CN116347998A - 免疫调节配方及相关方法 - Google Patents
免疫调节配方及相关方法 Download PDFInfo
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- CN116347998A CN116347998A CN202180070061.3A CN202180070061A CN116347998A CN 116347998 A CN116347998 A CN 116347998A CN 202180070061 A CN202180070061 A CN 202180070061A CN 116347998 A CN116347998 A CN 116347998A
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Abstract
一种用于免疫调节的组合物及相应的方法。该组合物包括由药学上可接受的载体与活性成分混合形成的乳剂。药学上可接受的载体占组合物的15wt%至85wt%。活性成分包括有效量的大麻提取物以提供外源性大麻素来源、有效量的大麻素增强剂以抑制大麻素水解酶、有效量的脂肪酸酰胺以通过随行效应增强大麻素活性、有效量的卡瓦胡椒提取物以减轻焦虑和有效量的生物碱以增强所述活性成分中的一种或多种活性成分的生物利用度。
Description
相关申请
本申请要求于2020年8月13日提交的美国临时专利申请63/065,301号的优先权,出于所有目的其全部内容通过引用并入本文。
技术领域
本公开涉及用于治疗和/或预防由冠状病毒感染引起的疾病或病症的方法和组合物。
背景技术
SARS-CoV-2(COVID-19)是一种表面有包膜状和刺突状突起的有义RNA病毒。冠状病毒可以感染包括人在内的多种脊椎动物。冠状病毒可表现为多种症状,从轻微到严重(例如流感、发烧、咳嗽、疲劳、呼吸急促、下呼吸道感染、肺炎、肺小血管纤维化伴血栓形成等),甚至死亡。冠状病毒还可能导致与免疫应答失控相关的并发症,例如弥散性血管内凝血(DIC)。疾病的严重程度可取决于感染个体的免疫系统效率和共病的存在。共同特征是强烈的炎症反应,表现为C反应蛋白(CRP)升高、促炎细胞因子(IL-6、IL-10、IL-1)产生、更高的TNF-α、中性粒细胞计数、D-二聚体和血尿素。SARS-CoV-2在人群中的传播率为0.8%–3%,高于普通流感,并以高亲和力与血管紧张素转换酶2(ACE2)结合以感染人。
发明内容
所公开的原理提供了一种用于针对冠状病毒进行免疫调节的组合物、一种制造该组合物的方法、和用于对抗和治疗冠状病毒以及在人中发现的由冠状病毒感染引起的症状的免疫调节方法。
在一个实施方式中,该组合物包括由药学上可接受的载体与活性成分混合形成的乳剂。药学上可接受的载体占组合物的15wt%至85wt%。活性成分包括有效量的大麻提取物以提供外源性大麻素来源、有效量的大麻素增强剂以抑制大麻素水解酶、有效量的脂肪酸酰胺以通过随行效应(entourage effect)增强大麻素活性、有效量的卡瓦胡椒提取物以减轻焦虑和有效量的生物碱以增强所述活性成分中的一种或多种活性成分的生物利用度。如本文所用,术语“有效量”是指在本领域技术人员的合理判断范围内,化合物可以显著诱导对所治疗病症的积极改变、但足够低以避免不期望的副作用的足够量。化合物的有效量可以随所治疗的特定病症、所治疗的生物对象的年龄和病症、病症的严重程度、治疗的持续时间以及本领域技术人员的知识和专业知识范围内的其他因素而变化。
在另一个实施方式中,制造组合物的方法可以包括将药学上可接受的载体与活性成分组合以形成溶液的步骤。活性成分包括有效量的大麻提取物以提供外源性大麻素来源、有效量的大麻素增强剂以抑制大麻素水解酶、有效量的脂肪酸酰胺以通过随行效应增强大麻素活性和有效量的生物碱以增强所述活性成分中的一种或多种活性成分的生物利用度。该方法还包括以下步骤:将溶液冷却至低于约60℃的温度,将卡瓦胡椒提取物添加至冷却的溶液,并进一步将冷却的溶液冷却至低于约0℃的温度以形成组合物。
附图说明
为了更完整地理解本公开及其优点,现参考以下描述和附图,其中:
图1说明了根据说明性实施方式的形成免疫调节组合物的方法的流程图;
图2说明了根据说明性实施方式的将药学上可接受的载体与活性成分组合以形成溶液的方法的流程图;以及
图3说明了根据说明性实施方式的使用免疫调节组合物治疗疾病的方法的流程图。
具体实施方式
以下详细描述包括本公开的示例性实施方式并且参考形成其一部分的附图。示出本文的附图以说明可以实践所公开的原理的实施方式。在不脱离本公开的范围的情况下,将使用可包括做出结构改变和修改的其他实施方式。
目前,COVID-19的支持治疗主要集中在病毒引起的副作用,如炎症和肺纤维化(公认的首要死亡原因),以及对症和呼吸支持(氧气治疗和体外膜氧合)。在某些情况下,会向患者施用恢复期血浆和免疫球蛋白G。通常用于对抗流感病毒的抗病毒药物和全身性皮质类固醇治疗对治疗COVID-19无效。为保护个体免受病毒侵害而开发的疫苗在预防感染方面并不完全有效。此外,一些疫苗已被证明对COVID-19病毒的突变体具有降低的作用。
SARS-CoV-2病毒如此“成功”并因此变得危险的原因之一是它可以抑制这种非特异性免疫反应。此外,它还能让人体细胞产生病毒蛋白PLpro(木瓜蛋白酶样蛋白酶)。PLpro有两个功能:它在新病毒颗粒的成熟和释放中发挥作用,以及它抑制1型干扰素的发展。干扰素(IFN)是一组信号传导蛋白,由宿主细胞产生并响应于多种病毒的存在而释放。IFN属于称为细胞因子的一大类蛋白质,细胞因子是用于细胞间通讯的分子,可触发免疫系统的保护性防御,从而帮助根除病原体。干扰素因其通过保护细胞免受病毒感染而“干扰”病毒复制的能力而得名。IFN还具有多种其他功能:它们激活免疫细胞,例如自然杀伤细胞和巨噬细胞;它们通过增加主要组织相容性复合体(MHC)抗原的表达来上调抗原呈递,从而增强宿主防御。某些感染症状,如发烧、肌肉疼痛和“流感样症状”,也是由IFN和其他细胞因子的产生所引起的。
大麻素(cannabinoids)可以下调细胞因子和趋化因子的产生,并且在某些模型中,上调T调节细胞以抑制炎症反应。内源性大麻素系统也参与免疫调节。例如,施用内源性大麻素或使用分解内源性大麻素的酶的抑制剂会导致免疫抑制和免疫介导的器官(如肝脏)损伤的恢复。在体内操纵内源性大麻素和/或使用外源性大麻素可以构成针对炎性疾病的有效治疗方式。
本文所公开的化合物可用作免疫调节的多受体方法(免疫能力加强剂)来对抗和治疗冠状病毒(例如COVID-19)以及包括多发性硬化症(MS)、莱姆病和淋巴瘤在内的其他自身免疫相关疾病的可能性。所公开的化合物的成分的公开制剂可以协同“免疫调节”或调节/增强免疫功能,并且还可以降低高血压。所公开的化合物可包括这样的组分(即成分),已显示出这些组分(即成分)调节SARS CoV-2病毒进入体内的组织中的ACE2表达并下调被病毒用于在ACE2位点进行S蛋白引发(S protein priming)的TMPRSS2(HHoffmann et al.,2020)。所公开的组分会刺激1型干扰素的释放,并对抗由病毒产生的物质PlPro,PlPro产生和释放新病毒并抑制1型干扰素的发展(Hoffmann et al.,2020)。所公开的化合物可以与CB2激动剂一起靶向经典的2型大麻素受体或CB2受体以释放干扰素。
ACE2代表血管紧张素转换酶2,其是一种位于人体中多种细胞表面的蛋白质。ACE2受体介导三种冠状病毒株进入细胞:SARS-CoV、NL63和SARS-CoV-2。ACE2受体无处不在,广泛表达于心脏、血管、肠道、肺(特别是2型肺细胞和巨噬细胞中)、肾脏、睾丸和大脑中。ACE2主要与细胞膜结合,很少以可溶形式存在于循环中。膜结合和可溶性ACE2的一个重要有益功能是将血管紧张素II降解为血管紧张素1-7。因此,ACE2受体限制了血管紧张素II与AT1受体结合所产生的几种不利影响,包括血管收缩、炎症加剧和血栓形成。血管紧张素1-7生成的增加也通过与G蛋白偶联Mas受体结合而触发反调节保护作用。
不幸的是,SARS-CoV2通过膜融合进入细胞会显著下调ACE2受体,从而使在膜外部的这些受体的催化作用丧失。据报道,增加的肺部炎症和凝结是通过ACE→血管紧张素II→AT1受体轴导致的增强和不受反抗的血管紧张素II作用的不良影响。感染SARS-CoV-2的患者显示出,与感染和疾病严重程度(例如,高龄、高血压、糖尿病、心血管疾病)相关的几个特征都存在不同程度的ACE2缺乏。关于所公开的化合物,由病毒入侵引起的ACE2下调可能对患有与上述病症相关的基线ACE2缺乏的人有害。病毒入侵后额外的ACE2缺乏可能会放大“不利”ACE→血管紧张素II→AT1受体轴与“保护性”ACE2→血管紧张素1-7→Mas受体轴之间的失调。在肺部,这种失调将有利于由不受血管紧张素1-7反抗的局部血管紧张素II过度活跃所引发的炎症和血栓形成过程的进展(Hoffmann et al.,2020)。ACE2很重要,因为它与SARS-CoV-2结合。ACE2氨基酸形成凹槽状的口袋,SARS-CoV-2的刺突刚好放入或“结合”该口袋。这就是SARS-CoV-2劫持细胞并开始复制,从而产生COVID-19感染的地方。因此,ACE2的表达越多,主题冠状病毒要侵入和传播的结合位点就越多。通过调节通路组织中ACE2表达,我们降低了冠状病毒侵入细胞的能力,这既降低了疾病易感性,也减少了当前感染个体的进入点。
虽然ACE2是病毒进入的受体,但TMPRSS2引发病毒刺突蛋白,因此对于SARS-CoV2进入宿主细胞至关重要。最近的研究表明,TMPRSS抑制剂阻止病毒进入。已显示一些大麻(C.sativa)提取物下调EpiOral和EpiIntestinal组织中的TMPRSS2基因表达(Wang etal.,2020)。
还显示出公开的组分刺激内源性白细胞介素-1受体以释放促抗炎细胞因子Il-1Ra,从而增强抗炎细胞因子IL-4、IL-10和IL-6肌细胞因子的释放。这会阻止COVID-19产生的“细胞因子风暴”。
可以使用所公开的化合物通过以多种方式调节免疫系统来减轻COVID-19的症状。所公开的化合物中的至少一种包括被FDA认为是天然的、GRAS的(通常认为是安全的)、作为营养补充剂出售的化合物,或者是内源性神经化学物质。所公开的化合物可集中于内源性大麻素系统。大麻素已证明了其下调细胞因子和趋化因子产生并上调T调节细胞(Treg)以抑制炎症反应的能力。内源性大麻素系统也参与免疫调节。例如,施用内源性大麻素或使用内源性大麻素分解酶的抑制剂导致免疫抑制和免疫介导的器官(如肝脏)损伤的恢复。在体内操纵内源性大麻素和/或使用外源性大麻素可以构成针对炎性疾病的有效治疗方式。
可以配制本文所公开的化合物以靶向人大麻素系统。例如,该化合物可靶向经典的1型大麻素受体(CB1)和2型大麻素受体(CB2)、GPR55和GPR119。此外,所公开的化合物可以靶向IL-1B以及TRPV离子通道。不同类型的eCBE的例子包括脂肪酸酰胺水解酶(FAAH)抑制剂。它增强了人体中大麻素的作用和持续时间。所选择的大麻素以及配方中的eCBE可以是天然存在的。所公开的化合物可利用已显示对CB2受体具有高亲和力的大麻素。CB2的刺激已被证明可以减少SARS-CoV-2患者的炎症反应,改善患者的整体状况。考虑到CB2减少大量细胞因子产生的能力,CB2的刺激在若干个检查点控制炎症级联。此外,通过利用来自多个来源的多种大麻素并通过eCBE增强它们的效果,我们创造了一种通常被称为“随行效应(Entourage effect)”的东西。随行效应是一种拟议的机制,通过这种机制,除四氢大麻酚(THC)外,大麻化合物与其(彼此)协同作用以调节植物(大麻素)的整体作用。除了大麻素系统,我们还靶向γ-氨基丁酸A型受体(GABAAR)以降低高血压并给予舒适感。
所公开的化合物的一些组分可以是内源性大麻素增强剂(eCBE),其可用于通过增加内源性大麻素的细胞外浓度来增强内源性大麻素系统的活性。所公开的化合物可包含eCBE和对CB2受体具有高亲和力的大麻素,因为刺激CB2受体可以减少SARS-CoV-2患者的炎症反应并释放干扰素(IFN)。用激动剂靶向大麻素受体会产生IL-1ra受体,这是一种重要的抗炎细胞因子。通过靶向大麻素系统,所公开的化合物可以增强IL-1ra的释放,从而刺激免疫系统产生抗炎细胞因子。抗炎细胞因子的产生阻止了新病毒的释放和产生。所公开的化合物还可以刺激“信使”干扰素的释放,它告诉身体哪个细胞被感染并通知相邻细胞增强它们的防御能力。可以配制所公开的化合物以靶向γ-氨基丁酸A型受体(GABAAR),其降低高血压并提供舒适感。
促炎细胞因子在感染性或非感染性起源的炎性疾病中起着核心作用。PAMP和DAMP触发细胞因子级联反应,该细胞因子级联反应最初由促炎细胞因子(IL-1、IL-6、IL-8、IL-12、IFN-γ、IL-18和TNF本身)组成(Srinivasan et al.,2017)。这些细胞因子通过激活局部和全身炎症反应来控制和解决炎症灶。TNF还触发阻断促炎细胞因子合成的抗炎细胞因子以及阻断促炎细胞因子作用的细胞因子抑制剂的细胞因子级联。在大多数情况下,炎症反应被成功解决。然而,过度产生细胞因子或无法停止促炎细胞因子的产生,会导致体循环中细胞因子浓度增加(“细胞因子风暴”)。这种持续的细胞因子产生会对宿主产生有害影响,导致低血压、血管内血栓形成、肺水肿和出血;如果任这个过程发展,它会导致多器官衰竭和死亡。这种情况通常被称为全身炎症反应综合征(SIRS)。该术语描述了导致血管通透性增加的广泛内皮炎症的临床表现。这种病症是一组不同病症例如细菌性脓毒症、局部缺血、烧伤、外伤和组织损伤以及失血性休克的启动病理过程。
很明显,促炎和抗炎介质之间的相互作用调节炎症反应。抗炎细胞因子,特别是IL-10,抑制促炎细胞因子合成和粘附分子表达,同时增加特定细胞因子抑制剂的水平。然而,抗炎细胞因子的过量产生可损害宿主通过抑制免疫细胞功能清除微生物的能力。如果不保持平衡,结果要么是过度的促炎反应,要么是免疫抑制和对继发感染的易感性增加。因此,细胞因子级联可通过启动炎症反应而对宿主有益;然而,促炎或抗炎内源性介质的过度产生或产生不足实际上可能对宿主有害(Srinivasan et al.,2017)。
迄今为止,针对促炎细胞因子(如TNF和IL-1β)的治疗策略已被证明对SIRS的治疗无效——促炎介质拮抗剂的多项临床试验表明没有改善,并且在某些情况下,存活率会恶化。促炎细胞因子对炎症反应的启动至关重要;然而,它们的水平可能在SIRS的临床体征和症状变得明显之前就已经达到峰值。此外,虽然过度炎症反应可能是一些脓毒症相关死亡病例的原因,但在许多其他情况下,主要的抗炎反应或整体细胞因子抑制可能才是原因,特别是在免疫系统较弱的人群中,例如新生儿或老年人。因此,最近的治疗方法更多地集中在免疫调节或免疫刺激介质上,例如粒细胞-单核细胞集落刺激因子或IL-7,它在淋巴细胞补给中具有重要作用。此外,在疾病进展后期出现的介质也可能有望在严重脓毒症和自身免疫性疾病的情况下对不受控制的炎症进行治疗干预。诸如HMGB1、线粒体DNA和热休克蛋白以及线粒体甲酰肽的DAMP是重要的晚期促炎介质。HMGB1最初被鉴定为DNA结合蛋白,现在被认为是脓毒症和SIRS的晚期介质。HMGB1在炎症反应期间由巨噬细胞和内皮细胞主动释放,也由坏死细胞被动释放。HMGB1在局部和全身介导许多促炎作用。针对HMGB1的抗体或拮抗剂在脓毒症和SIRS动物模型中具有保护作用。
另一种晚期促炎介质即巨噬细胞抑制因子最初被确定为巨噬细胞迁移的调节剂;它现在被认为是炎症反应的关键调节剂。在感染和脓毒症动物模型中,抗巨噬细胞抑制因子治疗显著提高了存活率。因此,这些“晚期”促炎介质可为SIRS的治疗提供新的治疗靶点。选择性靶向DAMP相关炎症反应同时允许对PAMP产生适当免疫反应的策略在SIRS和脓毒症的背景下特别令人感兴趣。外源性和内源性大麻素均抑制通过Toll样受体(TLR)刺激的巨噬细胞产生促炎细胞因子。TLR在巨噬细胞感知危险以触发炎症反应中起着至关重要的作用。更进一步地,麦卢卡蜂蜜(Manuka honey)的抗菌特性(使其有别于传统蜂蜜)也可以引入示例性所公开的配方中。甲基乙二醛是其活性成分,可能是产生这些抗菌作用的原因。此外,麦卢卡蜂蜜具有抗病毒、抗炎和抗氧化益处。
组合物的配制
在一般实施方式中,组合物是由活性成分与药学上可接受的载体混合形成的乳剂。活性成分可包括大麻提取物、大麻素增强剂、脂肪酸酰胺、卡瓦胡椒(kava)提取物和生物碱。在更具体的实施方式中,药学上可接受的载体是中链甘油三酯(MCT),大麻素增强剂是油酰胺,脂肪酸酰胺是十六酰胺乙醇(PEA),生物碱是胡椒碱。在一些实施方式中,组合物可包含卵磷脂。
MCT可以是己酸、辛酸、癸酸、月桂酸或其任何组合。本文所公开的化合物的MCT可通过本领域已知的各种分离技术从天然来源例如椰子油和/或棕榈仁油获得。MCT可用作制备本文公开的化合物的溶剂。例如,本文公开的化合物可以在MCT中制成酊剂形式。使用酊剂介质促进舌下粘膜吸收可能是有利的,这有助于患者插管的情况。
卡瓦胡椒提取物可包含一种或多种卡瓦内酯。卡瓦胡椒提取物中的卡瓦内酯可以是去甲氧基甲氧醉椒素、麻醉椒苦素、甲氧醉椒素(yangonin)、二氢麻醉椒苦素、二氢醉椒素、醉椒素(kavain)、10-甲氧基甲氧醉椒素、11-甲氧基甲氧醉椒素、11-羟基甲氧醉椒素、11-甲氧基-12-羟基脱氢醉椒素、7,8-二氢甲氧醉椒素、5-羟基醉椒素、5,6-二氢甲氧醉椒素、7,8-二氢醉椒素、5,6,7,8-四氢甲氧醉椒素、5,6-脱氢麻醉椒苦素、7,8-二氢麻醉椒苦素或其任何组合。
已证明卡瓦内酯可有效缓解焦虑。例如,已证明醉椒素无论亚基组成如何都能正向调节所有受体。醉椒素已证明α4β2δGABAAR有更大程度的增强。卡瓦内酯还显示出能够诱导由脊柱上位点引导的a和g脊柱运动系统衰减,并且据报道它还是CYP450酶(CYP1A2、2C9、2C19、2D6、3A4和4A9/11)的抑制剂,这有助于肌肉放松。此外,卡瓦内酯可以抑制钙通道,而各种卡瓦内酯可能会产生叠加作用,从而减少差不多70%的钙内流。因此,卡瓦内酯可促进对神经元放电的广泛抑制。
还发现一些卡瓦内酯可抑制钠通道,这进一步促进了抑制作用。卡瓦内酯可具有其他有益的精神活性属性。还证明了卡瓦内酯能够可逆地阻断血小板MAO B酶。已证明醉椒素有能力成为人MAO-B的良好效力体外抑制剂。醉椒素与MAO-A和MAO-B可逆且竞争性地相互作用。已证明甲氧醉椒素能够成为对MAO-A和MAO-B特别有效的MAO抑制剂。因此,卡瓦内酯的一些中枢作用(例如,抗焦虑)可由MAO抑制作用介导。卡瓦胡椒-卡瓦胡椒提取物能够成为完整血小板和破碎的血小板匀浆中MAO-B的可逆抑制剂。卡瓦胡椒吡喃酮的结构差异导致不同的MAO-B抑制效力。在至少一个例子中,选择的卡瓦胡椒吡喃酮的效力顺序是去甲氧基甲氧醉椒素>麻醉椒苦素>甲氧醉椒素>二氢麻醉椒苦素>二氢醉椒素>醉椒素。在这个例子中,两种最有效的卡瓦胡椒吡喃酮(去甲氧基甲氧醉椒素和麻醉椒苦素)促进了特别高的抑制模式。因此,为了抑制MAO-B的精神影响活性,包含富含卡瓦胡椒吡喃酮的提取物可能是有利的。
一种主要的抗焦虑卡瓦内酯-醉椒素在人重组体中的功能特性可包括使用双电极电压钳技术在非洲爪蟾卵母细胞中表达的α1β2、β2γ2L、αxβ2γ2L(x=1、2、3和5)、α1βxγ2L(x=1、2和3)和α4β2δGABAAR。已证明醉椒素无论亚基组成如何都能正向调节所有受体的能力,但在α4β2δ处显示出比α1β2γ2L GABAAR更高程度的增强(Ligresti et al.,2012)。相比CB2受体(Ki>10μM),甲氧醉椒素对人重组CB1受体具有亲和力(Ki=0.72μM)和选择性。甲氧醉椒素的CB1受体亲和力表明内源性大麻素系统可能有助于传统卡瓦酒和从卡瓦胡椒植物中获得的抗焦虑制剂的复杂的人精神药理学。
本领域已知卵磷脂包含糖脂、甘油三酯和磷脂。合适的磷脂的例子可以是磷酸胆碱(phosphate-dylcholine)、磷脂酰乙醇胺和磷脂酰肌醇。已证明大豆卵磷脂能够实现包封、控制释放和成功地将治疗因子递送到细胞内区域,在这些区域中,它们从其灵活的物理化学和生物物理特性(例如大的水性中心和生物相容性脂质、自组装、可调属性和高负载能力)中获得这些特性。SARS-CoV2使用肺作为其复制的动力装置。大豆卵磷脂可用于增加半衰期和靶向肺部的递送(用于气溶胶或可能可蒸发的产品)。
大豆卵磷脂脂质体作为药物载体,已证明具有治疗结核病(TB)的能力。大豆卵磷脂脂质体可以提供额外的生物学机制,即以较低的用量和最小的副作用实现抗TB药物的靶向施用,同时规避结核分枝杆菌菌株的耐药机制。纳米装置,如脂质体,提供了很需要的额外的生物学机制,即以较低的用量和最小的副作用实现抗TB药物的靶向施用,同时规避结核分枝杆菌菌株的耐药机制。在某些情况下,吸入的药物可能更适合作为治疗策略,因为它们能够到达支气管树的空洞病变,在那里细菌明显存在,并且结核分枝杆菌菌株迅速繁殖。与不含脂质体的可吸入干粉配方相比,在脂质体的帮助下,抗TB疗法的半衰期和靶向效率可以得到提高。然而,先前的研究记录了抗TB药物在脂质体中包埋的某些困难。在一个例子中,当乙硫异烟胺用于掺入脂质膜时,捕获效率增加到42%,但药物与脂质的当量摩尔比太低(为0.04),无法达到预期的治疗效果。脂质体是较小的球形人工囊泡,可由天然磷脂和无毒胆固醇制成(Cruz et al.,2009),旨在改善化合物在体内特定位置的生物分布。因此,它们被认为是生物活性化合物的载体,具有增强和/或改变与其相关的化合物的活性的能力。这种影响取决于化学组成和磷脂结构(Machado et al.,2014)。一种基于脱水和再水化过程来制备DRV型脂质体的方法,包括混合小的空脂质体悬浮液(在水中制备),混合后冷冻干燥。在温度(>Tt)和脂质浓度的特定条件下制备这种再水化导致获得具有高包封率的脂质体,称为DRV(“脱水再水化囊泡”)并允许高包封率(Frézard et al.,2005)。由于简单和低成本,用于生产纳米级脂质体的脂质膜水化的经典方法仍然被使用(Mertins,2004)。在本公开中,应用作为互补技术的雾化、冻干、搅拌、超声处理和冻融挤压使结构标准化。
大麻提取物可包含一种或多种大麻素。大麻素作用于神经胶质和神经元以抑制促炎分子的释放,促炎分子包括白细胞介素1(IL-1)、肿瘤坏死因子(TNF)α和一氧化氮(NO)(Molina-Holgado et al.,1997,2002;Shohami et al.,1997;Puffenbarger et al.,2000;Cabral et al.,2001),并增强抗炎细胞因子IL-4、IL-10(Klein et al.,2000)和IL-6(Molina-Holgado et al.,1998)的释放。具体来说,用激动剂靶向大麻素受体会产生IL-1ra,这是一种重要的抗炎细胞因子。然而,值得注意的是,CB1和CB2受体均调节内源性IL-1ra的释放。CB的神经保护作用机制可用于响应由CB1和CB2受体依赖性途径介导的炎症或兴奋性毒性损伤。此外,抗炎细胞因子IL-1ra是CB对神经元和神经胶质作用的重要介质,并且CB1和CB2受体均调节IL-1ra从原代培养的神经胶质细胞中释放。因此,通过靶向大麻素系统,我们可以通过增强Il1-ra的释放来介导Il-1,从而刺激免疫系统产生介导PLpro的作用的抗炎细胞因子,进而阻止新病毒释放和产生的作用。所公开的化合物和/或配方可刺激身体细胞“信使”干扰素的释放,它会告诉身体哪个细胞受到感染,并告诉相邻细胞加强其防御。
大麻提取物中的大麻素可以是以下中的任何一种:N-酰基乙醇胺、山柰酚、任意N-烷基酰胺类、芸香素、3,3'-二吲哚基甲烷、virodhamine、几内亚胡椒酰胺(guineesine)、大麻二酚(CBD)、任意四氢大麻酚(THC)异构体、萜烯类中的任何一种、蛇麻烯或其任何组合。与N-酰基乙醇胺键合的官能团的一些实例可包括亚油酰基、油酰基和棕榈酰基。N-酰基乙醇胺可作为FAAH抑制剂。N-酰基乙醇胺也可以靶向GPR55受体。不同浓度的山柰酚可作为MAGL和FAAH抑制剂。例如,山奈酚作为MAGL抑制剂在IC50<100nM的浓度下可以是治疗有效的。此外,山柰酚作为FAAH抑制剂在IC50<1μM的浓度下可以是治疗有效的。N-烷基酰胺在不同浓度下表现出对CB2受体的选择性亲和力。例如,N-烷基酰胺在Ki值<100nM的浓度下,在选择CB2受体方面可以是治疗有效的。N-烷基酰胺还表现出靶向(ECS)PPAR、离子通道、抑制AEA转运、部分FAAH抑制剂的能力。芸香素在不同浓度下表现出对CB2受体的选择性亲和力。例如,在Ki值<10μM的浓度下,芸香素在选择CB2受体方面可以是治疗有效的。3,3'-二吲哚基甲烷在不同浓度下对CB2受体表现出选择性亲和力。例如,3,3'-二吲哚基甲烷在Ki值的浓度下在选择CB2受体方面可以是治疗有效的。3,3'-二吲哚基甲烷是CB2受体的部分激动剂。Virodhamine(O-花生四烯酸乙醇胺(O-arachidonoyl ethanolamine);O-AEA)是一种内源性大麻素和非经典类花生酸。内源性大麻素增强剂(eCBE)是一种大麻素能药物,其可通过增加内源性大麻素的细胞外浓度来增强内源性大麻素系统的活性。不同类型的eCBE的例子包括脂肪酸酰胺水解酶(FAAH)抑制剂。它增强了人体中大麻素的作用和持续时间。
O-花生四烯酸乙醇胺是通过酯键连接的花生四烯酸和乙醇胺,与花生四烯酸乙醇胺(anandamide)中的酰胺键相反。Virodhamine作为CB1受体的拮抗剂和CB2受体的激动剂。人海马体中的virodhamine浓度与花生四烯酸乙醇胺的浓度相似,但在表达CB2的外周组织中virodhamine浓度可能是花生四烯酸乙醇胺的浓度的2到9倍。O-AEA是CYP2J2表氧化酶的抑制剂。总之,O-AEA作为CYP2J2的eCB抑制剂可以控制体内心血管CYP2J2的活性,并可能串扰心血管内源性大麻素和细胞色素P450系统之间的相互作用。几内亚胡椒酰胺可作为大麻素运输调节剂。几内亚胡椒酰胺可能抑制花生四烯酸乙醇胺和2-花生四烯酰甘油的细胞再摄取。这会导致被归类为大麻素的两种神经递质的活性增加。几内亚胡椒酰胺可以剂量依赖性地产生拟大麻(cannabimimetic)效应,这表现为强效的紧张症、镇痛、运动能力减退和体温过低效应。在不同浓度下,几内亚胡椒酰胺在体外也是一种单胺氧化酶抑制剂(MAOI)。例如,几内亚胡椒酰胺在IC50=139.2μM时可以是治疗有效的。几内亚胡椒酰胺已表现出抑制内毒素血症中促炎细胞因子产生的能力。因此,在所公开的化合物中包含几内亚胡椒酰胺是有利的。
CBD已证明通过CB2依赖机制调节炎症过程的能力。CBD可以通过增加AEA水平间接诱导CB2激活。CBD通过减少促炎细胞因子发挥其抗炎特性。已证明CBD能够充当免疫抑制剂,其机制可能涉及直接抑制各种免疫细胞类型的激活、诱导细胞凋亡和促进调节细胞,进而控制其他免疫细胞靶点。抑制的靶标可包括细胞因子,例如TNF-α、IFN-γ、IL-6、IL-1β、IL-2、IL-17A和趋化因子,例如CCL-2。通常,CBD可以通过抑制激酶级联和各种转录因子来抑制靶细胞,例如效应T细胞和小胶质细胞。例如,CBD诱导的磷酸化p38抑制可能导致AP-1或NF-κB活性受损。直接抑制靶细胞还可包括诱导IκB,这可能有助于降低NF-κB活性。CBD参与调节细胞诱导也是CBD控制免疫反应的机制的主要部分,已证明CBD诱导Treg和MDSC。最后,CBD诱导的细胞凋亡可能是许多靶细胞的重要机制。此外,Δ9-四氢大麻酚(Δ9-THC)可有效作用于TRPV2,适度调节TRPV3、TRPV4、TRPA1、TRPM8和Cb1。THC值:CB1亲和力(Ki)=10nM部分激动剂;CB2亲和力(Ki)=24nM部分激动剂。表1说明了参与介导大麻二酚作用的受体。
可以包括在组合物中的萜烯的一些实例可以是β-石竹烯((E)-BCP)和/或α-蛇麻烯。(E)-BCP可以选择性地与CB2受体结合(Ki=155±4nM),这可以使(E)-BCP成为功能性CB2激动剂。在与CB2受体结合后,(E)-BCP可抑制腺苷酸环化酶,其会导致细胞内钙瞬变并弱激活原代人单核细胞中的丝裂原激活的激酶Erk1/2和p38。(E)-BCP还可以抑制外周血中脂多糖(LPS)诱导的促炎细胞因子表达,并减弱单核细胞中LPS刺激的Erk1/2和JNK1/2磷酸化。(E)-BCP是食品中的功能性非精神活性CB2受体配体和大环抗炎大麻素。已证明(E)-BCP能够被口服生物利用。因此,包含(E)-BCP用于口服消费将是有利的。蛇麻烯,也称为α-石竹烯或α-蛇麻烯,是β-石竹烯的开环异构体。已证明蛇麻烯能够具有有效的抗炎活性。蛇麻烯具有局部和全身抗炎特性(Chaves et al.,2008),并且在局部、口服或通过气雾剂服用时是一种有效的镇痛剂(Rogerio et al.,2009)。蛇麻烯可通过诱导细胞凋亡产生抗肿瘤作用。β-石竹烯可以协同使用((Legault and Pichette,2007)。蛇草烯,又称α-石竹烯,是β-石竹烯的开环异构体。蛇麻烯在动物模型中具有与地塞米松相当的强大抗炎活性(Fernandes et al.,2007)。已证明蛇麻烯能够增加IL-8的分泌,IL-8是一种具有多种功能的趋化因子,这些功能包括促进血管生成,有助于伤口愈合,但通常与抗癌化合物无关(Satsu et al.,2004)。
已证明胡椒碱具有化学预防和抗氧化活性。此外,还已证明胡椒碱的免疫调节、抗癌、刺激、保肝、抗炎(Darshan and Doreswamy 2004)、抗菌(Yang et al 2002)和抗溃疡活性(Bai and Xu 2000)。胡椒碱还具有生物转化作用,可以通过增加药物的吸收、减缓药物的代谢或两者的结合来提高不同药物(如利福平、磺胺嘧啶、四环素和苯妥英)的生物利用度(Atal and others 1985;Wu 2007)。胡椒素可以刺激胰腺的消化酶,防止氧化损伤,降低脂质过氧化,并提高许多治疗药物的生物利用度。此外,胡椒碱的抗炎活性已在角叉菜胶诱导的大鼠爪水肿、棉球诱导的肉芽肿和巴豆油诱导的肉芽肿囊的大鼠模型中得到证实。胡椒物种的成分对负责白三烯和前列腺素生物合成的酶、5-脂氧合酶和COX-1分别显示出体外抑制活性。因此,掺入胡椒素来治疗伴有剧烈疼痛的炎性疾病是有利的。胡椒碱的刺激性成分是由于疼痛感受器(痛觉神经细胞)上的热感受和酸感受TRPV离子通道TRPV1和TRPA1的激活所致。已证明胡椒碱能够在不同浓度下以剂量依赖性方式抑制IL6和MMP13的表达并减少PGE2的产生。例如,胡椒碱在约10μg/ml和约100μg/ml之间的浓度下可以是治疗有效的。在另一个示例中,胡椒碱在约10μg/ml胡椒碱的浓度下在抑制PGE2方面是治疗有效的。因此,已证明胡椒碱能够通过Il-1b(细胞因子的IL家族的成员)产生抗炎、镇痛和抗关节炎作用。此外,胡椒碱可以将各种药物的生物利用度提高30%至200%。因此,将胡椒碱掺入治疗性化合物以帮助调节免疫功能以阻止SARS CoV-2等疾病的负面影响是有利的。
胡椒碱还可以激活TPRV离子通道。这些通道调节离子进入,介导与温度、压力和pH值感觉以及嗅觉、味觉、视觉和痛觉相关的各种神经信号传导过程。许多疾病涉及TRP通道功能障碍,包括神经性疼痛、炎症和呼吸系统疾病。已证明大麻素具有调节TRP通道的特定子集的能力。发现TRP辣椒素(TRPV)、TRP锚蛋白(TRPA)和TRP melastatin(TRPM)亚家族都含有可通过多种内源性、植物源性和合成大麻素调节的通道。据报道,来自上述三个亚家族的至少六个TRP通道介导大麻素活性:TRPV1、TRPV2、TRPV3、TRPV4、TRPA1和TRPM8。胡椒碱微溶于水(18℃时为40mg/L;Vasavirama和Upender 2014)。胡椒碱在水中的低溶解度及其溶出度差是胡椒碱吸收过程中的速率控制。由于胡椒碱的水溶性低,并且在高浓度下使用胡椒碱可能会对中枢神经系统和生殖系统产生毒性,因此胡椒碱的药物活性可能会受到限制(Veerareddy and others 2004;Pachauri and others 2015)。在本文公开的化合物的一些实施例中,可以掺入胡椒碱的脂质包封以增加胡椒碱和化合物的其他组分的生物利用度。
顺-9,10-十八烷酸酰胺(油酰胺,ODA)可用作睡眠诱导物质(Cravatt et al.,1995)。有人提出了“随行”效应(Lambert&Di Marzo,1999)。ODA可以通过对酶FAAH竞争性抑制来增强或延长内源性大麻素(例如AEA)的作用(Mechoulam et al.,1997)。此外,ODA可以作为一种完全的大麻素CB1受体激动剂。因此,除了其他受体的变构调节和由于脂肪酸酰胺水解酶抑制可能引起的随行效应外,ODA的作用可直接通过CB1受体介导。对ODA的一些研究表明,CYP1A2、CYP2B和CYP2C11的蛋白质水平和代谢活性下降,同时CYP2D2的代谢活性下降。油酰胺没有在报告基因实验中表现出与人孕烷X、组成型雄烷或芳基烃受体相互作用的趋势,并且不调节它们在原代人肝细胞中的靶标P450基因。体外油酰胺既不是参与调节异生素代谢(xenobiotic metabolism)的主要人核受体的激动剂也不是其拮抗剂。
十六酰胺乙醇(PEA)是一种脂肪酸酰胺,属于核因子激动剂类。已证明PEA具有与核受体结合的能力,通过这种能力发挥多种生物学效应,其中一些与慢性炎症和疼痛有关。在某些情况下,PEA表现出靶向过氧化物酶体增殖物激活受体α(PPAR-α)的趋势。PEA还表现出对大麻素样G偶联受体GPR55和GPR119的亲和力。通常,PEA可能不会表现出对大麻素受体CB1和CB2的亲和力。然而,PEA(或其他结构相关的N-酰基乙醇胺)的存在往往会通过“随从效应”增强花生四烯酸乙醇胺活性。此外,PEA可直接或间接刺激CB2受体(Re,Barbero,Miolo,&Di Marzo,2007)。PEA还展示了与CB1受体结合的能力(Lin,Lu,Wu,Huang,&Wang,2015)。PEA和OEA倾向于通过增殖物激活受体α(PPARα)或GPR119发挥其作用(Hansen&Artmann,2008)。还证明PEA能够改善结肠炎的所有宏观体征并减少促炎细胞因子。在存在急性或慢性炎症的情况下,PEA水平会发生变化,内源性大麻素系统(ECS)往往会失衡。在至少一种情况下,大麻素受体及其内源性配体的失调伴随着β-淀粉样蛋白诱导的神经炎症的发展和进展。还已证明PEA具有抗炎、抗伤害感受、神经保护和抗惊厥特性的能力。
花生四烯酸乙醇胺(AEA)、PEA和油酰乙醇胺(OEA)由膜磷脂通过N-酰基磷脂酰乙醇胺特异性磷脂酶D(NAPE-PLD)合成。PEA和OEA不与CB1R结合,但它们可以增强AEA在1型辣椒素瞬时受体电位通道(TRPV1)中的活性。AEA、PEA和OEA都被脂肪酸酰胺水解酶(FAAH)降解。OEA和PEA可以通过与AEA竞争FAAH(主要是OEA)或通过下调FAAH表达(主要是PEA)来提高AEA水平。大麻二酚(CBD)是大麻植物的一种非精神活性成分,可激活过氧化物酶体增殖物激活受体(PPAR)和TPRV1并抑制FAAH,因此可能会补偿患有ASD的儿童的较低水平的AEA、OEA和PEA。
所公开的化合物可包括表没食子儿茶素没食子酸酯(EGCG),其也称为表没食子儿茶素-3-没食子酸酯。已证明EGCG对CB1受体具有亲和力。EGCG是CB2激动剂和GABAA受体44的调节剂。所公开的化合物还可以包括鹰嘴豆芽素A。鹰嘴豆芽素A通常被称为类黄酮。鹰嘴豆芽素A是一种FAAH抑制剂。鹰嘴豆芽素A没有表现出与CB1或CB2受体或与FAAH-2有任何主要程度的相互作用的趋势。已证明鹰嘴豆芽素A能够抑制0.5μM AEA FAAH的水解,IC50值范围为约1.8μM至约2.4μM。已证明鹰嘴豆芽素A能够抑制足底注射福尔马林产生的细胞外信号调节激酶的脊髓磷酸化。CB1受体拮抗剂/反向激动剂AM251(30μg i.pl.)显著降低这两种化合物的作用。未证明鹰嘴豆芽素A(15mg·kg-1i.v.)能够增加大脑AEA浓度,但对10mg·kg-1i.v.AEA的作用产生了适度的增强作用。
所公开的化合物包括至少一种以下类黄酮:紫杉叶素、桑色素、槲皮素、非瑟酮、芹菜素和高良姜素。已证明所公开的类黄酮具有抑制与病毒感染和自身免疫性疾病相关的酶的能力。例如,所公开的类黄酮表现出抑制MAOB酶的能力,该酶在患病(例如,冠状病毒感染、自身免疫性疾病和癌症)期间表现出升高的水平。芹菜素是一种常见的膳食类黄酮,其大量存在于许多水果、蔬菜和中草药中,具有多种生理功能,如强大的抗炎、抗氧化、抗菌和抗病毒活性以及降压作用。已证明芹菜素能够通过多种生物学效应,例如触发细胞凋亡和自噬、诱导细胞周期停滞、抑制细胞迁移和侵袭以及刺激免疫反应,而在体外和体内抑制多种人癌症。已证明芹菜素能够开发为膳食补充剂或癌症疗法的辅助化疗剂。如上所述,麦卢卡蜂蜜的抗菌特性以及抗病毒、抗炎和抗氧化益处可添加到针对癌症的配方中。
所公开的化合物可包括姜黄素。已证明姜黄素(和白藜芦醇)能够通过上调PIAS3来抑制STAT3的组成型激活。姜黄素可作为MAO抑制剂(MAO-A和MAO-B)发挥作用。
通过靶向大麻素受体治疗SARS-CoV-2感染的组合物可包含由药学上可接受的载体与活性成分混合形成的乳剂。药学上可接受的载体可以占组合物的15wt%至85wt%。在组合物为液体形式的实施方式中,药学上可接受的载体可以为50wt%至85wt%。在组合物为凝胶形式的另一个实施方式中,药学上可接受的载体可以为15wt%至35wt%。活性成分可包括:有效量的大麻提取物以提供内源性大麻素来源、有效量的内源性大麻素增强剂以抑制内源性大麻素水解酶、有效量的脂肪酸酰胺以通过随行效应增强内源性大麻素活性、有效量的卡瓦胡椒提取物以减轻焦虑以及有效量的生物碱以增强所述活性成分中的一种或多种活性成分的生物利用度。
药学上可接受的溶剂可以是中链甘油三酯。中链甘油三酯可衍生自油,例如棕榈仁油和椰子油。例如,来自油的提取物可以是己酸、辛酸、癸酸、十二烷酸或其任何组合。在一个示例中,大麻素增强剂可以是油酰胺。脂肪酸可以是PEA和virodhamine中的至少一种。生物碱可以是胡椒碱。
大麻提取物的有效量可以为组合物的5wt%至40wt%。在组合物为液体形式的实施方式中,大麻提取物可以为5wt%至13wt%。在组合物为凝胶形式的另一个实施方式中,大麻提取物可以为15wt%至40wt%。脂肪酸伯酰胺的有效量可以为组合物的1.5wt%至6wt%。在组合物为液体形式的实施方式中,脂肪酸伯酰胺可以为1.5wt%至4wt%。在组合物为凝胶形式的另一个实施方式中,脂肪酸伯酰胺可以为2wt%至6wt%。脂肪酸酰胺的有效量可以为组合物的1.5wt%至11wt%。在组合物为液体形式的实施方式中,脂肪酸酰胺可以为1.5wt%至4wt%。在组合物为凝胶形式的另一个实施方式中,脂肪酸酰胺可以为5wt%至11wt%。生物碱的有效量可以为组合物的0.2wt%-3wt%。在组合物为液体形式的实施方式中,生物碱可以为0.2wt%至3wt%。在组合物为凝胶形式的另一个实施方式中,生物碱可以为0.5wt%至3wt%。
卡瓦胡椒提取物可以包含以下中的至少一种:去甲氧基甲氧醉椒素、麻醉椒苦素、甲氧醉椒素、二氢麻醉椒苦素、二氢醉椒素、醉椒素、10-甲氧基甲氧醉椒素、11-甲氧基甲氧醉椒素、11-羟基甲氧醉椒素、11-甲氧基-12-羟基脱氢醉椒素、7,8-二氢甲氧醉椒素、5-羟基醉椒素、5,6-二氢甲氧醉椒素、7,8-二氢醉椒素、5,6,7,8-四氢甲氧醉椒素、5,6-脱氢麻醉椒苦素和7,8-二氢麻醉椒苦素。卡瓦胡椒提取物的有效量可以为6.0wt%至35wt%。在组合物为液体形式的实施方式中,卡瓦胡椒提取物可以为6.0wt%至12.0wt%。在组合物为凝胶形式的另一个实施方式中,卡瓦胡椒提取物可以为15wt%至35.0wt%。
活性成分中的至少一些活性成分至少部分地被卵磷脂包封,并且卵磷脂的存在量可以为组合物的约2wt%。在组合物为液体形式的实施方式中,卵磷脂可以为0.2wt%至3wt%。在组合物为凝胶形式的另一个实施方式中,卵磷脂可以为0.5wt%至3wt%。至少部分被卵磷脂包封的活性成分可以包括生物碱。
大麻提取物可以包括大麻二酚(CBD)、四氢大麻酚(THC)、大麻萜酚、大麻酚和萜烯中的至少一种。在存在CBD的实施例中,CBD可包含大麻提取物中99.5%的大麻素。大麻提取物可包含全谱CBD或CBD分离物。大麻提取物的有效量可以为xx-8wt%。大麻提取物可以包含占组合物0.005wt%至0.03wt%的β-石竹烯。
所公开的化合物可以包括紫杉叶素、桑色素、槲皮素、非瑟酮、芹菜素和高良姜素中的至少一种。在一个实施方式中,所公开的组合物可以包含0.1wt%至3wt%的紫杉叶素、0.6wt%至4wt%的桑色素、1.0wt%至6wt%的槲皮素、2wt%至8wt%的非瑟酮、0.3wt%至2wt%的芹菜素以及8wt%至20wt%的高良姜素。在另一个实施方式中,所公开的组合物可以包含1wt%至15wt%的姜黄素。
所公开的组合物中成分的有效量可根据组合物的形式而变化。表2说明了液体形式的组合物中成分的有效量的一个实施例。表3说明了凝胶形式的组合物中成分的有效量的一个实施例。
组合物的制造
参考图1,提供了一种用于制造根据示例性实施方式的组合物的方法。流程图100开始于步骤102,其中将药学上可接受的载体与活性成分组合以形成溶液。活性成分可以包括有效量的大麻提取物以提供内源性大麻素来源、有效量的内源性大麻素增强剂以抑制内源性大麻素水解酶、有效量的脂肪酸酰胺以通过随行效应增强内源性大麻素活性、有效量的卡瓦胡椒提取物以减轻焦虑以及有效量的生物碱以增强所述活性成分中的一种或多种活性成分的生物利用度。如本文所用,术语“有效量”是指在本领域技术人员的合理判断范围内,化合物可以显著诱导对所治疗病症的积极改变、但足够低以避免不期望的副作用的足够量。化合物的有效量可以随所治疗的特定病症、所治疗的生物对象的年龄和病症、病症的严重程度、治疗的持续时间以及本领域技术人员的知识和专业知识范围内的其他因素而变化。
在步骤104中,将溶液冷却至低于约60℃的温度。
在步骤106中,将卡瓦胡椒提取物添加到冷却的溶液中。在大麻提取物包含大麻二酚分离物的实施方式中,可将β-石竹烯与卡瓦胡椒提取物一起添加到冷却的溶液中。在一些实施方式中,冷却的溶液被乳化以将一种或多种活性成分充分分散在整个载体中。在一个特定的实施方式中,乳化发生约1分钟。
在步骤108中,将冷却的溶液进一步冷却至低于约0℃的温度,从而形成组合物。在一个或多个非限制性实施方式中,在5至10小时之间的时间段内将溶液进一步稳定地冷却至低于约0℃的温度。在其他实施方式中,将溶液进一步冷却至低于约0℃的温度,然后保持5至10小时的时间段。
图2是根据说明性实施方式的将药学上可接受的载体与活性成分组合以形成溶液的步骤的流程图。流程图200开始于步骤202,其中在将任何活性成分与药学上可接受的载体组合之前将溶剂加热至约80℃的温度。
在步骤204中,当药学上可接受的载体的温度在约80℃至约90℃之间时,将卵磷脂溶解到药学上可接受的载体中以形成第一中间溶液。
在步骤206中,当第一中间溶液的温度在约70℃至约80℃之间时,将内源性大麻素增强剂溶解到第一中间溶液中以形成第二中间溶液。
在步骤208中,当第二中间溶液的温度在约70℃至约80℃之间时,将脂肪酸酰胺溶解到第二中间溶液中以形成第三中间溶液。
在步骤210中,当第三中间溶液的温度在约70℃至约85℃之间时,将生物碱溶解到第三中间溶液中以形成第四中间溶液。
在步骤212中,当第四中间溶液的温度在约70℃和约85℃之间时,将大麻提取物添加到第四中间溶液中以形成溶液。在一些实施方式中,将溶液乳化以将活性成分充分分散在整个载体中。在一个特定的实施方式中,乳化发生约1分钟。
在使用酊剂的实施例中,所公开的原理可以使用不同的方法(包括搅拌(均质化)和冷冻)来实现一定程度的封装。在其他制备中,该方法可以利用在线超声处理。
如本文所公开的,这些化合物和治疗已用于冠状病毒(例如,COVID-19)、自身免疫性疾病、肺纤维化、癌症和多发性硬化症,并取得了有利的结果。所公开的原理也可能对许多其他疾病有有利的结果。对于带状疱疹病毒爆发(带状疱疹)已观察到积极结果:在大约10分钟内经历的个人症状(感知疼痛)减少。所公开的原理是对“带状疱疹”疼痛特别有效的治疗。因此,所公开的原理也可用于治疗带状疱疹和COVID-19。所公开的原理也可用于全身炎症反应综合征(SIRS)。该术语描述了导致血管通透性增加的广泛内皮炎症的临床表现。由于这种病症(SIRS)是一组不同病症(例如细菌性脓毒症、局部缺血、烧伤、外伤和组织损伤)中的启动病理过程,因此所公开的原理也应被视为对这些病症的治疗。此外,一些患有遗传性“自身免疫疾病”从而使人“持续受伤”或“持续疼痛”或“身体和骨骼疼痛”人的使用了所公开的原理。这些人声称在摄入所公开的发明后“感觉更好”、“生活质量更好”、“第一次感觉正常”。个体在10-30分钟内表现出感觉更好或“正常”的感觉。
这种公开的配方的一个开端已被证明可以对抗COVID-19,在短短15分钟内起作用并减轻一些症状,并在几小时后完全感觉良好。SARS-CoV-2病毒必须克服人体的各种防御机制,包括其非特异性或先天免疫防御。在此过程中,受感染的体细胞会释放称为1型干扰素的信使物质。这些信使物质吸引自然杀伤细胞,自然杀伤细胞杀死受感染的细胞。
使用方法
所公开的化合物可用于靶向多个受体位点以实现免疫调节。所公开的化合物可以靶向1型(CB1)和2型(CB2)大麻素受体、GPR55、GPR119、PPAR-a、IL-1B,以及TPRV离子通道、GABBA、TLR和Ras/Raf/MAPK信号通路。所公开的化合物减少炎症反应并刺激I型干扰素的产生,I型干扰素是关键的抗病毒介质。通过这样做,所公开的化合物解决了Sars-Cov2对我们免疫系统的“欺骗”。由于Sars-Cov2已被证明具有高度促炎性,因此所公开的化合物可包含已被证明具有抗炎作用的大麻素。刺激CB2降低炎症反应,对于SARS-CoV-2患者来说,改善了患者的整体状况。考虑到CB2减少大量细胞因子33产生的能力,CB2的刺激在数个检查点控制炎症级联。使用所公开的化合物还可以利用TRPV1或辣椒素受体激动剂,因为TRPV1通道参与钙信号传导的调节,对许多细胞过程包括增殖、细胞凋亡、细胞因子分泌或T细胞激活至关重要。此外,TRPV1表现为参与细胞-环境串扰的多模式受体。因此,它不仅可以影响细胞行为,还可以影响细胞命运。68所公开的化合物可包括激活PPAR-a受体以抑制脂肪酸酰胺水解酶(FAAH)的其他组分,从而提高内源性大麻素花生四烯酸乙醇胺以及我们介绍的所有外源性大麻素的水平和作用;另外以减少炎症和刺激I型干扰素的产生为目的。所公开的化合物可以产生通常称为“随行效应”的东西。随行效应是一种拟议的机制,通过这种机制,大麻化合物与其(彼此)协同作用以调节大麻素的整体作用。炎症、焦虑和高血压是COVID-19的常见症状。因此,除了大麻素系统外,所公开的化合物还可以包括靶向γ-氨基丁酸A型受体(GABAAR)的天然成分。GABBA-A受体与炎症和高血压密切相关。GABA能成分特性包括抗高血压、抗焦虑和抗炎。GABA是成人大脑中的主要抑制性神经递质,在免疫系统中具有平行抑制作用。免疫细胞合成GABA并具有GABA分解代谢的机制。抗原呈递细胞(APC)表达功能性GABA受体并对GABA产生电生理反应。因此,免疫系统包含GABA信号传导所需的所有成分,而GABA本身可作为旁分泌或自分泌因子发挥作用。GABA能试剂直接作用于APC,减少MAPK信号并同样减少某些多发性硬化症模型中的后续适应性炎症反应。GABA受体转录物存在于免疫细胞中,GABA治疗减少外周巨噬细胞中炎性细胞因子的产生。GABA和GABA A型受体(GABA-A-R)激动剂降低细胞毒性免疫反应和皮肤迟发型超敏反应。用GABA进行治疗降低了1型糖尿病的非肥胖糖尿病小鼠模型中的T细胞自身免疫和炎症反应的发展。然而,GABA在适应性免疫反应中的作用位点仍然不清楚。
SARS-CoV-2病毒必须克服人体的各种防御机制,包括其非特异性或先天免疫防御。在此过程中,受感染的体细胞会释放称为1型干扰素的信使物质。这些信使物质吸引自然杀伤细胞,杀死受感染的细胞。SARS-CoV-2病毒如此“成功”并因此变得危险的原因之一是它可以抑制这种非特异性免疫反应。此外,它还能让被侵入的人体细胞产生病毒蛋白PLpro(木瓜蛋白酶样蛋白酶)。PLpro有两个功能:它在新病毒颗粒的成熟和释放中发挥作用,以及它抑制1型干扰素的发展。
所公开的组合物可用于治疗SARS-CoV-2感染。1型干扰素的释放会触发免疫系统对病毒感染作出反应。例如,刺激内源性白细胞介素-1受体以释放促抗炎细胞因子Il-1Ra,同时增强抗炎细胞因子IL-4、IL-10和IL-6的释放。抑制木瓜样蛋白酶的产生会降低冠状病毒酶处理病毒多聚蛋白以生成功能性复制酶复合物并使病毒传播的能力。ACE2表达调节降低了冠状病毒侵入细胞的能力。此外,ACE2表达调节降低了疾病易感性并减少了被感染个体的进入点。TMPRSS2基因表达的失调降低了冠状病毒在肺部复制的能力。此外,TMPRSS2基因表达的失调会引发体内病理学。
现在参考图3,根据说明性实施方式的使用免疫调节组合物治疗疾病的方法。流程图300开始于步骤302:刺激1型干扰素的释放。在步骤304中,抑制木瓜样蛋白酶的产生。在步骤306中,抑制促炎分子的释放。在步骤308中,在通路组织(gateway tissues)中调节ACE2表达以减少病毒结合位点的数量。在说明性实施方式中,其中疾病是由SARS-CoV-2引起的感染,调节ACE2表达以减少SARS-CoV-2结合位点的数量。在步骤310中,下调TMPRSS2基因表达。
虽然上面已经描述了根据本文公开的原理的各种实施方式,但是应当理解,它们仅以示例而非限制的方式呈现。因此,本公开的幅度和范围不应受任何上述示例性实施方式的限制,而应仅根据任意权利要求及其从本公开产生的等同物来定义。此外,在所描述的实施方式中提供了上述优点和特征,但不应将由此提出的权利要求的应用限制为实现任何或所有上述优点的过程和结构。
此外,此处提供的章节标题是为了与按照37C.F.R.1.77的建议保持一致,或以其他方式提供组织提示。这些标题不应限制或表征本公开可提出的任何权利要求中列出的发明。具体而言,举例来说,虽然标题提到“技术领域”,但权利要求不应受限于在该标题下选择的描述所谓领域的语言。此外,对作为背景技术信息的技术的描述不应被解释为承认某些技术是本公开中任何实施方式的现有技术。“发明内容”也不应被视为对已提出的权利要求中的实施方式的表征。此外,本公开中对单数“发明”的任何引用不应被用来争辩本公开中仅存在单一的新颖点。根据从本公开提出的多项权利要求的限制,可以列出多个实施方式,并且这些权利要求相应地限定了受其保护的实施方式及其等同物。在所有情况下,此类权利要求的范围应根据本公开内容根据其自身的优点来考虑,而不应受本文所列标题的限制。
此外,提供摘要是为了遵守37C.F.R.§1.72(b),其要求摘要能够让读者快速确定技术公开的性质。提出的理解是,它不会被用来解释或限制权利要求的范围或含义。此外,在前面的详细描述中,可以看出为了简化公开的目的,各种特征被组合在单个实施方式中。该公开的方法不应被解释为反映以下意图:要求保护的实施方式需要比每项权利要求中明确记载的特征更多。相反,如权利要求所反映的,发明主题在于少于单个公开实施方式的所有特征。因此,所附权利要求特此并入具体实施方式中,其中每个权利要求独立作为单独的实施方式。
Claims (20)
1.一种通过靶向大麻素受体治疗SARS-CoV-2感染的组合物,所述组合物包括:
由药学上可接受的载体与活性成分混合形成的乳剂,其中所述药学上可接受的载体占所述组合物的15wt%至85wt%,并且其中所述活性成分包含:
有效量的大麻提取物以提供外源性大麻素来源;
有效量的大麻素增强剂以抑制大麻素水解酶;
有效量的脂肪酸酰胺以通过随行效应增强大麻素活性;
有效量的卡瓦胡椒提取物以减轻焦虑;和
有效量的生物碱以增强所述活性成分中的一种或多种活性成分的生物利用度。
2.根据权利要求1所述的组合物,其中:
药学上可接受的溶剂是中链甘油三酯;
所述大麻素增强剂是油酰胺;
所述脂肪酸酰胺是十六酰胺乙醇(PEA);以及
所述生物碱是胡椒碱。
3.根据权利要求1所述的组合物,其中:
所述大麻提取物的有效量为所述组合物的5wt%至40wt%;
所述大麻素增强剂的有效量为所述组合物的1.5wt%至6wt%;
所述脂肪酸酰胺的有效量为所述组合物的1.5wt%至11wt%;以及
所述生物碱的有效量为所述组合物的0.2wt%至3wt%。
4.根据权利要求1所述的组合物,其中,所述活性成分中的至少一些活性成分至少部分地被卵磷脂包封,并且其中所述卵磷脂的存在量可以为所述组合物的约0.2wt%至3wt%。
5.根据权利要求4所述的组合物,其中,所述活性成分中的所述至少一些活性成分包括生物碱。
6.根据权利要求1所述的组合物,其中,所述大麻提取物包括大麻二酚(CBD)、四氢大麻酚(THC)、大麻萜酚、大麻酚、萜烯中的至少一种。
7.根据权利要求6所述的组合物,其中,所述CBD是所述大麻提取物中占99.5%的大麻素。
8.根据权利要求6所述的组合物,其中,所述大麻提取物包含CBD,并且其中所述CBD是全谱CBD或CBD分离物中的一种。
9.根据权利要求8所述的组合物,其中,所述CBD是所述CBD分离物,并且其中所述大麻提取物的有效量为8wt%。
10.根据权利要求8所述的组合物,其中,所述大麻提取物包含占所述组合物0.005wt%至0.03wt%的β-石竹烯。
11.一种制备用于治疗SARS-CoV-2感染的组合物的方法,所述方法包括以下步骤:
将药学上可接受的载体与活性成分组合以形成溶液,
其中所述活性成分包括:
有效量的大麻提取物以提供外源性大麻素来源,
有效量的大麻素增强剂以抑制大麻素水解酶,
有效量的脂肪酸酰胺以通过随行效应增强大麻素活性,和
有效量的生物碱以增强所述活性成分中的一种或多种活性成分的生物利用度;将所述溶液冷却至低于约60℃的温度;
将卡瓦胡椒提取物添加到冷却的溶液中;以及
将所述冷却的溶液进一步冷却至低于约0℃的温度以形成所述组合物。
12.根据权利要求11所述的方法,其中,将药学上可接受的载体与活性成分组合的步骤还包括在将所述活性成分与所述药学上可接受的载体组合之前将所述药学上可接受的载体加热到至少约80℃的温度。
13.根据权利要求11所述的方法,其中,将药学上可接受的载体与活性成分组合的步骤还包括当所述药学上可接受的载体的温度在约80℃至约90℃之间时将所述卵磷脂溶解到所述药学上可接受的载体中以形成第一中间溶液。
14.根据权利要求12所述的方法,其中,将药学上可接受的载体与活性成分组合的步骤还包括当所述第一中间溶液的温度在约70℃至约80℃之间时将所述大麻素增强剂溶解到所述第一中间溶液中以形成第二中间溶液。
15.根据权利要求13所述的方法,其中,将药学上可接受的载体与活性成分组合的步骤还包括当所述第二中间溶液的温度在约70℃至约80℃之间时将所述脂肪酸酰胺溶解到所述第二中间溶液中以形成第三中间溶液。
16.根据权利要求14所述的方法,其中,将药学上可接受的载体与活性成分组合的步骤还包括当所述第三中间溶液的温度在约70℃至约85℃之间时将所述生物碱溶解到所述第三中间溶液中以形成第四中间溶液。
17.根据权利要求15所述的方法,其中,将药学上可接受的载体与活性成分组合的步骤还包括当所述第四中间溶液的温度在约70℃和约85℃之间时将所述大麻提取物添加到所述第四中间溶液以形成所述溶液。
18.根据权利要求16所述的方法,还包括乳化所述溶液。
19.根据权利要求17所述的方法,其中,进一步冷却步骤进行约5小时至约10小时,并且其中将所述卡瓦胡椒提取物添加到所述冷却的溶液中还包括乳化所述冷却的溶液。
20.根据权利要求10所述的方法,其中,所述大麻提取物是大麻二酚分离物,并且其中所述方法还包括将β-石竹烯添加到所述冷却的溶液中。
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