CN114641297A - 使用高克拉夫特温度阴离子表面活性剂治疗皮肤病症 - Google Patents
使用高克拉夫特温度阴离子表面活性剂治疗皮肤病症 Download PDFInfo
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- CN114641297A CN114641297A CN202180006148.4A CN202180006148A CN114641297A CN 114641297 A CN114641297 A CN 114641297A CN 202180006148 A CN202180006148 A CN 202180006148A CN 114641297 A CN114641297 A CN 114641297A
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- krafft temperature
- surfactant
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- skin
- phosphate
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Abstract
本发明是用于治疗其中表皮屏障功能降低的皮肤病症(如当患者患有湿疹、特别是特应性皮炎时)的方法和组合物。通过使用含有高克拉夫特温度表面活性剂、优选阴离子表面活性剂的制剂，可以显著地改善表皮屏障功能并且可以降低表皮脂质的提取。
Description
技术领域
本发明涉及皮肤病症(如其中表皮屏障减少的湿疹)的治疗。表皮屏障功能可以通过使用含有高克拉夫特温度(Krafft temperature)阴离子表面活性剂的制剂得到显著改善。
背景技术
表皮屏障具有多种功能，包括维持水平衡、降低氧化应激、防御外来物质(如微生物和抗原)和防御紫外线损伤。整个表皮都参与表皮屏障，但角质层主要负责这些功能中的许多。角质层由在细胞之间具有细胞间脂质片层的数个角质细胞层组成。细胞间脂质片层主要由神经酰胺、胆固醇和脂肪酸组成。角质细胞含有吸湿性小化合物的混合物，所述吸湿性小化合物参与角质层中水合作用的生理维持。这些化合物统称为天然保湿因子(NMF)。表皮屏障会由于暴露于刺激物、不适当的皮肤护理、低环境湿度、局部用药、全身用药、以及病症(如特应性皮炎、红斑痤疮、糖尿病和高龄)而被损害。当表皮屏障减少时，角质层中的蛋白质和脂质会改变，并且经皮水分流失(TEWL)会增加，从而导致受损、受刺激的皮肤。治疗其中表皮屏障减少的表皮屏障功能障碍，以控制瘙痒、阻抑炎症并且恢复皮肤屏障。其中表皮屏障减少的表皮屏障功能障碍需要与造成过度增殖性皮肤疾病(如银屑病和角化病)的表皮屏障功能障碍不同的治疗。过度增殖性皮肤疾病可以用角质层分离剂治疗，以去除死皮细胞并且降低脱屑。角质层分离剂不应当用于治疗其中表皮屏障减少的表皮屏障功能障碍，因为表皮屏障的进一步降低是不期望的，并且此类剂将变干且进一步刺激皮肤。
润肤剂(如乳、霜和膏)通常用作局部治疗表皮屏障功能降低的一线疗法。润肤剂提供可以有助于恢复表皮屏障的水和脂质。对于乳剂(即，润肤霜或润肤乳)，通过使用乳化剂(通常是表面活性剂的共混物)将高含水量(大于20％)与封闭剂(矿脂、蜡、油、硅酮)组合以形成稳定的局部用产品。润肤霜或润肤乳是药物局部治疗的优选载体。润肤膏不一定需要添加表面活性剂，但发现“油腻感”通常是令人不快的，并且因此患者更喜欢施加霜或乳。
表面活性剂与角质层(特别是角质层的脂质)之间的相互作用已经用于解释为何一些表面活性剂高度刺激皮肤，而其他表面活性剂呈现相对惰性。从广义上讲，局部施加的表面活性剂可以改变角质层(SC)的屏障性质，这允许更大的潜在刺激物流入。刺激物可以是表面活性剂本身、来自局部用产品的另外的赋形剂、作为活性物质/赋形剂的痕量杂质带进局部用产品中的降解物或污染物、或者无意地与先前用基于表面活性剂的局部用产品给药的相同解剖部位接触的环境刺激物。当治疗诸如特应性皮炎(AD)的病症时，表面活性剂诱发的皮肤刺激的可能性明显增加，这在机制上与皮肤屏障功能下降有关(PeterM.Elias，Yutaka Hatano and Mary L.Williams.Basis for the barrier abnormalityin atopic dermatitis：Outside-inside-outside pathogenic mechanisms.J AllergyClin Immunol.2008 Jun；121(6)：1337-1343.doi：10.1016/j.jaci.2008.01.022)。
更具体地，三种概念性表面活性剂-角质层脂质相互作用改变皮肤的屏障性质：1)表面活性剂单体吸附至SC的表面上并且增加皮肤润湿性，2)表面活性剂与双层结构表皮脂质混合并且破坏该双层结构表皮脂质，以及3)表面活性剂胶束溶解/提取来自SC的脂质(Lemery E，Briancon S，Chevalier Y，Oddos T，Gohier A，Boyron O，BolzingerMA.Surfactants have multi-fold effects on skin barrier function.Eur JDermatol 2015；25(5)：424-35doi：10.1684/ejd.2015.2587)。阴离子表面活性剂十二烷基硫酸钠(SDS)的单体非常有效地吸附、混合和破坏皮肤脂质，并且SDS胶束有效地提取表皮脂质，这造成SDS的水溶液对皮肤具有高度刺激性。应当注意的是，与正常皮肤相比，阴离子表面活性剂将更快速地且更完全地与表皮屏障受损皮肤的双层结构表皮脂质混合，并且破坏该双层结构表皮脂质(步骤2)。
由于干燥、瘙痒皮肤的一线疗法通常是局部施加润肤霜或润肤乳，因此无法避免表面活性剂向屏障受损皮肤的施加。由于润肤乳剂是优选的局部治疗，制剂设计师尽力使用具有低刺激可能性的表面活性剂。某些非离子表面活性剂体积太大而无法与双层结构表皮脂质混合(机制步骤2)，并且已知是非常温和的。具体地，润肤乳剂的制剂设计师更喜欢具有大PEG头部基团的非离子表面活性剂，大PEG头部基团抑制这些表面活性剂向SC脂质基质中的渗透。此类表面活性剂包括聚(氧乙烯)-20脱水山梨糖醇月桂酸酯、PEG-12二甲聚硅氧烷(Lemery等人论文的结论)和鲸蜡醇聚醚-20(ceteth-20)。
表面活性剂引发的表皮脂质提取(表面活性剂诱发的皮肤刺激中的第三机制步骤)需要进一步说明。当将润肤霜或润肤乳涂抹至屏障受损皮肤中时，来自该制剂的水会使SC水合，而封闭剂会把水“捕获(trap)”在SC中以暂时恢复屏障功能并缓解皮肤刺激。如果在沐浴之后施加润肤剂，则皮肤保湿作用会被增强，因为保留在皮肤上的水加上来自乳剂的水会被封闭剂捕获，以延长皮肤屏障的恢复和刺激缓解。随着时间的推移，封闭剂会逐渐消失，并且SC的水合水会丢失；然后皮肤刺激会重新出现。润肤霜或润肤乳的益处持续时间取决于各种因素，但皮肤周围空气的相对湿度是主要因素。润肤剂可以在干燥环境中提供较短时间的缓解，而与之相比在更潮湿的环境中为6-8小时。如果润肤乳剂除了封闭剂之外还含有屏障恢复性脂质(例如，神经酰胺)，则可以显著地延长益处的持续时间。含有相似量的水和脂质的物理稳定的局部用产品需要制剂含有表面活性剂。如果润肤剂制剂中使用的表面活性剂与角质层的表皮脂质混合良好，则局部用产品会潜在地提取表皮脂质并且随着时间的推移减小皮肤的屏障功能。当表面活性剂胶束形成以溶解表皮脂质并完成提取过程时，发生该提取步骤。表皮脂质提取效率可以与皮肤屏障受损程度和刺激皮肤的可能性直接相关。
在机制上，在存在胶束的情况下发生表面活性剂引发的表皮脂质提取。当溶解在水中时，阴离子表面活性剂单体和非离子表面活性剂单体两者在特定浓度和温度范围内缔合以形成胶束。一旦表面活性剂的浓度高于临界胶束化浓度(CMC)，则表面活性剂溶液的物理性质就明显地变化，最明显的是该水溶液溶解大量脂质的能力。非离子表面活性剂几乎总是在室温以下自发地形成胶束。阴离子表面活性剂与非离子表面活性剂的不同之处在于：除了具有高于CMC的表面活性剂浓度之外，胶束的形成可能还需要将溶液加温至高于环境温度。阴离子表面活性剂形成胶束所需的最低温度被称为克拉夫特温度(由于弗里德里希·克拉夫特(Friedrich Krafft)在1894-1900年针对作为胶体的肥皂的工作而以其名字命名)。低于克拉夫特温度，使表面活性剂的浓度增加至CMC以上造成沉积的固体表面活性剂，而非胶束的形成。因此，克拉夫特温度是表面活性剂溶解的温度，所述温度受到浓度的影响。当表面活性剂的浓度增加至超过CMC时，特定阴离子表面活性剂的克拉夫特温度可以增加或减少多达几摄氏度。
只有存在足够的水以使表面活性剂保持在特定浓度和温度范围内时，胶束才能形成。虽然在实验室环境中过量的2％表面活性剂溶液可以在切离的人体皮肤上保持20小时，但大多数人将仅在沐浴、淋浴或游泳时经历表面活性剂引发的脂质提取。显著的表面活性剂引发的表皮脂质提取的最常见的“现实生活”场景是在于热水浴中长时间浸泡期间。
成人沐浴的可接受水温范围为38至43摄氏度(109.4°F)[关于安全沐浴温度和频率的艾伯塔省卫生服务程序，生效日期：2019年12月2日；extranet.ahsnet.ca/teams/policydocuments/1/clp-provincial-sh-safe-bath-temps-procedure.pdf]。如果43℃是最高的安全沐浴温度，则克拉夫特温度为44℃或更高的任何表面活性剂都将无法提取表皮脂质。含有克拉夫特温度等于或高于44℃的阴离子乳化剂的局部用乳剂可以安全地施加至具有屏障受损皮肤的患者，而不使其皮肤病症(例如，特应性皮炎)恶化。因此，高克拉夫特温度乳化剂(如烷基磷酸酯鲸蜡醇聚醚-10磷酸酯(TK＝53℃)和磷酸二鲸蜡酯(TK＝58℃)的共混物)将显著地改善用保湿局部用制剂治疗的患者的表皮屏障功能。用克拉夫特温度高于烫水(scalding water)温度的乳化剂配制未向患者提供更多益处，因为没有人会有意地在烫水中沐浴。根据消费品安全委员会[.accuratebuilding.com/services/legal/charts/hot_water_burn_scalding_graph]，成人如果暴露于130°F(54.4℃)的水中30秒则会遭受三度灼伤。
因此，在用含有提取表皮脂质的表面活性剂的润肤霜或润肤乳治疗屏障受损皮肤时，反复施用治疗会引发减弱的功效的循环。例如，如果患者具有降低的表皮屏障功能并且出现特应性皮炎(AD)，则可以提供具有说明书的润肤霜(具有药物活性成分或者不具有药物活性成分)，每天使用两次，其中在沐浴之后(在皮肤变干之前)立即施加。润肤霜使皮肤屏障恢复10-12小时，从而使患者在这一天中的大部分时间缓解其AD症状。假设患者每天沐浴，则在前24小时的两次施加期间已经与表皮脂质混合的表面活性剂在沐浴中形成胶束，溶解并提取表皮脂质，并且显著地降低患者的皮肤屏障。在沐浴之后立即施加润肤霜，从而恢复皮肤屏障。该每日循环重复四周或更久。患者经历减弱的功效(可能是其AD症状的10％或15％的净改善)，因为所使用的表面活性剂在沐浴期间形成胶束并且提取表皮脂质。如果使用不能形成胶束的表面活性剂，则功效不会减弱，并且润肤霜将具有最大功效(可能是AD症状的50％净改善)。该润肤霜也将是用于添加活性药物成分的最优载体，所述活性药物成分可以提供AD症状的甚至更大的改善。
需要一种润肤乳剂，所述润肤乳剂不提取表皮脂质并且因此不随着时间的推移造成减弱的临床功效。
发明内容
根据本发明，已经发现包含高克拉夫特温度阴离子表面活性剂的制剂降低表皮脂质的提取并且增加表皮屏障功能。改善表皮屏障功能导致异常脱屑的减少、弹性的改善和皮肤刚性的降低，从而造成皮肤刺激减小和皮肤水合作用增加。
附图说明
图1示出用高克拉夫特温度制剂和低克拉夫特温度制剂处理切离皮肤的结果。用含有高克拉夫特温度磷酸酯盐型表面活性剂的乳膏制剂(克拉夫特温度53℃，来自实施例2的制剂2)处理未造成神经酰胺提取。用含有低克拉夫特温度鲸蜡硬脂基硫酸钠表面活性剂的乳膏剂(爱宁达乳膏剂载体(Elidel Cream Vehicle)，来自实施例2的制剂5)处理在从人体皮肤中提取神经酰胺方面最有效。与4％月桂基硫酸钠阳性对照相比，在3次温水洗涤之后，从经制剂5处理的皮肤中提取更大量的神经酰胺。
具体实施方式
表皮屏障受损的皮肤可以使用含有一种或更多种高克拉夫特温度阴离子表面活性剂的润肤乳剂来治疗，而不会随着时间的推移减小临床功效。表面活性剂使组合物乳化，并且有助于润湿该制剂中任何活性物质或赋形剂的表面。如本文所使用的，术语“表面活性剂”意为能够降低水的表面张力和/或水与不混溶液体之间的界面张力的两亲物(一种具有共价结合的极性区和非极性区的分子)。克拉夫特温度高于48℃的任何阴离子表面活性剂都可以用于本发明。可以使用本领域已知的方法来确定阴离子表面活性剂的克拉夫特点，例如，参见Li，et al.，“Property Prediction on Surfactant by QuantitativeStructure-Property Relationship：Krafft Point and Cloud Point”，Journal ofDispersion Science and Technology，26：799-808，2005。此类表面活性剂可以包括但不限于烷基芳基磺酸钠、月桂基硫酸铵、椰油酰胺醚硫酸酯、椰油胺氧化物、椰油基甜菜碱、椰油基二乙醇酰胺、椰油基单乙醇酰胺、椰油基辛酸酯/癸酸酯、椰油酰两性基二乙酸二钠(disodium cocoampho-diacetate)、月桂醇聚醚磺基琥珀酸二钠、月桂基磺基乙酸二钠、月桂基磺基琥珀酸二钠、油酰胺基单乙醇胺磺基琥珀酸二钠、多库酯钠、十二烷基苯磺酸钠、棕榈酸钠、十六烷基磺酸钠、硬脂基硫酸钠、硬脂酸钠、二甲苯磺酸钠、鲸蜡基磷酸钾、C9-15烷基磷酸钾、C11-15烷基磷酸钾、C12-13烷基磷酸钾、C12-14烷基磷酸钾、月桂基磷酸钾、C8-10烷基乙基磷酸酯、C9-15烷基磷酸酯、C20-22烷基磷酸酯、蓖麻油磷酸酯、鲸蜡醇聚醚-10磷酸酯、鲸蜡醇聚醚-20磷酸酯、鲸蜡醇聚醚-8磷酸酯、鲸蜡硬脂基磷酸酯、鲸蜡基磷酸酯、二甲聚硅氧烷PEG-7磷酸酯、月桂基磷酸二钠、油烯基磷酸二钠、月桂基磷酸酯、肉豆蔻基磷酸酯、辛基癸基磷酸酯、油醇聚醚-10磷酸酯、油醇聚醚-5磷酸酯、油醇聚醚-3磷酸酯、油烯基乙基磷酸酯、油烯基磷酸酯、PEG-26-PPG-30磷酸酯、PPG-5鲸蜡硬脂醇聚醚-10磷酸酯、PPG-5鲸蜡醇聚醚-10磷酸酯、月桂基磷酸钠、月桂醇聚醚-4磷酸钠、硬脂基磷酸酯、DEA-鲸蜡基磷酸酯、DEA-油醇聚醚-10磷酸酯、DEA-油醇聚醚-3磷酸酯、DEA-C8-C18全氟烷基乙基磷酸酯、磷酸二鲸蜡酯、二月桂醇聚醚-10磷酸酯、二肉豆蔻基磷酸酯、二油烯基磷酸酯、三鲸蜡基磷酸酯、三鲸蜡硬脂醇聚醚-4磷酸酯、三月桂醇聚醚-4磷酸酯、三月桂基磷酸酯、三油烯基磷酸酯和三硬脂基磷酸酯。
常用的阴离子表面活性剂及其克拉夫特温度
*十四烷基硫酸钠是阴离子表面活性剂硬化剂7-乙基-2-甲基-4-十一烷基硫酸钠的常用(但不正确的)同义词。
在优选实施方案中，使用由Croda以商品名CRODAFOSTMCES制造的鲸蜡硬脂醇(CAS67762 30 0)、磷酸二鲸蜡酯(CAS 2197 63 9)和鲸蜡醇聚醚-10磷酸酯(CAS 50643-20-4)的乳化剂共混物。该可商购获得的乳化剂共混物是一种自乳化蜡，其主要是与10-20％磷酸二鲸蜡酯和10-20％鲸蜡醇聚醚-10磷酸酯组合的蜡质材料鲸蜡硬脂醇(其是鲸蜡醇(C16H34O)和硬脂醇(C18H38O)的混合物)。当与水共混时，自乳化蜡形成乳液。当向水中添加CRODAFOSTMCES时，其白发地形成pH为约3的乳液。可以添加调节pH的药剂，以将pH增加或减小至期望的值。制剂的pH可以根据组分的最优pH进行调节。pH应当介于3.5-9.0之间，优选地介于4.0-8.0之间。
优选地，根据本发明的组合物为下列形式之一：
水包油乳剂：该产品可以是包含疏水性组分的离散相和连续水相的乳剂，所述连续水相包含水和任选的一种或更多种极性亲水性赋形剂以及溶剂、助溶剂、盐、表面活性剂、乳化剂和其他组分。这些乳剂可以包含有助于使乳剂稳定的水溶性聚合物或水溶胀性聚合物。
油包水乳剂：该组合物可以是包含疏水性组分的连续相和水相的乳剂，所述水相包含水和任选的一种或更多种极性亲水性载体以及盐或其他组分。这些乳剂可以包含油溶性聚合物或油溶胀性聚合物以及一种或更多种乳化剂，以有助于使乳剂稳定。
亲水性软膏剂或疏水性软膏剂：该组合物是用疏水性基质(例如，矿脂、增稠或胶凝的水不溶性油等)配制，并任选地具有少量水溶性相。亲水性软膏剂通常含有一种或更多种表面活性剂或润湿剂。
微乳剂：这些是透明的、热力学稳定的各向同性液体体系，所述体系含有通常与助表面活性剂组合的油、水和表面活性剂。微乳剂可以是水连续型混合物、油连续型混合物或双连续型混合物。制剂还可以任选地含有多达60重量％的水。较高的水平可能在一些组合物中是适合的。助表面活性剂的类别包括短链醇、烷二醇和烷三醇、聚乙二醇和聚乙二醇醚、吡咯烷衍生物、胆汁盐、脱水山梨糖醇脂肪酸酯和聚氧乙烯脱水山梨糖醇脂肪酸酯。适用于微乳剂的亲水性组分包括一种或更多种二醇(如多元醇，如甘油、丙二醇、丁二醇、聚乙二醇(PEG))，环氧乙烷、环氧丙烷和/或环氧丁烷的无规共聚物或嵌段共聚物，每分子具有一个或更多个疏水性部分的聚烷氧基化表面活性剂，硅氧烷共聚多元醇，鲸蜡硬脂醇聚醚-6与硬脂醇的共混物，及其组合等。
气溶胶泡沫或喷雾剂：该产品可以是含有乳化蜡的醇/溶剂基溶液或者包含疏水性组分的离散相和连续水相的乳剂，所述连续水相包含水和任选存在的一种或更多种极性亲水性赋形剂以及溶剂、助溶剂、表面活性剂、乳化剂和其他组分。这些溶剂或乳剂泡沫浓缩物可以包含有助于使该乳剂稳定的水溶性聚合物或水溶胀性聚合物和腐蚀抑制剂，以提高制剂与包装之间的相容性。可以向包装中的溶剂或乳剂泡沫浓缩物中添加烃、氢氯氟烃(HCFC)或氯氟烃(CFC)气溶胶推进剂，所述包装被设计成保持压力，直至泡沫产品或喷雾产品被分配用于施加。
溶剂
根据本发明的组合物可以包含一种或更多种溶剂或助溶剂，所述溶剂或助溶剂改变皮肤渗透性或者制剂中含有的其他赋形剂的活性。溶剂包括但不限于乙醇、苯甲醇、丁醇、癸二酸二乙酯、二甘醇单乙醚、己二酸二异丙酯、二甲亚砜、乙酸乙酯、异丙醇、异硬脂酸异丙酯、肉豆蔻酸异丙酯、油醇、聚乙二醇、甘油、丙二醇和SD醇。
保湿剂
根据本发明的组合物可以包含附加的保湿剂以增加水合作用的水平。保湿剂可以是包含润湿剂的亲水性材料，或者可以是包含润肤剂的疏水性材料。适合的保湿剂包括但不限于：1，2，6-己三醇、2-乙基-1，6-己二醇、丁二醇、甘油、聚乙二醇200-8000、硬脂酸丁酯、鲸蜡硬脂醇、鲸蜡醇、鲸蜡酯蜡、棕榈酸鲸蜡酯、可可脂、椰子油、环甲硅油、二甲聚硅氧烷、二十二烷醇、羟基硬脂酸乙基己酯、脂肪酸、异硬脂酸甘油酯、月桂酸甘油酯、单硬脂酸甘油酯、油酸甘油酯、棕榈酸甘油酯、二硬脂酸乙二醇酯、硬脂酸乙二醇酯、异硬脂酸、异硬脂醇、羊毛脂、矿物油、柠檬烯、中链甘油三酯、薄荷醇、肉豆蔻醇、辛基十二烷醇、油酸、油醇、油酸油醇酯、橄榄油、石蜡、花生油、矿脂、Plastibase-50W和硬脂醇。
聚合物和增稠剂
对于某些应用，可能期望所配制的产品是用可溶性、可溶胀性或不溶性有机聚合物增稠剂(如天然聚合物和合成聚合物)或无机增稠剂(如丙烯酸酯共聚物、卡波姆1382、卡波姆共聚物B型、卡波姆均聚物A型、卡波姆均聚物B型、卡波姆均聚物C型、丙烯酰胺/丙烯酰基二甲基牛磺酸钠共聚物、羧基乙烯基共聚物、羧甲基纤维素、羧聚乙烯(carboxypolymethylene)、角叉菜胶、瓜尔胶、羟乙基纤维素、羟丙基纤维素、微晶蜡和甲基纤维素)增稠的。
附加组分
根据本发明的组合物可以与化妆品和药物局部用产品中常规存在的附加组分(如填充剂、载体和赋形剂)配制。可以向组合物中添加附加组分，所述附加组分包括但不限于消泡剂、防腐剂(例如，对羟基苯甲酸酯、苯甲醇、苯汞盐、氯甲酚)、抗氧化剂、螯合剂、稳定剂、缓冲剂、pH调节剂(优选造成酸性pH的药剂，包括但不限于葡萄糖酸内酯(gluconolatone)、柠檬酸、乳酸和α羟基酸)、皮肤渗透增强剂、皮肤保护剂(包括但不限于矿脂、石蜡、二甲聚硅氧烷、单异硬脂酸甘油酯、异硬脂酸异丙酯、异硬脂酸异硬脂酯、鲸蜡醇、鲸蜡基磷酸钾、鲸蜡基山嵛酸酯和山嵛酸)、络合剂(chelating agent)、成膜剂、染料、颜料、稀释剂、填充剂、香料、气溶胶产生剂、以及用于提高稳定性或美观性的其他赋形剂。虽然已知醇刺激皮肤并且从皮肤中提取水和脂质，但考虑到表皮屏障功能的改善，可以在含有高克拉夫特温度表面活性剂的制剂中包含醇。可以包含醇，以提高溶解度并且增加活性药剂的吸收。
根据所治疗的病症，根据本发明的组合物可以与或者不与药物活性剂配制。附加的活性剂包括但不限于蒽林(地蒽酚)、硫唑嘌呤、他克莫司、他匹那洛夫(Tapinarof)、煤焦油、甲氨蝶呤、甲氧沙林、乳酸铵、5-氟尿嘧啶、丙硫氧嘧啶、6-硫鸟嘌呤、柳氮磺胺吡啶、吗替麦考酚酯、富马酸酯、皮质类固醇(例如，阿氯米松(Aclometasone)、安西奈德、倍他米松、氯倍他索、氯可酮(Clocotolone)、莫米松、曲安西龙、氟轻松、醋酸氟轻松、氟氢缩松、二氟拉松、地奈德、去羟米松、地塞米松、哈西奈德、卤倍他索、氢化可的松、甲泼尼龙、泼尼卡酯(prednicarbate)、强的松)、促肾上腺皮质激素、维生素D类似物(例如，卡泊三烯(calcipotriene)、骨化三醇)、阿维A、他扎罗汀、环孢菌素、间苯二酚、秋水仙碱、阿达木单抗、优特克单抗(Ustekinumab)、英夫利昔单抗、磷酸二酯酶-4抑制剂(PDE-4抑制剂)(如罗氟司特(roflumilast))和抗生素(例如，红霉素、环丙沙星、甲硝唑)。
施用和剂量
可以通过任何适合的施用途径施用根据本发明的组合物，所述施用途径包括但不限于皮肤(局部)、经皮和粘膜(例如，舌下、颊、鼻)。在优选实施方案中，所述组合物是局部施用的。
适合的药物剂型包括但不限于乳剂、乳膏剂、洗剂、泡沫剂、微乳剂和纳米乳剂。
所述组合物可以每天施用一次或更多次，该组合物优选每天施用1-2次。
可以在兽用药品和人用药品中使用所述组合物，以用于治疗所有与表皮屏障功能障碍相关的疾病和病症，如增殖性皮肤病、炎症性皮肤病和变应性皮肤病。此类皮肤病包括但不限于发炎的角化紊乱，如特应性皮炎、银屑病(寻常型)、湿疹、痤疮、单纯性苔藓、晒伤、瘙痒、脂溢性皮炎、达里埃病(Darier disease)、海利-海利病(Hailey-Hailey disease)、肥厚性瘢痕、盘状红斑狼疮和脓皮病。在优选实施方案中，待治疗的皮肤病是特应性皮炎。
提供下列实施例，以使本领域普通技术人员能够制造和使用本发明的方法和组合物。这些实施例并不旨在限制发明人认为的本发明的范围。附加的优势和修改对于本领域技术人员而言将是显而易见的。
实施例1
根据下列配方制备乳膏剂。
制剂1
制剂2
制剂3
制剂4(美国专利号10,195,160-表1中Tapinarof 2b的制剂)
制剂5(爱宁达乳膏剂载体实施例14 EP 0786986的制剂)
实施例2
将0.0012克鲸蜡醇聚醚-10磷酸酯(Moravek，批号671-144-000-A-20190821-JHO)称取至20mL玻璃闪烁瓶中。将10.0113克蒸馏水添加至闪烁瓶中，将瓶盖紧并且放置在水浴中。温度从36.0℃逐渐升高至56.0℃。在52.5℃平衡150分钟之后，鲸蜡醇聚醚-10磷酸酯尚未溶解，并且样品在剧烈摇动时未起泡。表面活性剂保持为沉积在瓶底部的蜡状颗粒。在53.0℃平衡435分钟之后，鲸蜡醇聚醚-10磷酸酯已经溶解，并且样品在摇动时起泡。0.012％鲸蜡醇聚醚-10磷酸酯水溶液的克拉夫特温度被确定为53.0℃。
将0.0019克磷酸二鲸蜡酯(Sigma，二十六烷基磷酸酯，批号STBH2863)称取至20mL玻璃闪烁瓶中。将11.2262克蒸馏水添加至闪烁瓶中，将瓶盖紧并且放置在水浴中。温度从51.0℃逐渐升高至65.0℃。在57℃平衡120分钟之后，磷酸二鲸蜡酯尚未溶解，并且样品在剧烈摇动时未起泡。在58.0℃平衡450分钟之后，磷酸二鲸蜡酯已经溶解，并且样品在摇动时起泡。0.017％磷酸二鲸蜡酯水溶液的克拉夫特温度被确定为58.0℃。
将0.0024克鲸蜡硬脂基硫酸钠(BASF，Lanette E颗粒，批号0021826181)称取至20mL玻璃闪烁瓶中。将17.0763克蒸馏水添加至闪烁瓶中，将瓶盖紧并且放置在水浴中。温度从35.0℃逐渐升高至42.5℃。在40.0℃平衡805分钟之后，鲸蜡硬脂基硫酸钠尚未溶解，并且样品在剧烈摇动时轻微起泡。在42.5℃平衡365分钟之后，鲸蜡硬脂基硫酸钠已经溶解，并且样品在摇动时起泡。0.014％鲸蜡硬脂基硫酸钠水溶液的克拉夫特温度被确定为41.0℃。
实施例3
使用被取皮成500微米目标厚度的切离的人尸体皮肤来确定含有具有一系列克拉夫特温度范围的乳化剂的乳膏制剂提取表皮脂质的能力。从美国组织库中冷冻获得切离的人皮肤，并且储存在-20℃直至使用。将皮肤装载至直径为8mm的垂直型Franz池上，垂直型Franz池具有0.503cm2的提取面积和接受室(receptor chamber)，接受室填充有3.0ml恒温在32℃的含有0.01％硫酸庆大霉素的4％BSA水溶液(接受溶液)。使用外置活塞式移液器(positive displacement pipette)，将5微升剂量的乳膏剂添加至每个Franz池中(每cm2皮肤组织10mg乳膏剂)。扩散池保持在32±1℃的皮肤表面温度。在24小时孵育之后，用Q-tip清洁皮肤表面(湿Q-tip和干Q-tip三个循环)，以去除所施加的测试品的任何表面残留物。然后，用45℃温水洗涤皮肤表面三个循环。然后，从Franz池移除皮肤组织，并且剥离胶带。丢弃前两个胶带条。胶带剥离过程继续进行另外15次。收集15个胶带条，使用液相色谱串联质谱(LC/MS/MS)定量，并且标记为“角质层”。使用解剖刀分离表皮层和真皮层。收集表皮，并且使用含有氯仿/甲醇混合物的浴液从任何剩余的角质层和表皮中提取脂质。收集浴液，蒸发，并且溶解至适当的流动相中以通过HPLC/MS/MS分析定量。
根据文献(参考文献)，人体皮肤中存在12种常见的神经酰胺。N-木蜡酰基-植物鞘氨醇(N-lignoceroyl-phytosphingosine)(神经酰胺NP)和N-(2’-(R)-羟基木蜡酰基)-D-赤-植物鞘氨醇(神经酰胺AP)是人体皮肤中最多量的神经酰胺。除了在本脂质提取研究中定量神经酰胺NP和神经酰胺AP之外，还从本实施例中描述的胶带条和表皮提取浴液中定量N-木蜡酰基-D-赤-鞘氨醇(神经酰胺NS)和N-木蜡酰基-D-赤-鞘氨醇(神经酰胺NDS)。将经过3次温水(45℃)冲洗后从标记为“角质层”和“表皮”的样品中提取的神经酰胺NP、神经酰胺AP、神经酰胺NS和神经酰胺NDS的总纳克相加在一起，并且归一化成一平方厘米的人体皮肤。如图1中所示，用含有高克拉夫特温度磷酸酯盐型表面活性剂的乳膏制剂(来自实施例2的制剂2)处理皮肤未造成神经酰胺提取。在3次温水洗涤之后，经制剂2处理的皮肤中剩余的神经酰胺的量与在温水洗涤前24小时施加5微升水的切离皮肤(惰性对照)中剩余的神经酰胺的量相同。用含有低克拉夫特温度鲸蜡硬脂基硫酸钠表面活性剂的乳膏剂(来自实施例2的制剂5)处理的皮肤在从人皮肤中提取神经酰胺方面最有效。与4％月桂基硫酸钠阳性对照相比，在3次温水洗涤之后，从经制剂5处理的皮肤中提取更大量的神经酰胺。
实施例4
特应性皮炎临床研究使用湿疹面积和严重程度指数(EASI)作为经验证的评分系统，以衡量局部施加的产品的功效。EASI评分对特应性皮炎的两个方面的客观医师评价进行评估：1)疾病程度和2)临床病征。疾病程度的评分是通过分配与受影响的皮肤百分比相关的0至6的数字分数来完成的：0分＝0％的受影响皮肤；1分＝1-9％的皮肤受影响；2分＝10-29％的皮肤受影响；3分＝30-49％的皮肤受影响；4分＝50-69％的皮肤受影响；5分＝70-89％的皮肤受影响；以及6分＝90-100％的皮肤受影响。疾病程度评分与在4个身体部位(头颈部、躯干、上肢和下肢)处各自按照0-3的等级(0＝无，不存在；1＝轻度；2＝中度；3＝重度)对四种临床病征(红斑、硬结/丘疹、表皮脱落和苔藓样变)严重程度的评分相结合。允许一半的评分。每个身体部位将具有在从0至72范围内的评分，然后将通过对这四个评分取平均值(乘数0.2用于头颈部和上肢，而乘数0.3用于躯干和下肢)来获得最终EASI评分。因此，对于临床评估患者的每个时间点，最终EASI评分将在0至72的范围内。报告为“从基线的百分比变化”的EASI评分是临床评估在局部用产品施加的时间过程中特应性皮炎病变的改善或恶化的标准方法。作为示例，在治疗4周时EASI％CFB的1％增加将意味着用该乳膏剂治疗的全部患者平均具有恶化的特应性皮炎。可替代地，在治疗4周时EASI％CFB的55％减小将意味着疾病程度或临床病征的巨大改善，或者通常意味着特应性皮炎病变的疾病程度和临床病征两者的显著改善。
药物产品与载体(不具有活性药物成分的相同乳膏制剂)相比明显更好地治疗特应性皮炎的能力造成FDA药物产品的批准。因此，针对经临床评估用于治疗特应性皮炎的药物产品及其载体对照局部用乳膏产品均发布EASI评分。
将来自实施例2的制剂2每天一次向45个特应性皮炎患者给药达4周。对于用该高克拉夫特温度表面活性剂的共混物(鲸蜡醇聚醚-10磷酸酯为53.0℃，以及磷酸二鲸蜡酯为58.0℃)治疗的AD患者，EASI％CFB降低55.8％，并且仅1个患者抱怨施加部位灼伤。这与
载体制剂形成对照，
载体制剂在对136个AD患者每天两次给药4周之后具有EASI％CFB的1％增加。根据
包装说明书，该乳膏载体制剂含有低克拉夫特温度表面活性剂(41℃)鲸蜡硬脂基硫酸钠，并且有17个患者抱怨施加部位灼伤。
Claims (25)
1.一种用于治疗表皮屏障功能降低的方法，所述方法包括向需要此治疗的患者局部施用包含高克拉夫特温度表面活性剂、保湿剂和水的组合物，其中所述组合物不包含罗氟司特或角质层分离剂。
2.根据权利要求1所述的方法，其中所述高克拉夫特温度表面活性剂的量为0.1-20％w/w。
3.根据权利要求1所述的方法，其中所述组合物选自水包油乳剂、油包水乳剂、微乳剂或纳米乳剂、以及亲水性软膏剂或疏水软膏剂。
4.根据权利要求1所述的方法，其中所述组合物还包含至少一种选自以下组中的附加组分：溶剂、保湿剂、聚合物或增稠剂、消泡剂、防腐剂、抗氧化剂、螯合剂、稳定剂、缓冲剂、pH调节溶液、皮肤渗透增强剂、成膜剂、染料、颜料、气溶胶形成剂和香料。
5.根据权利要求1所述的方法，其中所述组合物具有3.5-9.0的pH。
6.根据权利要求1所述的方法，其中所述组合物包含适用于局部施用的载体。
7.根据权利要求1所述的方法，其中所述组合物还包含活性药物成分。
8.根据权利要求7所述的方法，其中所述活性药剂选自以下组中：蒽林、硫唑嘌呤、他克莫司、煤焦油、甲氨蝶呤、甲氧沙林、乳酸铵、5-氟尿嘧啶、丙硫氧嘧啶、6-硫鸟嘌呤、柳氮磺胺吡啶、吗替麦考酚酯、富马酸酯、皮质类固醇、促肾上腺皮质激素、维生素D类似物、阿维A、他扎罗汀、环孢菌素、间苯二酚、秋水仙碱、阿达木单抗、优特克单抗、英夫利昔单抗、抗生素、磷酸二酯酶-4抑制剂、及其组合。
9.根据权利要求1所述的方法，其中表皮屏障功能降低的所述患者患有湿疹。
10.根据权利要求9所述的方法，其中所述患者患有特应性皮炎、接触性皮炎和/或脂溢性皮炎。
11.一种药物组合物，其包含白矿脂、棕榈酸异丙酯、高克拉夫特温度表面活性剂、二甘醇单乙醚、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯和水，其中所述组合物不包含罗氟司特或角质层分离剂。
12.根据权利要求11所述的药物组合物，其中所述高克拉夫特温度表面活性剂是鲸蜡硬脂醇、磷酸二鲸蜡酯和鲸蜡醇聚醚-10磷酸酯的混合物。
13.根据权利要求12所述的药物组合物，其还包含己二醇。
14.根据权利要求11所述的药物组合物，其中所述高克拉夫特温度表面活性剂是阴离子表面活性剂。
15.根据权利要求11所述的药物组合物，其中所述高克拉夫特温度表面活性剂具有高于48℃的克拉夫特温度。
16.根据权利要求15所述的药物组合物，其中所述高克拉夫特温度表面活性剂具有高于50℃的克拉夫特温度。
17.根据权利要求16所述的药物组合物，其中所述高克拉夫特温度表面活性剂具有高于52℃的克拉夫特温度。
18.根据权利要求11所述的药物组合物，其中所述组合物不含活性药物成分。
19.一种组合物，其包含：
其中所述组合物不含活性药物成分。
20.一种组合物，其包含：
其中所述组合物不含活性药物成分。
21.一种用于降低表皮脂质的提取并增加表皮屏障功能的方法，所述方法包括向需要此治疗的患者局部施用包含高克拉夫特温度表面活性剂、保湿剂和水的制剂。
22.根据权利要求21所述的方法，其中所述高克拉夫特温度表面活性剂是阴离子表面活性剂。
23.根据权利要求21所述的方法，其中所述高克拉夫特温度表面活性剂具有高于48℃的克拉夫特温度。
24.根据权利要求23所述的方法，其中所述高克拉夫特温度表面活性剂具有高于50℃的克拉夫特温度。
25.根据权利要求24所述的方法，其中所述高克拉夫特温度表面活性剂具有高于52℃的克拉夫特温度。
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2021226370A1 (en) | 2021-11-11 |
| AU2021268977A1 (en) | 2022-04-21 |
| MX2022008735A (es) | 2022-09-19 |
| BR112022007459A2 (pt) | 2022-11-29 |
| IL292098A (en) | 2022-06-01 |
| US20220211730A1 (en) | 2022-07-07 |
| CA3153934A1 (en) | 2021-11-11 |
| JP2023502539A (ja) | 2023-01-24 |
| KR20220074935A (ko) | 2022-06-03 |
| US20230134782A1 (en) | 2023-05-04 |
| CA3153934C (en) | 2023-01-31 |
| EP4021456A1 (en) | 2022-07-06 |
| JP7437503B2 (ja) | 2024-02-22 |
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