CN1086575C - 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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CN1086575C
CN1086575C CN96195019A CN96195019A CN1086575C CN 1086575 C CN1086575 C CN 1086575C CN 96195019 A CN96195019 A CN 96195019A CN 96195019 A CN96195019 A CN 96195019A CN 1086575 C CN1086575 C CN 1086575C
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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气雾剂的含乙醇的药物制剂。

Description

用于制备无推进剂气雾剂的 新颖稳定药物组合物
本发明是有关用于制备一种无推进剂气雾剂的稳定的活性物质乙醇溶液形式的药物制剂。
在过去20年内，计量气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WO 91/14468中，其内容参见下文。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，认为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，通过使用活性物质的乙醇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更广谱的可吸入粒子。
用于本发明范围内的药物制剂的合适溶剂是含有至少70％(V/V)乙醇的溶液；优选的为含有至少85％(V/V)乙醇的溶液，而特别优选的为含有高于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乙醇，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的共溶剂，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，乙二醇醚，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的溶解性和可能增加活性物质的溶解性。
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％，特别是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，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betami-metics有：间羟舒喘灵酯     双甲苯喘定      脲喘宁          福莫特罗克喘素           酚丙喘宁        六甲双喘定      异丙喹喘宁三丁喘宁         吡丁醇          沙美特罗        叔丁氯喘通茶丙喘宁         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，赤式-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-乙氧羰基氨基-3-氰基-5-氟苯基)-2-(叔丁氨基)乙醇。有关抗胆碱药有：溴化异丙托品溴乙东茛菪碱氯化托螺吡咯二苯乙醇酸-N-β-氟乙基降托品溴化甲基阿托品有关类固醇有：丁地去炎松氯地米松(或其17，21-二丙酸氯地米松)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依匹那丁(Epinastin)有关PAF-拮抗剂：WEB2086(4-(2-氯苯基)-9-甲基-2-[3-(4-吗啉基)-3-丙酮-1-基]-6H-噻吩并-[3，2-f)[1，2，4]-三唑并[4，3-a][1，4]二氮杂)WEB2170(6-(2-氯苯基)-8，-9-二氢-1-甲基-8-[(4-吗啉基)羰基]-4H，7H-环戊烷并[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物质。
还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(存放期限)。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础计算为0.1至5毫克/100毫升，优选0.1至3毫克/100毫升，更优选为0.2至2毫克/100毫升，特别是0.9至1.1毫克/100毫升。
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，乙醇中含有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pH为3.0和4.5之间，优选为3.0和4.0之间，更优选为3.2和4.5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是赛拉托达斯(Seratrodast)                霉酚酸莫非替克普洛卡斯(Pranlukast)                   弃白通布迪少柯(Butixocort)                   丁地去炎松醋噁唑龙                               普罗米氟替卡松                              替泼尼旦(Tipredane)糠酸莫米他松                          衣可米松烯丁酯(IcomethasoneBeclomethasone，Douglas               enbutate)环强的松(Ciclometasone)               氯地氢可松氟考丁酯                              氯二氟美松醋噁唑龙                              别氯地米松环强的松                              阿利塞太(Alisactide)泼尼卡酯                              氢化可的松-丁酸酯巯氢可的松新戊酸酯                    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Methylpre-dnisolone Aceponate         双醋溴氟龙莫米他松                              糠酸莫米他松Hydrocortisone aceponate              莫米他松乌倍他素丙酸酯                        氨基导眠能去炎松                                氢化可的松甲基强的松                            氟甲松龙地塞米松                              倍他米松6α-甲-11β-羟孕酮                    氟二氯松肤氢松                                醋酸对氟米松21-去羟强的松龙丙酸酯                 去炎松二醋酸酯醋酸肤轻松                            甲哌地强龙醋丁二氟龙                            戊酸倍他米松异烟酸地塞米松                        二丙酸氯地米松己酸氟考龙                            氟甲酰龙己酸丙炎松                            氯泼尼醇甲酰烯龙                              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-丁酸酯二氟松                                Flucortin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表示一种沉积研究的比较结果，一方面是用标准市售计量气雾剂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进行的，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WO 91/14468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微米的喷咀挤压出两股射流)。表1：沉积研究
                      BINER            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/中心区比例     1.3(0.2)          1.3(0.2)
由表1清楚地表明，用所述喷雾器给药的本发明药物制剂的优点。
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，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-Radiometer Copenhagen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产物量。
表III列出另外的含有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     -
0.1N HCl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 (26)

1.一种用于吸入器中用于制备无推进剂的可吸入气雾剂的无推进剂的药物制剂，前提条件是在任何情况下不使用推进剂，其特征在于：将选自β-模拟剂、抗胆碱剂、抗过敏剂、PAF-拮抗剂、类固醇或其组合的药物活性物质以0.001-5.0％重量百分比的比例任选与药物上无害的助剂和/或香料一起溶解在至少70％体积/体积乙醇的无推进剂的溶剂中，溶剂的其余部分是水且任选包含助溶剂。
2.根据权利要求1的药物制剂，其特征在于，该活性物质选自β-摸拟剂、抗胆碱剂和/或抗过敏剂。
3.根据权利要求1或2的药物制剂，其特征在于，溶剂包含至少85％体积/体积的乙醇。
4.根据权利要求1或2的药物制剂，其特征在于，溶剂包含至少95％体积/体积的乙醇。
5.根据权利要求1或2的药物制剂，其特征在于，除活性物质外，该制剂包含一种或多种药物上无害的助剂和/或香料。
6.根据权利要求1或2的药物制剂，其特征在于，该溶剂包含至少85％体积/体积的乙醇，且在药物制剂中存在选自EDTA、柠檬酸、次氮基三乙酸及其盐的配合剂。
7.根据权利要求1或2的药物制剂，其特征在于，该溶剂包含至少96％体积/体积的乙醇且EDTA或其盐作为配合剂存在。
8.根据权利要求1或2的药物制剂，其特征在于，该活性物质为地奥利眠宁或其酸加成盐。
9.根据权利要求1或2的药物制剂，其特征在于，该活性物质为3-[(羟基双-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。
10.根据权利要求1或2的药物制剂，其特征在于，该活性物质为溴化异丙托品、溴乙东茛菪碱或氯化托螺吡咯。
11.根据权利要求1或2的药物制剂，其特征在于，该活性物质为类固醇且药物制剂包含无机酸或有机酸。
12.根据权利要求1或2的药物制剂，其特征在于，该活性物质为类固醇且溶剂包含至少96％体积/体积的乙醇。
13.根据权利要求1或2的药物制剂，其特征在于，该活性物质为类固醇且溶剂包含至少96％体积/体积的乙醇，且药物制剂包含选自EDTA、柠檬酸、次氮基三乙酸及其盐的配合剂。
14.根据权利要求1或2的药物制剂，其特征在于，该活性物质为类固醇且溶剂包含至少96％体积/体积的乙醇，且EDTA或其盐作为配合剂存在。
15.根据权利要求1或2的药物制剂，其特征在于，该活性物质为类固醇且溶剂包含至少96％体积/体积的乙醇，且药物制剂包含选自EDTA，柠檬酸，次氮基三乙酸及其盐的配合剂，其量为溶液的0.1-5mg/100ml。
16.根据权利要求1或2的药物制剂，其特征在于，该活性物质为类固醇且溶剂包含至少96％体积/体积的乙醇，且将制剂的pH值调整到3.2-4.5的水平。
17.根据权利要求1或2的药物制剂，其特征在于，该活性物质为类固醇且溶剂包含至少96％体积/体积的乙醇，药物制剂包含选自EDTA、柠檬酸、次氮基三乙酸及其盐的配合剂，且将制剂的pH值调整到3.2-4.5的水平。
18.根据权利要求1或2的药物制剂，其特征在于，该活性物质为类固醇且溶剂包含至少96％体积/体积的乙醇，且活性物质是9-去氟肤轻松或丁地去炎松。
19.根据权利要求1或2的药物制剂，其特征在于，该活性物质为选自9-去氟肤轻松或丁地去炎松的类固醇，溶剂包含至少96％体积/体积的乙醇，药物制剂包含选自EDTA、柠檬酸、次氮基三乙酸及其盐的配合剂，且将制剂的pH值调整到3.2-4.5的水平。
20.一种用于制备无推进剂的可吸入计量气雾剂的无推进剂的药物制剂，在每100ml含96％体积/体积的乙醇和4％体积/体积的水中，其包含1.667克的9-去氟肤轻松半水合物和1毫克的EDTA二钠，将该药物制剂的pH值调节到4.0。
21.一种用于制备无推进剂的可吸入计量气雾剂的无推进剂的药物制剂，在每100ml含90％体积/体积的乙醇和10％体积/体积的水中，其包含1.667克的9-去氟肤轻松半水合物和1毫克的EDTA二钠，将该药物制剂的pH值调节到4.0。
22.一种用于制备无推进剂的可吸入计量气雾剂的无推进剂的药物制剂，在每100ml含96％体积/体积的乙醇和4％体积/体积的水中，其包含1.333克的丁地去炎松和1毫克的EDTA二钠，将该药物制剂的pH值调节到4.0。
23.一种用于制备无推进剂的可吸入计量气雾剂的无推进剂的药物制剂，在每100ml含90％体积/体积的乙醇和10％体积/体积的水中，其包含1.333克的丁地去炎松和1毫克的EDTA二钠，将该药物制剂的pH调节到4.0。
24.根据权利要求1或2的药物制剂在直接制备无推进剂的肺可吸入的气雾剂中的用途。
25.根据权利要求24的用途，其特征在于药物制剂被喷雾器雾化，该雾化器通过被两个小喷嘴冲击的两股射流在高压下雾化该制剂，以便生产大小为1-10微米的可吸入颗粒的雾剂。
26.大小为1-10微米的可吸入颗粒的雾剂，其是由在高压下通过小喷嘴用喷雾器喷雾权利要求1或2定义的药物溶液而制备的。
CN96195019A 1995-06-27 1996-06-21 用于制备无推进气体的雾剂的新颖稳定药物组合物 Expired - Lifetime CN1086575C (zh)

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Families Citing this family (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9504265D0 (en) * 1995-03-03 1995-04-19 Medeva Plc Corticosteroid-containing pharmaceutical composition
BR9609307B1 (pt) * 1995-06-27 2010-03-09 preparação farmacêutica para produção de aerossóis inaláveis isentos de propelentes para administração nos pulmões, bem como aerossol compreendendo a mesma.
DE19653969A1 (de) * 1996-12-20 1998-06-25 Boehringer Ingelheim Kg Neue wässrige Arzneimittelzubereitung zur Erzeugung treibgasfreier Aerosole
US20030215396A1 (en) * 1999-09-15 2003-11-20 Boehringer Ingelheim Pharma Kg Method for the production of propellant gas-free aerosols from aqueous medicament preparations
US6598603B1 (en) * 1997-12-31 2003-07-29 Astra Aktiebolag Method for treating respiratory diseases
DE19808295A1 (de) 1998-02-27 1999-11-11 Boehringer Ingelheim Int Behälter für eine medizinische Flüssigkeit
DE19847968A1 (de) 1998-10-17 2000-04-20 Boehringer Ingelheim Pharma Verschlußkappe und Behälter als Zweikammer-Kartusche für Vernebler zur Erzeugung von Aerosolen
DE19940713A1 (de) 1999-02-23 2001-03-01 Boehringer Ingelheim Int Kartusche für eine Flüssigkeit
GB9904281D0 (en) * 1999-02-24 1999-04-21 Reneuron Ltd Transplantation
DE19954516A1 (de) * 1999-11-12 2001-05-17 Boehringer Ingelheim Int Epinastin-haltige Lösungen
US8820316B2 (en) * 2000-02-11 2014-09-02 Respironics Respiratory Drug Delivery (Uk) Ltd Drug delivery apparatus
GB0009583D0 (en) * 2000-04-18 2000-06-07 Glaxo Group Ltd Respiratory formulations
CA2427583C (en) * 2000-10-31 2008-02-12 Karin Drechsel Inhalable formulation of a solution containing a tiotropium salt
DE10062712A1 (de) * 2000-12-15 2002-06-20 Boehringer Ingelheim Pharma Neue Arzneimittelkompositionen auf der Basis von Anticholinergika und Corticosteroiden
US20020137764A1 (en) * 2000-10-31 2002-09-26 Karin Drechsel Inhalable formulation of a solution containing a tiotropium salt
US20020111363A1 (en) * 2000-10-31 2002-08-15 Karin Drechsel Inhalable formulation of a solution containing a tiotropium salt
US20020193392A1 (en) * 2000-11-13 2002-12-19 Christel Schmelzer Pharmaceutical compositions based on tiotropium salts of salts of salmeterol
DE10111843A1 (de) * 2001-03-13 2002-09-19 Boehringer Ingelheim Pharma Verbindungen zur Behandlung von inflammatorischen Erkrankungen
DE10130371A1 (de) * 2001-06-23 2003-01-02 Boehringer Ingelheim Pharma Neue Arzneimittelkompositionen auf der Basis von Anticholinergika, Corticosteroiden und Betamimetika
DE10136555A1 (de) 2001-07-27 2003-02-13 Boehringer Ingelheim Int Optimierte Verfahren zur Bestimmung der Aerosol-Partikelgrößenverteilung und Vorrichtung zur Durchführung derartiger Verfahren
US20040019073A1 (en) * 2002-04-11 2004-01-29 Boehringer Ingelheim Pharma Gmbh Co. Kg Aerosol formulation for inhalation containing a tiotropium salt
US20040166065A1 (en) * 2002-08-14 2004-08-26 Boehringer Ingelheim Pharma Gmbh & Co. Kg Aerosol formulation for inhalation comprising an anticholinergic
US7040314B2 (en) 2002-09-06 2006-05-09 Philip Morris Usa Inc. Aerosol generating devices and methods for generating aerosols suitable for forming propellant-free aerosols
US7056916B2 (en) 2002-11-15 2006-06-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Medicaments for the treatment of chronic obstructive pulmonary disease
US7849850B2 (en) * 2003-02-28 2010-12-14 Battelle Memorial Institute Nozzle for handheld pulmonary aerosol delivery device
DE10345065A1 (de) 2003-09-26 2005-04-14 Boehringer Ingelheim Pharma Gmbh & Co. Kg Aerosolformulierung für die Inhalation enthaltend ein Anticholinergikum
AR041873A1 (es) * 2003-10-30 2005-06-01 Pablo Cassara Srl Lab Una formulacion farmaceutica en aerosol adecuada para la inhalacion oral o nasal que contienen glucocorticoides en solucion estable al almacenamiento; un metodo para estabilzar formulaciones y uso de un agente estabilizante
DE102004001451A1 (de) 2004-01-08 2005-08-11 Boehringer Ingelheim International Gmbh Vorrichtung zum Haltern eines fluidischen Bauteiles
US7220742B2 (en) 2004-05-14 2007-05-22 Boehringer Ingelheim International Gmbh Enantiomerically pure beta agonists, process for the manufacture thereof and use thereof as medicaments
GB0427568D0 (en) * 2004-12-16 2005-01-19 Resolution Chemicals Ltd Particle-size reduction apparatus, and the use thereof
US8097614B2 (en) 2005-02-17 2012-01-17 Velcera Pharmaceuticals, Inc. Transmucosal administration of meloxicam compositions for treating and preventing disorders in non-human domesticated animals
CN101119706B (zh) * 2005-02-25 2013-04-17 奇斯药制品公司 用于加压计量吸入器的包含螯合剂的药物气雾制剂
CN101208316B (zh) 2005-08-15 2012-05-09 贝林格尔·英格海姆国际有限公司 制备β-模拟物的方法
US20070086957A1 (en) * 2005-10-10 2007-04-19 Thierry Bouyssou Combination of medicaments for the treatment of respiratory diseases
CA2649413A1 (en) 2006-02-14 2007-08-23 Battelle Memorial Institute Dissociated discharge ehd sprayer with electric field shield
DE102006023756A1 (de) * 2006-05-20 2007-11-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Ethanolhaltige Aerosolformulierung für die Inhalation
EP2077132A1 (en) 2008-01-02 2009-07-08 Boehringer Ingelheim Pharma GmbH & Co. KG Dispensing device, storage device and method for dispensing a formulation
CA2741078A1 (en) * 2008-10-23 2010-04-29 Sunovion Pharmaceuticals Inc. Arformoterol and tiotropium compositions and methods for use
US10011906B2 (en) 2009-03-31 2018-07-03 Beohringer Ingelheim International Gmbh Method for coating a surface of a component
EP2432531B1 (de) 2009-05-18 2019-03-06 Boehringer Ingelheim International GmbH Adapter, inhalationseinrichtung und zerstäuber
WO2011064163A1 (en) 2009-11-25 2011-06-03 Boehringer Ingelheim International Gmbh Nebulizer
BR112012012475B1 (pt) 2009-11-25 2020-03-03 Boehringer Ingelheim International Gmbh Nebulizador
US10016568B2 (en) 2009-11-25 2018-07-10 Boehringer Ingelheim International Gmbh Nebulizer
JP5874724B2 (ja) 2010-06-24 2016-03-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ネブライザ
WO2012130757A1 (de) 2011-04-01 2012-10-04 Boehringer Ingelheim International Gmbh Medizinisches gerät mit behälter
US9827384B2 (en) 2011-05-23 2017-11-28 Boehringer Ingelheim International Gmbh Nebulizer
WO2013152894A1 (de) 2012-04-13 2013-10-17 Boehringer Ingelheim International Gmbh Zerstäuber mit kodiermitteln
EP2835146B1 (en) 2013-08-09 2020-09-30 Boehringer Ingelheim International GmbH Nebulizer
US9744313B2 (en) 2013-08-09 2017-08-29 Boehringer Ingelheim International Gmbh Nebulizer
SI3139982T1 (sl) 2014-05-07 2022-05-31 Boehringer Ingelheim International Gmbh Razpršilnik
ES2874029T3 (es) 2014-05-07 2021-11-04 Boehringer Ingelheim Int Nebulizador
EA032850B1 (ru) 2014-05-07 2019-07-31 Бёрингер Ингельхайм Интернациональ Гмбх Контейнер, небулайзер и способ изготовления контейнера
US10603451B2 (en) 2014-11-20 2020-03-31 Boehringer Ingelheim Vetmedica Gmbh Container for an inhaler
CN111939143A (zh) * 2019-05-16 2020-11-17 鲁南制药集团股份有限公司 一种布地奈德溶液型气雾剂及其制备方法
KR102278414B1 (ko) 2019-12-03 2021-07-16 한전케이피에스 주식회사 벨트 교체용 공구
MX2023001201A (es) 2020-07-31 2023-05-03 Chemo Res S L Terapia combinada para la administracion por inhalacion.

Family Cites Families (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE632504A (zh) 1962-05-24
DE1952320C3 (de) 1969-10-17 1981-02-26 Licentia Patent-Verwaltungs-Gmbh, 6000 Frankfurt Vorrichtung zum Abdichten von zwei koaxial ineinander gelagerten um- oder gegenläufigen Wellen bei Wasserfahrzeugen
MX3864E (es) * 1975-05-27 1981-08-26 Syntex Corp Un proceso para prepara el compuesto cristalino 6-fluiro-11b 21-dihiroxi-16 17-isopropilidendioxipregna-1 4-dien-3 20-diona
JPS5529524A (en) * 1978-08-21 1980-03-01 Toyo Aerosol Kogyo Kk Powdery aerosol composition
JPS599539B2 (ja) 1979-11-13 1984-03-03 日本化薬株式会社 ニトログリセリン水溶液及びその製造法
US4289764A (en) * 1979-12-04 1981-09-15 Drythanol Ltd. Steroid compositions
DE3109783A1 (de) 1981-03-13 1982-10-07 Sanol Schwarz-Monheim Gmbh, 4019 Monheim Mit wasser zu einer etwa isotonischen nitroglycerinloesung aufloesbare zubereitung und derartige nitroglycerinloesung
US4383992A (en) * 1982-02-08 1983-05-17 Lipari John M Water-soluble steroid compounds
DE3246081A1 (de) 1982-12-13 1984-06-14 G. Pohl-Boskamp GmbH & Co Chemisch-pharmazeutische Fabrik, 2214 Hohenlockstedt Nitroglycerin-spray
JPS6183117A (ja) 1984-09-28 1986-04-26 Sumitomo Chem Co Ltd エアゾ−ル剤
US4615699A (en) 1985-05-03 1986-10-07 Alza Corporation Transdermal delivery system for delivering nitroglycerin at high transdermal fluxes
DE3544692A1 (de) 1985-12-18 1987-06-19 Bayer Ag Dihydropyridinspray, verfahren zu seiner herstellung und seine pharmazeutische verwendung
AU6907687A (en) * 1986-02-18 1987-08-20 Rorer Pharmaceutical Corporation Composition for treatment of asthmatic conditions using phenoxymethyl quinolines
JPH0645538B2 (ja) 1987-09-30 1994-06-15 日本化薬株式会社 ニトログリセリンスプレー剤
HU199678B (en) * 1988-07-08 1990-03-28 Egyt Gyogyszervegyeszeti Gyar Process for producing aerosols containing nitroglicerol
US5225183A (en) * 1988-12-06 1993-07-06 Riker Laboratories, Inc. Medicinal aerosol formulations
GB8828477D0 (en) * 1988-12-06 1989-01-05 Riker Laboratories Inc Medical aerosol formulations
US5136124A (en) 1988-12-14 1992-08-04 International Business Machines Corporation Method of forming conductors within an insulating substrate
GB8829478D0 (en) 1988-12-16 1989-02-01 Harris Pharma Ltd Formulations
US5370862A (en) * 1990-06-13 1994-12-06 Schwarz Pharma Ag Pharmaceutical hydrophilic spray containing nitroglycerin for treating angina
IT1243379B (it) 1990-07-27 1994-06-10 Giuliani Spa Composizione farmaceutica adatta alla somministrazione rettale di principi attivi che esplicano un'azione di medicazione a livello del colon prevalentemente di tipo topico
CA2094266C (en) * 1990-10-18 1999-06-01 Robert K. Schultz Aerosol formulations of beclomethasone-17,21-dipropionate
MX9203481A (es) * 1990-10-18 1992-07-01 Minnesota Mining & Mfg Formulaciones.
EP0504112A3 (en) 1991-03-14 1993-04-21 Ciba-Geigy Ag Pharmaceutical aerosol formulations
HUT67449A (en) * 1991-06-10 1995-04-28 Schering Corp Aerosol formulations containing 1,1,1,2,3,3,3-heptafluoropropane
DE4123663A1 (de) * 1991-07-17 1993-01-21 Schwabe Willmar Gmbh & Co Aerosol-zubereitung und verwendung eines treibmittels dafuer
IL103238A (en) 1991-09-25 1995-07-31 Fisons Plc Pressed aerosol preparations
US5674471A (en) * 1991-12-12 1997-10-07 Glaxo Group Limited Aerosol formulations containing P134a and salbutamol
US5736124A (en) * 1991-12-12 1998-04-07 Glaxo Group Limited Aerosol formulations containing P134a and particulate medicament
GB9202519D0 (en) 1992-02-06 1992-03-25 Glaxo Group Ltd Medicaments
DE4203306A1 (de) 1992-02-06 1993-08-12 Ig Spruehtechnik Gmbh Asthma oder pulmonal-aerosolzubereitungen mit lecithin
US5224183A (en) * 1992-07-23 1993-06-29 Alcatel Network Systems, Inc. Multiple wavelength division multiplexing signal compensation system and method using same
DK0673240T3 (da) * 1992-12-09 1999-10-11 Boehringer Ingelheim Pharma Stabiliserede medicinske aerosolopløsningsformuleringer
DE4340057A1 (de) 1993-11-24 1995-06-01 Falk Pharma Gmbh Budesonid-Arzneimittel zur Verbesserung der enteralen Flüssigkeitsresorption, insbesondere nach postoperativen Zuständen
DE4446891A1 (de) * 1994-12-27 1996-07-04 Falk Pharma Gmbh Stabile wäßrige Budesonid-Lösung
BR9609307B1 (pt) * 1995-06-27 2010-03-09 preparação farmacêutica para produção de aerossóis inaláveis isentos de propelentes para administração nos pulmões, bem como aerossol compreendendo a mesma.
US5958378A (en) * 1996-07-03 1999-09-28 Research Development Foundation High dose liposomal aerosol formulations containing cyclosporin A or budesonide
US6039932A (en) * 1996-09-27 2000-03-21 3M Innovative Properties Company Medicinal inhalation aerosol formulations containing budesonide
US6004537A (en) * 1998-12-18 1999-12-21 Baker Norton Pharmaceuticals, Inc. Pharmaceutical solution aerosol formulations containing fluoroalkanes, budesonide and formoterol
US20020137764A1 (en) * 2000-10-31 2002-09-26 Karin Drechsel Inhalable formulation of a solution containing a tiotropium salt

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