CN1304067C - 用于吸入疗法的气溶胶的形成设备 - Google Patents

用于吸入疗法的气溶胶的形成设备 Download PDF

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CN1304067C
CN1304067C CNB02811406XA CN02811406A CN1304067C CN 1304067 C CN1304067 C CN 1304067C CN B02811406X A CNB02811406X A CN B02811406XA CN 02811406 A CN02811406 A CN 02811406A CN 1304067 C CN1304067 C CN 1304067C
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C·C·赫戈斯
P·M·罗伊德
D·穆弗森
D·D·罗戈斯
M·J·温斯雷
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Alexza Pharmaceuticals Inc
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Abstract

本发明涉及吸入递送的含有小颗粒的气溶胶。具体地说,本发明涉及一种形成用于吸入治疗的含药物的气溶胶的设备。在本发明设备的一个方面,提供了一种用于吸入治疗的含药物的气溶胶的形成设备。该设备包括一外壳和一具有气体/蒸汽混合风道区的风道。该风道还包括一部件,它具有在其表面上涂布包含药物的组合物的金属基片。

Description

用于吸入疗法的气溶胶的形成设备
本申请是Lloyd等人的题为“递送生理活性化合物的方法和设备”的美国专利申请序列号10/057,198(2001年10月26日申请),和Wensley等人的题为“产生气溶胶的设备和方法”的美国专利申请序列号10/057,197(2001年10月26日申请)的部分继续申请,为了所有目的将它们都加入本文作为参考。本申请还要求Wensley等人的题为“产生气溶胶的设备和方法”的美国临时申请序列号60/296,225(2001年6月5日)的优先权,将其全部内容加入本文作为参考。
发明领域
本发明涉及吸入递送的含有小颗粒的气溶胶。具体地说,本发明涉及一种形成用于吸入治疗的含药物的气溶胶的设备。
发明背景
目前,有大量批准的用于吸入递送药物的设备,包括干粉吸入器、喷雾器和加压计量的剂量吸入器。然而,与特定药物一起,这些设备还递送大量赋形剂。
希望提供一种在没有赋形剂的情况下可以产生气溶胶的设备。提供这种设备是本发明的目的。
发明概述
本发明涉及吸入递送的含小颗粒的气溶胶。具体地说,本发明涉及一种形成用于吸入治疗的含药物的气溶胶的设备。
在本发明设备的一个方面,提供了一种用于递送吸入治疗的含药物的气溶胶的设备。该设备包括一外壳和一具有气体/蒸汽混合风道区的风道。该风道还包括一部件,它具有在其表面上涂布有包含药物的组合物的金属基片。
典型地,该设备还包括一加热器系统。优选,该加热器系统是一感应加热器系统。更优选,它是一具有铁氧体环(torriod)的感应加热器系统。
典型地,该风道沿气体/蒸汽混合区含有一有限的横截面积。优选,该风道还包括空气通过风道移动时引起紊流的装置。
典型地,该药物具有小于0.15的分解指数。优选,该药物具有小于0.10的分解指数。更优选,该药物具有小于0.05的分解指数。
典型地,组合物中的药物是以下分类中的一种:抗生素、抗惊厥药、抗抑郁药、止吐药、抗组胺药、抗震颤麻痹药、抗精神病药、抗焦虑药、用于勃起机能障碍的药、用于偏头痛的药、治疗酒精中毒的药、治疗成瘾的药、骨骼肌松弛药、非甾类消炎药、阿片样物质、其它止痛药和兴奋剂。
典型地,其中药物是抗生素,它选自以下化合物中的一种:头孢美唑;头孢唑啉;头孢氨苄;头孢西丁;头孢乙腈;头孢来星;头孢噻啶;头孢菌素类,例如头孢菌素C;头孢噻吩;头霉素类,例如头霉素A、头霉素B和头霉素C;头孢匹林;头孢拉定;氨苄青霉素;阿莫西林;海他西林;卡非西林;卡印西林;羧苄青霉素;戊青霉素;叠氨西林;苄青霉素;氯甲西林;氯唑西林;环青霉素;甲氧西林;萘夫西林;2-戊烯青霉素;青霉素类,例如青霉素N、青霉素O、青霉素S、青霉素V;氯丁青霉素;双氯西林;联苯青霉素;庚青霉素;和美坦西林。
典型地,其中药物是抗惊厥药,它选自以下化合物中的一种:加巴喷丁、硫加宾和氨己烯酸。
典型地,其中药物是抗抑郁药,它选自以下化合物中的一种:阿米替林、阿莫沙平、苯莫辛、布替林、氯丙米嗪、地昔帕明、度硫平、多塞平、丙米嗪、酮色林、洛非帕明、美地沙明、米安色林、马普替林、米氮平、去甲替林、普罗替林、曲丙米嗪、维洛沙秦、西酞普兰、可替宁、度洛西汀、氟西汀、氟伏沙明、米那普仑、尼索西汀、帕罗西汀、瑞波西汀、舍曲林、噻萘普汀、醋奋乃静、苯奈达林、溴法罗明、西立氯胺、氯伏胺、异丙烟肼、异卡波肼、吗氯贝胺、苯肼、苯乙肼、司来吉兰、西布曲明、反苯环丙胺、腺苷蛋氨酸、阿屈非尼、安麦角、氨磺必利、安哌齐特、苯乃静、安非他酮、卡罗沙酮、吉哌隆、咪唑克生、美曲吲哚、米那普仑、苯哒吗啉、奈法唑酮、诺米芬新、利坦色林、罗克吲哚、S-腺苷蛋氨酸、托芬那辛、曲唑酮、色氨酸、文拉法辛和扎螺酮。
典型地,其中药物是止吐药,它选自以下化合物中的一种:阿立必利、阿扎司琼、苯喹胺、溴必利、安其敏、氯丙嗪、桂利嗪、氯波必利、塞克利嗪、苯海拉明、地芬尼多、多拉斯琼甲磺酸盐、氟哌利多、格拉司琼、东莨菪碱(hyoscine)、劳拉西泮、甲氧氯普胺、美托哌丙嗪、昂丹司琼、奋乃静、普鲁米近、丙氯拉嗪、东莨菪碱(scopolamine)、三乙基吡拉嗪、三氟吡拉嗪、三氟普马嗪、曲美苄胺、托烷司琼、多潘立酮和帕洛诺司琼。
典型地,其中药物是抗组胺药,它选自以下化合物中的一种:阿扎他定、溴苯那敏、氯苯那敏、氯马斯汀、塞庚啶、右美托咪定、苯海拉明、多西拉敏、羟嗪、西替立嗪、非索非那定、氯雷他定和普鲁米近。
典型地,其中药物是抗震颤麻痹药、它选自以下化合物中的一种:金刚烷胺、巴氯芬、比哌立登、苯托品、奥芬那君、普环啶、三己芬迪、左旋多巴、卡比多巴、司来吉兰、苄甲炔胺、andropinirole、阿朴吗啡、苄丝肼、溴隐亭、布地品、卡麦角林、二氢麦角隐亭、依利罗地、依斯的明、麦角林普拉克索、加兰他敏、拉扎贝胺、麦角乙脲、马吲哚、美金刚、莫非吉兰、培高利特、普拉克索、丙戊茶碱、雷沙吉兰、remacemide、spheramine、特麦角脲、恩他卡朋和托卡朋。
典型地,其中药物是抗精神病药,它选自以下化合物中的一种:醋奋乃静、阿立必利、安哌齐特、苯哌利多、苯喹胺、溴哌利多、布拉氨酯、布他哌嗪、丙酰奋乃静、卡匹帕明、氯丙嗪、氯普噻吨、氯卡帕明、氯马克仑、氯哌噻吨、氯螺旋嗪、氯噻平、氰美马嗪、氟哌利多、氟哌噻吨、氟奋乃静、氟司必林、氟哌啶醇、美索哒嗪、美托奋乃酯、吗茚酮、五氟利多、哌氰嗪、奋乃静、匹莫齐特、匹哌马嗪、哌西他嗪、哌泊塞嗪、丙氯拉嗪、普马嗪、瑞莫必利、舍吲哚、螺哌隆、舒必利、硫利哒嗪、替沃噻吨、三氟哌多、三氟普马嗪、三氟吡拉嗪、齐拉西酮、佐替平、珠氯噻醇、氨磺必利、布他拉莫、氯氮平、美哌隆、奥氮平、喹硫平和利培酮。
典型地,其中药物是抗焦虑药,它选自以下化合物中的一种:甲氯喹酮、美托咪定、美托咪酯、阿地唑仑、利眠宁、氯苯西泮、氟西泮、劳拉西泮、氯普唑仑、咪达唑仑、阿吡坦、阿舍西隆、安非尼酮、阿扎环醇、溴异戊酰脲、丁螺环酮、N-氨甲酰基天冬氨酸钙、卡普托胺、卡普脲、卡波氯醛、卡波麻、氯醛甜菜碱、恩西拉嗪、氟辛克生、伊沙匹隆、来索吡琼、洛沙平、甲喹酮、甲乙哌酮、普萘洛尔、坦度螺酮、曲唑酮、佐匹克隆和唑吡坦。
典型地,其中药物是用于勃起机能障碍的药物,它选自以下化合物中的一种:cialis(IC351)、西地那非、vardenafil、阿朴吗啡、二醋酸阿朴吗啡、酚妥拉明和育亨宾。
典型地,其中药物是用于偏头痛的药物,它选自以下化合物中的一种:almotriptan、阿吡必利、可待因、二氢麦角胺、麦角胺、依来曲普坦、frovatriptan、异美汀、利多卡因、麦角乙脲、甲氧氯普胺、那拉曲坦、氧可酮、丙氧芬、利扎曲普坦、舒马普坦、托芬那酸、zolmitriptan、阿米替林、阿替洛尔、可乐定、塞庚啶、地尔硫、多塞平、氟西汀、赖诺普利、美西麦角、美托洛尔、纳多洛尔、去甲替林、帕罗西汀、苯噻啶(pizotifen)、苯噻啶(pizotyline)、普萘洛尔、普罗替林、舍曲林、噻吗洛尔、和维拉帕米。
典型地,其中药物是用于治疗酒精中毒的药物,它选自以下化合物中的一种:纳洛酮、纳曲酮和双硫仑。
典型地,其中药物是用于治疗成瘾的药物,它是丁丙诺啡。
典型地,骨骼肌松弛药,它选自以下化合物中的一种:巴氯芬、环苯扎林、奥芬那君、奎宁和替扎尼定。
典型地,其中药物是非甾类消炎药,它选自以下化合物中的一种:醋氯芬酸、阿明洛芬、氨芬酸、氨丙吡酮、阿米西群、苯洛芬、溴芬酸、丁苯羟酸、卡洛芬、胆碱、水杨酸盐、辛可芬、桂美辛、氯吡酸、氯美辛、双氯芬酸、依托度酸、吲哚洛芬、马泼尼酮、甲氨芬那酸盐、吡罗昔康、吡洛芬和托芬那酸盐。
典型地,其中药物是阿片样物质,它选自以下化合物中的一种:阿芬太尼、烯丙罗定、阿法罗定、阿尼利定、苯甲基吗啡、苯腈米特、丁丙诺啡、布托啡诺、卡比芬、西拉马朵、氯尼他秦、可待因、右吗拉胺、右旋丙氧吩、二乙酰吗啡、双氢可待因、地芬诺酯、地匹哌酮、芬太尼、氢吗啡酮、L-α乙酰基美沙酮、洛芬太尼、左吗啡、哌替啶、美沙酮、美普他酚、美托酮、吗啡、纳布啡、纳洛芬、氧可酮、阿片全碱、哌替啶、喷他佐辛、非那佐辛、瑞芬太尼、舒芬太尼和曲马朵。
典型地,其中药物是其它止痛药,它选自以下化合物中的一种:阿扎丙宗、苄哌立隆、苄达明、咖啡因、氯尼辛、依索庚嗪、氟吡汀、奈福泮、奥芬那君、丙帕他莫和丙氧芬。
典型地,其中药物是兴奋剂,它选自以下化合物中的一种:苯丙胺、布鲁辛、咖啡因、右芬氟拉明、右苯丙胺、麻黄碱、芬氟拉明、马吲哚、哌甲酯、匹莫林、芬特明和西布曲明。
在本发明方法的一个方面,提供了一种用于吸入治疗的含药物的气溶胶的形成方法。该方法涉及将涂布有包含药物的组合物的基片加热以形成一蒸汽,并将该蒸汽与一定体积的空气混合以便形成具有颗粒的气溶胶。形成的颗粒的质量中值空气动力直径稳定持续至少1秒钟。
典型地,通过将该基片移动穿过加热区将其加热。优选,加热区主要通过交变磁场感应的涡电流产生。
典型地,形成的气溶胶包括约109个颗粒/cc空气。
按照本发明的设备,典型地,该组合物中的药物是上述药物分类中的一种药物。
附图简述
正如附图中所述的,通过以下本发明的不同实施例的描述,其它特征和益处将变得显而易见,其中:
图1是使用本发明设备的实验室实例进行试验的整个系统的简图;
图2是图1所示的实例的顶视图、右端视图和正视图;
图3是图2所示实例的的部分横截面和部分侧视的简图;
图4是图2所示实例的部分横截面和部分端视的简图;
图5是图2所示实例的部分横截面和部分顶视的简图;
图6是使用报警设备的本发明设备的另一实例的横截面侧视简图;
图7是显示含有化合物的可拆卸部件安装在滑道内的图2所示的实例的可拆卸部件和可移动滑道的顶视图、左端视图和正视图;
图8是显示电驱动电路的图2所示的实例的加热元件的简图;
图9是使用文丘里管的本发明第二个实例的侧视简图;
图10是使用涂布有该化合物的薄壁管的本发明第四个实例的侧视简图;
图11是图10所示的实例的侧端简图;
图12是显示产生交变磁场的感应加热器系统的图10所示的实例的侧端简图;
图13是在薄壁管内使用流动限定器的图10所示的另一实例的侧视简图;
图14是对该化合物使用可膨胀容器的本发明第五个实例的侧视简图;
图15是在惰性环境中对该化合物使用一容器的本发明第六个实例的侧视简图;
图16是在化合物的表面上使用惰性环境的循环的图15所示的实例的侧视简图;
图17是使用含有涂布该化合物的颗粒的管的本发明第七个实例的侧视简图;
图18是使用加热系统加热在涂布颗粒上通过的气体的图17所示的实例的侧视简图;
图19是本文称之为“炉设备”的本发明第八个实例的侧视简图;
图20是使用梯度加热的本发明第九个实例的侧视简图;
图21是使用涂布有该化合物的细目筛的本发明第十个实例的侧视简图;
图22是图21所示的实例的顶视、右端和正视简图;
图23是小颗粒聚集成较大颗粒的速度的图;
图24是凝结系数(K)相对化合物的粒径的图;
图25是不同化合物,例如二苯醚、十六烷、香叶草基甲酸酯和己酸的蒸汽压力相对温度的图;
图26是在试验期间使用图1所示的系统给予不同狗的IV剂量和吸入剂量的血液水平的图;
图27是计算和试验质量中值直径(MMD)相对在10-310μg的范围内的化合物质量的图;
图28是计算和试验MMD相对在10-310μg的范围内的化合物质量的图;和
图29是气溶胶的理论粒径(直径)作为蒸发化合物与混合气体的体积之比的函数的图。
发明详述
定义
给定颗粒的“空气动力直径”是指具有与给定颗粒相同的沉降速度且密度为1g/mL(水的密度)的球形小滴的直径。
“气溶胶”是指固体或液体颗粒在气体中的悬浮。
“分解指数”是指由实施例7中所述的试验得到的数值。该数值是通过从1减去产生的气溶胶的百分比纯度确定的。
“药物”是指用于预防、诊断、治疗或治愈疾病、减轻疼痛、或者控制或改善人或动物内任何生理或病理紊乱的任何化学化合物。这些化合物时常列在the Physician′s Desk Reference(Medical EconomicsCompany,Inc.at Montvale,NJ,第56版,2002),将其加入本文作为参考。
例证药物包括如下:来自大麻的cannabanoid、THC、酮咯酸、芬太尼、吗啡、睾酮、布洛芬、可待因、烟碱、维生素A、醋酸维生素E、维生素E、甘油三硝酸酯、毛果芸香碱、墨斯卡林、庚酸睾酮、薄荷醇、phencaramkde、甲琥胺、依斯的明、普鲁米近、普鲁卡因、瑞叮醇、利多卡因、阿利马嗪、异山梨醇二硝酸酯、噻吗洛尔、甲普里隆、依他茶碱、丙氧芬、沙美特罗、维生素E琥珀酸酯、美沙酮、氧烯洛尔、异丙肾上腺素二酒石酸酯、依他喹酮、维生素D3、乙胺丁醇、利托君、奥莫康唑、可卡因、罗氮芥、氯胺酮、酮洛芬、西拉普利、普萘洛尔、舒芬太尼、奥西那林、prentoxapylline、睾酮丙酸酯、丙戊酸、醋丁洛尔、特布他林、地西泮、托吡酯、戊巴比妥、阿芬太尼HCl、罂粟碱、尼麦角林、氟康唑、扎鲁司特、睾酮醋酸酯、氟哌利多、阿替洛尔、甲氧氯普胺、依那普利、沙丁胺醇、酮替芬、异丙肾上腺素、胺碘酮HCl、齐留通、咪达唑仑、氧可酮、西洛他唑、丙泊酚、大麻隆、加巴喷丁、法莫替丁、劳拉西泮、纳曲酮、扑热息痛、舒马普坦、比托特罗、硝苯地平、苯巴比妥、酚妥拉明、13-顺式视黄酸、氢普拉明HCl、氨氯地平、咖啡因、佐匹克隆、曲马朵HCl、吡布特罗、纳洛酮、哌替啶HCl、曲美苄胺、那美芬、东莨菪碱、西地那非、卡马西平、丙卡特罗HCl、美西麦角、谷胱甘肽、奥氮平、唑吡坦、左吗啡、丁螺环酮及其混合物。
典型地,组合物中的药物是以下类型之一:抗生素、抗惊厥药、抗抑郁药、止吐药、抗组胺药、抗震颤麻痹药、抗精神病药、抗焦虑药、用于勃起机能障碍的药、用于偏头痛的药、用于治疗酒精中毒的药、治疗成瘾的药、骨骼肌松弛药、非甾类消炎药、阿片样物质、其它止痛药、cannabanoid和兴奋剂。
典型地,其中药物是抗生素,它选自以下化合物中的一种:头孢美唑;头孢唑啉;头孢氨苄;头孢西丁;头孢乙腈;头孢来星;头孢噻啶;头孢茵素类,例如头孢茵素C;头孢噻吩;头霉素类,例如头霉素A、头霉素B和头霉素C;头孢匹林;头孢拉定;氨苄青霉素;阿莫西林;海他西林;卡非西林;卡印西林;羧苄青霉素;戊青霉素;叠氮西林;苄青霉素;氯甲西林;氯唑西林;环青霉素;甲氧西林;萘夫西林;2-戊烯青霉素;青霉素类,例如青霉素N、青霉素O、青霉素S、青霉素V;氯丁青霉素;双氯西林;联苯青霉素;庚青霉素;和美坦西林。
典型地,其中药物是抗惊厥药,它选自以下化合物中的一种:加巴喷丁、硫加宾和氨己烯酸。
典型地,其中药物是抗抑郁药,它选自以下化合物中的一种:阿米替林、阿莫沙平、苯莫辛、布替林、氯丙米嗪、地昔帕明、度硫平、多塞平、丙米嗪、酮色林、洛非帕明、美地沙明、米安色林、马普替林、米氮平、去甲替林、普罗替林、曲丙米嗪、维洛沙秦、西酞普兰、可替宁、度洛西汀、氟西汀、氟伏沙明、米那普仑、尼索西汀、帕罗西汀、瑞波西汀、舍曲林、噻萘普汀、醋奋乃静、苯奈达林、溴法罗明、西立氯胺、氯伏胺、异丙烟肼、异卡波肼、吗氯贝胺、苯肼、苯乙肼、司来吉兰、西布曲明、反苯环丙胺、腺苷蛋氨酸、阿屈非尼、安麦角、氨磺必利、安哌齐特、苯乃静、安非他酮、卡罗沙酮、吉哌隆、咪唑克生、美曲吲哚、米那普仑、苯哒吗啉、奈法唑酮、诺米芬新、利坦色林、罗克吲哚、S-腺苷蛋氨酸、托芬那辛、曲唑酮、色氨酸、文拉法辛、和扎螺酮。
典型地,其中药物是止吐药,它选自以下化合物中的一种:阿立必利、阿扎司琼、苯喹胺、溴必利、安其敏、氯丙嗪、桂利嗪、氯波必利、塞克利嗪、苯海拉明、地芬尼多、多拉斯琼甲磺酸盐、屈大麻酚、氟哌利多、格拉司琼、东莨菪碱、劳拉西泮、甲氧氯普胺、美托哌丙嗪、昂丹司琼、奋乃静、普鲁米近、丙氯拉嗪、东莨菪碱、三乙基吡拉嗪、三氟吡拉嗪、三氟普马嗪、曲美苄胺、托烷司琼、多潘立酮和帕洛诺司琼。
典型地,其中药物是抗组胺药,它选自以下化合物中的一种:阿扎他定、溴苯那敏、氯苯那敏、氯马斯汀、塞庚啶、右美托咪定、苯海拉明、多西拉敏、羟嗪、西替立嗪、非索非那定、氯雷他定和普鲁米近。
典型地,其中药物是抗震颤麻痹药、它选自以下化合物中的一种:金刚烷胺、巴氯芬、比哌立登、苯托品、奥芬那君、普环啶、三己芬迪、左旋多巴、卡比多巴、司来吉兰、苄甲炔胺、andropinirole、阿朴吗啡、苄丝肼、溴隐亭、布地品、卡麦角林、二氢麦角隐亭、依利罗地、依斯的明、麦角林普拉克索、加兰他敏、拉扎贝胺、麦角乙脲、马吲哚、美金刚、莫非吉兰、培高利特、普拉克索、丙戊茶碱、雷沙吉兰、remacemide、spheramine、特麦角脲、恩他卡朋和托卡朋。
典型地,其中药物是抗精神病药,它选自以下化合物中的一种:醋奋乃静、阿立必利、安哌齐特、苯哌利多、苯喹胺、溴哌利多、布拉氨酯、布他哌嗪、丙酰奋乃静、卡匹帕明、氯丙嗪、氯普噻吨、氯卡帕明、氯马克仑、氯哌噻吨、氯螺旋嗪、氯噻平、氰美马嗪、氟哌利多、氟哌噻吨、氟奋乃静、氟司必林、氟哌啶醇、美索哒嗪、美托奋乃酯、吗茚酮、五氟利多、哌氰嗪、奋乃静、匹莫齐特、匹哌马嗪、哌西他嗪、哌泊塞嗪、丙氯拉嗪、普马嗪、瑞莫必利、舍吲哚、螺哌隆、舒必利、硫利哒嗪、替沃噻吨、三氟哌多、三氟普马嗪、三氟吡拉嗪、齐拉西酮、佐替平、珠氯噻醇、氨磺必利、布他拉莫、氯氮平、美哌隆、奥氮平、喹硫平和利培酮。
典型地,其中药物是抗焦虑药,它选自以下化合物中的一种:甲氯喹酮、美托咪定、美托咪酯、阿地唑仑、利眠宁、氯苯西泮、氟西泮、劳拉西泮、氯普唑仑、咪达唑仑、阿吡坦、阿舍西隆、安非尼酮、阿扎环醇、溴异戊酰脲、丁螺环酮、氨甲酰基天冬氨酸钙、卡普托胺、卡普脲、卡波氯醛、卡波麻、氯醛甜菜碱、恩西拉嗪、氟辛克生、伊沙匹隆、来索吡琼、洛沙平、甲喹酮、甲乙哌酮、普萘洛尔、坦度螺酮、曲唑酮、佐匹克隆和唑吡坦。
典型地,其中药物是用于勃起机能障碍的药物,它选自以下化合物中的一种:cialis(IC351)、西地那非、vardenafil、阿朴吗啡、二醋酸阿朴吗啡、酚妥拉明和育亨宾。
典型地,其中药物是用于偏头痛的药物,它选自以下化合物中的一种:almotriptan、阿吡必利、可待因、二氢麦角胺、麦角胺、依来曲普坦、frovatriptan、异美汀、利多卡因、麦角乙脲、甲氧氯普胺、那拉曲坦、氧可酮、丙氧芬、利扎曲普坦、舒马普坦、托芬那酸、zolmitriptan、阿米替林、阿替洛尔、可乐定、塞庚啶、地尔硫、多塞平、氟西汀、赖诺普利、美西麦角、美托洛尔、纳多洛尔、去甲替林、帕罗西汀、苯噻啶、苯噻啶、普萘洛尔、普罗替林、舍曲林、噻吗洛尔、和维拉帕米。
典型地,其中药物是用于治疗酒精中毒的药物,它选自以下化合物中的一种:纳洛酮、纳曲酮和双硫仑。
典型地,其中药物是用于治疗成瘾的药物,它是丁丙诺啡。
典型地,其中药物是骨骼肌松弛药,它选自以下化合物中的一种:巴氯芬、环苯扎林、奥芬那君、奎宁和替扎尼定。
典型地,其中药物是非甾类消炎药,它选自以下化合物中的一种:醋氯芬酸、阿明洛芬、氨芬酸、氨丙吡酮、阿米西群、苯洛芬、溴芬酸、丁苯羟酸、卡洛芬、胆碱、水杨酸盐、辛可芬、桂美辛、氯吡酸、氯美辛、双氯芬酸、依托度酸、吲哚洛芬、马泼尼酮、甲氯芬那酸盐、吡罗昔康、吡洛芬和托芬那酸盐。
典型地,其中药物是阿片样物质,它选自以下化合物中的一种:阿芬太尼、烯丙罗定、阿法罗定、阿尼利定、苯甲基吗啡、苯腈米特、丁丙诺啡、布托啡诺、卡比芬、西拉马朵、氯尼他秦、可待因、右吗拉胺、右旋丙氧吩、二乙酰吗啡、双氢可待因、地芬诺酯、地匹哌酮、芬太尼、氢吗啡酮、L-α乙酰基美沙酮、洛芬太尼、左吗啡、哌替啶、美沙酮、美普他酚、美托酮、吗啡、纳布啡、纳洛芬、氧可酮、阿片全碱、哌替啶、喷他佐辛、非那佐辛、瑞芬太尼、舒芬太尼和曲马朵。
典型地,其中药物是其它止痛药它选自以下化合物中的一种:阿扎丙宗、苄哌立隆、苄达明、咖啡因、氯尼辛、依索庚嗪、氟吡汀、奈福泮、奥芬那君、丙帕他莫和丙氧芬。
典型地,其中药物是cannabanoid,它是四氢大麻酚(例如,δ-8或δ-9)。
典型地,其中药物是兴奋剂,它选自以下化合物中的一种:苯丙胺、布鲁辛、咖啡因、右芬氟拉明、右苯丙胺、麻黄碱、芬氟拉明、马吲哚、哌甲酯、匹莫林、芬特明、和西布曲明。
“药物降解产物”是指因药物化学改性得到的化合物。该改性,例如,可以是热或光化学感应反应的结果。这些反应包括,但不限于,氧化和水解。
气溶胶的“质量中值空气动力直径”或“MMAD”是指气溶胶的一半微粒质量归因于空气动力直径大于MMAD的颗粒,一半归因于空气动力直径小于MMAD的颗粒的空气动力直径。
“稳定的气溶胶”是指气溶胶的构成颗粒的MMAD在一段时间内变化不超过50%的气溶胶。例如,MMAD为100nm的气溶胶在1秒钟内是稳定的,如果在1秒钟之后,它具有50nm-150nm的MMAD。优选,在一定时间内该MMAD变化不超过25%。更优选,在一定时间内MMAD变化不超过20%、15%、10%或5%。
气溶胶化设备
实施例1是根据狗体内试验描述的。然而,主要通过增加穿过其的气流就可以将该实施例容易地改进以适合人吸入。
参照图1-8,将描述本发明的气溶胶化设备的第一个实施例(1)。如图1所示的设备1可操作地与流量计4(例如,TSI 4100流量计)相连。将流量计4的读数送入图2所示的底盘8内的电子仪器。流量计4示于图1,在描述外壳10的虚线内。设备控制器20包括具有驱动开关22的Chembook N30W型便携式计算机(图3)和National InstrumentsI/O板(SC2345型)(未显示),它与计算机20相连控制设备1并控制试验期间收集的所有数据的记录。使用National Instruments′Labview软件程序开发执行这些功能的软件程序。
设备1和I/O板之间的连接是用电缆(例如,DB25,未显示)完成的。标准电源(例如,Condor F15-15-A+未显示)给设备1供电。使用吸入控制器30控制通过设备1经气管内管34吸入被麻醉的狗内的速度和体积。控制器30具有可编程的屏息延迟,它结束时,排气管线42中的排气阀40打开,使狗能够呼气。管线42内的过滤器50测定排气量及其组成,以监控任何呼出的药物。通过入口管线54、入口阀58、流量计4和入口管口59的源气体来自压缩空气钢筒(未显示)。
现在参照图3-5和7,将一剂量的化合物60沉积在不锈钢薄箔64上,以便化合物60的厚度小于10微米。在大多数情况下,化合物60是通过用有机溶剂制备该化合物溶液沉积的。然后用自动化泵系统将该混合物涂敷到箔基片上。如所示,整个薄箔64(例如,厚度为0.004英寸的302或304合金)的尺寸是0.7×2.9英寸,并且沉积化合物60的面积是0.35×1.6英寸。可以使用其它薄箔材料,但是不锈钢与类似铝的其它材料相比具有优点,因为它具有低得多的导热性值,同时热量增加不明显。由于薄箔64内产生的热量应保持在感兴趣的区域(即,加热/蒸发区70),因此导热性低是有帮助的。薄箔64应具有恒定的横截面,否则因为加热器感应的电流将不均匀。薄箔64保持在框架68内,这样使薄箔64的后缘在可移动滑道78上没有口缘,并且这样化合物60,一旦与空气混合,在如图3的箭头127所示的下游方向是不存在(free)的。框架68典型地由非导热材料制成,从而能够经受适当热量(例如,200℃)以及与该化合物的非化学反应(例如,DELRINAF,一种乙缩醛与TEFLON的共聚物)。
图7中所示的部件80,由其中安装有涂布化合物(60)的薄箔64的框架68组成。通过固定框架68的每个下游锥形端,从而与从每个滑道78的下游端突出的小杆86相贴,以将部件80固定在可移动滑道78内,如图7所示。滑道78由步进电机88驱动,如图3所示,这样沿实施例1的纵轴移动含有化合物60的部件80。这样依次移动不锈钢薄箔64通过交变磁场。(优选磁场限制在加热/蒸发区70,如图5所示,如本实验室实施例中)。使用铁氧体环90指导磁场并将其放在薄箔64下(例如,约0.05英寸下面)。如图5所示,受热区70大致是0.15×0.4英寸,从左至右运行的方向(即,从设备1的上游到下游端)具有较小的尺寸,并且穿过运行的方向(即,设备1的宽度)具有大的直径。
薄箔64起递送药物到受试者的基片和用于蒸发药物的加热元件的作用。加热元件64主要通过交变磁场感应的涡电流受热。交变磁场是在具有狭缝94(例如,0.10英寸宽)的铁氧体环90(例如,来自Fair-Rite公司)产生的,铁氧体环90用铜磁线的线圈98缠绕。当将交流电流通过线圈98时,在铁氧体环90内产生交变磁场。磁场填充由狭缝94形成的缝隙和从环90延伸出的磁场边缘线100,如图5和6所示。磁场线边缘线100贯穿加热元件64。当使用铁氧体磁心时,磁场交变的频率限制在小于1MHz。在本设备中,通常使用100-300kHz的频率。
涡电流的位置和几何学决定了薄箔64将受热的位置。由于磁场边缘线100穿过薄箔64两次,一次离开铁氧体环90,一次回来,产生两个电流环,并且方向相反。其中一个环围绕磁场线100(离开环90的)形成,另一个环围绕磁场线100(返回环90的)形成。电流环直接重叠在狭缝94的中心。由于它们方向相反,因此它们合在一起。因此在狭缝94的中心产生最大加热效果。
滑道78及其内容物位于风道102(由上风道段104和下风道段108构成),如图3所示。上风道段104是可拆卸的并且能够插入可移动滑道78、部件80和薄箔64。下风道段108安装在底盘8(装有电子仪器(未显示)、磁场发生器110、步进电机88和位置传感器(未显示))的上面。再次参照图1,在上风道段104安装有上游通道120以及将上风道段104与流量计4相连的入口管口59。将来自流量计4的读数输入安装在底盘8中的电子仪器。另外,在风道通道102的下游端,将出口124与钳口垫片126相连。在将化合物60给予狗期间,当与该系统相连时,空气被迫通过入口管线54、流量计4、风道102和出口124进入狗体内。
另外,在TC2线130端的高温计位于风道102内并用于测定薄箔64的温度。由于图1-7中所示实例的特定几何学,因此在加热区70之后获取薄箔64的温度读数。需要校正加热区70和测定区域之间的热衰减。收集温度数据并将其用于定量控制和验证并且不用于控制任何加热参数。第二个温度传感器位于出口124的TC1线132的末端,并用于监测递送到狗的空气的温度。
在该试验设备的优选实例中,可拆卸块140位于上风道段104,限制风道102的横截面积并在其中提供特定的混合几何学。在该优选实例中,相对薄箔64,风道140使上风道段104的顶盖降低(例如,至0.04英寸以内)。另外,块140含有挡板(例如,直径为0.04英寸的31根钢杆,未显示)。这些杆与薄箔垂直地取向并从上风道段104的上面延伸到小距离的薄箔内(例如,0.004英寸)。这些杆以交错图案放置并且具有尖的方形端,这样当空气通过它们时引起紊流。该紊流确保了蒸发的化合物与通过该设备的空气充分混合。
将参照图9描述本发明的气溶胶化设备的第二个实例(150),其中横截面积沿气体/蒸汽混合区受到限制。在该实例中,具有入口154、出口156的外壳10内的文丘里管152包括在入口154和出口156之间的喉道158,它用于限制通过文丘里管152的气体流量。此外,控制器160经过设计以控制通过阀164的空气的流量(以空气温度的热电偶168的读数为基础,它可以通过加热器166控制)。
块140直接位于加热区70上并产生加热/蒸发/混合区。在开始产生气溶胶之前,滑道78位于下游位置。滑道78及其内容物,然后被拉向上游进入该加热/蒸发/混合区70,同时通过下面详细描述的感应加热器系统向薄箔64施加能量。
本发明的设备任选配备有报警设备。报警设备的许多功能之一是警报设备的操作者化合物未蒸发或者不适当地蒸发。该报警设备也可用于警报操作者气体流速超出所需范围。图6是描述本发明的手持气溶胶化设备180的第三个实例的简图。正如所显示的,设备180包括上面讨论的设备150的许多构件,此外还包括报警设备170。在使用设备180期间,其中患者的吸入速率控制气流速率,来自报警设备170的信号将警报患者将吸入速度调整至所需范围。在这种情况下,控制器160将与报警设备170相连以发送流速不在所需范围内的所需信号。
图8所示的感应驱动电路190用于驱动设备1的感应-加热元件。电路190的目的是在围绕铁氧体磁心90缠绕的驱动线圈98内产生交流电。电路190由两个P-通道晶体管200和两个N-通道MOSFET晶体管202以桥构型排列组成。与钟脉冲发生器219相连的MOSFET晶体管200和202通过D-型触发器208经MOSFET晶体管驱动电路210成对地打开和关闭。D-型触发器208以金属丝捆扎以使该触发器的Q出口随钟发生信号的上升边交变地改变状态。一对MOSFET晶体管200与D-型触发器208上的Q出口相连并且另一对202与触发器208的非Q-出口相连。当Q高(5伏特)时,在该直流电源(未显示)和驱动线圈98与电容器的串联组合之间通过Q出口控制的这对MOSFET晶体管200产生一低的阻抗连接。当D-型触发器208改变状态并且非Q高时,从该电源到驱动线圈98和电容器220的串联组合的低阻抗连接颠倒过来。由于触发器208在钟发生信号的上升边改变状态,感应-加热元件的一个完整驱动循环需要两个触发器变化。该钟发生信号典型地调整为驱动线圈90和电容器220的串联组合的共振频率的两倍。钟信号频率可以人工或自动调整。
参照图9描述本发明的气溶胶化设备的第二个实例(150),其中其横截面积沿气体/蒸汽混合区也受到限制。在该实例中使用在外壳10内且具有入口154、出口156和入口154与出口156之间的喉道158的文丘里管152限制穿过文丘里管152的气体流量。控制器160经过设计以控制通过阀164的气体流量(以加热器166所致的来自气体温度的热电偶168的读数为基础)。
参照图10和11描述本发明的气溶胶化设备的第四个实例(300)。将气流通入在里面具有化合物60的涂层(310)的薄壁管302。气流的流速通过阀314控制。实例300以及其它的设备,能够使用电阻加热系统(320)快速加热,同时控制蒸发的化合物的流动方向。在用促动器330启动加热系统320之后,沿管302在加热/蒸发区340内通过电流,同时载体气(例如,空气、N2等)通过管302并与所得蒸汽混合。
图12显示了第四个实例所用的电阻加热系统320的交变加热系统。在这种情况下,感应加热器系统350由多个铁氧体360组成用于传导磁通量以蒸发化合物310。
图13显示第四个实例的变体,其中流量限制器370通过外壳(未显示)内的支撑体374安装在薄壁管302内以增加混合气体通过化合物310的表面的流量。
参照图14描述本发明的气溶胶化设备的实例400。就该实例而言,化合物60放置在可膨胀的容器402(例如,薄箔袋)内并通过电阻加热器406加热,它是由图14中所示的促动器410启动的。产生的蒸发化合物被迫进入容器420通过出口通道440并与流过管404的气体混合。当需要时,采用其它步骤阻止或延迟化合物60分解。这样的一个步骤是在加热期间除去或减少围绕60的氧。这可以通过例如在惰性环境中密封小容器外壳来实现。
参照图15描述本发明的气溶胶化设备的第六个实例500。在惰性环境或真空下将化合物60放置在外壳10内的容器502中并通过电阻加热器504(通过图15中所示的促动器508启动)加热。一旦化合物60蒸发,然后可以将其通过出口通道510排放到经过管520的气流中。
图16显示了设备500的变体,其中风扇530循环化合物60表面上的惰性气体。来自压缩气体钢筒(未显示)的惰性气体通过入口540和单向阀550进入并通过出口通道510离开到管502内。
参照图17描述本发明的第七个实例(600)。化合物(未显示),例如上面讨论的化合物60,以离散颗粒602(例如,氧化铝(矾土)、二氧化硅、涂布的二氧化硅、碳、石墨、硅藻土和其它常用于气相色谱的填充材料)沉积在基片上。将这些涂布的颗粒放置在第一个管604内,夹在过滤器606和608之间并通过电阻加热器610(通过促动器620启动)加热。由管604所得的蒸汽与通过第二个管625的空气或其它气体混合。
图18显示了设备600的变体,其中电阻加热器630加热空气,之后通过第一管604并在离散颗粒602上。
参照图19描述了本发明的气溶胶化设备的第九个实例700。化合物60沉积在室710内并通过电阻加热器715(通过促动器720启动)加热。加热时,通过将进入外壳10的惰性气体经惰性气体入口725和阀728经化合物的表面将一些化合物60蒸发并从室710排放。惰性气体和蒸发的化合物的混合物通过通道730,然后与穿过管735的气体混合。
参照图20描述本发明的气溶胶化设备的第九个实例800。导热基片802通过电阻加热器810在管820的上游端加热,并使热能能够沿基片802前进。当在特定位置观察时,这产生一加热速率(它是由导热基片的特征确定的)。通过改变材料及其横截面积,可以控制加热速率。在一端将电阻加热器埋入基片802中。然而,可以将其埋入两端或者沿基片的许多位置,并且仍然能够使温度梯度沿载体和/或基片移动。
参照图21和22描述本发明的气溶胶化设备的第十个实例900。将空气引导通过沉积有药物的细网眼金属筛902。筛902横穿风道通道910放置(例如,由18mm玻璃管构造)。筛的两边与带电的电容器920通过硅控整流器(SCR)922电连接构成一个电路。电容器的电荷经过计算并调整在这样的一个值,当驱动器930关闭SCR 922时,来自电容器920的能量转变成在筛902内上升的所需温度。
常规考虑
本发明的设备利用穿过化合物(60)表面的气流(例如空气)清扫掉蒸发的分子。与冷凝相反,该过程驱动蒸发,因此能够在相对适中的温度下形成气溶胶。烟碱(1mg,bp 247℃/745mm),例如,在本发明的设备内在约130℃下在不到2秒钟内蒸发。类似地,芬太尼(bp>300℃/760mm)在约190℃下以高达2mg的量蒸发。
使用本发明的设备产生的气溶胶的纯度是通过限制化合物(60)与高温接触的时间提高的。这是通过快速加热化合物的薄膜以蒸发它来实现的。然后在进入载体气流之后立即将该蒸汽冷却。
典型地,化合物60经受至少1,000℃/秒钟的温度升高。在某些情况下,化合物经受至少2,000℃/秒、5,000℃/秒、7,500℃或10,000℃/秒的温度升高。当涂布有薄膜(例如,厚度在10μ-10nm之间)时,易于在化合物内快速升高温度。化合物时常涂布有厚度在5μ-10nm、4μ-10nm、3μ-10nm、2μ-10nm、或者甚至1μ-10nm的薄膜。
快速升温和薄涂层确保了化合物基本上在短时间内蒸发。典型地,大于0.1mg、0.25mg、0.5mg、0.75mg或1mg的化合物从加热开始在小于100微秒内蒸发。时常地,相同量的化合物从加热开始在小于75微秒、50微秒、25微秒、或10微秒内蒸发。
在本发明的设备中因快速加热获益的化合物的实例包括亲脂物质#87和芬太尼。亲脂物质#87当在425℃下加热5分钟时90%以上都分解,但是温度低于350℃时仅20%分解。当加热时间降至30秒钟时物质的分解进一步降低至约12%,并且在10-50微秒时物质的分解降低至小于2%。芬太尼样品当加热至200℃持续30秒时完全分解,并且当加热持续10微秒时仅有15-30%分解。在设备1中蒸发芬太尼只有小于0.1%分解。
本发明的气溶胶含有MMAD在10nm-1μ之间,优选10nm-900nm,10nm-800nm,10nm-700nm,10nm-600nm,10nm-500nm,10nm-400nm,10nm-300nm,10nm-200nm,或者10nm-100nm的颗粒。产生的颗粒其尺寸稳定几秒钟(例如,1-3秒钟)。气溶胶粒径和接下来的稳定性是通过化合物蒸发的速度、载体气加入的速度和最终蒸汽与载体气的混合控制的。这种控制是使用许多方法实现的,该方法包括如下:(a)测定其质量并调节混合气体的流速;和/或,(b)调节化合物的蒸发速度(例如,通过改变加热过程中转移到化合物上的能量或者改变加入到加热区的化合物的量)。
所需粒径是通过将化合物以其蒸汽状态以这样的比例混入一定体积的载体气中实现的:当混合物的数量浓度达到约109个颗粒/mL时,获得以10nm-100nm的粒径范围存在持续1-3秒钟的颗粒。
图23是由数学模型计算的理论数据的图。参见“AerosolTechnology”W.C.Hinds,第二版1999,Wiley,New York。它显示了作为颗粒浓度的函数的该数量浓度的气溶胶聚集至其最初值的一半花费的时间(以秒计)。例如,1.0mg蒸发剂量的化合物(分子量为200,混入1升空气)在这一升中具有约3×1018个分子(颗粒)。这使得数量浓度是3×1015/cc。从图23外推,可以看到在该实例中颗粒数量减半时需要小于10微秒。因此,为了确保蒸发的化合物均匀混合,混合必须在非常短的时间内进行。图23还显示了当混合物的数量浓度达到约109个颗粒/cc时,为了通过吸入递送药物的目的,粒径是“稳定”的。
图23是针对凝结系数(K)为5×10-16m3/秒的气溶胶。该K值相当于粒径为200nm。随着粒径变化,其K值也可以变化。下表1给出了不同粒径的K值。当K增加时,气溶胶从特定粒径聚集到较大粒径所需的时间减少。从表1和图24可以看到,当颗粒在10nm-100nm的范围内时,改变K的效果趋于加速朝100nm粒径的聚集过程。
表1
  粒径(以nm计的直径)   凝结系数(xe-15m3/秒)
  1   3.11
  5   6.93
  10   9.48
  20   11.50
  50   9.92
  100   7.17
  200   5.09
  500   3.76
  1000   3.35
  2000   3.15
  5000   3.04
  10000   3.00
在产生特定粒径的气溶胶时,蒸发的化合物的质量与混合气体的体积之比是该控制条件。通过改变该比率,可以操作该粒径(参见图29)。然而,不是所有化合物和所有的气体,用相同的比率获得相同的粒径分布(PSD)。必须了解其它因素才能精确地预测最终粒径。化合物的密度、极性和温度是这些因素中的一些例子。此外,化合物是否亲水或疏水将影响最终粒径,这是由于通过从周围环境吸水因而该因素影响气溶胶的生长趋势。
为了简化用于预测最终粒径的设备,进行以下假设:
1.化合物为非极性的(或者具有弱极性)。
2.化合物与干燥的混合气体一起为疏水或亲水。
3.最终气溶胶在标准温度和压力下或者接近标准温度和压力。
4.凝结系数在该粒径范围内是恒定的,因此预测粒径稳定性的数量浓度是恒定的。
因此,在预测最终粒径时考虑以下变量:
1.化合物的蒸发量(以克计)。
2.混合到蒸发化合物中的气体体积(以cc计)。
3.以颗粒数/cc计的“稳定的”数量浓度。
4.气溶胶的几何学标准偏差(GSD)。
当GSD是1时,所有粒径是相同大小,因此粒径的计算成为将化合物的质量除以通过数量浓度给出的颗粒的数量并使用化合物的密度计算粒径。如果GSD不是1,那么该问题变得不同。当气溶胶从GSD为1变为GSD为1.35时,质量中值直径(MMD)将增加。MMD是在较小粒径的颗粒中和较大粒径的颗粒中存在相同量的物料的平衡点。由于当GSD变化时总量不变,并且由于存在大颗粒和小颗粒,因此当GSD增加时,由于颗粒的质量随着其直径的立方而增加,因此该MMD必定变大。因此较大颗粒实际上载有较大重量,并且该MMD变得较大而不能使质量平衡。
为了测定GSD变化的影响,可以用具有已知MMD、GSD、密度和数量浓度的气溶胶的单位体积的质量的公式。该公式来自Finlay的“The Mechanics of inhaled Pharmaceutical Aerosols”(2001,Academic出版社)。公式2.39描述了气溶胶的单位体积的质量是:
M=(pNπ/6)(MMD)3 exp[-9/2(lnσg)2]
其中:ρ=密度(以gm/cc计)
N=数量浓度(以颗粒/cc计)
MMD=质量中值直径(以cm计)
σg=GSD
M=气溶胶的单位体积的质量(以gms/cc计)
当气溶胶从一个GSD变为另一GSD,同时密度、数量浓度和质量保持不变时,如果考虑NMD变化,那么可以建立以下等式:
ρNπ/6(MMD1)3exp[-9/2(lnσg1)2]=ρNπ/6(MMD2)3exp[-9/2(lnσg2)2]
简化为:
(MMD1)3exp[-9/2(lnσg1)2]=(MMD2)3exp[-9/2lnσg2)2]
或者
(MMD1)3/(MMD2)3=exp[-9/2(lnσg2)2]/exp[-9/2(lnσg1)2]
如果设定第一种情况的GSD是1.0,那么:
exp[-9/2(1nσg1)2=1
并且因此:
(MMD1/MMD2)3=exp[-9/2(lnσg2)2]
或者:
MMD1/MMD2=exp[-3/2(lnσg2)2]
计算GSD变化时的NMD变化是有益的。解决MMD2为MMD1的函数并获得新的GSD2
MMD2=MMD1/exp[-3/2(lnσg2)2],其中σg1=1
为了计算MMD1,将化合物的质量除以颗粒的数量,然后使用化合物的密度计算其直径。
MMD1=(6C/ρNV)1/3,其中气溶胶的GSD是1
其中:C=化合物的质量(以gm计)
ρ=密度(以gm/cc计)(如前述)
N=数量浓度(以颗粒/cc计)(如前述)
V=混合气体的体积(以cc计)
将MMD1插入上面的等式中得到:
MMD2=(6C/ρNVπ)1/3[exp[-3/2(lnσg2)2],以厘米计。
可以由数量浓度、化合物的质量、化合物密度、混合气体的体积和气溶胶的GSD计算最终MMD。
所需的蒸发速率取决于所需获得的粒径。如果粒径在10nm-100nm的范围内,那么化合物,一旦蒸发,在大多数情况下必须混合到最大可能体积的空气中。该空气的体积是由肺生理机能决定的并且可以假定具有2升的合理上限。如果空气的体积限定小于2升(例如,500cc),那么将获得太大的颗粒,除非剂量极小(例如,小于50μg)。
在10nm-100nm的范围内,剂量可以是1-2mg。如果该剂量混入2升空气中,它将在1-2秒内吸入,所需且所希望的蒸发速率是在约0.5-约2mg/秒的范围内。
本发明的第一个实例示于图1并且是上面引证的原理在实验室已得到证明的基本设备。在实施例中详细描述了该设备。
在图9中所示的本发明第二个实例中,使用横截面减少的风道将通过化合物表面的空气的速度增加至约10米/秒。如果在1微秒内发生充分混合,那么气体与蒸发混合物必须经过以实现充分混合的距离必须不大于10毫米。然而,在化合物聚集到较大粒径之前发生充分混合是较理想的,这样所需的混合距离通常是约1毫米或更小。
在图10-13中所示的本发明第四个实例中,在加热过程中通过将空气在化合物的薄膜上清扫产生具有MMAD在10nm-100nm的范围内的气溶胶。由于在薄膜表面附近的化合物的部分压力降低,使得化合物在较低温度下蒸发。
图14所示的第五个实例、图15和16所示的第六个实例以及图19所示的第八个实例克服了在高温下某些化合物与氧快速反应的问题。为了解决该问题,将该化合物在可膨胀的容器内(第四个实例)、小容器外壳于真空下或含有少量,例如,约1-约10ml的惰性气体(第五个实例)中加热。一旦化合物蒸发并与惰性气体混合,同时该气态混合物保持在足够保持化合物在蒸发状态的温度下,然后将该气态混合物注入气流中。该体积的惰性气体也可以在受热化合物的表面上循环以有助于其蒸发,如图16所示。在第七个实例中,化合物以纯蒸汽加入到气体中。这涉及在炉或其它容器中将化合物蒸发,然后通过一个或多个混合喷嘴将蒸汽注入到空气或其它气流中。
在图17-18所示的第六个实例中,气体通过第一个管并在离散基片颗粒(具有大的表面积与质量比,并且涂布有该化合物)上。如图17所示,将这些颗粒加热以将化合物蒸发,或者将气体加热并且受热的气体蒸发该化合物,如图18所示。来自第一个管的气态混合物与通过第二个管的气体混合以将该混合物快速冷却,然后将其给予患者。
图20所示的第八个实例是与用于实验室试验的设备1类似的热梯度设备。该实例也具有一个移动加热区,但是没有任何移动部分,它是通过建立一个随时间从设备的一端到另一端横向的加热梯度实现的。当加热区移动时,化合物的暴露部分连续受热并蒸发。以这种方式可以长时间地将蒸发化合物加入到气流中。
图21-22所示的第九个实例是筛设备并优选产生含有MMAD大于100nm的颗粒的气溶胶。在该实例中,气体导向细网眼筛,由此将待给予患者的药物沉积。
上面的实例可以产生药物没有显著分解的气溶胶。实现这一点的同时,通过使用短时间的加热循环在控制粒径下保持了所需的蒸发速率。在化合物表面上的气流是这样建立的,当化合物受热并达到首先可以蒸发的温度时,所得化合物蒸汽将立即在空气中冷却。在这些优选实例中,这是在大于加热区的区域内延伸增加的速度和混合区实现的。结果,由于达到化合物蒸发温度的瞬间化合物蒸发,因此不需要精确控制温度。此外由于在蒸发点也存在混合,因此在蒸发的同时快速地实现冷却。
本发明用于人吸入药物递送必须适应人体和呼吸生理机能的限制。在公共卫生、环境、毒理学和辐射安全性的领域中已进行了许多颗粒沉积在肺中的研究。从这些研究中收集的大多数模型和体内数据,涉及人们暴露于它们呼吸的空气中均匀分布的气溶胶,其中受试者不主动地做任何事情,从而使肺中沉积的颗粒最小化或最大化。国际放射防护委员会(ICRP)模型是这样的实例。(参见James AC,StahlhofenW、Rudolph G、Egan MJ、Nixon W、Gehr P、Briant JK、 The respiratory tract deposition model proposed by the ICRP Task Group,Radiation Protection Dosimetry,1991;第38卷:第157-168页)。
然而,在气溶胶药物递送领域,使患者以药物在肺中最大化沉积的方式进行呼吸。这种呼吸通常包括完全呼气,然后深吸入,有时以在规定吸入流速范围内,例如,约10-约150升/分钟,接着持续屏气几秒钟。此外,理想地,气溶胶不均匀地分布在吸入空气中,但是以气溶胶丸剂载入前面部分的呼吸,接着是一定体积的清新空气,这样气溶胶被吸入肺中,并通过该体积的清新空气冲洗出传导性气道、支气管和气管。通常成年人深呼吸体积为约2-5升。为了确保在整个成年患者群中恒定递送,药物丸剂的递送应在吸入空气的头1-1.5升左右完成。
作为人吸入药物递送的限制的结果,化合物应以最小的时间蒸发,优选不大于1-2秒钟。正如前面讨论的,将蒸发温度保持最小也是有益的。为了在保持最小的温度下在2秒钟或更少的时间内蒸发化合物,快速空气移动,在约10-约120升/分钟的范围内,应流过化合物的表面。
由于人肺的生理学、颗粒生长的物理学以及所需化合物的物理化学,在使用本发明的设备时以下参数是最佳的:
(1)化合物应在约1-2秒内蒸发以产生超细范围的颗粒。
(2)应将化合物尽可能快地升高至蒸发温度。
(3)一旦蒸发,化合物应尽可能快地冷却。
(4)化合物应升高至最大温度持续最小时间以使分解最小化。
(5)空气或其它气体应快速通过化合物的表面以获得最大蒸发速率。
(6)空气或其它气体的加热应保持最小,即温度的增加不超过室温15℃。
(7)化合物应以恒定速率与空气或其它气体混合以具有恒定且可重复的粒径。
(8)气体速度增加当超过蒸发的化合物时,通过该设备的横截面积应降低。而且,当化合物的表面积增加时,气体的加热增加。
为图2-5、7和8所示的实例之一设计的参数是满足和平衡上面所列竞争参数的结果。含有MMAD在10nm-100nm之间的颗粒的气溶胶的一个特别重要要求是化合物,在需要在至少1秒钟的时间内蒸发的同时,也需要使每一部分的化合物经受尽可能短的加热时间。在本实施例中,化合物沉积在薄箔基片上并且沿加热该基片的薄箔基片扫过交变磁场,这样化合物在不超过约1秒钟的时间内相继蒸发。由于磁场的清扫作用,每一段化合物具有远低于1秒钟的加热时间。
在上面直接提到的实例中,化合物放在金属薄箔上。在下面所述的一个实施例中,使用不锈钢(302、304或316合金),其中表面经过处理以产生粗糙质地。可以使用其它薄箔材料,但是材料的表面和质地是重要的,这样当化合物为其液相时通过该化合物将其“湿润”,否则对液体化合物而言可以“滚成球”(将破坏设备的结构并显著改变挥发参数)。如果液体化合物“滚成球”;可以将化合物吹入并通过气流拾起,即使没有蒸发。这样导致递送没有控制和不希望的粒径。
由于不锈钢具有较低的导热值,热量没有显著增加,因此它与类似铝的材料相比具有益处。由于该过程产生的热量需要保持在感兴趣的直接区域,因此低的导热性是有帮助的。
实施例
下面的实施例进一步描述了本发明的方法和各种实例。这些实施例是描述的目的,并不意味着以任何方式限制权利要求书的范围。
实施例1
使用实例1的体内结果
在该实施例,实施例1中,设计将20μg-500μg之间的试验剂量的芬太尼,以超细粒径的范围内,以约800cc的空气递送给10kg的狗。试验时每只狗的肺体积约为600-700cc,并且该设备经过设计以将化合物以吸入的头一半递送到肺。由于这些参数值,该试验中的设备1可以认为是一个向人给予剂量的1/4等级设备。据信测量设备对人受试者的工作包括主要增加通过该设备的气流。将化合物加入到加热/蒸发/混合区的时间段经过调整,使得化合物蒸发到一定体积的空气中(该体积适用于狗肺解剖学所需的体积(600-700cc)和控制化合物与空气之比所需的体积。
以下是每一操作期间发生的事件的顺序:
1.在运行开始时,操作者触发吸入控制器30开始监控来自压力传感器240和输入流量计4的读数。
2.控制器30发信号到控制器20开始实例1并开始收集来自两个温度传感器和流量计4的数据。
3.在预编程的延迟之后,实例1开始产生气溶胶。(注:在控制器30开始和气溶胶开始产生之间存在约0.4秒钟的延迟)。
4.在独立的预编程延迟(从最初的触发器信号)之后,控制器30打开输入阀58开始在试验条件下被迫吸入到狗中。
5.在吸入期间实例1完成气溶胶的产生。
6.在整个吸入过程中控制器30监控流量计4和压力传感器240,并在满足预定体积或压力时关掉输入阀58的流动。(注:预定压力是防止伤害受试动物的安全特征。以预定体积终止呼吸是试验所需发生的。)
7.在保持屏气延迟(5秒钟)之后,打开排气阀40并使狗呼气。
8.呼出的气溶胶捕获到排气过滤器40上用于后面的分析。控制器30记录如下值:分散的体积、最终压力、空气脉冲的时间和平均流速。控制器20以微秒分辨率连续记录输入流速、排放流速、薄箔温度、钳口垫片温度、滑道位置、加热器开/关时间和其它内部诊断电参数。
3个重量匹配的beagle母狗以100μg静脉内丸剂剂量接受芬太尼。相同的狗吸入接受粒径为80nm(MMAD)的芬太尼UF(100μg气溶胶化并以两个连续活化的设备1给予,含有约50μg芬太尼基料)。通过图1所示的系统将该气溶胶给予麻醉的狗,目标递送体积是600-700ml空气,接着保持屏气5秒钟。给药之后,在2分钟-24小时的不同时间点获得血浆样品用于药动学分析。将留在设备1中的芬太尼回收并测定。使用验证的GC法测定芬太尼浓度,测定极限是0.2ng/ml。
将本实施例的血浆药动学与相同狗的静脉内(IV)芬太尼(100μg)相比。吸入芬太尼使得吸收快(Cmax,血浆中的最大浓度,11.6ng/ml以及Tmax,最大时间,2分钟)并且生物利用率高(84%)。吸入芬太尼的时间与IV芬太尼的接近相同。因此,吸入用的芬太尼UF具有与IV注射相似的接触图谱。
使用标准非间隔药动学方法计算每一动物的药动学参数。通过测定该数据确定血浆中的最大浓度(Cmax)和进行的最大时间(Tmax)。测定血浆浓度相对时间的曲线(AUC)下的面积。如下确定吸入的芬太尼的生物利用率(F):
F=(DIV/DINHAL)*(AUCINHAL/AUCIV)
其中D是剂量,AUC是最后可测定的时间点的AUC。
图26绘制了使用上面以实例1所述的设备1获得的狗的血液水平的数据(对IV剂量和吸入剂量)。
芬太尼气溶胶被快速吸收,在两个给药路径观察到相同的Tmax(2分钟,最早时间点)。芬太尼气溶胶的最大血浆浓度(11.6±1.9ng/ml)差不多是IV芬太尼(17.6±3.6ng/ml)的2/3。在IV给药6-8小时之后以及在吸入气溶胶3-4小时之后,血浆浓度低于定量测定极限。生物利用率计算是以观察至吸入给药的最后可测定时间点的AUC为基础。吸入研究的生物利用率是84%(以标称(未校正的)芬太尼剂量为基础)。
在IV(75.4分钟)和吸入剂量之后的平均血浆消除半衰期相似。在两种给药路径之后分布相半衰期(3-4分钟)也相似。在吸入之后药动学参数的动物间变异性低,相对标准偏差(RSD<25%)低于IV给药观察到的。
实施例2
使用实例1的体外结果
下表2汇总了使用实例1在体外测定芬太尼收集的数据。粒径是用Moudi阶式碰撞取样器测定的。
表2
  化合物质量(μg)   混合空气体积(cc)   MMAD(nm)   GSD
  20   400   71   1.9
  25   400   72-78   1.7-1.8
  50   400   77-88   1.7-185
  100   400   100-105   1.4-1.8
  200   400   103-123   1.6-1.9
  300   400   140-160   1.8-2.1
实施例3
使用实例1制备气溶胶细粒
在本实施例中,将实例1略作改动并改变流速,如下面讨论的,制备粒径范围在1-3微米的细气溶胶。
去掉风道段140并改变空气通道加热/蒸发区70。风道插入物(未显示)具有在薄箔上0.25英寸的“顶盖”。没有混合棒,因为在本实施例中不需要快速混合。由于这两个设备改变,因此与空气的混合小得多,故蒸汽/气溶胶烟雾与较少的空气混合并产生较大粒径的气溶胶。在本实施例中气流速率低于1升/分钟。再者,这能够使蒸汽与较少的空气混合,获得较大粒径的气溶胶。
用高荷载化合物的实例1中的薄箔64遇到一些操作问题。测定的化合物,邻苯二甲酸二辛酯(DOP),是一种油,并且在气溶胶化过程中,大量随风吹走并未气溶胶化。将3个另外设计的替代物解决该问题,包括改变沉积有该化合物的基片表面。在这三个替代物中,通过利用质地使该基片“夹持”该化合物。它们是:a)质构化薄箔;b)在薄箔上加上不锈钢筛;和,c)用不锈钢细筛代替薄箔。
本实施例的结果列于下表3:
表3
  基片类型   MMAD,微米   GSD  放出的剂量,μg
  质构化薄箔   1.49微米   1.9  97
  质构化薄箔   2.70微米   1.95  824
  仅有细筛   1.59微米   1.8  441
  仅有细筛   1.66微米   1.8  530
  筛在薄箔上   2.42微米   2.2  482
正如上面所示的,使用设备1仅仅通过改变化合物与混合空气的比例可以获得细小粒径。
实施例4
使用实例700的体外结果
将一罐部分填充DOP并放置在一个具有入口和出口的炉(未显示)内。将DOP用作测定化合物。该罐用氦气冲洗,然后加热该罐至其内容物的温度为350℃。将氦气泵送通过该罐并用于将DOP蒸汽带出出口。氦气和蒸发的化合物60的气态混合物通过喷嘴被加入到不同大小的混合管中。每个管中有空气以14升/分钟通过它们。喷嘴与流动方向垂直。该气态混合物与空气混合之后,将所得气溶胶加入到平行流动的扩散电池中用于粒径分析。结果列于下表4。
表4
  混合管径(ID)   MMAD   GSD
  4.8mm   65nm   1.3
  14mm   516nm   3.3
从上面可以看出,当管径增大时,粒径也增大。此外,当该直径较大时,GSD也较大。当管较大时,据信由于蒸发的气体以点来源加入,该气体加入到较小片段的混合气体中,导致不均匀混合,结果GSD大。
实施例5
使用实例800的体外结果
为了证实实例800的效力,在一4-英寸长的铝片的一端配置一个150-瓦的盒式加热器。该加热器用variac直流电变压器供电。铝片的厚度经过设计以确保在大致30秒钟内热量从铝片的一端横穿至另一端。
在铝片的上面,机械制造一个缺口以装该化合物并固定两个顶盖之一。用于化合物的缺口约为3.5英寸长和0.4英寸宽。缺口深0.025英寸,并填充有1mg的DOP。
第一个顶盖由加热表面之上0.04英寸放置的一块平玻璃片组成,产生一风道。在其出口端配备一出口以能够将空气抽入分析测定设备。使空气以15升/分钟的速度流过该风道。
在第二个构型中,顶盖用由玻璃制成的半圆柱体替换。这样使风道的横截面积增加了一个数量级。
对这两个构型测定粒径并显示受风道横截面积的影响。
得自热梯度试验的结果列于下表5:
表5
  盖大小和横截面   MMAD   GSD
  小   92nm   1.4
  大   650nm   未知
如上所示,结果证实横截面变大时,粒径也变大。
实施例6
使用实例900的体外结果
在制备气溶胶的本实施例中,风道通道910由直径为18mm的玻璃管构成。然而,该通道可以由任何合适材料制成横截面积相当的任何形状。在本实施例中选择筛大小、目和化合物的量,以便气体可以通过筛,并且一旦化合物沉积到其上面也没有干扰。
由于筛的内电阻低,即为0.01-0.2欧姆,因此电容器的放电速率(RC时间常数)快,并在几微秒的级别,即小于20微秒,优选在约2-约10微秒的范围内。通过电容器902放电和接下来的筛902加热,沉积的化合物快速蒸发。由于空气通过筛902移动,因此蒸发的化合物与空气快速混合并冷却。
该化合物沉积在由316不锈钢制成并且具有2.54cm×2.54cm的尺寸的不锈钢细筛上,例如200目。电容器的电流在一边与另一边之间通过。由于空气快速移动,该化合物以较低的温度蒸发,因此不需要将该筛加热至可与实施例1中的薄箔相比的温度。由于只要蒸汽一形成,气流恒定地从表面将化合物蒸汽带走,因此空气快速移动能够使化合物以较低蒸汽压蒸发。因此,化合物以较低温度蒸发而不会分解。
化合物沉积在筛上是通过化合物与有机溶剂混合直到化合物溶解实现的。然后将所得溶液涂敷到不锈钢细筛902上并使溶剂蒸发。然后将筛插入夹持器940上,从而将筛902的两侧与上面所述的电路电连接。
将一10,000mF电容器放电,同时使气体通过筛902。筛快速加热导致化合物快速蒸发为气体。因此所得蒸发的化合物混合到少量气体中。由于化合物的质量与混合气体的体积之比大,因此制得气溶胶细粒(1-3微米直径)。
实施例7
筛分药物以确定气溶胶化合意度的常规步骤
将药物(1mg)溶解或悬浮在最少量溶剂(例如,二氯甲烷或甲醇)中。将该溶液或悬液吸移到3cm×3cm的铝薄箔片的中间部分。将该涂布的薄箔围绕1.5cm直径小瓶的末端缠绕并用石蜡固定。将加热板预热至约300℃,并将该小瓶向下放置在薄箔侧。在开始挥发或分解之后,将小瓶在该加热板上放置10秒钟。除去该加热板之后,将小瓶冷却至室温。除去薄箔,小瓶用二氯甲烷萃取,接着用饱和NaHCO3水溶液萃取。将有机和含水萃取物一起摇荡,分离,并将有机萃取物在Na2SO4上干燥。取出有机溶液的等分试样并注入到逆相HPLC,通过吸收225nm光测定。优选通过该方法分离的药物的纯度大于85%的药物用于气溶胶化。这种药物具有小于0.15的分解指数。该分解指数是通过1减去纯度百分数(即,0.85)获得的。
本领域技术人员可以将前述实施例组合或者构成本发明的方法和设备的各种其它实施例和方面以使它们适应特定用途和条件。而且,这些改变和改进都合适、公正且打算在以下权利要求书的所有等价范围内。

Claims (10)

1、一种递送含药物的气溶胶用于吸入治疗的设备,包括:
一外壳;
在所述外壳内的风道,包括气体/蒸汽混合区,其中该风道包括一部件,并且其中该部件包括一金属基片,并且其中包含药物的组合物涂布到该基片上,
阀,用于控制所述风道内的气流;和
加热器系统,用于在所述外壳内加热金属基片以蒸发涂布到该基片上的药物。
2、如权利要求1的设备,其中加热器系统是电阻加热器。
3、如权利要求1的设备,其中该风道沿气体/蒸汽混合区含有一有限的横截面积。
4、如权利要求1的设备,其中金属基片包括不锈钢。
5、如权利要求1的设备,其中该加热器系统是一感应加热器系统。
6、如权利要求3的设备,其中该风道包括空气通过风道移动时引起紊流的装置。
7、如权利要求1的设备,其中该加热器系统以至少1000℃/秒的速率加热该金属基片。
8、如权利要求1的设备,其中涂布到基片上的药物的涂布厚度为10nm到10μm之间。
9、如权利要求8的设备,其中组合物中的药物具有小于0.15的分解指数。
10、如权利要求8的设备,其中组合物中的药物具有小于0.05的分解指数。
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US20030015196A1 (en) 2003-01-23
US7942147B2 (en) 2011-05-17
DE60236430D1 (en) 2010-07-01
CA2447354C (en) 2008-12-02
CA2646756C (en) 2010-10-26
AU2007207865B2 (en) 2010-06-03
WO2002098389A8 (en) 2006-10-12
HUP0401948A3 (en) 2008-04-28
CZ20033223A3 (cs) 2004-07-14
EP1392242A1 (en) 2004-03-03
CA2447210C (en) 2007-09-11
CA2447081C (en) 2010-02-23
US7766013B2 (en) 2010-08-03
US20030062042A1 (en) 2003-04-03
CN100496458C (zh) 2009-06-10
US20170281884A1 (en) 2017-10-05
NZ529296A (en) 2008-07-31
PL374048A1 (en) 2005-09-19
US20030015197A1 (en) 2003-01-23
AU2002311926B2 (en) 2007-12-06
EP1392263A2 (en) 2004-03-03
JP2004532881A (ja) 2004-10-28

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