CN101366699B - 用于控制释放药物活性成分的新型脂质组合物气雾剂 - Google Patents
用于控制释放药物活性成分的新型脂质组合物气雾剂 Download PDFInfo
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- CN101366699B CN101366699B CN200810210952.0A CN200810210952A CN101366699B CN 101366699 B CN101366699 B CN 101366699B CN 200810210952 A CN200810210952 A CN 200810210952A CN 101366699 B CN101366699 B CN 101366699B
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- Prior art keywords
- lipid
- medicine
- salt
- plasticizer
- stabilizing agent
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- 150000002632 lipids Chemical class 0.000 title claims abstract description 153
- 239000000203 mixture Substances 0.000 title claims abstract description 95
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- 238000013270 controlled release Methods 0.000 title abstract description 6
- 239000008186 active pharmaceutical agent Substances 0.000 title abstract description 4
- 208000006673 asthma Diseases 0.000 claims abstract description 28
- 210000002345 respiratory system Anatomy 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims description 126
- 239000000470 constituent Substances 0.000 claims description 87
- 150000003839 salts Chemical class 0.000 claims description 83
- 229960002052 salbutamol Drugs 0.000 claims description 73
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 72
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- 239000003381 stabilizer Substances 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 45
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- 238000002360 preparation method Methods 0.000 claims description 25
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Abstract
本发明涉及一种采用囊泡保护剂的脱水脂质囊泡新制剂。该制剂可控制药物活性物质的释放,并将其递送到呼吸***中,特别适用于哮喘的治疗。该制剂在吸入后使药物活性物质可在0至72小时内控制释放,将全身作用改变为局部作用,延长给药的治疗周期,增加药物的有效作用时间和稳定性,并且减小药物的剂量、减少药物对全身的副作用,全面降低药物的毒性。
Description
技术领域
本发明涉及脂质囊泡,特别是涉及哮喘及其它病症的治疗。
技术背景
哮喘是一种呼吸***慢性疾病,其中气道非连续地收缩,具有有关的炎症。这引起以下症状:诸如咳嗽,喘鸣,和呼吸浅促且胸闷。哮喘症状,从轻微的乃至危及生命,通常可被支气管扩张药或其药物组合控制。发达国家特别关注哮喘,原因在于它的流行性快速增加,影响高达四分之一的城市儿童。见Lilly CM.Diversity of asthma:Evolving concepts ofpathophysiology and lessons from genetics(哮喘的多样性:病理生理学的进化概念和来自遗传学的教导)。J Allergy Clin Immunol(***反应临床免疫杂志)。2005;115(4增刊):S526-31。
动物模型已经证实A2B拮抗药在呼吸炎症、纤维变性和气道重建中的作用,参见D.Zeng&R.Polosa(2006)欧洲呼吸道疾病.2006;26-27。哮喘的原因在于特殊类型的天然杀手细胞。这意味着经常没有用正确种类的药物活性成分治疗哮喘。例如,天然杀手T细胞似乎对于广泛使用的吸入器中的皮质类固醇具有耐受性,见Cromie,William J.哈佛大学公报(Harvard University Gazette),哈佛***公室,2006-03-16,2006年9月23日检索。
糖皮质激素是最广泛使用的具有预防哮喘的活性药物成分,诸如环索奈德,倍氯米松,布***,氟尼缩松,氟替卡松,莫米松,曲安西龙等。长期使用皮质类固醇具有许多副作用,特别是高剂量的类固醇可以引起骨质疏松症。当前长效的β-肾上腺素受体激动剂,包括持续释放的口服舒喘宁、sameterol、福莫特罗(formoterol)和班布特罗(bambuterol)是可用的。然而,美国食品和药品管理局(FDA)在2005年11月发布健康报告;警告长效β-2激动剂的使用可以导致症状的恶化,甚至有时导致死亡。研究报告 三种常见的含有药物活性成分沙美特罗(salmeterol)或福莫特罗(formoterol)的哮喘吸入器在美国每年可以引起五分之四与哮喘相关的死亡,并且应该从市场取缔,Ramanujan,Krishna(2006-06-09)。Cornell Chronicle Online(康奈尔新闻在线)。Cornell News Service(康奈尔新闻服务)。2006年9月23日检索。
支气管扩张药被推荐用于短期缓解所有患者的哮喘症状。对于持久性哮喘疾病,可用较高剂量的糖皮质激素可以用长效β-2激动剂,茶碱,白细胞三烯调节剂,或肥大细胞稳定剂。喘鸣和气短症状的控制一般用快速作用的支气管扩张药来实现。药物活性成分包括选择性β-2肾上腺素能受体激动剂,诸如沙丁胺醇(舒喘宁),叔丁喘宁,左旋沙丁胺醇(levalbuterol),和比托特罗。在较高的剂量下,某些药物活性成分可能由于其β-1激动活性可导致对心脏的副作用,诸如心率加快或血压升高。随着选择性药物的出现,这些副作用虽然已经变得不太常见,但患者还是必须谨慎避免频繁地使用这些药物,因为频繁使用这些药物可引起其功效下降,药效灵敏性下降,使症状恶化,最终可导致难治性哮喘和死亡。早期的、较低选择性的肾上腺素能受体激动剂,诸如吸入的麻黄碱和肾上腺素片剂也在使用中。这些药物的心脏副作用发生的比率类似于舒喘宁,Hendeles L,MarshikPL,等。Response to nonprescription epinephrine inhaler during nocturnalasthma(在夜间哮喘期间对于非处方肾上腺素吸入器的响应)Ann Allergyasthma Immunol(***反应哮喘免疫学年报);2005年12月;95(6):530-4,和Rodrigo GJ,Nannini LJ.Comparison between nebulized adrenaline and β-2agonists for the treatment of acute asthma.A meta-analysis of randomizedtrials(用于治疗急性哮喘的雾化的肾上腺素和β-2激动剂之间的比较.随机试验的元分析);Am J Emerg Med.(美国急救医学杂志);2006年3月;24(2):217-22。它们经由注射的使用已经减少了,原因就在于相关的副作用。现在它们通常存贮于袖珍形的,可控剂量的吸入器或哮喘储雾器(spacer)或喷雾器中。
以适当的载体靶向传递药物活性成分的尝试经常是不成功的。制备用于吸入的药物活性成分似乎是快速被吸收的,这使得需要频繁给药,同时也增加了全身的副作用。它还可以导致呼吸组织的粘膜损伤,所述损伤由 经鼻或经口吸入给药必需的氟烃推进剂、溶剂、或其它添加剂的反复使用所引起。携带药物活性成分的气雾剂微滴在提供最大的治疗益处时,应当避免多次给药。它应当在呼吸***中使药物活性成分控制释放,同时所述药物活性成分应当长期连续释放,用最小剂量的药物活性成分使平滑肌上的β-2激动剂维持在有效剂量上。开发用于这种治疗的适当载体制剂,药物活性成分治疗哮喘时伴随的副作用将会被减少。
Bystrom,K.,Nilsson,P.在美国RE38407(2001)中描述了通过肺部途径递送用脂质体包封镇痛药达到局部或全身镇痛的疼痛处理效果。Waldrep,J.C.,Knight,V.,Black,M.B.在美国5958378(1999)中采用约130-375mg/ml的磷脂,用于脂质体气雾剂递送约12-30mg/ml的药物活性成分,经由呼吸***治疗疾病。另外的脂质体治疗实例还包括用于呼吸道流感{Edwards,D.A.,Stone,H.A.:美国20050220720A1(2005)},肿瘤{Jin,T.,Zarif,L.,Mannino,R.:美国2006153217(2000)},局部呼吸道感染和囊性纤维变性{Hersch,E.M.,Petersen,E.A.,Proffitt,R.T.,Bracken,K.R.,Chiang,S-M.美国5958449(1999)}等。在Parmar,M.:美国20060051406A1(2006)中描述用Ca2+或Zn2+等共螯合物(cochleate)处理含有脂质体的两相聚合物溶液,以实现药物的有效递送。然而,脂质体囊泡既不易稳定储存,也不便于大量生产,因为大部分脂质容易分解,并且所述脂质体囊泡是数百纳米大小的,当分散在缓冲液中时其必须经历布朗运动,这可以导致脂质体囊泡的聚集和药物活性成分的渗漏。
Bystrom,K.,Nilsson,P.,美国6045828(1996)描述了开发用于吸入的脂质和药物活性成分的简单混合的粉末,其能够水化而形成脂质体。在该意义上,所述粉末是无水的。混有脂质粉末的制备方法采用具有低于37℃的相转换温度的磷脂。用于药物活性成分的迅速吸收的磷脂粉末公开在Weers,J.G.,Tarara,T.,Clark,A.:US 20040105820A1(2004)和Mezei,M.,Hung,O.:US RE38407(2004]中。
Radhakrishnan,R.:US 5049389(1991)公开了脂质颗粒剂型,其声称延长药物活性成分的释放,改善治疗比率,降低毒性,减少全身副作用,和稳定达数月。所述剂型特别适于哮喘的治疗。通过用脂肪酸酯修饰皮质类固醇而获得的新类固醇衍生物被结合在脂质体的脂质部分中用于经由 吸入的递送,导致实验动物呼吸道中延长的类固醇保留。在脂质体药物活性成分粉末中,包封在脂质体中的药物活性成分是均匀的,分散在载体中并且通过喷雾干燥和/或冷冻干燥转变为干粉。在吸入时,与脂质混合的药物活性成分在呼吸***中部分再水化和提供药物活性成分的释放。所谓的前体脂质体仅是药物活性成分和脂质的混合物,因此它难以包封药物并保持包封率,因为所述脂质体囊泡不仅可破裂或变形,并且所述药物活性成分可以在干燥和再水化过程期间从所述前体脂质体分离泄漏,而无论药物活性成分本身是水溶性的或水不溶性的。当然,一旦包封在再水化的脂质体囊泡中,药物活性成分必须等到细胞破坏所述囊泡时才得以释放。
从上面可以看到,对于使用脂质体或前体脂质体的药物活性成分的剂型,仍然有许多问题未解决。这些问题涉及对于释放速率进行适当控制的需要。
发明目的
本发明的主要目的是提供脱水的脂质囊泡组合物,其中所述药物活性成分可以成功包封在脂质体囊泡之内而在干燥和再水化过程期间不会破裂或变形,具有粒度可控制性和长期稳定性,所述脂质囊泡有效控制药物活性成分的效能。该组合物的一个相关目的是采用低剂量的药物活性成分降低药物毒性和全身性副作用并且整体提供所需的治疗效果。
发明概述
本发明涉及一种适用于哮喘治疗的新型脱水脂质囊泡制剂。特别是,所述组合物经由小粒径的气雾剂颗粒,使沉积在呼吸***中的药物活性成分有效控制释放,并且特别用于制备小气雾剂颗粒的吸入的和雾化的吸入的药物活性成分。
本发明的第一方面是提供可通过喷雾器或吸入器将各种药物活性成分递送到呼吸***组织中的脱水脂质囊泡的制剂处方。所述脱水脂质囊泡形成具有均匀和可控制的粒度,可以使药物活性成分被截留或包封,并且适合于将药物活性成分递送至呼吸***。
本发明的第二方面是提供对适用于吸入的水溶性和水不溶性药物活 性成分具有较高包封率的脱水脂质囊泡处方,其具有更低的毒性和副作用,可靶向到呼吸***组织并且在呼吸***组织中释放药物活性成分,不需要多次给药,并且以干燥形式提供长期而充分稳定的储存。
本发明的第三方面是所述脱水脂质囊泡药物活性成分组合物的药物活性成分在呼吸***中的控制释放,提供制备吸入给药且控制药物活性成分释放的脱水脂质囊泡组合物的方法;提供通过施用所述雾化的或/和吸入的脱水脂质体囊泡药物活性成分组合物来治疗哮喘的方法。
附图简述
图1脱水舒喘宁脱水脂质囊泡的TEM(透射电子显微镜)照片。
图2舒喘宁从脱水脂质囊泡到缓冲液中的释放图。
发明详述
根据本发明发现,当脂质体制备成含有稳定剂和/或增塑剂、诸如甘油时,舒喘宁及其它药物活性成分可以成功保留在脱水脂质囊泡中,用于在呼吸***组织中控制释放。所述稳定剂和/或增塑剂作为囊泡保护剂其作用,在冷冻干燥或喷雾干燥的干燥过程期间保持脂质体囊泡的形状,并且成为防止药物活性成分从脂质体囊泡渗漏的屏障。为了设计具有较高药物活性成分载药量以及能控制释放的最佳制剂,开发研究了许多不同的剂型,并且将所述许多不同的剂型与包含本发明组分的组合物以多种量和比例进行比较,以及与由全部种类的脂质或它们的混合物诸如卵磷脂、大豆磷脂、和合成的磷脂衍生物制备的常规脂质体进行比较。
在一个优选形式中,本发明提供通过吸入到呼吸***中来治疗哮喘的药物脂质组合物,所述组合物包含药用囊泡保护剂、药用脂质组分和药物活性成分的脱水脂质囊泡。
所述囊泡保护剂选自稳定剂和增塑剂。增塑剂是用于描述药物赋形剂功能的术语,但是各种不同的增塑剂没有共同的物理化学特性和化学结构。如在化学工业中通常认为,增塑剂是加入后可以给予柔性、可加工性、或伸展性的化学品。最频繁使用的是甘油,山梨糖醇,丙二醇,蔗糖和***胶也经常使用。本发明人通过参考结合在下列文献中的有关公开内 容:Michael E Aulton,(1988),Pharmaceutics:The science of Dosage DormDesign;international student edition(制药学:剂量形式设计;国际学生版)(1996),324页,Medical Division of Pearson Professional Ltd(皮尔逊专业公司医疗部,Churchill Livingstone,纽约,]。将乳糖,***胶等用作药物科学中的稳定剂或稳定试剂。对于其它的增塑剂和稳定剂,本发明人通过参考结合下列文献中的有关公开内容:Raymond C Rowe,Paul J Sheskey,和Sian C Owen,(2006),Handbook of pharmaceutical Excipients(药物赋形剂手册),第5版,药物出版社,Publications division of the Royal pharmaceuticalSociety of Great Britain,the American Pharmacists Association,USA(英国皇家药物学会出版部;和美国药师联合会,美国).,以及日本医药品添加剂协会(2005)医药品添加物事典,药事日报社,东京,日本。
所述稳定剂和/或增塑剂可在制备所述脂质囊泡以前和/或以后添加。
适合的候选载体保护剂是己二酸及其衍生物或盐,抗坏血酸及其衍生物或盐,天冬氨酸及其衍生物或盐,乙酰色氨酸及其衍生物或盐,N-乙酰苯胺及其衍生物或盐,氨基乙基磺酸及其衍生物或盐,丙氨酸及其衍生物或盐,***胶,亚硫酸氢钠,亚硫酸钠,精氨酸及其衍生物或盐,海藻酸及其衍生物或盐,苯甲酸及其衍生物或盐,异硬脂酸及其衍生物或盐,肌醇及其衍生物或盐,1,2-乙二胺及其衍生物或盐,异抗坏血酸及其衍生物或盐,赖氨酸及其衍生物或盐,可可脂,蓖麻蜡,黄原胶,木糖醇,柠檬酸及其衍生物或盐,甘氨酸及其衍生物或盐,甘油及其衍生物,葡糖酸及其衍生物或盐,谷氨酸及其衍生物或盐,肌酸酐,二异丙醇胺及其衍生物,二乙醇胺及其衍生物,环糊精,胱氨酸,半胱氨酸,二丁基羟基甲苯,酒石酸及其衍生物或盐,脂肪酸蔗糖酯,硬脂酸及其衍生物或盐,明胶,羊毛脂,鲸蜡醇,明胶,水解明胶,虫胶,D-山梨糖醇,失水山梨醇脂肪酸酯,山梨酸(sorbica acid)及其衍生物或盐,巯基乙酸及其衍生物或盐,硫氰酸钾,硫代苹果酸钠,麝香草酚,中链脂肪酸甘油三酯,葡聚糖,糊精,维生素E,D-葡萄糖二酸钙,生育酚及其同分异构体,氨丁三醇,烟酰胺,乳酸及其衍生物或盐,乳糖,脲,棉白糖,组氨酸及其衍生物或盐,羟丙基纤维素,氢醌(hyroquinone),苯丙氨酸,非那西丁,葡萄糖,延胡索酸及其衍生物或盐,丙二醇,肝素钠,聚维酮(povidone),顺丁烯二酸 及其衍生物或盐,丙二酸及其衍生物或盐,甘露糖醇,甲硫氨酸,十二烷基硫酸钠,苹果酸及其衍生物或盐,氢化油,芝麻油,山梨醇83(karion 83),二亚乙基三胺五乙酸及其衍生物或盐,琥珀酸二辛酯磺酸钠,聚二甲基硅氧烷-硅氧烷二氧化物混合物,失水山梨醇脂肪酸酯,甘油三乙酸酯,蓖麻油,邻苯二甲酸二乙酯/二丁酯,丁基邻苯二甲酰基甘醇酸丁酸酯,丙二醇(1,2-丙二醇),脂肪酸丙二醇酯,聚山梨醇酯,聚氧乙烯-聚氧丙烯二醇,聚乙二醇,十四烷酸异丙酯,棉籽油-豆油混合物,单硬脂酸甘油酯,亚油酸异丙酯,凡士林等。这些稳定剂和/或增塑剂可以作为混合物使用。
类似于甘油的优选候选物包括:
2-吡咯烷酮,
柠檬酸乙酰三丁酯,
柠檬酸乙酰三乙酯,
苯甲酸苄酯,
丁基邻苯二甲酰基甘醇酸丁酸酯
醋酞纤维素的相似相容物,
氯丁醇,
棉籽油-大豆油混合物,
糊精,
邻苯二甲酸二丁酯,
癸二酸二丁酯,
邻苯二甲酸二乙酯,
邻苯二甲酸二甲酯,
己二酸二辛酯,
邻苯二甲酸二辛酯,
D-山梨糖醇,
明胶,
甘油,
甘油的衍生物,
单硬脂酸甘油酯,
邻苯二甲酸羟丙甲纤维素的相似相容物
亚油酸异丙酯,
十四烷酸异丙酯,
山梨醇83(karion 83)
聚乙二醇,
甘露糖醇,
矿物油和羊毛脂醇,
棕榈酸
植物甾醇
聚乙二醇,
聚甲基丙烯酸酯的相似相容物,
聚氧乙烯-聚氧丙烯二醇,
聚山梨醇酯,
聚醋酸乙烯邻苯二甲酸酯
丙二醇,
芝麻油,
山梨醇
硬脂酸及其衍生物或盐,
甘油三乙酸酯,
柠檬酸三丁酯
三乙醇胺
柠檬酸三乙酯
及其混合物。
类似于乳糖的优选候选物选自以下列表:
***胶,
N-乙酰苯胺及其衍生物或盐,
乙酰色氨酸及其衍生物或盐,
己二酸
琼脂
丙氨酸及其衍生物或盐,
白蛋白
海藻酸及其衍生物或盐,
精氨酸(alginine)盐酸盐
氢氧化铝凝胶
硬脂酸铝
磺酸氨基乙酯及其衍生物或盐,
精氨酸及其衍生物或盐,
抗坏血酸及其衍生物或盐,
抗坏血酸棕榈酸酯
天冬氨酸及其衍生物或盐,
膨润土
苯扎氯铵
氯化苄乙氧铵
苯甲酸及其衍生物或盐,
丁基化羟基甲苯
可可脂,
D-葡萄糖二酸钙,
脲,
卡巴克络钠磺酸盐
羧甲基纤维素及其盐
羧基乙烯基聚合物
羧甲纤维素钙
羧甲纤维素钠
角叉菜胶
酪蛋白蛋白胨
蓖麻油,
蓖麻蜡,
醋酞纤维素的相似相容物,
长角豆属(ceratonia)
鲸腊醇,
氯丁醇,
柠檬酸及其衍生物或盐,
胶态二氧化硅
棉籽油-大豆油混合物,
肌酸酐,
环糊精,
半胱氨酸及其衍生物或盐,
胱氨酸,
葡聚糖,糊精,
糊精,
邻苯二甲酸二丁酯,
癸二酸二丁酯,
二丁基羟基甲苯,
二乙醇胺及其衍生物,
邻苯二甲酸二乙酯,
邻苯二甲酸二乙酯/邻苯二甲酸二丁酯,
丁基邻苯二甲酰基甘醇酸丁酸酯,
二亚乙基三胺五乙酸及其衍生物或盐,
二异丙醇胺及其衍生物,
邻苯二甲酸二甲酯,
己二酸二辛酯,
琥珀酸二辛酯磺酸钠,
甘草酸二钠
D-山梨糖醇,
乙二胺四乙酸盐
异抗坏血酸及其衍生物或盐,
乙基纤维素
乙二醇棕榈酸硬脂酸酯(ethylene glycol palmitostearate)
1,2-乙二胺及其衍生物或盐,
延胡索酸及其衍生物或盐,
果糖
明胶,
葡糖酸的衍生物或盐,
葡萄糖,
谷氨酸的衍生物或盐,
甘油及其衍生物诸如甘油单硬脂酸酯,
单硬脂酸甘油酯,
甘氨酸及其衍生物或盐,
瓜尔胶
肝素钠,
组氨酸及其衍生物或盐,
水化二氧化硅
氢化油,
水解明胶,
羟丙基纤维素,
羟丙甲纤维素(Hypromellose)
氢醌,
肌醇及其衍生物或盐,
转化糖
亚油酸异丙酯,
十四烷酸异丙酯,
异硬脂酸及其衍生物或盐,
山梨醇(karion)83,
乳酸及其衍生物或盐,
乳糖,
羊毛脂,
卵磷脂
赖氨酸及其衍生物或盐,
聚乙二醇,
硅酸铝镁
顺丁烯二酸及其衍生物或盐,
苹果酸及其衍生物或盐,
丙二酸及其衍生物或盐,
甘露糖醇,
中链脂肪酸甘油三酯,
甲硫氨酸,
微晶纤维素及其衍生物
矿物油和羊毛脂醇
单乙醇胺
烟酰胺,
果胶
凡士林,
非那西丁,
苯丙氨酸,
聚克立林钾
聚二甲基硅氧烷-硅氧烷二氧化物混合物,
聚氧乙烯聚氧丙烯二醇,
聚山梨醇酯,
聚乙烯醇
氯化钾
硫氰酸钾,
聚维酮(povidone),
1,2-亚丙基棓酸酯
丙二醇(1,2-丙二醇),
丙二醇海藻酸酯,
脂肪酸丙二醇酯,
丙二醇,
棉子糖
芝麻油,
荆芥穗
虫胶,
硅酸
乙酸钠,
海藻酸钠,
亚硫酸氢钠,
硼酸钠,
碳酸钠
辛酸钠
氯化钠,
十二烷基硫酸钠,
硬脂酰延胡索酸钠,
亚硫酸钠,
硫代苹果酸钠,
山梨酸及其衍生物或盐,
失水山梨醇脂肪酸酯,
山梨糖醇
硬脂酸及其衍生物或盐,明胶,
硬脂醇
脂肪酸蔗糖酯,
磺基丁基醚β-环糊精
硫
酒石酸及其衍生物或盐,
巯基乙酸及其衍生物或盐,
百里酚,
生育酚及其同分异构体,
海藻糖,
甘油三乙酸酯,
氨丁三醇,
维生素E,
棉白糖,
白蜡,
黄原胶,
木糖醇,
乙酸锌
氯化锌
及其混合物。
稳定剂和/或增塑剂与所述脂质的的合适摩尔比例是0.1%至40%的稳定剂和/或增塑剂;99.9%至60%的所述脂质。增塑剂与所述脂质的优选比例是1∶5至1∶50,诸如约1∶10。
药物活性成分通常包括:麻黄碱及其盐和酯类衍生物,伪麻黄碱及其盐和酯类衍生物,舒喘宁,茶碱,硫酸沙丁胺醇,沙甲胺醇,叔丁喘宁,奥西那林,非诺特罗,盐酸氯丙那林,甘草酸氯丙那林,妥洛特罗,5-(4-氨基-3,5-二氯苯基)-3-叔-丁基恶唑,5-(4-氨基-3,5-二氯苯基)-3-叔-丁基恶唑盐酸盐,克仑特罗盐酸盐,丙卡特罗,沙美特罗,海索那林,马布特罗,福莫特罗,甲氧那明,曲托喹酚,利米特罗,比托特罗,普罗托醇,瑞普特罗,吡布特罗,芬司匹利,异丙阿托品,异丙东莨菪碱,氨茶碱,二羟丙茶碱,胆茶碱,色甘酸钠,酮替芬,曲普利啶,曲尼司特,氯化铵,碘化钾,乙酰半胱氨酸,溴己新盐酸盐,羧甲司坦,氨溴索盐酸盐,愈创甘油醚,可待因,可待因磷酸盐,福尔可定,羟蒂巴酚,喷托维林柠檬酸盐,氯呱斯汀,磷酸苯丙呱林,美沙芬氢溴酸盐,奥昔拉定,依普拉酮,齐培丙醇,脱氧异丙嗪盐酸盐,福米诺苯,普罗吗酯,替培啶,苯佐那酯,普诺地嗪,noscactive药物成分,倍氯米松,倍他米松,布***,氯泼尼醇,可的松,可的伐唑,脱氧皮质酮,***,***,二氟可龙,氟可龙,氟可的松,氟米松,氟尼缩松,氟轻松,醋酸氟轻松,氟可托龙,醛甾酮,氟米龙,氟氢缩松,哈西奈德,氢化可的松,甲***,甲泼尼龙,帕拉米松,***龙,***,曲安西龙,硫酸奥西那林,异丙肾上腺素,肾上腺素,去甲肾上腺素,氟米松,甲羟松,氟替卡松,阿托品硝酸甲酯,异丙托溴铵,色甘酸钠,奈多罗米以及它们各自的药用盐或酯的一种或其中的几种。
作为治疗呼吸***病症的药物活性成分,例如,舒喘宁,特布他林(terbutalin)等是用于哮喘的药物。本发明人通过参考结合下列文献中的公 开内容:Bertram G.Katzung,(2001),Basic Clinical Pharmacology(基础临床药理学),第8版,医疗出版部,McGraw-Hill公司,美国。
药物活性成分与所述脂质组分的摩尔比通常是0.1%至200%。
优选的组合物中,舒喘宁在脱水脂质囊泡组合物中的浓度是0.1至300mg/ml。
所述优选的组合物是可以雾化成空气动力学直径--重量平均径(massmedian aerodynamic diameter)小于10μm的颗粒。
本发明提供一种治疗哮喘的方法,所述方法通过吸入途径将有效治疗量的脂质组合物用于需要治疗的患者,所述脂质组合物基本上由下列所组成:药物活性成分,选自增塑剂、稳定剂及其混合物的囊泡保护剂,和脂质组分,其被雾化成具有空气动力学直径--重量平均径小于10μm的气雾剂颗粒,并且在呼吸***中使药物活性成分的缓慢或控制释放。
在所述方法中,药物稳定剂和/或增塑剂脂质组合物形成脱水脂质囊泡,所述脱水脂质囊泡优选包含摩尔百分比为0.1%至40%的稳定剂和/或增塑剂,99.9%至60%的脂质,并且药物活性成分相对于所述脂质的摩尔百分比是0.01%至200%。
对于所述方法,所述药物活性成分可以包括:麻黄碱及其盐和酯类衍生物,伪麻黄碱及其盐和酯类衍生物,舒喘宁,茶碱,硫酸沙丁胺醇,沙甲胺醇,叔丁喘宁,奥西那林,非诺特罗,盐酸氯丙那林,甘草酸氯丙那林,妥洛特罗,5-(4-氨基-3,5-二氯苯基)-3-叔-丁基恶唑,5-(4-氨基-3,5-二氯苯基)-3-叔-丁基恶唑盐酸盐,克仑特罗盐酸盐,丙卡特罗,沙美特罗,海索那林,马布特罗,福莫特罗,甲氧那明,曲托喹酚,利米特罗,比托特罗,普罗托醇,瑞普特罗,吡布特罗,芬司匹利,异丙阿托品,异丙东莨菪碱,氨茶碱,二羟丙茶碱,胆茶碱,色甘酸钠,酮替芬,曲普利啶,曲尼司特,氯化铵,碘化钾,乙酰半胱氨酸,溴己新盐酸盐,羧甲司坦,氨溴索盐酸盐,愈创甘油醚,可待因,可待因磷酸盐,福尔可定,羟蒂巴酚,喷托维林柠檬酸盐,氯呱斯汀,磷酸苯丙呱林,美沙芬氢溴酸盐,奥昔拉定,依普拉酮,齐培丙醇,脱氧异丙嗪盐酸盐,福米诺苯,普罗吗酯,替培啶,苯佐那酯,普诺地嗪,noscactive药物成分,倍氯米松,倍他米松,布***,氯泼尼醇,可的松,可的伐唑,脱氧皮质酮,***,地 塞米松,二氟可龙,氟可龙,氟可的松(fluorocortisone),氟米松(flumethasone),氟尼缩松,氟轻松,醋酸氟轻松,氟可托龙(fluorocortolone),醛甾酮,氟米龙,氟氢缩松(flurandrenolone),哈西奈德,氢化可的松,甲***,甲泼尼龙,帕拉米松,***龙,***,曲安西龙,硫酸奥西那林,异丙肾上腺素,肾上腺素,去甲肾上腺素,氟米松(fluoromethasone),甲羟松,氟替卡松(fluticasone),阿托品硝酸甲酯,异丙托溴铵,色甘酸钠,奈多罗米和它们各自的药用盐或酯中的一种或其中的几种。
当选用舒喘宁时,其优选的浓度是0.1至300mg/ml脱水脂质囊泡组合物。
在另一方面,本发明提供用于治疗呼吸***疾病的吸入方法,所述吸入方法通过用有效治疗量的雾化脱水脂质囊泡组合物治疗患者,所述脂质囊泡组合物基本上由药物活性成分和脂质组分组成,其通过所述吸入给药途径雾化成多数空气动力学直径--重量平均径小于10μm的颗粒。
所述药物活性成分包括:麻黄碱及其盐和酯类衍生物,伪麻黄碱及其盐和酯类衍生物,舒喘宁,茶碱,硫酸沙丁胺醇,沙甲胺醇,叔丁喘宁,奥西那林,非诺特罗,盐酸氯丙那林,甘草酸氯丙那林,妥洛特罗,5-(4-氨基-3,5-二氯苯基)-3-叔-丁基恶唑,5-(4-氨基-3,5-二氯苯基)-3-叔-丁基恶唑盐酸盐,克仑特罗盐酸盐,丙卡特罗,沙美特罗,海索那林,马布特罗,福莫特罗,甲氧那明,曲托喹酚,利米特罗,比托特罗,普罗托醇,瑞普特罗,吡布特罗,芬司匹利,异丙阿托品,异丙东莨菪碱,氨茶碱,二羟丙茶碱,胆茶碱,色甘酸钠,酮替芬,曲普利啶,曲尼司特,氯化铵,碘化钾,乙酰半胱氨酸,溴己新盐酸盐,羧甲司坦,氨溴索盐酸盐,愈创甘油醚,可待因,可待因磷酸盐,福尔可定,羟蒂巴酚,喷托维林柠檬酸盐,氯呱斯汀,磷酸苯丙呱林,美沙芬氢溴酸盐,奥昔拉定,依普拉酮,齐培丙醇,脱氧异丙嗪盐酸盐,福米诺苯,普罗吗酯,替培啶,苯佐那酯,普诺地嗪,noscactive药物成分,倍氯米松,倍他米松,布***,氯泼尼醇,可的松,可的伐唑,脱氧皮质酮,***,***,二氟可龙,氟可龙,氟可的松(fluorocortisone),氟米松(flumethasone),氟尼缩松,氟轻松,醋酸氟轻松,氟可托龙(fluorocortolone),醛甾酮,氟米龙,氟氢缩松(flurandrenolone),哈西奈德,氢化可的松,甲***,甲泼尼龙,帕拉 米松,***龙,***,曲安西龙,硫酸奥西那林,异丙肾上腺素,肾上腺素,去甲肾上腺素,氟米松(fluoromethasone),甲羟松,氟替卡松(fluticasone),阿托品硝酸甲酯,异丙托溴铵,色甘酸钠,奈多罗米和它们各自的药用盐或酯,单独的它们或组合。
在选用舒喘宁的情况下,所述量通常是0.1-300mg/ml。
在还有的另一方面中,本发明提供制备可吸入的或可雾化的气雾剂颗粒的混悬液的方法,所述颗粒粒径多数(predominantly)小于10μm,是指脱水脂质体囊泡颗粒单独和/或其与所分散介质共同形成的颗粒,所述方法包括在水性混悬液中提供粒径小于10μm的脱水脂质体囊泡;和在产生空气动力学直径--重量平均径小于10μm的气雾剂颗粒的条件下吸入或雾化所述混悬液。
所述脂质颗粒包含不大于1.0μm的脱水脂质囊泡和/或胶束,所述用于治疗哮喘的组合物基本上由脂质组分和药物活性成分或它的盐或酯组成,适于通过吸入而递送到呼吸***中。
脱水的脂质囊泡形成方法
在开始用脂质、稳定剂和/或增塑剂和药物活性成分配制时,可以通过用于制备和筛分脂质体的任一种标准方法来制备本发明的脱水脂质囊泡。但是这仅是所述脂质体囊泡。在脂质体囊泡形成以前,可以将稳定剂或增塑剂添加在脂质溶液中或用脂质溶液添加以形成脂质混合脂质体囊泡。用于制备所述脂质体的方法包括脂质膜的水化,溶剂注射,反相蒸发和凝胶状磷脂质囊泡(vesicular phospholipids gels)方法,见Brandl,M.,Bachmann,D.,Reszka,R.,和Drechsler,M.Liposomale Zubereitung,ihre Herstellungund ihre Verwendung.DE 44 30 592.3(18.08.95提交)。PCT WO 96/05808并且见Brandl,M.,Tard,C.,Drechsler,M.,Bachmann,D.,Reszka,R.,Bauer,K.H.,等.(1997)。结合具体参考Adv.Drug Deliv.Rev.(药物递送进展综述),24,161。并结合参考下列文献中的具体信息:Ann.Rev.Biophys.Bioeng.(生物物理和生物工程年度回顾)9:467(1980)。通过反相蒸发方法制备的反相蒸发囊泡(REVs)结合参考美国专利4,235,871号中的描述。脂质膜的薄膜处理或通过注射技术的多层囊泡(MLVs)的制备结合参考美国专利4,737,923 号中的描述。其后面两个步骤,一般是将溶解在优选的适合的溶剂中的形成脂质体的脂质混合物在容器中蒸发以形成薄膜,所述薄膜是由水性缓冲液覆盖的。所述脂质膜水化而形成MLVs,一般粒径在约0.1至10μm之间。将REVs或MLVs进一步处理以产生较小的基本上均匀的脂质体混悬液,在0.02-2.0μm粒径范围内,优选在0.2-0.4μm范围内。一种有效的筛分方法包括经过具有选择的均一孔隙大小的聚碳酸酯膜或不对称的陶瓷过滤器挤出脂质体的水性混悬液,结合参考Ann.Rev.Biophys.Bioeng(生物物理和生物工程年度回顾),9:467(1980),和美国专利4,737,323号。聚碳酸酯膜的孔隙大小接近所述囊泡的大小。因而,所述囊泡的粒径一般控制为20至5000nm。选择地通过超声波或挤出处理REVs或MLVs以产生小的单层囊泡(SUVs),其特征在于粒径为0.02-0.07μm。另一种用于产生SUVs的优选方法是通过均化MLVs,其中使用用于乳液均化的商业使用类型的常规高压均质机。这里MLVs是循环经过均质机,周期性地对颗粒大小采样以确定MLVs在何时已经基本上转化成SUVs。通过使用例如通过参考结合于此的美国专利号4,752,425中描述的程序将所述药物活性成分包封在脂质体中。在脂质体囊泡形成以后,可以作为气雾剂载体的一些药物赋形剂,更具体而言是稳定剂和或增塑剂,可以添加在脂质体溶液中,并且通过立即冷却至-50℃以固定脂质体囊泡的形状和大小,然后冻干固体分散的团块。
在所述团块中的水分干燥以后,形成脱水脂质囊泡,所述药物活性成分包封在脱水脂质囊泡中,脱水脂质囊泡由稳定剂和/或增塑剂组成,但是在所述脂质囊泡中没有内水相。
常规和脱水的脂质囊泡
常规脂质体是含有纯脂质的脂质体,而本发明的脱水脂质囊泡是不含有内部水但是由脂质和稳定剂和/或增塑剂以及药物活性成分或备选地由两性脂质组分形成的脂质体。所述稳定剂和/或增塑剂用作囊泡保护剂,并且用来在没有水的情况下在冻干或喷雾干燥期间稳定所述脂质囊泡并且保持脂质囊泡的形状。
常规的和脱水的脂质囊泡都可以通过多种形成脂质囊泡的标准方法 制备。对于常规的脂质体,这些脂质包括二脂族脂质,诸如磷脂,二脂酰甘油酯,二脂族糖脂;所述稳定剂和/或增塑剂不专门用于保持其脂质体囊泡的形状。所述多种脂质组分占所述脂质体中的总非水组分的摩尔百分比约为99.9%-60%的量;稳定剂和/或增塑剂摩尔百分比占0.1%-40%之间的量。包封在两种脂质体中的药物活性成分的量是相对于所述脂质的摩尔百分比为0.01%-200%。所述脱水脂质囊泡是通过冷冻干燥或喷雾干燥所述常规脂质体而制备的产物,所述常规脂质体是用脂质和用于保存脂质囊泡的稳定剂和/或增塑剂形成的。
用于本发明的脂质包括三甲铵-丙烷(TAP),磷脂酰胆碱(PC),及其混合物等,诸如卵磷脂酰胆碱(EPC)和溶血磷脂酰胆碱(LPC),磷酯酰乙醇胺(PE),磷脂酰肌醇(PI),磷脂酰丝氨酸(PS),磷脂酸(PA)和磷脂酰甘油(PG),和它们的衍生物或混合物。这些脂质可以是完全饱和的或部分饱和的。它们可以是天然存在的或合成的。
DOPC和DOTAP是优选的脂质。脂质与磷脂、糖脂、胆固醇和蛋白质一起是生物膜的主要组分。脂质可以以许多不同的方式分类,并且可以细分成脂肪酸和它们的衍生物(例如DOPC和DOTAP),三酰甘油,蜡酯磷脂(磷酸甘油酯例如DOPC和鞘磷脂),鞘脂(不同于鞘磷脂的分子,其含有氨基醇神经鞘氨醇),类异戊二烯(由重复的异戊二烯单元构成的分子,异戊二烯单元是支链的五碳烃)。参考Trudy McKee和James RMcKee:(2003),生物化学:生命的分子基础,第三版;国际版,332页,McGraw-Hill公司,(2003)
类似于DOPC的脂质列表:
磷脂酰胆碱(PC)
1,2-二酰基-sn-甘油-3-乙基胆碱磷酸(EPC)-(磷脂)
磷酯酰乙醇胺(PE)
磷脂酰丝氨酸(PS)
磷脂酰肌醇(PI&PIP′s)
双(单酰基甘油)磷酸酯
磷脂酸(PA)
磷脂酰甘油(PG)
心磷脂(CA)
二酰基甘油酯(DG)
胆固醇(植物来源的)
和类似于DOTAP的脂质列表:
1,2-二酰基-3-三甲铵-丙烷(TAP)-(二醇)
1,2-二酰基-3-二甲铵-丙烷(DAP)-(二醇)
DC-胆固醇(DC-Chol)-(甾醇)
二甲基二(十八烷基)溴化铵(DDAB)-(烷基胺)
脱水脂质囊泡组合物可以配制成包括微量的脂肪醇,脂肪酸,和/或稳定剂和/或增塑剂,条件是这些较少脂质组分不显著降低脂质体对于粘膜或呼吸***组织的结合亲和性,基本上是不饱和的,没有毒性或刺激性,并且当脱水脂质囊泡在体外或/和在原位或/和在体内再水化或与水或任何缓冲液接触时共同控制或调节药物活性成分从脱水脂质囊泡释放的性质。
脱水脂质囊泡组合物的制备
根据本发明发现,当脂质体中含有高百分比的囊泡保护剂稳定剂和/或增塑剂时,所述囊泡保护剂稳定剂和/或增塑剂诸如甘油和脂肪酸蔗糖酯,其摩尔百分比一般地在0.1%~40%,在冷冻干燥或喷雾干燥和再水化过程期间或之后,舒喘宁或其它药物活性成分可以成功保持脂质囊泡形状并且保留在脂质体囊泡中延迟释放。
根据本发明另发现,本发明的药物活性成分/脂质/稳定剂和/或增塑剂组合物具有许多改善的性质,例如药物活性成分从脂质体囊泡的渗漏较少,降低药物的毒性和副作用,可控制药物的释放,改善药物的溶解度和包封率,药物活性成分在靶器官连续释放,不需要多次给药,延长药物的有效性和稳定性,它可以以干燥形式长期储存,在再水化时没有药物活性成分从脂质囊泡中显著渗漏,并且可以雾化或吸入以提供具有空气动力学直径--重量平均径小于10μm的气雾剂颗粒的均匀混合物。
为了实现上述全部优点,本发明组合脂质组分(包括稳定剂和/或增塑剂的,提供亲水性基团)以及药物活性成分以配制成新的高效药物活性成分脂质体组合物。改造所述组合物可增加药物活性成分载药量和控制呼吸系 统组织中药物活性成分的释放速率。本发明还提供用于增溶药物活性成分并且将它们结合在这样的脂质体组合物中的方法。另外,所述剂型容易灭菌,满足对于药物制剂的重要条件,并且很稳定,适于长期储存。
含有药物活性成分的脱水脂质囊泡组合物还可以含有任何适合的药用添加剂,稀释剂和/或赋形剂。这样的添加剂、稀释剂或赋形剂的实例,诸如氯化钠或氯化钾,水化的或脱水形式的磷酸二氢钠或磷酸氢二钠,水,盐水等,不限制本发明的范围,并且对于吸入制剂可以以在药学上可接受的任何需要或必要的量使用。药用稳定剂和/或增塑剂和赋形剂可被用于所述剂型。虽然稳定剂和/或增塑剂是优选的,但是所述组合物不局限于特定的甘油,并且可以采取在药物制剂中普遍使用和药用的其它任何适合的稳定剂和/或增塑剂。
在脱水脂质囊泡的制备中使用的缓冲液可以是选自下组的任何缓冲液:柠檬酸盐,碳酸盐,碳酸氢盐,乙酸盐,三羟甲基氨基甲烷,甘氨酸盐,卡可酸盐,马来酸盐,和如此其它的缓冲液,优选pH 7.4的磷酸盐缓冲液。
任何有机溶剂诸如低级醇,二甲氧基乙烷,二噁烷,四氢呋喃,四氢吡喃,二***,丙酮,二甲亚砜(DMSO),二甲基甲酰胺(DMF),和卤代烃,诸如氟利昂,乙腈,或其混合物,优选地氯仿/甲醇,可被用于制备脂质体的方法中。
脱水脂质囊泡的优选制备方法包括:
(1)以相对于所述脂质0.1-40摩尔%的稳定剂和/或增塑剂和0.1-200摩尔%的药物活性成分的量,混合稳定剂和/或增塑剂,以及干燥形式的药物活性成分;
(2)将所述混合物溶解在适合体积的有机溶剂、优选乙醇;
(3)将所述乙醇溶液注射到适合体积的pH 5.6-7.6的缓冲液中,然后转到(5);或,在氮气和/或真空下反复干燥获得的溶液,和/或,将所述干燥膜在适合的温度冷冻干燥适合的时间;
(4)将所述残余物再混悬在适合体积的pH 5.6-7.6的缓冲液中,优选pH 7.4的磷酸盐缓冲液中;
(5)通过振荡、搅拌或超声波处理、溶剂注射或其它任何适合的方 法形成脂质体;
(6)通过挤出或通过其它方法筛分(sizing)所述脂质体;和
(7)使用适合的和可接受的方法将所述脂质体消毒,用于将脂质体囊泡剂型灭菌;
(8)冷冻干燥或喷雾干燥所述脂质体囊泡以形成脱水脂质囊泡。
图1提供由这样一种方法制备的舒喘宁脱水脂质囊泡的TEM照片的图像。
制备本发明的组合物的方法不局限于以上列举的那些,而制备脱水脂质囊泡的其它方法诸如溶剂注射、薄膜水化、脱水-再水化和反蒸发同样是适合的。
优选的脱水囊泡的粒径是20-5000nm。水分含量一般小于所述粉末的15重量%,优选小于10重量%,更优选小于9%。
产物中组分的按重量计算的量通常如下:
用于商业产品的 量的范围 | 量的优选范围 | 最优选的范围 | |
增塑剂 | 0.1~99.9% | 1~99% | 10~80% |
稳定剂 | 0.1~99.9% | 1~99% | 10~80% |
脂质 | 0.1~99.9% | 1~99% | 10~80% |
药物活性成分 | 0.1~99.9% | 1~99% | 10~80% |
所述粉末将用于制备用于治疗呼吸***病症的粉末或液体气雾剂。
治疗应用
控释对于药物活性成分成功递送至呼吸***是非常重要的。已知影响吸入颗粒沉积到呼吸***中因素的列表,包括气雾剂或它的环境特征,呼吸***结构特征,吸入剂特征,和呼吸模式特征。图2显示两种脱水脂质囊泡制剂的释放曲线。
以小颗粒雾化脱水脂质囊泡和胶束的治疗应用和优点是众多的。吸入的雾化小颗粒将使包封在脱水脂质囊泡中的药物活性成分以足够高的量沉淀在呼吸组织中,以通过控制释放来容许最小的每日剂量给药,具有在 一段时期内延长释放的最大效果。所述药物活性成分从脱水脂质囊泡的控制释放预计延长每次给药以后的治疗活性,减少给药频率,进一步改善局部至全身性效果的比例,并且在呼吸***中提供增加的和延长的局部治疗效果。
在本发明中,将含有药物活性成分的脂质囊泡混悬或/和溶解在0.9%无菌盐水中或用0.9%无菌盐水稀释,在混合以后将所述混悬液放置在喷雾器中,可充分利用呼吸气雾剂直到在喷雾器或吸入器中不再有液体。在提供数据并评价新的吸入组合物的实施例中主要使用抗炎的药物活性成分舒喘宁,用于将雾化的或吸入的气雾剂颗粒吸入到呼吸***深处。本发明的范围不局限于舒喘宁作为药物活性成分。
在经过吸入途径给药的该组合物中使用的化合物类别的实例包括,但不限于,支气管扩张药,诸如硫酸奥西那林,氨茶碱,叔丁喘宁,舒喘宁,茶碱,麻黄碱,异丙肾上腺素,比托特罗,吡布特罗,肾上腺素,去甲肾上腺素,丙卡特罗,和沙美特罗;抗炎的药物活性成分,诸如舒喘宁,***,***龙,氢化可的松,氟米松,甲羟松,氟替卡松,曲安西龙,和氟尼缩松。
对于吸入,通过下列载体或方法实现所述递送:(a)利用气动的或超声波喷雾器雾化稀释的水性混悬液,(b)使用空气从配制的雾化器喷雾;在粉末中具有悬浮的干燥的脱水脂质囊泡的溶剂(c)用推进剂将干燥的颗粒喷雾到呼吸***中或(d)使用适合的装置将干燥的脂质体作为粉末气雾剂递送,条件是通过上述任一项方法的产生的气雾剂颗粒在0.02-20μm的粒径范围内。本发明的组合物一般具有高的包封率,好的稳定性,和延长的半衰期。
举下列实施例说明制备药物活性成分脱水脂质囊泡的方法,以及使用这些脱水脂质囊泡用于治疗间歇性呼吸***疾病的方法。
本发明的实施例
材料
舒喘宁[2-叔-丁基氨基-1-(4-羟基-3-羟基-甲基苯基)乙醇]购自亚邦化工公司(Yabang chemical industry Corporation(常州,江苏,中国)。EPC, SPC,DOTAP(1,2-二油酰-3-三甲铵丙烷),DOPC(二油酰磷脂酰胆碱),DSPC(二硬脂酰磷脂酰胆碱),鞘磷脂,神经酰胺-1-胆碱磷酸,和DMPC((二肉豆蔻基磷脂酰胆碱)购自Avanti极性脂质公司(Avanti Polar Lipids,Inc)(美国)。甘油及其它稳定剂或增塑剂和溶剂诸如氯仿[RDH(Riedel-de )]购自Kou Fling Hong Scientific Supplies Ltd.,三(羟甲基)氨基甲烷(Tris)(Sigma)购自Tin Hang Technology Ltd.,和磷酸二氢钾(AmershamBiosciences)购自Amersham Biosciences China Ltd(Amersham Biosciences中国有限公司)。全部溶剂,溶液和化学品是分析试剂等级。
实施例1
通过薄膜水化制备脂质体
通过常规脂质膜水化方法制备水性多层囊泡(MLV),并且随后通过挤出法产生小的单层囊泡(SUV)。将脂质和舒喘宁分别溶解在氯仿和甲醇中,然后将所述溶液以指定摩尔比的脂质和舒喘宁混合。将所述混合物在氮气流下干燥成均匀的脂质膜,然后在真空下过夜以除去残留的有机溶剂。将该脂质膜在10mM的Tris-等渗盐缓冲液(10mM的Tris,137mM氯化钠,和在25℃下,pH7.4)水化。将脂质的终浓度控制在5-20mg/ml。然后将所述混合物在80℃(超过所有脂质的转变温度)保持60分钟以使得所述脂质体结构固化。在固化期间,分别在开始的、中间的和末端的时间点将它用涡流搅拌3次,并且每一次连续搅拌5分钟。然后将得到的MLV使用10mL挤出机(Lipex Biomembranes Inc.,Vancouver,加拿大)经过直径为25mm的Whatman 100nm聚碳酸酯过滤器(Nuclepore,Pleasanton,CA)用数个循环挤出,直到粒径在50-200nm之内。
包封率的确定
将150μL新制备的脂质体样品用Avanti J-E离心机(JA-20,17400×g,6℃,和20min)通过可截留分子量为10KD虑份的Microcon Y-10离心过滤装置(Millipore)离心。在276nm下用分光光度法测定离心溶液中的舒喘宁浓度。该浓度表示所述脂质体的连续相中的舒喘宁浓度(非-包封的舒喘宁)。分光光度法还用作测定包括在脂质体的分散相和连续相中的舒喘宁的 总浓度。将无水乙醇添加到脂质体混悬液中以完全破裂所述脂质体并且将包封的舒喘宁完全溶解在溶液中。通过装备有恒温石英室的UV-VIS VarianCary 50分光光谱仪在278nm的波长下测量吸光度。用下式计算包封率(EE):
EE(%)=(C总-C游离)/C总×100
其中C游离是脂质体分散体/溶液的连续相中的未包封的舒喘宁的浓度,C总是脂质体分散体/溶液中的舒喘宁的总浓度。包封率是20-30%。
实施例2
通过溶剂注射技术制备脂质体
将部分DOPC或DOTAP,和药物活性成分(舒喘宁,0.04mmol)以摩尔比为1∶2的的混合物溶解在4ml的乙醇中。通过将脂质/药物活性成分/乙醇溶液注射到50ml的pH 7.4磷酸盐缓冲液中形成舒喘宁脂质体分散体。脂质体经过0.4或0.2μm的聚碳酸酯膜挤出形成大小均匀分布的脂质体囊泡。
包封率的确定
将150μL新制备的脂质体样品用Avanti J-E离心机(JA-20,17400×g,6℃,和20min)经过可截留分子量为10KD虑份的Microcon Y-10离心过滤装置(Millipore)离心。在276nm下用分光光度法确定离心溶液中的舒喘宁浓度。该浓度表示所述脂质体的连续相中的舒喘宁浓度(非-包封的舒喘宁)。分光光度法还用于测定包括在脂质体的分散相和连续相中的舒喘宁的总浓度。将无水乙醇添加到脂质体混悬液中以完全破裂所述脂质体并且将包封的舒喘宁完全溶解在所述溶液中。通过装有恒温石英室的UV-VISVarian Cary 50分光光谱仪在278nm的波长测量吸光度。用下式计算包封率(EE):
EE(%)=(C总-C游离)/C总×100
其中C游离是脂质体分散体/溶液的连续相中的未包封的舒喘宁的浓度,C总是脂质体分散体/溶液中的舒喘宁的总浓度。包封率是20-30%。
实施例3
通过凝胶状磷脂质囊泡制备脂质体
将1ml舒喘宁饱和水溶液,0.1g的甘油和2g的SPC通过高速或高速或高压匀质机在50℃下混合直到形成凝胶;然后将所述凝胶稀释在100ml的pH 7.4的磷酸盐缓冲液中以形成脂质体囊泡。
包封率的确定
将150μL新制备的脂质体样品用Avanti J-E离心机(JA-20,17400×g,6℃,和20min)经过可截留分子量为10KD虑份的Microcon Y-10离心过滤装置(Millipore)离心。在276nm下用分光光度法测定离心溶液中的舒喘宁浓度。该浓度表示在所述脂质体的连续相中的舒喘宁浓度(非-包封的舒喘宁)。分光光度法还用于测定包括在脂质体的分散相和连续相中的舒喘宁的总浓度。将无水乙醇添加到脂质体混悬液中以完全破裂所述脂质体并且将包封的舒喘宁完全溶解在所述溶液中。通过装有恒温石英室的UV-VISVarian Cary 50分光光谱仪在278nm的波长下测量吸光度。用下式计算包封率(EE):
EE(%)=(C总-C游离)/C总×100
其中C游离是脂质体分散体/溶液的连续相中的未包封的舒喘宁的浓度,C总是脂质体分散体/溶液中的舒喘宁的总浓度。包封率是50-70%。
实施例4
脱水脂质囊泡的制备
本实施例举例说明用于制备含有稳定剂和/或增塑剂的控制释放药物活性成分的脂质体组合物的方法。
将摩尔比为1∶10∶20的甘油、DOPC或DOTAP、和药物活性成分(舒喘宁,0.04mmol)溶解在4ml的乙醇中。通过将脂质/药物活性成分/乙醇溶液注射到50ml的pH 7.4的磷酸盐缓冲液中而形成脂质体舒喘宁分散体。经过0.4或0.2或0.1μm的聚碳酸酯膜挤出由此形成均匀大小分布的脂质体囊泡。将相对于DOPC或DOTAP摩尔比为200%的乳糖添加并溶解到脂质体混悬液中,并且立即用液氮或其他方法降低温度。将冰冻成冰块的脂质体混悬液放入-50℃冷冻干燥机,真空干燥直到形成由干燥乳糖粉末分散的脱水脂质囊泡。
脱水脂质囊泡的透射电子显微镜(TEM)观察
使用如上所述相同的方法制备MLV和SUV脂质体溶液。将全部脂质体的脂质浓度控制在10mg/ml。采用空白脂质体囊泡和包封舒喘宁的脂质体。在TEM观察以前,将10%的葡萄糖和1%的甘油添加到所述囊泡溶液中,然后将每一囊泡混悬液用纯水稀释100倍。将稀释的溶液滴在碳涂敷的400目电子显微镜铜格网(SPI Supplies批号1110207,Structure probe,Inc(结构探针公司),西切斯特PA,美国)上并且用液氮冷冻所述格网。将具有脂质体囊泡混悬液的冷冻格网在冷冻干燥机(FreeZon 6升冷冻干燥***,Labconco公司,美国)的隔室中在-40℃冷冻干燥72小时。最终,将所述格网密封到10mL玻璃注射管中,并且保留所述格网上的脂质体囊泡,通过TEM(FEI,Tecnai G220STEM,英国)观察。也可直接将干燥乳糖粉末分散的脱水脂质囊泡置于碳涂敷的400目电子显微镜铜格网(SPISupplies批号1110207,Structure probe,Inc(结构探针公司),西切斯特PA,美国)上通过TEM(FEI,Tecnai G220STEM,英国)直接观察。
包封率的确定
将一定量的脱水脂质囊泡粉末混合物溶解并悬浮在纯水中。然后,将150μL新制备的脂质体样品用Avanti J-E离心机(JA-20,17400×g,6℃,和20min)经过可截留分子量为10KD虑份的Microcon Y-10离心过滤装置(Millipore)离心。在276nm下用分光光度法测定离心溶液中的舒喘宁浓度。该浓度表示所述脂质体的连续相中的舒喘宁浓度(非-包封的舒喘宁)。分光 光度法还用于确定包括在脂质体的分散相和连续相中的舒喘宁的总浓度。将无水乙醇添加到脂质体混悬液中以完全破裂所述脂质体并且将包封的舒喘宁完全溶解在所述溶液中。通过装有恒温石英室的UV-VIS VarianCary 50分光光谱仪在278nm的波长下测量吸光度。用下式计算包封率(EE):
EE(%)=(C总-C游离)/C总×100
其中C游离是脂质体分散体/溶液的连续相中的未包封的舒喘宁的浓度,C总是脂质体分散体/溶液中的舒喘宁的总浓度。
实施例5
透析平衡期间脂质体中舒喘宁的保留和释放
将一定量的脱水脂质囊泡粉末混合物溶解并悬浮在纯水中。为了评价脂质体中的舒喘宁在体外的保留,通过膜透析在25℃进行透析相、连续相(分散介质)和分散相(脂质体内部)混悬液之间的平衡。释放介质是Tris-盐水缓冲液(pH 7.4),其是用于在脂质体制备期间水化脂质-舒喘宁薄膜的相同缓冲液,以便保持透析管中的脂质体和释放介质之间的渗透平衡。选择DOPC和DOTAP脂质体用于所述研究,原因在于它们具有相对高的包封率。
将6mL的每个脂质体样品转移到透析膜管(截留分子量为12-14KD;Spectrum Medical Industries(光谱医疗工业),洛杉矶,加利福尼亚州)并放在含有150mL的TBS的温度受控的烧杯中。将烧杯的内容物在整个实验期间在37℃的温度下在50rpm搅拌。在时间点15,30,45,60,90,120,150和180min,其后3h的每一小时和其后每3小时直到24h,分别取出5mL的透析介质。在每次取出之后加入新的透析介质。通过装备有恒温石英室的UV-VIS Varian Cary 50分光光谱仪在278nm的波长下测定样品的在释放介质中的舒喘宁浓度(C释放介质)。在相同的时间点,取出300μL的透析管中的脂质体。将150μL用Avanti J-E离心机(JA-20,17400×g,6℃,20min)经过可截留分子量为10KD虑份的Microcon Y-10离心过滤装置(Millipore) 离心。将离心溶液中的舒喘宁浓度确定为在瞬时时间点的脂质体的连续相中的舒喘宁浓度(C游离)。在用乙醇适当稀释以后,将另一个150μL脂质体确定为脂质体溶液中的舒喘宁的总浓度(C总)。C总和C游离的差为C内,其被认为是在相应的采样时间点的脂质体之内的舒喘宁浓度。
计算脂质体的连续相和分散相之间的包封分配系数(K游离/内=C游离/C内)和脂质体的连续相与释放介质之间的透析分配系数(K释放介质/游离=C释放介质/C游离)。
在脂质体周围形成漏槽条件下,K游离/内<1/10;停止透析,并且记录时间,并且测试C总和C游离随时间的变化,以计算包封的舒喘宁从脂质囊泡到缓冲液中的释放。图2显示包封的舒喘宁从两种脱水脂质囊泡的释放。
Claims (15)
1.一种通过吸入到呼吸***而用于治疗哮喘的药物脂质组合物,所述组合物包含药用增塑剂和稳定剂、药用脂质组分和药物活性成分的脱水脂质囊泡,所述增塑剂和稳定剂选自制剂学所使用的稳定剂和增塑剂,所述稳定剂和增塑剂是甘油或甘油与乳糖的组合。
2.权利要求1的组合物,其中所述稳定剂和增塑剂与所述脂质组分的摩尔比例是所述稳定剂和增塑剂占0.1%至40%,所述脂质占99.9%至60%的所述脂质。
3.权利要求1的组合物,其中所述药物活性成分包括:麻黄碱及其盐和酯类衍生物,伪麻黄碱及其盐和酯类衍生物,舒喘宁,茶碱,硫酸沙丁胺醇,沙甲胺醇,叔丁喘宁,奥西那林,非诺特罗,盐酸氯丙那林,甘草酸氯丙那林,妥洛特罗,5-(4-氨基-3,5-二氯苯基)-3-叔-丁基恶唑,5-(4-氨基-3,5-二氯苯基)-3-叔-丁基恶唑盐酸盐,克仑特罗盐酸盐,丙卡特罗,沙美特罗,海索那林,马布特罗,福莫特罗,甲氧那明,曲托喹酚,利米特罗,比托特罗,普罗托醇,瑞普特罗,吡布特罗,芬司匹利,异丙阿托品,异丙东莨菪碱,氨茶碱,二羟丙茶碱,胆茶碱,色甘酸钠,酮替芬,曲普利啶,曲尼司特,氯化铵,碘化钾,乙酰半胱氨酸,溴己新盐酸盐,羧甲司坦,氨溴索盐酸盐,愈创甘油醚,可待因,可待因磷酸盐,福尔可定,羟蒂巴酚,喷托维林柠檬酸盐,氯呱斯汀,磷酸苯丙呱林,美沙芬氢溴酸盐,奥昔拉定,依普拉酮,齐培丙醇,脱氧异丙嗪盐酸盐,福米诺苯,普罗吗酯,替培啶,苯佐那酯,普诺地嗪,noscactive药物成分,倍氯米松,倍他米松,布***,氯泼尼醇,可的松,可的伐唑,脱氧皮质酮,***,***,二氟可龙,氟可龙,氟可的松,氟米松,氟尼缩松,氟轻松,醋酸氟轻松,氟可托龙,醛甾酮,氟米龙,氟氢缩松,哈西奈德,氢化可的松,甲***,甲泼尼龙,帕拉米松,***龙,***,曲安西龙,硫酸奥西那林,异丙肾上腺素,肾上腺素,去甲肾上腺素,氟米松,甲羟松,氟替卡松,阿托品硝酸甲酯,异丙托溴铵,色甘酸钠,奈多罗米和它们各自的药用盐或酯,及其混合物。
4.权利要求3的组合物,其中药物活性成分与所述脂质组分的摩尔比是0.1%至200%。
5.权利要求3的组合物,其中舒喘宁在脱水脂质囊泡组合物的浓度是0.1至300mg/ml。
6.权利要求1的组合物,所述组合物可以雾化成颗粒,该颗粒多数空气动力学直径--重量平均径小于10μm,重量最大径小于35μm。
7.一种成形脂质组合物在制备用于治疗哮喘的药物中的应用,所述药物通过吸入途径给予需要该治疗的患者,并且在呼吸***中使药物活性成分缓慢释放或控制释放,所述成形脂质组合物基本由下列组成:所述药物活性成分,增塑剂和稳定剂,以及脂质组分,所述脂质组合物被雾化成空气动力学直径--重量平均径小于10μm的气雾剂颗粒,其中所述稳定剂和增塑剂选自制剂学所使用的稳定剂和增塑剂,所述稳定剂和增塑剂是甘油或甘油与乳糖的组合。
8.权利要求7的应用,其中所述组合物包含0.1%至40%(摩尔百分比)的所述稳定剂和增塑剂、99.9%至60%(摩尔百分比)的脂质,并且所述药物活性成分相对于所述脂质的摩尔百分比是0.01%至200%。
9.权利要求7的应用,其中所述药物活性成分包括:麻黄碱及其盐和酯类衍生物,伪麻黄碱及其盐和酯类衍生物,舒喘宁,茶碱,硫酸沙丁胺醇,沙甲胺醇,叔丁喘宁,奥西那林,非诺特罗,盐酸氯丙那林,甘草酸氯丙那林,妥洛特罗,5-(4-氨基-3,5-二氯苯基)-3-叔-丁基恶唑,5-(4-氨基-3,5-二氯苯基)-3-叔-丁基恶唑盐酸盐,克仑特罗盐酸盐,丙卡特罗,沙美特罗,海索那林,马布特罗,福莫特罗,甲氧那明,曲托喹酚,利米特罗,比托特罗,普罗托醇,瑞普特罗,吡布特罗,芬司匹利,异丙阿托品,异丙东莨菪碱,氨茶碱,二羟丙茶碱,胆茶碱,色甘酸钠,酮替芬,曲普利啶,曲尼司特,氯化铵,碘化钾,乙酰半胱氨酸,溴己新盐酸盐,羧甲司坦,氨溴索盐酸盐,愈创甘油醚,可待因,可待因磷酸盐,福尔可定,羟蒂巴酚,喷托维林柠檬酸盐,氯呱斯汀,磷酸苯丙呱林,美沙芬氢溴酸盐,奥昔拉定,依普拉酮,齐培丙醇,脱氧异丙嗪盐酸盐,福米诺苯,普罗吗酯,替培啶,苯佐那酯,普诺地嗪,noscactive药物成分,倍氯米松,倍他米松,布***,氯泼尼醇,可的松,可的伐唑,脱氧皮质酮,***,***,二氟可龙,氟可龙,氟可的松,氟米松,氟尼缩松,氟轻松,醋酸氟轻松,氟可托龙,醛甾酮,氟米龙,氟氢缩松,哈西奈德,氢化可的松,甲***,甲泼尼龙,帕拉米松,***龙,***,曲安西龙,硫酸奥西那林,异丙肾上腺素,肾上腺素,去甲肾上腺素,氟米松,甲羟松,氟替卡松,阿托品硝酸甲酯,异丙托溴铵,色甘酸钠,奈多罗米和它们各自的药用盐或酯,及其混合物。
10.权利要求7的应用,所述方法以舒喘宁在脱水脂质囊泡组合物中的浓度为0.1至300mg/ml。
11.雾化脱水脂质囊泡组合物在制备用于治疗呼吸***疾病的药物中的应用,所述药物通过吸入给药途径来治疗患者,所述脱水脂质囊泡组合物基本由药物活性成分、增塑剂和稳定剂、和脂质组分组成,其雾化成颗粒的空气动力学直径--重量平均径小于10μm,其中所述稳定剂和增塑剂选自制剂学所使用的稳定剂和增塑剂,所述稳定剂和增塑剂是甘油或甘油与乳糖的组合。
12.权利要求11的应用,其中所述药物活性成分包括:麻黄碱及其盐和酯类衍生物,伪麻黄碱及其盐和酯类衍生物,舒喘宁,茶碱,硫酸沙丁胺醇,沙甲胺醇,叔丁喘宁,奥西那林,非诺特罗,盐酸氯丙那林,甘草酸氯丙那林,妥洛特罗,5-(4-氨基-3,5-二氯苯基)-3-叔-丁基恶唑,5-(4-氨基-3,5-二氯苯基)-3-叔-丁基恶唑盐酸盐,克仑特罗盐酸盐,丙卡特罗,沙美特罗,海索那林,马布特罗,福莫特罗,甲氧那明,曲托喹酚,利米特罗,比托特罗,普罗托醇,瑞普特罗,吡布特罗,芬司匹利,异丙阿托品,异丙东莨菪碱,氨茶碱,二羟丙茶碱,胆茶碱,色甘酸钠,酮替芬,曲普利啶,曲尼司特,氯化铵,碘化钾,乙酰半胱氨酸,溴己新盐酸盐,羧甲司坦,氨溴索盐酸盐,愈创甘油醚,可待因,可待因磷酸盐,福尔可定,羟蒂巴酚,喷托维林柠檬酸盐,氯呱斯汀,磷酸苯丙呱林,美沙芬氢溴酸盐,奥昔拉定,依普拉酮,齐培丙醇,脱氧异丙嗪盐酸盐,福米诺苯,普罗吗酯,替培啶,苯佐那酯,普诺地嗪,noscactive药物成分,倍氯米松,倍他米松,布***,氯泼尼醇,可的松,可的伐唑,脱氧皮质酮,***,***,二氟可龙,氟可龙,氟可的松,氟米松,氟尼缩松,氟轻松,醋酸氟轻松,氟可托龙,醛甾酮,氟米龙,氟氢缩松,哈西奈德,氢化可的松,甲***,甲泼尼龙,帕拉米松,***龙,***,曲安西龙,硫酸奥西那林,异丙肾上腺素,肾上腺素,去甲肾上腺素,氟米松,甲羟松,氟替卡松,阿托品硝酸甲酯,异丙托溴铵,色甘酸钠,奈多罗米和它们各自的药用盐或酯,及其混合物。
13.权利要求11的应用,所述方法可采用舒喘宁或其它药物活性成分制备浓度为0.1至300mg/ml脱水脂质囊泡组合物混悬液。
14.一种制备粒径多数小于10μm的可吸入的或可雾化的气雾剂颗粒混悬液的方法,所述颗粒为脱水脂质囊泡的颗粒,所述方法包括将药用增塑剂和稳定剂、药用脂质组分和药物活性成分在水性混悬液中形成粒径小于10μm的脱水脂质囊泡;和在产生空气动力学直径--重量平均径小于10μm的气雾剂颗粒的条件下吸入或雾化所述混悬液,其中所述稳定剂和增塑剂选自制剂学所使用的稳定剂和增塑剂,所述稳定剂和增塑剂是甘油或甘油与乳糖的组合。
15.权利要求14的方法,其中所述脂质颗粒包含不大于5.0μm的脱水脂质囊泡和/或胶束,所述组合物基本上由脂质组分和药物活性成分或它的盐或酯组成,用于治疗哮喘,并且适合通过吸入递送到呼吸***中。
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2008
- 2008-08-15 CN CN200810210952.0A patent/CN101366699B/zh not_active Expired - Fee Related
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US20090047336A1 (en) | 2009-02-19 |
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