CN109069423A - 亲水性药物的肺部靶向递送 - Google Patents
亲水性药物的肺部靶向递送 Download PDFInfo
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- CN109069423A CN109069423A CN201780015457.1A CN201780015457A CN109069423A CN 109069423 A CN109069423 A CN 109069423A CN 201780015457 A CN201780015457 A CN 201780015457A CN 109069423 A CN109069423 A CN 109069423A
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- Prior art keywords
- sulfonate
- alkyl
- sulfate
- solubility
- straight chain
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- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims abstract description 38
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Abstract
最大粒径为200μm的水性悬浮液形式的药物组合物包含亲水性癌症药物的两亲性磺酸盐和/或硫酸盐或由其组成,其在水或含水体液中的溶解度小于0.1重量%。还公开了粉末形式的颗粒,其制备方法和悬浮液的制备方法,通过给予药物组合物治疗肺中的癌症、细菌或真菌感染的方法,以及根据本发明的方法设计组合物的方法。
Description
发明领域
本发明涉及将亲水性药物给予人体和动物体的特定部位,特别是肺部。更具体地,本发明涉及亲水性药物,特别是抗癌药物、抗真菌药和抗生素的给药。
背景技术
治疗窗代表了可以有效和安全地治疗疾病的药物剂量范围。其范围从看到显著治疗效果的剂量到由于不良反应抵消治疗益处的剂量。
大多数抗癌药物的治疗窗口较窄。此外,通常给药剂量的一小部分到达待治疗的部位。在通过口服摄入或血管内注射进行全身给药后,药物通过循环分布在整个身体中,导致整个身体受到影响。理想地,药物应专门针对期望的身体部位,例如需要治疗的器官或组织。这种有针对性的给药可以避免伤害身体的其他部分。这种给药旨在将药物引导至感兴趣的组织,同时避免大量药物到达不需要治疗的组织。
一个需要针对特定身体部位的药物的例子是抗癌药物阿霉素。通常认为,通过靶向药物递送可以显著改善阿霉素的治疗潜力,因为可以避免或至少显著降低其危险的副作用。阿霉素最危险的副作用是对心脏的损害。当阿霉素的累积剂量达到550mg/m2时,发生心脏副作用的风险显著增加。阿霉素心脏毒性的特征在于线粒体氧化磷酸化的剂量依赖性下降。阿霉素与铁相互作用产生的活性氧(ROS)可以破坏肌细胞,导致肌原纤维丢失和细胞质空泡化。这种过度损坏可能导致患者死亡。因此,希望保持阿霉素的心脏浓度尽可能低。
阿霉素广泛用于治疗肺部不同类型的恶性肿瘤,例如小细胞肺癌和肉瘤的肺转移,将阿霉素靶向递送至肺的发展具有巨大的治疗潜力。
分离的肺灌注是将药物靶向输送到肺部的发展最成熟的方法,是一种外科手术,在此过程中,肺部血液循环与通过身体其他部分与血液循环分离,药物被输送直接进入肺循环。这允许更高浓度的化学疗法到达肺部肿瘤。这种侵入性非常高的手术在技术上很复杂,并且对患者来说不安全。在侵入性手术的并发症中可以提及麻醉或药物反应,出血,感染,内脏器官损伤和血管损伤。因此,期望使用方便且微创的静脉内给药方式来制备药物递送系统,其仍然可以在所讨论的器官或/和组织中提供增加的药物浓度。
除了将药物专门施用于特定身体部位之外,有时希望将其靶向多于一个部位。例如,在实体癌肿瘤治疗中,将其浓度保持在肿瘤中的高水平同时在体循环中维持低浓度的药物以防止转移的传播可能是有益的。
当需要将活性药物成分快速靶向递送到肺部时,同样的考虑适用于治疗其他肺部疾病,如肺炎,念珠菌病,肺结核,以及慢性阻塞性肺病(COPD),也称为慢性阻塞性肺病(COLD),哮喘,囊性纤维化和其他健康问题。
许多药理学活性剂如上述药物是弱碱,因为它们包含一个或多个氨基。因此,它们与强酸和弱酸形成盐,通常以盐的形式给药。它们的常用药学上可接受的盐,特别是它们在含水体液中的盐酸盐,氢溴酸盐,磷酸盐,硫酸盐,乳酸盐,酒石酸盐等的溶解度通常高于游离碱的溶解度。因此,这些盐的水溶液用于静脉内输注而不是相应碱的水溶液。
对于对人或动物的给药,这种药物以阳离子两亲形式(以与药学上可接受的酸的盐的形式)提供。这种给药方式适用但不限于抗肿瘤药物,例如蒽环霉素,长春花生物碱,安吖啶,拓扑替康和伊立替康。
上述类型的阳离子两亲药物(CAD)与两亲阴离子表面活性剂如烷基硫酸盐或烷基磺酸盐反应,形成水不溶性络合物。
虽然仍满足有机碱盐与有机酸或无机酸的定义,但水不溶性络合物在某种程度上还通过非共价力连接。
通过使用上述“程序化药物递送”的概念,可以将例如待递送至特定组织或器官的所需量的药物进行设计和编程,例如通过药物递送制剂的含量或组成。然而,目前已知和使用的这些技术需要进一步改进,特别是关于旨在治疗肺部疾病,例如癌症,细菌和真菌感染的药物。
发明目的
本发明的主要目的是提供一种用于将包含一个或多个氨基官能团的药物靶向给药至肺部的药物组合物,其缺少已知的药物组合物的一个或多个缺点或至少表现出较轻的程度。
本发明的另一个目的是提供一种用于将包含一个或多个氨基官能团的药物靶向给药至肺部的药物组合物,其缺少本领域已知药物的已知组合物的一个或多个缺点或至少表现出较轻的程度。
本发明的另一个目的是提供一种设计这种药物组合物的方法,该方法在微创静脉注射给药方式后,在肺中提供所需的药物目标浓度。
通过研究本发明的以下简短描述,其优选实施方案和所附权利要求,本发明的其他目的将变得明显。
发明内容
本发明基于以下认识:含有氨基官能团的亲水性抗癌药物的两亲性直链烷基磺酸盐和直链烷烃硫酸盐颗粒的水性悬浮液是有价值的形式,通过这些形式可以以这样的方式给予这些药物,在微创静脉注射给药方式后,将它们的治疗效果集中在所需的器官,特别是肺部。亲水性抗癌药物的直链烷基磺酸盐和直链烷烃硫酸盐的重要特征是它们在水和含水体液中的低溶解度,25℃下小于0.1mg/mL。
然而,本发明背后的生物学的可能(但并非用于绑定约束)的解释是,在将这种抗癌药物的颗粒水悬浮液施用于体循环或肺或实体肿瘤时,药物颗粒将在给定的时间内达到身体的均衡分布。它们在水性介质中的溶解度非常低,但不是零。因此,它们将缓慢溶解在体液中,直至达到由其溶解度决定的平衡。由于溶解的物质不可逆地化学转化为降解产物,因此随着时间的推移,更多的物质溶解以维持平衡。只要通过溶解物质供给平衡,就可以局部保持稳态浓度的药物。
本发明还基于以下认识:含有氨基官能团的亲水性抗癌药物的两亲性直链烷基磺酸盐和直链烷烃硫酸盐的水性悬浮液是微创静脉内给药后这些药物可以靶向肺部(或在肺组织中积累)的特别有价值的形式。水悬浮液由粒径大于约5000nm的颗粒构成或包含粒径大于约5000nm的颗粒。
本发明水性悬浮液的一个重要特性是它们的低沉降速率。通常,给定种类颗粒的沉降速率随颗粒尺寸而增加。然而,可以通过增加水相的粘度和/或通过改变颗粒的表面性质(例如表面粗糙度)来防止增加甚至降低。
本发明提供包含一个或多个氨基的亲水性药物和水溶性烷基硫酸盐或烷基磺酸盐或两种或更多种这样的硫酸盐或磺酸盐的混合物的盐的固体颗粒。盐的一个重要特征是其在水中的低溶解度。换句话说,本发明的盐基本上不溶。“基本上不溶”是指在水或含水体液中的溶解度小于0.1重量%,特别是小于0.05重量%或0.02重量%。
本发明提供一种用水溶性烷基硫酸盐或烷烃磺酸盐或两种或更多种这样的硫酸盐或磺酸盐的混合物制备亲水性癌症药物的水不溶性盐的固体颗粒的方法。
本发明还提供了药物组合物,其包含一种或多种本发明的两亲磺酸盐和/或硫酸盐和液体载体。组合物可以通过任何合适的途径给药,例如通过动脉内,腹膜内,肌肉内,透皮或静脉内给药。通过使用包含本发明的两亲磺酸盐和硫酸盐的水性悬浮液的微创静脉内给药来给药是优选的。
本发明还提供了制备药物组合物的方法,该药物组合物包含固体颗粒形式的亲水性药物的水不溶性盐和水溶性烷基硫酸盐或烷基磺酸盐或者两种或更多种这样的硫酸盐或磺酸盐的混合物。
本发明的组合物可进一步包含缓冲剂和药学上可接受的赋形剂,例如重量摩尔渗透压浓度控制剂和粘度控制剂。由于使用的生产方法,该组合物另外含有盐或相应的离子,其由水溶性烷基硫酸盐或烷基磺酸盐的阳离子和抗癌药物的阴离子组成。优选使用碱金属烷基硫酸盐和碱金属烷烃磺酸盐,特别是烷基硫酸钠和烷基磺酸钾和烷基磺酸盐。
本发明的两亲性颗粒状磺酸盐和硫酸盐由具有抗癌活性的药理学试剂D和一种或多种硫酸盐或磺酸盐阴离子组成,所述药理学试剂D包含1至4个氨基,其中一个或多个被质子化。它们由公式(1)和(2)表示:
Dn+(R1SO3)- n (1)
Dn+(R2OSO3)- n (2)
其中R1是直链C6-C30烷基;R2是直链C6-C30烷基;n是1-4的整数。
优选R1和R2是直链C10-C20烷基,更优选直链C12-C18烷基,甚至更优选约直链C16烷基。因此,R1可以是任何直链C12,C13,C14,C15,C16,C17,C18烷基;R2可以是任何直链C12,C13,C14,C15,C16,C17,C18烷基。
优选的胶状颗粒的90%粒径为5000nm至100000nm,优选为20000nm至90000nm,最优选40000nm至80000nm。
根据本发明的一个优选方面,本发明包括尺寸大于胶体颗粒的颗粒及其水性悬浮液,例如尺寸最大达50μm或100μm的颗粒,以及它们的悬浮液。
可以通过例如离心或冷沉淀将本发明的颗粒与水相分离。如果通过离心分离,由水溶性烷基硫酸盐或烷基磺酸盐的阳离子和抗癌药物的阴离子组成的伴随盐或相应离子与水相一起去除。所得粉末(如果需要,另外干燥)保持胶体的粒度至少50%,更优选至少80%。为了促进在水性介质中的再悬浮,粉末可以包含再悬浮促进剂,例如葡萄糖,乳糖或白蛋白。或者,本发明的颗粒可以通过蒸发(包括冷沉淀)水性介质来产生;在这种情况下,它们将与包含水溶性烷基硫酸盐或烷基磺酸盐的阳离子和抗癌药物的阴离子的伴随盐混合;如果需要,可以将它们与重悬浮促进剂混合。
根据本发明的另一个优选方面,本发明的悬浮液可以包含对需要治疗的肿瘤的表面抗原具有亲和力的微载体颗粒(例如通过包括适当的抗体结构)。
本发明的两亲性磺酸盐和硫酸盐的优选药理学活性剂D包括但不限于:阿霉素,表柔比星,柔红霉素,伊达比星,米托蒽醌,长春碱,长春新碱,长春瑞滨,安吖啶,托泊替康,伊立替康。
根据本发明的另一个优选方面,合适的抗生素具有与下列物质相似的亲水性,如:氨基糖苷类,安沙霉素类,碳青霉烯类,头孢菌素类,糖肽类,达托霉素,大环内酯类,噁唑烷酮类,青霉素类,喹诺酮类(环丙沙星,依诺沙星,加替沙星,吉米沙星,左氧氟沙星,洛美沙星,莫西沙星,诺氟沙星,氧氟沙星,曲伐沙星,格帕沙星,司帕沙星,替马沙星),磺胺类,四环素类(多西环素,四环素,米诺环素,土霉素),抗分枝杆菌药物(氯法齐明,氨苯砜,卷曲霉素,环丝氨酸,乙胺丁醇,乙硫异烟胺,异烟肼,吡嗪酰胺,利福平,利福喷汀,链霉素)。
合适的抗真菌药物具有与下列物质类似的亲水性:多烯抗真菌类(两性霉素B,杀念菌素,菲律宾菌素,哈霉素,纳他霉素,制霉菌素),棘白菌素类(阿尼芬净,卡泊芬净,米卡芬净),唑类抗真菌药物(即不同结构的咪唑,三唑和噻唑抗真菌药物)。
根据本发明,还公开了一种治疗人的疾病的方法,包括给予所述人治疗有效量的本发明的药物组合物或包含本发明的两亲性颗粒状磺酸盐或硫酸盐粉末的药物组合物。优选的给药方法是通过输注或注射到静脉或动脉中。另一种优选的给药方法是通过输注或注射到外周循环中给予实体瘤或者另一靶组织。第三种优选的给药方法是通过输注或直接注射到实体瘤或靶组织中。根据本发明的一个优选方面,优选通过一次或多次推注给药。
根据本发明,提供了一种用于方便和微创静脉内给药的药物输送系统,其能够在延长的时间段内在肺中提供所需浓度的药物,例如超过一小时或六小时或甚至一天或更长时间。根据本发明的一个优选方面,本发明提供了一种控制特定靶器官或组织与其他器官和组织之间药物分布比例的方法。
多西环素是四环素类的广谱抗生素,可用于治疗许多感染,包括细菌,原生动物和蠕虫。与所有四环素类抗生素一样,由于可能会破坏骨骼和牙齿的发育,因此在妊娠期和8岁以下的儿童时期禁用它。向肺部靶向递送多西环素可降低全身毒性并显著改善该药物的治疗特性,并使其可用于儿科。
另一个例子是抗真菌药物两性霉素B,其通常静脉内用于肺部真菌感染。它是治疗某些真菌感染的唯一有效方法,因其严重且可能致命的副作用而众所周知。通常,应注意输注后发生严重的急性反应,包括高烧,颤抖,低血压,厌食,恶心,呕吐,头痛,呼吸困难和呼吸急促,嗜睡和全身无力。将两性霉素B靶向递送至肺部能够降低药物剂量,并因此显著提高肺念珠菌病治疗的效率和安全性。
根据本发明,还公开了一种设计药物组合物的方法,所述药物组合物在预定时期内,在选自肺、其他器官和实体瘤的人或动物的治疗靶,提供具有预定浓度的包含1-4个氨基的药理学活性剂D的硫酸盐或磺酸盐,由式(1)或(2)表示或它们的混合物:
Dn+(R1SO3)- n (1)
Dn+(R2OSO3)- n (2)
式中R1是直链C6-C30烷基;R2是直链C6-C30烷基;n是1-4的整数;其中,所述方法包括:
i)确定Dn +(R1SO3 -)n和/或Dn+(R2OSO3 -)n对于各种碳链长度X,Y在水性溶剂中的溶解度;
ii)确定在向对象或动物施用所述药理学活性剂D后,所述药理学活性剂的所述硫酸盐或磺酸盐的溶解度与所述药物活性剂D在所述治疗靶中的预期浓度之间的相关性;
iii)基于所述器官或组织中所述药理学活性剂D的所需浓度,确定所述药理学活性剂的所述硫酸盐或磺酸盐在所述溶剂中的目标溶解度;
iv)确定对应于所述目标溶解度的碳链长度X,Y;
v)提供包含如此确定的碳链长度X,Y的所述药理学活性剂的硫酸盐或磺酸盐;
vi)提供流体载体;
vii)将包含如此确定的碳链长度X,Y的所述药理学活性剂的所述硫酸盐或磺酸盐与流体载体组合,用量能够在所述时间段内保持所述浓度。
根据本发明的一个优选方面,在含水有机溶剂中确定溶解度,例如含水醇,特别是含水乙醇,浓度为5%至50%,优选10%至30%(v/v)。也可使用其它与水混溶的溶剂和表面活性剂,如低分子量酮,酰胺,酯,酰胺,亚砜和白蛋白。
根据本发明的一个优选方面,药物组合物包含至少两种不同的由式(1)或(2)表示的本发明的硫酸盐或磺酸盐的混合物或至少两种不同的硫酸盐或磺酸盐,其中一种由式表示(1)且另一个由式(2)表示。
优选的药理学活性剂D选自但不限于:抗癌药物,例如抗肿瘤药物,蒽环霉素类(阿霉素,表柔比星,柔红霉素,伊达比星,米托蒽醌),长春花生物碱类(长春碱,长春新碱,长春瑞滨),安吖啶,拓扑替康和伊立替康;例如抗生素类,氨基糖苷类,安沙霉素类,碳青霉烯类,头孢菌素类,糖肽类,达托霉素,大环内酯类,噁唑烷酮类,青霉素类,喹诺酮类(环丙沙星,依诺沙星,加替沙星,吉米沙星,左氧氟沙星,洛美沙星,莫西沙星,诺氟沙星,氧氟沙星,曲伐沙星,格帕沙星,司帕沙星替马沙星),磺胺类,四环素类(多西环素,四环素,米诺环素,土霉素),抗分枝杆菌药物(氯法齐明,氨苯砜,卷曲霉素,环丝氨酸,乙胺丁醇,乙硫异烟胺,异烟肼,吡嗪酰胺,利福平,利福喷汀,链霉素);例如,抗真菌药,多烯抗真菌类(两性霉素B,杀念菌素,菲律宾菌素,哈霉素,纳他霉素,制霉菌素),棘白菌素类(阿尼芬净,卡泊芬净,米卡芬净),唑类抗真菌药物(即不同结构的咪唑,三唑和噻唑抗真菌药物)。组合物还优选包含悬浮液。
优选的流体载体是水或含水介质,其中所述药理学活性剂D的硫酸盐或磺酸盐不溶或基本上不溶。“基本上不溶”应理解为小于0.1重量%,特别是小于0.05重量%或0.02重量%的溶解度。该组合物可以设计用于动脉内,腹膜内,肌肉内,透皮或静脉内给药。上述步骤可以以任何合适的顺序执行。
药理学活性剂D的所述硫酸盐或磺酸盐的优选形式是平均粒径(N)在5μm至100μm的粉末或悬浮液。更优选20μm至90μm,或40μm至80μm。所述药物组合物的优选形式是水性悬浮液。
根据本发明,还公开了制备本发明药物组合物的方法,该方法包括:提供非两亲性的所述药物(D)与无机或有机酸所成的盐的第一水性溶液;提供包含相当于所述盐的量的式(Na或K)+(R1SO3)-的烷基磺酸的钠盐或钾盐或者式(Na或K)+(R2OSO3)-的烷基硫酸的钠盐或钾盐的第二水性溶液;将所述第一和第二溶液混合。虽然在该方法中可以使用钠盐和钾盐以外的盐,但是它们的使用不是优选的。优选地,R1是直链C6-C30烷基;R2是直链C6-C30烷基;n是1-4的整数。优选地,R1和R2是直链C10-C20烷基,更优选直链C12-C18烷基,最优选约直链C12-C16烷基。
此外,本发明提供用于治疗肺病的所述药物组合物或两亲性颗粒状磺酸盐或硫酸盐粉末。这些疾病可能是癌症,真菌或细菌感染/疾病。
现在通过其许多非限制性实施例更详细地说明本发明。
附图说明
图1是显示阿霉素烷基硫酸盐在30%乙醇水溶液中的溶解度与烷基链长度相关性的图。
图2是显示阿霉素烷基磺酸盐在30%乙醇水溶液中的溶解度与烷基链长度相关性的图。
图3是显示米托蒽醌烷基硫酸盐在30%乙醇水溶液中的溶解度与烷基链长度相关性的图。
图4是显示米托蒽醌烷基磺酸盐在30%乙醇水溶液中的溶解度与烷基链长度相关性的图。
图5是显示依立替康烷基磺酸盐在10%乙醇水溶液中的溶解度与烷基链长度相关性的图。
图6是显示长春瑞滨烷基磺酸盐在20%乙醇水溶液中的溶解度与烷基链长度相关性的图。
图7是显示与带有烷基磺酸盐的多西环素络合物在20%乙醇水溶液中的溶解度与烷基磺酸盐的烷基链长度相关性的图。
图8是显示与带有烷基硫酸盐的多西环素络合物在20%乙醇水溶液中的溶解度与烷基硫酸盐的烷基链长度相关性的图。
图9是显示与带有烷基磺酸盐的两性霉素B络合物在30%乙醇水溶液中的溶解度与烷基磺酸盐的烷基链长度相关性的图。
图10是显示Wistar大鼠肺中阿霉素浓度与络合物在30%乙醇水溶液中溶解度相关性的图。
图11是显示加利福尼亚兔的肺中阿霉素浓度与络合物在30%乙醇水溶液中溶解度相关性的图。
图12是显示Wistar大鼠肺中多西环素浓度与络合物在20%乙醇水溶液中溶解度相关性的图。
图13是显示Wistar大鼠血清中多西环素浓度与络合物在20%乙醇水溶液中溶解度相关性的图。
图14是显示在肺中测量的药物(即阿霉素)的量与络合物的平均粒度之间的关系的图。
指数(对于图1-9)和对数(对于图10-13)趋势线及其方程是使用Microsoft Excel软件获得的。
发明详述
应该理解,本发明不限于本文所公开的具体配置、方法步骤和材料,因为这些配置、方法步骤和材料可以在一定程度上变化。还应理解,本文所用术语的目的仅是描述具体实施方式,不用来构成限制,因为本发明的范围仅受所附权利要求书及其等价形式的限制。
本文引用的所有参考文献通过引用全文纳入本文以用于所有目的,就好像将各篇单独的出版物、专利或专利申请特定和单独地通过引用全文纳入本文用于所有目的一样。
参考本文提供的以下定义,附图和示例性公开,可以最好地理解本发明。
在本申请中,除非另有说明,否则术语“肺病”包括原发性急性支气管炎,急性呼吸窘迫综合征(ARDS),石棉沉滞症,哮喘,支气管扩张,毛细支气管炎,毛细支气管炎闭塞性肺炎(BOOP),支气管肺发育不良,丝心病,慢性支气管炎,球孢子菌病(Cocci),慢性阻塞性肺病(COPD),隐源性组织性肺炎(COP),囊性纤维化,肺气肿,汉坦病毒肺综合征,组织胞浆菌病,人类肺炎病毒,过敏性肺炎,流感,中东呼吸综合征,非结核分枝杆菌,百日咳,尘肺病(黑肺病),不同来源的肺炎,原发性睫状运动障碍,原发性肺动脉高压,肺动脉高压,肺纤维化,肺血管疾病,呼吸道合胞病毒,结节病,严重急性呼吸系统综合症,矽肺病,睡眠呼吸暂停和婴儿猝死死亡综合症。
例如,多西环素(DOX)是四环素类的广谱抗生素,可用于治疗许多感染,包括细菌,原生动物和蠕虫。
另一个例子是抗真菌药物两性霉素B(ampB),其通常静脉内用于肺部真菌感染。它是治疗某些真菌感染的唯一有效方法,因其严重且可能致命的副作用而众所周知。
在本申请中,除非另有说明,否则术语肺癌包括原发性癌症,例如非小细胞肺癌,小细胞肺癌以及肺中的继发性肿瘤,淋巴管瘤病,间皮瘤。
材料和方法
通过在3000rpm下离心足够量的新鲜获得的胶体30-90分钟,倾析上清液,加入10mL水并摇动混合物,然后重复离心,摇动和洗涤3次来测定乙醇水溶液的溶解度。将最终离心的离心液在室温下空气干燥72小时,然后真空干燥24小时。通过在室温下搅拌24小时,将一部分干燥的离心液(20mg)重悬于6mL乙醇水溶液(EtOH)中。将混合物在3000rpm下离心10分钟,并将上清液通过0.2微米过滤器过滤以除去未溶解的固体产物的聚集体。通过UV方法测定化合物的溶解度。通过激光衍射法完成粒度分析。
用于体内研究的组合物是新鲜制备的或通过稀释浓缩物获得的。对于体内研究,使用大鼠和兔子:选择体重为300g±30g的60-75天的雌性Wistar大鼠和体重为2000g±250g的75-90天的加利福尼亚品种雄性兔。对于在特定时间点测试的每种制剂,使用4只大鼠或3只兔子。通过向大鼠的尾部单次推注给予不同的含阿霉素的制剂,阿霉素总剂量为5mg/kg,并且通过在耳缘静脉中1ml/min的缓慢流速给予兔。处死后立即将动物器官和组织在液氮中深度冷冻。
确定肺组织中阿霉素和多西环素的生物分布。
从肺的不同部位取出总重约1g的五片或六片肺组织。将样品用含有HCl的乙醇水溶液在7000rpm下均化20秒,并在11000rpm下均化10秒。将获得的匀浆涡旋30分钟并以3000rpm离心30分钟。将上清液用一氯乙酸溶液处理并温育1小时,然后将得到的混合物以15000rpm离心15分钟。分别用荧光分析和高效液相色谱法测定最终上清液中的阿霉素和多西环素(DOC)浓度。
实施例1
制备阿霉素烷基硫酸盐和烷烃磺酸盐的悬浮液
室温下向盐酸阿霉素(DOX Cl)(50mL,1mg/mL)在锥形瓶中的5%葡萄糖水溶液中加入5-10%摩尔过量的在盐酸阿霉素相同溶剂中的Na+(R1SO3)-或Na+(R2OSO3)-的溶液。在该实施例和其它实施例中可使用林格溶液或0.9%盐水或磷酸盐缓冲盐水或另一种重量摩尔渗透压浓度为270-300mOsm/L的水溶液代替5%葡萄糖水溶液。目视监测胶体形成过程。加完后,将混合物额外涡旋或摇动30分钟至7天的时间。然后将获得的悬浮液直接使用或放置在冰箱中储存。通过UV方法在495或233nm测定组合物中阿霉素的浓度。对于取样,将等分试样的胶体用甲醇(过量甲醇>20:1)稀释。
实施例2
制备米托蒽醌(MIT)烷基硫酸盐和烷烃磺酸盐的悬浮液
室温下向剧烈搅拌的米托蒽醌二盐酸盐(40mL,0.2mg/mL)在锥形瓶中的5%葡萄糖水溶液中加入含有0.03mmol在米托蒽醌二盐酸盐相同溶剂中的Na+(R1SO3)-或Na+(R2OSO3)-的溶液。目视监测黑色胶体的形成。胶体缓慢分解成黑色沉淀物和浅色上清液。完成添加后,将所得混合物搅拌额外的时间(1至7天)。悬浮液组合物可以直接使用或储存在冰箱中以备后用。通过UV方法在662,611或242nm测定胶体中米托蒽醌的浓度。对于取样,将等分试样的胶体用甲醇稀释至>20:1。
实施例3
制备伊立替康(IRI)烷基硫酸盐和烷烃磺酸盐的悬浮液
室温下向剧烈搅拌的盐酸伊立替康三水合物(5mL,4mg/mL)的去离子水溶液中加入含有Na+(R1SO3)-或Na+(R2OSO3)-的去离子水溶液。目视监测胶体的形成。完成添加后,将所得混合物搅拌2天,并将混合物在3000rpm下离心10分钟。静置后,白色胶体缓慢分解成白色沉淀和几乎无色的上清液。用5%水性葡萄糖代替上清液。通过涡旋10分钟将沉淀物重新悬浮在水中。然后将得到的组合物直接使用或储存在冰箱中备用。通过UV方法在360,255或220nm下测定胶体或悬浮液中的伊立替康的浓度。对于取样,将等分试样的产物用甲醇(过量甲醇>20:1)稀释。
实施例4
制备长春瑞滨(VIN)烷基硫酸盐和烷烃磺酸盐的悬浮液
室温下向剧烈搅拌的酒石酸长春瑞滨(2mL,5mg/mL)在锥形瓶中的5%葡萄糖水溶液中加入含有一当量在酒石酸长春瑞滨中使用的相同溶剂中的Na+(R1SO3)-或Na+(R2OSO3)-的溶液。目视监测胶体的形成。加完后,将得到的混合物涡旋或摇动7天。静置后,胶体缓慢分解成沉淀物和澄清的上清液。悬浮液可直接使用或储存在冰箱中以备将来使用。通过UV方法在268或212nm测定悬浮液中长春瑞滨的浓度。对于取样,将等分试样的胶体用甲醇(过量甲醇>20:1)稀释。
实施例5
制备多西环素(DOC)烷基硫酸盐和烷烃磺酸盐的悬浮液
室温下向盐酸多西环素(50mL,1mg/mL)在锥形瓶中的5%葡萄糖水溶液中加入5-10%摩尔过量的在盐酸多西环素中使用的相同溶剂中的Na+(R1SO3)-或Na+(R2OSO3)-的溶液。在该实施例和其它实施例中可使用林格溶液或0.9%盐水或磷酸盐缓冲盐水或另一种重量摩尔渗透压浓度为270-300mOsm/L的水溶液代替5%葡萄糖水溶液。加完后,将混合物额外涡旋或摇动30分钟至7天的时间。然后将获得的悬浮液直接使用或放置在冰箱中储存。通过UV方法在273和345nm测定组合物中多西环素的浓度。对于取样,将等分试样的胶体用甲醇(过量甲醇>20:1)稀释。
实施例6
制备两性霉素B(ampB)烷基硫酸盐和烷烃磺酸盐的悬浮液
室温下向两性霉素B(2mL,浓度0.5mg/mL)在锥形瓶中的5%葡萄糖水溶液中加入5-10%摩尔过量的在两性霉素B中使用的相同溶剂中的Na+(R1SO3)-或Na+(R2OSO3)-的溶液。在该实施例和其它实施例中可使用林格溶液或0.9%盐水或磷酸盐缓冲盐水或另一种重量摩尔渗透压浓度为270-300mOsm/L的水溶液代替5%葡萄糖水溶液。加完后,将混合物额外涡旋或摇动30分钟至3天的时间。然后将获得的悬浮液直接使用或放置在冰箱中储存。通过UV方法在410或385nm测定组合物中两性霉素B的浓度。对于取样,将等分试样的胶体用甲醇(过量甲醇>20:1)稀释。
实施例7
阿霉素(DOX)烷基硫酸盐和烷烃磺酸盐的悬浮液在30%乙醇水溶液中的溶解度
根据材料和方法中描述的一般方法测定溶解度。结果总结在表1中并显示在图1和2中。
表1.
表1.阿霉素烷基硫酸盐和烷烃磺酸盐的悬浮液在30%乙醇(v/v)中的溶解度
实施例8
米托蒽酮烷基硫酸盐和烷烃磺酸盐的悬浮液在30%乙醇水溶液中的溶解度
根据材料和方法中描述的一般方法测定溶解度。结果总结在表2中并显示在图3和4中。
表2.
表2.米托蒽酮烷基硫酸盐和烷烃磺酸盐的悬浮液在30%乙醇(v/v)中的溶解度
实施例9
伊立替康(IRI)烷烃磺酸盐在10%乙醇水溶液中的溶解度
根据材料和方法中描述的一般方法测定溶解度。结果总结在表3中。
表3.
表3.伊立替康烷烃磺酸盐的悬浮液在30%乙醇(v/v)中的溶解度
实施例10
长春瑞滨链烷磺酸盐(VIN)在20%乙醇水溶液中的溶解度。
根据材料和方法中描述的一般方法测定溶解度。结果总结于表4和图6。
表4.
表4.长春瑞滨链烷磺酸盐在20%乙醇水溶液中的溶解度
实施例11
多西环素(DOC)烷烃磺酸盐和烷基硫酸盐的悬浮液在20%乙醇水溶液中的溶解度
根据材料和方法中描述的一般方法测定溶解度。结果总结在表5中。
实施例12
两性霉素B(ampB)烷烃磺酸盐的悬浮液在30%乙醇水溶液中的溶解度
根据材料和方法中描述的一般方法测定溶解度。结果总结于表6和图9。
表5.
表5.多西环素(DOC)烷烃磺酸盐和烷基硫酸盐的悬浮液在20%乙醇水溶液中的溶解度。
表6.
实施例13和14
体内分析Wistar大鼠肺内阿霉素(DOX)的分布
静脉内单次推注后4小时,Wistar大鼠中阿霉素磺酸盐在30%乙醇水溶液中的溶解度与肺中阿霉素浓度的增加之间的关系(参见图10)。
阿霉素盐酸盐的水溶液,阿霉素烷烃硫酸盐的水悬浮液和阿霉素烷基磺酸盐的水悬浮液通过单次推注给予尾部。动物在4小时后通过单次推注注射到尾部处死;总阿霉素剂量为5mg/kg。根据上述方法测定肺中阿霉素的浓度。结果总结于表7和图10。从表中可以看出,在血清中测定的阿霉素的浓度不依赖于阿霉素盐的性质。
表7.阿霉素(DOX)的量以μg/kg±SD表示,差异相对于对照Cl-DOX(1)表示。实施例14
实施例15
体内分析阿霉素(DOX)在加利福尼亚兔肺中的分布
阿霉素和盐酸阿霉素的络合物的悬浮液通过1ml/分钟的缓慢流速给予兔耳缘静脉,总阿霉素剂量为1.25mg/kg。给药后4小时后处死动物。根据上述方法测定肺和股肌中阿霉素的浓度。结果总结在表8和图11中。从表8可以看出,与盐酸阿霉素相比,络合物股肌中阿霉素的浓度(表示系统浓度)没有增加。
表8.阿霉素(DOX)的量以μg/kg±SD表示,差异相对于对照Cl-DOX(1)表示。
实施例16
图示了静脉注射后4小时后阿霉素的非共价络合物在30%乙醇水溶液中的溶解度与加利福尼亚兔肺中阿霉素浓度增加之间的关系,参见图11。
实施例17
体内分析多西环素(DOC)在Wistar大鼠肺和血清中的分布
多西环素和盐酸多西环素的络合物的悬浮液通过单次推注给予尾部,总多西环素剂量为3mg/kg。给药后30分钟后处死动物。根据上述方法测定肺和血清中多西环素的浓度。结果总结在表9中。从表中可以看出,与盐酸多西环素相比,非共价络合物血清中多西环素的浓度降低。
实施例18
图示了静脉内单次推注后30分钟后多西环素(DOC)的络合物在20%乙醇水溶液中的溶解度与Wistar大鼠肺中多西环素浓度增加之间的关系的说明,参见图12。
实施例19
图示了静脉内单次推注后30分钟后多西环素络合物在20%乙醇水溶液中的溶解度与Wistar大鼠血清中多西环素浓度降低之间的关系,参见图13。
表9.多西环素(DOX)的量以ng/ml±SD表示,并且差异表示为对照
实施例20
制备多西环素(DOX)的胶体非共价络合物,其在30%乙醇水溶液(EtOH)中具有所需的溶解度。
该实施例说明了在特定溶剂中具有确定溶解度的非共价络合物的制备。
任务:使用在30%乙醇水溶液中具有偶数碳原子的烷烃磺酸盐制备阿霉素的胶体非共价络合物,溶解度为0.1mg/mL。
我们假设烷烃磺酸盐基团中碳原子数的影响是累加的。我们还假设在30%乙醇水溶液中具有溶解度y的连续函数。
在实施例5(参见图2)中获得的函数(f1)表示碳原子数x与溶解度y之间的关系。
y=f1(x)=1754.71710exp(-0.74429x)(方程1)
使用以下函数(f2),可以执行反向计算,即从给定的溶解度Y计算碳原子数X:
x=f2(y)=-1/0.7442855697ln(y/1754.71709855)(方程2)
对于y=0.1mg/mL的溶解度,函数f2使x等于13.20628。
假设碳原子在基团中的累加行为,我们可以计算出C12和C14磺酸盐(具有最接近溶解度的相邻磺酸盐)的比例,以提供建议的C13.20628基团:
1当量的C13.20628等于0.397当量的C12和0.603当量的C14的混合物。
根据实施例1中描述的典型方法制备具有确定的C12和C14磺酸盐比例的胶体络合物。根据上述一般方法测定络合物的溶解度,发现0.098713mg/mL。
实施例21
Wistar大鼠肺内阿霉素检测量(μg/kg)与悬浮液粒径的关系。通过单次推注将含有阿霉素和14个碳的硫酸盐的络合物的水悬浮液,即具有不同粒径的C14H29OSO3Na-络合物给予尾部。给药后4小时处死动物;阿霉素的总量为5mg/kg。根据上述方法测定肺中阿霉素的浓度。结果总结在图14和表10中。结果显示约40-90μm的粒度在靶向肺组织方面特别有利。
Claims (19)
1.一种包含两亲性颗粒状磺酸盐和/或硫酸盐的固体颗粒的水性悬浮液形式的药物组合物,由包含1至4个氨基且其中一个或多个被质子化的药理学活性剂D和具有亲水性药物相应数量的硫酸根或磺酸根阴离子构成,所述颗粒在水或含水体液中的溶解度小于0.1重量%,其中90%或更多的颗粒的尺寸在5000nm至100000nm的范围内,其中所述两亲性颗粒状磺酸盐或硫酸盐分别由式(1)和(2)表示:
Dn+(R1SO3)- n (1);
Dn+(R2OSO3)- n (2);
其中,R1是直链C10-C20烷基;R2是直链C10-C20烷基;n是1-4的整数,D选自:抗癌药物、抗细菌药物和抗真菌药物。
2.如权利要求1所述的组合物,进一步包含缓冲剂和药学上可接受的赋形剂,例如重量摩尔渗透压浓度控制剂和粘度控制剂。
3.如权利要求1或2所述的组合物,其中R1和R2是直链C12-C18烷基。
4.一种制备权利要求1-3任一项所述的药物组合物的方法,包括:提供所述药物与无机或有机酸形成的盐的非两亲性的第一水性溶液;提供包含相当于所述盐的量的式(Na或K)+(R1SO3)-的烷基磺酸的钠盐或钾盐或者式(Na或K)+(R2OSO3)-的烷基硫酸的钠盐或钾盐的第二水性溶液;将所述第一和第二溶液混合。
5.如权利要求4所述的方法,其中,R1是直链C10-C20烷基;R2是直链C10-C20烷基;n是1-4的整数。
6.如权利要求5所述的方法,其中,R1和R2是直链C12-C18烷基。
7.两亲性颗粒状磺酸盐或硫酸盐粉末,包含具有1至4个氨基且其中一个或多个被质子化的药理学活性剂D和对应于质子化氨基的数目的多个硫酸根或磺酸根阴离子,或者由具有1至4个氨基且其中一个或多个被质子化的药理学活性剂D和对应于质子化氨基的数目的多个硫酸根或磺酸根阴离子构成,通过式(1)和(2)表示:
Dn+(R1SO3)- n (1)
Dn+(R2OSO3)- n (2)
其中,R1是直链C10-C20烷基;R2是直链C10-C20烷基;n是1-4的整数。
8.如权利要求7所述的两亲性颗粒状磺酸盐或硫酸盐粉末,其中,R1和R2是直链C12-C18烷基。
9.如权利要求7-8中任一项所述的两亲性颗粒状磺酸盐或硫酸盐粉末,其中,所述颗粒尺寸最大达100μm。
10.如权利要求7-8中任一项所述的两亲性颗粒状磺酸盐或硫酸盐粉末,其中,所述颗粒尺寸为20μm–90μm或40μm-80μm。
11.如权利要求7-10中任一项所述的两亲性颗粒状磺酸盐或硫酸盐粉末,包含再悬浮促进剂和/或盐酸或氢溴酸的钠盐或钾盐。
12.一种设计药物组合物的方法,所述药物组合物在预定时期内,对例如人或动物肺部的治疗靶,提供具有预定浓度的由式(1)或(2)表示的包含1-4个氨基的药理活性剂D的硫酸盐或磺酸盐,或它们的混合物:
Dn+(R1SO3)- n (1)
Dn+(R2OSO3)- n (2)
其中,R1是直链C10-C20烷基;R2是直链C10-C20烷基;n是1-4的整数;其中,所述方法包括:
i)确定Dn+(R1SO3)- n和/或Dn+(R2OSO3)- n对于各种碳链长度X,Y在水性溶剂中的溶解度;
ii)确定在向对象或动物施用所述药理学活性剂D后,所述药理学活性剂的所述硫酸盐或磺酸盐的溶解度与所述药物活性剂D在所述治疗靶中的预期浓度之间的相关性;
iii)基于所述药理学活性剂D在肺中的所需浓度,确定所述药理学活性剂的所述硫酸盐或磺酸盐在所述溶剂中的目标溶解度;
iv)确定对应于所述目标溶解度的碳链长度X,Y;
v)提供包含如此确定的碳链长度X,Y的所述药理学活性剂的硫酸盐或磺酸盐;
vi)提供流体载体;
vii)将包含如此确定的碳链长度X,Y的所述药理学活性剂的所述硫酸盐或磺酸盐与流体载体组合,用量能够在所述时间段内保持所述浓度。
13.如权利要求12所述的方法,其中,在含水有机溶剂中确定溶解度,例如含水醇,特别是含水乙醇,浓度为5%至50%,优选10%至30%(v/v)。
14.如权利要求12或13所述的方法,其中,D选自:阿霉素,表柔比星,柔红霉素,伊达比星,米托蒽醌,长春碱,长春新碱,长春瑞滨,安吖啶,托泊替康,伊立替康。
15.如权利要求12或13所述的方法,其中,D选自:氨基糖苷类,安沙霉素类,碳青霉烯类,头孢菌素类,糖肽类,达托霉素,大环内酯类,噁唑烷酮类,青霉素类,喹诺酮类,磺胺类,四环素类,米诺环素类,土霉素类,氯法齐明,氨苯砜,卷曲霉素,环丝氨酸,乙胺丁醇,乙硫异烟胺,异烟肼,吡嗪酰胺,利福平,利福喷汀,链霉素,两性霉素B,杀念菌素,菲律宾菌素,哈霉素,纳他霉素,制霉菌素,棘白菌素类,咪唑,三唑和噻唑。
16.一种治疗人类肺部疾病,例如癌症、细菌或真菌感染或其他肺部疾病的方法,包括向所述人施用治疗有效量的权利要求1-3中任一项的药物组合物或包含权利要求7-11中任一项所述的两亲性颗粒状磺酸盐或硫酸盐粉末的药物组合物。
17.如权利要求16所述的方法,其中,所述施用是通过灌注、输注或注射到静脉或动脉中。
18.权利要求16的方法,其中,通过输注或注射到外周循环(即静脉内注射),输注或直接注射到实体瘤中,或通过一次或多次推注施用于实体瘤。
19.如权利要求18所述的方法,其中,所述实体瘤是肺肿瘤,肾肿瘤,肝肿瘤,胰腺肿瘤,乳腺肿瘤,前列腺肿瘤。
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PCT/EP2017/025035 WO2017153052A1 (en) | 2016-03-07 | 2017-03-03 | Targeted delivery of hydrophilic drugs to lung |
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GB1155037A (en) * | 1965-07-08 | 1969-06-11 | Conrado Folch Vazquez | Salts of Tetracycline Antibiotics |
WO1999047543A2 (en) * | 1998-03-18 | 1999-09-23 | University Technology Corporation | Sustained-release composition including amorphous polymer |
WO2003099346A2 (en) * | 2002-05-24 | 2003-12-04 | Angiotech International Ag | Compositions and methods for coating medical implants |
US20060134204A1 (en) * | 2004-12-21 | 2006-06-22 | Wong Patrick S | Complexes made using low solubility drugs |
WO2009100222A1 (en) * | 2008-02-08 | 2009-08-13 | Qps Llc | Non-polymeric compositions for controlled drug delivery |
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KR20170054459A (ko) * | 2014-09-10 | 2017-05-17 | 더블 본드 파마슈티컬스 에이비 | 친수성 약물의 표적 전달 방법 |
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2017
- 2017-03-03 EP EP17709909.0A patent/EP3426228A1/en not_active Withdrawn
- 2017-03-03 CN CN201780015457.1A patent/CN109069423A/zh active Pending
- 2017-03-03 WO PCT/EP2017/025035 patent/WO2017153052A1/en active Application Filing
- 2017-03-03 US US16/076,179 patent/US20210186879A1/en not_active Abandoned
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WO1999047543A2 (en) * | 1998-03-18 | 1999-09-23 | University Technology Corporation | Sustained-release composition including amorphous polymer |
WO2003099346A2 (en) * | 2002-05-24 | 2003-12-04 | Angiotech International Ag | Compositions and methods for coating medical implants |
US20060134204A1 (en) * | 2004-12-21 | 2006-06-22 | Wong Patrick S | Complexes made using low solubility drugs |
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US20210186879A1 (en) | 2021-06-24 |
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