CN101027057A - 用于药物输送的二酮哌嗪盐、二酮吗啉盐或二酮二氧杂环己烷盐 - Google Patents
用于药物输送的二酮哌嗪盐、二酮吗啉盐或二酮二氧杂环己烷盐 Download PDFInfo
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Abstract
本发明提供了一种生物活性试剂输送组合物,所述组合物包括二酮哌嗪羧酸盐。本发明还提供了用于制备和使用所述生物活性试剂输送组合物的相关方法。
Description
相关申请
本申请根据35 U.S.C.§119(e)要求2004年8月23日递交的美国临时专利申请60/603,761的优先权。
技术领域
本发明一般属于与小分子和大分子药物相关的药物输送领域。更具体地,本发明涉及2,5-二酮哌嗪盐、它们在形成包括治疗剂、预防剂和诊断剂的药物中的用途、用于药物输送的稳定试剂和系统。
背景技术
药物输送在药学领域中是一项具有持久挑战性的工作,特别是当药物在服药患者体内的场所不稳定和/或难以被吸收时。一类这种药物包括2,5-二酮哌嗪,该化合物由以下所示的通式1的化合物来表示,其中,E=N。
式1
已经表明这些2,5-二酮哌嗪可用在药物释放中,特别是那些带有酸性R基团的2,5-二酮哌嗪(参见例如,标题为“Self AssemblingDiketopiperazine Drug Delivery System”的US专利5,352,461,标题为“Method For Making Self-Assembling Diketopiperazine Drug DeliverySystem”的5,503,852,标题为“Microparticles For Lung DeliveryComprising Diketopiperazine”的6,071,497和标题为“Carbon-SubstitutedDiketopiperazine Delivery System”的6,331,318,上述文献通过引用全文插入此处,尤其是以上文献关于二酮哌嗪和二酮哌嗪作为媒介的药物输送系统的教导)。二酮哌嗪可以形成混入药物的颗粒或形成药物可以吸附到其上的颗粒。药物和二酮哌嗪的组合可以使药物稳定性改善。这些颗粒可以通过各种给药途径来给予。作为干粉,这些颗粒可以根据颗粒尺寸通过吸入输送到呼吸系统的特定区域。另外,可以将颗粒制得足够小用于混入静脉悬浮液剂型中。还可以采用混入悬浮液、药片或胶囊中的颗粒;或采用溶在适当溶剂中的颗粒进行口服输送。这些二酮哌嗪也可以促进缔合药物的吸收。虽然如此,但是当二酮哌嗪是二酸或是以二酸形式存在时仍会出现很多困难,因为这些二酸在非碱性pH下(即,中性或酸性pH)溶解受限。还出现另一个难点,原因是这些二酸二酮哌嗪可以与一些药物形成不利的缔合。
因此,需要一种二酮哌嗪组合物,该组合物在中性和/或酸性pH下具有高溶解度,并且需要一种以上组合物在制造治疗组合物中的使用方法。
发明内容
本发明提供了一种改善的药物释放系统,所述药物释放系统包括杂环化合物的羧酸盐以及一种或更多种药物的组合。在本发明的一个实施方式中,杂环化合物形成混合有待释放药物的微粒。这些微粒包括微胶囊,该微胶囊具有仅由杂环化合物构成的外壳或具有由杂环化合物与一种或更多种药物组合构成的外壳。本发明的杂环化合物包括,但不限于,二酮哌嗪、二酮吗啉和二酮二氧杂环己烷和它们的取代类似物。本发明的杂环组分包括带有相对杂原子(opposing heteroatom)和未成键电子对的刚性六元环。
具体优选的实施方式包括,但不限于,3,6-二(4-氨基丁基)-2,5-二酮哌嗪的衍生物,例如,3,6-二(琥珀酰-4-氨基丁基)-2,5-二酮哌嗪、3,6-二(马来酰-4-氨基丁基)-2,5-二酮哌嗪、3,6-二(柠康酰-4-氨基丁基)-2,5-二酮哌嗪、3,6-二(戊二酰-4-氨基丁基)-2,5-二酮哌嗪、3,6-二(丙二酰-4-氨基丁基)-2,5-二酮哌嗪、3,6-二(草酰-4-氨基丁基)-2,5-二酮哌嗪和3,6-二(富马酰-4-氨基丁基)-2,5-二酮哌嗪(此后被称为“富马酰基二酮哌嗪”或“FDKP”)。另外,前述化合物的不对称衍生物也是本发明考虑的。然而,此处应特别注意到,2,5-二天冬氨酰-3,6-二酮哌嗪和2,5-二谷氨酰-3,6-二酮哌嗪的锂盐(以下进一步限定)被认为不包括在本发明的范围内,并且同样因此特别要求放弃被保护。
可用在本发明的药物释放系统中的典型药物包括,但不限于,胰岛素和其它荷尔蒙、肽、蛋白质、多糖(例如肝磷脂)、核酸(例如,质粒、低聚核苷酸、反意或siRNA)、脂类和脂多糖、抗凝血剂、细胞毒素试剂、抗原和抗体以及具有生物活性的有机分子,例如,抗生素、消炎试剂、抗病毒试剂、血管活性和神经活性试剂中的一些。
在本发明的一个实施方式中,提供了一种根据如下式1的杂环化合物的药学上可接受盐:
式1
其中,R1或R2包括至少一个羧酸官能团,E1和E2包括N或O,所述盐还包括至少一种阳离子。在另一实施方式中,杂环化合物包括二酮哌嗪。在另一实施方式中,羧酸基团位于末端。在药学上可接受盐的另一实施方式中,R1和R2包括4-X-氨基丁基,X选自由琥珀酰、戊二酰、马来酰和富马酰组成的组。在另一实施方式中,阳离子选自由钠、钾、钙、锂、三乙胺、丁基胺、二乙醇胺和三乙醇胺组成的组。
在本发明的另一实施方式中,药学上可接受盐不是2,5-二天冬氨酰-3,6-二酮哌嗪或2,5-二谷氨酰-3,6-二酮哌嗪的锂盐。
在本发明的实施方式中,提供了一种治疗组合物,该组合物包括根据式1的杂环化合物的药学上可接受盐,其中,R1或R2包括至少一个羧酸官能团;E1和E2包括N或O;所述盐还包括至少一种阳离子;该组合物还包括一种生物活性试剂。适于包括在本发明的组合物中的生物活性试剂包括荷尔蒙、抗凝血剂、免疫调节剂、细胞毒素试剂、抗生素、抗病毒试剂、反意序列、抗原、抗体和其活性片段和其类似物。在一个实施方式中,生物活性试剂是胰岛素。
在另一实施方式中,本发明的治疗组合物被配制成液体,例如,溶液或悬浮液。
在另一实施方式中,本发明的治疗组合物是沉淀物,该沉淀物被配制成适于口服、口腔给药、直肠给药或阴道给药的固体剂型。固体剂型可以是胶囊、药片和栓剂。
在一个实施方式中,本发明的治疗组合物是干粉,所述干粉的颗粒具有约0.5微米-10微米的直径。在该实施方式的一个方面中,干粉适于肺部给药。
在本发明的另一实施方式中,提供了一种制备用于药物释放的固体组合物的方法,所述方法包括:制备包含生物活性试剂和杂环化合物的药学上可接受盐在溶剂中的溶液,并将所述溶剂通过如下方法除去,所述方法选自由蒸馏、蒸发和冻干法组成的组。在一个实施方式中,该杂环化合物的药学上可接受盐具有根据式1的结构,其中,R1或R2包括至少一个羧酸官能团,E1和E2包括N或O,所述盐还包括至少一种阳离子。
在本发明的另一实施方式中,制备用于药物输送的固体组合物的方法还包括如下步骤:将所述固体微粉化以形成干粉。
在本发明的实施方式中,提供了一种制备用于药物输送的干粉的方法,所述方法包括,将杂环化合物的药学上可接受盐和生物活性试剂的溶液喷雾干燥以形成干粉,其中,所述干粉释放生物活性试剂。在一个实施方式中,该杂环化合物的药学上可接受盐具有根据式1的结构,其中,R1或R2包括至少一个羧酸官能团,E1和E2包括N或O,所述盐还包括至少一种阳离子。在另一实施方式中,干粉的颗粒适于肺部释放。在另一实施方式中,干粉的颗粒具有小于2的粗糙度。
在本发明的实施方式中,提供了一种用于输送生物活性试剂的组合物,其中,所述组合物包括杂环化合物的药学上可接受盐和生物活性试剂,经喷雾干燥形成干粉使得所述干粉释放所述生物活性试剂。在一个实施方式中,所述杂环化合物的药学上可接受盐具有根据式1的结构,其中,R1或R2包括至少一个羧酸官能团,E1和E2包括N或O,所述盐还包括至少一种阳离子。在另一实施方式中,干粉的颗粒适于肺部释放。在另一实施方式中,干粉的颗粒具有小于2的粗糙度。
在本发明的另一实施方式中,提供了一种用于药物输送的微粒系统,所述系统包括杂环化合物的药学上可接受盐和生物活性试剂的组合物,并且其中,所述组合物释放生物活性试剂。在一个实施方式中,杂环化合物的药学上可接受盐具有根据式1的结构,其中,R1或R2包括至少一个羧酸官能团,E1和E2包括N或O,所述盐还包括至少一种阳离子。所述生物活性试剂还可以包括荷尔蒙、抗凝血剂、免疫调节剂、细胞毒素试剂、抗生素、抗病毒试剂、反意序列、抗原、抗体和其活性片段和其类似物。
在本发明的另一实施方式中,微粒系统的组合物是干粉,该干粉在肺部系统中释放生物活性试剂。组合物还可以被输送到肺部系统中。微粒系统的组合物可以在被输送到肺部系统后被吸收到全身血液循环中或局部作用于肺脏中。
在本发明的实施方式中,微粒系统的组合物包括用于药物输送的液体,其中,二酮哌嗪促进生物活性试剂的吸收。在一个实施方式中,口服该液体。
在本发明的另一实施方式中,微粒系统的组合物包括沉淀物,其中,二酮哌嗪促进生物活性试剂的吸收。在一个实施方式中,口服该沉淀物。
在本发明的实施方式中,提供了一种用于将颗粒输送到肺部系统中的方法,所述方法包括:经由吸入给予需要治疗的患者以干粉形式的有效量的生物活性试剂,所述干粉通过如下方法制备:将包括杂环化合物的药学上可接受盐和生物活性试剂的组合物的溶液喷雾干燥,其中,所述干粉在所述肺部系统中释放所述生物活性试剂。在一个实施方式中,该杂环化合物的药学上可接受盐具有根据式1的结构,其中,R1或R2包括至少一个羧酸官能团,E1和E2包括N或O,所述盐还包括至少一种阳离子。
附图说明
图1描述了由根据本发明的一个方面的富马酰二酮哌嗪(FDKP)二钠盐制备的颗粒的激光衍射颗粒尺寸分析。(A)制备方法A;(B)制备方法B。
图2描述了通过激光衍射测定的根据本发明的教导制备的包含25%胰岛素(w∶w)的FDKP二钠盐的配制品的颗粒尺寸。
图3描述了根据本发明的教导制备的包含25%胰岛素的FDKP二钠盐的喷雾干燥微粒制剂的扫描电子显微镜图(SEM)。
图4描述了与对照冻干的粉末(阴影线)相比,根据本发明的教导制备的包含25%胰岛素的FDKP二钠盐/胰岛素配制品的喷雾干燥微粒(点画线)的加速稳定性研究。
图5描述了与对照冻干的粉末相比,溶液浓度对根据本发明的教导制备的包含25%胰岛素的FDKP二钠盐/胰岛素配制品的喷雾干燥微粒的胰岛素稳定性的影响。
图6描述了根据本发明的教导通过溶剂/反溶剂沉淀方法形成的胰岛素/FDKP二钠盐微粒的SEM分析。
图7描述了通过激光衍射测定的根据本发明的教导制备的包含25%胰岛素(w∶w)的FDKP二铵盐/胰岛素配制品的喷雾干燥微粒的颗粒尺寸。
图8描述了通过激光衍射测定的根据本发明的教导制备的包含50%胰岛素(w∶w)的FDKP二铵盐/胰岛素配制品的喷雾干燥微粒的颗粒尺寸。
图9描述了通过激光衍射测定的根据本发明的教导制备的包含25%胰岛素(w∶w)的琥珀酰二酮哌嗪(SDKP)二铵盐的喷雾干燥微粒的颗粒尺寸。
图10描述了根据本发明的教导采用25%胰岛素配制的FDKP铵盐的SEM。
图11描述了根据本发明的教导采用25%胰岛素配制的SDKP铵盐的SEM。
图12描述了与对照冻干的粉末相比,根据本发明的教导制备的包含25%或50%胰岛素的FDKP二铵盐/胰岛素配制品的喷雾干燥微粒的加速稳定性研究。
图13描述了与对照冻干的粉末相比,在进行根据本发明的教导制备的包含25%或50%胰岛素的FDKP二铵盐/胰岛素配制品的喷雾干燥微粒的加速稳定性研究期间,A21降解物的生成。
图14描述了与对照冻干的粉末相比,根据本发明的教导制备的包含25%胰岛素的SDKP二铵盐/胰岛素配制品的喷雾干燥微粒的加速稳定性研究。
图15描述了与对照冻干的粉末相比,在进行根据本发明的教导制备的包含25%胰岛素的SDKP二铵盐/胰岛素配制品的喷雾干燥微粒的加速稳定性研究期间,A21降解物的生成。
图16描述了根据本发明的教导制备的包含浓度增加的胰岛素的喷雾干燥FDKP二钠盐/胰岛素颗粒的空气动力学性能。
图17描述了根据本发明的教导制备的包含浓度增加的胰岛素的喷雾干燥FDKP二铵盐/胰岛素颗粒的空气动力学性能。
术语定义
在阐述本发明以前,对此后使用的某些术语提供一些解释是有益的。
酸性:在本文中,“酸性”指pH范围为0到至多6,但不包括6。
碱性:在本文中,“碱性”指pH范围为8到至多14,但不包括14。
生物试剂:见以下“药物”。
货物:见以下“药物”。
二酮哌嗪:在本文中,“二酮哌嗪”或“DKP”包括二酮哌嗪和其衍生物和修饰物,这些衍生物和修饰物落在式1的范围内。
药物:在本文中,“药物”、“货物”或“生物试剂”指与本文所讨论的微粒混合的具有药学活性的试剂。实例包括蛋白质和肽(其中,蛋白质被定义为由100个或更多个氨基酸残基构成,肽是小于100个氨基酸残基),例如,胰岛素和其它荷尔蒙;多糖,例如,肝磷脂;核酸,例如,质粒、低聚核苷酸、反意序列或siRNA;脂类和脂多糖;和具有生物活性的有机分子,例如,抗生素、消炎试剂、抗病毒试剂、血管活性和神经活性试剂中的一些。具体实例包括荷尔蒙、抗凝血剂、免疫调节剂、细胞毒素试剂、抗生素、抗病毒试剂、反意序列、抗原和抗体。
干粉:在本文中,“干粉”指未悬浮在或未溶解在推进剂、载体或其它液体中的精细颗粒组合物。这并不意味着其暗示所有水分子全部不存在。
微粒:在本文中,术语“微粒”包括微胶囊,该微胶囊具有仅由二酮哌嗪构成的外壳或具有由二酮哌嗪与一种或更多种药物组合构成的外壳。它还包括微球(包含分散在整个球体的药物)、不规则形状的颗粒和如下颗粒,即其中药物被涂敷在该颗粒的表面上或填充到其中的空隙中的颗粒。
中性:在本文中,“中性”指pH范围为6到至多8,但不包括8。
弱碱性:在本文中,“弱碱性”指pH范围为8到至多10,但不包括10。
具体实施方式
本发明提供了一种改善的药物输送系统,该药物释放系统包括杂环化合物的羧酸盐,以及一种或更多种药物。在本发明的一个实施方式中,杂环化合物形成混合有待输送药物的微粒。这些微粒包括微胶囊,该微胶囊具有仅由杂环化合物构成的外壳或具有由杂环化合物与一种或更多种药物组合构成的外壳。本发明的杂环化合物包括,但不限于,二酮哌嗪、二酮吗啉和二酮二氧杂环己烷和它们的取代类似物。本发明的杂环组分包括带有相对杂原子和未成键电子对的刚性六元环。
本发明的一个方面包括一种药物输送系统,该药物释放系统包括杂环化合物的羧酸盐以及一种或更多种药物的组合。在本发明的一个实施方式中,杂环化合物形成混合有待输送药物的微粒。这些微粒包括微胶囊,该微胶囊具有仅由杂环化合物构成的外壳或具有由杂环化合物与一种或更多种药物组合构成的外壳。这种外壳可以围绕核心材料。这些外壳还可以围绕或构成要么是实心的要么是空心的或其组合的微球,该微球包含一种或更多种分散在整个球体和/或吸附在球体表面上的药物。外壳还可以仅围绕具有不规则形状的微粒或围绕这种微粒与前述微球组合的微粒。
在用于肺部释输送放的优选实施方式中,微粒为约0.1微米到约10微米(以直径计)。在药物输送系统中,这些微粒具有令人希望的尺寸分布和良好的药物耐受性。
本发明的杂环化合物包括,但不限于,二酮哌嗪、二酮吗啉和二酮二氧杂环己烷和它们取代类似物。这些杂环组分包括带有相对杂原子和未成键电子对的刚性六元环。二酮哌嗪和其类似物的通式示于如下式1化合物中。
式1
在式1化合物中,在1位和4位上的环原子E1和E2是O或N。分别位于3位和6位的侧链R1和R2中的至少一个包含羧酸基团(即,OR)。在本发明的一个实施方式中,这些羧酸基团沿着侧链(R1和/或R2)作为悬垂基团(pendent group),在另一实施方式中,羧酸位于链内(酯),在另一实施方式中,羧酸基团是末端基。
合成二酮哌嗪的通用方法是本领域已知的,并且已经在美国专利5,352,461、5,503,852和6,331,318中进行了描述,这些文献通过以上引用已经引入和插入此处。在本发明的优选实施方式中,二酮哌嗪是3,6-二(4-氨基丁基)-2,5-二酮哌嗪的衍生物,该化合物可以通过氨基酸赖氨酸的缩合形成。示例性的衍生物包括,3,6-二(琥珀酰-4-氨基丁基)-(即琥珀酰二酮哌嗪或SDKP)、3,6-二(马来酰-4-氨基丁基)-、3,6-二(柠康酰-4-氨基丁基)-、3,6-二(戊二酰-4-氨基丁基)-、3,6-二(丙二酰-4-氨基丁基)-、3,6-二(草酰-4-氨基丁基)-和3,6-二(富马酰-4-氨基丁基)-2,5-二酮哌嗪(此后被称为富马酰二酮哌嗪或FDKP)。另外,前述化合物的不对称衍生物也是本发明考虑的。然而,此处特别注意到,2,5-二天冬氨酰-3,6-二酮哌嗪和2,5-二谷氨酰-3,6-二酮哌嗪的锂盐被认为不包括在本发明的范围内,并且同样因此特别要求放弃被保护。这些要求放弃被保护的化合物的游离酸分别描述在如下式2和式3中。
式2
(5-羧甲基-3,6-二氧代-哌嗪-2-基)-乙酸
式3
3-[5-(2-羧基-乙基)-3,6-二氧代-哌嗪-2-基]-丙酸
为了方便,式2的化合物此后将被称为2,5-二天冬氨酰-3,6-二酮哌嗪。式3的化合物此后被称为2,5-二谷氨酰-3,6-二酮哌嗪。应理解到,所有基于式1的其它杂环化合物被认为在本发明的范围内。
为了示例性目的,二酮哌嗪盐和它们的衍生物将被详细描述。这些化合物是本发明的优选实施方式。然而,这不排除基于式1化合物的其它杂环化合物。
在2005年8月23日递交并且标题为“Pulmonary Delivery of Inhibitorsof Phosphodiesterase Type 5”的共同待审美国专利申请XX/XXX.XXX中、以及美国临时申请60/603,764中描述了DKP盐用于输送磷酸二酯酶5型抑制剂的用途,该文献通过引用全文插入此处。在标题为“Method For DrugDelivery To The Pulmonary System”的US专利6,428,771中公开了利用DKP微粒进行肺部药物输送,该文献通过引用全文插入此处。
二酮哌嗪有利于生物活性试剂穿过生物组织进行转细胞运输,但是它们不是促渗剂。促渗剂是一种通过破坏细胞膜改善药物穿过生物组织的运动的化合物。促渗剂的实例是表面活性剂和皂类。二酮哌嗪既不在生物体外也不在生物体内破坏细胞膜。体外研究表明,FDKP不会破坏细胞膜或紧密连接,并且也不会危及细胞的发育能力。二酮哌嗪/胰岛素粉末组合物在肺部表面的生理学pH下可溶,并且在吸入后快速溶解。一旦溶解了,DKP有利于胰岛素的被动细胞间运输。
申请人已经发现,经改善的二酮哌嗪组合物在中性和/或酸性pH下具有高溶解度。申请人还发现了,可以在经改善的二酮哌嗪和有益的药物之间形成治疗配合物。
本发明的盐可以通过如下方法制备:将二酮哌嗪游离酸与在以下实施例1和2中所描述的适当碱反应。在优选的实施方式中,盐是药学上可接受盐,例如,二酮哌嗪的钠(Na)、钾(K)、锂(Li)、镁(Mg)、钙(Ca)、铵、或一、二或三烷基铵(源自三乙胺、丁基胺、二乙醇胺、三乙醇胺或吡啶等)盐。该盐可以是单盐、二盐或混合盐。还可以考虑二酮哌嗪的更高级别盐,在二酮哌嗪中,R基团包含一个以上酸基团。在本发明的另一方面,碱性试剂可以与DKP混合以形成DKP的药物盐,结果该药物是DKP的反阳离子。
对于药物输送,生物活性试剂或具有治疗性、预防性或诊断活性的药物可以利用二酮哌嗪输送。根本上来说,生物活性试剂与本发明的二酮哌嗪颗粒缔合。在本文中,“缔合”意指,通过将二酮哌嗪与生物活性试剂共沉淀、喷雾干燥或键合(络合)等方法形成生物活性试剂-二酮哌嗪组合物。所得二酮哌嗪颗粒包括那些已经截留、封装和/或被生物活性试剂涂敷的颗粒。尽管没有最终确定缔合的确切机理,但认为缔合是物理截留(分子缠结)以及包括氢键、范德华力和吸附的静电吸引的作用。
可以与本发明的二酮哌嗪颗粒缔合的生物活性试剂包括,但不限于,有机或无机化合物、蛋白质或各种其它化合物,包括营养剂,例如,维生素、矿物质、氨基酸、碳水化合物、糖和脂肪。在优选的实施方式中,药物包括在口内输送后在由GI管道运输后在循环系统中释放的生物活性试剂。在另一优选的实施方式中,材料是在肺部或鼻内输送后在循环系统中释放的生物活性试剂。在另一优选的实施方式中,材料是在鼻内输送后在中枢神经系统中释放的生物活性试剂。另外,药物可以通过例如直肠组织、阴道组织和/或口腔组织的黏膜组织吸收。生物活性试剂的非限定性实例包括,蛋白质和肽(其中,蛋白质被定义为由100个或更多个氨基酸残基构成,肽是小于100个氨基酸残基),例如,胰岛素和其它荷尔蒙;多糖,例如,肝磷脂;核酸,例如,质粒、低聚核苷酸、反意或siRNA;脂类和脂多糖;和具有生物活性的有机分子,例如,抗生素、消炎试剂、血管活性试剂(包括用于治疗勃起功能障碍的试剂)和神经活性试剂中的一些。具体的非限定性实例包括类固醇、荷尔蒙、减充血药、抗凝血剂、免疫调节剂、细胞毒素试剂、抗生素、抗病毒试剂、麻醉剂、镇静剂、抗抑郁剂、大麻类物质、抗凝血剂、反意试剂、抗原和抗体。在一些情况下,蛋白质可以是抗体或抗原,该抗体或抗原否则将不得不通过注射给药以引起适当响应。更具体地,可以与本发明的二酮哌嗪组合物缔合的化合物包括:胰岛素、肝磷脂、降钙素、非氨酯(felbamate)、甲状旁腺激素和其片段、生长激素、红细胞生长素、胰高血糖素样肽-1、生长激素释放激素、卵泡刺激素、色甘酸、酯联素(adiponectin)、RNAse、脑肠肽(ghrelin)、齐多夫定、去羟肌苷(didanosine)、四氢大麻酚(即,大麻类物质)、阿托品、粒性白细胞群刺激因子、拉莫三嗪(lamotrigine)、绒毛膜促性腺激素释放因子、黄体释放激素、β-牛乳糖和阿加曲班(Argatroban)。例如每分子可以缔合具有宽分子量范围(例如100-500000克每摩尔)的化合物。
包括金属、放射性同位素、不透射线试剂和X射线阻碍试剂的显影剂也可以混入二酮哌嗪输送系统中。放射性同位素和不透射线试剂包括镓、锝、铟、锶、碘、钡和磷。
另外,药物可以是各种形式,例如,无电荷的分子、金属或有机盐,或前体药物。对于酸性药物,在一些情况下可以使用金属盐、胺或有机阳离子(例如,季铵)。
在一些实施方式中,药物包括在口内输送后在由胃肠道运输后在循环系统中释放的生物活性试剂。在另一些实施方式中,生物活性试剂在肺部或鼻内输送后在循环系统中释放。在另一些实施方式中,生物活性试剂在鼻内输送后在中枢神经系统中释放。另外,药物可以通过例如直肠组织、阴道组织和/或口腔组织的黏膜组织吸收。
这些生物试剂中的一些具有如下性质:在胃酸中不稳定、通过胃肠膜扩散缓慢、在生理学pH下可溶性差和/或在胃肠道中易于被酶破坏。生物试剂释放到血流中以前与二酮哌嗪盐组合,以使它们在胃肠道中受到保护。在优选的实施方式中,二酮哌嗪不是生物活性的,并且不会改变治疗试剂的药学性质。
为了将一种或更多种药物与DKP盐缔合,将该药物和DKP盐优选在溶液或悬浮液中混合,并随后干燥。任一种组分可以作为溶质或悬浮质。在不同的实施方式中,将混合物喷雾干燥或冻干。
喷雾干燥是一种热处理方法,用于由各种溶液或悬浮液形成、负载或干燥颗粒固体。使用喷雾干燥用于形成干燥的颗粒医药品的用途是本领域中已知,然而,过去,由于喷雾干燥方法的性质,该方法与生物大分子(包括,蛋白质、肽和核酸)药物不相容性,使其使用受到局限。在喷雾干燥期间,溶液或悬浮液通过气溶胶化(aerosolization)形成液滴,然后将其通过具有充足热能的经加热的气流,以在收集颗粒以前将颗粒中的水和溶剂蒸发到理想水平。入口温度是离开气流源的气流的温度,该入口温度水平可以根据被处理的大分子的不稳定性来选择。出口温度是入口温度、干燥产物所需热负荷以及其它因素的函数。
令人出乎意料,本发明人已经测定,本发明的颗粒具有随着生物活性试剂含量的增加而改善的空气动力学性能,这一点在其它颗粒中未曾见到。本发明的喷雾干燥颗粒的可吸入分数(%rf)(直径在0.5-5.8微米的颗粒的百分率)随着胰岛素含量的增加而增加,而非如以前预期的随着含量增加而降低。因此,使用本发明的方法,可以形成二酮哌嗪微粒,该微粒具有比以前可达到的生物活性试剂含量更高的生物活性试剂含量。
另外,令人惊讶地,本发明人已经测定,随着FDKP二钠盐在初始溶液中的浓度增加,经喷雾干燥的FDKP二钠盐/胰岛素组合物的胰岛素稳定性增加。稳定性通过在40℃/75%的相对湿度下17天后胰岛素的损耗来测量。例如,由包含37mg/mL(FDKP二钠盐/胰岛素的总重)固体的溶液喷雾干燥得到的粉末损耗8.5%的胰岛素。作为比较,由包含45mg/mL固体的溶液喷雾干燥得到的粉末损耗4.5%的胰岛素,而由包含67mg/mL固体的溶液喷雾干燥得到的粉末损耗2.7%的胰岛素。
在另一项观测报告中,发现入口温度对胰岛素的稳定性具有令人惊讶的影响。数据表明,粉末中胰岛素的稳定性随着入口温度的增加而增加,该稳定性通过在40°/75%RH下17天后胰岛素的损耗来测量。例如,在180℃的入口温度下喷雾干燥的粉末损耗约4%的胰岛素。作为比较,在200℃的入口温度下喷雾干燥的粉末损耗<1%的胰岛素。
在本发明的实施方式中,提供了一种适用于输送到肺部系统中的微粒,其中,该微粒具有小于2的粗糙度。受喷雾干燥影响的本发明的另一方面是通过粗糙度衡量的颗粒形貌,粗糙度即由颗粒尺寸分布和颗粒密度计算的该颗粒的比面积与表面积的比。可以控制干燥操作以提供具有例如粗糙度的特定特征的干燥颗粒。经喷雾干燥的颗粒的粗糙度是颗粒的表面形貌的量度,例如,折叠度或褶合度。
先前认为,需要粗糙度大于2以得到具有足够分散性的颗粒,从而形成自由流动的粉末。令人惊讶地,本发明已经制备出了适于肺部释放、具有小于2粗糙度的颗粒。
可以以液体或固体剂型服用本发明的微粒配制品。这些剂型可以包括溶液、悬浮液、干粉、药片、胶囊、栓剂、用于透皮输送的贴剂等。这些不同剂型具有独特但相互重叠的优点。固体剂型使药物散装运输便利,并可以改善药物的稳定性。它们还可以根据微粒的尺寸形成能够通过吸入被特别给药到鼻黏膜内或肺部深处的微粒。即使当二酮哌嗪以溶液形式输送,它也可以促进所缔合药物的吸收。DKP盐中的一些(例如,钠盐和钾盐)与游离酸相比在中性和酸性pH下具有改善的稳定性,这可以使得在胃中对经口服的固体剂型的吸收改善了。
可以选择二酮哌嗪盐的反阳离子以制备具有各种溶解性的盐。这些变化的溶解性使得溶解速率和/或固有溶解度不同。通过控制DKP盐的溶解速率,还可以控制DKP盐/药物组合物中的药物吸收速率以提供具有立即释放和/或持续释放特征的配制品。例如,有机化合物的钠盐在生物系统中具有高度易溶的特征,而钙盐在生物系统中具有仅仅微溶的特征。因此,由DKP钠盐/药物组合物组成的配制品使药物立即吸收,而由DKP钙盐/药物组合物组成的配制品使药物吸收较慢。包含后二两种配制品组合的配制品可以用于使药物立即吸收,接着使吸收持续一定时期。
生物活性试剂的二酮哌嗪盐配制品可以口服。取决于微粒的化学性质和尺寸,该颗粒通过胃肠道的上皮衬里吸收到血流或淋巴系统中。可替换地,组合物可以以溶液形式服用,其中,DKP盐有利于药物的吸收。另外,微粒可以以完全溶解并且在溶解后被吸收的悬浮液剂型形式或固体剂型形式服用。
对于肠胃外给药,小于5微米的微粒易于通过用于静脉内给药的针孔。合适的药学载体(例如,磷酸盐缓冲盐水)是已知的并且是商业可得的。类似地,微粒可以皮下、肌肉或腹腔内注射或植入。另外,微粒可以置于可植入装置内以利于持续释放和/或可控释放。
对于局部给药或透皮给药,微粒可以利用适于给药载体和场所的方法悬浮于适用于给药的合适药学载体中。例如,微粒可以在pH约为7.4的缓冲盐溶液中或在例如矿物油的药膏中给药到眼中。剂型依赖于待释放的化合物以及释放的速率。微粒或聚集形成膜、圆片或药片的微粒与被混合的化合物一起可以以药膏、乳膏或贴剂形式给药到皮肤上。合适的药学载体是已知的并且是商业可得的。还可以考虑黏膜给药,包括,口腔给药、阴道给药、直肠给药、鼻内给药。
肺部输送可以利用包括本发明微粒的干粉非常有效地完成,并且可以导致快速吸收到循环系统(血流)中。干粉吸入器是本领域已知的,在两篇标题均为“Unit Dose Capsules and Dry Powder Inhaler”的U.S.专利申请09/621,092和10/655,153中描述了特别合适的吸入器系统,这些文献通过引用全文插入此处。在标题为“Method for Drug Delivery to the PulmonarySystem”的U.S.专利6,428,771中可以找到关于利用包括二酮哌嗪的微粒的肺部输送系统的信息,该文献通过引用全文插入此处。以下实施例意欲说明本发明的一个或更多个实施方式,但并不意味着将本发明限制于以下所述。
实施例
实施例1:FDKP二钠盐的制备方法A
将13克富马酰二酮哌嗪(FDKP)(28.73mmol,1当量)置于装有回流冷凝器、磁力搅拌棒和温度计的250mL 3口圆底烧瓶中。该反应在氮气氛下进行。将水(150mL)和50%氢氧化钠(4.48g,1.95当量)依次加入烧瓶中。将所得黄色溶液加热到50℃,并保持2小时。然后,将溶液热滤以除去任意不可溶物质。将水通过旋转蒸发从样品中除去。将获得的固体在真空烘箱中(50℃,30英寸汞柱)干燥整夜。然后,分析该盐的水分含量(Karl Fischer)和钠含量(元素分析和滴定)。该盐的产率为约90%到约95%。
分子式:C20H26N4Na2O8·1.4809H2O
通过Karl Fischer滴定测定的%水:5.1%
元素分析:
计算值C 45.92 H 5.58 N 10.71 Na 8.79
测试值C 45.05 H 5.23 N 10.34 Na 9.18
滴定:97%二钠盐(重量百分比)
表1.激光衍射颗粒尺寸分析(制备方法A颗粒)
Lot# | X10 | X16 | X50 | X84 | X90 | X99 | VMD | GSD |
制备方法A | 1.60μm | 1.44μm | 2.89μm | 4.60μm | 5.47μm | 19.20μm | 3.70μm | 1.59 |
Lot# | 颗粒尺寸 | ||
<3μm | 0.5-5μm | 细颗粒分数(<5.8μm) | |
制备方法A | 53.39% | 87.91% | 91.46% |
VMD=体积中值直径;GSD=几何标准偏差
实施例2.FDKP二钠盐的制备方法B
将13克FDKP(28.73mmol,1当量)和乙醇(150mL)置于装有回流冷凝器、磁力搅拌棒和温度计的250mL 3口圆底烧瓶中。该反应在氮气氛下进行。将浆液加热到50℃。将氢氧化钠50%w/w的水溶液(4.71g,2.05当量)一次性加入。将所得浆液在50℃下加热2小时。然后,将反应物冷却到室温(20-30℃),并真空过滤分离出固体。将获得的盐采用乙醇(300mL)和丙酮(150mL)洗涤,并在真空烘箱中(50℃,30英寸汞柱)干燥整夜。不需进行进一步纯化。然后,分析该盐的水分含量(Karl Fischer)和钠含量(元素分析和滴定)。该盐的产率为约90%到约95%。
分子式:C20H26N4Na2O8·1.4503H2O
通过Karl Fischer滴定测定的%水:5%
元素分析:
计算值C 45.97 H 5.57 N 10.72 Na 8.8
测试值C 46.28 H 5.26 N 10.60Na 8.96
滴定:98.8%二钠盐(重量百分比)
表2.激光衍射颗粒尺寸分析(制备方法B颗粒)
Lot# | X10 | X16 | X50 | X84 | X90 | X99 | VMD | GSD |
制备方法A | 1.55μm | 1.36μm | 3.11μm | 5.53μm | 6.64μm | 14.04μm | 3.76μm | 1.75 |
Lot# | 颗粒尺寸 | ||
<3μm | 0.5-5μm | 细颗粒分数(<5.8μm) | |
制备方法A | 47.37% | 80.13% | 86.01% |
VMD=体积中值直径;GSD=几何标准偏差
实施例3.FDKP二锂盐的制备方法A
将10克FDKP(22.10mmol,1当量)和100mL水置于装有回流冷凝器、磁力搅拌棒和温度计的200mL 3口圆底烧瓶中。该反应在氮气氛下进行。在另一单独烧瓶中,制备氢氧化锂(1.81g,1.95当量)在40mL水中的水性溶液。一旦所有氢氧化锂已经溶解了,将该溶液一次性加入FDKP的水性浆液中。将所得溶液加热到50℃,并保持1小时。然后,将反应物冷却到室温,并过滤以除去任意不可溶颗粒。将水通过旋转蒸发从样品中除去。将获得的固体在真空烘箱中(50℃,30英寸汞柱)干燥整夜。然后,分析该盐的水分含量(Karl Fischer)和锂含量(元素分析和滴定)。该盐的产率为约98%。
分子式:C20H26N4Li2O8·0.0801H2O
Karl Fischer:0.31%
元素分析:
计算值C 51.57 H 5.66 N 12.03 Li 2.98
测试值C 50.98 H 5.74 N 11.95 Li 2.91
滴定:98.3%二锂盐(重量百分比)
实施例4.FDKP二钾盐的制备方法A
将12克FDKP(26.52mmol,1当量)置于装有回流冷凝器、磁力搅拌棒和温度计的250mL 3口圆底烧瓶中。该反应在氮气氛下进行。将氢氧化钾(0.5N,105g,1.98当量)加入该烧瓶中。将所得溶液加热到50℃,并保持2小时。然后,将反应物冷却到室温,并将水通过旋转蒸发从样品中除去。将获得的固体在真空烘箱中(50℃,30英寸汞柱)干燥整夜。然后,分析该盐的水分含量(Karl Fischer)和钾含量(元素分析和滴定)。该盐的产率为约95%到约98%。
分子式:C20H26N4K2O8·0.4529 H2O
Karl Fischer:4.98%
元素分析:
计算值C 44.75 H 5.05 N 10.44 K 14.56
测试值C 44.88 H 4.74 N 10.36 K 14.34
滴定:97.0%二钾盐(重量百分比)
实施例5.FDKP二钾盐的制备方法B
将10克FDKP(22.10mmol,1当量)和乙醇(150mL)置于装有回流冷凝器、磁力搅拌棒和温度计的250mL 3口圆底烧瓶中。该反应在氮气氛下进行。将浆液加热到50℃。将氢氧化钾(10 N,4.64g,2.10当量)一次性加入。将所得浆液在50℃下保持最少3小时。将反应物冷却到室温(20-30℃),并真空过滤分离出固体。将获得的盐采用乙醇(100mL)和丙酮(200mL)洗涤,并在真空烘箱中(50℃,30英寸汞柱)干燥整夜。不需进一步纯化。然后,分析该盐的水分含量(Karl Fischer)和钾含量(元素分析和滴定)。该盐的产率为约94%到约98%。
分子式:C20H26N4K2O8·0.6386 H2O
Karl Fischer:2.13%
元素分析:
计算值C 44.47 H 5.09N 10.37 K 14.47
测试值C 44.48 H 5.03N 10.31 K 13.92
滴定:97%二钾盐(重量百分比)
实施例6.FDKP二钠-胰岛素微粒的制备方法A
将2.5克FDKP二钠盐(制备方法A)置于装有磁力搅拌棒的250mL烧杯中。将原料悬浮于75mL的去离子水中。将胰岛素(0.84g)加入FDKP盐的悬浮液中。将所得浆液采用NH4OH滴定至8.3pH以形成溶液。将FDKP二钠盐和胰岛素溶液采用去离子水调至体积100mL,并通过0.22μm的聚醚砜膜过滤。将该溶液利用BUCHIMini Spray Dryer B-191(Buchi Labortechnik AG,Switzerland)在如下条件下喷雾干燥。
入口温度设置为170℃
出口温度=75℃
最大采气量的80%
雾化=600l/hr干燥氮气
最大物料泵吸速率的25%(8.5ml/min)
喷嘴冷却器回水22℃
实施例7.FDKP二钠-胰岛素微粒的制备方法B
将5克FDKP二钠盐(制备方法B)置于装有磁力搅拌棒的250mL烧杯中。将原料悬浮于75mL的去离子水中。将胰岛素(1.68g)加入FDKP盐的悬浮液中。将所得浆液采用NH4OH滴定至8.3pH以形成溶液。将FDKP二钠盐和胰岛素溶液采用去离子水调至体积100mL,并通过0.22μm的聚醚砜膜过滤。将该溶液利用BUCHIMini Spray Dryer B-191(Buchi Labortechnik AG,Switzerland)在如下条件下喷雾干燥。
入口温度设置为149℃
出口温度=75℃
最大采气量的80%
雾化=600l/hr干燥氮气
最大物料泵吸速率的25%(8.5ml/min)
喷嘴冷却器回水23℃
实施例8.表征FDKP二钠-胰岛素微粒
将实施例6和7中所描述的微粒进行激光衍射颗粒尺寸分析(SympatecGmbH,Germany)(图1A和1B)。实施例6的颗粒具有87.93%的平均可吸入分数(根据0.5-5.8微米的USP定义),具有1.60的标准偏差和1.82的%CV(变差系数)。实施例7的颗粒具有81.36%的平均可吸入分数,具有4.20的标准偏差和5.16的%CV。
实施例9.FDKP二钠-胰岛素的肺部给药
将包含FDKP二钠盐和胰岛素的干粉在开始进餐时吸入。包含干粉的颗粒优选具有约0.5-5.8微米的尺寸。精确的剂量遵医嘱,但通常为每剂量约5-150单位胰岛素。由这种给药方案进行胰岛素吸收模拟生理学上第一阶段的胰岛素释放,并削弱了餐后血糖偏移。
实施例10.口服剂型的制备方法
将实施例6或7中所描述的经喷雾干燥的FDKP二钠/胰岛素粉末装入硬质凝胶胶囊中。该胶囊可以包含约50-100mg的粉末。实施例6和7中制备的FDKP盐/胰岛素粉末中胰岛素为25重量%,胰岛素活性为约26单位/mg。因此,50mg为约1300单位,这明显高于通常剂量。将约2-30mg FDKP盐/胰岛素粉末与甲基纤维素(本领域已知的其它增量剂)混合以弥补所需质量差额。
实施例11.口服FDKP二钠-胰岛素
将包含FDKP盐和胰岛素的胶囊饭前服用。精确的剂量遵医嘱,但通常服用量为每剂量约10-150单位胰岛素。随后的胰岛素吸收削弱了餐后血糖偏移。这种口服胰岛素配制品用于替代患有糖尿病的患者的饭前胰岛素注射。另外,通过胃肠道吸收的胰岛素模拟了内原胰岛素分泌。内原胰岛素通过胰腺分泌到门脉循环中。口服后吸收的胰岛素也会直接进入门脉循环中。因此,胰岛素给药的口服途径使胰岛素输送到肝脏中的作用场所中,为控制葡萄糖水平提供了可能性,同时限制对胰岛素的系统药物暴露(systemic exposure)。利用胰岛素和FDKP二酸形式组合的口服胰岛素输送受FDKP二酸在低pH环境的胃肠道中溶解性差的阻碍。然而,FDKP盐提供了局部缓冲作用,该作用促进了它们在低pH下溶解。
实施例12.FDKP二钠盐的制备方法C
将5克富马酰二酮哌嗪(FDKP,221.01mmol,1当量),水(200mL)和10 N氢氧化钠(21.9mL,437.61mmol,1.98当量)加入装有回流冷凝器、悬臂式搅拌器、氮气入口和温度计的1升4口圆底烧瓶中。将混合物加热到50℃以得到黄色溶液,将乙醇(650mL)在15分钟内加入。当添加完成后,将浆液在50℃下保持30-60分钟。将反应混合物真空过滤,并将经分离的固体采用乙醇(150mL)和丙酮(150mL×2)洗涤,并在真空烘箱中(50℃,30英寸汞柱)干燥整夜。不需进行进一步纯化。分析该盐的水分含量(Karl Fischer)和钾含量(元素分析和滴定)。该盐的产率为约90%到约95%。
Karl Fischer:7.19%
元素分析:
计算值C 44.91 H 5.70N 10.47 Na 8.6
测试值C 45.29 H 5.47N 10.59 Na 8.24
滴定:98.8%二钠盐(重量百分比)
以下是根据本发明的各种配制品所描述的各种方法。
实施例13.通过喷雾干燥制备的FDKP盐/胰岛素粉末
将FDKP二钠盐(5g)溶于去离子水中(150mL),并加入胰岛素(1.69g)。将悬浮液的pH采用氢氧化铵(NH4OH)调节至8.3以得到溶液,该溶液采用去离子水稀释到200mL并过滤。该溶液采用以下条件喷雾干燥:
入口温度-200℃
出口温度-80℃
雾化气体-600升N2/hr
处理气体-最大量的80%
将喷雾喷嘴冷却到28℃
分析所得颗粒的空气动力学性质,数据列于表3中。
表3.经喷雾干燥的FDKP二钠/胰岛素的空气动力学性质
样品 | %rf | %倒空 | %rf填充 | Mmad | gsd | 入口℃ | %负载 | LOD |
具有25%胰岛素的FDKP二钠盐(w∶w) | 44.5 | 85.6 | 38.1 | 3.1 | 1.9 | 200 | 25.00 | 5.4 |
表3示出了:可吸入分数(%rf)(该分数是直径为0.5-5.8微米的颗粒的百分率),卸载过程中从药桶中倒出的粉末的百分率(%倒空),每单位填充量中可吸入部分的百分率(%rf填充,%rf×%倒空,这测量了在从药桶中倒出的粉末中可吸入颗粒的%)、质量中值空气动力学直径(mmad),入口℃(以摄氏度计的入口温度),负载百分率(%负载-颗粒中胰岛素的含量,以重量%计)和干燥过程中的损耗(LOD)(粉末中残余水的量度,以当粉末在烘箱中干燥整夜时所除去的%挥发性原料来表达)。
通过激光衍射测量的颗粒尺寸具有约2μm-15μm的尺寸范围,数据列于表4中和图2中。
表4
Lot# | Run | X10 | X50 | X90 | VMD | GSD | 细颗粒分数(<5.8μm) |
具有25%胰岛素的FDKP二钠盐(w∶w) | 168 | 2.14μm | 5.88μm | 15.16μm | 7.76μm | 2.10 | 49.21% |
利用扫描电子显微镜(SEM)研究颗粒的形貌。具有代表性的SEM示于图3中。颗粒形貌为塌陷的空心球体。
二钠盐/胰岛素颗粒的稳定性在加速室温条件下(400°/75%相对湿度[RH])进行评估。与通过冻干法制备的对照配制品相比,经喷雾干燥的颗粒具有极高的胰岛素稳定性,该胰岛素稳定性通过胰岛素的降解来测量(图4)。
评估在喷雾干燥以前的FDKP二钠盐/25%胰岛素溶液的初始浓度对最终颗粒稳定性的影响。数据(图5)表明,颗粒中胰岛素的稳定性随着溶液浓度的增加而增加,该稳定性根据在40°/75%RH下17天后通过胰岛素的损耗来测量。
实施例14.采用有机溶剂进行的FDKP盐/胰岛素溶液的溶剂/反溶剂沉淀
沉淀使用谐波超声雾化来控制。也可应用交替气穴法以及高剪切混合和均质化。
将FDKP的二钠盐(5g)溶于去离子水(80mL)中。将胰岛素(0.65g)加入该溶液中以产生悬浮液。将悬浮液的pH采用NH4OH调节至8.3以得到溶液,该溶液采用去离子水稀释到100mL并过滤。颗粒通过如下方法沉淀:将胰岛素/FDKP二钠盐的溶液与乙醇以1∶5的比通过一个在20kHz和40kHz频率下振动的双入口雾化料斗(duel inletatomization horn)抽吸。将沉淀物收集在包含乙醇(200mL)的媒介瓶中。沉淀后,将材料采用乙醇洗涤,并通过旋转蒸发或通过将氮气鼓泡吹过悬浮液来干燥。颗粒包含12.5重量%胰岛素。颗粒形貌通过SEM评估(图6)。
图6A(10k×)和图6B(20k×)所示的颗粒在1-5微米的范围内,同时在较低的放大倍数下,看到在10-40微米范围内的颗粒(图6C,2.5k×和图6D,1.0k×)。如下是本发明人的非约束性假设:在此项研究中所利用的干燥方法使初始颗粒重结晶成更大的次级颗粒,并且,使用将有机组分和水性组分在整个干燥过程(例如喷雾干燥)中维持在恒定比的方法可以维持初级颗粒而没有形成明显数量的次级颗粒。
实施例15.二铵盐的原位形成和配制品
FDKP或SDKP(琥珀酰DKP)二铵盐/胰岛素颗粒通过喷雾干燥形成。对于包含25%胰岛素的FDKP铵盐/胰岛素配制品给出了典型的过程。
将FDKP(5g)悬浮于去离子水(150mL)中,并采用氢氧化铵(NH4OH)滴定至7.5-8.0pH。将胰岛素(1.69g)加入所得溶液(FDKP)中以得到悬浮液。将悬浮液的pH采用氢氧化铵(NH4OH)调节至8.3以得到溶液,该溶液采用去离子水稀释到200mL并过滤。该粉末在如下条件下通过喷雾干燥溶液制备。
入口温度-200℃
出口温度-80℃
雾化气体-600升N2/hr
处理气体-最大量的80%
将喷雾喷嘴冷却到28℃
二铵盐的%rf比二钠盐的%rf高约10%。反阳离子对颗粒性能具有很大影响。而且,50%FDKP铵盐/胰岛素粉末的%rf与相应的25%FDKP铵盐/胰岛素粉末的%rf是相当的。这点令人惊讶,因为由FDKP游离酸通过冻干法制备的颗粒的%rf随着胰岛素的增加而降低。
分析所得颗粒的空气动力学性质,数据列于表5中。
表5.经喷雾干燥的FDKP二铵/胰岛素和SDKP二铵/胰岛素的空气动力学性质
样品 | %rf | %倒空 | %rf填充 | mmad | gsd | 入口℃ | %负载 | LOD |
具有25%胰岛素的FDKP二铵盐(w∶w) | 52.1 | 88.7 | 46.2 | 2.9 | 1.9 | 200 | 25.00 | 6.6 |
具有50%胰岛素的FDKP二铵盐(w∶w) | 55.7 | 85.4 | 47.5 | 2.9 | 1.8 | 200 | 50.00 | 6.2 |
具有25%胰岛素的 | 56.0 | 90.1 | 55.7 | 3.0 | 2.0 | 200 | 25.00 | 3.8 |
SDKP二铵盐(w∶w) |
通过激光衍射测量颗粒尺寸,数据列于表6和图7-9中。
表6
Lot# | Run | X10 | X50 | X90 | VMD | GSD | 细颗粒分数(<5.8μm) |
具有25%胰岛素的FDKP二铵盐(w∶w) | 078 | 1.70μm | 4.10μm | 8.40μm | 4.68μm | 1.86 | 72.13% |
包含25%胰岛素(w∶w)的FDKP二铵盐制剂的颗粒尺寸通过激光衍射测定,实验表明:采用25%胰岛素配制的FDKP铵盐的尺寸范围为约1.7μm-8.4μm(图7和表7)。
表7
Lot# | Run | X10 | X50 | X90 | VMD | GSD | 细颗粒分数(<5.8μm) |
具有50%胰岛素的FDKP二铵盐(w∶w) | 076 | 1.57μm | 4.51μm | 8.79μm | 4.97μm | 1.91 | 66.95% |
包含50%胰岛素(w∶w)的FDKP二铵盐制剂的颗粒尺寸通过激光衍射测定,实验表明:采用50%胰岛素配制的FDKP铵盐的尺寸范围为约1.6μm-8.8μm(表8)。
表8
Lot# | Run | X10 | X50 | X90 | VMD | GSD | 细颗粒分数(<5.8μm) |
具有25%胰岛素的SDKP二铵盐(w∶w) | 084 | 1.66μm | 4.64μm | 9.27μm | 5.17μm | 1.92 | 64.69% |
包含25%胰岛素(w∶w)的SDKP二铵盐制剂的颗粒尺寸通过激光衍射测定,实验表明:采用25%胰岛素配制的SDKP铵盐的尺寸范围为约1.7μm-9.3μm。
利用扫描电子显微镜研究颗粒的形貌。具有代表性的SEM示于图10(FDKP)和图11(SDKP)中。颗粒形貌为塌陷的空心球体。
二铵盐/胰岛素颗粒的原位成盐和配制品的稳定性在加速室温条件下(40°/75%RH)进行评估。与通过冻干法制备的对照配制品相比,经喷雾干燥的颗粒具有很高的胰岛素稳定性,该胰岛素稳定性通过胰岛素的降解(FDKP,图12;SDKP,图14)和去氨基降解物的形成(A21)(FDKP,图13;SDKP,图15)来测量。
实施例16.表征经喷雾干燥的微粒
经喷雾干燥的FDKP盐/胰岛素颗粒在空气动力学性能中具有令人惊讶、出乎意料的趋势。先前观察到,由DKP游离酸微粒形成的含胰岛素微粒的空气动力学性能随着胰岛素含量的增加而降低,上述含胰岛素微粒通过将胰岛素负载到DKP游离酸微粒上、并将溶剂通过冻干法除去来制备。例如,25%负载的颗粒的%rf(可吸入分数)显著低于5%负载的颗粒的%rf。对于包含胰岛素的经喷雾干燥的FDKP盐微粒,观察到相反的趋势。随着胰岛素负载的增加,%rf增加。
制备具有11.4%、50.0%、70.0%或90.0%胰岛素含量(w∶w)的FDKP二钠盐的喷雾干燥粉末。图16表明,随着胰岛素负载的增加,%rf增加。
在具有11.4%、50.0%、70.0%或90.0%胰岛素含量(w∶w)的经喷雾干燥的FDKP二铵盐/胰岛素粉末中,也观察到类似的趋势。
评估在喷雾干燥以前的FDKP二钠盐溶液的初始浓度对最终胰岛素稳定性的影响。数据表明,粉末中的胰岛素稳定性随着溶液浓度的增加而增加,稳定性通过在40°/75%的相对湿度下17天后胰岛素的损耗来测量。例如,由包含37mg/mL固体的溶液喷雾干燥得到的粉末损耗8.5%的胰岛素。作为比较,由包含45mg/mL固体的溶液喷雾干燥得到的粉末损耗4.5%的胰岛素,而由包含67mg/mL固体的溶液喷雾干燥得到的粉末损耗2.7%的胰岛素。
评估用于喷雾干燥FDKP二钠盐和胰岛素的溶液以形成包含50%胰岛素的颗粒的入口温度对最终颗粒胰岛素稳定性的影响。数据表明,粉末中胰岛素的稳定性随着入口温度的增加而增加,该稳定性通过在40°/75%RH下17天后胰岛素的损耗来测量。例如,在180℃的入口温度下喷雾干燥的粉末损耗约4%的胰岛素。作为比较,在200℃的入口温度下喷雾干燥的粉末损耗<1%的胰岛素。
另外,本发明人出乎意料地发现,适用于肺部输送的这些颗粒具有约1的粗糙度。
除非另有指明,本说明书和权利要求书中使用的表示成分的数量、以及表示分子量、反应条件等性质的所有数字都应当被理解为:在所有情况下,用术语“大约”加以了修饰。因此,除非有相反含义的说明,本说明书和所附权利要求书中示出的数量参数都是约数,它们可以根据本发明想要获得的性质而变动。至少,并且并非对权利要求书范围等同原则的应用加以限制,每个数量参数至少应按照报道的有效数字的数,以及应用普通的凑整技术来解释。虽然示出本发明宽广范围的数字范围和参数是约数,但是特别实施例中所示的数值却被尽可能地精确报道。但是,任何数值,必然含有一定误差,这是它们各自的检验测量方法中发现的标准偏差必然导致的。
除非本文另有指明,或与上下文明显矛盾,描述本发明的上下文中使用的术语“一个”、“一种”和“该”(“所述”)以及类似提法应当被理解为既包括单数又包括复数。本文中数值范围的引述仅仅用作速记方法,其包括该范围内每个单独的值。除非本文另有指明,每个单独的值被包括进说明书,就像它们在本文个别引述一样。本文所述的所有方法都可以以任何合适的顺序来进行,除非本文另有指明,或与上下文明显矛盾。除非另有指明,本文提供的任何及所有例子,或者示例性的语言(例如,“例如”)仅用来更好地阐述本发明,而非对发明范围加以限制。说明书中任何语句都不应被解释为:表示对本发明的实践来说必要的、未被要求保护的要素。
本文公开的本发明的替换性要素或实施方式的分组不应被理解为限制。每个组成员可被个别提到和被个别要求保护,或以与该组其它成员或本文中找到的其它要素的任何组合被提到和要求保护。可以预见到,为了方便和/或可专利性的理由,组中的一个或多个成员可被包括进一组或从中删除。当任何此类包括或删除发生时,说明书在本文中被看作为含有经过改动的组,因此满足对所附权利要求书中所用的任意和全部马库什组的支持。
本文中描述了本发明的优选实施方式,其包括发明人已知用来开展本发明的最佳模式。当然,在阅读前述说明书的基础上,对这些优选实施方式中的改动对于本领域普通技术人员来说将是明显的。本发明的发明人期待本领域技术人员合适地采用此类改动,发明人希望本发明以除了本文特别描述的方式之外的方式被实现。因此,只要适用法律允许,本发明包括对所附权利要求中提到的主体进行的所有改动和等同物。此外,所有可能的变化中,上面提到的要素的任何组合都被包括进本发明,除非本文另有指明,或与上下文明显矛盾。
此外,本说明书中提到了大量参考文献,包括专利和印刷出版物。上述参考文献和印刷出版物中的每种在此都通过引用被个别地整体包括进本文。
最后,应当理解,本文公开的本发明实施方式是为了阐述本发明的原理。可以进行的其它改动也落在本发明的范围内。因此,举例而言,而非限制,可按照本文的教导来使用本发明的替代性构造。因此,本发明不被限制为:与本文所述和所示出的完全一致。
Claims (36)
2.如权利要求1所述的药学上可接受盐,其中,所述杂环化合物包括二酮哌嗪。
3.如权利要求1所述的药学上可接受盐,其中,所述羧酸基团位于末端。
4.如权利要求3所述的药学上可接受盐,其中,R1和R2包括4-X-氨基丁基,并且其中,X选自由琥珀酰基、戊二酰基、马来酰基和富马酰基组成的组。
5.如权利要求4所述的药学上可接受盐,其中,X是富马酰基。
6.如权利要求1所述的药学上可接受盐,其中,所述阳离子选自由钠、钾、钙、锂、三乙胺、丁基胺、二乙醇胺和三乙醇胺组成的组。
7.如权利要求6所述的药学上可接受盐,其中,所述阳离子是钠。
8.一种治疗组合物,所述组合物包括根据式1的杂环化合物的药学上可接受盐:
式1
其中,R1或R2包括至少一个羧酸官能团;
E1和E2包括N或O;
所述盐还包括至少一种阳离子;且
所述组合物还包括一种生物活性试剂。
9.如权利要求8所述的治疗组合物,其中,所述生物活性试剂选自由荷尔蒙、抗凝血剂、免疫调节剂、细胞毒素试剂、抗生素、抗病毒试剂、反意序列、抗原、抗体和其活性片段和其类似物组成的组。
10.如权利要求9所述的治疗组合物,其中,所述生物活性试剂包括胰岛素。
11.如权利要求8所述的治疗组合物,其中,所述组合物被配制成液体。
12.如权利要求11所述的治疗组合物,其中,所述液体是溶液或悬浮液。
13.如权利要求8所述的治疗组合物,其中,所述组合物包括沉淀物。
14.如权利要求13所述的治疗组合物,其中,所述沉淀物被配制成适于口服、口腔给药、直肠给药或阴道给药的固体剂型。
15.如权利要求14所述的治疗组合物,其中,所述固体剂型选自由胶囊、药片和栓剂组成的组。
16.如权利要求8所述的治疗组合物,其中,所述组合物包括干粉。
17.如权利要求16所述的治疗组合物,其中,所述干粉的颗粒具有约0.5微米到约10微米的直径。
19.如权利要求18所述的方法,所述方法还包括将所述固体微粉化以形成干粉的步骤。
21.如权利要求20所述的方法,其中,所述干粉的颗粒适用于肺部输送。
22.如权利要求20所述的方法,其中,所述干粉的颗粒具有小于2的粗糙度。
24.如权利要求23所述的组合物,其中,所述干粉的颗粒适于肺部输送。
25.如权利要求23所述的组合物,其中,所述干粉的颗粒具有小于2的粗糙度。
27.如权利要求26所述的微粒系统,其中,所述生物活性试剂选自由荷尔蒙、抗凝血剂、免疫调节剂、细胞毒素试剂、抗生素、抗病毒试剂、反意序列、抗原、抗体和其活性片段和其类似物组成的组。
28.如权利要求26所述的微粒系统,其中,所述组合物是干粉,其在肺部系统中释放所述生物活性试剂。
29.如权利要求26所述的微粒系统,其中,所述药物被输送到所述肺部系统中。
30.如权利要求26所述的微粒系统,其中,所述生物活性试剂被吸收到全身血液循环中。
31.如权利要求26所述的微粒系统,其中,所述生物活性试剂局部作用在肺脏中。
32.如权利要求26所述的微粒系统,其中,所述组合物包括用于药物输送的液体,其中,所述二酮哌嗪促进所述生物活性试剂的吸收。
33.如权利要求32所述的微粒系统,其中,所述液体被口服。
34.如权利要求26所述的微粒系统,其中,所述组合物包括沉淀物,其中,所述二酮哌嗪促进所述生物活性试剂的吸收。
35.如权利要求34所述的微粒系统,其中,所述沉淀物被口服。
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