CN102686205A - 局部四环素组合物 - Google Patents
局部四环素组合物 Download PDFInfo
- Publication number
- CN102686205A CN102686205A CN2010800544246A CN201080054424A CN102686205A CN 102686205 A CN102686205 A CN 102686205A CN 2010800544246 A CN2010800544246 A CN 2010800544246A CN 201080054424 A CN201080054424 A CN 201080054424A CN 102686205 A CN102686205 A CN 102686205A
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- Prior art keywords
- oil
- acid
- ppg
- compositions
- skin
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Abstract
一种局部治疗的疏水性易碎性的组合物,其包括载体,所述载体包含(a)约60重量%至约99重量%的至少一种疏水油;(b)选自由脂肪醇、脂肪酸和蜡组成的组的至少一种粘度改性剂的和(c)四环素抗生素,其特征在于,至少部分四环素抗生素悬浮于所述组合物中;所述组合物的粘度与无四环素抗生素的载体的粘度相比至少高约30%;并高于无粘度改性剂的疏水油和四环素抗生素的粘度;粘度改性剂的量可任选地降低至少基于重量的量,所述至少基于重量的量将会增加无四环素抗生素的载体的粘度至少30%;其中所述四环素在所述组合物中化学稳定至少六个月;其中超过约90%的四环素未分解;其中当在添加有液化或压缩气体喷射剂的气溶胶容器中包封时,所述组合物在从容器释放时提供在施加剪切力时易于破碎的质量至少为良好的易碎泡沫。
Description
相关申请的交叉参考
根据美国专利法119(e),本申请要求2009年10月2日提交的美国临时申请61/248,144号,题目为“无表面活性剂无水发泡组合物、易碎(breakable)泡沫及其用途(Surfactant-Free Water-FreeFoamable Compositions,Breakable Foams and Their Uses)”;2010年4月8日提交的美国临时申请61/322,148号,题目为“无表面活性剂无水发泡组合物、易碎泡沫及其用途”;2010年5月31日提交的美国专利临时申请61/349,911号,题目为“无表面活性剂无水发泡组合物、易碎泡沫及其用途”;2010年9月22日提交的美国专利临时申请61/385,385号,题目为“无表面活性剂无水发泡组合物、易碎泡沫和凝胶及其用途(Surfactant-Free Water-FreeFoamable Compositions,Breakable Foams and Gels and TheirUses)”;2010年5月4日提交的美国专利临时申请61/331,126号,题目为“具有流变调节剂的组合物、凝胶和泡沫及其用途(Compositions,Gels and Foams with Rheology Modulators andUses Thereof)”;以及2010年9月7日提交的美国专利临时申请61/380,568号,题目为“无表面活性剂无水发泡组合物和易碎泡沫及其用途”的优先权的权益,在此将其全部内容整体引入以作参考。
背景技术
四环素为广谱抗生素,其常规用于口服治疗皮肤病症,如痤疮(acne)和红斑痤疮(rosacea)。然而,尽管它们的治疗价值高,但四环素非常不稳定,已知与包括水、各种质子物质和氧化剂的许多制剂赋形剂不相容。
局部四环素(topical tetracycline)为第一种批准用于痤疮治疗的局部抗生素,由于活性成分的经皮问题已限制其使用(Adisen E等人,“Topical tetracycline in the treatment of acnevulgaris”,J Drugs Dermatol.2008;7:953-5)。该产品的载体为包括矿脂(其在痤疮和红斑痤疮的面部处理的情况下油腻且不稳定)的软膏类。
已知意于同外源质子液体混合的四环素疏水组合物。它们包括浓度大于5%的疏水非吸湿硅酮增稠剂,优选硅酮弹性体。该混合导致四环素基本上溶解,因而致使其适于局部递送(delivery)。此类产品需要在对病人给药前混合两种组分,因而是麻烦的,并且不具有或仅有一点实用或可行的价值;此外,如果在治疗前保留一段时间,此类产品会降解并形成降解产物。
发明内容
本申请涉及稳定的包含四环素的油质凝胶制剂、可发泡制剂和泡沫以及它们的治疗用途。
本申请还涉及无表面活性剂的可发泡制剂和泡沫,以及或无表面活性剂和聚合剂的可发泡制剂和泡沫。在一个或多个实施方案中,提供疏水溶剂作为药物载体的部分。例如某些药物需要疏水溶剂以便使它们溶解。
在一个或多个实施方案中,提供疏水溶剂以促进或增强药物的皮内渗透或递送。在一个或多个实施方案中,提供疏水溶剂从而在靶点具有闭合(occlusive)作用,例如在治疗位点为破损皮肤时,疏水溶剂的闭合作用是期望的。本申请进一步涉及包括疏水溶剂的组合物及其用途。本申请进一步描述在施加温和剪切力如柔和摩擦时液化的半固体凝胶组合物。
在一个或多个实施方案中,提供局部治疗的疏水性易碎性的组合物,其包括
a.载体,其包括
i.约60重量%至约99重量%的至少一种疏水油
ii.选自由脂肪醇、脂肪酸和蜡组成的组的至少两种粘度改性剂
b.四环素抗生素,
其特征在于
(i)至少部分所述四环素抗生素悬浮于所述组合物中;
(ii)所述组合物的粘度比无四环素抗生素的载体的粘度高至少约30%;并比无粘度改性剂的疏水油和四环素抗生素的粘度高;
(iii)可任选地降低粘度改性剂的量,降低的量基于重量至少为将使无四环素抗生素的载体的粘度增加至少30%的量。
其中所述四环素在所述组合物中化学稳定至少六个月,六个月内超过约90%的四环素未分解;
其中当在添加有液化或压缩气体喷射剂的气溶胶容器中包封时,所述组合物在从容器释放时提供在施加剪切力时易于破碎的质量至少为良好的易碎泡沫。
在本领域中已知基于高含量水、与表面活性剂、泡沫佐剂和聚合剂组合可以容易地配制泡沫。如文献中所描述的,疏水溶剂可具有去泡沫作用,使基于疏水溶剂的泡沫的配制具有挑战性。为了克服该挑战,现有技术需要使用大量充当发泡剂的表面活性剂。已知表面活性剂是刺激性的,特别是离子表面活性剂,重复使用可引起皮肤干燥,所以期望降低它们在意于治疗皮肤或粘膜的药物学组合物中的使用。现有技术进一步教导引入泡沫佐剂如脂肪醇和脂肪酸作为泡沫促进剂,还引入聚合剂(例如,胶凝剂)作为泡沫稳定剂,这可延长泡沫的塌缩时间(collapse time)。还可将蜡引入这些表面活性剂类制剂,但如所预期的,在环境温度下为固体的蜡易于沉淀。
在用(a)无表面活性剂和/或(b)无聚合剂和/或(c)无水和/或(e)无短链醇和/或(f)无多元醇的疏水溶剂制备油质载体和药物学组合物时,待克服的技术问题是多重的,包括发现提供发泡性质的表面活性剂的适合替代品;发现适合的更换,优选无需具有与表面活性剂一起存在的泡沫佐剂(替代品),如果存在所述泡沫佐剂,则将尤其辅助促进泡沫并作为表面活性剂的助剂,优选无需具有与表面活性剂一起存在的聚合剂(替代品),如果存在所述聚合剂,则将尤其辅助延长泡沫的稳定性。
本发明令人惊讶地发现,在疏水溶剂类泡沫的情况下通过由脂肪醇、脂肪酸和蜡组成的粘度改性剂可有利地消除和替代表面活性剂。蜡拥有几种优于其他发泡剂的有利条件,如优秀的皮肤相容性、几乎无化学反应性,确保活性成分稳定、以及有效的皮肤闭合,辅助降低皮肤水份流失并可增强活性剂的皮肤渗透。虽然蜡给制备发泡组合物(foamable composition)和泡沫带来它们自己附加的问题,包括它们趋于固化并从制剂析出以及封阻容器(canister)阀门,对此,需要设计制剂以便在添加喷射剂的有效量时不负面干扰该制剂,以及制剂为可摇动的和均质的,并至少在使用前的温和或合理的摇动时易于重整(reform)。
另一挑战是如何调整流变性,其主要表现在添加喷射剂前后制剂的粘度,以便在此之前可显示凝胶样性质,而在添加后在容器中可摇动。此外,该组合物应该能够产生泡沫,当应用于靶标时既不是液体也不非常粘,而是舒适及便于应用的。此外,凝胶和泡沫能够显示药物学目的的等价性时可基本上降低毒理学和试验的成本。
引入或添加到上述物质是如何提供下述制剂的方面,在该制剂中不稳定的活性成分,如易于降解的四环素,可仍然保留充分地化学稳定性达延长的一段时间,以使允许合理的或可接受的分解量(例如,可被常规药物管理局所接受),它们保留提供治疗作用或者预防或缓解紊乱或疾病的能力(下文中为“化学稳定”)。进一步的挑战为提供和给药其中特别是当活性剂不溶时活性剂为均质的组合物。此外,制剂应当避免如果应用到敏感靶标可受到刺激或者重复使用时可引起消耗或干燥或疼痛的物质的使用。
引入或添加上述物质是如何提供物理稳定的下述制剂的方面,所述制剂在从压力容器中释放时至少是短期稳定的,作为暴露于皮肤温度的结果是不破碎的。在皮肤上结构稳定至少一分钟的泡沫称为“短期稳定”。在物理稳定性的另一方面,包括喷射剂的发泡制剂保留均质性,并且在摇动后至少一分钟不分离至任何显著程度(下文中为“物理稳定”)。
在一方面,局部治疗的疏水性易碎性的组合物包括载体和四环素抗生素,所述载体包括约60重量%至约99重量%的至少一种疏水油和选自由脂肪醇、脂肪酸和蜡组成的组的至少一种粘度改性剂;其特征在于,至少部分所述四环素抗生素悬浮于所述组合物中,所述组合物的粘度比无四环素抗生素的载体的粘度高至少约30%;并高于无粘度改性剂的疏水油和四环素抗生素的粘度;其中在25℃下储存至少两个月后所述组合物保留至少90%最初存在于所述组合物中的四环素;其中当在添加有液化或压缩气体喷射剂的气溶胶容器中包封时,所述组合物在从容器释放时提供在施加剪切力时易于破碎的质量至少为良好的易碎泡沫。
在一个或多个实施方案中,至少两个月后,存在的四环素为初始存在的四环素的至少95%或至少97%。
在一个或多个实施方案中,至少三个月后,存在的四环素为初始存在的四环素的至少90%或至少95%或至少97%。
在一个或多个实施方案中,至少六个月后,存在的四环素为初始存在的四环素的至少90%或至少95%或至少97%。
在一个或多个实施方案中,所四环素的存在量由HPLC测定。
在一个或多个实施方案中,所述粘度增加为协同增加,从而载体粘度和疏水油与四环素抗生素的粘度的组合小于所述组合物的粘度。
在一个或多个实施方案中,所述疏水易碎载体在添加喷射剂前为凝胶的形式;其中所述凝胶在施加温和剪切力时容易液化和扩散。
在一个或多个实施方案中,所述疏水易碎载体为泡沫形式;其中所述泡沫具有大于约3分钟的塌缩时间。
在一个或多个实施方案中,除喷射剂以外的组合物与喷射剂的比为约100∶1至约100∶25。
在一个或多个实施方案中,所述至少一种疏水油选自由以下组成的组:矿物油、烃油、酯油、二羧酸的酯、甘油三酯油、植物来源的油、动物来源的油、不饱和或多不饱和油、甘油二酯、PPG烷基醚、精油、硅油、液体石蜡、异链烷烃、聚α烯烃、聚烯烃、聚异丁烯、合成异烷烃、异十六烷、异十二烷、苯甲酸烷基酯、辛酸烷基酯、苯甲酸C12-C15烷基酯、辛酸C12-C15烷基酯、山嵛酸二十烷酯(arachidyl behenate)、丙酸二十烷酯、月桂酸苄酯、肉豆蔻酸苄酯、棕榈酸苄酯、双(辛基十二烷基硬脂酰)二聚二亚油酸酯、肉豆蔻酸丁酯、硬脂酸丁酯、鲸蜡硬脂醇乙基己酸酯、鲸蜡硬脂醇异壬酸酯(cetearyl isononanoate)、乙酸十六烷酯(cetyl acetate)、乙基己酸十六烷酯、乳酸十六烷酯、肉豆蔻酸十六烷酯、辛酸十六烷酯、棕榈酸十六烷酯、蓖麻酸十六烷酯、油酸癸酯、二甘醇二乙基己酸酯、二甘醇二辛酸酯、二甘醇二异壬酸酯、二甘醇二异壬酸酯、二乙基己酸酯、己二酸二乙基己酯、苹果酸二乙基己酯、琥珀酸二乙基己酯、己二酸二异丙酯、二聚酸二异丙酯(diisopropyl dimerate)、癸二酸二异丙酯、二异硬脂醇二聚二亚油酸酯(diisostearyl dimmerdilinoleate)、二异硬脂醇富马酸酯、苹果酸二辛酯、癸二酸二辛酯、油酸十二烷基酯、棕榈酸乙基己基酯、羊毛脂酸的酯衍生物、椰油酸乙基己酯、乙基己酸乙基己酯、羟基硬脂酸乙基己酯、异壬酸乙基己酯、棕榈酸乙基己酯、壬酸乙基己酯、硬脂酸乙基己酯、硬脂酸十六烷基酯、月桂酸己酯、月桂酸异戊酯、异十六烷基山嵛酸异十六烷基酯(isocetyl isocetylbehenate)、羊毛脂酸异十六烷基酯、棕榈酸异十六烷基酯、硬脂酸异十六烷基酯、水杨酸异十六烷基酯、硬脂酸异十六烷基酯、硬脂酰硬脂酸异十六烷基酯、辛酸异十六烷基十八烷基酯(isocetearyl octanoate)、乙基己酸异癸酯、异壬酸异癸酯、油酸异癸酯、异壬酸异壬酯、油酸异癸酯、癸酸异己酯、辛酸异壬酯、异硬脂酸异丙酯、羊毛脂酸异丙酯、月桂酸异丙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、硬脂酸异丙酯、山嵛酸异十八烷基酯、柠檬酸异十八烷基酯、芥酸异十八烷基酯(isostearylerucate)、甘醇酸异十八烷基酯、异壬酸异十八烷基酯、异硬脂酸异十八烷基酯、乳酸异十八烷基酯、亚油酸异十八烷基酯、亚麻酸异十八烷基酯、苹果酸异十八烷基脂、新戊酸异十八烷基酯、棕榈酸异十八烷基酯、水杨酸异十八烷基酯、酒石酸异十八烷基酯、异壬酸异十三烷基酯、异壬酸异十三烷基酯、乳酸月桂酯、乳酸肉豆蔻酯、肉豆蔻酸肉豆蔻酯、新戊酸肉豆蔻酯、丙酸肉豆蔻酯、肉豆蔻酸辛基十二醇酯、新戊二醇二癸酸酯、辛基十二醇、硬脂酸辛酯、棕榈酸辛酯、山嵛酸辛基十二醇酯、羟基硬脂酸辛基十二醇酯、肉豆蔻酸辛基十二醇酯、硬脂酰硬脂酸辛基十二醇酯、油基芥酸酯(oleyl erucate)、油基乳酸酯、油基油酸酯、肉豆蔻酸丙酯、丙二醇单肉豆蔻醚乙酸酯、丙二醇二癸酸酯、丙二醇二辛酸酯、丙二醇二辛酸酯、马来酸化大豆油、癸酸十八烷基酯、庚酸十八烷基酯、丙酸十八烷基酯、乙酸生育酚酯(tocopheryl acetate)、亚油酸生育酚酯、油酸甘油酯、乙基己酸十三烷基酯、异壬酸十三烷基酯、柠檬酸三异十六烷基酯、亚历山大月桂树油、鳄梨油、杏子油(apricotstone oil)、大麦油、琉璃苣籽油、金盏花油、金盏花坚果树油、芥花油、辛酸/癸酸甘油三酯蓖麻油、椰子油、玉米油、棉油、棉籽油、月见草油、亚麻油、花生油、榛子油、甘油聚醚三乙酸酯(glycereth triacetate)、甘油三庚酸酯、甘油三辛酸酯、十一酸甘油三酯(glyceryl triundecanoate)、大麻籽油、荷荷巴油、苜蓿油(lucerne oil)、玉米胚油、髓油(marrow oil)、小米油、新戊二醇二辛酸酯/二癸酸酯、橄榄油、棕榈油、西番莲油、季戊四醇四硬脂酸酯、罂粟油、蓖麻酸丙二醇酯、菜籽油、黑麦油、红花油、芝麻油、牛油树脂、豆油(soya oil)、大豆油、甜杏仁油、葵花油、蒜芥油(sysymbrium oil)、丁香油、茶树油、核桃油、小麦胚甘油酯、小麦胚油、PPG-2丁醚、PPG-4丁醚、PPG-5丁醚、PPG-9丁醚、PPG-12丁醚、PPG-14丁醚、PPG-15丁醚、PPG-15十八烷基醚、PPG-16丁醚、PPG-17丁醚、PPG-18丁醚、PPG-20丁醚、PPG-22丁醚、PPG-24丁醚、PPG-26丁醚、PPG-30丁醚、PPG-33丁醚、PPG-40丁醚、PPG-52丁醚、PPG-53丁醚、PPG-10十六烷基醚、PPG-28十六烷基醚、PPG-30十六烷基醚、PPG-50十六烷基醚、PPG-30异十六烷基醚、PPG-4月桂醚、PPG-7月桂醚、PPG-2甲醚、PPG-3甲醚、PPG-3肉豆蔻醚、PPG-4肉豆蔻醚、PPG-10油基醚、PPG-20油基醚、PPG-23油基醚、PPG-30油基醚、PPG-37油基醚、PPG-40丁醚、PPG-50油基醚、PPG-11十八烷基醚、鲱鱼油、鳕鱼肝油、鲑鱼油、环甲基硅酮、二甲基聚硅氧烷、聚二甲基硅氧烷(dimethicone)、环氧改性的硅油、脂肪酸改性的硅油、氟基改性的硅油、甲基苯基聚硅氧烷、苯基聚三甲基硅氧烷和聚醚基改性的硅油。
在一个或多个实施方案中,所述脂肪醇在其碳骨架中具有至少12个碳原子;和其中所述脂肪酸在其碳骨架中具有至少12个碳原子。
在一个或多个实施方案中,所述脂肪醇和所述脂肪酸具有大于约40℃的熔点。
在一个或多个实施方案中,所述脂肪醇选自由月桂醇、十四烷醇、十六烷醇、十八烷醇、二十烷醇(arachidyl alcohol)、二十二烷醇、二十四烷醇、二十六烷醇、二十八烷醇、三十烷醇、三十四烷醇组成的组;和其中所述脂肪酸选自由十二烷酸、十四烷酸、十六烷酸、十七烷酸、十八烷酸、二十烷酸、二十二烷酸、二十四烷酸、二十六烷酸、二十七烷酸、二十八烷酸、三十烷酸、三十二烷酸、三十三烷酸、三十四烷酸和三十五烷酸组成的组。
在一个或多个实施方案中,所述脂肪醇或所述脂肪酸的碳链被羟基取代,例如,所述脂肪酸的碳链为12羟基硬脂酸。
在一个或多个实施方案中,蜡选自由植物蜡、巴西棕榈蜡、小烛树蜡、小冠巴西棕榈蜡、甘蔗蜡、藤蔓蜡(retamo wax)、荷荷巴油、动物蜡、蜂蜡、石油衍生蜡、固体石蜡、聚乙烯以及其衍生物组成的组。
在一个或多个实施方案中,所述粘度改性剂为包括(i)至少一种脂肪醇和至少一种脂肪酸;或(ii)至少一种脂肪醇和至少一种蜡;或(iii)至少一种脂肪酸和至少一种蜡;或者(iv)至少一种脂肪醇、至少一种脂肪酸和至少一种蜡的组合。
在一个或多个实施方案中,所述疏水易碎载体基本上无表面活性剂、质子溶剂、极性非质子溶剂和硅酮增稠剂。
在一个或多个实施方案中,所述疏水易碎载体基本上无表面活性剂、聚合胶凝剂、多元醇、短链醇和硅酮增稠剂。
在一个或多个实施方案中,所述疏水易碎载体包含小于约0.4%;或小于约0.2%;或小于约0.1%的表面活性剂、质子溶剂、极性非质子溶剂和硅酮增稠剂。
在一个或多个实施方案中,所述四环素抗生素选自由四环素、土霉素、去甲金霉素、强力霉素、赖氨甲四环素、甲基氯环素、甲烯土霉素、二甲胺四环素、吡甲四环素、金霉素和替加环素(tigecycline)组成的组,例如,所述四环素抗生素为疏水的。
在一个或多个实施方案中,所述四环素抗生素以游离碱形式、水合物形式、盐形式或配合物形式存在,例如,所述四环素抗生素在pH7.0(缓冲液/氯仿)下的分布常数的Log等于或小于约0.2。
在一个或多个实施方案中,所述四环素抗生素在碳5、6和7位不包括任何羟基,例如,所述四环素抗生素选自二甲胺四环素和强力霉素的组;或为二甲胺四环素。
在一个或多个实施方案中,所述组合物进一步包括另外的活性剂。
在一个或多个实施方案中,所述另外的活性剂选自由以下组成的组:活性草本提取物、杀螨剂(acaricides)、老年斑和角质去除剂、过敏原、α-羟基酸、镇痛剂、雄性激素、抗痤疮剂、抗过敏剂、抗衰老剂、抗菌剂、抗生素、抗灼烧剂(antiburnagent)、抗癌剂、去屑剂、抗抑郁剂、抗皮炎剂、消水肿剂、抗真菌剂(antifungal agent)、抗组胺剂、抗蠕虫剂(antihelminth)、抗角化过度剂、抗感染剂、抗炎剂、抗刺激剂、降血脂剂、抗微生物剂、抗霉菌剂、抗氧化剂、抗寄生虫剂、抗增殖剂、止痒剂、抗银屑病剂、抗红斑痤疮剂、抗皮脂溢剂、防腐剂、防膨胀剂、抗病毒剂、抗疣剂、抗皱剂、抗酵母剂、收敛剂、β-羟基酸、过氧化苯甲酰、局部心血管剂、化疗剂、皮质类固醇、免疫原性物质、二羧酸、消毒剂、雌性激素、杀真菌剂(fungicide)、头发生长调节剂、半抗原、激素、羟基酸、免疫抑制剂、免疫调节剂(immunoregulating agent)、免疫调制剂(immunomodulator)、免疫刺激剂、杀虫剂、驱虫剂、角质软化剂、内酰胺、局部麻醉剂、润滑剂、遮蔽剂、金属、金属氧化物、杀疥虫药(mitocide)、神经肽、非甾族抗炎剂、氧化剂、灭虱剂、肽、农药、蛋白质、光动力治疗剂、黄体酮、游离基清除剂、加脂剂(refatting agent)、类视黄醇、治愈剂(sanative)、灭疥疮剂、镇静剂、美黑剂、皮肤防护剂、皮肤增白剂、类固醇、类固醇激素、血管活化剂、血管收缩剂、血管扩张剂、维生素、维生素A、维生素A衍生物、维生素B、维生素B衍生物、维生素C、维生素C衍生物、维生素D、维生素D衍生物、维生素D类似物、维生素F、维生素F衍生物、维生素K、维生素K衍生物、伤口愈合剂和疣去除剂。
在一个或多个实施方案中,其中,当在使用人类或猪的皮肤的弗朗茨细胞(Franz-cell)体外模型中试验时,在皮肤中提供高于经皮所转移的相应量的四环素的量。
在一个或多个实施方案中,其中,当在使用人类或猪的皮肤的弗朗茨细胞体外模型中试验时,皮肤中四环素的量与经皮给药所转移的相应量之间的比高于约100∶1;或在约100∶1和约10∶1之间;或在约10∶1和约2∶1之间;或者大于1∶1。
在一个或多个实施方案中,其中当在使用人类或猪的皮肤的弗朗茨细胞体外模型中试验时,在所述疏水性易碎性的组合物中的所述四环素的浓度高于致使所述四环素具有治疗效果的足够浓度的皮肤内递送的最低浓度。
在一个或多个实施方案中,其中在应用于治疗靶点时所述组合物防止四环素抗生素的降解。
在另一方面,一种预防、治疗或缓解皮肤科、眼科、妇科或粘膜紊乱的症状的方法,其包括向靶区域局部应用本文所述的疏水性治疗组合物。
在一个或多个实施方案中,其中所述紊乱包括细菌感染、炎症、氧化应激和神经变性和/或凋亡作为病因之一。
在一个或多个实施方案中,所述紊乱选自由以下组成的组:皮肤病症脓肿,痤疮、聚合性痤疮、暴发性痤疮、寻常痤疮、痤疮疤痕、急性发热性嗜中性白细胞皮肤病、急性淋巴管炎、变应性接触性皮炎、秃头症、足癣(athlete′s foot)、特应性皮炎、细菌性皮肤感染、脱发、基底细胞癌、水疱、腋臭、大疱性类天疱疮、灼伤、胼胝念珠菌病(calluses candidiasis)、痈(carbuncles)、蜂窝组织炎、化学灼伤、水痘、胆脂瘤、胆碱能性荨麻疹、日光的慢性效应、唇疱疹、寒冷性荨麻疹、粉刺(comedones)、鸡眼、匐行疹、皮肤脓疮(cutaneous abscess)、皮肤幼虫移行症、肤蛆病、黑斑(dark spots)、寄生虫妄想症(delusional parasitosis)、痛性脂肪病(Dercum disease)、皮炎、疱疹样皮炎、皮肤疼痛、皮肤炎症、皮肤划痕现象、皮肤真菌病(dermatophytosis)、药疹和药物反应、汗疱、外胚层发育不良、湿疹、深脓疱、表皮囊肿、表皮坏死、丹毒、丹毒、红斑、剥落性皮炎、多形性红斑、结节性红斑、毛囊炎、真菌指甲感染、真菌皮肤感染、疖、坏疽、生殖器疱疹、环状肉芽肿、头虱、化脓性汗腺炎(hidradenitis suppurativa)、荨麻疹(hives)、毛囊炎、多毛症、多汗症、少汗症、鱼鳞癣、脓疱病、炎性痤疮、嵌甲、擦烂、刺激性接触性皮炎、缺血性坏死、瘙痒、股癣(jock itch)、卡波西肉瘤、毛发角化病、慢性单纯性苔癣、扁平苔癣、硬化性苔癣、淋巴结炎、淋巴结炎、淋巴管炎、恶性黑色素瘤、肥大细胞增多症、麻疹、黑色素瘤、黑色素瘤、汗疹、痣、触染性软疣、MRSA、坏死性皮下感染、坏死性筋膜炎、坏死性肌炎、结节状丘疹脓疱型粉刺、非炎性粉刺、钱币状皮炎、口腔疱疹、脂膜炎、类银屑病、甲沟炎、寄生性皮肤感染、天疱疮、光过敏、光损伤、光刺激、光敏感、丘疹、虱病、口周皮炎、面疱(pimples)、玫瑰糠疹、苔癣样糠疹、玫瑰糠疹、毛发红糠疹、接触毒漆引起的皮疹(poison ivy)、术后(post-operative)或外科术后(post-surgical)皮肤病、压迫性溃疡、压迫性荨麻疹、瘙痒症、须部假性毛囊炎、牛皮癣、PUPPP、紫癜、脓疱、脓性肉芽肿、疹、癣菌病、红斑痤疮、玫瑰疹、风疹、疥疮、皮肤烫伤综合征、伤疤、硬皮病、皮脂囊肿、脂溢性皮炎、脂溢性角化病、带状疱疹、皮肤老化、皮肤癌、皮肤瘤、皮肤赘生物、皮疹、皮肤溃疡、鳞状细胞癌、金黄色葡萄球菌烫伤样皮肤综合征(staphylococcal scalded skin syndrome)、停滞性皮炎、史蒂文斯-约翰逊综合征(Stevens-Johnson syndrome)、晒伤、太阳斑、热灼伤、体癣、股癣(tinea cruris)、脚癣、花斑癣、中毒性表皮坏死松解症、皮肤外伤或损伤、水痘带状疱疹病毒、维生素D缺乏、病毒性皮肤感染、白癜风、疣、水性荨麻疹(waterhives)、皱纹、干燥症、酵母皮肤感染和带状疱疹;体腔或粘膜表面紊乱,鼻、嘴、眼、耳、呼吸系统、阴道、尿道或直肠的紊乱,衣原体感染、淋病感染、乙型肝炎、疱疹、HIV/AIDS、人乳头瘤病毒(HPV)、生殖器疣、细菌性阴道炎、念珠菌病、软下疳、腹股沟肉芽肿、性病淋巴肉芽肿、粘脓性宫颈炎(MPC)、触染性软疣、非淋病性尿道炎(NGU)、滴虫病、外阴紊乱、外阴痛(vulvodynia)、外阴疼痛、酵母感染、外阴萎缩、外阴上皮内瘤样病变(VIN)、接触性皮炎、盆腔炎、子宫内膜炎、输卵管炎、卵巢炎、生殖器癌、子宫颈癌、外阴癌、阴道癌、阴道干燥、性交困难、肛门和直肠疾病、肛门脓疮/瘘管、肛门癌、肛裂、肛门疣、克罗恩氏病、痔疮、肛门瘙痒(anal itch)、肛门瘙痒症(pruritus ani)、大便失禁、便秘、结肠和直肠息肉;眼部紊乱,眼布血丝(eye redness)、眼痛或光敏感、视力模糊、视觉丧失、视觉障碍-飞蚊症(floater)、闪光、失真、光晕等、痒/灼烧、流泪/流脓(discharge)、感觉眼内有异物、眼睑问题、复视;眼部过敏、眼睑炎、白内障、中心性浆液性脉络膜视网膜病变、色觉问题、角膜擦伤、角膜水肿、角膜溃疡、结膜炎、隐形眼镜并发症、泪囊炎、模糊远视、干眼、视网膜静脉周围炎(Eale’sdisease)、巩膜外层炎、眼睑外翻、眼睑内翻、眼睑蜂窝性组织炎、眼疲劳、聚焦痉挛、青光眼、急性青光眼、虹膜炎、圆锥形角膜、莱姆病(lyme disease)、黄斑变性、黄斑水肿、黄斑裂孔、眼药物毒性、重症肌无力、瘢痕性眼天疱疮、眼性偏头痛、老花眼、泪管堵塞(obstructed tear duct)、视神经炎、视神经中风(optic nerve stroke)、眶骨骨折、眼眶蜂窝组织炎、小水疱病、翼状胬肉、复发性角膜糜烂、视网膜动脉阻塞、视网膜脱离、视网膜裂孔、视网膜静脉阻塞、结节病、巩膜炎、窦病、斜视(眼部失调)、结膜下出血、颞动脉炎、甲状腺相关性眼病、倒睫、睑瘤、眼睑抽搐(眼睑肌纤维颤搐)、葡萄膜炎、玻璃体脱离和玻璃体积血。
在一个或多个实施方案中,所述紊乱选自由皮肤感染、痤疮、红斑痤疮、眼部感染、眼红斑痤疮、眼睑炎、干眼、沙眼和青光眼组成的组。
在一个或多个其他具体实施方案中,将药物载体配制成基本上(substantially)无弹性体。在一个或多个其他具体实施方案中,将药物载体配制为实质上(essentially)无弹性体。在一个或多个其他具体实施方案中,将药物载体配制成基本上无硅酮。在一个或多个其他具体实施方案中,将药物载体配制成实质上无硅酮。在一个或多个其他具体实施方案中,药物载体配制有小于约30%的硅酮、或小于约25%的硅酮、或小于约20%的硅酮、或小于约15%的硅酮、或小于约10%的硅酮、或小于约7.5%的硅酮、或小于约5%的硅酮、或小于约2%的硅酮、或小于约1%的硅酮、或小于约0.5%的硅酮。
具体实施方式
本发明涉及用于局部给药的疏水易碎四环素制剂,其中所述制剂为以下形式:(i)在施加温和剪切力时易于液化和扩散的油凝胶;或(ii)油泡沫;其中所述油泡沫在从气溶胶罐分散(dispensing)时是稳定的,并且在施加温和剪切力时易于分解和扩散。
本发明的制剂适用于对皮肤和粘膜、眼、鼻腔、耳道和阴道的局部给药。
医用产品的特点为长期稳定性。本文的组合物令人惊讶地稳定。随着加速稳定性研究,它们显示期望的结构,不会在与表面接触时立即破碎,在治疗区上易于扩散并且吸收快。
在一个或多个实施方案中,所述组合物具有可接受的至少六个月的保存期限。在一个或多个实施方案中,泡沫组合物(foam composition)具有可接受的至少一年的保存期限。在一个或多个实施方案中,泡沫组合物在环境温度下具有可接受的至少15个月、或至少18个月或至少21个月或至少两年的保存期限。
在一个或多个实施方案中,稳定性尤其是关于以下的广泛努力和研究的产物:消除表面活性剂;消除水;组分的选择;与活性剂各单独组分的试验(相容性研究);在气密避光容器中储存的具有适当的Aw值(例如<9)的组分的组合。
在一个或多个实施方案中,当在室温下、两个月的时间后制剂中大于约90%的活性剂不分解时,将活性剂认定为是化学稳定的。在一个或多个实施方案中,所述时间为六个月。在一个或多个实施方案中,大于约88%的活性剂不分解。在一个或多个实施方案中,活性剂在40℃下的组合物中化学稳定。
在一个或多个实施方案中,将药物载体配制为基本上无短链醇,如乙醇、丙醇或丁醇。在一个或多个实施方案中,将药物载体配制为实质上无短链醇。在一个或多个实施方案中,将药物载体配制为实质上无脂肪醇或脂肪酸的衍生物。在一个或多个其他具体实施方案中,将药物载体配制为实质上无多元醇。在一个或多个其他具体实施方案中,将药物载体配制为基本上无表面活性剂和/或短链醇和/或多元醇。在一个或多个其他具体实施方案中,将药物载体配制为实质上无表面活性剂和/或短链醇和/或多元醇。在一个或多个实施方案中,提供实质上无水的组合物。在一个或多个实施方案中,提供无表面活性剂、也无短链醇和/或无多元醇的组合物。在一个或多个实施方案中,提供基本上无聚合物的组合物。在其他实施方案中,实质上是无聚合物的。在另外的实施方案中,组合物无聚合剂。在一个或多个实施方案中,聚合剂具有至少约1000道尔顿的分子量。
在一个或多个实施方案中,组合物实质上无水;聚合剂;表面活性剂;短链醇;或多元醇的两种或多种。在一个或多个实施方案中,组合物实质上无水;聚合剂;表面活性剂;短链醇;或多元醇的三种或多种。在一个或多个实施方案中,组合物实质上无水;聚合剂;表面活性剂;短链醇;或多元醇的四种或多种。在一个或多个实施方案中,组合物实质上无水;聚合剂;表面活性剂;短链醇;或多元醇。
在一个或多个其他具体实施方案中,将药物载体配制为基本上无弹性体。在一个或多个其他具体实施方案中,将药物载体配制为实质上无弹性体。在一个或多个其他具体实施方案中,将药物载体配制为基本上无硅酮。在一个或多个其他具体实施方案中,将药物载体配制为实质上无硅酮。在一个或多个其他具体实施方案中,药物载体配制有小于约30%的硅酮、或小于约25%的硅酮、或小于约20%的硅酮、或小于约15%的硅酮、或小于约10%的硅酮、或小于约7.5%的硅酮、或小于约5%的硅酮、或小于约2%的硅酮、或小于约1%的硅酮、或小于约0.5%的硅酮。
定义
所有%值均基于重量(w/w)而提供。
在一个或多个实施方案中,无论短语用于表示大于X%还是小于X%的浓度,其还可包括X%,或者大于约X%或小于约X%,其还可包括约X%。
在一个或多个实施方案中,术语“约”具有其在药物学和化妆品制剂的背景下的常用含义,从而允许合理的可实现相同效果的量的变化。通过本文的术语“约”,其意指如上所表示的,还指数字或数字范围可以在加减多达30%的实施方案内变化。所以,在该实施方案中,如果提供“约1”的数,那么该量可上至1.3或从0.70起。在其他实施方案中,可反映出加或减20%的变化。还在进一步的实施方案中,可描述加或减10%的变化。还在进一步的实施方案中,可描述加或减5%的变化。如本领域技术人员将理解的,在制备组合物中存在某些合理的灵活性,以便在连续改变一种或多种成分时,即使所述量稍微落在所述范围之外也可制成成功的制剂。因此,为了允许该可能性,用约来修饰量。在一个或多个其他实施方案中,可将数字理解为不带前缀约。
本文所使用的术语“触变性(thixotropic)”,是指在施加剪切力时制剂显示显著的粘度降低。
本文所使用的术语“无水”是指组合物不包含、或基本上不包含游离或未缔合或吸收水。类似地,“无水”或“基本上无水”的载体包含至多附带的和痕量的水。
本文的术语“单一相”是指组合物或载体的液体组分充分混合,固体组分,若有的话,也溶于或悬浮于组合物中。基本上单一相是指组合物和载体根本上或本质上为如上所解释的单一相,但也可存在少量能够形成或可形成分离相的材料,该材料总计小于组合物或载体的约5%,优选小于约3%,更优选小于约1%。“单一相”或“基本上单一相”在发泡组合物的情况中,即使在向组合物或载体添加喷射剂后,也同样适用上述意思。
如本文所使用的术语“不稳定的活性剂”是指在环境条件下暴露在空气、光、皮肤或水时,在小于一天,某些情况下为小于一小时内氧化和/或降解的活性剂。
如本文所使用的术语“辅助表面活性剂”是指本身不能令人满意地形成和稳定水乳中的油的化合物,但当与表面活性剂组合使用时,此类辅助表面活性剂可促进表面活性剂的乳化力,从而产生稳定的乳液。例如,脂肪醇如十六烷醇、或脂肪酸如硬脂酸可起辅助表面活性剂的作用。十六烷醇和十八烷醇为可使用表面活性剂与水乳化的蜡状疏水物质。在某些情况下,辅助表面活性剂本身可通过,例如向脂肪酸添加碱如三乙醇胺而产生也被称为“皂”(强阴离子表面活性剂)的脂肪酸盐来转换成表面活性剂或皂。
如本文所使用的,“多元醇”的鉴定为在其分子结构中包含至少两个羟基的有机物质。
凝胶和泡沫的介绍(presentation)
本发明的局部治疗的疏水性易碎性的组合物可作为凝胶或泡沫存在。本文所使用的术语“易碎”涉及在从容器中分散时作为凝胶或作为泡沫是稳定的组合物,然而在施加温和剪切力时易于分解和扩散。
在本发明中令人惊讶地发现,某些组合物在气溶胶容器中包封和添加喷射剂时,提供释放如本文所述的良好至优质量的易碎泡沫的可摇动和均质的发泡组合物,所述组合物包括与可为至少一种脂肪醇和/或至少一种脂肪酸、和/或至少一种蜡、及其两种以上的混合物的粘度改性剂;和悬浮活性剂一起的疏水溶剂;无任何表面活性剂。
所得泡沫药物学上相当于各自的凝胶(添加喷射剂之前),这是由于泡沫一旦分散,喷射剂立即蒸发,给药时的组合物类似于凝胶的组合物。这是重要的实用优点,因为可通过一次提供所述凝胶和泡沫而不是两次(分别提供)来进行此类研究,从而节约许多药物开发活动,包括使用大量动物的昂贵且长期的毒理学研究和数以千计的患者的临床试验。
凝胶
本发明凝胶的主要基本组分,包括(a)至少一种疏水油、(b)至少一种粘度改性剂和(c)四环素抗生素。疏水油的浓度在约60重量%和约99重量%之间,在一个或多个实施方案中浓度在约60重量%和约95重量%之间,或在约65重量%和约99重量%之间,或在约65重量%和约95重量%之间,或在约70重量%和约95重量%之间,或在约75重量%和约95重量%之间,或在约80重量%和约95重量%之间,或在约85重量%和约99重量%之间,或在约85重量%和约95重量%之间。
令人惊讶地是,我们发现,在向疏水油添加粘度改性剂使此类油的粘度增加时,甚至少量悬浮的四环素抗生素也使组合物的粘度协同增加。凝胶是稳定的,其在从容器如管分散时保持其粘度,而且在施加温和剪切力时易于液化和扩散。此外,当凝胶为油质时,其易于吸收至应用部位如皮肤,几分钟后表面看上去并感觉不到任何油性或油腻。
四环素与疏水油、脂肪醇、脂肪酸和蜡的一种或多种的混合物组合具有强烈的协同效应,并增加制剂粘度。例如,含有0.50%盐酸二甲胺四环素的制剂的粘度高出无四环素的相同制剂粘度的约三倍。制剂粘度效应与四环素的浓度直接相关:四环素的浓度越高,制剂的粘度越高。在某些情况下,似乎当活性成分以约0.50%的浓度存在时,或者在某些实施方案中,当载体的粘度超过约25,000cps时,盐酸二甲胺四环素的粘度增加效应达到稳定水平。
因此,在一种或多种实施方案中,提供含有同脂肪醇和/或脂肪酸和/或蜡协同组合的至少一种疏水油和四环素的凝胶,其中通过添加活性成分到大于约30%、或大于约50%、或大于约100%、或大于约200%、或大于约300%、或大于约500%来增加制剂的粘度。
在一个或多个实施方案中,制剂粘度的增加与活性剂的浓度相关。
在一个或多个实施方案中,制剂的粘度与活性剂的浓度成正比例:活性成分的浓度越高,制剂的粘度越高。
在一个或多个实施方案中,当活性成分的浓度增加时,活性成分的粘度增加效应达到稳定水平。
在一个或多个实施方案中,当活性成分以小于约10%、小于约5%、小于约1%、小于约0.5%、小于约0.1%、小于约0.05%、小于约0.01%的浓度存在时,含有四环素的制剂的粘度为样品制剂的粘度的两倍。
在一个或多个实施方案中,凝胶的粘度高于约10000cPs;或在约1000cPs和约100000cPs之间;或在约5000cPs和约50000cPs之间;或在约10000cPs和约30000cPs之间。
在一个或多个实施方案中,组合物的粘度的增加为至少约100%,载体的粘度为小于约12,000cPs;或小于约8,000cPs;或小于约2,000cPs。在一个或多个实施方案中,载体的粘度大于约1,000cPs;或大于约1,300cPs;或大于约1,500cPs;或大于约1,800cPs或大于约2000cPs。在一个或多个实施方案中,载体的粘度大于约150cPs;或大于约300cPs,或大于约500cPs或大于约800cPs。
在一个或多个实施方案中,粘度的改变在约50%和约100%之间。在一个或多个实施方案中,粘度的改变在约100%和约500%之间。在一个或多个实施方案中,粘度的改变在约500%和约1000%之间。在一个或多个实施方案中,粘度的改变在约1000%和约1500%之间。在一个或多个实施方案中,粘度的改变在约1500%和约2000%之间。在一个或多个实施方案中,粘度的改变在约2000%和约2500%之间。在一个或多个实施方案中,粘度的改变在约50%和约3000%之间。在一个或多个实施方案中,粘度的改变在约150%和约1000%之间。在一个或多个实施方案中,粘度的改变在约1000%和约2500%之间。在一个或多个实施方案中,粘度的改变在约100%和约2500%之间;在约100%和约1500%之间;或在约100%和约2000%之间;或在约100%和约1500%之间;或在约100%和约1000%之间。
凝胶组合物具有稳定四环素抗生素和防止其降解的独特性质。例如,当将含有约83%疏水油、约4.5%蜡、约6%脂肪醇和5%脂肪酸和约1%微粉化盐酸二甲胺四环素的凝胶施用至新取下并且湿润的皮肤并在陪替氏培养皿(Petri dish)中保存时,在空气和光下暴露6小时,产品保持基本上稳定。此外,甚至当含1%二甲胺四环素的疏水凝胶的样品施用至皮肤并直接暴露在阳光下两天时,如通过皮肤颜色的保持所示,也不存在明显降解。作为四环素抗生素,特别是二甲胺四环素,已知对空气、水合光的降解敏感,该保护作用是独特的。
在另外的观察中,在二甲胺四环素免受环境因素(湿、光和空气)的影响时,如本文进一步例举的在体外弗朗茨细胞模型、抗菌试验模型和抗炎模型中其向皮肤的有效释放所表明的那样,其没有受到阻碍或紧密地包封(encapsulated)。
泡沫
本领域技术人员期望应当需要表面活性剂以便促进泡沫的产生。
然而,令人惊讶地是,当将如上所述的包括(a)至少一种疏水油、(b)至少一种粘度改性剂和(c)四环素抗生素的凝胶组合物引入用气溶胶阀关闭并用喷射剂加压的气溶胶罐时,其产生易碎泡沫,即从容器分散时稳定,然而在施加温和剪切力时易于破碎和扩散的泡沫。在凝胶的情况下,泡沫易于吸收至应用部位如皮肤,几分钟后表面看上去并感觉不到任何油性或油腻。
发泡喷射剂
适合的喷射剂的实例包括压缩气体、挥发性烃如丁烷、丙烷、异丁烷和氟碳气体,或其混合物。
在实施方案中,喷射剂为疏水的,并且其与组合物中的油可混合。
在某些实施方案中,不同于作为非臭氧消除的喷射剂的含氯氟烃(CFC),氟烃喷射剂在非可燃的发泡组合物的生产中特别有用。
此类喷射剂包括,但不限于不含有氯原子的氢氟烃(HFC)喷射剂,就其本身而论,完全不用担心由含氯氟烃或其他氯化烃造成的平流层臭氧破坏。根据本发明该方面的示例性非可燃喷射剂包括由DuPont制造的喷射剂,注册商标为Dymel,例如1,1,1,2四氟乙烷(Dymel 134)和1,1,1,2,3,3,3七氟丙烷(Dymel227)、1,1二氟乙烷(Dymel 152)和1,1,1,3,3,3六氟丙烷。HFC具有0.00的臭氧消耗潜能值(Ozone Depletion Potential),因此,允许其用作气溶胶制品的喷射剂。
然而,在另外的实施方案中,喷射剂为自身发泡的喷射剂,即,具有小于治疗靶点(如皮肤)的温度的沸点的挥发性液体。后发泡喷射剂的实例为异戊烷(bp=26℃)。
在实施方案中,除喷射剂以外的组合物与喷射剂的比为约100∶1至约100∶25之间,或约100∶3至约100∶30之间,或约100∶5至约100∶20之间或约100∶8至约100∶16之间,或约100∶20至约100∶50之间。
在一个或多个实施方案中,通过使用例如阀上袋(a bag onvalve,BOV)或罐式气溶胶系统中的罐,用与制剂分离的喷射剂可消除或有助于消除泡沫制剂。BOV系统由气溶胶阀和焊接袋组成。使用BOV系统,将压缩气体或其他喷射剂引入至袋外部的气溶胶罐,并充当袋内部产品的喷射剂。使用此系统使其可以减少制剂中喷射剂的量,但仍能够从具有期望质量的泡沫的容器中排出。所以借助实施例,袋中的喷射剂的浓度在约1%至3%之间;或在约2%至4%之间;在约3%至5%之间(制剂与喷射剂的比分别为100∶1至100∶3;100∶2至100∶4;100∶3至5)。
泡沫性质
根据本文一个或多个实施方案制造的发泡组合物非常易于使用。当应用到哺乳动物(即,人类或动物)的疼痛体表时,发泡组合物为泡沫状态,允许自由施用而不溢出。在进一步施加机械力后,例如,通过在体表上摩擦组合物,其在表面自由扩散并快速吸收。
在一个或多个实施方案中,发泡组合物为单一相溶液。在一个或多个实施方案中,发泡组合物基本上为单一向溶液。在某些情况中,活性剂为不溶且作为均质悬浮液存在时,制剂是浑浊(turbid)或混浊的(cloudy)。
在一个或多个实施方案中,泡沫组合物在环境温度下具有至少一年、或至少两年的可接受的保存期限。化妆品或医药用途的产品特性为长期稳定性。喷射剂(其为低分子量烃或HFC的混合物)倾向于损害稳定性。本文的发泡组合物令人惊讶地甚至在不存在表面活性剂下稳定。随着加速的稳定性研究,它们证实期望的结构;它们形成在与表面接触时不会立即破碎的微小气泡结构。它们易于在治疗面上扩散并快速吸收。
所述组合物还应自由流动,允许其流过容器,例如气溶胶容器的口,并产生可接受的泡沫。包含大量半固体疏水油,例如白矿脂,作为乳液油相的主要成分的组合物,将可以显示高粘度和弱流动性,并可为发泡组合物的不适合的候选。因此,在一个或多个实施方案中,半固体疏水油为组合物的辅助组分,例如为小于发泡组合物的约25重量%、小于约20重量%、小于约15重量%、小于约10重量%、小于约5重量%存在。在其他实施方案中,由于喷射剂的溶剂作用使制剂稀释并能够流动,或者在制剂作为凝胶或软膏而存在时,或者当添加溶剂如苯甲酸烷基酯以减少粘度时,它们可以较高的量存在。
泡沫质量
泡沫质量可如下分级:
E级(优):外观非常丰富和乳脂状,不显示任何气泡结构或显示非常细微(微小)的气泡结构;不快速变弱(dull);在皮肤上扩散时,泡沫保留乳脂性,看上去并不湿。
G级(良好):外观丰富和乳脂状,非常小的气泡大小,比优的泡沫更快地“变弱”,在皮肤上扩散时泡沫保留乳脂性,不变湿。
FG级(一般好):可见适度量乳脂,可见气泡结构;在皮肤上扩散时产品迅速变弱,并且外观粘度变得有点低。
F级(一般):可见非常少的乳脂,比“一般好”的泡沫大的气泡结构,在皮肤上扩散时外观变薄变湿。
P级(差):未见乳脂,大气泡结构,当在皮肤上扩散时外观变得非常薄且湿。
VP级(非常差):干燥泡沫,大的非常弱的气泡,难以在皮肤上扩散。
当从气溶胶容器释放时,可局部施用的泡沫典型地为E或G级质量。较小的气泡说明泡沫更稳定,其在从容器放出时不立即自发塌缩。较细的泡沫结构看上去和感觉上更光滑,因而增加了其可用性和吸引力。
泡沫密度
泡沫的另一性质为当从气溶胶罐释放时测量的比重或密度。典型地,泡沫具有小于0.5g/mL;或小于0.3g/mL;或小于0.2g/mL;或小于0.1g/mL的比重,根据它们的组成以及喷射剂的浓度。在一个或多个实施方案中,泡沫密度约小于0.3g/mL。
摇动性
“摇动性”是指组合物包含一定或足够的流动性从而允许组合物在摇动时混合或重新混合。即,其具有流体或半流体性质。在试验部分进一步描述摇动性。在一个或多个特定限制的实施方案中,制剂摇动性较差,但仍然是可流动的。
易碎性/塌缩时间(collapse time)
泡沫的另外方面为易碎性。从容器中产生的泡沫的稳定性与易碎性之间的平衡非常微妙:一方面泡沫应优选不“快速破碎”,即,其从加压容器中释放时应为稳定的并且作为暴露于皮肤温度的结果不破碎;另一方面,其应为“易碎的”,即,在施加温和剪切力时其应易于扩散、分解并吸收至皮肤或膜中。易碎泡沫是热稳定的,但在剪切力下破碎。泡沫的剪切力易碎性相对于热诱导的易碎性是明显的优点。热敏泡沫可在暴露于皮肤温度时立即开始塌缩,因此不能施用到手上及随后再递送至疼痛部位。
泡沫的塌缩时间表示其温敏趋向性及其至少在短期内稳定的能力,从而允许使用者有足够的时间来将泡沫处理和施用于靶区域,而无需匆忙地或担心其可能快速塌缩、液化或消失,作为热敏性指标的塌缩时间通过分散给定量的泡沫并连续拍摄其在36℃下的温育期间随时间的外观来测定。可通过在约37℃的正常体温下在体表如手指上施用泡沫样品来测量简单塌缩时间(Simple collapse time)。
油可引起泡沫不耐热并“快速破碎”。然而,在本文的某些实施方案中,尽管存在高油含量,但相当意外地,泡沫基本上是热稳定的。“基本上热稳定”是指在约35至37℃下施用到温热皮肤或体表时泡沫在约30秒内不塌缩。因此,在一个或多个实施方案中,泡沫的简单塌缩时间大于约30秒或大于约1分钟或大于约两分钟。在一个或多个限制的实施方案中,简单塌缩时间可为稍小于30秒,但不小于约20秒。在一个或另外或任选的实施方案中,通过将泡沫样品引入36℃下的温育器来测量塌缩时间,泡沫的塌缩时间大于30秒或大于约1分钟或大于约两分钟。
水活性(water activity)
本文所使用的术语“水活性”,活性表示物质的吸湿性;或物质从其周围吸收水分的趋向性。微生物需要水分来生长和繁殖,此类水需求是物质水活性方面最好的定义。溶液的水活性表示为Aw=P/Po,其中P为溶液的水蒸汽压,Po为相同温度下纯水的蒸汽压。每个微生物具有限定的Aw,在其以下将不会生长;例如,对于链球菌(Streptococci)、克雷伯氏杆菌属物种(Klebsiella spp)、大肠杆菌(Escherichia coli)、产气夹膜梭杆菌(Clostridium perfringens)和假单胞菌属物种(Pseudomonas spp),Aw值为0.95。金黄色葡萄球菌(Staphylococcus aureus)为最具耐性的,可在Aw低至0.86下繁殖,真菌可在Aw至少0.7下存活。在一个或多个实施方案中,凝胶和泡沫组合物中疏水油浓度足以提供选自(1)约0.8至约0.9;(2)约0.7至约0.8;和(3)小于约0.7的范围内的Aw值。通过在加压包装中递送制剂不允许被制剂所吸收的湿度,因此,不能破坏组合物的无水特性。
四环素
根据本发明首要的活性剂为四环素化合物(本文中为“四环素”或“四环素类”)或在碱中基本上稳定的其药物学可接受盐或水合物。四环素类的特征在于由四个线性融合的六元碳环组成的碳骨架(八氢并四苯-2-羧酰胺骨架)。它们被定义为“具有八氢并四苯-2-羧酰胺骨架的聚酮的亚类”。它们统称为“多环并四苯羧酰胺”。
四环素的非限制性实例包括天然产生的四环素、氯四环(Chlortetracycline)、土霉素和去甲金霉素、半合成强力霉素、赖氨甲四环素、甲基氯环素、甲烯土霉素、二甲胺四环素、吡甲四环素、金霉素和替加四环素。
四环素可以以游离碱形式、水合物形式、盐形式或配合物形式存在。例如,二甲胺四环素可以以碱形式,以及水合物或盐酸盐而存在。
显而易见地,各种四环素类具有不同的亲水/疏水特性。例如,Log Kp(pH7.0下的分布常数的Log;缓冲液/CHCl3)为1.91,是指其为高度亲水的。强力霉素的Log Kp为0.2;二甲胺四环素的Log Kp为-1.6,这表示该化合物的疏水特性(参见Leive L等人,“Tetracyclines of various hydrophobicities as a probe forpermeability of Escherichia coli outer membrane”,AntimicrobialAgents and Chemotherapy 1984:25,539-544)。在任何四环素化合物适合作为根据本发明的活性剂的同时,优选更加疏水的四环素化合物。因此,在本发明的实施方案中,选择具有Log Kp等于或小于约0.2的活性剂。
在实施方案中,由于在碳5、6和7位不包括任何羟基的事实,四环素抗生素为疏水的。
在某些实施方案中,四环素选自由强力霉素和二甲胺四环素组成的组;在某些实施方案中,四环素为二甲胺四环素。
根据本发明,四环素基于发泡组合物的重量以约0.001%至约10%范围内的量;或以约0.025%至约6%范围内的量;或以约0.1%至约3%范围内的量使用。
根据本发明的四环素不溶或部分可溶于全部组合物中,其全部或部分悬浮。已知每一化学化合物在不同溶剂或组合物中具有不同的溶解度,因此不可能提供不溶或部分可溶或悬浮在组合物中的化合物的总清单。然而,如本文所例举的,任何四环素活性剂作为如果视觉或显微镜观察显示油质组合物中此类活性剂的晶体或颗粒的不溶或部分可溶或悬浮的都是适合的。
在另外的实施方案中,四环素的浓度由其抑制离体(ex-vivo)人类皮肤模型中调亡发生的能力所确定;或由其抑制离体人类皮肤模型中促炎性细胞因子的产生的能力所确定。在可选的实施方案中,当使用人类或猪的皮肤在弗朗茨细胞的体外模型中试验时,四环素的浓度高于产生皮内递送的足够浓度四环素的最低浓度。
疏水油
术语“疏水油”涉及在环境温度下在蒸馏水中具有每100mL小于约1gm、或每100mL小于约0.5gm、或每100mL小于约0.1gm的溶解度的材料。疏水油在环境温度(室温)下,例如约20至30℃为液体。
在实施方案中,局部治疗的组合物包括至少一种疏水油,所述疏水油选自由矿物油、烃油、酯油、甘油三酯油、植物来源的油、动物来源的油、不饱和或多不饱和油、甘油二酯、PPG烷基醚、和硅油组成的组。
如本文所例举的,已发现,以上列出疏水油的组的每一组分均与疏水四环素,如二甲胺四环素和强力霉素相容。
烃油的非限制性实例包括矿物油、液体石蜡、异链烷烃、聚α烯烃、聚烯烃、聚异丁烯、合成异烷烃、异十六烷和异十二烷。
酯油的非限制性实例包括苯甲酸烷基酯、辛酸烷基酯、苯甲酸C12-C15烷基酯、辛酸C12-C15烷基酯、山嵛酸二十烷酯、丙酸二十烷酯、月桂酸苄酯、肉豆蔻酸苄酯、棕榈酸苄酯、双(辛基十二烷基硬脂酰)二聚二亚油酸酯、肉豆蔻酸丁酯、硬脂酸丁酯、鲸蜡硬脂醇乙基己酸酯、鲸蜡硬脂醇异壬酸酯、乙酸十六烷酯、乙基己酸十六烷酯、乳酸十六烷酯、肉豆蔻酸十六烷酯、辛酸十六烷酯、棕榈酸十六烷酯、蓖麻酸十六烷酯、油酸癸酯、二甘醇二乙基己酸酯、二甘醇二辛酸酯、二甘醇二异壬酸酯、二甘醇二异壬酸酯、二乙基己酸酯、己二酸二乙基己酯、苹果酸二乙基己酯、琥珀酸二乙基己酯、己二酸二异丙酯、二聚酸二异丙酯、癸二酸二异丙酯、二异硬脂醇二聚二亚油酸酯、二异硬脂醇富马酸酯、苹果酸二辛酯、癸二酸二辛酯、油酸十二烷基酯、棕榈酸乙基己基酯、羊毛脂酸的酯衍生物、椰油酸乙基己酯、乙基己酸乙基己酯、羟基硬脂酸乙基己酯、异壬酸乙基己酯、棕榈酸乙基己酯、壬酸乙基己酯、硬脂酸乙基己酯、硬脂酸十六烷基酯、月桂酸己酯、月桂酸异戊酯、异十六烷基山嵛酸异十六烷基酯、羊毛脂酸异十六烷基酯、棕榈酸异十六烷基酯、硬脂酸异十六烷基酯、水杨酸异十六烷基酯、硬脂酸异十六烷基酯、硬脂酰硬脂酸异十六烷基酯、辛酸异十六烷基十八烷基酯(isocetearyl octanoate)、乙基己酸异癸酯、异壬酸异癸酯、油酸异癸酯、异壬酸异壬酯、油酸异癸酯、癸酸异己酯、辛酸异壬酯、异硬脂酸异丙酯、羊毛脂酸异丙酯(isopropyllanolate)、月桂酸异丙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、硬脂酸异丙酯、山嵛酸异十八烷基酯、柠檬酸异十八烷基酯、芥酸异十八烷基酯(isostearyl erucate)、甘醇酸异十八烷基酯、异壬酸异十八烷基酯、异硬脂酸异十八烷基酯、乳酸异十八烷基酯、亚油酸异十八烷基酯、亚麻酸异十八烷基酯、苹果酸异十八烷基脂、新戊酸异十八烷基酯、棕榈酸异十八烷基酯、水杨酸异十八烷基酯、酒石酸异十八烷基酯、异壬酸异十三烷基酯、异壬酸异十三烷基酯、乳酸月桂酯、乳酸肉豆蔻酯、肉豆蔻酸肉豆蔻酯、新戊酸肉豆蔻酯、丙酸肉豆蔻酯、肉豆蔻酸辛基十二醇酯、新戊二醇二癸酸酯、辛基十二醇、硬脂酸辛酯、棕榈酸辛酯、山嵛酸辛基十二醇酯、羟基硬脂酸辛基十二醇酯、肉豆蔻酸辛基十二醇酯、硬脂酰硬脂酸辛基十二醇酯、油基芥酸酯(oleyl erucate)、油基乳酸酯、油基油酸酯、肉豆蔻酸丙酯、丙二醇单肉豆蔻醚乙酸酯、丙二醇二癸酸酯、丙二醇二辛酸酯、丙二醇二辛酸酯、马来酸化大豆油、癸酸十八烷基酯、庚酸十八烷基酯、丙酸十八烷基酯、乙酸生育酚酯(tocopheryl acetate)、亚油酸生育酚酯、油酸甘油酯、乙基己酸十三烷基酯、异壬酸十三烷基酯、柠檬酸三异十六烷基酯。
甘油三酯和植物来源的油的非限制性实例包括亚历山大月桂树油、鳄梨油、杏子油(apricot stone oil)、大麦油、琉璃苣籽油、金盏花油、金盏花坚果树油、芥花油、辛酸/癸酸甘油三酯蓖麻油、椰子油、玉米油、棉油、棉籽油、月见草油、亚麻油、花生油、榛子油、甘油聚醚三乙酸酯(glycereth triacetate)、甘油三庚酸酯、甘油三辛酸酯、十一酸甘油三酯(glyceryltriundecanoate)、大麻籽油、荷荷巴油、苜蓿油、玉米胚油、髓油(marrow oil)、小米油、新戊二醇二辛酸酯/二癸酸酯、橄榄油、棕榈油、西番莲油、季戊四醇四硬脂酸酯、罂粟油、蓖麻酸丙二醇酯、菜籽油、黑麦油、红花油、芝麻油、牛油树脂、豆油(soya oil)、大豆油、甜杏仁油、葵花油、蒜芥油、丁香油、茶树油、核桃油、小麦胚甘油酯、小麦胚油。
PPG烷基醚的非限制性实例包括PPG-2丁醚、PPG-4丁醚、PPG-5丁醚、PPG-9丁醚、PPG-12丁醚、PPG-14丁醚、PPG-15丁醚、PPG-15十八烷基醚、PPG-16丁醚、PPG-17丁醚、PPG-18丁醚、PPG-20丁醚、PPG-22丁醚、PPG-24丁醚、PPG-26丁醚、PPG-30丁醚、PPG-33丁醚、PPG-40丁醚、PPG-52丁醚、PPG-53丁醚、PPG-10十六烷基醚、PPG-28十六烷基醚、PPG-30十六烷基醚、PPG-50十六烷基醚、PPG-30异十六烷基醚、PPG-4月桂醚、PPG-7月桂醚、PPG-2甲醚、PPG-3甲醚、PPG-3肉豆蔻醚、PPG-4肉豆蔻醚、PPG-10油基醚、PPG-20油基醚、PPG-23油基醚、PPG-30油基醚、PPG-37油基醚、PPG-40丁醚、PPG-50油基醚、PPG-11十八烷基醚。根据本发明的优选的PPG烷基醚包括PPG-15十八烷基醚、PPG-2丁基醚和PPG-9-13丁基醚。
动物来源的油的非限制性实例包括鲱鱼油、鳕鱼肝油和鲑鱼油。
硅油的非限制性实例包括环甲基硅酮、二甲基聚硅氧烷、聚二甲基硅氧烷、环氧改性的硅油、脂肪酸改性的硅油、氟基改性的硅油、甲基苯基聚硅氧烷、苯基聚三甲基硅氧烷和聚醚基改性的硅油。
粘度改性剂
本发明的背景下的粘度改性剂为当添加到疏水油时促进以易碎油凝胶或易碎油泡沫形式的疏水易碎载体的产生的试剂。术语“易碎”是指油凝胶或泡沫的独特性质,其中所述油凝胶或泡沫在从容器分散时是稳定的,但在施加温和剪切力时易于破碎和扩散。
至少一种粘度改性剂选自由脂肪醇、脂肪酸和蜡组成的组,其中所述脂肪醇和/或脂肪酸在它们的碳骨架中具有至少12个碳原子。
脂肪醇和脂肪酸
优选地,脂肪醇和/或脂肪酸和/或蜡在环境温度下为固体。在某些实施方案中,脂肪醇和/或脂肪酸和/或蜡或其混合物具有大于约40℃的熔点。
在本发明的实施方案中,脂肪醇选自由月桂醇、十四烷醇、十六烷醇、十八烷醇、二十烷醇、二十二烷醇、二十四烷醇、二十六烷醇、二十八烷醇、三十烷醇、三十四烷醇组成的组。在本发明的实施方案中,脂肪酸选自由十二烷酸、十四烷酸、十六烷酸、十七烷酸、十八烷酸、二十烷酸、二十二烷酸、二十四烷酸、二十六烷酸、二十七烷酸、二十八烷酸、三十烷酸、三十二烷酸、三十三烷酸、三十四烷酸和三十五烷酸组成的组。
在某些实施方案中,所述脂肪醇或所述脂肪酸的碳链被羟基取代;在另外的实施方案中,所述脂肪酸为12-羟基硬脂酸。
蜡
可用作部分粘度改性剂的蜡包括植物蜡(plant wax),如巴西棕榈蜡、小烛树蜡、小冠巴西棕榈蜡、甘蔗蜡、藤蔓蜡和荷荷巴油;动物蜡,如蜂蜡;石油衍生蜡,包括作为饱和正和异烷烃、环烷烃以及烷基-和环烷烃基-取代的芳族化合物的混合物的固体石蜡;和聚乙烯及相关衍生物。
在实施方案中,蜡选自由以下组成的组:蔬菜蜡(vegetablewax)、蜂蜡、中国蜡、棉花蜡、杨梅蜡(bayberry wax)、小烛树蜡、巴西棕榈蜡、蓖麻蜡、古巴棕榈蜡、梧牙草蜡、杉木蜡(firwax)、亚麻蜡、花蜡、脂肪蜡、日本蜡、砂蜡(sandy wax)、羊毛脂蜡、小冠巴西棕榈蜡、棕榈蜡、米糠蜡、米油蜡、紫胶蜡、豆蜡(soy wax)、甘蔗蜡、肉豆蔻蜡(ucuhuba wax)、氢化油、氢化蓖麻油、氢化棉籽油或氢化荷荷巴油、貂蜡、褐煤蜡、地蜡、PEG-6蜂蜡、瑞佐(rezo)蜡、废麦芽粕蜡(spent grain wax)、硬脂基二甲基硅氧烷、固体石蜡、石蜡58-62℃蜡、石蜡51-53℃蜡、石蜡42-44℃蜡、合成矿蜡、费-托蜡、多洛克森(duroxon)蜡或聚麦克恩(polymekon)蜡、合成蜡、阿尔巴瑟(albacer)蜡、艾特兰西(atlasene)蜡、BASF蜡、卡迪斯(cardis)蜡、神经酰胺(ceramid)、糖蜡(glycol wax)、柔印蜡(flexo wax)或噁唑啉蜡以及如“The Complete Technology Book on Wax and Polishes,Publisher:Asia Pacific Business Press Inc.,2006”中所述的其他蜡。
脂肪醇、脂肪酸和蜡的混合物
应理解,需要至少一种粘度改性剂,但预期大于一种粘度改性剂的组合。在某些实施方案中,优选两种粘度改性剂的组合。在某些实施方案中,粘度改性剂组合包含至少一种脂肪醇和至少一种脂肪酸;或至少一种脂肪醇和至少一种蜡;或至少一种脂肪酸和至少一种蜡;或至少一种脂肪醇、至少一种脂肪酸和至少一种蜡。
在一个或多个实施方案中,脂肪醇与脂肪酸之比或脂肪醇与蜡之比的范围为约100∶1至约1∶100;或约90∶1至约1∶45;或约80∶1至约1∶40;或约70∶1至约1∶35;或约60∶1至约1∶30;或约50∶1至约1∶25;或约40∶1至约1∶20;或约30∶1至约1∶15;或约20∶1至约1∶10;或约15∶1至约1∶5;或约10∶1至约1∶1;或在如1∶20至20∶1或优选从1∶10至10∶1、或1∶4至4∶1、或2∶3或3∶2之间的任何范围。
在某些实施方案中,粘度改性剂的总浓度可为约0.1重量%至约40重量%;或约0.4重量%至约18重量%;或约1重量%至约12重量%。
在某些其他实施方案中,组合物包括来自两种类型的粘度改性剂(例如,至少一种脂肪醇和至少一种脂肪酸;或至少一种脂肪醇和至少一种蜡;或至少一种脂肪酸和至少一种蜡);各类的浓度分别在以下任一范围内:(i)约0.1%和约1%之间、(ii)约1%和约5%之间、(iii)约5%和约10%之间或(iv)约10%和约20%之间。
另外的活性剂
由于可用四环素治疗的病症通常与另外的病症,如由其他微生物(除细菌以外)引起的炎症和感染相关,所以适用于下述紊乱或基本上在同一患者中发生的其他紊乱的治疗的四环素和另外的活性剂的组合对于患者病症的同时治疗是有用的。
适合的活性剂包括但不限于活性草本提取物、杀螨剂(acaricides)、老年斑和角质去除剂、过敏原、α-羟基酸、镇痛剂、雄性激素、抗痤疮剂、抗过敏剂、抗衰老剂、抗菌剂、抗生素、抗灼烧剂(antiburn agent)、抗癌剂、去屑剂、抗抑郁剂、抗皮炎剂、消水肿剂、抗真菌剂(antifungal agent)、抗组胺剂、抗蠕虫剂(antihelminth)、抗角化过度剂、抗感染剂、抗炎剂、抗刺激剂、降血脂剂、抗微生物剂、抗霉菌剂、抗氧化剂、抗寄生虫剂、抗增殖剂、止痒剂、抗银屑病剂、抗红斑痤疮剂、抗皮脂溢剂、防腐剂、防膨胀剂、抗病毒剂、抗疣剂、抗皱剂、抗酵母剂、收敛剂、β-羟基酸、过氧化苯甲酰、局部心血管剂、化疗剂、皮质类固醇、免疫原性物质、二羧酸、消毒剂、雌性激素、杀真菌剂(fungicide)、头发生长调节剂、半抗原、激素、羟基酸、免疫抑制剂、免疫调节剂(immunoregulating agent)、免疫调制剂(immunomodulator)、免疫刺激剂、杀虫剂、驱虫剂、角质软化剂、内酰胺、局部麻醉剂、润滑剂、遮蔽剂、金属、金属氧化物、杀恙虫药(mitocide)、神经肽、非甾族抗炎剂、氧化剂、灭虱剂、肽、农药、蛋白质、光动力治疗剂、黄体酮、游离基清除剂、加脂剂(refatting agent)、类视黄醇、治愈剂(sanative)、灭疥疮剂、镇静剂、美黑剂、皮肤防护剂、皮肤增白剂、类固醇、类固醇激素、血管活化剂、血管收缩剂、血管扩张剂、维生素、维生素A、维生素A衍生物、维生素B、维生素B衍生物、维生素C、维生素C衍生物、维生素D、维生素D衍生物、维生素D类似物、维生素F、维生素F衍生物、维生素K、维生素K衍生物、伤口愈合剂和疣去除剂。
不相容的赋形剂和不期望的赋形剂
在某些实施方案中,组合物无矿脂、表面活性剂、质子溶剂、某些极性非质子溶剂和硅酮增稠剂;在某些实施方案中,发泡组合物基本上无此类赋形剂。在本文的背景下,术语“基本上无”指组合物包含的矿脂、表面活性剂、质子溶剂、某些极性非质子溶剂和硅酮增稠剂的累积总量小于约0.4%。优选地,所述组合物包括的矿脂、表面活性剂、质子溶剂、某些极性非质子溶剂和硅酮增稠剂累积小于约0.2重量%,更优选小于约0.1%。
表面活性剂
已将表面活性剂依据其离子特性分成各种亚类,即,非离子表面活性剂、阴离子、阳离子、两性离子、酸碱两性(amphoteric)和两亲表面活性剂。根据本发明,所有种类的表面活性剂都是不期望的,因为(i)发现它们引起四环素抗生素的降解;和(ii)已知它们通常拥有刺激潜能。
根据本发明不期望的非离子表面活性剂类型的非限制性实例包括:(i)聚氧乙烯脱水山梨糖醇酯(聚山梨醇酯),如聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60和聚山梨醇酯80;(ii)脱水山梨糖醇酯,如脱水山梨糖醇单月桂酸酯和脱水山梨糖醇单油酸酯;(iii)聚氧乙烯脂肪酸酯,如PEG-8硬脂酸酯、PEG-20硬脂酸酯、PEG-40硬脂酸酯、PEG-100硬脂酸酯、PEG-150双硬脂酸酯、PEG-8月桂酸酯、PEG-10月桂酸酯、PEG-12月桂酸酯、PEG-20月桂酸酯、PEG-8油酸酯、PEG-9油酸酯、PEG-10油酸酯、PEG-12油酸酯、PEG-15油酸酯和PEG-20油酸酯;(iv)PEG-脂肪酸二酯;(v)脂肪醇的聚乙二醇(PEG)醚;(vi)甘油酯,如单硬脂酸甘油酯、单月桂酸甘油酯、单棕榈酸甘油酯和单油酸甘油酯;(vii)PEG-脂肪酸单和二酯混合物;(viii)聚乙二醇脂肪酸酯;(ix)丙二醇脂肪酸酯;(x)单和二甘油酯;(xi)蔗糖酯(蔗糖与脂肪酸的单酯、二酯和三酯)和(xii)聚乙二醇烷基酚。
在另外的实施方案中,术语“基本上无表面活性剂”指其中粘度改性剂和表面活性剂之比为10∶1或5∶1之间;或20∶1和10∶1之间或100∶1和20∶1之间的组合物。
在本发明的背景下,当脂肪醇、脂肪酸和某些蜡为两亲性时,这些物质在发泡乳液组合物中作为独立表面活性剂不是有效的,这是由于它们的乳化能力非常弱并进一步由于它们本身的发泡能力弱。因此,构成本发明的粘度改性剂的脂肪醇、脂肪酸和某些蜡是不期望的。
质子溶剂
质子溶剂,如短链醇、二醇类和甘油与四环素类不相容,因而它们是不期望的。
非质子极性溶剂
我们发现,某些极性非质子溶剂与四环素抗生素类不相容。因此,非质子极性溶剂,如二甲基亚砜(DMSO)、二甲基甲酰胺(DMF)、乙腈、丙酮、甲基乙基酮、1,4-二噁烷和四氢呋喃(THF)、N-甲基吡咯烷酮、吡啶、哌啶、二甲基甲酰胺、N-甲基-2-吡咯烷酮和1-甲基-2-吡咯烷酮和氮酮(1-十二烷基氮杂环庚烷-2-酮)是不期望的。
硅酮增稠剂
硅酮增稠剂包括一种或多种聚硅氧烷衍生组分。此类聚硅氧烷典型地交联,并具有类橡胶特性,需要它们在油中,通常在硅油中可溶解。此类硅酮增稠剂的实例为ST-Elastomer10(Dow Corning),其为高分子量二甲基硅氧烷交联聚合物(12%)在环戊硅氧烷(环甲基硅酮、硅酮溶剂)中的混合物。关于活性剂在局部施用后的皮肤中的生物利用度,可想象到交联共聚物将产生会阻塞皮肤渗透的不渗透膜,因而是不期望的。此外,在易碎泡沫的背景下,已知环甲基硅酮为消泡剂,因而其以高浓度在易碎疏水组合物中存在是不期望的。
在一个或多个其他具体实施方案中,将药物载体配制为基本上无弹性体。在一个或多个其他具体实施方案中,将药物载体配制为实质上无弹性体。在一个或多个其他具体实施方案中,将药物载体配制为基本上无硅酮。在一个或多个其他具体实施方案中,将药物载体配制为实质上无硅酮。在一个或多个其他具体实施方案中,药物载体配制有小于约30%的硅酮、或小于约25%的硅酮、或小于约20%的硅酮、或小于约15%的硅酮、或小于约10%的硅酮、或小于约7.5%的硅酮、或小于约5%的硅酮、或小于约2%的硅酮、或小于约1%的硅酮、或小于约0.5%的硅酮。
矿脂
矿脂,也称为“凡士林”,由于其油腻性质因而可能是不利的。已知在施用后其留下油腻和粘腻的感觉并且偶然沾污衣服。因此,根据本发明,白矿脂及其他半固体油不是优选的疏水油。此外,含有大量半固体疏水油,例如白矿脂,作为乳液油相的主要成分的组合物将可能显示高粘度和弱流动性,可为发泡组合物不适当的候选。因此在一个或多个实施方案中,半固体疏水油为组合物中的辅助组分,例如以小于疏水性易碎性的组合物的约25重量%、小于约20重量%、小于约15重量%、小于约10重量%、小于约5重量%存在。在其他实施方案中,已制备含有大于50%的矿脂的制剂,其产生优质的泡沫,塌缩时间超过3分钟。
皮肤渗透
令人惊讶的是,尽管四环素类(特别是二甲胺四环素)在中性pH下为疏水是事实,但它们甚至在0.05%的浓度下也不溶于疏水油。所以,出现了在任何大于0.1%的浓度时多数四环素悬浮而不是溶解。尽管直观地期望局部施用后药物在皮肤中的生物利用度低,但如体外经皮试验所示,施用后的皮肤中发现大量四环素。施用包括1%二甲胺四环素和4%二甲胺四环素的疏水性易碎性的组合物24小时后的皮肤中所发现的量分别为9.49和43.12μg/cm2。给药区(delivery area)的皮肤的重量约为100mg,这意味着暴露24小时后皮肤中二甲胺四环素的浓度对于1%制剂约为皮肤的90μg/gr,对于4%制剂约为430μg/gr。根据文献,对于二甲胺四环素的最小抑制浓度(MIC)为小于4μg/mL,因此,可总结为,皮肤中所发现的浓度是充分的,或者甚至高于治疗细菌皮肤感染所需的浓度。
甚至更令人惊讶地是,虽然四环素很好地渗透入皮肤,但四环素不透过皮肤。这是本发明的组合物非常重要的特征,因为在进行局部施用时其使全身副反应的可能性最小化。在一个或多个实施方案中,不存在或存在可忽略的经皮递送。在一个或多个实施方案中,皮肤内与经皮递送的比为约或大于100∶1。
这意味着目前二甲胺四环素的疏水载体在药物皮内,而不是经皮靶向递送中是独特的。
在实施方案中,当在使用人类或猪的皮肤的弗朗茨细胞体外模型中试验时,疏水性易碎性的组合物中四环素的浓度高于杀灭皮肤细菌如葡萄球菌属(staphylococcus)和链球菌属(streptococcus)菌株所需的四环素的最低皮内浓度。
因此,在实施方案中,其中当在使用人类或猪的皮肤的弗朗茨细胞体外模型中试验时,所述组合物提供高于经皮递送的相对量的皮肤内四环素的量。在某些实施方案中,当在使用人类或猪的皮肤的弗朗茨细胞体外模型中试验时,皮肤中四环素的量与经皮递送的相对量之间的比高于约100;或在100和10之间;或在10和2之间;或者大于1。
抗菌作用
体外研究揭示包括1%二甲胺四环素和4%二甲胺四环素的疏水性易碎性的组合物抑制化脓性链球菌(streptococcuspyogenes)、绿脓假单胞杆菌(pseudomonas aeruginosa)、金黄色葡萄球菌(staphylococcus aureus),以及金黄色葡萄球菌的耐二甲氧基苯青霉素(methicillin)菌株(MRSA)的生长。所述制剂还对抗痤疮中的病原微生物(causative microorganism),痤疮丙酸杆菌(propionbacterium acnes)有效。
该结果是预料之外的,由于二甲胺四环素主要悬浮在组合物中,因此使其预期的抗菌作用的利用度最小化。
包括四环素的组合物的抗炎和抗凋亡作用
当炎症诱发后治疗时该二甲胺四环素的效果是令人惊讶的,如文献所教导的,“用二甲胺四环素预治疗,而非治疗后,显著减弱单一神经病变大鼠中增加的促炎性细胞因子释放以及氧化和氮化应激(pre-treatment,but not post-treatment,withminocycline markedly attenuated increased pro-inflammatorycytokines release and oxidative and nitrosative stress inmononeuropathic rats)。”(参见,例如Padi SS,Kulkarni SK,“Minocycline prevents the development of neuropathic pain,butnot acute pain:possible anti-inflammatory and antioxidantmechanisms”,Eur J Pharmacol.2008;601:79-87)。相比之下,当二甲基四环素包含在本发明的疏水性易碎性的组合物中并施用于UV损伤诱导后的皮肤样品时,通过测量半胱天冬酶(caspase)3活性,其显著降低凋亡;并提升皮肤细胞活力。
在实施方案中,通过在离体人皮肤模型中四环素抑制凋亡发生的能力;或通过其降低半胱天冬酶3活性的能力或通过其降低促炎性细胞因子的发生的能力来确定四环素的浓度。
应用领域
本公开的疏水易碎四环素凝胶和泡沫组合物适用于治疗任何损伤表面。在一个或多个实施方案中,发泡载体适用于对皮肤、体表、体腔或粘膜表面给药,例如鼻、口、眼、呼吸系统、阴道、尿道或直肠的腔和/或粘膜以及耳道(本文各自可互换地定义为“靶点”)。
基于四环素的抗菌性质,加上特定四环素化合物(如二甲胺四环素和强力霉素)的抗炎、抗氧化和神经保护作用可预期许多病症。
通过选择适合的四环素化合物,或四环素与至少一种另外的活性剂的组合,本公开的组合物在治疗具有各种皮肤科紊乱之一的动物或人类患者中是有用的,所述紊乱包括,但不限于此处以字母排列方式提供的列表:脓肿,痤疮、聚合性痤疮、暴发性痤疮、寻常痤疮、痤疮疤痕、急性发热性嗜中性白细胞皮肤病、急性淋巴管炎、变应性接触性皮炎、秃头症、足癣、特应性皮炎、细菌性皮肤感染、脱发、基底细胞癌、水疱、腋臭、大疱性类天疱疮、灼伤、胼胝念珠菌病、痈、蜂窝组织炎、化学灼伤、水痘、胆脂瘤、胆碱能性荨麻疹、日光的慢性效应、唇疱疹、寒冷性荨麻疹、粉刺、鸡眼、匐行疹、皮肤脓疮、皮肤幼虫移行症、肤蛆病、黑斑、寄生虫妄想症、痛性脂肪病、皮炎、疱疹样皮炎、皮肤疼痛、皮肤炎症、皮肤划痕现象、皮肤真菌病、药疹和药物反应、汗疱、外胚层发育不良、湿疹、深脓疱、表皮囊肿、表皮坏死、丹毒、丹毒、红斑、剥落性皮炎、多形性红斑、结节性红斑、毛囊炎、真菌指甲感染、真菌皮肤感染、疖、坏疽、生殖器疱疹、环状肉芽肿、头虱、化脓性汗腺炎、荨麻疹、毛囊炎、多毛症、多汗症、少汗症、鱼鳞癣、脓疱病、炎性痤疮、嵌甲、擦烂、刺激性接触性皮炎、缺血性坏死、瘙痒、股癣、卡波西肉瘤、毛发角化病、慢性单纯性苔癣、扁平苔癣、硬化性苔癣、淋巴结炎、淋巴结炎、淋巴管炎、恶性黑色素瘤、肥大细胞增多症、麻疹、黑色素瘤、黑色素瘤、汗疹、痣、触染性软疣、MRSA、坏死性皮下感染、坏死性筋膜炎、坏死性肌炎、结节状丘疹脓疱型粉刺、非炎性粉刺、钱币状皮炎、口腔疱疹、脂膜炎、类银屑病、甲沟炎、寄生性皮肤感染、天疱疮、光过敏、光损伤、光刺激、光敏感、丘疹、虱病、口周皮炎、面疱、玫瑰糠疹、苔癣样糠疹、玫瑰糠疹、毛发红糠疹、接触毒漆引起的皮疹、术后或外科术后皮肤病、压迫性溃疡、压迫性荨麻疹、瘙痒症、须部假性毛囊炎、牛皮癣、PUPPP、紫癜、脓疱、脓性肉芽肿、疹、癣菌病、红斑痤疮、玫瑰疹、风疹、疥疮、皮肤烫伤综合征、伤疤、硬皮病、皮脂囊肿、脂溢性皮炎、脂溢性角化病、带状疱疹、皮肤老化、皮肤癌、皮肤瘤、皮肤赘生物、皮疹、皮肤溃疡、鳞状细胞癌、金黄色葡萄球菌烫伤样皮肤综合征、停滞性皮炎、史蒂文斯-约翰逊综合征、晒伤、太阳斑、热灼伤、体癣、股癣、脚癣、花斑癣、中毒性表皮坏死松解症、皮肤外伤或损伤、水痘带状疱疹病毒、维生素D缺乏、病毒性皮肤感染、白癜风、疣、水性荨麻疹、皱纹、干燥症、酵母皮肤感染和带状疱疹。
同样地,本公开的凝胶或泡沫组合物适用于治疗体腔或粘膜表面,例如鼻、嘴、眼、耳、呼吸系统、阴道、尿道或直肠的表面和/或粘膜的紊乱。此类病症的非限制性实例包括衣原体感染、淋病感染、乙型肝炎、疱疹、HIV/AIDS、人乳头瘤病毒(HPV)、生殖器疣、细菌性阴道炎、念珠菌病、软下疳、腹股沟肉芽肿、性病淋巴肉芽肿、粘脓性宫颈炎(MPC)、触染性软疣、非淋病性尿道炎(NGU)、滴虫病、外阴紊乱、外阴痛、外阴疼痛、酵母感染、外阴萎缩、外阴上皮内瘤样病变(VIN)、接触性皮炎、盆腔炎、子宫内膜炎、输卵管炎、卵巢炎、生殖器癌、子宫颈癌、外阴癌、阴道癌、阴道干燥、性交困难、肛门和直肠疾病、肛门脓疮/瘘管、肛门癌、肛裂、肛门疣、克罗恩氏病、痔疮、肛门瘙痒、肛门瘙痒症、大便失禁、便秘、结肠和直肠息肉。
在一个或多个实施方案中,疏水易碎凝胶对于眼内给药特别有用。与通常的眼用软膏在眼睛上产生油腻膜并使视觉模糊不同,首次眨眼后凝胶便液化,并将在眼表面上扩散。
基于四环素的抗菌性质,加上特定四环素化合物(如二甲胺四环素和强力霉素)的抗炎、抗氧化和神经保护作用可预期的眼部病症可根据它们的症状以非限制形式分类如下:眼布血丝、眼痛或光敏感、视力模糊、视觉丧失、视觉障碍-飞蚊症、闪光、失真、光晕等、痒/灼烧、流泪/流脓、感觉眼内有异物、眼睑问题、复视。
相关病症的实例包括黄斑变性、老化相关的黄斑变性、“干”黄斑变性和“湿”黄斑变性,它们与光损伤和凋亡相关,与凋亡相关的白内障,青光眼、开角型青光眼、闭角型青光眼(与视神经死亡和凋亡相关),视网膜病、增生性糖尿病视网膜病(凋亡),黄斑水肿(炎症),结膜炎、葡萄膜炎和沙眼(感染)。
可通过本发明的疏水易碎四环素组合物治疗的眼部病症;或其并发症可由所述组合物治疗的此类病症的非限制性实例,以其字母顺序提供于此:过敏、眼睑炎、白内障、中心性浆液性脉络膜视网膜病变、色觉问题、角膜擦伤、角膜水肿、角膜溃疡、结膜炎、隐形眼镜并发症、泪囊炎、模糊远视、干眼、视网膜静脉周围炎、巩膜外层炎、眼睑外翻、眼睑内翻、眼睑蜂窝性组织炎、眼疲劳、聚焦痉挛、青光眼、急性青光眼、虹膜炎、圆锥形角膜、莱姆病、黄斑变性、黄斑水肿、黄斑裂孔、眼药物毒性、重症肌无力、瘢痕性眼天疱疮、眼性偏头痛、老花眼、泪管堵塞、视神经炎、视神经中风、眶骨骨折、眼眶蜂窝组织炎、小水疱病、翼状胬肉、复发性角膜糜烂、视网膜动脉阻塞、视网膜脱离、视网膜裂孔、视网膜静脉阻塞、结节病、巩膜炎、窦病、斜视(眼部失调)、结膜下出血、颞动脉炎、甲状腺相关性眼病、倒睫、睑瘤、眼睑抽搐(眼睑肌纤维颤搐)、葡萄膜炎、玻璃体脱离和玻璃体积血。
根据所述组合物的吸湿性,其进一步适用于治疗和预防术后粘连(post-surgical adhesions)。粘连是在组织表面之间形成不正常结合的疤痕。术后粘连的形成为在导致切口、烧灼、缝合或其他方式的外伤后组织自身修复时的手术的自然结果。当包括适当的预防剂时,泡沫适用于治疗或预防术后粘连。泡沫的使用特别有利,这是因为泡沫可在体腔中扩展,并渗透入任何其他可选的给药方法都不能达到的隐藏部位。
在一个或多个实施方案中,提供预防或改善或治疗光损伤或辐射损伤或光老化或降低已知伴随凋亡细胞死亡的皮肤病理中的氧化应激或炎症或其任意两种或多种中使用的组合物。
在一个或多个实施方案中,提供用于预防或改善或治疗紊乱的组合物,具有选自以下列表的至少一种性质或活性的四环素组合物,所述列表包括再生、抗凋亡、抗炎、抗光损伤、抗辐射损伤和抗光老化。
在一个或多个实施方案中,提供用于预防保护或改善或治疗UVB诱导的皮肤损伤的包括四环素的组合物。
在一个或多个实施方案中,提供包括四环素,用于预防、保护或改善或治疗包括增加的凋亡和/或降低的细胞活力的症状的紊乱的组合物,其中制剂起降低凋亡和/或增加细胞活力的作用。在一个或多个实施方案中,提供用于降低凋亡和/或增加细胞活力的组合物。
在一个或多个实施方案中,提供包括四环素,通过降低已知伴随凋亡细胞死亡的包括红斑痤疮(rosacea)和脓包性皮炎(impetigo)的皮肤病理中的氧化应激和炎症而用于预防或改善或治疗紊乱的组合物。
在一个或多个实施方案中,提供四环素组合物,所述组合物在UVB诱导的皮肤损伤时具有再生、或抗凋亡、或抗炎、或抗光损伤活性、以及或抗光老化、或保护和或治疗性质,或者其降低凋亡和或增加细胞活力,或者在降低伴随凋亡细胞死亡的包括红斑痤疮和脓包性皮炎的皮肤病理中的氧化应激和炎症,或者抗菌活性,或者其任意两种或多种。
化妆品用途
在一个或多个实施方案中,组合物可用于化妆品用途。例如,可用作化妆品制剂的部分来预防美容紊乱(cosmeticdisorder)或改善皮肤。
给药
本文所公开的组合物可作为凝胶或泡沫而被施用至靶点。必要时,可每小时、2小时、3小时、四小时、六小时或八小时、十二小时、每日、隔日或间歇地给药。出于遵从低频率给药的原因,可优选例如每日两次或每日一次给药。在需要延长的或长期治疗的情况下,提供较高的初始剂量,随后逐步减少至较低的维持剂量,如果发生进一步的疾病发作,可增加剂量。
实施例
以非限制性方式参考以下实施例描述本发明。以下实施例例举本文所述的发泡组合物及方法。实施例仅为了说明目的,并不意于限制。它们本身将表现出许多变化,并完全在意图范围内。
材料
适用于发泡组合物生产的示例性可能成分公开于此。也可令人满意地使用其他制造商的等同材料。
A部分-凝胶制剂
实施例1-凝胶的一般制造步骤
以下步骤用于生产以下实施例中所述的凝胶样品,其中依赖所使用的成分的类型和性质,仅进行与各制剂相关的步骤。
步骤1:将疏水油加热至60至70℃。
步骤2:将脂肪醇(如果存在),脂肪酸(如果存在),蜡(如果存在)添加到疏水油,并混合制剂直至完全熔化。
步骤3:将制剂冷却至30至40℃,添加四环素抗生素并混合制剂直至获得均质性。
步骤4:在搅拌下将制剂冷却至室温,并包封进适合的容器中。
因为本领域技术人员将理解,通过非限制性实例以下仅简要陈述试验。
用具有轴(spindle)SC4-25的Brookfield LVDV-II+PRO在环境温度以及20、10、5和1RPM下测量粘度。通常在10RPM下测量粘度。然而,在约50,000CP的轴的明显上限下,可测量1RPM下的粘度,尽管数值为较高数量级。
化学稳定性:色谱分析四环素抗生素的量。在制剂制备后并以其后适当的时间间隔进行分析。在5℃、25℃和40℃的一个或多个温度下将样品典型地储存在可控温度的保温箱中几周或几个月。在适当的时间间隔下,将样品从保温箱除去,并测量活性剂的浓度。
实施例2-低粘度凝胶制剂
适用于局部药物学组合物的不同疏水油通常为具有低粘度的液体油。如表2所述,当这些油原样用于活性剂局部递送时,它们尤其具有两个非期望的性质:(1)由于其低粘度,它们倾向于滴下并易于流动,因而对于患者来说易于施用在皮肤上,(2)它们具有不良的悬浮性质,导致非溶解性活性成分(API)快速沉降。
表2-低粘度油质制剂
如制剂001P和002P所示,矿物油和大豆油的混合物具有低粘度。制剂001和002,示出在添加盐酸二甲胺四环素后,制剂的粘度保持不变,活性成分沉积。
实施例3-粘度改善的矿物油类制剂
如表3a所述,评价四环素与脂肪醇、脂肪酸和蜡的组合对制剂粘度的影响。制备含有矿物油与脂肪醇、脂肪酸或蜡的混合物的制剂,在添加四环素即盐酸二甲胺四环素的前后测量它们的粘度。下表3a表示添加四环素前后制剂粘度的结果,以及由于活性成分的添加使粘度增加的百分比。
表3a-四环素与脂肪醇、脂肪酸和蜡的组合
非常令人惊讶地是,发现向矿物油类制剂003至005B中添加盐酸二甲胺四环素导致粘度非常大量的增加,尽管使用非常低量的盐酸二甲胺四环素,即0.1%。该完全预料之外的结果显示四环素,即使在非常低的浓度下与脂肪醇、脂肪酸或蜡的组合,也对油质制剂的粘度具有强协同效应。
然后,如表3b和3c所述,研究当活性成分与矿物油、脂肪醇、脂肪酸和蜡的混合物组合时添加不同浓度的四环素对矿物油类制剂的影响。
表3b-油质制剂
表3c-油质制剂
四环素与矿物油、脂肪醇、脂肪酸和蜡的混合物的组合具有强协同效应并增加制剂粘度。含有0.5%盐酸二甲胺四环素的制剂的粘度比安慰剂(placebo formulation)的粘度高约3倍。对制剂粘度的作用与四环素的浓度直接相关:四环素浓度越高,制剂的粘度越高。制剂238中,显示当活性成分以约0.50%的浓度存在时,盐酸二甲胺四环素的粘度增加作用达到稳定水平。
在一个或多个实施方案中,提供含有矿物油和与脂肪醇和/或脂肪酸和/或蜡协同组合的四环素的油质制剂,其中通过添加活性成分使制剂的粘度增加大于约50%、大于约100%、大于约200%、大于约300%、大于约500%。
在一个或多个实施方案中,提供含有疏水油、与固化剂协同组合的活性成分的油质制剂,其中通过添加活性成分使制剂的粘度增加大于约50%、大于约100%、大于约200%、大于约300、大于约500%。
在一个或多个实施方案中,制剂粘度增加与活性剂的浓度相关。
在一个或多个实施方案中,制剂的粘度直接与活性剂的浓度成比例:活性成分的浓度越高,制剂粘度越高。
在一个或多个实施方案中,当活性成分的浓度增加时,活性成分的粘度增加效果达到稳定水平。
在一个或多个实施方案中,当活性成分以小于约10%、小于约5%、小于约1%、小于约0.5%、小于约0.1%、小于约0.05%、小于约0.01%的浓度存在时,含有活性成分的制剂的粘度为样品制剂的粘度的两倍。
实施例4-粘度改善的蔬菜油类制剂
如表4a所述制备含不同蔬菜油,如大豆油和椰子油的制剂,以研究四环素与脂肪醇的组合对制剂粘度的影响。
表4a-基于蔬菜油的制剂
与矿物油类制剂所观察到的现象形成对比,当四环素与脂肪醇组合时,蔬菜油类制剂未观察到粘度的增加。
然后,当如表4b所述,研究当活性成分与蔬菜油、脂肪醇、脂肪酸和蜡的混合物组合时四环素的添加对蔬菜油类制剂的影响。
表4b-粘度改善的基于蔬菜油的制剂
如表4b所示,未曾预料到,四环素与疏水油、脂肪醇、脂肪酸和蜡的混合物的组合具有强协同增稠效应并增加制剂的粘度。含有1.15%盐酸二甲胺四环素的制剂的粘度约比安慰剂的粘度高两倍。此外,对制剂粘度的影响与四环素的浓度直接相关:四环素的浓度越高,制剂的粘度越高。
因此,在一个或多个实施方案中,提供含有蔬菜油、与脂肪醇、脂肪酸和蜡协同组合的四环素的油质制剂,其中通过添加活性成分使制剂的粘度增加大于约50%、大于约100%、大于约200%、大于约300、大于约500%。
在另一实验中,制剂244B凝胶的样品在40℃下储存6个月,并试验二甲胺四环素含量的均一性。发现二甲胺四环素均质地分散于制剂中,即使在40℃下延长温育后也保持如此。此外,制剂中的二甲胺四环素的测试在40℃下储存6个月后并未改变。因此,在一个或多个实施方案中,提供疏水凝胶制剂,其中四环素均质地分散于凝胶并在40℃下温育6个月后保持均质分散和稳定。
B部分-泡沫制剂
实施例5-泡沫的一般制造步骤
以下步骤用于生产以下实施例中所述的泡沫样品,其中依赖所使用的成分的类型和性质仅进行与各制剂相关的步骤。
步骤1:在室温下混合疏水油如矿物油。在室温下在搅拌下添加其他溶剂如硅酮(如果存在)直至获得制剂均质性。
步骤2:将制剂加热至70至80℃,添加固体化合物如脂肪醇、脂肪酸和蜡,混合直至完全溶解。
步骤3:将制剂冷却至30至40℃,并在搅拌下添加活性剂直至获得制剂均一性。
步骤4:在用阀门缩紧、用喷射剂加压并装配有适用于泡沫分散的驱动器的气溶胶容器中包封制剂。
可选地,可以使用计量式剂量以获得泡沫的期望递送和/或重复测量剂量。
步骤5:使用烃类气体或气体混合物进行加压。填充容器然后在50℃下的温水浴中温热30秒,其后迅速充分摇动。
试验
通过非限制性实例,以下简要描述表征泡沫性质及其稳定性的某些试验。
塌缩时间
通过分散给定量的泡沫并在36℃下温育期间随时间顺序拍摄其外观来测定作为热稳定性的量度的塌缩时间。塌缩时间结果定义为当泡沫高度达到其初始高度的50%时的时间,或者如果在比如说180秒后泡沫还未达到起初始高度的50%,则将塌缩时间记录为>180。通过说明,第一泡沫可保持其初始高度的100%达3分钟,第二泡沫可在3分钟后达到其初始高度的90%,第三泡沫可在3分钟后达到其初始高度的70%,第四泡沫可在3分钟后达到其初始高度的51%,不论这四种情况中的每一种,都将塌缩时间记录为>180秒,由于为了患者容易应用到靶点的实用目的,大部分泡沫保持完整大于180秒。如果泡沫例如在比如说100秒后达到其初始高度的50%,则将记录为具有100秒的塌缩时间。对于评价为在皮肤温度下保持结构稳定性至少1分钟的泡沫产品是有用的。在皮肤上结构稳定至少一分钟的泡沫定义为“短期稳定”载体或泡沫。
密度
泡沫产品分散于已知体积和重量的预先称量的管中。进行填入管的泡沫的质量的重复测量并计算密度。
粘度
用具有轴SC4-25的Brookfield LVDV-II+PRO在环境温度以及10、5和1RPM下测量粘度。通常在10RPM下测量粘度。然而,在~>50,000CP的轴的大约明显上限下,可测量1RPM下的粘度,尽管数值为较高数量级。除非另作说明,否则提供预发泡沫制剂的粘度(PFF)。由于发泡制剂不得不在密封的加压容器或瓶中储存,所以用常规喷射剂尝试并测量发泡制剂的粘度是不现实的。为了模拟含喷射剂的发泡制剂的粘度,加入等重的戊烷(低挥发性烃),与预发泡制剂混合并静置过夜。然后如上所述测量粘度。
化学稳定性
在从各种加压容器中释放的泡沫中色谱分析所存在的活性剂的量。在基线下并在其后适当的时间间隔下进行分析。在5℃、25℃和40℃的一个或多个温度下,将容器典型地储存在可控温度的温育器中。在适当的时间间隔下除去容器,测量泡沫样品中活性剂的量。
气泡大小
由气泡构成的泡沫包埋在液体中。气泡大小和分布反应于泡沫的视觉结构和平滑度。泡沫的气泡大小通过在玻璃滑块上分散泡沫样品,用装配有微距镜头的数码相机拍摄泡沫表面的照片来测定。相对于校准标准模板测量约30个气泡的直径。然后确定统计参数如平均气泡直径、标准偏差和四分位数(quartile)。测量直径还可用图像分析软件处理。所使用的相机为装配有θ微距镜头(ref:APO MAXEO 150mm F2.8EX DGHSM)的Nikon D40X相机(分辨率10MP)。剪裁所获得的照片以保持400像素×400像素的平方区域。
显微观察
光学显微镜能够观察并测量从几毫米低至一微米的颗粒。光学显微镜受可见光波长的限制,因此用于测量大于800纳米的、实际从1微米(1,000纳米)的粒径。
摇动性
摇动性表示当摇动填充的加压容器时使用者能够感觉/听见液体内含物的存在的程度。用普通的温和力而不是用有力的摇动或过度的力的摇动。当在摇动期间使用者不能感觉内容物的运动时,产品可被认为是不可摇动的。该性质可在需要摇动影响内容物的适当分散的情况下特别重要。
摇动性评分表
离心
在该步骤中所使用的离心充当刺激待研究液体制剂老化的应激条件。在这些条件下,所施加的离心力促进分散球体的凝聚或分散固体的沉降,导致损失所期望的制剂性质。
还可在较高rpm下在较短时间或在较低rpm下在较长时间内进行离心,考虑到由制剂经历的G力比在制剂的保存期限中其将暴露至其中的1G大许多倍。离心还可在较高rpm下进行相同时间,比如说3000或10,000rpm以刺激极高的应激水平。
实施例6-无表面活性剂的疏水泡沫制剂
表面活性剂已知为有用的发泡剂,因此对于生产无表面活性剂的良好质量的泡沫并不明显。如下表6所示,含有或不含有环甲基硅酮的包含重矿物油和轻矿物油的混合物的制剂001F和002F未能产生泡沫并仅从加压容器中释放出液体。以下鉴定了适用于油质载体发泡的除常规表面活性剂以外的化合物。
表6-油质组合物
制剂 | 001F | 002F |
成分 | %w/w | %w/w |
重矿物油 | 75.00 | 70.00 |
轻矿物油 | 25.00 | 25.00 |
环甲基硅酮 | - | 5.00 |
总计 | 100.00 | 100.00 |
喷射剂A46 | 12.00 | 12.00 |
结果 | ||
泡沫质量 | 差 | 差 |
因为它们有助于皮肤感觉性质,所以将硅油如环甲基硅酮包含在制剂中主要作为化妆剂。挥发性环甲基硅酮可帮助降低可存在于油质制剂中的油腻的皮肤感觉。
实施例7-含有脂肪酸或脂肪醇的无表面活性剂的泡沫
两种脂肪酸用于同重矿物油、轻矿物油和环甲基硅酮组合,并测试其发泡性质。如下表7a所述,含有异硬脂酸(液体脂肪酸)的制剂003F未产生泡沫而仅仅产生气泡液体。含有硬脂酸(固体脂肪酸)的制剂004F初始产生一般好质量的泡沫,但并不稳定,10秒后塌缩。同样,含有脂肪醇的组合物产生一般好质量的快速塌缩的泡沫(表7b)。因此,在不存表面活性剂下,甚至在合理的高浓度中,单独的脂肪酸或单独的脂肪醇也不足以稳定疏水泡沫。
表7a-含有脂肪酸的组合物
表7b-含有脂肪醇的组合物
制剂 | 005 | 006 | 007 | 009 |
成分 | %w/w | %w/w | %w/w | %w/w |
重矿物油 | 60.00 | 60.00 | 60.00 | 60.00 |
轻矿物油 | 25.00 | 25.00 | 25.00 | 25.00 |
环甲基硅酮 | 5.00 | 5.00 | 5.00 | 5.00 |
十四烷醇(C14) | 10.00 | - | - | - |
十六烷醇(C16) | - | 10.00 | - | - |
十八烷醇(C18) | - | - | 10.00 | - |
二十二烷醇(C22) | - | - | - | 10.00 |
总计 | 100.00 | 100.00 | 100.00 | 100.00 |
喷射剂A46 | 12.00 | 12.00 | 12.00 | 12.00 |
结果 | ||||
泡沫质量 | 一般 | 一般 | 一般 | 一般好 |
塌缩时间(sec) | 10 | 10 | 10 | 10 |
泡沫密度(/mL) | - | - | - | 0.160 |
PFF粘度(cP) | 206 | 938 | 585 | 3839 |
实施例8-含有脂肪酸和脂肪醇的组合的无表面活性剂的疏水泡沫制剂
制备制剂,其包含脂肪酸和脂肪醇的组合,并检查它们的发泡性质。如下表8所述,制剂010(包含硬脂酸和十四烷醇)和制剂017(包含异硬脂酸和十八烷醇)不产生有质量的泡沫而仅产生气泡液体。
然而,令人惊讶地是,如制剂011、012、013和014所示,硬脂酸与十六烷醇、十八烷醇、十六十八醇或二十二烷醇的组合(无任何表面活性剂)产生具有细小气泡结构的良好质量泡沫。如制剂011和016所示,可在硅油存在与不存在下成功地生产此类泡沫,而不管硅酮的消泡作用。此外,含有硬脂酸与十八烷醇或二十二烷醇的组合的制剂012和014产生稳定的泡沫,其在36℃下180秒后不塌缩。因此,已发现脂肪醇和脂肪酸的组合具有协同效应并且在油质组合物的情况下具有有效的发泡性质,从而实现热稳定的易碎泡沫。有趣的是,虽然使用十六烷醇和十八烷醇二者的组合导致预泡沫制剂的粘度显著降低,但十六烷醇和十八烷醇实现了最低的平均气泡大小。
表8-含有各种脂肪酸和脂肪醇的油质组合物
制剂 | 010 | 011 | 012 | 013 |
成分 | %w/w | %w/w | %w/w | %w/w |
重矿物油 | 60.00 | 60.00 | 60.00 | 60.00 |
轻矿物油 | 25.00 | 25.00 | 25.00 | 25.00 |
环甲基硅酮 | 5.00 | 5.00 | 5.00 | 5.00 |
十四烷醇 | 5.00 | - | - | - |
十六烷醇 | - | 5.00 | - | - |
十八烷醇 | - | - | 5.00 | - |
十六十八醇 | - | - | - | 5.00 |
二十二烷醇 | - | - | - | - |
异硬脂酸 | - | - | - | - |
硬脂酸 | 5.00 | 5.00 | 5.00 | 5.00 |
总计 | 100.00 | 100.00 | 100.00 | 100.00 |
喷射剂A46 | 12.00 | 12.00 | 12.00 | 12.00 |
喷射剂AP-70 | - | - | - | - |
结果 | ||||
泡沫质量 | 一般 | 良好 | 良好 | 良好 |
塌缩时间(sec) | 10 | 30 | >180 | 30 |
泡沫密度(g/mL) | - | 0.142 | 0.157 | 0.210 |
气泡大小(微米) | - | 60 | 74 | 137 |
PFF粘度(cP) | 107 | 22763 | 23866 | 107 |
表8-续
制剂 | 014 | 015 | 016 | 017 |
成分 | %w/w | %w/w | %w/w | %w/w |
重矿物油 | 60.00 | 57.00 | 60.00 | 60.00 |
轻矿物油 | 25.00 | 25.00 | 30.00 | 25.00 |
环甲基硅酮 | 5.00 | 5.00 | - | 5.00 |
十四烷醇 | - | 3.00 | - | - |
十六烷醇 | - | - | - | - |
十八烷醇 | - | 5.00 | 5.00 | 5.00 |
十六十八醇 | - | - | - | - |
二十二烷醇 | 5.00 | - | - | - |
异硬脂酸 | - | - | - | 5.00 |
硬脂酸 | 5.00 | 5.00 | 5.00 | - |
总计 | 100.00 | 100.00 | 100.00 | 100.00 |
喷射剂A46 | 12.00 | - | 12.00 | 12.00 |
喷射剂AP-70 | - | 8.00 | - | - |
结果 | ||||
泡沫质量 | 良好 | 良好 | 良好 | 一般 |
塌缩时间(sec) | >180 | >180 | >180 | 10 |
泡沫密度(g/mL) | 0.139 | 0.082 | 0.100 | - |
气泡大小(微米) | 139 | - | - | - |
PFF粘度(cP) | 5023 | 18987 | - | - |
实施例9-含有脂肪醇、脂肪酸和蜡的无表面活性剂的疏水泡沫制剂
制备含有脂肪酸、脂肪醇和蜡的组合的制剂并检查它们的发泡性质。如下表9a所示,含有脂肪醇和低量硬脂酸的制剂018未产生有质量的泡沫,而产生非常快速塌缩的一般好质量的泡沫。令人惊讶地是,氢化蓖麻油和蜂蜡(二者室温下均为固体蜡)的添加(制剂19中)增强了泡沫质量并获得36℃下稳定的质量为良好的泡沫。此外,含有蜡的制剂在施用于皮肤上时油腻感觉较小。因此,发现与脂肪醇和脂肪酸组合的蜡在无表面活性剂下生产高质量(high quality)泡沫中是有用的。
表9a-含有蜡的疏水泡沫组合物
制剂 | 018 | 019 |
成分 | %w/w | %w/w |
重矿物油 | 63.00 | 59.50 |
轻矿物油 | 25.00 | 25.00 |
环甲基硅酮 | 5.00 | 5.00 |
氢化蓖麻油 | - | 1.50 |
蜂蜡 | - | 2.00 |
十六十八醇 | 2.50 | 2.50 |
十八烷醇 | 1.50 | 1.50 |
二十二烷醇 | 1.00 | 1.00 |
硬脂酸 | 2.00 | 2.00 |
总计 | 100.00 | 100.00 |
喷射剂A46 | 12.00 | 12.00 |
结果 | ||
泡沫质量 | 一般好 | 良好 |
塌缩时间(sec) | 10 | 120 |
泡沫密度(g/mL) | - | 0.207 |
气泡大小(微米) | 155 | 79 |
制备另外的单独含有蜡以及与脂肪酸或脂肪醇组合的制剂,并检查它们的发泡性质。如下表9b所述,单独含有蜂蜡或含有蜂蜡与氢化蓖麻油组合的制剂021、021b和022未产生有质量的泡沫而仅产生气泡液体。单独含有氢化蓖麻油的制剂020产生60秒后塌缩的质量为一般好的泡沫。另一方面,如制剂023所示,蜂蜡、氢化蓖麻油和脂肪醇的组合增强了泡沫质量并且产生了在36℃下稳定大于180秒的良好质量泡沫。然而,仅由蜂蜡、氢化蓖麻油和脂肪酸的组合而没有脂肪醇的制剂024和024b产生快速塌缩的一般好的泡沫。这显示出油质泡沫组合物中脂肪醇和蜡二者存在的重要性。此外,不能仅使用蜡如氢化蓖麻油或蜂蜡代替脂肪酸,但蜡可用于促进较低水平脂肪酸的存在而不危害泡沫性质。
表9b-含有蜡的疏水泡沫组合物
制剂 | 020 | 021 | 021b | 022 | 023 | 024 | 024b |
成分 | %w/w | %w/w | %w/w | %w/w | %w/w | %w/w | %w/w |
重矿物油 | 60.00 | 60.00 | 60.00 | 60.00 | 60.00 | 60.00 | 60.00 |
轻矿物油 | 25.00 | 25.00 | 30.00 | 25.00 | 25.00 | 25.00 | 25.00 |
环甲基硅酮 | 5.00 | 5.00 | - | 5.00 | 5.00 | 5.00 | 5.00 |
氢化蓖麻油 | 10.00 | - | - | 5.00 | 2.50 | 2.50 | 5.00 |
蜂蜡 | - | 10.00 | 10.00 | 5.00 | 2.50 | 2.50 | 2.50 |
十八烷醇 | - | - | - | - | 5.00 | - | - |
硬脂酸 | - | - | - | - | - | 5.00 | 5.00 |
总计 | 100.00 | 100.00 | 100.00 | 100.00 | 100.00 | 100.00 | 100.00 |
喷射剂A46 | 12.00 | 12.00 | 12.00 | 12.00 | 12.00 | 12.00 | 12.00 |
结果 | |||||||
泡沫质量 | 一般好 | 一般 | 一般 | 一般 | 良好 | 一般好 | 一般好 |
塌缩时间(sec) | 10 | 10 | 10 | 10 | >180 | 10 | 10 |
实施例10-含有不同疏水油的四环素泡沫制剂
制备含有大豆油、辛基十二醇、中链甘油三酯(MediumChain Triglycerides,MCT)油和椰子油(它们为其他疏水油实例)的二甲胺四环素泡沫制剂。评价参数如泡沫质量、塌缩时间和密度。如表10所述,在含有这些疏水油的不同组合物中获得36℃下不塌缩的良好质量泡沫。椰子油,其本身为半固体糊状油,与液体大豆油组合使用。
表10-含有不同疏水油的泡沫制剂
注:所有泡沫为高质量的并且在36℃下的塌缩时间超过100秒,泡沫密度小于0.3g/ml,制剂能够经受4个冻溶循环,并仍产生36℃下的塌缩时间超过100秒的高质量泡沫。上述制剂,在不添加喷射剂下,为半固体凝胶状均质组合物,未观察到成分的分离或沉降。
实施例11-含有蜡的四环素泡沫制剂
研究含有矿物油、固体石蜡、喷射剂和四环素的制剂的发泡性质。如下表11所示,尽管缺少脂肪醇和脂肪酸,但是含有盐酸二甲胺四环素的制剂产生具有36℃下的超过1分钟的塌缩时间的易碎泡沫。
表11-含有蜡的四环素泡沫制剂
实施例12-矿脂类发泡组合物
根据实施例1中所述的一般制造步骤,制备含有与液体油、脂肪醇和蜡组合的高量矿脂的泡沫制剂。如表12a所述,在含有矿脂的不同组合物中获得有质量的易碎泡沫。预泡沫制剂是粘性半固体。当添加喷射剂时,制剂是可摇动的,表明气溶胶容器内的制剂是液体。
表12a-含有矿脂的油质制剂
制剂 | A1 | A2 | A3 | A8 |
白矿脂 | 70.00 | 50.00 | 50.00 | 91.00 |
葡萄籽油 | - | 15.00 | - | - |
荷荷巴油 | 15.00 | 15.00 | 15.00 | - |
矿物油 | 5.00 | 9.00 | 10.00 | - |
小麦胚油 | - | - | 15.00 | - |
固体石腊51-53 | - | 2.00 | 5.00 | - |
蜂蜡 | 1.00 | 1.00 | - | 1.00 |
十六十八醇 | 4.00 | 4.00 | 4.00 | 4.00 |
氢化蓖麻油 | 3.00 | 2.00 | - | 3.00 |
环甲基硅酮5-NF | 1.00 | 1.00 | - | - |
二十二烷醇 | 1.00 | 1.00 | 1.00 | 1.00 |
总计 | 100 | 100 | 100 | 100 |
喷射剂A70 | 10.00 | 10.00 | 10.00 | 10.00 |
结果 | ||||
泡沫质量 | 优 | 优 | 优 | 优 |
泡沫密度(g/mL) | 0.159 | 0.154 | 0.175 | 0.226 |
36℃下的塌缩时间(sec) | >180 | >180 | >180 | >180 |
平均气泡大小(微米) | - | - | 150 | - |
在一个或多个实施方案中,提供包括矿脂、可选地液体油、脂肪醇和蜡的发泡制剂,其中制剂产生有质量的易碎泡沫。
根据实施例1中所述的一般制造步骤,还制备没有蜡而包含与液体油和脂肪醇组合的大量矿脂的泡沫制剂。如表12b所示,在含有矿脂而无蜡的不同组合物中获得有质量的易碎泡沫。预泡沫制剂为粘性半固体。在添加喷射剂时,制剂是可摇动的,表明气溶胶容器中的制剂为液体。
表12b-含有矿脂的油质制剂
制剂 | A4 | A5 | A6 | A7 |
白矿脂 | 50.00 | 70.00 | 70.00 | 75.00 |
小麦胚油 | - | 10.00 | - | - |
荷荷巴油 | - | 5.00 | - | - |
鳄梨油 | 15.00 | - | - | - |
椰子油 | 15.00 | - | - | - |
矿物油 | 10.00 | 3.00 | 20.00 | 20.00 |
牛油树脂 | 5.00 | 5.00 | 5.00 | - |
十六十八醇 | 4.00 | 4.00 | 4.00 | 4.00 |
环甲基硅酮5-NF | - | 2.00 | - | - |
二十二烷醇 | 1.00 | 1.00 | 1.00 | 1.00 |
总计 | 100 | 100 | 100 | 100 |
喷射剂A70 | 10.00 | 10.00 | 10.00 | 10.00 |
结果 | ||||
泡沫质量 | 良好 | 优 | 优 | 优 |
泡沫密度(g/mL) | 0.200 | 0.197 | 0.140 | 0.175 |
36℃下的塌缩时间(sec) | 175 | >180 | >180 | >180 |
在一个或多个实施方案中,提供具有可选地牛油树脂的包含矿脂和脂肪醇的发泡制剂,其中所述制剂产生有质量的易碎泡沫。在一个或多个实施方案中,提供具有可选地牛油树脂的包括矿脂、可选地液体油,和脂肪醇的发泡制剂,其中所述制剂产生有质量的易碎泡沫。
C部分-四环素组合物的另外性质
实施例13-四环素抗生物在无表面活性剂的疏水制剂中的稳定性。
四环素抗生素已知为非常不稳定的活性剂,被广泛普遍使用的药物学赋形剂所降解。例如,已发现二甲胺四环素在几天内被不同的亲水溶剂(例如水、甘油、PCA钠、丙二醇和聚乙二醇)、被水分散聚合物(例如黄原胶、泊咯沙姆(poloxamers)、卡波姆(carbomers)、甲基纤维素、CMC钠)以及被表面活性剂(例如聚山梨醇酯、脱水山梨糖醇酯、聚氧烷基酯以及羊毛脂类表面活性剂)所降解。因此,本文所述的四环素抗生素长期稳定发泡组合物的实现是主要的挑战,并需要大量的研究和创造性。
以下实施例说明疏水制剂,即表13a、13b(i)和13b(ii)中所述的238和244B中泡沫的物理稳定性和盐酸二甲胺四环素(“MCH”)的化学稳定性。在加速稳定性研究中,在40℃下储存样品,并通过HPLC测定盐酸二甲胺四环素的浓度。2个月、3个月和6个月储存后的稳定性试验结果示于表13b(i)和13b(ii)。
表13a-40℃下温育的泡沫制剂的组成
制剂 | 238 | 244B |
成分 | %w/w | %w/w |
重矿物油 | 58.14 | - |
轻矿物油 | 25.00 | 4.44 |
环甲基硅酮 | 5.00 | 5.00 |
椰子油 | - | 23.60 |
大豆油 | - | 50.00 |
羊毛脂 | - | - |
氢化蓖麻油 | 1.50 | 2.00 |
蜂蜡 | 2.00 | 2.00 |
十六十八醇 | 2.50 | 3.50 |
十八烷醇 | 1.50 | 1.50 |
二十二烷醇 | 1.00 | 1.10 |
十四烷醇 | - | 2.50 |
Aerosil(SiO2) | 0.25 | 0.25 |
硬脂酸 | 2.00 | 3.00 |
盐酸二甲胺四环素 | 1.11 | 1.11 |
总计 | 100.00 | 100.00 |
喷射剂A46 | - | 12.00 |
喷射剂AP-70 | 8.00 | - |
结果 | ||
泡沫质量 | 优 | 优 |
塌缩时间(sec) | >180 | >180 |
泡沫密度(g/mL) | 0.237 | 0.284 |
表13b(i)-含有盐酸二甲胺四环素的泡沫组合物的化学稳定性
表13b(ii)-含有盐酸二甲胺四环素的泡沫组合物的物理稳定性
NM=未测量
令人惊讶地是,尽管已知四环素抗生素不稳定,但在40℃下储存后的两种制剂的加速稳定性结果显示了制剂中活性剂的最低降解。因此,本文公开的制剂显示出四环素抗生素延长的加速稳定性和显著的物理稳定性。
这些结果进一步说明发现短期、中期和或长期时间内化学稳定以及物理稳定的无表面活性剂和无水的制剂是困难、复杂、预料之外的和非显而易见的成就。试验和鉴定与活性剂化学相容的单一物质是不充分的。结合本身相容的多种物质可能导致整体不相容。化学相容性物质的发现与知识不能推测组合物的物理稳定性,反之亦然。在个体制剂组分和活性剂之间进行相容性试验不保证也不实现物理稳定性。发现可导致不存在表面活性剂下物理稳定制剂的成分的组合本身就是预料之外的。
实施例14-与皮肤接触时疏水凝胶或泡沫制剂vs.对照凝胶中二甲胺四环素的稳定性的药物比较
该研究的目的是分析在暴露于皮肤后二甲胺四环素的降解。试验两种样品:
a.疏水二甲胺四环素制剂#244,含有25%轻矿物油、5%环甲基硅酮、25%椰子油、28.5%大豆油(疏水油);2%氢化蓖麻油、2.5%蜂蜡(蜡);5%十八烷醇、1%二十二烷醇(脂肪醇)、5%硬脂酸(脂肪酸)和约1%微粉化盐酸二甲胺四环素。
b.对照二甲胺四环素凝胶,其在其他组分之中还包括硅酮和ST弹性体10等,在与包括水、乙醇和丙二醇的附加组分在施用之前将它们混合。
将样品施用至新取的猪耳皮肤并储存在陪替氏培养皿中,在35℃下暴露在空气和光下6小时;通过液相色谱监控盐酸二甲胺四环素及其4-epi降解物的浓度。
如下表14所示,对照凝胶显示二甲胺四环素快速降解。暴露6小时后二甲胺四环素含量降低了34%,其4-epi降解物的浓度达到19.4%,示出对照凝胶产品未将所有抗生素量以其活性形式递送至皮肤。
形成明显对比的是,尽管已知二甲胺四环素不稳定,但是“244”令人惊讶地,6h后的皮肤稳定性结果显示活性剂非常低的降解;4-epi降解物的含量仅达到3.3%,未观察到二甲胺四环素量的可检测的降低。因此,泡沫制剂在与皮肤接触时具有对四环素抗生素的活性保护作用,并在几小时内防止其在治疗靶点的降解。
由于这些观察的结果,预期疏水性易碎性的组合物保护四环素抗生素免受降解;因此在施用后不损失其效力的情况下,用于湿润且暴露于外面空气(top air)和/或光的身体部位和表面的治疗。
如医学领域已知的,药物作用的持续与其在治疗位点以其活性形式的停留直接相关;因此可总结为,与相同药物的其他形式相比(如果有的话),本疏水易碎四环素组合物将提供长期治疗并促进以更低的频率给药。
表14-含有盐酸二甲胺四环素的组合物的皮肤稳定性结果
对照硅酮凝胶 | 244制剂 | |
初始二甲胺四环素的皮肤浓度 | 96.90 | 92.20 |
初始4-epi降解物的皮肤浓度 | 2.60 | 0.80 |
35℃下6h后二甲胺四环素的皮肤浓度 | 64.00 | 93.70 |
35℃下6h后4-epi降解物的皮肤浓度 | 19.40 | 3.30 |
实施例15:非活性成分的安全性
易碎疏水四环素制剂的所有非活性成分的目的是用于局部使用并列于目前的FDA非活性成分数据库中;所使用的浓度不超过数据库中所给出的最大浓度。作为实施例,表15列出制剂244的制剂非活性成分的急性剂量效应,表明所有这些成分可通常视为安全(GRAS)。
表15:制剂244的制剂非活性成分的急性剂量效应
实施例16:眼睛刺激研究-HET CAM
化合物引起不可逆或严重的眼部刺激或腐蚀的可能性可通过观察在暴露于试验化学品后在卵的绒毛尿囊膜(chorioallantoic membrane,CAM)中发生的不利变化来检测(Luepke,N.P.,Kemper,F.H.“The HET-CAM Test:An Alternativeto the Draize Eye Test.”Fd Chem.Toxic.(1986)24,495-496)。在温育箱中旋转受精鸡蛋9天,其后丢弃任何有缺陷的蛋。除去气囊(air cell)周围的壳,并提取内膜以暴露绒毛尿囊膜。将试验化学品添加到膜并使其接触达5分钟。检测膜的血管损伤并记录损伤发生所花费的时间。根据损伤发生的速度评价刺激性。为了验证HET-CAM数据,阳性和阴性对照以及载体对照与试验项平行试验。
对于各试验项,测定平行测定蛋(replicate egg)的平均评分。刺激评分(IS)解释如下:
刺激评分 | 刺激分类 |
0-0.9 | 无刺激 |
1-4.9 | 轻微刺激 |
5-8.9 | 适度刺激 |
9-21 | 重度刺激 |
如表16所示,使用体外刺激HET-CAM,未稀释的FXFM244,表明无刺激迹象。
表16:含1%和4%二甲胺四环素的制剂244的HET CAM研究
治疗 | 刺激评分 | 分类 |
阴性对照 | 0 | 无刺激 |
阳性对照 | 17.09 | 严重 |
制剂244B(1%) | 0 | 无刺激 |
制剂244A(4%) | 0 | 无刺激 |
FXFM244-安慰剂 | 0 | 无刺激 |
这些观察的结果中,疏水易碎四环素组合物特别适用于治疗眼部病症,以及其他使敏感皮肤和粘膜区域疼痛的病症。特别地,组合物不包括任何已知引起眼部和另外的敏感区域刺激的表面活性剂。
基于四环素的抗菌性加上某些四环素化合物(如二甲胺四环素和强力霉素)的抗炎、抗氧化、抗凋亡和神经保护作用可预期的眼部病症包括,可由其特征以非限制形式分类如下:眼布血丝、眼痛或光敏感、视力模糊、视觉丧失、视觉障碍-飞蚊症、闪光、失真、光晕等、痒/灼烧、流泪/流脓、感觉眼内有异物、眼睑问题、复视。
相关病症的实例包括与光损伤和凋亡相关的黄斑变性、老化相关的黄斑变性、“干”黄斑变性和“湿”黄斑变性,与凋亡相关的白内障,青光眼、开角型青光眼、闭角型青光眼(与视神经死亡和凋亡相关),视网膜病、增生性糖尿病视网膜病(凋亡),黄斑水肿(炎症),结膜炎、葡萄膜炎和沙眼(感染)。
可通过本发明的疏水易碎四环素组合物治疗的眼部病症的非限制性实例;或其并发症可由所述组合物治疗的此类病症;以其字母顺序提供于此:过敏、眼睑炎、白内障、中心性浆液性脉络膜视网膜病变、色觉问题、角膜擦伤、角膜水肿、角膜溃疡、结膜炎、隐形眼镜并发症、泪囊炎、模糊远视、干眼、视网膜静脉周围炎、巩膜外层炎、眼睑外翻、眼睑内翻、眼睑蜂窝性组织炎、眼疲劳、聚焦痉挛、青光眼、急性青光眼、虹膜炎、圆锥形角膜、莱姆病、黄斑变性、黄斑水肿、黄斑裂孔、眼药物毒性、重症肌无力、瘢痕性眼天疱疮、眼性偏头痛、老花眼、泪管堵塞、视神经炎、视神经中风、眶骨骨折、眼眶蜂窝组织炎、小水疱病、翼状胬肉、复发性角膜糜烂、视网膜动脉阻塞、视网膜脱离、视网膜裂孔、视网膜静脉阻塞、结节病、巩膜炎、窦病、斜视(眼部失调)、结膜下出血、颞动脉炎、甲状腺相关性眼病、倒睫、睑瘤、眼睑抽搐(眼睑肌纤维颤搐)、葡萄膜炎、玻璃体脱离和玻璃体积血。
实施例17:制剂244的抗菌作用的体外证明
如表11所示,体外研究中揭示了含1%和4%二甲胺四环素的制剂244抑制化脓性链球菌、绿脓假单胞杆菌、金黄色葡萄球菌,以及金黄色葡萄球菌的耐二甲氧基苯青霉素菌株(MRSA)的生长。制剂还对抗痤疮中的病原微生物,痤疮丙酸杆菌有效。对照抗生素产品,即梭链孢素软膏(Fucidin Ointment)(含有2%梭链孢酸(fucidic acid))仅对链球菌属菌株有效。
很明显,即使四环素抗生素悬浮也观察到该作用,并且没有预料到易于获得在陪替氏培养皿上的迁移,这对于分泌其抗菌活性是必需的。
表17:体外抗菌作用:制剂244、梭链孢素软膏和安慰剂之间的比较-抑制直径(mm)
*0=无效;≥30=非常有效
这些观察的结果中,预期本发明的疏水易碎四环素组合物在任何可用凝胶或泡沫治疗的、包括细菌组分作为其病因之一的病症或疾病的治疗中是有效的。
这些观察的结果中,疏水易碎四环素组合物特别适用于任何涉及作为直接病因或作为次要并发症的涉及微生物感染的病症的治疗,所述微生物对四环素治疗敏感。
基于四环素的抗菌性质、加上某些四环素化合物(如二甲胺四环素和强力霉素)的抗炎、抗氧化和神经保护作用可预期的皮肤病症包括,以非限制方式包括,例如:蜂窝组织炎、皮肤脓疮、丹毒、红斑、毛囊炎、疖和痈、化脓性汗腺炎、脓疱病、深脓疱、淋巴结炎、淋巴管炎、MRSA感染、坏死性皮下感染和金黄色葡萄球菌烫伤样皮肤综合征。
同样,本发明的组合物适用于可通过凝胶或泡沫治疗的任何涉及细菌感染的眼病、阴道感染和靶点的任何附加感染的治疗。
在涉及二次感染如特应性皮炎和其他瘙痒和干燥症的病症的任何情况下,相同的组合物是可适用的。
实施例18:二甲胺四环素的皮肤递送和协同生物可利用度
使用弗朗茨细胞体外扩散系统试验二甲胺四环素的经皮渗透。该系统通常用于试验从半固体局部剂型的通过皮肤的药物。由于类似于人类皮肤的渗透特性,根据OECD起草(draft)的新指南428(Draft New Guideline 428)使用猪的皮肤。采用以下实验参数:
-试验两种制剂:2441%和2444%(分别包括1%和4%二甲胺四环素)。
-使用垂直弗朗茨扩散细胞(PermeGear,1.77cm2的区域,14ml受体流体)。
-使用6种细胞试验4%制剂,使用5种细胞试验1%制剂。使用一种细胞作为“阴性对照”(无任何应用样品)。将大约500mg产品置于各细胞中。
-在基线和施用后3、6、9和24小时时对接收室取样。在24小时的时间点,如下处理皮肤:
-应将连续19个带(9和10)转移进两个单独的含3mL提取液的小瓶中(“角质层(Stratum Corneum)1”和“角质层2”)。
-切割圆形皮肤区域(1.77cm2)并转移至3mL提取液(有活力的皮肤-VS样品)小瓶中。
表18:体外皮肤递送:制剂244(1%和4%)
从该实验中可得出以下结论:
1.经皮递送:暴露24小时后,接受细胞中发现的量在分析方法的定量极限(LOQ)之下(LOQ=2μg/mL)。该结果清楚地表明无来 自FMFX244泡沫制剂的药物的全身吸收。因此可总结为FMFX244泡沫的局部给药不应涉及任何全身副作用。
2.皮肤内递送(递送至皮肤内):暴露24小时后皮肤中二甲胺四环素的总平均量,对于1%制剂为9.5μg/cm2,对于4%制剂为43μg/cm2。递送区皮肤的重量约为100mg,其意味着暴露24小时后皮肤中二甲胺四环素的浓度,对于1%制剂约为皮肤的90μg/gr,对于4%制剂约为430μg/gr。根据文献,二甲胺四环素的最小抑制浓度(MIC)为小于4μg/mL,因此,可总结为皮肤中发现的浓度足以治疗细菌皮肤感染。
明显地,即使四环素抗生素被悬浮也观察到该皮肤渗透特性(profile),并且没有预料到其便于迁移入皮肤。
这些观察的结果中,疏水易碎四环素组合物特别适用于发生于皮肤中的任何皮肤病症的治疗。
基于四环素的抗菌性质,加上特定四环素化合物(如二甲胺四环素和强力霉素)的抗炎、抗氧化、抗凋亡和神经保护作用可预期的皮肤病症包括,以非限制形式包括,例如:脓肿、痤疮、痤疮疤痕、急性发热性嗜中性白细胞皮肤病、变应性接触性皮炎、秃头症、足癣、特应性皮炎、基底细胞癌、水疱、腋臭、灼伤、胼胝念珠菌病、痈、蜂窝组织炎、水痘、胆碱能性荨麻疹、日光的慢性效应、唇疱疹、寒冷性荨麻疹、黑头粉刺、鸡眼、皮肤脓疮、皮肤幼虫移行症、肤蛆病、黑斑、寄生虫妄想症、皮炎、皮肤划痕现象、皮肤真菌病、药疹和药物反应、汗疱、深脓疱、表皮囊肿、丹毒、丹毒、红斑、剥落性皮炎、多形性红斑、结节性红斑、毛囊炎、真菌指甲感染、疖、生殖器疱疹、环状肉芽肿、头虱、化脓性汗腺炎、荨麻疹、毛囊炎、多毛症、多汗症、少汗症、鱼鳞癣、脓疱病、嵌甲、擦烂、刺激性接触性皮炎、瘙痒、股癣、毛发角化病、慢性单纯性苔癣、扁平苔癣、硬化性苔癣、淋巴结炎、淋巴管炎、肥大细胞增多症、麻疹、黑色素瘤、汗疹、痣、触染性软疣、MRSA、坏死性皮下感染、钱币状皮炎、口腔疱疹、脂膜炎、类银屑病、甲沟炎、光过敏、光损伤、光刺激、光敏感、丘疹、口周皮炎、面疱、玫瑰糠疹、苔癣样糠疹、玫瑰糠疹、毛发红糠疹、接触毒漆引起的皮疹、压迫性溃疡、压迫性荨麻疹、瘙痒症、须部假性毛囊炎、牛皮癣、PUPPP、紫癜、脓疱、脓性肉芽肿、疹、癣菌病、红斑痤疮、玫瑰疹、风疹、疥疮、皮脂囊肿、脂溢性皮炎、脂溢性角化病、带状疱疹、皮肤癌、皮疹、金黄色葡萄球菌烫伤样皮肤综合征、停滞性皮炎、史蒂文斯-约翰逊综合征、晒伤、体癣、股癣、脚癣、花斑癣、中毒性表皮坏死松解症、水痘带状疱疹病毒、维生素D缺乏、水性荨麻疹、干燥症、带状疱疹。
实施例19:含1%和4%二甲胺四环素的制剂244的抗凋亡作用的离体研究
皮肤的UVB照射已知降低细胞活力、总抗氧化能力,同时增加炎症(促炎性细胞因子分泌)和表皮细胞凋亡的水平。
用制剂244预处理
用制剂244(安慰剂,1%和4%二甲胺四环素)局部处理器官培养中人类皮肤样品24小时,然后用UVB(400mJ/cm2)照射并温育额外的72小时。照射后24h通过测量表皮细胞片(epidermalsheet)的半胱天冬酶3活性的程度来测量凋亡激活。
表19a和表19b表明在UVB照射皮肤器官培养后制剂244对表皮细胞凋亡和活力的作用(有或无二甲胺四环素)。如表19a所示,由FXFM244以剂量依赖的方式显著降低凋亡激活。
如表19b所示,当通过MTT分析测量时,在照射后72小时细胞活力增加。一组涉及凋亡的调节子(mediator)属于天冬氨酸特异的半胱氨酸蛋白酶或半胱天冬酶。该家族的成员,半胱天冬酶-3已鉴定为哺乳动物细胞凋亡的关键调节子。概括地说,随着半胱天冬酶活化的增加,将接着发生较高百分比的细胞死亡。
表19a:UVB照射后制剂244对皮肤器官培养中凋亡激活的作用
表19b:制剂244对皮肤器官培养活力的作用
注:观察到在细胞与安慰剂相接触的情况下,照射引起细胞活力的降低。另一方面,与含有二甲胺四环素的制剂接触的细胞,与安慰剂相比,在照射前后均观察到较高的作为细胞再生标志的细胞活力。因此,包括二甲胺四环素的本制剂能够防止在照射的情况下的细胞死亡,并且甚至可刺激或引发细胞再生。
UV损伤诱导后用制剂244的治疗
用UVB(400mJ/cm2)照射器官培养中人类皮肤样品并温育额外72小时。然后将制剂2444%施用于皮肤,并在处理后24h通过测量表皮细胞片中半胱天冬酶3活性的程度来测量凋亡激活。
如表19c所示,制剂4%治疗导致表皮细胞凋亡约60%的降低。
表19c:制剂244的治疗效果(照射后施用)
半胱天冬酶3活性(斜率/min) | |
对照 | 118 |
244–4%MCH | 46 |
总结
这些结果表明,在UVB诱导的日光损伤或任何其他与阳光或其他光(如,激光)暴露相关的病症的情况下,制剂244具有保护性质。因此能够降低皮肤光损伤和光老化,更普遍地降低在已知伴随凋亡的细胞死亡的皮肤病理中的氧化应激和炎症。
明显地,即使四环素抗生素被悬浮时也观察到该皮肤渗透特性,并且未预料到其便于迁移入组织并提供期望的抗凋亡作用。
这些观察的结果中,疏水易碎四环素组合物特别适用于任何包括凋亡作为其病因之一的病症的治疗。
实施例20-相容性研究
步骤:在25℃和40℃与各种赋形剂一起温育作为悬浮液的盐酸二甲胺四环素(“MCH”)最多60天或达到怀疑降解时的时间点。以下详述MCH和试验赋形剂之间的比。目测为指示相容性的主要标准。完整的MCH悬浮液为淡黄色;任何颜色的改变(如,变为深橘色、红色、绿色、褐色和黑色)表明氧化或降解。
以MCH:赋形剂为1∶250的比试验疏水溶剂与MCH的相容性。发现二甲基异山梨醇、甘油、乙醇、丙二醇、丁二醇、PEG200、己二醇、PEG 400、二甲基亚砜和二甘醇单乙醚与MCH不 相容。
以MCH:赋形剂对于油性软化剂(emollient)为1∶250、对于蜡为1∶50的比试验油性软化剂和蜡与MCH的相容性。发现氢化蓖麻油、蓖麻油、椰油甘油酯(cocoglyceride)、己二酸二异丙酯、矿物油、椰子油、蜂蜡、MCT油、环甲基硅酮、异十二烷、鲸蜡硬脂醇辛酸酯、胶化矿物油、肉豆蔻酸异丙酯、PPG 15十八烷基醚、重矿物油、辛基十二醇、白矿脂、矿脂、石蜡51-53、石蜡58-62、金盏花油、牛油树脂、葡萄籽油、杏仁油、荷荷巴油、鳄梨油、花生油、小麦胚油和硬脂与MCH相容。发现石榴籽油与MCH不相容。
在表面活性剂在矿物油(之前矿物油显示与MCH相容)中溶解后,试验MCH与疏水表面活性剂的相容性。以MCH:赋形剂为1∶50的比试验表面活性剂与MCH的相容性。发现PEG 150二硬脂酸酯、月桂醚(laureth)4、PEG40氢化蓖麻油、PEG 75羊毛脂、葡聚糖P20二硬脂酸酯、PEG100硬脂酸酯、单硬脂酸甘油酯、PEG40硬脂酸酯、蒙塔诺(montanov)S(椰油醇(cocoylalcohol)(和)C12-20烷基葡糖苷)、乳酸烷基酯、本顿(benton)凝胶、SPAN60、脱水山梨糖醇倍半硬脂酸酯、SPAN40、SPAN80、吐温(Tween)20、吐温60、鲸蜡醇聚醚2(ceteth 2)、蔗糖硬脂酸酯D1813、鲸蜡硬脂醇聚醚(ceteareth)20、硬脂醇聚醚(steareth)2/硬脂醇聚醚21、甲基葡糖倍半硬脂酸酯(methyl glucosesesquistearate)、油醇聚醚(Oleth)20和PPG20甲基葡糖醚与MCH 不相容。发现蔗糖硬脂酸酯D1803、蔗糖硬脂酸酯D1807和蔗糖硬脂酸酯D1811与MCH相容;然而不是它们中的所有都溶于油(如1811、1813)。
以MCH:赋形剂为1∶50的比试验泡沫佐剂与MCH的相容性。发现异十八烷醇、二十二烷醇、十八烷醇、十六烷醇、油醇、十四烷醇、十六十八醇、棕榈酸、硬脂酸和油酸与MCH相容。异硬脂酸与MCH不相容。
以MCH:赋形剂为1∶50的比试验添加剂与MCH的相容性。发现Aerosil和薄荷醇与MCH相容。二氧化钛和乙基纤维素与MCH 不相容。
试验添加剂与MCH的相容性。将最小质量的水(100μg)添加到MCH,悬浮于具有已证实的相容性的赋形剂,从而鉴定水是否可在抗氧化剂存在与不存在下增强氧化/降解。平行的,将抗氧化剂添加到包括水的MCH悬浮液中。还将抗氧化剂添加到已发现与MCH不相容的赋形剂中。水的添加引起MCH的快速降解。抗氧化剂α-生育酚、BHA/BHT和没食子酸丙酯的添加并不防止MCH降解。在水存在下,相容的赋形剂变得不相容。抗氧化剂的添加不改变该结果。
实施例21-颜色和染色研究
部分A-颜色改变
在25℃、30℃和40℃下在3个月中温育含1%二甲胺四环素的制剂238和216的样品。该时期后,施用(actuate)泡沫产品并观察到颜色变化。在所有三个温度下3个月后观察到最低到无变化。
部分B-染色
在人类皮肤上施用大量MCH244 4%以观察是否发生任何皮肤染色。当约30秒后观察时,在皮肤上摩擦泡沫后注意到最低到无皮肤染色。
Claims (32)
1.一种局部治疗的疏水性易碎性的组合物,其包括
载体,所述载体包括约60重量%至约99重量%的至少一种疏水油和选自由脂肪醇、脂肪酸和蜡组成的组的至少一种粘度改性剂;和
四环素抗生素,
其特征在于
-至少部分所述四环素抗生素被悬浮于所述组合物中;
-所述组合物的粘度比无四环素抗生素的载体的粘度高至少约30%;并高于无所述粘度改性剂的所述疏水油和所述四环素抗生素的粘度;和
其中在25℃下储存至少六个月后,所述组合物保留至少90%的最初存在于所述组合物的四环素;和
其中当在添加有液化或压缩气体喷射剂的气溶胶容器中包封时,所述组合物在从容器释放时提供在施加剪切力时易于破碎的质量至少为良好的易碎泡沫。
2.根据权利要求1所述的局部治疗的组合物,其中所述粘度增加为协同增加,以便使所述载体粘度和疏水油与四环素抗生素的粘度的组合小于所述组合物的粘度。
3.根据权利要求1所述的局部治疗的组合物,其中所述疏水易碎载体在添加喷射剂前为凝胶的形式;其中所述凝胶在施加温和剪切力时容易液化和扩散。
4.根据权利要求1所述的局部治疗的组合物,其中所述疏水易碎载体为泡沫形式;其中所述泡沫具有大于约3分钟的塌缩时间。
5.根据权利要求3所述的局部治疗的组合物,其中除喷射剂以外的组合物与喷射剂的比为约100∶1至约100∶25。
6.根据权利要求1所述的局部治疗的组合物,其中所述至少一种疏水油选自由以下组成的组:矿物油、烃油、酯油、二羧酸的酯、甘油三酯油、植物来源的油、动物来源的油、不饱和或多不饱和油、甘油二酯、PPG烷基醚、精油、硅油、液体石蜡、异链烷烃、聚α烯烃、聚烯烃、聚异丁烯、合成异烷烃、异十六烷、异十二烷、苯甲酸烷基酯、辛酸烷基酯、苯甲酸C12-C15烷基酯、辛酸C12-C15烷基酯、山嵛酸二十烷酯、丙酸二十烷酯、月桂酸苄酯、肉豆蔻酸苄酯、棕榈酸苄酯、双(辛基十二烷基硬脂酰)二聚二亚油酸酯、肉豆蔻酸丁酯、硬脂酸丁酯、鲸蜡硬脂醇乙基己酸酯、鲸蜡硬脂醇异壬酸酯、乙酸十六烷酯、乙基己酸十六烷酯、乳酸十六烷酯、肉豆蔻酸十六烷酯、辛酸十六烷酯、棕榈酸十六烷酯、蓖麻酸十六烷酯、油酸癸酯、二甘醇二乙基己酸酯、二甘醇二辛酸酯、二甘醇二异壬酸酯、二甘醇二异壬酸酯、二乙基己酸酯、己二酸二乙基己酯、苹果酸二乙基己酯、琥珀酸二乙基己酯、己二酸二异丙酯、二聚酸二异丙酯、癸二酸二异丙酯、二异硬脂醇二聚二亚油酸酯、二异硬脂醇富马酸酯、苹果酸二辛酯、癸二酸二辛酯、油酸十二烷基酯、棕榈酸乙基己基酯、羊毛脂酸的酯衍生物、椰油酸乙基己酯、乙基己酸乙基己酯、羟基硬脂酸乙基己酯、异壬酸乙基己酯、棕榈酸乙基己酯、壬酸乙基己酯、硬脂酸乙基己酯、硬脂酸十六烷基酯、月桂酸己酯、月桂酸异戊酯、异十六烷基山嵛酸异十六烷基酯、羊毛脂酸异十六烷基酯、棕榈酸异十六烷基酯、硬脂酸异十六烷基酯、水杨酸异十六烷基酯、硬脂酸异十六烷基酯、硬脂酰硬脂酸异十六烷基酯、辛酸异十六烷基十八烷基酯、乙基己酸异癸酯、异壬酸异癸酯、油酸异癸酯、异壬酸异壬酯、油酸异癸酯、癸酸异己酯、辛酸异壬酯、异硬脂酸异丙酯、羊毛脂酸异丙酯、月桂酸异丙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、硬脂酸异丙酯、山嵛酸异十八烷基酯、柠檬酸异十八烷基酯、芥酸异十八烷基酯、甘醇酸异十八烷基酯、异壬酸异十八烷基酯、异硬脂酸异十八烷基酯、乳酸异十八烷基酯、亚油酸异十八烷基酯、亚麻酸异十八烷基酯、苹果酸异十八烷基脂、新戊酸异十八烷基酯、棕榈酸异十八烷基酯、水杨酸异十八烷基酯、酒石酸异十八烷基酯、异壬酸异十三烷基酯、异壬酸异十三烷基酯、乳酸月桂酯、乳酸肉豆蔻酯、肉豆蔻酸肉豆蔻酯、新戊酸肉豆蔻酯、丙酸肉豆蔻酯、肉豆蔻酸辛基十二醇酯、新戊二醇二癸酸酯、辛基十二醇、硬脂酸辛酯、棕榈酸辛酯、山嵛酸辛基十二醇酯、羟基硬脂酸辛基十二醇酯、肉豆蔻酸辛基十二醇酯、硬脂酰硬脂酸辛基十二醇酯、油基芥酸酯、油基乳酸酯、油基油酸酯、肉豆蔻酸丙酯、丙二醇单肉豆蔻醚乙酸酯、丙二醇二癸酸酯、丙二醇二辛酸酯、丙二醇二辛酸酯、马来酸化大豆油、癸酸十八烷基酯、庚酸十八烷基酯、丙酸十八烷基酯、乙酸生育酚酯、亚油酸生育酚酯、油酸甘油酯、乙基己酸十三烷基酯、异壬酸十三烷基酯、柠檬酸三异十六烷基酯、亚历山大月桂树油、鳄梨油、杏子油、大麦油、琉璃苣籽油、金盏花油、金盏花坚果树油、芥花油、辛酸/癸酸甘油三酯蓖麻油、椰子油、玉米油、棉油、棉籽油、月见草油、亚麻油、花生油、榛子油、甘油聚醚三乙酸酯、甘油三庚酸酯、甘油三辛酸酯、十一酸甘油三酯、大麻籽油、荷荷巴油、苜蓿油、玉米胚油、髓油、小米油、新戊二醇二辛酸酯/二癸酸酯、橄榄油、棕榈油、西番莲油、季戊四醇四硬脂酸酯、罂粟油、蓖麻酸丙二醇酯、菜籽油、黑麦油、红花油、芝麻油、牛油树脂、豆油、大豆油、甜杏仁油、葵花油、蒜芥油、丁香油、茶树油、核桃油、小麦胚甘油酯、小麦胚油、PPG-2丁醚、PPG-4丁醚、PPG-5丁醚、PPG-9丁醚、PPG-12丁醚、PPG-14丁醚、PPG-15丁醚、PPG-15十八烷基醚、PPG-16丁醚、PPG-17丁醚、PPG-18丁醚、PPG-20丁醚、PPG-22丁醚、PPG-24丁醚、PPG-26丁醚、PPG-30丁醚、PPG-33丁醚、PPG-40丁醚、PPG-52丁醚、PPG-53丁醚、PPG-10十六烷基醚、PPG-28十六烷基醚、PPG-30十六烷基醚、PPG-50十六烷基醚、PPG-30异十六烷基醚、PPG-4月桂醚、PPG-7月桂醚、PPG-2甲醚、PPG-3甲醚、PPG-3肉豆蔻醚、PPG-4肉豆蔻醚、PPG-10油基醚、PPG-20油基醚、PPG-23油基醚、PPG-30油基醚、PPG-37油基醚、PPG-40丁醚、PPG-50油基醚、PPG-11十八烷基醚、鲱鱼油、鳕鱼肝油、鲑鱼油、环甲基硅酮、二甲基聚硅氧烷、聚二甲基硅氧烷、环氧改性的硅油、脂肪酸改性的硅油、氟基改性的硅油、甲基苯基聚硅氧烷、苯基聚三甲基硅氧烷和聚醚基改性的硅油。
7.根据权利要求1所述的局部治疗的组合物,其中所述脂肪醇在其碳骨架中具有至少12个碳原子;和其中所述脂肪酸在其碳骨架中具有至少12个碳原子。
8.根据权利要求1所述的局部治疗的组合物,其中所述脂肪醇和所述脂肪酸具有大于约40℃的熔点。
9.根据权利要求9所述的局部治疗的组合物,其中所述脂肪醇选自由月桂醇、十四烷醇、十六烷醇、十八烷醇、二十烷醇、二十二烷醇、二十四烷醇、二十六烷醇、二十八烷醇、三十烷醇、三十四烷醇组成的组;和其中所述脂肪酸选自由十二烷酸、十四烷酸、十六烷酸、十七烷酸、十八烷酸、二十烷酸、二十二烷酸、二十四烷酸、二十六烷酸、二十七烷酸、二十八烷酸、三十烷酸、三十二烷酸、三十三烷酸、三十四烷酸和三十五烷酸组成的组。
10.根据权利要求7所述的局部治疗的组合物,其中所述脂肪醇或所述脂肪酸的碳链被羟基取代。
11.根据权利要求10所述的局部治疗的组合物,其中所述脂肪酸的碳链为12-羟基硬脂酸。
12.根据权利要求1所述的局部治疗的组合物,其中所述蜡选自由植物蜡、巴西棕榈蜡、小烛树蜡、小冠巴西棕榈蜡、甘蔗蜡、藤蔓蜡、荷荷巴油、动物蜡、蜂蜡、石油衍生蜡、固体石蜡、聚乙烯以及其衍生物组成的组。
13.根据权利要求1所述的局部治疗的组合物,其中所述粘度改性剂为包括(i)至少一种脂肪醇和至少一种脂肪酸;或(ii)至少一种脂肪醇和至少一种蜡;或(iii)至少一种脂肪酸和至少一种蜡;或者(iv)至少一种脂肪醇、至少一种脂肪酸和至少一种蜡的组合。
14.根据权利要求1所述的局部治疗的组合物,其中所述疏水易碎载体基本上无表面活性剂、质子溶剂、极性非质子溶剂和硅酮增稠剂。
15.根据权利要求1所述的局部治疗的组合物,其中所述疏水易碎载体基本上无表面活性剂、聚合胶凝剂、多元醇、短链醇和硅酮增稠剂。
16.根据权利要求15所述的局部治疗的组合物,其中所述疏水易碎载体包含小于约0.4%;或小于约0.2%;或小于约0.1%的表面活性剂、质子溶剂、极性非质子溶剂和硅酮增稠剂。
17.根据权利要求1所述的局部治疗的组合物,其中所述四环素抗生素选自由四环素、土霉素、去甲金霉素、强力霉素、赖氨甲四环素、甲基氯环素、甲烯土霉素、二甲胺四环素、吡甲四环素、金霉素和替加环素组成的组。
18.根据权利要求1所述的局部治疗的组合物,其中所述四环素抗生素为疏水的。
19.根据权利要求1所述的局部治疗的组合物,其中所述四环素抗生素以游离碱形式、水合物形式、盐形式或配合物形式存在。
20.根据权利要求19所述的局部治疗的组合物,其中所述四环素抗生素在pH7.0(缓冲液/氯仿)下的分布常数的Log等于或小于约0.2。
21.根据权利要求18所述的局部治疗的组合物,其中所述四环素抗生素在碳5、6和7位不包括任何羟基。
22.根据权利要求18所述的局部治疗的组合物,其中所述四环素抗生素选自二甲胺四环素和强力霉素的组;或为二甲胺四环素。
23.根据权利要求1所述的局部治疗的组合物,其进一步包括另外的活性剂。
24.根据权利要求23所述的局部治疗的组合物,其中所述另外的活性剂选自由以下组成的组:活性草本提取物、杀螨剂、老年斑和角质去除剂、过敏原、α-羟基酸、镇痛剂、雄性激素、抗痤疮剂、抗过敏剂、抗衰老剂、抗菌剂、抗生素、抗灼烧剂、抗癌剂、去屑剂、抗抑郁剂、抗皮炎剂、消水肿剂、抗真菌剂、抗组胺剂、抗蠕虫剂、抗角化过度剂、抗感染剂、抗炎剂、抗刺激剂、降血脂剂、抗微生物剂、抗霉菌剂、抗氧化剂、抗寄生虫剂、抗增殖剂、止痒剂、抗银屑病剂、抗红斑痤疮剂、抗皮脂溢剂、防腐剂、防膨胀剂、抗病毒剂、抗疣剂、抗皱剂、抗酵母剂、收敛剂、β-羟基酸、过氧化苯甲酰、局部心血管剂、化疗剂、皮质类固醇、免疫原性物质、二羧酸、消毒剂、雌性激素、杀真菌剂、头发生长调节剂、半抗原、激素、羟基酸、免疫抑制剂、免疫调节剂、免疫调制剂、免疫刺激剂、杀虫剂、驱虫剂、角质软化剂、内酰胺、局部麻醉剂、润滑剂、遮蔽剂、金属、金属氧化物、杀恙虫药、神经肽、非甾族抗炎剂、氧化剂、灭虱剂、肽、农药、蛋白质、光动力治疗剂、黄体酮、游离基清除剂、加脂剂、类视黄醇、治愈剂、灭疥疮剂、镇静剂、美黑剂、皮肤防护剂、皮肤增白剂、类固醇、类固醇激素、血管活化剂、血管收缩剂、血管扩张剂、维生素、维生素A、维生素A衍生物、维生素B、维生素B衍生物、维生素C、维生素C衍生物、维生素D、维生素D衍生物、维生素D类似物、维生素F、维生素F衍生物、维生素K、维生素K衍生物、伤口愈合剂和疣去除剂。
25.根据权利要求1所述的组合物,其中,当在使用人类或猪的皮肤的弗朗茨细胞体外模型中试验时,在皮肤中提供比经皮转移的相对量高的四环素的量。
26.根据权利要求25所述的组合物,其中,当在使用人类或猪的皮肤的弗朗茨细胞体外模型中试验时,皮肤中四环素的量与经皮转移的相对量之间的比高于约100∶1;或在约100∶1和约10∶1之间;或在约10∶1和约2∶1之间;或者大于1∶1。
27.根据权利要求1所述的组合物,其中当在使用人类或猪的皮肤的弗朗茨细胞体外模型中试验时,在所述疏水性易碎性的组合物中的所述四环素的浓度高于致使所述四环素具有治疗效果的足够浓度的皮肤内递送的最低浓度。
28.根据权利要求1所述的组合物,其中所述组合物防止四环素抗生素在应用到治疗靶点时的降解。
29.一种预防、治疗或缓解皮肤科、眼科、妇科或粘膜紊乱的症状的方法,其包括:向靶区域局部应用前述权利要求任一项所述的疏水性治疗组合物。
30.根据权利要求29所述的方法,其中所述紊乱包括细菌感染、炎症、氧化应激和神经变性和/或凋亡作为其病因之一。
31.根据权利要求29所述的方法,其中所述紊乱选自由以下组成的组:皮肤病症脓肿、痤疮、聚合性痤疮、暴发性痤疮、寻常痤疮、痤疮疤痕、急性发热性嗜中性白细胞皮肤病、急性淋巴管炎、变应性接触性皮炎、秃头症、足癣、特应性皮炎、细菌性皮肤感染、脱发、基底细胞癌、水疱、腋臭、大疱性类天疱疮、灼伤、胼胝念珠菌病、痈、蜂窝组织炎、化学灼伤、水痘、胆脂瘤、胆碱能性荨麻疹、日光的慢性效应、唇疱疹、寒冷性荨麻疹、粉刺、鸡眼、匐行疹、皮肤脓疮、皮肤幼虫移行症、肤蛆病、黑斑、寄生虫妄想症、痛性脂肪病、皮炎、疱疹样皮炎、皮肤疼痛、皮肤炎症、皮肤划痕现象、皮肤真菌病、药疹和药物反应、汗疱、外胚层发育不良、湿疹、深脓疱、表皮囊肿、表皮坏死、丹毒、丹毒、红斑、剥落性皮炎、多形性红斑、结节性红斑、毛囊炎、真菌指甲感染、真菌皮肤感染、疖、坏疽、生殖器疱疹、环状肉芽肿、头虱、化脓性汗腺炎、荨麻疹、毛囊炎、多毛症、多汗症、少汗症、鱼鳞癣、脓疱病、炎性痤疮、嵌甲、擦烂、刺激性接触性皮炎、缺血性坏死、瘙痒、股癣、卡波西肉瘤、毛发角化病、慢性单纯性苔癣、扁平苔癣、硬化性苔癣、淋巴结炎、淋巴结炎、淋巴管炎、恶性黑色素瘤、肥大细胞增多症、麻疹、黑色素瘤、黑色素瘤、汗疹、痣、触染性软疣、MRSA、坏死性皮下感染、坏死性筋膜炎、坏死性肌炎、结节状丘疹脓疱型粉刺、非炎性粉刺、钱币状皮炎、口腔疱疹、脂膜炎、类银屑病、甲沟炎、寄生性皮肤感染、天疱疮、光过敏、光损伤、光刺激、光敏感、丘疹、虱病、口周皮炎、面疱、玫瑰糠疹、苔癣样糠疹、玫瑰糠疹、毛发红糠疹、接触毒漆引起的皮疹、术后或外科术后皮肤病、压迫性溃疡、压迫性荨麻疹、瘙痒症、须部假性毛囊炎、牛皮癣、PUPPP、紫癜、脓疱、脓性肉芽肿、疹、癣菌病、红斑痤疮、玫瑰疹、风疹、疥疮、皮肤烫伤综合征、伤疤、硬皮病、皮脂囊肿、脂溢性皮炎、脂溢性角化病、带状疱疹、皮肤老化、皮肤癌、皮肤瘤、皮肤赘生物、皮疹、皮肤溃疡、鳞状细胞癌、金黄色葡萄球菌烫伤样皮肤综合征、停滞性皮炎、史蒂文斯-约翰逊综合征、晒伤、太阳斑、热灼伤、体癣、股癣、脚癣、花斑癣、中毒性表皮坏死松解症、皮肤外伤或损伤、水痘带状疱疹病毒、维生素D缺乏、病毒性皮肤感染、白癜风、疣、水性荨麻疹、皱纹、干燥症、酵母皮肤感染和带状疱疹;
体腔或粘膜表面紊乱,鼻、嘴、眼、耳、呼吸系统、阴道、尿道或直肠的紊乱,衣原体感染、淋病感染、乙型肝炎、疱疹、HIV/AIDS、人乳头瘤病毒(HPV)、生殖器疣、细菌性阴道炎、念珠菌病、软下疳、腹股沟肉芽肿、性病淋巴肉芽肿、粘脓性宫颈炎(MPC)、触染性软疣、非淋病性尿道炎(NGU)、滴虫病、外阴紊乱、外阴痛、外阴疼痛、酵母感染、外阴萎缩、外阴上皮内瘤样病变(VIN)、接触性皮炎、盆腔炎、子宫内膜炎、输卵管炎、卵巢炎、生殖器癌、子宫颈癌、外阴癌、阴道癌、阴道干燥、性交困难、肛门和直肠疾病、肛门脓疮/瘘管、肛门癌、肛裂、肛门疣、克罗恩氏病、痔疮、肛门瘙痒、肛门瘙痒症、大便失禁、便秘、结肠和直肠息肉;
眼部紊乱,眼布血丝、眼痛或光敏感、视力模糊、视觉丧失、视觉障碍-飞蚊症、闪光、失真、光晕等、痒/灼烧、流泪/流脓、感觉眼内有异物、眼睑问题、复视;
眼部过敏、眼睑炎、白内障、中心性浆液性脉络膜视网膜病变、色觉问题、角膜擦伤、角膜水肿、角膜溃疡、结膜炎、隐形眼镜并发症、泪囊炎、模糊远视、干眼、视网膜静脉周围炎、巩膜外层炎、眼睑外翻、眼睑内翻、眼睑蜂窝性组织炎、眼疲劳、聚焦痉挛、青光眼、急性青光眼、虹膜炎、圆锥形角膜、莱姆病、黄斑变性、黄斑水肿、黄斑裂孔、眼药物毒性、重症肌无力、瘢痕性眼天疱疮、眼性偏头痛、老花眼、泪管堵塞、视神经炎、视神经中风、眶骨骨折、眼眶蜂窝组织炎、小水疱病、翼状胬肉、复发性角膜糜烂、视网膜动脉阻塞、视网膜脱离、视网膜裂孔、视网膜静脉阻塞、结节病、巩膜炎、窦病、斜视(眼部失调)、结膜下出血、颞动脉炎、甲状腺相关性眼病、倒睫、睑瘤、眼睑抽搐(眼睑肌纤维颤搐)、葡萄膜炎、玻璃体脱离和玻璃体积血。
32.根据权利要求30所述的方法,其中所述紊乱选自由皮肤感染、痤疮、红斑痤疮、眼部感染、眼红斑痤疮、眼睑炎、干眼、沙眼和青光眼组成的组。
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Families Citing this family (140)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8512718B2 (en) | 2000-07-03 | 2013-08-20 | Foamix Ltd. | Pharmaceutical composition for topical application |
IL152486A0 (en) * | 2002-10-25 | 2003-05-29 | Meir Eini | Alcohol-free cosmetic and pharmaceutical foam carrier |
US20070292359A1 (en) * | 2002-10-25 | 2007-12-20 | Foamix Ltd. | Polypropylene glycol foamable vehicle and pharmaceutical compositions thereof |
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US20130338122A1 (en) | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
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US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
RU2504383C1 (ru) * | 2012-07-10 | 2014-01-20 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Омский государственный аграрный университет имени П.А. Столыпина" | Способ лечения острых послеродовых эндометритов у коров |
US10507245B2 (en) | 2012-07-19 | 2019-12-17 | Luis Felipe Vejarano Restrepo | Ophthalmic formulation and method for ameliorating presbyopia |
EP2877184B1 (en) | 2012-07-27 | 2019-09-04 | Glia Llc | Compositions and treatment for eye diseases and disorders |
US9180091B2 (en) | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
EP2968088A4 (en) | 2013-03-15 | 2016-08-17 | Leading Edge Innovations Llc | ESSENTIALLY NON-CLEAN SUBMICROMETER DISPERSION HYDROPHOLE SUBSTANCES HAVING A WATER-MIXABLE SOLVENT |
US20140322428A1 (en) | 2013-03-15 | 2014-10-30 | Leading Edge Innovations, LLC | Compositions having an oil-in-water dispersion of submicron particles to enhance foods and beverages |
AU2014235779B2 (en) * | 2013-03-15 | 2015-11-26 | NanoRx, Inc. | Metadichol liquid and gel nanoparticle formulations |
DE102013217242A1 (de) * | 2013-08-29 | 2015-03-05 | Beiersdorf Ag | Emulgatorfreie, hautkonditionierende, kosmetische oder dermatologische Zubereitung mit Peelingwirkstoffen |
US9474720B2 (en) | 2013-11-04 | 2016-10-25 | BioPharmX, Inc. | Dosage form comprising an active ingredient and a plurality of solid porous microcarriers |
US9226890B1 (en) | 2013-12-10 | 2016-01-05 | Englewood Lab, Llc | Polysilicone base for scar treatment |
US20170007507A1 (en) * | 2014-02-07 | 2017-01-12 | Coty Inc. | Free standing color cosmetic stick |
EP3107890A4 (en) * | 2014-02-18 | 2017-07-05 | Elevance Renewable Sciences, Inc. | Branched-chain esters and methods of making and using the same |
US20160184431A1 (en) | 2014-03-11 | 2016-06-30 | Promius Pharma Llc | Topical compositions comprising a corticosteroid |
MX2016011842A (es) * | 2014-03-11 | 2017-02-02 | Promius Pharma Llc | Composiciones tópicas de corticosteroides. |
MX2016014281A (es) | 2014-05-22 | 2017-02-22 | Therapeuticsmd Inc | Formulaciones y terapias de reemplazo de combinación de hormonas naturales. |
RU2016141135A (ru) | 2014-07-29 | 2018-08-28 | Терапьютиксмд, Инк. | Трансдермальный крем |
AU2014407159B2 (en) | 2014-09-23 | 2018-05-10 | Colgate-Palmolive Company | Non-greasy personal care compositions |
US9895311B2 (en) | 2014-09-25 | 2018-02-20 | Pharmiva Ab | Foam-forming compositions and methods for delivering an active to a body cavity |
CN104352527A (zh) * | 2014-10-20 | 2015-02-18 | 中山百鸥医药科技有限公司 | 鱼肝油在治疗妇科病中的用途 |
WO2016070194A1 (en) * | 2014-10-31 | 2016-05-06 | Pomega, Inc. | Formulations containing pomegranate seed oil, rosa canina fruit oil and inula viscosa oleoresin or extract |
KR102332621B1 (ko) * | 2014-11-21 | 2021-12-01 | 삼성전자주식회사 | 신호 송수신 회로 및 이를 포함하는 전자 장치 |
DE102015121112A1 (de) * | 2014-12-23 | 2016-06-23 | Kalle Gmbh | Biozid-freies, vorbefeuchtetes Schwammtuch |
EP3258907B1 (en) | 2015-02-19 | 2019-07-17 | Unilever Plc. | Fast rinsing cleansing composition |
AU2016224863A1 (en) | 2015-02-25 | 2017-10-12 | Sun Pharma Advanced Research Company Ltd | Nanoparticulate composition |
JP6793715B2 (ja) | 2015-03-23 | 2020-12-02 | バイオファーミクス・インコーポレイテッドBioPharmX, Inc. | テトラサイクリンの皮膚用医薬組成物 |
EP3285728B1 (en) | 2015-04-23 | 2019-12-18 | The Procter and Gamble Company | Concentrated personal cleansing compositions and methods |
CN107530245B (zh) | 2015-04-23 | 2021-05-04 | 宝洁公司 | 浓缩型个人清洁组合物和用途 |
CN107530247B (zh) | 2015-04-23 | 2021-09-07 | 宝洁公司 | 浓缩型个人清洁组合物 |
US10952950B2 (en) | 2015-04-23 | 2021-03-23 | The Procter And Gamble Company | Concentrated personal cleansing compositions and methods |
KR101875997B1 (ko) * | 2015-05-04 | 2018-07-06 | 엔 앤드 엔 파마세우티칼스 인크. | 엔-메탄노카르바티미딘을 이용한 대상포진의 치료방법 |
KR20180003548A (ko) * | 2015-05-12 | 2018-01-09 | 라이온 가부시키가이샤 | 안과용 조성물 |
HUE059066T2 (hu) | 2015-05-21 | 2022-10-28 | Dermavant Sciences GmbH | Topikus gyógyszerkészítmények |
US11617724B2 (en) | 2015-05-21 | 2023-04-04 | Dermavant Sciences GmbH | Topical pharmaceutical compositions |
DE102015209752A1 (de) * | 2015-05-28 | 2016-12-01 | Beiersdorf Ag | Sprühfähige hochviskose kosmetische Zubereitung |
US20200405637A1 (en) * | 2015-06-19 | 2020-12-31 | Global Health Solutions Llc | Oil-based wound care compositions and methods |
US10675243B2 (en) * | 2015-06-19 | 2020-06-09 | Global Health Solutions Llc | Petrolatum-based compositions comprising cationic biocides |
US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
US20190307778A1 (en) * | 2015-08-20 | 2019-10-10 | Foamix Pharmaceuticals Ltd. | Tetracycline management of egfr inhibitor associated dermatoses |
US9617504B2 (en) * | 2015-09-22 | 2017-04-11 | Scott Robert Sorenson | Non-medicated personal care cleansing solution and a method of synthesizing the same |
US20170121098A1 (en) | 2015-11-02 | 2017-05-04 | American Sterilizer Company | Non-aspirating transport gel dispenser |
US11931379B2 (en) * | 2015-12-22 | 2024-03-19 | Johnson & Johnson Consumer Inc. | Stable foaming composition and method of use |
WO2017131214A1 (ja) | 2016-01-29 | 2017-08-03 | 日産化学工業株式会社 | 水溶性有効成分の放出が制御された経皮吸収組成物 |
WO2017173044A1 (en) | 2016-04-01 | 2017-10-05 | Therapeuticsmd Inc. | Steroid hormone compositions in medium chain oils |
WO2017173071A1 (en) | 2016-04-01 | 2017-10-05 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical composition |
US11103428B2 (en) | 2016-04-15 | 2021-08-31 | Nusil Technology Llc | Surfactant free silicone emulsion |
WO2017197196A1 (en) | 2016-05-11 | 2017-11-16 | Bayer Healthcare Llc | Whipped gel formulations |
CA3023714C (en) | 2016-05-11 | 2022-07-19 | Bayer Healthcare Llc | Whipped formulations |
CN105833279B (zh) * | 2016-05-30 | 2021-06-22 | 傅远桥 | 皮肤多种损伤创面治疗的外用药物组合物及其制备方法 |
MX2020012139A (es) | 2016-09-08 | 2021-01-29 | Vyne Pharmaceuticals Inc | Composiciones y metodos para tratar rosacea y acne. |
GB201615693D0 (en) | 2016-09-15 | 2016-11-02 | Combinatorx Infection Ltd | Combinations |
US11185486B2 (en) | 2016-10-21 | 2021-11-30 | The Procter And Gamble Company | Personal cleansing compositions and methods |
CN109843253B (zh) | 2016-10-21 | 2022-11-08 | 宝洁公司 | 皮肤清洁组合物和方法 |
JP7020941B2 (ja) * | 2017-02-03 | 2022-02-16 | 日本精化株式会社 | 化粧料 |
US11602303B2 (en) | 2017-02-10 | 2023-03-14 | Mauricio De Maio Domingos | Methods and systems for preventing, correcting, transforming, and modifying facial, aesthetics, and consulting patients regarding the same |
US10675231B2 (en) * | 2017-02-17 | 2020-06-09 | The Procter & Gamble Company | Packaged personal cleansing product |
US11383084B2 (en) * | 2017-04-27 | 2022-07-12 | Palo Alto Investors | Treatment of dermatological conditions via neuromodulation |
US11602493B2 (en) | 2017-05-11 | 2023-03-14 | Beiersdorf Ag | Gel formulations |
DK3628002T3 (da) | 2017-05-23 | 2023-06-06 | Pharmiva Ab | Skumdannende sammensætninger til fremføring af et aktivt stof til en legemshulhed |
WO2018234865A1 (en) * | 2017-06-20 | 2018-12-27 | Foamix Pharmaceuticals Ltd. | STABLE TOPICAL COMPOSITIONS OF TETRACYCLINE |
EP3691728A4 (en) | 2017-10-04 | 2021-06-30 | Pneuma Respiratory, Inc. | ELECTRONIC BREATH-ACTUATED INLINE DROPLET DISPENSER AND METHOD OF USE |
EP3706843A4 (en) | 2017-11-08 | 2021-08-25 | Pneuma Respiratory, Inc. | ELECTRONIC BREATHED INLINE DROPLET DISPENSER WITH SMALL VOLUME AMPOULE AND METHOD OF USE |
FR3075532A1 (fr) * | 2017-12-14 | 2019-06-21 | Orange | Procede de generation d’un signal multiporteuse, procede de demodulation, produit programme d’ordinateur et dispositifs correspondants. |
EP3735249A1 (en) | 2018-01-07 | 2020-11-11 | Dr. Reddy's Laboratories Ltd. | Minocycline for treating inflammatory skin conditions |
EP3743047A1 (en) * | 2018-01-26 | 2020-12-02 | The Procter & Gamble Company | Methods and compositions for reducing the feeling of vaginal dryness |
US10285998B1 (en) | 2018-04-04 | 2019-05-14 | The Menopause Method, Inc. | Composition and method to aid in hormone replacement therapy |
GB201813876D0 (en) | 2018-08-24 | 2018-10-10 | Antibiotx As | Treatment |
JP2022506799A (ja) | 2018-11-02 | 2022-01-17 | ユニオン セラピューティクス エー/エス | 皮膚炎の症状を処置するためのハロゲン化サリチルアニリド |
WO2020089467A1 (en) | 2018-11-02 | 2020-05-07 | UNION therapeutics A/S | Dosage regimen |
US11497718B2 (en) | 2018-11-13 | 2022-11-15 | Dermavant Sciences GmbH | Use of tapinarof for the treatment of atopic dermatitis |
US10588871B1 (en) | 2019-06-28 | 2020-03-17 | Nexzol Pharma, Inc. | Transdermal formulation for the treatment of pain and/or inflammation |
AU2020301119A1 (en) * | 2019-06-28 | 2022-01-20 | Nexzol Pharma, Inc. | Transdermal formulations |
EP4003302A1 (en) | 2019-07-31 | 2022-06-01 | Journey Medical Corporation | Compositions and methods and uses thereof |
BE1027141B1 (nl) | 2019-08-30 | 2020-10-15 | Oystershell Nv | Polyisobuteen voor gebruik bij behandeling of preventie van infectie door geleedpotigen |
US11590073B2 (en) | 2020-06-09 | 2023-02-28 | The Procter & Gamble Company | Methods and compositions for reducing the feeling of vaginal dryness |
WO2022006187A1 (en) * | 2020-06-30 | 2022-01-06 | Np Pharma Holdings, Llc | Methods of using cannabinoid compositions for inducing and promoting sleep |
WO2022122136A1 (en) | 2020-12-09 | 2022-06-16 | Symrise Ag | Compositions comprising one or more (bio)-alkanediols with antioxidants |
IT202100002126A1 (it) * | 2021-02-02 | 2022-08-02 | Binar S R L | Calzature ipoallergeniche e metodo per prevenire la dermatite allergica da contatto acd |
CN112829395B (zh) * | 2021-02-05 | 2023-07-04 | 义乌市皓祺服饰有限公司 | 一种防水透气冲锋衣面料的制备方法 |
WO2022256101A1 (en) * | 2021-06-04 | 2022-12-08 | Demary Dean | Systems, devices, and/or methods for human hygiene |
WO2022271848A1 (en) | 2021-06-22 | 2022-12-29 | Pneuma Respiratory, Inc. | Droplet delivery device with push ejection |
EP4108234A1 (en) * | 2021-06-25 | 2022-12-28 | RaDes GmbH | Topical pharmaceutical formulation |
WO2023064477A1 (en) * | 2021-10-13 | 2023-04-20 | Pneuma Respiratory, Inc. | Compositions for delivery of cannabinoids |
WO2023097309A1 (en) | 2021-11-29 | 2023-06-01 | Ironwood Pharmaceuticals, Inc. | Pharmaceutical compositions for the treatment of visceral pain |
WO2023204972A1 (en) * | 2022-04-19 | 2023-10-26 | Cargill, Incorporated | Process for solvent recovery in vegetable oil extraction |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050069566A1 (en) * | 2003-08-04 | 2005-03-31 | Foamix Ltd. | Foam carrier containing amphiphilic copolymeric gelling agent |
US20080167376A1 (en) * | 2003-09-25 | 2008-07-10 | Dmi Biosciences, Inc. | Methods and products which utilize N-acyl-L-aspartic acid |
US20080188445A1 (en) * | 2007-02-02 | 2008-08-07 | Warner Chilcott Company Inc. | Tetracycline compositions for topical administration |
US20080188446A1 (en) * | 2007-02-02 | 2008-08-07 | Warner Chilcott Company Inc. | Tetracycline compositions for topical administration |
WO2009072007A2 (en) * | 2007-12-07 | 2009-06-11 | Foamix Ltd. | Carriers, formulations, methods for formulating unstable active agents for external application and uses thereof |
US20090180970A1 (en) * | 2002-10-25 | 2009-07-16 | Foamix Ltd. | Foamable composition combining a polar solvent and a hydrophobic carrier |
Family Cites Families (1199)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1159250A (en) | 1914-05-01 | 1915-11-02 | Frank Moulton | Vaginal irrigator. |
US1666684A (en) | 1926-01-15 | 1928-04-17 | Carstens Mfg Co H | Vaginal douche |
US1924972A (en) | 1929-04-15 | 1933-08-29 | Carl J Beckert | Stabilized egg product |
US2085733A (en) | 1935-07-15 | 1937-07-06 | John C Bird | Shaving cream |
US2390921A (en) | 1943-03-23 | 1945-12-11 | Ethel Hudson Clark | Applicator for facial creams |
US2524590A (en) | 1946-04-22 | 1950-10-03 | Carsten F Boe | Emulsion containing a liquefied propellant gas under pressure and method of spraying same |
US2586287A (en) | 1948-12-11 | 1952-02-19 | Colagte Palmolive Peet Company | Aluminum sulfamate antiperspirant preparation |
US2617754A (en) | 1949-08-29 | 1952-11-11 | Procter & Gamble | Cosmetic cream |
US3062715A (en) | 1953-11-18 | 1962-11-06 | George S Pfaus | Vaginal tablet |
US2767712A (en) | 1954-03-01 | 1956-10-23 | Neil S Waterman | Medicinal applicator |
GB808104A (en) | 1955-01-04 | 1959-01-28 | Udylite Res Corp | Electrodeposition of copper from aqueous alkaline cyanide solutions |
GB808105A (en) | 1956-06-15 | 1959-01-28 | Ici Ltd | New pharmaceutical compositions |
US3092555A (en) | 1958-04-21 | 1963-06-04 | Roy H Horn | Relatively collapsible aerosol foam compositions |
US3144386A (en) | 1958-05-09 | 1964-08-11 | Merck & Co Inc | Mastitis aerosol foam |
US2968628A (en) | 1958-10-17 | 1961-01-17 | Shulton Inc | Propellant composition |
US3178352A (en) | 1959-02-27 | 1965-04-13 | Erickson Roy | Shaving method and composition therefor |
US3141821A (en) | 1959-03-17 | 1964-07-21 | Lehn & Fink Products Corp | Synergistic combination of alkyl sulfonates, alkylaryl sulfonates and topical antibacterial agents for local antisepsis |
US3004894A (en) | 1959-04-07 | 1961-10-17 | Upjohn Co | Therapeutic composition comprising tetracycline and a dioxolane |
GB922930A (en) | 1959-09-21 | 1963-04-03 | Sunnen Joseph | Spermicidal composition and method of making same |
US3142420A (en) | 1959-11-09 | 1964-07-28 | Neotechnic Eng Ltd | Metering dispenser for aerosol with fluid pressure operated piston |
US3092255A (en) | 1960-02-05 | 1963-06-04 | Robert F Hohman | Sorting apparatus |
US3067784A (en) | 1960-04-14 | 1962-12-11 | Esta Medical Lab Inc | Adapter connecting aerosol container valve stem to dispenser for filling said dispenser |
NL270627A (zh) | 1960-10-26 | |||
US3154075A (en) | 1960-11-02 | 1964-10-27 | Norwich Pharma Co | Vaginal applicator |
GB998490A (en) | 1961-06-03 | 1965-07-14 | Albert Fritz Albach | A foam projector |
DE1926796U (de) | 1961-10-12 | 1965-11-11 | Heidolph Elektro K G | Geblaese. |
NL285082A (zh) | 1962-02-28 | |||
US3261695A (en) | 1962-12-24 | 1966-07-19 | Gen Foods Corp | Process for preparing dehydrated foods |
US3330730A (en) | 1962-08-03 | 1967-07-11 | Colgate Palmolive Co | Pressurized emulsion quick breaking foam compositions |
US3252859A (en) | 1962-10-24 | 1966-05-24 | Masti Kure Company Inc | Colloidal silica-oil composition and method of using same |
US3244589A (en) | 1962-10-26 | 1966-04-05 | Sunnen | Alkyl phenoxy polyethoxy ether spermicidal aerosol |
US3298919A (en) | 1962-12-26 | 1967-01-17 | Dow Corning | Shaving cream containing polysiloxanes |
US3383280A (en) | 1963-01-09 | 1968-05-14 | Miles Lab | Dermatological abradant stick-type applicator |
FR1355607A (fr) | 1963-01-22 | 1964-03-20 | Perfectionnements aux sondes canules et leurs applications | |
US3149543A (en) | 1963-03-04 | 1964-09-22 | Ingersoll Rand Co | Non-lubricated piston |
GB1026831A (en) | 1963-05-31 | 1966-04-20 | Mediline Ag | Preparations for use in feminine hygiene |
US3824303A (en) | 1963-07-24 | 1974-07-16 | Yardley Of London Inc | Collapsible foam pre-electric shave lotion containing diester lubricants |
GB1081949A (en) | 1963-08-12 | 1967-09-06 | Avon Prod Inc | Improvements in cosmetic mask |
US3333333A (en) | 1963-08-14 | 1967-08-01 | Rca Corp | Method of making magnetic material with pattern of embedded non-magnetic material |
US3236457A (en) | 1963-08-21 | 1966-02-22 | John R Kennedy | Composite spray container assembly |
US3263867A (en) | 1963-12-26 | 1966-08-02 | Valve Corp Of America | Metering button-type aerosol actuator |
US3395214A (en) | 1964-01-09 | 1968-07-30 | Scholl Mfg Co Inc | Antiperspirant composition providing a readily collapsible sprayable foam |
US3278093A (en) | 1964-01-13 | 1966-10-11 | Valve Corp Of America | Metering and non-metering aerosol actuator button |
GB1052724A (zh) | 1964-04-27 | |||
US3303970A (en) | 1964-07-14 | 1967-02-14 | Jerome Marrow | Device for simultaneously dispensing from plural sources |
US3395215A (en) | 1964-10-15 | 1968-07-30 | Colgate Palmolive Co | Pressurized lotion composition |
US3384541A (en) | 1964-10-28 | 1968-05-21 | William G. Clark | Spermicidal vaginal pharmaceutical concentrate for producing nonaqueous foam with aerosol propellants |
US3263869A (en) | 1964-11-03 | 1966-08-02 | Calmar Inc | Liquid dispenser with overcap |
US3342845A (en) | 1964-11-05 | 1967-09-19 | Upjohn Co | Terphenyl triisocyanates |
US3419658A (en) | 1965-01-25 | 1968-12-31 | Du Pont | Nonaqueous aerosol foams containing mineral oil |
US3346451A (en) | 1965-01-27 | 1967-10-10 | S E Massengill Company | Concentrated liquid lactic acid douche preparation containing aromatics |
US3301444A (en) | 1965-08-12 | 1967-01-31 | Oel Inc | Aerosol metering valve |
US3456052A (en) | 1965-09-28 | 1969-07-15 | Garrett Lab Inc | Aerosol composition containing butoxymonoether of a polyoxyalkylene glycol |
GB1121358A (en) | 1965-10-21 | 1968-07-24 | Bristol Myers Co | Aerosol manufacture |
US3849569A (en) | 1965-12-02 | 1974-11-19 | Glaxo Lab Ltd | Composition containing procaine penicillin |
BE692228A (zh) | 1966-01-10 | 1967-07-05 | ||
US3401849A (en) | 1966-05-24 | 1968-09-17 | Robert L. Weber | Low force metering valve |
US3886084A (en) | 1966-09-29 | 1975-05-27 | Champion Int Corp | Microencapsulation system |
US3377004A (en) | 1966-10-03 | 1968-04-09 | Gen Mills Inc | Metered dispensing container |
GB1201918A (en) | 1966-12-21 | 1970-08-12 | Bespak Industries Ltd | Improvements in or relating to valves for pressurised dispensers |
US3527559A (en) | 1967-01-05 | 1970-09-08 | Standard Pharmacal Corp | Dense aqueous aerosol foam depilatory compositions containing a mixture of alkaline metal and alkali metal thioglycolates and a fatty alcohol-alkylene oxide wax emulsifying agent |
US3366494A (en) | 1967-02-15 | 1968-01-30 | Du Pont | Pressurized aerosol food emulsions |
US3561262A (en) | 1967-10-26 | 1971-02-09 | Magnaflux Corp | Water soluble developer |
US3540448A (en) | 1968-01-17 | 1970-11-17 | Joseph Sunnen | Rechargeable applicator for dispensing substances in a foam condition |
DE1926796A1 (de) | 1968-05-27 | 1970-03-19 | Dudiuyt Jean Paul | Verfahren zum Herstellen eines Gemisches aus einem Wirkstoff mit einer Traegerfluessigkeit zur Austreibung aus einem dichten Behaelter sowie Sonnenschutzmittel |
US3563098A (en) | 1968-06-28 | 1971-02-16 | Rex Chainbelt Inc | Automatic quick release mechanism |
US3559890A (en) | 1968-09-03 | 1971-02-02 | William R Brooks | Foam dispenser |
US3878118A (en) | 1968-09-06 | 1975-04-15 | Wilkinson Sword Ltd | Self-heating chemical compositions |
US3667461A (en) | 1968-11-05 | 1972-06-06 | Paul A Zamarra | Disposable syringe |
CA975500A (en) | 1969-02-06 | 1975-09-30 | Joseph G. Spitzer | Structures such as applicator pads for cleaning and other purposes, propellant compositions for forming the same, and process |
US3866800A (en) | 1969-02-12 | 1975-02-18 | Alberto Culver Co | Non-pressurized package containing self-heating products |
US3966090A (en) | 1969-02-17 | 1976-06-29 | Dart Industries Inc. | Package for dispensing an antiseptic composition |
US4001391A (en) | 1969-04-18 | 1977-01-04 | Plough, Inc. | Means for depositing aerosol sprays in buttery form |
US3819524A (en) | 1969-06-17 | 1974-06-25 | Colgate Palmolive Co | Cosmetic composition for thermal dispensing |
US3577518A (en) | 1969-07-18 | 1971-05-04 | Nat Patent Dev Corp | Hydrophilic hairspray and hair setting preparations |
US3787566A (en) | 1969-07-29 | 1974-01-22 | Holliston Labor Inc | Disinfecting aerosol compositions |
BE759520A (fr) | 1969-11-28 | 1971-04-30 | Aspro Nicholas Ltd | Compositions d'aspirine |
GB1353381A (en) | 1971-02-04 | 1974-05-15 | Wilkinson Sword Ltd | Substituted p-menthanes and compositions containing them |
GB1351761A (en) | 1971-02-04 | 1974-05-01 | Wilkinson Sword Ltd | Substituted p-menthane carboxamides and compositions containing them |
GB1351762A (en) | 1971-02-14 | 1974-05-01 | Wilkinson Sword Ltd | Tobacco and tobacco-containing manufactures |
CA958338A (en) | 1971-03-08 | 1974-11-26 | Chung T. Shin | Antiperspirant powder aerosol compositions containing aluminum chloride and water soluble aluminum compounds and methods of preparation |
US3770648A (en) | 1971-07-12 | 1973-11-06 | Bristol Myers Co | Anhydrous aerosol foam |
US3912667A (en) | 1971-09-13 | 1975-10-14 | Spitzer Joseph G | Structures such as applicator pads for cleaning and other purposes, propellant compositions for forming the same and process |
BE788788A (fr) | 1971-09-13 | 1973-03-13 | Treuhandvereinigung Ag | Produit pour conserver, favoriser et retablir la chevelure et procede de fabrication de ce produit |
SE358308B (zh) | 1971-11-26 | 1973-07-30 | Pharmacia Ab | |
US3997467A (en) | 1971-11-26 | 1976-12-14 | Pharmacia Aktiebolag | Foam forming composition |
CH1917171A4 (zh) | 1971-12-30 | 1975-04-30 | ||
JPS4892282U (zh) | 1972-02-05 | 1973-11-06 | ||
US3963833A (en) | 1972-06-02 | 1976-06-15 | Colgate-Palmolive Company | Antiperspirant composition and method containing a dihydro-benzofuran and an astringent metal salt |
US3841525A (en) | 1972-06-14 | 1974-10-15 | N Siegel | Aerosol spray device with cam activator |
US3849580A (en) | 1972-09-05 | 1974-11-19 | American Home Prod | Aerosol dispensing system for anhydrous edible fat compositions |
US3751562A (en) | 1972-09-22 | 1973-08-07 | Princeton Biomedix | Medicated gelled oils |
US3970584A (en) | 1973-02-14 | 1976-07-20 | S. C. Johnson & Son, Inc. | Aerosol package containing a foam-forming emulsion and propellent system |
US4439416A (en) | 1973-03-23 | 1984-03-27 | Colgate-Palmolive Company | Self-heating shaving composition |
GB1423179A (en) | 1973-05-16 | 1976-01-28 | Wilkinson Sword Ltd | Pressurised shaving foam dispensers |
YU36328B (en) | 1973-07-18 | 1983-06-30 | Elastin Werk Ag | Method of manufacturing red foils for packing sausages |
US4110426A (en) | 1973-07-24 | 1978-08-29 | Colgate-Palmolive Company | Method of treating skin and hair with a self-heated cosmetic |
US3865275A (en) | 1973-07-30 | 1975-02-11 | Raymond Lee Organization Inc | Apparatus for operating an aerosol can |
US3929985A (en) | 1974-01-18 | 1975-12-30 | Richardson Merrell Inc | Anhydrous candicidin foam compositions |
DE2501548A1 (de) | 1974-01-25 | 1975-07-31 | Procter & Gamble | Mundbehandlungsmittel |
GB1457671A (en) | 1974-01-31 | 1976-12-08 | Wilkinson Sword Ltd | Flavour |
US3923970A (en) | 1974-03-29 | 1975-12-02 | Carter Wallace | Stable aerosol shaving foams containing mineral oil |
US3962150A (en) | 1974-04-10 | 1976-06-08 | Richardson-Merrell Inc. | Foam producing cleansing compositions |
US3953591A (en) | 1974-04-29 | 1976-04-27 | The Procter & Gamble Company | Fatty acid, polysiloxane and water-soluble polymer containing skin conditioning emulsion |
US3966632A (en) | 1974-06-06 | 1976-06-29 | G. D. Searle & Co. | Vegetable oil emulsion |
US4145411A (en) | 1974-09-05 | 1979-03-20 | Colgate-Palmolive Company | Pressurized foaming shaving composition |
JPS5729213B2 (zh) | 1974-11-12 | 1982-06-21 | ||
US4052513A (en) | 1974-12-13 | 1977-10-04 | Plough, Inc. | Stable topical anesthetic compositions |
US3952916A (en) | 1975-01-06 | 1976-04-27 | Warner-Lambert Company | Automatic dispenser for periodically actuating an aerosol container |
US4019657A (en) | 1975-03-03 | 1977-04-26 | Spitzer Joseph G | Aerosol containers for foaming and delivering aerosols |
US3970219A (en) | 1975-03-03 | 1976-07-20 | Spitzer Joseph G | Aerosol containers for foaming and delivering aerosols and process |
US4018396A (en) | 1975-05-05 | 1977-04-19 | Bechtel International Corporation | Embedded housing for ore crusher |
US3993224A (en) | 1975-09-08 | 1976-11-23 | Aerosol Investments, Ltd. | Spout for two-component resin dispenser |
DE2608226A1 (de) | 1976-02-28 | 1977-09-08 | Haarmann & Reimer Gmbh | Mittel mit physiologischer kuehlwirkung |
US4100426A (en) | 1976-03-10 | 1978-07-11 | Square D Company | Load controlling means |
IL49491A (en) | 1976-04-29 | 1979-09-30 | Rosenberg Peretz | Quickly-attachable connector for plastic pipes |
US4102995A (en) | 1976-05-13 | 1978-07-25 | Westwood Pharmaceuticals Inc. | Tar gel formulation |
US4124149A (en) | 1976-07-19 | 1978-11-07 | Spitzer Joseph G | Aerosol container with position-sensitive shut-off valve |
CA1089368A (en) | 1976-08-02 | 1980-11-11 | Daniel C. Geary | Polyethoxylated fatty alcohol in antiperspirant sticks |
IL52045A (en) | 1976-08-25 | 1979-12-30 | Mundipharma Ag | Sprayable germicidal foam compositions |
US4252787A (en) | 1976-12-27 | 1981-02-24 | Cambridge Research And Development Group | Anti-fertility composition and method |
US4310510A (en) | 1976-12-27 | 1982-01-12 | Sherman Kenneth N | Self administrable anti-fertility composition |
US4083974A (en) | 1977-03-07 | 1978-04-11 | The Upjohn Company | Topical steroidal anti-inflammatory preparations containing polyoxypropylene 15 stearyl ether |
JPS5744429Y2 (zh) | 1977-04-14 | 1982-10-01 | ||
US4386104A (en) | 1977-04-19 | 1983-05-31 | Nazzaro Porro Marcella | Process for the treatment of acne |
IT1114950B (it) | 1977-12-30 | 1986-02-03 | Porro Marcella | Composizioni per il trattamento e la terapia di acne |
GB2004746B (en) | 1977-10-03 | 1982-03-10 | Scherico Ltd | Stable hopical anaesthetic compositions |
JPS5639815Y2 (zh) | 1977-11-25 | 1981-09-17 | ||
SE7713618L (sv) | 1977-12-01 | 1979-06-02 | Astra Laekemedel Ab | Lokalanestetisk blandning |
US4160827A (en) | 1978-02-06 | 1979-07-10 | The Upjohn Company | Metronidazole phosphate and salts |
US4229432A (en) | 1978-04-19 | 1980-10-21 | Bristol-Myers Company | Antiperspirant stick composition |
US4603812A (en) | 1978-06-27 | 1986-08-05 | The Dow Chemical Company | Foam-generating pump sprayer |
US4178373A (en) | 1978-08-21 | 1979-12-11 | William H. Rorer, Inc. | Coal tar gel composition |
US4214000A (en) | 1978-10-30 | 1980-07-22 | Johnson & Johnson | Zinc salt of all-trans-retinoic acid for the treatment of acne |
JPS5569682U (zh) | 1978-11-08 | 1980-05-13 | ||
JPS5569682A (en) | 1978-11-20 | 1980-05-26 | Toyo Aerosol Kogyo Kk | Foam shrinkable composition |
US4213979A (en) | 1978-12-18 | 1980-07-22 | Plough, Inc. | Stable sprayable hydrocortisone product |
US4954487A (en) | 1979-01-08 | 1990-09-04 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions |
US4439441A (en) | 1979-01-11 | 1984-03-27 | Syntex (U.S.A.) Inc. | Contraceptive compositions and methods employing 1-substituted imidazole derivatives |
US4226344A (en) | 1979-02-06 | 1980-10-07 | Booth, Inc. | Constant flow valve actuator |
CH639913A5 (en) | 1979-03-16 | 1983-12-15 | Aerosol Service Ag | Container for receiving and delivering a liquid substance |
US4230701A (en) | 1979-03-21 | 1980-10-28 | Hoffmann-La Roche Inc. | Administration of biologically active vitamin D3 and vitamin D2 materials |
US4335120A (en) | 1979-03-21 | 1982-06-15 | Hoffmann-La Roche Inc. | Administration of biologically active vitamin D3 and vitamin D2 materials |
US4278206A (en) | 1979-04-13 | 1981-07-14 | Ae Development Corporation | Non-pressurized dispensing system |
US4241048A (en) | 1979-05-01 | 1980-12-23 | Bristol-Myers Company | Suspension composition of benzocaine |
JPS55153712A (en) | 1979-05-18 | 1980-11-29 | Kao Corp | Insulin pharmaceutical preparation and its production |
US4268499A (en) | 1979-06-07 | 1981-05-19 | Dow Corning Corporation | Antiperspirant emulsion compositions |
US4241149A (en) | 1979-07-20 | 1980-12-23 | Temple University | Canal clathrate complex solid electrolyte cell |
DE2931469A1 (de) | 1979-08-02 | 1981-02-26 | Bayer Ag | Oberflaechenversiegelte formkoerper aus zelligen polyurethan-elastomeren und verfahren zu deren herstellung |
JPS5854931B2 (ja) | 1979-09-04 | 1983-12-07 | トヨタ自動車株式会社 | ブロ−チ盤 |
US4271149A (en) | 1979-09-21 | 1981-06-02 | West Agro-Chemical, Inc. | Germicidal iodine compositions with enhanced iodine stability |
US4299826A (en) | 1979-10-12 | 1981-11-10 | The Procter & Gamble Company | Anti-acne composition |
EP0032309A3 (en) | 1980-01-10 | 1981-08-05 | Imperial Chemical Industries Plc | Production of catalyst component, catalyst and use thereof |
US4309995A (en) | 1980-01-28 | 1982-01-12 | Sacco Susan M | Vaginal irrigation apparatus |
JPS56135416A (en) | 1980-03-27 | 1981-10-22 | Mitsubishi Chem Ind Ltd | Pharmaceutical preparation for skin |
SE8004580L (sv) | 1980-06-19 | 1981-12-20 | Draco Ab | Farmaceutisk beredning |
US4338211A (en) | 1980-06-30 | 1982-07-06 | The Procter & Gamble Company | Liquid surfactant skin cleanser with lather boosters |
US4508705A (en) | 1980-07-02 | 1985-04-02 | Lever Brothers Company | Skin treatment composition |
US4323582A (en) | 1980-07-21 | 1982-04-06 | Siegel Norman H | Method of treating animals and humans for internal and external parasites |
JPS601113Y2 (ja) | 1980-07-22 | 1985-01-12 | 三菱電機株式会社 | 円形照明器具の包装体 |
JPS5914282B2 (ja) | 1980-07-31 | 1984-04-04 | 株式会社神戸製鋼所 | 拡管抽伸方法 |
US4329990A (en) | 1980-08-07 | 1982-05-18 | Sneider Vincent R | Expanding swab applicator |
US4325939A (en) | 1980-09-22 | 1982-04-20 | Richardson-Vicks Inc. | Zinc derivatives and their use in dental compositions |
US4305936A (en) | 1980-10-09 | 1981-12-15 | Dermik Laboratories | Topical corticosteroid formulations |
US4292250A (en) | 1980-11-17 | 1981-09-29 | Wisconsin Alumni Research Foundation | Vitamin D derivatives |
EP0052404B1 (en) | 1980-11-19 | 1987-05-27 | THE PROCTER & GAMBLE COMPANY | Non-yellowing topical pharmaceutical composition |
DE3071101D1 (en) | 1980-11-27 | 1985-10-24 | Chinoin Gyogyszer Es Vegyeszet | Antimycotic synergistic pharmaceutical compositions and process for the preparation thereof |
DE3147726A1 (de) | 1980-12-03 | 1982-06-24 | Leo Pharmaceutical Products Ltd. A/S (Loevens kemiske Fabrik Produktionsaktieselskab), 2750 Ballerup | Antibiotische komplexe, verfahren zu ihrer herstellung und pharmazeutische mittel, die diese verbindungen enthalten |
US4352808A (en) | 1980-12-12 | 1982-10-05 | Schering Corporation | 3-Aralkyloxy-2,3-dihydro-2-(imidazolylmethyl)benzo(b)thiophenes and related derivatives, their use as antimicrobials and pharmaceutical formulations useful therefore |
US4323694A (en) | 1981-04-13 | 1982-04-06 | Finetex, Inc. | Benzoic acid esters |
US4522948A (en) | 1981-04-24 | 1985-06-11 | Syntex (U.S.A.) Inc. | Spermicidal substituted 1-(cycloalkyl)alkylimidazoles |
US4393066A (en) | 1981-06-05 | 1983-07-12 | Garrett David M | Method for treatment of herpetic lesions |
US4607101A (en) | 1981-08-27 | 1986-08-19 | Jaye-Boern Laboratories, Inc. | Method of treating acne vulgaris with a composition containing carbamide peroxide |
US4877805A (en) | 1985-07-26 | 1989-10-31 | Kligman Albert M | Methods for treatment of sundamaged human skin with retinoids |
US4469674A (en) | 1981-09-03 | 1984-09-04 | Richardson-Vicks Inc. | Stable oral compositions containing zinc and fluoride compounds |
US4440320A (en) | 1981-11-30 | 1984-04-03 | Wernicke Steven A | Foam dispensing apparatus |
LU83876A1 (fr) | 1982-01-15 | 1983-09-02 | Oreal | Composition cosmetique destinee au traitement des fibres keratiniques et procede de traitement de celles-ci |
LU83949A1 (fr) | 1982-02-16 | 1983-09-02 | Oreal | Composition destinee au traitement des matieres keratiniques contenant au moins un polymere cationique et au moins un latex anionique |
US5087618A (en) | 1982-05-18 | 1992-02-11 | University Of Florida | Redox carriers for brain-specific drug delivery |
US4529605A (en) | 1983-01-12 | 1985-07-16 | Una E. Lynch | Bathing oil composition |
US4661340A (en) | 1983-06-06 | 1987-04-28 | Interkemia Vegyipari Gazdasagi Tarsasag | Quail egg based stabilized foam compositions for cosmetic purposes |
GB8315787D0 (en) | 1983-06-08 | 1983-07-13 | Briggs J H | Coolant spray |
JPS601113A (ja) | 1983-06-20 | 1985-01-07 | Kao Corp | 養毛・育毛料 |
US4552872A (en) | 1983-06-21 | 1985-11-12 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions containing corticosteroids |
NL8302559A (nl) | 1983-07-18 | 1985-02-18 | Philips Nv | Elektrolytische kondensator. |
GB8330969D0 (en) | 1983-11-21 | 1983-12-29 | Wellcome Found | Promoting healing |
US4612193A (en) | 1983-12-23 | 1986-09-16 | Del Laboratories, Inc. | Sty ointment and method of using the same |
GB8402748D0 (en) | 1984-02-02 | 1984-03-07 | Dunlop Ltd | Intravaginal device |
US4985459A (en) | 1984-02-08 | 1991-01-15 | Richardson-Vicks, Inc. | Analgesic and anti-inflammatory compositions comprising diphenhydramine and methods of using same |
US4912124A (en) | 1984-02-23 | 1990-03-27 | Ortho Pharmaceutical Corporation | Antifungal dermatological solution |
NZ207341A (en) | 1984-03-01 | 1988-02-29 | Harvey Alex Ind Ltd | Device containing chemical impregnants for insertion into a body cavity of an animal |
US4628063A (en) | 1984-03-08 | 1986-12-09 | Dana P. Brigham | Antiviral pharmaceutical preparations and methods for their use |
US4574052A (en) | 1984-05-31 | 1986-03-04 | Richardson-Vicks Inc. | Crackling aerosol foam |
GB8416638D0 (en) | 1984-06-29 | 1984-08-01 | Beecham Group Plc | Topical treatment and composition |
ATE37209T1 (de) | 1984-08-06 | 1988-09-15 | Ciba Geigy Ag | Verfahren zum leimen von papier mit anionischen, hydrophoben leimungsmitteln und kationischen retentionsmitteln. |
US4595526A (en) | 1984-09-28 | 1986-06-17 | Colgate-Palmolive Company | High foaming nonionic surfacant based liquid detergent |
SE8404895L (sv) | 1984-10-01 | 1986-03-17 | Torkel Ingemar Fischer | Medel for en overkenslighetstest |
IE58110B1 (en) | 1984-10-30 | 1993-07-14 | Elan Corp Plc | Controlled release powder and process for its preparation |
CA1261276A (en) | 1984-11-09 | 1989-09-26 | Mark B. Grote | Shampoo compositions |
US4701320A (en) | 1984-11-29 | 1987-10-20 | Lederle (Japan), Ltd. | Composition stably containing minocycline for treating periodontal diseases |
US4627973A (en) | 1984-12-14 | 1986-12-09 | Charles Of The Ritz Group Ltd. | Skin mousse |
AU5078885A (en) | 1984-12-20 | 1986-06-26 | Warner-Lambert Company | Non-irritant detergent |
US4673569A (en) | 1985-02-12 | 1987-06-16 | Faberge Incorporated | Mousse hair composition |
ATE52185T1 (de) | 1985-03-01 | 1990-05-15 | Procter & Gamble | Milder reinigungsschaum. |
US5002680A (en) | 1985-03-01 | 1991-03-26 | The Procter & Gamble Company | Mild skin cleansing aerosol mousse with skin feel and moisturization benefits |
US4639367A (en) | 1985-03-18 | 1987-01-27 | Product Resources International, Inc. | Aerosol foam |
AU5549486A (en) | 1985-03-18 | 1986-10-13 | Product Resources International, Inc. | Exothermic stable foam compositions |
US4752465A (en) | 1985-09-20 | 1988-06-21 | Product Resources International, Inc. | Aerosol foam |
US5094853A (en) | 1985-04-26 | 1992-03-10 | S. C. Johnson & Son, Inc. | Method of preparing a water-soluble stable arthropodicidally-active foam matrix |
US4965063A (en) | 1985-05-24 | 1990-10-23 | Irene Casey | Cleaner and disinfectant with dye |
DE3521713A1 (de) | 1985-06-18 | 1986-12-18 | Henkel KGaA, 4000 Düsseldorf | Oel-in-wasser-emulsionen mit verbessertem viskositaetsverhalten |
US4672078A (en) | 1985-07-03 | 1987-06-09 | Schering-Plough Corporation | Urea stabilized with a lactone in various pharmaceutical and cosmetic preparations |
GB8519426D0 (en) | 1985-08-01 | 1985-09-04 | Ici Plc | Composition for personal care products |
US4806262A (en) | 1985-08-14 | 1989-02-21 | The Procter & Gamble Company | Nonlathering cleansing mousse with skin conditioning benefits |
EP0213827A3 (en) | 1985-08-14 | 1988-04-06 | The Procter & Gamble Company | Nonfoaming cleansing mousse with skin conditioning benefits |
AU6175586A (en) | 1985-09-11 | 1987-03-12 | Chesebrough-Pond's Inc. | Petroleum jelly, mild detergent anhydrous base compositions |
FR2591331A1 (fr) | 1985-12-10 | 1987-06-12 | Drevet Jean Baptiste | Dispositif de distribution de fractions dosees d'un produit contenu dans un recipient pressurise |
US4837378A (en) | 1986-01-15 | 1989-06-06 | Curatek Pharmaceuticals, Inc. | Topical metronidazole formulations and therapeutic uses thereof |
GB8607570D0 (en) | 1986-03-26 | 1986-04-30 | Euro Celtique Sa | Vaginal pharmaceutical preparation |
JPS62241701A (ja) | 1986-04-11 | 1987-10-22 | Maeda Kogyo Kk | 自転車用ハブのクイツクレリ−ズ装置 |
CA1291036C (en) | 1986-04-23 | 1991-10-22 | Edwin I. Stoltz | Nasal administration of drugs |
DE3614515A1 (de) | 1986-04-29 | 1987-11-05 | Pfeiffer Erich Gmbh & Co Kg | Austragvorrichtung fuer medien |
FR2598392B1 (fr) | 1986-05-09 | 1988-08-26 | Oreal | Conditionnement pour deux recipients pressurises |
PH25150A (en) | 1986-06-05 | 1991-03-13 | Ciba Geigy Ag | Novel pharmaceutical preparation for topical application |
US4770634A (en) | 1986-06-11 | 1988-09-13 | Pellico Michael A | Method for treating teeth with foamable fluoride compositions |
JPS62299423A (ja) | 1986-06-18 | 1987-12-26 | Mazda Motor Corp | 車両用空気調和装置 |
US4837019A (en) | 1986-08-11 | 1989-06-06 | Charles Of The Ritz Group Ltd. | Skin treatment composition and method for treating burned skin |
US4906453A (en) | 1986-08-12 | 1990-03-06 | Jumpeer Nails, Inc. | Mousse product |
DE3628531A1 (de) | 1986-08-22 | 1988-02-25 | Merz & Co Gmbh & Co | Verschaeumbare cremes |
EP0315648B1 (en) | 1986-09-05 | 1992-04-01 | The Upjohn Company | Sebum-dissolving nonaqueous minoxidil formulation |
WO1988001863A1 (en) | 1986-09-12 | 1988-03-24 | The Upjohn Company | Foams for delivery of minoxidil |
LU86585A1 (fr) | 1986-09-15 | 1988-04-05 | Oreal | Composition sous forme de mousse aerosol a base d'un polymere derive de cellulose quaternise et de polymere anionique |
JPH0778019B2 (ja) | 1986-11-08 | 1995-08-23 | 久光製薬株式会社 | 泡状エアゾ−ル消炎鎮痛製剤 |
EP0270316A3 (en) | 1986-12-04 | 1989-12-06 | Pfizer Inc. | Topical compositions comprising 1-substituted imidazoles and nsaids for treatment of acne |
US4822613A (en) | 1986-12-15 | 1989-04-18 | S. C. Johnson & Son, Inc. | Water-soluble foamable insecticidally-active compositions |
US4822614A (en) | 1986-12-19 | 1989-04-18 | S. C. Johnson & Son, Inc. | Bioactive film-forming composition for control of crawling insects and the like |
US5389677B1 (en) | 1986-12-23 | 1997-07-15 | Tristrata Inc | Method of treating wrinkles using glycalic acid |
US4863900A (en) | 1987-01-15 | 1989-09-05 | The Research Foundation Of State University Of New York | Method for reducing viral transmission with poly-L-histidine |
JPS63119420U (zh) | 1987-01-30 | 1988-08-02 | ||
DE3704907A1 (de) | 1987-02-17 | 1988-08-25 | Bayer Ag | Topisch anwendbare zubereitungen von gyrase-inhibitoren in kombination mit kortikosteroiden |
US4828837A (en) | 1987-03-30 | 1989-05-09 | Liposome Technology, Inc. | Non-crystalline minoxidil composition, its production and application |
AU1388388A (en) | 1987-04-01 | 1988-10-06 | Dak-Laboratoriet A/S | Benzoic acid derivatives and use thereof |
LU86839A1 (fr) | 1987-04-10 | 1988-12-13 | Oreal | Composition cosmetique detergente et moussante,retardant le regraissage des cheveux |
WO1988008316A1 (en) | 1987-04-21 | 1988-11-03 | Chattan Nominees Pty. Ltd. | Vaginal douche |
FR2615173B1 (fr) | 1987-05-13 | 1989-08-18 | Valois | Valve doseuse pour liquide charge d'un propulseur liquide ou gaz liquefie, utilisable en position inversee |
US4867967A (en) | 1987-06-04 | 1989-09-19 | Crutcher Wilbert L | Method for the treatment of pseudofolliculitis barbae |
US4780309A (en) | 1987-06-16 | 1988-10-25 | Warner-Lambert Company | Edible aerosol foam compositions and method of preparing same |
US4849117A (en) | 1987-06-17 | 1989-07-18 | Sanitek Products, Inc. | Concentrated composition for forming an aqueous foam |
US4885282A (en) | 1987-07-02 | 1989-12-05 | Thornfeldt Carl R | Treatment of hyperhidrosis, ichthyosis and wrinkling |
US4898246A (en) | 1987-07-06 | 1990-02-06 | Total Walther Feuerschutz Gmbh | Quick release valve for sprinkler head |
US5196405A (en) | 1987-07-08 | 1993-03-23 | Norman H. Oskman | Compositions and methods of treating hemorrhoids and wounds |
US4847068A (en) | 1987-08-06 | 1989-07-11 | Johnson & Johnson Consumer Products, Inc. | Skin care compositions |
US4913893A (en) | 1987-08-28 | 1990-04-03 | Clairol Incorporated | Aerosol hair setting composition containing an alginate |
CA1273576A (en) | 1987-09-16 | 1990-09-04 | Patrick A. Beauchamp | Topical treatment for diseased skin disorders |
US4981677A (en) | 1987-09-23 | 1991-01-01 | L'oreal | Petrolatum-containing aerosol foam concentrate |
DE309353T1 (de) | 1987-09-23 | 1991-02-07 | L'oreal, Paris, Fr | Hautbehandlungsmittel als aerosolschaum, das vasiline enthaelt. |
US4784842A (en) | 1987-09-25 | 1988-11-15 | Jean London | Therapeutic composition for treatment of cuts, burns and abrasions |
US4772427A (en) | 1987-12-01 | 1988-09-20 | Colgate-Palmolive Co. | Post-foaming gel shower product |
US5143717A (en) | 1987-12-30 | 1992-09-01 | Code Blue Medical Corporation | Burn foam and delivery system |
ATE74003T1 (de) | 1988-01-14 | 1992-04-15 | Akzo Nv | Waessriges pharmazeutisches praeparat. |
US5536743A (en) | 1988-01-15 | 1996-07-16 | Curatek Pharmaceuticals Limited Partnership | Intravaginal treatment of vaginal infections with buffered metronidazole compositions |
JP2643217B2 (ja) | 1988-01-22 | 1997-08-20 | エーザイ株式会社 | 脂溶性物質水性液 |
US5719197A (en) | 1988-03-04 | 1998-02-17 | Noven Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
US4849211A (en) | 1988-03-16 | 1989-07-18 | Schrauzer Gerhard N | Product and method for the treatment of acne and other skin disorders |
US4897262A (en) | 1988-03-22 | 1990-01-30 | Playtex Jhirmack, Inc. | Non-aerosol hair spray composition |
DE3811081A1 (de) | 1988-03-30 | 1989-10-12 | Schering Ag | Verwendung von topisch applizierbaren praeparaten zur behandlung der altershaut |
LU87187A1 (fr) | 1988-03-31 | 1989-10-26 | Oreal | Association de derives de pyrimidine et de derives d'acide salicylique pour induire et stimuler la croissance des cheveux et diminuer leur chute |
US4992478A (en) | 1988-04-04 | 1991-02-12 | Warner-Lambert Company | Antiinflammatory skin moisturizing composition and method of preparing same |
US4873078A (en) | 1988-04-22 | 1989-10-10 | Plough, Inc. | High-gloss, high-shine lipstick |
GB8811409D0 (en) | 1988-05-13 | 1988-06-15 | Unilever Plc | Cosmetic composition |
US5378730A (en) | 1988-06-09 | 1995-01-03 | Alza Corporation | Permeation enhancer comprising ethanol and monoglycerides |
GB8813766D0 (en) | 1988-06-10 | 1988-07-13 | Efamol Holdings | Essential fatty acid compositions |
US4827378A (en) | 1988-06-15 | 1989-05-02 | Rockwell International Corporation | Jack coaxial connector EMI shielding apparatus |
US5217707A (en) | 1988-06-16 | 1993-06-08 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. | Pharmaceutical composition and process for the preparation thereof |
EP0349875A3 (en) | 1988-07-07 | 1991-09-25 | General Electric Company | Paintable elestomeric compositions |
US4902281A (en) | 1988-08-16 | 1990-02-20 | Corus Medical Corporation | Fibrinogen dispensing kit |
US4950420A (en) | 1988-08-31 | 1990-08-21 | Nalco Chemical Company | Antifoam/defoamer composition |
US4855294A (en) | 1988-09-06 | 1989-08-08 | Theratech, Inc. | Method for reducing skin irritation associated with drug/penetration enhancer compositions |
GB8821129D0 (en) | 1988-09-09 | 1988-10-12 | Unilever Plc | Cosmetic composition |
JPH02191223A (ja) | 1988-10-04 | 1990-07-27 | Otsuka Pharmaceut Co Ltd | 鉄補給用発泡製剤 |
US5135915A (en) | 1988-10-14 | 1992-08-04 | Genentech, Inc. | Method for the treatment of grafts prior to transplantation using TGF-.beta. |
US5186857A (en) | 1988-11-14 | 1993-02-16 | Imaginative Research Associates, Inc. | Self-foaming oil compositions and process for making and using same |
GB8828013D0 (en) | 1988-12-01 | 1989-01-05 | Unilever Plc | Topical composition |
US4970067A (en) | 1988-12-12 | 1990-11-13 | Helene Curtis, Inc. | Method and composition to condition hair and impart semi-permanent hair set retention properties |
US5262407A (en) | 1988-12-16 | 1993-11-16 | L'oreal | Use of salicylic derivatives for the treatment of skin aging |
FR2640942A1 (en) | 1988-12-23 | 1990-06-29 | Suchard Sa Jacobs | Container of the aerosol type for delivering, in the form of a foam, metered quantities of product, particularly of food product |
ES2052879T3 (es) | 1988-12-27 | 1994-07-16 | Osaka Shipbuilding | Composicion de aerosol. |
JP2960445B2 (ja) | 1988-12-28 | 1999-10-06 | 株式会社大阪造船所 | エアゾール用組成物 |
FR2641185B1 (fr) | 1988-12-29 | 1991-04-05 | Oreal | Composition de rasage pour la peau a base de polyorganosiloxanes a fonction acyloxyalkyle et procede de mise en oeuvre |
JP2741230B2 (ja) | 1989-01-11 | 1998-04-15 | 株式会社コーセー | 泡状無水化粧料 |
LU87449A1 (fr) | 1989-02-09 | 1990-09-19 | Oreal | Procede de fabrication de mousses utilisables dans les domaines cosmetique et pharmaceutique et mousses obtenues par ce procede |
US4919934A (en) | 1989-03-02 | 1990-04-24 | Richardson-Vicks Inc. | Cosmetic sticks |
US4996193A (en) | 1989-03-03 | 1991-02-26 | The Regents Of The University Of California | Combined topical and systemic method of administration of cyclosporine |
US5019375A (en) | 1989-03-14 | 1991-05-28 | The Procter & Gamble Company | Low residue antiperspirant creams |
DE69030698T2 (de) | 1989-03-17 | 1997-10-02 | Taisho Pharmaceutical Co Ltd | Aerosolzusammensetzung zur äusserlichen verwendung |
US5221696A (en) | 1989-03-29 | 1993-06-22 | Alcon Laboratories, Inc. | Use of monoacyl phosphoglycerides to enhance the corneal penetration of ophthalmic drugs |
DE69020211T2 (de) | 1989-04-05 | 1995-11-02 | Kao Corp | Kosmetische Doppelemulsionszusammensetzung. |
US5071648A (en) | 1989-04-06 | 1991-12-10 | Merocel Corporation | Polymeric broad-spectrum antimicrobial materials |
US5204093A (en) | 1989-04-06 | 1993-04-20 | Victor Steven A | Shaving cream composition for the treatment of acne vulgaris and pseudofolliculitis barbae and method of producing and using same |
US5618798A (en) | 1989-04-20 | 1997-04-08 | Bar-Shalom; Daniel | Use of sucralfate to treat baldness |
US5221534A (en) | 1989-04-26 | 1993-06-22 | Pennzoil Products Company | Health and beauty aid compositions |
GB8909559D0 (en) | 1989-04-26 | 1989-06-14 | Smith Kline French Lab | Pharmaceutical compositions |
US4874794A (en) | 1989-04-28 | 1989-10-17 | Lidak Biopharmaceuticals | Inflammatory disease treatment |
US5322683A (en) | 1989-05-01 | 1994-06-21 | Leonard Mackles | Anhydrous aerosol foam |
US5002540A (en) | 1989-05-22 | 1991-03-26 | Warren Kirschbaum | Intravaginal device and method for delivering a medicament |
GB8911853D0 (en) | 1989-05-23 | 1989-07-12 | Ici Plc | Co2 blown integral skin foams |
CA1337279C (en) | 1989-06-06 | 1995-10-10 | Robert J. Borgman | Intravaginal treatment of vaginal infections with buffered metronidazole compositions |
US5208031A (en) | 1989-06-06 | 1993-05-04 | Kelly Patrick D | Sexual lubricants containing zinc as an anti-viral agent |
JPH0310636A (ja) | 1989-06-09 | 1991-01-18 | Matsushita Electric Works Ltd | 床下野菜保存庫 |
US5122519A (en) | 1989-06-27 | 1992-06-16 | American Cyanamid Company | Stable, cosmetically acceptable topical gel formulation and method of treatment for acne |
MX21452A (es) | 1989-07-07 | 1994-01-31 | Ciba Geigy Ag | Preparaciones farmaceuticas que se administran en forma topica. |
JPH0350289A (ja) | 1989-07-17 | 1991-03-04 | Shiseido Co Ltd | 非乳化型泡沫エアゾール組成物 |
US5560859A (en) | 1989-07-26 | 1996-10-01 | Pfizer Inc. | Post foaming gel shaving composition |
US4981367A (en) | 1989-07-28 | 1991-01-01 | Stranco, Inc. | Portable mixing apparatus |
JP2741105B2 (ja) | 1989-07-28 | 1998-04-15 | 久光製薬株式会社 | 泡状エアゾール製剤 |
JPH0383914A (ja) | 1989-08-18 | 1991-04-09 | W R Grace & Co | ドラッグキャリアー |
US5219877A (en) | 1989-09-25 | 1993-06-15 | Bristol-Myers Squibb Company | Lauryl alcohol as skin penetration enhancer for topical imidazole agents |
IL95952A0 (en) | 1989-10-19 | 1991-07-18 | Sterling Drug Inc | Aerosol composition for topical medicament |
US5439670A (en) | 1989-11-28 | 1995-08-08 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US5508033A (en) | 1989-12-06 | 1996-04-16 | Societe D'engrais Composes Mineraux Et Amendments | Utilization of algae extract for the preparation of pharmaceutical, cosmetic, food or agricultural compositions |
DK0504301T3 (da) | 1989-12-07 | 2004-05-03 | Instead Inc | Fremgangsmåde ved opsamling af vaginalt sekret |
US5295984A (en) | 1989-12-07 | 1994-03-22 | Ultrafem, Inc. | Vaginal discharge collection device and intravaginal drug delivery system |
WO1991008733A1 (en) | 1989-12-20 | 1991-06-27 | Schering Corporation | Stable cream and lotion bases for lipophilic drug compositions |
US4966779A (en) | 1989-12-21 | 1990-10-30 | Basf Corporation | Stable, water miscible emulsion comprising a fat-soluble vitamin |
US5733572A (en) | 1989-12-22 | 1998-03-31 | Imarx Pharmaceutical Corp. | Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles |
US4963351A (en) | 1989-12-26 | 1990-10-16 | Bhn Associates | Shaving aid |
US5100917A (en) | 1989-12-29 | 1992-03-31 | Merrell Dow Pharmaceuticals Inc. | Novel a-nor-steroid-3-carboxylic acid derivatives |
US5104645A (en) | 1990-02-02 | 1992-04-14 | The Proctor & Gamble Company | Antidandruff shampoo compositions |
SE9000485D0 (sv) | 1990-02-09 | 1990-02-09 | Pharmacia Ab | Foamable composition for pharmaceutical use, use thereof and method of treatment |
US5164367A (en) | 1990-03-26 | 1992-11-17 | Procyte Corporation | Method of using copper(ii) containing compounds to accelerate wound healing |
US5130121A (en) | 1990-04-17 | 1992-07-14 | Isp Investments Inc. | Skin care compositions containing discrete microdroplets of an oil in water stabilized by in situ polymerization of water-soluble vinyl monomer |
US5007556A (en) | 1990-04-18 | 1991-04-16 | Block Drug Company, Inc. | Metering dispenser |
US5156765A (en) | 1990-05-15 | 1992-10-20 | Fox Valley Systems, Inc. | Aerosol foam marking compositions |
US5112359A (en) | 1990-06-04 | 1992-05-12 | Clairol, Inc. | Hair colorants |
JP3649341B2 (ja) | 1990-06-15 | 2005-05-18 | 株式会社資生堂 | 複合体及び複合体の組成物及び乳化剤組成物並びに乳化組成物 |
JPH0451958A (ja) | 1990-06-18 | 1992-02-20 | Mitsubishi Materials Corp | 循環式トイレ汚物処理剤 |
US5034220A (en) | 1990-06-20 | 1991-07-23 | Gaf Chemicals Corporation | Non-aerosol shaving gel |
US5336692A (en) | 1990-06-28 | 1994-08-09 | Medicis Pharmaceutical Corporation | Ointment base and method of use |
IT1243379B (it) | 1990-07-27 | 1994-06-10 | Giuliani Spa | Composizione farmaceutica adatta alla somministrazione rettale di principi attivi che esplicano un'azione di medicazione a livello del colon prevalentemente di tipo topico |
US5108556A (en) | 1990-09-14 | 1992-04-28 | Minnesota Mining And Manufacturing Company | Process for preparing tertiary perfluoroamines |
US5091111A (en) | 1990-09-19 | 1992-02-25 | S. C. Johnson & Son, Inc. | Aqueous emulsion and aersol delivery system using same |
US5114718A (en) | 1990-09-20 | 1992-05-19 | The Procter & Gamble Company | Sustained release compositions for treating periodontol disease |
GB9021546D0 (en) | 1990-10-04 | 1990-11-21 | Beecham Group Plc | Novel composition |
FR2668927B1 (fr) | 1990-11-09 | 1993-01-08 | Oreal | Composition cosmetique anhydre sous forme aerosol pour la formation d'une mousse. |
US5073371A (en) | 1990-11-30 | 1991-12-17 | Richardson-Vicks, Inc. | Leave-on facial emulsion compositions |
DE9016291U1 (zh) | 1990-11-30 | 1991-03-28 | Kali-Chemie Pharma Gmbh, 3000 Hannover, De | |
WO1992011839A1 (en) | 1991-01-08 | 1992-07-23 | Leonard Mackles | Anhydrous aerosol |
AU1411992A (en) | 1991-01-15 | 1992-08-27 | Robert A Bok | A composition containing a tetracycline and use for inhibiting angiogenesis |
US5227163A (en) | 1991-01-18 | 1993-07-13 | Clilco, Ltd. | Lice-repellant compositions |
DE4102506C2 (de) | 1991-01-29 | 1999-11-25 | Pfeiffer Erich Gmbh & Co Kg | Austragvorrichtung für Medien |
CA2101947A1 (en) | 1991-02-05 | 1992-08-06 | Jurgen Buil | Fire extinguishing and protection agent |
US5948682A (en) | 1991-02-22 | 1999-09-07 | Sembiosys Genetics Inc. | Preparation of heterologous proteins on oil bodies |
US5650554A (en) | 1991-02-22 | 1997-07-22 | Sembiosys Genetics Inc. | Oil-body proteins as carriers of high-value peptides in plants |
US6753167B2 (en) | 1991-02-22 | 2004-06-22 | Sembiosys Genetics Inc. | Preparation of heterologous proteins on oil bodies |
US5663208A (en) | 1991-03-01 | 1997-09-02 | Warner-Lambert Company | Antifungal wound healing compositions and methods for preparing and using same |
US5648380A (en) | 1991-03-01 | 1997-07-15 | Warner-Lambert Company | Anti-inflammatory wound healing compositions and methods for preparing and using same |
US5658956A (en) | 1991-03-01 | 1997-08-19 | Warner-Lambert Company | Bioadhesive-wound healing compositions and methods for preparing and using same |
IT1247138B (it) | 1991-03-06 | 1994-12-12 | Dompe Farmaceutici Spa | Composizione farmaceutica idrofila contenente ketoprofene sale di lisina per uso topico. |
JPH04282311A (ja) | 1991-03-08 | 1992-10-07 | Koike Kagaku Kk | エアゾール型発泡性傷口消毒剤 |
US5279819A (en) | 1991-03-18 | 1994-01-18 | The Gillette Company | Shaving compositions |
EP0576605A4 (en) | 1991-03-19 | 1994-06-08 | Vithal J Rajadhyaksha | Compositions and method comprising aminoalcohol derivatives as membrane penetration enhancers |
US5389676A (en) | 1991-03-22 | 1995-02-14 | E. B. Michaels Research Associates, Inc. | Viscous surfactant emulsion compositions |
AU658608B2 (en) | 1991-03-25 | 1995-04-27 | Astellas Pharma Europe B.V. | Topical preparation containing a suspension of solid lipid particles |
US5167950A (en) | 1991-03-28 | 1992-12-01 | S. C. Johnson & Son | High alcohol content aerosol antimicrobial mousse |
DE4110973A1 (de) | 1991-04-05 | 1992-10-08 | Haarmann & Reimer Gmbh | Mittel mit physiologischem kuehleffekt und fuer diese mittel geeignete wirksame verbindungen |
JP3100416B2 (ja) | 1991-04-11 | 2000-10-16 | オカモト株式会社 | ムース状潤滑剤 |
HU209605B (en) | 1991-04-15 | 1994-09-28 | Chinoin Gyogyszer Es Vegyeszet | Process for production of wather-free transdermal preparation |
IT1247529B (it) | 1991-04-24 | 1994-12-17 | Poli Ind Chimica Spa | Composizioni farmaceutiche in forma di schiuma per somministrazione intravaginale, cutanea e orale |
US5204090A (en) | 1991-05-30 | 1993-04-20 | Bristol Myers Squibb | Waterproof high-SPF sunscreen compositions |
US5164357A (en) | 1991-06-05 | 1992-11-17 | Appleton Papers Inc. | Thermally-responsive record material |
FR2677544B1 (fr) | 1991-06-14 | 1993-09-24 | Oreal | Composition cosmetique contenant un melange de nanopigments d'oxydes metalliques et de pigments melaniques. |
US5221530A (en) | 1991-06-24 | 1993-06-22 | Helene Curtis, Inc. | Mild conditioning shampoo with a high foam level containing an anionic surfactant-cationic acrylate/acrylamide copolymer conditioning agent |
DE4210165A1 (de) | 1991-07-30 | 1993-02-04 | Schering Ag | Transdermale therapeutische systeme |
DE4127630A1 (de) | 1991-08-21 | 1993-02-25 | Bruno Jesswein | Zweikomponenten-druckdose, insbesondere fuer 2k-schaeume |
GB9118028D0 (en) | 1991-08-21 | 1991-10-09 | Secr Defence Brit | Improved transdrmal formulations |
JP2969398B2 (ja) | 1991-09-12 | 1999-11-02 | 花王株式会社 | 無水泡沫清浄清拭剤 |
US5643600A (en) | 1991-09-17 | 1997-07-01 | Micro-Pak, Inc. | Lipid vesicles containing avocado oil unsaponifiables |
EP0564656B1 (en) | 1991-09-27 | 1999-02-03 | Nof Corporation | Cosmetic composition and emulsion composition |
GB2260079B (en) | 1991-10-01 | 1995-08-09 | American Cyanamid Co | Pharmaceutical composition containing felbinac |
US5230897A (en) | 1991-10-31 | 1993-07-27 | G. D. Searle & Co. | Transdermal pentamidine |
US5236707A (en) | 1991-11-08 | 1993-08-17 | Dallas Biotherapeutics, Inc. | Stabilization of human interferon |
AU3136593A (en) | 1991-11-22 | 1993-06-15 | Richardson-Vicks Inc. | Combined personal cleansing and moisturizing compositions |
DE4140474C2 (de) | 1991-12-09 | 1995-07-13 | Schuelke & Mayr Gmbh | Hautpflegeadditiv |
US5294365A (en) | 1991-12-12 | 1994-03-15 | Basf Corporation | Hydroxypolyethers as low-foam surfactants |
IT1253711B (it) | 1991-12-17 | 1995-08-23 | Alfa Wassermann Spa | Formulazioni farmaceutiche vaginali contenenti rifaximin e loro uso nel trattamento delle infezioni vaginali |
US5252246A (en) | 1992-01-10 | 1993-10-12 | Allergan, Inc. | Nonirritating nonionic surfactant compositions |
EP0552612A3 (en) | 1992-01-22 | 1993-10-20 | Hoffmann La Roche | Methods for determining and isolating compounds which bind directly to nucleosolic proteins |
JP3146052B2 (ja) | 1992-01-31 | 2001-03-12 | プレスコ株式会社 | エアゾールマッサージ剤 |
US5318774A (en) | 1992-02-28 | 1994-06-07 | Richardson-Vicks Inc. | Composition and method for imparting an artificial tan to human skin |
ES2187505T3 (es) | 1992-04-02 | 2003-06-16 | Sembiosys Genetics Inc | Elementos cis de proteinas de cuerpo oleoso como señales reguladoras. |
US5344051A (en) | 1992-04-27 | 1994-09-06 | Insta-Foam Products, Inc. | Two-component foam dispensing apparatus |
ZA932947B (en) | 1992-04-28 | 1993-10-27 | Schering Plough Healthcare | Applicator for semisolid medications |
US5409706A (en) | 1992-05-04 | 1995-04-25 | Imaginative Research Associates, Inc. | Anhydrous foaming composition containing low concentrations of detergents and high levels of glycerin and emollients such as oils and esters |
US5254334A (en) | 1992-05-04 | 1993-10-19 | Imaginative Research Associates, Inc. | Anhydrous foaming composition containing low concentrations of detergents and high levels of glycerin amd emollients such as oils and esters |
IL105595A0 (en) | 1992-05-15 | 1993-09-22 | Akzo Nv | Applicator for introducing a cream-type substance into a woman's vagina |
AU4116993A (en) | 1992-05-18 | 1993-12-13 | Procter & Gamble Company, The | Coolant compositions |
US5389305A (en) | 1992-06-03 | 1995-02-14 | Colgate Palmolive Co. | High foaming nonionic surfactant base liquid detergent |
DK0644746T3 (da) | 1992-06-11 | 1999-12-20 | Theratech Inc | Anvendelse af glycerin til moderering af transdermal lægemiddelafgivelse |
US5346135A (en) | 1992-06-16 | 1994-09-13 | Vincent Edward C | Spraying apparatus for blending liquids in a gaseous spray system |
US5300286A (en) | 1992-07-14 | 1994-04-05 | Dow Corning Corporation | Silicone emulsion for personal care application |
EP0652774B1 (en) | 1992-07-28 | 1997-05-07 | The Procter & Gamble Company | Pharmaceutical composition for topical use containing a crosslinked cationic polymer and an alkoxylated ether |
FI933979A0 (fi) | 1992-09-10 | 1993-09-10 | Mcneil Ppc Inc | Bioeroderbar anordning foer dosering av aktiva ingredienser |
MX9305615A (es) | 1992-09-14 | 1994-05-31 | Walter P Smith | Composicion para el acondicionamiento de la piel, su aplicacion y fabricacion. |
JPH06100414A (ja) | 1992-09-18 | 1994-04-12 | Osaka Aerosol Ind Corp | エアゾール用組成物 |
US6096756A (en) | 1992-09-21 | 2000-08-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists |
US5413775A (en) | 1992-09-29 | 1995-05-09 | Amerchol Corporation | Hairsprays and acrylic polymer compositions for use therein |
IT1255895B (it) | 1992-10-20 | 1995-11-17 | Laura Chiodini | Composizioni farmaceutiche contenenti una calcitonina |
DE69332954D1 (de) | 1992-10-21 | 2003-06-12 | Gynetech Lab Inc | Abgabesystem bestehend aus einem vaginaschwamm |
EP0596304B1 (de) | 1992-10-31 | 1998-04-01 | Th. Goldschmidt AG | Kosmetische oder pharmazeutische Zubereitungen |
DE4238860A1 (de) | 1992-11-19 | 1994-05-26 | Medicon Gmbh | Hautschutzmittel zum Schutz der menschlichen Haut |
US5308643A (en) | 1992-11-30 | 1994-05-03 | Osipow Lloyd I | Self-lather generating shaving compositions |
JP3328344B2 (ja) | 1992-12-22 | 2002-09-24 | タイホー工業株式会社 | 発泡型洗浄艶出し剤の発泡状態保持時間を制御する方法 |
JPH06263630A (ja) | 1993-03-10 | 1994-09-20 | Lion Corp | ビタミンa類可溶化点眼剤 |
DE4309900C1 (de) | 1993-03-26 | 1994-06-30 | Goldschmidt Ag Th | Verfahren zur Herstellung von amphoteren Tensiden |
JPH06279228A (ja) | 1993-03-30 | 1994-10-04 | Kao Corp | 発泡性組成物 |
US5326557A (en) | 1993-04-06 | 1994-07-05 | Dow Corning Corporation | Moisturizing compositions containing organosilicon compounds |
US5807571A (en) | 1993-05-06 | 1998-09-15 | Lts Lohmann Therapie-Systeme Gmbh | Transdermal therapeutic systems for administering indole serotonin agonists |
US5576016A (en) | 1993-05-18 | 1996-11-19 | Pharmos Corporation | Solid fat nanoemulsions as drug delivery vehicles |
ES2176244T3 (es) | 1993-05-19 | 2002-12-01 | Hisamitsu Pharmaceutical Co | 3-l-mentoxipropano-1,2-diol como agente solubilizador externa que lo contiene. |
WO1994027562A1 (en) | 1993-05-21 | 1994-12-08 | Henkel Corporation | Mild shampoo composition |
JP3161869B2 (ja) | 1993-05-24 | 2001-04-25 | 株式会社ダイゾー | 油中水型エアゾール組成物およびその製法 |
US5635469A (en) | 1993-06-10 | 1997-06-03 | The Procter & Gamble Company | Foaming cleansing products |
US5447725A (en) | 1993-06-11 | 1995-09-05 | The Procter & Gamble Company | Methods for aiding periodontal tissue regeneration |
US5384308A (en) | 1993-06-14 | 1995-01-24 | Henkin; R. I. | Composition and method for enhancing wound healing |
US5744155A (en) | 1993-08-13 | 1998-04-28 | Friedman; Doron | Bioadhesive emulsion preparations for enhanced drug delivery |
US5398846A (en) | 1993-08-20 | 1995-03-21 | S. C. Johnson & Son, Inc. | Assembly for simultaneous dispensing of multiple fluids |
US6596260B1 (en) | 1993-08-27 | 2003-07-22 | Novartis Corporation | Aerosol container and a method for storage and administration of a predetermined amount of a pharmaceutically active aerosol |
FR2709666B1 (fr) | 1993-09-07 | 1995-10-13 | Oreal | Composition cosmétique ou dermatologique constituée d'une émulsion huile dans eau à base de globules huileux pourvus d'un enrobage cristal liquide lamellaire. |
JP2978043B2 (ja) | 1993-09-16 | 1999-11-15 | 高砂香料工業株式会社 | (2s)−3−{(1r,2s,5r)−[ 5−メチル−2−(1−メチルエチル)シクロヘキシル ]オキシ}−1,2−プロパンジオール,その製造方法および用途 |
US5766632A (en) | 1993-10-01 | 1998-06-16 | Legere Pharmaceuticals, Ltd. | Method of using lectins for contraception |
FR2710854B1 (fr) | 1993-10-08 | 1995-12-01 | Oreal | Emulsion huile-dans-eau utilisable pour l'obtention d'une crème. |
US5578315A (en) | 1993-12-01 | 1996-11-26 | Rutgers, The State University Of New Jersey | Mucosal adhesive device for long-acting delivery of pharmaceutical combinations in oral cavity |
FR2713486B1 (fr) | 1993-12-14 | 1996-02-09 | Scophysa | Nouvelles compositions pour mousses, notamment mousses rectales, et mousses ainsi obtenues. |
CA2177682C (en) | 1993-12-23 | 1999-12-28 | Sekhar Mitra | Antimicrobial wipe compositions |
US5527822A (en) | 1993-12-29 | 1996-06-18 | Forest Laboratories, Inc. | Method of treatment of traumatic brain injury |
DE9422052U1 (de) | 1994-01-04 | 1997-10-30 | Wuerth Adolf Gmbh & Co Kg | Befüllgerät zum Befüllen eines wiederbefüllbaren Ausgabebehälters und wiederbefüllbarer Ausgabebehälter |
JP3530564B2 (ja) | 1994-02-03 | 2004-05-24 | 株式会社ノエビア | エアゾールフォーム化粧料 |
DE4405127A1 (de) | 1994-02-18 | 1995-08-31 | Henkel Kgaa | Haarbehandlungsmittel |
US5514367A (en) | 1994-02-28 | 1996-05-07 | Estee Lauder, Inc. | Skin tanning compositions and methods for their preparation and use |
US5925669A (en) | 1994-03-22 | 1999-07-20 | Molecular/Structural Bio Technologies, Inc. | Carrier compositions for anti-neoplastic drugs |
US5658749A (en) | 1994-04-05 | 1997-08-19 | Corning Clinical Laboratories, Inc. | Method for processing mycobacteria |
IL109230A (en) | 1994-04-05 | 1998-08-16 | Agis Ind 1983 Ltd | Anti-fungal composition containing bifonazole and fluocinonide |
US5429815A (en) | 1994-04-11 | 1995-07-04 | Chesebrough-Pond's Usa Co., Division Of Conopco, Inc. | Stable single-phase self-foaming cleanser |
FR2719467B1 (fr) | 1994-05-05 | 1996-05-31 | Oreal | Utilisation de flavonoïdes pour préserver et/ou renforcer les propriétés mécaniques des cheveux et procédé de protection des cheveux utilisant ces composés. |
ES2079320B1 (es) | 1994-05-17 | 1996-10-16 | Cusi Lab | Disolucion oftalmica a base de un diclofenaco y tobramicina y sus aplicaciones. |
US5902574A (en) | 1994-05-23 | 1999-05-11 | The Gillette Company | Shaving preparation for improved shaving comfort |
US5545401A (en) | 1994-06-02 | 1996-08-13 | Shanbrom; Edward | Antiviral, spermicidal vaginal gel and foam containing low molecular weight povidone-iodine |
FR2720635B1 (fr) | 1994-06-03 | 1996-07-26 | Oreal | Compositions cosmétiques antisolaires et utilisations. |
US6221381B1 (en) | 1994-06-28 | 2001-04-24 | The University Of British Columbia | Enhancing milk production by adding to feed a nonionic surfactant coated on a carrier |
MA23592A1 (fr) | 1994-06-30 | 1995-12-31 | Procter & Gamble | Compositions pour les soins corporels contenant des copolymeres greffes elastomeres thermoplastiques |
US5679324A (en) | 1994-07-08 | 1997-10-21 | The Procter & Gamble Co. | Aerosol foamable fragrance composition |
FR2722431B1 (fr) | 1994-07-12 | 1996-09-13 | Lir France Sa | Distributeur double pour produits fluides |
US5869529A (en) | 1994-07-20 | 1999-02-09 | Agis Industries (1983) Ltd. | Topical preparation for the prevention and treatment of lesions and sores associated with a herpes virus |
US5444092A (en) | 1994-07-20 | 1995-08-22 | Collins; Jerry | Method and composition for treating psoriasis |
JP3173330B2 (ja) | 1994-07-20 | 2001-06-04 | トヨタ自動車株式会社 | 車両用ロックアップクラッチのスリップ制御装置 |
GB9414699D0 (en) | 1994-07-21 | 1994-09-07 | Slagel David | Aqueous foamable composition |
US5512555A (en) | 1994-07-21 | 1996-04-30 | Merck & Co., Inc. | Method of treating sweat-related conditions using finasteride, epristeride and a cholestan-3-one |
JPH0840899A (ja) | 1994-07-29 | 1996-02-13 | Tokyo Tanabe Co Ltd | 硝酸オキシコナゾールのエアゾール剤 |
JP3241542B2 (ja) | 1994-07-29 | 2001-12-25 | 高砂香料工業株式会社 | (−)−n−イソプレゴールの精製方法及びその方法で得られた(−)−n−イソプレゴールを含有するシトラス系香料組成物 |
DE4428096A1 (de) | 1994-08-09 | 1996-02-15 | Wella Ag | Zweikammerbehälter |
US5656586A (en) | 1994-08-19 | 1997-08-12 | Rhone-Poulenc Inc. | Amphoteric surfactants having multiple hydrophobic and hydrophilic groups |
US5547989A (en) | 1994-08-19 | 1996-08-20 | Schering-Plough Healthcare Products, Inc. | Compositions for treating corns and calluses |
KR970705374A (ko) | 1994-08-26 | 1997-10-09 | 레이서 제이코버스 코넬리스 | 개인용 세정 조성물(personal cleansing compositions) |
JP3558393B2 (ja) | 1994-08-29 | 2004-08-25 | 株式会社ダイゾー | 起泡性エアゾール組成物 |
TW460296B (en) | 1994-09-01 | 2001-10-21 | Janssen Pharmaceutica Nv | Topical ketoconazole emulsion compositions without sodium sulfite |
US5976555A (en) | 1994-09-07 | 1999-11-02 | Johnson & Johnson Consumer Products, Inc. | Topical oil-in-water emulsions containing retinoids |
JP3604177B2 (ja) | 1994-09-14 | 2004-12-22 | 日東電工株式会社 | 経皮吸収製剤 |
US5500211A (en) | 1994-09-22 | 1996-03-19 | The Gillette Company | Soap-free self-foaming shave gel composition |
US5905092A (en) | 1994-09-27 | 1999-05-18 | Virotex Corporation Reel/Frame | Topical antibiotic composition providing optimal moisture environment for rapid wound healing that reduces skin contraction |
US5955414A (en) | 1994-10-05 | 1999-09-21 | S. C. Johnson & Son, Inc. | Cleaning foam having fluorinated stain repellent and low flammability |
US5540853A (en) | 1994-10-20 | 1996-07-30 | The Procter & Gamble Company | Personal treatment compositions and/or cosmetic compositions containing enduring perfume |
CA2180454A1 (en) | 1994-11-08 | 1996-05-17 | Toshihiko Terao | External preparation for skin protection |
US5567420A (en) | 1994-11-16 | 1996-10-22 | Mceleney; John | Lotion which is temporarily colored upon application |
US5788664A (en) | 1994-11-30 | 1998-08-04 | Scalise; Gaspare | Suppository applicator |
GB9424562D0 (en) | 1994-12-06 | 1995-01-25 | Giltech Ltd | Product |
US5641480A (en) | 1994-12-08 | 1997-06-24 | Lever Brothers Company, Division Of Conopco, Inc. | Hair care compositions comprising heteroatom containing alkyl aldonamide compounds |
JP3355257B2 (ja) | 1994-12-09 | 2002-12-09 | 太陽化学株式会社 | 化粧料 |
US5529770A (en) | 1994-12-09 | 1996-06-25 | West Agro, Inc. | Viscous liquid conditioning topical germicides |
DE4444238A1 (de) | 1994-12-13 | 1996-06-20 | Beiersdorf Ag | Kosmetische oder dermatologische Wirkstoffkombinationen aus Zimtsäurederivaten und Flavonglycosiden |
FR2728166A1 (fr) | 1994-12-19 | 1996-06-21 | Oreal | Composition topique contenant un antagoniste de substance p |
WO1996019183A1 (en) | 1994-12-21 | 1996-06-27 | Cosmederm Technologies | Formulations and methods for reducing skin irritation |
WO1996019921A1 (en) | 1994-12-23 | 1996-07-04 | Commonwealth Scientific And Industrial Research Organisation | Iodine biocidal material |
DE4446891A1 (de) | 1994-12-27 | 1996-07-04 | Falk Pharma Gmbh | Stabile wäßrige Budesonid-Lösung |
US5616136A (en) | 1995-01-09 | 1997-04-01 | Med-Safe Systems, Inc. | Quick release needle removal apparatus |
US5534261A (en) | 1995-01-17 | 1996-07-09 | University Of Southern California | Retinoid-based compositions and method for preventing adhesion formation using the same |
FR2729855A1 (fr) | 1995-01-26 | 1996-08-02 | Oreal | Utilisation d'un antagoniste de cgrp dans une composition cosmetique, pharmaceutique ou dermatologique et composition obtenue |
US5523078A (en) | 1995-02-03 | 1996-06-04 | Michael E. Baylin | Method of preparing and composition for treatment of hair and scalp |
US5587149A (en) | 1995-02-06 | 1996-12-24 | R.P. Scherer Corporation | Topical application emulsions |
FR2730932B1 (fr) | 1995-02-27 | 1997-04-04 | Oreal | Nanoemulsion transparente a base de lipides amphiphiles non-ioniques fluides et utilisation en cosmetique ou en dermopharmacie |
FR2730930B1 (fr) | 1995-02-27 | 1997-04-04 | Oreal | Utilisation d'inhibiteurs de no-synthase pour diminuer l'effet irritant cutane de produits utilises dans le domaine cosmetique ou pharmaceutique |
GB9504265D0 (en) | 1995-03-03 | 1995-04-19 | Medeva Plc | Corticosteroid-containing pharmaceutical composition |
US5558872A (en) | 1995-03-07 | 1996-09-24 | Healthpoint Medical Limited Partnership | Gelled mineral oil skin protectant |
US5618850A (en) | 1995-03-09 | 1997-04-08 | Focal, Inc. | Hydroxy-acid cosmetics |
US5783202A (en) | 1995-03-14 | 1998-07-21 | Soltec Research Pty. Ltd. | Pediculicidal mousse composition for killing head lice |
DE69630878T2 (de) | 1995-03-29 | 2004-11-11 | Shionogi & Co., Ltd. | Gelatinekapsel mit eingestellter wasseraktivität |
JPH08277209A (ja) | 1995-04-07 | 1996-10-22 | Taisho Pharmaceut Co Ltd | 育毛剤 |
US5585104A (en) | 1995-04-12 | 1996-12-17 | The Procter & Gamble Company | Cleansing emulsions |
EP0738510A3 (fr) | 1995-04-20 | 2005-12-21 | L'oreal | Utilisation d'un inhibiteur d'HMG-coenzyme A-reductase pour lutter contre le vieillissement de la peau et pour traiter l'acné. Composition comprenant au moins un inhibiteur HMG-coenzyme A reductase et au moins un actif possédant des propriétes desquamantes |
FR2733417B1 (fr) | 1995-04-25 | 1997-06-06 | Oreal | Emulsion huile-dans-eau moussante a base de tensio-actifs non-ioniques, d'une phase grasse et d'un polymere cationique ou anionique reticule et utilisation en application topique |
GB9510856D0 (en) | 1995-05-27 | 1995-07-19 | Cussons Int Ltd | Cleaning composition |
UY24246A1 (es) | 1995-06-06 | 1996-06-14 | Neutrogena Corp | Vehiculos tropicos que contienen acido azelaico solubilizado y estabilizado |
CA2224798A1 (en) | 1995-06-22 | 1997-01-09 | Matthew T. Scholz | Stable hydroalcoholic compositions |
JP3542665B2 (ja) | 1995-07-07 | 2004-07-14 | 株式会社資生堂 | 抗老化皮膚外用剤、コラーゲン架橋阻害皮膚外用剤及び抗紫外線皮膚外用剤 |
US5705472A (en) | 1995-07-18 | 1998-01-06 | Petroferm Inc. | Neutral aqueous cleaning composition |
FR2736824B1 (fr) | 1995-07-18 | 1997-10-10 | Fabre Pierre Dermo Cosmetique | Composition capillaire a base de minoxidil a faible teneur en solvant gras |
DE29512760U1 (de) | 1995-08-08 | 1995-11-16 | Wella Ag | Druckgasbehälter zum Abgeben von Schaum |
TW504387B (en) | 1995-09-06 | 2002-10-01 | Kao Corp | Emulsified, water-in-oil type composition and skin cosmetic preparation |
US5881493A (en) | 1995-09-14 | 1999-03-16 | D. B. Smith & Co. Inc. | Methods for applying foam |
CN1062129C (zh) | 1995-09-14 | 2001-02-21 | 徐荣祥 | 药物基质及其用途 |
JPH0984855A (ja) | 1995-09-25 | 1997-03-31 | Kyoto Yakuhin Kogyo Kk | 直腸または膣への薬物投与用のエアゾール製剤 |
JPH0999553A (ja) | 1995-10-09 | 1997-04-15 | Fujitsu Ltd | インクジェットヘッド |
JP3425019B2 (ja) | 1995-10-16 | 2003-07-07 | カネボウ株式会社 | 油性泡状クレンジング化粧料 |
US6221823B1 (en) | 1995-10-25 | 2001-04-24 | Reckitt Benckiser Inc. | Germicidal, acidic hard surface cleaning compositions |
EP0870497B1 (en) | 1995-12-14 | 2004-04-07 | Taisho Pharmaceutical Co. Ltd | Aerosol preparation |
FR2742986B1 (fr) | 1995-12-29 | 1998-01-30 | Rhone Poulenc Chimie | Compositions cosmetiques pour le cheveu ou la peau a base de copolyesters sulfones a motifs polyorganosiloxanes |
US5716611A (en) | 1996-01-02 | 1998-02-10 | Euro-Celtique, S.A. | Emollient antimicrobial formulations containing povidone iodine |
US5846983A (en) | 1996-02-09 | 1998-12-08 | Mayo Foundation For Medical Education And Research | Colonic delivery of nicotine to treat inflammatory bowel disease |
US5889028A (en) | 1996-02-09 | 1999-03-30 | Mayo Foundation For Medical Education And Research | Colonic delivery of nicotine to treat inflammatory bowel disease |
US5843411A (en) | 1997-02-06 | 1998-12-01 | Topix Pharmaceuticals Inc. | Stabilization of ascorbic acid, ascorbic acid derivatives and/or extracts containing ascorbic acid for topical use |
US5759524A (en) | 1996-02-09 | 1998-06-02 | The Procter & Gamble Company | Photoprotective compositions |
AUPN814496A0 (en) | 1996-02-19 | 1996-03-14 | Monash University | Dermal penetration enhancer |
US5912007A (en) | 1996-02-29 | 1999-06-15 | Warner-Lambert Company | Delivery system for the localized administration of medicaments to the upper respiratory tract and methods for preparing and using same |
US6251369B1 (en) | 1996-03-05 | 2001-06-26 | Sultan Dental Products | Dental fluoride foam |
FR2745716B1 (fr) | 1996-03-07 | 1998-04-17 | Oreal | Emulsions huile-dans-eau moussantes pressurisables ultrafines |
WO1997039745A1 (en) | 1996-04-19 | 1997-10-30 | Sloan-Kettering Institute For Cancer Research | Use of inhaled retinoids in the prevention of cancer |
US5910382A (en) | 1996-04-23 | 1999-06-08 | Board Of Regents, University Of Texas Systems | Cathode materials for secondary (rechargeable) lithium batteries |
IT1283042B1 (it) | 1996-05-21 | 1998-04-07 | Condea Augusta Spa | Composizioni cosmetiche deodoranti e/o antitraspiranti |
US5797955A (en) | 1996-06-11 | 1998-08-25 | Walters; David J. | Pressure application unit for positioning vertebra |
US5833961A (en) | 1996-06-25 | 1998-11-10 | Inolex Investment Corporation | Polyester-based suncreen formulations |
US6204285B1 (en) | 1996-07-01 | 2001-03-20 | Sepracor Inc. | Methods and compositions for treating urinary incontinence using enantiomerically enriched (R,R)-glycopyrrolate |
US5716621A (en) | 1996-07-03 | 1998-02-10 | Pharmadyn, Inc. | Nonocclusive drug delivery device and process for its manufacture |
CA2260126C (en) | 1996-07-10 | 2007-04-17 | Calgon Vestal, Inc. | Triclosan skin wash with enhanced efficacy |
DE19631221C2 (de) | 1996-08-02 | 1999-07-01 | Beiersdorf Ag | Schaumförmige Lichtschutzzubereitungen mit einem Gehalt an wasserlöslichen Lichtschutzfiltersubstanzen und grenzflächenaktiven Substanzen |
AU725954B2 (en) | 1996-08-15 | 2000-10-26 | Board Of Trustees Of Southern Illinois University, The | Enhancement of antimicrobial peptide activity by metal ions |
US5833963A (en) | 1996-08-20 | 1998-11-10 | Bristol-Myers Squibb Company | Non-tacky and quick-drying aqueous-based antiperspirant compositions |
US5837270A (en) | 1996-08-26 | 1998-11-17 | Burgess; Nelson Leon | Topical anti-acne composition |
US5741509A (en) | 1996-08-26 | 1998-04-21 | Alvin S. Berlat | Silicone wound dressing |
EP0829259A1 (en) | 1996-09-04 | 1998-03-18 | Warner-Lambert Company | Foam/gel with microbeads and/or fine particles |
US6271295B1 (en) | 1996-09-05 | 2001-08-07 | General Electric Company | Emulsions of silicones with non-aqueous hydroxylic solvents |
US5952392A (en) | 1996-09-17 | 1999-09-14 | Avanir Pharmaceuticals | Long-chain alcohols, alkanes, fatty acids and amides in the treatment of burns and viral inhibition |
US7060253B1 (en) | 1996-09-20 | 2006-06-13 | Mundschenk David D | Topical formulations and delivery systems |
FR2754451B1 (fr) | 1996-10-14 | 1998-11-06 | Oreal | Creme auto-moussante |
WO1998017282A1 (en) | 1996-10-23 | 1998-04-30 | Vertex Pharmaceuticals Incorporated | Methods of using sucrose octasulfate to treat or prevent enveloped virus infection |
US6093408A (en) | 1996-10-25 | 2000-07-25 | The Procter & Gamble Company | Skin care compositions |
IT1287114B1 (it) | 1996-10-31 | 1998-08-04 | Recordati Chem Pharm | Composizioni farmaceutiche antierpetiche per applicatori topici, contenenti aciclovir |
JP2986552B2 (ja) | 1996-11-04 | 1999-12-06 | ザ、プロクター、エンド、ギャンブル、カンパニー | シリコーンエマルジョンを含むヘアムース組成物 |
BR9713348A (pt) | 1996-11-12 | 2000-08-08 | Dov Tamarkin | Método para tratamento de distúrbios dermatológicos |
FR2755854B1 (fr) | 1996-11-15 | 1998-12-24 | Oreal | Nanoemulsion a base de lipides amphiphiles non-ioniques et cationiques et utilisations |
EP0889719B1 (de) | 1996-11-16 | 2003-04-02 | Wella Aktiengesellschaft | Mittel zur färbung und entfärbung von fasern |
US5906992A (en) | 1996-11-21 | 1999-05-25 | Colgate Palmolive Company | Foam cleaning compositions |
AUPO379596A0 (en) | 1996-11-22 | 1996-12-19 | Soltec Research Pty Ltd | Percutaneous delivery system |
US5951544A (en) | 1996-12-04 | 1999-09-14 | Laser Industries Ltd. | Handpiece assembly for laser apparatus |
US5759579A (en) | 1996-12-05 | 1998-06-02 | American Home Products Corporation | Pharmaceutical suspension systems |
US5695551A (en) | 1996-12-09 | 1997-12-09 | Dow Corning Corporation | Water repellent composition |
US5856452A (en) | 1996-12-16 | 1999-01-05 | Sembiosys Genetics Inc. | Oil bodies and associated proteins as affinity matrices |
US5672634A (en) | 1996-12-23 | 1997-09-30 | Isp Investments Inc. | Crosslinked PVP-I2 foam product |
US5879469A (en) | 1997-01-06 | 1999-03-09 | Deeay Technologies Ltd. | Dishwashing method and detergent composition therefor |
US6582711B1 (en) | 1997-01-09 | 2003-06-24 | 3M Innovative Properties Company | Hydroalcoholic compositions thickened using polymers |
SE520811C2 (sv) | 1997-01-17 | 2003-08-26 | Ponsus Ab | Hudskyddspreparat innehållande lipofila och hydrofila komponenter, förfarande för framställning och användning därav |
IN186803B (zh) | 1997-02-05 | 2001-11-10 | Panacea Biotec Ltd | |
ES2133090B1 (es) | 1997-02-21 | 2000-04-01 | Uriach & Cia Sa J | Nuevo aplicador para la administracion de medicaciones semisolidas. |
WO1998034604A1 (en) | 1997-02-11 | 1998-08-13 | Bernard Salafsky | ANTI-PARASITIC ACTION OF N,N-DIETHYL-m-TOLUAMIDE (DEET) AND FORMULATIONS THAT PROLONG ITS ACTIVITY IN THE SKIN |
WO1998036733A2 (en) | 1997-02-24 | 1998-08-27 | Michael Albert Kamm | Topical pharmaceutical composition comprising a cholinergic agent or a calcium channel blocker |
JP3050289B2 (ja) | 1997-02-26 | 2000-06-12 | 日本電気株式会社 | 出力バッファ回路の出力インピーダンス調整回路 |
US6433068B1 (en) | 1997-03-07 | 2002-08-13 | David S. Morrison | Hydrocarbon gels as suspending and dispersing agents and products |
FR2760637B1 (fr) | 1997-03-11 | 1999-05-28 | Fabre Pierre Dermo Cosmetique | Extrait de goudron de houille a teneur reduite en hydrocarbures aromatiques, procede d'obtention et preparations dermo-cosmetiques |
US5922331A (en) | 1997-03-26 | 1999-07-13 | Chanel, Inc. | Skin cream composition |
US5951989A (en) | 1997-04-07 | 1999-09-14 | Heymann; Warren R. | Method for the treatment of dry skin |
USH2043H1 (en) | 1997-05-23 | 2002-08-06 | The Procter & Gamble Company | Skin care compositions |
US6599513B2 (en) | 1997-05-27 | 2003-07-29 | Sembiosys Genetics Inc. | Products for topical applications comprising oil bodies |
ATE386439T1 (de) | 1997-05-27 | 2008-03-15 | Sembiosys Genetics Inc | Verwendungen von ölkörpern |
US6183762B1 (en) | 1997-05-27 | 2001-02-06 | Sembiosys Genetics Inc. | Oil body based personal care products |
US6372234B1 (en) | 1997-05-27 | 2002-04-16 | Sembiosys Genetics Inc. | Products for topical applications comprising oil bodies |
US6217887B1 (en) | 1997-06-04 | 2001-04-17 | The Procter & Gamble Company | Leave-on antimicrobial compositions which provide improved immediate germ reduction |
JP3113610B2 (ja) | 1997-06-04 | 2000-12-04 | 東洋ガスメーター株式会社 | ガスメーター用伝送装置の取付具 |
EP0884045A1 (en) | 1997-06-06 | 1998-12-16 | Pfizer Products Inc. | Self-tanning dihydroxyacetone formulations having improved stability and providing enhanced delivery |
US20050276836A1 (en) | 1997-06-11 | 2005-12-15 | Michelle Wilson | Coated vaginal devices for vaginal delivery of therapeutically effective and/or health-promoting agents |
KR100477498B1 (ko) | 1997-06-13 | 2005-03-18 | 다이쇼 세이야꾸 가부시끼가이샤 | 에어로졸제 |
JPH11111A (ja) | 1997-06-13 | 1999-01-06 | Kagoshima Pref Gov | 養魚用飼料 |
FR2765799B1 (fr) | 1997-07-08 | 1999-08-27 | Oreal | Composition brillante contenant des huiles aromatiques epaissies par un alkylether de polysaccharide |
ATE210954T1 (de) | 1997-08-18 | 2002-01-15 | Neubourg Stephanie | Schaum-hautschutzcreme |
JP3553767B2 (ja) | 1997-08-22 | 2004-08-11 | 三洋電機株式会社 | 移載介助装置 |
SE9703226D0 (sv) | 1997-09-08 | 1997-09-08 | Astra Ab | New pharmaceutical composition |
US5885581A (en) | 1997-09-11 | 1999-03-23 | Merz, Incorporated | Composition and method for improvement of the appearance of scars |
US5939376A (en) | 1997-09-25 | 1999-08-17 | Colgate Palmolive Company | Liquid cleaning compositions containing an organic ester foam control agent |
US6241971B1 (en) | 1997-09-25 | 2001-06-05 | The Procter & Gamble Company | Hair styling compositions comprising mineral salt, lipophilic material, and low levels of surfactant |
US6214318B1 (en) | 1997-10-02 | 2001-04-10 | Oms Holdings Llc | Aerosol ointment compositions for topical use |
US6075056A (en) | 1997-10-03 | 2000-06-13 | Penederm, Inc. | Antifungal/steroid topical compositions |
FR2769299B1 (fr) | 1997-10-03 | 1999-12-31 | Oreal | Ensemble de conditionnement et de distribution bi-produits |
AUPO983897A0 (en) | 1997-10-17 | 1997-11-06 | Soltec Research Pty Ltd | Topical antifungal composition |
US5961957A (en) | 1997-10-20 | 1999-10-05 | Mcanalley; Bill H. | Foam compositions |
US5911981A (en) | 1997-10-24 | 1999-06-15 | R.I.T.A. Corporation | Surfactant blends for generating a stable wet foam |
US5865347A (en) | 1997-10-27 | 1999-02-02 | William T. Wilkinson | Multi-chamber dispenser for flowable materials |
JP3450680B2 (ja) | 1997-10-28 | 2003-09-29 | 高砂香料工業株式会社 | パラ−メンタン−3,8−ジオールの製造方法 |
CA2306837C (en) | 1997-10-28 | 2007-05-08 | Asivi, Llc. | Treatment of female sexual dysfunction |
US5877216A (en) | 1997-10-28 | 1999-03-02 | Vivus, Incorporated | Treatment of female sexual dysfunction |
ES2318233T3 (es) | 1997-11-10 | 2009-05-01 | Strakan International Limited | Sistemas mejoradores de la penetracion y reductores de la irritacion que comprenden testosterona. |
DE29720316U1 (de) | 1997-11-17 | 1998-01-29 | Andris Raimund Gmbh & Co Kg | Zweikammer-Dosierspender |
US5849042A (en) | 1997-11-19 | 1998-12-15 | Bristol-Myers Squibb | Hair dye compositions containing 2,3 dialkyl-4-aminophenol and a 2-alkyl-1-naphthol |
US5871720A (en) | 1997-11-20 | 1999-02-16 | Colgate-Palmolive Company | Cosmetic compositions with DBS and functionalized silicones |
WO1999029336A1 (en) | 1997-12-05 | 1999-06-17 | Eli Lilly And Company | Glp-1 formulations |
TWI225793B (en) | 1997-12-25 | 2005-01-01 | Ajinomoto Kk | Cosmetic composition |
JP3050289U (ja) | 1997-12-29 | 1998-06-30 | 丸隆株式会社 | ペット動物室内排泄用具 |
DE19802206A1 (de) | 1998-01-22 | 1999-07-29 | Beiersdorf Ag | Lipidreduzierte, fließfähige Zubereitungen |
FR2774595A1 (fr) | 1998-02-06 | 1999-08-13 | Rech D Innovation Et De Dev Ce | Emulsion pour l'administration transdermique de steroides |
DE19805918A1 (de) | 1998-02-13 | 1999-08-19 | Beiersdorf Ag | Lipidreduzierte Zubereitungen |
US6110966A (en) | 1998-02-20 | 2000-08-29 | Medi-Cell Laboratories, Inc. | Triple action complex |
DE19807774A1 (de) | 1998-02-24 | 1999-08-26 | Beiersdorf Ag | Verwendung von Flavonen bzw. Flavanonen bzw. Flavonoiden zum Schutze von Ascorbinsäure und/oder Ascorbylverbindungen gegen Oxidation |
US6017912A (en) | 1998-02-27 | 2000-01-25 | Bussell; Letantia | Topical fluoroquinolone antibiotics in an alcohol and acetone vehicle |
JP3514105B2 (ja) | 1998-02-27 | 2004-03-31 | ティアック株式会社 | 記録媒体記録再生装置 |
KR100491202B1 (ko) | 1998-03-04 | 2005-05-25 | 데이진 가부시키가이샤 | 활성형 비타민 d3 유제성 로션제 |
US6121210A (en) | 1998-03-12 | 2000-09-19 | Dap Products Inc. | Foamable silicone oil compositions and methods of use thereof |
WO1999045784A1 (fr) | 1998-03-12 | 1999-09-16 | Oji Paper Co., Ltd. | Bactericides |
US5990100A (en) | 1998-03-24 | 1999-11-23 | Panda Pharmaceuticals, L.L.C. | Composition and method for treatment of psoriasis |
AUPP310798A0 (en) | 1998-04-22 | 1998-05-14 | Soltec Research Pty Ltd | Vehicle system for a composition comprising a piperidinopyrimidine derivative |
US5919830A (en) | 1998-04-30 | 1999-07-06 | Gopalkrishnan; Sridhar | Stable non-aqueous blends for personal care compositions |
US6649175B1 (en) | 1998-05-04 | 2003-11-18 | Schering-Plough Healthcare Products, Inc. | Skin barrier composition |
GB9810949D0 (en) | 1998-05-22 | 1998-07-22 | Hewlett Healthcare Limited | Formulation |
FR2779637B1 (fr) | 1998-06-15 | 2000-09-01 | Oreal | Compositions cosmetiques photoprotectrices, contenant un nanopigment d'oxyde metallique et un terpolymere acrylique et utilisation de ces compositions pour proteger les matieres keratiniques contre le rayonnement ultraviolet |
US6706290B1 (en) | 1998-07-06 | 2004-03-16 | Olvai E. Kajander | Methods for eradication of nanobacteria |
FR2780879B1 (fr) | 1998-07-09 | 2002-09-20 | Oreal | Composition cosmetique photoprotectrice contenant un tensio-actif anionique, un compose filtrant le rayonnement ultraviolet et un compose cationique ou zwitterionique amphiphile et son utilisation |
US6146664A (en) | 1998-07-10 | 2000-11-14 | Shaklee Corporation | Stable topical ascorbic acid compositions |
US6124362A (en) | 1998-07-17 | 2000-09-26 | The Procter & Gamble Company | Method for regulating hair growth |
US6071541A (en) | 1998-07-31 | 2000-06-06 | Murad; Howard | Pharmaceutical compositions and methods for managing skin conditions |
JP4017758B2 (ja) | 1998-08-04 | 2007-12-05 | 高砂香料工業株式会社 | 冷感剤組成物 |
DE19835239A1 (de) | 1998-08-04 | 2000-02-24 | Johnson & Johnson Gmbh | Schäumende Ölzubereitung und deren Verwendung |
GB9817817D0 (en) | 1998-08-14 | 1998-10-14 | Unilever Plc | Cosmetic composition |
HUP0104168A3 (en) | 1998-08-20 | 2003-04-28 | 3M Innovative Properties Co | Spray on bandage and drug delivery system |
JP3712868B2 (ja) | 1998-09-02 | 2005-11-02 | 株式会社カネボウ化粧品 | エアゾール組成物 |
US8263580B2 (en) | 1998-09-11 | 2012-09-11 | Stiefel Research Australia Pty Ltd | Vitamin formulation |
AUPP583198A0 (en) | 1998-09-11 | 1998-10-01 | Soltec Research Pty Ltd | Mousse composition |
US6087310A (en) | 1998-09-23 | 2000-07-11 | Castrol Limited | Skin cleaning compositions and uses comprising a polymer latex emulsion |
EP1117398A2 (en) | 1998-09-28 | 2001-07-25 | Merck & Co., Inc. | A method for treating inflammatory diseases by administering a thrombin inhibitor |
US6914057B1 (en) | 1998-09-28 | 2005-07-05 | The Research Foundation Of State University Of New York | Inhibitor of cataract formation |
US6607716B1 (en) | 1998-09-29 | 2003-08-19 | Tech Labs, Inc. | Pediculicidal compositions, a kit, and methods of use |
RU2134052C1 (ru) | 1998-10-07 | 1999-08-10 | Нерушай Сергей Алексеевич | Способ аэрозольного нанесения парфюмерных жидкостей и устройство для его осуществления |
US6287546B1 (en) | 1998-10-09 | 2001-09-11 | Colgate-Palmolive Company | Shampoos with stabilizers |
JP3876081B2 (ja) | 1998-10-22 | 2007-01-31 | 東洋エアゾール工業株式会社 | フォーム形成用エアゾール組成物 |
US6110477A (en) | 1998-10-30 | 2000-08-29 | Topix Pharmaceuticals Inc. | Stabilization of ascorbic acid, ascorbic acid derivatives and/or extracts containing ascorbic acid for topical use |
US7521068B2 (en) | 1998-11-12 | 2009-04-21 | Elan Pharma International Ltd. | Dry powder aerosols of nanoparticulate drugs |
US5980904A (en) | 1998-11-18 | 1999-11-09 | Amway Corporation | Skin whitening composition containing bearberry extract and a reducing agent |
US6344218B1 (en) | 1998-11-23 | 2002-02-05 | The Procter & Gamble Company | Skin deodorizing and santizing compositions |
DE19855097A1 (de) | 1998-11-28 | 2000-05-31 | Wella Ag | Pigmenthaltiges, verschäumbares Gel |
US20010006654A1 (en) | 1998-12-09 | 2001-07-05 | L'oreal | Compositions and methods for treating hair and skin using aqueous delivery systems |
US6087317A (en) | 1998-12-10 | 2000-07-11 | Dow Corning Corporation | Particle size stable silicone emulsions |
US6486207B2 (en) | 1998-12-10 | 2002-11-26 | Nexmed (Holdings), Inc. | Compositions and methods for amelioration of human female sexual dysfunction |
US6262128B1 (en) | 1998-12-16 | 2001-07-17 | 3M Innovative Properties Company | Aqueous foaming compositions, foam compositions, and preparation of foam compositions |
FR2787325B1 (fr) | 1998-12-17 | 2001-01-26 | Oreal | Nanoemulsion a base d'esters gras de sorbitan oxyethylenes ou non oxyethylenes, et ses utilisations dans les domaines cosmetique, dermatologique et/ou ophtalmologique |
FR2787728B1 (fr) | 1998-12-23 | 2001-01-26 | Oreal | Nanoemulsion a base d'esters gras d'acide phosphorique, et ses utilisations dans les domaines cosmetique, dermatologique, pharmaceutique et/ou ophtalmologique |
JP2000191429A (ja) | 1998-12-28 | 2000-07-11 | Kao Corp | 発泡性化粧料 |
WO2000038731A1 (en) | 1998-12-28 | 2000-07-06 | Taisho Pharmaceutical Co.,Ltd. | External preparation |
FR2787703B1 (fr) | 1998-12-29 | 2001-01-26 | Oreal | Nanoemulsion a base d'ethers gras ethoxyles ou d'esters gras ethoxyles, et ses utilisations dans les domaines cosmetique, dermatologique et/ou ophtalmologique |
FR2788007B1 (fr) | 1999-01-05 | 2001-02-09 | Oreal | Nanoemulsion a base de copolymeres blocs d'oxyde d'ethylene et d'oxyde de propylene, et ses utilisations dans les domaines cosmetique, dermatologique et/ou ophtalmologique |
US6486168B1 (en) | 1999-01-08 | 2002-11-26 | 3M Innovative Properties Company | Formulations and methods for treatment of mucosal associated conditions with an immune response modifier |
US6270781B1 (en) | 1999-01-08 | 2001-08-07 | Maxim Pharmaceuticals, Inc. | Method and compositions for topical treatment of damaged tissue using reactive oxygen metabolite production or release inhibitors |
FR2789371B1 (fr) | 1999-02-05 | 2001-04-27 | Sofab | Distributeur de produits chimiquement instables |
EP1025836A1 (en) | 1999-02-08 | 2000-08-09 | F. Hoffmann-La Roche Ag | Cosmetic light screening composition |
TWI262930B (en) | 1999-02-10 | 2006-10-01 | Mitsui Chemicals Inc | High-durability flexible polyurethane cold molded foam and process for producing the same |
US6423329B1 (en) | 1999-02-12 | 2002-07-23 | The Procter & Gamble Company | Skin sanitizing compositions |
US6224888B1 (en) | 1999-02-12 | 2001-05-01 | The Procter & Gamble Company | Cosmetic compositions |
JP3641152B2 (ja) | 1999-02-17 | 2005-04-20 | 株式会社ヤクルト本社 | 皮膚外用剤 |
US7374779B2 (en) | 1999-02-26 | 2008-05-20 | Lipocine, Inc. | Pharmaceutical formulations and systems for improved absorption and multistage release of active agents |
US6305578B1 (en) | 1999-02-26 | 2001-10-23 | Wella Aktiengesellshaft | Device for mixing, foaming and dispensing liquids from separate compressed-gas containers |
US6761903B2 (en) | 1999-06-30 | 2004-07-13 | Lipocine, Inc. | Clear oil-containing pharmaceutical compositions containing a therapeutic agent |
IL129102A0 (en) | 1999-03-22 | 2000-02-17 | J P M E D Ltd | An emulsion |
ES2298932T3 (es) | 1999-03-31 | 2008-05-16 | Firmenich Sa | Composicion saborizante que contiene cubebol y por lo menos agente refrescante. |
US6383471B1 (en) | 1999-04-06 | 2002-05-07 | Lipocine, Inc. | Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents |
US6264964B1 (en) | 1999-04-14 | 2001-07-24 | Conopco, Inc. | Foaming cosmetic products |
JP3777499B2 (ja) | 1999-04-16 | 2006-05-24 | ゼファーマ株式会社 | 抗真菌組成物 |
US6284802B1 (en) | 1999-04-19 | 2001-09-04 | The Procter & Gamble Company | Methods for regulating the condition of mammalian keratinous tissue |
ES2388425T5 (es) | 1999-04-23 | 2020-02-12 | Leo Pharma As | Composición farmacéutica no acuosa para uso dérmico para tratar la psoriasis que comprende una vitamina D, un corticoesteroide y un componente disolvente |
US6433003B1 (en) | 1999-04-23 | 2002-08-13 | Arthur M. Bobrove | Method for treating hyperhidrosis in mammals |
GB9909711D0 (en) | 1999-04-27 | 1999-06-23 | Unilever Plc | Mousse forming hair treatment composition |
FR2793479B1 (fr) | 1999-05-10 | 2001-06-29 | Lir France Sa | Distributeur double pour produits fluides ou pateux |
AU4841700A (en) | 1999-05-12 | 2000-11-21 | Nitromed, Inc. | Nitrosated and nitrosylated potassium channel activators, compositions and methods of use |
US6168576B1 (en) | 1999-05-24 | 2001-01-02 | Irene N. Reynolds | Device for dispensing vaginal medication |
US6518228B1 (en) | 1999-05-27 | 2003-02-11 | Clairol Incorporated | Ultra-mild, clear, aqueous, foamable skin cleanser |
US6395300B1 (en) | 1999-05-27 | 2002-05-28 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
JP2003500427A (ja) | 1999-05-28 | 2003-01-07 | ユニリーバー・ナームローゼ・ベンノートシヤープ | 発泡性シャワーオイル組成物 |
JP2000351726A (ja) | 1999-06-08 | 2000-12-19 | Lion Corp | エアゾール製剤 |
JP2000354623A (ja) | 1999-06-14 | 2000-12-26 | Shiigeru Kk | 消臭剤及び消臭スプレー |
GB9913951D0 (en) | 1999-06-15 | 1999-08-18 | Unilever Plc | Mousse-forming shampoo compositions |
US6113888A (en) | 1999-06-15 | 2000-09-05 | Neutrogena Corporation | Self-tanning mousse |
US6190365B1 (en) | 1999-06-21 | 2001-02-20 | Chun Lim Abbott | Vaginal douche applicator and method of vaginal deodorization using the same |
KR100352088B1 (ko) | 1999-06-21 | 2002-09-12 | 한미약품공업 주식회사 | 미녹시딜 함유 외용 에멀젼 조성물 |
US6524594B1 (en) | 1999-06-23 | 2003-02-25 | Johnson & Johnson Consumer Companies, Inc. | Foaming oil gel compositions |
JP2001002526A (ja) | 1999-06-23 | 2001-01-09 | Koike Kagaku Kk | 泡沫エアゾール組成物 |
NL1012419C2 (nl) | 1999-06-23 | 2000-12-28 | Airspray Nv | Spuitbus voor het afgeven van een vloeistof. |
US6551604B1 (en) | 1999-06-28 | 2003-04-22 | The Procter & Gamble Company | Skin care compositions |
US6762158B2 (en) | 1999-07-01 | 2004-07-13 | Johnson & Johnson Consumer Companies, Inc. | Personal care compositions comprising liquid ester mixtures |
WO2001001949A1 (en) | 1999-07-01 | 2001-01-11 | Johnson And Johnson Consumer Companies, Inc. | Cleansing compositions |
FR2795643B1 (fr) | 1999-07-02 | 2004-06-11 | Oreal | Composition cosmetique raffermissante comprenant au moins un hydroxystilbene en association avec de l'acide ascorbique |
JP4058199B2 (ja) | 1999-07-06 | 2008-03-05 | ポーラ化成工業株式会社 | 温感パック |
WO2001005366A1 (en) | 1999-07-15 | 2001-01-25 | Playtex Products, Inc. | Sunscreen aerosol composition |
US6548074B1 (en) | 1999-07-22 | 2003-04-15 | Elizabeth Arden Co., Division Of Conopco, Inc. | Silicone elastomer emulsions stabilized with pentylene glycol |
FR2796925B1 (fr) | 1999-07-29 | 2001-10-05 | Valois Sa | Distributeur a tete de distribution articulee |
AU7389300A (en) | 1999-08-02 | 2001-02-19 | First Horizon Pharmaceutical Corporation | Methods of administration of glycopyrrolate compositions |
US6303552B1 (en) | 1999-08-04 | 2001-10-16 | Napier International Technologies, Inc. | Aerosol paint stripper compositions |
DE19938757A1 (de) | 1999-08-16 | 2001-02-22 | Beiersdorf Ag | Kosmetische oder dermatologische Zubereitungen vom Typ Öl-in-Wasser |
DE60012026T2 (de) | 1999-08-26 | 2004-12-30 | Ganeden Biotech, Inc., San Diego | Verwendung von emu-öl als träger für fungizide, antibakterielle und antivirale arzneien |
US6777591B1 (en) | 1999-08-27 | 2004-08-17 | Sembiosys Genetics Inc. | Legume-like storage protein promoter isolated from flax and methods of expressing proteins in plant seeds using the promoter |
US6308863B1 (en) | 1999-09-02 | 2001-10-30 | Owens-Brockway Plastic Products Inc. | Dual chamber package for pressurized products |
US6479058B1 (en) | 1999-09-02 | 2002-11-12 | Mccadden Michael E. | Composition for the topical treatment of poison ivy and other forms of contact dermatitis |
JP4394775B2 (ja) | 1999-09-03 | 2010-01-06 | 株式会社ダイゾー | 油中水型泡状エアゾール組成物およびその製造方法 |
JP4045475B2 (ja) | 1999-09-06 | 2008-02-13 | 東洋紡績株式会社 | 核酸・蛋白質精製装置 |
US6986883B2 (en) | 1999-09-09 | 2006-01-17 | Discus Dental, Inc. | Increased peroxide content tooth bleaching gel |
AU3887301A (en) | 1999-09-20 | 2001-04-24 | Procter & Gamble Company, The | Article for the delivery of foam products |
US6437006B1 (en) | 1999-09-27 | 2002-08-20 | American Cyanamid Company | Pharmaceutical carrier formulation |
US6528086B2 (en) | 1999-09-28 | 2003-03-04 | Zars, Inc. | Methods and apparatus for drug delivery involving phase changing formulations |
FR2798849B1 (fr) | 1999-09-29 | 2001-11-23 | Oreal | Composition de lavage des matieres keratiniques, a base d'un agent tensio actif detergent, d'un homopolymere de dialkyl diallyl ammonium et d'un terpolymere acrylique |
US6790435B1 (en) | 1999-10-01 | 2004-09-14 | Unilever Home & Personal Care Usa Division Of Conopco, Inc. | Antiperspirant compositions comprising microemulsions |
US6667045B2 (en) | 1999-10-01 | 2003-12-23 | Joseph Scott Dahle | Topical applications for skin treatment |
FR2799369B1 (fr) | 1999-10-08 | 2001-12-21 | Oreal | Association d'escine et de sulfate de dextran et son utilisation |
US6186367B1 (en) | 1999-10-19 | 2001-02-13 | Valley Design Inc. | Metered liquid squeeze dispenser |
FR2799963B1 (fr) | 1999-10-22 | 2002-07-19 | Oreal | Emulsions contenant au moins un filtre uv organique insoluble et une silicone organomodifiee non-filtrante |
US6080394A (en) | 1999-11-08 | 2000-06-27 | Dow Corning Corporation | Polar solvent-in-oil emulsions and multiple emulsions |
US20030077301A1 (en) | 1999-12-16 | 2003-04-24 | Maibach Howard I. | Topical pharmaceutical composition for the treatment of inflammatory dermatoses |
UA66796C2 (uk) | 1999-12-27 | 2004-06-15 | Univ Nat Pharmaceutical | Лікарський засіб "профезоль-пінний" для лікування променевих уражень шкіри |
US6967023B1 (en) | 2000-01-10 | 2005-11-22 | Foamix, Ltd. | Pharmaceutical and cosmetic carrier or composition for topical application |
IL133969A0 (en) | 2000-01-10 | 2001-04-30 | Thixo Ltd | Thixotropic compositions containing unsaturated oils and food products containing the same |
US7001690B2 (en) | 2000-01-18 | 2006-02-21 | Valence Technology, Inc. | Lithium-based active materials and preparation thereof |
US6528033B1 (en) | 2000-01-18 | 2003-03-04 | Valence Technology, Inc. | Method of making lithium-containing materials |
FR2804015B1 (fr) | 2000-01-21 | 2005-12-23 | Oreal | Nanoemulsion contenant des lipides amphiphiles et un polymere non ionique et utilisations |
FR2804016B1 (fr) | 2000-01-21 | 2006-07-28 | Oreal | Nanoemulsion contenant des lipides amphiphiles et un ester de peg et utilisations |
AU2001231189A1 (en) | 2000-01-27 | 2001-08-07 | Childrens Hospital Research Foundation | Transdermal anesthetic and vasodilator composition and methods for topical administration |
FR2804666B1 (fr) | 2000-02-04 | 2002-06-14 | Oreal | Distributeur pour le stockage d'au moins deux composants et la distribution selective soit d'un constituant seul, soit de leur melange, et procede pour sa mise en oeuvre |
US6780443B1 (en) | 2000-02-04 | 2004-08-24 | Takasago International Corporation | Sensate composition imparting initial sensation upon contact |
NL1014389C2 (nl) | 2000-02-15 | 2001-08-16 | Dija Zeist Bv | Bruiningspreparaat voor de huid. |
US20040161447A1 (en) | 2000-02-17 | 2004-08-19 | Leonard Paul | Liquid foam producing compositions and dispensing system therefor |
KR100690469B1 (ko) | 2000-02-22 | 2007-03-09 | 칼라 액세스, 인크. | 겔화된 수성 화장용 조성물 |
EP1269357A4 (en) | 2000-02-22 | 2005-10-12 | Metacarta Inc | SPANISH CODING AND DISPLAYING INFORMATION |
DE10008896A1 (de) | 2000-02-25 | 2001-08-30 | Beiersdorf Ag | Kosmetische und dermatologische Lichtschutzformulierungen mit einem Gehalt an Benzotriazolderivaten und Alkylnaphthalaten |
DE10008837A1 (de) | 2000-02-25 | 2001-08-30 | Henkel Kgaa | Treibgashaltiges Zahnreinigungsmittel |
US6664287B2 (en) | 2000-03-15 | 2003-12-16 | Bethesda Pharmaceuticals, Inc. | Antioxidants |
IL135222A (en) | 2000-03-22 | 2005-06-19 | Univ Ben Gurion | Compositions containing molecular iodine |
DE20006099U1 (de) | 2000-04-01 | 2000-07-06 | Megaplast Gmbh & Co Kg | Dosierpumpenspender mit wenigstens zwei Dosierpumpen |
US6649571B1 (en) | 2000-04-04 | 2003-11-18 | Masi Technologies, L.L.C. | Method of generating gas bubbles in oleaginous liquids |
US6437004B1 (en) | 2000-04-06 | 2002-08-20 | Nicholas V. Perricone | Treatment of skin damage using olive oil polyphenols |
FR2807322B1 (fr) | 2000-04-10 | 2004-02-20 | Oreal | Composition, notamment cosmetique, comprenant de l'acide ascorbique en association avec un derive d'acide ascorbique |
US7758888B2 (en) | 2000-04-21 | 2010-07-20 | Sol-Gel Technologies Ltd. | Composition exhibiting enhanced formulation stability and delivery of topical active ingredients |
JP2002012513A (ja) | 2000-04-24 | 2002-01-15 | Kanebo Ltd | 尿素含有ホイップ状化粧料 |
US6358541B1 (en) | 2000-05-03 | 2002-03-19 | David S. Goodman | Topical preparation for the treatment of hair loss |
US6410036B1 (en) | 2000-05-04 | 2002-06-25 | E-L Management Corp. | Eutectic mixtures in cosmetic compositions |
AU2001257534A1 (en) | 2000-05-05 | 2001-11-20 | R.P. Scherer Technologies, Inc. | Oil-in-water emulsion formulation containing hydroquinone and retinol |
US6433024B1 (en) | 2000-05-08 | 2002-08-13 | Karl F. Popp | Topical anti-acne composition |
AU2001248715B2 (en) | 2000-05-08 | 2005-10-13 | Pfizer Products Inc. | Skin protectant spray compositions |
FR2808685B1 (fr) | 2000-05-12 | 2004-10-08 | Sanofi Synthelabo | Compositions pharmaceutiques pour administration transdermique d'agents anti-inflammatoires |
JP2001326952A (ja) | 2000-05-15 | 2001-11-22 | Nec Corp | 放送確認システム、放送確認方法及び装置、放送確認プログラムを記録した記録媒体 |
FR2809010B1 (fr) | 2000-05-22 | 2002-07-12 | Oreal | Nanoemulsion a base de polymeres anioniques, et ses utilisations notamment dans les domaines cosmetique, dermatologique, pharmaceutique et/ou ophtalmologique |
JP4653282B2 (ja) | 2000-05-23 | 2011-03-16 | 昭和薬品化工株式会社 | ミノサイクリン含有組成物 |
DE10028638A1 (de) | 2000-06-09 | 2001-12-20 | Schuelke & Mayr Gmbh | Lagerstabile Zusammensetzungen von Glycerinmonoalkylethern |
WO2001095728A1 (en) | 2000-06-13 | 2001-12-20 | Fd Management, Inc. | Cosmetic composition for stressed skin under extreme conditions |
AU2001272015A1 (en) | 2000-06-23 | 2002-01-08 | Combe International Ltd. | Stable foam for use in disposable wipe |
US20020164381A1 (en) | 2000-06-30 | 2002-11-07 | Medicis Pharmaceutical Corporation | Mitocidal compositions and methods |
US8512718B2 (en) | 2000-07-03 | 2013-08-20 | Foamix Ltd. | Pharmaceutical composition for topical application |
CA2313659A1 (en) | 2000-07-06 | 2002-01-06 | Barry J. Barclay | B complex vitamin compositions that protect against cellular damage caused by ultraviolet light |
DE10033414B4 (de) | 2000-07-08 | 2004-02-19 | Wella Aktiengesellschaft | Klares, zweiphasiges, schaumbildendes Aerosol-Haarpflegeprodukt |
US6468989B1 (en) | 2000-07-13 | 2002-10-22 | Dow Pharmaceutical Sciences | Gel compositions containing metronidazole |
FR2811564B1 (fr) | 2000-07-13 | 2002-12-27 | Oreal | Nanoemulsion contenant des polymeres non ioniques, et ses utilisations notamment dans les domaines cosmetique, dermatologique, pharmaceutique et/ou ophtalmologique |
DE10035930A1 (de) | 2000-07-21 | 2002-01-31 | Clariant Gmbh | Feinemulsionen |
US20020035070A1 (en) | 2000-07-26 | 2002-03-21 | The Procter & Gamble Company | Method of regulating hair growth using metal complexes of oxidized carbohydrates |
FR2812191B1 (fr) | 2000-07-28 | 2003-10-17 | Oreal | Utilisation d'agonistes du recepteur des prostaglandines e2 (ep-3) pour attenuer, diminuer ou stopper la pousse des cheveux et des poils dans des preparations cosmetiques |
JP4166931B2 (ja) | 2000-08-02 | 2008-10-15 | ポーラ化成工業株式会社 | 発熱フォーム化粧料 |
US20040198706A1 (en) | 2003-03-11 | 2004-10-07 | Carrara Dario Norberto R. | Methods and formulations for transdermal or transmucosal application of active agents |
US6514487B1 (en) | 2000-08-08 | 2003-02-04 | Teresa Leigh Barr | Foam and gel oat protein complex and method of use |
WO2002015873A2 (en) | 2000-08-22 | 2002-02-28 | The Procter & Gamble Company | Personal care compositions containing adhesive elastomeric polymer and inorganic colloid |
WO2002015860A1 (en) | 2000-08-24 | 2002-02-28 | Tim Ioannides | Topical antioxidant having vitamin c and method of combination with topical agent by user |
US6299023B1 (en) | 2000-08-24 | 2001-10-09 | Miles Arnone | Device for dispensing two substances in a user selectable ratio with replaceable cartridges |
FR2813189B1 (fr) | 2000-08-31 | 2003-02-28 | Oreal | Creme cosmetique moussante pour le traitement des peaux grasses |
WO2002022086A2 (en) | 2000-09-14 | 2002-03-21 | Quantum Energy Technologies | Application of water nanoclusters to skin |
WO2002024161A1 (fr) | 2000-09-21 | 2002-03-28 | Taisho Pharmaceutical Co., Ltd. | Suppositoires soutenus dans le rectum inférieur |
AUPR048600A0 (en) | 2000-10-02 | 2000-10-26 | Soltec Research Pty Ltd | Pharmaceutical vehicle |
DE10049147A1 (de) | 2000-10-04 | 2002-04-25 | Wella Ag | Haarwachsprodukt mit Wachsen, nicht-flüchtigen Ölen und flüchtigen, hydrophoben Stoffen |
FR2814959A1 (fr) | 2000-10-09 | 2002-04-12 | Menarini France | Nouveau dispositif de pulverisation pour formes pharmaceutiques a base d'agent anti-inflammatoire et les formes ainsi realisees |
US6547063B1 (en) | 2000-10-10 | 2003-04-15 | The Procter & Gamble Company | Article for the delivery of foam products |
GB2367809A (en) | 2000-10-12 | 2002-04-17 | Bespak Plc | Metering valve with collapsible chamber |
FR2815616B1 (fr) | 2000-10-20 | 2003-01-24 | Oreal | Ensemble de distribution destine a la distribution extemporanee de deux produits |
US6403069B1 (en) | 2000-10-20 | 2002-06-11 | Colgate-Palmolive Company | High oil clear emulsion with elastomer |
US20040018228A1 (en) | 2000-11-06 | 2004-01-29 | Afmedica, Inc. | Compositions and methods for reducing scar tissue formation |
DE10058384B4 (de) | 2000-11-24 | 2004-12-16 | Wella Aktiengesellschaft | Kosmetisches oder dermatologisches Mittel in Form eines cremigen Permanentschaums oder einer stabil aufgeschäumten Creme, deren Verwendung und Verfahren zur Herstellung des Mittels |
US6299032B1 (en) | 2000-11-27 | 2001-10-09 | George W. Hamilton | Disposable actuator with cap opener for aerosol cans |
US6969521B1 (en) | 2000-11-28 | 2005-11-29 | Avon Products, Inc. | Aerosol insect repellent composition having low VOC content and method of applying same to the skin |
WO2002043490A1 (en) | 2000-11-28 | 2002-06-06 | Avon Products, Inc. | Foaming insect repellent compositions |
US20050013853A1 (en) | 2000-11-29 | 2005-01-20 | Irit Gil-Ad | Anti-proliferative drugs |
US6774100B2 (en) | 2000-12-06 | 2004-08-10 | Imaginative Research Associates, Inc. | Anhydrous creams, lotions and gels |
GB0030068D0 (en) | 2000-12-11 | 2001-01-24 | Lawrence Malcolm | Highway vehicular traffic flow control |
JP3497466B2 (ja) | 2000-12-12 | 2004-02-16 | 高砂香料工業株式会社 | 温感組成物 |
US20060254597A1 (en) | 2000-12-14 | 2006-11-16 | 40J's Llc | Method of treatment of atrophic vaginitis by topical clitoral menthol or a related cooling compound |
DE10063342A1 (de) | 2000-12-19 | 2002-06-20 | Beiersdorf Ag | Selbstschäumende oder schaumförmige Zubereitungen |
US6749860B2 (en) | 2000-12-22 | 2004-06-15 | Kimberly-Clark Worldwide, Inc. | Absorbent articles with non-aqueous compositions containing botanicals |
US20040079361A1 (en) | 2001-01-17 | 2004-04-29 | Clayton Colin D. | Medicinal aerosols |
FR2819427B1 (fr) | 2001-01-18 | 2003-04-11 | Oreal | Nanoemulsion translucide, son procede de fabrication et ses utilisations dans les domaines cosmetique, dermatologique et/ou ophtalmologique |
US20030013692A1 (en) | 2001-01-19 | 2003-01-16 | Gullans Steven R. | Methods of treating neurological disorders |
EP1357905A2 (en) | 2001-02-05 | 2003-11-05 | Michael Albert Kamm | A treatment of oesophageal motility disorders and gastro-oesophageal reflux disease |
DE10110336A1 (de) | 2001-03-03 | 2002-09-12 | Clariant Gmbh | Tensidfreie kosmetische, dermatologische und pharmazeutische Mittel |
KR20040052489A (ko) | 2001-03-06 | 2004-06-23 | 셀러지 파마세우티칼스, 인크 | 비뇨생식기 장애 치료용 화합물 및 그 방법 |
MXPA03008108A (es) | 2001-03-07 | 2003-12-12 | Procter & Gamble | Composicion topica que comprende un agente cosmetico enlazante de derivado aromatico funcional. |
US7419958B2 (en) | 2001-03-26 | 2008-09-02 | Dana-Farber Cancer Institute, Inc. | Method of attenuating reactions to skin irritants |
DE60200946T2 (de) | 2001-03-26 | 2005-09-01 | 3M Innovative Properties Co., St. Paul | Dossierventil für einen dosierinhalator mit verbessertem fluss |
EP1372605A2 (en) | 2001-03-27 | 2004-01-02 | Galen (Chemicals) Limited | Intravaginal drug delivery devices for the administration of an antimicrobial agent |
US6977082B2 (en) | 2001-03-29 | 2005-12-20 | The Dial Corporation | High efficacy antibacterial compositions having enhanced esthetic and skin care properties |
JP2002302419A (ja) | 2001-03-30 | 2002-10-18 | Aldeep Cosmetics Japan Inc | 化粧用組成物 |
NZ529308A (en) | 2001-04-05 | 2005-03-24 | Collagenex Pharm Inc | Tetracycline compounds comprising a tetracycline and a controlled release agent to provide delivery at a dose below that required for antibiotic activity |
US6848597B2 (en) | 2001-04-18 | 2005-02-01 | James A. Vlodek | Methods and apparatus for extruding foam through orifices |
US20030053980A1 (en) | 2001-04-30 | 2003-03-20 | The Gillette Company | Shaving compositions containing highly lubricious water soluble polymers |
US6682726B2 (en) | 2001-04-30 | 2004-01-27 | The Gillette Company | Self-foaming shaving lotion |
MXPA03009995A (es) * | 2001-05-09 | 2004-06-30 | Univ Michigan | Uso de composiciones para tratar rosacea. |
US20020187181A1 (en) | 2001-05-14 | 2002-12-12 | 3M Innovative Properties Company | System for delivering cosmetics and pharmaceuticals |
ITMI20011019A1 (it) | 2001-05-17 | 2002-11-17 | Carlo Ghisalberti | Sostanze furiliche per uso topico |
WO2002096374A2 (en) | 2001-05-31 | 2002-12-05 | Upsher-Smith Laboratories, Inc. | Dermatological compositions and methods comprising alpha-hydroxy acids or derivatives |
US7270828B2 (en) | 2001-06-20 | 2007-09-18 | The Procter & Gamble Company | Personal care composition comprising hydrophobic gel |
EP1397118A1 (en) | 2001-06-20 | 2004-03-17 | The Procter & Gamble Company | Personal care composition comprising polyol-in-silicone emulsion |
FR2826292B1 (fr) | 2001-06-22 | 2004-01-23 | Rhodia Chimie Sa | Emulsions huile dans huile comprenant une silicone, dispersions de telles emulsions et utilisation |
US6428772B1 (en) | 2001-06-25 | 2002-08-06 | Blistex Inc. | Acne treatment composition with cooling effect |
US6544562B2 (en) | 2001-06-25 | 2003-04-08 | Blistex Inc. | Acne treatment including dual-package system |
WO2003002082A1 (en) | 2001-06-26 | 2003-01-09 | The Procter & Gamble Company | Pressurized anhydrous antiperspirant emulsions |
JP2003012511A (ja) | 2001-06-27 | 2003-01-15 | Rohto Pharmaceut Co Ltd | エアゾール組成物 |
WO2003002426A1 (fr) | 2001-06-27 | 2003-01-09 | Kanebo,Limited | Melangeur/extracteur |
US20030053961A1 (en) | 2001-07-13 | 2003-03-20 | Eccard Wayne Ellis | Mousse forming compositions comprising quaternary ammonium agents |
US20060194773A1 (en) | 2001-07-13 | 2006-08-31 | Paratek Pharmaceuticals, Inc. | Tetracyline compounds having target therapeutic activities |
DE10134786A1 (de) | 2001-07-17 | 2003-02-06 | Beiersdorf Ag | Schäumbare Zubereitungen |
JP5137289B2 (ja) | 2001-08-03 | 2013-02-06 | 武田薬品工業株式会社 | 安定な乳化組成物 |
DE10138495B4 (de) | 2001-08-04 | 2004-11-11 | Beiersdorf Ag | Nachschäumende Zubereitungen und deren Verwendung |
JP2005504756A (ja) | 2001-08-08 | 2005-02-17 | マリア・アントニア・ガルシア−オルメド・ドミンゲス | 注射可能な泡製剤および新規な医薬的適用 |
WO2003013439A2 (en) | 2001-08-09 | 2003-02-20 | Croda, Inc. | Anti-irritants |
JP4707279B2 (ja) | 2001-08-09 | 2011-06-22 | ポーラ化成工業株式会社 | クールダウン効果を有するマッサージ用の化粧料 |
JP2004537482A (ja) | 2001-08-11 | 2004-12-16 | アベンティス・フアーマ・リミテッド | 加圧エアゾール・ディスペンサ |
US6638981B2 (en) | 2001-08-17 | 2003-10-28 | Epicept Corporation | Topical compositions and methods for treating pain |
US20030049218A1 (en) | 2001-08-28 | 2003-03-13 | Amit Patel | Antiperspirant deodorant emulsion |
ATE429947T1 (de) | 2001-08-29 | 2009-05-15 | Pharmakodex Ltd | Vorrichtung zur topischen verabreichung |
US6709663B2 (en) | 2001-08-31 | 2004-03-23 | Healthpoint, Ltd. | Multivesicular emulsion drug delivery systems |
US6479060B1 (en) | 2001-09-04 | 2002-11-12 | Healthpoint, Ltd. | Elegant hydrogenated castor oil ointments |
FR2829693B1 (fr) | 2001-09-20 | 2004-02-27 | Oreal | Creme cosmetique moussante |
DE10147820A1 (de) | 2001-09-27 | 2003-04-10 | Beiersdorf Ag | Selbstschäumende, schaumförmige, nachschäumende oder schäumbare kosmetische oder dermatologische Zubereitungen mit einem Gehalt an Wachsen bzw. bei Raumtemperatur festen und/oder halbfesten Lipiden |
US7931533B2 (en) | 2001-09-28 | 2011-04-26 | Igt | Game development architecture that decouples the game logic from the graphics logics |
US20030185839A1 (en) | 2001-10-05 | 2003-10-02 | Podolsky Daniel K. | Methods and compositions for treating dermal lesions |
CA2462291A1 (en) | 2001-10-05 | 2003-04-17 | The General Hospital Corporation | Methods and compositions for treating dermal lesions |
CA2463308C (en) | 2001-10-10 | 2010-12-14 | Exxonmobil Research And Engineering Company | Biodegradable non-toxic gear oil |
US20030082120A1 (en) | 2001-10-26 | 2003-05-01 | Milstein Harold J. | Method for reducing systemic effects of aging, effects of aging on the skin, and incidence of skin damage from sun exposure using antibiotics of the tetracycline family |
WO2003035015A1 (fr) | 2001-10-26 | 2003-05-01 | Taiyo Kagaku Co., Ltd. | Composition d'un aerosol huileux expansible |
US7255869B2 (en) | 2001-10-30 | 2007-08-14 | The Procter & Gamble Company | Anhydrous cosmetic compositions containing polyols |
DE10154324A1 (de) | 2001-11-06 | 2003-08-07 | Merz Pharma Gmbh & Co Kgaa | Topisch applizierbare Zusammensetzungen mit externer Wirkstoffdepotbildung, deren Herstellung sowie deren Verwendung |
DE10155956A1 (de) | 2001-11-09 | 2003-05-22 | Beiersdorf Ag | Selbstschäumende, schaumförmige, nachschäumende oder schäumbare kosmetische oder dermatologische Zubereitungen |
MXPA04004478A (es) | 2001-11-13 | 2004-08-11 | Procter & Gamble | Composiciones que contienen enzimas estabilizadas con ciertos osmoprotectores y metodos para utilizarls en el cuidado personal. |
DE10155792A1 (de) | 2001-11-14 | 2003-05-22 | Beiersdorf Ag | Selbstschäumende, schaumförmige, nachschäumende oder schäumbare kosmetische oder dermatologische Zubereitungen mit einem Gehalt an Siloxanelastomeren |
WO2004043469A1 (en) | 2001-11-16 | 2004-05-27 | Klysz Beatrice M | Anti-aging skin care composition and uses thereof |
DE10159002A1 (de) | 2001-11-30 | 2003-06-18 | Clariant Gmbh | Verwendung von mehrphasigen Mittel zum Verschäumen aus Schaumspendern |
FR2833246B1 (fr) | 2001-12-06 | 2005-06-24 | Beatrice France Touteau | Dispositif pour actionner simultanement deux aerosols contenant deux produits a melanger au moment de leur utilisation |
US6531118B1 (en) | 2001-12-11 | 2003-03-11 | Avon Products, Inc. | Topical compositions with a reversible photochromic ingredient |
CA2471400A1 (en) | 2001-12-20 | 2003-07-03 | Femmepharma, Inc. | Vaginal delivery of drugs |
SE0104421D0 (sv) | 2001-12-21 | 2001-12-21 | Ponsus Pharma Ab | New composition |
US6765001B2 (en) | 2001-12-21 | 2004-07-20 | Medicis Pharmaceutical Corporation | Compositions and methods for enhancing corticosteroid delivery |
US20030118515A1 (en) | 2001-12-21 | 2003-06-26 | Robert Jew | Cosmetic composition containing carbon dioxide |
US20030129259A1 (en) | 2001-12-28 | 2003-07-10 | Avon Products, Inc. | Topical lightening compostitions and methods of use |
JP4549625B2 (ja) | 2002-01-05 | 2010-09-22 | 株式會社アモーレパシフィック | 人参サポニン代謝産物を有効成分とする微細乳化粒子及びその製造方法、並びにこれを含有する皮膚老化防止用の化粧料組成物 |
US7192601B2 (en) | 2002-01-18 | 2007-03-20 | Walker Edward B | Antimicrobial and sporicidal composition |
US6992049B2 (en) | 2002-01-31 | 2006-01-31 | Exxonmobil Research And Engineering Company | Lubricating oil compositions |
NZ517094A (en) | 2002-02-08 | 2005-03-24 | Advanced Animal Technology Ltd | Improvements in and relating to substance delivery device |
EP1475381A1 (en) | 2002-02-14 | 2004-11-10 | Quimversion, S.L. | Aluminium and hexamethylenetetramine complex and the applications thereof |
US6589216B1 (en) | 2002-02-20 | 2003-07-08 | Abbott Research Group, Inc. | Vaginal douches, vaginal douche applicators and methods of vaginal douching |
US6682511B2 (en) | 2002-02-21 | 2004-01-27 | Robert Wallace Besoyan | Brief protector |
US6691898B2 (en) | 2002-02-27 | 2004-02-17 | Fomo Products, Inc. | Push button foam dispensing device |
US7635463B2 (en) | 2002-02-27 | 2009-12-22 | Pharmain Corporation | Compositions for delivery of therapeutics and other materials |
AU2003213787A1 (en) | 2002-03-06 | 2003-09-22 | Cellegy Pharmaceuticals, Inc. | Compositions and methods for the treatment of anorectal disorders |
US20050281766A1 (en) | 2002-03-11 | 2005-12-22 | Avon Products, Inc. | Method of improving the aesthetic appearance of epithelia |
US6736860B2 (en) | 2002-03-12 | 2004-05-18 | Unilever Home & Personal Care Usa Division Of Conopco, Inc. | Gradual permanent coloring of hair using dye intermediates dissolved in alkaline water with fatty alcohol |
US6848601B2 (en) | 2002-03-14 | 2005-02-01 | Homax Products, Inc. | Aerosol systems and methods for mixing and dispensing two-part materials |
US20030180347A1 (en) | 2002-03-19 | 2003-09-25 | W.F. Young, Incorporated | Patch for the delivery of topical agents |
DE60333350D1 (de) | 2002-03-19 | 2010-08-26 | Airspray Int Bv | Abgabeeinheit |
WO2003082225A1 (fr) | 2002-03-28 | 2003-10-09 | Hakuto Co., Ltd. | Procede de stabilisation de mousse pour mousse cosmetique |
EP1496773B1 (en) | 2002-04-12 | 2006-08-30 | Dreamwell, Ltd. | Cassette bedding system |
US8192749B2 (en) | 2003-04-16 | 2012-06-05 | Galderma Laboratories Inc. | Methods of simultaneously treating ocular rosacea and acne rosacea |
US8846039B2 (en) | 2002-04-26 | 2014-09-30 | Asan Laboratories Company (Cayman), Limited | Method for ameliorating pruritus |
US6875438B2 (en) | 2002-04-27 | 2005-04-05 | Aventis Pharma Deutschland Gmbh | Preparations for topical administration of substances having antiandrogenic activity |
CA2384922C (en) | 2002-05-03 | 2008-09-02 | Purepharm Inc. | Topical glycopyrrolate product for the reduction of sweating |
US20050153943A1 (en) | 2002-05-06 | 2005-07-14 | Ashley Robert A. | Methods of simultaneously treating mucositis and fungal infection |
EP1503723B1 (en) | 2002-05-10 | 2009-06-17 | Unilever PLC | Hair conditioning compositions |
US6783027B2 (en) | 2002-05-15 | 2004-08-31 | The Procter & Gamble Company | Metered-dose underarm product and package |
US20030215472A1 (en) | 2002-05-16 | 2003-11-20 | Bonda Craig A | Methods and compositions employing a dialkyl amide |
CA2485677C (en) | 2002-05-20 | 2011-07-19 | Collagenex Pharmaceuticals, Inc. | Methods of treating allergic reactions |
JP4050094B2 (ja) | 2002-05-28 | 2008-02-20 | 株式会社三谷バルブ | 定量バルブ機構およびエアゾール製品 |
US6723309B1 (en) | 2002-06-10 | 2004-04-20 | Jeffrey Alan Deane | Hair cleansing conditioner |
FR2840903B1 (fr) | 2002-06-13 | 2005-01-28 | Oreal | Derive de glucose et de vitamine f, compositions le comprenant et utilisations pour ameliorer l'etat des poils et des cheveux |
US7763587B2 (en) | 2002-06-13 | 2010-07-27 | L'oreal S.A. | Derivative of glucose and of vitamin F, compositions comprising it, uses and preparation process |
US7163669B2 (en) | 2002-06-19 | 2007-01-16 | J.M. Huber Corporation | Cosmetic compositions comprising calcium silicates |
JP4286154B2 (ja) | 2002-06-26 | 2009-06-24 | 株式会社ダイゾー | 複数内容物吐出用の包装容器、その包装容器を用いた包装製品およびその包装製品の製造方法 |
JP2004026605A (ja) | 2002-06-27 | 2004-01-29 | Asahi Fiber Glass Co Ltd | ガラス繊維ヤーン用集束剤及びそれを用いたガラス繊維ヤーン |
US20040002550A1 (en) | 2002-06-28 | 2004-01-01 | Mercurio Anthony Fred | Post foaming compositions |
US6785629B2 (en) | 2002-07-02 | 2004-08-31 | Agilent Technologies, Inc. | Accuracy determination in bit line voltage measurements |
JP3833972B2 (ja) | 2002-07-08 | 2006-10-18 | 古河電気工業株式会社 | ワイヤハーネスの組立システム |
DE10233330B4 (de) | 2002-07-22 | 2007-04-26 | Sasol Germany Gmbh | Mikroemulsion enthaltend UV-Lichtschutzfilter und/oder Antischuppenmittel |
US7137536B2 (en) | 2002-07-22 | 2006-11-21 | Seaquist Perfect Dispensing Foreign, Inc. | Inverted aerosol dispenser |
US6897195B2 (en) | 2002-07-24 | 2005-05-24 | Nanjing Zhongshi Chemical Co. | Composition of menthol and menthyl lactate, its preparation method and its applications as a cooling agent |
US20020182162A1 (en) | 2002-08-07 | 2002-12-05 | Mohsen Shahinpoor | Nitric oxide (NO) donor+cGMP-PDE5 inhibitor as a topical drug for enhanced hair growth |
FR2843373B1 (fr) | 2002-08-12 | 2005-03-04 | Jean Augustin | Dispositif de conditionnement et d'application d'un produit sous forme fluide |
US7939170B2 (en) | 2002-08-15 | 2011-05-10 | The Rockefeller University | Water soluble metal and semiconductor nanoparticle complexes |
UA81638C2 (ru) | 2002-08-26 | 2008-01-25 | С.Л.А. Фарма Аг | Композиция метронидазола для местного применения для лечения заболеваний аноректального и перианального участков |
US6770607B2 (en) | 2002-09-12 | 2004-08-03 | Unilever Home & Personal Care Usa, Division Of Conopco, Inc. | Viscoelastic cleansing gel with micellar surfactant solutions |
US7906473B2 (en) | 2002-09-13 | 2011-03-15 | Bissell Homecare, Inc. | Manual spray cleaner |
US6968982B1 (en) | 2002-09-18 | 2005-11-29 | Burns Caleb E S | Multiple-mist dispenser |
GB0221697D0 (en) | 2002-09-18 | 2002-10-30 | Unilever Plc | Novel compouds and their uses |
US7179481B2 (en) | 2002-09-19 | 2007-02-20 | Kimberly-Clark Worldwide, Inc. | Vaginal health products |
US6949037B2 (en) | 2002-09-27 | 2005-09-27 | Richard A. Enos | Quick-release fastener for releasably attaching lacrosse stick head to shaft |
EP1402784B1 (en) | 2002-09-30 | 2008-11-12 | Kao Corporation | Foamable oil-in-water type emulsion |
FR2845672B1 (fr) | 2002-10-09 | 2006-02-10 | Airlessystems | Distributeur de produit fluide |
IL152486A0 (en) | 2002-10-25 | 2003-05-29 | Meir Eini | Alcohol-free cosmetic and pharmaceutical foam carrier |
EP1567113A4 (en) | 2002-10-24 | 2006-11-08 | G & R Pharmaceuticals Llc | ANTIFUNGAL PREPARATIONS |
US20050186142A1 (en) | 2002-10-25 | 2005-08-25 | Foamix Ltd. | Kit and composition of imidazole with enhanced bioavailability |
US20160158261A1 (en) | 2002-10-25 | 2016-06-09 | Foamix Pharmaceuticals Ltd. | Antibiotic Kit and Composition and Uses Thereof |
US20080317679A1 (en) | 2002-10-25 | 2008-12-25 | Foamix Ltd. | Foamable compositions and kits comprising one or more of a channel agent, a cholinergic agent, a nitric oxide donor, and related agents and their uses |
US9211259B2 (en) | 2002-11-29 | 2015-12-15 | Foamix Pharmaceuticals Ltd. | Antibiotic kit and composition and uses thereof |
US8486376B2 (en) | 2002-10-25 | 2013-07-16 | Foamix Ltd. | Moisturizing foam containing lanolin |
US7704518B2 (en) | 2003-08-04 | 2010-04-27 | Foamix, Ltd. | Foamable vehicle and pharmaceutical compositions thereof |
US8119109B2 (en) | 2002-10-25 | 2012-02-21 | Foamix Ltd. | Foamable compositions, kits and methods for hyperhidrosis |
US7700076B2 (en) | 2002-10-25 | 2010-04-20 | Foamix, Ltd. | Penetrating pharmaceutical foam |
US8900554B2 (en) | 2002-10-25 | 2014-12-02 | Foamix Pharmaceuticals Ltd. | Foamable composition and uses thereof |
US20070292359A1 (en) | 2002-10-25 | 2007-12-20 | Foamix Ltd. | Polypropylene glycol foamable vehicle and pharmaceutical compositions thereof |
US9265725B2 (en) | 2002-10-25 | 2016-02-23 | Foamix Pharmaceuticals Ltd. | Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof |
US20070292461A1 (en) | 2003-08-04 | 2007-12-20 | Foamix Ltd. | Oleaginous pharmaceutical and cosmetic foam |
US20080031907A1 (en) | 2002-10-25 | 2008-02-07 | Foamix Ltd. | Cosmetic and pharmaceutical foam |
US9668972B2 (en) | 2002-10-25 | 2017-06-06 | Foamix Pharmaceuticals Ltd. | Nonsteroidal immunomodulating kit and composition and uses thereof |
US20050271596A1 (en) | 2002-10-25 | 2005-12-08 | Foamix Ltd. | Vasoactive kit and composition and uses thereof |
US20060233721A1 (en) | 2002-10-25 | 2006-10-19 | Foamix Ltd. | Foam containing unique oil globules |
US20080138296A1 (en) | 2002-10-25 | 2008-06-12 | Foamix Ltd. | Foam prepared from nanoemulsions and uses |
US7820145B2 (en) | 2003-08-04 | 2010-10-26 | Foamix Ltd. | Oleaginous pharmaceutical and cosmetic foam |
US20120156144A1 (en) | 2002-10-25 | 2012-06-21 | Foamix | Foamable Compositions, Kits and Methods for Hyperhidrosis |
US8119150B2 (en) | 2002-10-25 | 2012-02-21 | Foamix Ltd. | Non-flammable insecticide composition and uses thereof |
EP1556009B2 (en) | 2002-10-25 | 2021-07-21 | Foamix Pharmaceuticals Ltd. | Cosmetic and pharmaceutical foam |
US20050205086A1 (en) | 2002-10-25 | 2005-09-22 | Foamix Ltd. | Retinoid immunomodulating kit and composition and uses thereof |
US20070292355A1 (en) | 2002-10-25 | 2007-12-20 | Foamix Ltd. | Anti-infection augmentation foamable compositions and kit and uses thereof |
US20080206161A1 (en) | 2002-10-25 | 2008-08-28 | Dov Tamarkin | Quiescent foamable compositions, steroids, kits and uses thereof |
US20060018937A1 (en) | 2002-10-25 | 2006-01-26 | Foamix Ltd. | Steroid kit and foamable composition and uses thereof |
US20060193789A1 (en) | 2002-10-25 | 2006-08-31 | Foamix Ltd. | Film forming foamable composition |
US8093290B2 (en) | 2002-10-28 | 2012-01-10 | Givaudan Sa | Coolant solutions and compositions comprising the same |
JP2004250435A (ja) | 2002-11-21 | 2004-09-09 | Dai Ichi Seiyaku Co Ltd | 育毛用組成物 |
JP4282311B2 (ja) | 2002-11-26 | 2009-06-17 | 三洋電機株式会社 | 製氷装置 |
CN1723009A (zh) | 2002-12-12 | 2006-01-18 | 诺伊堡皮肤护理两合公司 | 稳定泡沫膏 |
GB0229071D0 (en) | 2002-12-13 | 2003-01-15 | Unilever Plc | Cosmetic method and composition for enhancing attractiveness |
US20040191196A1 (en) | 2002-12-16 | 2004-09-30 | Dov Tamarkin | Novel conjugate compounds and dermatological compositions thereof |
FR2848847B1 (fr) | 2002-12-18 | 2005-10-14 | Coletica | Composition cosmetique ou dermopharmaceutique comprenant une enzyme insoluble en milieu aqueux, ainsi que ses utilisations |
US7842791B2 (en) | 2002-12-19 | 2010-11-30 | Nancy Jean Britten | Dispersible pharmaceutical compositions |
FR2848998B1 (fr) | 2002-12-20 | 2006-04-07 | Oreal | Dispositif de distributeur comportant des moyens permettant de distribuer deux produits dans des proportions variables |
WO2004060322A2 (en) | 2003-01-02 | 2004-07-22 | Femmepharma Holding Company, Inc. | Pharmaceutical preparations for treatments of diseases and disorders of the breast |
WO2004064769A2 (en) | 2003-01-21 | 2004-08-05 | Hector Herrera | Methods for making and using topical delivery agents |
EP1592420B1 (en) | 2003-01-24 | 2014-01-01 | Stiefel Research Australia Pty Ltd | Clindamycin phosphate foam |
US20040151756A1 (en) | 2003-02-04 | 2004-08-05 | Richards Anthony P. | Edible low density high surface area drug vehicle, method of manufacturing low density high surface area drug vehicle |
AU2004210201B2 (en) | 2003-02-06 | 2009-10-08 | Cipla Limited | Topical immunotherapy and compositions for use therein |
CA2515731C (en) | 2003-02-12 | 2012-07-24 | Connetics Australia Pty Ltd | Sunscreen hydroethanolic foam |
US6841547B2 (en) | 2003-02-28 | 2005-01-11 | Albert Einstein College Of Medicine Of Yeshevia University | Method for decreasing low density lipoprotein |
US20040175347A1 (en) | 2003-03-04 | 2004-09-09 | The Procter & Gamble Company | Regulation of mammalian keratinous tissue using hexamidine compositions |
GB0305010D0 (en) | 2003-03-05 | 2003-04-09 | Unilever Plc | Changing colours |
US6843390B1 (en) | 2003-03-17 | 2005-01-18 | Joe G. Bristor | Multiple fluid closed system dispensing device |
US7357950B2 (en) | 2003-03-21 | 2008-04-15 | Elizabeth Anne Mazzio | Topical treatment for dyshidrosis (pompholyx) and dry skin disorders |
US20040192754A1 (en) | 2003-03-24 | 2004-09-30 | Shapira Nathan Andrew | Methods for treating idiopathic hyperhidrosis and associated conditions |
WO2004084973A2 (en) | 2003-03-24 | 2004-10-07 | Becton, Dickinson And Company | Invisible antimicrobial glove and hand antiseptic |
DE10315936A1 (de) | 2003-04-03 | 2004-10-28 | Ing. Erich Pfeiffer Gmbh | Austragsvorrichtung für zumindest ein Medium |
GB0308585D0 (en) | 2003-04-14 | 2003-05-21 | Pz Cussons Int Ltd | Cleaning composition |
US20040229803A1 (en) | 2003-04-22 | 2004-11-18 | Pharmacia Corporation | Compositions of a cyclooxygenase-2 selective inhibitor and a potassium ion channel modulator for the treatment of pain, inflammation or inflammation mediated disorders |
US20040220187A1 (en) | 2003-04-22 | 2004-11-04 | Pharmacia Corporation | Compositions of a cyclooxygenase-2 selective inhibitor and a sodium ion channel blocker for the treatment of pain, inflammation or inflammation mediated disorders |
US7575739B2 (en) | 2003-04-28 | 2009-08-18 | Foamix Ltd. | Foamable iodine composition |
DE10319771B4 (de) | 2003-05-02 | 2005-03-17 | Koenig & Bauer Ag | System zur Inspektion eines Druckbildes |
JP2004353084A (ja) | 2003-05-08 | 2004-12-16 | Sanyo Electric Co Ltd | 蒸発装置の固定部材 |
FR2854821B1 (fr) | 2003-05-16 | 2006-12-08 | Oreal | Ensemble pour le conditionnement et la distribution d'un produit, notamment sous forme d'un echantillon |
JP4232535B2 (ja) | 2003-05-20 | 2009-03-04 | セイコーエプソン株式会社 | プリンタ整備システム、印刷制御サーバ、クライアント、それらに関する方法及びそれらに関するプログラム |
US7222802B2 (en) | 2003-05-23 | 2007-05-29 | Meadwestvaco Corporation | Dual sprayer with external mixing chamber |
BR0318319A (pt) | 2003-05-25 | 2006-07-18 | Yuwan Wang | métodos de preparação e formulações/composições sustentadas pelo uso de dimeticona como veìculo |
US7186416B2 (en) | 2003-05-28 | 2007-03-06 | Stiefel Laboratories, Inc. | Foamable pharmaceutical compositions and methods for treating a disorder |
AU2003238685B2 (en) | 2003-05-30 | 2009-10-08 | De Paoli Ambrosi, Gianfranco | A formulation for chemical peeling |
US20050079228A1 (en) | 2003-05-30 | 2005-04-14 | Ashish Jaiswal | Clear, stable topical compositions of clarithromycin and processes for their preparation |
US20050208083A1 (en) | 2003-06-04 | 2005-09-22 | Nanobio Corporation | Compositions for inactivating pathogenic microorganisms, methods of making the compositons, and methods of use thereof |
JP4018032B2 (ja) | 2003-06-17 | 2007-12-05 | 高砂香料工業株式会社 | 毛髪及び身体洗浄剤組成物 |
EP1643990B8 (en) | 2003-06-18 | 2007-05-09 | Galderma S.A. | Metronidazole-based green tinted topical pharmaceutical composition |
JP2007526224A (ja) | 2003-06-19 | 2007-09-13 | ザ プロクター アンド ギャンブル カンパニー | シリコーン中ポリオール型エマルション |
US20050042182A1 (en) | 2003-08-13 | 2005-02-24 | Moshe Arkin | Topical compositions of urea |
CA2530474C (en) | 2003-07-03 | 2009-04-14 | Japan Science And Technology Agency | Remedy for sarcoidosis and method of treating the same |
US20070140999A1 (en) | 2003-07-18 | 2007-06-21 | Hill Dermaceuticals, Inc. | Topical skin care composition containing refined peanut oil |
WO2005009416A1 (en) | 2003-07-24 | 2005-02-03 | Ranbaxy Laboratories Limited | Modified release compositions for minocycline |
US7226230B2 (en) | 2003-07-28 | 2007-06-05 | Raymond Liberatore | Spreader |
US20080069779A1 (en) | 2003-08-04 | 2008-03-20 | Foamix Ltd. | Foamable vehicle and vitamin and flavonoid pharmaceutical compositions thereof |
US8486374B2 (en) | 2003-08-04 | 2013-07-16 | Foamix Ltd. | Hydrophilic, non-aqueous pharmaceutical carriers and compositions and uses |
US8795693B2 (en) | 2003-08-04 | 2014-08-05 | Foamix Ltd. | Compositions with modulating agents |
CA2536482C (en) | 2003-08-25 | 2012-07-24 | Foamix Ltd. | Penetrating pharmaceutical foam |
US20060140990A1 (en) | 2003-09-19 | 2006-06-29 | Drugtech Corporation | Composition for topical treatment of mixed vaginal infections |
US20050084551A1 (en) | 2003-09-26 | 2005-04-21 | Jensen Claude J. | Morinda citrifolia-based oral care compositions and methods |
FR2860143B1 (fr) | 2003-09-26 | 2008-06-27 | Oreal | Composition cosmetique comprenant un polymere sequence et une huile siliconee non volatile |
AU2004275900B2 (en) | 2003-09-29 | 2010-04-29 | Deb Ip Limited | High alcohol content gel-like and foaming compositions |
GB2406330B (en) | 2003-09-29 | 2005-12-07 | Bespak Plc | A dispensing apparatus |
CA2528818C (en) | 2003-10-03 | 2010-08-10 | Collegium Pharmaceutical, Inc. | Topical aerosol foams |
FR2860502B1 (fr) | 2003-10-07 | 2007-09-14 | Valois Sas | Valve doseuse et dispositif de distribution de produit fluide comportant une telle valve |
GB0323908D0 (en) | 2003-10-11 | 2003-11-12 | Nupharm Lab Ltd | Pharmaceutical foam formulation |
EP1689494B1 (en) | 2003-10-14 | 2008-12-03 | Showa Denko K.K. | Agent for skin external use containing salt of ascorbic acid derivative, method for stabilizing the agent for skin external use |
FR2860976B1 (fr) | 2003-10-20 | 2006-02-10 | Ravi Shrivastava | Nouvelles compositions synergiques pour ameliorer la biodisponibilite et l'efficacite des acides gras polyinsatures pour le traitement des troubles du fonctionnement cerebral. |
US7419498B2 (en) | 2003-10-21 | 2008-09-02 | Nmt Medical, Inc. | Quick release knot attachment system |
AU2004287448A1 (en) | 2003-10-31 | 2005-05-19 | The Procter & Gamble Company | Skin care composition containing dehydroacetic acid and skin care actives |
JP5019880B2 (ja) | 2003-11-06 | 2012-09-05 | ユニリーバー・ナームローゼ・ベンノートシヤープ | ビタミンb3、ビタミンb6及び有機酸を含む改善された化粧品組成物 |
KR20060108693A (ko) | 2003-11-06 | 2006-10-18 | 더 리서치 파운데이션 오브 스테이트 유니버시티 오브 뉴욕 | 습진의 치료 방법 |
US8157788B2 (en) | 2003-11-06 | 2012-04-17 | Paolo L. Manfredi | Multi-site drug delivery platform |
MXPA06005512A (es) | 2003-11-17 | 2006-08-17 | Procter & Gamble | Composicion antitranspirante y aplicador de la misma. |
DE10354051A1 (de) | 2003-11-17 | 2005-06-16 | Beiersdorf Ag | Spender mit kosmetischen Zubereitungen, die Hilfsmittel zur Gängighaltung des Spenders enthalten |
RU2322241C2 (ru) | 2003-11-21 | 2008-04-20 | Пфайзер Продактс Инк. | Применение антибиотиков в качестве адъювантов вакцин |
US20050115988A1 (en) | 2003-12-01 | 2005-06-02 | Brian Law | Multiple liquid foamer |
US20050123496A1 (en) | 2003-12-08 | 2005-06-09 | Unilever Home & Personal Care Usa, Division Of Conopco, Inc. | Self foaming non-aqueous personal wash cleansers with little or no surfactant |
DE10361022A1 (de) | 2003-12-23 | 2005-07-28 | Merckle Gmbh Chem.-Pharm. Fabrik | Topische Zubereitungen enthaltend Dimethylsulfoxid und Dexpanthenol |
AU2004312546B2 (en) | 2003-12-30 | 2010-10-14 | Gilead Sciences, Inc. | Phosphonates, monophosphonamidates, bisphosphonamidates for the treatment of viral diseases |
IL159729A0 (en) | 2004-01-06 | 2004-06-20 | Doron I Friedman | Non-aqueous composition for oral delivery of insoluble bioactive agents |
EP1727522A2 (en) | 2004-02-04 | 2006-12-06 | Foamix Ltd. | Cosmetic and pharmaceutical foam with solid matter |
US7225518B2 (en) | 2004-02-23 | 2007-06-05 | Boston Scientific Scimed, Inc. | Apparatus for crimping a stent assembly |
JP4381169B2 (ja) | 2004-02-27 | 2009-12-09 | 花王株式会社 | 毛髪化粧料 |
CN1946431B (zh) | 2004-03-03 | 2011-12-07 | 雷文斯治疗公司 | 用于肉毒毒素的局部施用和透皮递送的组合物和方法 |
EP1725132A2 (en) | 2004-03-18 | 2006-11-29 | Bodypoint Designs, Inc. | Pivoting side mount and quick release assembly for a pelvic stabilization device |
DE102004016710B4 (de) | 2004-04-05 | 2020-11-19 | Greppmayr GmbH | Formulierung zur Fußpflege |
WO2005097068A1 (en) | 2004-04-08 | 2005-10-20 | Novartis Ag | Pimecrolimus foam composition containing hexylene glycol, optionally oleyl alcohol, dimethylisosorbide and/or medium chain triglycerides |
AU2005235308B2 (en) | 2004-04-19 | 2011-12-01 | Strategic Science & Technologies, Llc | Transdermal delivery of beneficial substances effected by a hostile biophysical environment |
NL1026031C2 (nl) | 2004-04-23 | 2005-10-25 | Airspray Nv | Afgiftesamenstel. |
AU2005204341A1 (en) | 2004-04-28 | 2005-11-17 | Foamix Ltd. | Body cavity foams |
US20050244354A1 (en) | 2004-04-30 | 2005-11-03 | Sam Speron | Oxygenated personal care products |
JP2005314323A (ja) | 2004-04-30 | 2005-11-10 | Sato Pharmaceutical Co Ltd | 育毛剤組成物 |
WO2005115336A2 (en) | 2004-05-15 | 2005-12-08 | Collegium Pharmaceutical, Inc. | Sprayable formulations for the treatment of acute inflammatory skin conditions |
US7083125B2 (en) | 2004-05-17 | 2006-08-01 | S.C. Johnson & Son, Inc. | Detachable tube assembly |
US7143909B2 (en) | 2004-05-21 | 2006-12-05 | Sonoco Development, Inc. | Reconfigurable metered material dispenser |
WO2005117813A1 (en) | 2004-05-26 | 2005-12-15 | L'oreal | Cosmetic mousse formulations |
ITBO20040338A1 (it) | 2004-05-28 | 2004-08-28 | Progine Farmaceutici Srl | Erogatore per nebulizzazione vaginale |
US20050268416A1 (en) | 2004-06-03 | 2005-12-08 | Sommers J E | Foldable lotion applicator |
JP4368250B2 (ja) | 2004-06-09 | 2009-11-18 | ポーラ化成工業株式会社 | ポスト・フォーム剤形の温感化粧料 |
FR2871698B1 (fr) | 2004-06-17 | 2008-07-04 | Galderma Sa | Composition sous forme de spray comprenant une association d'actifs pharmaceutiques et une phase huileuse |
FR2871696B1 (fr) | 2004-06-17 | 2006-11-10 | Galderma Sa | Composition topique pour le traitement du psoriasis |
US8211449B2 (en) | 2004-06-24 | 2012-07-03 | Dpt Laboratories, Ltd. | Pharmaceutically elegant, topical anhydrous aerosol foam |
JP4355264B2 (ja) | 2004-06-25 | 2009-10-28 | ポーラ化成工業株式会社 | 温感非水フォーム化粧料 |
US7207655B2 (en) | 2004-06-28 | 2007-04-24 | Eastman Kodak Company | Latency stirring in fluid ejection mechanisms |
US6991789B2 (en) | 2004-06-29 | 2006-01-31 | Allergas, Inc. | Methods of modulating intracellular degradation rates of toxins |
US20060008432A1 (en) | 2004-07-07 | 2006-01-12 | Sebastiano Scarampi | Gilsonite derived pharmaceutical delivery compositions and methods: nail applications |
UA93354C2 (ru) | 2004-07-09 | 2011-02-10 | Гилиад Сайенсиз, Инк. | Местный противовирусный препарат |
WO2006017232A1 (en) | 2004-07-12 | 2006-02-16 | Taro Pharmaceuticals Industries Ltd. | Topical gel formulation comprising insecticide and its preparation thereof |
EP1778216A1 (en) | 2004-07-19 | 2007-05-02 | Warner-Lambert Company LLC | Formulation for stimulating hair growth |
JP4557624B2 (ja) | 2004-07-29 | 2010-10-06 | 株式会社吉野工業所 | 定量注出器 |
WO2006010589A2 (en) | 2004-07-29 | 2006-02-02 | Mipharm S.P.A. | Post foaming gel mousse |
US20060029565A1 (en) | 2004-08-09 | 2006-02-09 | The Gillette Company | Self-heating shave foam product |
WO2006017846A2 (en) | 2004-08-12 | 2006-02-16 | Triaccess Technologies, Inc. | Low noise optical receiver |
KR101243526B1 (ko) | 2004-08-31 | 2013-03-20 | 스티펠 리서치 오스트레일리아 피티와이 리미티드 | 마이크로에멀젼 및 서브마이크론 에멀젼 방법 및 조성물 |
KR100623013B1 (ko) | 2004-09-04 | 2006-09-19 | 김영대 | 나노에멀션, 그의 용도 및 제조방법 |
WO2006032144A1 (en) | 2004-09-23 | 2006-03-30 | Arc Pharmaceuticals, Inc. | Pharmaceutical compositions and methods relating to inhibiting fibrous adhesions or inflammatory disease using fucans from various echinoderm sources |
PT1791791T (pt) | 2004-09-27 | 2019-09-12 | Special Water Patents B V | Métodos e composições para tratamento de água |
FR2875797B1 (fr) | 2004-09-30 | 2006-11-24 | Oreal | Ensemble de distribution destine a la distribution extemporanee de deux produits |
BRPI0404595A (pt) | 2004-10-26 | 2006-06-13 | Natura Cosmeticos Sa | nanoemulsão óleo-em-água, composição cosmética e produto cosmético compreendendo a mesma, processo para preparação da dita nanoemulsão |
DE102004052986A1 (de) | 2004-11-02 | 2006-05-04 | Lindal Ventil Gmbh | Vorrichtung zum Mischen von zwei unterschiedlichen Komponenten |
US7350673B2 (en) | 2004-11-19 | 2008-04-01 | Glynntech, Inc. | Metered dose squeeze dispenser |
US20060110415A1 (en) | 2004-11-22 | 2006-05-25 | Bioderm Research | Topical Delivery System for Cosmetic and Pharmaceutical Agents |
US8080560B2 (en) | 2004-12-17 | 2011-12-20 | 3M Innovative Properties Company | Immune response modifier formulations containing oleic acid and methods |
FR2880802B1 (fr) | 2005-01-14 | 2008-12-19 | Sederma Soc Par Actions Simpli | Composition cosmetique ou dermopharmaceutique contenant un extrait d'euglene |
WO2006081327A2 (en) | 2005-01-25 | 2006-08-03 | University Of Vermont And State Agricultural College | Small molecules that reduce fungal growth |
CA2595692A1 (en) | 2005-01-28 | 2006-08-03 | Basf Aktiengesellschaft | Use of a water-in-water emulsion polymers in the form of a thickener for cosmetic preparations |
US20060177392A1 (en) | 2005-02-10 | 2006-08-10 | William Walden | Oil-based composition for acne |
US20060193813A1 (en) | 2005-02-11 | 2006-08-31 | L'oreal | Nanoemulsion containing a hydroxylated urea compound |
GB0506141D0 (en) | 2005-03-24 | 2005-05-04 | Transphase Ltd | A topical compostion and its uses |
WO2006099687A1 (en) | 2005-03-24 | 2006-09-28 | Ensign Laboratories Pty Ltd | Sunscreen aerosol spray |
US20060222675A1 (en) | 2005-03-29 | 2006-10-05 | Sabnis Ram W | Personal care compositions with color changing indicator |
CA2610135A1 (en) | 2005-04-19 | 2006-10-19 | Foamix Ltd. | Apparatus and method for releasing a measured amount of content from a container |
US20070069046A1 (en) | 2005-04-19 | 2007-03-29 | Foamix Ltd. | Apparatus and method for releasing a measure of content from a plurality of containers |
US9084734B2 (en) | 2005-05-05 | 2015-07-21 | Danisco Us Inc. | Peptide personal care compositions and methods for their use |
CA2610662A1 (en) | 2005-05-09 | 2007-05-18 | Foamix Ltd. | Foamable vehicle and pharmaceutical compositions thereof |
WO2006122158A2 (en) | 2005-05-10 | 2006-11-16 | Xanthone Plus International, Llc | Skin care compositions containing xanthones |
EP1879595B1 (en) | 2005-05-10 | 2014-09-24 | Dermipsor Ltd | Compositions and methods for treating hyperproliferative epidermal diseases |
US20060260655A1 (en) * | 2005-05-23 | 2006-11-23 | Martin William R | Asbestos removal process |
PL1917072T3 (pl) | 2005-06-01 | 2014-01-31 | Glaxosmithkline Ip Dev Ltd | Formulacja witaminowa |
US20060272199A1 (en) | 2005-06-02 | 2006-12-07 | Bmc Manufacturing, Llc | Aqueous gel candle for use with a warming device |
US8211874B2 (en) | 2005-06-03 | 2012-07-03 | Galderma Laboratories Inc. | Inhibition of thrombin generation |
CA2611577A1 (en) | 2005-06-07 | 2007-09-07 | Foamix Ltd. | Antibiotic kit and composition and uses thereof |
WO2007085899A2 (en) | 2005-07-06 | 2007-08-02 | Foamix Ltd. | Foamable arthropocidal composition for tropical application |
US20070009607A1 (en) | 2005-07-11 | 2007-01-11 | George Jones | Antibacterial/anti-infalmmatory composition and method |
US20070015738A1 (en) | 2005-07-15 | 2007-01-18 | Walker Stephen G | Use of non-antibacterial tetracycline formulations for inhibiting bacterial spores from becoming infectious vegetative cells |
EP2862561B1 (en) | 2005-07-18 | 2019-10-30 | The Procter and Gamble Company | Method for conditioning hair with an aerosol cream mousse |
WO2007085902A2 (en) | 2005-07-19 | 2007-08-02 | Foamix Ltd. | Foamable composition combining a polar solvent and a hydrophobic carrier |
US20080152596A1 (en) | 2005-07-19 | 2008-06-26 | Foamix Ltd. | Polypropylene glycol foamable vehicle and pharmaceutical compositions thereof |
EP1745769B1 (en) | 2005-07-22 | 2008-10-15 | Wella Aktiengesellschaft | Hair treatment method using dry foam as mechanical support for hair |
CN100531515C (zh) | 2005-07-22 | 2009-08-19 | 鸿富锦精密工业(深圳)有限公司 | 具有改良电源区块的印刷电路板 |
DE102005037844A1 (de) | 2005-08-04 | 2007-04-05 | Intendis Gmbh | Wasserfreies Mehr-Phasen-Gel-System |
US20070036831A1 (en) | 2005-08-09 | 2007-02-15 | Nanobio Corporation | Nanoemulsion compositions having anti-inflammatory activity |
CA2632183A1 (en) | 2005-08-25 | 2007-03-01 | Philip R. Houle | Treatment systems for delivery of sensitizer solutions |
FR2890559B1 (fr) | 2005-09-13 | 2011-06-24 | Galderma Sa | Mousses dermatologiques a base de metronidazole et emulsions pour la preparation |
DE202006004676U1 (de) | 2005-09-28 | 2007-02-08 | Neubourg Skin Care Gmbh & Co. Kg | Hautpflegeprodukte |
WO2007050543A2 (en) | 2005-10-24 | 2007-05-03 | Collegium Pharmaceutical, Inc. | Topical pharmaceutical foam composition |
US20070134174A1 (en) | 2005-11-03 | 2007-06-14 | Christopher Irwin | Personal care composition |
JP2007131539A (ja) | 2005-11-08 | 2007-05-31 | Koike Kagaku Kk | 冷感泡沫化粧料 |
US20070148194A1 (en) | 2005-11-29 | 2007-06-28 | Amiji Mansoor M | Novel nanoemulsion formulations |
JP4885529B2 (ja) | 2005-12-08 | 2012-02-29 | 住友重機械工業株式会社 | 放射線検出ユニットおよび放射線検査装置 |
US20070160548A1 (en) | 2005-12-13 | 2007-07-12 | Playtex Products, Inc. | Moisturizing sunless tanning composition |
US20070142263A1 (en) | 2005-12-15 | 2007-06-21 | Stahl Katherine D | Color changing cleansing composition |
US20070148112A1 (en) | 2005-12-28 | 2007-06-28 | Avon Products, Inc. | Foaming, color-changing topical composition and method of imparting a cosmetic effect |
US20070166273A1 (en) | 2006-01-19 | 2007-07-19 | Krivulka Joseph J | Skin treatment educational kit |
WO2007082698A1 (en) | 2006-01-19 | 2007-07-26 | Disphar International B.V. | Foam-forming composition |
WO2007103555A2 (en) | 2006-03-08 | 2007-09-13 | Nuviance, Inc. | Transdermal drug delivery compositions and topical compositions for application on the skin |
US20070224143A1 (en) | 2006-03-21 | 2007-09-27 | Kamedis Ltd. | Cosmetic and pharmaceutical foam carrier |
MX2008012155A (es) | 2006-03-22 | 2008-10-03 | Procter & Gamble | Producto en aerosol que comprende una composicion concentrada que genera espuma que comprende materiales particulados. |
US7252816B1 (en) | 2006-03-29 | 2007-08-07 | Dow Pharmaceutical Sciences | Topical acne vulgairs medication with a sunscreen |
EP2206494B1 (en) | 2006-03-31 | 2015-12-02 | Stiefel Research Australia Pty Ltd | Foamable suspension gel |
WO2008075207A2 (en) | 2006-04-04 | 2008-06-26 | Foamix Ltd. | Anti-infection augmentation foamable compositions and kit and uses thereof |
US20070264317A1 (en) | 2006-05-15 | 2007-11-15 | Perrigo Israel Pharmaceuticals Ltd. | Imiquimod cream formulation |
US20070281999A1 (en) | 2006-05-31 | 2007-12-06 | The Dial Corporation | Alcohol-containing antimicrobial compositions having improved efficacy |
JP4892282B2 (ja) | 2006-06-09 | 2012-03-07 | アルプス電気株式会社 | 電気接点用潤滑組成物 |
WO2008110872A2 (en) | 2006-06-23 | 2008-09-18 | Foamix Ltd. | Foamable compositions and kits comprising one or more of a channel agent, a cholinergic agent, a nitric oxide donor, and related agents and their uses |
US7826675B2 (en) | 2006-07-04 | 2010-11-02 | Hewlett-Packard Development Company, L.P. | Feature-aware image defect removal |
ES2530390T3 (es) | 2006-07-05 | 2015-03-02 | Foamix Pharmaceuticals Ltd | Vehículo espumante de ácido carboxílico y composiciones farmacéuticas del mismo |
EP2046121B1 (en) | 2006-07-14 | 2012-08-22 | Stiefel Research Australia Pty Ltd | Fatty acid pharmaceutical foam |
NO343857B1 (no) | 2006-07-18 | 2019-06-24 | Meda Ab | Immunresponsmodifiserende skumformuleringer |
US20080031908A1 (en) | 2006-07-25 | 2008-02-07 | L'oreal | Oily cosmetic composition in aerosol form |
JP2008040899A (ja) | 2006-08-08 | 2008-02-21 | Fuji Xerox Co Ltd | 印刷制御装置、プログラム及び方法 |
MX2009002536A (es) | 2006-09-08 | 2009-04-14 | Foamix Ltd | Composicion espumable coloreada o coloreable y espuma. |
ES2315123B1 (es) | 2006-09-25 | 2009-12-30 | Divasa-Farmavic, S.A. | Composiciones farmaceuticas estables de tetraciclinas en solucion, procedimiento para su obtencion y sus usos. |
HUP0600765A2 (en) | 2006-10-06 | 2008-10-28 | Istvan Piller | Container for stable carbondioxide foam, process for producing stable carbondioxide foam and method for using of foam |
US20080260655A1 (en) | 2006-11-14 | 2008-10-23 | Dov Tamarkin | Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses |
WO2009007785A2 (en) | 2006-11-14 | 2009-01-15 | Foamix Ltd. | Stable non-alcoholic foamable pharmaceutical emulsion compositions with an unctuous emollient and their uses |
WO2008152444A2 (en) | 2006-11-29 | 2008-12-18 | Foamix Ltd. | Foamable waterless compositions with modulating agents |
CN101557796A (zh) | 2006-12-15 | 2009-10-14 | 宝洁公司 | 护肤组合物 |
EP2104489A2 (en) | 2006-12-26 | 2009-09-30 | FemmePharma Holding Company, Inc. | Topical administration of danazol |
US20080292560A1 (en) | 2007-01-12 | 2008-11-27 | Dov Tamarkin | Silicone in glycol pharmaceutical and cosmetic compositions with accommodating agent |
JP2010515766A (ja) | 2007-01-16 | 2010-05-13 | オイスターシェル エヌ.ブイ. | 節足動物を死滅させるための発泡性組成物及びその使用 |
PT103661B (pt) | 2007-02-23 | 2010-09-07 | Hovione Farmaciencia S A | Processo de preparação de minociclina base cristalina |
GB0703909D0 (en) | 2007-02-28 | 2007-04-11 | Neuropharm Ltd | Treatment of anxiety disorders |
FR2915891B1 (fr) | 2007-05-10 | 2012-05-11 | Oreal | Composition sous forme de mousse comprenant un polymere silicone |
US9511016B2 (en) | 2007-06-12 | 2016-12-06 | Epicentrx, Inc. | Topical composition for treating pain |
US8636982B2 (en) | 2007-08-07 | 2014-01-28 | Foamix Ltd. | Wax foamable vehicle and pharmaceutical compositions thereof |
WO2009056991A2 (en) | 2007-09-04 | 2009-05-07 | Foamix Ltd. | Device for delivery of a foamable composition |
EA017174B1 (ru) | 2007-09-30 | 2012-10-30 | Меда Аб | Композиция на основе силиконового геля и лекарственное средство для лечения ран с уменьшенной степенью рубцевания |
US20090130029A1 (en) | 2007-11-21 | 2009-05-21 | Foamix Ltd. | Glycerol ethers vehicle and pharmaceutical compositions thereof |
US9439857B2 (en) | 2007-11-30 | 2016-09-13 | Foamix Pharmaceuticals Ltd. | Foam containing benzoyl peroxide |
WO2010041141A2 (en) | 2008-10-07 | 2010-04-15 | Foamix Ltd. | Oil-based foamable carriers and formulations |
WO2009087578A2 (en) | 2008-01-08 | 2009-07-16 | Foamix Ltd. | Sensation modifying topical composition foam |
CA2712120A1 (en) | 2008-01-14 | 2009-07-23 | Foamix Ltd. | Poloxamer foamable pharmaceutical compositions with active agents and/or therapeutic cells and uses |
US8652443B2 (en) | 2008-02-14 | 2014-02-18 | Precision Dermatology, Inc. | Foamable microemulsion compositions for topical administration |
ES2330291B1 (es) * | 2008-02-29 | 2010-10-18 | Lipotec Sa | Peptidos utiles en el tratamiento de la piel, mucosas y/o cuero cabelludo y su uso en composiciones cosmeticas o farmaceuticas. |
RU2010140682A (ru) | 2008-03-05 | 2012-04-10 | Пэрэтек Фамэсьютикэлс, Инк. (US) | Способ лечения пациента от инфекции, фармацевтическая композиция (варианты) и лекарственное средство |
KR101672511B1 (ko) | 2008-03-06 | 2016-11-03 | 아나코르 파마슈티칼스 인코포레이티드 | 소염제로써 붕소가 함유된 소분자 |
US20120141384A1 (en) | 2008-05-06 | 2012-06-07 | Dov Tamarkin | Antibacterial conjugated boronic acids and pharmaceutical compositions thereof |
JP5551685B2 (ja) * | 2008-05-14 | 2014-07-16 | オトノミ―,インク. | 制御放出型コルチコステロイド組成物、および耳の疾患を処置する方法 |
US20110212157A1 (en) | 2008-06-26 | 2011-09-01 | Anterios, Inc. | Dermal delivery |
US8253882B2 (en) | 2008-08-07 | 2012-08-28 | Sharp Kabushiki Kaisha | Display device |
KR101616663B1 (ko) | 2008-08-08 | 2016-04-28 | 인터디지탈 패튼 홀딩스, 인크 | 버퍼 상태를 보고하기 위한 방법 및 장치 |
KR20110090892A (ko) | 2008-10-31 | 2011-08-10 | 모베르그 데르마 아베 | 두 개 이상의 침투 증강제의 조합으로 구성되는 국소 조성물 |
WO2010068465A2 (en) | 2008-11-25 | 2010-06-17 | Citrix Systems. Inc. | Systems and methods for maintaining persistence by a backup virtual server |
ES2364692T3 (es) | 2008-12-23 | 2011-09-12 | Intendis Gmbh | Composición espumable esencialmente libre de ingredientes farmacéuticamente activos para el tratamiento de la piel humana. |
JP5213734B2 (ja) | 2009-01-22 | 2013-06-19 | サンウエーブ工業株式会社 | フラップ扉付きキャビネット |
WO2010093382A1 (en) | 2009-02-12 | 2010-08-19 | Collegium Pharmaceutical, Inc. | Foamable benzoyl peroxide compositions for topical administration |
DK2400951T3 (en) * | 2009-02-25 | 2018-12-03 | Mayne Pharma Llc | TOPICAL FOAM COMPOSITION |
US20120164087A1 (en) | 2009-04-24 | 2012-06-28 | Carter Daniel C | Human Serum Albumin-Based Topical Ointment for Treatment of Acne, Psoriasis, Egfr-Induced Toxicity, Premature Skin Aging and Other Skin Conditions |
CA2760186C (en) | 2009-04-28 | 2019-10-29 | Foamix Ltd. | Foamable vehicle and pharmaceutical compositions comprising aprotic polar solvents and uses thereof |
PT104644B (pt) | 2009-06-26 | 2012-11-06 | Hovione Farmaciencia S A | Formulação tópica contendo uma tetraciclina e método de tratamento de infecções cutâneas usando a mesma |
US8255186B2 (en) | 2009-07-09 | 2012-08-28 | Air Liquide Large Industries U.S. Lp | Presenting dynamic SCADA data |
WO2011013009A2 (en) | 2009-07-29 | 2011-02-03 | Foamix Ltd. | Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses |
WO2011013008A2 (en) | 2009-07-29 | 2011-02-03 | Foamix Ltd. | Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, breakable foams and their uses |
WO2011026094A2 (en) | 2009-08-31 | 2011-03-03 | Collegium Pharmaceutical, Inc. | Stable aerosol topical foams comprising a hypochlorite salt |
US9849142B2 (en) | 2009-10-02 | 2017-12-26 | Foamix Pharmaceuticals Ltd. | Methods for accelerated return of skin integrity and for the treatment of impetigo |
US8871184B2 (en) | 2009-10-02 | 2014-10-28 | Foamix Ltd. | Topical tetracycline compositions |
US20140121188A1 (en) | 2009-10-02 | 2014-05-01 | Foamix Ltd. | Compositions for the improved treatment of acne and related disorders |
GB2474930B (en) | 2009-10-02 | 2012-07-04 | Foamix Ltd | Topical tetracycline compositions |
US20140186269A1 (en) | 2013-01-03 | 2014-07-03 | Foamix Ltd. | Vehicle compositions essentially free of pharmaceutically active agents for the improved treatment of acne and related disorders |
US8735377B1 (en) | 2010-02-04 | 2014-05-27 | Susan Anna Sipos | Methods of treating herpes zoster |
US20110212035A1 (en) | 2010-02-26 | 2011-09-01 | Collegium Pharmaceutical, Inc. | Emollient foams for treatment of dermatoses |
US8623330B2 (en) | 2010-03-18 | 2014-01-07 | Precision Dermatology, Inc. | Emollient foams for treatment of seborrheic dermatitis |
US8592380B2 (en) | 2010-03-26 | 2013-11-26 | Precision Dermatology, Inc. | Aerosol foams comprising clindamycin phosphate |
US20120070390A1 (en) | 2010-04-21 | 2012-03-22 | Phillips D Howard | Topical drug delivery system with dual carriers |
CA2776482C (en) | 2010-05-04 | 2022-06-07 | Foamix Ltd. | Compositions, gels and foams with rheology modulators and uses thereof |
US8784780B2 (en) | 2010-06-11 | 2014-07-22 | Precision Dermatology, Inc. | High oil-content emollient aerosol foam compositions |
US8978936B2 (en) | 2010-07-12 | 2015-03-17 | Foamix Pharmaceuticals Ltd. | Apparatus and method for releasing a unit dose of content from a container |
AU2011289407B2 (en) | 2010-08-11 | 2015-06-18 | Philadelphia Health & Education Corporation | Novel D3 dopamine receptor agonists to treat dyskinesia in Parkinson's disease |
US20120064136A1 (en) | 2010-09-10 | 2012-03-15 | Nanobio Corporation | Anti-aging and wrinkle treatment methods using nanoemulsion compositions |
US20120093876A1 (en) | 2010-10-13 | 2012-04-19 | Aciex, Inc. | Ophthalmic Formulations, Methods Of Manufacture And Methods of Normalizing Meibomian Gland Secretions |
US8895537B2 (en) | 2010-10-29 | 2014-11-25 | Infirst Healthcare Ltd. | Compositions and methods for treating cardiovascular diseases |
FR2969492B1 (fr) | 2010-12-23 | 2013-07-05 | Galderma Res & Dev | Mousses dermatologiques obtenues a partir d'un gel ou d'une suspension contenant de l'adapalene |
CA2861357C (en) | 2011-01-19 | 2022-08-23 | Laboratory Skin Care, Inc. | Topical minocycline compositions and methods of using the same |
WO2013009586A1 (en) | 2011-07-08 | 2013-01-17 | The Research Foundation Of State University Of New York | Topical minocycline ointment for suppression of allergic skin responses |
JP2014532717A (ja) | 2011-11-03 | 2014-12-08 | プレシジョン ダーマトロジー インコーポレイテッドPrecision Dermatology, Inc. | 反応性噴射剤を使用した安定な皮膚用エアゾールフォーム |
US8801680B2 (en) | 2012-03-14 | 2014-08-12 | Becton, Dickinson And Company | Angled retracting sheath for safety needle |
US20150164922A1 (en) | 2012-03-15 | 2015-06-18 | Foamix Pharmaceuticals Ltd. | Use of tetracycline compositions for wound treatment and skin restoration |
US20130251644A1 (en) | 2012-03-22 | 2013-09-26 | Precision Dermatology, Inc. | Cyclodextrin-Based Microemulsions, and Dermatological Uses Thereof |
CA2775393C (en) | 2012-05-02 | 2014-04-29 | Samy Saad | Topical non-aqueous pharmaceutical formulations |
CN104429120B (zh) | 2012-05-15 | 2019-01-15 | 瑞典爱立信有限公司 | 用于网络辅助的装置对装置通信的干扰管理 |
CA2878462A1 (en) | 2012-07-13 | 2014-01-16 | Paratek Pharmaceuticals, Inc. | Tetracycline compounds for treating neurodegenerative disorders |
PT106679B (pt) | 2012-11-27 | 2015-03-25 | Hovione Farmaciencia Sa | Formulações tópicas de tetraciclinas, sua preparação e usos |
US8778365B1 (en) | 2013-01-31 | 2014-07-15 | Merz Pharmaceuticals, Llc | Topical compositions and methods for making and using same |
CA2902171A1 (en) | 2013-02-22 | 2014-08-28 | Stiefel Laboratories, Inc. | Non-aqueous solid stabilized emulsions |
WO2014134394A1 (en) | 2013-02-28 | 2014-09-04 | Precision Dermatology, Inc. | Topical formulations of corticosteroids with enhanced bioavailability |
US20140243300A1 (en) | 2013-02-28 | 2014-08-28 | Precision Dermatology, Inc. | Controlling the Bioavailability of Active Ingredients in Topical Formulations |
EP2968372A1 (en) | 2013-03-15 | 2016-01-20 | ReVance Therapeutics, Inc. | Minocycline derivatives |
CA2914583C (en) | 2013-06-04 | 2019-06-18 | Vyome Biosciences Pvt. Ltd. | Coated particles and compositions comprising same |
EP3010487A4 (en) | 2013-06-17 | 2016-12-07 | Contract Pharmaceuticals Ltd | NON-AEROSOL FOAM FOR TOPICAL ADMINISTRATION |
US9474720B2 (en) | 2013-11-04 | 2016-10-25 | BioPharmX, Inc. | Dosage form comprising an active ingredient and a plurality of solid porous microcarriers |
WO2015075640A1 (en) | 2013-11-20 | 2015-05-28 | Lupin Limited | Stable pharmaceutical formulation(s) of tetracycline antibiotic |
PT107433B (pt) | 2014-01-28 | 2018-12-04 | Hovione Farm S A | Processo de redução e controlo do tamanho de partícula |
WO2015153864A2 (en) | 2014-04-02 | 2015-10-08 | Hopkins Patricia T | Methods for treating inflammatory conditions |
US9841142B2 (en) | 2014-12-22 | 2017-12-12 | Rockwell Automation Technologies, Inc. | Single-wire industrial safety system with safety device diagnostic communication |
JP6793715B2 (ja) | 2015-03-23 | 2020-12-02 | バイオファーミクス・インコーポレイテッドBioPharmX, Inc. | テトラサイクリンの皮膚用医薬組成物 |
US20160287615A1 (en) | 2015-04-03 | 2016-10-06 | BioPharmX, Inc. | Novel encapsulation of fluorescent, photo-sensitive, or oxygen-sensitive active ingredient for topical application |
WO2016205172A1 (en) | 2015-06-15 | 2016-12-22 | Banner Life Sciences Llc | Soft lozenges comprising corticosteroids |
AU2016294504B2 (en) | 2015-07-13 | 2019-07-18 | Dr. Reddy's Laboratories, Ltd. | Topical retinoid compositions |
WO2017030555A1 (en) | 2015-08-17 | 2017-02-23 | Bhalani Vinayak T | Topical film delivery system |
WO2017029647A1 (en) | 2015-08-20 | 2017-02-23 | Meir Eini | Tetracycline management of egfr inhibitor associated dermatoses |
PT108978B (pt) | 2015-11-24 | 2020-03-09 | Hovione Farm S A | Sais de tetraciclinas |
MX2020012139A (es) | 2016-09-08 | 2021-01-29 | Vyne Pharmaceuticals Inc | Composiciones y metodos para tratar rosacea y acne. |
CN111343969A (zh) | 2017-10-24 | 2020-06-26 | 格兰马克药品有限公司 | 阿达帕林和米诺环素的局部药物组合物 |
-
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- 2010-10-01 US US13/499,709 patent/US10029013B2/en active Active
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- 2018-03-06 US US15/913,574 patent/US10086080B2/en not_active Expired - Fee Related
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- 2018-06-27 US US16/019,623 patent/US10967063B2/en active Active
- 2018-12-28 US US16/235,986 patent/US10946101B2/en active Active
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-
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- 2019-02-20 US US16/280,921 patent/US10821187B2/en active Active
- 2019-04-17 US US16/387,381 patent/US10835613B2/en active Active
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- 2020-02-28 US US16/805,201 patent/US20200261586A1/en active Pending
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- 2020-10-01 US US17/061,018 patent/US20210069335A1/en not_active Abandoned
- 2020-10-09 US US17/066,752 patent/US20210023226A1/en not_active Abandoned
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090180970A1 (en) * | 2002-10-25 | 2009-07-16 | Foamix Ltd. | Foamable composition combining a polar solvent and a hydrophobic carrier |
US20050069566A1 (en) * | 2003-08-04 | 2005-03-31 | Foamix Ltd. | Foam carrier containing amphiphilic copolymeric gelling agent |
US20080167376A1 (en) * | 2003-09-25 | 2008-07-10 | Dmi Biosciences, Inc. | Methods and products which utilize N-acyl-L-aspartic acid |
US20080188445A1 (en) * | 2007-02-02 | 2008-08-07 | Warner Chilcott Company Inc. | Tetracycline compositions for topical administration |
US20080188446A1 (en) * | 2007-02-02 | 2008-08-07 | Warner Chilcott Company Inc. | Tetracycline compositions for topical administration |
WO2009072007A2 (en) * | 2007-12-07 | 2009-06-11 | Foamix Ltd. | Carriers, formulations, methods for formulating unstable active agents for external application and uses thereof |
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US11331278B2 (en) | 2015-09-16 | 2022-05-17 | Dfb Soria, Llc | Delivery of drug nanoparticles and methods of use thereof |
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US11191717B2 (en) | 2017-03-15 | 2021-12-07 | Dfb Soria, Llc | Topical therapy for the treatment of skin malignancies using nanoparticles of taxanes |
US11633349B2 (en) | 2017-03-15 | 2023-04-25 | Dfb Soria, Llc | Topical therapy for the treatment of skin malignancies using nanoparticles of taxanes |
US11497726B2 (en) | 2018-03-16 | 2022-11-15 | Dfb Soria, Ll. | Topical therapy for the treatment of cervical intraepithelial neoplasia (CIN) and cervical cancer using nanoparticles of taxanes |
CN115463091A (zh) * | 2022-10-27 | 2022-12-13 | 新基元(北京)医药科技有限公司 | 一种改善稳定性的米诺环素泡沫剂 |
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