KR102633321B1 - Pharmarceutical composition for preventing or treating of age-related macular degeneration - Google Patents
Pharmarceutical composition for preventing or treating of age-related macular degeneration Download PDFInfo
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- KR102633321B1 KR102633321B1 KR1020210060802A KR20210060802A KR102633321B1 KR 102633321 B1 KR102633321 B1 KR 102633321B1 KR 1020210060802 A KR1020210060802 A KR 1020210060802A KR 20210060802 A KR20210060802 A KR 20210060802A KR 102633321 B1 KR102633321 B1 KR 102633321B1
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- age
- macular degeneration
- related macular
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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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 COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- 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
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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- 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
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Abstract
본 발명은 노인성 황반변성의 예방 또는 치료를 위한 약학 조성물에 관한 것이다. 노인성 황반변성은 선진국에서는 성인 실명 원인 1위 질환이나, 노인성 황반변성의 대부분을 차지하는 건성의 경우 현재로서는 치료법이 전무하여 노인성 황반변성의 최대 난제인 실정이다.
본 발명에 따른 니코틴아마이드(nicotinamide), 또는 이의 유도체를 유효성분으로 포함하는 약학조성물 및 식품 조성물은 노인성 황반변성에서 망막상피세포의 퇴화를 구조적, 기능적으로 현저하게 회복시키는 효과가 있으므로, 의료 분야에서 크게 이용될 수 있을 것으로 기대된다.The present invention relates to a pharmaceutical composition for preventing or treating age-related macular degeneration. Age-related macular degeneration is the number one cause of blindness in adults in developed countries, but dryness, which accounts for most of age-related macular degeneration, currently has no treatment, making it the biggest challenge in age-related macular degeneration.
The pharmaceutical composition and food composition containing nicotinamide or a derivative thereof as an active ingredient according to the present invention have the effect of significantly restoring the degeneration of retinal epithelial cells in age-related macular degeneration, both structurally and functionally, and are therefore used in the medical field. It is expected that it will be of great use.
Description
본 발명은 노인성 황반변성의 예방 또는 치료를 위한 약학 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating age-related macular degeneration.
노인성 황반변성(age-related macular degeneration: AMD)은 나이가 들면서 망막의 황반부에 여러 가지 변화가 동반되어 생기는 질병이다. 나이가 증가함에 따라 발생율이 증가하며, 선진국에서는 성인 실명 원인 1위 질환으로 전세계적으로 약 2억명 정도의 환자가 있는 것으로 알려져 있다. 따라서 우리나라에서도 앞으로 노인 인구가 증가함에 따라서 그 발생 빈도는 더욱 증가하리라 예상된다. 황반은 망막이라고 하는 신경 조직의 중심 부위를 말하는데, 빛 자극에 반응하는 광수용체 세포가 밀집되어 있어 중심 시력을 담당한다. 노인성 황반변성은 노화가 진행됨에 따라 이러한 황반부 광수용체 세포가 소실되어 시력 장애를 일으키는 것으로, ① 습성 또는 삼출성 형태와 ② 건성 또는 비삼출성 형태로 나눌 수 있다. Age-related macular degeneration (AMD) is a disease that occurs with various changes in the macular part of the retina as one ages. The incidence rate increases with age, and in developed countries, it is the number one cause of blindness in adults and is known to have approximately 200 million patients worldwide. Therefore, as the elderly population increases in Korea, the frequency of occurrence is expected to increase further. The macula refers to the central part of the nervous tissue called the retina. It is densely packed with photoreceptor cells that respond to light stimulation and is responsible for central vision. Age-related macular degeneration causes visual impairment due to loss of photoreceptor cells in the macular area as aging progresses. It can be divided into ① wet or exudative form and ② dry or non-exudative form.
습성(wet=neovascular, exudative) 형태는 망막 밑에 맥락막 신생혈관이 자라는 경우로 항혈관내피성장인자 항체(Anti-vascular endothelial growth factor (VEGF) monoclonal antibody)를 안구내 주사하는 방법으로 치료한다. 건성(dry=atrophic) 형태는 AMD의 대부분을 차지하며 망막에 드루젠(drusen)이나 색소이상(pigmentary abnormality), 또는 망막상피의 위축(atrophy)과 같은 병변이 생긴 경우를 말한다. 건성 중 진행성 황반변성을 지도형 위축(geographic atrophy: GA)라고 하는데, 현재로서는 치료법이 전무하여 노인성 황반변성의 최대 난제인 실정이다.The wet (wet = neovascular, exudative) form is when choroidal neovascularization grows under the retina and is treated with intraocular injection of anti-vascular endothelial growth factor (VEGF) monoclonal antibody. Dry (atrophic) form accounts for the majority of AMD and refers to lesions such as drusen, pigmentary abnormality, or atrophy of the retinal epithelium. Dry progressive macular degeneration is called geographic atrophy (GA), and there is currently no treatment, making it the biggest challenge in age-related macular degeneration.
따라서 본 발명은 상기와 같은 문제의 해결을 위해 고안된 것으로, 본 발명은 노인성 황반변성의 예방 또는 치료를 위한 약학 조성물에 관한 것이다. 본 발명의 약학조성물은 습성뿐만 아니라 치료법이 전무한 건성의 노인성 황반변성에서도 매우 현저한 치료 효과를 발휘하였으므로, 의료 분야에서 크게 이용될 수 있을 것으로 기대된다.Therefore, the present invention was designed to solve the above problems, and the present invention relates to a pharmaceutical composition for preventing or treating age-related macular degeneration. The pharmaceutical composition of the present invention is expected to be widely used in the medical field because it has shown a significant therapeutic effect not only in wet but also in dry age-related macular degeneration for which there is no treatment.
본 발명의 목적은 노인성 황반변성의 예방 또는 치료를 위한 약학조성물을 제공하는 것이다. The purpose of the present invention is to provide a pharmaceutical composition for preventing or treating age-related macular degeneration.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.
이하, 본원에 기재된 다양한 구체예가 도면을 참조로 기재된다. 하기 설명에서, 본 발명의 완전한 이해를 위해서, 다양한 특이적 상세사항, 예컨대, 특이적 형태, 조성물 및 공정 등이 기재되어 있다. 그러나, 특정의 구체예는 이들 특이적 상세 사항 중 하나 이상 없이, 또는 다른 공지된 방법 및 형태와 함께 실행될 수 있다. 다른 예에서, 공지된 공정 및 제조 기술은 본 발명을 불필요하게 모호하게 하지 않게 하기 위해서, 특정의 상세사항으로 기재되지 않는다. "한 가지 구체예" 또는 "구체예"에 대한 본 명세서 전체를 통한 참조는 구체예와 결부되어 기재된 특별한 특징, 형태, 조성 또는 특성이 본 발명의 하나 이상의 구체예에 포함됨을 의미한다. 따라서, 본 명세서 전체에 걸친 다양한 위치에서 표현된 "한 가지 구체예에서" 또는 "구체예"의 상황은 반드시 본 발명의 동일한 구체예를 나타내지는 않는다. 추가로, 특별한 특징, 형태, 조성, 또는 특성은 하나 이상의 구체예에서 어떠한 적합한 방법으로 조합될 수 있다.DETAILED DESCRIPTION OF THE INVENTION Various embodiments described herein are described below with reference to the drawings. In the following description, various specific details, such as specific forms, compositions, and processes, are set forth in order to provide a thorough understanding of the invention. However, certain embodiments may be practiced without one or more of these specific details or in conjunction with other known methods and forms. In other instances, well-known processes and manufacturing techniques are not described in specific detail so as not to unnecessarily obscure the invention. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, form, composition or characteristic described in connection with the embodiment is included in one or more embodiments of the invention. Accordingly, the phrases “in one embodiment” or “an embodiment” expressed in various places throughout this specification do not necessarily refer to the same embodiment of the invention. Additionally, particular features, shapes, compositions, or properties may be combined in any suitable way in one or more embodiments.
명세서에서 특별한 정의가 없으면 본 명세서에 사용된 모든 과학적 및 기술적인 용어는 본 발명이 속하는 기술분야에서 당업자에 의하여 통상적으로 이해되는 것과 동일한 의미를 가진다.Unless there is a special definition in the specification, all scientific and technical terms used in the specification have the same meaning as commonly understood by a person skilled in the art in the technical field to which the present invention pertains.
본 발명의 일 구체예에서 “노인성 황반변성(Age-related macular degeneration: AMD)”이란, 나이가 들면서 망막의 황반부에 여러 가지 변화가 동반되어 생기는 질병이다. 나이가 증가함에 따라 발생율이 증가하며, 선진국에서는 성인 실명 원인 1위 질환으로 전세계적으로 약 2억명 정도의 환자가 있는 것으로 알려져 있다. 따라서 우리나라에서도 앞으로 노인 인구가 증가함에 따라서 그 발생 빈도는 더욱 증가하리라 예상된다. 황반은 망막이라고 하는 신경 조직의 중심 부위를 말하는데, 빛 자극에 반응하는 광수용체 세포가 밀집되어 있어 중심 시력을 담당한다. 노인성 황반변성은 노화가 진행됨에 따라 이러한 황반부 광수용체 세포가 소실되어 시력 장애를 일으키는 것으로, ① 습성 또는 삼출성 형태와 ② 건성 또는 비삼출성 형태로 나눌 수 있다. In one embodiment of the present invention, “Age-related macular degeneration (AMD)” is a disease that occurs with various changes in the macular part of the retina as one ages. The incidence rate increases with age, and in developed countries, it is the number one cause of blindness in adults and is known to have approximately 200 million patients worldwide. Therefore, as the elderly population increases in Korea, the frequency of occurrence is expected to increase further. The macula refers to the central part of the nervous tissue called the retina. It is densely packed with photoreceptor cells that respond to light stimulation and is responsible for central vision. Age-related macular degeneration causes visual impairment due to loss of photoreceptor cells in the macular area as aging progresses. It can be divided into ① wet or exudative form and ② dry or non-exudative form.
습성(wet=neovascular, exudative) 형태는 망막 밑에 맥락막 신생혈관이 자라는 경우로 항혈관내피성장인자 항체(Anti-vascular endothelial growth factor (VEGF) monoclonal antibody)를 안구내 주사하는 방법으로 치료한다. 건성(dry=atrophic) 형태는 AMD의 대부분을 차지하며 망막에 드루젠(drusen)이나 색소이상(pigmentary abnormality), 또는 망막상피의 위축(atrophy)과 같은 병변이 생긴 경우를 말한다. 건성 중 진행성 황반변성을 지도형 위축(geographic atrophy: GA)라고 하는데, 현재로서는 치료법이 전무하여 노인성 황반변성의 최대 난제인 실정이다.The wet (wet = neovascular, exudative) form is when choroidal neovascularization grows under the retina and is treated with intraocular injection of anti-vascular endothelial growth factor (VEGF) monoclonal antibody. Dry (atrophic) form accounts for the majority of AMD and refers to lesions such as drusen, pigmentary abnormality, or atrophy of the retinal epithelium. Dry progressive macular degeneration is called geographic atrophy (GA), and there is currently no treatment, making it the biggest challenge in age-related macular degeneration.
본 발명의 일 구체예에서 “니코틴아마이드(nicotinamide)”란, 비타민 B 복합체의 일종으로 식물에서는 니코틴산과 공존하여 광범위하게 분포하고, 동물의 생체 내에서 산화환원 조효소인 NAD+ 또는 NADP+의 성분으로 존재한다. 좁은 의미에서 니아신으로도 언급된다.In one embodiment of the present invention, “nicotinamide” is a type of vitamin B complex and is widely distributed in plants, coexisting with nicotinic acid, and exists as a component of NAD+ or NADP+, a redox coenzyme, in animals. . It is also referred to in a narrow sense as niacin.
니아신아마이드로도 알려진 니코틴아마이드는 식품에서 발견되며 식이 보충제 및 약물로 사용되는 비타민 B3의 한 형태이다. 보충제로, 펠라그라(pellagra, 니아신 결핍으로 발생하는 질환)를 예방하고 치료하기 위해 경구복용으로도 사용된다.Nicotinamide, also known as niacinamide, is a form of vitamin B3 found in foods and used as a dietary supplement and medication. As a supplement, it is also used orally to prevent and treat pellagra (a disease caused by niacin deficiency).
상기 니코틴아마이드는 하기 화학식 1로 표시된다.The nicotinamide is represented by the following formula (1).
[화학식 1][Formula 1]
본 발명의 일 구체예에서 “니코틴아마이드의 유도체”란, 상기 화학식 1로 표시되는 니코틴아마이드의 분자 구조 가운데 일부분이 변화하여 생긴 화합물을 의미한다. 본 발명에 있어서, 상기 니코틴아마이드의 유도체는 하기 화학식 2 또는 화학식 3으로 표시되는 것이나, 이제 제한되는 것은 아니다.In one embodiment of the present invention, “derivative of nicotinamide” refers to a compound produced by changing part of the molecular structure of nicotinamide represented by Formula 1 above. In the present invention, the nicotinamide derivative is represented by the following formula (2) or formula (3), but is not limited thereto.
[화학식 2][Formula 2]
[화학식 3][Formula 3]
본 발명의 일 구체예에서 “약학조성물”이란, 특정한 목적을 위해 투여되는 조성물을 의미한다. 본 발명의 목적상, 본 발명의 약학조성물은 노인성 황반변성을 예방 또는 치료하는 것이며, 이에 관여하는 화합물 및 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 포함할 수 있다. 또한 본 발명에 따른 약학 조성물은 조성물 총 중량에 대하여 본 발명의 유효성분을 0.1 내지 50 중량%로 포함한다. 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 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, “pharmaceutical composition” means a composition administered for a specific purpose. For the purpose of the present invention, the pharmaceutical composition of the present invention is to prevent or treat age-related macular degeneration, and may include a compound involved therein and a pharmaceutically acceptable carrier, excipient, or diluent. Additionally, the pharmaceutical composition according to the present invention contains 0.1 to 50% by weight of the active ingredient of the present invention based on the total weight of the 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, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Examples include, but are not limited to, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
구체적으로, 본 발명의 노인성 황반변성의 예방 및 치료를 위한 약학조성물은 바람직하게는 상기 화학식 1 내지 화학식 3으로부터 선택되는 어느 하나의 화합물, 또는 이의 약학적으로 허용 가능한 염, 광학이성질체, 수화물 및 용매화물로부터 선택되는 화합물을 포함한다.Specifically, the pharmaceutical composition for preventing and treating age-related macular degeneration of the present invention preferably contains any one compound selected from Formulas 1 to 3, or a pharmaceutically acceptable salt, optical isomer, hydrate, and solvate thereof. It includes compounds selected from.
상기 약학적으로 허용 가능한 염은 인체에 독성이 낮고 모화합물의 생물학적 활성과 물리화학적 성질에 악영향을 주지 않아야 한다. 약학적으로 허용 가능한 염은 약학적으로 허용 가능한 유리산과 염기 화합물의 산부가염 등이 가능하나, 이에 제한되지는 않는다.The pharmaceutically acceptable salt should have low toxicity to the human body and not adversely affect the biological activity and physicochemical properties of the parent compound. Pharmaceutically acceptable salts include, but are not limited to, acid addition salts of pharmaceutically acceptable free acids and base compounds.
본 발명에 따른 화합물의 바람직한 염의 형태로는 무기산 또는 유기산과의 염을 들 수 있다. 이때, 무기산은 염산, 황산, 질산, 인산, 과염소산, 브롬산 등이 사용될 수 있다. 또한, 유기산은 초산, 메탄설폰산, 에탄설폰산, p-톨루엔설폰산, 푸마린산, 말레산, 말론산, 프탈산, 숙신산, 젖산, 구연산, 시트르산, 글루콘산, 타타르산, 살리실산, 말산, 옥살산, 벤조산, 엠본산, 아스파르트산, 글루탐산 등이 사용될 수 있다. 유기염기 부가염 제조에 사용될 수 있는 유기염기는 트리스(하이드록시메틸)메틸아민, 디사이클로헥실아민 등이다. 아미노산 부가염 제조에 사용될 수 있는 아미노산은 알라닌, 글라이신 등의 천연아미노산이다. 상기 예시된 무기산, 유기산, 유기염기 및 아미노산 외에 다른 산 또는 염기가 사용될 수 있음은 당해 기술분야에서 통상의 기술을 가진 자에게 자명할 것이다. 또한 상기 염은 통상적인 방법으로 제조될 수 있다. Preferred salt forms of the compounds according to the present invention include salts with inorganic acids or organic acids. At this time, the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, etc. In addition, organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, Oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, etc. can be used. Organic bases that can be used to prepare organic base addition salts include tris(hydroxymethyl)methylamine and dicyclohexylamine. Amino acids that can be used to produce amino acid addition salts are natural amino acids such as alanine and glycine. It will be apparent to those skilled in the art that other acids or bases may be used in addition to the inorganic acids, organic acids, organic bases, and amino acids exemplified above. Additionally, the salt can be prepared by conventional methods.
한편, 본 발명에 따른 화합물들은 비대칭 탄소 중심을 가질 수 있으므로 R 또는 S 이성질체 또는 라세믹 화합물로서 존재할 수 있으며 이들 모든 광학이성질체 및 혼합물은 본 발명의 범위에 포함될 수 있다.Meanwhile, the compounds according to the present invention may have an asymmetric carbon center and therefore may exist as R or S isomers or racemic compounds, and all of these optical isomers and mixtures may be included within the scope of the present invention.
그 외에도, 화학식 1 내지 화학식 3으로 표시되는 화합물의 수화물 또는 용매화물 형태도 본 발명의 범위에 포함될 수 있다. In addition, hydrate or solvate forms of the compounds represented by Formulas 1 to 3 may also be included in the scope of the present invention.
한편, 본 발명에서, "예방"은 본 발명의 약학조성물을 이용하여 노인성 황반변성으로 인해 발생한 증상을 차단하거나, 그 증상을 억제 또는 지연시키는 모든 행위라면 제한없이 포함할 수 있다. Meanwhile, in the present invention, “prevention” may include without limitation any act of blocking, suppressing or delaying symptoms caused by age-related macular degeneration using the pharmaceutical composition of the present invention.
또한, 본 발명에서, "치료"는 본 발명의 약학조성물을 이용하여 노인성 황반변성으로 인해 발생한 증상이 호전되거나 이롭게 되는 모든 행위라면 제한없이 포함할 수 있다.Additionally, in the present invention, “treatment” may include, without limitation, any action that improves or benefits symptoms caused by age-related macular degeneration by using the pharmaceutical composition of the present invention.
본 발명에서 상기 약학조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학조성물은 바람직하게는 동물, 더욱 바람직하게는 포유동물, 가장 바람직하게는 인간을 대상으로 하는 것을 특징으로 할 수 있다. In the present invention, the pharmaceutical composition may be in the form of a capsule, tablet, granule, injection, ointment, powder, or beverage. The pharmaceutical composition is preferably used in animals, more preferably in mammals, and most preferably in humans. It can be characterized as being targeted.
본 발명의 일 구체예에서 “투여”란, 어떠한 적절한 방법으로 환자에게 본 발명의 조성물을 도입하는 것을 의미하며, 본 발명의 조성물의 투여경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 구체적으로는 경구 투여, 복강 내 투여, 정맥 내 투여, 근육 내 투여, 피하 투여, 피내 투여, 비내 투여, 폐내 투여, 직장내 투여, 강내 투여, 복강 내 투여, 경막 내 투여, 또는 안구 내 투여의 형태로 이루어질 수 있고, 상기 안구 내 투여는 보다 구체적으로는 유리체강내 주입술(intravitreal injection), 안구 뒤 주입술(retrobulbar injection), 결막하 주입술(subconjunctival injection), 테논낭하 주입술(sub-tenon injection), 또는 안구내 점안의 형태로 이루어질 수 있으나, 이에 제한되지는 않는다. 본 발명에서 유효량은 질환의 종류, 질환의 중증도, 조성물에 함유된 유효 성분 및 다른 성분의 종류 및 함량, 제형의 종류 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료 기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다. 성인의 경우, 상기 치료용 약학조성물을 1회 50ml~500ml의 양으로 체내에 투여 가능하며, 화합물일 경우 0.1ng/kg-10㎎/kg, 모노클로날 항체일 경우 0.1ng/kg-10㎎/kg의 용량으로 투여될 수 있다. 투여간격은 1일 1회 내지 12회일 수 있으며, 1일 12회 투여할 경우에는 2시간마다 1회씩 투여할 수 있다. 또한 본 발명의 약학조성물은 목적하고자 하는 치료를 위해 단독 또는 당업계에 공지된 다른 치료법, 예를 들어 화학요법제, 방사선 및 수술과 같이 투여될 수 있다. 또한 본 발명의 약학조성물은 면역 반응을 증진하기 위하여 고안된 다른 치료, 예를 들어 당업계에 주지된 것과 같은 어쥬번트 또는 사이토카인(또는 사이토카인을 코딩하는 핵산)과 혼합하여 투여될 수 있다. 바이오리스틱(biolistic) 전달 또는 생체 외(ex vivo) 처리와 같은 다른 표준 전달 방법들이 사용될 수도 있다. 생체 외 처리에서 예를 들어 항원제시 세포들(APCs), 수지상세포들, 말초혈액 단핵구 세포들, 또는 골수세포들을 환자 또는 적당한 공여자로부터 얻어서 본 약학조성물로 생체 외에서 활성화된 후 그 환자에게 투여될 수 있다.In one embodiment of the present invention, “administration” means introducing the composition of the present invention into a patient by any appropriate method, and the route of administration of the composition of the present invention is through any general route as long as it can reach the target tissue. may be administered. Specifically, oral administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, intranasal administration, intrapulmonary administration, intrarectal administration, intravenous administration, intraperitoneal administration, intrathecal administration, or intraocular administration. It may be done in the form of intraocular administration, and more specifically, intravitreal injection, retrobulbar injection, subconjunctival injection, sub-tenon injection, or It may be in the form of an intraocular drop, but is not limited thereto. In the present invention, the effective amount refers to the type of disease, the severity of the disease, the type and content of the active ingredient and other ingredients contained in the composition, the type of dosage form, and the patient's age, weight, general health condition, gender and diet, administration time, and route of administration. and secretion rate of the composition, treatment period, and concurrently used drugs. For adults, the therapeutic pharmaceutical composition can be administered into the body in an amount of 50ml to 500ml at a time, 0.1ng/kg-10mg/kg for compounds, and 0.1ng/kg-10mg for monoclonal antibodies. It can be administered at a dose of /kg. The administration interval can be from 1 to 12 times a day, and when administered 12 times a day, the drug can be administered once every 2 hours. In addition, the pharmaceutical composition of the present invention can be administered alone or in combination with other treatments known in the art, such as chemotherapy, radiation, and surgery, for the desired treatment. Additionally, the pharmaceutical composition of the present invention can be administered in combination with other treatments designed to enhance immune responses, such as adjuvants or cytokines (or nucleic acids encoding cytokines) such as those well known in the art. Other standard delivery methods, such as biolistic delivery or ex vivo processing, may also be used. In ex vivo processing, for example, antigen presenting cells (APCs), dendritic cells, peripheral blood mononuclear cells, or bone marrow cells can be obtained from a patient or a suitable donor, activated in vitro with the pharmaceutical composition, and then administered to the patient. there is.
본 발명의 일 구체예에서 “식품 조성물”이란, 본 발명에서 목적으로 하는 적응증의 예방 또는 개선을 위해 다양하게 이용되는 것으로서, 본 발명의 조성물을 유효성분으로 포함하는 식품조성물은 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 분말, 과립, 정제, 캡슐, 과자, 떡, 빵 등의 형태로 제조될 수 있다. 본 발명의 식품조성물은 독성 및 부작용이 거의 없는 기존의 식품용 섭취물로부터 개량되어 구성된 것이므로 예방 목적으로 장기간 복용 시에도 안심하고 사용할 수 있다. 본 발명의 조성물이 식품조성물에 포함될 때 그 양은 전체 중량의 0.1 내지 100%의 비율로 첨가할 수 있다. 여기서, 상기 식품조성물이 음료 형태로 제조되는 경우 지시된 비율로 상기 식품조성물을 함유하는 것 외에 특별한 제한점은 없으며 통상의 음료와 같이 여러가지 향미제 또는 천연탄수화물 등을 추가 성분으로서 함유할 수 있다. 즉, 천연탄수화물로서 포도당 등의 모노사카라이드, 과당 등의 디사카라이드, 슈크로스 등의 및 폴리사카라이드, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜 등을 포함할 수 있다. 상기 향미제로서는 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등) 등을 들 수 있다. 그 외 본 발명의 식품조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성풍미제 및 천연풍미제 등의 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 통상적으로 본 발명의 조성물 100 중량부 당 0.1 내지 100 중량부의 범위에서 선택되는 것이 일반적이나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, “food composition” refers to something that is used in various ways to prevent or improve the indications targeted by the present invention, and a food composition containing the composition of the present invention as an active ingredient includes various types of food, for example. For example, it can be manufactured in the form of beverages, gum, tea, vitamin complex, powder, granules, tablets, capsules, cookies, rice cakes, bread, etc. The food composition of the present invention has been improved from existing food ingredients with little toxicity and side effects, so it can be safely used even when taken for a long period of time for preventive purposes. When the composition of the present invention is included in a food composition, it can be added in an amount of 0.1 to 100% of the total weight. Here, when the food composition is manufactured in the form of a beverage, there are no special restrictions other than containing the food composition in the indicated ratio, and various flavoring agents or natural carbohydrates can be contained as additional ingredients like ordinary beverages. That is, natural carbohydrates include monosaccharides such as glucose, disaccharides such as fructose, common sugars such as polysaccharides such as sucrose, dextrin, and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. can do. Examples of the flavoring agent include natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.). In addition, the present invention The food composition includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH regulators, It may contain stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. These components can be used independently or in combination. The ratio of these additives is usually per 100 parts by weight of the composition of the present invention. It is generally selected in the range of 0.1 to 100 parts by weight, but is not limited thereto.
본 발명의 일 구체예에서, 니코틴아마이드(nicotinamide), 또는 이의 유도체를 유효성분으로 포함하는 노인성 황반변성의 예방 또는 치료용 약학조성물을 제공하고, 상기 노인성 황반변성은 건성, 또는 습성인 것인 노인성 황반변성의 예방 또는 치료용 약학조성물을 제공하며, 상기 노인성 황반변성은 드루젠(drusen), 색소이상(pigmentary abnormality), 또는 망막상피의 위축(atrophy)을 동반하는 것인 노인성 황반변성의 예방 또는 치료용 약학조성물을 제공하며, 상기 위축은 지도형 위축(geographic atrophy)인 것인 노인성 황반변성의 예방 또는 치료용 약학조성물을 제공한다.In one embodiment of the present invention, a pharmaceutical composition for preventing or treating age-related macular degeneration is provided, comprising nicotinamide or a derivative thereof as an active ingredient, wherein the age-related macular degeneration is dry or wet. Provided is a pharmaceutical composition for prevention or treatment of age-related macular degeneration, wherein age-related macular degeneration is accompanied by drusen, pigmentary abnormality, or atrophy of the retinal epithelium. It provides a pharmaceutical composition for preventing or treating age-related macular degeneration, wherein the atrophy is geographic atrophy.
상기 니코틴아마이드는 하기 화학식 1로 표시되는 것이며, 상기 니코틴아마이드 유도체는 하기 화학식 2 또는 화학식 3으로 표시되는 것이다.The nicotinamide is represented by Formula 1 below, and the nicotinamide derivative is represented by Formula 2 or Formula 3 below.
[화학식 1] [Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
본 발명의 다른 구체예에서, 니코틴아마이드(nicotinamide), 또는 이의 유도체를 유효성분으로 포함하는 노인성 황반변성의 예방 또는 개선용 식품조성물을 제공하고, 상기 노인성 황반변성은 건성, 또는 습성인 것인 노인성 황반변성의 예방 또는 개선용 식품조성물을 제공하며, 상기 노인성 황반변성은 드루젠(drusen), 색소이상(pigmentary abnormality), 또는 망막상피의 위축(atrophy)을 동반하는 것인 노인성 황반변성의 예방 또는 개선용 식품조성물을 제공하며, 상기 위축은 지도형 위축(geographic atrophy)인 것인 노인성 황반변성의 예방 또는 개선용 식품조성물을 제공한다.In another embodiment of the present invention, a food composition for preventing or improving age-related macular degeneration is provided comprising nicotinamide or a derivative thereof as an active ingredient, wherein the age-related macular degeneration is dry or wet. Provides a food composition for preventing or improving age-related macular degeneration, wherein the age-related macular degeneration is accompanied by drusen, pigmentary abnormality, or atrophy of the retinal epithelium. It provides a food composition for preventing or improving age-related macular degeneration, wherein the atrophy is geographic atrophy.
상기 니코틴아마이드는 하기 화학식 1로 표시되는 것이며, 상기 니코틴아마이드 유도체는 하기 화학식 2 또는 화학식 3으로 표시되는 것이다.The nicotinamide is represented by Formula 1 below, and the nicotinamide derivative is represented by Formula 2 or Formula 3 below.
[화학식 1] [Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
이하 상기 본 발명을 단계별로 상세히 설명한다.Hereinafter, the present invention will be described in detail step by step.
본 발명에 따른 니코틴아마이드(nicotinamide), 또는 이의 유도체를 유효성분으로 포함하는 약학조성물 및 식품 조성물은 노인성 황반변성에서 망막상피세포의 퇴화를 구조적, 기능적으로 현저하게 회복시키는 효과가 있다.Pharmaceutical compositions and food compositions containing nicotinamide or a derivative thereof as an active ingredient according to the present invention are effective in significantly structurally and functionally restoring retinal epithelial cell degeneration in age-related macular degeneration.
도 1은 본 발명의 일 실시예에 따른, 렌티바이러스를 이용하는 방법으로 제조한 노인성 황반변성 동물모델이 목적과 같이 제조되었는지 확인한 결과이다.
도 2는 본 발명의 일 실시예에 따른, 렌티바이러스를 이용하여 제조한 노인성 황반변성 동물모델에서 투여한 후보물질에 따른 노인성 황반변성 치료 효과를 망막상피세포에서 구조적으로 확인한 결과이다.
도 3은 본 발명의 일 실시예에 따른, 요오드산 나트륨을 이용하여 제조한 노인성 황반변성 동물모델에서 투여한 후보물질에 따른 노인성 황반변성 치료 효과를 망막상피세포에서 구조적으로 확인한 결과이다.
도 4는 본 발명의 일 실시예에 따른, 요오드산 나트륨을 이용하여 제조한 노인성 황반변성 동물모델에서 투여한 후보물질에 따른 노인성 황반변성 치료 효과를 망막상피세포에서 기능적으로 확인한 결과이다.Figure 1 shows the results of confirming whether an age-related macular degeneration animal model manufactured by a method using a lentivirus according to an embodiment of the present invention was manufactured as intended.
Figure 2 shows the results of structural confirmation in retinal epithelial cells of the treatment effect for age-related macular degeneration according to the candidate substance administered in an age-related macular degeneration animal model prepared using lentivirus according to an embodiment of the present invention.
Figure 3 shows the results of structural confirmation in retinal epithelial cells of the treatment effect for age-related macular degeneration according to the candidate substance administered in an age-related macular degeneration animal model prepared using sodium iodate according to an embodiment of the present invention.
Figure 4 shows the results of functional confirmation in retinal epithelial cells of the treatment effect for age-related macular degeneration according to the candidate substance administered in an age-related macular degeneration animal model prepared using sodium iodate according to an embodiment of the present invention.
이하, 본 발명을 하기의 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be explained in detail by the following examples. However, the following examples only illustrate the present invention, and the content of the present invention is not limited by the following examples.
실시예Example
실시예 1. 노인성 황반변성 동물 모델의 제조 및 후보물질 투여Example 1. Preparation of age-related macular degeneration animal model and administration of candidate substances
노인성 황반변성 동물 모델은 종래 공지된 방법(Kaneko, H. et al. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 471, 325-330, doi:10.1038/nature09830. 2011.)과 동일하게 수행하였다. 상기 방법은 망막색소상피(Retina pigment epithelium: RPE) 내에 축적된 Alu RNA에 의해 지도형 위축을 발생시키는 방법이다. 구체적으로, GFP(green fluorescence protein) 표지된 Alu RNA 발현 렌티바이러스 벡터(Alu RNA expressing lentival vector) 0.8 X 108 genome copy(GC)/㎕ 농도로 마이크로리터 주사기 (WPI, 10 microliter syringe)에 로딩하여 준비하고, 8-10 주령 C57BL/6 마우스를 마취하고, 0.5%의 페닐에프린(phenylephrine) 및 0.5%의 트로픽아마이드(tropicamide)로 동공을 산동시켰다. 이후, 마우스의 눈꺼풀을 열고, 눈을 돌출시키고, 각막 표면에 점탄성 용액을 1방울 적용시킨 이후, 망막을 시각화 하기 위해 각막의 표면에 작은 원형 커버 슬라이드를 놓았다. 30 게이지 주사바늘로 각막 주변(Limbus) 1mm 떨어진 위치에 작은 절개를 만들고, 절개를 통해, 마이크로리터 주사기의 33 게이지 매선용 바늘(Blunt needle)을 넣고, 저항이 느껴지는 지점(망막하 공간, subretinal space)까지 주사바늘을 접근시켰다. 불필요한 조직 손상을 방지하기 위해 조심스럽고 부드럽게 바이러스를 1 ㎕ 주입한 이후, 20-30초 기다리고, 천천히 마이크로리터 주사기 바늘을 철회하였다. 망막 출혈이 없고, 망막하 수포(bleb)가 잘 형성되었는지 확인한 후 안구 표면에 항생연고를 도포하였다. 모든 실험 과정에서, 마우스의 체온을 유지하기 위해 온열 패드 위에서 실험을 수행하였다. 2주 후, 마우스로부터 안구 시료를 수득하여 망막색소상피 전체 봉입 면역염색(RPE whole mount immunostatining)을 수행하였다. Age-related macular degeneration animal model was performed in the same manner as the previously known method (Kaneko, H. et al. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 471, 325-330, doi:10.1038/nature09830. 2011.) carried out. This method causes geographic atrophy by Alu RNA accumulated in the retina pigment epithelium (RPE). Specifically, GFP (green fluorescent protein) labeled Alu RNA expressing lentiviral vector was loaded into a microliter syringe (WPI, 10 microliter syringe) at a concentration of 0.8 Prepared, 8-10 week old C57BL/6 mice were anesthetized and their pupils were dilated with 0.5% phenylephrine and 0.5% tropicamide. Afterwards, the eyelids of the mouse were opened, the eye was protruded, and one drop of viscoelastic solution was applied to the corneal surface, and a small circular cover slide was placed on the surface of the cornea to visualize the retina. Make a small incision 1mm away from the cornea using a 30-gauge needle, insert a 33-gauge Blunt needle of a microliter syringe through the incision, and inject into the point where resistance is felt (subretinal space). ) was brought close to the injection needle. After carefully and gently injecting 1 μl of virus to prevent unnecessary tissue damage, wait 20-30 seconds and slowly withdraw the microliter syringe needle. After confirming that there was no retinal hemorrhage and that subretinal blebs were well formed, antibiotic ointment was applied to the ocular surface. During all experiments, experiments were performed on a heating pad to maintain the mouse's body temperature. Two weeks later, eye samples were obtained from mice and retinal pigment epithelium whole encapsulation immunostaining (RPE whole mount immunostatining) was performed.
한편, 바이러스를 이용한 방법 이외에 화학적 방법의 노인성 황반변성 동물 모델을 추가로 제조하였다. 이를 위해서 상기와 동일하게 8-10 주령 C57BL/6 마우스를 준비하고, 요오드산 나트륨(Sodium iodate, NAIO3)을 20mg/Kg 농도로 꼬리 정맥을 통해 혈관내 주사하였다. 6일 후에, 망막 전위도(Electroretinogram: ERG)를 시행하고, 마우스로부터 안구 시료를 수득하여 망막색소상피 전체 봉입 면역염색(RPE whole mount immunostatining)을 수행하였다.Meanwhile, in addition to the method using the virus, an animal model of age-related macular degeneration using a chemical method was additionally prepared. For this purpose, 8-10 week old C57BL/6 mice were prepared in the same manner as above, and sodium iodate (NAIO 3 ) was intravascularly injected at a concentration of 20 mg/Kg through the tail vein. Six days later, electroretinogram (ERG) was performed, eye samples were obtained from mice, and RPE whole mount immunostatining was performed on the retinal pigment epithelium.
노인성 황반변성 치료용 후보물질은 하기 표 1의 화합물을 이용하였으며, 상기 두 종류의 동물 모델을 제조하기 위한 렌티바이러스 또는 요오드산 나트륨을 투여하기 3일 전부터 안구 시료를 수득하는 날까지 1000mg/Kg/day의 농도로 매일 복강내 주사(Intraperitoneal injection)하였다.Candidate substances for the treatment of age-related macular degeneration were the compounds shown in Table 1 below, and were dosed at 1000 mg/Kg/day from 3 days before administration of lentivirus or sodium iodate to the day of obtaining eye samples to prepare the two types of animal models. Intraperitoneal injection was performed daily at a daily concentration.
실시예 2. 망막상피세포 형태 확인을 통한 후보물질의 노인성 황반변성 치료 효과 확인Example 2. Confirmation of the treatment effect of candidate substances on age-related macular degeneration through confirmation of retinal epithelial cell morphology.
망막상피세포 형태 확인을 위한 망막세포 염색은 하기의 순서로 진행하였다. 먼저, 수득한 안구 시료를 1% 파라포름알데하이드(paraformaldehyde)로 1시간 동안 고정하고, 근육(Muscle), 각막(Cornea), 수정체(Lens), 및 신경망막세포(Neural retina)를 제거한 후, Sclera/Choroid/RPE complex를 방사상(radial)으로 총 8개로 절편하였다. 각 절편 조직을 5%의 소혈청 알부민(bovine serum albumin), 2%의 NDS(normal donkey serum), 및 0.3%의 트리톤 X-100(Triton™ X-100)이 포함된 인산완충생리식염수 (Phosphate-buffered saline) 용액에서 1시간 동안 블럭(blocking)하고, 세척한 후, 4℃에서 항 ZO-1 항체로 오버나잇 반응시켰다(overnight incubation). 이후 3회 세척하고, 실온에서 2차 항체와 1시간 반응시킨 후, 다시 세척하고, 조직을 슬라이드에 도말한 후 봉입하였다. 이를 형광현미경으로 관찰하였다. Retinal cell staining to confirm retinal epithelial cell morphology was performed in the following order. First, the obtained eye sample was fixed with 1% paraformaldehyde for 1 hour, the muscle, cornea, lens, and neural retina were removed, and then Sclera The /Choroid/RPE complex was sectioned radially into a total of 8 pieces. Each section tissue was cultured in phosphate-buffered saline containing 5% bovine serum albumin, 2% normal donkey serum (NDS), and 0.3% Triton™X-100. -buffered saline) solution for 1 hour, washed, and incubated overnight with anti-ZO-1 antibody at 4°C. Afterwards, it was washed three times, reacted with secondary antibody at room temperature for 1 hour, washed again, and the tissue was smeared on a slide and encapsulated. This was observed with a fluorescence microscope.
동물모델이 렌티바이러스를 이용한 모델인 경우에는 세포퇴화 면적/GFP 발현 면적(Transduction area)으로 비교하였으며, 동물모델이 요오드산 나트륨을 이용한 모델인 경우에는 세포퇴화 면적/전체 망막상피세포 면적으로 비교하였다.If the animal model was a model using lentivirus, comparison was made based on cell degeneration area/GFP expression area (Transduction area), and if the animal model was a model using sodium iodate, comparison was made based on cell degeneration area/total retinal epithelial cell area. .
실시예 2-1. 렌티바이러스를 이용한 동물 모델에서의 효과 확인Example 2-1. Confirmation of effectiveness in animal models using lentivirus
먼저, 상기 실시예 1에서 렌티바이러스를 이용하는 방법으로 제조한 노인성 황반변성 동물모델이 목적과 같이 제조되었는지 확인한 결과를 도 1에 나타내었다. 도 1에서, 대조군으로서 GFP를 발현하는 렌티바이러스를 형질도입 하였을 때에는 정상 망막상피세포에서 구조적 변화가 발생하지 않았으나(좌측), Alu RNA를 발현하는 렌티바이러스를 형질도입 하였을 때에는 망막상피세포가 세포퇴화되어 망막상피세포의 크기가 커지고, 모양이 불규칙해진 것으로 나타났다(우측). 이를 통해 렌티바이러스를 이용하는 방법으로 목적하는 노인성 황반변성 동물모델이 잘 제조되었음을 확인할 수 있었다.First, the results of confirming whether the age-related macular degeneration animal model prepared by the method using lentivirus in Example 1 was manufactured as intended is shown in Figure 1. In Figure 1, when a lentivirus expressing GFP was transduced as a control, no structural changes occurred in normal retinal epithelial cells (left), but when a lentivirus expressing Alu RNA was transduced, retinal epithelial cells showed cell degeneration. It was found that the retinal epithelial cells increased in size and became irregular in shape (right). Through this, it was confirmed that the target age-related macular degeneration animal model was successfully manufactured using the lentivirus method.
렌티바이러스를 이용하여 제조한 노인성 황반변성 동물모델에서 투여한 후보물질에 따른 노인성 황반변성 치료 효과를 확인한 결과는 도 2에 나타내었다.The results of confirming the treatment effect of age-related macular degeneration according to candidate substances administered in an age-related macular degeneration animal model prepared using lentivirus are shown in Figure 2.
실험 결과, 화합물을 투여하지 않은 대조군(Alu RNA)의 경우 전형적인 노인성 황반변성의 지도형 위축(geographic atrophy)을 나타내었다. 화학식 1을 투여(Alu RNA + NAM treatment)한 경우 망막상피세포의 크기 증가가 관찰되나, 대조군(Alu RNA)에 비하여는 망막상피세포의 크기가 확연히 작았다. 화학식 2를 투여(Alu RNA + NMN treatment)한 경우에는 망막상피세포의 퇴화가 관찰되지 않고, 정상 망막상피세포에 가까운 구조를 보였으며, 화학식 3을 투여(Alu RNA + NR treatment)한 경우에는 소수의 망막상피세포에서 약간의 크기 증가가 관찰되었으나, 전체적으로는 정상 망막상피세포에 가까운 구조를 보였다. 상기 결과로부터 렌티바이러스를 이용한 동물 모델에서 망막상피세포 퇴화의 구조적 회복 정도는 화학식 2(NMN) > 화학식 3(NR) > 화학식 1(NAM)의 순서로 치료 효과가 현저한 것을 알 수 있었다.As a result of the experiment, the control group (Alu RNA) that did not administer the compound showed geographic atrophy, typical of age-related macular degeneration. When Formula 1 was administered (Alu RNA + NAM treatment), an increase in the size of retinal epithelial cells was observed, but the size of retinal epithelial cells was significantly smaller than that of the control group (Alu RNA). When Formula 2 was administered (Alu RNA + NMN treatment), no degeneration of retinal epithelial cells was observed and a structure close to normal retinal epithelial cells was observed, and when Formula 3 was administered (Alu RNA + NR treatment), a small number of retinal epithelial cells were observed. A slight increase in size was observed in the retinal epithelial cells, but the overall structure was similar to that of normal retinal epithelial cells. From the above results, it was found that the degree of structural recovery of retinal epithelial cell degeneration in the animal model using lentivirus had a significant therapeutic effect in the following order: Formula 2 (NMN) > Formula 3 (NR) > Formula 1 (NAM).
실시예 2-2. 요오드산 나트륨을 이용한 동물 모델에서의 효과 확인Example 2-2. Confirmation of effects in animal models using sodium iodate
상기 실시예 1에서 요오드산 나트륨을 이용하는 방법으로 제조한 노인성 황반변성 동물모델에서 투여한 후보물질에 따른 노인성 황반변성 치료 효과를 확인한 결과는 도 3에 나타내었다.The results of confirming the treatment effect for age-related macular degeneration according to the candidate substance administered in the age-related macular degeneration animal model prepared by using sodium iodate in Example 1 are shown in Figure 3.
실험결과, 화합물을 투여하지 않은 대조군(NaIO3)의 경우 망막상피세포의 형체를 알아보기 어려울 정도로 세포 퇴화가 일어난 반면에, 화학식 1을 투여(NaIO3 + NAM treatment)한 경우 망막상피세포의 형태는 회복되었으나, 망막상피세포 크기가 정상보다는 큰 것으로 나타났다. 화학식 2를 투여(NaIO3 + NMN treatment)하거나, 화학식 3을 투여(NaIO3 + NR treatment)한 경우에는 망막상피세포의 퇴화가 관찰되지 않고, 정상 망막상피세포에 가까운 구조를 보였다. 상기 결과로부터 요오드산 나트륨을 이용한 동물 모델에서 망막상피세포 퇴화의 구조적 회복 정도는 화학식 2(NMN) = 화학식 3(NR) > 화학식 1(NAM)의 순서로 치료 효과가 현저한 것을 알 수 있었다.As a result of the experiment, in the case of the control group (NaIO 3 ) that did not administer the compound, cell degeneration occurred to the extent that it was difficult to recognize the shape of the retinal epithelial cells, whereas in the case of administration of Formula 1 (NaIO 3 + NAM treatment), the shape of the retinal epithelial cells recovered, but the retinal epithelial cell size was found to be larger than normal. When Formula 2 was administered (NaIO 3 + NMN treatment) or Formula 3 was administered (NaIO 3 + NR treatment), no degeneration of retinal epithelial cells was observed and a structure close to that of normal retinal epithelial cells was observed. From the above results, it was found that the degree of structural recovery of retinal epithelial cell degeneration in an animal model using sodium iodate had a significant therapeutic effect in the following order: Formula 2 (NMN) = Formula 3 (NR) > Formula 1 (NAM).
실시예 3. 객관시 시력 측정을 통한 후보물질의 노인성 황반변성 치료 효과 확인Example 3. Confirmation of the treatment effect of candidate substances on age-related macular degeneration through objective visual acuity measurement
요오드산 나트륨을 이용한 동물 모델의 경우, 모델링 6일 후에 망막 전위도(Electroretinogram: ERG) 검사를 수행하고, 그 결과를 도 4에 나타내었다.In the case of the animal model using sodium iodate, an electroretinogram (ERG) test was performed 6 days after modeling, and the results are shown in Figure 4.
실험결과, 화합물을 투여하지 않은 대조군(NaIO3)의 경우 B-wave amplitude는 20.44 μV 로 저하되어 있으나, 화학식 1을 투여(NaIO3 + NAM treatment)한 경우 B-wave amplitude는 44.64 μV 로 회복되었다. 또한 B-wave amplitude는 화학식 2를 투여(NaIO3 + NMN treatment)한 경우 87.17 μV 로, 화학식 3을 투여(NaIO3 + NR treatment)한 경우 59.87 μV 로 회복되어, 요오드산 나트륨을 이용한 동물 모델에서 약물에 의한 기능적 회복(객관적 시력 상승; ERG 상에서의 B-wave amplitude)은 화학식 2(NMN) > 화학식 3(NR) > 화학식 1(NAM)의 순서로 치료 효과가 현저한 것을 알 수 있었다.As a result of the experiment, in the control group (NaIO3) where no compound was administered, the B-wave amplitude decreased to 20.44 μV, but when Formula 1 was administered (NaIO3 + NAM treatment), the B-wave amplitude recovered to 44.64 μV. In addition, the B-wave amplitude recovered to 87.17 μV when Formula 2 was administered (NaIO3 + NMN treatment) and 59.87 μV when Formula 3 was administered (NaIO3 + NR treatment), indicating that the drug was effective in an animal model using sodium iodate. It was found that functional recovery (objective increase in visual acuity; B-wave amplitude on ERG) had a significant therapeutic effect in the following order: Formula 2 (NMN) > Formula 3 (NR) > Formula 1 (NAM).
상기 실시예 1 내지 3의 결과로부터, 니코틴아마이드(nicotinamide), 또는 이의 유도체가 노인성 황반변성의 예방 또는 치료에 현저한 효과가 있음을 알 수 있었다.From the results of Examples 1 to 3, it was found that nicotinamide, or a derivative thereof, was significantly effective in preventing or treating age-related macular degeneration.
이상에서 본 발명에 대하여 상세하게 설명하였지만 본 발명의 권리범위는 이에 한정되는 것은 아니고, 청구범위에 기재된 본 발명의 기술적 사상을 벗어나지 않는 범위 내에서 다양한 수정 및 변형이 가능하다는 것은 당 기술분야의 통상의 지식을 가진 자에게는 자명할 것이다.Although the present invention has been described in detail above, the scope of the present invention is not limited thereto, and it is known in the art that various modifications and variations are possible without departing from the technical spirit of the present invention as set forth in the claims. It will be self-evident to those with knowledge.
Claims (12)
상기 노인성 황반변성은 지도형 위축(geographic atrophy)을 동반하는 건성 노인성 황반변성인 것이고,
상기 니코틴아마이드 유도체는 하기 화학식 2 또는 화학식 3으로 표시되는 것인, 약학조성물:
[화학식 2]
[화학식 3]
.
A pharmaceutical composition for preventing or treating age-related macular degeneration containing a nicotinamide derivative as an active ingredient,
The age-related macular degeneration is dry age-related macular degeneration accompanied by geographic atrophy,
The nicotinamide derivative is a pharmaceutical composition represented by the following formula (2) or formula (3):
[Formula 2]
[Formula 3]
.
상기 노인성 황반변성은 지도형 위축(geographic atrophy)을 동반하는 건성 노인성 황반변성인 것이고,
상기 니코틴아마이드 유도체는 하기 화학식 2 또는 화학식 3으로 표시되는 것인, 식품조성물:
[화학식 2]
[화학식 3]
.A food composition for preventing or improving age-related macular degeneration containing a nicotinamide derivative as an active ingredient,
The age-related macular degeneration is dry age-related macular degeneration accompanied by geographic atrophy,
The nicotinamide derivative is a food composition represented by the following formula (2) or (3):
[Formula 2]
[Formula 3]
.
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Non-Patent Citations (2)
| Title |
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| Cell Stem Cell, 20(5), pp.635-647(2017) 1부.* |
| Redox Biology, vol.34, 문서번호 101552, pp.1-13(2020) 1부.* |
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