TW201328694A - 用於治療皮膚疾病及病狀之包含7-(1h-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉之醫藥組合物 - Google Patents
用於治療皮膚疾病及病狀之包含7-(1h-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉之醫藥組合物 Download PDFInfo
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- TW201328694A TW201328694A TW101141967A TW101141967A TW201328694A TW 201328694 A TW201328694 A TW 201328694A TW 101141967 A TW101141967 A TW 101141967A TW 101141967 A TW101141967 A TW 101141967A TW 201328694 A TW201328694 A TW 201328694A
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- skin
- ylmethyl
- tetrahydro
- imidazol
- quinoline
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Abstract
本發明係關於一種治療有需要之患者之皮膚疾病及皮膚病狀的方法,其包括投與治療有效量之醫藥組合物,該醫藥組合物包含治療有效量之7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其個別對映異構體或其互變異構體或其醫藥學上可接受之鹽。
Description
本申請案主張2011年11月10日申請之美國臨時申請案第61/558,104號之權益,其揭示內容據此以全文引用的方式併入本文中。
本發明係關於一種治療有需要之患者之皮膚疾病及皮膚病狀的方法,其包括投與一種醫藥組合物,該醫藥組合物包含治療有效量之7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其對映異構體或其互變異構體或其醫藥學上可接受之鹽。
已藉由分子及藥理學方法表徵三種α1及三種α2腎上腺素激導性受體。此等α受體之活化會引起具有適用治療作用之生理反應。α腎上腺素激導性促效劑作用於周邊血管結構以使血管收縮且藉此改善發炎性皮膚病症之症狀,包括紅斑或發紅。α腎上腺素激導性促效劑適用於眼黏膜組織以治療結膜發紅(充血)、作為治療過敏性鼻炎之去充血劑適用於鼻黏膜且適用於適於治療及治癒痔瘡之經直腸黏膜投藥。
H.E.Baldwin在Journal of Drugs in Dermatology 2012,第11卷(6),第725-730頁中描述對紅斑痤瘡(rosacea)及相關皮膚疾病之診斷及實際治療。
美國專利第6,680,062號揭示用於治療皮膚之表面化妝品及醫藥組合物。
美國專利申請公開案第2012/0035123號描述用於治療皮膚疾病之化合物組合。
美國專利第7,812,049號揭示一種治療由紅斑痤瘡所致之紅斑之包括羥間唑啉的方法。羥間唑啉為一種選擇性α-1促效劑及部分α-2促效劑表面去充血劑。
化合物7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉稱為強力α1及α2腎上腺素激導性受體泛促效劑。7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉之外消旋混合物及兩種對映異構體揭示於美國專利第7,323,477 B2號中。美國專利第7,943,641號揭示一種用於治療青光眼或眼高血壓之包含(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉之組合物。
目前已發現(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉之醫藥組合物適用於治療皮膚疾病及皮膚病狀。
本發明係關於用於治療皮膚疾病及皮膚病狀之含有7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉作為活性成分的醫藥組合物。
在另一態樣中,本發明係關於用於治療皮膚疾病及皮膚病狀之含有(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉作為活性成分的醫藥組合物。
在另一態樣中,本發明係關於用於治療皮膚疾病及皮膚病狀之含有(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉作為活性成分的醫藥組合物。
在另一態樣中,本發明係關於一種治療有需要之患者之皮膚疾病的方法,其包括投與一種醫藥組合物,該醫藥組合物包含治療有效量之7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其醫藥學上可接受之鹽。
在另一態樣中,本發明係關於一種治療有需要之患者之皮膚疾病的方法,其包括投與一種醫藥組合物,該醫藥組合物包含治療有效量之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其醫藥學上可接受之鹽。
在另一態樣中,本發明係關於一種治療有需要之患者之皮膚疾病的方法,其包括投與一種醫藥組合物,該醫藥組合物包含治療有效量之(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其醫藥學上可接受之鹽。
在另一態樣中,本發明係關於一種改良有需要之患者之皮膚疾病的方法,其包括投與一種醫藥組合物,該醫藥組合物包含治療有效量之7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其醫藥學上可接受之鹽。
在另一態樣中,本發明係關於一種改良有需要之患者之皮膚疾病的方法,其包括投與一種醫藥組合物,該醫
藥組合物包含治療有效量之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其醫藥學上可接受之鹽。
在另一態樣中,本發明係關於一種改良有需要之患者之皮膚疾病的方法,其包括投與一種醫藥組合物,該醫藥組合物包含治療有效量之(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其醫藥學上可接受之鹽。
化合物可經由不同途徑投與,包括(但不限於)表面皮膚敷用有效劑量、直接注射、或可進一步增加長久作用持續時間之調配物(諸如緩慢釋放丸粒)、懸浮液、凝膠劑、溶液、乳膏劑、軟膏劑、泡沫物、乳液、微乳液、乳劑(milk)、貼片、漿液(serum)、氣霧劑、噴霧劑、分散物、微膠囊、囊泡、微粒、濕布、乾布、面布(facial cloth)、或持續傳遞裝置,諸如此項技術中已知之任何適合藥物傳遞系統。
在本發明之一個態樣中,提供一種治療有需要之患者之皮膚疾病及皮膚病狀的方法,其包括以下、基本上由以下組成或由以下組成:投與治療有效量之醫藥組合物,該醫藥組合物包含以下、基本上由以下組成或由以下組成:治療有效量之7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其對映異構體或其互變異構體或其醫藥學上可接受之鹽。
在本發明之另一態樣中,提供一種治療有需要之患者
之皮膚疾病及皮膚病狀的方法,其包括以下、基本上由以下組成或由以下組成:投與治療有效量之醫藥組合物,該醫藥組合物包含以下、基本上由以下組成或由以下組成:治療有效量之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其互變異構體或其醫藥學上可接受之鹽。
在本發明之另一態樣中,提供一種治療有需要之患者之皮膚疾病及皮膚病狀的方法,其包括以下、基本上由以下組成或由以下組成:投與治療有效量之醫藥組合物,該醫藥組合物包含以下、基本上由以下組成或由以下組成:治療有效量之(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其互變異構體或其醫藥學上可接受之鹽。
應將「皮膚疾病」理解為與所列疾病相關之任何病狀、病患或病痛。
可用含有7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其對映異構體:(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉作為活性成分之醫藥組合物治療之皮膚疾病及皮膚病狀包括(但不限於)紅斑痤瘡、爆發性紅斑痤瘡(rosacea fulminans)、曬傷、牛皮癬、絕經相關潮熱、與潮熱相關之潮紅及發紅、與潮熱相關之紅斑、由睾丸切除異位性皮炎(orchiectomyatopic dermatitis)所致之潮熱、由昆蟲咬傷引起之發紅及發癢之治療、光老化、脂溢性皮炎、粉刺、過敏性皮炎、面部毛細血管擴張(先前存在之小血管的擴張)、血管擴張(angioectasias)、鼻贅(rhinophyma)
(伴有濾泡擴張之鼻肥大)、粉刺樣皮疹(可滲出或結殼)、灼燒感或刺痛感、皮膚紅斑、伴有皮膚血管擴張之皮膚活動過度、萊爾氏症候群(Lyell's syndrome)、史蒂文斯-約翰遜症候群(Stevens-Johnson syndrome)、與痔瘡相關之局部發癢及不適、痔瘡、輕型多形性紅斑(erythema multiforme minor)、重型多形性紅斑、結節性紅斑、眼虛腫(eye puffiness)、蕁麻疹、瘙癢、紫癜、靜脈曲張、接觸性皮炎、異位性皮炎、錢幣狀皮炎(nummular dermatitis)、全身性剝脫性皮炎、瘀滯性皮炎(stasis dermatitis)、慢性單純性苔癬(lichen simplex chronicus)、口周皮炎(perioral dermatitis)、須部假性毛囊炎(pseudofolliculitis barbae)、環狀肉芽腫(granuloma annulare)、光化性角化病(actinic keratosis)、基底細胞癌、鱗狀細胞癌、濕疹。
引起紅斑痤瘡之皮膚病狀可由以下誘發:攝取辛辣食品、灑精、巧克力、熱飲料或酒精飲料、溫度變化、熱、曝露於紫外線或紅外線輻射、暴露於低相對濕度、皮膚暴露於強風或空氣流、皮膚暴露於界面活性劑、刺激劑、刺激性皮膚表面試劑及化妝品或心理壓力。
在任何既定情況下欲投與之化合物之實際量皆將由醫師在考慮相關情況下確定,該等相關情況諸如為病狀嚴重性、患者年齡及重量、患者之一般身體狀況、病狀之病因及投藥途徑。
在本發明之另一態樣中,提供一種治療皮膚疾病之方
法,其中包含治療有效量之4-溴-N-(咪唑啉-2-亞基)-1H-苯并咪唑-5-胺、基本上由治療有效量之4-溴-N-(咪唑啉-2-亞基)-1H-苯并咪唑-5-胺組成或由治療有效量之4-溴-N-(咪唑啉-2-亞基)-1H-苯并咪唑-5-胺組成之醫藥組合物係選自表面皮膚敷劑,其包含懸浮液、凝膠劑、溶液、乳膏劑、洗劑、軟膏劑、泡沫物、乳液、微乳液、乳劑、貼片、漿液、氣霧劑、噴霧劑、分散物、微膠囊、囊泡、微粒、濕布、乾布、面布、可進一步增加長久作用持續時間之敷劑及調配物(諸如緩慢釋放丸粒)、直接注射液、或持續傳遞裝置,諸如此項技術中已知之任何適合藥物傳遞系統。本發明之醫藥組合物可用於表面投與,包括溶液、凝膠劑、洗劑乳膏劑、軟膏劑、泡沫物、摩絲(mousses)、乳液、微乳液、乳劑、漿液、氣霧劑、噴霧劑、分散物、貼片、膠束、脂質體、微膠囊、囊泡及其微粒。
可用作表面載劑之乳液(諸如乳膏劑及洗劑)及其製備揭示於Remington:The Science and Practice of Pharmacy 282-291(Alfonso R.Gennaro編,第19版,1995)中,其據此以引用的方式併入本文中。
適用於本發明中之凝膠劑揭示於Remington:The Science and Practice of Pharmacy 1517-1518(Alfonso R.Gennaro編,第19版,1995)中,其據此以引用的方式併入本文中。適用於本發明之其他凝膠劑揭示於美國專利第6,387,383號、美國專利第6,517,847號及美國專利第
6,468,989號中。
在本發明之另一態樣中,提供一種藉由向有需要之患者投與含有7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉作為活性成分之醫藥組合物來改良皮膚疾病之方法,該等皮膚疾病包括(但不限於):紅斑痤瘡、爆發性紅斑痤瘡、曬傷、牛皮癬、絕經相關潮熱、與潮熱相關之潮紅及發紅、與潮熱相關之紅斑、由睾丸切除異位性皮炎所致之潮熱、由昆蟲咬傷引起之發紅及發癢之治療、光老化、脂溢性皮炎、粉刺、過敏性皮炎、面部毛細血管擴張(先前存在之小血管的擴張)、血管擴張、鼻贅(伴有濾泡擴張之鼻肥大)、粉刺樣皮疹(可滲出或結殼)、灼燒感或刺痛感、皮膚紅斑、伴有皮膚血管擴張之皮膚活動過度、萊爾氏症候群、史蒂文斯-約翰遜症候群、與痔瘡相關之局部發癢及不適、痔瘡、輕型多形性紅斑、重型多形性紅斑、結節性紅斑、眼虛腫、蕁麻疹、瘙癢、紫癜、靜脈曲張、接觸性皮炎、異位性皮炎、錢幣狀皮炎、全身性剝脫性皮炎、瘀滯性皮炎、慢性單純性苔癬、口周皮炎、須部假性毛囊炎、環狀肉芽腫、光化性角化病、基底細胞癌、鱗狀細胞癌、濕疹。
在本發明之另一態樣中,提供一種藉由向有需要之患者投與含有(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉作為活性成分之醫藥組合物來改良皮膚疾病之方法,該等皮膚疾病包括(但不限於):紅斑痤瘡、爆發性紅斑痤瘡、曬傷、牛皮癬、絕經相關潮熱、與潮熱相關之
潮紅及發紅、與潮熱相關之紅斑、由睾丸切除異位性皮炎所致之潮熱、由昆蟲咬傷引起之發紅及發癢之治療、光老化、脂溢性皮炎、粉刺、過敏性皮炎、面部毛細血管擴張(先前存在之小血管的擴張)、血管擴張、鼻贅(伴有濾泡擴張之鼻肥大)、粉刺樣皮疹(可滲出或結殼)、灼燒感或刺痛感、皮膚紅斑、伴有皮膚血管擴張之皮膚活動過度、萊爾氏症候群、史蒂文斯-約翰遜症候群、與痔瘡相關之局部發癢及不適、痔瘡、輕型多形性紅斑、重型多形性紅斑、結節性紅斑、眼虛腫、蕁麻疹、瘙癢、紫癜、靜脈曲張、接觸性皮炎、異位性皮炎、錢幣狀皮炎、全身性剝脫性皮炎、瘀滯性皮炎、慢性單純性苔癬、口周皮炎、須部假性毛囊炎、環狀肉芽腫、光化性角化病、基底細胞癌、鱗狀細胞癌、濕疹。
在本發明之另一態樣中,提供一種藉由向有需要之患者投與含有(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉作為活性成分之醫藥組合物來改良皮膚疾病之方法,該等皮膚疾病包括(但不限於):紅斑痤瘡、爆發性紅斑痤瘡、曬傷、牛皮癬、絕經相關潮熱、與潮熱相關之潮紅及發紅、與潮熱相關之紅斑、由睾丸切除異位性皮炎所致之潮熱、由昆蟲咬傷引起之發紅及發癢之治療、光老化、脂溢性皮炎、粉刺、過敏性皮炎、面部毛細血管擴張(先前存在之小血管的擴張)、血管擴張、鼻贅(伴有濾泡擴張之鼻肥大)、粉刺樣皮疹(可滲出或結殼)、灼燒感或刺痛感、皮膚紅斑、伴有皮膚血管擴張之皮膚活動過
度、萊爾氏症候群、史蒂文斯-約翰遜症候群、與痔瘡相關之局部發癢及不適、痔瘡、輕型多形性紅斑、重型多形性紅斑、結節性紅斑、眼虛腫、蕁麻疹、瘙癢、紫癜、靜脈曲張、接觸性皮炎、異位性皮炎、錢幣狀皮炎、全身性剝脫性皮炎、瘀滯性皮炎、慢性單純性苔癬、口周皮炎、須部假性毛囊炎、環狀肉芽腫、光化性角化病、基底細胞癌、鱗狀細胞癌、濕疹。
在本發明之另一態樣中,提供一種減輕與以下相關之皮膚刺激的方法:表面敷用治療有效量之7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉之紅斑痤瘡治療方案,用治療有效量之7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉治療毛細血管擴張或血管擴張之方法,且因此,其亦包括減輕與出現紅斑痤瘡相關之發紅的方法。
在本發明之另一態樣中,提供一種減輕與以下相關之皮膚刺激的方法:表面敷用治療有效量之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉之紅斑痤瘡治療方案,用治療有效量之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉治療毛細血管擴張或血管擴張之方法,且因此,其亦包括減輕與出現紅斑痤瘡相關之發紅的方法。
在本發明之另一態樣中,提供一種減輕與以下相關之皮膚刺激的方法:表面敷用治療有效量之(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉之紅斑痤瘡治療方案,用治療有效量之(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉治療毛細血管擴張或血管擴張之方法,且因此,
其亦包括減輕與出現紅斑痤瘡相關之發紅的方法。
在本發明之另一態樣中,提供一種治療皮膚疾病之方法,該等皮膚疾病包括(但不限於):由攝取辛辣食品、巧克力、灑精、熱飲料或酒精飲料、溫度變化、熱、曝露於紫外線或紅外線輻射、暴露於低相對濕度、皮膚暴露於強風或空氣流、皮膚暴露於界面活性劑、刺激劑、刺激性皮膚表面試劑及化妝品或心理壓力誘發之紅斑痤瘡。
(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉可與如美國專利第7,491,383 B2號中揭示之功效增強組分一起調配。
在本發明之另一態樣中,提供一種包含包裝材料及含於該包裝材料內之醫藥藥劑之製品,其中該醫藥藥劑在治療上有效地治療皮膚疾病且其中該包裝材料包含指示該醫藥藥劑可用於治療皮膚疾病之標籤且其中該醫藥藥劑包含有效量之7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其鹽。
在本發明之另一態樣中,提供一種包含包裝材料及含於該包裝材料內之醫藥藥劑之製品,其中該醫藥藥劑在治療上有效地治療皮膚疾病且其中該包裝材料包含指示該醫藥藥劑可用於治療皮膚疾病之標籤且其中該醫藥藥劑包含有效量之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其鹽。
在本發明之另一態樣中,提供一種包含包裝材料及含
於該包裝材料內之醫藥藥劑之製品,其中該醫藥藥劑在治療上有效地治療皮膚疾病且其中該包裝材料包含指示該醫藥藥劑可用於治療皮膚疾病之標籤且其中該醫藥藥劑包含有效量之(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其鹽。
在本發明之另一態樣中,提供一種治療有需要之患者之眼部疾病及病狀的方法,其包括以下、基本上由以下組成或由以下組成:投與治療有效量之醫藥組合物,該醫藥組合物包含以下、基本上由以下組成或由以下組成:治療有效量之7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其對映異構體或其互變異構體或其醫藥學上可接受之鹽。
在本發明之另一態樣中,提供一種治療有需要之患者之眼部疾病及病狀的方法,其包括以下、基本上由以下組成或由以下組成:投與治療有效量之醫藥組合物,該醫藥組合物包含以下、基本上由以下組成或由以下組成:治療有效量之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其互變異構體或其醫藥學上可接受之鹽。
在本發明之另一態樣中,提供一種治療有需要之患者之眼部疾病及病狀的方法,其包括以下、基本上由以下組成或由以下組成:投與治療有效量之醫藥組合物,該醫藥組合物包含以下、基本上由以下組成或由以下組成:治療有效量之(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其互變異構體或其醫藥學上可接受之鹽。
應將「眼部疾病」理解為與所列疾病相關之任何病狀、病患或病痛。
可用含有7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其對映異構體:(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉作為活性成分之醫藥組合物治療之眼部疾病及病狀包括(但不限於):眼部紅斑痤瘡、翼狀胬肉(pterygium)、發紅、充血、結膜充血、角膜新血管生成、眼部瘢痕類天皰瘡(ocular cicatricial pemphygoid)及史蒂文斯-約翰遜症候群。
(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉化合物具有有益於持續活性之生理化學及藥物動力學性質,特別是當連續傳遞藥物(例如藉由皮膚貼片向皮膚連續傳遞)時。
如此處所用之「醫藥組合物」意謂適於向人類患者投與以達成疾病治療之組合物。在一個實施例中,本發明化合物調配成醫藥學上可接受之鹽,其進一步包括一或多種適於皮膚敷用之有機或無機載劑或賦形劑。醫藥學上可接受之賦形劑可包括一或多種皮膚穿透劑、保濕劑、防腐劑、膠凝劑、防護劑、水包油乳液、油包水乳液、水包油包水乳液及矽包水包油乳液。醫藥組合物可包含賦形劑、黏合劑、潤滑劑、溶劑、崩解劑或皮膚穿透增強劑且將較佳以表面方式投與。以組合物總重量計,活性成分以約0.01重量%至約20重量%且較佳以約0.1重
量%至約10重量%之量使用。
「醫藥學上可接受之鹽」係指保留游離鹼之生物有效性及性質且藉由與無機酸(諸如鹽酸、氫溴酸、硫酸、硝酸、磷酸)或有機酸(諸如乙酸、羥基乙酸、丙酸、乳酸、丙酮酸、丙二酸、反丁烯二酸、順丁烯二酸、乙二酸、酒石酸、丁二酸、蘋果酸、抗壞血酸、苯甲酸、鞣酸(tannic acid)、帕莫酸(pamoic acid)、檸檬酸、甲基磺酸、乙烷磺酸、苯磺酸、甲酸、水楊酸及其類似物)(Handbook of Pharmaceutical Salts,P.Heinrich Stahal及Camille G.Wermuth(編),Verlag Helvetica Chemica Acta-Zürich,2002,329-345)反應獲得之彼等鹽。
在本發明之另一態樣中,提供一種治療皮膚疾病及皮膚病狀之方法,其中包括治療有效量之7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉、基本上由治療有效量之7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉組成或由治療有效量之7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉組成之醫藥組合物係選自表面皮膚敷劑、直接注射液、可進一步增加長久作用持續時間之敷劑及調配物(諸如緩慢釋放丸粒)、懸浮液、凝膠劑、溶液、乳膏劑、軟膏劑、泡沫物、乳液、微乳液、乳劑、漿液、氣霧劑、噴霧劑、分散物、微膠囊、囊泡、微粒、濕布、乾布、面布。
在本發明之另一態樣中,提供一種治療皮膚疾病及皮膚病狀之方法,其中包括治療有效量之(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉、基本上由治療有效量之
(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉組成或由治療有效量之(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉組成之醫藥組合物係選自表面皮膚敷劑、直接注射液、可進一步增加長久作用持續時間之敷劑及調配物(諸如緩慢釋放丸粒)、懸浮液、凝膠劑、溶液、乳膏劑、軟膏劑、泡沫物、乳液、微乳液、乳劑、漿液、氣霧劑、噴霧劑、分散物、微膠囊、囊泡、微粒、濕布、乾布、面布。
在本發明之另一態樣中,提供一種治療皮膚疾病及皮膚病狀之方法,其中包含治療有效量之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉、基本上由治療有效量之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉組成或由治療有效量之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉組成之醫藥組合物係選自表面皮膚敷劑、直接注射液、可進一步增加長久作用持續時間之敷劑及調配物(諸如緩慢釋放丸粒)、懸浮液、凝膠劑、溶液、洗劑、乳膏劑、軟膏劑、泡沫物、乳液、微乳液、乳劑、漿液、氣霧劑、噴霧劑、分散物、微膠囊、囊泡、微粒、濕布、皂、清潔棒、乾布、面布。
本發明可與表面敷用藥劑之紅斑痤瘡治療聯合使用,該等藥劑諸如為阿維菌素(avermectin)家族之巨環內酯、稱為米爾貝黴素(milbemycin)之巨環內酯、其他α1或α2受體促效劑、類視色素(retinoid)、植物鞘氨醇(phytosphingosine)、綠茶提取物、杜鵑花酸(azaleic acid)。
本發明亦可與其他類別之化合物聯合使用,該等化合物諸如為:抗微生物劑(諸如抗寄生蟲劑、抗細菌劑、抗真菌劑、抗病毒劑);甲硝噠唑(Metronidazole)、伊維黴素(ivermectin)、克林達黴素(clindamycin)、紅黴素(erythromycin)、四環素(tetracycline)、多西環素(doxycycline)、二甲胺四環素(minocycline);類固醇及非類固醇消炎劑(諸如皮質類固醇、他克莫司(tacrolimus)、吡美莫司(pimecrolimus)、環孢靈A(cyclosporine A));抗血管生成劑;抗分支桿菌劑(諸如達普松(dapsone));遮光劑防曬霜(Sunscreensor sunblock)或如同遮光劑/防曬霜一般起作用之任何物質(諸如二氧化鈦、氧化鋅、阿伏苯宗(avobenzone));抗氧化劑(諸如維生素C、維生素E、槲皮素(quercetin)、白藜蘆醇(resveratrol));其他α促效劑(諸如溴莫尼定(brimonidine)、羥間唑啉、氯壓定(clonidine));β阻斷劑(諸如納多洛爾(nadolol)、普萘洛爾(propanolol)、卡維洛爾(carvedilol));抗組織胺;類視色素(諸如維甲酸(tretinoin)、阿達帕林
(adapalene)、他紮羅汀(tazarotene)、異維甲酸(isotretinoin)、視黃醛(retinaldehyde));過氧化苯甲醯;薄荷腦(Menthol)及其他「冷卻」劑;乙醯磺胺鈉及衍生物;抗真菌劑(諸如咪唑衍生物、多烯化合物、烯丙胺化合物);絲胺酸蛋白酶(激肽釋放素(kallikrein))抑制劑(諸如胺基己酸)。
本發明不限於例示實施例之範疇中,該等例示實施例僅意欲作為對本發明之特定態樣之說明。除本文揭示之修改之外,本發明之各種修改亦將為熟習此項技術者藉由仔細閱讀如最初申請之說明書(包括申請專利範圍)所顯而易知。意欲所有此等修改皆將屬於隨附申請專利範圍之範疇。
大鼠血流量分析
背景
紅斑痤瘡可藉由熱暴露來觸發。對身體變冷之生理交感神經系統介導性反應為皮膚血管收縮且對身體變暖之反應為皮膚血管括張。作用於交感神經系統流出之α-腎上腺素激導性促效劑可調控反應於溫度變化之皮膚血流量。
方法
雷射多普勒微血管灌注監測器(laser Doppler microvascular perfusion monitor)(雷射多普勒流量測定技術,LDP)用於監測後足墊之微血管結構中之紅血球灌注。雷射多普勒流量測定計(LDP)為來自英國Oxford Optronix有限公司之OxyFlo微血管灌注監測器。
簡言之,向麻醉之無毛CD大鼠之一個後足墊以表面方式一次性或重複(每日一次連續4日)敷用15 μL測試物品且向另一足墊敷用15 μL媒劑。
在末次投與測試物品後直至8小時之各種時間點,對於每個溫度間隔,每15秒持續4分鐘量測並記錄動態血流量變化,持續5個間隔(22℃→37℃→4℃→37℃→22℃)。將大鼠置於37℃熱墊上以提高其溫度及置於冰墊上以使其溫度降低至4℃。比較兩個爪中之血流量程度。
第1圖展示在以0.1%濃度向皮膚單次表面給藥之後,表面(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉顯著抑制37℃誘發之血管擴張多達4小時。在表面給藥4日(每日一次)之後,統計顯著抑制之持續時間增加至至少6小時。藥物治療爪與媒劑治療爪之間的雷射多普勒記錄之峰1(首個8分鐘加熱及冷卻間隔)的AUC差異%即計算為血流量抑制%。資料為每組8-10只大鼠之平均抑制值%。
此資料說明表面(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-
四氫-喹啉可抑制大鼠之熱誘發之皮膚血管擴張(或總體皮膚血流量),且一次表面敷用(15 μl 0.1%凝膠劑)之作用持續至少4小時。在重複給藥4日之後,存在至少6小時之延長持續時間。
活體外人類皮膚滲透性分析
將人類離體軀幹皮膚切割成多個足夠大以安裝在標稱2 cm2靜態Franz擴散槽上的較小切片。用由含0.1% Oleth-20之0.1×磷酸鹽緩衝溶液組成之受體溶液填充真皮受體區室達最大限度,且使表皮腔室(罩(chimey))向周圍實驗室環境敞開。將槽置於擴散裝置中,在該裝置中與真皮下側接觸之受體溶液在約600 RPM下經磁力攪拌且維持其溫度以達成32.0±1.0℃之皮膚表面溫度。
為保證各皮膚切片之完整性,在敷用測試產品之前測定其氚化水滲透性。3H2O吸收小於1.56 μL-equ/cm2之皮膚試樣視為可接受。
對於各供體,向同一供體皮膚之三(3)個複本切片敷用(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉,從而持續指定給藥持續時間評估三(3)個供體。均勻分散每個皮膚切片5 mg調配物/cm2之劑量且使用玻璃棒擦入皮膚表面中。
在指定時間點及在研究給藥持續時間結束時,完全移除受體溶液且保留預定體積等分試樣以便後續分析。在
收集末個受體樣品之後,移除供體區室(罩),且清潔皮膚表面兩次以自皮膚表面收集任何未吸收調配物。在表面清潔之後,皮膚經膠帶剝離以移除角質層。膠帶剝離物於乙腈中提取隔夜且分析其相關化合物之含量。接著自擴散槽移除皮膚,分割成表皮及真皮,且分別對於表皮及真皮,各皮膚樣品係於50%:50%(v/v)乙醇/水或50%:50%(v/v)甲醇水中提取隔夜。分析皮膚切片樣品之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉含量。所有樣品皆儲存在約-20℃(±15℃)下以待分析。藉由串聯有質譜之液相層析(PLC/MS)對(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉進行定量分析。
供體內之重複實驗經平均化且計算各關鍵參數之標準偏差。接著整理供體內平均值且計算供體間群體平均值與平均值標準誤差。
第2圖以在0.58%(w/w)劑量之後出現在皮膚下受體溶液中之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉之通量形式展示經皮吸收速率。
第3圖以回收之質量形式展示在使0.58%(w/w)劑量對離體人類軀幹皮膚之48小時劑量暴露之後(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉在各皮膚層中之分佈。
資料表明在使用活體外Franz擴散槽下,(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉確實滲透進入且穿過離體人類軀幹皮膚。在18及36小時時間點時通量速率增大(第2圖)及表皮中之濃度較高(第3圖)表明藥物儲存
在皮膚中,此與重複給藥之後作用持續時間長久及持續時間延長一致。
LL-37誘發之皮膚發炎小鼠模型
背景
相較於正常皮膚,紅斑痤瘡皮膚伴有LL-37導管素(cathelicidin)含量增加。將LL-37皮內注射入小鼠體內會誘發類似於在紅斑痤瘡皮膚中所見之皮膚發炎(Yamasaki 2007)。
方法
向BALB/c小鼠之耳背側表面敷用(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉凝膠劑或其相應媒劑。在敷用之後一小時,左耳用LL-37肽皮內注射且右耳用磷酸鹽緩衝鹽水(PBS)注射。在直至用LL-37注射後8小時之各種時間點用數位測徑規(Mitutoyo)進行耳厚度量測。耳腫脹為發炎指示。
第4圖展示在用(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉表面治療之後,在6小時及9小時對LL-37誘發之皮膚發炎之統計顯著抑制。資料為每組9-10只小鼠之平均值。
資料表明表面投與(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉具有與治療紅斑痤瘡相關之消炎作用。
紫外線B誘發之小鼠曬傷模型
背景
紅斑痤瘡可藉由曝露於紫外(UV)光來觸發。使無毛小鼠曝露於UVB輻射會產生持續至少48小時之特徵在於紅斑、皮膚血管擴張、觸覺過敏及發炎之曬傷樣反應。
方法
在120 mJ/cm2強度下使俯臥且其左側經覆蓋之SKH1無毛小鼠曝露於UVB 91秒。在輻射之後約30分鐘,向背部及耳背側表面之區域以表面方式敷用(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉凝膠劑或其相應媒劑。在直至UVB輻射後48小時之各種時間點,進行以下評估:
1.藉由使用ImagePro Premier(Media Cybernetics)軟體對數位照片進行影像分析來觀測曝露及未曝露耳中之血管結構面積。將影像轉化成灰階,擴大且向影像應用基於各耳之基線像素值之定限(thresholding)。定限使所要「對象」特徵(亦即血管結構網狀結構)與背景(亦即皮膚組織)區分。接著定量「對象」像素且報導為血管結構面積。
2.使用比色計(Konica Minolta)觀測曝露及未曝露背部上之紅斑。
3.使用漆刷測試進行觸覺過敏評估。藉由歷經35分鐘
每5分鐘用小漆刷輕撫小鼠側腹來評估過敏性。行為反應經如下計分:0,無反應;1,伴有試圖離開刷之輕度尖叫;2,由刷引起劇烈尖叫,咬刷且強烈試圖逃脫。將在八個時間點時之計分加和,因此各小鼠之最大過敏計分可為16。曝露(右)及未曝露(左)側腹經獨立計分。
第5圖展示在UVB曝露之後30分鐘向背部進行之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉表面給藥使紅斑(用比色計量測)統計顯著減少至接近基線程度持續至少48小時。資料為每組6只小鼠之值的平均值。
第6圖展示在UVB曝露之後30分鐘向耳進行之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉表面給藥產生統計顯著的皮膚血管收縮(如皮膚血管結構面積減小所量度)至接近基線程度持續至少48小時。資料為每組6只小鼠之值的平均值。
第7圖展示在UVB曝露之後30分鐘向背部進行之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉表面給藥使在UVB輻射之後4小時評估之觸覺過敏(根據對漆刷撫摸之反應來計分)統計顯著降低。UV曝露側與對照側兩者之過敏性皆存在降低。資料為每組6只小鼠之值的平均值。
資料表明表面投與(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉對作為許多皮膚疾病及病狀之徵象及症狀之發炎、紅斑(發紅)及過敏具有持久有益作用。研究結果與對曬傷、紅斑痤瘡及牛皮癬之治療具有特別
相關性。
第1圖展示表面(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉抑制大鼠爪中37℃誘發之皮膚血管擴張,在單次敷用之後持續治療後至少4小時且在4次每日敷用之後持續治療後至少6小時。
第2圖以出現在離體人類軀幹皮膚製備物中之皮膚下受體溶液中之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉的通量形式展示經皮吸收速率。
第3圖以回收之質量形式展示在48小時劑量暴露於離體人類軀幹皮膚之後(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉之分佈。
第4圖展示在用(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉表面治療之後,對LL-37誘發之小鼠皮膚發炎之抑制。
第5圖展示在用(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉治療之後,UVB誘發之小鼠皮膚紅斑(發紅)之持續至少48小時的減輕。
第6圖展示在用(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉治療之後,小鼠耳中UVB誘發之皮膚血管擴張之持續至少48小時的降低。
第7圖展示在用(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉治療之後4小時,UVB曝露小鼠皮膚中之觸覺
過敏降低。
Claims (15)
- 一種治療罹患皮膚病狀之患者之該等皮膚病狀的方法,其包括用包含治療有效量之7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其個別對映異構體或其個別互變異構體或其醫藥學上可接受之鹽的醫藥組合物治療該患者。
- 如申請專利範圍第1項之方法,其中該醫藥組合物包含(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉。
- 如申請專利範圍第1項之方法,其中該醫藥組合物包含(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉。
- 如申請專利範圍第1項之方法,其中該所治療之病狀係選自:紅斑痤瘡(rosacea)、爆發性紅斑痤瘡(rosacea fulminans)、曬傷、牛皮癬、絕經相關潮熱、與潮熱相關之潮紅及發紅、與潮熱相關之紅斑、由睾丸切除異位性皮炎(orchiectomyatopic dermatitis)所致之潮熱、由昆蟲咬傷引起之發紅及發癢之治療、光老化、脂溢性皮炎、粉刺、過敏性皮炎、面部毛細血管擴張(先前存在之小血管的擴張)、血管擴張(angioectasias)、鼻贅(rhinophyma)(伴有濾泡擴張之鼻肥大)、粉刺樣皮疹(可滲出或結殼)、灼燒感或刺痛感、皮膚紅斑、伴有皮膚血管擴張之皮膚活動過度、萊爾氏症候群(Lyell's syndrome)、史蒂文斯-約翰遜症候群(Stevens-Johnson syndrome)、與痔瘡相關之局部發癢及不適、痔瘡、輕型多形性紅斑(erythema multiforme minor)、重型多形性紅斑、結節性紅斑、眼虛腫(eye puffiness)、蕁麻疹、瘙癢、紫癜、靜脈曲張、接觸性皮炎、異位性皮炎、錢幣狀皮炎(nummular dermatitis)、全身性剝脫性皮炎、瘀滯性皮炎(stasis dermatitis)、慢性單純性苔癬(lichen simplex chronicus)、口周皮炎(perioral dermatitis)、須部假性毛囊炎(pseudofolliculitis barbae)、環狀肉芽腫(granuloma annulare)、光化性角化病(actinic keratosis)、基底細胞癌、鱗狀細胞癌及濕疹。
- 如申請專利範圍第1項之方法,其中該病狀為紅斑痤瘡。
- 如申請專利範圍第1項之方法,其中該病狀為牛皮癬。
- 如申請專利範圍第1項之方法,其中該病狀為爆發性紅斑痤瘡。
- 如申請專利範圍第1項之方法,其中該病狀為面部毛細血管擴張。
- 如申請專利範圍第1項之方法,其中該病狀為皮膚紅斑。
- 如申請專利範圍第1項之方法,其中該醫藥組合物呈適於表面皮膚投與之調配物形式、呈懸浮液、凝膠劑、溶液、乳膏劑、洗劑、軟膏劑、泡沫物、乳液、微乳液、乳劑(milk)、漿液(serum)、氣霧劑、噴霧劑、分散物、微膠囊、囊泡、微粒、濕布、乾布、面布(facial cloth)或直接注射液。
- 一種包含包裝材料及含於該包裝材料內之醫藥藥劑之製品,其中該醫藥藥劑在治療上有效地治療皮膚病狀且其中該包裝材料包含指示該醫藥藥劑可用於治療皮膚病狀之標籤且其中該醫藥藥劑包含治療有效量之7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其對映異構體。
- 如申請專利範圍第11項之製品,其中該醫藥藥劑包含治療有效量之(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉。
- 一種治療罹患眼部紅斑痤瘡、翼狀胬肉(pterygium)或結膜充血之患者之眼部紅斑痤瘡、翼狀胬肉或結膜充血的方法,其包括用包含治療有效量之7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉或其個別對映異構體或其個別互變異構體或其醫藥學上可接受之鹽的醫藥組合物治療該患者。
- 如申請專利範圍第13項之方法,其中該醫藥組合物包含(R)-(-)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉。
- 如申請專利範圍第13項之方法,其中該醫藥組合物包含(S)-(+)-7-(1H-咪唑-4-基甲基)-5,6,7,8-四氫-喹啉。
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US9283217B2 (en) | 2011-11-10 | 2016-03-15 | Allergan, Inc. | Pharmaceutical compositions comprising 7-(1 H-imidazol-4-ylmethyl)-5,6,7,8-tetrahydro-quinoline for treating skin diseases and conditions |
EP2994120B1 (en) * | 2013-05-06 | 2019-10-09 | Allergan, Inc. | Alpha adrenergic agonists for the treatment of tissue trauma |
FR3061434B1 (fr) * | 2017-01-04 | 2019-07-12 | Pierre Fabre Dermo-Cosmetique | Composition cosmetique comprenant une association d'huile de pongamia et de pentylene glycol 4-t-butylcyclohexanol pour lutter contre la rosacee |
RU2727695C1 (ru) * | 2020-02-13 | 2020-07-22 | Мурад Умарович Магомедов | Способ комплексного лечения ринофимы |
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DE69930252T2 (de) * | 1998-05-08 | 2006-12-14 | The University Of Miami, Miami | Verwendung von tetracyclinen zur behandlung von störungen der meibomschen drüsen |
WO2004073708A1 (en) * | 1998-12-17 | 2004-09-02 | Dean Thomas R | Brinzolamide and brimonidine for treating ocular conditions |
US20010049369A1 (en) * | 2000-02-10 | 2001-12-06 | Jablonski Monica M. | Brimonidine compositions and methods for retinal degeneration |
US6468989B1 (en) | 2000-07-13 | 2002-10-22 | Dow Pharmaceutical Sciences | Gel compositions containing metronidazole |
US6387383B1 (en) | 2000-08-03 | 2002-05-14 | Dow Pharmaceutical Sciences | Topical low-viscosity gel composition |
US20020198209A1 (en) | 2001-05-03 | 2002-12-26 | Allergan Sales Inc. | Compositions having enhanced pharmacokinetic characteristics |
US6680062B2 (en) | 2001-10-05 | 2004-01-20 | Color Access, Inc. | Anti-irritating rosacea treatment |
US7030149B2 (en) * | 2002-04-19 | 2006-04-18 | Allergan, Inc. | Combination of brimonidine timolol for topical ophthalmic use |
US20040146539A1 (en) * | 2003-01-24 | 2004-07-29 | Gupta Shyam K. | Topical Nutraceutical Compositions with Selective Body Slimming and Tone Firming Antiaging Benefits |
US7439241B2 (en) | 2003-05-27 | 2008-10-21 | Galderma Laboratories, Inc. | Compounds, formulations, and methods for treating or preventing rosacea |
US20050020600A1 (en) * | 2003-07-23 | 2005-01-27 | Scherer Warren J. | Methods of treating cutaneous flushing using selective alpha-2-adrenergic receptor agonists |
KR20060109947A (ko) * | 2003-11-20 | 2006-10-23 | 오쎄라 파마슈티걸즈, 인크. | 황반 변성 및 다른 안과 질환의 개선 |
US7812049B2 (en) | 2004-01-22 | 2010-10-12 | Vicept Therapeutics, Inc. | Method and therapeutic/cosmetic topical compositions for the treatment of rosacea and skin erythema using α1-adrenoceptor agonists |
CN104490884A (zh) * | 2004-05-25 | 2015-04-08 | 桑斯罗萨医药发展公司 | 治疗或预防炎症性皮肤疾病的化合物、制剂及方法 |
US20070203144A1 (en) * | 2006-01-17 | 2007-08-30 | Allergan, Inc. | Use of Memantine and Brimonidine to Attenuate Vitreoretinal Vascular Endothelial Growth Factor (VEGF) Protein Levels in Animals |
US7323477B2 (en) * | 2006-02-02 | 2008-01-29 | Allergan, Inc. | 7-((1H-imidazol-4-yl)methyl)-5,6,7,8-tetrahydroquinoline |
RU2321399C1 (ru) * | 2006-06-01 | 2008-04-10 | Федеральное государственное учреждение "Нижегородский научно-исследовательский кожно-венерологический институт Федерального агентства по здравоохранению и социальному развитию" | Способ лечения больных розацеа |
WO2008124151A2 (en) * | 2007-04-09 | 2008-10-16 | Avicena Group, Inc. | Use of creatine compounds for the treatment of eye disorders |
US20090061020A1 (en) * | 2007-08-31 | 2009-03-05 | Theobald Klaus P | Brimonidine Compositions for Treating Erythema |
US8455548B2 (en) * | 2007-10-18 | 2013-06-04 | Allergan, Inc. | Method of treating sensorimotor disorders with alpha-2 adrenergic receptor agonists |
PT2320911E (pt) * | 2008-08-01 | 2014-11-11 | Eye Therapies Llc | Composições de vasoconstrição e métodos de utilização |
US20100203165A1 (en) * | 2008-08-01 | 2010-08-12 | Gerald Horn | Compositions and methods for treatment of disorders or conditions of the eye |
FR2942138A1 (fr) * | 2009-02-16 | 2010-08-20 | Galderma Res & Dev | Association de composes pour le traitement ou la prevention des affections dermatologiques |
EP2493309A4 (en) * | 2009-10-26 | 2013-05-01 | Galderma Pharma Sa | METHODS OF TREATING OR PREVENTING ACUTE ERYTHEMA |
US8394800B2 (en) * | 2009-11-19 | 2013-03-12 | Galderma Laboratories, L.P. | Method for treating psoriasis |
EP2552448B1 (en) * | 2010-03-26 | 2019-04-24 | Galderma Research & Development | Improved compositions comprising brimonidine for safe and effective treatment of telangiectasia |
KR20170018974A (ko) * | 2010-03-26 | 2017-02-20 | 갈데르마 리써어치 앤드 디벨로프먼트 | 홍반의 유효하고 안전한 치료를 위한 개선된 방법 및 조성물 |
CA2810267A1 (en) * | 2010-08-06 | 2012-02-09 | Galderma Research & Development | Combination of compounds for treating or preventing skin diseases |
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