CN110522744A - 用于改善肺功能和用于预防和/或治疗辐射诱发的肺并发症的材料和方法 - Google Patents
用于改善肺功能和用于预防和/或治疗辐射诱发的肺并发症的材料和方法 Download PDFInfo
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- CN110522744A CN110522744A CN201910496164.0A CN201910496164A CN110522744A CN 110522744 A CN110522744 A CN 110522744A CN 201910496164 A CN201910496164 A CN 201910496164A CN 110522744 A CN110522744 A CN 110522744A
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Abstract
本发明提供了用于改善肺功能的治疗组合物及其用途。在一实施方案中,该治疗组合物包括选自赖氨酸、甘氨酸、苏氨酸、缬氨酸、酪氨酸、天冬氨酸、异亮氨酸、色氨酸、天冬酰胺和丝氨酸的一种或多种游离氨基酸;和电解质。在一实施方案中,本发明可用于预防或治疗辐射诱发的长期性肺并发症。
Description
相关申请的交叉引用
本申请要求于2013年3月11日提交的申请号为61/775,754的美国临时申请的权益,其全部内容以引用的方式纳入本文。
背景技术
常见的恶性肿瘤的疗法,放射治疗,可严重损害对辐射敏感性非常高的器官——肺。辐射可引起广泛的肺病,包括急性肺泡炎/肺炎、晚期慢性肺纤维化和各种呼吸功能障碍如呼吸困难和肺水肿。
在辐射诱发的肺损伤急性期,炎症为主要病理和生理特征。肺组织的初始损伤导致如巨噬细胞和嗜中性粒细胞等炎性细胞的浸润;单核细胞的病灶聚集;炎性细胞因子如转化生长因子β(TGF-β)、白介素1α (IL-lα)和肿瘤坏死因子(TNFα)等水平升高以及肺功能的下降。
辐射也诱发晚期肺纤维化——一种潜伏期纤维增生疾病,其特征为在肺上和肺内,通常在损伤或感染部位,由纤维状、结缔性基质大分子 (例如胶原蛋白、纤连蛋白和蛋白聚糖)逐渐地、不可逆地替代正常的薄壁细胞。由成纤维细胞的激活和增殖导致的纤维组织的过量形成破坏了正常的肺结构和功能。例如,纤维组织的积累使肺泡壁增厚,减小空气空间,并导致上皮损伤或甚至肺泡萎陷。
患有肺病(例如肺炎和肺纤维化)的患者遭受不同程度的运动性呼吸困难,在后期为端坐呼吸、发绀和呼吸衰竭。目前,尚未出现治疗辐射诱发的肺纤维化的方法。辐射诱发的肺纤维化的平均存活时间约为2 到3年。
辐射诱发的肺病不仅对患者生活质量造成破坏性影响,而且有时甚至比原发肿瘤或癌症更具生命威胁性。因此,辐射诱发的肺病如肺纤维化的风险已成为主要的剂量限制性因素,且有时甚至妨碍放射治疗的使用。
急需能用于预防和治疗辐射诱发的肺损伤和并发症的治疗制剂。通过下面的公开内容将清楚地知道,本发明具有的上述和其他益处。
发明简述
本发明提供了用于改善肺功能的材料和方法。在一实施方案中,本发明用于预防和/或治疗辐射诱发的肺损伤和肺并发症,包括辐射诱发的肺泡炎、肺炎和肺纤维化。
在一实施方案中,本发明的组合物被配制为口服给药。在另一实施方案中,组合物被配制为经肺给药。
在优选的实施方案中,本发明提供了用于改善肺功能和/或用于预防和/或治疗辐射诱发的肺损伤和肺并发症的方法,其中该方法包括将有效量的组合物给药到需要这些治疗的患者或受试者,该组合物包括基本上由或由L-赖氨酸、L-甘氨酸、L-苏氨酸,L-缬氨酸,L-酪氨酸,L-天冬氨酸,L-异亮氨酸和L-丝氨酸组成;选自Na+、Ca2+、Mg2+、HCO3 -和Cl-的一种或多种电解质;和任选的治疗上可接受的载体、缓冲剂和调味剂。
在一实施方案中,治疗组合物的总渗透压大约为从165mOsm到300 mOsm,或其间的任何值。在一实施方案中,组合物的pH大约为从2.0 到8.6,或其间的任何值。
在一实施方案中,本发明可用于预防和/或治疗辐射诱发的肺并发症。在一具体的实施方案中,本发明可用于预防和/或治疗电离辐射诱发的肺并发症。在某些实施方案中,本发明可用于预防和/或治疗辐射诱发的肺并发症,其包括但不限制于肺泡炎、肺炎和肺纤维化。
在某些实施方案中,本发明可用于治疗肺部疾病,其包括支气管哮喘、肺炎、支气管扩张、间质性肺疾病、急性和/或慢性肺炎、慢性阻塞性肺病(COPD)、哮喘、矽肺和肺损伤。
附图说明
图1A到H显示了肺功能测试的结果。简言之,小鼠接受剂量为8Gy 的辐射。照射二十四小时后,用本发明的治疗组合物对小鼠进行为期14 天的治疗。照射后六个月,根据本发明处理的小鼠与对照相比,功能得到改善。数据表明该治疗组合物改善了肺功能,且可用于治疗辐射诱发的长期肺并发症。
发明详述
本发明提供了用于改善肺功能的治疗组合物和方法。在一实施方案中,本发明用于预防和/或治疗辐射诱发的肺损伤和肺并发症,包括辐射诱发的肺泡炎、肺炎和肺纤维化。
在一实施方案中,组合物被配制为口服给药。在另一实施方案中,组合物被配制为经肺给药。
在优选的实施方案中,本发明提供了用于改善肺功能和/或用于预防和/或治疗辐射诱发的肺损伤和肺并发症的方法,其中该方法包括将有效量的组合物给药到需要这些治疗的患者或受试者,该组合物包括基本上由或由L-赖氨酸、L-甘氨酸、L-苏氨酸,L-缬氨酸,L-酪氨酸,L-天冬氨酸,L-异亮氨酸和L-丝氨酸组成;选自Na+、Ca2+、Mg2+、HCO3 -和Cl-的一种或多种电解质;和任选的治疗上可接受的载体、缓冲剂和调味剂。
该组合物可在肺损伤之前、期间和/或之后给药到患者或受试者,且可以每天一次或多次给药。
有利地,在一实施方案中,本发明的组合物可用于预防或治疗辐射诱发的长期肺并发症。在一实施方案中,用本发明的组合物从照射起24 小时开始对接受剂量为8Gy辐射的小鼠进行为期14天的治疗。照射后六个月,进行肺功能测试、电生理、放射学和组织病理学检查。与对照相比,用本发明组合物处理的小鼠表现出改善的肺功能、电生理、放射学和组织病理学特征。
用于改善肺功能的治疗组合物
在一实施方案中,本发明提供了用于改善肺功能的治疗组合物,其中该组合物包括、基本上由或由一种或多种游离氨基酸组成,其选自赖氨酸、甘氨酸、苏氨酸、缬氨酸、酪氨酸、天冬氨酸、异亮氨酸、色氨酸、天冬酰胺和丝氨酸;和任选的治疗上可接受的载体、电解质、缓冲剂和调味剂。
在一实施方案中,本发明提供了改善肺功能的治疗组合物,其中该组合物包括、基本上由或由赖氨酸、甘氨酸、苏氨酸、缬氨酸、酪氨酸、天冬氨酸、异亮氨酸、色氨酸和丝氨酸组成;和任选的治疗上可接受的载体、电解质、缓冲剂和调味剂。
在另一实施方案中,本发明提供了改善肺功能的治疗组合物,其中该组合物包括、基本上由或由赖氨酸、甘氨酸、苏氨酸、缬氨酸、酪氨酸、天冬氨酸、异亮氨酸和丝氨酸组成;和任选的治疗上可接受的载体、电解质、缓冲剂和调味剂。
在一实施方案中,本发明提供了改善肺功能的治疗组合物,其中该组合物包括、基本上由或由选自L-赖氨酸、L-甘氨酸、L-苏氨酸、L-缬氨酸、L-酪氨酸、L-天冬氨酸、L-异亮氨酸、L-色氨酸、L-天冬酰胺和 L-丝氨酸的一种或多种游离氨基酸组成;和任选的治疗上可接受的载体、电解质、维他命、缓冲剂和调味剂。
在一实施方案中,本发明提供了改善肺功能的治疗组合物,其中该组合物包括、基本上由或由L-赖氨酸、L-甘氨酸、L-苏氨酸、L-缬氨酸、 L-酪氨酸、L-天冬氨酸、L-异亮氨酸、L-色氨酸和L-丝氨酸组成;和任选的治疗上可接受的载体、电解质、缓冲剂和调味剂。
在另一实施方案中,本发明提供了改善肺功能的治疗组合物,其中该组合物包括、基本上由或由L-赖氨酸、L-甘氨酸、L-苏氨酸、L-缬氨酸、L-酪氨酸、L-天冬氨酸、L-异亮氨酸和L-丝氨酸组成;和任选的治疗上可接受的载体、电解质、缓冲剂和调味剂。
在一实施方案中,包含在治疗组合物中的游离氨基酸可以中性形式或盐形式存在。
在一实施方案中,治疗组合物还包括选自Na+、Ca2+、Mg2+、HCO3 -、 CO3 2-和Cl-的一种或多种电解质。
在一实施方案中,组合物的总渗透压大约为从165mOsm到300 mOsm,或其间的任何值,包括但不限制于230mOsm到280mOsm、 250mOsm到260mOsm和200mOsm到220mOsm。在另一实施方案中,组合物的总渗透压为低于165mOsm的任何值。
在某些实施方案中,每种游离氨基酸的浓度可以是从4mM到40 mM,或其间任何值,其中组合物的总渗透压大约为从230mOsm到280 mOsm。或者,如果氨基酸浓度基于mg/l计算,每种游离氨基酸可以从 100mg/l到8000mg/l的浓度存在,或其间任何值,其中组合物的总渗透压大约为从240mOsm到280mOsm。
在某些具体的实施方案中,治疗组合物包括一种或多种游离氨基酸,各自以如下浓度存在:赖氨酸浓度为约730到6575mg/l或其间任何值;天冬氨酸浓度为约532到4792mg/l或其间任何值;甘氨酸浓度为约300 到2703mg/l或其间任何值;异亮氨酸浓度为约525到4722mg/l或其间任何值;苏氨酸浓度为约476到4288mg/l或其间任何值;酪氨酸浓度为约725到6523mg/l或其间任何值;缬氨酸浓度为约469到4217mg/l或其间任何值;色氨酸浓度为约817到7352mg/l或其间任何值;天冬酰胺浓度为约528到4756mg/l或其间任何值;和/或丝氨酸浓度为约420到 3784mg/l或其间任何值;其中组合物的总渗透压大约为从165mOsm到300mOsm或其间任何值。
在某些具体的实施方案中,治疗组合物包括一种或多种游离氨基酸,各自以如下浓度存在:赖氨酸浓度为约730到6575mg/l或其间任何值;天冬氨酸浓度为约532到4792mg/l或其间任何值;甘氨酸浓度为约300 到2703mg/l或其间任何值;异亮氨酸浓度为约525到4722mg/l或其间任何值;苏氨酸浓度为约100到4288mg/l或其间任何值;酪氨酸浓度为约725到6523mg/l或其间任何值;缬氨酸浓度为约469到4217mg/l或其间任何值;和/或丝氨酸浓度为约420到3784mg/l或其间任何值;其中组合物的总渗透压大约为从165mOsm到300mOsm或其间任何值。
在一实施方案中,本发明提供了一种制剂,其包括以下成分:赖氨酸(11-21mOsm)、天冬氨酸(3-13mOsm)、甘氨酸(19-29mOsm)、异亮氨酸(19-29mOsm)、苏氨酸(19-29mOsm)、酪氨酸(0.5-5mOsm)、缬氨酸(19-29mOsm)、色氨酸(5-20mOsm)、天冬酰胺(3-13mOsm) 和/或丝氨酸(3-8mOsm)或这些成分的子集。
在一实施方案中,组合物的pH大约为从2.0到8.6,或其间的任何值。在某些实施方案中,组合物的pH大约为从2.0到5.0或其间任何值,包括例如2.0到4.2和2.0到3.6。在某些实施方案中,组合物的pH大约为从7.3到7.5或其间任何值,包括例如约7.4。在某些实施方案中,组合物的pH大约为从4.0到8.5或其间任何值,包括例如5.0到8.2、6.0 到8.0、7.1到7.9和约7.4。
在具体的实施方案中,本发明的组合物不包括葡萄糖、谷氨酰胺、甲硫氨酸和/或乳酸。
在一具体的实施方案中,组合物包括游离氨基酸形式的赖氨酸、甘氨酸、苏氨酸、缬氨酸和酪氨酸。在又一具体的实施方案中,组合物包括游离氨基酸形式的赖氨酸、甘氨酸、苏氨酸、缬氨酸、酪氨酸、天冬氨酸、异亮氨酸、色氨酸、天冬酰胺和丝氨酸。
在又一实施方案中,组合物包括由选自赖氨酸、甘氨酸、苏氨酸、缬氨酸、酪氨酸、天冬氨酸、异亮氨酸、色氨酸、天冬酰胺或丝氨酸的相同或不同的氨基酸构成的一种或多种二肽。
在一实施方案中,组合物不包含谷氨酰胺和/或甲硫氨酸;和任何能够水解成谷氨酰胺和/和甲硫氨酸的二肽、低聚肽、多肽或蛋白质。
在替代的实施方案中,组合物可包括游离氨基酸谷氨酰胺和任选的一种或多种含谷氨酰胺的二肽,其中游离氨基酸谷氨酰胺和含有谷氨酰胺的二肽的总浓度低于300mg/l或任何低于300mg/l的浓度,例如 100mg/l、50mg/l、10mg/l、5mg/l、1mg/l、0.5mg/l或0.01mg/l。
在另一替代的实施方案中,治疗组合物可包括游离氨基酸甲硫氨酸和任选的一种或多种含甲硫氨酸的二肽,其中游离氨基酸甲硫氨酸和含有甲硫氨酸的二肽的总浓度低于300mg/l或任何低于300mg/l的浓度,例如100mg/l、50mg/l、10mg/l、5mg/l、1mg/l、0.5mg/l或0.01mg/l。
在一实施方案中,治疗组合物不包含任何包括任何单糖、二糖、低聚糖、多糖和碳水化合物在内的糖类。在一具体的实施方案中,治疗组合物不包含葡萄糖和/或任何能够水解成葡萄糖的二糖、低聚糖、多糖和碳水化合物。在一具体的实施方案中,组合物不包含乳糖。在另一具体的实施方案中,治疗组合物不含有果糖和/或半乳糖和/或任何能够水解成果糖和半乳糖的任何二糖、低聚糖、多糖和碳水化合物。
在替代的实施方案中,治疗组合物可包括单糖葡萄糖和任选的一种或多种含有葡萄糖的非乳糖的二糖,其中单糖葡萄糖和含有葡萄糖的二糖的总浓度小于3g/l或任何低于3g/l的浓度,例如1g/l、500mg/l、300 mg/l、100mg/l、50mg/l、10mg/l、5mg/l、1mg/l、0.5mg/l或0.01mg/l。
在某些实施方案中,治疗组合物包括一种或多种电解质,其选自例如Na+;K+;HCO3 -;CO3 2-;Ca2+;Mg2+;Fe2+;Cl-;磷酸根离子,例如 H2PO4 -、HPO4 2-和PO4 3-;锌;碘;铜;铁;硒;铬和钼。在可选的实施方案中,组合物不包括HCO3 -或CO3 2-。在另一个替代的实施方案中,组合物包括HCO3 -和CO3 2-,其总浓度小于5mg/l或低于5mg/l的浓度值。
在进一步的实施方案中,治疗组合物包括一种或多种维生素,其包括但不限制于维生素A、维生素C、维生素D(例如维生素D1、D2、 D3、D4和/或D5)、维生素E、维生素B1(硫胺素)、维生素B2(例如核黄素)、维生素B3(烟酸或烟酰胺)、维生素B5(泛酸)、维生素B6(吡哆醇)、维生素B7(生物素)、维生素B9(例如(folate)叶酸或叶酸 (folic acid))、维生素B12(钴胺素)和维生素K(例如维生素K1、 K2、K3、K4和K5)和胆碱。
在某些实施方案中,组合物不包含选自低聚糖、多糖和碳水化合物;低聚肽或多肽或蛋白质;血脂;短链、中链和/或长链脂肪酸;和/或含有一种或多种上述营养成分的食物的一种或多种成分。
在一实施方案中,H2PO4 -、HPO4 2-和PO4 3-等磷酸根离子用于缓冲本发明的组合物。在一实施方案中,治疗组合物使用HCO3 -或CO3 2-作为缓冲剂。在另一实施方案中,治疗组合物不使用HCO3 -或CO3 2-作为缓冲剂。
本文使用的术语“基本上由…组成”将成分和步骤的范围限制在指定的材料或步骤,这些实质上不影响本发明的基本特征和新特征,即用于改善肺功能的组合物和方法。例如,通过使用“基本上由…组成”,治疗组合物不包含任何未指定的成分,其包括但不限制于游离氨基酸、二肽,低聚肽或多肽或蛋白质;和单糖、二糖、低聚糖,多糖和碳水化合物,其对肺功能有直接有利或不利的治疗效果。此外,通过使用术语“基本上由…组成”,组合物可包括对肺功能不具有治疗效果的物质;这些成分包括不影响肺功能的载体、辅料、佐剂、调味剂等等。
如本文使用的术语“寡肽”,是指由三到二十个氨基酸组成的肽。如本文使用的“寡糖”,是指由三到二十个单糖组成的糖类。
肺功能的改善
在一实施方案中,本发明提供了用于改善肺功能的方法,其中该方法包括将本发明的治疗组合物给药到需要这种治疗的受试者。
在一实施方案中,组合物被配制为口服给药。在另一实施方案中,组合物被配制为经肺给药。
在一具体的实施方案中,本发明提供了用于改善肺功能和/或用于预防和/或治疗辐射诱发的肺损伤和肺并发症的方法,其中该方法包括将有效量的组合物给药到需要这些治疗的患者或受试者,该组合物包括、基本上由或由选自赖氨酸、甘氨酸、苏氨酸、缬氨酸、酪氨酸、天冬氨酸、异亮氨酸、色氨酸、天冬酰胺和丝氨酸的一种或多种游离氨基酸组成;一种或多种电解质;和任选的治疗上可接受的载体、电解质、缓冲剂和调味剂。
在一具体的实施方案中,本发明提供了用于改善肺功能和/或用于预防和/或治疗辐射诱发的肺损伤和肺并发症的方法,其中该方法包括将有效量的组合物给药到需要这些治疗的患者或受试者,该组合物包括、基本上由或由L-赖氨酸、L-甘氨酸、L-苏氨酸、L-缬氨酸、L-酪氨酸、L- 天冬氨酸、L-异亮氨酸和L-丝氨酸组成,选自Na+、Ca2+、Mg2+、HCO3 -和Cl-的一种或多种电解质;和任选的治疗上可接受的载体、缓冲剂和调味剂。
在一实施方案中,本发明可用于预防和治疗辐射诱发的肺并发症。在某些实施方案中,本发明可用于预防和治疗辐射诱发的肺并发症,其包括但不限制于肺泡炎、肺炎和肺纤维化。
在一实施方案中,将治疗组合物给药到接受辐射的受试者,且该组合物可在辐射之前、期间、之后给药。
在一实施方案中,本发明可用于预防和和治疗肺损伤或肺部炎症引起的肺并发症。在一个实施方案中,该组合物可在肺损伤之前、期间和/ 或之后给药到患者或受试者,且可以每天一次或多次给药。
在某些实施方案中,本发明可用于预防和治疗肺炎、肺纤维化和/或辐射(例如电离辐射)、细胞毒性化学治疗剂、质子疗法;污染物、毒物、外伤、吸烟、例如类风湿性关节炎的自身免疫疾病、药物(例如胺碘酮、博莱霉素、白消安、甲氨蝶呤和呋喃妥因)、石棉和感染(例如病毒、细菌、真菌和寄生虫感染)诱发的其他肺部疾病或并发症。
在某些实施方案中,本发明可用于治疗肺部疾病,其包括支气管哮喘、肺炎、支气管扩张、间质性肺病、急性和/或慢性肺炎、慢性阻塞性肺病(COPD)、哮喘、矽肺和肺损伤。
在某些实施方案中,本发明可用于预防和/或治疗受试者的肺炎和/ 或肺纤维化,该受试者接受了用于癌症或肿瘤的放射疗法。
在某些实施方案中,本发明可用于预防和/或治疗受试者的肺炎和/ 或肺纤维化,该受试者意外地暴露在辐射中,例如常规受到空间辐射的宇航员和飞行员、由于核事故、战争行为或恐怖主义而暴露在辐射中的受试者。
如本文使用的术语“肺纤维化(pulmonary fibrosis)”或“肺纤维化 (lungfabrosis)”是指肺上和/或肺内的纤维、结缔组织或瘢痕组织和/ 或基质大分子(例如胶原、纤连蛋白、蛋白聚糖)的异常形成或积累。
如本文使用的术语“肺炎”是指其普通意义,其指肺组织的炎症。
如本文使用的术语“治疗”或任何其语法变化(例如治疗(treat)、治疗(treating)和治疗(treatment)等)包括但不限制于减轻疾病或病症的症状;和/或降低、阻滞、抑制、减少或影响疾病或病症的进展、严重程度和/或范围。
如本文所用的术语“预防”或任何其语法变化(例如预防(prevent)、预防(preventing)和预防(prevent)等)包括但不限制于延缓症状发作、预防疾病复发、增加症状发作之间的潜伏期或其组合。如本文所用的预防不需要完全没有症状。
如本文所用的术语“有效量”是指能够治疗或改善疾病或病症或其他能够产生预期治疗效果的剂量。
如本文所用术语“受试者”或“患者”描述了一种生物体,包括例如灵长类动物的哺乳动物,可向其提供根据本发明的组合物的治疗。可从公开的治疗方法受益的哺乳动物种类包括但不限制于猿、黑猩猩、猩猩、人、猴;诸如狗、猫、马、牛、猪、绵羊、山羊、鸡、小鼠、大鼠、豚鼠和仓鼠的驯化和实验动物。
在一实施方案中,需要本发明治疗的受试者或患者已经接受或将要接受能够引起肺损伤剂量的辐射(如电离辐射)。在某些实施方案中,需要本发明治疗的受试者或患者已经接受或将要接受的辐射剂量至少为 1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、 55、60、65、70、80、85、90、95或100Gy的辐射。在某些实施方案中,需要本发明治疗的受试者或患者已经接受或将要接受的辐射剂量为每天 0.1、0.3、0.5、0.7、0.9、1.0、1.1、1.2、1.3、1.4、1.5、1,6、1.7、1.8、 1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.7、3.0、3.2、3.5或4.0Gy的辐射。
在一实施方案中,需要本发明治疗的受试者或患者已经接受或将要接受胸部放疗。
在一实施方案中,需要本发明治疗的受试者或患者患有肺损伤、肺炎或肺部感染。
在一实施方案中,本发明不包括在胃肠道中预防或治疗疾病、紊乱或并发症。在一实施方案中,本发明不包括预防或治疗名称为“用于改善胃肠功能的材料和方法”的PCT/US2011/053265中公开的疾病、紊乱或并发症。
制剂和给药
本发明提供了包括治疗有效量的本发明组合物和任选的药学上可接受载体的治疗组合物或药物组合物。这些药物载体可以是无菌液体,例如水。治疗组合物还包括辅料、佐剂、调味剂等等。在一实施方案中,治疗组合物和其中包含的所有成分都是无菌的。
在一实施方案中,本发明的治疗组合物被配制为口服给药。在另一个实施方案中,本发明的治疗组合物被配制为经肺给药。
术语“载体”是指稀释剂、佐剂、辅料或赋形剂,该化合物与所述载体一起给药。合适的药物载体例子在E.W.马丁编著的《Remington's Pharmaceutical Sciences》中描述。这种组合物包含治疗有效量的治疗组合物以及合适的载体,以为患者提供合适的给药形式。
本发明还提供包括一个或多个容器的药物包或试剂盒,该容器填充有一种或多种成分,例如化合物、载体或本发明的药物组合物。
在某些实施方案中,所述组合物以适合于递送到肺部的形式制备。例如,液体药物组合物可在肺部递送的使用前冻干,其中将冻干的组合物粉碎以得到由所需尺寸范围内的颗粒组成的细碎干粉。在另一个实例中,喷雾干燥可用于得到干粉形式的液体药物组合物,且该过程可在产生由期望尺寸范围内的颗粒组成的基本上无定形的细碎干粉的条件下进行。对于用于制备干粉形式的药物组合物,参见例如WO 96/32149;WO 97/41833;WO 98/29096;和专利号为5,976,574;5,985,248;6,001,336 和6,875,749的美国专利,这些文献以引用方式的纳入本文。此外,干粉形式的药物组合物可在计量吸入剂中制备和分配为水或非水的溶液或悬浮液。
表面活性剂可以添加到药物组合物中,以减少干粉粘附到分配气溶胶的递送装置壁上。用于此预期用途的合适的表面活性剂包括但不限制于山梨糖醇三油酸酯,大豆卵磷脂和油酸等。适合于非水悬浮干粉形式的肺给药的设备是市售的。这些设备的例子包括万托林定量吸入器 (Glaxo Inc.,Research Triangle Park,N.C.)和色甘酸钠吸入器(IntalInhaler)(Fisons,Corp.,贝德福德,马萨诸塞州)。也参见专利号为5,522,378;5,775,320;5,934,272;5,960,792的美国专利中描述的气溶胶递送设备;且通过引用纳入本文。
在另一个实施方案中,药物组合物可在控释系统中递送。在一个实施方案中,可以使用泵(参见Langer,supra:Sefton,1987,CRC Crit. Ref.Biomed.Eng.14:201;Buchwald等,1980,Surgery 88:507;和 Saudek等,1989,N.Engl.J.Med.321:574)。在另一个实施方案中,可使用聚合材料(参见控释的医学应用(Medical Applications of ControlledRelease),Langer和Wise(编辑)、CRC出版社、Boca Raton,Fla.(1974);控制药物生物利用、药物产品设计和性能(Controlled Drug Bioavailability, Drug Product Design andPerformance),Smolen和Ball(编辑)、Wiley,纽约(1984);Ranger和Peppas,J.Macromol.Sci.Rev.Macromol.Chem.23:61 (1983);还参见Levy等,1985,Science 228:190;During等,1989,Ann. Neurol.25:351;Howard等,1989,J.Neurosurg.71:105)。
在一个实施方案中,药物包或试剂盒还包括给药的说明书,例如在有效剂量方面和/或参考的给药时间,例如从暴露于辐射、化疗或质子治疗起经过的时间。例如,对于接受或即将接受辐射的受试者,组合物的治疗剂量基于辐射源、被照射的身体部分和/或照射后已经经过的时间来确定。对于接受或即将接受化疗的受试者,组合物的治疗剂量基于化疗试剂的类型、化疗试剂的剂量和/或化疗后过去的时间来确定。对于接受或即将接受质子治疗的受试者,组合物的治疗剂量基于受试者接受质子治疗的剂量和/或质子治疗后过去的时间来确定。
本发明的组合物可给药到正在接受标准途径治疗的受试者,包括口服、吸入或胃肠外给药,其包括静脉内、皮下、局部、经皮、皮内、粘膜、腹腔内、肌肉内、囊内、眶内、心内、经气管、皮下、关节内、囊下,蛛网膜下,脊柱内,硬膜外和胸骨内注射,输液,和电穿孔,与任何医疗设备或物体的成分插入(暂时或永久)受试者体内共同给药。
具体实施方式
下文是举例说明用于实践本发明的程序和实施方案的实例。该实例不应被解释为限制。
实施方案1——用于改善肺功能的治疗组合物
该实施方案提供用于改善肺功能和用于预防和/或治疗的辐射诱发的肺并发症的制剂。
小鼠接受剂量为8Gy的辐射。照射二十四小时后,用本发明的治疗组合物对小鼠进行为期14天的处理。照射后六个月,进行肺功能测试、电生理、放射学和组织病理学检查。
如图1A到H所示,用本发明的组合物处理的小鼠表现出改善的肺功能、电生理、放射学和组织病理学特征。
在本文中引用的包括出版物、专利申请和专利的所有参考文献通过引用纳入本文,其程度如同每篇参考文献被单独地和具体地指出通过引用纳入本文,并在本文中整体阐述。
术语“一(a)”和“一个(an)”和“该(the)”和描述本发明的文本中使用的类似的指代解释为包括单数和复数,除非本文另有说明或与本文明显矛盾。
本文数值范围的叙述仅旨在用作单独提及的每个落在该范围内的单独值的速记方法,除非本文另外指出,每个单独值被并入说明书中,好像其在本文中单独引用一样。除非另有说明,本文提供的所有精确值代表相应近似值(例如如果情况合适,在具体指数或测量方面提供的所有精确示例值可被认为也提供相应的由“大约”修饰的近似测量值)。
本文提供的任何和所有实施方案或示例性语言(例如“如”)仅仅旨在更好地举例说明本发明,并不对本发明的范围构成限制,除非另有说明。说明书中的任何语言都不应被解释为表示任何元素对本发明的实践是必不可少的,除非有尽可能明确的陈述。
在元素或多种元素方面使用“包括(comprising)”、“具有(having)”、“包括(including)”或“包含(containing)”的本发明的任何方面或实施方案的描述旨在为说明书中有“包括(consists of)”、“基本上包括(consists essentially of)”或“基本包含(substantially comprises)”特定的元素或多种元素的类似方面或实施方案提供支持,除非另有说明或与上下文明显矛盾(例如本文中描述为包括特定元素的组合物应该被理解为也描述包括该元素的组合物,除非另有说明或与上下文明显矛盾。
应当理解的是,本文描述的实例和实施方案仅用于说明的目的,且根据本发明的不同修改或变化对本领域技术人员来说是显而易见的,并包括在本申请的理念和范围内。
Claims (8)
1.一种治疗组合物在制备预防和/或治疗肺部疾病的药物中的用途,所述治疗组合物包括L-赖氨酸、L-甘氨酸、L-苏氨酸、L-缬氨酸、L-酪氨酸、L-天冬氨酸、L-异亮氨酸和L-丝氨酸;和任选的治疗上可接受的载体、电解质、缓冲剂和调味剂。
2.根据权利要求1所述的用途,其中所述治疗组合物由L-赖氨酸、L-甘氨酸、L-苏氨酸、L-缬氨酸、L-酪氨酸、L-天冬氨酸、L-异亮氨酸和L-丝氨酸;和任选的治疗上可接受的载体、电解质、缓冲剂和调味剂组成。
3.根据权利要求1所述的用途,其中所述治疗组合物包括或由L-赖氨酸、L-甘氨酸、L-苏氨酸、L-缬氨酸和L-酪氨酸;和任选的治疗上可接受的载体、电解质、缓冲剂和调味剂组成。
4.根据权利要求1所述的用途,其中所述肺部疾病包括肺纤维化、支气管哮喘、肺炎、支气管扩张、间质性肺病、急性和/或慢性肺炎、慢性阻塞性肺病(COPD)、哮喘和矽肺。
5.根据权利要求1所述的用途,其中所述治疗组合物不包括游离氨基酸谷氨酰胺或含有谷氨酰胺的二肽,或如果游离氨基酸谷氨酰胺或含有谷氨酰胺的二肽,或游离氨基酸谷氨酰胺和含有谷氨酰胺的二肽都存在,游离氨基酸谷氨酰胺和含有谷氨酰胺的二肽的总浓度小于50mg/l;其中所述组合物不包括葡萄糖,或如果存在葡萄糖,葡萄糖的浓度小于1g/l;和其中所述组合物不包括游离氨基酸甲硫氨酸或含有甲硫氨酸的二肽,或如果游离氨基酸甲硫氨酸或含有甲硫氨酸的二肽或游离氨基酸甲硫氨酸和含有甲硫氨酸的二肽都存在,游离氨基酸甲硫氨酸和含有甲硫氨酸的二肽的总浓度小于100mg/l。
6.根据权利要求1所述的用途,其中所述治疗组合物包括选自Na+、Ca2+、Mg2+、HCO3 -和Cl-的一种或多种电解质。
7.根据权利要求1所述的用途,其中所述治疗组合物具有从165mOsm到300mOsm的总渗透压。
8.根据权利要求1所述的用途,其中所述治疗组合物为口服给药。
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JP6378307B2 (ja) | 2013-03-11 | 2018-08-22 | ユニバーシティ オブ フロリダ リサーチ ファンデーション インコーポレーティッド | 肺機能を改善するためならびに放射線誘発肺合併症の予防および/または処置のための物質および方法 |
KR20170058820A (ko) * | 2015-11-19 | 2017-05-29 | 주식회사 유진테크 머티리얼즈 | 유기 4족 화합물을 포함하는 전구체 조성물 및 이를 이용한 박막 형성 방법 |
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CN109964499B (zh) | 2016-11-21 | 2023-04-04 | 惠普发展公司,有限责任合伙企业 | 用于存在识别的方法、设备和系统 |
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