CN104334131B - 眼科药物递送装置和使用方法 - Google Patents
眼科药物递送装置和使用方法 Download PDFInfo
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- CN104334131B CN104334131B CN201380027999.2A CN201380027999A CN104334131B CN 104334131 B CN104334131 B CN 104334131B CN 201380027999 A CN201380027999 A CN 201380027999A CN 104334131 B CN104334131 B CN 104334131B
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Abstract
本发明提供用于向受试者的眼睛递送眼科药剂的弹性材料和这种材料的使用方法。
Description
相关申请的交叉引用
本申请要求2012年3月27日提交的美国临时申请No.61/616,039的优先权,将其全部内容并入本文作为参考。
关于联邦资助研究的声明
本发明部分地使用来自联邦政府在NIH/NEI Grant No.:5RO1EY001894-33的名称为“Metabolism of the Trabecular Meshwork”和NIH/NEI Grant No.:5K08EY019726-02的名称为“NEI Mentored Clinical Scientist Development Award.”下的基金进行的。因此,联邦政府具有本发明的某些权利。
背景技术
发明领域
本发明涉及用于向受试者的眼睛递送眼科药剂的方法和材料。
相关技术的说明
青光眼的特征在于至少部分由于穿过小梁网的房水流出量减少导致的眼内压。用于治疗青光眼的许多当前疗法包括经由滴眼剂向眼睛局部给药药物。然而,局部给药具有许多缺点,因为许多药物穿透角膜的能力差,和/或可能也具有不期望的副作用,比如表面刺激和发红。此外,一些证实的研究表明患者当给药局部药物(例如,滴眼剂)时具有许多困难,因此,局部青光眼药物对于患者的顺应性和依附性差。
有证据表明青光眼患者和医务人员都喜欢眼部注射,在目前的局部给药过程中其可以一年给药3-4次。
发明简述
本发明通过提供用于将眼科药剂直接给药到受试者的眼睛中的眼科药物递送装置解决了采用眼科药剂的治疗中所未满足的需要。
本发明的一个方面提供了用于闭塞受试者眼睛的巩膜上静脉内静脉血流的弹性材料,包括、由其组成、或基本上由其组成:
(a)具有内径的中心开孔;和
(b)至少1mm的外径,
其中当将该弹性材料置于眼睛上时,内径部分被拉伸以适合围绕眼睛的中纬线,并且当收缩时,眼睛巩膜上静脉内的静脉血流被闭塞。
在一个实施方案中,所述弹性材料包括选自圆形、卵圆形、椭圆形、长方形和正方形的形状。
在另一个实施方案中,所述弹性材料包括约2mm至约40mm的外径。
在其它实施方案中,柔性材料的内径为约2mm至约20mm。
在另一个实施方案中,弹性材料包括硅橡胶材料。
本发明的另一个方面提供一种增加患有青光眼的受试者的眼睛中房水流出的方法,包括、由其组成、或基本上由其组成:
(a)将根据本发明的弹性材料置于眼睛的中纬线周围,从而闭塞巩膜静脉内的静脉血流;
(b)经由巩膜静脉给药治疗有效量的眼科药剂;和
(c)从眼睛移除所述弹性材料。
在另一个方面,本发明提供一种向房水流出系统递送眼科药剂的方法,包括、由其组成、或基本上由其组成:
(a)将根据本发明的弹性材料置于眼睛的中纬线周围,从而闭塞巩膜静脉内的静脉血流;
(b)经由巩膜静脉给药治疗有效量的眼科药剂;和
(c)从眼睛移除所述弹性材料。
本发明的另一个方面提供一种向眼睛的前房递送眼科药剂的方法,包括、由其组成、或基本上由其组成:
(a)将根据本发明的弹性材料置于眼睛的中纬线周围,从而闭塞巩膜静脉内的静脉血流;
(b)经由巩膜静脉给药治疗有效量的眼科药剂;和
(c)从眼睛移除所述弹性材料。
本发明的另一个方面提供一种诱发受试者的青光眼样病症的方法,包括、由其组成、或基本上由其组成:
(a)将根据本发明的弹性材料置于眼睛的中纬线周围,从而闭塞巩膜静脉内的静脉血流;
(b)经由巩膜静脉给药治疗有效量的眼科药剂和粘弹性药剂;和
(c)从眼睛移除所述弹性材料。
在一个实施方案中,所述眼科药剂包括流出增加剂、类固醇、α受体激动剂、β受体拮抗剂、碳酸酐酶抑制剂、肾上腺素能剂、生理学活性肽和/或蛋白、抗肿瘤剂、抗生素、镇痛药、抗炎剂、肌肉松弛剂、抗癫痫剂、抗溃疡剂、抗过敏剂、强心剂、抗心律不齐剂、血管舒张剂、抗高血压剂、抗糖尿病剂、抗高脂血症剂、抗凝血剂、溶血剂、抗结核剂、激素、麻醉药拮抗剂、破骨抑制剂(osteoclastic suppressant)、成骨促进剂、血管生成抑制剂、抗菌剂、非甾体抗炎药(NSAID)、糖皮质激素或其他抗炎皮质类固醇、生物碱镇痛剂比如阿片镇痛剂、抗病毒剂比如核苷抗病毒剂或非核苷抗病毒剂、抗良性前列腺肥大(BPH)剂、抗真菌化合物、抗增殖化合物、抗青光眼化合物、免疫调节化合物、细胞转运/迁移阻止剂、细胞因子PEG化药剂、α-阻断剂、抗雄激素、抗胆碱能剂、嘌呤能药剂(purinergic agent)、多巴胺能药剂、局部麻醉剂、香草素、氧化亚氮抑制剂、抗细胞凋亡剂、巨噬细胞活化抑制剂、抗代谢剂、神经保护剂、钙通道阻滞剂、γ-氨基丁酸(GABA)拮抗剂、α激动剂、抗精神病剂、酪氨酸激酶抑制剂、核苷化合物、和核苷酸化合物、及其类似物、衍生物、可药用盐、酯、前药、共药(codrug)、其保护形式、及其组合。
在某些实施方案中,流出增加剂包括依他尼酸(ethacrynic acid)或其任何类似物或衍生物。
在其它实施方案中,眼科药剂与粘弹性药剂一起给药。在某些实施方案中,粘弹性药剂选自(Abbott Laboratories Inc.,Abbott Park,Illinois,USA)、OVD、OVD、(Alcon Laboratories,Inc.,Fort Worth,Texas,USA)及其组合。在其它实施方案中,眼科药剂与粘弹性药剂的比例为3:1。
另一个方面提供本文描述和阐述的所有内容。
附图简述
在以下说明书中结合附图解释本发明的前述方面及其它特征,其中:
图1为本发明的弹性材料的一个实施方案的平面图和剖视图。
图2a显示根据本发明的一个实施方案将弹性材料最初置于眼睛上。图2b显示根据本发明的一个实施方案将弹性材料拉伸在眼睛上。图2c显示提供根据本发明的一个实施方案,将弹性材料应用于受试者的眼睛的状况的侧视图。
图3为显示使用本发明的一个实施方案将ECA注射到巩膜静脉的功效的图和相关数据。
图4为显示使用本发明的一个实施方案将ECA注射到巩膜静脉的功效的图和相关数据。
图5为显示加入依他尼酸使眼内压(IOP)比对照降低更多的图。
图6为显示注射ECA+Healon混合物的小鼠比注射BSS的小鼠(对照[con])或没有注射的小鼠具有更低的平均IOP水平的图。
图7为显示在巩膜注射Ethacrist纳米颗粒之后小鼠中IOP的结果的图。(a)巩膜上注射Ethacrist纳米颗粒(不含Healon)的小鼠;(b)Ethacrist纳米颗粒+Healon(3:1比例);和(c)BSS(对照)。
图8为显示在眼房内注射Ethacrist纳米颗粒之后小鼠中IOP的结果的图,包括(a)高浓度(10μg/μl)的纳米颗粒或(b)低浓度(1μg/μl)的纳米颗粒。
图9为显示在结膜下注射Ethacrist纳米颗粒之后小鼠中IOP的结果的图,包括(a)高浓度(1μg/μl)的纳米颗粒或(b)低浓度(0.1μg/μl)的纳米颗粒。
图10为显示在小鼠中巩膜静脉注射3:1比例的Ethacrist纳米颗粒与healon组合的功效的图。
发明详述
为了促进本发明原理的理解的目的,现在对优选的实施方案进行参考,并且使用特定的语言描述这些优选的实施方案。然而,应当理解该特定语言不意欲限制本发明的范围,对于本文所阐述发明的改变和其他修饰是本发明所属领域的技术人员通常想到。
定义
除非另有定义,否则本文使用的所有术语具有如本发明所属领域的普通技术人员通常理解的相同的含义。在描述本发明实施方案的装置、方法等和如何制备和使用它们时,本文中讨论了一些术语以向实施者提供额外的指导。应当理解,相同的事物可以用多于一种方式表述。因此,可以对本文讨论的任何一个或多个术语应用替代性的语言和同义词。术语是否在本文中详细阐述或讨论并不重要。提供了某些同义词或可替代的方法、材料等。除非有明确说明,否则一个或一些同义词或同等物的详述并不排除其它同义词或同等物的使用。
本文使用的术语“一个”和“一种”指一个或多于一个(即,至少一个)该术语的语法对象。例如,“一个”要素指至少一个要素,且可以包括多于一个要素。
如本文使用的术语“患者”或“受试者”旨在包括人类和非人类动物。示例性的人类受试者包括患有眼部病症例如青光眼的人类患者。术语“非人类动物”包括所有脊椎动物,例如非哺乳动物(比如鸡、两栖动物、爬行动物)和哺乳动物比如非人灵长类动物、驯养动物和/或农业有用的动物(比如绵羊、狗、猫、母牛、猪等),以及啮齿类动物(比如小鼠、大鼠、仓鼠、豚鼠等)。
如本文使用的术语“治疗有效的”或“有效量”指有效地引起期望效果的化合物(例如,眼科药剂、流出增加剂等)的剂量。如本文使用的该术语也可指在动物、哺乳动物或人类中产生期望体内作用(比如降低眼内压、炎症等)的有效量。活性化合物可以在宽的剂量范围内有效,通常以可药用有效量给药。然而,应当理解实际给药的化合物的量通常由医生根据相应情形确定,包括治疗的病症、选择的给药途径、实际给药的化合物、个体患者的年龄、体重和应答、患者症状的严重程度等。
如本文使用的术语“给药(administration)”或“给药(administering)”指通过任何合适的途径提供、接触和/或递送化合物比如眼科药剂或流出增加剂以获得预期效果。这些化合物可以以多种方式向受试者给药,所述方式包括,但不限于口服、舌下、肠胃外(例如静脉内、皮下、皮内、肌内、关节内、动脉内、滑膜内、胸骨内、鞘内、损伤内(intralesional)或颅内注射)、透皮、局部、含服、直肠、阴道、鼻、眼、吸入和植入。在某些实施方案中,肠胃外给药化合物。在某些实施方案中,静脉内给药化合物。
“可药用”指联邦或州政府的管理机构已批准的或可获批准的,或者是记载在美国药典或其他通常认可的药典中的用于动物的,更特别地用于人类的。其可以为不是生物学或以其他方式不期望的材料,即所述材料可以给药至个体而不会以有害的方式引起与组合物中包含的任何组分的任何不期望的生物学作用或相互作用。
术语化合物的“可药用盐”指可药用的盐,并且具有母体化合物的期望药理学活性。这样的盐包括例如酸加成盐和碱加成盐。
术语“激动剂”指可以结合受体以产生或增加分子活性和细胞活性的化合物。激动剂可以是直接结合受体的配体。或者,激动剂可以通过例如下述方式间接结合受体:(a)与直接结合受体的另外的分子或蛋白质形成复合物,或(b)以其它方式引起另一种化合物修饰,使得该另一种化合物直接结合受体。
术语“拮抗剂”指可以结合受体以降低或抑制分子活性和细胞活性的化合物。拮抗剂可以是直接结合受体的配体。或者,拮抗剂可以通过例如下述方式间接结合受体:(a)与直接结合受体的另外的分子或蛋白质形成复合物,或(b)以其它方式引起另一种化合物修饰,使得该另一种化合物直接结合受体。
如本文使用的、包括但不限于“肽”或“蛋白质”或任何其他的术语用于指两种或多种氨基酸的链。该术语进一步包括进行了翻译后修饰的肽,例如糖基化、乙酰化、磷酸化、酰胺化、由已知的保护/封端基团衍生化、蛋白酶剪切、或由非天然存在氨基酸进行修饰。
如下参照优选的实施方案阐述本发明。
本发明的弹性材料提供用于闭塞受试者眼睛的巩膜静脉内静脉血流,主要特征为其具有:具有内径的中心开孔、至少1mm的外径,其中当将该弹性材料置于眼睛上时,内径部分拉伸以适合围绕眼睛的中纬线,并且当收缩时,眼睛巩膜静脉内的静脉血流被闭塞。
弹性材料的形状和尺寸
图1为本发明的弹性材料的一个实施方案的平面图和剖视图。该图中如10所示的本发明的弹性材料包括弹性材料片、由其组成、或基本上由其组成,所述弹性材料片具有中心开孔1与内径2、及外径3。
材料的平面形状(即,弹性材料的外圆周长的轮廓)不受特别的限制,可以采取许多不同形状的形式,包括但不限于圆形、卵圆形、椭圆形、长方形、正方形等。在某些实施方案中,材料的形状为正方形。在其它实施方案中,形状为基本上圆形。如本文使用的术语“基本上圆形”不限于近似真实的圆形,但是包括椭圆形和伸长椭圆形。在某些实施方案中,材料的形状为真实的圆形。
只要其可以置于眼睛上且由护理者容易操作(即,容易置于眼睛上,拉伸等),则本发明的弹性材料的尺寸也不受特别的限制。在某些实施方案中,材料包括通常如图1所示的形状。在这样的实施方案中,外径3为约1mm至约20mm、2mm至约20mm、3mm至约20mm、4mm至约20mm、5mm至约20mm、6mm至约20mm、7mm至约20mm、8mm至约20mm、9mm至约20mm、10mm至约20mm、11mm至约20mm、12mm至约20mm、13mm至约20mm、14mm至约20mm、15mm至约20mm、16mm至约20mm、17mm至约20mm、18mm至约20mm、19mm至约20mm、约1mm至约30mm、1mm至约40mm、5mm至约30mm、5mm至约40mm、8mm至约30mm、8mm至约40mm、10mm至约30mm、10mm至约40mm、15mm至约30mm、15mm至约40mm、20mm至约30mm、20mm至约40mm、22mm至约30mm、22mm至约40mm、25mm至约30mm、25mm至约40mm、30mm至约40mm、以及35mm至约40mm,以便护理者握紧材料以便拉伸中心开孔1。在其它实施方案中,内径2具有充分的尺寸,当拉伸时,其能够适合围绕眼睛的中纬线,并且当释放为其松弛状态时,收缩使得巩膜静脉的静脉血流被闭塞。在某些实施方案中,内径2为约1mm至约10mm、2mm至约10mm、3mm至约10mm、4mm至约10mm、5mm至约10mm、6mm至约10mm、7mm至约10mm、8mm至约10mm、9mm至约10mm、1mm至约20mm、2mm至约20mm、3mm至约20mm、4mm至约20mm、5mm至约20mm、6mm至约20mm、7mm至约20mm、8mm至约20mm、9mm至约20mm、10mm至约20mm、11mm至约20mm、12mm至约20mm、13mm至约20mm、14mm至约20mm、15mm至约20mm、16mm至约20mm、17mm至约20mm、18mm至约20mm、19mm至约20mm。
本文中,内缘部分1a指沿着中心开孔的内部圆周的弹性材料的部分。内缘部分1a包括通常不超过约0.3mm的厚度。在某些实施方案中,内缘部分包括的厚度为0.05-0.3mm、0.1-0.3mm或0.13-0.23mm。类似地,外缘部分4通常被设定为不超过约0.3mm。在某些实施方案中,外缘部分4为0.05-0.3mm、0.15-0.3mm和0.17-0.3mm。内缘部分和外缘部分都可以形成具有基本上均匀的厚度。在某些实施方案中,内缘部分可以形成具有从内缘至外缘部分递减的厚度,以使得内缘部分比外缘部分厚。外径部分3a的厚度通常设定为不超过约0.4mm。在某些实施方案中,外径部分3a包括的厚度为约0.08-0.4mm、0.2-0.4mm和0.33-0.38mm。在某些实施方案中,外径部分包括的厚度大于0.03mm,或者大于外缘部分和内缘部分的最大厚度。
弹性材料组合物
本发明的弹性材料包括能够延伸中心开孔约1%至50%、5%至40%和10%至40%的弹性样材料,其中该弹性样材料具有恢复其原始形状的倾向。实际上且如图2a所示,材料10位于眼睛30上,使得中心开孔位于眼睛的中纬线40上。然后,将材料20拉伸,使得中心开孔1大于眼睛的中纬线(图2b)。然后,使材料20松驰,其中在其松弛状态下,中心开孔围绕眼睛的中纬线40收缩,使得巩膜静脉50内的静脉血流被闭塞(图2c)。该闭塞引起静脉变得膨胀,使护理者易于接触和看到巩膜上静脉。合适的弹性样材料是优选地生物学惰性的那些,并且可以包括但不限于弹性体(elastomer)(弹性聚合物)材料比如聚氨酯、聚乙烯、硅氧烷弹性物(elastics)(例如SilasticTM硅氧烷材料)、热塑性弹性体比如苯乙烯-乙烯/丁烯-苯乙烯(SEBS)、苯乙烯-乙烯/丙烯-苯乙烯(SEPS)、乙烯-丙烯共聚物/聚丙烯(EPDM-PP)、聚醚嵌段酰胺(PEBAX)、聚氨酯或其他可硫化弹性体比如硅酮橡胶、胶乳、聚丁二烯、氟化弹性体、聚氯丁烯、聚异戊二烯材料等。在某些实施方案中,弹性材料包括SilasticTM硅氧烷。
使用方法
本文描述的弹性材料允许将眼科药剂眼部递送至受试者眼睛的巩膜静脉窦(Schlemm’s Canal)和小梁网流出物,极大增强了这些药剂对眼睛的作用。例如,将某些青光眼药剂直接递送到巩膜静脉窦和小梁网将允许药剂持续作用数周至数月,并且可以成为目前所使用青光眼药物的局部给药(例如,滴眼液)的替代。本文所述方法可用于开发药物储库,重要地是,允许在医生办公室中容易地递送这些药剂,并且可以重复进行。
本发明的一个方面提供一种将眼科药剂递送至受试者眼睛的房水流出系统的方法,包括将如本文所述的弹性材料置于眼睛的中纬线周围,从而闭塞巩膜静脉内的静脉血流,经由巩膜静脉给药治疗有效量的眼科药剂,和从眼睛移除所述弹性材料。
本发明的另一个方面提供一种将眼科药剂递送至眼睛的前房的方法,包括将如本文所述的弹性材料置于眼睛的中纬线周围,从而闭塞巩膜静脉内的静脉血流,经由巩膜静脉给药治疗有效量的眼科药剂,使得眼科药剂被递送到眼睛的前房,和从眼睛移除所述弹性材料。
本发明的仍然另一方面提供一种增加患有青光眼的受试者的眼睛中房水流出的方法,包括将如本文所述的弹体材料置于眼睛的中纬线周围,从而闭塞巩膜静脉内的静脉血流,经由巩膜静脉给药治疗有效量的眼科药剂,和从眼睛移除所述弹性材料。
如本文使用的术语“眼科药剂”旨在涵盖当向哺乳动物给药时提供局部或全身生理学或药理学作用的所有药剂,包括而不限于在下述说明书中指出的任何具体药物及其类似物、衍生物、可药用盐、酯、前药、共药和保护形式。在某些实施方案中,药物为具有分子量小于1000amu的小分子。例如,药物可以是具有分子量小于或等于约750amu、500amu、450amu、400amu、350amu、或小于或等于约300amu的小分子。
许多不同的眼科药剂都可以加入到本文所述装置中。例如,合适的药剂包括流出量增加剂、类固醇、α受体激动剂、β受体拮抗剂、碳酸酐酶抑制剂、肾上腺素能剂、生理学活性肽和/或蛋白、抗肿瘤剂、抗生素、镇痛药、抗炎剂、肌肉松弛剂、抗癫痫剂、抗溃疡剂、抗过敏剂、强心剂、抗心律不齐剂、血管舒张剂、抗高血压剂、抗糖尿病剂、抗高脂血症剂、抗凝血剂、溶血剂、抗结核剂、激素、麻醉药拮抗剂、破骨抑制剂、成骨促进剂、血管生成抑制剂、抗菌剂、非甾体抗炎药(NSAID)、糖皮质激素或其他抗炎皮质类固醇、生物碱镇痛剂比如阿片镇痛剂、抗病毒剂比如核苷抗病毒剂或非核苷抗病毒剂、抗良性前列腺肥大(BPH)剂、抗真菌化合物、抗增殖化合物、抗青光眼化合物、免疫调节化合物、细胞转运/迁移阻止剂、细胞因子PEG化药剂、α-阻断剂、抗雄激素、抗胆碱能剂、嘌呤能药剂(purinergic agent)、多巴胺能药剂、局部麻醉剂、香草素、氧化亚氮抑制剂、抗细胞凋亡剂、巨噬细胞活化抑制剂、抗代谢剂、神经保护剂、钙通道阻滞剂、γ-氨基丁酸(GABA)拮抗剂、α激动剂、抗精神病剂、酪氨酸激酶抑制剂、核苷化合物、和核苷酸化合物、及其类似物、衍生物、可药用盐、酯、前药、共药和保护形式,以及基因递送药剂比如但不限于慢病毒剂(lentiviruses)等。
合适的NSAID包括双氯芬酸、etoldolac、fenoprofen、夫洛非宁、氟比洛芬、布洛芬、吲哚洛芬、酮洛芬、酮咯酸、氯诺昔康、吗拉宗、萘普生、哌立索唑、吡洛芬、普拉洛芬、舒洛芬、琥布宗、tropesin、希莫洛芬、扎托洛芬、齐留通和佐美酸,及其类似物、衍生物、可药用盐、酯、前药、共药和保护形式。
合适的碳酸酐酶抑制剂包括布林唑胺、乙酰唑胺、醋甲唑胺、二氯磺胺、乙氧苯唑胺和多佐胺,及其类似物、衍生物、可药用盐、酯、前药、共药和保护形式。
合适的肾上腺素能剂包括溴莫尼定、阿可乐定、布那唑嗪、左倍他洛尔、levobunalol、卡替洛尔、异丙肾上腺素、非诺特罗、美替洛尔和克仑特罗,及其类似物、衍生物、可药用盐、酯、前药、共药和保护形式。
合适的α受体激动剂包括溴莫尼定及其类似物、衍生物、可药用盐、酯、前药、共药和保护形式。
合适的β受体拮抗剂包括倍他洛尔和噻吗洛尔,及其类似物、衍生物、可药用盐、酯、前药、共药和保护形式。
合适的抗病毒剂包括奈伟拉平(neviripine),及其类似物、衍生物、可药用盐、酯、前药、共药和保护形式。
合适的生物碱镇痛药包括脱氢吗啡(desmorphine)、地佐辛、二氢吗啡、依他佐辛、乙基吗啡、格拉非宁、氢吗啡酮、isoladol、凯托米酮(ketobenidone)、p-lactophetide、左啡诺、moptazinol、美他唑嗪(metazocin)、美托酮、吗啡、纳布啡、纳美芬、纳洛芬、纳洛酮、去甲左啡诺、去甲吗啡、oxmorphone、喷他佐辛、phenperidine、phenylramidol、曲马多和维米醇,及其类似物、衍生物、可药用盐、酯、前药、共药和保护形式。
合适的糖皮质激素包括21-乙酰氧基孕烯醇酮、阿氯米松、阿尔孕酮、乙酸阿奈可他(anacortave acetate)、安西奈德、倍氯米松、倍他米松、布地奈德、氯泼尼松、氯倍他索、氯倍他松、氯可托龙、氯泼尼醇、皮质酮、可的松、可的伐唑、地夫可特、地奈德、去羟米松、二氟拉松、二氟可龙、difuprednate、甘草次酸、氟扎可特、氟氯奈德、氟米松、氟尼缩松、氟轻松、醋酸氟轻松、氟氯奈德、氟米松、氟尼缩松、氟可丁酯、氟可龙、氟米龙、醋酸氟培龙、氟泼尼龙、氟氢缩松、丙酸氟替卡松、氢可他酯、氢化可的松、甲泼尼松、甲泼尼龙、帕拉米松、泼尼松龙、泼尼松龙21-二乙基氨基乙酸酯、醋酸氟泼尼定、福莫可他、氯替泼诺碳酸乙酯甲羟松、莫米松糠酸酯、泼尼卡酯、泼尼松龙、泼尼松龙25-二乙基氨基乙酸酯、泼尼松龙磷酸钠、泼尼松、泼尼松戊酸酯、泼尼立定、曲安西龙、曲安奈德、苯曲安奈德和己曲安奈德,及其类似物、衍生物、可药用盐、酯、前药、共药和保护形式。
其它合适的类固醇包括哈西奈德、丙酸乌倍他索(halbetasol propionate)、卤米松、醋酸卤泼尼松、异氟泼尼龙、氯替泼诺碳酸乙酯、马泼尼酮、利美索龙和替可的松,及其类似物、衍生物、可药用盐、酯、前药、共药和保护形式。
合适的BPH药物包括非那甾胺和奥沙特隆,及其类似物、衍生物、可药用盐、酯、前药、共药和保护形式。
合适的抗菌化合物包括卷曲霉素,包括卷曲霉素IA、卷曲霉素IB、卷曲霉素IIA和卷曲霉素IIB;卡波霉素,包括卡波霉素A;卡芦莫南;头孢克洛、头孢羟氨苄、头孢孟多、头孢曲嗪、头孢西酮、头孢唑啉、头孢拉宗、头孢卡品酯、头孢克定、头孢地尼、头孢托仑、头孢克肟(cefime)、头孢他美(ceftamet)、头孢甲肟、cefmetzole、头孢米诺、头孢地嗪、头孢尼西、头孢哌酮、头孢雷特、头孢噻肟、头孢替坦、头孢替安、头孢西丁、头孢咪唑、头孢匹胺、头孢匹罗、头孢丙烯、头孢沙定、头孢磺啶、头孢他啶、头孢特仑、头孢替唑、头孢布烯、头孢噻呋、头孢唑肟、头孢曲松、头孢呋辛、头孢唑喃、头孢氨苄、头孢来星(cephalogycin)、头孢噻啶、头孢菌素C、头孢噻吩、头孢匹林、头霉素比如头霉素C、头孢拉定、金霉素;克拉霉素、克林霉素、氯甲西林、氯莫环素、氯唑西林、环己西林、达氟沙星、地美环素(demeclocyclin)、越霉素A、双氯青霉素、双氯青霉素、地红霉素、强力霉素、依匹西林、红霉素A、乙胺丁醇(ethanbutol)、芬贝西林、氟氧头孢、氟苯尼考、氟氯青霉素、氟甲喹、福提霉素A、福提霉素B、磷霉素(forfomycin)、呋喃他酮(foraltadone)、夫西地酸、庆大霉素、葡烟腙、胍甲环素、海他西林、伊达比星、亚胺培南、异帕米星、交沙霉素、卡那霉素、优霉素(leumycin)比如优霉素A1、林可霉素、洛美沙星、氯碳头孢、赖甲环素、美洛培南(meropenam)、美坦西林、美他环素、甲氧西林、美洛西林、小诺米星(micronaomicin)、麦迪霉素比如麦迪霉素A1、米卡霉素、米诺环素、丝裂霉素比如丝裂霉素C、拉氧头孢、莫匹罗星、萘夫西林、奈替米星、诺卡迪安(norcardian)比如诺卡迪安A、竹桃霉素、土霉素、帕尼培南(panipenam)、帕珠沙星、培那西林、青霉素比如青霉素G、青霉素N和青霉素O、青霉素二酸、戊基青霉素(pentylpenicillin)、培洛霉素、非奈西林、匹哌环素、哌拉西林、吡利霉素、匹氨西林、pivcefalexin、泊非霉素、propiallin、喹那西林、核糖霉素、利福布汀、利福米特、利福平、利福霉素SV、利福喷汀、利福霉素SV、利福喷汀、利福昔明、利替培南酯、rekitamycin、罗利环素、罗沙米星、罗红霉素、西索米星、司帕沙星、大观霉素、链脲星、磺苄西林、舒他西林、酞氨西林、替考拉宁、替莫西林、四环素、thostrepton、泰妙菌素、替卡西林、替吉莫南、替米考星、妥布霉素、tropospectromycin、曲伐沙星、泰乐菌素和万古霉素,及其类似物、衍生物、可药用盐、酯、前药、共药和保护形式。
抗增殖/抗有丝分裂药和前药包括天然产物比如长春花生物碱(例如长春碱、长春新碱和长春瑞滨)、紫杉醇、表鬼臼毒素(例如依托泊苷、替尼泊苷)、抗生素(例如放线菌素、柔红霉素、多柔比星和伊达比星)、蒽环类、米托蒽醌、博来霉素、普卡霉素(光神霉素)和丝裂霉素、酶(例如L-天冬酰胺酶);抗血小板前药;抗增殖/抗有丝分裂烷基化前药比如氮芥(双氯乙基甲胺、环磷酰胺及类似物、美法仑、苯丁酸氮芥)、乙烯亚胺和甲基蜜胺(六甲蜜胺和噻替派)、磺酸烷基酯-白消安、亚硝基脲(卡莫司汀(BCNU)和类似物、链佐星)、三氮烯、达卡巴嗪(DTIC);抗增殖/抗有丝分裂的抗代谢药比如叶酸类似物(甲氨蝶呤)、嘧啶类似物(氟尿嘧啶、氟尿苷和阿糖胞苷)、嘌呤类似物和相关抑制剂(巯嘌呤、硫鸟嘌呤、喷司他丁和2-氯脱氧腺苷(克拉屈滨);铂配位络合物(顺铂、卡铂)、丙卡巴肼、羟基脲、米托坦、氨鲁米特;激素(例如,雌激素、孕激素);抗凝血剂(例如肝素、合成肝素盐及其它凝血酶抑制剂);溶解纤维蛋白的前药比如组织纤溶酶原激活剂、链激酶和尿激酶、阿司匹林、双嘧达莫、噻氯匹定、氯吡格雷、阿昔单抗;抗迁移药;抗分泌药(breveldin);抗炎药比如皮质类固醇(皮质醇、可的松、氟氢可的松、氟轻松、泼尼松、泼尼松龙、甲泼尼龙、曲安西龙、倍他米松和地塞米松)、NSAIDS(水杨酸及衍生物、阿司匹林、对乙酰氨基酚、吲哚和茚乙酸(吲哚美辛、舒林酸和依托度酸)、杂芳基乙酸(托美丁、双氯芬酸和酮咯酸)、芳基丙酸(例如布洛芬和衍生物)、邻氨基苯甲酸(甲芬那酸和甲氯灭酸)、烯醇酸(吡罗昔康、替诺昔康、保泰松和oxyphenthatrazone)、萘丁美酮、金化合物(金诺芬、金硫葡糖、硫代苹果酸金钠);免疫抑制剂(例如环孢霉素、他克莫司(FK-506)、西罗莫司(雷帕霉素)、硫唑嘌呤和麦考酚酸莫酯);血管生成剂比如血管内皮生长因子(VEGF)、成纤维细胞生长因子(FGF);血管紧张素受体阻断剂;氧化氮供体;反义寡核苷酸及其组合;细胞周期抑制剂、mTOR抑制剂、生长因子信号转换激酶抑制剂、新血管形成抑制剂、血管生成抑制剂和细胞凋亡抑制剂,及其类似物、衍生物、可药用盐、酯、前药、共药和保护形式。
在某些实施方案中,眼科药剂包括流出剂(outflow agent)。如本文使用的术语“流出增加剂”指能够增加眼睛中房水流出,从而缓解眼睛内眼内压的那些药剂。
在某些实施方案中,所述流出增加剂包括依他尼酸(其为[2,3-二氯-4-(2-亚甲基-1-氧代丁基)苯氧基]乙酸)或其任何类似物、盐或衍生物。依他尼酸及其盐、衍生物和类似物以及给药这些化合物的优选的方法详细描述在美国专利No.3,255,241、4,757,089、5,306,731、5,458,883、5,863,948、6,126,957和6,534,082中,将其全部内容通过引用并入本文。
在某些实施方案中,所述增加剂包括依他尼酸衍生物和类似物,其可以或不可以包括巯基反应性部分。示例性的药剂包括,但不限于:2-[2,3-二氯-4-[(Z)-2-甲基丁-2-烯酰基]苯氧基]乙酸、2-[2,3-二氯-4-(3-甲基丁-2-烯酰基)苯氧基]乙酸、2-[2,3-二氯-4-(2-亚甲基丁酰基)苯氧基]-2-(2,3-二羟基丙氧基)乙酸、[(2S,3R,4R)-1,3,4,5-四羟基戊-2-基]-2-[2,3-二氯-4-(2-亚甲基丁酰基)苯氧基]乙酸酯、2-(2,3-二氯-4-(2,3-二甲基丁酰基)苯氧基]乙酸等。
在某些实施方案中,所述增加剂包括依他尼酸衍生物和类似物,其包含巯基反应性部分。在某些实施方案中,所述增加剂包括依他尼酸硫醇缩合物。实例包括但不限于依他尼酸-L-半胱氨酸(即,S-[2-[4-(羧基甲氧基)-2,3-二氯苯甲酰基]丁基]-L-半胱氨酸)、依他尼酸-半胱胺(即,2-(4-(2-((2-氨基乙硫基)甲基)丁酰基)2,3-二氯苯氧基)乙酸)、依他尼酸-谷胱甘肽(即,2-氨基-5-(3-(2-(4-(羧基甲氧基)-2,3-二氯苯甲酰基)丁硫基)-1-(羧基甲氨基)-1-氧代丙烷-2-基氨基)-5-氧代戊酸)、依他尼酸-硫代水杨酸(2-(2-(4-(羧基甲氧基)2,3-二氯苯甲酰基)丁硫基)苯甲酸)、依他尼酸-N-乙酰半胱氨酸(2-乙酰氨基-3-(2-(4-(羧基甲氧基)-2,3-二氯苯甲酰基)丁硫基)丙酸)、依他尼酸-N-乙酰半胱胺(即,2-(4-(2-((2-乙酰氨基乙硫基)甲基)丁酰基)-2,3-二氯苯氧基)乙酸)、或其任何盐。
在其它实施方案中,所述增加剂为依他尼酸-L-半胱氨酸(即,S-[2-[4-(羧基甲氧基)-2,3-二氯苯甲酰基]丁基]-L-半胱氨酸)或其任何盐。
在另一个实施方案中,所述增加剂为2-[2,3-二氯-4-[2-(甲基-巯基甲基)丁酰基]苯氧基]乙酸。
在另一个实施方案中,所述增加剂包括苯氧基乙酸、2,3-二氯苯氧基乙酸、2,4-二氯苯氧乙酸,或其任何类似物或衍生物。在一个实施方案中,所述增加剂包括苯氧基乙酸、2,3-二氯苯氧基乙酸、或2,4-二氯苯氧基乙酸衍生物(其为非-SH反应性的)。在某些实施方案中,非-SH反应性的苯氧基乙酸衍生物包括茚达立酮(即,6,7-二氯-2-甲基-1-氧代-2-苯基-5-茚满基氧代乙酸)、替尼酸(即,2-(2,3-二氯-4-(噻吩-2-羰基)苯氧基)乙酸)、或其任何盐。
本发明的仍然另一方面提供一种诱发受试者的青光眼样病症的方法,包括将如本文所述的弹性材料置于眼睛的中纬线周围,从而闭塞巩膜静脉内的静脉血流,经由巩膜静脉给药治疗有效量的眼科药剂和粘弹性药剂,和从眼睛移除所述弹性材料。
如本文使用的术语“青光眼样病症”指存在与青光眼相关的症状和/或病症的任何病症,比如眼内压升高和/或视神经损伤。该定义内还包括病症比如低眼压(hypotony)情形中的眼内压升高,比如在青光眼外科手术之后或与葡萄膜炎有关的情形中。
在其它实施方案中,眼科药剂与粘弹性药剂一起给药。如本文使用的术语“粘弹性药剂”指能够使眼睛的前房膨胀以允许递送另外的化合物和/或手术器械的任何药剂。合适的粘弹性药剂包括但不限于OVD、OVD、等。在其它实施方案中,眼科药剂与粘弹性药剂的比例为3:1。
在某些实施方案中,粘弹性药剂在眼科药剂之前给药。在其它实施方案中,粘弹性药剂与眼科药剂同时给药。在仍然其他实施方案中,粘弹性药剂在眼科药剂之后给药。
本发明进一步提供药物组合物,其包括本文所述的眼科药剂、任选地粘弹性药剂和可药用载体。如本文使用的术语“药物组合物”指如本文所述的至少一种眼科药剂与惰性的或活性的载体的组合,所述载体使该组合物在体内、体外或间接体内特别适用于诊断或治疗用途。在某些实施方案中,药物组合物包括眼科药剂和粘弹性药剂。“可药用载体”指任何标准的药物载体,比如磷酸盐缓冲盐水溶液、水、乳剂(例如,比如油/水或水/油乳液)、各种类型的润湿剂、稀释剂和赋形剂。组合物也可以包括稳定剂和防腐剂。例如载体、稳定剂和佐剂。(参见例如Martin,Remington's Pharmaceutical Sciences,15th Ed.,MackPubl.Co.,Easton,Pa.(1975))。
药物组合物通常制备为在耐受的(可接受的)稀释剂比如盐水、磷酸缓冲盐水或其他生理学耐受稀释剂等中的溶液,形成水性药物组合物。
给药途径可以是静脉内(I.V.)、肌内(I.M.)、皮下(S.C.)、皮内(I.D.)、腹膜内(I.P.)、肿瘤内等,其导致引起期望的应答。另外的给药方法可以包括局部给药(滴眼剂)、结膜下、眼房内、眼周或玻璃体内注射或通过外科手术放入结膜囊中的球囊式导管或眼科插入物引入。在优选的实施方案中,给药途径是注射到巩膜静脉中。
组合物的治疗剂量可以根据例如化合物的给药方式、患者的健康状态和病症、及开处方医生的判断而变化。本文描述的眼科药剂在药物组合物中的比例或浓度可以根据许多因素变化,所述因素包括剂量、化学性质(例如疏水性)和给药途径。例如,本文所述眼科药剂可以以包含约0.1至约10%w/v所述药剂的水性生理学缓冲溶液提供。某些典型的剂量范围为每天约1μg/kg至约1g/kg体重。剂量很可能取决于变量如疾病或病症的类型和进展程度、特定患者的整体健康状态、所选择化合物的相对生物学功效、赋形剂的配方、及其给药途径。有效剂量可以从来源于体外或动物模型试验系统的剂量反应曲线外推得出。在一个实施方案中,给药所述剂量至少一次。随后的剂量可以如所指定的给药。
实施例
通过下述实施例进一步阐述本发明的方法和材料,其不应当被看作限制本发明的范围,其仅作为示例提供。
实施例1.经由巩膜静脉连同或不连同healon直接注射依他尼酸(EthacrinicAcid)(ECA)的效果
使用TonoLab装置测量小鼠两只眼睛的基准眼内压。将一片胶乳手套置于小鼠眼睛的中纬线上。最初,使用玻璃微套管将(a)单独的依他尼酸溶液或(b)盐水注射到每只小鼠的右眼边缘(limbus)的巩膜静脉中。注射所述溶液或盐水直到在所述边缘360度都观察到发白。然后,从眼睛上除去胶乳片。之后,每日和每周测量所有小鼠两只眼睛的眼内压。单独的依他尼酸注射液在第2天产生其最强作用;然而,一些作用维持直到第7天。上述方案的结果提供在表1中以及显示在图4中,其中依他尼酸标注为ECA(正方形),盐水对照为BSS(三角形),和未处理的对照为对照(菱形)。
表1
接着,将依他尼酸与healon以3:1比例混合。再次,使用玻璃微套管注射依他尼酸/healon溶液或BSS溶液(作为对照)。依他尼酸/healon溶液在第2周产生其最强作用,但是持续3周。结果提供在表2以及显示在图3中,其中依他尼酸/healon标注为正方形,BSS标注为菱形,并且未注射的对照标注为三角形。
表2.
表2 续表
实施例2.缓释递送Ethacrist(依他尼酸+L-半胱氨酸)缓释纳米颗粒对眼内压(IOP)的影响
实施例2.1:为了测试对于患有青光眼的患者,注射到巩膜静脉中的依他尼酸(ECA)纳米颗粒(不含healon)的缓释释放是否可以长期降低眼内压,给8只C57Bl6小鼠的右眼注射Ethacrist纳米颗粒(不含healon)(4只小鼠)或平衡盐溶液(BSS)(4只小鼠),注射到边缘的巩膜静脉中。基准IOP在注射之前用啮齿类TonoLabTM装置测量,然后每周测量。进行裂隙灯检查,以评价结膜发红、前房中炎症和角膜云翳。
如图7a所示,所有4只小鼠(标记为“第1、2、3和4组”)都显示在第3周IOP显著降低,在第4周最终恢复到基准。
实施例2.2:为了测试粘弹性healon或类似化合物是否延长ethacrist纳米颗粒的IOP-降低作用,给6只C57Bl6小鼠的右眼注射3:1比例的ethacrist纳米颗粒加healon(3只小鼠)或BSS(3只小鼠)。基准IOP在注射之前用啮齿类TonoLabTM装置测量,此后每周测量。进行裂隙灯检查,以评价结膜发红、前房中炎症和角膜云翳。
图10中的图表显示巩膜静脉注射3:1比例的ethacrist纳米颗粒与healon的组合在第3周显著降低了IOP,其持续8周。
实施例2.3:测试ethacrist纳米颗粒递送的其他方法。结膜下递送显示在图9a和9b(高浓度和低浓度的ethacrist纳米颗粒)中,眼房内递送显示在图8a和8b(高浓度和低浓度的ethacrist纳米颗粒)中。基准IOP在注射之前用啮齿类TonoLabTM装置测量,此后每周测量。进行裂隙灯检查,以评价结膜发红、前房中炎症和角膜云翳。
图7-9中的图表显示下述结果∶图7a显示给小鼠巩膜注射ethacrist纳米颗粒(不含Healon),图7b显示巩膜注射ethacrist纳米颗粒+Healon(3:1比例),和图7c显示巩膜上注射BSS(对照);图8a显示眼房内注射ethacrist纳米颗粒,包括高浓度(10μg/μl)的纳米颗粒,和图8b显示眼房内注射低浓度(1μg/μl)的纳米颗粒;图9a-b显示结膜下注射ethacrist纳米颗粒,包括高浓度(1μg/μl)(图9a)或低浓度(0.1μg/μl)(图9b)的纳米颗粒。在所有这些图中,每个单独的“组”代表单独的小鼠。
上述结果表明对于降低IOP,巩膜注射Ethacrist纳米颗粒似乎优于眼房内注射和结膜下注射。另外,在降低IOP方面,巩膜注射Ethacrist纳米颗粒与healon(3:1比例)的混合物似乎优于单独的纳米颗粒。
本说明书中提及的任何专利或出版物均表明了本发明所属领域技术人员的水平。这些专利和出版物通过引用并入本文中,其程度如同将每个单独的出版物具体而单独地通过引用并入本文一样。
本领域技术人员容易理解,本发明特别适合实施所述目的和获得所述结果和优点,以及其中固有的目的、结果和优点。本发明的实施例以及本文所述的方法是优选的实施方案的目前代表,其是示例性的,而不意欲作为本发明范围的限制。本领域技术人员将可以进行其变化和其他应用,它们均涵盖在如权利要求的范围所定义的本发明的精神之内。
Claims (12)
1.一种用于闭塞受试者眼睛的巩膜静脉内静脉血流的弹性材料,包括:
(a)具有内径的中心开孔;和
(b)至少1mm的外径;
其中当将该弹性材料置于眼睛上时,内径部分被拉伸以适合围绕眼睛的中纬线,并且当收缩时,眼睛巩膜静脉内的静脉血流被闭塞。
2.根据权利要求1的弹性材料,其中所述材料包括选自圆形、长方形、正方形的形状。
3.根据权利要求1的弹性材料,其中所述材料包括2mm至40mm的外径。
4.根据权利要求1的弹性材料,其中所述材料的内径为2mm至20mm。
5.根据权利要求1的弹性材料,其中所述弹性材料包括硅橡胶材料。
6.一种用于增加患有青光眼的受试者的眼睛中房水流出的系统,包含:权利要求1-5中任一项所述的弹性材料和用于经巩膜静脉给药的眼科药剂,其中所述眼科药剂选自流出增加剂、类固醇、α受体激动剂、β受体拮抗剂、碳酸酐酶抑制剂、肾上腺素能剂、生理学活性肽和/或蛋白、抗肿瘤剂、抗生素、镇痛药、抗炎剂、肌肉松弛剂、抗溃疡剂、抗过敏剂、强心剂、抗心律不齐剂、血管舒张剂、抗高血压剂、抗糖尿病剂、抗高脂血症剂、抗凝血剂、溶血剂、抗结核剂、激素、麻醉药拮抗剂、破骨抑制剂、成骨促进剂、血管生成抑制剂、抗菌剂、非甾体抗炎药(NSAID)、糖皮质激素或其他抗炎皮质类固醇、生物碱镇痛剂、抗病毒剂、抗良性前列腺肥大(BPH)剂、抗真菌化合物、抗增殖化合物、抗青光眼化合物、免疫调节化合物、细胞转运/迁移阻止剂、细胞因子PEG化药剂、α-阻断剂、抗雄激素、抗胆碱能剂、嘌呤能药剂、多巴胺能药剂、局部麻醉剂、香草素、氧化亚氮抑制剂、抗细胞凋亡剂、巨噬细胞活化抑制剂、抗代谢剂、神经保护剂、钙通道阻滞剂、γ-氨基丁酸(GABA)拮抗剂、抗精神病剂、酪氨酸激酶抑制剂、核苷化合物、核苷酸化合物、及其可药用盐、酯、及其组合。
7.根据权利要求6的系统,其中所述流出增加剂包括依他尼酸。
8.如权利要求6-7中任一项的系统,其中进一步包含用于与所述眼科药剂一起给药的粘弹性药剂。
9.根据权利要求8的系统,其中所述粘弹性药剂选自OVD、OVD、及其组合。
10.根据权利要求8的系统,其中所述眼科药剂与粘弹性药剂的比例为3:1。
11.根据权利要求6的系统,其中所述生物碱镇痛剂是阿片镇痛剂。
12.根据权利要求6的系统,其中所述抗病毒剂是核苷抗病毒剂或非核苷抗病毒剂。
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