CN109982704B - 药物制剂 - Google Patents
药物制剂 Download PDFInfo
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- CN109982704B CN109982704B CN201780046136.8A CN201780046136A CN109982704B CN 109982704 B CN109982704 B CN 109982704B CN 201780046136 A CN201780046136 A CN 201780046136A CN 109982704 B CN109982704 B CN 109982704B
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Abstract
本发明提供了一种适于口腔给药的药物组合物,该药物组合物包含2‑(1,5‑二甲基‑3‑苯基‑1H‑吡咯‑2‑基)‑N‑(4‑(4‑(5‑氟嘧啶‑2‑基)哌嗪‑1‑基)苯基)‑2‑氧代乙酰胺的颗粒。还提供了一种适于肠胃外给药的药物组合物,其中该组合物包含2‑(1,5‑二甲基‑3‑苯基‑1H‑吡咯‑2‑基)‑N‑(4‑(4‑(5‑氟嘧啶‑2‑基)哌嗪‑1‑基)苯基)‑2‑氧代乙酰胺。该组合物可用于治疗有需要的对象的真菌感染。
Description
技术领域
本发明涉及一种包含吡咯化合物的药物制剂。具体地,本发明涉及适于口腔给药的药物组合物,涉及适于肠胃外给药的药物组合物,以及该组合物在预防或治疗真菌疾病中的用途。本发明还涉及一种生产如本文所述的药物组合物的方法。
背景技术
侵袭性真菌感染被公认为免疫受损宿主的疾病。在过去的二十年中,记录的真菌感染病例的数量显著上升。部分原因是由于对真菌感染的认识的提高和诊断的改善。然而,该发病率增加的主要原因是易感个体人数大幅增加。这是由于许多因素造成的,包括新的和积极的免疫抑制疗法、重症监护病人的存活率增加、移植手术的数量增加以及全世界更多的抗生素使用。
在某些患者组中,真菌感染发生频率高;肺移植受者定植和感染真菌生物体的频率最高达20%,并且同种异体造血干细胞移植受者中真菌感染高达15%(Ribaud et al.,1999,Clin Infect Dis.28:322-30)。
最近人们越来越意识到真菌致敏、定植、过敏和局部感染对现有呼吸道疾病恶化的影响。这里真菌涉及哮喘、COPD、支气管扩张和囊性纤维化。过敏性支气管肺曲霉病(ABPA)是由真菌定植、通常由烟曲霉(Apsergillus fumigatus)定植引起的下呼吸道病症。哮喘患者中ABPA的发生率为0.7%-3.5%,囊性纤维化中ABPA的发生率为7%-9%。
目前有四类可用于治疗系统性真菌感染的抗真菌药。这些抗真菌药是多烯(例如两性霉素B),唑类(例如酮康唑或伊曲康唑),棘白菌素(例如卡泊芬净)和氟胞嘧啶。
多烯是20世纪50年代首次引入的最古老的抗真菌剂。其确切的作用方式仍不清楚,但多烯仅对其外膜中含有固醇的生物体有效。已经提出,两性霉素B与膜固醇相互作用以产生孔,该孔允许细胞质成分渗漏,随后细胞死亡。
唑类通过经由细胞色素P450依赖性机制抑制14α-脱甲基酶而起作用。这导致膜固醇麦角固醇的消耗和固醇前体的积累,从而引起质膜的流动性和结构改变。棘白菌素通过抑制细胞壁合成酶β-葡聚糖合酶而起作用。这导致异常的细胞壁形成、渗透敏感性和细胞裂解。
氟胞嘧啶是嘧啶类似物,其干扰细胞嘧啶代谢,以及DNA、RNA和蛋白质合成。但是,对氟胞嘧啶的普遍抗性限制了其治疗用途。
可以看出,迄今为止,目前可用的抗真菌剂主要仅作用于两种细胞靶标:膜固醇(多烯和唑类)和β-葡聚糖合酶(棘白菌素)。
对唑类和多烯的抗性已被广泛报道,仅留下最近引入的棘白菌素来对抗侵袭性真菌感染。随着棘白菌素的使用增加,真菌的抗性将不可避免地出现。
亟需识别新类型的抗真菌剂,以给患者带来积极的治疗结果。
吡咯化合物也已被识别为抗真菌剂。WO 2009/130481公开了可以用于预防或治疗真菌疾病的吡咯化合物。
发明内容
本发明人已经发现吡咯化合物2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)-2-氧代乙酰胺(式(I)化合物)是一种特别有效的抗真菌剂。它在酶抑制和真菌抑制测试中表现出高效力,并且具有良好的生物利用度和低毒性。测试已表明,该吡咯化合物抑制很多种真菌的生长,特别是人致病真菌曲霉菌(Aspergillus)。相比于其他吡咯化合物,这种特定化合物已经表现出对曲霉属中更广泛的物种具有活性。此外,已表明当与已知的抗真菌药伏立康唑相比时,该化合物表现出增强的体内功效,特别是对丝孢菌属真菌(Scedosporium fungi)表现出改善的功效。因此,化合物2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)-2-氧代乙酰胺可以用于有效地治疗很多种真菌感染和真菌疾病。这些结果在申请号为PCT/GB2015/053546的国际专利申请中进行了描述,其全部内容通过引用并入本文。
本发明人已经认识到需要吡咯化合物2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)-2-氧代乙酰胺的有效制剂。需要该化合物的具有高生物利用度和最小副作用的制剂,以在临床应用中获得最佳益处。还需要能够容易地给药至有需要的患者的2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)-2-氧代乙酰胺的制剂。
因此,本发明提供了一种适于口腔给药的药物组合物,其中该组合物包含式(I)化合物或其药学上可接受的盐的喷雾干燥颗粒,
2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)-2-氧代乙酰胺。
在一个方面中,该适于口腔给药的组合物包含式(I)化合物的喷雾干燥颗粒。在一个方面中,式(I)化合物基本上是无定形的。在一个方面中,该药物组合物还包含一种或多种辅料。在一个方面中,该组合物包含辅料羟丙基甲基纤维素乙酸琥珀酸酯(HPMCAS)。在一个方面中,式(I)化合物与辅料的质量比为1:100至1:1,例如1:15至1:2。在一个方面中,药物组合物包含可通过喷雾干燥包含有机溶剂的溶液而获得的颗粒,该有机溶剂选自二氯甲烷、甲醇及其混合物。在一个方面中,药物组合物是固体口腔剂型或液体口腔剂型的形式。在一个方面中,液体口腔剂型还包含药学上可接受的缓冲液,该缓冲液的pKa在6.0至8.0的范围内。在一个方面中,该缓冲液是1mM至200mM的磷酸缓冲液,其中该组合物被缓冲至约pH7。在一个方面中,该药物还包含一种或多种药学上可接受的粘合剂和/或载体和/或辅料和/或稀释剂和/或佐剂。
本发明还提供了一种适于肠胃外给药的药物组合物,其包含(i)式(I)化合物或其药学上可接受的盐,(ii)环糊精或改性环糊精,和(iii)聚乙二醇。
在一个方面中,适于肠胃外给药的组合物包含10wt%至40wt%的环糊精或改性环糊精,和/或10wt%至40wt%的聚乙二醇。在一个方面中,环糊精或改性环糊精是羟丙基-β-环糊精。在一个方面中,聚乙二醇是PEG300或PEG400。在一个方面中,该组合物还包含聚乙烯吡咯烷酮(聚维酮)。在一个方面中,式(I)化合物或其药学上可接受的盐以1mg/mL至10mg/mL的浓度存在。在一个方面中,该组合物还包含一种或多种药学上可接受的载体和/或辅料和/或稀释剂和/或佐剂。
本发明还提供了一种如本文所述的药物组合物,其用在治疗有需要的人或动物对象的方法中,特别是用在预防或治疗对象中的真菌感染的方法中。类似地,本发明提供了一种预防或治疗有需要的人或动物对象中的真菌感染的方法,所述方法包含对人或动物对象施用治疗有效量的如本文所述的药物组合物;和本文所述的药物组合物在制备用于预防或治疗有需要的人或动物对象中的真菌感染的药物中的用途。
本发明还提供了一种生产药物组合物的方法,该药物组合包含式(I)化合物或其药学上可接受的盐,其中所述方法包含喷雾干燥式(I)化合物或其盐的溶液。在一个方面中,该方法包括:(i)将一种或多种辅料溶解在溶剂中;(ii)将式(I)化合物加入步骤(i)所产生的溶液中;以及(iii)喷雾干燥步骤(ii)所产生的溶液。
本发明还提供了一种适于口腔给药的药物组合物,其中该组合物包含式(I)化合物或其药学上可接受的盐的基本上无定形的颗粒。
本发明的组合物是有益的,因为它们提供了式(I)化合物的极高生物利用度并且具有最小的副作用。
附图说明
图1展示了根据如实施例5所述的发明,从式(I)化合物的制剂的人体试验中获得的药代动力学数据。y轴:血浆Cmax(μg/mL);x轴:时间,以小时为单位。
图2显示了根据如实施例5所述的发明,从式(I)化合物的制剂的人体试验中获得的药代动力学数据。y轴:血浆Cmax(μg/mL);x轴:式(I)化合物的剂量(mg/kg)。
图3显示了根据如实施例5所述的发明,从式(I)化合物的制剂的人体试验中获得的药代动力学数据。y轴:血浆AUC0-C(μg.h/mL);x轴:式(I)化合物的剂量(mg/kg)。
具体实施方式
如本文所用,药学上可接受的盐是与药学上可接受的酸或碱形成的盐。药学上可接受的酸包括:无机酸,例如:盐酸、硫酸、磷酸、二磷酸、氢溴酸、氢碘酸或硝酸;和有机酸,例如:柠檬酸、富马酸、马来酸、苹果酸、抗坏血酸、琥珀酸、酒石酸、苯甲酸、乙酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、甲酸、乙酸、丙酸、乙醇酸、乳酸、丙酮酸、草酸、水杨酸、三氯乙酸、苦味酸、三氟乙酸、肉桂酸、双羟萘酸(pamoic)、丙二酸、扁桃酸、双亚乙基水杨酸、乙二磺酸、葡萄糖酸、柠康酸、天冬氨酸、硬脂酸、棕榈酸、EDTA、对氨基苯甲酸或谷氨酸;硫酸盐、硝酸盐、磷酸盐、高氯酸盐、硼酸盐、乙酸盐、苯甲酸盐、羟基萘甲酸盐、甘油磷酸盐或酮戊二酸盐。药学上可接受的无机或有机酸加成盐的进一步示例包括文献[Journal ofPharmaceutical Science,66,2(1977)]中所列出的药学上可接受的盐,其是本领域技术人员已知的。药学上可接受的碱包括碱金属(例如钠或钾)和碱土金属(例如钙或镁)的氢氧化物,以及有机碱,如烷基胺、芳烷基胺和杂环胺、赖氨酸、胍、二乙醇胺和胆碱。药学上可接受的酸加成盐还包括本发明的化合物所能形成的水合物。酸加成盐可以作为化合物合成的直接产物而获得。或者,可以将游离碱溶于含有适当的酸的合适溶剂中,并通过蒸发溶剂分离盐或通过其他方式分离盐和溶剂。利用本领域技术人员已知的方法,可使活性物质的化合物与标准低分子量溶剂形成溶剂化物。
除另有说明外,本文所提到的百分比均为重量百分比(wt%)。
本发明提供了一种适于口腔给药的药物组合物,其中该组合物包含式(I)化合物或其药学上可接受的盐的喷雾干燥颗粒,
2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)-2-氧代乙酰胺。
优选地,所述组合物包含式(I)化合物的喷雾干燥颗粒。最优选地,所述组合物包含游离碱形式的式(I)化合物。
喷雾干燥是一种众所周知的技术,其用于生产基本无定形的物质(例如药学活性物质,比如药)颗粒。喷雾干燥对于生产热敏性材料的固体颗粒尤其有益,并相对于其他干燥技术而言具有能够获得广泛一致的粒径的优点。任何合适的喷雾干燥装置都可用于干燥所述物质,而且许多喷雾干燥器都可商购获得。例如,喷雾干燥器可以是单效喷雾干燥器或多效喷雾干燥器。通常优选多效喷雾干燥器,因为它们可用于产生均匀的粒径。在对本领域技术人员而言易于获得的标准参考文献中对喷雾干燥器进行了描述,例如文献[S.Mujumdar,Handbook of Industrial Drying,CRC Press 2014],其描述了喷雾干燥技术及其最佳选择。
优选地,适于口腔给药的药物组合物包含基本无定形的式(I)化合物。无定形颗粒是一种缺乏长程晶序的颗粒。优选地,式(I)化合物超过50%无定形,例如超过70%无定形,更优选地超过90%无定形,还更优选地超过95%无定形,更优选地超过99%无定形,例如超过99.5%无定形或超过99.9%无定形。因此,基本无定形的颗粒是其中式(I)化合物具有低结晶度含量的颗粒,例如结晶度小于50%,例如结晶度小于30%,优选地小于10%,尤其是小于5%,例如结晶度小于1%,例如结晶度小于0.5%或小于0.1%。结晶度可以利用那些本领域技术人员熟知的方法测量。存在许多检测无定形颗粒的方法,其是本领域技术人员已知的,并且其能够用于确定颗粒是无定形的还是结晶的。这些方法包括但不限于粉末X射线衍射、差示扫描量热法、动态蒸汽吸附法、等温微量热法、反相气相色谱法、近红外光谱法和固态NMR。
优选地,适于口腔给药的药物组合物包含式(I)化合物的颗粒,该颗粒具有约0.5μm至约1000μm的平均粒径,更优选为约1μm至约500μm,例如约5μm至约100μm,例如约20μm至约50μm。术语“平均粒径”是指被称为D50的值。术语D50是指50vol%的颗粒具有小于该值的直径,50vol%的颗粒具有大于该值的直径。可以利用本领域已知的标准激光衍射粒径分析技术测量平均粒径。测量干粉的粒径的仪器的一个示例是由Malvern Instruments Ltd(Worcestershire,UK)制造的Mastersizer 2000。
优选地,适于口腔给药的药物组合物包含可通过喷雾干燥含有有机溶剂的溶液而获得的颗粒。优选地,该有机溶剂是选自二氯甲烷、丙酮、甲醇和乙醇的一种或多种溶剂。更优选地,该溶剂是选自二氯甲烷、丙酮、甲醇和乙醇中的两种或多种溶剂的混合物。还更优选地,该溶剂是二氯甲烷和/或丙酮与甲醇和/或乙醇的混合物。典型地,二氯甲烷和/或丙酮与甲醇和/或乙醇的比率为1:1至5:1,例如2:1至4:1,例如3:1。例如,该溶剂通常是二氯甲烷和甲醇的混合物,其中二氯甲烷与甲醇的比率为2:1至4:1,例如3:1。最优选地,溶剂为3:1比率的二氯甲烷和甲醇。溶剂的比率可通过质量或体积确定;优选体积比。
优选地,适于口腔给药的药物组合物还包含一种或多种辅料。本领域技术人员已知的药学上可接受的辅料包括,例如:粘合剂,如糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、聚乙烯吡咯烷酮(聚维酮)、甲基纤维素、乙基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、蔗糖和淀粉;填充剂和载体,例如玉米淀粉、明胶、乳糖、蔗糖、微晶纤维素、高岭土、甘露醇、磷酸二钙、氯化钠和海藻酸;和润滑剂,例如硬脂酸镁、硬脂酸钠和其它硬脂酸金属盐、硬脂酸甘油酯、硬脂酸、硅油、滑石蜡、油和硅胶。还可使用调味剂,例如薄荷、冬青油、樱桃调味料等。有可能需要加入着色剂以使剂型易于识别。还可以用本领域公知的方法对片剂进行包衣。
更优选地,适于口腔给药的药物组合物包含辅料,所述的辅料选自:(i)纤维素或改性纤维素,例如羟丙甲纤维素(Hypromellose)、羟丙基纤维素、羟丙基甲基纤维素(HPMC)、羟丙基甲基纤维素乙酸酯(HPMCA)和羟丙基甲基纤维素乙酸琥珀酸酯(HPMCAS);以及(ii)乙烯基吡咯烷酮-乙酸乙烯酯共聚物,该共聚物中乙烯基吡咯烷酮与乙酸乙烯酯的质量比为10:1至1:10,例如5:1至1:5,例如3:1至1:1,例如2:1至1:1,例如3:2(其还可表示为6:4),例如Kollidon VA64或Kollidon VA64 Fine,其二者均可从BASF公司获得;优选为Kollidon VA64。药物组合物可以包含(i)和(ii)的混合物。更优选地,适于口腔给药的药物组合物包含根据可选项(i)的纤维素基辅料。最优选的辅料包括HPMC、HPMCA和HPMCAS,尤其更优选HPMCAS。
HPMCAS是羟丙基甲基纤维素乙酸琥珀酸酯。聚合物中乙酰基和琥珀酰基的含量能够决定HPMCAS的性质。L型HPMCAS表示具有高的琥珀酰基取代:乙酰基取代比率的聚合物;典型地,14-18wt%的琥珀酰基含量和5-9wt%的乙酰基含量。M型HPMCAS表示具有低比率的聚合物;典型地,10-14wt%的琥珀酰基含量和7-11wt%的乙酰基含量。H型HPMCAS典型地包含4-8wt%的HPMCAS琥珀酰基含量和10-14wt%的乙酰基含量。L型HPMCAS通常在pH≥5.5左右溶解,M型HPMCAS通常在pH≥6.0左右溶解,而H型HPMCAS通常在pH≥6.8左右溶解。通常,HPMCAS包含12-28wt%的甲氧基和4-28%的羟丙氧基。HPMCAS易于从供应商处商购获得,例如从Shin-Etsu公司(产品AQOAT)处和从Ashland公司(“AquaSolve”)处获得。任何本领域技术人员已知的合适的HPMCAS均可使用。
优选地,当适于口腔给药的药物组合物中存在辅料时,式(I)化合物与辅料的质量比为1:100至1:1。更优选地,式(I)化合物与辅料的质量比为1:50至1:1,例如1:25至1:1.5,例如1:15至1:2,例如1:10、1:7、1:5、1:4或1:3。最优选地,式(I)化合物与辅料的质量比为1:9至1:11,例如1:10,或为1:3至1:5,例如1:4。式(I)化合物与辅料的质量比1:4可通过例如式(I)化合物与辅料的质量比4:16来实现。
本发明适于口腔给药的药物组合物典型地含有1wt%至50wt%的式(I)化合物;更典型地,为4wt%至40wt%,例如7wt%至30wt%。例如,药物组合物可以包含5wt%至20wt%,例如8wt%至15wt%,例如9wt%至11wt%,例如10wt%的式(I)化合物。例如,包含约10wt%式(I)化合物的组合物可以利用仅含式(I)化合物的组合物和辅料(例如HPMCAS)、用1:9的质量比(式(I)化合物:HPMCAS)来生产。或者,药物组合物可以包含10wt%至40wt%的式(I)化合物,例如15wt%至30wt%,例如18wt%至22wt%,例如约20wt%。例如,可以利用仅含式(I)化合物的组合物和辅料(例如HPMCAS)、用4:16的质量比(式(I)化合物:HPMCAS)来生产包含20wt%式(I)化合物的组合物。
适于口腔给药的药物组合物还可以包含一种或多种药学上可接受的粘合剂和/或载体和/或辅料(即,在上述辅料之外进一步包含)和/或稀释剂和/或佐剂。
适于口腔给药的药物可以优选地呈现为:离散单元,例如胶囊、小袋或片剂,其各自含有预定量的活性剂;粉末或颗粒;溶液或悬浮液,其中活性剂存在于水性液体或非水性液体中;或者水包油液体乳液或油包水液体乳液;或者丸,等等。优选地,适于口腔给药的药物组合物为(i)固体口腔剂型或(ii)液体口腔剂型的形式。更优选地,适于口腔给药的药物组合物为固体口腔剂型的形式。
固体口腔剂型包括例如片剂和胶囊。固体口腔给药剂型可以含有与活性化合物一起存在的:增溶剂,例如环糊精或改性环糊精;稀释剂,例如乳糖、葡萄糖、蔗糖、纤维素、玉米淀粉或马铃薯淀粉;润滑剂,例如二氧化硅、滑石、硬脂酸、硬脂酸镁或硬脂酸钙,和/或聚乙二醇;粘合剂,例如淀粉、阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素或聚乙烯基吡咯烷酮;分解剂,例如淀粉、海藻酸、藻酸盐或淀粉羟乙酸钠;泡腾混合物;染料;甜味剂;润湿剂,如卵磷脂、聚山梨醇酯、月桂基硫酸盐;以及通常用于药物制剂的无毒和药理学上无活性的物质。这种药物制剂可以以任何已知的方式制备,例如通过混合、制粒、压片、包糖衣或薄膜包衣工艺制得。
片剂可以通过压制或模制来制备,可选地具有一种或多种辅助成分。压制的片剂可以通过在合适的机器中压制自由流动形式(如粉末或颗粒形式)的活性剂(可选地,该活性剂与粘合剂、润滑剂、惰性稀释剂、防腐剂、表面活性剂或分散剂混合)来制备。模制的片剂可以通过在合适的机器中模制用惰性液体稀释剂润湿的粉末状化合物的混合物来制备。片剂可以任选地被包衣或刻痕,并且可以被制成能够提供活性剂的缓慢或可控释放。
其它固体口腔剂型包括锭剂和软锭剂,所述锭剂包含处于调味基质中的活性剂,所述调味基质通常是蔗糖和阿拉伯胶或黄芪胶,所述软锭剂包含处于惰性基质中的活性剂,所述惰性基质例如明胶和甘油,或蔗糖和阿拉伯胶。
液体口腔剂型包括溶液、糖浆、乳液和悬浮液。溶液可以含有增溶剂,例如环糊精或改性环糊精。糖浆可以含有作为载体的例如蔗糖或蔗糖与甘油和/或甘露醇和/或山梨醇。液体口腔剂型包括漱口水,所述漱口水包含处于合适的液体载体中的活性剂。
优选地,当适于口腔给药的药物组合物为液体口腔剂型的形式时,该液体口腔剂型还包含药学上可接受的缓冲液,该缓冲液的pKa在6.0至8.0范围内,优选为pH 7左右,例如pH 6.5至pH 7.5,例如pH 7.0至pH 7.5,优选地约为pH 7.1至pH 7.3,例如约pH7.2。能够将溶液的pH保持在该范围内的任何药学上可接受的缓冲液均能使用。例如,合适的缓冲剂盐包括柠檬酸盐(例如柠檬酸钠/柠檬酸)、磷酸盐(例如Na2HPO4/NaH2PO4)和碳酸盐(例如碳酸钠/碳酸氢钠)。优选为磷酸缓冲液。缓冲液的盐浓度能够是任何合适的盐浓度,以产生所期望的液体口腔制剂。通常,缓冲液中的盐浓度被选择用来维持溶液的pH在所期望的值,例如在pH 7左右(例如pH 7.2)。典型地,盐浓度为1mM至200mM,例如5mM至100mM,例如10mM至50mM,例如20mM至40mM,例如25mM左右、30mM左右或35mM左右。
因此,本发明适于口腔给药的优选组合物包含式(I)化合物或其药学上可接受的盐的喷雾干燥颗粒,其中式(I)化合物是基本无定形的,并且其中该组合物还包含一种或多种辅料。
适于口腔给药的本发明更优选组合物包含式(I)化合物的喷雾干燥颗粒,其中式(I)化合物是基本无定形的,并且其中该组合物还包含辅料羟丙基甲基纤维素乙酸琥珀酸酯(HPMCAS)。
适于口腔给药的本发明还更优选组合物包含式(I)化合物的喷雾干燥颗粒,其中式(I)化合物是基本无定形的,并且其中该组合物还包含辅料HPMCAS,其中式(I)化合物与辅料的质量比为1:100至1:1,优选地为1:15至1:2。
适于口腔给药的本发明更优选组合物包含式(I)化合物的喷雾干燥颗粒,其中式(I)化合物是基本无定形的并且可通过喷雾干燥含有有机溶剂的溶液而获得,该有机溶剂选自二氯甲烷、甲醇及其混合物,并且其中该组合物还包含辅料HPMCAS,并且其中式(I)化合物与辅料的质量比为1:15至1:2。
适于口腔给药的本发明最优选组合物包含式(I)化合物的喷雾干燥颗粒,其中式(I)化合物是基本无定形的,并且其中该组合物包含10wt%的式(I)化合物和90wt%的HPMCAS(即,式(I)化合物与HPMCAS的质量比为1:9)。式(I)化合物最优选地可通过喷雾干燥二氯甲烷:甲醇的3:1v/v混合物而获得。
类似地,适于口腔给药的本发明最优选组合物包含式(I)化合物的喷雾干燥颗粒,其中式(I)化合物是基本无定形的,并且其中该组合物包含20wt%的式(I)化合物和80wt%的HPMCAS(即,式(I)化合物与HPMCAS的质量比为1:4)。式(I)化合物最优选地可通过喷雾干燥二氯甲烷:甲醇的3:1v/v混合物而获得。
本发明还提供了一种适于口腔给药的药物组合物,其中该组合物包含式(I)化合物或其药学上可接受的盐的基本无定形颗粒。所述组合物如本文所述。
更优选地,本发明提供了一种包含式(I)化合物的适于口腔给药的药物组合物,其中式(I)化合物是基本无定形的,并且该组合物还包含HPMCAS,其中式(I)化合物与HPMCAS的质量比约为1:3至1:5,例如1:4,或约为1:8至1:10,例如约为1:9。因此,本发明提供了一种包含式(I)化合物和HPMCAS的适于口腔给药的药物组合物,其中式(I)化合物是基本无定形的,并且该组合物包含10wt%的式(I)化合物和90wt%的HPMCAS。本发明还提供了一种包含式(I)化合物和HPMCAS的适于口腔给药的药物组合物,其中式(I)化合物是基本无定形的,并且该组合物包含20wt%的式(I)化合物和80wt%的HPMCAS。
本发明还提供了一种生产药物组合物的方法,该药物组合物包含式(I)化合物或其药学上可接受的盐,
2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)-2-氧代乙酰胺,
其中所述方法包括喷雾干燥式(I)化合物或其盐的溶液。
任何合适的喷雾干燥技术均可使用。喷雾干燥如上所述。
优选地,生产适于口腔给药的药物组合物的方法包括以下步骤:
i)将一种或多种辅料溶解在溶剂中;
ii)将式(I)化合物加入到步骤(i)所产生的溶液中;以及
iii)喷雾干燥步骤(ii)所产生的溶液。
优选地,一种或多种辅料中的一种或多种为本文所述的辅料。更优选地,所述一种或多种辅料为(i)如本文所述的纤维素或改性纤维素,或(ii)如本文所述的乙烯基吡咯烷酮-乙酸乙烯酯共聚物,或(i)和(ii)的混合物。最优选地,所述辅料是如本文所述的HPMCAS。
优选地,所述溶剂是如本文所述的有机溶剂。更优选地,所述溶剂是二氯甲烷和/或丙酮与甲醇和/或乙醇的混合物。还更优选地,所述溶剂是二氯甲烷和甲醇的混合物,其中二氯甲烷与甲醇的比率为2:1至4:1,例如3:1。最优选地,所述溶剂是3:1比率的二氯甲烷:甲醇。
例如,因此本发明提供了一种生产如本文所述的适于口腔给药的药物组合物的方法,其中:
-辅料为羟丙基甲基纤维素乙酸琥珀酸酯(HPMCAS);
-溶剂是二氯甲烷和甲醇的混合物,其中二氯甲烷与甲醇的体积比为5:1至1:1;
-溶剂中辅料的浓度为5%至20%w/v;以及
-式(I)化合物被加入到辅料溶于所述溶剂所形成的溶液中,以得到质量百分比0.5%至10%的浓度。
更优选地,本发明提供了一种生产如本文所述的适于口腔给药的药物组合物的方法,其中:
-辅料为羟丙基甲基纤维素乙酸琥珀酸酯(HPMCAS);
-溶剂是二氯甲烷和甲醇的混合物,其中二氯甲烷与甲醇的体积比为4:1至2:1;
-溶剂中辅料的浓度为7%至18%w/v;以及
-式(I)化合物被加入辅料溶于溶剂所形成的溶液中,以得质量百分比0.5%至6%的浓度。
还更优选地,本发明提供了一种产生如本文所述的适于口腔给药的药物组合物的方法,其中:
-辅料为羟丙基甲基纤维素乙酸琥珀酸酯(HPMCAS)。
-溶剂是二氯甲烷和甲醇的混合物,其中二氯甲烷与甲醇的体积比约为3:1;以及
-(i)溶剂中辅料的浓度为约7wt%至约11wt%;并且式(I)化合物被加入到辅料溶于溶剂所形成的上述溶液中,以得到质量百分比为约0.5%至约2%的浓度;或
(ii)溶剂中辅料的浓度约为12%至约18%;并且式(I)化合物被加入到辅料溶于溶剂所形成的上述溶液中,以得到质量百分比约3%至约5%的浓度。
最优选地,本发明提供了一种生产适于口腔给药的药物组合物的方法,该方法包括:
i)将HPMCAS按约7wt%至约11wt%(例如约9wt%)的浓度溶解到溶剂中,其中该溶剂为二氯甲烷:甲醇的3:1v/v混合物;
ii)将式(I)化合物加入到步骤(i)所产生的溶液中以形成式(I)化合物的溶液,其中式(I)化合物的质量百分比浓度为约0.5%至约2%(例如质量百分比浓度约1%);以及
iii)对步骤(ii)所产生的溶液进行喷雾干燥。
类似地,本发明提供了一种生产适于口腔给药的药物组合物的方法,该方法包括:
i)将HPMCAS按约12wt%至约18wt%(例如约16wt%)的浓度溶解到溶剂中,其中该溶剂为二氯甲烷:甲醇的3:1v/v混合物;
ii)将式(I)化合物加入到步骤(i)所产生的溶液中以形成式(I)化合物的溶液,其中式(I)化合物的浓度为质量百分比约3%至约5%(例如质量百分比约4%);以及
iii)对步骤(ii)所产生的溶液进行喷雾干燥。
本发明还提供了一种适于肠胃外给药的药物组合物,该药物组合物包含:
(i)式(I)化合物或其药学上可接受的盐,
2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)-2-氧代乙酰胺
(ii)环糊精或改性环糊精,和
(iii)聚乙二醇。
药学上可接受的盐如本文所述。优选地,适于肠胃外给药的药物组合物包含式(I)化合物。更优选地,适于肠胃外给药的药物组合物包含游离碱形式的式(I)化合物。
优选地,环糊精以占药物组合物总重量的10wt%至40wt%的量存在。典型地,组合物中存在的环糊精的量为20wt%至30wt%,例如约25wt%。
优选地,聚乙二醇以占药物组合物总重量的10wt%至40wt%的量存在。典型地,组合物中存在的聚乙二醇的量为20wt%至30wt%,例如约25wt%。
适于肠胃外给药的药物组合物可以包含任何合适的环糊精或其混合物。典型的环糊精含有许多葡萄糖单体,该单体一个环中有6至8个单元,这些单体形成锥形。环糊精通常表示为α(alpha)-环糊精(包含6元糖环分子),β(beta)-环糊精(包含7元糖环分子)或γ(gamma)-环糊精(包含8元糖环分子)。由于环糊精内部疏水且外部亲水,它们能够与疏水化合物形成复合物。因此它们可以提高这种化合物的溶解度和生物利用度。FDA通常认为α-、β-和γ-环糊精都是安全的。环糊精(CD)能够通过各种方式改性,同时仍适于在本发明的组合物中使用。例如,已知的改性环糊精包括羟乙基-β-CD(HE-β-CD)、羟丙基-β-CD(HP-β-CD)、磺基丁醚-β-CD(SBE-β-CD)、甲基-β-CD(M-β-CD)、二甲基-β-CD(DM-β-CD/DIMEB)、随机二甲基化-β-CD(RDM-β-CD)、随机甲基化-β-CD(RM-β-CD)/RAMEB)、羧甲基-β-CD(CM-β-CD)、羧甲基乙基-β-CD(CME-β-CD)、二乙基-β-CD(DE-β-CD)、三-O-甲基-β-CD(TRIMEB)、三-O-乙基-β-CD(TE-β-CD)、三-O-丁酰基-β-CD(TB-β-CD)、三-O-戊酰基-β-CD(TV-β-CD)、二-O-己酰基-β-CD(DH-β-CD)、葡糖基-β-CD G1-β-CD麦芽糖基-β-CD(G2-β-CD)和2-羟基-3-三甲基-氨丙基-β-CD(HTMAPCD)。在标准参考文献中公开了环糊精及其在药物制剂中的用途,例如文献[和Szejtli,Cyclodextrins in Pharmacy,Springer,1993],其描述了特定环糊精在药物制剂中的优势。
优选地,环糊精选自羟丙基-β-环糊精和磺丁基醚-β-环糊精(Captisol)及其混合物。优选为羟丙基-β-环糊精。
适于肠胃外给药的药物组合物可以包含任何合适的聚乙二醇或其混合物。例如,该组合物可以包含任何批准用于静脉内使用的聚乙二醇。能够使用的聚乙二醇包括PEG200~PEG500,例如PEG300和/或PEG400。优选为PEG300和PEG400,而最优选PEG400。
正如本领域技术人员将理解,术语“PEG”后的数字(例如“PEG300”中的300)是指PEG分子的平均分子量。因此,PEG400通常在每个聚合物分子中包含大约9个乙二醇单元,并且PEG300通常在每个聚合物分子中包含7个乙二醇单元。然而,正如本领域技术人员将理解,许多可商购获得的PEG是多分散的。一般而言,分子量分布能够以其重均分子量(Mw)和其数均分子量(Mn)来进行统计学上的表征,其比率通常称作多分散指数(Mw/Mn)。Mw和Mn均能用常规的技术进行测量,例如,通过质谱分析。
优选地,适于肠胃外给药的药物组合物包含一种或多种分散剂,例如低分子量聚维酮(聚乙烯基吡咯烷酮)。优选地,聚维酮不含内毒素。聚维酮可从商业供应商处购得,例如Ashland(Plasdone)。优选地,聚维酮的K-值为5至20,例如10至18。例如,聚维酮的标称分子量可以约为4000,且K值可以为约10至约14。或者,聚维酮的标称分子量可以约为10000,且K值可以为约15至约18。K值是聚合物的平均聚合度和固有粘度的函数,并且能够从聚合物水性溶液的运动学粘度计算得到。优选地,聚维酮的Tg(玻璃化转换温度)为约110℃至约130℃,例如约120℃至约126℃。药物组合物可以包含两种或更多种聚维酮的混合物。
优选地,当适于肠胃外给药的药物组合物包含聚维酮或其混合物时,相对于该组合物的总质量,聚维酮或其混合物以0.1wt%至5wt%的量存在,更优选地为0.5wt%至2wt%,还更优选地约为1wt%。
优选地,存在于适于肠胃外给药的药物组合物中的式(I)化合物的浓度为1mg/mL至10mg/mL。更优选地,适于肠胃外给药的药物组合物中的式(I)化合物的浓度为2mg/mL至7mg/mL,例如3mg/mL至5mg/mL,例如4mg/mL。
适于肠胃外给药的药物组合物还可以包含一种或多种药学上可接受的载体和/或辅料和/或稀释剂和/或佐剂。例如,所述组合物可含有作为载体的例如无菌水,或者该组合物可以是无菌、水性的等渗盐水溶液的形式。
优选地,适于肠胃外给药的药物组合物被调节至最终pH为约pH 4至约pH 8。
更优选地,适于肠胃外给药的药物组合物被调节至最终pH为约pH 4至约pH 6,例如约pH 4.5至约pH 5.5,例如约pH 5,例如pH 5.0。可以用任何药学上可接受的酸或碱调节药物组合物的pH。优选为磷酸。
优选的药物组合物无菌且无热原。
因此本发明的适于肠胃外给药的优选组合物包含:
-10wt%至40wt%的环糊精或改性环糊精;
-10wt%至40wt%的聚乙二醇;以及
-分散剂,例如聚维酮。
例如,本发明适于肠胃外给药的组合物可以包含:
-1mg/mL至10mg/mL的式(I)化合物或其药学上可接受的盐;
-10wt%至40wt%的羟丙基-β-环糊精;
-10wt%至40wt%的PEG300或PEG400;以及
-分散剂,例如聚维酮,其中聚维酮如本文所述;以及
其中该组合物的pH被调节为约pH 4至约pH 8。
本发明适于肠胃外给药的更优选的组合物包含:
-1mg/mL至10mg/mL的式(I)化合物或其药学上可接受的盐;
-10wt%至40wt%的羟丙基-β-环糊精;
-10wt%至40wt%的PEG300或PEG400;以及
-分散剂,例如聚维酮,其中聚维酮如本文所述;以及
其中该组合物的pH被调节为约pH 4至约pH 6。
本发明适于肠胃外给药的还更优选的组合物包含:
-3mg/mL至5mg/mL的式(I)化合物;
-20wt%至30wt%的羟丙基-β-环糊精;
-20wt%至30wt%的PEG300或PEG400,优选PEG400;以及
-0.1wt%至5wt%的聚维酮;以及
其中该组合物的pH被调节为约pH 4.5至约pH 5.5。
本发明适于肠胃外给药的最优选的组合物包含:
-4mg/mL(相对于该组合物的最终体积)的式(I)化合物
-25wt%的羟丙基-β-环糊精;
-25wt%的PEG400;
-1wt%的聚乙烯基吡咯烷酮(聚维酮);
-用于将药物组合物的pH调节至pH5.0的足量磷酸;以及
-水,补足至100%。
如本文所述,本发明的药物组合物还能够包含一种或多种佐剂,例如局部麻醉剂、防腐剂或缓冲液。
药学上可接受的粘合剂包括溶液粘合剂和干粘合剂。溶液粘合剂溶解在溶剂(例如水或醇可用于湿法制粒过程)中。示例包括明胶、纤维素、纤维素衍生物、聚乙烯基吡咯烷酮、淀粉、蔗糖和聚乙二醇。干粘合剂在湿法制粒步骤之后、或者作为直接粉末压缩(DC)配方的一部分被加入到粉末混合物中。示例包括纤维素、甲基纤维素、聚乙烯基吡咯烷酮和聚乙二醇。
药物载体包括脂质体、纳米球、胶束、蛋白质-DNA复合物、纳米凝胶和天然溶剂如水溶液和非水溶液。
可用作辅料、稀释剂或载体的其他物质包括:阿拉伯胶、藻酸盐、海藻酸、乙酸铝、苯甲醇、对羟基苯甲酸丁酯、丁基化羟基甲苯、柠檬酸、碳酸钙、小烛树蜡、交联羧甲基纤维素钠、糖果糖、胶体二氧化硅、纤维素、磷酸钙、巴西棕榈蜡、玉米淀粉、羧甲基纤维素钙、硬脂酸钙、EDTA二钠钙、共聚维酮、氢化蓖麻油、无水磷酸氢钙、氯化十六烷基吡啶、盐酸半胱氨酸、交联聚维酮、磷酸氢二钠、二甲基硅油、赤藓红钠、乙基纤维素、明胶、甘油单油酸酯、甘油、甘氨酸、单硬脂酸甘油酯、甘油山嵛酸酯、羟丙基纤维素、羟丙基甲基纤维素、羟丙甲纤维素(hypromellose)、HPMC邻苯二甲酸酯、乳糖、硬脂酸镁、甘露醇、甲基纤维素、碳酸镁、矿物油、氧化镁、甲基对羟基苯甲酸酯、聚维酮、聚山梨醇酯80、聚环氧乙烷、泊洛沙姆(polaxamer)407或188、碳酸氢钾、山梨酸钾、马铃薯淀粉、磷酸、聚氧硬脂酸酯、羟基乙酸淀粉钠、交联羧甲基纤维素钠、十二烷基硫酸钠、淀粉、二氧化硅、苯甲酸钠、硬脂酸、蔗糖、山梨酸、碳酸钠、糖精钠、海藻酸钠、硅胶、山梨糖醇单油酸酯、硬脂酰富马酸钠、氯化钠、偏亚硫酸氢钠、柠檬酸钠脱水物、羧甲基纤维素钠、琥珀酸、丙酸钠、二氧化钛、滑石、三乙酸甘油酯和柠檬酸三乙酯。
如本文所述的药物组合物可以包含式(I)化合物的颗粒,其中平均粒径(如本文所述)通过微粉化或纳米化技术进行了粒径减小。
本发明的组合物特别有利,因为它们提供了生物利用度提高的式(I)化合物。如本文所用,生物利用度被定义为使得药,例如式(I)化合物,当静脉内施用时具有100%的生物利用度。本发明的适于口腔给药的药物组合物特别有益,因为它们能够提供具有高的生物利用度的式(I)化合物。优选地,本发明的组合物提供了具有至少50%的生物利用度的式(I)化合物,更优选地为至少70%,例如至少80%,还更优选地至少90%,例如至少95%。如本领域技术人员将理解的,生物利用度可由多个因素决定,包括施用该组合物的对象的性质(年龄、体重、性别等)。因此,1个对象组中的阴性结果不是决定性的。
生物利用度可由药代动力学(PK)研究来确定,其中血浆药物浓度被确定为静脉内(IV)和血管外(如口腔)给药后的时间函数。绝对生物利用度(Fabs)是曲线(AUC)(非静脉内)下的剂量(D)-校正面积除以AUC(静脉内)下的剂量(D)-校正面积。如本文所用,通过口腔给药途径(PO)施用的药的Fabs的计算如下:
本发明的组合物在治疗有需要的人或动物对象的医学病症中是有用的。
因此,本发明提供了一种如本文所述的药物组合物,其在有此需要的人或动物对象的治疗方法中使用。优选地,本发明提供了一种如本文所述的药物组合物,其在有此需要的人或动物对象的治疗中使用,其中所述治疗包含预防或治疗对象的真菌感染。
本发明还提供了一种预防或治疗有需要的人或动物对象的真菌感染的方法,所述方法包括对人或动物对象施用治疗有效量的如本文所述的药物组合物。
本发明还提供了如本文所述的药物组合物在制备用于预防或治疗有需要的人或动物对象的真菌感染的药物中的用途。
本发明的药物组合物可以用在人或动物对象的治疗方法中,其中所述治疗包括将该组合物与如本文所述的进一步抗真菌剂联合给药。
可以对有需要的患者施用治疗有效量的本发明的组合物。例如,通常根据(例如)要被治疗的对象的年龄、体重和症状,疾病的类型和严重程度,以及给药的频率和途径,以一定的量施用该组合物,例如为对象提供最高达每kg体重200mg式(I)化合物的日剂量,例如最高达每kg体重100mg或最高达每kg体重50mg,例如每kg体重0.001mg至200mg或每kg体重0.001mg至50mg。优选地,日剂量水平为最高达每kg体重200mg,例如最高达每kg体重150mg,最高达每kg体重100mg,最高达每kg体重50mg,或最高达每kg体重40mg。日剂量水平例如为每kg体重至少1mg,每kg体重至少2mg,或每kg体重至少5mg。在一个实施例中,日剂量水平为0.05mg至2g,优选地为0.1mg为10mg。适当的剂量水平可由本领域的医生很容易地确定。
在本发明的组合物与第二抗真菌剂一起施用的情况下,第二抗真菌剂通常在该药所使用的标准剂量或其以下施用。通过这种方式,已知的抗真菌剂可以按比目前所使用的更低的剂量施用,由此使得毒性作用降低。
本发明的组合物可以用于治疗或预防真菌疾病。优选地,所述真菌疾病包含真菌感染,所述真菌例如子囊菌(Ascomycete)。优选地,真菌疾病包含选自以下属的生物体的感染:犁头霉属(Absidia);枝顶孢霉属(Acremonium);链格孢属(Alternaria);曲霉属(Aspergillus);离蠕孢属(Bipolaris);芽生菌属(Blastomyces);白粉菌属(Blumeria);枝孢属(Cladosporium);球孢子菌属(Coccidioides);刺盘孢属(Colletotrichium);弯孢霉属(Curvularia);脑胞内原虫属(Encephalitozoon);附球菌属(Epicoccum);表皮癣菌属(Epidermophyton);外瓶霉属(Exophiala);突脐蠕孢属(Exserohilum);镰刀菌属(Fusarium);组织胞浆菌属(Histoplasma);小球腔菌属(Leptosphaeria);小孢霉属(Microsporum);球腔菌属(Mycosphaerella);脉孢菌属(Neurospora),拟青霉属(Paecilomyces);青霉菌属(Penicillium);疫霉属(Phytophthora);单轴霉属(Plasmopara);肺囊虫属(Pneumocystis);梨孢属(Pyricularia);腐霉属(Pythium);柄锈菌属(Puccinia);丝核菌属(Rhizoctonia);根毛霉属(Rhizomucor);丝孢菌属(Scedosporium);帚霉属(Scopulariopsis);毛癣菌属(Trichophyton);毛孢子菌属(Trichosporon);和黑粉菌属(Ustilago)。
优选地,真菌疾病包含曲霉属(Aspergillus),丝孢菌属(Scedosporium)或镰刀菌属(Fusarium)的生物体的感染,例如真菌疾病包含由曲霉属(Aspergillus)或丝孢菌属(Scedosporium)的生物体的感染,特别是曲霉属(Aspergillus)。在一个实施例中,真菌疾病包括由曲霉属(Aspergillus)的生物体引起的感染。在另一个实施例中,真菌疾病包含由丝孢菌属(Scedosporium)的生物体引起的感染。
优选地,真菌疾病包含选自以下种的生物体的感染:伞枝犁头霉(Absidiacorymbifera);枝顶孢霉属内的菌种(Acremonium spp);链格孢菌(Alternariaalternata);黄曲霉(Aspergillus flavus);烟曲霉(Aspergillus fumigatus);构巢曲霉(Aspergillus nidulans);黑曲霉(Aspergillus niger);寄生曲霉(Aspergillusparasiticus);土曲霉(Aspergillus terreus);离蠕孢属内的菌种(Bipolaris spp);皮炎芽生菌(Blastomyces dermatitidis);禾本科布氏白粉菌(Blumeria graminis);芽枝状枝孢菌素菌(Cladosporium cladosporoides);分支孢子菌(Cladosporium herbarium);粗球孢子菌(Coccidioides immitis);Coccidioides posadasii;新月弯孢霉(Curvularialunata);三叶草刺盘子孢(Colletotrichium trifolii);兔脑炎原虫(Encephalitozooncuniculi);黑附球菌(Epicoccum nigrum);絮状表皮癣菌(Epidermophyton floccosum);外瓶霉属内的菌种(Exophiala spp);嘴突凸脐蠕孢(Exserohilum rostratum);禾谷镰刀菌(Fusarium graminarium);茄病镰刀菌(Fusarium solani);拟分枝抱镰刀菌(Fusariumsporotrichoides);荚膜组织胞浆菌(Histoplasma capsulatum);颖枯壳小球腔菌(Leptosphaeria nodorum);犬小孢子菌(Microsporum canis);禾生球腔菌(Mycosphaerella graminicola);Paecilomyces lilanicus;拟青霉(Paecilomycesvarioti);黄青霉(Penicillium chrysogenum);辣椒疫霉菌(Phytophthora capsici);致病疫霉(Phytophthora infestans);霜霉病(Plasmopara viticola);耶氏肺孢子虫(Pneumocystis jiroveci);禾冠柄锈菌(Puccinia coronata);禾柄锈菌(Pucciniagraminis);稻瘟霉(Pyricularia oryzae);极腐霉(Pythium ultimum);立枯丝核菌(Rhizoctonia solani);根毛霉菌属内的菌种(Rhizomucor spp);根霉菌属内的菌种(Rhizopus spp);尖端赛多孢子菌(Scedosporium apiospermum);赛多孢(Scedosporiumprolificans);丝孢菌属菌种d(Scedosporium species d);短帚霉(Scopulariopsisbrevicaulis);须毛癣菌(Trichophyton mentagrophytes);指间毛癣菌(Trichophytoninterdigitale);红色毛癣菌(Trichophyton rubrum);阿氏丝孢酵母(Trichosporonasahii);白吉利毛孢子菌(Trichosporon beigelii);和玉蜀黍黑粉菌(Ustilagomaydis)。
优选地,真菌疾病包含由烟曲霉(A.fumigatus),黄曲霉(A.flavus),土曲霉(A.terreus),黑曲霉(A.niger),A.lentulus,尖端赛多孢子菌(S.apiospermum),赛多孢(S.prolificans),或丝孢菌属菌种d(S.species d)引起的感染。优选地,真菌疾病包含由烟曲霉(A.fumigatus),黄曲霉(A.flavus),土曲霉(A.terreus)或黑曲霉(A.niger)引起的感染。在一个实施例中,真菌疾病包括由赛多孢(S.prolificans)引起的感染。
可用本发明的组合物预防或治疗的真菌疾病的例子包括系统性感染和浅表性感染。真菌疾病包括由曲霉种引起的侵袭性真菌疾病,例如曲霉病,还包括这些感染的局部形式。例如,真菌疾病包括由曲霉种引起的侵袭性真菌疾病,例如曲霉病,还包括这些感染的局部形式。本发明的组合物对由曲霉种引起的疾病特别有用,对于该疾病需要毒性低于两性霉素的杀真菌药。本发明还用于治疗皮肤病感染。
在一个实施例中,本发明的药物组合物是用于预防或治疗由曲霉种引起的疾病。由曲霉种引起的疾病包括由烟曲霉(A.fumigatus),黄曲霉(A.flavus),土曲霉(A.Terreus)和黑曲霉(A.niger)引起的疾病。
可以用本发明的药物组合物预防或治疗的系统性感染的例子包括:肺曲霉病(pulmonary aspergillosis),例如在免疫抑制患者(如骨髓受者或AIDS患者)中;系统性曲霉病(systemic aspergillosis);鼻脑毛霉菌病(rhinocerebral mucomycosis);芽生菌病(blastomycosis);组织胞浆菌病(histoplasmosis);球孢子菌病(coccidiomycosis);副球孢子菌病(paracoccidiomycosis);瘢痕疙瘩性芽生菌病(lobomycosis);孢子丝菌病(sporotrichosis);着色芽生菌病(chromoblastomycosis);暗色丝孢霉病(phaeohyphomycosis);和播散性孢子丝菌病(disseminated sporotrichosis)。
能够用本发明的药物组合物预防或治疗的浅表性感染的例子包括:环虫;足癣;和甲癣(指甲感染)。
由真菌引起、或其中真菌加剧过敏反应、并且可用本发明的药物组合物预防或治疗的疾病或症状包括:过敏性支气管肺曲霉病(ABPA);哮喘,真菌致敏性严重哮喘(SAFS),囊性纤维化真菌定植,鼻窦炎(rhinosinusitis)和窦炎(sinusitis)。例如,疾病可以是由于真菌致敏引起的,或者疾病可以是过敏性支气管肺曲霉病(ABPA)或哮喘。
本文所述的药物组合物可与第二抗真菌剂组合施用。优选地,所述药物组合物与所述第二抗真菌剂分开施用或相继施用。例如,本发明的组合物和第二抗真菌剂可以作为试剂盒提供。因此所述试剂盒包含本发明的组合物和第二抗真菌剂。
第二抗真菌剂可以是本领域技术人员将认为在此情况下有用的任何合适的抗真菌剂。例如,本文所述的任何症状都能以其方式治疗。
特别地,合适的抗真菌剂类别包括唑类,多烯类,嘌呤核苷酸抑制剂,嘧啶核苷酸抑制剂,甘露聚糖抑制剂,蛋白质延长因子抑制剂,几丁质合成酶抑制剂,β-葡聚糖合酶抑制剂,棘白菌素,烯丙胺,抗HSP90抗体,杀菌/渗透诱导蛋白质产品和多氧霉素。不属于上述类别的其他合适的抗真菌剂包括化合物5-氟-1,3-二氢-1-羟基-2,1-benzoxaborale(AN269),5-氯-1,3-二氢-1-羟基-2,1-benzoxaborale(AN2718)和艾芬净喷(icofungipen)。
例如,第二抗真菌剂可以选自唑类,多烯类,嘌呤核苷酸抑制剂,嘧啶核苷酸抑制剂,甘露聚糖抑制剂,蛋白质延长因子抑制剂,棘白菌素,烯丙胺,抗HSP90抗体,杀菌/通透性诱导蛋白质产品或多氧霉素,或以下化合物中的一种:5-氟-1,3-二氢-1-羟基-2,1-benzoxaborale(AN269),5-氯-1,3-二氢-1-羟基-2,1-benzoxaborale(AN2718),艾芬净喷,VT116或SCY078。
VT116是2-吡啶乙醇,α-(2,4-二氟苯基)-β,β-二氟-α-(1H-四唑-1-基甲基)-5-[4-(2,2,2-三氟乙氧基)苯基]-,(αR)-,
且SCY078 078(又名MK-3118)是enfumafungin的半合成衍生物,4H-1,4a-丙桥-2H-菲并[1,2-c]吡喃-7-羧酸,15-[(2R)-2-氨基-2,3,3-三甲基丁氧基]-8-[(1R)-1,2-二甲基丙基]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-十二氢-1,6a,8,10a-四甲基-14-[5-(4-吡啶基)-1H-1,2,4-三唑-1-基]-,(1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R):
优选的唑类是克霉唑,益康唑,联苯苄唑,布康唑,芬康唑,氟康唑,异康唑,伊曲康唑,酮康唑,咪康唑,奥昔康唑,舍他康唑,硫康唑,噻康唑,艾沙康唑,雷夫康唑,泊沙康唑,特康唑和伏立康唑,卢立康唑。优选的棘白菌素是阿尼芬净(anidulafungin),卡泊芬净,米卡芬净和比安芬格(biafungin)。优选的烯丙胺是特比萘芬,布替萘芬,阿莫罗芬和萘替芬。优选的多烯是两性霉素B和制霉菌素。嘌呤核苷酸抑制剂或嘧啶核苷酸抑制剂的优选示例是氟胞嘧啶。优选的甘露聚糖抑制剂是普拉霉素。优选的蛋白质延长因子抑制剂是粪壳菌素及其类似物。优选的多氧霉素是尼可霉素Z。
特别优选的第二抗真菌剂是卡泊芬净,米卡芬净,阿尼芬净,两性霉素B,伏立康唑,泊沙康唑,艾沙康唑,氟康唑和伊曲康唑。
合成
式(I)化合物为2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)-2-氧代乙酰胺,或其药学上可接受的盐。
2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)-2-氧代乙酰胺
本文描述了式(I)化合物的一种合成途径。一般而言,式(I)化合物可以通过式(II)化合物与式(III)化合物的反应来合成。通常该反应在有机溶剂和碱的存在下进行。优选地,该溶剂为二氯甲烷或四氢呋喃,所述碱为三乙胺或吡啶。通常该反应初始在0℃进行,同时加入试剂,然后在室温下搅拌直到反应完成。式(III)化合物通常可从商业来源获得或可通过已知方法制备。
式(II)化合物可以通过式(IV)化合物优选地与草酰氯反应来制备。通常该反应在有机溶剂中进行。优选地,该溶剂为二氯甲烷。通常该反应初始在0℃进行,同时加入试剂,然后在室温下搅拌直到反应完成。
在上述反应中所提及的所有原始材料均从商业来源获得,或者可通过与已知方法类似的方法来制备。
以下实施例用于解释本发明,而不是旨在限制本发明的范围。在这方面,重要的是理解实施例部分中所用的特定分析方法仅设计为提供抗真菌活性的指示。有许多可用于测定这种活性的分析方法,因此任何一种特定分析方法中的阴性结果都不是决定性的。
实施例
实施例1:式(I)化合物(2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)-2-氧代乙酰胺)的合成
式(I)化合物的合成在申请号为PCT/GB2015/053546的国际专利申请中进行了描述。与式(I)化合物的合成相关的信息通过引用并入此处。以下实施例复制自该专利申请。
以下合成方案提供了以下物质的合成方法:
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2-羟基亚氨基-3-氧代-3-苯基丙酸乙酯(A)
将亚硝酸钠(1.07Kg,45.62mol)的水(4L)溶液缓慢加入到乙酸苯甲酰乙酯(2Kg,10.41mol)的冰醋酸(6L)溶液中,在0-10℃下保持2h。产物在添加过程中开始沉淀。将反应物料温热至室温并再搅拌1h。加入水(2.5L),将混合物再搅拌1h。抽吸过滤,用水(2L)洗涤。将固体溶于三氯甲烷(8L)中,用水(2×500mL)、盐水溶液(2×500mL)洗涤,用无水硫酸钠干燥,真空浓缩至干燥,得到2.0Kg(86%)2-羟基亚氨基-3-氧代-3-苯基丙酸乙酯A,为白色固体。[TLC系统:乙酸乙酯:石油醚(3:7);Rf值:0.28]。
5-甲基-3-苯基-1H-吡咯-2,4二羧酸二乙酯(B)
将乙酰乙酸乙酯(329g,2.53mol)、锌粉(443g,6.78mol)和无水乙酸钠(463g,5.65mol)加入冰醋酸(800mL)中形成的混合物加热至60℃。在剧烈搅拌下,在约1h内,将A(500g,2.26mol)的冰醋酸(1.5L)溶液分三份加入。在加入期间温度迅速上升至约93℃。将反应混合物在60-75℃保持3h。在15分钟内向反应物料中加入额外的锌粉(221g,3.39mol),并且将混合物在60-75℃下搅拌1h,冷却至室温并过滤固体。真空蒸发滤液,并将残留物与甲苯(2×500mL)共同蒸馏。向残留物中加入水(5L)和乙酸乙酯(1L),搅拌至得到两层澄清层。相继用水(2×500mL)、饱和碳酸氢盐溶液(2×500mL),盐水(2×500mL)洗涤有机层,用无水硫酸钠干燥,并浓缩得到360g胶状粗产物。将其与二氯甲烷:石油醚的混合物(200mL:1200mL;1:6)在室温下搅拌15min,过滤并用石油醚(100mL)洗涤,得到250g(36%)5-甲基-3-苯基-1H-吡咯-2,4二羧酸二乙酯B,为灰白色固体。[TLC系统:乙酸乙酯:石油醚(3:7);Rf 值:0.45]。类似地,将1.5Kg(500g×3)的A分三次转化为500g(245g(36%)+255g(37%)+250g(36%))的B。
1,5-二甲基-3-苯基-1H-吡咯-2,4-二羧酸二乙酯(C)
在0℃下,在1h内将B(1Kg,3.322mol)的无水四氢呋喃(4L)溶液加入到氢化钠(60%w/w;254g,6.644mol)的无水四氢呋喃(4L)浆液中。将反应物料温热至室温并搅拌1h,然后再次冷却至0℃。在1/2h内加入甲基碘(517mL;8.305mol),将反应混合物在室温下搅拌18h。用冰水(100mL)淬灭并加入1N盐酸(2L)。分离有机层,并用二氯甲烷(2×500mL)萃取水层。合并的有机层相继用盐水(2×200mL)洗涤,用无水硫酸钠干燥,浓缩至干燥,得到950g(91%)的1,5-二甲基-3-苯基-1H-吡咯-2,4-二羧酸二乙酯C,为黄色固体[TLC系统:乙酸乙酯:石油醚(3:7);Rf值:0.56]。
1,5-二甲基-3-苯基-1H-吡咯-2,4-二羧酸(D)
将氢氧化钠(1.21Kg,30.25mol)的水(3.6L)溶液加入到C(950g,3.025mol)的乙醇(5L)溶液中,加热回流15h。在减压条件下蒸发乙醇,残留物用水(1L)稀释并冷却至0℃。缓慢加入浓盐酸(2L)以将pH调节至大约2,同时保持温度低于10℃并搅拌1h。将沉淀的固体过滤,用水(1L)和石油醚(1L)洗涤,并在60℃下真空干燥,得到550g(70%)1,5-二甲基-3-苯基-1H-吡咯-2,4-二羧酸D,为白色固体。[TLC系统:乙酸乙酯:石油醚(3:7);Rf值:0.15]。
1,2-二甲基-4-苯基-1H-吡咯(E)
将E(550g,2.123mol)悬浮在乙醇胺(1.5L)中的悬浮液加热至175℃(在N2下)并保持1h。将反应混合物冷却至室温,用水(500mL)稀释,并用乙酸乙酯(3×200mL)萃取。将合并的有机层相继用水(2×100mL)和盐水(2×100mL)洗涤,用无水硫酸钠干燥,在低于40℃的温度下真空浓缩,以得到粗产物。用5%乙酸乙酯的石油醚溶液作为洗脱剂在中性氧化铝上进行快速柱层析,得到280g(77%)1,2-二甲基-4-苯基-1H-吡咯E,为白色固体。[TLC系统:乙酸乙酯:石油醚(3:7);Rf值:0.75]。
(1,5-二甲基-3-苯基-1H-吡咯-2-基)-氧代-乙酰氯(F)
在0℃下将草酰氯(116mL,1.286mol)缓慢加入到E(250g,1.169mol)的无水二氯甲烷(3×200mL)冷却溶液中。将反应混合物温热至室温并搅拌1h。真空蒸发溶剂至干燥,得到340g(89%)1,5-二甲基-3-苯基-1H-吡咯-2-基)-氧代-乙酰氯F,为棕色油状液体。[TLC系 统:乙酸乙酯:石油醚(3:7);Rf值:0.65]。
4-硝基苯基哌嗪(G)
在100℃下将1-氯-4-硝基苯(650g,4.140mol)的二甘醇二甲醚(1L)溶液加入到哌嗪(2.84Kg,33.12mol)的二甘醇二甲醚(500mL)溶液中,并将所得物料在100℃搅拌6h。将混合物冷却至40-45℃,加入水(5L);温热至室温并搅拌1h。过滤沉淀的固体,用水(1L)、石油醚(500mL)洗涤并干燥,得到700g(81%)4-硝基苯基哌嗪G,为黄色固体。[TLC系统:乙酸乙酯:石油醚(3:7);Rf值:0.70]。
5-氟-2-[4-(4-硝基-苯基)-哌嗪-1-基]-嘧啶(H)
将2-氯-5-氟嘧啶(281g,2.12mol)加入到悬浮在二甘醇二甲醚(2.5L)中的4-硝基苯基哌嗪G(400g,1.93mol)和碳酸钾(532g,3.85mol)悬浮液中,将得到的混合物在100℃下搅拌6h。完成后,将混合物冷却至0℃并过滤,将固体置于水(5L)中并搅拌30min。过滤悬浮液,将固体滤饼用水(1L)、石油醚(1L)洗涤,真空条件下干燥,得到500g(85%)5-氟-2-[4-(4-硝基-苯基)-哌嗪-1-基]-嘧啶H,为黄色固体。[TLC系统:乙酸乙酯:石油醚(3:7);Rf值:0.70]。
4-[4-(5-氟-嘧啶-2-基)-哌嗪-1-基]-苯胺(I)
在65℃下将连二亚硫酸钠(1.27Kg,7.32mol)的水(6L)溶液加入到悬浮在甲醇(6L)中的H(500g,1.83mol)和碳酸氢钠(614g,7.32mol)悬浮液中。将所得混合物在65℃下搅拌2h。将反应物料冷却至10-15℃并过滤。残留物分配在水(2L)和乙酸乙酯(5L)之间,将有机层用水(2L)、盐水(2L)洗涤,用无水硫酸钠干燥。真空浓缩,得到290g(64%)4-[4-(5-氟-嘧啶-2-基)-哌嗪-1-基]-苯胺I,为固体。[TLC系统:甲醇:三氯甲烷(1:9);Rf值:0.50]。
2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-{4-[4-(5-氟-嘧啶-2-基)-哌嗪-1-
基]-苯基}-2-氧代-乙酰胺
在0℃下将F(332g,1.27mol)的二氯甲烷(3L)溶液加入到被搅拌着的I(290g,1.06mol)和三乙胺(294mL,2.12mol)的二氯甲烷(3L)的溶液中。将反应混合物温热至室温并搅拌30min。将反应混合物用水淬灭并用二氯甲烷(6×500mL)萃取。将合并的有机层相继用饱和碳酸氢钠溶液(1.5L)、水(1L)、盐水(1.5L)洗涤,最后用无水硫酸钠干燥。将有机层与中性氧化铝(1Kg)在室温下搅拌30min并过滤。将滤液真空浓缩,得到粗制化合物,将该粗制化合物用乙醚(300mL)洗涤,然后用乙醇(3L)在80℃下研磨1h并冷却至室温,过滤,用乙醇(500mL)洗涤,然后用己烷(200mL)洗涤,干燥,得到340g(64%)2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-{4-[4-(5-氟-嘧啶-2-基-哌嗪-1-基]-苯基}-2-氧代-乙酰胺,为黄色固体。[TLC系统:乙酸乙酯:石油醚(1:1);Rf值:0.65]。
图1提供了2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-{4-[4-(5-氟-嘧啶-2-基)-哌嗪-1-基]-苯基}-2-氧代-乙酰胺的NMR数据(1H NMR(400MHz,CDCl3))。在MS谱499.1[M+H]+处检测到信号。
实施例2:式(I)化合物的抗真菌活性
数据表明,2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)-2-氧代乙酰胺能够抑制很多种真菌的生长,这在申请号为PCT/GB2015/053546的国际专利申请中进行了介绍。其中与式(I)化合物的生物活性相关的信息通过引用并入本文。
PCT/GB2015/053546描述了将式(I)化合物的抗真菌活性与各种参考化合物进行比较的实验。PCT/GB2015/053546中所描述的实验表明,式(I)化合物能够以MIC(Minimuminhibitory concentration,“最低抑制浓度”;即,与无药对照组相比抑制>80%的生物体生长的最低药物浓度)抑制真菌生物体的生长,如下所示:
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式(I)化合物对S.dehoogii,S.boydii和S.aurantiacum也显示出良好的抗真菌活性。
PCT/GB2015/053546还描述了在小鼠模型中对式(I)化合物进行体内测试的实验。该申请中的数据显示,式(I)化合物在侵袭性曲霉菌病的小鼠模型中具有优异的功效,并且式(I)化合物能够降低烟曲霉(A.fumigatus)感染的小鼠中的半乳甘露聚糖指数。相对于使用抗真菌剂伏立康唑的对照实验,式(I)化合物还能提高感染大网膜孢(Lomentosporaprolificans)FMR 3569的小鼠的存活率。
在PCT/GB2015/053546中所描述的体内实验中,式(I)化合物通过灌胃口服给药。PCT/GB2015/053546中式(I)化合物的给药并不是用本发明的制剂实现的。
实施例3:PK实验-啮齿动物体内实验以确定式(I)化合物的优选口腔给药制剂
在大鼠体内PK研究中考察了各种制剂以确定对动物和人给药的最佳口腔给药制剂。
通过静脉注射(IV)以10mg/kg的剂量对大鼠施用式(I)化合物。赋形剂包含15%羟丙基-β-环糊精(Kelptose HPB肠胃外等级)、5%DMSO和注射用水。使用前将制剂用≤0.22μm的聚醚砜(PES)膜过滤器进行过滤。施用的剂量体积为5mL/kg。在静脉注射给药5min后,在异氟烷麻醉下从舌下静脉取0.2mL血样并储存在EDTA中。分析前,离心(1500×g,10min,ca.4℃)分离血浆,并冻存在–70℃。通过LC-MS/MS进行分析以计算式(I)化合物的血浆浓度。对应于100%生物利用度(根据定义),典型的AUC值(AUCIV)记录为13500ng.h/ml。随后用AUCIV值来计算如上所述的示例性口腔给药制剂的生物利用度。
制剂1
式(I)化合物的结晶样品配制在PEG300中。该制剂以10mg/kg(剂量体积=5mL/kg)的剂量对大鼠口服给药(灌胃)。在口服给药5min后,在异氟烷麻醉下从舌下静脉取0.2mL血样并储存在EDTA中。然后,在给药后0.5h、1h、2h、4h、8h、12h和24h提取样本。PK数据(根据IV制剂确定)显示,对应于49%的生物利用度(F),AUCPO(0-24h)为6610ng.h/ml。
制剂2
式(I)化合物的结晶样品配制在90%PEG300:10%TPGS(d-α-生育酚聚乙二醇1000琥珀酸酯)的溶液中。TPGS是一种已知的生物利用度增强剂,其作为药物溶解剂和沉淀抑制剂起作用,由于其存在被证明在其他不溶化合物的制剂中有益而被加入进来。当作为由PEG300/TPGS组成的赋形剂中的溶液、以150mg/kg的剂量(制剂浓度;15mg/mL)进行口服给药时,雄性和雌性禁食大鼠中的AUCPO(0-24h)值分别为34271ng.h/ml和76963ng.h/ml,分别相当于17%和38%的生物利用度值。然而,当长时间施用该制剂时,观察到腹泻的副作用,表明该制剂不适合临床给药。
制剂3和制剂4
通过喷射研磨将式(I)化合物的结晶样品微粒化至最终粒径D(v0.9)=6.7μm,随后悬浮在HPMC(75%)和SDS(十二烷基硫酸钠0.05%)的混合物中。将该制剂(制剂3)以150mg/kg的剂量对雄性和雌性大鼠口服给药。对雄性和雌性大鼠,PK实验得到的AUCPO(0-24h)值分别为9004ng.h/ml和26286ng.h/ml,分别相当于4.5%和13%的生物利用度。
以类似的方法对式(I)化合物进行纳粒化并配制在HPMC/SDS中,如同制备制剂3那样(以得到制剂4),并对雄性和雌性大鼠口服给药。在雄性和雌性大鼠中,PK实验得到的AUCPO(0-24h)值分别为17785ng.h/ml和40272ng.h/ml,分别相当于9%和20%的生物利用度。
制剂3和制剂4均未产生式(I)化合物的足够的生物利用度。此外,PK实验显示式(I)化合物的最大血浆浓度的时间(Tmax)显著地延迟了,这意味着吸收延迟/不完全。
制剂5
用羟丙基甲基纤维素乙酸琥珀酸酯(HPMCAS)与式(I)化合物进行配制(10%w/w式(I)化合物:90%HPMCAS)。该制剂由二氯甲烷:甲醇为3:1v/v的溶液喷雾干燥。将该制剂置于20mM磷酸缓冲液(悬浮液)中、以10mg/kg的剂量口服给药至雄性和雌性大鼠。在雄性和雌性大鼠中,PK实验得到的AUCPO(0-24h)值分别为13202ng.h/ml和27774ng.h/ml,表明在雄性和雌性大鼠中生物利用度均>95%。
不同于制剂2,制剂5对雄性和雌性大鼠均是耐受的,无肠道紊乱。这使得可以进行1-3个月的毒理学研究。在此期间,雄性和雌性大鼠均对制剂5具有良好的耐受性。
制剂2和制剂5的比较
对用制剂2和制剂5进行的PK实验的结果进行比较,其中以相同剂量(50mg/kg)口服给药28天,每日两次(BID)。这些数据表明,与制剂2相比,用制剂5获得了更好的暴露,同时还具有进一步的益处:不存在与制剂2相关联的胃肠道副作用。
实施例4:PK实验-用于确定式(I)化合物的优选口腔给药制剂的食蟹猴体内实验
在食蟹猴的体内PK研究中考察了各种制剂以确定对动物和人给药的最佳口腔给药制剂。
通过静脉注射以10mg/kg的剂量对雄性和雌性食蟹猴施用式(I)化合物。IV制剂如实施例3所述。PK实验得出典型的AUC值(AUCIV)为18000ng.h/ml。随后用AUCIV值来计算如上所述的示例性口腔给药制剂的生物利用度。
制剂2
用如上所述的制剂2进行研究。以10mg/kg的剂量水平(剂量体积5mL/kg)对雄性和雌性食蟹猴口服给药式(I)化合物。用连接至合适注射器的23G针通过股部穿刺(静脉/动脉)5分钟获得2mL血样,注入市售K2EDTA管中。样本在该制剂给药后0.25h、0.5h、1h、2h、4h、8h、12h和24h获得。血样置于冰上直至以1600×g(10mins,ca.5℃)离心分离血浆。通过LC-MS/MS进行分析以计算式(I)化合物的血浆浓度。PK实验得到在雄性和雌性对象中的AUCPO(0-24h)值分别为14915ng.h/ml和8192ng.h/ml,这表明在雄性和雌性对象中的生物利用度分别为83%和46%。
不幸的是,对于食蟹猴也观察到了如在大鼠实验(参见上述实施例3)中所观察到的胃肠性问题(尤其是腹泻)。用PEG/TPGS赋形剂进行为期1个月的研究表明,尽管使用抗腹泻药物(Diosmectite;“Smecta”,给药后4h每只动物1袋(3g)),但腹泻仍是一个主要问题。这些研究表明,尽管式(I)化合物具有良好的口腔给药生物利用度,但制剂2仍不太可能适于临床给药。
制剂5
用实施例3中所述的制剂5进行研究。以10mg/kg的剂量水平(剂量体积:5mg/kg;式(I)化合物的制剂浓度为2mg/mL,对应于20mg/mL的喷雾干燥颗粒)对雄性和雌性食蟹猴口服给药式(I)化合物。
将如针对制剂5所述的制备的颗粒悬浮在不同的缓冲液组合物/体积中。如上所述的PK实验所得到的AUCPO(0-24h)值如下:
可以看出,当使用低缓冲液盐浓度(20mM)和高缓冲液体积(10mL)时,或者当使用低缓冲液体积(5mL)但较高的缓冲强度(40mL)时,观察到了高的AUCPO(0-24h)值。在这些情况下,使用10ml 20mM磷酸缓冲液观察到生物利用度>90%,使用5ml40mM磷酸缓冲液观察到生物利用度>70%。(观察到用5ml 40mm缓冲液给药的雌性对象获得的结果有轻微变化,这导致该对象组中的生物利用度明显较差)。
以各种剂量的制剂5在食蟹猴中进行的研究表明完全没有胃肠道副作用;因此,与上述制剂2相比,该制剂在哺乳动物中的耐受性更好。在重复给药后获得了高药物水平,其中在剂量之间观察到了改善的剂量比例。
制剂2和制剂5的比较
对用制剂2和制剂5进行的PK实验的结果进行比较,其中以相同剂量(50mg/kg)口服给药14天,每日两次(BID)。这些数据表明,与制剂2相比,用制剂5获得了更好的暴露,同时还具有进一步的益处:不存在与制剂2相关联的胃肠道副作用。
在大鼠和食蟹猴中获得的上述数据表明,当式(I)化合物以上述制剂5的形式配制时,在大鼠和食蟹猴中均观察到优异的药代动力学。该制剂具有良好的耐受性,并且与基于溶剂的赋形剂如PEG/TPGS相比尤其有益,因为没有观察到如果临床使用时可能需要用止泻治疗进行干预的GI症状。与基于溶剂的制剂相比,使用该制剂在AUC和Cmax中的剂量比例也更好。
制剂6
将式(I)化合物配制在25%DMSO:75%PEG300(%v/v)的溶液中(赋形剂中的化合物浓度:2mg/mL)。以10mg/kg的剂量(给药剂量体积:5mL/kg)对雄性和雌性食蟹猴口服给药所述制剂。用连接至合适注射器的23G通过股部穿刺(静脉/动脉)5分钟得到2mL血样,注入市售K2EDTA管中。在该制剂给药后0.25h、0.5h、1h、2h、4h、8h、12h和24h取样。血样置于冰上直至以1600×g(10mins,ca.5℃)离心分离血浆。通过LC-MS/MS进行分析以计算式(I)化合物的血浆浓度。PK实验得到的AUCPO(0-24h)值在雄性和雌性对象中分别为2900ng.h/ml和1480ng.h/ml,表明在雄性和雌性对象中的生物利用度分别为16%和8%。
制剂7
如上所述,开发了一种基于脂质的制剂(Catalent),其用于促进式I化合物的溶解(并因此提高生物利用度),并在食蟹猴中进行测试。以10mg/kg的剂量对雄性和雌性食蟹猴口服给药该制剂。在雄性和雌性中,PK实验得到的AUCPO(0-24h)值分别为3282ng.h/ml和1924ng.h/ml,分别表示18%和11%的非常低的生物利用度。
实施例5:PK实验-体内人体试验
根据本发明的组合物,采用喷雾干燥制剂进行研究。如实施例4中对制剂5所描述的,该制剂由悬浮在20mM磷酸缓冲液中的20%式(I)化合物/80%HPMCAS化合物组成。在施用制剂剂量后取血样,并如上所述测定式(I)化合物的血浆浓度。
进行初始实验以确定改变制剂的给药剂量的效果。结果见下表。
#中位值。
+给药后12h和24h的浓度(用于潜在重复剂量目的)。
$AUC0-t值,目前仅从0-72h取值,以防止揭盲。
在上表中:Tmax=观察到式(I)化合物的最大浓度的时间;Cmax=观察到的最大浓度;AUCA-B=PK血浆曲线vs时间曲线下的面积,其中A是时间=0h,B=曲线被确定的时间;t1/2=明显的终末消除半衰期;CL=清除;Cn(n=12,24)=在指定时间点的式(I)化合物的浓度;MRT=平均滞留期;VSS=稳态分布体积。
如图1至3所示,作为给药剂量的函数的Cmax和AUC0-∞图显示出良好的剂量比例(Cmax:比例=1.18;AUC:比例=1.30)。观察到了ca.95%+的优异的生物利用度。
Claims (44)
1.一种适于口腔给药的药物组合物,其中所述组合物包括式(I)化合物或其药学上可接受的盐的喷雾干燥颗粒,
2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)-2-氧代乙酰胺。
2.根据权利要求1所述的药物组合物,其特征在于,包括式(I)化合物的喷雾干燥颗粒。
3.根据权利要求1所述的药物组合物,其特征在于,所述式(I)化合物是基本无定形的。
4.根据权利要求1所述的药物组合物,其特征在于,所述组合物还包括一种或多种辅料。
5.根据权利要求4所述的药物组合物,其特征在于,所述组合物包括辅料羟丙基甲基纤维素乙酸琥珀酸酯(HPMCAS)。
6.根据权利要求5所述的药物组合物,其特征在于,式(I)化合物与辅料的质量比为1:100至1:1。
7.根据权利要求6所述的药物组合物,其特征在于,式(I)化合物与辅料的所述质量比为1:15至1:2。
8.根据权利要求1所述的药物组合物,其特征在于,所述颗粒能够通过喷雾干燥包含有机溶剂的溶液而获得,所述有机溶剂选自二氯甲烷、甲醇及其混合物。
9.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物还包含一种或多种药学上可接受的粘合剂。
10.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物还包含一种或多种药学上可接受的载体。
11.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物还包含一种或多种药学上可接受的辅料。
12.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物还包含一种或多种药学上可接受的稀释剂。
13.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物还包含一种或多种药学上可接受的佐剂。
14.根据权利要求1所述的药物组合物,其特征在于,包括式(I)化合物的喷雾干燥颗粒,所述式(I)化合物是基本无定形的,所述组合物还包括一种或多种辅料,并且式(I)化合物与辅料的质量比为1:100至1:1。
15.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物是固体口腔给药剂型的形式。
16.根据权利要求15所述的药物组合物,其特征在于,所述药物组合物为颗粒形式或片剂形式。
17.根据权利要求14所述的药物组合物,其特征在于,所述药物组合物为固体口腔给药剂型的形式。
18.根据权利要求17所述的药物组合物,其特征在于,所述药物组合物为颗粒形式或片剂形式。
19.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物是液体口腔给药剂型的形式。
20.根据权利要求14所述的药物组合物,其特征在于,所述药物组合物是液体口腔给药剂型的形式。
21.根据权利要求19所述的药物组合物,其特征在于,所述液体口腔给药剂型还包含药学上可接受的缓冲液,所述缓冲液的pKa在6.0至8.0范围内。
22.根据权利要求21所述的药物组合物,其特征在于,所述缓冲液是1mM至200mM的磷酸缓冲液,其中所述组合物被缓冲至约pH 7。
23.一种适于肠胃外给药的药物组合物,包括:(i)式(I)化合物或其药学上可接受的盐的喷雾干燥颗粒,
2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)-2-氧代乙酰胺,
(ii)环糊精或改性环糊精,和
(iii)聚乙二醇。
24.根据权利要求23所述的药物组合物,其特征在于,包括:
-10wt%至40wt%的环糊精或改性环糊精;和/或
-10wt%至40wt%的聚乙二醇。
25.根据权利要求23所述的药物组合物,其特征在于,所述环糊精或改性环糊精是羟丙基-β-环糊精。
26.根据权利要求23所述的药物组合物,其特征在于,所述聚乙二醇是PEG300或PEG400。
27.根据权利要求23所述的药物组合物,其特征在于,所述药物组合物还包含聚乙烯基吡咯烷酮(聚维酮)。
28.根据权利要求23所述的药物组合物,其特征在于,所述式(I)化合物或其药学上可接受的盐以1mg/mL至10mg/mL的浓度存在。
29.根据上述权利要求23所述的药物组合物,其特征在于,所述药物组合物还包含一种或多种药学上可接受的载体。
30.根据上述权利要求23所述的药物组合物,其特征在于,所述药物组合物还包含一种或多种药学上可接受的辅料。
31.根据上述权利要求23所述的药物组合物,其特征在于,所述药物组合物还包含一种或多种药学上可接受的稀释剂。
32.根据上述权利要求23所述的药物组合物,其特征在于,所述药物组合物还包含一种或多种药学上可接受的佐剂。
33.根据权利要求23所述的药物组合物,其特征在于,包括:
-相对于所述组合物的最终体积的4mg/mL的式(I)化合物;
-25wt%的羟丙基-β-环糊精;
-25wt%的PEG400;
-1wt%的聚乙烯基吡咯烷酮(聚维酮);
-用于将药物组合物的pH调节至pH5.0的足量磷酸;以及
-水,补足至100%。
34.一种生产药物组合物的方法,所述药物组合物包含式(I)化合物或其药学上可接受的盐,
2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)
-2-氧代乙酰胺,
其中所述方法包括喷雾干燥式(I)化合物或其盐的溶液。
35.根据权利要求34所述的方法,其特征在于,包括:
i)将一种或多种辅料溶解在溶剂中;
ii)将式(I)化合物加入到步骤(i)所产生的溶液中;以及
iii)喷雾干燥步骤(ii)所产生的溶液。
36.根据权利要求35所述的方法,其特征在于:
-辅料为羟丙基甲基纤维素乙酸琥珀酸酯(HPMCAS);
-溶剂是二氯甲烷和甲醇的混合物,其中二氯甲烷与甲醇的体积比为5:1至1:1;
-溶剂中辅料的浓度为5%至20%w/v;以及
-式(I)化合物被加入到辅料溶于溶剂所形成的溶液中,以得到质量百分比0.5%至10%的浓度。
37.一种药物组合物,其中所述组合物包括式(I)化合物或其药学上可接受的盐的喷雾干燥颗粒,
2-(1,5-二甲基-3-苯基-1H-吡咯-2-基)-N-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)苯基)-2-氧代乙酰胺。
38.根据权利要求37所述的药物组合物,其特征在于,所述药物组合物包括式(I)化合物的喷雾干燥颗粒。
39.根据权利要求37所述的药物组合物,其特征在于,所述式(I)化合物是基本无定形的。
40.根据权利要求37所述的药物组合物,其特征在于,所述药物组合物还包括一种或多种辅料。
41.根据权利要求37所述的药物组合物,其特征在于,所述颗粒能够通过喷雾干燥包含乙醇的溶液而获得。
42.根据权利要求37所述的药物组合物,其特征在于,所述药物组合物为溶液、糖浆、乳液或悬浮液的形式。
43.根据权利要求37所述的药物组合物,其特征在于,所述药物组合物包括式(I)化合物的喷雾干燥颗粒,其中,所述式(I)化合物是基本无定形的并且所述颗粒能够通过喷雾干燥包含乙醇的溶液而获得,所述药物组合物为溶液、糖浆、乳液或悬浮液的形式。
44.根据权利要求1-33和37-43中任一项所述的药物组合物在制备用于预防或治疗人或动物对象的真菌感染所需的药物中的应用。
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