CN114144493A - 治疗和减轻酒精诱导的皮肤潮红的组合物和方法 - Google Patents
治疗和减轻酒精诱导的皮肤潮红的组合物和方法 Download PDFInfo
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Abstract
本申请涉及用于预防和治疗包括酒精诱导的皮肤潮红在内的酒精诱导的超敏反应的药物组合物。
Description
与相关申请的交叉引用
本申请要求2019年5月23日提交的美国临时申请号62/852,000的优先权,所述临时申请整体通过参考并入本文。
发明概述
本申请涉及药物组合物,其包含治疗有效量的4-甲基吡唑或其可药用盐、水合物、多晶型物或溶剂化物以及可药用载体;其中所述药物组合物被配置成用于口服给药;并且其中所述药物组合物还包含至少一种可用于掩盖4-甲基吡唑的气味的药物惰性包衣。在某些实施方式中,所述至少一种药物惰性包衣选自由羟基烷基纤维素、抗粘剂、增塑剂、糖、甲基丙烯酸酯共聚物、羟基烷基纤维素和水溶性聚合物组成的组。在某些实施方式中,所述药物组合物被配置成选自粉剂、片剂、锭剂、口香糖、丸剂、胶囊、微胶囊、囊片、口服崩解片剂、渗透控释口服递送系统或其任何组合的口服剂型。某些实施方式还包含n-乙酰半胱氨酸、蛇葡萄素、Withania somifera/南非醉茄、L-胱氨酸、S-乙酰谷胱甘肽、钼、铁、锌、铁螯合剂、L-抗坏血酸、L-苏氨酸或其任何组合。在某些实施方式中,所述铁螯合剂包含姜黄素、檞皮素、六磷酸肌醇(IP6)或其任何组合。在某些实施方式中,所述可药用载体是水。在某些实施方式中,所述药物组合物还包含掩味剂、气味掩蔽剂或其组合。在某些实施方式中,所述4-甲基吡唑的治疗有效量是约10至约20mg/kg之间的量。在某些实施方式中,所述4-甲基吡唑的治疗有效量是产生约0.1μmol/L的血浆浓度的量。
某些实施方式涉及药物组合物,其包含治疗有效量的4-甲基吡唑或其可药用盐、水合物、多晶型物或溶剂化物以及可药用载体;其中所述药物组合物被配置成用于透皮给药。在某些实施方式中,所述药物组合物还包含n-乙酰半胱氨酸、蛇葡萄素、Withaniasomifera/南非醉茄、L-胱氨酸、S-乙酰谷胱甘肽、钼、铁、锌、铁螯合剂、L-抗坏血酸、L-苏氨酸或其任何组合。在某些实施方式中,所述铁螯合剂包含姜黄素、檞皮素、六磷酸肌醇或其任何组合。
某些实施方式涉及在受试者中治疗和/或预防酒精诱导的超敏反应的方法,所述方法包括给药本文中公开的药物组合物。在某些实施方式中,所述酒精诱导的超敏反应选自潮红、心率加快、心悸、低血压、恶心、头晕、头痛、呕吐、腹泻、胃部不适、共济失调、意识模糊、荨麻疹、系统性皮炎、过敏性鼻炎、支气管收缩、哮喘性支气管收缩加重、心血管性虚脱、过敏性结膜炎、特应性皮炎、嗜酸细胞性食道炎、过敏性反应、慢性支气管炎和慢性阻塞性肺病(COPD)及其任何组合。在某些实施方式中,酒精潮红的特征在于面部发红、皮肤温度升高、心率加快、舒张压降低或其任何组合。在某些实施方式中,所述药物组合物在所述受试者摄入酒精之前给药。在某些实施方式中,所述药物组合物在所述受试者摄入酒精之前约60分钟至约15分钟给药。在某些实施方式中,所述药物组合物在所述受试者摄入乙醇的同时或在所述受试者摄入乙醇之后给药。
某些实施方式涉及在受试者中消除从乙醇形成的乙醛的方法,所述方法包括给药本文中所描述的药物组合物。
某些实施方式涉及在受试者中减少和/或消除口腔、食道、胃、大肠及其组合中从乙醇形成的乙醛的方法,所述方法包括给药本文中所描述的药物组合物。
某些实施方式涉及在受试者中降低和/或消除血液中乙醛水平的方法,所述方法包括给药本文中所描述的药物组合物。
某些实施方式涉及在受试者中减少和/或消除来自于消化道的乙醛的方法,所述方法包括给药本文中所描述的药物组合物。
某些实施方式涉及在受试者中抑制线粒体醛脱氢酶2(ALDH2)的方法,所述方法包括给药本文中所描述的药物组合物。
某些实施方式涉及在受试者中降低由受试者摄入乙醇引起的疾病或障碍的风险的方法,所述方法包括给药本文中所描述的药物组合物。
在某些实施方式中,所述疾病或障碍选自上呼吸消化道癌、消化道癌或乳腺癌。在某些实施方式中,所述上呼吸消化道癌包括食道癌、口咽癌、下咽癌、喉癌、头或颈部癌。在某些实施方式中,所述消化道癌包括胃癌或结肠癌。在某些实施方式中,所述疾病或障碍包括迟发性阿兹海默氏病、高血压、心肌梗塞、帕金森氏病、肌萎缩性脊髓侧索硬化症和脑缺血。
某些实施方式涉及在受试者中阻断乙醛的组胺释放效应的方法,所述方法包括给药本文中所描述的药物组合物。
某些实施方式涉及在受试者中阻断酒精诱导的乙醛产生的方法,所述方法包括给药本文中所描述的药物组合物。在某些实施方式中,所述受试者对于被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu487lys、或rs671的醛脱氢酶2(ALDH2)等位基因来说是杂合或纯合的。
某些实施方式还包括测试所述受试者中被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因的存在。在某些实施方式中,测试所述受试者中被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因的存在包括:从所述受试者获得呼气样品;测量所述呼气样品中的乙醇和乙醛水平;以及确定所述呼气样品中乙醛水平与乙醇水平的比率,其中乙醛水平与乙醇水平的比率为约23.3或更高表明被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因的存在;并且如果所述受试者具有约23.3或更高的乙醛水平与乙醇水平的比率,则向所述受试者给药本文中公开的药物组合物。在某些实施方式中,测量呼气样品中的乙醇和乙醛水平通过半导体气相色谱来进行。在某些实施方式中,所述呼气样品在摄入酒精之后获得。在某些实施方式中,测试所述受试者中被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因的存在包括:从所述受试者获得生物样品;从所述生物样品分离基因组DNA;鉴定被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因的存在;以及如果所述被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因存在,则向所述受试者给药本文中描述的药物。在某些实施方式中,所述生物样品是拭子样品。在某些实施方式中,所述生物样品是血液样品。
详细描述
本申请涉及用于预防和治疗包括酒精诱导的皮肤潮红在内的酒精诱导的超敏反应的药物组合物。
人们出于各种不同的社交、娱乐和医用目的而摄入酒精,其化学名称为乙醇。当在本文中使用时,术语“酒精”和“乙醇”可互换使用。过量摄入酒精会对包括肝、脑、骨骼肌和心肌在内的多种组织造成损伤,并造成相当大的公共卫生发病率和死亡率。酒精的许多这些效应由酒精代谢期间在两步途径中产生的乙醛介导,在所述途径中酒精被醇脱氢酶(ADH)氧化成乙醛,其进而由醛脱氢酶(ALDH)这种肝脏线粒体酶快速代谢成乙酸。
ADH和ALDH基因表现出多态性,这调节酒精氧化能力的个体差异(Bosron等,肝脏病学1986,6,502-510)。东亚人群带有醇脱氢酶亚型2的变体等位基因(ADH2*2),其编码具有R47H氨基酸替换的ADH酶(Matsuo等,癌症学2006,27(5),1018-1023;Tamakoshi等,酒精2003,38,407-410)。所述H47 ADH酶是“超活性的”,表现出与由“典型”等位基因(ADH2*1)编码的活性较低的R47 ADH酶相比Vmax高出约40倍(Bosron等,肝脏病学1986,6,502-510;Yoshida等,Prog.Nucleic Acid Res.Mol.Biol.1991,40,255-287)。ADH2*2等位基因与乙醛的积累相关(Crabb等,Proc.Nutr.Soc.2004,63(1),49-63)。
在东亚人群中还普遍存在醛脱氢酶亚型2的变体等位基因(ALDH2*2,并且也被称为Glu487lys、ALDH2*487lys、Glu504lys或rs671),其编码具有E487K氨基酸替换的ALDH酶(Chen等,Am.J.Hum.Genet.1999,65(3),795-807)。所述K487 ALDH酶表现出减少活性,与由“典型”等位基因(ALDH2*1)编码的活性更高的E487 ALDH2酶相比导致乙醛去除速率降低40%-90%,使得表达所述变体等位基因的人表现出降低或缺失的ALDH2活性。
乙醛与诸如面部潮红、心动过速、呼吸短促、头晕、恶心、呕吐和头痛的急性症状有关,还与上消化道癌症、乳腺癌、肝病、阿兹海默氏病、高血压和心肌梗塞的长期健康风险提高有关(参见等,Gut 2004,53,871-876;Yokoyama等,Jpn.J.Clin.Oncol.2003,33(3),111-121;Ohsawa等,J.Hum.Genet.2003,48,404-409;以及其中引用的参考文献)。表达具有降低或缺失的ALDH2活性的ALDH2*2等位基因的人在饮用少量乙醇时表现出与酒精相关的敏感性例如面部潮红、心动过速等(Goedde等,Hum.Genet.1992,88,344-346;Xiao等,J.Clin.Invest.1995,96,2180-2186)。因此,在ALDH2活性降低或缺失的人中降低乙醛水平可能有助于降低这些人在摄入乙醇时所经历的急性系统和长期健康风险。
4-甲基吡唑(也被称为甲吡唑或4-MP)抑制醇脱氢酶(ADH)这种作为两步代谢消除途径的一部分而氧化酒精的酶,在所述途径中乙醇被ADH氧化成乙醛,其进而被醛脱氢酶(ALDH)氧化成乙酸。
在某些实施方式中,在本文描述的方法中使用的化合物可以被配制成药物组合物。本发明的药物组合物可以包含本文中描述的化合物或其可药用盐以及可药用载体。此类组合物可以任选地包含可用于预防和治疗包括酒精诱导的皮肤潮红在内的酒精诱导的超敏反应的至少一种另外的治疗剂。
本发明的化合物可以以常规方式用于控制本文中描述的疾病,包括但不限于酒精诱导的超敏反应,包括酒精诱导的皮肤潮红,并用于治疗疾病或降低影响的进展或严重程度。此类治疗方法、它们的剂量水平和要求,可以由本领域普通技术人员从可用的方法和技术中选择。例如,本发明的化合物可以以制药学上可接受的方式并以有效降低病症的发病率和严重程度的量与可药用佐剂组合,用于给药到具有酒精诱导的超敏反应包括酒精诱导的皮肤潮红或对其易感的患者。
在本文公开的每个实施方式中,所述化合物和方法可用于需要此类治疗的、也可被称为“需要的”受试者或在其身上使用。当在本文中使用时,短语“需要的”意味着所述受试者已被认为对所述特定方法或治疗有需求,并且所述治疗已因该特定目的而提供给所述受试者。
术语“患者”和“受试者”是可互换的,并且可以被认为是指可以用本发明的化合物治疗的任何活生物体。因此,术语“患者”和“受试者”可以包括但不限于任何非人类哺乳动物、灵长动物或人类。在某些实施方式中,所述“患者”或“受试者”是哺乳动物,例如小鼠、大鼠、其他啮齿动物、兔、狗、猫、猪、牛、绵羊、马、灵长动物或人类。在某些实施方式中,所述患者或受试者是成人、儿童或婴儿。在某些实施方式中,所述患者或受试者是人类。
当在本文中使用时,术语“组合”、“组合的”和相关术语是指根据本发明所述的治疗剂的同时或顺序给药。例如,所描述的化合物可以与另一种治疗剂以分开的单位剂型同时或顺序给药或以单一单位剂型一起给药。因此,本发明提供了一种单一单位剂型,其包含所描述的化合物、另外的治疗剂和可药用载体、佐剂或介质(vehicle)。当患者或个体同时暴露于两种药剂时,所述两种或更多种药剂通常被认为是“联合”给药的。在许多实施方式中,当患者或个体在特定靶组织或样品中(例如脑中、血清中等)同时显示出两种或更多种药剂的治疗相关水平时,所述药剂被认为是“联合”给药的。
术语“可药用赋形剂”是指可以与本发明的化合物一起给药到患者并且不破坏其药理活性的无毒赋形剂。可以在这些组合物中使用的可药用赋形剂包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白例如人血清白蛋白、缓冲物质例如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素基物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、聚乙二醇和羊毛脂。可以在本发明的药物组合物中使用的可药用赋形剂包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白例如人血清白蛋白、缓冲物质例如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素基物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、羊毛脂和自乳化药物递送系统(SEDDS)例如α-生育酚、聚乙二醇1000琥珀酸酯或其他类似的聚合物递送基质。
当在本文中使用时,术语“治疗有效量”是指在组织、系统、动物、个体或人类中引发研究人员、兽医、医生或其他临床医生正在寻求的生物学或医学反应的活性化合物或药剂的量,所述反应包括下述一者或多者:(1)预防所述疾病;例如在可能易患疾病、病症或障碍但尚未经历或表现出所述疾病的病理或症状的个体中预防所述疾病、病症或障碍,(2)抑制所述疾病;例如在正经历或表现出疾病、病症或障碍的病理或症状的个体中抑制所述疾病、病症或障碍(即停止所述病理和/或症状的进一步发展),以及(3)改善疾病;例如在正经历或表现出疾病、病症或障碍的病理或症状的个体中改善所述疾病、病症或障碍(即逆转所述病理和/或症状)。在某些实施方式中,化合物的治疗有效量代表特定化合物的每日剂量。在某些实施方式中,所述特定化合物的每日剂量可以作为单次每日剂量给药,也可以分为两个或更多个等量或不等量的剂量在一天内给药。
本文描述的化合物可以形成其酸加成盐。应当理解,为了在医学中使用,本文中描述的化合物的盐应该是可药用的。适合的可药用盐对于本领域技术人员来说是显而易见的,并包括那些在J.Pharm.Sci.,1977,66,1-19中描述的可药用盐,例如与无机酸如盐酸、氢溴酸、硫酸、硝酸或磷酸;和有机酸如琥珀酸、马来酸、乙酸、富马酸、柠檬酸、酒石酸、苯甲酸、对甲苯磺酸、甲磺酸或萘磺酸形成的酸加成盐。本发明在其范围内包括所有可能的化学计量和非化学计量形式。本文描述的化合物的可药用盐包括化合物的常规无毒性盐或季铵盐,例如来自无毒性有机酸或无机酸的盐。例如,此类常规无毒性盐包括那些衍生自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐;以及由有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、磺胺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙二磺酸、草酸、异硫羰酸等制备的盐。在其他情况下,所描述的化合物可以含有一个或多个酸性官能团,并因此能够与可药用碱形成可药用盐。这些盐同样可以在给药介质或剂型制造过程中原位制备,或通过将采取游离酸形式的纯化化合物与适合的碱例如可药用金属阳离子的氢氧化物、碳酸盐或碳酸氢盐、氨或与可药用的有机伯胺、仲胺或叔胺单独地反应来制备。代表性的碱金属或碱土金属盐包括锂盐、钠盐、钾盐、钙盐、镁盐和铝盐等。可用于形成碱加成盐的代表性有机胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等。
本文中描述的化合物可以以晶体或非晶体形式制备,并且如果是晶体的,可以任选地被溶剂化,例如作为水合物。本发明在其范围内包括化学计量的溶剂化物(例如水合物)以及含有可变量的溶剂(例如水)的化合物。本文中描述的某些化合物能够以立体异构形式存在(例如非对映异构体和对映异构体),并且本发明扩展到这些立体异构形式中的每一者及其混合物,包括外消旋体。不同的立体异构形式可以通过常用方法相互分离,或者任何给定的异构体可以通过立体特异性或不对称合成来获得。本发明还扩展到任何互变异构形式及其混合物。
尽管与本文中描述的相似或等效的任何方法和材料可用于本发明的实施方式的实践或试验,但现在描述优选的方法、装置和材料。
或者,本发明的化合物可用于组合物和方法中,用于在延长的时间段内治疗或保护个体以对抗本文中描述的病症,包括但不限于神经变性疾病。所述化合物可以单独地或与本发明的其他化合物一起以与此类化合物在药物组合物中的常规使用相一致的方式用于此类组合物中。例如,本发明的化合物可以与在疫苗中常规使用的可药用佐剂组合并以预防有效量给药,以在延长的时间段内保护个体以对抗本文中描述的疾病,包括但不限于神经变性疾病。
本申请涉及药物组合物,其包含治疗有效量的4-甲基吡唑或其可药用盐、水合物、多晶型物或溶剂化物以及可药用载体;其中所述药物组合物被配置成用于口服给药。
在某些实施方式中,所述药物组合物还包含至少一种可用于掩盖4-甲基吡唑的气味的药物惰性包衣。在其他实施方式中,本文中描述的药物组合物可以被包封。在某些实施方式中,包封介质包括但不限于胶囊、软凝胶套、凝胶套、包衣或其任何组合。在某些实施方式中,包衣可以包括但不限于薄膜、蜡、清漆、釉料、聚合物包衣、糖包衣、多糖基包衣、肠溶包衣或其组合。
在某些实施方式中,所述至少一种药物惰性包衣选自由羟基烷基纤维素、羟丙基纤维素、抗粘剂、增塑剂,糖、甲基丙烯酸酯共聚物、羟基烷基纤维素和水溶性聚合物组成的组。抗粘剂的实例包括但不限于滑石(Alphafil 500)、二氧化硅、二氧化硅水凝胶、微晶纤维素、碱金属硬脂酸盐、淀粉及其组合。增塑剂的实例包括但不限于丙二醇、甘油、三羟甲基丙烷、聚乙二醇、癸二酸二丁酯、乙酰化甘油单酯、邻苯二甲酸二乙酯、三醋精、三乙酸甘油酯、乙酰柠檬酸三乙酯、柠檬酸三乙酯及其组合。水溶性聚合物的实例包括但不限于羟丙基纤维素、羟丙基甲基纤维素、阿拉伯胶、羧甲基纤维素钠、糊精、海藻酸、乙基纤维素树脂、明胶、瓜尔胶、液体葡萄糖、甲基纤维素、预明胶化淀粉、藻酸钠、淀粉、玉米醇溶蛋白、聚乙烯吡咯烷酮、乙烯基吡咯烷酮-乙酸乙烯酯共聚物、乙酸乙烯酯-巴豆酸共聚物、丙烯酸乙酯-甲基丙烯酸共聚物及其组合。
在某些实施方式中,所述药物组合物被配置成选自粉剂、片剂、锭剂、口香糖、丸剂、胶囊、微胶囊、囊片、口服崩解片剂、渗透控释口服递送系统或其任何组合的口服剂型。
本文中描述的适于口服给药的制剂可以采取胶囊、扁囊剂、丸剂、片剂、锭剂(使用调味基料,通常为蔗糖和阿拉伯胶或黄蓍胶)、粉剂、颗粒剂的形式,或作为在水性或非水性液体中的溶液或悬浮液,或作为水包油或油包水液体乳液,或作为酏剂或糖浆,或作为锭剂(使用惰性基质例如明胶和甘油或蔗糖和阿拉伯胶)和/或作为漱口水等,其各自含有预定量的本发明的化合物作为活性成分。本文中描述的化合物也可以作为大丸剂、冲剂或糊剂给药。
在用于口服给药的固体剂型(胶囊、片剂、丸剂、糖衣丸、粉剂、颗粒剂等)中,将活性成分与一种或多种可药用载体例如柠檬酸钠或磷酸二钙和/或下述任一者混合:填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸;粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶;保湿剂,例如甘油;崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;溶解阻滞剂,例如石蜡;吸收加速剂,例如季铵化合物;润湿剂,例如鲸蜡醇、单硬脂酸甘油酯和非离子表面活性剂;吸附剂,例如高岭土和膨润土;润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠及其混合物;以及着色剂。在胶囊、片剂和丸剂的情况下,所述药物组合物还可以包含缓冲剂。相似类型的固体组合物也可用作软壳和硬壳明胶胶囊中的填充剂,使用诸如乳糖或奶糖以及高分子量聚乙二醇等的赋形剂。
片剂可以任选地与一种或多种辅助成分(赋形剂)一起通过压制或模制来制造。压制片剂可使用粘合剂(例如明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如羟基乙酸淀粉钠或交联羧甲基纤维素钠)、表面活性剂或分散剂来制备。模制片剂可以在适合的机器中制备,其中将粉状化合物的混合物用惰性液体稀释剂润湿。如果使用固体载体,所述制剂可以采取片剂形式,以粉末或颗粒形式置于硬质明胶胶囊中,或采取锭剂或含片形式。固体载体的量将是可变的,例如约0.01至800mg,优选地约0.01mg至400mg或约3mg至约400mg。当使用液体载体时,所述制剂可以例如采取糖浆、乳液、软明胶胶囊、无菌可注射液体例如安瓿或非水性液体悬液的形式。当所述组合物采取胶囊形式时,任何常规包封都是合适的,例如在硬质明胶胶囊壳中使用上述载体。
片剂和其他固体剂型例如糖衣丸、胶囊、丸剂和颗粒剂,可以任选地被刻痕或制备成具有包衣和外壳,例如肠溶包衣和药物配制领域中公知的其他包衣。可选地或此外,它们可以使用例如不同比例的羟丙基甲基纤维素以提供所需的释放特性、其他聚合物基质、脂质体和/或微球来配制,以便提供其中的活性成分的缓慢或受控释放。它们可以被配制成用于快速释放,例如被冷冻干燥。它们可以通过例如通过细菌截留过滤器过滤,或通过以无菌固体组合物的形式并入灭菌剂来灭菌,所述无菌固体组合物在即将使用前可以溶解在无菌水或某些其他无菌可注射介质中。这些组合物还可以任选地包含遮光剂,并且可以是仅仅或优选地在胃肠道的特定部分中,优选地以延迟方式释放出活性成分的组合物。可以使用的包埋组合物的实例包括聚合物质和蜡。如果合适的话,所述活性成分也可以采取含有一种或多种上述赋形剂的微包胶的形式。
本发明的化合物的用于口服给药的液体剂型包括可药用乳液、微乳剂、溶液、悬液、糖浆和酏剂。除了活性成分之外,所述液体剂型可以含有本领域中常用的惰性稀释剂,例如水或其他溶剂、增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、油类(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃甲醇、聚乙二醇和失水山梨糖醇的脂肪酸酯及其混合物。
除了惰性稀释剂之外,口服组合物还可以包括佐剂,例如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂、着色剂、增香剂和防腐剂。
除了活性化合物之外,悬液还可以包含悬浮剂,例如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇和失水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶,以及它们的混合物。
用于治疗所需的活性成分或其活性盐或衍生物的量不仅随所选的具体盐而变,而且随给药途径、待治疗病症的本质以及患者的年龄和状况而变,并且最终将由主治医师或临床医生酌情决定。一般而言,本领域技术人员理解如何将在模型系统、通常为动物模型中获得的体内数据外推至另一个系统例如人类。在某些情况下,这些外推可能仅基于动物模型与另一种动物例如哺乳动物、优选为人类的体重的比较,但更通常情况下,这些外推不仅仅基于体重,而是包含各种不同因素。代表性因素包括患者的类型、年龄、体重、性别、饮食和医疗状况、疾病的严重程度、给药途径、药理学考虑因素例如所使用的特定化合物的活性、功效、药代动力学和毒理学特征,是否使用药物递送系统,正在进行治疗或预防的是急性还是慢性疾病状态,或者除了本发明的化合物之外并作为药物组合的一部分是否还给药其他活性化合物。使用本发明的化合物和/或组合物治疗疾病病症的剂量方案根据上文提到的各种不同因素来选择。因此,所采用的实际剂量方案可能变化很大并因此可能偏离优选的剂量方案,本领域技术人员将会认识到,可以对超出这些典型范围之外的剂量和剂量方案进行试验,并在适合情况下用于本发明的方法中。
所需剂量可以方便地以单一剂量或作为以适当间隔给药的分剂量例如作为每天两个、三个、四个或更多个分剂量存在。所述分剂量本身可以进一步分到例如多个分立的松散间隔的给药中。每日剂量可分为若干个例如2、3或4个部分给药,尤其是在认为适当时给药相对大的量时。取决于个体行为,如果适合,可能需要向上或向下偏离所指示的每日剂量。
在某些实施方式中,本文公开的药物组合物还可以包含n-乙酰半胱氨酸、蛇葡萄素、Withania somifera/南非醉茄、L-胱氨酸、S-乙酰谷胱甘肽、钼、铁、锌、铁螯合剂(姜黄素/檞皮素/IP6)、L-抗坏血酸、L-苏氨酸或其任何组合。在某些实施方式中,所述铁螯合剂包括姜黄素、檞皮素、六磷酸肌醇(IP6)或其任何组合。在某些实施方式中,所述可药用载体是水。在某些实施方式中,所述药物组合物还包含掩味剂、气味掩蔽剂或其组合。
在某些实施方式中,所述4-甲基吡唑的治疗有效量是约0.1至约200mg/kg之间的量。在某些实施方式中,所述4-甲基吡唑的治疗有效量是约10至约20mg/kg之间的量。在其他实施方式中,所述4-甲基吡唑的治疗有效量是产生约0.01μmol/L至约10μmol/L的血浆浓度的量。在其他实施方式中,所述4-甲基吡唑的治疗有效量是产生约0.1μmol/L的血浆浓度的量。
本文中的实施方式还涉及药物组合物,其包含治疗有效量的4-甲基吡唑或其可药用盐、水合物、多晶型物或溶剂化物以及可药用载体;其中所述药物组合物被配置成用于透皮给药。
在某些实施方式中,所述药物组合物还可以包含n-乙酰半胱氨酸、蛇葡萄素、Withania somifera/南非醉茄、L-胱氨酸、S-乙酰谷胱甘肽、钼、铁、锌、铁螯合剂(姜黄素/檞皮素/IP6)、L-抗坏血酸、L-苏氨酸或其任何组合。在某些实施方式中,所述铁螯合剂包含姜黄素、檞皮素、六磷酸肌醇或其任何组合。
本文中还描述了在受试者中治疗和/或预防酒精诱导的超敏反应的方法,所述方法包括给药本文中描述的药物组合物。在某些实施方式中,所述酒精诱导的超敏反应选自潮红、心率加快、心悸、低血压、恶心、头晕、头痛、呕吐、腹泻、胃部不适、共济失调、意识模糊、荨麻疹、系统性皮炎、过敏性鼻炎、支气管收缩、哮喘性支气管收缩加重、心血管性虚脱、过敏性结膜炎、特应性皮炎、嗜酸细胞性食道炎、过敏性反应、慢性支气管炎和慢性阻塞性肺病(COPD)及其任何组合。在某些实施方式中,酒精潮红的特征在于面部发红、皮肤温度升高、心率加快、舒张压降低或其任何组合。在某些实施方式中,所述药物组合物在所述受试者摄入酒精之前给药。
在某些实施方式中,所述药物组合物在所述受试者摄入酒精之前约60分钟至约15分钟给药。在某些实施方式中,所述药物组合物在所述受试者摄入酒精的同时或所述受试者摄入酒精后给药。
还公开了在受试者中消除从酒精产生的乙醛的方法,所述方法包括给药本文中描述的药物组合物。
本文还描述了在受试者中减少和/或消除在口腔、食道、胃、大肠或其组合中从酒精形成的乙醛的方法,所述方法包括给药本文中描述的药物组合物。研究显示,在摄入后即刻,乙醛在这些区室中而不是在血流中最为丰富(Salaspuro M P,乙醛、微生物和消化道癌症(Acetaldehyde,microbes and cancer of the digestive tract),Crit Rev Clin LabSci 2003;40:183-208;Salaspuro M.,乙醛作为消化道癌症中的共同特性和累积致癌物(Acetaldehyde as a common denominator and cumulative carcinogen in digestivetract cancers),Scand J Gastroenterol 2009;44:912-25;Salaspuro M.,乙醛和胃癌(Acetaldehyde and gastric cancer),J Dig Dis 2011;12:51-9)。
本文中还描述了在受试者中降低和/或消除血液中乙醛水平的方法,所述方法包括给药本文中描述的药物组合物。
本文中还描述了在受试者中从消化道减少和/或消除乙醛的方法,所述方法包括给药本文中描述的药物组合物。
本文中还描述了在受试者中抑制线粒体醛脱氢酶2(ALDH2)的方法,所述方法包括给药本文中描述的药物组合物。
本文中还描述了在受试者中降低由在受试者中摄入酒精引起的疾病或障碍的风险的方法,所述方法包括给药本文中描述的药物组合物。在某些实施方式中,所述疾病或障碍选自上呼吸消化道癌、消化道癌或乳腺癌。在某些实施方式中,所述上呼吸消化道癌包括食道癌、口咽癌、下咽癌、喉癌、头或颈部癌。在某些实施方式中,所述消化道癌包括胃癌或结肠癌。在某些实施方式中,所述疾病或障碍包括迟发性阿兹海默氏病、高血压、心肌梗塞、帕金森氏病、肌萎缩性脊髓侧索硬化症和脑缺血。
某些实施方式涉及在受试者中阻断乙醛的组胺释放效应的方法,所述方法包括给药本文中公开的药物组合物。
某些实施方式涉及在受试者中阻断酒精诱导的乙醛产生的方法,所述方法包括给药本文中公开的药物组合物。
在某些实施方式中,所述受试者对于被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因来说是杂合或纯合的。
某些实施方式还包括测试所述受试者中被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因的存在。
在某些实施方式中,测试所述受试者中被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因的存在包括:从所述受试者获得呼气样品;测量所述呼气样品中的酒精和乙醛水平;以及确定所述呼气样品中乙醛水平与酒精水平的比率,其中乙醛水平与酒精水平的比率为约23.3或更高表明存在被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因;并且如果所述受试者具有约23.3或更高的乙醛水平与酒精水平的比率,则向所述受试者给药根据权利要求1或权利要求12所述的药物组合物。
在某些实施方式中,测量所述呼气样品中的酒精和乙醛水平通过半导体气相色谱来进行。
在某些实施方式中,所述呼气样品在摄入酒精后获得。
在某些实施方式中,测试所述受试者中被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因的存在包括:从所述受试者获得生物样品;从所述生物样品分离基因组DNA;鉴定被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因的存在;以及如果所述被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因存在,则向所述受试者给药根据权利要求1或权利要求12所述的药物组合物。在某些实施方式中,所述生物样品是拭子样品。在某些实施方式中,所述生物样品是血液样品。
尽管为了清楚理解的目的已经通过说明和示例的方式对上述发明进行了一些详细的描述,但对于本领域技术人员来说,实施某些改变和修改将是显而易见的。因此,描述和实例不应被解释为限制本发明的范围,本发明的范围由随附的权利要求书限定。尽管本公开已参考其某些优选版本相当详细地进行了描述,但其他版本也是可能的。因此,本申请的精神和范围不应限于本文中描述的优选版本的描述。
尽管与本文中描述的那些相似或等效的组合物、材料和方法可用于本发明的实践或测试,但本文描述了适合的制剂、方法和材料。本文中提到的所有出版物均整体通过参考并入。在有冲突的情况下,以包括定义在内的本说明书为准。此外,下面讨论的特定实施方式仅仅是说明性的,而不意欲是限制性的。
在包括摘要和附图在内的本说明书中公开的所有特征以及公开的任何方法或过程中的所有步骤,可以以任何组合方式进行组合,除了其中这些特点和/或步骤中的至少一些是相互排斥的组合之外。除非另有明确说明,否则在包括摘要和附图在内的本说明书中公开的每个特征均可被用于相同、等效或相似目的的可选特点替换。因此,除非另有明确说明,否则所公开的每个特征仅仅是一系列通用的等效或相似特点中的一个实例。除了本文中描述的那些之外,本申请的其他各种不同修改对于本领域技术人员来说从前面的描述也是显而易见的。此类修改也意图落于随附的权利要求书的范围之内。
除非另有指明,否则在本说明书和权利要求书中使用的所有表示成分的数量、性质如分子量、反应条件等的数字,应该被理解为在所有情况下都被术语“约”修饰。当在本文中使用时,术语“约”意味着给定值的加或减10%。例如,“约50%”意味着在45%-55%的范围内。因此,除非有相反的说明,否则在本说明书和随附的权利要求书中阐述的数值参数是近似值,其可以根据本发明试图获得的所需特性而变。至少,并且不试图将等效性原则的应用限于权利要求书的范围,每个数值参数至少应根据报告的有效数字的数目并通过应用普通的舍入技术来解释。尽管阐述本发明的广泛范围的数值范围和参数是近似值,但在具体实例中阐述的数值尽可能精确地报告。然而,任何数值都固有地包含由在它们相应的试验测量中存在的标准偏差所必然产生的某些误差。
本文中对值的范围的叙述仅旨在用作单个地指称落于所述范围内的每个单独值的速记方法。除非在本文中另有说明,否则每个单独的值都被并入到本说明书中,如同它在本文中被单独地叙述一样。除非在本文中另有说明或与上下文明显矛盾,否则本文中描述的所有方法都可以以任何适合的顺序进行。本文中提供的任何和所有实例或示例性语言(如“例如”)的使用仅仅旨在更好地阐明本发明,并不对另外要求保护的本发明的范围构成限制。本说明书中的任何语言均不应被解释为表明任何未要求保护的要素对本发明的实践来说是必不可少的。
本文公开的本发明的可选要素或实施方式的分组不应被解释为限制。每个组成员都可以单独地或者与组的其他成员或本文中存在的其他要素以任何组合的方式被提及和要求保护。预计出于方便和/或可专利性的原因,一个组的一个或多个成员可能被包含在一个组中,或从一个组中删除。当发生任何此类包含或删除时,本说明书被视为包含修改后的组,从而满足在随附的权利要求书中使用的所有马库什组的书面描述。
本文中描述了本发明的某些实施方式,包括本发明人已知的用于实施本发明的最佳模式。当然,对于本领域的普通技术人员来说,在阅读上述描述后,这些描述的实施方式的变化将变得显而易见。本发明人期望专业技术人员适当地采用此类变化,并且本发明人意图以不同于本文中具体描述的方式来实践本发明。因此,本发明包括本文随附的权利要求书中叙述的主题内容的被适用法律所允许的所有修改和等同物。此外,除非在本文中另有说明或与上下文明显矛盾,否则本发明在所有可能的变化形式中涵盖上述要素的任何组合。
本文公开的具体实施方式可能在权利要求书中使用“由……组成”或“基本上由……组成”而不是“包含”的语言来进一步限制。当在无论是提交的还是根据修改添加的权利要求书中使用时,过渡性术语“由……组成”排除权利要求书中未指定的任何要素、步骤或成分。过渡性术语“基本上由……组成”将权利要求书的范围限制到指定的材料或步骤,以及那些不会对基本和新颖特征产生实质性影响的材料或步骤。如此要求保护的本发明的实施方式在本文中被固有地或明确地描述和启用。
最后,应当理解,本文公开的本发明的实施方式是对本发明原理的说明。可以采用的其他修改在本发明的范围之内。因此,作为示例而非限制,可以根据本文中的教导使用本发明的可选配置。因此,本发明不限于完全如所示和描述的那些内容。
Claims (38)
1.一种药物组合物,其包含治疗有效量的4-甲基吡唑或其可药用盐、水合物、多晶型物或溶剂化物以及可药用载体;其中所述药物组合物被配置成用于口服给药;并且其中所述药物组合物还包含至少一种可用于掩盖4-甲基吡唑的气味的药物惰性包衣。
2.如权利要求1所述的药物组合物,其中所述至少一种药物惰性包衣选自由羟基烷基纤维素、抗粘剂、增塑剂,糖、甲基丙烯酸酯共聚物、羟基烷基纤维素和水溶性聚合物组成的组。
3.如权利要求1所述的药物组合物,其中所述药物组合物被配置成选自粉剂、片剂、锭剂、口香糖、丸剂、胶囊、微胶囊、囊片、口服崩解片剂、渗透控释口服递送系统或其任何组合的口服剂型。
4.如权利要求1所述的药物组合物,其还包含n-乙酰半胱氨酸、蛇葡萄素、Withaniasomifera/南非醉茄、L-胱氨酸、S-乙酰谷胱甘肽、钼、铁、锌、铁螯合剂、L-抗坏血酸、L-苏氨酸或其任何组合。
5.如权利要求4所述的药物组合物,其中所述铁螯合剂包含姜黄素、檞皮素、六磷酸肌醇(IP6)或其任何组合。
6.如权利要求1所述的药物组合物,其中所述可药用载体是水。
7.如权利要求1所述的药物组合物,其还包含掩味剂、气味掩蔽剂或其组合。
8.如权利要求1所述的药物组合物,其中所述4-甲基吡唑的治疗有效量是约10mg/kg至约20mg/kg之间的量。
9.如权利要求1所述的药物组合物,其中所述4-甲基吡唑的治疗有效量是产生约0.1μmol/L的血浆浓度的量。
10.一种药物组合物,其包含治疗有效量的4-甲基吡唑或其可药用盐、水合物、多晶型物或溶剂化物以及可药用载体;其中所述药物组合物被配置成用于透皮给药。
11.如权利要求10所述的药物组合物,其还包含n-乙酰半胱氨酸、蛇葡萄素、Withaniasomifera/南非醉茄、L-胱氨酸、S-乙酰谷胱甘肽、钼、铁、锌、铁螯合剂、L-抗坏血酸、L-苏氨酸或其任何组合。
12.如权利要求11所述的药物组合物,其中所述铁螯合剂包含姜黄素、檞皮素、六磷酸肌醇或其任何组合。
13.一种在受试者中治疗和/或预防酒精诱导的超敏反应的方法,所述方法包括向所述受试者给药根据权利要求1或权利要求12所述的药物组合物。
14.如权利要求13所述的方法,其中所述酒精诱导的超敏反应选自潮红、心率加快、心悸、低血压、恶心、头晕、头痛、呕吐、腹泻、胃部不适、共济失调、意识模糊、荨麻疹、系统性皮炎、过敏性鼻炎、支气管收缩、哮喘性支气管收缩加重、心血管性虚脱、过敏性结膜炎、特应性皮炎、嗜酸细胞性食道炎、过敏性反应、慢性支气管炎和慢性阻塞性肺病(COPD)及其任何组合。
15.如权利要求14所述的方法,其中酒精潮红的特征在于面部发红、皮肤温度升高、心率加快、舒张压降低或其任何组合。
16.根据权利要求13所述的方法,其中所述药物组合物在所述受试者摄入酒精之前给药。
17.根据权利要求13所述的方法,其中药物组合物在所述受试者摄入酒精之前约60分钟至约15分钟给药。
18.根据权利要求13所述的方法,其中所述药物组合物在所述受试者摄入酒精的同时或在所述受试者摄入酒精之后给药。
19.一种在受试者中消除从酒精形成的乙醛的方法,所述方法包括向所述受试者给药根据权利要求1或权利要求12所述的药物组合物。
20.一种在受试者中减少和/或消除口腔、食道、胃、大肠或其组合中的从酒精形成的乙醛的方法,所述方法包括向所述受试者给药根据权利要求1或权利要求12所述的药物组合物。
21.一种在受试者中降低和/或消除血液中乙醛水平的方法,所述方法包括向所述受试者给药根据权利要求1或权利要求12所述的药物组合物。
22.一种在受试者中减少和/或消除来自于消化道的乙醛的方法,所述方法包括向所述受试者给药根据权利要求1或权利要求12所述的药物组合物。
23.一种在受试者中抑制线粒体醛脱氢酶2(ALDH2)的方法,所述方法包括向所述受试者给药根据权利要求1或权利要求12所述的药物组合物。
24.一种在受试者中降低由受试者摄入酒精引起的疾病或障碍的风险的方法,所述方法包括向所述受试者给药根据权利要求1或权利要求12所述的药物组合物。
25.如权利要求24所述的方法,其中所述疾病或障碍选自上呼吸消化道癌、消化道癌或乳腺癌。
26.如权利要求24所述的方法,其中所述上呼吸消化道癌包括食道癌、口咽癌、下咽癌、喉癌、头或颈部癌。
27.如权利要求24所述的方法,其中所述消化道癌包括胃癌或结肠癌。
28.如权利要求24所述的方法,其中所述疾病或障碍包括迟发性阿兹海默氏病、高血压、心肌梗塞、帕金森氏病、肌萎缩性脊髓侧索硬化症和脑缺血。
29.一种在受试者中阻断乙醛的组胺释放效应的方法,所述方法包括向所述受试者给药权利要求1或权利要求12所述的药物组合物。
30.一种在受试者中阻断酒精诱导的乙醛产生的方法,所述方法包括向所述受试者给药权利要求1或权利要求12所述的药物组合物。
31.如权利要求13-30中的任一项所述的方法,其中所述受试者对于被称为glu487lys、ALDH2*2或ALDH2*487lys的醛脱氢酶2(ALDH2)等位基因来说是杂合或纯合的。
32.如权利要求13-30中的任一项所述的方法,其还包括测试所述受试者中被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因的存在。
33.如权利要求32所述的方法,其中测试所述受试者中被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因的存在包括:从所述受试者获得呼气样品;测量所述呼气样品中的酒精和乙醛水平;以及确定所述呼气样品中乙醛水平与酒精水平的比率,其中乙醛水平与酒精水平的比率为约23.3或更高表明存在被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因;并且如果所述受试者具有约23.3或更高的乙醛水平与酒精水平的比率,则向所述受试者给药根据权利要求1或权利要求12所述的药物组合物。
34.如权利要求33所述的方法,其中测量所述呼气样品中的乙醇和乙醛水平通过半导体气相色谱来进行。
35.如权利要求33所述的方法,其中所述呼气样品在摄入酒精后获得。
36.如权利要求32所述的方法,其中测试所述受试者中被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因的存在包括:从所述受试者获得生物样品;从所述生物样品分离基因组DNA;鉴定被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因的存在;以及如果所述被称为Glu487lys、ALDH2*2、ALDH2*487lys、Glu504lys或rs671的醛脱氢酶2(ALDH2)等位基因存在,则向所述受试者给药根据权利要求1或权利要求12所述的药物组合物。
37.如权利要求33所述的方法,其中所述生物样品是拭子样品。
38.如权利要求33所述的方法,其中所述生物样品是血液样品。
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US201962852000P | 2019-05-23 | 2019-05-23 | |
US62/852,000 | 2019-05-23 | ||
PCT/US2020/034273 WO2020237172A1 (en) | 2019-05-23 | 2020-05-22 | Compositions and methods for the treatment and mitigation of alcohol-induced skin flushing |
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KR20240074388A (ko) | 2022-11-21 | 2024-05-28 | 대한민국(질병관리청 국립보건연구원장) | 당뇨병 예측 또는 진단용 hectd4 snp 마커 및 이의 용도 |
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US6565876B1 (en) * | 1999-04-22 | 2003-05-20 | Sigma-Tau Healthscience S.P.A. | Carnitine and inositol phosphate-containing composition useful as dietary supplement or drug |
US20130150419A1 (en) * | 2004-03-03 | 2013-06-13 | Raptor Therapeutiacs Inc. | 4-methylpyrazole formulations for inhibiting ethanol intolerance |
US20170252312A1 (en) * | 2014-09-15 | 2017-09-07 | Biohit Oyj | Preparations for treatment and prevention of alcohol flushing and alcohol-induced hypersensitivity reactions |
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TW271400B (zh) * | 1992-07-30 | 1996-03-01 | Pfizer | |
US6419956B1 (en) * | 1999-12-30 | 2002-07-16 | Ancile Pharmaceuticals | Odor-masking coating for a pharmaceutical preparation |
AU2008226947B2 (en) * | 2007-03-08 | 2014-07-17 | The Board Of Trustees Of The Leland Stanford Junior University | Mitochondrial aldehyde dehydrogenase-2 modulators and methods of use thereof |
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US6565876B1 (en) * | 1999-04-22 | 2003-05-20 | Sigma-Tau Healthscience S.P.A. | Carnitine and inositol phosphate-containing composition useful as dietary supplement or drug |
US20130150419A1 (en) * | 2004-03-03 | 2013-06-13 | Raptor Therapeutiacs Inc. | 4-methylpyrazole formulations for inhibiting ethanol intolerance |
US20170252312A1 (en) * | 2014-09-15 | 2017-09-07 | Biohit Oyj | Preparations for treatment and prevention of alcohol flushing and alcohol-induced hypersensitivity reactions |
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JP2022536408A (ja) | 2022-08-15 |
KR20220012903A (ko) | 2022-02-04 |
TW202110437A (zh) | 2021-03-16 |
EP3973030A4 (en) | 2023-05-31 |
WO2020237172A1 (en) | 2020-11-26 |
US20220226286A1 (en) | 2022-07-21 |
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