CN115484960A - 病毒感染的治疗 - Google Patents
病毒感染的治疗 Download PDFInfo
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- CN115484960A CN115484960A CN202180032680.3A CN202180032680A CN115484960A CN 115484960 A CN115484960 A CN 115484960A CN 202180032680 A CN202180032680 A CN 202180032680A CN 115484960 A CN115484960 A CN 115484960A
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Abstract
本发明的特征在于通过施用富含硫的组合物来治疗病毒感染,例如由包膜病毒引起的感染。
Description
背景技术
病毒感染对全球健康造成巨大威胁。当治疗细菌感染时,多种抗生素可用于单一感染,并且单一抗生素可用于治疗多种不同的细菌感染。相反,对于病毒感染,批准的治疗很有限。此外,批准的抗病毒药物靶标较窄,并且通常仅对单一病毒株有效。另一个挑战是病毒突变快速,从而产生对抗病毒疗法的抗性。尽管特异性病毒侵入哺乳动物细胞,但哺乳动物细胞都具有相同的基本机制。因此,有效的抗病毒治疗需要足够高的剂量以破坏病毒,但又不会高到伤害宿主。考虑到这些挑战,急需开发广谱抗病毒药物,该抗病毒药物具有高的抗药性屏障,并且对广泛的病毒靶标有效。
发明内容
本发明涉及用于治疗病毒感染的组合物和方法。
一方面,本发明的特征在于一种治疗或预防由包膜病毒引起的受试者病毒感染的方法。该方法包括以足以治疗或预防病毒感染的量和持续时间向受试者施用药物组合物,该组合物具有90-99.9%(w/w)单质α硫、0.01-10%(w/w)高极性组分和药学上可接受的载体和/或赋形剂。包膜病毒可以是DNA病毒、RNA病毒或反转录病毒。
在一些实施方案中,包膜病毒是DNA病毒。DNA病毒可以是例如疱疹病毒科、痘病毒科或多形包膜病毒科。疱疹病毒科可以是例如单纯疱疹病毒、水痘带状疱疹病毒、巨细胞病毒或EB病毒。痘病毒科可以是例如天花病毒、牛痘病毒、绵羊痘病毒、口疮病毒、猴痘病毒或牛痘病毒。
在一些实施方案中,包膜病毒是RNA病毒。RNA病毒可以是例如披膜病毒科、沙粒病毒科、黄病毒科、正粘病毒科、副粘病毒科、布尼雅病毒科、弹状病毒科、丝状病毒科、冠状病毒科、博尔纳病毒科或动脉炎病毒科。披膜病毒科可以是例如风疹病毒、东马脑炎病毒、西马脑炎病毒、委内瑞拉马脑炎病毒、西门利克森林病毒、辛德比斯病毒、罗斯河病毒、巴马森林病毒、基孔肯雅病毒、马亚罗病毒、欧尼恩病毒、乌纳病毒或图那特病毒。沙粒病毒科可以是例如淋巴细胞性脉络丛脑膜炎病毒或拉沙热。黄病毒科可以是例如登革热病毒、丙型肝炎病毒、黄热病毒、西尼罗病毒或寨卡病毒。正粘病毒科可以是例如甲型流感病毒、乙型流感病毒、丙型流感病毒、鲑传染性贫血病毒或托高土流感病毒。副粘病毒科可以是例如麻疹病毒、流行性腮腺炎病毒、呼吸道合胞病毒(RSV)、牛瘟病毒、犬瘟热病毒或人副流感病毒(HPIV)。HPIV可以是例如HPIV-1、HPIV-2、HPIV-3或HPIV-4。布尼雅病毒科可以是例如加利福尼亚脑炎病毒或辛诺柏病毒;弹状病毒科是狂犬病病毒或水泡性口炎病毒。丝状病毒科可以是例如埃博拉病毒或马尔堡病毒。冠状病毒科可以是例如α冠状病毒、β冠状病毒、δ冠状病毒或γ冠状病毒。β冠状病毒可以是例如与中东呼吸综合征相关的冠状病毒(MERS-CoV)、严重急性呼吸综合征冠状病毒(SARS-CoV)或严重急性呼吸综合征冠状病毒2(SARS-CoV-2)。博尔纳病毒科可以是例如博尔纳病病毒。动脉炎病毒科可以是例如动脉炎病毒或马动脉炎病毒。
在一些实施方案中,包膜病毒是反转录病毒。反转录病毒可以是例如逆转录病毒科或嗜肝DNA病毒科。逆转录病毒科可以是例如人类免疫缺陷(HIV)病毒。HIV可以是HIV-1或HIV-2。嗜肝DNA病毒科可以是例如乙型肝炎病毒。
在一些实施方案中,方法包括治疗由非HIV或AIDS的包膜病毒引起的病毒感染。
在一些实施方案中,方法包括治疗由非病毒性肝炎的包膜病毒引起的病毒感染。
在一些实施方案中,方法包括治疗由非RSV的包膜病毒引起的病毒感染。
在一些实施方案中,组合物包括约99%(w/w)零价硫和约1%(w/w)高极性组分。高极性组分可选自硫酸钠、连多硫酸钠和硫代硫酸钠。
在一些实施例中,高极性组分选自连多硫酸钠、连多硫酸钾、连多硫酸铵、连多硫酸钙、硫代硫酸钠、硫代硫酸钾、硫代硫酸铵、硫代硫酸钙、硫酸钠、硫酸钾、硫酸铵、重亚硫酸钠、重亚硫酸钾、重亚硫酸铵、重亚硫酸钙、氯化钠、氯化钾、氯化铵、氯化钙、醋酸钠、棕榈酸钠、棕榈酸钾和月桂酸铵。
在一些实施方案中,组合物包括单质α硫以及一种或多种高极性组分,其比例为约10至约150份单质α硫比1份高极性组分(w/w),用于肠内、局部或胃肠外施用。
在一些实施方案中,组合物被配制用于肠内施用,并且单质α硫和高极性组分一起以约10mg至约10000mg(例如约400mg)的量存在。
在一些实施方案中,组合物是胶囊。
在一些实施方案中,组合物包括第二治疗剂。第二治疗剂可以是抗病毒剂(例如,抗逆转录病毒药物)、抗病毒疫苗、抗真菌剂、抗细菌剂、抗炎剂、抗寄生虫剂、膳食补充剂或止痛剂。抗病毒剂可以是例如瑞德西韦、法匹拉韦(favipiravir)、法维拉韦(favilavir)、EIDD-2801、加利地韦(galidesivir)、SNG001、洛匹那韦、利托那韦或其组合。抗细菌剂可以是例如阿奇霉素或环丙沙星。抗炎剂可以是例如托珠单抗。抗寄生虫剂可以是例如氯喹或羟基氯喹。膳食补充剂可以是例如维生素C。止痛药可以是例如对乙酰氨基酚。
在一些实施方案中,组合物通过以下产生:提供包括-2氧化态硫的第一无机化合物,并使第一无机化合物与包括+4氧化态硫的第二无机化合物在酸性pH下反应。反应产生组合物,该组合物包括:(i)90-99%(w/w)单质α硫和0.01-10%(w/w)高极性组分;以及(ii)其中组合物包括至少96%易于生物转化为硫化氢的生物活性零价硫。
定义
“单质α硫”是指具有式S8的正交单质硫。单质α硫以SS(环辛基硫醚分子)存在,但也可以包括S7(环庚基硫醚分子)和S6(环己基硫醚分子)。
“单质β硫”是指具有式S8的单斜晶系单质硫,主要由环辛硫醚分子组成。
“高极性组分”是指分子中含有至少一个离子键或一个高极性共价键的化合物。高极性组分包括例如连多硫酸钠、连多硫酸钾、连多硫酸铵、连多硫酸钙、硫代硫酸钠、硫代硫酸钾、硫代硫酸铵、硫代硫酸钙、硫酸钠、硫酸钾、硫酸铵、重亚硫酸钠、重亚硫酸钾、重亚硫酸铵、重亚硫酸钙、氯化钠、氯化钾、氯化铵、氯化钙、醋酸钠、棕榈酸钠、棕榈酸钾和月桂酸铵。高极性组分还包括含有高极性O-H共价键的分子,例如水、醇、多元醇、连多硫酸、羧酸和/或山梨糖醇单硬脂酸酯。高极性组分还包括其分子含有高极性N-H共价键的化合物,例如伯胺、氨基酸、伯酰胺、肽和蛋白质。
“连多硫酸盐”是指式-O3S-Sn-SO3 -的阴离子或基团(例如,其中n是1-60的整数,优选1-20,更优选1、2、3、4、5或6)。
“零价硫”是指氧化态为零的硫原子,根据本领域技术人员公知的一套约定规则进行计算(例如,每个环辛基硫分子(S8)含有8个零价硫原子,每个硫代硫酸根离子(S2O3 -2)含有一个零价硫原子,并且每个连多硫酸根离子含有“n”个零价硫原子。零价硫可在硫烷硫化合物中发现。
“零价硫含量”是指在含有单质α硫和高极性组分的组合物中存在的零价硫的量,该高极性组分例如是连多硫酸钠、连多硫酸钾、连多硫酸铵、连多硫酸钙、硫代硫酸钠、硫代硫酸钾、硫代硫酸铵、硫代硫酸钙、硫酸钠、硫酸钾和硫酸铵。
“硫烷硫”是指还原氧化态的不稳定的、高反应性的硫原子与另一个硫原子共价键合,化合价为0或-1。硫烷硫化合物可以包括例如全硫化物、多硫化物、连多硫酸盐、多硫烷、硫代牛磺酸、硫代硫酸盐和/或单质硫。在酶(诸如胱硫醚酶、3-巯基丙酮酸硫酸转移酶和/或罗丹宁)的参与下,可在厌氧半胱氨酸硫代谢中形成硫烷硫化合物。酶促H2S生成途径中的最后一步通常涉及含有硫烷硫的种类。含有硫烷硫的化合物可通过激活或灭活酶(诸如,例如含有铁或钼原子的氧化还原酶,例如黄嘌呤氧化酶、醛氧化酶和苹果酸脱氢酶)参与细胞调节过程。
“肠内”是指涉及胃肠道任何部分的施用。肠内施用可以包括例如以片剂、胶囊或滴剂的形式经口施用、经胃营养管施用、十二指肠营养管施用或直肠施用。
“局部”是指局部或全身施用,特别是皮肤外用、吸入、滴眼液和/或滴耳液。
“肠胃外”是指通过口服以外的方式施用本发明的组合物,特别是通过向体内注射液体的形式。胃肠外施用可以包括例如静脉内、动脉内、骨内输注、肌内、脑内、脑室内和皮下施用。
“抗炎药物”是指通过减少炎症而起作用的药剂或物质。
“膳食补充剂”是指作为食品补充剂或营养补充剂的药剂、物质、和/或物质的混合物,旨在补充饮食和提供营养,诸如维生素、矿物质、纤维、脂肪酸或氨基酸,这些物质在人的饮食中可能缺失或不能以足够的量消耗。
“无机物”是指非有机化合物的化合物。
“氧化态”是指当根据本领域技术人员熟知的一套约定规则对电子进行计数时,定义为原子可能具有的电荷的物质分子中原子的氧化程度的量度。
“酸”是指阿伦尼乌斯酸、布朗斯特德-劳里酸和/或路易斯酸。阿伦尼乌斯酸是当溶解在水中时增加氢离子浓度的物质。布朗斯特德-劳里酸是将质子给予布朗斯特德-劳里碱的物质。路易斯酸是接受来自另一种类的一对电子的种类。
“硫化氢”是指具有式H2S的化合物,其由哺乳动物体的许多细胞少量产生并具有多种生物信号功能(例如平滑肌松弛剂、血管舒张剂、增加NMDA受体的反应、促进长期增强和参与记忆形成)。
“增加硫化氢水平”是指提高哺乳动物体内产生的硫化氢水平(例如,通过胱硫醚β合酶和胱硫醚γ裂解酶从半胱氨酸)提取至少约5%、10%、20%、30%、40%、50%、60%、70%、80%、90%或100%,与对照参考样本相比。可以使用本领域已知的任何有用的方法来确定硫化氢的水平。
“治疗”是指为了对抗疾病或疾患并获得有益的或所需的结果,诸如临床结果,对患者进行管理方案。有益的或期望的结果可以包括但不限于改善生活质量、缓解或改善一种或多种症状或病症;减少疾病、疾患或病症的程度;稳定(即,不恶化)疾病、疾患或病症的状态;预防疾病、疾患或病症的传播;延迟或减缓疾病、疾患或病症的进展;改善或缓解疾病、疾患或病症;以及缓解(无论是部分缓解还是全部缓解),无论是可检测还是不可检测。
“受试者”是指哺乳动物(例如人或非人)。
“有效量”试剂的用量是指足以产生有益或所需结果的试剂的量(例如,治疗病毒感染),并且因此,与没有施用组合物的硫化氢和/或硫烷硫水平相比,该组合物的量足以实现体内硫化氢和/或硫烷硫水平的增加。
“组合物”是指包含本文所述物质的系统,物质可选地用可接受的赋形剂配制,并在政府管理机构批准下作为治疗哺乳动物疾病或促进和维持总体健康的治疗方案的一部分而制造或销售。可以配制药物组合物,例如,用于以单位剂型(例如,片剂、胶囊、小胶囊、凝胶帽或糖浆)口服施用;用于局部施用(例如,作为乳膏、凝胶剂、洗剂或软膏剂);用于静脉内施用(例如,作为无菌溶液或胶体分散体,不含微粒栓子并在适于静脉内使用的溶剂体系中);或在本文所述的任何其它制剂中。
“可接受的赋形剂”或“可接受的载体”是指本文所述物质以外的任何成分(例如,能够悬浮或溶解活性物质和/或物质的载体,例如凡士林和聚乙二醇),并且在患者中具有无毒和非炎的性质。赋形剂可以包括例如:防粘剂、抗氧化剂、粘合剂、涂料、压缩助剂、崩解剂、染料(着色剂)、软化剂、乳化剂、填料(稀释剂)、成膜剂或涂料、香精、香料、助流剂(流动增强剂)、润滑剂、防腐剂、印刷油墨、吸附剂、悬浮剂或分散剂、胶体稳定剂、甜味剂和水。示例性赋形剂包括但不限于:丁基化羟基甲苯(BHT)、碳酸钙、磷酸钙(二元)、硬脂酸钙、交联羧甲基纤维素、交联聚乙烯吡咯烷酮、柠檬酸、交联聚维酮、乙基纤维素、明胶、羟丙基纤维素、羟丙基甲基纤维素、乳糖、硬脂酸镁、麦芽糖醇、甘露醇、甲基纤维素、尼泊金甲酯、微晶纤维素、聚乙二醇、聚乙烯吡咯烷酮、聚维酮、预胶化淀粉、尼泊金丙酯、虫胶、二氧化硅、羧甲基纤维素钠、羟乙酸淀粉钠、山梨醇、淀粉(玉米)、硬脂酸、蔗糖、滑石、二氧化钛和木糖醇。赋形剂还可以包括稀释剂(例如、盐水和水性缓冲液)、水性载体和非水性载体,例如水、乙醇、多元醇(诸如甘油、丙二醇、聚乙二醇等)及其合适的混合物、植物油(诸如橄榄油)和可注射的有机酯(诸如油酸乙酯)。
如本文所用,术语“约”是指所列举值的平均值±10%。
“冠状病毒”是一种感染人并引起呼吸道感染的病毒。冠状病毒可引起受试者的肺炎,包括但不限于:引起中东呼吸综合征(MERS)(也称作MERS-CoV)的β冠状病毒、引起严重急性呼吸综合征(SARS)(也称作SARS-CoV)的β冠状病毒和引起CoVID-19的SARS-CoV-2病毒,CoVID-19是一种以发热、咳嗽和呼吸短促为特征的呼吸系统疾病,其可发展成肺炎和呼吸衰竭。
如本文所用,术语“包膜病毒”指具有脂质双层包膜的病毒。
如本文所用,术语“DNA病毒”是指以DNA为遗传物质并利用DNA依赖性DNA聚合酶复制的病毒。
如本文所用,术语“RNA病毒”是指以RNA为遗传物质并利用RNA依赖性RNA聚合酶进行复制的病毒。
如本文所用,术语“逆转录病毒”是指以RNA为遗传物质并利用逆转录酶进行复制的病毒。
具体实施方式
本发明涉及用于治疗由包膜病毒引起的病毒感染的组合物和方法。本文所述的组合物包括高生物利用度的硫化氢前药,其特别适用于抗包膜病毒。本发明的高度生物可利用的富含零价硫的组合物含有至少96%的易于生物转化为硫化氢的生物活性零价硫。包膜病毒被源于感染细胞外膜的脂质双层包裹。通常,病毒对病毒靶向药物的抗性比对宿主细胞靶向药物的抗性更容易发展。硫化氢和/或硫化氢衍生的硫烷硫靶向病毒包膜。因此,包膜病毒很难例如通过突变对本文所述的组合物产生抗性。此外,组合物可保护细胞免受病毒感染诱导的氧化应激,并增强受试者的免疫系统,例如患有病毒感染或有患病毒感染的风险。将在下面更详细地描述组合物和方法。
富含硫的组合物
高生物利用度的富含零价硫的组合物的制备
在一个实施方案中,高生物利用度的富含零价硫的组合物通过以下概述的过程I获得,以制备2.7kg批量的包含高生物利用度的零价硫的组合物。起始材料列于表1中,合适的设备列于表2中。
表1:起始材料
*含有约30%水和70%NaHS
表2:设备
过程I
向装有高扭矩搅拌器(显示为7-8)的200L主反应容器中含有的20L蒸馏水中,在快速搅拌下分批加入4.890kg Na2S2O5。希望在3-5分钟内完成加入,并应当努力防止粉末形成团块。将7.090kg NaHS.xH2O溶解在装有低扭矩搅拌器的80L辅助反应容器中含有的15L蒸馏水中。使用Kitasato-Buchner组件在减压下将NaHS溶液过滤通过3张Whatman#1滤纸。滤液收集在19L容器中。应当注意,通常只有极少量的杂质保留在滤纸上。
接着,洗涤80L辅助反应容器,并将过滤的NaHS溶液从19L容器转移到80L辅助反应容器。将30L蒸馏水加入到含有过滤的NaHS溶液的80L辅助反应容器中。将1.458kg浓硫酸(98%)倒入10L容器中含有的2.25kg冰和2.25kg蒸馏水的搅拌混合物中。接下来的两个步骤应同时进行,并且应持续40分钟。立即将600mL Na2S2O5溶液倒入含有搅拌的NaHS溶液的辅助反应容器中,并在良好搅拌的情况下开始将稀硫酸溶液(5.958kg)加入(从加料漏斗)到同一容器中。搅拌应产生一直到螺旋桨的涡流。佩戴全面罩(装有吸酸筒),向装有Na2S2O5溶液的主反应容器中加入2.5kg冰。在快速搅拌下开始倒入小份浓硫酸(4.95kg)。交替加入酸和冰以防止溶液升温。测量两个反应容器中溶液的温度。200L主反应容器中的溶液(Na2S2O5+H2SO4)的温度应该约为0℃,80L辅助反应容器中的溶液(NaHS+一点Na2S2O5+H2SO4)的温度应该在30-35℃之间。向200L反应容器(Na2S2O5+H2SO4)中加入5kg冰块,然后在快速搅拌下(显示速度刻度为24.5-25),将80L辅助反应容器(NaHS+一点Na2S2O5+H2SO4)中的溶液注入其中。该操作应花费约10分钟,并且搅拌应产生一直到螺旋桨的涡流。在混合这两种溶液时,反应混合物应从无色变为金黄色,流动性增加,有一些起泡,并分离出黄色沉淀。测量反应混合物的最终温度及其pH值。温度应在25-30℃之间,pH应接近3。继续快速搅拌90分钟。搅拌应产生一直到螺旋桨的涡流。
使反应混合物在室温下静置24小时不受干扰。在该阶段结束时,黄色沉淀物应当以相对致密的物质的形式位于容器的底部。在不扰动沉淀物的情况下,通过倾析或虹吸将尽可能多的液相转移到不同的容器中。将剩余在反应容器中的材料(约20L)转移到40L塑料或玻璃容器中,并搅拌1小时以获得均匀的浆料。使用Buchner-Kitasato组件通过#1Whatman滤纸过滤浆料。用1L蒸馏水洗涤滤饼或直到滤液显示不为酸性。为了防止沟流,应当在滤饼形成裂缝之前进行洗涤。洗涤后立即保持施加真空10分钟以上。过度干燥将导致高度致密的滤饼,并且将在随后的步骤中造成很大困难。推荐使用橡胶或塑料过滤坝(或类似装置)。将相对干燥的滤饼转移到10L塑料容器中,并加入7L纯无水乙醇。搅拌至固体全部悬浮,并保持搅拌1小时。如果悬浮液太稠,则加入更多的无水乙醇。通过#1Whatman滤纸过滤悬浮液,用200mL无水乙醇洗涤滤饼,将橡胶坝放置在顶部并保持施加真空不超过10分钟。过度干燥将导致高度致密的滤饼,并且将在随后的步骤中造成很大困难。将滤饼转移至大型玻璃或不锈钢托盘上进行室温风干。干燥约4天或直至恒重且无乙醇气味。干燥产物是由易碎团块和不可吸收粉末组成的材料。将团块和筛子分解,以确保材料通过325标准筛子。
过程I产生含有约99%零价硫和约1%高极性组分(例如硫酸钠以及痕量连多硫酸钠和硫代硫酸钠)的产物(SG-1002,也称作SG1002)。
在一些实施方案中,可以使用过程I的变化来获得类似的材料。此类过程包括但不限于以下步骤:
过程II
使用硫化钠代替氢硫化钠,并按照本领域技术人员熟知的规则调节反应物的量,诸如按照过程I中详细描述的方法增加酸的量。
过程III
使用亚硫酸钠代替偏重亚硫酸钠,并按照本领域技术人员熟知的规则,按照过程I中详细描述的方法调节反应物的量。
过程IV
使用硫化钠代替氢硫化钠以及亚硫酸钠代替焦亚硫酸钠,并按照本领域技术人员熟知的规则,按照过程I中详细描述的方法调节反应物的量。
过程V
使用浓盐酸代替浓硫酸,等摩尔替换,并按照I中详细描述的方法进行。
过程VI
使用浓盐酸代替浓硫酸,等摩尔替换,并按照过程II中详细描述的方法进行。
过程VII
使用浓盐酸代替浓硫酸,等摩尔替换,并按照处III中详细描述的方法进行。
过程VIII
使用浓盐酸代替浓硫酸,等摩尔替换,并按照过程IV中详细描述的方法进行。
过程IX
使用钾盐代替钠盐,并按照本领域技术人员熟知的规则,按照过程I中详细描述的方法调节试剂的量。
在一些实施方案中,在过程中使用的反应物可以包括任何包含负2氧化态的硫的化合物和包含正4氧化态的硫的另一种化合物,以及可选的酸和/或催化剂。
在其它实施方案中,真空辅助过滤可以由压力辅助过滤和/或离心代替。在其它实施方案中,可以使用密闭反应器,热交换冷却系统可以代替冰添加,喷雾干燥可以代替空气干燥,并且可以省略一个和/或多个步骤(例如,用醇洗涤)。应当理解,涉及较大或较小操作规模的实施方案也在本发明的范围之内。
高生物利用度的富含零价硫的组合物的表征
干燥筛分产物的标准产率为2.7kg具有以下性质的无色、无味、蓬松、浅黄色微晶粉末:
·熔化范围:平均熔化温度在约117℃和约121℃±2-3℃之间(例如,熔化发生在118-120℃、116-119℃或119-120℃之间)。
·零价硫含量(w/w):90-99.9%(例如91%、92%、93.5%、94%、96%、96.5%、97.1%、97.5%、98%、98.6%、98.9%或99.5%)
·单质α硫含量(w/w):90-99.9%(例如91%、92%、93.5%、94%、96%、97.1%、97.5%、98%、98.6%、98.9%或99.5%)
·高极性组分(w/w):0.01-10%(例如、0.02%、0.1%、0.25%、0.5%、0.8%、1%、1.5%、2%、3%、4%、5%、5.5%、6%、7%、8%、9%、9.5%或9.9%)
·25℃下在水中的溶解度:0%
·在二硫化碳中的溶解度:87-97%
·表观密度(拍实):-0.6g/ml
·中值粒度分布:约26和约33微米之间(例如26.5、27、27.3、28、28.5、29、29.5、30、31.3、32、32.5或32.9)
·钠含量:~0.03%
·氧含量(以差计):-0.12%
通过遵守过程I获得的组合物由富含零价硫的微晶组成;其在二硫化碳中的溶解度低于α硫(菱形硫),并含有可测量量的钠和氧。该组合物的X-射线衍射图谱与α硫的X-射线衍射图谱一致。
用于获得本文所述数据的方法包括以下步骤。通过将6mL二硫化碳加入到0.500g最终产物中并测定残留物的重量,获得该组合物在二硫化碳中的溶解度。通过亚硫酸分解测定零价硫含量,考虑到亚硫酸分解将S8中的所有硫原子转化为硫代硫酸盐,而Na+-O3S-Sn-SO3 -Na+中仅有(n-1)个硫原子,不校正硫解。钠含量由美国Galbraith Laboratories测定(GLI Procedure ME-70)。使用购自Horiba Instruments的Partia LA-950激光衍射粒度分析仪测量粒度分布。
不受任何假设的限制,上述材料的高生物利用度可能与晶体表面的亲水性有关,这又可能与高极性基团诸如-SO3Na和/或=SO3Na2的存在有关。这些基团可以是存在于连多硫酸盐分子中的那些基团(Na+-O3S-Sn-SO3 -Na+,例如,其中n=1、2或3)、硫代硫酸盐或硫酸盐。高极性基团诸如-SO3Na可以与水合水分子缔合,并且在某些情况下可以进行阳离子交换,产生例如-SO3H基团。此外,这种独特的微晶材料表面的亲水性与纯α或β单质硫晶体表面的疏水性形成鲜明对比。相反,纯α或β单质硫完全可溶于二硫化碳。同样不受任何假设或理论的限制,普通α硫的低生物利用度很可能与其表面的疏水性直接相关。
在一些实施方案中,组合物可以是微米级或纳米级的,包括富含α硫的颗粒,但总是被改性以具有亲水性表面。同样在本发明范围内的类似组合物可以通过本领域已知的任何化学、电化学、机械化学、声化学、光化学、微波辅助、生物化学和/或生物技术方法获得。包含单质β硫和表面改性极性基团的组合物进一步构成本发明的实施方案。正如所确立的,单质α硫在加热时转化为β硫,反之亦然。
高生物利用度的富含零价硫的组合物中零价硫含量的测定
一方面,可使用本文所述的方法来测定本发明组合物的零价硫含量,以测量α硫、硫代硫酸钠和连多硫酸钠中零价硫的百分比(w/w)。本文所述的测定零价硫含量的亚硫酸分解方法不校正,这是考虑到连多硫酸盐分子的亚硫酸分解终止于三硫代酸盐,如方程式(ii)所示,因此,存在于每个连多硫酸盐分子中的一个零价硫原子逃过亚硫酸分解而不转化为硫代硫酸盐(方程式(ii))。然而,由于本文公开的组合物的钠含量很小,因此在计算%零价硫时引入的误差相应也很小。亚硫酸分解的详细分析描述于Koh等人,Anal.Sci.6:3-14,1990。
按照Morris等人,Anal.Sci.20:1037-1039,1948报道的定量测定芳烃中单质硫的体积法进行亚硫酸分解反应方程式(i)和(ii)。与Morris等人的方法相比,本发明所述的亚硫酸分解方法以几种方式得到了改进,包括使用正十六烷基吡啶鎓氯化物作为亚硫酸分解催化剂。
方程式(i)S8+8SO3 2-→8S2O3 2-
方程式(ii)-O3S-Sn-SO3 -+(n-1)SO3 2-→(n-1)S2O3 2-+-O3S-S-SO3 -
表3中示出了试剂溶液和溶液的制备方法。
表3:试剂溶液和制备方法
为了测定零价硫含量,称取0.160g±10mg组合物放入250mL锥形瓶中。向烧瓶中加入10mL 15% Na2SO3溶液。将烧瓶置于水浴中并加热直至水沸腾。然后加入0.5ml 1%十六烷基吡啶氯化物一水合物溶液,继续加热直至固体完全消失。使烧瓶内的内容物冷却至室温,并在烧瓶内放置磁力搅拌棒。搅拌下,加入15mL甲醛溶液、25mL 6N溶液、10mL 10%KI溶液、1mL 0.5%可溶性淀粉指示液。所得溶液应当是无色的。使用25mL滴定管用0.2N KIO3溶液滴定烧瓶中的内容物。滴定开始时,烧瓶中的内容物变为琥珀色,但颜色很快消失。当接近等效点时,要非常小心,以免越出。当滴定溶液的液滴不产生颜色变化时,达到终点。
方程式(iii):滴定反应IO3 -+5l-+6H++6S2O3 2-→6l -+3S4O6 2-+3H2O
方程式(iv):
%零价硫*=(VKIO3(mL)×NKIO3×32.07×100)/(1000×样品重量(g))
*易发生亚硫酸分解
病症和疾患
本文所述的组合物可用于治疗病毒感染,例如由包膜病毒引起的病毒感染。包膜病毒可以是DNA病毒、RNA病毒或反转录病毒。
在一些实施方案中,包膜病毒是DNA病毒。DNA病毒可以是例如疱疹病毒科、痘病毒科或多形包膜病毒科。疱疹病毒科可以是例如单纯疱疹病毒、水痘带状疱疹病毒、巨细胞病毒或EB病毒。痘病毒科可以是例如天花病毒、牛痘病毒、绵羊痘病毒、口疮病毒、猴痘病毒或牛痘病毒。
在一些实施方案中,包膜病毒是RNA病毒。RNA病毒可以是例如披膜病毒科、沙粒病毒科、黄病毒科、正粘病毒科、副粘病毒科、布尼雅病毒科、弹状病毒科、丝状病毒科、冠状病毒科、博尔纳病毒科或动脉炎病毒科。披膜病毒科可以是例如风疹病毒、东马脑炎病毒、西马脑炎病毒、委内瑞拉马脑炎病毒、西门利克森林病毒、辛德比斯病毒、罗斯河病毒、巴马森林病毒、基孔肯雅病毒、马亚罗病毒、欧尼恩病毒、乌纳病毒或图那特病毒。沙粒病毒科可以是例如淋巴细胞性脉络丛脑膜炎病毒或拉沙热。黄病毒科可以是例如登革热病毒、丙型肝炎病毒、黄热病毒、西尼罗病毒或寨卡病毒。正粘病毒科可以是例如甲型流感病毒、乙型流感病毒、丙型流感病毒、鲑传染性贫血病毒或托高土流感病毒。副粘病毒科可以是例如麻疹病毒、流行性腮腺炎病毒、呼吸道合胞病毒(RSV)、牛瘟病毒、犬瘟热病毒或人副流感病毒(HPIV)。HPIV可以是例如HPIV-1、HPIV-2、HPIV-3或HPIV-4。布尼雅病毒科可以是例如加利福尼亚脑炎病毒或辛诺柏病毒;弹状病毒科是狂犬病病毒或水泡性口炎病毒。丝状病毒科可以是例如埃博拉病毒或马尔堡病毒。冠状病毒科可以是例如α冠状病毒、β冠状病毒、δ冠状病毒或γ冠状病毒。β冠状病毒可以是例如与中东呼吸综合征相关的冠状病毒(MERS-CoV)、严重急性呼吸综合征冠状病毒(SARS-CoV)或严重急性呼吸综合征冠状病毒2(SARS-CoV-2)。博尔纳病毒科可以是例如博尔纳病病毒。动脉炎病毒科可以是例如动脉炎病毒或马动脉炎病毒。
在一些实施方案中,包膜病毒是反转录病毒。反转录病毒可以是例如逆转录病毒科或嗜肝DNA病毒科。逆转录病毒科可以是例如人类免疫缺陷(HIV)病毒。HIV可以是HIV-1或HIV-2。嗜肝DNA病毒科可以是例如乙型肝炎病毒。
在一些实施方案中,方法包括治疗由非HIV或AIDS的包膜病毒引起的病毒感染。
在一些实施方案中,方法包括治疗由非病毒性肝炎的包膜病毒引起的病毒感染。
在一些实施方案中,方法包括治疗由非RSV的包膜病毒引起的病毒感染。
β冠状病毒感染
本文所述的药物组合物可用于治疗β冠状病毒(例如MERS-CoV,SARS-CoV或SARS-CoV-2)感染。β冠状病毒是冠状病毒的一种,引起肺外涉及的呼吸道感染。β冠状病毒可进一步分为四个谱系:谱系A(包括HCoV-OC43和HCoV-HKU1)、谱系B(包括SARS、SARS-CoV-2)、谱系C(包括BtCoV-HKU4、BtCoV-HKU5和MERS)和谱系D(包括BtCoV-HKU9)。这些病毒在人类群体中是特有的,并且在新生儿、老年人和患有潜在疾病的个体中引起更严重的疾病,在这些群体中下呼吸道感染的发生率更高。
SARS-CoV-2感染
本文所述的药物组合物可用于治疗SARS-CoV-2感染。CoVID-19是由SARS-CoV-2冠状病毒引起的呼吸道感染。SARS-CoV-2可以从人传播到人(例如,彼此密切接触的人(例如,在6英尺之内)并且通过被SARS-CoV-2病毒感染的人咳嗽或打喷嚏时产生的呼吸液滴并且液滴可以与另一人接触(例如,接触鼻、口、眼和/或吸入肺中),从而使该人暴露于病毒。也可以通过接触被病毒污染的表面,然后接触他们自己的口、鼻或眼,使人暴露于SARS-CoV-2。CoVID-19症状发作前的潜伏期约为暴露于SARS-CoV-2后2-14天。该疾病的症状可包括发烧、咳嗽和呼吸困难。症状的严重程度可以从轻度(例如,无报道症状)到重度疾病,包括导致死亡的疾病。老年人和具有潜在健康状况的所有年龄段的人都处于发展成严重疾病的较高风险中。如果受试者已经暴露于被诊断为患有该疾病的人、最近旅行到CoVID-19暴发的地点、是老年人或者是免疫受损的人,那么他们可能有患CoVID-19的风险。本领域技术人员可基于症状或诊断检测(例如,ELISA、检测SARS-CoV-2抗体的侧向流色谱免疫分析或AbbotID NOWTM平台)将受试者诊断为患有CoVID-19。
药物组合物
本文所述的方法包括施用含有高度生物可利用的富含零价硫的组合物的药物组合物,或本文所述高度生物可利用的富含零价硫的组合物之一与第二治疗剂(例如,抗炎药物、抗生素、抗病毒(例如抗逆转录病毒)剂和/或膳食补充剂)的组合。
药物组合物可以通过本领域已知的各种方法施用。正如本领域技术人员所理解的,施用途径和/或方式将根据所需结果而变化。药物组合物可配制成胃肠外、鼻内、局部、口服或局部施用,诸如通过透皮途径,用于预防和/或治疗性治疗。药物组合物可以胃肠外(例如,通过静脉内、肌内或皮下注射)、或通过口服摄取、或通过局部施用、或关节内注射在受血管或癌症状况影响的区域施用。其它施用途径包括血管内、动脉内、瘤内、腹膜内、心室内、硬膜外以及鼻、眼、巩膜内、眼眶内、直肠、局部或气雾剂吸入施用。缓释施用也具体地包括在本发明中,通过诸如积存注射或可侵蚀的植入物或组分的方式。因此,本发明提供了用于胃肠外施用的组合物,其包含溶解、胶态分散或悬浮在可接受的载体中的上述试剂,所述载体优选为水性载体,例如水、缓冲水、生理盐水、PBS等。组合物可含有接近生理条件所需的药学上可接受的辅助物质,诸如pH调节剂和缓冲剂、张力调节剂、润湿剂、活性剂等。
治疗组合物可以是溶液的形式、用于植入的胶态分散体、悬浮液、乳剂、输注装置或递送装置,或其可以作为干粉存在,在使用前直接使用或用水或其它合适的载体重构。组合物可制成片剂、胶囊剂(例如硬明胶胶囊剂和软明胶胶囊剂)、液体或口服缓释片剂;或用于静脉内、鞘内、皮下或胃肠外施用的液体;或局部施用的乳膏或软膏,或局部施用的聚合物或其它缓释载体。
发现了本领域公知的制备制剂的方法,例如《雷明顿药物科学(RemingtonsPharmaceutical Sciences)》(2012,第22版)和《美国药典:国家处方集(The UnitedStates Pharmacopeia:The National Formulary)(USP 41NF 36)》,于2018年出版。用于肠胃外施用的制剂可例如包含赋形剂、无菌水、盐水、聚亚烷基二醇(诸如聚乙二醇)、植物来源的油或氢化萘。生物相容的、可生物降解的丙交酯聚合物、丙交酯/乙交酯共聚物或聚氧乙烯-聚氧丙烯共聚物可用于控制物质的释放。纳米颗粒制剂(例如,可生物降解的纳米颗粒、固体脂质纳米颗粒、脂质体)可用于控制物质的生物分布。其它潜在有用的递送系统包括乙烯-乙酸乙烯酯共聚物颗粒、渗透泵、鞘内泵、可植入输注系统和脂质体。制剂中物质的浓度根据许多因素而变化,包括待施用药物的剂量和施用途径。
为了通过某些施用途径施用本发明的组合物,可能需要用防止其失活的材料涂覆该组合物或者用该材料共同施用该组合物。例如,可在适当的载体(例如脂质体或稀释剂)中向受试者施用该组合物。药学上可接受的稀释剂包括生理盐水和含水缓冲液。脂质体包括水包油包水CGF乳液以及常规脂质体(Strejan等人,J.Neuroimmunol.7:27-41,1984)。药学上可接受的载体包括用于临时制备无菌可注射胶体溶液或分散体的无菌水溶液或分散体和无菌粉末。此类介质和试剂在药学活性物质中的用途是本领域已知的,并且包括在本发明中,除非任何常规介质或试剂与活性物质不相容。补充活性物质也可掺入组合物中。
治疗组合物通常在制造和储存条件下必须是无菌的和稳定的。该组合物可配制成悬浮液、微乳剂、脂质体或其它适合于高药物浓度的有序结构。载体可以是溶剂或分散介质,其含有例如水、乙醇,凡士林(例如)、多元醇(例如甘油、丙二醇和液体聚乙二醇等)及其合适的混合物,其以不同的百分比(例如,在本文所述的分散介质中为按重量5、10、15、20、25、30、35、40、45或50%)配制。例如,可以通过使用诸如卵磷脂的涂层,通过在分散的情况下保持所需的颗粒尺寸以及通过使用表面活性剂来保持适当的流动性。在许多情况下,组合物中优选包括等渗剂,例如糖、多元醇,诸如甘露醇、山梨醇或氯化钠。可注射组合物的延长吸收可通过在组合物中包括延迟吸收的试剂(例如单硬脂酸盐和明胶)来实现。胶体分散体可以通过加入本领域公知的试剂而稳定。
本文所述的组合物可通过常规灭菌技术灭菌或无菌过滤。得到的含水分散体可以原样包装使用或者冷冻干燥,在施用之前将冷冻干燥的制剂与无菌的含水载体结合。制剂的pH通常为3-11,更优选5-9或6-8,最优选7-8,诸如7-7.5。所得固体或半固体形式的组合物可以多个单剂量单位包装,每个单位含有固定量的组合物,诸如片剂或胶囊的密封包装。固体形式的组合物也可以包装在容器中,用于柔性量,诸如在设计用于局部应用的乳膏或软膏的可挤压管中。
本发明的一些制剂包括但不限于:硬明胶胶囊制剂,其含有例如100mg至400mg本发明的高生物利用度的富含零价硫的组合物;悬浮液制剂,其含有约5-20%(5.5%、6%、6.5%、7%、8%、10%、15%、17%或19%)本发明的高生物利用度的富含零价硫的组合物和凡士林(例如)或聚乙二醇;或约5-20%(5.5%、6%、6.5%、7%、8%、10%、15%、17%或19%)本发明的高生物利用度的富含零价硫的组合物在水或油中的胶体分散体。
无菌可注射胶态悬浮液可通过将所需量的活性化合物与上述一种或多种组分的组合按需混合在适当的溶剂中,然后可选地进行灭菌微滤来制备。通常,通过将活性化合物掺入无菌载体来制备分散体,该无菌载体含有碱性分散介质以及来自以上列举的那些的所需其它组分。调节给药剂量方案以提供最佳的所需反应(例如,治疗或预防反应)。例如,可以施用单个丸,可以随着时间施用几个分开的剂量或者可以根据治疗或预防情况的紧急情况按比例减少或增加剂量。例如,本发明的组合物可以通过皮下注射每周施用一次或两次或者通过皮下注射每月施用一次或两次。
配制剂量单位形式的胃肠外组合物以易于施用和剂量均匀性是特别有利的。本文所用的剂量单位形式是指适于作为待治疗对象的整体剂量的物理上离散的单位;每单位含有预定量的活性化合物,计算该活性化合物的预定量以产生所需的治疗或预防效果,可选地,与所需药物载体结合。本发明的剂量单位形式的规格由以下所决定并直接取决于:(a)活性物质的独特特性和所要达到的特殊治疗或预防效果,以及(b)复合此类活性物质用于治疗个体的敏感性的本领域固有的局限性。
当本发明的物质作为药物施用于人和动物时,它们可以单独施用或作为药物组合物施用,该药物组合物含有例如1-100%(更优选10-100%,诸如90-100%)的活性成分,可选地与一种或多种药学上可接受的载体或赋形剂组合。
含有有效量的组合物可施用于预防性或治疗性治疗。在预防性应用中,组合物可施用于具有临床确定的病毒感染发展倾向或易感性增加的患者。本发明的组合物可以以足以延迟、减少或优选防止病毒感染发作的量施用于患者(例如人)。在治疗应用中,以足以治愈或至少部分阻止病毒感染症状及其并发症(例如病毒感染症状,例如咳嗽或肺炎)的量向已患有病毒感染的患者(例如人)施用组合物。足以实现该目的的量被定义为“治疗有效剂量”足以显著改善与病毒感染相关的某些症状的化合物的量。例如,在病毒感染的治疗中减少、预防、延迟、抑制或阻止疾病或病症的任何症状的药剂或物质将是治疗有效的。治疗有效量的药剂或物质不是治疗疾病或病症所需的,而是提供对疾病或病症的治疗,使得延迟、阻止或预防疾病或病症的发作,或改善疾病或病症症状,或改变疾病或病症的时期,或例如减轻个体中的严重程度或加速康复。
当本发明的物质和制剂与其它药剂联合治疗施用时,它们可以依次或同时施用于个体。可替代地,药物组合物可以包括本文所述的物质或制剂(可选地与本文所述的药学上可接受的赋形剂联合)与本领域已知的另一种治疗剂或预防剂的组合。
所配制的试剂可以作为试剂盒包装在一起。非限制性实例包括试剂盒,该试剂盒含有例如两种丸剂、丸剂和粉末剂、栓剂和药瓶中的液体、两种外用乳膏等。试剂盒可包括有助于向患者施用单位剂量的可选组分,诸如用于重构粉末形式的小瓶、用于注射的注射器、定制的静脉内递送系统、吸入器等。另外,单位剂量试剂盒可含有用于制备和施用组合物的说明。试剂盒可被制造为用于一个患者的单次使用单位剂量、用于特定患者的多种用途(以恒定剂量或其中各个化合物的效力可随着治疗进程而变化);或者试剂盒可以含有适于向多个患者施用的多个剂量(“散装”)。试剂盒部件可以组装在纸箱、泡罩包装、瓶、管等中。
剂量
本发明的药物组合物通过本领域技术人员已知的常规方法配制成药学上可接受的剂型。本发明药物组合物中活性成分的实际剂量水平可以改变,以获得有效量的活性成分,从而达到特定患者所需的治疗效果、组合物和施用方式,而对患者没有毒性。所选择的剂量水平将取决于各种药代动力学因子,包括所用的本发明特定组合物的活性、施用途径、施用时间、使用的特定试剂的吸收速率、治疗的持续时间、与所用特定组合物联合使用的其它药物、物质和/或材料、被治疗患者的年龄、性别、体重、状况、总体健康状况和既往病史、以及医学领域众所周知的类似因素。具备本领域普通技术的医师或兽医可以容易地确定并开出所需药物组合物的有效量。例如,医师或兽医可以以低于所需的水平开始药物组合物中使用的本发明物质的剂量,以达到所需的治疗效果,并逐渐增加剂量,直到达到所需的效果。通常,本发明组合物的适宜日剂量将是有效产生治疗效果的最低剂量的物质的量。此类有效剂量通常取决于上述因素。治疗组合物的有效日剂量可作为2、3、4、5、6或更多个子剂量在一天中以适当的间隔分开施用,可选地以单位剂型施用。
治疗剂量水平可以包括例如约10mg至约10000mg(例如约10mg至约100mg,例如约10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg或100mg;例如约100mg至约1000mg,例如约200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg或1000mg;例如约1000mg至约2000mg,例如约1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg、1800mg、1900mg或2000mg;例如约2000mg至约3000mg,例如约2100mg、2200mg、2300mg、2400mg、2500mg、2600mg、2700mg、2800mg、2900mg或3000mg;例如约3000mg至约4000mg,例如约3100mg、3200mg、3300mg、3400mg、3500mg、3600mg、3700mg、3800mg、3900mg或4000mg;例如约4000mg至约5000mg,例如约4100mg、4200mg、4300mg、4400mg、4500mg、4600mg、4700mg、4800mg、4900mg或5000mg;例如约5000mg至约6000mg,例如约5100mg、5200mg、5300克、5400mg、5500mg、5600mg、5700mg、5800mg、5900mg或6000mg;例如约6000mg至约7000mg,例如约6100mg、6200mg、6300mg、6400mg、6500mg、6600mg、6700mg、6800mg、6900mg或7000mg;例如约7000mg至约8000mg,例如约7100mg、7200mg、7300mg、7400mg、7500mg、7600mg、7700mg、7800mg、7900mg或8000mg;例如约8000mg至约9000mg,例如约8100mg、8200mg、8300mg、8400mg、8500mg、8600mg、8700mg、8800mg、8900mg或9000mg;例如约9000mg至约10000mg,例如约9100mg、9200mg、9300mg、9400mg、9500mg、9600mg、9700mg、9800mg、9900mg或10000mg)的活性富含零价硫的组合物。在一些实施方案中,治疗剂量水平为每天约800mg至约1600mg(例如约800mg、850mg、900mg、1000mg、1050mg、1100mg、1200mg、1300mg、1400mg、1450mg、1500mg、1550mg或1600mg)的活性富含零价硫的组合物口服施用于患有本文所述的大多数症状、综合征和病理状况的平均体重的成人。在一些实施方案中,预防剂量水平为约100mg至约1200mg(例如约100mg、110mg、140mg、200mg、250mg、300mg、350mg、400mg、460mg、700mg、750mg、800mg、900mg、1000mg、1100mg。在一些实施方案中,口服剂量水平为约2400mg/天或更高(例如约2450mg、2500mg、3000mg、3500mg、4000mg、8000mg或10000mg/天)。对于儿童,例如患有癌症的儿童,可以滴定剂量(例如,剂量可以逐渐增加,直到出现胃肠道毒性的征兆,诸如腹泻或恶心)。在优选的实施方案中,高生物利用度的富含零价硫的组合物对于口服施用是非常安全的,并且随着治疗的进行,大多数患者能够耐受更高的剂量。
在其它实施方案中,本发明的高生物利用度的富含零价硫的组合物对于局部施用是安全的。局部施用的可接受剂型可配制成乳膏、洗剂、糊剂、凝胶和/或软膏剂,其含有高生物利用度的富含零价硫的组合物。
适于施用于人类受试者的最终剂型可包含一种高生物利用度的富含零价硫的组合物作为药理学活性剂或进一步包含:其它活性剂,诸如α硫辛酸、肉碱、酒石酸肉碱、富马酸肉碱、辅酶Q10、硒、α酮戊二酸、α酮戊二酸钾、α酮戊二酸二乙酯、草酰乙酸、草酰乙酸钠、草酰乙酸二乙酯、2-氧代-3-(乙氧羰基)-戊二酸二乙酯、L-胱氨酸、对乙酰氨基酚、磺胺类药物、NSAID、皮质类固醇、牛磺酸、维生素、益生元;另一种抗癌药物,包括但不限于另一种促细胞分裂素(例如靶向线粒体电子传输链的药物)、烷基化剂(例如丙卡巴嗪、达卡巴嗪、六甲蜜胺、顺铂)、氨甲蝶呤、嘌呤拮抗剂(例如巯嘌呤、硫鸟嘌呤、克拉屈滨、喷司他丁)、嘧啶拮抗剂(例如氟尿嘧啶、阿糖胞苷、氮杂胞苷)、植物生物碱(例如长春花碱、依托泊苷、托泊替康)、激素剂(例如他莫昔芬、氟他胺)、抗生素(例如阿霉素、柔红霉素、丝裂霉素、博来霉素)和mitocans(例如二氯乙酸钠和3-溴丙酮酸)。
联合疗法
本发明提供了用于治疗或预防受试者病毒感染的方法,该方法通过向受试者施用本文所述的组合物以及一种或多种另外的治疗剂。其中用两种或更多种药剂的联合疗法来治疗受试者,可以依次(例如,间隔1天、间隔2天、间隔3天、间隔1周、间隔1个月、间隔6个月或更长)或基本上同时(例如,在1天内)施用药剂。两种或更多种药剂可被配制为单一药物组合物或可作为分开的药物组合物施用。两种或更多种药剂可以通过相同施用途径或不同施用途径施用。两种或更多种药剂可以以相同频率或不同频率施用。
抗病毒剂
在一些实施方案中,本文所述的组合物与一种或多种抗病毒剂联合施用。在一些实施方案中,抗病毒剂是瑞德西韦。在一些实施方案中,所述抗病毒剂是法匹拉韦。在一些实施方案中,抗病毒剂是法维拉韦。在一些实施方案中,抗病毒剂是EIDD-2801。在一些实施方案中,抗病毒剂是加利地韦。在一些实施方案中,抗病毒剂是SNG001。在一些实施方案中,抗病毒剂是洛匹那韦、利托那韦或洛匹那韦与利托那韦的组合。在一些实施方案中,抗病毒剂是洛匹那韦。在一些实施方案中,抗病毒剂是利托那韦。
抗病毒疫苗
在一些实施方案中,本文所述的组合物与疫苗(例如,在受试者中引发针对病毒的免疫应答的组合物,该病毒例如为β冠状病毒,诸如SARS-CoV疫苗、SARC-CoV-2疫苗或MERS-CoV疫苗)。疫苗可以与组合物基本上同时施用(例如,在相同药物组合物中或在分开的药物组合物中)或者可以在组合物之前或之后施用(例如在1天、2天、5天、1周、2周、3周、1个月、2个月、6个月或12个月或更长时间内)。
抗真菌剂
在一些实施方案中,本文所述的组合物与一种或多种抗真菌剂联合施用。在用于治疗有此需要的受试者的感染的上述联合疗法的一些实施方案中,抗真菌剂为阿尼芬净、卡泊芬净、米卡芬净、两性霉素B、杀念珠菌素、非律平(filipin)、哈霉素、那他霉素、制霉菌素、龟裂杀菌素、联苯苄唑、布康唑、克霉唑、益康唑、芬替康唑、异康唑、酮康唑、卢立康唑、咪康唑、奥莫康唑、奥昔康唑、舍他康唑、硫康唑、噻康唑、三唑、阿巴康唑、艾氟康唑、氟环唑、氟康唑、艾沙康唑、伊曲康唑、泊沙康唑、丙环唑、雷夫康唑、特康唑、伏立康唑、阿巴芬净、阿莫罗芬、布替萘芬、萘替芬、特比萘芬、环吡酮、氟胞嘧啶、灰黄霉素、托萘酯或十一碳烯酸。
抗细菌剂
在一些实施方案中,本文所述的任何一种组合物与一种或多种抗细菌剂联合施用。上述联合治疗的一些实施方案用于治疗有此需要的受试者的感染,抗细菌剂是阿米卡星、庆大霉素、卡那霉素、新霉素、奈替米星、妥布霉素、帕罗霉素、链霉素、大观霉素、格尔德霉素、除莠霉素、利福昔明、氯碳头孢、厄他培南、多尼培南、亚胺培南/西司他丁、美罗培南、头孢羟氨苄、头孢唑林、头孢噻吩、头孢氨苄、头孢克洛、头孢孟多、头孢西丁、头孢丙嗪、头孢呋辛、头孢克肟、头孢地尼、头孢地托伦、头孢哌酮、头孢噻肟、头孢泊肟、头孢噻嗪、头孢噻布汀、头孢唑肟、头孢曲松、头孢吡肟、头孢洛林酯(ceftaroline fosamil)、头孢托罗、替考拉宁、万古霉素、特拉万星、达巴万星、奥利万星、克林霉素、洁霉素、达托霉素、阿奇霉素、克拉霉素、地红霉素、红霉素、罗红霉素、醋竹桃霉素、泰利霉素、螺旋霉素、氨曲南、呋喃唑酮、呋喃妥因、利奈唑胺、泼斯唑胺(posizolid)、瑞德唑胺(radezolid)、托瑞唑胺(torezolid)、阿莫西林、氨苄西林、阿洛西林、卡宾西林、氯唑西林、双氯西林、氟氯西林、美洛西林、甲氧西林、萘西林、草酸西林、青霉素g、青霉素v、哌拉西林、青霉素g、替莫西林、替卡西林、阿莫西林克拉维酸盐、氨苄西林/舒巴坦、哌拉西林/他唑巴坦、替卡西林/克拉维酸盐、杆菌肽、粘菌素、多粘菌素b、环丙沙星、依诺沙星、加替沙星、吉米沙星、左氧氟沙星、洛美沙星、莫西沙星、萘啶甲酸、诺氟沙星、氧氟沙星、曲伐沙星、格雷帕沙星、司帕沙星、替马沙星、磺胺米隆、磺胺乙酰胺、磺胺嘧啶、磺胺嘧啶银、磺胺二甲氧嘧啶、磺胺甲基咪唑、磺胺甲恶唑、磺胺酰亚胺、柳氮磺吡啶、磺胺异恶唑、甲氧苄啶-磺胺甲恶唑(tmp-smx)、磺酰胺基金霉素、地美环素、多西环素、二甲胺四环素、土霉素、四环素、氯法齐明、氨苯砜、卡卷曲霉素、环丝氨酸、乙胺丁醇(bs)、乙硫异烟胺、异烟肼、吡嗪酰胺、利福平、利福布汀、利福喷丁、链霉素、胂凡纳明、氯霉素、磷霉素、夫西地酸、甲硝唑、莫匹罗星、平板霉素、奎奴普丁/达福普丁、砜霉素、老虎霉素、替硝唑和甲氧苄啶。
在一些实施方案中,抗细菌剂是阿奇霉素。在一些实施方案中,抗细菌剂是环丙沙星。上述列表是本领域技术人员已知的用于治疗感染的抗细菌剂的实例,而非限制本发明的范围。
抗炎剂
在一些实施方案中,本文所述的组合物与一种或多种抗炎剂联合施用。在一些实施方案中,抗炎剂是托珠单抗。在一些实施方案中,抗炎剂是沙立芦单抗。在一些实施方案中,抗炎剂是AmnioBoost。在一些实施方案中,抗炎剂是来氟米特。在一些实施方案中,抗炎剂是氨甲蝶呤。在一些实施方案中,抗炎剂是柳氮磺吡啶。在一些实施方案中,抗炎剂是abatercept。在一些实施方案中,抗炎剂是利妥昔单抗。在一些实施方案中,抗炎剂是托珠单抗。在一些实施方案中,抗炎剂是阿那白滞素。在一些实施方案中,抗炎剂是阿达莫单抗。在一些实施方案中,抗炎剂是依那西普。在一些实施方案中,抗炎剂是英夫利西单抗。在一些实施方案中,抗炎剂是聚乙二醇结合赛托珠单抗。在一些实施方案中,抗炎剂是戈利木单抗。
抗寄生虫剂
在一些实施方案中,抗寄生虫剂是羟基氯喹。在一些实施方案中,抗寄生虫剂是氯喹。
膳食补充剂
组合物可与一种或多种膳食补充剂联合施用,以促进和/或维持总体健康。膳食补充剂的实例包括但不限于维生素(例如维生素A、维生素B1、B2、B3、B5、B6、B7、B9、B12、维生素C、维生素D、维生素E和维生素K)、矿物(例如钾、氯、钠、钙、镁、磷、锌、铁、锰、铜、碘、硒和钼)、草药或植物(例如圣约翰草、卡瓦、喜来芝和中草药)、氨基酸(例如甘氨酸、丝氨酸、蛋氨酸、半胱氨酸、天冬氨酸、谷氨酸、谷氨酰胺、色氨酸和苯丙氨酸)以及浓缩物、组分、提取物和/或上述任何物质的组合。
止痛剂
组合物可与止痛剂或退烧剂联合施用。例如,组合物可以与对乙酰氨基酚一起施用。组合物可与布洛芬一起施用。
其他实施方案
虽然已经结合本发明的特定实施方案描述了本发明,但是应当理解,能够进行进一步的修改,并且本申请旨在覆盖总体上遵循本发明的原理的本发明的任何变化、使用或改变,并且包括在本发明所属领域内的已知或常规实践内的与本发明的此类偏离,并且可以应用于上文阐述的基本特征。
所有出版物、专利和专利申请通过引用以其整体并入本文,其程度如同每个单独的出版物、专利或专利申请被具体地和单独地指明通过引用以其整体并入。
Claims (23)
1.一种治疗或预防由包膜病毒引起的受试者病毒感染的方法,所述方法包含以足以治疗或预防病毒感染的量和持续时间向所述受试者施用药物组合物,所述组合物包含90-99.9%(w/w)单质α硫、0.01-10%(w/w)高极性组分和药学上可接受的赋形剂。
2.根据权利要求1所述的方法,其中,所述包膜病毒是DNA病毒。
3.根据权利要求2所述的方法,其中,所述DNA病毒是疱疹病毒科、痘病毒科或多形包膜病毒科。
4.根据权利要求3所述的方法,其中:
所述疱疹病毒科是单纯疱疹病毒、水痘带状疱疹病毒、巨细胞病毒或EB病毒;或者
所述痘病毒科是天花病毒、牛痘病毒、绵羊痘病毒、口疮病毒、猴痘病毒或牛痘病毒。
5.根据权利要求1所述的方法,其中,所述包膜病毒是RNA病毒。
6.根据权利要求5所述的方法,其中,所述RNA病毒是披膜病毒科、沙粒病毒科、黄病毒科、正粘病毒科、副粘病毒科、布尼雅病毒科、弹状病毒科、丝状病毒科、冠状病毒科、博尔纳病毒科或动脉炎病毒科。
7.根据权利要求6所述的方法,其中:
所述披膜病毒科是风疹病毒、东马脑炎病毒、西马脑炎病毒、委内瑞拉马脑炎病毒、西门利克森林病毒、辛德比斯病毒、罗斯河病毒、巴马森林病毒、基孔肯雅病毒、马亚罗病毒、欧尼恩病毒、乌纳病毒或图那特病毒;
所述沙粒病毒科是淋巴细胞性脉络丛脑膜炎病毒或拉沙热;
所述黄病毒科是登革病毒、丙型肝炎病毒、黄热病毒、西尼罗病毒或寨卡病毒;
所述正粘病毒科是甲型流感病毒、乙型流感病毒、丙型流感病毒、鲑传染性贫血病毒或托高土流感病毒;
所述副粘病毒科是麻疹病毒、流行性腮腺炎病毒、呼吸道合胞病毒(RSV)、牛瘟病毒、犬瘟热病毒或人副流感病毒(HPIV);
所述布尼雅病毒科是加利福尼亚脑炎病毒或辛诺柏病毒;
所述弹状病毒科是狂犬病毒或水泡性口炎病毒;
所述丝状病毒科是埃博拉病毒或马尔堡病毒;
所述冠状病毒科是α冠状病毒、β冠状病毒、δ冠状病毒或γ冠状病毒;
所述博尔纳病毒科是博尔纳病病毒;或者
所述动脉炎病毒科是动脉炎病毒或马动脉炎病毒。
8.根据权利要求7所述的方法,其中,所述HPIV是HPIV-1、HPIV-2、HPIV-3或HPIV-4。
9.根据权利要求7所述的方法,其中,所述β冠状病毒是与中东呼吸综合征相关的冠状病毒(MERS-CoV)、严重急性呼吸综合征冠状病毒(SARS-CoV)或严重急性呼吸综合征冠状病毒2(SARS-CoV-2)。
10.根据权利要求9所述的方法,其中,所述β冠状病毒是SARS-CoV-2。
11.根据权利要求1所述的方法,其中,所述包膜病毒是反转录病毒。
12.根据权利要求11所述的方法,其中,所述反转录病毒是逆转录病毒科或嗜肝DNA病毒科。
13.根据权利要求12所述的方法,其中:
所述逆转录病毒科是人类免疫缺陷(HIV)病毒;或者
所述嗜肝DNA病毒科是乙型肝炎病毒。
14.根据权利要求13所述的方法,其中,所述HIV是HIV-1或HIV-2。
15.根据权利要求1至14中任一项所述的方法,其中,所述组合物包含约99%(w/w)零价硫和约1%(w/w)高极性组分,其中所述高极性组分选自硫酸钠、连多硫酸钠和硫代硫酸钠。
16.根据权利要求1至14中任一项所述的方法,其中,所述高极性组分选自连多硫酸钠、连多硫酸钾、连多硫酸铵、连多硫酸钙、硫代硫酸钠、硫代硫酸钾、硫代硫酸铵、硫代硫酸钙、硫酸钠、硫酸钾、硫酸铵、重亚硫酸钠、重亚硫酸钾、重亚硫酸铵、重亚硫酸钙、氯化钠、氯化钾、氯化铵、氯化钙、醋酸钠、棕榈酸钠、棕榈酸钾和月桂酸铵。
17.根据权利要求1至16中任一项所述的方法,其中,所述组合物包含单质α硫以及一种或多种高极性组分,其比例为约10至约150份单质α硫比1份高极性组分(w/w),用于肠内、局部或胃肠外施用。
18.根据权利要求17所述的方法,其中,所述组合物被配制用于肠内施用,并且所述单质α硫和所述高极性组分一起以约400mg的量存在。
19.根据权利要求1至18中任一项所述的方法,其中,所述组合物是胶囊。
20.根据权利要求1至19中任一项所述的方法,其中,所述组合物包含第二治疗剂。
21.根据权利要求20所述的方法,其中,所述第二治疗剂是抗病毒剂、抗病毒疫苗、抗真菌剂、抗细菌剂、抗炎剂、抗寄生虫剂、膳食补充剂或止痛剂。
22.根据权利要求21所述的方法,其中:
所述抗病毒剂是瑞德西韦、法匹拉韦、法维拉韦、EIDD-2801、加利地韦、SNG001、洛匹那韦、利托那韦或其组合;
所述抗细菌剂是阿奇霉素或环丙沙星,
所述抗炎剂是托珠单抗,
所述抗寄生虫剂是氯喹或羟基氯喹;
所述膳食补充剂是维生素C;或者
所述止痛剂是对乙酰氨基酚。
23.根据权利要求1至22中任一项所述的方法,其中,所述组合物通过以下步骤产生:
(a)提供包含-2氧化态硫的第一无机化合物;以及
(b)使所述第一无机化合物与包含+4氧化态硫的第二无机化合物在酸性pH下反应,其中所述反应产生的组合物包含:
(i)90-99%(w/w)单质α硫和0.01-10%(w/w)高极性组分;以及
(ii)其中所述组合物包含至少96%易于生物转化为硫化氢的生物活性零价硫。
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