CN112469402B - 可口服给药且缓释的药物剂型 - Google Patents
可口服给药且缓释的药物剂型 Download PDFInfo
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- CN112469402B CN112469402B CN201980049223.8A CN201980049223A CN112469402B CN 112469402 B CN112469402 B CN 112469402B CN 201980049223 A CN201980049223 A CN 201980049223A CN 112469402 B CN112469402 B CN 112469402B
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Abstract
本发明涉及药物剂型,其可口服给药并缓释,且包含(3S)‑3‑(4‑氯‑3‑苯基‑{[(2S,3R)‑2‑(4‑氯苯基)‑4,4,4‑三氟‑3‑甲基丁酰基]氨基}苯基)‑3‑环丙基丙酸钠,以及制备所述剂型的方法及其用于治疗和/或预防疾病、特别用于治疗和/或预防以下疾病的用途:心脏疾病、肾脏疾病、肺疾病和眼部疾病,中枢神经系统的疾病,纤维性疾病和炎症性疾病以及代谢性疾病。
Description
本发明涉及包括(3S)-3-(4-氯-3-{[(2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰基]氨基}苯基)-3-环丙基丙酸钠的可口服给药的缓释药物剂型以及制备所述剂型的方法以及它们用于治疗和/或预防疾病、特别是治疗和/或预防以下疾病的用途:心脏疾病、肾脏疾病、肺疾病和眼部疾病,中枢神经系统的疾病,纤维性疾病和炎症性疾病以及代谢性疾病。
WO 2012/139888公开了式(I)化合物(3S)-3-(4-氯-3-{[(2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰基]氨基}苯基)-3-环丙基丙酸
以及其在实施例22中的制备。式(I)化合物充当可溶性鸟苷酸环化酶的激活剂。文献还公开了所记载的化学化合物通常可转变为片剂、可口服给药的悬浮剂和可口服给药的溶液。这些药物剂型排他性地代表快速释放药物组合物。
如果疾病需要长期治疗,或为了长期预防疾病,需要保持服用药剂的频率尽可能低。这样不仅对患者而言更方便,而且还通过减少无规律服用的缺点而增加了治疗可靠性。所需的服用频率的降低,例如从一天给药两次降至一天给药一次,可通过由活性成分从剂型缓释而延长治疗上有效的血浆水平来实现。
此外,在服用具有缓释的活性成分的剂型之后,可以通过使血浆水平时间曲线平滑来防止副作用。通过使峰-谷比例最小化,即通过避免在给予快速释放药物剂型后经常观察到的高血浆活性成分浓度,可减少与浓度峰值相关的不想要的副作用。因此,应开发这样的缓释药物剂型。本文中,选择渗透释放系统以确保活性成分在可变的、预先确定的时期内均匀的、长效的和完全的释放的所需特性。与其他延迟释放给药系统相比,渗透释放系统的特征在于,例如,释放特性可通过调节壳厚度来灵活地调节(Kaushal,A.M.,Garg,S.AnUpdate on Osmotic Drug Delivery Patents.Pharmaceutical Technology.2003.13(1):8-97)。
渗透释放系统也称为胃肠治疗系统(GITS)或口腔渗透系统(OROS)。通过渗透压来控制活性成分的长效且均匀的释放。
渗透释放系统可分成单室系统(初级渗透泵(elementary osmotic pump))和双室系统(推拉式系统(push-pull systems))。
在单室系统中,一种或多种渗透活性物质与活性成分混合并压缩。这些核被具有至少一个孔口的半透膜包围。该半透膜,下文称为壳,对于核的组分是不可渗透的,但允许水通过渗透从外面进入。然后渗入的水通过产生的渗透压由壳中的一个或多个孔口释放溶解或悬浮形式的活性成分。全部活性成分释放和释放速率实质上可通过壳的厚度和孔隙率、核的组成以及孔口的数量和大小来控制。
在双室系统中,一个室包括活性成分,另一个室包括渗透活性物质。这两个室可通过柔性分隔壁来分隔。该核同样被在包含活性成分的室的一侧具有至少一个孔口的壳包围。
关于渗透释放系统的制备方法的优点、制剂方面、使用形式和信息尤其记载于下面的出版物中:
·Kaushal,A.M.,Garg,S.:″An Update on Osmotic Drug Delivery Patents″,Pharmaceutical Technology 2003,13,8-97.
·Kumar,P.和Mishra,B.:″An Overview of Recent Patents on Oral OsmoticDrug Delivery Systems″,Recent Patents on Drug Delivery&Formalution2007,1,236-255.
·Verma,R.K.,Mishra,B.,Garg,S.:″Osmotically controlled oral drugdelivery″,Drug Development and Industrial Pharmacy 2000,26,695-708.
·Verma,R.K.,Krishna,D.M.,Garg,S.:″Formalution aspects in thedevelopment of osmotically controlled oral drug delivery systems″,Journal ofControlled Release 2002,79,7-27.
·Sareen.R.,Jain,N.,Kumar,D.:″An Insight to Osmotic Drug Delivery″,Current Drug Delivery 2012,9,285-296.
·Malaterre,V.,Ogorka,J.,Loggia,N.,Gurny,R.:″Oral osmotically drivensystems:30years of development and clinical use″,European Journal ofPharmaceutics and Biopharmaceutics 2009,73,311-323.
·US 4,327,725
·US 4,765,989
·US 20030161882
·EP-A 1024793
在本发明上下文中,式(I)化合物应配制成渗透释放系统的形式以实现长效的和均匀的释放。
经常使用的亲水性可溶胀聚合物为——特别是在双室系统的情况下——聚环氧乙烷(WO 2006/072367)。出乎意料地,式(I)化合物不能以常规方式与作为亲水性可溶胀聚合物的聚环氧乙烷配制成渗透释放系统的形式。在含式(I)化合物的渗透释放系统的制备方法过程中,在制粒期间产生熔化现象。所发生的低效的制备方法产生不满足药物产品的要求和规格的剂型。
当使用式(I)化合物和作为亲水性可溶胀聚合物的聚环氧乙烷时,在使用辊进行干法制粒期间,观察到所获得的部分颗粒的一致性变化。颗粒组分互相熔合得到类似于凝固熔体的硬的塑料样材料,其不适合用于进一步处理。必须放弃计划的生产工艺。只有在力气、材料和时间的高支出的情况下,才可能通过磨碎和筛分来粉碎所述凝固熔体,这使得生产工艺效率低下,并且在产品的可重现的药物质量方面也不可靠。
在用高支出进行筛分的含活性成分的辊式颗粒的进一步处理过程中,压缩片剂的过程中还有其他不利影响。早在进料漏斗中,观察到“桥形成”,这意味着由于颗粒的粗糙表面,使颗粒相互捕获。因此,准备用于压缩的混合物在没有额外搅拌的情况下不可流动。因此准备用于压缩的作为混合物的颗粒的连续压片是不可能的。此处,同样,必须放弃该制备工艺。压片机的机器零件如打孔器、模板和回转台显示用于压缩的包含活性成分的混合物的显著附着。获得的少量片剂显示顶裂趋势,其中由于从压片机排出时或在处理期间,片剂的上部分和下部分部分地或全部地水平地从主体部分分离并形成帽(cap)。这样的片剂不满足可接受的药物质量的需求,不再适合使用。
当取得并分析制粒前包含活性成分的粉末混合物的、筛分前塑料样材料的、粉碎和筛分后塑料样材料的和研磨筛上的残余物的各种样品时,发现式(I)化合物的含量的明显变化。由在制粒前包含活性成分的粉末混合物中100%的所声称的活性成分含量开始,样品示出了107%至120%的含量值,基于所声称的活性成分含量计。所述一致地升高的含量值很可能是由于以下事实:在制备期间仅一些辊式颗粒熔体和式(I)化合物以非均匀形式存在。具有这种活性成分含量偏差的药物剂型是不可接受的,并且不能用于进一步开发。必须假定,测得的粉末混合物的含量变化也导致由此制得的片剂的含量变化,且因此这些片剂不符合药典的要求,例如含量一致性(欧洲药典第9版;2.9.40不Uniformity of DosageUnits”)。
出乎意料地,通过用该式(I)化合物的钠盐,即式(II)的(3S)-3-(4-氯-3-{[(2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰基]氨基}苯基)-3-环丙基丙酸钠,替换式(I)化合物
可以获得渗透释放系统,其既没有所描述的含式(I)化合物的渗透释放系统的不利性质,也没有在所描述的含式(I)化合物的渗透释放系统的制备期间出现的缺点。当使用式(II)化合物时,在各工艺步骤期间不存在熔化现象或观察到其他缺点。制备工艺可在无任何无计划的中断的情况下完成。含量测定得出的结果与关于所声称的活性成分含量的说明相符。
与式(II)化合物和聚环氧乙烷的混合物相比,式(I)化合物和聚环氧乙烷的混合物的不同行为还可通过测量所讨论的物质本身以及其以1∶1的比例的研磨物(二元混合物)的DSC(差示扫描量热法)热分析图证明。在热分析图中可以观察到的变化指示了粉末混合物的可处理性。包含等量的式(I)化合物和聚环氧乙烷的研磨物没有表现出可归属于式(I)化合物的熔化峰(图1)。活性化合物的熔化峰的消失、亲水性可溶胀聚合物的熔化峰的拓宽和熔化的更早发生与所提及的可处理性缺陷相关。因此,熔化过程甚至在50℃至60℃的温度下开始。这些温度可在渗透释放系统的制备期间发生,并且引起所述熔化现象。除了聚环氧乙烷的熔化峰之外,包含等量的式(II)化合物和聚环氧乙烷的研磨物还显示了可归属于式(II)化合物的另外的熔化峰(图2)。式(II)化合物的熔距在研磨中减小;然而,其是处于在渗透释放系统的制备期间未达到的温度范围。另外,与式(I)化合物相比,式(II)化合物不会降低聚环氧乙烷的熔融温度。因此,在该组合中未观察到熔化现象。式(II)化合物与黄原胶、乙烯基吡咯烷酮/乙酸乙烯酯共聚物(Kollidon VA 64)、聚乙烯吡咯烷酮(PVP 25)、羟丙纤维素(HPC LM)、甲基丙烯酸和甲基丙烯酸甲酯的阴离子共聚物(Eudragit L100,Eudragit RL PO)以1∶1的比例研磨物同样显示了位于较高温度范围内的式(II)化合物的熔化峰(图3至图8)。由于这些聚合物是无定形的,因此在测量范围内未看到可归属于所述聚合物的熔化峰。式(II)化合物和聚丙烯酸的研磨物的热分析图未显示可归属于式(II)化合物的熔化峰(图9)。这本身表明,在达到聚丙烯酸的玻璃化转变温度之后,式(II)化合物随着温度升高而溶解。由于玻璃化转变温度为约106℃,因此在使用聚丙烯酸作为亲水性可溶胀聚合物的渗透释放系统的制备期间的熔化现象不是预期的。
已努力制备了大量的式(I)化合物的其他药学上可接受的盐。它们包括式(I)化合物的钾盐、胆碱盐、碳酸氢盐、碳酸钠盐、(二乙氨基)乙醇盐、L-赖氨酸盐、氨丁三醇盐、N-甲基-D-葡萄糖胺盐、L-精氨酸盐、碳酸氢钠盐和碳酸氢钾盐。当开发一种药物剂型时,一个重要的要求是可重现地分离出确定的结晶形式的活性成分。无定形形式不适合用于制备药物剂型,因为,经常地,它们具有较低的热力学稳定性和对配制药物剂型而言不利的性质,例如差的可微粉性(micronizability)、粘着性或差的可压片性(tabletability)。另外,活性成分的结晶形式应具有可重现的生物利用度并在微粉化工艺期间保持稳定以使得不发生转化和重结晶。
出乎意料地,现已发现,仅式(I)化合物的钠盐可以结晶形式获得且式(II)化合物的钠盐的结晶形式具有所描述的有利性质。在下文中,该结晶形式被称为式(II)化合物的变型1结晶形式。
所测试的式(I)化合物的所有其他盐皆不能以结晶形式获得,并且因此式(II)化合物优选用于制备渗透释放系统。
本发明提供包含式(II)的(3S)-3-(4-氯-3-{[(2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰基]氨基}苯基)-3-环丙基丙酸钠的固体的可口服给药的缓释药物剂型,其特征在于80%的式(II)化合物在2-24、优选4-20小时的时间段内释放,根据USP释放方法(USP 39;第<711>章Dissolution(溶出度))使用设备2(浆法)和章节“Release properties(释放特性)”中的陈述测量。
适合用于将式(II)化合物配制成渗透释放系统的形式的有双室系统(推拉式系统)和单室系统(初级渗透泵)。双室系统和单室系统均由被壳和任选地包衣包覆的核组成。在渗透释放系统中,式(II)化合物可以以结晶形式或无定形形式存在或作为包含结晶部分和无定形部分的混合物存在。在渗透释放系统中,式(II)化合物优选以结晶形式存在。在渗透释放系统中,式(II)化合物优选以微粉化形式存在。
本发明还提供固体的可口服给药的缓释药物剂型,其包括式(II)的(3S)-3-(4-氯-3-{[(2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰基]氨基}苯基)-3-环丙基丙酸钠,
其特征在于药物剂型是基于渗透释放系统。
本发明提供包括式(II)化合物的固体可口服给药的缓释药物剂型,其特征在于药物剂型是基于渗透的单室系统。
本发明提供包括式(II)化合物的固体可口服给药的缓释药物剂型,其特征在于药物剂型是基于渗透的双室系统。
在一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,且其中核包括式(II)化合物和至少一种亲水性可溶胀聚合物。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,且其中核包括式(II)化合物和至少一种亲水性可溶胀聚合物,所述亲水性可溶胀聚合物优选地选自由以下物质组成的列表:聚环氧乙烷,黄原胶,纤维素衍生物例如羟丙纤维素、羟丙基甲基纤维素或羧甲基纤维素钠,淀粉衍生物例如羧甲基淀粉钠,乙烯基吡咯烷酮/乙酸乙烯酯共聚物,聚乙烯吡咯烷酮,甲基丙烯酸共聚物例如甲基丙烯酸/甲基丙烯酸甲酯共聚物,和聚丙烯酸,或优选地选自由以下物质组成的列表:聚环氧乙烷、黄原胶、羟丙纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、羧甲基淀粉钠、乙烯基吡咯烷酮/乙酸乙烯酯共聚物,和聚丙烯酸。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,且其中核包括:式(II)化合物;至少一种亲水性可溶胀聚合物,其优选地选自由以下物质组成的列表:聚环氧乙烷,黄原胶,纤维素衍生物例如羟丙纤维素、羟丙基甲基纤维素或羧甲基纤维素钠,淀粉衍生物例如羧甲基淀粉钠,乙烯基吡咯烷酮/乙酸乙烯酯共聚物,聚乙烯吡咯烷酮,甲基丙烯酸共聚物例如甲基丙烯酸/甲基丙烯酸甲酯共聚物,和聚丙烯酸,或其优选地选自由以下物质组成的列表:聚环氧乙烷、黄原胶、羟丙纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、羧甲基淀粉钠、乙烯基吡咯烷酮/乙酸乙烯酯共聚物,和聚丙烯酸;任选地至少一种药物常规助剂;和任选地渗透活性添加剂。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,且其中核包括:式(II)化合物;至少一种亲水性可溶胀聚合物,其选自由以下物质组成的列表:聚环氧乙烷、黄原胶,和乙烯基吡咯烷酮/乙酸乙烯酯共聚物,或选自由以下物质组成的列表:聚环氧乙烷和黄原胶;任选地至少一种其他亲水性可溶胀聚合物;任选地至少一种药物常规助剂;和任选地渗透活性添加剂。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,且其中核包括式(II)化合物、亲水性可溶胀聚合物聚环氧乙烷、任选地至少一种其他亲水性可溶胀聚合物、任选地至少一种药物常规助剂和任选地渗透活性添加剂。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,且其中核包括:0.5重量%至50重量%的式(II)化合物;40重量%至99.5重量%的至少一种亲水性可溶胀聚合物,其优选地选自由以下物质组成的列表:聚环氧乙烷,黄原胶,纤维素衍生物例如羟丙纤维素、羟丙基甲基纤维素或羧甲基纤维素钠,淀粉衍生物例如羧甲基淀粉钠,乙烯基吡咯烷酮/乙酸乙烯酯共聚物,聚乙烯吡咯烷酮,甲基丙烯酸共聚物例如甲基丙烯酸/甲基丙烯酸甲酯共聚物,和聚丙烯酸,或其选自由以下物质组成的列表:聚环氧乙烷、黄原胶、羟丙纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、羧甲基淀粉钠、乙烯基吡咯烷酮/乙酸乙烯酯共聚物,和聚丙烯酸,特别优选地选自聚环氧乙烷、黄原胶,和乙烯基吡咯烷酮/乙酸乙烯酯共聚物,非常特别地优选地为聚环氧乙烷;任选地至少一种药物常规助剂;和任选地渗透活性添加剂。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,且其中核包括1重量%至40重量%的式(II)化合物;50重量%至99重量%的至少一种亲水性可溶胀聚合物,其优选地选自由以下物质组成的列表:聚环氧乙烷,黄原胶,纤维素衍生物例如羟丙纤维素、羟丙基甲基纤维素或羧甲基纤维素钠,淀粉衍生物例如羧甲基淀粉钠,乙烯基吡咯烷酮/乙酸乙烯酯共聚物,聚乙烯吡咯烷酮,甲基丙烯酸共聚物例如甲基丙烯酸/甲基丙烯酸甲酯共聚物,和聚丙烯酸,或其选自由以下物质组成的列表:聚环氧乙烷、黄原胶、羟丙纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、羧甲基淀粉钠、乙烯基吡咯烷酮/乙酸乙烯酯共聚物,和聚丙烯酸,特别优选地选自聚环氧乙烷,黄原胶,和乙烯基吡咯烷酮/乙酸乙烯酯共聚物,非常特别地优选地为聚环氧乙烷;任选地至少一种药物常规助剂和任选地渗透活性添加剂。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,且其中核包括2重量%至20重量%的式(II)化合物;60重量%至90重量%的至少一种亲水性可溶胀聚合物,其优选地选自由以下物质组成的列表:聚环氧乙烷,黄原胶,纤维素衍生物例如羟丙纤维素、羟丙基甲基纤维素或羧甲基纤维素钠,淀粉衍生物例如羧甲基淀粉钠,乙烯基吡咯烷酮/乙酸乙烯酯共聚物,聚乙烯吡咯烷酮,甲基丙烯酸共聚物例如甲基丙烯酸/甲基丙烯酸甲酯共聚物,和聚丙烯酸,或其选自由以下物质组成的列表:聚环氧乙烷、黄原胶、羟丙纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、羧甲基淀粉钠、乙烯基吡咯烷酮/乙酸乙烯酯共聚物,和聚丙烯酸,特别优选地选自聚环氧乙烷、黄原胶,和乙烯基吡咯烷酮/乙酸乙烯酯共聚物,非常特别地优选地为聚环氧乙烷;任选地至少一种药物常规助剂和任选地渗透活性添加剂。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,且其中核包括2重量%至10重量%的式(II)化合物;70重量%至85重量%的至少一种亲水性可溶胀聚合物,其优选地选自由以下物质组成的列表:聚环氧乙烷,黄原胶,纤维素衍生物例如羟丙纤维素、羟丙基甲基纤维素或羧甲基纤维素钠,淀粉衍生物例如羧甲基淀粉钠,乙烯基吡咯烷酮/乙酸乙烯酯共聚物,聚乙烯吡咯烷酮,甲基丙烯酸共聚物例如甲基丙烯酸/甲基丙烯酸甲酯共聚物和聚丙烯酸,或其优选地选自由以下物质组成的列表:聚环氧乙烷、黄原胶、羟丙纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、羧甲基淀粉钠、乙烯基吡咯烷酮/乙酸乙烯酯共聚物,和聚丙烯酸,特别优选地选自聚环氧乙烷、黄原胶,和乙烯基吡咯烷酮/乙酸乙烯酯共聚物,非常特别地优选地为聚环氧乙烷;任选地至少一种药物常规助剂;和任选地渗透活性添加剂。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,且其中核包括
·0.5重量%至50重量%的式(II)化合物,
·10重量%至50重量%的黄原胶,
·5重量%至40重量%的乙烯基吡咯烷酮/乙酸乙烯酯共聚物,
任选地至少一种其他亲水性可溶胀聚合物,任选地至少一种其他药物常规助剂和任选地渗透活性添加剂。
重量百分比在每种情况下基于核的总质量计。
优选地,渗透性单室系统包括作为核的必要组分之一的亲水性水可溶胀的聚合物黄原胶。这是阴离子杂多糖,其可商业获得,例如名称为(由Rhodia制备)或“Xanthan FN/>normal”(由Jungbunzlauer Ladenburg GmbH制备)。它以10-50重量%、优选25-40重量%的量存在,基于核组分的总质量计。
核的另一必要组分为乙烯基吡咯烷酮/乙酸乙烯酯共聚物。该共聚物是本身已知的且可以以任何所需单体混合比制备。例如,商业可得的VA64(由BASF制备)——其被优选使用——为60∶40共聚物。它通常具有约45000至约70000的重均分子量,通过光散射测量确定。核中乙烯基吡咯烷酮/乙酸乙烯酯共聚物的量为5-40重量%,优选15-25重量%,基于核组分的总质量计。
另外存在——如果合适——于核中的亲水性可溶胀聚合物为,例如,羟丙纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、羧甲基淀粉钠、聚丙烯酸或其盐。
本发明还提供制备渗透释放系统的方法,其特征在于将核的组分彼此混合,制粒并压片,将所得的核用壳包覆,最后使壳具有一个或多个适合用于式(II)化合物离去的孔口。
本发明还提供制备根据本发明的渗透性单室系统的方法,其中将核的组分彼此混合,任选地经受湿法制粒或干法制粒,然后压片,并将所得的核用壳包覆。在活性化合物一侧,使壳具有一个或多个孔口。或者,在该方法步骤中,可省却一个或多个孔口的引入并且首先可施用包衣,例如光保护包衣和/或有色包衣。在这种情况下,仅在已经用一层或多层其他包衣包覆后,才使片剂两侧在每种情况下均具有孔口,孔口在每种情况下由外部到达至内部核,即横贯包衣和壳,并适合用于式(II)化合物离去。
在本发明的一个优选实施方案中,当制备渗透性单室系统时,使核组分经受湿法制粒,因为该方法步骤导致片剂核组分具有更好的湿润性,因其之故,进入胃肠液的的核渗透较好,从而经常导致活性成分更快且更完全的释放。
在另一个实施方案中,渗透释放系统的核由两层——活性成分层和渗透层——组成。该类型的渗透性双室系统详细描述于例如DE3417113 C2、WO 2006/072367或WO 2010/060564,其公开内容均通过引用纳入本文。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,并且其中核由活性成分层和渗透层组成。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成,具有至少一个孔口,并且其中核由活性成分层和渗透层组成,且活性成分层为粘度为40至100mPa·s(以5%浓度水溶液测量,25℃)的聚环氧乙烷,且渗透层的至少一种亲水性可溶胀聚合物为粘度为5000-8000mPa·s(以1%浓度水溶液测量,25℃)的聚环氧乙烷。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,并且其中核由活性成分层和渗透层组成,且活性成分层包括1重量%至50重量%的式(II)化合物;20重量%至99重量%的至少一种亲水性可溶胀聚合物,其优选地选自由以下物质组成的列表:聚环氧乙烷,黄原胶,纤维素衍生物例如羟丙纤维素、羟丙基甲基纤维素或羧甲基纤维素钠,淀粉衍生物例如羧甲基淀粉钠,乙烯基吡咯烷酮/乙酸乙烯酯共聚物,聚乙烯吡咯烷酮,甲基丙烯酸共聚物例如甲基丙烯酸/甲基丙烯酸甲酯共聚物,和聚丙烯酸,或其选自由以下物质组成的列表:聚环氧乙烷、黄原胶、羟丙纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、羧甲基淀粉钠、乙烯基吡咯烷酮/乙酸乙烯酯共聚物,和聚丙烯酸,特别优选地选自聚环氧乙烷、黄原胶,和乙烯基吡咯烷酮/乙酸乙烯酯共聚物,非常特别地优选地为聚环氧乙烷;任选地至少一种渗透活性添加剂;以及任选地至少一种药物常规助剂。
在另一个实施方案中,活性成分层包括1重量%至45重量%、优选地1重量%至30重量%、特别优选地2重量%至20重量%的式(II)化合物;30重量%至99重量%、优选地50重量%至99重量%、特别优选地60重量%至98重量%的至少一种亲水性可溶胀聚合物;任选地至少一种渗透活性添加剂;以及任选地至少一种药物常规助剂。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,并且其中核由活性成分层和渗透层组成,且活性成分层包括1重量%至50重量%的式(II)化合物;20重量%至99重量%的聚环氧乙烷,优选地粘度为40-100mPa·s(以5%浓度水溶液测量,25℃)的聚环氧乙烷;任选地至少一种其他亲水性可溶胀聚合物;任选地至少一种渗透活性添加剂;以及任选地至少一种药物常规助剂。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,并且其中核由活性成分层和渗透层组成,且活性成分层包括1重量%至45重量%的式(II)化合物;30重量%至99重量%的聚环氧乙烷,优选地粘度为40-100mPa·s(以5%浓度水溶液测量,25℃)的聚环氧乙烷;任选地至少一种其他亲水性可溶胀聚合物;任选地至少一种渗透活性添加剂;以及任选地至少一种药物常规助剂。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,并且其中核由活性成分层和渗透层组成,且活性成分层包括1重量%至30重量%的式(II)化合物;50重量%至99重量%的聚环氧乙烷,优选地粘度为40-100mPa·s(以5%浓度水溶液测量,25℃)的聚环氧乙烷;任选地至少一种其他亲水性可溶胀聚合物;任选地至少一种渗透活性添加剂;以及任选地至少一种药物常规助剂。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,并且其中核由活性成分层和渗透层组成,且活性成分层包括2重量%至20重量%的式(II)化合物;60重量%至98重量%的聚环氧乙烷,优选地粘度为40-100mPa·s(以5%浓度水溶液测量,25℃)的聚环氧乙烷;任选地至少一种其他亲水性可溶胀聚合物;任选地至少一种渗透活性添加剂;以及任选地至少一种药物常规助剂。
重量百分比在每种情况下基于活性成分层的总质量计。
粘度为40-100mPa·s(以5%浓度水溶液测量,25℃)的聚环氧乙烷的粘度优选使用合适的Brookfield粘度计和合适的转子在合适的转速下测量;特别是使用Brookfield粘度计Model RVT和1号转子在50rpm的转速下或使用相当的型号在相应的条件下(转子,转速)测量。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,且其中核由上述活性成分层中的一层和渗透层组成,其中渗透层包括40重量%至90重量%、优选地50重量%至80重量%的至少一种亲水性可溶胀聚合物,其优选地选自由以下物质组成的列表:聚环氧乙烷,黄原胶,纤维素衍生物例如羟丙纤维素、羟丙基甲基纤维素或羧甲基纤维素钠,淀粉衍生物例如羧甲基淀粉钠,乙烯基吡咯烷酮/乙酸乙烯酯共聚物,聚乙烯吡咯烷酮,甲基丙烯酸共聚物例如甲基丙烯酸/甲基丙烯酸甲酯共聚物,和聚丙烯酸,或其选自由以下物质组成的列表:聚环氧乙烷、黄原胶、羟丙纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、羧甲基淀粉钠、乙烯基吡咯烷酮/乙酸乙烯酯共聚物,和聚丙烯酸,优选地选自聚环氧乙烷、黄原胶,和乙烯基吡咯烷酮/乙酸乙烯酯共聚物,非常特别地优选地为聚环氧乙烷;10重量%至60重量%、优选地20重量%至50重量%的至少一种渗透活性添加剂;以及任选地至少一种药物常规助剂。
渗透层中使用的亲水性可溶胀聚合物优选为聚环氧乙烷。粘度为5000-8000mPa·s(以1%浓度水溶液测量,25℃)的聚环氧乙烷是特别优选的。
粘度为5000-8000mPa·s(以1%浓度水溶液测量,25℃)的聚环氧乙烷的粘度使用合适的Brookfield粘度计和合适的转子在合适的转速下测量,特别是使用Brookfield粘度计Model RVF的和2号转子在2rpm的转速下或使用相当型号在相应的条件下(转子,转速)测量。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,并且其中核由活性成分层和渗透层组成,其中活性成分层包括:0.5重量%至65重量%的式(II)化合物;20重量%至99.5重量%的至少一种亲水性可溶胀聚合物,其优选地选自由以下物质组成的列表:聚环氧乙烷,黄原胶,纤维素衍生物例如羟丙纤维素、羟丙基甲基纤维素或羧甲基纤维素钠,淀粉衍生物例如羧甲基淀粉钠,乙烯基吡咯烷酮/乙酸乙烯酯共聚物,聚乙烯吡咯烷酮,甲基丙烯酸共聚物例如甲基丙烯酸/甲基丙烯酸甲酯共聚物,和聚丙烯酸,或其选自由以下物质组成的列表:聚环氧乙烷、黄原胶、羟丙纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、羧甲基淀粉钠、乙烯基吡咯烷酮/乙酸乙烯酯共聚物,和聚丙烯酸,优选地选自聚环氧乙烷、黄原胶,和乙烯基吡咯烷酮/乙酸乙烯酯共聚物,非常特别地优选地为聚环氧乙烷;任选地至少一种渗透活性添加剂;以及任选地至少一种药物常规助剂;且渗透层包括40重量%至90重量%的至少一种亲水性可溶胀聚合物,所述亲水性可溶胀聚合物优选地选自由以下物质组成的列表:聚环氧乙烷,黄原胶,纤维素衍生物例如羟丙纤维素、羟丙基甲基纤维素或羧甲基纤维素钠,淀粉衍生物例如羧甲基淀粉钠,乙烯基吡咯烷酮/乙酸乙烯酯共聚物,聚乙烯吡咯烷酮,甲基丙烯酸共聚物例如甲基丙烯酸/甲基丙烯酸甲酯共聚物,和聚丙烯酸,或其选自由以下物质组成的列表:聚环氧乙烷、黄原胶、羟丙纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、羧甲基淀粉钠、乙烯基吡咯烷酮/乙酸乙烯酯共聚物,和聚丙烯酸,优选地选自聚环氧乙烷、黄原胶,和乙烯基吡咯烷酮/乙酸乙烯酯共聚物,非常特别地优选地为聚环氧乙烷;10重量%至60重量%的渗透活性添加剂;以及任选地至少一种药物常规助剂。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,并且其中核由活性成分层和渗透层组成,其中活性成分层包括:1重量%至50重量%的式(II)化合物,20重量%至99重量%的聚环氧乙烷、优选粘度为40-100mPa·s(以5%浓度水溶液测量,25℃)的聚环氧乙烷,任选地至少一种渗透活性添加剂以及任选地至少一种药物常规助剂,且渗透层包括:40重量%至90重量%的聚环氧乙烷、优选粘度为5000-8000mPa·s(以1%浓度水溶液测量,25℃)的聚环氧乙烷,10重量%至60重量%的渗透活性添加剂以及任选地至少一种药物常规助剂。
在另一个实施方案中,活性成分层包括:1重量%至45重量%、优选1重量%至30重量%、特别优选2重量%至20重量%的式(II)化合物,30重量%至99重量%、优选50重量%至99重量%、特别优选60重量%至98重量%的粘度为40-100mPa·s(以5%浓度水溶液测量,25℃)的聚环氧乙烷,任选地至少一种渗透活性添加剂以及任选地至少一种药物常规助剂,且渗透层包括:40重量%至90重量%、优选50重量%至80重量%的粘度为5000-8000mPa·s(以1%浓度水溶液测量,25℃)的聚环氧乙烷,10重量%至60重量%、优选20重量%至50重量%的至少一种渗透活性添加剂,以及任选地至少一种药物常规助剂。
在另一个实施方案中,渗透释放系统由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,并且其中核由活性成分层和渗透层组成,其中活性成分层包括:2重量%至20重量%的式(II)化合物、60重量%至98重量%的粘度为40-100mPa·s(以5%浓度水溶液测量,25℃)的聚环氧乙烷,任选地至少一种渗透活性添加剂以及任选地至少一种药物常规助剂,且渗透层包括:50重量%至80重量%的粘度为5000-8000mPa·s(以1%浓度水溶液测量,25℃)的聚环氧乙烷、20重量%至50重量%的渗透活性添加剂,以及任选地至少一种药物常规助剂。
在另一个实施方案中,渗透释放系统由上述渗透释放系统之一组成,其中壳由乙酸纤维素或乙酸纤维素和聚乙二醇的混合物组成。
在另一个实施方案中,渗透释放系统为上述渗透释放系统之一,其中80%的式(II)化合物在2小时至24小时、优选地4小时至20小时、特别优选地5小时至16小时后释放(根据USP释放方法(USP 39;第<711>章,Dissolution(溶出度))使用设备2(浆法)和章节“Release properties(释放特性)”中的陈述测量)。
在另一个实施方案中,渗透释放系统为上述渗透释放系统之一,其中渗透释放系统符合关于含量均一性的要求(欧洲药典第9版;2.9.40“Uniformity of Dosage Units(剂量单位均一性)”)。
在另一个实施方案中,渗透释放系统为上述渗透释放系统之一,其中渗透释放系统中式(II)化合物的标准偏差百分比小于7%,优选小于6%,更优选小于5%,最优选小于4%,由确定的n=10各含量计算。
在本发明上下文中,亲水性可溶胀聚合物为本领域技术人员已知的通过吸收水溶胀的所有药学上可接受的聚合物化合物。优选使用至少一种亲水性可溶胀聚合物选自由以下物质组成的列表:聚环氧乙烷,黄原胶,纤维素衍生物例如羟丙纤维素、羟丙基甲基纤维素或羧甲基纤维素钠,淀粉衍生物例如羧甲基淀粉钠,乙烯基吡咯烷酮/乙酸乙烯酯共聚物,聚乙烯吡咯烷酮,甲基丙烯酸共聚物例如甲基丙烯酸/甲基丙烯酸甲酯共聚物,和聚丙烯酸,或选自由以下物质组成的列表:聚环氧乙烷,黄原胶,纤维素衍生物例如羟丙纤维素、羟丙基甲基纤维素或羧甲基纤维素钠,淀粉衍生物例如羧甲基淀粉钠,乙烯基吡咯烷酮/乙酸乙烯酯共聚物,聚乙烯吡咯烷酮,和甲基丙烯酸共聚物例如甲基丙烯酸/甲基丙烯酸甲酯共聚物。
此外,优选使用至少一种亲水性可溶胀聚合物选自由以下物质组成的列表:聚环氧乙烷、黄原胶、羟丙纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、羧甲基淀粉钠、乙烯基吡咯烷酮/乙酸乙烯酯共聚物,和聚丙烯酸,或选自由以下物质组成的列表:聚环氧乙烷、黄原胶、羟丙纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、羧甲基淀粉钠,和乙烯基吡咯烷酮/乙酸乙烯酯共聚物;特别优选使用黄原胶、聚环氧乙烷,和乙烯基吡咯烷酮/乙酸乙烯酯共聚物或其混合物。
此外,优选使用至少一种亲水性可溶胀聚合物选自由以下物质组成的列表:聚环氧乙烷、黄原胶、Kollidon VA64、PVP 25、Eudragit L100、Eudragit RL PO、HPC LM和聚丙烯酸,或选自由以下物质组成的列表:聚环氧乙烷、黄原胶、Kollidon VA 64、PVP 25、Eudragit L100、Eudragit RL PO和HPC LM;特别优选使用聚环氧乙烷。
此外,特别优选使用至少一种亲水性可溶胀聚合物选自由以下物质组成的列表:聚环氧乙烷(符合欧洲药典(第9版)专论“Macrogols,High Molecular Mass(聚乙二醇,高分子量)”;粘度5000-8000mPa·s;以1%浓度水溶液测量,25℃;POLYOXTM水溶性树脂NF WSRN-80;Dow)和聚环氧乙烷(符合欧洲药典(第9版)专论“Macrogols,High Molecular Mass(聚乙二醇,高分子量)”;粘度40-100mPa·s;以5%浓度水溶液测量,25℃;POLYOXTM水溶性树脂NF WSR N-80;Dow)。
在本发明上下文中,适合作为亲水性可溶胀聚合物的淀粉衍生物有玉米淀粉、小麦淀粉、稻淀粉和马铃薯淀粉,取代的淀粉如羧甲基淀粉及其盐、羟乙基淀粉,或其混合物。
在本发明上下文中,适合作为亲水性可溶胀聚合物的纤维素衍生物有甲基纤维素(MC)、羟甲基丙基纤维素(HPMC)、羟丙纤维素(HPC)、羧甲基纤维素钠(Na-CMC)、羟乙基纤维素(HEC),或其混合物。
所提及的亲水性可溶胀聚合物可以其本身或与其他亲水性可溶胀聚合物组合使用。
或者,一些亲水性可溶胀聚合物可在核中用作药学上可接受的助剂,例如用作粘合剂或崩解剂。如果这样的物质在核中的比例基于核的质量计为10%以上,则在本发明上下文中这样的物质为亲水性可溶胀聚合物。
在本发明上下文中渗透活性添加剂为,例如,可接受的用于制药工业的所有水溶性物质,例如,在药典中、在“Hager”和“Remington Pharmaceutical Science”或其他文献(Sareen.R.,Jain,N.,Kumar,D.,Current Drug Delivery,9,(2012),285-296)中提及的水溶性助剂。特别地,可以使用无机酸或有机酸的水溶性盐或在水中具有高溶解度的非离子有机物质,例如,碳水化合物,尤其是糖、糖醇或氨基酸。例如,渗透活性添加剂可选自无机盐如碱金属或碱土金属如锂、钠、钾、镁、钙的氯化物盐、硫酸盐、碳酸盐和碳酸氢盐,及其磷酸盐、磷酸氢盐或磷酸二氢盐、乙酸盐、琥珀酸盐、苯甲酸盐、柠檬酸盐或抗坏血酸盐。还可以使用戊糖类如阿拉伯糖、核糖或木糖,己糖类如葡萄糖、果糖、半乳糖或甘露糖,二糖类如蔗糖、麦芽糖或乳糖,或三糖类如棉子糖。水溶性氨基酸包括甘氨酸、亮氨酸、丙氨酸或甲硫氨酸。优选使用氯化钠。
在本发明上下文中,药物常规助剂为,例如,缓冲剂如碳酸氢钠,粘合剂如羟丙纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮或乙烯基吡咯烷酮/乙酸乙烯酯共聚物(VA64),崩解剂如羧甲基淀粉钠,润滑剂如硬脂酸镁,湿润剂如月桂基硫酸钠,流动调节剂如细分散的二氧化硅,保护性胶体如EP-B-0277092(第5页,第10-25行)中记载的,增塑剂如例如EP-B-0277092(第5页,第29-32行)中记载的,表面活性剂如例如EP-B-0277092(第5页,第33-44行)中记载的,载体材料如例如EP-B-0277092(第5页,第45-47行)中记载的,以及一种或多种彩色颜料例如,用于在活性成分层和渗透层之间区分的两层中的一层中的氧化铁。合适的保护性胶体为,例如,甲基化的纤维素衍生物,例如甲氧基含量为约27.0-32.0%且取代程度为约1.75-2.1的甲基纤维素或含量为约16.0-30.0%甲氧基和4.0-32.0%羟丙氧基的甲基羟丙纤维素。合适的增塑剂为,例如,丙三醇、柠檬酸三乙酯、酞酸二乙酯或癸二酸二乙酯。合适的表面活性剂为,例如,烷基硫酸盐类的阴离子表面活性剂,例如钠、钾或镁的正十二烷基硫酸盐、正十四烷基硫酸盐、正十六烷基硫酸盐或正十八烷基硫酸盐;烷基醚硫酸盐,例如钠、钾或镁的正十二烷基氧乙基硫酸盐、正十四烷基氧乙基硫酸盐、正十六烷基氧乙基硫酸盐或正十八烷基氧乙基硫酸盐;或烷烃磺酸盐,例如钠、钾或镁的正十二烷磺酸盐、正十四烷磺酸盐、正十六烷磺酸盐或正十八烷磺酸盐。合适的表面活性剂还有脂肪酸多羟基醇酯类的非离子的表面活性剂,如失水山梨糖醇单月桂酸酯、失水山梨糖醇单油酸酯、失水山梨糖醇单硬脂酸酯或失水山梨糖醇单棕榈酸酯,失水山梨糖醇三硬脂酸酯或三油酯;脂肪酸多羟基醇酯的聚氧亚乙基加合物,如聚氧亚乙基失水山梨糖醇单月桂酸酯、聚氧亚乙基失水山梨糖醇单油酸酯、聚氧亚乙基失水山梨糖醇单硬脂酸酯、聚氧亚乙基失水山梨糖醇单棕榈酸酯、聚氧亚乙基失水山梨糖醇三硬脂酸酯或聚氧亚乙基失水山梨糖醇三油酸酯;聚乙二醇脂肪酯,如聚氧乙基硬脂酸盐、聚乙二醇400硬脂酸盐、聚乙二醇2000硬脂酸盐,特别是/>(BWC)或/>(ICI)型的环氧乙烷环氧丙烷嵌段共聚物。合适的载体材料为,例如,乳糖,蔗糖,山梨糖醇,甘露醇,淀粉例如马铃薯淀粉、玉米淀粉或支链淀粉,或纤维素。
在单室系统和在双室系统中,渗透的活性成分释放系统的壳由对核的组分不可渗透的水可渗透成膜材料组成。这样的壳材料原则上是已知的且记载于,例如,EP1024793中。适合用作壳材料的为,例如,酰化的纤维素衍生物。
酰化的纤维素衍生物(纤维素酯)为被乙酰基单取代至三取代的纤维素或被乙酰基单取代至二取代的且被另一个不同于乙酰基的酰基取代的纤维素,例如乙酸纤维素、三乙酸纤维素、乙酸乙基氨基甲酸纤维素、乙酸苯二甲酸纤维素、乙酸甲基氨基甲酸纤维素、乙酸丁二酸纤维素、乙酸二甲基氨基乙酸纤维素、乙酸乙基碳酸纤维素、乙酸氯乙酸纤维素、乙酸乙基草酸纤维素、乙酸甲基磺酸纤维素、乙酸丁基磺酸纤维素、乙酸丙酸纤维素、乙酸二乙基氨基乙酸纤维素、乙酸基乙酸纤维素(cellulose acetatoacetate)、乙酸月桂酸纤维素、乙酸对甲苯磺酸纤维素、乙酸丁酸纤维素,和选自以下的壳材料:纤维素醚如乙基纤维素或其他乙酸纤维素衍生物以及琼脂乙酸盐和直链淀粉乙酸盐。
适合用于壳的材料还有乙基纤维素和多聚环氧化物、环氧烷烃的共聚物和烷基缩水甘油醚、聚二醇类和聚乳酸衍生物及其其他衍生物。此外,还可以使用本身水不溶性的丙烯酸酯的混合物(例如丙烯酸乙酯和甲基丙烯酸甲酯的共聚物)。
在本发明上下文中,优选用作壳材料的是乙酸纤维素或乙酸纤维素和聚乙二醇的混合物。
用于制备渗透性药物释放系统的壳的量和成分以已知方式影响胃肠液的进入速率。原则上,随着壳材料的量增加,胃肠液的进入速率降低。
如果需要,可在壳上施加包衣,例如光保护包衣和/或有色包衣。特别合适的材料是例如聚合物如聚乙烯醇、羟丙基纤维素和/或羟丙基甲基纤维素,如果合适,与合适的增塑剂例如聚乙二醇或聚丙二醇以及颜料例如二氧化钛或氧化铁结合。举例而言,可提及使用通过首先将聚乙烯醇和聚乙二醇3350在室温下溶解于水中并在搅拌下混合而获得的膜包衣进行包覆。逐渐地,在搅拌下添加滑石、二氧化钛和氧化铁。包衣悬浮液可施加至片剂核,使用,例如,合适的包衣装置,例如平滑包衣机(smooth coater)。或者,可以糖包衣代替包衣。一般而言,使用水性或有机的包衣介质来施用这样的包衣。在本发明上下文中,术语包衣还包括通过另一种方法例如无溶剂方法施用的壳的包衣。
所使用的包衣也可以是成品包衣。它们已经包含助剂的混合物并溶于水中并施用。可提及的实例为Opadry II 85F230009橙(基于Colorcon PVA的成品包衣),其包含部分水解的聚乙烯醇、滑石、聚乙二醇(PEG3350)、二氧化钛、红色氧化铁、黄色氧化铁和聚山梨酯80(Tween 80)。
本发明的渗透性药物释放系统的壳具有至少一个孔口或通道,通过此孔口或通道,活性成分与其他核成分一起缓慢离去。孔口通过激光打孔、机械钻孔或例如通过穿孔被引入壳中。壳中可存在一个或多个孔口。孔口的尺寸(直径)优选为0.2至1.6mm,更优选为0.3至1.2mm。孔口的性质及其制备方法本身是已知的,并且记载于例如US 4063064、US4088864、US 3916899或EP-B-0277092中。任选地存在的包衣同样可具有一个或多个孔口。
在所述实施方案中优选用作渗透活性添加剂的是至少一种无机酸或有机酸的水溶性盐,特别优选地为氯化钠。
在所述实施方案中优选用作药物常规助剂的是粘合剂,例如羟丙纤维素,润滑剂例如硬脂酸镁,流动调节剂例如细分散的二氧化硅,和彩色颜料例如氧化铁。
为制备渗透性双室系统,可以,例如,将活性成分层的组分混合并使它们经受湿法制粒或干法制粒、优选干法制粒,将渗透层的组分混合并制粒,然后在双层压片机上压缩这两组颗粒以得到双层片剂。然后将所得到的内部核用壳包衣。使壳在活性成分一侧具有一个或多个孔口。或者,可省却在该方法步骤中提供一个或多个孔口。在这种情况下,仅在已经用一层或多层包衣进行包覆之后,才使片剂两侧各自具有孔口,在每种情况下孔口由外部延伸至内部核,即伸展横越包衣和壳。
优选地,在渗透性双室系统的制备中,将活性成分层的组分和渗透层的组分各自进行制粒。特别是通过辊式制粒法进行。
本发明还提供一种制备所提及的渗透释放系统的方法,其特征在于将核的组分彼此混合、制粒并压片,将所得的核用壳包覆,并最终使壳具有一个或多个适合于式(II)化合物离去的孔口。
本发明还提供一种制备所提及的渗透释放系统的方法,其特征在于将活性成分层的组分混合并制粒,并将渗透层的组分混合并制粒,随后将这两组颗粒在双层压片机上压缩得到双层片剂,然后将所得到的核用壳包覆,并使壳在活性成分一侧具有一个或多个孔口。
由于活性成分的物理化学性质,根据本发明优选渗透性双室系统(推拉式系统),其中使活性成分层和渗透层分离,例如并且优选配制成双层片剂。此处,与渗透性单室系统相比优点在于在更长的时间内更均一的释放率,以及减少内吸所需的过量活性成分的可能性。
本发明还提供式(II)化合物(3S)-3-(4-氯-3-{[(2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰基]氨基}苯基)-3-环丙基丙酸钠
还提供了变型1结晶形式的式(II)化合物,其特征在于化合物的X-射线衍射图在8.1、22.3和22.6°的2θ角处具有最大峰。
还提供了变型1结晶形式的式(II)化合物,其特征在于化合物的X射线衍射图在8.1、17.2、18.8、22.3和22.6°的2θ角处具有最大峰。
还提供了变型1结晶形式的式(II)化合物,其特征在于化合物的X射线衍射图在6.5、8.1、17.2、18.8、22.3、22.6和25.5°的2θ角处具有最大峰。
还提供了变型1结晶形式的式(II)化合物,其特征在于化合物的X射线衍射图在6.5、8.1、16.4、17.2、18.0、18.8、19.4、22.3、22.6和25.5°的2θ角处具有最大峰。
还提供了变型1结晶形式的式(II)化合物,其特征在于化合物的IR谱在3381、1691和1565cm-1处具有最大谱带。
还提供了变型1结晶形式的式(II)化合物,其特征在于化合物的IR谱在3381、1691、1565、1524和1419cm-1处具有最大谱带。
还提供了变型1结晶形式的式(II)化合物,其特征在于化合物的IR谱在3381、3066、1691、1565、1524、1419和1101cm-1处具有最大谱带。
还提供了变型1结晶形式的式(II)化合物,其特征在于化合物的IR谱在3381、3066、2975、1691、1565、1524、1419、1135、1101和817cm-1处具有最大谱带。
变型1结晶形式的式(II)化合物可由式(I)化合物制备。无定形形式的式(I)化合物的制备公开于WO 2012/139888的实施例22。结晶形式的式(I)化合物的制备公开于EP17204842.3(作为WO 2019/105881公布)。无定形形式的式(I)化合物和结晶形式的化合物均同样适合用于在下文描述的方法中制备结晶变型1的式(II)化合物。
当由式(I)化合物制备式(II)化合物时,存在式(I)化合物差向异构化为式(III)的(3S)-3-(4-氯-3-{[(2R,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰基]氨基}苯基)-3-环丙基丙酸的风险,
或式(II)化合物差向异构化为式(IV)的(3S)-3-(4-氯-3-{[(2R,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰基]氨基}苯基)-3-环丙基丙酸钠的风险,
因此,例如,在使用氢氧化钠水溶液制备式(II)化合物期间或当使用的溶剂是甲醇或乙醇时,存在明显的差向异构化。结果,相关量的式(III)和(IV)的化合物以这样的反应制备,从而减少了所需式(II)化合物的收率。因此,差向异构化应避免。出乎意料地,在下文所述的制备方法中,存在比较少的该副反应。
为制备结晶变型1的式(II)化合物,将式(I)化合物,优选地在保护性气体气氛下,例如在氮气气氛下,溶解于极性非质子溶剂中。适合用作极性非质子溶剂的有,例如,乙腈、甲苯、甲基叔丁基醚(MTBE)或四氢呋喃(THF);优选使用乙腈。随后使用氢氧化钠,优选地为固体形式。将混合物搅拌,优选搅拌若干小时。过滤后,将获得的固体用极性非质子溶剂洗涤并干燥。
特别是溶剂的选择、所使用的氢氧化钠的量和固体形式的氢氧化钠的使用导致合成期间式(I)化合物的不想要的差向异构化减少。
特别是对于较大量的(千克规模)式(II)化合物的制备,存在这种可能性,即在反应期间部分固体氢氧化钠未被转化并且在过滤后保留在获得的固体中。由此,开发了一种替代的制备方法(制备方法2)。
在一个替代的制备方法中,将式(I)化合物,优选地在保护性气体气氛下,例如在氮气气氛下,溶解于极性非质子溶剂中并优选地过滤。适合用作极性非质子溶剂的有,例如,乙腈、甲苯、甲基叔丁基醚(MTBE)或四氢呋喃(THF);优选使用乙腈。将溶液冷却,并且优选地,在-20℃至50℃、特别优选地-10℃至10℃、非常特别地优选地0℃的温度下,添加溶解于合适的极性非质子溶剂中的空间要求高的(sterically demanding)醇钠,例如叔丁醇钠或2-甲基丁-2-醇钠。空间要求高的醇钠的用量优选为0.7-1.0摩尔当量、特别优选0.9-1.0摩尔当量且非常特别优选0.98摩尔当量,基于式(I)化合物计。适合用作极性非质子溶剂的有,例如,乙腈、甲苯、甲基叔丁基醚(MTBE)、2-甲基四氢呋喃或四氢呋喃(THF);优选使用THF。在空间要求高的醇钠的加入期间,可添加结晶变型1的式(II)化合物的晶种。这导致了更有效的析出和更高的收率。晶种可例如通过制备方法1制备。将混合物在-20℃至20℃、优选-5℃至5℃、特别优选0℃下搅拌,优选持续若干小时。过滤后,将获得的固体用极性非质子溶剂洗涤并干燥。
出乎意料地,碱的量——与使用的式(I)化合物的量有关——对差向异构化程度有强烈影响。相对于式(I)化合物计,0.7-1.0摩尔当量、优选0.9-1.0摩尔当量且特别优选0.98摩尔当量的碱,是有利的。
或者,变型1结晶形式的式(II)化合物可通过将无定形形式的式(II)化合物或另一种变型的式(II)化合物溶于极性溶剂例如四氢呋喃、异丙醇或甲醇中并随后结晶来制备。
本发明提供结晶变型1的式(II)化合物的制备,其特征在于将式(I)化合物溶解于极性非质子溶剂中,添加选自由氢氧化钠或空间要求高的醇钠组成的列表的碱,并在搅拌后将沉淀的固体分离并干燥。
本发明提供结晶变型1的式(II)化合物的制备,其特征在于将式(I)化合物在本案中溶解于极性非质子溶剂中,向其中添加选自氢氧化钠或空间要求高的醇钠组成的列表的碱,并在搅拌后将沉淀的固体分离并干燥。
本发明提供结晶变型1的式(II)化合物的制备,其特征在于将式(I)化合物在本申请情况下溶解于极性非质子溶剂(优选乙腈、甲苯、甲基叔丁基醚(MTBE)或四氢呋喃(THF),特别优选乙腈)中,向其中添加选自氢氧化钠或空间要求高的醇钠组成的列表的碱,并在搅拌后将沉淀的固体分离并干燥。
如果使用的碱是氢氧化钠,则优选使用固体形式的氢氧化钠。
本发明提供结晶变型1的式(II)化合物的制备,其特征在于将式(I)化合物在本申请情况下溶解于乙腈中,向其中添加固体形式的氢氧化钠,并在搅拌后将沉淀的固体分离并干燥。
碱的用量优选为0.7-1.0摩尔当量,特别优选0.9-1.0摩尔当量且非常特别地优选0.98摩尔当量,基于式(I)化合物计。
空间要求高的醇钠包括本领域技术人员已知的化学结构比甲醇钠或乙醇钠更复杂的所有合适的醇钠。优选的空间要求高的醇钠有,例如,叔丁醇钠或2-甲基丁-2-醇钠。
本发明提供结晶变型1的式(II)化合物的制备,其特征在于空间要求高的醇钠为叔丁醇钠或2-甲基丁-2-醇钠。
本发明提供结晶变型1的式(II)化合物的制备,其特征在于将式(I)化合物在本申请情况下溶解于极性非质子溶剂(优选乙腈、甲苯、甲基叔丁基醚(MTBE)或四氢呋喃(THF),特别优选乙腈)中,向其中添加选自氢氧化钠、叔丁醇钠和2-甲基丁-2-醇钠组成的列表的碱,并在搅拌后将沉淀的固体分离并干燥。
本发明提供结晶变型1的式(II)化合物的制备,其特征在于将式(I)化合物在本申请情况下溶解于乙腈中,向其中添加叔丁醇钠,并在搅拌后将沉淀的固体分离并干燥。
本发明提供结晶变型1的式(II)化合物的制备,其特征在于将式(I)化合物在本申请情况下溶解于乙腈中,向其中添加2-甲基丁-2-醇钠,并在搅拌后将沉淀的固体分离并干燥。
碱的用量优选为0.7-1.0摩尔当量,特别优选0.9-1.0摩尔当量且非常特别优选0.98摩尔当量,基于式(I)化合物计。
本发明提供结晶变型1的式(II)化合物的制备,其特征在于将式(I)化合物在本申请情况下溶解于乙腈中,向其中添加基于式(I)化合物计0.7-1.0摩尔当量、特别优选0.9-1.0摩尔当量且非常特别优选0.98摩尔当量的量的叔丁醇钠,并在搅拌后将沉淀的固体分离并干燥。
本发明提供结晶变型1的式(II)化合物的制备,其特征在于将式(I)化合物在本申请情况下溶解于乙腈中,向其中添加基于式(I)化合物计0.7-1.0摩尔当量、特别优选0.9-1.0摩尔当量且非常特别优选0.98摩尔当量的量的叔丁醇钠,并在搅拌后将沉淀的固体分离并干燥。
碱的添加和随后的搅拌彼此独立地在-20℃至50℃、优选-20℃至20℃、特别优选-10℃至10℃、非常特别优选0℃的温度下进行。
任选地,结晶变型1的式(II)化合物的晶种可在反应期间添加。
根据本发明的式(II)化合物和根据本发明的剂型具有有价值的药理学性质,并可用于治疗和/或预防人和动物的病症。
在本发明上下文中,术语“治疗(treatment)”或“治疗(treating)”包括抑制、延迟、阻止、减轻、减弱、限制、降低、遏制、击退或治愈疾病、病况、障碍、损伤或健康问题、或此类状态和/或此类状态的症状的发生、过程或进展。术语“疗法(therapy)”在本文中被理解为与术语“治疗”同义。
在本发明的上下文中,术语“预防(prevention)”、“预防(prophylaxis)”和“防止(preclusion)”同义使用,并且是指避免或降低感染、经历、遭受或患有疾病、病况、障碍、损伤或健康问题、或此类状态和/或此类状态的症状的发生或进展的风险。
疾病、病况、障碍、损伤或健康问题的治疗或预防可能是部分的或完全的。
根据本发明的式(II)化合物和根据本发明的剂型导致血管舒张、血小板聚集抑制和血压降低,并且它们也增加冠脉血流量和微循环。这些效应通过可溶性鸟苷酸环化酶的直接非血红素依赖性活化和细胞内cGMP水平升高而介导。
根据本发明的式(II)化合物和根据本发明的剂型尤其适合用于治疗和/或预防:肾脏疾病和心肾疾病,特别是慢性肾疾病(CKD)和糖尿病性肾病(DKD);心脏疾病和心血管疾病,特别是心力衰竭(HFpEF和HFrEF),心肌梗死,心绞痛,心肌病、高血压和动脉硬化;肺和心肺疾病,特别是肺动脉高压(PH);中枢神经系统的疾病,特别是痴呆;骨病,特别是成骨不全;血栓栓塞性病症;肌营养不良;缺血;血管病;微循环障碍;纤维性病症,特别是系统性硬化病,特别是年龄相关性黄斑变性;炎症性疾病;和代谢性疾病,特别是代谢综合征、血脂异常和糖尿病。
根据本发明的式(II)化合物和根据本发明的剂型可用于治疗和/或预防心脏病症、心脏血管病症和心肺病症,如,例如高血压(hypertension)、心力衰竭、冠心病、稳定的和不稳定的心绞痛、肺动脉高血压(PAH)和继发性形式的肺动脉高压(PH)、慢性血栓栓塞性肺动脉高压(CTEPH)、肾脏高血压、外周血管和心脏血管的病症、心律失常、房性和室性心律失常和传导受损例如I-III度房室传导阻滞、室上性快速性心律失常、心房颤动、心房扑动、心室纤颤、心室扑动、室性快速型心律失常、尖端扭转性室性心动过速、房性期外收缩和室性期外收缩、房室交界区早搏(AV-junctional extrasystoles)、病态窦房结综合征、晕厥、房室折返性心动过速(AV nodes reentry tachycardia)、午-帕-怀三氏综合征、急性冠状动脉综合征(ACS)、自身免疫心脏病症(心包炎、心内膜炎、valvolitis、主动脉炎、心肌病)、拳师犬心肌病(boxer cardiomyopathy)、微动脉瘤,休克如心源性休克、感染性休克和过敏性休克。
根据本发明的式(II)化合物和根据本发明的剂型可用于治疗和/或预防血栓栓塞性病症和缺血如心肌缺血,心肌梗死,中风,心脏肥大,暂时的和缺血性的发作(transistory and ischaemic attacks),先兆子痫,炎症性心血管疾病,冠状动脉和外周动脉的痉挛,水肿的形成例如肺水肿、脑水肿、肾脏水肿或心力衰竭诱导的水肿,受损的外周灌注,再灌注损伤,动脉的和静脉的血栓形成,微量白蛋白尿,心力衰竭,内皮功能障碍,微血管损伤和大血管损伤(血管炎),以及用于预防再狭窄,例如血栓溶解疗法、经皮的经腔血管成形术(percutaneous transluminal angioplasties)(PTA)、经皮穿腔的冠状动脉血管成形术(percutaneous transluminal coronary angioplasties)(PTCA)、心脏移植、搭桥手术,和微血管损伤和大血管损伤(血管炎),增加的血纤蛋白原水平和低密度LDL水平以及增加的纤溶酶原激活物抑制剂1(PAI-1)的浓度,以及用于治疗和/或预防勃起功能障碍和女性性功能障碍。
在本发明上下文中,术语“肺动脉高压”包括其原发性和继发性亚型,如根据DanaPoint分类法按照它们相应的病因学所定义的[参见D.Montana和G.Simonneau,在:A.J.Peacock等人(编辑),Pulmonary Circulation.Diseases and their treatment,第三版,Hodder Arnold Publ.,2011,第197-206页;M.M.Hoeper等人,J.Am.Coll.Cardiol.,2009,54(1),第85页-第96页]。它们包括,特别是,在第1类中的肺动脉高血压(PAH),其尤其包括特发性和家族性形式(分别为IPAH和FPAH),急性肺动脉高压,特别是急性呼吸窘迫综合征(ARDS)、急性肺损伤(ALI)和婴儿呼吸窘迫综合征(IRDS)。PAH还包括新生儿的持续性肺动脉高压和与以下疾病相关的疾病相关性肺动脉高压(APAH):与胶原性疾病、先天性系统性肺分流病变、门静脉高压症、HIV感染、特定药物和药剂(例如食欲抑制剂)的摄入相关,与具有明显静脉/毛细血管成分的病症如肺静脉闭塞性病症和肺毛细血管血管瘤病相关,或与其他病症相关,如甲状腺的病症、糖原贮积病、高雪氏病、遗传性毛细血管扩张、血红蛋白变异、骨髓增生病症和脾切除术相关。Dana Point分类法第2类包括患有病因性左心脏病症如室性的、房性的或心脏瓣膜的病症的PH患者。第3类包括与肺病例如与慢性阻塞性肺病(COPD)相关的肺动脉高压的形式、间质性肺疾病(ILD)、肺纤维化(IPF)和/或低氧血症、睡眠呼吸暂停、肺泡通气不足、慢性高原病、遗传性畸形。第4类包括患有慢性血栓性和/或栓塞性病症的PH患者,例如在近端和远端肺动脉的血栓栓塞性阻塞(CTEPH)或非血栓形成的栓塞(例如由肿瘤病症、寄生虫、异物导致)的情况下。肺动脉高压的较不常见的形式,如在患有结节病、组织细胞增多症X或淋巴管瘤病的患者中的肺动脉高压,总结于第5类。
在本发明上下文中,术语“心力衰竭”包括急性和慢性形式的心力衰竭,及其具体或相关的疾病类型,如急性代偿性心力衰竭、右心力衰竭、左心力衰竭、全心里衰竭、缺血性心肌病、扩张性心肌病(dilatative cardiomyopathy)、肥厚型心肌病、特发性心肌病、先天性心脏缺损、心脏瓣膜缺损、与心脏瓣膜缺损相关的心力衰竭、二尖瓣狭窄、二尖瓣闭锁不全、主动脉瓣狭窄、主动脉瓣关闭不全、三尖瓣狭窄、三尖瓣闭锁不全、肺动脉瓣狭窄、肺动脉瓣闭锁不全、联合心脏瓣膜缺损、心肌的炎症(心肌炎)、慢性心肌炎、急性心肌炎、病毒性心肌炎、糖尿病的心力衰竭、酒精性心肌病、心脏贮积病症和舒张性和收缩性心力衰竭、射血分数降低的心力衰竭(HFrEF)、射血分数保留心力衰竭(HFpEF)。
根据本发明的式(II)化合物和根据本发明的剂型还适合用于治疗和/或预防代谢性疾病。在本发明上下文中,代谢性疾病为,例如,萄糖代谢的病症和与葡萄糖代谢障碍相关的并发症。葡萄糖代谢的病症为,例如,糖尿病(1型或2型)、胰岛素抗药性、葡萄糖耐受不良、高血糖症、低血糖、高胰岛素血症或hypoinsulinaemia。与葡萄糖代谢障碍相关的病症为,例如,微血管病和大血管病、糖尿病视网膜病变、糖尿病神经病变、糖尿病肾病、延迟的/受损的伤口愈合、糖尿病足、组织缺血、四肢溃疡、坏疽、代谢性酸中毒、酮病、血脂异常、心肌梗死、急性冠状动脉综合征、稳定的或不稳定的心绞痛、心肌病、心力衰竭、心律失常、血管再狭窄、外周动脉闭塞疾病、肥胖症、X综合征、脂肪代谢障碍、动脉硬化或高血压。根据本发明的式(II)化合物和根据本发明的剂型还适合用于保持、改善和恢复胰细胞的功能,特别是用于保持、改善和恢复胰的β细胞的数量和大小。
在本发明上下文中,代谢性疾病还包括脂肪代谢的病症如,例如,脂质代谢障碍、低脂蛋白血症、血脂异常、高甘油三酯血症、高脂血症、混合型高脂血症(combinedhyperlipidaemias)、高胆固醇血症、aβ脂蛋白血症(aβlipoproteinaemia)、sitosterolaemia、黄瘤病、丹吉尔病、脂肪过多、肥胖、动脉硬化和代谢综合征。根据本发明的式(II)化合物和根据本发明的剂型适合用于治疗和/或预防与代谢性疾病相关的心血管疾病。
根据本发明的式(II)化合物和根据本发明的剂型还适合用于治疗和/或预防肌肉的或神经肌肉的病症。表述“肌肉的或神经肌肉的病症”涉及影响肌肉和/或它们对神经系统的直接控制的医学状况。它们可能是后天患有的或具有遗传起源。肌肉的或神经肌肉的病症特别是杜兴肌营养不良(DMD)、贝克肌营养不良(BMD)、先天性肌营养不良症、三好肌病、Miyoshi肌病、埃-德二氏肌营养不良、面肩胛肱型肌营养不良、肢带肌营养不良、肌强直性营养不良、眼咽肌营养不良、重症肌无力、朗-爱二氏肌无力综合征和夏-马-图三氏病(Charcot-Marie-Tooth disease)。
此外,根据本发明的式(II)化合物和根据本发明的剂型可用于治疗和/或预防原发性和继发性雷诺现象、微循环障碍、跛脚、耳聋、耳鸣、外周和自主神经病、糖尿病微血管病、糖尿病视网膜病变、CREST综合征、红斑性症、甲真菌病和风湿性病症。
根据本发明的式(II)化合物和根据本发明的剂型还可用于治疗和/或预防器官或组织的缺血相关的和/或再灌注相关的损害,以及用作人和动物来源的器官、器官部位、组织或组织部位的灌注和保存溶液的添加剂,特别是用于外科手术或移植医药领域。
根据本发明的式(II)化合物和根据本发明的剂型还适合用于治疗和/或预防肾脏疾病,特别是肾功能不全和肾功能衰竭。在本发明上下文中,术语“肾功能不全”和“肾功能衰竭”包括其急性和慢性表现(慢性肾疾病;CKD)和基础的或相关的肾脏病症,如肾灌注不足、透析中低血压、梗阻性尿路病、肾小球病、肾小球肾炎、急性肾小球肾炎、肾小球硬化症、小管间质性疾病;肾病病症如原发性和先天性肾病、肾炎、免疫肾病如肾移植排斥和免疫复合物-诱导的肾病、毒性物质诱导的肾病、造影剂诱导的肾病、糖尿病肾病和非糖尿病肾病、糖尿病肾病(DKD)、肾盂肾炎、肾囊肿、肾硬化、高血压肾硬化和肾病综合征,它们在诊断上可例如通过以下来表征:异常降低的肌酸酐和/或水排泄物,异常升高的尿素、氮、钾和/或肌酸酐的血药浓度,改变的肾脏的酶(例如谷氨酰基合成酶)的活性,改变的尿渗量或尿量,升高的微量白蛋白尿,巨白蛋白尿,肾小球(glomerulae)和小动脉病变,管状扩张,高磷酸盐血症和/或透析需要。本发明还包括根据本发明的剂型用于治疗和/或预防肾功能不全的后遗症的用途,所述肾功能不全的后遗症例如高血压、肺水肿、心力衰竭、尿毒症、贫血、电解质紊乱(例如高钾血症、低钠血症)和骨代谢和碳水化合物代谢中的紊乱。
另外,根据本发明的式(II)化合物和根据本发明的剂型适合用于治疗和/或预防泌尿生殖系统的病症,例如良性前列腺综合征(BPS),良性前列腺增生(BPH),良性前列腺增大(BPE),膀胱出口梗阻(BOO),下尿路综合征(LUTS),间质性膀胱炎,膀胱过度活动症(OAB),失禁例如混合性尿失禁、急迫性尿失禁、压力性尿失禁或充溢性尿失禁(MUI、UUI、SUI、OUI),骨盆痛,勃起功能障碍,女性性功能障碍、阴道萎缩、性交困难或萎缩性阴道炎。
根据本发明的式(II)化合物和根据本发明的剂型还适合用于治疗和/或预防哮喘病、慢性阻塞性肺疾病(COPD)、急性呼吸性窘迫综合征(ARDS)和急性肺损伤(ALI)、α-1抗胰蛋白酶缺乏症(AATD)、肺纤维化、肺气肿(例如香烟烟雾诱导的肺气肿)、肺静脉高压、间质性肺病、睡眠呼吸暂停、肺泡通气不足障碍、高海拔下的慢性暴露、新生儿肺病症、肺泡毛细血管异型增生、镰状细胞贫血、凝血功能障碍、慢性血栓栓塞、肿瘤相关性肺栓塞、结缔组织病症、狼疮、血吸虫病、结节病、慢性支气管炎、毛细血管性肺血管瘤病;组织细胞增多症X,淋巴管瘤病和由于腺病、纤维性纵隔炎和囊性纤维化病(CF)导致的肺血管受压。
本发明中描述的根据本发明的式(II)化合物和根据本发明的剂型还是用于控制以NO/cGMP系统的紊乱为特征的中枢神经系统疾病的活性化合物和剂型。它们特别适合用于改善认知障碍后的知觉、注意力、学习或记忆,所述认知障碍如特别是与情境/疾病/综合征相关出现的那些,如轻度认知障碍、年龄相关的学习和记忆缺陷、年龄相关的记忆障碍、痴呆,血管性痴呆、混合型痴呆、中风后出现的痴呆(中风后痴呆)、创伤后颅脑损伤、一般注意集中障碍、存在学习和记忆问题的儿童的注意集中障碍、阿尔茨海默尔病、路易体痴呆、伴有额叶退化的痴呆(包括皮克式综合征)、帕金森氏病、进行性核性麻痹、伴有皮质基底变性的痴呆、肌侧索硬化症(amyolateral sclerosis)(ALS)、亨延顿氏病、脱髓鞘症、多发性硬化症、丘脑退化、克-雅(Creutzfeld-Jacob)痴呆、HIV痴呆、伴有痴呆的精神分裂症或科萨科夫精神病、宾斯万格痴呆(皮层下动脉硬化性脑病)、伴有皮层下梗死和脑白质病的脑常染色体显性动脉病(iCADASIL或CADASIL综合征)、无症状神经认知障碍(ANI)、多发性硬化症(MS)(包括临床孤立综合征(CIS)、复发缓解型MS(RRMS)、原发性进行性MS(PPMS)和继发性进行性MS(SPMS))、多系统萎缩(MSA)、帕金森氏病、帕金森氏附加症(Parkinson’splus)、进行性核上麻痹(PSP,斯-里-奥三氏综合征)、注意力缺陷综合征(ADS)和注意缺陷多动症(ADHS)。它们还适合用于治疗和/或预防中枢神经系统病症如焦虑、紧张和压抑的状态,CNS相关的性功能障碍和睡眠障碍,以及用于防治食物、兴奋剂和成瘾物质的摄入的病理性紊乱。它们还适合用于治疗和/或预防损伤,例如创伤性脑损伤(TBI),包括例如,脑震荡和脑损伤(CTE);或非创伤性中风(包括局部缺血性中风、微动脉瘤或缺氧);脑损害;认知损害;脑损伤;神经变性病症或神经性疼痛。它们也适合用于治疗和/或预防张力失常,例如全身性、局灶性、部分的、植物性的、急性张力障碍反应以及遗传/原发性张力失常和运动失调,包括急性、慢性/迟发性和非运动性运动失调以及左旋多巴诱导运动障碍(LID)。它们也适合用于治疗和/或预防以突触可塑性和突触过程减少为特征的病症,例如脆性X染色体综合征、Rett综合征、Williams综合征、Renpenning综合征、自闭症谱系病症(包括自闭症、Asperger综合征或广泛性发展障碍(pervasive development disorder))。它们也适用于治疗和/或预防精神的、情感的或心理的病症,例如双相障碍、精神分裂症、一般性精神病、药物诱导的精神病、妄想症、感情分裂性精神病、强迫观念与行为的病症(OCD)、抑郁症、焦虑症、恐慌症或创伤后应激障碍(PTSD)。
此外,根据本发明的式(II)化合物和根据本发明的剂型还适合用于控制脑血流量,并因此成为控制偏头痛的有效剂。它们还适合用于预防和防治脑梗死后遗症(Apoplexia cerebri)如中风、大脑缺血和颅脑损伤。根据本发明的剂型同样可用于控制疼痛状态。
另外,根据本发明的式(II)化合物和根据本发明的剂型具有抗炎作用且因此可用作抗炎剂用于治疗和/或预防败血病(SIRS)、多器官功能衰竭(MODS、MOF)、肾的炎症性疾病、慢性肠炎症(IBD、克罗恩病、UC)、胰腺炎、腹膜炎、类风湿病症和炎症性皮肤病症。
根据本发明的式(II)化合物和根据本发明的剂型还适合用于治疗和/或预防急性疼痛、中枢性疼痛综合征、化学疗法诱导的神经病和神经性疼痛、糖尿病性神经病变、纤维肌痛、炎性痛、神经性疼痛、手术后疼痛、强直性疼痛或内脏痛。
根据本发明的式(II)化合物和根据本发明的剂型还适合用于治疗和/或预防内部器官(例如肺、心脏、肾脏、骨髓以及尤其是肝脏)的纤维性病症,以及皮肤病性纤维化和纤维性眼病。在本发明上下文中,术语“纤维性病症”包括特别是病症如肝纤维化、肝硬化、肺纤维化,心内膜心肌纤维化症、肾病、肾小球肾炎、间质性肾纤维化、糖尿病导致的纤维性损害、骨髓纤维化和类似的纤维变性病症,硬皮病,系统性硬化病,硬斑病,瘢痕疙瘩,肥厚性瘢痕,痣,糖尿病性视网膜病变,增生性玻璃体视网膜病变和结缔组织的病症(例如肌瘤(sarkoidosis))。根据本发明的剂型同样可以用于治疗脂肪性肝炎、特别是非酒精性脂肪性肝炎(NASH),用于促进伤口愈合,用于控制术后瘢痕,例如青光眼手术后,以及美容上用于老化和角质化皮肤。
根据本发明的式(II)化合物和根据本发明的剂型还适合用于治疗和/或预防骨病,例如且优选地成骨不全(OI);骨折;骨愈合受损;佝偻病;骨软化症;无血管性骨坏死;佩吉特氏病;骨发育不全;骨质减少;由骨转移引起的骨溶解性病损;放射治疗或化学疗法;牙周炎;高钙血症;骨坏死;骨肉瘤;溶骨性转移;家族性扩张性骨质溶解;膨胀性骨骼增生和特发性增生;青少年佩吉特氏病;坎-恩二氏疾病;假体松弛;periprostetic osteolysis;锁骨颅骨发育不良(CCD);多发性骨髓瘤;牙槽骨质丢失;由于固定术或性激素缺乏导致的骨丢失;与选自以下的疾病相关的骨丢失:恶病质、厌食症、脱发和炎症性疾病,所述炎症性疾病选自类风湿性关节炎、银屑病关节炎、银屑病、脊椎关节炎、SLE、系统性硬化病、转移性癌症和炎性肠病;骨关节炎、截骨术后骨愈合受损、婴儿特发性骨丢失、脊柱变形、骨质疏松症、原发性骨质疏松症、继发性骨质疏松症和特别是骨质疏松症、非由性激素缺乏引起的原发性骨质疏松症或继发性骨质疏松症。
根据本发明的式(II)化合物和根据本发明的剂型还适合用于治疗和/或预防胃肠括约肌功能障碍,如失弛缓症、括约肌痉挛和高血压括约肌,特别是下食道括约肌(LES)失弛缓症、食道失弛缓症、痉挛性LES、血压LES(HTNLES)、幽门括约肌(幽门)失弛缓症、幽门痉挛(pylorospasm)、幽门高压症、回盲括约肌或瓣膜(ICV)失弛缓症、高血压ICV、痉挛性ICV或ICV痉挛、奥狄括约肌功能障碍(SOD)、奥狄括约肌失弛缓症、痉挛的奥狄括约肌、高血压的奥狄括约肌、肛门内括约肌(IAS)失弛缓症、IAS高血压、痉挛性IAS或IAS抽筋。在另一个实施方案中,所述胃肠道括约肌功能障碍由神经学的、代谢的、内分泌的或神经变性的病症引起。
此外,根据本发明的式(II)化合物和根据本发明的剂型适合用于治疗和/或预防眼部疾病,在本发明的上下文中,其包括,例如,以下病症:年龄相关性黄斑变性(AMD),包括干性(非渗出性)和湿性(渗出性,新生血管型)AMD;脉络膜新血管生成(CNV);脉络膜新生血管膜(CNVM);囊样斑点水肿(CME);视网膜外膜(ERM)和黄斑穿孔(macular perforation);与近视相关的脉络膜新血管生成;血管样条纹和血管条纹;视网膜脱离;糖尿病性视网膜病变;非增生型糖尿病性视网膜病变(NPDR);糖尿病黄斑水肿(DME);视网膜色素上皮的萎缩性变化和肥厚性变化;视网膜静脉闭塞;脉络膜视网膜静脉闭塞;黄斑水肿;与视网膜静脉闭塞相关的黄斑水肿;视网膜色素变性;斯塔加德疾病(Stargardt's disease);早产儿视网膜病;青光眼;炎症性眼病症,例如葡萄膜炎、巩膜炎或眼内炎;白内障;折光异常,例如近视,远视,散光和圆锥角膜;由缺氧导致的角膜血管生成(例如通过接触镜的广泛使用);翼状胬肉结膜,角膜下水肿和角膜内水肿。
由于它们的活性特性,根据本发明的式(II)化合物和根据本发明的剂型特别适合用于治疗和/或预防心脏血管的和心肺的病症,如原发性形式和继发性形式的肺动脉高压、心力衰竭、心绞痛和高血压,以及血栓栓塞性病症、缺血、血管病、微循环障碍、肾功能不全、纤维性病症和动脉硬化。
优选地,根据本发明的式(II)化合物和根据本发明的剂型适合用于治疗和/或预防肾脏疾病和心肾疾病,特别是慢性肾疾病(CKD)和糖尿病性肾病(DKD);心脏疾病和心血管疾病,特别是心力衰竭(HFpEF和HFrEF)、心肌梗死、心绞痛、心肌病、高血压和动脉硬化;肺和心肺疾病,特别是肺动脉高压(PH);眼部疾病,特别是非增生型糖尿病性视网膜病变(NPDR)和糖尿病黄斑水肿(DME);中枢神经系统的疾病,特别是痴呆;骨病,特别是成骨不全;血栓栓塞性病症;肌营养不良;缺血;血管病;微循环障碍;纤维性病症,特别是系统性硬化病;炎症性疾病;和代谢性疾病,特别是代谢综合征、血脂异常和糖尿病。
优选地,根据本发明的式(II)化合物和根据本发明的剂型适合用于治疗和/或预防肾脏疾病和心肾疾病,特别是慢性肾疾病(CKD)。
优选地,根据本发明的式(II)化合物和根据本发明的剂型适合用于治疗和/或预防眼部疾病,特别是非增生型糖尿病性视网膜病变(NPDR)和糖尿病性黄斑水肿(DME)。
优选地,根据本发明的式(II)化合物和根据本发明的剂型适合用于治疗和/或预防心血管疾病,特别是心力衰竭,包括射血分数降低的心力衰竭(HFrEF)和射血分数保留的心力衰竭(HFpEF)。
优选地,根据本发明的式(II)化合物和根据本发明的剂型适合用于治疗和/或预防心肺的病症,特别是肺动脉高压。
优选地,根据本发明的式(II)化合物和根据本发明的剂型适合用于治疗和/或预防中枢神经系统的疾病,特别是痴呆,包括血管性痴呆和混合形式的痴呆。
优选地,根据本发明的式(II)化合物和根据本发明的剂型适合用于治疗和/或预防“肌肉的或神经肌肉的病症”,特别是杜氏肌营养不良(Duchenne muscular dystrophy)(DMD)和贝克肌营养不良(BMD)。
本发明还提供根据本发明的式(II)化合物和根据本发明的剂型用于治疗和/或预防镰状细胞贫血的用途,其中受损伤的患者接受合成的血液代用品,以及用于保存血液代用品的用途。
本发明还提供根据本发明的式(II)化合物和根据本发明的剂型用于治疗和/或预防多囊卵巢综合征(PCOS)的用途。
本发明还提供根据本发明的式(II)化合物和根据本发明的剂型用于治疗和/或预防先兆子痫的用途。
本发明还提供根据本发明的式(II)化合物和根据本发明的剂型用于治疗和/或预防病症、尤其是前述病症的用途。
本发明还提供根据本发明的式(II)化合物和根据本发明的剂型在用于治疗和/或预防病症、尤其是前述病症的方法中的用途。
本发明进一步提供一种用于治疗和/或预防病症、尤其是前述病症的方法,使用有效量的根据本发明的式(II)化合物或至少一种的根据本发明的剂型。
根据本发明的式(II)化合物或根据本发明的剂型可单独使用或,如果需要,与其他活性化合物组合使用。本发明进一步提供药剂,其包含至少一种根据本发明的剂型和一种或多种其他活性化合物、尤其是用于治疗和/或预防前述病症的活性化合物。适合用于组合的活性化合物的优选实例包括:
·有机硝酸酯类和NO供体,例如硝普钠、硝酸甘油、单硝酸异山梨酯、双硝酸异山梨酯、吗多明或SIN-1,和吸入性NO;
·增加cGMP浓度的其他物质,例如原卟啉IX(protoporphyrine IX),花生四烯酸或苯肼衍生物;
·NO合成酶底物,例如N-羟胍衍生物、L-精氨酸衍生物、N-烷基-N′-羟胍衍生物、N-芳基-N′-羟胍衍生物或胍衍生物;
·抑制环单磷酸鸟苷(cGMP)和/或环单磷酸腺苷(cAMP)的降解的化合物,例如磷酸二酯酶(PDE)1、2、3、4、5、9和/或10的抑制剂,尤其是PDE 4抑制剂如罗氟司特或revamilast,和PDE 5抑制剂如西地那非、伐地那非、他达拉非、乌地那非、达生他非、阿伐那非、米罗那非或罗地那非(lodenafil);
·鸟苷酸环化酶的NO非依赖性的但血红素依赖性的刺激剂,尤其是利奥西呱、nelociguat、vericiguat、praliciguat(IW-1973)、olinciguat(IW-1701)和在WO 00/06568、WO 00/06569、WO 02/42301、WO03/095451、WO 2011/147809、WO 2012/004258、WO2012/028647和WO 2012/059549中的;
·前列环素类似物和IP受体激动剂,例如并且优选伊洛前列素、贝前列素、曲罗列尼尔、依前列醇、NS-304、selexipag或ralinepag;
·内皮缩血管肽受体拮抗剂,例如并且优选波生坦、达卢生坦、安立生坦、macicentan或西他生坦(sitaxsentan);
·人嗜中性细胞弹性蛋白酶(HNE)的抑制剂,例如并且优选西维来司他或DX-890(Reltran);
·抑制信号传导级联的化合物,特别是来自以下物质的组:酪氨酸激酶抑制剂,例如并且优选达沙替尼、尼洛替尼、波舒替尼、瑞戈非尼、索拉非尼、舒尼替尼、西地尼布、阿西替尼、替拉替尼、伊马替尼、布利尼布(brivanib)、帕唑帕尼、伐他拉尼、吉非替尼、埃罗替尼、拉帕替尼、卡纽替尼、来妥替尼、培利替尼、司马沙尼、马赛替尼或坦度替尼;
·Rho激酶抑制剂,例如并且优选法舒地尔、Y-27632、SLx-2119、BF-66851、BF-66852、BF-66853、KI-23095或BA-1049;
·如用于例如治疗慢性阻塞性肺病(COPD)或支气管哮喘的抗阻塞剂,例如并且优选,以吸入的方式或以内吸收的方式给药的β-受体模拟物(例如贝多拉君)或以吸入的方式给药的抗毒蕈碱能物质;
·如例如用于治疗慢性阻塞性肺病(COPD)、支气管哮喘或肺纤维化的抗炎剂和/或免疫抑制剂,如,例如并且优选以内吸收的方式或以吸入的方式给药的皮质类甾醇类、氟替卡松(flutiform)、吡非尼酮、乙酰半胱氨酸、硫唑嘌呤或BIBF-1120;
·化疗药物,如例如用于治疗肺或其他器官中的肿瘤的那些;
·用于肺的病症的全身性和/或吸入性治疗的活性化合物,所述病症例如囊性纤维化病(α-1-抗胰蛋白酶、氨曲南、依伐卡托(ivacaftor)、卢马卡托(lumacaftor)、阿他卢仑、阿米卡星、左氧氟沙星)、慢性阻塞性肺疾病(COPD)(LAS40464、PT003、SUN-101)、急性呼吸窘迫综合征(ARDS)和急性肺损伤(ALI)(干扰素-β-1a、traumakines)、阻塞性睡眠呼吸窒息症(VI-0521)、支气管扩张(甘露醇、环丙沙星)、闭塞性细支气管炎(环孢菌素、氨曲南)和败血病(帕昔单抗、万汶、ART-123);
·用于治疗肌营养不良症的活性化合物,例如艾地苯醌;
·抗血栓形成剂,例如并且优选来自以下物质的组:血小板聚集抑制剂、抗凝血剂或致纤溶作用物质(profibrinolytic substance);
·改变脂质代谢的活性化合物,例如且优选来自以下物质的组:甲状腺受体激动剂、胆固醇合成抑制剂,例如且优选HMG-CoA还原酶抑制剂或鲨烯合成抑制剂、ACAT抑制剂、CETP抑制剂、MTP抑制剂、PPAR-α、PPAR-γ和/或PPAR-δ激动剂、胆固醇吸收抑制剂、脂肪酶抑制剂、多聚胆汁酸吸附剂、胆汁酸重吸收抑制剂和脂蛋白(a)拮抗剂;
·抑制新生血管发生的活性化合物,例如并且优选VEGF和/或PDGF信号通道的抑制剂、整联蛋白信号通道的抑制剂、血管生成素-Tie信号通道的抑制剂、PI3K-Akt-mTor信号通道的抑制剂、Ras-Raf-Mek-Erk信号通道的抑制剂、MAPK信号通道的抑制剂、FGF信号通道的抑制剂、1-磷酸-鞘氨醇信号通道的抑制剂、内皮细胞增殖的抑制剂或诱导凋亡的活性成分;
·降低血管壁渗透性(水肿形成)的活性化合物,例如并且优选皮质类甾醇类、ALK1-Smad1/5信号通道的抑制剂、VEGF和/或PDGF信号通道的抑制剂、环加氧酶抑制剂、血管舒缓素-激肽系统的抑制剂或1-磷酸-鞘氨醇信号通道的抑制剂;
·降低氧化性应激下对视网膜的损害的活性化合物,例如并且优选抑制剂补体系统,尤其是补体C5a受体的拮抗剂,或5-HT1A受体的激动剂;
·抗氧化剂和自由基清除剂;
·活性降血压化合物,例如并且优选来自以下物质的组:钙拮抗剂、血管紧张素AII拮抗剂、ACE抑制剂、β-受体阻断剂、α-受体阻断剂、利尿药、磷酸二酯酶抑制剂、sGC刺激剂、cGMP提肌、ECE抑制剂,血管肽酶抑制剂和/或盐皮质激素受体拮抗剂;
·抗心律不齐药,例如钠通道阻断剂、β-受体阻断剂、钾通道阻断剂或钙通道阻断剂;
·α-1-肾上腺素受体拮抗剂;
·中枢作用的α-2-肾上腺素受体激动剂;
·咪唑啉I-l受体激动剂;
·多巴胺D1受体激动剂;
·5-HT2拮抗剂;
·加压素拮抗剂;
·钙通道敏化物;
·支气管扩张剂,例如β-2-肾上腺素受体激动剂、抗胆碱剂、茶碱或PDE抑制剂;
·皮质类固醇类,例如泼尼松龙;
·PGD2受体拮抗剂;
·非甾体抗哮喘药,例如β-2-肾上腺素受体激动剂或β-2-肾上腺素受体激动剂和皮质类甾醇类的联合;
·非甾体抗炎药(NSAIDs)和选择性环氧化酶-2(COX-2)抑制剂;
·用于超重和肥胖的药剂,例如甲基苯丙胺、二乙胺苯丙酮、苯丁胺、苄非他明、苯甲曲秦、马吲哚、奥利司他、西布曲明或利莫纳班和联合药如,例如,苯丁胺/托吡酯、安非他酮/纳曲酮、西布曲明/二甲双胍、安非他酮SR/唑尼沙胺SR、沙美特罗、昔萘酸盐/氟替卡松;氯卡色林、苯丁胺/托吡酯、西替司他、艾塞那肽、利拉糖肽、二甲双胍、CORT-108297、卡格列净(canagliflozin)、甲基吡啶铬、GSK-1521498、LY-377604、美曲普汀、奥尼匹肽、P-S7AS3、PSN-821、沙美特罗昔萘酸盐/氟替卡松、生长激素(重组体)、替莫瑞林、替索芬辛、维奈哌利、唑尼沙胺、贝洛拉尼、白藜芦醇、苏比替罗、四氢次大麻酚(tetrahydrocannabivarin)和β-拉帕醌;
·腺苷酸环化酶抑制剂,例如考福新;
·正性肌力物质,例如地高辛;
·用于治疗勃起功能障碍的药剂,例如前列地尔;
·用于痴呆的药物,如乙酰胆碱酯酶抑制剂,例如多奈哌齐、加兰他敏和卡巴拉汀;或NMDA受体拮抗剂,例如美金刚;
·用于治疗精神障碍的药剂,例如多巴胺D4受体拮抗剂,如氯氮平;多巴胺D2受体拮抗剂,如奈莫必利(nemonaprid);混合多巴胺D1/D2受体拮抗剂,如珠氯噻醇;GABA A受体调节剂,如卡马西平;钠通道抑制剂,如拉莫三嗪;单胺氧化酶抑制剂,如吗氯贝胺;三环抗抑郁剂,如阿米替林、地昔帕明、丙米嗪、阿莫沙平、去甲替林或氯米帕明;选择性血清素再摄取抑制剂(SSRIs),如帕罗西汀、氟西汀或citralopram、多虑平、曲唑酮(trazodonc)或阿戈美拉汀;选择性去肾上腺素再摄取抑制剂(SNRls)如文拉法辛;或多巴胺能抗抑制药如安非他酮;
·神经内肽酶的抑制剂(NEP抑制剂),如沙库比曲(sacubitril)、omapatrilate或亚甲蓝,AVE-7688,或与血管紧张素受体阻断剂(例如缬沙坦)(例如LCZ696)双重组合(‘ARNIs’);
·钠尿肽,例如心房钠尿肽(ANP,阿那立肽),B-型钠尿肽或脑钠尿肽(BNP,奈西立肽)、C-型钠尿肽(CNP)和尿扩张素;
·抗糖尿病药,例如并且优选来自以下物质的组:胰岛素和胰岛素衍生物、磺脲、双胍类、氯茴苯酸衍生物、葡糖苷酶抑制剂、PPAR-γ激动剂、GLP 1受体激动剂、胰高血糖素拮抗剂、胰岛素敏化物、CCK1受体激动剂、二肽基肽酶4的抑制剂(二肽基肽酶IV抑制剂)、SGLT 2抑制剂、瘦素受体激动剂、钾通道拮抗剂和糖原异生和/或糖原分解的兴奋中涉及的肝脏的酶类的抑制剂;
·抗感染药,例如并且优选来自以下物质的组:抗细菌活性物质、抗真菌活性物质和/或抗病毒活性物质;和/或
·用于治疗青光眼的物质,例如并且优选以下物质的组:肾上腺素能药物、β-受体阻断剂、碳酸酐酶抑制剂、拟副交感神经药和前列腺素;和/或
·用于治疗骨病的物质,例如并且优选双磷酸盐类、维生素D或其代谢产物、雷奈酸锶、选择性雌激素受体调节剂(SERM)、甲状旁腺素或其类似物和/或RANKL(核因子kappa-B配体的受体激活剂)调节剂。
抗血栓形成剂优选地应理解为意指来自以下物质的组的化合物:血小板聚集抑制剂、抗凝血剂或致纤溶作用物质。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与血小板聚集抑制剂联合给药,所述血小板聚集抑制剂例如并且优选阿司匹林、氯吡格雷、噻氯匹定或双嘧达莫。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与凝血酶抑制剂联合给药,所述凝血酶抑制剂例如并且优选希美拉加群、美拉加群、达比加群、比伐卢定或克赛。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与GPIIb/IIIa拮抗剂联合给药,所述GPIIb/IIIa拮抗剂例如并且优选普罗非班或阿昔单抗。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与因子Xa抑制剂联合给药,所述因子Xa抑制剂例如并且优选利伐沙班、阿哌沙班、非德沙班、雷扎沙班、磺达肝素、依达肝素(idraparinux)、DU-176b、PMD-3112、YM-150、KFA-1982、EMD-503982、MCM-17、MLN-1021、DX 9065a、DPC 906、JTV 803、SSR-126512或SSR-128428。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与肝素或低分子量(LMW)肝素衍生物联合给药。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与维生素K拮抗剂联合给药,所述维生素K拮抗剂例如并且优选香豆素、苯丙香豆素(phenprocumon)或华法林。
降血压剂优选地应理解为意指来自以下物质的组的化合物:钙拮抗剂、血管紧张素AII拮抗剂、ACE抑制剂、内皮缩血管肽拮抗剂、肾素抑制剂、α-受体阻断剂、β-受体阻断剂、盐皮质激素受体拮抗剂和利尿药。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与钙拮抗剂联合给药,所述钙拮抗剂例如并且优选硝苯地平、氨氯地平、维拉帕米或地尔硫卓。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与α1肾上腺素受体拮抗剂联合给药,所述α1肾上腺素受体拮抗剂例如并且优选哌唑嗪。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与β受体阻断剂联合给药,所述β受体阻断剂例如并且优选普萘洛尔、阿替洛尔、噻吗洛尔、吲哚洛尔、阿普洛尔、氧烯洛尔、喷布洛尔、布拉洛尔、美替洛尔、纳多洛尔、甲吲洛尔、卡拉洛尔(carazalol)、索他洛尔、美托洛尔、倍他洛尔、塞利洛尔、比索洛尔、卡替洛尔、艾司洛尔、拉贝洛尔、卡维地洛、阿达洛尔、兰地洛尔、奈必洛尔、依泮洛尔或布新洛尔。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与血管紧张素AII拮抗剂联合给药,所述血管紧张素AII拮抗剂例如并且优选氯沙坦、坎地沙坦、缬沙坦、替米沙坦或恩布沙坦(embursatan)。
在本发明的一个优选实施方案中,根据本发明的剂型与ACE抑制剂联合给药,所述ACE抑制剂例如并且优选依那普利、卡托普利、赖诺普利、雷米普利、地拉普利、福辛普利、奎诺普利(quinopril)、培哚普利或川多普利。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与内皮缩血管肽拮抗剂联合给药,所述内皮缩血管肽拮抗剂,例如并且优选波生坦、达卢生坦、安立生坦或西他生坦。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与肾素抑制剂联合给药,所述肾素抑制剂例如并且优选阿利吉仑、SPP-600或SPP-800。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与盐皮质激素受体拮抗剂联合给药,所述盐皮质激素受体拮抗剂例如螺内酯或依普利酮,特别优选地与非类固醇类的盐皮质激素受体拮抗剂如非奈利酮(finerenone)联合给药。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与利尿药联合给药,所述利尿药例如并且优选呋塞米、布美他尼、托拉塞米、苄氟噻嗪、氯噻嗪、氢氯噻嗪、氢氟噻嗪、甲氯噻嗪、泊利噻嗪、三氯噻嗪、氯噻酮、吲达帕胺、美托拉宗、喹乙宗、乙酰唑胺、双氯非那胺、醋甲唑胺、甘油、异山梨醇、甘露醇、阿米洛利或氨苯喋啶。
脂质代谢改性剂应优选地理解为意指来自以下物质的组的化合物:CETP抑制剂;甲状腺受体激动剂;胆固醇合成抑制剂如HMG-CoA还原酶抑制剂或鲨烯合成抑制剂;ACAT抑制剂;MTP抑制剂;PPAR-α、PPAR-γ和/或PPAR-δ激动剂;胆固醇吸收抑制剂;多聚胆汁酸吸附剂;胆汁酸重吸收抑制剂;脂肪酶抑制剂和脂蛋白(a)拮抗剂。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与CETP抑制剂联合给药,所述CETP抑制剂例如并且优选托塞曲匹(CP-5294/4)、JJT-705或CETP疫苗(Avant)。
在本发明的一个优选实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与甲状腺受体激动剂联合给药,所述甲状腺受体激动剂例如并且优选D-甲状腺素、3,5,3′-三碘甲状腺原氨酸(T3)、CGS 23425或阿昔替罗(CGS 26214)。
在本发明的一个优选实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与HMG-CoA还原酶抑制剂联合给药,所述HMG-CoA还原酶抑制剂来自他汀类,例如并且优选洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、罗舒伐他汀或匹伐他汀。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与鲨烯合成抑制剂联合给药,所述鲨烯合成抑制剂例如并且优选BMS-188494或TAK-475。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与ACAT抑制剂联合给药,所述ACAT抑制剂例如并且优选阿伐麦布(avasimib)、亚油甲苄胺、帕替麦布(pactimib)、依鲁麦布(eflucimib)或SMP-797。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与MTP抑制剂联合给药,所述MTP抑制剂例如并且优选英普他派、BMS-201038、R-103757或JTT-130。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与PPAR-γ激动剂联合给药,所述PPAR-γ激动剂例如并且优选吡格列酮或罗格列酮。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与PPAR-6激动剂联合给药,所述PPAR-6激动剂例如并且优选GW 501516或BAY 68-5042。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与胆固醇吸收抑制剂联合给药,所述胆固醇吸收抑制剂例如并且优选依泽替米贝(ezetimib)、替奎安或帕马奎苷。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与脂肪酶抑制剂联合给药,所述脂肪酶抑制剂例如并且优选奥利司他。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与多聚胆汁酸吸附剂联合给药,所述多聚胆汁酸吸附剂例如并且优选考来烯胺、考来替泊、colesolvam、考来胶或考来替兰(colestimide)。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与胆汁酸重吸收抑制剂联合给药,所述胆汁酸重吸收抑制剂例如并且优选ASBT(=IBAT)抑制剂,例如AZD-7806、S-8921、AK-105、BARI-1741、SC-435或SC-635。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与脂蛋白(a)拮抗剂联合给药,所述脂蛋白(a)拮抗剂例如并且优选gemcabene钙盐(CI-1027)或烟酸。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与乙酰胆碱酯酶抑制剂联合给药,所述乙酰胆碱酯酶抑制剂例如并且优选多奈哌齐、加兰他敏或卡巴拉汀。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与NMDA受体拮抗剂联合给药,所述NMDA受体拮抗剂例如并且优选美金刚。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与sGC刺激剂联合给药,所述sGC刺激剂例如并且优选利奥西呱、nelociguat、维利西呱(vericiguat)、praliciguat(IW-1973)或olinciguat(IW-1701)。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与抗糖尿病药联合给药,所述抗糖尿病药例如并且优选二甲双胍。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与SGLT-2抑制剂联合给药,所述SGLT-2抑制剂例如并且优选达格列净、恩格列净(empagliflozin)、卡格列净(canagliflozin)、依格列净(ipragliflozin)和/或托格列净(tofogliflozin)。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与用于治疗骨病的物质联合给药,所述用于治疗骨病的物质如例如并且优选维生素D或其代谢产物、雷奈酸锶、选择性雌激素受体调节剂(SERM)和/或RANKL调节剂。
在一个优选的实施方案中,根据本发明的式(II)化合物或根据本发明的剂型与双磷酸盐类联合给药,所述双磷酸盐类例如并且优选羟乙磷酸盐、氯屈膦酸盐、替鲁膦酸、特立帕肽、帕米膦酸二钠、奈立膦酸盐(neridronate)、奥帕膦酸盐、阿屈膦酸盐、伊班膦酸盐、利塞膦酸盐或唑来膦酸盐。
本发明还提供式(II)化合物,优选为变型1结晶形式,其用于治疗和/或预防疾病。
本发明还提供式(II)化合物,优选为变型1结晶形式,其用于治疗和/或预防肾脏疾病和心肾疾病,特别是慢性肾疾病(CKD)和糖尿病性肾病(DKD);心脏疾病和心血管疾病,特别是心力衰竭(HFpEF和HFrEF)、心肌梗死、心绞痛、心肌病、高血压和动脉硬化;肺和心肺疾病,特别是肺动脉高压(PH);中枢神经系统的疾病,特别是痴呆;骨病,特别是成骨不全;血栓栓塞性病症;肌营养不良;缺血;血管病;微循环障碍;纤维性病症,特别是系统性硬化病;眼部疾病;炎症性疾病;和代谢性疾病,特别是代谢综合征、血脂异常和糖尿病。
本发明还提供式(II)化合物,优选为变型1结晶形式,其用于治疗和/或预防肾脏疾病和心肾疾病,特别是慢性肾疾病(CKD)和糖尿病性肾病(DKD)。
本发明还提供式(II)化合物,优选为变型1结晶形式,其用于治疗和/或预防心脏疾病和心血管疾病,特别是心力衰竭(HFpEF和HFrEF)、心肌梗死、心绞痛、心肌病、高血压和动脉硬化。
本发明还提供式(II)化合物,优选为变型1结晶形式,其用于治疗和/或预防肺和心肺疾病,特别是肺动脉高压(PH)。
本发明还提供式(II)化合物,优选为变型1结晶形式,其用于治疗和/或预防中枢神经系统的疾病,特别是痴呆。
本发明还提供式(II)化合物,优选为变型1结晶形式,其用于治疗和/或预防中枢神经系统的疾病,特别是血管性痴呆和阿尔茨海默型痴呆。
本发明还提供式(II)化合物,优选为变型1结晶形式,其用于治疗和/或预防代谢性疾病,特别是代谢综合征、血脂异常和糖尿病。
本发明还提供根据本发明的包含式(II)化合物——优选为变型1结晶形式——的渗透释放系统用于治疗和/或预防疾病的用途。
本发明还提供根据本发明的包含式(II)化合物——优选为变型1结晶形式——的渗透释放系统用于治疗和/或预防以下疾病的用途:肾脏疾病和心肾疾病,特别是慢性肾疾病(CKD)和糖尿病性肾病(DKD);心脏疾病和心血管疾病,特别是心力衰竭(HFpEF和HFrEF)、心肌梗死、心绞痛、心肌病、高血压和动脉硬化;肺和心肺疾病,特别是肺动脉高压(PH);中枢神经系统的疾病,特别是痴呆;骨病,特别是成骨不全;血栓栓塞性病症;肌营养不良;缺血;血管病;微循环障碍;纤维性病症,特别是系统性硬化病;眼部疾病;炎症性疾病;和代谢性疾病,特别是代谢综合征、血脂异常和糖尿病。
本发明还提供根据本发明的包含式(II)化合物——优选为变型1结晶形式——的渗透释放系统用于治疗和/或预防以下疾病的用途:肾脏疾病和心肾疾病,特别是慢性肾疾病(CKD)和糖尿病性肾病(DKD)。
本发明还提供根据本发明的包含式(II)化合物——优选为变型1结晶形式——的渗透释放系统用于治疗和/或预防以下疾病的用途:心脏疾病和心血管疾病,特别是心力衰竭(HFpEF和HFrEF)、心肌梗死、心绞痛、心肌病、高血压和动脉硬化。
本发明还提供根据本发明的包含式(II)化合物——优选为变型1结晶形式——的渗透释放系统用于治疗和/或预防以下疾病的用途:肺和心肺疾病,特别是肺动脉高压(PH)。
本发明还提供根据本发明的包含式(II)化合物——优选为变型1结晶形式——的渗透释放系统用于治疗和/或预防以下疾病的用途:中枢神经系统的疾病,特别是痴呆。
本发明还提供根据本发明的包含式(II)化合物——优选为变型1结晶形式——的渗透释放系统用于治疗和/或预防以下疾病的用途:中枢神经系统的疾病,特别是血管性痴呆和阿尔茨海默型痴呆。
本发明还提供根据本发明的包含式(II)化合物——优选为变型1结晶形式——的渗透释放系统用于治疗和/或预防以下疾病的用途:代谢性疾病,特别是代谢综合征、血脂异常和糖尿病。
本发明还提供包含式(II)化合物以及一种或多种其他活性成分的药剂,所述其他活性成分选自有机硝酸酯类、NO供体、cGMP-PDE抑制剂、鸟苷酸环化酶刺激剂、抗血栓药、抗高血压药、MR拮抗剂、IP受体激动剂、具有抗炎作用的化合物、抗痴呆剂(antidementives)、抗糖尿病药、改变脂肪代谢的活性化合物和用于治疗骨病和肌肉病症的活性化合物。
在根据本发明的剂型中,式(II)化合物的存在量优选地为约1-240mg,特别优选地其量为约1mg至120mg,非常特别地优选地其量为约2.5mg至50mg。本发明提供根据本发明的上述药物剂型,其包含的式(II)化合物的量优选为1mg、2mg、2.5mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、12mg、15mg、20mg、25mg、30mg、35mg、40mg、50mg、60mg、70mg、75mg、80mg、90mg、100mg、110mg、120mg、125mg、150mg、175mg、200mg、225mg和240mg。式(II)化合物的量是指药物剂型中的标称量,在某些情况下,可能会额外存在过量多达20%的量的活性成分。
通常,已发现有利的是每天给予约0.01至10mg/kg体重以获得有效效果。
然而,在某些情况下,可能需要偏离规定的量,具体取决于体重、给药途径、对活性成分的个体反应、制剂的性质以及给药时间或给药间隔。因此,在某些情况下,以小于上述最小量的量进行处理可能就足够,而在其他情况下,则必须超过上述上限。如果给予较大量,建议将它们分成一天中几个单独的剂量。
实验部分
缩写和首字母缩写
cp 厘泊
HPLC 高压/高效液相色谱
K 开尔文
min 分钟
ml 毫升
μl 微升
mm 毫米
μm 微米
mPa 毫帕
Ph.Eur. 欧洲药典
s 秒
r 转
USP 美国药典
UV 紫外
工作实施例
示例性化合物1
(3S)-3-(4-氯-3-{[(2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰基]氨基}苯
基)-3-环丙基丙酸钠的结晶变型1
制备方法1
在氮气气氛下,向反应容器中填充1425g的式(I)化合物(WO2012/139888、实施例22和EP17204842.3(作为WO 2019/105881公开)中公开的制备)和13.3kg的乙腈。搅拌混合物直到溶液已经形成。添加117g的固体氢氧化钠并将所得悬浮液剧烈搅拌25小时。将悬浮液过滤。将所获得的固体用1.2kg乙腈洗涤并在减压下在30℃下干燥19小时。
收率:1375g(92%)
式(II)化合物的含量:96.4%(HPLC方法1)
式(III)化合物的含量:<0.20%(HPLC方法2)
钠含量:4.8%
XRPD:变型1
制备方法2
在氮气气氛下,向反应容器中填充34.4kg乙腈和4.0kg式(I)化合物(含量测定99.1%)(WO 2012/139888、实施例22和EP17204842.3(作为WO 2019/105881公开)中公开的制备)。将混合物在20℃下搅拌。将所得溶液过滤并用3kg乙腈洗涤过滤器。将滤液冷却至0℃。在-5℃至+5℃的温度下,缓慢添加3.9kg的叔丁醇钠(含量测定19.6%)的四氢呋喃溶液。在添加约2/3的叔丁醇钠溶液后,添加式(II)化合物的结晶变型1的晶种。在计量添加完成后,使用另外的3.0kg四氢呋喃清洗用于计量添加的管线。将所得混合物在0℃下搅拌17小时。将悬浮液过滤并将获得的固体用5.6kg的冷乙腈洗涤两次。将产物在减压下在40℃下干燥16小时。
收率:4.0kg(97%)
式(II)化合物的含量:98.7%(HPLC方法1)
式(III)化合物的含量:0.19%(HPLC方法2)
钠含量:4.4%
XRPD:变型1
分析方法
HPLC方法1:
含量测定试验和杂质试验在反相HPLC柱上使用210nm的UV检测进行。固定相为Zorbax Eclipse Plus RRHD C18 HPLC柱(50mm×2.1mm,粒度1.8μm)或合适的替代品。
为最大峰的最佳分离,选择梯度洗脱。流动相的梯度示于下表1中。
流动相A为含0.1%三氟乙酸的水,流动相B为含0.1%三氟乙酸的乙腈。
表1
时间[min] | %A | %B |
0.0 | 95 | 5 |
25.0 | 20 | 80 |
流速为1.0ml/min,柱温为20℃,注射体积为2μl。试验溶液通过溶解于等份数的乙腈和水的混合物中至浓度为0.46mg/ml来制备。
定量通过外部校准使用参比标准或通过质量平衡进行。式(II)化合物的保留时间为约16.2min,式(III)化合物的保留时间为约12.0min。
HPLC方法2:
杂质试验在正相HPLC柱上使用220nm的UV检测进行。固定相为Chiralpak AD-HHPLC柱(250mm×4.6mm,粒度5μm)或合适的替代品。
为最大峰的最佳分离,选择等度洗脱。
流动相由93体积%的异己烷与7体积%的含0.2%三氟乙酸和1%水的2-丙醇的混合物组成。
流速为1.25ml/min,柱温为30℃,注射体积为5μl。试验溶液通过溶于异己烷和2-丙醇(3/1,以体积计)的混合物中至浓度为0.5mg/ml来制备。
定量通过外部校准使用参比标准进行。式(II)化合物的保留时间为约11.4min,式(III)化合物的保留时间为约9.7min。
方法3(钠分析):
钠通过ICP-MS方法以半定量归纳分析的方式进行分析。样品制备通过使用硝酸进行微波消化而进行。
方法4-用于测量式(I)化合物的变型1结晶形式的x射线衍射:
表2:式(I)化合物的结晶变型1的X射线衍射
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式(I)化合物的结晶变型1的X射线衍射图示于图10中。
方法5-测量式(I)化合物的变型1结晶形式的IR谱:
表3:式(I)化合物的结晶变型1的IR谱
式(I)化合物的结晶变型1的IR谱示于图11中。
渗透释放系统及其制备示于下文。渗透释放系统经常包含过量的活性成分,这是因为,出于技术原因,一些活性成分保留在渗透释放系统中。
渗透释放系统1(双室系统,聚环氧乙烷作为亲水性可溶胀聚合物)
片剂组成,以mg/片计:
核
活性成分层
渗透层
壳
在约5至6小时后,80%的式(II)化合物已经释放。式(II)化合物从渗透释放系统1的释放曲线示于图12中。
渗透释放系统2(双室系统,聚环氧乙烷作为亲水性可溶胀聚合物)
片剂组成,以mg/片计:
核
活性成分层
渗透层
壳
在约6小时后,80%的式(II)化合物已经释放。式(II)化合物从渗透释放系统2的释放曲线示于图13中。
渗透释放系统3(双室系统,聚环氧乙烷作为亲水性可溶胀聚合物)
片剂组成,以mg/片计:
活性成分层和渗透层(核)的组成对应工作实施例2。
壳
在约11小时后,80%的式(II)化合物已经释放。式(II)化合物从渗透释放系统3的释放曲线示于图14中。
渗透释放系统4(双室系统,聚环氧乙烷作为亲水性可溶胀聚合物)
片剂组成,以mg/片计:
活性成分层和渗透层(核)的组成对应工作实施例2。
壳
在约15小时后,80%的式(II)化合物已经释放。式(II)化合物从渗透释放系统4的释放曲线示于图15中。
渗透释放系统5(双室系统,聚环氧乙烷作为亲水性可溶胀聚合物)
片剂组成,以mg/片计:
核
活性成分层
渗透层
壳
测试渗透释放系统5的式(II)化合物的含量(活性成分含量)(n=10)。基于100%的声称的活性成分含量计,测得活性成分最小含量为93.8%,活性成分最大含量为103.7%。标准偏差为3.1%。
在约10小时后,80%的式(II)化合物已经释放。式(II)化合物从渗透释放系统5的释放曲线示于图16中。
渗透释放系统6(双室系统,聚环氧乙烷作为亲水性可溶胀聚合物)
片剂组成,以mg/片计:
核
活性成分层
渗透层
壳
测试渗透释放系统6的式(II)化合物的含量(活性成分含量)(n=10)。基于100%的声称的活性成分含量计,测得活性成分最小含量为96.3%,活性成分最大含量为101.2%。标准偏差为1.4%。
在约10小时后,80%的式(II)化合物已经释放。式(II)化合物从渗透释放系统6的释放曲线示于图17中。
渗透释放系统7(双室系统,Kollidon VA 64作为亲水性可溶胀聚合物)
片剂组成,以mg/片计:
核
活性成分层
渗透层
壳
在约8.5小时后,80%的式(II)化合物已经释放。式(II)化合物从渗透释放系统7(其另外用6mg的包衣组合物包覆,如下文所述)的释放曲线示于图18中。
渗透释放系统8(单室系统,Kollidon VA 64和黄原胶作为亲水性可溶胀聚合物)
片剂组成,以mg/片计:
核
壳
在约18小时后,80%的式(II)化合物已经释放。式(II)化合物从渗透释放系统8的释放曲线示于图19中。
渗透释放系统9(单室系统.聚环氧乙烷作为亲水性可溶胀聚合物)
片剂组成,以mg/片计:
核
壳
在约14小时后,80%的式(II)化合物已经释放。式(II)化合物从渗透释放系统9的释放曲线示于图20中。
*粘度5%浓度水溶液(25℃,Brookfield粘度计Model RVT,1号转子,转速:50rpm):40-100mPa·s(例如POLYOXTM水溶性树脂NF WSR N-80;Dow)
**粘度1%浓度水溶液(25℃,Brookfield粘度计粘度计Model RVF,2号转子,转速:2rpm):5000-8000mPa·s(例如POLYOXTM水溶性树脂NF WSR凝结剂;Dow)
任选地,可将包衣施用于所述的渗透释放系统。对于渗透释放系统5、6和7,制备具有以下组成的包衣并将其以6mg/渗透释放系统的量施用。
包衣
本领域技术人员知晓包衣的量可根据例如渗透释放系统的大小和表面来调节。此处,以百分比表示的包衣组分的组成保持不变。
渗透释放系统1-6的制备:
为制备活性成分层,将微粉化形式的式(II)化合物、羟丙基甲基纤维素(符合欧洲药典(第9版)专论“Hypromellose(羟丙甲纤维素)”,粘度5mPa·s;以2%浓度水溶液测量,25℃)和聚环氧乙烷(符合欧洲药典(第9版)专论“Macrogols,High Molecular Mass(聚乙二醇,高分子量)”;粘度40-100mPa·s;以5%浓度水溶液测量,25℃;POLYOXTM水溶性树脂NFWSR N-80;Dow)在混合器中混合。将该预混物筛分,再次混合,然后通过辊式制粒使其经受干法制粒,最后筛分。将获得的颗粒与细分散的二氧化硅(符合欧洲药典(第9版)专论“Silica,colloidal anhydrous(二氧化硅,胶质无水)”;二氧化硅,200)混合。在添加经筛分的硬脂酸镁(符合欧洲药典(第9版)专论“Magnesium Stearate(硬脂酸镁)”)后,进行最后的混合,得到混合物,其准备用于压缩。
为制备渗透层,将氧化铁红(例如CAS号1309-37-1)、羟丙基甲基纤维素(符合欧洲药典(第9版)专论“Hypromellose(羟丙甲纤维素)”;粘度5mPa·s;以2%浓度水溶液测量,25℃)、聚环氧乙烷(符合欧洲药典(第9版)专论“Macrogols,High Molecular Mass(聚乙二醇,高分子量)”;粘度5000-8000mPa·s;以1%浓度水溶液测量,25℃;POLYOXTM水溶性树脂NF WSR凝结剂;Dow)和氯化钠(符合欧洲药典(第9版)专论“Sodium Chloride(氯化钠)”)在混合器中混合。使该预混物经受干法制粒,然后筛分。添加经筛分的硬脂酸镁(符合欧洲药典(第9版)专论“Magnesium Stearate(硬脂酸镁)”),然后进行最后的混合,得到混合物,其准备用于压缩。
通过在双层压片机上压片制备双层片剂。首先,使压片机适应活性成分层(片剂的下部分)的压片重量。然后将用于渗透层的颗粒(片剂的上部分)添加至预压制的片剂的下部分,由此获得双层片剂核(直径约8mm)的相应的总片剂重量。
为制备壳,将乙酸纤维素(符合欧洲药典(第9版)专论“Cellulose acetate(乙酸纤维素)”)溶于丙酮。将包含聚乙二醇3350(符合欧洲药典(第9版)专论“Macrogols(聚乙二醇)”;平均分子量3350g/mol)的水溶液添加至乙酸纤维素溶液,并将它们混合。使用适合用于有机包衣的包衣装置,将该溶液喷洒在双层片剂的片剂核上。
使用例如半自动钻孔机,在活性成分层一侧的壳上钻大小(直径)约1mm的孔。通过颜色区分活性成分层和渗透层是可能的。活性成分层为白色至轻微橙色。由于所添加的氧化铁,渗透层为橙红色。
任选地,可施加包衣,其就其本身而言可任选包含助剂,如用于着色的颜料。为此,将聚乙烯醇(符合欧洲药典(第9版)专论“Poly(vinyl alcohoD(聚(乙烯醇))”)和聚乙二醇3350(符合欧洲药典(第9版)专论“Macrogols(聚乙二醇)”;平均分子量3350g/mol)在室温下溶于水中并在搅拌下混合。在搅拌下,一次少量地添加滑石(符合欧洲药典(第9版)专论“Talc(滑石)”)、二氧化钛(符合欧洲药典(第9版)专论“Titanium dioxide(二氧化钛)”)和氧化铁(例如CAS号为1309-37-1的氧化铁红和CAS号为51274-00-1或20344-49-4的氧化铁黄)。使用合适的包衣装置,例如Glatt包衣机,将获得的包衣悬浮液施加至片剂核。对于渗透释放系统5和6,进行这样的包覆。
渗透释放系统7的制备:
为制备活性成分层,将微粉化形式的式(II)化合物、羟丙基甲基纤维素(符合欧洲药典(第9版)专论“Hypromellose(羟丙甲纤维素)”,粘度5mPa·s;以2%浓度水溶液测量,25℃)和Kollidon VA 64(符合欧洲药典(第9版)专论“Copovidone(共聚维酮)”)在混合器中混合。将该预混物筛分,再次混合,然后通过辊式制粒使其经受干法制粒,并最后筛分。将获得的颗粒与细分散的二氧化硅(符合欧洲药典(第9版)专论“Silica,colloidalanhydrous(二氧化硅,胶质无水)”;二氧化硅,200)混合。在添加经筛分的硬脂酸镁(符合欧洲药典(第9版)专论“Magnesium Stearate(硬脂酸镁)”)后,进行最后的混合,得到混合物,其准备用于压缩。
为制备渗透层,将氧化铁红(例如CAS号1309-37-1)、羟丙基甲基纤维素(符合欧洲药典(第9版)专论“Hypromellose(羟丙甲纤维素)”;粘度5mPa·s;以2%浓度水溶液测量,25℃),聚环氧乙烷(符合欧洲药典(第9版)专论“Macrogols,High Molecular Mass(聚乙二醇,高分子量)”;粘度5000-8000mPa·s;以1%浓度水溶液测量,25℃;POLYOXTM水溶性树脂NF WSR N-80;Dow)和氯化钠(符合欧洲药典(第9版)专论“Sodium Chloride(氯化钠)”)在混合器中混合。
使该预混物经受干法制粒,然后筛分。添加经筛分的硬脂酸镁(符合欧洲药典(第9版)专论“Magnesium Stearate(硬脂酸镁)”),然后进行最后的混合,得到混合物,其准备用于压缩。
通过在双层压片机上压片制备双层片剂。首先,使压片机适应活性成分层(片剂的下部分)的压片重量。然后将用于渗透层的颗粒(片剂的上部分)添加至预压制的片剂的下部分,由此获得双层片剂核(直径约8mm)的相应的总片剂重量。
为制备壳,将乙酸纤维素(符合欧洲药典(第9版)专论“Cellulose acetate(乙酸纤维素)”)溶于丙酮。将包含聚乙二醇3350(符合欧洲药典(第9版)专论“Macrogols(聚乙二醇)”;平均分子量3350g/mol)的水溶液添加至乙酸纤维素溶液,并将它们混合。使用适合用于有机包衣的包衣装置,将该溶液喷洒在双层片剂的片剂核上。
使用半自动钻孔机,在活性成分层一侧的壳上钻大小(直径)约1mm的孔。通过颜色区分活性成分层和渗透层是可能的。活性成分层为白色至轻微橙色。由于所添加的氧化铁,渗透层为橙红色。
随后,使用包含用于着色的颜料的包衣进行包覆。为此,将聚乙烯醇(符合欧洲药典(第9版)专论“Poly(vinyl alcohol)(聚(乙烯醇))”)和聚乙二醇3350(符合欧洲药典(第9版)专论“Macrogols(聚乙二醇)”;平均分子量3350g/mol)在室温下溶于水中并在搅拌下混合。在搅拌下,一次少量地添加滑石(符合欧洲药典(第9版)专论“Talc(滑石)”)、二氧化钛(符合欧洲药典(第9版)专论“Titanium dioxide(二氧化钛)”)和氧化铁(例如CAS号为1309-37-1的氧化铁红和CAS号为51274-00-1或20344-49-4的氧化铁黄)。或者,具有同样组成的成品包衣可悬浮在水中。在合适的包衣装置中,将获得的包衣水悬浮液喷洒至片剂核。
渗透释放系统8的制备:
将微粉化形式的式(II)化合物、黄原胶(“Xanthan FN normal”(由Jungbunzlauer Ladenburg GmbH制备)符合欧洲药典(第9版)专论“Xanthangum(黄原胶)”,Kollidon VA 64(符合欧洲药典(第9版)专论“Copovidone(共聚维酮)”)、氯化钠(符合欧洲药典(第9版)专论“Sodium Chloride(氯化钠)”)、碳酸氢钠和羧甲基淀粉钠(淀粉乙醇酸钠)在混合器中混合(预混)。将羟丙基甲基纤维素(符合欧洲药典(第9版)专论“Hypromellose(羟丙甲纤维素)”;粘度3mPa·s;以2%浓度水溶液测量,25℃)溶于水中(制粒液体)。
将预混物引入流化床制粒机中,并在流化床中用制粒液体制粒。然后将颗粒在流化床中干燥。将经干燥和筛分的颗粒与细分散的二氧化硅(符合欧洲药典(第9版)专论“Silica,colloidal anhydrous(二氧化硅,胶质无水)”;二氧化硅,200)混合。添加经筛分的硬脂酸镁(符合欧洲药典(第9版)专论“Magnesium Stearate(硬脂酸镁)”),然后进行最后的混合,得到混合物,其准备用于压缩。
使用约9mm的片剂直径和约50-60N的片剂断裂强度进行压片。
为制备壳,将乙酸纤维素(符合欧洲药典(第9版)专论“Cellulose acetate(乙酸纤维素)”)溶于丙酮中。将包含聚乙二醇3350(符合欧洲药典(第9版)专论“Macrogols(聚乙二醇)”;平均分子量3350g/mol)的水溶液添加至乙酸纤维素溶液并将它们混合。使用适合用于有机包衣的包衣装置,将溶液喷洒在片剂核上。
使用半自动钻孔机在壳上钻大小(直径)约1mm的孔。
渗透释放系统9的制备:
为制备片剂核,将微粉化形式的式(II)化合物、羟丙基甲基纤维素(符合欧洲药典(第9版)专论“Hypromellose(羟丙甲纤维素)”,粘度5mPa·s;以2%浓度水溶液测量,25℃)、氯化钠(符合欧洲药典(第9版)专论“Sodium Chloride(氯化钠)”)和聚环氧乙烷在混合器中混合。将该预混物筛分,再次混合,然后与细分散的二氧化硅(符合欧洲药典(第9版)专论“Silica,colloidal anhydrous(二氧化硅,胶质无水)”;二氧化硅,200)混合。添加经筛分的硬脂酸镁(符合欧洲药典(第9版)专论“Magnesium Stearate(硬脂酸镁)”),然后进行最后的混合,得到混合物,其准备用于压缩。或者,可使预混物通过辊式制粒经受干法制粒并最终筛分。
使用约8mm的片剂直径和约80-110N的片剂断裂强度进行压片。
为制备壳,将乙酸纤维素(符合欧洲药典(第9版)专论“Cellulose acetate(乙酸纤维素)”)溶于丙酮中。将包含聚乙二醇3350(符合欧洲药典(第9版)专论“Macrogols(聚乙二醇)”;平均分子量3350g/mol)的水溶液添加至乙酸纤维素溶液,并将它们混合。使用适合用于有机包衣的包衣装置,将溶液喷洒在片剂核上。
使用,例如,半自动钻孔机,在壳上钻大小(直径)约1mm的孔。
除非详细说明,否则用于制备渗透释放系统的物质是指本领域技术人员已知的在使用的药物助剂,并且如果列在药典之一中,则其满足欧洲药典(Ph.Eur.9)、美国药典(USP41和NF 36)和/或日本药典(JP,第17版)的药典专论的相应要求。
释放特性
活性成分由片剂的释放通过美国药典USP 39(第<711>章Dissolution(溶出度))的方法使用设备2(浆法试验)确定。为确定释放率,将片剂引入USP设备2的各释放容器中,并在将未溶出成分过滤掉后,通过HPLC测定已进入溶液的活性成分的量。使用的释放介质为磷酸盐缓冲液pH 6.8,不添加表面活性剂,USP设备2的浆式搅拌器的转速为100转每分钟。除非另有所述,否则测定至少六个试样的释放率。在每种情况下,报告所释放的活性成分的平均量。
图12示出了式(II)化合物从渗透释放系统1的释放百分比随时间的变化。
图13示出了式(II)化合物从渗透释放系统2的释放百分比随时间的变化。
图14示出了式(II)化合物从渗透释放系统3的释放百分比随时间的变化。
图15示出了式(II)化合物从渗透释放系统4的释放百分比随时间的变化。
图16示出了式(II)化合物从渗透释放系统5的释放百分比随时间的变化。
图17示出了式(II)化合物从渗透释放系统6的释放百分比随时间的变化。
图18示出了式(II)化合物从渗透释放系统7的释放百分比随时间的变化。
图19示出了式(II)化合物从渗透释放系统8的释放百分比随时间的变化。
图20示出了式(II)化合物从渗透释放系统9的释放百分比随时间的变化。
二元物理混合物的热分析研究
为了表示热分析研究中的相容性,首先将式(II)和(I)的化合物与等份数的亲水性可溶胀聚合物装入扁平的圆形钵中,并使用研磨棒,研磨成均匀粉末混合物(比例为1∶1的研磨物,二元混合物)。作为亲水性可溶胀聚合物研究的有:聚环氧乙烷(符合欧洲药典(第9版)专论“Macrogols,High Molecular Mass(聚乙二醇,高分子量)”;粘度40-100mPa·s;以5%浓度水溶液测量,25℃;POLYOXTM水溶性树脂NF WSR N-80;Dow);黄原胶(“XanthanFNnormal”,由Jungbunzlauer Ladenburg GmbH制备),符合欧洲药典(第9版)专论“Xanthan gum(黄原胶)”;乙烯基吡咯烷酮/乙酸乙烯酯共聚物(KollidonVA 64),符合欧洲药典(第9版)专论“Copovidone(共聚维酮)”;聚乙烯吡咯烷酮(PVP25),符合欧洲药典(第9版)专论“Povidone(聚维酮)”;甲基丙烯酸/甲基丙烯酸甲酯共聚物(L100),符合欧洲药典(第9版)专论“Methacrylic acid-MethylMethacrylate Copolymer(甲基丙烯酸-甲基丙烯酸甲酯共聚物)(1:1)”;甲基丙烯酸/甲基丙烯酸甲酯共聚物(/>RL PO),符合欧洲药典(第9版)专论“AmmonioMethacrylate Copolymer(季胺基甲基丙烯酸酯共聚物)(TYPE A)”;羟丙基纤维素(HPC LMNisso),符合欧洲药典(第9版)专论“Hydroxypropylcellulose(羟丙纤维素)”;和聚丙烯酸(符合欧洲药典(第9版)专论“Carbomers(卡波姆)”;名称:聚丙烯酸,MW1,080,000平均MN135,000;Acros Organics)。
对物理混合物和相应的各组分以热分析的方式进行表征。在差示扫描量热仪上记录热分析图。为此,在每种情况下,在铝盘中,在氮气(50ml/min)下,使用10K/min的加热速率,将约5mg的样品加热至所讨论的化合物熔点的终点。
图1示出了式(I)化合物、聚环氧乙烷以及式(I)化合物与聚环氧乙烷的二元混合物的热分析图。
图2示出了式(II)化合物、聚环氧乙烷以及式(II)化合物与聚环氧乙烷的二元混合物的热分析图。
图3示出了式(II)化合物、黄原胶以及式(II)化合物与黄原胶的二元混合物的热分析图。
图4示出了式(II)化合物、乙烯基吡咯烷酮/乙酸乙烯酯共聚物以及式(II)化合物与乙烯基吡咯烷酮/乙酸乙烯酯共聚物的二元混合物的热分析图。
图5示出了式(II)化合物、PVP25以及式(II)化合物与PVP25的二元混合物的热分析图。
图6示出了式(II)化合物、HPC LM以及式(II)化合物与HPC LC的二元混合物的热分析图。
图7示出了式(II)化合物、Eudragit L100以及式(II)化合物与EudragitL100的二元混合物的热分析图。
图8示出了式(II)化合物、Eudragit RL PO以及式(II)化合物与Eudragit RL PO的二元混合物的热分析图。
图9示出了式(II)化合物、聚丙烯酸以及式(II)化合物与聚丙烯酸的二元混合物的热分析图。
Claims (8)
1.渗透释放系统,其由核和壳组成,其中壳由对核的组分不可渗透的水可渗透材料组成并且具有至少一个孔口,且其中核包括式(II)的(3S)-3-(4-氯-3-{[(2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰基]氨基}苯基)-3-环丙基丙酸钠和至少一种亲水性可溶胀聚合物,其中所述亲水性可溶胀聚合物选自聚环氧乙烷、黄原胶、羟丙纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、羧甲基淀粉钠、乙烯基吡咯烷酮/乙酸乙烯酯共聚物、聚乙烯吡咯烷酮、甲基丙烯酸/甲基丙烯酸甲酯共聚物和聚丙烯酸,
2.根据权利要求1所述的渗透释放系统,其中核包括由活性成分层和渗透层组成的双室系统。
3.根据权利要求2所述的渗透释放系统,其中活性成分层包括
·1重量%至50重量%的式(II)化合物,
·20重量%至99重量%的至少一种亲水性可溶胀聚合物,
任选地至少一种渗透活性添加剂以及任选地至少一种药物常规助剂,
且渗透层包括
·40重量%至90重量%的至少一种亲水性可溶胀聚合物,
·10重量%至60重量%的渗透活性添加剂
以及任选地至少一种药物常规助剂。
4.根据权利要求1-3中任一项所述的渗透释放系统,其中至少一种亲水性可溶胀聚合物为聚环氧乙烷。
5.根据权利要求1-3中任一项所述的渗透释放系统,其中至少一种亲水性可溶胀聚合物为黄原胶。
6.制备根据权利要求1-3中任一项所述的渗透释放系统的方法,其特征在于将核的组分彼此混合、制粒并压片,将所得的核用壳包覆,并最终使壳具有一个或多个适合于式(II)化合物离去的孔口。
7.制备根据权利要求2-3中任一项所述的渗透释放系统的方法,其特征在于
·将活性成分层的组分混合并制粒并且
·将渗透层的组分混合并制粒,
·随后将两组颗粒在双层压片机上压缩得到双层片剂,
·然后将所得的核用壳包覆且
·使壳在活性成分一侧具有一个或多个孔口。
8.一种变型1结晶形式的式(II)化合物的制备方法,其特征在于,将式(I)化合物溶于极性非质子溶剂中,
向其中添加选自由氢氧化钠、叔丁醇钠或2-甲基丁-2-醇钠的碱,并在搅拌后将沉淀的固体分离并干燥;
其中,所述变型1结晶形式的式(II)化合物的X射线衍射图在8.1、17.2、18.8、22.3和22.6°的2θ角处具有最大峰。
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DE102010040233A1 (de) | 2010-09-03 | 2012-03-08 | Bayer Schering Pharma Aktiengesellschaft | Bicyclische Aza-Heterocyclen und ihre Verwendung |
DE102010043379A1 (de) | 2010-11-04 | 2012-05-10 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 6-Fluor-1H-Pyrazolo[4,3-b]pyridine und ihre Verwendung |
UY34856A (es) * | 2012-07-03 | 2013-12-31 | Bayer Pharma AG | Formas de presentación farmacéuticas que contienen 5-cloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4- morfolinil)-fenil]-1,3-oxazolidin-5-il}-metil)-2-tiofencarboxamida |
MX2020005646A (es) | 2017-12-01 | 2020-08-20 | Bayer Pharma AG | Procedimiento para la preparacion de (3s)-3-(4-cloro-3-{[(2s,3r)-2 -(4-clorofenil)-4,4,4-trifluor-3-metilbutanoil]amino}fenil)-3-aci do ciclo-propilpropanoico y su forma cristalina para uso como principio activo farmaceutico. |
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2019
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- 2019-07-19 BR BR112020026644-2A patent/BR112020026644A2/pt not_active Application Discontinuation
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- 2019-07-19 WO PCT/EP2019/069561 patent/WO2020020789A1/de unknown
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- 2019-07-19 JP JP2021503578A patent/JP2021532113A/ja active Pending
- 2019-07-19 AU AU2019311234A patent/AU2019311234A1/en not_active Abandoned
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- 2019-07-19 MA MA053368A patent/MA53368A/fr unknown
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- 2019-07-19 KR KR1020217004994A patent/KR20210035235A/ko not_active Application Discontinuation
- 2019-07-19 UY UY0001038308A patent/UY38308A/es unknown
- 2019-07-19 CN CN201980049223.8A patent/CN112469402B/zh active Active
- 2019-07-19 CA CA3107169A patent/CA3107169A1/en active Pending
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2021
- 2021-01-11 IL IL280083A patent/IL280083A/en unknown
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- 2021-01-20 CL CL2021000160A patent/CL2021000160A1/es unknown
- 2021-01-20 DO DO2021000015A patent/DOP2021000015A/es unknown
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MA53368A (fr) | 2021-06-02 |
BR112020026644A2 (pt) | 2021-03-23 |
AU2019311234A1 (en) | 2021-02-04 |
EP3826627B1 (de) | 2023-10-18 |
CL2021000160A1 (es) | 2021-06-04 |
EP3826627A1 (de) | 2021-06-02 |
DOP2021000015A (es) | 2021-02-15 |
CA3107169A1 (en) | 2020-01-30 |
PH12021550170A1 (en) | 2021-09-13 |
EP3826627C0 (de) | 2023-10-18 |
IL280083A (en) | 2021-03-01 |
UY38308A (es) | 2020-02-28 |
TW202019402A (zh) | 2020-06-01 |
KR20210035235A (ko) | 2021-03-31 |
ECSP21003707A (es) | 2021-02-26 |
CO2021000450A2 (es) | 2021-01-29 |
JOP20210019A1 (ar) | 2021-01-24 |
PE20210415A1 (es) | 2021-03-04 |
CR20210043A (es) | 2021-03-09 |
CN112469402A (zh) | 2021-03-09 |
MX2021000904A (es) | 2021-03-31 |
JP2021532113A (ja) | 2021-11-25 |
WO2020020789A1 (de) | 2020-01-30 |
SG11202100369WA (en) | 2021-02-25 |
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