CN102231980A - 包含氧清除剂的苏芬太尼(sufentanil)固体剂型和其使用方法 - Google Patents
包含氧清除剂的苏芬太尼(sufentanil)固体剂型和其使用方法 Download PDFInfo
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- CN102231980A CN102231980A CN2009801465319A CN200980146531A CN102231980A CN 102231980 A CN102231980 A CN 102231980A CN 2009801465319 A CN2009801465319 A CN 2009801465319A CN 200980146531 A CN200980146531 A CN 200980146531A CN 102231980 A CN102231980 A CN 102231980A
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- fentanyl
- dosage form
- soviet union
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- solid
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Abstract
本发明提供有效使包含苏芬太尼(sufentanil)的固体剂型中氧化降解产物的存在降至最低或消除的组合物和方法。
Description
相关申请案交叉参考
本申请案主张于2008年11月21日提出申请的美国申请案第12/275,485号的优先权益,所述申请案的整体内容以引用的方式并入本文中。
技术领域
本发明涉及有效使包含苏芬太尼的固体剂型中氧化降解产物的存在降至最低或消除的组合物、方法和系统。所述包含苏芬太尼的固体剂型包装于实质上氧不可渗透的容器中,所述容器包括至少一种氧清除材料。
背景技术
许多用于诊断性评价中的医药调配物和试剂对氧及/或湿气敏感。这些医药调配物和试剂暴露于氧或湿气可干扰医药剂或试剂的稳定性和功效。
对于液体(苏芬太(Sufenta))或干粉形式的苏芬太尼(詹森医药公司(JanssenPharmaceuticals)、江森麦蒂公司(Johnson Matthey,Inc.)、泰科公司(Covidien))来说,还未报道苏芬太尼的氧化降解。
已显示,耐湿气包装是芬太奴(Fentora)(芬太尼(fentanyl)口腔片)的关键要求(瑟法隆给欧洲药品管理局(EMEA)的关于芬太奴的市场准入的申请(Cephalonapplication for Marketing Authorisation of Fentora to the European Medicines Agency(EMEA));2007年2月21日,p4)。同样地,关于Abstral(芬太尼舌下片,先前称为“Rapinyl”,且在2008年6月由欧洲药品管理局(EMEA)的人用药品委员会(Committeefor Medicinal Products for Human Use,CHMP)批准),其产品特性的汇总描述片剂应储存在初始的泡罩包装中以保护其免于湿气(英国许可药品的电子药品概要(ElectronicMedicines Compendium(eMC)for UK licensed medicines),最近更新2009年8月1日)。
对于药物的干粉形式或固体芬太尼剂型来说,还未报道苏芬太尼同源物芬太尼的氧化降解。
本发明者已开发出固体苏芬太尼剂型(片剂),且惊讶地发现在调配、制成片和储存后出现降解。本发明者还惊讶地发现,在调配物中纳入抗氧化剂(例如丁羟甲苯(BHT))及/或在低剂量固体苏芬太尼剂型的包装中使用干燥剂并不能使降解停止。在使用水性及/或有机溶剂制备且随后在各种条件下调配、制成片并储存的固体苏芬太尼剂型中观察到苏芬太尼的降解。
业内仍需要开发具体医药调配物和包装系统,以确保诸如苏芬太尼等药物可以降解降至最低且维持活性药物的完整性的方式调配并储存低剂量固体剂型。
发明内容
固体苏芬太尼药物剂型提供于含有氧清除剂的初级包装中,其中相对于在没有氧清除剂的情况下包装的固体苏芬太尼药物剂型,与氧清除剂一起包装的固体苏芬太尼药物剂型中苏芬太尼的氧化降解产物的百分比降至最低或消除。
经包装固体苏芬太尼药物剂型可在选自由5℃和环境湿度、25℃,60%相对湿度和40℃,75%相对湿度组成的群组的条件下储存至少6个月,其中在储存之后,相对于在没有氧清除剂的情况下包装的固体苏芬太尼药物剂型,与氧清除剂一起包装的固体苏芬太尼药物剂型中苏芬太尼的氧化降解产物的百分比降至最低或消除。
经包装固体苏芬太尼药物剂型具有从约5mg到约25mg的质量、从约5mcl到约25mcl的体积、从约2mg到约10mg的质量或从约2mcl到约10mcl的体积。
经包装固体苏芬太尼药物剂型具有从约0.7mm到约1.0mm或从约0.75mm到约0.95mm的厚度,且可包含5mcg、10mcg、15mcg、20mcg、30mcg、40mcg、50mcg、60mcg、70mcg、80mcg或100mcg苏芬太尼。
经包装固体苏芬太尼药物剂型可盛放于药物递送分配器(例如药匣或单剂量施药器)且初级包装可为箔袋。
还提供防止固体苏芬太尼药物剂型氧化降解的方法。
附图说明
图1提供5mcg苏芬太尼剂型的总RS%对时间(0、0.5、1、2和3个月)的图形描绘,所述苏芬太尼剂型是使用标准调配物制得且随后在5℃和环境湿度下其自身(5μg)在HDPE瓶中或在含有氧清除剂(斯泰比罗(Stabilox)穆尔蒂索伯技术公司(Multisorb Technologies);5μg-R)的HDPE瓶中储存。名称“总RS%”(总相关物质%)在本文中与术语“SDP%(苏芬太尼降解产物%)互换使用。两个术语均用于阐述例如在HPLC(高效液相色谱)分析之后,“相关物质”(苏芬太尼降解产物)的峰面积相对于苏芬太尼的总峰面积的百分比。
图2提供5mcg苏芬太尼剂型的总RS%对时间(0、0.5、1、2和3个月)的图形描绘,所述苏芬太尼剂型是使用标准调配物制得且随后在25℃和60%相对湿度下其自身(5μg)在HDPE瓶中或在含有氧清除剂(5μg-R_斯泰比罗,在HDPE中)的HDPE瓶中储存。
图3提供5mcg苏芬太尼剂型的总RS%对时间(0、0.5、1、2和3个月)的图形描绘,所述苏芬太尼剂型是使用标准调配物制得且随后在40℃和75%相对湿度下其自身(5μg)在HDPE瓶中或在含有氧清除剂(5μg-R_斯泰比罗,在HDPE中)的HDPE瓶中储存。
图4提供5mcg苏芬太尼剂型的总RS%对时间(0、0.5、1、2、3和6个月)的图形描绘,所述苏芬太尼剂型是使用标准调配物制得且随后在5℃和环境湿度下在含有干燥剂(5μg-干燥剂,在HDPE中)的HDPE瓶中或在含有氧清除剂(5μg-R_斯泰比罗,在HDPE中)的HDPE瓶中储存。
图5提供5mcg苏芬太尼剂型的总RS%对时间(0、0.5、1、2、3和6个月)的图形描绘,所述苏芬太尼剂型是使用标准调配物制得且随后在25℃和60%相对湿度下在含有干燥剂(5μg-干燥剂,在HDPE中)的HDPE瓶中或在含有氧清除剂(5μg-R_斯泰比罗,在HDPE中)的HDPE瓶中储存。
图6提供5mcg苏芬太尼剂型的总RS%对时间(0、0.5、1、2、3和6个月)的图形描绘,所述苏芬太尼剂型是使用标准调配物制得且随后在40℃和75%相对湿度下在含有干燥剂(5μg-干燥剂,在HDPE中)的HDPE瓶中或在含有氧清除剂(5μg-R_斯泰比罗,在HDPE中)的HDPE瓶中储存。
具体实施方式
I.介绍
本文提供有效使包含苏芬太尼的固体剂型中氧化降解产物的存在降至最低或消除的组合物、方法和系统。
以下揭示内容阐述构成本发明的组合物、方法和系统。本发明并不限于本文阐述的具体剂型、装置、方法、系统、试剂盒或医药条件,因此当然可有所改变。还应了解,本文所用的术语仅用于阐述特定实施例的目的,而并非想要限制本发明的范围。
必须注意,除非本文另有明确说明,否则本文和随附权利要求书中所使用的单数形式“一(a、an)”和“所述”包括复数个指示物。因此,例如,提及“药物调配物”包括多种所述调配物,且提及“药物递送装置”包括包含药物剂型和用于容纳、储存和递送所述剂型的递送装置的系统。
除非另外定义,否则本文所用的所有技术和科学术语一般具有与本发明所属领域的技术人员通常所了解相同的意义。尽管任何类似或等同于本文所阐述者的方法、装置和材料可用于本发明的实践或测试中,但现在阐述优选的方法、装置和材料。
本文所讨论公开案仅因为其揭示内容先于本申请案的申请日期而提供。绝不能由于揭示内容为先前发明而理解为承认本发明无权先于所述揭示内容。
如本文所用,就用于缓解疼痛(实现镇痛)的许多药物中的任一者而言,使用术语“镇痛剂”。
就投予给个体后使得镇痛的药物而言,本文中使用术语“镇痛药”,例如苏芬太尼或苏芬太尼同源物,例如阿芬太尼(alfentanil)、芬太尼、罗芬太尼(lofentanil)、卡芬太尼(carfentanil)、瑞芬太尼(remifentanil)、曲芬太尼(trefentanil)或米芬太尼(mirfentanil)。词语“镇痛药”并不限于苏芬太尼、苏芬太尼同源物或包含苏芬太尼或苏芬太尼同源物的调配物。
本文使用术语“抗氧化剂”指能够减缓或防止其它分子氧化的分子或分子的组合。氧化作用是电子从一种物质转移到氧化剂的化学反应。氧化反应可产生自由基。抗氧化剂通常通过移除自由基中间体来终止这些链反应,并通过自身被氧化来抑制其它氧化反应。
就经配置以容纳一种或一种以上药物剂型、通常供应1到5天的可更换的单次使用的一次性药匣而言,本文使用术语“药匣”。在一个实例性实施例中,药匣容纳足以用于1到5天治疗的药物剂型,例如40片片剂用于48到72小时治疗。
药匣可包含智能药匣辨识系统,所述智能药匣辨识系统具有位于药匣上的物理键控特征、位于药匣上的条形码、位于药匣上的磁性标签、位于药匣上的RFID标签、位于药匣上的电子微芯片或其组合。药匣可包含一个或一个以上装运片剂,其中在分配药物剂型之前分配至少一个装运片剂。
就盛放药物剂型且通常经配置以容纳1到5天药物剂型的供应的药匣而言,使用术语“可更换药匣”或“一次性药匣”,其中药匣经设计在分配装置中使用且使用后丢弃。
如本文所用术语“降解”是指“药物”、“药品”或“药理活性剂”(例如含苏芬太尼的固体剂型中的苏芬太尼)在储存期间的任何变化,例如通过药物或调配物中所含的其它组份/赋形剂的水解及/或氧化。
如本文所用术语“降解剂”是指暴露于“药物”、“药品”或“药理活性剂”(例如含苏芬太尼的固体剂型中的苏芬太尼)并产生不想要的副产物的试剂(例如氧化剂或湿气(水))。
如本文所用术语“降解保护剂”是指保护“药物”、“药品”或“药理活性剂”(例如含苏芬太尼的固体剂型中的苏芬太尼)免于降解的任何材料,例如氧清除剂、干燥剂、抗氧化剂或其组合。
就对水具有亲和性且从其周围环境吸收或吸附湿气,从而控制直接环境中湿气的呈固体、液体或凝胶形式的吸附剂而言,本文使用术语“干燥剂”。
术语“药物”、“药品”、“药理活性剂”、“治疗剂”等在本文中可互换使用且一般是指改变动物的生理机能且可通过经口腔粘膜途径有效投予的任一物质。
本文中使用的“调配物”和“药物调配物”是指含有至少一种医药活性物质的物理组合物,其可以用于递送给个体的多种剂型中的任一者提供。剂型可作为菱形片、药丸、胶囊、薄膜、条带、液体、贴片、膜、口香糖、凝胶、喷雾或其它形式提供给患者。
术语“水凝胶形成制剂”是指在很大程度上缺乏水且当与水溶液(例如体液,且尤其是口腔粘膜的体液)接触时以原位形成水合凝胶的方式吸收水的固体调配物。凝胶的形成遵循独特的崩解(或侵蚀)动力学,同时允许随时间释放治疗剂。另外,术语“水凝胶形成制剂”阐述在很大程度上缺乏水且当与水溶液(例如体液,且尤其是口腔中的体液)接触时转化成释放药物的膜的固体调配物。所述膜使得可用于药物释放和吸收的表面积增加且因此能够较快的进行药物吸收。
如本文所用术语“氧清除剂”是指添加到药物调配物或试剂中以减少或消除不希望的氧化产物的生成的化学物质。一般来说,“氧清除剂”有效吸收氧。术语“氧清除剂”可与术语“氧清除元素”和“氧吸收剂”互换使用。
如本文所用术语“药物递送分配器”是指直接盛放药物、药品或药理活性剂的容器。实例包括药匣、单剂量施药器、多剂量施药器、热塑性托盘、泡罩包、柔性容器和刚性容器。
如本文所用术语“药物剂型”是指含有至少一种用于递送给个体的药物、药品或药理活性剂的物理实体。其可呈菱形片、药丸、片剂、胶囊、薄膜、条带、粉末、贴片、膜、凝胶、喷雾、口香糖或其它形式。
如本文所用术语“初级包装”是指直接盛放药物、药品或药理活性剂的容器。实例包括箔袋、塑料容器、塑料膜容器、泡罩包、玻璃容器等。
实例性箔袋包含以下中的一者或一者以上:铝、锌、镍、锡、铁、铜、铬、钴、银、金、镁、锰、铅、镀锌铁和金属氧化物。
就含有从约2微克(mcg)到约200mcg苏芬太尼(例如,5mcg、10mcg、15mcg、20mcg、30mcg、40mcg、50mcg、60mcg、70mcg、80mcg、90mcg或100mcg或100mcg以上苏芬太尼)的量的苏芬太尼的小体积剂型而言,本文使用术语“小体积含苏芬太尼药物剂型”。
就为固体(例如菱形片、药丸、片剂、薄膜或条带)的剂型而言,本文使用术语“固体剂型”或“固体药物剂型”。
术语“个体”包括需要利用含苏芬太尼的固体剂型治疗的任一个体,其通常为成年或幼年的哺乳动物(例如,人、犬科动物、猫科动物、马科动物、牛科动物、有蹄动物等)。术语“个体”和“患者”在本文中可互换使用。
就几乎不允许氧透过材料的材料而言,本文使用术语“实质上氧不可渗透材料”。
氧化降解的抑制
许多药物对氧化降解敏感。特别地,当药物以占总药物调配物低百分比存在时,此可能成为问题。为了使包含氧化敏感的活性药物的药物调配物和由此一调配物制成的剂型(例如,固体苏芬太尼剂型)中杂质的存在降至最低或消除,调配物中通常采用防腐剂和抗氧化剂以解决此问题。在大多数情况下,此足以使氧化降解产物的生成降至最低或消除。
已知还没有针对液体(苏芬太)、干粉形式的苏芬太尼(詹森医药公司、江森麦蒂公司、泰科公司)或针对芬太尼的经口腔粘膜形式报导过苏芬太尼的氧化降解,因此本发明者惊讶地发现调配、制成片并储存后固体苏芬太尼剂型中出现降解。本发明者还惊讶地发现,在调配物中纳入抗氧化剂(例如BHT)及/或在包装中使用干燥剂并不能使降解停止。在使用水性及/或有机溶剂制备且随后在各种条件下调配、制成片并储存的低剂量固体苏芬太尼剂型中观察到苏芬太尼的降解。
揭示用于保护固体药物剂型中的氧化敏感的活性药物(例如苏芬太尼)免于氧化降解的方法和组合物。在一些情形中,所述方法涉及在药物剂型的包装中纳入氧清除剂。以此方式,在使活性药物免于氧化降解的条件下制备和储存药物剂型(例如苏芬太尼片剂),由此促使药物剂型长时期储存。
可采用经设计以使活性药物对氧及/或湿气的暴露降至最低的包装技术提供对抗氧暴露的额外保护。实例性包装技术包括使用初级包装,其中单独采用一种以上的氧清除材料或组合使用干燥剂。
在一种实例性方法中,将抗氧化剂(例如BHT)纳入药物调配物中,药物递送分配器(例如,药匣)盛放所述药物剂型,且氧清除剂纳入药物递送分配器的初级包装中,其中药物递送分配器与初级包装中的氧清除剂之间可能存在气体交换。
在另一实例性方法中,将抗氧化剂(例如BHT)纳入药物调配物中,将干燥剂纳入盛放所述药物剂型的药物递送分配器(例如,药匣)中,且氧清除剂纳入初级包装中,其中药物递送分配器与初级包装之间可能存在气体交换。
在相关方法中,通过将药物(例如苏芬太尼)提供于包含至少一种氧清除材料的氧不可渗透初级包装(例如箔袋)中来减少或消除所述药物的氧化降解。
在再一实施例中,将抗氧化剂及/或干燥剂纳入用于制作药物递送分配器或初级包装的材料中。在另一实施例中,药物递送分配器或初级包装材料由抗氧化剂包装材料构成。
在优选实施例中,药物递送分配器是由暴露于含有医药活性剂(例如苏芬太尼)的固体剂型时不会生成降解产物的材料构成。用于包装的实例性材料包括玻璃、聚丙烯、聚乙烯(例如,高密度聚乙烯(HDPE)或低密度聚乙烯(LDPE))、聚酯、聚苯乙烯、聚酰胺、氟聚合物(例如阿克拉(ACLAR))、乙烯共乙烯醇(EVOH)、聚碳酸酯、聚氨酯、聚偏二氯乙烯(PVDC)、聚乙烯醇(PVA)、其共聚物或其掺合物。
用于制造单剂量施药器的实例性材料包括(但不限于)TecoFlex EG 80A、聚异戊二烯、Zylar 220;NAS 30(NEOS NOVA)、Versaflex、CL2242(GLS公司)、KR01(雪弗龙菲利普公司(Chevron Phillips))、豪森聚合物(Housing Polymer)、Delrin缩醛(杜邦(DuPont))、聚酯(瓦拉斯(Valox);赛拉尼斯(Celanex))、聚丙烯、ProFax PD702(贝思博(Basell))等。
抗氧化剂
医药调配物中通常采用的抗氧化剂包括(但不限于)维他命E、抗坏血酸、BHT(丁羟甲苯)、BHA(丁羟茴香醚)、没食子酸丙酯、棕榈酸抗坏血酯、双黄酮等。可将抗氧化剂纳入氧化敏感的药物(例如苏芬太尼)的调配物中,特别地当以低剂量固体剂型提供时。
氧清除剂
适宜氧清除剂包括可吸收氧的任一有机或无机材料,例如铁氧化物粉末、亚铁盐(例如硫酸亚铁或氯化亚铁)、亚硫酸盐、亚硫酸氢盐、还原性硫化合物(例如连二亚硫酸盐)、抗坏血酸及/或其盐、异抗坏血酸及/或其盐、还原性有机化合物(例如邻苯二酚和对苯二酚、丁羟甲苯(BHT)、丁羟茴香醚(BHA))。参见(例如)美国专利公开案第20060076536号、第20070084144号、第20060260967号。
许多氧清除剂和湿气吸收剂市场上可买到且可单独或以包装购买,例如斯泰比罗(穆尔蒂索伯技术公司)、环己烯丙烯酸甲酯(EMCM)聚合物(雪弗龙菲利普化学公司(Chevron-Phillips Chemical Company)或汽巴精化公司(Ciba′s Specialty Chemical′s)的SHELFPLUS.TM.。
氧清除剂可以颗粒、罐、包、胶囊、粉末、固体材料、片剂的形式或作为包装材料自身的一部分纳入包装中。
干燥剂
例如,在固体苏芬太尼剂型的包装中可使用任一市售干燥剂。干燥剂可作为颗粒、罐、包、胶囊、粉末、固体材料、纸、板、片剂、粘着贴片和膜提供,且可经形成用于特定应用,包括可注射模制塑料。实例性固体干燥剂包括硅胶(硅酸钠)、铝硅酸盐、活性氧化铝、沸石、分子筛、蒙脱土(montmorillonite clay)、氧化钙和硫酸钙。
在一些实施例中,一种或一种以上干燥剂可用于药物递送分配器中,例如在含有药物剂型的药匣或单剂量施药器内、或在用于含药物的药物递送分配器的初级包装内部,作为保护固体药物剂型免于湿气的手段。实例性位置包括在剂型或递送途径中或与其邻近、在片剂盒或药匣中或与其邻近、在分配装置的其它组件中或与其邻近、形成为分配装置的可注射模制组件、和装置内或外面的任一其它位置,其中干燥剂充分紧密靠近药物剂型以吸收湿气。
固体剂型
一般来说,提供含有从约2mcg到约200mcg苏芬太尼的小体积固体剂型。在一个实例性实施例中,每一剂型含有从约2mcg到约100mcg苏芬太尼、从约4mcg到约50mcg苏芬太尼、从约6mcg到约40mcg苏芬太尼、从约8mcg到约30mcg苏芬太尼或从约10mcg到约20mcg苏芬太尼。所述剂型仅含有苏芬太尼或与另一药物(例如苯并二氮呯,例如三唑仑)组合。
制造包含苏芬太尼的固体剂型(例如片剂、药丸、胶囊、条带、膜、粉末、菱形片、薄膜、贴片、膜或其它形式)的工艺通常涉及使用水性及/或有机溶剂。
含苏芬太尼的固体剂型具有从约1mg到约100mg的质量或从约1mcL到约100mcL的体积。更特定来说,所述剂型的质量从约1mg到约:100mg、90mg、80mg、70mg、60mg、50mg、40mg、30mg、29mg、28mg、27mg、26mg、25mg、24mg、23mg、22mg、21mg、20mg、19mg、18mg、17mg、16mg、15mg、14mg、13mg、12mg、11mg、10mg、9mg、8mg、7mg、6mg或5mg;或体积为从约1mcL到约:100mcL、90mcL、80mcL、70mcL、60mcL、50mcL、40mcL、30mcL、29mcL、28mcL、27mcL、26mcL、25mcL、24mcL、23mcL、22mcL、21mcL、20mcL、19mcL、18mcL、17mcL、16mcL、15mcL、14mcL、13mcL、12mcL、11mcL、10mcL、9mcL、8mcL、7mcL、6mcL或5mcL。
更特定来说,含苏芬太尼的固体剂型的质量为从约1到约8mg、从约2到约10mg、从约3到约15mg、从约4到约20mg、从约5到约25mg,或体积为从约1到约8mcl、从约2到约10mcl、从约3到约15mcl;从约4到约20mcl或从约5到约25mcl。在一个实例性实施例中,所述片剂的质量为5.85mg。
含苏芬太尼的固体剂型、片剂或NanoTabsTM的厚度为从约0.25到约5.0mm;从约0.5到约2.5mm、从约0.6到约2.0mm、从约0.7到约1.0mm、从约0.75到约0.95mm,例如约0.85mm;且直径从约1.0到约10.0mm、从约2.0到约5.0mm、从约2.5到约4.0mm、从约3.0到约3.5mm,例如约3.0mm。
用于经口腔粘膜递送类鸦片(例如苏芬太尼)的组合的片剂通常侵蚀时间为从约2分钟到约40分钟、从约3分钟到约30分钟、从约4分钟到约25分钟、从约5分钟到约20分钟、从约5分钟到约15分钟、从约30秒到约15分钟、从约1分钟到约15分钟或从约6分钟到约12分钟。
固体剂型可具有基本上任一形状,其实例包括具有平面、凹面或凸面的圆盘、椭圆形、球形、具有三个或三个以上边缘和平面、凹面或凸面的多边形。固体剂型可对称或不对称,且可具有允许受控、方便且容易的储存、处理、包装或给药的特征或几何形状。
剂型通常具有生物粘着特性且当与水溶液接触时可形成水凝胶。
用于制备含苏芬太尼的固体剂型的典型调配物和用于制备其的方法阐述于美国专利公开案第20080166404号和第20070207207号中。实例性调配物是生物粘着剂且包含从约0.04%到约4%苏芬太尼、从约0.08%到约1.7%苏芬太尼或从约0.1%到约2.0%苏芬太尼,例如约0.04%、0.08%、0.1%、0.2%、2.25%、0.3%、0.35%、0.4%、0.45%、0.5%、0.55%、0.6%、0.65%、0.7%、0.75%、0.8%、0.85%、0.9%、0.95%、1.0%、1.1%、1.2%、1.3%、1.4%、1.5%、1.6%、1.7%、1.8%、1.9%、2.0%、2.2%、2.2%、2.4%、2.5%、2.6%、2.8%、3.0%、3.2%、3.5%或4%苏芬太尼。一般来说,调配物作为实质上均相组合物提供,其包含苏芬太尼、生物粘着剂、粘合剂、水凝胶形成赋形剂、填充剂、润滑剂和影响溶解时间及/或药物稳定性的其它赋形剂和要素中的一者或一者以上。药物调配物和固体剂型不会起泡,其也不会包含药物微粒粘附至载剂粒子表面的规则混合物(ordered mixture),其中载剂粒子实质上大于药物微粒。
包含调配物的剂型的溶解一般依赖于pH,例如在约4到8的pH范围内。
在雷明顿的医药科学(Remington′s Pharmaceutical Sciences)(第17版,1985)中可找到许多用于含苏芬太尼的固体剂的适宜无毒的医药上可接受的载剂。
应了解,使用所属领域的技术人员惯常采用的程序(例如直接压制、湿造粒等),将含苏芬太尼的调配物转化成含苏芬太尼的固体剂型用于递送给个体。制备含苏芬太尼的固体剂型的工艺通常涉及使用水性及/或有机溶剂且针对每一调配物进行优化以获得高剂量含量均匀性。
药匣和单剂量施药器
用于盛放药物剂型的药匣可为圆柱形、盘形、螺旋形、直线形、不规则形状,或可采取允许药物分配装置以控制方式分配的药物剂型的任一装配形式。
在本发明一个实施例中,药匣可盛放足以用于1到5天治疗的药物剂型,例如可用于48到72小时治疗的40片片剂。
为防止未使用的药物剂型吸收湿气或者在使用之前暴露于湿气,可提供药匣或其它药物分配装置作为密封药物剂型免于暴露于湿气的手段。此举可通过使用含有干燥剂或其它吸收剂或吸附剂材料的药匣以吸收或吸附在使用之前或正常使用期间渗入药匣的湿气来完成。
干燥剂是呈固体、液体或凝胶形式的吸附剂,其对水具有亲和性并吸收或吸附周围环境的湿气,因此控制直接环境中的湿气。任何市售干燥剂都可使用。所述市售干燥剂通常采用颗粒、罐、包、胶囊、粉末、固体材料、纸、板、片剂、粘着贴片和膜形式,且可经成形用于具体应用,包括可注射模制塑料。存在许多类型的固体干燥剂,包括硅胶(硅酸钠,其是固体而不是凝胶)、铝硅酸盐、活性氧化铝、沸石、分子筛、蒙脱土、氧化钙和硫酸钙或其它干燥剂,其中任一者均可用于实践本发明。
在一个实施例中,使用单剂量施药器(SDA)作为固体苏芬太尼药物剂型的药物递送分配器。在此实施例中,SDA包含于氧不可渗透的初级包装中。在另一实施例中,SDA包含于氧可渗透的初级包装中。在再一实施例中,初级包装包含于氧不可渗透的二次包装中。
SDA内可含有所述剂型,可将药物剂型附接或附着至其,及/或可提供对抗湿气、潮湿和光的密封。可由患者、医疗服务提供者或其它使用者手动操纵单剂量施药器以将所述剂型置于适当位置处用于药物递送。
SDA可作为一对钳形针、注射器、棒或杆、吸管、垫、胶囊、杯、汤匙、条带、试管、施药器、滴管、贴片、粘着垫、粘着膜、喷雾器、雾化器或适于将单一药物剂型施加于个体的口腔粘膜(例如舌下间隙的口腔粘膜)的任一其它形式提供。如所属领域的技术人员应了解,SDA设计可有所变化,只要其有效的以在分配过程中保持药物剂型的完整性的方式将药物剂型(例如片剂)置于想要的位置(例如舌下间隙)中即可。使用之后,丢弃SDA。
剂型可提供于由具有剂型置于其中的凹陷(“泡罩”)的模制塑料或压层(在本文中称为“泡罩包”)组成的药物递送分配器。泡罩包可具有或可不具有预形成或模制部分且可用于包装任一类型的SDA。
SDA可提供于儿童多耐药药物分配器(MDD)中,其可用于分配其中盛放的剂型或可用于储存多个SDA。
在一个实施例中,SDA用作药物递送分配器且MDD用作初级包装。
在分配药物剂型之前,SDA和MDD内的所述剂型保持干燥。
干燥剂可以或可以不包括在药物递送分配器中且氧清除剂通常包括在初级包装中。
效用
医药调配物中与活性医药成份(API)一起留下的、在调配期间产生或在API或经调配药物剂型老化时产生的杂质可能会成为问题。即使少量存在的所述杂质也可影响医药产品的功效和安全性。必须分析并鉴别医药产品中的杂质。优选的,活性药物(例如,苏芬太尼)降解产物的总量不超过给定药物剂型中活性药物物质的量的5%、4%、3%、2%、1%、0.9%、0.8%、0.7%、0.6%、0.5%、0.4%、0.3%、0.2%、0.1%或更少。国际药品注册协调会议(International Conference on Harmonization,ICH)提供了关于杂质控制的准则。
可通过在药物剂型的包装中纳入氧清除剂来减少或消除药物剂型(例如包含苏芬太尼的固体剂型)中的氧化降解产物。
前面的阐述仅说明了本发明的原理。应了解,所属领域的技术人员将能够设想各种布置,所述各种布置尽管本文并未明确地阐述或显示但体现本发明原理且包括在本发明的精神和范围内。此外,本文叙述本发明的原理、方面和实施例的所有陈述以及其具体实例打算涵盖其结构和功能等效物二者,所述等效物包括目前已知等效物和将来开发的等效物二者。因此,本发明的范围并不打算限于本文所显示和阐述的实例性实施例。
实例
实例1:在存在和不存在氧清除剂的情况下对固体苏芬太尼剂型的稳定性研究。
实施研究以评价包含5mcg苏芬太尼质量为5.85mg的片剂的稳定性,所述片剂已在有或没有氧清除剂的不同环境条件下在高密度聚乙烯(HDPE)瓶中储存0.5个月、1个月、2个月和3个月。
储存条件为以下:
(1)5℃,在环境湿度下
(2)25℃和60%相对湿度(RH)
(3)40℃和75%相对湿度(RH)
5mcg苏芬太尼调配物包括存于甘露醇、羟丙基甲基纤维素、硬脂酸、硬脂酸镁、磷酸氢钙和丁羟甲苯(BHT)的基质中的0.128%苏芬太尼柠檬酸盐,其如下所示。
评价在HDPE瓶中储存之后的T=0和2周、1个月、2个月、3个月和6个月时,在有或没有氧清除剂(斯泰比罗穆尔蒂索伯公司)的情况下储存的固体苏芬太尼剂型的HPLC曲线。通过在以下所阐明条件下的HPLC分析评价苏芬太尼的稳定性。如所属领域的技术人员应了解,以下所阐明的条件是用于HPLC分析的实例性条件且并于打算限制其它可能的分析方法。
用于分析苏芬太尼降解产物的样品是在溶液中提供约50μg/mL(苏芬太尼)的NanoTabsTM复合材料。在实施方法时,计算获得约50μg/mL的标称浓度所需的NanoTabsTM的数量和体积,然后将等于大约30%样品体积的量的萃取溶液吸取到容器中,将混合物超声波15分钟,随后用20mM磷酸铵缓冲液稀释到体积并充分混合。使用玻璃注射器来通过0.45μm密理博(Millipore)Millex尼龙注射器式过滤器过滤上清液。将最初的1mL的滤液丢弃,然后使用剩余滤液填充HPLC 9mm TFE/SIL/TFE蓝色盖容器,随后进行HPLC分析。
表1A显示在5℃和环境湿度下储存之后固体苏芬太尼剂型存在的降解产物的HPLC分析结果,如由在HDPE瓶中储存2周、1个月、2个月、3个月和6个月之后相对保留时间(RRT)处的峰0.37、0.50和0.56所证实。
表1A.5mcg苏芬太尼片剂在5℃和环境湿度下的稳定性评价
Total Deg.=总降解报告为占总苏芬太尼峰面积的百分比(%)。
表1B显示在5℃和环境湿度下储存之后固体苏芬太尼剂型存在的降解产物的HPLC分析结果,如由在含有氧清除剂的HDPE瓶中储存T=0、2周、1个月、2个月、3个月和6个月之后相对保留时间(RRT)处的峰0.37、0.50和0.56所证实。
表1B.5mcg苏芬太尼片剂在5℃/环境湿度下在含有氧清除剂的HDPE瓶中储存 时的稳定性评价
图1显示5mcg苏芬太尼剂型的总RS%对时间(0、0.5、1、2和3个月),所述苏芬太尼剂型是使用标准调配物制得并随后在5℃和环境湿度下其自身(5μg)在HDPE瓶中或在含有氧清除剂(斯泰比罗穆尔蒂索伯技术公司;5μg-R)的HDPE瓶中储存。名称“总RS%”(总相关物质%)与术语“SDP%(苏芬太尼降解产物%)指相同情况且可与其互换使用,是“相关物质”(苏芬太尼降解产物)的峰面积相对于苏芬太尼的总峰面积的百分比。
表2A显示在25℃和60%RH下储存之后固体苏芬太尼剂型存在的降解产物的HPLC分析结果,如由在HDPE瓶中储存T=0、2周、1个月、2个月、3个月和6个月之后相对保留时间(RRT)处的峰0.37、0.50、0.54和0.56所证实。
表2A.5mcg苏芬太尼片剂在25℃和60%RH下在HDPE瓶中的稳定性评价.
表2B显示在25℃和60%RH下储存之后固体苏芬太尼剂型存在的降解产物的HPLC分析结果,如由在含有氧清除剂(斯泰比罗)的HDPE瓶中储存T=0、2周、1个月、2个月、3个月和6个月之后相对保留时间(RRT)处的峰0.37、0.50和0.56所证实。
表2B.5mcg苏芬太尼片剂在25℃和60%RH下在含有氧清除剂的HDPE瓶中储 存时的稳定性评价
图2显示5mcg苏芬太尼剂型的总RS%对时间(0、0.5、1、2和3个月),所述苏芬太尼剂型是使用标准调配物制得并随后在25℃和60%湿度下其自身(5μg)在HDPE瓶中或在含有氧清除剂(5μg-R)的HDPE瓶中储存。
表3A显示在40℃和75%RH下储存之后固体苏芬太尼剂型存在的降解产物的分析结果,如由在HDPE瓶中储存T=0、2周、1个月、2个月、3个月和6个月之后相对保留时间(RRT)处的峰0.37、0.50、0.54和0.56所证实。
表3A.5mcg苏芬太尼片剂在40℃和75%RH下在HDPE瓶中储存的稳定性评价
表3B显示在40℃和75%RH下储存之后固体苏芬太尼剂型存在的降解产物的HPLC分析结果,如由在含有氧清除剂(斯泰比罗)的HDPE瓶中储存T=0、2周、1个月、2个月、3个月和6个月之后相对保留时间(RRT)处的峰0.37、0.50和0.56所证实。
表3B.5mcg苏芬太尼片剂在40℃和75%RH下在含有氧清除剂的HDPE瓶中储 存时的稳定性评价
图3显示5mcg苏芬太尼剂型的总RS%对时间(0、0.5、1、2和3个月),所述苏芬太尼剂型是使用标准调配物制得并随后在40℃和75%湿度下其自身(5μg)在HDPE瓶中或在含有氧清除剂(5μg-R)的HDPE瓶中储存。
表4显示固体苏芬太尼剂型在5℃和环境湿度下在有或没有氧清除剂的HDPE瓶中储存之后存在的降解产物的HPLC分析结果,报告为总RS%对时间。
表4.5mcg苏芬太尼片剂在5℃和环境湿度下在有或没有氧清除剂的HDPE瓶中
储存的稳定性评价
时间(月) | 总RS%(+氧清除剂) | 总RS%(没有氧清除剂) |
0 | 0.16 | 0.58 |
0.5 | 0.77 | |
1 | 0.35 | 0.84 |
2 | 0.32 | 1.00 |
3 | 0.28 | 1.23 |
6 | 0.14 | 1.6 |
表5显示固体苏芬太尼剂型在25℃和60%RH下在有或没有氧清除剂的HDPE瓶中储存0、0.5、1、2、3和6个月之后存在的降解产物的HPLC分析结果,报告为总RS%对时间。
表5.5mcg苏芬太尼片剂在25℃和60%RH下在有或没有氧清除剂的HDPE瓶中
储存的稳定性评价
时间(月) | 总RS%(+氧清除剂) | 总RS%(没有氧清除剂) |
0 | 0.16 | 0.58 |
0.5 | 0 | 1.26 |
1 | 0 | 1.39 |
2 | 0 | 2.15 |
3 | 0.1 | 2.15 |
6 | 0.13 | 2.64 |
表6.5mcg苏芬太尼片剂在40℃与75%RH下在有或没有氧清除剂的HDPE瓶中
储存的稳定性评价
时间(月) | 总RS%(+氧清除剂) | 总RS%(没有氧清除剂) |
0 | 0.16 | 0.58 |
0.5 | 0.14 | 1.43 |
1 | 0.28 | 1.66 |
2 | 0.39 | 2.14 |
3 | 0.51 | 2.19 |
6 | 0.77 | 2.17 |
实例1中所呈现的结果显示,通过在存在氧清除剂的情况下储存固体苏芬太尼药物剂型(例如,片剂)减少或消除所述固体苏芬太尼剂型在储存之后的苏芬太尼降解产物的生成。
实例2:在存在干燥剂或氧清除剂的情况下对固体苏芬太尼剂型的稳定性研究。
实施研究以评价包含5mcg苏芬太尼质量为5.85mg的片剂的稳定性,所述片剂已在存在氧清除剂或干燥剂的不同环境条件下在高密度聚乙烯(HDPE)瓶中储存0.5个月、1个月、2个月、3个月和6个月。所用干燥剂为1g硅胶小袋储存条件为以下:
5℃,环境湿度下;
25℃和60%相对湿度(RH);和
40℃和75%相对湿度(RH)。
苏芬太尼调配物和HPLC程序的细节提供于以上实例1中。
在HDPE瓶中储存0.5个月、1个月、2个月、3个月和6个月之后,评价在存在斯泰比罗或干燥剂的情况下储存的固体苏芬太尼剂型的HPLC曲线。
表7显示固体苏芬太尼剂型在HDPE瓶中在5℃和环境湿度下储存之后存在的降解产物的HPLC分析结果,报告为在T=0时和在存在氧清除剂(5μg-R_斯泰比罗)或干燥剂(5μg-干燥剂)的情况下在0.5个月、1个月、2个月、3个月和6个月时的%总SDP。
表7.5mcg苏芬太尼片剂在5℃下在存在氧清除剂或干燥剂的HDPE瓶中储存的
稳定性评价.
表8显示固体苏芬太尼剂型在HDPE瓶中在25℃和60%RH下储存之后存在的降解产物的HPLC分析结果,报告为在T=0时和在存在氧清除剂(5μg-R)或干燥剂(5μg-干燥剂)的情况下在0.5个月、1个月、2个月、3个月和6个月时的%总SDP。
表8.5mcg苏芬太尼片剂在25℃和60%RH下在存在氧清除剂或干燥剂的HDPE
瓶中储存的稳定性评价.
表9显示固体苏芬太尼剂型在HDPE瓶中在40℃和75%RH下储存之后存在的降解产物的HPLC分析结果,报告为在T=0时和在存在氧清除剂(5μg-R_斯泰比罗)或干燥剂(5μg-干燥剂)的情况下在0.5个月、1个月、2个月、3个月和6个月时的%总SDP。
表9.5mcg苏芬太尼片剂在40℃和75%RH下在存在氧清除剂或干燥剂的HDPE
瓶中储存的稳定性评价。
实例3:在药匣中在存在氧清除剂的情况下对固体苏芬太尼剂型的稳定性分析
在包含40片片剂和斯泰比罗的药匣中储存之后对固体苏芬太尼剂型的稳定性实施进一步研究。实施研究以评价包含10mcg苏芬太尼且质量为5.85mg的片剂在药匣中在存在氧清除剂(斯泰比罗)的不同储存条件下储存1个月、2个月和3个月后的稳定性。
储存条件为以下:
25℃和60%相对湿度(RH);和
40℃和75%相对湿度(RH)。
苏芬太尼调配物为:0.256%苏芬太尼柠檬酸盐存于甘露醇、羟丙基甲基纤维素、硬脂酸、硬脂酸镁、磷酸氢钙和丁羟甲苯(BHT)的基质中。
表10A和B显示固体苏芬太尼剂型在HDPE瓶或由各种材料制成且含有氧清除剂的药匣中在25℃和60%RH下储存之后存在的降解产物的HPLC分析结果,如由在T=0、1个月、2个月和3个月时在相对保留时间(RRT)时的峰0.36、0.49/0.50和0.54/0.55所证实。
表10A.在25℃和60%RH下在HDPE瓶中或在存在氧清除剂的药匣中储存的10
mcg苏芬太尼片剂的稳定性评价
<QL是指小于定量限值。
表10B.10mcg苏芬太尼片剂在25℃和60%RH中在存在氧清除剂的药匣中储存
的稳定性评价。
表11A和B显示固体苏芬太尼剂型在HDPE瓶或由各种材料制成且含有氧清除剂的药匣中在40℃和75%RH下储存之后存在的降解产物的HPLC分析结果,如由在T=0、1个月、2个月和3个月时在相对保留时间(RRT)时的峰0.36、0.49/0.50和0.54/0.55所证实。
表11A.10mcg苏芬太尼片剂在40℃和75%RH下在存在氧清除剂的药匣中储存
的稳定性评价。
表11B.10mcg苏芬太尼片剂在40℃和75%RH下在存在氧清除剂的药匣中储存
的稳定性评价。
实例4:在单剂量施药器(SDA)中在存在氧清除剂的情况下对固体苏芬太尼剂型 的稳定性研究。
对存于固体苏芬太尼剂型中的苏芬太尼在SDA中储存之后的稳定性实施进一步研究。实施研究以评价包含20mcg苏芬太尼且质量为5.85mg的片剂在SDA中在存在氧清除剂的不同储存条件下储存1个月、2个月、3个月和6个月之后的稳定性。
储存条件为以下:
5℃,环境湿度下;
25℃和60%相对湿度(RH);和
40℃和75%相对湿度(RH)。
苏芬太尼白调配物提供于以上实例3中。在SDA中使用以上实例1中所提供的条件储存1个月、2个月、3个月和6个月之后,评价固体苏芬太尼剂型在存在氧清除剂的情况下储存的HPLC曲线。
表12A和B显示固体苏芬太尼剂型在SDA中且包装有氧清除剂的情况下在25℃和60%RH下储存之后存在的降解产物的HPLC分析的结果,如由在T=0、1个月、2个月和3个月时相对保留时间(RRT)时的峰0.36、0.49/0.50和0.54/0.55所证实。
表12A.20mcg苏芬太尼片剂在2到8℃和环境湿度下在包装有氧清除剂的SDA
中储存的稳定性评价
时间 | 个别未指明的苏芬太尼相关杂质(RS%) | 总计(%) |
T=0 | 未检测到杂质 | N/A |
T=1个月 | 未检测到杂质 | N/A |
T=2个月 | 未检测到杂质 | N/A |
T=3个月 | 未检测到杂质 | N/A |
表12B.20mcg苏芬太尼片剂在25℃和60%RH下在包装有氧清除剂的SDA中储
存的稳定性评价
时间 | 个别未指明的苏芬太尼相关杂质(RS%) | 总计(%) |
T=0 | 未检测到杂质 | N/A |
T=1个月 | 未检测到杂质 | N/A |
T=2个月 | 未检测到杂质 | N/A |
T=3个月 | 未检测到杂质 | N/A |
表12C.20mcg苏芬太尼片剂在40℃和75%RH下在包装有氧清除剂的SDA中储
存的稳定性评价。
时间 | 个别未指明的苏芬太尼相关杂质(RS%) | 总计(%) |
T=0 | 未检测到杂质 | N/A |
T=1个月 | 未检测到杂质 | N/A |
T=2个月 | 未检测到杂质 | N/A |
T=3个月 | 未检测到杂质 | N/A |
Claims (25)
1.一种经包装固体苏芬太尼(sufentanil)药物剂型,其包含:
(a)固体苏芬太尼药物剂型,其具有从约5mg到约25mg的质量或从约5mcl到约25mcl的体积,所述片剂包含;
(b)初级包装,其含有所述固体苏芬太尼药物剂型和氧清除剂,其中相对于在没有氧清除剂的情况下包装的固体苏芬太尼药物剂型,与所述氧清除剂一起包装的固体苏芬太尼药物剂型中的苏芬太尼氧化降解产物的百分比降至最低或消除。
2.根据权利要求1所述的经包装固体苏芬太尼药物剂型,其中所述药物剂型具有从约2mg到约10mg的质量或从约2mcl到约10mcl的体积。
3.根据权利要求1所述的经包装固体苏芬太尼药物剂型,其中所述药物剂型具有从约0.7mm到约1.0mm或从约0.75mm到约0.95mm的厚度。
4.根据权利要求1所述的经包装固体苏芬太尼药物剂型,其中苏芬太尼在所述固体苏芬太尼药物剂型中的量选自由5mcg、10mcg、15mcg、20mcg、30mcg、40mcg、50mcg、60mcg、70mcg、80mcg和100mcg苏芬太尼组成的群组。
5.根据权利要求2所述的经包装固体苏芬太尼药物剂型,其中苏芬太尼在所述固体苏芬太尼药物剂型中的量选自由5mcg、10mcg、15mcg、20mcg、30mcg、40meg、50mcg、60mcg、70mcg、80mcg和100mcg苏芬太尼组成的群组。
6.根据权利要求3所述的经包装固体苏芬太尼药物剂型,其中苏芬太尼在所述固体苏芬太尼药物剂型中的量选自由5mcg、10mcg、15mcg、20mcg、30mcg、40mcg、50mcg、60mcg、70mcg、80mcg和100mcg苏芬太尼组成的群组。
7.根据权利要求4所述的经包装固体苏芬太尼药物剂型,其中当所述固体苏芬太尼药物剂型在选自由5℃与环境湿度、25℃与60%相对湿度和40℃与75%相对湿度组成的群组的条件下储存至少6个月时,相对于在没有氧清除剂的情况下包装的固体苏芬太尼药物剂型,与所述氧清除剂一起包装的固体苏芬太尼药物剂型中的苏芬太尼氧化降解产物的百分比降至最低或消除。
8.根据权利要求5所述的经包装固体苏芬太尼药物剂型,其中当所述固体苏芬太尼药物剂型在选自由5℃与环境湿度、25℃与60%相对湿度和40℃与75%相对湿度组成的群组的条件下储存至少6个月时,相对于在没有氧清除剂的情况下包装的固体苏芬太尼药物剂型,与所述氧清除剂一起包装的固体苏芬太尼药物剂型中的苏芬太尼氧化降解产物的百分比降至最低或消除。
9.根据权利要求4所述的经包装固体苏芬太尼药物剂型,其进一步包含用于盛放所述固体苏芬太尼药物剂型的药物递送分配器。
10.根据权利要求9所述的经包装固体苏芬太尼药物剂型,其中所述药物递送分配器是药匣。
11.根据权利要求9所述的经包装固体苏芬太尼药物剂型,其中所述药物递送分配器是单剂量施药器。
12.根据权利要求9所述的经包装固体苏芬太尼药物剂型,其中所述初级包装是箔袋。
13.根据权利要求5所述的经包装固体苏芬太尼药物剂型,其进一步包含用于盛放所述固体苏芬太尼药物剂型的药物递送分配器。
14.根据权利要求13所述的经包装固体苏芬太尼药物剂型,其中所述药物递送分配器是药匣。
15.根据权利要求13所述的经包装固体苏芬太尼药物剂型,其中所述药物递送分配器是单剂量施药器。
16.根据权利要求13所述的经包装固体苏芬太尼药物剂型,其中所述初级包装是箔袋。
17.一种用于防止固体苏芬太尼药物剂型氧化降解的方法,其包含:
(a)将固体苏芬太尼药物剂型提供于药物递送分配器中,所述固体苏芬太尼药物剂型具有从约5mg到约25mg的质量或从约5mcl到约25mcl的体积;
(b)进一步提供氧清除剂;
(c)将所述药物递送分配器和所述氧清除剂置于初级包装中,所述初级包装由实质上氧不可渗透材料制成,其中相对于在没有氧清除剂的情况下包装并储存后的固体苏芬太尼药物剂型中的苏芬太尼氧化降解产物的百分比,在存在氧清除剂的情况下包装并储存后的所述固体苏芬太尼药物剂型中的苏芬太尼氧化降解产物的百分比降至最低或消除。
18.根据权利要求17所述的方法,其中所述固体药物剂型具有从约2mg到约10mg的质量或从约2mcl到约10mcl的体积。
19.根据权利要求17所述的方法,其中所述固体药物剂型具有从约0.7mm到约1.0mm或从约0.75mm到约0.95mm的厚度。
20.根据权利要求17所述的方法,其中苏芬太尼在所述固体药物剂型中的量选自由5mcg、10mcg、15mcg、20mcg、30mcg、40mcg、50mcg、60mcg、70mcg、80mcg和100mcg苏芬太尼组成的群组。
21.根据权利要求20所述的方法,其中所述固体苏芬太尼药物剂型在选自由5℃与环境湿度、25℃与60%相对湿度和40℃与75%相对湿度组成的群组的条件下储存至少6个月。
22.根据权利要求20所述的方法,其中所述药物递送分配器是药匣。
23.根据权利要求22所述的方法,其中所述药匣包含干燥剂。
24.根据权利要求20所述的方法,其中所述药物递送分配器是单剂量施药器。
25.根据权利要求20所述的方法,其中所述初级包装是箔袋。
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KR20110099017A (ko) | 2011-09-05 |
AU2009316874A1 (en) | 2011-07-07 |
NZ593512A (en) | 2012-12-21 |
IL212880A0 (en) | 2011-07-31 |
WO2010059504A1 (en) | 2010-05-27 |
CA2743261A1 (en) | 2010-05-27 |
EP2367537B1 (en) | 2012-10-17 |
CA2743261C (en) | 2016-11-01 |
ES2396150T3 (es) | 2013-02-19 |
AU2009316874B2 (en) | 2016-06-16 |
US20100130551A1 (en) | 2010-05-27 |
RU2011125316A (ru) | 2012-12-27 |
IL212880A (en) | 2015-08-31 |
BRPI0921519B1 (pt) | 2021-10-13 |
US8945592B2 (en) | 2015-02-03 |
PT2367537E (pt) | 2013-01-22 |
BRPI0921519A2 (pt) | 2017-05-30 |
MX2011005370A (es) | 2011-09-15 |
JP2012509325A (ja) | 2012-04-19 |
CN102231980B (zh) | 2014-07-16 |
SG171786A1 (en) | 2011-07-28 |
DK2367537T3 (da) | 2013-01-07 |
RU2530579C2 (ru) | 2014-10-10 |
EP2367537A1 (en) | 2011-09-28 |
BRPI0921519A8 (pt) | 2021-09-28 |
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