CN111212637A - 含苯甲酸酯的组合物治疗甘氨酸脑病的用途 - Google Patents
含苯甲酸酯的组合物治疗甘氨酸脑病的用途 Download PDFInfo
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Abstract
本公开涉及可用于抑制甘氨酸脑病的进展的药物组合物和制剂。所述药物组合物和制剂可以包含甘油三苯甲酸酯。所述药物组合物和制剂可以包含甘油二苯甲酸酯。所述药物组合物和制剂可以经口服施用于患者。
Description
背景
1.技术领域
本公开总体上涉及可用于治疗疾病和失调症的药物组合物和/或制剂。更具体地，本公开涉及用于治疗甘氨酸脑病的包含甘油三苯甲酸酯和/或甘油二苯甲酸酯的药物组合物和/或制剂。
2.背景技术
肉桂，是肉桂树的棕色树皮，是甜点、糖果、巧克力等的常用香料和调味材料。它还具有用作药物的悠久历史。中世纪医师在药物中使用肉桂来治疗各种失调症，包括关节炎、咳嗽、声音嘶哑、喉咙痛等。除含有锰、膳食纤维、铁和钙外，肉桂还包含三种主要化合物-肉桂醛、乙酸肉桂酯和肉桂醇。摄入后，这三种活性化合物分别通过氧化和水解转化为肉桂酸。然后，肉桂酸在肝脏中被β-氧化成苯甲酸盐。该苯甲酸盐以钠盐(苯甲酸钠)或苯甲酰基-CoA的形式存在。
苯甲酸钠由于其抗微生物特性而成为被广泛使用的食品防腐剂。作为UcephanTM的组分，它也具有医学上的重要性，UcephanTM是食品和药物管理局(FDA)批准的药物，用于治疗与高氨血症相关的肝代谢缺陷，诸如尿素循环障碍。本发明人探索了苯甲酸钠在雌性SJL/J小鼠中治疗复发缓解型EAE的疾病过程中的新用途(参见Brahmachari andPahan,“Sodium benzoate,a food additive and a metabolite of cinnamon,modifies Tcells at multiple steps and inhibits adoptive transfer of experimentalallergic encephalomyelitis,”J.Immunol.,2007,Jul 1；179(1):275-83，其全部内容通过引用明确地并入本申请)。
本发明人还发现苯甲酸钠抑制小鼠的多发性硬化症(MS)的疾病过程。本发明人还发现，苯甲酸钠会上调一种称为DJ-1的蛋白质，这是一种有益的神经保护性蛋白质，对诸如帕金森氏病(PD)和阿尔茨海默氏病(AD)的神经退行性疾病有影响(参见Khasnavis andPahan,“Sodium Benzoate,a Metabolite of Cinnamon and a Food Additive,Upregulates Neuroprotective Parkinson Disease Protein DJ-1in Astrocytes andNeurons,”Journal of Neuroimmune Pharmacology,June 2012,Volume 7,Issue 2,pp424-435，其全部内容通过引用明确地并入本申请)。
此外，已经发现在患有不同的神经退行性疾病诸如AD和PD的患者的大脑中，神经营养因子的水平降低，神经营养因子诸如脑源性神经营养因子(BDNF)和神经营养蛋白-3(NT-3)。最近，本发明人描述了苯甲酸钠会增加脑细胞中BDNF和NT-3的产生，表明它可能对神经退行性疾病有益(参见Jana et al.,“Up-regulation of neurotrophic factors bycinnamon and its metabolite sodium benzoate:therapeutic implications forneurodegenerative disorders,”J.Neuroimmune Pharmacol.,2013Jun；8(3):739-55，其全部内容通过引用明确并入本申请)。
然而，苯甲酸钠被迅速代谢并从体内排出。因此，至少与尿素循环障碍有关，苯甲酸钠通常每天施用三至四次，以确保从血流中持续去除有毒的氨。
发明内容
本公开涉及用于治疗甘氨酸脑病的组合物和方法。一方面，公开了一种抑制甘氨酸脑病的进展的方法。该方法包括向有需要的患者施用有效量的包含甘油三苯甲酸酯和/或甘油二苯甲酸酯的药物组合物。
本公开还涉及药物、药物组合物和/或制剂的制造。一方面，本发明涉及甘油三苯甲酸酯和/或甘油二苯甲酸酯化合物用于制备用于治疗甘氨酸脑病的药物、药物组合物和/或制剂的用途。
在另外的实施方案中，本公开涉及使用用于抑制甘氨酸脑病的进展的制剂的方法。该方法包括向有需要的患者施用有效量的该制剂，该制剂包含约1g/1ml的甘油三苯甲酸酯。
前面已经相当广泛地概述了本公开的特征和技术优点，以便可以更好地理解以下的详细描述。在下文中将描述形成本申请的权利要求的主题的本公开的其他特征和优点。本领域技术人员应当理解，所公开的概念和特定实施方案可以容易地用作修改或设计用于实现本公开的相同目的的其他实施方案的基础。本领域技术人员还应该意识到，这样的等同实施方案不脱离如所附权利要求书中阐述的本公开的精神和范围。
具体实施方式
下面描述各种实施方案。通过参考以下详细描述，可以更好地理解实施方案的各种元素的关系和功能。然而，实施方案不限于本文明确公开的实施方案。应当理解，在某些情况下，可能已经省略了对于理解本文公开的实施方案不必要的细节。
尽管苯甲酸钠可以用于治疗某些疾病或失调症，但它很快被代谢并从体内排出。因此，本发明人发现了苯甲酸钠的持续释放和缓慢释放形式，其允许减少施用方案并提高患者依从性。
本公开提供了仅需要每天一次施用药物组合物的甘氨酸脑病的治疗。在一些方面，用于甘氨酸脑病的治疗可以包括每天两次施用药物组合物。在某些方面，本文公开的药物组合物(和/或制剂)包含甘油三苯甲酸酯(也称为三苯精)。在其他方面，本文公开的药物组合物(和/或制剂)包含甘油二苯甲酸酯。在一些方面，本文公开的药物组合物(和/或制剂)同时包含甘油三苯甲酸酯和甘油二苯甲酸酯。
甘油二苯甲酸酯和甘油三苯甲酸酯将在体内缓慢形成苯甲酸钠，因为这些分子将在肠中被各种脂肪酶裂解。因此，假设，与苯甲酸钠相比，甘油二苯甲酸酯和甘油三苯甲酸酯将显示出大大改善的治疗效果。
在一些实施方案中，公开了用于抑制甘氨酸脑病的进展的治疗。在甘氨酸脑病中，体内甘氨酸水平升高。甘氨酸水平升高会导致许多有害状况。已知甘氨酸会与苯甲酸酯反应形成马尿酸。然后马尿酸可以通过尿排出。
苯甲酸钠是目前治疗甘氨酸脑病的唯一方法，但是，由于苯甲酸钠如此之快地从体内分泌，因此需要频繁(每天多次)用高剂量的该化合物治疗患者。例如，婴儿可能需要大约每6小时以约2.8gm/d的剂量接受治疗。由于如此高的剂量，正在接受治疗的患者通常会困倦并遇到其他问题。
然而，本发明人发现甘油三苯甲酸酯和/或甘油二苯甲酸酯化合物可以用作苯甲酸钠的缓慢释放制剂，因为这些化合物将需要被脂肪酶裂解以释放苯甲酸盐。
本文考虑的一些治疗包括向有此需要的患者施用有效量的包含甘油三苯甲酸酯和/或甘油二苯甲酸酯的药物组合物。根据本公开，可以每天一次施用该治疗。在一些方面，该治疗可包括每天两次施用。
在本公开预期的治疗方法中，甘油三苯甲酸酯和/或甘油二苯甲酸酯可以单独使用或与药学上可接受的载体或赋形剂一起用于组合物中。如本文所用，术语“药学上可接受的载体”是指任何类型的无毒的惰性固体、半固体或液体填充剂、稀释剂、包囊材料或制剂助剂。可以用作药学上可接受的载体的材料的一些实例是：糖，诸如乳糖、葡萄糖和蔗糖；淀粉，诸如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，诸如羧甲基纤维素钠、乙基纤维素和乙酸纤维素；黄芪胶粉(powdered tragacanth)；麦芽；明胶；滑石；赋形剂，诸如可可脂和栓剂蜡(suppository waxes)；油，诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油；二醇，诸如丙二醇；酯，诸如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂诸如氢氧化镁和氢氧化铝；海藻酸；无热原水；等渗盐水；林格氏溶液；乙醇；和磷酸盐缓冲溶液；以及根据配方设计师的判断该组合物中也可以存在其他无毒的相容性润滑剂(诸如十二烷基硫酸钠和硬脂酸镁)以及着色剂、释放剂、包衣剂、甜味剂、矫味剂和芳香剂、防腐剂和抗氧化剂。其他合适的药学上可接受的赋形剂描述于"Remington's Pharmaceutical Sciences(雷明顿药物科学),"Mack Pub.Co.,New Jersey,1991，其内容通过引用明确并入本文。
在某些实施方案中，甘油三苯甲酸酯和/或甘油二苯甲酸酯可以经口服施用于人和其他动物。甘油三苯甲酸酯和/或甘油二苯甲酸酯可以被配制用于施用，并且配制方法是本领域众所周知的(参见，例如，Remington:The Science and Practice of Pharmacy(雷明顿：药学科学与实践),Mack Publishing Company,Easton,Pa.,19th Edition(1995))。
本文公开的任何制剂可用于治疗/抑制甘氨酸脑病的进展。在一些实施方案中，本公开涉及使用用于抑制甘氨酸脑病的进展的制剂的方法。该方法包括向有需要的患者施用有效量的制剂。在一些实施方案中，该制剂包含1g/1mg的甘油三苯甲酸酯。在一些实施方案中，该制剂可包含甘油二苯甲酸酯代替或附加于甘油三苯甲酸酯。
在一些实施方案中，该制剂可以是持续释放制剂，这意味着它们在延长的时间段内稳定地释放甘油三苯甲酸酯(和/或甘油二苯甲酸酯)。在其他实施方案中，该制剂可以是延迟释放制剂，这意味着它们在比施用后立即释放的时间晚的时间释放甘油三苯甲酸酯(和/或甘油二苯甲酸酯)。
在一些实施方案中，该制剂经口服施用于患者。在一些实施方案中，总日剂量可分为多个剂量，诸如两个或三个基本相等的剂量，并在一天内的不同时间施用。在一些实施方案中，基于50kg的患者，每天可向患者施用约1.25g至约15g的甘油三苯甲酸酯。
根据本发明使用的药物组合物可以是无菌的无热原的液体溶液或悬浮液、包衣胶囊、冻干粉剂或本领域已知的其他形式。
用于口服施用的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这样的固体剂型中，活性化合物与至少一种惰性的、药学上可接受的赋形剂或载体(诸如柠檬酸钠或磷酸二钙)和/或以下混合：a)填充剂或增量剂诸如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；b)粘合剂，诸如，例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶；c)润湿剂，诸如甘油；d)崩解剂，诸如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠；e)溶液缓凝剂，诸如石蜡；f)吸收促进剂，诸如季铵化合物；g)润湿剂，诸如，例如乙酰醇和甘油单硬脂酸酯；h)吸收剂，诸如高岭土和膨润土；和i)润滑剂，诸如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及它们的混合物。在胶囊、片剂和丸剂的情况中，剂型还可包含缓冲剂。
相似类型的固体组合物也可以用作软填充和硬填充明胶胶囊中的填充剂，该胶囊使用诸如乳糖或牛奶糖的赋形剂以及高分子量聚乙二醇等。
片剂、糖衣丸、胶囊剂、丸剂和颗粒剂的固体剂型可以用包衣和外壳诸如肠溶包衣和药物配制领域众所周知的其他包衣制备。它们可以任选地包含乳浊剂(opacifyingagents)，并且也可以是它们任选地以延迟方式在肠道的特定部分中仅释放或优选释放活性成分的组合物。可以使用的包埋组合物的实例包括聚合物质和蜡。
活性化合物也可以与一种或多种如上所述的赋形剂呈微囊形式。片剂、糖衣丸、胶囊剂、丸剂和颗粒剂的固体剂型可以用包衣和外壳诸如肠溶包衣、控释包衣和药物配制领域众所周知的其他包衣制备。在这种固体剂型中，活性化合物可以与至少一种惰性稀释剂诸如蔗糖、乳糖或淀粉混合。按照常规做法，这些剂型还可以包含除惰性稀释剂以外的其他物质，例如压片润滑剂和其他压片助剂诸如硬脂酸镁和微晶纤维素。在胶囊、片剂和丸剂的情况中，剂型还可以包含缓冲剂。它们可以任选地包含乳浊剂，并且也可以是它们任选地以延迟方式在肠道的特定部分中仅释放或优选释放活性成分的组合物。可以使用的包埋组合物的实例包括聚合物质和蜡。
用于口服施用的液体剂型包括药学上可接受的乳剂、微乳剂、溶液剂、混悬剂、糖浆剂和酏剂。除活性化合物外，液体剂型还可包含本领域常用的惰性稀释剂，诸如，例如水或其他溶剂、增溶剂和乳化剂，诸如乙醇、异丙醇、碳酸乙酯、EtOAc、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、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、四氢糠醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯，及它们的混合物。除惰性稀释剂外，口服组合物还可包含佐剂，诸如湿润剂、乳化剂和悬浮剂、甜味剂、调味剂和加香剂。
本公开的组合物的有效量通常包括足以抑制(例如减慢或停止)甘氨酸脑病的进展的任何量。可以与载体材料组合以产生单一剂型的活性成分(甘油三苯甲酸酯和/或甘油二苯甲酸酯)的量将根据所治疗的宿主和特定的施用方式而变化。然而，应理解，任何特定患者的具体剂量水平将取决于多种因素，包括所用具体化合物的活性、年龄、体重、总体健康状况、性别、饮食、施用时间、施用途径、排泄速率、药物组合以及接受治疗的特定失调症或疾病的严重程度。对于给定情况的治疗有效量可以通过常规实验容易地确定，并且在普通临床医生的技能和判断之内。
根据本公开的治疗方法，通过以这样的量和以达到所需结果需要的时间向患者施用有效量的甘油三苯甲酸酯和/或甘油二苯甲酸酯来减慢或停止患者(诸如人或低等哺乳动物)的失调症的进展。有效减慢或停止疾病或失调症的进展的化合物的量可以指以适用于任何医学治疗的合理的益处/风险比足以治疗疾病或失调症的化合物的量。
然而，将理解，本公开的化合物和组合物的总日用量将由主治医师在合理的医学判断范围内决定。任何特定患者的具体治疗有效剂量水平将取决于多种因素，包括正在治疗的疾病或失调症以及失调症的严重性；所用特定化合物的活性；使用的具体组合物；患者的年龄、体重、总体健康状况、性别和饮食；施用时间、施用途径和所用特定化合物的排泄速率；治疗的持续时间；与所使用的特定化合物组合或同时使用的药物；以及医学领域众所周知的因素。
要施用于温血动物诸如人的本公开的化合物(诸如甘油三苯甲酸酯和/或甘油二苯甲酸酯)的“有效量”或剂量，可以根据待治疗的失调症而变化。与甘氨酸脑病有关，基于50kg的患者，甘油三苯甲酸酯(和/或甘油二苯甲酸酯)的有效量可以为每天约1.25g至约15g。例如，有效量可以是每50kg患者每天约1.25g、约2.5g、约4g、约5g、约7.5g、约10g或约12g。在一些实施方案中，有效量可以是每50kg患者每天约1.25g至约10g、约1.25g至约7g、约1.25g至约4g或约1.25g至约2g。
实施例
将进行实验以测试甘油三苯甲酸酯(三苯精)和/或甘油二苯甲酸酯在甘氨酸脑病的治疗中的功效。发明人将向小鼠(C57/BL6)注射甘氨酸脱羧酶siRNA(每3天20μg/小鼠)，以产生甘氨酸脑病样病症。
然后，小鼠将用不同剂量(25mg/kg体重/天至200mg/kg体重/天)的甘油三苯甲酸酯和/或甘油二苯甲酸酯经口服治疗。此后，将测量血清中的甘氨酸。用分光光度法确定每种不同治疗的有效性。
根据本公开，无需过度实验即可进行和实施本文公开和要求保护的所有组合物和方法。尽管本发明可以以许多不同的形式体现，但是在此详细描述了本发明的特定优选示例。本公开是本发明原理的示例，并且不旨在将本发明限制于所示的特定实施方式。另外，除非明确相反地指出，否则术语“一个/种”的使用旨在包括“至少一个/种”或“一个或多个/种”。例如，“化合物”旨在包括“至少一种化合物”或“一种或多种化合物”。
以绝对术语或以近似术语给出的任何范围旨在涵盖这两者，并且本文中使用的任何定义旨在阐明而不是限制。尽管阐述本发明的广泛范围的数值范围和参数是近似值，但是在具体实例中阐述的数值被尽可能精确地报道。然而，任何数值都固有地包含某些误差，这些误差必定是由它们各自的测试测量中发现的标准偏差引起的。此外，本文公开的所有范围应理解为涵盖其中包含的任何和所有子范围(包括所有分数和整数值)。
此外，本发明涵盖本文描述的一些或所有各种实施方式的任何和所有可能的组合。还应当理解，对本文描述的当前优选实施方案的各种改变和修改对于本领域技术人员将是显而易见的。可以在不脱离本发明的精神和范围并且不减少其预期优点的情况下进行这种改变和修改。因此，意图是这样的改变和修改被所附权利要求覆盖。
Claims (16)
1.一种抑制甘氨酸脑病的进展的方法，包括：向有需要的患者施用有效量的包含甘油三苯甲酸酯的药物组合物。
2.根据权利要求1所述的方法，其中所述药物组合物每天一次施用于所述患者。
3.根据权利要求1或2所述的方法，其中基于50kg的患者，所述有效量为每天约1.25g至约15g。
4.根据权利要求1至3中任一项所述的方法，其中所述药物组合物与药学上可接受的载体或赋形剂一起配制。
5.根据权利要求1至4中任一项所述的方法，其中所述药物组合物经口服施用。
6.根据权利要求1至5中任一项所述的方法，其中所述组合物包含甘油二苯甲酸酯。
7.一种抑制甘氨酸脑病的进展的方法，包括：向有需要的患者施用有效量的包含甘油二苯甲酸酯的药物组合物。
8.根据权利要求7所述的方法，其中所述组合物包含甘油三苯甲酸酯。
9.根据权利要求7或8所述的方法，其中所述药物组合物每天一次施用于所述患者。
10.根据权利要求7至9中任一项所述的方法，其中基于50kg的患者，所述有效量为每天约1.25g至约15g。
11.根据权利要求7至10中任一项所述的方法，其中所述药物组合物与药学上可接受的载体或赋形剂一起配制。
12.根据权利要求7至11中任一项所述的方法，其中所述药物组合物经口服施用。
13.一种使用制剂抑制甘氨酸脑病进展的方法，包括：
向有需要的患者施用有效量的所述制剂，所述制剂包含约1g/1ml的甘油三苯甲酸酯。
14.根据权利要求13所述的方法，其中所述制剂选自持续释放制剂和延迟释放制剂。
15.根据权利要求13或14所述的方法，其中所述制剂经口服施用于所述患者。
16.根据权利要求13至15中任一项所述的方法，其中基于50kg的患者，每天约1.25g至约15g的甘油三苯甲酸酯被施用于所述患者。
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| US20160331714A1 (en) * | 2014-01-17 | 2016-11-17 | Rush University Medical Center | The use of a benzoate containing composition in urea cycle disorders and neurodegenerative disorders |
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| US20150011611A1 (en) * | 2012-02-10 | 2015-01-08 | Whitehead Institute For Biomedical Research | Inhibition of the glycine cleavage system for treatment of cancer |
| US20160331714A1 (en) * | 2014-01-17 | 2016-11-17 | Rush University Medical Center | The use of a benzoate containing composition in urea cycle disorders and neurodegenerative disorders |
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| Title |
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| CHRISTOFFEL PETRUS STEPHANUS BADENHORST: "A new perspective on the importance of glycine conjugation in the metabolism of aromatic acids", 《DRUG METABOLISM REVIEWS》 * |
| JENNICA L. ZARO: "Lipid-based drug carriers for prodrugs to enhance drug delivery", 《THE AAPS JOURNA》 * |
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