CN103261162A - 由[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]-氨基甲酸乙酯和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸制成的新型多组分晶体 - Google Patents
由[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]-氨基甲酸乙酯和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸制成的新型多组分晶体 Download PDFInfo
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Abstract
本发明涉及新型多组分晶体、其制备及其用途,用于通过同时作用于由肌肉紧张或关节变性病造成的疼痛以及由发炎过程造成的疼痛,来治疗疼痛病况,特别是不清楚缘由的疼痛。所述新型多组分晶体含有[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯(氟吡汀)和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸(双氯芬酸)作为唯一的活性成分组合,并可以通过以1.0:0.9~1.0:1.1的摩尔比将所述两种组分溶于惰性有机溶剂中并随后对所述复合化合物进行结晶而制得。
Description
本发明涉及[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸的新型多组分晶体、其制造以及其在药物制剂方面的用途。根据本发明的多组分晶体通过同时对由肌肉紧张或关节变性病造成的疼痛以及对由发炎过程造成的疼痛发挥作用而适用于治疗疼痛病况、尤其是不清楚缘由的疼痛。
[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯,也称作氟吡汀,是一种集中发挥非***样物质镇痛的药剂,其不会引发天然或合成***样物质的典型副作用如呼吸抑制、便秘、耐药性的发展、物理或生理依赖性或成瘾的风险。氟吡汀是一种能够使得增加的肌肉紧张正常化的活性成分。
氟吡汀是具有新型特定的和治疗相关的性质的新种镇痛剂的原型。在本文中,氟吡汀的作用模式不是基于直接作用,而是基于间接功能的NMDA对抗效应。该机理导致三种不同的作用原理:镇痛、减轻肌肉紧张和神经保护。氟吡汀的各种作用是单分子作用机理的结果,即氟吡汀作为选择性神经元钾通道开放剂的作用(选择性神经元钾通道开放剂=SNEPCO)(参见例如Kornhuber J等(1999);Kornhuber J等(1999a)),其代表疼痛治疗方面的新原理。
作为这些多重作用的结果,氟吡汀展示了独特和广泛的药理学作用光谱。氟吡汀适用于治疗和预防急性和慢性疼痛,包括:神经性疼痛,神经痛,由癌症疾病造成的疼痛,血管运动性头痛和偏头痛,在手术之后的、在伤害、烧伤之后的、痛经时的疼痛病况,牙痛和关节炎疼痛。
对于常规镇痛剂量,预期氟吡汀的抗炎效果仅是最小程度,因为在动物实验中仅在非常高的剂量(>30mg/kg体重)下观察到了显著的抗炎作用。在治疗和预防疼痛方面,氟吡汀主要对特别是由肌肉紧张、肌肉痉挛和肌肉僵硬造成的疼痛有效。其对于治疗背部疼痛特别有效,在所述背部疼痛中,就这种紧张造成的背部疼痛原因是发炎和/或不发炎引起的而言,无法总是在个体情况中明确确定出清晰的鉴别诊断。
马来酸氟吡汀能够与各种解痛物品如与***(EP0977736)、与神经激肽拮抗剂(WO2007/1128056)、与曲马多(EP1697005)或者还有扑热息痛(EP207193)组合。
2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸(双氯芬酸)属于非甾族消炎药(NSAIDS)类别。其非选择性抑制环加氧酶(COX)I和II,所述环加氧酶(COX)I和II用于在有机体中产生调和炎症的***素。
双氯芬酸是在轻度到中度疼痛和炎症的情况中例如在风湿病、挫伤、扭伤和关节病的情况中作为钠盐或钾盐使用的药物物质。在化学式上,其属于苯基乙酸。双氯芬酸展示了退热、镇痛、消炎和抗风湿的功效。
与氟吡汀相比,双氯芬酸也可以组合制剂的方式得到。已知的商标名为例如(双氯芬酸和米索前列醇)、(可待因和双氯芬酸)、和(双氯芬酸和维生素B的组合)、(双氯芬酸和肝素)、(双氯芬酸和邻甲苯海拉明)、(双氯芬酸和邻甲苯海拉明)、Tobrafen(双氯芬酸和托普霉素)、Voltamicin(双氯芬酸和艮他霉素)。然而,双氯芬酸与选择性钾通道开放剂(SNEPCO)的药物组合至今是未知的。
在科学出版物(Diamantis,W;Gordon,R.Postgrad Med J1987,63Suppl3(29-34))中讨论同时施用马来酸氟吡汀和各种NSAIDS。已经在非常低的剂量下(小鼠,15mg/kg;大鼠,35mg/kg),马来酸氟吡汀以与各种剂量的NSAIDS镇痛剂组合的方式提高了扑热息痛、乙酰水杨酸和双氯芬酸的镇痛(即疼痛感抑制)活性。
在DE 36 65 538中公开了氟吡汀盐与各种非甾族消炎药剂的协同组合。此处已经发现,通过与某些非甾族消炎物质的组合,惊奇地协同提高了马来酸氟吡汀的作用,其中同时消炎药剂的作用也协同提高。在这方面,作为马来酸盐、葡糖酸盐或盐酸盐使用氟吡汀。
氟吡汀盐和双氯芬酸钠的单独组分的纯物理混合物,如同在DE 3665 538.4中所公开的,展示了单独组分的不同溶解度和不同溶解速度,从而从胃肠道中不能实现均匀吸收。而且,因为活性成分的不同晶体形式和不同密度而观察到物质分离。因此,对于这些混合物不能期望具有良好生物可利用性的组分的稳定制剂。
通过活性成分与合适的第二活性成分形成多组分晶体,形成了新固体材料,其物理性质与单独组分的物理性质显著不同。其中在本文中影响的参数是溶解度、溶解速度、熔点以及粒子形状和大小。
EP 2 123 626 A1请求保护度洛西汀与适用于疼痛治疗的至少一种共晶体形成物的共晶体。度洛西汀是选择性五羟色胺-降肾上腺素再摄取抑制剂类别的活性成分并尤其用于治疗抑郁和焦虑性障碍。可提及度洛西汀和S-萘普生的共晶体为共晶体。
关于结晶和光谱性质,多组分晶体与其两种组分的纯物理混合物也不同。特别地,用于检测这些新化合物的固态性质的合适测量方法是X射线粉末衍射(XRPD)、固体核磁共振光谱(13C-CP/MAS-NMR)或者还有差示扫描量热法(DSC)。
本发明的目的是提供一种展示选择性钾通道开放剂(SNEPCO)氟吡汀的独特镇痛作用以及双氯芬酸的抑制炎症和镇痛活性的新物质,且所述新物质易于配制成药物的固体施用形式而不展示物理混合物的典型问题如不同的生物可利用性或在生产过程期间分离。
而且,所述新的药物形式应有效抵抗尤其由紧张造成的疼痛以及由发炎过程造成的疼痛,从而治疗的内科医生即使对于不清楚缘由的疼痛仍能够施用药物而不会因此使患者面临额外的不能接受的副作用。
根据本发明,通过[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯(氟吡汀)和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸(双氯芬酸)的新型多组分晶体、尤其是通过含有组分[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯(氟吡汀)和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸(双氯芬酸)作为唯一的活性成分组合的多组分晶体,实现所述目的。
在本发明的意义中,将多组分晶体理解为由中性组分或离子组分构成的晶体,其中中性组分用于结晶,但在结晶成多组分晶体期间,也会产生离子组分。由此,多组分晶体为共晶体、盐、溶剂合物或包含共晶体以及盐部分的混合形式。
在本发明的意义中,共晶体是由两种以上中性化合物构成的结晶结构。
与起始材料的纯物理混合物相比,根据本发明的多组分晶体的有利特征在于,改变的物理-化学性质,所述改变的物理-化学性质例如影响溶解度、稳定性、吸湿性、处理和片剂形成性质并有助于多组分晶体的明确表征。
惊奇地,发明人已经发现,通过对氟吡汀溶液和双氯芬酸溶液进行加热,能够形成新型的多组分晶体即[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯(氟吡汀)和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸(双氯芬酸)的共晶体,其随后在所述溶液冷却时发生结晶。这是出人意料的,因为直至现在,从羧酸类别中,仅有未支化的链烷(或链烯)羧酸制得了氟吡汀盐。即使利用结构类似的苯甲酸,也未与氟吡汀一起得到盐或共晶体。
在一个实施方案中,根据本发明的氟吡汀和双氯芬酸的多组分晶体的特征在于,在2θ=3~80℃的衍射角范围内利用0.00922°的步长宽度使用Cu Kα1辐射和Johansson锗单晶单色仪测得的X射线粉末衍射图在2θ=6.1±0.2°处具有特征峰。
优选地,多组分晶体另外的特征在于,在2θ=4.9±0.2°、7.7±0.2°和19.6±0.2°处还具有特征峰。尤其优选的是,其在2θ=11.1±0.2°、12.3±0.2°、14.6±0.2°、20.9±0.2°、22.5±0.2°、24.2±0.2°和24.8±0.2°处另外还具有特征峰。
在优选实施方案中,根据本发明的氟吡汀和双氯芬酸的多组分晶体的特征在于具有基本如图1中所示的X射线粉末衍射图。
而且,根据本发明的氟吡汀和双氯芬酸的多组分晶体的优选特征在于,具有如图2中所示的DSC(差示扫描量热法)热分析图。其在50~300℃范围内具有100~115℃范围内的特征熔化吸热峰,开始温度为96.9±2℃且最大峰值在107.2±3℃。
优选地,根据本发明的氟吡汀和双氯芬酸的多组分晶体另外的特征在于,其IR谱图(KBr小球)在3431±1cm-1、3221±1cm-1、2989±1cm-1、1688±1cm-1、1576±1cm-1、1507±1cm-1、1453±1cm-1、1381±1cm-1、1259±1cm-1、1156±1cm-1、1126±1cm-1、1069±1cm-1、832±1cm-1和776±1cm-1处具有特征峰。优选地,根据本发明的氟吡汀和双氯芬酸的多组分晶体的特征在于,其IR谱图基本与图3中的谱图类似。
优选地,氟吡汀和双氯芬酸的新型多组分晶体由等摩尔量的两种组分构成,其中由于其形成微观上均匀的化合物,所以此外最高10%、优选最高5%、尤其优选最高2%的摩尔比的最小偏差仍包括在本发明内。由此,组分的摩尔比优选在1:0.9~1:1.1的范围内,优选1:0.95~1:1.05,更优选1:0.98~1:1.02。尤其优选地,组分的摩尔比为1:1。
本发明的主题也是用于制造根据本发明的氟吡汀和双氯芬酸的多组分晶体的方法。优选地,基于该目的,将基础形式的氟吡汀与双氯芬酸一起添加至合适的惰性有机溶剂、优选非质子溶剂、尤其优选甲苯中,并在优选加热至50~80℃的温度下溶解。随后,在将溶液冷却至室温之后,使得根据本发明的氟吡汀和双氯芬酸的多组分晶体结晶为白色、细的结晶沉淀物。
本发明的主题还是一种药物制剂,其含有根据本发明的多组分晶体。
根据本发明的药物制剂含有任选混合有其他药理学活性或药物活性物质的、[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸的新型多组分晶体。以已知的方式完成药物的制造,其中可使用已知的和常规药物赋形剂以及其他常规载体和稀释剂。
用于确定根据本发明的制剂用于治疗和预防目的的有效施用量的方法对于本领域技术人员是已知的。为了能够使用根据本发明的制剂的镇痛效果(尤其是通过影响肌肉紧张疼痛)以及抗炎效果,施用50mg~1000mg、优选200mg~800mg的日用剂量。
根据本发明的[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸的新型多组分晶体,由于其物理性质,从而在其草本制剂加工(galenic processing)成固体药物形式的方面具有惊奇的性质。利用根据本发明的新多组分晶体,避免了基础化合物(例如马来酸盐、盐酸盐、甲磺酸盐等)以及酸组分(例如钠或钾)的药物非活性组分,所述非活性组分通常存在于纯物理混合物中,有利地,在固体口服施用形式的情况中,这导致施用的量下降且施用形式所需要的体积下降。多组分晶体的均一形状也有利地防止了组分在加工期间的分离并以此方式有助于其确切剂量。
每天可以施用1~5次、优选1~3次、优选2次的施用单位。
能够以药理学或医学已知的各种方式如通过口服、肠胃外、腹膜内、静脉内、舌下、肌肉内、直肠、透皮、皮下、脂肪内(intraadiposally)、关节内或鞘内来施用根据本发明的药物制剂。优选口服施用药物制剂。
用于口服施用的合适施用形式包括片剂、泡腾片、囊、软胶囊、丸、粉末、颗粒、小球等。
活性成分从根据本发明的药物制剂中的释放能够快速发生或延缓发生。
作为药学可接受的载体或填料,可以使用各种常规赋形剂如纤维素衍生物、淀粉衍生物、乳糖、甘露糖醇、右旋糖、蔗糖、碳酸钙、氧化镁、硬脂酸镁、滑石、淀粉、明胶、***胶等或常规惰性溶剂。
固体施用形式任选地包含另外的常规赋形剂如助流剂、结合剂、填充剂(例如二氧化硅、特别是多孔无定形二氧化硅“Syloid”,卡波姆、瓜尔胶、纤维素、微晶纤维素、纤维素醚、纤维素酯、聚乙烯吡咯烷酮以及共聚维酮)、释放剂、润滑剂、崩解剂(例如交联的聚乙烯吡咯烷酮、羧甲基淀粉钠、羧甲基纤维素钠、淀粉、交联羧甲基纤维素钠、交聚维酮、瓜尔胶、primogel)、抗氧化剂、调味剂、染料、助溶剂(例如环糊精和环糊精衍生物)和/或乳化剂(例如卵磷脂、果胶)。
固体施用形式能够涂布有蔗糖、纤维素衍生物、聚丙烯酸酯衍生物、邻苯二甲酸酯衍生物或其他合适物质,或者可以对所述固体施用形式进行处理以使其具有延长的或延缓的作用以使其连续释放预定量的活性成分。
因此,本发明还包含药物制剂,所述药物制剂的特征是具有充当延缓组分的聚合物膜涂层并任选地含有释放剂、结合剂、颜料或其他药物赋形剂。优选地,聚合物膜涂层包含至少一种选自下列的聚合物:甲基丙烯酸、甲基丙烯酸酯(例如和/或)、丙烯酸酯和甲基丙烯酸酯的共聚物、丙烯酸和甲基丙烯酸的共聚物及其酯、或其混合物。
通过溶解或悬浮,也能够得到适用于输注或注射的液体制剂。
作为非水溶剂,例如能够使用丙二醇、聚乙二醇和/或有机酯如油酸乙酯。油的实例为石油以及动物、植物或合成油如花生油、蓖麻油、芝麻油、棉籽油、玉米油、麦芽油、大豆油、矿物油、橄榄油、向日葵籽油或肝油、尤其是鱼肝油。
通过与非水溶剂或油混合,能够得到能够特别地填充入软胶囊中的粘稠到半固体的制剂。这些囊,尽管其具有100~800mg的相对高的活性成分含量,但因为其弹性包膜和内容物的稠度而易于吞咽。
关于根据本发明的、活性成分氟吡汀和双氯芬酸的新型多组分晶体,已经发现,二醇衍生物如二乙二醇单乙基醚或聚乙二醇、表面活性剂如甘油衍生物以及增稠剂如聚乙烯吡咯烷酮的混合物是用于软胶囊制剂的合适载体物质。中性助溶剂(分散剂和表面活性剂)如甘油酯(也称作聚氧甘油酯)、辛酰己酰(caprylocaproyl)聚亚烃基二醇醚、或糖酯可稳定并匀化具有根据本发明的活性成分的混合物。
由于根据本发明的、活性成分氟吡汀和双氯芬酸的新型多组分晶体的极性小,所以液体到半固体的制剂也适用于透皮施用,与组分马来酸氟吡汀和双氯芬酸钠的混合物形成鲜明对比。对于根据本发明的、活性成分氟吡汀和双氯芬酸的多组分晶体,特别适合作为载体的是包含卡波姆、一种或几种脂肪酸酯、聚乙二醇和一种或几种低分子量醇的混合物。
惊奇地,根据DE 19 705 555 A1中公开的方法,通过将活性成分与多孔无定形二氧化硅混合,能够得到粒状材料,能够将其压制成具有高达600mg活性成分的片剂而无问题。在本发明的一个实施方案中,在片剂中含有根据本发明的、活性成分氟吡汀和双氯芬酸的多组分晶体,所述片剂优选还含有药学可接受的填料如无定形二氧化硅。优选地,在一个药片中,基于片剂的总重量,含有0.5~8%的多孔无定形二氧化硅。
利用DE 36 65 538中公开的方法通过动物模型能够表现两种组分氟吡汀和双氯芬酸的协同作用。将其中公开的方法并入本文中以作为参考。
在疼痛和炎症模型中利用根据本发明的共晶体(盐)获得的效果与DE 36 65 538的试验结果在定性上具有可比性。结合制剂的优势,根据本发明的、活性成分氟吡汀和双氯芬酸的多组分晶体比单独组分的纯物理混合物明显优异。
另外,本发明的一方面是根据本发明的多组分晶体的用途,用于治疗和预防急性和慢性疼痛,只要是尚未排除炎性成分的疼痛,包括:神经性疼痛,背部疼痛,神经痛,由纤维性肌痛造成的疼痛,血管运动性头痛和/或偏头痛或紧张造成的头痛,在手术之后的、在伤害、烧伤、化学烧伤之后的、痛经时的疼痛病况,预防肌肉紧张,牙痛和关节炎疼痛。优选的施用持续时间为1~2天至6周。
利用有利的组合作用以抵抗非炎症造成的疼痛(例如肌肉紧张造成的疼痛)和炎症疼痛,新活性成分特别适用于治疗肌骨骼***包括背部不清楚缘由的疼痛,因为此处,如同已知的,发炎过程和肌肉紧张发生的特别频繁。
例如,在例如具有约50~800mg的总重量下能够制造不同大小的片剂。其含有上述量的复合活性成分以及常规载体和/或稀释剂和/或赋形剂。还能够提供这些片剂用于施用部分剂量。以类似方式,例如还能够配制其他制剂如明胶胶囊或延缓形式。
为了快速溶解作用和改善的生物可利用性,还可以以软胶囊形式施用根据本发明的、活性成分氟吡汀和双氯芬酸的新型多组分晶体。此处,活性成分均匀分布即悬浮、溶解或部分溶解在软凝胶基质中。尽管存在其他成分,但这些囊因为其软壳而仍易于吞咽。
根据附图和实施方案,对本发明进行更详细地说明,但不限制本发明。
在附图中显示了:
图1是氟吡汀和双氯芬酸的多组分晶体的X射线粉末衍射图;
图2是比较方式的双氯芬酸、氟吡汀以及氟吡汀和双氯芬酸的多组分晶体的X射线粉末衍射图;
图3是氟吡汀和双氯芬酸的多组分晶体的DSC(差示扫描量热法)热分析图;
图4是根据本发明的、活性成分氟吡汀和双氯芬酸的多组分晶体的IR谱图;
图5是根据本发明的、活性成分氟吡汀和双氯芬酸的多组分晶体的1H NMR谱图;以及
图6是根据本发明的、活性成分氟吡汀和双氯芬酸的多组分晶体的13C CPMAS NMR谱图。
实施方案
实施例1:制备[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸的根据本发明的多组分晶体
在氩气气氛下,将12.0g的[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯(氟吡汀)和11.8g的2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸(双氯芬酸)添加至500ml的甲苯中,将混合物加热至60℃并在60℃下进一步保持30分钟。在冷却至20℃之后,将溶液静置过夜。在该时间期间内,形成白色细结晶沉淀物。将后者过滤出并在真空中干燥12小时。
作为产物,得到了15.7g(66%)白色晶体针状物。所述产物在101~103℃的温度下熔化。
通过IR谱图(图4)和1H NMR谱图(DMSO-d6,400MHz)(图5)确认了多组分晶体的结构。
实施例2:利用X射线粉末衍射对多组分晶体进行分析
利用Bruker AXS公司的D8Advance粉末衍射仪对根据实施例1得到的化合物实施X射线粉末衍射分析,将所述衍射仪的规格和测量参数示于下表中。
表1:用于X射线粉末衍射的仪器规格和测量参数
将以此方式确定的X射线粉末衍射图示于图1中。将多组分晶体的衍射图与用于其制备的组分[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸的衍射图的比较示于图2中。
将根据实施例1得到的氟吡汀和双氯芬酸的多组分晶体的X射线粉末衍射图的信号位置示于表2中。
表2:根据实施例1的氟吡汀-双氯芬酸的X射线粉末衍射谱图的信号位置
2θ/° | 相对强度/% |
4.90 | 47 |
6.14 | 67 |
7.67 | 38 |
11.06 | 33 |
12.29 | 28 |
14.56 | 40 |
19.55 | 38 |
20.85 | 24 |
22.48 | 46 |
24.23 | 48 |
24.75 | 39 |
实施例3:利用DSC(差示扫描量热法)对多组分晶体进行分析
表3:用于DSC(差动量热法)的仪器规格和测量参数
通过NETZSCH公司的程序Proteus(版本4.8.5)对热分析图进行了评估。将得到的热分析图示于图3中。
实施例4:利用13C CP/MAS NMR对多组分晶体进行分析
在100.62MHz的13C共振频率下在Avance400(companyBRUKER,Rheinstetten)上测量得到所有谱图。在测量期间,试样在10.0kHz的旋转频率(“魔角自旋”,MAS)下在4mm双共振试样头中旋转。关于CP实验(“横向极化”,CP),使用5.23μs的1H90°脉冲和10ms的持续时间接触脉冲。谱图的宽度为250ppm(25252Hz)。
对具有5.0s重复速率的13000个FID进行了累积。在这方面,记录了1600个数据点并以16384个总点数进行傅里叶变化(“零点充满”)。
化学位移与四甲基硅烷(TMS,sTMS=0.0ppm)相关。作为参考,在各次实验之后,对作为第二外部标准的金刚烷进行测量(S金刚烷=28.72,37.77ppm)。
将多组分晶体的以及起始组分[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸的13CCP/MAS NMR谱图示于图6中。
实施例5:含有150mg根据本发明的[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸的多组分晶体的软胶囊
Claims (15)
1.多组分晶体,其特征在于,其由[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯(氟吡汀)和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸(双氯芬酸)构成。
2.如权利要求1所述的多组分晶体,其中[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯与2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸的摩尔比为0.9:1.0~1.1:1.0。
3.如权利要求1或2所述的多组分晶体,其特征在于,其X射线粉末衍射图在2θ=6.1±0.2°处具有特征峰。
4.如权利要求3所述的多组分晶体,其另外的特征在于,其X射线粉末衍射图在2θ=4.9±0.2°、7.7±0.2°和19.6±0.2°处具有特征峰。
5.如权利要求3或4所述的多组分晶体,其另外的特征在于,其X射线粉末衍射图在2θ=11.1±0.2°、12.3±0.2°、14.6±0.2°、20.9±0.2°、22.5±0.2°、24.2±0.2°和24.8±0.2°处具有特征峰。
6.如权利要求1~5中任一项所述的多组分晶体,其特征在于,其DSC热分析图在100~115℃的范围内具有熔化吸热峰,开始温度为96.9±2℃且最大峰值在107.2±3℃。
7.用于制备权利要求1~6中任一项的多组分晶体的方法,所述方法包括如下步骤:
a)以1.0:0.9至1.0:1.1的摩尔比将[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]氨基甲酸乙酯和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸溶于惰性有机溶剂中;以及
b)对所述复合化合物进行结晶。
8.药物制剂,其包含权利要求1~6中任一项的多组分晶体作为活性成分组合。
9.根据权利要求8的药物制剂,其为软胶囊的形式。
10.透皮药物制剂,其包含权利要求1~6中任一项的多组分晶体作为活性成分。
11.如权利要求8或9所述的口服药物制剂或如权利要求10所述的透皮药物制剂,其中所述药物制剂在每施用单位中含有50~1000mg的权利要求1~6中任一项的多组分晶体作为活性成分。
12.权利要求1~6中任一项的多组分晶体、权利要求8或9的口服药物制剂和/或权利要求10的透皮药物制剂的用途,用于治疗和预防急性和慢性疼痛,包括:神经性疼痛,神经痛,由癌症疾病造成的疼痛,紧张性头痛,血管运动性头痛和偏头痛,在手术之后的、在伤害、烧伤、化学烧伤之后的、痛经时的疼痛病况,牙痛和关节炎疼痛,以及用于治疗炎症疼痛或不清楚缘由的疼痛。
13.权利要求1~6中任一项的多组分晶体、权利要求8或9的口服药物制剂和/或权利要求10的透皮药物制剂的用途,用于治疗和预防肌肉紧张、肌肉痉挛和肌肉僵硬,尤其是用于治疗不清楚缘由的背部疼痛。
14.权利要求1~6中任一项的多组分晶体、权利要求8或9的口服药物制剂和/或权利要求10的透皮药物制剂的用途,用于同时治疗由不同原因造成的疼痛,特别是炎性疼痛和由肌肉紧张造成的疼痛。
15.制备药物制剂的方法,所述方法包括将权利要求1~6中任一项的复合化合物与基于二醇、助溶剂和赋予粘度的试剂如PVP的溶剂混合并将混合物引入软明胶胶囊中。
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DE102010063612.6 | 2010-12-20 | ||
DE102010063612A DE102010063612A1 (de) | 2010-12-20 | 2010-12-20 | Neue Multikomponentenkristalle aus ([2-Amino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-carbamidsäureethylester und 2-[2-[(2,6-Dichlorphenyl)-amino]-phenyl]-essigsäure |
PCT/EP2011/073441 WO2012084975A1 (de) | 2010-12-20 | 2011-12-20 | Neue multikomponentenkristalle aus ([2-amino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-carbamidsäureethylester und 2-[2-[(2,6-dichlorphenyl)-amino]-phenyl]-essigsäure |
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CN103261162A true CN103261162A (zh) | 2013-08-21 |
CN103261162B CN103261162B (zh) | 2016-06-15 |
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CN201180061511.9A Expired - Fee Related CN103261162B (zh) | 2010-12-20 | 2011-12-20 | 由[2-氨基-6-(4-氟-苯甲基氨基)-吡啶-3-基]-氨基甲酸乙酯和2-[2-[(2,6-二氯苯基)-氨基]-苯基]乙酸制成的新型多组分晶体 |
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US (1) | US9149468B2 (zh) |
EP (2) | EP2655328B1 (zh) |
CN (1) | CN103261162B (zh) |
CA (1) | CA2821311A1 (zh) |
DE (1) | DE102010063612A1 (zh) |
EA (1) | EA022016B1 (zh) |
ES (1) | ES2563210T3 (zh) |
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WO (1) | WO2012084975A1 (zh) |
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DE102010063609A1 (de) * | 2010-12-20 | 2012-06-21 | Awd.Pharma Gmbh & Co. Kg | Neue Multikomponentenkristalle aus ([2-Amino-6-(4-fluoro-benzylamino)-pyridin-3yl)-carbamidsäureethylester und einer Arylpropionsäure |
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US4778799A (en) * | 1985-01-23 | 1988-10-18 | Ulrich Tibes | Synergistic combination of flupirtin and non-steroidal antiphlogistic |
CN1917876A (zh) * | 2003-12-16 | 2007-02-21 | Cns生物有限公司 | 方法和组合物 |
EP2123626A1 (en) * | 2008-05-21 | 2009-11-25 | Laboratorios del Dr. Esteve S.A. | Co-crystals of duloxetine and co-crystal formers for the treatment of pain |
WO2009152142A1 (en) * | 2008-06-09 | 2009-12-17 | Awd. Pharma Gmbh & Co. Kg | Sulfonate salts of flupirtine |
Family Cites Families (7)
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DE3601195A1 (de) | 1985-01-23 | 1986-07-24 | Degussa Ag, 6000 Frankfurt | Synergistische kombination von flupirtin und nicht-steroidalen antiphlogistika |
FI855016A (fi) | 1985-06-28 | 1986-12-29 | Degussa | Synergistisk kombination av flupirtin och 4-acetamido-fenol. |
DE19705555A1 (de) | 1997-02-13 | 1998-08-20 | Ulrich Dr Posanski | Pharmazeutische Präparate der Thioctsäure zur oralen Anwendung |
DE19716984A1 (de) | 1997-04-23 | 1998-10-29 | Asta Medica Ag | Verfahren zur Herstellung von reinem Flupirtin-Maleat und dessen Modifikation A |
US7553858B2 (en) | 2003-12-17 | 2009-06-30 | Meda Pharma Gmbh & Co. Kg | Combination of flupirtine and tramadol |
JP2009535364A (ja) | 2006-05-03 | 2009-10-01 | シーエヌエスバイオ ピーティーワイ リミテッド | 炎症性疼痛の治療のための方法および組成物 |
US8183267B2 (en) * | 2008-06-09 | 2012-05-22 | Awd. Pharma Gmbh & Co. Kg | Carboxylic acid salts of 2-amino-3-carbethoxyamino-6-(4-fluoro-benzylamino)-pyridine |
-
2010
- 2010-12-20 DE DE102010063612A patent/DE102010063612A1/de not_active Withdrawn
-
2011
- 2011-12-20 EA EA201300601A patent/EA022016B1/ru not_active IP Right Cessation
- 2011-12-20 US US13/992,247 patent/US9149468B2/en not_active Expired - Fee Related
- 2011-12-20 CA CA2821311A patent/CA2821311A1/en not_active Abandoned
- 2011-12-20 EP EP11805489.9A patent/EP2655328B1/de not_active Not-in-force
- 2011-12-20 WO PCT/EP2011/073441 patent/WO2012084975A1/de active Application Filing
- 2011-12-20 ES ES11805489.9T patent/ES2563210T3/es active Active
- 2011-12-20 CN CN201180061511.9A patent/CN103261162B/zh not_active Expired - Fee Related
- 2011-12-20 PL PL11805489T patent/PL2655328T3/pl unknown
- 2011-12-20 EP EP15194938.5A patent/EP3020705A1/de not_active Withdrawn
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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US4778799A (en) * | 1985-01-23 | 1988-10-18 | Ulrich Tibes | Synergistic combination of flupirtin and non-steroidal antiphlogistic |
CN1917876A (zh) * | 2003-12-16 | 2007-02-21 | Cns生物有限公司 | 方法和组合物 |
EP2123626A1 (en) * | 2008-05-21 | 2009-11-25 | Laboratorios del Dr. Esteve S.A. | Co-crystals of duloxetine and co-crystal formers for the treatment of pain |
WO2009152142A1 (en) * | 2008-06-09 | 2009-12-17 | Awd. Pharma Gmbh & Co. Kg | Sulfonate salts of flupirtine |
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EP2655328B1 (de) | 2015-11-18 |
WO2012084975A1 (de) | 2012-06-28 |
EP2655328A1 (de) | 2013-10-30 |
US9149468B2 (en) | 2015-10-06 |
US20130261157A1 (en) | 2013-10-03 |
DE102010063612A1 (de) | 2012-06-21 |
CN103261162B (zh) | 2016-06-15 |
EP3020705A1 (de) | 2016-05-18 |
EA201300601A1 (ru) | 2013-09-30 |
EA022016B1 (ru) | 2015-10-30 |
ES2563210T3 (es) | 2016-03-11 |
PL2655328T3 (pl) | 2016-07-29 |
CA2821311A1 (en) | 2012-06-28 |
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