CN1856306A - 含有抗胆碱剂的供吸入用的气雾剂 - Google Patents
含有抗胆碱剂的供吸入用的气雾剂 Download PDFInfo
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Abstract
本发明是关于供吸入用的医药制剂,其含有作为唯一活性物质的一种化学式1的化合物,其中X-为一种阴离子,其优选选自氯化物、溴化物、碘化物、硫酸盐、磷酸盐、甲磺酸盐、硝酸盐、马来酸盐、醋酸盐、柠檬酸盐、富马酸盐、酒石酸盐、草酸盐、琥珀酸盐、苯甲酸盐及对-甲苯磺酸盐中,溶剂为乙醇或乙醇与水的混合物,至少一种药理可接受的酸及视需要的其他药理可接受的赋形剂和/或络合剂。
Description
本发明是关于供吸入用的医药制剂,其含有作为唯一活性物质的一种化学式1的化合物
其中
X-为一种阴离子,其优选选自氯化合物、溴化物、碘化物、硫酸盐、磷酸盐、甲磺酸盐、硝酸盐、马来酸盐、醋酸盐、柠檬酸盐、富马酸盐、酒石酸盐、草酸盐、琥珀酸盐、苯甲酸盐及p-甲苯磺酸盐,溶剂为乙醇或乙醇与水的混合物,至少一种药理可接受的酸及视需要的其他药理可接受的赋形剂和/或络合剂。
化学式1的化合物是从WO 02/32899中得知。其具有有价值的药理学特性并可作为高效抗胆碱能药在治疗呼吸系统疾病中特别在治疗炎性和/或阻塞性呼吸系统疾病方面,尤其为治疗哮喘或COPD(慢性阻塞性肺病)中提供治疗益处。
本发明是关于这些化合物的液体活性物质调配剂,其可通过吸入给药;根据本发明的该液体调配剂必须满足高质量标准。根据本发明的调配剂可经口或鼻吸入。为获得该活性物质在肺中的最佳分布,可方便地借助于适当的吸入器而使用无推进剂气体的液态调配剂。这种调配剂的吸入使用也可以经口或鼻进行。尤其合适的是这样一种吸入器,其能够在几秒内将治疗所需剂量的少量液态调配剂雾化成一种适合吸入治疗的气雾剂。在本发明范围内,优选的喷雾器为其中的量少于100微升,优选为少于50微升,最佳为少于20微升的活性物质溶液,其可优选地以一次或两次喷射雾化以形成一种平均颗粒大小小于20微米,优选地小于10微米的气雾剂,因此该气雾剂的可吸入部分已相当于治疗有效量。
这种用于一计量量的供吸入液态医药组合物的无推进气剂的给药装置详细描述于,例如,国际专利申请WO 91/14468“雾化器件及方法”及WO97/12687(参阅图6a与6b及其附图说明)。在这种喷雾器中,一种医药溶液通过一高达600巴的高压转移和喷射用于肺部的气雾剂。在本说明书的范围内清楚地引用了上述文献的全部内容。在这种吸入器中,该溶液调配剂是储存在一储存器中,重要的是,使所应用的活性物质调配剂在储存时是足够稳定,同时使其可根据其药用目的直接给药,而可以无须任何进一步的处理。而且,其必须不含有任何可以与这种吸入器以相互作用以至于损害该吸入器或产生气雾剂的溶液的医药性质的成分。
为了雾化该溶液,使用例如在WO 94/07607或WO 99/16530号专利中所描述的一种特殊喷嘴。本文清楚地引用了这两个公开文件。
发明内容
本发明的目的旨在提供一种化学式1的化合物的调配剂,其满足为允许使用上述吸入器进行溶液的最佳雾化而所需的高标准。根据本发明的活性物质调配剂必须具有充分高的医药质量,也就是在几年存储期,优选为至少一年,更佳为两年其应具有医药稳定性。
这些无推进气剂的溶液调配物也必须能够是使用一种吸入器而在低压下进行雾化,由取出物质所产生的气雾剂在一特定范围内是可再现性的。
在本发明范围内,优选使用其中阴离子X-是选自以下的化学式1的化合物:氯化物、溴化物、碘化物、硫酸盐、磷酸盐、甲磺酸盐、硝酸盐、马来酸盐、醋酸盐、柠檬酸盐、富马酸盐、酒石酸盐、草酸盐、琥珀酸盐、苯甲酸盐及p-甲苯磺酸盐。
优选地,可应用化学式1的盐,其中X-是指一种选自氯化物、溴化物、4-甲苯硫酸盐及甲烷硫酸盐中选出的阴离子。
在本发明的范围内,尤其优选的为含有其中X-是溴化物的化学式1的化合物的调配剂。
涉及化学式1的化合物在本发明范围内通常包含这化合物的所有可能的非晶及结晶变体。涉及的化学式1的化合物在本发明范围内也包含可由这化合物形成的所有可能的溶剂合物及水合物。
在本发明范围内涉及的化合物1′被认定是涉及一种在盐1中包含的如下化学式的药理活性阳离子:
在根据本发明的调配剂中,化合物1是以溶解于乙醇或乙醇与水的混合物中而存在。
根据本发明,该调配剂优选地仅含有化学式1的一种单盐。然而,该调配物剂也可含有化学式1的不同盐的混合物。含有不是化学式1的盐的活性物质的调配剂并非本发明的主题。
基于药理活性阳离子1′的比例,化学式1的化合物在本发明的医药制剂中的浓度为每100毫升约4至2000毫克,根据本发明,优选为每100毫升约8至1600毫克。根据本发明,特别优选的为100毫升该调配剂含有约80至约1360毫克的1′。
如果所用的化学式1的化合物为其中X-为溴化物的则是特别优选的化合物,根据本发明的1的比例为每100毫升医药制剂约5至2500毫克,优选为每100毫升医药制剂约10至2000毫克。根据本发明,最佳的为100毫升该调配剂含有约100至1700毫克的1。
根据本发明的调配剂含有作为溶剂的纯乙醇或乙醇与水的混合物。如果使用乙醇-水混合物,则在这些混合物中存在的乙醇的重量百分比优选在5%至99%的乙醇范围内,更优选为10%至96%的醇范围。根据本发明最佳的是所应用的作为溶剂的乙醇-水混合物含有50%至92%的乙醇,最佳为69%至91%。
也可使用乙醇及水以外的其他共溶剂。然而,较佳地,根据本发明不使用其他溶剂。
根据本发明的调配剂含有用于调整pH值的医药可接受的有机酸或无机酸。根据本发明的该调配剂的pH值优选介于2.5至6.5之间,更佳介于3.0至5.0之间,根据本发明最佳为介于3.5至4.5之间。
优选的无机酸实例选自盐酸、氢溴酸、硝酸、硫酸及磷酸中。
尤其合适的有机酸实例选自抗坏血酸、柠檬酸、苹果酸、酒石酸、马来酸、琥珀酸、富马酸、乙酸、甲酸及丙酸中。根据本发明优选的无机酸为盐酸及硫酸,其中盐酸尤为优选。有机酸中抗坏血酸,富马酸及柠檬酸较佳,柠檬酸尤其优选。如果需要,也可应用上述酸的混合物,尤其为具有除其本身酸性之外的其他特性的酸,例如可用作调味剂或抗氧化剂的酸,诸如柠檬酸或抗坏血酸。
如果需要,可使用药理可接受的碱以精确地滴定pH值。合适的碱包含例如碱金属氢氧化物及碱金属碳酸盐。优选的碱金属离子为钠。如果应用这种碱,则必须谨慎以确保包含于最终医药调配剂中的所得盐与上述酸在药理学上是相容的。
根据本发明的调配剂可含有作为其他成分的络合剂。在本发明范围内络合剂意味着它是能够进入配位键的分子。优选地,通过这种化合物阳离子可以络合,特别是金属阳离子。根据本发明的调配剂优选含有乙二胺四乙酸(EDTA)或其一种已知盐,例如EDTA钠或EDTA二钠二水合物作为络合剂。优选地,可应用乙二胺四乙酸钠,视需要以其水合物形式应用,更佳地以其二水合物形式。如果在本发明的调配剂内应用络合剂,其含量优选为每100毫升本发明的调配剂为1至100毫克,更佳为每100毫升5至50毫克。优选地,根据本发明的调配剂含有一种络合剂,其量为每100毫升本发明的调配剂为约6至30毫克,更佳为每100毫升为约7至20毫克。
如乙二胺四乙酸钠类似地也可使用可与EDTA或其盐相比较的其他添加物,其具有配位特点且可替代而应用,诸如例如氮基三乙酸及其盐。
其他药理学可接受的赋形剂也可加入至根据本发明的调配剂中。在本文中,佐剂和添加剂意味着任何药理学可接受的且是治疗有用的物质,其不是活性物质,但是为了改善活性物质调配剂的品质其可在药理学适宜的溶剂中与活性物质共同配制。优选地,这些物质没有治疗价值或在本文所需治疗中无可觉察的或至少没有不需要的药理学作用。该佐剂和添加剂包含例如稳定剂、抗氧化剂和/或防腐剂(其可延长最终医药调配剂的储存期)、及调味剂、维生素和/或所属技术领域所熟知的添加剂。该添加剂也包含药理学可接受的盐,例如诸如氯化钠。
举例而言,优选的赋形剂包含抗氧化剂,诸如抗坏血酸(但是未用来校正pH)、维生素A、维生素E、生育酚及相似的存在于人体内的维生素或原维生素。
可加入防腐剂以保护该调配剂免受病源菌污染。适宜的防腐剂为现有技术中所熟知的防腐剂,尤其为氯苄烷铵或苯甲酸或苯甲酸盐(诸如苯甲酸钠),其浓度中现有技术中已知。优选地,将氯苄烷铵加入至本发明的调配剂中。氯苄烷铵的量介于每100毫升调配物的1毫克至50毫克之间,优选为每100毫升约7至15毫克,更佳为每100毫升约9至12毫克。然而,根据本发明,不含有任何防腐剂的调配剂尤为优选。
优选的调配剂除了作为溶剂的乙醇或乙醇/水混合物和化学式1的化合物外,仅包含氯苄烷铵、乙二胺四乙酸钠和校正pH所需的酸。
含有化学式1的化合物的本发明的医药调配剂优选地可用于上述一种吸入器中以产生根据本发明的无推进气剂的气雾剂。在这点上,我们将再一次清楚地提及上述专利文献,其内容以引用形式列入本说明书。
如开始所述,该优选的吸入器的另一改进的实施方案公开在WO97/12687号专利(参阅尤其图6a和6b及其相关说明书页次)。这喷雾器(Respimat)可方便地用于产生根据本发明的可吸入气雾剂。由于其圆柱形状及轻巧大小,该器件可由患者随时携带。该喷雾器在高压下通过小喷嘴喷射出限定体积量的该医药调配剂,以产生可吸入的气雾剂。
该优选的雾化器基本由一个上腔室部分、一个泵腔、一喷嘴、一拉紧机构、一弹簧腔、一弹簧和一储存容器组成,其特征为
-一个泵腔,其固定于上腔室部分且在其一端载有一个具有喷嘴或喷嘴排列的喷嘴体,
-一个带有阀体的筒状活塞,
-一个从动凸缘,空腔柱体固定在其中,且其位于上腔室部分,
-一个位于上腔室部分的拉紧机构,
-一个弹簧腔,有弹簧位于其中,其通过旋转轴承可旋转地固定于该上腔室部分,
-一个下腔室部分,其装配在轴向的弹簧腔上。
带有阀体的筒状活塞相当于在WO 97/12687中所揭示的一个装置。其部分凸进该泵腔的圆柱体,且装置成可在该圆柱体中可轴向移动。特别参阅上述国际申请案中的图1-4,尤其是图3-及其相关说明书页次。在该弹簧松开的时间,带有阀体的筒状活塞在其高压端向该流体(已定量的活性物质溶液)上施加5至60Mpa(约50至600巴)的压力,优选为10至60Mpa(约100至600巴)。每次启动时优选10至50微升体积,10至20微升体积更佳,同时10至15微升体积尤其优选。
该阀体优选装置于该筒状活塞的朝向喷嘴体的端部。
喷嘴体中的喷嘴优选为微结构,亦即由微工程生产。微结构的喷嘴体公开于例如WO 99/16530中;本文引用了该说明书的内容,尤其为图1及其相关说明。
举例而言,喷嘴体是由两块坚固相互连结的玻璃和/或硅片组成,其中至少一个具有一个或多个微结构的通道,其连接喷嘴入口端和喷嘴出口端。在喷嘴出口端至少有一个2至10微米深及5至15微米宽的圆形或非圆形开口,其深度优选为4.5至6.5微米,长度为7至9微米。
如果有多个喷嘴开口(优选为两个),则喷嘴体中的喷嘴的喷射方向可彼此平行前进或可在喷嘴开口方向彼此相对倾斜。在一个其出口端有至少两个喷嘴口的喷嘴体情况下,喷射方向可以彼此相对倾斜20度至160度角,优选为60度至150度角,最佳为80度至100度角。
喷嘴开口优选为以10至200微米的间距,优选为10至100微米间距,更佳为30至70微米进行排列。50微米间距为最佳。
因此喷射方向在喷嘴开口区域汇合。
如上所述,该液态医药制剂以高达600巴、优选为200至300巴的进入压力撞击该喷嘴体,然后通过喷嘴开口雾化成可吸入的气雾剂。该气雾剂的优选的颗粒大小为20微米,优选为3至10微米。
该拉紧机构含有一个弹簧,优选为一圆柱形螺旋状压缩弹簧作为机械能的储器。该弹簧作为一弹簧构件作用于从动凸缘,其移动由阻塞构件的位置决定。该从动凸缘的移动受上止动器和下止动器精确限制。该弹簧优选在一能量联动装置(例如一螺旋滑移齿轮传动箱)上通过拉紧外部转矩(其在上腔室部分相对下腔室部分的弹簧腔转动时产生)。这种情况下,该上腔室部分及该从动凸缘含有一单速或多速键槽齿轮。
该带有啮合锁定面的阻塞构件以环形安装在从动凸缘周围。举例而言其由一塑料或金属制成的环构成,该环是辐射状弹性可变形的。该环安装在垂直于雾化器轴的平面上。将弹簧拉紧后,该阻塞构件的锁定表面滑进从动凸缘通道并防止弹簧松开。该阻塞构件通过一按钮启动。该启动按钮与该阻塞构件连接或偶连。为了启动该截止构件,将启动按钮平行移向环形平面,优选为进入该雾化器,因此可变形环在该环形平面中变形。WO97/20590中详细描述了该截止构件的结构。
下腔室部分是轴向推过弹簧腔并覆盖轴承、轴驱动器及液体储存容器。
当启动该雾化器时,该上腔部分相对于下腔部分转动,下腔部分带有弹簧腔。同时弹簧通过螺旋滑移齿轮箱被压缩并拉紧,然后该制动构件自动啮合。转动角度优选为360度的整数部分,例如180度。同时当弹簧拉紧时,上腔室部分中的从动构件以给定量移动,筒状活塞被拉回至泵腔中的圆柱体内部,结果储存器中一些液体被吸入喷嘴前面的高压腔中。
如果需要,含有可雾化液体的多个可替代的储存器可以一个接一个地移入喷雾器中,然后使用。该储存器含有本发明的气雾剂制剂。
该雾化过程是通过轻轻按压启动按钮而开始。然后制动构件打开从动构件的通道。拉紧的弹簧推动活塞进入泵腔中的圆柱体。液体以喷雾形式从雾化器的喷嘴中喷出。
该结构的进一步细节描述在PCT申请案WO 97/12683及WO 97/20590中,本文对其进行了引用。
该雾化器(喷雾器)构件由适于其功能的材料制成。雾化器腔及-如果功能允许-其他部分优选由塑料制成,例如通过注射模塑。为了医药应用,使用生理学可接受的材料。
WO 97/12687的图6a/b显示了Respimat喷雾器,其可将根据本发明的水性气雾剂制剂方便地吸入。
图6a显示了一个通过带有拉紧弹簧时的雾化器的纵向部分,图6b显示了一个通过松开弹簧时的雾化器的纵向部分。
上腔室部分(51)含有泵腔(52),在其端部装配有雾化器喷嘴用的固定器(53)。在该固定器中为喷嘴体(54)和一过滤器(55)。在从动凸缘(56)中固定阻塞构件的筒状活塞(57)部分突入泵腔的圆柱体内。在其端部,该筒状活塞带有阀体(58)。该筒状活塞由垫圈(59)密封。上腔室部分的内部为止动器(60),当弹簧放松时从动凸缘保持在其上。止动器(61)位于从动凸缘上面,当弹簧拉紧时从动凸缘保持在其上。弹簧拉紧后,阻塞构件(62)滑动在上腔室部分中的止动器(61)和支承件(63)之间。启动按钮(64)连接到阻塞构件上。上腔室部分在口承(65)处终止,并由可移动的保护帽(66)封闭。
有压缩弹簧(68)的弹簧腔(67)通过扣合片(69)和旋转轴承可旋转地装配在上腔室部分。下腔室部分(70)可推过弹簧腔。弹簧腔内部有要雾化液体(72)的可替代的储存器(71)。该储存器由止动器(73)封闭,通过其筒状活塞可突入储存器,且将其末端浸入液体(提供活性物质溶液)中。
机械式计数器的轴(74)装配在弹簧腔的外部。驱动小齿轮(75)位于面向上腔室部分的轴的端部。轴上是滑动器(76)。
上述喷雾器适于雾化根据本发明的气雾剂制剂以形成一种适合吸入的气雾剂。
在另一优选的实施方案中,根据本发明的医药调配剂是使用上面描达的喷雾器给药,其中使用一种可替代的储存容器,其含有根据本发明的医药调配剂,其内有一种如在WO 99/43571中描述的气体-及液体-密封容器。现将描述该容器结构的一些细节;以下描述中引用的参考数字与在WO99/43571中公开的参考数字相符。WO 99/43571所揭示的内容以引用形式列入下列描述中。
因此,为了投与本发明的调配剂,尤其优选为使用一种气体-及液体-密封容器作为一种在无推进气剂的雾化器中用于医药液体的可替代的容器,其公开于WO 99/43571中,其包括一种筒状活塞形式的引取管接头,该容器包括:
-一两端密封的箔袋(11,21,31),其中,至少一端用一焊接缝(13,23,32)封闭,其实质上以与该袋轴成直角而行进,并且该箔袋由于在该容器的内部与其外周间的压力差小于300hPa(300毫巴)的外部压力而变形,
-一形状稳定的凸缘(15,25,34),其牢固地附于箔袋并且构成一可拆卸的连接件以插装容器到引取管接头(67)上,
-凸缘中的导向管道(42,54)。
-同时在导向管道中形成一密封位点(56,64,74)和/或一环绕于该引取管接头的压力配合件(55,66,77),
-及一用于在该导向管道区的液体取出点,筒状活塞在使用时插入其中以浸入该医药液体中。
如果应用上述技术(Respimat)雾化本发明的调配剂,在该吸入器的所有操作(喷雾启动)中所传输的量相当于限定量的至少97%、优选至少98%,其容许公差范围不超过此量的25%量的限定量,优选为20%。优选地,传输5至30毫克调配剂,最佳为5至20毫克调配剂,作为每一次启动的限定量。
然而,根据本发明的调配剂也可以通过不同于上述吸入器的吸入器进行雾化,例如喷气流吸入器或超声波喷雾器。
本发明也是关于一种吸入套件,其由一种上述本发明的医药制剂及一种适于雾化这种医药制剂的吸入器组成。本发明优选关于一种吸入套件,其由一种上述本发明的医药制剂及上述Respimat吸入器组成。
以下所示的调配剂的实例作为描述而非将本发明的主题限定于由实例所示的组合物。
1.调配剂的实例
100毫升医药制剂含有:
实例 | 1(1′-溴化物)(毫克) | 氯苄烷铵(毫克) | 乙二胺四乙酸二钠二水合物(毫克) | 柠檬酸(毫克) | 用乙醇/水混合物定容至100毫升(%质量/质量) |
1 | 2000 | 10 | 10 | 3 | 50/50 |
2 | 1000 | 5 | - | 3 | 70/30 |
3 | 1500 | - | 10 | 5 | 70/30 |
4 | 500 | - | 20 | 2 | 70/30 |
5 | 150 | - | 10 | 3 | 90/10 |
6 | 250 | - | 10 | 2 | 90/10 |
7 | 750 | - | - | 4 | 90/10 |
8 | 150 | - | - | 3 | 90/10 |
9 | 250 | - | - | 4 | 95/5 |
10 | 500 | - | - | 3 | 95/5 |
11 | 100 | 5 | - | 3 | 95/5 |
按照与现有技术熟知的相似方法制备本发明的调配剂,例如通过在乙醇或乙醇/水溶剂中溶解调配剂的成分。
Claims (16)
2.如权利要求1的医药制剂,其含有至少一种化学式1的化合物,其中X-选自氯化物、溴化物、4-甲苯硫酸盐和甲烷硫酸盐。
3.如权利要求1或2的医药制剂,其含有作为溶剂的乙醇和水的混合物,乙醇的量在这些混合物中的比例范围为5%至99%。
4.如权利要求1至3中之一的医药制剂,其含有作为溶剂的乙醇和水的混合物,乙醇的量在这些混合物中的比例范围为10%至96%。
5.如权利要求1至4中之一的医药制剂,其中该药理学可接受的酸选自无机酸的盐酸、氢溴酸、硝酸、硫酸及磷酸,或有机酸的抗坏血酸、柠檬酸、苹果酸、酒石酸、马来酸、琥珀酸、富马酸、醋酸、甲酸及丙酸。
6.如权利要求1至5中之一的医药制剂,其特征为pH为2.5至6.5。
7.如权利要求1至6中之一的医药制剂,其特征为每100毫升溶液中1′的含量为约4至2000毫克。
8.如权利要求1至7中之一的医药制剂,其特征为其含有一种络合剂作为另一种成分。
9.如权利要求1至8中之一的医药制剂,其特征为每100毫升溶液中络合剂的含量为约1至100毫克。
10.如权利要求1至9中之一的医药制剂,其特征为其含有氯苄烷铵作为助剂。
11.如权利要求10的医药制剂,其特征为每100毫升溶液中氯苄烷铵的含量为1至50毫克。
12.一种如权利要求1至11中之一的医药制剂的应用,其用于制备一种用于治疗呼吸道疾病的医药组合物。
13.一种吸入使用如权利要求1~12中之一的医药制剂的方法,其是通过经口或鼻途径进行。
14.一种权利要求1至13中之一的医药制剂的应用,其用于在按WO91/14468的吸入器或描述于WO 97/12687的图6a和6b中的吸入器中进行雾化。
15.一吸入套件,其由一如权利要求1至14中之一的医药制剂和一适于雾化这种医药制剂的吸入器所组成。
16.如权利要求15的吸入套件,其中该吸入器为Respimat。
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