CN102753159A - 包含异丙酚的药物组合物 - Google Patents
包含异丙酚的药物组合物 Download PDFInfo
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- CN102753159A CN102753159A CN2010800524007A CN201080052400A CN102753159A CN 102753159 A CN102753159 A CN 102753159A CN 2010800524007 A CN2010800524007 A CN 2010800524007A CN 201080052400 A CN201080052400 A CN 201080052400A CN 102753159 A CN102753159 A CN 102753159A
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- propofol
- oral
- described compositions
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Abstract
本发明提供了包括活性成分异丙酚的新型药物组合物。优选地,异丙酚溶解于至少一种半氟化烷烃中。优选是液体或凝胶样的组合物可任选地包含其他赋形剂。其可用作胶囊中的填充材料,用作口腔喷雾剂或鼻喷雾剂,或用作肺部施用的气溶胶。其对于跨粘膜施用异丙酚是特别有用的。
Description
描述
背景
异丙酚(2,6-二异丙基苯酚,MW 178.27)是被称为有效静脉内麻醉剂的药理学活性化合物。其通常用于引起麻醉和麻醉维持两方面。其特征是其快速起效(onset of action)和其相对温和的副作用。
物理学上,异丙酚是在约19℃熔化的高度亲脂性化合物。在室温下,其具有油的外观。其在水或水性缓冲液中的溶解度可忽略不计,这使异丙酚尤其制备用于静脉内施用,还有用于其他途径来说是具有高度挑战性的化合物。该分子的唯一可电离基团是其羟基,然而由于其pKa为11,其不适合形成水溶性盐。在6-8.5的pH下,异丙酚的辛醇/水分配系数是6761∶1。
异丙酚首先由英国药物公司ICI(现在为AstraZeneca)研发成溶解的静脉内制剂,其包含大量的增溶剂一种不太容易耐受的赋形剂。引入市场之后不久,若干例过敏反应的报道导致该制剂退市。几年后,AstraZeneca开发了如今仍在使用的商标为的新型异丙酚制剂。该产品是包含1%异丙酚和作为分散相的10%大豆油和作为乳化剂的1.2%纯化的蛋黄卵磷脂的o/w-乳液。结合的水相包含2.25%的甘油和少量的EDTA和氢氧化钠。近几年来,一般的乳液制剂也已变得可在许多国家获得。
异丙酚被用于普通麻醉、通过机械手段吸氧的成人的镇静和手术镇静的诱导和维持。还处于实验阶段的其他临床用途包括用于控制癫痫持续状态、治疗头痛,特别是偏头痛、控制焦虑和急性脑损伤中的神经保护。例如在WO00/54588A1中教导的,这些用途经常只需要亚催眠剂量的异丙酚。
与用于麻醉中的其他化合物相比,异丙酚具有显著的安全性特征。其副作用通常是温和的且容易控制。单次剂量异丙酚的催眠作用通常在几分钟内逐渐消失。其快速起效和苏醒连同其遗忘作用已使该化合物非常适用于镇静和麻醉。与相似药物相比,其好像不引发呕吐。
典型的副作用中有伴随诱导剂量的血压降低和暂时的呼吸暂停。通常观察到轻微的肌阵挛运动。异丙酚乳液的另一个常见问题是其在注射或输注部位产生局部疼痛,由于该原因用局部麻醉剂例如利多卡因预处理某些患者。认为溶于乳液水相中的小部分异丙酚导致了这种疼痛。罕见但更严重的是张力障碍、高脂血症、胰腺炎和所谓的异丙酚输注综合征。在长期输注与儿茶酚胺和/或皮质甾类组合的高剂量异丙酚之后,在病情严重的患者中已发生了这种可能致命的代谢紊乱。
最近,异丙酚的其他静脉内制剂已被临床检测或引入市场。例如,已研究了带有仅5%大豆油和6%卵磷脂的1%异丙酚乳液。可能的是该制剂可能伴有较低风险的高脂血症和胰腺炎。同时,发现注射部位的疼痛甚至比用更明显。
其他制剂例如异丙酚-和异丙酚依赖更高比例的中链甘油三酯(MCT)取代乳液的油组分中的长链甘油三酯(LCT)。推测与LCT相比,成人和幼儿患者都更好地耐受MCT。然而,其也可释放有毒化合物例如乙酰乙酸酯、β-羟基丁酸酯和辛酸酯。
对于异丙酚,已建议的非乳液制剂包括水溶液,其中药物成分在环糊精的帮助下以溶解形式存在。环糊精是能够与客体分子形成包合络合物的水溶性环状低聚糖。特别地,已研究了分别带有羟丙基-β-环糊精和带有磺基丁基醚-β-环糊精的异丙酚溶液。然而,没有确定这些制剂的药代动力学是否与异丙酚乳液相当。然而,高剂量的环糊精通常伴有溶血作用和肾毒性。
US5,496,537描述了包含氢氟碳推进剂(propellant)的异丙酚气溶胶制剂。然而,对于可能不能进行所需要的呼吸运动的年幼和年老患者来讲推进剂推动的制剂吸入并不容易。另外,尚未确定异丙酚的肺部耐受性。
因此,需要进一步改进异丙酚制剂。例如,需要不产生载体相关的毒性作用例如高脂血症或溶血的制剂。另外,需要允许以方便、灵活且无痛的方式施用异丙酚的制剂和方法。
因此,本发明的目标是提供不具有目前已知制剂的一种或多种缺点的异丙酚制剂。另一个目标是提供以安全、可耐受且对患者友好的方式施用异丙酚的方法。以本说明书和专利权利要求书为基础,其他目标将变得明显。
发明概述
第一方面,本发明提供包含治疗有效量的异丙酚和半氟化烷烃的药物组合物。组合物通常是液体制剂或凝胶。在优选的实施方式中,异丙酚溶解于半氟化烷烃。组合物中异丙酚的浓度可以是1wt.-%或更高,例如5wt.-%或更高。
又一方面,本发明提供基于半氟化烷烃的异丙酚组合物的用途。在特别的实施方式中,局部施用该组合物,例如至口腔粘膜或鼻粘膜,或通过吸入局部施用该组合物。临床上,其可用于镇静或麻醉的诱导或维持。其他治疗用途包括防止或治疗头痛,例如偏头痛、防止或治疗呕吐,例如化疗引发的呕吐、控制癫痫持续状态、焦虑症或提供脑创伤中的神经保护。
又一方面,本发明提供包含这种异丙酚组合物的药物剂型例如软胶囊、口腔喷雾剂、口服凝胶、口服液体、鼻喷雾剂或呈定量气雾剂或雾化器溶液形式的可吸入气溶胶、以及包含该组合物的包装、容器或试剂盒。
从以下详细说明得出本发明的另外其他方面将是明显的。
发明详述
根据本发明的第一方面,提供了包含治疗有效量的异丙酚和半氟化烷烃的药物组合物。
如本文所用的,药物组合物是包含与至少一种药物赋形剂组合的至少一种药理学活性成分或诊断剂的组合物。
异丙酚指药理学活性化合物2,6-二(丙-2-基)苯酚(CAS号2078-54-8),或任何其盐、溶剂化物、络合物、共轭物和衍生物。优选地,用游离形式的非衍生异丙酚实施本发明,因为其也存在于目前可用的异丙酚药物产品中,例如
药物有效量是指对于产生期望的药理学效应有用的剂量、浓度或强度。根据患者(例如,成年的或年幼的、健康的或患病的)和期望的作用类型(例如,是镇静、麻醉,还是控制头痛),异丙酚的治疗有效量可显著不同。
半氟化烷烃是烷烃的一些氢原子已被氟取代的直链或支链烷烃。在优选的实施方式中,用于本发明中的半氟化烷烃(SFA)包括至少一种非氟化烃片段和至少一种全氟化烃片段。特别有用的是根据通式F(CF2)n(CH2)mH,具有一个非氟化烃片段与一个全氟化烃片段相连的SFA,或根据通式F(CF2)n(CH2)m(CF2)oF,两个全氟化烃片段被一个非氟化烃片段隔开的SFA。
本文使用的另一种命名法是将以上提及的具有两个或三个片段的SFA分别称为RFRH和RFRHRF,其中RF表示全氟化烃片段,RH表示非氟化片段。可选择地,该化合物可分别被称为FnHm和FnHmFo,其中F是指全氟化烃片段,H表示非氟化片段,且n、m和o是各个片段的碳原子数目。例如,F3H3用来表示全氟丙基丙烷。另外,这种类型的命名法通常用于具有直链片段的化合物。因此,除非另外指明,否则应认为F3H3指1-全氟丙基丙烷,而不是2-全氟丙基丙烷、1-全氟异丙基丙烷或2-全氟异丙基丙烷。
优选地,根据通式F(CF2)n(CH2)mH和F(CF2)n(CH2)m(CF2)oF的半氟化烷烃具有从3至30个碳原子范围内的片段大小,即n、m和o独立地选自从3至20的范围。还在US6,262,126、EP-A965334、EP-A965329和EP-A2110126中描述了在本发明的内容中有用的SFA,这些文件的公开内容并入本文。
在其他的实施方式中,半氟化烷烃是根据式RFRH的化合物,其片段RF和RH是直链的且各自(但彼此独立地)具有从3至20个碳原子。在另一个特别的实施方式中,全氟化片段是直链的且包含从4至12个碳原子,和/或非氟化片段是直链的且包含从4至8个碳原子。优选的SFA特别包括化合物F4H5、F4H6、F6H4、F6H6、F6H8和F6H10。目前实施本发明最优选的是F4H5、F6H6和F6H8。
任选地,该组合物可包含多于一种的SFA。例如,为了达到具体的目标特性例如特定密度或粘度,对SFA组合可能是有用的。如果使用SFA的混合物,另外优选的是混合物包含F4H5、F4H6、F6H4、F6H6、F6H8和F6H10中的至少一种,且特别是F4H5、F6H6和F6H8中的至少一种。在另一个实施方式中,混合物包含选自F4H5、F4H6、F6H4、F6H6、F6H8和F6H10中的至少两个成员,且特别是选自F4H5、F6H6和F6H8中的至少两个成员。
液体SFA是化学或生理学上惰性、无色且稳定的。其典型密度从1.1至1.7g/cm3变化,且其表面张力可低至19mN/m。RFRH类型的SFA是不溶于水的,而且是略微两亲的,具有与增大的非氟化片段的尺寸相关的增强的亲脂性。
RFRH类型的液体SFA正被商业用于眼科,特别是用于展开重新敷用的视网膜,用于长期填塞作为玻璃体液替代物(H.Meinert等人,EuropeanJournal of Ophthalmology,第10(3)卷,第189-197页,2000)和在玻璃体-视网膜手术之后作为残余硅油的洗出液。实验上,其也已被用作血液替代物(H.Meinert等人,Biomaterials,Artificial Cells,and ImmobilizationBiotechnology(生物材料、人造细胞和固定生物技术)第21(5)卷,第583-95页,1993)。这些应用已确定SFA为生理上耐受良好的化合物。
另一方面,SFA尚未用作迄今被批准的药物产品中的赋形剂。
现在本发明人已令人惊奇地发现SFA不仅能够溶解出乎预料高的量的异丙酚;而且所得的溶液在其他方面也是非常有优势的。例如,当对皮肤或粘膜施用时,其表现出优越的散布行为。同时,其不产生有机溶剂施用于皮肤或粘膜时通常观察到的任何刺激。另外,由于SFA提供了现有制剂例如的无类脂替代物,其避免了载体介导的高脂血症问题。
SFA中异丙酚的溶解性是明显的。就包括最优选的一些成员,即F4H5、F6H6和F6H8的大多数SFA而言,异丙酚是自由混溶的,在其他SFA中其显示出非常高的溶解度。已发现SFA溶液具有高达960mg/mL的异丙酚浓度是可能的。因此,本发明还提供了高度浓缩的异丙酚液体制剂。为能够安全且方便的给药和施用,本发明的组合物应通常具有从约0.001wt.-%至约90wt.-%范围内的强度(即,异丙酚浓度)。在其他实施方式中,异丙酚浓度分别从约0.01wt.-%至约80wt.-%,或从约0.1wt-%至约50wt.-%,或从约1wt.-%至约20wt.-%,或从约2wt.-%至约20wt.-%。在其他实施方式中,强度为约1wt.-%或更高,例如约2wt.-%、5wt.-%、10wt.-%、20wt.-%或25wt.-%。
兼具异丙酚的高溶解能力、良好的散布行为和对例如粘膜无刺激的效果还能够非注射施用异丙酚来获得全身疗效。例如,本发明的组合物可被设计成浓溶液(例如2至20wt.-%)以跨粘膜(例如,口腔或舌下)施用。组合物中的高药物浓度对活性成分通过粘膜屏障进入血流内的吸收提供了高的驱动力。同时,优越的散布行为保证了制剂与粘膜的紧密接触。由于异丙酚是小的且亲脂性的分子,在这些情况下可期望其将通过粘膜快速吸收。
可选择地,可通过常规口腔途径即咽下来施用组合物。任选地,液体填充的硬胶囊或软胶囊可用作该目的的剂型。对于更灵活的给药方案,从合适的玻璃或塑料容器分配的简单口服溶液也是有用的。
对于大多数目的,充分利用SFA对异丙酚的高溶解能力并将组合物设计成完全是溶液的,即其中包含的全部或基本上全部的药物成分是溶解形式将是有优势的。
优选地,组合物是液体形式或凝胶形式。如本文所用的,借助于其流变学特性限定凝胶。可用作药物剂型的凝胶是半固体的:当施加低剪切力时其表现得像固体,而高于特定的力阈值,所谓的“屈服点”,其表现得像粘性流体。取决于期望的施用部位和方式,例如为了实现在施用的局部部位更长时间的滞留,将本发明的组合物设计成凝胶而不是液体溶液可能是有用的。另一方面,如果组合物用作舌下胶囊的填充材料、作为口腔黏膜喷雾剂或鼻喷雾剂或作为可吸入气溶胶的话,液体形式是特别有优势的。
为将组合物转化成凝胶,可加入合适的凝胶形成赋形剂或赋形剂的混合物。这些赋形剂可以是与SFA或与其内溶解有药物成分的SFA混溶的固体材料例如固体SFA,或其可以是像胶体一样溶解在SFA内并形成产生半固体行为的相关分子的三维网络的材料。能够在无水体系中胶凝化的赋形剂的实例包括胶体二氧化硅(热解法二氧化硅)例如200,特定三萜(例如在DE102004030044A1中教导的)、N-硬脂酰基-L-丙氨酸甲酯、脱水山梨糖醇单硬脂酸酯和亲脂性纤维素衍生物例如乙基纤维素。
无论是液体形式或凝胶形式,如果需要的话,组合物可包含其他药物赋形剂。例如,其可掺入生理上可接受的其他有机溶剂,例如乙醇、丙酮、乙酸乙酯、异丙醇、甘油、丙二醇、聚乙二醇、液体石蜡、甘油三酯油、氢氟碳化合物例如HFA 134a和/或HFA 227、液体单酸甘油酯或甘油二酯或类似溶剂。取决于已被选择的SFA,这些溶剂的溶解力可被限制,这可以限制可以掺入的溶剂的量。为了改变组合物的性质例如密度、粘度、表面张力或蒸气压,这些溶剂的存在可以是有用的。为了更好地溶解组合物中还需要的另一种赋形剂,这些溶剂的存在也可能是有用的,如果该赋形剂不易于溶解在所选的SFA中的话。
如果期望以雾化形式施用组合物,例如口内用气溶胶、鼻用气溶胶或肺部用气溶胶,掺入推进剂例如HFA 134a和/或HFA 227可能是有用的。
取决于期望的具体用途,加入亲水性有机溶剂以还掺入某一少量的水可能是或可能不是可取的。在一个优选的实施方式中,本发明的组合物基本不含水。
任选地,组合物可包含表面活性剂。为了增强制剂与水性液体例如与口腔粘膜或鼻粘膜的粘液的相互作用,表面活性剂的掺入可能是有用的,且其还可改善组合物的散布,特别是在湿润的身体表面的分散。任选地,可使用多于一种的表面活性剂。合适的表面活性剂可选自就期望的施用途径来讲是生理上可接受的非离子型表面活性剂、阴离型表面活性剂、阳离子型表面活性剂和两性离子表面活性剂。可能有用的表面活性剂的实例包括天然的和纯化的卵磷脂、半合成的磷脂、泊洛沙姆、聚乙二醇化的甘油酯、d-α-生育酚聚乙二醇1000琥珀酸酯、聚山梨醇20、聚山梨醇80、失水山梨糖醇单油酸酯、M-1944CS、M-2125CS、 44/14、767和PEG 300、400或1750的单和二脂肪酸酯。
另外,例如如果制剂中的一种赋形剂易于氧化降解的话,组合物可包括任选地与增效剂组合的抗氧化剂。可能合适的抗氧化剂和增效剂的实例包括维生素E或维生素E衍生物,例如维生素E-TPGS、番茄红素和其衍生物、没食子酸酯、丁基羟基茴香醚和丁羟甲苯。
可按需加入的其他药物赋形剂包括着色剂、调味剂、掩味剂、甜味剂、生物粘合剂、粘度改进剂、稳定剂、防腐剂以及类似物。合适的脂溶性调味剂的实例包括精油例如薄荷油和桉树油、樟脑和薄荷醇。有用的防腐剂的实例包括山梨酸、羟苯甲酸甲酯、羟苯甲酸乙酯、羟苯甲酸丙酯、羟苯甲酸丁酯和羟苯甲酸苄酯、苯甲酸、苄醇、氯化丁醇、苯酚、苯氧乙醇、氯甲酚和间甲酚。然而,在优选的实施方式中,组合物基本不含类脂例如甘油三酯或磷脂以避免脂质有关的毒性如高脂血症。
另一方面,并与目前已知的异丙酚制剂相反,由于本发明的组合物优选是无水制剂,其将通常不需要掺入防腐剂。因此,本发明的其他实施方式是包括异丙酚和至少一种SFA的无水、无防腐剂组合物。由于防腐剂通常与有害反应的危害例如过敏症有关,能够提供不易于被微生物污染的无防腐剂组合物是本发明的相当大的优势。
在其他具体实施方式中,本发明的组合物是无菌的。在将其填充到合适的初级包装工具中之后,通过对制剂灭菌例如通过高压或γ-杀菌可实现无菌。可选择地,组合物可无菌过滤,然后无菌填充到无菌初级包装如玻璃管瓶或塑料管瓶中并密封。
又一方面,本发明还涉及包含本文所述的组合物的剂型。剂型应理解为适合施用的药物组合物或药物产品的类型。例如,可包含组合物的所关注的剂型是软质明胶胶囊、(内服)口腔喷雾剂、(内服)口服液体、(内服)口服凝胶、鼻喷雾剂、定量气雾剂、雾化器溶液、滴耳剂、直肠灌肠剂以及类似剂型。
软质明胶胶囊的优选类型设计为口服或口内施用。像大多数常规胶囊制剂一样,其可简单地用于吞咽。为了口内施用,可改动胶囊壳以容易咀嚼破碎,以使液体或凝胶样组合物释放到口腔中。由于异丙酚的特性和其在组合物中的高浓度,由此药物可通过口腔粘膜例如舌下、牙龈或口腔粘膜被吸收到血流中。带有用于口内施用的液体或半固体填充物的软质明胶胶囊的具体优点是其兼具固体剂型的典型优点(准确的剂量、方便处理和施用、稳定性高和保质期长)与口腔粘膜的吸收能力,这导致药理学效应的快速启动,而没有生物利用度限制的首过效应的任何可能性。
可选择地,如果以其他口内剂型施用组合物例如口内液体或喷雾剂,这些实施方式的优点是应用灵活的给药方案是特别容易的。例如,可容易地调整剂量以将期望的药理学效应(例如,无论是镇静、麻醉或控制偏头痛)、患者的类型(患病的或健康的、成年的或年幼的)考虑在内。另外,用于口腔粘膜吸收的口内液体或喷雾剂的施用允许剂量-效果型(dosing-to-effect)治疗,其中施用连续剂量直到在患者身上观察到期望疗效。
在其他实施方式中,组合物用于鼻施用。根据该用途,组合物可提供为鼻喷雾剂或以雾化气溶胶的形式提供,调整气溶胶液滴尺寸分布和流体动力学以实现鼻粘膜上的高度气溶胶沉积。小的亲脂性分子通过鼻粘膜吸收到血流中是可能的,且由于本发明的组合物包含高浓度的药物成分,而且处于耐受良好的载体中,其非常适合于实现该施用途径。另外,已发现可使用带有喷嘴的常规鼻用喷雾瓶容易地雾化本发明的组合物,产生直径约0.1至10μm的液滴。
实际上,根据其中组合物被包装并以带有喷嘴的喷雾瓶提供的实施方式具有其他优点:其既可用于口内施用又可用于鼻施用。
如提及的,使用例如计量剂量的吸入器或雾化器,还可通过吸入将组合物施用到肺内。这是可能的因为即使当吸入时,SFA是高度生物相容的且是生理上惰性的。
优选地,本发明提供的组合物和剂型用作可从接受异丙酚受益的所有患者的药物。特别地,提出诱导或保持麻醉或镇静、防止或治疗头痛例如偏头痛、治疗或防止呕吐例如化疗引发的呕吐、脑创伤或损伤中的中枢神经组织保护(神经保护)和控制焦虑的医疗用途是特别有优势的。
另外,该组合物和剂型还可用作牲畜和宠物两者的兽医药剂。特别地,推荐诱导和/或保持麻醉和镇静和控制焦虑方面的用途。
以下实施例用于说明本发明;然而,这些实施例不应理解为限制本发明的范围。
实施例
实施例1
在无菌条件下,在搅拌下向100mL的全氟丁基戊烷(F4H5)中加入1mg(5.6*10-3mmol)的异丙酚以形成澄清的溶液。再搅拌15分钟后,无菌过滤溶液并填充到随后被密封的无菌棕色玻璃管瓶中。
实施例2
在无菌条件下,在搅拌下向1mL的全氟丁基戊烷(F4H5)中加入1mg(5.6*10-3mmol)的异丙酚以形成澄清的溶液。再搅拌15分钟后,无菌过滤溶液并填充到随后被密封的无菌棕色玻璃管瓶中。
实施例3
在无菌条件下,在搅拌下向1mL的全氟丁基戊烷(F4H5)中加入100mg(0.56mmol)的异丙酚以形成澄清的溶液。再搅拌15分钟后,无菌过滤溶液并填充到随后被密封的无菌棕色玻璃管瓶中。
实施例4
在无菌条件下,在搅拌下向1mL的全氟丁基戊烷(F4H5)中加入1g(5.6mmol)的异丙酚以形成澄清的溶液。再搅拌15分钟后,无菌过滤溶液并填充到随后被密封的无菌棕色玻璃管瓶中。
实施例5
在无菌条件下,在搅拌下向1mL的全氟己基辛烷(F6H8)中加入100mg(0.56mmol)的异丙酚以形成澄清的溶液。再搅拌15分钟后,无菌过滤溶液并填充到随后被密封的无菌棕色玻璃管瓶中。
实施例6
在无菌条件下,在搅拌下向0.5mL的全氟己基辛烷(F6H8)和0.5mL的全氟丁基戊烷(F4H5)中加入100mg(0.56mmol)的异丙酚以形成澄清的溶液。再搅拌15分钟后,无菌过滤溶液并填充到随后被密封的无菌棕色玻璃管瓶中。
实施例7
在无菌条件下,在搅拌下向1mL的全氟己基辛烷(F6H8)中加入1g(5.6mmol)的异丙酚以形成澄清的溶液。再搅拌15分钟后,无菌过滤溶液并填充到随后被密封的无菌棕色玻璃管瓶中。
实施例8
在无菌条件下,在搅拌下向1mL的全氟丁基戊烷(F4H5)中加入100mg(0.56mmol)的异丙酚和2mg(4.6*10-3mmol)的α-生育酚以形成澄清的溶液。再搅拌15分钟后,无菌过滤溶液并填充到随后被密封的无菌棕色玻璃管瓶中。
实施例9
在无菌条件下,在搅拌下向1mL的全氟己基辛烷(F6H8)中加入100mg(0.56mmol)的异丙酚和30mg(7*10-2mmol)的α-生育酚以形成澄清的溶液。再搅拌15分钟后,无菌过滤溶液并填充到随后被密封的无菌棕色玻璃管瓶中。
实施例10
在无菌条件下,在搅拌下向1mL的全氟丁基戊烷(F4H5)中加入100mg(0.56mmol)的异丙酚和10mg(6.6*10-2mmol)的樟脑以形成澄清的溶液。再搅拌15分钟后,无菌过滤溶液并填充到随后被密封的无菌棕色玻璃管瓶中。
实施例11
在无菌条件下,在搅拌下向1mL的全氟丁基戊烷(F4H5)中加入100mg(0.56mmol)的异丙酚和100mg(2.2mmol)的乙醇以形成澄清的溶液。再搅拌15分钟后,无菌过滤溶液并填充到随后被密封的无菌棕色玻璃管瓶中。
实施例12
在无菌条件下,在搅拌下向1mL的全氟己基己烷(F6H6)中加入100mg(0.56mmol)的异丙酚和100mg(2.2mmol)的乙醇以形成澄清的溶液。再搅拌15分钟后,无菌过滤溶液并填充到随后被密封的无菌棕色玻璃管瓶中。
实施例13
类似于实施例1,制备具有400mg/g的标称异丙酚含量的两份异丙酚溶液。作为溶剂,第一份溶液包括全氟丁基戊烷(F4H5),而第二份溶液包含全氟己基辛烷(F6H8)。未使用其他成分。为了检测其稳定性,各份溶液的样品管瓶分别储存在25℃/60%RH、30℃/65%RH和40℃/75%RH下。在储存一个月之后和储存三个月之后,用GC/MS根据Ph.Eur.2.2.2分析样品。结果,所有样品中的异丙酚含量远高于标称值的95%,且还远高于制备溶液之后立即测量的实际含量的95%,从而表明制剂良好的稳定性。表1详细地示出了结果。所示百分比是相对于标称异丙酚含量而言的。
表1
实施例14
类似于实施例13,可替代地使用全氟丁基戊烷(F4H5)或全氟己基辛烷(F6H8)作为唯一的溶剂制备具有300mg/g的标称异丙酚含量的两份异丙酚溶液。对三只麻醉过的Wistar大鼠经口腔施用每种制剂的表示每Kg体重100mg异丙酚的量。具体地,将重348±24g的Wistar大鼠随机分成实验组(对于每组n=3)。对动物预充氧并用氯胺酮(10%,Pfizer,Karlsruhe,Germany)和甲苯噻嗪(BayerVital,Leverkusen,Germany)麻醉。将血管导管(Portex,Smiths medical,Kent,UK)放置于股动脉和股静脉中。将麻醉过的动物以仰卧姿势放置,剖开颈前并进行气管切开术。为了避免受试化合物的胃部或肠部位移,接着结扎相邻的食道。通过将血管导管连接到标准压力传感器上监测动脉血压。通过心电图(ECG)监测心率。使用直肠探头连续监测体温,并使用电热垫维持体温正常。用持续静脉输注氯胺酮和甲苯噻嗪维持麻醉直到实验完成。通过校准的特定多通道在线记录器(MedIS,Medical Device Integration System,HochschuleMannheim,Germany)监测并采集动脉压和ECG。用Fabian新生儿呼吸器(Acutronic Medical Systems AG,Hirzel,Switzerland)以压力控制模式(IPPV),且FiO2为0.5、潮气量为6ml/kg,呼吸末正压(positive end expiratory pressure)为3cm H2O且呼吸率为70-80min-1给动物通气。
在口腔内放置受试化合物(基准值)之前,收集基准血液样品(0.2μl)。使用实验用移液管将基于F4H5和F6H8的异丙酚制剂以大药丸施用到动物的颊囊内。每只动物接受100mg/kg体重的各溶液。平均每只动物接受34±2mg的异丙酚。在口腔施用受试化合物之后的第5、10、15、30、60、90和120分钟收集血液样品(0.2μl)。离心样品并储存在-20℃直到分析。用质谱(MS)和高效液相色谱(HPLC)进行异丙酚浓度的测定。
结果,血液动力学监测提供了制剂被良好耐受的证据。没有观察到心跳频率和动脉血压的变化。
在基于F4H5的制剂的情况下,在10分钟之后且在基于F6H8的制剂的情况下,在15分钟之后,通过高于100ng/ml的平均血浆水平升高表示异丙酚的全身吸收。在采样时间内,120分钟之后,观察到基于F4H5制剂的最大血浆水平为334ng/ml,且60分钟之后,在基于F6H8的制剂的情况下为259ng/ml。然而,至少对于基于F4H5的制剂来讲,在实验结束时显示还未达到实际最大血浆水平。表2中提供了全部采样时间的浓度。一般来讲,例如,在特别护理背景下,该异丙酚浓度稍微低于在使用异丙酚常规麻醉中通常观察到的那些浓度,尽管这样,仍认为对镇静是有效的。
表2
Cav:平均异丙酚血浆浓度(n=3)
SD:标准差
Claims (15)
1.一种药物组合物,包括治疗有效量的异丙酚和半氟化烷烃。
2.根据权利要求1所述的组合物,其中所述半氟化烷烃是式
RFRH
或式
RFRHRF
的化合物,
其中RF是带有20个或更少的碳原子的全氟化烃片段,且
其中RH是带有3至20个碳原子的非氟化烃片段。
3.根据权利要求2所述的组合物,其中所述半氟化烷烃是式
RFRH
的化合物,
其中RF是带有3至10个碳原子的直链全氟化烃片段,且
其中RH是带有3至10个碳原子的直链烷基。
4.根据权利要求3所述的组合物,其中所述半氟化烷烃选自F4H5、F6H6和F6H8。
5.根据任一前述权利要求所述的组合物,其中异丙酚的浓度为约1wt.-%或更高。
6.根据任一前述权利要求所述的组合物,其中所述组合物中包含的基本上所有异丙酚为溶解形式。
7.根据任一前述权利要求所述的组合物,所述组合物为液体或凝胶形式。
8.根据任一前述权利要求所述的组合物,所述组合物基本上不含类脂,例如甘油三酯或磷脂。
9.一种药物剂型,包含任一前述权利要求所述的组合物。
10.根据权利要求9所述的剂型,所述剂型选自软胶囊或口腔喷雾剂、鼻喷雾剂、可吸入气溶胶、口服凝胶和口服液体。
11.一种药物试剂盒,所述药物试剂盒包含容器和位于其中的权利要求1至8所述的组合物,其中所述容器包含用于雾化所述组合物的工具。
12.权利要求1至8所述的组合物或权利要求9或10所述的剂型作为药物的用途。
13.根据权利要求12所述的用途,其中所述药物用于口服施用、口腔粘膜施用或鼻施用。
14.根据权利要求12或13所述的用途,其中所述药物用于诱导麻醉、镇静,用于脑损伤的神经保护,或用于治疗偏头痛或呕吐。
15.权利要求1至8所述的组合物或权利要求9或10所述的剂型作为兽医药剂的用途。
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CA2834855C (en) | 2011-05-25 | 2020-12-29 | Novaliq Gmbh | Topical pharmaceutical composition based on semifluorinated alkanes |
EP2714008B1 (en) | 2011-05-25 | 2016-12-14 | Novaliq GmbH | Pharmaceutical composition for administration to nails |
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AU2013314303B2 (en) | 2012-09-12 | 2018-01-18 | Novaliq Gmbh | Semifluorinated alkane compositions |
PT2708228T (pt) * | 2012-09-12 | 2018-10-09 | Novaliq Gmbh | Composições de lavagem ocular |
MX363182B (es) | 2012-09-12 | 2019-03-13 | Novaliq Gmbh | Composiciones que comprenden mezclas de alcanos semifluorados. |
JP6503349B2 (ja) | 2013-07-23 | 2019-04-17 | ノバリック ゲーエムベーハー | 安定化された抗体組成物 |
EP2944324A1 (de) * | 2014-05-13 | 2015-11-18 | LTS LOHMANN Therapie-Systeme AG | Verwendung von semifluorierten Alkanen in transdermalen therapeutischen Systemen |
JP2017531011A (ja) | 2014-10-16 | 2017-10-19 | ザ ボード オブ トラスティーズ オブ ザ リーランド スタンフォード ジュニア ユニバーシティ | 麻酔のための新規の方法、化合物および組成物 |
US11154513B2 (en) | 2015-09-30 | 2021-10-26 | Novaliq Gmbh | Semifluorinated compounds |
EP3495023B1 (en) | 2015-09-30 | 2020-04-22 | Novaliq GmbH | Semifluorinated compounds and their compositions |
WO2017220625A1 (en) | 2016-06-23 | 2017-12-28 | Novaliq Gmbh | Topical administration method |
EP3515420B1 (en) | 2016-09-22 | 2023-11-08 | Novaliq GmbH | Pharmaceutical compositions for use in the therapy of blepharitis |
KR20190057338A (ko) | 2016-09-23 | 2019-05-28 | 노바리크 게엠베하 | 시클로스포린을 포함하는 안과 조성물 |
AU2018253944B2 (en) | 2017-04-21 | 2022-09-15 | Dermaliq Therapeutics, Inc. | Iodine compositions |
EP3621601A1 (en) | 2017-05-12 | 2020-03-18 | Novaliq GmbH | Pharmaceutical compositions comprosing semifluorinated alkanes for the treatment of contact lense-related conditions |
US11723861B2 (en) | 2017-09-27 | 2023-08-15 | Novaliq Gmbh | Ophthalmic compositions comprising latanoprost for use in the treatment of ocular diseases |
US11896559B2 (en) | 2017-10-04 | 2024-02-13 | Novaliq Gmbh | Opthalmic compositions comprising F6H8 |
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