CN101804230B - 流阻调节的气雾化活性剂给药 - Google Patents

流阻调节的气雾化活性剂给药 Download PDF

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CN101804230B
CN101804230B CN2010101368205A CN201010136820A CN101804230B CN 101804230 B CN101804230 B CN 101804230B CN 2010101368205 A CN2010101368205 A CN 2010101368205A CN 201010136820 A CN201010136820 A CN 201010136820A CN 101804230 B CN101804230 B CN 101804230B
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安德鲁·克拉克
卡洛斯·舒勒
史蒂夫·帕博简
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Nektar Therapeutics
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Abstract

本发明涉及向病人肺部运送活性剂制剂的方法和装置。活性剂制剂可以是干粉形式，也可以是喷雾形式或与喷射剂混合的形式。该活性剂制剂在初始阶段以较低的吸入流速给药，提高了活性剂的生物利用度。

Description

流阻调节的气雾化活性剂给药
本申请为国际申请日1999年10月7日，国际申请号PCT/US99/23698于2001年4月9日进入中国国家阶段，申请号99811894.x，发明名“流阻调节的气雾化活性剂给药”的分案申请。
发明领域
本发明涉及活性剂制剂的肺部给药。更具体地，涉及活性剂制剂经深部肺吸收来提高活性剂全身生物利用度的肺部给药方法和装置。通过调节气雾化活性剂的气流速度来提高生物利用度，而这种调节无需病人操作和流速监控。
发明背景
有效地给药是任何成功药物治疗的关键因素。已有的许多给药途径各有利弊。丸剂、胶囊和酏剂等口服给药可能是最方便的方法，但是许多药物在其被吸收以前就在消化道降解了。皮下注射是包括蛋白质在内的全身给药的有效途径，但是病人认可的较少。由于每天一次或多次注射象胰岛素这样的药往往会引起病人的抱怨，其他一些给药途径应运而生，例如经皮、鼻腔内、直肠内、阴道内和肺部给药。
本发明的具体兴趣在于肺部给药，该方法借助于病人吸入活性剂制剂使得分散体中的活性药物可以到达肺的末梢(肺泡)区域。这可借助于一种填有气雾化活性剂制剂的病人驱动吸入装置或装有供雾化和运送活性剂的压缩气体或喷射剂的药物分散或气雾剂装置来完成。
已发现某些药物易于经肺泡吸收而直接进入血液循环。肺部给药有望用于运送其他途径难以给药的蛋白质和多肽。肺部给药对于全身和局部给药治疗肺部疾病均有效。
Elliot等在Aust.Paediatr.J(1987)23：293-297中描述了将半合成人胰岛素经呼吸道喷雾给予6个糖尿病患儿，虽然与皮下给予相比其吸收效率较低(20-25％)，但仍可见其潜在的对这些儿童糖尿病的控制。Laube等在US5320094中提及了Elliot和许多研究并强调：尽管肺部给予了胰岛素，但是病人经治疗后其血糖水平并未降低到正常范围内。Laube等推测这是给药方法本身引起药物在给药系统和/或咽部的损失所造成的，因为药物在肺部的最大沉积才有利于改善对血糖的控制。为了最大程度地运送药物，Laube等将气雾吸入剂的吸入流速控制在30升/分钟以下、优选约17升/分钟。控制流速的给药系统包括一个贮存胰岛素的药物室、一个抽出胰岛素的出口孔和一个限速孔。
共同受让的US60/078212验证了上述假说，并指出：与高吸入流速相比，以低于17升/分钟的速度经肺部给予胰岛素可在更短的时间内提高血中胰岛素的含量。
Rubsamen等在US5364838和US5672581中描述了计量雾化胰岛素给药。通过感应测得的病人的吸入流速和呼吸体积，胰岛素自动释放进入吸入通道。一个监测装置连续向微处理器传送信息，当微处理器测得呼吸循环达到最佳时，微处理器就开启阀门释放胰岛素。吸入流速为0.1-0.2L/秒，吸入体积为0.1-0.8L。
WO 97/40819中描述了较慢的吸入流速是增加经肺部给药和沉积的关键因素。为获得预设的流速(15-60升/分钟)，装置的阻力设计为0.12-0.21(cm H2O)1/2。EPO 692990B1描述了适用于干粉吸入剂的解聚体，并且指出：有必要降低气流速度对吸入粉末气雾剂给药剂量和/或可吸入部分的依赖性。与没有可变几何条件(geometry)相比，升高流速时解聚体会改变载有粉末的空气通过的通道的几何条件，增加了低压的液滴的数量，这样就可在一定流速范围内提供更有效的解聚。
为了有效地经肺以一种舒适和可重现的方式运送活性剂，我们决定需要保持一种较低的初始流速后再高流速。
发明概述
相应地，另一方面，本发明涉及向病人肺部运送气雾化活性剂制剂的装置。该装置包括一种用于控制气雾化活性剂制剂流速以产生所需初始流速的流阻调节器。该流阻调节器调节阻力无需流速监控和病人操作。
另一方面，本发明涉及向病人肺部运送活性剂制剂的方法。该方法包括在气雾化活性剂制剂初始阶段被施以较高的流阻，然后再给予较低的流阻。
附图简述
图1为本发明一个干粉活性剂制剂给药装置的实施方式略图。
图2为图1装置给药的气雾剂浓度曲线。
图3为图1装置中流阻调节器阻力-时间曲线。
图4为相应于图3中阻力的流速阻力。
图5为本发明气流调节器和相应的装置流速的叠加曲线。
图6为病人使用不同流阻的图1装置尽全力吸入时的吸入速率曲线。
图7为病人使用不同流阻的图1装置尽全力吸入时的吸入体积曲线。
图8为病人使用不同流阻的图1装置的舒适吸入速率曲线。
图9为病人使用不同流阻的图1装置以舒适速率吸入时的吸入体积曲线。
发明详述
本发明提供经肺给予活性剂制剂的方法和装置，其中吸入活性剂的流阻随时间变化。本发明令人惊奇之处在于其可以一种舒适和可重现的方式增高血液中活性剂的水平。
定义
在此描述的“活性剂”包括一种试剂、药物、化合物、可提供某些有益或有效药理作用的物质或混合物组成的组合物。这包括食品、食品添加剂、营养品、药物、疫苗、维生素和其他有益的试剂。在此该术语进一步包括可产生局部或全身生理或药理活性的物质。活性剂可以运送包括抗生素、抗病毒药、抗肿瘤药、止痛剂、抗炎药和支气管扩展药，可以是有机或无机化合物，包括但不限于作用于外周神经、肾上腺受体、胆硷能受体、骨骼肌、心血管系统、平滑肌、血液循环系统，骨结合点(synoptic sites)、神经效感器结点、内分泌和激素系统、免疫系统、生殖系统、骨骼系统、自体有效系统、消化和排泄系统、组胺系统、中枢神经系统的药物。适宜的药物可选自如多糖、甾族化合物、催眠药和镇静剂、精神能量剂、镇定剂、抗惊厥剂、肌肉松弛剂、抗帕金森病剂、止痛剂、抗炎药、肌肉紧张剂、抗微生物药、抗疟药、激素包括避孕药、拟交感神经剂、有生理作用的多肽和蛋白质、利尿剂、脂质调节剂、抑雄性激素剂、抗寄生虫剂、肿瘤药、抗肿瘤剂、降血糖药、营养药和滋补剂、生长滋补剂、脂肪、抗肠炎药、电解质、疫苗和诊断试剂。
适用于本发明的活性剂实施例包括但不限于胰导素、降钙素、红细胞生成素(EPO)、因子VIII、因子IX、蜂蜡酶(ceredase)、蜡状酶(cerezyme)、环孢菌素、粒细胞集落刺激因子(GCSF)、α-1蛋白酶抑制剂、依降钙素、粒细胞巨嗜细胞集落刺激因子(GMCSF)、生长激素、人生长激素(HGH)、生长激素释放激素(GHRH)、肝素、低分子肝素(LMWH)、α-干扰素、β-干扰素、γ-干扰素、白介素-2、促黄体激素释放激素(LHRH)、促生长素抑制剂、促生长素抑制剂类似物包括奥曲肽、加压素类似物、促卵泡成熟激素(FSH)、类胰岛素生长因子、胰岛素调理素、白介素-1受体拮抗剂、白介素-3、白介素-4、白介素-6、白介素-10、巨嗜细胞集落刺激因子(M-CSF)、神经生长因子、甲状旁腺激素(PTH)、胸腺素α-1、II b/IIIa抑制素、α-1抗胰蛋白酶、呼吸道合胞体病毒抗体、囊纤维化转膜调节剂(CFTR)基因、脱氧核糖核酸酶(Dnase)、杀菌/渗透性增长蛋白质(BPI)、抗-CMV抗体、白介素-1受体、13-顺维生素A酸、羟乙基磺酸戊双脒、硫酸舒喘宁、硫酸异丙喘宁、二丙酸倍氯米松、乙酰去炎松、丙酮丁地去炎松、溴化异丙托品、氟替卡松、色甘酸钠、酒石酸麦角胺及其类似物、兴奋剂和上述兴奋剂的抗兴奋剂。活性剂可进一步包含核酸，如单纯核酸分子、病毒媒介物、与病毒有关的颗粒、与核酸有关的或掺入脂类中的或含脂类的材料、质体DNA或RNA或其他适于细胞尤其是肺泡细胞转染或变异的核酸结构。活性剂可以有不同的形式，如水溶或水不溶，带电或不带电分子，分子络合物成分或可药用盐。活性剂可以是天然或合成物，或者模拟天然生成或通过加减一种或多种氨基酸合成的活性剂。另外，活性剂还可包括用作疫苗的活体减弱或灭活病毒。
“气雾化活性剂制剂”表示上述定义之活性剂的适于肺部给药的制剂。气雾化活性剂制剂可以是干粉形式，也可以用于喷雾的是溶液、悬浮液或浆液，或可以是与适宜的低沸点易挥发性喷射剂混合。容易理解，可以有一种以上活性剂掺入气雾化活性剂制剂中并且使用单数术语“试剂”不排除使用两种或更多种这样的试剂。
“吸入流速”表示运送气雾化活性剂制剂时的流速。
气雾化活性剂制剂中活性剂的用量必须确保运送能获得所需效果的治疗有效量。具体实践中，这会随具体试剂、疾病的严重性和所需疗效的不同而变化。然而，该装置一般适于运送0.001-100mg/天、优选0.01-100mg/天的剂量。
本发明至少部分地基于意料不到的观察结果，即与恒速而非高吸入流速相比，以较低的初始吸入流速给予病人活性剂时的生物利用度提高。
适于本发明的活性剂制剂包括用于喷雾的干粉、溶液、悬浮液或浆液和混悬于或溶于喷射剂中的颗粒。适用于本发明的干粉包括无定形、晶体活性剂和无定形与晶体活性剂的混合物。选择适宜的干粉活性剂粒径以确保其能穿透进入肺泡，即优选质量中间粒径(MMD)等于或低于10μm、优选低于7.5μm和最优选低于5μm，一般为0.1-5μm。粉末运送剂量效率(DDE)大于30％，一般大于40％，优选大于50并且往往大于60％，气雾剂的粒径分布约为1.0-5.0μm质量中间粒径(MMAD)，一般为1.5-4.5μm MMAD并且优选1.5-4.0μm MMAD。这些干粉活性剂的水分含量低于约10重量％，一般低于5重量％，优选低于3重量％。这样的活性剂粉末见WO95/24183和WO96/32149中的描述，在此引入作为参考。然而，也可以运送粒径大一些的颗粒，例如MMD为10-30μm而其MMAD低于5.0μm的颗粒。这样的颗粒见WO97/44013和WO98/31346中的描述，其公开的内容在此引入作为参考。
优选在可获得无定形粉末的条件下喷雾干燥制备干粉活性剂制剂。一般为晶体的大批活性剂溶于生理可接受的的缓冲液中，典型地为pH 2-9的柠檬酸缓冲液。活性剂溶解后的浓度为0.01-1重量％，一般为0.1-0.2重量％。用常规的如从Niro A/S(丹麦)和Buchi(瑞士)等供应商购得到设备进行溶液的喷雾干燥，所得产品基本为无定形粉末。这种无定形粉末也可在适于获得无定形结构产品的条件下，通过冷冻干燥、真空干燥或蒸发干燥适宜的活性剂溶液而制得。制得的无定形活性剂制剂经碾碎或研磨获得所需粒径的颗粒。干粉活性剂也可以呈晶体形式。大批晶体活性剂经研磨或气流磨处理可获得晶体干粉。
本发明活性剂粉末可选择性地与适于呼吸和肺部给药的药用载体或赋形剂结合。当需要降低给药粉末中活性剂的浓度时，载体可以用作填充剂。然而，载体同时也可改善粉末分散装置中粉末的分散性，使得活性剂的传递更有效且重现性好，并且可改善活性剂的可操作性，例如流动性和稠度，以促进颗粒的制造和填充。此类赋形剂包括但不限于：(a)碳水化合物，例如单糖如果糖、半乳糖，葡萄糖，D-甘露糖，山梨糖等；二糖如乳糖、海藻糖、纤维二糖等；环糊精如2-羟丙基-β-环糊精；和多糖如棉子糖、麦芽糖糊精、右旋糖酐等；(b)氨基酸，例如甘氨酸、精氨酸、天门冬氨酸、谷氨酸、半胱氨酸、赖氨酸等；(c)有机酸和碱的有机盐，例如柠檬酸钠、抗坏血酸钠、葡糖酸镁、葡糖酸钠、氨丁三醇盐酸盐等；(d)多肽及蛋白质，例如天冬甜素、人血清白蛋白、明胶等；(e)糖醇，例如甘露醇、木糖醇等。优选的载体为乳糖、海藻糖、棉子糖、麦芽糖糊精、甘氨酸、柠檬酸钠、人血清白蛋白和甘露醇。
干粉活性剂制剂的运送可使用WO96/09085中描述的吸入治疗系统生产的干粉吸入器，在此引入作为参考但做一定的改进以控制流阻。也可以采用Laube等在US5320094所描述的计量吸入器，或采用US4338931中描述的病人驱动装置，在此一并引入作为参考。
喷雾溶液通过市售活性剂制剂溶液气雾化制得。该溶液可通过发射量仪给药，它是一个以大丸(bolus)剂量运送气雾剂的可控喷雾器，如Raindrop，由Puritan Bennett制造的，其使用见Laube等所描述。其他运送溶液、悬浮液或浆液的方法在Rubsamen等的US5672581中有所描述。采用振动、压电组件的装置见Ivri等在US5586550中的描述，在此一并引入作为参考。
喷射剂系统可包括溶解于喷射剂的活性剂或分散于喷射剂的颗粒。Rubsamen等在US5672581中描述了这两种制剂类型。在此一并引入作为参考。
为了获得提高的活性剂的生物利用度，有必要对上述装置加以改进以控制活性剂制剂的初始吸入流速。我们发现一旦达到初始期的低吸入流速，就可解除流速限制并且可允许较高的流速。如果没有达到较高的流速，病人将放弃并停止吸入。
按照本发明，在少于10秒内、优选少于5秒内并常在3-5内应达到低于15升/分钟、优选低于10升/分钟、经常是5-10升/分钟的流速。经过这样的初始流速限制期后，流速限制就可以解除了，流速将是病人吸入的正常流速。这个流速在15-80升/分钟之间、通常为15-60升/分钟、更常为15和30升/分钟。为了达到上述流速，将流阻调节器引入装置中。装置中的压力传感器将确定吸入的开始。流阻调节器设置为较高阻力，大约0.4-2(cm H2O)1/2/SLM(SLM是在标准温度和压力下每分钟的体积)、通常在0.4-1.5(cm H2O)1/2/SLM并且经常采用0.5-1.0(cm H2O)1/2/SLM之间的阻力以获得上述所需的流速。当初始期的限速流通过时就会被压力传感器测得，并且在预设的时间段内流阻调节器会重新调节以提供所需的较小阻力。这种阻力为0-0.3(cm H2O)1/2/SLM、通常为0-0.25(cm H2O)1/2/SLM、更常在0-0.2(cm H2O)1/2/SLM之间。因此，患者的正常的舒适吸入流速得以实现。流速调节器的示例系统如图1所示。在这个系统中，流速调节器是装置(104)中一个用以控制吸入空气流速的阀(100)，它安装在吸入空气歧管(102)上。测流计(106)和计算机(108)仅用于来评估病人对流速限制所做的反应。压力传感器(110)测得吸入开始并启动阀(100)。尽管本例中的流速调节器是微处理器驱动的阀，也可采用简单的机械阀调节系统。另外，为了感应吸入的开始，可使用流量传感器和压力传感器。
根据本发明的另一特征，发现颗粒在咽喉的碰撞与流速和气动粒径的平方成正比，即有下列等式成立：
I＝kd2Q
I＝与咽喉碰撞的颗粒数目
k＝正比常数
d＝颗粒的MMAD
Q＝流速
根据上述公式可知：采用本发明初始低流速有可能在不增加在咽喉碰撞颗粒数量的情况下运送大颗粒，这确保大多数活性制剂在低流速期得以被运送。最初，当低流速和高浓度气雾剂即气雾剂中的颗粒数目达到高峰时，颗粒将优先地在肺深部释放而不是在咽喉部碰撞，因此提高了活性制剂的生物利用度。
图1装置释放出的气雾剂的浓度如图2所示。对于0.5升气雾剂，曲线表明最初的0.1-0.2升的浓度是最高的，随后即逐渐下降。因此对于避免与咽喉的碰撞和提高生物利用度来说，气雾剂的初始部分以低流速运送是很重要的。实现这个目的的流速调节器阻力轮廓图如图3中所示。开始的3秒期内阻力较高(0.65(cm H2O)1/2/SLM)，然后开启阀并将阻力调为正常运送阻力(0.15(cm H2O)1/2/SLM)。图4所示的流速可见，初始期的吸入流速大约为10SLM然后调高为25-30SLM。本发明另一个流速调节器的阻力轮廓图和其对应的流速轮廓图如图5所示。在初始的5秒内阻力由高调至低(0.9-0.20(cm H2O)1/2/SLM)。从图5中的流速可见，吸入流速在初始3秒内低于20SLM然后调高为30SLM。在所有的例子中，因为最初的0.1-0.2升中气雾剂的浓度是最高的，运送大部分活性制剂将在最初的3秒期间完成。这就增加了活性制剂向肺深部的运送从而增加了生物利用度。
下述实施例是对本发明的说明，但并不是对本发明范围加以限制的解释。对于本领域技术人员来说，根据本发明所公开的内容、附图及权利要求，对这些实施例所做的变化及其等价内容是显而易见的。
实施例
实施例1
为了确定流阻和流速的关系，10名志愿者，5男5女在3种被要求不同的阻力下尽全力和以舒适的呼吸速度吸入。结果见图6-9。图6和7是男女受试者的尽全力吸入和舒适吸入速度的流速。图8和9表示在上述阻力下尽全力和以舒适吸入速度时的吸入气雾体积。
维持10升/分钟的舒适流速的的阻力大约为0.3(cm H2O)1/2/SLM。另外，由于随着阻力的增加吸入变得困难和不舒适，因此较高流阻下运送的气雾剂体积下降。事实上，与恒定低阻流给药时的体积相比，如果经过初始高阻力给药后降低阻力，则吸入体积不会显著下降。
实施例2
材料和方法
材料
结晶的人类锌胰岛素，26.3U/mg，来自Eli Lilly和Company，Indianapolis，IN并经过反相HPLC检测纯度大于99％。USP标准的甘露醇来自Roquette公司(Gurnee，IL)。甘氨酸购自Sigma化学公司(St.Louis，Missouri)。USP标准的柠檬酸钠二水合物来自J.T.Baker(Phillipsburg，NJ).
粉末生产
将块状结晶胰岛素溶解于含甘露醇和甘氨酸的柠檬酸钠缓冲液中，最终固体浓度为7.5mg/ml和pH为6.7±0.3。喷雾干燥器的入口温度为110-120℃，进样速度为5ml/min，出口温度为70-80℃。溶液过0.22μm滤器，然后在Buchi喷雾干燥器中喷雾干燥成白色无定形胰岛素细粉。所得的粉末贮存在密闭加盖的容器中置于干燥环境下(＜10％RH)。
粉末分析
将粉末分散于Sedisperse A-11(Micrometrics，Norcross，GA)，采用Horiba CAPA-700粒径分析仪液体离心沉淀法测得粉末的粒径分布。采用Karl Fischer技术通过Mitsubishi CA-06湿度仪测定粉末的水分含量。用阶式撞击取样器(Graseby Andersen，Smyrna，GA)测定气雾剂粒径分布。用吸入治疗系统生产的气雾器测定运送剂量效率(DDE)，类似于WO96/09085中的描述。DDE定义为装置喷射2.5秒后被真空抽出(30升/分钟)捕获于玻璃纤维滤器(德国，47mm直径)中的量占标示装量的百分比，该标示装量为气雾剂装置中除去喷嘴的发泡包装里的量。用滤器中所收集的粉末量除以发泡包装中的粉末量即得DDE。
以人胰岛素为参考标准，将一定量胰岛素粉末用蒸馏水溶解，与用于喷雾的胰岛素溶液比较粉末处理前后胰岛素的完整性。用反相
HPLC的保留时间和峰面积确定胰岛素分子在处理过程中是否发生了化学变化或降解。用UV测定胰岛素的浓度(于278nm)并确定是否含有不溶性聚集物(于400nm)。同时还测定了开始和重建后溶液的pH值。用偏振光显微镜验证其无定形性征。
体内实验
为了考察吸入速度对胰岛素生物利用度的影响，采用图1所示的给药系统分别给予24个受试者2mg胰岛素。每个治疗包括各两次吸入1mg。吸入器采用如US5,740,794中所述的吸入治疗系统吸入器(SanCarlos，CA)，在此引入作为参考。治疗如下：
A.粒径为3.6μMMAD(大PSD)的胰岛素吸入给药，采用标准呼吸操作法和吸入器(无梯度)。
B.粒径为3.6μMMAD(大PSD)的胰岛素吸入给药，采用图1(梯度)所示的吸入体系将吸入速度限定在大约10升/分钟。
C.粒径为2.6μMMAD(小PSD)的胰岛素吸入给药，采用图1(梯度)所示的吸入体系将吸入速度限制在大约10升/分钟。
胰岛素干粉制剂的平均粒径小于5微米。吸入器分散粉末并在装药室产生约240ml的药物气雾剂云(烟雾)。装药室的体积对深度吸入呼吸(大于2L)来说是个次要部分。装药室如此设计是为了在吸入气雾的过程中使外界的空气进入装药室将气雾剂压出室而深入至肺。
分别于给药前的第30和15分钟和吸入后第0(恰在胰岛素给药之前)、5、10、20、30、45、60、90、120、180、240、300和360分钟，从24受试者中采集足以提供最少1ml血浆的血液置于经肝素处理的试管中。第360分钟血样中胰岛素的生物利用度如表I所示，单位为uU.min/ml(每毫升血浆中微单位胰岛素)。这些图表明：初期低流速再高流速吸入胰导素的生物利用度高于连续高流速吸入(例B与例A比较平均增长11％)。初始低流速吸入加上小粒径特性进一步提高了
生物利用度(例C与例B比较平均增长242％)。
表1
Figure GSA00000048223500121
上述各种出版物、专利或专利申请的公开内容在本说明书中引入作为参考，所引用程度仍保持其原有特殊性和独立性。

Claims (5)

1.一种用于调节运送气雾化活性剂到病人肺部的装置，所述装置包括阀，其能在病人吸入的初始阶段在吸入方向上提供阻力为0.4-2(厘米H2O)1/2/SLM的高流阻并随后在吸入的过程中打开以提供较低的流阻，所述较低流阻允许以较高流速通过装置，其中所述较低流阻的阻力为0-0.3(厘米H2O)1/2/SLM。
2.如权利要求1的装置，其中与所述高流阻对应的流速等于或低于15升/分钟。
3.如权利要求1的装置，其中与所述较低流阻对应的流速为15-80升/分钟。
4.如权利要求1的装置，其中所述高流阻在少于10秒的初始时间内提供。
5.如权利要求1的装置，其中所述高流阻在少于5秒的初始时间内提供。
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