CN101022800B - 用于治疗骨折的药物组合物 - Google Patents
用于治疗骨折的药物组合物 Download PDFInfo
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- CN101022800B CN101022800B CN2005800225540A CN200580022554A CN101022800B CN 101022800 B CN101022800 B CN 101022800B CN 2005800225540 A CN2005800225540 A CN 2005800225540A CN 200580022554 A CN200580022554 A CN 200580022554A CN 101022800 B CN101022800 B CN 101022800B
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- fracture
- bone
- benzamidine
- callus
- acid
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Abstract
本文中公开的是治疗骨折的组合物,包括作为医学上有效成分的N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒或其药物学上可接受盐。本发明的组合物可以显著减少骨痂体积,增加骨痂的骨密度和强度,并降低骨痂中结缔组织和软骨组织的含量,从而促进在骨折愈合过程中形成的骨痂的减少和骨化。因此,本发明的组合物对于骨折治疗是有用的。
Description
技术领域
本发明一般地涉及用于治疗骨折的药物组合物,并且更具体地涉及包括N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒或药物学上可接受盐的药物组合物。
背景技术
骨折是在骨中的折断或裂缝,带有骨、骺板或关节面的连续性的完全或不完全中断。骨折主要由一些类型的骨创伤造成。该创伤可能作为机动车事故、工作场所中的事故、身体虐待、重复性压迫例如训练、举重等的结果而发生。正常的日程活动可能导致患有削弱骨的疾病的人骨折,所述疾病例如骨质疏松症、骨癌或代谢异常。根据骨折线(fracture line)(骨折后产生的沿骨骺末端的线),骨折可以被分成线性骨折、青枝骨折、横骨折、斜骨折、螺旋形骨折、节段性骨折、粉碎性骨折、扭伤骨折、受压骨折、凹陷骨折等等。
通常,在骨折后,血管损伤发生,导致局部出血和血块。另外,骨折部位周围的骨基质断裂或破裂,伴有骨细胞死亡。因此,在骨折愈合过程期间,在骨折部位周围的骨外膜(perilsteum)和骨内膜的骨原细胞增生活跃以在骨折部位附近形成细胞组织以及随后与骨折部位整合的同时,血块和受损骨细胞和骨基质被巨噬细胞除去。在骨折部位的结缔组织中,骨组织通过小的软骨片段(small cartilage fragment)的软骨骨化而生成,或者未成熟骨通过膜内骨化被形成。因此,间充组织的膜内骨化和软骨骨化在骨折部位的结缔组织中被同时观察到。以这种方式不规则形成的未成熟骨的小梁临时连接到折断的骨片段的末端,导致骨痂的形成。在骨折部位中形成的骨痂的编织骨随着愈合过程的进展逐渐被再吸收,并经受重排,导致板层骨发育。
通常,骨折愈合主要被分成3个阶段:炎性期、骨修复期和重建期。
在炎性期中,由于骨折部位附近的组织被损伤以及血肿充满骨折间隙,炎症应答发生。
在骨修复期中,在软痂形成的同时,血肿从骨折间隙被除去并被肉芽组织取代。根据成骨机理,两个过程同时进行:软骨骨化,其中软痂被重建成硬痂,和纤维/膜内骨化,其中通过骨原细胞形成新骨。
在重建期中,新形成的骨组织通过破骨细胞骨吸收和成骨细胞骨形成的协调作用在长期的时间内被延伸,伴有骨畸形的修正和骨缺陷的加固。
在重建期中,骨折病人的生活无大的困难,因为新形成的骨已经变硬到某种程度,但在修复期中的新生骨组织尚不硬到足以使病人毫无困难地进行日常生活。另外,修复期是长期的。因此,具有通过促进复杂的骨折愈合过程缩短修复期以及使折断的骨再生成完整骨的功能对于骨折治疗在临床上是重要的。
存在许多骨折愈合的促进剂.具有生理活性功能的肽,例如骨形态发生蛋白(BMPs)和转化生长因子(TGFs),被发现与骨折愈合过程有关(Proc.Natl.Acad.Sci.,USA,vol.87,pp.2220-2224(1989)).同样,经研究,利用磷酸二酯酶(phosphodiesterase,PDE)抑制剂提高细胞内环AMP水平可以导致骨量增加.例如,据报道,每天皮下注射通用PDE抑制剂pentoxipylline或选择性PDE4抑制剂咯利普兰(rolipram)的小鼠被观察到具有提高的骨无机质密度的脊椎和股骨,并显示了骨皮质增生(Bone,vol.27.,第6版,pp.811-817(2000)).
如上所述,骨发生和骨折愈合受到长期关注,并且从多个角度对骨折愈合过程进行了广泛的研究,包括遗传因子、青春期影响、造血效应、固定装置影响、骨移植、其它愈合促进因子等等(Kawamura,M和Urist MR.,Clin.Orthop.,236,240-248,1988)。
骨折愈合要求显著的一段时间,并且由于老年人口的增加,骨质疏松症病人往往更多地经受骨折。缺乏在骨折愈合中的有用性的期望,目前可得的治疗骨质疏松症的治疗剂,例如钙、雌激素、降钙素、活性维生素D、双磷酸盐等等,被发现仅仅通过阻止骨密度降低来降低骨折风险,但没有连接折断的骨或生成骨组织的功能。骨质疏松的致病机理可以由长期保持负骨稳态(negative bone homeostasis)导致的稀薄骨基质来解释,该负骨稳态是由于遗传或体质性素因、具有正常骨吸收的骨形成停滞、以及具有正常骨形成的增加的骨吸收。因此,治疗骨质疏松症的治疗剂对于骨折的治疗无效,因为治愈机理在骨折和骨质疏松之间有相当不同。
由于骨折和骨质疏松之间的机理差异,具有抑制骨吸收的功能的抗骨质疏松剂,可以阻止骨形成,因而实际上延迟了骨折愈合过程。例如,双磷酸盐剂因卡膦酸二钠被报道延迟施用该因卡膦酸二钠大鼠的股骨的骨折愈合(Li C et al.,J.Bone Miner Res.2001Mar;16(3):429-36)。还存在报道,描述了尽管用因卡膦酸盐的预处理对于骨折愈合无影响直至骨折后16周,但是用因卡膦酸盐的连续治疗增加了骨痂,但导致重建过程的延迟(Li J et al.,J.Bone Miner Res.1999Jun;14(6):969-79)。
bFGF,已知为与骨质疏松高度相关的骨形成生物标记,被报道为与骨折愈合没有关系(Xu et al.,Chin.J.Traumatol.6,160-166,2003)。
由于这些理由,目前可得的骨质疏松治疗剂不适合应用于骨折。因此,存在对骨折药物的紧迫需求,所述骨折药物对骨折具有大的治疗效果,而不管与骨质疏松的关联。
由本发明人进行的对骨折愈合广泛和深入的研究导致了本发明,发现了N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒和4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒,其已由本发明人开发成治疗骨质疏松的药剂(Korean Pat.Unexamined Publication No.10-2003-8654),可以增强在骨折愈合过程中形成的骨痂的骨密度和强度并且促进结缔组织中的软骨骨化和膜内骨化,因此尽管骨质疏松和骨折机理之间巨大的差异仍展现出对骨折的优良愈合效果。
发明内容
因此,紧记在现有技术中发生的上面的问题,作出了本发明,本发明的一个目标是提供治疗骨折的药物组合物,其包括N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒、4-{5-[4-(5--异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒及其药物学上可接受盐。
本发明的另一个目标是提供使用该组合物治疗骨折的方法。
附图说明
图1是光学显微照片,显示了骨折诱导后取出的用Masson氏三色染色的第8根肋骨的切片组织样本。
优选实施方式
本发明涉及治疗骨折的药物组合物,包括由下面的化学式1表示的苄脒化合物或其药物学上可接受盐。
化学式1
其中,R是氢原子或羟基基团。
化学式1的苄脒化合物可以以本领域中已知的药物学可接受盐的形式被使用。用药物学可接受的自由酸制备的酸加成盐是优选的。适合在本发明中使用的自由酸可以是无机酸或有机酸。无机酸的例子包括盐酸、溴酸、硫酸、磷酸等等,而有机酸的例子可以是柠檬酸、乙酸、乳酸、酒石酸、富马酸、蚁酸、丙酸、草酸、三氟乙酸、甲磺酸、苯磺酸、马来酸、苯甲酸、葡糖酸、乙醇酸、琥珀酸、4-吗啉代乙磺酸、樟脑磺酸、4-硝基苯磺酸、羟基-O-磺酸、4-甲苯磺酸、半乳糖醛酸、扑酸、谷氨酸和天冬氨酸。
化学式1的苄脒化合物可以根据已知的方法制备(Lee,Sung-Eun,Synthesis and Biological Activity of Natural Products and Designed NewHybrid Compounds for the Treatment of LTB4Related Disease,BusanNational University,博士学位论文,1999.8)。
本文中所使用的术语“骨折”是指骨的多种物理损伤的一种,基于骨的连续性的完全或不完全中断;其根据解剖位置(骨骺、骨骺端、骨干、关节内、近端、中段、远端等)、骨折程度(完全、不完全)骨折方向(横向、斜向、螺旋形、纵向)、开放伤口的存在(开放、封闭)、骨折数(单纯性、线性、节段式、粉碎性等)、骨折稳定性(稳定、不稳定)、骨折移位等来分类。
相比于未治疗组,用根据本发明的化学式1的苄脒化合物治疗的组被发现具有剂量依赖模式的体积上显著降低的骨痂,但具有剂量依赖模式的骨密度和骨强度的增加,具有显著性(p<0.01或p<0.05)。
与未治疗相比,用化学式1的苄脒化合物治疗使得在显著提高骨组织含量的同时显著减少结缔组织和软骨组织中的骨痂(p<0.01或p<0.05)。结缔组织和软骨组织中的减少和骨组织中的增加都是剂量依赖性的。
另外,与未治疗相比,在骨折愈合过程的早期中,在用化学式1的苄脒化合物治疗后骨痂中的破骨细胞数显著增加(p<0.01),并且该增加模式是剂量依赖的。
在骨折愈合过程的后期中,与未治疗组相比,用化学式1的苄脒化合物治疗的组具有破骨细胞数显著降低的骨痂(p<0.01),其表明骨化已经进展到一定程度.
总之,化学式1的苄脒化合物是骨折的有效药物,具有促进在骨折愈合过程中形成的骨痂的降低和骨化的功能。更详细地,本发明的苄脒化合物在骨折愈合过程的早期中增加骨痂的细胞成分并且在骨折愈合过程的后期中促进软骨骨化和膜内骨化。
本发明的组合物可以进一步包括至少一种与化学式1的苄脒化合物或其药物学上可接受盐有等价或相似功能的有效成分。
本发明的组合物可以进一步包括一种或更多药物学可接受载体。适当的载体可以选自盐水、无菌水、Ringer’s溶液、缓冲盐溶液、葡萄糖溶液、麦芽糖糊精溶液、甘油、乙醇及其组合,并且如果必要的话,可以进一步补充其它通常的添加剂例如抗氧化剂、缓冲液、稳定剂(static agent)等。与稀释剂、分散剂、表面活性剂、粘结剂和润滑剂结合,本发明的组合物还可以被配制成可注射剂型例如水溶液、悬液、乳液等,药丸,胶囊,颗粒和片剂。而且,取决于成分或疾病的类型,可以使用本领域已知的或在Remington′s PharmaceuticalScience((最新版),Mack Publishing Company,Easton PA)中公开的方法制备该制剂。
根据目的,本发明的组合物可以口服或胃肠外给药(例如静脉内、皮下、腹内或局部)。本发明的组合物的剂量根据体重、年龄、性别、健康状态、饮食、给药时间周期、给药途径、排泄速度、疾病严重程度等变化。当所有这些因素都被考虑,化学式1的苄脒化合物以1天约10至1,000mg/kg的剂量给药一次或许多次,并且更优选1天约50至500mg/kg的剂量。
对于骨的物理损伤包括骨折的预防和治疗,本发明的组合物可以被单独使用或与外科手术、激素治疗、化疗和/或生物应答控制剂结合使用。
通过下面的实施例可以获得对本发明更好的理解,这些实施例被描述是为了举例说明,而不被解释成对本发明的限制。
实施例:在肋骨骨折诱导大鼠模型中促进骨折愈合的效应
测定化学式1的苄脒化合物对经受肋骨骨折的大鼠模型中的骨折的疗效。从肋骨骨折诱导2天后开始,该苄脒化合物的给药被持续1、2、3和4周。观察体重、体重增加、骨痂体积、骨密度、骨强度以及骨组织病理学中的变化。
1.实验动物和饲养管理
使总共80只S.D.大鼠(10周龄,BioGenomics,Korea)在被用于试验之前适应实验室环境12天。当以2只或3只的密度被置于塑料笼中时,实验动物在受控温度(20至25℃)和湿度(30至35%)下被保持在饲养室中。在12小时的光暗周期下,大鼠被允许自由获得饲料和自来水。
2.样品的制备和给药
10mg和50mg N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒被完全溶解在5ml无菌蒸馏水中。从外科手术的第2天起,该溶液中的苄脒化合物以每kg体重10mg和50mg的剂量1天1次口服给药1、2、3和4周。
3.肋骨骨折的诱导
所有的实验动物都用盐酸酮胺和盐酸甲苯噻嗪麻醉,并经受诱导在第8根和第9根肋骨上的骨折的手术.在这点上,所述肋骨用手术刀横向切断.在骨折诱导后,折断的肋骨被装配,以互相对准,并且伤口腔通过皮肤缝合被封闭.
4.体重和体重增加的变化
在手术前1天、手术日、给药日以及给药后7、14、21和28天时测量所有实验动物的体重。为了减少由于饲料摄入引起的个体间差异,所有实验动物在测量日被禁食18小时或更长。同样,为了使个体动物的体重变化的差异最小化,计算从手术日至给药后7、14和28天的时期中的体重增加。
结果在下面的表1中给出。
表1
如表1可见,在所有的实验周期内没有观察到体重增加的显著变化,表明几乎没有可归因于实验材料的施用或实验动物间的个体差异的误差。
5.骨痂体积
在处死日,在折断的第8和第9根肋骨周围形成的骨痂被与相邻的组织分离并从所有的实验动物中取出。测量被摘出的骨痂以毫米计的长直径和短直径。使用下面的数学式1从测量值计算出骨痂的体积。
式1
骨痂体积=1/2×(a×b2)
a:骨痂的长直径,
b:骨痂的短直径。
结果在下面的表2中给出。
表2
*:与对照相比的显著性(p<0.01)
如从表2明显可见的,相比于未治疗对照组,在苄脒化合物给药组中,骨折愈合的骨痂的体积以剂量依赖模式显著减小(p<0.01).
因此,化学式1的苄脒化合物被发现促进在骨折愈合过程中形成的骨痂的减少。
6.组织病理学观察
在骨折诱导后摘出的第8根肋骨在10%中性福尔马林中被固定,随后通过用新鲜溶液1天更换1次脱钙溶液(2.24%甲酸,0.5N氢氧化钠)脱钙5天。在脱钙完成后,肋骨被嵌入石蜡中。石蜡包埋的组织以3至4um的厚度被切片,用苏木素-伊红或Masson’s三色染色并通过光学显微镜观察。
结果在图1中给出。
如图1所示,相对于未治疗组,苄脒化合物给药组被发现在所有给药时间期间内在骨痂中具有增加的骨组织,并且骨组织的增加行为被观察到是剂量依赖的。
因此,化学式1的苄脒化合物可以促进骨折后形成的骨痂中的骨形成。
使用Analysis Image处理系统(SIS Germany),从上面制备的肋骨组织样本,检测骨痂中结缔组织、软骨和骨组织的量,并在下面的表3至5中被表示为百分比。
而且,使用Analysis Image处理系统(SIS Germany)测量骨痂中破骨细胞数,尤其是在骨折表面上的200μm2的面积内的细胞数,在所述表面处软骨固化开始发生。
结果在下面的表6中给出。
表3
*:与对照相比显著性(p<0.01)
**:与对照相比显著性(p<0.05)
在表3中可见,相比于未治疗组,苄脒化合物给药组剂量依赖性地显著降低了骨痂组织中的结缔组织含量(p<0.01或p<0.05)
结果,化学式1的苄脒化合物被鉴定为可以促进骨折后形成的骨痂内骨组织取代结缔组织,即骨化。
表4
*:与对照相比显著性(p<0.01)
如从表4明显可见,相比于未治疗组,在苄脒化合物给药组中,骨痂组织内的软骨组织以剂量依赖模式被显著降低(p<0.01)。
因此,化学式1的苄脒化合物被鉴定为可以促进骨折后形成的骨痂内骨组织取代软骨组织,即软骨骨化。
表5
*:与对照相比显著性(p<0.01)
**:与对照相比显著性(p<0.05)
如从表5中可见,相比于未治疗组,在苄脒化合物给药组中,骨痂内的骨组织以剂量依赖模式被显著增加(p<0.01或p<0.05)。
因此,化学式1的苄脒化合物被鉴定为可以促进在骨折愈合过程期间形成的骨痂的骨化。
表6
*:与对照相比显著性(p<0.01)
从表6可见,在骨折愈合过程的早期中,相比于非治疗组,在苄脒化合物给药组中,骨痂中破骨细胞的数量显著增加(p<0.01),并且破骨细胞的数量被发现随着剂量增加而增加.因此,化学式1的苄脒化合物的给药导致在骨折愈合过程的早期中骨痂内细胞成分的剂量依赖性增加.
在骨折愈合过程的后期中,相比于未治疗组,用化学式1的苄脒化合物治疗的组具有破骨细胞数显著减少的骨痂,这表明骨化已经进行到一定程度。
总之,化学式1的苄脒化合物作为骨折药物是非常有用的,具有促进骨折后形成的骨痂骨化的功能。
7.骨痂的骨密度的测量
使用双能X线吸收光光度法(dual-energy x-ray absorptiometry)(DEXA,PXImus;Lunar Medison,WI)测量骨折诱导后取出的第9根肋骨骨痂周围的骨密度,骨密度以mg/cm2计算,在表7中示出。
表7
*:与对照相比显著性(p<0.01)
**:与对照相比显著性(p<0.05)
如从表7的数据明显可见,相比于非治疗对照,苄脒化合物给药组的骨痂骨密度增加,具有显著性(p<0.01或p<0.05),并且骨密度随着剂量增加而增加。
因此,化学式1的苄脒化合物被鉴定为可以增加骨折后形成的骨痂的骨密度。
8.骨痂骨强度的测量
通过使用Instron材料测试系统(Instron material testing system)(Instron 6022;Instron,USA;速度20mm/min),利用三点弯曲试验(three points bending test),测定骨折面附近的骨强度,在所述骨折面处在骨折诱导后取出的第9根肋骨中形成有骨痂。
结果在下面的表8中被给出。
表8
*:与对照相比显著性(p<0.01)
**:与对照相比显著性(p<0.05)
如在表8中可见,相比于未治疗组,苄脒化合物给药组的骨强度以剂量依赖性模式增加,具有显著性(p<0.01或p<0.05)。
结果,化学式1的苄脒化合物被鉴定为可以增加骨折后形成的骨痂的骨强度。
9.统计学
所有数字被表示为平均值±标准偏差,并借助SPSS(Release6.1.3.,SPSS Inc.,USA)使用Mann-Whitney U-Wilcoxon Rank Sum试验分析相对于对照的差异的统计学显著性。
同样地,N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒的甲磺酸盐和盐酸盐,以及4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒及其甲磺酸盐和盐酸盐被发现表现出与上面相同的愈合效果。
制备实施例:
1.粉剂的制备
化学式1的苄脒化合物 2g
乳糖 0.5g
甘露醇 0.5g
所述成分被混合并被装入密封袋中,以制备粉剂。
2.片剂的制备
化学式1的苄脒化合物 100mg
玉米淀粉 50mg
微晶纤维素 50mg
乳糖 100mg
聚乙烯吡咯酮 15mg
硬脂酸镁 2mg
使用通用压片法将所述成分的混合物制备成片剂。
3.胶囊的制备
化学式1的苄脒化合物 100mg
玉米淀粉 50mg
微晶纤维素 50mg
乳糖 100mg
聚乙烯吡咯酮 15mg
硬脂酸镁 2mg
根据典型的步骤,将所述成分的混合物装入明胶胶囊中,以得到胶囊剂。
4.软胶囊的制备
化学式1的苄脒化合物 100mg
豆油 400mg
卵磷脂 20mg
明胶 200mg
根据典型的步骤,由所述成分的混合物制备软胶囊。
5.注射剂的制备
化学式1的苄脒化合物 10μg/ml
稀盐酸BP 至pH 3.5
可注射氯化钠BP 最多1ml
用稀盐酸BP调节适当体积的可注射氯化钠BP中的化学式1的苄脒化合物溶液至pH 3.5,并且用可注射氯化钠BP调节其体积。在充分混合后,溶液被装入透明玻璃制成的5ml I型安瓿瓶中,然后软化,使得溶液在上层空气格下(under the upper grid of air)被封装。通过在120℃高压灭菌15分钟或更长,获得注射剂。
工业实用性
本发明的组合物可以显著减少骨痂体积,增加骨痂的骨密度和强度,并降低骨痂中结缔组织和软骨组织的含量,从而促进在骨折愈合过程中形成的骨痂的减少和骨化。因此,本发明的组合物对于骨折治疗是有用的。
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