CN114929207A - 利奥西呱的调节释放型药物组合物 - Google Patents
利奥西呱的调节释放型药物组合物 Download PDFInfo
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- CN114929207A CN114929207A CN202080091994.6A CN202080091994A CN114929207A CN 114929207 A CN114929207 A CN 114929207A CN 202080091994 A CN202080091994 A CN 202080091994A CN 114929207 A CN114929207 A CN 114929207A
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- riociguat
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Abstract
本发明涉及利奥西呱或其可药用盐的调节释放型药物组合物。特别地,本发明的组合物是稳定的,具有制剂特征并且还在24小时时间段内提供延长的治疗有效的血浆水平。本发明还涉及制备这样的组合物的方法。
Description
技术领域
本发明涉及利奥西呱(riociguat)或其可药用盐的调节释放型药物组合物(modified release pharmaceutical composition)。特别地,本发明的组合物是稳定的,具有制剂特征并且还在24小时时间段内提供延长的治疗有效血浆水平。本发明还涉及制备这样的组合物的方法。
背景技术
利奥西呱,3,5-二氨基-6-(2,3-二氯苯基)-1,2,4-三嗪,具有化学式C20H19FN8O2和以下结构式:
利奥西呱是可溶性鸟苷酸环化酶(soluble guanylate cyclase,sGC)的刺激剂,并且可用于治疗肺高压(pulmonary hypertension),所述sGC是心肺***中的酶并且是一氧化氮(NO)的受体。
美国专利No.7,173,037公开了利奥西呱及其相关化合物,以及它们的可药用盐。
利奥西呱在美国以品牌作为用于治疗慢性血栓栓塞性肺高压和肺动脉高压(pulmonary arterial hypertension)的立即释放型片剂形式获批,剂量范围为0.5mg至2.5mg TID施用(一天3次)。
现有市售的利奥西呱片剂制剂一旦片剂到达胃部就提供对活性成分的立即释放。利奥西呱的绝对生物利用度很高,为约94%,并且在药物施用之后1.5小时内观察到血浆浓度峰值。因此,由于吸收速率快,立即释放型片剂的施用可导致更高频率的不良药理学事件。立即释放型片剂剂型的另一个缺点是使用这些片剂达到的血浆浓度是周期性的,在施用药物之后出现峰值,随后在下一次施用药物之前出现谷值(trough)。
因此,存在并持续有对含有利奥西呱的调节释放型药物组合物的需要,其在目标时间段内具有可靠的较慢吸收,以减少给药间隔期间药物血浆浓度的波动,这可以解决与使用利奥西呱相关的一些问题。此外,可以使实现所期望治疗效果所需的药物量最小化,这可以提高药物的安全性和耐受性谱。
需要提供在目标时间段内具有可靠吸收并且同时具有批量制造(bulkmanufacturing)产品所期望的良好制剂特征的利奥西呱的调节释放型药物组合物。
发明概述
在一个一般方面中,提供了调节释放型药物组合物,其包含利奥西呱和一种或更多种释放延迟剂。
在另一个一般方面中,提供了适合于一天一次或一天两次施用的利奥西呱的调节释放型药物组合物。
利奥西呱的调节释放可通过使用基质剂型、储库剂型(reservoir dosage form)、多颗粒剂型、黏膜黏附性剂型或渗透剂型来实现。
在另一个一般方面中,提供了调节释放型药物组合物,其包含利奥西呱与一种或更多种释放延迟剂和一种或更多种可药用赋形剂的基质。在利奥西呱释放期期间,剂型的基质基本上保持完整。剂型的基质通过扩散和/或侵蚀来释放利奥西呱。
在另一个一般方面中,提供了调节释放型药物组合物,其包含:含有利奥西呱的核芯;在所述核芯上的任选的屏障包衣;以及包含一种或更多种释放延迟剂的至少一层包衣。
在另一个一般方面中,提供了调节释放型药物组合物,其包含:
(a)持续释放组分,其包含含有利奥西呱和一种或更多种释放延迟剂的多个颗粒;和
(b)立即释放组分,其包含包衣在持续释放组分上的利奥西呱。
在另一个一般方面中,提供了调节释放型药物组合物,其包含含有利奥西呱、一种或更多种渗透原(osmogen)和任选的一种或更多种释放延迟剂的核芯,以及半透性包衣。半透性包衣包含一种或更多种水不溶性聚合物。该剂型可主要通过渗透压来递送利奥西呱。
在另一个一般方面中,提供了稳定的调节释放型药物组合物,其包含利奥西呱、一种或更多种释放延迟剂和任选的一种或更多种可药用赋形剂,其中所述组合物在40℃和75%相对湿度下稳定至少一个月。
调节释放型药物组合物的实施方案可包括以下特征中的一种或更多种。例如,可药用赋形剂可包括一种或更多种的填充剂、黏合剂、崩解剂、助流剂/润滑剂/抗黏剂、渗透原、增塑剂等。
在另一个一般方面中,提供了治疗高血压的方法,其包括向患者经口施用治疗有效量的包含利奥西呱和一种或更多种释放延迟剂的调节释放型药物组合物形式的利奥西呱。
代表性的调节释放型药物组合物包括片剂、胶囊剂、颗粒剂、丸粒剂(pellet)、微片剂(minitablet)、填充有微片剂和/或丸粒剂的胶囊剂、或填充在袋剂中的颗粒剂。
本发明的一个或更多个实施方案的细节在以下描述中阐述。本发明的其他特征、目的和优点将从描述中显而易见。
发明详述
本发明的发明人出人意料地发现,可开发稳定的利奥西呱调节释放型药物组合物,所述药物组合物适合于一天一次或一天两次的施用,在目标时间段内具有可靠的吸收。根据本发明的组合物还具有批量制造产品所期望的良好制剂特征(例如流动性、可压缩性、含量均匀性等)。
本发明涉及用于治疗肺高压的利奥西呱的经口调节释放型组合物。利奥西呱的调节型释放可通过使用基质剂型、多颗粒剂型、储库剂型、黏膜黏附性剂型或渗透剂型来实现。
除非本文另有说明,否则术语“利奥西呱”应理解为包括所述化合物的任何可药用形式和盐。利奥西呱可以以结晶或无定形形式存在。本发明的药物组合物包含约0.5mg至约7.5mg的利奥西呱。通常来说,本发明的调节释放型组合物包含按重量计约0.5%至10%的利奥西呱。
本文中使用的术语“约”意指在所述数值的合理的附近,例如正或负10%或5%内。
如上文和说明书通篇使用的术语“调节释放型药物组合物”包括这样的剂型,所述剂型含有提供药物从剂型中延长释放或者立即释放和延长释放的组合的组分。术语“延长释放”可以替代地以“持续释放”、“控制释放”或“延迟释放”使用。
如上文和说明书通篇使用的术语“组分”是指含有利奥西呱的粉末、颗粒(particle)、团粒、颗粒(granule)、丸粒、微片、微胶囊、片剂、核芯和其上的包衣/层或本领域技术人员已知的任何固体物理形式。
如上文和说明书通篇使用的术语“释放延迟剂”是指减慢药物从药物组合物中释放的任何材料或物质。释放延迟剂可以是聚合物或非聚合物。在不同的递送***中,术语“释放延迟剂”可以以不同的术语使用,例如,渗透剂型中的“携带剂(entraining agent)”,黏膜黏附性剂型中的“黏膜黏附性聚合物”等。
除了释放延迟剂之外,本发明的剂型还可以包含一种或更多种可药用的赋形剂,如稀释剂、黏合剂、崩解剂、助流剂、/润滑剂/抗黏剂、渗透原、增塑剂等。
合适的稀释剂的一些实例包括但不限于糖粉(powdered sugar)、磷酸钙、硫酸钙、微晶纤维素、粉状纤维素、乳糖、甘露糖醇、高岭土、氯化钠、干淀粉和山梨糖醇。稀释剂可以以按组合物重量计5%至90%的量存在。
合适的黏合剂的一些实例包括但不限于聚乙烯吡咯烷酮、黄原胶、纤维素衍生物例如羧甲基纤维素、甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙甲纤维素、明胶、淀粉和预胶凝淀粉。黏合剂可以以按组合物重量计1%至20%的量存在。
合适的崩解剂的一些实例包括但不限于交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、预胶凝淀粉、低取代羟丙基纤维素和羟基乙酸淀粉钠。崩解剂可以以按组合物重量计0.5%至20%的量存在。
合适的润滑剂或助流剂或抗黏剂的一些实例包括但不限于滑石、二氧化硅胶体、硬脂酸、植物油、硬脂酸钙、硬脂酸锌和硬脂酸镁。润滑剂可以以按组合物重量计0.1%至10%的量存在。
合适的渗透原的一些实例包括但不限于氯化钾、硫酸镁、硫酸钙、氯化镁、氯化钠、氯化锂、硫酸钾、碳酸钠、亚硫酸钠、硫酸锂、氯化钾、硫酸钠、d-甘露糖醇、尿素、山梨糖醇、肌醇、棉子糖、蔗糖、葡萄糖、亲水性聚合物例如纤维素聚合物,及其混合物。渗透原可以以按组合物重量计10%至20%的量存在。
合适的增塑剂的一些实例包括但不限于邻苯二甲酸二丁酯、癸二酸二丁酯、邻苯二甲酸二乙酯、邻苯二甲酸二甲酯、柠檬酸三乙酯、苯甲酸苄酯、脂肪酸的丁酯和乙二醇酯、矿物油、油酸、硬脂酸、鲸蜡醇、硬脂醇、蓖麻油、玉米油、椰子油和樟脑油。增塑剂可以以按组合物重量计0.01%至20%的量存在。
可并入到剂型中的另一些赋形剂包括但不限于防腐剂、抗氧化剂或制药工业中常用的任何其他赋形剂。
基质剂型:
在一个实施方案中,将利奥西呱包埋到可侵蚀或不可侵蚀的聚合物基质中。可侵蚀基质包括在存在或不存在酸或碱的情况下在水性介质中可侵蚀或可溶胀或可溶解以使聚合物基质充分离子化以引起侵蚀或溶解的基质。当与水性介质接触时,可侵蚀的聚合物基质吸收水并形成水溶胀凝胶或“基质”,从而截留(entrap)利奥西呱。水溶胀基质在使用环境中逐渐侵蚀、溶胀、崩解、分散或溶解,从而控制利奥西呱释放到使用环境中。
用于制备水可溶胀、可侵蚀或可溶性基质的聚合物的一些实例包括但不限于天然存在的多糖,例如几丁质、壳聚糖、右旋糖酐和普鲁兰多糖(pullulan);琼脂胶、***胶、刺梧桐树胶(gum karaya)、槐豆胶、黄蓍胶、卡拉胶、瓜尔胶、黄原胶和硬葡聚糖;淀粉,例如糊精和麦芽糖糊精;亲水胶体,例如果胶;褐藻胶,例如藻酸铵、藻酸钠、藻酸钾或藻酸钙,藻酸丙二醇酯;明胶;胶原;和纤维素例如甲基乙基纤维素、羧甲基纤维素、羧甲基乙基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙甲纤维素、邻苯二甲酸羟丙甲纤维素、乙酸琥珀酸羟丙甲纤维素、乙酸偏苯三酸羟丙甲纤维素和乙基羟乙基纤维素。
在不可侵蚀的基质***中,利奥西呱分布在惰性基质中。药物通过扩散通过惰性基质来释放。适用于惰性基质的材料的一些实例包括但不限于乙烯和乙酸乙烯酯的共聚物、丙烯酸甲酯-甲基丙烯酸甲酯共聚物、聚氯乙烯和聚乙烯;乙基纤维素、乙酸纤维素、交联聚乙烯吡咯烷酮和脂肪化合物,例如巴西棕榈蜡(carnauba wax)、微晶蜡和甘油三酯。
可侵蚀或不可侵蚀聚合物释放延迟剂可以以按组合物重量计10%至70%的量存在。
本发明的调节释放型基质剂型通常可使用本领域公知的标准技术来制备。通常来说,它们可通过将利奥西呱、释放延迟剂和其他赋形剂干混,随后使用溶剂将混合物制粒直至获得合适的制粒(granulation)来制备。制粒可通过本领域已知的方法来进行。可将湿颗粒在流化床干燥器中干燥,将其筛分并研磨至合适尺寸。可将润滑剂与干燥的颗粒混合以获得最终剂型。释放延迟剂可以颗粒内或颗粒外使用或以这两种情况使用。
或者,可使用对单独或与一种或更多种释放延迟剂和一种或更多种可药用赋形剂组合的含有利奥西呱的粉末状或颗粒状组合物进行的直接压制来制备基质剂型。
在另一个实施方案中,多颗粒基质剂型包含含有利奥西呱的多个颗粒,每个颗粒包含利奥西呱与所选择以形成如下基质的一种或更多种释放延迟剂的混合物:所述基质能够限制利奥西呱溶出到水性介质中的速率。可用于该实施方案的释放延迟剂通常是水不溶性材料,例如蜡、纤维素或其他水不溶性聚合物。如果需要的话,基质可以任选地与可用作黏合剂或渗透性调节剂的水溶性材料一起配制。
可用于制备这些剂型的释放延迟剂的一些实例包括微晶纤维素、蜡(例如石蜡)、改性植物油(modified vegetable oil)、巴西棕榈蜡、氢化蓖麻油、蜂蜡等,以及合成聚合物例如聚氯乙烯、聚乙酸乙烯酯、乙酸乙烯酯和乙烯的共聚物、聚苯乙烯等。可任选地配制成基质的水溶性黏合剂或释放延迟剂包括水溶性聚合物,例如羟丙基纤维素、羟丙甲纤维素、甲基纤维素、聚乙烯吡咯烷酮、聚环氧乙烷、聚乙烯醇、黄原胶、卡拉胶和其他这样的天然和合成材料。
多颗粒基质通常可通过挤出/滚圆方法(extrusion/spheronization process)来制备。对于该方法,可将利奥西呱用黏合剂进行湿团聚(wet-mass),通过穿孔板或模具挤出,并置于旋转盘(rotating disk)上。可将挤出物分解成块,可将所述块在旋转板上圆化(round)成球体、球状体或圆棒。
或者,可通过制备蜡颗粒来制备多颗粒基质。在该方法中,可将期望量的利奥西呱与液体蜡一起搅拌以形成均质混合物,将其冷却,并随后使其通过筛网以形成颗粒。
用于制备多颗粒基质的另一些方法可涉及使用有机溶剂以帮助将利奥西呱与释放延迟剂混合。利奥西呱和释放延迟剂可与溶剂组合以形成糊状物,并随后使该糊状物通过筛网以形成颗粒,然后可从中去除溶剂。
或者,可将利奥西呱和释放延迟剂与一种或更多种溶剂组合以完全溶解释放延迟剂,并且可将所得溶液(其可以含有固体药物颗粒)喷雾干燥以形成颗粒剂型。当释放延迟剂是高分子量合成聚合物例如纤维素醚或纤维素酯时,该技术可以是优选的。通常用于该方法的溶剂可包括丙酮、乙醇、异丙醇、乙酸乙酯,以及两种或更多种的混合物。
在另一个实施方案中,多颗粒基质可通过熔体喷雾凝结方法(melt spraycongeal process)来形成。熔体凝结核芯可包含释放延迟剂。
基于未包衣核芯的质量,释放延迟剂可以以按重量计至少10%至70%存在于核芯中。
用于熔体喷雾凝结方法的释放延迟剂选自蜡、长链醇、脂肪酸酯、乙二醇化脂肪酸酯、磷酸甘油酯、聚氧乙烯烷基醚、长链羧酸、糖醇及其混合物。示例性释放延迟剂包括高度纯化形式的蜡,例如巴西棕榈蜡、白色和黄色蜂蜡、地蜡(ceresin wax)、微晶蜡和石蜡;长链醇,例如硬脂醇、鲸蜡醇和聚乙二醇;脂肪酸酯(也称为脂肪或甘油酯),例如棕榈酸异丙酯、肉豆蔻酸异丙酯、单油酸甘油酯、单硬脂酸甘油酯、棕榈硬脂酸甘油酯(glycerylpalmitostearate)、单烷基-、二烷基-和三烷基甘油酯的混合物,包括单山嵛酸-、二山嵛酸-和三山嵛酸甘油酯的混合物、甘油三硬脂酸酯、甘油三棕榈酸酯和氢化植物油,包括氢化棉籽油;乙二醇化脂肪酸酯,例如聚乙二醇硬脂酸酯和聚乙二醇二硬脂酸酯;聚氧乙烯烷基醚;聚乙氧基化蓖麻油衍生物;长链羧酸例如硬脂酸;以及糖醇,例如甘露糖醇和赤藓糖醇。
多颗粒通过包括以下步骤的熔体凝结方法(melt-congeal process)来制备:(a)形成包含利奥西呱和释放延迟剂的熔融混合物;(b)将步骤(a)的熔融混合物递送至雾化装置以从熔融混合物形成微滴;以及(c)使来自步骤(b)的微滴凝结以形成多颗粒。
多颗粒还可以与一种或更多种可药用赋形剂混合或共混以形成合适的剂型。合适的剂型可包括片剂、胶囊剂、袋剂、用于构成(constitution)的经口散剂等。
在形成熔体喷雾凝结多颗粒之后,所述多颗粒可任选地用任何常规的包衣进行包衣,所述常规包衣例如保护膜包衣、提供药物持续释放的包衣或提供味道掩蔽的包衣。
包衣可包括常规增塑剂和其他赋形剂,例如防黏剂(anti-tack agent)、助流剂等。包衣可通过常规仪器来施加,例如通过锅体包衣机(pan coater)、流化床包衣机,例如顶部喷雾、切向喷雾或底部喷雾来施加。
渗透剂型
将利奥西呱并入到渗透递送装置或渗透泵中。渗透泵包含含有被半透性包衣包围的渗透有效组合物的核芯。半透性包衣对于水是可渗透的,但溶解在水中的溶质通常不能容易地扩散通过包衣。
在本发明的一个实施方案中,将利奥西呱并入到包含第一层和第二层的双层片剂核芯中,所述第一层包含利奥西呱、一种或更多种释放延迟剂和一种或更多种渗透原,所述第二层包含一种或更多种水溶胀性聚合物、任选的一种或更多种渗透原。双层片剂核芯被半透性包衣包围,所述半透性包衣含有通过激光打孔(laser drilling)制备到剂型中的一个或更多个开口或孔口。在这类剂型中使用的释放延迟剂也被称为携带剂。携带剂携带药物以帮助通过一个或更多个孔口来递送药物。
释放延迟剂或携带剂可以是单一材料或材料的混合物。非交联聚环氧乙烷可用作携带剂。另一些合适的携带剂的一些实例包括但不限于羟丙基纤维素、羟丙甲纤维素、甲基纤维素、羟乙基纤维素和聚乙烯吡咯烷酮,以及这些聚合物与聚环氧乙烷的混合物。组合物中存在的释放延迟剂或携带剂的量可以为按组合物重量计15%至95%。
合适的水溶胀性聚合物的一些实例包括但不限于羟基乙酸淀粉钠、交联羧甲基纤维素钠、分子量为30,000至5,000,000的聚(甲基丙烯酸羟烷基酯);κ卡拉胶、分子量为10,000至360,000的聚乙烯吡咯烷酮;阴离子和阳离子水凝胶;聚电解质络合物;与乙二醛交联的具有低乙酸残留的聚(乙烯醇);甲基纤维素的混合物;交联琼脂和羧甲基纤维素;N-乙烯基内酰胺的水溶胀性聚合物等。这样的聚合物可以以按组合物重量计0.5%至20%的量存在。
用于半透性包衣的合适材料的一些实例包括但不限于酰化纤维素、二酰化纤维素、三酰化纤维素、乙酸纤维素、二乙酸纤维素、三乙酸纤维素、乙酸琼脂、三乙酸直链淀粉、β-乙酸葡聚糖、乙醛乙酸二甲酯、乙酸乙基氨基甲酸纤维素(cellulose acetate ethylcarbamate)、聚酰胺、聚氨酯、磺化聚苯乙烯、乙酸邻苯二甲酸纤维素、乙酸甲基氨基甲酸纤维素、乙酸琥珀酸纤维素、乙酸二甲基氨基乙酸纤维素、乙酸乙基氨基甲酸纤维素、乙酸氯乙酸纤维素、二棕榈酸纤维素、二辛酸纤维素、二癸酸纤维素(cellulose dicaprylate)、二戊酸纤维素、乙酸戊酸纤维素、乙酸琥珀酸纤维素、丙酸琥珀酸纤维素、甲基纤维素、乙酸对甲苯磺酸纤维素、乙酸丁酸纤维素、交联聚(苯乙烯磺酸钠)、聚(乙烯基苄基三甲基氯化铵)等。
片剂上的半透膜包衣以对应于按片剂核芯重量计2%至30%的重量存在。
本文中使用的表述“孔口”包括通过机械程序钻透半透膜的一个或更多个孔。或者,其可通过在半透膜中并入可侵蚀元件(例如明胶塞)来形成。
本发明的渗透泵可通过标准技术来制造。例如,在一个实施方案中,可容纳在隔室的与通道(passageway)相邻的一个区域中的药物和其他赋形剂可被压制成尺寸对应于药物将占据的隔室区域的内部尺寸的固体,或者可将药物和其他赋形剂与溶剂一起通过常规方法(例如球磨(ball-milling)、压延(calendaring)、搅拌或辊磨(roll-milling))混合成固体或半固体形式,并随后压制成预先选择的形状。接下来,可将亲水性聚合物层以类似的方式布置成与药物层接触,并且可将这两层用半透性壁包围。药物制剂和亲水性聚合物的分层可通过常规的两层压制技术来制造。可通过将所压制的层模制、喷涂或浸入壁形成材料或释放延迟剂中来应用壁。
或者,渗透剂型的核芯可以是三层片剂核芯。三层片剂核芯包含:含有利奥西呱和其他赋形剂的第一层,含有更高量的利奥西呱和其他赋形剂的第二层以及作为推送层(push layer)并且不含利奥西呱的第三层。在三层渗透剂型中,药物以受控方式从第一含药物层,并随后以受控方式从第二含药物层依次释放,以在延长的时间段内提供上升的释放速率。
储库剂型
在本发明的另一个实施方案中,提供了这样的组合物,其包含含有利奥西呱的核芯和在组合物(例如片剂或珠)的一个或更多个外表面上的释放延迟包衣。可将常规的立即释放型压制片剂至少部分地用包含释放延迟剂的包衣进行包衣,或者作为替代地,使用其中并入了利奥西呱的可药用珠,并随后将珠至少部分地通过包含释放延迟剂的包衣进行包衣。在一些实施方案中,另外的屏障包衣可存在于核芯与包衣之间。
例如,包衣可以由这样的聚合物构成,所述聚合物对于水或水性介质基本上或完全不渗透,或者在水或水性介质或生物液体中可缓慢侵蚀和/或与水或水性介质或生物液体接触时溶胀。包衣还可包括常规的黏合剂、增塑剂、填充剂、润滑剂、着色剂、压制助剂(compression aid)等。
用于包衣的合适聚合物的一些实例包括但不限于丙烯酸酯、甲基丙烯酸酯、丙烯酸或其酯的共聚物、纤维素及其衍生物,例如乙基纤维素、乙酸丙酸纤维素、聚乙烯和聚乙烯醇等。
组合物中存在的聚合物的量可以为按组合物重量计1%至30%。
多颗粒剂型
提供了包含多颗粒的组合物,其中颗粒被一种或更多种释放延迟剂包衣以提供利奥西呱的调节型释放。多颗粒颗粒剂包含利奥西呱和一种或更多种赋形剂。单独颗粒的尺寸通常为约50微米至约2mm,但是尺寸在该范围之外的珠也是可用的。
多颗粒组合物可使用本领域技术人员已知的技术来制备,包括但不限于挤出和滚圆、湿法制粒、流化床制粒和旋转床制粒的技术。另外,多颗粒也可以以以下来制备:通过药物分层技术(例如粉末包衣)将利奥西呱组合物(药物加赋形剂)构建在粒子核芯(seedcore)(例如非pareil粒子)上,或者通过喷洒利奥西呱在合适黏合剂溶液中的溶液或分散体将利奥西呱组合物施加到流化床(例如wurster包衣机或旋转处理器)中的粒子核芯上。
在本发明的另一个实施方案中,提供了这样的药物组合物,其并入了能够在约10小时至约24小时内释放利奥西呱的控制释放型珠和立即释放型珠。该实施方案的药物组合物通常包含量为按组合物总重量的重量计约10%至约50%的立即释放型利奥西呱珠和量为按组合物总重量的重量计约50%至约90%的控制释放型利奥西呱珠。
可将这些多颗粒压制成片剂剂型,或者作为替代地,可将这些多颗粒填充到胶囊剂或袋剂中。
黏膜黏附性剂型
在另一个实施方案中,提供了包含一种或更多种释放延迟剂的利奥西呱的调节释放型药物组合物。用于此类剂型的释放延迟剂也被称为黏膜黏附性聚合物。
黏膜黏附性聚合物是能够黏附至胃肠道衬里黏膜的天然或合成聚合物。黏膜黏附性聚合物可以作为包衣或作为药物递送基质的一部分应用。将黏膜黏附性聚合物包含在组合物中以通过组合物与GI道壁的黏附来提高胃肠道滞留。
合适的黏膜黏附性聚合物的一些实例包括但不限于聚卡波非(polycarbophil)(与二乙烯基乙二醇交联的聚丙烯酸)、壳聚糖、葡聚糖钠、聚-L-天冬氨酸、聚苯乙烯磺酸、聚乙烯基硫酸酯/盐、聚谷氨酸、牛血清白蛋白、ficoll、酸性(高等电点)明胶、聚凝胺、聚乙烯基甲基咪唑、聚半乳糖胺、聚季铵化合物、谷醇溶蛋白、聚亚胺、二乙基氨基乙基葡聚糖、聚乙烯基吡啶、聚乙烯吡咯烷酮、聚硫代二乙基氨基甲基乙烯、聚组氨酸、聚对氨基苯乙烯、聚氧乙烷(polyoxethane)、共聚甲基丙烯酸酯、聚酰胺胺和阳离子型淀粉。
黏膜黏附性聚合物可以以按组合物重量计0.1%至20%的量存在。
黏膜黏附性组合物可以是以下形式:片剂、胶囊剂、多颗粒组合物或渗透装置。
本发明的黏膜黏附性组合物可通过将利奥西呱、黏膜黏附性聚合物和其他赋形剂混合,随后进行如前所述的湿法制粒、直接压制、挤出或滚圆方法来制备。
在本发明的另一个实施方案中,提供了多层固体组合物,其包含(a)含有利奥西呱和至少一种可药用赋形剂的立即释放第一层,以及(b)包含利奥西呱的持续释放第二层,其中立即释放层和持续释放层任选地被不含药物的赋形剂层隔开。在形成多层片剂时,所述层可通过常规湿法制粒或干法制粒(压实)技术或本领域已知的任何其他技术来制备。然后可使用常规的多层压片设备对所述层进行压制并组合以形成多层片剂。持续释放层包含一种或更多种如上提及用于持续释放基质体系的释放延迟聚合物。另外,所有层可任选地包含一种或更多种可药用赋形剂。
在另一个实施方案中,提供了稳定的调节释放型药物组合物,其包含利奥西呱、一种或更多种释放延迟剂和一种或更多种可药用赋形剂。
本文中使用的术语“稳定”意指活性成分在其整个储存和使用期间保持与其在其制造时所具有的基本上相同的特性和特征,使得在组合物储存和递送的时间段内所述组合物为患者提供基本上相同的治疗益处。
在另一个实施方案中,本文中所述的组合物在40℃和75%相对湿度下储存至少1个月(例如3个月、6个月、12个月、24个月等)之后,保留了利奥西呱的至少80%效力。
在另一个实施方案中,本发明提供了利奥西呱的调节释放型药物组合物,其中当组合物在37℃下在标准USP旋转桨装置中以75rpm经受包含900mL含有0.1%SLS的0.05M pH6.8磷酸钾缓冲液的测试介质时,在1小时内释放不超过15%的利奥西呱,并且在16小时内释放不少于70%的利奥西呱。
在一个替代实施方案中,当组合物在37℃下在标准USP旋转桨装置中以75rpm经受包含900mL含有0.1%SLS的0.05M pH 6.8磷酸钾缓冲液的测试介质时,在1小时内释放不超过10%的利奥西呱,并且在16小时内释放不少于75%的利奥西呱。
本发明通过以下实施例进行举例说明,提供的所述实施例是本发明的示例而不限制本发明的范围。
实施例1:延长释放型渗透片剂
程序:
通过在快速混合制粒机中使用含有溶解在乙醇中的聚维酮的黏合剂溶液对利奥西呱、聚环氧乙烷和聚维酮的粉末混合物进行制粒来制备用于制备药物层的颗粒。将制备的颗粒在流化床干燥器中干燥,并将经干燥的颗粒筛分以获得合适尺寸的颗粒,将其用硬脂酸镁润滑。
通过使用快速混合制粒机使用含有溶解在乙醇中的聚维酮的黏合剂溶液来对聚环氧乙烷、聚维酮、氯化钾和氧化铁红的粉末混合物进行制粒来制备用于制备推送层的颗粒。将制备的颗粒在流化床干燥器中干燥,并将经干燥的颗粒筛分以获得合适的尺寸,将其还用硬脂酸镁润滑。
将在上述步骤中制备的用于药物层和推送层的颗粒使用具有适当工具的双层压制机进行压制以提供双层核芯片剂。
通过喷洒乙酸纤维素和聚乙二醇在丙酮/水混合物中的溶液,对半透膜进行包衣以包围双层核芯片剂。
在靠近药物层的隔室窄端(narrow end)处的半透膜钻通直径为约0.6±0.3mm、并且深度为0.5±0.3mm的用于药物释放的合适孔口。
使用体外溶出测试装置使用下面给出的溶出条件来确定溶出数据:
实施例2:延长释放型基质片剂
Sr.No. | 成分 | mg/片剂 |
1 | 利奥西呱 | 2.50 |
2 | 羟丙甲纤维素 | 22.50 |
3 | 微晶纤维素 | 123.50 |
4 | 硬脂酸镁 | 1.50 |
5 | 纯化水 | Q.S. |
通过使用快速混合制粒机,使用含有溶解在水中的羟丙甲纤维素的黏合剂溶液,对利奥西呱、微晶纤维素和羟丙甲纤维素的粉末混合物进行制粒来制备颗粒。将制备的颗粒干燥并用硬脂酸镁润滑并使用具有适当工具的压制机进行压制以提供片剂。
实施例3:延长释放型储库片剂
通过使用含有溶解在水中的聚维酮的黏合剂溶液,对利奥西呱、微晶纤维素和乳糖一水合物的粉末混合物进行制粒来制备颗粒。将颗粒干燥并用硬脂酸镁润滑并使用具有适当工具的压制机进行压制以提供片剂。
通过喷洒乙基纤维素、羟丙甲纤维素和柠檬酸三乙酯在二氯甲烷和异丙醇的溶剂混合物中的溶液对片剂进行包衣。
虽然本发明已根据其具体实施方案进行了描述,但某些修改和等同方案对于本领域技术人员而言将是明显的,并且旨在包括在本发明的范围内。
Claims (20)
1.调节释放型药物组合物,其包含利奥西呱和一种或更多种释放延迟剂。
2.根据权利要求1所述的药物组合物,其中所述组合物包含约0.5mg至约7.5mg的利奥西呱。
3.根据权利要求1所述的药物组合物,其中所述释放延迟剂选自水溶胀性聚合物、水不溶性聚合物和非聚合物材料。
4.根据权利要求1所述的药物组合物,其中所述组合物包含:
a.核芯,其包含利奥西呱、一种或更多种渗透原、和任选的一种或更多种释放延迟剂;以及
b.半透性包衣,其包含一种或更多种释放延迟剂。
5.根据权利要求4所述的药物组合物,其中所述释放延迟剂以按所述组合物的重量计15%至95%的量存在。
6.根据权利要求4所述的药物组合物,其中所述渗透原以按所述组合物的重量计2%至55%的量存在。
7.根据权利要求4所述的药物组合物,其中所述半透性包衣中的所述释放延迟剂是水不溶性聚合物。
8.根据权利要求7所述的药物组合物,其中所述水不溶性聚合物以按所述组合物的重量计2%至30%的量存在。
9.根据权利要求4所述的药物组合物,其中所述核芯是包含第一层和第二层的双层片剂,所述第一层包含利奥西呱、一种或更多种释放延迟剂和一种或更多种渗透原,所述第二层包含水溶胀性聚合物。
10.根据权利要求9所述的药物组合物,其中所述水溶胀性聚合物以按所述组合物的重量计0.5%至20%的量存在。
11.根据权利要求4所述的药物组合物,其中所述核芯包含利奥西呱、聚环氧乙烷和氯化钾。
12.根据权利要求1所述的药物组合物,其中所述利奥西呱包埋在一种或更多种释放延迟剂的基质中。
13.根据权利要求12所述的药物组合物,其中所述释放延迟剂以按所述组合物的重量计10%至70%的量存在。
14.根据权利要求1所述的药物组合物,其中所述组合物包含:
a.含有利奥西呱的核芯;
b.在所述核芯上的任选的屏障包衣;以及
c.包含一种或更多种释放延迟剂的至少一层包衣。
15.根据权利要求14所述的药物组合物,其中所述释放延迟剂以按所述组合物的重量计1%至30%的量存在。
16.根据权利要求1所述的药物组合物,其中所述组合物为以下形式:片剂、胶囊剂、颗粒剂、丸粒剂、微片剂、填充有微片剂和/或丸粒剂的胶囊剂、或填充在袋剂中的颗粒剂。
17.根据权利要求1所述的药物组合物,其中所述组合物适合于一天一次施用。
18.根据权利要求1所述的药物组合物,其中所述组合物适合于一天两次施用。
19.根据权利要求1所述的药物组合物,其中所述组合物在40℃和75%相对湿度下储存至少一个月之后保留所述组合物中所述利奥西呱的至少80%效力。
20.根据权利要求1所述的药物组合物,其中所述组合物当在37℃下在标准USP旋转桨装置中以75rpm经受包含900mL含有0.1%SLS的0.05M pH 6.8磷酸钾缓冲液的测试介质时,在1小时内释放不超过15%的利奥西呱,并且在16小时内释放不少于70%的利奥西呱。
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CN105596311A (zh) * | 2015-12-29 | 2016-05-25 | 郑州大明药物科技有限公司 | 一种利奥西呱口服固体制剂及其制备方法 |
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