CN111787918A - 用于皮肤病学病况增强治疗的局部和全身性治疗的组合 - Google Patents
用于皮肤病学病况增强治疗的局部和全身性治疗的组合 Download PDFInfo
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Abstract
本文公开对炎性皮肤病比如牛皮癣和特应性皮炎(湿疹)的治疗,其使用局部给予卤化呫吨比如玫瑰红以及给予一种或多种互补靶向的全身性皮肤病学治疗,优选的治疗应对炎性途径并且不是为COX‑1和/或COX‑2抑制剂的NSAID。互补靶向的全身性治疗的成分的实例包括:皮质类固醇,包括倍他米松二丙酸盐和醋酸氟轻松;地蒽酚;维生素D类似物,包括卡泊三醇;和类视黄醇,非生物制剂包括甲氨蝶呤、环孢素、羟基脲,和富马酸盐包括二富马酸甲酯;以及一种或多种生物制剂,包括对TNF‑α的抗体或含互补位的抗体部分,对促炎性细胞因子白细胞介素‑12、白细胞介素‑23和白细胞介素‑17的抗体,和TNF抑制剂。本文还公开对其它上皮组织比如消化道内壁的治疗。
Description
与有关申请的交叉引用
本申请要求于2017年11月29日提交的US临时申请号62/592,086的优先权,其公开内容通过援引并入本文。
发明领域
本发明涉及的领域是皮肤病学和因此改善的治疗方案。
发明背景
用于治疗过增殖或炎性皮肤病学病况的药理学途径传统地依赖使用各种单试剂全身性治疗、单试剂局部治疗(单药治疗)或其它局部给予模式比如光疗法,它们全部轮换使用以避免毒性或间歇使用以降低炎症和应对常常散发出现的症状。这些疾病是慢性、终身性的并且难以治理。
基础病因是难以预测和应对的,并且向在广泛症状表现之前的干预提出挑战。在这些疾病的治理当中,常常必需监测患者中的药物副作用,如牛皮癣中使用环胞素和甲氨蝶呤的情况(McClure et al.,2001Drug Safety 25:913-927)或者用依次或间断途径轮换药物以避免毒性或增加顺从。
在牛皮癣和特应性皮炎两者当中,T-细胞均驱动患者的疾病。典型治疗靶向基础炎症或皮肤细胞增殖或降低活动过度的免疫细胞功能。局部类固醇是最常见处方的对过增殖皮肤障碍的治疗;然而,长期使用局部皮质类固醇霜剂可以导致皮肤变薄,萎缩纹并且带来全身性作用。局部神经钙蛋白抑制剂已牵涉于恶性的罕见情况中。
所谓的PUVA治疗牵涉使用补骨脂素并且暴露于给予皮肤的UVA光(长波紫外光)。该治疗具有的缺点是增加皮肤老化和皮肤癌易感性以及患者在医师办公室参加多期光治疗的不便。
局部和口服的磷酸二酯酶-4抑制剂也已用来在这些病况中靶向免疫细胞。甲氨蝶呤、环胞素、富马酸酯、阿维A、阿来西普是应对这些疾病的小分子途径,全部都具有不同水平的副作用和效力。
更新的生物学试剂如阿达木单抗、古塞库单抗(guselkumab)、依法珠单抗、依那西普、英利昔单抗、阿巴西普、戈利木单抗和乌司奴单抗(ustekinumab)昂贵且具有不同组合的副作用,尤其是潜在的结核再激活、增加感染风险、恶化脱髓鞘病况、肝毒性和心血管并发症。
一部分患者在单试剂治疗之后并不改善,所述治疗针对的是炎性途径比如TNF-α抑制(例如古塞库单抗,英利昔单抗,阿达木单抗,培舍珠单抗和戈利木单抗),IL-17A抑制(司库奴单抗(secukinumab)和伊卡组单抗),IL-6抑制(sarilumab)和用最新生物学试剂(古塞库单抗)的IL-23的α-亚单位p19的抑制和IL-12/IL-23抑制。使用目前批准用于牛皮癣、湿疹或光化性角化病的其它局部或全身性药物发生这类"混合"应答结果,这强调了需要个人化治疗和能够具备单独药物的预测性的应答生物标记物。
在上述引用的活性剂中,依法珠单抗和阿来西普已停用。
更多的皮肤病况可以不完全应答这种单一疗法,原因是由于全身性毒性而需要较低剂量或绕开单一疗法试剂活性的抗性发展。额外地,过增殖皮肤障碍的表现和基因驱动因素存在人种差异,并且例如特应性皮炎(AD)发病机理的年龄差异取决于儿童期或成人期中的表现。这由于缺少儿童AD临床研究而进一步复杂化,因为儿童的常见处方是最初批准用于成人的药物,而成人的基础疾病可能是被其它炎性标记物所驱动的。因为这些问题,存在改善效力和安全性的可观空间。
将局部试剂的组合用于湿疹显示一些前景(Kim et al.,DermatolTher.2016Mar-Apr;29(2):120-125),并且组合常常用于牛皮癣(Feldman et al.,AmHealth Drug Benefits 2016Dec 9(9):504-513);然而,这些组合中有许多并未实现令人满意的应答。
口服益生菌、益生元和合生元甚至已用于牛皮癣和湿疹两者当中并且引起一些皮肤症状改善(Notay et al.,Am J Clin Dermatol.201718(6):721-732)。
局部应对牛皮癣下皮肤的免疫细胞功能障碍而无全身性免疫抑制的治疗策略是在治疗剂开发中高度需要的(Lowes et al.,Annu Rev Immunol 2014 32:227-255)。目前使用的一种方法是光动力疗法(PDT),包括UVB第一线疗法(Wu et al.,Chem Commun 201854:7629-7632)。这些治疗已显示使得牛皮癣组织学正常化,其通过诱导T-细胞和角质形成细胞的细胞凋亡引起髓性炎性树突状细胞和病理细胞因子减少(IL-17,INF-γ和IL-22)[Johnson-Huang et al.,J Invest Derm 2010130(11):2654-2663]。
为了更佳理解牛皮癣中的潜在免疫药物靶标,研究者已比较了病变和非病变皮肤的免疫标记物和牛皮癣病损中的基因过表达,其牵涉mDCs、CD4+T-细胞和INF-γ可诱导基因在病变皮肤中的过表达[Yao et al.,PLos One July 16,2008,3(7):e2737]。在该研究中,比较了病变和非病变皮肤活体检查以阐明疾病的细胞和生物化学标记物。
进一步使得治疗挑战复杂化的是消化道显得能够驱动或触发皮肤病学病况,这可能是应答消化道中的刺激。研究已显示消化道细菌在湿疹发展中发挥作用(D’Mello etal.,Int J Mol Sci.2016Jul;17(7):1144),其可以通过促进TH17应答而在牛皮癣中发挥作用(Zákostelská et al.,PLoS One.2016Jul 19;11(7):e0159539)。
无论原因如何,异常免疫-炎性反应一旦开始就难以用常规治疗使其停止。
局部递送的疾病细胞特异性呫吨类的应用是发明人中一位或多位已描述的新复合途径(例如在US No.8,974,363中),其公开整体并入本文)。该途径最大化局部效力同时最小化患者对所施用试剂的全身性暴露,并且最小化作为结果的全身性不良作用的潜力。
一位或多位发明人已显示某些特定类别试剂(例如某些卤化呫吨类的某些配制剂,诸如0.001%至10%玫瑰红二钠的盐水溶液,称为"PH-10"并且正在临床测试中用于治疗牛皮癣和湿疹)的局部使用能够引起不仅这些病况中标志症状如瘙痒和红斑的减少而且还引起在病况病因的基础基因上的直接修饰,这能够导致障碍的长期减轻。可能的是,用局部PH-10靶向角质形成细胞的不恰当信号转导通知能够影响局部炎症的免疫应答,并且可以充当促进特定疾病应答的辅助角色。额外地,卤化呫吨具有抗微生物剂(例如抗菌,抗真菌和/或抗寄生物)特性(Kim et al.,Nanomaterials(Basel).2016Dec;6(12):243),其能影响疾病的基础驱动因素。
PH-10是局部水凝胶配制剂,其产生玫瑰红二钠向上皮组织的选择性递送[Wachter et al.,Lasers Surg Med 2003 32(2):101-110]。体外研究展示,玫瑰红在存在于生物学系统中时能够在很低浓度或在暴露于有关光波长的情况下被光活化。光活化的玫瑰红产生单线态氧(Neckers,J Photochem Photobiol A 1989 47:1-29;Lee et al.,Photochem Photobiol1987 45(1):79-86)和可以诱导靶标组织中的选择性局部细胞破裂,导致细胞死亡和/或释放细胞因子介导物,其牵涉于在光动力疗法之后的有益免疫应答中(Diezel et.al.,Dermatol Monatsschr 1980;166:793-797;Neuner et al.,PhotochemPhotobiol 1994;59:182-188;Boehncke et al.,Lancet Mar.26,1994 343:801)。
在生物学系统中的持续光照下,玫瑰红可以光漂白为无活性状态(Tongai etal.,J Toxicol Sci 1979;4:115-125;Heitz and Wilson,Mississippi Agriculture andForestry Experiment Station Publication1978;8532:35-48),潜在产生自限性光活化活性。额外地,在光存在下真皮内注射玫瑰红导致多形核白细胞聚集和组胺释放并伴随增加的兔皮肤红斑。该效果可以用共同给予β-胡萝卜素逆转(Ranadive et al.,J Nutr1989119:690-701)。
额外地,玫瑰红产生的自由基已牵涉于氧化氮消耗伴光辐射当中(Singh et al.,Arch Biochem Biophys 1995 324(2):367-373)并且在巨噬细胞中无光辐射(Zamani etal.,J Immunotoxicol 2014 11(4):367-375)。最近的临床研究已在评价皮肤病学病况比如牛皮癣(NCT01247818,NCT00941278)和特应性皮炎(NCT00690807)中的玫瑰红,且不存在活性的光活化。
发明概要
本发明是组合某些局部治疗模式和有效量的一种或多种某些全身性治疗模式所得到的不可预期且出人意料的增效的结果,所述局部治疗模式尤其是使用卤化呫吨试剂的某些局部免疫调节治疗比如指向抗微生物-或角质形成细胞-的治疗,所述卤化呫吨试剂是比如下文称为PH-10的那种。该组合能够增进两种治疗模式的治疗活性,并且与分开使用组分治疗所一般实现的那些相比该组合能够使得发病率无显著增加或甚至总体减少。
递送局部的卤化呫吨类能够导致特应性皮炎和牛皮癣两者中瘙痒症的快速减轻,以及皮肤病在治疗28天之后清除。瘙痒症的这种快速减对患者有益并且伴随有限的卤化呫吨全身性暴露,原因是卤化呫吨类并不通过皮肤和未暴露的周围或全身性组织。该有限的卤化呫吨全身性暴露可以是由于卤化呫吨类的抗微生物活性(也即抗细菌、抗真菌和/或抗寄生物活性)或卤化呫吨类的已知免疫调节活性(US专利号9,107,887)。无论原因如何,某些基因标记物在这样的治疗之后改变,并且作为变化结果的基因标记物指出这些卤化呫吨类令人惊讶地并非通过一般抗炎性基因或以与目前疗法相同的方式起作用,而是作用于导致或促进炎性皮肤病的备择基因。
然而,对于通常使用以及对于疾病广泛散布、严重或以难以用局部试剂完全覆盖的形式存在的情况,使用互补的治疗模式提供增效的益处,特别是在其贡献抗炎活性来补充通过局部施用卤化呫吨类提供的活性的情况下。使用这种互补的治疗能够具有在增效相互作用方面的进一步优势,其允许一种或两种治疗以减少的剂量或以更短持续时间(相对单药治疗单独使用时所需)使用,同时保持高效力,由此降低不希望的不良作用。
尤其是,针对导致皮肤细胞过度增殖的自免疫应答使用有效的局部治疗比如用例如PH-10或又一卤化的含呫吨的组合物局部施用,和与之结合的一种或多种全身性皮肤病学治疗(特别是应对一种或多种炎性途径的那些)是有高度吸引力的,原因是该组合产生独特地有益健康的组合:在靶向抗炎性途径的全身性抗炎性或生物学试剂存在下,将患者的皮肤病暴露于卤化呫吨的抗微生物效果以及角质形成细胞调节性效果。这种组合的效果能够在给予卤化呫吨之前、在给予卤化呫吨时或在局部给予之后提高。
因为局部施用适于重复治疗,优选实施方式是例如通过持续给予全身性免疫调节治疗持续强化基础炎症治疗,同时一次或多次给予局部呫吨。作为备择实施方式,局部给予呫吨能够在开始全身性抗炎治疗之后进行。
将局部皮肤治疗与全身性抗炎治疗方案组合的益处能够使得否则不希望的全身性治疗变得可行。从而,因为联合疗法的全身性组成部分的效能增加而可能的是,减少的全身性剂量给药方案以及相称的全身性治疗不良作用的减少。此外,因为局部治疗(也即局部呫吨)的不良作用特征并不与绝大多数全身性治疗重合,与能够产生不希望的增效不良作用的在先组合相比,组合的局部和全身性皮肤病学治疗本身就更加安全且更有吸引力的。
除了应用于皮肤之外,本发明还可用于其它上皮组织比如消化道内壁或生殖道的疾病。
附图说明
附图构成本说明书的一部分。
图1举例说明活组织检查分析,其通过人类牛皮癣患者小组的基因阵列结果的主成分分析(PCA)进行,所述患者的病变皮肤(LS)应答(应答者)使用PH-10的局部呫吨治疗。过增殖皮肤障碍的基因表达标记物用下述比较:1)在第1天基线的非病变皮肤(基线.NL);2)在第1天的病变牛皮癣皮肤(基线.LS),在施用配制剂媒介物28天之后的病变牛皮癣皮肤(第29天.LS),和在6天不治疗之后用0.005%玫瑰红局部呫吨治疗28天之后的病变牛皮癣皮肤(第64天.LS)。第64天病变皮肤群聚基线非病变皮肤的特征。三位数字是患者标识。测试相当于Kim et al.,J Invest Dermatol 2016 136:2173-2182和Krueger et al.,JAllergy Clin Immunol2015 136(1):116-124中讨论的那些;
图2A和2B直至图7A和7B显示牛皮癣相关的单独基因的mRNA基因标记物身份,如各图近顶端所示(分别是KRT16,CTLA4,IL19,S100A12,S100A7A和IL36A),其表达的mRNA量在第64天在应答者(R;2A)和非应答者(NR;2B)等中归一化;在不同时间点(基线,第29天和第64天)在非病变(NL)和病变(LS)牛皮癣皮肤中按分子应答同期组群(应答者和非应答者)的最小二乘均值mRNA log 2(表达/hARP)水平(qRT-PCR)。星号指出组间的统计学显著差异*p<0.05,**p<0.01,***p<0.001;
图8A和8B直至图11A和11B显示如各图近顶端表示的免疫组织化学标记物(分别是Thickness,Langerin,CD3,CD11)的降低的表达,条件是在用PH-10治疗的患者中在不同时间点(基线、第29天和第64天)在应答者(R;A)和非应答者(NR;B)中在非病变(NL)和病变(LS)牛皮癣皮肤中。星号描述组间的统计学显著差异*p<0.05,**p<0.01,***p<0.001);
图12显示通过RT-PCR评价的表达的mRNA的图,展示从安慰剂给药的最后1天至PH-10给药的最后1天在整个研究群体中病变皮肤中角蛋白-16(KRT16)表达的统计学显著下降,表示为最小二乘均值(LS均值)vs基线NL、基线LS、第29天LS和第64天LS;
图13A和图13B是正常人类皮肤的共焦荧光显微图:局部PH-10(左)vs H&E染色(右)。来自Wachter et al.,Lasers Surg Med 200332:101;
图14是示意图,显示斑块简图和如标记的顺序活组织检查位置,用于评价在单个斑块中连续28天媒介物(第二活组织检查,在第29个研究日)和PH-10(第三活组织检查,在第64日)vs基线(第一活组织检查)的效果;在第一活组织检查中于第-7日/基线同时收集相邻正常皮肤;
图15包含单个靶标斑块的两种放大率的照片:基线(左侧),在施用媒介物之后(中间)和在施用PH-10之后(右侧);
图16A和16B是非病变(NL)和病变(LS)牛皮癣皮肤的免疫组织化学(IHC)染色的显微照片:研究中的应答者(16A)和非应答者(16B)的基线(BL),在施用媒介物之后(D29)和在施用PH-10之后(D64)照片;
图17显示全部可评价患者的非病变(NL)皮肤和病变(LS)牛皮癣皮肤的基因阵列结果的PCA:基线(BL)、第29天和第64天,DEG FCH>2和fdr<0.05,与Kim et al.,J InvestDermatol 2016 136:2173-2182和Krueger et al.,J Allergy Clin Immunol 2015 136(1):116-124中展示的数据类似地分析;
图18A和18B显示数据组中全部基因的PCA微阵列数据。那些数据用来鉴定"分子应答者"的同期组群,患者D64/LS的PC-1值低于非病变(BL/NL)皮肤基线PC-1值的第90百分位。对于这些应答者,LS组织中的基因表达在PH-10治疗之后类似基线NL皮肤。为DEG FCH>2和fdr<0.05显示数据;
图19A和19B是热图(Heatmap)概览,展示在非病变(NL)皮肤和病变(LS)牛皮癣皮肤中按分子应答同期组群的最小二乘均值mRNA log2(表达/hARP)水平(qRT-PCR):应答者(19A)和非应答者(19B)的基线(BL)、第29天(D29)和第64天(D64),与Kim et al.,J InvestDermatol 2016136:2173-2182和Krueger et al.,J Allergy Clin Immunol 2015136(1):116-124中展示的数据类似地分析;
图20A和20B是图,显示非病变(NL)皮肤和病变(LS)牛皮癣皮肤中按分子应答同期组群的ICOS表达:应答者(20A)和非应答者(20B)的基线(BL),第29天(D29)和第64天(D64);和
图21是图,显示在单次局部施用作为DMSO配制剂的14C-玫瑰红之后于24小时的皮肤放射性浓度,所述配制剂施用至250cm2面积的Goettingen小型猪背部皮肤(人皮肤吸收研究的普通模型)。
优选实施方式详述
本发明预期治疗过增殖皮肤障碍即下文讨论和举例说明的表皮中皮肤细胞更新速率增加的方法,其包括给予治疗有效量的局部用卤化呫吨药物组合物,和与之组合的治疗有效量的全身性抗炎剂。
本发明也特别预期治疗牛皮癣和湿疹的方法,其包括给予治疗有效量的卤化呫吨药物组合物,和与之组合的治疗有效量的全身性免疫系统下调试剂。
下文讨论的14C-标记的玫瑰红的非临床局部施用研究显示,玫瑰红大部分保持在角质层中、在表皮和真皮中存在的量减少。在进行的研究中并无放射性达到血浆。然而,如信使RNA(mRNA)的PCA所测定,在临床试验参与者皮肤中的免疫标记物被下调。
这些结果意味着,局部施用PH-10所影响的是角质形成细胞,而全身性药物抑制来自更深层皮肤和来自其它远端器官的其它基因表达。这指出的是,能够通过使用卤化呫吨局部治疗来治疗角质形成细胞从而不同地治疗皮肤的不同部分并且用全身性药物来治疗其它组织。
通过PH-10局部治疗降低活性的(下调的)基因包括KRT16,CTLA4,IL19,S100A12,S100A7A和IL36A。从图2A、3A、4A、5A、6A和7A结果可见,那些基因的活性降低是至少在基线病变皮肤与第64天(即在4周PH-10治疗之后)的病变皮肤之间统计学显著的。
此外,PH-10施用4周如RT-PCR所评显著(FC>1.5,p<0.05)下调IL-17A、IL-22、IL-26、IL-36和角蛋白mRNAs,而基因阵列结果的PCA分析显示向非病变皮肤的改变,其中某些治疗后活体检查群聚于非病变皮肤特征中。在PH-10施用之后病变皮肤中显著改善的途径包括所公开的牛皮癣转录物组和由IL-17、IL-22和干扰素介导的细胞应答。
在本文称为"应答者"的受试者小组中,包括IL-23、IL-17、IL-22、S100A7、Il-19、IL-36和CXCL1的"牛皮癣相关的"基因被有效地正常化。也即,所治疗的病变皮肤具有上述基因的基因表达值,其位于基线非病变皮肤中存在的那些的相同范围内。这些应答者中的免疫组织化学指出在治疗区域活体检查中降低的髓性(CD11c+)树突状细胞和T-细胞表达。
"应答者"构成可评价受试者的27百分比。据信的是,在"应答者"与"非应答者"之间的差异随其角质形成细胞在PH-10施用时的再生阶段而变化。角质形成细胞在其分化的基底细胞阶段与脱落角质细胞阶段之间平均需要约3个月(约12周)。
本文和图21中提供的数据展示,放射性标记的玫瑰红在局部施用至小型猪皮肤表面时并不透过皮肤进入更底层的组织或血浆中。小型猪频繁地在药物研究中用作人类皮肤模型。Nunoya et al.,J Toxicol Pathol 2007 20:125-132。玫瑰红向角质层和表皮的这种局部递送示于图13A中的人类皮肤。
用除NSAID以外的全身性抗炎剂比如免疫系统下调试剂治疗和与之联合的局部作用的局部卤化呫吨给药的组合靶向基础疾病是特别有吸引力的,原因是其最大化对皮肤的潜在治疗作用,同时减少炎症和过度增殖。导致疾病的可视症状的炎症和过度增殖能够因此通过针对不同炎症因子的两种药物的作用而被降低。
治疗的这些方面是特别重要的,原因是可变的皮肤更新速率和更新基底膜和补充皮肤需要的多至12周的时间。在与进一步针对皮肤病学疾病特异性炎症标记物的全身性治疗组合的情况下,对基础发病机理的效果在局部给予位点和在未经治疗的位点均是增效的,包括接近和远离施用位点的那些。
在组合局部治疗和全身性靶向治疗(比如局部呫吨给药与靶向生物制剂组合)的情况下许多优势积累增长。短语"靶向全身性"和"全身性靶向"在本文中同义。因为局部呫吨给药对炎性皮肤病具有独特的破坏效果,将该模式与经由正交路径靶向炎性通路的途径(比如靶向TNF-α、IL-17、IL-12或IL-23通路或者炎症和过度增殖所牵涉的基因过表达的那些)组合,能够在经治疗的皮肤或消化道中产生增强的效力。
例如,通过在局部呫吨给药的情况下用全身性治疗来降低炎症,用局部治疗处理的故障角质形成细胞能够对免疫系统可见并且减少炎症;由于PH-10治疗,不直接用PH-10或相似卤化呫吨组合物治疗的任何组织的应答也能够被增加至免疫学活化,原因是全身性治疗反击疾病炎症特征的遮掩而不干扰卤化呫吨给药的免疫应答发展。
卤化呫吨组合物给药导致的过度增殖的减少通过降低免疫抑制和发炎组织的生理学要求进一步放大这些优势。因为在该上下文中全身性靶向治疗不需要实现完全控制或根除牛皮癣或湿疹性皮肤而是起到增加局部治疗活性的作用,所以全身性治疗能够以减少的剂量给予,由此最小化潜在的不良作用和使得组合治疗与在先全身性组合相比更安全且更有吸引力。局部治疗组分导致的针对角质形成细胞的应答增加提供反击已阻扰了许多全身性治疗的抗性问题的手段,对抗在全身性试剂失效时更换疗法的重复需求。
在某些情况下能够希望的是,在局部治疗之前开始全身性靶向治疗,例如在疾病负担很高或广泛或在疾病快速增殖可能使得有效给药局部治疗困难或更低效的情况下。以该方式,全身性治疗能够用来在给予局部治疗之前控制炎症以便增强疾病对局部治疗的应答性。在保持于全身性治疗控制下的同时用局部治疗比如局部施用的卤化呫吨类治疗残留疾病提供消除残留病变负担同时刺激对在某些情况下复发的长期免疫的手段,由此改善最终结果。
预期的全身性组合治疗的实例包括小分子(分子量约900或更低)和蛋白质活性剂。用于预期的治疗方法的示例性全身性活性剂包括但不限于下述:局部呫吨局部治疗和与之组合的1)一种或多种全身性TNF-α抑制剂,比如阿达木单抗,培舍珠单抗,依那西普,戈利木单抗,古塞库单抗或英利昔单抗;2)一种或多种全身性的IL-17A抑制剂,比如伊卡组单抗,布罗达单抗(brodalumab)或司库奴单抗,或混合型IL-12/IL-23抑制剂,比如乌司奴单抗(ustekinumab)或瑞莎珠单抗(risankizumab);3)一种或多种IL-6抑制剂比如sarilumab;4)一种或多种apremilast,crisaborole和其它磷酸二酯酶-4(PDE4)抑制剂,和特别是能够与局部呫吨治疗比如与施用在皮肤上或直接施用至消化道的卤化呫吨组合的PDE4C抑制剂;5)一种或多种全身性免疫下调试剂,包括甲氨蝶呤,环胞素和硫唑嘌呤,能够经由将过度增殖的驱动因子暴露于局部治疗发挥有益作用。
并不预期的是,用为COX-1和/或COX-2抑制剂的NSAID比如阿司匹林、布洛芬、萘普生、吲哚美辛、美洛昔康、对乙酰氨基酚、塞来考昔等作为全身性抗炎剂与卤化呫吨组合。
一般来说,单一疗法剂量给药计划通过在早期阶段临床试验确定最大耐受剂量(MTD)来设置。MTD(或其类似变化)然后传播至后期阶段临床试验用于评价效力和更详细的安全评价。在完成临床测试之后,这些MTD常常成为确定的治疗剂量。
能够在本发明中与局部表面治疗组合的许多全身性试剂的示范性治疗有效的给药量计划提供于表1中。
表1
示范性全身性免疫调节试剂或靶向抗癌试剂
因为加和效果,在用于局部表面治疗比如下文描述的那些的情况下,本发明的组合治疗和治疗方法一般允许使用靶向全身性试剂,其水平位于或小于计划使用该全身性试剂的典型剂量比如描述于表1的那些。然而,表1提供的治疗有效的剂量给药量计划为开始治疗提供有用指导,治疗有效剂量能够被滴定为护理指定患者的医师认为适当的减少量。
靶向全身性抗炎治疗口服或经肠胃外给予,一般运用可商购组合物比如表1举例说明的那些。表1中未列出的全身性靶向药物产品的治疗有效的剂量给药量能够得自所述产品的标签。
两种药物能够实质上同时地,间隔一个或多个小时、天或周给予。此外,全身性治疗能够作为稳定化方案在局部角质形成细胞作用性卤化呫吨给药的数周或月之前开始。
预期组合物的卤化呫吨组分的递送在组合物具有接近生理学pH的pH值(即大约pH7)和特别是pH大于约4是最有利的,由此确保卤化呫吨在组合物中保持二碱式形式。从而,在优选的实施方式中,组合物的pH值是约4至约10,和更优选约5至约9,和最优选约pH 6至约pH 8。
卤化呫吨优选溶解或分散在亲水媒介物中以使得卤化呫吨组分分配进入皮肤组织的优先程度最大化。相应地,在优选的实施方式中,媒介物含有最小的可能干扰这种分配的非亲水组分。
局部施用组合物的优选配制剂含有在亲水、优选含水媒介物中的:
1)在适当药物组合物中的卤化呫吨比如特别优选的玫瑰红(4,5,6,7-四氯-2’,4',5',7'-四碘荧光素),或又一卤化呫吨,包括赤藓红B,焰红染料B,4,5,6,7-四溴-2’,4',5',7'-四碘荧光素,2’,4,5,6,7-五氯-4',5',7'-三碘荧光素,4,4’,5,6,7-五氯-2',5',7'-三碘荧光素,2’,4,5,6,7,7’-六氯-4’,5’-二碘荧光素,4,4’,5,5’,6,7-六氯-2’,7’-二碘荧光素,2’,4,5,5’,6,7-六氯-4’,7’-二碘荧光素,4,5,6,7-四氯-2’,4’,5’-三碘荧光素,4,5,6,7-四氯-2’,4’,7’-三碘荧光素,4,5,6,7-四溴-2’,4’,5’-三碘荧光素,和4,5,6,7-四溴-2’,4’,7’-三碘荧光素。
优选形式的玫瑰红二钠具有下式:
局部表面组合物的该优选实施方式的一些细节描述于U.S.专利No.5,998,597,No.6,331,286,No.6,493,570和No.8,974,363,其公开通过援引全部并入本文。本发明的该优选实施方式在此描述为与牛皮癣和湿疹特别相关。
然而,本发明还能够用于治疗其它过增殖皮肤或上皮疾病,包括但不限于溃疡性结肠炎,克罗恩病,光化性角化病,寻常痤疮,并且不期望由此限制。示范性适应症还包括治疗:特应性皮炎(湿疹)和牛皮癣,其是慢性、忽重忽轻性-复发性炎性皮肤病;牛皮癣和脓疱性牛皮癣;赖特综合征;皮肤溃疡,包括淤滞性皮炎、淤积性溃疡、缺血性溃疡、镰状细胞腿溃疡、糖尿病性溃疡、炎性溃疡;湿疹性疾病和湿疹性反应;各种鱼鳞病;特应性皮炎;良性和恶性的增殖障碍,比如良性上皮肿瘤和错构瘤;恶化前和恶性上皮肿瘤,包括光化性角化病、基底细胞癌、鳞状细胞癌和角化棘皮瘤;良性和恶性的附件肿瘤;色素产生细胞肿瘤,包括恶性黑色素瘤、日光性雀斑样痣、痣和咖啡牛乳色斑(cafe-au-lait);肉瘤;淋巴瘤;血管障碍;比如血管瘤和葡萄酒色痣;微生物感染,比如细菌、真菌、酵母、寄生物或其它感染;疣;和痤疮。
预期的含卤化呫吨组合物一般含有治疗有效量的卤化呫吨。卤化呫吨的示范性治疗有效量是大约0.0001%至约0.01%重量,和甚至更优选约0.0005%至约0.005%的浓度,和最优选该浓度是大约0.001%至大约0.05%的卤化呫吨。上述预期的含卤化呫吨组合物的剂量施用如下文讨论提供组合物的治疗有效剂量。
2)一种或多种粘度增加剂,总称粘度增加剂(viscosity builder)或仅"增加剂",其水平足以实现在环境室温比如25℃的约10至约1000cps的组合物粘度。粘度增加剂一般选自包括下述的组:纤维素和纤维素衍生物比如淀粉,藻酸盐,和各种羧甲基纤维素及其衍生物,特别是中至高粘度的那些比如USP羧甲纤维素。
其它预期的增加剂包括中和或部分中和的聚(丙烯酸或(甲基)丙烯酸)均聚物和共聚物,比如以名称934P销售的那些,其描述于US专利No.2,798,053,No.2,909,462和No.3,330,729,以及以名称940销售的更高分子量的聚合物。934P据称制备自丙烯酸,其与约0.75至约2重量百分比的多烯丙基聚醚比如据称每分子含平均至少3个烯丙基多烯丙基季戊四醇或多烯丙基蔗糖交联,其中烯丙基通过醚键键合。
增加剂存在的量提供在温度25℃和1个大气压约10至约1000厘泊(cps)的组合物粘度。更优选,粘度增加剂提供约50至约500cps的粘度,和甚至更优选该粘度为约75至约250cps。
3)第三种成分是选自氯化、磷酸和硝酸钠、钾、钙和镁的水溶性电解质,其中该电解质以约0.1至约2%重量的浓度存在,或另选以足够的水平存在从而提供约100mOsm/kg至约600mOsm/kg的质量渗透摩尔浓度。更优选,卤化呫吨组合物的质量渗透摩尔浓度大于250mOsm/kg,和最优选大约300-500mOsm/kg。
电解质优选是氯化钠。电解质优选存在的浓度是约0.5至约1.5%重量,和甚至更优选的浓度是约0.8至约1.2%,和最优选的浓度是大约0.9%,存在于生理学盐水中。
亲水、优选含水的媒介物优选仅是符合局部组合物使用标准的水。媒介物的多至约20百分比体积能够是一种或多种C1-C6单或多羟基醇比如甲醇,乙醇,丙醇,异丙醇,丁醇,仲丁醇,甘油,乙二醇,丙二醇,1,2-丁二醇,2,3-丁二醇,赤藓糖醇,苏糖醇,三羟甲基丙烷,山梨醇等。更优选,醇在预期的组合物中以媒介物的小于约10百分比体积,和更优选小于约5百分比体积存在。
如上文所讨论的卤化呫吨药物组合物的典型治疗有效剂量以约0.5mL/100cm2病变皮肤至约2mL/100cm2病变皮肤,和最优选约1mL/100cm2病变皮肤局部给予。该剂量一般相应于约1mg至约15mg卤化呫吨的患者累积剂量(其显著低于用于诊断性肝测试或肿瘤学应用的那些剂量)。
能够治疗的皮肤表面的量不受已知限制。然而由于施用困难而常常排除头皮。其它排除情况是活体检查的安全排除,并且没有已知理由阻止将卤化呫吨药物组合物用于面部。
卤化呫吨药物组合物已施用过的最大治疗面积之一是600cm2。成人的总皮肤表面是约20,900cm2。大于30%的皮肤表面的任何病患都视为严重(6,270cm2),并且这可能是任何局部治疗能覆盖的最大面积。还存在的问题是过增殖中的未出疹皮肤(仍不可视)。
另选地理解,本发明使用下述式1化合物,其中R1独立地是F,Cl,Br,I,H或C1-C4烷基;R2,R3,R4,和R5独立地是Cl,H或I,其中至少一个取代基选自R2,R3,R4,R5是I和至少一个是Cl或H;和R6独立地是H或C1-C4烷基;R11是H或C1-C4烷基;R12是H或C1-C7酰基;和全部(a)互变异构体形式;(b)阻转异构体,(c)式2(下文)描述的封闭内酯形式,(d)式2描述的内酯形式的对映体,及其(e)药学上可接受的盐。
术语"生理学上可接受的盐"和"药学上可接受的盐"的各种语法形式是指药物工业一般使用的任何非毒性阳离子比如碱金属、碱土金属、和铵盐,包括钠、钾、锂、钙、镁、钡、铵和精蛋白锌盐,其能够通过本领域已知方法制备。预期的阳离子提供水溶性呫吨盐。优选,盐是一碱式或二碱式盐形式的钠盐,钾盐,钙盐和铵盐。读者可参照Berge,J.Pharm.Sci.1977 68(1):1-19的一般使用的生理学(或药学上)可接受的酸和碱的列表,其与药物化合物形成生理学上可接受的盐。
卤化呫吨药物组合物的pH值能够通过本领域技术人员已知的任何适宜手段调节。组合物能够被缓冲或者pH值通过加酸或碱调节。
由于卤化呫吨或其生理学上可接受的盐是弱酸,取决于卤化呫吨浓度和/或电解质浓度,组合物的pH值可以不需要使用缓冲剂和/或pH值调节剂。然而特别优选的是组合物不含缓冲剂,允许其在给予后符合生物学环境。
还优选的是,药物组合物不包括任何防腐剂,它们中许多能够有害地干扰药物组合物或其配制剂,或可以使得卤化呫吨组合物活性组分的递送复杂化或与之相互作用或干扰该递送。在使用防腐剂的情况下,咪脲是优选防腐剂,原因是其无论是在药物组合物中或给药时都不与卤化呫吨类相互作用。
在作为单一活性成分治疗应用时,已推荐在使用卤化呫吨药物组合物之后用可见光源对组合物已施用的皮肤区域进行活性辐射。该教导于US专利号8,974,363。本发明治疗方法中不需要并且优选并不使用在卤化呫吨药物组合物施用后的可见光活性辐射。
本文公开的药物配对可宽泛地用于影响人类和其它动物皮肤和有关器官的各种病况的改善治疗。药物配对的卤化呫吨部分能够直接地或实质上邻近地施用至待治疗组织,包括皮肤、甲、头皮和口腔的那些,而全身性部分则经口、颊部、经静脉内、经肌肉内、皮下等肠胃外给药的熟知方法全身给予。
根据本发明的优选实施方式,提供患者中过增殖皮肤障碍比如牛皮癣或湿疹的治疗方法。该方法包括用局部表面治疗和与之组合的一种或多种全身性治疗来治疗患者(有需要的受试者),其中所述局部表面治疗包含表面给予治疗有效量的包含媒介物的药物组合物,所述媒介物含有溶解或分散在其中的卤化呫吨比如4,5,6,7-四氯-2′,4′,5′,7′-四碘荧光素(也即玫瑰红),或其生理学上可接受的盐。
卤化呫吨的优选浓度和/或其药物组合物的剂量所取决于的因素包括但不限于患病皮肤的量,病变皮肤或斑块的数量和位置。对于消化道障碍,比如溃疡性结肠炎或克罗恩病,呫吨制剂能够配制用于口服给予和吞咽。
卤化呫吨组合物通常局部给予,尽管其能够配制用于口服给予和如上文所述给予以治疗消化道障碍比如溃疡性结肠炎或克罗恩病。
预期的治疗方法用于有需要的哺乳动物。治疗的哺乳动物能够是灵长类比如人类,猿比如黑猩猩或大猩猩,猴比如短尾猴或猕猴,实验室动物比如大鼠、小鼠或兔,伴侣动物比如犬、猫、马,或食品动物比如奶牛或肉牛、绵羊、羔羊、猪、山羊、美洲驼等。
一般将各预期的组合物反复体内给予至有需要的哺乳动物直至治疗的皮肤病况被减少至希望程度比如无法检测到。从而,给予至有需要的哺乳动物能够在1天、每日、每周、每月或在数月至数年期间内多次发生,如治疗医师指导。
结果:
媒介物治疗4周并不显著改变核心IL-23/IL-17-调节基因的表达或总体疾病转录物组(用主成分分析,PCA)。然而,使用PH-10治疗4周如RT-PCR评价显著(FC>1.5,p<0.05)(FC=变化倍数;p=统计学p-值)下调IL-17A、IL-22、IL-26、IL-36和角蛋白16mRNAs。基因阵列结果的PCA分析显示向非病变皮肤的改变,其中某些治疗后活体检查群聚于非病变皮肤特征(图17和18)。
通过PH-10给药显著改善的途径包括所公开的牛皮癣转录物组和由IL-17、IL-22和干扰素介导的细胞应答。为了强化对使用PH-10的免疫和牛皮癣相关性基因调节的分析,在治疗4周之后基于PCA分析将患者划分为应答者vs.非应答者(与基线非病变皮肤比较)(图18A和18B)。
利用该途径,大于500种疾病相关性基因在用PH-10治疗4周之后下调并且包括IL-23、IL-17、IL-22、S100A7、IL-19、IL-36和CXCL1的宽范围的中心"牛皮癣相关的"基因的表达被有效地正常化;也即,经治疗的病变皮肤具有的值在基线非病变皮肤的相同范围内(图19A和19B)。
还测量到包括ICOS和CTLA4的T-细胞活化标记物的降低表达,所显示的变化平行于用IHC方法测得的髓性(CD11c+)树突状细胞和T-细胞的减少(图20A和20B)。与第29天相比,这两种标记物在第64天显著降低。
结论:
这些结果确立的是,PH-10具有调节牛皮癣炎症、包括该疾病的关键细胞因子驱动物的高度显著的能力,但是仅一部分患者将病变表型逆转至非病变皮肤的状态。该类"混合"的应答结果也随目前批准用于牛皮癣的其它局部或全身性药物发生,这强调需要个人化治疗和能够具备单独药物的预测性应答生物标记物。
重要地,在病变活体检查中媒介物不引起这些相同标记物的任何可检测的变化。
物质和方法
简介:
PH-10是局部水凝胶配制剂,其产生玫瑰红二钠(RB)向上皮组织的选择性递送(图13A和13B)。RB是光活化时能够产生单线态氧的荧光素衍生物,但之前并未确立其在寻常性牛皮癣中的治疗机理。
研究群体
在2期临床试验中录用30名患者,所述试验在美国的3个中心进行;适宜的患者显示躯干或肢端轻度至中度的直径至少5cm的适应活组织检查的牛皮癣病变。录用的受试者主要是男性(63%)和白人(77%),年龄中位数是45和年龄范围是18-70。多数受试者患牛皮癣超过5年(93%),根据研究者斑块评价得分在基线显示中度疾病(73%)。21名受试者完成了28天媒介物给药、7天活组织检查恢复间隔、随后28天PH-10施用的全部研究过程,并且具有全套(基线:病变和非病变;第29天和第64天仅病变)的可评价活体检查。额外受试者在第29天和第64天的病变活体检查之间具有显著差异,并且包括在应答者分析组中。
免疫组织化学
对全部受试者活体检查的白细胞进行免疫组织化学。冷冻组织切片用苏木精(Thermo fisher Scientific)和曙红(Shandon)或用鼠抗-人单克隆抗体染色(Fuentes-Duculan et al.,J Invest Dermatol 2010130:2412-2422)。用生物素标记的马抗-小鼠抗体(Vector Laboratories)来放大抗生物素蛋白-生物素复合物的主信号并用色原-3-氨基-9-乙基咔唑(Sigma-Aldrich)显像。用图像分析软件(Image J,1.38x版本,NationalInstitutes of Health)人工计数每毫米的正染色细胞,并按mm表皮线性长度报告(Fuentes-Duculan et al.,J Invest Dermatol 2010130:2412-2422)。
微阵列
RNA从21名受试者的全厚度皮肤活体检查(NL,LS,基线;第29和64天LS)提取。与基线非病变活体检查比较,基于PCA分析将患者划分为应答者。RNA用Mini试剂盒(Qiagen,Valencia,CA)提取。对于各HGU 133 2.0基因芯片,逆转录、放大和标记2μg总RNA(Guttman-Yassky et al.,J Immunol 2008181(10):7420-7427)。研究依照关于微阵列实验的最简信息(Minimum Information About a Microarray Experiment)指南进行。
分析用R软件(R-project.org)和bioconductor包(bioconductor.org)进行。用Harshlight包检查CEL文件的空间伪像(Suarez-Farinas et al.,BMC Bioinformatics2005 6:294)。用affyQCReport包获得经典微阵列质量控制报告。表达值通过用GCRMA算法获得。
在至少2个样品中具有大于0.1的标准偏差(SD)和大于3的表达值的探针组保留用于进一步分析(13405探针组)。表达值用混合效果模型建模,将时间作为固定效果而患者作为随机因子。模型估计和假设测试在limma框架中进行。用矫正的-t检验来评价兴趣比较,并且对多元假设用Benjamini-Hochberg途径调节所得p-值。倍数变化(FCH)大于2且错误发现率(FDR)小于0.05的探针组被选用为PH-10调节的基因。如前文描述,对数个基因进行PT-PCR。
皮肤穿透研究
将14C-玫瑰红(1mg/mL,在DMSO中)施用至250cm2面积的Goettingen小型猪背部皮肤(人类皮肤吸收研究的一般模型)。在给药后0.5小时开始以规律间隔从暴露动物收集血浆,在血浆中收集放射性。类似地,在适当时间点从动物笼收集尿和粪便。
在168小时结束时,收集皮肤的施用位点。评价全部这些样品的放射性和计算每剂量给药的放射性元素累积率。直方图制备自以20um深度间隔在皮肤中测量的放射性。
该研究的结果指出,在除皮肤以外的任何其他组织中并未收集到放射性。在任何时间点的血浆中未获得放射性指出,在局部给予之后无全身性暴露。在24小时之后,皮肤中的放射性浓度在角质层中最大并且随表皮中的深度降低,在表皮和真皮中几乎没有观察到放射性。
方法:
在30名寻常性牛皮癣患者中进行PH-10的机理聚焦性研究:用依次的媒介物和活性药物治疗各4周(注册的临床试验NCT02322086)。在治疗之前(基线)和在媒介物治疗终点(第29天)和在PH-10治疗终点(第64天)(图14和15)收集皮肤活体检查。
媒介物vs PH-10治疗的效果用下述评价:细胞免疫浸润,牛皮癣的驱动细胞因子和总疾病转录物组,使用免疫组织化学(图16)和用U133 2.0Plus阵列和RT-PCR进行基因表达测量(图17至图20A和20B)。
本文引用的各专利、专利申请和文章通过援引并入。本文所用的冠词"一种"和"一个"是指一个或多于一个(即至少一个)的冠词语法客体。本文引用的各专利、专利申请和文章通过援引并入。
前文描述和实例期望是示例性的并且并不视为限制。在本发明主旨和范围内的其它变化是可能的并且本身对本领域技术人员来说是容易的。例如,除了本文详述的可适用于皮肤之外,本发明还可用于其它上皮组织比如消化道内壁或生殖道的疾病。
Claims (15)
1.上皮组织过增殖障碍的治疗方法,其包括向有需要的哺乳动物局部给予治疗有效量的卤化呫吨亲水药物组合物,和与之组合的治疗有效量的靶向的全身性抗炎剂。
3.根据权利要求1的方法,其中所述局部给予的卤化呫吨药物组合物含有浓度为约0.0001%至约0.01%重量的卤化呫吨或其药学上可接受的盐。
4.根据权利要求3的方法,其中所述局部给予的卤化呫吨药物组合物含有粘度增加剂,其存在的量提供在温度25℃和1个大气压为约10至约1000厘泊(cps)的组合物粘度。
5.根据权利要求4的方法,其中所述局部给予的卤化呫吨药物组合物含有水溶性电解质,其存在的浓度为约0.1至约2%重量或另选地以足够的水平存在从而提供大于约100mOsm/kg至约600mOsm的质量渗透摩尔浓度。
6.根据权利要求1的方法,其中所述靶向的全身性抗炎剂是小分子或蛋白质活性剂,其不是为COX-1和/或COX-2抑制剂的NSAID。
7.根据权利要求1的方法,其中所述靶向的全身性抗炎剂是TNF-α抑制剂,IL-17A抑制剂,混合型IL-12/IL-23抑制剂,IL-6抑制剂和磷酸二酯酶-4抑制剂中的一种或多种。
8.根据权利要求7的方法,其中所述TNF-α抑制剂是阿达木单抗,培舍珠单抗,依那西普,戈利木单抗,古塞库单抗和英利昔单抗中的一种或多种。
9.根据权利要求7的方法,其中所述IL-17A抑制剂是伊卡组单抗,布罗达单抗或司库奴单抗中的一种或多种。
10.根据权利要求7的方法,其中所述IL-12/IL-23抑制剂是乌司奴单抗或瑞莎珠单抗中的一种或多种。
11.根据权利要求7的方法,其中所述IL-6抑制剂是sarilumab。
12.根据权利要求7的方法,其中所述磷酸二酯酶-4抑制剂是isapremilast或crisaborole中的一种或多种。
13.根据权利要求1的方法,其中所述靶向的全身性抗炎剂是免疫系统下调试剂,其是甲氨蝶呤、环胞素和硫唑嘌呤中的一种或多种。
14.根据权利要求1的方法,其中所述靶向的全身性抗炎剂最初以最大耐受剂量给予。
15.根据权利要求1的方法,其中所述上皮组织是皮肤。
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