TWI442944B - 一種泡沫懸浮凝膠 - Google Patents
一種泡沫懸浮凝膠 Download PDFInfo
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- TWI442944B TWI442944B TW096111492A TW96111492A TWI442944B TW I442944 B TWI442944 B TW I442944B TW 096111492 A TW096111492 A TW 096111492A TW 96111492 A TW96111492 A TW 96111492A TW I442944 B TWI442944 B TW I442944B
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- Prior art keywords
- suspension gel
- gel
- active agent
- foam
- agent
- Prior art date
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Description
本發明係關於至少一種略溶至不溶於水之活性劑之局部遞送,且特別是關於一種含過氧化苯於水相之泡沫懸浮凝膠。
在醫藥活性劑之局部施用上存在許多挑戰,一主要的目標即是實現活性劑之經皮傳送至治療位置。組成物須具有所欲之化妝品性質。施用應簡單且不會於皮膚上產生明顯殘留。此外,組成物不應導致刺激、不適或不便。
許多抗真菌和抗菌劑用於局部治療表皮感染,有些抗生素,如四環素(tetracycline)及克林達黴素(clindamycin),也用於治療直接或間接由細菌導致之粉刺及其他皮膚病。使用克林達黴素的全身性副作用之一為結腸炎,其係具有危險性,甚至能致命。因此,在治療粉刺上,傾向於局部施用克林達黴素。由Pharmacia-Upjohn製造之麗歐迅(Cleocin T®),其成份包括克林達黴素磷酸鹽(clindamycin phosphate),於體外不具活性,但在活體中水解成具抗菌活性之克林達黴素。麗歐迅現有凝膠、乳液、及外用藥水形式,且被用於青春痘的局部治療。
其他製造商己生產之局部配方裡包括一略溶至不溶於於水之醫藥活性劑(例如:過氧化苯)及一第二醫藥活性劑(例如:克林達黴素)的產品。例如,由德美克製藥公司(Dermik Laboratories)製造之BenzaClin®及由史帝富藥
廠(Stiefel Laboratories)製造之Duac®皆含有過氧化苯和克林達黴素的成份。BenzaClin®及Duac®可以外用凝膠之形式獲得。其他則涉及含有過氧化苯及克林達黴素之懸浮泡沫,但該泡沫含有油脂,並且除一分散乳化劑(dispersing emulsifier)外,更需要一界面活性劑。見美國專利公告2005/0186147。
乳液、凝膠及油基(oil-based)泡沫具有較大塗抹範圍的缺點,並且可能會殘餘油狀殘留物。油脂也會加重粉刺病情。藥水型式則很容易溢出治療位置,因此難以控制藥水的使用量。
本發明係提供一組成物,包含至少一醫藥活性化合物,並能有效進行局部施藥,此組成物係為非流動的、易搽敷的、及不易殘留之泡沫懸浮凝膠型式。本發明之懸浮凝膠組成物係提供對於少量施藥於欲施藥區堿的良好控制。
本發明係提出一種水性泡沫凝膠,用於局部施用至少一種活性組成物,此活性組成物為略溶至不溶於水。因此,根據本發明之一方面,提供一略溶至不溶於水之第一活性劑以及一種或多種增稠劑。第一活性劑之重量百分比至多為40%,例如:0.5~40%、1~20%、2~10%、0.5%、1%、2%、3%、4%、5%、10%、15%、20%、25%、30%、35%或40%,並且懸浮於一水相中。增稠劑之重量百分比介於大約0.1%
至大約2%之間,例如:0.1%、0.2%、0.5%、1.0%、1.5%或2.0%,其中此凝膠為水性並且形成一均勻之泡沫。
本發明亦提供一種水性的,且用以局部施用一第一及一第二活性組成物之泡沫懸浮凝膠,而第一活性組成物係為略溶至不溶於水。
根據本發明之另一方面,提供一種水性之泡沫懸浮凝膠,包括或其組成為:重量百分比至多為40%,例如0.5~40%、1~20%、2~10%、0.5%、1%、2%、3%、4%、5%、10%、15%、20%、25%、30%、35%、或40%之重量百分比的一第一活性劑,其係微溶至不溶於水,且懸浮於一水相中;重量百分比至多為40%,例如:0.1~10%、5~40%、0.1%、0.2%、0.5%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、20%、25%、30%、35%、或40%之重量百分比的第二活性劑;重量百分比介於大約0.1%至大約2%間,例如:0.1%、0.2%、0.5%、1.0%、1.5%或2.0%之重量百分比的一種或多種之增稠劑;其中此凝膠為水性且形成一均勻之泡沫。
根據本發明之再一方面,提供一種水性的泡沫懸浮凝膠,包括或其組成為:重量百分比至多為40%,例如:0.5~40%、1~20%、2~10%、0.5%、1%、2%、3%、4%、5%、10%、15%、20%、25%、30%、35%、或40%之重量百分比的第一活性劑,其係微溶
至不溶於水,且懸浮於水相;重量百分比至多為40%,例如:0.1~10%、5~40%、0.1%、0.2%、0.5%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、20%、25%、30%、35%、或40%之重量百分比的第二活性劑;重量百分比介於大約0.1%至大約2%之間,例如0.1%、0.2%、0.5%、1.0%、1.5%或2.0%之重量百分比的增稠劑;其中此凝膠係為水性、黏度小於20000厘泊且形成一均勻之泡沫。
根據本發明之又一方面,提供一種水性的泡沫懸浮凝膠,包括或其組成為:懸浮於水相且重量百分比介於大約1%至大約8%之過氧化苯;重量百分比介於大約0.025%至大約2%之類視色素;以及重量百分比介於大約0.5%至大約2%之三仙膠;其中此凝膠為水性且形成一均勻之泡沫。
根據本發明之再一方面,本發明提供一種水性的泡沫懸浮凝膠,包括或其組成為:重量百分比介於大約1%至大約25%之過氧化苯,其係作為一單獨之活性組成物並懸浮於一水相中;以及重量百分比介於大約0.5%至大約2%之三仙膠;其中該凝膠為水性且形成一均勻之泡沫。
根據本發明之另一方面,本發明提供一種水性的泡沫
懸浮凝膠,包括或其組成為:懸浮於水相且重量百分比介於大約1%至大約8%之第一活性組成物,該第一活性組成物包括過氧化苯;重量百分比介於大約0.5%至大約4%之第二活性組成物,該第二活性組成物包括與克林達黴素磷酸鹽(clindamycin phosphate)結合之類視色素;以及重量百分比介於大約0.5%至大約2%之三仙膠;其中該凝膠為水性且形成一均勻之泡沫。
根據本發明之某些實施例,該泡沫懸浮凝膠為無酒精之泡沫懸浮凝膠。在某些實施例裡,該凝膠為自容器(例如:一加壓容器)釋放後行沫化之後起泡(post-foaming)凝膠。
根據本發明之另一方面,本發明在於提供一種用於治療皮膚病症狀之方法。一種治療皮膚病症狀之方法包括或由需搭配一泡沫懸浮膠接觸感染個體之皮膚之程序所組成,其中該泡沫懸浮凝膠係依據本發明所製成。在某些實施例裡,該方法供做粉刺之經皮治療。
在一實施例中,本發明之泡沫懸浮凝膠包括或其組成為一第一活性劑以及一第二活性劑。第一活性劑之重量百分比至多為40%,其係懸浮於一水相,並且略溶至不溶於水,此第一活性劑係選自於過氧化苯、類視色素、吡咯抗微生物劑(azole antimicrobial agent)及其混合物所組成之族群。第二活性劑之重量百分比至多為40%,且其係選自於抗菌劑、抗真菌劑、抗生素、免疫調節劑、縮氨酸、
維生素、維生素衍生物、吡咯、氧化物及其混合物所組成族群。其中若第一活性劑為過氧化苯而第二活性劑為抗生素,則泡沫懸浮凝膠包含一額外之活性組成物。
在一更進一步之實施例中,第一活性劑係為過氧化苯且第二活性劑係磺胺醋鈉(sodium sulfacetamide)。於本發明再一實施例中,第一活性劑係為吡咯抗微生物劑且第二活性劑係水楊酸(salicylic acid)。在另一實施例中,第一活性劑係為沉澱硫(precipitated sulfur)且第二活性劑係為磺胺醋鈉。
在另一實施例中,該泡沫懸浮凝膠可包括一作為單獨活性組成物之過氧化苯。在某些實施例中,本發明之泡沫懸浮凝膠可包括或其組成為一略溶至不溶於水且懸浮於水相之第一活性劑、可選擇性之第二活性劑、可選擇性之第三活性劑、一或多種增稠劑以及可選擇性之一或多種賦形劑,例如:選自於分散/潤濕劑、pH調整劑、界面活性劑、化學性防曬劑、推進劑、抗氧化劑、額外添加之發泡劑、螫合/多價螫合(chelating/sequestering)劑、溶劑、香精、著色劑及防腐劑所組成之群組。其中凝膠係為水性且形成一均勻泡沫。
在本發明之另一方面,本發明提供一種製造水性的泡沫懸浮凝膠的方法,可包括或由以下步驟依任意順序所組成:懸浮一第一活性劑於一水相中,其中第一活性劑係為略溶至不溶於水,藉此以形成一懸浮液;藉由添加一足夠
量之增稠劑增加懸浮液之黏度以維持該第一活性劑於懸浮液中;添加一第二活性劑;其中該泡沫懸浮凝膠最終黏度小於40000厘泊,且泡沫懸浮凝膠可包括酒精或不含酒精。
在本發明之另一方面,本發明提供一種水性泡沫凝膠,該水性泡沫凝膠包括或其組成為:懸浮於水相且重量百分比為大約1%至大約10%之過氧化苯;重量百分比大約0.5%至大約2%之克林達黴素酸鹽;重量百分比大約1%至大約2%之三仙膠;其中此凝膠係為水相且形成一均勻之泡沫。
在本發明之再一方面中,本發明提供一種水性泡沫凝膠,該水性泡沫凝膠可包括或其組成為:重量百分比介於大約4%至大約8%間之過氧化苯,其係作為單獨活性組成物且懸浮於一水相中;重量百分比介於大約0.5%至大約4%間之三仙膠;其中此凝膠係為水性且形成一均勻之泡沫。
在另一實施例中,本發明提供一種水性泡沫凝膠,該水性泡沫凝膠包括或其組成為:重量百分比介於大約1%至大約8%間之第一活性劑,包括懸浮於水相之過氧化苯;重量百分比介於大約0.5%至大約4%間之第二活性劑,包括一與克林達黴素磷酸鹽結合之類視色素;重量百分比大約0.5%至大約2%之三仙膠;其中此凝膠係為水性且形成一均勻之泡沫。
在本發明之更另一目的中,本發明提供一水性泡沫懸浮凝膠,此水性泡沫懸浮凝膠包括或其組成為:懸浮於水相且重量百分比在大約4%至大約8%間之過氧化苯;一重量百分比在大約0.025%至大約2%間之類視色素;重量百分比在大約0.5%至大約2%間之三仙膠;其中凝膠係為水性且形成一均勻之泡沫。
其餘更多組成物之實施例及製造方法係如同上述,並且描述於以下詳細之實施例中。
除非文中另有提及,字詞”活性劑”、”活性化合物”、”至少一醫藥活性化合物”及”醫藥活性劑”於此可交互替換使用,且為有關一具醫藥的、藥理學的或治療效果之物質。
如同文中所使用的,字詞”投治”、”施藥”及其相似之字詞係為有關在醫療及化妝品用途中,傳送特定組成物至一目標以提供一總合為淨正面效果之任何方法。
本文於此可交互替換使用之字詞”抗生素”及”抗菌劑”係指一可抑制細菌細胞之生長、毒性或殺死細菌之化合物。於此使用之該字詞”抗微生物劑”係指一可抑制微生物如細菌(抗菌劑)、真菌(抗真菌劑)、病毒(抗病毒劑)或寄生生物(抗寄生生物劑)之生長之物質。抗生素包括如由各種微生物(例如:細菌、真菌、放射菌類)產生之
物質、其異體(variant)、及人造之抗菌劑。於本技藝具有通常知識者可知可用於本發明之眾多抗生素。參考:Hardman及Limbard編(2001),古德曼吉爾曼治療學的藥理學基礎,第47章,麥格羅‧希爾國際出版公司(Chapter 47 of Goodman & Gilman’ s The Pharmacological Basis of Therapeutics,Hardman and Limbard eds.,2001,McGraw-Hill);Goodman等編(2005),古德曼吉爾曼治療學的藥理學基礎(Goodman & Gilman’s The Pharmacological Basis of Therapeutics,Goodman,et al.,eds.,2005)及Kucers等著抗生素之使用:抗菌、抗真菌及抗病毒藥物之臨床回顧,牛津大學出版社(1997)(Kucers,et al.,The Use of Antibiotics:A Clinical Review of Antibacterial,Antifungal,and Antiviral Drugs,Oxford Univ.Press(1997))。
本文於此所使用字詞”林可黴素抗生素”係指一最初從林可鏈黴菌(Streptomyces lincolnensis)菌種中發現之抗生素。例舉之抗生素包括林可黴素、克林達黴素及其醫藥可接受鹽類(pharmaceutically acceptable salt)及酯類,包括其鹽酸鹽及磷酸鹽。該林可黴素之資料載於如美國專利號第3,475,407、3,509,127、3,544,551及3,513,155號之專利案中。
本文於此所使用之字詞”分散劑”係指一添加至懸浮介質之界面活性物質藉此以提升均勻度並分散極細固體粒子至最大程度,其通常為膠體塗料。參考Lewis著。
Hawley簡明化學辭典,第14版(2002)(Lewis,Hawley’s Condensed Chemical Dictionary,14th Edition,2002)。一分散劑亦可以其親水親油平衡(hydrophile-lipophile balance,HLB)值來表示。相似地,於此使用之字詞”潤濕劑”係指一界面活性劑,當加入水中時,該界面活性劑可藉由減低水的表面張力而使水能更容易穿透或是散布於其他材料之表面。參考:Lewis著,Hawley簡明化學辭典,第14版(2002)(Lewis,Hawley’s Condensed Chemical Dictionary,14th Edition,2002)。一潤濕劑亦可以其親水親油值表示,如同此處所述,一單一界面活性劑可能具有如界面活性劑、分散劑及潤濕劑的任何或全部之活性。
如同本文於此所使用之字詞,一活性劑或組成物、醫藥活性劑或組成物之”有效劑量”或”治療有效劑量”所指之該字詞係為同義,係指藥理活性劑於施藥後可足夠產生一淨正面效果之量。當隨時間不斷重覆施以治療有效劑量之投治時,可致使症狀獲得大部分緩解。藥理活性劑之有效劑量受各別症狀或症狀處理方法、症狀嚴重程度、治療的期間、使用化合物之特殊成份及類似因素影響。
如同本文於此所使用之字詞”可發泡(foamable)”係指組成物可以形成泡沫狀。例如搽敷於濕或乾的皮膚上之後,該組成物可激起或自行發泡為泡沫狀。此組成物可自一裝置給藥時形成泡沫,而此裝置係為給藥時可混入空氣或蒸氣於凝膠中之裝置,例如:一空氣吸引起泡施配器
(air aspirated foaming dispenser)。該組成物可自一氣溶膠(aerosol)容器中給藥時形成泡沫,例如:一與懸浮凝膠混合之液化推進劑協助泡沫之形成。
如同本文於此所使用,該字詞”均勻的”或”同質的”係指整體上完全的均勻,即一均勻的混合物。
於此使用之字詞”pH”係指以一適合的、嚴格標準化的電勢測定的儀器(pH儀)給定之pH值,該pH儀係使用對氫離子活性敏感之指示電極、一玻璃電極及一合適之參考電極並可重現pH值在0.02之範圍內。在只需近似之pH值即可狀況下,可使用替代電極(alternate electrode)、pH指示劑及/或酸鹼試紙。
如同本文於此使用之字詞,一活性化合物之”醫藥可接受鹽”,該字詞係指一為醫藥上可接受且具有根源化合物(parent compound)中欲保留之藥理活性的鹽類。此類鹽包括:(1)加酸鹽類,與無機酸如鹽酸、氫溴酸、硫酸、硝酸、磷酸及其類似者形成之鹽類;或是與有機酸如醋酸、丙酸(propionic acid)、正己酸(hexanoic acid)、3-環戍基丙酸(cyclopentanepropionic acid)、甘醇酸(glycolic acid)、丙酮酸(pyruvic acid)、乳酸(lactic acid)、丙二酸(malonic acid)、琥珀酸(succinic acid)、蘋果酸(malic acid)、馬來酸(maleic acid)、富馬酸(fumaric acid)、酒石酸(tartaric acid)、檸檬酸(citric acid)、苯甲酸(benzoic acid)、3-(4-羥基苯甲醯基)苯甲酸(3-(4-hydroxybenzoyl)benzoic acid)、肉桂酸
(cinnamic acid)、扁桃酸(mandelic acid)、甲基磺酸(methanesulfonic acid)、乙基磺酸(ethanesulfonic acid)、1,2乙基二磺酸(1,2-ethane-disulfonic acid)、2-羥基乙基磺酸(2-hydroxyethanesulfonic acid)、苯磺酸(benzenesulfonic acid)、4-氯苯磺酸(4-chlorobenzenesulfonic acid)、2-萘磺酸(2-naphthalenesulfonic acid)、4-甲苯磺酸(4-toluenesulfonic acid)、樟腦磺酸(camphorsulfonic acid)、4-甲基雙環[2,2,2]-辛2烯基-1羥酸(4-methylbicyclo[2,2,2]-oct-2-ene-lcarboxylic acid)、葡萄酸(glucoheptonic acid)、3-苯丙酸(3-phenyl propionic acid)、三甲基乙酸(trimethylacetic acid)、三級丁基乙酸(tertiary butylacetic acid)、十二硫酸(lauryl sulfuric acid),葡萄糖酸(gluconic acid)、殼氨酸(glutamic acid)、羥基萘甲酸(hydroxynaphthoic acid)、水楊酸(salicylic acid)、硬脂酸(stearic acid)、己二烯二酸(muconic acid)及其類似物;或(2)根源化合物中之一酸性質子被一金屬離子,例如鹼金屬離子、鹼土金屬離子或一鋁離子所取代形成之鹽類;或(3)根源化合物中之一酸性質子被與有機鹼如乙醇胺(ethanolamine)、二乙醇胺(diethanolamine)、三乙醇胺(triethanolamine)及其類似物配位所形成之鹽類。
如同本文於此使用之字詞,該字詞”前驅藥”係指當此前驅藥以投治一目標時,於活體中釋放活性劑之任何化
合物。活性劑之前驅藥以修改一個或數個活性劑之官能基製備而成,其方式為此些修改之官能基可在活體中被破壞而釋放出原來之根源化合物。前驅藥包括活性劑中之羥基、胺基、硫氫基族群鍵結與任何官能基(即保護基)鍵結之化合物,而該保護基係可在活體中被破壞而重新產生各別之自由羥基、胺基、硫氫基之族群。例舉之前驅藥包括但不限於官能基被一個或多個保護基所保護之活性劑,而此些保護基係列於T.W.Greene及P.G.M Wuts著,有機合成中的保護基,第3版,約翰威廉父子出版公司,於紐約(1999)出版(T.W.Greene and P.G.M Wuts,Protective Groups inorganic Synthesis,3rd edition,John Wiley & Sons,New York,1999),以及Harrison與Harrison等著,有機合成方法概要,第1-8卷,約翰威廉父子出版公司(1971-1996)出版(Harrison and Harrison et al.,Compendium of Synthetic Organic Methods,Vols.1-8(John Wiley and Sons,1971-1996)),部分內容係以上述文獻之全部內容做為參考併入於此。在製備前驅藥上有效之代表性羥基保護基包括醯基群(例如:甲醯基(formyl)、乙酮基(acetyl)及三氟乙醯基(trifluoroacetyl))、烷醚(alkyl ethers)、磷酸醚(phosphate ethers)、磷酸酯(phosphate esters)及其類似物。在製備前驅藥上有效之代表性胺基保護基包括醯基(例如:甲醯基、乙酮基及三氟乙醯基)、苄氧基羰基(benzyloxycarbonyl,CBZ),特丁氧基羰基
(tert-butoxycarbonyl,Boc)及其類似物。
於此所使用之字詞”溶解度”或”可溶”係指一物質(例如:固體)溶解於另一物體(例如:液體)之量。溶解度一般在溫度15℃至25℃之間進行測量,且以W/V表示。如同於此使用之溶解度,溶質於液體中之溶解度範圍如下:極易溶1份溶質溶於小於1份溶劑之中
易溶1份溶質溶於1份至10份溶劑之中
可溶1份溶質溶於10份至30份溶劑之中
略溶1份溶質溶於30份至100份溶劑之中
微溶1份溶質溶於100份至1000份溶劑之中
極微溶1份溶質溶於1000份至10000份溶劑之中
幾乎不溶或不溶1份溶質溶於10000份以上之溶劑中
溶解度範圍可從公開藥典中獲得,包括美國藥典(USP)、歐洲藥典(EP)、英國藥典(BP)及Sweetman(2004)編,Sweetman(2004)著,馬丁代爾氏大藥典,英國醫學出版社出版(Martindale;The Complete Drug Reference,Sweetman,2004,Pharmaceutical Press)及Martindale著,馬丁代爾氏大藥典,第31版(1996),Amer Pharmaceutical Assn出版(Martindale,Martindale:The Extra Pharmacopoeia,31st Edition.,1996,Amer Pharmaceutical Assn),其部分內容係併入於此參考。
如同本文於此所使用字詞”治療”係指對生物之活
性、功能、健康、症狀產生影響之程序,且於此程序中維持、增加、減少或作用於上述之機能而能於某種程度上與一般健康且良好適應之生物一致。
如同本文於此所使用字詞”載劑”係指一化合物,該化合物只具賦形劑或具有須攜帶活性劑之組成物,但本身不具醫藥或治療效果之成份。
其它本文於此所使用之字詞以其該領域習用之意義定義者為準。
本發明提供一簡單及精緻之泡沫懸浮凝膠,係可於形成一均勻之泡沫之懸浮情況下,維持至少一活性劑的化學及物理性質之穩定。該泡沫懸浮凝膠係為水性及可選擇性地設計成不含酒精及/或不含油份之泡沫懸浮凝膠。本發明之懸浮凝膠係為具發泡性、機械剪力可破壞的,但非所謂含酒精之快速破滅(quick-break)泡沫。
再者,在罐中或容器中之凝膠配方設計可為一後起泡凝膠,該後起泡凝膠自罐中釋放後始行發泡。此創新之配方提供延長之耐儲時間,同時具有簡易施用之特性。例如,過氧化苯己知能降解克林達黴素。然而,於此所述之泡沫懸浮凝膠配方設計可有效地提供穩定和使用上方便兩大優點。
在某些實施例中,該泡沫懸浮凝膠係為不含油份。於此考慮下,如同本文於此使用之字詞”不含油份”係指組
成物中包含低於重量百分比1%之油份。在某些實施例中,該泡沫懸浮凝膠係為不含酒精。在這方面,如同本文於此使用之字詞”不含酒精”係指成份中包含低於重量百分比1%之酒精。此處所指之酒精包括乙醇、異丙醇、丙醇、丁醇或其他短鍵之脂肪族醇類。在某些實施例中,該泡沫懸浮凝膠係為不含油份及不含酒精之泡沫懸浮凝膠。
本發明之泡沫懸浮凝膠之成份可包括或由一微溶至不溶於水之第一活性劑、一水相、一增稠劑及水所組成。該泡沫懸浮凝膠可括一第二活性劑。該泡沫懸浮凝膠可選擇性地包括一或多個pH調整劑(即酸、鹼、緩衝劑、緩衝對)、潤濕劑/分散劑、界面活性劑、防曬劑、第三活性劑、抗氧化劑、額外添加之發泡劑、螫合/多價螫合劑或推進劑。該泡沫懸浮凝膠可為不含酒精及/或不含油份之泡沫懸浮凝膠。
於泡沫懸浮凝膠中之該第一活性劑係為略溶至不溶水且分散或懸浮於水相之中。略溶至不溶於水之活性劑之例舉範疇包括例如止痛劑、麻醉劑、消炎劑、解熱劑、抗微生物劑如抗菌劑、抗生素及抗真菌劑、抗憂鬱劑(如三環素鹽酸(nortriptyline hydrochloride),抗癲癇劑(如甲琥胺(methsuximide)、***(Phenobarbital)、普里米酮(primidone))、抗瘧劑(如奎寧硫酸鹽(quinine
sulfate))、抗偏頭痛劑(如雙氫麥角胺甲磺酸鹽(dihydroergotamine mesylate)、麥角胺酒石酸鹽(ergotamine tartrate)、二甲麥角新鹼馬來酸鹽(methysergide maleate)、抗腫瘤劑(如睪內酯(testolactone))、免疫抑制劑、抗原生動物劑(如甲硝噠唑(metronidazole))、抗焦慮劑、抗精神病劑、抗組胺劑、心臟血管劑、皮質類固醇、性賀爾蒙、止咳劑(如美沙芬氫溴酸鹽(dextromethorphan hydrobromide,呱芬那辛(guaifenesin)、特平咳錠(terpin hydrate))、皮膚科用藥、診斷用藥(如靛胭脂(indigotindisulfonate sodium))、消毒劑、多巴胺能劑(dopaminergic agent)(如阿朴嗎啡鹽酸鹽(apomorphine hydrochloride))、抗毒蕈鹼劑(如阿托品(atropine)、異丙碘銨(isopropamide iodide)、普環啶鹽酸鹽(procyclidine hydrochloride))、擬副交感神經藥(如毒扁豆鹼水楊酸(physostigmine salicylate))、擬交感神經藥(如鹽酸賽洛唑(xylometazoline hydrochloride)、異舒普林鹽酸鹽(isoxsuprine hydrochloride))、甲狀腺劑及抗甲狀腺劑(如碘酒、左甲狀腺素鈉(levothyroxine sodium))、肌肉鬆弛劑(如肌安寧(carisoprodol)、美索巴莫(methocarbamol))、興奮劑及厭食劑(如鹽酸多沙普侖(doxapram hyfrochloride))、腸胃劑、免疫調節劑、縮氨酸(peptides)、維他命及維他命衍生物、吡咯、氧化物及羥基嘌呤(如咖啡因(caffeine))、鹽類或其衍生物,及
其混合物。
於一些較佳之實施例中,第一活性劑係選自由抗菌劑、抗生素、抗真菌劑、免疫調節劑、縮氨酸(peptides)、維他命及維他命衍生物、吡咯、氧化物、鹽類或其衍生物以及其混合物所組成之族群。於某些實施例中,第一活性劑係選自由過氧化苯、類視色素、類固醇、吡咯抗微生物劑、沉澱硫以及其混合物所組成之族群。
該第一醫藥活性化合物之合適濃度範圍可為,例如重量百分比至多為40%,如在大約0.5%-40%、1-20%、2-10%之重量百分比間,或大約0.5%、0.8%、1%、1.5%、2%、2.5%、3%、5%、7.5%、10%、15%、20%、25%、30%、35%、或40%之重量百分比。
在某些實施例中,該第一活性劑為過氧化苯(BPO),該過氧化苯含量可在大約1%至25%、大約1%至8%、大約2%至8%、大約4%至8%、大約4%至10%之間,例如,大約1%、1.5%、2%、2.5%、3%、4%、5%、6%、7%、7.5%、8%、9%、9.5%、10%、15%、20%或25%。
舉例之止痛劑、消炎劑及解熱劑例如包括氨基馬尿酸(aminohippuric acid)、阿尼利定(anileridine)、阿斯匹靈(aspirin)、可待因(codeine)、可待因硫酸鹽(codeine sulfate)、消炎痛(indomethacin)、酒石酸左旋嗎汎(levorphanol tartrate)、鎮痛新(pentazocine)、鎮痛新鹽酸鹽(pentazocine hydrochloride)、萘磺酸右丙氧芬(propoxyphene napsylate)、鹽類或其衍生物,及
其混合物。
例舉之麻醉劑包括,如苯坐卡因(benzocaine)、氨苯丁酯(butamben)、古柯鹼(***e)、二丁卡因(dibucaine)、達克羅寧鹽酸鹽(dyclonine hydrochloride)、丁卡因(tetracaine)、鹽類或其衍生物、及其混合物。
例舉之抗菌劑包括,如氯雷素(chloramphenicol)、氯四環素鹽酸鹽(chlortertracycline)、氯碘羥喹(clioquinol)、去甲氯四環素(demeclocycline)、地美環素鹽酸鹽(demeclocycline hydrochloride)、紅黴素(erythromycin)、鹽酸甲烯土黴素(methacycline hydrochloride)、奈啶酸(nalidixic acid)、咐喃西林(nitrofurazone)、土黴素(oxytetracycline)、土黴素鈣鹽(oxytetracycline calcium)、青黴素(penicillinds)(如青黴素G(penicillinG)、青黴素苄星(penicillin benzathine)、青黴素G鈉(penicillin G sodium)及青黴素V苄星(penicillin V benzathine))、吡嗪酰胺(pyrazinamide)、磺胺嘧啶(sulfadiazine)、磺胺甲唑(sulfamethizole)、磺胺甲噁唑(sulfamethoxazole)、磺胺吡啶(sulfapyridine)、磺胺異愕唑(sulfisoxazole)、四環素(tetracycline)、鹽類或其衍生物、及其混合物。
例舉之抗組胺劑包括,如鹽酸賽克利(cyclizine hydrochloride)、鹽酸賽庚啶(cyproheptadine
hydrochloride)、羥嗪巴莫酸酯(hydroxyzine pamoate)、酒石酸苯茚胺(phenindamin tartrate)、馬來酸狄普(thiethylperazine maleate)、鹽類或其衍生物、及其混合物。
例舉之抗焦慮藥包括,如利眠寧(chlordiazepoxide)、安定(diazepam)、達啶醇(droperidol)、氟杬醇(haloperidol)、去甲羥基安定(oxazepam)、戍巴比妥(pentobarbital)、派迷清(pimozide)、硫塞辛(thiothixene)、泰爾阿羅佩(triazolam)、鹽類或其衍生物,及其混合物。
例舉之心臟血管藥包括,如醋硝香豆醇(acenocoumarol)、醋洋地黃毒苷(acetyldigitoxin)、阿可樂定鹽酸鹽(apraclonidine hydrochloride)、依那普利拉(enalaprilat)、氫氟噻嗪(hydroflumethiazide)、甲氟噻嗪(methyclothiazide)、尼非待平(nifedipine)、奎尼定硫酸酯(quinidine sulfate)、三甲***(trichlormethiazide)、鹽類或其衍生物,及其混合物。
例舉之皮質類固醇包括,如倍它美松(betamethasone)、倍它美松醋酸酯(betamethasone acetate)、倍它美松戍酸酯(betamethasone valerate)、可羅貝他梭丙酸酯(clobetasol propionate)、地索寧(desonide)、氟米松丙酮酸酯(flumethasone pivalate)、氟西奈得丙酮(fluocinolone acetonide)、氟甲松龍
(fluorometholone)、甲基脫氫皮醇(methylprednisolone)、甲基脫氫皮醇醋酸(methylprednisolone acetate)、脫氫皮醇(prednisolone)、脫氫皮醇醋酸(predniosolone acetate)、脫氫皮醇半琥珀酸(prednisolone hemisuccinate)、脫氫可體松(prednisone)、鹽類或其衍生物、及其混合物。
例舉之皮膚科用藥包括,如研磨劑、二西催定(acitretin)、阿達派林(adapalene)、過氧化苯(benzoyl peroxide)、爐甘石(calamine)、得膚寧(calcipotriene)、地蔥酚(dithranol)、依曲替酯(etretinate)、反丁烯二酸(fumaric acid)、異維A酸(isotretinoin)、金屬氧化物、輕石(pumice)、硫代嘧啶氧鋅(pyrithione zine)、水楊酸(salicylic acid)、硫化硒(selenium sulfide)、沈澱硫(precipitated sulfur)、他卡西醇(tacalcitol)、雲母(talc)、焦油(tars)、二氧化鈦(titanium dioxide)、揣特寧(tretinoin)、氧化鋅(zinc oxide)、鹽類或其衍生物、及其混合物。
例舉之消毒劑包括,如抗壞血酸棕櫚酸酯(ascorbyl palmitate)、苯甲酸(benzoic acid)、氯丁醇(chlorobutanol)、氯甲酚(chlorocresol)、氯二甲苯酚(chloroxylenol)、哈拉宗(halazone)、對羥基苯甲酸甲
酯(methylparaben)、迷他芬(nitromersol)、苯汞基醋酸鹽(phenylmercuric acetate)、苯汞基硝酸鹽(phenylmercuric nitrate)、對羥苯甲丙酯(propylparaben)、山梨酸(sorbic acid)、麝香草酚(thymol)、鹽類或其衍生物、及其混合物。
例舉之維他命及營養劑包括,如維他命A、維他命E、、維他命K、維他命B12(cyanocobalamin)、羥鈷胺素(hydroxocobalamin)、尼亞新(niacin)、糖精(saccharin)、維他命B1(thiamine mononitrate)、鹽類或其衍生物、及其混合物。
例舉之性賀爾蒙包括,如去氫孕酮(dydrogesterone)、***氫基可體松西比歐酸酯(estradiol cypionate)、愛斯球皮佩特(estropipate)、炔諾酮乙酸酯(norethindrone acetate)、氧甲氫龍(oxandrolone)、康復龍(oxymetholone)、康力龍(stanozolol)、鹽類或其衍生物、及其混合物。
例舉之腸胃藥包括、如比沙可啶(bisacodyl)、多庫酯鈣(docusate calcium)、多庫酯鈉(docusate sodium)、氫氧化鎂(magnesium hydroxide)、辛納塞(sennosides)、硫沙拉辛(sulfasalazine)、鹽類或其生物、及其混合物。
其他略溶至不溶於水的重要之活性劑包括,如貝奈克酯鹽酸鹽(betadex)、氫氧化鈣(calcium hydroxide)、硫酸鈣(calcium sulfate)、樟腦(camphor)、戒酒硫
(disulfiram)、乙基香草醛(ethyl vanillin)、馬來酸甲基麥角新(methylergonovine maleate)、罌粟鹼鹽酸鹽(papaverine hydrochloride)、八乙酸蔗糖酯(sucrose octaacetate)、香草醛(vanillin)、鹽類或其衍生物、及其混合物
更多略至不溶於水之活性劑的例示可從相關文獻中獲得,例如Sweetman(2004)著,馬丁代爾氏大藥典,英國醫學出版社出版(Martindale:The Complete Drug Reference,Sweetman,2004,Pharmaceutical Press)及Marindale著,馬丁代爾氏大藥典,第31版(1996),Amer.Pharmaceutical Assn出版(Marindale,Martindale:The Extra Pharmacopoeia,31st Edition.,1996,Amer.Pharmaceutical Assn),其內容係合併於此做為參考。
在一實施例中,第一活性劑係為過氧化苯,過氧化苯(CAS化學編號94-36-0)係可例如於商業上由美國密蘇里州聖路易市Sigma-Aldrich公司購得。
在一實施例中,第一活性劑係為一或多種吡咯抗微生物劑或抗真菌劑,如一或多種之咪唑(imidazole)或***(triazole),包括其硝酸鹽形式。咪唑可例如為克霉唑(clotrimazole)、咪康唑(miconazole)、甲硝達唑(metronidazole)、酮康唑(ketoconazole)、益康唑(econazole)、布康唑(butoconazole)、奧昔康唑(oxiconazole)、硫康唑(sulconazole)、或其混合物。
***可例如為阿伯康唑(albaconazole)、立福康唑(ravuconazole),伏立康唑(voriconazole)、泊沙康唑(posaconazole)、特康唑(terconazole)、伊曲康唑(itraconazole)及氟康唑(fluconazole)。在一實施例中,該吡咯抗微生物劑係為甲硝達唑。在一實施例中,該吡咯抗微生物劑係為酮康唑。更進一步關於吡咯抗微生物劑可從相關文獻中獲得,例如:Goodman等編(2005),古德曼吉爾曼治療學的藥理學基礎,第11版,麥格羅‧希爾國際出版公司Goodman and Gilman’s The Pharmacological Basis of Therapeutics,Goodman,et al.,eds.,11th Edition,2005,McGraw-Hill。其他更多可應用於此處之抗微生物劑和/或抗真菌劑,其作為非限制目的之範例例如包括環匹羅司(ciclopirox)、環匹羅司乙醇胺(ciclopirox olamin)、特平那芬(terbinafine)、茶樹油(tea tree oil)、葛西弗唯(griseofulvin)、十一碳烯酸(undecylenic acid)、水楊酸、托萘酯(tolnaftate)、兩性黴素(amphotericin)、殺念珠菌素(candicidin)、氟胞嘧啶(flucytosine)、游黴素(natamycin)、制霉菌素(nystain)、十一烯酸(undecenoic acid)、鹽類或其衍生物、及其混合物。
在一實施例中,該第一活性劑係為一或多種之類視色素,如維他命A、順式或反式之視黃醇(retinol,cis or trans)、順式或反式之視黃醛(retinal,cis or trans)、順式A酸(retinoic acid,cis)、維甲酸(tretinoin)、羥
基-逆轉-視黃醇(hydroxyretroretinol)、二去氫A酸(didehydroretinoic acid)、依曲替酯(etretinate)、視黃基棕櫚酯(retinyl palmitate)、β-胡蘿蔔素(β-carotene)、他札羅汀(tazarotene)、二西催定、阿達派林、鹽類或其衍生物、及其混合物。關於類視色素更深入資料可從相關文獻中獲得,例如上述古德曼吉爾曼治療學的藥理學基礎(Goodman and Gilman’s The Pharmacological Basis of Therapeutics)。
該第二活性劑係可為任何適合局部施藥之醫藥活性劑。該第二活性劑係可溶於水,或略溶至不溶於水中。該第二活性劑可影響藥物反應(pharmaceutical response),而該藥物反應係可為補助第一活性劑,或因需要而獨立於第一活性劑。該第二活性劑可為,如抗微生物劑諸如抗菌劑、抗生素及抗真菌劑、免疫調節劑、縮氨酸、維他命及維他命衍生物、吡咯、氧化物、鹽類或其衍生物、及其混合物。在一實施例中,該第二活性劑係為一抗痘劑(anti-acne agent)。
在一實施例中,該第二活性劑係選自於林可黴素抗生素(例如:克林達黴素、林可黴素)、類視色素、磺胺醋鈉(sodium sulfacetamide)或水楊酸所組成之族群。
該第二醫藥活性化合物之合適濃度可為,例如重量百分比之濃度至多為大約2%、5%、7%、10%、12%、15%、20%、25%、30%、35%或40%,例如重量百分比大約在0.01%~10%、
0.1%~8%、0.2%~5%、0.5%~2%或5%~40%範圍內,或重量百分比大約為0.1%、0.2%、0.5%、0.8%、1%、1.5%、2%、2.5%、3%、5%、6%、7%、7.5%、8%、8.5%、9%、9.5%、10%、12%、15%、20%、25%、30%、35%或40%。
在一實施例中,該第二活性劑係為克林達黴素、一醫藥可接受鹽或其前驅藥。克林達黴素係為一抗生素且其為具有通常知識者所熟知之化學式為甲基7-氯-6,7,8-三去氧-6-(1-甲基-順式-4-丙基-左旋-2-咯烷甲醯胺基)-1-硫基-左旋-蘇式-α-右旋-半乳辛喃糖(methyl 7-chloro-6,7,8-trideoxy-6-(1-methyl-trans-4-propy 1-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-α-D-galacto-octo-pyranoside)或甲基7-氯-6,7,8-三去氧-6-[[(1-甲基-4-丙基-2-咯烷基)羰基]氨基]-1-硫基-左旋-蘇式-α-右旋-半乳辛喃糖(methyl 7-chloro-6,7,8-trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl]amino]-1-thio-L-threo-α-D-galacto-octo-pyranoside)。如同本文於此所使用之字詞,單獨該字詞”克林達黴素”即包括克林達黴素之自由基及醫藥可接受鹽及其酯類。例舉之克林達黴素之醫藥可接受鹽及其酯包括,但不限於克林達黴素鹽酸鹽(clindamycin hydrochloride)、克林達黴素磷酸鹽(clindamycin phosphate)、克林達黴素棕櫚酸酯(clindamycin palmitate)及克林達黴素棕櫚酸酯鹽酸鹽(clindamycin palmitate hydrochloride)。克林達黴素
鹽類或酯類可用於本發明之組成物,如克林達黴素磷酸鹽。
克林達黴素的使用、性質、及合成方法於1979年7月13日公告之Stoughton的美國專利第3,969,516號專利、於1969年公告之Bierkenmeyer的美國專利第3,475,407號專利、於1969年公告之美國專利案第3,487,068號專利、於1970年公告之Kagan與Magerlein的美國專利案第3,509,127及3,544,551號專利、於1970年公告之Bierkenmeyer與Kagan的美國專利案第3.513,155號專利、Morozowich與Sinkula之1971年公告之美國專利案第3,580,904號及1972年公告之美國專利案第3,655,855號之專利、於1973年公告之美國專利案第3,714,141號專利、於1986年公告之美國專利案第4,568,741號專利、於1984年公告之美國專利案第4,710,565號專利中提出。上述所有專利文件之內容係合併於此做為參考。
關於克林達黴素之其他資訊載於以下文獻中,例如Magerlein等著,抗菌銀劑化學療法雜誌,727頁(1966)(Magerlein,et al.,Antimicrob.Ag.Chemother.727(1966);Birkenmeyer及Kagan著,藥物化學雜誌,卷13,616頁(1970)(Birkenmeyer and Kagan,J.Med.Chem.,13,616(1970));Oesterling著,醫藥科學雜誌,卷59,63頁(1970)(Oesterling,J.Pharm Sci.59,63(1970));McGehee等著,美國醫學科學雜誌,卷256,
279頁(1968)(McGehee,et al.,Am.J.Med.Sci.256,279(1968));D.A.Leigh著,抗菌化學療法雜誌,卷7(增刊A),第3頁(1981)(D.A.Leigh,J.Antimicrob.Chemother.7(Supplement A),3(1981));JE Gray等著,毒理學與應用藥理學,卷21,516頁(1972)(JE Gray et al.,Toxicol.Appl.Pharmacol.21,516(1972)),以及L W Brown及W F Beyer著,藥物分析資料,卷10,75-91頁,K.Florey編,美國學術通訊社,紐約(1981)出版(L W Brown and W F Beyer in Analytical Profiles of Drug Substances,Vol.10,K.Florey,editor(Academic Press,New York,1981),pages 75-91)。
克林達黴素磷酸鹽及克林達黴素鹽酸鹽係為商業上可獲得自例如美國密蘇里州聖路易之Sigma-Aldrich公司(Sigma-Aldrich,St.Louis,MO)及美國伊利諾州芝加哥之雅培公司(Abbott Laboratories,Chicago,IL)之物質。
在一實施例中,該第二活性劑係為一或多種之類視色素,如維他命A、順式或反式之視黃醇、順式或反式之視黃醛、順式A酸、維甲酸、羥基-逆轉-視黃醇、二去氫A酸、依曲替酯、視黃基棕櫚酯、β-胡蘿蔔素、他札羅汀、二西摧定、阿達派林、鹽類或其衍生物、及其混合物。
在一實施例中,該第二活性劑係為磺胺醋鈉。
在某些實施例中,該第一活性劑及第二活性相同,但該第一活性劑係為懸浮且該第二活性劑係分解或溶解於溶質中。按此方法,該懸浮之第一活性劑相較於溶解之第
二活性劑具有不同之釋放速率(release of rate)。藉由適化(tailoring)釋放速率,可對該活性組成物之穿透速率(penetration of rate)產生有利的影響。例如,在某些實施例中,該溶解之活性劑更迅速地穿透表皮,反觀懸浮之活性劑因抑制在低釋放速率下因而穿透能力較低。具有通常知識者可知悉其他適化活性劑之方法以展現有利之穿透速率。
在某些實施例中,該第二活性劑係選自於抗菌劑、抗生素、抗真菌劑、免疫調節劑、縮氨酸、維他命、維他命衍生物、吡咯、氧化物、鹽類或其衍生物、及其混合物所組成之族群。在某些實施例中,該第二活性劑係選自於林可黴素抗生素、類視色素、磺胺醋鈉、水楊酸、鹽類或其衍生物、及其混合物所組成之族群。在某些實施例中,該第二活性劑係為一林可黴素抗生素,如林可黴素或克林達黴素、鹽類或其衍生物、或其混合物;或為一大環內酯抗生素(macrolide antibiotic),其他包括作為非限制目的之例示如克拉黴素(clarithromycin)、阿奇黴素(azithromycin)、紅黴素(erythromycin)、鹽類或其衍生物、或其混合物。在一實施例中,該第二活性劑係為克林達黴素磷酸鹽且其含量係介於大約0.2%至大約2.5%間,例如大約0.2%、0.5%、0.8%、1%、1.5%、2%或2.5%。
如需要,該第二活性劑可為可溶或略溶至不溶於水。該第二活性劑可分解、溶解或形成一懸浮液。
在某些實施例中,該第一活性劑或該第二活性劑係為一類視色素。在某些實施例中,該類視色素係選自於由維他命A、順式或反式之視黃醇、順式或反式之視黃醛、順式A酸、維甲酸、羥基-逆轉-視黃醇、去二氫A酸、依曲替酯、視黃基棕櫚酯、β-胡蘿蔔素、他札羅汀、二西催定、阿達派林、鹽類或其衍生物、及其混合物所組之族群。
在一實施例中,該第一活性劑係為過氧化苯且該第二活性劑係為克林達黴素磷酸鹽。在另一實施例中,該第一活性劑係為維甲酸且該第二活性劑係為克林達黴素磷酸鹽。又另一實施例中,第一活性劑係為甲硝達唑且該第二活性劑係為磺胺醋鈉。在另一實施例中,該第一活性劑係為過氧化苯且該第二活性劑係為維甲酸。
在某些實施例中,其中若該第二活性劑包括一抗生素,該第二活性劑則較佳地包括另一額外之活性劑。在某些實施例中,該第二活性劑包括或由一或多種之抗生素及一額外之活性劑所組成。
在某些實施例中,該泡沫懸浮凝膠更包括一第三活性劑。該第三活性劑可為適於局部施藥之醫藥活性劑。該第三活性可溶於水,或略溶至不溶於水。
在某些實施例中,該第三活性劑可為例如抗菌劑、抗生素、抗真菌劑、免疫調節劑、縮氨酸、維他命、及維他
命衍生物、吡咯、氧化物、鹽類或其衍生物,及其混合物。在某些實施例中,該第三活性劑係為一與第一或第二活性劑相異之局部施用抗痘劑。任何該領域具通常知識者所習知之局部抗痘劑而作為一泡沫懸浮凝膠之第三活性劑皆包含於其中。例舉之抗痘劑包括類視色素、抗生素、吡咯抗微生物劑、維他命及其類似物。
在某些實施例中,該抗痘劑係為一抗生素、抗微生物吡咯、類視色素、或維他命(例如:維他命A、維他命B、維他命C、維他命E)。如需要,該第三活性劑為可溶或略溶至不溶於水。該第三活性劑可分解、溶解、或懸浮於凝膠中。
在某些實施例中,如上所述,該第三活性劑係為一防曬劑。
略溶至不溶於水之(即厭水性的)活性劑須一分散劑或潤濕劑以覆蓋厭水性粒子之表面,藉此以降低其表面張力。該分散劑及潤濕劑可為相同之藥劑或為兩相異之藥劑。分散劑/潤濕劑可助於將厭水性粒子維持在配方基質(formulation matrix)間,並幫助厭水性活性劑在皮膚表面之散佈。美國專利案第5,470,884號之專利即探討關於配方中含有過氧化苯之分散劑/潤濕劑所具有之益處。
在一某些實施例中,該水相可包括一分散劑/潤濕劑。可使用該分散劑/潤濕劑以促進水相中該第一活性劑
之懸浮。在某些實施例中,該分散劑/潤濕劑係為一界面活性劑。
在本發明之泡沫懸浮凝膠中,略溶至不溶於水之活性劑係懸浮於水相,可藉由在水相中包含一分散劑/潤濕劑以促進懸浮。該分散劑/潤濕劑可使略溶至不溶於水之活性劑分散或為水所沾濕。
該分散劑/潤濕劑可具有界面活性劑之特性。合適之分散劑/潤濕劑可打散水中大部份的略溶至不溶於水的活性劑的厭水性粒子成一次性之粒子(primary particle),且能輕易重新分散己沈降之粒子。
在某些實施例中,該分散劑/潤濕劑係為一非離子性(non-ionic)之界面活性劑。用於本發明泡沫懸浮凝膠之例示之分散劑/潤濕劑包括二辛烷基磺基丁二酸酯鈉(sodium dioctyl sulfosuccinate)、Brij®-30(聚乙二醇月桂基醚(Laureth-4))、Brij®-58(醇聚乙二醇醚(Ceteth-20))及Brij®-78(硬脂酸酯(Steareth-20))、Brij®-721(硬脂酸酯-21)、Crillet-1(聚山梨醇酯(Polysorbate 20))、Crillet-2(聚山梨醇酯40)、Crillet-3(聚山梨醇酯60)、Crillet-45(聚山梨醇酯80)、Myrj-52(聚乙二醇-40硬脂酸鹽(PEG-40 Stearate))、Myrj-53(聚乙二醇-50硬脂酸鹽)、普盧蘭尼克(Pluronic®)F77(泊洛沙姆217(Poloxamer 217))、普盧蘭尼克F87(泊洛沙姆237)、普盧蘭
尼克F98(泊洛沙姆288)、普盧蘭尼克L 62(泊洛沙姆182)、普盧蘭尼克L64(泊洛沙姆184)、普盧蘭尼克F68(泊洛沙姆188)、普盧蘭尼克L81(泊洛沙姆231)、普盧蘭尼克L92(泊洛沙姆282)、普盧蘭尼克L101(泊洛沙姆331)、普盧蘭尼克P103(泊洛沙姆333)、普盧蘭尼克F108 NF(泊洛沙姆338)、普盧蘭尼克F 127 NF(泊洛沙姆407)。在某些實施例中,該分散劑/潤濕劑係為普盧蘭尼克F68(泊洛沙姆188)。在一實施例中,該分散劑/潤濕劑係為普盧蘭尼克(泊洛沙姆)。於一實施例中,該分散劑/潤濕劑係為普盧蘭尼克F68(泊洛沙姆188)。普盧蘭尼克聚合物可商業上購自BASF(美國和德國)。
如需要,其他種類繁多之界面活性亦可用於本發明泡沫化合物。這些界面活性劑例如包括聚氧乙烯脂肪醚(polyoxyethylene fatty ethers)、聚氧乙烯脂肪酯(polyoxyethylene fatty esters)、脂肪酸(fatty acid)、硫酸鹽脂肪酸(sulfate fatty acids)、磷酸鹽脂肪酸(phosphated fatty acids)、磺酸鹽琥珀酸脂(sulfosuccinates)、兩性界面活性劑(amphoteric surfactant)、非離子性泊洛沙姆(non-ionic poloxamer)、非離子性美羅沙潑(non-ionic meroxapol)、石油衍生物、脂肪胺(aliphatic amine)、聚矽氧烷(polysiloxane)衍生物、山梨聚糖
脂肪酸酯(sorbitan fatty acid ester)、其醫藥可接受鹽、及其混合物。在此考量下於特定較佳之實施例中,該界面活性劑可選自於由聚乙二醇月桂基醚-4、聚乙二醇二月桂酸鹽(PEG-2 dilaurate)、硬脂醯酸(stearic acid)、硫酸月桂酸鈉(sodium lauryl sulfate)、硫代丁二酸鈉(dioctyl sodium sulfosuccinate)、椰子兩性丙酸鹽(cocoamphopropionate)、泊洛沙姆188、美羅沙潑258、三乙醇胺(triethanolamine)、二矽酮(dimethicone)、聚山梨醇酯60、月桂酸單硬脂酸酯(sorbitan monostearate)、其醫藥可接受鹽、及其混合物所組成之族群。
本文所提及之其他一般所熟知能有效用於製備泡沫組成物之界面活性劑當視為在本發明範圍之內。這些其他界面活性劑例如包括列於CTFA化妝品成份字典,第二版,美國化妝品盥洗用品香水協會(1977),華盛頓特區十三街1133號,郵編20005(CTFA Cosmetic Ingredient Dictionary,Second Edition,The Cosmetic Toiletry and Fragrance Association,Inc.,1133 Fifteenth Street,N.W.,Washington,D.C.20005,1977)之界面活性劑,其上述內容係合併於此作為參考。
該泡沫懸浮凝膠一般含有上限在大約1%、2%、3%、4%、5%重量百分比之分散劑/潤濕劑,例如介於0.2%至0.5%、0.5至3%。
在某些實施例中,該泡沫懸浮凝膠係含有大約0.2%、0.5%、0.8%、1%、1.5%、2%、3%、4%、5%之分散劑/潤濕劑。
在某些實施例中,該分散劑/潤濕劑具有界面活性劑之性質,且該泡沫懸凝膠不須一額外之界面活性劑。一般可任意選擇是否包括界面活性劑。
在某些實施例中,該增稠劑可視為一分散劑加上一增稠劑使用。在此配方設計下,該泡沫懸浮凝膠不須特別的分散劑/潤濕劑或額外之界面活性劑。然亦可選擇性地增加額外之特別的分散劑/潤濕劑或額外之界面活性劑。
一分散劑/潤濕劑一般不認為其亦可為一發泡劑。事實上,上述形式之界面活性劑可抑制發泡作用。有效之沾濕發生在當吸附界活性劑分子之內聚力最小化之時。藉由一給定之潤濕劑而增加相對於厭水區域的親水區域之範圍,在厭水區域間之內聚力因而能達到最小。相似地,降低相對於親水區域的厭水區域之範圍,使厭水區域間之內聚力降至最低。為促生良好之發泡作用,吸附界面活性劑分子之內聚力須高於使良好之沾濕作用發生所須之內聚力。因此一良好之潤濕劑一般認為其亦為一不良之發泡劑,反之亦然。可參照由培加蒙通訊社出版之Schönfeldt所著之表面活
性環氧乙烷添加物(1969)(Schönfeldt,Surface Active Ethylene Oxide Adducts,1969,Pergamon Press)之第128頁。
該泡沫懸浮凝膠係包含一或多種之增稠劑或懸浮劑,且該增稠劑或懸浮劑可提供一合適之黏度及有能力維持一略溶至不溶於水之活性劑於一懸浮液中。該增稠劑大致上可為化學惰性,且其可為人造或天然形成之增稠劑。
增稠劑之量須足夠使略溶至不溶於水之活性劑維持在懸浮液中,同時維持一可有效且均勻自容器中釋放之流動性凝膠。該泡沫懸浮凝膠可含至多大約5%之增稠劑,通常至多大約為3%或2%。在某些實施例中,該泡沫懸浮凝膠含有範圍在大約0.1%~2%、0.8%~1.5%之增稠劑,例如,大約0.1%、0.2%、0.5%、0.8%、1%、1.3%、1.5%、2%之增稠劑。在某些實施例中,增稠劑之含量將導致黏度最高為大約40000厘泊之泡沫懸浮凝膠,例如在黏度範圍在大約1000至大約20000厘泊之泡沫懸浮凝膠。
該增稠劑大致上可為對其他組成物有化學惰性之增稠劑,且其可為人造或天然形成之增稠劑。在某些實施例中,該增稠劑係為一親水膠體(hydrocolloid),例如選自於瓊脂(agar)、藻酸鹽(alginate)、阿糖基木聚糖(arabinoxylan)、角叉膠(carrageenan)、羧甲基纖維素(carboxymethylcellulose)、羥丙基甲基纖維素(hydroxypropyl methylcellulose)、纖維素
(cellulose)、卡特蘭多醣(curdlan)、白明膠(gelatin)、結蘭膠(gellan)、β-葡聚醣(β-glucan)、關華豆膠(guar gum)、***膠(gum arabic)、刺槐豆膠(locust bean gum)、果膠(pectin)、澱粉質(starch)、碳聚物(carbomer)、丙烯酸共酸物(acrylate copolymers)、矽酸(silica)、三仙膠(xanthan gum)、鹽類或其衍生物、及其混合物所組成之族群。在某些實施例中,該增稠劑係為一天然膠,例如選自於由***膠、黃蓍膠(tragacanth gum)、三仙膠、角叉膠、藻酸鹽膠、果膠、關華豆膠、鹽類或其衍生物、及其混合物所組成之族群。
在某些實施例中,該增稠劑係為三仙膠或碳聚物。在某些實施例中,該增稠劑係為三仙膠。在某些實施例中,該增稠劑可選自由親水膠體、天然膠及其混合物所組成之族群。
在某些實施例中,該增稠劑係為三仙膠,而該三仙膠可為食品級或醫藥級(USP/NF)之三仙膠。例示之適合用於本發明之泡沫懸浮凝膠之三仙膠包括黃原F(Keltrol F)、黃原膠11K(Xantural 11K)、黃原膠75(Xantural 75)、黃原膠180(Xantural 180)。食品級及醫藥級/化妝品級之三仙膠配方可自商業上獲得,例如自美國喬治亞州亞特蘭大的CP Kelco公司。
本發明之泡沫懸浮凝膠係為水性。
該泡沫懸浮凝膠包含至少大約20%、30%、40%、50%、
60%、65%、70%、75%、80%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%之水份。在某些實施例中,該泡沫懸浮凝膠含有範圍在大約86%~95%、87%~94%、87%~95%、88%~93%或89%~92%之水份。在某些實施例中,該泡沫懸浮凝膠包括至少大約30%之水份。
水份之含量可使用該領域習知之技術測定,包括如使用庫侖計(Metrohm KF,黑里紹,史瓦濟蘭)。
該泡沫懸浮凝膠包括一pH-調整劑,如酸、鹼、緩衝對、緩衝劑。在某些實施例中,該pH-調整劑係為一緩衝劑,例如一用以穩定所欲之pH值之緩衝對。該選定之緩衝劑或緩衝對係視包括於凝膠中之活性組成物而定。一合適之緩衝物可具有一接近或位於所欲之pH值之解離常數值(pKa)。
在某些實施例中,該所欲之pH值係為一酸性之pH值。用以維持一酸性pH值之緩衝劑之例舉包括,如檸檬酸/檸檬鹽(citric acid/citrate)、醋酸/醋酸鹽(acetic acid/acetate)、必辛(BICINE)、海派斯(HEPES)、三羥甲基氨基甲烷(Trizma)。在某些實施例中,該所欲之pH值係為一中性之pH值。例示之用以維持一中性pH值之緩衝劑包括海派斯、六甲基磷酸三胺(TRIS)、磷酸/磷酸鹽、三羥甲基氨基甲烷。於某些實施例中,該所欲之pH值係為一鹼性之pH值。例示之用以維持一鹼性
pH值之緩衝劑包括六甲基磷酸三胺(TRIS)、三羥甲基氨基甲烷(Trizma)、海派斯(HEPES)、碳酸鹽/二碳酸鹽。上述及額外之生物緩衝物(biological buffer)可獲得自美國密蘇里州聖路易的Sigma-Aldrich公司(Sigma-Aldrich,St.Louis,MO)或德國達姆施塔特的默克公司(Merck,Darmstadt,Germany)。該緩衝劑亦可為一氨基酸,例如氨基乙酸(glycine)、組氨酸(histidine)、精氨酸(arginine)、賴氨酸(lysine)、氨羰丙氨酸(asparagines)、天冬氨酸(aspartic acid)、谷氨酸鹽(glutamine)、谷氨酸(glutamic acid)。在某些實例中,可適當地加入酸或鹼,如鹽酸、氫氧化鈉、氫氧化鉀以達到適當之pH值。
在包含過氧化苯及克林達黴素之配方中,該緩衝對可為檸檬酸和檸檬鹽。
該緩衝劑或緩衝對之含量可在濃度大約1%以下,通常在大約0.3%、0.5%、0.7%或在濃度範圍介於大約0.1%~10%、0.3%~0.8%間。該泡沫懸浮凝膠可含大約0.1%、0.2%、0.3%、0.4%、0.5%、0.6%、0.8%、0.9%或1.0%之重量百分比之緩衝劑或緩衝對。
在某些實施例中,該pH-調整劑係為一緩衝劑或緩衝對,如氨基酸、檸檬酸鹽緩衝物、磷酸鹽緩衝物、二碳酸鹽(bicarbonate)緩衝物、六甲基磷酸三胺緩衝物或海派斯緩衝物。在某些實施例中,該泡沫懸浮凝膠之pH值係介於大約3~9、大約4~9、大約4~6或大約4~5.5間。在
某些實施例中,該泡沫懸浮凝膠之pH值係為大約4、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、5.0、5.1、5.2、5.3、5.4或5.5。
在某些實施例中,該泡沫懸浮凝可包括一或多種之抗氧化劑或自由基去除劑(free radical scavenger)以維持所欲之化學或物理之性質。合適之抗氧化劑不會自行起始活性劑之分解動作且可溶於本發明之配方中。例示之抗氧化劑包括氧氣、對苯二酮(quinone)、輔酶Q(co-enzyme Q)、可聚合單體(polymerizable monomer)、丁羥甲醚(butylated hydroxyanisole,BHA)、丁羥甲苯(butylated hydroxytoluene,BHT)、抗壞血酸(ascorbic acid)、抗壞血棕櫚酸酯(ascorbyl palmitate)、特丁基對苯二酚(t-butyl hydroquinone)、乙二胺四乙酸二鈉(disodium ethylenediamine tetraacetic acid,EDTA)、異抗壞血酸(erythorbic acid)、橄欖油(olea eurpaea oil)、噴替鹽五鈉(pentasodium penetetate)、噴替酸(pentetic acid)、丙基五倍子酸鹽(propyl gallate)、抗壞血鹽鈉(sodium ascorbate)、偏亞硫酸氫鈉(sodium metabisulfite)、亞硫酸鈉(sodium sulfite)、生殖醇(tocopheryl)、及乙酸生育酯(tocopheryl acetate)。
抗氧化劑含量之濃度至多大約為0.5%,更通常至多大約為0.1%或0.2%之重量百分比,例如大約0.1%、0.15%、0.2%、0.25%、0.3%、0.4%或0.5%。
可任意選擇是否包含抗氧化劑。在某些實施例中,該泡沫懸浮凝膠可為不含抗氧化劑之泡沫懸浮凝膠。
螫合/多價螫合劑可助於延遲伴隨二價跡量金屬陽離子而形成自由基之起始。配方中添加螫合劑可有利於填裝於金屬容器之配方。螫合/多價螫合劑之一例為乙二胺四乙酸(ethylenediamine tetraacetic acid,EDTA)。
一螫合/多價螫合劑含量之濃度至多大約為0.5%,更通常至多大約為0.1%或0.2%之重量百分比,例如大約0.1%、0.15%、0.2%、0.25%、0.3%、0.4%或0.5%。
在某些實施例中,本發明之泡沫懸浮凝膠更包括一或多個防曬劑、遮光劑、防曬霜或任何其他陽光阻絕(sun-blocking)成份或陽光阻絕劑。任何該領域具通常知識者所熟知之防曬劑皆適合用於本發明,包括UVA及UVB之防曬劑。
例示之防曬劑包括氨基苯甲酸(Aminobenzoic acid,4-Aminobenzoic acid)、艾波苯酮(Aavobenzone,4-tert-butyl-4-methoxydibenzoylmethane)、二苯基酮-2(Benzophenone-2,Bis(2,4-Dihydroxyphenyl)Methanone)、二苯基酮-3(Benzophenone-3,Oxybenzone)、二苯基酮-4(Benzophenone-4,Sulisobenzone)、二苯基酮-5(Benzophenone-5,Sulsobenzone sodium)、二苯基酮-8(Benzophenone-8,
Dioxybenzone)、苯亞甲基樟腦(Benzylidene Camphor,3-(4-Methylbenzylidene)-d-1 camphor)、西諾沙酯(Cinoxate)、依莰舒(Ecamsule,Terephthalylidene dicamphor sulfonic acid)、乙氧基乙基4-基苯甲酸(Ethoxylated ethyl 4-aminobenzoic acid,PEG25 PABA,即Uvinuli® P25)、水楊酸三甲環己酯(Homosalate,Homomethyl salicylate)、異戍基甲氧肉桂酸鹽(Isoamylmethoxycinnamate,Isopentenyl-4-methoxycinnamate)、異丙基苯基水酸鹽(Isopropylbenzyl salicylate)、薄荷基氨茴酸鹽(Menthyl anthranilate,Methyl 2-aminobenzoate)、麥光素濾光環XL(Mexoryl XL,(phenol,2-(2H-benzotriazol-2-yl)-4-methyl-6[2-methyl-3-[1,3.3.3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propyl]Octyl dimethyl PABA)、桂皮酸鹽(Octinoxate,Octyl methoxycinnamate)、水楊酸鹽(Octyl salicylate,2-Ethylhexyl Salicylate)、辛枯桸(Octocrylene,2-cyano-3,3-dephenyl acrylic acid,2-ethyl hexyl ester)、乙基己基三酮(Octyl triazone,2,4,6-Trianalino-(p-Carbo-2’-ethylhexyl-1’oxy)1,3,5-Triazine)、派帝美O(Padimate 0,2-Ethylhexyl 4-dimethylaminobenzoate)、苯基苯并咪唑磺酸(Phenylbenzimidazole sulfonic acid,2-Phenylbenzimidazole-5-sulfonic acid)及其鉀、鈉、
三乙醇胺鹽類、N,N,N-三甲基-40(氧代菠-3-烷叉甲基)苯銨甲硫酸鹽(N,N,N-Trimethyl-4-(oxoborn-3-ylidenemethyl)anilinium methylsulfate)、水楊酸鹽類(鉀、鈉及三乙醇胺)、Tinosorb® M(2,2’-Methylene-bis-6-(2H-benzotriazol-2yl)-4-(tetramethyl-butyl)-1.1,3.3-phenol)、二氧化鈦、三乙醇胺水楊酸鹽(Triethanolamine salicylate)、氧化鋅、鹽類或其衍生物、及其混合物。額外之合適遮光劑成份載於,例如International Publication NO.WO2004/071479,及其共有(co-owned)、同在審查中(co-pending)之美國專利申請案11/187,217號,並以其上揭露之內容係合併於此做為參考。
該組成物一般包含佔總重大約1%至25%之重量百分比之一或多種防曬劑。在某些實施例中,該泡沫懸浮凝膠包括一或多種防曬劑,且該防曬劑之總重量百分比在大約2%~10%、4%~8%、2%~6%或大約1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、13%、14%、15%、20%或25%。
在某些實施例中,該防曬劑係為可分散水的(water dispersable)、惰性之防曬劑,如二氧化鈦。
在某些選擇性之實施例中,本發明較佳實施例之泡沫懸浮凝膠更包括一揮發性之溶劑,例如醇。合適之醇包括
低級烷醇(lower alkanol,C1-C6 alcohols)。烷醇可為丁醇、異丁醇、丙醇、異丙醇、乙醇、甲醇及其混合物。在某些實施例中,該烷醇為乙醇。在一實施例中,該揮發性溶劑(例如:酒精)含量佔總成分至多為大約5%之重量百分比,例如1%、2%、3%、4%或5%。在某些實施例中,可選擇是否加入揮發性溶劑或酒精,因此該配方設計可不含酒精。
本發明之泡沫懸浮凝膠可包括一推進劑。該推進劑可分散於凝膠、溶解於凝膠或鋪於凝膠之上層或下層,視該泡沫懸浮凝膠基(foamable suspension gel base)及推進劑之間之相對密度而定。使用之氣溶膠推進劑之例舉包括,如烴類(hydrocarbon)、含氟氯烴類(chlorofluorocarbon)、二甲基醚(dimethyl ether)、氫氟烴類(hydrofluorocarbon)、壓縮氣體或其混合物。
推進劑之最大量可藉由與該組成物中之其他成份之混溶性決定,並藉此以形成一混合物,如均勻混合物。用於該組成中推進劑之最低限量可藉由所欲之泡沫特性、及其大致或完全排空容器之能力決定之。
該推進劑濃度含量最高可為大約20%,通常至多大約5%或10%,如介於相對於組成總量大約2~15%、3~10%、4~7%之重量百分比之範圍,例如重量百分比大約在2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%或15%。在一實施例中,加入該泡沫懸浮凝膠中之推進劑量為大約
每50克本發明所述之泡沫懸浮凝膠基搭配大約2.8克之丙烷/丁烷。
在一實施例中,該推進劑係為丙烷和丁烷之混合物。本發明之組成物可被裝填於一聚醯胺-聚亞胺-內襯(polyamide-imide-lined)鋁罐中且搭配作為推進劑之丙烷/丁烷混合物加壓。在一實施例中,該推進劑可包括或由丙烷、正丁烷、異丁烷及戍烷之混合物所組成。在一例示之實施例中,該推進劑可包括或由大約55%之丙烷、大約30%之正丁烷、大約15%之異丁烷所組成。
雖氟氯碳化物(CFCs)亦可作為推進劑使用,但由於環保因素考量,推進劑可為烴類,特別為丙烷、丁烷、戍烷或其混合物。其他合適之推進劑包括二甲基醚、氮氣、氬氣、氫氟碳化物例如134a及227,及其任何前述物質之混合物。
在某些實施例中,該泡沫懸浮凝膠包括防腐劑、潤膚劑、濕潤劑或其他該領域具通常知識者熟知之醫藥可接受賦形劑。
除上述列舉之賦形劑外,任何其他之醫藥用可接受賦形劑,且為該領域具通常知識者所習知而可為有效用之局部組成物,亦可使用於上述之組成物。另外,任何無毒、惰性及有效之局部載劑可用調製於此所述之組成物。常用於調製其他投治人體之局部治療組成物、為人所熟知之載劑亦可有效用於本發明之組成物。該領域之具通常知識者
所熟知之賦形劑之例舉載於Budavari等編輯之默克索引第13版(默克公司,羅威,紐澤西州(2001))(The Merck Index,Thirteenth Edition,Budavari et al.,Eds.,Merck & Co.,Inc.,Rahway,N.J.(2001));美國化妝品盥洗用品香水協會之國際化妝品原料字典和手冊,第10版(2004)(The CTFA(Cosmetic,Toiletry,and Fragrance Association)International Cosmetic Ingredient Dictionary and Handbook,Tenth Edition(2004));以及美國食品和藥物管理署之藥物暨研究中心管理處於1996年1月出版之非活性成份指南(the”Inactive Ingredient Guide”,U.S.Food and Drug Administration(FDA)Center for Drug Evaluation and Research(CDER)Office of Management,January 1996),並以上所述之內容係合併於此做為參考。有效的醫藥可接受賦形劑、載劑、稀釋液之例舉包括蒸餾水、生理食鹽水、林嘉氏溶液(Ringer’s solution)、葡萄糖溶液、漢克氏液(Hank’s solution)、二甲基亞(DMSO),該上述物質包含於可適用於此之物質範圍內。
額外其他非活性成份、有效配方設計及施藥程序為該領域所習知且載於標準參考手冊,如Gilman等編,培加蒙通訊社於1990年出版的第8版古德曼吉爾曼治療學的藥理學基礎,(Goodman and Gillman’s:The Pharmacological Bases of Therapeutics,8th Ed.,Gilman et al.Eds.Pergamon Press(1990);美國賓州伊斯頓的麥克出版公司1990年出
版的雷明頓醫藥科學,第17版(Remington’s Pharmaceutical Sciences,17th Ed.,Mack Publishing Co.,Easton,Pa.(1990)),上述兩者之全部內容係合併於此作為參考。
該泡沫懸浮凝膠係有一合適平衡黏度,且該合適平衡黏度係維持一或多種活性劑於懸浮液中,且不因過黏而無法自容器中排出。該懸浮凝膠具一可流動凝膠應有之黏度且該黏度允許凝膠可自容器中輕易且均勻排出。一凝膠具足以維持一或多種之活性劑於懸浮液中黏度,其有助於維持活性劑的化學及物理之穩定。
在某些實施例中,該泡沫懸浮凝膠在25℃下係具小於大約40,000、20,000、15,000或10,000厘泊之最終黏度。在某些實施例中,該泡沫懸浮凝膠在25℃下係具大約5,000、6,000、7,000、8,000、9,000、10,000、12,000、15,000、18,000、20,000、25,000、30,000、35,000或40,000厘泊之黏度。在某些實施例中,該泡沫懸浮凝膠在25℃下係具大約1,000~20,000、50,000~15,000、6,000~12,000或7,000~10,000厘泊之黏度。在某些實施例中,該泡沫懸浮凝膠於25℃下係具大約5,000~15,000厘泊之黏度。
該泡沫懸凝膠之黏度可以一合適之黏度測量裝置測量。技術包括:(i)Brookfield Synchro-lectric迴轉軸
黏度計(rotating spindle viscometer),其中將懸浮凝膠導入軸心部分且黏度係在一溫度範圍下測量,(ii)Brookfield錐板式黏度計(Cone & Plate Viscometer),其中將泡沫樣品導入鈍錐與固定平板之間且該泡沫之流變係於一溫度及切變力範圍下測量。
於一特定之較佳實施例中,本發明之泡沫懸浮凝膠係具有一可允許其藉由一驅動器(actuator)遞藥之黏度。
本發明之泡沫懸浮凝膠具有一足以維持活性劑於懸浮液中之密度。然而,該密度可高或低於包含於該凝膠中之活性劑密度。
在某些實施例中,25℃下該泡沫懸浮凝膠濃縮液之密度至少大約為0.8g/ml,其範圍介於大約0.8~1.5g/ml之間,例如於25℃下為大約0.8g/ml、0.9g/ml、0.95g/ml、1g/ml、1.05g/ml、1.1g/ml、1.15g/ml、1.2g/ml、1.25g/ml、1.3g/ml、1.35g/ml、1.4g/ml、1.45g/ml或1.5g/ml之密度。
對比之下,自容器中給藥後,該分散泡沫之泡沫密度於25℃下較佳地大約為0.6至0.9g/ml。
本發明之泡沫凝膠密度可以一合適密度量測儀器測量。技術包括:(i)比重瓶/稱重每加侖容量,其中該泡沫懸浮凝膠係固定溫度下小心導入一己知容量與重量之固定容器中,及(ii)電子密度/比重計,其中一泡沫懸浮凝膠之緩流係於一固定溫度下導入一流通槽,藉由振盪物
體方法(oscillating body method)測定密度。
該泡沫懸浮凝膠之pH值視包含於配方中之活性劑而定。該最終pH值可助於活性劑之化學及物理性質穩定。
在包括過氧化苯及克林達黴之泡沫懸浮凝膠之實施例中,該pH值為酸性,其範圍介於大約4.0~5.1或4.2~4.6或4.4~5.1間,例如為大約4.00、4.05、4.10、4.15、4.20、4.25、4.30、4.35、4.40、4.45、4.50、4.55、4.60、4.65、4.70、4.75、4.80、4.85、4.90、4.95、5.00、5.05或5.10。
pH值可以該領域所習知之技術測量,例如使用一pH計及一合適之探針。
包含於該泡沫懸浮凝膠之粒子大小應夠小以維持於凝膠中懸浮而不沉澱下來,以及使泡沫凝膠施藥時具平滑觸感且自容器釋放時不阻塞出口管道。該活性劑粒子不應過小以致於形成無法以搖動方式再分散之緊密結塊,或不應過大以致泡沫懸浮凝膠中沉澱或使得泡沫具有顆粒感。該粒子可為均勻大小或其大小分佈在一直徑範圍內。在一實施例中,超過大約90%之活性劑粒子係為同一大小(即單分散)。
在某些實施例中活性劑之粒子大小係具平均直徑落於大約0.5~100微米範圍內,通常小於大約20或15微米,更常於一小於大約10微米之平均直徑,通常在大約5微
米至10微米之之範圍內,平均直徑例如是大約5微米、6微米、7微米、8微米、9微米、10微米、20微米或50微米。
粒子大小可以該領域所習知之技術測定,例如包括使用顯微鏡(例如:100X或200X之倍率)進行目視測量。
粒子沉澱之程度及速率可以該領域所習知之技術監視及定量,如將等分試樣以液體分散穩定分析儀測量。用以定量濁度或一懸浮凝膠之物理穩定之設備為可購得之設備,例如購自Formulaction(1’Union(近土魯斯),法國)。
本發明之泡沫懸浮凝膠可填裝於一容器中,在某些實施例中,該容器係經加壓。於容器中之壓力應足使泡沫凝膠有效排出。該加壓容器中之壓力不應過大以致於該凝膠釋出時無法使用或無法控制釋放量。再者,較低之壓力則用於自加壓容器釋放之後起泡凝膠。
在本發明之某些實施例中,該泡沫懸浮凝膠係於一單一之容器中,該容器可為一加壓之容器,在其他實施例中,泡沫懸浮凝膠可於數個容器中。
在某些實施例中,該凝膠係為一後起泡凝膠,其自容器中釋放後始行起泡,其該容器為例如泵或加壓容器。
在某些實施例中,該容器係為一非加壓容器,如泵、管件、瓶體、罐體或任何適於配藥之包裝或裝置。
在某些實施例中,該泡沫懸浮凝膠係包括一氣溶膠推
進劑。在某些實施例中,該容器係為經加壓且額外包括一推進劑。於該加壓容器之壓力於21~25℃下係介於大約5磅/平方吋表壓力至大約110磅/平方吋表壓力間,例如於21~25℃下大約5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、100或110磅/平方吋表壓力。
在某些實施例中,該加壓容器係加壓至大約63~80磅/平方吋表壓力,例如,於21~25℃時測量為大約63磅/平方吋表壓力、64磅/平方吋表壓力、65磅/平方吋表壓力、66磅/平方吋表壓力、67磅/平方吋表壓力、68磅/平方吋表壓力、69磅/平方吋表壓力、70磅/平方吋表壓力、71磅/平方吋表壓力、72磅/平方吋表壓力、73磅/平方吋表壓力、74磅/平方吋表壓力、75磅/平方吋表壓力、76磅/平方吋表壓力、78磅/平方吋表壓力、79磅/平方吋表壓力或80磅/平方吋表壓力。
如同本文於此所使用,穩定度係指於該泡沫懸浮凝膠中一或多種之活性劑化學或物理性質之完整度。一或多種之活性劑可能施以如氧化或化學降解之測試。
活性劑之氧化為可監視及量化,例如使用依照氧化作用之有無或氧化之程度而變色之色指示劑,如碘化鉀。碘化鉀於無氧化作用下為無色、於氧化作用下轉為黃色及於更進一步氧化下變為褐色。顏色之改變可使用分光光度計定量,例如ColorQuest Color Measurement System,商
業上可獲得自美國維吉尼亞州賴斯頓市之Hunter Associates Laboratory。
活性劑之化學降解為可監視及量化,例如使用高性能液相層析儀(high performance loquid chromatography,HPLC)。高性能液相層析儀之使用為該領域所習知之技術。參考例如Lough(1996)等編,高性能液相層析儀:基本原理與實踐,克魯維爾學術出版公司(High Performance Liquid Chromatography:Fundamental Principles and Practice,Lough,et al.,eds.,1996,Kluwer Academic Pub);及Meyer著,實用高性能液相層析儀(2004),約翰威廉父子出版公司(Meyer,Practical High-performance Liquid Chromatography,2004,John Wiley & Sons)。降解可藉由代表未降解之活性劑(例如:過氧化苯或克林達黴素)峰之輸出數據中,量測該峰(例如:峰高及峰下面積)之減少量;及/或量測代表降解之活性劑(例如:苯甲酸或克林達黴素亞碸單體(clindamycin sulfoxide isomer)峰之增加量,以定量降解程度。
穩定度可視時間和溫度而定。於5℃、25℃、30℃下經至少大約3、4、5、6個月後至少大約90%、93%、95%或97%之未降解活性劑可於懸浮凝膠中檢測得。例如,於25℃下經至少6個月該泡沫懸浮凝膠可維持至少大約80%、85%、90%之未降解活性劑。於5℃下經至少12或24個月該泡沫懸浮凝膠可維持至少大約90%、95%、96%、97%、98%之未降解活性劑。未降解活性劑之量可藉由與新製得
之凝膠或與生成之降解活性劑對照而測得。
在某些實施例中,於該泡沫懸浮凝膠中該第一及第二活性劑於5℃、25℃、30℃下經至少3、4、5、6個月後可化學及物理穩定。在某些實施例中,於該泡沫懸浮凝膠中該第一及第二活性劑於5℃下經至少12或24個月後可化學及物理穩定。
本發明亦提供一治療的及預防疾病的處置皮膚病症狀之方法,且該方法係為一藉由局部施用本發明之泡沫懸浮凝膠之泡沫於感染區域之方法。適用本發明之泡沫懸浮凝膠之治療的皮膚病症狀之例示包括皮疹(rashes)、濕疹(eczema)、接觸性皮膚炎(contact dermatitis)、粉刺(包括青春痘(acne vulgaris)及酒槽鼻(acne rosacea))、真菌感染及細菌感染。該泡沫懸浮凝膠係特別適用於治療粉刺。
粉刺可藉由施用該泡沫懸浮凝膠之泡沫於皮膚之其粉刺損害處或損害將發生處,治療及預防性地治療粉刺。該泡沫係一般於皮膚上磨擦直到泡沫完全破裂。如需要或在醫護人員指導下,該泡沫可每日施用一、二、三、四或更多次。該破裂泡沫可留於皮膚上或視需要而洗去,視施用之目的而定。該泡沫可選擇性地作為面膜施用或於使用後洗去。
在其他較佳之實施例中,本發明之較佳組成物可與額
外之醫藥劑型結合使用以提升其於治療皮膚疾病或不適,特別是粉刺。在此考量下,本發明之較佳組成物可為食物療法之一部份進行投藥,且該食物療法係額外包括任何其他為該領域具通常知識之人所習知且有效於皮膚病學之不適的治療之醫藥及/或醫藥劑型。相似地,一不同於此所指之醫藥活性組成物可添入本發明之較佳組成物以提升其於治療皮膚疾病或不適。因此,此一額外醫藥活性組成物或額外醫藥劑型可搭配於此所指之較佳組成物,直接或間接地、隨附或連續地施用於一病患上。
在此考量之一實施例中,本發明之較佳組成物及額外醫藥劑型可同一時間投治於一病患。在一可選擇之實施例,本發明之較佳組成物及額外醫藥劑型其中之一可於晨間投治及其另一可於夜間投治。
本發明之泡沫懸浮凝膠基之製造方法涉及數個相繼結合之相的製備。此主要係該略溶至不溶於水之第一活性劑的微粒性質所致。
在一方法中,一濃縮凝膠(gel concentrate)係藉由結合水及增稠劑製備。之後,該第一活性劑與一分散/潤濕劑混合以於混合時產生一均勻分散體。持續混合含有該第一活性劑的分散液以防止該第一活性劑沉澱至混合容器底部並形成固體”塊狀物”。
隨後,於攪拌時將凝膠濃縮液摻入含有第一活性劑之分散液,以產生一物理穩定且維持該第一活性劑於懸浮液
中之凝膠。於凝膠中該第一活性劑(及其他活性劑)之粒子大小可經由碾磨程序(milling process)降低。
在該懸浮凝膠計畫包含一或多種第二活性劑之情況,進行依序之以下步驟。於一分離容器中製造一含有增稠劑及該第二活性劑之凝膠。當該第二活性劑為一林可抗生素如克林達黴素磷酸鹽,無須pH調整劑。即該包含克林達黴素磷酸鹽之溶液的pH值係低於pH5.5、pH5.2或pH5,例如pH4至4.5(如4、4.1、4.2、4.3、4.4或4.5)。
隨後,包含該第一活性劑之凝膠與一包含該第二活性劑之凝膠混合,形成一含有該第一活性劑及該第二活性劑(及其他活性劑)之泡沫懸浮凝膠基。
該泡沫懸浮凝膠基可繼續於填充操作中充入各容器中。閥件係安裝於罐上且壓摺到位(crimp into place)。在加壓容器中,一已計量之推進劑經閥注入以完成配方設計。填充罐體之另一方法涉及單液相(single-liquid-phase)之填充,其中該組成物保持溫熱及確保均勻性,隨後進行壓摺及推進劑之注入。又另一方法涉及調製整體組成物且包括推進劑、分散包裝(in bulk)、加壓及隨後注入該配方至一壓摺氣溶膠罐(crimped aerosol can)。
依據此方法製造之該組成物較佳地以適於局部施用之氣溶膠劑型。因此,上述之製造方法可額外包括充填容器的另外步驟,且該容器搭配一推進劑,而該推進劑適合作用於組成物之氣溶膠自容器傳送。
本發明醫藥配方之效力視是否達到適當之配方組合、容器及閥組件而定。
該己配好之醫藥泡沫組成物係較佳地於容器中充填成氣溶膠。該組成物可使用為該領域所習知之單一步驟或多重步驟之程序充填於容器中。
該容器須選擇可提供氣溶膠配方一長久之上架期限。因此,該容器須關於容納其中之組成物為化學惰性,以便其不影響配方之穩定或容器之操作及完整。另外,該容器須能承受產品所須之壓力、抗蝕及抵抗儲存其中之產品可能的化學或物理變化,如形成阻塞孔洞之粒子。當本發明組成物含有界面活性劑及酸時更為重要,此兩成份己知可增加腐蝕之可能性。
適於氣溶膠合適容器之選擇基於其製造方法之適應性、配方成份之相容性、產品設計之壓力之耐受能力、設計上之喜好及製造公司關於美觀性以及成本之考量。適用之容器可例如由不銹鋼、鋁、玻璃、塑膠或其混合物所製造。該容器可更使用一或多個保護鍍膜如硝酸鈉、苯甲酸鈉(sodium benzoate)、鄰硝基苯甲酸銨(ammonium m-nitrobenzoate)、嗎啉(morpholine)、2-甲基丁酰基團(2-methyl butynoyl)、環氧大豆油(Expoxol 9-5)、谷氨酸肌氨酸鈉(sodium n-lauroylsarcosinate)、苯酚(phenolic)、環氧基樹脂(epoxy)或乙烯樹脂(vinyl)之鍍膜,以提升配方相容性或安全操作。任何其他己知之氣溶
膠容器包及保護鍍膜預期用於本發明可一般有效。
該容器亦可包括兩個或更多之隔間(compartment),且隔間可允許最終之組成物分解成物理上分離之部分直到該組成物經由閥組件自容器中給藥。
以泡沫組成物填充氣溶膠容器之己知方法包括低溫充填(cold fill)、封蓋充填(under the cup)、及加壓充填(經閥)。充填氣溶膠容器之諸方法為該領域具通常知識之人所熟知且載於氣霧劑手冊(Wayne E.,杜蘭,考德威爾,紐澤西州)((The Aerosol Handbook(Wayne E.Dorland,Caldwell,NJ))及氣霧劑技術手冊(R.E.Krieger.,馬拉巴,佛羅里達州(the Handbook of Aerosol Technology,(R.E.Krieger.Malabar,FL)),其內容係合併於此做為參考。
在冷溫充填方法中,濃縮液及推進劑兩者均須冷卻至-30℉至-40℉。該冷凍之產品濃縮液係定量供入一等低溫之容器,隨後注入低溫、液化之氣體。當注入足量之推進劑後,安置閥組件於容器上。
在加蓋填充之方法中,該方法係利用一於容器突出部形成一緊封環(tight seal)之填充頭(filling head)。該填充頭於容器上方支承一閥件同時經由容器之開口注入加壓之推進劑。
在加壓填充之方法中,該產品濃縮液係定量置入容器中,安置閥組件於容器上,及液化加壓之氣體經由閥桿(stem)計量供入容器。加壓填充係用於大部分醫藥氣溶膠
之填充。
閥組件之功能係為容許填充罐內容物以所欲之型式、所欲之速率排放及於使用計量閥(metered valve)之情況下排放適當之量或劑量。因此,該閥組件須對所欲放出之產品型式具有貢獻。尤其氣溶膠閥一般具有一大半徑之傳送噴口以容許泡沫之傳送。另外,該閥組件容許該氣溶膠組成物連續或定量地自容器中釋出。
用於製造該閥組件之材料須對於經該組件輸出之氣溶膠配方為惰性。可用於製造該各種閥組件之材料有塑膠、橡膠、鋁、不銹鋼及其混合物。一般之氣溶膠閥組件由以下之部分所組成:致動器(actuator)、閥桿(stem)、襯墊(gasket)、彈簧、裝座杯(mounting cup)、外罩殼(housing)及內浸管(dip tube)。當容器為直立或倒立時,閥件亦可容許產品之放出。所有型式之閥件為該領域具通常知識者所己知,包括噴霧閥(spray valve)、傾斜襯墊閥(sliding gasket valve)、偏斜襯墊閥(deflecting gasket valve)及傾斜動作閥(tilt action valve),上述之閥件設想其同樣可用於傳送本發明之組成物。
計量閥係為每次閥件作動即傳送一特定量之產品所設計。計量閥通常於當該配方為一強效藥物或需精確劑量之目的下所使用。於計量閥系統中,一輔助閥室(auxiliary valve chamber)藉由其容積或尺寸調節排出材料量。
該閥組件可更包括一附件以促進本發明之泡沫醫藥組成物之遞送。
任何於此所述之活性組成物之合適劑量為該領域具通常知識者所熟知,及選定該合適之劑量以使前述之微生物或/及真菌感染症狀之治療達到最佳效果。大約0.001毫克至大約5000毫克每公斤人體重量之活性組成物之劑量程度己知可有效用於治療疾病、不適及本文於此提及之症狀。該活性劑典型之有效量一般包括大約0.001毫克至大約100毫克每天每公斤病患重量。此外,可了解該組成物之劑量可以單一或複數個劑量單位施用,以提供一所欲之治療效果。
如需要,其他治療劑可與上述之組成物結合使用。該醫藥活性組成物可與載劑結合以產生單一劑量型,其該醫藥活性組成物之量將視治療對象、疾病、不適或症狀之性質,及活性組成物之性質而定。
該較佳之醫藥組成物可每日以一單一或複數劑量給定。在一較佳之實施例中,該醫藥組成物係每日施用一至三次。如所需為較佳之施藥策略,則開始以每日兩次低劑量施用並緩慢增加至較高之劑量。該醫藥活性組成物可與載劑結合以產生單一劑量型,其該醫藥活性組成物之量將視治療對象、疾病、不適或症狀之性質及活性組成物之性質而定。
然而,可了解對於任何特殊之病患之特定劑量視各種
因素而定,包括特定醫藥活性組成物之活性、病患之年齡、體重、健康狀況、性別及飲食、施藥時間、***率、可能之藥物併用(drug combination)、所治療之特殊症狀嚴重程度及施藥之型式。該領域具通常知識者可了解上述因素之變化性且可確立一不超出常規實驗程度之劑量。
該最理想之醫藥配方可由該領域具通常知識者視諸考量如特殊之醫藥活性劑之併用及所欲之劑量而定,以決定該醫藥配方。參考例如雷明頓醫藥科學,第18版,1435-1712頁,麥克出版公司,伊斯頓,賓州,郵編18042(1990)“Remington’s Pharmaceutical Sciences,18th ed.(1990,Mack Publishing Co.,Easton,PA 18042),PP.1435-1712”,其所揭露內容係合併於此做為參考。此配方可影響物理狀態、穩定、活體中之釋放速率及必需脂質之活體中清除速率。
以下實施例係用以說明,非以限制本發明所提出欲保護之標的。
樣品1
包含過氧化苯及克林達黴素之泡沫懸浮凝膠之例示
此樣品示範該泡沫懸浮凝膠之實施例之製造,該泡沫懸浮凝膠包括過氧化苯及克林達黴素。
成份
於凝膠基各成份最終濃度:
樣品2
包含過氧化苯及克林達黴素之泡沫懸浮凝膠基之例示
樣品3
包含過氧化苯及克林達黴素及防曬劑之泡沫懸浮凝膠之例示
於樣品3A、3B及3C,該紫外光吸收組成物係為最後加入該泡沫懸浮凝膠之組成物。包含一或多之種防曬劑之該泡沫懸浮凝膠係持續混合直至該紫外光吸收劑均勻地分散至該凝膠。
樣品4
包含過氧化苯及克林達黴素及類視色素之泡沫懸浮凝膠之例示
於樣品4A、4B及4C該紫外光吸收組成物係為最後加入該泡沫懸浮凝膠之組成物。類視色素之最終濃度可介於大約0.025%至0.10%之重量百分比之間。額外包含作為第三活性劑之一或多種類視色素之該泡沫懸浮凝膠係持續混合直至該類視色素均勻地分散至該凝膠。
樣品5~9
包含過氧化苯;過氧化苯及磺胺醋鈉;甲硝噠唑及磺胺醋鈉;吡咯抗生素及水楊酸之泡沫懸浮凝膠之例示
於此所述之樣品及實施例係僅供做說明之目的,於該領域具通常知識者,於不脫離本發明之精神與其後所附之專利申請範圍內,當可做各種之更動與潤飾。於此引述之
所有出版物、專利及專利申請案,其全文內容特此係合併做為各種用述之參考。
第1圖繪示為在pH5.0及儲存於5℃環境下一包含過氧化苯及克林達黴素之示範泡沫懸浮凝膠之穩定度資料。
第2圖繪示為在pH5.0及儲存於25℃環境下一包含過氧化苯及克林達黴素之示範泡沫懸浮凝膠之穩定度資料。
第3圖繪示為在pH4.5及儲存於5℃環境下一包含過氧化苯及克林達黴素之示範泡沫懸浮凝膠之穩定度資料。
第4圖繪示為在pH4.5及儲存於25℃環境下一包含過氧化苯及克林達黴素之示範泡沫懸浮凝膠之穩定度資料。
Claims (19)
- 一種於加壓容器中之水性泡沫懸浮凝膠,該水性泡沫懸浮凝膠包含:包含水之水相(aqueous phase);1%至25%以重量計之過氧化苯(benzoyl peroxide)作為惟一活性劑,其懸浮於該水相中,一增稠劑,一推進劑,及其中該泡沫懸浮凝膠包含至少30%水、不含油且在25℃具有5000至15,000厘泊之黏度,且其中該懸浮的活性成分顆粒之平均直徑係為0.5至100微米的範圍內,且該泡沫懸浮凝膠當由該加壓容器中分送時形成一均勻氣溶膠。
- 一種於加壓容器中之水性泡沫懸浮凝膠,該水性泡沫懸浮凝膠包含:包含水之水相;一種活性劑之組合物,其係由下列組成:懸浮於該水相中之1%至8%以重量計之過氧化苯;及分解、溶解或懸浮於該水相中之0.025%至2%以重量計之類視色素(retinoid);一增稠劑;以及一推進劑;該泡沫懸浮凝膠包含至少30%水、不含油且在25℃ 具有5000至15,000厘泊之黏度,且其中該懸浮的活性成分顆粒之平均直徑係為0.5至100微米的範圍內,且該泡沫懸浮凝膠當由該加壓容器中分送時形成一均勻氣溶膠。
- 如申請範圍第1項所述之懸浮凝膠,其中過氧化苯係以2%至8%以重量計之量存在。
- 如申請範圍第1項所述之懸浮凝膠,其中過氧化苯係以4%至10%以重量計之量存在。
- 如申請範圍第1至4項中任一項所述之懸浮凝膠,其中該增稠劑係選自由瓊脂、藻酸鹽、阿糖基木聚糖、角叉膠、羧甲基纖維素、羥丙基甲基纖維素、纖維素、卡特蘭多醣、白明膠、結蘭膠、β-葡聚醣、關華豆膠、***膠、刺槐豆膠、果膠、澱粉質、碳聚物、丙烯酸共聚物、矽酸、三仙膠、其鹽類及其混合物所組成之族群。
- 如申請範圍第1至4項中任一項所述之懸浮凝膠,其中該增稠劑係三仙膠。
- 如申請範圍第1至4項中任一項所述之懸浮凝膠,其中該增稠劑係以至多5重量%之量存在。
- 如申請範圍第1至4項中任一項所述之懸浮凝膠,其中該增稠劑係以0.1%至2%以重量計之量存在。
- 如申請範圍第1至4項中任一項所述之懸浮凝膠,其中該推進劑係選自由烴類、含氟氯烴類、二甲基醚、氫氟烴類、壓縮氣體、及其混合物所組成之族群。
- 如申請範圍第1至4項中任一項所述之懸浮凝膠,其中該推進劑係為烴類推進劑。
- 如申請範圍第1至4項中任一項所述之懸浮凝膠,其中該推進劑係以3%至10%以重量計之量存在。
- 如申請範圍第1至4項中任一項所述之懸浮凝膠,更包括一潤濕劑。
- 如申請範圍第12項所述之懸浮凝膠,其中該濕潤劑係非離子性界面活性劑。
- 如申請範圍第12項所述之懸浮凝膠,其中該濕潤劑係以0.2%至5%以重量計之量存在。
- 如申請範圍第1至4項中任一項所述之懸浮凝膠,其中該懸浮凝膠不含酒精。
- 如申請範圍第1至4項中任一項所述之懸浮凝膠,更包括一pH調整劑。
- 如申請範圍第16項所述之懸浮凝膠,其中該懸浮凝膠具有4至5.5間之pH值。
- 如申請範圍第1至4項中任一項所述之懸浮凝膠,其中該泡沫懸浮凝膠包含至少70%水。
- 一種如申請範圍第1至18項中任一項所述之泡沫懸浮凝膠用於製造供治療粉刺的藥劑之用途。
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2007
- 2007-03-29 BR BRPI0709674-7A patent/BRPI0709674A2/pt not_active Application Discontinuation
- 2007-03-29 AU AU2007273935A patent/AU2007273935B2/en not_active Ceased
- 2007-03-29 EP EP07825280.6A patent/EP2010133B1/en active Active
- 2007-03-29 WO PCT/IB2007/002958 patent/WO2008007224A2/en active Application Filing
- 2007-03-29 PL PL07825280T patent/PL2010133T3/pl unknown
- 2007-03-29 CA CA2647127A patent/CA2647127C/en not_active Expired - Fee Related
- 2007-03-29 PL PL10159385T patent/PL2206494T3/pl unknown
- 2007-03-29 US US11/730,011 patent/US8158109B2/en not_active Expired - Fee Related
- 2007-03-29 ES ES10159385.3T patent/ES2560540T3/es active Active
- 2007-03-29 KR KR1020087026472A patent/KR101368107B1/ko not_active IP Right Cessation
- 2007-03-29 MX MX2008012526A patent/MX2008012526A/es active IP Right Grant
- 2007-03-29 EP EP10159385.3A patent/EP2206494B1/en not_active Not-in-force
- 2007-03-29 ES ES07825280.6T patent/ES2582654T3/es active Active
- 2007-03-30 TW TW096111492A patent/TWI442944B/zh not_active IP Right Cessation
- 2007-03-30 AR ARP070101347A patent/AR060234A1/es not_active Application Discontinuation
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Also Published As
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TW200744667A (en) | 2007-12-16 |
US8758728B2 (en) | 2014-06-24 |
US20140248220A1 (en) | 2014-09-04 |
PL2010133T3 (pl) | 2017-08-31 |
US8158109B2 (en) | 2012-04-17 |
CA2647127C (en) | 2015-10-06 |
AR060234A1 (es) | 2008-06-04 |
AU2007273935A1 (en) | 2008-01-17 |
EP2010133A2 (en) | 2009-01-07 |
CA2647127A1 (en) | 2008-01-17 |
US20070237724A1 (en) | 2007-10-11 |
PL2206494T3 (pl) | 2016-06-30 |
EP2206494B1 (en) | 2015-12-02 |
EP2010133A4 (en) | 2010-07-14 |
US20130280309A1 (en) | 2013-10-24 |
ES2560540T3 (es) | 2016-02-19 |
KR101368107B1 (ko) | 2014-03-14 |
MX2008012526A (es) | 2008-10-14 |
KR20090005102A (ko) | 2009-01-12 |
WO2008007224A2 (en) | 2008-01-17 |
BRPI0709674A2 (pt) | 2011-12-06 |
ES2582654T3 (es) | 2016-09-14 |
WO2008007224A3 (en) | 2008-04-17 |
US20110318278A1 (en) | 2011-12-29 |
AU2007273935B2 (en) | 2011-08-18 |
EP2206494A1 (en) | 2010-07-14 |
EP2010133B1 (en) | 2016-05-04 |
US8475770B2 (en) | 2013-07-02 |
US9265726B2 (en) | 2016-02-23 |
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