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CN1189096A - 用于制备无推进气体的雾剂的新颖稳定药物组合物 - Google Patents

用于制备无推进气体的雾剂的新颖稳定药物组合物 Download PDF

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CN1189096A
CN1189096A CN96195019A CN96195019A CN1189096A CN 1189096 A CN1189096 A CN 1189096A CN 96195019 A CN96195019 A CN 96195019A CN 96195019 A CN96195019 A CN 96195019A CN 1189096 A CN1189096 A CN 1189096A
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伯恩哈德·弗罗因德
迈克尔·克鲁格
伯恩德·齐伦伯格
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Abstract

本发明是有关用于制备无推进剂的雾剂的含乙醇的药物制剂。

Description

用于制备无推进气体的   雾剂的新颖稳定 药物组合物
本发明是有关用于制备一种无推进气体的雾剂的呈稳定含乙醇的活性物质溶液形式的药物制剂。
在过去20年内，计量雾剂的使用已成为治疗阻碍性肺疾病，特别是气喘的既定成份。通常是使用氟氯烃作为推进气体。自从这类推进气体的臭氧破坏性潜能被公认后，有越来越多的努力进行替代物的开发。其中一种替代物为喷雾器的开发，其中药物学活性物质的水溶液在高压下喷出而产生可吸入的粒子雾。这种喷雾器的优点是不需要任何推进气体。
有些喷雾器描述于例如PCT专利申请WO91/14468中，其内容在下文中作为参考。于其中所描述的喷雾器中，使用高压将含有活性物质的限定体积的溶液通过小喷咀喷出而产生可吸入的气雾剂，其优选粒度为1至10，更优选为2至5微米。
至今，都假设，使用含推进气体的传统计量气雾剂时可在气雾中得到最佳的肺结合粒子的量。如今令人惊异地发现，通过使用含乙醇的活性物质溶液并和，例如，上述喷雾器配合，就可产生比通常用含推进气体的计量气雾剂的情况好得多的可吸入粒子谱。
适用于本发明范围内的药物制剂的溶剂是含有至少70％(V/V)乙醇的溶液；优选的为含有至少85％(V/V)乙醇的溶液，而特别优选的为有高于95％(V/V)乙醇含量的溶液。其浓度是以体积百分比(V/V)表示，其余部分是水。最特别优选的是已含有少量水的，例如96％，的乙醇，以致它不再具有吸湿性并不会共沸挥发。
除水之外，该溶剂可包含其他的共溶剂且药物制剂也可含有调味剂和其他药用赋形剂。共溶剂的实例为含有羟基或其他极性基团，例如醇，特别是异丙醇，二醇，特别是丙二醇，聚乙二醇，聚丙二醇，二醇醚，甘油，聚氧乙烯醇和聚氧乙烯脂肪酸酯。共溶剂适用于增加赋形剂和可能的活性物质的溶解性。
经溶解的药物物质在成品药物制剂中的比例为0.001至5％，优选的为0.05至3％，最好是0.01至2％之间，所有百分比都是以重量计。药物物质的最大浓度决定于其在溶剂中的溶解度以及达到所要治疗效果所需的剂量。
在新颖制剂中作为药物活性剂可以使用适于通过吸入给药并可溶于所指定溶剂中的任何物质。这些物质可包括，特别是，β-模拟剂(betamimetics)，抗胆碱药，抗过敏性药，PAF-拮抗剂和特别是类固醇及这些活性物质的组合。
特别提出以下各种作为实例：溴化地奥利眠宁(Tiotropium bromide)，3-[(羟基二-2-噻吩基乙酰基)氧基]-8，8 -二甲基-8-氮鎓双环[3.2.1]辛-6-烯-溴化物有关β-模拟剂有：班布特罗(Bambuterol)比托特罗(Bitolterol)脲喘宁              福莫特罗(Formoterol)克喘素              酚丙喘宁            双喘定              异丙喹喘宁三丁喘宁            吡丁醇              沙美特罗(Salmetenl) 叔丁气喘通茶丙喘宁            舒喘宁              磺丁喘宁            叔丁喘宁1-(2-氟-4-羟基苯基)-2-[4-(1-苯并咪唑基)-2-甲基-2-丁氨基]乙醇，赤基(erychro)-5′-羟基-8′-(1-羟基-2-异丙氨基丁基)-2H-1，4-苯并噁嗪-3-(4H)-酮，1-(4-氨基-3-氯-5-三氟甲基苯基)-2-叔丁氨基)乙醇，1-(4-乙氧羰氨基-3-氰基-5-氟苯基)-2-(叔丁氨基)乙醇。有关抗胆碱剂有：溴化异丙托品溴乙东茛菪碱气化托螺吡咯二苯乙醇酸-N-β-氟乙基降托品甲溴化物有关类固醇有：丁地去炎松二丙酸氯地米松地塞米松-21-异烟碱酸酯9-去氟肤轻松有关抗过敏药有：色甘酸二钠奈多罗米(Nedocromil)依匹斯订(Epinastin)有关PAF-拮抗剂：WEB 2086(4-(2-氯苯基)-9-甲基-2-[3-(4-吗啉基)-3-丙酰-1-基]-6H-噻吩并-[3，2-f][1，2，4]-三唑并[4，3-a][1，4]二氮杂)WEB 2170(6-(2-氯苯基)-8，-9-二氢-1-甲基-8-[(4-吗啉基)羰基]-4H，7H-环戊[4，5]噻吩并[3，2-f][1，2，4]三唑并[4，3-a][1，4]二氮杂)
本发明药物制剂可含有其他赋形剂例如大豆卵磷脂或表面活性剂。
此外也令人惊奇地发现添加有机或无机酸，优选是和配合物成形剂组合，可以改善含类固醇制剂的稳定性(存放稳定性)。发现这点对于含有9-去氟肤轻松(Flunisolide)或其水合物或半水合物或丁地去炎松作为活性物质并含有乙醇作为其溶剂的药物制剂特别有用。
无机酸的实例包括盐酸，硫酸或磷酸；有机酸的实例包括抗坏血酸，柠檬酸，苹果酸，酒石酸，顺丁烯二酸，丁二酸，反丁烯二酸，乙酸，甲酸，丙酸等。
酸在成品药物制剂中的含量，在每一情况中都要进行选择，以使溶液的PH值介于2.0至7.0之间，特别是3.0至4.0之间。
于一优选实施方案中，本发明药物制剂还含有一配合物成形剂。配合物成形剂的实例包括EDTA，柠檬酸，次氮基三乙酸及其盐。配合物成形剂的含量以成品药物制剂为基计算为0.1至3毫克/100毫升，优选为0.2至2毫克/100毫升，特别是0.9至1.1毫克/100毫升之间。
优选的配合物成形剂为EDTA(乙二胺四乙酸或其盐，例如二钠盐)。本发明优选的药物制剂在作为溶剂的乙醇(96％V/V)中，含有1.667％9-去氟肤轻松(Flunisolide)，并另外含有0.01％(V/V)EDTA作为配合物成形剂并通过由添加酸而将其PH值调节到PH3.0至4.0之间。
可在本发明药物制剂中用作活性成份的类固醇的实例有赛拉托达斯(Seratrodast)              霉酚酸酯(MycopHenolate mofetil)普洛卡斯(Pranlukast)                 齐鲁顿(Zileuton)布迪少柯(Butixocort)                 丁地去炎松醋噁唑龙                             普美屈耳(Promedrol)氟替卡松                             替泼尼旦(Tipredane)莫米松糠酸酯                         衣可米松烯丁酯(Icomethasone氯地米松(Beclomethasone，Douglas)    enbutate)环米松(Ciclometasone)                氯地氢可松氟考丁酯                             氯二氟美松醋噁唑龙                             别氯地米松环米松                               阿利塞太(Alisactide)泼尼卡酯(Prednicarbate)              氢化可的松-丁酸酯丙酸酯巯氢可的松特戊酸酯                   别氯地米松二丙酸酯氯曲松(Lotrisone)                    克霉唑-HC地泼罗酮                             氟替卡松丙酸酯6-甲氢化泼尼松                       双醋溴氟龙莫米松                               糠酸莫米松酯氢化可的松(Hydrocortisone aceponate) 莫米松乌倍他素丙酸酯                       氨基导眠能去炎松                               氢化可的松甲基强的松                           氟米龙地塞米松                             倍他米松6α-甲-11β-羟孕酮                   氟二氯松丙酮化肤氢松                         醋酸对氟米松21-去羟强的松丙酸酯                  去炎松二醋酸酯肤轻松                               甲哌地强龙醋丁二氟龙                           戊酸倍他米松异烟碱酸地塞米松                     二丙酸氯地米松氟考龙                           氟甲酰龙氟烃氢化泼泥松                   氯泼尼醇甲酰勃龙                         氯氟美松酮甲地松                           9-去氟肤轻松氯氟松                           氟噁米松氯氟美松                         氢化可的松-17-丁酸酯双醋二氟松                       氟考酸醋酸环戊酮缩去炎松               二丙酸倍他米松可的伐唑                         金刚烷酸倍他米松氟但噻(Fluodexan)                腈环氧雄烷丁地去炎松                       氯氟美松酮地美丹(Demetex)                  曲美辛诺龙苯奈托宁(Trimacinolon
                             Benetonid)9α-氯-6α-氟-11β，17α-二羟基-16α-甲基-3-氧基-1，4-雄甾二烯-17β-羧酸甲酯-17-丙酸酯。
表I所示是一种沉积研究的比较结果，一方面是用标准市售计量雾剂Inhacort(9-去氟肤轻松，二氯甲烷，三氯氟甲烷，二氯四氟乙烷，山梨糖醇三油酸酯)＝MDI，而另一方面是用含有9-去氟肤轻松在96％(V/V)乙醇中的本发明药物制剂而进行的，它是用上述PCT申请案WO91/14468中的喷雾器实施的(BINEB；技术数据：药物制剂给药体积为15微升，压力约300巴，从两个大小为5×8微米的喷咀挤压2次)。
         表1：沉积研究
                  BINEB         MDI
肺(％)            39.7(9.9)      15.3(5.1)
口(％)            39.9(9.4)      66.9(7.1)
呼出部分(％)      10.4(4 9)      1.4(1.3)
中心肺区(％)      10.7(2.5)      4.5(1.8)
中肺区(％)        14.9(3.6)      5.4(1.9)
周围肺区(％)      14.1(4.3)      5.4(1.4)
周围区/中央区比例 1.3(0.2)       1.3(0.2)
由表I清楚地表明，本发明药物制剂用所述喷雾器给药时的优点。实施例：
9-去氟肤轻松半水合物-6α-氟-11β，16α，17α，21-四氢孕甾-1，4-二烯-3，20-16-丙酮化物半水合物，其分子量为442.5。在BINEB中使用时，每剂量为将250微克的9-去氟肤轻松溶解在15微升溶液中以制成1.667％(克/100毫升)的浓度。
使用96％乙醇作为溶剂。此外，成品药物制剂中含有1毫克/100毫升的EDTA-二钠。该药物制剂的PH值是用0.1N HCl调到PH4。
以类似上述实验方式，制备含有丁地去炎松(Budesonide)作为活性物质的制剂。
制成下列药物制剂混合物，其中含有9-去氟肤轻松-半水合物作为活性物质。表II
实验号 组合 乙醇含量％(V/V)     pH EDTA二钠含量，毫克/100毫升
    1    1     85     3.6     0
    2    A     96     3.6     0
    3    B     85     7.0     0
    4   AB     96     7.0     0
    5    C     85     3.6     1
    6   AC     96     3.6     1
    7   BC     85     7.0     1
    8  ABC     96     7.0     1
9-去氟肤轻松(Flunisolide)  半水合物的含量为1，666.7毫克/100毫升。溶液的PH值是用1N HCl调节并用PH计，PH 1162-RadiometerCopenhagen进行测定。样品转移到5毫升安瓿中并在80℃避光下储存。组合AC在30天储存后产品显示出最低的分解量。
表III列出另外的含EDTA二钠作为配合物成形剂的制剂实例。
表III
    成份   I含量，毫克/100毫升   II含量，毫克/100毫升   III含量，毫克/100毫升   IV含量，毫克/100毫升
9-去氟肤轻松半水合物     1667     1667     1667     1667
EDTA二钠     1     1     1     1
0.1NHCl   至PH3.6   至PH3.2   至PH3.2   至PH3.6
薄荷醇      -      -     -     -
乙醇96％   至100毫升   至100毫升   至100毫升   至100毫升
加入助剂薄荷醇是在必要时用以掩蔽类固醇的苦味。
将上述制剂包装在5毫升安瓿中并在80℃下储存。由于其小量的分解产物，优选的制剂是制剂III。
表IV列出丁地去炎松(Budesonide)的一些制剂实例。
表IV
    成份 I含量，毫克/100毫升 II含量，毫克/100毫升 III含量，毫克/100毫升 IV含量，毫克/100毫升 V含量，毫克/100毫升
丁地去炎松     1333     1333     1333     1333     1333
EDTA二钠     1     1     1     -
0.1NHCl至PH     3.2     3.2     3.6     4.0     4.0
乙醇96％加到     100     100     100     100     100
在密封的玻璃安瓿中在80℃下储存3个月后，以HPLC测定分解产物的量。其中制剂IV和V表示有最小的分解产物量。

Claims (20)

1.一种用于制备无推进气体雾剂的药物制剂，它包含药物活性物质，必要时，药物上无害的助剂和/或香料，其特征在于，药物制剂含有至少70％(V/V)乙醇以作为溶剂。
2.根据权利要求1的药物制剂，其特征在于，它含有96％(V/V)乙醇作溶剂。
3.根据权利要求1或2的药物制剂，其特征在于，该活性物质是适于以吸入法给药并选自β-摸拟剂，抗胆碱剂，抗过敏剂及/或PAF-拮抗剂。
4.根据权利要求1至3的药物制剂，其特征在于，在药物制剂中所溶解的药物产品的比例按体积计为0.001～5.0％。
5.一种用于制备无推进气体雾剂的药物制剂，它包含一种类固醇，必要时，药物上无害的助剂和/或香料，其特征在于，该药物制剂含有作为溶剂的至少85％(V/V)的乙醇，必要时，还有一种配合物成形剂。
6.根据权利要求5的药物制剂，其特征在于，该溶剂为96％(V/V)的乙醇。
7.根据权利要求6的药物制剂，其特征在于，配合物成形剂是EDTA或其盐。
8.根据权利要求5或7的药物制剂，其特征在于，该配合物成形剂的含量为0.1至5毫克/100毫升溶液。
9.根据权利要求5至8中之一的药物制剂，其特征在于，该制剂的PH值是经调节到3.2至4.5之间。
10.根据权利要求5至9中之一的药物制剂，其特征在于，该活性物质为9-去氟肤轻松或丁地去炎松。
11.根据权利要求1至6中之一的药物制剂，其特征在于，该活性物质为地奥利眠宁(Tiotropium)或其酸加成盐。
12.根据权利要求1至6中之一的药物制剂，其特征在于，该活性物质为3-[(羟基二-2-噻吩基乙酰基)氧基]-8，8-二甲基-8-氮鎓双环[3，2，1]辛-6-烯或其酸加成盐。
13.一种用于制备无推进气体的计量雾剂的药物制剂，它在每100毫升的96％(V/V)乙醇中含有1.667克的9-去氟肤轻松(Flunisolide)半水合物和1毫克的EDTA二钠，该药物制剂的PH值是经调节到4.0。
14.一种用于制备无推进气体的计量雾剂的药物制剂，它在每100毫升的90％(V/V)乙醇中含有1.667克的9-去氟肤轻松(Flunisolide)半水合物和1毫克的EDTA二钠，该药物制剂的PH值是经调整到4.0。
15.一种用于制备无推进气体的计量雾剂的药物制剂，它在每100毫升的96％(V/V)乙醇中含有1.333克的丁地去炎松(Budesonide)和1毫克的EDTA二钠，该药物制剂的PH值是经调整到4.0。
16.一种用于制备无推进气体的计量雾剂的药物制剂，它在每100毫升的90％(V/V)乙醇中含有1.333克的丁地去炎松(Budesonide)和1毫克的EDTA二钠，该药物制剂的PH值是经调整到4.0。
17.一种在具有至少70体积％乙醇的溶液中含有药物活性物质的药物制剂，在制备以吸入给药所用的无推进气体的组合物中的用途。
18.一种根据权利要求1至16中之一的所述药物制剂作为以吸入给药用的无推进气体的组合物的用途。
19一种制备根据权利要求1所述药物制剂的方法，其特征在于，将药物活性物质溶于至少70％V/V的乙醇中。
20.一种药物活性物质输送系统，它包括根据权利要求1至16中之一的所述制剂和无推进气体的喷雾器相组合而构成。
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US20020141944A1 (en) 2002-10-03
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US20060127322A1 (en) 2006-06-15
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KR19990028408A (ko) 1999-04-15
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PE11098A1 (es) 1998-03-17
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ZA965411B (en) 1996-12-27
SI0835098T1 (en) 2003-02-28
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AU6414496A (en) 1997-01-30
WO1997001329A1 (de) 1997-01-16
ES2183001T3 (es) 2003-03-16

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