CN1098680C - 适于喷雾的悬浮液制剂及其制备方法 - Google Patents
适于喷雾的悬浮液制剂及其制备方法 Download PDFInfo
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Abstract
本发明涉及经吸入施用的药物。具体地说，本发明涉及一种制剂，它包含几乎所有颗粒粒径都小于12微米的氟替卡松丙酸酯，一种或多种表面活性剂，一种或多种缓冲剂和水。还涉及一种治疗呼吸性疾病的方法，包括经吸入施用有效量的所定义制剂
Description
本发明涉及含有氟替卡松酯的药物的改进或含有氟替卡松酯的药用组合物。具体地说本发明涉及经吸入施用氟替卡松丙酸酯的新制剂。
据GB 2088877记载和要求保护的氟替卡松丙酸酯是S-氟甲基6a，9a-二氟-11b-羟基-16a-甲基-17a-丙酰氧基-3-氧杂雄甾-1，4-二烯17b硫代羧酸酯的通用名称，它是一种已知具有局部抗炎活性的皮质类固醇激素。业已发现以含有细颗粒药物的干粉或气雾剂形式施用氟替卡松丙酸酯可有效地治疗哮喘病，所述细颗粒药物一般通过微粉化制备。一般来说，氟替卡松丙酸酯气雾剂借助于计量剂量的吸入器施用，所设计的吸入器在每次驱动或“喷雾”时喷放出确定剂量的药物。但是对某些患者而言，特别是儿童和老年患者，配合计量剂量的吸入器吸入药物有困难，不能有效地运用这种施用方式。此外，还有部分患者发现吸入干粉有困难或感到不适。因此，就需要有一种适于喷雾的含氟替卡松丙酸酯的药物制剂。
本发明一方面提供一种适于喷雾的制剂，它包含：(a)氟替卡松丙酸酯，几乎所有颗粒粒径均小于12微米；(b)一种或多种表面活性剂；(c)一种或多种缓冲剂；及(d)水。
氟替卡松丙酸酯可运用本领域已知的方法制备，如GB 2088877中所公开的方法。由此也可以制备氟替卡松丙酸酯的溶剂化物，因此本发明可扩大到含有生理可接受的氟替卡松丙酸酯溶剂化物的制剂。可使用常规方法，如微粉化减小结晶颗粒的粒径，以使在施用喷雾制剂时将基本上所有的药物都吸入肺部。适宜的粒径范围是0.5-12微米，例如1-6微米。
为将氟替卡松丙酸酯引入肺部，喷雾制剂的雾滴直径是重要参数。雾滴直径在一定程度上取决于所用喷雾器的类型，如是否采用面罩或接口和压缩气体的压力或流速以及喷雾制剂的物理性质。喷雾制剂是非均相分散的，即雾滴直径分布在一定范围内。一般平均雾滴直径范围是0.5-15微米，优选0.5-10微米，更优选小于5微米。
本发明的制剂含有的氟替卡松丙酸酯宜占制剂固体组份总重的0.5-10％(w/w)，优选1-9％(w/w)，尤其优选1.5-6.5％(w/w)。
吸入施用时，本发明制剂中使用的表面活性剂须是在生理上可接受的。该范畴内的表面活性剂包括如脱水山梨醇三油酸酯(司盘R85)，脱水山梨醇单油酸酯，脱水山梨醇单月桂酸酯，聚氧乙烯(20)脱水山梨醇单月桂酸酯，聚氧乙烯(20)脱水山梨醇单油酸酯，天然卵磷脂，油酰聚氧乙烯(2)醚，硬脂酰聚氧乙烯(2)醚，月桂酰聚氧乙烯(4)醚，氧化乙烯和氧化丙烯的嵌段共聚物，合成的卵磷脂，二甘醇二油酸酯，油酸四氢糠酯，油酸乙酯，甘油单油酸酯，聚乙二醇400和甘油单月桂酸酯。
用于本发明制剂的特别优选的表面活性剂是脱水山梨醇单月桂酸酯和聚氧乙烯(20)脱水山梨醇单月桂酸酯(也被称为聚山梨醇酯20)。
本发明制剂中含有的表面活性剂宜占制剂固体组份总重的0.25-0.75％(w/w)，优选0.4-0.6％(w/w)，尤其优选0.45-0.55％(w/w)。
本发明制剂优选含有脱水山梨醇单月桂酸酯与聚氧乙烯(20)脱水山梨醇单月桂酸酯的比例是1∶7.5-1∶8.25，如1∶7.7-1∶8.1。
将本发明制剂缓冲到PH约5-约7，优选约6。在吸入施用时，适宜的缓冲剂是生理可接受的。这类缓冲剂包括柠檬酸缓冲剂和磷酸盐缓冲剂，其中磷酸盐缓冲剂是优选的。特别优选用于本发明制剂的缓冲剂是二水合磷酸二氢钠和无水磷酸氢二钠。
本发明的制剂最好是等渗的。可通过加入适宜的盐，如氯化钠调节制剂的等渗性。
在优选的实施方案中，本发明制剂还含有足量的氯化钠或其它适宜的可药用盐以提供等渗组合物，
在一个特别优选的实施方案中，本发明提供了一种适于喷雾使用的制剂，该制剂组成如下：(a)0.5-2.2mg氟替卡松丙酸酯(微粉化的)；(b)0.12-0.18mg聚氧乙烯(20)脱水山梨醇单月桂酸酯；(c)0.015-0.025mg脱水山梨醇单月桂酸酯；(d)18.5-19mg二水合磷酸二氢钠；(e)3.2-3.7mg无水磷酸氢二钠；(f)9.4-9.8mg氯化钠；和(g)注射用水至2.0ml。
因此可知，根据优选实施方案的制剂应组成如下：(a)0.25-1.1mgml-1氟替卡松丙酸酯(微粉化的)；(b)0.06-0.09mgml-1聚氧乙烯(20)脱水山梨醇单月桂酸酯；(c)0.0075-0.0125mgml-1脱水山梨醇单月桂酸酯；(d)9.25-9.5mgml-1二水合磷酸二氢钠；(e)1.6-1.85mgml-1无水磷酸氢二钠；(f)4.7-4.9mgml-1氯化钠；和(g)水。
在放置后，本发明的制剂形成弱絮凝悬浮液，但出人意料的是该悬浮液经过温和搅拌就很容易再分散得到具有良好喷施特性的适于在普通喷雾器中使用的悬浮液，即使是在长时间贮藏后也是如此。
可运用本领域技术人员熟知的技术测定本发明制剂的物理化学稳定性和可药用性。例如，本发明的制剂在长时间贮藏后可运用HPLC测定法测定组份的化学稳定性。
本发明制剂喷雾时的粒径分布可运用常规技术测量，如运用级联冲击法或运用“双空气采集器(Twin Impinger)”分析法。本文采用的“双空气采集器”分析法是指在英国药典(British Pharmacopaeia)1988，附录XVII C的第A204-207页定义的“测定使用装置A加压吸入的喷射沉积剂量的方法”。运用这类技术可计算制剂的“可吸入百分率”。本文采用的“吸入百分率”是指使用上述双空气采集器方法，每次加压在低采集室中采集到的活性成分量占每次加压喷射出的活性成分总量的百分率。发现本发明制剂的可吸入百分率是10％或更高，如10-50％，例如15-35％(以药物重量计)。
可采用制备悬浮液制剂的常规方法制备本发明的制剂。具代表性的是在将氟替卡松丙酸酯加到含剩余赋形剂的本体 液中之前，使氟替卡松丙酸酯与少量表面活性剂溶液接触以使其润湿。不断地混合对于维持均匀的悬浮液是必要的。宜采用常规蒸汽灭菌法将总悬浮液灭菌。宜将悬浮液等量分装到无菌容器，例如单位剂量容器(如小瓶或安瓿)中，这些容器宜用热塑性塑料模塑制成。
另一方面，本发明包括一种治疗呼吸疾病，如哮喘的方法，该方法包括经吸入施用有效量的本文所述制剂。
因此，本发明的制剂可经喷雾器喷施，在这种情况下宜将等量的悬浮液制剂填装到上述无菌容器中。或者，也可将本发明的制剂用作滴鼻剂。这样，宜将等量悬浮液制剂填装到适于这种用药途径的无菌小容量容器中。
通过下列非限定性实施例进一步说明本发明。实施例1
mg氟替卡松丙酸酯(微粉化的) 0.525聚氧乙烯(20)脱水山梨醇单月桂酸酯 0.14脱水山梨醇单月桂酸酯 0.018二水合磷酸二氢钠 18.80无水磷酸氢二钠 3.50氯化钠 9.60注射用水 至2.00ml
可见按照实施例1制备的制剂组成如下：约0.26mgml-1氟替卡松丙酸酯(微粉化的)；约0.07mgml-1聚氧乙烯(20)脱水山梨醇单月桂酸酯；约0.009mgml-1脱水山梨醇单月桂酸酯；约9.4mgml-1二水合磷酸二氢钠；约1.75mgml-1无水磷酸氢二钠；约4.8mgml-1氯化钠；和水。
将按照实施例1制备的制剂填装到喷雾器中。测定喷雾时的粒径分布，以其作为双空气采集器装置第2层(细颗粒部分)的氟替卡松丙酸酯的百分率和级联冲击器装置第2-7层(细颗粒部分)的氟替卡松丙酸酯的百分率，得到的值分别是18.5％和18.2％。实施例2
mg氟替卡松丙酸酯(微粉化的) 2.10聚氧乙烯(20)脱水山梨醇单月桂酸酯 0.16脱水山梨醇单月桂酸酯 0.02二水合磷酸二氢钠 18.80无水磷酸氢二钠 3.50氯化钠 9.60注射用水 至2.00ml
可见按照实施例2制备的制剂组成如下：约1.05mgml-1氟替卡松丙酸酯(微粉化的)；约0.08mgml-1聚氧乙烯(20)脱水山梨醇单月桂酸酯；约0.01mgml-1脱水山梨醇单月桂酸酯；约9.4mgml-1二水合磷酸二氢钠；约1.75mgml-1无水磷酸氢二钠；约4.8mgml-1氯化钠；和水。
将按照实施例2制备的制剂填装到喷雾器中。如实施例1测定喷雾的粒径分布。双空气采集器装置试验得到的值是22.1％，级联冲击装置试验得到的值为21.6％。
Claims (42)
1.一种适于喷雾的向肺部释放有效量药剂的悬浮液制剂，所述制剂含有：
(a)氟替卡松丙酸酯，其颗粒粒径小于12微米；
(b)一种或多种表面活性剂；
(c)一种或多种缓冲剂；及
(d)水。
2.权利要求1的制剂，其中氟替卡松丙酸酯的粒径是1-6微米。
3.权利要求1或2的制剂，其中氟替卡松丙酸酯占制剂固体组份总重的0.5-10％。
4.权利要求1或2的制剂，其中该制剂含有两种表面活性剂。
5.权利要求3的制剂，其中该制剂含有两种表面活性剂。
6.权利要求1、2和5中任一权利要求的制剂，其中表面活性剂占制剂固体组份总重的0.25-0.75％。
7.权利要求3的制剂，其中表面活性剂占制剂固体组份总重的0.25-0.75％。
8.权利要求4的制剂，其中表面活性剂占制剂固体组份总重的0.25-0.75％。
9.权利要求1、2、5、7和8中任一权利要求的制剂，其中的表面活性剂选自脱水山梨醇三油酸酯、脱水山梨醇单油酸酯、脱水山梨醇单月桂酸酯、聚氧乙烯(20)脱水山梨醇单月桂酸酯、聚氧乙烯(20)脱水山梨醇单油酸酯、天然卵磷脂、油酰聚氧乙烯(2)醚、硬脂酰聚氧乙烯(2)醚、月桂酰聚氧乙烯(4)醚、氧化乙烯和氧化丙烯嵌段共聚物、合成卵磷脂、二甘醇二油酸酯、油酸四氢糠酯、油酸乙酯、甘油单油酸酯、聚乙二醇400和甘油单月桂酸酯。
10.权利要求3的制剂，其中的表面活性剂选自脱水山梨醇三油酸酯、脱水山梨醇单油酸酯、脱水山梨醇单月桂酸酯、聚氧乙烯(20)脱水山梨醇单月桂酸酯、聚氧乙烯(20)脱水山梨醇单油酸酯、天然卵磷脂、油酰聚氧乙烯(2)醚、硬脂酰聚氧乙烯(2)醚、月桂酰聚氧乙烯(4)醚、氧化乙烯和氧化丙烯嵌段共聚物、合成卵磷脂、二甘醇二油酸酯、油酸四氢糠酯、油酸乙酯、甘油单油酸酯、聚乙二醇400和甘油单月桂酸酯。
11.权利要求4的制剂，其中的表面活性剂选自脱水山梨醇三油酸酯、脱水山梨醇单油酸酯、脱水山梨醇单月桂酸酯、聚氧乙烯(20)脱水山梨醇单月桂酸酯、聚氧乙烯(20)脱水山梨醇单油酸酯、天然卵磷脂、油酰聚氧乙烯(2)醚、硬脂酰聚氧乙烯(2)醚、月桂酰聚氧乙烯(4)醚、氧化乙烯和氧化丙烯嵌段共聚物、合成卵磷脂、二甘醇二油酸酯、油酸四氢糠酯、油酸乙酯、甘油单油酸酯、聚乙二醇400和甘油单月桂酸酯。
12.权利要求6的制剂，其中的表面活性剂选自脱水山梨醇三油酸酯、脱水山梨醇单油酸酯、脱水山梨醇单月桂酸酯、聚氧乙烯(20)脱水山梨醇单月桂酸酯、聚氧乙烯(20)脱水山梨醇单油酸酯、天然卵磷脂、油酰聚氧乙烯(2)醚、硬脂酰聚氧乙烯(2)醚、月桂酰聚氧乙烯(4)醚、氧化乙烯和氧化丙烯嵌段共聚物、合成卵磷脂、二甘醇二油酸酯、油酸四氢糠酯、油酸乙酯、甘油单油酸酯、聚乙二醇400和甘油单月桂酸酯。
13.权利要求9的制剂，其中的表面活性剂是脱水山梨醇单月桂酸酯和聚氧乙烯(20)脱水山梨醇单月桂酸酯。
14.权利要求10、11和12中任一权利要求的制剂，其中的表面活性剂是脱水山梨醇单月桂酸酯和聚氧乙烯(20)脱水山梨醇单月桂酸酯。
15.权利要求13的制剂，其中脱水山梨醇单月桂酸酯与聚氧乙烯(20)脱水山梨醇单月桂酸酯的比是1∶7.5至1∶8.25。
16.权利要求14的制剂，其中脱水山梨醇单月桂酸酯与聚氧乙烯(20)脱水山梨醇单月桂酸酯的比是1∶7.5至1∶8.25。
17.权利要求1、2、5、7、8、10、11、12、13、15和16中任一权利要求的制剂，该制剂被缓冲到PH5-7。
18.权利要求3的制剂，该制剂被缓冲到PH5-7。
19.权利要求4的制剂，该制剂被缓冲到PH5-7。
20.权利要求6的制剂，该制剂被缓冲到PH5-7。
21.权利要求9的制剂，该制剂被缓冲到PH5-7。
22.权利要求14的制剂，该制剂被缓冲到PH5-7。
23.权利要求1、2、5、7、8、10、11、12、13、15、16、18、19、20、21和22中任一权利要求的制剂，它是等渗的。
24.权利要求3的制剂，它是等渗的。
25.权利要求4的制剂，它是等渗的。
26.权利要求6的制剂，它是等渗的。
27.权利要求9的制剂，它是等渗的。
28.权利要求14的制剂，它是等渗的。
29.权利要求17的制剂，它是等渗的。
30.权利要求1、2、5、7、8、10、11、12、13、15、16、18、19、20、21、22、24、25、26、27、28和29中任一权利要求的制剂，它含有：
(a)0.25-1.1mg ml-1微粉化的氟替卡松丙酸酯；
(b)0.06-0.09mg ml-1聚氧乙烯(20)脱水山梨醇单月桂酸酯；
(c)0.0075-0.0125mg ml-1脱水山梨醇单月桂酸酯；
(d)9.25-9.5mg ml-1二水合磷酸二氢钠；
(e)1.6-1.85mg ml-1无水磷酸氢二钠；
(f)4.7-4.9mg ml-1氯化钠；和
(g)水。
31.权利要求3的制剂，它含有：
(a)0.25-1.1mg ml-1微粉化的氟替卡松丙酸酯；
(b)0.06-0.09mg ml-1聚氧乙烯(20)脱水山梨醇单月桂酸酯；
(c)0.0075-0.0125mg ml-1脱水山梨醇单月桂酸酯；
(d)9.25-9.5mg ml-1二水合磷酸二氢钠；
(e)1.6-1.85mg ml-1无水磷酸氢二钠；
(f)4.7-4.9mg ml-1氯化钠；和
(g)水。
32.权利要求4的制剂，它含有：
(a)0.25-1.1mg ml-1微粉化的氟替卡松丙酸酯；
(b)0.06-0.09mg ml-1聚氧乙烯(20)脱水山梨醇单月桂酸酯；
(c)0.0075-0.0125mg ml-1脱水山梨醇单月桂酸酯；
(d)9.25-9.5mg ml-1二水合磷酸二氢钠；
(e)1.6-1.85mg ml-1无水磷酸氢二钠；
(f)4.7-4.9mg ml-1氯化钠；和
(g)水。
33.权利要求6的制剂，它含有：
(a)0.25-1.1mg ml-1微粉化的氟替卡松丙酸酯；
(b)0.06-0.09mg ml-1聚氧乙烯(20)脱水山梨醇单月桂酸酯；
(c)0.0075-0.0125mg ml-1脱水山梨醇单月桂酸酯；
(d)9.25-9.5mg ml-1二水合磷酸二氢钠；
(e)1.6-1.85mg ml-1无水磷酸氢二钠；
(f)4.7-4.9mg ml-1氯化钠；和
(g)水。
34.权利要求9的制剂，它含有：
(a)0.25-1.1mg ml-1微粉化的氟替卡松丙酸酯；
(b)0.06-0.09mg ml-1聚氧乙烯(20)脱水山梨醇单月桂酸酯；
(c)0.0075-0.0125mg ml-1脱水山梨醇单月桂酸酯；
(d)9.25-9.5mg ml-1二水合磷酸二氢钠；
(e)1.6-1.85mg ml-1无水磷酸氢二钠；
(f)4.7-4.9mg ml-1氯化钠；和
(g)水。
35.权利要求14的制剂，它含有：
(a)0.25-1.1mg ml-1微粉化的氟替卡松丙酸酯；
(b)0.06-0.09mg ml-1聚氧乙烯(20)脱水山梨醇单月桂酸酯；
(c)0.0075-0.0125mg ml-1脱水山梨醇单月桂酸酯；
(d)9.25-9.5mg ml-1二水合磷酸二氢钠；
(e)1.6-1.85mg ml-1无水磷酸氢二钠；
(f)4.7-4.9mg ml-1氯化钠；和
(g)水。
36.权利要求17的制剂，它含有：
(a)0.25-1.1mg ml-1微粉化的氟替卡松丙酸酯；
(b)0.06-0.09mg ml-1聚氧乙烯(20)脱水山梨醇单月桂酸酯；
(c)0.0075-0.0125mg ml-1脱水山梨醇单月桂酸酯；
(d)9.25-9.5mg ml-1二水合磷酸二氢钠；
(e)1.6-1.85mg ml-1无水磷酸氢二钠；
(f)4.7-4.9mg ml-1氯化钠；和
(g)水。
37.权利要求23的制剂，它含有：
(a)0.25-1.1mg ml-1微粉化的氟替卡松丙酸酯；
(b)0.06-0.09mg ml-1聚氧乙烯(20)脱水山梨醇单月桂酸酯；
(c)0.0075-0.0125mg ml-1脱水山梨醇单月桂酸酯；
(d)9.25-9.5mg ml-1二水合磷酸二氢钠；
(e)1.6-1.85mg ml-1无水磷酸氢二钠；
(f)4.7-4.9mg ml-1氯化钠；和
(g)水。
38.权利要求30的制剂，它含有：
(a)0.26mg ml-1微粉化的氟替卡松丙酸酯；
(b)0.07mg ml-1聚氧乙烯(20)脱水山梨醇单月桂酸酯；
(c)0.009mg ml-1脱水山梨醇单月桂酸酯；
(d)9.4mg ml-1二水合磷酸二氢钠；
(e)1.75mg ml-1无水磷酸氢二钠；
(f)4.8mg ml-1氯化钠；和
(g)水。
39.权利要求31、32、33、34、35、36或37的制剂，它含有：
(a)0.26mg ml-1微粉化的氟替卡松丙酸酯；
(b)0.07mg ml-1聚氧乙烯(20)脱水山梨醇单月桂酸酯；
(c)0.009mg ml-1脱水山梨醇单月桂酸酯；
(d)9.4mg ml-1二水合磷酸二氢钠；
(e)1.75mg ml-1无水磷酸氢二钠；
(f)4.8mg ml-1氯化钠；和
(g)水。
40.权利要求30的制剂，它包含：
(a)1.05mg ml-1微粉化的氟替卡松丙酸酯；
(b)0.08mg ml-1聚氧乙烯(20)脱水山梨醇单月桂酸酯；
(c)0.01mg ml-1脱水山梨醇单月桂酸酯；
(d)9.4mg ml-1二水合磷酸二氢钠；
(e)1.75mg ml-1无水磷酸氢二钠；
(f)4.8mg ml-1氯化钠；和
(g)水。
41.权利要求31、32、33、34、35、36或37的制剂，它包含：
(a)1.05mg ml-1微粉化的氟替卡松丙酸酯；
(b)0.08mg ml-1聚氧乙烯(20)脱水山梨醇单月桂酸酯；
(c)0.01mg ml-1脱水山梨醇单月桂酸酯；
(d)9.4mg ml-1二水合磷酸二氢钠；
(e)1.75mg ml-1无水磷酸氢二钠；
(f)4.8mg ml-1氯化钠；和
(g)水。
42.一种制备权利要求1-41中任一权利要求的制剂的方法，它包括使氟替卡松丙酸酯与表面活性剂溶液接触，并将所得的药物/表面活性剂溶液与该制剂中的其它组份混合。
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| PL (1) | PL180318B1 (zh) |
| PT (1) | PT760649E (zh) |
| RU (1) | RU2161485C2 (zh) |
| SI (1) | SI0760649T1 (zh) |
| TW (1) | TW438604B (zh) |
| WO (1) | WO1995031964A1 (zh) |
| ZA (1) | ZA954101B (zh) |
Families Citing this family (50)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4484247B2 (ja) * | 1995-02-24 | 2010-06-16 | エラン ファーマ インターナショナル，リミティド | ナノ粒子分散体を含有するエアロゾル |
| GB9610341D0 (en) * | 1996-05-17 | 1996-07-24 | Andaris Ltd | Formulation for inhalation |
| US20060165606A1 (en) | 1997-09-29 | 2006-07-27 | Nektar Therapeutics | Pulmonary delivery particles comprising water insoluble or crystalline active agents |
| SE9704186D0 (sv) * | 1997-11-14 | 1997-11-14 | Astra Ab | New composition of matter |
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| US8820316B2 (en) * | 2000-02-11 | 2014-09-02 | Respironics Respiratory Drug Delivery (Uk) Ltd | Drug delivery apparatus |
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| US6858593B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6787532B2 (en) | 2000-08-05 | 2004-09-07 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivatives |
| US6858596B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivative |
| US6777400B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6750210B2 (en) | 2000-08-05 | 2004-06-15 | Smithkline Beecham Corporation | Formulation containing novel anti-inflammatory androstane derivative |
| GB0019172D0 (en) | 2000-08-05 | 2000-09-27 | Glaxo Group Ltd | Novel compounds |
| US6777399B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6759398B2 (en) | 2000-08-05 | 2004-07-06 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative |
| UA77656C2 (en) | 2001-04-07 | 2007-01-15 | Glaxo Group Ltd | S-fluoromethyl ester of 6-alpha, 9-alpha-difluoro-17-alpha-[(2-furanylcarbonyl)oxy]-11-beta-hydroxy-16- alpha-methyl-3-oxoandrosta-1,4-dien-17-beta-carbothioacid as anti-inflammatory agent |
| US6667344B2 (en) | 2001-04-17 | 2003-12-23 | Dey, L.P. | Bronchodilating compositions and methods |
| US20030055026A1 (en) * | 2001-04-17 | 2003-03-20 | Dey L.P. | Formoterol/steroid bronchodilating compositions and methods of use thereof |
| TWI324518B (en) | 2001-12-19 | 2010-05-11 | Nektar Therapeutics | Pulmonary delivery of aminoglycosides |
| ATE464880T1 (de) | 2002-02-04 | 2010-05-15 | Elan Pharma Int Ltd | Arzneistoffnanopartikel mit lysozym- oberflächenstabilisator |
| DE60325459D1 (de) | 2002-02-19 | 2009-02-05 | Resolution Chemicals Ltd | Auf lösungsmitteln basierende sterilisation von steroiden |
| GB2389530B (en) | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
| WO2004032980A1 (en) * | 2002-10-04 | 2004-04-22 | Elan Pharma International Limited | Gamma irradiation of solid nanoparticulate active agents |
| US20040208833A1 (en) * | 2003-02-04 | 2004-10-21 | Elan Pharma International Ltd. | Novel fluticasone formulations |
| EP1454636A1 (en) * | 2003-03-04 | 2004-09-08 | Dompé S.P.A. | Sterilization of glucocorticoid drug particles for pulmonary delivery |
| US7811606B2 (en) * | 2003-04-16 | 2010-10-12 | Dey, L.P. | Nasal pharmaceutical formulations and methods of using the same |
| US8912174B2 (en) * | 2003-04-16 | 2014-12-16 | Mylan Pharmaceuticals Inc. | Formulations and methods for treating rhinosinusitis |
| US9808471B2 (en) * | 2003-04-16 | 2017-11-07 | Mylan Specialty Lp | Nasal pharmaceutical formulations and methods of using the same |
| US7842232B2 (en) * | 2003-05-22 | 2010-11-30 | Elan Pharma International, Ltd. | Sterilization of dispersions of nanoparticulate active agents with gamma radiation |
| US20040265238A1 (en) * | 2003-06-27 | 2004-12-30 | Imtiaz Chaudry | Inhalable formulations for treating pulmonary hypertension and methods of using same |
| TWI359675B (en) | 2003-07-10 | 2012-03-11 | Dey L P | Bronchodilating β-agonist compositions |
| DE10347994A1 (de) | 2003-10-15 | 2005-06-16 | Pari GmbH Spezialisten für effektive Inhalation | Wässrige Aerosol-Zubereitung |
| PE20050941A1 (es) | 2003-12-16 | 2005-11-08 | Nycomed Gmbh | Suspensiones acuosas de ciclesonida para nebulizacion |
| EP1574222B1 (en) | 2004-03-12 | 2011-02-09 | Cipla Ltd. | Sterilization process for steroids |
| GB0410995D0 (en) * | 2004-05-17 | 2004-06-23 | Norton Healthcare Ltd | Heat sterilization of glucocorticosteroids |
| GB0425266D0 (en) * | 2004-11-16 | 2004-12-15 | Norton Healthcare Ltd | Pharmaceutical manufacturing process |
| GB0427568D0 (en) * | 2004-12-16 | 2005-01-19 | Resolution Chemicals Ltd | Particle-size reduction apparatus, and the use thereof |
| US20090311335A1 (en) * | 2008-06-12 | 2009-12-17 | Scott Jenkins | Combination of a triptan and an nsaid |
| CN102166219B (zh) * | 2010-05-25 | 2013-04-17 | 杭州天龙药业有限公司 | 一种鼻腔给药制剂及其应用 |
| US8765725B2 (en) | 2012-05-08 | 2014-07-01 | Aciex Therapeutics, Inc. | Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof |
| DK3517541T3 (da) | 2012-05-08 | 2020-09-07 | Nicox Ophthalmics Inc | Polymorf form af fluticasonpropionat |
| CN103505412A (zh) * | 2012-06-26 | 2014-01-15 | 上海臣邦医药科技有限公司 | 一种吸入用丙酸氟替卡松混悬液的制备方法 |
| WO2014007771A2 (en) | 2012-07-05 | 2014-01-09 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Inhalation compositions comprising muscarinic receptor antagonist |
| US20150165037A1 (en) | 2012-07-05 | 2015-06-18 | Arven llac Sanayi Ve Ticaret A.S. | Inhalation compositions comprising corticosteroid and sorbitol |
| WO2014007781A2 (en) | 2012-07-05 | 2014-01-09 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Inhalation compositions |
| US10111957B2 (en) | 2012-07-05 | 2018-10-30 | Arven Ilac Snayi ve Ticaret A.S. | Inhalation compositions comprising glucose anhydrous |
| DE102012111077A1 (de) * | 2012-11-16 | 2014-05-22 | Justus-Liebig-Universität Giessen | Optimierung von Vernebelungseigenschaften einer Lösung oder eines Kolloids |
| US9815865B2 (en) | 2013-01-07 | 2017-11-14 | Nicox Ophthalmics, Inc. | Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof |
| PL3494962T3 (pl) | 2014-09-15 | 2021-12-06 | Verona Pharma Plc | Ciekła wziewna kompozycja farmaceutyczna zawierająca RPL554 |
| AU2019287541A1 (en) | 2018-06-14 | 2021-01-21 | Astrazeneca Uk Limited | Methods for treating and preventing symptoms of asthma with a corticosteroid pharmaceutical composition |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993017665A1 (en) * | 1992-03-06 | 1993-09-16 | Sievers Robert E | Methods and apparatus for drug delivery using supercritical solutions |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225183A (en) * | 1988-12-06 | 1993-07-06 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
| US5118494A (en) * | 1990-03-23 | 1992-06-02 | Minnesota Mining And Manufacturing Company | Use of soluble fluorosurfactants for the preparation of metered-dose aerosol formulations |
| EP0616525B1 (en) * | 1991-12-12 | 1995-09-27 | Glaxo Group Limited | Pharmaceutical aerosol formulation |
| US5658549A (en) * | 1991-12-12 | 1997-08-19 | Glaxo Group Limited | Aerosol formulations containing propellant 134a and fluticasone propionate |
| CZ288032B6 (cs) * | 1991-12-18 | 2001-04-11 | Aktiebolaget Astra | Farmaceutický prostředek pro podání inhalací |
| GB9419536D0 (en) * | 1994-09-28 | 1994-11-16 | Glaxo Inc | Medicaments |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993017665A1 (en) * | 1992-03-06 | 1993-09-16 | Sievers Robert E | Methods and apparatus for drug delivery using supercritical solutions |
Non-Patent Citations (2)
| Title |
|---|
| 《中药药剂学》1986年11月第1版 1986-01-01 曹春林主编；上海科学技术出版社 * |
| DRUGINVESTIGATION1994年第8卷第3期 1994-03-01 AINGE,G.等 * |
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