CN112673257A - 通过超快速冷冻制得的表面改性的治疗活性颗粒的组合物 - Google Patents
通过超快速冷冻制得的表面改性的治疗活性颗粒的组合物 Download PDFInfo
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- CN112673257A CN112673257A CN201980055623.XA CN201980055623A CN112673257A CN 112673257 A CN112673257 A CN 112673257A CN 201980055623 A CN201980055623 A CN 201980055623A CN 112673257 A CN112673257 A CN 112673257A
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Abstract
本发明描述了药物组合物,所述药物组合物包含少于10%的赋形剂并且作为纳米聚集体存在。这些药物组合物已被证明表现出改善的特性,诸如改善的可雾化性和空气动力学性能。本发明还提供了制备如本文所公开的药物组合物的方法及其用途。
Description
本申请要求2018年7月24日提交的美国临时申请No.62/702,674的优先权,其全部内容通过引用合并于此。
技术领域
本公开总体上涉及药物和药物制造领域。更具体地,本公开涉及组合物及制备药物组合物的方法,该药物组合物包含少量赋形剂和治疗剂并且配制为纳米聚集体。
背景技术
直到最近,向肺部递送的雾化抗真菌药物还仅限于两性霉素B(Le和Schiller,2010;Borro等人,2008)。但是,Hilberg等人于2008年报道,吸入伏立康唑(voriconazole)比吸入两性霉素B能够更有效地治疗侵袭性肺曲霉病(IPA),证实了Tolman等人(2009a)最初报道的雾化伏立康唑制剂成功治疗IPA患者,这些患者之前在吸入或不吸入两性霉素B的情况下口服或注射伏立康唑时治疗失败。
Tolman等人报道通过雾化将吸入的伏立康唑递送至肺部(Tolman等人,2009a;Tolman等人,2009b)。但是,肺组织中伏立康唑的浓度在6小时后下降至最低可检测浓度以下(Tolman等人,2009a)。此外,雾化制剂的功效也非常低,在以磺丁基醚-β-环糊精钠(SBECD)作为赋形剂时仅有5.9%(w/w)。尚未证实通过肺部途径递送SBECD的安全性,并且这种高含量非活性成分可能引起严重的副作用(Wong 1993)。Sinha等人和Arora等人分别报道了使用聚丙交酯-共-乙交酯纳米颗粒(Sinha等人,2013)和聚丙交酯微粒(Arora等人,2015)制得用于干粉吸入(DPI)的伏立康唑制剂,但这些颗粒的载药量较低,分别为31%w/w和20%w/w)。Arora等人报道了另一种使用亮氨酸作为赋形剂制得的用于DPI的伏立康唑粉末制剂(Arora等人,2016)。但是,所有这些DPI粉末制剂均包含FDA尚未批准用于吸入药物的非GRAS赋形剂。Beinbom等人还使用颗粒工程技术(即薄膜冷冻,TFF)开发出适合干粉吸入的无定形态和结晶态伏立康唑制剂(Beinbom等人,2012a;Beinbom等人,2012b)。但是,无定形态制剂中包含75%(w/w)赋形剂,因此功效低,并且基于小鼠模型的体内药代动力学数据,药物吸收效率低并且清除速度快。在肺部和血浆中,结晶态制剂的AUC0-24h均明显高于无定形态制剂,两者在肺部分别为452.6μg·h/g和232.1μg·h/g,在血浆中分别为38.4μg·h/g和18.6μg·h/g。但是,结晶态制剂的气雾剂性能较差(FPF 37.8%)。
最近,研究人员基于模型提出,与离散的微米级颗粒和纳米颗粒相比,包含药物纳米颗粒的纳米聚集体在肺部的分布更有利,并且具有更高的上皮覆盖率(Longest和Hindle,2017)。聚集体是呈颗粒形式的固体物质,由通过强烈的分子间或分子内凝聚力结合在一起的颗粒的组合组成(Chiou和Riegelman,1971)。在计算模型中测试三种不同形式的颗粒药物(包括布地奈德(budesonide)和丙酸氟替卡松(fluticasone propionate)的常规微粒、纳米聚集体及真正的纳米气雾剂)时,丙酸氟替卡松的纳米聚集体的总吸收效率比常规微粒高57倍。尽管真正的纳米气雾剂具有更出色的吸收效率,但尚无可用于将真正的纳米气雾剂输送至小气道的实际设备,因此,纳米聚集体为将药物靶向至小气道提供了最佳方法。根据Longest等人的报道,缓慢溶出的纳米聚集体被认为具有改善的药物吸收和分布(Longest和Hindle,2017)。
TFF是一种颗粒工程技术,采用高达10,000K/s的超快速冷冻速度(Engstrom等人,2008)。由于过冷程度高,TFF被成功地用于生产纳米结构聚集体(Sinswat等人,2008)。喷雾干燥是另一种生产用于DPI的微米级或纳米级颗粒的常用技术。但是,在喷雾干燥的干燥过程中形成颗粒通常要比TFF的冷冻过程花费更长的时间(Wisniewski 2015),从而使颗粒生长时间更长,产生更大粒径的颗粒。因此,典型的喷雾干燥方法不具有如Longest和Hindle(2017)所述的纳米聚集体的增强吸收和微剂量的优势。因此,仍然需要开发作为纳米聚集体的其他药物组合物,使其表现出改善的特性,诸如增强的雾化效果。
发明内容
本公开提供了作为纳米聚集体的包含治疗剂和赋形剂的药物组合物、其制造方法及其使用方法。在一些实施例中,本公开提供了药物组合物,其包含:
(A)治疗剂;以及
(B)赋形剂,其中赋形剂占药物组合物的少于约10重量%;
其中药物组合物配制为纳米聚集体,该纳米聚集体包含治疗剂的纳米颗粒,并且治疗剂的纳米颗粒的表面包含赋形剂的离散域,并且其中赋形剂的离散域减小治疗剂的纳米颗粒之间的接触面积。
在一些实施例中,治疗剂以结晶态存在。在其他实施例中,治疗剂以无定形态存在。在一些实施例中,赋形剂占药物组合物的约9%w/w至约1%w/w,诸如占药物组合物的约6%w/w至约2%w/w。在一些实施例中,赋形剂占药物组合物的约3%w/w。在其他实施例中,赋形剂占药物组合物的约5%w/w。
在一些实施例中,赋形剂的离散域包含赋形剂在表面上的一个或多个不连续域。在其他实施例中,赋形剂的离散域包含邻近且连续的赋形剂层。在一些实施例中,赋形剂可溶于水。在一些实施例中,赋形剂在室温下为固体。在一些实施例中,赋形剂为糖醇,诸如甘露醇。在一些实施例中,赋形剂在药物组合物中作为纳米域存在。在一些实施例中,赋形剂的纳米域具有约50nm至约500nm诸如约100nm至约200nm的尺寸。
在一些实施例中,药物组合物具有约1.5μm至约7.5μm诸如约2.5μm至约6.5μm的质量中值空气动力学直径。在一些实施例中,药物组合物不包含蜡赋形剂。在一些实施例中,药物组合物不包含疏水性赋形剂。在一些实施例中,治疗剂选自下组,该组由以下各项组成:抗癌药、抗真菌剂、精神病治疗剂诸如镇痛药、意识水平改变剂诸如麻醉剂或催眠药、非甾体类抗炎药(NSAIDS)、驱虫剂、β-激动剂、抗痤疮药、抗心绞痛药、抗心律失常药、抗哮喘药、抗菌剂、抗良性前列腺肥大剂、抗凝剂、抗抑郁药、抗糖尿病药、止吐药、抗癫痫药、抗痛风药、抗高血压药、抗炎药、抗疟疾药、抗偏头痛药、抗毒蕈碱药、抗肿瘤药、抗肥胖药、抗骨质疏松药、抗帕金森氏病药、抗增殖剂、抗原虫药、抗甲状腺药、镇咳药、抗尿失禁药、抗病毒剂、抗焦虑剂、食欲抑制剂、β-受体阻滞剂、心脏正性肌力药、化疗药物、认知增强剂、避孕药、皮质类固醇、Cox-2抑制剂、利尿剂、勃起功能障碍改善剂、祛痰剂、肠胃病药、组胺受体拮抗剂、免疫抑制剂、角质剥脱剂、脂质调节剂、白三烯抑制剂、大环内酯类、肌肉松弛剂、神经安定药、营养剂、阿片类镇痛药、蛋白酶抑制剂和镇静剂。在一些实施例中,治疗剂为抗真菌剂,诸如唑类抗真菌药物。在一些实施例中,唑类抗真菌药物为伏立康唑。在一些实施例中,药物组合物进一步包含一种或多种另外的赋形剂。在一些实施例中,药物组合物进一步包含一种或多种另外的治疗剂。
在一些实施例中,药物组合物配制用于通过以下途径施用:口服、脂肪内、动脉内、关节内、颅内、皮内、病变内、肌内、鼻内、眼内、心包内、腹膜内、胸膜内、前列腺内、直肠内、鞘内、气管内、瘤内、脐内、阴道内、静脉内、囊内、玻璃体内、脂质体内、局部、粘膜、肠胃外、直肠、结膜下、皮下、舌下、外用、经皮、阴道、以乳剂的形式、以脂质组合物的形式、经由导管、经由灌洗、经由连续输注、经由输注、经由吸入、经由注射、经由局部递送或经由局部灌注。在一些实施例中,药物组合物配制用于经由吸入施用。
在一些实施例中,药物组合物配制用于与吸入器一起使用,该吸入器为例如固定剂量组合吸入器、单剂量干粉吸入器、多剂量干粉吸入器、多单位剂量干粉吸入器、定量吸入器或加压定量吸入器。在一些实施例中,吸入器为胶囊型吸入器(capsule-basedinhaler)。在一些实施例中,吸入器为低阻力吸入器。在其他实施例中,吸入器为高阻力吸入器。在一些实施例中,吸入器在约10L/min至约150L/min诸如约20L/min至约100L/min的流速下使用。在一些实施例中,吸入器具有0.5kPa至约5kPa的压差。在一些实施例中,压差为1kPa、2kPa或4kPa。在一些实施例中,吸入器具有约0.1mg至约50mg的加载剂量。在一些实施例中,吸入器具有约0.1mg至约10mg的加载剂量。在其他实施例中,吸入器具有约5mg至约50mg诸如约5mg至约25mg的加载剂量。在一些实施例中,吸入器被配置为从依次加载的一个或多个单位剂量中递送一个或一系列剂量。在一些实施例中,吸入器被配置为从一个单位剂量中递送一个剂量。在其他实施例中,吸入器被配置为从一个单位剂量中递送一系列剂量。在其他实施例中,吸入器被配置为从依次加载的一系列胶囊中各自递送一个剂量。在其他实施例中,吸入器被配置为从依次加载的一系列胶囊中递送一系列剂量。
在另一个方面,本公开提供了治疗或预防有此需要的患者的疾病或疾患的方法,其包括向患者施用治疗有效量的如本文所述的药物组合物,该药物组合物包含有效治疗疾病或疾患的治疗剂。在一些实施例中,疾病或疾患在肺部。在一些实施例中,疾病或疾患为感染,诸如真菌感染。在一些实施例中,治疗剂为抗真菌剂,诸如唑类抗真菌剂。在一些实施例中,治疗剂为伏立康唑。
在另一个方面,本公开提供了制备药物组合物的方法,其包括:
(A)将治疗剂和赋形剂与溶剂混合以形成前体溶液,其中赋形剂以少于10%w/w的量存在;
(B)将前体溶液沉积到表面上,该表面处于适合于引起溶剂冷冻的温度下;以及
(C)除去溶剂,以获得药物组合物。
在一些实施例中,溶剂为两种或更多种溶剂的混合物。在一些实施例中,溶剂的混合物包含水。在一些实施例中,溶剂为有机溶剂。在一些实施例中,有机溶剂为乙腈。在其他实施例中,有机溶剂为1,4-二噁烷。在一些实施例中,溶剂为水与有机溶剂的混合物,诸如水与乙腈的混合物。在一些实施例中,两种或更多种溶剂的混合物包含约10%v/v至约90%v/v的所述有机溶剂。在一些实施例中,该混合物包含约40%v/v至约60%v/v的有机溶剂诸如约50%v/v的有机溶剂。在其他实施例中,该混合物包含约20%v/v至约40%v/v的有机溶剂诸如约30%v/v的有机溶剂。在一些实施例中,治疗剂和赋形剂占前体溶液的少于10%w/v,诸如占前体溶液的约0.5%w/v至约5%w/v。在一些实施例中,治疗剂和赋形剂占前体溶液的约1%w/v。在其他实施例中,治疗剂和赋形剂占前体溶液的约3%w/v。
在一些实施例中,表面在旋转。在一些实施例中,温度为约0℃至约-200℃。在一些实施例中,温度为约0℃至约-120℃,诸如约-50℃至约-90℃。在一些实施例中,温度为约-60℃。在其他实施例中,温度为约-125℃至约-175℃,诸如约-150℃。在一些实施例中,溶剂在减小的压力下除去。在一些实施例中,溶剂经由冻干除去。在一些实施例中,冻干在约-20℃至约-100℃诸如约-40℃的冻干温度下进行。在一些实施例中,减小的压力低于250mTorr,诸如约100mTorr。
在一些实施例中,方法进一步包括在减小的压力下加热药物组合物。在一些实施例中,将药物组合物加热至约0℃至约30℃的温度,诸如约室温或约25℃。在一些实施例中,减小的压力低于250mTorr,诸如约100mTorr。在一些实施例中,该减小的压力与冻干过程中的减小的压力相同。
在另一个方面,本公开提供了根据本文所述的方法制备的药物组合物。
通过下面详细的描述,本公开的其他目的、特点和优点将会变得显而易见。然而,应当理解,虽然指示了本发明的具体实施例,但是详细描述和具体实施例仅以说明的方式给出,因为通过此详细描述,在本发明的精神和范围内的各种变化和修改对于本领域技术人员将变得显而易见。
附图说明
以下附图构成本说明书的一部分并包括在本说明书内,以进一步说明本公开的某些方面。通过参考这些附图中的一个或多个附图,结合在此呈现的具体实施例的详细描述,可以更好地理解本公开。
图1显示了(a)伏立康唑粉末;(b)TFF-VCZ;(c)TFF-VCZ-MAN 95:5;(d)TFF-VCZ-MAN 70:30;(e)TFF-VCZ-MAN 50:50;(f)TFF-MAN的XRPD。
图2显示了(a)TFF-MAN;(b)TFF-VCZ;(c)TFF-VCZ-MAN 95:5;(d)TFF-VCZ-MAN 50:50的调制DSC。
图3A-3J显示了TFF-VCZ-MAN的SEM图像:(图3A)TFF-VCZ;(图3B)TFF-VCZ-MAN 95:5;(图3C)TFF-VCZ-MAN 70:30;(图3D)TFF-VCZ-MAN 50:50;(图3E)TFF-VCZ-MAN 25:75;(图3F)TFF-MAN;(图3G)雾化TFF-VCZ-MAN 95:5;(图3H)雾化TFF-VCZ-MAN50:50;(图31)TFF-VCZ-MAN 25:75,在Franz池中处理5min后;(图3J)TFF-VCZ-MAN 95:5,在Franz池中处理5min后。
图4A-4F显示了(图4A)TFF-VCZ和(图4B)TFF-VCZ-MAN 95:5的SEM图像;(图4C)TFF-VCZ;(图4D)TFF-VCZ-MAN 95:5的3D形貌图;并且示出(图4E)TFF-VCZ和(图4F)TFF-VCZ-MAN 95:5颗粒之间的接触面积和距离。
图5显示了通过DP4吹入器得到的雾化TFF-VCZ-MAN 95:5的AFM形貌图。
图6显示了TFF-VCZ-MAN粉末制剂的SSA(n=3;平均值±SD)。
图7A-7C显示了TFF-VCZ-MAN 50:50的SEM/EDX数据:(图7A)SEM图像;(图7B)斑点A的元素分析结果;(图7C)斑点B的元素分析结果。
图8A和8B显示了FT-IR(图8A,3500cm-1至3100cm-1区域;图8B,1290cm-1至1230cm-1区域):(a)伏立康唑粉末;(b)TFF-VCZ;(c)TFF-VCZ-MAN 95:5;(d)TFF-VCZ-MAN 70:30;(e)TFF-VCZ-MAN 50:50;(f)TFF-MAN。
图9A和9B显示了(图9A)TFF-VCZ和(图9B)TFF-VCZ-MAN 90:10的1D CP-MAS谱图;13C谱图(左侧谱图)和19F谱图(右侧谱图)。
图10A和10B显示了以下2D 1H-13C HETCOR谱图:(图10A)TFF-VCZ;和(图10B)TFF-VCZ-MAN 90:10。
图11显示了TFF-VCZ-MAN干粉制剂的FPF(定量剂量百分比)(n=3;平均值±SD)。
图12从左到右按剪切时间显示了TFF-VCZ-MAN 95:5的空气动力学粒径分布特征:0min;15min;30min;60min(n=3;平均值±SD)。
图13A和13B按剪切时间显示了TFF-VCZ-MAN 95:5的空气动力学特性:(a线)FPF,递送剂量百分比;(b线)FPF,定量剂量百分比;(c线)MMAD;和(d线)GSD(n=3;平均值±SD)。
图14A和14B按照在25℃/60%RH下的储存时间显示了TFF-VCZ-MAN 95:5的空气动力学特性:(a线)FPF,递送剂量百分比;(b线)FPF,定量剂量百分比;(c线)MMAD;和(d线)GSD(n=3;平均值±SD)。
图15显示了伏立康唑累积释放率(%):(a线)TFF-VCZ-PVPK25 25:75(无定形);(b线)TFF-VCZ-MAN 25:75;(c线)TFF-VCZ-MAN 50:50;(d线)TFF-VCZ-MAN 95:5(n=3;平均值±SD)。
图16显示了冷冻过程的图像。
图17A-17D显示了以下AFM形貌图:(a)制剂#2(尺寸5μm×5μm)和(b)制剂#4(尺寸2μm×2μm);以及对应的以下3D形貌图:(c)制剂#2和(d)制剂#4。
图18A-18F显示了伏立康唑纳米聚集体的SEM图像:(a)制剂#1、(b)制剂#2、(c)制剂#3、(d)制剂#4、(e)制剂#5和(f)制剂#6。
图19A-19F显示了雾化伏立康唑纳米聚集体的SEM图像:(a)-(b)制剂#7和(c)-(f)制剂#6。
图20显示了以下XRPD:(a)伏立康唑粉末、(b)TFF-伏立康唑、(c)制剂#6(小规模)、(d)制剂#6(大规模)和(e)TFF-甘露醇。
具体实施方式
在本公开的一些方面,药物组合物包含纳米聚集体。这些组合物可通过诸如薄膜冷冻等方法进行制备,并且包含治疗剂和赋形剂。在一些实施例中,这些组合物还表现出改性的雾化作用或者提供了其他药物特性。
本文还提供了制备和使用这些组合物的方法。这些组合物的详细信息如下文所详述。
I.药物组合物
在一些方面,本公开提供了包含治疗剂和赋形剂的药物组合物,其中赋形剂占组合物的少于约10%w/w。这些药物组合物可进一步包含一种或多种另外的治疗剂或一种或多种另外的赋形剂。此类组合物可使用诸如薄膜冷冻等方法进行制备。这些方法包括将治疗剂和赋形剂在溶剂中的溶液冷冻,然后在减压和/或低温条件下除去该溶剂。使用薄膜冷冻法制备药物组合物的方法描述于:美国专利申请No.2010/0221343;Watts等人,2013;Engstrom等人,2008;Wang等人,2014;Thakkar等人,2017;O'Donnell等人,2013;Lang等人,2014a;Lang等人,2014b;Carvalho等人,2014;Beinbom等人,2012a;Beinborn等人,2012b;Zhang等人,2012;Overhoff等人,2008;Overhoff等人,2007a;Overhoff等人,2007b;Watts等人,2010;Yang等人,2010;DiNunzio等人,2008;Yang等人,2008;Purvis等人,2007;Liu等人,2015;Sinswat等人,2008;以及美国专利No.8,968,786,这些文献通过援引并入本文。
此类药物组合物可作为纳米聚集体存在,该纳米聚集体包含通过分子间或分子内凝聚力吸引或结合在一起的纳米颗粒的组合。在本文所述的药物组合物中,纳米聚集体可包含一个或多个药物颗粒,这些药物颗粒被赋形剂的离散的不连续纳米域包被。不希望受任何理论的约束,据信赋形剂的纳米域可包括约25nm、50nm、75nm、100nm、125nm、150nm、175nm、200nm、225nm、250nm、275nm、300nm、325nm、350nm、375nm、400nm、425nm、450nm、475nm、500nm、525nm、550nm、575nm、600nm、625nm或650nm或可衍生自其中的任何范围的尺寸。赋形剂的这些纳米域可包括约25nm至约750nm、约50nm至约500nm或约100nm至约200nm的尺寸。不希望受任何理论的约束,据信这些纳米域可作为离散的组合物存在,这些组合物在包含治疗剂的纳米聚集体的表面上形成点。药物组合物可进一步包括约2.5μm至约7.5μm、约3.0μm至约6.0μm、约4.0μm至约6.0μm或约2.5μm、2.75μm、3.0μm、3.25μm、3.5μm、3.75μm、4μm、4.25μm、4.5μm、4.75μm、5μm、5.25μm、5.5μm、5.75μm、6.0μm、6.25μm、6.5μm、6.75μm、7.0μm、7.25μm、至约7.5μm或可衍生自其中的任何范围的质量中值空气动力学直径。
A.治疗剂
本发明方法和组合物中所用的“治疗剂”是指当施用于人或动物时可提供治疗或药理作用的任何物质、化合物、药物、药剂或其他主要活性成分。当组合物中存在治疗剂时,组合物中治疗剂的含量在组合物总重量的约50%w/w至约99%w/w之间、在约70%w/w至约99%w/w之间、在约90%w/w至约97%w/w之间或在约95%w/w至约97%w/w之间。在一些实施例中,治疗剂的量为约50%w/w、60%w/w、70%w/w、80%w/w、90%w/w、91%w/w、92%w/w、93%w/w、94%w/w、95%w/w、96%w/w、97%w/w至约99%w/w或可衍生自其中的任何范围。
合适的亲脂性治疗剂可以是任何水溶性不佳的生物活性剂或其盐、异构体、酯、醚或其他衍生物,其包括但不限于抗癌药、抗真菌剂、精神病治疗剂诸如镇痛药、意识水平改变剂诸如麻醉剂或催眠药、非甾体类抗炎药(NSAIDS)、驱虫剂、抗痤疮药、抗心绞痛药、抗心律失常药、抗哮喘药、抗菌剂、抗良性前列腺肥大剂、抗凝剂、抗抑郁药、抗糖尿病药、止吐药、抗癫痫药、抗痛风药、抗高血压药、抗炎药、抗疟疾药、抗偏头痛药、抗毒蕈碱药、抗肿瘤药、抗肥胖药、抗骨质疏松药、抗帕金森氏病药、抗增殖剂、抗原虫药、抗甲状腺药、镇咳药、抗尿失禁药、抗病毒剂、抗焦虑剂、食欲抑制剂、β-激动剂、β-受体阻滞剂、心脏正性肌力药、化疗药物、认知增强剂、避孕药、皮质类固醇、Cox-2抑制剂、利尿剂、勃起功能障碍改善剂、祛痰剂、肠胃病药、组胺受体拮抗剂、免疫抑制剂、角质剥脱剂、脂质调节剂、白三烯抑制剂、大环内酯类、肌肉松弛剂、神经安定药、营养剂、阿片类镇痛药、蛋白酶抑制剂或镇静剂。
治疗剂的非限制性实例可包括7-甲氧基蝶啶、7-甲基蝶啶、阿巴卡韦、阿巴芬净、阿巴瑞克、醋丁洛尔、萘嵌戊烷、对乙酰氨基酚、乙酰苯胺、乙酰唑胺、醋酸己脲、阿维A、阿伐斯汀、腺嘌呤、腺苷、阿拉曲沙星、阿苯达唑、沙丁胺醇、阿氯芬酸、阿地白介素、阿仑单抗、阿夫唑嗪、阿利维A酸、阿洛巴比妥、别嘌呤醇、全反式维甲酸(ATRA)、阿洛普令、阿普唑仑、阿普洛尔、六甲蜜胺、氨磷汀、阿米洛利、氨鲁米特、氨基比林、盐酸胺碘酮、阿米替林、氨氯地平、异戊巴比妥、阿莫地喹、阿莫沙平、安非他明、两性霉素、两性霉素B、氨苄青霉素、安普那韦、安吖啶、亚硝酸异戊酯、异戊巴比妥、阿那曲唑、氨力农(anrinone)、蒽、蒽环类药物、阿普比妥、三氧化二砷、天冬酰胺酶、阿司匹林、阿司咪唑、阿替洛尔、阿托伐他汀、阿托伐醌、阿特拉津、阿托品、阿托品硫唑嘌呤、金诺芬、阿扎胞苷、阿扎丙宗、硫唑嘌呤、阿嗪米特、阿奇霉素、氨曲南、巴氯芬、巴比妥、活BCG、贝克拉胺、倍氯米松、苄氟噻嗪、苯那普利、贝尼地平、贝诺酯(benorylate)、苯哌利多、苯他西泮、苯甲酰胺、苯并蒽、苄星青霉素、盐酸苯海索、苄硝唑、苯二氮卓类、苯甲酸、羟萘苄芬宁、倍他米松、贝伐单抗(安维汀)、贝沙罗汀、苯扎贝特、比卡鲁胺、联苯苄唑、比哌立登、比沙可啶、比生群、博来霉素、博来霉素、硼替佐米、布林佐胺、溴西泮、甲磺酸溴隐亭、溴哌利多、溴替唑仑、布地奈德、布美他尼、安非他酮、白消安、布他比妥、氨苯丁酯、布替萘芬盐酸、正丁巴比妥、正丁巴比妥(布特萨)、布康唑、硝酸布康唑、对羟基苯甲酸丁酯、咖啡因、骨化二醇、钙泊三醇、骨化三醇、卡普睾酮、坎苯达唑、樟脑、喜树碱、喜树碱类似物、坎地沙坦、卡培他滨、辣椒素、卡托普利、卡马西平、甲亢平、呋喃丹、卡铂、卡溴脲、甲亢平、卡莫司汀、头孢孟多、头孢唑啉、头孢克肟、头孢他啶、头孢呋辛酯、塞来昔布、头孢拉定、西立伐他汀、塞替利嗪、西妥昔单抗、苯丁酸氮芥、氯霉素、氯氮卓、氯美噻唑、氯喹、氯噻嗪、氯苯那敏、盐酸氯丙胍、氯丙嗪、氯磺丙脲、氯普噻吨、毒死蜱、金霉素、氯噻酮、氯唑沙宗、胆钙化醇、西洛他唑、西咪替丁、桂利嗪、西诺沙星、环丙贝特、盐酸环丙沙星、西沙必利、顺铂、西酞普兰、克拉屈滨、克拉霉素、富马酸氯马斯汀、氯碘羟喹、氯巴占、氯法拉滨、氯苯吩嗪、氯贝丁酯、克罗米芬、氯米帕明、氯硝西泮、氯吡格雷、氯噻西泮、克霉唑、氯唑西林、氯氮平、可卡因、可待因、秋水仙素、粘菌素、结合雌激素、皮质酮、可的松、醋酸可的松、赛克力嗪、环己巴比妥、环苯扎林、环丁烷-螺环巴比妥酸盐、环乙烷-螺环巴比妥酸盐、环庚烷-螺环巴比妥酸盐、环己烷-螺环巴比妥酸盐、环戊烷-螺环巴比妥酸盐、环磷酰胺、环丙烷-螺环巴比妥酸盐、环丝氨酸、环孢素、赛庚啶、盐酸赛庚啶、阿糖胞苷、胞嘧啶、达卡巴嗪、更生霉素、达那唑、丹蒽醌、丹曲林钠、氨苯砜、阿法达贝泊汀、达罗地平、柔红霉素、地考喹酯、脱氢表雄酮、地拉韦啶、地美环素、地尼白介素、去氧皮质酮、去氧米松、地塞米松、右旋苯丙胺、右氯苯那敏、右芬氟拉明、右雷佐生、右丙氧芬、海洛因、泛影酸、地西泮、二氮嗪、双氯酚、滴丙酸、双氯芬酸、双香豆素、去羟肌苷、二氟尼柳、洋地黄毒苷、地高辛、双氢可待因、二氢马烯雌酮、甲磺酸双氢麦角胺、双碘喹啉、盐酸地尔硫卓、糠酸二氯尼特、茶苯海明、地莫拉明、二硝托胺、薯蓣皂苷元、盐酸地芬诺酯、联苯、双嘧达莫、地红霉素、丙吡胺、双硫仑、敌草隆、多西他赛、多潘立酮、多奈哌齐、多沙唑嗪、盐酸多沙唑嗪、多柔比星(中性)、盐酸多柔比星、多西环素、丙酸屈他雄酯、氟哌利多、二羟丙茶碱、棘球白素、益康唑、硝酸益康唑、依法韦仑、玫瑰树碱、依那普利、恩莫单抗、依诺昔酮、肾上腺素、表鬼臼毒素衍生物、表柔比星、阿法依伯汀、头孢他啶、去氢马烯雌酮、马烯雌酮、麦角钙化留醇、麦角胺酒石酸盐、厄洛替尼、红霉素、雌二醇、雌莫司汀、雌三醇、雌酮、依他尼酸、乙胺丁醇、炔己蚁胺、乙硫异烟胺、盐酸普罗吩胺、4-氨基苯甲酸乙酯(苯佐卡因)、羟苯乙酯、炔雌醇、依托度酸、依托咪酯、依托泊甙、依曲替酯(etretinate)、依西美坦、非尔氨酯、非洛地平、芬苯达唑、腈苯唑、芬布芬、芬氯磷、芬氯酸、芬氟拉明、非诺贝特、非诺多泮、非诺洛芬、苯氧威、拌种咯、芬太尼、芬替康唑、非索非那定、非格司亭、非那雄胺、醋酸氟卡胺、氟尿苷、氟达拉滨、氟康唑、氟康唑、氟胞嘧啶、咯菌腈、氟氢可的松、氟氢可的松醋酸酯、氟芬那酸、氟桂利嗪、盐酸氟桂利嗪、氟尼缩松、氟硝西泮、氟可龙、伏草隆、芴、氟尿嘧啶、盐酸氟西汀、氟甲睾酮、三氟噻吨癸酸酯、癸酸氟哌噻吨、氟西泮、氟比洛芬、丙酸氟替卡松、氟伐他汀、叶酸、福辛普利、磷苯妥英钠、夫罗曲普坦、呋塞米、氟维司群、呋喃唑酮、加巴喷丁、G-BHC(林丹)、吉非替尼、吉西他滨、吉非贝齐、吉妥珠单抗、格拉非宁、格列本脲、格列齐特、格列美脲、格列吡嗪、格鲁米特、格列本脲、三硝酸甘油酯(硝酸甘油)、醋酸戈舍瑞林、格帕沙星、灰黄霉素、愈创甘油醚、醋酸胍那苄、鸟嘌呤、盐酸氯氟菲醇、氟哌啶醇、氢氯噻嗪、庚巴比妥、海洛因、橙皮素、六氯苯、己巴比妥、醋酸组氨瑞林、氢化可的松、氢氟噻嗪、羟基脲、莨菪碱、次黄嘌呤、替伊莫单抗、布洛芬、伊达比星、烯丙丁巴比妥、异环磷酰胺、ihydroequilenin、甲磺酸伊马替尼、亚胺培南、吲达帕胺、茚地那韦、吲哚美辛、吲哚洛芬、干扰素α-2a、干扰素α-2b、碘达胺、碘番酸、异菌脲、厄贝沙坦、依立替康、艾沙康唑、异卡波肼、异康唑、异鸟嘌呤、异烟肼、异丙基巴比妥酸盐、异丙隆、异山梨醇二硝酸酯、单硝酸异山梨酯、伊拉地平、伊曲康唑、伊曲康唑、伊曲康(Itra)、伊维菌素、酮康唑、酮洛芬、酮咯酸、凯林、拉贝洛尔、拉米夫定、拉莫三嗪、毛花戒丙、兰索拉唑(Ianosprazole)、L-DOPA、来氟米特、来那度胺、来曲唑、亚叶酸钙、醋酸亮丙瑞林、左旋咪唑、左氧氟沙星、利多卡因、利谷隆、赖诺普利、洛美沙星、洛莫司汀、洛哌丁胺、氯雷他定、劳拉西泮、洛美沙星(lorefloxacin)、氯甲西泮、甲磺酸氯沙坦、洛伐他汀、马来酸麦角乙脲、盐酸马普替林、氯苯咪吲哚、甲苯达唑、盐酸美克洛嗪、甲氯芬那酸、美达西泮、甲地高辛、醋酸甲羟孕酮、甲芬那酸、盐酸甲氟喹、醋酸甲地孕酮、美法仑、溴美喷酯、甲丙氨酯、美普他酚、巯嘌呤、美沙拉秦、美司钠、美索达嗪、美雌醇、美沙酮、甲喹酮、美索巴莫、美芬妥英、甲氨蝶呤、甲氧沙林、甲琥胺、甲氯噻嗪、哌甲酯、甲苯比妥、甲基-对羟基苯甲酸酯、甲泼尼龙、甲睾酮、甲乙哌酮、美西麦角、甲氧氯普胺、美托拉宗、美托洛尔、甲硝唑、盐酸米安色林、咪康唑、咪达唑仑、米非司酮、米格列醇、米诺环素、米诺地尔、丝裂霉素C、米托坦、米托蒽醌、霉酚酸酯、吗茚酮、孟鲁司特、吗啡、盐酸莫西沙星、萘丁美酮、纳多洛尔、纳布啡、萘啶酸、诺龙、萘并萘、萘、萘普生、盐酸那拉曲坦、那他霉素、奈拉滨、奈非那韦、奈韦拉平、盐酸尼卡地平、烟碱酰胺、烟酸、醋硝香豆素、硝苯地平、尼鲁米特、尼莫地平、尼莫唑、尼索地平、硝西泮、呋喃妥因、呋喃西林、尼扎替丁、若莫单抗、炔诺酮、诺氟沙星、炔诺孕酮、盐酸去甲替林、制霉菌素、雌二醇、氧氟沙星、奥氮平、奥美拉唑、奥莫康唑、盐酸昂丹司琼、奥普瑞白介素、奥硝唑、奥沙利铂、奥沙尼喹、奥克生太、奥沙普秦、奥沙米特、奥沙西泮、奥卡西平、奥芬达唑、奥昔康唑、氧烯洛尔、羟布宗、盐酸羟苄利明、紫杉醇、帕利夫明、帕米膦酸盐、对氨水杨酸、泮托拉唑、甲乙双酮、盐酸帕罗西汀、培加酶、培门冬酶、聚乙二醇非格司亭、培美曲塞二钠、青霉胺、硝酸戊四醇酯、戊唑辛、喷他佐辛、戊巴比妥、戊巴比妥、喷司他丁、己酮可可碱、奋乃静、奋乃静匹莫齐特、苝、苯乙酰脲、非那西丁、菲、苯茚二酮、苯巴比妥、巴比妥酚盐、酚酞、酚苄明、盐酸酚苄明、苯氧甲基青霉素、苯琥胺、保泰松、苯妥英、吲哚洛尔、吡格列酮、哌泊溴烷、吡罗昔康、马来酸苯噻啶、铂化合物、普卡霉素、多烯类、多粘菌素B、卟吩姆钠、泊沙康唑(Posa)、普拉克索、普拉睾酮、普伐他汀、吡喹酮、哌唑嗪、盐酸哌唑嗪、泼尼松龙、泼尼松、扑米酮、丙巴比妥、丙磺舒、普罗布考、甲基苄肼、丙氯拉嗪、黄体酮、盐酸氯胍、异丙嗪、丙泊酚、残杀威、普萘洛尔、尼泊金丙酯、丙硫氧嘧啶、前列腺素、伪麻黄碱、蝶啶-2-甲基巯基、蝶啶-2-硫醇、蝶啶-4-甲基巯基、蝶啶-4-巯基、蝶啶-7-甲基1-巯基、蝶啶-7-巯基、双羟萘酸噻嘧啶、吡嗪酰胺、芘、吡啶斯的明、乙胺嘧啶、喹硫平、米帕林、喹那普利、奎尼丁、硫酸奎尼丁、奎宁、硫酸奎宁、雷贝拉唑钠、盐酸雷尼替丁、拉布立酶、雷夫康唑、瑞格列奈、双环辛巴比妥、利舍平、类视黄醇、利福布丁、利福平、利福喷汀、利美索龙、利培酮、利托那韦、利妥昔单抗、利扎曲普坦、苯甲酸酯、罗非考昔、盐酸罗匹尼罗、罗格列酮、糖精、沙丁胺醇、水杨酰胺、水杨酸、沙奎那韦、沙格司亭、仲丁巴比妥、司可巴比妥、舍他康唑、舍吲哚、盐酸舍曲林、辛伐他汀、西罗莫司、索拉非尼、司帕沙星、螺旋霉素、螺内酯、二氢睾丸酮、司坦唑醇、司他夫定、己烯雌酚、链佐星、士的宁、硫康唑、硝酸硫康唑、磺胺醋酰、磺胺嘧啶、磺胺甲基嘧啶、磺胺二甲嘧啶、磺胺甲噁唑、磺胺、磺胺噻唑、舒林酸、苯甲酰磺胺、磺胺醋酰、磺胺嘧啶、磺胺多辛、磺胺异噁唑、磺胺甲嘧啶、磺胺甲基异噁唑、磺胺吡啶、柳氮磺胺吡啶、磺吡酮、舒必利、舒噻美、琥珀酸舒马曲坦、马来酸舒尼替尼、他克林、他克莫司、他布比妥、柠檬酸他莫昔芬、坦索罗辛、蓓萨罗丁、紫杉烷类、他扎罗汀、替米沙坦、替马西泮、替莫唑胺、替尼泊苷、替诺昔康、特拉唑嗪、盐酸特拉唑嗪、盐酸特比萘芬、硫酸特布他林、特康唑、特非那定、睾内酯、睾酮、四环素、四氢大麻酚、四氧普林、沙利度胺、蒂巴因、可可碱、茶碱、噻苯达唑、甲砜霉素、硫鸟嘌呤、硫利达嗪、噻替哌、thotoin、胸腺嘧啶、盐酸噻加宾、替勃龙、噻氯匹定、替硝唑、噻康唑、替罗非班、盐酸替扎尼定、妥拉磺脲、甲苯磺丁脲、托卡朋、托吡酯、托泊替康、托瑞米芬、托西莫单抗、曲马多、曲妥珠单抗、盐酸曲唑酮、维甲酸、曲安西龙、氨苯蝶啶、三唑仑、三唑类、三氟丙嗪、甲氧苄啶、马来酸曲米帕明、三亚苯、曲格列酮、氨丁三醇、托吡卡胺、曲伐沙星、泰巴氨酯、泛癸利酮(辅酶Q10)、十一碳烯酸、尿嘧啶、尿嘧啶氮芥、尿酸、丙戊酸、戊柔比星、缬沙坦、万古霉素、盐酸文拉法辛、氨己烯酸、戊烯巴比妥、长春碱、长春新碱、长春瑞滨、伏立康唑、黄嘌呤、扎鲁司特、齐多夫定、齐留通、唑来膦酸盐、唑来膦酸、佐米曲坦、唑吡坦和佐匹克隆。
在特定的方面,治疗剂可以是伏立康唑或唑类化合物大类的其他成员。示例性的抗真菌唑类包括:a)咪唑类,诸如咪康唑、酮康唑、克霉唑、益康唑、奥莫康唑、联苯苄唑、布康唑、芬替康唑、异康唑、奥昔康唑、舍他康唑、硫康唑和噻康唑;b)三唑类,诸如氟康唑、伊曲康唑、艾沙康唑、雷夫康唑、泊沙康唑、伏立康唑、特康唑;以及c)噻唑类,诸如阿巴芬净。可用于该方法中的其他药物包括但不限于:甲状腺机能亢进药物,诸如甲亢平;抗癌剂,如细胞毒性剂,诸如表鬼臼毒素衍生物、紫杉烷类、博来霉素、蒽环类药物以及铂化合物和喜树碱类似物。以下治疗剂还可包括其他抗真菌抗生素诸如难溶于水的棘球白素、多烯类(例如,两性霉素B和那他霉素)以及抗菌剂(例如,多粘菌素B和粘杆菌素)和抗病毒药物。治疗剂还可包括精神疾病治疗剂诸如抗精神病药、抗抑郁药或止痛药和/或安定药诸如苯二氮卓类。治疗剂还包括意识水平改变剂或麻醉剂,诸如丙泊酚。本组合物及其制备方法可用于制备药物组合物,这些药物组合物具有适当的药代动力学特性以用作治疗药物。
在一些实施例中,本文所述的组合物可包括长效β-激动剂(LABA)。长效β-激动剂的一些非限制性实例包括福莫特罗诸如富马酸福莫特罗、沙美特罗诸如昔萘酸沙美特罗、班布特罗、盐酸克伦特罗、茚达特罗、奥洛他特罗、普罗托醇、阿贝地特罗、沙美胺醇、维兰特罗、阿福特罗、卡莫特罗、SK-PF-610355、GSK-159797、GSK-597901、GSK-159802、GSK-642444、GSK-678007或本领域已知的其他长效β-激动剂。
在其他实施例中,本文所述的组合物可包括长效毒蕈碱拮抗剂(LAMA)。长效毒蕈碱拮抗剂的一些非限制性实例包括噻托溴铵、阿地溴铵、第若铵、异丙托溴铵、氧托溴铵、达托铵、格隆溴铵或格隆溴铵衍生物或本领域中一致的其他长效毒蕈碱拮抗剂诸如美国专利申请No.2009/0181935、PCT专利申请No.WO 2010/007561和PCT专利申请No.WO 2008/035157中所教导的那些,这些专利申请以援引方式并入本文。
在其他实施例中,本文所述的组合物可包括皮质类固醇,特别是适于吸入的皮质类固醇。皮质类固醇的一些非限制性实例包括二丙酸倍氯米松、布地奈德、氟尼松、丙酸氟替卡松、糠酸氟替卡松、糠酸莫米松、环索奈德、棕榈酸罗氟萘德、曲安奈德或其他本领域中已知的其他皮质类固醇。
在其他实施例中,本文所述的组合物可包含一种或多种抗生素。一些抗生素类别包括青霉素、头孢菌素类、碳青霉烯、大环内酯类、氨基糖苷类、喹诺酮类(包括氟喹诺酮类)、磺酰胺类和四环素类。在一些实施例中,组合物可包含针对特定细菌类型的窄谱抗生素。在一些抗菌素的非限制性实例中,包括青霉素、头孢菌素、多粘菌素、利福霉素、利比霉素、喹诺酮和磺酰胺。在抑菌抗生素的一些非限制性实例中,包括大环内酯类、林可酰胺类或四环素类。在一些实施例中,抗生素为:氨基糖苷类,诸如卡那霉素和链霉素;安沙霉素类,诸如利福昔明和格尔德霉素;羧苄青霉素,诸如氯碳头孢;碳青霉烯,诸如厄他培南、亚胺培南;头孢菌素,诸如头孢氨苄、头孢克肟、头孢吡肟和头孢吡普;糖肽,诸如万古霉素或替考拉宁;林可酰胺,诸如林可霉素和克林霉素;脂肽,诸如达托霉素;大环内酯,诸如克拉霉素、螺旋霉素、阿奇霉素和泰利霉素;单杆菌酰胺,诸如氨曲南;硝基呋喃,诸如呋喃唑酮和呋喃妥英;噁唑烷酮,诸如利奈唑胺;青霉素类,诸如阿莫西林、阿洛西林、氟氯西林和青霉素G;抗生素多肽,诸如杆菌肽、多粘菌素B和粘菌素;喹诺酮类,诸如环丙沙星、左氧氟沙星和加替沙星;磺胺类药物,诸如磺胺嘧啶银盐、磺胺米隆、磺胺二甲氧嘧啶或磺胺吡啶;或四环素类,诸如地美环素、强力霉素、米诺环素、土霉素或四环素。在一些实施例中,组合物包含对分枝杆菌起作用的药物,诸如环丝氨酸、卷曲霉素、乙硫异烟胺、利福平、利福布丁、利福喷丁和链霉素。可设想的其他抗生素包括胂凡纳明、氯霉素、磷霉素、夫西地酸、甲硝唑、莫匹罗星、平板霉素、奎奴普丁、达福普丁、甲砜霉素、替加环素、替硝唑或甲氧苄啶。
在一些实施例中,组合物还可包含一种或多种抗真菌剂,诸如上文所述的那些。一些抗真菌剂包括但不限于两性霉素B(一种唑类抗真菌化合物)、棘球白素或氟胞嘧啶。唑类抗真菌化合物的一些非限制性实例包括:a)咪唑类,诸如咪康唑、酮康唑、克霉唑、益康唑、双醚康唑、联苯苄唑、布康唑、芬替康唑、异康唑、奥昔康唑、舍他康唑、硫康唑和噻康唑;b)三唑类,诸如氟康唑、伊曲康唑、艾沙康唑、雷夫康唑、泊沙康唑、伏立康唑、特康唑;以及c)噻唑类,诸如阿巴芬净。
在一些实施例中,组合物可进一步包含一种或多种抗病毒剂诸如核苷类,例如阿昔洛韦、泛昔洛韦、伐昔洛韦、喷昔洛韦和更昔洛韦,或其他抗病毒剂,诸如聚乙二醇化干扰素、干扰素α-2b、拉米夫定、阿德福韦、替比夫定、恩替卡韦或替诺福韦。
B.赋形剂
在一些方面,本公开包含配制到药物组合物中的一种或多种赋形剂。在一些实施例中,本文所用的赋形剂为水溶性赋形剂。这些水溶性赋形剂包括糖类,例如二糖,诸如蔗糖、海藻糖或乳糖;三糖,诸如果糖、葡萄糖、半乳糖或棉子糖;多糖,诸如淀粉或纤维素;或糖醇,诸如木糖醇、山梨糖醇或甘露醇。在一些实施例中,这些赋形剂在室温下为固体。糖醇的一些非限制性实例包括赤藓糖醇、苏糖醇、阿拉伯糖醇、木糖醇、核糖醇、甘露醇、山梨糖醇、半乳糖醇、果糖醇、艾杜糖醇、肌醇、庚七醇、异麦芽酮糖醇、麦芽糖醇、乳糖醇、麦芽三糖醇、麦芽四糖醇或聚葡糖醇。在一些方面,本发明的药物组合物可进一步不含疏水性或蜡赋形剂诸如蜡和油。疏水性赋形剂的一些非限制性实例包括氢化油和部分氢化油、棕榈油、大豆油、蓖麻油、巴西棕榈蜡、蜂蜡、棕榈蜡、白蜡、蓖麻蜡或羊毛脂。另外,本公开可进一步包含一种或多种氨基酸或其酰胺或酯衍生物。在一些实施例中,所用的氨基酸可以是20种经典氨基酸之一,诸如甘氨酸、丙氨酸、缬氨酸、异亮氨酸、亮氨酸、蛋氨酸、苯丙氨酸、酪氨酸、色氨酸、丝氨酸、苏氨酸、天冬酰胺、谷氨酰胺、半胱氨酸、硒半胱氨酸、脯氨酸、精氨酸、组氨酸、赖氨酸、天冬氨酸或谷氨酸。这些氨基酸可以是D或L取向,或者可以是α-氨基酸、β-氨基酸、γ-氨基酸或δ-氨基酸。在其他实施例中,可使用常见的非经典氨基酸之一,诸如肉碱、GABA、羧基谷氨酸、左旋甲状腺素、羟脯氨酸、硒代蛋氨酸、β-丙氨酸、鸟氨酸、瓜氨酸、脱氢丙氨酸、δ-氨基乙酰丙酸或2-氨基异丁酸。
在一些方面,药物组合物中赋形剂的量为约0.5%w/w至约10%w/w、约1%w/w至约10%w/w、约2%w/w至约8%w/w或约2%w/w至约5%w/w。药物组合物中赋形剂的量占药物组合物总重量的约0.5%w/w、0.75%w/w、1%w/w、1.25%w/w、1.5%w/w、1.75%w/w、2%w/w、2.5%w/w、3%w/w、3.5%w/w、4%w/w、4.5%w/w、5%w/w、6%w/w、7%w/w、8%w/w、9%w/w、至约10%w/w或可衍生自其中的任何范围。在一个实施例中,药物组合物中赋形剂的量为药物组合物总重量的2%w/w至5%w/w。
II.制造方法
因此,在一个方面,本公开提供了可使用薄膜冷冻方法制备的药物组合物。此类方法描述于美国专利申请No.2010/0221343和Watts等人(2013)中,这两篇文献通过援引并入本文。在一些实施例中,这些方法包括将药物组合物的成分溶于溶剂中以形成前体溶液。溶剂可以是水或有机溶剂。可以使用的有机溶剂的一些非限制性实例包括挥发性有机溶剂,诸如1,4-二噁烷、乙腈、丙酮、甲醇、乙醇、异丙醇、二氯甲烷、氯仿、四氢呋喃、叔丁醇、二甲基亚砜、N,N-二甲基甲酰胺、乙醚、乙酸乙酯、乙酸异丙酯、乙酸丁酯、乙酸丙酯、甲苯、己烷、庚烷、戊烷或它们的组合。在一些实施例中,前体溶液可包含少于10%w/v的治疗剂和赋形剂。前体溶液可包含少于0.5%w/v、1%w/v、2%w/v、3%w/v、4%w/v、5%w/v、6%w/v、7%w/v、8%w/v、9%w/v或10%w/v或可衍生自其中的任何范围的治疗剂和赋形剂。
该前体溶液可沉积到表面上,该表面处于引起前体溶液冷冻的温度下。在一些实施例中,该温度可能低于环境压力下溶液的凝固点。在其他实施例中,可在表面上施加减小的压力,使溶液在低于环境压力下的凝固点的温度下冷冻。表面也可在移动的传送带式系统上旋转或移动,从而使前体溶液均匀地分布在表面上。另选地,前体溶液可按照形成平坦表面的方式施加至表面上。
将前体溶液施加到表面上后,可除去溶剂以获得药物组合物。可采用任何适当的除去溶剂的方法,包括在减压或高温或冻干条件下蒸发。在一些实施例中,冻干可包括减小的压力和/或降低的温度。此类降低的温度可以为25℃至约-200℃、20℃至约-175℃、约20℃至约-150℃、0℃至约-125℃、-20℃至约-100℃、-75℃至约-175℃或-100℃至约-160℃。温度为约-20℃、-30℃、-35℃、-40℃、-45℃、-50℃、-55℃、-60℃、-70℃、-80℃、-90℃、-100℃、-110℃、-120℃、-130℃、-140℃、-150℃、-160℃、-170℃、-180℃、-190℃、至约-200℃或可衍生自其中的任何范围。另外,溶剂可在低于500mTorr、450mTorr、400mTorr、375mTorr、350mTorr、325mTorr、300mTorr、275mTorr、250mTorr、225mTorr、200mTorr、175mTorr、150mTorr、125mTorr、100mTorr、75mTorr、50mTorr或25mTorr的减小的压力下除去。
使用这些方法制备的组合物可能表现出脆性,使得通过设备加工时,组合物易于剪切成较小的颗粒。这些组合物具有高表面积,并且表现出改善的组合物的流动性。此类流动性可通过例如卡尔指数或其他类似的指标来测量。特别地,可通过比较粉末的堆积密度与粉末的振实密度来测量卡尔指数。当组合物通过辅助设备进行处理以递送药物时,此类化合物可表现出有利的卡尔指数,并且可能导致颗粒得到更好的剪切以产生更小的颗粒。
III.定义
当在权利要求和/或说明书中与术语“包括”一起使用时,单词“一”的使用可以意味着“一个”,但是它也与“一个或多个”“至少一个”和“一个或多于一个”的含义一致。如本文所用,“另一”可以表示至少第二或更多者。
如本文所用,术语“药”、“药物”、“治疗剂”和“治疗活性剂”可互换使用,表示在人或动物体内引起治疗或药理作用并且用于治疗疾病、障碍或其他病症的化合物。在一些实施例中,这些化合物已经过并且获得有关向活体动物给药的监管批准。
除非明确指出仅指代替代方案或替代方案是互斥的,否则权利要求中的术语“或”的使用是指“和/或”。如本文所用,“另一”可以表示至少第二或更多者。
如本说明书和权利要求书所用,词语“包含(comprising)”(以及“包含”的任何形式,诸如“包含(comprise)”和“包含(comprises)”)、“具有(having)”(以及“具有”的任何形式,诸如“具有(have)”和“具有(has)”)、“包括(including)”(以及“包括”的任何形式,诸如“包括(includes)”和“包括(include)”)或“含有(containing)”(以及“含有”的任何形式,诸如“含有(contains)”和“含有(contain)”)是非遍举的或开放式的,不排除额外的、未述及的要素或方法步骤。
如本说明书所用,术语“显著”(以及“显著”的任何形式,诸如“显著地”)并非意在暗示两个值之间的统计差异,而仅意在暗示暗示参数的重要性或差异范围。
在整个本申请中,术语“约”用于表示值包括用于确定该值的设备、方法的固有误差变化或者研究对象或实验研究之间存在的变化。除非另有定义,否则术语“约”是指所示值的±10%。
如本文所用,就特定组分而言,术语“实质上不含”或“实质上无”在本文中用于指没有将特定组分故意配制到组合物中和/或特定组分仅作为污染物或以痕量存在。存在于该组合物中的所有容器、副产物及其他材料的总量少于2%。术语“大体上不含”或“大体上无”表示组合物包含少于1%的特定组分。术语“基本上不含”或“基本上无”包含少于0.5%的特定组分。
如本文所用,术语“域”是指组合物的特定区域,其实质上由单一材料构成,该材料的其特征与组合物的其他组分不同。“离散域”是指组合物的单独区域,该区域彼此不同并且与组合物的其他区域彼此分开。该域可实质上由组合物中的单个元素组成。这些域可能是不连续的,使得离散域作为多个彼此不接触的域存在。
如本文所用,术语“纳米颗粒”具有其常规和普通的定义,是指表现为整体单元而不是颗粒内单个分子的离散颗粒。纳米颗粒可具有约1nm至约10,000nm的尺寸,超细纳米颗粒具有1nm至100nm的尺寸,细颗粒具有100nm至2,500nm的尺寸,并且粗颗粒具有2,500nm至10,000nm的尺寸。在一些实施例中,本文所述的纳米聚集体可包含多个纳米颗粒的组合物,并且具有约10nm至约100μm的尺寸。
虽然在本发明的广泛范围内所示的数字范围和参数为近似值,但具体实施例中所示的数值会尽可能准确地报告。但是,任何数值固有地含有某些必然产生自它们各自测量值和参数范围内的标准偏差的误差。
通过下面详细的描述,本公开的其他目的、特点和优点将会变得显而易见。然而应当理解,具体实施方式和特定的实施例在指示本公开的具体实施例时,只是用于示范,因为根据此具体实施方式,在本公开的精神和范围内的各种变化和改进对于本领域技术人员将显而易见。
IV.实例
为便于更好地理解本公开,提供了以下具体实施例的实例。本领域技术人员应当理解,以下实例中所公开的技术代表发明人发现的在本公开的实践中发挥良好作用的技术,因此可以认为构成其实践的优选方式。然而,根据本公开,本领域的技术人员应当理解,在不脱离本公开的精神和范围的情况下,可以对所公开的特定实施例进行许多改变并且仍获得相同或相似的结果。以下实例不应理解为限制或定义本公开的完整范围。
实例1-讨论与结果
A.伏立康唑干粉制剂的理化特性
利用TFF技术生产包含甘露醇的结晶态伏立康唑粉末制剂(见表1)。主要采用XRPD和mDSC测定制剂的结晶度。包含甘露醇的TFF-VCZ粉末制剂被鉴定为结晶,如图1和2所示。TFF-VCZ-MAN粉末制剂的XRPD中表现出伏立康唑特征峰,对应于伏立康唑散装粉末(例如,12.4°2θ和13.6°2θ)和δ-甘露醇(例如,9.5°2θ和20.2°2θ),如图1所示。这些结果表明,粉末制剂由结晶伏立康唑和δ-甘露醇组成。在TFF-VCZ-MAN粉末制剂中,随着甘露醇含量(%w/w)减少,δ-甘露醇的峰强度降低,并且当粉末制剂包含5%(w/w)甘露醇时,无法检测到对应于δ-甘露醇的峰。TFF-MAN干粉主要为δ型,而XRPD检测到痕量α型和β型(分别为13.5°2θ和14.5°2θ)。
表1.使用薄膜冷冻(TFF)技术研究的伏立康唑干粉制剂的总结。
mDSC也确认了TFF-VCZ-MAN粉末制剂的结晶度。图2显示,在TFF-VCZ-MAN 95:5和TFF-VCZ-MAN 50:50中未检测到玻璃化转变,仅检测到有对应于伏立康唑和甘露醇的熔融的吸热峰。TFF-VCZ具有在130.86℃处的熔融吸热峰,其熔融热为105.3J/g。当用百分比分数(w/w)计算TFF-VCZ-MAN粉末中伏立康唑的预期熔融热时,TFF-VCZ-MAN 95:5和TFF-VCZ-MAN 50:50中伏立康唑的熔融热分别为100.0J/g和52.6J/g。TFF-VCZ-MAN 95:5中伏立康唑的实测熔融热为95.1J/g,TFF-VCZ-MAN 50:50中伏立康唑的实测熔融热为33.7J/g,分别为预期值的95.1%和64.0%。TFF-MAN具有在167.31℃处的熔融吸热峰,其熔融热为187.5J/g。TFF-VCZ-MAN 95:5和TFF-VCZ-MAN 50:50中甘露醇的预期熔融热分别为9.38J/g和93.8J/g。甘露醇的实测熔融热分别为2.63J/g和63.2J/g,并且分别为预期值的28.0%和67.4%。表2列出了通过mDSC测得的两种制剂中伏立康唑与甘露醇(伏立康唑:甘露醇,w/w)的组成比。使用1H-NMR通过对质子峰积分来计算这些比率。TFF-VCZ-MAN 95:5的一个质子的理论比为1:0.1009,计算出的实验比为1:0.0992,表示在TFF-VCZ-MAN 95:5中检出预期甘露醇的98.3%。在TFF-VCZ-MAN 50:50的情况下,利用1H-NMR检出预期甘露醇的100%。
表2.利用1H-NMR定量比较TFF-VCZ-MAN 95:5和TFF-VCZ-MAN 50:50中的伏立康唑和甘露醇。
TFF-VCZ-MAN粉末的颗粒形貌如图3所示。在TFF-VCZ粉末中观察到微米级颗粒的团聚,并且在其他TFF-VCZ-MAN粉末制剂中也发现了这些颗粒。在包含更高含量的甘露醇的TFF-VCZ-MAN中粉末观察到更多的多孔基质。图4所示的TFF-VCZ和TFF-VCZ-MAN 95:5粉末的3D形貌和图示证实,TFF-VCZ-MAN 95:5粉末的表面纹理粗糙,而TFF-VCZ粉末的表面纹理光滑。图5中TFF-VCZ-MAN 95:5粉末的高分辨率形貌表明,TFF-VCZ-MAN 95:5粉末是由约150-500nm纳米颗粒组成的纳米聚集体。这些TFF-VCZ-MAN粉末的SSA如图6所示。TFF-VCZ粉末表现出最低的SSA(8.36m2/g),而TFF-MAN干粉的多孔基质表现出最高的SSA(17.11m2/g)。SSA随TFF-VCZ-MAN粉末制剂中添加的甘露醇增加而提高。借助图7所示的SEM/EDX,通过氮、氧和氟的检测结果鉴定出微米级颗粒由伏立康唑纳米聚集体组成。通过氧的检测结果(不含氮和氟),将多孔基质鉴定为甘露醇。
TFF-VCZ粉末的FT-IR峰图与伏立康唑散装粉末的FT-IR峰图相匹配,并且还发现包含不同量的甘露醇的TFF-VCZ-MAN粉末具有相同的峰图。还在TFF-VCZ-MAN粉末中发现TFF-MAN的峰图。因此,在TFF-VCZ-MAN粉末中仅观察到对应于TFF-VCZ和TFF-MAN的峰,并且在TFF-VCZ-MAN粉末的FT-IR谱图中未发现新的峰,如图8所示。利用ssNMR得到的1D 13C和19F CP-MAS谱图如图9所示。伏立康唑与甘露醇不存在13C峰的谱图重叠,并且在19F谱图中具有所有共振。在TFF-VCZ和TFF-VCZ-MAN中表现出相同的谱图。此外,TFF-VCZ-MAN 90:10谱图中的13C和19F尖峰确认了伏立康唑和甘露醇的结晶度。TFF-VCZ-MAN 90:10的2D 1H-13CHETCOR谱图与TFF-VCZ的谱图的比较见图10。未观察到来自TFF-VCZ-MAN 90:10的伏立康唑和甘露醇之间的分子间交叉峰。
B.体外气雾剂性能和稳定性
利用NGI测定TFF-VCZ-MAN粉末制剂的空气动力学粒度分布,并且FPF(定量剂量百分比)如图11所示。基于FPF(定量剂量百分比)数据,由90%至97%(w/w)伏立康唑组成的TFF-VCZ-MAN粉末制剂表现出最高的雾化效果。TFF-VCZ-MAN 97:3的FPF(定量剂量百分比)明显高于(p<0.05)TFF-VCZ的FPF,FPF(定量剂量百分比)改善了66%。包含90%至97%(w/w)伏立康唑的TFF-VCZ-MAN粉末的气雾剂性能无显著差异(p>0.05)。当组合物包含多于10%(w/w)的甘露醇时,TFF-VCZ-MAN粉末制剂的气雾剂性能下降。
还通过使用NGF测量FPF,研究了物理力对TFF-VCZ-MAN 95:5粉末制剂气雾剂性能的影响。如图12和13所示,在不同的剪切时间监测粒径分布和气雾剂性能的变化。在15min、30min和60min时,FPF(定量剂量百分比)分别为44.3%、47.5%和42.4%,并且FPF(递送剂量百分比)分别为68.7%、73.6%和69.5%。在施加剪切力之前,FPF的初始值为40.0%(定量剂量百分比),并且FPF的初始值为58.8%(递送剂量百分比)。虽然还观察到MMAD从初始时间的3.7μm改变为15min、30min和60min时的3.2μm、3.0μm和3.1μm,但GSD未见显著变化。
在25℃/60%RH条件下进行稳定性研究,并监测TFF-VCZ-MAN 95:5粉末制剂的纯度和气雾剂性能在13个月内的变化,结果如图14所示。在测试期间,TFF-VCZ-MAN 95:5中伏立康唑的纯度不变,并且未检测到降解物。在稳定性研究中,为比较气雾剂性能,对每个时间点的FPF(定量剂量百分比)、FPF(递送剂量百分比)、MMAD和GSD进行了比较。在13个月内,FPF(定量剂量百分比)和FPF(递送剂量百分比)均无统计学显著差异(两者p值均大于0.05)。1个月后,GSD较初始值明显下降(p<0.05),而MMAD在13个月内无任何差异(p>0.05)。
C.伏立康唑干粉制剂的讨论
在TFF-VCZ-MAN粉末制剂的溶出度测试中,使用pH 7.4PBS作为接收介质,并且Franz池的供应室顶部覆盖有石蜡膜,以防止溶媒产生蒸发损失。对结晶态TFF-VCZ-MAN95:5与无定形态TFF-VCZ-PVPK25 25:75的溶出度进行比较,结果表明结晶态干粉在测试期间的累积药物释放率明显较低(p<0.05),如图15所示。无定形态TFF-VCZ-PVPK25在3小时内的累积伏立康唑释放率为63.2%w/v,而结晶态TFF-VCZ-MAN 95:5的累积伏立康唑释放率仅为22.8%。TFF-VCZ-MAN 25:75和TFF-VCZ-MAN 50:50在3小时内的累积伏立康唑释放率分别为46.3%和35.3%。
D.伏立康唑干粉制剂的表征
伏立康唑(Beinborn等人,2012b;Ramos和Diogo,2016)和甘露醇(Yu等人,1998)具有高结晶趋势,并且玻璃化转变温度低于室温。因此,除非伏立康唑与甘露醇之间存在强烈的分子间相互作用以防止结晶,否则假定TFF-VCZ-MAN处于结晶态。基于XRPD数据和1D CP-MAS谱图的锐度,TFF-VCZ-MAN粉末制剂处于结晶态,表明伏立康唑与甘露醇之间不存在足够强的相互作用。
虽然XRPD可用于表征粉末的结晶度,但它可能无法检测制剂中少量的无定形态。因此,对TFF-VCZ-MAN粉末进行mDSC分析,结果表明TFF-VCZ-MAN干粉处于结晶态,因为仅检测到伏立康唑和甘露醇的两个吸热峰。但是,观察到甘露醇的熔点降低,尤其是在TFF-VCZ-MAN 95:5中。TFF-VCZ-MAN 95:5中甘露醇的熔融热可能较低,因为在温度达到甘露醇的熔点之前,溶于熔融伏立康唑中的甘露醇的量相对较少。另外,TFF-VCZ-MAN 95:5中的甘露醇颗粒通常为100-200nm,并且这些纳米级颗粒可降低熔融热。为确认甘露醇在表现出低熔点的TFF-VCZ-MAN粉末中的功效,利用1H-NMR测定伏立康唑与甘露醇之间的分子比。虽然NMR通常用于定性分析,但也可以使用定量NMR分析(Espina等人,2009;Pauli等人,2012)。在TFF-VCZ-MAN 95:5和TFF-VCZ-MAN 50:50中,伏立康唑与甘露醇之间的实验分子比均与理论值非常吻合。此外,通常使用13C和19F ssNMR确认结晶多态性并且鉴定固体剂型中的低含量无定形药物(Correa-Soto等人,2017;Offerdahl等人,2005)。TFF-VCZ和TFF-VCZ-MAN90:10的13C和19F CP-MAS谱图中的伏立康唑共振的峰位和线宽相同,确认其结晶度,并且表明不存在可定量的无定形物含量。
FTIR用于研究伏立康唑与甘露醇之间的化学相互作用。伏立康唑的羟基基团与其降解途径相关(Shaikh和Patil,2012),它在存在分子间相互作用的情况下可能是活性最高的位点。如果发生这种情况,伏立康唑的FT-IR峰将在3100cm-1与3500cm-1之间偏移(Silverstein等人,2005)。在此范围内,存在两个对应于伏立康唑的峰,其分别在3118.9cm-1和3198.4cm-1处。在所有TFF-VCZ-MAN和TFF-VCZ粉末制剂中均观察到这两个峰,但未发现这两个峰发生偏移。在该范围内,在3276.6cm-1处观察到甘露醇的峰,并且未观察到偏移。如果甘露醇与伏立康唑的芳族仲胺之间存在相互作用,可能在1230cm-1与1300cm-1之间观察到峰偏移(Silverstein等人,2005)。在该范围内,在1241.5cm-1、1248.8cm-1、1268.5cm-1和1277.6cm-1处检测到伏立康唑的四个峰,但是当伏立康唑粉末制剂中包含甘露醇时,未发现明显的峰偏移。因此,这些FT-IR数据支持,TFF-VCZ-MAN粉末制剂中的伏立康唑与甘露醇之间无相互作用或相互作用非常弱。
虽然FT-IR通常用于鉴定构象和分子间相互作用,但ssNMR能够为结构研究提供更深入的原子级信息(Tian等人,2017)。在本研究中,利用1D 13C和19F CP-MAS考察构象变化。在TFF-VCZ与TFF-VCZ-MAN 90:10之间,所有伏立康唑峰的化学位移无差异。此外,采集2D13C-1H HETCOR谱图,以便以更高的分辨率研究结构扰动。该结果确认在直接维度上不存在13C化学位移变化。在给定的分辨率下,所有脂族和芳族质子在间接维度上的化学位移也未见可观察到的变化。此外,利用2D 13C-1H HETCOR检测药物-赋形剂相互作用。在给定的谱图强度下,未观察到伏立康唑与甘露醇之间的分子间交叉峰(即相互作用)。
在TFF-VCZ-MAN粉末制剂中观察到两种不同形状的颗粒,并且基于观察到的TFF-VCZ和TFF的颗粒形态,最初认为微米级颗粒为伏立康唑,多孔基质为甘露醇。为确认这一点,利用SEM/EDX对这些颗粒的化学组成进行确认。但是,在初始SEM/EDX运行期间,检测到的氧、氟和氮的位置相互重叠,表明存在由伏立康唑和甘露醇组成的颗粒。稍后确定了原因。由于EDX的测量深度为微米级,因此检测光束穿过所检测的TFF-VCZ-MAN 50:50粉末的整个颗粒深度。为克服这一问题,将粉末广泛地分散在样品架上的碳带上,并执行斑点分析,以测定两种不同形态的颗粒的化学组成。通过斑点分析,基于氧、氮和氟的化学组成,将微米级颗粒鉴定为伏立康唑纳米聚集体,而将多孔基质鉴定为甘露醇(表现出包含氧但不含氮和氟的化学组成)。因此,可以得出结论,在TFF过程中,结晶态甘露醇与结晶态伏立康唑发生了相分离。
虽然图5中的AFM图像显示TFF-VCZ-MAN粉末是纳米聚集体,但BET数据也支持形成了伏立康唑纳米聚集体。当SEM图像显示TFF-VCZ颗粒比TFF-MAN的高多孔基质大得多时,TFF-MAN的比表面积仅比TFF-VCZ大两倍。这可能是因为伏立康唑颗粒是具有比SEM图像上可见的更大比表面积的纳米聚集体。
E.甘露醇的含量影响气雾剂性能和溶出速率
TFF-VCZ-MAN粉末中甘露醇的含量影响其形态。当包含少量甘露醇时,由于TFF过程中发生的高过冷度而阻止了颗粒生长,从而形成了亚微米级甘露醇颗粒(Engstrom等人,2008)。这些颗粒存在于伏立康唑纳米聚集体的表面,并且改变了它们的表面纹理。在雾化过程中,并未从伏立康唑纳米聚集体的表面取出这些亚微米级甘露醇颗粒。这可能是由于难以从表面除去纳米级颗粒。虽然内聚力和粘附力与颗粒直径成正比,但去除力(重力、振动力和离心力)与直径的立方成正比(Hinds,1999)。因此,亚微米级甘露醇颗粒难以与伏立康唑纳米聚集体分离,并且雾化过程中伏立康唑纳米聚集体的表面仍然保持粗糙,从而使雾化效果更高。随着TFF-VCZ-MAN粉末中甘露醇含量的增加,产生较大的多孔甘露醇基质。这些基质不仅存在于伏立康唑纳米聚集体颗粒的表面,而且还围绕这些纳米聚集体颗粒。由于较大的多孔甘露醇基质使它们保持在一起,因此组装成多个伏立康唑纳米聚集体。这些聚集体结构在雾化过程中得以保留。因此,这些大的聚集颗粒降低了包含超过10%(w/w)甘露醇的TFF-VCZ-MAN粉末制剂的气雾剂性能。
DPI制剂的气雾剂性能密切依赖于颗粒的内聚力和粘附力。这些力包括范德华力、吸附液膜的表面张力和静电力(Hickey等人,1994)。所有这些因素均受颗粒形状和尺寸、表面粗糙度/纹理、相对湿度、温度、颗粒接触持续时间和速度的影响(Hinds,1999;Beach等人,2002;Tan等人,2016;Price等人,2002)。在这些力中,范德华力最重要(Hinds1999)。由于范德华力是分子间偶极子引起的吸引力,因此当颗粒表面之间的距离达到分离距离时,范德华力大大降低(Hinds 1999)。因此,较粗糙的表面可通过保持更远的平均颗粒距离来显著降低范德华力。表面粗糙度不仅影响范德华力,而且影响由表面水分引起的表面张力。光滑的颗粒表面和较高的相对湿度导致更强的表面张力。但是,静电力取决于粒径。大于0.1μm的颗粒可能产生静电力(Hinds 1999)。该吸引静电力对于较大的颗粒更强,并且还与相对湿度相关;低湿度使颗粒上的电荷保留更长时间。尽管如此,通常认为静电力小于范德华力和表面张力(Hinds 1999)。因此,颗粒的表面粗糙度和纹理对于DPI制剂的气雾剂性能具有重要作用。
由不同含量的甘露醇引起的粉末制剂的形态变化显著影响TFF-VCZ-MAN粉末制剂的气雾剂性能。颗粒的内聚力和粘附力的变化改变气雾剂的性能,并且这些力的降低与颗粒之间的接触面积减小(Beach等人,2002)以及颗粒之间更远的距离相关(Hinds 1999)。包含少量亚微米甘露醇颗粒的TFF-VCZ-MAN纳米聚集体的接触面积显著减小,并且伏立康唑颗粒之间的距离进一步分开,如图4所示。与TFF-VCZ粉末相比,TFF-VCZ-MAN 99:1粉末的FPF(定量剂量百分比)得到显著改善(p<0.05)。在制剂中加入高达3%(w/w)的甘露醇时,均存在添加甘露醇所引起的这一改善。通过将1%(w/w)甘露醇加入包含97%至100%(w/w)伏立康唑的制剂中,使FPF(定量剂量百分比)提高了约5%。此外,TFF-VCZ-MAN 95:5粉末的喷射剂量比TFF-VCZ粉末高约30%(分别为68%和36%,数据未显示)。这一增强的喷射剂量是由于减小了颗粒对设备的粘附力。由于TFF生产的TFF-VCZ-MAN粉末中包含极少量的水分(小于0.1%w/w,数据未显示),并且伏立康唑和甘露醇不吸湿,因此预期这些颗粒的表面张力相对较低。在低湿度环境中储存粉末可能产生静电力,但这些力被认为比范德华力和表面张力小得多(Hinds 1999)。因此,通过改变表面纹理来减小接触面积并增加颗粒距离,主要涉及降低TFF-VCZ-MAN粉末制剂的内聚力和粘附力,这些内聚力和粘附力的降低改善了气雾剂性能。Young等人同样描述了气雾剂性能与颗粒之间的分离能之间的关系(Young等人,2002),与我们的结果高度一致。
TFF-VCZ-MAN粉末中不同含量的甘露醇不仅影响气雾剂性能,而且影响溶出速率。包含较高含量的甘露醇的TFF-VCZ-MAN粉末表现出较高的溶出速率,并且这一结果可通过甘露醇更快润湿粉末来解释。对于包含大量甘露醇的TFF-VCZ-MAN粉末,包封伏立康唑的周围甘露醇颗粒会很快润湿并且溶出。因此,伏立康唑纳米聚集体在短时间内被溶媒包围,并且溶出速率加快。TFF-VCZ-MAN 25:75粉末的SEM图显示,在Franz池上,大多数甘露醇颗粒在5min内溶出,而此时在TFF-VCZ-MAN 95:5粉末的伏立康唑纳米聚集体表面上仍然观察到亚微米级甘露醇颗粒。这表明当粉末制剂中仅包含少量甘露醇时,伏立康唑纳米聚集体不会快速润湿。
F.TFF过程的益处
利用TFF制得伏立康唑粉末制剂的高效纳米聚集体。尽管之前已经报道了不含载体的DPI制剂(Yazdi和Smyth,2016a;Yazdi和Smyth,2016b),但DPI制剂中通常包含载体。但是,基于载体的DPI制剂通常具有低药效。此外,还有许多因素,诸如载体颗粒的粒径(Du等人,2014)、粒径分布(Steckel和Muller,1997)和表面形貌(Du等人,2014;Flament等人,2004),影响雾化过程中粉末气雾剂性能,并且此类因素对沉积的剂量均匀性具有负面影响(Du等人,2017)。通过使用TFF,在低至3%(w/w)甘露醇的情况下,可获得TFF-VCZ-MAN纳米聚集体的最高气雾剂性能;因此,优化的TFF-VCZ-MAN粉末制剂的功效可高达97%(w/w)。在赋形剂含量极低的情况下的这一高药效使得只需递送较少的粉末,并且可以消除通常由载体引起的药效低和沉积剂量不均匀的问题。
高效DPI制剂也可通过其他技术(诸如研磨)进行制备。尽管通过研磨产生的适合递送至肺部的颗粒尺寸仅有几微米,但这些颗粒仍被视为单个离散的微米级颗粒。根据Longest和Hindle的研究(2017),利用TFF制得的作为纳米聚集体的伏立康唑DPI制剂可具有显著更高的总肺吸收效率和剂量分布均匀度。预期这些伏立康唑纳米聚集体能够更好地覆盖上皮中存在真菌菌落的部位。TFF之所以能够生产纳米聚集体,是因为其能够在高达10,000K/s的冷冻速率下快速成核,实现更窄的粒径分布和更低的奥斯特瓦尔德熟化率,从而产生大量核,并且防止冷冻过程中的颗粒生长(Engstrom等人,2008;Overhoff等人,2009)。未冻结通道的小尺寸及未冻结溶液的迅速增加的粘度(Engstrom等人,2008)使伏立康唑纳米聚集体具有类似的尺寸。
颗粒的表面改性也可以通过TFF来完成。Begat等人之前报道使用疏水性材料诸如卵磷脂、亮氨酸和硬脂酸镁对颗粒进行表面改性。虽然经干式机械融合方法(例如机械融合)处理的颗粒由于表面自由能下降,在包含或不含载体的情况下均表现出改善的气雾剂性能(Begat等人,2005;Begat等人,2009),但是该方法基于原料药与力控制剂(例如卵磷脂、亮氨酸和硬脂酸镁)的共混。机械融合方法需要将机械能输入制剂中,并且可能导致药物的化学不稳定性增加。此外,由于共混可能使聚集体解聚,因此通过共混进行表面改性可能仅适用于离散的微米级颗粒,而不适用于纳米聚集体。Kawashima等人也报道了通过各种方法(诸如机械剪切混合、冷冻或喷雾干燥)对颗粒进行表面改性(Kawashima等人,1998)。借助亲水性添加剂诸如轻质无水硅酸(AEROSIL),使疏水性颗粒的表面转化为亲水性表面,并且经过表面改性的颗粒在体外具有改善的吸入行为。但是,该方法使用离散的微米级药物颗粒,无法用于纳米聚集体。因此,用其他方法处理的这些离散的微米级颗粒无法获得如Longest和Hindle(2017)所述的那些纳米聚集体的增强的吸收和微剂量性能。但是,利用TFF,无需能量输入即可对颗粒表面进行改性。利用相分离的亚微米级甘露醇颗粒(其单独存在于药物纳米聚集体的表面)对伏立康唑纳米聚集体进行表面改性,因为其快速冷冻速率阻止了颗粒生长。
使用TFF技术成功开发出旨在干粉吸入的结晶态伏立康唑粉末制剂的高效(高达97%w/w)纳米聚集体。将少量甘露醇用作单一赋形剂,通过以相分离的亚微米级结晶态甘露醇作为表面纹理改性剂,有利地增强了伏立康唑纳米聚集体的气雾剂性能。利用TFF制得的吸入用伏立康唑干粉可作为侵袭性肺曲霉病的可行的局部治疗选择,其具有高雾化效率和药物载量,同时具有与纳米聚集体在气道中沉积相关联的潜在益处。
实例2-材料与一般方法
A.材料
购得以下材料:伏立康唑(Carbosynth,San Diego,CA);25(D-Basf,Ludwigshafen,Germany);乙腈(HPLC级,Fisher Scientific,Pittsburgh,PA);三氟乙酸(TFA)(HPLC级,Fisher Scientific,Pittsburgh,PA);Tuffryn膜过滤器(25mm,0.45μm,Pall Corporation,Port Washington,NY)。使用经过滤的水(Evoqua,Warrendale,PA),无热原甘露醇PF则由Roquette America Inc.(Geneva,IL)捐赠。
B.使用TFF制备干粉吸入用粉末
将甘露醇和伏立康唑(30%-100%w/w)粉末溶于乙腈与水(50:50v/v)的混合物中,并且使溶液中的固体含量保持为1%w/v。从10cm的高度将大约15μL的各种溶液滴加到旋转的低温冷却(-60℃)不锈钢滚筒上。将冷冻样品收集到充满液氮的不锈钢容器中,并且转移至-80℃的冷冻柜中,然后转移至冻干机中。利用VirTis Advantage冻干机(VirTisCompany Inc.,Gardiner,NY)除去溶剂。将样品在-40℃下放置21小时,然后使温度在21小时内缓慢升至25℃,在25℃下再放置21小时以使其干燥。在干燥过程中,压力保持为100mTorr。
C.X射线粉末衍射(XRPD)
利用X射线衍射仪(MiniFlex 600,Rigaku Co.,Tokyo,Japan)在5-35°2θ的角度范围内(步长0.02°,3°/min,40kV,15mA)测定粉末样品的结晶度。
D.扫描电子显微镜(SEM)
利用SEM(Zeiss Supra 40V SEM,Carl Zeiss,Heidenheim an der Brenz,Germany)鉴定样品的表面形貌。将粉末的等分试样放在碳带上,并且用60/40Pd/Au溅涂20分钟,然后捕获图像。
E.调制差示扫描量热法(mDSC)
利用配备冷冻冷却系统(RCS40,TA Instruments,New Castle,DE)的Q20型差示扫描量热仪(TA Instruments,New Castle,DE)对粉末样品进行热分析。在调制DSC中,调制周期为50s,调制幅度为1℃,并且平均加热速率为5℃/min。在检测过程中,利用TAInstruments制造的Tzero盘和Tzero密封盖固定样品,并且在将盘放入样品架中之前,用20G注射器针头在顶盖上打孔。
F.扫描电子显微镜-能量色散X射线光谱(SEM/EDX)
利用SEM/EDX(Hitachi S5500 SEM/STEM,Hitachi America,Tarrytown,NY)鉴别通过TFF制得的粉末的元素。
G.原子力显微镜(AFM)
在本研究过程中使用两种不同类型的原子力显微镜。利用Asylum MFP-3D AFM(Oxford Instruments,Oxfordshire,United Kingdom)获得通过TFF制得的颗粒的三维(3D)表面形貌图,该仪器配备带铝涂层的MikroMasch HQ:NSC15悬臂(NanoWorld AG,Switzerland),其共振频率为325kHz,力常数为40N/m,并且典型尖端半径为8nm。用碳带将粉末固定在AFM圆盘上,并且使用压缩氮气吹掉未牢固粘附至碳带的颗粒。采用轻敲模式进行形貌分析,其中扫描速率为1.00Hz,设定值为1.08V,并且积分增益为20.0。针对每个样品优化了反馈滤波器、驱动幅度和驱动频率,并以512×512的分辨率采集所有图像。利用Gwyddion软件(Necas和Klapetek,2012)(64位Windows版2.50)生成3D形貌图。
为获得纳米聚集体的图像,利用Park XE-100AFM(Park systems,Suwon,Korea),该仪器配备带铝涂层的Nanosensors PPP-NCHR悬臂(NanoWorld AG,Switzerland),其共振频率为330kHz,力常数为42N/m,并且尖端半径小于7nm。首先在380μm单面抛光的P型硅晶片上涂覆20(VWR,Radnor,PA),然后加载粉末样品进行AFM分析。将20(1.5%w/v)预先溶于HPLC级甲醇(Fisher Scientific,Pittsburgh,PA)中。使用移液管将溶液滴到硅晶片上,并且用压缩氮气除去溶液。将粉末放入DP4吹入器(Penn-Century Inc.,Wyndmoor,PA)中,并且使用3mL注射器雾化到硅晶片上。将雾化粉末加载到硅晶片上后,使用压缩氮气除去未牢固粘附至硅晶片上的粉末固体。在轻敲模式下采用512×512的分辨率和0.30Hz的扫描速率采集图像。针对每个样品优化AFM的其他值。利用Gwyddion软件(Necas和Klapetek,2012)(64位Windows版2.50)对形貌图进行处理。
H.空气动力学粒径分布分析
利用新一代药用撞击器(NGI)(MSP Co.Shoreview,MN)检测空气动力学粒径,该撞击器与高容量泵(HCP5型,Copley Scientific,Nottingham,UK)和临界流量控制器(TPK2000型,Copley Scientific,Nottingham,UK)连接。将包含TFF粉末(约5-10mg)的#3HPMC胶囊(VCaps plus,Capsugel,Morristown,NJ)放入高阻力RS01干粉吸入器(Plastiape,Osnago,Italy)中,并且通过USP吸入口分散到NGI中,所用流速为60L/min,每次致动持续4秒。在整个检测中,不使用预分离器。NGI收集板涂覆有2%w/v聚山梨醇酯20的甲醇溶液,并且在使用前干燥20min。雾化后,用水和乙腈(50:50v/v)的混合物萃取粉末,并且利用HPLC分析伏立康唑的含量。使用Copley吸入器测试数据分析软件(CITAS)3.10版(CopleyScientific,Nottingham,UK),根据沉积在设备、吸入口、第1级至第7级和微孔收集器(MOC)计算质量中值空气动力学直径(MMAD)、几何标准偏差(GSD)和细颗粒分数(FPF)。
I.高效液相色谱(HPLC)
利用Dionex Ultimate 3000HPLC系统(Sunnyvale,CA)和Shimadzu DGU 14A脱气机(Shimadzu,Kyoto,Japan)测量伏立康唑含量。利用Waters Xbridge C18色谱柱(4.6×150mm,3.5μm)(Milford,MA)。方法详情如下:采用等度方法测量空气动力学特性,所用流动相为40/60(v/v)水/乙腈(含0.1%(v/v)TFA),流速为0.8mL/min,洗脱时间为4min;在稳定性研究中,使用梯度方法分析化学降解物。在梯度方法中,含有0.1%(v/v)TFA的乙腈溶液在14min内从25%(v/v)逐渐增至95%(v/v),并且与含有0.1%(v/v)TFA的水溶液混合,流速为0.8mL/min。在这两种方法中,均在254nm的检测波长和25℃下分析样品。使用15μL的进样体积,对50ng/mL与100Ug/mL之间的线性进行评估。
J.溶液核磁共振(溶液NMR)
利用1H NMR计算TFF-VCZ-MAN粉末中伏立康唑与甘露醇之间的重量比。所有1H NMR谱图均在25℃下在VNMR 600(Varian,Palo Alto,CA)波谱仪上在600MHz的条件下在二甲基亚砜-d6(DMSO-d6)中中记录。记录相对于2.47ppm DMSO-d6的化学位移。
K.固态核磁共振(ssNMR)
ssNMR实验采用Bruker Avance III HD 400MHz波谱仪(Bruker,Billerica,MA)在25℃下进行,魔角自旋(MAS)频率为12kHz。Bruker 4mm三谐振HFX探针在双谐振模式下使用,调谐至1H/13C或1H/19F频率。所有样品均在环境条件下装到4mm ZrO2转子(Wilmad-LabGlass,PA)中。在一维(1D)13C和19F交叉极化(CP)MAS实验中,针对1H通道采用80-100kHz范围内线性增加的功率水平和2ms的接触时间以增强CP效率在80kHz的场强下使用高功率SPINAL64质子去耦。在二维(2D)13C-1H CP异核相关性(HETCOR)实验中采用相同的功率参数、接触时间、MAS频率。利用金刚烷胺作为内标校准13C化学位移,并且参考38.48ppm处的乙基13C峰。
L.傅立叶变换红外光谱(FT-IR)
利用配备Smart OMNI-SamplerTM的NicoletTM iSTM 50FT-IR(ThermoFisherScientific,Waltham,MA)研究TFF-VCZ-MAN粉末的伏立康唑与甘露醇之间的分子间活性。该测量采用干粉状样品,在孔径为150、分辨率为4且扫描次数为32次的条件下记录光谱范围4000-700cm-1内的谱图。
M.Brunauer-Emmett-Teller(BET)比表面积(SSA)分析
利用MonosorbTMMS-21型快速表面积分析仪(Quantachrome Instruments,BoyntonBeach,FL)通过单点BET法测量TFF-VCZ-MAN粉末的SSA。样品在环境温度下用20psi氮气中脱气24小时,以除去表面杂质。利用氮气/氦气(30:70v/v)的混合物作为吸附气体。
N.抗剪切力试验
为测试TFF-VCZ-MAN 95:5粉末的抗剪切力性能,将粉末放入不锈钢容器中(内径27/8英寸,高41/4英寸),并且通过以85rpm的转速滚动容器进行预剪切。分别在15min、30min和60min采集粉末样品,并且将其空气动力学特性与初始条件进行比较。
O.溶出度测试
利用体外溶出法定量测定通过TFF技术处理的粉末中伏立康唑的溶出度。使用Franz池设备区分通过TFF制得的粉末中释放的伏立康唑。利用与高容量泵(HCP5型,CopleyScientific,Nottingham,UK)和临界流量控制器(TPK 2000型,Copley Scientific,Nottingham,UK)连接的新一代药用撞击器(NGI)(MSP Co.Shoreview,MN)将雾化粉末加载到Tuffryn膜过滤器(25mm,0.45μm,Pall Corporation,Port Washington,NY)上。用实验室胶带挡住NGI顶盖上第2级的五个喷嘴,仅留1个喷嘴打开。放置Tuffryn膜过滤器,并且用实验室胶带将其固定在第2级打开的喷嘴下方的收集杯上。将包含TFF粉末(约5-10mg)的#3HPMC胶囊(VCaps plus,Capsugel,Morristown,NJ)放入高阻力RS01干粉吸入器(Plastiape,Osnago,Italy)中,并且通过USP吸入口分散到NGI中,所用流速为60L/min,每次致动持续4秒。不使用预分离器。雾化后,从收集杯上小心地移除加载有粉末(约0.5-1mg)的膜过滤器,并且将其置于Franz池的接收室顶部,该接收室之前已填充经过脱气的10mM磷酸盐缓冲盐水(PBS,pH 7.4,5mL)。将供应室置于膜过滤器上,并且用捏夹将膜过滤器固定在接收室与供应室之间。使用封口膜覆盖供应室的顶部。溶出度测试在37℃的漏槽条件(sink condition)下进行,同时在接收室中用磁力搅拌棒不断搅拌。分别以0min、20min、40min、60min、120min和180min的时间间隔抽取溶媒(150μL),在不经稀释的情况下进行HPLC分析。每次采样后,更换新鲜溶媒。
P.溶出过程中雾化颗粒的收集和SEM样品的制备
利用与高容量泵(HCP5型,Copley Scientific,Nottingham,UK)和临界流量控制器(TPK 2000型,Copley Scientific,Nottingham,UK)连接的快速筛选撞击器(FSI)(Copley Scientific,Nottingham,UK)记录雾化TFF-VCZ-MAN粉末在溶出度测试前后的SEM图像。将包含TFF粉末(约5-10mg)的#3HPMC胶囊(VCaps plus,Capsugel,Morristown,NJ)放入高阻力RS01干粉吸入器(Plastiape,Osnago,Italy)中,并且分散到设置在FSI中的玻璃纤维过滤器(MSP Co.Shoreview,MN)中,以收集空气动力学粒径为5μm或更小的颗粒。将颗粒收集到过滤器上后,通过轻敲过滤器上的碳带,将这些颗粒转移至预先附接至SEM样本的碳带上,并且记录SEM图像。
为记录溶出度测试期间的SEM图像,将FSI上加载有粉末的玻璃纤维过滤器剪成圆形(直径25mm)。然后在37℃下将玻璃纤维滤膜置于Franz池的供应室与接收室之间,该池已预先填充有PBS(pH 7.4)。将滤膜在Franz池中放置5min,然后置于-80℃的冷冻柜中冷冻1小时。在25℃下,利用VirTis Advantage冻干机(VirTis Company Inc.,Gardiner,NY)在5小时内除去溶剂。将轻敲玻璃纤维过滤器上预先附接至SEM样本的碳带,以转移TFF-VCZ-MAN粉末,并且如上所述记录SEM图像。
Q.稳定性研究
按照抗剪切力试验所述,在玻璃瓶中对TFF-VCZ-MAN 95:5干粉进行预剪切。将7.6mg至8.4mg经过预剪切的粉末装填到#3HPMC胶囊(Capsugel,Morristown,NJ)中。将装有粉末的14个胶囊转移至闪烁瓶中,并且用氮气将药瓶吹扫20s,然后盖上盖子。将药瓶密封在铝箔(13×15cm)中,该药瓶内部预先经氮气吹扫30s,然后将铝箔保存在25℃/60%RH下。在1个、3个、6个、13个月的各个时间点进行纯度和气雾剂性能测试。
R.统计分析
实例3:扩大生产伏立康唑组合物和吸入器测试
1.结果
A.监测-60℃和-150℃下的冷却过
表3列出了不同制剂和工艺条件。图16显示了两种不同温度下的冷冻过程图像。利用包含伏立康唑和甘露醇(95:5w/w)的水/ACN(50:50v/v)溶液,其中固体载量为1%(w/v)和3%(w/v)(表3中的制剂#2、#4、#6和#7)。在-60℃下,两种固体载量不同的溶液均表现为冷冻过程完成,并且在200ms或更短时间内达到热平衡。在约1/30ms时观察到样品圆盘的边缘成核现象,但在-60℃时冻结从圆盘的中心向边缘发展。相比之下,固体载量为1%(w/v)和3%(w/v)的溶液在-150℃下在1/60ms或更短时间内开始成核,并且在整个样品盘中均匀冷却。但是,截至200ms时未达到热平衡。
表3:制剂和工艺参数列表
B.利用TFF制得的伏立康唑纳米聚集体的物理特性
图17显示了在两个不同温度下处理的伏立康唑纳米聚集体的高分辨率形貌。表明在较低温度(-150℃)下形成的伏立康唑纳米聚集体(制剂#4)由较小的纳米颗粒组成。在-150℃下处理时,观察到小至200nm的纳米颗粒,而在-60℃下则发现约500nm的纳米颗粒(制剂#2)。
图18比较了使用不同工艺参数形成的伏立康唑纳米聚集体的颗粒形貌。当使用水/乙腈(30:70v/v)(制剂#1)作为溶剂体系时,观察到多孔结构的甘露醇的粒径超过20μm。用其他溶剂体系制得的伏立康唑纳米聚集体表现出甘露醇纳米颗粒对伏立康唑纳米颗粒的表面纹理改性。较低的工艺温度导致在测试的固体载量范围(1%~3%w/v)内得到较小的颗粒。
图19显示了在-60℃和-150℃(分别为制剂#7和#6)制备的雾化伏立康唑纳米聚集体的SEM图像。这表明纳米聚集体由小至200nm的纳米颗粒组成。虽然伏立康唑纳米聚集体主要保留为微米级纳米聚集体,但观察到雾化后未完全解聚的形状不规则的纳米聚集体。通过DP4吹入器雾化后,这些纳米颗粒的表面仍保持经改性的纹理。
C.与扩大规模制备产物的物理和空气动力学特性的比较
表4列出了以小规模(200mg)和大规模(90g)制备的伏立康唑纳米聚集体的空气动力学特性和水分含量。另外,图20比较了各种粉末制剂的结晶度。大规模制备产物与小规模制备相比,使用低阻力RS00设备在60L/min的流速下测得的FPF(定量剂量百分比,分别为35.6%和37.0%)、FPF(递送剂量百分比,分别为49.5%和48.5%)和MMAD(分别为3.69μm和3.52μm)无显著差异(p>0.05)。另外,TGA分析结果表明,两个批次的水分含量均小于0.1%(w/w)。小规模与大规模制备的伏立康唑纳米聚集体的XRPD谱图未表现出任何模式差异。
表4.按规模比较理化和空气动力学特性
D.体外气雾剂性能
i.共溶剂、工艺温度和固体载量
利用NGI评估共溶剂、工艺温度和固体载量对未经改性的伏立康唑纳米聚集体气雾剂特性的影响。结果如表5所示。当固体载量(1%)和工艺温度(-60℃)固定时(制剂#1~3)时,共溶剂中不同的水与乙腈的比率改变了伏立康唑纳米聚集体的气雾剂特性。随着水的比率从30%(v/v)增加至50%(v/v)和70%(v/v),FPF(定量剂量百分比)从34.3%提高至37.9%和45.6%。另外,FPF(递送剂量百分比)有所提高(分别为53.1%、61.2%和69.9%),而MMAD则有所减小(分别为3.41μm、3.31μm和3.09μm)。
表5.按溶剂体系、工艺温度和固体载量列出的气雾剂特性
Plastiape低阻力RS-00设备,流速60L/min(n=3;平均值±SD)未经改性的粉末
还确认了工艺温度的影响。当工艺温度从-60℃降至-150℃,同时固体载量(1%)和共溶剂(水/ACN 50:50v/v)固定时(制剂#2和#4)时,FPF(定量剂量百分比)从37.9%显著提高至46.7%(p<0.05)。但是,FPF(递送剂量百分比)和MMAD未发生显著变化(分别为61.2%和67.5%以及3.31μm和3.27μm)(p>0.05)。
固体载量也影响气雾剂特性。如图5所示,较高的固体载量导致较低的气雾剂特性。当粉末未经改性时,随着固体载量从1%增加至2%和3%(制剂#4~6)时,FPF(定量剂量百分比)从46.7%降至41.3%和37.0%。FPF(递送剂量百分比)也从67.5%降至60.9%和48.5%。固体载量为1%和2%(制剂#4和#5)时的MMAD无显著差异(分别为3.27μm和3.24μm,p>0.05),而固体载量为3%(制剂#6)时的MMAD则明显更大(3.52μm,p<0.05)。
ii.按设备
使用四种不同类型的Plastiape设备:低阻力和高阻力RS00以及低阻力和高阻力RS01评估伏立康唑纳米聚集体(制剂#6)的气雾剂性能。表6显示了不同浓度对气雾剂性能的影响评估结果。采用低阻力RS00设备在90L/min、60L/min和30L/min的流速下得到的FPF(定量剂量百分比)分别为48.6%、45.8%和27.0%,并且FPF(递送剂量百分比)分别为63.7%、63.9%和48.9%。随着流速从90L/min降至60L/min和30L/min,MMAD从3.22μm增加至3.36μm和4.32μm。采用高阻力RS00设备在60L/min和30L/min下得到的FPF(定量剂量百分比)分别为34.7%和30.7%。采用高阻力RS00设备在60L/min和30L/min下得到的MMAD分别为3.76μm和3.83μm。采用低阻力RS01设备在90L/min、60L/min和30L/min的流速下得到的FPF(定量剂量百分比)分别为40.1%、35.8%和27.0%,并且MMAD分别为4.28μm、4.37μm和5.34μm。采用高阻力RS01在60L/min和30L/min的流速下得到的FPF(定量剂量百分比)分别为31.7%和20.2%,而MMAD分别为4.48μm和5.06μm。一般而言,在原位气雾剂性能测试中,采用低阻力设备在相同流速下得到更高的空气动力学性能,并且采用RS00设备得到的空气动力学性能优于采用RS01得到的结果。
表6.按设备列出的气雾剂特性
iii.按剂量
使用高阻力RS00和高阻力RS01设备测试了不同剂量载量对气雾剂性能的影响。结果如表7所示。当加载剂量从10mg增加至15mg和20mg时,使用高阻力RS00设备在60L/min的流速下得到的气雾剂特性FPF(定量剂量百分比)(分别为34.7%、33.8%和31.8%)、FPF(递送剂量百分比)(分别为55.0%、55.5%和51.5%)和MMAD(分别为3.76μm、3.77μm和3.84μm)无显著变化(p>0.05)。当加载剂量为10mg和20mg时,采用高阻力RS01设备在60L/min的流速下得到的FPF(定量剂量百分比)(分别为31.7%和25.3%)、FPF(递送剂量百分比)(分别为48.5%和37.4%)和MMAD(分别为4.48μm和5.21μm)存在显著差异(p<0.05)。
表7.按剂量列出的气雾剂特性
表8.按设备基于压降列出的气雾剂
·n=3
·载量:15.0mg/胶囊(固定)
2.讨论
A.利用TFF制备伏立康唑纳米聚集体的工艺设计空间
必须考虑TFF中所用的冷冻过程的设计空间内的工艺参数,并且在开发和后续扩大过程中了解其影响,包括:溶剂体系、工艺温度、固体载量和批量大小。利用低阻力RS00设备在60L/min的流速下测定工艺设计空间,因为利用低阻力RS00设备进行雾化更依赖于吸入流速和制剂的特征。这种依赖性能够区分通过不同工艺设计参数制成的制剂的雾化。
B.溶剂体系
使用TFF制得的达那唑无定形固体分散体的理化特性不受两种不同溶剂(叔丁醇和乙腈)的影响(Overhoff等人,2007);但是,具有使用TFF生产的PVP K12或PVP K30的伏立康唑的结晶度、形貌和气雾剂性能有所不同,其取决于溶剂组合物(包含水和1,4-二噁烷)(Beinbom等人,2012)。本研究中所用的水和乙腈的共溶剂体系被用于开发使用TFF制得的他克莫司制剂和伏立康唑制剂(Watts等人,2013;Moon等人,2019)。
虽然未观察到结晶度差异,但是在不同的溶剂组合物中观察到形貌差异。此外,当溶剂组合物改变时,观察到空气动力学特性的显著趋势。在不经粉末调节的情况下,包含较高比例的水的溶剂组合物表现出增强的雾化效果。该结果可能涉及两个因素:共溶剂体系的粘度和低温相分离。
在水和乙腈的共溶剂体系中,粘度随含水量的增加而提高(Thompson等人,2006;Cunningham等人,1967)。在冷冻过程中,高粘度可能阻碍分子的运动。因此,分子在冷冻状态下分布更均匀,并且未冻结通道中的溶质浓度可能不发生显著增加。溶剂的低粘度使分子在冷冻过程中运动更多,并且可能发生分子团聚。结果,未冻结通道中的溶质浓度提高。由于利用TFFE制得的伏立康唑粉末为结晶态纳米聚集体,因此较高的溶质浓度可能由于分子之间较短的距离而诱导形成更大的纳米颗粒。
尽管TFF涉及超快速过冷,但水/ACN溶剂体系的冷冻过程在-60℃下仍然需要200ms。因此,在200ms的冷冻时间内,使用低粘度溶剂可能导致更高的分子团聚程度,引起气雾剂性能下降。Beinborn等人在之前有关使用TFF制得的伏立康唑的研究中也观察到这种趋势(Beinborn等人,2012)。当使用水和1,4-二噁烷二元溶剂体系生产包含PVP K12或PVP K30的结晶态伏立康唑粉末时,用1,4-二噁烷/水(20:80v/v)制得的TFF颗粒与用1,4-二噁烷/水(50:50v/v)制得的颗粒相比,获得了更高的结晶度。尽管1,4-二噁烷的粘度高于水,但1,4-二噁烷/水(20:80v/v)的粘度高于1,4-二噁烷/水(50:50v/v)(Besbes等人,2009)。因此,共溶剂体系的粘度是影响冻干后气雾剂性能的因素之一。
防止低温相分离是通过使用含水量更高的共溶剂体系来增强气雾剂性能的另一种可能。共溶剂体系由水和乙腈组成,并且当包含35%-88%(v/v)的乙腈时,冷冻过程中的相分离是众所周知的(Gu等人,1994;Zarzycki等人,2006)。在-1.32℃以下发生相分离后(Zarzycki等人,2006),未冷冻的溶剂将分离为88%(v/v)乙腈相和65%(v/v)水相,并且溶质可能移动至溶质具有较高溶解度的相中(Gu等人,1994)。
这种低温相分离发生在制剂#1中,该制剂用水/ACN(30:70v/v)在-60℃下进行处理。伏立康唑纳米聚集体中的5%(w/w)甘露醇用作表面纹理改性剂(Moon等人,2019)。因此,在结晶态伏立康唑纳米聚集体表面上观察到的甘露醇为纳米颗粒,如图18中其他制剂的SEM图像所示。但是,观察到约20μm的多孔甘露醇颗粒,其形貌与TFF-甘露醇相同(Moon等人,2019)。在制剂#1中生成该尺寸的甘露醇颗粒时,由于较少量的甘露醇可用于表面纹理改性,因此降低了甘露醇对表面纹理改性的效果,从而导致雾化效果较差。
尽管TFF的过冷可能由于超快速冷冻而最大程度减少相分离并且产生非常小的冰通道(Moon等人,2016),但-60℃的工艺温度仍可实现水/ACN的少量相分离(30:70v/v),促进冷冻期间(长达200ms)的团聚和甘露醇的浓度增加。但是,水/ACN(70:30v/v)在冷冻期间未发生相分离(Gu等人,1994;Zarzycki等人,2006)。因此,不太可能发生由低温相分离引起的团聚和浓度增加。
C.工艺温度
除溶剂组合物以外,工艺温度也影响使用TFF制成的结晶态伏立康唑纳米聚集体的气雾剂性能。较低的工艺温度导致较高的过冷度,从而产生较小的冰通道并且阻止颗粒生长(Overhoff等人,2009;Engstrom等人,2008)。在本研究中,当温度为-150℃时,采用超快速过冷表现出快得多的成核速度。在-150℃下的这种过冷阻止了颗粒生长,使伏立康唑纳米聚集体中产生较小的纳米颗粒,通过AFM和SEM观察到这些纳米聚集体由小至200nm的纳米颗粒组成。相比之下,在-60℃下处理时,使用AFM观察到的粒径为500nm左右。当伏立康唑纳米聚集体由较小的纳米颗粒组成时,它们在吸入过程中更有可能解聚为较小的颗粒,从而提高气雾剂性能。
有趣的是,在-150℃下较高的过冷度所引起的气雾剂性能的增强与在-60℃的较低过冷度下使用水/ACN(70:30v/v)的共溶剂体系所产生的较高的性能相当。在这两种工艺条件(制剂#3和#4)下,FPF(定量剂量百分比)和MMAD无显著差异(p>0.05)。
D.固体载量
增加固体载量是减少使用TFF生产粉末制剂时的制造时间的方法之一。但是,较高的固体载量通常损害气雾剂性能。在不经改性或物理剪切的条件下,使用1%(w/v)的固体载量制得的伏立康唑纳米聚集体的堆积密度为约30mg/cm3。因此,为加快制造过程,将固体载量增加至3%(w/v),其对应的的堆积密度为30mg/cm3。当固体载量增加至3%(w/v)时,最初应用两种优化的工艺参数:水/ACN(70/30v/v)溶剂体系和-150℃的加工温度。但是,由于伏立康唑在水/ACN(70/30v/v)中的溶解度低,因此固体载量3%(w/v)不适用。因此,选择水/ACN(50/50v/v)。
虽然采用3%(w/v)的固体载量得到的堆积密度与由1%(w/v)得到的冻干后的堆积密度相似,但结果是粉末调节之前的气雾剂性能较低。但是,通过适当的改性可以改善性能,使其与采用1%(w/v)的固体载量和优化的工艺参数所制得的伏立康唑纳米聚集体(制剂#4)相当。因此,使用经过粉末调理的制剂#6进行雾化测试。
E.批量大小
直到最近,TFF方法仍然使用注射器或分液漏斗滴加溶液。结果是溶液需要更长时间冷冻。这是扩大TFF方法的主要障碍。为加快冷冻过程,使用2通道蠕动泵,通过TFF方法生产无定形美洛昔康(Jermain等人,2019)。但是,在针对伏立康唑的该研究中,将通道数增加至8条,并且将溶液的进料速度优化为25mL/min。同时,将低温转筒的转速从10rpm增加至20rpm,以避免冷冻的样品盘在较高的进料速率下相互重叠。
转速的增加缩短了冷冻样品在低温转筒上的保留时间。在收集到包含液氮的托盘中之前,这一时间从4s缩短为2s。但是,由于TFF的超快速冷冻,冷冻过程通常需要不到几百毫秒的时间(Overhoff等人,2007),并且预计低温转筒转速的增加不影响冷冻过程。对于本研究中的制剂#6,在不到1/60s内发生成核(见图18),并且冷冻样品在收集到托盘中之前不到2s内即达到热平衡。
-150℃下的超快速过冷加快了成核速率,并且增加了形成的冰晶数量(Rambhatla等人,2004;Overhoff等人,2009)。因此,在整个冷冻样品中观察到均匀的成核。此外,由于液滴的大小相近,因此无论规模如何,冷冻过程与制备规模无关,并且冷冻样品的结果也不存在显著差异。借助总体上相似的冷冻过程,以小规模制得的产物的理化和空气动力学特性与更大规模下制得的产物相当。
决定在TFF方法扩大中使用蠕动泵后,还对冻干机的容量进行了测试。表4中的数据还确认,利用3层AdVantage Pro冻干机冻干90g伏立康唑纳米聚集体与利用1层AdVantage 2.0冻干机冻干200mg伏立康唑纳米聚集体之间无差异。因此,当使用3层AdVantage Pro冻干机时,适合使用蠕动泵以25mL/min的进料溶液流速扩大TFF方法。
F.采用不同设备和流速时,设备与伏立康唑纳米聚集体的相互作用
在开发通过DPI递送的药品的过程中,就气雾剂性能而言,设备设计或选择与制剂开发同等重要。使用不同的DPI设备可使相同的粉末制剂得到不同的雾化效果(Parumasivam等人,2017)。本研究对市售Plastiape RS01和RS00设备进行测试,将其应用于市场上或开发中的许多DPI产品(Armer等人,2016;Elkins等人,2014;Roscigno等人,2017)。RS01和RS00设备采用相同的递送技术:将胶囊从其外壳中提起,并且高速旋转(干粉吸入器RS01:使用方法:Plastiape;(可得自:plastiape.com/en/content/1635/dry--powder-inhaler--rs01--how--use)。但是,RS01设备中的粉末通过两个孔将胶囊排空,而RS00设备中的粉末通过具有较长吹嘴的胶囊的八个较小的孔排出。相比之下,在具有相同类型的阻力下使用相同流速进行比较时,使用RS00设备得到的伏立康唑纳米聚集体的总体气雾剂性能更优。
使用RS00设备获得的这一更高的性能可能是由于RS00设备的穿孔系统所产生的孔较小。当伏立康唑纳米聚集体离开胶囊时,较小的孔可能有助于较大的伏立康唑纳米聚集体发生解聚,并且其较小的尺寸导致更小的MMAD和更高的FPF。这可能是用于DPI的伏立康唑纳米聚集体的独特特征,因为它们由脆性纳米聚集体构成。使用喷雾干燥或研磨制得的用于DPI的其他粉末制剂可能不被视为纳米聚集体。因此,当粉末排出胶囊时,孔的尺寸可能对总体性能无显著影响。
比较低阻力和高阻力的RS01和RS00设备,在60L/min和30L/min的流速下,两种低阻力设备的性能通常优于高阻力设备。另外,低阻力设备相对于高阻力设备表现出更高的ED。然而,使用低阻力设备进行粉末解聚和微分散取决于患者的吸入流速(Dal Negro RW,2015),导致不同吸入流速下的雾化效果的变化。在本研究中,在两种低阻力设备中也观察到这一结果。尽管使用低阻力RS00设备在90L/min的流速下实现了最大程度的雾化,但是在流速为30L/min时,观察到FPF(定量剂量百分比)显著下降(18.8%)。在使用低阻力RS01设备时,观察到类似的趋势。在使用低阻力RS01时,当流速从60L/min下降至30L/min时,FPF(定量剂量百分比)也发生明显下降(8.8%)。但是,在使用高阻力RS00设备时,在流速为60L/min和30L/min时,FPF(定量剂量百分比)仅相差4.0%,并且尽管观察到ED存在显著差异,但MMAD无显著差异(p>0.05)。高阻力RS00设备在由足够的湍流方案引起的60L/min与30L/min之间表现出吸入流速独立性(Dal Negro RW,2015)。因此,尽管从气雾剂性能的角度来看,低阻力RS00设备的性能更出色,但这些性能可能在各个患者之间存在很大差异,从而导致效率差异。但是,就高阻力RS01设备而言,未观察到60L/min与30L/min之间的流速独立性,确认RS00设备中较小的孔有助于伏立康唑纳米聚集体的雾化。
G.不同剂量载量
在使用TFF冷冻之前,伏立康唑纳米聚集体在调节之前的堆积密度通常为约30mg/cm3,与溶液的固体载量(1%-3%w/v)无关。但是,通过调节或外部施加的物理剪切应力,堆积密度逐渐增加至高达100mg/cm3。对伏立康唑纳米聚集体进行调节,以使其具有约60mg/cm3的堆积密度,并且用#3HPMC胶囊评估粉末装填量的影响。由于#3胶囊的容量为0.3mL,因此可将最多约20mg调节后的伏立康唑纳米聚集体插入胶囊中。因此,在每粒胶囊10-20mg的剂量范围内,对伏立康唑纳米聚集体的气雾剂性能进行了评估。高阻力RS00和RS01设备在60L/min的流速下使用,并且执行Tukey-Kramer HSD测试以比较不同粉末水平之间的结果。
虽然高阻力RS00设备在FPF(定量剂量百分比)、FPF(递送剂量百分比)和MMAD方面未表现出显著差异(p>0.05),但使用高阻力RS01设备时,在剂量为10mg和20mg时得到的性能有所不同(p<0.05)。就伏立康唑纳米聚集体而言,使用高阻力RS00设备得到的气雾剂性能的一致性可能是较小的孔有助于雾化粒径分布窄的颗粒的结果。
3.材料和方法
A.材料
伏立康唑USP购自Aurobino Pharma Ltd.(Hyderabad,India)。HPLC级乙腈(ACN)、甲醇和三氟乙酸(TFA)购自Fisher Scientific(Pittsburgh,PA)。使用经内部过滤的水(Evoqua,Warrendale,PA),无热原甘露醇PF则由Roquette America Inc.(Geneva,IL)捐赠。
B.粉末制剂的制备
将伏立康唑(95%w/w)和甘露醇(5%w/w)溶于乙腈和水的混合物(30:70、50:50或70:30v/v)中,使溶液中的固体含量为1%-3%(w/v)。对该溶液进行超声处理,直至获得澄清的溶液。然后将溶液从大约10cm的高度滴到旋转的低温冷却(-60℃或-150℃)不锈钢转筒上。在小规模制备,使用带有注射器针头(18号)的10mL注射器将溶液给料至转筒上。在大规模制备过程中,利用配备高性能精密铂固化硅泵管线(16号,Cole-Parmer,Vernon Hills,IL)的蠕动泵(Cole-Parmer,Vernon Hills,IL)以25mL/min的流速将溶液递送至转筒上。在冷冻过程中,将冷冻样品收集到装有液氮的不锈钢冻干机托盘中,并且转移至-80℃的冷冻柜中以除去多余的液氮,然后将样品转移至冻干机中。利用VirTis Advantage 2.0或VirTis Advantage Pro台式托盘冻干机(VirTisCompany Inc.,Gardiner,NY)升华溶剂并且使样品干燥。在初次干燥过程中,将搁板在-40℃下保持20h,然后将搁板温度在20h内线性升高至25℃,然后在25℃下保持20h。在25℃下进行20h的二次干燥。在冻干过程中,压力保持在100mTorr。
C.X射线粉末衍射(XRPD)
使用X射线衍射仪(MiniFlex 600,Rigaku Co.,Tokyo,Japan)在5-40°2θ的范围内(步长0.02°,2°/min,40kV,15mA)鉴定粉末结晶度。
D.扫描电子显微镜(SEM)
利用SEM(Zeiss Supra 40V SEM,Carl Zeiss,Heidenheim an der Brenz,Germany)测定粉末样品的表面形貌,并且鉴定雾化后的纳米颗粒。为鉴定表面形貌,将粉末的等分试样放在碳带上,并且用60/40Pd/Au溅涂20nm的厚度后捕获图像。为测定纳米颗粒,将1-2mg粉末放入DP4吹入器(Penn-Century Inc.,Wyndmoor,PA)中,并且使用3mL注射器将其雾化到380μm单面抛光的P型硅晶片上,用60/40Pd/Au溅涂5nm的厚度后捕获图像。
E.原子力显微镜(AFM)
为获得纳米聚集体的图像,利用Asylum MFP-3D AFM(Oxford Instruments,Oxfordshire,United Kingdom),该仪器配备镀金MikroMasch Hi'Res-C15/Cr-Au悬臂(nanoWorld AG,Neuchatel,Switzerland),其共振频率为325kHz,力常数为40N/m,并且典型尖端半径为1nm。利用DP4吹入器(Penn-Century Inc.,Wyndmoor,PA)将粉末固定到硅晶片上。将1-2mg粉末放入吹入器中,并且使用3mL注射器将其雾化到380μm单面抛光的P型硅晶片上。加载粉末后,利用压缩氮气吹掉未牢固粘附至晶片的多余粉末。在轻敲模式下采用1.00Hz的扫描速率进行形貌分析。针对每个样品优化AFM的其他值。使用512×512分辨率采集图像,并且利用Gwyddion软件(64位Windows版2.50)(Necas和Klapetek,2012)进行处理。
F.粉末调节
将1.3g粉末加入60mL Pyrex瓶中。将样品瓶以60rpm的转速旋转30min以剪切粉末,并且在室温下储存于干燥剂中。
G.空气动力学粒径分布分析
利用新一代药用撞击器(NGI)(MSP Co.Shoreview,MN)测量粉末的空气动力学特性,该仪器配备临界流量控制器(TPK型,MSP Corporation,Shoreview,MN)高容量泵(HCP5型,MSP Corporation,Shoreview,MN)。将大约5-20mg粉末制剂插入#3HPMC胶囊(plus,Morristown,NJ)中,并且利用Plastiape RS01或RS00 DPI通过USP吸入口分散,总气流体积为4L。不使用预分离器。将1.5%(w/v)聚山梨醇酯20的甲醇溶液施加至NGI收集板上进行涂覆,并且在使用前使其干燥20min。分散后,使用含0.1%(v/v)TFA的水和乙腈混合物(50:50v/v)萃取粉末,并且使用HPLC分析伏立康唑含量。使用Copley吸入器测试数据分析软件(CITAS)3.10版(Copley Scientific,Nottingham,UK),计算MMAD、几何标准偏差(GSD)和细颗粒分数(FPF)。
H.高效液相色谱(HPLC)
为定量分析伏立康唑含量,使用与Shimadzu DGU 14A脱气机(Shimadzu,Kyoto,Japan)和Waters Xbridge C18色谱柱(4.6×150mm,3.5μm)(Milford,MA)连接的DionexUltimate 3000HPLC system(Sunnyvale,CA)。采用等度方法,其中流动相为含0.1%(v/v)TFA的40/60(v/v)水/乙腈,流速为0.8mL/min,在25℃下洗脱4min。使用254nm的波长测定样品浓度。使用7μL的注射体积,对伏立康唑浓度在62.5ng/mL和500μg/mL之间的标准曲线进行线性研究。
I.Brunauer-Emmett-Teller(BET)比表面积(SSA)分析
为测量SSA,利用MonosorbTMMS-21型快速表面积分析仪(QuantachromeInstruments,Boynton Beach,FL)。在环境温度下,使用20psi的氮气对粉末制剂样品脱气24h以上。利用氮气与氦气的混合物(30:70v/v)作为吸附气体。
J.热重分析(TGA)
执行TGA以测量粉末制剂中的水分含量。利用Mettler TGA/DSC 1型热重分析仪(Columbus,OH)。将约2-5mg样品放入氧化铝坩埚(Mettler-Toledo,Columbus,OH)中,并且盖上坩埚盖。将坩埚以5℃/min的升温速率从25℃加热至150℃。通过比较25℃与125℃之间样品重量的减少量来计算样品的水分含量。
K.在不同温度下冷冻的照片
为监测TFF中不同工艺温度之间的冷冻速率差异,利用Canon EOS Rebel SL1型DSLR相机(Canon USA,Melville,NY)捕获冷冻过程的图像,该相机配备18-55mm IS STM镜头(Canon USA,Melville,NY),所用帧速率为60帧/秒,并且分辨率为1280×720。将捕获的图像裁剪为约200×200,仅显示样品。
L.统计分析
***
鉴于本公开,可以在不进行过度实验的情况下进行和执行本文所公开和要求保护的所有组合物和方法。尽管已经根据优选的实施例描述了本公开的组合物和方法,但是对于本领域技术人员而言将显而易见的是,在不背离本公开的概念、精神和范围的情况下,可以对本文所述的方法以及方法的步骤或所述步骤的顺序施加变化。更具体地,将显而易见的是,化学上和生理上均相关的某些药剂可以代替本文所述的药剂,同时将实现相同或相似的结果。对于本领域技术人员显而易见的所有此类类似替代和修改都被认为落入由所附权利要求所限定的本公开的精神、范围和概念内。
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Claims (89)
1.一种药物组合物,包含:
(A)治疗剂;以及
(B)赋形剂,其中所述赋形剂占所述药物组合物的少于约10重量%;
其中所述药物组合物配制为纳米聚集体,所述纳米聚集体包含所述治疗剂的纳米颗粒,并且所述治疗剂的纳米颗粒的表面包含所述赋形剂的离散域,并且其中所述赋形剂的离散域减小所述治疗剂的纳米颗粒之间的接触面积。
2.根据权利要求1所述的药物组合物,其中所述治疗剂以结晶态存在。
3.根据权利要求1所述的药物组合物,其中所述治疗剂以无定形态存在。
4.根据权利要求1-3中任一项所述的药物组合物,其中所述赋形剂占所述药物组合物的约9%w/w至约1%w/w。
5.根据权利要求4所述的药物组合物,其中所述赋形剂占所述药物组合物的约6%w/w至约2%w/w。
6.根据权利要求5所述的药物组合物,其中所述赋形剂占所述药物组合物的约3%w/w。
7.根据权利要求5所述的药物组合物,其中所述赋形剂占所述药物组合物的约5%w/w。
8.根据权利要求1-7中任一项所述的药物组合物,其中所述赋形剂的离散域包含所述赋形剂在所述表面上的一个或多个不连续域。
9.根据权利要求1-7中任一项所述的药物组合物,其中所述赋形剂的离散域包含邻近且连续的赋形剂层。
10.根据权利要求1-9中任一项所述的药物组合物,其中所述赋形剂是可溶于水的。
11.根据权利要求1-10中任一项所述的药物组合物,其中所述赋形剂为糖醇。
12.根据权利要求11所述的药物组合物,其中所述赋形剂为甘露醇。
13.根据权利要求1-12中任一项所述的药物组合物,其中所述赋形剂作为所述药物组合物中的纳米域存在。
14.根据权利要求13所述的药物组合物,其中所述赋形剂的纳米域具有约50nm至约500nm的尺寸。
15.根据权利要求14所述的药物组合物,其中所述赋形剂的纳米域的尺寸为约100nm至约200nm。
16.根据权利要求1-15中任一项所述的药物组合物,其中所述药物组合物具有约1.5μm至约7.5μm的质量中值空气动力学直径。
17.根据权利要求16所述的药物组合物,其中所述质量中值空气动力学直径为约2.5μm至约6.5μm。
18.根据权利要求1-17中任一项所述的药物组合物,其中所述药物组合物不包含蜡赋形剂。
19.根据权利要求18所述的药物组合物,其中所述药物组合物不包含疏水性赋形剂。
20.根据权利要求1-19中任一项所述的药物组合物,其中所述治疗剂选自下组,该组由以下各项组成:抗癌药、抗真菌剂、精神病治疗剂诸如镇痛药、意识水平改变剂诸如麻醉剂或催眠药、非甾体类抗炎药(NSAIDS)、驱虫剂、β-激动剂、抗痤疮药、抗心绞痛药、抗心律失常药、抗哮喘药、抗菌剂、抗良性前列腺肥大剂、抗凝剂、抗抑郁药、抗糖尿病药、止吐药、抗癫痫药、抗痛风药、抗高血压药、抗炎药、抗疟疾药、抗偏头痛药、抗毒蕈碱药、抗肿瘤药、抗肥胖药、抗骨质疏松药、抗帕金森氏病药、抗增殖剂、抗原虫药、抗甲状腺药、镇咳药、抗尿失禁药、抗病毒剂、抗焦虑剂、食欲抑制剂、β-受体阻滞剂、心脏正性肌力药、化疗药物、认知增强剂、避孕药、皮质类固醇、Cox-2抑制剂、利尿剂、勃起功能障碍改善剂、祛痰剂、肠胃病药、组胺受体拮抗剂、免疫抑制剂、角质剥脱剂、脂质调节剂、白三烯抑制剂、大环内酯类、肌肉松弛剂、神经安定药、营养剂、阿片类镇痛药、蛋白酶抑制剂和镇静剂。
21.根据权利要求20所述的药物组合物,其中所述治疗剂为抗真菌剂。
22.根据权利要求21所述的药物组合物,其中所述抗真菌剂为唑类抗真菌药物。
23.根据权利要求22所述的药物组合物,其中所述唑类抗真菌药物为伏立康唑。
24.根据权利要求1-23中任一项所述的药物组合物,其中所述药物组合物进一步包含一种或多种另外的赋形剂。
25.根据权利要求1-24中任一项所述的药物组合物,其中所述药物组合物进一步包含一种或多种另外的治疗剂。
26.根据权利要求1-25中任一项所述的药物组合物,其中所述药物组合物经配制,用于口服、脂肪内、动脉内、关节内、颅内、皮内、病变内、肌内、鼻内、眼内、心包内、腹膜内、胸膜内、前列腺内、直肠内、鞘内、气管内、瘤内、脐内、阴道内、静脉内、囊内、玻璃体内、脂质体内、局部、粘膜、肠胃外、直肠、结膜下、皮下、舌下、外用、经皮、阴道、以乳剂的形式、以脂质组合物的形式、经由导管、经由灌洗、经由连续输注、经由输注、经由吸入、经由注射、经由局部递送或经由局部灌注施用。
27.根据权利要求26所述的药物组合物,其中所述药物组合物经配制,用于经由吸入施用。
28.根据权利要求1-27中任一项所述的药物组合物,其中所述药物组合物经配制,用于与吸入器一起使用。
29.根据权利要求28所述的药物组合物,其中所述吸入器为固定剂量组合吸入器、单剂量干粉吸入器、多剂量干粉吸入器、多单位剂量干粉吸入器、定量吸入器或加压定量吸入器。
30.根据权利要求29所述的药物组合物,其中所述吸入器为胶囊型吸入器。
31.根据权利要求28-30中任一项所述的药物组合物,其中所述吸入器为低阻力吸入器。
32.根据权利要求28-30中任一项所述的药物组合物,其中所述吸入器为高阻力吸入器。
33.根据权利要求28-32中任一项所述的药物组合物,其中所述吸入器以约10L/min至约150L/min的流速使用。
34.根据权利要求33所述的药物组合物,其中所述流速为约20L/min至约100L/min。
35.根据权利要求28-34中任一项所述的药物组合物,其中所述吸入器具有0.5kPa至约5kPa的压差。
36.根据权利要求35所述的药物组合物,其中所述压差为1kPa、2kPa或4kPa。
37.根据权利要求28-36中任一项所述的药物组合物,其中所述吸入器具有约0.1mg至约50mg的加载剂量。
38.根据权利要求37所述的药物组合物,其中所述吸入器具有约0.1mg至约10mg的加载剂量。
39.根据权利要求37所述的药物组合物,其中所述吸入器具有约5mg至约50mg的加载剂量。
40.根据权利要求39所述的药物组合物,其中所述加载剂量为约5mg至约25mg。
41.根据权利要求1-40中任一项所述的药物组合物,其中所述吸入器被配置为从依次加载的一个或多个单位剂量中递送一个或一系列剂量。
42.根据权利要求41所述的药物组合物,其中所述吸入器被配置为从一个单位剂量中递送一个剂量。
43.根据权利要求41所述的药物组合物,其中所述吸入器被配置为从一个单位剂量中递送一系列剂量。
44.根据权利要求41所述的药物组合物,其中所述吸入器被配置为从依次加载的一系列胶囊中各自递送一个剂量。
45.根据权利要求41所述的药物组合物,其中所述吸入器被配置为从依次加载的一系列胶囊中递送一系列剂量。
46.一种治疗或预防有此需要的患者的疾病或疾患的方法,包括向所述患者施用治疗有效量的根据权利要求1-45中任一项所述的药物组合物,所述药物组合物包含有效治疗所述疾病或疾患的治疗剂。
47.根据权利要求46所述的方法,其中所述疾病或疾患在肺部。
48.根据权利要求46或47所述的方法,其中所述疾病或疾患为感染。
49.根据权利要求46-48中任一项所述的方法,其中所述感染为真菌感染。
50.根据权利要求49所述的方法,其中所述治疗剂为抗真菌剂。
51.根据权利要求50所述的方法,其中所述治疗剂为唑类抗真菌剂。
52.根据权利要求51所述的方法,其中所述治疗剂为伏立康唑。
53.一种制备药物组合物的方法,包括:
(A)将治疗剂和赋形剂与溶剂混合以形成前体溶液,其中所述赋形剂以少于10%w/w的量存在;
(B)将所述前体溶液沉积到表面上,所述表面处于适合于引起所述溶剂冷冻的温度;以及
(C)除去所述溶剂,以获得药物组合物。
54.根据权利要求53所述的方法,其中所述溶剂为两种或更多种溶剂的混合物。
55.根据权利要求54所述的方法,其中所述溶剂的混合物包含水。
56.根据权利要求55所述的方法,其中所述溶剂为有机溶剂。
57.根据权利要求56所述的方法,其中所述有机溶剂为乙腈。
58.根据权利要求56所述的方法,其中所述有机溶剂为1,4-二噁烷。
59.根据权利要求53-57中任一项所述的方法,其中所述溶剂为水与有机溶剂的混合物。
60.根据权利要求59所述的方法,其中所述溶剂为水与乙腈的混合物。
61.根据权利要求53-60中任一项所述的方法,其中所述两种或更多种溶剂的混合物包含约10%v/v至约90%v/v的有机溶剂。
62.根据权利要求61所述的方法,其中所述混合物包含约40%v/v至约60%v/v的所述有机溶剂。
63.根据权利要求62所述的方法,其中所述混合物包含约50%v/v的所述有机溶剂。
64.根据权利要求61所述的方法,其中所述混合物包含约20%v/v至约40%v/v的所述有机溶剂。
65.根据权利要求64所述的方法,其中所述混合物包含约30%v/v的所述有机溶剂。
66.根据权利要求53-65中任一项所述的方法,其中所述治疗剂和赋形剂占所述前体溶液的少于10%w/v。
67.根据权利要求66所述的方法,其中所述治疗剂和赋形剂占所述前体溶液的约0.5%w/v至约5%w/v。
68.根据权利要求67所述的方法,其中所述治疗剂和赋形剂占所述前体溶液的约1%w/v。
69.根据权利要求67所述的方法,其中所述治疗剂和赋形剂占所述前体溶液的约3%w/v。
70.根据权利要求53-69中任一项所述的方法,其中所述表面是旋转的。
71.根据权利要求53-70中任一项所述的方法,其中所述温度为约0℃至约-200℃。
72.根据权利要求71所述的方法,其中所述温度为约0℃至约-120℃。
73.根据权利要求72所述的方法,其中所述温度为约-50℃至约-90℃。
74.根据权利要求73所述的方法,其中所述温度为约-60℃。
75.根据权利要求72所述的方法,其中所述温度为约-125℃至约-175℃。
76.根据权利要求73所述的方法,其中所述温度为约-150℃。
77.根据权利要求53-76中任一项所述的方法,其中所述溶剂在减小的压力下除去。
78.根据权利要求77所述的方法,其中所述溶剂经由冻干除去。
79.根据权利要求78所述的方法,其中所述冻干在约-20℃至约-100℃的冻干温度下进行。
80.根据权利要求79所述的方法,其中所述冻干温度为约-40℃。
81.根据权利要求77-80中任一项所述的方法,其中所述减小的压力小于250mTorr。
82.根据权利要求81所述的方法,其中所述减小的压力为约100mTorr。
83.根据权利要求53-82中任一项所述的方法,其中所述方法进一步包括在减小的压力下加热所述药物组合物。
84.根据权利要求83所述的方法,其中将所述药物组合物加热至约0℃至约30℃的温度。
85.根据权利要求84所述的方法,其中所述温度为约室温或约25℃。
86.根据权利要求83-85中任一项所述的方法,其中所述减小的压力小于250mTorr。
87.根据权利要求86所述的方法,其中所述减小的压力为约100mTorr。
88.根据权利要求83-87中任一项所述的方法,其中所述减小的压力与所述冻干过程中的减小的压力相同。
89.一种根据权利要求53-88中任一项所述的方法制得的药物组合物。
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CN113484469A (zh) * | 2021-06-30 | 2021-10-08 | 中国科学院青海盐湖研究所 | 水合盐体系相变储能材料纳米尺度相分离的原位表征方法 |
CN113484469B (zh) * | 2021-06-30 | 2022-11-18 | 中国科学院青海盐湖研究所 | 水合盐体系相变储能材料纳米尺度相分离的原位表征方法 |
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JP2021530551A (ja) | 2021-11-11 |
WO2020023614A1 (en) | 2020-01-30 |
EP3827260A4 (en) | 2022-05-04 |
KR20210038583A (ko) | 2021-04-07 |
AU2019311086A1 (en) | 2021-02-04 |
CA3106618A1 (en) | 2020-01-30 |
BR112021001290A2 (pt) | 2021-04-27 |
MX2021000796A (es) | 2021-06-15 |
US20210338671A1 (en) | 2021-11-04 |
IL280342A (en) | 2021-03-25 |
EP3827260A1 (en) | 2021-06-02 |
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