CN105520922A - 用于改进的药物动力学的氟喹诺酮气雾剂制剂 - Google Patents
用于改进的药物动力学的氟喹诺酮气雾剂制剂 Download PDFInfo
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- CN105520922A CN105520922A CN201510965138.XA CN201510965138A CN105520922A CN 105520922 A CN105520922 A CN 105520922A CN 201510965138 A CN201510965138 A CN 201510965138A CN 105520922 A CN105520922 A CN 105520922A
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- levofloxacin
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Abstract
本发明涉及抗微生物剂领域。特别地,本发明涉及与二价或三价阳离子一起配制的并具有改进的肺部可利用性的气雾化的氟喹诺酮在治疗和处理肺部和上呼吸道的细菌感染中的用途。
Description
本申请是2009年10月06日提交的发明名称为“用于改进的药物动力学的氟喹诺酮气雾剂制剂”的第200980143627.X号中国发明专利申请的分案申请。
相关申请
本申请要求2008年10月7号提交的第61/103,501号美国临时申请的优先权,其整体以引用的方式明确地并入本文。
发明领域
本发明涉及抗微生物剂领域。特别地,本发明涉及具有改进的肺部可利用性的与二价或三价阳离子一起配制的气雾化的氟喹诺酮在治疗和处理肺和上呼吸道的细菌感染中的用途。
背景
由于给亲水和疏水化合物提供有效阻隔的第二外膜的存在,革兰氏阴性菌比革兰氏阳性菌在本质上更耐抗生素。因此,少数种类的抗生素可用于治疗革兰氏阴性感染。实际上,仅有几种典型的β-内酰胺、氨基糖苷和氟喹诺酮对于绿脓假单胞菌(Pseudomonasaeruginosa)具有体外抗菌活性,并且表现出临床效用,不出乎意料地,耐这样的抗生素的发展有充分的记录。
呼吸道疾病折磨着全世界数百万人,其导致疾苦、经济损失以及过早死亡,其包括鼻腔或四鼻窦(左半球和右半球、额窦、上颌窦、筛窦和蝶窦)或喉部、气管或肺部(支气管、细支气管、肺泡)的急性感染、亚急性感染以及慢性感染。
由革兰氏阴性菌引起的肺部感染代表着特别的挑战。通常在痰、肺部上皮细胞衬液、肺泡巨噬细胞和支气管粘膜中发现病原体。在患有囊性纤维化、COPD、慢性支气管炎、支气管扩张、急性和慢性肺炎以及许多其它肺部感染的患者中,周期性地观察到肺部感染的急性恶化。这些恶化的预防以及它们的治疗通常很难,特别当包含诸如绿脓假单胞菌(Pseudomonasaeruginosa)和洋葱伯克霍尔德氏菌群(Burkholderiacepaciacomplex)的高抗病原体时。对于大部分治疗方案,需要高剂量来维持在感染部位的有效浓度。对于氨基糖苷而言,肾毒性和耳毒性还直接与持续提高的血清抗生素浓度有关。为了实现对患者的最佳结果,临床医生通常使用两种或多种诸如头孢他啶和妥布霉素的抗生素的组合,所述抗生素为了达到抗生素协同的目的以高剂量给药2周(J.G.denHollander等人,“SynergismbetweentobramycinandceftazidimeagainstaresistantPseudomonasaeruginosastrain,testedinaninvitropharmacokineticmodel”(在体外药物动力学模型中测试的妥布霉素与头孢他啶间防止绿脓假单胞菌(Pseudomonasaeruginosa)菌株耐药性的协同作用),Antimicrob.AgentsChemother.(1997),41,95-100)。例如,成功的治疗需要每8小时给予头孢他啶或通过连续注入来给予头孢他啶,从而使得血清浓度高于最小抑菌浓度的时间最大化(M.Cazzola等人,“Deliveringantibacterialstothelungs:Considerationsforoptimizingoutcomes”(向肺部递送抗微生物剂:使结果最优化的考虑事项),Am.J.Respir.Med.(2002),1,261-272)。
确保高的局部浓度以及低的全身暴露的直接向感染部位进行的抗生素的气雾剂给予代表了治疗肺部感染的有吸引力的替代方案。将气雾化的妥布霉素用于治疗患有囊性纤维化的患者的假单胞细菌感染。该技术背后的依据是向感染部位直接给予药物,由此缓解通过标准的静脉内方法来产生高血清浓度的需求。气雾剂给药的优点是许多患者能够自己给予抗生素,并且该治疗方法能够取消漫长的住院治疗的需要(M.E.Hodson,“Antibiotictreatment:Aerosoltherapy”(抗菌治疗:气雾剂疗法),Chest(1988),94,156S-160S;和M.S.Zach“Antibioticaerosoltreatment”(抗菌气雾剂治疗),Chest(1988),94,160S-162S)。然而,妥布霉素是目前在美国仅有的FDA-认证的气雾剂抗生素。而且,当其在处理囊性纤维化患者的周期性感染中持续起重要作用时,由于耐药性的发展,无意中减少了其临床效用。另外,由于妥布霉素对囊性纤维痰的成分的高结合性,一定程度地减少了气雾剂给药之后达到的总高浓度的影响。因此,亟需改进的气雾化的抗生素。
概述
本发明涉及具有改进的肺部可利用性的与二价或三价阳离子一起配制的气雾化的氟喹诺酮在治疗和处理肺和上呼吸道的细菌感染中的用途。某些方法包括治疗肺部感染,其包括给予有需要的个体有效量的与二价或三价阳离子结合的左氧氟沙星或氧氟沙星的气雾剂溶液,所述气雾剂溶液具有改进的肺部可利用性和左氧氟沙星或氧氟沙星的暴露。
提供了用于治疗肺部感染的方法。某些这样的方法包括给予患有肺部感染的人包含左氧氟沙星或氧氟沙星和二价或三价阳离子的溶液的气雾剂,从而达到至少1200mg/L的最大肺部痰浓度(C最大值)和至少1500h·mg/L的肺部痰曲线下面积(AUC)。在更多的实施方案中,提供了用于治疗慢性肺部感染的方法。某些这样的方法能够包括给予患有慢性肺部感染的个体包含左氧氟沙星或氧氟沙星和二价或三价阳离子的溶液的气雾剂。在更多的实施方案中,提供了药物组合物。某些这样的组合物能够包含基本上由80mg/ml至120mg/ml的左氧氟沙星或氧氟沙星和160mM至220mM的二价或三价阳离子组成的水溶液,其中所述溶液的pH为5至7,并且重量摩尔渗透压浓度为300mOsmol/kg至500mOsmol/kg。
某些实施方案包括治疗肺部感染的方法,所述方法包括给予患有所述肺部感染的人包含左氧氟沙星或氧氟沙星和二价或三价阳离子的溶液的气雾剂,从而达到至少约1200mg/L的最大肺部痰浓度(C最大值)和至少约1500h·mg/L的肺部痰曲线下面积(AUC)。
某些实施方案包括治疗慢性肺感染的方法,该方法包括给予患有慢性肺部感染的个体包含左氧氟沙星或氧氟沙星和二价或三价阳离子的溶液的气雾剂。
某些实施方案包括药物组合物,该组合物包含基本上由约80mg/ml至约120mg/ml的左氧氟沙星或氧氟沙星和约160mM至约240mM的二价或三价阳离子组成的水溶液,其中所述溶液的pH为约5至约7,并且重量摩尔渗透压浓度为约300mOsmol/kg至约500mOsmol/kg。
附图简述
图1示出在盐水中配制的左氧氟沙星(LVX)的静脉内给药、气雾剂给药之后,或与MgCl2一起配制的左氧氟沙星的气雾剂给药之后,大鼠的血浆左氧氟沙星浓度的图表。
图2示出在用盐水、Ca+、Mg+2或Zn2+配制的左氧氟沙星气雾剂的单独的10mg/kg给药之后,大鼠肺匀浆的左氧氟沙星回收的图表。
图3示出用于在药物的气雾剂给予后反卷积血清左氧氟沙星浓度的药物动力学模型的示意图。
图4示出在通过气雾剂途径或静脉内途径给予50mg的LVX盐溶液之后,血浆左氧氟沙星(LVX)浓度的图表。
图5示出在50mg可呼吸药物剂量的左氧氟沙星盐溶液的气雾剂给药之后,残留在肺房室中的药物的估计量的图表,其中使用血清数据的反卷积来估计残留药物的量。
图6示出在单独静脉内给予或单独气雾剂给予左氧氟沙星盐溶液之后,正常健康志愿者和囊性纤维化患者的血清左氧氟沙星浓度的图表。剂量显示为估计的RDD;20mg和40mg的RDD分别表示43.3mg和86.6mg的喷雾器载荷剂量。
图7示出在普通盐水中配制的装载于喷雾器中的43.4mg(估计可呼吸递送剂量(RDD)为20mg)和装载于喷雾器中的86.6mg(估计的RDD为40mg)的单独气雾剂给药之后,残留在7名健康志愿者肺部和9名CF患者肺部中的左氧氟沙星的平均量的反卷积估计值的图表。
图8A示出在普通盐水中配制的单独20mg可呼吸药物剂量(在喷雾器中装载43.4mg的左氧氟沙星)之后,CF患者的肺上皮细胞衬液中估计的左氧氟沙星浓度的图表。图8B示出在普通盐水中配制的单独40mg可呼吸药物剂量(在喷雾器中装载86.6mg)之后,CF患者的肺上皮细胞衬液中估计的左氧氟沙星浓度的图表。
图9示出在普通盐水中配制的左氧氟沙星的单独IV注入或单独气雾剂给药之后,CF个体的痰左氧氟沙星浓度的图表。剂量显示为估计的RDD;20mg和40mg的RDD分别表示43.3mg和86.6mg的喷雾器载荷量。
图10示出在左氧氟沙星的多种剂量和给药途径(在普通盐水中配制的气雾剂给药)之后,描述CF个体的模拟痰左氧氟沙星浓度的图表。
图11示出在使用估计的相当于86.6mg载荷药物剂量的40mg可呼吸药物剂量(RDD)气雾剂给予50mg/ml的用MgCl2或盐水配制的LVX之后,囊性纤维化患者的痰左氧氟沙星(LVX)浓度的图表。
图12示出在具有50mg/ml或100mg/ml左氧氟沙星溶液的180mg剂量或具有100mg/ml左氧氟沙星溶液的240mg剂量的气雾剂给予之后,囊性纤维化患者的左氧氟沙星的算术平均血清浓度的图表。治疗为每天一次连续7天。所述50mg/ml的左氧氟沙星制剂包含100mM氯化镁和150mM乳糖,并且所述100mg/ml的左氧氟沙星包含200mM氯化镁并且不含乳糖。
图13示出在具有50mg/ml或100mg/ml左氧氟沙星溶液的180mg剂量或具有100mg/ml左氧氟沙星溶液的240mg剂量的气雾剂给予之后,囊性纤维化患者的左氧氟沙星的算术平均痰浓度的图表。治疗为每天一次连续7天。所述50mg/ml的左氧氟沙星制剂包含100mM氯化镁和150mM乳糖,并且所述100mg/ml的左氧氟沙星包含200mM氯化镁并且不含乳糖。
图14示出与含氯化镁溶液的制剂相比,盐水中配制的左氧氟沙星在单独雾状给药之后,囊性纤维化患者的平均痰左氧氟沙星水平的图表。使用ParieFlow喷雾器,使用具有相同的网头设计和孔径尺寸的震动网技术来喷雾上述两种制剂。左氧氟沙星盐溶液的喷雾器载荷剂量为87mg,并且对于使用氯化镁的制剂,左氧氟沙星的喷雾器载荷剂量为180mg。通过增加用87/180(0.48)的氯化镁制剂获得的观察到的痰左氧氟沙星浓度来将数据标准化至87mg剂量。
图15示出在气雾剂给予10mg/kg剂量或20mg/kg剂量的与MgCl2或不与MgCl2一起配制的左氧氟沙星(LVX)之后,小鼠的肺炎克雷伯氏菌(K.pneumoniae)ATCC43816/肺的log菌落形成单位(CFU)的变化的图表。
图16示出在气雾剂给予125mg/kg、63mg/kg或32mg/kg的具有MgCl2的左氧氟沙星(LVX)、或腹膜内给予(IP)125mg/kg、63mg/kg或32mg/kg左氧氟沙星之后,小鼠急性肺部感染模型的绿脓假单胞菌(P.aeruginosa)ATCC27853/肺的log菌落形成单位(CFU)的图表。所示数值为平均值±SDlogCFU/肺。治疗组(n=8)在24小时内接受2剂量的抗生素(对于每一剂量的气雾剂给药与IP给药的对比,p<0.05)。
图17示出在每天两次气雾剂给予60mg/kg、30mg/kg或15mg/kg具有MgCl2的左氧氟沙星(LVX)、或每天两次腹膜内给予60mg/kg、30mg/kg或15mg/kg的左氧氟沙星之后,鼠科动物慢性肺部感染模型的绿脓假单胞菌(P.aeruginosa)NH57388A/肺的log菌落形成单位(CFU)的图表。在氯化镁中配制左氧氟沙星的气雾剂剂量。所示数值为平均值±SDlogCFU/肺部。治疗组(n=8)在72小时内每天接受2剂量的抗生素(对于相同剂量的气雾剂与腹膜内的对比,p<0.05)。
图18示出在每天两次气雾剂给予60mg/kg左氧氟沙星、60mg/kg妥布霉素或400mg/kg氨曲南之后,或每天一次气雾剂给予120mg/kg左氧氟沙星之后,鼠科动物急性致死性肺部感染模型的绿脓假单胞菌(P.aeruginosa)ATCC27853/肺的log菌落形成单位(CFU)的图表。在氯化镁中配制左氧氟沙星的气雾剂剂量。治疗组(n=8)在48小时内接受药物。所示数值为平均值±SDlogCFU/肺。(p<0.05)。
图19示出鼠科动物致死性肺部感染模型中感染绿脓假单胞菌(P.aeruginosa)ATCC27853的小鼠随着时间推移的存活百分比的图表,和用每天两次气雾剂给予60mg/kg的左氧氟沙星、60mg/kg妥布霉素或400mg/kg氨曲南,或用每天一次气雾剂给予120mg/kg左氧氟沙星治疗的小鼠随着时间推移的存活百分比图表。在氯化镁中配制左氧氟沙星的气雾剂剂量。小鼠的治疗组(n=8)在48小时内接受药物。在感染后的9天监测存活。
图20示出在每天两次气雾剂给予60mg/kg的左氧氟沙星、60mg/kg妥布霉素或400mg/kg氨曲南之后,鼠科动物慢性肺部感染模型中绿脓假单胞菌(P.aeruginosa)NH57388A/肺的log菌落形成单位(CFU)的图表。连续三天,每天两次对治疗组进行治疗。在氯化镁中配制左氧氟沙星的气雾剂剂量。所示数值为平均值±SDlogCFU/肺。左氧氟沙星气雾剂比氨曲南或未治疗的对照小鼠导致更低的细菌数量(p<0.05)。
详述
本发明涉及抗微生物剂领域。特别地,本发明涉及具有改进的肺部可利用性和由此更好的杀菌活性的与二价或三价阳离子一起配制的气雾化的氟喹诺酮在治疗和处理肺和上呼吸道的细菌感染中的用途。
如果能够安全地增加抗微生物剂在感染部位的浓度,则可以减少与耐抗微生物剂病原体有关的许多问题。例如,通过以高浓度直接给予感染部位抗微生物剂来治疗肺部感染,而不引起抗微生物剂的大的全身浓度。另外,本文公开的某些实施方案是递送药物组合物来治疗肺部细菌感染的改进方法。更具体地,本文所描述的是具有二价或三价阳离子的氟喹诺酮制剂,该制剂实现了氟喹诺酮在人体中的期望的有利于增加功效并减少出现耐药性的药物动力学模式。
因此,本文所述的某些实施方案包括方法和包含氟喹诺酮的组合物,其中延迟了在气雾剂之后从肺组织或上呼吸道到全身循环的吸收。在某些这样的实施方案中,氟喹诺酮以不明显减少其抗微生物活性的方式与二价阳离子络合。这样的配合物可以用于治疗、维持或预防感染。另外,相比于未与二价或三价阳离子络合的氟喹诺酮,这样的配合物在感染部位(例如,上呼吸系统和/或下呼吸系统)能够显示出更高的药物浓度和更高的功效。
本发明的某些实施方案涉及治疗肺部感染的方法以及与二价或三价阳离子一起配制的左氧氟沙星或氧氟沙星的组合物。已经发现本文描述的特别的方法和组合物实现了在个体肺部中左氧氟沙星或氧氟沙星的改进的可利用性。抗微生物剂增加的肺部可利用性有利于治疗肺部感染,并且特别有利于治疗诸如囊性纤维化和慢性阻塞性肺病的疾病状态,其包括例如慢性支气管炎、支气管扩张和某些哮喘。
使用与诸如增加肺部药物浓度和/或肺部保留药物的持续时间的因素相关的多个药效学-药物动力学参数能够标示出改进的肺部可利用性。这样的因素能够包括肺部痰曲线下面积(AUC)和最大肺部痰浓度(C最大值)。
通常,给予肺部气雾化的抗微生物剂能够提供肺部的高浓度,而不引起高全身浓度。然而,本文提供的方法和组合物意料外地实现了增加的肺部可利用性。
通常,本文提供的组合物能够包含与二价或三价阳离子一起配制的左氧氟沙星或氧氟沙星溶液,所述阳离子例如Mg2+。在某些实施方案中,所述组合物能够缺少特定的赋形剂,例如乳糖。使用装置能够给予所述组合物,并且所述组合物能够用于治疗种类繁多的细菌,所述装置例如喷雾器或直接插入动物气管的微喷气雾剂装置。另外,本文提供的方法和组合物可以包含另外的用于治疗肺部感染和与肺部感染相关疾病的活性剂,其中所述肺部感染例如囊性纤维化和包括慢性支气管炎和某些哮喘的慢性阻塞性肺部疾病。
定义
术语“给药(administration)”或“给药(administering)”是指给予脊椎动物一定剂量的抗微生物药物组合物的方法。给药的优选方法能够依赖多种因素而变化,例如药物组合物的成分、潜在的细菌感染部位或实际的细菌感染部位、涉及的微生物以及实际的微生物感染的严重性。
“载体”或“赋形剂”为用于促进给予化合物,例如用于增加化合物的溶解性的化合物或材料。固体载体包括,例如淀粉、乳糖、磷酸二钙、蔗糖和高岭土。液体载体包括,例如无菌水、盐水、缓冲剂、非离子表面活性剂和诸如油、花生油和芝麻油的食用油。此外,可以包括诸如在本领域中常用的多种佐剂。在文献中描述了这些和其它这样的化合物,例如在MerckIndex,Merck&Company,Rahway,NJ.中描述的。例如在以其整体以引用的方式并入本文的Gilmanetal.(Eds.)(1990);Goodman和Gilman的ThePharmacologicalBasisofTherapeutics(治疗学的药理学基础),第八版,PergamonPress中描述了药物组合物中包含多种成分的考虑。
如本文所用的“诊断”是有助于鉴定和表征健康或疾病状态的化合物、方法、系统或装置。能够用于标准检验的诊断是本领域已知的。
术语“哺乳动物”以其通常的生物学含义使用。因此,其具体包括人、牛、马、狗和猫,但还包括许多其它物种。
术语“微生物感染”是指宿主有机体中入侵的病原微生物的不期望的增殖或存在。其包括正常存在于哺乳动物或其它有机体体内或身体上的微生物的过度增长。更广泛地,微生物感染能够是微生物群体的存在损害宿主哺乳动物的任何情况。因此,当过多数量的微生物群体存在于哺乳动物体内或身体上时,或当微生物群体存在的影响损害哺乳动物的细胞或其它组织时,微生物感染发生。
术语“药物可接受的载体”或“药物可接受的赋形剂”包括任何和所有溶剂、分散介质、包衣、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂(absorptiondelayingagent)等。用于药物活性物质的这样的介质和药剂的使用为本领域公知。除目前与活性成分不相容的任何常规介质或药剂之外,预期将其用于治疗组合物。还能将补充活性成分并入组合物。
术语“药物可接受的盐”是指保留本发明化合物的生物可利用性和特性的盐,且其不是生物学的或其他不需要的盐。在许多情况下,本发明的化合物能通过存在的氨基和/或羧基或与其相似的基团形成酸和/或碱盐。能用无机酸和有机酸形成药物可接受的酸加成盐。能从其获得盐的无机酸包括,例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。能从其获得盐的有机酸包括,例如醋酸、丙酸、萘甲酸、油酸、棕榈酸、双羟萘酸(扑酸)、硬脂酸、羟基乙酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、抗坏血酸、葡庚糖酸、葡糖醛酸、乳酸、乳糖酸、酒石酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。能用无机碱和有机碱形成药物可接受的碱加成盐。能从其获得盐的无机碱包括,例如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝等;特别优选的是铵、钾、钠、钙和镁盐。能从其获得盐的有机碱包括,例如伯胺、仲胺和叔胺,取代的胺,其包括自然产生取代的胺、环胺、碱性离子交换树脂等,具体地例如异丙胺、三乙胺、二乙胺、三乙胺、三丙胺、组氨酸、精氨酸、赖氨酸、苯乙苄胺、N-甲基葡糖胺和乙醇胺。其它酸包括十二烷基硫酸、萘-1,5-二磺酸、萘-2-磺酸和糖精。
“溶剂化物”是指由溶剂和氟喹诺酮抗微生物剂、其代谢物或盐的相互作用形成的化合物。合适的溶剂化物为包括水合物在内的药物可接受的溶剂化物。
在诸如细菌的微生物对抗微生物剂反应的环境中,术语“易感性”是指微生物对于抗微生物剂存在的敏感度。因此,增加易感性是指在微生物细胞周围的介质中较低浓度的抗微生物剂将抑制微生物。这相当于说明微生物对抗微生物剂更敏感。在大多数情况中,将减少该抗微生物剂的最低抑菌浓度(MIC)。MIC90能够包括抑制90%有机体生长的浓度。
“治疗有效量”或“药物有效量”是指如本发明公开的具有治疗效果的氟喹诺酮抗微生物剂。在治疗中有效的氟喹诺酮抗微生物剂的剂量为治疗有效量。因此,如本文所用的治疗有效量是指如由临床试验结果和/或模型动物感染研究所判断的产生期望治疗效果的氟喹诺酮抗微生物剂的那些量。在特定的实施方案中,按预定剂量给予氟喹诺酮抗微生物剂,因此治疗有效量为所述给予的剂量的量。该量和氟喹诺酮抗微生物剂的量能由本领域技术人员常规确定且依赖诸如所涉及的特殊微生物菌株的若干因素而变化。该量还能依赖于患者的身高、体重、性别、年龄和病史。对于预防治疗,治疗有效量为对预防微生物感染有效的量。
“治疗效果”在某种程度上缓解感染的一种或多种症状,且包括治愈感染。“治愈”是指除去活性感染的症状,包括将在感染中涉及的那些存活的微生物的过多成员全部或基本除去至在传统检测确定开始的点或以下。然而,急性或慢性感染的某些长期或永久影响可即使在得到治愈之后仍存在(例如大面积组织损伤)。如本文使用的“治疗效果”的定义为统计学上显著减少的负载宿主的细菌、耐药性出现、肺部功能或如通过人临床结果或动物研究所检测的感染症状或功能状态的改善。
如本文所用的“治疗(Treat)”、“治疗(treatment)”或“治疗(treating)”是指为了预防和/或治疗目的给予药物组合物。术语“预防性治疗”是指治疗还未被感染但易患特定感染或以其他方式处于特定感染危险中的患者,使得感染的进攻减少。术语“治疗性治疗”是指对已经被感染的患者给予治疗,所述感染可以为急性或慢性感染。治疗可以消除病原体,或者可以减少负载在组织上的病原体,所述治疗导致患者症状的检测改善或肺功能检查的检测改善。因此,在优选的实施方案中,治疗是给予哺乳动物(治疗或预防目的)治疗有效量的氟喹诺酮抗微生物剂。
药物动力学(PK)涉及体内抗微生物剂浓度的时间过程。药效学(PD)涉及体内药物动力学与抗菌效力之间的关系。PK/PD参数与具有抗菌活性的抗微生物剂暴露有关。抗微生物剂的杀伤率依赖于抗微生物剂的作用方式,并且通过杀伤所需的持续时间(时间依赖性),或单独增加浓度的影响(浓度依赖性),或作为浓度-时间曲线下面积(AUC)的随着时间推移吸收的测定。可以使用不同的PK/PD参数来预测具有多种作用机理的抗微生物剂的治疗效果。可以将PK/PD参数用于测定抗微生物组合物的可利用性,例如,在肺部体系中组合物的抗微生物剂的可利用性和/或在血浆/血清中组合物的抗微生物剂的生物利用度。
“AUC/MIC比”是PK/PD参数的一个实例。将AUC定义为体内(在动物或人体内)抗微生物剂的血浆/血清或感染部位的浓度-时间曲线下的面积。例如,感染部位和/或检测浓度的部位能够包括肺部系统的一部分,例如支气管液和/或痰。因此,AUC可以为基于血清和肺部组织(痰、上皮细胞衬液或全部组织的均浆)中浓度的血清AUC或肺部AUC。AUC(0-t)能够包括时间零点至具体时间“t”的曲线下面积。AUC(0- 无穷)能够包括从时间零点至无穷大的曲线下面积。通过将单独抗微生物剂的24小时AUC除以体外测定的相同抗微生物剂的MIC来确定AUC/MIC比。通过AUC/MIC比的数值来较好地预测具有剂量依赖性杀伤的抗微生物剂(例如氟喹诺酮)活性。AUC:MIC比还能够防止选择耐药细菌。
“C最大值:MIC”比是另一种PK:PD参数。其描述了与MIC有关的血浆或组织的最大药物浓度。氟喹诺酮和氨基糖苷是C最大值:MIC可以预测体内细菌杀伤的实例,其中能够抑制耐药性。
“高于MIC的时间”(T>MIC)是另一种PK/PD参数。其表示给药间隔的百分比,其中血浆或感染部位水平高于MIC。通过T>MIC比的数值来较好地预测具有时间依赖性杀伤的抗微生物剂(例如,β-内酰胺抗生素或单环内酰胺抗生素)的活性。
术语“给药间隔”是指在多个给药方案中,给予药物的两个连续剂量之间的时间。例如,在口服给予环丙沙星的情况下,其每日给予两次(常规疗程为400mgb.i.d)和在口服给予左氧氟沙星的情况下,其每日给予一次(500mg或750mgq.d.),给药间隔分别为12小时和24小时。
如本文所用的药物的体内浓度的“高峰期”的定义为当药物浓度不小于其最大血浆或感染部位浓度的50%时,药物给药间隔的时间。在某些实施方案中,“高峰期”用于描述抗微生物剂量的间隔。
估计的“可呼吸递送剂量”是使用喷雾器或其它气雾剂递送装置给予患者肺部的药物剂量或药物量。从呼吸模拟装置的吸气阶段中估计RDD,该装置被设计为具有1:1的吸气与呼气比的每分钟15次呼吸的欧洲标准模式,并且从喷雾器发出的颗粒的尺寸测量值为约5微米或更小。
改进的可利用性
抗生素的抑制率依赖于抗生素的作用方式,并且通过抗生素杀伤所需的持续时间(时间依赖性)或增加抗生素浓度的效果(浓度依赖性)确定。氟喹诺酮的特征为浓度依赖性、时间-杀伤活性,其中治疗效果需要高于感染病原体MIC的高局部峰值浓度。
氟喹诺酮在感染的人、动物和体外模型中的功效与AUC:MIC比和C最大值:MIC比有关。已经进行了大量的体外研究来测定具有极短半衰期的高浓度左氧氟沙星(如大鼠模型和人体PK模型所预测)在靶组织中是否导致细菌杀伤优于在具有更长滞留时间的情况下所观察到的细菌杀伤。在这些研究中,在标准杀伤曲线和体外中空纤维检测中,评估为MIC的0.018倍至1024倍的左氧氟沙星浓度。在这些检测中,高浓度的左氧氟沙星快速杀菌并且在10分钟至20分钟内达到其杀伤的最大水平。不管将左氧氟沙星保持在该水平还是被给予10分钟的半衰期,维持这种杀伤水平。另外,发现没有耐药性。因此,对于易感有机体和耐药有机体,特别配制的左氧氟沙星的高剂量和快速递送是快速杀菌的。
在一个实施方案中,使用吸入疗法,通过直接给予肺部与二价或三价阳离子结合的左氧氟沙星,来增加感染部位的左氧氟沙星浓度,由此在“突变选择窗”(MSW)中减少左氧氟沙星的时间量。这样的治疗方法实现了更广泛的病原体覆盖范围(包括耐左氧氟沙星菌株),进一步阻止了耐药性的发展,并且导致左氧氟沙星疗法的更短疗程。
某些实施方案包含具有改善的肺部可利用性的左氧氟沙星或氧氟沙星的组合物,其中增加的肺部AUC为左氧氟沙星或氧氟沙星的改进肺部可利用性的标示。在某些实施方案中,增加能够为至少约10%、20%、30%、40%、50%、75%、100%、150%、200%、250%、300%和500%。例如,增加能够与不含二价或三价阳离子的组合物,和/或具有某些赋形剂(例如乳糖)的组合物,和/或以某种速率给予肺的组合物,和/或某种可呼吸递送剂量有关。在某些实施方案中,提供的方法包括实现由肺AUC来标示的改进的肺部可利用性,所述肺AUC大于约400h.mg/L、约500h.mg/L、约600h.mg/L、约700h.mg/L、约800h.mg/L、约900h.mg/L、约1000h.mg/L、约1100h.mg/L、约1200h.mg/L、约1300h.mg/L、约1400h.mg/L、约1500h.mg/L、约1600h.mg/L、约1700h.mg/L、约1800h.mg/L、约1900h.mg/L、约2000h.mg/L、约2100h.mg/L、约2200h.mg/L、约2300h.mg/L、约2400h.mg/L、约2500h.mg/L、约2600h.mg/L、约2700h.mg/L、约2800h.mg/L、约2900h.mg/L、约3000h.mg/L、约3100h.mg/L、约3200h.mg/L、约3300h.mg/L、约3400h.mg/L、约3500h.mg/L、约3600h.mg/L、约3700h.mg/L、约3800h.mg/L、约3900h.mg/L、约4000h.mg/L、约4100h.mg/L、约4200h.mg/L、约4300h.mg/L、约4400h.mg/L和约4500h.mg/L。例如,在支气管液、全部肺组织的均浆或痰中能够检测该增加。
在某些实施方案中,增加的肺部C最大值能够为左氧氟沙星或氧氟沙星制剂的改进的肺部可利用性的标示。在某些这样的实施方案中,增加能够为至少约50%、75%、100%和150%。例如,增加能够与不含二价或三价阳离子的组合物,和/或具有某些赋形剂(例如乳糖)的组合物,和/或以某种速率给予肺的组合物,和/或某种可呼吸递送剂量有关。在某些实施方案中,提供的方法包括实现由肺C最大值所标示的改进的肺部可利用性,所述肺C最大值大于约300mg/L、约400mg/L、约500mg/L、约600mg/L、约700mg/L、约800mg/L、约900mg/L、约1000mg/L、约1100mg/L、约1200mg/L、约1300mg/L、约1400mg/L、约1500mg/L、约1600mg/L、约1700mg/L、约1800mg/L、约1900mg/L、约2000mg/L、约2100mg/L、约2200mg/L、约2300mg/L、约2400mg/L、约2500mg/L、约2600mg/L、约2700mg/L、约2800mg/L、约2900mg/L、约3000mg/L、约3100mg/L、约3200mg/L、约3300mg/L、约3400mg/L、约3500mg/L、约3600mg/L、约3700mg/L、约3800mg/L、约3900mg/L、约4000mg/L、约4100mg/L、约4200mg/L、约4300mg/L、约4400mg/L、约4500mg/L、约4600mg/L、约4700mg/L、约4800mg/L、约4900mg/L和5000mg/L。例如,在支气管分泌物、上皮细胞衬液、肺部均浆和痰中能够检测该增加。
在更多的实施方案中,血清AUC或血清C最大值的减少能够为使用制剂的左氧氟沙星或氧氟沙星的肺部可利用性增加和长期暴露的标示。在某些这样的实施方案中,减少能够为至少约1%、5%、10%、20%或50%。例如,减少能够与不含二价或三价阳离子的组合物,和/或具有某些赋形剂(例如乳糖)的组合物,和/或以某种速率作为溶液或其他组合物给予肺部的组合物有关。在某些实施方案中,左氧氟沙星制剂的特征能够为AUC:MIC90大于约200、300、400、500、600、700、800、900和1000。在某些这样的实施方案中,AUC能够为肺部AUC。
在某些实施方案中,肺组织(痰、ELF、组织均浆)的浓度的特征能够为PK-PD指数C最大值:MIC90大于约20、40、60、80、100、120、140、160、180、200、220、240、260、280、300、320、340、340、360、380、400、420、440、460、480、500、520、540、560、580和600。
测量左氧氟沙星或氧氟沙星制剂的改进的可利用性的参数的增加或减少能够与不含二价或三价阳离子的左氧氟沙星或氧氟沙星制剂,不含乳糖的左氧氟沙星或氧氟沙星制剂,和/或具有较低浓度的左氧氟沙星或氧氟沙星制剂有关。
治疗或预防方法
在某些实施方案中,提供了用于治疗动物的微生物感染的方法,所述动物具体地包括哺乳动物,该方法通过用氟喹诺酮抗微生物剂来治疗患有这样的肺部感染的动物,所述抗微生物剂与二价或三价阳离子一起配制的并且具有改善的肺部可利用性。在某些实施方案中,在气雾剂形成和吸入之后,可以给予氟喹诺酮抗微生物剂。因此,该治疗方法特别适合治疗涉及微生物菌株的肺部感染,由于需要高剂量水平(其能够引起不期望的副作用),或由于缺少任何临床有效的抗微生物剂,所以使用口服递送或肠胃外递送的抗微生物剂难以治疗所述涉及微生物菌株的肺部感染。在一个这样的实施方案中,可以将该方法用于直接给予感染部位氟喹诺酮抗微生物剂。这样的方法可以减少全身暴露,并且使得微生物感染部位的抗微生物剂的量最大化。作为减少选择耐药微生物频率的方法,该方法还适合治疗与对氟喹诺酮抗微生物剂敏感的微生物有关的感染。作为增加抗微生物剂在微生物感染部位量的方法,该方法还适合治疗与以其他方式耐氟喹诺酮抗微生物剂的微生物有关的感染。通过诊断具有细菌感染特征症状的个体,可以认为该个体是被能够发展耐药性的细菌感染,所述细菌为已知带有耐药菌株的细菌种,或为已知带有耐药菌株的群的成员。另外,可以培养微生物,并且将认定其为已知具有耐药菌株的种或为已知具有耐药菌株的群成员的细菌。
在某些实施方案中,以足以克服细菌出现耐药性的水平、或足以增加杀伤效果使得耐药性不具有发展机会的水平,给予与二价或三价阳离子一起配制的氟喹诺酮抗微生物剂气雾剂。
在某些实施方案中,可以与其它气雾剂抗生素、口服抗生素或肠胃外抗生素结合或交替治疗顺序的方式作为治疗或预防给予氟喹诺酮气雾剂治疗。通过非限制性的实例,其可以包括妥布霉素和/或其它氨基糖苷类气雾剂、氨曲南和/或其它β-巴坦或单-巴坦(bactam)类气雾剂、环丙沙星和/或其它氟喹诺酮类气雾剂、阿奇霉素和/或其它大环内脂类或酯内酮类气雾剂、四环素和/或其它四环素类、奎奴普汀和/或其它链酶杀阳菌素类、利奈唑胺和/或其它噁唑烷酮类、万古霉素和/或其它糖肽类、氯霉素和/或其它苯丙醇类、以及粘杆菌素和/或其它多粘菌素类气雾剂。
此外,本文提供的组合物和方法能够包括与另外的活性剂结合或交替治疗顺序作为治疗或预防给予的氟喹诺酮气雾剂治疗。如上所述,某些这样的另外的药剂包括抗生素。更多另外的作用剂能够包括支气管扩张药、抗胆碱能药、糖皮质激素、类花生酸抑制剂及其组合。支气管扩张药的实例包括沙丁胺醇、左旋沙丁胺醇、特布他林、非诺特罗、特布他林、吡布特罗、丙卡特罗、比托特罗、利米特罗、卡布特罗、妥布特罗、瑞普特罗、沙美特罗、福莫特罗、阿福特罗、班布特罗、克伦特罗、茚达特罗、茶碱、罗氟司特、西洛司特。抗胆碱能药的实例包括异丙托溴铵和噻托溴铵。糖皮质激素的实例包括强的松、氟替卡松、布地奈德、莫米松、环索奈德和倍氯米松。类花生酸的实例包括孟鲁司特、普仑司特、扎鲁司特、齐留通、雷马曲班和塞曲司特。更多另外的作用剂能够包括百慕时(pulmozyme)、高渗盐水、恢复CF中氯通道功能的作用剂、吸入的β-兴奋剂、吸入的抗毒蕈碱剂、吸入的皮质甾类和吸入或口服的磷酸二酯酶抑制剂。更多另外的作用剂包括CFTR调节剂,例如VX-770、阿他卢仑(atluren)、VX-809。更多另外的药剂包括恢复呼吸道表面液体的药剂,例如地纽福索(denufosol)、甘露醇、GS-9411、和SPI-8811。更多另外的药剂能够包括抗炎剂,例如布洛芬、西地那非和斯伐他汀。
药物组合物
对于本文所述的方法,可使用吸入器给予具有提高的肺部可利用性的与二价或三价阳离子一起配制的氟喹诺酮抗微生物剂。在某些实施方案中,以适用于气雾剂形式的药物组合物的形式制备本文所公开的氟喹诺酮抗微生物剂,其具有良好的口感、储存稳定性和患者安全性以及耐受性。在某些实施方案中,为了耐受性、抗微生物活性和稳定性可最优化制成的氟喹诺酮的异构体含量。
制剂能够包含二价或三价阳离子。例如,该二价或三价阳离子能够包含镁、钙、锌、铜、铝和铁。在某些实施方案中,溶液包含氯化镁、硫酸镁、氯化锌或氯化铜。在某些实施方案中,二价或三价阳离子浓度能够为约25mM至约400mM、约50mM至约400mM、约100mM至约300mM、约100mM至约250mM、约125mM至约250mM、约150mM至约250mM、约175mM至约225mM、约180mM至约220mM以及约190mM至约210mM。在某些实施方案中,该浓度为约200mM。在某些实施方案中,氯化镁、硫酸镁、氯化锌或氯化铜的浓度能够为约5%至约25%、约10%至约20%以及约15%至约20%。在某些实施方案中,氟喹诺酮与二价或三价阳离子的比可以为1:1至2:1或1:1至1:2。
如本文所述使用的非限制性的氟喹诺酮包括左氧氟沙星、氧氟沙星、环丙沙星、依诺沙星、加替沙星、吉米沙星、洛美沙星、莫西沙星、诺氟沙星、培氟沙星、司帕沙星、加雷沙星、西他沙星和DX-619。
制剂能够具有的诸如左氧氟沙星或氧氟沙星的氟喹诺酮浓度大于约50mg/ml、约60mg/ml、约70mg/ml、约80mg/ml、约90mg/ml、约100mg/ml、约110mg/ml、约120mg/ml、约130mg/ml、约140mg/ml、约150mg/ml、约160mg/ml、约170mg/ml、约180mg/ml、约190mg/ml和约200mg/ml。在某些实施方案中,制剂能够具有的诸如左氧氟沙星或氧氟沙星的氟喹诺酮浓度为约50mg/ml至约200mg/ml、约75mg/ml至约150mg/ml、约80mg/ml至约125mg/ml、约80mg/ml至约120mg/ml、约90mg/ml至约125mg/ml、约90mg/ml至约120mg/ml和约90mg/ml至约110mg/ml。在某些实施方案中,该浓度为约100mg/ml。
制剂的重量摩尔渗透压浓度能够为约300mOsmol/kg至约500mOsmol/kg、约325mOsmol/kg至约450mOsmol/kg、约350mOsmol/kg至约425mOsmol/kg和约350mOsmol/kg至约400mOsmol/kg。在某些实施方案中,制剂的重量摩尔渗透压浓度大于约300mOsmol/kg、约325mOsmol/kg、约350mOsmol/kg、约375mOsmol/kg、约400mOsmol/kg、约425mOsmol/kg、约450mOsmol/kg、约475mOsmol/kg和约500mOsmol/kg。
制剂的pH能够为约4.5至约8.5、约5.0至约8.0、约5.0至约7.0、约5.0至约6.5、约5.5至约6.5和约6.0至约6.5。
所述制剂能够包含常规的药物载体、赋形剂等(例如甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、交联羧甲基纤维素钠、葡萄糖、明胶、蔗糖、碳酸镁等),或诸如湿润剂、乳化剂、加溶剂、pH缓冲剂等(例如醋酸钠、柠檬酸钠、环糊精衍生物、脱水山梨糖醇单月桂酸酯、三乙醇胺醋酸酯、三乙醇胺油酸酯等)的辅助物质。在某些实施方案中,所述制剂能够缺少常规药物载体、赋形剂等。某些实施方案包括不含乳糖的制剂。某些实施方案包含浓度小于约10%、5%、1%或0.1%的乳糖。在某些实施方案中,所述制剂基本上包含左氧氟沙星或氧氟沙星以及二价或三价阳离子。
在某些实施方案中,制剂能够包含浓度为约75mg/ml至约150mg/ml的左氧氟沙星、浓度为约150mM至约250mM的氯化镁、约5至约7的pH;约300mOsmol/kg至约600mOsmol/kg的重量摩尔渗透压浓度,并且不含乳糖。
在某些实施方案中,制剂包含浓度为约100mg/ml的左氧氟沙星、浓度为约200mM的氯化镁、约6.2的pH、约383mOsmol/kg的重量摩尔渗透压浓度,并且不含乳糖。在某些实施方案中,制剂基本上由浓度为约90mg/ml至约110mg/ml的左氧氟沙星、浓度为约180mM至约220mM的氯化镁、约5至约7的pH、约300mOsmol/kg至500mOsmol/kg的重量摩尔渗透压浓度组成,并且不含乳糖。
给药
以治疗有效剂量给予与二价或三价阳离子一起配制的并具有提高的肺部可利用性的氟喹诺酮抗微生物剂,所述剂量例如足以给前面描述的疾病状态提供治疗的剂量。当然,给予的活性化合物的量依赖治疗的个体和疾病状态、患病的严重性、给药的方式和安排以及处方医师的判断;例如,对于左氧氟沙星的气雾剂给予的可能剂量范围为每天约20mg至300mg,分别用于较长或较短的肺部半衰期的所选择的活性剂。在某些实施方案中,对于左氧氟沙星的气雾剂给予的可能剂量范围为约20mg至300mgBID(每日两次)。
能通过为相似用途服务的任何可接受的给予药剂的方式给予本文公开的氟喹诺酮抗微生物剂或其药物可接受的盐,所述方式包括但不限于气雾剂吸入。以其整体以引用的形式并入的第2006-0276483号美国专利申请公开描述了递送的方法、设备和组合物。
药物可接受的组合物包括固体、半固体、液体和气雾剂型,例如散剂、液体剂、悬浮剂、络合剂、脂质体、颗粒剂等。优选地,以适用于精确剂量的单一给药的单位剂型提供所述组合物。
能单独地或以某些替换物的形式,与常规的药物载体、赋形剂等(例如甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、交联羧甲基纤维素钠、葡萄糖、明胶、蔗糖、碳酸镁等)结合给予氟喹诺酮抗微生物剂。必要时,药物组合物还能包含少量的无毒辅助物质,例如湿润剂、乳化剂、加溶剂、pH缓冲剂等(例如醋酸钠、柠檬酸钠、环糊精衍生物、脱水山梨糖醇单月桂酸酯、三乙醇胺醋酸酯、三乙醇胺油酸酯等)。通常,取决于预期的给药方式,以重量计,药物制剂包含约0.005%至95%,优选地为约0.5%至50%的本发明的化合物。制备这样的剂型的实际方法对本领域技术人员来说为已知的或显而易见的,例如,参见Remington'sPharmaceuticalSciences(雷氏药学大全),MackPublishingCompany,Easton,Pennsylvania。
在一个优选的实施方案中,所述组合物采取单位剂型的形式,例如包含液体、悬浮的固体、干燥的粉末、lyophilate或其它组合物的瓶,并由此所述组合物可包含活性成分以及诸如乳糖、蔗糖、磷酸二钙等的稀释剂;诸如硬脂酸镁等的润滑剂以及诸如淀粉、阿拉伯树胶、聚乙烯吡咯烷、明胶、纤维素、纤维素衍生物等的粘合剂。
能通过例如将如上所定义的活性化合物以及任选的药物佐剂溶解、分散等在载体(例如水、盐水、水性右旋糖、丙三醇、乙二醇、乙醇等)中以形成溶液或悬浮液来制备液态药物可给予的组合物。在气雾剂产生和吸入之前,能以液体溶液或悬浮液、乳剂或适用于溶解或悬浮在液体中的固体形式的常规形式制备待气雾化的溶液。包含在这样的气雾剂组合物中的活性化合物的百分比高度依赖其特性以及所述化合物的活性和个体的需要。然而,溶液中活性成分的百分比为0.01%至90%为适合使用的,且如果所述组合物为固体时所述百分比将更高,随后将其稀释至上述百分比。在某些实施方案中,在溶液中,组合物包含1.0%至50.0%的活性剂。
能以每日约1、2、3、4或更多次,每周1、2、3、4、5、6、7或更多次,每月1、2、3、4、5、6、7、8、9、10或更多次的频率给予本文所述的组合物。在特定的实施方案中,每日给予两次所述组合物。
气雾剂递送
对于肺部给药,避免上呼吸道,而对中和下呼吸道给药。可通过经口和喉吸入气雾剂来完成肺部药物递送。通常,质量中质空气流动力学直径(MMAD)大于约5微米的颗粒不能达到肺;反而,它们倾向于压迫喉的后部并被吞下且能口服吸收。直径为约2至约5微米的颗粒足够小以能达到上肺区域至中肺区域(传导性气道),但太大而不能到达肺泡。更小的颗粒,即约0.5至约2微米的颗粒能到达肺泡区域。尽管非常小的颗粒可被呼出,但是直径小于约0.5微米的颗粒还能通过沉降沉积在肺泡区域。
在一个实施方案中,基于进行本文公开的MMAD主要为约2至约5微米的氟喹诺酮抗微生物剂气雾剂的形成来选择喷雾器。在一个实施方案中,氟喹诺酮抗微生物剂的递送量为呼吸感染提供治疗效果。喷雾器能递送包含质量中质空气流动力学直径为约2微米至约5微米且几何标准差小于或等于约2.5微米、质量中质空气流动力学直径为约2.5微米至约4.5微米且几何标准差小于或等于约1.8微米以及质量中质空气流动力学直径为约2.8微米至约4.3微米且几何标准差小于或等于约2微米的气雾剂。在某些实施方案中,能使用振动网式喷雾器(vibratingmeshnebulizer)制备气雾剂。振动网式喷雾器的实例包括PARI喷雾器或使用PARIeFlow技术的喷雾器。在第4,268,460号;第4,253,468号;第4,046,146号;第3,826,255号;第4,649,911号;第4,510,929号;第4,624,251号;第5,164,740号;第5,586,550号;第5,758,637号;第6,644,304号;第6,338,443号;第5,906,202号;第5,934,272号;第5,960,792号;第5,971,951号;第6,070,575号;第6,192,876号;第6,230,706号;第6,349,719号;第6,367,470号;第6,543,442号;第6,584,971号;第6,601,581号;第4,263,907号;第5,709,202号;第5,823,179号;第6,192,876号;第6,644,304号;第5,549,102号;第6,083,922号;第6,161,536号;第6,264,922号;第6,557,549号;和第6,612,303号美国专利中提供了更多的喷雾器实例,所有专利均以其整体以引用的形式并入本文。能和本文所述的制剂一起使用的喷雾器的更多商业实例包括由Aerogen生产的RespirgardPro和Go;由Aradigm生产的和AERxEssenceTM;由Respironics,Inc.生产的FreewayFreedomTM、Sidestream、Ventstream和I-neb;以及由PARI,GmbH生产的PARIPARI另外的非限制性实例,第6,196,219号美国专利以其整体以引用的形式并入本文。
能够用气雾剂剂量给予肺的左氧氟沙星或氧氟沙星的量能够包括至少约20mg、约30mg、约40mg、约50mg、约60mg、约70mg、约80mg、约90mg、约100mg、约110mg、约120mg、约125mg、约130mg、约140mg、约150mg、约160mg、约170mg、约180mg、约190mg、约200mg、约210mg、约220mg、约230mg、约240mg、约250mg、约260mg、约270mg、约280mg、约290mg、约300mg、约310mg、约320mg、约330mg、约340mg、约350mg、约460mg、约470mg、约480mg、约490mg、约500mg、约510mg、约520mg、约530mg、约540mg、约550mg、约560mg、约570mg、约580mg、约590mg、约600mg、约610mg、约620mg、约630mg、约640mg、约650mg、约660mg、约670mg、约680mg、约690mg、约700mg、约710mg、约720mg、约730mg、约740mg、约750mg、约760mg、约770mg、约780mg、约790mg和约800mg,所述气雾剂剂量例如可呼吸药物剂量(RDD)。在某些实施方案中,能够用气雾剂剂量给予肺的左氧氟沙星或氧氟沙星的量能够包括至少约20mg、50mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg、1050mg、1100mg、1150mg、1200mg、1250mg、1300mg、1350mg、1400mg、1450mg和1500mg,所述气雾剂剂量例如可呼吸药物剂量(RDD)。
能够以小于约10分钟、约5分钟、约4分钟、约3分钟、约2分钟和约1分钟的方式向肺部给予气雾剂。
适应症
本文所述方法和组合物能够用于治疗肺部感染和病症。这样的病症的实例能够包括囊性纤维化、肺炎和慢性阻塞性肺病,其包括慢性气支管炎和某些哮喘。某些实施方案包括治疗包含一种或多种细菌的感染,所述细菌选自绿脓假单胞菌(Pseudomonasaeruginosa)、荧光假单胞菌(Pseudomonasfluorescens)、食酸假单胞菌(Pseudomonasacidovorans)、产碱假单胞菌(Pseudomonasalcaligenes)、恶臭假单胞菌(Pseudomonasputida)、嗜麦芽寡养单胞菌(Stenotrophomonasmaltophilia)、嗜水气单胞菌(Aeromonashydrophilia)、大肠杆菌(Escherichiacoli)、弗氏柠檬酸杆菌(Citrobacterfreundii)、鼠伤寒沙门氏菌(Salmonellatyphimurium)、伤寒沙门氏菌(Salmonellatyphi)、副伤寒沙门氏菌(Salmonellaparatyphi)、肠炎沙门氏菌(Salmonellaenteritidis)、痢疾志贺菌(Shigelladysenteriae)、弗氏志贺菌(Shigellaflexneri)、索氏志贺菌(Shigellasonnei)、阴沟肠杆菌(Enterobactercloacae)、产气肠杆菌(Enterobacteraerogenes)、肺炎克雷伯氏菌(Klebsiellapneumoniae)、产酸克雷伯氏菌(Klebsiellaoxytoca)、粘质沙雷氏菌(Serratiamarcescens)、摩氏摩根菌(Morganellamorganii)、奇异变形杆菌(Proteusmirabilis)、普通变形杆菌(Proteusvulgaris)、产碱普罗威登斯菌(Providenciaalcalifaciens)、雷氏普罗威登斯菌(Providenciarettgeri)、斯氏普罗威登斯菌(Providenciastuartii)、乙酸钙不动杆菌(Acinetobactercalcoaceticus)、溶血不动杆菌(Acinetobacterhaemolyticus)、小肠结肠炎耶尔森菌(Yersiniaenterocolitica)、鼠疫耶尔森菌(Yersiniapestis)、假结核耶尔森菌(Yersiniapseudotuberculosis)、中间耶尔森菌(Yersiniaintermedia)、百日咳博德特氏菌(Bordetellapertussis)、副百日咳博德特氏菌(Bordetellaparapertussis)、支气管败血性博德特氏菌(Bordetellabronchiseptica)、流感嗜血杆菌(Haemophilusinfluenzae)、副流感嗜血杆菌(Haemophilusparainfluenzae)、溶血性嗜血杆菌(Haemophilushaemolyticus)、副溶血性嗜血杆菌(Haemophilusparahaemolyticus)、杜克雷氏嗜血杆菌(Haemophilusducreyi)、多杀性巴氏杆菌(Pasteurellamultocida)、溶血性巴氏杆菌(Pasteurellahaemolytica)、幽门螺杆菌(Helicobacterpylori)、胎儿弯曲杆菌(Campylobacterfetus)、空肠弯曲杆菌(Campylobacterjejuni)、大肠弯曲杆菌(Campylobactercoli)、伯氏疏螺旋菌(Borreliaburgdorferi)、霍乱弧菌(Vibriocholera)、副溶血性弧菌(Vibrioparahaemolyticus)、嗜肺性军团杆菌(Legionellapneumophila)、单核细胞增多性李斯特氏菌(Listeriamonocytogenes)、淋病奈瑟氏菌(Neisseriagonorrhoeae)、脑膜炎奈瑟氏菌(Neisseriameningitidis)、洋葱伯克霍尔德氏菌(Burkholderiacepacia)、土拉弗朗西斯氏菌(Francisellatularensis)、金氏菌属(Kingella)和莫拉氏菌属(Moraxella)。在某些实施方案中,由革兰氏阴性厌氧菌引起肺部感染。在某些实施方案中,肺部感染包含一种或多种细菌,所述细菌选自脆弱拟杆菌(Bacteroidesfragilis)、吉氏拟杆菌(Bacteroidesdistasonis)、拟杆菌属(Bacteroides)3452A同族群、普通拟杆菌(Bacteroidesvulgatus)、卵形拟杆菌(Bacteroidesovalus)、多形拟杆菌(Bacteroidesthetaiotaomicron)、单形拟杆菌(Bacteroidesuniformis)、埃氏拟杆菌(Bacteroideseggerthii)和内脏拟杆菌(Bacteroidessplanchnicus)。在某些实施方案中,由革兰氏阳性菌引起肺部感染。在某些实施方案中,肺部感染包含一种或多种细菌,所述细菌选白喉棒状杆菌(Corynebacteriumdiphtheriae)、溃疡棒状杆菌(Corynebacteriumulcerans)、肺炎链球菌(Streptococcuspneumoniae)、无乳链球菌(Streptococcusagalactiae)、化脓性链球菌(Streptococcuspyogenes)、米勒氏链球菌(Streptococcusmilleri);链球菌属(G群)(Streptococcus(GroupG));链球菌属(C/F群)(Streptococcus(GroupC/F));粪肠球菌(Enterococcusfaecalis)、屎肠球菌(Enterococcusfaecium)、金黄色葡萄球菌(Staphylococcusaureus)、表皮葡萄球菌(Staphylococcusepidermidis)、腐生性葡萄球菌(Staphylococcussaprophyticus)、中间葡萄球菌(Staphylococcusintermedius)、猪葡萄球菌猪亚种(Staphylococcushyicussubsp.hyicus)、溶血性葡萄球菌(Staphylococcushaemolyticus)、人葡萄球菌(Staphylococcushominis)和解糖葡萄球菌(Staphylococcussaccharolyticus)。在某些实施方案中,由革兰氏阳性厌氧菌引起肺部感染。在某些实施方案中,由一种或多种细菌引起肺部感染,所述细菌选自难辨梭状芽孢杆菌(Clostridiumdifficile)、产气荚膜梭状芽孢杆菌(Clostridiumperfringens)、破伤风梭状芽孢杆菌(Clostridiumtetini)和肉毒梭状芽孢杆菌(Clostridiumbotulinum)。在某些实施方案中,由耐酸细菌引起肺部感染。在某些实施方案中,由一种或多种细菌引起肺部感染,所述细菌选自结核分枝杆菌(Mycobacteriumtuberculosis)、鸟分枝杆菌(Mycobacteriumavium)、胞内分枝杆菌(Mycobacteriumintracellulare)和麻风分枝杆菌(Mycobacteriumleprae)。在某些实施方案中,由非典型细菌引起肺部感染。在某些实施方案中,由一种或多种细菌引起肺部感染,所述细菌选自肺炎衣原体(Chlamydiapneumoniae)和肺炎枝原体(Mycoplasmapneumoniae)。
实施例
比较例1-氟喹诺酮在大鼠药物动力学模型中的给药
该实施例涉及氟喹诺酮盐溶液的气雾剂给药和静脉内给药。将大鼠药物动力学模型用于比较氟喹诺酮的静脉内给药和肺部给药。给予雄性Sprague-Dawley大鼠(CharlesRivers)10mg/kg剂量的左氧氟沙星、环丙沙星、加替沙星、诺氟沙星或吉米沙星。使用微喷气雾剂装置(PennCentury,Philadelphia,PA)通过侧尾静脉给予药剂,或对正位于气管分叉之上的肺部给予药剂。在0.9%无菌盐水中配制左氧氟沙星,使其浓度为5mg/ml(IV)和60mg/ml(气雾剂)。
在各个时间点,通过留置颈静脉插管从2-6只大鼠中采集约0.3ml血液样品,并将其收集在肝素锂管中。在安乐死之后,收集支气管肺泡灌洗液(BAL)和肺组织。使用HPLC检验来测定血浆、肺组织和BAL中的左氧氟沙星浓度,并且使用WinNonlin(PharsightCorporation,v5.0)分析该数据。对照标准曲线确定样品浓度。
测定血清AUC(0-无穷)(从时间零点至无穷大的浓度时间曲线下面积)、血清MRT(平均保留时间)、血清t1/2(半衰期)、BALAUC、MAT(平均吸收时间)和F(生物利用度),并且在表1中显示。
表1
与静脉内给药相比,环丙沙星、加替沙星、诺氟沙星或吉米沙星的气雾剂给药导致BALAUC显著增加。与静脉内给药相比,左氧氟沙星的气雾剂给药没有表现出BALAUC的这样的显著增加。另外,左氧氟沙星表现出从肺部至血清的快速吸收。因此,左氧氟沙星盐溶液的气雾剂给药没有导致药物到肺的可利用性显著增加。
比较例2-具有二价阳离子的左氧氟沙星在大鼠中的气雾剂给药
该实施例涉及一系列研究,其包括具有二价阳离子和乳糖的左氧氟沙星的气雾剂给药,以及左氧氟沙星盐溶液的IV或气雾剂给药。给予大鼠10mg/kg左氧氟沙星(LVX)盐溶液或与CaCl2、MgCl2或Zn+2一起配制的LVX。表2表示用于这些研究的左氧氟沙星制剂。
表2
在一项研究中,测量包括C最大值(最大血清浓度)、CL/F(体内总清除率/生物利用度)的药物动力学参数,并在表3中显示。图1显示左氧氟沙星血浆浓度与时间的图表,其中通过气雾剂、静脉注射或具有MgCl2的气雾剂来给予左氧氟沙星。
表3
可以使用两房室药物动力学模型来描述静脉内给药和气雾剂给药的血浆左氧氟沙星时间曲线的区别。静脉内给药后的血浆AUC与通过具有Mg+2的气雾剂给药后的血浆AUC相似(分别为3.79hr.mg/L与3.72hr.mg/L)。这表明来自肺的二价络合抗生素的生物利用度接近100%。气雾剂给药后的左氧氟沙星的平均保留时间(MRT)比静脉内给药后的平均保留时间更长(0.88小时与0.70小时)。该吸收延迟与BAL中的BAL左氧氟沙星AUC(0-6h)的增加(静脉内给药与气雾剂给药分别为1.6hr.mg/L与8.3hr.mg/L),和平均吸收时间(MAT)的18倍增加有关。
在另一研究中,测量气雾剂给予包含盐水、Zn2+、Ca+2或Mg+2的制剂后的左氧氟沙星水平,并且测定药物动力学参数。表4和图2概述了该结果。
表4
与在盐水中配制的左氧氟沙星相比,与Ca+2和Mg+2络合的左氧氟沙星的气雾剂给药引起更长的血浆半衰期和更长的MAT,这表明较慢的肺到血浆的清除率(表4)。与静脉内左氧氟沙星或在盐水中配制的气雾化的左氧氟沙星相比,与Ca+2或Mg+2一起配制的左氧氟沙星产生2倍至5倍高的BAL和肺部组织的左氧氟沙星C最大值和AUC(表4,图2)。这些数据表明与二价阳离子络合的气雾剂左氧氟沙星在治疗肺部感染中将产生更高效力。
实施例3-药物动力学建模和反卷积分析
该实施例涉及建模肺部的药物浓度。将药物动力学反卷积方法用于测定给药之后肺部的残留药物量。在难于直接测量和/或直接测量产生多种结果的情况下,这样的方法特别有用,例如使用痰样品测量肺部的药物浓度。
使用非房室方法或房室方法能够测定血清和尿样的药物动力学参数,并且使用反卷积能够计算随时间推移的肺部药物浓度。该方法已经被报导用于妥布霉素的气雾剂递送,其中5.6mg/kg剂量表示约9%的生物利用度和3小时内的吸收,这与经验得出的数据一致(CooneyG.F.等人,“Absolutebioavailabilityandabsorptioncharacteristicsofaerosolizedtobramycininadultswithcysticfibrosis”(患有囊性纤维化的成人的气雾化的妥布霉素的绝对生物利用度和吸收特性),J.ClinicalPharmacol.(1994),34,255-259,其整体以引用的方式并入本文)。
在图3中概述了反卷积方法的实例。该分析比较了气雾剂给药和静脉内给药之后的药物表现与药物排除,从而确定随着时间推移残留在肺部(吸收房室)的药物量。为了估计肺部的药物浓度,将该量除以每个个体的肺上皮细胞衬液(ELF)(epitheliallungfluid)体积(25ml)的估计值。然后,将非房室药物动力学分析应用于这些预期的肺部药物浓度以确定AUCs。
能够通过以喷雾器或其它呼吸递送装置递送的可呼吸药物剂量为50mg的左氧氟沙星盐溶液或与Mg+2络合的左氧氟沙星的人类或动物气雾剂给药完成反卷积方法的应用,由此产生的血浆药物浓度分布曲线和计算的药物动力学参数如图4和表5及表6所示。在对单一健康志愿者进行5分钟的IV注射左氧氟沙星之后,使用WinNonlin和如表5所列的药物动力学参数来分析血清左氧氟沙星浓度。在不同的时刻,该志愿者通过PARIeFlow震动网式喷雾器接受单独的左氧氟沙星气雾剂给药(RDD=50mg)。图4显示在IV给药或气雾剂给药之后的血清左氧氟沙星浓度对比。使用图3描述的PK模型,在气雾剂给药之后使用左氧氟沙星IV给药的血清PK数据(表5显示的PK参数)反卷积血清中测量的左氧氟沙星血清浓度。结果如表6所示,其表示随时间推移肺部残留的左氧氟沙星的估计量(以mg为单位)。
表5
参数 | 单位 | 估计值 |
AUC | hr.mg/L | 3.14 |
K10_HL | hr | 0.92 |
α | 1/hr | 6.85 |
β | 1/hr | 0.11 |
α_HL | hr | 0.10 |
β_HL | hr | 6.50 |
A | mg/L | 2.05 |
B | mg/L | 0.30 |
C最大值 | mg/L | 1.88 |
CL | L/hr | 15.93 |
AUMC | hr.hr.mg/L | 26.78 |
MRT | hr | 8.49 |
Vss | L | 135.29 |
V2 | L | 114.03 |
CLD2 | L/hr | 111.26 |
表6
能够将这些数据用于计算作为时间函数的肺部残留的左氧氟沙星量(以mg为单位)。图5和表6显示随时间推移肺部残留的药物估计量的实例,但是在1.2小时之后,5分钟内给予的50mg可呼吸药物剂量仅有10%残留在肺部。该实验证明反卷积方法的效用。
比较例4-具有盐水的左氧氟沙星的气雾剂给药和全身给药
该实施例涉及在盐水溶液中使用估计可呼吸药物剂量为20mg或40mg的左氧氟沙星(喷雾器载荷剂量分别为43.3mg和86.6mg)配制的左氧氟沙星的气雾剂给药和全身给药。使用PARIeFlow高效喷雾器,给予正常的健康志愿者和稳定的CF个体两种剂量水平左氧氟沙星的单独气雾剂剂量(使用IV制剂)。
在每次给药之后,收集安全性、耐受性和药物动力学数据(血清、痰以及尿排泄物)。用3.6ml的在盐水中稀释至等渗的溶液载荷喷雾器,对于20mg可呼吸药物剂量组,浓度为11.9mg/ml,并且对于40mg可呼吸药物剂量组,浓度为23.8mg/ml。对于20mgRDD和40mgRDD,这些体积分别相当于43.3mg和86.6mg左氧氟沙星的“载荷”剂量。表7概述了盐水中配制的左氧氟沙星的喷雾器载荷剂量与相应的估计的RDD。
表7
共同给予(AstraZeneca)以最小化在吸入期间吞咽的任何左氧氟沙星的口服吸收。每个个体在初诊接受左氧氟沙星的静脉给药和气雾剂盐溶液给药,以产生用于与气雾剂左氧氟沙星给药相比的药物动力学数据,并使用eFlow装置来估计递送溶液的耐受性。
使用Anapharm(QuebecCity,加拿大)的认证的HPLC检验来分析血清和尿的左氧氟沙星浓度。发展痰左氧氟沙星检验,并且使用血清检验来交叉验证。
血清数据:静脉注入之后的血清左氧氟沙星浓度适合使用迭代重加权最小二乘回归(WinNonlin)的二房室开放性药物动力学模型。对观察的1/y权重进行回归。通过最小化目标函数和检验加权残差图来评估拟合优度。使用反卷积法来分析由气雾剂给药产生的血清左氧氟沙星浓度,从而估计气雾剂给药在肺部的滞留时间(GibaldiM.andPerrierD.“Pharmacokinetics”(药物动力学),第二版.MarcelDekker:NewYork,1982,其整体以引用的方式并入本文)。在实施例3中描述了药物动力学模型和用于反卷积分析的方法。简单地说,该分析对比了气雾剂给药和静脉给药之后的药物表现和排除,以确定随时间推移残留在肺(吸收房室)中的药物量。为了估计肺部的药物浓度,将该量除以每个个体的肺上皮细胞衬液(ELF)体积(25ml)的估计值。随后,将非房室药物动力学分析应用于这些预期的肺部药物浓度以确定AUC值。
痰数据:使用非房室药物动力学方法(GibaldiM.和PerrierD.“Pharmacokinetics”(药物动力学),第二版.MarcelDekker:NewYork,1982,其整体以引用的方式并入本文)来分析痰浓度数据。使用线性梯形法则来估计痰浓度与时间曲线下面积。由于仅从0.5小时至8小时来收集痰,进行从末期阶段和初始阶段的向前或向后地推算,从而生成二次药物动力学参数的估计值(C最大值、AUC)。
从血清左氧氟沙星浓度数据的反卷积中估计用于肺部暴露产生的诸如AUC:MIC和C最大值:MIC的PK-PD参数。在CF个体中每天给予两次估计可呼吸剂量为20mg至120mg的左氧氟沙星,在左氧氟沙星对绿脓假单胞菌(P.aeruginosa)的MIC的不同值计算参数的实例。测量源自CF分离株的临床分离株的左氧氟沙星MIC分布(MIC50、MIC90和MIC模式)(TraczewskiMM和BrownSD.,“InVitroactivityofdoripenemagainstP.aeruginosaandBurkholderiacepaciaisolatesfrombothcysticfibrosisandnon-cysticfibrosispatients”(多利培南抗从囊性纤维化患者和非囊性纤维化患者二者中分离的抗绿脓假单胞菌(P.aeruginosa)和洋葱伯克霍尔德氏菌(Burkholderiacepacia)的体外活性).AntimicrobAgentsChemother2006;50:819-21,其整体以引用的方式并入本文)。
剂量概要:在研究中,招募了一共7个普通健康志愿者(NHV)和9个患有CF的个体。所有的个体完成了治疗的所有阶段;在表8中提供了剂量概要。9个囊性纤维化个体中的7个接受了20mg和40mg的可呼吸药物剂量水平,而再给予2个个体用沙丁胺醇预处理的20mg剂量水平。1秒钟内的用力呼气量(FEV1)。
表8
血清中左氧氟沙星药物动力学:图6显示IV给药和气雾剂给药之后的普通个体和CF个体的平均血清左氧氟沙星浓度。在NHV个体和CF个体中的总左氧氟沙星的清除率分别为17.2L/h和14.1L/h。气雾剂给药之后的血清左氧氟沙星浓度通常与用静脉内给药观察的那些血清左氧氟沙星浓度相当,特别在1小时后-给药之后。使用模型-独立分析对比IV给药或气雾剂给药的左氧氟沙星AUC,该对比表明对于普通志愿者,与50mgIV给药相比,气雾剂给药的低气雾剂剂量和高气雾剂剂量的左氧氟沙星暴露分别为(平均值+/-SD)35.6%+/-9.4%和59.4%+/-16.6%,对于CF个体,其分别为27.9%+/-3.3%和51.1%+/-11.2%。
血清反卷积分析:在所有个体中,成功地反卷积气雾剂给药后的血清左氧氟沙星浓度,允许估计随时间推移吸收(肺)房室的药物量(图7)。从肺至血清的吸收在CF个体中的发生显著慢于健康普通志愿者;在给药后的至少0.5小时,50%的肺部剂量明显残留在肺部。使用25ml肺上皮细胞衬液(ELF)体积估计的文献值,在图8A和图8B中显示单独气雾剂给药后CF患者的ELF中的左氧氟沙星的估计浓度(Rennard,S,G.等人,“Estimationofvolumeofepithelialliningfluidrecoveredbylavageusingureaasamarkerofdilution”(使用作为稀释标记的脲估计通过灌洗回收的上皮细胞衬液体积).J.Appl.Physio.60:532-8,其整体以引用的方式并入本文)。在低量给药和高量给药结束时,CF患者的ELF中的平均预期C最大值浓度分别超过500μg/ml和1000μg/ml。当随时间推移结合时,对于健康个体的低量给药和高量给药,肺液的预期的平均+/-SD左氧氟沙星AUC为365+/-338和710+/-471,对于CF患者的低量给药和高量给药,该值为354+/-274和1199+/-1147。
痰的左氧氟沙星药物动力学:图9显示CF个体的低量气雾剂给药和高量气雾剂给药之后的痰的左氧氟沙星浓度。对于至少1小时的使用左氧氟沙星气雾剂的后给药,在两种气雾剂给药水平后的痰左氧氟沙星浓度明显高于使用50mgIV给药获得的那些。浓度趋于在给药的第一个2小时期间快速下降,这与从肺部的药物吸收一致。痰左氧氟沙星浓度在患者中和患者间可变,但是在观察期内,通常86.6mg的载荷剂量不提供更高的浓度。
求气雾剂给药后源自CF个体的痰的左氧氟沙星浓度的平均值,并且将其与通过其它途径给药获得的浓度比较。图10描述了两种气雾剂剂量水平,在5分钟内对相同个体注入的50mgIV剂量,以及750mg的口服剂量(本文未描述的另外的研究)的CF个体的建模痰浓度;表9显示测量的痰左氧氟沙星浓度的C最大值、AUC和半衰期值。
表9
参数 | 50mg IV | 20mg气雾剂 | 40mg气雾剂 | 750mg口服 |
C最大值(mg/L) | 0.8 | 86.2 | 211.5 | 8.7 |
AUC(hr.mg/L) | 2.5 | 67.1 | 171.4 | 93.4 |
T1/2(h) | 3.8 | 0.9 | 1.3 | 6.7 |
尽管750mg口服左氧氟沙星剂量导致持续时间更长的痰的药物浓度,但低至20mg的气雾剂剂量产生10倍以上的峰值浓度。
图6显示给予普通健康志愿者和CF患者单独的RDD为20mg或40mg的盐水中制备的左氧氟沙星和IV剂量的左氧氟沙星制剂(Levaquin)之后的血清左氧氟沙星浓度。将这些数据用于进行上述的药物动力学反卷积。图7表示反卷积的结果,该结果显示随时间推移残留在肺中的左氧氟沙星估计量。与普通健康志愿者相比,CF患者的左氧氟沙星残留在肺部的时间更长(图7)。明显地,在痰中观察到的左氧氟沙星浓度与反卷积分析中预期的ELF浓度一致(图8A和图8B对比图9和表9)。
PK-PD分析:药物动力学与绿脓假单胞菌(P.aeruginosa)敏感性数据的结合允许评估期望的体内药效作用。氟喹诺酮的PK-PD参数包括24小时AUC:MIC和C最大值:MIC的比。非常高的C最大值:MIC比对快速微生物杀伤和耐药性抑制是重要的。
能够将来自每天两次给予左氧氟沙星以及绿脓假单胞菌(P.aeruginosa)的MIC数据的反卷积分析的PK-PD分析与模拟的ELFPK数据的结果(由肺部左氧氟沙星的量除以ELF体积产生)用于计算绿脓假单胞菌(P.aeruginosa)的左氧氟沙星PK-PD指数。表10表示左氧氟沙星的特定给药方案的预测的PK-PD指数(C最大值:MIC;24小时AUC:MIC)。
表10
例如,每天的剂量为20mgBID左氧氟沙星、C最大值:MIC=248;24小时AUC:MIC=350;以及左氧氟沙星MIC=2mg/L。该模拟表明对于超过90%的绿脓假单胞菌(P.aeruginosa)CF隔离株,通过所有方案将得到C最大值:MIC>20的主要靶值。另外,在较低剂量下,对于大多数菌株将获得24小时AUC:MIC>300的次要PK-PD靶值,但是在即将进行的临床研究中评估的预期较高剂量下,还可以覆盖超过90%的隔离株。
比较例5-30mg/ml和50mg/ml的与MgCl
2
一起配制的左氧氟沙星溶
液的气雾剂给药
该实施例涉及30mg/ml和50mg/ml的与MgCl2一起配制的左氧氟沙星溶液对CF患者的气雾剂给药。表11表示具有MgCl2和乳糖的左氧氟沙星制剂。
表11
30mg/ml | 50mg/ml | |
左氧氟沙星,mg/ml(mM) | 30(81.6) | 50(136) |
镁,mg/ml(mM) | 1.5(60) | 2.4(100) |
氯,mg/ml(mM) | 4.3(120) | 7.1(200) |
乳糖,mg/ml(mM) | 51.4(150) | 51.4(150) |
pH值 | 6.3 | 6.3 |
重量摩尔渗透压浓度,mOsmol/kg | 314 | 400 |
使用eFlow高效喷雾器(PARIPharma,Munich,德国),8个稳定的CF患者接受载荷量为78mg、175mg和260mg(分别相当于RDD40mg、80mg和120mg)的与MgCl2一起配制的左氧氟沙星。相隔1周给予升高的剂量。连续4周,每隔一周给予7个CF患者的单独组单独剂量为750mg的口服左氧氟沙星。通过HPLC分析血清样品和痰样品的左氧氟沙星。使用非房室药物动力学方法来分析血清左氧氟沙星浓度和痰左氧氟沙星浓度数据。表12显示平均药物动力学参数。
表12
PK-PD数据此前显示对于氟喹诺酮,C最大值:MIC比为与最佳微生物杀伤和防止耐药性相关的PK-PD参数。具有MgCl2的左氧氟沙星的气雾剂给药提供了达到绿脓假单胞菌(P.aeruginosa)的C最大值:MIC比>40的痰浓度。相反,750mg的口服左氧氟沙星剂量产生了1.1的比。这些数据表明具有MgCl2的左氧氟沙星的气雾剂给药提供了在痰中的高度暴露,该暴露大于使用口服左氧氟沙星可达到的那些。
比较例6-40mgRDD的在盐水或MgCl
2
中配制的左氧氟沙星在CF患
者中的气雾剂给药的比较
该实施例涉及使用40mg左氧氟沙星的估计可呼吸药物剂量(RDD)的具有MgCl2的左氧氟沙星或左氧氟沙星盐溶液的气雾剂给药。左氧氟沙星盐溶液的浓度为23.8mg/ml,并且在含MgCl2/乳糖的制剂中左氧氟沙星的浓度为30mg/ml(参见表11)。CF患者通过气雾剂递送接受40mg可呼吸药物剂量的左氧氟沙星:7个患者接受盐水中配制的左氧氟沙星;10个患者接受相同估计RDD的与MgCl2一起配制的左氧氟沙星。多次采取痰试样直至24小时,并且使用HPLC/荧光法来测定左氧氟沙星浓度。图11显示随着时间推移在痰中测量的平均左氧氟沙星浓度。相对于相同剂量的在盐水中递送的左氧氟沙星,使用MgCl2递送的左氧氟沙星在痰中保持更长时间和更高浓度。
此外,对于左氧氟沙星盐溶液的气雾剂给药,在CF痰中的PK参数的对比(实施例4-表8)表明通过与镁络合从而实现明显更高的痰C最 大值和AUC(例如,对于40mg可呼吸剂量,C最大值为211.5ml/L左氧氟沙星与388ml/L左氧氟沙星:Mg,以及AUC为171.4h.mg/L左氧氟沙星/盐水与851h.mg/LMg左氧氟沙星:Mg)。
实施例7:在多达14天内,气雾剂给予含MgCl
2
加乳糖的制剂之后
CF患者的左氧氟沙星药物动力学
在第一天,CF患者每次治疗接受约40mg、80mg或120mg的可呼吸递送剂量(每次治疗的载荷剂量为78mg、175mg或260mg),然后每天两次给药,持续14天。使用表11所示的制剂。使用标准非房室PK方法和房室PK方法来生成血清、痰和尿的PK参数(GibaldiM,PerrierB.,“Pharmacokinetics”(药物动力学),第二版,NewYork:Marcel-Dekker;1982,其整体以引用的方式并入本文)。测定血清和痰的PK参数,并且分别在表13和表14中显示。左氧氟沙星盐溶液给药的比较(实施例4)表明通过与镁络合实现了明显较高的痰C最大值和AUC(例如,对于40mg可呼吸剂量,C最大值为211.5mg/L左氧氟沙星对448.97mg/L左氧氟沙星:Mg,以及AUC为171.4h.mg/L左氧氟沙星对420.54h.mg/L左氧氟沙星:Mg(第一天))。
表13
表14
实施例8-50mg/ml和100mg/ml与MgCl
2
一起配制的左氧氟沙星溶液
的气雾剂给药
该实施例涉及气雾剂给予CF患者50mg/ml和100mg/ml的与MgCl2一起配制的左氧氟沙星溶液,剂量为180mg和240mg。表15显示具有MgCl2的左氧氟沙星制剂。
表15
50mg/ml | 100mg/ml | |
左氧氟沙星,mg/ml | 50 | 100 |
镁,mg/ml(mM) | 2.4(100) | 4.9(200) |
氯,mg/ml(mM) | 7.1(200) | 14.2(400) |
乳糖,mg/ml(mM) | 51.4(150) | 0(0) |
pH值 | 6至8 | 6至8 |
重量摩尔渗透压浓度,mOsmol/kg | 300至500 | 300至500 |
使用PARIeFlow喷雾器,使用具有35L头结构的震动网技术,通过吸入给予具有MgCl2的左氧氟沙星。在研究的阶段1,个体以随机安排确定的顺序接受单独的180mg剂量的特定制剂(50mg/ml或100mg/ml),然后是7天的洗脱期,并且在阶段2个体接受单独的180mg剂量的其它制剂(50mg/ml或100mg/ml)。随后,在阶段3期间连续7天每天一次240mg的剂量。使用HPLC/荧光法来测量左氧氟沙星的血清浓度和痰浓度。
对于左氧氟沙星的血清浓度,在给予180mg的100mg/ml的制剂之后,左氧氟沙星血清浓度的算术平均值略高于给予50mg/ml制剂之后的算术平均值(图12)。表16概述了在7天内,每天一次吸入给予CF患者单独180mg剂量的50mg/ml或100mg/ml的溶液之后的左氧氟沙星的药物动力学参数,以及每天一次吸入给予CF患者240mg的100mg/ml的溶液之后的左氧氟沙星的药物动力学参数。100mg/ml制剂的C最大值和AUC(无穷)平均值为35%和22%,其高于50mg/ml制剂的相应值。
表16
基于给予180mg的100mg/ml的制剂之后的6.78小时的t1/2平均值,每天一次给药的累积量应该为约9%。在给予240mg的100mg/ml的制剂之后,C最大值平均值有1.33倍的增加,这类似于给药水平的增加量。在QD×7日,给予240mg之后,第7天的AUC(0-t)为AUC(0-24)或给药间隔期间的AUC,其应该相当于单独给药后的AUC(无穷)。将240mg剂量水平的14,771h.ng/ml平均AUC(0-t)修正至180mg剂量水平,相对于在单独180mg剂量的相同制剂的给药之后检测到的9,848±3,813h.ng/ml的AUC(无穷),该修正导致11,078h.ng/ml的估计值。这说明单独和多重气雾剂给予100mg/ml制剂的左氧氟沙星之后,左氧氟沙星药物动力学的线性。6.40小时至7.49小时的全部三种治疗的算数平均t1/2相当。
对于左氧氟沙星的痰浓度,在给予180mg的50mg/ml或100mg/ml的制剂之后,痰浓度算数平均值、C最大值和AUC相近(图13)。表17概述了在7天内,每天一次吸入给予CF患者单独180mg剂量的50mg/ml或100mg/ml的溶液之后的左氧氟沙星的痰药物动力学参数,以及每天一次吸入给予CF患者240mg的100mg/ml的溶液之后的左氧氟沙星的痰药物动力学参数。
表17
在100mg/ml制剂的180mg剂量和240mg剂量之间,C最大值为2,932,121ng/ml至4,690,808ng/ml,其有1.6倍的增加(表17)。由于少数患者和个体间的变化,该增加量与约1.33倍的预期增加适度地一致。相反,AUC从1,960,771h.ng/ml[AUC(无穷)]至4,507,180h.ng/ml[AUC(0-24)]有2.3倍的增加。3.55小时至4.58小时的所有这些治疗的算数平均t1/2相当(表16)。
这些结果显示痰的左氧氟沙星暴露与血清的左氧氟沙星暴露相比具有更高的数量级(表16和表17)。然而,痰的左氧氟沙星暴露与血清的左氧氟沙星暴露的比相对不依赖于制剂和剂量,并且对于C最大值,上述比的平均值为约260,000%,并且对于AUC,上述比的平均值为约25,000%(表18)。
表18
对于两种制剂,痰暴露相似。考虑到240mgQD×7日-方案的潜在堆积,在给予180mg和240mg的100mg/ml制剂之后,全身暴露和痰暴露与剂量成比例,并且在单独剂量与多重剂量之间一致。
表19比较了实施例4和8所示的喷雾制剂之后的左氧氟沙星AUC结果和C最大值结果,作为测试的各个制剂的RDD或喷雾器载荷剂量的原始结果或标准化结果。
表19
剂量标准化的AUC和C最大值PK参数表明使用实施例8的制剂的痰的左氧氟沙星暴露显著增加,所述制剂包含与Mg2+一起配制的左氧氟沙星,而实施例4的制剂不含Mg2+。图14还显示了实施例4制剂和实施例8制剂之间的左氧氟沙星痰浓度的区别。
实施例9-小鼠肺部感染模型
将小鼠肺部感染模型用于比较氟喹诺酮的静脉内给药与肺部给药的功效。通过气管内滴注使用肺炎克雷伯氏菌(Klebsiellapneumoniae)ATCC43816来感染每组的8只小鼠。感染之后24小时,使用微喷气雾剂生成装置(PennCentury,Philadelphia,PA)每天两次(BID)给予小鼠10mg/kg或20mg/kg的气雾剂剂量。开始治疗后的24小时,将动物处死,并且将其肺部取出、均质化并将其置于培养皿上以确定菌落数。表20显示该研究中使用的制剂。
表20
在测试的各个剂量中,相对于在盐水中配制的左氧氟沙星,与MgCl2一起配制的左氧氟沙星产生大于1log的微生物杀伤(图15)。该结果与实施例2的大鼠中测定的增加的肺部浓度一致。
实施例10-与MgCl
2
一起配制的左氧氟沙星气雾剂在小鼠肺部感染模
型中的功效
该实施例涉及具有MgCl2的左氧氟沙星的气雾剂给药,以及左氧氟沙星盐溶液的腹膜内给药。随后研究的目的是测定由绿脓假单胞菌(P.aeruginosa)引起的急性肺部感染和慢性肺部感染中这些疗法的功效。
抗微生物剂:从独立的供应商购买左氧氟沙星(LKTLaboratories,St.Paul,MN)、妥布霉素(Sicorpharmaceuticals,Irvine,CA)和氨曲南(MPBiomedicals,Solon,OH)。在各个实验开始之前,制备各个抗生素的新鲜原液。在水中稀释与MgCl2一起配制的左氧氟沙星;在0.9%盐水中稀释左氧氟沙星和妥布霉素,在7%碳酸氢钠水溶液中稀释氨曲南。表21显示该研究使用的制剂。
表21
细菌菌株MIC检测:在这些研究中使用绿脓假单胞菌(P.aeruginosa)ATCC27853和NH57388A。根据CLSI参考方法(“Methodsfordilutionofantimicrobialsusceptibilitytestforbacteriathatgrowaerobically”(有氧成长微生物的抗菌敏感性测试的稀释方法).第七版:ClinicalandLaboratoryStandardsInstitute(2006)M&-A7,其整体以引用的方式并入本文),通过微量肉汤稀释检验确定MIC。以100μl的最终体积来进行该检验。调节细菌悬浮液来生成5x105CFU/ml的细胞密度。在培养基中制备浓度等于2倍最高期望最终浓度的抗生素,然后将该抗生素直接稀释至96孔微量滴定板。在35℃孵育微量滴定板24小时,并且通过使用微量滴定板读数器(MolecularDevices)在600nm读取,以及使用微量滴定板读数镜通过目视观察来读取。MIC被定义为在完全抑制有机体的明显增长时的抗生度最低浓度。
小鼠:从HarlanWestCoast(Germantown,CA)获得雌性Swiss小鼠(5周至6周龄)。在由实验动物使用与管理委员会认可的协议下进行所有研究。
假单胞菌藻酸盐的制备:在37℃下,在震动(170rpm)的条件下,在50ml的Mueller-hinton肉汤(Mueller-hintonbroth)(MHB)中培育绿脓假单胞菌(P.aeruginosa)NH57388A,时间为24小时至28小时。通过离心(在4℃下,23,000xg,30分钟)收集细菌细胞,并且将其悬浮于3ml至6ml的MHB中。收集上清液,并将其放置在80℃水浴中30分钟。通过向150ml冰冷的99%乙醇中加入上清液来沉淀藻酸盐。用无菌细菌环来收集沉淀的藻酸盐,并且用无菌盐水洗涤几次。然后将纯化的藻酸盐悬浮于10ml无菌盐水中并且剧烈搅拌,从而形成均质的悬浮液。测量藻酸盐浓度,并且将其调节至2mg/ml至3mg/ml的浓度。
抗生素的气雾剂给药:使用连接于FMJ-250高压注射器(High-PressureSyringe)(PennCentury,Philadelphia,PA)的微喷气雾剂装置(MicroSprayerModelIA-C,PennCentury,Philadelphia,PA)来喷雾抗生素。该装置产生质量中质直径为16μM至22μM的喷雾。对于给药,麻醉各个小鼠(以4L/分钟的速度,在5%异氟醚的氧气中进行),并且通过上颌牙,以40°至45°的角度安全地放置各个小鼠,将微喷气雾剂尖端插入分叉点,并且给予50μl的体积。
药物动力学:给予小鼠(n=3/时间点)单独的60mg/kg气雾剂剂量的与MgCl2一起配制的左氧氟沙星或20mg/kgIP剂量的左氧氟沙星。在给药之后的0.08小时、0.16小时、0.25小时、0.5小时、0.75小时、1.0小时、2.0小时、3.0小时和4.0小时,处死小鼠并且收集其肺部。使用HPLC方法,测量以左氧氟沙星或与MgCl2一起配制的左氧氟沙星的形式给予的左氧氟沙星肺部均浆浓度。在从未处理动物中收集的新鲜的小鼠肺部均浆中制备分析标准物(0.05mg/L至100mg/L)。使用双倍体积的4%三氯乙酸来混合两种化合物的肺部均浆或标准物,涡旋,然后使用在4℃至10℃下放置的冷冻的Eppendorf5415c离心机在12,000rpm下离心10分钟。使用在10℃下放置的温度控制自动注射器,直接向HPLC上注射上清液的等分部分(25μl)。由峰面积与标准浓度构成标准曲线,并且使用加权线性回归(MicrosoftExcel,Seattle,WA)拟合数据。从这些标准曲线中计算肺部均浆的左氧氟沙星浓度。使用WinNonlin(Pharsight,MountainView,CA)来测定肺部药物动力学参数。
急性小鼠肺部感染模型:在35℃下,在MHB中使绿脓假单胞菌(P.aeruginosa)ATCC27853生长过夜。通过在600nm的吸光度与预定的平板菌落计数法的相互关系,将细菌悬浮液调节至约1x105CFU/ml至6x105CFU/ml。通过在第1天和第3天腹腔(IP)注射150mg/kg的环磷酰胺(Baxter,Deerfield),使雌性Swiss小鼠中性白细胞减少。在第4天,使用连接至1ml注射器的弯曲口服灌胃尖端,通过气管内滴注(IT)0.05ml的接种物来感染小鼠。感染后24小时开始抗生素治疗,并且每天一次或两次给药,持续24小时或48小时。使用微喷气雾剂装置来喷雾抗生素。在异氟醚麻醉(以4L/分钟的速度,在5%异氟醚的氧气中进行)下,进行所有的感染和气雾剂治疗。在开始治疗之前处死小鼠的未处理组(n=8)以确定基线细菌数。在最后的抗生素给药之后12小时至16小时,通过二氧化碳窒息来处死处理的动物(n=8)。将肺部无菌地移除,并且在1ml无菌盐水中将其均质化(Pro200homogenizer,ProScientific,Monroe,CT)。将一系列的10倍稀释的均质化肺部置于Mueller-hinton琼脂(MHA)上,并且计算菌落。对于存活研究,在治疗结束后7天或感染后一共9天之后,观察小鼠(n=10)。
慢性小鼠肺部感染模型:在37℃下,在震动(170rpm)条件下,在50ml的MHB中培养绿脓假单胞菌(P.aeruginosa)NH57388A,时间为24小时至28小时。通过离心(在4℃下,23000xg,30分钟)来收集细菌细胞,并且将其悬浮在3ml至6ml的MHB中(Hoffmann,N.T.B.等人,2005.“NovelmousemodelofchronicPseudomonasaeruginosalunginfectionmimickingcysticfibrosis”(模拟囊性纤维化的慢性绿脓假单胞菌(Pseudomonasaeruginosa)肺部感染新小鼠模型).InfectImmun73:2504-14,其整体以引入方式并入本文)。在藻酸盐悬浮液中稀释(1:10)细菌悬浮液以生成约108CFU/ml。在感染前4天,使用单独150mg/kgIP剂量的环磷酰胺,通过暂时的中性白细胞减少来实现感染的初步建立。在第4天,在异氟醚麻醉下,使用连接至1ml注射器的弯曲的珠-尖口服灌注来感染小鼠。在感染后24小时开始抗生素治疗,并且通过IP途径或通过使用微喷装置的气雾剂,连续三天每天两次给予各种浓度的抗生素。在最后治疗之后12小时至16小时,如上所述的处死小鼠,并且测定肺部的菌落数。
统计分析:通过对数秩(log-rank)和Mann-WhitneyU检测(4.03版本的GraphPadPrism)来分别分析存活和肺部细菌数。P值<0.05被认为是统计学显著的。
抗生素的最小抑菌浓度
表22显示用于动物研究的绿脓假单胞菌(P.aeruginosa)菌株的最小抑菌浓度(MIC)。妥布霉素是药效最大的体外抗生素,其MIC小于1μg/ml,与MgCl2一起配制的左氧氟沙星和左氧氟沙星的MIC为1μg/ml和2μg/ml,以及对于两种菌株,氨曲南的MIC为4μg/ml。
表22
小鼠药物动力学
表23显示与MgCl2一起配制的左氧氟沙星和左氧氟沙星的标准化肺部药物动力学参数。60mg/kg与MgCl2一起配制的左氧氟沙星的气雾剂给药产生左氧氟沙星AUC值和C最大值值为使用标准化左氧氟沙星腹膜内给药剂量达到的数值的9和30倍以上。
表23
在急性和慢性肺部感染模型中,与MgCl
2
一起配制的左氧氟沙星气雾
剂对比全身性左氧氟沙星
在急性肺部感染模型中,使用125mg/kg、62.5mg/kg和32mg/kg与MgCl2一起配制的左氧氟沙星的气雾剂治疗,分别产生5.9logCFU、4.6logCFU和2.3logCFU的肺部细菌数量减少(图16)。使用125mg/kg、62.5mg/kg和32mg/kg的左氧氟沙星的全身治疗分别产生3.5logCFU、2.7logCFU和0.65logCFU减少。在每一剂量基础上,与MgCl2一起配制的左氧氟沙星气雾剂的细菌数量减少大于使用IP左氧氟沙星观察到的细菌数量减少(p<0.05)。
在慢性肺部感染模型中,使用60mg/kg、30mg/kg和15mg/kg的左氧氟沙星盐溶液的腹膜内治疗分别产生0.15log、0.32log和0.83log的细菌数量增加(图17)。相反,使用60mg/kg、30mg/kg和15mg/kg与MgCl2一起配制的左氧氟沙星的气雾剂给药分别产生1.26log、0.62log和0.07log的细菌数量减少。总体而言,在两个感染模型中,在每一剂量基础的剂量上,使气雾化的与MgCl2一起配制的左氧氟沙星治疗的小鼠的肺部细菌量显著低于全身性左氧氟沙星(对于与MgCl2一起配制的左氧氟沙星与全身左氧氟沙星的对比,p<0.05)。
在急性致死性肺部感染模型中左氧氟沙星、妥布霉素和氨曲南气雾剂
在急性肺部感染模型中,为了比较与MgCl2一起配制的左氧氟沙星、妥布霉素和氨曲南的效果,用绿脓假单胞菌(P.aeruginosa)ATCC27853感染小鼠并且连续两天每天两次通过气雾剂途径治疗。由于毒性,将妥布霉素限制至60mg/kg的最大剂量,并且将氨曲南限制至400mg/kg的最大剂量。另外,由于治疗需要麻醉,每天给药的最大次数限定为2次。
如图18所示,与MgCl2一起配制的左氧氟沙星、妥布霉素和氨曲南的气雾剂给药分别产生4.10logCFU、2.70logCFU和0.24logCFU每肺的的平均减少(对于与MgCl2一起配制的左氧氟沙星与氨曲南的比较,p<0.05)。明显地,以每天一次给药或每天两次给药的形式给予每日总剂量相同的与MgCl2一起配制的左氧氟沙星导致肺部绿脓假单胞菌(P.aeruginosa)数产生相似的减少。
在9天内监测存活。如图19所示,三天后,所有未治疗的小鼠死于感染。使用800mg/kg/天(400mg/kgBID)的气雾化氨曲南的治疗在本研究使用的抗生素中具有最低的存活率(20%),并且与未治疗的小鼠相比没有显著不同(p>0.05)。使用120mg/kg/天(60mg/kgBID)的妥布霉素的治疗产生60%的存活率,该存活率与对照相比有统计上的差异(p<0.05)。以120mg/kgQD或60mg/kgBID的形式,使用120mg/kg/天的与MgCl2一起配制的左氧氟沙星的治疗产生100%的存活率,其存活率显著不同于未治疗对照或氨曲南(p<0.05),但是并非显著地不同于妥布霉素(p=0.056)。
在慢性肺部感染模型中左氧氟沙星、妥布霉素和氨曲南气雾剂
气雾化的与MgCl2一起配制的左氧氟沙星、气雾化的妥布霉素和气雾化的氨曲南分别产生3.3logCFU、2.9logCFU和1.25logCFU的平均减少(图20)。与氨曲南或未治疗的对照组相比,妥布霉素或与MgCl2一起配制的左氧氟沙星的气雾化剂量产生明显较低的细菌数量(p<0.05)。
这些体内研究表明在急性和慢性的绿脓假单胞菌(P.aeruginosa)肺部感染模型中,与MgCl2一起配制的左氧氟沙星的气雾剂给药比全身给药产生更大的抗菌杀伤。明显地,与MgCl2一起配制的左氧氟沙星的每天两次给药减少了肺部细菌量,其与使用气雾化的妥布霉素和氨曲南观察到的肺部细菌量减少程度类似或更高(图18)。该肺部的细菌量减少转化为改善的存活(图19)。
另外,单独给予与MgCl2一起配制的左氧氟沙星与每天两次给予与MgCl2一起配制的左氧氟沙星的对比显示出类似的细菌杀伤和存活,这说明用与MgCl2一起配制的左氧氟沙星对患者进行每天一次的治疗是可能的。对于多重给药,药物的每天一次给予特别有利,因为多重给药对于患者不方便,并且能够导致对治疗的依从性差。
尽管本文已经显示和描述了本发明的优选实施方案,仅以实例的方式来提供这样的实施方案对于本领域技术人员是显而易见的。对于本领域技术人员而言,将出现的许多变化、改变和替换没有背离本发明。应当明白在实践本发明时,可以采用本文所述的本发明实施方案的多种替代方案。其旨在下列权利要求规定的本发明的范围,由此包括这些权利要求范围内的方法及其结构及其等效体。
本说明书中涉及的所有公开、专利和专利申请以引用的方式并入本文,如同具体并且单独指出的各个单独的公开、专利或专利申请以引用的方式并入。
Claims (79)
1.包含左氧氟沙星或氧氟沙星以及二价或三价阳离子的溶液在制备用于治疗肺部感染的气雾剂中的用途,其中所述气雾剂能够达到至少1200mg/L的最大肺部痰浓度(C最大值)和至少1500h·mg/L的肺部痰曲线下面积(AUC),其中所述溶液包含浓度为约50mM至约400mM的二价或三价阳离子,以及浓度为约50mg/ml至约200mg/ml的左氧氟沙星或氧氟沙星。
2.如权利要求1所述的用途,其中所述溶液基本上由左氧氟沙星或氧氟沙星以及二价阳离子或三价阳离子组成。
3.如权利要求1所述的用途,其中所述溶液不含乳糖。
4.如权利要求1所述的用途,其中所述气雾剂能够达到至少1700mg/L的最大肺部痰浓度(C最大值)。
5.如权利要求1所述的用途,其中所述气雾剂能够达到至少2000mg/L的最大肺部痰浓度(C最大值)。
6.如权利要求1所述的用途,其中所述气雾剂能够达到至少3000mg/L的最大肺部痰浓度(C最大值)。
7.如权利要求1所述的用途,其中所述气雾剂能够达到至少4000mg/L的最大肺部痰浓度(C最大值)。
8.如权利要求1所述的用途,其中所述气雾剂能够达到至少1700h·mg/L的肺部痰曲线下面积(AUC)。
9.如权利要求1所述的用途,其中所述气雾剂能够达到至少2000h·mg/L的肺部痰曲线下面积(AUC)。
10.如权利要求1所述的用途,其中所述气雾剂能够达到至少3000h·mg/L的肺部痰曲线下面积(AUC)。
11.如权利要求1所述的用途,其中所述气雾剂能够达到至少4000h·mg/L的肺部痰曲线下面积(AUC)。
12.如权利要求1所述的用途,其中所述溶液包含浓度为约100mM至约300mM的二价或三价阳离子,以及浓度为约75mg/ml至约150mg/ml的左氧氟沙星或氧氟沙星。
13.如权利要求1所述的用途,其中所述溶液包含浓度为约150mM至约250mM的二价或三价阳离子,以及浓度为约90mg/ml至约125mg/ml的左氧氟沙星或氧氟沙星。
14.如权利要求1所述的用途,其中所述溶液的重量摩尔渗透压浓度为约300mOsmol/kg至约600mOsmol/kg,并且pH为约5至约8。
15.如权利要求1所述的用途,其中所述溶液的重量摩尔渗透压浓度为约350mOsmol/kg至约425mOsmol/kg,并且pH为约5至约6.5。
16.如权利要求1所述的用途,其中所述溶液的pH为约5.5至约6.5。
17.如权利要求1所述的用途,其中所述二价或三价阳离子选自镁、钙、锌、铜、铝和铁。
18.如权利要求1所述的用途,其中所述溶液包含氯化镁。
19.如权利要求1所述的用途,其中所述溶液包含浓度为约90mg/ml至约110mg/ml的左氧氟沙星或氧氟沙星,包含浓度为约175mM至约225mM的氯化镁,包含约5至约7的pH;包含约300mOsmol/kg至约500mOsmol/kg的重量摩尔渗透压浓度,并且不含乳糖。
20.如权利要求1所述的用途,其中所述气雾剂用于治疗患有肺部病症的患者的肺部感染,所述肺部病症选自囊性纤维化、慢性阻塞性肺病、慢性支气管炎、支气管扩张和哮喘。
21.如权利要求1所述的用途,其中所述肺部感染包含一种或多种细菌,所述细菌选自绿脓假单胞菌(Pseudomonasaeruginosa)、荧光假单胞菌(Pseudomonasfluorescens)、食酸假单胞菌(Pseudomonasacidovorans)、产碱假单胞菌(Pseudomonasalcaligenes)、恶臭假单胞菌(Pseudomonasputida)、嗜麦芽寡养单胞菌(Stenotrophomonasmaltophilia)、嗜水气单胞菌(Aeromonashydrophilia)、大肠杆菌(Escherichiacoli)、弗氏柠檬酸杆菌(Citrobacterfreundii)、鼠伤寒沙门氏菌(Salmonellatyphimurium)、伤寒沙门氏菌(Salmonellatyphi)、副伤寒沙门氏菌(Salmonellaparatyphi)、肠炎沙门氏菌(Salmonellaenteritidis)、痢疾志贺菌(Shigelladysenteriae)、弗氏志贺菌(Shigellaflexneri)、索氏志贺菌(Shigellasonnei)、阴沟肠杆菌(Enterobactercloacae)、产气肠杆菌(Enterobacteraerogenes)、肺炎克雷伯氏菌(Klebsiellapneumoniae)、产酸克雷伯氏菌(Klebsiellaoxytoca)、粘质沙雷氏菌(Serratiamarcescens)、摩氏摩根菌(Morganellamorganii)、奇异变形杆菌(Proteusmirabilis)、普通变形杆菌(Proteusvulgaris)、产碱普罗威登斯菌(Providenciaalcalifaciens)、雷氏普罗威登斯菌(Providenciarettgeri)、斯氏普罗威登斯菌(Providenciastuartii)、乙酸钙不动杆菌(Acinetobactercalcoaceticus)、溶血不动杆菌(Acinetobacterhaemolyticus)、小肠结肠炎耶尔森菌(Yersiniaenterocolitica)、鼠疫耶尔森菌(Yersiniapestis)、假结核耶尔森菌(Yersiniapseudotuberculosis)、中间耶尔森菌(Yersiniaintermedia)、百日咳博德特氏菌(Bordetellapertussis)、副百日咳博德特氏菌(Bordetellaparapertussis)、支气管败血性博德特氏菌(Bordetellabronchiseptica)、流感嗜血杆菌(Haemophilusinfluenzae)、副流感嗜血杆菌(Haemophilusparainfluenzae)、溶血性嗜血杆菌(Haemophilushaemolyticus)、副溶血性嗜血杆菌(Haemophilusparahaemolyticus)、杜克雷氏嗜血杆菌(Haemophilusducreyi)、多杀性巴氏杆菌(Pasteurellamultocida)、溶血性巴氏杆菌(Pasteurellahaemolytica)、幽门螺杆菌(Helicobacterpylori)、胎儿弯曲杆菌(Campylobacterfetus)、空肠弯曲杆菌(Campylobacterjejuni)、大肠弯曲杆菌(Campylobactercoli)、伯氏疏螺旋菌(Borreliaburgdorferi)、霍乱弧菌(Vibriocholera)、副溶血性弧菌(Vibrioparahaemolyticus)、嗜肺性军团杆菌(Legionellapneumophila)、单核细胞增多性李斯特氏菌(Listeriamonocytogenes)、淋病奈瑟氏菌(Neisseriagonorrhoeae)、脑膜炎奈瑟氏菌(Neisseriameningitidis)、洋葱伯克霍尔德氏菌(Burkholderiacepacia)、土拉弗朗西斯氏菌(Francisellatularensis)、金氏菌属(Kingella)和莫拉氏菌属(Moraxella)。
22.如权利要求1所述的用途,其中由革兰氏阴性厌氧菌引起所述肺部感染。
23.如权利要求1所述的用途,其中由选自脆弱拟杆菌(Bacteroidesfragilis)、吉氏拟杆菌(Bacteroidesdistasonis)、拟杆菌属(Bacteroides)3452A同族群、普通拟杆菌(Bacteroidesvulgatus)、卵形拟杆菌(Bacteroidesovalus)、多形拟杆菌(Bacteroidesthetaiotaomicron)、单形拟杆菌(Bacteroidesuniformis)、埃氏拟杆菌(Bacteroideseggerthii)和内脏拟杆菌(Bacteroidessplanchnicus)的一种或多种细菌引起所述肺部感染。
24.如权利要求1所述的用途,其中由革兰氏阳性细菌引起所述肺部感染。
25.如权利要求1所述的用途,其中由选自白喉棒状杆菌(Corynebacteriumdiphtheriae)、溃疡棒状杆菌(Corynebacteriumulcerans)、肺炎链球菌(Streptococcuspneumoniae)、无乳链球菌(Streptococcusagalactiae)、化脓性链球菌(Streptococcuspyogenes)、米勒氏链球菌(Streptococcusmilleri);链球菌属(G群)(Streptococcus(GroupG));链球菌属(C/F群)(Streptococcus(GroupC/F));粪肠球菌(Enterococcusfaecalis)、屎肠球菌(Enterococcusfaecium)、金黄色葡萄球菌(Staphylococcusaureus)、表皮葡萄球菌(Staphylococcusepidermidis)、腐生性葡萄球菌(Staphylococcussaprophyticus)、中间葡萄球菌(Staphylococcusintermedius)、猪葡萄球菌猪亚种(Staphylococcushyicussubsp.hyicus)、溶血性葡萄球菌(Staphylococcushaemolyticus)、人葡萄球菌(Staphylococcushominis)和解糖葡萄球菌(Staphylococcussaccharolyticus)的一种或多种细菌引起所述肺部感染。
26.如权利要求1所述的用途,其中由革兰氏阳性厌氧菌引起所述肺部感染。
27.如权利要求1所述的用途,其中由选自难辨梭状芽孢杆菌(Clostridiumdifficile)、产气荚膜梭状芽孢杆菌(Clostridiumperfringens)、破伤风梭状芽孢杆菌(Clostridiumtetini)和肉毒梭状芽孢杆菌(Clostridiumbotulinum)的一种或多种细菌引起所述肺部感染。
28.如权利要求1所述的用途,其中由耐酸细菌引起所述肺部感染。
29.如权利要求1所述的用途,其中由选自结核分枝杆菌(Mycobacteriumtuberculosis)、鸟分枝杆菌(Mycobacteriumavium)、胞内分枝杆菌(Mycobacteriumintracellulare)和麻风分枝杆菌(Mycobacteriumleprae)的一种或多种细菌引起所述肺部感染。
30.如权利要求1所述的用途,其中由非典型细菌引起所述肺部感染。
31.如权利要求1所述的用途,其中由选自肺炎衣原体(Chlamydiapneumoniae)和肺炎枝原体(Mycoplasmapneumoniae)的一种或多种细菌引起所述肺部感染。
32.如权利要求1所述的用途,其中所述气雾剂的质量中质空气流动力学直径为约2微米至约5微米,几何标准差小于或等于约2.5微米。
33.如权利要求1所述的用途,其中所述气雾剂的质量中质空气流动力学直径为约2.5微米至约4.5微米,几何标准差小于或等于约1.8微米。
34.如权利要求1所述的用途,其中所述气雾剂的质量中质空气流动力学直径为约2.8微米至约4.3微米,几何标准差小于或等于约2微米。
35.如权利要求1所述的用途,其中用震动网式喷雾器制备所述气雾剂。
36.如权利要求35所述的用途,其中所述震动网式喷雾器为PARIE-喷雾器。
37.如权利要求1所述的用途,其中所述气雾剂能够实现可呼吸药物剂量(RDD)为至少约20mg的左氧氟沙星或氧氟沙星。
38.如权利要求1所述的用途,其中所述气雾剂能够实现可呼吸药物剂量(RDD)为至少约100mg的左氧氟沙星或氧氟沙星。
39.如权利要求1所述的用途,其中所述气雾剂能够实现可呼吸药物剂量(RDD)为至少约125mg的左氧氟沙星或氧氟沙星。
40.如权利要求1所述的用途,其中所述气雾剂能够实现可呼吸药物剂量(RDD)为至少约150mg的左氧氟沙星或氧氟沙星。
41.如权利要求1所述的用途,其中喷雾至少约100mg的载荷剂量。
42.如权利要求1所述的用途,其中喷雾至少约200mg的载荷剂量。
43.如权利要求1所述的用途,其中喷雾至少约300mg的载荷剂量。
44.如权利要求1所述的用途,其中在小于约10分钟内能够给予肺部所述气雾剂。
45.如权利要求1所述的用途,其中在小于约5分钟内能够给予肺部所述气雾剂。
46.如权利要求1所述的用途,其中在小于约3分钟内能够给予肺部所述气雾剂。
47.如权利要求1所述的用途,其中在小于约2分钟内能够给予肺部所述气雾剂。
48.如权利要求1所述的用途,其中所述气雾剂与另外的活性剂共同给药,所述活性剂选自抗生素、支气管扩张药、抗胆碱能药、糖皮质激素、类花生酸抑制剂、CFTR调节剂、恢复呼吸道表面液体的药剂、抗炎剂及其组合。
49.如权利要求48所述的用途,其中所述共同给药包括吸入所述另外的活性剂。
50.如权利要求48所述的用途,其中所述抗生素选自妥布霉素、氨曲南、环丙沙星、阿奇霉素、四环素、奎奴普汀、利奈唑胺、万古霉素和氯霉素、粘杆菌素及其组合。
51.如权利要求48所述的用途,其中所述支气管扩张药选自沙丁胺醇、左旋沙丁胺醇、特布他林、非诺特罗、特布他林、吡布特罗、丙卡特罗、比托特罗、利米特罗、卡布特罗、妥布特罗、瑞普特罗、沙美特罗、福莫特罗、阿福特罗、班布特罗、克伦特罗、茚达特罗、茶碱、罗氟司特、西洛司特及其组合。
52.如权利要求48所述的用途,其中所述抗胆碱能药选自异丙托溴铵、噻托溴铵及其组合。
53.如权利要求48所述的用途,其中所述糖皮质激素选自强的松、氟替卡松、布地奈德、莫米松、环索奈德、倍氯米松及其组合。
54.如权利要求48所述的用途,其中所述CFTR调节剂为VX-770、阿他卢仑、VX-809及其组合。
55.如权利要求48所述的用途,其中所述恢复呼吸道表面液体的药剂选自地纽福索、甘露醇、GS-9411、SPI-8811及其组合。
56.如权利要求48所述的用途,其中所述抗炎剂选自布洛芬、西地那非、斯伐他汀及其组合。
57.如权利要求48所述的用途,其中所述类花生酸选自孟鲁司特、普仑司特、扎鲁司特、齐留通、雷马曲班、塞曲司特及其组合。
58.如权利要求1所述的用途,其中每天一次给予所述气雾剂。
59.如权利要求1所述的用途,其中每天两次给予所述气雾剂。
60.包含左氧氟沙星或氧氟沙星以及二价或三价阳离子的溶液在制备用于治疗慢性肺部感染的气雾剂中的用途,其中所述气雾剂能够达到至少1200mg/L的最大肺部痰浓度(C最大值)和至少1500h·mg/L的肺部痰曲线下面积(AUC),其中所述溶液包含浓度为约50mM至约400mM的二价或三价阳离子,以及浓度为约50mg/ml至约200mg/ml的左氧氟沙星或氧氟沙星。
61.如权利要求60所述的用途,其中所述溶液基本上由左氧氟沙星或氧氟沙星以及二价或三价阳离子组成。
62.如权利要求60所述的用途,其中所述溶液不包含乳糖。
63.如权利要求60所述的用途,其中所述气雾剂用于治疗患有肺部病症的患者的慢性肺部感染,所述肺部病症选自囊性纤维化、慢性阻塞性肺病、慢性支气管炎、支气管扩张、肺炎和哮喘。
64.如权利要求60所述的用途,其中所述溶液包含浓度为约100mM至约300mM的二价或三价阳离子,以及浓度为约75mg/ml至约150mg/ml的左氧氟沙星或氧氟沙星。
65.如权利要求60所述的用途,其中所述溶液包含浓度为约150mM至约250mM的二价或三价阳离子,以及浓度为约90mg/ml至约125mg/ml的左氧氟沙星或氧氟沙星。
66.如权利要求60所述的用途,其中所述溶液的重量摩尔渗透压浓度为约300mOsmol/kg至约600mOsmol/kg,并且pH为约5至约8。
67.如权利要求60所述的用途,其中所述溶液的重量摩尔渗透压浓度为约350mOsmol/kg至约425mOsmol/kg,并且pH为约5至约6.5。
68.如权利要求60所述的用途,其中所述溶液的pH为约5.5至约6.5。
69.如权利要求60所述的用途,其中所述二价或三价阳离子选自镁、钙、锌、铜、铝和铁。
70.如权利要求60所述的用途,其中所述溶液包含氯化镁。
71.如权利要求60所述的用途,其中所述气雾剂还与另外的活性剂共同给药,所述活性剂选自抗生素、支气管扩张药、抗胆碱能药、糖皮质激素、类花生酸抑制剂及其组合。
72.如权利要求71所述的用途,其中所述共同给药包括吸入所述另外的活性剂。
73.如权利要求71所述的用途,其中所述抗生素选自妥布霉素、氨曲南、环丙沙星、阿奇霉素、四环素、奎奴普汀、利奈唑胺、万古霉素和氯霉素、粘杆菌素及其组合。
74.如权利要求71所述的用途,其中所述支气管扩张药选自沙丁胺醇、左旋沙丁胺醇、特布他林、非诺特罗、特布他林、吡布特罗、丙卡特罗、比托特罗、利米特罗、卡布特罗、妥布特罗、瑞普特罗、沙美特罗、福莫特罗、阿福特罗、班布特罗、克伦特罗、茚达特罗、茶碱、罗氟司特、西洛司特及其组合。
75.如权利要求71所述的用途,其中所述抗胆碱药选自异丙托溴铵、噻托溴铵及其组合。
76.如权利要求71所述的用途,其中所述糖皮质激素选自强的松、氟替卡松、布地奈德、莫米松、环索奈德、倍氯米松及其组合。
77.如权利要求71所述的用途,其中所述类花生酸选自孟鲁司特、普仑司特、扎鲁司特、齐留通、雷马曲班、塞曲司特及其组合。
78.如权利要求60所述的用途,其包括每天一次给予所述气雾剂。
79.如权利要求60所述的用途,其包括每天两次给予所述气雾剂。
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WO2008025560A1 (en) * | 2006-09-01 | 2008-03-06 | Pari Pharma Gmbh | Methods for taste masking of nebulised compositions for nasal and pulmonary inhalation therapy |
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CN109486739A (zh) * | 2018-11-23 | 2019-03-19 | 上海海洋大学 | 一种诱导副溶血性弧菌产生左氧氟沙星耐药性的方法 |
CN109486739B (zh) * | 2018-11-23 | 2022-02-01 | 上海海洋大学 | 一种诱导副溶血性弧菌产生左氧氟沙星耐药性的方法 |
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