CN116348143A - 治疗皮肤炎的方法 - Google Patents
治疗皮肤炎的方法 Download PDFInfo
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- CN116348143A CN116348143A CN202180056449.8A CN202180056449A CN116348143A CN 116348143 A CN116348143 A CN 116348143A CN 202180056449 A CN202180056449 A CN 202180056449A CN 116348143 A CN116348143 A CN 116348143A
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Abstract
本发明涉及一种治疗皮肤炎的方法和β‑1肾上腺素受体拮抗剂用于制备治疗皮肤炎的药物组合物的用途，包括向有需要的受试者施用包含治疗有效量的β‑1肾上腺素受体拮抗剂的药物组合物的步骤。
Description
相关申请案的交互参照
本申请主张2020年8月14日提交的美国临时申请案号63/065,723的优先权的利益。通过引用将上述申请案的全部内容并入本文中。
本发明涉及一种治疗皮肤炎的方法和β-1肾上腺素受体拮抗剂用于制备治疗皮肤炎的药物组合物的用途。
皮肤炎(Dermatitis)是一个广义的术语，其涵盖具有不同病因的一系列炎症性皮肤病症；常见的皮肤炎症状包括红斑(erythema)、鳞屑(scaling)、痂皮(crusting)、水疱(vesicles)、搔痒(itching)，以及慢性发炎(chronic inflammation)引起的皮肤增厚。
皮肤炎的主要治疗方法集中于使用保湿剂的基础皮肤护理，以及使用类固醇及免疫抑制剂的局部性治疗；然而，长期使用局部性类固醇及免疫抑制剂治疗皮肤炎会产生不良后果，例如皮肤变薄且容易感染，以及皮肤灼伤/刺激且罹患皮肤癌的风险增加。除此之外，一些皮肤炎患者对于这些治疗无反应(即对类固醇、免疫抑制剂具有治疗抗性)，并继续遭受广泛的皮肤损伤及强烈的搔痒，导致身体及精神上的失能。
综上所述，对于皮肤炎的治疗需求尚未被满足，因此本发明可用以解决此需求以及其他需求。
发明内容
本发明提供一种治疗皮肤炎的方法。
本发明提供一种β-1肾上腺素受体拮抗剂用于制备治疗皮肤炎的药物组合物的用途。
在一实施例中，本发明揭露了一种治疗皮肤炎的方法，包括向有需要的受试者施用包含治疗有效量的β-1肾上腺素受体拮抗剂的药物组合物的步骤。
在一实施例中，本发明揭露了一种β-1肾上腺素受体拮抗剂用于制备治疗皮肤炎的药物组合物的用途，包括向有需要的患者施用包含治疗有效量的β-1肾上腺素受体拮抗剂的药物组合物的步骤。
本专利中使用的术语「该发明」、「此发明」以及「本发明」系指在广泛的指代本专利的所有主题及以下的权利要求；包含这些术语的叙述应被理解为不限制此处描述的主题或限制以下权利要求的含义或范围。
本专利所涵盖的本发明的实施例，系由以下的权利要求而非此发明内容来定义；此发明内容为本发明各个方面的高度概述，并介绍了以下实施方式部分进一步叙述的一些概念。此发明内容并非倾向于定义权利要求的主题的关键或基本技术特征，也非旨在单独使用以定义权利要求主题所涵括的范围，应通过参考整份说明书的合适段落、任何或所有附图及每个权利要求来理解主题。
搭配所附附图以及以下的详细描述阅读，将使本发明变得更加明显易懂。
以下，参照所附附图已详细描述本发明的说明性实施例。
图1(A)为对高剂量类固醇无反应的湿疹患者的照片图像，而图1(B)则为在其湿疹患者于局部患部施用倍他洛尔治疗2天后的照片图像；
图2(A)至图2(C)为局部患部施用倍他洛尔至表皮生长因子受体酪氨酸激酶抑制剂(奥希替尼)诱导的湿疹患者在第0天(图2(A))、第2天(图2(B))以及第7天(图2(C))的功效的照片图像；
图3(A)以及图3(B)为皮肤炎控制不佳的患者在治疗前(图3(A))以及在局部患部施用倍他洛尔治疗2天后(图3(B))的照片图像；
图4(A)以及图4(B)为皮肤炎控制不佳的患者在治疗前(图4(A))以及在局部患部施用倍他洛尔治疗4周后(图4(B))的照片图像。
图5(A)以及图5(B)为皮肤炎控制不佳的患者在治疗前(图5(A))以及在局部患部施用倍他洛尔治疗7天后(图5(B))的照片图像。
实施方式
以下内容将搭配附图，通过特定的具体实施例说明本发明的技术内容，熟悉此技术的人士可由本说明书所揭示的内容轻易地了解本发明的其他优点与功效。本发明亦可通过其他不同的具体实施例加以施行或应用。本说明书中的各项细节亦可基于不同观点与应用，在不背离本发明的精神下，进行各种修饰与变更。
如本文所用，冠词「一」及「一个」系指代冠词的一个或多个(即，至少一个)语法对象。
用语「个体」和「患者」可交互使用，且是指被诊断出罹患有皮肤炎、疑似罹患有皮肤炎、易于罹患皮肤炎或其中需要预防皮肤炎的哺乳动物，后者包括即将接受表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗癌症的患者；受试者或患者包括灵长类动物，较佳地为人类。
拮抗剂的「有效量」系指与未治疗的受试者相比之下，其产生所需效果；例如，减轻皮肤炎的症状及体征至少1％的β-1肾上腺素受体拮抗剂的量。
如本文所用，术语「治疗」系指治疗性治疗及预防性或预防性措施；需要治疗的人包括已经患有皮肤炎的人，以及容易患上皮肤炎的人或需要预防皮肤炎的人。
本文中的所有数字可以理解为由「约」修饰；如本文所用，术语「约」旨在涵盖±10％的变化。
本发明涉及一种β-1肾上腺素受体拮抗剂用于制备治疗皮肤炎的药物组合物的用途，包括向有需要的患者施用包含治疗有效量的β-1肾上腺素受体拮抗剂的药物组合物的步骤。
如本文所用，皮肤炎是任何形式的皮肤发炎，且通常涉及发痒、皮肤干燥或在肿胀及红斑的皮肤上出现的皮疹；皮肤炎的其他症状及体征包括水疱、渗出物、硬皮或皮屑剥落。皮肤癌的非限制性实施例包括异位性皮肤炎(湿疹)、标靶治疗诱导的皮肤炎、类固醇抗药性皮肤炎、接触性皮肤炎、脂溢性皮肤炎(例如头皮屑)以及脂肪性皮肤炎。
如本文所用，标靶治疗包括通过干扰癌症发生及癌症生长所需的特定靶向分子，而非通过简单的干扰快速分裂的细胞(例如常规的化疗)来抑制癌细胞生长的药物，例如激酶抑制剂、血管生成抑制剂、表皮生长因子受体(EGFR)抑制剂(例如表皮生长因子受体酪氨酸激酶抑制剂，EGFR-TKI)、HER2/neu受体或其组合。
在一些实施例中，所述皮肤炎基本上没有裂缝或糜烂。
在一些实施例中，药物组合物包含β-1肾上腺素受体拮抗剂；在其他实施例中，药物组合物基本上不含β-2肾上腺素受体拮抗剂、非选择性β肾上腺素受体拮抗剂、抗体(例如针对IL4RA或IL-25的抗体)或其组合。
β-1肾上腺素受体拮抗剂可与药学上可接受的载体一起施用。
药物组合物可配制为全身(例如口服或静脉内)、皮内、皮下、肌内或局部等方式给药。在一些实施例中，可将药物组合物配制成以下形式之一用于局部递送：软膏、乳霜、溶液、凝胶、混悬液、喷剂或洗剂；在其他实施例中，药物组合物可被配制成用于缓释或持续释放的形式。
β-1肾上腺素受体拮抗剂的非限制性实例包括阿替洛尔(atenolol)、倍他洛尔(betaxolol)、比索洛尔(bisoprolol)、艾司洛尔(esmolol)、醋丁洛尔(acebutolol)、美托洛尔(metoprolol)、奈比洛尔(nebivolol)或其组合。
在一实施例中，所述用于制备治疗皮肤炎的药物组合物进一步包括至少一种对皮肤炎有效的治疗剂；此类治疗剂包括但不限于类固醇(例如泼尼松龙(prednisolone)、甲泼尼龙(methylprednoslone)、倍他米松(betamethasone)、地塞米松(dexamethasone)、氯倍他索(clobetasole)等)、抗组织胺(例如左西替利嗪(levocitrezine)、右旋氯苯那敏(dexchlorpheniramine)、非索非那定(fexofenadine)、地氯雷他定(desloratadine)、羟嗪(hydroxyzine)等)、免疫调节剂(例如硫唑嘌呤(azathioprine)、胺甲喋呤(methotrexate)、环孢素(cyclosporine)、他克莫司(tacrolimus)或吡美莫司(pimecrolimus))、抗生素(例如夫西地酸(fusidic acid))或光疗法。在某些实施例中，用于治疗皮肤炎的上述治疗剂可与包含β-1肾上腺素受体拮抗剂的药物组合物一起组合使用。
当包含β-1肾上腺素受体拮抗剂的药物组合物与至少一种用于治疗皮肤炎的治疗剂，组合施用或交替施用时，可能需要更少的包含β-1肾上腺素受体拮抗剂的药物组合物、更少的给药时间点及/或增加的时间间隔来达到治疗效果。
除此之外，本领域技术人员可针对特定类型的皮肤炎，轻易地确定待施用的包含β-1肾上腺素受体拮抗剂的药物组合物的合适剂量；例如，皮肤炎的严重程度及类型、患者的年龄、体重、性别、合并症以及给予患者服用的其他药物。
本领域技术人员将认知到较佳的剂量是在有需要的患者中产生治疗效果的剂量，例如减轻皮肤炎的症状和体征。在某些实施例中，在特定天数(例如7天、1个月等)内每天施用一剂；在其他实施例中，可在一天内(每2、4、6或12小时等)施用多剂。本发明还考虑每天多次施用，并施用多天。
本发明的实施例通过以下实施例说明，这些实施例不应以任何方式解释为对其范围施加限制；相反地，应当清楚地理解，在阅读本文的内容后，本领域技术人员在不脱离本发明的精神的情况下，可能不得不求助于各种其他实施例、修改及其等同物。在以下实施例中描述的研究期间，除非另有说明， 否则遵循常规程序；为了说明的目的，下面描述了一些实验过程。
实施例1
一名手部湿疹患者已使用高强度外用类固醇(一天施用两次氯倍他索软膏，共施用一周)治疗，但没有任何改善，其表现为红斑及鳞屑(参考图1(A))；其后以0.25％(w/w)的倍他洛尔凝胶对该名患者的局部患部每天施用2次进行治疗，持续2天后，红斑及鳞屑明显消退(参考图1(B))。
实施例2
一名由表皮生长因子受体抑制剂(奥希替尼)诱导的全身性皮肤炎(湿疹)患者，其接受类固醇治疗(一天施用两次甲泼尼龙(20mg)，共施用21天)但没有任何改善(参考图2(A))；其后以倍他洛尔凝胶对该名患者的局部患部每天施用2次进行治疗，于治疗2天后及7天后进行观察，其皮肤炎具有明显改善(参考图2(B)以及图2(C))。
实施例3
一名全身性皮肤炎控制不佳的患者，使用高剂量口服类固醇(一天施用两次甲泼尼龙(20mg)，共施用14天)治疗但没有任何改善，其表现为全身性红斑皮疹(参考图3(A))；其后以0.25％(w/w)的倍他洛尔凝胶对该名患者的局部患部每天施用2次进行治疗，持续2天后，红斑皮疹完全消退(参考图3(B))。
实施例4
一名患有手部皮肤炎的中年男性患者，施用局部类固醇软膏(一天施用两次氯倍他索软膏(0.025％)，共施用21天)、口服抗组织胺药物(一天施用一次地氯雷他定(5mg)+一天施用两次羟嗪(25mg)，共施用21天)以及免疫抑制剂(一天施用两次环孢素(100mg)，共施用28天)进行治疗，但其鳞屑及慢性发炎并没有任何改善(参考图4(A))；其后以0.25％(w/w)的倍他洛尔凝胶对该名患者的局部患部每天施用2次进行治疗，持续4周后，鳞屑及发炎完全消退(参考图4(B))。
实施例5
一名患有手部皮肤炎的患者，未施用任何治疗(参考图5(A))；其后仅以0.25％(w/w)的倍他洛尔凝胶对该名患者的局部患部每天施用2次进行治疗，持续7天后，红斑及发炎具有明显改善(参考图5(B))。
综上所述，β-1肾上腺素受体拮抗剂，相较于一般类固醇、抗组织胺及免疫抑制剂等常规治疗剂，针对皮肤炎确实有明显的治疗能力，具有无法预期的功效；虽然实施例仅使用倍他洛尔作为特定的β-1肾上腺素受体拮抗剂，但其仅为例示性的β-1肾上腺素受体拮抗剂，并不因此限制β-1肾上腺素受体拮抗剂中仅有倍他洛尔具有治疗皮肤炎的功效。
上述实施例仅例示性说明本发明的原理及功效，而非用于限制本发明。任何熟习此项技术的人士均可在不违背本发明的精神及范畴下，对上述实施例进行修饰与改变。因此，本发明的权利保护范围，应如本发明权利要求所列。
Claims (10)
- 一种β-1肾上腺素受体拮抗剂用于制备治疗皮肤炎的药物组合物的用途，包括向有需要的受试者施用包含治疗有效量的β-1肾上腺素受体拮抗剂的药物组合物的步骤。
- 如权利要求1所述的用途，其中该皮肤炎为异位性皮肤炎(湿疹)。
- 如权利要求1所述的用途，其中该皮肤炎由表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)所诱导产生。
- 如权利要求1所述的用途，其中该皮肤炎具有类固醇抗性。
- 如权利要求1所述的用途，其中该皮肤癌为脂肪性皮肤炎。
- 如权利要求1所述的用途，其中该β-1肾上腺素受体拮抗剂选自阿替洛尔(atenolol)、倍他洛尔(betaxolol)、比索洛尔(bisoprolol)、艾司洛尔(esmolol)、醋丁洛尔(acebutolol)、美托洛尔(metoprolol)、奈比洛尔(nebivolol)或其组合。
- 如权利要求1所述的用途，其中进一步包括施用类固醇、抗组织胺、免疫调节剂、抗生素、光疗法或其组合的步骤。
- 如权利要求7所述的用途，其中该免疫调节剂为环孢素(cyclosporine)、他克莫司(tacrolimus)或吡美莫司(pimecrolimus)。
- 如权利要求1所述的用途，其中该药物组合物基本上不含抗体。
- 如权利要求1所述的用途，其中该抗体为针对IL4RA或IL-25的抗体。
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| US20230293460A1 (en) | 2023-09-21 |
| EP4197532A1 (en) | 2023-06-21 |
| TW202206059A (zh) | 2022-02-16 |
| WO2022033581A1 (zh) | 2022-02-17 |
| EP4197532A4 (en) | 2024-10-23 |
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