CN116963717A - 具有抗真菌性能的局部用罗氟司特制剂 - Google Patents
具有抗真菌性能的局部用罗氟司特制剂 Download PDFInfo
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- CN116963717A CN116963717A CN202180092906.9A CN202180092906A CN116963717A CN 116963717 A CN116963717 A CN 116963717A CN 202180092906 A CN202180092906 A CN 202180092906A CN 116963717 A CN116963717 A CN 116963717A
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- Prior art keywords
- malassezia
- roflumilast
- tinea
- fungal
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Abstract
本发明涉及治疗真菌感染的方法,其包括向有此需要的受试者局部施用抗真菌有效量的罗氟司特。优选地,局部施用的罗氟司特用于治疗真菌感染、真菌生长和/或对真菌马拉色菌过敏。患者还可能患有脂溢性皮炎、头皮屑、度普利尤单抗面部发红、花斑癣、花斑糠疹、圆癣、足癣、甲癣、手癣、股癣、体癣、面癣、头癣和/或难辨认癣。局部施用的罗氟司特为一种快速且有效的抗真菌剂,并且代表当前抗真菌治疗的一种可行的替代方案。
Description
技术领域
本发明涉及具有抗真菌性能的PDE4抑制剂用于治疗真菌感染、由真菌感染引起的炎症、或治疗毛发、皮肤或指甲的真菌感染和真菌过度生长的用途。更具体地,本发明涉及使用局部施用的罗氟司特治疗真菌感染的方法。
背景技术
皮肤、指甲和毛发的真菌感染
细菌、病毒和真菌都是健康人类和动物皮肤的微生物区系的一部分。马拉色菌属(Malassezia spp.)是一种微观单细胞真菌属(或酵母),其是皮肤表面天然发现的最常见的真菌之一。马拉色菌属中最常见和最有名的种是糠秕马拉色菌(Malassezia furfur)(“M.furfur”)、球形马拉色菌(Malassezia globosa)、限制马拉色菌(Malasseziarestricta)和厚皮马拉色菌(Malassezia pachydermatis)。
马拉色菌通常生活在真皮表层上,主要生活在皮脂丰富的区域诸如躯干、面部、头皮、耳朵、前额、鼻唇沟、眉间和胡须区域。它是皮肤微生物群的共生生物体,通常以增强身体防御能力并帮助保护免疫系统免受危险病原体的侵害而已知。具体而言,已证明马拉色菌刺激免疫系统产生细胞因子白细胞介素-17等细胞因子,以介导促炎分子的产生,这些促炎分子参与控制这些病原体并防止皮肤上真菌过度生长。然而,如果这种免疫过程被破坏,例如,如果没有释放细胞因子,或者如果产生白细胞介素-17的免疫细胞缺失,则马拉色菌就会生长并感染皮肤。真菌有效地成为皮肤上的过敏原,造成皮肤微生物群的不平衡,并最终触发免疫系统对炎症的过度反应。当马拉色菌在其生命期间通过未知的分子变化从酵母转变为菌丝形式(分支的丝状真菌结构)时,也可能不受控制地增殖并获得致病能力。
虽然真菌共生与疾病表现之间的因果关系仍然不完整,但是致病性马拉色菌业已与多种皮肤病有关,包括脂溢性皮炎、头皮屑、糠秕孢子菌性毛囊炎、特应性皮炎、花斑癣和花斑糠疹,这些皮肤病在临床上通常表现为色素减退或过度色素沉着的斑疹、斑块、鳞状丘疹或菌斑形式的皮肤病损,并伴有不同程度的红斑。对于脂溢性皮炎,除了异常的免疫应答或真菌活性外,人们还认为马拉色菌可能因皮脂产生过多而参与疾病发病机制,这可能触发亲脂性酵母菌过度生长。其他可能触发对马拉色菌的应答的潜在病理机制和潜在疾病因素包括皮肤屏障功能缺陷、激素波动(尤其是影响皮脂产生的那些激素波动)、神经系统因素和外源性因素诸如缺乏阳光和饮食失调。
致病性马拉色菌也已与度普利尤单抗(dupilumab)面部发红(DFR)和炎症有关。度普利尤单抗通过阻断IL-4受体α来抑制IL-4和IL-13并且是首个治疗中重度特应性皮炎的生物治疗方法。度普利尤单抗治疗的已知副作用之一是在开始度普利尤单抗治疗几个月后出现湿疹性面部皮疹。在实践中,已发现DFR影响了大约5-10%的用度普利尤单抗治疗的患者并且持续施用度普利尤单抗会加剧DFR。由于显著地改善了特应性皮炎,患者通常不愿意停止度普利尤单抗治疗。在de Beer等人的JAAD CASE REPORTS Vol 5(10)第888-891页(2019)中,认为马拉色菌过敏是DFR的可能原因,因为糠秕马拉色菌(M.furfur)可能容易穿透受损的皮肤屏障功能(由于特应性皮炎)并局部损害并激活角质形成细胞,从而增强炎症(另请参阅Strong,Colby,Oral and Topical Antifungals Beneficial for DupilumabFacial Redness in Atopic Dermatitis,Dermatology Advisor,Published onlineOct.27,2021;dermatologyadvisor.com/home/topics/dermatitis/oral-and-topical-antifungals-beneficial-for-dupilumab-facial-redness-in-ad/)。度普利尤单抗面部发红已用皮质类固醇和局部钙调神经磷酸酶抑制剂治疗。在最近的一篇皮肤病治疗文章中,发现口服和局部用抗真菌剂对接受度普利尤单抗治疗后出现度普利尤单抗面部发红(DFR)和炎症的特应性皮炎(AD)的患者有效(-Rubiano MF,Casas M,Balaguera-Orjuela V,et al.Dupilumab facial redness:Clinical characteristics andproposed treatment in a cohort.Dermatol Ther.Published online September 21,2021.doi:10.1111/dth.15140)。这些结果提供了致病性马拉色菌与DFR之间更强的联系。
虽然诸如马拉色菌的真菌引起的感染仅限于皮肤和毛发的最外层(浅表真菌病),但其他真菌通过渗透到皮肤、毛发和指甲的角化层并触发宿主的病理改变而引起皮肤真菌病。例如,称为皮肤癣菌的真菌可以寄生在角质细胞层,引起皮肤癣菌病。
皮肤癣菌分为三个属:毛癣菌属(Trichophyton)、小孢子菌属(Microsporum)和表皮癣菌属(Epidermophyton)。毛癣菌属包括红色毛癣菌(T.rubrum)、须癣毛癣菌(T.mentagrophytes)、疣状毛癣菌(T.verrucosum)、紫色毛癣菌(T.violaceum)、许兰毛癣菌(T.schoenleinii)、断发毛癣菌(T.tonsurans)、同心性毛癣菌(T.concentricum)和马毛癣菌(T.equinum)。小孢子菌属包括犬小孢子菌(M.canis)、石膏样小孢子菌(M.gypseum)、奥杜盎小孢子菌(M.audouinii)、库克小孢子菌(M.cookei)、马小孢子菌(M.equinum)、铁锈色小孢子菌(M.ferrugineum)、鸡小孢子菌(M.gallinae)和猪小孢子菌(M.nanum)。表皮癣菌属包括絮状表皮癣菌种(E.floccosum)。最常见的皮肤癣菌是红色毛癣菌(T.rubrum)、断发毛癣菌(T.tonsurans)和须癣毛癣菌(T.mentagrophytes)。由于皮肤癣菌以角蛋白为食,它们通常会感染表皮角质细胞层、指甲和毛囊,引起浅表病变。皮肤癣菌病(真菌性皮肤病)的名称因部位而异。疾病名称及括号内的其相关俗名为:足癣(香港脚)、甲癣或甲真菌病、手癣、股癣(tinea cruris)(股癣(jock itch))、体癣(tinea corporis)(体癣(serpigo))、面癣、头癣(tinea capitis)(头皮癣(scald head))和难辨认癣(tinea incognito)。
由上述真菌和酵母菌引起的真菌感染的具体实例是甲真菌病(主要由皮肤真菌引起,包括毛癣菌属(Trichophyton spp.)、表皮癣菌属(Epidermophyton spp.)和小孢子菌属(Microsporum spp.))。甲真菌病是甲床和甲板的慢性、持续性真菌、酵母菌和/或霉菌感染,导致指甲增厚和变色,有时伴有疼痛和残疾。由于毛囊根部或指甲本身下方的真菌感染,影响指甲或头皮的真菌感染非常难以治疗。由于指甲生长时间长且甲板难以穿透,甲真菌病也特别难以治疗。类似的情况也发生在头皮和毛干被感染的头癣中。因此,在甲真菌病和头癣中,症状的消除非常缓慢,可能需要数个月或长达一年或更长时间。
真菌感染的常规治疗
目前,真菌感染使用局部抗真菌剂、角质层分离剂(可以减少剥落和鳞屑的脱皮剂)和/或口服药物来控制。然而,这些治疗方法经常失败或引起安全问题,这限制了它们的使用。例如,虽然口服药物通常比局部用药更有效,但因为它们作用于全身而不是局部,口服药物的副作用可能严重得多。已知的副作用非常严重,例如包括肝脏和/或心脏毒性、头痛、头晕、极度疲倦、精力不足、流感样症状、呼吸或吞咽困难、癫痫、胃灼热、抑郁、胃部不适和药物不良相互反应。类似地,虽然局部用皮质类固醇是有效的抗炎剂,但已知长期使用中高效力的皮质类固醇会导致灼烧感、刺痛、肿胀、发红、变色和皮肤敏感,并可能触发或恶化其他皮肤病,诸如痤疮、红斑痤疮、口周皮炎、毛细血管扩张(小血管破裂)和皮纹(妊娠纹)。
常见的局部抗真菌治疗剂包括含有环吡酮的药物;包括以下的药物:咪康唑(和/>)、克霉唑/>
布替萘芬(Lotrimin)、特比萘芬/>阿莫罗芬和/>萘替芬/>托萘酯艾氟康唑/>和酮康唑/>其他也可用于清除真菌感染的药物包括对羟基苯甲酸乙酯、氟胞嘧啶、水杨酸、二硫化硒和十一碳烯酸。
环吡酮胺(ciclopirox olamine)(也称为和)是一种用于局部皮肤病的合成抗真菌剂,其对三价金属阳离子具有高亲和力。环吡酮(Ciclopirox)通常作为溶液施用于头皮、指甲以及指甲周围和下方的皮肤。然而,虽然环吡酮可以改善指甲的状况,但它可能无法完全治愈指甲真菌。此外,可能需要6个月或更长时间才能有任何迹象表明受感染的指甲有所改善。此外,环吡酮局部用溶液是易燃的,并且可能有副作用,诸如施用部位发红、刺激、瘙痒、灼烧、起泡、肿胀或施用部位渗出、受影响的指甲或周围区域疼痛、指甲变色或形状改变以及指甲向内生长。
酮康唑霜剂通常用于治疗体癣(癣;导致身体不同部位出现红色鳞状皮疹的真菌性皮肤感染)、股癣、足癣、花斑癣(导致胸部、背部、手臂、腿部或颈部棕色或浅色斑点的真菌感染)以及皮肤酵母菌感染。处方酮康唑洗发剂用于治疗花斑癣。然而,酮康唑可能会引起副作用,诸如发质变化、头皮水泡、皮肤干燥、瘙痒、油性或干性毛发或头皮、刺激、瘙痒或施用部位刺痛、皮疹、荨麻疹、呼吸或吞咽困难,以及施用部位发红、压痛、肿胀、疼痛或发热。
因此,本领域需要改进受真菌感染(包括指甲、毛发和皮肤的真菌感染)影响的患者的治疗选择。具体而言,非常需要高效的杀真菌剂,其a)快速并完全根除指甲、毛发和皮肤的真菌感染,b)减少由于马拉色菌感染引起的面部发红或炎症,治疗马拉色菌感染和/或因治疗中度至重度特应性皮炎而引起的马拉色菌过敏。本发明提供了局部施用的罗氟司特作为当前抗真菌治疗的可行且成功的替代方案。
局部施用的罗氟司特
已知罗氟司特适合治疗炎症性疾病。含有罗氟司特的组合物用于人类医学和兽医学,并且已被提议用于治疗和预防包括但不限于以下的疾病:炎症和过敏原诱导的气道疾病(例如支气管炎、哮喘、COPD);皮肤病(例如增殖性、炎症性和过敏原引起的皮肤病)以及胃肠道区域中的全身性炎症(例如克罗恩病和溃疡性结肠炎)。
罗氟司特及其合成描述于US 5,712,298(“'298专利”)中,该专利通过引用并入本文*(*:除非另有说明,否则通过引用并入本文的参考文献出于所有目的以其整体并入)。人们早已认识到,具有磷酸二酯酶(PDE)抑制性能的药物化合物,诸如罗氟司特,可用于治疗牛皮癣和特应性皮炎('298专利,第11栏第52-61行)和其他慢性炎症和过敏原诱发的皮肤病。为了治疗此类皮肤病,已经描述了用于局部施用的罗氟司特乳液、混悬剂、凝胶或溶液('298专利,第12栏,第37-64行)。
已经发现,局部施用如罗氟司特的强效药物来治疗皮肤病会提供优异的递送、降低的全身暴露并且更方便患者使用。化合物的分子结构最终决定了药物穿过产品所施用组织的上皮的能力。对于皮肤局部施用,制剂组分的选择决定了配方师(formulator)可以实现的最大皮肤渗透。乳膏、洗剂、凝胶、软膏和泡沫只是一些更常见的局部用产品形式,这些产品含有用于施用于皮肤的活性药物成分(API)。
发明内容
根据本发明,已发现局部施用的罗氟司特除了其作为PDE4抑制剂的已知抗炎性能外,还表现出抗真菌性能。这些特性使得局部用罗氟司特成为治疗真菌感染;毛发、皮肤或指甲的真菌过度生长;以及真菌过敏引起的炎症的最佳治疗方法。局部用罗氟司特显著且快速地减少马拉色菌属真菌,并具有较高的脂溢性皮炎治疗成功率,其中第8周的研究者整体评估(Investigator Global Assessment)0.3%罗氟司特的成功率为73.8%,相比之下,溶媒(vehicle)泡沫的成功率为40.9%。快速且成功的治疗结果表明,局部施用的罗氟司特是有效的抗真菌剂,并且为当前抗真菌治疗提供了可行的替代选择。
附图说明
图1示出了用于测试罗氟司特的抗真菌活性的体外微量稀释药敏试验的结果。如图1和表B所示,已证明罗氟司特对马拉色菌具有抗真菌活性。
具体实施方式
罗氟司特是式(I)的化合物
其中R1为二氟甲氧基,R2为环丙基甲氧基,且R3为3,5-二氯吡啶-4-基。
该化合物的化学名称为N-(3,5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺(INN:罗氟司特)。
己二醇(hexylene glycol)(Pharma Grade.USP/NF)为式(II)的2-甲基-2,4-戊二醇
鲸蜡硬脂醇(CAS 67762 30 0)、磷酸二鲸蜡酯(CAS2197 63 9)和鲸蜡醇聚醚-10磷酸酯(ceteth-10phosphate)(CAS 50643-20-4)的乳化剂共混物由Croda以商品名CRODAFOSTM CES制造。使用相同的原材料和工艺制造CRODAFOSTM CES PHARMA,但经过强化的质量控制和释放测试,并使用命名法鲸蜡硬脂醇、磷酸鲸蜡硬脂酯和鲸蜡醇聚醚-10磷酸酯以符合命名药用赋形剂的标准做法。
这种市售可得的乳化剂共混物为一种自乳化蜡,主要为蜡质物质鲸蜡硬脂醇(其为鲸蜡醇(C16H34O)和硬脂醇(C18H38O)的混合物)与10-20%磷酸二鲸蜡酯(磷酸鲸蜡硬脂酯)和10-20%鲸蜡醇聚醚-10磷酸酯(鲸蜡硬脂醇聚醚-10磷酸酯)的组合。自乳化蜡与水共混时形成乳液。当将CRODAFOSTM CES添加到水中时,它会自发形成pH值约为3的乳液。添加氢氧化钠溶液以将pH值提高到所需值。
可用于治疗真菌感染或真菌过度生长的局部用罗氟司特产品制剂包括但不限于气溶胶、泡沫、喷雾、乳液(也可称为乳膏、洗剂或软膏)、凝胶(两相或单相)、液体、软膏、糊剂、洗发剂、混悬剂和系统。这些为含有药物活性成分的剂型的药典分类学(compendiataxonomy)中的二级术语(美国药典<1151>)。在一个优选的实施方案中,局部用罗氟司特产品制剂包含泡沫。更优选地,局部用罗氟司特产品制剂包含ARQ154 Foam。
罗氟司特可以通过本领域已知的方法制备(例如参见'298专利和美国申请序列号14/075,035)。罗氟司特制剂还公开于美国专利号9,884,050、美国申请序列号15/712,900、美国申请序列号16/426,492、美国申请序列号16/426,492、美国申请序列号16/563,435和美国申请序列号16/778,845,其公开内容全部并入本文。
优选地,用于治疗真菌感染的局部用制剂包含含有0.005-2.0%、优选0.3%的罗氟司特的组合物,其可以为以下形式之一:
水包油乳液:该产品可以为这样的制剂,其中将己二醇;磷酸二鲸蜡酯与鲸蜡醇聚醚-10磷酸酯的自乳化蜡共混物;和/或溶剂添加到包含疏水性组分的离散相和连续水相的乳液中,所述连续水相包含水和任选存在的一种或多种极性亲水性赋形剂以及另外的溶剂、共溶剂、盐、表面活性剂、乳化剂和其他组分。这些乳液可包含有助于稳定乳液的水溶性或水溶胀性聚合物。优选地,乳化剂为磷酸二鲸蜡酯与鲸蜡醇聚醚-10磷酸酯的自乳化蜡共混物。
气溶胶泡沫:当水包油乳液产物浓缩物与液体推进剂混合并且推进剂与乳液的内部油相共混时,可以产生该产物。水包油乳液中的乳化剂还充当发泡剂。当快速破裂的泡沫从容器中喷出时会产生泡沫,但泡沫会在相对较短的时间内塌陷。这种类型的泡沫用于将产物浓缩物施用于大面积,而无需手动擦拭或铺展该产物。并且,由于泡沫快速塌陷,活性药物可以更迅速地获得。当使用在有机相和水相中溶解度均有限的乳化剂时,会产生稳定的泡沫。在推进剂/油相和水相之间的界面处,乳化剂或乳化蜡浓缩,以形成称为“薄片”的薄膜。该薄片的具体组成决定了泡沫的结构强度和一般特性。厚而密的层状薄片产生非常结构化的泡沫,该泡沫能够支撑其自身的重量。可以将一种或多种极性亲水性赋形剂以及另外的溶剂、共溶剂、盐、表面活性剂、乳化剂和其他组分添加到乳液产物浓缩物中。这些乳液可包含有助于稳定乳液的水溶性或水溶胀性聚合物。优选地,乳化剂为磷酸二鲸蜡酯与鲸蜡醇聚醚-10磷酸酯的自乳化蜡共混物。
增稠的水性凝胶:这些系统包括已通过如下所述的合适的天然、改性天然或合成增稠剂增稠的水相。或者,增稠的水性凝胶可以使用合适的聚乙氧基化物烷基链表面活性剂或其他非离子、阳离子或阴离子体系来增稠。
增稠的水醇性(hydroalcoholic)凝胶:这些系统包括水和醇的共混物作为极性相,该极性相已通过如下所述的合适的天然、改性天然或合成聚合物增稠。或者,增稠的水醇性凝胶可以使用合适的聚乙氧基化物烷基链表面活性剂或其他非离子、阳离子或阴离子体系来增稠。醇可以为乙醇、异丙醇或其他药学上可接受的醇。
亲水性凝胶:这些为其中连续相包含至少一种除水之外的水溶性或水分散性亲水组分的系统。制剂还可以任选地含有至多60重量%的水。在一些组合物中更高的水平可能是合适的。合适的亲水性组分包括一种或多种二醇,诸如多元醇,诸如甘油、丙二醇、丁二醇、聚乙二醇(PEG);环氧乙烷、环氧丙烷和/或环氧丁烷的无规或嵌段共聚物;每分子具有一个或多个疏水部分的聚烷氧基化表面活性剂;有机硅共聚醇(copolyol);鲸蜡硬脂醇聚醚-6与硬脂醇的共混物;及其组合等。
油包水乳液:组合物可以为这样的制剂,其中将罗氟司特掺入包括疏水性组分的连续相和水相的乳液中,所述水相包括水和任选存在的一种或多种极性亲水性载体以及盐或其他组分。这些乳液可包含油溶性或油溶胀性聚合物以及一种或多种有助于稳定乳液的乳化剂。优选地,乳化剂为磷酸二鲸蜡酯和鲸蜡醇聚醚-10磷酸酯的自乳化蜡共混物。
亲水性或疏水性软膏:用疏水性基质(例如凡士林、增稠或胶凝化的水不溶性油等)来配制组合物,并且任选具有少量水溶性相。亲水性软膏通常含有一种或多种表面活性剂或润湿剂。
溶剂
根据本发明的组合物可包含一种或多种溶剂或共溶剂,以获得所需活性成分在局部用产品中的溶解度水平。溶剂还可以改变皮肤渗透性或制剂中所含其他赋形剂的活性。溶剂包括但不限于丙酮、乙醇、苯甲醇、丁醇、癸二酸二乙酯、二乙二醇单乙醚、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、N-甲基吡咯烷酮、聚乙二醇、甘油、丙二醇和SD醇。当治疗患有炎症的患者时,溶剂优选不为乙醇、异丙醇或变性酒精(denatured alcohol)。
保湿剂
根据本发明的组合物可包含保湿剂以增加水合水平。保湿剂可以为包括湿润剂的亲水材料,或者可以为包括润滑剂的疏水材料。合适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、鲸蜡基酯蜡、棕榈酸鲸蜡酯、可可脂、椰子油、环聚二甲基硅氧烷、聚二甲基硅氧烷、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、油酸油酯、橄榄油、石蜡、花生油、凡士林、Plastibase-50W、白凡士林、棕榈酸异丙酯和硬脂醇。
表面活性剂和乳化剂
根据本发明的组合物任选地可以包含一种或多种表面活性剂,以乳化组合物并帮助润湿活性物或赋形剂的表面。如本文所用,术语“表面活性剂”是指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(具有共价结合的极性和非极性区域二者的分子)。表面活性剂包括但不限于烷基芳基磺酸钠、Amerchol-CAB、月桂基硫酸铵、杏仁油PEG-6酯、Arlacel、苯扎氯铵、Ceteareth-6、Ceteareth-12、Ceteareth-15、Ceteareth-30、鲸蜡硬脂醇/Ceteareth-20、乙基己酸鲸蜡硬脂酯、Ceteth-10、Ceteth-2、Ceteth-20、Ceteth-23、Choleth-24、椰油酰胺醚硫酸盐、椰油胺氧化物、椰油甜菜碱、椰油二乙醇酰胺、椰油单乙醇酰胺、椰油辛酸酯/癸酸酯、椰油两性二乙酸二钠、月桂基聚乙二醇醚磺基琥珀酸二钠、月桂基磺基乙酸二钠、月桂基磺基琥珀酸二钠、油酰氨基单乙醇胺磺基琥珀酸二钠、多库酯钠、Laureth-2、Laureth-23、Laureth-4、月桂酸二乙醇酰胺、卵磷脂、甲氧基PEG-16、甲基葡糖醇聚醚-10、甲基葡糖醇聚醚-20、甲基葡萄糖倍半硬脂酸酯、Oleth-2、Oleth-20、PEG 6-32硬脂酸酯、PEG-100硬脂酸酯、PEG-12甘油月桂酸酯、PEG-120甲基葡萄糖二油酸酯、PEG-15椰油胺、PEG-150二硬脂酸酯、PEG-2硬脂酸酯、PEG-20甲基葡萄糖倍半硬脂酸酯、PEG-22甲基醚、PEG-25丙二醇硬脂酸酯、PEG-4二月桂酸酯、PEG-4月桂酸酯、PEG-45/十二烷基二醇共聚物、PEG-5油酸酯、PEG-50硬脂酸酯、PEG-54氢化蓖麻油、PEG-6异硬脂酸酯、PEG-60氢化蓖麻油、PEG-7甲基醚、PEG-75羊毛脂、PEG-8月桂酸酯、PEG-8硬脂酸酯、Pegoxol7硬脂酸酯、季戊四醇椰油酸酯、Poloxamer124、Poloxamer 181、Poloxamer 182、Poloxamer188、Poloxamer 237、Poloxamer407、聚甘油-3油酸酯、聚氧化乙烯醇、聚氧化乙烯脂肪酸酯、聚氧乙烯20鲸蜡硬脂基醚、聚氧乙烯40氢化蓖麻油、聚氧乙烯40硬脂酸酯、聚氧乙烯6和聚氧乙烯32、聚氧乙烯甘油硬脂酸酯、聚氧乙烯硬脂酸酯、聚山梨酯20、聚山梨酯40、聚山梨酯60、聚山梨酯65、聚山梨酯80、PPG-26油酸酯、PROMULGENTM 12、丙二醇二乙酸酯、丙二醇二辛酸酯、丙二醇单硬脂酸酯、二甲苯磺酸钠、脱水山梨醇单油酸酯、脱水山梨醇单棕榈酸酯、脱水山梨醇单硬脂酸酯、Steareth-2、Steareth-20、Steareth-21、Steareth-40、牛脂甘油酯和乳化蜡。优选地,乳化剂为磷酸二鲸蜡酯和鲸蜡醇聚醚-10磷酸酯的自乳化蜡共混物。
聚合物和增稠剂
对于某些应用,可能需要配制用可溶性、可溶胀性或不溶性有机聚合物增稠剂(诸如天然和合成聚合物)或无机增稠剂(诸如丙烯酸酯共聚物、卡波姆1382、B型卡波姆共聚物、A型卡波姆均聚物、B型卡波姆均聚物、C型卡波姆均聚物、羧基乙烯基共聚物、羧甲基纤维素、羧基聚亚甲基、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)增稠的产品。
其他组分
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其他组分诸如填充剂、载体和赋形剂一起配制。在一个优选的实施方案中,填充剂、载体和赋形剂适合于局部施用。可以将包括但不限于以下的其他组分添加到组合物中以提高稳定性或美观性:消泡剂、防腐剂(例如对羟基苯甲酸酯、苯甲醇、苯基汞盐、氯甲酚、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯)、抗氧化剂、螯合剂、稳定剂、缓冲剂、pH调节溶液、皮肤渗透促进剂、成膜剂、染料、颜料、稀释剂、膨胀剂、香料和其他赋形剂。
取决于所治疗的其他病症,可将根据本发明的组合物与其他活性剂一起配制。其他活性剂包括但不限于NSAID(例如阿司匹林、布洛芬、酮洛芬、萘普生)、阿普司特、JAK抑制剂(例如托法替尼、鲁索替尼、奥拉西特)、白三烯抑制剂(例如齐留通、扎鲁司特、孟鲁司特)、肥大细胞稳定剂(例如奈多罗米、色甘酸钠、酮替芬、吡嘧司特)、蒽林(地蒽酚)、硫唑嘌呤、他克莫司、吡美莫司、煤焦油、甲氨蝶呤、甲氧沙林、水杨酸、乳酸铵、尿素、羟基脲、5-氟尿嘧啶、丙硫尿嘧啶、6-硫鸟嘌呤、柳氮磺吡啶、替麦考酚酯、富马酸酯、皮质类固醇(例如阿氯米松、安西奈德、倍他米松、氯倍他索、氯可龙、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、甲基强的松奥龙、泼尼卡酯、泼尼松)、促肾上腺皮质激素、维生素D类似物(例如卡泊三烯、骨化三醇)、阿维A、他扎罗汀、环孢菌素、间苯二酚、苯烯莫德、秋水仙碱、支气管扩张剂(例如β-激动剂、抗胆碱能药、茶碱)和抗生素(例如红霉素、环丙沙星、甲硝唑)。
根据所治疗的具体真菌感染,根据本发明的组合物可以与其他抗真菌剂一起配制。其他抗真菌药物包括但不限于含有以下的药物:咪康唑(Daktarin、Micatin和Monistat)、环吡酮胺(Batrafen、Loprox、Penlac和Stieprox)、克霉唑(Canesten、Hydrozole)、布替萘芬(Lotrimin Ultra、Mentax)、特比萘芬(Lamisil、Terbisil、Zabel)、阿莫罗芬(Curanail、Loceryl、Locetar和Odenil)、萘替芬(Naftin)、托萘酯(Tinactin)、酮康唑(Nizoral)、灰黄霉素、咪唑类(联苯苄唑、氯咪唑、益康唑、芬替康唑、异康唑、咪康唑、奥昔康唑、舍他康唑、硫康唑、噻康唑)、三唑(氟康唑、伊曲康唑、泊沙康唑(Noxafil)、伏立康唑(Vfend))、苯并咪唑(噻苯达唑)、对羟基苯甲酸乙酯、氟胞嘧啶、水杨酸、二硫化硒和十一碳烯酸。或者,其他抗真菌剂可以作为单独的组合物施用。
根据本发明的组合物可以与常见的局部用抗炎剂一起配制,所述局部用抗炎剂包括但不限于戊酸二氟可龙、氟轻松、氟氢缩松、丙酸卤倍他索、安西奈德、地索米松、二氟拉松、哈西奈德、戊酸倍他米松、二醋酸二氟拉松、丙酸氟替卡松、糠酸莫米松、曲安奈德、新戊酸氯可龙、醋酸氟轻松、丙酸氟替卡松、戊酸氢化可的松、糠酸莫米松、地奈德、丁酸氢化可的松、丁酸丙酸氢化可的松、戊酸氢化可的松、泼尼卡酯、二丙酸倍他米松增强的丙酸氯倍他索、二丙酸阿氯米松、氢化可的松(碱,≥2%)、氢化可的松(碱,<2%)、钙调神经磷酸酶抑制剂和醋酸氢化可的松。或者,抗炎剂可以作为单独的组合物施用。
施用和剂量
根据本发明的组合物可以通过任何合适的施用途径施用,包括但不限于口服、直肠、肠胃外(例如皮内、皮下、肌内、静脉内、髓内、动脉内、鞘内、硬膜外)、眼部、吸入、雾化、皮肤(局部)、透皮和粘膜(例如舌下、颊、鼻)。在一个优选的实施方案中,组合物为局部施用的。
合适的药物剂型包括但不限于乳液、混悬剂、喷雾、油剂、软膏剂、脂肪软膏剂、乳膏剂、糊剂、凝胶剂、泡沫透皮贴剂和溶液剂(例如注射剂、口服剂)。
组合物的每剂量单元优选含有0.005-2%w/w、更优选0.05-1%w/w、最优选0.1-0.5%w/w的量的罗氟司特、罗氟司特的盐、罗氟司特的N-氧化物或其盐。
组合物优选含有其量为0.1%至20%w/w、更优选0.25%至8%w/w、最优选0.5%至2%w/w的己二醇。
组合物在制剂中优选含有磷酸酯表面活性剂,其量足以产生具有均匀小球尺寸的稳定乳液。磷酸酯表面活性剂的浓度通常可以为1.0%至25%w/w之间的任何浓度。对于不同的施用形式,优选的浓度可以不同。在一个优选的实施方案中,当制剂为乳膏剂或软膏剂时,磷酸酯表面活性剂的浓度为2.5%至20%,更优选浓度范围为5%至15%,最优选浓度为约10%w/w。当制剂为泡沫形式时,浓度优选为1.0%-10%,更优选为1.0%-10%,且最优选为2%。优选地,磷酸酯表面活性剂以磷酸二鲸蜡酯和鲸蜡醇聚醚-10磷酸酯的自乳化蜡共混物的形式提供。
组合物优选含有足以在制剂中获得所需活性成分溶解度水平的量的溶剂。溶剂的量优选为10-30%(w/w)。溶剂与水的比率优选为1:10至20:1。优选地,溶剂为二甘醇单乙醚(DEGEE)。
将含有罗氟司特的局部用制剂以足以获得所需药理作用的量施用于皮肤,所述药理作用通常为改善真菌感染的迹象和/或症状。所施用的制剂的量可以根据制剂中所含的罗氟司特的量、制剂中罗氟司特的浓度以及制剂的施用频率而变化。一般而言,制剂的施用频率为每周一次至每天若干次,优选每隔一天一次至每天三次,最优选每天一次或两次。
组合物可在兽医和人类医学中用于治疗和预防皮肤、指甲和毛发的真菌感染。优选地,组合物用于治疗马拉色菌属(Malassezia spp.)、毛癣菌属(Trichophyton spp.)、表皮癣菌属(Epidermophyton spp.)和小孢子菌属(Microsporum spp.)真菌的真菌感染或真菌过度生长。马拉色菌属(Malassezia spp.)优选地为糠秕马拉色菌(Malassezia furfur)(“M.furfur”)、球形马拉色菌(Malassezia globosa)、限制马拉色菌(Malasseziarestricta)和/或厚皮马拉色菌(Malassezia pachydermatis)。更优选地,所述组合物用于治疗增殖性和炎性真菌感染,诸如脂溢性皮炎、头皮屑、度普利尤单抗(dupilumab)面部发红、花斑癣(tinea versicolor)、花斑糠疹(pityriasis versicolor)、圆癣和皮肤癣菌病,包括足癣(香港脚)、甲癣或甲真菌病、手癣、股癣(tinea cruris)(股癣(jock itch))、体癣(tinea corporis)(体癣(serpigo))、面癣、头癣(头皮癣)和难辨认癣(tinea incognito)。
含有罗氟司特的局部施用制剂可以通过局部施用的药物制剂制造领域中典型使用的方法来制备。为了制备单相制剂诸如液体,可以将制剂的成分组合并混合,直至获得活性成分的均匀溶液或混悬剂。为了制备多相制剂诸如乳液,例如可以分别将水相和油相的组分合并且混合直至获得均质溶液,然后可以将水溶液和油溶液合并且混合,诸如通过剪切混合以形成制剂。所述一种或多种药物活性物可以用赋形剂或其他活性物质溶解(分子分散)、与赋形剂或其他活性物质络合、或与赋形剂或其他活性物质缔合,或者可以为颗粒状(无定形或结晶)。可以将油相添加到水相中,或者可以将水相添加到油相中。可以在诸如50-90℃的升温下或在20-30℃的室温下,或在室温与升温之间的温度下合并且混合各相。
提供以下实施例以使本领域普通技术人员能够制备和使用本发明的方法和组合物。这些实施例并非旨在限制本发明人所认为的其发明的范围。其他优点和修改对于本领域技术人员来说将是显而易见的。
实施例1
使用ARQ 154泡沫样品制备本发明的制剂,下文称为制剂1,其包含浓度为0.3%w/w的罗氟司特和溶媒(0.2%MP,0.05%PP)。将制剂1局部施用于6.5x105CFU/g的糠秕马拉色菌(M.furfur)真菌。如下表所示,局部施用制剂1后24小时,剩余的糠秕马拉色菌(M.furfur)的量为5.3×103CFU/g,对数减少为2.1。该数据表明局部施用的罗氟司特制剂(制剂1)成功地减少了糠秕马拉色菌(M.furfur)真菌的量。
制剂1:ARQ 154泡沫,0.3%罗氟司特(0.2% MP,0.05% PP),批号:PGW-C01127
实施例2
使用ARQ 154泡沫样品制备比较制剂,在下文中称为比较制剂1,其仅包含溶媒(0.2%MP,0.05%PP)(无罗氟司特)。将比较制剂1局部施用于6.5x105CFU/g的糠秕马拉色菌(M.furfur)真菌。如下表所示,局部施用比较制剂1后24小时,剩余的糠秕马拉色菌(M.furfur)的量为5.6x104CFU/g,对数减少为1.1。该数据表明局部施用的比较制剂1在减少糠秕马拉色菌(M.furfur)真菌的量方面不如罗氟司特制剂(制剂1)那么成功。
比较制剂1:ARQ 154泡沫,溶媒(0.2% MP,0.05% PP),批号:PGT-C01231
实施例3
使用ARQ 154泡沫样品制备比较制剂,下文称为比较制剂2,其仅包含溶媒(不含防腐剂且不含罗氟司特)。将比较制剂2局部施用于6.5x105CFU/g的糠秕马拉色菌(M.furfur)真菌。如下表所示,局部施用比较制剂2后24小时,剩余的糠秕马拉色菌(M.furfur)的量为3.2x104CFU/g,对数减少为1.3。该数据表明局部施用的比较制剂2在减少糠秕马拉色菌(M.furfur)真菌的量方面不如罗氟司特制剂(制剂1)那么成功。
比较制剂2:ARQ 154泡沫,溶媒(不含防腐剂),批号:2020-091-02
因此,实施例1-3说明局部施用的罗氟司特为一种快速且有效的抗真菌剂,并且提供了常规局部用抗真菌制剂的可行替代方案。
实施例4
根据以下配方制备罗氟司特乳膏。
配方A
配方B
实施例5
马拉色菌对罗氟司特的体外敏感性
利用三种念珠菌作为所有测试的内部对照分离株来确定马拉色菌对罗氟司特的体外敏感性。这三种分离株为白色念珠菌(C.albicans)(ATCC(美国典型培养物保藏中心)90028)、克柔念珠菌(C.krusei)(ATCC 6258)和近平滑念珠菌(C.parapsilosis)(ATCC22019)。除了对罗氟司特进行测试之外,所有药敏试验均分别使用酮康唑和氢化可的松作为阳性和阴性对照化合物来进行。所有测定均置于设定为32℃的加湿培养箱中,总共历时7天。每个测定在温育12小时后进行评估,并且在温育后每24小时评估一次,总共历时7天。对未处理对照中每种病原体的目视生长情况以及最小抑制浓度(MIC)值的确定进行了评估。与第0天时的基线相比,真菌负荷减少了3-log10 CFU/mL的浓度被定义为最小杀真菌浓度(MFC),并通过量化第7天微孔板中发现的真菌负荷来确定。
使用Rojas方法(Rojas FD等人,Antifungal susceptibility of Malasseziafurfur,Malassezia sympodialis,and Malassezia globose to azoledrugs andamphotericin B evaluated using a broth microdilution method.2014.MedicalMycology.52:641-646),其中液体肉汤培养基为添加了1.8%的葡萄糖、1%的蛋白胨、0.5%的牛胆汁、0.5%的麦芽提取物、1%的甘油、0.5%的吐温40和0.05%的吐温80的RPMI1640。使用圆底96孔微孔板。在无菌盐水中制备接种物,并在补充的RPMI中稀释至最终目标浓度0.5x105至2.5x105CFU/mL。酮康唑阳性对照和氢化可的松阴性对照的数据如表A所示。为了验证改良的液体肉汤培养基没有显著改变该内部对照分离株的酮康唑敏感性,可以将临床实验室标准协会(Clinical Laboratory Standards Institute,CLSI)公开的预期值与表A中的值进行比较。内部对照分离株克柔念珠菌(C.krusei)(ATCC 6258)的CLSI预期值为0.12–1(在24小时时)和0.25–1(在48小时时)。如表A所示,酮康唑对克柔念珠菌(C.krusei)(ATCC 6258)分离株的效果略低于根据CLSI指南预期的效果。对于内部对照分离株近平滑念珠菌(C.parapsilosis)(ATCC 22019),酮康唑的预期CLSI值为0.03–0.25(在24小时时)和0.06–0.5(在48小时时)的确与0.5的2天值(表A)一致。阴性对照氢化可的松没有表现出抗真菌活性。
体外微量稀释药敏测定
表A.使用Rojas方法测试酮康唑阳性对照和氢化可的松阴性对照的体外微量稀释药敏测定的结果。
如表B所示,与氢化可的松阴性对照相比,罗氟司特提供可对马拉色菌的抗真菌活性。第2天,罗氟司特的MIC值在32至128mg/L之间。使用Rojas方法未证明罗氟司特对被测试的念珠菌具有抗真菌活性。
表B.使用Rojas方法测试罗氟司特的体外微量稀释药敏测定的结果。
实施例6.
确定马拉色菌的水平
脂溢性皮炎为一种常见的慢性炎症性皮肤病,其特征为红斑、鳞状斑块,通常具有淡黄色、油性、潮湿和/或油腻的外观,影响皮脂腺丰富的区域。经常受累的部位包括头皮(包括耳后区域)、眉毛、耳朵、鼻唇沟、眼睑、躯干和褶皱区域。
以0.3%的泡沫制剂形式向10名患有脂溢性皮炎的受试者施用局部用罗氟司特,每日一次,持续两周。使用四根皮肤拭子从每个参与者的两个采集点获取样品。在两个时间点从治疗区域采集两根皮肤拭子,从未治疗区域采集两根皮肤拭子。第一个时间点为治疗第一天以建立基线,第二个时间点为15天后。通过擦拭(Zymo R1109 DNA/RNACollectionTube w/Swab)2cm x 2cm或3cm x 3cm的皮肤表面区域2-4分钟来收集样品,每个采集点2根拭子(将2根拭子放在一起),同时旋转拭子。对于未经处理的部位,从肩部/后三角肌区域采集样品。对于治疗区域,如果存在脂溢性皮炎(SD),则从面部的鼻翼褶皱区采集样品。如果该区域不存在SD,则从体内最能代表SD疾病过程的区域采集样品。样品在运至Microbac实验室之前现场储存于-80℃并用干冰运输。样品在处理前储存在-80℃下的MicrobacLaboratories。
适合qPCR的糠秕马拉色菌(Malassezia furfur)、球形马拉色菌(Malasseziaglobosa)、限制马拉色菌(Malassezia restricta)和/或马拉色菌属(Malassezia spp.)的引物/探针在2017年公开于Current Microbiology第74卷第671-677页的经同行评审的文章“Real-Time PCR Identification of Six Malassezia Species”上确定。通过从美国典型培养物保藏中心(ATCC)采购糠秕马拉色菌(Malassezia furfur)、球形马拉色菌(Malassezia globosa)、限制马拉色菌(Malassezia restricta)细胞,以及从IntegratedDNATechnologies(IDT)采购合成DNA来确立对照物。
初步测试和验证通过以下方式完成:
a.使用每个靶标的已知浓度生成应答曲线。
b.应答曲线还用于确定测定的检测限(Limit of Detection,LOD)和定量限(Limit of Quantitation,LOQ)。
使用Microbac内部标准操作程序进行qPCR分析。使用Qiagen DNEasy试剂盒(经修改)完成DNA提取,然后对来自受试者的每个拭子所提取的DNA针对每个靶标进行qPCR单一分析。在初始分析期间,对基因拷贝(gene copy,gc)数和循环阈值(Cycle threshold,Ct)值进行分析。结果表明,在经过处理的基线和经过处理的第15天样品之间出现数量级下降,而未经处理的基线和第15天的样品大致相当。发现对于治疗部位具有统计学意义。当使用适用于糠秕马拉色菌(Malassezia furfur)、球形马拉色菌(Malassezia globosa)、限制马拉色菌(Malassezia restricta)和整个马拉色菌属(Malassezia spp.)的qPCR探针时,十名受试者中的七名在被治疗区域中的马拉色菌基因计数(糠秕马拉色菌(Malasseziafurfur)、球形马拉色菌(Malassezia globosa)和/或限制马拉色菌(Malasseziarestricta))随时间推移出现了数量级下降。九名受试者在未治疗区域中的马拉色菌基因计数没有变化,而一名参与者的基因计数有所减少。
Claims (25)
1.治疗有此需要的受试者的真菌感染的方法,其包括向所述受试者施用治疗有效量的罗氟司特或其药学上可接受的盐,其中所述真菌感染由马拉色菌属(Malassezia spp.)引起。
2.根据权利要求1所述的方法,其中所述罗氟司特是局部施用的。
3.根据权利要求1所述的方法,其中所述马拉色菌属选自糠秕马拉色菌(M.furfur)、限制马拉色菌(M.restricta)和球形马拉色菌(M.globosa)。
4.根据权利要求3所述的方法,其中所述马拉色菌属为糠秕马拉色菌(M.furfur)。
5.根据权利要求1所述的方法,其中所述真菌感染包括毛发、皮肤或指甲的真菌过度生长。
6.根据权利要求1所述的方法,其中所述受试者患有脂溢性皮炎、头皮屑、度普利尤单抗面部发红、花斑癣、花斑糠疹、圆癣、足癣、甲癣、手癣、股癣、体癣、面癣、头癣或难辨认癣。
7.根据权利要求6所述的方法,其中所述受试者患有脂溢性皮炎。
8.根据权利要求1所述的方法,其中所述组合物包含适合于局部施用的载体。
9.根据权利要求1所述的方法,其中所述组合物选自气溶胶、泡沫、喷雾、乳液、凝胶、液体、软膏、糊剂、洗发剂、混悬液和系统。
10.根据权利要求9所述的方法,其中所述组合物为泡沫。
11.根据权利要求1所述的方法,其中所述组合物包含0.3%w/w的罗氟司特。
12.根据权利要求1所述的方法,其中所述组合物包含罗氟司特、白凡士林、棕榈酸异丙酯、鲸蜡硬脂醇、磷酸二鲸蜡酯、鲸蜡醇聚醚-10磷酸酯、己二醇、二甘醇单乙醚、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯和水。
13.根据权利要求1所述的方法,其中所述组合物由以下物质组成:
0.3%w/w的罗氟司特,
10.0%w/w的白凡士林,
5.0%w/w的棕榈酸异丙酯,
10.0%w/w的鲸蜡硬脂醇、磷酸二鲸蜡酯和鲸蜡醇聚醚-10磷酸酯的共混物,
2.0%w/w的己二醇,
25.0%w/w的二甘醇单乙醚,
0.2%w/w的对羟基苯甲酸甲酯,
0.05%w/w的对羟基苯甲酸丙酯,和
适量加至100(47.45%)的净化水。
14.根据权利要求1所述的方法,其还包括施用其他抗真菌剂和/或抗炎剂。
15.根据权利要求14所述的方法,其中所述其他抗真菌剂选自包括以下的药物:咪康唑、环吡酮胺、克霉唑、布替萘芬、特比萘芬、阿莫罗芬、萘替芬、托萘酯、酮康唑、艾氟康唑、灰黄霉素、咪唑类、三唑、伏立康唑、苯并咪唑、对羟基苯甲酸乙酯、氟胞嘧啶、水杨酸、二硫化硒和十一碳烯酸。
16.根据权利要求14所述的方法,其中所述其他抗炎剂为皮质类固醇或钙调神经磷酸酶抑制剂。
17.减少由于马拉色菌感染引起的面部发红或炎症、治疗马拉色菌感染和/或马拉色菌过敏的方法,其包括向需要这种治疗的患者局部施用有效量的罗氟司特。
18.根据权利要求17所述的方法,其中所述马拉色菌过敏是由于用度普利尤单抗治疗引起的。
19.根据权利要求17所述的方法,其中所述罗氟司特以不含乙醇、异丙醇或变性酒精的组合物施用。
20.根据权利要求19所述的方法,其中所述组合物包含罗氟司特、白凡士林、棕榈酸异丙酯、鲸蜡硬脂醇、磷酸二鲸蜡酯、鲸蜡醇聚醚-10磷酸酯、己二醇、二甘醇单乙醚、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯和水。
21.根据权利要求17所述的方法,其中所述马拉色菌过敏是由糠秕马拉色菌(M.furfur)、限制马拉色菌(M.restricta)和/或球形马拉色菌(M.globosa)引起的。
22.根据权利要求17所述的方法,其还包括施用抗炎剂。
23.治疗有此需要的受试者的真菌感染、真菌过度生长和/或对马拉色菌属过敏的方法,其包括向所述受试者局部施用治疗有效量的罗氟司特或其药学上可接受的盐,其中所述真菌感染或过度生长是由马拉色菌属引起的。
24.减轻由治疗中度至重度特应性皮炎引起的面部发红和炎症的方法,其包括向需要这种治疗的受试者局部施用治疗有效量的罗氟司特或其药学上可接受的盐,其中所述面部发红和炎症是由马拉色菌属感染引起的。
25.根据权利要求24所述的方法,其中所述马拉色菌属感染曾经或目前正在用度普利尤单抗治疗。
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