CN101163481A - 改进的加环利定制剂 - Google Patents
改进的加环利定制剂 Download PDFInfo
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- CN101163481A CN101163481A CNA2006800137968A CN200680013796A CN101163481A CN 101163481 A CN101163481 A CN 101163481A CN A2006800137968 A CNA2006800137968 A CN A2006800137968A CN 200680013796 A CN200680013796 A CN 200680013796A CN 101163481 A CN101163481 A CN 101163481A
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- gacyclidine
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Abstract
用于直接给药至内耳或中耳的加环利定的改进的制剂。
Description
本申请要求2005年3月4日申请的系列号60/658,207的利益。将系列号60/658,207在此全部引入作为参考。
发明领域
本发明涉及用于治疗中耳和内耳疾病的加环利定及其它治疗剂的改进的制剂。
发明背景
许多治疗剂当系统给药(即经口服、静脉或肌内注射)时具有副作用,其阻止了以最佳剂量递送。这是因为其他身体和神经系统细胞与循环的足量治疗剂接触,而由于在别处的全身性副作用,靶细胞不能接受最佳剂量。当对组织特异性药物递送正确制剂时,如此递送的有效治疗剂将具有最小的副作用,且仍然对靶向神经组织有效。
如目前理解,耳呜通常为多种神经障碍的一个症状,包括牙齿或面神经的损伤,颞下颌关节(TMJ)疾病、对气味、味道和接触的过敏和听觉皮层或下丘的损伤。耳鸣还通常伴有这些基础神经系统疾病障碍的其它表现,如梅尼尔(氏)病、疼痛、焦虑、抑郁和偏头痛。因而,期望治疗其中基础神经障碍存在的准确位点,其不限于,但可以包括耳蜗、听神经、牙齿或面神经及中枢神经系统的听觉皮层或下丘。当没有外部声音时,患者感觉到耳鸣,像是体内的声音。临床上,期望的治疗为抑制对不适当的声音的知觉而没有妨碍工作和日常生活中正常功能的副作用。
因此,所需的适宜治疗将需要给予有效的CNS活性药物,以减轻相关神经不适当的簇发,所述神经将声音知觉报告到听觉皮层。给予有效的CNS活性药物用于治疗中耳和内耳疾病,如耳呜,所述CNS活性药物用于减轻特定神经组织的自发和可能是强直的簇发,而不损伤其它主要功能,如听觉或平衡。因为这些药物对整个神经系统的一般活性,当系统给药时,其具有特定的限制。为了克服这些全身性副作用和得到改善的治疗结果,同时使副作用最小化,期望的是将所述药物给予至耳呜起源的部位,如中耳或内耳。直接给药至中耳或内耳使医疗提供者最佳化治疗程序,以避免或最小化了组织损伤和副作用。由不当的剂量配药引起的该器官中的组织损伤的结果对听觉和平衡很重要,并且所述损伤可包括对有关毛细胞或神经、螺旋神经节或迷路系统有关的听力的不可逆地损伤。在某些情况下,给药到内耳或耳蜗的化合物可进入脑脊液(CSF)中,如果有效的CNS活性剂到达CSF,其可能具有不希望的副作用,因为它作用于不是其靶点的神经细胞。因此,对脑和脊髓有非故意的作用。任何对这些细胞和组织的破坏都将导致对重要的感官如听觉的严重后果。而且,除了期望递送药物穿过圆窗外,递送到中耳的化合物也可被部分地吸收到暴露的脉管系统中并进入体循环或通过沿咽鼓管向下被口腔、咽喉、胃或胃肠道吸收。
因此,为了达到期望的结果而没有不希望的副作用,给药方法、部位、装置和制剂都很重要。因此,本领域一直需要治疗剂的改进制剂,所述治疗剂是用于递送至中耳或内耳或其他需要治疗的特定部位而特别设计的。本发明满足了这一需要。
附图简述
图1.图像表示在玻璃小瓶中在室温下加环利定的溶液浓度的降低与pH的函数和通过选择的辅料使溶液浓度增加。
图2.图像表示在37℃下加环利定对聚丙烯小瓶的吸附与pH的函数和选择的辅料(存在1mM的总加环利定;过量)的调节效应。
图3.图像表示在聚丙烯小瓶中25μM的加环利定的损失与pH的函数,有和没有SOLUTOL(没有过量的加环利定)。
图4.图像表示在54℃或56℃下,加环利定碱形式的化学稳定性和其酸形式的化学不稳定性。
图5.图像表示在较低温度下加环利定酸形式(pH2)的化学稳定性增加。注意:分解速率的出人意外地巨大温度依赖性。
图6.图像表示在37℃下,在乳酸化林格溶液中,加环利定的分解在pH7.4比在pH5.5或6.0慢。
图7.图像表示在55℃,在林格溶液中,加环利定的溶液浓度随着pH在7.3至8.1之间增加而降低,并且在较高的pH下哌啶的生成减少。
图8.图像表示在pH 6.7至7.2之间,在55℃和在林格溶液中,0.3%的聚山梨酯80增加加环利定的溶液浓度和加环利定的化学稳定性。
图9.图像表示在林格溶液中,在55℃下,随着pH在6.7至7.2之间增加,加入的0.3%的聚山梨酯80降低加环利定分解速率。
发明详述
本发明提供加环利定和其它适于给药至中耳和内耳的药物的制剂。这些制剂可用于治疗疾病比如耳鸣、梅尼尔(氏)病、眩晕、中耳炎和内耳炎症和感染、噪音或某些类型的创伤导致的听力丧失、及物理(例如外科手术)或化学创伤引起的神经学损伤。
定义:
(a)如本文使用的“载体分子(carrier molecule)”为有助于将活性剂保留在溶液或混悬液中的分子。表面活性剂(其与水不溶性或微溶性分子形成络合物并使所述络合物溶于水的两亲性分子)为一类载体分子。
(b)“溶解促进剂”增加加环利定在液体制剂中的溶解度。溶解促进剂包括载体分子,特别是表面活性剂和有机溶剂。
(c)如本文使用的“溶解性”为化合物溶解到溶液中或用溶解促进剂将其保留在溶液中的性质。
(d)如本文使用的“溶液浓度”为存在于液体制剂中随机选择的等分部分的每单位体积加环利定的浓度。
(e)如本文使用的“化学稳定性”指基本上不存在加环利定分解,所述分解通过哌啶形成测定。如果加环利定在37℃下在4天内分解成哌啶使其初始加环利定溶液浓度损失10%或更少,那么加环利定制剂增加了化学稳定性。
(f)如本文使用的“辅料(excipient)”为加入制剂的添加剂,其有助于使所述制剂成为药学可接受的。辅料包括提供适当的粘度的共溶剂(比如醇、二醇、DMSO、二甲基乙酰胺)、矿物、抗菌剂等。也可使用包括表面活性剂的载体分子作为辅料。
加环利定(1-(2-甲基-1-噻吩-2-基-环己基)-哌啶盐酸盐;GK11)为众所周知的化合物。加环利定的盐酸盐的化学结构显示如下:
如本文使用的“加环利定”包括加环利定的酸加成盐(acid salt)和碱形式及光学异构体和几何异构体。“加环利定衍生物”具有较小的修饰而没有改变其母核骨架,如乙酸盐衍生物或将甲基加到氮上。“加环利定类似物”改变了其母核骨架,如碳取代环上的硫或氮。参见Geneste等人,Eur.J.Med.14,301-08,1979)。在此描述的制剂发明将增加包含噻吩-2-基环的加环利定衍生物和类似物。
加环利定的酸和碱形式可以根据美国专利6,107,495制备。加环利定的酸形式的氯化物盐极易溶于水或无缓冲的生理学可接受的溶液如林格溶液,且将形成包含至多150mg/ml的氯化物盐,pH约为4.4。游离碱形式的加环利定微溶于水,并粘附塑料表面。在生理学pH向溶液中加入过量的加环利定游离碱导致溶解的加环利定终浓度≤0.02mg/ml,且pH≤7.7,加环利定在林格溶液中的游离碱形式将与溶解的二氧化碳反应,生成溶解的加环利定的酸形式,且在pH 7.6,得到浓度约为0.02mg/ml的加环利定。通过HPLC测定在pH 9.5(0.05M的CAPSO缓冲剂;0.1M的NaCl;加入0.3mg/ml加环利定)下,在室温放置2天后,0.0006mg/ml的加环利定保留在溶液中。
用于注射到内耳或中耳的药物一般在生理学相容的溶液和pH中配制。然而,在生理学pH(例如6.8-7.4)和在生理学pH下的各种缓冲液中,加环利定部分为可溶性盐形式,且部分为不带电的游离碱形式,其微溶于水性溶剂。因此,当在生理学pH的水溶液中配制时,加环利定形成能溶解的微聚集体,其最终吸附到容器中,和/或融合成大的聚集体并从溶液中沉淀出。在制备所述制剂期间,微聚集体可以从溶液中过滤、离心出,或者可粘附到包含该制剂的容器或注射装置的壁上。在这些条件下,递送的药物量将既不是期望的量也不是用于递送的制剂量。这样的制剂的制备将是不可靠的,其使在每次制备进行中药物在制剂中的浓度不同,且将必然导致功效降低。而且,当温变增加时,所述药物变得更难溶。当温度增加时,pKa的改变引起酸碱平衡向碱形式移动。
本发明的实施方案提供了解决该问题的几种溶液。在某些实施方案中,用选择的溶解促进剂(例如载体分子(包括表面活性剂)和某些有机溶剂)配制加环利定以通过将所述游离碱形式保留在溶液/清澈的混悬液中来增加化学稳定性和表观溶解度。在其它实施方案中,将加环利定制剂成冻干粉末,用特定的赋形剂(vehicle)重构以确保快速溶解和正确的溶液浓度、可滤性和化学稳定性。在其它实施方案中,将加环利定制剂成游离碱固体(具有用于植入的特定形状,如块状、球状或丸状颗粒),其缓慢地溶解进入生理性液体或缓冲液中以提供治疗剂量。如本文描述制剂的加环利定可以单独给药或与如下所述的一种或多种另外的治疗剂组合给药。使用本发明的制剂,可以在生理学可接受的pH下,将期望剂量的加环利定直接递送到靶组织(例如耳蜗)。
包括溶解促进剂的加环利定酸性和碱性制剂
可以在加入酸(例如盐酸)或碱(例如碳酸氢钠或氢氧化钠)来达到期望范围pH的赋形剂中以其酸或碱形式(或二者混和物)配制加环利定。然而,酸性加环利定水性制剂的显著的和意想不到的问题是所述化合物的热化学不稳定性。在溶液中,加环利定以一比一的比例分解成包括哌啶的多种产物。包含在酸性加环利定制剂(即pH<7.0)中载体分子的,一般以0.1%至10%的浓度,出乎意料地引起溶解度增加(增加了溶液浓度)和化学稳定性增加(参见实施例6)。
用碱性制剂的显著的问题是碱性形式加环利定的在想要递送溶液的各种生理学可接受的赋形剂中的不溶性。也在本文中,包含在碱性加环利定制剂(pH>7)中的载体分子,一般以0.1%至10%的浓度,引起加环利定的溶解度增加,防止了加环利定从溶液中沉淀,减少了加环利定在容器壁上的吸附,且增加了加环利定的化学稳定性。
最佳制剂包括一种或多种溶解促进剂。可使用如在实施例3中描述的常规方法,确定任意包括在加环利定制剂中的具体溶解促进剂的量。
应该注意到用空气中的环境二氧化碳平衡溶液pH是一个缓慢的过程,其可能花费几个小时。当使用碳酸氢钠、碳酸钠或氢氧化钠来调节溶液pH时,这点特别值得注意。溶解促进剂改善了加环利定在赋形剂中的溶解度。在某些实施方案中,所述溶解促进剂被认为降低了制剂混合物的极性,从而促进了药物与所述溶解促进剂的相互作用且有助于将药物保留在溶液中。这样的溶解促进剂的实例包括,但不限于二甲基乙酰胺、生理学可接受的多元醇(例如丙二醇、甘油)、聚乙二醇(PEG)和醇(例如乙醇)。
在其它实施方案中,所述溶解促进剂为可溶性赋形剂载体分子,其将与药物结合。所述载体分子将结合的药物保留在均匀的溶液中。然后,所述载体分子代谢或从患者排出,所述药物发挥其生物效应。在本发明中有用的载体分子包括,但不限于结合疏水性分子的蛋白质(例如人或牛血清白蛋白、胎球蛋白或结合疏水性物质或防止水不溶性物质成核和沉积的任意水溶性蛋白质);衍生的卟啉或corins;带负电的环状有机分子,其具有结合空腔(“冠状化合物”);药学可接受的相转移剂;离子交换树脂;哌嗪二酮(DKP),比如TECHNOSPHERES(在二赖氨酸哌嗪二酮的每个赖氨酸侧链上单衍生的丁二酰基)、二谷氨酸DKP、二门冬氨酸DKP及其它在分子中具有净负电荷的衍生的DKP;水溶性脂质;微团;脂质体(单层和多层囊泡);脂肪酸和水溶性脂质(例如胆酸、鹅脱氧胆酸(chenic acid)、脱氧胆酸、心磷脂、胆酰甘氨酸、chenylglycine、脱氧胆酰甘氨酸、牛黄胆酸、chenyltaurine、脱氧胆酰牛磺酸);硫苷脂(在糖的3′位上具有硫酸酯的半乳糖脑苷脂);神经节苷脂;N-乙酰-D-神经氨酸;磷脂酰肌醇;分子中具有净负电荷的可溶性碳水化合物(例如羧甲基纤维素);衍生的碳水化物及这些载体的衍生物和混合物。
其它有用的载体分子包括,但不限于β-环糊精(例如磺基丁基醚环糊精,比如CAPTISOL)和表面活性剂如12-羟基硬脂酸的聚氧乙烯酯(例如SOLUTOLHS15)和聚山梨酯,比如聚山梨酯20、聚山梨酯60和聚山梨酯80(例如TWEEN)。表面活性剂作为酸性和碱性加环利定制剂的载体分子特别有用。认为加入表面活性剂以吸附或将加环利定部分从溶剂(例如在微团、脂质体和可溶性包衣的聚集体中)中分离,从而减少了其作为薄膜结合贮藏容器表面、粘附注射装置元件(注射器、针、导管、抗菌过滤器、输送泵储器、泵送机械等)或形成可见的或不可见的微聚集体的利用率,根据尺寸、可以将某些微聚集体从溶液中沉淀出、从溶液中分离或俘获在过滤装置(比如抗菌过滤器)中。
例如,向包含加环利定的溶液加入2-20%(w/w)CAPTISOL(CyDex,Lenexa,KS)、0.1-20%TWEEN80(聚山梨酯80,ICI Americas)或0.1-20%SOLUTOLHS 15(BASF)改善了溶解性。在室温下,CAPTISOL、TWEEN80和SOLUTOLHS 15,每克载体分子可以分别保存0.004、0.01和0.02克的加环利定碱在溶液中(见实施例3)。
在一个实施方案中,加环利定以1nM至5mM的浓度存在,聚山梨酯80(例如TWEEN80)以0.001%至30%(重量/重量[w/w])的浓度存在。一个优选的实施方案包括50μM至5mM的加环利定和0.1%至20%(w/w)的聚山梨酯80(例如TWEEN80)。一般所述载体分子的摩尔浓度等于或高于药物的浓度。可以在适宜的赋形剂如290-300mOsm的林格溶液中制剂加环利定和所述载体分子。
在某些实施方案中,将一种或多种溶解促进剂与赋形剂和化学品组合,其可以作为成品含水凝胶或在置于组织部位后凝胶(凝固)的液体施用,所述赋形剂和化学品将形成立体刚性材料。凝胶剂可以通过将包含药物的赋形剂和溶解促进剂与凝胶基质混合制备,所述凝胶基质比如,但不限于透明质酸、羧甲基纤维素或pleuronic acid。如此制备的凝胶将缓慢地将药物带入到围绕递送部位的生理溶液中。
辅料
本发明的制剂可包括辅料。这些包括,但不限于d-α生育酚聚乙二醇1000琥珀酸酯(TPGS)、环糊精、单硬脂酸乙二醇酯、硬脂酸甘油酯、甘油单/二辛酸酯/癸酸酯、山萮酸甘油酯、单油酸甘油酯、单硬脂酸甘油酯、棕榈硬脂酸甘油酯、卵磷脂、泊洛沙姆188、聚乙二醇、油酸聚甘油酯、聚氧乙烯(40)硬脂酸酯、聚山梨酯20、聚氧乙烯脱水山梨醇脂肪酸酯、聚氧乙烯硬脂酸酯、月桂酸丙二醇酯、十二烷基硫酸钠、硬脂酰富马酸钠、脱水山梨醇酯(脱水山梨醇脂肪酸酯)、蔗糖八乙酸酯、硬脂酸及其它用于增溶或乳化水不溶性药物的药学可接受的辅料。上述辅料的实例包括载体分子和表面活性剂。其它上述没有列出的可接受的辅料包括醇、二醇、甘油、矿物、蛋白质和帮助确保制剂药学可接受的性质的添加剂。参见PharmaceuticalExcipients(Drugs and the Pharmaceutical Sciences,v.94),David E.Bugay,Marcel Dekker AG,Basel,1999;Handbook of Pharmaceutical Excipients,Raymond Rowe,Paul Sheskey,和Sian Owen,Eds.,APhA Publications FifthEdition,Washington,DC,2006。本领域技术人员可以从这些辅料中选择以制备适于在动物或人中使用的制剂。这样的制剂将包括,但不局限于适于非肠道给药的可溶性制剂。参见Mark Gibson,在Pharmaceutical Preformulationand Formulation 中:A Practical Guide from Candidate Drug Selection toCommercial Dosage Form,Interpharm/CRC,Boca Raton,2004。
对于治疗用途,所述赋形剂可以是药学可接受的赋形剂,比如林格溶液、乳酸化林格溶液、人造外淋巴(参见Konishi等人,1973)、等渗盐水等。优选地,所述制剂pH为5至10,优选pH为6.5至8.5;生理学可接受的渗透压为280至310mOsm,优选为290-300;当所述制剂被制备用于中耳和内耳给药时,优选类似于外淋巴的离子组合物。递送至患者的制剂优选的生理学可接受的pH范围为6.8-7.4±0.5。
水性赋形剂
用于体内给药的制剂具有与液体非肠道制剂相似的组分,且其为本领域技术人员众所周知的。内耳流体(外淋巴)的组成是独特的,因为声音的运动通过该流体传输,所以所述支载药物的赋形剂与该流体相容是很重要。下述为药学可接受的水性赋形剂及其组分的实例。
表1
溶液名称 | 浓度mMoL | pH | ||||
Na+ | K+ | Ca++ | Cl- | 乳酸根 | ||
乳酸化的林格注射液USP(Ringer’s Lactate)NDC0074-7953-09 | 130 | 4 | 1.36 | 109 | 28 | 6.0-7.5通常pH=6.6 |
溶液名称 | 浓度mMoL | pH | ||||
Na+ | K+ | Ca++ | Cl- | 乳酸根 | ||
林格注射液USP(Ringer’s Solution)NDC0338-0105-04 | 147 | 4 | 2.24 | 156 | 0 | 5.0-7.5通常pH=5.5 |
人外淋巴[概括的数据来自Wangemann&Schacht,1996] | 浓度mMoL | 蛋白质mg/dl | pH | ||||
Na+ | K+ | Ca++ | Cl- | 碳酸氢根 | |||
148 | 4.2 | 1.3 | 119 | 21 | 178 | 7.3 |
来自文献的人造外淋巴组分的一个实例为(由Konishi等人改进,ActaOtolaryng 76:410-418):
145mM NaCl 8.4738g/L
2.7mM KCl 0.2013g/L
2.0mM MgSO4 0.2408g/L
1.2mM CaCl2 0.1764g/L
5.0mM HEPES 1.1915g/L
pH 7.3-7.4
渗透压(Osmolality)
对于内耳给药,所述药物制剂的渗透压很重要,因为毛细胞和相关支持细胞对制剂的离子强度很敏感。通过利用凝固点渗透压力计(AdvancedInstruments Model 3MO Plus)测定市售获得的林格溶液(Baxter Healthcare)和乳酸化林格溶液(Abbott Laboratories)的渗透压。测定的林格溶液和乳酸化林格溶液的渗透压分别为288±2和255±2mOsm。测定的人外淋巴的渗透压为300mOsm,参见Morris等人,AmJOtol10,148-9,1989。在使用前,一般通过加入氯化钠,调节用于中耳或内耳的制剂的最终渗透压为280至310mOsm(优选290-300)。该渗透压范围的安全性已经通过将适宜制备的试液直接注射至豚鼠的耳蜗证实了。
液体制剂的贮藏
1.加环利定的酸性或游离碱形式的冻干制剂
加环利定或组合制剂的冷冻干燥提供了贮藏制剂药物的方便的方法,其使长期贮藏期的化学分解最小化。可将加环利定的酸性形式从包含填充剂的冷冻水性赋形剂中冻干使有助于重构。填充剂的实例包括,但不限于乳糖、甘露醇、海藻糖或葡萄糖。当加环利定不与另一种治疗剂组合时,用于加环利定冷冻干燥的优选赋形剂是水。当其与另一种治疗剂组合时,其以在水中冷冻干燥所需的浓度不足以溶解形成均匀的溶液,可选择另一种适宜的赋形剂或加入辅料以提高混合物的溶解度。这些赋形剂是本领域技术人员已知的。当所述冻干的加环利定制剂不含溶解促进剂时,这些冻干制剂的重构赋形剂将包含溶解促进剂。然后当需要时,医师在重构赋形剂中重构所述药物的冻干形式,所述赋形剂含有需要的辅料和适宜的载体分子或表面活性剂以帮助所述固体快速溶解,提供化学稳定性和将所述治疗剂以特定的浓度保存在溶液中,作为加环利定酸形式的真溶液或作为酸/碱性形式混合物的支载混悬液或者完全的游离碱形式。适当地调节所述重构赋形剂的pH以得到应用所需的最终期望的pH。
在其它实施方案中,可以使用加环利定的碱性形式以改善其在冻干制剂中的化学稳定性。可以容易地通过在冷冻干燥前将至少1当量的碱加入到加环利定盐酸盐的水溶液中使其转化成碱性形式(例如,适宜的中和碱包括,但不限于氢氧化钠或碳酸钠)制备该制剂。该包含药物的溶液也可以包含通常在冻干制剂中使用的支撑剂(caking agents),如乳糖、甘露醇、海藻糖或葡萄糖。在冷冻干燥前,可以加入固体辅料如环糊精以化学稳定或辅助再溶(重构)所述的冻干的加环利定碱。使用前,可以即刻向所述冻干制剂中加入液态添加剂,比如聚山梨酯80、SOLUTOLHS 15或阳离子脂质作为重构赋形剂的部分。在用于重构所述干燥粉末的溶液例如林格溶液中可使用足量的酸,例如盐酸,使得当所述干燥制剂溶解时获得期望的pH。所述重构pH将部分取决于加环利定制剂所需溶液的稳定性。如在实施例6中描述的,加环利定分解的速率在较高的pH下较慢。对于重构溶液的长时间贮藏,期望较高的pH。视需要,在递送至预定部位前,可通过加入酸例如盐酸来降低所述制剂的pH至生理pH,例如pH 6.8至7.4。可以通过两个腔的装置(duallumen device)内部的共溶剂气流或在装载递送装置前立即原位调节所述重构的冻干制品或溶液制剂以获得最终期望的pH和制剂。
2.贮藏容器
聚合物表面比如聚丙烯、聚氨基甲酸酯、聚酰亚胺和聚氯乙烯对加环利定具有明显的亲合力,其可与用于保存加环利定溶液浓度的制剂辅料和载体分子竞争。根据本发明制备的加环利定溶液优选保存于酸洗涤的玻璃容器中,所述玻璃容器具有惰性的聚合物衬垫或帽,例如聚四氟乙烯(PTFE)。因为与上述类似的理由,期望避免所述制剂与用选择的聚合材料制造的容器、导管、过滤器或其它装置接触,所述聚合材料例如聚丙烯、聚氨基甲酸酯、聚氯乙烯或硅酮橡胶。当这点是不可能时,作为所述制剂接触面的衬垫(liners)的含氟聚合物比如PTFE的使用可有助于使加环利定的损失最小化,如可使用制剂比如纳米颗粒制剂,其对加环利定具有比对在递送药物中使用的其它聚合物或表面活性剂更高的亲合力。
包括固体加环利定游离碱的制剂
本发明的其它制剂包括固体加环利定游离碱,其为加环利定的对热更化学稳定的形式,尤其在体温,例如37℃。可以以固体游离碱形式给予固体加环利定,例如,以在水性赋形剂中的混悬液或凝胶制剂(例如源自,但不限于羧甲基纤维素、hayaluronic acid和普卢兰尼酸(pluronic acid),如上述说明制备,不同在于调节所述药物制剂的pH以使其包含游离碱形式的药物而不是可溶性酸性形式或游离碱和酸性形式的混合物)。
在其它实施方案中,将固体加环利定游离碱吸附到固体载体比如胶原海绵上或吸附到或包封在颗粒制剂比如纳米颗粒制剂(例如可溶蚀的聚乳酸(polylactate)/聚羟乙酸(polyglycolate)聚合物)中,或者与经设计用于缓释药物的聚合材料共同制剂,所述聚合材料比如薄膜非可溶蚀性聚合基质(例如硅橡胶),药物穿过聚合材料迁移到表面,然后释放到靶组织(参见下文)。固体载体如薄膜或包衣的使用导致加环利定的缓释,如在加环利定迁移到聚合物表面或与生理流体接触后将其转化成可溶性酸加成盐形式。这样的缓释聚合物固体载体作为在装置上的薄膜使用以调节药物释放的速率,所述装置如涂布的植入电极、包衣颗粒或其中存在药芯与可渗透的薄膜包衣的物质。这样的包衣的实例包括,但不局限于硅橡胶或硅酮橡胶、聚氨基甲酸酯和聚氯乙烯。
可以将固体载体,如包括固体加环利定游离碱和可溶蚀的聚合物载体的纳米颗粒,悬浮在用于治疗给药的药学可接受的赋形剂中。纳米颗粒具有穿过抗菌过滤器和容易摄入到靶细胞的特别的优点。
在某些实施方案中,将固体游离碱形式的加环利定制剂成在水性赋形剂中、吸附到胶原海绵,或悬浮在含水凝胶制剂中的混悬液。可以将酸形式的加环利定的水溶液例如氯化物盐与足量的碱比如碳酸钠混合,以将其转化成碱性形式。这可在溶液中进行以形成加环利定碱的含水混悬液,然后,将其制剂成凝胶,或者调节已经制剂成凝胶的pH为酸形式,以在凝胶内原位产生游离碱。类似地,可在用酸性形式的加环利定浸渍后,在胶原海绵内原位制备游离碱,然后用适宜的碱调节pH以产生期望的内在化的、吸附的加环利定碱负载的海绵。
可选地,因为碱性形式的加环利定可溶于有机溶剂比如乙醇、异丙醇、丙酮、二氯甲烷或二甲亚砜中,可将溶于有机溶剂中的碱形式的加环利定溶液应用到胶原海绵上以用碱形式的加环利定浸渍所述海绵,在蒸发溶剂后留下固体药物。
纳米颗粒
作为固体载体,纳米颗粒特别有用。在注射到耳蜗前,将纳米颗粒制剂穿过抗菌过滤器以确保无菌。参见,例如Prakobvaitayakit等人,AAPSPharmaSciTech 4(4),E71,2003;U.S.专利6,139,870。
1.材料
可使用可生物降解的和不可降解的物质形成纳米颗粒。参见Orive等人,Cancer Therapy 3,131-38,2005;Lu等人Adv Drug Deliv Rev 56,1621-33,2004。用于纳米颗粒制剂的可生物蚀解的聚合物可以由乳酸和乙醇酸制备。这样的聚合物为市售获得的(例如,得自Lakeshore Biomaterials,Birmingham,AL),并且测定的生物降解率为2-3周至12-16个月的。可以使用这样的聚合物制备纳米颗粒,其将在已知的一段时间内释放药物。
2.纳米颗粒的制造方法
可以使用多种方法制备适宜粒径的纳米颗粒(例如10-1000nm)。这些方法包括汽化法,比如自由喷气膨胀、激光汽化、电火花腐蚀、电爆炸(electroexplosion)和化学气相沉淀;物理方法,包括机械性磨碎(例如“pearlmilling″技术,Elan Nanosystems)、超临界CO2和溶剂替换后(solvent displacement)的界面沉淀。所述溶剂替换法(solvent displacement method)具有实施相对简单的优点。通过该方法制备的纳米颗粒的粒径对聚合物在所述有机溶剂中的浓度;混合速率;和在该方法中应用的表面活性剂敏感。
可以使用天然的表面活性剂,如胆酸或牛磺胆酸盐来制备小的纳米颗粒(<100nm),或者使用其作为在制剂中的增溶和稳定辅料。牛磺胆酸,由胆酸和牛磺酸形成的共轭物,为完全可代谢的磺酸表面活性剂。也已知牛磺胆酸的类似物,牛熊去氧胆酸(TUDCA)具有神经保护和抗细胞凋亡性质;参见Rodrigues等人,Proc Natl Acad Sci USA 100,6087-92,2003。TUDCA为一种天然存在的胆汁酸,且其为牛磺酸和熊去氧胆碱(UDCA)的共轭物。也可以在本发明的方法中使用其它天然存在的阴离子(例如半乳糖脑苷脂硫酸盐)、中性(例如乳糖基酰基鞘氨醇)或两性离子表面活性剂(例如鞘磷脂、磷脂酰胆碱、棕榈酰肉碱)来制备纳米颗粒或作为增溶和化学稳定的辅料。
3.混合技术
当通过溶剂替换法制备纳米颗粒时,500rpm或更快的搅拌速度被认为是最适宜的。在混合期间减慢溶剂交换速率生成较大的颗粒。连续流动混合器可以提供必要的湍流以确保小的粒径。在本发明的方法中可使用以制备小的纳米颗粒(<100nm)的一种类型的连续流动混合装置被称为Wiskind混合器;参见Hansen等人,J Phys Chem 92,2189-96,1988。在其它实施方案中,可使用超声破碎器(sonilators或sonicators)及其它类型的超声装置;可以通过流过匀浆器比如Gaulin类型的匀浆器或使用超临界CO2装置来制备纳米颗粒。
4.颗粒筛选
尺寸排阻色谱法(SEC),其为凝胶过滤层析的一种方法,可用于从游离药物上分离结合的颗粒或选择适宜的包含药物的纳米颗粒的粒径范围。市售的各种SEC介质(例如,来自GE Healthcare,Amersham Biosciences,Uppsala,Sweden)对于球状蛋白质的分子量筛截范围为200,000(Superdex 200);至约1,000,000(Superose 6);至大于108(Sephacryl 1000;适于SEC分离病毒和>1μm的小颗粒)。如果不能在直接混合时获得适宜的纳米颗粒均匀性,那么使用SEC产生高度均匀的包含药物的颗粒,即除去参与他们的制备的其它成分(例如溶剂和表面活性剂)。可通过旋风分离器、离心、膜滤法和通过使用其它分子筛装置、交联的凝胶/材料和膜按粒径分离颗粒。其它种类固体颗粒包括,但不限于制备的颗粒,比如TECHNOSPHERE,其可在颗粒制成后制剂。可以通过治疗剂包衣TECHNOSPHERE或将其制备成药物载体均相的颗粒。根据DKP具有酸性或碱性侧链,可以选择这样的颗粒以得到在酸性条件下不溶和在中性/碱性条件下可溶或反之亦然的颗粒。
根据环境,所述颗粒可以由可溶性的、可溶蚀的或非可溶蚀的材料组成。如一个实施方案,碱性形式的加环利定可被制剂在均相的硅橡胶或硅聚合物材料内,其在通过所述材料扩散后释放到与生理溶液接触的表面。可在标准独立递送装置中使用该包含药物的聚合材料或将其涂布在另一个装置上。在另一个实施方案中,可以将固体碱性形式的药物制剂成具有延迟或减慢释放药物的包衣颗粒。在其它实施方案中,可以有浓缩药物的药芯储库,使用膜来调节药物的释放。
加环利定和其它治疗剂的薄膜组合物
可以将治疗剂如碱性形式的加环利定制剂成在聚合物基质或层内的“俘获的(entrapped)”化合物,如可溶性溶液或者“植入物”如在聚合物基质内的不溶性非均匀的聚集体/晶体。聚合物基质的实例包括,但不局限于硅橡胶或硅酮橡胶、聚氨基甲酸酯和聚氯乙烯。所述治疗剂将通过扩散、刺激释放(经由电荷;电泳)、机械压(经由孔道表层加压至挤压药物)或侵蚀从聚合包衣释放,浸蚀是为了露出不能扩散到聚合物表面的治疗剂。
在其它实施方案中,多层膜包含内层或外层,所述内层包含纯药物或用膜覆盖的浓缩的药物/基质层,所述外层将调节来自内层的药物的释放。在考虑通过治疗的性质确定的各种病症、治疗效果所需的时间长度、期望的释放速率特征后,建立期望的释放速率。外层可以是可溶蚀的聚合物,使开始时不释放治疗剂,直到外层被浸蚀。
包衣的孔径将通过所述聚合物包衣的交联量来确定释放速率。最适宜的孔径将符合要递送的物质的种类及其需要量。在某些实施方案中,当存在不同的环境pH或不同的电荷时,可以改变组合物的pH和聚合物膜以诱导膜孔变化以适应不同的扩散速率,所述电荷为通过装置例如耳蜗植入物的电极串的膜处理来诱导。
在某些实施方案中,通过特定设计的孔再填充最内层,以再充满下层,并提供更长时间的释放。使用该种类的聚合物包衣以根据治疗剂提供拟零级释放速率(pseudo zero order release)几周和几月,直到所述药物被耗尽。如果这些涂层具有再填充的储库,则它们可用于慢性病症。不可再填充的包衣一般用于急性病症。
在其它实施方案中,所述薄膜包含且同时递送用于各种目的的多种治疗剂。例如,可同时使用多种治疗剂抑制耳蜗植入物植入后的感染和炎症以及耳鸣。
在其它实施方案中,将薄膜在装置上成层,其包含带电荷的治疗剂,比如酸形式的加环利定。然后可根据电极的电荷减速或减慢治疗剂流出(elution)。
其它治疗剂
本发明制备制剂,并根据施用和递送方法单独或与加环利定组合将治疗剂给药至耳蜗、内耳、中耳、听觉皮层、下丘或其它适宜的部位,所述治疗剂在生理学可接受的条件下具有很小的溶解度。例如,可以将其它有效的CNS药物共同制剂以治疗伴有耳呜前庭障碍。例如,抑制炎症、免疫应答或纤维变性的药物对与耳呜治疗剂组合可能是有益的。抗生素药物也可以与所述耳鸣治疗剂共同制剂或混合以同时获得预防或治疗感染和治疗耳鸣的益处。因为该方法的侵入性,很难将多种药物分别地递送至患者的中耳或内耳。组合治疗通过同时治疗一种或多种疾病向患者提供了益处,同时使医师更方便。下述为可以与加环利定组合的多种药剂的实例。
这些治疗剂包括,但不限于用于听力恢复的那些(例如,神经营养因子和对促进听力恢复有用的其它生长因子和蛋白质)、DNA、RNA、RNAi、siRNA、成视网膜细胞瘤蛋白及口袋蛋白家族(pocket family ofprotein)的其它成员、具有插入有用的基因的基因治疗质粒、降低耳蜗中听觉阈值的抗纤维变性剂、用于诱导毛细胞分裂的细胞周期抑制剂拮抗剂和前列腺素类,例如但不限于迷索前列醇或拉坦前列素等等。其它的治疗剂包括抗生素,用于治疗癌症的药物,抗菌药,抗病毒药,消炎药如甾体类,包括但不限于甲基泼尼松龙、地塞米松、曲安奈德,抗氧剂(包括,但不限于中和或防止自由基和超氧化物类的药剂;超氧化物歧化酶模拟物;过氧化物酶或过氧化物酶模拟物,比如依布硒;还原剂(比如二硫化物类)和抗细胞凋亡剂(比如,但不限于胱冬酶,包括胱冬酶3、9和/或12抑制剂,其被认为预防毛细胞死亡)以预防噪音、创伤和年龄依赖性听力丧失。这些制剂也尤其适于单独或在单一制剂中与一种或多种这些种类的药物组合给药NMDA受体拮抗剂至耳蜗、内耳或中耳。
根据本发明,可用于治疗中耳和内耳疾病的治疗化合物包括目前市售的那些,如抗焦虑药、抗抑郁药、选择性5-羟色胺重摄取抑制剂(SSRI)、钙离子通道阻滞药、钠通道阻滞药、抗偏头痛药(例如氟苯桂嗪)、肌松药、安眠药和抗惊厥药,包括抗癫痫剂。下述提供这样的化合物的实例。
抗惊厥药
抗惊厥药包括巴比妥酸盐(例如甲苯比妥和戊巴比妥钠);苯二氮类,比如阿普唑仑(XANAX、劳拉西泮、氯硝西泮、二钾氯氮和地西泮(VALIUM);GABA类似物,如噻加宾、加巴喷丁(α2δ拮抗剂,NEURONTIN)和β-羟基丙酸;乙内酰脲,比如5,5-二苯基-2,4-咪唑啉酮(苯妥英,DILANTIN)和磷苯妥英钠;苯三嗪类,如拉莫三嗪;琥珀酰亚胺类,比如甲琥胺和乙琥胺;5H-二苯并氮-5-甲酰胺(卡马西平);奥卡西平;α-正丙基戊酸钠二聚物;非尔氨酯、左乙拉西坦、扑米酮;唑尼沙胺;托吡酯;和丙戊酸钠。
NMDA受体拮抗剂
有许多已知的NMDA受体抑制剂,一般将其分成五类。如下所述的每个化合物包括其范围内的活性代谢物、类似物、衍生物,在结构类似物系列(SAR)中制备的化合物及具有类似的治疗作用的几何异构体或光学异构体。
NMDA受体谷氨酸结合位点的竞争剂
竞争NMDA受体的谷氨酸结合位点的拮抗剂包括LY 274614(十氢-6-(膦酰基甲基)-3-异喹啉羧酸)、LY 235959[(3S,4aR,6S,8aR)-十氢-6-(膦酰基甲基)-3-异喹啉羧酸]、LY 233053((2R,4S)-rel-4-(1H-四唑-5-基-甲基)-2-哌啶羧酸)、NPC 12626(α-氨基2-(2-膦酰基乙基)-环己烷丙酸)、还原的和氧化的谷胱甘肽、carbamathione、AP-5(5-膦酰基-正缬氨酸)、CPP(4-(3-膦酰基丙基)-2-哌嗪-羧酸)、CGS-19755(seifotel、顺-4(膦酰基甲基)-2-哌啶-羧酸)、CGP-37849((3E)-2-氨基-4-甲基-5-膦酰基-3-戊烯酸)、CGP 39551((3E)-2-氨基-4-甲基-5-膦酰基-3-戊烯酸-1-乙酯)、SDZ 220-581[(αS)-α-氨基2′-氯-5-(膦酰基甲基)-[1,1′-二苯基]-3-丙酸]和S-亚硝基谷胱甘肽(nitrosoglutathione)。参见Gordon等人,2001;Ginski和Witkin,1994;Calabresi等人,2003;Hermann等人,2000;Kopke等人,2002;Ikonomidou和Turski,2002;Danysz和Parsons,1998。
作用于NMDA受体连接的离子通道的非竞争性抑制剂
非竞争性或无竞争性的且作用于受体连接的离子通道的拮抗剂包括金刚烷胺、阿替加奈(CERESTAT、CNS1102)、卡罗维林、右羟吗喃、右美沙芬、富洛伦尼斯、伊波加因、氯胺酮、利多卡因、美金刚、地佐环平(MK-801)、neramexane(MRZ 2/579,1,3,3,5,5-五甲基-环己烷胺)、NPS 1506(delucemine,3-氟-γ-(3-氟苯基)-N-甲基-苯丙胺盐酸盐)、苯环利定、替来他明和瑞马西胺。参见Palmer,2001;Hewitt,2000;Parsons等人,1995;Seidman和Van DeWater,2003;Danysz等人,1994;Ikonomidou和Turski,2002;Feldblum等人,2000;Kohl和Dannhardt,2001;Mueller等人,1999;Sugimoto等人,2003;Popik等人,1994;Hesselink等人,1999。
作用于NMDA受体的多胺结合位点或其附近的拮抗剂
认为作用于NMDA受体的多胺结合位点或其附近的拮抗剂包括阿坎酸、蚶碱、conantokin-G、依利罗地(SL 82-0715)、氟哌啶醇、艾芬地尔、曲索罗地(CP-101,606)和Ro 25-6981[(±)-(R,S)-α-(4-羟基苯基)-β-甲基-4-(苯甲基)-1-哌啶丙醇]。参见Mayer等人,2002;Kohl和Dannhardt,2001;Ikonomidou和Turski,2002;Lynch等人,2001;Gallagher等人,1996;Zhou等人,1996;1999;Lynch和Gallagher,1996;Nankai等人,1995。
作用于NMDA受体的甘氨酸结合位点或其附近的拮抗剂
认为作用于NMDA受体的甘氨酸结合位点或其附近的拮抗剂包括氨基环丙烷羧酸(ACPC)、7-氯犬尿烯酸、D-环丝氨酸,加维斯替奈(GV-150526)、GV-196771A(4,6-二氯-3-[(E)-(2-氧-1-苯基-3-吡咯烷亚基(pyrrolidinylidene))甲基]-1H-吲哚-2-羧酸一钠盐)、利可替奈(ACEA 1021),MRZ-2/576(8-氯-2,3-二氢哒嗪并[4,5-b]喹啉-1,4-二酮-5-氧化物2-羟基-N,N,N-三甲基-乙铵盐),L-701,324(7-氯-4-羟基-3-(3-苯氧基苯基)-2(1H)-喹啉酮(quinolinone))、HA-966(3-氨基-1-羟基-2-吡咯烷酮)和ZD-9379(7-氯-4-羟基-2-(4-甲氧基-2-甲基苯基)-1,2,5,10-四-hydropyridanizo[4,5-b]喹啉-1,10-二酮钠盐)。Peterson等人,2004;Danysz和Parsons,2002;Ginski和Witkin,1994;Petty等人,2004;Danysz和Parsons,1998。
作用于NMDA受体的变构氧化还原调节位点的拮抗剂
认为作用于变构氧化还原调节位点起作用的拮抗剂包括氧化的和还原的谷胱甘肽、S-亚硝基谷胱甘肽、硝普钠、依布硒和双硫仑(通过其代谢物DETC-Meso和carbamathione起作用)。参见Hermann等人,2000;Ogita等人,1998;Herin等人,2001,Ningaraj等人,2001;Kopke等人,2002.
某些NMDA受体拮抗剂,尤其是谷胱甘肽及其类似物(S-亚硝基谷胱甘肽和carbamathione),可与受体上的一个以上位点相互作用。
CNQX(1,2,3,4-四氢-7-硝基-2,3-二氧代-6-喹噁啉腈)和DNQX(1,4-二氢-6,7-二硝基-2,3-喹噁啉二酮)结合非NMDA谷氨酸受体。可在本发明的方法中使用这些和谷氨酸受体的其它拮抗剂或激动剂。
优选的是如本文公开的NMDA受体拮抗剂抑制NMDA受体,而不抑制AMPA受体。其原因是认为对AMPA受体的抑制导致了听力损伤。相反,希望选择性抑制NMDA受体以预防神经元的细胞凋亡、细胞程序性死亡的引发。与仅通过谷氨酸活化的AMPA受体不同,除谷氨酸外,NMDA受体需要共激动剂。用于NMDA受体的生理共激动剂为甘氨酸或D-丝氨酸。NMDA受体而非AMPA受体也结合还原的谷胱甘肽、氧化的谷胱甘肽和S-亚硝基谷胱甘肽。谷胱甘肽,γ-谷氨酰基-半胱氨酰基-甘氨酸被认为是NMDA受体的谷氨酸和甘氨酸结合位点之间的桥,在两个部位共价结合。NMDA受体的活化导致钙离子通过连接的离子通道进入神经元并引发ca2+诱导的细胞凋亡。细胞内钙活化NMDA受体相关的神经元形式的一氧化氮合酶(nNOS)、钙蛋白酶、胱冬酶和其它与氧化细胞损伤有关的系统。NMDA受体的抑制将预防神经元死亡。
特异性亚型的NMDA受体拮抗剂
各种特定亚型的NMDA受体激动剂是已知的,并可用于本发明的方法。例如某些NMDA受体拮抗剂,如蚶碱、argiotoxin 636,Co 101244(PD 174494、Ro 63-1908、1-[2-(4-羟基苯氧基)乙基]-4-[(4-甲基苯基)甲基4-哌啶醇]、despiramine、右美沙芬、右羟吗喃、依利罗地、氟哌啶醇、艾芬地尔、美金刚、philanthotoxin 343、Ro-25-6981([(±)-(R*,S*)-α-(4-羟基苯基)-β-甲基-4-(苯基甲基)-1-哌啶丙醇]),曲索罗地(CP-101,606),Ro 04-5595(1-[2-(4-氯苯基)乙基]-1,2,3,4-四氢-6-甲氧基-2-甲基-7-异喹啉醇)、CPP[4-(3-膦酰基丙基)-2-哌嗪羧酸]、conantokin G、精胺和亚精胺对该受体的NR2B(NR1A/2B)亚型具有中等或高选择性。NVP-AAM077[[[[(1S)-1-(4-溴苯基)乙基]氨基](1,2,3,4-四氢-2,3-二氧代-5-喹噁啉基)甲基]-膦酸]是一种NR2A亚型的特异性拮抗剂。参见Nankai等人,1995;Gallagher等人,1996;Lynch和Gallagher,1996;Lynch等人,2001;Zhou等人,1996;Zhou等人,1999;Kohl和Dannhardt,2001,Danysz和Parsons,2002。
特别有用的拮抗剂比如1-[菲-2-羰基)哌嗪-2,3-二羧酸(Feng等人,Br JPharmacol 141,508-16,2004),其对该受体的NR2D和2C亚型具有高选择性。
非NMDA受体拮抗剂的有用的治疗剂
根据本发明可以配制并给药的其它有用的治疗剂包括去甲替林、amytriptyline、氟西汀(PROZAC)、盐酸帕罗西汀(PAXIL)、曲米帕明、奥卡西平(TRILEPTAL)、乙哌立松、迷索前列醇(一种前列腺素E1类似物)、拉坦前列素(一种前列腺素Fiti类似物)、褪黑激素和甾体(例如孕烯诺龙、曲安奈德、甲泼尼龙、及其它抗炎甾体)。
根据本发明,也可以配制并给药N-型钙离子通道阻滞药如Piralt(Takizawa等人,Cereb Blood Flow Metab 15,611-8,1995)。
治疗方法
如上所述的加环利定对治疗哺乳动物(包括家畜和同伴动物)和特别是人有用。它们尤其用于治疗耳鸣,包括与神经障碍有关的耳呜,所述神经障碍比如梅尼尔(氏)病、疼痛、焦虑、抑郁症和偏头痛。
本发明的制剂可以通过各种方法给药。例如,可使用蜗窗导管(roundwindow cathether)(例如美国专利6,440,102和6,648,873)。
可选地,可将制剂加入纱布条用于外耳和中耳之间(例如美国专利6,120,484)或吸收到胶原海绵或其它的固体载体中(例如美国专利4,164,559)。
视需要,可将本发明的制剂加入凝胶制剂中(例如美国专利4,474,752和6,911,211)。也可以通过直接注射进入中耳、内耳或耳蜗给予本发明的制剂(例如美国专利6,377,849和序列号11/337,815)。
本发明的制剂也可以经由植入的泵和递送系统穿过针直接进入中耳或内耳(耳蜗)或穿过耳蜗植入物口针电极通道或其它制备的递送药物的通道递送,比如但不限于用针穿过颞骨进入耳蜗。
其它选择包括经由泵穿过涂布在多通道电极或具有特定的植入药物递送通道(途径)的电极上的薄膜递送,为此目的所述电极进入到所述薄膜。在其它实施方案中,酸性或碱性固体加环利定可以从外部或内部植入的泵送系统的储库递送。
加环利定的酸性或碱性制剂通过植入的药物递送系统而递送
对于向耳呜患者的长期递送,需要方便的递送方法如植入的药物递送系统。对于在这种系统中的使用,可将药物与适宜的辅料制剂成的均相的酸性或碱性形式加环利定或酸性或碱性形式的混合物,以确保化学稳定性和适当的溶液浓度。
本发明的制剂也可以从电极表面上的负载药物的薄膜或储库经流出在递送,所述电极包含在植入在中耳或内耳中的电极聚合物基质或其它递送物质内。加环利定可以经由在向电极充电后推动带电的加环利定运动的电泳法从负载药物的电极释放。
也可以将加环利定碱压成或制成多种固体形式,如但不限于片剂,其可以被植入或经受通过移动液流而缓慢浸蚀。然后,通过从递送系统的储库中溶液或用流体浸蚀这样的固体形式及赋形剂悬浮的纳米颗粒,所述流体为从患者中抽出并用药物饱和后返回到所述患者。
将在本文公开的内容中引用的所有专利、专利申请和参考文献特别地引入本文作为参考。上述公开的内容大体上地描述了本发明。通过参照下述具体实施例可获得更完整的理解,提供所述实施例仅仅用于说明的目的,而不意味着限制本发明的范围。
实施例1
评价加环利定的化学稳定性和溶解度的方法
该实施例描述了可用于测定加环利定在多种制剂中的化学稳定性和溶液浓度的分析方法。
方法A(快速;仅仅测定加环利定的溶液浓度)
使用Surveyor HPLC系统(Thermo Electron)测定加环利定。使用购自TheNest Group(SoutUboro,MA)的Grace Vydac C8 MASS SPEC柱(cat#_208MS5210;S/N NE981208-3-7)用于这些分析。色谱柱保存在30℃。在12mm×32mm自动进样器的小瓶中(Thermo Electron,A4954-010)制备样品,并保存在20℃的自动进样器中,
为了使精确度最大化,使用“满环(full-loop)”注射的方法,其中从所述小瓶中取出80.7μL,填满20μL注射环。将包含在20μL的注射环中的全部样品加样到C8色谱柱。然后,以300μL/分钟的流速以梯度洗脱样品,所述梯度洗脱液由包含0.1%(体积/体积)的三氟乙酸的水(缓冲剂A)和包含0.1%(体积/体积)的三氟乙酸的乙腈(缓冲剂B)组成。所述梯度步骤包括用100%缓冲剂A洗脱0至5分钟;80%的缓冲剂A--20%的缓冲剂B洗脱5至15分钟;100%的缓冲剂B洗脱15至20分钟和100%的缓冲剂A洗脱20至25分钟。
通过使用Thermo Electron PDA UV检测器在234nm监测柱洗脱液。可容易地检测到在第10.0分钟从柱洗脱的加环利定的溶液浓度为1μM。在经过UV检测器至AQA质谱仪(Thermo Electron)后,通过联合柱洗脱液证实了加环利定的存在。通过使用质谱仪检测在适当的洗脱位置的加环利定,所述质谱仪为正离子模式,具有选择性离子监控器(SIM),加环利定的质/荷比(m/z)为264。
方法B(化学稳定性的测定:同时测定加环利定和哌啶)
为了监测哌啶形成,将购自Agilent Technologies的Zorbax SB-CN柱(25×0.46cm,5μm;PN 880975,SN USS F01 3866)保存在30℃下,用50%缓冲剂A和50%缓冲剂B组成的混合物以150μL/分洗脱60分钟。缓冲剂A由包含0.1三氟乙酸的水组成,缓冲剂B由包含0.1%三氟乙酸的乙腈组成。将来自该柱的流出物与AQA单一四极杆质谱仪(Thermo Electron)和SurveyorPDA检测器(UV监测器,Thermo Electron)连接。在232nm监测柱流出物,通过利用PDA检测器收集在200至300nm之间的扫描。在注射在ZorbaxSB-CN柱后28.1分钟,通过PDA检测器检测加环利定。也通过SIM(选择性离子监控器)监测柱流出物,通过利用AQA质谱仪得到质/荷(m/z)比为264.46(对于加环利定,m+1)和86.16(对于哌啶,m+1)。在注射到ZorbaxSB-CN柱上后28.3分钟,通过质谱仪检测加环利定(m/z=264和86)。在注射到Zorbax SB-CN柱上后16.0分钟,通过质谱仪检测哌啶(仅有m/z=86)。使用PDA(UV监测器)不能检测到哌啶。
实施例2
加环利定在溶液中的保存
在二甲亚砜(DMSO)或水中制备加环利定(加环利定盐酸盐)的储备溶液(0.1M)。然后,将这些溶液的等分试样(10μL)加入到10.0mL的乳酸化林格溶液(pH 6.6)、包含100μM的NaOH的乳酸化林格溶液(pH 7.5)或0.1N的HCl(pH1.0)中,得到100μM的最终药物浓度。将这些药物溶液的等分试样转移到自动取样小瓶中,保存在20℃直到用HPLC分析。结果概括在表2中。
表2.加环利定在多种制剂中随时间的浓度
1∶1000稀释的DMSO药物储备液(0.1%终浓度) | |||
0-3小时 | 3-6小时 | 16-19小时 | |
乳酸化林格溶液,pH 7.5 | 97.5μM | 90.4μM | 79.3μM |
乳酸化林格溶液,pH 6.6 | 96.0μM | 94.9μM | 91.3μM |
0.1N HCl | 100.3μM | 100.2μM | 100.6μM |
1∶1000稀释的含水药物储备液 |
乳酸化林格溶液,pH 7.5 | 88.2μM | 72.0μM | 59.7μM |
乳酸化林格溶液,pH 6.6 | 95.1μM | 92.6μM | 87.7μM |
0.1N HCl | 99.4μM | 99.8μM | 100.2μM |
如表2所示,在生理条件(例如,溶于乳酸化林格溶液溶液中,pH 6.6,或者溶于已经将其pH调节至7.5的乳酸化林格溶液中)下的加环利定溶液没有以使用的最初浓度保存加环利定。相反,在室温下,在酸性条件(0.1的HCl,其pH为1.0,表2)下溶解的加环利定保存几天。向小瓶中加入酸,明显降低了加环利定在溶液中的浓度,增加了加环利定的可检测量。这显示出在表2中证实的加环利定的浓度随着时间的降低主要是由于所述化合物从溶液中沉淀。
如表2证实的,0.1%的DMSO延迟了溶液中加环利定的损失。较高浓度的DMSO,比如0.1-100%可进一步改善了加环利定保留在溶液中的能力。
实施例3
加环利定的溶解度
当与水接触时,加环利定盐酸盐几乎立即生成透明溶液,至多最终浓度为550mM。然而,如果将100mM的盐酸盐溶液稀释到缓冲的水溶液中,使最终浓度为1mM,则在高于pH 7观察加环利定的沉淀。
图1表示在将10μL的100mM的盐酸盐加入到0.99mL的缓冲溶液中后,保存在溶液中的加环利定的量。此后,将混合物仍保存在室温下两天。所述缓冲溶液包含100mM的氯化钠和50mM浓度的下述缓冲物质中的一种,在pH等于缓冲液的pKa(即,缓冲液为50%的酸形式和50%的碱形式)下的:MES、Bis-Tris、MOPSO、MOPS、TAPSO、Tris、Tricine、TAPS、CHES、AMPSO或CAPSO(Sigma Chemical Company,St.Louis,MO)
通过使用从VWR获得的SympHony玻璃甘汞微组合pH电极(Cat.No.14002-776)测定混合物的pH。在pH 7.00±0.01(25℃;在20℃为7.02)、4.01±0.01(25℃;在20℃为4.00)和10.00(25℃;在20℃为10.05)下的Oakton标准参比溶液从Cole-Parmer获得。使用这些标准pH溶液将装有SympHony电极的Cole-Parmer Model 5996-60型pH计校准至在参比溶液的0.01pH单位内。
当所述混合物的pH比pH 7高时,在24小时内,加环利定从溶液沉淀出并下沉到玻璃自动进样器小瓶(Thermo Electron,A4954-010)的底部,呈可见的白色加环利定碱沉淀物。在高于pH 7下,在所述混合物中包括0.1%的SOLUPHORP(BASF)不会增加加环利定溶解度。在pH 9.7,在存在(图1)或不存在(没有显示)SOLUPHORP下,在室温下保存二天后,保存在溶液中的加环利定的量仅仅为2.6μM,是加入的加环利定的0.26%。相反,在混合物中包括0.1%的CAPTISOL、TWEEN80或SOLUTOLHS15在高pH下保存在溶液中的加环利定的量分别增加至约14、42或96μM(1.4、4.2或9.6%的加入的加环利定)。
在37℃进行前述步骤,将样品保存在聚丙烯小瓶(VWR#_20170-710,2mL小瓶)中。结果显示在图2中。在pH 6观察到溶液中加环利定的损失,且至pH 9.2时,在存在或不存在0.1%的SOLUPHORP下,保存在溶液中的加环利定的浓度仅仅为约1μM(加入的总加环利定的0.1%)。如前所述,向所述混合物中加入0.1%的TWEEN80或SOLUTOLHS15使在高pH下保存在溶液中的加环利定的量增加到约20或32μM的浓度(分别为加入的总加环利定的2.0或3.2%)。在37℃下将0.1%的CAPTISOL加入到在聚丙烯容器中的混合物中不会导致环利定的碱性形式的明确的溶解度(没有达到稳定水平)。
因为聚丙烯降低了100μM保存在溶液的加环利定的量,在不存在过量沉淀的加环利定下测定SOLUTOLHS15保存25μM加环利定的能力。在0.15M氯化钠中制备包含25μM的加环利定溶液,通过加入碳酸氢钠或盐酸调节这些溶液的pH。某些这些溶液也含有0.1%的SOLUTOLHS15。在37℃下聚丙烯小瓶中培养1或3天后,测定加环利定保存在这些溶液中的浓度。
图3显示了加环利定从溶液中的损失与pH的函数。在高于pH6下,观察加环利定的损失,损失量随pH的增大而增加。尽管在培养三天后的结果与在37℃培养一天后获得的结果相似,在培养三天的样品中,在低pH下观察到的损失增加可能反映了由于分解的损失。尽管根据在图2中显示的结果,0.1%的SOLUTOLHS15应当能够将25μM的加环利定保存在溶液中,但包含0.1%的SOLUTOL对在这些条件下观察到的损失没有影响。这些结果表明在不存在过量沉淀的加环利定下,0.1%的SOLUTOLHS15不能有效地与聚丙烯小瓶竞争加环利定。尽管辅料可以增溶加环利定(图1和2),但溶液遇到的其它聚合材料,如聚丙烯小瓶对加环利定具有比辅料更高的亲合力。
实施例4
加环利定的化学稳定性
通过在玻璃自动进样器小瓶中混合含0.0LmL的100mM加环利定和0.01mL的1.0M盐酸的0.98mL的水制备一组样品。在这些样品中,加环利定为完全可溶的,溶液pH为2.0。通过在玻璃自动进样器小瓶中混合含0.01mL的100mM加环利定和0.01mL的0.15M氢氧化钠的0.97mL的水制备第二组样品。混合后,加环利定从这些样品中的溶液中沉淀出,加环利定碱的悬浮液pH为10.4。然后,在54或56℃,在多个时间长度培养这两组样品。在54或56℃培养后,将0.01mL的1.0M盐酸加入到包含加环利定碱的悬浮液(0.5mM过量的氢氧化钠,pH 10.4)的样品中,将加环利定转化成可溶性酸形式,并将这些悬浮液转化成清澈的溶液(pH2.1)。在54或56℃培养后,使用方法B(实施例1)分析两组样品剩余的加环利定和形成的哌啶。
如图4所示,碱性形式的加环利定比酸形式的化学稳定性高200-400倍。在54℃,悬浮在1.5mM的氢氧化钠中的1.0mM的加环利定的分解速率为0.0013天-1,与之相比,在10mM的盐酸中为0.52天-1。样品中加环利定的损失完全可以解释为损失的每分子的加环利定按化学当量分解形成一分子的哌啶。
在从5℃至56℃的培养温度范围内用酸形式的环利定进行类似的试验。这些试验的结果概括在图5中。所述分解速度有很高的温度依赖性。在5℃,分解速度非常慢,且很难测定,除非通过测定哌啶形成。在5℃,当通过哌啶形成来确定,分解速度为约0.0001天-1,或者当通过根据Airhenius关系在较高温度下速率的外推法确定,为0.000055天-1。由于分解,加环利定(酸形式)损失10%的所需时间在5℃为3年,在23℃为53天,在37℃为3.8天,在56℃为3.3小时。
这些数据证实了在高于体温的较低温度下加环利定的化学稳定性增加。
为了测定在接近生理条件下加环利定的分解速率,在pH 5.5、6.0或7.4的乳酸化林格溶液中制备100μM的加环利定。通过加入盐酸或碳酸氢盐钠(0.13mM)调节这些乳酸化林格溶液溶液的pH。在37℃,在酸洗涤的玻璃自动进样器中培养这些样品的0.40mL等分试样不同的时间段,然后分析剩余的加环利定和哌啶形成。为了分析这些样品的加环利定和哌啶,首先用二氯甲烷提取所述样品,然后反萃取到稀盐酸中。为了分析0.40ml的样品,加入50μL的1.0M氢氧化钠和0.8mL二氯甲烷。在强力混合后,使水层和二氯甲烷层分离。向0.4mL的二氯甲烷相中加入20μL的1.0M盐酸和0.78mL的水。在强力混合后,使水层和二氯甲烷层分离,分析水层中的加环利定和哌啶。该提取步骤是除去存在于样品中的盐以最佳化哌啶的检测所必需的。
如图6所示,在pH 5.5和6.0下的哌啶形成的速率几乎相等,但实质上比pH 7.4的慢。表3概括了通过对在图6中显示的数据的一级衰变的拟合方程获得的速率。在37℃,pH 5.5或6.0,加环利定分解的速率与加环利定的酸形式的速率相当,而在pH 7.4下,该速率仅为预期的酸形式的速率的62%。这说明在pH 7.4和37℃下,仅仅62%的加环利定为酸形式,且说明加环利定的表观pKA为7.6。这点还证实在较高pH的溶液中占优势的加环利定的游离碱比在较低pH溶液中占优势的酸形式更稳定。
表3.加环利定在37℃的稳定性
pH | 损失10%的时间(37℃,乳酸化林格溶液) |
5.5 | 3.7±0.1天 |
6.0 | 3.82±0.03天 |
7.4 | 6.1±0.4天 |
实施例5
pH对加环利定分解和溶解度的影响
在酸洗涤的玻璃小瓶中制备一系列包含100μM在林格溶液中的加环利定的样品。向10.0mL的林格溶液(Baxter Healthcare Corporation)中加入10μL的0.100M加环利定盐酸盐和0.020、0.040、0.080或0.160mL的0.100M碳酸氢钠。然后,在55℃培养这些样品24小时。在55℃培养后,从每种样品中采集0.400mL的等分试样,且然后分析加环利定和哌啶。
用二氯甲烷萃取加环利定和哌啶,然后,如在实施例4中所述反萃取至稀释的含水酸中。在55℃,通过使用在55℃标准化的pH计测定每个样品的pH。pH计,电极和标准与在实施例3中描述的相同。图7表示在多种pH值下于55℃在林格溶液中培养加环利定得到的结果。在图7中,加环利定浓度以空心圆形表示;哌啶以空心正方形表示;加环利定和哌啶的总量以实心圆表示。明显地,按哌啶形成与加环利定的损失不等判断,存在分解和从溶液中沉淀的加环利定的损失。由于随着pH从7.6至8.1的增加哌啶和加环利定的浓度总量降低表明沉淀。如按哌啶形成来测定,伴随沉淀,分解速度也随着pH 7.6至8.1降低,再次证实在较高的pH下化学稳定性增加。
实施例6
pH和聚山梨酯80(TWEEN80)对加环利定稳定性的影响
在酸洗涤的玻璃小瓶中制备一系列包含100μM加环利定和0.3%的聚山梨酯80(TWEEN80)的林格溶液的样品。向10.0mL的林格溶液(BaxterHealthcare Corporation)中加入10μL的100mM加环利定盐酸盐、0.030g的聚山梨酯80和0.02、0.04、0.08、0.16或0.32mL的100mM碳酸氢钠。然后,在55℃培养这些样品24小时。在55℃培养后,从每种样品中采集0.4mL的等分试样,分析加环利定和哌啶。用二氯甲烷萃取加环利定和哌啶,然后,如在实施例4中所述反萃取至稀释的含水酸中。在55℃,通过使用在55℃标准化的pH计测定每个样品的pH。所述pH计,电极和标准与在实施例3中描述的相同。
图8表明在55℃和在多种pH值下在包含0.3%的聚山梨酯80的林格溶液中培养加环利定得到的结果。在图8中,加环利定浓度以空心圆形表示;哌啶以空心正方形表示;加环利定和哌啶的总量以实心圆表示。不存在由于沉淀的加环利定的损失,因为加环利定的浓度或加环利定与哌啶的总量似乎与pH无关。当通过哌啶形成测定时,在0.3%的聚山梨酯80存在下,加环利定的分解也大量较少。在0.3%的聚山梨酯80存在下,从100μM的加环利定中形成的哌啶的量从在pH 6.7下的4.5μM至在pH 8.2下的0.92μM变化。在pH值高于7下,聚山梨酯80有助于将加环利定保存在溶液中,并且即使在pH低于7下,大大延迟加环利定分解的速率。
图9显示了在存在和不存在0.3%的聚山梨酯80下,根据形成的哌啶的浓度确定的加环利定分解速率的比较。在55℃,加环利定的酸形式的分解速度(参见实施例4)为0.73天-1。在0.3%的聚山梨酯80存在下,加环利定的分解速率降低为在pH 6.7下该速率的6.4%和在pH 8.2下该速率的1.3%。相反,在不存在加入的辅料下,相对分解速率从在pH 7.3下该速率的51%至在pH 8.1下该速率的48%变化。聚山梨酯80明显对抵抗加环利定的热分解提供了保护,而且提高了在高于7的pH值下加环利定的溶解度。这些结果证实提高加环利定的碱性形式的溶解度的试剂也增加了其化学稳定性,并且甚至在溶解度不是问题的pH范围下也是这样。
实施例7
加环利定从游离碱形式的悬浮液中的洗脱
该实施例描述了可用于测定加环利定在多种制剂中的稳定性的分析方法。
为了测定加环利定游离碱的悬浮液的溶液性质,将2.8mg的游离碱粉末悬浮在连续搅拌下的玻璃小瓶中的20.0mL的乳酸化林格溶液中,加入或不加入0.13mM的碳酸氢钠。如在实施例3中所述,通过利用pH计监测这些溶液的pH。如在实施例1中所述,通过HPLC测定加环利定的浓度。这些溶液的平均温度为23℃,在21℃至25℃之间变化。将从这些溶液得到的结果概括在表3中。
没有加入加环利定或碳酸氢钠的乳酸化林格溶液的初始pH为6.7,在加入2.8mg的加环利定后,增加至7.4至7.7之间。在加入固体后,加环利定的浓度在10天内增加至152至162μM之间的平衡浓度。包含0.13mM的碳酸氢钠的乳酸化林格溶液的初始pH为7.4,接近生理pH,在加入2.8mg的加环利定后,增加至7.5至7.6之间。加环利定的浓度在10天内增加至73至77μM的平衡浓度。
基于这些结果,给予固体加环利定碱将导致加环利定缓释进入溶液中,其将花费几天至接近最终平衡浓度。在开始pH接近生理pH时,在平衡下获得的最大浓度为约75μM的加环利定溶液。两周后,两个溶液仍然保存加入的大多数初始加环利定游离碱,呈固体悬浮液。即使在几个月后,可见加环利定固体的量似乎没有改变。通过两种溶液获得的加环利定的平衡浓度仅仅分别为加入到不加入或加入碳酸氢钠的乳酸化林格溶液溶液中加环利定碱总量的30%或14%。这些数据(表4)证实了给予包含加环利定游离碱的固体制剂的适用性。
表4.固体游离碱混悬液中加环利定的洗脱
时间(天) | 乳酸化林格溶液133μM的NaHCO3 | 没有调节pH的乳酸化林格溶液 | ||
加环利定(μM) | pH | 加环利定(μM) | pH | |
00.6251.101.545.799.8512.914.0 | 020.737.146.2±0.376.3±0.377.2±0.572.9±1.175.7±2.0 | 7.437.547.587.517.62 | 056.479.888.3±2.4124.4±14.5152.4±0.7162.2±1.4157.9±3.6 | 6.717.667.447.467.38 |
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Claims (42)
1.制剂,其包括:
加环利定;
赋形剂;和
一种或多种选自溶解促进剂和辅料的组分。
2.权利要求1的制剂,其包括溶解促进剂。
3.权利要求2的制剂,其中所述溶解促进剂为载体分子。
4.权利要求3的制剂,其中所述载体分子为表面活性剂。
5.权利要求4的制剂,其中所述表面活性剂选自聚山梨酯和12-羟基硬脂酸的聚氧乙烯酯。
6.权利要求5的制剂,其中所述聚山梨酯为聚山梨酯80。
7.权利要求3的制剂,其中所述载体分子为β-环糊精。
8.权利要求1的制剂,其包括辅料。
9.权利要求8的制剂,其中所述辅料选自二甲亚砜(DMSO)、二甲基乙酰胺、生理学可接受的多元醇和醇。
10.权利要求1的制剂,其中所述赋形剂为生理学可接受的。
11.权利要求1的制剂,其中加环利定以0.01至5mM的浓度存在。
12.权利要求1的制剂,其具有280-310mOsm的渗透压。
13.权利要求1的制剂,其pH为5-10。
14.权利要求1的制剂,其pH为5.0-6.0。
15.权利要求1的制剂,其pH为6.0-7.9。
16.权利要求1的制剂,其中所述加环利定为加环利定碱。
17.权利要求1的制剂,其中所述加环利定为酸加成盐形式。
18.权利要求1的制剂,其中所述加环利定为加环利定碱和加环利定酸加成盐形式的混合物。
19.权利要求16、17或18的制剂,其包括载体分子。
20.权利要求19的制剂,其包括辅料。
21.权利要求1的制剂,其包括:
加环利定,浓度为1nM至5mM;和
聚山梨酯80,浓度为0.001%至30%(重量/重量)。
22.权利要求1的制剂,其还包括第二种治疗剂。
23.权利要求1的制剂,其中低于10%的加环利定在37℃下在4天内分解,所述分解通过哌啶的形成来测定。
24.固体载体,其包括固体加环利定游离碱。
25.权利要求24的固体载体,其为纳米颗粒。
26.权利要求25的固体载体,其悬浮在生理学可接受的赋形剂中。
27.权利要求24的固体载体,其选自胶原海绵、凝胶骨架、凝胶、聚合物基质和薄膜。
28.权利要求24的固体载体,其被涂布在装置上。
29.权利要求28的固体载体,其中所述装置为可植入的电极。
30.制备加环利定制剂的方法,其包括用包含溶解促进剂的赋形剂重构包含加环利定的冻干制剂。
31.权利要求30的方法,其中所述溶解促进剂提高了所述加环利定的化学稳定性。
32.通过冻干包括下列组分的制剂而制备的加环利定的冻干制剂:
加环利定;
赋形剂;和
一种或多种选自固体载体和辅料的组分。
33.向哺乳动物的中耳或内耳给药加环利定的方法,其包括向有此需要的哺乳动物给药:
(1)液体制剂,其包括加环利定、赋形剂和一种或多种选自溶解促进剂和辅料的组分;或
(2)固体载体,其包括固体加环利定游离碱。
34.权利要求33的方法,其中所述固体载体为悬浮在生理学可接受的赋形剂中的纳米颗粒。
35.权利要求33的方法,其中所述制剂为通过圆窗膜直接注射到中耳或内耳中而给药。
36.权利要求33的方法,其中所述制剂为通过耳蜗植入电极直接注射到内耳中而给药。
37.权利要求33的方法,其中所述制剂为使用选自蜗窗导管、海绵、凝胶和纱布条的装置给药。
38.权利要求33的方法,其中所述制剂为通过使用穿透鼓膜的针直接注射到中耳中而给药。
39.权利要求33的方法,其中所述制剂为通过外科手术植入到中耳中而给药。
40.权利要求33的方法,其中所述哺乳动物为人。
41.权利要求33的方法,其中所述人患有选自下述的疾病:耳呜、梅尼尔氏病、眩晕、中耳炎、内耳炎、感染、听力丧失和神经学损伤。
42.权利要求1的制剂,其包括
加环利定,浓度为50μM至5mM;和
聚山梨酯80,浓度为0.001%至30%(重量/重量)。
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US65820705P | 2005-03-04 | 2005-03-04 | |
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EP (2) | EP1861104A4 (zh) |
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US20060205789A1 (en) | 2006-09-14 |
EP1861104A2 (en) | 2007-12-05 |
US20120208848A1 (en) | 2012-08-16 |
WO2006096518A2 (en) | 2006-09-14 |
US20110136870A1 (en) | 2011-06-09 |
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