WO2024181660A1 - Composition including shilajit for preventing and treating alzheimer's disease - Google Patents
Composition including shilajit for preventing and treating alzheimer's disease Download PDFInfo
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- WO2024181660A1 WO2024181660A1 PCT/KR2023/021995 KR2023021995W WO2024181660A1 WO 2024181660 A1 WO2024181660 A1 WO 2024181660A1 KR 2023021995 W KR2023021995 W KR 2023021995W WO 2024181660 A1 WO2024181660 A1 WO 2024181660A1
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- shilajit
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- alzheimer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/02—Medicinal preparations containing materials or reaction products thereof with undetermined constitution from inanimate materials
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- 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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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
Definitions
- the present invention relates to a composition for preventing and treating Alzheimer's dementia comprising shilajit.
- Shilajit is a dense aggregate of plant organic matter containing plant fibers and minerals in a sticky matrix, formed when plants native to high-altitude areas such as the Himalayas were compressed at high temperature and high pressure in rock layers due to tectonic movements.
- Shilajit is mainly composed of humus and is composed of benzoic acid, fatty acids, ichiol, ellagic acid, etc., and has physiologically active substances such as dibenzo-alpha-phyllon, humic acid, and fulvic acid, so it has been traditionally used in countries surrounding the Himalayas to strengthen overall body function, prevent aging, lower blood sugar, heal wounds, strengthen brain function, increase bone density, strengthen immune function, and treat arthritis and high blood pressure.
- U.S. Patent No. 5,405,613 discloses that adding shilajit or an extract thereof to a vitamin/mineral preparation enhances the vitality restoring activity of the vitamin/mineral preparation;
- U.S. Patent No. 6,440,436 discloses a method for purifying the bioactive components of shilajit, and describes in detail that the shilajit extract purified by the method can be used as a skin protection and care preparation, or as a pharmaceutical or nutritional preparation.
- Korean Patent No. 10-0521249 reports that a composition containing shilajit or an extract thereof has the activity of improving sexual function and enhancing reproductive function by strengthening the metabolic function of the entire body, and thus enables nutritional strengthening, improving sexual function, and treating infertility.
- the purpose of the present invention is to provide a pharmaceutical composition for preventing and treating Alzheimer's dementia containing shilajit or a functional health food composition for preventing and improving Alzheimer's dementia containing shilajit composition.
- the present invention provides a pharmaceutical composition for preventing and treating Alzheimer's dementia or a functional health food composition for preventing and improving Alzheimer's dementia comprising a shilajit composition.
- the composition is characterized in that it contains shilajit at a concentration of 25 to 1500 ⁇ g/ml.
- the composition is characterized in that it alleviates neurotoxicity caused by the accumulation of amyloid beta, and more specifically, it alleviates inflammation caused by the accumulation of amyloid beta by suppressing the expression of interleukin-1 ⁇ .
- a pharmaceutical composition for preventing and treating Alzheimer's dementia and a functional health food composition for preventing and improving Alzheimer's dementia comprising the shilajit composition of the present invention have the effect of alleviating neurotoxicity caused by accumulation of amyloid beta, and thus can be utilized for preventing, treating, and improving Alzheimer's dementia.
- Figure 1 shows the results of confirming changes in the activity of nerve cells (SH-SY5Y) treated with the composition of Shilajit A, B or C of the present invention.
- Figure 2 shows the results of the Shilajit composition of the present invention regulating the neurotoxicity of amyloid beta.
- Figure 3 shows the results of controlling inflammation caused by amyloid beta by the Shilajit composition of the present invention.
- the present invention provides a pharmaceutical composition for preventing and treating Alzheimer's dementia comprising a shilajit composition.
- composition is characterized by alleviating neurotoxicity caused by accumulation of amyloid beta, and more specifically, by alleviating inflammation caused by accumulation of amyloid beta by inhibiting the expression of interleukin-1 ⁇ .
- the above composition is characterized in that it contains shilajit in a concentration of 25 to 1500 ⁇ g/ml, preferably in a concentration of 50 to 1000 ⁇ g/ml, more preferably in a concentration of 100 to 500 ⁇ g/ml. If the shilajit is contained in a concentration of 25 ⁇ g/ml or less, the effect of alleviating neurotoxicity caused by accumulation of amyloid beta may be minimal, and if the shilajit is used in excess of 1500 ⁇ g/ml, neurotoxicity may increase due to impurities contained in the shilajit.
- a pharmaceutical composition for preventing and treating Alzheimer's dementia comprising the shilajit composition of the present invention contains the shilajit composition as an active ingredient and exhibits a preventive or therapeutic effect on Alzheimer's dementia.
- the active ingredient extract of the present invention is a natural extract, it is expected that there will be less concern about side effects when administered to a body over a long period of time compared to other synthetic drugs.
- Alzheimer's disease used in the present invention refers to dementia caused by Alzheimer's disease, and if it is caused by inflammation due to amyloid beta, it is included in the scope of the present invention.
- the term "prevention" used in the present specification means preventing the onset of the disease and symptoms mentioned herein by prophylactically administering a preparation such as a pharmaceutical composition to a healthy patient. It also includes prophylactically administering such a preparation to a patient in the pre-stage of the disease to be treated.
- treatment used in the present specification includes not only treating the disease mentioned herein, but also preventing the onset of the disease and symptoms mentioned herein by prophylactically administering a combination preparation such as a combination preparation or pharmaceutical composition to a healthy patient.
- the composition of the present invention may additionally contain auxiliary agents such as pharmaceutically suitable and physiologically acceptable carriers, excipients, and diluents.
- pharmaceutically acceptable carrier refers to a component other than the active substance of a composition, specifically a pharmaceutical composition.
- Carriers, excipients, and diluents that may be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.
- diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants may be used.
- Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations can be prepared by mixing the extract with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc.
- excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, etc.
- lubricants such as magnesium stearate and talc are also used.
- Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives can be included.
- Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and transdermal preparations.
- Non-aqueous solvents and suspending agents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
- Suppository bases may include witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin, etc.
- the dosage of the composition may be appropriately adjusted depending on the patient's condition, age, weight, degree of disease, administration route, etc., and may be sufficiently administered once a day at regular intervals or several times a day at regular intervals depending on the judgment of a doctor or pharmacist.
- the dosage may be 0.0001 mg/kg/day to 1000 mg/kg/day, preferably 0.01 to 500 mg/kg, and more preferably 0.01 mg/kg to 100 mg/kg based on the active ingredient content, but is not limited thereto.
- the above dosage is an example of an average case and the dosage may be higher or lower depending on individual differences.
- composition according to the present invention can be administered to mammals, including humans, by various routes.
- the administration method can be any method commonly used, and for example, it can be administered orally, rectally, or by intravenous, intramuscular, or subcutaneous injection.
- composition of the present invention can be formulated and used in oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, or in parenteral formulations in the form of transdermal agents, suppositories, and sterile injectable solutions, according to a conventional method.
- oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols
- parenteral formulations in the form of transdermal agents, suppositories, and sterile injectable solutions, according to a conventional method.
- the composition of the present invention may be administered alone, but may generally be administered mixed with a pharmaceutical carrier selected in consideration of the mode of administration and standard pharmaceutical practice.
- composition of the present invention may be administered orally, intrabuccally or sublingually in the form of tablets containing starch or lactose, or in the form of capsules containing alone or with excipients, or in the form of elixirs or suspensions containing chemicals to impart flavor or color.
- Such liquid preparations may be formulated with pharmaceutically acceptable excipients such as suspending agents (e.g., methylcellulose, semi-synthetic glycerides such as witepsol, or glyceride mixtures such as mixtures of apricot kernel oil and PEG-6 esters or mixtures of PEG-8 and caprylic/capric glycerides).
- suspending agents e.g., methylcellulose, semi-synthetic glycerides such as witepsol, or glyceride mixtures such as mixtures of apricot kernel oil and PEG-6 esters or mixtures of PEG-8 and caprylic/capric glycerides.
- the present invention provides a functional health food composition for preventing and improving Alzheimer's dementia, comprising a shilajit composition.
- composition is characterized by alleviating neurotoxicity caused by accumulation of amyloid beta, and more specifically, by alleviating inflammation caused by accumulation of amyloid beta by inhibiting the expression of interleukin-1 ⁇ .
- the above composition is characterized in that it contains shilajit in a concentration of 25 to 1500 ⁇ g/ml, preferably in a concentration of 50 to 1000 ⁇ g/ml, and more preferably in a concentration of 100 to 500 ⁇ g/ml. If the shilajit is contained in a concentration of 25 ⁇ g/ml or less, the effect of alleviating neurotoxicity caused by accumulation of amyloid beta may be minimal, and if the shilajit is used in excess of 1500 ⁇ g/ml, neurotoxicity may increase due to impurities contained in the shilajit.
- the functional health food composition for preventing and improving Alzheimer's dementia comprising the shilajit composition of the present invention, contains the shilajit composition as an effective ingredient and exhibits a prevention or improvement effect on Alzheimer's dementia.
- the functional health food according to the present invention may be various foods, beverages, food additives, etc.
- the functional health food composition for preventing Alzheimer's dementia, comprising the shilajit composition of the present invention may be manufactured and processed in forms including, but not limited to, tablets, capsules, powders, granules, liquids, pills, etc., for the purpose of preventing or improving Alzheimer's dementia.
- the term "functional health food (health functional food)" used in the present invention refers to a food manufactured and processed using raw materials or ingredients having functionality useful to the human body according to Act No. 6727 on Health Functional Foods, and means being consumed for the purpose of obtaining a useful effect for health purposes, such as regulating nutrients for the structure and function of the human body or physiological effects.
- the functional health food of the present invention may contain conventional food additives, and its suitability as the "food additive” is determined by the specifications and criteria for the relevant item according to the general provisions and general test methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety, unless otherwise specified.
- Food Additives Codex Items listed in the "Food Additives Codex” include, for example, chemical synthetic substances such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, calciphilic pigment, and guar gum; mixed preparations such as sodium L-glutamate preparations, alkaline agents added to noodles, preservative preparations, and tar color preparations.
- chemical synthetic substances such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid
- natural additives such as persimmon pigment, licorice extract, crystalline cellulose, calciphilic pigment, and guar gum
- mixed preparations such as sodium L-glutamate preparations, alkaline agents added to noodles, preservative preparations, and tar color preparations.
- the functional health food of the present invention may contain additives such as appropriate carriers, excipients, and diluents used in the manufacture of conventional foods in the usual amounts.
- additives such as appropriate carriers, excipients, and diluents used in the manufacture of conventional foods in the usual amounts.
- a health functional food in tablet form can be made by granulating a mixture of the extract, which is an active ingredient, with excipients, binders, disintegrants, and other additives using a conventional method, and then adding a lubricant, etc. to perform compression molding, or directly compressing the mixture.
- the health functional food in tablet form can contain a maturing agent, etc., if necessary, and can also be coated with an appropriate coating agent, if necessary.
- hard capsules can be manufactured by filling a mixture of an active ingredient, an extract, and additives such as excipients, or a granular or coated granular material thereof, into a regular hard capsule
- soft capsules can be manufactured by filling a capsule base such as gelatin with a mixture of an active ingredient, an extract, and additives such as excipients.
- the soft capsules may contain a plasticizer such as glycerin or sorbitol, a coloring agent, a preservative, etc., as needed.
- a pill-shaped functional health food can be prepared by molding a mixture of an active ingredient, an extract, and an excipient, a binder, a disintegrant, etc., by an appropriate method, and, if needed, can be coated with white sugar or another appropriate coating agent, or starch, talc, or a suitable substance to form a pill.
- a granular functional health food can be manufactured into a granular form by a mixture of an active ingredient, an extract, and an excipient, a binder, a disintegrant, etc., by an appropriate method, and, if needed, can contain a flavoring agent, a flavoring agent, etc.
- Shilajit is a substance found in the rocks of the Himalayas, and is made by the slow decomposition of plants. When the minerals in the rocky mountains are continuously heated by direct sunlight, they are emulsified and produced as plant resin or gum, which is collected, purified, and used for food. Shilajit contains various and abundant minerals and various components, but there are concerns about heavy metal and fungal contaminants. Therefore, in this invention, E. coli and heavy metal tests were performed on three types of Shilajit (Silajit A, B, and C).
- Table 1 below shows the test results for the shilajit of the present invention.
- test results show that the shilajit A, B and C of the present invention contain heavy metals at levels that meet the daily intake limits of the US FDA and the Korean FDA, and thus are judged to be usable for food or pharmaceutical purposes.
- a shilajit A, B, or C composition was prepared at a concentration of 50 ⁇ g/mL, 100 ⁇ g/mL, 250 ⁇ g/mL, 500 ⁇ g/mL, or 1000 ⁇ g/mL, and then treated in a culture dish seeded with 5x10 3 cells/well of neural cells (SH-SY5Y).
- the neural cells treated with the above-mentioned shilajit A, B, or C at different concentrations were cultured for 24 hours, and then the MTS assay was performed to analyze the cell viability of the neural cells.
- Figure 1 shows the results of confirming the activity changes of nerve cells (SH-SY5Y) treated with the composition of shilajit A, B or C of the present invention.
- Panel A shows the results for shilajit A;
- panel B shows the results for shilajit B;
- panel C shows the results for shilajit C.
- shilajit alleviates neurotoxicity caused by amyloid beta when amyloid beta, which is toxic to nerve cells, is treated together with shilajit.
- amyloid beta is toxic to nerve cells and induces cell death.
- a neurotoxic reaction occurs when amyloid beta is deposited due to some stimulus, and neurotoxicity occurs due to the external stimulus and amyloid beta deposition.
- amyloid beta 1-42 (A ⁇ 1-42 ), which is known to be the most toxic among amyloid beta, was used.
- Figure 2 shows the results of regulating the neurotoxicity of amyloid beta by shilajit of the present invention.
- Panel A shows the results of measuring neuronal activity through an MTS assay after treating a culture dish containing 5x10 4 cells/well of neural cells (SH-SY5Y) with 3 ⁇ M A ⁇ 1-42 , 10 ⁇ M A ⁇ 1-42 , or 30 ⁇ M A ⁇ 1-42 , and culturing for 24 hours;
- Panel B shows the results of measuring neuronal activity using the MTS assay after 24 h of culture in culture dishes seeded with 5x103 cells/well of neuronal (SH-SY5Y) cells treated with 3 ⁇ M A ⁇ 1-42 and 100 ⁇ g/mL, 250 ⁇ g/mL, or 500 ⁇ g/mL shilajit A, shilajit B, or shilajit C.
- shilajit B and C were confirmed to have a better neuroprotective effect than shilajit A, and the neuroprotective effect increased in the range of 100 to 250 ⁇ g/mL, but when it exceeded 250 ⁇ g/mL, the neuroprotective effect actually decreased.
- the shilajit of the present invention protects nerve cells from neurotoxicity caused by amyloid beta. Accordingly, in the present invention, an acute neuroinflammation mouse model using amyloid beta was established and the neuroprotective effects of shilajit A, B, and C were analyzed.
- Figure 3 shows the results of inflammation control by the shilajit composition of the present invention.
- Panel A shows the results of analyzing the expression level of the inflammatory response substance interleukin-1 ⁇ (cleaved interleukin-1 ⁇ ) by Western blotting in the case where differentiated macrophages were not treated with anything; treated only with LPS (Lipopolysaccharide); treated simultaneously with LPS (Lipopolysaccharide) and an inflammatory substance, A ⁇ 1-42 9 ⁇ M; and treated simultaneously with LPS (Lipopolysaccharide), A ⁇ 1-42 9 ⁇ M, and shilajit A, B, or C at 0.25 or 0.5 mg/ml.
- LPS Lipopolysaccharide
- Panel B shows the results of analyzing the expression level of the inflammatory response substance interleukin-1 ⁇ (cleaved interleukin-1 ⁇ ) in the case where an acute neuroinflammation mouse model using amyloid beta was treated with A ⁇ 1-42 (200 pmole/5 ⁇ l).
- Panel C shows the results of analyzing the level of interleukin-1 ⁇ expression when shilajit 75 mg/kg or 150 mg/kg and A ⁇ 1-42 (200 pmole/5 ⁇ l) were treated simultaneously in a mouse model of acute neuroinflammation using amyloid beta;
- MCC950 (10 mg/kg) and A ⁇ 1-42 (200 pmole/5 ⁇ l) which inhibits NLRP3 inflammosome stimulation induced by A ⁇ 1-42 , were treated simultaneously;
- the acute neuroinflammation mouse model using the amyloid beta was prepared by intracerebroventricular (icv) injection of A ⁇ 1-42 (200 pmole/5 ⁇ l).
- the shilajit of the present invention can be used as a pharmaceutical composition or functional food composition for preventing and treating Alzheimer's disease caused by accumulation of amyloid beta, as it alleviates neuroinflammation related to amyloid beta when directly treated with cells or consumed through diet.
- a pharmaceutical composition for preventing and treating Alzheimer's dementia and a functional health food composition for preventing and improving Alzheimer's dementia comprising the shilajit composition of the present invention have the effect of alleviating neurotoxicity caused by accumulation of amyloid beta, and thus can be utilized for preventing, treating, and improving Alzheimer's dementia.
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Abstract
Description
본 발명은 실라짓을 포함하는 알츠하이머성 치매 예방 및 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing and treating Alzheimer's dementia comprising shilajit.
실라짓(Shilajit)은 히말라야와 같은 고산지역에서 자생하던 식물이 지각변동에 의해 암석층에서 고온 고압으로 압축되어 형성된 것으로 점착성의 기질에 식물성 섬유와 미네랄이 포함된 식물성 유기물의 밀집체이다. 실라짓은 부식질을 주성분으로 하며 벤조산, 지방산, 이키올, 엘라그산등으로 구성되며 디벤조 알파파일론, 후민산 및 풀빅사과 같은 생리활성물질을 가지고 있어 전통적으로 히말라야 주변국들에서 전반적인 신체 기능 강화, 노화 방지, 혈당강하, 상처치유, 두뇌 기능 강화, 골밀도 증가, 면역기능 강화, 관절염 및 고혈압 치료제로 이용되어져 왔다.Shilajit is a dense aggregate of plant organic matter containing plant fibers and minerals in a sticky matrix, formed when plants native to high-altitude areas such as the Himalayas were compressed at high temperature and high pressure in rock layers due to tectonic movements. Shilajit is mainly composed of humus and is composed of benzoic acid, fatty acids, ichiol, ellagic acid, etc., and has physiologically active substances such as dibenzo-alpha-phyllon, humic acid, and fulvic acid, so it has been traditionally used in countries surrounding the Himalayas to strengthen overall body function, prevent aging, lower blood sugar, heal wounds, strengthen brain function, increase bone density, strengthen immune function, and treat arthritis and high blood pressure.
미국특허 제 5405613호에는 실라짓 또는 그 추출물을 비타민/미네랄 제제에 첨가하면 비타민/미네랄 제제의 원기회복 활성을 증진시키는 효과가 있음이 개시하고 있으며; 미국특허 제 6440436호에는 실라짓의 생활성 성분을 정제하는 방법이 개시되어 있으며, 이 방법으로 정제한 실라짓 추출물을 피부 보호 및 관리 제제로 이용하거나, 약학적 또는 영양학적 제제로 이용할 수 있음을 상술하고 있다. 또한 한국등록특허 제 10-0521249호에는 실라짓 또는 그 추출물을 함유하는 조성물이 신체 전반의 신진대사 기능을 강화함으로써 성기능을 개선하고 생식 기능을 증강시키는 활성이 있어, 자양강장, 성기능 개선 및 불임 치료 등이 가능하다는 결과가 보고된바 있다.U.S. Patent No. 5,405,613 discloses that adding shilajit or an extract thereof to a vitamin/mineral preparation enhances the vitality restoring activity of the vitamin/mineral preparation; U.S. Patent No. 6,440,436 discloses a method for purifying the bioactive components of shilajit, and describes in detail that the shilajit extract purified by the method can be used as a skin protection and care preparation, or as a pharmaceutical or nutritional preparation. In addition, Korean Patent No. 10-0521249 reports that a composition containing shilajit or an extract thereof has the activity of improving sexual function and enhancing reproductive function by strengthening the metabolic function of the entire body, and thus enables nutritional strengthening, improving sexual function, and treating infertility.
그러나 실라짓은 전통적인 약제로서 광범위하게 사용되고 있음에도 신경염증에 관련된 연구가 진행된 바 없으며 특히 아밀로이드 베타의 축적으로 유도되는 신경염증 및 이를 통한 알츠하이머성 치매와 같은 질병에 대한 치료효과 또한 전혀 알려진 바 없다.However, despite its widespread use as a traditional medicine, shilajit has not been studied in relation to neuroinflammation, and in particular, its therapeutic effect on neuroinflammation induced by amyloid beta accumulation and diseases such as Alzheimer's disease through it is also unknown.
본 명세서에서 언급된 특허문헌 및 참고문헌은 각각의 문헌이 참조에 의해 개별적이고 명확하게 특정된 것과 동일한 정도로 본 명세서에 참조로 삽입된다. The patent documents and references mentioned in this specification are incorporated by reference into this specification to the same extent as if each document was individually and specifically designated by reference.
본 발명은 실라짓을 포함하는 알츠하이머성 치매 예방 및 치료용 약제학적 조성물 또는 실라짓 조성물을 포함하는 알츠하이머성 치매 예방 및 개선용 기능성 건강식품 조성물을 제공하는데 목적이 있다.The purpose of the present invention is to provide a pharmaceutical composition for preventing and treating Alzheimer's dementia containing shilajit or a functional health food composition for preventing and improving Alzheimer's dementia containing shilajit composition.
본 발명의 다른 목적 및 기술적 특징은 이하의 발명의 상세한 설명, 청구의 범위 및 도면에 의해 보다 구체적으로 제시된다. Other objects and technical features of the present invention are more specifically presented in the detailed description of the invention, the claims and the drawings below.
본 발명은 실라짓 조성물을 포함하는 알츠하이머성 치매 예방 및 치료용 약제학적 조성물 또는 알츠하이머성 치매 예방 및 개선용 기능성 건강식품 조성물을 제공한다. The present invention provides a pharmaceutical composition for preventing and treating Alzheimer's dementia or a functional health food composition for preventing and improving Alzheimer's dementia comprising a shilajit composition.
상기 조성물은 실라짓이 25 내지 1500㎍/㎖의 농도로 포함된 것을 특징으로 한다. 상기 조성물은 아밀로이드 베타의 축적으로 인한 신경세포 독성을 완화하는 것을 특징으로 하며 상세하게는 인터루킨-1β의 발현을 억제하여 아밀로이드 베타의 축적으로 인해 발생하는 염증을 완화하는 것을 특징으로 한다.The composition is characterized in that it contains shilajit at a concentration of 25 to 1500 μg/ml. The composition is characterized in that it alleviates neurotoxicity caused by the accumulation of amyloid beta, and more specifically, it alleviates inflammation caused by the accumulation of amyloid beta by suppressing the expression of interleukin-1β.
본 발명의 실라짓 조성물을 포함하는 알츠하이머성 치매 예방 및 치료용 약제학적 조성물 및 알츠하이머성 치매 예방 및 개선용 기능성 건강식품 조성물은 아밀로이드 베타의 축적으로 인한 신경세포 독성을 완화하는 효과가 있어 알츠하이머성 치매의 예방, 치료 및 개선에 활용 가능하다.A pharmaceutical composition for preventing and treating Alzheimer's dementia and a functional health food composition for preventing and improving Alzheimer's dementia comprising the shilajit composition of the present invention have the effect of alleviating neurotoxicity caused by accumulation of amyloid beta, and thus can be utilized for preventing, treating, and improving Alzheimer's dementia.
도 1은 본 발명의 실라짓 A, B 또는 C 조성물을 처리한 신경세포(SH-SY5Y)의 활성변화를 확인한 결과를 보여준다. Figure 1 shows the results of confirming changes in the activity of nerve cells (SH-SY5Y) treated with the composition of Shilajit A, B or C of the present invention.
도 2는 본 발명의 실라짓 조성물이 아밀로이드 베타의 신경세포독성을 조절하는 결과를 보여준다.Figure 2 shows the results of the Shilajit composition of the present invention regulating the neurotoxicity of amyloid beta.
도 3은 본 발명의 실라짓 조성물의 아밀로이드 베타에 의한 염증을 조절한 결과를 보여준다.Figure 3 shows the results of controlling inflammation caused by amyloid beta by the Shilajit composition of the present invention.
본 발명은 실라짓 조성물을 포함하는 알츠하이머성 치매의 예방 및 치료용 약제학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing and treating Alzheimer's dementia comprising a shilajit composition.
상기 조성물은 아밀로이드 베타의 축적으로 인한 신경세포 독성을 완화하는 것을 특징으로 하며 상세하게는 인터루킨-1β의 발현을 억제하여 아밀로이드 베타의 축적으로 인해 발생하는 염증을 완화하는 것을 특징으로 한다.The above composition is characterized by alleviating neurotoxicity caused by accumulation of amyloid beta, and more specifically, by alleviating inflammation caused by accumulation of amyloid beta by inhibiting the expression of interleukin-1β.
상기 조성물은 실라짓이 25 내지 1500㎍/㎖의 농도로 포함된 것을 특징으로 하며, 바람직하게는 50 내지 1000㎍/㎖의 농도로 포함되는 것을 특징으로 하며, 보다 바람직하게는 100 내지 500㎍/㎖의 농도로 포함되는 것을 특징으로 한다. 상기 실라짓이 25㎍/㎖이하의 농도로 포함되면 아밀로이드 베타의 축적으로 인한 신경세포 독성을 완화효과가 미미할 수 있으며 상기 실라짓이 1500㎍/㎖의 농도를 초과하여 사용되면 실라짓에 포함된 불순물로 인하여 신경세포 독성이 증가할 수 있다.The above composition is characterized in that it contains shilajit in a concentration of 25 to 1500 μg/ml, preferably in a concentration of 50 to 1000 μg/ml, more preferably in a concentration of 100 to 500 μg/ml. If the shilajit is contained in a concentration of 25 μg/ml or less, the effect of alleviating neurotoxicity caused by accumulation of amyloid beta may be minimal, and if the shilajit is used in excess of 1500 μg/ml, neurotoxicity may increase due to impurities contained in the shilajit.
본 발명의 실라짓 조성물을 포함하는 알츠하이머성 치매의 예방 및 치료용 약제학적 조성물은 실라짓 조성물을 유효성분으로 함유하여 알츠하이머성 치매의 예방 또는 치료효과를 나타낸다.A pharmaceutical composition for preventing and treating Alzheimer's dementia comprising the shilajit composition of the present invention contains the shilajit composition as an active ingredient and exhibits a preventive or therapeutic effect on Alzheimer's dementia.
본 발명의 유효성분 추출물은 천연추출물이라는 점에 비추어 볼 때 다른 합성 의약품에 비하여 장기간에 걸친 생체 투여시 부작용의 염려가 적을 것으로 기대된다. 본 발명에서 사용하는 알츠하이머성 치매(Alzheimer's disease)란 알츠하이머 질환으로 야기되는 치매로서, 아밀로이드 베타에 의한 염증으로 인하여 야기되는 것이라면 본 발명의 범위에 포함된다. 본 명세서에서 사용된 용어 "예방"이란 건강한 환자에게 제약 조성물과 같은 제제를 예방적으로 투여하여 본원에서 언급한 질병 및 증상의 발병을 방지하는 것을 의미하는 용어이다. 또한, 치료할 질병의 전단계에 있는 환자에게 그러한 제제를 예방적으로 투여하는 것도 포함하는 의미이다. 본 명세서에서 사용된 용어 "치료"란 본원에서 언급한 질병을 치료하는 것뿐만 아니라, 병용 제제 또는 제약 조성물과 같은 조합 제제를 건강한 환자에게 예방적으로 투여하여 본원에서 언급한 질병 및 증상의 발병을 방지하는 것을 포함한다. 본 발명의 조성물은 약제학적으로 적합하고 생리학적으로 허용되는 담체, 부형제 및 희석제 등의 보조제를 추가로 함유하는 것일 수 있다. 본 명세서에서 "약제학적으로 허용되는 담체"란 조성물, 구체적으로 의약 조성물의 활성 물질을 제외한 성분을 지칭하는 용어이다. 본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용할 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제, 경피제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (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. 상기 조성물의 투여량은 환자의 상태, 연령, 체중, 질환 정도, 투여 경로 등에 따라서 적절히 조절할 수 있으며, 의사 또는 약사의 판단에 따라 일정 시간 간격으로 1일 1회 또는 일정 시간 간격으로 1일 수회에 걸쳐 충분할 투여할 수도 있다. 예컨대, 상기 투여량은 유효성분 함량 기준으로, 0.0001㎎/㎏/day 내지 1000㎎/㎏/day, 바람직하게는 0.01 내지 500㎎/㎏, 더욱 바람직하게는 0.01㎎/㎏ 내지 100㎎/㎏일 수 있으나, 이에 제한되는 것은 아니다. 상기한 투여량은 평균적인 경우를 예시한 것으로서 개인적인 차이에 따라 그 투여량이 높거나 낮을 수 있다. 본 발명의 조성물의 1일 투여량이 상기 투여 용량 미만이면 유의성 있는 효과를 얻을 수 없으며, 그 이상을 초과하는 경우 비경제적일 뿐만 아니라 상용량의 범위를 벗어나므로 바람직하지 않은 부작용이 나타날 우려가 발생할 수 있으므로, 상기 범위로 하는 것이 좋다. 본 발명에 따른 조성물은 인간을 포함하는 포유동물에 다양한 경로로 투여될 수 있다. 투여 방식은 통상적으로 사용되는 모든 방식일 수 있으며, 예컨대, 경구, 직장 또는 정맥, 근육, 또는 피하 주사에 의해 투여될 수 있다. 본 발명의 조성물은 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 또는 경피제, 좌제 및 멸균 주사용액의 형태의 비경구 제형 등으로 제형화하여 사용될 수 있다. 본 발명의 조성물을 인간에게 적용하는 구체예에 있어서, 본 발명의 조성물은 단독으로 투여될 수 있으나, 일반적으로 투여방식과 표준 약제학적 관행(standard phamaceutical practice)을 고려하여 선택된 약제학적 담체와 혼합되어 투여될 수 있다. 예를 들면, 본 발명의 조성물은 전분 또는 락토오즈를 함유하는 정제 형태로, 또는 단독 또는 부형제를 함유하는 캡슐 형태로, 또는 맛을 내거나 색을 띄게 하는 화학 약품을 함유하는 엘릭시르 또는 현탁제 형태로 경구, 구강내 또는 혀밑 투여될 수 있다. 이러한 액체 제제는 현탁제(예를 들면, 메틸셀룰로오즈, 위텝솔(witepsol)과 같은 반합성 글리세라이드 또는 행인유(apricot kernel oil)와 PEG-6 에스테르의 혼합물 또는 PEG-8과 카프릴릭/카프릭 글리세라이드의 혼합물과 같은 글리세라이드 혼합물)와 같은 약제학적으로 허용 가능한 첨가제와 함께 제형화될 수 있다. In light of the fact that the active ingredient extract of the present invention is a natural extract, it is expected that there will be less concern about side effects when administered to a body over a long period of time compared to other synthetic drugs. Alzheimer's disease used in the present invention refers to dementia caused by Alzheimer's disease, and if it is caused by inflammation due to amyloid beta, it is included in the scope of the present invention. The term "prevention" used in the present specification means preventing the onset of the disease and symptoms mentioned herein by prophylactically administering a preparation such as a pharmaceutical composition to a healthy patient. It also includes prophylactically administering such a preparation to a patient in the pre-stage of the disease to be treated. The term "treatment" used in the present specification includes not only treating the disease mentioned herein, but also preventing the onset of the disease and symptoms mentioned herein by prophylactically administering a combination preparation such as a combination preparation or pharmaceutical composition to a healthy patient. The composition of the present invention may additionally contain auxiliary agents such as pharmaceutically suitable and physiologically acceptable carriers, excipients, and diluents. As used herein, the term "pharmaceutically acceptable carrier" refers to a component other than the active substance of a composition, specifically a pharmaceutical composition. Carriers, excipients, and diluents that may be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. When formulating, diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants may be used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations can be prepared by mixing the extract with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives can be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and transdermal preparations. Non-aqueous solvents and suspending agents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin, etc. The dosage of the composition may be appropriately adjusted depending on the patient's condition, age, weight, degree of disease, administration route, etc., and may be sufficiently administered once a day at regular intervals or several times a day at regular intervals depending on the judgment of a doctor or pharmacist. For example, the dosage may be 0.0001 mg/kg/day to 1000 mg/kg/day, preferably 0.01 to 500 mg/kg, and more preferably 0.01 mg/kg to 100 mg/kg based on the active ingredient content, but is not limited thereto. The above dosage is an example of an average case and the dosage may be higher or lower depending on individual differences. If the daily dosage of the composition of the present invention is less than the above dosage, no significant effect can be obtained, and if it exceeds it, it is not only uneconomical but also goes beyond the range of commercial dosages, so there is a concern that undesirable side effects may occur. Therefore, it is recommended to use the above range. The composition according to the present invention can be administered to mammals, including humans, by various routes. The administration method can be any method commonly used, and for example, it can be administered orally, rectally, or by intravenous, intramuscular, or subcutaneous injection. The composition of the present invention can be formulated and used in oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, or in parenteral formulations in the form of transdermal agents, suppositories, and sterile injectable solutions, according to a conventional method. In specific embodiments where the composition of the present invention is applied to humans, the composition of the present invention may be administered alone, but may generally be administered mixed with a pharmaceutical carrier selected in consideration of the mode of administration and standard pharmaceutical practice. For example, the composition of the present invention may be administered orally, intrabuccally or sublingually in the form of tablets containing starch or lactose, or in the form of capsules containing alone or with excipients, or in the form of elixirs or suspensions containing chemicals to impart flavor or color. Such liquid preparations may be formulated with pharmaceutically acceptable excipients such as suspending agents (e.g., methylcellulose, semi-synthetic glycerides such as witepsol, or glyceride mixtures such as mixtures of apricot kernel oil and PEG-6 esters or mixtures of PEG-8 and caprylic/capric glycerides).
본 발명은 실라짓 조성물을 포함하는 알츠하이머성 치매 예방 및 개선용 기능성 건강식품 조성물을 제공한다.The present invention provides a functional health food composition for preventing and improving Alzheimer's dementia, comprising a shilajit composition.
상기 조성물은 아밀로이드 베타의 축적으로 인한 신경세포 독성을 완화하는 것을 특징으로 하며 상세하게는 인터루킨-1β의 발현을 억제하여 아밀로이드 베타의 축적으로 인해 발생하는 염증을 완화하는 것을 특징으로 한다.The above composition is characterized by alleviating neurotoxicity caused by accumulation of amyloid beta, and more specifically, by alleviating inflammation caused by accumulation of amyloid beta by inhibiting the expression of interleukin-1β.
상기 조성물은 실라짓이 25 내지 1500㎍/㎖의 농도로 포함된 것을 특징으로 하며 바람직하게는 50 내지 1000㎍/㎖의 농도로 포함되는 것을 특징으로 하며, 보다 바람직하게는 100 내지 500㎍/㎖의 농도로 포함되는 것을 특징으로 한다. 상기 실라짓이 25㎍/㎖이하의 농도로 포함되면 아밀로이드 베타의 축적으로 인한 신경세포 독성을 완화효과가 미미할 수 있으며 상기 실라짓이 1500㎍/㎖의 농도를 초과하여 사용되면 실라짓에 포함된 불순물로 인하여 신경세포 독성이 증가할 수 있다.The above composition is characterized in that it contains shilajit in a concentration of 25 to 1500 μg/ml, preferably in a concentration of 50 to 1000 μg/ml, and more preferably in a concentration of 100 to 500 μg/ml. If the shilajit is contained in a concentration of 25 μg/ml or less, the effect of alleviating neurotoxicity caused by accumulation of amyloid beta may be minimal, and if the shilajit is used in excess of 1500 μg/ml, neurotoxicity may increase due to impurities contained in the shilajit.
본 발명의 실라짓 조성물을 포함하는 알츠하이머성 치매 예방 및 개선용 기능성 건강식품 조성물은 실라짓 조성물을 유효성분으로 함유하여 알츠하이머성 치매의 예방 또는 개선효과를 나타낸다. 본 발명에 따른 기능성 건강식품은 각종 식품, 음료, 식품 첨가제 등 일 수 있다. 본 발명의 실라짓 조성물을 포함하는 알츠하이머성 치매 예방용 기능성 건강식품 조성물은 알츠하이머성 치매의 예방 또는 개선의 목적으로, 정제, 캅셀, 분말, 과립, 액상, 환 등을 포함하지만 이에 한정하지 않는 형태로 제조 및 가공할 수 있다. 본 발명에서 사용된 용어 "기능성 건강식품(건강기능식품)"은 건강기능식품에 관한 법률 제 6727 호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다. 본 발명의 기능성 건강식품은 통상의 식품 첨가물을 포함할 수 있으며, 상기 "식품 첨가물"로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안정청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다. 상기 "식품 첨가물 공전"에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성물, 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류등을 들 수 있다.The functional health food composition for preventing and improving Alzheimer's dementia, comprising the shilajit composition of the present invention, contains the shilajit composition as an effective ingredient and exhibits a prevention or improvement effect on Alzheimer's dementia. The functional health food according to the present invention may be various foods, beverages, food additives, etc. The functional health food composition for preventing Alzheimer's dementia, comprising the shilajit composition of the present invention, may be manufactured and processed in forms including, but not limited to, tablets, capsules, powders, granules, liquids, pills, etc., for the purpose of preventing or improving Alzheimer's dementia. The term "functional health food (health functional food)" used in the present invention refers to a food manufactured and processed using raw materials or ingredients having functionality useful to the human body according to Act No. 6727 on Health Functional Foods, and means being consumed for the purpose of obtaining a useful effect for health purposes, such as regulating nutrients for the structure and function of the human body or physiological effects. The functional health food of the present invention may contain conventional food additives, and its suitability as the "food additive" is determined by the specifications and criteria for the relevant item according to the general provisions and general test methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety, unless otherwise specified. Items listed in the "Food Additives Codex" include, for example, chemical synthetic substances such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, calciphilic pigment, and guar gum; mixed preparations such as sodium L-glutamate preparations, alkaline agents added to noodles, preservative preparations, and tar color preparations.
본 발명의 기능성 건강식품은 통상의 식품 제조에 사용되는 적절한 담체, 부형제, 희석제 등의 첨가제를 통상의 함량으로 포함할 수 있다. 예컨대, 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드The functional health food of the present invention may contain additives such as appropriate carriers, excipients, and diluents used in the manufacture of conventional foods in the usual amounts. For example, various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickeners (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, and protective colloids.
증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 이러한 성분들은 독립적으로 또는 조합하여 사용할 수 있으며, 그 사용량에는 특별한 제한이 없으나, 유효성분인 추출물 100 중량부 당 0 내지 20 중량부 범위에서 선택되는 것이 일반적이다. 예를 들어, 정제 형태의 건강기능식품은 유효성분인 추출물을 부형제, 결합제, 붕해제, 및 다른 첨가제와의 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축성형하거나, 상기 혼합물을 직접 압축 성형할 수 있다. 또한, 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수 있으며, 필요에 따라 적당한 제피제로 제피할 수도 있다.It may contain thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. These ingredients may be used independently or in combination, and there is no particular limitation on the amount of use, but it is generally selected from the range of 0 to 20 parts by weight per 100 parts by weight of the extract, which is an active ingredient. For example, a health functional food in tablet form can be made by granulating a mixture of the extract, which is an active ingredient, with excipients, binders, disintegrants, and other additives using a conventional method, and then adding a lubricant, etc. to perform compression molding, or directly compressing the mixture. In addition, the health functional food in tablet form can contain a maturing agent, etc., if necessary, and can also be coated with an appropriate coating agent, if necessary.
캅셀 형태의 건강기능식품 중 경질캅셀제는 통상의 경질캅셀에 유효성분인 추출물을 부형제 등의 첨가제와의 혼합물 또는 그의 입상물 또는 제피한 입상물을 충진하여 제조할 수 있으며, 연질캅셀제는 유효성분인 추출물을 부형제 등의 첨가제와의 혼합물을 젤라틴 등 캅셀기제에 충진하여 제조할 수 있다. 상기 연질캅셀제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다. 환 형태의 기능성 건강식품은 유효성분인 추출물과 부형제, 결합제, 붕해제 등과의 혼합물을 적당한 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 적당한 제피제로 제피를, 또는 전분, 탈크 또는 적당한 물질로 환의를 입힐 수도 있다. 과립형태의 기능성 건강식품은 유효성분인 추출물과 부형제, 결합제, 붕해제 등과의 혼합물을 적당한 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다. 본원 발명의 상기 부형제, 결합제, 붕해제, 활택제, 교미제, 착향제 등에 대한 용어 정의는 당업계에 공지된 문헌에 기재된 것으로 그 기능 등이 동일 내지 유사한 것들을 포함한다(대한약전 해설편, 문성사, 한국약학대학협의회, 제 5 개정판, p33-48, 1989).Among capsule-shaped health functional foods, hard capsules can be manufactured by filling a mixture of an active ingredient, an extract, and additives such as excipients, or a granular or coated granular material thereof, into a regular hard capsule, and soft capsules can be manufactured by filling a capsule base such as gelatin with a mixture of an active ingredient, an extract, and additives such as excipients. The soft capsules may contain a plasticizer such as glycerin or sorbitol, a coloring agent, a preservative, etc., as needed. A pill-shaped functional health food can be prepared by molding a mixture of an active ingredient, an extract, and an excipient, a binder, a disintegrant, etc., by an appropriate method, and, if needed, can be coated with white sugar or another appropriate coating agent, or starch, talc, or a suitable substance to form a pill. A granular functional health food can be manufactured into a granular form by a mixture of an active ingredient, an extract, and an excipient, a binder, a disintegrant, etc., by an appropriate method, and, if needed, can contain a flavoring agent, a flavoring agent, etc. The definitions of terms for the excipients, binders, disintegrants, lubricants, maturing agents, flavoring agents, etc. of the present invention are those described in literature known in the art and include those having the same or similar functions (Commentary on the Korean Pharmacopoeia, Munsungsa, Korean Pharmaceutical Colleges Council, 5th revised edition, p. 33-48, 1989).
하기에서 실시예를 통해 본 발명을 상세히 설명한다.The present invention is described in detail below through examples.
실시예 Example
1. 실라짓의 중금속 분석 1. Heavy metal analysis of Shilajit
실라짓(Shilajit)은 히말라야 산맥의 바위에서 발견되는 물질로 식물의 느린 분해로 만들어진다. 암석산맥의 미네랄이 지속적인 직사광선에 과열되면 유화되어 식물의 레진이나 검처럼 산출되며 이를 수집하여 정화하여 식용하게 된다. 실라짓은 다양하고 풍부한 미네랄 및 다양한 성분을 함유하고 있으나 중금속, 곰팡이 오염물질에 대한 우려가 있다. 따라서 본 발명에서는 실라짓 3종(실라짓 A, B 및 C)에 대한 대장균 및 중금속 검사를 수행하였다. Shilajit is a substance found in the rocks of the Himalayas, and is made by the slow decomposition of plants. When the minerals in the rocky mountains are continuously heated by direct sunlight, they are emulsified and produced as plant resin or gum, which is collected, purified, and used for food. Shilajit contains various and abundant minerals and various components, but there are concerns about heavy metal and fungal contaminants. Therefore, in this invention, E. coli and heavy metal tests were performed on three types of Shilajit (Silajit A, B, and C).
하기 표 1은 본 발명의 실라짓에 대한 검사결과를 보여준다.Table 1 below shows the test results for the shilajit of the present invention.
검사결과 본 발명의 실라짓 A, B 및 C는 미국 FDA 및 한국 FDA의 일일 섭취 제한량을 충족하는 수준의 중금속이 함유되어 식품 또는 의약용으로 사용 가능한 것으로 판단된다.The test results show that the shilajit A, B and C of the present invention contain heavy metals at levels that meet the daily intake limits of the US FDA and the Korean FDA, and thus are judged to be usable for food or pharmaceutical purposes.
2. 실라짓 조성물의 신경세포 독성 평가2. Evaluation of neurotoxicity of Shilajit composition
본 발명에서는 실라짓 조성물의 신경세포 독성을 평가하기 위하여 실라짓 A, B 또는 C 조성물을 50㎍/㎖, 100㎍/㎖, 250㎍/㎖, 500㎍/㎖ 또는 1000㎍/㎖으로 제조한 후 신경세포(SH-SY5Y) 5x103cells/well을 분주한 배양접시에 처리하였다. 상기 실라짓 A, B, 또는 C를 농도별로 처리한 신경세포를 24시간동안 배양한 후 MTS 어세이를 수행하여 신경세포의 세포활성(cell viability)을 분석하였다.In the present invention, to evaluate the neurotoxicity of a shilajit composition, a shilajit A, B, or C composition was prepared at a concentration of 50 μg/mL, 100 μg/mL, 250 μg/mL, 500 μg/mL, or 1000 μg/mL, and then treated in a culture dish seeded with 5x10 3 cells/well of neural cells (SH-SY5Y). The neural cells treated with the above-mentioned shilajit A, B, or C at different concentrations were cultured for 24 hours, and then the MTS assay was performed to analyze the cell viability of the neural cells.
도 1은 본 발명의 실라짓 A, B 또는 C 조성물을 처리한 신경세포(SH-SY5Y)의 활성변화를 확인한 결과를 보여준다. 패널 A는 실라짓 A에 대한 결과를 보여주며; 패널 B는 실라짓 B에 대한 결과를 보여주며; 패널 C는 실라짓 C에 대한 결과를 보여준다. Figure 1 shows the results of confirming the activity changes of nerve cells (SH-SY5Y) treated with the composition of shilajit A, B or C of the present invention. Panel A shows the results for shilajit A; panel B shows the results for shilajit B; and panel C shows the results for shilajit C.
실험결과 본 발명의 실라짓 A을 250㎍/㎖ 이상으로 처리하게 되면 신경세포의 활성이 약간 감소하는 것으로 확인되었다. 본 발명의 실라짓 B는 1000㎍/㎖까지 처리하여도 신경세포의 활성을 감소시키지 않는 것으로 확인되었다. 또한 본 발명의 실라짓 C는 500㎍/㎖까지 처리하여도 신경세포의 활성을 감소시키지 않았으며 1000㎍/㎖으로 처리하는 경우 신경세포의 활성이 약간 증가하는 것으로 확인되었다. As a result of the experiment, it was confirmed that when Shilajit A of the present invention was treated at 250㎍/㎖ or more, the activity of nerve cells was slightly reduced. It was confirmed that Shilajit B of the present invention did not reduce the activity of nerve cells even when treated at up to 1000㎍/㎖. In addition, it was confirmed that Shilajit C of the present invention did not reduce the activity of nerve cells even when treated at up to 500㎍/㎖, and when treated at 1000㎍/㎖, the activity of nerve cells was slightly increased.
3. 실라짓 조성물의 신경세포 보호효과 분석3. Analysis of the neuroprotective effect of the Shilajit composition
본 발명에서는 신경세포에 독성을 나타내는 아밀로이드 베타(Amyloid β)와 실라짓을 함께 처리하는 경우 아밀로이드 베타로 인한 신경독성을 실라짓이 완화시키는지 여부를 확인하였다. In the present invention, it was confirmed whether shilajit alleviates neurotoxicity caused by amyloid beta when amyloid beta, which is toxic to nerve cells, is treated together with shilajit.
아밀로이드 베타는 신경세포에 독성을 나타내며 세포사멸을 유도한다는 것이 알려져 있다. 신경세포 독성 반응은 어떤 자극에 의해 아밀로이드 베타의 침착이 일어나게 되고 상기 외부 자극과 아밀로이드 베타의 침착에 의해 신경세포 독성이 발생하게 되는 것이다.It is known that amyloid beta is toxic to nerve cells and induces cell death. A neurotoxic reaction occurs when amyloid beta is deposited due to some stimulus, and neurotoxicity occurs due to the external stimulus and amyloid beta deposition.
본 발명에서 아밀로이드 베타 중 가장 독성이 강하다고 알려져 있는 아밀로이드 베타 1-42(Aβ1-42)를 사용하였다. 도 2는 본 발명의 실라짓이 아밀로이드 베타의 신경세포독성을 조절하는 결과를 보여준다. 패널 A는 신경세포(SH-SY5Y) 5x104cells/well을 분주한 배양접시에 Aβ1-42 3μM, Aβ1-42 10μM 또는 Aβ1-42 30μM을 처리한 후 24시간 배양하여 MTS 에세이를 통해 신경세포활성을 측정한 결과를 보여주며; 패널 B는 신경세포(SH-SY5Y) 5x103cells/well을 분주한 배양접시에 Aβ1-42 3μM과 실라짓 A, 실라짓 B, 또는 실라짓 C을 100㎍/㎖, 250㎍/㎖, 또는 500㎍/㎖로 처리한 후 24시간 배양하여 MTS 에세이를 통해 신경세포활성을 측정한 결과를 보여준다.In the present invention, amyloid beta 1-42 (Aβ 1-42 ), which is known to be the most toxic among amyloid beta, was used. Figure 2 shows the results of regulating the neurotoxicity of amyloid beta by shilajit of the present invention. Panel A shows the results of measuring neuronal activity through an MTS assay after treating a culture dish containing 5x10 4 cells/well of neural cells (SH-SY5Y) with 3 μM Aβ 1-42 , 10 μM Aβ 1-42 , or 30 μM Aβ 1-42 , and culturing for 24 hours; Panel B shows the results of measuring neuronal activity using the MTS assay after 24 h of culture in culture dishes seeded with 5x103 cells/well of neuronal (SH-SY5Y) cells treated with 3 μM Aβ 1-42 and 100 μg/mL, 250 μg/mL, or 500 μg/mL shilajit A, shilajit B, or shilajit C.
실험결과 신경세포(SH-SY5Y)에 Aβ1-42 3μM을 처리하게 되면 신경세포의 활성이 급격히 감소하는 것이 확인되었으며 Aβ1-42의 농도가 증가함에 따라 신경세포활성이 감소하는 것으로 확인되었다. The experimental results showed that when 3 μM of Aβ 1-42 was treated on neurons (SH-SY5Y), the activity of the neurons rapidly decreased, and that the activity of the neurons decreased as the concentration of Aβ 1-42 increased.
신경세포에 Aβ1-42 3μM과 실라짓 A, B, 또는 C를 100㎍/㎖, 250㎍/㎖, 또는 500㎍/㎖로 처리하여 신경세포의 활성을 분석한 결과 실라짓 A, B, 및 C 모두에서 Aβ1-42에 의한 신경세포독성을 완화시키는 것으로 확인되었다. 실라짓 A의 경우 Aβ1-42 3μM과 실라짓 A 100㎍/㎖을 처리하는 경우 신경독성이 2배 정도 회복되었으며 실라짓 A의 농도가 증가함에 따라 신경세포의 회복정도가 감소하는 것으로 확인되었다. 이에 반하여 실라짓 B 및 C의 경우 실라짓 A보다 우수한 신경세포 보호 효과가 있는 것으로 확인되었으며 100 내지 250㎍/㎖의 범위에서는 신경세포 보호 효과가 증가하다가 250㎍/㎖를 초과하게 되면 신경세포 보호 효과가 오히려 감소하는 것으로 확인되었다. When nerve cells were treated with 3 μM Aβ 1-42 and 100 μg/mL, 250 μg/mL, or 500 μg/mL of shilajit A, B, or C to analyze the activity of nerve cells, it was confirmed that shilajit A, B, and C alleviated the neurotoxicity caused by Aβ 1-42 . In the case of shilajit A, when treated with 3 μM Aβ 1-42 and 100 μg/mL of shilajit A, neurotoxicity was recovered by about 2-fold, and it was confirmed that the degree of nerve cell recovery decreased as the concentration of shilajit A increased. In contrast, shilajit B and C were confirmed to have a better neuroprotective effect than shilajit A, and the neuroprotective effect increased in the range of 100 to 250 μg/mL, but when it exceeded 250 μg/mL, the neuroprotective effect actually decreased.
4. 신경염증 동물모델을 이용한 실라짓 조성물의 신경세포 보호효과 분석4. Analysis of the neuroprotective effect of the Shilajit composition using an animal model of neuroinflammation
상기 결과에 따르면 본 발명의 실라짓은 아밀로이드 베타로 인한 신경세포 독성으로부터 신경세포를 보호하는 것으로 확인되었다. 이에 본 발명에서는 아밀로이드 베타를 이용한 급성 신경염증 마우스 모델을 구축하고 실라짓 A, B, 및 C로 인한 신경보호 효과를 분석하였다. According to the above results, it was confirmed that the shilajit of the present invention protects nerve cells from neurotoxicity caused by amyloid beta. Accordingly, in the present invention, an acute neuroinflammation mouse model using amyloid beta was established and the neuroprotective effects of shilajit A, B, and C were analyzed.
도 3은 본 발명의 실라짓 조성물의 염증조절 결과를 보여준다. 패널 A는 분화된 대식세포에 아무것도 처리하지 않은 경우; LPS(Lipopolysaccharide)만을 처리한 경우; LPS(Lipopolysaccharide)와 염증 유도물질인 Aβ1-42 9μM을 동시에 처리한 경우; 및 LPS(Lipopolysaccharide), Aβ1-42 9μM, 및 실라짓 A, B, 또는 C를 0.25, 또는 0.5㎎/㎖로 동시에 처리한 경우에 대하여 염증반응물질인 인터루킨-1β(Cleaved 인터루킨-1β)의 발현정도를 웨스턴 블라팅으로 분석한 결과를 보여주며 패널 B는 아밀로이드 베타를 이용한 급성 신경염증 마우스 모델에 Aβ1-42 (200 pmole/5㎕)을 처리한 경우; Aβ1-42에 의한 유도되는 NLRP3 inflammosome 자극을 억제하는 MCC950 (10 mg/kg)과 Aβ1-42 (200 pmole/5㎕)을 동시에 처리한 경우; 실라짓 75㎎/㎏ 또는 150㎎/㎏과 Aβ1-42 (200 pmole/5㎕)을 동시에 처리한 경우의 인터루킨-1β 발현정도를 분석한 결과를 보여주며 패널 C는 아밀로이드 베타를 이용한 급성 신경염증 마우스 모델에 Aβ1-42 (200 pmole/5㎕)을 처리한 경우; Aβ1-42에 의한 유도되는 NLRP3 inflammosome 자극을 억제하는 MCC950 (10 mg/kg)과 Aβ1-42 (200 pmole/5㎕)을 동시에 처리한 경우; 실라짓 75㎎/㎏ 또는 150㎎/㎏과 Aβ1-42 (200 pmole/5㎕)을 동시에 처리한 경우의 TNFα 발현정도를 분석한 결과를 보여준다. 상기 아밀로이드 베타를 이용한 급성 신경염증 마우스 모델은 Aβ1-42 (200 pmole/5㎕)을 뇌실주입(intracerebroventricular, i.c.v.)하는 방법으로 제조하였다. Figure 3 shows the results of inflammation control by the shilajit composition of the present invention. Panel A shows the results of analyzing the expression level of the inflammatory response substance interleukin-1β (cleaved interleukin-1β) by Western blotting in the case where differentiated macrophages were not treated with anything; treated only with LPS (Lipopolysaccharide); treated simultaneously with LPS (Lipopolysaccharide) and an inflammatory substance, Aβ 1-42 9 μM; and treated simultaneously with LPS (Lipopolysaccharide), Aβ 1-42 9 μM, and shilajit A, B, or C at 0.25 or 0.5 mg/㎖. Panel B shows the results of analyzing the expression level of the inflammatory response substance interleukin-1β (cleaved interleukin-1β) in the case where an acute neuroinflammation mouse model using amyloid beta was treated with Aβ 1-42 (200 pmole/5 μl). When MCC950 (10 mg/kg) and Aβ 1-42 (200 pmole/5㎕), which inhibits NLRP3 inflammosome stimulation induced by Aβ 1-42 , were treated simultaneously; Panel C shows the results of analyzing the level of interleukin-1β expression when shilajit 75 mg/kg or 150 mg/kg and Aβ 1-42 (200 pmole/5㎕) were treated simultaneously in a mouse model of acute neuroinflammation using amyloid beta; When MCC950 (10 mg/kg) and Aβ 1-42 (200 pmole/5㎕) , which inhibits NLRP3 inflammosome stimulation induced by Aβ 1-42 , were treated simultaneously; This shows the results of analyzing the level of TNFα expression when 75 mg/kg or 150 mg/kg of shilajit and Aβ 1-42 (200 pmole/5㎕) were simultaneously treated. The acute neuroinflammation mouse model using the amyloid beta was prepared by intracerebroventricular (icv) injection of Aβ 1-42 (200 pmole/5㎕).
분석결과 LPS(Lipopolysaccharide), Aβ1-42 9μM, 및 실라짓 A, B, 또는 C를 0.25, 또는 0.5㎎/㎖로 동시에 처리한 경우 염증반응물질인 인터루킨-1β(Cleaved 인터루킨-1β)의 발현정도가 감소하는 것이 확인되었다. 또한 Aβ1-42에 의한 NLRP3 inflammosome 자극을 억제하는 양성대조군으로 MCC950을 사용하여 염증 유도 후 실라짓을 2회 식이로 공급한 실험동물의 뇌조직을 분쇄하여 인터루킨-1β를 ELISA를 통해 측정하였을 때 양성대조군 MCC950의 수준으로 인터루킨-1β의 수준이 감소한 것으로 확인되었다. 하지만 모든 실험조건에서 TNFα 농도는 대조군과 비교하였을 때 변화가 없었다.The results of the analysis showed that when LPS (Lipopolysaccharide), Aβ 1-42 9 μM, and shilajit A, B, or C were simultaneously treated at 0.25 or 0.5 mg/mL, the expression level of cleaved interleukin-1β, an inflammatory response substance, decreased. In addition, when MCC950 was used as a positive control group that inhibits NLRP3 inflammosome stimulation by Aβ 1-42 , and shilajit was fed twice as a diet after inducing inflammation, the brain tissue of the experimental animals was ground and measured for interleukin-1β through ELISA. The level of interleukin-1β was confirmed to have decreased to the level of the positive control group MCC950. However, the concentration of TNFα did not change compared to the control group in all experimental conditions.
따라서 본 발명의 실라짓을 세포에 직접 처리하거나 식이를 통해 섭취하게 되면 아밀로이드 베타 관련 신경염증을 완화하므로 아밀로이드 베타의 축적에 의해 야기되는 알츠하이머의 예방 및 치료를 위한 약제학적 조성물 또는 기능성 식품조성물로사용 가능할 것으로 판단된다.Therefore, it is judged that the shilajit of the present invention can be used as a pharmaceutical composition or functional food composition for preventing and treating Alzheimer's disease caused by accumulation of amyloid beta, as it alleviates neuroinflammation related to amyloid beta when directly treated with cells or consumed through diet.
본 명세서에서 설명된 구체적인 실시예는 본 발명의 바람직한 구현예 또는 예시를 대표하는 의미이며, 이에 의해 본 발명의 범위가 한정되지는 않는다. 본 발명의 변형과 다른 용도가 본 명세서 특허청구범위에 기재된 발명의 범위로부터 벗어나지 않는다는 것은 당업자에게 명백하다. The specific embodiments described in this specification are meant to represent preferred embodiments or examples of the present invention, and the scope of the present invention is not limited thereby. It will be apparent to those skilled in the art that modifications and other uses of the present invention do not depart from the scope of the invention described in the claims of this specification.
본 발명의 실라짓 조성물을 포함하는 알츠하이머성 치매 예방 및 치료용 약제학적 조성물 및 알츠하이머성 치매 예방 및 개선용 기능성 건강식품 조성물은 아밀로이드 베타의 축적으로 인한 신경세포 독성을 완화하는 효과가 있어 알츠하이머성 치매의 예방, 치료 및 개선에 활용 가능하다.A pharmaceutical composition for preventing and treating Alzheimer's dementia and a functional health food composition for preventing and improving Alzheimer's dementia comprising the shilajit composition of the present invention have the effect of alleviating neurotoxicity caused by accumulation of amyloid beta, and thus can be utilized for preventing, treating, and improving Alzheimer's dementia.
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| CARRASCO-GALLARDO CARLOS, FARÍAS GONZALO A., FUENTES PATRICIO, CRESPO FERNANDO, MACCIONI RICARDO B.: "Can Nutraceuticals Prevent Alzheimer's Disease? Potential Therapeutic Role of a Formulation Containing Shilajit and Complex B Vitamins", ARCHIVES OF MEDICAL RESEARCH, vol. 43, no. 8, 1 November 2012 (2012-11-01), MX , pages 699 - 704, XP093205245, ISSN: 0188-4409, DOI: 10.1016/j.arcmed.2012.10.010 * |
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| WHANG WANKYUNN, LEE SUKJIN, RYU HYESUNG, : "Development of Simultaneous Analysis Method for Multi-Compounds Content of New Shilajit Using HPLC-UV and the Cognitive Enhancing Effect: Mongolian Shilajit", NATURAL PRODUCT COMMUNICATIONS, vol. 16, no. 7, 1 January 2021 (2021-01-01), pages 1 - 10, XP093205251, DOI: 10.1177/1934578X2110 * |
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