CN115397747A - 加压分配容器 - Google Patents
加压分配容器 Download PDFInfo
- Publication number
- CN115397747A CN115397747A CN202180011442.4A CN202180011442A CN115397747A CN 115397747 A CN115397747 A CN 115397747A CN 202180011442 A CN202180011442 A CN 202180011442A CN 115397747 A CN115397747 A CN 115397747A
- Authority
- CN
- China
- Prior art keywords
- dispensing container
- valve
- pressurised dispensing
- seals
- container
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 50
- 239000000203 mixture Substances 0.000 claims abstract description 47
- 239000003380 propellant Substances 0.000 claims abstract description 36
- 238000007789 sealing Methods 0.000 claims abstract description 34
- 229920000642 polymer Polymers 0.000 claims abstract description 31
- 229920002943 EPDM rubber Polymers 0.000 claims abstract description 23
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229920001577 copolymer Polymers 0.000 claims abstract description 15
- NPNPZTNLOVBDOC-UHFFFAOYSA-N 1,1-difluoroethane Chemical compound CC(F)F NPNPZTNLOVBDOC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000012530 fluid Substances 0.000 claims abstract description 8
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- -1 bromobutyl Chemical group 0.000 claims description 20
- 229920001971 elastomer Polymers 0.000 claims description 12
- 230000003068 static effect Effects 0.000 claims description 12
- 229920001897 terpolymer Polymers 0.000 claims description 10
- 229920005557 bromobutyl Polymers 0.000 claims description 9
- 229920005549 butyl rubber Polymers 0.000 claims description 9
- OJOWICOBYCXEKR-KRXBUXKQSA-N (5e)-5-ethylidenebicyclo[2.2.1]hept-2-ene Chemical compound C1C2C(=C/C)/CC1C=C2 OJOWICOBYCXEKR-KRXBUXKQSA-N 0.000 claims description 8
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- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
一种加压分配容器(10)包括用于待分配产品的容器(11)和固定到所述容器的阀,其中,所述容器容纳喷射剂,所述喷射剂包含1,1‑二氟乙烷或其衍生物并可选地包括乙醇。所述阀包括阀杆(15)、阀体(16,18)和一个或更多个密封件(20,21),所述阀杆能在所述阀体内滑动,所述一个或更多个密封件与所述阀杆配合以调节流体的排放。该阀还包括用于将该阀密封到该分配容器的密封垫圈(14)。所述一个或更多个密封件(20,21)由(i)弹性体组合物形成,(i)弹性体组合物优选为包含乙烯‑丙烯‑二烯三元共聚物的弹性体组合物。密封垫圈(14)由包含异丁烯聚合物或其共聚物的(ii)弹性体组合物形成。
Description
本发明涉及一种加压分配容器和用在该加压分配容器中的弹性体密封材料。加压分配容器可用于分配气溶胶形式的加压流体。加压分配容器用作药物分配装置,例如加压定量气溶胶吸入器装置(pMDI)和适用于分配药物的医用检查装置。
例如从GB1201918已知的是,提供一种分配设备,其中来自加压分配容器的流体通过阀以受控方式释放,该阀包括弹性体密封件,该弹性体密封件是环形的并且与滑动阀杆协作以打开和关闭流体端口。FR-A-2,549,568、WO95/02651和GB2148912以及PCT/GB96/01551各自公开了这种分配设备的其他实例。
药物应用的良好密封性能所需的必要材料特性包括:化学相容性(溶胀)、拉伸强度、永久压缩形变、应力松弛、弹性模量、法规依从性、对液体和气体的低渗透性、低水平的可浸提物和可沥滤物以及浸提后的稳定特性。
除了对良好的工程性质的要求之外,还需要卫生性质,包括低水平的可提取物和可浸出物,否则其可能将药物产品的杂质增加至不可接受的水平,还可能与药物产品、媒介物或赋形剂反应。在这方面,从pMDI分配的产品通常以喷射剂基质中的溶液或悬浮液提供,这在用于吸入疗法的药物化合物的分配中是特别常见的。用于分配装置如pMDI中的计量阀通常由金属和/或热塑性零件和弹性体橡胶零件的混合物构成。
用于密封药物定量气溶胶吸入器的已知橡胶化合物包括基于硫化合成或天然橡胶聚合物的传统技术的那些。
待分配的产品通常以在醇或非醇基质中的溶液或悬浮液提供,这在用于吸入疗法的药物化合物的分配中是特别常见的。
典型的设备包括氢氟烷烃(HFA)挥发性喷射剂,例如常规喷射剂,如HFA134a,并具有液相,其中产物与醇载体一起在容器内是易溶的。用于阀密封件的典型材料是合成橡胶,例如氯丁橡胶。
本发明的目的是提供一种可与基于1,1-二氟乙烷的喷射剂一起使用的加压分配容器。此外,加压分配容器还可适于与其他低全球变暖喷射剂或其组合一起使用。此外,例如当HFA134a和HFA227中的一种或更多种与1,1-二氟乙烷组合使用时,加压分配容器也可适于与喷射剂如1,1,1,2-四氟乙烷(HFA134a)或1,1,1,2,3,3,3-七氟丙烷(HFA227)一起使用。
因此,在第一方面,本发明提供一种加压分配容器,所述加压分配容器包括用于待分配产品的容器和固定到所述容器的阀,其中,所述容器容纳喷射剂,所述喷射剂包含1,1-二氟乙烷或其衍生物和可选地醇(例如,乙醇),
其中,所述阀包括阀杆、阀体以及一个或更多个密封件,所述阀杆能在所述阀体内滑动,所述一个或更多个密封件与所述阀杆协作以用于调节流体的排放,
其中,所述阀还包括用于将所述阀密封到所述分配容器的密封垫圈,
其中,所述一个或更多种密封件由(i)弹性体组合物形成,所述(i)弹性体组合物优选为包含乙烯-丙烯-二烯三元共聚物的弹性体组合物,以及
所述密封垫圈由包含异丁烯聚合物或其共聚物的(ii)弹性体组合物形成。
在第一方面,喷射剂优选地包含HFA152a和可选地醇(例如,乙醇)或由HFA152a和可选地醇(例如,乙醇)组成。与常规氯氟烃喷射剂相比,据报道HFA152a具有零臭氧消耗潜势、较低的全球变暖潜势和较短的大气寿命。
在第一方面,喷射剂可替代地包含HFA152a和HFA134a的组合和可选地醇(例如,乙醇)或由HFA152a和HFA134a的组合和可选地醇(例如,乙醇)组成。在第一方面,喷射剂可替代地包含HFA152a和HFA227ea的组合和可选地醇(例如,乙醇)或由HFA152a和HFA227ea的组合和可选地醇(例如,乙醇)组成。
附图
通过举例的方式提供以下附图以帮助理解本发明的某些方面:
图1仅以举例的方式示出了加压分配容器。
图2示出了与填充罐的稳定性储存相关的水分含量(ppm)数据,其中,密封垫圈包含乙烯-丙烯-二烯三元共聚物(EPDM)。
图3示出了数据,该数据表明:与仅包含EPDM作为主要大气垫圈密封件的类似阀构造相比,使用包含溴丁基(典型地,例如异丁烯聚合物)垫圈的根据本发明的混合阀构造可以实现更少量的静态泄漏。
图4示出了数据,该数据表明:与仅包含EPDM作为主要大气垫圈密封件的类似阀构造相比,使用包含溴丁基(典型地,例如异丁烯聚合物)垫圈的根据本发明的混合阀构造可以实现较低的水分进入量。
密封垫圈(也被称为静态密封件)
在本发明中,密封垫圈由(ii)包含异丁烯聚合物或其共聚物的弹性体组合物形成。
与可被称为一个或多个动态密封件的与阀杆配合的一个或多个密封件相反,密封垫圈也可被称为静态密封件。
密封垫圈的目的是提供阀和分配容器之间的密封,从而防止分配容器的内容物泄漏,例如喷射剂的泄漏。可论证地重要的是,如果不是更重要的话,密封垫圈防止不想要的成分(例如水分)进入容器中,这些不想要的成分可能对待分配的产品(例如药物或药品)具有有害的影响。例如,喷射剂悬浮液中过量水分的存在可通过药物颗粒附聚导致细颗粒质量的降低,从而降低活性药物成分(API)的治疗效果。水分也可导致API制剂的氧化。
本发明人已经发现,(ii)包含异丁烯聚合物或其共聚物的弹性体组合物在喷射剂是或包含1,1-二氟乙烷(例如HFA152a)或其衍生物时提供特别有效的密封。虽然不希望受理论束缚,但HFA152a具有比常规喷射剂(如HFA134a)更高的偶极矩,并且因此可能更具吸湿性,从而导致更多的水分进入容器中。令人惊讶地,本发明人发现常规EPDM聚合物在基于1,1-二氟乙烷的喷射剂的水分进入测试中表现不佳。喷射剂通常与醇(例如乙醇)一起提供。本发明人进一步发现,当存在醇时,水分进入容器被混合。当喷射剂包括醇(例如乙醇)时,本文所述的弹性体组合物(ii)令人惊讶地提供有效的防潮层。
根据本发明的密封垫圈还可以在氦气渗透性、低偶极矩、渗透性和随温度的蠕变行为的低变化、对溶解在喷射剂中的抗性和低吸水率方面与本文所述的喷射剂相容。
(ii)包含异丁烯聚合物或其共聚物的弹性体组合物
(ii)弹性体组合物包含异丁烯聚合物或其共聚物,例如聚异丁烯、聚丁烯、丁基橡胶、卤化丁基橡胶及其衍生物中的一种或更多种。更优选地,弹性体组合物包含丁基橡胶或溴丁基橡胶。丁基橡胶是由异丁烯和少量二烯烃例如异戊二烯(2-甲基丁-1,3-二烯)制成的共聚物。
通常,丁基橡胶包含约97%的异丁烯和约3%的异戊二烯,并且丁基橡胶可以使用氯化铝催化剂聚合。卤化丁基橡胶如溴代丁基橡胶和氯代丁基橡胶可以通过用溴/氯处理丁基橡胶来制备。应当理解,如本文所用的术语“异丁烯聚合物”旨在涵盖卤化聚合物。
(ii)弹性体组合物可以进一步包含(a)用于异丁烯聚合物或其共聚物的交联剂;和任选的(b)用于交联剂的促进剂。
应当理解,(ii)弹性体组合物可以包含异丁烯聚合物或其共聚物与另一种聚合物(如氯取代的二烯聚合物)的共混物。例如,可以使用丁基橡胶(例如溴代丁基橡胶)和聚氯丁二烯的共混物。聚氯丁二烯与非极性丁基的共混是有利的,因为其允许静电荷的耗散。在自动阀组装过程中和/或在塑料袋中储存期间积聚静电荷可能导致密封件自粘附并在阀组装中造成问题。如果存在,交联剂(也称为固化剂)提供或促进网络形成以产生三维聚合物网络结构。交联剂可以通过与聚合物链上的官能团反应而起作用。交联剂通常包含硫或含硫化合物。交联剂优选基本上不含任何过氧化物固化剂,例如过氧化二异丙苯。
促进剂,如果存在的话,优选包括衍生自取代的二硫代碳酸或其衍生物的多硫化物化合物。多硫化物化合物优选衍生自取代的黄原酸或其衍生物,优选ROC(S)SH型,其中,R通常为烷基。多硫化物化合物中的取代基团通常包含异丙基。多硫化物化合物优选包含三个或更多个桥连硫原子,更优选3,4或5个桥连硫原子。多硫化物化合物优选基本上不含氮、磷和金属元素。有利地,多硫化物化合物包含二异丙基黄原酰多硫化物或由二异丙基黄原酰多硫化物组成。弹性体组合物(ii)通常包含基于组合物中的加速剂和聚合物的总重量的至多3重量%的加速剂,更通常包含基于组合物中的加速剂和聚合物的总重量的至多1.5重量%的加速剂,还更通常包含基于加速剂和聚合物的总重量的至多1重量%的加速剂。
弹性体组合物(ii)中促进剂与交联剂的重量比优选在从1:1到3:1的范围内,更优选地在从1:1到2:1的范围内。
应理解,(ii)弹性体组合物可进一步含有一种或更多种添加剂、加工助剂、交联剂、促进剂和/或填料。它也可以与另外的聚合物或共聚物共混。
包含(ii)弹性体组合物的密封垫圈可以通过常规成型技术生产,例如压塑和/或挤出。
交联反应的引发可以通过任何已知的常规技术实现,例如将制剂加热到至少固化反应温度,固化反应温度通常在130-200℃的范围内。优选的方法包括通过压塑形成橡胶复合物条(通常约1mm厚)。模制温度通常在160-180℃的范围内。固化时间通常为1-10分钟。模制带优选地在空气烘箱中在150℃下典型地后固化1小时。
然后可以使用冲压装置将条制成垫圈。
如本文所述的促进剂在根据本发明的(ii)弹性体组合物中的使用可以消除在交联过程中对游离硫的需要。本文所述的促进剂优选作为液体提供,并且优选与聚合物混溶以提供均匀分散体。已经发现,使用这种促进剂有利于填料分散,并且可以避免对单独的增塑剂的需要。增塑剂的存在是不希望的,因为它们倾向于从材料中浸出。相反,本文所述的促进剂形成或为交联网络的一部分,因此不会浸出到药物介质中。在根据本发明的密封件组合物中,促进剂通常在交联反应期间几乎完全消耗。这导致更清洁的橡胶,并且可萃取物减少。通常,在交联反应过程中基本上不产生亚硝胺。
包含异丁烯聚合物或其共聚物的弹性体组合物描述于例如WO03/078538A1中。
一个或多个密封件(也被称为一个动态密封件或多个动态密封件)
所述一个或多个密封件由(i)弹性体组合物形成,(i)弹性体组合物优选为包含乙烯-丙烯-二烯三元共聚物的弹性体组合物。
因为一个或多个密封件与可在阀体中滑动的阀杆配合,所以这种密封件也可被称为动态密封件。这些密封件的机械性能对于提供产品和喷射剂的耐久性和一致计量是重要的。与乙烯-丙烯-二烯三元共聚物(EPDM)相比,丁基橡胶可显示出较差的压缩永久变形特性,因此当用作本文所述类型的加压分配容器中的动态密封件时,使它们次优。相反,包含乙烯-丙烯-二烯三元共聚物的弹性体组合物(i)具有非常好的机械性能并表现出降低的压缩永久变形,从而使其作为动态密封件更有效。此外,本发明人已发现,当使用包含1,1-二氟乙烷或由1,1-二氟乙烷组成的喷射剂(例如HFA152a)时,包含异丁烯聚合物或其共聚物的弹性体组合物提供有效的泄漏和水分密封(即静态密封)。
用于(i)弹性体组合物的优选的乙烯-丙烯-二烯三元共聚物包含40至70重量%的乙烯、30至50重量%的丙烯和0.5至9重量%的量的ENB(亚乙基降冰片烯)。
更优选地,三元共聚物优选包含45-65重量%乙烯、35-45重量%丙烯和2-8重量%ENB。更优选地,三元共聚物包含50至60重量%乙烯、38至43重量%丙烯和3至7重量%ENB。最优选地,三元共聚物包含约50重量%乙烯、约45重量%丙烯和约5重量%ENB。
乙烯含量可以通过ASTM D3900测定。丙烯含量可以通过ASTM D3900测定。ENB含量可以通过ASTM D6047测定。
三元共聚物可以使用约束几何催化剂***制备。例如,茂金属约束几何催化剂***,例如基于钛单环戊二烯基的催化剂***,优选具有引入其中的硅烷基团。
三元共聚物优选具有10至90,更优选20至80,更优选30至70,还更优选30至50的门尼粘度(ML 1+4,125℃)。最优选地,三元共聚物具有约40的门尼粘度(ML 1+4,125℃)。门尼粘度可以通过ASTM D1646测定。门尼粘度的单位是门尼单位,MU。
优选地,三元共聚物的密度为0.84至0.90g/cm3,更优选0.85至0.87g/cm3,还更优选约0.86g/cm3。密度可以通过ASTM D297测定。
优选地,三元共聚物具有<0.1重量%的灰分含量和<0.4重量%的总挥发物含量。优选地,三元共聚物具有中等分子量分布。
应当理解,(i)弹性体组合物,例如乙烯-丙烯-二烯三元共聚物,可以进一步含有一种或多种添加剂、加工助剂、交联剂、促进剂和/或填料。它也可以与另外的聚合物或共聚物共混。
包含(i)弹性体组合物(例如乙烯-丙烯-二烯三元共聚物)的密封件可以通过常规成型技术,例如压塑和/或挤出来生产。
包含乙烯-丙烯-二烯三元共聚物的弹性体组合物描述于例如WO2017/021698A1中。
总则
除非另有说明,以下描述适用于本发明的所有方面。
现在将进一步描述本发明。在以下段落中,更详细地定义了本发明的不同方面。如此定义的每个方面可以与任何其他一个或多个方面组合,除非清楚地相反指示。特别地,被指示为优选或有利的任何特征可以与被指示为优选或有利的任何其他一个或多个特征组合。
本文所用的术语“密封件”旨在涵盖存在于例如药物分配装置(如定量吸入器)中的任何密封件或其部分,包括但不限于静态或动态的垫圈和密封件。应当理解,密封件可以作为单独的部件提供,或者可以与阀一体地形成,即共同模制。这里使用的术语“密封垫圈”主要用于指静态密封件。
密封件或垫圈还可包括填料,优选矿物填料和/或无机填料。为了使多核芳烃化合物的形成最小化,矿物填料比炭黑优选。合适的实例包括硅酸镁、硅酸铝、氧化钛、氧化锌、碳酸钙、氧化镁、碳酸镁、硅酸镁铝、氢氧化铝、滑石、高岭土和粘土中的任一种,包括其两种或更多种的组合。优选地,填料是或包含硅酸镁、滑石、煅烧粘土、纳米颗粒粘土、高岭土和/或氨基硅烷涂覆的粘土或用钛或锆酸盐偶联剂涂覆的粘土中的一种或多种。填料通常以1-65重量%,优选2-60重量%,更优选5-55重量%的量存在于密封材料中。
适当时,密封件或垫圈可以进一步包括加工助剂,优选低分子量聚乙烯、硬脂酸或有机或非有机硬脂酸酯。加工助剂(例如硬脂酸)可以以至多1重量%的量提供在密封垫圈中。
适当时,密封件或垫圈可进一步包括固化剂或交联剂。例如,密封件或垫圈可以进一步包括过氧化物固化剂、硫或含硫化合物。然而,过氧化物固化剂(例如二烷基过氧化物)比其他固化剂(例如硫)优选,因为其使用使由材料与使用中的醇之间的接触产生的提取物(例如2-巯基苯并噻唑,N-亚硝胺,巯基苯并噻唑二硫化物)的形成最小化。所述固化剂或交联剂(例如,二烷基过氧化物)可以以至多7重量%的量提供在所述密封件中。
所述密封件或垫圈还可包含增强剂、增塑剂、粘合剂、稳定剂、加工助剂、缓凝剂、结合剂、抗氧化剂、润滑剂、颜料、蜡、树脂、抗臭氧剂、主促进剂、次促进剂和/或交联活化剂中的一种或更多种。这些中的一种或更多种可以以高达1重量%的量提供在密封件中。例如,抗氧化剂(例如,辛基化二苯胺)可以以至多0.7重量%的量包含。
应当理解,某些成分可以具有一种以上的效果。例如,氧化锌可用作活化剂和填料。类似地,氧化镁可用作酸吸收剂和填料。
在大多数药物应用中,还需要提取或洗涤固化的弹性体以除去由固化反应和模塑过程产生的表面残余物和副产物。因此,密封件或垫圈优选经受洗涤和/或萃取以减少或消除萃取物和/或可浸出物。例如,溶剂提取和/超临界流体提取。优选醇萃取。密封件或垫圈的醇萃取(例如乙醇萃取)优选在制造密封件或垫圈之后且在组装阀之前进行。该步骤减少或消除了提取物和/或可浸出物。在该方法中,将密封件/垫圈组件装入玻璃柱中并通过回流乙醇洗涤。
适当时,如果需要,密封件或垫圈也可以与热塑性塑料(例如,PBT、尼龙和/或聚缩醛)共模塑。
本发明涉及一种加压分配容器。实例包括药物定量气溶胶吸入器装置、注射器和自动注射器。本文所述的密封件和垫圈的优选用途是在用于分配药物的加压药物定量气溶胶吸入器装置中。
该容器例如可以由基本上不透气和水的任何合适的塑料或金属或玻璃材料制成。合适的塑料材料的例子是聚酯。
图1仅以举例的方式示出了加压分配容器10。加压分配容器10仅作为本发明的可能应用的一个示例示出。本领域技术人员将理解,本发明的其他应用是可能的,并且因此,以下对加压分配容器10的描述不应被视为限制性的。
加压分配容器10可以包括分配容器11,产品12存储在分配容器11中以便定量分配。阀可以通过箍13保持在适当位置以密封分配容器11,箍13被压合到分配容器11的开口颈部。该阀还包括用于将阀密封到分配容器11的密封垫圈14。密封垫圈14可以是静态密封件。
该阀包括阀杆15、阀体16,18和一个或更多个密封件20,21,阀杆15能在阀体16,18内滑动,所述一个或更多个密封件20,21与阀杆15配合以调节流体的排放。
所述一个或更多个密封件20,21可包括内密封件20和外密封件21。内密封件20和外密封件21均可与阀杆15形成动态滑动密封。
本发明适用于各种计量阀,图1的例子只是一种可能的设计。本发明适用于计量阀,该计量阀包括但不限于毛细保持阀和快充快排阀。在文献US6,095,182、GB2401099、GB2340477、EP0803449和EP0801009中更详细地描述了这种计量阀的操作,并且为了更全面地理解计量阀和MDI的操作,读者可以参考这些文献。
本文所用的术语“药物”旨在涵盖可递送或施用至人或动物的任何药物、化合物、组合物、药剂、试剂或产品,例如药物、药品、生物制品和医药产品。实例包括抗过敏药、镇痛药、支气管扩张药、抗组胺药、治疗性蛋白质和肽、镇咳药、心绞痛制剂、抗生素、抗炎制剂、激素或磺胺,例如血管收缩胺、酶、生物碱或类固醇,包括其两种或更多种的组合。具体地,实例包括异丙肾上腺素[α-(异丙胺甲基)原儿茶醇]、去氧肾上腺素、苯丙醇胺、胰高血糖素、肾上腺素、胰蛋白酶、肾上腺素、麻黄碱、那可丁、可待因、阿托品、肝素、***、二氢***酮、麦角胺、东莨菪碱、美沙吡林、氰钴胺素、特布他林、利米特罗、沙丁胺醇、氟尼缩松、秋水仙碱、吡布特罗、倍氯米松、奥西那林、芬太尼和二氢***、链霉素、青霉素、普鲁卡因青霉素、四环素、金霉素和羟基四环素、促肾上腺皮质激素和肾上腺皮质激素(例如,可的松、氢化可的松、醋酸氢化可的松和***龙)、胰岛素、色甘酸钠和莫米松,包括其两种或更多种的组合。
药物可以作为游离碱或作为本领域常规的一种或多种盐使用,例如乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、酒石酸氢盐、溴化物、依地酸钙、樟脑磺酸盐、碳酸盐、氯化物、柠檬酸盐、二盐酸盐、依地酸盐、乙二磺酸盐、雌酚盐、乙磺酸盐、富马酸盐、氟西汀、葡糖酸盐、谷氨酸盐、乙醇酰胂酸盐、己基间苯二酚盐、氢溴酸盐、盐酸盐、羟基萘甲酸盐、碘化物、羟乙基磺酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、硝酸甲酯、甲基硫酸盐、粘酸盐、萘磺酸盐、硝酸盐、双羟萘酸盐、(双羟萘酸盐)、泛酸盐、磷酸盐、二磷酸盐、聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、碱式乙酸盐、琥珀酸盐、硫酸盐、单宁酸盐、酒石酸盐和三乙基碘,包括其两种或更多种的组合。也可以使用阳离子盐,例如碱金属,例如Na和K,以及铵盐和本领域已知为药学上可接受的胺的盐,例如甘氨酸、乙二胺、胆碱、二乙醇胺、三乙醇胺、十八烷基胺、二乙胺、三乙胺、1-氨基-2-丙醇-氨基-2-(羟甲基)丙烷-1,3-二醇和1-(3,4-二羟基苯基)-2异丙胺乙醇。
药物通常是适于吸入的药物,并且可以以用于此目的的任何合适形式提供,例如作为粉末或作为在溶剂或载体液体(例如乙醇)中的溶液或悬浮液。
例如,药物可以是适合于治疗哮喘的药物。实例包括沙丁胺醇、倍氯米松、沙美特罗、氟替卡松、福莫特罗、特布他林、色甘酸钠、布***和氟尼缩松以及生理学上可接受的盐(例如硫酸沙丁胺醇、昔萘酸沙美特罗、丙酸氟替卡松、二丙酸倍氯米松和硫酸特布他林)、溶剂化物和酯,包括其两种或更多种的组合。也可以使用单独的异构体,例如,R-沙丁胺醇。应当理解,药物可以包含一种或多种活性成分,其例子是氟替状的,并且可以任选地与合适的载体例如液体载体一起提供。如果需要,可以包括一种或多种表面活性剂。
包含两种活性成分的制剂的其他实例包括:倍氯米松和福莫特罗;布***和福莫特罗;沙美特罗和氟替卡松;沙丁胺醇和异丙托溴铵;以及福莫特罗和莫米松。包含三种活性成分的制剂的实例包括:福莫特罗、溴环扁吡酯和莫米松;以及倍氯米松、溴环扁吡酯和福莫特罗。
在本文所述的加压分配容器中,待分配的流体通常包括作为载液中的溶液或悬浮液的液体或颗粒产品。载液可优选包含醇,例如乙醇。可以存在一种或多种表面活性剂。油酸和/或甘油中的一种或两种也可以被包括在载液中。
现在将参考以下实例进一步描述本发明。
实例
图2示出了与填充罐的稳定性储存相关的水分含量(ppm)数据,其中密封垫圈包含EPDM。时间:T03=3个月;和T06=6个月。条件:40/75=温度40℃,相对湿度75%。
在40℃/75%RH下储存3个月和6个月之后,水分进入高于当使用常规HFA134a喷射剂时预期的。这可能表明HFA152a比HFA134a更吸湿,可能是由于其更大的偶极矩。结果表明常规EPDM聚合物在该喷射剂的水分进入试验中表现不好。
相反,本发明人已发现,如果密封垫圈包含如本文所述的包含异丁烯聚合物或其共聚物的(ii)弹性体组合物,则在类似条件下水分含量降低。根据本发明的密封垫圈还可以在低氦气渗透性、低偶极矩、渗透性和随温度的蠕变行为的低变化,对喷射剂中的溶解的抗性和低吸水率方面与本文所述的喷射剂相容。
以下进一步示例基于6个月的两个关键性能要求分析:
1.静态泄漏-通过最大限度地减少经由主要大气密封垫圈的泄漏,在产品有效期内将喷射剂蒸气密封在储液罐中;以及
2.水分进入-通过最大限度地减少经由主要大气密封垫圈的进入,防止大气水分在产品有效期内渗透储液罐。
尽管全EPDM阀能够满足所需的USP(美国药典)泄漏规格,具有替代的低GWP(全球变暖潜势)喷射剂(HFA152a),但在本发明中已经开发了EPDM/溴丁基混合阀选项以(i)提供优良的静态泄漏性能和(ii)减少水分进入的量,所述水分进入的量通常与吸湿材料的使用有关,例如喷射剂HFA152a和含有赋形剂(例如乙醇)的HFA152a混合物。
图3中提供的研究数据显示,与仅包含EPDM作为主要大气垫圈密封的类似阀构造相比,使用包含溴丁基(通常例如异丁烯聚合物)垫圈的根据本发明的混合阀构造可实现较低量的静态泄漏。提供了喷射剂HFA152a自身和与乙醇组合的数据。
图4中提供的研究数据表明,与仅包含EPDM作为主要大气垫圈密封的类似阀构造相比,使用包含溴丁基(通常例如异丁烯聚合物)垫圈的根据本发明的混合阀构造可实现较低的水分进入量。提供了喷射剂HFA152a自身和与乙醇组合的数据。
由于HFA152a与pMDI应用中使用的以前的喷射剂相比分子(分子大小、扩散系数和偶极矩)十分不同,本发明已经通过分析和实验确定了pMDI阀弹性体的有利组合,以解决与HFA喷射剂152a相关的挑战性性能特征。
使用的方法
填充:
包装目标填充重量:10g(有和没有乙醇)
含乙醇包装:15%
测试:
泄露测试n=30个包装/时点
水分测试n=3个包装/时点
储存:
所有包装均在环境条件下储存2周隔离期,随后在40℃/75%RH条件下储存所列测试段。
根据欧洲药品管理局标准ICH主题Q1A(R2)/步骤5/新药物质和产品的稳定性试验/稳定性试验指南进行泄漏和水分进入试验:新药物物质和产品的稳定性试验(CPMP/ICH/2736/99)(2003年8月)。
泄漏:
T0=2周环境储存之后测试的包装。
T6=在40℃/75RH下6个月之后测试的包装。在24小时稳定性之后取初始重量,然后在7天环境储存之后取第二重量。
水分进入:
使用库仑计的卡尔费歇尔滴定法。
T3=在40℃/75%RH烘箱中3个月之后进行的测试。
T6=在40℃/75%RH烘箱中6个月之后进行的测试。
Claims (20)
1.一种加压分配容器,所述加压分配容器包括用于待分配产品的容器和固定到所述容器的阀,其中,所述容器容纳喷射剂,所述喷射剂包含1,1-二氟乙烷或其衍生物和可选地乙醇,
其中,所述阀包括阀杆、阀体以及一个或更多个密封件,所述阀杆能在所述阀体内滑动,所述一个或更多个密封件与所述阀杆协作以用于调节流体的排放,
其中,所述阀还包括用于将所述阀密封到所述分配容器的密封垫圈,
其中,所述一个或更多个密封件由(i)弹性体组合物形成,所述(i)弹性体组合物优选为包含乙烯-丙烯-二烯三元共聚物的弹性体组合物,以及
所述密封垫圈由包含异丁烯聚合物或其共聚物的(ii)弹性体组合物形成。
2.根据权利要求1所述的加压分配容器,其中,所述喷射剂包含:
a)HFA152a和可选地乙醇;
b)HFA152a和HFA134a的组合和可选地乙醇;或
c)HFA152a和HFA227ea的组合和可选地乙醇。
3.根据权利要求1或2所述的加压分配容器,其中,所述(ii)弹性体组合物包含聚异丁烯、聚丁烯、丁基橡胶、卤化丁基橡胶及其衍生物中的一种或更多种。
4.根据权利要求3所述的加压分配容器,其中,所述(ii)弹性体组合物包含溴丁基橡胶。
5.根据前述权利要求中任一项所述的加压分配容器,其中,所述(i)弹性体组合物包含乙烯-丙烯-二烯三元共聚物,所述三元共聚物包含45至65重量%的乙烯、40至50重量%的丙烯和0.5至9重量%的量的ENB(亚乙基降冰片烯),其中,所述三元共聚物具有10至90的门尼粘度(ML 1+4,125℃)。
6.根据前述权利要求中任一项所述的加压分配容器,其中,所述一个或更多个密封件和/或所述密封垫圈还包括矿物填料和/或无机填料,所述矿物填料和/或所述无机填料的量优选为1至10重量%。
7.根据权利要求6所述的加压分配容器,其中,所述矿物填料和/或所述无机填料选自硅酸镁、硅酸铝、氧化钛、氧化锌、碳酸钙、氧化镁、碳酸镁、硅酸铝镁、氢氧化铝、滑石、高岭土和粘土中的一种或更多种。
8.根据前述权利要求中任一项所述的加压分配容器,其中,所述一个或更多个密封件和/或所述密封垫圈还包括加工助剂,所述加工助剂优选为低分子量聚乙烯、硬脂酸或有机或非有机硬脂酸盐。
9.根据前述权利要求中任一项所述的加压分配容器,其中,所述一个或更多个密封件和/或所述密封垫圈还包括固化剂。
10.根据前述权利要求中任一项所述的加压分配容器,其中,所述一个或更多个密封件和/或所述密封垫圈还包括增强剂、增塑剂、粘合剂、稳定剂、缓凝剂、结合剂、抗氧化剂、润滑剂、颜料、蜡、树脂、抗臭氧剂、主促进剂、次促进剂或活化剂中的一种或更多种。
11.根据前述权利要求中任一项所述的加压分配容器,其中,所述密封垫圈被限定为静态的,因为所述密封垫圈密封在所述阀的非运动零件之间。
12.根据前述权利要求中任一项所述的加压分配容器,其中,所述一个或更多个密封件被限定为动态的,因为所述一个或更多个密封件密封在所述阀的运动零件之间。
13.根据前述权利要求中任一项所述的加压分配容器,其中,所述一个或更多个密封件安装在所述阀体上。
14.根据前述权利要求中任一项所述的加压分配容器,其中,所述一个或更多个密封件安装在所述阀杆上。
15.根据权利要求14所述的加压分配容器,其中,第一密封件安装在所述阀体上,并且第二密封件安装在所述阀杆上。
16.根据前述权利要求中任一项所述的加压分配容器,其中,所述阀是连续喷射阀。
17.根据前述权利要求中任一项所述的加压分配容器,其中,所述阀还包括计量腔室,并且所述阀是计量阀。
18.根据权利要求17所述的加压分配容器,其中,所述计量阀的所述计量腔室是永久的。
19.根据权利要求17或18所述的加压分配容器,其中,所述计量腔室完全由刚性部件构成,所述刚性部件诸如为由选自聚酯、尼龙、乙缩醛等、不锈钢、陶瓷、玻璃等中的一种或更多种材料形成的部件。
20.根据前述权利要求中任一项所述的加压分配容器,所述加压分配容器是一种药物分配装置;并且可选地,其中,所述药物分配装置是药物定量气溶胶吸入器装置。
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- 2020-02-05 GB GBGB2001537.6A patent/GB202001537D0/en not_active Ceased
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2021
- 2021-01-26 GB GB2211660.2A patent/GB2607500B/en active Active
- 2021-01-26 CA CA3168854A patent/CA3168854A1/en active Pending
- 2021-01-26 US US17/797,417 patent/US20230082549A1/en active Pending
- 2021-01-26 CN CN202180011442.4A patent/CN115397747A/zh active Pending
- 2021-01-26 BR BR112022015395A patent/BR112022015395A2/pt unknown
- 2021-01-26 JP JP2022548181A patent/JP7447289B2/ja active Active
- 2021-01-26 AU AU2021217798A patent/AU2021217798B2/en active Active
- 2021-01-26 WO PCT/GB2021/050175 patent/WO2021156602A1/en active Application Filing
- 2021-01-26 EP EP21702703.6A patent/EP4100337A1/en active Pending
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2024
- 2024-02-28 JP JP2024028119A patent/JP2024052867A/ja active Pending
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JP2023512840A (ja) | 2023-03-29 |
EP4100337A1 (en) | 2022-12-14 |
GB2607500A (en) | 2022-12-07 |
GB202001537D0 (en) | 2020-03-18 |
GB202020387D0 (en) | 2021-02-03 |
JP2024052867A (ja) | 2024-04-12 |
WO2021156602A1 (en) | 2021-08-12 |
JP7447289B2 (ja) | 2024-03-11 |
AU2021217798A1 (en) | 2022-09-15 |
US20230082549A1 (en) | 2023-03-16 |
BR112022015395A2 (pt) | 2022-09-27 |
GB202211660D0 (en) | 2022-09-21 |
CA3168854A1 (en) | 2021-08-12 |
GB2607500B (en) | 2023-11-29 |
AU2021217798B2 (en) | 2024-06-20 |
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