CN1747738B - 缓释抗感染剂 - Google Patents
缓释抗感染剂 Download PDFInfo
- Publication number
- CN1747738B CN1747738B CN2003801065342A CN200380106534A CN1747738B CN 1747738 B CN1747738 B CN 1747738B CN 2003801065342 A CN2003801065342 A CN 2003801065342A CN 200380106534 A CN200380106534 A CN 200380106534A CN 1747738 B CN1747738 B CN 1747738B
- Authority
- CN
- China
- Prior art keywords
- liposome
- amikacin
- infective
- described purposes
- infection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Abstract
本发明所提供之一是一种处理或改善囊性纤维变性患者肺部感染的方法,该方法给予患者肺部一种有效剂量的脂质体/复方抗感染剂,其中(i)给药量为相应单方药量的50%或更少,或(ii)剂量为每天一次或更少,或(iii)以上两者。
Description
本申请要求于2002年10月29日提交的美国临时申请60/421,923提交的优先权。
本项缓释技术适用于例如借助脂质体和类脂复合物经吸入方式给药,通过缓释作用、靶向能力及增强病灶部位对药物的吸收对肺和全身提供一种长期的处理效果。本发明包括一种脂质体抗感染剂,以及应用脂质体或类脂复方抗感染剂处理囊性纤维变性(CF)患者肺部感染的方法。意想不到的是,用新配方进行处理所需要的剂量远低于本行业中已知的有效剂量。
就象Goodman和Gilman在“The Pharmaceutical Basis ofTherapeutics”[治疗学的药物基础]第八版中所报道的那样,“自从发现肾毒症及耳毒症的发生与氨基糖苷累集的浓度有关之后,减少肾功能损害患者体内这类药物的滞留剂量就变得极为关键”。由于不管病人是否已存在损伤,氨基糖苷类都能造成前庭或听觉机能失调及肾毒性,因此普遍来讲降低该类药物的滞留剂量非常重要。本发明可显著降低氨基糖苷类的滞留剂量。
囊性纤维变性病人肺里有大量粘液和/或唾沫分泌物、多发伴随性感染以及起源于细菌繁殖的生物被膜。所有这些分泌液和物质均对于抗感染剂有效的靶向抗感染作用造成障碍。本发明可以克服这些障碍,并且可以降低剂量(在数量或频率上),因此可降低药物在病人体内的负荷。
对于一般肺部感染来说,本发明所提供的给药方案提供了一种降低药物负荷的途径。
发明内容
本发明所提供的之一是脂质体/复方抗感染剂的用于制备一种药物的用途,其中所述药物用于处理或改善囊性纤维变性患者肺部感染,包括给予患者肺部一种有效剂量的脂质体/复方抗感染剂,其中(i)给药量为相应单方药量的50%或更少,或(ii)剂量为每天一次或更少,或(iii)以上两者
本发明也提供一种处理或改善患病动物肺部感染的方法,该方法包括给予患病动物肺部包含有效剂量的脂质体/复方抗感染剂,其中(i)给药量为相应单方药量的50%或更少,或(ii)剂量为每2天一次或更少。
附图概述
图1:囊性纤维变性病人痰液/生物被膜的横切面图。
图2:本发明中药物靶向作用及存贮效果的图示。
图3和4:不同形式丁胺卡那霉素的细菌学图示。
图5:脂质体/复方丁胺卡那霉素和妥布霉素缓释作用的图示。
图6:单方或者复方环丙沙星的数据。
图7:使用不同给药方案在肺中药物残留量的图示。
发明的详细描述
本申请揭示一种处理或改善肺部感染的方法,如囊性纤维变性病人的感染,该方法包给药用类脂颗粒胶囊化的抗感染剂(如抗生素)。
抗感染剂是抵抗感染的药剂,例如抗细菌、分支杆菌、真菌、病毒或者原生动物的感染。
本发明中所指的抗感染剂包括但并不仅限于以下几类:氨基糖苷类(如链霉素,庆大霉素,妥布霉素,丁胺卡那霉素,奈替米星,卡那霉素等);四环素类(如金霉素,土霉素,甲烯土霉素,强力霉素,米诺四环素等);磺胺类(如磺胺,磺胺嘧啶,磺胺甲噁唑(sulfamethaoxazole),磺胺异噁唑,磺醋酰胺等);对-氨基苯甲酸,二氨基嘧啶(如甲氧苄啶等,常与磺胺甲噁唑、吡嗪酰胺等联合使用);喹诺酮类(如萘啶酸,西诺沙星,环丙沙星和氟哌酸等);青霉素类(如青霉素G,青霉素V,氨苄西林,阿莫西林,巴氨西林,羧苄西林,卡茚西林,替卡西林,阿洛西林,美洛西林,哌拉西林等);耐青霉素酶青霉素(如甲氧苯青霉素,苯甲西林,氯唑西林,双氯青霉素,萘夫西林等);第一代先锋霉素类(如头孢羟氨苄,头孢氨苄,头孢菌素,先锋霉素,头孢匹林,头孢唑林等);第二代先锋霉素类(如头孢克洛,头孢羟唑,头孢尼西,头孢西丁,头孢替坦,头孢呋辛,头孢呋肟酯,头孢美唑,头孢罗齐,氯拉卡比,头孢胺四唑等);第三代先锋霉素类(如头孢平,头孢哌酮,氨噻肟头孢菌素,头孢去甲噻肟,头孢曲松,头孢他定,头孢克肟,头孢泊肟,头孢布坦等);其他β-内酰胺类(如亚胺培南,美罗培南,氨曲南,克拉维酸,舒巴克坦,三唑巴坦等);β-内酰胺酶抑制剂(如克拉维酸酸),氯霉素,大环内酯类(例如红霉素,阿奇霉素,克拉霉素等);林可霉素,氯林可霉素,大观霉素,多粘菌素B,多聚喹碘(例如多粘菌素A,B,C,D,E1(粘菌素A)或E2,粘菌素B或C等),粘菌素,万古霉素,杆菌肽素,异烟肼,利福平,乙胺丁醇,乙硫异烟胺,氨基水杨酸,环丝氨酸,卷曲霉素,砜类(如氨苯砜,亚磺氨苯砜钠等),氯法齐明,沙利度胺,或其它任何可以进行类脂胶囊化的抗菌制剂。抗感染剂可以包括抗真菌剂,包括多烯抗真菌剂(如两性霉素B,制霉菌素,那他霉素,及其它同类物),氟胞嘧啶,咪唑类(如咪康唑,克霉唑,益康唑,酮康唑,及其它同类物),三唑类(如伊曲康唑,氟康唑,及其它同类物),灰黄霉素,特康唑,环吡酮布康唑,环吡酮胺,卤普罗近,托萘酯,萘替芬,特比萘芬,或其它任何可以进行类脂胶囊化或复方化的抗真菌制剂。在讨论及实施例中主要是指丁胺卡那霉素,但本申请范围并不仅限于这种抗感染剂。也可以使用联合药物。
特别优选的抗感染剂包括氨基糖苷类,喹诺酮类,多烯抗真菌剂以及多粘菌素类。
在肺感染中(如在囊性纤维病人中),可用本发明的方法处理的有假单胞菌属(例如绿脓假单胞菌,少动假单胞菌,恶臭假单胞菌,萤光假单胞菌,食酸假单胞菌),葡萄球菌,耐甲氧苯青霉素金黄色葡萄球菌(MRSA),链球菌(包括肺炎链球菌),大肠杆菌,克雷伯氏菌属,肠杆菌属,沙雷氏菌,嗜血杆菌属,鼠疫耶尔森(氏)菌,类鼻疽伯克霍尔德氏菌,洋葱(cepacia)伯克霍尔德氏菌,唐菖蒲(gladioli)伯克霍尔德菌,multivorans伯克霍尔德氏菌,越南(Vietnamiensis)伯克霍尔德氏菌,结核分支杆菌,鸟分枝杆菌复合体(MAC)(鸟分枝杆菌和细胞内分枝杆菌),堪萨斯分枝杆菌素,蟾蜍分枝杆菌,海分枝杆菌,溃疡分枝杆菌,偶发分枝杆菌复合物(偶发分枝杆菌和龟分枝杆菌)感染。
在本发明的一个实施例中包括一种服用脂质体/复方丁胺卡那霉素的处理方法。
这里所讨论的“脂质体或类脂复方”抗感染剂,或“脂质体/复方”抗感染剂,或“Lip-抗感染剂”,或“Lip-An”是抗感染剂组份的任何形式,其中至少抗感染剂重量的1%与类脂相关联,其可以是与类脂复合物的一部份,或作为一种脂质体,该脂质体中的抗生素可以在液相中或脂质双层的疏水相中、或位于脂质体双层界面中间的头部(headgroup)区。优选地,至少5%,或至少10%,或至少20%,或至少25%是具有这种关联性的。这种关联通过过滤器进行分离而测量,其中类脂或类脂相关联药物存留而单方药剂在滤出液中。
利用脂质体/复方抗感染剂处理较以前已知的处理方法所需的剂量明显降低。在一个优选的实施方案中,人的服药剂量为每天低于100mg氨基葡糖苷。在另一个优选的实施方案中,每2天或每3天服药约30~50mg。与其它非脂质体或类脂复合物抗感染剂所推荐使用的剂量进行比较,预计脂质体/复方抗感染剂在其它动物中所使用的剂量也应该相应地降低。这是一种意料之外的低剂量。
对于下述没有提供特定剂量的那些,本发明中优选的剂量是最低单方药量(当然可以是其盐类)的50%或更低、35%或更低、20%或更低、或10%或更低。如果是通过喷雾器将药物传送到肺部,则在14天的疗程后,可以使肺中菌落形成单位(CFU)降低一个数量级。相对的单方药量是可用于本发明服药疗程中的累积药量。在本章中所定义的相对的最低单方药量是“相对单方药量”。
尽管本发明的实施方案优选的是用于人类,但其中非囊性纤维变性的处理实施方案也适用于任何动物。对某种特定的动物所使用的相应剂量可根据不同的动物进行测量。
优选的给药方案是每天一次或更少。在优选的实施方案中,给药方案是隔天、每3天、每周一次或更少。例如,给药方案可以是隔天一次或更少,采用的剂量为相应单方剂量的50%或更少。或者,例如给药也可以每天一次,剂量为相应单方剂量的35%或更少。
为处理本发明中所指的感染,临床医生将使用一种有效数量的药物,而这种有效数量应达到处理、减轻、改善、消除或者预防需要处理的疾病或需要防御或处理的病症的一种或多种症状,或者能对疾病或病症的病理产生临床可识别的改变。“改善”包括降低需防治的动物感染的发病率或严重程度。在特定的实施方案中,有效剂量指可以在肺部感染症状出现后,能够处理或改善症状的剂量。在其他特定的实施方案中,有效剂量指能够处理或改善需防治的动物感染的平均发病率或严重程度(如统计学研究的测量结果)。
基于脂质体或者其他类脂的传递系统可以以喷雾、粉状或气溶胶的形式进行吸入,或者以鞘内方式给药。优选的给药途径为吸入法。与单方或母方形式相比,该剂型的总结果是给药频率的减少及处理指数的增加。脂质体或者脂质复合物具有很大的优势,这是由于它们与肺纹理或肺表面活性物质具相容性,对药物具保护作用。
本发明包括处理肺革兰氏阴性菌感染的方法。一种普遍处理的感染是囊性纤维变性病人的慢性肺部感染。已知利用丁胺卡那霉素处理肺部感染(如囊性纤维变性病人)的方法是通过吸入法每天给予大约200-600毫克丁胺卡那霉素或者四环素。在本发明的一个实施方案中,处理方法是每天给予100毫克或更低的丁胺卡那霉素(如果服药频率低,可标准化为每天给予100毫克或更低的量)。在另一个实施方案中,处理方案为每天给予60毫克或者更少的丁胺卡那霉素。在又一个实施方案中,采取的是每2天给药不多于一次,每次大约30-50毫克。最优选的实施方案包括每隔一天或者每3天给药约30-50毫克。
已知利用妥布霉素处理成人及6岁或6岁以上儿童肺部感染的方法,一般药量为300毫克,每天2次。在本发明的一个优选的实施方案中,处理方法是每天服用100毫克或更少的妥布霉素。在另一个实施方案中,实施的是每天服用60毫克或更少的妥布霉素。在又一个实施方案中,采取的是2天给药不多于一次,每次大约30-50毫克。最优选的实施方案包括每隔一天或者每3天给药约30-50毫克。
在本发明的配方中所使用的类脂可以是合成的、半合成的或者天然类脂,包括磷脂类、维生素E、类固醇、脂肪酸、糖蛋白类如白蛋白、阴性类脂和阳性类脂。磷脂类包括卵磷酸卵磷酯(EPC)、卵磷脂酰甘油(EPG)、卵磷脂酰肌醇(EPI)、卵磷脂酰丝氨酸(EPS)、磷脂酰乙醇胺(EPE)和卵磷脂酸(EPA);大豆的类似物,大豆磷酸卵磷酯(SPC);SPG,SPS,SPI,SPE,和SPA;氢化的蛋类和大豆类似物(例如,HEPC,HSPC);由甘油中2、3位脂肪酸的酯键所组成的包含12-26个碳原子的其他磷脂,以及由甘油中第1位的不同首基(head group)所组成的磷脂,包括胆碱、甘油、肌醇、丝氨酸、氨基乙醇、以及相应的磷脂酸。这些脂肪酸的碳链可以是饱和的或者不饱和的,而磷脂可以由不同碳链长度及不同饱和度的脂肪酸所组成。尤其是配方的成份中可包含一种二棕榈酰磷脂酰胆碱(DPPC),它像二油醇磷酸卵磷酯(dioleoylphosphatidylcholine)(DOPC)一样,是天然的肺表面活性剂的一种重要成份。其他成份还包括二肉豆蔻酰磷脂酰胆碱(DMPC)、以及二肉豆蔻酰磷脂酰甘油(DMPG)、二棕榈酰磷脂酰胆碱(DPPC)、和二软酯酰卵磷酯(DPPG)、二硬脂酰卵磷脂(DSPC)、二硬脂酰卵磷酯(DSPG)、dioleyl-脑磷酯(DOPE)、以及混合磷脂如棕榈酰硬脂酰磷酸卵磷酯(palmitoylstearoylphosphatidylcholine)(PSPC)和棕榈酰硬脂酰磷脂酰甘油(palmitoylstearoylphosphatidylglycerol)(PSPG)、(PSPG)、三酰基甘油、二酰基甘油、seranide、鞘氨醇、鞘磷脂和单酰化磷脂如单-油酰基-脑磷酯(MOPE)。
所使用的类脂可以包括铵盐脂肪酸、磷脂类和甘油酯、类固醇、磷脂酰甘油(PGs)、磷脂酸(PAs)、磷脂酰肌醇(PCs)、磷脂酰肌醇(Pls)和磷脂酰丝氨酸(PSs)。脂肪酸包括饱和或不饱和的碳链长度为12-26个碳原子的脂肪酸。某些特例包括:肉豆蔻胺、十六胺、月桂胺和硬脂酰胺、二月桂酰乙基磷酸胆碱(DLEP)、二肉豆蔻酰乙基磷酸胆碱(DMEP)、二棕榈酰乙基磷酸胆碱(DPEP)和二硬脂酰乙基磷酸胆碱(DSEP),氯化N-(2,3-二(9(Z)十八烯基氧(octadecenyloxy))-丙(prop)-1-基-N,N,N-三甲基铵(DOTMA)和1,2-双(油酰氧基)-3-(三甲铵)丙烷(DOTAP)。类固醇包括胆固醇和麦角固醇。PGs,PAs,PIs,PCs和PSs包括DMPG,DPPG,DSPG,DMPA,DPPA,DSPA,DMPI,DPPI,DSPI,DMPS,DPPS和DSPS,DSPC,DPPC,DMPC,DOPC,以及卵PC。
由磷酸卵磷酯(如DPPC)所组成的脂质体或类脂复合物可以协助肺内细胞如肺泡巨噬细胞吸收药物,并且能帮助肺内抗感染剂的持续释放(Gonzales-Rothi et al.(1991))。阴性类脂(例如PG,PA,PS和PI,)除能够减少粒子聚集之外,还在吸入剂组份的缓释及组份在肺内的运输(胞吞转运作用(transcytosis))以使全身吸收中起作用。人们认为甾醇类化合物能影响药物组份的释放及渗漏特性。
脂质体是内含液相容积的完全闭合的类脂双层膜。脂质体可以是单层囊泡(含单个的双层膜)或者多层囊泡(含多个双层膜的典型的洋葱样结构,相互之间由一液体层分隔)。双层膜由两个脂质单层所组成,每个单层含一疏水性的″尾″区和一亲水性的“头”区。双层膜的结构是:疏水性(非极性)“尾”区类脂单层朝向脂质双层膜的中央,而亲水性的“头”部朝向双层膜的水相。类脂复合物是类脂和掺入的抗感染剂之间的联系物。这种联系可以是共价的、离子的、静电的、非共价的或立体的。这类复合物是非脂质体,并且不会捕获多余的水溶性溶解物。这类复合物的例子包括两性霉素B的类脂复合物(Janoff等,Proc.Nat Acad.Sci.,85:61226126,1988)以及心肌磷脂与阿霉素的复合物。
类脂包合物是一种三维的、笼子一样的结构,包含一种或多种类脂,这种结构可以捕获一种具生物学活性的试剂。这样的包合物属于本发明的范畴之内。
脂质体前体是当与某种水溶性液体接触时可形成脂质体或者类脂复合物的组份。搅拌或者其它混合方式是必需的。这样的脂质体前体属于本发明的范畴之内。
脂质体可由多种方法制备(如见,Bally,Cullis等.BiotechnolAdv.5(1):194,1987).Bangham的操作(J.Mol.Biol.,J Mol Biol.13(1):238-52,1965)制备普通的多层囊泡(MLV).Lenk等(美国,专利号分别为4,522,803、5,030,453和5,169,637),Fountain等(美国,专利号为4,588,578)以及Cullis等(美国,专利号为4,975,282)揭示了制备多层脂质体的方法,在其每层液体隔层里有大致相等的层间溶质分布。Paphadjopoulos等在,(美国,专利号为4,235,871)中揭示了通过反相蒸发法制备寡层脂质体的方法。
单层囊泡可以通过多种技术经MLV产生,例如,Cullis等(美国,专利号为5,008,050)以及Loughrey等(美国,专利号为5,059,421)的挤压法。可以利用声裂法和匀浆化从大的脂质体生产较小的单层脂质体(见,例如,Paphadjopoulos等,Biochim.Biophys.Acta.,135:624-638,1967;Deamer,美国,专利号为4,515,736;以及Chapman等,Liposome Technol.,1984,pp.1-18)。
Bangham等(J.Mol.Biol.,1965,13:238-252)最初制备脂质体的方法包括将磷脂悬浮到一种有机溶剂中,随后蒸发至干,在反应容器中留下一层磷脂膜。然后加入适量的水相,使混合物进行″膨胀″,所产生的包含多层脂囊(MLV)的脂质体通过机械方法进行分散。这种制备法为Papahadjopoulos等(Biochim.Biophys,Acta.,1967,135:624-638)所描述的通过声波处理生产小单层囊泡及大单层囊泡的方法提供了基础。
生产大的单层囊泡(LUV)的技术如反相蒸发法、注入过程和清洁剂稀释,均可应用于生产脂质体。对这些方法的综述以及生产脂质体的其他方法见“脂质体”,Marc Ostro,等,Marcel Dekker公司,NewYork,1983,第1章,其有关部分在这里被引为参考文献。也可见Szoka,Jr.等.,(1980,Ann.Rev.Biophys.Bioeng.”,9:467),其有关部分在这里也被作为参考文献。
其它用于制备囊泡的方法包括那些能形成反相蒸发囊泡(REV)的方法(Papahadjopoulos等.,美国,专利号4,235,871)。另一类可利用的脂质体是那些具有大致相同溶质层分布特点的脂质体。这类脂质体被Lenk等在美国专利4,522,803中命名为稳定的多层囊泡(SPLV),并包括Fountain等在美国专利4,588,578中所描述的单相囊泡以及以上所描述的冷冻和融解的多层囊泡(FATMLV)。
多种甾醇及其水溶性衍生物例如胆固醇和半琥珀酸酯已经被用于制备脂质体;特别见于Janoff等,美国专利4,721,612,1988年1月26日出版,题目为“甾族脂质体”。Mayhew等描述了一种减少抗细菌制剂及抗病毒制剂毒性的方法,该方法利用含α-生育酚及其特定衍生物的脂质体将上述药剂胶囊化。此外,多种生育酚及其水溶性衍生物也被用于制备脂质体,见Janoff等美国专利号5,041,278。
形成脂质体或者类脂复合物的过程涉及一个″溶剂注入″的过程。该过程包括在少量的(优选最少量的)过程合适的溶剂里溶解一种或多种类脂,以形成类脂悬浮液或溶液(优选溶液),然后将该溶液注入到含生物活性制剂的水溶性介质中。典型的过程合适溶剂是能够通过例如透析之类的过程清洗掉的溶剂。进行冷/热循环的组合物优选通过溶剂注入而形成,优选的为乙醇注入。优选的溶剂为酒精。“乙醇注入”是溶剂注入过程的一种,即在少量的(优选最少量的)的酒精里溶解一种或多种类脂,以形成类脂溶液,然后将该溶液注入到含生物活性制剂的水性介质中。“少”量溶剂是指在注入过程里可以形成脂质体或者类脂复合物的合适的量。该过程可见于以下的文献中Lee等,美国专利申请10/634,144,2003年8月4日提交;Pilkiewicz等,美国专利申请10/383,173,2003年3月5日提交;以及Boni等,美国专利申请10/383,004,2003年3月5日提交。以上申请在此全部被引为参考文献。
脂质体或脂质复合物的分筛可以由多种方法完成,本行业熟练技术人员非常熟悉并且普遍使用的方法如挤压法、声裂法和匀浆法。挤压法是将脂质体在一定的压力下,用规定孔径大小的滤器进行一次或多次过滤。滤器通常是由聚碳酸酯制造的,但也可以由其它任何耐用材料制备,只要该材料不与脂质体相互反应,而且在挤压时能耐足够的压力即可。优选的滤器包括“直线滤过”型滤器,因为该滤器一般能承受本发明中优选的挤压过程所需的高压。也可以使用“弯曲型”滤器。挤压法也可以使用非对称的滤器,如AnotecOTM滤器,该滤器涉及通过一种多孔径的分支型氧化铝滤器挤压脂质体。
脂质体或类脂复合物也可以用声裂法进行分筛,该方法是利用声波的能量破裂或剪切脂质体,可以使其自然形成更小的脂质体。声裂法是通过将含有脂质体悬液的玻璃管浸入到一种震动的声波中,该声波由一种“浴室型”的超声破碎器产生。或者也可以使用一种探头型的超声破碎器,其声波能量是通过钛探头与脂质体悬液的直接接触时的震动而产生的。匀浆法及研磨仪如Gifford Wood匀浆器、Poltron或MicrofluidizerTM也可用来将大的脂质体或类脂复合物破碎成小的脂质体或类脂复合物。
所形成的脂质体/复合物可以使用在本行业中所熟知的方法分散成均质物;例如正切流动过滤。在这个过程中,大小不同的异质脂质体或类脂复合物流过正切流动过滤器,从而形成具有上限和/或下限尺寸大小的脂质体聚合物。当使用两种具有不同孔径的过滤器时,直径小于第一种过滤器孔径的脂质体可以通过该过滤器。该滤液可通过第二种过滤器进行正切流动过滤,第二次过滤的孔径小于第一次。这种过滤器的产物是具有第一和第二种过滤器所分别规定的上下限孔径大小范围之内的脂质体/复合物的聚合体。
Mayer等发现可以利用跨膜离子梯度来解决与亲脂性的、可电离的生物活性制剂的有效捕获相关的问题,如蒽环类抗生素或长春花碱类等抗肿瘤制剂。该类跨膜梯度除了可诱导更有效的捕获外,还能增加抗感染剂在脂质体/复合物中的滞留。
脂质体/复方抗感染剂具有持续的抗感染效果及较低的毒性,因此可以减少给药频率并提高处理指数。在临床前的动物实验中,与同等剂量的吸入性妥布霉素(并非脂质体或者类脂复方)相比,脂质体/复方丁胺卡那霉素在给药后不久直至给药24小时后,在肺内的药物水平是妥布霉素的二到几百倍之多。另外,脂质体/复方丁胺卡那霉素可将这种药效保持到超过24个小时。在用于模拟囊性纤维变性病人中可见的假单胞菌感染的动物模型中,与单方氨基糖苷类比较,脂质体/复方丁胺卡那霉素可明显减轻动物的肺部感染。
肺表面活性剂使得肺在呼吸时可以扩张和收缩。这种作用可以通过用类脂和蛋白质的组合物涂敷肺来完成。类脂呈现的是一种单层,其疏水性碳链朝向外侧。类脂占肺表面活性剂的80%,类脂的主要成份为磷脂酰胆碱,其中50%为二棕榈酰磷脂酰胆碱(DPPC)(Veldhuizen等,1998)。表面活性蛋白(SP)的功能是维持表面活性剂的结构,并协助呼吸时肺表面活性剂的扩张和收缩。在这些蛋白中,SP-B和SP-C尤其具有溶解特性,可以溶解脂质体(Hagwood等,1998;Johansson,1998)。人们相信这种溶解特性可以促进随后对脂质体的连续分解,并通过释放其内容物而发挥一种存贮作用。这种脂质体的分解自然发生,可通过自然裂解由细胞外排作用所排出的板层状小体所证实(Ikegami&Jobe,1998)。脂质体除了可由肺表面活性剂所同化,也可由巨噬细胞通过吞噬作用直接进行消化(Couveur等,1991;Gonzales-Roth等,1991;Swenson等,1991)。肺泡巨噬细胞对脂质体的摄取是药物传递到病灶部位的另一种方法。
优选的用来形成吸入性脂质体或脂质复合物的类脂,与发现于肺表面活性剂中的内源性类脂类似。脂质体由双层膜组成,可以捕获所需的药剂。这些同心双层可构成多层脂囊,其中药剂可捕获于不同层的类脂之内或层与层之间的液相空间中。本发明使用独特的方法生产独特的脂质体和脂质体/药物复合物。这些方法和该类方法的产品都是本发明的一部分。
用于本发明中优选的类脂与药剂的比率是小于3比1。更优选的类脂与药剂的比率是小于2.5比1。此外,产品在透析一段时间之后,其中游离的抗感染剂的比例会降低。
这里所描述的全部方法均很容易适用于大规模及无菌生产。最终脂质体的大小可以通过修改类脂的组成、浓度、辅料及加工的参数进行调整。
处理例如绿脓假单胞菌那样的传染病的一个障碍是药物在上皮细胞的痰液/生物被膜屏障内部的渗透(图1),绿脓假单胞菌是造成囊性纤维变性患者慢性疾病的首要原因。在图1中,环形表示脂质体/复方抗感染剂,符号″+″表示单方抗感染剂,符号″-″表示粘蛋白、藻酸盐和DNA,实心条符号表示绿脓假单胞菌。这种屏障由包埋于藻酸盐中的集落型和浮游的绿脓假单胞菌或来源于细菌的胞外多糖,以及来源于破损的粒细胞中的DNA和肺上皮细胞中的粘蛋白所组成,以上物质均含负电荷(Costerton,等,1999)。这些负电荷相互结合,并且阻止带正电荷的药物(例如氨基糖苷类)的渗透,使其生物学功能失效(Mendelman等,1985)。将抗感染剂捕获于脂质体或者类脂复合物中,可以屏蔽或者部分屏蔽抗感染剂与痰液/生物被膜的非特异性结合,从而使脂质体或者类脂复合物(内含氨基葡糖苷)可以进行渗透(图1)。
研究发现丁胺卡那霉素对细菌酶具有高度抵抗力,因此能比其它氨基糖苷类包括妥布霉素和庆大霉素处理更大比例的临床敏感分离株(Price等,1976)。尤其是绿脓假单胞菌分离株对丁胺卡那霉素的敏感性远大于其他氨基糖苷类(Damaso等,1976)。
从图2中可清楚地看出脂质体/复方丁胺卡那霉素的缓释效应及存贮效应。在该研究中,大鼠通过气管和静脉途径给予妥布霉素,也通过气管途径给予相同剂量(4毫克/每只大鼠)的脂质体/复方丁胺卡那霉素。数据显示,只有脂质体/复方丁胺卡那霉素能达到缓释及存贮效果。事实上,在给药后24小时,只有脂质体/复方丁胺卡那霉素在动物肺内具有明显的药量,而两种妥布霉素配方均显示阴性水平,主要原因是全身的快速吸收。这种脂质体/复方抗感染剂能使氨基葡糖苷在肺中增加100倍以上,这种现象支持具缓释效果的脂质体/复方抗感染剂的服药频率可以远低于现在通用的TOBITM配方(Chiron公司,AMERYVILLE,CA)的观点。
而且,由于痰液/生物被膜的表面与抗感染剂结合,其存在能阻碍单方氨基糖苷类的渗透(图1)。因此,妥布霉素的剂量在超过1000μg/克肺组织时才能在囊性纤维变性病人中具有处理效果。而脂质体/复方丁胺卡那霉素能克服这一缺点。因此,与单方妥布霉素比较,脂质体/复方丁胺卡那霉素药效的持续时间要长得多。这种结合与渗透的简易性也可以作为一种方法,利用此方法脂质体/复方丁胺卡那霉素可显著降低细菌的耐药性,而这种耐药性在体内的抗菌药物剂量低于最低抑制浓度时经常出现。
丁胺卡那霉素的药物动力学是在大鼠中以气管内(IT)给予单方妥布霉素或者脂质体/复方丁胺卡那霉素之后确定的。这些数据是与尾静脉注射单方妥布霉素后药物在肺部的分布进行比较的。在所有的实验中,给药剂量为4mg/只大鼠。正如在图2所见的一样,与注射相比,气管内给药所传送的氨基葡糖苷的数量要大得多。脂质体/复方抗感染剂技术与气管或静脉给予妥布霉素所产生的贮存效果相比,在给药后24小时,脂质体/复方丁胺卡那霉素在肺中的药量提高同样在100倍以上。因此,与单方妥布霉素相比,脂质体丁胺卡那霉素配方中药物处理水平的持续时间要长。
特别是当氨基糖苷类与囊性纤维变性病人痰液的结合导致抗感染剂生物活性的降低时,这种结合成为人们关心的问题(Hunt等,1995)。为确定脂质体/复方丁胺卡那霉素是否能长时间保留生物学活性,通过气管内滴注法给予正常大鼠脂质体/复方丁胺卡那霉素。然后分别在2小时或24小时通过支气管肺泡灌洗(BAL)移出药物,以确定其生物学活性。样品通过超滤及随后的过滤(0.2微米)进行浓缩,以去除所污染的肺部微生物。丁胺卡那霉素浓度的确定采用TDX仪,而其生物学活性利用米勒·欣顿(Mueller Hinton)肉汤稀释分析(绿脓假单胞菌)进行测定。结果见以下的表1。
如上表所示,在给药24小时后,所获得的过滤的脂质体/复方丁胺卡那霉素在米勒·欣顿肉汤分析中仍能杀死绿脓假单胞菌,最低抑菌浓度为4。在2小时所得到的MIC是2,该结果与过滤的脂质体/复方丁胺卡那霉素贮存液类似。因此,脂质体/复方丁胺卡那霉素在肺里24个小时后仍具有活性。24小时时,相同剂量的单方妥布霉素在支气管肺泡灌洗液中已检测不到。这表明脂质体/复方抗感染剂配方不仅在肺中持续存在,而且可以长时间有效渗透痰液/生物被膜。这些数据与图2和表II(在下面)的事实结合起来表明,脂质体/复方丁胺卡那霉素在长时间释放单方抗感染剂的同时,在肺里也能长期维持高水平的抗感染剂,这种现象支持该系统可长时间产生缓释效果的理论。这种效果应当能显著降低假单胞菌属的生物负荷及由于抗感染剂水平降低产生的耐药性。
作为体外演示脂质体/复方丁胺卡那霉素的缓释作用及其持续抗感染效果的实验,将该配方与患者的痰液共同培养,患者具有含PAO1株粘液样假单胞菌的慢性阻塞性肺疾病(COPD)。脂质体/复方丁胺卡那霉素也与含PAO1株粘液样假单胞菌的藻酸盐共培养。在两种情况下,均观察到对假单胞菌长期持续的、增强的杀灭作用,如表II中所示:
经典杀菌曲线不适用于脂质体/复方抗感染剂技术,这是因为脂质体配方具有缓释作用及促进抗感染的效果。直至丁胺卡那霉素的释放,脂质体/复合物能保护该药物免受痰液及藻酸盐的破坏。丁胺卡那霉素释放时,能观察到对细菌完全的杀灭效果,这与缓释及持续抗感染模型是一致的,不存在对抗感染剂的干扰或灭活作用。
用一种慢性肺部感染模型来研究脂质体/复方丁胺卡那霉素的有效性(Cash等,1979)。该模型是将包埋于琼脂糖小球基质中的绿脓假单胞菌滴入到大鼠的气管中。建立这种粘液样假单胞菌动物模型是为了模仿囊性纤维变性病人中所见的假单胞菌感染。与囊性纤维变性临床特征相关的包括:相似的肺病理学;免疫复合物紊乱的出现;以及由绿脓假单胞菌菌株所产生的粘液样表型转化(Cantin和Woods,1999)。用分离于囊性纤维变性病人中的大于107菌落形成单位(CFU)的粘液样假单胞菌(PAO1株)感染大鼠肺,然后分别用以下配方进行处理:(a)单方氨基葡糖苷(b)作为非药物对照的类脂载体本身(c)脂质体/复方丁胺卡那霉素。另外,首先在改进的Kirby-Bauer培养皿上对以上不同配方体外杀灭绿脓假单胞菌的能力进行了筛选。
各种脂质体/复方丁胺卡那霉素配方的测试是基于其不同的类脂组成或不同的生产参数,导致在体外实验中不同的杀灭区域。本实验的设计是为了确定脂质体/复方氨基葡糖苷相对于单方氨基葡糖苷药效的增加。将空白对照类脂组份、两种不同的脂质体/复方丁胺卡那霉素配方、单方丁胺卡那霉素和单方妥布霉素进行了比较,单方药剂中的氨基葡糖苷与脂质体/复方抗感染剂配方中的浓度相同。另外,也采用了10倍高剂量的单方丁胺卡那霉素和10倍高剂量的单方妥布霉素。药物以气管内方式给药,时间为7天以上。结果(图3)表明,两种配方的脂质体/复方丁胺卡那霉素(类脂组成不同)可以显著减少CFU水平,其减少CFU的能力高于10倍剂量的单方丁胺卡那霉素和单方妥布霉素。在图中,Lip-An-14是指DPPC/Chol/DOPC/DOPG(42∶45∶4∶9)以及10mg/ml丁胺卡那霉素,Lip-An-15是DDPC/Chol(1∶1)也为10mg/ml。在此,所有的类脂-类脂和类脂-药物均以重量表示。
下一个实验(图4)是用于证实脂质体/复方丁胺卡那霉素的缓释作用及其持续的抗感染能力。给药剂量是每隔一天一次共14天,作为与前面实验中每天一次共7天的比较。结果表明,与单方丁胺卡那霉素或单方妥布霉素比较,两种配方中的脂质体/复方丁胺卡那霉素(类脂组成不同)的效果均增加10-100倍(减少CFU水平的能力更高)。人每日剂量600毫克(或者大约375毫克/平方米)相当于大鼠每日剂量9.4毫克。因此数据可以直接对应于在病人中增加效果10到100倍。应当指出的是,在该模型中,可观察到的最佳效果是两个对数的减少。在唾沫分析中,绿脓假单胞菌100倍的降低可对应于肺功能的改进(Ramsey,等1993)。脂质体/复方丁胺卡那霉素配方的缓释效果表明,与单方氨基葡糖苷比较,复方低剂量和/或低频率给药可以更好地抑制细菌的生长。
在一个慢性肺部感染模型中研究了脂质体/复方丁胺卡那霉素的效果,该模型是将包埋于琼脂糖小球基质中的绿脓假单胞菌通过气管滴入到Sprague/Dawley大鼠中。3天后,开始每天给予单方丁胺卡那霉素或者脂质体/复方丁胺卡那霉素(图3)或者每隔一天给药(图4),剂量按氨基葡糖苷的量计算为1毫克/大鼠或者10毫克/大鼠,按脂质体/复方丁胺卡那霉素计算为1毫克/大鼠,空白脂质体(类脂载体)为对照,每组5只大鼠。
对实验进行14天后的大鼠肺(冷冻)均化后分析氨基葡糖苷的含量及活性。用TDX仪进行临床化学分析,通过涂布枯草芽孢杆菌的琼脂平板测量抑菌区进行生物活性分析。
结果示于表III。
药品重量为没有任何盐的形式进行标准化。
表ⅡI结果表明,在两种脂质体/复方抗感染剂配方中均存在氨基葡糖苷,且具有活性,而单方氨基葡糖苷即使在10倍剂量时也检测不到。这些结果更进一步明确了脂质体/复方抗感染剂的缓释特性,而且也证实剩余的抗感染剂仍然具有活性。在上述配方中,只有单方妥布霉素(0.1μg/ml)在肾中具有可检测的氨基葡糖苷水平。
脂质体/复方丁胺卡那霉素的缓释及存储效应在图5中进一步得到了展示。利用与检测药效时相同的琼脂糖小球,通过气管滴注包被于琼脂糖小球基质内的绿脓假单胞菌,造成大鼠慢性肺部感染,然后以相同剂量(2毫克/大鼠)通过气管内给予大鼠单方妥布霉素或者脂质体/复方丁胺卡那霉素(配方Lip-An-14)。以微克抗感染剂/每克肺组织进行测量所得的数据显示,脂质体/复方抗感染剂具有缓释及存储效果,而单方妥布霉素在24个小时时肺中已检测不到药物,其主要原因估计是全身的快速吸收。大鼠肺中脂质体/复方抗感染剂这种100倍以上抗感染效果的增加,支持缓释的脂质体/复方抗感染剂较现在通过的TOBITM配方服药频率可以明显减少的观点。
丁胺卡那霉素的药物动力学是用大鼠如下测定的,在大鼠中通过气管内(IT)给予单方妥布霉素或者脂质体/复方丁胺卡那霉素。剂量采用的是2毫克/大鼠。脂质体/复方抗感染剂技术的储存效果是通过与气管内给予单方妥布霉素进行比较来证实的,给药后24小时,感染肺中脂质体/复方丁胺卡那霉素仍具有100倍以上的药量。因此,与单方妥布霉素相比,脂质体配方中药物处理水平的持续时间要长。
图7显示抗感染剂在肺中显著的滞留时间及药效累积效应,该结果证实可采用相对较低的服药频率。每次剂量是4小时,通过吸入法(在大鼠中,每组3只大鼠,如上)给予雾状的脂质体丁胺卡那霉素(1∶1的DPPC/Chol.),15mg/ml的丁胺卡那霉素。给药分别是在第1天、3天和5天;或第1天、2天、3天、4天和第5天。标有数据符号的大鼠分别在服药后被处死。使用的配方与实施例中一致。
类似的抗感染剂可用于处理细胞内感染如肺炭疽和土拉菌病。在肺炭疽中,炭疽芽孢通过气溶胶到达肺泡。所吸入的芽胞由肺泡中的肺巨噬细胞所吞噬,并将其携带到局部气管支气管淋巴结或通过淋巴系统运到纵隔淋巴结(Pile等,1998;Gleiser等,1968)。巨噬细胞既是感染途径的重要部分,又是全身吸入性炭疽宿主自毁的主要参与成份。脂质体/复方抗感染剂技术除协助缓释及靶向以外,还可以增强细胞对药物的吸收,也可以利用肺泡巨噬细胞及肺上皮细胞进行药物的靶向及传递。拥有这些特性被认为有利于处理这类细胞内感染,这类感染发生于肺部而且是由巨噬细胞转运的。更重要的是:这些特性使得含有疾病因子的细胞可以吞噬脂质体/复方抗感染剂,从而使其抗感染效果更强。抗感染剂将以靶向作用的方式在细胞内释放,因此在其扩散之前,即可以发挥其抗感染的作用。这种胶囊化的药物可以是已经经过认证的药物,如环丙沙星,四环素,erthyromycin或者丁胺卡那霉素。已经研发了脂质体/复方环丙沙星。
在一项研究中,给小鼠服用上述复合药物,与气管内给予单方环丙沙星和口服环丙沙星进行了比较,三种药物的给药剂量相同(图6)。每只小鼠的剂量是15毫克/千克,每组3只小鼠。脂质体/复方环丙沙星的配比是二棕榈酰磷脂酰胆碱/胆固醇为9∶1,环丙沙星的量是3mg/ml,该配方的生产与实施例中的一致。药物与类脂的比率是12.5∶1的重量比。与口服环丙沙星相比,脂质体/复方环丙沙星比单方环丙沙星在肺中的药量高出两个数量级。而且,只有脂质体/复方环丙沙星在24个小时之后在肺里仍可检测到,而口服药剂在不到两小时即无法检测。该数据证实,使用脂质体/复方环丙沙星及其它抗感染剂如氨基糖苷类、四环素类及大环内酯类可处理及预防生物恐怖分子所用的细胞内疾病。
制造脂质体/复方药剂的一种方法典型地包括室温进行酒精注入,该温度低于配方所用的类脂的转换温度。脂质体是以小的单层囊(SUV)形式与包含用于胶囊化的生物活性制剂的水或醇溶液混合。将乙醇注入到该混合物中。该混合物立即形成片层状类脂或单层囊泡(MLV)。如果形成片层状类脂,在去除乙醇后可诱导形成单层囊泡(MLV),这可以通过离心、透析或透析过滤等进行喷洒或清洗进行。MLV的直径范围典型地在大约0.1和3.0μm之间。
或者,所采用的类脂也可溶解于乙醇中形成类脂乙醇溶液。将类脂-乙醇溶液注入到水或者含需胶囊化的生物活性制剂分子的醇溶液中。全部制备过程是在类脂的最低相位转变温度以下进行的。该混合物立即形成片层状类脂或单层囊泡(MLV)(10)。片层状类脂在去除乙醇后可诱导形成单层囊泡(MLV),乙醇的去除可以采用离心、透析或透析过滤等进行喷洒或清洗。MLV的直径范围典型地在大约0.1和3.0μm之间。
类脂 | 摩尔比 | 类脂/丁胺卡那霉素,w/w |
DPPC | --- | 1.1 |
类脂 | 摩尔比 | 类脂/丁胺卡那霉素,w/w |
DPPC/DOPG | 9∶1 | 1.0 |
DPPC/DOPG | 7∶1 | 3.9 |
DPPC/DOPG | 1∶1 | 2.8 |
DPPC/DOPG | 1∶2 | 2.7 |
DOPG | --- | 2.6 |
DPPC/胆固醇 | 19∶1 | 1.0 |
DPPC/胆固醇 | 9∶1 | 1.2 |
DPPC/胆固醇 | 4∶1 | 1.7 |
DPPC/胆固醇 | 13∶7 | 2.1 |
DPPC/胆固醇 | 1∶1 | 2.7 |
DPPC/DOPC/胆固醇 | 8.55∶1∶0.45 | 2.0 |
DPPC/DOPC/胆固醇 | 6.65∶1∶0.35 | 3.0 |
DPPC/DOPC/胆固醇 | 19∶20∶1 | 2.5 |
DPPC/DOPG/胆固醇 | 8.55∶1∶0.45 | 3.8 |
DPPC/DOPG/胆固醇 | 6.65∶1∶0.35 | 4.1 |
DPPC/DOPG/胆固醇 | 19∶20∶1 | 4.2 |
DPPC/DOPC/DOPG/胆固醇 | 42∶4∶9∶45 | 3.7 |
DPPC/DOPC/DOPG/胆固醇 | 59∶5∶6∶30 | 3.7 |
多种含有丁胺卡那霉素的配方是根据实施例中的方法制备的,就象下面所总结的一样:
其它制备脂质体/复方抗感染剂的资料可在专利PCT/US03/06847里找到,提交日期为2003年3月5日,其全部资料在此作为参考。
实施例
以下是制备150mL脂质体/复方丁胺卡那霉素的详细描述。
总起始体积=1.5L
乙醇含量=23.5%(v/v)
类脂组成:DPPC/Chol(1∶1摩尔比)
起始[类脂]=7.6mg/ml
起始[丁胺卡那霉素硫酸盐]=57.3mg/ml
最终产品体积=150mL。
I)配制和注入:
7.47克DPPC和3.93克胆固醇在50℃水浴中直接溶于352.5mL乙醇内。85.95g硫酸丁胺卡那霉素直接溶于1147.5mL PBS缓冲液中。然后是用10N氢氧化钠或氢氧化钾将该溶液的pH值滴定至大约为6.8。
将352.5mL乙醇/类脂加入或注入到1147.5mL丁胺卡那霉素/缓冲液中,使起始体积成为1.5L。将乙醇/类脂用一台蠕动泵以30mL/min(也称注入率)的频率抽到丁胺卡那霉素/缓冲液中,然后将其置于反应器中,并在室温以150RPM转速在搅拌器上进行快速搅拌。
将该产品在室温搅拌20-30分钟。
II)透析过滤或″冲洗″的步骤:
将混合器连接于一台蠕动泵及透析过滤盒。透析过滤盒是分子量的cut-off为500千道尔顿的空膜纤维。将产品从反应器中抽出,通过透析过滤盒然后再在室温注入到混合器中。透析过滤盒所产生的反压力约为7磅/平方英寸。通过反压力使单方丁胺卡那霉素和乙醇通过空膜纤维,留下脂质体丁胺卡那霉素(产品)。将该产品在室温冲洗8次。将新配的PBS缓冲液(通过另一台蠕动泵)加入到反应器中,以补偿渗出液,使产品体积保持恒定。
将产品进行浓缩。
出版物和参考文献包括但不限于专利和专利申请,在此全部引入以供参考。任何要求优先权的专利申请在此也与上述出版物和参考文献相同的方式引入以供参考。
本发明的重点在于描述优选的实施方案,本行业普通技术人员显然明确的是,优选的仪器及方法可进行适当改变,而且本发明也能以与这里所特别描述的不同的方式实施。因此,本发明也包括以下权利要求中所定义的提纲和规定范围内的全部改动。
参考文献:
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Claims (20)
1.脂质体抗感染制剂的用于制备一种药物的用途,其中所述药物用于处理或改善患者肺部感染,包括通过肺部给予患者一种有效剂量的脂质体抗感染制剂,其中所述的脂质体抗感染制剂包括类脂组分和抗感染剂,其中所述的类脂组分包括甾醇和磷脂酰胆碱,并且所述的类脂与抗感染剂的重量比为2.5∶1以下,其中所述的抗感染剂是氨基葡糖苷。
2.权利要求1所述的用途,其中的给药方案是每天一次或更少。
3.权利要求1所述的用途,其中的给药方案是每2天一次或更少。
4.权利要求1所述的用途,其中的给药方案是每3天一次或更少。
5.权利要求1所述的用途,其中的抗感染剂是丁胺卡那霉素。
6.权利要求5所述的用途,其中的给药方案是每天一次或更少。
7.权利要求5所述的用途,其中的给药方案是每2天一次或更少。
8.权利要求5所述的用途,其中的给药方案是每3天一次或更少。
9.权利要求1所述的用途,其中所需处理或改善的感染是一种假单胞菌,葡萄球菌,耐甲氧苯青霉素金黄色葡萄球菌(MRSA),链球菌,大肠杆菌,克雷伯氏菌属,肠杆菌属,沙雷式菌属,嗜血杆菌,鼠疫耶尔森(氏)菌,类鼻疽伯克霍尔德氏菌,洋葱伯克霍尔德菌,唐菖蒲伯克霍尔德菌,multivorans伯克霍尔德氏菌,越南伯克霍尔德氏菌,结核分支杆菌,鸟分枝杆菌复合体(MAC),堪萨斯分枝杆菌,蟾分枝杆菌,海分枝杆菌,溃疡分枝杆菌,或者偶发分枝杆菌复合体感染。
10.权利要求1所述的用途,其中所需处理或改善的感染是一种假单胞菌感染。
11.权利要求1所述的用途,其中所需处理或改善的感染是一种绿脓假单胞菌感染。
12.权利要求1所述的用途,其中的有效量是指在肺感染症状已经出现后可有效处理或改善的量。
13.权利要求1所述的用途,其中的抗感染剂是硫酸丁胺卡那霉素。
14.权利要求1所述的用途,其中所述的磷脂酰胆碱是DPPC,所述的甾醇是胆固醇。
15.脂质体丁胺卡那霉素制剂的用于制备一种药物的用途,其中所述药物用于处理或改善患者肺部感染,包括通过肺部给予患者一种有效剂量的脂质体抗感染制剂,其中所述的脂质体丁胺卡那霉素制剂包括类脂组分和丁胺卡那霉素,其中所述的类脂组分包括胆固醇和DPPC,并且所述的类脂与抗感染剂的重量比为2.5∶1以下。
16.权利要求15所述的用途,其中所述的丁胺卡那霉素以硫酸丁胺卡那霉素的形式提供。
17.权利要求1至16任意一项所述的用途,其中所述的患者是囊性纤维变性患者。
18.权利要求15或16所述的用途,其中所述的DPPC与所述的甾醇的摩尔比为约1∶1。
19.权利要求15或16所述的用途,其中所述的类脂与所述的丁胺卡那霉素的重量比为1.1∶1或更低。
20.权利要求9所述的用途,其中所需处理或改善的感染是为少动假单胞菌、恶臭假单胞菌、萤光假单胞菌和食酸假单胞菌,肺炎链球菌感染。
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