KR102473858B1 - Use of Xylazine for enhancing visual acuity - Google Patents
Use of Xylazine for enhancing visual acuity Download PDFInfo
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- KR102473858B1 KR102473858B1 KR1020200033442A KR20200033442A KR102473858B1 KR 102473858 B1 KR102473858 B1 KR 102473858B1 KR 1020200033442 A KR1020200033442 A KR 1020200033442A KR 20200033442 A KR20200033442 A KR 20200033442A KR 102473858 B1 KR102473858 B1 KR 102473858B1
- Authority
- KR
- South Korea
- Prior art keywords
- xylazine
- present
- formula
- pharmaceutical composition
- hydrogen
- Prior art date
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Abstract
본 발명은 시력 증강 목적을 갖는 자일라진(xylazine) 및 이의 유도체의 용도에 관한 것으로, 구체적으로 자일라진, 이의 유도체, 이들의 약학적으로 허용 가능한 염, 또는 이들의 수화물을 유효성분으로 포함하는 시력 증강용 약학적 조성물, 의약외품 조성물, 식품 조성물, 및 상기 약학적 조성물을 인간을 제외한 개체에 투여하는 단계를 포함하는 시력 증강 방법에 관한 것이다.
본 발명의 자일라진은 암반응에서 우수한 빛 수용성 향상 효과를 나타내므로, 약학적 조성물, 의약외품 조성물 또는 식품 조성물에 유효성분으로 포함되어 시력 증강제 등의 개발에 이용될 수 있다.The present invention relates to the use of xylazine and its derivatives for the purpose of enhancing eyesight, and specifically, vision comprising xylazine, a derivative thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient. It relates to a pharmaceutical composition for enhancement, a quasi-drug composition, a food composition, and a vision enhancement method comprising administering the pharmaceutical composition to a subject other than a human.
Since the xylazine of the present invention exhibits an excellent light receptivity enhancing effect in the dark reaction, it can be included as an active ingredient in a pharmaceutical composition, quasi-drug composition, or food composition and used in the development of vision enhancers and the like.
Description
본 발명은 시력 증강 목적을 갖는 자일라진(xylazine) 및 이의 유도체의 용도에 관한 것으로, 구체적으로 자일라진, 이의 유도체, 이들의 약학적으로 허용 가능한 염, 또는 이들의 수화물을 유효성분으로 포함하는 시력 증강용 약학적 조성물, 의약외품 조성물, 식품 조성물, 및 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 시력 증강 방법에 관한 것이다.The present invention relates to the use of xylazine and its derivatives for the purpose of enhancing eyesight, and specifically, vision comprising xylazine, a derivative thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient. It relates to a pharmaceutical composition for enhancement, a quasi-drug composition, a food composition, and a vision enhancement method comprising administering the pharmaceutical composition to a subject.
사물을 인지하는 안구는 눈의 가장 안쪽 층에 존재하는, 빛의 수용과 같은 시각 기능에 대한 중요한 역할을 수행하는 막-유사 조직으로 이루어지고, 망막은 10개의 층, 예를 들어 외부로부터 하기 순서로 형성된 망막색소상피층(Retinal pigment epithelium), 신경상피층(Photoreceptor layer), 외경계막(External limiting membrane), 외과립층(Outer nuclear layer), 외망상층(Outer plexiform layer), 내과립층(Inner nuclear layer), 내망상층(Inner plexiform layer), 신경절세포층(Ganglion cell layer), 신경섬유층(Nerve fiber layer) 및 내경계막(Internal limiting membrane)으로 분류된다. 외부 세계로부터 망막에 조사된 빛은 내경계막측으로부터 망막에 전달되고 신경상피층에 존재하는 광수용체 세포로서 시각 세포(간상 세포 및 원추 세포)에 의해 수신된다. 시각 세포에서, 빛은 신경 신호로 전환되고, 신호는 망막에 존재하는 다양한 신경 세포에 의해 처리되고, 정보는 최종적으로 시신경을 통해 망막의 표면에 존재하는 신경절 세포로부터 대뇌 중심에 전달된다.The eyeball that recognizes objects is composed of a membrane-like tissue that plays an important role for visual functions such as light reception, which is present in the innermost layer of the eye, and the retina consists of 10 layers, for example, in the following order from the outside Retinal pigment epithelium, photoreceptor layer, external limiting membrane, outer nuclear layer, outer plexiform layer, inner nuclear layer ), inner plexiform layer, ganglion cell layer, nerve fiber layer, and internal limiting membrane. Light irradiated to the retina from the outside world is transmitted to the retina from the inner limiting membrane side and received by visual cells (rod cells and cone cells) as photoreceptor cells present in the neuroepithelial layer. In the visual cells, light is converted into nerve signals, the signals are processed by various nerve cells present in the retina, and information is finally transmitted from the ganglion cells present on the surface of the retina to the cerebral center via the optic nerve.
고도로 발달된 기술 문명 속에서 각종 환경오염, 텔레비젼의 과다시청, 개인용 컴퓨터, 전자 오락기 등 디스플레이 기기의 과다사용 등으로 인해 야간 운전이나 야간 작업시 암순응 능력이 저하되는 등 시력 저하 현상을 나타내고 있다. 이러한 시력 저하 현상을 방지하기 위하여 각종 의약품, 자연식품 등을 즐겨 찾고 있으며, 이중 의약품으로는 안토시아노사이드(Y Levy, et al., Eye (1998) 12, 967-969)를 주성분으로 한 시력 증강제가 국내외에서 널리 사용되고 있다.In a highly developed technological civilization, various environmental pollution, excessive viewing of TV, excessive use of display devices such as personal computers and electronic games, etc., show deterioration of eyesight such as reduced dark adaptation ability during night driving or night work. In order to prevent such deterioration of eyesight, various medicines and natural foods are being sought. Enhancers are widely used at home and abroad.
한편, 자일라진(xylazine)은 사람이 아닌 포유동물과 같은 동물에서 진정 작용, 근육이완 또는 진통에 주로 사용되는 화합물로 알려져 있다. 그러나, 자일라진의 시력 증강제로서의 연구는 미미한 실정이다.Meanwhile, xylazine is known as a compound mainly used for sedation, muscle relaxation, or pain relief in non-human animals such as mammals. However, research on xylazine as an eye enhancer is insignificant.
이러한 배경하에, 본 발명자들은 시력 증강제를 개발하고자 예의 노력연구한 결과, 자일라진은 암반응에서 빛에 대한 반응성을 향상시킴으로써, 시력 증강 효과를 나타냄을 확인하여, 본 발명을 완성하였다.Under this background, the inventors of the present invention conducted diligent research to develop a visual acuity enhancing agent, and as a result, it was confirmed that xylazine exhibits a visual acuity enhancing effect by improving the responsiveness to light in a dark reaction, and thus completed the present invention.
본 발명의 하나의 목적은 하기 화학식 1로 표시되는 화합물, 이의 약학적으로 허용가능한 염, 또는 이들의 수화물을 유효성분으로 포함하는 시력 증강용 약학적 조성물을 제공하는 것이다:One object of the present invention is to provide a pharmaceutical composition for enhancing eyesight comprising a compound represented by Formula 1 below, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient:
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1 및 R2는 각각 독립적으로 메틸 또는 에틸;R 1 and R 2 are each independently methyl or ethyl;
R3 내지 R5는 각각 독립적으로 수소, 히드록실 또는 메틸;R 3 to R 5 are each independently hydrogen, hydroxyl or methyl;
R6은 수소, 아세틸 또는 퓨란카보닐;R 6 is hydrogen, acetyl or furancarbonyl;
R7 및 R8은 모두 수소이거나, 함께 옥소를 형성함.R 7 and R 8 are both hydrogen or together form oxo.
본 발명의 다른 하나의 목적은 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 시력 증강 방법을 제공하는 것이다.Another object of the present invention is to provide a vision enhancement method comprising administering the pharmaceutical composition to a subject.
본 발명의 또 다른 하나의 목적은 하기 화학식 1로 표시되는 화합물, 이의 약학적으로 허용가능한 염, 또는 이들의 수화물을 유효성분으로 포함하는 시력 증강용 의약외품 조성물을 제공하는 것이다:Another object of the present invention is to provide a quasi-drug composition for enhancing eyesight comprising a compound represented by Formula 1 below, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient:
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1 및 R2는 각각 독립적으로 메틸 또는 에틸;R 1 and R 2 are each independently methyl or ethyl;
R3 내지 R5는 각각 독립적으로 수소, 히드록실 또는 메틸;R 3 to R 5 are each independently hydrogen, hydroxyl or methyl;
R6은 수소, 아세틸 또는 퓨란카보닐;R 6 is hydrogen, acetyl or furancarbonyl;
R7 및 R8은 모두 수소이거나, 함께 옥소를 형성함.R 7 and R 8 are both hydrogen or together form oxo.
본 발명의 또 다른 하나의 목적은 자일라진 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 시력 증강용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for enhancing eyesight comprising xylazine or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명의 하나의 양태는 하기 화학식 1로 표시되는 화합물, 이의 약학적으로 허용가능한 염, 또는 이들의 수화물을 유효성분으로 포함하는 시력 증강용 약학적 조성물을 제공한다:In order to achieve the above object, one aspect of the present invention provides a pharmaceutical composition for enhancing eyesight comprising a compound represented by Formula 1 below, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient:
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1 및 R2는 각각 독립적으로 메틸 또는 에틸;R 1 and R 2 are each independently methyl or ethyl;
R3 내지 R5는 각각 독립적으로 수소, 히드록실 또는 메틸;R 3 to R 5 are each independently hydrogen, hydroxyl or methyl;
R6은 수소, 아세틸 또는 퓨란카보닐;R 6 is hydrogen, acetyl or furancarbonyl;
R7 및 R8은 모두 수소이거나, 함께 옥소를 형성함.R 7 and R 8 are both hydrogen or together form oxo.
예컨대, 상기 화학식 1로 표시되는 화합물은For example, the compound represented by Formula 1
1. 자일라진(xylazine; N-(2,6-디메틸페닐)-5,6-디하이드로 -4H-1,3-티아진-2-아민),1. xylazine (N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazine-2-amine),
2. N-메시틸-5,6-디하이드로-4H-1,3-티아진-2-아민,2. N-mesityl-5,6-dihydro-4H-1,3-thiazin-2-amine;
3. 2-(2-에틸-6-메틸아닐리노)-4,5-디하이드로-6H-1,3-티아진-6-온,3. 2-(2-ethyl-6-methylanilino)-4,5-dihydro-6H-1,3-thiazin-6-one;
4. N-(2-에틸-6-메틸페닐)-N-(6-옥소-5,6-디하이드로-4H-1,3-티아진-2-일)아세트아미드,4. N-(2-ethyl-6-methylphenyl)-N-(6-oxo-5,6-dihydro-4H-1,3-thiazin-2-yl)acetamide;
5. N-(2-에틸-6-메틸페닐)-N-(6-옥소-5,6-디하이드로-4H-1,3-티아진-2-일)-2-퓨라미드,5. N-(2-ethyl-6-methylphenyl)-N-(6-oxo-5,6-dihydro-4H-1,3-thiazin-2-yl)-2-puramide;
6. 3-(5,6-디하이드로-4H-1,3-티아진-2-일아미노)-2,4-디메틸페놀,6. 3-(5,6-dihydro-4H-1,3-thiazin-2-ylamino)-2,4-dimethylphenol;
7. N-(2,6-디메틸페닐)-N-(6-옥소-5,6-디하이드로-4H-1,3-티아진-2-일)-3- 퓨라미드,7. N-(2,6-dimethylphenyl)-N-(6-oxo-5,6-dihydro-4H-1,3-thiazin-2-yl)-3-puramide;
8. N-(2-에틸-6-메틸페닐)-5,6-디하이드로-4H-1,3-티아진-2-아민,8. N-(2-ethyl-6-methylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine;
9. N-(2,6-디에틸페닐)-5,6-디하이드로-4H-1,3-티아진-2-아민,9. N-(2,6-diethylphenyl)-5,6-dihydro-4H-1,3-thiazine-2-amine;
10. N-(5,6-디하이드로-4H-1,3-티아진-2-일)-N-(2,6-디메틸페닐)아세트아미드,10. N-(5,6-dihydro-4H-1,3-thiazin-2-yl)-N-(2,6-dimethylphenyl)acetamide;
11. N-(2,3,5,6-테트라메틸페닐)-5,6-디하이드로-4H-1,3-티아진-2-아민, 또는11. N-(2,3,5,6-tetramethylphenyl)-5,6-dihydro-4H-1,3-thiazine-2-amine, or
12. 4-(5,6-디하이드로-4H-1,3-티아진-2-일아미노)-3,5-디메틸페놀일 수 있다.12. 4-(5,6-dihydro-4H-1,3-thiazin-2-ylamino)-3,5-dimethylphenol.
본 발명은 종래 진정작용, 근육이완 또는 진통(鎭痛)의 목적으로 사용되는 자일라진의 전혀 새로운 용도를 발견한 것이 특징으로, 자일라진을 조절된 농도로 투여시 암반응 조건에서 빛에 대한 반응성이 현저히 향상됨을 발견한 것에 기초한다. 구체적으로, 본 발명자들은 실험용 원숭이 모델을 고정하기 위한 운동을 제한하는 수준의 용량으로 자일라진을 함유하는 마취제를 투여한 경우, 케타민 또는 조레틸을 투여한 경우에 비해 암반응 조건에서 현저히 향상된 빛에 대한 반응성을 나타내는 것을 확인하였다.The present invention is characterized by the discovery of a completely new use of xylazine, which is conventionally used for the purpose of sedation, muscle relaxation, or analgesia. based on what was found to be significantly improved. Specifically, when the present inventors administered an anesthetic containing xylazine at a dose limiting movement for fixing a laboratory monkey model, compared to the case of administering ketamine or zoretil, the present inventors observed significantly improved light response under dark reaction conditions. Reactivity was confirmed.
본 발명의 용어, "자일라진(xylazine)"은 하기 화학식 1-1의 구조를 갖는 화합물을 의미한다. 자일라진은 진정 효과, 근육이완 효과, 진통 효과 등의 다양한 약리학적 특성을 가지고 있다고 알려져 있으나, 이의 시력 증강 효과는 알려진 바 없었으며, 본 발명자에 의하여 최초로 규명되었다.As used herein, the term "xylazine" refers to a compound having a structure represented by Formula 1-1 below. Xylazine is known to have various pharmacological properties such as sedation, muscle relaxation, and analgesia, but its visual acuity enhancing effect has not been known and was first identified by the present inventors.
[화학식 1-1][Formula 1-1]
본 발명의 용어, "약학적으로 허용 가능한 염"은 양이온과 음이온이 정전기적 인력에 의해 결합하고 있는 물질인 염 중에서도 약제학적으로 사용될 수 있는 형태의 염을 의미하며, 통상적으로 금속염, 유기염기와의 염, 무기산과의 염, 유기산과의 염, 염기성 또는 산성 아미노산과의 염 등이 될 수 있다. 예를 들어, 금속염으로는 알칼리 금속염(나트륨염, 칼륨염 등), 알칼리 토금속염(칼슘염, 마그네슘염, 바륨염 등), 알루미늄염 등이 될 수 있고; 유기염기와의 염으로는 트리에틸아민, 피리딘, 피콜린, 2,6-루티딘, 에탄올아민, 디에탄올아민, 트리에탄올아민, 시클로헥실아민, 디시클로헥실아민, N,N-디벤질에틸렌디아민 등과의 염이 될 수 있으며; 무기산과의 염으로는 염산, 브롬화수소산, 질산, 황산, 인산 등과의 염이 될 수 있고; 유기산과의 염으로는 포름산, 아세트산, 트리플루오로아세트산, 프탈산, 푸마르산, 옥살산, 타르타르산, 말레인산, 시트르산, 숙신산, 메탄술폰산, 벤젠술폰산, p-톨루엔술폰산 등과의 염이 될 수 있으며; 염기성 아미노산과의 염으로는 아르기닌, 라이신, 오르니틴 등과의 염이 될 수 있고; 산성 아미노산과의 염으로는 아스파르트산, 글루탐산 등과의 염이 될 수 있다.As used herein, the term "pharmaceutically acceptable salt" refers to a salt in a form that can be used pharmaceutically among salts in which cations and anions are bonded by electrostatic attraction, and is usually combined with metal salts and organic bases. salts, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. For example, the metal salt may be an alkali metal salt (sodium salt, potassium salt, etc.), an alkaline earth metal salt (calcium salt, magnesium salt, barium salt, etc.), aluminum salt and the like; Salts with organic bases include triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine It can be a salt with; Salts with inorganic acids may be salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like; Salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like; A salt with a basic amino acid may be a salt with arginine, lysine, ornithine, and the like; A salt with an acidic amino acid may be a salt with aspartic acid or glutamic acid.
본 발명의 용어, "시력(visual acuity)"은 눈의 빛에 대해 반응하는 능력을 의미하는 것으로, 본 발명에서 구체적으로 시각세포인 원추 세포 또는 간상 세포의 빛에 대한 반응 능력을 의미하는 것일 수 있으나, 이에 제한되는 것은 아니다.As used herein, the term "visual acuity" refers to the ability of the eye to respond to light, and in the present invention, it may specifically mean the ability of cone cells or rod cells, which are visual cells, to respond to light. However, it is not limited thereto.
본 발명의 용어, "증강"은 자일라진 또는 이의 유도체를 포함하는 조성물의 투여로 시력과 관련된 파라미터를 이롭게 변경하는 모든 작용을 의미하는 것으로, 본 발명에서 구체적으로 빛에 대한 반응성 향상을 의미하는 것일 수 있으며, 보다 구체적으로 암반응에서 빛의 반응성 향상을 의미하는 것일 수 있으나, 이에 제한되는 것은 아니다. 상기 본 발명의 용어, "암반응"은 암순응과 혼용하여 사용할 수 있으며, 이와 대응되는 용어인 "명반응" 역시 "명순응"과 혼용할 수 있다.As used herein, the term "enhancement" refers to any action that beneficially changes parameters related to visual acuity by administration of a composition containing xylazine or a derivative thereof, and in the present invention, it specifically refers to enhancement of responsiveness to light. It may, more specifically, may mean an improvement in the reactivity of light in the dark reaction, but is not limited thereto. The term "dark response" of the present invention can be used interchangeably with dark adaptation, and the corresponding term "light response" can also be used interchangeably with "light adaptation".
본 발명에서, 상기 시력 증강은 암반응에서 빛에 대한 반응성 향상을 통해 달성되는 것일 수 있다.In the present invention, the enhancement of visual acuity may be achieved by improving responsiveness to light in a dark reaction.
본 발명의 구체적인 일 실시예에서는, 케타민(ketamine)과 자일라진을 투여한 경우, 케타민을 단독으로 투여한 경우 및 조레틸(zoletile)을 단독으로 투여한 경우와 비교하여 암반응에서 빛의 수용성이 현저히 향상되는 것을 확인하였다(도 3). 이는, 자일라진은 암반응에서 빛의 수용성을 현저히 향상시키므로, 시력 증강에 유용하게 사용될 수 있음을 시사하는 것이다.In a specific embodiment of the present invention, compared to the case of administering ketamine and xylazine, the case of administering ketamine alone, and the case of administering zoletile alone, the acceptance of light in the dark reaction is significantly It was confirmed that the improvement (FIG. 3). This suggests that xylazine can be usefully used for visual acuity enhancement because it significantly improves light acceptance in the dark reaction.
본 발명의 약학적 조성물은 야맹증 등의 완화 또는 개선에 사용될 수 있다. 또는 야맹증이 발병하지 않은 경우라도 야간 작업 등 조도가 낮은 열악한 환경에서의 시력 향상을 위해 사용될 수 있다.The pharmaceutical composition of the present invention can be used to alleviate or improve night blindness. Alternatively, even when night blindness is not developed, it can be used to improve eyesight in poor environments with low illumination such as night work.
본 발명의 약학적 조성물은, 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 추가로 포함할 수 있는데, 상기 담체는 비자연적 담체(non-naturally occuring carrier)를 포함할 수 있다.The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent, and the carrier may include a non-naturally occurring carrier.
구체적으로, 상기 약학적 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, 폴리카프로락톤(polycaprolactone), 폴리락틱액시드(Poly Lactic Acid), 폴리-L-락틱액시드(poly-L-lactic acid), 광물유 등을 들 수 있다. Specifically, carriers, excipients and diluents that may be included in the pharmaceutical composition 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, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, polycaprolactone, polylactic acid ( Poly Lactic Acid), poly-L-lactic acid, Mineral oil etc. are mentioned.
상기 약학적 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 구체적으로 본 발명의 약학적 조성물은 안구 외용제형, 즉 점안투여하기 적합한 형태일 수 있으며, 예를 들어, 점안제, 크림제, 연고제, 겔제 또는 로션제로 제형화하여 사용될 수 있으나, 이에 제한되는 것은 아니다. The pharmaceutical composition may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods. Specifically, the pharmaceutical composition of the present invention may be in the form of an external ocular dosage form, that is, a form suitable for eye drop administration, and may be formulated into, for example, eye drops, creams, ointments, gels, or lotions, but is not limited thereto. .
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. When formulated, it may be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 추출물과 이의 분획물들에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘 카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용될 수 있다. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient such as starch, calcium carbonate, It may be prepared by mixing sucrose or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium styrate and talc may also be used.
경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당 되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. Liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. have.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제 등이 포함될 수 있다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다.Formulations for parenteral administration may include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, suppositories, and the like. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
본 발명의 약학적 조성물에 포함된 화학식 1의 화합물의 함량은 특별히 이에 제한되지 않으나, 최종 조성물 총 중량을 기준으로 0.0001 내지 80 중량%, 0.0001 내지 50 중량%, 보다 구체적으로 0.01 내지 20 중량%의 함량으로 포함될 수 있다.The content of the compound of
본 발명의 다른 하나의 양태는 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 시력 증강 방법을 제공한다.Another aspect of the present invention provides a vision enhancement method comprising administering the pharmaceutical composition to a subject.
이때, 상기 '시력' 및 '증강'에 대한 설명은 전술한 바와 같다.At this time, the description of the 'visual acuity' and 'enhancement' is as described above.
본 발명의 약학적 조성물은 시력 증강 효과를 나타내므로, 이를 개체에 투여하는 단계를 포함하는 본 발명의 방법은 시력 증강에 유용하게 활용될 수 있다.Since the pharmaceutical composition of the present invention exhibits a visual acuity enhancing effect, the method of the present invention comprising the step of administering it to a subject can be usefully utilized for visual acuity enhancement.
본 발명의 용어, "개체"는 인간을 포함한 모든 동물, 예를 들어, 원숭이, 개, 고양이, 토끼, 모르모트, 랫트, 마우스, 소, 양, 돼지, 염소, 조류, 어류 등을 의미하고, 구체적인 예로, 인간을 포함한 포유동물일 수 있으나, 이에 제한되는 것은 아니다.As used herein, the term "subject" refers to all animals including humans, for example, monkeys, dogs, cats, rabbits, guinea pigs, rats, mice, cows, sheep, pigs, goats, birds, fish, etc. For example, it may be mammals including humans, but is not limited thereto.
본 발명의 용어, "투여"는 적절한 방법으로 개체에게 상기 조성물을 도입하는 것을 의미하며, 투여 경로는 목적 조직에 도달할 수 있는 한 다양한 경로를 통하여 투여될 수 있다. 구체적으로, 본 발명의 약학적 조성물은 경구, 정맥 내, 피하, 피 내, 비강 내, 복강 내, 근육 내, 경피 등으로 투여될 수 있고, 국부적 치료를 위해 필요하다면 병변 내 투여를 포함하는 적합한 방법 및 경로에 의해 투여될 수 있다. 예를 들어, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관 내 주사에 의해 투여될 수 있으나, 이에 제한되는 것은 아니다.As used herein, the term "administration" refers to introducing the composition into a subject by an appropriate method, and the route of administration may be administered through various routes as long as it can reach the target tissue. Specifically, the pharmaceutical composition of the present invention can be administered orally, intravenously, subcutaneously, intradermally, intranasally, intraperitoneally, intramuscularly, transdermally, etc., and, if necessary, suitable for local treatment, including intralesional administration. It can be administered by methods and routes. For example, it may be administered by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebrovascular injection, but is not limited thereto.
본 발명의 시력 증강 방법으로 상기 약학적 조성물을 약학적으로 유효한 양으로 투여할 수 있다.According to the vision enhancement method of the present invention, the pharmaceutical composition may be administered in a pharmaceutically effective amount.
본 발명에서 용어, "약학적으로 유효한 양"은 의학적 치료 또는 예방에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료 또는 예방하기에 충분한 양을 의미하며, 유효 용량 수준은 질환의 중증도, 약물의 활성, 환자의 연령, 체중, 건강, 성별, 환자의 약물에 대한 민감도, 사용된 본 발명 조성물의 투여 시간, 투여 경로 및 배출 비율 치료기간, 사용된 본 발명의 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 단독으로 투여하거나 공지된 익상편 치료제와 병용하여 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하다.As used herein, the term "pharmaceutically effective amount" means an amount sufficient to treat or prevent a disease at a reasonable benefit/risk ratio applicable to medical treatment or prevention, and the effective dose level is dependent on the severity of the disease and the activity of the drug. , patient's age, weight, health, sex, patient's sensitivity to drugs, administration time of the composition of the present invention used, route of administration and excretion rate treatment period, including drugs used in combination or simultaneous use with the composition of the present invention used factors and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered alone or in combination with a known therapeutic agent for pterygium. It is important to administer the amount that can obtain the maximum effect with the minimum amount without side effects in consideration of all the above factors.
또한, 상기 약학적 조성물의 투여량은 사용목적, 질환의 중독도, 환자의 연령, 체중, 성별, 기왕력, 또는 유효성분으로서 사용되는 물질의 종류 등을 고려하여 당업자가 결정할 수 있다. 예를 들어, 본 발명의 약학적 조성물은 성인 1인당 1㎎/㎏ 내지 200㎎/㎏, 구체적으로 1㎎/㎏ 내지 100㎎/㎏, 더욱 구체적으로 20 내지 40㎎/㎏로 투여할 수 있고, 본 발명의 조성물의 투여빈도는 특별히 이에 제한되지 않으나, 1일 1회 투여하거나 또는 용량을 분할하여 수회 투여할 수 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.In addition, the dose of the pharmaceutical composition can be determined by those skilled in the art in consideration of the purpose of use, the degree of addiction of the disease, the patient's age, weight, sex, history, or the type of substance used as an active ingredient. For example, the pharmaceutical composition of the present invention can be administered at 1 mg/kg to 200 mg/kg, specifically 1 mg/kg to 100 mg/kg, and more specifically 20 to 40 mg/kg per adult, , The frequency of administration of the composition of the present invention is not particularly limited thereto, but may be administered once a day or administered several times by dividing the dose. The dosage is not intended to limit the scope of the present invention in any way.
구체적인 예로서, 본 발명의 약학적 조성물은 유효성분의 실제 사용량을 기준으로, i) 혈관주사에 의해 투여하는 경우, 0.001 내지 1 mg/kg bw(단위 mg/kg bw는 체중 1 kg 당 유효성분의 투여량 mg을 의미함)로, ii) 근육주사에 의해 투여하는 경우, 0.005 내지 10 mg/kg bw로 조절하여 투여하는 등 투여 방법에 따라 투여량을 결정할 수 있다. 또한, 개체별 민감도에 차이가 있을 수 있으므로, 실제 적용 가능한 투여량은 상기 혈관주사에 의한 투여 및 근육주사에 의한 투여 방법에서 제시한 투여량의 0.1% 내지 1000% 사이에서 결정될 수 있다. 혈관주사 또는 근육주사 이외의 방법으로 투여하는 경우, 예컨대, 점안액으로 안구에 직접 투여하는 경우에도 상기 제시한 투여량의 0.1% 내지 1000% 범위에서 결정되는 용량으로 투여할 수 있으며, 이러한 경우에도 개체별 민감도에 따른 차이를 고려하여야 하며 이에 따른 추가적인 편차가 존재할 수 있다. 예컨대, 상기 약학적 조성물의 투여는 1일 1회 투여하거나 용량을 분할하여 수회 투여할 수 있으며, 정기적인 투여가 아니더라도 시력 증강을 필요로 하는 경우 적정 용량으로 투여할 수 있다. 그러나, 상기 투여량은 예시일 뿐, 본 발명의 범주가 이에 한정되는 것은 아니다.As a specific example, the pharmaceutical composition of the present invention, based on the actual amount of the active ingredient, i) when administered by intravascular injection, 0.001 to 1 mg / kg bw (unit mg / kg bw is the active ingredient per kg of body weight ii) In the case of administration by intramuscular injection, the dosage may be determined according to the administration method, such as administration by adjusting to 0.005 to 10 mg/kg bw. In addition, since there may be differences in individual sensitivity, the actual applicable dosage may be determined between 0.1% and 1000% of the dosage suggested in the administration by intravascular injection and administration by intramuscular injection. When administered by a method other than intravascular injection or intramuscular injection, for example, when administered directly to the eye as an eye drop, it can be administered at a dose determined in the range of 0.1% to 1000% of the above-mentioned dose, and even in this case, the subject Differences according to individual sensitivities should be considered, and additional deviations may exist accordingly. For example, the pharmaceutical composition may be administered once a day or administered several times by dividing the dose, and may be administered in an appropriate dose when vision enhancement is required even if not regularly administered. However, the dosage is only an example, and the scope of the present invention is not limited thereto.
구체적인 예로서, 본 발명의 약학적 조성물은 유효성분의 실제 사용량을 기준으로, 남성에 투여하는 양의 50 내지 90%를 여성에 투여할 수 있다. 그러나, 상기 투여량은 예시일 뿐, 본 발명의 범주가 이에 한정되는 것은 아니다.As a specific example, the pharmaceutical composition of the present invention can be administered to women at 50 to 90% of the amount administered to men based on the actual amount of the active ingredient. However, the dosage is only an example, and the scope of the present invention is not limited thereto.
본 발명의 또 다른 하나의 양태는 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 시력 증강용 의약외품 조성물을 제공한다.Another aspect of the present invention provides a quasi-drug composition for enhancing eyesight comprising the compound of
구체적인 예로서, 본 발명의 약학적 조성물은 유효성분의 실제 사용량을 기준으로, i) 혈관주사에 의해 투여하는 경우, 0.001 내지 1 mg/kg bw(단위 mg/kg bw는 체중 1 kg 당 유효성분의 투여량 mg을 의미함)로, ii) 근육주사에 의해 투여하는 경우, 0.005 내지 10 mg/kg bw로 조절하여 투여하는 등 투여 방법에 따라 투여량을 결정할 수 있다. 또한, 개체별 민감도에 차이가 있을 수 있으므로, 실제 적용 가능한 투여량은 상기 혈관주사에 의한 투여 및 근육주사에 의한 투여 방법에서 제시한 투여량의 0.1% 내지 1000% 사이에서 결정될 수 있다. 혈관주사 또는 근육주사 이외의 방법으로 투여하는 경우, 예컨대, 점안액으로 안구에 직접 투여하는 경우에도 상기 제시한 투여량의 0.1% 내지 1000% 범위에서 결정되는 용량으로 투여할 수 있으며, 이러한 경우에도 개체별 민감도에 따른 차이를 고려하여야 하며 이에 따른 추가적인 편차가 존재할 수 있다. 예컨대, 상기 약학적 조성물의 투여는 1일 1회 투여하거나 용량을 분할하여 수회 투여할 수 있으며, 정기적인 투여가 아니더라도 시력 증강을 필요로 하는 경우 적정 용량으로 투여할 수 있다. 그러나, 상기 투여량은 예시일 뿐, 본 발명의 범주가 이에 한정되는 것은 아니다.As a specific example, the pharmaceutical composition of the present invention, based on the actual amount of the active ingredient, i) when administered by intravascular injection, 0.001 to 1 mg / kg bw (unit mg / kg bw is the active ingredient per kg of body weight ii) In the case of administration by intramuscular injection, the dosage may be determined according to the administration method, such as administration by adjusting to 0.005 to 10 mg/kg bw. In addition, since there may be differences in individual sensitivity, the actual applicable dosage may be determined between 0.1% and 1000% of the dosage suggested in the administration by intravascular injection and administration by intramuscular injection. When administered by a method other than intravascular injection or intramuscular injection, for example, when administered directly to the eye as an eye drop, it can be administered at a dose determined in the range of 0.1% to 1000% of the above-mentioned dose, and even in this case, the subject Differences according to individual sensitivities should be considered, and additional deviations may exist accordingly. For example, the pharmaceutical composition may be administered once a day or administered several times by dividing the dose, and may be administered in an appropriate dose when vision enhancement is required even if not regularly administered. However, the dosage is only an example, and the scope of the present invention is not limited thereto.
본 발명의 또 다른 하나의 양태는 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 시력 증강용 의약외품 조성물을 제공한다.Another aspect of the present invention provides a quasi-drug composition for enhancing eyesight comprising the compound of
본 발명의 또 다른 하나의 양태는 자일라진 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 시력 증강용 식품 조성물을 제공한다. Another aspect of the present invention provides a food composition for enhancing eyesight comprising xylazine or a pharmaceutically acceptable salt thereof as an active ingredient.
이때, 상기 용어 '자일라진', '약학적으로 허용 가능한 염', '시력' 및 '증강'의 정의는 전술한 바와 같다.In this case, the definitions of the terms 'xylazine', 'pharmaceutically acceptable salt', 'visual acuity' and 'enhancement' are as described above.
본 발명에서 용어, "식품"은 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올음료, 비타민 복합제, 건강기능식품 등의 통상적인 의미에서의 식품을 모두 포함하며, 본 발명의 숲개밀 추출물 또는 이의 분획물을 포함할 수 있는 한, 이에 제한되지 않는다. 또한 환제, 분말, 과립, 침제, 정제, 캡슐 또는 액제 등의 형태를 포함할 수 있다.As used herein, the term "food" refers to meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, chewing gum, dairy products including ice cream, various soups, beverages, tea, drinks, and alcoholic beverages. , Vitamin complexes, including all foods in the conventional sense, such as health functional foods, and are not limited thereto, as long as they can include the Brasil wheat extract or a fraction thereof of the present invention. It may also include forms such as pills, powders, granules, infusions, tablets, capsules or liquids.
본 발명에서 용어, "건강기능식품"은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, '기능성'은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻는 것을 의미한다. 한편, 건강식품은 일반식품에 비해 적극적인 건강유지나 증진 효과를 가지는 식품을 의미하고, 건강보조식품은 건강 보조 목적의 식품을 의미하는데, 경우에 따라, 건강기능식품, 건강식품, 건강보조식품의 용어는 혼용될 수 있다. 본 발명의 건강기능식품은 당 업계에서 통상적으로 사용되는 방법에 의하여 제조 가능하다. 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고 휴대성이 뛰어날 수 있다.In the present invention, the term "health functional food" refers to food manufactured and processed using raw materials or ingredients having useful functionalities for the human body in accordance with Health Functional Food Act No. 6727, and 'functionality' refers to the structure of the human body. and to obtain useful effects for health uses such as regulating nutrients with respect to functions or physiological actions, and the like. On the other hand, health food refers to food that has an active health maintenance or promotion effect compared to general food, and health supplement food refers to food for the purpose of supplementing health. In some cases, the terms of health functional food, health food, and health supplement food can be mixed. The health functional food of the present invention can be prepared by a method commonly used in the art. It can be manufactured in various types of formulations, and unlike general drugs, it has the advantage of not having side effects that can occur when taking drugs for a long time by using food as a raw material, and can have excellent portability.
상기 식품 조성물 제조 시에는 당 업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있으며, 그 종류는 특별히 제한되지 않는다. 예를 들어, 통상의 식품과 같이 여러 가지 생약 추출물, 식품학적으로 허용 가능한 식품보조첨가제 또는 천연 탄수화물 등을 추가 성분으로 포함할 수 있으며, 이에 제한되지 않는다.When preparing the food composition, it may be prepared by adding raw materials and ingredients commonly added in the art, and the type is not particularly limited. For example, it may include various herbal extracts, food-acceptable food additives, or natural carbohydrates as additional ingredients, like conventional foods, but is not limited thereto.
본 발명의 자일라진은 시력 증강 효과를 나타낼 수 있다면 식품 조성물에 다양한 중량%로 포함될 수 있다. 구체적으로 식품 조성물의 총 중량 대비 0.00001 내지 100 중량% 또는 0.01 내지 80 중량%로 포함될 수 있으나, 이에 제한되지 않는다. 건강 및 위생을 목적으로 장기간 섭취할 경우에는 상기 범위 이하의 함량을 포함할 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.Xylazine of the present invention can be included in various weight percent in food compositions if it can exhibit a visual acuity enhancing effect. Specifically, it may be included in 0.00001 to 100% by weight or 0.01 to 80% by weight based on the total weight of the food composition, but is not limited thereto. In the case of long-term intake for health and hygiene purposes, the content below the above range may be included, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
본 발명의 자일라진 또는 이의 유도체는 암반응에서 우수한 빛에 대한 반응성 향상 효과를 나타내므로, 약학적 조성물, 의약외품 조성물 또는 식품 조성물에 유효성분으로 포함되어 시력 증강제 등의 개발에 이용될 수 있다.Since xylazine or a derivative thereof of the present invention exhibits an excellent light responsiveness improvement effect in the dark reaction, it can be included as an active ingredient in a pharmaceutical composition, quasi-drug composition, or food composition and used in the development of vision enhancers and the like.
도 1은 망막전위를 측정하기 위한, 일렉트로-레티노-그램(Electro-retino-gram; ERG) 테스트를 하기 위한 실험 장면 및 그 방법을 나타낸다.
도 2는 데이터 분석 방법을 나타내는 것으로, 가는 실선은 실제 40개 눈의 실험 데이터 값에 해당하며, 굵은 실선은 그 평균 값에 해당한다.
도 3은 ERG 테스트 중 암반응에서 자일라진의 영향을 나타내는 것으로, A는 눈의 구조를 나타낸 이미지, B는 ERG 테스트 암반응 0.01 빛의 세기(ERG dark-adapted 0.01)에서 망막전위 변화를 나타낸 그래프, C는 ERG 테스트 암반응 3 빛의 세기(ERG dark-adapted 3)에서 망막전위 변화를 나타낸 그래프, D는 ERG 테스트 암반응 10 빛의 세기(ERG dark-adapted 10)에서 망막전위 변화를 나타낸 그래프에 해당한다. 실험군으로는 케타민과 자일라진을 병용하였으며, 비교군으로 케타민 또는 졸레틸을 단독으로 사용한 군을 사용하였다. 각 실험군 및 비교군에 대해 획득한 그래프를 그릴 때, 초기 시간에 대한 전위 값을 일치시키는 영점 조정을 하였다. (이때, *p<0.05, **p<0.01, ***p<0.001)
도 4는 ERG 테스트 명반응에서 자일라진의 영향을 나타내는 것으로, A는 ERG 테스트 명반응 3 빛의 세기(ERG light-adapted 3)에서 망막전위 변화를 나타낸 그래프, B는 ERG 테스트 명반응 빛의 60 Hz 깜빡임(ERG light-adapted 30 Hz flicker)에서 망막전위 변화를 나타낸 그래프에 해당한다.
도 5는, 상기 도 3 및 도 4에 나타난 그래프들에 대한, 영점 조정에 의해 초기 시간에 대한 전위 값을 일치시키지 않은 그래프들을 중첩하여 나타낸 도이다.
도 6은 ERG 테스트 암반응 3 빛의 세기(dark-adapted 3 ERG)에서 동량의 자일라진이 수컷에 비해 암컷의 망막전위에 보다 큰 변화를 유발함을 나타낸 도이다. 그래프의 세로축은 마이크로볼트(μV) 단위이며, 가로축은 밀리초(msec) 단위이다. 검은색 선은 암컷에 대한 결과를, 회색 선은 수컷에 대한 결과를 나타낸다.1 shows an experimental scene and method for performing an electro-retino-gram (ERG) test for measuring retinal potential.
2 shows a data analysis method, the thin solid line corresponds to the experimental data values of 40 eyes, and the thick solid line corresponds to the average value.
Figure 3 shows the effect of xylazine on the dark response during the ERG test, A is an image showing the structure of the eye, B is a graph showing the change in retinal potential at the ERG test dark response 0.01 light intensity (ERG dark-adapted 0.01), C Corresponds to a graph showing changes in retinal potential at ERG test
Figure 4 shows the effect of xylazine on the ERG test light response, A is a graph showing the change in retinal potential in the ERG test
FIG. 5 is a diagram showing the graphs shown in FIGS. 3 and 4 by overlapping graphs in which potential values at initial times are not matched by zero point adjustment.
6 is a diagram showing that the same amount of xylazine induces a greater change in retinal potential in females than in males in the ERG test dark-adapted 3 light intensity (dark-adapted 3 ERG). The vertical axis of the graph is in microvolt (μV) units, and the horizontal axis is in millisecond (msec) units. The black line represents the female results, and the gray line represents the male results.
이하, 하기 실시예에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples are only for exemplifying the present invention, and the scope of the present invention is not limited only to these.
실험예 1. 실험동물Experimental Example 1. Experimental animals
실험에 사용된 원숭이는 시노몰구스(cynomolgus) 원숭이라고도 불리는 게잡이 원숭이(Macaca fascicularis)로서, 특별히 CITES(the convention on International Trade in Endangered Species of Wild Fauna and Flora) 및/또는 동물보호법 등을 고려하여 실험용 목적으로 사육된 것을 베트남 및 중국에서 수입하였다. 우리는 4세 및 7세의 성숙한 원숭이를 사용하였다. 총 20마리의 원숭이는 10마리의 수컷과 10마리의 암컷으로 구성하였다. 원숭이들은 적어도 30일 동안 실험 시설에 적응기간을 가졌다. B 바이러스 감염(Cercopithecine herpesvirus), 결핵(tuberculosis), 살모넬라증(salmonellosis), 세균성 이질(shigellosis), 여시니아증(yersiniosis) 및 내부- 또는 외부-기생충, 및 원숭이 두창(monkey pox), 홍역(measles) 등을 포함하는 다른 동물매개 질환(zoonotic diseases)으로부터 자유로웠다. 검역기간(quarantine period) 동안, 질병 스크리닝을 위해 실시된 검사의 결과는 각각의 원숭이를 추적할 수 있도록 실험 시설 보관소에 보관하였다. 상기 본 발명에서 진행한 동물실험은 동물실험윤리위원회(Institutional Animal Care and Use Committee, IACUC)의 심의를 통과하였다.The monkey used in the experiment was a crab-eater (Macaca fascicularis), also called a cynomolgus monkey. Those bred for experimental purposes were imported from Vietnam and China. We used adult monkeys aged 4 and 7 years. A total of 20 monkeys consisted of 10 males and 10 females. The monkeys were allowed to acclimate to the experimental facility for at least 30 days. Cercopithecine herpesvirus, tuberculosis, salmonellosis, shigellosis, yersiniosis and endo- or ectoparasites, and monkey pox, measles free from other zoonotic diseases, including During the quarantine period, the results of tests performed for disease screening were kept in laboratory facility archives to track each monkey. The animal experiments conducted in the present invention passed the deliberation of the Institutional Animal Care and Use Committee (IACUC).
실험예Experimental example 2. 2. 망막전위도검사물체Electroretinogram test object ( ( ElectroretinographyElectroretinography ; ERG); ERG)
ERG 테스트는 국제임상시각전기생리학회(International Society for Clinical Electrophysiology of Vision; ISCEV, Daphne L. McCulloch 2015)의 표준 프로토콜을 따랐으며, RETIcom 플래시(Ronald Consult S & F GmbH, Germany)를 사용하였다. 접지 전극(ground electrode)은 이마의 중앙에 삽입하였으며, 기준 전극(reference electrode)은 외안각(lateral canthi)의 바깥쪽으로 설정하였다. 국소마취제로 0.5% 프로파라케인 하이드로클로라이드 점안액(proparacaine hydrochloride ophthalmic solution; Alcaine®, Alcon, USA)을 각막에 도포하고, 각막 보호를 위해 2% 하이프로멜로스 용액(hypromellose solution; Hycell ophthalmic solution, Samil pharm., Korea)을 도포하였다. 이후, ERGjetTM 각막 렌즈 전극을 0.2% 포비돈-요오드 용액(povidone-iodone solution)으로 세척 후 각막에 위치시켰다. 파형을 모니터링하여 전기적 간섭에 의해 생성된 아티팩트(artifacts)를 확인하였다. 광원인 Mini-Ganzfeld를 테스트를 위해 각막 앞에 위치시켰으며, 한 쪽 눈을 테스트하는 동안, 다른 쪽 눈에 들어가는 빛은 패치로 차단하였다(도 1). ISCEV 표준 ERG 시리즈에 정의된 프로토콜의 적응 상태를 다음과 같이 인용한다:The ERG test followed the standard protocol of the International Society for Clinical Electrophysiology of Vision (ISCEV, Daphne L. McCulloch 2015) and used a RETIcom flash (Ronald Consult S & F GmbH, Germany). A ground electrode was inserted in the center of the forehead, and a reference electrode was set outside the lateral canthi. 0.5% proparacaine hydrochloride ophthalmic solution (Alcaine®, Alcon, USA) was applied to the cornea as a local anesthetic, and 2% hypromellose solution (Hycell ophthalmic solution, Samil pharm., Korea) was applied. Then, the ERGjetTM corneal lens electrode was washed with 0.2% povidone-iodone solution and placed on the cornea. The waveform was monitored to identify artifacts created by electrical interference. A light source, Mini-Ganzfeld, was placed in front of the cornea for testing, and while testing one eye, light entering the other eye was blocked with a patch (FIG. 1). We cite the adaptation status of the protocol defined in the ISCEV standard ERG series as follows:
1. 암순응 0.01 ERG - 양극 세포(bipolar cells)에서의 간상(rod) 집중 응답1. Dark adaptation 0.01 ERG - rod focused response in bipolar cells
2. 암순응 3 ERG - 광수용체(photoreceptors) 및 간상(rod) 및 원추(cone) 시스템의 양극 세포에서 발생하는 결합 응답; 간상 우세2. scotopic 3 ERG - coupled response that occurs in photoreceptors and bipolar cells of the rod and cone system; rod predominance
3. 암순응 10 ERG - 광수용체 기능을 반영하는 강화된 a-파와 결합 응답3.
4. 암순응 진동 전위(oscillatory potentials) - 주로 무축삭 세포(amacrine cells)로부터의 응답4. Oscillatory potentials - responses mainly from amacrine cells
5. 명순응 3 ERG - 간상 시스템의 응답; a-파는 원추형 광수용체 및 원추형 off-양극 세포로부터 발생; b-파는 on- 및 off-원추형 양극세포로부터 발생5. Photopic 3 ERG - response of the rod system; a-waves arise from cone photoreceptors and cone off-polar cells; b-waves arise from on- and off-conical bipolar cells
6. 명순응 30 Hz 깜빡임 ERG - 민감한 원추-경로-집중 응답6. Photopic 30 Hz Blink ERG - Sensitive Cone-Path-Concentration Response
실험예Experimental example 3. 데이터 분석 방법 3. Data analysis method
실제 40개 눈의 실험 데이터 값의 평균 값을 산출하였으며, 결과는 평균±표준 오차(SE)로 표시하였다(도 2). 정상적으로 분산된 데이터 내 또는 사이의 차이점은 일원분산분석(one-way ANOVA)을 사용하여 분석한 후, Bonferroni post hoc 테스트를 수행하였다. 통계적 유의성은 *p<0.05, **p<0.01, ***p<0.001로 설정하였다.The average value of the experimental data values of the actual 40 eyes was calculated, and the results were expressed as mean ± standard error (SE) (FIG. 2). Differences within or between normally distributed data were analyzed using one-way ANOVA followed by Bonferroni post hoc tests. Statistical significance was set at *p<0.05, **p<0.01, ***p<0.001.
실시예Example 1. One. 자일라진을xylazine 투여한 동물모델의 제조 Manufacturing of administered animal models
마취 전 16시간 동안 원숭이를 금식시켰으며, 과도한 침흘림을 방지하기 위하여 마취제 주입 15분 전 아트로핀(0.01 mg/kg)을 사전 투약하였다. 이후 시각 반응을 확인하기 용이하도록 동공을 확장시키기 위하여 0.5% 트로피카마이드(tropicamide) 및 0.5% 페닐데프린 HCl(phenylephrine HCl)을 포함하는 Mydrin-P Ophthalmic Solution(Santen Pharmaceutical Co., Japan) 방울을 양쪽 눈 동공에 주입하였다. 다음으로 7:0.6 mg/kg 비율의 케타민 HCl 및 자일라진 HCl(xylazine HCl; Rompun®, Byer) 혼합물을 근육주사하여 투여함으로써 동물모델을 준비하였다.Monkeys were fasted for 16 hours before anesthesia, and atropine (0.01 mg/kg) was pre-administered 15 minutes before anesthetic injection to prevent excessive drooling. Afterwards, drops of Mydrin-P Ophthalmic Solution (Santen Pharmaceutical Co., Japan) containing 0.5% tropicamide and 0.5% phenylephrine HCl were added to dilate the pupil to facilitate visual response. It was injected into the pupil of both eyes. Next, an animal model was prepared by intramuscularly administering a mixture of ketamine HCl and xylazine HCl (xylazine HCl; Rompun®, Byer) at a ratio of 7:0.6 mg/kg.
비교예 1 및 2: 케타민 또는 조레틸을 투여한 동물모델의 제조Comparative Examples 1 and 2: Preparation of animal models administered with ketamine or zoretil
7:0.6 mg/kg 비율의 케타민 HCl 및 자일라진 HCl(xylazine HCl; Rompun®, Byer) 혼합물 대신에 각각 10 mg/kg의 케타민 HCl(ketamine HCl; Ketamine 50®, Yuhan Co., Ltd, Korea) 및 25 mg/mL의 졸라제팜(zolazepam) 및 동량의 틸레타민(tiletamine)으로 구성된 4 mg/kg의 조레틸(Zoletil 50®, Virbac)을 투여하는 것을 제외하고는 상기 실시예 1과 동일한 방법으로 동물모델을 제조하였다.Instead of a mixture of ketamine HCl and xylazine HCl (xylazine HCl; Rompun®, Byer) at a ratio of 7:0.6 mg/kg, each 10 mg/kg of ketamine HCl (
실시예 2. 암반응에서 자일라진의 영향 분석Example 2. Analysis of the influence of xylazine in the dark reaction
암반응에서 자일라진의 빛에 대한 반응성 향상 효과를 확인하기 위하여, 상기 세 종류의 마취제에 대하여 0.01, 3 및 10 빛의 세기를 주었을 때 망막전위의 반응을 비교 분석하였다.In order to confirm the effect of improving the responsiveness of xylazine to light in the dark response, the responses of retinal potentials were compared and analyzed when light intensities of 0.01, 3, and 10 were given to the three types of anesthetics.
그 결과, 도 3에서 볼 수 있듯이, 케타민과 자일라진을 투여한 경우, 케타민을 투여한 경우 및 조레틸을 투여한 경우와 비교하여 빛에 대한 반응성이 현저히 향상되는 것을 확인하였다.As a result, as can be seen in FIG. 3 , it was confirmed that when ketamine and xylazine were administered, the responsiveness to light was remarkably improved compared to ketamine and zoretil.
상기 결과를 통해, 자일라진은 암반응에서 빛에 대한 반응성을 현저히 향상시키므로, 시력 증강 효과를 나타낼 수 있음을 알 수 있었다.Through the above results, it was found that since xylazine significantly improves the responsiveness to light in the dark reaction, it can exhibit an effect of enhancing eyesight.
실시예Example 3. 명반응에서 3. In the light reaction 자일라진의of xylazine 영향 분석 Impact Analysis
명반응에서 자일라진의 빛 수용성 향상 효과를 확인하기 위하여, 상기 세 종류의 마취제에 대하여 3 빛의 세기 또는 빛의 30 Hz 깜빡임을 주었을 때 망막전위의 반응을 비교 분석하였다.In order to confirm the effect of xylazine on improving light receptivity in the light response, the retinal potential response was compared and analyzed when 3 light intensities or 30 Hz flickering of light were applied to the three types of anesthetics.
그 결과, 도 4에서 볼 수 있듯이, 케타민과 자일라진을 투여한 경우, 케타민을 투여한 경우 및 조레틸을 투여한 경우와 비교하여 빛에 대한 반응성에 변화가 미미함을 확인하였다.As a result, as can be seen in FIG. 4 , it was confirmed that the change in reactivity to light was insignificant compared to the case of administration of ketamine and xylazine, the case of administration of ketamine, and the case of administration of zoretil.
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로서 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art to which the present invention pertains will be able to understand that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, the embodiments described above should be understood as illustrative in all respects and not limiting. The scope of the present invention should be construed as including all changes or modifications derived from the meaning and scope of the claims to be described later and equivalent concepts rather than the detailed description above are included in the scope of the present invention.
Claims (10)
[화학식 1]
상기 화학식 1에서,
R1 및 R2는 각각 독립적으로 메틸 또는 에틸;
R3 내지 R5는 각각 독립적으로 수소 또는 메틸;
R6은 수소;
R7 및 R8은 모두 수소임.
A pharmaceutical composition for improving the eyesight of an individual in a low-illumination environment or a patient with night blindness, comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient:
[Formula 1]
In Formula 1,
R 1 and R 2 are each independently methyl or ethyl;
R 3 to R 5 are each independently hydrogen or methyl;
R 6 is hydrogen;
R 7 and R 8 are both hydrogen.
[화학식 1]
상기 화학식 1에서,
R1 및 R2는 각각 독립적으로 메틸 또는 에틸;
R3 내지 R5는 각각 독립적으로 수소 또는 메틸;
R6은 수소;
R7 및 R8은 모두 수소임.
A quasi-drug composition for enhancing visual acuity of an individual in a low-illumination environment or a patient with night blindness, comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient:
[Formula 1]
In Formula 1,
R 1 and R 2 are each independently methyl or ethyl;
R 3 to R 5 are each independently hydrogen or methyl;
R 6 is hydrogen;
R 7 and R 8 are both hydrogen.
[화학식 1]
상기 화학식 1에서,
R1 및 R2는 각각 독립적으로 메틸 또는 에틸;
R3 내지 R5는 각각 독립적으로 수소 또는 메틸;
R6은 수소;
R7 및 R8은 모두 수소임.A food composition for improving the eyesight of an individual in a low-illumination environment or a patient with night blindness, comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient:
[Formula 1]
In Formula 1,
R 1 and R 2 are each independently methyl or ethyl;
R 3 to R 5 are each independently hydrogen or methyl;
R 6 is hydrogen;
R 7 and R 8 are both hydrogen.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5459133A (en) | 1992-06-05 | 1995-10-17 | Telor Ophthalmic Pharmaceuticals, Inc. | Methods and products for treating presbyopia |
US6066675A (en) * | 1996-09-13 | 2000-05-23 | The Regents Of The University Of California | Method for treatment of retinal diseases |
WO2007084473A2 (en) | 2006-01-17 | 2007-07-26 | Allergan, Inc. | The use of memantine and brimonidine to attenuate vitreoretinal vascular endothelial growth factor (vegf) protein levels in animals |
WO2018111619A1 (en) | 2016-12-15 | 2018-06-21 | Imprimis Pharmaceuticals, Inc. | Pharmaceutical formulations for treating glaucoma and methods for fabricating and using thereof |
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2020
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5459133A (en) | 1992-06-05 | 1995-10-17 | Telor Ophthalmic Pharmaceuticals, Inc. | Methods and products for treating presbyopia |
US6066675A (en) * | 1996-09-13 | 2000-05-23 | The Regents Of The University Of California | Method for treatment of retinal diseases |
WO2007084473A2 (en) | 2006-01-17 | 2007-07-26 | Allergan, Inc. | The use of memantine and brimonidine to attenuate vitreoretinal vascular endothelial growth factor (vegf) protein levels in animals |
WO2018111619A1 (en) | 2016-12-15 | 2018-06-21 | Imprimis Pharmaceuticals, Inc. | Pharmaceutical formulations for treating glaucoma and methods for fabricating and using thereof |
Non-Patent Citations (1)
Title |
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JOURNAL OF PHARMACEUTICAL RESEARCH (2019), 18(4), PP. 727~733 |
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