CN105193720B - 含有吲哚满酮衍生物悬浮液制剂的胶囊药物剂型 - Google Patents
含有吲哚满酮衍生物悬浮液制剂的胶囊药物剂型 Download PDFInfo
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- CN105193720B CN105193720B CN201510660732.8A CN201510660732A CN105193720B CN 105193720 B CN105193720 B CN 105193720B CN 201510660732 A CN201510660732 A CN 201510660732A CN 105193720 B CN105193720 B CN 105193720B
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Abstract
本发明涉及含有活性物质3‑Z‑[1‑(4‑(N‑((4‑甲基‑哌嗪‑1‑基)‑甲基羰基)‑N‑甲基‑氨基)‑苯胺基)‑1‑苯基‑亚甲基]‑6‑甲氧羰基‑2‑吲哚满酮‑单乙磺酸盐的悬浮液制剂,含有该悬浮液制剂的胶囊药物剂型,制备该悬浮液制剂的方法,制备包含该悬浮液制剂的胶囊的方法,以及用于最终胶囊的包装材料。
Description
本申请是申请号为200980121067.8的中国发明专利申请(名称:含有吲哚满酮衍生物悬浮液制剂的胶囊药物剂型,申请日:2009年6月4日)的分案申请。
本发明涉及含有活性物质3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮(indolinone)-单乙磺酸盐的悬浮液制剂,含有该悬浮液制剂的胶囊药物剂型,制备该悬浮液制剂的方法,制备包含该悬浮液制剂的胶囊的方法,以及用于最终胶囊的包装材料。
发明背景
一些药理学活性的物质可具有使其难以配制为常用给药形式的生物医药和/或物理化学性质。该物质可方便地以液体形式,在亲脂性或亲水性载体系统中,作为溶液或悬浮液,与单一载体赋形剂混合,或与数种成份构成的复合载体介质混合而给予。该液体制剂在软明胶胶囊中的胶囊化有效地提供了一种给药该药理学活性物质的便利方式。
溶液
为配制基于溶液的制剂,载体必须溶解活性物质。较差吸收的药物可通过增加药物在胆汁酸存在下的溶出速率而达成改良的胃肠(GI)吸收。在胃肠道内,胆汁盐表现为生物清洁剂,当其与磷脂混合时,形成热力学上稳定混合的微团。在许多情况下,制剂的选择受限于溶剂容量,而在其它情况下,药物不会在任一脂质制剂中充分地溶解。
载体介质可经设计以自发地在胃中形成乳化液或微乳化液,以有利于药理学活性物质的吸收。这些体系通常称为自动(微-)乳化药物递送系统(SEDDS或SMEDDS)。其必须精确制备,即使是在组合物中的细微偏差也不能容许,否则会不可逆地干扰该体系并破坏其有益特性。例如,活性物质可能沉淀析出,这是由于胶囊制剂溶出性质上改变的结果。此沉淀过程可为不可逆的,且导致患者的服药不足。胶囊制剂的乳化性质也可能被改变,且在给药时,乳化液可能不会在胃中形成。因此,具药理学活性的物质可能不会正确地或可再现地被吸收。
悬浮液
因悬浮液代表热力学不稳定的多相体系,故在这些体系的开发期间,必须要考虑多种特性。从颗粒生长方面,以及从具有不同溶出度的潜在多晶形式中重结晶作用方面,或从沉降物的成块作用有关的沉降作用方面,必须确保悬浮液制剂的物理稳定性。这些因素可影响活性物质自剂型中释放,且从而改变产品贮存期患者曝露的程度。因此,活性物质在单一载体赋形剂中或在载体体系中溶解度不是物理稳定体系的前提条件。
亲脂性载体体系
通常采用亲脂性赋形剂作为水份屏蔽体系,以保护化学不稳定物质。就该目的而言,不同类型的脂肪类或蜡类可施加于固体剂型或其制备中间体上,以防止周围水蒸气或氧的迁移,改善活性物质的化学稳定性。将药物热熔包合至亲脂性粘合剂中也可防止与水份接触。由于固体疏水性体系崩解较差,故在这些体系中药物释放是延迟的,与在低粘稠液体脂质制剂中的药物释放相比。该延迟的药物释放通过改良的药物递送体系中活性物质的具体血浆性质反映(Ritschel W.等人,Die Tablette,2002,2nd ed.,ECV,Aulendorf,p267f)。因此,液体体系的粘度是至关重要的参数,必须小心地调整以确保充足的药物释放。
实际上,亲脂性或“脂质”制剂是具有许多特性的多种制剂组。这是由于高达五类赋形剂的共混所致,所述赋形剂包括纯甘油三酯油类、经过混合的甘油酯、亲脂性表面活性剂、亲水性表面活性剂及水溶性共溶剂。
品质评价
制剂的性能可由测量其相对生物利用度而评价,即将其生物利用度与活性物质水溶液的生物利用度作比较。若该体系显示相当的(comparable)生物利用度,与溶出速率无关而与药物渗透性相关,则活性物质的系统前(pre-systemic)或系统(systemic)代谢作用将决定系统曝露。因此,(脂质)悬浮液也可显示令人满意的患者曝露,这是由于活性物质在生理学条件内的充分溶出所致。
3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐是具有有价值的药理学性质的新发明物质,尤其用于治疗肿瘤性疾病(oncological diseases)、免疫性疾病(immunologicdiseases)或涉及免疫成份的病理学病症或纤维变性疾病。
该物质的化学结构如下式(I)所示。
式(I)
该物质的碱公开于WO 01/27081中,单乙磺酸盐形式公开于WO 2004/013099中,在WO 2004/017948中公开了其在治疗免疫性疾病或涉及免疫成份的病理学病症的用途,在WO2004/096224中公开了其在治疗肿瘤性疾病的用途,在WO 2006/067165中公开了其在治疗纤维变性疾病的用途,在WO 2007/141283中公开了其它的盐形式。
本发明目的是对于上述药物提供口服药物剂型,其对于治疗所需的剂量范围满足充分的化学稳定性以及生物利用度要求,及适合此产品的包装材料。此类具体的释放特性在关于该药物的现有技术中是未知的。
发明概述
本发明的第一方面为活性物质3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐的制剂,其包含所述活性物质的悬浮液。
本发明的另一方面为上述制剂,其中所述活性物质的悬浮液为3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐的粘稠悬浮液,其包含载体、增稠剂和任选的助流剂/增溶剂。
本发明的另一方面为上述制剂,其中所述载体选自甘油、乙酰化甘油单酯(acetylated monoglycerides)、玉米油甘油酯(corn oil glycerides)、辛酸-癸酸甘油三酯(caprylic-capric triglycerides)、中链甘油三酯(medium chain triglycerides)、中链偏甘油酯(medium chain partial glycerides)、辛酸/癸酸/亚油酸甘油三酯(caprylic/capric/linoleic triglycerides)、辛酸/癸酸/琥珀酸甘油三酯(caprylic/capric/succinic triglycerides)、丙二醇二辛酸酯/二癸酸酯(propylene glycoldicaprylate/dicaprate)、油酸乙酯、甘油单/二油酸酯(glycerol mono/dioleate)、甘油单亚油酸酯(glycerol monolinolate)、聚乙二醇甘油癸酰基癸酸酯(macrogolglycerolcaprylocaprate)、聚乙二醇甘油亚油酸酯(macrogolglycerol linoleate)、油酸、液体或半固体低/中等粘稠聚乙二醇(例如聚乙二醇300、聚乙二醇400、聚乙二醇600)、聚氧乙烯蓖麻油(polyoxyl castor oil)、聚氧乙烯氢化蓖麻油、丙二醇单辛酸酯(propylene glycolmonocaprylate)、丙二醇单月桂酸酯、精制动物衍生油(refined animal derived oil)、精制大豆油、精制植物油、山梨聚糖单硬脂酸酯(sorbitan monostearate)、甘油三醋酸酯(tracetin)、柠檬酸三乙酯,或其混合物。
在本发明的一个优选实施方案中,所述载体为脂质(亲脂性)载体。
在本发明的一个优选实施方案中,所述载体选自下列脂质(亲脂性)载体:乙酰化甘油单酯、玉米油甘油酯、中链甘油三酯、中链偏甘油酯、辛酸-癸酸甘油三酯、辛酸/癸酸/亚油酸甘油三酯、辛酸/癸酸/琥珀酸甘油三酯、丙二醇二辛酸酯/二癸酸酯、油酸乙酯、甘油单/二油酸酯、甘油单亚油酸酯、聚乙二醇甘油癸酰基癸酸酯、聚乙二醇甘油亚油酸酯、油酸、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、丙二醇单辛酸酯、丙二醇单月桂酸酯、精制动物衍生油、精制大豆油、精制植物油、山梨聚糖单硬脂酸酯或其混合物。
本发明的另一方面为上述制剂,其中增稠剂选自半固体高粘稠或固体聚乙二醇(例如聚乙二醇1000至20000),优选聚乙二醇1000至6000,优选聚乙二醇4000,或形成油凝胶(oleogel forming)的赋形剂,例如胶态二氧化硅或膨润土,或高粘度的亲脂性或两亲性赋形剂,例如蜂蜡、甘油单硬脂酸酯、氢化植物油、部分氢化植物油或硬脂。
在本发明的一个优选实施方案中,增稠剂选自形成油凝胶的赋形剂,例如胶态二氧化硅或膨润土,或高粘度的亲脂性或两亲性赋形剂,例如蜂蜡、甘油单硬脂酸酯、氢化植物油、部分氢化植物油或硬脂。
在另一个优选实施方案中,所述制剂还包含助流剂/增溶剂。
本发明的另一方面为上述制剂,其中助流剂/增溶剂选自卵磷脂。
本发明的另一方面为上述制剂,其包含3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐在中链甘油三酯、硬脂和卵磷脂中的粘稠悬浮液。
本发明的另一方面为上述制剂,其进一步包含一种或多种聚乙二醇甘油和/或增溶剂,例如月桂酰基聚乙二醇甘油酯(lauroyl macrogolglycerides)、亚油酰基聚乙二醇甘油酯(linoleoyl macrogolglycerides)、聚乙二醇甘油癸酰基癸酸酯、聚乙二醇甘油亚油酸酯、油酰基聚乙二醇甘油酯(oleoyl macrogolglycerides)、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、聚山梨酸酯及丙二醇单月桂酸酯。
本发明的另一方面为上述制剂,其中聚乙二醇甘油选自聚乙二醇甘油羟基硬脂酸酯(macrogolglycerol hydrocystearate)或聚乙二醇甘油蓖麻醇酸酯(macrogolglyceolricinoleate)。
本发明的另一方面为包含胶囊壳与胶囊制剂的胶囊,其特征在于胶囊制剂包含上述制剂。
本发明的另一方面为上述胶囊,其特征在于胶囊为软明胶胶囊。
本发明的另一方面为上述胶囊,其特征在于胶囊壳包含甘油作为增塑剂。
本发明的另一方面为包含胶囊壳与胶囊制剂的胶囊,其特征在于胶囊制剂包含上述制剂,以及胶囊为硬明胶或羟丙基甲基纤维素(HPMC)胶囊、聚乙烯醇聚合物胶囊或普鲁兰胶囊(pullulan capsule),任选具有封口(sealing)或密封带(banding)。
本发明的另一方面为上文所定义的制剂或上文所定义的胶囊,其用作药物。
本发明的另一方面为上文所定义的制剂或上文所定义的胶囊,其用作具有抗增殖活性的药物组合物。
本发明的另一方面为上文所定义的制剂或上文所定义的胶囊,其用于治疗选自肿瘤性疾病、免疫性疾病或涉及免疫成份的病理学病症及纤维变性疾病的疾病或病症。
本发明的另一方面为上文所定义的制剂或上文所定义的胶囊在制备药物中的用途,所述药物用于治疗选自肿瘤性疾病、免疫性疾病或涉及免疫成份的病理学病症及纤维变性疾病的疾病或病症。
本发明的另一方面为一种治疗和/或预防疾病或病症的方法,所述疾病或病症选自肿瘤性疾病、免疫性疾病或涉及免疫成份的病理学病症及纤维变性疾病,其特征在于每日一次或数次向患者口服给药有效量的上文所定义的制剂或上文所定义的胶囊。
本发明的另一方面为上文所定义的制剂或上文所定义的胶囊,其以0.1毫克至20毫克活性物质/kg体重,优选0.5毫克至4毫克活性物质/kg体重的剂量范围使用。
本发明的另一方面为适于包装胶囊的玻璃容器或柔性/硬质塑料容器,其包含一个或多个上文所定义的胶囊。
本发明的另一方面为适于包装胶囊的铝袋或双重多袋,其包含一个或多个上文所定义的胶囊。
本发明的另一方面为适于包装胶囊的塑料(例如PVC、PVDC或)泡罩包装,其包含一个或多个上文所定义的胶囊,任选使用铝袋的外包装。
本发明的另一方面为适于包装胶囊的铝泡罩包装,其包含一个或多个上文所定义的胶囊。
附图说明
图1-软明胶胶囊(A)与脂质悬浮液制剂(B)在不同相对湿度条件(r.H.,以%表示)下因吸潮的质量增加(Dm,以%表示)。
图2-所使用卵磷脂的量对软明胶胶囊随时间(以分钟表示)的体外溶出行为(以溶出%表示)的影响。(A)优选30%量的卵磷脂,(B)优选75%量的卵磷脂,(C)优选90%量的卵磷脂,(D)优选量的卵磷脂(等于100%),(E)优选200%量的卵磷脂,(F)0%卵磷脂。
图3-硬脂的熔程(melting range)对软明胶胶囊随时间(以分钟表示)的体外溶出行为(以溶出%表示)的影响。(A)33℃-40℃的熔程,(B)40℃-44℃的熔程。
图4-在大鼠中经24小时测定活性物质的水溶液(S)与不同载体体系(P1、P2及P3)中的绝对生物利用度(以BA%表示)的比较-误差棒表示标准偏差。
发明详述
已令人惊讶地发现包含液体制剂的软明胶胶囊满足对于使用药物3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐进行治疗所需剂量范围的充分生物利用度的要求,所述液体制剂包含3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐在中链甘油三酯、硬脂和卵磷脂中的粘稠悬浮液。该液体制剂由所述活性物质的脂质悬浮液组成。
含有脂质悬浮液的此类软明胶胶囊的优点为水不太可能被吸收至制剂中。该剂型被分成三个不同部分(compartments),即(a)亲水性胶囊壳,和(b)疏水性载体系统,(c)悬浮于该疏水性载体体系中的活性物质的轻微吸湿性粉末。由于环境水份,故水含量可在这些不同部分内变化。其会扩散迁移,直到达成平衡状态。水含量可影响药品的不同性质,如活性物质的化学稳定性(主要经由水解作用)或胶囊壳的弹性。本发明体系中的水吸收主要是在胶囊壳中。这可由水蒸气吸收实验,以及质量增加与胶囊软化的关联性而证实(示于图1中)。吸水率不会进一步影响药物的化学稳定性。其由本发明体系的在70℃下1个月的压力稳定性研究,以及由长期(3年)与加速(6个月)稳定性研究结果而确认。
另外,研究已证实当储存于紧密包装材料中时,本发明的胶囊没有质量增加或粘附问题。因此,关于该胶囊的建议包装为例如alu/alu泡罩包装与HDPE瓶。
一般而言,软明胶胶囊具有胶囊壳,其由明胶、一种或多种增塑剂,特别是甘油,任选其它辅助物质如染料、着色剂颜料、矫味剂、糖、寡糖或多糖制成,和胶囊制剂(或胶囊填充物),其含有溶剂、佐剂及一或多种药理学活性的物质。此处所用术语明胶不仅包括如欧洲药典中的未改性明胶,而且也包含改性明胶(如琥珀酸化的明胶)。
如前文所述,本发明涉及活性物质3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐的脂质悬浮液制剂。
在本发明的一个优选实施方案中,活性物质3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐的脂质悬浮液制剂包含3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐在脂质载体、增稠剂和助流剂/增溶剂中的粘稠悬浮液。
在本发明的另一个优选实施方案中,3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐的量占该脂质悬浮液制剂的1至90重量%,优选10至50%。
为避免上述物理稳定性问题,如重结晶作用或颗粒生长,活性物质必须为完全不溶或溶于载体中。亲脂性、亲水性及两亲性赋形剂与混合物的溶解度筛选揭示了用于配制上述脂质悬浮液的多种可能载体。本发明脂质悬浮液的这些脂质载体的选择代表了本发明的方面。
因此,在一个优选实施方案中,对于活性物质3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐的适宜载体或载体成份为乙酰化甘油单酯、玉米油甘油酯、油酸乙酯、甘油单/二油酸酯、甘油单亚油酸酯、聚乙二醇甘油癸酰基癸酸酯、聚乙二醇甘油亚油酸酯、中链偏甘油酯、中链甘油三酯、辛酸-癸酸甘油三酯、辛酸/癸酸/亚油酸甘油三酯、辛酸/癸酸/琥珀酸甘油三酯、丙二醇二辛酸酯/二癸酸酯、油酸聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、丙二醇单辛酸酯、丙二醇单月桂酸酯、精制动物衍生油、精制大豆油、精制植物油、山梨聚糖单硬脂酸酯、甘油三醋酸酯、柠檬酸三乙酯,或其混合物。
稳定性问题如活性物质的水解性降解,也可因亲水性载体成份所造成。因此,以亲水性聚乙二醇为基础的载体体系一般比疏水性载体(如脂质载体)的稳定性更差。
根据本发明,最优选的脂质载体为中链甘油三酯。其含量为脂质悬浮液制剂的1至90重量%,优选10至70%。适宜的中链甘油三酯可为市售产品MiglyolMiglyolMiglyolMiglyol或Miglyol
增稠剂调整悬浮液的粘度。它稳定悬浮液体系,确保最优加工,且保证充足胶囊品质,尤其是就内含物均匀性或溶出行为而言。在一个优选实施方案中,用于本发明的适宜的增稠剂形成油凝胶的赋形剂,例如胶态二氧化硅或膨润土,或高粘度的亲脂性或两亲性赋形剂,例如蜂蜡、甘油单硬脂酸酯、氢化植物油、部分氢化植物油或硬脂。
上述悬浮液制剂中,最优选的增稠剂为硬脂(hard fat)。其含量优选为悬浮液制剂的1至30重量%,最优选10至30重量%。最适宜的硬脂具有30℃至44℃的熔程,最优选33℃至40℃的熔程。适宜的商购产品为33/01、W35或378。硬脂的最适合熔程的测定如图3所示如下进行,通过测量硬脂的熔程对体外溶出行为随时间的影响。
卵磷脂是在软明胶胶囊中载体-体系的常用赋形剂。其在胶囊化期间作为高浓缩悬浮液的助流剂使用,预防导管与泵的堵塞,并确保经胶囊化制剂的高品质均匀性。此外,卵磷脂作为表面活性剂,其可在药物吸收的体外溶出测试以及体内测试期间,改善制剂-液滴的分布。而且,也可改善活性物质晶体的润湿程度。适宜的卵磷脂可为市售产品
已令人惊讶地发现,达到一定含量的卵磷脂可用以改善成品胶囊的溶出行为。体外溶出测试期间,过度的量没有显示额外的益处,如图2所示。
在本发明的一个优选实施方案中,卵磷脂的量占脂质悬浮液制剂的0.1至10重量%,最优选0.25至2.5%。
在另一个实施方案中,本发明涉及活性物质3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐的脂质悬浮液制剂,其包含3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐在中链甘油三酯、硬脂、卵磷脂以及一种或多种聚乙二醇甘油(macrogolglycerols),例如聚乙二醇甘油-羟基硬脂酸酯(macrogolglycerol-hydroxystearate)(如以名称HRE 40PH销售)或聚乙二醇甘油-蓖麻醇酸酯(macrogolglycerol-ricinoleate)(也称为聚氧乙烯蓖麻油,如以名称EL、RH40或RO 35PH销售)中的粘稠悬浮液。
在本发明的一个优选实施方案中,聚乙二醇甘油的量占脂质悬浮液制剂的0.1至50重量%,最优选0.3至10%。
三种载体体系(亲水性P3、亲脂性P1,及具有表面活性剂的亲脂性P2半固体悬浮液制剂,如前所述)在非临床研究中测试了生物利用度,且确认其全部可作为活性物质3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐口服剂型的适合选项。
但是,由于生物利用度的缘故,由图4所示结果可知,优选包含3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐在中链甘油三酯、硬脂和卵磷脂中的粘稠悬浮液的脂质(亲脂性)悬浮液制剂。
因此,图4是在大鼠中经24小时测定本发明活性物质的水溶液(S)相对于不同载体体系(P1、P2和P3)中的绝对生物利用度(以BA%表示)的比较结果。实验描述于下文。
因此,图4显示关于根据本发明活性物质的水溶液(S)对不同载体系统(P1、P2及P3)在大鼠中经测试24小时的绝对生物利用度(BA,以%表示)的比较结果。实验在下文描述。
下表示出了测试载体体系的成分(半固体悬浮液制剂)。
*针对100百分比的数量的细微偏差可由舍入误差所造成
将半固体悬浮液充填至硬明胶胶囊(Capsugel,编号Y0303490)。各胶囊含有大约15至20mg的制剂。这些胶囊以类似强饲法(gavage)的特殊装置,施加至大鼠。为了比较,由强饲法施加含有0.5%Natrosol 250HX的水溶液。为了计算绝对生物利用度,另一组大鼠以静脉内方式服用溶于5%葡萄糖溶液中的化合物(水溶液(S))。每组使用5只雄性HanWistar大鼠(品系:CrlGlxBrlHan:WI)。血液取样时间为服药后0.5小时、1小时、2小时、4小时、8小时、24小时,且血浆通过确认有效的HPLC/MS/MS方法分析。自血浆含量时间曲线,由线性梯形规则计算曲线下面积(AUC)。将口服制剂的剂量标准化AUC除以静脉内制剂的剂量标准化AUC,计算绝对生物利用度。由图4所示的实验结果可知,活性物质的水溶液(S:11%)及不同载体体系(P1:14%、P2:10%及P3:10%)的生物利用度类似,但是,对于水溶液(S)与载体体系(P1),当相较于载体体系(P2)与(P3)时,个体间的偏差(生物利用度的标准偏差)较小(2.8与4.1vs 7.4与7.1),显示测试的制剂(P1、P2及P3)对溶液(S)的实际完全相对生物利用度,但在载体体系(P2)与(P3)中存在较高偏差。
本发明还涉及由胶囊壳与胶囊制剂(或胶囊填充物)组成的胶囊药物剂型,其特征在于胶囊制剂(或胶囊填充物)包含如前述的脂质悬浮液制剂。胶囊药物剂型可为软明胶胶囊、硬明胶胶囊或羟丙甲基纤维素(HPMC)胶囊、聚乙烯醇聚合物胶囊或普鲁兰胶囊。
在硬明胶胶囊或羟丙甲基纤维素(HPMC)胶囊、聚乙烯醇聚合物胶囊或普鲁兰胶囊的情况下,胶囊中的填充物可进一步封口(sealed)或用密封带密封(banded)。
在本发明的一个优选实施方案中,胶囊为软明胶胶囊,其由胶囊壳(包含明胶、一或多种增塑剂以及任选的其它辅助物质),和胶囊制剂(或胶囊填充物)组成,其特征在于该胶囊制剂(或胶囊填充物)包含如前述的脂质悬浮液制剂。
根据本发明的胶囊药物剂型,尤其是软明胶胶囊,可储存于适宜的玻璃容器或柔性/硬质塑料容器中,优选非PVC基材料,或在塑料(如PVC、PVDC或)泡罩包装中,任选具有铝外包装(铝袋),或在铝泡罩包装中,由如PA/Al/PVC的底箔及铝帽盖箔组成,后者极具防水作用。因此,容器可经设计以对胶囊药物剂型进行特定保护,尤其是软明胶胶囊,如保护其隔绝光线、氧或水。柔性塑料容器可包括其它保护如其它铝包装形式。
根据本发明的胶囊药物剂型可由文献中已知制造胶囊的常规方法制成。根据本发明的软明胶胶囊可由文献中已知制造软明胶胶囊的常规方法制成,如“旋转孔模方法(rotary die procedure)”,如公开于Swarbrick,Boylann,Encyclopedia ofpharmaceutical technology,Marcel Dekker,1990,vol.2,pp 269ff,或在Lachmann等,“The Theory and Practice of Industrial Pharmacy”,2nd版,pagesl 404-419,1976,或其它方法,如公开于Jimerson R.F.等,“Soft gelatin capsule update”DrugDev.Ind.Pharm.,vol.12,No.8-9,pp.1133-44,1986。
脂质悬浮液制剂可由文献中已知制造制剂的常规方法制成,即在预定温度下将各成份以预定顺序混合,从而获得均化的悬浮液。
或者,脂质悬浮液制剂可根据实施例10中所述的步骤制成,这也是本发明的一个方面。
活性物质的脂质悬浮液制剂、含有同样物质的成品软明胶胶囊及包装成品的软明胶胶囊的包装材料,由下文实施例和附图进行说明。实施例仅作为示例性说明,不能认为是限制性的。
载体体系(制剂)、软明胶胶囊、包装材料及活性物质脂质悬浮液制剂的制备方法的实施例
所有实施例中的活性物质为3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐。
实施例1
脂质基载体体系
*针对100百分比的数量的细微偏差可由舍入误差所造成
实施例2
具有其它表面活性剂的脂质基载体体系
*针对100百分比的数量的细微偏差可由舍入误差所造成
实施例3
亲水性载体体系
成份 | [%]* |
活性物质 | 31.75 |
甘油85% | 3.17 |
纯水 | 4.76 |
聚乙二醇600 | 58.10 |
聚乙二醇4000 | 2.22 |
*针对100百分比的数量的细微偏差可由舍入误差所造成
实施例4
含有50毫克活性物质的软明胶胶囊
制剂A | 制剂B | 制剂C | ||
成份 | 功能 | mg/胶囊 | mg/胶囊 | mg/胶囊 |
活性物质* | 活性成份 | 60.20 | 60.20 | 60.20 |
中链甘油三酯 | 载体 | 40.95 | 53.70 | 54.00 |
硬脂 | 增稠剂 | 38.25 | 25.50 | 25.50 |
卵磷脂 | 润湿剂/助流剂 | 0.60 | 0.60 | 0.30 |
明胶 | 成膜剂 | 72.25 | 72.25 | 72.25 |
甘油85% | 增塑剂 | 32.24 | 32.24 | 32.24 |
二氧化钛 | 着色剂 | 0.20 | 0.20 | 0.20 |
氧化铁A | 着色剂 | 0.32 | 0.32 | 0.32 |
氧化铁B | 着色剂 | 0.32 | 0.32 | 0.32 |
胶囊总重量 | 245.33 | 245.33 | 245.33 |
*这些数字是指乙磺酸盐的量(干重为基准),相当于游离碱的标识量
实施例5
含有100毫克活性物质的软明胶胶囊
制剂A | 制剂B | 制剂C | ||
成份 | 功能 | mg/胶囊 | mg/胶囊 | mg/胶囊 |
活性物质* | 活性成份 | 120.40 | 120.40 | 120.40 |
中链甘油三酯 | 载体 | 81.90 | 107.40 | 106.8 |
硬脂 | 增稠剂 | 76.50 | 51.00 | 51.00 |
卵磷脂 | 润湿剂/助流剂 | 1.20 | 1.20 | 1.80 |
明胶 | 成膜剂 | 111.58 | 111.58 | 111.58 |
甘油85% | 增塑剂 | 48.79 | 48.79 | 48.79 |
二氧化钛 | 着色剂 | 0.36 | 0.36 | 0.36 |
氧化铁A | 着色剂 | 0.06 | 0.06 | 0.06 |
氧化铁B | 着色剂 | 0.17 | 0.17 | 0.17 |
胶囊总重量 | 440.96 | 440.96 | 440.96 |
*这些数字是指乙磺酸盐的量(干重为基准),相当于游离碱的标识量
实施例6
含有125毫克活性物质的软明胶胶囊
制剂A | 制剂B | 制剂C | ||
成份 | 功能 | mg/胶囊 | mg/胶囊 | mg/胶囊 |
活性物质* | 活性成份 | 150.50 | 150.50 | 150.50 |
中链甘油三酯 | 载体 | 102.375 | 134.25 | 133.5 |
硬脂 | 增稠剂 | 95.625 | 63.75 | 63.75 |
卵磷脂 | 润湿剂/助流剂 | 1.50 | 1.50 | 2.25 |
明胶 | 成膜剂 | 142.82 | 142.82 | 142.82 |
甘油85% | 增塑剂 | 62.45 | 62.45 | 62.45 |
二氧化钛 | 着色剂 | 0.47 | 0.47 | 0.47 |
氧化铁A | 着色剂 | 0.08 | 0.08 | 0.08 |
氧化铁B | 着色剂 | 0.22 | 0.22 | 0.22 |
胶囊总重量 | 556.04 | 556.04 | 556.04 |
*这些数字是指乙磺酸盐的量(干重为基准),相当于游离碱的标识量
实施例7
含有150毫克活性物质的软明胶胶囊
制剂A | 制剂B | 制剂C | ||
成份 | 功能 | mg/胶囊 | mg/胶囊 | mg/胶囊 |
活性物质* | 活性成份 | 180.60 | 180.60 | 180.60 |
中链甘油三酯 | 载体 | 122.85 | 161.10 | 160.20 |
硬脂 | 增稠剂 | 114.75 | 76.50 | 76.50 |
卵磷脂 | 润湿剂/助流剂 | 1.80 | 1.80 | 2.70 |
明胶 | 成膜剂 | 142.82 | 142.82 | 142.82 |
甘油85% | 增塑剂 | 62.45 | 62.45 | 62.45 |
二氧化钛 | 着色剂 | 0.47 | 0.47 | 0.47 |
氧化铁A | 着色剂 | 0.08 | 0.08 | 0.08 |
氧化铁B | 着色剂 | 0.22 | 0.22 | 0.22 |
胶囊总重量 | 626.04 | 626.04 | 626.04 |
*这些数字是指乙磺酸盐的量(干重为基准),相当于游离碱的标识量
实施例8
含有200毫克活性物质的软明胶胶囊
制剂A | 制剂B | 制剂C | ||
成份 | 功能 | mg/胶囊 | mg/胶囊 | mg/胶囊 |
活性物质* | 活性成份 | 240.80 | 240.80 | 240.80 |
中链甘油三酯 | 载体 | 163.30 | 214.80 | 216.00 |
硬脂 | 增稠剂 | 153.50 | 102.00 | 102.00 |
卵磷脂 | 润湿剂/助流剂 | 2.40 | 2.40 | 1.20 |
明胶 | 成膜剂 | 203.19 | 203.19 | 203.19 |
甘油85% | 增塑剂 | 102.61 | 102.61 | 102.61 |
二氧化钛 | 着色剂 | 0.57 | 0.57 | 0.57 |
氧化铁A | 着色剂 | 0.90 | 0.90 | 0.90 |
氧化铁B | 着色剂 | 0.90 | 0.90 | 0.90 |
胶囊总重量 | 868.17 | 868.17 | 868.17 |
*这些数字是指乙磺酸盐的量(干重为基准),相当于游离碱的标识量
实施例9
上述实施例4至8中软明胶胶囊的包装材料,可为玻璃容器、柔性/硬质塑料容器或PVC/PVDC泡罩包装,任选在铝袋内或alu/alu泡罩包装。
实施例10
下文中,描述了活性物质脂质悬浮液制剂的制备方法以及关于胶囊化的方法。
a.将硬脂与部分中链甘油三酯在加工单元中预混合。接着添加卵磷脂、剩余的中链甘油三酯及活性物质。混合悬浮液、均化、脱气,及最后过筛,得到制剂(充填混合物)。
b.将明胶基本物质成份(甘油、水及明胶)混合并在高温下溶解。然后,添加其相应的色料,并混合,得到带有颜色的明胶物质。
c.调整胶囊化机器后,使用旋转孔模(rotary-die)方法,将充填混合物与带有颜色的明胶物质加工成软明胶胶囊。该方法公开于如Swarbrick,Boylann,Encyclopedia ofpharmaceutical technology,Marcel Dekker,1990,vol.2,pp 269ff。
d.初步干燥是使用旋转干燥器进行。对于最后的干燥步骤,将胶囊放置在托盘上。干燥在15-26℃与低相对湿度下进行。
e.在目视检查100%胶囊以分离已变形或渗漏胶囊后,将胶囊进行大小筛选。
f.最后,使用平版印刷技术或喷墨印刷技术,将胶囊做印记。或者,胶囊印记可使用带状印刷技术制成,其中明胶带是在胶囊化步骤c之前做印记。
综上所述,本发明包括但不限于以下技术方案:
1.活性物质3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐的制剂,其包含所述活性物质的悬浮液。
2.技术方案1的制剂,其中所述活性物质的悬浮液为包含载体与增稠剂的3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐的粘稠悬浮液。
3.技术方案2的制剂,其中所述载体选自乙酰化甘油单酯、玉米油甘油酯、油酸乙酯、甘油单/二油酸酯、甘油单亚油酸酯、甘油、聚乙二醇甘油癸酰基癸酸酯、聚乙二醇甘油亚油酸酯、中链偏甘油酯、中链甘油三酯、辛酸-癸酸甘油三酯、辛酸/癸酸/亚油酸甘油三酯、辛酸/癸酸/琥珀酸甘油三酯、丙二醇二辛酸酯/二癸酸酯、油酸、液体或半固体低/中等粘稠聚乙二醇、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、丙二醇单辛酸酯、丙二醇单月桂酸酯、精制动物衍生油、精制大豆油、精制植物油、山梨聚糖单硬脂酸酯、甘油三醋酸酯、柠檬酸三乙酯,或其混合物。
4.技术方案2的制剂,其中增稠剂选自半固体高粘稠或固体聚乙二醇、形成油凝胶的赋形剂、高粘度的亲脂性或两亲性赋形剂,和硬脂。
5.技术方案2的制剂,其中所述载体为脂质(亲脂性)载体。
6.技术方案2的制剂,其进一步包含助流剂/增溶剂。
7.技术方案6的制剂,其中所述助流剂/增溶剂选自卵磷脂。
8.技术方案7的制剂,其包含3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐在中链甘油三酯、硬脂和卵磷脂中的粘稠悬浮液。
9.技术方案1至8中任一项的制剂,其进一步包含一种或多种聚乙二醇甘油和/或增溶剂。
10.技术方案9的制剂,其中所述聚乙二醇甘油选自聚乙二醇甘油羟基硬脂酸酯或聚乙二醇甘油蓖麻醇酸酯。
11.包含胶囊壳与胶囊制剂的胶囊,其特征在于所述胶囊制剂包含技术方案1至10中任一项的制剂。
12.技术方案11的胶囊,其特征在于所述胶囊为软明胶胶囊。
13.技术方案11的胶囊,其特征在于所述胶囊壳包含甘油作为增塑剂。
14.技术方案11的胶囊,其特征在于所述胶囊为硬明胶胶囊或羟丙基甲基纤维素(HPMC)胶囊、聚乙烯醇聚合物胶囊或普鲁兰胶囊,任选地具有封口或密封带。
15.技术方案1至10中任一项的制剂或技术方案11至14中任一项的胶囊,其用作药物。
16.技术方案1至10中任一项的制剂或技术方案11至14中任一项的胶囊,其用作具有抗增殖活性的药物组合物。
17.技术方案1至10中任一项的制剂或技术方案11至14中任一项的胶囊,其用于治疗选自肿瘤性疾病、免疫性疾病或涉及免疫成份的病理学病症及纤维变性疾病的疾病或病症。
18.技术方案1至10中任一项的制剂或技术方案11至14中任一项的胶囊在制备用于治疗选自肿瘤性疾病、免疫性疾病或涉及免疫成份的病理学病症及纤维变性疾病的疾病或病症的药物中的用途。
19.治疗和/或预防选自肿瘤性疾病、免疫性疾病或涉及免疫成份的病理学病症及纤维变性疾病的疾病或病症的方法,其特征在于每日一次或数次向患者口服给药有效量的技术方案1至10中任一项的制剂或技术方案11至14中任一项的胶囊。
20.技术方案1至10中任一项的制剂或技术方案11至14中任一项的胶囊,其以0.1毫克至20毫克活性物质/kg体重的剂量范围使用。
21.适于包装胶囊的玻璃容器或柔性/硬质塑料容器,其含有一种或多种技术方案11至14中任一项的胶囊。
22.适于包装胶囊的任选具有铝外包装的塑料泡罩包装或铝泡罩包装,其含有一种或多种技术方案11至14中任一项的胶囊。
Claims (9)
1.活性物质3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮-单乙磺酸盐的制剂,其包含所述活性物质在1至90重量%的中链甘油三酯、1至30重量%的硬脂和0.1至10重量%的卵磷脂中的粘稠脂质悬浮液。
2.权利要求1的制剂,其中所述活性物质在10至70重量%的中链甘油三酯、10至30重量%的硬脂和0.25至2.5重量%的卵磷脂中的脂质悬浮液。
3.包含胶囊壳与胶囊制剂的胶囊,其特征在于所述胶囊制剂包含权利要求1或2的制剂。
4.权利要求3的胶囊,其特征在于所述胶囊为软明胶胶囊。
5.权利要求3的胶囊,其特征在于所述胶囊壳包含甘油作为增塑剂。
6.权利要求3的胶囊,其特征在于所述胶囊为硬明胶胶囊或羟丙基甲基纤维素(HPMC)胶囊、聚乙烯醇聚合物胶囊或普鲁兰胶囊,任选地具有封口或密封带。
7.权利要求1或2的制剂或权利要求3至6中任一项的胶囊,其用作药物。
8.权利要求1或2的制剂或权利要求3至6中任一项的胶囊,其用作具有抗增殖活性的药物组合物。
9.权利要求1或2的制剂或权利要求3至6中任一项的胶囊,其用于治疗选自肿瘤性疾病、免疫性疾病或涉及免疫成分 的病理学病症及纤维变性疾病的疾病或病症的用途。
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