CN1708300A - 特应性皮炎的预防或治疗用口服剂 - Google Patents
特应性皮炎的预防或治疗用口服剂 Download PDFInfo
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- CN1708300A CN1708300A CNA200380102398XA CN200380102398A CN1708300A CN 1708300 A CN1708300 A CN 1708300A CN A200380102398X A CNA200380102398X A CN A200380102398XA CN 200380102398 A CN200380102398 A CN 200380102398A CN 1708300 A CN1708300 A CN 1708300A
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- Prior art keywords
- hydroxyproline
- acylated derivatives
- salt
- proline
- feedstuff
- Prior art date
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Abstract
通过本发明可以提供含有羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐的特应性皮炎的预防或治疗用口服剂、饮食品、饲料、食品添加剂或饲料添加剂,特别提供含有0.1~90重量%的羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐的该口服剂、饮食品、饲料、食品添加剂或饲料添加剂。
Description
技术领域
本发明涉及含有羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐的特应性皮炎的预防或治疗用口服剂、饮食品、饲料、食品添加剂和饲料添加剂。
背景技术
根据日本厚生劳动省的免疫学调查,报道了约30%的人口患有各种形式的过敏性疾病。关于特应性皮炎,特别地报道了不仅是幼儿,在成人中其患病率也增加,同时也报道了难治病的增加。
现在,作为过敏性疾病的治疗药,使用抗组胺剂、甾体药物、抗过敏药(参照《医学的进展》(医学のあゆみ),180卷,1期,70页,1997)。
抗组胺剂和抗过敏药对于减轻搔痒感的效果有速效性,但只不过是对抗疗法。
甾体药在被大量或长期使用时,有诱发感染症、降低肾上腺皮质机能、扩张毛细血管、皮肤萎缩等副作用,并非安全性治疗药。
作为具有特应性皮炎的预防或治疗效果的药品或饮食品,报道了乌龙茶提取物(参照特开平10-77231号公报)、棉子糖[参照FOODStyle 21,2卷,4期,262-265页,1998]、带蜂蜜的树脂[参照FOODStyle 21,2卷,4期,55-56页,1998]等。
已知通过外用羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐,可以发挥特应性皮炎的预防或治疗效果(参见国际公开第02/06225号册)。另外,已知配合有羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐的抗风湿药和创伤治疗药(参照特开平8-337526号公报)。但是,还不知道通过口服羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐,可以发挥特应性皮炎的预防或治疗效果。
公开内容
本发明的目的是提供安全的特应性皮炎的预防或治疗用口服剂、饮食品、饲料、食品添加剂和饲料添加剂。
本发明涉及以下(1)~(14)。
(1)一种特应性皮炎的预防或治疗用口服剂,含有羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐。
(2)如上述(1)所述的口服剂,含有0.1~90重量%的羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐。
(3)如上述(1)或(2)所述的口服剂,其中羟脯氨酸的N-酰化衍生物的酰基为碳原子数1~24的酰基。
(4)如上述(1)~(3)的任一项所述的一种口服剂,其中羟脯氨酸的N-酰化衍生物为N-乙酰化衍生物、N-丙酰化衍生物、N-丁酰化衍生物或异丁酰化衍生物。
(5)一种特应性皮炎的预防或治疗用饮食品或饲料,含有羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐。
(6)如上述(5)所述的饮食品或饲料,含有0.1~90重量%的羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐。
(7)如上述(5)或(6)所述的饮食品或饲料,其中羟脯氨酸的N-酰化衍生物的酰基为碳原子数1~24的酰基。
(8)如上述(5)~(7)的任一项所述的饮食品或饲料,其中羟脯氨酸的N-酰化衍生物为N-乙酰化衍生物、N-丙酰化衍生物、N-丁酰化衍生物或异丁酰化衍生物。
(9)一种特应性皮炎的预防或治疗用食品添加剂或饲料添加剂,含有羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐。
(10)如上述(9)所述的食品添加剂或饲料添加剂,含有0.1~90重量%的羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐。
(11)如上述(9)或(10)所述的食品添加剂或饲料添加剂,其中羟脯氨酸的N-酰化衍生物的酰基为碳原子数1~24的酰基。
(12)如上述(9)~(11)的任一项所述的食品添加剂或饲料添加剂,其中羟脯氨酸的N-酰化衍生物为N-乙酰化衍生物、N-丙酰化衍生物、N-丁酰化衍生物或异丁酰化衍生物。
(13)一种特应性皮炎的预防或治疗方法,其特征在于口服或摄取有效量的羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐。
(14)羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐在用于特应性皮炎的预防或治疗用口服剂、食品、饲料、食品添加剂或饲料添加剂的制造中的应用。
本发明中使用的羟脯氨酸,可以为任一种羟脯氨酸的立体异构体。即,通过羟脯氨酸的脯氨酸为D型或L型,或羟基的位置为3位或4位,或其立体异构体顺式或反式,而有8种立体异构体,而任一种化合物都可以用于本发明。
作为具体的羟脯氨酸,可以列举出顺式-4-羟基-L-脯氨酸、顺式-4-羟基-D-脯氨酸、顺式-3-羟基-L-脯氨酸、顺式-3-羟基-D-脯氨酸、反式-4-羟基-L-脯氨酸、反式-4-羟基-D-脯氨酸、反式-3-羟基-L-脯氨酸、反式-3-羟基-D-脯氨酸。
羟脯氨酸作为胶原中的主要构成氨基酸成分或作为弹性蛋白的构成氨基酸,是广泛存在于自然界中的氨基酸的一种,例如可以通过将来源于猪或牛等动物的胶原进行酸水解,并用常规方法精制制造。
反式-4-羟基-L-脯氨酸,可以使用从拟无核酸菌(Amycolatopsis)属或指孢囊菌(Dactylosporangium)属中分离出的脯氨酸4位氢氧化酶(特开平7-313179)来制造。另外,顺式-3-羟基-L-脯氨酸,可以使用从链霉菌(Streptomyces)属中分离出的脯氨酸3位氢氧化酶(特开平7-322885)来制造(Bioindustry,14卷,31期,1997年)。
使用上述的来源于微生物的酶所制造的羟脯氨酸品质优异,更优选作为本发明中使用的羟脯氨酸。
作为本发明中使用的羟脯氨酸的N-酰化衍生物,可以列举出上述的各种羟基氨基酸的立体异构体的N-酰化衍生物。作为该N-酰化衍生物的酰基,可以列举出碳原子数1~24,更优选碳原子数1~12,特别优选碳原子数1~6的酰基,具体地可以列举出例如甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、新戊酰基、己酰基、庚酰基、辛酰基、壬酰基、癸酰基、十一酰基、十二酰基等,特别优选乙酰基、丙酰基、丁酰基、异丁酰基。
作为羟脯氨酸或羟脯氨酸的N-酰化衍生物的盐,可以列举出钠、钾、锂等碱金属盐,钙、镁等碱土金属盐,铵盐、单乙醇胺、二乙醇胺、三乙醇胺、三异丙醇胺等的胺加成盐和精氨酸、赖氨酸等的碱性氨基酸的加成盐等。
羟脯氨酸的N-酰化衍生物可通过公知的方法进行调制。例如,羟脯氨酸的N-酰化衍生物,可以通过使用亚硫酰氯、碳酰氯等的卤化剂来将直链或支链的碳原子数1~24的饱和或不饱和脂肪酸转变为酰氯、酰溴等卤化物后,使其与上述的羟脯氨酸进行缩合,或将脂肪酸转变成酸酐后,使其与羟脯氨酸进行反应来制造。
作为脂肪酸,例如可以单独或组合使用甲酸、乙酸、丙酸、丁酸、异丁酸、戊酸、异戊酸、新戊酸、己酸、庚酸、辛酸、壬酸、癸酸、十一酸、十二酸等脂肪酸。
以下示出经由酰卤化物的羟脯氨酸的N-酰化衍生物的制造方法。
将脂肪酸分散于二氯甲烷、氯仿、四氯化碳、苯、甲苯、二甲苯、正己烷等溶剂中,向其中添加1~5倍当量的卤化剂使其反应,获得脂肪酰卤化物。然后,将羟脯氨酸溶解或分散在溶剂中,将所得溶液保持在5~70℃,同时添加相当于羟脯氨酸0.3~3.0倍当量的上述脂肪酰卤化物,通过酰化反应可以制造羟脯氨酸的N-酰化衍生物。
作为用于酰化反应的溶剂,可以列举出水、甲醇、乙醇、异丙醇、异丁醇、丙酮、甲苯、四氢呋喃、乙酸乙酯、N,N-二甲基甲酰胺,二甲基亚砜等,可以将它们单独或混合使用。将羟脯氨酸溶解或分散于溶剂中时,可以根据需要向溶剂中溶解或分散相对于羟脯氨酸的0.8~2.0倍当量的氢氧化钠、氢氧化钾等碱性物质。
要获得羟脯氨酸的N-酰化衍生物的盐时,在以盐的形式获得羟脯氨酸的N-酰化衍生物的情况下,可以直接精制;在以游离形式获得的情况下,可以使其溶解或混悬于适当的溶剂中,加入碱而形成盐。
精制可以使用例如结晶化法,色谱法等常规方法。
作为具体的羟脯氨酸的N-酰化衍生物,例如可以列举出N-乙酰基-顺式-4-羟基-L-脯氨酸、N-乙酰基-顺式-4-羟基-D-脯氨酸、N-乙酰基-顺式-3-羟基-L-脯氨酸、N-乙酰基-顺式-3-羟基-D-脯氨酸、N-乙酰基-反式-4-羟基-L-脯氨酸、N-乙酰基-反式-4-羟基-D-脯氨酸、N-乙酰基-反式-3-羟基-L-脯氨酸、N-乙酰基-反式-3-羟基-D-脯氨酸、N-丙酰基-顺式-4-羟基-L-脯氨酸、N-丙酰基-顺式-4-羟基-D-脯氨酸、N-丙酰基-顺式-3-羟基-L-脯氨酸、N-丙酰基-顺式-3-羟基-D-脯氨酸、N-丙酰基-反式-4-羟基-L-脯氨酸、N-丙酰基-反式-4-羟基-D-脯氨酸、N-丙酰基-反式-3-羟基-L-脯氨酸、N-丙酰基-反式-3-羟基-D-脯氨酸、N-丁酰基-顺式-4-羟基-L-脯氨酸、N-丁酰基-顺式-4-羟基-D-脯氨酸、N-丁酰基-顺式-3-羟基-L-脯氨酸、N-丁酰基-顺式-3-羟基-D-脯氨酸、N-丁酰基-反式-4-羟基-L-脯氨酸、N-丁酰基-反式-4-羟基-D-脯氨酸、N-丁酰基-反式-3-羟基-L-脯氨酸、N-丁酰基-反式-3-羟基-D-脯氨酸、N-异丁酰基-顺式-4-羟基-L-脯氨酸、N-异丁酰基-顺式-4-羟基-D-脯氨酸、N-异丁酰基-顺式-3-羟基-L-脯氨酸、N-异丁酰基-顺式-3-羟基-D-脯氨酸、N-异丁酰基-反式-4-羟基-L-脯氨酸、N-异丁酰基-反式-4-羟基-D-脯氨酸、N-异丁酰基-反式-3-羟基-L-脯氨酸、N-异丁酰基-反式-3-羟基-D-脯氨酸等。
在本发明的特应性皮炎的预防或治疗用口服剂、饮食品、饲料、食品添加剂或饲料添加剂中,羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐,可以单独或混合使用顺式/反式-4-羟基-L/D-脯氨酸、顺式/反式-3-羟基-L/D-脯氨酸或它们的各种N-酰化衍生物或其盐。
本发明的特应性皮炎的预防或治疗用口服剂、饮食品、饲料、食品添加剂或饲料添加剂中的羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐的含量,可以根据目的效果在宽范围内进行增减,例如为0.1~90重量%,优选为1~70重量%,特别优选为5~50重量%。
在本发明的特应性皮炎的预防或治疗用口服剂、饮食品、饲料、食品添加剂或饲料添加剂中,除了上述必要成分外,还可以适当含有适于各用途的添加剂。
本发明的口服剂含有羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐,根据需要也可以含有药理学允许的一种或一种以上的载体,进一步根据需要还可以含有用于其它治疗的有效成分。
本发明的口服剂,可以根据需要将羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐与载体一起混合,用在制剂学技术领域中熟知的任意方法来制造。
在将本发明的口服剂进行制剂化时,可以使用赋形剂、粘合剂、崩解剂、润滑剂、分散剂、混悬剂、乳化剂、稀释剂、缓冲剂、抗氧化剂、细菌抑制剂等添加剂。
作为口服剂的剂型,可以列举出片剂、散剂、颗粒剂、乳剂、糖浆剂、胶囊剂等。例如,口服剂的剂型为片剂、散剂、颗粒剂等时,可以添加乳糖、白糖、葡萄糖、蔗糖、甘露糖醇、山梨糖醇等糖类;马铃薯、小麦、玉米等的淀粉;碳酸钙、硫酸钙、碳酸氢钠、氯化钠等的无机物;甘草粉末、龙胆粉末等植物粉末等的赋形剂,淀粉、琼脂、明胶粉末、结晶纤维素、羧甲基纤维素钠、羧甲基纤维素钙、碳酸钙、碳酸氢钠、海藻酸钠等崩解剂,硬脂酸镁、滑石粉、氢化植物油、聚乙二醇、硅油等润滑剂,聚乙烯醇、羟丙基纤维素、甲基纤维素、乙基纤维素、羧甲基纤维素、明胶、淀粉浆等粘合剂,脂肪酸酯等表面活性剂、甘油等增塑剂等,来进行制剂化。
口服剂的剂型为糖浆剂等液体调制物时,可以添加水、蔗糖、山梨糖醇、果糖等糖类,聚乙二醇、丙二醇等二醇类,芝麻油、橄榄油、大豆油等油类,对羟基苯甲酸酯类等防腐剂、草莓调味剂、薄荷油等调味剂类等,来进行制剂化。
本发明的口服剂中的羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐的浓度,可以根据口服剂的种类和通过给予该口服剂所期望达到的效果等来适当选择,作为羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐,通常为0.1~90重量%,优选为1~70重量%,特别优选为5~50重量%。
本发明的口服剂的给药量根据给药方式、被给药者的年龄、体重的不同而不同,但是通常对于成人,每天作为羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐的有效量,为100~10000mg,优选为100~2000mg,特别优选为200~1000mg,每天给药1次或分数次进行给药。
本发明的口服剂也可以与其他的甾体药物等抗瘙痒剂合并使用。
作为甾体药物,可以使用氢化泼尼松龙、氢化可的松、地塞米松、倍他米松等糖皮质激素类,氟氢可的松、醇固酮等盐皮质激素等,而优选使用糖皮质激素剂。
另外,在本发明中所谓“特应性皮炎的预防”是指通过日常给药或摄取本发明的特应性皮炎预防剂,以达到(a)完全防止特应性皮炎的发病,(b)降低发病率或(c)抑制发病时的症状等的效果。
本发明的食品添加剂可以通过与上述说明口服剂同样的方法来调制。食品添加剂通常可根据需要混合或溶解其他的食品添加剂来加工制造成例如粉末、颗粒、微丸、片剂、各种液体制剂的形态。
作为本发明的饮食品,可以列举出在饮食品中添加了羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐的饮食品。
本发明的饮食品,可以在饮食品中添加羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐,另外可以通过使用一般的饮食品的制造方法进行加工制造。
本发明的饮食品,例如可以使用流化床制粒、搅拌制粒、挤出制粒、转动制粒、气流制粒、压缩成型制粒、破碎制粒、喷雾制粒、喷射制粒等制粒方法,锅包衣(pan loating)、流化床包衣、干式包衣等包衣方法,吹干(puff drying)、过剩水蒸气法、发泡垫法、微波加热法等膨化方法,挤出制粒机或挤压机等挤出方法等进行制造。
本发明的饮食品可以为果汁类、清凉饮食品水、茶类、乳酸菌饮料、发酵乳、冷饮、黄油、奶酪、酸奶、加工乳、脱脂乳等乳制品,火腿、香肠、汉堡等畜肉制品,鱼糕、鱼卷、鱼丸等鱼肉熟制品,鸡蛋卷、蒸蛋羹等蛋制品,小甜饼干、果冻、口香糖、糖果、点心等糕点类,面包类、面条类、咸菜类、熏制品、干品、调料煮品、盐腌品、汤类、调味料等任意形式。
另外,本发明的饮食品例如可以为粉末食品、薄片状食品、瓶装食品、罐装食品、软包装食品、胶囊食品、片状食品、流质食品、饮食品剂等形式。
本发明的饮食品可以作为特应性皮炎的预防或治疗用健康食品或功能性食品等的饮食品使用。
在本发明的饮食品或食品添加剂中,还可以添加一般地用于饮食品中的食品添加剂、例如甜味剂、着色剂、防腐剂、增粘稳定剂、抗氧化剂、发色剂、漂白剂、防霉剂、胶基、苦味剂、酶、光泽剂、酸味剂、调味剂、乳化剂、强化剂、制造用剂、香料、香辛料提取物等。
向本发明的饮食品中添加的羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐,或本发明的食品添加剂的添加量可以根据饮食品的种类和摄取该饮食品所期望获得的效果进行适当选择,但作为羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐,通常添加0.1~90重量%,优选1~70重量%,特别优选5~50重量%。
本发明的饮食品的摄取量根据摄取形态、摄取者的年龄、体重而不同,但是通常对于成人,每天作为羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐的有效量,为100~10000mg,优选为100~2000mg,特别优选为200~1000mg,每天摄取1次或分数次进行摄取。对摄取时间没有特别的限定,通常为1天~1年,优选为1周~3个月。
本发明的饲料添加剂,可以通过与本发明的口服剂同样的方法来调制。饲料添加剂通常根据需要混合或溶解其他的饲料添加物来加工制造成例如粉末、颗粒、微丸、片剂、各种液体制剂的形态。
本发明的饲料只要是对哺乳类、鸟类等动物的过敏性皮炎的预防或治疗用的饲料,作为宠物用饲料、家畜用饲料、家禽用饲料等任何饲料均可。例如,适用于猴子、狗、猫、大鼠和小鼠等宠物用的过敏性皮炎的预防或治疗用饲料。
本发明的饲料,可以在饲料中添加羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐或本发明的饲料添加剂,除此之外可以通过使用一般的饲料的制造方法进行加工制造。
作为饲料,可以列举出谷物类、糟糠类、植物油渣类、动物性饲料、其他饲料、精制品、或它们的混合物等。
作为谷物类,例如可以列举出高粱、小麦、大麦、燕麦、黑麦、糙米、荞麦、谷子、黍、稷、玉米、大豆等。
作为糟糠类,例如可以列举出米糠、脱脂米糠、皮糠、末粉、小麦、胚芽、麦糠、粒糠、玉米糠、玉米胚芽等。
作为植物油渣类,例如可以列举出大豆油渣、大豆粉、亚麻仁油油渣、棉子油渣、花生油渣、红花油渣、椰子油渣、棕榈油渣、芝麻油渣、葵花油渣、菜籽油渣、木棉油渣、芥子油渣等。
作为动物性饲料,例如可以列举出北洋粗粉、进口粗粉、国产粗粉、沿海粗粉等鱼粉、鱼汁、肉粉、肉骨粉、血粉、分解毛、骨粉、家畜用处理副产物、羽毛粉、蚕蛹、脱脂乳粉、酪蛋白、干燥乳清粉等。
作为其他饲料,例如可以列举出紫花苜蓿、干草块、苜蓿草粉、洋槐粉末等植物茎叶类,玉米蛋白面筋、粗粉、玉米面筋饲料、玉米浆等玉米加工工业副产品,淀粉等淀粉加工品、酵母、啤酒渣、麦芽根、酒渣、酱油渣等发酵工业产物,柑桔加工渣、豆腐渣、咖啡渣、可可渣等农产制造副产物、木薯、蚕豆、瓜果粉、海藻、磷虾、螺旋藻、绿藻、矿物等。
作为精制品,例如可以列举出酪蛋白、白蛋白等蛋白质,氨基酸、淀粉、纤维素、蔗糖、葡萄糖等糖质,矿物质、维生素等。
本发明的饲料,例如可以使用流化床制粒、搅拌制粒、挤出制粒、转动制粒、气流制粒、压缩成型制粒、破碎制粒、喷雾制粒、喷射制粒等制粒方法,锅包衣、流化床包衣、干式包衣等包衣方法,吹干(puffdrying)、过剩水蒸气法、发泡垫法、微波加热法等膨化方法,挤出制粒机或挤压机等挤出方法等进行制造。
向本发明的饲料中添加的羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐,或本发明的饲料添加剂的添加量,可以根据饲料的种类和摄取该饲料所期望获得的效果进行适当选择,作为羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐,通常添加0.1~90重量%,优选为1~70重量%,特别优选为5~50重量%。
本发明的饲料的摄取量根据摄取形态、摄取动物的种类、该动物的年龄、体重等而不同,但是通常对于动物,每天作为羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐的有效量为100~10000mg,优选100~2000mg,特别优选为200~1000mg,每天摄取1次或分数次进行摄取。对摄取时间没有特别的限定,通常为1天~1年,优选为1周~3个月。
以下示出研究通过羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐的特应性皮炎的预防或治疗效果的试验例。
试验例1使用发生特应性皮炎的模型小鼠的耳廓浮肿的抑制评价
在试验中使用了NC/Nga小鼠(5周龄,从Charles River公司购买)。饲养条件为室温22±2℃,湿度35±15%,自由摄取饲料和水。
从9天前涂布半抗原,开始表1示出的试验饲料给药。试验饲料是通过向粉末饲料CE-2(日本CLEA社制)中充分混合0.25重量%的N-乙酰基-反式-4-羟基-L-脯氨酸或0.50重量%的反式-4-羟基-L-脯氨酸来调制。将含有N-乙酰基-反式-4-羟基-L-脯氨酸的饲料设为饲料1,将含有反式-4-羟基-L-脯氨酸的饲料设为饲料2,对照饲料使用粉末饲料CE-2。
表1
成分 | 饲料1(重量%) | 饲料2(重量%) |
粉末饲料CE-2 | 99.75 | 99.5 |
N-乙酰基-反式-4-羟基-L-脯氨酸 | 0.25 | 0 |
反式-4-羟基-L-脯氨酸 | 0 | 0.5 |
作为半抗原,使用将1.5重量%的二硝基氯苯(DNCB)溶解于由20体积%的橄榄油和80体积%的丙酮液组成的溶液中所形成的溶液。
小鼠是以每试验组3只进行分组的,在开始给予饲料后的9天后、10天后、13天后、14天后,在右耳廓部的两面分别涂布20μl的1.5%的DNCB。
从开始涂布半抗原那天开始,使用PESCOCK DIAL THICKNESSGAUGE(尾崎制作所制)每日一次测定右耳廓的厚度。
表2示出了将耳廓浮肿的增加量作为相对DNCB未处理小鼠的耳廓浮肿的增加值的相对值,根据下述式1算出的结果。
(式1)
相对耳廓浮肿的增加量(%)=[(A1×B2)/(A2×B1)]×100
A1:被检小鼠的经过数日后的耳廓厚度
A2:被检小鼠的试验开始时的耳廓厚度
B1:未处理小鼠的经过数日后的耳廓厚度
B2:未处理小鼠的试验开始时的耳廓厚度
表2
DNCB处理 | 饲料 | 相对耳廓浮肿的增加量(%) | |
第23天 | 第27天 | ||
- | CE-2 | 100.00±2.7 | 100.0±2.7 |
+ | CE-2 | 642.0±23.7 | 478.9±38.0 |
+ | 饲料1 | 565.7 ±40.5 | 390.2±37.0 |
+ | 饲料2 | 510.7±78.2 | 369.8±62.6 |
相对于在对照饲料喂养组中的由DNCB诱发的耳廓浮肿,在含有0.25%的N-乙酰基-反式-4-羟基-L-脯氨酸的饲料喂养组和含有0.5%的反式-4-羟基-L-脯氨酸的饲料喂养组中,耳廓浮肿被明显地抑制。
试验例2使用发生特应性皮炎的模型小鼠的IgE浓度的评价
对于试验例1中使用的发生特应性皮炎的模型小鼠,在开始给予试验饲料27天后,从右大腿部采血。将采血样品进行离心分离后,回收血清,用ELISA测定血清中的IgE浓度,结果示于表3。
表3
DNCB处理 | 饲料 | 血清中的IgE浓度(ng/ml) |
- | CE-2 | 62.5±20.8 |
+ | CE-2 | 833.3±128.1 |
+ | 饲料1 | 365.7±103.4 |
+ | 饲料2 | 441.0±274.3 |
相对于在对照饲料喂养组中的由涂布DNCB导致的血清中的IgE浓度上升,在含有0.25%的N-乙酰基-反式-4-羟基-L-脯氨酸的饲料喂养组和含有0.5%的反式-4-羟基-L-脯氨酸的饲料喂养组中,由涂布DNCB导致的血清中的IgE浓度的上升被有统计学意义地被抑制。
试验例3使用发生特应性皮炎的模型小鼠的肥大细胞数评价
对于试验例1使用的发生特应性皮炎的模型小鼠,在给予试验饲料开始27天后,将耳廓部组织冻结包埋于Tissue-TekO.C.T.compound(Sakura精机株式会社)中。在低温保持器中制成6μm的薄切片后,进行甲苯胺蓝染色,计测肥大细胞数,结果示于表4中。
表4
DNCB处理 | 饲料 | 肥大细胞密度(细胞数/mm2) |
- | CE-2 | 9.8±5.8 |
+ | CE-2 | 33.2±10.8 |
+ | 饲料1 | 17.1±2.1 |
+ | 饲料2 | 17.4±2.3 |
相对于在对照饲料喂养组中的由涂布DNCB导致的在炎症部位的肥大细胞密度的增加,在含有0.25%的N-乙酰基-反式-4-羟基-L-脯氨酸的饲料喂养组和含有0.5%的反式-4-羟基-L-脯氨酸的饲料喂养组中,涂布DNCB引起的肥大细胞密度的增加被明显抑制。
以上结果显示口服摄取羟脯氨酸或羟脯氨酸的N-酰化衍生物对于特应性皮炎的预防或治疗是有效的。
以下示出本发明的实施例。
具体实施方式
实施例1含有羟脯氨酸的N-酰化衍生物的片剂的制造
用常规方法制造含有N-乙酰基-反式-4-羟基-L-脯氨酸的片剂。即,均匀地混合表5中记载的各成分,将该混合物用单冲打片机进行打片,获得直径为5mm,重量为15mg的片剂。
表5
成分 | 量(g) |
N-乙酰基-反式-4-羟基-L-脯氨酸 | 10.0 |
乳糖 | 90.0 |
干燥玉米淀粉 | 2.0 |
滑石粉 | 1.8 |
硬脂酸镁 | 0.2 |
实施例2含有羟脯氨酸的N-酰化衍生物的颗粒剂的制造
将实施例1中获得的片剂进行粉碎、制粒、筛分,获得20-50目的颗粒剂。
实施例3含有羟脯氨酸的N-酰化衍生物的饮食品的制造
含有N-乙酰基-反式-4-羟基-L-脯氨酸的饮食品,是通过均匀地搅拌溶解表6中记载的各成分,加入精制水使总量成为1000ml来制造的。另外,所谓表6中的适量,对于香料、色素是指用于通常的饮食品的制造的量,对于精制水是指用于加至其他成分,使总量成为1000ml的必要的量。
表6
成分 | 量(g) |
N-乙酰基-反式-4-羟基-L-脯氨酸 | 5.0 |
苯甲酸钠 | 1.0 |
果糖 | 10.0 |
香料 | 适量 |
色素 | 适量 |
精制水 | 适量 |
实施例4含有羟脯氨酸的N-酰化衍生物的糖的制造
含有由表7记载的各成分组成的N-乙酰基-反式-4-羟基-L-脯氨酸的糖,可以通过常规方法进行制造。
表7
成分 | 量(g) |
N-乙酰基-反式-4-羟基-L-脯氨酸 | 1.0 |
粉末山梨糖醇 | 98.75 |
香料 | 0.2 |
山梨糖醇蜂蜜酒 | 0.05 |
工业实用性
通过本发明可以提供安全的特应性皮炎的预防或治疗用口服剂、饮食品、饲料、食品添加剂或饲料添加剂。
Claims (14)
1.一种特应性皮炎的预防或治疗用口服剂,含有羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐。
2.如权利要求1所述的口服剂,含有0.1~90重量%的羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐。
3.如权利要求1或2所述的口服剂,其中羟脯氨酸的N-酰化衍生物的酰基为碳原子数1~24的酰基。
4.如权利要求1~3的任一项所述的口服剂,其中羟脯氨酸的N-酰化衍生物为N-乙酰化衍生物、N-丙酰化衍生物、N-丁酰化衍生物或异丁酰化衍生物。
5.一种特应性皮炎的预防或治疗用饮食品或饲料,含有羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐。
6.如权利要求5所述的饮食品或饲料,含有0.1~90重量%的羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐。
7.如权利要求5或6所述的饮食品或饲料,其中羟脯氨酸的N-酰化衍生物的酰基为碳原子数1~24的酰基。
8.如权利要求5~7的任一项所述的饮食品或饲料,其中羟脯氨酸的N-酰化衍生物为N-乙酰化衍生物、N-丙酰化衍生物、N-丁酰化衍生物或异丁酰化衍生物。
9.一种特应性皮炎的预防或治疗用食品添加剂或饲料添加剂,含有羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐。
10.如权利要求9所述的食品添加剂或饲料添加剂,含有0.1~90重量%的羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐。
11.如权利要求9或10所述的食品添加剂或饲料添加剂,其中羟脯氨酸的N-酰化衍生物的酰基为碳原子数1~24的酰基。
12.如权利要求9~11的任一项所述的食品添加剂或饲料添加剂,其中羟脯氨酸的N-酰化衍生物为N-乙酰化衍生物、N-丙酰化衍生物、N-丁酰化衍生物或异丁酰化衍生物。
13.一种特应性皮炎的预防或治疗方法,其特征在于口服或摄取有效量的羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐。
14.羟脯氨酸或羟脯氨酸的N-酰化衍生物或其盐在用于特应性皮炎的预防或治疗用口服剂、饮食品、饲料、食品添加剂或饲料添加剂的制造中的应用。
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WO2007129725A1 (ja) * | 2006-05-09 | 2007-11-15 | Kyowa Hakko Bio Co., Ltd. | 肝障害抑制剤 |
EP2946779A1 (en) | 2007-02-22 | 2015-11-25 | Beiersdorf AG | Cosmetic and pharmaceutical applications of n-acetylhydroxyproline |
US8338404B2 (en) | 2007-09-11 | 2012-12-25 | Kyowa Hakko Bio Co., Ltd. | Composition and method for reducing allergen |
KR20120123301A (ko) * | 2009-12-10 | 2012-11-08 | 가부시키가이샤 롯데 | 아토피성 피부염 예방제 |
WO2019103506A2 (ko) * | 2017-11-24 | 2019-05-31 | 전북대학교 산학협력단 | N-아세틸 또는 n-아실 아미노산을 포함하는 아토피 또는 가려움증 치료용 조성물 |
CN114340612A (zh) * | 2019-05-24 | 2022-04-12 | 斯特姆德公司 | 包含n-酰基氨基酸作为有效成分的用于预防或治疗哮喘、鼻炎或结膜炎的组合物 |
AU2020283844B2 (en) * | 2019-05-24 | 2023-12-21 | Stemdr Inc. | Composition for preventing or treating asthma, rhinitis or conjunctivitis, comprising N-acyl amino acid as active ingredient |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3932638A (en) * | 1967-09-14 | 1976-01-13 | Franco-Chimie S.A.R.L. | Compositions and methods for wound healing |
US3988466A (en) * | 1973-06-01 | 1976-10-26 | Kyowa Hakko Kogyo Co., Ltd. | Prevention of gastric lesions |
US5827874A (en) * | 1995-05-05 | 1998-10-27 | Meyer; Hans | Methods of treating pain and inflammation with proline |
EP1159952B1 (en) * | 1999-03-02 | 2009-01-14 | Kyowa Hakko Kogyo Co., Ltd. | N-Acetylhydroxyproline for improving the moisture retention function of the epidermis |
WO2002006225A1 (fr) * | 2000-07-19 | 2002-01-24 | Kyowa Hakko Kogyo Co., Ltd. | Agents de prevention ou de traitement de la dermite atopique |
US20040048772A1 (en) * | 2001-01-05 | 2004-03-11 | Ryusuke Nakagiri | Preventives for arthritis |
CA2433714C (en) * | 2001-01-05 | 2009-03-03 | Kyowa Hakko Kogyo Co., Ltd. | Arthritis preventing or treating agent |
EP1547594A4 (en) * | 2002-09-30 | 2007-08-29 | Kyowa Hakko Kogyo Kk | PREVENTION OR TREATMENT OF DECUBITUS HORNS |
-
2003
- 2003-10-31 AU AU2003301757A patent/AU2003301757A1/en not_active Abandoned
- 2003-10-31 WO PCT/JP2003/014022 patent/WO2004039368A1/ja active Application Filing
- 2003-10-31 EP EP03809872A patent/EP1559425A4/en not_active Withdrawn
- 2003-10-31 KR KR1020057007246A patent/KR20050072118A/ko not_active Application Discontinuation
- 2003-10-31 US US10/532,721 patent/US20060034781A1/en not_active Abandoned
- 2003-10-31 JP JP2004548111A patent/JPWO2004039368A1/ja active Pending
- 2003-10-31 CN CNA200380102398XA patent/CN1708300A/zh active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111971037A (zh) * | 2017-11-24 | 2020-11-20 | 斯特姆德公司 | 用于治疗特应症或瘙痒症的包含n-乙酰基氨基酸或n-酰基氨基酸的组合物 |
Also Published As
Publication number | Publication date |
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US20060034781A1 (en) | 2006-02-16 |
AU2003301757A1 (en) | 2004-05-25 |
KR20050072118A (ko) | 2005-07-08 |
EP1559425A4 (en) | 2007-12-19 |
WO2004039368A1 (ja) | 2004-05-13 |
EP1559425A1 (en) | 2005-08-03 |
JPWO2004039368A1 (ja) | 2006-02-23 |
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