CN111491619A - 用于离子电渗透皮递送曲坦化合物的耐低温的组合物 - Google Patents
用于离子电渗透皮递送曲坦化合物的耐低温的组合物 Download PDFInfo
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- CN111491619A CN111491619A CN201880082074.0A CN201880082074A CN111491619A CN 111491619 A CN111491619 A CN 111491619A CN 201880082074 A CN201880082074 A CN 201880082074A CN 111491619 A CN111491619 A CN 111491619A
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- skin
- triptan compound
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- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 claims abstract description 20
- -1 triptan compound Chemical class 0.000 claims abstract description 16
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Abstract
本发明涉及适合于离子电渗透皮递送曲坦化合物的耐低温的组合物,其包含‑曲坦化合物的盐,优选琥珀酸舒马曲坦,‑多胺,‑一种或更多种二羧酸,‑0.5至10.0重量%(基于组合物的总重量计)的一种或更多种单羧酸,和‑水或含水溶剂混合物。本发明另外涉及该组合物作为离子电渗贴剂的集成组件,优选作为贴剂的阳极储库的用途。
Description
技术领域
本发明涉及适合于离子电渗透皮递送曲坦化合物,优选舒马曲坦的耐低温的组合物。
背景技术
肠胃外施用的透皮途径相比于其它施用的途径提供了许多有利之处。通过皮肤施用药物的方法和装置在药学领域是公知的。典型地,通过使用被动透皮系统(例如透皮治疗系统,TTS)进行透皮施用,所述系统通过扩散过程以限定的速率通过皮肤递送药物物质。因此,对于某些类型的药物物质,透皮药物递送是非常低效的。尤其是,离子化的药物通常不能以治疗有效的速率被动地渗透通过皮肤。
离子电渗的过程最初由LeDuc在1908年描述,并且甚至更早地描述于US 222,276(1879)和US 486,902(1892)中。从那时起,离子电渗已在商业上用于递送带离子电荷的治疗药物分子,如毛果芸香碱、利多卡因、地塞米松和芬太尼。
通常,离子电渗是依赖于这样的基本原理的递送方法,即施加电流可以提供外部能量,以使药物离子能够或增强穿过皮肤,大概是通过增加药物通过皮肤的膜的渗透性实现。当将带正电荷的离子(例如阳离子活性试剂)放置在离子电渗系统的阳极之中或之下时,那么这些离子(在施加电流时)将被迫从阳极移开,并切遵循电场方向朝向放置在邻近皮肤区域上的阴极。在该过程中,增强或促进了阳离子药物通过皮肤的运输。离子电渗可以与不同形式的活性药物成分一起使用,最有利地与带电荷的那些一起使用,它们因此在电场内直接移动穿过屏障(例如皮肤)。
在离子电渗中,不同于上文描述的扩散控制的透皮递送,相对于活性成分的皮肤通量水平,装置的皮肤接触面积和装置内的活性成分浓度不太重要。活性成分通过皮肤的递送在很大程度上取决于所施加的电流,通过该电流可以促使活性成分进入皮肤。
典型的离子电渗药物递送系统包括电解电气系统,该电解电子系统包括待粘附至患者的不同(优选邻近)的皮肤区域的阳极和阴极,每个电极通过电线连接至远程电源(通常是由微处理器控制电气仪表)。已经发布了这种类型的装置,包括具有精益构造的系统(例如,US 5,685,837或US 6,745,071)以及更精密的系统,这些系统基本上是专家已知的。已将利多卡因和芬太尼的离子电渗透皮系统引入美国市场。
通过离子电渗的透皮药物输送是复杂的过程,其可以通过各种参数,如电解质的浓度,离子强度,电极材料的类型、组成和粘度,离子电渗的时间、皮肤电阻或电极的面积大小来影响。通常,对于这些参数对离子电渗过程的各种影响知之甚少。
此外,为了满足严格的盖伦(galenic)要求,透皮离子电渗装置必须含有具有限定的离子强度的限定的电解质浓度,以确保活性物质以期望和恒定的速率传输至皮肤中,和确保透皮施用剂量是安全并且治疗有效的。
“-Patch”(TEVA Pharmaceuticals Industries,Ltd.,用于偏头痛的急性治疗的舒马曲坦离子电渗透皮系统)看起来满足上述盖伦要求。然而,该舒马曲坦组合物在低的温度时不稳定。其要求15℃以上的储存和运输条件。将舒马曲坦组合物暴露至低于15℃的温度导致组合物的不可逆的液化(粘度损失,“漏出”贴剂)和月桂酸的沉淀。
发明内容
鉴于上述,因此本发明的主要目的在于提供曲坦组合物,优选舒马曲坦组合物,其在低的温度,特别是在处于或低于15℃的温度时是稳定的(耐低温稳定性)。特别地,目的在于避免晶体沉淀和保持或甚至提高曲坦组合物与原始Zecuity制剂相比的粘度。_
鉴于上述目的,本发明提供了用于离子电渗透皮递送曲坦化合物,优选舒马曲坦的改进的组合物。
具有上文描述的不利之处的根据US-A 8,366,600的舒马曲坦离子电渗透皮组合物包含
大约3.0%至约5.0%的琥珀酸舒马曲坦;
大约84%至约88%的水;
大约4.0%至约7.0%的烷基化的甲基丙烯酸酯共聚物;
大约1.0%至约6.0%的脂肪酸(例如约1.0%至约5.0%的月桂酸和大约0.05%至约0.75%的己二酸);和
大约0.05%至约0.75%的对羟基苯甲酸甲酯。
根据US-A 8,366,600的组合物展现出多胺(烷基化的甲基丙烯酸酯共聚物)的碱性基团与月桂酸和己二酸的酸性官能(以1为化合价计算)之间的等摩尔比例,从而中和组合物的pH值。
在本发明中,在制剂中增加多胺的量,并且多胺,优选E100的必要的中和通过增加的量的有机酸,特别是增加的量的二羧酸,例如己二酸和/或琥珀酸来进行。对用于TTS中而言必要的粘度可以通过提高溶液的固含量来实现。在多胺和二羧酸的量方面的该改变出人意料地改进了曲坦组合物的耐低温稳定性。
优选的多胺Eudragit E 100由下述三种不同的甲基丙烯酸酯单体制成:比例为约2:1:1的甲基丙烯酸二甲氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯。Eudragit E 100具有碱性官能。这些碱性官能在目前的pH时看起来是质子化的(聚阳离子型),提供了足够的组合物电导率用于其离子电渗透皮应用。该组合物具有比根据US-A 8,366,600的组合物更高的电导率,这是有利的,因为可以将较低的电压用于实现期望的电流。
物料的粘度可以通过调节溶液的固含量而任意调节。因此可以优化计量添加和转移至垫中的物料。以该方式可以使商业贴剂(由于粘度降低)的潜在漏出最小化;因此改进耐低温稳定性。
因此,本发明涉及用于离子电渗透皮递送曲坦化合物的盐的组合物,其包含:
-曲坦化合物的盐,优选琥珀酸盐,
-多胺,
-二羧酸,
-单羧酸,
-水或含水溶剂混合物;和
-任选的一种或更多种添加剂。
在另外的实施方案中,该组合物包含介于10.0与60.0重量%之间的一种或更多种烷基化的甲基丙烯酸酯多胺共聚物,介于0.5与10重量%之间的曲坦化合物的盐,优选舒马曲坦,介于1.0与10.0重量%之间的一种或更多种二羧酸,介于1.0与10.0重量%之间的单羧酸,任选的一种或更多种添加剂和水。
本发明另外包括所述组合物作为用于离子电渗透皮贴剂的组件的用途。
本发明另外包括所述组合物在用于离子电渗透皮施用曲坦化合物,优选舒马曲坦至需要用曲坦化合物治疗的受试者的方法中的用途。
具体实施方式
根据本发明的组合物包含水或含水溶剂混合物。优选地,水或溶剂混合物的份额为至少30重量%,更优选40重量%,相对于组合物的总重量计。根据另外的实施方案,水含量或所述溶剂混合物的份额在40至80重量%范围内。
术语“含水溶剂混合物”通常包括含有水和至少一种另外的溶剂的液体混合物,所述另外的溶剂通常选自极性的、可与水混溶的溶剂,例如醇(例如乙醇、异丙醇、甘油)。
根据本发明的优选实施方案,多胺为Eudragit E 100,其由下述三种不同的甲基丙烯酸酯单体制成:比例为约2:1:1的甲基丙烯酸二甲氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯。
优选地,多胺的份额为介于10.0与30.0重量%之间,优选介于15.0与25.0重量%之间(基于组合物的总重量计)。
在本发明的另外的实施方案中,组合物另外包含至少一种二羧酸和至少一种单羧酸。具体而言,与根据US-A 8,366,600的用于离子电渗装置的曲坦化合物的组合物相比,使一种或多种二羧酸的量增加。已发现,增加的量的多胺连同增加的量的一种或多种有机酸,具体而言,增加的量的二羧酸,例如己二酸和/或琥珀酸一起,改进了组合物的耐低温稳定性。
通过组合上文讨论的多胺与一种或更多种二羧酸和一种或更多种单羧酸,获得对应的多胺盐。这些多胺盐通常是水溶性的并且在水中溶解时形成聚合物电解质。包含所述多胺盐的本组合物特别适合作为离子电渗装置中的曲坦类,优选舒马曲坦的载体或储库。
术语“二羧酸”通常包括被两个羧酸官能团取代的有机化合物,所述化合物包括直链、支链和环状化合物,所述化合物可以是饱和的或不饱和的。例如,二羧酸可以选自C4至C10二羧酸。二羧酸的实例包括琥珀酸、戊二酸、己二酸和庚二酸;优选的是琥珀酸和己二酸。
在另外的实施方案中,组合物可以含有包含至少两种二羧酸的组合。
优选地,组合物中的一种或多种二羧酸的总量为介于0.5与10.0重量%之间,优选介于1.0与5.0重量%之间(基于组合物的总重量计)。
术语“单羧酸”通常包括被一个羧酸官能团取代的有机化合物,所述化合物包括直链、支链和环状化合物,所述化合物可以是饱和的或不饱和的。例如,单羧酸可以选自C6至C22单羧酸。单羧酸的实例包括饱和酸,如癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸和花生酸,或含有双键的那些,如肉豆蔻油酸、棕榈油酸、油酸和亚油酸;优选的是月桂酸。
在另外的实施方案中,组合物可以含有包含至少两种单羧酸的组合。
优选地,组合物中的一种或多种单羧酸的总量为介于0.5与5.0重量%之间,优选介于2.0与4.0重量%之间(基于组合物的总重量计)。
通常调节一种或多种单羧酸和一种或多种二羧酸的量,从而至少足以使一种或多种多胺和/或存在于所述组合物中的其它化合物溶解,以获得具有期望的性质,特别是半固体稠度以及皮肤粘合性质的水凝胶组合物。
碱性官能(来自多胺)比游离酸官能(例如来自月桂酸、己二酸、琥珀酸等)的比例优选为1.25以上,更优选1.28以上并且最优选1.30以上。如下计算该比例:
酸的量[克]x分子量x化合价=酸摩尔数
(己二酸和琥珀酸的化合价为2,不同之处在于结合至舒马曲坦的琥珀酸(其化合价为1)的对应量;月桂酸的化合价为1)。
多胺:
多胺的量[克]x 0.18(=Eudragit的碱值,根据制造商说明书)=克KOH(碱的当量)。
克KOH/56.11(=KOH的分子量)=碱摩尔数
碱/酸比例:
“碱摩尔数”比“酸摩尔数”的比例为碱/酸比例。
术语“曲坦化合物”包括曲坦类化合物、衍生物和盐。该术语还包括含有2-(1H-吲哚-3-基)-N,N-二甲基乙胺结构部分的化合物。曲坦化合物的实例包括,但不限于,阿莫曲坦、夫罗曲坦、依利曲坦、佐米曲普坦、利扎曲普坦、舒马曲坦、那拉曲坦及其药学上可接受的盐。优选的曲坦为舒马曲坦和优选的盐为琥珀酸盐。
如上文所描述,将本发明的组合物配制为含水组合物,特别是配制为水凝胶组合物。在另外的实施方案中,所述含水组合物具有3至8,优选4.0至6.0或最优选4.3至5.8的pH。
通常,优选调节和保持所述含有水的组合物中的pH,从而在将组合物施加至皮肤时(例如在透皮或离子电渗施用期间),它们基本上不影响皮肤的pH。
根据本发明的组合物可以任选含有一种或更多种另外的添加剂。所述添加剂包括,但不限于选自包括下组的添加剂:溶解促进剂、皮肤渗透促进剂、防腐剂和抗微生物剂。
在此方面,术语“溶解促进剂”通常涉及能够提高阳离子活性试剂在组合物内的溶解度的化合物。这可以通过调节所述阳离子活性试剂与组合物中存在的其它组分之间可能的相互作用或通过另外引入合适的赋形剂来实现。
替代地,可以通过改变活性试剂的晶体变型实现其溶解性。溶解促进剂的实例包括,但不限于,水;二醇,如丙二醇和甘油;一元醇,如乙醇、丙醇和更高级的醇;二甲亚砜(DMSO)、二甲基甲酰胺、N,N-二甲基乙酰胺、N-取代的烷基-氮杂环烷基-2-酮。如上文已经描述,选自二羧酸的组的化合物特别有效地用于增强一种或更多种多胺的溶解性。
另外,术语“皮肤渗透促进剂”特别包括能够提高皮肤对于组合物中所含有的活性试剂,特别是阳离子活性试剂的渗透性的化合物。由于皮肤渗透性方面的该提高,也提高了一种或多种活性试剂渗透通过皮肤并且进入血液循环的速率。通过使用所述皮肤渗透促进剂导致的增强的渗透可以通过使用本领域通常已知的扩散池(diffusion cell)设备测量活性试剂扩散通过动物或人类皮肤的速率来分析和确认。
渗透促进剂的实例包括,但不限于,二甲亚砜(DMSO)、N,N-二甲基乙酰胺(DMA)、癸基甲基亚砜(C10MSO)、聚乙二醇单月桂酸酯(PEGML)、丙二醇(PG)、丙二醇单月桂酸酯(PGML)、甘油单月桂酸酯(GML)、卵磷脂、1-取代的烷基氮杂环烷基-2-酮、特别是1-正十二烷基氮杂环庚烷-2-酮、醇等。渗透促进剂也可以选自植物油,例如红花油、棉籽油或玉米油。也可以使用包含两种或更多种不同渗透催进剂的组合。
另外,术语“抗微生物剂”通常包括能够防止微生物在药物配制剂中,特别是在根据本发明的组合物中生长的试剂。合适的抗微生物剂的实例包括,但不限于,氯己定的盐,如丁基氨基甲酸碘代丙炔酯、重氮烷基脲、氯己定二葡糖酸盐、乙酸氯己定、氯己定羟乙基磺酸盐和盐酸氯己定。也可以使用其它阳离子抗微生物剂如苯扎氯铵、苄索氯铵、三氯卡班、聚六亚甲基双胍、十六烷基氯化吡啶鎓、甲苄索氯铵。
其它抗微生物剂包括,但不限于,卤化酚类化合物,如2,4,4'-三氯-2-羟基二苯醚(三氯生);对氯间二甲苯酚(PCMX);对羟基苯甲酸甲酯;和短链醇,如乙醇、丙醇等。优选地,一种或多种所述抗微生物剂的总浓度在0.01至2重量%范围内,相对于其中包括它的组合物的总重量计。
在另外的实施方案中,组合物可以包含介于0.01与1.0重量%之间,优选介于0.09与0.2重量%之间,更优选约0.10的对羟基苯甲酸甲酯(尼泊金,nipagine)。
根据另外的实施方案,本发明的组合物具有粘合性质,以确保组合物在透皮药物施用的整个时间期间在施加的位置处保持与皮肤直接和完全接触。可以通过将一种或更多种粘合性聚合物引入所述组合物来获得粘合性。适合于该目的的粘合性聚合物是技术人员通常已知的。优选地,将具有粘合性质的多胺或多胺盐用作一种或多种所述粘合性聚合物。
优选地,本发明的组合物是自粘性的。为了使得组合物自粘,它们可以另外含有选自增粘剂的组的一种或更多种添加剂,该组包括,但不限于,烃树脂、松香衍生物、二醇(如甘油、1,3-丁二醇、丙二醇、聚乙二醇)。
本发明另外涉及可以由组合上文描述的实施方案的两个或更多个或由组合贯穿本发明的上文描述的实施方案的任一个的上述描述提及的一个或更多个单独的特征产生的本发明的任意实施方案。
通常,本发明的组合物可以通过常规的方法制造。宽泛地讲,本发明的组合物可通过将各种成分(即曲坦、多胺、酸、添加剂)溶解或分散在水或含水溶剂混合物中而获得。然后可以将得到的混合物铺展在平坦的表面上或倾倒至模具中或挤出,然后使其固化以获得具有期望的形状的水凝胶组合物。
本发明另外包括一种或多种上文描述的组合物作为离子电渗贴剂的集成组件,优选作为贴剂的阳极储库的用途。优选地,在制造期间将这样的组合物引入所述离子电渗贴剂,以形成贴剂的阳极储库。上文提及的施用形式可通过本领域通常已知的制造方法获得。EP-A 2 285 362示出了可以如何将一种或多种上述组合物包括在离子电渗装置中。
该方法另外包括用于透皮施用的离子电渗方法。通常,上文提及的方法包括下述步骤:将根据本发明的组合物施加至所述受试者的皮肤,和使得组合物中含有的活性试剂,例如舒马曲坦从其中释放和透过皮肤渗透和进入所述受试者的血液循环。通过离子电渗增强该过程。
实施例
在下文借助于实施例连同附图阐述本发明及其有效性。
图1显示了根据US-A 8,366,600的组合物在4℃和15℃时随时间流逝的粘度下降。
方法
电导率测量通过VWR EC 300电导仪来进行。
通过Seven Compact pH/离子计S220测量pH。
粘度测量通过Thermo Scientific Haake RheoStress 6000流变仪进行。
实验程序
采用标准实验室设备(搅拌器、水浴、玻璃仪器)制备组合物。如下制备包含Eudragit E 100的组合物:
1.用水填充反应器容器
2.在连续搅拌下添加对羟基苯甲酸甲酯(尼泊金,Nipagin)
3.预混合添加至容器中的Eudragit E100、月桂酸和己二酸
4.将溶液加热至80℃维持2h,同时连续搅拌
5.将溶液冷却至25℃。
最终组成和测量的关键参数汇总于表1(根据US-A 8,366,600的组合物)、2(具有增加的量的Eudragit E 100和己二酸的组合物)中。
表1:根据US-A 8,366,600的组合物的组成和参数
对比实施例(US-A 8,366,600,第[0063]段)
*参见表2下的解释
具有增加的量的Eudragit E 100和己二酸的耐低温的组合物(实施例1-7)
通过增加的量的己二酸和Eudragit E 100获得耐低温的组合物。得到的制剂及其关键参数示于表2中。
表2:具有Eudragit E 100和己二酸和月桂酸的耐低温的组合物
*
-差(在4℃在3天或更短之后不可逆地沉淀;降低的粘度)
+好(在4℃在3天之后可逆地沉淀;稳定的粘度)
++非常好(在4℃在在几周之后非常少的可逆沉淀,非常小的晶体;稳定的粘度)
+++优异(在4℃在在几周之后没有沉淀;稳定的粘度)
实施例3的耐低温稳定性示于图2中。
临床前研究
通过使用根据US-A 8,366,600第[0063]段的对比实施例(参见表1)和根据本发明的实施例4(参见表2)的组合物,按每个制剂在3只雌性SPF小型猪中进行临床前研究。将两个含有相同制剂的离子电渗透皮贴剂(一个经活化和一个未活化)以贴皮方式在每只动物上放置4小时的时间。贴剂中的所有药物垫含有104mg琥珀酸舒马曲坦。暴露时间为4小时。在以下时间点进行才采血:处理前,和处理后15分钟,30分钟,60分钟,90分钟,2、3、4、4.5、5、6、8、10、12和16小时。使用用于样品制备的固相萃取,然后LC-MS/MS,测定血浆样品中的舒马曲坦的浓度。研究的结果示于图3中。
图3显示了使用根据对比实施例和根据实施例4的组合物的舒马曲坦的时间依赖性血浆浓度。
Claims (12)
1.用于离子电渗透皮递送曲坦化合物的盐的组合物,其包含:
-曲坦化合物的盐,
-多胺,
-一种或更多种二羧酸,
-0.5至10.0重量%(基于组合物的总重量计)的一种或更多种单羧酸,和
-水或含水溶剂混合物。
2.根据权利要求1所述的组合物,其中所述曲坦化合物为含有2-(1H-吲哚-3-基)-N,N-二甲基乙胺结构部分的化合物。
3.根据权利要求2所述的组合物,其中所述曲坦化合物为阿莫曲坦、夫罗曲坦、依利曲坦、佐米曲普坦、利扎曲普坦、舒马曲坦或那拉曲坦,优选舒马曲坦。
4.根据权利要求1-3任一项所述的组合物,其中所述盐为琥珀酸盐。
5.根据权利要求1-4任一项所述的组合物,其中所述一种或更多种二羧酸选自C4至C10二羧酸。
6.根据权利要求5所述的组合物,其中所述一种或更多种二羧酸选自琥珀酸、戊二酸、己二酸和庚二酸,优选选自琥珀酸和己二酸。
7.根据权利要求1-6任一项所述的组合物,其中所述多胺由下述三种不同的甲基丙烯酸酯单体制成:甲基丙烯酸二甲氨基乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯。
8.根据权利要求1-7任一项所述的组合物,其中所述一种或更多种单羧酸选自C6至C22单羧酸。
9.根据权利要求1-8任一项所述的组合物,其中所述一种或更多种单羧酸选自癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、肉豆蔻油酸、棕榈油酸、油酸和亚油酸。
10.根据权利要求1-9任一项所述的组合物,其另外包含一种或更多种添加剂。
11.根据权利要求1所述的组合物作为离子电渗贴剂的集成组件,优选作为所述贴剂的阳极储库的用途。
12.用于透皮施用曲坦化合物的离子电渗方法,所述方法包括以下步骤:将根据权利要求1所述的组合物施加至受试者的皮肤,和使得所述组合物中含有的所述曲坦化合物从其中释放和透过皮肤渗透和进入所述受试者的血液循环,其中通过离子电渗增强该过程。
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CN104027885A (zh) * | 2008-06-19 | 2014-09-10 | 纽帕特公司 | 用于曲坦类化合物离子电渗疗法的多胺增强制剂 |
US20100209484A1 (en) * | 2009-02-13 | 2010-08-19 | Hoo-Kyun Choi | Transdermal Triptan Delivery System |
WO2011046927A1 (en) * | 2009-10-13 | 2011-04-21 | Nupathe,Inc. | Transdermal methods and systems for the delivery of rizatriptan |
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WO2019121297A1 (en) | 2019-06-27 |
BR112020010146A2 (pt) | 2020-10-13 |
CN111491619B (zh) | 2024-06-07 |
US20200330434A1 (en) | 2020-10-22 |
JP7263359B2 (ja) | 2023-04-24 |
JP2021506865A (ja) | 2021-02-22 |
EP3727331A1 (en) | 2020-10-28 |
CA3086494A1 (en) | 2019-06-27 |
US11464760B2 (en) | 2022-10-11 |
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