CN1684701A - 眼科冲洗液及方法 - Google Patents
眼科冲洗液及方法 Download PDFInfo
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- CN1684701A CN1684701A CNA038233452A CN03823345A CN1684701A CN 1684701 A CN1684701 A CN 1684701A CN A038233452 A CNA038233452 A CN A038233452A CN 03823345 A CN03823345 A CN 03823345A CN 1684701 A CN1684701 A CN 1684701A
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Abstract
提供一种在眼科操作中通过持续冲洗围手术的眼科应用的溶液。这些溶液包括发挥抑制炎症、抑制疼痛、有效散瞳(扩大瞳孔)和/或降低眼内压作用的多种药物,其中所选择的多种药物靶向多分子靶,以达到多种不同的生理功能,并且所述多种药物以稀释浓度包含于平衡盐溶液载体中。
Description
I.发明领域
本发明涉及外科的冲洗液及方法,尤其是在眼科操作中所应用的冲洗液。
II.发明背景
眼科手术通常需要应用生理性冲洗液以保护和维持眼内组织的生理完整性。通常需要冲洗液的眼科手术操作的实例有白内障手术、角膜移植手术、玻璃体视网膜的手术以及青光眼的小梁切除手术。
用于眼科手术冲洗的溶液包括生理盐水、乳酸盐林格氏溶液和Hartmann’s乳酸盐林格氏溶液,但是由于存在不利于角膜和内皮作用的潜在因素,这些溶液不是最佳的。其它的水性溶液包括试剂如电解质、用于pH调节的缓冲剂、谷胱甘肽和/或能源如右旋糖,可较好地保护眼组织,但不能处理其它与手术相关的生理过程。一种经常用于眼科冲洗的溶液是Garabedian等在美国专利4,550,022号公开的缓冲电解质和谷胱甘肽溶液两个部分,所述公开书特别通过引用结合到本发明中。仅在使用前将所述溶液的两个部分混合以确保稳定性。配制这些溶液的目的是为了在手术期间保持眼组织的健康。
已经计划通过添加治疗药物改良常规的水性冲洗液。例如,Gan等在美国专利5,523,316号公开的添加一种或多种控制眼内压的药物的冲洗液。在Gan等人公开的专利(所有的公开内容均通过引用结合到本发明中)中用于控制眼内压的药物的特别的实例是β-阻滞剂(例如,β肾上腺素能受体拮抗剂)和α-2肾上腺素能受体激动剂。还将毒覃碱激动剂、碳酸酐酶抑制剂、血管生长抑制的(angiostatic)甾族化合物和前列腺素作为控制眼内压的药物种类列入参考中。设计只用于控制眼内压的药物。
另一个改良溶液的实例公开于国际PCT申请WO94/08602中,发明者的名字是Gan等,其通过引用结合到本发明中。这一申请书公开了在眼科冲洗液中包含散瞳剂,如肾上腺素。由国际PCT申请WO95/16435(发明者的名字是Cagle等)提供另一个实例,该实例公开了在眼科冲洗液中包含非甾体抗炎药(NSAIDs)。
Thomas于美国专利5,811,446号中公开局部眼科溶液,该溶液可包含组氨酸,并且该溶液可包含至少一种其它的活性药物如抗-青光眼的药物(例如噻吗洛尔或去氧肾上腺素)、甾族化合物或NSAID。这一参考文献讲授了抑制眼科操作引起的炎症的组合物的应用。通过滴入眼睛的盲管给予所述溶液。
Yanni的美国专利5,624,893包括含有一种修复损伤的药物(如甾族化合物或生长因子),和/或一种疼痛介质(如NSAID、缓激肽拮抗剂、或神经激肽-1拮抗剂)的组合物。计划将所述组合物用于治疗和预防与激光辐射和光切除(photoablation)有关的角膜云翳。
尽管许多局部应用的药物是可获得的或已经计划用于治疗眼睛的炎症、散瞳(进行多种类型的眼科手术的典型需要),或用于控制眼内压,但过去没有尝试将这些药物的组合在围手术期的眼科冲洗液中应用,将所述冲洗液以能使其对多种治疗药物提供持续的、可控的传递这样一种传递方式在操作的全过程中应用于眼组织,所述治疗药物可作用于多分子靶点,以发挥多种生理功能。
按照惯例应用各种眼科药物传递的方法,这些方法的每一种都有局限性。这些局限性可能包括角膜和结膜中毒、组织损伤、眼球穿孔、视神经损伤、视网膜中动脉和/或中静脉闭塞、直接的视网膜药物中毒以及全身性的副作用。例如,滴眼用的局部药物由于眼睛的天然防护外表而经常被阻止到达靶器官眼睛的部位。许多情况下,只有很少百分比的应用于眼睛外表的药物可准确地达到所期望治疗的作用部位。
在外科操作中,眼科药物传递的一个困难是用合适的短暂控制达到期望的治疗浓度水平。最期望的药动学效果是能够快速地达到治疗浓度的范围并且以后能够将所述药物浓度维持在恒定的水平。通过眼科药物传递的常规方法是无法达到所述期望的。当期望同时传递多于一种药物时,达到相同的药动学效应的挑战在很大程度上被混合。一组独特的可发挥渗透角膜上皮的药物的效应的因素,包括所述分子的大小、它的化学结构和它的溶解特性。
为使药物的有效传递浓度到达眼睛的后部,经常将药物以非常高的剂量全身给予。这些水平是克服血-视网膜屏障所必需的,当来自于血流的所选择药物分子作用时,所述血-视网膜屏障保护眼睛的后部。对于外科操作,有时将注射用药物溶液直接注射到眼睛的后部。当需要较高的局部浓度时以及当渗透性差的药物需要传递时,采用结膜下和眼球周围的眼周注射。白内障手术中采用房室内的注射将药液直接注射到房室前。当房室内的注射提供达到浓度的快速方法的同时,可能引起有关的角膜中毒。然而,这种方法却面临着这样的事实,即由于眼睛的天然循环过程,所述药物可被快速地除去。因此,可注射性溶液快速地丧失了它们的治疗的益处,经常被迫需要频繁地、能引起中毒危险的大剂量注射的应用。可将持续释放的制剂,如含有微胶囊的粘性凝胶注射到眼内以持续较长的作用时间。然而,在达到局部的药物治疗浓度方面可能会有某些拖延。因此,在眼科操作中存在着对传递眼科药物的可控方法的需要。
III.发明概要
本发明提供在眼睛局部传递多种活性药物的溶液,所述活性药物在多种不同的分子靶上发挥作用,可以在围手术期内抑制炎症、抑制疼痛、有效散瞳(瞳孔扩大)和/或降低眼内压。本发明所述的溶液和方法应用至少第一种和第二种治疗药物,所述治疗药物从抗炎药、止痛剂、散瞳药和降低眼内压的药物(降“IOP”药)的生理功能的分类中选择,所述第二种药物提供至少一种不同于由第一种药物提供的一种功能或多种功能的生理功能。优选在大部分的手术过程中应用所述溶液在手术部位持续冲洗眼组织。
本发明的这一方面的溶液可包含:(a)一种或多种抗炎药结合一种或多种止痛药,并且还可任选包含一种或多种降IOP药和/或散瞳药;(b)一种或多种抗炎药结合一种或多种降IOP药,并且任选一种或多种止痛药和/或散瞳药;(c)一种或多种抗炎药结合一种或多种散瞳药,并且任选一种或多种止痛药和/或降IOP药;(d)一种或多种止痛药结合一种或多种降IOP药,并且任选一种或多种抗炎药和/或散瞳药;(e)一种或多种止痛药结合一种或多种散瞳药,并且任选一种或多种抗炎药和/或降IOP药;或者(f)一种或多种散瞳药结合一种或多种降IOP药,并且任选一种或多种抗炎药和/或止痛药。
本发明提供一种溶液,所述溶液在生理性电解质载体液体中构成多种药物的低浓度的混合物,可直接抑制局部的疼痛介质、炎症介质、降低眼内压和/或引起散瞳。本发明也提供了含有这些药物的冲洗液在围手术期的传递方法,即直接作用在手术部位,在这一部位,所述冲洗液在局部的受体和酶的水平预先发挥限制疼痛和炎症、降低眼内压和/或散瞳的作用。由于本发明的局部围手术期的传递方法,可期望立即达到用比全身给药传递方法(例如静脉内、肌肉内、皮下和口服)或注射所需药物更低的剂量即可达到的治疗效果。当在大部分的手术过程中采用持续冲洗,依照本发明的优选方面,所用的药物浓度可能比采用单独应用滴入法或眼内注射的药物浓度低。
本发明与其它用于眼内手术期间传递的活性药物的其它类型的组合物和方法相比有几个优点。用于局部的滴入灌注的液体组合物滴入眼睛的药物在传递限定剂量时,不是总能提供精确的方法,因为在应用中药滴的一部分可被眨眼排出也可被引流排出。此外,在眼内或局部眼科操作中在手术操作开始之前滴入法传递到眼睛的传递剂量可将随后应用的正常的冲洗液提前有效稀释和排出,因此降低了所述药物的治疗效果。
另外,依照本发明在眼内或局部眼科操作中通过冲洗可传递的药物的超时增加使得所述药物较低的浓度可作为冲洗液应用,这样可降低眼睛中毒的危险。由于药动学的原因,仅在手术前传递的药物剂量将以多种浓度给药并表现出作为时间函数的效应,在开始应用后达到效能的峰值一段时间,然后紧接着由于浓度的逐渐下降效应递减。局部滴注药物后独特的药动学参数将依赖于每一种药物的溶解特性、所述媒介组合物以及pH、等渗重量摩尔浓度、所述制剂的张力和粘性而各有不同。本发明的一个优点是所述冲洗液在眼的手术部位可提供维持恒定的活性药物的浓度,因此维持了恒定的治疗效果。
本发明提供了传递到眼睛的可控的、部位-特异性药物,所述药物具有增加眼科治疗的效果和降低副作用的双重目的。在冲洗期间可快速达到治疗浓度的范围,并随后维持在有效的恒定浓度。
本发明也提供了用于手术过程中用于持续冲洗手术部位或伤口的稀释冲洗液的药剂化合物的制备方法。所述方法限定溶于生理性电解质载体液体中的止痛药、抗炎药、散瞳药和/或降低眼内压的药物(降“IOP”药)的大部分,除了对局部麻醉剂外,优选包含的每种药物浓度不高于100,000纳摩尔,并更优选不高于10,000纳摩尔,在局部麻醉中可应用到不高于100,000,000纳摩尔的浓度,优选不高于10,000,000纳摩尔,更优选不高于1,000,000纳摩尔,并且仍更加优选不高于100,000纳摩尔。
本发明提供在手术期间,将多种受体拮抗剂和激动剂以及酶抑制剂和酶激活剂的稀释的组合直接传递到眼睛的伤口或手术或操作部位,用于抑制疼痛和炎症、降低或控制眼内压,和/或促进散瞳的治疗性或诊断性操作的方法。由于在操作中以一种持续的方式(in acontinuous fashion)将所述溶液中的活性成份局部直接应用于眼内的组织,所以所述药物可在极低的剂量下有效地应用,这些剂量是相对于当同样药物全身应用(例如,口服、肌肉内、皮下或静脉内)、或单独应用例如滴入或通过眼内注射时达到治疗效果所需要的那些剂量而言的。
本文使用的术语“局部”包括药物在伤口或其它手术或操作部位内以及周围应用,并包括口服、皮下、静脉内和肌肉内给药。如在本文中始终应用的,术语“冲洗”主要表示伤口或解剖结构用液体流冲洗。本文使用的术语“持续”包括不间断的应用、以频繁的间隔的重复的应用,应用频率足以基本维持所用药物在局部的预定治疗浓度,而且除了短暂的中断如允许应用其它药物或操作设备或由于手术技术外,这些应用都是连续的,使得在所述伤口或手术部位局部维持基本恒定的预定的局部治疗浓度。
除非另外指明,本文使用的术语“伤口”意思是包括外科伤口、手术/插入性部位以及创伤性伤口。
除非另外指明,本文使用的术语“手术”和“操作”的每一种意思是包括外科的、治疗的和诊断的操作。
将含有选择的治疗药物的冲洗液在手术部位的眼组织局部和围手术期应用,如眼内应用于眼内操作和眼睛外部的应用于外表操作。本文使用的术语“围手术期的”包括操作中的应用、操作前和操作中的应用、操作中和操作后的应用、以及操作前、操作中和操作后的应用。优选地,在操作前和/或操作后以及在操作中应用所述溶液。最优选在操作开始之前、或明显的组织创伤之前在伤口或外科手术部位应用所述冲洗液,并且在操作期间持续不断应用,以预先阻断疼痛和炎症、抑制眼内压增高,和/或引起散瞳。在本发明的一个优选的方面,在手术创伤前和手术创伤的大部分时间内,和/或在可能需要散瞳时和/或可能需要控制眼内压时的期间内,在所述操作的主要部分自始至终地持续冲洗。
用本发明的方法和溶液进行冲洗的药物的低剂量应用的优点有三重。避免了全身性的副作用,所述副作用经常限制这些药物的应用。此外,本发明的溶液中所选择的用于特殊应用的药物与相关的介质具有高度的特异性,这些药物依靠介质发挥作用。通过低剂量应用就可保持这种特异性。最后,这些活性药物在每个手术操作中的费用低。
更特别地:(1)局部应用保证了靶向位点的已知浓度,而不用担心病人间在代谢、血流等方面的变异性;(2)由于直接传递的模式,几乎在瞬间获得了治疗浓度并且由此提供了改良的剂量控制;和(3)活性药物局部直接应用到伤口或手术部位还基本减少了药物在穿过细胞外的过程中的降解,例如首次通过(first-pass)代谢和第二次通过代谢,如果所述药物是全身给予(如口服、静脉内、皮下或肌肉内),则将会发生降解。这对于那些代谢极快的活性肽类药物尤其如此。因此,局部应用允许采用那些以别的方式不能进行治疗应用的化合物或药物。局部、持续传递到伤口或手术部位将药物的降解或代谢减低到最小化,而同时还提供可能已降解的药物部分的持续补充,以保证在手术操作过程中始终维持局部的治疗浓度,以足以维持受体占有量。
根据本发明,在手术过程中始终在围手术期的局部应用所述溶液可产生预先止痛、抗炎和/或控制眼内压(如果应用降IOP药)的效果,以及维持散瞳(如果应用散瞳药)。为使预先抗炎、止痛(对于某些应用)、眼内压下降(对于某些应用)和散瞳(对于某些应用)的效果达到最大化,最优选将本发明的溶液在手术前、手术中和手术后应用。通过在局部很大的手术创伤开始之前,占有靶向受体或未激活的靶器官的酶或激活的靶器官的酶,本发明溶液的药物可调整特殊的通道以预先抑制靶器官的病理性过程。在炎症介质和过程可以产生组织损害之前,如果依照本发明预先抑制了炎症介质和过程,并且同样预先抑制了增加眼内压的介质,那么所述益处比这些过程开始之后再给予更充分。
本发明的冲洗液包括药物的联合应用,每一种溶液在多种受体或酶上发挥作用。因此所述药物可同时发挥抗病理性过程的效果,所述病理性过程包括疼痛和炎症,和/或增加眼内压的调节过程。期望这些药物的作用是协同的,这样本发明的多种受体拮抗剂和抑制激动剂在联合应用时可提供与单独药物的效果不成比例地(disproportionately)增加效果。
对围手术期的应用,所述溶液应该产生与目前的冲洗液应用有关的手术部位疼痛和炎症的临床上的显著减低,由此减少了病人手术后的止痛需要,并且合适时,可允许病人更早康复。也期望预先控制眼内压可减少手术后眼内压升高过程的治疗需要。
IV
优选实施方案详述
本发明提供围手术期在眼组织局部应用的冲洗液,包括眼内的和局部的应用,所述溶液包括多种发挥抑制炎症、抑制疼痛、有效散瞳(瞳孔扩张),和/或降低或控制眼内压作用的药物,其中所述多种药物被选择作用于多种、不同的靶分子以达到多种不同的生理功能。本发明的冲洗液是在生理性液体冲洗载体中的多种疼痛/炎症抑制剂、降IOP药,和/或散瞳药的稀释液。适宜的所述载体为可包括生理性电解质的水性溶液,如生理盐水或乳酸盐林格氏溶液。更优选地,所述载体包括足够的能提供生理性平衡盐溶液的电解质、细胞能源、缓冲剂和自由基清除剂。
依据本发明的溶液可包括(a)一种或多种抗炎药与一种或多种止痛剂联合,并且还可任选包括一种或多种降低眼内压(降“IOP”药)的药物和/或散瞳药;(b)一种或多种抗炎药与一种或多种降IOP药联合,并且还可任选包括一种或多种止痛剂和/或散瞳药;(c)一种或多种抗炎药与一种或多种散瞳药联合,并且还可任选包括一种或多种止痛剂和/或降IOP药;(d)一种或多种止痛剂与一种或多种降IOP药联合,并且还可任选包括一种或多种抗炎药和/或散瞳药;(e)一种或多种止痛剂与一种或多种散瞳药联合,并且还可任选包括一种或多种抗炎药和/或降IOP药;或(f)一种或多种散瞳药与一种或多种降IOP药联合,并且还可任选包括一种或多种抗炎药和/或止痛剂。
本发明的这些溶液的任何一种也可包括一种或多种抗生素。适于本发明应用的抗生素包括卷须霉素、庆大霉素、托普霉素和吡啶羧酶。其它适于围手术期的眼内应用的抗生素也被本发明包括在内。适合本发明的冲洗液含有的一种抗生素(卷须霉素)的合适的浓度是0.01mM到10mM,优选0.05mM到3mM,最优选0.1mM到1mM。不同的抗生素将按不同的,如可被容易地限定的浓度应用。
在本发明的每一种外科溶液中,所述药物以低浓度被包含于其中并且以低剂量在局部传递,所述低浓度和低剂量是相对于常规给药方法为达到所期望的治疗效果所需要的浓度和剂量而言的。通过全身(例如静脉内、皮下、肌肉内或口服)给药的途径传递相同剂量的药物是不可能获得相等的治疗效果的,因为全身给药需经历首次通过和第二次通过代谢。
可部分地以每种药物的解离常数Kd为基础来测定其浓度。本文使用的术语“解离常数”意欲包括其各自的激动剂受体或拮抗剂受体相互作用的平衡解离常数和其各自的酶激活剂或酶抑制剂相互作用的平衡抑制常数两者。优选包含的每种药物的低浓度为0.1到10,000乘以Kd,但环加氧酶抑制剂除外,它依赖于所选择的具体抑制剂而可能需要更大的浓度。优选地,包含的每种药物的浓度为1.0到1,000乘以Kd,而最优选约100乘以Kd。将这些浓度在没有代谢的转换的局部传递部位按照稀释量的需要而调节。选择用于所述溶液的准确的药物和药物的浓度,依据具体的应用而各有不同。
通过将多种作用于不同受体和酶分子靶的药剂混合使外科手术用的溶液构成了一个新的治疗方法。迄今为止,药理学策略已集中于开发可选择性针对个体的受体亚型和酶同工型的高特异性的药物,从而介导对个体神经递质和激素信号的反应。这一标准的药理学策略尽管被广泛接受但却并非完美,因为许多其他的药物可同时对启动和维持生理学功效起作用。此外,尽管单个受体亚型或酶的失活,其他受体亚型或酶的活化以及导致的信号传递常可触发一系列的作用。这就说明用单一的受体特异性的药物来阻断由多种递质起作用的病理生理过程是相当困难的。因此,仅以特异性的个体受体亚型为靶向可能是无效的。
相对于标准的药理学治疗方法,所述外科手术用溶液的治疗方法是基于这一原理,即需要同时作用于不同分子靶的联合药物来抑制导致病理生理状态发展的全部事件。此外,取代单独以特异性受体亚型为靶向,所述外科手术用溶液是由以在不同的细胞生理过程中起作用的普通分子机理为靶向的药物组成,该细胞生理过程涉及疼痛和炎症的发展、眼内压的减低和瞳孔散大的促进。以这种方式,在感受伤害、炎症和眼内压增加的途径中另外的受体和酶的级联作用可由所述外科手术用溶液减至最小。在这些病理生理途径中,所述外科手术用溶液能抑制“上游”和“下游”两者的级联作用(即在病理生理途径的分散和会聚的两个点处)。
在眼科手术过程中使用的本发明的优选溶液包含一种或多种抗炎剂与一种或多种散瞳剂的联合。根据所给予的手术操作或所治疗的疾病是否伴有较高的疼痛或眼内压增高的发生率,这样的优选溶液也可分别包含一种或多种止痛剂和/或一种或多种IOP降压剂。
这些药剂以稀释的浓度被包含于如前面所述任一载体的生理的水性载体中,如,平衡盐溶液。该溶液也可包含增粘剂,如,生物可相容的和生物可降解的多聚物,以延长在眼内的停留时间。根据本发明的指导来决定所述药剂的浓度,在外科手术过程中直接局部用于眼组织。所述溶液的应用在围手术期进行,即:手术中;手术前和手术中;手术中和手术后;或手术前、手术中和手术后。所述药物可以稳定的一个部分或二个部分的溶液提供,或可以冻干的形式提供,在使用前向其中加入一个部分或二个部分的载体液体。
现在进一步描述眼科药物的功能分类,它将有益于本发明的眼科冲洗液在围手术期的应用。
A.抗炎剂
用于本发明的眼科溶液中的优选抗炎剂包括局部甾体类、局部非甾体类抗炎剂(NSAIDs)和适于眼内使用的特别类型的抗炎剂,如局部抗组胺剂、肥大细胞抑制剂和诱导型一氧化氮合酶(iNOS)抑制剂。本发明也打算包括以下作为疼痛/炎症抑制剂描述的其他抗炎剂,以及此处未公开的适于眼用的其他抗炎剂。
认为适用于本发明的甾体化合物的实例包括地塞米松、氟米龙和强的松龙。认为合适的NSAIDS的实例包括氟比洛芬、舒洛芬、双氯芬酸、酮洛芬和酮咯酸。NSAID的选择部分取决于不会导致过多的出血的测定。认为合适的抗组胺剂的实例包括左卡巴斯汀、依美斯汀和奥洛他定。认为合适的肥大细胞抑制剂的实例包括色甘酸钠、洛度沙胺和奈多罗米。适用于本发明的用作抗组胺剂和肥大细胞抑制剂的药物的实例包括酮替芬和氮斯汀。认为合适的iNOS抑制剂包括NG-一甲基-L-精氨酸、1400W、二亚苯基碘鎓(diphenyleneiodium)、S-甲基异硫脲、S-(氨基乙基)异硫脲、L-N6-(1-亚氨基乙基)赖氨酸、1,3-PBITU和2-乙基-2-硫假脲(thiopseudourea)。
B.
止痛剂
本文使用的关于眼科用的溶液和方法的术语“止痛剂”打算包括提供止痛的药物和提供局部麻醉的药物两者。用于本发明的眼科用溶液的优选止痛剂包括局部用的麻醉剂和局部用的类阿片。本发明也意欲包括下述作为疼痛/炎症抑制剂的其它止痛剂、以及其它未在本文公开、但适宜于眼科应用的止痛剂。
被认为适于本发明应用的局部麻醉的实例包括利多卡因、丁卡因、布比卡因和丙美卡因。被认为适于本发明应用的类阿片的实例包括吗啡、芬太尼和氢吗啡酮。
C.
散瞳剂
用于本发明的眼科用溶液的优选散瞳剂(在手术期间扩张瞳孔)包括拟交感神经药(包括α-1肾上腺素受体激动剂)和抗胆碱能药物(包括抗毒覃碱)。当期望较长的作用时可选择抗胆碱能药物,因为它们既可提供睫状肌麻痹(眼睫毛的肌肉麻痹)也可提供散瞳,例如,托吡卡胺显示有将近4-6小时的半衰期。然而,对于许多操作,将优选α-1肾上腺素受体激动剂,因为它们只提供散瞳而不提供睫状肌麻痹。因此α-1肾上腺素受体激动剂的作用较短,在手术操作期间引起散瞳而在操作完成后短时间内可使瞳孔恢复到它的正常状态。合适的作用于α-1受体的肾上腺素受体激动剂的实例包括新福林、肾上腺素和羟甲唑啉。合适的抗胆碱能药物的实例包括托吡卡胺、环戊通、阿托品和后马托品。本发明也意欲包括其它引起散瞳的药物,特别是短期作用的散瞳药。
D.
降低眼内压的药物
用于本发明的眼科溶液的优选的降低眼内压的药物包括β肾上腺素受体拮抗剂、碳酸酐酶抑制剂、α-2肾上腺素受体激动剂和前列腺素激动剂。被认为合适的β肾上腺素受体拮抗剂的实例包括噻吗洛尔、美替洛尔和左布诺洛尔。被认为合适的碳酸酐酶抑制剂的实例包括布林唑胺和多佐胺。被认为合适的α-2肾上腺素受体激动剂的实例包括阿可乐定、溴莫尼定和羟甲唑啉。其它适于眼科应用的α-2肾上腺素受体激动剂和下述的炎症/疼痛抑制剂也可在本发明的溶液中合适地发挥降IOP药的作用。被认为合适的前列腺素激动剂包括拉坦前列素、曲伏前列素和比马前列素。当抑制炎症是溶液期望的首要效果并需要控制IOP时,可选择非前列腺素激动剂的合适的降IOP药;以避免前列腺素可增强手术后炎症的可能性。本发明也意欲包括其它减少眼内压的药物。
E.
疼痛/炎症抑制剂
下述药物(本文称为疼痛/炎症抑制剂)可适于在本发明的眼科用溶液和方法中作为止痛剂和/或抗炎药应用。本领域技术人员依照本发明可以容易地确定用于特定的眼科应用的具体的药物种类,以及在一类药物中的个别的药物。
例如,已经通过比较由几种冲洗液,特别是角叉菜胶、Freund’s佐剂、碱和巴豆油的局部应用而引起的炎症反应,研究了兔的眼科炎症模型。所述方法包括在给白色、新西兰雌兔的眼睛应用各种刺激物后测量下述可检测的参数:角膜水肿和延德耳氏效应(裂隙灯活体显微镜检法)、角膜厚度(生物测厚计)和眼房水的前列腺素E2的水平(R.I.A)、总蛋白(Weichselbaum技术)、白蛋白、白蛋白/球蛋白比例(Doumas技术)和白细胞(库尔特粒度仪)。
验证研究发现1-4%巴豆油(40μl)可产生水肿和延德耳氏效应,并显示所述水肿和延德耳氏效应的比例随巴豆油浓度而增加。超声测厚计在角膜厚度变化(3-168小时)的测量中显示从第8小时到第168小时呈剂量依赖性反应(p<0.01)。在局部应用3%巴豆油(40μl)24小时后,发现葡萄膜炎以及在眼房水中发现前列腺素E2的水平(4.50±0.40pg/0.1ml对比260.03±2.03pg/0.1ml)、总蛋白(0.25±0.05g/l对比2.10±0.08g/l)、白蛋白、白蛋白/球蛋白比例和白细胞都有相当的增加。所有获得的数据均有统计学的显著意义(p<0.01)。
局部应用3%巴豆油(40μl)对评估前房的炎症过程和检测眼内的穿透效应是最合适的。认为在这种模型中的炎症机制包括花生四烯酸的途径的激活,伴随出现血-眼房水屏障的击穿从而使得高分子量的蛋白质进入房水。
可采用上述模型测定局部应用药物,例如通过冲洗,在抑制炎症过程中和发挥其它眼科功能上的效应。每种刺激物在兔的眼睛中使用后,将待评估的一个给定的药物或药物的联合应用到该家兔的眼睛。
所述溶液可适宜地包括从下述各类受体拮抗剂和激动剂以及酶激活剂和酶抑制剂中选择的药物,每类药物通过不同的分子作用机制发挥抑制疼痛和炎症的作用:(1)5-羟色胺受体拮抗剂;(2)5-羟色胺受体激动剂;(3)组胺受体拮抗剂;(4)缓激肽受体拮抗剂;(5)血管舒缓素抑制剂;(6)速激肽受体拮抗剂,包括神经激肽1和神经激肽2亚型受体拮抗剂;(7)降钙素基因相关肽(CGRP)受体拮抗剂;(8)白细胞介素受体拮抗剂;(9)在花生四烯酸代谢的合成途径的活性酶的抑制剂,包括(a)磷脂酶抑制剂,包括PLA2同工型抑制剂和PLCγ同工型抑制剂,(b)环加氧酶抑制剂,和(c)脂加氧酶抑制剂;(10)类前列腺素受体拮抗剂,包括类花生酸EP-1和EP-4亚型受体拮抗剂和血栓烷亚型受体拮抗剂;(11)白三烯受体拮抗剂包括白三烯B4亚型受体拮抗剂和白三烯D4亚型受体拮抗剂;(12)类阿片受体激动剂,包括μ-类阿片、δ-类阿片和κ-类阿片亚型受体激动剂;(13)嘌啉受体激动剂和拮抗剂,包括P2X受体拮抗剂和P2Y受体激动剂;(14)三磷酸腺苷(ATP)-敏感型钾通道开放剂;(15)局部麻醉剂;和(16)α-2肾上腺素受体激动剂。上述药物的每一种具有作为抗炎药的功能和/或作为止痛剂,例如镇痛药的功能。从这些化合物的种类中选择的药物对于具体应用是特别适用的。
1.
5-羟色胺受体拮抗剂
5-羟色胺(5-HT)被认为是通过刺激末梢的感受伤害的神经元上的5-羟色胺2(5-HT2)和/或5-羟色胺3(5-HT3)受体而产生疼痛。大多数研究者赞同在末梢的感受伤害的神经元上的5-HT3受体介导由5-HT产生的直接的疼痛感觉。除了抑制5-HT引起的疼痛外,5-HT3受体拮抗剂,通过抑制感受伤害的神经元受体的激活,也可抑制神经原性炎症。5-HT2受体的活化也可在末梢疼痛和神经性原的炎症中发挥作用。本发明的溶液的一个目标是阻断疼痛和炎症过程的大部分。因此,5-HT2和5-HT3受体拮抗剂二者均可被合适地应用,在本发明的溶液中既可以单独应用也可以一起应用。认为阿米替林(ElavilTM)是可用于本发明的潜在的、合适的5-HT2受体拮抗剂。胃复安(ReglanTM)在临床上是用作止吐药的,但却表现出与5-HT3受体的适度的亲和性并能在这一受体上抑制5-HT的作用,可能抑制从血小板释放出的5-HT引起的疼痛。因此,它也可合适地在本发明中应用。
其它潜在的、合适的5-HT2受体拮抗剂包括丙咪嗪、曲唑酮、去郁敏、酮色林。其它合适的5-HT3拮抗剂包括西沙必利和昂丹司琼。将本发明的溶液中应用的这些药物的治疗和优选的浓度列于表1。
表1
疼痛/炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
5-羟色胺2受体拮抗剂:
阿米替林 0.1-1,000 50-500
丙咪嗪 0.1-1,000 50-500
曲唑酮 0.1-2,000 50-500
去郁敏 0.1-1,000 50-500
酮色林 0.1-1,000 50-500
5-羟色胺3受体拮抗剂:
托烷司琼 0.01-100 0.05-50
胃复安 10-10,000 200-2,000
西沙必利 0.1-1,000 20-200
昂丹司琼 0.1-1,000 20-200
2.
5-羟色胺受体激动剂
已知5-HT1A、5-HT1B和5-HT1D受体可抑制腺苷酸环化酶的活性。因此溶液中包括这些低剂量的5-羟色胺1A、5-羟色胺1B和5-羟色胺1D受体激动剂应该抑制神经元介导的疼痛和炎症。因为5-羟色胺1E和5-羟色胺1F受体激动剂也抑制腺苷酸环化酶,因此期望这些受体激动剂具有同样的作用。
丁螺环酮是用于本发明的潜在的、合适的1A受体激动剂。舒马曲坦是潜在的、合适的1A、1B、1D和1F受体激动剂。潜在的、合适的1B和1D受体激动剂是双氢麦角胺。合适的1E受体激动剂是麦角新碱。表2提供了这些受体激动剂的治疗和优选的浓度。
表2
疼痛和炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
5-羟色胺1A激动剂:
5-羧基酰氨基色胺 1-1,000 10-200
舒马曲坦 1-1,000 10-200
5-羟色胺1B激动剂:
CP93129 0.1-1,000 10-100
舒马曲坦 1-1,000 10-200
5-羟色胺1D激动剂:
那拉曲坦 0.1-1,000 10-100
舒马曲坦 1-1,000 10-200
5-羟色胺1E激动剂:
麦角新碱 10-2,000 100-1,000
5-羟色胺1F激动剂:
舒马曲坦 1-1,000 10-200
3.
组胺受体拮抗剂
可将组胺受体拮抗剂有效地包括在所述冲洗液中。通常用作止吐药的异丙嗪(PhenerganTM)可有效地阻断H1受体,并成为本发明中潜在的、合适的用药。其它潜在的、合适的H1受体拮抗剂包括特非那定、苯海拉明、阿米替林、美吡拉敏和曲普利啶。由于阿米替林还是有效的5-羟色胺2受体拮抗剂,所以它在本发明的应用中具有双重的功效。将每一种所述H1受体拮抗剂的合适的治疗和优选的浓度列于表3。
表3
疼痛和炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
组胺1受体拮抗剂:
异丙嗪 0.1-1,000 50-200
苯海拉明 0.1-1,000 50-200
阿米替林 0.1-1,000 50-500
特非那定 0.1-1,000 50-500
美吡拉敏(pyrilamine) 0.1-1,000 5-200
曲普利啶 0.01-100 5-20
4.
缓激肽受体拮抗剂
通常将缓激肽受体分为缓激肽1(B1)和缓激肽2(B2)两个亚型。这些药物是肽类(小蛋白),因为它们将被消化掉,因此它们不能口服应用。B2受体的拮抗剂阻断缓激肽引起的急性疼痛和炎症。B1受体拮抗剂抑制慢性炎症疾患的疼痛。根据应用,本发明的溶液可合适地包括缓激肽B1和缓激肽B2受体拮抗剂的任何一种或两者均包括。用于本发明的潜在的、合适的缓激肽1受体拮抗剂包括:D-Arg-(Hyp3-Thi5-D-Tic7-Oic8)-BK的[des-Arg10]衍生物(“HOE 140的[des-Arg10]衍生物”,可从Hoechst Pharmaceuticals获得);和[Leu8]des-Arg9-BK。潜在的、合适的缓激肽2受体拮抗剂包括:[D-Phe7]-BK;D-Arg-(Hyp3-Thi5,8-D-Phe7)-BK(“NPC 349”);D-Arg-(Hyp3-D-Phe7)-BK(“NPC 567”)和D-Arg-(Hyp3-Thi5-D-Tic7-Oic8)-BK(“HOE 140”)。表4提供了合适的治疗和优选的浓度。
表4
疼痛/炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
缓激肽1受体拮抗剂:
[Leu8]des-Arg9-BK 1-1,000 50-500
HOE140的[des-Arg10]衍生物 1-1,000 50-500
[Leu9][des-rg9]卡里定 0.1-500 10-200
缓激肽2受体拮抗剂:
[D-Phe7]-BK 100-10,000 200-5,000
NPC 349 1-1,000 50-500
NPC 567 1-1,000 50-500
HOE 140 1-1,000 50-500
5.
血管舒缓素抑制剂
所述肽类缓激肽是重要的疼痛和炎症介质。缓激肽是由血浆中的高分子量的激肽原在血管舒缓素作用下产生的裂解产物。因此,认为血管舒缓素抑制剂在抑制缓激肽产生和导致的疼痛和炎症中有治疗作用。用于本发明的潜在的、合适的血管舒缓素抑制剂是抑肽酶。将本发明的溶液应用的有效地、优选的浓度列于下表5中。
表5
疼痛/炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
血管舒缓素抑制剂:
抑肽酶 0.1-1,000 50-500
6.
速激肽受体拮抗剂
速激肽(TKs)是一个结构相关的包括P物质、神经激肽A(NKA)和神经激肽B(NKB)的肽类家族。在末梢神经元是TKs的主要来源。TKs的一个重要而普遍的功效是神经元的刺激,但是其它功效包括内皮依赖性血管扩张、血浆蛋白外渗、肥大细胞募集和脱颗粒以及炎症细胞的刺激。由于上述由TK受体的活化介导的生理作用的联合作用,TK受体的靶向是促进止痛和治疗神经元性炎症的合理方法。
a.
神经激肽1亚型受体拮抗剂
P物质激活称为NK1的神经激肽亚型受体。潜在的、合适的P物质拮抗剂是([D-Pro9[γ螺旋-内酰胺]Leu10,Trp11]气拉明-(1-11))(“GR82334”)。其它用于本发明的潜在的、合适的作用于NK1受体的拮抗剂是:1-亚氨基-2-(2-甲氧基-苯基)-乙基)-7,7-二苯基-4-全氢化异吲哚酮(3aR,7aR)(“RP 67580”);和2S,3S-顺式-3-(2-甲氧基苄基氨基)-2-二苯甲基奎宁环(“CP 96,345”)。将这些药物的合适的浓度列于表6。
表6
疼痛/炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
神经激肽1亚型受体拮抗剂
GR 82334 1-1,000 10-500
CP 96,345 1-10,000 100-1,000
RP 67580 0.1-1,000 100-1,000
b.
神经激肽2亚型受体拮抗剂
神经激肽A是一种与P物质共同定位(colocalized)于感觉神经元并且也可以促进炎症和疼痛的肽。神经激肽A激活称为NK2的特异性神经激肽受体。潜在的、合适的NK2拮抗剂的实例包括:(S)-N-甲基-N-[4-(4-乙酰基氨基-4-苯基哌啶基)-2-(3,4-二氯苯基)丁基]苯甲酰胺(“(±)-SR 48968”);Met-Asp-Trp-Phe-Dap-Leu(“MEN 10,627”);以及cyc(Gln-Trp-Phe-Gly-Leu-Met)(“L 659,877”)。表7提供了这些药物的合适的浓度。
表7
疼痛/炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
神经激肽2亚型受体拮抗剂:
MEN 10,627 1-1,000 10-1,000
L 659,877 10-10,000 100-10,000
(±)-SR 48968 10-10,000 100-10,000
7.
CGRP受体拮抗剂
降钙素基因相关肽(CGRP)也是与P物质共同定位于感觉神经元,并且有血管扩张的作用和增强P物质作用的一种肽。潜在的、合适的CGRP受体拮抗剂的实例是I-CGRP-(8-37),CGRP的一个截短的变型。这种多肽抑制CGRP受体的激活。表8提供了这种药物的合适的浓度。
表8
疼痛/炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
CGRP受体拮抗剂:
I-CGRP-(8-37) 1-1,000 10-500
8.
白介素受体拮抗剂
白介素的归类是细胞因子,是由白细胞及其它对炎症介质应答的细胞产生的一个肽的家族。白介素(IL)可以是有效的末梢痛觉过敏的药物。潜在的、合适的IL-1β受体拮抗剂的实例是Lys-D-Pro-Thr,它是IL-1β的一个截短的变型。这种三肽抑制IL-1β受体的激活。表9提供了这种药物的合适的浓度。
表9
疼痛/炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
白介素受体拮抗剂:
Lys-D-Pro-Thr 1-1,000 10-500
9.
在花生四烯酸的代谢的合成途径发挥作用的酶的抑制剂
a.
磷脂酶抑制剂
由磷脂酶A2(PLA2)引起的花生四烯酸的产生引起级联反应,级联反应产生了大量的已知为类花生酸的炎症介质。在这个途径的整个过程中有许多阶段可被抑制,从而减少这些炎症介质的产生。下面给出抑制这些不同的阶段的实例。
PLA2酶的同工型的抑制抑制了花生四烯酸从细胞膜中的释放,由此抑制了前列腺素和白三烯的产生,导致炎症和疼痛的减轻。潜在的、合适的PLA2同工型抑制剂的实例是manoalide。这一药物的合适的浓度包括在表10中。磷脂酶C(PLC)同工型的抑制也将导致类前列腺素和白三烯产生的减少,并因此将导致疼痛和炎症的减轻。PLC异构体同工型的实例是1-[6-((17β-3-甲氧基雌-1,3,5(10)-三烯-17-基)氨基)己基]-1H-吡咯-2,5-二酮。
表10
疼痛/炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
PLA2同工型抑制剂:
monoalide 100-100,000 500-10,000
b.
环加氧酶抑制剂
非甾体抗炎药(NSAIDs)被广泛用作抗炎和止痛药物。这些药物的分子靶是I型和II型环加氧酶(COX-1和COX-2)。COX-1的组成活性和COX-2的诱导活性二者导致能引起疼痛和炎症的前列腺素的合成。
目前市场上的NSAIDs(双氯芬酸、萘普生、消炎痛、布洛芬等)通常都是两种COX同工型的非选择性抑制剂,但可对COX-1表现出比COX-2更大的选择性,尽管这个比例依照不同的化合物有所不同。应用COX-1和COX-2抑制剂阻断前列腺素的形成比试图阻断天然的配体与7种所描述的类前列腺素受体亚型间的相互作用表现出更好的治疗策略。
用于本发明的潜在的、合适的环加氧酶抑制剂是酮洛芬、酮咯酸和消炎痛。表11提供了用于所述溶液的这些药物的治疗和优选的浓度。对于某些应用,可能也适合将COX-2特异性抑制剂(例如,相对于COX-2更选择COX-1)作为抗炎/止痛剂应用。潜在的、合适的COX-2抑制剂包括罗非考昔(MK 966)、SC-58451、塞来考昔(SC-58125)、美洛昔康、尼美舒利、双氯芬酸、NS-398、L-745,337、RS57067、SC-57666和氟舒胺。
表11
疼痛/炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
环加氧酶抑制剂:
酮咯酸 100-10,000 500-5,000
酮洛芬 100-10,000 500-5,000
消炎痛 1,000-500,000 10,000-200,000
c.
脂加氧酶抑制剂
抑制脂加氧酶可抑制白三烯如白三烯B4的产生,白三烯已知是一种的重要的炎症和疼痛介质。潜在的、合适的5-脂加氧酶拮抗剂的实例是2,3,5-三甲基-6-(12-羟基-5,10-十二碳二炔基)-1,4-苯醌(“AA861”),表12提供了所列药物的合适浓度。
表12
疼痛/炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
脂加氧酶抑制剂:
AA 861 100-10,000 500-5,000
10.
类前列腺素受体拮抗剂
作为花生四烯酸的代谢物而产生的特异性类前列腺素通过激活类前列腺素受体而介导它们的炎性作用。特异性类前列腺素拮抗剂类的实例是类花生酸EP-1和EP-4亚型受体拮抗剂和血栓烷亚型受体拮抗剂。潜在的、合适的前列腺素E2受体拮抗剂是8-氯二苯并[b,f][1,4]氧氮杂(oxazepine)-10(11H)-羧酸、2-乙酰基酰肼(“SC 19220”)。潜在的、合适的血栓烷亚型受体拮抗剂是[15-[1α,2β(5Z),3β,4α]-7-[3-[2-(苯基氨基)-羰基]肼基]甲基]-7-氧代二环-[2,2,1]-庚-2-基]-5-庚酸(“SQ 29548”)。将这些药物的合适的浓度列于表13中。
表13
疼痛/炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
类花生酸EP-1拮抗剂:
SC 19220 100-10,000 500-5,000
11.
白三烯受体拮抗剂
白三烯(LTB4、LTC4和LTD4)是花生四烯酸代谢中5-脂加氧酶途径的产物,所述代谢途径经酶产生并具有重要的生物学特性。白三烯涉及很多病理性疾患包括炎症。潜在的、合适的白三烯B4受体拮抗剂的实例是SC(+)-S-7-(3-(2-(环丙基甲基)-3-甲氧基-4-[(甲基氨基)-羰基]苯氧基(丙氧基)-3,4-二氢-8-丙基-2H-1-苯并吡喃-2-丙酸(“SC53228”)。表14提供了这一药物用于本发明实践的潜在的、合适的浓度。其它潜在的、合适的白三烯B4受体拮抗剂包括[3-[2-(7-氯-2-喹啉基)乙烯基]苯基][[3-(二甲基氨基-3-氧代丙基)硫代]甲基]硫代丙酸(“MK 0571”)以及药物LY 66,071和ICI 20,3219。MK 0571也用作LTD4亚型受体拮抗剂。
表14
疼痛/炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
白三烯B4拮抗剂:
SC 53228 100-10,000 500-5,000
12.
类阿片受体激动剂
类阿片受体的激活导致抗-感受伤害的效应,因此,这些受体的激动剂是受期待的。类阿片受体包括μ-类阿片、δ-类阿片和κ-类阿片亚型受体。潜在的、合适的μ-类阿片受体激动剂的实例是芬太尼和Try-D-Ala-Gly-[N-MePhe]-NH(CH2)-OH(“DAMGO”)。潜在的、合适的δ-类阿片受体激动剂的实例是[D-Pen2,D-Pen5]脑啡肽(“DPDPE”)。潜在的、合适的κ-类阿片受体激动剂的实例是(反式)-3,4-二氯-N-甲基-N-[2-(1-吡咯烷烯基)环己基]-苯乙酰胺(“U 50,488”)。这些药物的每一种的合适的浓度列于表15中。
表15
疼痛/炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
μ-类阿片激动剂:
DAMGO 0.1-100 0.5-20
Sufentanyl 0.01-50 1-20
芬太尼 0.1-500 10-200
PL 017 0.05-50 0.25-10
δ-类阿片激动剂:
DPDPE 0.1-500 1.0-100
κ-类阿片激动剂
U 50,488 0.1-500 1.0-100
13.
嘌啉受体拮抗剂和激动剂
通过与P2嘌啉受体(purinoceptors)之间的相互作用,细胞外的ATP发挥着信号分子的作用。嘌啉受体的一个主要类型是P2X嘌啉受体,它是控制内部离子通道中Na+、K+和Ca2+渗透的配体门控离子通道。用于本发明的潜在的、合适的P2X/ATP嘌啉受体拮抗剂包括,例如,苏拉明和吡哆醛磷酸盐-6-偶氮基苯基-2,4-二磺酸(“PPADS”)。表16提供了这些药物的合适的浓度。已知P2Y受体(一种G-蛋白偶合的受体)激动剂有使平滑肌松弛的作用,该作用通过三磷酸肌醇(IP3)水平升高及随后的细胞内钙离子增加而产生。一个P2Y受体激动剂的实例是2-me-S-ATP。
表16
疼痛/炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
嘌啉受体拮抗剂:
苏拉明 100-100,000 10,000-100,000
PPADS 100-100,000 10,000-100,000
14.
三磷酸腺苷(ATP)-敏感型钾通道开放剂
用于本发明实践的潜在的、合适的三磷酸腺苷(ATP)-敏感型K+通道开放剂包括:(-)吡那地尔;色满卡林;尼可地尔;米诺地尔;N-氰基-N’-[1,1-二甲基-[2,2,3,3-3H]丙基]-N”-(3-吡啶基)胍(“P 1075”);和N-氰基-N’-(2-硝酰基乙基)-3-吡啶羧基亚氨基酰胺(pyridinecarboximidamide)单甲烷磺酸酯(“KRN 2391”)。这些药物的浓度列于表17。
表17
疼痛/炎症抑制剂的治疗和优选的浓度
药物种类 治疗浓度(
nM) 优选浓度(
nM)
ATP-敏感型K+ 通道开放剂:
色满卡林 10-10,000 100-10,000
尼可地尔 10-10,000 100-10,000
米诺地尔 10-10,000 100-10,000
P 1075 0.1-1,000 10-1,000
KRN 2391 1-10,000 100-1,000
(-)吡那地尔 1-10,000 100-1,000
15.
局部麻醉剂
优选将本发明的溶液在外科操作全过程中持续灌注应用以便预先抑制疼痛和炎症。临床将局部麻醉剂(如利多卡因、布比卡因等)用作止痛剂,并且已知其可逆地与神经轴的膜上的钠离子通道相结合,由此抑制轴索的传导和疼痛信号从末梢向脊髓传送。局部麻醉剂利多卡因的极低浓度或亚临床浓度的局部传递已显示可抑制神经损伤的放电(Bisla K和Tanalian DL,利多卡因在治愈角膜上皮损伤中的浓度依赖性效应,Invest Ophthalmol Vis Sci 33(11),3029-3033页,1992)。因此,局部麻醉剂除了减少疼痛信号外,当以极低浓度传递时,也有抗炎的特性。
在冲洗液中包含极低浓度或“亚麻醉”浓度的局部麻醉剂可提供有利的抗炎作用,而避免使患者暴露于与目前局部麻醉剂的临床使用剂量相关的全身毒性反应。因此,在极低浓度时,局部麻醉剂适合在本发明中应用。用于本发明实践的代表性局部麻醉剂的实例包括,但不限于,苯佐卡因、布比卡因、氯普鲁卡因、可卡因、etiodocaine、利多卡因、甲哌卡因、普莫卡因、丙胺卡因、普鲁卡因、丙美卡因、罗哌卡因、丁卡因、二丁卡因、QX-222、ZX-314、RAC-109、HS-37及其药学上的活性对映体。尽管不希望受任何特殊的理论的束缚,但某些局部麻醉剂被认为是通过抑制电压门控钠离子通道而起作用(参见Guo X等,“局部麻醉剂对电压门控阳离子通道的抑制的比较”,Ann.N.Y.Acad.Sci.625:181-199(1991))。局部麻醉剂的特别有用的药学上的活性对映体包括,例如,布比卡因的R-对映体。为了本发明的目的,局部传递的麻醉剂所用的浓度通常在约125到约100,000,000nM的范围内,更优选约1,000到约10,000,000nM,而最优选约225,000到约1,000,000nM。在一个实施方案中,本发明的溶液含有至少一个局部传递浓度不大于750,000nM的局部麻醉剂。在另一个实施方案中,本发明的溶液含有至少一个局部传递浓度不大于500,000nM的局部麻醉剂。下面所列是有代表性的特殊的局部麻醉剂的有用浓度。
表18
特殊的局部麻醉剂的治疗和优选的浓度
浓度(nM)
治疗浓度 优选浓度 更优选浓度
局部麻醉剂:
利多卡因 500-1,600,000 4,000-1,200,000 900,000-1,100,000
布比卡因 125-400,000 1,000-300,000 225,000-275,000
16.
α-2肾上腺素能受体激动剂
含有肾上腺素能胺受体家族的所有单独的9个受体属于与G-蛋白相关的受体超家族。所述肾上腺素能家族的分类(将其分为三个不同的亚家族,即α1(alpha-1)、α2(alpha-2)和β(beta)),是基于连接的数量、功能和对第二信使的研究。每一种肾上腺素能受体亚家族本身由三个同源的受体亚型组成,所述受体亚型通过重组受体的克隆和药理学特征而定义。在不同亚家族(α1对α2对β)的肾上腺素能受体间,在跨膜结构域中的氨基酸的同一性在36-73%范围内。然而,在同一亚家族成员(α1A对α1B)之间膜结构域间的同一性通常是70-80%。这些不同的受体亚型调节两种生理性激动剂,肾上腺素和去甲肾上腺素的作用。
不同的肾上腺素能受体类型与独特的G-蛋白组偶合并因此能够激活不同的信号转导效应器。α1、α2和β亚家族的分类不仅限定与信号转导机制相关的受体,而且引起它们对各种天然的和合成的肾上腺素胺的识别能力的不同。在这一点上,发展了很多选择性配体并应用它们来鉴定这些受体的每一型的药理学特性。α-1受体的功能性应答已在某些系统中表现出刺激磷脂酰肌醇更新和促进细胞内钙离子(通过Gq)的释放,同时α-2受体的刺激抑制了腺苷酰环化酶(通过Gi)。与此相反,β受体的功能性应答与腺苷酰环化酶活性的增加和细胞内钙离子的增加(通过Gs)结合在一起。
目前认可存在三种不同的α-1受体亚型,这三种亚型均表现出对拮抗剂哌唑嗪的高亲和性(亚纳摩尔)。α-1肾上腺素能受体再分成三个称为α1A、α1B和α1D的不同的亚型,主要是以大量的配体与内在的受体和克隆受体的结合的研究为基础的。所述克隆的受体的药理学特性导致原有分类的修订,原来被称为α1C的亚型相当于药理学上定义的α1A受体。α1A-D受体亚型被激动剂占据导致磷脂酶C的激活、刺激PI分解、产生作为第二信使的IP3和细胞内钙离子的增加。
已经在哺乳动物细胞内对三种不同的α-2受体亚型进行了克隆、测序和表达,它们分别称为α2A(α2-C10)、α2B(α2-C2)、α2C(α2-C4)。这些亚型不仅在它们的氨基酸组成上不同,而且其药理学模式和分布也不同。原先以啮齿类动物组织的放射性配体结合的研究为基础提出了一个另外的α2-受体亚型,α2D(基因rg20),但目前认为代表了一种与人α2A受体同源的种类。
所有三种α2A受体亚型的信号转导途径的功能性是相同的;每种都是通过Gi/o与腺苷酰环化酶负偶合。此外,也已报道α2A和α2B受体调节激活G-蛋白与钾离子通道(受体-开放)的偶合,同时抑制G-蛋白与钙离子通道的联系。
α-2肾上腺素能受体在药理学上被定义为对拮抗剂可立宁(Ki=0.5-25μM)、阿替美唑(Ki=0.5-2.5μM)和咪唑克生(Ki=21-35μM)的高亲和性,以及对α-1受体拮抗剂哌唑嗪的低亲和性。相对于α-1肾上腺素能受体类而言,对α-2肾上腺素能受体类更具选择性的激动剂是UK 14,304、BHT920和BHT933。羟甲唑啉与α2A-受体亚型高亲和性和高选择性地结合(KD=3μM),但是另外也与α-1肾上腺素能受体和5-HT1受体高亲和性地结合。一个额外的复杂的因素是α-2肾上腺素能受体的配体也与非肾上腺素能受体咪唑啉的结合位点高亲和性(nM)地结合,所述配体是咪唑啉(可乐定、咪唑克生)和其它(羟甲唑啉和UK 14304)。此外,α2A-肾上腺素能受体的药理学存在种群变异性。迄今为止,对其它特异性受体,亚型-选择性α-2肾上腺素能受体的配体仅表现出极小的选择性或无选择性,因此亚型选择性药物的治疗特性仍在开发研究中。
一个被认为α-2受体激动剂可能会有潜在作用的治疗领域是作为麻醉剂的附属药品,用于控制疼痛和阻断神经性炎症。组织损伤后刺激交感神经系统释放去甲肾上腺素,并因此影响伤害感受器的活性。α-2受体激动剂,如可乐定,可抑制去甲肾上腺素在神经纤维终端的释放并因此可能直接产生末梢部位的止痛(无需CNS的作用)。初级传入神经元从其中枢和末梢释放神经递质的能力使它们能发挥双重的、传递感觉的和“传出”或“局部效应器”的功能。所述术语“神经性炎症”被用于描述感觉神经的传出功能,该功能包括在“前馈”模式中与炎症过程有关的传递感觉的神经肽的释放。引起传递感觉的神经肽从感觉神经的末梢释放的药物,如辣椒素,可产生疼痛、炎症并可增加血管的渗透性,导致血浆外渗。阻断神经肽从感觉神经末梢释放的药物(P物质、CGRP)被预言具有止痛和抗炎的作用。这一作用的机制已在其它显示末梢止痛和抗炎作用的药物,如舒马曲坦和吗啡中确立,所述两种药物分别作用在5-HT1和μ-类阿片受体上。这两种药物均是激活受体的激动剂,它们与α-2受体共享信号转导的共有机制。UK14304,象舒马曲坦一样,通过在α-2受体上的预先结合作用,在硬脑(脊)膜中已表现出阻断血浆外渗的作用。
在膝关节内窥镜手术结束后,关节内注射所述药物的效果研究中获得了支持可乐定末梢止痛作用的证据((Gentili,M等(1996)Pain 64:593-596))。可乐定被认为显示了非鸦片制剂的抗-感受伤害的性质,这将可能允许其作为手术后止痛剂的替换品应用。在已进行的评估手术后期间静脉内给予可乐定的止痛效果的研究中,发现可乐定可延迟疼痛的发生并减少疼痛得分。因此,大量研究已证实作用于α-2肾上腺素能受体上的药物可发挥手术中和手术后的止痛作用,表明这些受体是新药物治疗疼痛的良好的治疗靶子。
从作用的分子和细胞的机制来定义α-2受体激动剂,如UK14304,当手术中将冲洗液直接应用到组织时,期望这些化合物在初级传入神经的末梢显示出抗-感受伤害的作用。
α-2受体激动剂适用于本发明中,既可作为单独的药物传递也可与其它抗疼痛和/或抗炎药物联合传递,以抑制疼痛和炎症。用于本发明的实践的代表性的α-2受体激动剂包括,例如:可乐定;右美托咪定;羟甲唑啉;((R)-(-)-3’-(2-氨基-1-羟乙基)-4’-氟-甲磺酰基苯胺(methanesulfoanilide)(NS-49);2-[(5-甲基苯并-1-噁-4-嗪-6-基)亚氨基]咪唑啉(AGN-193080);AGN 191103和AGN 192172,如Munk.S等描述(J.Med.Chem.39:3533-3538(1996));5-溴-N-(4,5-二氢-1H-咪唑-2-基)-6-喹喔啉胺(UK14304);5,6,7,8-四氢-6-(2-丙烯基)-4H-噻唑[4,5-d]氮杂-2-胺(BHT 920);6-乙基-5,6,7,8-四氢-4H-氧杂吡咯并(oxaazolo)[4,5-d]氮杂-2-胺(BHT933),5,6-二羟基-1,2,3,4-四氢-1-萘基-咪唑啉(A-54741)。
表19
α-2肾上腺素能受体激动剂的治疗和优选的浓度
化合物
可接受的治疗
有效的治疗浓
优选浓度
最优选浓
浓度(nM)
度(nM)
(nM)
度(nM)
可乐定 0.002-200,000 0.01-50,000 0.1-10,000 10-2,000
右美托咪定 0.002-200,000 0.01-50,000 0.1-10,000 10-2,000
UK 14303 0.002-200,000 0.01-50,000 0.1-10,000 10-2,000
羟甲唑啉 0.001-100,000 0.01-25,000 0.05-15,000 5-10,000
NS-49 0.002-200,000 0.01-50,000 0.1-10,000 0-2,000
AGN192172 0.005-100,000 0.1-25,000 1-5,000 10-1,000
AGN193080 0.005-100,000 0.1-25,000 1-5,000 10-1,000
AGN191103 0.002-200,000 0.1-25,000 1-5,000 10-1,000
A-54741 0.002-200,000 0.1-50,000 1-10,000 10-2.000
BHT920 0.003-200,000 0.3-50,000 3-30,000 30-5,000
BHT933 0.003-200,000 0.3-50,000 3-30,000 30-5,000
F.
多功能的药物
在本发明的另一个方面,考虑显示出多于一种上述功能类型的效应的具体药物,来选择包含在眼科冲洗液中的优选药物。前面描述的α-2肾上腺素能受体激动剂提供了这一实例,因为它们可以发挥降IOP药和抑制炎症和疼痛的药物的双重功能。例如,羟甲唑啉通过抑制传递感觉的神经递质的释放来抑制眼睛的炎症(Fuder H.,J.Ocul.Pharmacol.,10:109-123(1994))。羟甲唑啉也可象散瞳药一样通过在α-1肾上腺素能受体上的兴奋作用发挥功能,并也可通过在α-2肾上腺素能受体上的兴奋作用降低IOP(Chu T.等,Pharmacology,53:259-270(1996))。除了抗炎效应外,NSAIDs也适用于抑制手术中的瞳孔缩小,因此具有扩散瞳孔的性质。当这种多功能的药物与其它可提供至少一种未由所述多功能药物提供的额外的眼科功能的一种或多种药物结合时,所述药物可适合于在本发明的眼科冲洗液中应用。
除了选择多功能的药物,避免这些局部应用的药物的毒性副作用也是重要的。局部应用的一个优点是显著地减少了全身的副作用。然而,必须考虑到这些药物的局部作用,例如用高浓度的局部麻醉剂或甾族化合物可降低伤口的愈合。因此,优选可有效地抑制神经元的放电同时避免伤口愈合问题的低浓度的局部麻醉剂在本发明中应用(Bisla K,等,Invest Ophthalmol.Vis.Sci.33:3029-3033(1992))。由于已经证实NSAIDs控制眼科手术后的炎症中象甾族化合物一样有效(Dadeya S.等,J.Pediatr.Ophthalmol.Strabismus.,39:166-168(2002)),因此优选NSAIDs以避免甾族化合物的潜在的非特异性的有害作用。
根据不同的眼科手术操作的特殊需要,包括两种或多种药物的本发明的多种合适的冲洗液可依照本发明配制,但每一种溶液可不包括从所有已经命名的功能性种类中取出的药物(例如止痛剂、抗炎药、散瞳药和降IOP药)。例如,一种依照本公开配制的用于白内障手术的冲洗液可以不需要止痛剂,因为这个过程不象玻璃体切除术那样痛。
G.
冲洗载体
本发明的活性药物在生理性液体冲洗载体中是可溶的。所述载体适合为可含有生理性电解质的水性溶液,如生理盐水或乳酸盐林格氏液。更优选所述载体包括一种或多种佐剂,并优选所有下述佐剂:足够的电解质以提供生理性平衡盐溶液;细胞的能源;缓冲剂和自由基清除剂。一种合适的溶液(下面的实施例中称为”优选的平衡盐溶液”)包括:从50到500mM的钠离子、从0.1到50mM的钾离子、从0.1到5mM的钙离子、从0.1到5mM的镁离子、从50到500mM的氯离子以及从0.1到10mM的磷酸盐的电解质;浓度在从10到50mM的碳酸氢盐缓冲液;选自右旋糖和葡萄糖的细胞的能源,浓度为1到25mM;和浓度在从0.05到5mM的作为自由基清除剂(例如,抗氧化剂)的谷胱甘肽。当将所述冲洗液的pH控制在5.5和8.0之间是合适的,优选pH为7.4。
V.
应用方法
本发明的溶液已经在多种手术/干预性操作,包括手术、诊断和治疗技术中应用。在眼科手术中的围手术期应用所述冲洗液。如上述定义的,所述术语“围手术期的”包括操作中的应用、操作前和操作中的应用、操作中和操作后的应用、以及操作前、操作中和操作后的应用。优选地,在操作前和/或操作后以及在操作中应用所述溶液。最优选在操作开始之前,优选在明显的组织创伤之前在伤口或外科手术部位应用所述冲洗液,并且在操作期间或大部分时间持续不断应用冲洗液,以优先阻断疼痛和炎症,抑制眼内压增高,和/或引起散瞳。如前面定义的,本发明的冲洗液的持续应用可以实行不中断的应用,或频繁地重复和频繁地冲洗伤口或操作部位,以充分地维持所用药物预定的局部治疗浓度,或者由于手术技术的需要,应用中冲洗液流可能有间歇的中断。在操作结束时,可增加所述治疗药物的额外的量,例如眼内注射含有同样或较高浓度活性药物的冲洗液的额外的量,或通过眼内注射或局部应用在粘弹性凝胶中的所述药物。
在不存在代谢转换时,所列的本发明的溶液中的每一种药物的浓度是所述药物局部传递到所述手术部位的浓度,以在手术部位达到预定的有效水平。由于在操作中所述药物局部应用直接到达所述手术部位,因此这种溶液应用了这些疼痛和炎症抑制剂的极低的剂量。
在本发明的每种外科溶液中包含于低浓度的所述药物,并以相对于采用全身给药方法以在所述操作部位达到期望的治疗效果所需的浓度和剂量要低的剂量局部传递。
VI.
实施例
下述是依照本发明的适合于眼科操作的示例性制剂。
实施例1
表20、21和22中描述了用于白内障摘除术期间的本发明的示例性的眼科溶液。这种溶液,以及下述表23-25的溶液,仅通过举例的方法提供,并不打算限制本发明。相信本发明的溶液的抗炎作用对白内障特别有用,可有效地减少术后囊状斑点水肿(CME)的发生,或促进囊状斑点水肿的消解。这些示例性的溶液和本文下述的其它示例性的眼科冲洗液根据包含在前述的优选平衡盐溶液中的每种药物的浓度提供。通过非限制性实施例,所述溶液可适合以500ml袋装供应,这是在操作中应用冲洗液的典型用量。
表20
示例性白内障溶液
药物种类 药物 浓度(Nm)
治疗浓度
优选浓度
最优选浓度
抗炎药 氟比洛芬 10-1,000,000 100-100,000 1,000-10,000
降I0P药 噻吗洛尔 10-1,000,000 100-100,000 1,000-10,000
散瞳药 去氧肾上腺素 50-500,000 500-100,00 1,000-10,000
表21
可替代的示例性白内障溶液
药物种类 药物 浓度(Nm)
治疗浓度
优选浓度
最优选浓度
抗炎药 酮洛芬 10-1,000,000 100-100,000 1,000-10,000
降IOP药 噻吗洛尔 10-1,000,000 100-100,000 1,000-10,000
散瞳药 托吡卡胺 10-1,000,000 100-100,000 1,000-10,000
表22
可替代的示例性白内障溶液
药物种类 药物 浓度(Nm)
治疗浓度
优选浓度
最优选浓度
散瞳药、降IOP药 羟甲唑啉 10-1,000,000 100-100,000 1,000-10,000
抗炎药 氟比洛芬 10-1,000,000 100-100,000 1,000-10,000
实施例2
表23提供了含有可有效减少炎症和可为侵入性眼科手术,如滤帘切除术提供散瞳的多种药物的相似的冲洗液。
表23
示例性的滤帘切除术溶液
药物种类 药物 浓度(Nm)
治疗浓度
优选浓度
最优选浓度
抗炎药 泼尼松龙 10-1,000,000 100-100,000 1,000-10,000
抗炎药 氟比洛芬 10-1,000,000 100-100,000 1,000-10,000
降IOP药 噻吗洛尔 10-1,000,000 100-100,000 1,000-10,000
散瞳药 去氧肾上腺素 50-500,000 500-100,000 1,000-10,000
实施例3
适合于广泛的眼科手术或眼后室操作,例如玻璃体切除术中应用的冲洗液,通过加入局部麻醉剂而提供增加的止痛作用。表24和25提供了本发明的这种含有局部麻醉剂的溶液。
表24
示例性局部麻醉的眼科溶液
药物种类 | 药物 | 浓度(Nm) | ||
治疗浓度 | 优选浓度 | 最优选浓度 | ||
降IOP药 | 噻吗洛尔 | 10-1,000,000 | 100-100,000 | 1,000-10,000 |
抗炎药 | 氟比洛芬 | 10-1,000,000 | 100-100,000 | 1,000-10,000 |
散瞳药 | 托吡卡胺 | 10-1,000,000 | 100-100,000 | 1,000-10,000 |
止痛药 | 利多卡因 | 1,000-100,000,000 | 10,000-10,000,000 | 100,000-1,000,000 |
表25
可替代的示例性局部麻醉的眼科溶液
药物种类 | 药物 | 浓度(Nm) | ||
治疗浓度 | 优选浓度 | 最优选浓度 | ||
降IOP药 | 噻吗洛尔 | 10-1,000,000 | 100-100,000 | 1,000-10,000 |
抗炎药 | 氟比洛芬 | 10-1,000,000 | 100-100,000 | 1,000-10,000 |
散瞳药 | 托吡卡胺 | 10-1,000,000 | 100-100,000 | 1,000-10,000 |
止痛药 | 布比卡因 | 125-400,000 | 1,000-300,000 | 225,000-275,000 |
当本发明的优选实施方案已经被举例说明和描述后,在不背离本发明的精神和范围下,应该理解可对公开的溶液和方法进行各种改变。例如,可能会发现可替代的疼痛抑制剂、炎症抑制剂、降IOP药和散瞳药,这可以增加或代替依照本文公开所包含的药物。因此打算由此授予的本专利的范围只受附加的权利要求书的定义的限制。
Claims (39)
1.一种在眼科手术中用于在围手术期抑制炎症、抑制疼痛、有效散瞳和/或降低眼内压的方法,该方法包括在眼科操作中用在液体冲洗载体中含有至少第一种和第二种药物的溶液持续冲洗眼组织,所选择的第一种和第二种药物作用于多种不同的分子靶,每种药物选自多种生理功能类别的抗炎药、止痛剂、散瞳药和降低眼内压的药物(降“IOP”药),所述第二种药物提供至少一种不同于由第一种药物提供的一种或多种功能的生理功能。
2.权利要求1的方法,其中所述溶液含有选自甾族化合物、非甾体抗炎药(NSAIDS)、抗组胺药、肥大细胞抑制剂和诱导型一氧化氮合酶抑制剂(iNOS)的抗炎药。
3.权利要求2的方法,其中:如果选择甾族化合物,则它选自地塞米松、氟米龙和泼尼松龙;如果选择NSAID,它选自氟比洛芬、舒洛芬、双氯芬酸、酮洛芬和酮咯酸;如果选择抗组胺药,它选自左卡巴斯汀、依美斯汀、奥洛他定、酮替芬和氮斯汀;如果选择肥大细胞抑制剂,它选自色甘酸二钠、洛度沙胺、奈多罗米、酮替芬和氮斯汀;而如果选择iNOS的抑制剂,它选自NG-一甲基-L-精氨酸、1400W、二亚苯基碘鎓、S-甲基异硫脲、S-(氨基乙基)异硫脲、L-N6-(1-亚氨基乙基)赖氨酸、1,3-PBITU和2-乙基-2-硫假脲。
4.权利要求1的方法,其中所述溶液含有选自局部麻醉剂和类阿片的止痛剂。
5.权利要求4的方法,其中:如果选择局部麻醉剂,则它选自利多卡因、丁卡因、布比卡因和丙美卡因;如果选择类阿片,它选自吗啡、芬太尼和氢吗啡酮。
6.权利要求1的方法,其中所述溶液含有选自α-1肾上腺素能受体激动剂和抗胆碱能药的散瞳药。
7.权利要求6的方法,其中:如果选择α-1肾上腺素能受体激动剂,则它选自去氧肾上腺素、肾上腺素和羟甲唑啉;而如果选择抗胆碱能药,它选自托吡卡胺、环戊通、阿托品和后马托品。
8.权利要求1的方法,其中所述溶液含有选自β肾上腺素能受体拮抗剂、碳酸酐酶抑制剂、α-2肾上腺素能受体激动剂和前列腺素激动剂的降IOP药。
9.权利要求8的方法,其中:如果选择β肾上腺素能受体拮抗剂,则它选自噻吗洛尔、美替洛尔和左布诺洛尔;如果选择碳酸酐酶抑制剂,它选自布林唑胺和多佐胺;如果选择α-2肾上腺素能受体激动剂,它选自阿可乐定、溴莫尼定和羟甲唑啉;如果选择前列腺素激动剂,它选自拉坦前列素、曲伏前列素和比马前列素。
10.权利要求1的方法,其中所述溶液中包含的第一种和第二种药物的每一种的浓度不大于100,000nM。
11.权利要求1的方法,其中所述溶液中包含的第一种和第二种药物的每一种的浓度不大于10,000nM。
12.权利要求1的方法,其中所述液体冲洗载体还含有佐剂,所述佐剂选自足以提供生理平衡的盐溶液的电解质、细胞能源、缓冲剂、自由基清除剂及其混合物。
13.权利要求1的方法,其中所述液体冲洗载体还含有足以提供生理平衡的盐溶液的电解质、细胞能源、缓冲剂和自由基清除剂。
14.权利要求12或13的方法,其中:如果选择电解质,它含有50到500mM的钠离子、0.1到50mM的钾离子、0.1到5mM的钙离子、0.1到5mM的镁离子、50到500mM的氯离子以及0.1到10mM的磷酸盐;如果选择缓冲剂,它含有浓度在10到50mM的碳酸氢盐;如果选择细胞能源,它选自右旋糖和葡萄糖且其存在的浓度在1到25mM;而如果选择自由基清除剂,它含有浓度在0.05到5mM的谷胱甘肽。
15.权利要求1的方法,其中所述第一种和第二种药物包括:(a)一种或多种抗炎药联合一种或多种止痛药,并且还可任选包括一种或多种降IOP药和/或散瞳药;(b)一种或多种抗炎药联合一种或多种降IOP药,以及任选一种或多种止痛药和/或散瞳药;(c)一种或多种抗炎药联合一种或多种散瞳药,以及任选一种或多种止痛药和/或降IOP药;(d)一种或多种止痛药联合一种或多种降IOP药,以及任选一种或多种抗炎药和/或散瞳药;(e)一种或多种止痛药联合一种或多种散瞳药,以及任选一种或多种抗炎药和/或降IOP药;或者(f)一种或多种散瞳药联合一种或多种降IOP药,以及任选一种或多种抗炎药和/或止痛药。
16.权利要求1的溶液,其中所述溶液含有NSAID、噻吗洛尔和去氧肾上腺素。
17.权利要求1的溶液,其中所述溶液含有NSAID、噻吗洛尔和托吡卡胺。
18.权利要求1的溶液,其中所述溶液含有羟甲唑啉和NSAID。
19.权利要求1的溶液,其中所述溶液含有甾族化合物、NSAID、噻吗洛尔和去氧肾上腺素。
20.权利要求1的溶液,其中所述溶液含有噻吗洛尔、NSAID、托吡卡胺和局部麻醉剂。
21.一种用于在眼科操作中抑制炎症、抑制疼痛、有效散瞳和/或在操作期间降低眼内压的围手术期的冲洗液,它包括在液体冲洗载体中的至少第一种和第二种药物,所选择的第一种和第二种药物在多个不同的分子靶上发挥作用,每种药物从抗炎药、止痛剂、散瞳药和降低眼内压的药物(降“IOP”药)的生理功能类别中选择,所述第二种药物提供至少一种不同于由第一种药物提供的一种或多种功能的生理功能,每一种药物包含的浓度不大于100,000nM。
22.权利要求21的溶液,其中所述溶液含有选自以下的抗炎药:甾族化合物、非甾体抗炎药(NSAIDS)、抗组胺药、肥大细胞抑制剂和诱导型一氧化氮合酶抑制剂(iNOS)。
23.权利要求22的溶液,其中:如果选择甾族化合物,则它选自地塞米松、氟米龙和泼尼松龙;如果选择NSAID,它选自氟比洛芬、舒洛芬、双氯芬酸、酮洛芬和酮咯酸;如果选择抗组胺药,它选自左卡巴斯汀、依美斯汀、奥洛他定、酮替芬和氮斯汀;如果选择肥大细胞抑制剂,它选自色甘酸二钠、洛度沙胺、奈多罗米、酮替芬和氮斯汀;而如果选择iNOS的抑制剂,它选自NG-一甲基-L-精氨酸、1400W、二亚苯基碘鎓、S-甲基异硫脲、S-(氨基乙基)异硫脲、L-N6-(1-亚氨基乙基)赖氨酸、1,3-PBITU和2-乙基-2-硫假脲。
24.权利要求21的溶液,其中所述溶液含有选自局部麻醉剂和类阿片的止痛剂。
25.权利要求24的溶液,其中:如果选择局部麻醉剂,则它选自利多卡因、丁卡因、布比卡因和丙美卡因;如果选择类阿片,它选自吗啡、芬太尼和氢吗啡酮。
26.权利要求21的溶液,其中所述溶液含有选自α-1肾上腺素能受体激动剂和抗胆碱能药的散瞳药。
27.权利要求26的溶液,其中:如果选择α-1肾上腺素能受体激动剂,则它选自去氧肾上腺素、肾上腺素和羟甲唑啉;如果选择抗胆碱能药,它选自托吡卡胺、环戊通、阿托品和后马托品。
28.权利要求21的溶液,其中所述溶液含有选自以下的降IOP药:β肾上腺素能受体拮抗剂、碳酸酐酶抑制剂、α-2肾上腺素能受体激动剂和前列腺素激动剂。
29.权利要求28的溶液,其中:如果选择β肾上腺素能受体拮抗剂,则它选自噻吗洛尔、美替洛尔和左布诺洛尔;如果选择碳酸酐酶抑制剂,它选自布林唑胺和多佐胺;如果选择α-2肾上腺素能受体激动剂,它选自阿可乐定、溴莫尼定和羟甲唑啉;而如果选择前列腺素激动剂,它选自拉坦前列素、曲伏前列素和比马前列素。
30.权利要求21的溶液,其中所述溶液包含的第一种和第二种药物中的每一种的浓度不大于10,000nM。
31.权利要求21的溶液,其中所述液体冲洗载体还含有佐剂,所述佐剂选自足以提供生理平衡的盐溶液的电解质、细胞能源、缓冲剂、自由基清除剂及其混合物。
32.权利要求21的溶液,其中所述液体冲洗载体还含有足以提供生理平衡的盐溶液的电解质、细胞能源、缓冲剂和自由基清除剂。
33.权利要求31或32的溶液,其中:如果选择电解质,它含有50到500mM钠离子、0.1到50mM的钾离子、0.1到5mM的钙离子、0.1到5mM的镁离子、50到500mM的氯离子以及0.1到10mM的磷酸盐;如果选择缓冲剂,它含有浓度在10到50mM的碳酸氢盐;如果选择细胞能源,它选自右旋糖和葡萄糖且其存在的浓度在1到25mM;而如果选择自由基清除剂,它含有浓度在0.05到5mM的谷胱甘肽。
34.权利要求21的溶液,其中所述第一种和第二种药物包括:(a)一种或多种抗炎药联合一种或多种止痛药,并且还可任选包括一种或多种降IOP药和/或散瞳药;(b)一种或多种抗炎药联合一种或多种降IOP药,以及任选一种或多种止痛药和/或散瞳药;(c)一种或多种抗炎药联合一种或多种散瞳药,以及任选一种或多种止痛药和/或降IOP药;(d)一种或多种止痛药联合一种或多种降IOP药,以及任选一种或多种抗炎药和/或散瞳药;(e)一种或多种止痛药联合一种或多种散瞳药,以及任选一种或多种抗炎药和/或降IOP药;或者(f)一种或多种散瞳药联合一种或多种降IOP药,并且任选一种或多种抗炎药和/或止痛药。
35.权利要求21的溶液,其中所述溶液含有NSAID、噻吗洛尔和去氧肾上腺素。
36.权利要求21的溶液,其中所述溶液含有NSAID、噻吗洛尔和托吡卡胺。
37.权利要求21的溶液,其中所述溶液含有羟甲唑啉和NSAID。
38.权利要求21的溶液,其中所述溶液含有甾族化合物、NSAID、噻吗洛尔和去氧肾上腺素。
39.权利要求21的溶液,其中所述溶液含有噻吗洛尔、NSAID托吡卡胺和局部麻醉剂。
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CN1684701A true CN1684701A (zh) | 2005-10-19 |
CN1684701B CN1684701B (zh) | 2012-10-17 |
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CNA2008101376172A Pending CN101327325A (zh) | 2002-07-30 | 2003-07-30 | 眼科冲洗液及方法 |
CN2012103206331A Pending CN103143022A (zh) | 2002-07-30 | 2003-07-30 | 眼科冲洗液及方法 |
CN038233452A Expired - Lifetime CN1684701B (zh) | 2002-07-30 | 2003-07-30 | 眼科冲洗液及方法 |
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CN2012103206331A Pending CN103143022A (zh) | 2002-07-30 | 2003-07-30 | 眼科冲洗液及方法 |
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US (10) | US20040072809A1 (zh) |
EP (1) | EP1534313B1 (zh) |
JP (11) | JP2006504661A (zh) |
CN (3) | CN101327325A (zh) |
AU (2) | AU2003261304A1 (zh) |
BE (1) | BE2015C078I2 (zh) |
CA (2) | CA2493581C (zh) |
CY (1) | CY2015055I1 (zh) |
DK (1) | DK1534313T3 (zh) |
ES (1) | ES2397574T3 (zh) |
FR (1) | FR15C0090I2 (zh) |
HK (1) | HK1081455A1 (zh) |
HU (1) | HUS1500069I1 (zh) |
LU (1) | LU92923I2 (zh) |
NL (1) | NL300784I2 (zh) |
PT (1) | PT1534313E (zh) |
SI (1) | SI1534313T1 (zh) |
WO (1) | WO2004010894A2 (zh) |
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- 2003-07-30 CN CN2012103206331A patent/CN103143022A/zh active Pending
- 2003-07-30 DK DK03772122.2T patent/DK1534313T3/da active
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2006
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2009
- 2009-12-11 AU AU2009248461A patent/AU2009248461B2/en not_active Expired
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2010
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2012
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101347620B (zh) * | 2007-07-20 | 2012-04-25 | 天津药业研究院有限公司 | 一种药物组合物及其在制备治疗青光眼的药物中的应用 |
CN105555363A (zh) * | 2013-05-06 | 2016-05-04 | 长庚医疗财团法人高雄长庚纪念医院 | 医药组成物及其用途 |
CN105555363B (zh) * | 2013-05-06 | 2019-03-12 | 长庚医疗财团法人高雄长庚纪念医院 | 医药组成物及其用途 |
CN105213418A (zh) * | 2015-11-11 | 2016-01-06 | 中国人民解放军第四军医大学 | 一种眼科术前用复方滴眼液及其制备方法 |
CN105213418B (zh) * | 2015-11-11 | 2019-01-22 | 中国人民解放军第四军医大学 | 一种眼科术前用复方滴眼液及其制备方法 |
CN107137713A (zh) * | 2017-05-12 | 2017-09-08 | 浙江工贸职业技术学院 | 一种眼科手术后用冲洗液及其制备方法 |
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