2022007689-appb-img-000005
    Figure PCTKR2022007689-appb-img-000005
    [화학식 3][Formula 3]
    Figure PCTKR2022007689-appb-img-000006
    Figure PCTKR2022007689-appb-img-000006
  2. 제1항에 있어서, 상기 화학식 1~3의 항암제는 아밀로이드 전구체 단백질의 발현량을 감소시키는 것을 특징으로 하는 알츠하이머성 치매의 예방 또는 치료용 약학 조성물.The pharmaceutical composition for preventing or treating Alzheimer's dementia according to claim 1, wherein the anticancer agents of Chemical Formulas 1 to 3 reduce the expression level of amyloid precursor protein.
  3. 제1항에 있어서, 상기 화학식 1~3의 항암제는 Bim 단백질의 발현량을 감소시키며, pAKT 단백질의 발현량을 증가시키는 것을 특징으로 하는 알츠하이머성 치매의 예방 또는 치료용 약학 조성물.The pharmaceutical composition for preventing or treating Alzheimer's dementia according to claim 1, wherein the anticancer agents of Chemical Formulas 1 to 3 decrease the expression level of Bim protein and increase the expression level of pAKT protein.
  4. 제1항에 있어서, 조성물의 총 중량에 대하여, 0.1 내지 100 중량%의 유효성분을 포함하는 것을 특징으로 하는 알츠하이머성 치매의 예방 또는 치료용 약학 조성물.The pharmaceutical composition for the prevention or treatment of Alzheimer's dementia according to claim 1, which comprises 0.1 to 100% by weight of the active ingredient, based on the total weight of the composition.
  5. 제1항에 있어서, 상기 유효성분 이외에 약학적으로 허용가능한 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토덱스트린 용액, 글리세롤, 에탄올, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 중에서 선택된 1종 이상의 담체를 더 함유하는 것을 특징으로 하는 알츠하이머성 치매의 예방 또는 치료용 약학 조성물.According to claim 1, in addition to the active ingredient, pharmaceutically acceptable saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, lactose, dextrose, sucrose, sorbitol, mannitol, Starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, stearic acid A pharmaceutical composition for preventing or treating Alzheimer's dementia, further comprising at least one carrier selected from magnesium and mineral oil.
  6. 제1항에 있어서, 상기 유효성분 이외에 약학적으로 허용 가능한 항산화제, 완충액, 정균제, 희석제, 계면활성제, 결합제, 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제 및 보존제 중에서 선택된 1종 이상의 보조제를 더 함유하는 것을 특징으로 하는 알츠하이머성 치매의 예방 또는 치료용 약학 조성물.According to claim 1, in addition to the active ingredient, at least one adjuvant selected from pharmaceutically acceptable antioxidants, buffers, bacteriostats, diluents, surfactants, binders, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents and preservatives A pharmaceutical composition for the prevention or treatment of Alzheimer's dementia, characterized in that it further contains.
  7. 인간을 제외한 동물에게 제1항 내지 제6항 중 어느 한 항에 따른 약학 조성물을 투여하는 단계;를 포함하는 것을 특징으로 하는 알츠하이머성 치매의 예방 또는 치료방법.A method for preventing or treating Alzheimer's dementia, comprising: administering the pharmaceutical composition according to any one of claims 1 to 6 to a non-human animal.
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