CN110678172A - 用于治疗创伤性脑损伤的氨基酸组合物及其使用方法 - Google Patents
用于治疗创伤性脑损伤的氨基酸组合物及其使用方法 Download PDFInfo
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Abstract
本披露提供了包含确定的氨基酸组分的药物组合物，以及用于治疗创伤性脑损伤的方法，所述方法包括向有需要的受试者施用有效量的组合物。
Description
相关申请的交叉引用
本申请要求于2017年4月28日提交的美国序列号62/491,796的优先权。
背景技术
创伤性脑损伤(TBI)的特征在于：由于对脑的急性外力导致脑正常功能的破坏。TBI可以是轻度的，不会导致长期残疾，但也是全世界死亡和残疾的主要原因。支链氨基酸(BCAA)补充已经显示可逆转TBI在小鼠中的影响，并且正在开发许多有前景的治疗。然而，仍然需要可以治疗患有创伤性脑损伤的患者的治疗剂。
发明内容
本文提供了具有确定的氨基酸组分的、可用于治疗创伤性脑损伤的组合物。
还提供了治疗创伤性脑损伤的方法，该方法包括向有需要的受试者施用有效量的本文所述的药物组合物，该药物组合物包含确定的氨基酸组分和药学上可接受的载体。
具体实施方式
除非另外说明，否则权利要求书和说明书中使用的术语是如下所述定义的。
必须指出，除非上下文另外清楚地指明，否则如本说明书及所附权利要求书中所用，单数形式“一个/一种(a/an)”和“该/所述(the)”包括复数指示物。
定义
“氨基酸”是指具有氨基基团(-NH2)、羧酸基团(-C(＝O)OH)和通过中心碳原子键合的侧链的有机化合物，并且包括必需氨基酸和非必需氨基酸、以及天然氨基酸和非天然氨基酸。
如下所示，成蛋白质性(proteogenic)氨基酸除其全名外还以三字母和单字母的缩写为人所知。对于给定的氨基酸，这些缩写在本文可互换使用。例如，Leu、L或亮氨酸均指氨基酸亮氨酸；Ile、I或异亮氨酸均指氨基酸异亮氨酸；Val、V或缬氨酸均指氨基酸缬氨酸；Arg、R或精氨酸均指氨基酸精氨酸；以及Gln、Q或谷氨酰胺均指氨基酸谷氨酰胺。同样，非天然氨基酸衍生物N-乙酰半胱氨酸可互换地称为“NAC”或“N-乙酰半胱氨酸”。氨基酸能以D-或L-异构体存在。除非另外指明，否则本文所指的氨基酸是氨基酸的L-异构体。
表1.氨基酸名称和缩写
| 氨基酸 | 三字母 | 单字母 |
| 丙氨酸 | Ala | A |
| 精氨酸 | Arg | R |
| 天冬酰胺 | Asn | N |
| 天冬氨酸 | Asp | D |
| 半胱氨酸 | Cys | C |
| 谷氨酸 | Glu | E |
| 谷氨酰胺 | Gln | Q |
| 甘氨酸 | Gly | G |
| 组氨酸 | His | H |
| 异亮氨酸 | Ile | I |
| 亮氨酸 | Leu | L |
| 赖氨酸 | Lys | K |
| 甲硫氨酸 | Met | M |
| 苯丙氨酸 | Phe | F |
| 脯氨酸 | Pro | P |
| 丝氨酸 | Ser | S |
| 苏氨酸 | Thr | T |
| 色氨酸 | Trp | W |
| 酪氨酸 | Tyr | Y |
| 缬氨酸 | Val | V |
本文所述的“药物组合物”包含至少一个氨基酸和药学上可接受的载体或赋形剂。在一些实施例中，该药物组合物用作治疗剂、营养制品、医疗食品或补充剂。
如本文所使用的，术语“药学上可接受的”是指如下氨基酸、材料、赋形剂、组合物和/或剂型，它们在合理的医学判断范围内适合用于与人和动物的组织接触而没有过度的毒性、刺激性、过敏反应、或其他问题或并发症，与合理益处/风险比相称。
如果组合物、制剂或产品提供有益的临床效果，则其是“治疗性的”。通过减轻疾病的进展和/或缓解该疾病的一种或多种症状可以显示出有益的临床效果。
如本文所使用的，术语“有效量”意指足以显著地和积极地改变待治疗的症状和/或病症(例如，提供积极的临床反应)的氨基酸或药物组合物的量。用于药物组合物中的活性成分的有效量将随以下因素而变化：所治疗的具体病症、病症的严重性、治疗持续时间、同步疗法的性质、所使用的一种或多种具体活性成分、所使用的一种或多种具体药学上可接受的赋形剂和/或一种或多种具体药学上可接受的载体、以及在主治医师的知识和专门技能范围内的类似因素。
如本文所使用的，“单位剂量(unit dose/unit dosage)”意指为了方便、安全或监测而在单个包装或容器中制备的药物的量或剂量。“单位剂量(unit dose/unit dosage)”包含如下一种或多种呈市售使用形式的药物产品，其具有活性成分和非活性组分(赋形剂)的特定混合物，呈具体的构型(例如像，胶囊壳)，并分配为具体的剂量。
药物组合物可含有如下量的氨基酸：至少约0.5g、1g、1.5g、2g、2.5g、3g、3.5g、4g、4.5g、5g、5.5g、6g、7g、8g、9g、10g、11g、12g、13g、14g、15g、20g、25g、30g、35g、40g、45g、50g、55g、60g、65g、70g、75g、或多于75g。
组合物中氨基酸重量百分比和氨基酸比率的测定
氨基酸组合物或混合物中一种或多种具体氨基酸的重量比是该组合物或混合物中一种或多种具体氨基酸的重量相比该组合物或混合物中存在的氨基酸总重量之比。该值通过将该组合物或混合物中一种或多种具体氨基酸的重量除以该组合物或混合物中存在的所有氨基酸的重量来计算。
药物组合物
本披露的一个方面提供了包含确定的氨基酸组分的药物组合物。这些药物组合物由单个氨基酸或游离氨基酸和氨基酸衍生物组成，并且可以包括一种或多种药学上可接受的赋形剂。
本披露的一个方面提供了一种组合物，该组合物包含游离氨基酸和一种或多种药学上可接受的赋形剂，其中所述氨基酸由以下组成：亮氨酸、异亮氨酸和缬氨酸，加上以下的一种或多种：
(i)精氨酸和赖氨酸；
(ii)谷氨酰胺、N-乙酰半胱氨酸和甘氨酸；
(iii)甲硫氨酸；以及
(iv)脯氨酸，
作为其确定的氨基酸组分。
在一些实施例中，所述氨基酸由以下组成：亮氨酸、异亮氨酸、缬氨酸、精氨酸、赖氨酸、谷氨酰胺、N-乙酰半胱氨酸、甘氨酸、甲硫氨酸、和脯氨酸。
在一些实施例中，所述氨基酸由以下组成：亮氨酸、异亮氨酸、缬氨酸、精氨酸、和赖氨酸。
在一些实施例中，所述氨基酸由以下组成：亮氨酸、异亮氨酸、缬氨酸、谷氨酰胺、N-乙酰半胱氨酸、和甘氨酸。
在一些实施例中，所述氨基酸由以下组成：亮氨酸、异亮氨酸、缬氨酸、精氨酸、赖氨酸、谷氨酰胺、N-乙酰半胱氨酸、和甘氨酸。
在一些实施例中，所述氨基酸由以下组成：亮氨酸、异亮氨酸、缬氨酸、精氨酸、赖氨酸、谷氨酰胺、N-乙酰半胱氨酸、甘氨酸、和甲硫氨酸或脯氨酸。
在一些实施例中，所述氨基酸由以下组成：亮氨酸、异亮氨酸、缬氨酸、精氨酸、赖氨酸、谷氨酰胺、N-乙酰半胱氨酸、甘氨酸、甲硫氨酸和脯氨酸。
在一些实施例中，所述氨基酸由以下组成：亮氨酸、异亮氨酸、缬氨酸、精氨酸、赖氨酸、谷氨酰胺、N-乙酰半胱氨酸、和甘氨酸。
在一些实施例中，存在的氨基酸的总重量在5g和75g之间。
氨基酸组合物的生产
用于制造组合物的氨基酸可以被附聚和/或被速溶以帮助分散和/或溶解。
本披露的氨基酸组合物可以使用来自以下来源的氨基酸和氨基酸衍生物来制造，或者可以使用其他来源：例如，FUSI-BCAATM速溶化的共混物(重量比为2:1:1的L-亮氨酸、L-异亮氨酸和L-缬氨酸)、FUSILTM速溶化的L-亮氨酸、L-精氨酸HCl、L-谷氨酰胺，并且其他氨基酸可从味之素株式会社(Ajinomoto Co.,Inc)获得；N-乙酰半胱氨酸可从斯百全化学公司(Spectrum Chemical)获得。
为了生产本披露的氨基酸组合物，可以使用以下一般步骤：起始材料(单个氨基酸和赋形剂)可以在共混单元中共混，随后验证共混均匀性和氨基酸含量，并且将共混粉末填充到棒状包装或其他单位剂型中。棒状包装或其他单位剂型的内容物可在用于口服施用时分散在水中。
制剂
本披露的药物组合物可以呈如下形式，该形式适用于口服使用(例如作为片剂、锭剂、硬或软胶囊、水性或油性悬浮液、乳液、可分散的粉末或颗粒、糖浆或酏剂、医疗食品产品、营养制品)，适用于局部使用(例如作为霜剂、软膏剂、凝胶、或者水性或油性溶液或悬浮液)，适用于通过吸入施用(例如作为细碎的粉末)，或者适用于肠胃外施用(例如作为无菌水性或油性溶液用于静脉内、皮下、肌内给药或作为直肠给药的栓剂)。
赋形剂
本披露的氨基酸组合物可以与一种或多种赋形剂一起复合或配制。合适的赋形剂的非限制性实例包括促味剂、食用香料、缓冲剂、防腐剂、稳定剂、粘合剂、压实剂、润滑剂、分散增强剂、崩解剂、调味剂、甜味剂和着色剂。
在一些实施例中，该赋形剂包含缓冲剂。合适的缓冲剂的非限制性实例包括柠檬酸、柠檬酸钠、碳酸镁、碳酸氢镁、碳酸钙和碳酸氢钙。
在一些实施例中，该赋形剂包含防腐剂。合适的防腐剂的非限制性实例包括抗氧化剂，例如α-生育酚和抗坏血酸盐，以及抗微生物剂，例如对羟基苯甲酸酯、氯丁醇和苯酚。
在一些实施例中，该组合物包含作为赋形剂的粘合剂。合适的粘合剂的非限制性实例包括淀粉、预胶化淀粉、明胶、聚乙烯吡咯烷酮、纤维素、甲基纤维素、羧甲基纤维素钠、乙基纤维素、聚丙烯酰胺、聚乙烯噁唑烷酮(polyvinyloxoazolidone)、聚乙烯醇、C12-C18脂肪酸醇、聚乙二醇、多元醇、糖、寡糖、及其组合。
在一些实施例中，该组合物包含作为赋形剂的润滑剂。合适的润滑剂的非限制性实例包括硬脂酸镁、硬脂酸钙、硬脂酸锌、氢化植物油、sterotex、聚氧乙烯单硬脂酸酯、滑石、聚乙二醇、苯甲酸钠、月桂基硫酸钠、月桂基硫酸镁、和轻质矿物油。
在一些实施例中，该组合物包含作为赋形剂的分散增强剂。合适的分散剂的非限制性实例包括作为高HLB乳化剂表面活性剂的淀粉、藻酸、聚乙烯吡咯烷酮、瓜尔胶、高岭土、黄原胶、膨润土、纯木纤维素、羟基乙酸淀粉钠、异非晶形(isoamorphous)硅酸盐和微晶纤维素。
在一些实施例中，该组合物包含作为赋形剂的崩解剂。在一些实施例中，该崩解剂是非泡腾崩解剂。合适的非泡腾崩解剂的非限制性实例包括淀粉(例如玉米淀粉、马铃薯淀粉、其预胶化淀粉和改性淀粉)，甜味剂，粘土(例如膨润土)，微晶纤维素，藻酸盐，羟基乙酸淀粉钠，树胶(例如琼脂、瓜尔豆、刺槐豆、刺梧桐、果胶和黄芪胶)。在一些实施例中，该崩解剂是泡腾崩解剂。合适的泡腾崩解剂的非限制性实例包括碳酸氢钠与柠檬酸结合，以及碳酸氢钠与酒石酸结合。
在一些实施例中，该赋形剂包含调味剂。调味剂可以选自合成调味油和调味芳香剂；天然油；来自植物、叶、花和果实的提取物；及其组合。在一些实施例中，该调味剂选自肉桂油；冬青油；薄荷油；三叶草油；干草油；茴香油；桉树；香草；柑橘油，例如柠檬油、橙油、葡萄油和葡萄柚油；以及水果香精，包括苹果、桃、梨、草莓、覆盆子、樱桃、李子、菠萝和杏。
在一些实施例中，该赋形剂包含甜味剂。合适的甜味剂的非限制性实例包括葡萄糖(玉米糖浆)、右旋糖、转化糖、果糖及其混合物(当不用作载体时)；糖精及其各种盐，例如钠盐；二肽甜味剂，例如阿斯巴甜；二氢查耳酮化合物，甘草甜素；甜菊(SteviaRebaudiana)(甜菊糖苷)；蔗糖的氯代衍生物，例如三氯蔗糖；以及糖醇，例如山梨糖醇、甘露糖醇、木糖醇等。还考虑了氢化淀粉水解产物和合成甜味剂3,6-二氢-6-甲基-1,2,3-氧杂噻嗪-4-酮-2,2-二氧化物，特别是其钾盐(安赛蜜(acesulfame-K))、以及钠盐和钙盐。
在一些实施例中，该组合物包含着色剂。合适的着色剂的非限制性实例包括食品、药品和化妆品(FD&C)着色剂，药品和化妆品着色剂(D&C)，以及外用药品和化妆品着色剂(Ext.D&C)。着色剂可用作染料或其相应的色淀。
具体的赋形剂可包括以下的一种或多种：柠檬酸，卵磷脂(例如Alcolec F100)，甜味剂(例如三氯蔗糖、三氯蔗糖微粉化的NF、安赛蜜(例如Ace-K))，分散增强剂(例如黄原胶(例如Ticaxan Rapid-3)，调味剂(例如香草蛋奶沙司#4306、天然橙WONF#1326、酸橙865.0032U和柠檬862.2169U)，苦味掩蔽剂(例如936.2160U)，以及天然或人工着色剂(例如FD&C黄6)。
治疗方法
本披露的一个方面提供了治疗创伤性脑损伤的方法，所述方法包括向有需要的受试者施用有效量的本文所述的药物组合物。
本披露的组合物可以通过多种已知的创伤性脑损伤动物模型例如液压冲击损伤模型(Cole等人,2010；366-371,PNAS,2010年1月5日,第107卷,第1期)和受控性皮层撞击模型(Romine等人,2014；J.Vis.Exp.[可视化实验杂志]2014年8月5日；(90):e51781)进行测试。还可由来自宾夕法尼亚大学的Akiva Cohen，根据协议临床试验管治(clinicaltrials.gov)ID：NCT01860404在临床上对组合物进行测试，其测试了损伤72小时内施用治疗后的反应时间。
本披露的一个方面提供了用于治疗创伤性脑损伤的方法，该方法包括向有需要的受试者施用有效量的本文所述的组合物。
本披露的一个方面提供了本文所述的组合物，该组合物用作药物。
本披露的一个方面提供了本文所述的组合物，该组合物用作治疗创伤性脑损伤的药物。
本披露的一个方面提供了本文所述的组合物用于制备治疗创伤性脑损伤的药物的用途。
在一些实施例中，已经诊断出该受试者患有创伤性脑损伤。
尽管已经参照优选实施例和各种替代实施例特别示出且描述了本发明，但相关领域的技术人员应该理解的是，在不脱离本发明的精神和范围的情况下可以在形式和细节上做出多种改变。
出于所有目的，在本说明书的主体内引用的所有参考文献、已出版的专利和专利申请均以其全文通过引用而特此并入。
Claims (8)
1.一种组合物，该组合物包含游离氨基酸和一种或多种药学上可接受的赋形剂，其中所述氨基酸由以下组成：亮氨酸、异亮氨酸和缬氨酸，加上以下的一种或多种：
a.精氨酸和赖氨酸；
b.谷氨酰胺、N-乙酰半胱氨酸和甘氨酸；
c.甲硫氨酸；以及
d.脯氨酸，
作为其确定的氨基酸组分。
2.如权利要求1所述的组合物，其中所述氨基酸由以下组成：亮氨酸、异亮氨酸、缬氨酸、精氨酸、赖氨酸、谷氨酰胺、N-乙酰半胱氨酸、甘氨酸、甲硫氨酸、和脯氨酸。
3.如权利要求1所述的组合物，其中所述氨基酸由以下组成：亮氨酸、异亮氨酸、缬氨酸、精氨酸、和赖氨酸。
4.如权利要求1所述的组合物，其中所述氨基酸由以下组成：亮氨酸、异亮氨酸、缬氨酸、谷氨酰胺、N-乙酰半胱氨酸、和甘氨酸。
5.如权利要求1所述的组合物，其中所述氨基酸由以下组成：亮氨酸、异亮氨酸、缬氨酸、精氨酸、赖氨酸、谷氨酰胺、N-乙酰半胱氨酸、和甘氨酸。
6.如权利要求1所述的组合物，其中所述氨基酸由以下组成：亮氨酸、异亮氨酸、缬氨酸、精氨酸、赖氨酸、谷氨酰胺、N-乙酰半胱氨酸、甘氨酸、和甲硫氨酸或脯氨酸。
7.如权利要求1-6中任一项所述的组合物，其中存在的氨基酸的总重量在5g和75g之间。
8.一种用于治疗创伤性脑损伤的方法，该方法包括向有需要的受试者施用有效量的如权利要求1-7中任一项所述的组合物。
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- 2018-04-27 WO PCT/US2018/029908 patent/WO2018201024A1/en active Application Filing
- 2018-04-27 CN CN201880035067.5A patent/CN110678172A/zh active Pending
- 2018-04-27 JP JP2019558411A patent/JP2020517703A/ja active Pending
- 2018-04-27 EP EP18724718.4A patent/EP3615018A1/en not_active Withdrawn
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| US20200163919A1 (en) | 2020-05-28 |
| WO2018201024A1 (en) | 2018-11-01 |
| JP2020517703A (ja) | 2020-06-18 |
| US11617731B2 (en) | 2023-04-04 |
| EP3615018A1 (en) | 2020-03-04 |
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