CN113194924B - 制备包含task-1和task-3通道抑制剂的药物剂型的方法及其在呼吸障碍治疗中的用途 - Google Patents
制备包含task-1和task-3通道抑制剂的药物剂型的方法及其在呼吸障碍治疗中的用途 Download PDFInfo
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- CN113194924B CN113194924B CN201980077910.0A CN201980077910A CN113194924B CN 113194924 B CN113194924 B CN 113194924B CN 201980077910 A CN201980077910 A CN 201980077910A CN 113194924 B CN113194924 B CN 113194924B
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- polysorbate
- methoxypyridin
- methanone
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Abstract
本发明涉及一种制备包含有效和选择性的TASK‑1和/或TASK‑3通道抑制剂的药物剂型的方法,以及通过所述制备方法获得的剂型用于治疗和/或预防呼吸障碍,包括睡眠相关的呼吸障碍,例如阻塞性和中枢性睡眠呼吸暂停和打鼾的用途。
Description
本申请涉及一种制备包含有效和选择性的TASK-1和/或TASK-3通道抑制剂的药物剂型的方法,以及通过该制备方法获得的剂型用于治疗和/或预防呼吸障碍,包括睡眠相关的呼吸障碍,如阻塞性和中枢性睡眠呼吸暂停和打鼾的用途。
钾通道是几乎无处不在的膜蛋白,其参与大量不同的生理过程。这也包括膜电位和神经元和肌细胞的电兴奋性的调节。钾通道分成三大类,其中跨膜结构域的数量不同(2、4或6)。其中两个成孔结构域的两侧是四个跨膜结构域的钾通道类别被称作K2P通道(两孔结构域K+)。在功能上,K2P通道以基本与时间和电压无关的方式介导K+背景电流,并且对静息膜电位维持的贡献至关重要。K2P通道家族包括15个成员,它们基于序列、结构和功能的相似性分成6个亚族:TWIK(串联孔结构域氟烷抑制的K+通道)、TREK(TWIK相关的K+通道)、TASK(TWIK相关的酸敏感K+通道)、TALK(TWIK相关的碱性pH活化的K+通道)、THIK(串联孔结构域氟烷抑制的K+通道)和TRESK(TWIK相关的脊髓K+通道)。
特别感兴趣的是TASK(TWIK相关的酸敏感K+通道)亚族的TASK-1(KCNK3或K2P3.1)和TASK-3(KCNK9或K2P9.1)。在功能上,这些通道的特征在于,在电压无关性动力学的维持过程中,“泄漏”或“背景”电流流经它们,其中它们通过提高或降低活性而响应许多生理和病理影响。TASK通道的特征是对细胞外pH变化的灵敏反应:通道在酸性pH下被抑制并在碱性pH下被活化。
TASK-1和TASK-3通道在呼吸调节中起作用。这两种通道均在脑干的呼吸中枢的呼吸神经元中表达,尤其是在产生呼吸节律的神经元(具有前包钦格复合体(complex)的腹侧呼吸组)中表达,在去甲肾上腺素能的蓝斑(Locuscaeruleus)中表达以及在中缝核的5-羟色胺能神经元中表达。由于pH依赖性,此处TASK通道具有传感器功能,其将细胞外pH的变化转化为相应的细胞信号[Bayliss等人,PflugersArch.467,917-929(2015)]。TASK-1和TASK-3还在颈动脉球(Glomus caroticum)(测量血液的pH以及O2和CO2含量,并将信号传递至脑干中的呼吸中枢以调节呼吸的副神经节)中表达。显示TASK-1基因敲除小鼠对缺氧和常氧性高碳酸血症的通气反应降低(呼吸频率和潮气量提高)[Trapp等人,J.Neurosci.28,8844-8850(2008)]。此外,已在舌下神经(Nervushypoglossus)(在保持上呼吸道通畅中具有重要作用的XII颅神经)的运动神经元中发现TASK-1和TASK-3通道[Berg等人,J.Neurosci.24,6693-6702(2004)]。
在麻醉猪的睡眠呼吸暂停模型中,在纳摩尔范围内阻滞TASK-1通道的钾通道阻滞剂的鼻腔给药导致抑制咽部呼吸道肌肉组织的塌陷,并导致上呼吸道的负压反射的敏感化。推测钾通道阻滞剂的鼻腔给药将上呼吸道中的机械感受器去极化,并经由负压反射的活化而导致上呼吸道的肌肉组织的活性增加,由此稳定上呼吸道和防止塌陷。经由上呼吸道的这种稳定化,TASK通道阻滞对阻塞性睡眠呼吸暂停以及打鼾非常重要[Wirth等人,Sleep 36,699-708(2013);Kiper等人,Pflugers Arch.467,1081-1090(2015)]。
阻塞性睡眠呼吸暂停(OSA)是以上呼吸道阻塞的反复发作为特征的睡眠相关的呼吸障碍。当吸气时,通过两个反向力的相互作用来确保上呼吸道的通畅。上呼吸道的肌肉组织的扩张作用抵消了使腔收缩的腔内负压。隔膜和其它呼吸辅助肌的主动收缩在呼吸道中产生负压,从而构成呼吸的驱动力。上呼吸道的稳定性极大取决于上呼吸道的扩张肌的协调和收缩性质。
颏舌肌(Musculus genioglossus)在OSA的发病机理中起到决定性作用。在扩张补偿机制的意义上,颏舌肌的活性随咽内压力降低而提高。受舌下神经支配,其驱动舌头向前和向下,由此增宽咽部呼吸道[Verse等人,Somnologie 3,14-20(1999)]。上呼吸道的扩张肌的张拉尤其借助鼻腔/咽中的机械感受器/牵张感受器调节[Brouillette等人,J.Appl.Physiol.Respir.Environ.Exerc.Physiol.49,772-779(1979)]。在患有严重睡眠呼吸暂停的睡眠患者中,通过上呼吸道的局部麻醉,可以观察到颏舌肌的活性的额外降低[Berry等人,Am.J.Respir.Crit.Care Med.156,127-132(1997)]。OSA患者由于心血管疾病,如高血压、心肌梗塞和中风而具有高死亡率和发病率[Vrints等人,Acta Clin.Belg.68,169-178(2013)]。
在中枢性睡眠呼吸暂停的情况下,由于脑功能受损或呼吸调节受损,出现呼吸驱动力的阵发式抑制。中枢呼吸障碍造成机械呼吸停止,即在这些发作过程中没有呼吸活动;包括隔膜在内的所有呼吸肌暂时静息。在中枢性睡眠呼吸暂停的情况下,没有上呼吸道的阻塞。
在原发性打鼾的情况下,同样没有上呼吸道的阻塞。然而,由于上呼吸道收缩,吸入和呼出的空气的流速提高。这与放松的肌肉组织结合造成口腔和咽部的软组织在空气流中颤动。这种轻微振动随后产生典型的打鼾噪声。
阻塞性打鼾(上呼吸道阻力综合征、严重打鼾、低通气综合征)由在睡眠过程中上呼吸道的反复部分阻塞造成。这造成呼吸道阻力增加,从而造成呼吸功增加,伴随胸内压显著波动。在吸气过程中,胸内负压的发展可达到与由于在OSA过程中的完全呼吸道阻塞而遇到的那些值类似的值。对心脏、循环和睡眠质量的病理生理学后果与阻塞性睡眠呼吸暂停相当。如同在OSA中,可推测发病机理是在睡眠时的吸气过程中咽扩张肌的反射机制受损。阻塞性打鼾通常是OSA的初级阶段[Hollandt等人,HNO 48,628-634(2000)]。
当前可用于打鼾和OSA治疗的可能性是有限的。自20世纪80年代以来已知旨在降低上呼吸道的阻力和打鼾的表面活性物质的混合物[Widdicombe等人,Eur Resp J 1,785-791(1988)]。这些混合物包含氯化钠、丙三醇、聚山梨醇酯80和苯扎氯铵。从在狗——通过注射将这些混合物给药至狗的咽部——中进行的实验中可以得出结论,这些混合物降低了上呼吸道的阻力,增加了吸气和呼气时颏舌肌的活性,并减少了打鼾噪声。Widdicombe的文章中未提及OSA,并且在该模型中也未显示可预防导致呼吸暂停的上呼吸道塌陷。因此,Widdicombe和Davies的模型不能预测OSA。
基于丙三醇、聚山梨醇酯80、氯化钠和0.15%山梨酸钾(不含苯扎氯铵)的组合物在市场上以作为打鼾的疗法。在哥本哈根的大学州立医院(University StateHospital)的一项研究中,研究了与不含聚山梨醇酯80的相比,鼻腔给药对于改善打鼾的功效。和不含聚山梨醇酯80的都实现了对打鼾的显著改善[丹麦哥本哈根大学州立医院神经内科报告.The effect of nasalapplication of and Polyglycoside 80on snoring and sleep apnoea,1989,[http://www.chrapat.sk/img/klinicka-dokumentacia.pdf]。
WO-A 2012/010358要求保护一种药物产品,该药物产品包含含有液体抗打鼾物质的容器,其中该容器包含液体出口部分,该液体出口部分构造成将液体抗打鼾物质以射流形式直接递送至鼻道中。液体抗打鼾物质为抗打鼾溶液,其包含氯化钠、丙三醇、聚山梨醇酯和乙二胺四乙酸钠以及任选地作为防腐剂的山梨酸钾。WO-A 2012/010358没有公开呼吸暂停或OSA的疗法。EP-B 2595685记载了所述物质用于治疗打鼾和呼吸停止(呼吸暂停)的用途。
目前尚无用于OSA治疗的药物疗法。手术和口腔器械的功效有限。治疗标准是采用持续气道正压通气(CPAP)系统进行的治疗。然而,由于造成患者的不适,该疗法的依从率仅为50-70%,并且该系统平均每晚使用时间不超过4小时。
从WO-A 2017/097792和WO-A 2017/097671、WO-A 2018/015196、EP 17176046.5(未公开)和PCT/CN2017/088237(未公开)中获知新型物质,所述新型物质可作为有效和选择性的TASK-1和/或TASK-3通道抑制剂,特别适于原样治疗和/或预防呼吸障碍,包括睡眠相关的呼吸障碍,例如阻塞性和中枢性呼吸暂停和打鼾以及其他障碍。因此,其中公开的有效和选择性的TASK-1和/或TASK-3通道抑制剂代表了CPAP系统的替代品,用于治疗睡眠相关的呼吸障碍,例如阻塞性和中枢性睡眠呼吸暂停和打鼾。因此,与目前的治疗标准(OSA疗法:CPAP系统)相比,有效和选择性的TASK-1和/或TASK-3通道抑制剂可提高患者对治疗和/或预防呼吸障碍,包括睡眠相关的呼吸障碍,如阻塞性和中枢性睡眠呼吸暂停和打鼾的依从率。为此,这种替代疗法应简单舒适地使用,并且不会干扰人的睡眠。此外,这种替代疗法应使得夜间睡眠不被打扰,无需重复给药,仅需睡前给予一次日剂量。
从WO-A 2017/097792和WO-A 2017/097671、WO-A 2018/015196、EP 17176046.5(未公开)和PCT/CN2017/088237(未公开)已知的TASK-1和/或TASK-3通道抑制剂是对光、温度和氧化敏感的活性化合物,它们在制剂的制备过程中以及在非缓冲水溶液中的储存过程中发生不希望的降解。此外,已知的有效和选择性的TASK-1和/或TASK-3通道抑制剂在水中的溶解性差,不足以在有限的给药量(对于鼻腔给药约50至300μl)中容纳药理活性所需量的活性成分。使用批准和/或已知用于鼻腔给药和咽部给药途径的增溶剂,例如共溶剂(例如聚乙二醇400(PEG400))或表面活性剂(例如聚山梨醇酯80),可以实现所需的溶解度;然而,尽管存在已知的增溶剂,但在水溶液中观察到已知有效和选择性的TASK-1和/或TASK-3通道抑制剂的溶解速率较低,这导致制备过程中的加工时间显著延长以及所用活性化合物相关的不希望的降解。
从WO-A 2018/114501和WO-A 2018/114503已知的有效和选择性的TASK-1和/或TASK-3通道抑制剂的水性制剂包含聚乙二醇400或丙三醇、至少一种选自pH调节剂的助剂、至少一种选自增溶剂的助剂、至少一种选自稳定剂的助剂。
现有技术中记载的包含TASK-1和/或TASK-3通道抑制剂的制剂的缺点是,在制备过程中可能已经形成了活性化合物的降解产物,并且可能发生不希望的变色。此外,在储存过程中活性化合物的降解可能增加。此外,制剂的制备——即使是约100ml的少量——仅由于活性化合物的溶解度不足而花费大量时间(>24h)。
此外,用于治疗和/或预防呼吸障碍的药理活性物质应存在于被认为具有中性味道的药物制剂中,特别是在将包含药理活性物质的药物制剂(verum)与不包含任何药理活性物质的那些制剂(安慰剂)进行比较时还存在。
因此,本发明的目的是提供一种制备基于有效和选择性的TASK-1和/或TASK-3通道抑制剂的稳定水性制剂的改进方法,所述制剂用于治疗和/或预防呼吸障碍,包括睡眠相关的呼吸障碍,例如阻塞性和中枢性睡眠呼吸暂停和打鼾,该方法确保在制备和储存过程中活性化合物在所得水性制剂中具有足够的稳定性,并且还允许活性化合物以足够高的浓度溶解,而在制备过程中没有任何不希望的高时间消耗。
此外,本发明的另一个目的是提供基于有效和选择性的TASK-1和/或TASK-3通道抑制剂的水性制剂,其用于治疗和/或预防呼吸障碍,包括睡眠相关的呼吸障碍,例如阻塞性和中枢性睡眠呼吸暂停和打鼾,所述水性制剂被认为具有中性味道。
令人惊讶地,已发现当将TASK-1和/或TASK-1通道抑制剂预先溶解在表面活性剂(例如聚山梨醇酯80)和/或共溶剂(例如PEG 400)中时,可缩短有效和选择性的TASK-1和/或TASK-3通道抑制剂的溶解速率,从而显著减少制备水性制剂的时间。本文中,同样令人惊讶地,已发现当同样将稳定剂预先溶解在表面活性剂和/或共溶剂的混合物中,然后才添加TASK-1和/或TASK-3通道抑制剂时,可避免在制剂的制备和储存过程中不希望的变色和降解产物。
本发明的制剂的另一个预料不到的效果在于其可通过使用甜味剂来掩盖所用的表面活性剂和药理活性物质组分的味道。
本发明提供一种制备稳定的药物制剂的方法,其特征在于:
在第一步中,首先加入至少一种聚氧乙烯脱水山梨糖醇脂肪酸酯作为增溶剂和/或首先加入PEG 400作为共溶剂,将至少一种抗氧化剂和治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐溶解于其中,随后加入至少一种pH调节剂、水和任选的丙三醇、聚氧乙烯脱水山梨糖醇脂肪酸酯或PEG400和任选的至少一种甜味剂,所得溶液的pH为6.8至8.2,优选6.8至7.8。
本发明提供可通过本发明的方法获得的药物制剂。
在本发明的方法的一个优选实施方案中,首先加入至少一种聚氧乙烯脱水山梨糖醇脂肪酸酯作为增溶剂和/或PEG 400作为共溶剂,然后加入抗氧化剂,随后将治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐溶解于其中。
在本发明的方法的另一个优选实施方案中,首先:
-制备初级溶液(A),其包含至少一种聚氧乙烯脱水山梨糖醇脂肪酸酯(聚山梨醇酯)和/或PEG 400以及至少一种抗氧化剂的,在进一步的步骤中,将治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐溶解在该混合物中,并将所述混合物添加到以下溶液中,
-溶液(B),其包含至少一种pH调节剂、水和任选的丙三醇或PEG400以及任选的至少一种甜味剂,所得溶液的pH为6.8至8.2,优选6.8至7.8。
优选地,将初级溶液(A)添加至溶液(B)在15至30min的时间内,优选在30min内进行。还可将溶液(B)转移至预溶液(A)中。
在本发明的方法的一个特别优选的实施方案中,在第一步中,首先加入至少一种聚氧乙烯脱水山梨糖醇脂肪酸酯,然后加入抗氧化剂,随后将治疗有效量的(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮溶解于其中,然后加入至少一种pH调节剂、任选的至少一种甜味剂和水。
在本发明的方法的一个非常特别优选的实施方案中,在第一步中,首先加入至少一种聚氧乙烯脱水山梨糖醇脂肪酸酯,然后加入抗氧化剂,随后将治疗有效量的(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮溶解于其中,然后加入至少一种pH调节剂、至少一种甜味剂和水。
在本发明的方法的一个同样非常特别优选的实施方案中,在第一步中,首先加入至少一种聚氧乙烯脱水山梨糖醇脂肪酸酯,然后加入抗氧化剂,随后将治疗有效量的(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮溶解于其中,然后加入至少一种pH调节剂和水。
在本发明的方法的另一个特别优选的实施方案中,在第一步中,首先加入至少一种聚氧乙烯脱水山梨糖醇脂肪酸酯,然后加入抗氧化剂,随后溶解治疗有效量的(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮,然后加入至少一种pH调节剂、丙三醇或PEG 400、任选的甜味剂和水。
在本发明的方法的另一个特别优选的实施方案中,在第一步中,首先加入PEG400,然后加入抗氧化剂,随后溶解治疗有效量的(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮,然后加入至少一种pH调节剂、至少一种聚氧乙烯脱水山梨糖醇脂肪酸酯、任选的甜味剂和水。
在本发明的方法的另一个特别优选的实施方案中,在第一步中,首先加入至少一种聚氧乙烯脱水山梨糖醇脂肪酸酯,然后加入抗氧化剂,随后溶解治疗有效量的(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮,然后加入至少一种pH调节剂、丙三醇或PEG 400、至少一种甜味剂和水。
本发明的药物制剂包含至少一种聚氧乙烯脱水山梨糖醇脂肪酸酯、至少一种抗氧化剂和治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐、任选的丙三醇或PEG 400以及任选的至少一种甜味剂、至少一种pH调节剂和水,所得溶液的pH为6.8至8.2,优选6.8至7.8。
优选地,本发明的药物制剂包含至少一种聚氧乙烯脱水山梨糖醇脂肪酸酯(聚山梨醇酯)作为增溶剂和/或共溶剂、至少一种抗氧化剂和治疗有效量的(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮、至少一种甜味剂、任选的至少一种pH调节剂和水,所得溶液的pH为6.8至8.2,优选6.8至7.8。
特别优选地,本发明的药物制剂包含至少一种聚氧乙烯脱水山梨糖醇脂肪酸酯(聚山梨醇酯)作为增溶剂和/或共溶剂、至少一种抗氧化剂和治疗有效量的(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮、至少一种甜味剂、至少一种pH调节剂和水,所得溶液的pH为6.8至8.2,优选6.8至7.8。
特别优选地,本发明的药物制剂包含至少一种聚氧乙烯脱水山梨糖醇脂肪酸酯(聚山梨醇酯)作为增溶剂和/或共溶剂、至少一种抗氧化剂和治疗有效量的(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮、任选的甜味剂、至少一种pH调节剂和水,所得溶液的pH为6.8至8.2,优选6.8至7.8。
在一个实施方案(A)中,本发明的制剂包含:
-1至21重量%的聚氧乙烯脱水山梨糖醇脂肪酸酯,
-0.001至0.20重量%的抗氧化剂,
-0.002至0.10重量%的治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐,
-0.3至25重量%的丙三醇,和
-53.5至98重量%的物质浓度为25至200mM的缓冲溶液。
优选地,本发明的制剂(A)包含:
-2.5至16重量%的聚氧乙烯脱水山梨糖醇脂肪酸酯,
-0.002至0.1重量%的抗氧化剂,
-0.005至0.07重量%的治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐,
-1至12重量%的丙三醇,和
-71至96重量%的物质浓度为25至200mM的缓冲溶液。
非常特别优选地,本发明的制剂(A)包含:
-5至13重量%的聚氧乙烯脱水山梨糖醇脂肪酸酯,
-0.005至0.05重量%的抗氧化剂,
-0.006至0.06重量%的治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐,
-2至6重量%的丙三醇,和
-80.5至92重量%的物质浓度为25至200mM的缓冲溶液。
在另一个实施方案(B)中,本发明的制剂包含:
-1至20重量%的聚氧乙烯脱水山梨糖醇脂肪酸酯,
-0.001至0.2重量%的抗氧化剂,
-0.002至0.10重量%的治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐,
-3.0至60重量%的PEG 400,和
-19至95.5重量%的物质浓度为25至200mM的缓冲溶液。
优选地,本发明的制剂(B)包含
-2.5至15重量%的聚氧乙烯脱水山梨糖醇脂肪酸酯,
-0.002至0.10重量%的抗氧化剂,
-0.005至0.07重量%的治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐,
-6至36重量%的PEG 400,和
-48至91重量%的物质浓度为25至200mM的缓冲溶液。
特别优选地,本发明的制剂(B)包含:
-5至13重量%的聚氧乙烯脱水山梨糖醇脂肪酸酯,
-0.005至0.05重量%的抗氧化剂,
-0.006至0.06重量%的治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐,
-12至23.5重量%的PEG 400,和
-63至82.5重量%的物质浓度为25至200mM的缓冲溶液。
非常特别优选地,本发明的制剂(A)和(B)包含4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮作为TASK-1和/或TASK-3通道抑制剂。
在另一个实施方案(C)中,本发明的制剂包含:
-1至21重量%的聚氧乙烯脱水山梨糖醇脂肪酸酯,
-0.001至0.2重量%的抗氧化剂,
-0.002至0.1重量%的治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐,
-0.01至6重量%的甜味剂,和
-72至98.5重量%的物质浓度为25至200mM的缓冲溶液。
优选地,本发明的制剂(C)包含:
-2.5至16重量%的聚氧乙烯脱水山梨糖醇脂肪酸酯,
-0.002至0.1重量%的抗氧化剂,
-0.005至0.07重量%的治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐,
-0.02至1重量%的甜味剂,和
-82.5至97重量%的物质浓度为25至200mM的缓冲溶液。
特别优选地,本发明的制剂(C)包含:
-5至13重量%的聚氧乙烯脱水山梨糖醇脂肪酸酯,
-0.005至0.05重量%的抗氧化剂,
-0.006至0.06重量%的治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐,
-0.05至0.2重量%的甜味剂,和
-86至94重量%的物质浓度为25至200mM的缓冲溶液。
非常特别优选地,本发明的制剂(C)包含(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮作为TASK-1和/或TASK-3通道抑制剂。
在另一个实施方案(C‘)中,本发明的制剂包含:
-1.4至22.7重量%的聚氧乙烯脱水山梨糖醇脂肪酸酯,
-0.001至0.2重量%的抗氧化剂,
-0.002至0.1重量%的(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐,
-0至4重量%的甜味剂,和
-73至98.5重量%的物质浓度为25至200mM的缓冲溶液。
优选地,本发明的制剂(C‘)包含:
-2.9至15.8重量%的聚氧乙烯脱水山梨糖醇脂肪酸酯,
-0.002至0.1重量%的抗氧化剂,
-0.005至0.07重量%的(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐,
-0.01至2重量%的甜味剂,和
-82至97重量%的物质浓度为25至200mM的缓冲溶液。
特别优选地,本发明的制剂(C‘)包含:
-5.4至13重量%的聚氧乙烯脱水山梨糖醇脂肪酸酯,
-0.005至0.05重量%的抗氧化剂,
-0.006至0.05重量%的(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐,
-0.02至1重量%的甜味剂,和
-85.9至94.5重量%的物质浓度为25至200mM的缓冲溶液。
在另一个实施方案(D)中,本发明的制剂包含:
-1至21重量%的聚氧乙烯脱水山梨糖醇脂肪酸酯,
-0.001至0.2重量%的抗氧化剂,
-0.002至0.1重量%的治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐,
-0.3至25重量%的丙三醇,
-0.01至5.5重量%的甜味剂,和
-48至98重量%的物质浓度为25至200mM的缓冲溶液。
优选地,本发明的制剂(D)包含:
-2.5至16重量%的聚氧乙烯脱水山梨糖醇脂肪酸酯,
-0.002至0.1重量%的抗氧化剂,
-0.005至0.07重量%的治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐,
-1至12重量%的丙三醇,
-0.02至1重量%的甜味剂,和
-70至96重量%的物质浓度为25至200mM的缓冲溶液。
特别优选地,本发明的制剂(D)包含:
-5至13重量%的聚氧乙烯脱水山梨糖醇脂肪酸酯,
-0.005至0.05重量%的抗氧化剂,
-0.006至0.06重量%的治疗有效量的至少一种TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐,
-2.5至6重量%的丙三醇,
-0.05至0.3重量%的甜味剂,和
-80至92重量%的物质浓度为25至200mM的缓冲溶液。
非常特别优选地,本发明的制剂(D)包含4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮作为TASK-1和/或TASK-3通道抑制剂。
本发明的合适的聚氧乙烯脱水山梨糖醇脂肪酸酯为例如聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80。优选聚山梨醇酯80。
合适的抗氧化剂为例如丁基羟基茴香醚或丁羟甲苯。优选丁基羟基茴香醚。
本发明的合适的甜味剂为例如三氯蔗糖或山梨糖醇。优选三氯蔗糖。
在一个优选的实施方案中,抗氧化剂、优选丁基羟基茴香醚以粉碎的形式存在;特别优选地,晶体的直径小于1mm。
在一个优选的实施方案中,TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或药学上可接受的盐以微粉化的形式存在,其平均粒径(x50)为1至8μm且上限(x90)为20μm。
优选使用选自以下的缓冲溶液:磷酸盐缓冲液、2-(4-(2-羟乙基)-1-哌嗪基)乙磺酸(HEPES)、2-氨基-2-(羟甲基)丙-1,3-二醇(TRIS)和3-(N-吗啉代)丙磺酸(MOPS)。
特别优选地,磷酸盐缓冲溶液包含磷酸二氢钠二水合物和磷酸氢二钠以及水,其pH为7.0。
特别优选地,HEPES缓冲溶液包含2-(4-(2-羟乙基)-1-哌嗪基)乙磺酸和水,用氢氧化钠水溶液调节至pH 7.6。
特别优选地,TRIS缓冲溶液包含2-氨基-2-(羟甲基)丙烷-1,3-二醇和水,用盐酸调节至pH 8.0。
特别优选地,MOPS缓冲溶液包含3-(N-吗啉代)丙磺酸和水,用氢氧化钠水溶液调节至pH 7.5。
非常特别优选地,pH调节剂为磷酸盐缓冲溶液或2-(4-(2-羟乙基)-1-哌嗪基)乙磺酸(HEPES)。
本发明提供可通过本发明的方法获得的用于鼻腔或咽部给药的药物制剂。
本发明的稳定的药物制剂可任选地包含其他助剂。
在本发明的上下文中,助剂的实例为稳定剂、增稠剂、防腐剂、用于调节张力的物质、芳香物质、香料或染料。
在本发明的上下文中,增稠剂为例如天然橡胶、海藻酸、果胶、淀粉和淀粉衍生物、明胶、泊洛沙姆(聚氧丙烯/聚氧乙烯嵌段共聚物)、纤维素衍生物、丙烯酸聚合物或乙烯基聚合物。
在本发明的上下文中,活性成分定义为TASK-1和/或TASK-3通道抑制剂或其水合物、溶剂化物、多晶型物或代谢物或其药学上可接受的盐。
本发明的稳定的药物制剂为例如那些制剂,其中所述至少一种TASK-1和/或TASK-3通道抑制剂选自WO 2017/097671、WO 2017/097792、WO 2018/015196和EP17176046.5以及PCT/CN2017/088237中记载的式(I)的化合物及其盐、溶剂化物和盐的溶剂化物。这些化合物的合成记载于WO 2017/097792中。
优选的式(I)的化合物选自表1的化合物:
来自WO 2017/097671、WO 2017/097792、WO 2018/015196,以及
EP17176046.5和PCT/CN2017/088237的化合物及其水合物、溶剂化物、多晶型物或代谢物或其药学上可接受的盐。
特别优选选自以下化合物的化合物,及其水合物、溶剂化物、多晶型物或代谢物或其药学上可接受的盐。
非常特别优选选自以下化合物的化合物,及其水合物、溶剂化物、多晶型物或代谢物或其药学上可接受的盐。
本发明的稳定药物制剂还为其中所述至少一种TASK-1和/或TASK-3通道抑制剂选自以下的那些制剂:
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮和/或(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮及其水合物、溶剂化物、多晶型物或代谢物或其药学上可接受的盐。
本发明的稳定的药物制剂还为其中所述至少一种TASK-1和/或TASK-3通道抑制剂为(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮的那些制剂。
本发明的稳定的药物制剂还为其中所述至少一种TASK-1和/或TASK-3通道抑制剂为(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮的那些制剂。
本发明的另一个实施方案为本发明的稳定的药物制剂,其用于鼻腔或咽部给药以治疗和/或预防疾病。
本发明的另一个实施方案为本发明的稳定的药物制剂,其用于鼻腔或咽部给药,以用于治疗和/或预防呼吸障碍、睡眠相关的呼吸障碍、阻塞性睡眠呼吸暂停、中枢性睡眠呼吸暂停、打鼾、心律不齐、心率失常、神经变性疾病、神经炎性疾病和神经免疫性疾病的方法中。
本发明的另一个实施方案为本发明的稳定的药物制剂,其用于鼻腔或咽部给药,以用于治疗和/或预防呼吸障碍、睡眠相关的呼吸障碍、阻塞性睡眠呼吸暂停、中枢性睡眠呼吸暂停、打鼾、心律不齐、心率失常、神经变性疾病、神经炎性疾病和神经免疫性疾病的方法中,其中鼻腔或咽部给药通过鼻喷雾剂、滴鼻剂、鼻腔溶液、粉末吸入器、雾化器、定量喷雾剂或半固体凝胶辅助进行。
本发明的另一个实施方案为本发明的稳定的药物制剂,其用于鼻腔或咽部给药,以用于治疗和/或预防呼吸障碍、睡眠相关的呼吸障碍、阻塞性睡眠呼吸暂停、中枢性睡眠呼吸暂停、打鼾、心律不齐、心率失常、神经变性疾病、神经炎性疾病和神经免疫性疾病的方法中。
本发明的另一个实施方案为本发明的稳定的药物制剂,其用于鼻腔或咽部给药,以用于治疗和/或预防呼吸障碍、睡眠相关的呼吸障碍、阻塞性睡眠呼吸暂停、中枢性睡眠呼吸暂停、打鼾、心律不齐、心率失常、神经变性疾病、神经炎性疾病和神经免疫性疾病的方法中。
本发明的另一个实施方案为本发明的稳定的药物制剂,其用于鼻腔或咽部给药,以用于治疗和/或预防阻塞性睡眠呼吸暂停或打鼾的方法中,所述药物制剂包含:
治疗有效量的TASK-1和/或TASK-3通道抑制剂(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮或(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮和/或其水合物、溶剂化物、多晶型物或代谢物或其药学上可接受的盐于1.0至21重量%的聚山梨醇酯80、0.001重量%至0.2重量%的丁基羟基茴香醚以及至少一种其他助剂中,其溶解于物质浓度为25至200mM的磷酸盐或HEPES缓冲溶液中,将制剂的pH调节至6.8至8.2。
本发明的另一个实施方案为本发明的稳定的药物制剂,其用于鼻腔或咽部给药,以用于治疗和/或预防阻塞性睡眠呼吸暂停或打鼾的方法中,所述药物制剂包含:
治疗有效量的TASK-1和/或TASK-3通道抑制剂(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮和/或其水合物、溶剂化物、多晶型物或代谢物或其药学上可接受的盐于1.0至21重量%的聚山梨醇酯80、0.001重量%至0.2重量%的丁基羟基茴香醚、0.3至24.5重量%的丙三醇以及至少一种其他助剂中,其溶解于物质浓度为25至200mM的磷酸盐或HEPES缓冲溶液中,将制剂的pH调节至6.8至8.2,优选6.8至7.8。
本发明的另一个实施方案为本发明的稳定的药物制剂,其用于鼻腔或咽部给药,以用于治疗和/或预防阻塞性睡眠呼吸暂停或打鼾的方法中,所述药物制剂包含:
治疗有效量的TASK-1和/或TASK-3通道抑制剂(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮和/或其水合物、溶剂化物、多晶型物或代谢物或其药学上可接受的盐于1.0至21重量%的聚山梨醇酯80、0.001重量%至0.2重量%的丁基羟基茴香醚、3至60重量%的PEG 400和至少一种其他助剂中,其溶解于物质浓度为25至200mM的磷酸盐或HEPES缓冲溶液中,将制剂的pH调节至6.8至8.2,优选6.8至7.8。
本发明的另一个实施方案为本发明的稳定的药物制剂,其用于鼻腔或咽部给药,以用于治疗和/或预防阻塞性睡眠呼吸暂停或打鼾的方法中,所述药物制剂包含:
治疗有效量的TASK-1和/或TASK-3通道抑制剂(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮和/或其水合物、溶剂化物、多晶型物或代谢物或其药学上可接受的盐于1.0至21重量%的聚山梨醇酯80、0.001重量%至0.2重量%的丁基羟基茴香醚、0.05至0.25重量%的三氯蔗糖以及至少一种其他助剂中,其溶解于物质浓度为25至200mM的磷酸盐或HEPES缓冲溶液中,将制剂的pH调节至6.8至8.2,优选6.8至7.8。
本发明的制剂可以单独使用或如果需要与一种或多种其它药理活性物质组合使用,只要这种组合不会导致不合意和不可接受的副作用。因此本发明还提供包含至少一种本发明的制剂和一种或多种其他活性成分的药剂,其尤其用于治疗和/或预防上述疾病。适于该目的的组合活性成分的优选实例包括:
·呼吸兴奋剂,例如和优选茶碱、多沙普仑(Doxapram)、尼可刹米(Nikethamide)或咖啡因;
·精神兴奋化合物,例如和优选莫达非尼(Modafinil)或阿莫达非尼(Armodafinil);
·苯丙胺(Amphetamine)和苯丙胺衍生物,例如和优选苯丙胺、甲基苯丙胺或哌甲酯(Methylphenidate);
·羟色胺(Serotonin)再摄取抑制剂,例如和优选氟西汀(Fluoxetine)、帕罗西汀(Paroxetine)、西酞普兰(Citalopram)、依他普仑(Escitalopram)、舍曲林(Sertraline)、氟伏沙明(Fluvoxamine)或曲唑酮(Trazodone);
·羟色胺前体,例如和优选L-色氨酸;
·选择性羟色胺去甲肾上腺素再摄取抑制剂,例如和优选文拉法辛(Venlafaxine)或度洛西汀(Duloxetine);
·去甲肾上腺素能和特异性羟色胺能的抗抑郁药,例如和优选米氮平(Mirtazapine);
·选择性去甲肾上腺素再摄取抑制剂,例如和优选瑞波西汀(Reboxetine);
·三环抗抑郁药,例如和优选阿米替林(Amitriptyline)、普罗替林(Protriptyline)、多塞平(Doxepine)、三甲丙咪嗪(Trimipramine)、丙咪嗪(Imipramine)、氯米帕明(Clomipramine)或地昔帕明(Desipramine);
·α2-肾上腺素能激动剂,例如和优选可乐定(Clonidine);
·GABA激动剂,例如和优选巴氯芬(Baclofen);
·α拟交感神经药,例如和优选赛洛唑啉(Xylometazoline)、羟甲唑啉(Oxymetazoline)、苯肾上腺素(Phenylephrine)、萘甲唑啉(Naphazoline)、四氢唑啉(Tetryzoline)或曲马唑啉(Tramazoline);
·糖皮质激素,例如和优选氟替卡松(Fluticasone)、布地奈德(Budesonide)、倍氯米松(Beclometasone)、莫米松(Mometasone)、替可的松(Tixocortol)或去炎松(Triamcinolone);
·大麻素受体激动剂;
·碳酸酐酶(Carboanhydrase)抑制剂,例如和优选乙酰唑胺(Acetazolamide)、醋甲唑胺(Methazolamide)或双氯非那胺(Diclofenamide);
·阿片(Opioid)和苯二氮受体拮抗剂,例如和优选氟马西尼(Flumazenil)、纳洛酮(Naloxone)或纳曲酮(Naltrexone);
·胆碱酯酶抑制剂,例如和优选新斯的明(Neostigmine)、吡啶斯的明(Pyridostigmine)、毒扁豆碱(Physostigmine)、多奈哌齐(Donepezil)、加兰他敏(Galantamine)或卡巴拉汀(Rivastigmine);
·N-甲基-D-天冬氨酸酯和谷氨酸酯拮抗剂,例如和优选金刚烷胺(Amantadine)、美金刚(Memantine)或沙贝鲁唑(Sabeluzole);
·烟碱受体激动剂;
·白三烯受体拮抗剂,例如和优选孟鲁司特(Montelukast)或Tripelukast;
·多巴胺受体拮抗剂,例如和优选Dromperidon、甲氧氯普胺(Metoclopramide)或苯甲酰胺-、丁酰苯-或吩噻嗪-衍生物;
·食欲抑制剂,例如和优选西布曲明(Sibutramine)、托吡酯(Topiramate)、芬特明(Phentermine)、脂肪酶抑制剂或大麻素受体拮抗剂;
·质子泵抑制剂,例如和优选泮托拉唑(Pantoprazole)、奥美拉唑(Omeprazole)、埃索美拉唑(Esomeprazole)、兰索拉唑(Lansoprazole)或雷贝拉唑(Rabeprazole);
·有机硝酸酯和NO供体,例如硝普钠、硝酸甘油、单硝酸异山梨酯、硝酸异山梨酯、吗多明(Molsidomine)或SIN-1以及吸入性NO;
·抑制环单磷酸鸟苷(cGMP)和/或环单磷酸腺苷(cAMP)降解的化合物,例如磷酸二酯酶(PDE)1、2、3、4和/或5的抑制剂,尤其是PDE 5抑制剂,如西地那非(Sildenafil)、伐地那非(Vardenafil)、他达拉非(Tadalafil)、乌地那非(Udenafil)、达生他非(Dasantafil)、阿伐那非(Avanafil)、米罗那非(Mirodenafil)或Lodenafil;
·NO和血红素非依赖性的可溶性鸟苷酸环化酶(sGC)活化剂,例如特别是WO 01/19355、WO 01/19776、WO 01/19778、WO 01/19780、WO 02/070462和WO 02/070510中记载的化合物;
·NO非依赖性但血红素依赖性的可溶性鸟苷酸环化酶(sGC)刺激剂,例如特别是利奥西呱(Riociguat)、Vericiguat,和WO 00/06568、WO 00/06569、WO 02/42301、WO 03/095451、WO 2011/147809、WO 2012/004258、WO 2012/028647和WO 2012/059549中记载的化合物;
·前列环素类似物和IP受体激动剂,例如和优选伊洛前列素(Iloprost)、贝前列素(Beraprost)、曲前列环素(Treprostinil)、依前列醇(Epoprostenol)或Selexipag;
·内皮素受体拮抗剂,例如和优选波生坦(Bosentan)、达卢生坦(Darusentan)、安倍生坦(Ambrisentan)或西他生坦(Sitaxsentan);
·抑制人中性粒细胞弹性蛋白酶(HNE)的化合物,例如和优选西维来司他(Sivelestat)或DX-890(Reltran);
·抑制细胞外基质的降解和改变的化合物,例如和优选基质金属蛋白酶(MMPs)的抑制剂,尤其是基质溶素、胶原酶、明胶酶和聚蛋白多糖酶(在本上下文中特别是MMP-1、MMP-3、MMP-8、MMP-9、MMP-10、MMP-11和MMP-13)和金属弹性蛋白酶(MMP-12)的抑制剂;
·阻断5-羟色胺结合到其受体上的化合物,例如和优选5-HT2B受体的拮抗剂,如PRX-08066;
·生长因子、细胞因子和趋化因子的拮抗剂,例如和优选TGF-β、CTGF、IL-1、IL-4、IL-5、IL-6、IL-8、IL-13和整合素的拮抗剂;
·Rho激酶抑制化合物,例如和优选法舒地尔(Fasudil)、Y-27632、SLx-2119、BF-66851、BF-66852、BF-66853、KI-23095或BA-1049;
·影响心脏能量代谢的化合物,例如和优选依托莫司(Etomoxir)、二氯乙酸盐、雷诺嗪(Ranolazine)或曲美他嗪(Trimetazidine);
·抑制信号转导级联的化合物,例如和优选选自激酶抑制剂,特别选自酪氨酸激酶和/或丝氨酸/苏氨酸激酶抑制剂,例如和优选尼达尼布(Nintedanib)、达沙替尼(Dasatinib)、尼洛替尼(Nilotinib)、博舒替尼(Bosutinib)、瑞格非尼(Regorafenib)、索拉非尼(Sorafenib)、舒尼替尼(Sunitinib)、西地尼布(Cediranib)、阿西替尼(Axitinib)、替拉替尼(Telatinib)、伊马替尼(Imatinib)、布立尼布(Brivanib)、帕唑帕尼(Pazopanib)、瓦他拉尼(Vatalanib)、吉非替尼(Gefitinib)、埃罗替尼(Erlotinib)、拉帕替尼(Lapatinib)、卡奈替尼(Canertinib)、来他替尼(Lestaurtinib)、培利替尼(Pelitinib)、Semaxanib或坦度替尼(Tandutinib);
·例如用于治疗慢性阻塞性肺病(COPD)或支气管哮喘的抗阻塞剂,例如和优选选自吸入或全身给药的β-肾上腺素能受体激动剂(β-模拟物)和吸入给药的抗毒蕈碱(Anti-muscarinergic)物质;
·抗炎、免疫调节、免疫抑制和/或细胞毒性剂,例如和优选选自全身或吸入给药的皮质类固醇以及富马酸二甲酯、芬戈莫德(Fingolimod)、醋酸格拉替雷(Glatirameracetate)、β-干扰素、那他珠单抗(Natalizumab)、特立氟胺(Teriflunomide)、米托蒽醌(Mitoxantrone)、免疫球蛋白、乙酰基半胱氨酸、孟鲁司特(Montelukast)、Tripelukast、硫唑嘌呤(Azathioprine)、环磷酰胺、羟基脲、阿奇霉素(Azithromycin)、干扰素-γ、吡非尼酮(Pirfenidone)或依那西普(Etanercept);
·抗纤维化剂,例如和优选溶血磷脂酸受体1(LPA-1)拮抗剂、CTGF抑制剂、IL-4拮抗剂、IL-13拮抗剂、TGF-β拮抗剂或吡非尼酮(Pirfenidone);
·抗血栓形成剂,例如和优选选自血小板聚集抑制剂、抗凝血剂和促溶纤(profibrinolytisch)物质;
·降血压活性成分,例如和优选选自钙拮抗剂、血管紧张素AII拮抗剂、ACE抑制剂、血管肽酶(Vasopeptidase)抑制剂、内皮素拮抗剂、肾素抑制剂、α受体阻滞剂、β受体阻滞剂、盐皮质激素受体拮抗剂和利尿剂;和/或
·改变脂肪代谢的活性成分,例如和优选选自甲状腺受体激动剂、胆固醇合成抑制剂,例如和优选HMG-CoA还原酶抑制剂或角鲨烯合成抑制剂、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、聚合胆汁酸吸附剂、胆汁酸再吸收抑制剂和脂蛋白(a)拮抗剂。
在本发明的一个优选实施方案中,本发明的制剂与β-肾上腺素能受体激动剂联合给药,所述受体激动剂例如和优选舒喘灵(Albuterol)、异丙肾上腺素(Isoproterenol)、奥西那林(Metaproterenol)、特布他林(Terbutalin)、非诺特罗(Fenoterol)、福莫特罗(Formoterol)、瑞普特罗(Reproterol)、沙丁胺醇(Salbutamol)或沙美特罗(Salmeterol)。
在本发明的一个优选实施方案中,本发明的制剂与抗毒蕈碱物质联合给药,所述抗毒蕈碱物质例如和优选异丙托溴铵(Ipratropiumbromide)、噻托溴铵(Tiotropiumbromide)或氧托溴铵(Oxitropiumbromide)。
在本发明的一个优选实施方案中,本发明的制剂与皮质类固醇联合给药,所述皮质类固醇例如和优选强的松(Prednisone)、泼尼松龙(Prednisolone)、甲基泼尼松龙(Methylprednisolone)、去炎松(Triamcinolone)、地塞米松(Dexamethasone)、倍他米松(Betamethasone)、倍氯米松(Beclomethasone)、氟尼缩松(Flunisolide)、布地奈德(Budesonide)或氟替卡松(Fluticasone)。
抗血栓形成剂优选理解为是指选自血小板聚集抑制剂、抗凝血剂和促纤溶物质的化合物。
在本发明的一个优选实施方案中,本发明的制剂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和优选阿司匹林、氯吡格雷(Clopidogrel)、噻氯匹定(Ticlopidine)或双嘧达莫(Dipyridamole)。
在本发明的一个优选实施方案中,本发明的制剂与凝血酶抑制剂联合给药,所述凝血酶抑制剂例如和优选希美加群(Ximelagatran)、美拉加群(Melagatran)、达比加群(Dabigatran)、比伐卢定(Bivalirudin)或克赛(Clexane)。
在本发明的一个优选实施方案中,本发明的制剂与GPIIb/IIIa拮抗剂,例如和优选替罗非班(Tirofiban)或阿昔单抗(Abciximab)联合给药。
在本发明的一个优选实施方案中,本发明的制剂与因子Xa抑制剂联合给药,所述因子Xa抑制剂例如和优选利伐沙班(Rivaroxaban)、阿哌沙班(Apixaban)、Fidexaban、雷扎沙班(Razaxaban)、磺达肝癸钠(Fondaparinux)、艾卓肝素(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。
在本发明的一个优选实施方案中,本发明的制剂与肝素或与低分子量(LMW)肝素衍生物联合给药。
在本发明的一个优选实施方案中,本发明的制剂与维生素K拮抗剂,例如和优选香豆素联合给药。
抗高血压药优选理解为是指选自钙拮抗剂、血管紧张素AII拮抗剂、ACE抑制剂、内皮素拮抗剂、肾素抑制剂、α受体阻滞剂、β受体阻滞剂、盐皮质激素受体拮抗剂和利尿剂的化合物。
在本发明的一个优选实施方案中,本发明的制剂与钙拮抗剂联合给药,所述钙拮抗剂例如和优选硝苯地平(Nifedipine)、氨氯地平(Amlodipine)、维拉帕米(Verapamil)或地尔硫卓(Diltiazem)。
在本发明的一个优选实施方案中,本发明的制剂与α-1受体阻滞剂,例如和优选哌唑嗪(Prazosin)联合给药。
在本发明的一个优选实施方案中,本发明的制剂与β受体阻滞剂联合给药,所述β受体阻滞剂例如和优选普萘洛尔(Propranolol)、阿替洛尔(Atenolol)、噻吗洛尔(Timolol)、吲哚洛尔(Pindolol)、阿普洛尔(Alprenolol)、氧烯洛尔(Oxprenolol)、喷布洛尔(Penbutolol)、布拉洛尔(Bupranolol)、美替洛尔(Metipranolol)、纳多洛尔(Nadolol)、甲吲洛尔(Mepindolol)、卡拉洛尔(Carazalol)、索他洛尔(Sotalol)、美托洛尔(Metoprolol)、倍他洛尔(Betaxolol)、塞利洛尔(Celiprolol)、比索洛尔(Bisoprolol)、卡替洛尔(Carteolol)、艾司洛尔(Esmolol)、拉贝洛尔(Labetalol)、卡维地洛(Carvedilol)、阿达洛尔(Adaprolol)、兰替洛尔(Landiolol)、奈必洛尔(Nebivolol)、依泮洛尔(Epanolol)或布新洛尔(Bucindolol)。
在本发明的一个优选实施方案中,本发明的制剂与血管紧张素AII拮抗剂联合给药,所述血管紧张素AII拮抗剂例如和优选氯沙坦(Losartan)、坎地沙坦(Candesartan)、缬沙坦(Valsartan)、替米沙坦(Telmisartan)或恩布沙坦(Embusartan)。
在本发明的一个优选实施方案中,本发明的制剂与ACE抑制剂联合给药,所述ACE抑制剂例如和优选依那普利(Enalapril)、卡托普利(Captopril)、赖诺普利(Lisinopril)、雷米普利(Ramipril)、地拉普利(Delapril)、福辛普利(Fosinopril)、奎诺普利(Quinopril)、培哚普利(Perindopril)或群多普利(Trandopril)。
在本发明的一个优选实施方案中,本发明的制剂与内皮素拮抗剂联合给药,所述内皮素拮抗剂例如和优选波生坦(Bosentan)、达卢生坦(Darusentan)、安倍生坦(Ambrisentan)或西他生坦(Sitaxsentan)。
在本发明的一个优选实施方案中,本发明的制剂与肾素抑制剂联合给药,所述肾素抑制剂例如和优选阿利吉仑(Aliskiren)、SPP-600或SPP-800。
在本发明的一个优选实施方案中,本发明的制剂与盐皮质激素受体拮抗剂,例如和优选安体舒通(Spironolactone)、依普利酮(Eplerenone)或Finerenon联合给药。
在本发明的一个优选实施方案中,本发明的制剂与利尿剂联合给药,所述联合给药例如和优选速尿(Furosemide)、布美他尼(Bumetanide)、托拉塞米(Torsemide)、苄氟噻嗪(Bendroflumethiazide)、氯噻嗪(Chlorothiazide)、氢氯噻嗪(Hydrochlorothiazide)、氢氟噻嗪(Hydroflumethiazide)、甲氯噻嗪(Methyclothiazide)、泊利噻嗪(Polythiazide)、三氯甲噻嗪(Trichlormethiazide)、氯噻酮(Chlorthalidone)、吲达帕胺(Indapamide)、美托拉宗(Metolazone)、喹乙宗(Quinethazone)、乙酰唑胺(Acetazolamide)、二氯磺胺(Dichlorphenamide)、醋甲唑胺(Methazolamide)、Glycerolin、异山梨醇、甘露醇、阿米洛利(Amiloride)或氨苯蝶啶(Triamterene)。
脂质代谢调节剂优选理解为是指选自CETP抑制剂、甲状腺受体激动剂、胆固醇合成抑制剂的化合物,如HMG-CoA还原酶抑制剂或角鲨烯合成抑制剂,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、聚合胆汁酸吸附剂、胆汁酸再吸收抑制剂、脂肪酶抑制剂和脂蛋白(a)拮抗剂。
在本发明的一个优选实施方案中,本发明的制剂与CETP抑制剂联合给药,所述CETP抑制剂例如和优选托彻普(CP-529 414)、JJT-705或CETP疫苗(Avant)。
在本发明的一个优选实施方案中,本发明的制剂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和优选D-甲状腺素、3,5,3'-三碘甲腺原氨酸(T3)、CGS 23425或阿昔替罗(Axitirome)(CGS 26214)。
在本发明的一个优选实施方案中,本发明的制剂与选自他汀类的HMG-CoA还原酶抑制剂联合给药,所述HMG-CoA还原酶抑制剂例如和优选洛伐他汀(Lovastatin)、辛伐他汀(Simvastatin)、普伐他汀(Pravastatin)、氟伐他汀(Fluvastatin)、阿托伐他汀(Atorvastatin)、瑞舒伐他汀(Rosuvastatin)或匹伐他汀(Pitavastatin)。
在本发明的一个优选实施方案中,本发明的制剂与角鲨烯合成抑制剂,例如和优选BMS-188494或TAK-475联合给药。
在本发明的一个优选实施方案中,本发明的制剂与ACAT抑制剂联合给药,所述ACAT抑制剂例如和优选阿伐麦布(Avasimibe)、甲亚油酰胺(Melinamide)、帕替麦布(Pactimibe)、依鲁麦布(Eflucimibe)或SMP-797。
在本发明的一个优选实施方案中,本发明的制剂与MTP抑制剂,例如和优选Implitapid、BMS-201038、R-103757或JTT-130联合给药。
在本发明的一个优选实施方案中,本发明的制剂与PPAR-γ激动剂,例如和优选吡格列酮(Pioglitazone)或罗格列酮(Rosiglitazone)联合给药。
在本发明的一个优选实施方案中,本发明的制剂与PPAR-δ激动剂,例如和优选GW501516或BAY 68-5042联合给药。
在本发明的一个优选实施方案中,本发明的制剂与胆固醇吸收抑制剂,例如和优选依泽替米贝(Ezetimibe)、替奎安(Tiqueside)或帕马苷(Pamaqueside)联合给药。
在本发明的一个优选实施方案中,本发明的制剂与脂肪酶抑制剂,例如和优选奥利司他(Orlistat)联合给药。
在本发明的一个优选实施方案中,本发明的制剂与聚合胆汁酸吸附剂联合给药,所述聚合胆汁酸吸附剂例如和优选消胆胺(Cholestyramine)、考来替泊(Colestipol)、Colesolvam、考来胶(CholestaGel)或Colestimid。
在本发明的一个优选实施方案中,本发明的制剂与胆汁酸再吸收抑制剂联合给药,所述胆汁酸再吸收抑制剂例如和优选ASBT(=IBAT)抑制剂,例如AZD-7806、S-8921、AK-105、BARI-1741、SC-435或SC-635。
在本发明的一个优选实施方案中,本发明的制剂与脂蛋白(a)拮抗剂,例如和优选Gemcabene钙(CI-1027)或烟酸联合给药。
特别优选的是本发明的制剂与选自以下的一种或多种其他活性物质的组合:呼吸兴奋剂、精神兴奋药、羟色胺再摄取抑制剂、去甲肾上腺素能、羟色胺能和三环抗抑郁药、sGC刺激剂、盐皮质激素受体拮抗剂、抗炎剂、免疫调节剂、免疫抑制剂和细胞毒素剂。
如果需要,本发明的制剂也可以与一种或多种医疗技术设备或辅助设备联合使用,只要这不造成不希望和不可接受的副作用。适合用于这样的联合应用的医疗设备和辅助设备例如和优选为:
·用于呼吸道正压通气的设备,例如和优选CPAP(连续气道正压通气)设备、BiPAP(双相气道正压通气)设备和IPPV(间歇正压通气)设备;
·舌下神经的神经刺激器;
·口内辅助设备,例如和优选凸出支具(Protrusionsspangen);
·鼻用一次性阀;
·鼻支撑器。
在一个实施方案中,在鼻腔给药的情况下,剂量为每天大约0.1μg至500μg。在另一个实施方案中,在鼻腔给药的情况下,剂量为每天大约1μg至250μg。在另一个实施方案中,在鼻腔给药的情况下,剂量为每天大约1μg至100μg。在另一个实施方案中,每天一次在睡前通过鼻腔途径给予每天大约0.1μg至500μg,或每天大约1μg至250μg,或每天大约1μg至100μg的剂量。在一个实施方案中,每天一次给予每天大约0.1μg至500μg,或每天大约1μg至250μg,或每天大约1μg至100μg的剂量,每个鼻孔各一半。在一个实施方案中,每天一次在睡前给予每天大约0.1μg至500μg,或每天大约1μg至250μg,或每天大约1μg至100μg的剂量,每个鼻孔各一半。
然而,在一些情况下可能有必要偏离所述量,特别地取决于体重、给药途径、对活性成分的个体反应、制剂性质和给药的时间或间隔。因此在一些情况下使用少于上述最小量来管理可能是足够的,而在另一些情况下,则有必要超过所提到的上限。如果给予更大的量,则可建议将它们在一天内分成几个单剂量。
实施例
缩写列表
HPLC方法
方法1(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基
吡啶-2-基)甲酮
未稀释的样品在Hewlett-Packard/Agilent HPLC和UHPLC仪器(DE)上通过反相HPLC分析。然后将2.0μl的样品溶液施加到不锈钢的金属柱上,例如Agilent Eclipse PlusRRHD C18(150mm x 3.0mm,粒径为1.8μm),其保持在25℃的温度下(流速0.5ml/min)。
使用在10min内10-45%(体积/体积),接着在5min内45-80%(体积/体积),然后在5min内80%(体积/体积)的B梯度对样品进行分析,流动相由溶剂A(H2O,含1ml三氟乙酸)和溶剂B(乙腈;Riedel-de DE,含1ml三氟乙酸)组成。使用UV检测器在238nm下通过外标法(ESTD)检查制剂。
方法2(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-
3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮
将样品用水和甲醇的混合物稀释,然后在Hewlett-Packard/Agilent HPLC或UHPLC仪器(DE)上通过反相HPLC分析。然后将3.0μl的样品溶液施加到不锈钢的金属柱上,例如Waters Acquity UPLC HSS T3(50mm x 2.1mm,粒径为1.8μm),其保持在40℃的温度下(流速10ml/min)。
使用在2.5min内5-30%(体积/体积),接着在5.5min内30-50%(体积/体积),接着在1min内50-80%(体积/体积),然后在1min内80%(体积/体积)的B梯度对样品进行分析,流动相由溶剂A(0.77g乙酸铵/1l的H2O,用氨将pH值调节至约9)和溶剂B(乙腈;Riedel-deDE)组成。使用UV检测器在220nm下通过外标法(ESTD)检查制剂的降解产物的含量和面积百分比。
方法3(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-
3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮
将样品用水和乙腈的混合物稀释,然后在Hewlett-Packard/Agilent HPLC或UHPLC仪器(DE)上通过反相HPLC分析。然后将4.0μl的样品溶液施加到不锈钢的金属柱上,例如Waters Acquity UPLC BEH Phenyl(100mm x 2.1mm,粒径为1.7μm),其保持在50℃的温度下(流速0.5ml/min)。
使用在10min内5-51%(体积/体积),接着在7min内51-68%(体积/体积),接着在3min内68-90%(体积/体积),然后在10min内90%(体积/体积)的B梯度对样品进行分析,其中流动相由溶剂A(114mg乙酸铵和0.49ml的冰醋酸/1l的H2O,pH约4)和溶剂B(乙腈;Riedel-de DE)组成。使用UV检测器在238nm下通过外标法(ESTD)检查制剂。
制备顺序的实施例
实施例1将(初级溶液A)加入到B)中(本发明)
对于两亲相,选择合适的容器,该容器允许用磁力搅拌棒或叶片搅拌器以200至300rpm的搅拌速度搅拌。首先在该容器中装入(占待制备的全部材料的)10体积%的聚山梨醇酯80。随后,在搅拌下加入0.02%(重量/体积)的丁基羟基茴香醚(BHA),并使其溶解。通过在研钵中预先粉碎BHA,可显著减少溶解时间。仅在BHA完全溶解后,在搅拌下加入0.015%(重量/体积)微粉化的活性化合物(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮。
在另一个容器中制备水相,该容器足够大以容纳批次的全部物料,并且也必须配备有搅拌器。首先加入约70%的所需WFI。在200至300rpm的搅拌下,将缓冲盐磷酸氢二钠和磷酸二氢钠二水合物(总量为0.063mM磷酸盐,pH 7.0)溶解。一旦缓冲盐完全溶解,加入2.5体积%的丙三醇或20体积%的PEG 400(参见表2、3、4),并将混合物搅拌至均匀。
当活性化合物完全溶解于两亲相中时,在30分钟内将两亲相添加至水相中。
用于两亲相的容器用WFI冲洗3次,以确保两亲相的转移是定量的。随后,如果需要,使用10浓度%的HCl或1N NaOH将整体制剂的pH调节至6.8至7.2。
然后使用WFI将整体制剂补足至最终质量。
实施例2(本发明)
对于两亲相,选择合适的容器,该容器允许用磁力搅拌棒或叶片搅拌器以200至300rpm的搅拌速度进行搅拌,并且足够大以容纳批次的全部物料。首先在该容器中装入(占待制备的全部材料的)10体积%的聚山梨醇酯80。随后,在搅拌下加入0.02%(重量/体积)的BHA,并使其溶解。通过在研钵中预先粉碎BHA,可显著减少溶解时间。仅在BHA完全溶解后,在搅拌下加入0.015%(重量/体积)微粉化的活性化合物(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮。
在另一个容器中制备水相,该容器也必须配备有搅拌器。首先加入约70%的所需WFI。在200至300rpm的搅拌下,将缓冲盐磷酸氢二钠和磷酸二氢钠二水合物(总量为0.063mM磷酸盐,pH 7.0)溶解。一旦缓冲盐完全溶解,加入2.5体积%的丙三醇或20体积%的PEG 400(参见表2),并将混合物搅拌至均匀。
当活性化合物完全溶解于两亲相中时,在30分钟内将整个水相添加至两亲相中。
如果需要,使用10浓度%的HCl或1N NaOH将pH调节至6.8至7。
然后使用WFI将整体制剂补足至最终质量。
实施例3(比较实施例)
首先将约70%的所需WFI装入合适的容器中,该容器足够大以容纳批次的全部物料,并允许使用磁力搅拌棒或叶片搅拌器以200至300rpm的搅拌速度进行搅拌。在搅拌下,将缓冲盐磷酸氢二钠和磷酸二氢钠二水合物(总量为0.063mM磷酸盐,pH 7.0)引入该容器中。一旦缓冲盐完全溶解,加入2.5体积%的丙三醇或20体积%的PEG 400(参见表2、3、4),并将混合物搅拌至均匀。随后,在30分钟的时间内,在搅拌下加入10体积%的聚山梨醇酯80。一旦聚山梨醇酯完全溶解,添加0.02%(重量/体积)的BHA,并使其溶解。通过在研钵中预先粉碎BHA,可显著减少溶解时间。仅在BHA完全溶解后,在搅拌下加入0.015%(重量/体积)微粉化的活性化合物(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮。在活性化合物也完全溶解后,如果需要,使用10浓度%的HCl或1N NaOH将整体制剂的pH值调节至6.8至7.2。
然后使用WFI将整体制剂补足至最终质量。
实施例4(本发明)
首先将20体积%的PEG 400(参见表2)装入合适的容器中,该容器足够大以容纳批次的全部材料,并允许使用磁力搅拌棒或叶片搅拌器以200至300rpm的搅拌速度进行搅拌。在搅拌下向该容器中加入0.02%(重量/体积)的BHA,并使其溶解。通过在研钵中预先粉碎BHA,可显著减少溶解时间。随后,在搅拌下加入0.015%(重量/体积)微粉化的活性化合物(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮。一旦活性化合物也完全溶解,加入约70%的所需WFI,并将混合物搅拌至均匀。随后,将缓冲盐磷酸氢二钠和磷酸二氢钠二水合物(总量为0.063mM磷酸盐,pH 7.0)溶解。然后在30分钟的时间内,在搅拌下添加10体积%的聚山梨醇酯80。一旦聚山梨醇酯也完全溶解,如果需要,使用10浓度%的HCl或1N NaOH将整体制剂的pH调节至6.8至7.2。
然后使用WFI将整体制剂补足至最终质量。
实施例5(本发明)
首先将10体积%的聚山梨醇酯80装入合适的容器中,该容器足够大以容纳批次的全部物料,并允许使用磁力搅拌棒或叶片搅拌器以200至300rpm的搅拌速度进行搅拌。在搅拌下向该容器中加入0.02%(重量/体积)的BHA,并使其溶解。通过在研钵中预先粉碎BHA,可显著减少溶解时间。随后,在搅拌下加入0.015%(重量/体积)微粉化的活性化合物(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮。一旦活性化合物也完全溶解,加入2.5体积%的丙三醇或20体积%的PEG 400(参见表2),并将混合物搅拌至均匀。随后,加入约70%的所需WFI。一旦形成均质溶液,在搅拌下添加缓冲盐磷酸氢二钠和磷酸二氢钠二水合物(总量为0.063mM磷酸盐,pH 7.0)。一旦缓冲盐也溶解,如果需要,使用10浓度%的HCl或1N NaOH将整体制剂的pH调节至6.8至7.2。
然后使用WFI将整体制剂补足至最终质量。
实施例6(本发明)
首先将10体积%的聚山梨醇酯80装入合适的容器中,该容器足够大以容纳批次的所有物料,并允许使用磁力搅拌棒或叶片搅拌器以200至300rpm的搅拌速度进行搅拌。在搅拌下向该容器中加入0.02%(重量/体积)的BHA,并使其溶解。通过在研钵中预先粉碎BHA,可显著减少溶解时间。然后在搅拌下加入0.015%(重量/体积)微粉化的活性化合物。一旦活性化合物也完全溶解,添加约70%的所需WFI,并将混合物搅拌至均匀。随后,添加缓冲盐磷酸氢二钠和磷酸二氢钠二水合物(总量为0.063mM磷酸盐,pH 7.0),并使其溶解。然后加入2.5体积%的丙三醇或20体积%的PEG 400(参见表2、3、4),并再次将混合物搅拌至均匀。一旦缓冲盐也溶解,检查整体制剂的pH。如果pH值不在6.8至7.2之间,则使用10浓度%的HCl或1N NaOH进行重新调节。
然后使用WFI将整体制剂补足至最终质量。
实施例7(比较实施例)
首先将10体积%的聚山梨醇酯80装入合适的容器中,该容器足够大以容纳批次的所有物料,并允许使用磁力搅拌棒或叶片搅拌器以200至300rpm的搅拌速度进行搅拌。在搅拌下向该容器中加入0.015%(重量/体积)微粉化的活性化合物。一旦活性化合物完全溶解,添加约70%的所需WFI。一旦形成均质溶液,在搅拌下添加缓冲盐磷酸氢二钠和磷酸二氢钠二水合物(总量为0.063mM磷酸盐,pH 7.0)。然后加入2.5体积%的丙三醇或20体积%的PEG 400(参见表2、3、4),并再次将混合物搅拌至均匀。随后,在搅拌下加入0.02%(重量/体积)的BHA,并使其溶解。通过在研钵中预先粉碎BHA,可显著减少溶解时间。一旦BHA也溶解,检查整体制剂的pH值。如果pH值不在6.8至7.2之间,则使用10浓度%的HCl或1N NaOH进行重新调节。
然后使用WFI将整体制剂补足至最终质量。
表2:
使用的活性化合物:(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮
*比较实施例
对于本发明的方法的其他实施方案,进行制备实施例1、3、6和7以评估制备时间。根据实施例1和6以及比较实施例3和7,对本发明的两种方法进行实验。在每种情况下,在添加缓冲盐之后添加三氯蔗糖。
表3:
使用的活性化合物:(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-
基)(6-甲氧基吡啶-2-基)甲酮
表4:
使用的活性化合物:(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮
Claims (8)
1.一种制备稳定的药物制剂的方法,其特征在于:在第一步中,首先加入聚山梨醇酯80作为增溶剂,将丁基羟基茴香醚和(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮或其药学上可接受的盐溶解于其中,随后加入一种pH调节剂、水和三氯蔗糖,所得溶液的pH为6.8至8.2,
其中,所述的药物制剂包含:
-5.4至13重量%的聚山梨醇酯80,
-0.005至0.05重量%的丁基羟基茴香醚,
-0.006至0.05重量%的(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮或其药学上可接受的盐,
-0.02至1重量%的三氯蔗糖,和,
-85.9至94.5重量%的物质浓度为25至200mM的缓冲溶液作为所述pH调节剂,其中,所述pH调节剂为磷酸盐缓冲盐或2-(4-(2-羟乙基)-1-哌嗪基)乙磺酸,且所述磷酸盐缓冲盐为磷酸氢二钠和磷酸二氢钠二水合物。
2.根据权利要求1所述的方法,其特征在于所述的药物制剂包含:
-10重量%的聚山梨醇酯80,
-0.02重量%的丁基羟基茴香醚,和,
-0.015重量%的(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮或其药学上可接受的盐。
3.根据权利要求1所述的方法,其特征在于所述的药物制剂包含:
-10重量%的聚山梨醇酯80,
-0.02重量%的丁基羟基茴香醚,和,
-0.015重量%的(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮。
4.根据权利要求1-3中任意一项所述的方法,其特征在于:首先加入聚山梨醇酯80作为增溶剂,然后加入丁基羟基茴香醚,随后将(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮或其药学上可接受的盐溶解于其中。
5.根据权利要求1-3中任意一项所述的方法,其特征在于:首先
-制备初级溶液(A),其包含聚山梨醇酯80和丁基羟基茴香醚,在进一步的步骤中,将(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮溶解在聚山梨醇酯80和丁基羟基茴香醚的混合物中,并将所得初级溶液(A)添加到以下溶液中,
-溶液(B),其包含磷酸盐缓冲盐、水以及三氯蔗糖,所得溶液的pH为6.8至8.2。
6.根据权利要求1-3中任意一项所述的方法,其特征在于:首先
-制备初级溶液(A),其包含聚山梨醇酯80和丁基羟基茴香醚,在进一步的步骤中,将(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮溶解在聚山梨醇酯80和丁基羟基茴香醚的混合物中,并将所得所得初级溶液(A)添加到以下溶液中,
-溶液(B),其包含2-(4-(2-羟乙基)-1-哌嗪基)乙磺酸、水以及三氯蔗糖,所得溶液的pH为6.8至8.2。
7.根据权利要求1-3中任意一项所述的方法,其特征在于:在第一步中,首先加入聚山梨醇酯80,然后加入丁基羟基茴香醚,随后将(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮溶解于其中,然后加入磷酸盐缓冲盐、三氯蔗糖和水。
8.根据权利要求1-3中任意一项所述的方法,其特征在于:在第一步中,首先加入聚山梨醇酯80,然后加入丁基羟基茴香醚,随后将(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-异丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮杂双环[3.2.1]辛-8-基)甲酮溶解于其中,然后加入2-(4-(2-羟乙基)-1-哌嗪基)乙磺酸、三氯蔗糖和水。
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