CN101594860A - Adam抑制剂 - Google Patents
Adam抑制剂 Download PDFInfo
- Publication number
- CN101594860A CN101594860A CNA2007800464343A CN200780046434A CN101594860A CN 101594860 A CN101594860 A CN 101594860A CN A2007800464343 A CNA2007800464343 A CN A2007800464343A CN 200780046434 A CN200780046434 A CN 200780046434A CN 101594860 A CN101594860 A CN 101594860A
- Authority
- CN
- China
- Prior art keywords
- acid
- ascorbic acid
- extract
- adam
- ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 108091022885 ADAM Proteins 0.000 title claims abstract description 59
- 102000029791 ADAM Human genes 0.000 title claims abstract description 57
- 239000003112 inhibitor Substances 0.000 title claims abstract description 23
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- 229960005070 ascorbic acid Drugs 0.000 claims abstract description 74
- 235000010323 ascorbic acid Nutrition 0.000 claims abstract description 73
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- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 9
- 230000005764 inhibitory process Effects 0.000 claims description 6
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Abstract
本发明提供一种ADAM抑制剂,其能够防止或改善由于ADAM活性增加所引起的疾病。该ADAM抑制剂包括右述通式(1)所示的抗坏血酸衍生物或其盐。式中,R表示碳原子数1~22的直链或支化的烷基。
Description
技术领域
本发明涉及新的ADAM抑制剂。
背景技术
已知称之为ADAM(a disintegrin and metalloprotease,解聚素和金属蛋白酶)的一组膜型金属蛋白酶是在细胞间和细胞外基质间相互作用上具有重要作用的酶,并且与细胞的分化和增殖、轴突的伸长和髓鞘形成等密切相关(例如非专利文献1)。此外,已知ADAM与基质金属蛋白酶(MMP)相似,具有从细胞表面切断肝素结合性EGF样生长因子(HB-EGF)、肿瘤坏死因子(TNF)、转化生长因子(TGF)等各种生长因子和细胞因子、淀粉样蛋白前体蛋白质(APP)以及其它许多膜蛋白,使之在细胞外游离的作用。ADAM在各种恶性肿瘤(神经胶质瘤、肺癌、乳腺癌等)和风湿病、阿尔茨海默氏病患者大脑皮质等病理组织中高表达,促进细胞的增殖和浸润,或者诱导在癌细胞的浸润中必需的血管新生(例如非专利文献2-6),抑制ADAM的活性被认为在防止癌和风湿病、阿尔茨海默氏病等的疾病的发展上是非常重要的。
非专利文献1:Yang P,Baker KA,Hagg T.The ADAMsfamily:Coordinators of nervous system development,plasticityand repair.Prog Neurobiol 2006;79:73-94。
非专利文献2:Arribas J,B ech-S erra JJ,Santiago-Josefat B.ADAMs,cell migration and cancer.Cancer Metastasis Rev 2006;25:57-68。
非专利文献3:Kodama T,Ideda E,Okada A等人,ADAM12is selectively overexpressed in human glioblastomas and isassociated with glioblastoma cell proliferation and shedding ofheparin-binding epidermal growth factor.Am J Pathol 2004;165:1743-53。
非专利文献4:Liu PC,Liu X,Li Y等人,Identification ofADAM10 as a Major Source of HER2 Ectodomain SheddaseActivity in HER2 Overexpressing Breast Cancer Cells.CancerBiol Ther 2006;5:657-64。
非专利文献5:Rocks N,Paulissen G,Quesada Calvo F等人,Expression of a disintegrin and metalloprotease (ADAM andADAMTS)enzymes in human non-small-cell lung carcinomas(NSCLC).Br J Cancer 2006;94:724-30。
非专利文献6:Asakura,M等人,2002.Cardiac hypertrophyis inhibited by antagonism of ADAM12 processing of HB-EGF:metalloproteinase inhibitors as a new therapy.Nat.Med.8:35-40。
发明内容
发明要解决的问题
一方面,作为ADAM抑制剂,已知有TAPI-1{N-(R)-(2-(羟氨基羰基)甲基)-4-甲基戊酰基-L-Nal-L-丙氨酸2-氨基乙基酰胺(L-Nal:L-3-(2’-萘基)丙氨酸)}和TAPI-2{N-(R)-(2-(羟氨基羰基)甲基)-4-甲基戊酰基-L-叔丁基-甘氨酰基-L-丙氨酸2-氨基乙基酰胺},但这些物质的ADAM抑制能力并不充分,另外,作为皮肤外用剂的安全性没有被确认。因此,寻求开发更安全有效的药物。
本发明是鉴于上述情况而作出的,其目的是提供ADAM抑制剂,该ADAM抑制剂具有ADAM抑制作用,能够防止或改善由于ADAM活性增加而导致的疾病。
用于解决问题的方案
ADAM存在于细胞表面上,是使HB-EGF、TNF-α、TGF-α等生长因子和细胞因子、淀粉样蛋白前体等从细胞膜游离和活化的酶。由于癌变的信号和外源性刺激,这些ADAM被活化或表达亢进,并促进HB-EGF等生长因子和细胞因子的游离和活化以及细胞的分化、增殖、游走,这被认为是诱发癌症、风湿病或阿尔茨海默氏病等疾病或使它们恶化的重要机制之一。因此,可认为,通过抑制ADAM活性而抑制细胞的分化、增殖和浸润,从而能够防止或改善癌症、风湿病或阿尔茨海默氏病等疾病的诱发或发展。另外,本发明并不仅仅适用于由ADAM活性增加而引起的疾病,例如通过适用于因表皮细胞的过度增殖而引起的皱纹,能够防止或改善皱纹。
因此,在对能够抑制ADAM的新的化合物的探索中,发现某些种类的抗坏血酸衍生物及其盐具有高的ADAM抑制活性,从而完成了本发明。
本发明是ADAM抑制剂,其特征在于包括下述通式(1)所示的抗坏血酸衍生物或其盐。
式中,R表示碳原子数1~22的直链或支化的烷基。
本发明的抗坏血酸衍生物通过阻断或抑制ADAM的活性而防止异常的细胞分化、增殖、游走。
此外,本发明是ADAM抑制方法,其特征在于将上述ADAM抑制剂施用于皮肤而防止或改善由于ADAM活性增加而导致的疾病。
发明的效果
本发明的ADAM抑制剂可抑制组织中存在的ADAM的活性,能够非常有效地抑制细胞表面上的各种生长因子和细胞因子的游离和活化以及细胞分化、增殖、游走。
根据本发明的ADAM抑制方法,使用上述ADAM抑制剂,能够有效防止或改善由于ADAM的活性增加而导致的疾病。
具体实施方式
以下说明本发明的最佳实施方案。
本发明中所使用的抗坏血酸衍生物或其盐用下述通式(1)表示:
式中,R表示碳原子数1~22的直链或支化的烷基。
本发明的化合物即抗坏血酸衍生物(1)中的R是碳原子数1~22的直链或支化的烷基,优选碳原子数4~18的直链或支化的烷基,更优选碳原子数12~18的直链或支化的烷基。作为所述基团,例如是甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基、庚基、辛基、2-乙基己基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、十九烷基、二十烷基、二十一烷基、二十二烷基等;优选是丁基、异丁基、叔丁基、戊基、己基、庚基、辛基、2-乙基己基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基等;更优选是十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基等。
作为本发明的抗坏血酸衍生物,可以列举出例如2-O-甲基抗坏血酸、2-O-乙基抗坏血酸、2-O-丙基抗坏血酸、2-O-异丙基抗坏血酸、2-O-丁基抗坏血酸、2-O-异丁基抗坏血酸、2-O-叔丁基抗坏血酸、2-O-戊基抗坏血酸、2-O-己基抗坏血酸、2-O-庚基抗坏血酸、2-O-辛基抗坏血酸、2-O-(2-乙基己基)抗坏血酸、2-O-壬基抗坏血酸、2-O-癸基抗坏血酸、2-O-十一烷基抗坏血酸、2-O-十二烷基抗坏血酸、2-O-十三烷基抗坏血酸、2-O-十四烷基抗坏血酸、2-O-十五烷基抗坏血酸、2-O-十六烷基抗坏血酸、2-O-十七烷基抗坏血酸、2-O-十八烷基抗坏血酸、2-O-十九烷基抗坏血酸、2-O-二十烷基抗坏血酸、2-O-二十一烷基抗坏血酸、2-O-二十二烷基抗坏血酸等。在这些当中,尤其优选的是2-O-十二烷基抗坏血酸、2-O-十八烷基抗坏血酸。
本发明中所使用的抗坏血酸衍生物除了游离酸以外还包括医学上可接受的盐的形式。作为这些盐,例如可以列举出钠盐、钾盐等碱金属盐,钙盐、镁盐等碱土金属盐、甲胺盐、二甲胺盐、三甲胺盐、甲基哌啶盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐、赖氨酸盐等胺盐,铵盐,或者碱性氨基酸盐等,但不限于这些。
抗坏血酸衍生物及其盐可以按照公知的制备方法来制备。
虽然没有限定,但本发明的包含抗坏血酸衍生物或其盐的ADAM抑制剂可以制成皮肤外用剂、散剂、颗粒、安瓿、注射液等形式使用。
在将本发明的ADAM抑制剂在皮肤外用剂中使用的情况下,抗坏血酸衍生物或其盐的配合量根据使用形式和制品形式等而不同,对此没有特定限制,例如,基于总量,该配合量优选为0.001~10质量%,更优选0.005~5质量%,还进一步优选0.01~1质量%。
在本说明书中,“皮肤外用剂”包括化妆品、药品、准药品等。同样,其剂型包括水溶液系、增溶系、乳化系、油液系、凝胶系、糊料系、软膏系、气溶胶系、水-油双相系、水-油-粉末三相等任意剂型。另外,还包括担载于片状基剂上的制剂。
另外,皮肤外用剂可采用的制品形式和用途也是任意的,例如,该皮肤外用剂可以作为化妆水、乳液、霜剂、面膜等面部用、身体用或头皮用外用剂使用。
皮肤外用剂可以如下制备:在上述抗坏血酸衍生物或其盐的基础上,根据需要适当配合化妆品、药品等皮肤外用剂中常用的其它任意成分,根据目的剂型通过常规方法来制备。例如,可以将抗坏血酸衍生物或其盐与下述成分中的一种或两种以上配合来制备皮肤外用剂。
作为紫外线吸收剂,可以列举出例如对氨基苯甲酸(下文简称PABA)、PABA单甘油酯、N,N-二丙氧基PABA乙酯、N,N-二乙氧基PABA乙酯、N,N-二甲基PABA乙酯、N,N-二甲基PABA丁酯、N,N-二甲基PABA甲酯等苯甲酸类紫外线吸收剂,N-乙酰基邻氨基苯甲酸高薄荷基酯等邻氨基苯甲酸类紫外线吸收剂,水杨酸戊酯、水杨酸薄荷基酯、水杨酸高薄荷基酯、水杨酸辛酯、水杨酸苯酯、水杨酸苄酯、水杨酸对异丙醇苯基酯等水杨酸类紫外线吸收剂,肉桂酸辛酯、4-异丙基肉桂酸乙酯、2,5-二异丙基肉桂酸甲酯、2,4-二异丙基肉桂酸乙酯、2,4-二异丙基肉桂酸甲酯、对甲氧基肉桂酸丙酯、对甲氧基肉桂酸异丙酯、对甲氧基肉桂酸异戊基酯、对甲氧基肉桂酸辛酯(对甲氧基肉桂酸2-乙基己酯)、对甲氧基肉桂酸2-乙氧基乙酯、对甲氧基肉桂酸环己基酯、α-氰基-β-苯基肉桂酸乙酯、α-氰基-β-苯基肉桂酸2-乙基己酯、单-2-乙基己酰基-二对甲氧基肉桂酸甘油酯、三甲氧基肉桂酸甲基双(三甲基硅氧烷)甲硅烷基异戊酯等肉桂酸类紫外线吸收剂,3-(4’-甲基苄叉基)-d,l-樟脑,3-苄叉基-d,l-樟脑,尿刊酸,尿刊酸乙酯,2-苯基-5-甲基苯并噁唑;2,2’-羟基-5-甲基苯基)苯并三唑;2-(2’-羟基-5’-叔辛基苯基)苯并三唑;2-(2’-羟基-5’-甲基苯基苯并三唑;二苄连氮;二茴香酰基甲烷;4-甲氧基-4’-叔丁基二苯甲酰基甲烷;5-(3,3-二甲基-2-亚降冰片基)-3-戊烷-2-酮,二吗啉代哒嗪酮等,可以使用它们的任意一种或两种以上。
作为紫外线散射剂,可以列举出氧化钛、微粒氧化钛、氧化锌、微粒氧化锌、氧化铁、微粒氧化铁、氧化铈等的粉末。
这些紫外线散射剂通常使用针状、纺锤状、球状、粒状的粉末。另外,粒径为0.1μm以下的微粒粉末是优选的。
疏水化处理的紫外线散射剂也是优选的,所述处理例如是甲基氢化聚硅氧烷(Methyl Hydrogen Polysiloxane)、硅烷偶联剂等的有机硅处理;金属皂处理;全氟烷基磷酸二乙醇胺盐、全氟烷基硅烷等氟处理;糊精脂肪酸酯处理等。
作为液体油脂,例如可以列举出鳄梨油、山茶油、海龟油、澳洲坚果油、玉米油、貂油、橄榄油、菜籽油、蛋黄油、芝麻油、桃仁油、小麦胚芽油、山茶花油、蓖麻油、亚麻子油、红花油、棉籽油、苏子油、大豆油、花生油、茶籽油、榧子油、米糠油、泡桐油、日本桐油、霍霍巴油、胚芽油、三甘油等。
作为固体油脂,例如可以列举出可可脂、椰子油、马脂、硬化椰子油、棕榈油、牛脂、羊脂、硬化牛脂、棕榈仁油、猪脂、牛骨脂、木蜡核油、硬化油、牛脚脂、木蜡、硬化蓖麻油等。
作为蜡,例如可以列举出蜂蜡、小烛树蜡、棉蜡、巴西棕榈蜡、杨梅蜡、白蜡、鲸蜡、褐煤蜡、米糠蜡、羊毛脂、木棉蜡、乙酰化羊毛脂、液状羊毛脂、甘蔗蜡、羊毛脂脂肪酸异丙酯、月桂酸己酯、还原羊毛脂、希蒙德木蜡、硬质羊毛脂、紫胶蜡、POE羊毛脂醇醚、POE羊毛脂醇醋酸酯、POE胆固醇醚、羊毛脂脂肪酸聚乙二醇、POE氢化羊毛脂醇醚等。
作为烃油,例如可以列举出液体石蜡、地蜡、角鲨烷、姥鲛烷、石蜡、纯地蜡、角鲨烯、凡士林、微晶蜡、聚乙烯蜡、费-托合成蜡(Fischer-Tropsch wax)等。
作为高级脂肪酸,例如可以列举出月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、山嵛酸、油酸、十一碳烯酸、妥尔油脂肪酸、亚油酸、亚麻酸、二十碳五烯酸(EPA)、二十二碳六烯酸(DHA)等。
作为高级醇,例如可以列举出直链醇(例如月桂醇、鲸蜡醇、硬脂醇、山嵛醇、肉豆蔻醇、油醇、十八十六醇等);支链醇(例如单硬脂基甘油醚(鲨肝醇)、2-癸基十四烷醇、羊毛脂醇、胆固醇、植物甾醇、己基十二烷醇、辛基十二烷醇等)等。
作为合成酯油,可以列举出肉豆蔻酸异丙酯、辛酸十六烷基酯、肉豆蔻酸辛基十二烷基酯、棕榈酸异丙酯、硬脂酸丁酯、月桂酸己酯、肉豆蔻酸十四烷基酯、油酸癸酯、二甲基辛酸己基癸酯、乳酸十六烷基酯、乳酸十四烷基酯、乙酰化羊毛脂、硬脂酸异十六烷酯、异硬脂酸异十六烷酯、12-羟基硬脂酸胆固醇酯、二-2-乙基己酸乙二醇酯、二季戊四醇脂肪酸酯、单异硬脂酸N-烷基二醇酯、二癸酸新戊二醇酯、苹果酸二异硬脂酯、二-2-庚基十一烷酸甘油酯、三羟甲基丙烷三-2-乙基己酸酯、三羟甲基丙烷三异硬脂酸酯、季戊四醇四-2-乙基己酸酯、三-2-乙基己酸甘油酯、三辛酸甘油酯、三异棕榈酸甘油酯、三羟甲基丙烷三异硬脂酸酯、2-乙基己酸十六烷基酯、棕榈酸2-乙基己基酯、三肉豆蔻酸甘油酯、三-2-庚基十一烷酸甘油酯、蓖麻油脂肪酸甲酯、油酸油酯、乙酰甘油酯、棕榈酸2-庚基十一烷基酯、己二酸二异丁酯、N-月桂酰基-L-谷氨酸-2-辛基十二烷基酯、己二酸二-2-庚基十一烷基酯、月桂酸乙酯、癸二酸二-2-乙基己酯、肉豆蔻酸2-己基癸酯、棕榈酸2-己基癸酯、己二酸2-己基癸酯、琥珀酸2-乙基己酯、柠檬酸三乙酯、聚氧乙烯-聚氧丙烯无规聚合物甲醚等。
作为硅油,例如可以列举出链状聚硅氧烷(例如聚二甲基硅氧烷、聚甲基苯基硅氧烷、聚二苯基硅氧烷等);环状聚硅氧烷(例如八甲基环四硅氧烷、十甲基环五硅氧烷、十二甲基环六硅氧烷等)、形成三维网状结构的硅酮树脂、硅酮橡胶、各种改性聚硅氧烷(氨基改性聚硅氧烷、聚醚改性聚硅氧烷、烷基改性聚硅氧烷、氟改性聚硅氧烷等)等。
此外,可以列举出聚乙二醇、甘油、1,3-丁二醇、赤藓醇、山梨醇、木糖醇和麦芽糖醇等保湿剂;纤维素、羟乙基纤维素、羟丙基纤维素、甲基羟丙基纤维素、甲基纤维素、羧甲基纤维素、榅桲籽、角叉菜胶、果胶、甘露聚糖、可得然胶(curdlan)、硫酸软骨素、淀粉、半乳聚糖、硫酸皮肤素、糖原、阿拉伯树胶、硫酸乙酰肝素、透明质酸、透明质酸钠、黄芪胶、硫酸角质素、软骨素、黄原胶、硫酸粘液素、羟乙基瓜尔豆胶、羧甲基瓜尔豆胶、瓜尔豆胶、右旋糖苷、硫酸角质、刺槐豆胶、琥珀聚糖、栝楼仁酸、壳多糖、脱乙酰壳多糖、羧甲基壳多糖、琼脂等增粘剂;乙醇等低级醇;丁基羟基甲苯、维生素E、肌醇六磷酸钙镁等抗氧化剂;苯甲酸、水杨酸、山梨酸、对羟基苯甲酸烷基酯、六氯酚等抗菌剂;酰基肌氨酸(例如月桂酰N-肌氨酸钠)、谷胱甘肽、柠檬酸、苹果酸、酒石酸、乳酸等有机酸;维生素A及其衍生物,维生素B6盐酸盐、维生素B6三棕榈酸盐、维生素B6二辛酸盐、维生素B2及其衍生物、维生素B12、维生素B15及其衍生物等维生素B类,抗坏血酸、抗坏血酸硫酸酯(盐)、抗坏血酸磷酸酯(盐)、抗坏血酸二棕榈酸酯等维生素C类,α-生育酚、β-生育酚、δ-生育酚、维生素E醋酸酯等维生素E类,维生素D类,维生素H,泛酸,泛酰巯基乙胺(pantetheine)等维生素;烟酰胺、烟酸苄酯、γ-谷维素、尿囊素、甘草酸(盐)、甘草亭酸及其衍生物、2-羟基-4-异丙基环庚三烯酮、没药醇、桉油精、百里酚、肌醇、皂苷类如柴胡皂苷、胡萝卜皂苷、丝瓜皂苷和无患子皂苷、泛醇乙基醚、乙炔基雌二醇、氨甲环酸、熊果苷、千金藤素和胎盘提取物等多种药品;羊蹄、苦参、日本萍蓬草、橙、鼠尾草、欧蓍草、锦葵、当药、百里香(thyme)、当归、云杉、白桦、问荆、丝瓜、欧洲七叶树、虎耳草、金车花、百合、艾蒿、芍药、芦荟、栀子、日本花柏、西洋山楂提取物、贯叶连翘提取物、鸢尾属提取物、儿茶提取物、银杏叶提取物、欧百里香提取物、茴香提取物、乌龙茶提取物、睡莲提取物、营实提取物、毛叶香茶菜提取物、黄芩提取物、黄柏提取物、野芝麻提取物、甘草提取物、栀子提取物、红茶提取物、西河柳提取物、委陵菜提取物(Tormentilla Extract)、玫瑰提取物、丝瓜提取物、薄荷提取物、迷迭香提取物及蜂王浆提取物等植物提取物;色素;失水山梨醇单月桂酸酯、失水山梨醇单棕榈酸酯、失水山梨醇倍半油酸酯、失水山梨醇三油酸酯、聚氧乙烯山梨糖醇酐单月桂酸酯、聚氧乙烯山梨糖醇酐单硬脂酸酯、聚乙二醇单油酸酯、聚氧乙烯烷基醚、聚乙二醇二醚、月桂酰二乙醇酰胺、脂肪酸异丙醇酰胺、麦芽糖醇羟基脂肪酸醚、烷基化多糖、烷基葡糖苷、糖酯等非离子型表面活性剂;硬脂基三甲基氯化铵、苯扎氯铵、月桂基氧化胺等阳离子型表面活性剂;棕榈酸钠、月桂酸钠、十二烷酸钠、月桂基硫酸钾、烷基硫酸三乙醇胺醚、土耳其红油、线性十二烷基苯硫酸、聚氧乙烯硬化蓖麻子油马来酸酯、酰基甲基牛磺酸等阴离子型表面活性剂;两性表面活性剂;中和剂;δ-生育酚、丁基羟基甲苯等抗氧化剂;以及苯氧基乙醇、对羟基苯甲酸酯等防腐剂。
上述成分为例示,本发明不限于这些成分。另外,这些成分可以按照符合期望的形式的配方适当组合来配合。
本发明的ADAM抑制剂可以作为目的是防止或改善由于ADAM活性升高所引起的疾病的药物而使用。在所述用途中,为了将本发明的ADAM抑制剂制成制剂,用通常的方法形成例如散剂、颗粒剂、安瓿、注射液、等渗液等。即,在制备口服固体制剂时,添加赋型剂以及根据需要而进一步添加粘合剂、湿润剂、崩解剂、表面活性剂、润滑剂、分散剂、矫味剂、矫臭剂等,然后用常规方法制成片剂、包衣片剂、颗粒、胶囊剂等。
作为所使用的赋型剂,例如可以列举出乳糖、葡萄糖、山梨醇、玉米淀粉等,作为粘合剂,例如可以列举出聚乙烯醇、聚乙烯醚、乙基纤维素、阿拉伯树胶、明胶、羟丙基纤维素、聚乙烯吡咯烷酮等,作为崩解剂,可以列举出碳酸钙、柠檬酸钙、糊精、淀粉、明胶粉末等,作为润滑剂,可以列举出碳酸钙、柠檬酸钙、滑石、聚乙二醇等,作为着色剂,可以列举出可可粉、薄荷芳香酸、薄荷油等。这些片剂、颗粒剂可以根据需要用糖衣、明胶衣等适当包衣。
在制备注射剂时,根据需要添加pH调节剂、缓冲剂、表面活性剂、增溶剂、溶剂、稳定剂、保存剂等,通过常规方法制成皮下、肌内、静脉内注射剂。
在本发明的抑制ADAM的方法中,抗坏血酸衍生物或其盐可以在皮肤上应用,并且只要能达成本发明的目的,能够以任意形式施用于皮肤,另外,可以单独应用,或者可以与其它任意成分一起配合来应用。另外,对施用的皮肤部位没有限制,包括含头皮在内的身体表面的所有皮肤。另外,可以通过内服、注射来应用。
另外,本发明的包含抗坏血酸衍生物或其盐的ADAM抑制剂的用途不限于治疗或预防由于上述ADAM活化导致的皮肤细胞增殖和分化而受到不良影响的各种疾病,还包括通过抑制ADAM活性而能够发挥效果的任意用途,例如,本发明不仅适用于由于ADAM活性升高所引起的疾病,而且通过应用于由于表皮细胞过度增殖而引起的皱纹,还能够防止或改善皱纹。
实施例
以下通过实施例来进一步详细说明本发明。本发明不限于这些实施例。这里的配合量为质量%。
1.新的ADAM抑制剂的探索
ADAM活性抑制效果如下评价:以在ADAM的作用下从人淋巴瘤来源的U937细胞的膜切断并游离的TNF-α为指标,来评价药物带来的TNF-α游离抑制效果。用本方法筛选各种化合物,探索新的ADAM抑制剂。
将人淋巴瘤来源的U937细胞接种至48孔板中,调节细胞数为1×105个细胞/0.25ml,在37℃下培养过夜。添加含有5μg/ml或30μg/ml的抗坏血酸衍生物的培养基,在37℃下孵育30分钟进行预处理。此后,添加10nM PMA(佛波醇酯:12-O-四癸酰基佛波醇醋酸酯;Sigma P8139),在37℃下培养6小时。处理结束后,回收培养上清,离心,将不含细胞的上清在-20℃下冷冻保存。使用R&D公司的hTNF-αDuo-Set ELISA试剂盒来实施游离的hTNF-α的分析,将各培养上清用培养基稀释5倍,分别添加100μl到96孔板中,根据R&D公司的操作程序测定。测定试剂盒测定各孔的450~570nm的吸光度,由标准曲线求出试样浓度。以0%抑制对照(仅含PMA的培养基)的吸光度为A0,以100%抑制对照(仅培养基)的吸光度为A100,以及以试样的吸光度为AS,通过下式算出抑制率(%)。
抑制率(%)=(A0-AS)/(A0-A100)×100
结果,在本发明的抗坏血酸衍生物中,确认尤其碳原子数多的2-O-十二烷基抗坏血酸、2-O-十八烷基抗坏血酸具有高的HB-EGF游离抑制效果,表明抑制了ADAM活性。各抗坏血酸衍生物的游离抑制率在表1中示出。
表1
以下示出了含有本发明的抗坏血酸衍生物或其盐的制剂例,但本发明不限于这些制剂例。
制剂例1:注射剂
(配方)
2-O-十二烷基抗坏血酸 100mg
氯仿 5ml
吐温-80 100mg
无菌蒸馏水 10ml
(制法)
将100mg微粉化的2-O-十二烷基抗坏血酸溶于5ml氯仿中,添加10mg吐温-80并混合,用微孔过滤器过滤灭菌后,用无菌蒸发器蒸发至干。添加10ml无菌蒸馏水,剧烈混合后,用超声波处理,封入安瓿中,制备注射剂。
制剂例2:乳液
(配方) 质量%
硬脂酸 2.5
鲸蜡醇 1.5
凡士林 5.0
液体石蜡 5.0
聚氧乙烯(10mol)单油酸酯 2.0
聚乙二醇1500 3.0
三乙醇胺 1.0
羧基乙烯基聚合物 0.05
2-O-十二烷基抗坏血酸 2.0
亚硫酸氢钠 0.01
对羟基苯甲酸乙酯 0.2
香料 适量
纯化水 余量
(制法)
将羧基乙烯基聚合物溶于少量纯化水中(A相)。在剩余的纯化水中添加聚乙二醇1500、三乙醇胺和2-O-十二烷基抗坏血酸,加热溶解,保持在70℃(水相)。混合其它成分,加热熔解,保持在70℃(油相)。将油相添加到水相中,进行预备乳化,添加A相,用均质混匀器均一乳化,乳化后在充分混合的同时冷却到30℃,获得乳液。
制剂例3:化妆水
(配方) 质量%
乙醇 5.0
羧基乙烯基聚合物 0.3
聚氧乙烯(15mol)油基醚 0.8
1,3-丁二醇 5.0
2-O-十八烷基抗坏血酸 2.0
柠檬酸 0.03
柠檬酸钠 0.07
对羟基苯甲酸甲酯 0.1
纯化水 余量
(制法)
在纯化水中溶解柠檬酸、柠檬酸钠和2-O-十八烷基抗坏血酸,形成水相。另一方面搅拌溶解其它成分,将其添加到水相中并均质化,获得化妆水。
制剂例4:霜剂
(配方) 质量%
硬脂酸 2.0
硬脂醇 7.0
氢化羊毛脂 2.0
2-辛基十二烷基醇 6.0
聚氧乙烯(25mol)鲸蜡醇醚 3.0
甘油单硬脂酸酯 2.0
2-O-十二烷基抗坏血酸 2.0
2-O-十八烷基抗坏血酸 2.0
1,3-丁二醇 5.0
乙二胺四乙酸三钠 0.1
甘草亭酸钠 0.1
维生素E醋酸酯 0.3
对羟基苯甲酸乙酯 0.3
纯化水 余量
(制法)
将2-O-十二烷基抗坏血酸、2-O-十八烷基抗坏血酸、1,3-丁二醇、乙二胺四乙酸三钠和甘草亭酸钠添加到纯化水中,保持在70℃,形成水相。另一方面,混合其它成分,加热熔解,保持在70℃,形成油相。在水相中添加油相,进行预备乳化,用均质混匀器均一乳化,然后冷却到30℃,获得霜剂。
制剂例5乳液
(配方) 质量%
聚二甲基硅氧烷 3.0
十甲基环五硅氧烷 4.0
乙醇 5.0
甘油 6.0
1,3-丁二醇 5.0
2-O-十二烷基抗坏血酸 0.5
2-O-十八烷基抗坏血酸 0.5
聚氧乙烯甲基葡糖苷 3.0
葵花籽油 1.0
角鲨烷 2.0
氢氧化钾 0.1
六偏磷酸钠 0.05
羟丙基-β-环糊精 0.1
4-甲氧基水杨酸钾 1.0
甘草酸二钾 0.05
枇杷叶提取物 0.1
L-谷氨酸钠 0.05
茴香提取物 0.1
酵母提取物 0.1
熏衣草油 0.1
地黄提取物 0.1
二吗啉代哒嗪酮 0.1
黄原胶 0.1
羧基乙烯基聚合物 0.1
丙烯酸/甲基丙烯酸烷基酯共聚物(PEMULEN TR-1) 0.1
铁丹 适量
氧化铁黄 适量
对羟基苯甲酸酯 适量
纯化水 余量
制剂例6乳液
(配方) 质量%
聚二甲基硅氧烷 3.0
十甲基环五硅氧烷 4.0
乙醇 5.0
甘油 6.0
1,3-丁二醇 5.0
2-O-十八烷基抗坏血酸 1.0
聚氧乙烯甲基葡糖苷 3.0
葵花籽油 1.0
角鲨烷 2.0
氢氧化钾 0.1
六偏磷酸钠 0.05
羟丙基-β-环糊精 0.1
4-甲氧基水杨酸钾 1.0
甘草酸二钾 0.05
枇杷叶提取物 0.1
L-谷氨酸钠 0.05
茴香提取物 0.1
酵母提取物 0.1
熏衣草油 0.1
地黄提取物 0.1
二吗啉代哒嗪酮 0.1
黄原胶 0.1
羧基乙烯基聚合物 0.1
丙烯酸/甲基丙烯酸烷基酯共聚物(PEMULEN 0.1
TR-1)
铁丹 适量
氧化铁黄 适量
对羟基苯甲酸酯·BR>@ 适量
纯化水 余量
制剂例7乳液
(配方) 质量%
聚二甲基硅氧烷 2.0
山嵛醇 1.0
鲨肝醇 0.5
甘油 5.0
1,3-丁二醇 7.0
2-O-十二烷基抗坏血酸 0.5
2-O-十八烷基抗坏血酸 1.0
氨甲环酸甲酰胺盐酸盐 0.7
赤藓醇 2.0
硬化油 3.0
角鲨烷 6.0
季戊四醇四(2-乙基己酸酯) 2.0
异硬脂酸聚氧乙烯甘油酯 1.0
单硬脂酸聚氧化乙烯甘油酯 1.0
氢氧化钾 适量
六偏磷酸钠 0.05
苯氧基乙醇 适量
羧基乙烯基聚合物 0.1
纯化水 余量
制剂例8乳液
(配方) 质量%
聚二甲基硅氧烷 2.0
山嵛醇 1.0
鲨肝醇 0.5
甘油 5.0
1,3-丁二醇 7.0
2-O-十八烷基抗坏血酸 1.0
氨甲环酸甲酰胺盐酸盐 0.7
赤藓醇 2.0
硬化油 3.0
角鲨烷 6.0
季戊四醇四(2-乙基己酸酯) 2.0
异硬脂酸聚氧乙烯甘油酯 1.0
单硬脂酸聚氧乙烯甘油酯 1.0
氢氧化钾 适量
六偏磷酸钠 0.05
苯氧基乙醇 适量
羧基乙烯基聚合物 0.1
纯化水 余量
制剂例9乳液
(配方) 质量%
液体石蜡 7.0
凡士林 3.0
十甲基环五硅氧烷 2.0
山嵛醇 0.5
甘油 5.0
二丙二醇 7.0
2-O-十二烷基抗坏血酸 1.0
2-O-十八烷基抗坏血酸 1.0
聚乙二醇1500 2.0
霍霍巴油 1.0
异硬脂酸 0.5
硬脂酸 0.5
山嵛酸 0.5
季戊四醇四(2-乙基己酸酯) 3.0
2-乙基己酸鲸蜡酯 3.0
单硬脂酸甘油酯 1.0
单硬脂酸聚氧化乙烯甘油酯 1.0
氢氧化钾 0.1
六偏磷酸钠 0.05
甘草亭酸硬脂酯 0.05
L-精氨酸盐酸盐 0.1
蜂王浆提取物 0.1
酵母提取物 0.1
姜黄提取物 0.1
生育酚醋酸酯 0.1
乙酰化透明质酸钠 0.1
乙二胺四乙酸三钠 0.05
4-叔丁基-4’-甲氧基二苯甲酰基甲烷 0.1
对甲氧基肉桂酸2-乙基己酯 0.1
羧基乙烯基聚合物 0.15
对羟基苯甲酸酯 适量
纯化水 余量
香料 适量
制剂例10乳液
(配方) 质量%
凡士林 5.0
山嵛醇 0.5
鲨肝醇 0.5
甘油 7.0
1,3-丁二醇 7.0
2-O-十三烷基抗坏血酸 1.0
2-O-十四烷基抗坏血酸 1.0
1,2-戊二醇 1.0
木糖醇 3.0
聚乙二醇20000 2.0
硬化油 2.0
霍霍巴油 2.0
角鲨烷 5.0
异硬脂酸 0.5
季戊四醇四(2-乙基己酸酯) 2.0
聚氧乙烯硬化蓖麻油 0.5
月桂基二甲基氨基醋酸甜菜碱 0.4
氢氧化钾 适量
焦亚硫酸钠 0.01
六偏磷酸钠 0.05
甘草酸二钾 0.05
三甲基甘氨酸 3.0
熊果苷 3.0
鹿蹄草提取物 0.1
野芝麻提取物 0.1
香姜(Lempuyang)提取物 0.1
酵母提取物 0.1
生育酚醋酸酯 0.1
硫代牛磺酸 0.1
苦参提取物 0.1
铁丹 适量
榅桲籽提取物 0.1
羧基乙烯基聚合物 0.2
苯氧基乙醇 适量
纯化水 余量
制剂例11乳液
(配方) 质量%
凡士林 5.0
聚二甲基硅氧烷 2.0
山嵛醇 0.6
鲨肝醇 0.5
二丙二醇 2.0
1,3-丁二醇 4.0
2-O-十五烷基抗坏血酸 10.0
2-O-十八烷基抗坏血酸 3.0
木糖醇 1.0
聚乙二醇1500 1.0
角鲨烷 5.0
三2-乙基己酸甘油酯 2.0
视黄醇醋酸酯 0.03
视黄醇(150万单位) 0.01
聚氧乙烯硬化蓖麻油 0.5
氨甲环酸甲酰胺盐酸盐 0.7
甘草酸二钾 0.1
2-O-乙基-L-抗坏血酸 0.1
酵母提取物 0.1
儿茶提取物 0.1
芍药提取物 0.1
射干提取液 0.1
HEDTA三钠 0.05
黄原胶 0.1
羧基乙烯基聚合物 0.15
纯化水 余量
香料 适量
制剂例12化妆水
(配方) 质量%
乙醇 5.0
甘油 1.0
1,3-丁二醇 5.0
2-O-十八烷基抗坏血酸 3.0
2-O-十六烷基抗坏血酸 10.0
聚氧乙烯聚氧丙烯癸基十四烷基醚 0.2
六偏磷酸钠 0.03
三甲基甘氨酸 1.0
聚天冬氨酸钠 0.1
α-生育酚2-L-抗坏血酸磷酸二酯钾 0.1
2-O-乙基-L-抗坏血酸 0.1
绿茶提取物 0.1
山毛榉提取物 0.1
桃仁提取物 0.1
胡椒薄荷提取物 0.1
鸢尾根提取物 0.1
HEDTA三钠 0.1
羧基乙烯基聚合物 0.05
氢氧化钾 0.02
苯氧基乙醇 适量
纯化水 余量
香料 适量
制剂例13化妆水
(配方) 质量%
甘油 2.0
1,3-丁二醇 4.0
2-O-十七烷基抗坏血酸 1.0
2-O-十八烷基抗坏血酸 1.0
赤藓醇 1.0
聚氧乙烯甲基葡糖苷 1.0
聚氧乙烯硬化蓖麻油 0.5
L-抗坏血酸2-葡糖苷 2.0
木糖醇 0.1
柠檬酸 0.02
柠檬酸钠 0.08
苯氧基乙醇 适量
N-椰油酰基L-精氨酸乙基酯·DL-吡咯烷酮羧酸 0.1
纯化水 余量
制剂例14化妆水
(配方) 质量%
甘油 2.0
1,3-丁二醇 4.0
2-O-十二烷基抗坏血酸 1.0
2-O-十八烷基抗坏血酸 1.0
赤藓醇 1.0
聚氧乙烯甲基葡糖苷 1.0
聚氧乙烯硬化蓖麻油 0.5
L-抗坏血酸2-葡糖苷 2.0
木糖醇 0.1
柠檬酸 0.02
柠檬酸钠 0.08
苯氧基乙醇 适量
N-椰油酰基L-精氨酸乙基酯·DL-吡咯烷酮羧酸 0.1
纯化水 余量
制剂例15化妆水
(配方) 质量%
乙醇 10.0
二丙二醇 1.0
2-O-十二烷基抗坏血酸钠盐 1.0
2-O-十三烷基抗坏血酸钠盐 1.0
聚乙二醇1000 1.0
聚氧乙烯甲基葡糖苷 1.0
霍霍巴油 0.01
三2-乙基己酸甘油酯 0.1
聚氧乙烯硬化蓖麻油 0.2
聚甘油二异硬脂酸酯 0.15
N-硬脂酰基-L-谷氨酸钠 0.1
柠檬酸 0.05
柠檬酸钠 0.2
氢氧化钾 0.4
甘草酸二钾 0.1
盐酸精氨酸 0.1
L-抗坏血酸2-葡糖苷 2.0
黄芩提取物 0.1
虎耳草提取物 0.1
野芝麻提取物 0.1
百里香提取物 0.1
马郁兰(marjoram)提取物 0.1
氨甲环酸 1.0
乙二胺四乙酸三钠 0.05
对甲氧基肉桂酸2-乙基己酯 0.01
二丁基羟基甲苯 适量
对羟基苯甲酸酯 适量
海洋深层水 3.0
纯化水 余量
香料 适量
制剂例16化妆水
(配方) 质量%
聚二甲基硅氧烷 1.0
乙醇 3.0
山嵛醇 0.3
甘油 5.0
二丙二醇 5.0
2-O-十四烷基抗坏血酸 0.1
2-O-十八烷基抗坏血酸 0.1
赤藓醇 1.0
聚乙二醇4000 1.0
角鲨烷 0.4
2-乙基己酸鲸蜡酯 0.1
N-硬脂酰基-L-谷氨酸钠 0.2
氯化镁 0.1
氯化精氨酸 0.1
氨乙基亚磺酸 0.1
乙二胺四乙酸三钠 0.1
对羟基苯甲酸酯 适量
纯化水 余量
香料 适量
制剂例17化妆水
(配方) 质量%
乙醇 40.0
二丙二醇 1.0
2-O-十二烷基抗坏血酸 0.1
2-O-十五烷基抗坏血酸 0.1
聚氧乙烯聚氧丙烯癸基十四烷基醚 0.1
无水硅酸 1.0
水杨酸 0.1
柠檬酸钠 0.2
对苯酚磺酸锌 0.2
甘草酸二钾 0.1
盐酸吡哆醇 0.1
L-丝氨酸 0.1
L-薄荷醇 0.05
HEDTA三钠 0.05
纤维素粉末 1.0
膨润土 0.8
纯化水 余量
制剂例18化妆水
(配方) 质量%
乙醇 40.0
二丙二醇 1.0
2-O-十八烷基抗坏血酸钾盐 0.1
聚氧乙烯聚氧丙烯癸基十四烷基醚 0.1
无水硅酸 1.0
水杨酸 0.1
柠檬酸钠 0.2
对苯酚磺酸锌 0.2
甘草酸二钾 0.1
盐酸吡哆醇 0.1
L-丝氨酸 0.1
L-薄荷醇 0.05
HEDTA三钠 0.05
纤维素粉末 1.0
膨润土 0.8
纯化水 余量
制剂例19凝胶
(配方) 质量%
聚二甲基硅氧烷 5.0
甘油 2.0
1,3-丁二醇 5.0
2-O-十二烷基抗坏血酸 0.1
2-O-十八烷基抗坏血酸 0.1
聚乙二醇1500 3.0
聚乙二醇20000 3.0
辛酸鲸蜡酯 3.0
柠檬酸 0.01
柠檬酸钠 0.1
六偏磷酸钠 0.1
甘草酸二钾 0.1
L-抗坏血酸2-葡糖苷 2.0
L-抗坏血酸磷酸酯镁 0.1
生育酚醋酸酯 0.1
黄芩提取物 0.1
百里香提取物 0.1
虎耳草提取物 0.1
乙二胺四乙酸三钠 0.1
黄原胶 0.3
丙烯酸/甲基丙烯酸烷基酯共聚物(PEMULEN TR-2) 0.05
琼脂粉末 1.5
苯氧基乙醇 适量
二丁基羟基甲苯 适量
纯化水 余量
制剂例20面膜
(配方 ) 质量%
乙醇 10.0
1,3-丁二醇 6.0
2-O-十二烷基抗坏血酸 1.0
2-O-十八烷基抗坏血酸 1.0
聚乙二醇4000 2.0
橄榄油 1.0
澳洲坚果油 1.0
羟基硬脂酸植物甾醇酯 0.05
乳酸 0.05
乳酸钠 0.1
L-抗坏血酸硫酸酯二钠 0.1
α-生育酚2-L-抗坏血酸磷酸二酯钾 0.1
维生素E醋酸酯 0.1
鱼胶原 0.1
硫酸软骨素钠 0.1
羧甲基纤维素钠 0.2
聚乙烯醇 12.0
对羟基苯甲酸酯 适量
纯化水 余量
香料 适量
制剂例21面膜
(配方) 质量%
乙醇 3.0
甘油 5.0
1,3-丁二醇 6.0
2-O-十八烷基抗坏血酸 1.0
2-O-十六烷基抗坏血酸 1.0
聚乙二醇1500 5.0
聚氧乙烯甲基葡糖苷 2.0
三2-乙基己酸甘油酯 1.0
六偏磷酸钠 0.05
羟丙基-β-环糊精 0.1
甘草酸二钾 0.1
枇杷叶提取物 0.1
L-谷氨酸钠 0.1
茴香提取物 0.1
金缕梅提取物 0.1
黄柏提取物 0.1
地黄提取物 0.1
桉叶油 0.05
二吗啉代哒嗪酮 0.1
黄原胶 0.05
羧基乙烯基聚合物 0.5
丙烯酸/甲基丙烯酸烷基酯共聚物(PEMULEN TR-1) 0.05
氢氧化钾 0.05
苯氧基乙醇 适量
纯化水 余量
制剂例22面膜
(配方) 质量%
乙醇 3.0
甘油 5.0
1,3-丁二醇 6.0
2-O-十八烷基抗坏血酸 1.0
聚乙二醇1500 5.0
聚氧乙烯甲基葡糖苷 2.0
三2-乙基己酸甘油酯 1.0
六偏磷酸钠 0.05
羟丙基-β-环糊精 0.1
甘草酸二钾 0.1
枇杷叶提取物 0.1
L-谷氨酸钠 0.1
茴香提取物 0.1
金缕梅提取物 0.1
黄柏提取物 0.1
地黄提取物 0.1
桉叶油 0.05
二吗啉代哒嗪酮 0.1
黄原胶 0.05
羧基乙烯基聚合物 0.5
丙烯酸/甲基丙烯酸烷基酯共聚物(PEMULEN TR-1) 0.05
氢氧化钾 0.05
苯氧基乙醇 适量
纯化水 余量
制剂例23霜剂
(配方) 质量%
液体石蜡 3.0
凡士林 1.0
聚二甲基硅氧烷 1.0
硬脂醇 1.8
山嵛醇 1.6
甘油 8.0
二丙二醇 5.0
2-O-十八烷基抗坏血酸 5.0
2-O-十二烷基抗坏血酸 5.0
澳洲坚果油 2.0
硬化油 3.0
角鲨烷 6.0
硬脂酸 2.0
羟基硬脂酸胆固醇酯 0.5
2-乙基己酸鲸蜡酯 4.0
聚氧乙烯硬化蓖麻油 0.5
自乳化型单硬脂酸甘油酯 3.0
氢氧化钾 0.15
六偏磷酸钠 0.05
三甲基甘氨酸 2.0
α-生育酚2-L-抗坏血酸磷酸二酯钾 1.0
生育酚醋酸酯 0.1
甜茶提取物 0.1
对羟基苯甲酸酯 适量
乙二胺四乙酸三钠 0.05
4-叔丁基-4’-甲氧基二苯甲酰基甲烷 0.05
二对甲氧基肉桂酸单-2-乙基己酸甘油酯 0.05
色素 适量
羧基乙烯基聚合物 0.05
纯化水 余量
制剂例24霜剂
(配方) 质量%
液体石蜡 8.0
凡士林 3.0
聚二甲基硅氧烷 2.0
硬脂醇 3.0
山嵛醇 2.0
甘油 5.0
二丙二醇 4.0
2-O-十七烷基抗坏血酸 3.0
2-O-十八烷基抗坏血酸 3.0
海藻糖 1.0
季戊四醇四(2-乙基己酸酯) 4.0
单异硬脂酸聚氧乙烯甘油酯 2.0
单硬脂酸聚氧乙烯甘油酯 1.0
亲油型单硬脂酸甘油酯 2.0
柠檬酸 0.05
柠檬酸钠 0.05
氢氧化钾 0.015
油溶性甘草提取物 0.1
视黄醇棕榈酸酯(100万单位) 0.25
生育酚醋酸酯 0.1
对羟基苯甲酸酯 适量
苯氧基乙醇 适量
二丁基羟基甲苯 适量
乙二胺四乙酸三钠 0.05
4-叔丁基-4’-甲氧基二苯甲酰基甲烷 0.01
对甲氧基肉桂酸2-乙基己酯 0.1
β-胡萝卜素 0.01
聚乙烯醇 0.5
羟乙基纤维素 0.5
羧基乙烯基聚合物 0.05
纯化水 余量
香料 适量
制剂例25霜剂
(配方) 质量%
液体石蜡 8.0
凡士林 3.0
聚二甲基硅氧烷 2.0
硬脂醇 3.0
山嵛醇 2.0
甘油 5.0
二丙二醇 4.0
2-O-十八烷基抗坏血酸 3.0
海藻糖 1.0
季戊四醇四(2-乙基己酸酯) 4.0
单异硬脂酸聚氧乙烯甘油酯 2.0
单硬脂酸聚氧乙烯甘油酯 1.0
亲油型单硬脂酸甘油酯 2.0
柠檬酸 0.05
柠檬酸钠 0.05
氢氧化钾 0.015
油溶性甘草提取物 0.1
视黄醇棕榈酸酯(100万单位) 0.25
生育酚醋酸酯 0.1
对羟基苯甲酸酯 适量
苯氧基乙醇 适量
二丁基羟基甲苯 适量
乙二胺四乙酸三钠 0.05
4-叔丁基-4’-甲氧基二苯甲酰基甲烷 0.01
对甲氧基肉桂酸2-乙基己酯 0.1
β-胡萝卜素 0.01
聚乙烯醇 0.5
羟乙基纤维素 0.5
羧基乙烯基聚合物 0.05
纯化水 余量
香料 适量
制剂例26霜剂
(配方) 质量%
凡士林 2.0
聚二甲基硅氧烷 2.0
乙醇 5.0
山嵛醇 0.5
鲨肝醇 0.2
甘油 7.0
1,3-丁二醇 5.0
2-O-十二烷基抗坏血酸 1.0
2-O-十八烷基抗坏血酸 1.0
聚乙二醇20000 0.5
霍霍巴油 3.0
角鲨烷 2.0
羟基硬脂酸植物甾醇酯 0.5
季戊四醇四(2-乙基己酸酯) 1.0
聚氧乙烯硬化蓖麻油 1.0
氢氧化钾 0.1
焦亚硫酸钠 0.01
六偏磷酸钠 0.05
甘草亭酸硬脂酯 0.1
泛醇乙基醚 0.1
熊果苷 7.0
氨甲环酸 1.0
生育酚醋酸酯 0.1
透明质酸钠 0.05
对羟基苯甲酸酯 适量
乙二胺四乙酸三钠 0.05
4-叔丁基-4’-甲氧基二苯甲酰基甲烷 0.1
二对甲氧基肉桂酸单-2-乙基己酸甘油酯 0.1
氧化铁黄 适量
黄原胶 0.1
羧基乙烯基聚合物 0.2
纯化水 余量
制剂例27霜剂
(配方) 质量%
液体石蜡 10.0
聚二甲基硅氧烷 2.0
甘油 10.0
1,3-丁二醇 2.0
2-O-十二烷基抗坏血酸 1.0
2-O-十八烷基抗坏血酸 1.0
赤藓醇 1.0
聚乙二醇1500 5.0
角鲨烷 15.0
季戊四醇四(2-乙基己酸酯) 5.0
氢氧化钾 0.1
六偏磷酸钠 0.05
生育酚醋酸酯 0.05
对羟基苯甲酸酯 适量
羟丙基甲基纤维素 0.3
聚乙烯醇 0.1
羧基乙烯基聚合物 0.2
丙烯酸/甲基丙烯酸烷基酯共聚物(PEMULEN TR-2) 0.1
纯化水 余量
制剂例28霜剂
(配方) 质量%
液体石蜡 10.0
聚二甲基硅氧烷 2.0
甘油 10.0
1,3-丁二醇 2.0
2-O-十八烷基抗坏血酸 1.0
赤藓醇 1.0
聚乙二醇1500 5.0
角鲨烷 15.0
季戊四醇四(2-乙基己酸酯) 5.0
氢氧化钾 0.1
六偏磷酸钠 0.05
生育酚醋酸酯 0.05
对羟基苯甲酸酯 适量
羟丙基甲基纤维素 0.3
聚乙烯醇 0.1
羧基乙烯基聚合物 0.2
丙烯酸/甲基丙烯酸烷基酯共聚物(PEMULEN TR-2) 0.1
纯化水 余量
制剂例29两相型霜剂
(配方) 质量%
聚二甲基硅氧烷 5.0
十甲基环五硅氧烷 25.0
三甲基硅氧基硅酸酯 5.0
聚氧乙烯-甲基聚硅氧烷共聚物 2.0
二丙二醇 5.0
2-O-十二烷基抗坏血酸 0.01
2-O-十八烷基抗坏血酸 0.01
糊精棕榈酸酯包覆的微粒氧化锌(60nm) 15.0
甘草酸二钾 0.02
谷胱甘肽 1.0
硫代牛磺酸 0.05
苦参提取物 1.0
对羟基苯甲酸酯 适量
苯氧基乙醇 适量
乙二胺四乙酸三钠 适量
对甲氧基肉桂酸2-乙基己酯 7.5
二甲基二硬脂基铵水辉石 0.5
球状聚丙烯酸烷基酯粉末 5.0
丁基乙基丙二醇 0.5
纯化水 余量
香料 适量
上述制剂例1~29的注射剂或皮肤外用剂均具有高的ADAM抑制效果。
Claims (4)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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JP2007016536A JP2008184387A (ja) | 2007-01-26 | 2007-01-26 | Adam阻害剤 |
JP016536/2007 | 2007-01-26 |
Publications (1)
Publication Number | Publication Date |
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CN101594860A true CN101594860A (zh) | 2009-12-02 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CNA2007800464343A Pending CN101594860A (zh) | 2007-01-26 | 2007-12-27 | Adam抑制剂 |
Country Status (7)
Country | Link |
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US (1) | US20100113590A1 (zh) |
EP (1) | EP2123272A4 (zh) |
JP (1) | JP2008184387A (zh) |
KR (1) | KR20090112629A (zh) |
CN (1) | CN101594860A (zh) |
TW (1) | TW200835506A (zh) |
WO (1) | WO2008090717A1 (zh) |
Cited By (1)
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CN103370620A (zh) * | 2010-12-28 | 2013-10-23 | 大日本住友制药株式会社 | 阿尔茨海默病的诊断药和诊断方法 |
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FR2955493B1 (fr) * | 2010-01-28 | 2012-02-24 | Oreal | Utilisation de derives d'acide ascorbique en coloration des fibres keratiniques humaines, composition les comprenant, procede de coloration et dispositif |
JP5888667B2 (ja) * | 2010-04-30 | 2016-03-22 | 国立大学法人名古屋大学 | Adam作用阻害物質のスクリーニング方法、仮足の保持方法、仮足保持剤、仮足の制御物質のスクリーニング方法、及びadam作用阻害剤 |
DE102013208865A1 (de) * | 2013-05-14 | 2014-11-20 | Beiersdorf Ag | Stabilisierte Zubereitungen mit einem Gehalt an Ascorbinsäure und Phosphationen |
EP3156040A4 (en) * | 2014-06-10 | 2018-03-14 | Ajinomoto Co., Inc. | Cosmetic composition containing 3-o-alkyl-l-ascorbic acid or salt thereof |
CN113543764B (zh) * | 2019-03-04 | 2024-06-11 | 丸善制药株式会社 | 外用剂 |
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JPS62221611A (ja) * | 1986-03-20 | 1987-09-29 | Kanebo Ltd | 皮膚化粧料 |
JPH07112966B2 (ja) * | 1986-03-26 | 1995-12-06 | 鐘紡株式会社 | 皮膚化粧料 |
JPH0667834B2 (ja) * | 1989-03-09 | 1994-08-31 | 二郎 藤本 | 抗腫瘍剤 |
JPH04128225A (ja) * | 1989-09-12 | 1992-04-28 | Kokuritsu Gan Center Souchiyou | 抗腫瘍剤 |
JPH045214A (ja) * | 1990-04-21 | 1992-01-09 | Atsushi Nonaka | アスコルビン酸誘導体を含む化粧品及び外用薬 |
JPH0558892A (ja) * | 1991-09-06 | 1993-03-09 | Jiro Fujimoto | 発癌防止剤 |
TW325997B (en) * | 1993-02-02 | 1998-02-01 | Senju Pharma Co | Pharmaceutical composition for preventing and treating retinal diseases |
WO1996030012A1 (en) * | 1995-03-24 | 1996-10-03 | Defeudis Francis V | Methods for treating conditions associated with excess nitric oxide |
-
2007
- 2007-01-26 JP JP2007016536A patent/JP2008184387A/ja active Pending
- 2007-12-27 CN CNA2007800464343A patent/CN101594860A/zh active Pending
- 2007-12-27 KR KR1020097010609A patent/KR20090112629A/ko not_active Application Discontinuation
- 2007-12-27 EP EP07860343A patent/EP2123272A4/en not_active Withdrawn
- 2007-12-27 US US12/524,543 patent/US20100113590A1/en not_active Abandoned
- 2007-12-27 WO PCT/JP2007/075121 patent/WO2008090717A1/ja active Application Filing
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103370620A (zh) * | 2010-12-28 | 2013-10-23 | 大日本住友制药株式会社 | 阿尔茨海默病的诊断药和诊断方法 |
CN103370620B (zh) * | 2010-12-28 | 2016-01-20 | 大日本住友制药株式会社 | 阿尔茨海默病的诊断药和诊断方法 |
CN105548561A (zh) * | 2010-12-28 | 2016-05-04 | 大日本住友制药株式会社 | 阿尔茨海默病的诊断药和诊断方法 |
US10393757B2 (en) | 2010-12-28 | 2019-08-27 | Dainippon Sumitomo Pharma Co., Ltd. | Diagnostic drug and diagnostic method for Alzheimer's disease |
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TW200835506A (en) | 2008-09-01 |
EP2123272A4 (en) | 2010-04-21 |
JP2008184387A (ja) | 2008-08-14 |
US20100113590A1 (en) | 2010-05-06 |
KR20090112629A (ko) | 2009-10-28 |
WO2008090717A1 (ja) | 2008-07-31 |
EP2123272A1 (en) | 2009-11-25 |
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