TW201906626A - 預防近視用組成物及機能性食品 - Google Patents
預防近視用組成物及機能性食品 Download PDFInfo
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- TW201906626A TW201906626A TW107116438A TW107116438A TW201906626A TW 201906626 A TW201906626 A TW 201906626A TW 107116438 A TW107116438 A TW 107116438A TW 107116438 A TW107116438 A TW 107116438A TW 201906626 A TW201906626 A TW 201906626A
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- ophthalmic composition
- myopia
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Abstract
本發明課題在於提供一種有效用於近視或者眼部疾病的預防或處置的眼科用組成物。尤其是提供一種對易患近視且易惡化的成長期之孩童或青年層,甚而會逐漸出現白內障、青光眼、視網膜剝離、視網膜病變、黃斑病變、脈絡膜新生血管形成、眼後葡萄腫及視神經病變等老年性眼部疾病的中老年層屬有效的眼科用組成物、包含該眼科用組成物的機能性食品、及可尋求該組成物及機能性食品的篩選方法。 解決手段為,藉由含有選自由藏紅花酸及其藥學上可容許之鹽,以及銀杏葉萃取物所成群組的至少1種成分的眼科用組成物或機能性食品,可解決上述課題。
Description
本發明係有關於一種用於近視或者眼部疾病的預防或處置的組成物及機能性食品。更詳而言之,本發明係有關於一種對易患近視或近視易惡化的年齡層,尤為成長期之孩童或青年層屬有效的組成物、對眼部疾病的風險提高的中老年層亦屬有效的組成物、及包含該組成物的機能性食品。
近視的頻率有人種差異。尤其是亞洲人居多,其中日本人為容易近視的人種,-5D以上之深度近視的比例亦高。此外,近年來,近視逐漸全球性地增加,在日本,裸眼視力未達1.0的兒童的比例亦逐年增加。又,已知近視在7歲至12歲的學童期會急遽惡化(參照非專利文獻1)。
根據其發病機制,近視可分類為折射性近視、調節性近視(假性近視)及軸性近視,學童期的近視惡化則主要為軸性近視。人類的眼睛在出生後不久為遠視,隨著成長期的眼軸伸長,遠視的程度逐漸變小,進入學童期視力便轉為正常。此視力正常化現象後的眼軸伸長直接涉及近視,而且眼軸長度一旦伸長,便無法使其復原。從而,一般認為抑制成長期至學童期之期間的眼軸伸長,對於近視預防或處置係屬有效(參照非專利文獻2)。再者,不單在成長期,成人的眼軸也會伸長,據稱成人的眼軸伸長為各種眼部疾病的風險因子,眼軸過度伸長的結果之深度近視,屬其併發症之白內障、青光眼、視網膜剝離、視網膜病變、黃斑病變、脈絡膜新生血管形成、眼後葡萄腫及視神經病變等眼部疾病的危險性會提高(參照非專利文獻2)。因此,抑制眼軸伸長,不僅可因預防近視而獲得QOL改善,亦有關於終至失明之嚴重眼部疾病的預防。
關於對此近視惡化(眼軸過度伸長)的抑制,有人探討各種方法。對此等抑制眼軸伸長相關的過去臨床研究結果進行後設分析,結果按阿托品點眼藥水、哌侖西平眼軟膏、角膜塑型、周邊部散焦型軟式隱形眼鏡、累進多焦點眼鏡之順序對於眼軸長度顯示出統計上顯著的抑制效果。然而,其中仍存留有尚待解決之課題,例如阿托品點眼藥水所顯現的副作用、或角膜塑型等之費用負擔的問題或其手段極繁瑣,而且配戴眼鏡的效果有限等(參照非專利文獻3)。
此外,有人進行此近視惡化(眼軸伸長)之風險因子相關的研究,而指出年齡、性別、遺傳、社會・生活環境等與眼軸伸長息息相關(參照非專利文獻4)。尤其是近距離作業(閱讀寫字、VDT(Visual Display Terminals)作業)的增加及隨之而生的日光(尤為360~400nm的紫光)暴露不足,係屬眼軸伸長之風險因子備受矚目(參照非專利文獻5)。然而,在現代日本社會,要改變讀書、閱讀寫字、VDT作業等以屋內為主的生活型態為不實際者,而要求一種在頻繁從事此種近距離作業而缺乏紫光暴露的生活環境下也能抑制近視惡化的方法。
另一方面,就近視相關之研究,有人自1970年代起便開始嘗試利用動物來闡明眼軸伸長的機制,Wiesel與Raviola以恆河猴(rhesus monkey)證實近視與眼軸伸長的相關性(參照非專利文獻6)。其後,也有人以樹鼩、雞等其他動物來進行,而研究出近視動物模型(參照非專利文獻7,8)。有人報導多種與眼軸伸長、罹患近視有關之基因,EGR-1/ZENK1亦為其中之一。就EGR-1基因剔除小鼠,可看出眼軸伸長與出現近視,暗示EGR-1與眼軸伸長有關(參照非專利文獻9)。然而,經剔除EGR-1的小鼠雖可看出眼軸伸長與近視的惡化,而對於僅為多數存在的近視相關基因之一的EGR-1,尚未確定在體外可增強其表現的藥劑,在體外實際上是否可抑制眼軸伸長而抑制近視惡化。 [先前技術文獻] [非專利文獻]
[非專利文獻1]醫學的進程,Vol.253, No.2, 2015年。 [非專利文獻2]眼科,第58卷6號,635-641, 2016年。 [非專利文獻3]醫學的進程,Vol.245, No.10, 2013年。 [非專利文獻4]Ophthalmologica, Vol.235, 78-86, 2016。 [非專利文獻5]坪田一男著,「你的孩子,如果放任不管就容易近視」ISBN978-4-7993-2041-9(出版公司:Discover 21,發行年月:2017年2月)。 [非專利文獻6]Nature, Vol.266, 66-68, March 1977。 [非專利文獻7]Brain Res, Vol.124, 154-157, 1977。 [非專利文獻8]Science, Vol.201, 1249-1251, 1978。 [非專利文獻9]Investigative Ophthalmology & Visual Science, Vol.48, 11-17, January 2007。 [非專利文獻10]Nat Neurosci, Vo.2, 705-712, 1999。
[發明所欲解決之課題]
一般而言,罹患近視與環境因素及遺傳原因有關已廣為人知。近來,於屋外的生活或活動減少、於室內的生活或活動增加,以及隨著智慧型手機、遊戲機、電腦、液晶電視等的普及,從孩童到高齡者的廣大年齡層便逐漸在長時間使用此等設備的環境下生活,造成近視出現之近距離作業的增加與屋內作業所引起的紫光暴露不足唯有惡化一途。基於此種背景,便強烈要求與預防近視有關的方法或組成物、或者可尋求該方法或組成物篩選方法。尤其是,有鑑於上述EGR-1基因與眼軸伸長有關,只要可篩選出可誘導EGR-1基因的表現之物質,再將該物質以食品、醫藥品、或其他方法導入至體內,便可有效地預防近視或眼部疾病。
本發明目的在於提供一種有效用於近視或者眼部疾病的預防或處置的組成物。尤其是提供一種對易患近視且易惡化的成長期之孩童或青年層,甚而白內障、青光眼、視網膜剝離、視網膜病變、黃斑病變、脈絡膜新生血管形成、眼後葡萄腫及視神經病變等眼部疾病之風險提高的中老年層屬有效的眼科用組成物、包含該眼科用組成物的機能性食品、及可尋求該組成物及機能性食品的篩選方法。 [解決課題之手段]
為解決上述課題,本案發明人等進行各種研究的結果發現出具有增強與眼軸伸長有關之EGR-1基因的表現之效果的成分,同時發現出在近視動物模型中可抑制眼軸伸長,而且可預防近視惡化的成分,終至完成本發明。從而,本發明之組成物可適用於與眼軸伸長有關之近視或者眼部疾病的預防或處置。亦即,本發明之要旨係如下記載。
[1]一種眼科用組成物,其係用於近視或者眼部疾病的預防或處置,且含有選自由藏紅花酸及其藥學上可容許之鹽,以及銀杏葉萃取物所成群組的至少1種成分。 [2]如[1]之眼科用組成物,其係進一步含有藏紅花酸及其藥學上可容許之鹽,以及銀杏葉萃取物以外的類胡蘿蔔素類及/或多酚類。 [3]如[1]或[2]之眼科用組成物,其中前述近視為軸性近視。 [4]如[1]至[3]中任一項之眼科用組成物,其係供成長期之兒童用。 [5]如[1]至[4]中任一項之眼科用組成物,其中前述近視為深度近視。 [6]如[1]或[2]之眼科用組成物,其中前述眼部疾病為隨年齡增長所引起的眼部疾病。 [7]如[1]或[2]之眼科用組成物,其中前述眼部疾病為由深度近視所引起的併發症。 [8]如[6]或[7]之眼科用組成物,其中前述眼部疾病為白內障及後眼部疾病。 [9]如[8]之眼科用組成物,其中前述後眼部疾病為選自由青光眼、視網膜剝離、黃斑裂孔、中央窩視網膜分裂、脈絡膜新生血管形成、眼後葡萄腫、近視性黃斑病變、及近視性神經病變所成群組的至少一種。 [10]如[1]至[9]中任一項之眼科用組成物,其係用於抑制眼軸伸長。 [11]如[1]至[10]中任一項之眼科用組成物,其係用於增強EGR-1之表現。 [12]一種用於近視或者眼部疾病的預防或處置之機能性食品,其係含有選自由藏紅花酸及其藥學上可容許之鹽,以及銀杏葉萃取物所成群組的至少1種成分。 [13]一種機能性食品,其係包含如[1]至[11]中任一項之眼科用組成物。 [14]一種有效用於近視或者眼部疾病的預防或處置之物質的篩選方法,其特徵在於以有無增強EGR-1表現之效果為指標。 [15]一種眼科用組成物,其係含有EGR-1表現增強劑。 [16]如[15]之眼科用組成物,其中前述EGR-1表現增強劑係包含抗氧化性植物萃取物。 [17]如[15]或[16]之眼科用組成物,其係用於抑制眼軸伸長。 [18]一種眼科用組成物,其係含有眼軸伸長抑制劑。 [19]如[18]之眼科用組成物,其中眼軸伸長抑制劑係包含抗氧化性植物萃取物。 [20]如[15]至[19]中任一項之眼科用組成物,其係用於近視或者眼部疾病的預防或處置。 [21]一種眼科用組成物,其係供近距離作業者用及/或者屋內作業者用,且含有選自由藏紅花酸及其藥學上可容許之鹽,以及銀杏葉萃取物所成群組的至少1種成分。 [22]如[21]之眼科用組成物,其係供兒童用。 [發明之效果]
根據本發明,可提供一種有效用於近視或者眼部疾病的預防或處置的眼科用組成物、包含其之機能性食品、及可尋求該組成物及機能性食品的篩選方法。尤其是,本發明之眼科用組成物對於易患近視且易惡化的成長期之孩童或青年層,甚而白內障、青光眼、視網膜剝離、視網膜病變、黃斑病變、脈絡膜新生血管形成、眼後葡萄腫及視神經病變等眼部疾病之風險提高的中老年層,可適用於各症狀・疾病的預防或處置。
又,本發明之篩選方法可取得能提升眼軸伸長抑制效果或EGR-1表現的物質,而有用於能有效改善近視或眼部疾病之眼科用組成物或機能性食品等的開發。
[實施發明之形態]
以下就本發明之眼科用組成物、機能性食品及篩選方法詳細加以說明。就本發明,只要包含其要旨,則不限於以下實施形態,係包含變形例及應用例。
<眼科用組成物/第1實施形態> 本發明之眼科用組成物的第1實施形態係含有抗氧化性植物萃取物或源於其之成分,較佳為類胡蘿蔔素類、多酚類。此等成分係具有調節基因(EGR-1)表現之機能,而此基因(EGR-1)表現係與可能造成軸性近視或各種眼部疾病的眼軸伸長有關。因此,含有此等成分的眼科用組成物可發揮維持視力之效果,對於易患近視且易惡化的年齡層(成長期之孩童、青年層等)特別有效果。又,對於眼軸伸長研判為原因之一的白內障、青光眼、視網膜剝離、視網膜病變、黃斑病變、脈絡膜新生血管形成、眼後葡萄腫及視神經病變等眼部疾病亦屬有效。此眼科用組成物,除屬必需成分的抗氧化性植物萃取物或源於其之成分外,在不損及本發明之效果的範圍內亦可包含其他成分。以下,就本發明之眼科用組成物所含有的成分詳細加以說明。
作為本發明之眼科用組成物所含有的類胡蘿蔔素類,可舉出藏紅花酸、藏紅花酸之藥學上可容許之鹽、梔子萃取物(山梔子)、梔子色素、藏紅花萃取物、發芽青花菜萃取物、花椰菜苗萃取物、紅甜椒萃取物、β-胡蘿蔔素、葉黃素、玉米黃質、蝦青素、金盞花色素萃取物、紅甜椒、紅甜椒色素、西洋人參萃取物、辣椒萃取液、杜仲葉萃取物、紅花萃取物、羅布麻萃取物等。此外,括弧內為別稱。
多酚類係與類胡蘿蔔素類同樣地具有抗氧化作用,為具有植物所含之苦味、澀味、色素之成分的化合物的總稱。作為本發明之眼科用組成物所含有的多酚,可舉出銀杏葉萃取物、山竹萃取物、草莓種子萃取物、核桃多酚、瓜拿納萃取物、爪哇薑萃取物、川皮苷、藍莓葉萃取物、倪藤萃取物、葡萄白藜蘆醇、越橘萃取物、溫普萃取物、Gnetin C、ε-葡萄素、白藜蘆醇、葡萄種子萃取物、黑大豆種皮多酚、黑豆種皮多酚、黑加侖萃取物、薑黃素、白類薑黃素、多甲氧基類黃酮(PMF)、二氫槲皮素、水飛薊萃取物、水飛薊素、水飛薊賓、αG橙皮苷、橙皮苷、甲基橙皮苷、源於柳橙之芸香糖苷、橙皮素、碧蘿芷、寡酚、亞麻木質素、香芹萃取物、智利酒果萃取物、奇異果種子萃取物、紫蘇果實萃取物、紅紫蘇萃取物、紫蘇葉、野櫻莓萃取物、藍靛果萃取物、花青素-3-葡萄糖苷、白背櫟萃取萃取物、巴西莓萃取物、卡姆果萃取物、家板栗多酚、大豆異黃酮、柑橘果實萃取物、海藻多酚、浮石萃取物、橄欖果實萃取物、酢橘果皮萃取物、蓮藕萃取物、薑黃萃取物、紫花紫錐菊(紫花馬藺菊)、荷葉萃取物(蓮葉)、管花肉蓯蓉、芭樂葉萃取物、桑葉萃取物、紅花萃取物、玉米穗黃萃取物、五層龍萃取物、車前草萃取物(車前子)、野山楂萃取物、陳皮萃取物、田七人參萃取物、甜茶萃取物、魚鱗雲杉萃取液、魚腥草萃取物、菊薯萃取物、羅布麻萃取物、綠茶萃取物等。此外,括弧內為別稱。
就上述類胡蘿蔔素類或多酚類而言,較佳為抑制眼軸長度的伸長之作用優良,同時可發揮附加特性(例如保全性、穩定性等)等者。
基於上述觀點,就類胡蘿蔔素類,較佳為藏紅花酸、藏紅花酸之藥學上可容許之鹽、梔子萃取物(山梔子)、梔子色素、藏紅花萃取物、β-胡蘿蔔素、葉黃素、玉米黃質、蝦青素、金盞花色素萃取物、紅甜椒、紅甜椒色素、紅花萃取物、羅布麻萃取物,更佳為藏紅花酸、藏紅花酸之藥學上可容許之鹽、梔子萃取物(山梔子)、梔子色素、藏紅花萃取物,再更佳為藏紅花酸、藏紅花酸之藥學上可容許之鹽。
基於上述觀點,就多酚類,較佳為銀杏葉萃取物、山竹萃取物、草莓種子萃取物、核桃多酚、瓜拿納萃取物、爪哇薑萃取物、川皮苷、藍莓葉萃取物、黑加侖萃取物、薑黃素、白類薑黃素、香芹萃取物、智利酒果萃取物、多甲氧基類黃酮(PMF),更佳為銀杏葉萃取物、山竹萃取物、草莓種子萃取物、核桃多酚、瓜拿納萃取物、爪哇薑萃取物,再更佳為銀杏葉萃取物。
此外,本說明書中所稱「近視」,為軸性近視,意指因眼軸伸長所造成的近視。眼軸伸長可利用調節麻痺劑或散瞳劑檢測出來。亦即,此處所稱近視,係指由裸眼原本的焦點偏移所引起者,已去除由水晶體或睫狀體經焦點調節的部分,係有別於消除暫時的眼睛疲勞(睫狀肌疲勞)便會復原之近視,例如調節性近視(假性近視)。從而,此處所稱近視,亦可定義為「視覺機能變差」、「視力變差」、「看遠方的能力變差」、「看遠處物品的能力變差」、「眼睛的基本性能變差」、「原本的視力變差」或者「焦點偏移」。
更詳而言之,近視係指成像於視網膜之前方而無法於遠處對焦之症狀,係由眼軸長度變長而發生。此種近視有別於因眼部疲勞(眼睛疲勞)、調節痙攣、調節緊繃等,睫狀體暫時麻痺,導致水晶體的動作惡化所引起的症狀(以下,方便上稱為「調節功能異常」),係不可逆地無法復原。調節功能異常,傳統上亦稱假性近視或調節緊繃性近視,此等為暫時性的調節痙攣或調節緊繃所引起的功能異常,非為近視。就調節功能異常,即便放任此症狀不管也不會轉移至近視,係屬使眼睛休息便會改善、或透過以眼藥水抑制睫狀體的痙攣而消除水晶體的緊繃等便會改善之症狀,惟根據此種改善手段並無法治癒近視。例如,一般而言,推行消除近視等者係以調節功能異常為對象,而非針對近視。從而,當調節功能異常與近視同時存在時,藉由使眼睛休息,僅能消除調節功能異常。
從而,本發明係用於近視或者主要因此近視而出現之眼部疾病的預防或處置者,其特徵在於,與用來改善例如因眼部疲勞(眼睛疲勞)、調節痙攣、調節緊繃等,睫狀體暫時麻痺,導致水晶體的動作惡化所引起的調節功能異常者本質且根本上不同。
又,本說明書中所稱「眼部疾病」,係指眼睛相關疾病,尤為因近視所引起的眼部疾病,具體而言可舉出白內障或後眼部疾病。本說明書中所稱「後眼部疾病」,係指玻璃體、視網膜、脈絡膜、鞏膜或視神經之疾病,具體而言係包含青光眼、視網膜剝離、黃斑裂孔、中央窩視網膜分裂、脈絡膜新生血管形成、眼後葡萄腫、近視性黃斑病變、近視性神經病變。然而,本實施形態不受此等定義所限制,可廣泛適用於眼軸伸長所涉及之症狀・疾病等。
此外,此處所稱近視或者眼部疾病的預防或處置,係指抑制近視惡化(眼軸伸長),亦即抑制與乳兒期至學童期之正常的眼軸伸長(正常的正視化)不同之異常的眼軸伸長,而預防、治療隨之而生的併發症。亦即,此處所稱近視或者眼部疾病的預防或處置,非僅預防或處置前段落(第0022段落)所述之近視,亦可定義為「眼軸伸長所引起之折射變化或者角膜曲率半徑變化的正常化」、「護持健康的眼睛成長」、「護持成長期的眼睛」、「維持視覺機能」或者「眼睛的抗老化」。
以下,就本發明之眼科用組成物的第1實施形態特佳含有的藏紅花酸、藏紅花酸之藥學上可容許之鹽、銀杏葉萃取物詳細加以說明。
藏紅花酸為天然色素的一群,屬分類為類胡蘿蔔素的成分之一。藏紅花酸為具有強力抗氧化作用之成分,可由梔子(茜草科梔子屬:Gardenia augusta MERRIL var.、grandiflora HORT.、Gardenia jasminoides ELLIS)的果實、藏紅花(鳶尾科番紅花屬:Crocus sativus)的柱頭以高純度萃取出來。
此藏紅花酸一般係藉由將屬類胡蘿蔔素系黃色色素之藏紅花素(藏紅花酸之二龍膽二糖酯)水解而得。藏紅花素係含於梔子的果實、藏紅花的柱頭之乾燥物等,作為用來獲得藏紅花素的工業原料,較佳使用梔子的果實。
由植物基原萃取出藏紅花素的方法不特別限定,可採用例如由粉碎之梔子的乾燥果實,使用水或醇(例如甲醇、乙醇等)、或彼等之混合液進行萃取等的周知方法。就萃取條件,例如使用水・醇混合液時,較佳為0~50℃、1~18小時,更佳為30~40℃、2~4小時。萃取操作一般係進行多次。
工業上,藏紅花素的水解較佳為使用鹼之水解。又,水解亦可於攪拌及/或加熱下進行。較佳於攪拌下,以20~70℃進行水解,係以40~60℃進行1~24小時,較佳為進行3~5小時。
藏紅花素的水解為使用鹼之水解時,一般而言,水解結束後,藉由對反應液適量添加鹽酸、硫酸、磷酸等無機酸、或檸檬酸等有機酸的水溶液,而調成pH4.0以下,較佳為pH1.0~3.0,可使藏紅花酸析出。其後,藉由將析出藏紅花酸之混合液進行離心分離、或過濾,可將藏紅花酸以糊狀固體物回收。
所得藏紅花酸,由於通常在固體物表面附著有酸、中和鹽及源自原料之雜質,以去除該雜質為目的,而進行洗淨處理。該處理可採用例如使用足量的水清洗糊狀固體物等周知之方法來進行。其次,使用例如盤式通風乾燥機或真空乾燥機等,較佳在氮氣環境下以超過50℃左右的溫度,將例如經水洗之固體物乾燥,可去除殘留於固體物的水。
基於雜質較少之觀點,藏紅花酸其純度較佳為50質量%以上,而只要可獲得能發揮有效性的藏紅花酸含量,則不限定於此純度。此外,藏紅花酸的純度能以純藏紅花酸的色值為基準來算出。色值可依循常見方法,以「化學合成品以外的食品添加物 自主規格(第二版)」,日本食品添加物協會編,「梔子黃色素」為參考來算出。
就藏紅花酸而言,可如上述藉由將植物等天然物所含之藏紅花素水解而得,亦可使用化學合成品。又,也可使用含於梔子果實、梔子萃取物、藏紅花萃取物等天然物者。基於安全性或純度觀點,更佳由梔子黃色素(食品標示例)獲得藏紅花酸。
作為藏紅花酸之藥理學上可容許之鹽,可舉出例如鈉、鉀等鹼金屬鹽;鎂、鈣等鹼土金屬鹽;吡啶、二甲胺、二乙胺、乙醇胺等醫藥上可容許之有機胺化合物的鹽等。
作為市售藏紅花酸製劑,可例示例如Riken Vitamin股份有限公司製Chrovit(註冊商標)。「Chrovit P (商品名)」為藏紅花酸含量75%以上的粉末狀態,「Chrovit 2.5WD(商品名)」為藏紅花酸含量2.5%以上的水分散性製劑。
本發明之眼科用組成物中的藏紅花酸或其藥學上可容許之鹽的定性・定量方法,只要為科學上的適當方法則不特別限定,能以例如使用ODS管柱與濃度梯度移動相(TFA水溶液→TFA水-甲醇溶液)的高效液相層析法將試料分離,以all-trans-藏紅花酸或13-cis-藏紅花酸等為標準物,使用光二極體陣列檢測器來定性・定量受驗物質。
銀杏葉萃取物係以槲皮素或山奈酚、花青素原等多種類黃酮與銀杏內酯所代表的萜烯內酯為主成分的植物萃取物,為具有血流改善之效果的萃取物,可由乾燥銀杏葉(Ginkgo biloba. L.),藉由常見方法萃取出來。
作為市售銀杏葉萃取物,可例示例如銀杏葉甘草萃取物(Indena Japan股份有限公司製)、銀杏萃取液BG-50(香榮興業股份有限公司製)、銀杏萃取物-FM (TAMA BIOCHEMICAL股份有限公司製)、銀杏萃取物-F (TAMA BIOCHEMICAL股份有限公司製)、銀杏葉萃取物C(丸善製藥股份有限公司製)。
本發明之眼科用組成物所含有之藏紅花酸、藏紅花酸之藥學上可容許之鹽、銀杏葉萃取物等抗氧化性植物萃取物或源於其之成分的含量不特別限定,就其每日之摻混量,為0.001~5000mg/day,較佳為0.01~1000 mg/day,更佳為0.01~500mg/day。
本發明之眼科用組成物,由於含有具有增強與抑制眼軸伸長有關之EGR-1基因的表現之效果的上述成分,而適用於作為EGR-1表現增強用,且適用於作為眼軸伸長抑制用。再者,本發明之眼科用組成物係適用於與眼軸伸長有關之近視(尤為軸性近視)或者眼部疾病(尤為選自由青光眼、視網膜剝離、黃斑裂孔、中央窩視網膜分裂、脈絡膜新生血管形成、眼後葡萄腫、近視性黃斑病變、及近視性神經病變所成群組的至少一種之後眼部疾病)的預防或處置。以下針對屬此種眼科用組成物之較佳實施形態的醫藥及食品詳細加以說明。
<醫藥> 將本發明之眼科用組成物作成醫藥時,可添加藥學上可容許之賦形劑等而製成醫藥製劑。本發明之醫藥,只要可用於近視或者眼部疾病的預防或處置則不特別限定,可製成眼藥水、口服劑(錠劑、膠囊劑、顆粒劑、細粒劑、粉劑、咀嚼錠、片劑等固體製劑、或液劑、糖漿等液體製劑)、注射劑等。此等當中,基於容易發揮本發明之效果的觀點,較佳為眼藥水、口服劑。本發明之眼科用組成物可配合各者的性質狀態、用途等,包含上述成分以外的其他添加劑。
將本發明之眼科用組成物作為醫藥使用時,對象症狀・疾病只要是眼軸伸長研判為原因之一者則不特別限定,較佳為近視、眼部疾病。以近視而言,較佳為軸性近視,尤以易患軸性近視且容易發生惡化的成長期之兒童、青年層的軸性近視為更佳。就眼部疾病而言,較佳為白內障、青光眼、視網膜剝離、視網膜病變、黃斑病變、脈絡膜新生血管形成、眼後葡萄腫及視神經病變,尤以白內障、青光眼、視網膜剝離、黃斑裂孔、中央窩視網膜分裂、脈絡膜新生血管形成、眼後葡萄腫、近視性黃斑病變、近視性神經病變為更佳。
將本發明之眼科用組成物作成醫藥使用時,其對象為需要近視或者眼部疾病的預防或處置的人,特別是近視,其中為易患軸性近視且容易發生惡化的成長期之兒童或青年層,具體而言主要為未達20歲的兒童及20多歲~30多歲的青年層,較佳為2歲~15歲,更佳為6歲~12歲的成長期兒童。此外,對於白內障、青光眼、視網膜剝離、黃斑裂孔、中央窩視網膜分裂、網膜水腫、糖尿病視網膜病變、視網膜色素病變、黃斑水腫、糖尿病黃斑病變、近視性黃斑病變、老年黃斑病變、近視性神經病變等老年性眼部疾病風險提高的中老年層,亦可配合各者之症狀而合宜地使用。
將本發明之眼科用組成物供近距離作業者用及/或者屋內作業者用而使用時,只要是有眼軸伸長之風險因子的人則不特別限定,其對象為主要頻繁從事屋內之近距離作業的人,或者主要不常在屋外暴露於紫光(360~400nm的可見光)下的人。尤以花費在讀書、閱讀寫字、電腦、電視、電視遊戲的時間較長的兒童或學童為佳,亦較佳為不常在屋外活動的高齡者。
(眼藥水) 將本發明之眼科用組成物作成眼藥水使用時,係至少考量藏紅花酸或其藥學上可容許之鹽等抗氧化性植物萃取物或源於其之成分對水的溶解性及穩定性,而選自水性眼藥水、使用時溶解之眼藥水、懸浮性眼藥水、油性眼藥水、眼軟膏等。例如藏紅花酸由於為兼具親水結構與親油結構的類胡蘿蔔素水溶性,因此,本發明之眼科用組成物的劑形,一般可製成水性眼藥水或懸浮性眼藥水。
眼藥水中,除上述成分外,尚可摻混其他的有效成分(藥理活性成分、生理活性成分等)。此種成分的種類不特別限制,可例示例如消除充血成分、眼肌調節藥成分、抗發炎藥成分、收斂劑成分、抗組織胺劑成分、抗過敏藥成分、維生素類、胺基酸類、抗菌劑成分、糖類、高分子化合物或其衍生物、纖維素或其衍生物、局部麻醉藥成分、上述成分以外的青光眼治療成分、上述成分以外的白內障治療成分等。
對於眼藥水,在不損及本發明之效果的範圍內,可進一步依據其用途或形態,依循常見方法適宜選擇各種的成分或添加物,併用一種或更多而含有之。作為此等成分或添加物,可舉出例如液劑等的調製一般所使用的擔體、香料或冷卻劑、防腐劑、殺菌劑或抗菌劑、pH調節劑、螯合劑、穩定劑、等滲壓劑、緩衝劑、增稠劑等各種添加劑。以下係例示眼藥水所使用的代表性成分,但不限定於此等。
作為擔體,可舉出例如水、含水乙醇等水性溶媒。此外,當各種成分難溶於水性溶媒時,亦可使用可溶劑。作為可溶劑,可舉出例如聚氧乙烯硬化蓖麻油、硬脂酸聚氧乙烯40、聚維酮、聚山梨醇酯80等。
作為香料或冷卻劑,可舉出例如萜烯類(具體而言為茴香腦、丁香酚、樟腦、香葉醇、桉油醇、莰醇、薄荷醇、檸檬烯、龍腦等。此等可為d體、l體或dl體任一種)、精油(茴香油、清涼薄荷油、肉桂油、留蘭香油、薄荷水、薄荷油、胡椒薄荷油、香檸檬油、尤加利油、玫瑰油等)等。
作為防腐劑、殺菌劑或抗菌劑,可舉出例如泊利氯銨、鹽酸烷基二胺基乙基甘胺酸、苯甲酸鈉、乙醇、氯化苄烷銨、氯化本索寧、葡萄糖酸氯己啶、氯丁醇、山梨酸、山梨酸鉀、去水乙酸鈉、對羥基苯甲酸甲酯、對羥基苯甲酸乙酯、對羥基苯甲酸丙酯、對羥基苯甲酸丁酯、硫酸羥基喹啉、苯乙醇、苯甲醇、雙胍化合物(具體而言為聚六亞甲基雙胍或其鹽酸鹽等)、GLOKYL (RHODIA公司製商品名)等。
作為pH調節劑,可舉出例如鹽酸、氫氧化鈉、氫氧化鉀、氫氧化鈣、氫氧化鎂、三乙醇胺、單乙醇胺、二異丙醇胺、硫酸、磷酸等。
作為螯合劑,可舉出例如抗壞血酸、乙二胺四乙酸四鈉、乙二胺四乙酸鈉、檸檬酸等。
作為穩定劑,可舉出例如乙二胺四乙酸鈉水合物、聚維酮、聚山梨醇酯80、二丁基羥基甲苯、氨丁三醇、甲醛磺酸鈉(雕白粉)、生育酚、焦亞硫酸鈉、單乙醇胺、單硬脂酸銨、單硬脂酸甘油等。
作為等滲壓劑,可舉出例如氯化鉀、氯化鈉、濃甘油、葡萄糖、D-甘露醇等。
作為緩衝劑,可舉出例如檸檬酸鈉水合物、乙酸鈉水合物、碳酸氫鈉、三羥甲基胺基甲烷、硼酸、硼砂、磷酸氫鈉水合物、磷酸二氫鈉等。
作為增稠劑,可舉出例如羧基乙烯基聚合物、聚維酮、聚乙烯醇(部分皂化物)、羥乙基纖維素、羥丙基甲基纖維素、甲基纖維素、甘油等。
本發明之眼藥水較佳含有0.001~1質量%的藏紅花酸或其藥學上可容許之鹽等抗氧化性植物萃取物或源於其之成分,更佳含有0.01~0.1質量%。又,其他的添加劑,可於期望發揮本發明之效果、或不妨害本發明之效果的範圍內摻混。其含量不特別限定,以組成物中的含量計較佳為0.001~1質量%左右。
眼藥水的pH只要調成3~10即可,基於使用感觀點較佳為4~9,基於使用感觀點更佳為5~8.5。
供填充本發明之眼藥水的容器,可不限周知之點眼容器地使用。作為點眼容器,一般可使用可對眼睛滴下眼藥水之形狀,例如具備噴嘴,且於噴嘴的前端具備容器口之形狀者。又,作為供容納本發明之眼藥水的點眼容器,可為容器上安裝有與其個別成形之噴嘴之構造者、及噴嘴部(液體注出部)與容器本體一體成型之構造者(例如1次用盡型眼藥水等)之任一種。
供容納本發明之眼藥水的容器,只要一般採塑膠製即可。就該塑膠容器的構成材質,不特別限制,可舉出例如聚對苯二甲酸乙二酯、聚丙烯酸酯、聚萘二甲酸乙二酯、聚碳酸酯、聚乙烯、聚丙烯、聚醯亞胺的任1種、此等之共聚物、或此等2種以上之混合物。尤其是基於易隨擠出程度等而發揮本案發明之效果的觀點,較佳為聚對苯二甲酸乙二酯、聚丙烯酸酯、聚萘二甲酸乙二酯或此等之共聚物、或此等2種以上之混合物。
本發明之眼藥水可填充於以此種材料為主材料的透明容器(具備觀察到雜質也不會對其造成妨礙之程度的透明性之容器),亦可填充於遮光容器。遮光例如可藉由對透明容器材料添加著色劑來進行,亦可藉由將容器以收縮薄膜或外盒等覆蓋來遮光。又,就容器的容量,為了易隨擠出程度等而進一步發揮本發明之效果,較佳為0.5~50mL左右,更佳為3~20mL左右。
此外,就供容納本發明之眼藥水的容器所具備的噴嘴,對於其構造或構成素材亦不特別限制。就噴嘴之構造,只要是作為眼藥水容器的噴嘴一般所採用的構造即可;又,就噴嘴之構成素材,可例示例如與上述塑膠容器之構成素材相同者。基於改善本發明之眼藥水的除液,且可抑制滴下量的不均之觀點,宜為包含聚乙烯、或聚丙烯作為構成素材的噴嘴。作為聚乙烯的種類,可舉出高密度聚乙烯、低密度聚乙烯等,其中宜為包含低密度聚乙烯作為構成素材的噴嘴。
(眼藥水的製造方法) 本發明之眼藥水能以本業者所慣用・熟知的方法來調製。例如,只要藉由使各成分分散於水等擔體後,若有必要時添加可溶劑,視需求加熱,並使用均質機等予以均勻化、溶解或乳化,再以pH調整劑調整pH來調製。又,作為製劑的滅菌方法,可選擇高壓釜滅菌、過濾滅菌等方法。
(使用方法) 本發明之眼藥水的用法、用量係隨患者的症狀、年齡等而變更,通常只要以1日約1~6次、1次約滴下1~2滴即可。
(口服劑:固體製劑) 本發明之眼科用組成物可作成例如錠劑、膠囊劑、顆粒劑、粉劑等固體製劑。口服劑有攜帶性優良,且可由口中容易地攝取一定量的優點。口服劑的形狀,係考量取用容易性及攝取容易性來設計其形狀、重量、大小、顏色等。對於固體製劑,可依據其用途或形態,依循常見方法適宜選擇各種的成分或添加物,併用一種或更多而含有之。作為此等成分或添加物,例如除上述藏紅花酸或其藥學上可容許之鹽等抗氧化性植物萃取物或源於其之成分、類胡蘿蔔素類、多酚類等成分以外,尚可摻混賦形劑、潤滑劑、黏合劑、崩解劑等。又,亦可視需求使用防腐劑、抗氧化劑、著色劑、甜味劑等添加物。以下例示固體製劑所使用的代表性成分,但不限定於此等。
作為賦形劑,可舉出例如D-山梨糖醇、甘露糖醇、木糖醇等糖醇、葡萄糖、白糖、乳糖、果糖等糖類、結晶纖維素、羧甲基纖維素鈉、交聯羧甲基纖維素鈉、磷酸氫鈣、小麥澱粉、米澱粉、玉米澱粉、馬鈴薯澱粉、糊精、β-環糊精、輕質無水矽酸、氧化鈦、鋁鎂矽酸鹽、滑石、高嶺土、橄欖油等。
作為黏合劑,可舉出例如甲基纖維素、乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素等纖維素衍生物、聚乙烯吡咯啶酮、聚乙烯醇、丙烯酸系高分子、明膠、阿拉伯膠、聚三葡萄糖、α化澱粉、洋菜、黃蓍膠、海藻酸鈉、海藻酸丙二醇酯等。
作為崩解劑,可舉出例如澱粉、低取代度羥丙基纖維素、羧甲基纖維素鈣、交聯羧甲基纖維素鈉、羥丙基澱粉、部分α化澱粉等。
作為潤滑劑,可舉出例如硬脂酸、硬脂酸鎂、硬脂酸鈣、硬脂酸聚氧乙烯、鯨蠟醇、滑石、硬化油、蔗糖脂肪酸酯、二甲基聚矽氧烷、蜜蠟、白蜂蠟等。
此等添加劑可於不妨害本發明之效果的範圍內摻混。
(口服劑(固體製劑)的製造方法) 要將本發明之眼科用組成物作成固體製劑時,能以本業者所慣用・熟知的方法來調製。可例示例如藉由將組成物進行捏合並使其通過篩網,再進行成型而得到擠出造粒物,並將此擠出造粒物粉碎、整粒的方法;對前述組成物添加捏合水,藉由立式造粒機進行成型的攪拌造粒後,使用Comil進行粉碎、篩濾的方法;及將前述製劑組成物以輥輾壓機壓縮後,以輥式造粒機進行粉碎、篩濾的方法;於攪拌造粒後進行流動層乾燥的方法。又,例如藉由直接壓錠來製造時,只要將組成物混合後,直接投入打錠機進行打錠即可。
(口服劑:液狀製劑) 本發明之眼科用組成物亦可作成例如糖漿、飲劑等液狀製劑。液狀製劑中,除上述成分以外,尚可摻混溶劑、增溶劑、懸浮劑、等滲壓劑、緩衝劑、舒緩劑等。又,亦可視需求使用防腐劑、抗氧化劑、著色劑、甜味劑等添加物。此等添加劑可於不妨害本發明之效果的範圍內摻混。
作為溶劑,可舉出例如水、醇、丙二醇、聚乙二醇、芝麻油、玉米油等。
作為增溶劑,可舉出例如聚乙二醇、丙二醇、D-甘露醇、苯甲酸苯甲酯、乙醇、三胺基甲烷、膽固醇、三乙醇胺、碳酸鈉、檸檬酸鈉等。
作為懸浮劑・乳化劑,可舉出例如硬脂醯基三乙醇胺、月桂基硫酸鈉、月桂基胺基丙酸、卵磷脂、氯化苄烷銨、氯化本索寧、單硬脂酸甘油等界面活性劑;例如聚乙烯醇、聚乙烯吡咯啶酮、羧甲基纖維素鈉、甲基纖維素、羥甲基纖維素、羥乙基纖維素、羥丙基纖維素等親水性高分子;例如蟲膠蠟、蜜蠟、巴西棕櫚蠟、鯨蠟、羊毛脂、液狀羊毛脂、還原羊毛脂、硬質羊毛脂、環狀羊毛脂、羊毛脂蠟、堪地里拉蠟、野漆果蠟、褐煤蠟、紫膠蠟、米糠蠟等蠟類等。
作為等滲壓劑,可舉出例如氯化鈉、甘油、D-甘露醇等。作為緩衝劑,可舉出例如磷酸鹽、乙酸鹽、碳酸鹽、檸檬酸鹽等緩衝液等。作為舒緩劑,可舉出例如苯甲醇等。作為防腐劑,可舉出例如對羥基苯甲酸酯類、氯丁醇、苯甲醇、苯乙醇、去水乙酸、山梨酸等。作為抗氧化劑,可舉出例如亞硫酸鹽、抗壞血酸等。
要將本發明之眼科用組成物製成液狀製劑時,可使用一般方法。要製成液狀製劑時,係至少考量藏紅花酸或其藥學上可容許之鹽等抗氧化性植物萃取物或源於其之成分對水的溶解性及穩定性。例如藏紅花酸由於為兼具親水結構與親油結構的類胡蘿蔔素水溶性,因此,本發明之眼科用組成物的劑形,一般可製成水性製劑或懸浮性製劑。
本發明之口服劑(固體製劑、液狀製劑)的投予量可依據對象疾病及狀態、疾病的程度、對象者的年齡、體重等來適宜設定。就藏紅花酸量,每日為0.075~75mg/day,更佳為0.1~25mg/day,再更佳為0.25~10 mg/day。就藏紅花酸以外的萃取物量,每日為0.1~5000 mg/day,更佳為1~1000mg/day,再更佳為10~300 mg/day。就投予次數,可為每日1次或多次。
<食品> 本發明之眼科用組成物可使其含於食品而提供。作為此種機能性食品,可舉出健康食品、機能性標示食品、健康輔助食品、營養機能食品、特別用途食品、特定保健用食品或一般食品等。此等食品由於包含本發明之眼科用組成物,可針對需要近視或者眼部疾病的預防或處置的人,尤為近視,其中為易患軸性近視且易發生惡化的成長期之兒童或青年層、白內障、青光眼、視網膜剝離、視網膜病變、黃斑病變、脈絡膜新生血管形成、眼後葡萄腫及視神經病變等老年性眼部疾病之風險提高的中老年層,配合各者之症狀合宜地攝取。又,除此等以外,對於因眼軸伸長所引起的症狀・疾病,亦可作為眼軸伸長抑制用,可望有改善效果等而廣泛地攝取。
就此等食品的形狀,可舉出果汁、清涼飲料、飲劑、茶等液狀、小圓餅、錠片、顆粒粉末、粉末、膠囊等固態、糊漿、膠凍、湯、調味料、沙拉醬等半流動狀等。
具體而言,可例示米飯;包含披薩、英式鬆餅、小圓餅、貝果、福克西亞、牛角麵包的各種麵包類;包含蕎麥麵、烏龍麵、冬粉、中華麵、速食麵、杯麵的各種麵類;包含義大利麵條、通心粉、筆管麵、千層麵的各種義大利麵類;清涼飲料、碳酸飲料、營養飲料、果實飲料、乳酸飲料、運動飲料等飲料;咖哩塊、燉菜、各種湯類;冰淇淋、冰雪酪、剉冰等冰涼甜點;飴糖、餅乾、糖果、口香糖、巧克力、錠片型零食、點心零食、小圓餅、膠凍、果醬、奶油、其他烘培點心等甜點類;魚板、半片(日式魚漿加工物)、火腿、香腸等水產・畜產加工食品;加工乳、發酵乳等乳製品;沙拉油、油炸油、人造奶油、美乃滋、酥油、泡沫乳油、沙拉醬等油脂及油脂加工食品;醬料、沙拉醬、味噌、醬油、醬汁等調味料;湯、燉菜、沙拉、熟食、香鬆、醃製物;其他各種形態之健康・營養輔助食品等。
再者,可使其含有本發明之眼科用組成物而提供的食品中亦包含營養補充品(散劑、顆粒劑、軟膠囊、硬膠囊、錠劑、咀嚼錠、速崩錠、糖漿、液劑等)。
又,對於寵物等動物用之飼料,亦可使其含有本發明之眼科用組成物。
此等食品均可藉由本業者所熟知之方法,添加藏紅花酸或其藥學上可容許之鹽來製造。
食品中可視需求添加添加物。作為此類添加物,可舉出例如葡萄糖、果糖、蔗糖、麥芽糖、山梨糖醇、甜菊素、甜茶素、玉米糖漿、乳糖、甘露醇、糊精、檸檬酸、檸檬酸鈉、酒石酸、蘋果酸、琥珀酸、乳酸、L-抗壞血酸、dl-α-生育酚、異抗壞血酸鈉、甘油、丙二醇、甘油脂肪酸酯、聚甘油脂肪酸酯、蔗糖脂肪酸酯、山梨糖醇酐脂肪酸酯、阿拉伯膠、鹿角菜膠、酪蛋白、明膠、果膠、洋菜、維生素C、維生素B類、維生素E、菸鹼酸醯胺、泛酸鈣、胺基酸類、鈣鹽類、界面活性劑、色素、香料、保存劑等。
本發明中的食品可附加有:具有近視或者眼部疾病(例如白內障、青光眼、視網膜剝離、黃斑裂孔、中央窩視網膜分裂、網膜水腫、糖尿病視網膜病變、視網膜色素病變、黃斑水腫、糖尿病黃斑病變、近視性黃斑病變、老年性黃斑病變、近視性神經病變等後眼部疾病)的預防作用、同改善作用等之意旨的標示。又,本發明中的食品可附加有:易患近視(其中的軸性近視)且容易發生惡化的成長期兒童用;白內障、視網膜剝離、青光眼、黃斑病變、脈絡膜新生血管形成等老年性後眼部疾病之風險提高的中老年層用;因眼軸伸長所引起的症狀・疾病用;眼軸伸長抑制用等標示。
以上,本發明之眼科用組成物、醫藥(眼藥水、口服劑等)、食品(機能性食品、特定保健用食品等),對於易患近視或近視易惡化的年齡層,尤為成長期之孩童或青年層係屬有效。尤其是可抑制視力變差(罹患近視、近視惡化),可發揮抑制主要為未達20歲的兒童及20多歲~30多歲的青年層,較佳為2歲~15歲,更佳為6歲~12歲之成長期孩童所容易發生的眼軸長度伸長的作用效果。又,對於白內障、青光眼、視網膜剝離、視網膜病變、黃斑病變、脈絡膜新生血管形成、眼後葡萄腫及視神經病變等老年性後眼部疾病之風險提高的中老年層亦屬有效。
<眼科用組成物/第2實施形態> 本發明之眼科用組成物的第2實施形態為一種含有EGR-1表現增強劑的眼科用組成物。此處所稱EGR-1表現增強劑,係指可增強已知與抑制眼軸伸長有關之EGR-1基因的表現強度的物質。本發明之眼科用組成物由於含有此EGR-1表現增強劑,而能夠適用於眼軸伸長研判為原因之一的近視或眼部疾病的預防或處置。本發明之眼科用組成物可發揮維持視力之效果,尤其是對於易患近視且易惡化的年齡層(成長期之孩童、青年層等)係屬有效果。而且,對於眼軸伸長研判為原因之一的白內障、視網膜剝離、青光眼、黃斑病變、脈絡膜新生血管形成等後眼部疾病亦屬有效。
EGR-1表現增強劑較佳包含抗氧化性植物萃取物。作為此抗氧化性植物萃取物,可舉出包含類胡蘿蔔素類、多酚類之植物萃取物作為較佳實例。此外,作為類胡蘿蔔素類、多酚類,於此亦可同樣地例示本發明之第1實施形態中所例示者。
上述類胡蘿蔔素類當中,基於EGR-1表現增強效果(抑制眼軸長度伸長之效果)更優良之觀點,較佳為藏紅花酸、藏紅花酸之藥學上可容許之鹽、梔子萃取物(山梔子)、梔子色素、藏紅花萃取物、β-胡蘿蔔素、葉黃素、玉米黃質、蝦青素、金盞花色素萃取物、紅甜椒、紅甜椒色素、紅花萃取物、羅布麻萃取物,更佳為藏紅花酸、藏紅花酸之藥學上可容許之鹽、梔子萃取物(山梔子)、梔子色素、藏紅花萃取物,再更佳為藏紅花酸、藏紅花酸之藥學上可容許之鹽。
多酚類中,基於EGR-1表現增強效果(抑制眼軸長度伸長之效果)更優良之觀點,較佳為銀杏葉萃取物、山竹萃取物、草莓種子萃取物、核桃多酚、瓜拿納萃取物、爪哇薑萃取物、川皮苷、藍莓葉萃取物、黑加侖萃取物、薑黃素、白類薑黃素、香芹萃取物、智利酒果萃取物、多甲氧基類黃酮(PMF),更佳為銀杏葉萃取物、山竹萃取物、草莓種子萃取物、核桃多酚、瓜拿納萃取物、爪哇薑萃取物,再更佳為銀杏葉萃取物。
本發明之眼科用組成物中的EGR-1表現增強劑的含量,只要視可獲得本發明之效果的範圍則不特別限定,例如為0.001~20質量%,較佳為0.01~10質量%,更佳為0.1~5質量%。
作為含有EGR-1表現增強劑的本發明之眼科用組成物的較佳實施形態,可舉出醫藥、食品。將本發明之眼科用組成物作成醫藥、食品時亦可含有的其他成分等的具體說明,可應用第1實施形態中的說明。此外,第1實施形態中記載為抗氧化性植物萃取物或源於其之成分之處,可替換理解為「EGR-1表現增強劑」。
<眼科用組成物/第3實施形態> 本發明之眼科用組成物的第3實施形態為一種含有眼軸伸長抑制劑的眼科用組成物。此處所稱眼軸伸長抑制劑,係指具有抑制眼軸伸長效果的物質,含有其之眼科用組成物可適用於眼軸伸長研判為原因之一的近視或眼部疾病的預防或處置。本發明之眼科用組成物可發揮維持視力之效果,尤其是對於易患近視且易惡化的年齡層(成長期之孩童、青年層等)係屬有效果。而且,對於眼軸伸長研判為原因之一的白內障、視網膜剝離、青光眼、黃斑病變、脈絡膜新生血管形成等後眼部疾病亦屬有效。
作為眼軸伸長抑制劑,可舉出例如上述之EGR-1表現增強劑,具體而言為抗氧化性植物萃取物,較佳為類胡蘿蔔素類、多酚類等,更佳為藏紅花酸、藏紅花酸之藥學上可容許之鹽、銀杏葉萃取物、山竹萃取物、草莓種子萃取物、核桃多酚、瓜拿納萃取物、爪哇薑萃取物,再更佳為藏紅花酸、藏紅花酸之藥學上可容許之鹽、銀杏葉萃取物,特佳可舉出藏紅花酸、藏紅花酸之藥學上可容許之鹽。將含有眼軸伸長抑制劑的眼科用組成物作成醫藥、食品的情形亦包含於本發明。其他成分等的具體說明可應用第1實施形態中的說明。此外,第1實施形態中記載為抗氧化性植物萃取物或源於其之成分之處,可替換理解為「眼軸伸長抑制劑」。
<有效用於近視或者眼部疾病的預防或處置之物質的篩選方法> 以已知與眼軸伸長有關的EGR-1基因表現強度為指標,可篩選出有效用於近視或者眼部疾病的預防或處置的物質。EGR-1基因已知與眼軸長度的伸展有關,具有增強此基因表現之效果的物質堪稱有抑制眼軸伸長之效果。
本發明之篩選方法係至少包含:(1)以試驗物質或陰性對照物質對細胞、組織、個體等進行處理之步驟(下稱「處理步驟」);(2)測定細胞或者組織、或受驗體之細胞或者組織中的EGR-1基因的表現量之步驟(下稱「測定步驟」)。
作為上述試驗物質,較佳為選自由類胡蘿蔔素類、多酚類、及彼等之藥學上可容許之鹽所成群組的至少1種。尤其是類胡蘿蔔素類當中,較佳使用藏紅花酸,多酚類當中較佳使用銀杏葉萃取物,但不限於此。又,以選自上述群組的2種以上物質作為試驗物質時,其中1種較佳為藏紅花酸或銀杏葉萃取物。此時,作為藏紅花酸或銀杏葉萃取物以外的物質,較佳為以與藏紅花酸或銀杏葉萃取物之相乘效果而促進EGR-1的上升之物質,但不限於此。具體而言,試驗物質可僅採用藏紅花酸,亦可採用藏紅花酸及銀杏葉萃取物。
上述處理步驟中,對細胞或組織以試驗物質等進行處理時,可藉由本業者所熟知的方法來進行。例如,可在培養細胞之培養基中添加上述試驗物質等培養一定時間(例如1~72小時)。又,亦可使試驗體(人類或其他動物)攝取包含試驗物質等的組成物1次或多次。
上述測定步驟中,可藉由本業者所熟知的方法來測定細胞或組織的EGR-1基因表現。例如,可藉由定量RT-PCR法來測定細胞或組織之EGR-1mRNA的表現。又,亦可藉由螢光素酶報導基因化驗,依循常見方法來測定EGR-1基因表現水準。
亦即,詳而言之,本發明之篩選方法係一種供篩選具有透過含有選自由類胡蘿蔔素類、多酚類、及彼等之藥學上可容許之鹽所成群組的至少1種而產生之眼軸伸長抑制效果或EGR-1表現效果的物質的方法,可謂包含以下步驟之方法:(a)準備添加有選自由類胡蘿蔔素類、多酚類、及彼等之藥學上可容許之鹽所成群組的至少1種試驗物質的試驗體之步驟(稱(a)步驟);(b)測定上述試驗體的EGR-1表現之步驟(稱(b)步驟);及(c)選擇可看出EGR-1表現效果的試驗體,並選擇該試驗體所含之試驗物質作為眼軸伸長抑制物質或EGR-1表現增強物質之步驟(稱(c)步驟)。
上述(a)步驟中,係將包含連結有EGR-1基因之報導基因的核酸導入篩選所使用的細胞內,並對該細胞導入選自由類胡蘿蔔素類、多酚類、及彼等之藥學上可容許之鹽所成群組的至少1種試驗物質而形成試驗體。
作為報導基因,可利用例如綠色螢光蛋白質(GFP)基因、螢光素酶基因等,只要是本業者則可容易地選出。又,包含報導基因的核酸,只要是可於實施本發明之篩選方法的細胞內使報導基因表現者則可為任意者,可舉出例如質體載體、病毒載體等。
本發明之篩選所使用的細胞,只要是可發揮EGR-1基因之機能,而且可使上述報導基因表現(可發揮功能)的細胞則可為任意細胞,而且可源自於任何物種。例如,可使用哺乳類細胞(小鼠、大鼠、人類等)、或鳥類細胞(小雞等)。
於此,就添加於試驗體的試驗物質而言,可先將其濃度循序稀釋,而調製成包含多種濃度之試驗物質的試驗體。又,包含陰性對照物質的對照實驗,除包含陰性對照物質以外,亦可與試驗體同樣地準備。
使用如此調製之試驗體,供予以下(b)步驟。
上述(b)步驟為測定上述試驗體的EGR-1表現之步驟。例如為根據上述報導基因的表現,來測定EGR-1表現之步驟。此時,報導基因的表現的變化,只要是本業者則可容易地測定、檢測出來。例如,使用如GFP或螢光素酶等發光性蛋白質之基因作為報導基因時,可將細胞培養後,將細胞溶解,再將溶解物移至適於測定發光的孔板來測定發光;或者,亦可直接測定源自經培養之細胞的發光。作為測定所使用的儀器,可使用例如周知之光度計等。
上述(c)步驟中,要選出眼軸伸長抑制作用或使EGR-1表現之作用較強的物質,只要選擇上述(b)步驟中所測得之EGR-1表現量大於對照實驗的試驗體即可。亦即,使用發光性蛋白質之基因作為報導基因時,只要選擇發光量較大的試驗體。
根據本發明之篩選方法所得之眼軸伸長抑制物質或EGR-1表現增強物質,以提升眼軸伸長抑制效果或EGR-1上升效果為目的,或者以有效改善近視或者眼部疾病為目的,可摻混於眼科用組成物或機能性食品等。 [實施例]
根據實施例與比較例更詳細地說明本發明。
[實驗1] (穩定表現株的製作) 進行EGR-1誘導效果的確認實驗。首先準備人類胎兒腎細胞株(HEK293T)、與經導入EGR-1基因之慢病毒載體(製品名「Cignal Lenti EGR-1 Reporter(luc)」,Quiagen公司)。於第1天,對24孔孔盤播種人類胎兒腎細胞株,於5% CO2
保溫箱中、37℃下使其生長24小時。於第2天,形質導入慢病毒150μL/孔,進一步添加12μL的SureENTRY形質導入試劑(Quiagen公司),於5%CO2
保溫箱中、37℃下放置一夜。其後,將慢病毒與Medium(介質)一併去除,使用嘌呤黴素(1μg/mL)進行篩選。藉由此種程序,即製成基因導入與EGR-1活性相關之-Firefly-Luciferase而成的HEK293T細胞株(穩定表現株)。
(基因表現解析) 其次,進行使用螢光素酶之基因表現解析。解析係使用多模式平板讀數儀(製品名「Synergy HTX」,BioTek公司)。將基因導入與EGR-1活性相關之-Firefly-Luciferase而成的HEK293T細胞株,以1×104
個/孔播種於96孔孔盤。使細胞於孔盤底面植活後,添加試驗試劑,於24小時後使用Promega公司製Luciferase assay system進行發光強度的測定。
作為試驗試劑,係使用藏紅花酸(Chrovit P, Riken Vitamin股份有限公司製)、銀杏葉萃取物(銀杏葉甘草萃取物,Indena Japan股份有限公司製)、核桃多酚(核桃多酚-P10,Oryza Oil&Fat Chemical股份有限公司製)、山竹萃取物(Mangostin Aqua,日本新藥股份有限公司製)、草莓種子萃取物(草莓種子萃取物-P,Oryza Oil&Fat Chemical股份有限公司製)、瓜拿納萃取物(瓜拿納萃取物粉末,日本粉末股份有限公司製)、爪哇薑萃取物(爪哇薑萃取物粉末,HOSODA SHC股份有限公司製),且作為EGR-1表現之陽性對照組的PMA(12-肉豆蔻酸酯 13-乙酸酯,abcam公司製)。以濃度最終成為0.25mg/mL的方式將上述試驗試劑溶於DMSO(二甲基亞碸),於常溫(約20℃)下放置一夜,其後進行離心並將上清液添加於細胞培養液,而得到0.25mg/mL的試驗試劑。
此外,在改變濃度的試驗中,係使用Chrovit P。Chrovit P為藏紅花酸含量75%以上的粉末,將此Chrovit P溶於DMSO(二甲基亞碸)成100mg/mL,於常溫(約20℃)下放置一夜。其後,進行離心並將上清液添加於細胞培養液,而得到0.125mg/mL的試驗試劑、與0.25mg/mL的試驗試劑。
(結果) 圖1為表示添加上述各種試驗試劑時與未添加時之誘導EGR-1表現之結果的圖表。圖2為表示改變作為試驗試劑使用之藏紅花酸(Chrovit P)的濃度時之結果的圖表。由圖1可知,與僅添加不含試驗試劑之DMSO時相比,添加0.25mg/mL的藏紅花酸(Chrovit P)時之結果,發光強度達5.7倍,與作為陽性對照的PMA相比亦可看出顯著差異。亦即,可確認藏紅花酸所產生的顯著EGR-1誘導效果。又,可確認銀杏葉萃取物的發光強度亦達3.8倍左右,而且其他的試驗試劑亦為與作為陽性對照之PMA同等的發光強度。
又,由圖2可知,添加0.125mg/mL的Chrovit P時之結果、與添加0.25mg/mL的Chrovit P時之結果,與僅添加不含試驗試劑之DMSO時相比係明顯增強。亦即,實施與DMSO之Dunnett檢定的結果,採0.125mg/mL時為5.0倍(P<0.01),採加倍濃度的0.25mg/mL時為5.2倍(P<0.005),分別為極顯著,於體外因藏紅花酸而使EGR-1表現顯著增強。
非專利文獻9、10為報導EGR-1誘導效果與眼軸長度之關係的研究論文,其驗證經基因剔除EGR-1之小鼠可看出眼軸伸長(非專利文獻9),以及,若人為抑制眼軸伸長則可增強EGR-1表現(非專利文獻10)。然而,其中能以細胞層次增強EGR-1表現的藥劑能以個體層次抑制眼軸伸長,其結果,是否能從而抑制近視惡化還未能驗證。因此,以下實施近視模型動物之眼軸伸長的驗證試驗。
[實驗2] 於實驗2中,係進行近視模型動物之眼軸伸長的驗證試驗。小鼠係使用C57BL/6J小鼠(公、3週大)。對小鼠在光環境(12小時/12小時)下,從3週大至6週大餵食控制組飼料群(MF,Oriental Yeast工業股份有限公司)或0.003% Chrovit P混合飼料(Oriental Yeast工業股份有限公司)。
(測定裝置、測定程序) 作為測定裝置,係使用頻譜域光同調斷層掃描(Envisu R4310, Leica公司製)、小鼠用紅外線光反射器(Infrared photorefractor for mice)、與Version 1.0.15b3,堀內電機製作所股份有限公司製)。此外,小鼠用紅外線光反射器為由Prof.F Schaeffel(Steinbeis Transfer Center, Germany)製作之改良成可辨識小鼠眼睛的裝置,係使用紅外線LED照射小鼠的眼睛,並與此同時使用紅外線攝影機感測由眼睛射出的紅外線反射光,而由反射光的形狀與強度來判斷近視程度的裝置。此裝置係於近視研究領域廣泛使用,亦可比較整個研究室的數據。折射係採用取得穩定的值後將100次平均所得的值。針對各群實施welch-t檢定,將P值為0.05以下者評為顯著(以”*”表示於圖表中)、將0.01以下者評為極顯著(以”**”表示於圖表中)。
作為試驗試劑,為了在測定時使瞳孔穩定而使用Mydrin P(註冊商標,參天製藥股份有限公司)。又,使用三種混合麻醉(美托咪錠鹽酸鹽(Dimotor/註冊商標,日本全藥工業股份有限公司)、咪達唑侖(Dormicum/註冊商標,Astellas製藥股份有限公司)、布托菲諾酒石酸鹽(Vetorphale/註冊商標,Meiji Seika股份有限公司)),且為了解除麻醉而使用阿替美唑鹽酸鹽(Antisedan/註冊商標,日本全藥工業股份有限公司)、戊巴比妥鈉(Somnopentyl/註冊商標,共立製藥股份有限公司)。
試驗係首先測定眼參數。此測定係(1)對眼睛滴下Mydrin P(註冊商標)使兩眼散瞳,(2)將三種混合麻醉投予至腹腔內而施予麻醉,(3)以小鼠用紅外線光反射器量測折射,(4)以頻譜域光同調斷層掃描測定眼軸長度。
其次,對小鼠戴上眼鏡。具體而言,係以剪刀剪除頭頂部的皮膚,以牙科用Super Bond(4-META/MMA-TBB樹脂)將由3D印表機作成的眼鏡用支柱黏接於頭蓋骨上,對左眼安裝0Diopter鏡片、對右眼安裝-30Diopter鏡片。
接著,(a)使用Antisedan(註冊商標)消除麻醉,(b)分成各飼料群予以飼養(此時,眼鏡的鏡片弄髒時則隨時清潔),(c)達6週大後再度測定上述之眼參數。
(結果) 圖3為眼軸長度測定的結果、圖4為折射測定的結果。由圖3之結果,就於體外[實驗1]確認EGR-1表現增強作用之餵食Chrovit P的0.003%混合飼料的誘發近視小鼠(圖表中的0.003%),與餵食控制組飼料的小鼠(圖表中的control)相比可顯著(p<0.05)抑制眼軸伸長。又,由圖4之結果,與未誘發近視之小鼠(圖表中的0D之control)相比,因誘發近視(圖表中的-30D之control)而使折射(Diopter)顯著(P<0.01)降低,係使小鼠誘發明顯的近視。又,就同樣地餵食Chrovit P飼料的誘發近視小鼠(圖表中的-30D之0.003 %),與餵食控制組飼料的小鼠(圖表中的-30D之control)相比折射明顯(P<0.05)較高,近視誘發由藏紅花酸顯著抑制。亦即,於體外藏紅花酸可顯著預防近視惡化。此外,經確認藉由篩選出於體外具有EGR-1表現增強作用的藥物,可有效地篩選出生物體中實際的眼軸伸長抑制成分。
圖1為表示對本發明之眼科用組成物所含之成分的EGR-1基因表現之效果的圖表。 圖2為表示改變本發明之眼科用組成物所含之試驗試劑的含量時對EGR-1基因表現之效果的圖表。 圖3為實驗2中所得之眼軸長度測定的結果。 圖4為實驗2中所得之折射測定的結果。
Claims (22)
- 一種眼科用組成物,其係用於近視或者眼部疾病的預防或處置,且含有選自由藏紅花酸及其藥學上可容許之鹽,以及銀杏葉萃取物所成群組的至少1種成分。
- 如請求項1之眼科用組成物,其係進一步含有藏紅花酸及其藥學上可容許之鹽,以及銀杏葉萃取物以外的類胡蘿蔔素類及/或多酚類。
- 如請求項1或2之眼科用組成物,其中前述近視為軸性近視。
- 如請求項1至3中任一項之眼科用組成物,其係供成長期之兒童用。
- 如請求項1至4中任一項之眼科用組成物,其中前述近視為深度近視。
- 如請求項1或2之眼科用組成物,其中前述眼部疾病為隨年齡增長所引起的眼部疾病。
- 如請求項1或2之眼科用組成物,其中前述眼部疾病為由深度近視所引起的併發症。
- 如請求項6或7之眼科用組成物,其中前述眼部疾病為白內障及後眼部疾病。
- 如請求項8之眼科用組成物,其中前述後眼部疾病為選自由青光眼、視網膜剝離、黃斑裂孔、中央窩視網膜分裂、脈絡膜新生血管形成、眼後葡萄腫、近視性黃斑病變、及近視性神經病變所成群組的至少一種。
- 如請求項1至9中任一項之眼科用組成物,其係用於抑制眼軸伸長。
- 如請求項1至10中任一項之眼科用組成物,其係用於增強EGR-1之表現。
- 一種用於近視或者眼部疾病的預防或處置之機能性食品,其係含有選自由藏紅花酸及其藥學上可容許之鹽,以及銀杏葉萃取物所成群組的至少1種成分。
- 一種機能性食品,其係包含如請求項1至11中任一項之眼科用組成物。
- 一種有效用於近視或者眼部疾病的預防或處置之物質的篩選方法,其特徵在於以有無增強EGR-1表現之效果為指標。
- 一種眼科用組成物,其係含有EGR-1表現增強劑。
- 如請求項15之眼科用組成物,其中EGR-1表現增強劑係包含抗氧化性植物萃取物。
- 如請求項15或16之眼科用組成物,其係用於抑制眼軸伸長。
- 一種眼科用組成物,其係含有眼軸伸長抑制劑。
- 如請求項18之眼科用組成物,其中眼軸伸長抑制劑係包含抗氧化性植物萃取物。
- 如請求項15至19中任一項之眼科用組成物,其係用於近視或者眼部疾病的預防或處置。
- 一種眼科用組成物,其係供近距離作業者用及/或者屋內作業者用,且含有選自由藏紅花酸及其藥學上可容許之鹽,以及銀杏葉萃取物所成群組的至少1種成分。
- 如請求項21之眼科用組成物,其係供兒童用。
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