CN113347975B - 用于治疗侵蚀性手骨关节炎的孟鲁司特 - Google Patents
用于治疗侵蚀性手骨关节炎的孟鲁司特 Download PDFInfo
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- CN113347975B CN113347975B CN201980089991.6A CN201980089991A CN113347975B CN 113347975 B CN113347975 B CN 113347975B CN 201980089991 A CN201980089991 A CN 201980089991A CN 113347975 B CN113347975 B CN 113347975B
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- montelukast
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Abstract
本发明涉及用于治疗侵蚀性手骨关节炎的孟鲁司特。根据该用途,孟鲁司特可以以任何合适的药物组合物的形式经口或表面施用。用孟鲁司特治疗的患有侵蚀性手骨关节炎的患者在临床症状和在放射学参数方面均显示出改善,并且还报道了疼痛减轻和手功能改善。
Description
技术领域
本发明涉及侵蚀性手骨关节炎(erosive hand osteoarthritis)的药理学控制(pharmacological management)。
背景技术
骨关节炎是影响整个关节(包括透明软骨、软骨下骨、滑膜、韧带和关节囊)的退行性关节病,并且特征在于关节软骨的退化、软骨下骨改变和关节边缘处骨赘形成,并且通常与疼痛相关。通常与骨关节炎相关的关节包括膝、髋和手。
就涉及遗传因素、发病机制和疾病进程而言,与膝和髋相比,侵蚀性手骨关节炎显示是单独的、基本上不同的疾病子集,如Ramoneda et al.,Joint and bone assessmentin hand osteoarthritis,Clin.Rheumatol.,2014,33(1),11-19所公开的。
文章Stern et al.,Association of erosive hand osteoarthritis with asingle nucleotide polymorphism on the gene encoding interleukin-1 beta,Osteoarthritis Cartilage,2003,11(6),394-402还确定了存在针对于手骨关节炎,并且特别是针对于侵蚀性手骨关节炎的遗传因素,即,该文章公开了侵蚀性手骨关节炎与包含白介素-1b(interleukin-1b,IL-1b)5810单核苷酸多态性的基因组区域之间的相关性。类似地,文章Ramoneda et al.,Immunogenic aspects of erosive osteoarthritis of thehand in patients from northern Italy,Scand.J.Rheumatol,2011,40,139-144还报道了对侵蚀性手骨关节炎的一些遗传倾向。
手骨关节炎的特定特征是其同时影响多个手关节,这使其成为异质性和复杂的病症。然而,与负重关节(例如膝和髋)的骨关节炎相比,手骨关节炎传统上受到更少的关注。
手骨关节炎的临床特征包括手关节的骨增大和畸形,有时伴随软组织肿胀(Zhanget al.,EULAR evidence-based recommendations for the diagnosis of handosteoarthritis:report of a task force of ESCISIT,Ann.Rheum.Dis.,2009,68:8-17)。手骨关节炎的症状包括疼痛、僵硬、关节畸形以及功能损伤,包括握力、手移动性和灵活性降低,从而导致受影响患者的生活品质降低。
侵蚀性手骨关节炎是特别严重的手骨关节炎形式,其主要特征是中央侵蚀和软骨下骨板的塌陷。侵蚀性手骨关节炎可影响第一腕掌(carpometacarpal,CMC)关节以及指间关节。与非侵蚀性手骨关节炎相比,侵蚀性手骨关节炎的特征在于突然发作、更明显的疼痛和功能损伤、更快的进展、炎症和更差的结果。
手骨关节炎是高度普遍的,其中成人患病率为20至30%,与年龄相关提高,在60岁之后达到50%患病率,如在Gabay et al.,Symptomatic Effects of Chondroitin 4 andChondroitin 6 sulfate on hand osteoarthritis,Arthritis Rheum.,2011,63(11),3383-3391中所报道。在手骨关节炎的风险因素中,年龄可能是最重要的,其中随着衰老患病率提高。此外,手骨关节炎也与性别有关,并且在女性中比在男性中更加普遍,这表明激素对患病率的影响。另一些常见的风险因素是肥胖、职业因素和遗传因素。
关于侵蚀性手骨关节炎,女性的患病率(9.9%)高于男性(3.3%),如在Haugen etal.Prevalence,incidence and progression of hand osteoarthritis in the generalpopulation:the Framingham Osteoarthritis Study,Ann.Rheum.Dis.2011,70(9),1581-1586中所报道。在具有手疼痛或具有症状性手骨关节炎的群体中,侵蚀性手骨关节炎的患病率分别为约7%和10%。然而,在来自二级护理的具有症状性手骨关节炎的群体中,患病率上升至25%。
手骨关节炎,并且特别是侵蚀性手骨关节炎的药物治疗,带来了与髋或膝骨关节炎的药物治疗不同的特定挑战。因此,不仅疼痛管理是主要目的,而且改善手功能性也是至关重要的,由于其对受影响患者的生活品质产生巨大影响。
因此,在2018年更新的针对手骨关节炎管理的EULAR建议(Kloppenburg et al.,Ann.Rheum.Dis,2018)中,指出管理手骨关节炎的主要目的是控制症状(例如疼痛和僵硬)并优化手功能,以使活动、参与和生活品质最大化。患有手骨关节炎的患者不应该用常规或生物疾病改变抗风湿药物进行治疗,因为无法证明其效力。
本领域中已公开了用于管理手骨关节炎的不同的治疗选择,例如,如在AltmanR.D.,Pharmacological therapies for osteoarthritis of the hand,Drugs Aging,2010,27(9),729-745中所公开的。目前的治疗选择仅包括镇痛剂,例如对乙酰氨基酚;经口非甾体抗炎药(nonsteroidal anti-inflammatory drug,NSAID),例如萘普生(naproxen)、右酮洛芬(dexketoprofen)、布洛芬(ibuprofen)或双氯芬酸(diclofenac);经口阿片样物质,例如曲马多(tramadol);以及经口皮质类固醇。然而,这些药物可涉及通常随年龄而提高的严重不良作用,并因此,可不将其推荐用于患有手骨关节炎的患者。
在安全性方面,例如用NSAID双氯芬酸钠或用辣椒素(capsaicin)进行的表面治疗是优选的,尽管效力可能并不完全令人满意。
报道的针对在患有手骨关节炎的患者中疼痛减轻和改善功能的另一些药物是硫酸软骨素和葡糖胺,尽管可用来支持其效力的证据有限。
另一些治疗选择包括关节内皮质类固醇或透明质酸,但其仅显示出适度的症状性效力,并且该效力无法与当针对膝和髋骨关节炎治疗进行这些干预时的效力结果具有可比性。
总之,目前的药物治疗仅集中于减轻症状,并且迄今为止可用的选择已显示对疼痛控制几乎没有效力并且频繁地涉及不期望的副作用,特别是来源于使用经口NSAID的副作用。
在另一方面,手术也不是好的选择,因为针对手骨关节炎的手术干预比针对膝或髋骨关节炎的手术干预的效果差得多。
因此,目前没有针对手骨关节炎并且特别是针对侵蚀性手骨关节炎的有效的药物治疗,其既无法阻止疾病的进展,也无法有效减轻疾病症状。
在文章Fanning et al.,Montelukast sodium as a treatment forexperimental osteoarthritis in mice,Osteoarthr.Cartil.,2009,17(增刊1),S282中公开了孟鲁司特(montelukast)在小鼠膝骨关节炎实验模型中的用途,其中使用内侧半月板失稳术(destabilization of the medial meniscus,DMM)将小鼠右膝经手术诱导为骨关节炎。由于DMM模型与由于半月板损伤而处于骨关节炎风险中的人的相似性,提议用孟鲁司特进行治疗可在接近于半月板修复时间的患者中延迟初期骨关节炎的进展。然而,如预期的那样,由于涉及侵蚀性手骨关节炎发作的特定遗传因素,没有公开或提议有关孟鲁司特用于治疗人手复杂性侵蚀性骨关节炎的用途。
鉴于侵蚀性手骨关节炎的高患病率,其对受影响患者的生活品质的高影响以及可用的不成功治疗选择,需要针对该病症的新的安全和有效的药物治疗。
发明详述
本发明的目的是用于在人对象中治疗侵蚀性手骨关节炎的孟鲁司特或其可药用盐。
本发明的另一个方面是在患者中治疗侵蚀性手骨关节炎的方法,其包括向有此需要的患者施用有效量的孟鲁司特或其可药用盐的步骤。
本发明的另一个方面是孟鲁司特或其可药用盐用于制备用于在人对象中治疗侵蚀性手骨关节炎的药物的用途。
本发明的作者出人意料地发现,孟鲁司特(其是用于治疗哮喘和减轻季节性变态反应的症状的白三烯受体拮抗剂)对于治疗手骨关节炎,并且特别是治疗侵蚀性手骨关节炎是有效的。
在本说明书以及权利要求书中,没有数量词修饰的名词不仅包括具有一个/种成员(单数)的方面,还包括具有多于一个/种成员(复数)的方面。
本文中使用的提及量时的术语“约/大约”意指包含合格量的某些偏差,即±5%。
本文中公开的数值范围意指包含落入该范围内的任何数以及其下限和上限。
侵蚀性手骨关节炎
本发明涉及侵蚀性手骨关节炎的治疗。在本发明的上下文中,“治疗”意指对人对象的治疗。
受手骨关节炎影响的患者根据标准方法进行诊断,所述方法是医师(专家或普通实践者)所公知的,通常组合临床和放射学观察。
手骨关节炎主要表现为远指间(distal interphalangeal,DIP)关节(海伯顿结节(Heberden’s node))、近指间(proximal interphalangeal,PIP)关节(布夏达结节(Bouchard’s node))和拇指基关节的疼痛和肿胀;通常存在具有或不具有畸形的骨增大,例如如在Arden et al.,Atlas of Osteoarthritis,2014,Springer Healthcare,ISBN978-1-910315-15-6中所公开的。
例如,如在E Altman et al.The American College of Rheumatology criteriafor the classification of osteoarthritis of the hand,Arthritis Rheum.,1990,33,1601-1610中公开的ACR(美国风湿病学会(American College of Rheumatology))的标准被广泛遵循。根据这些标准,当具有手疼痛、酸痛或僵硬以及以下的3或4项时,则诊断为手骨关节炎:i)10个选择关节中的2个或更多个的硬组织增大,ii)2个或更多个远指间(DIP)关节的硬组织增大,iii)少于3个肿胀的掌指(metacarpophalangeal,MCP)关节,以及iv)10个选择关节中的至少1个的畸形;其中10个选择关节是双手的第二和第三远指间(DIP)关节、第二和第三近指间(PIP)关节以及第一腕掌(carpometacarpal,CMP)关节。
或者,根据如在Zhang et al.,EULAR evidence-based recommendations forthe diagnosis of hand osteoarthritis:report of a task force of ESCISIT,Ann.Rheum.Dis.,2009,7,17中公开的EULAR(欧洲抗风湿病联盟,European LeagueAgainst Rheumatism)的标准,可在具有以下的年龄超过40岁的成人中进行手骨关节炎的可靠临床诊断:(i)使用时疼痛,(ii)间歇性症状;以及(iii)仅在早晨是轻微的或在任何给定时间具有影响一个或数个关节的不活动僵硬。
关于放射学评估,普通射线照片(plain radiograph)适合于诊断手骨关节炎,即双手的后前位射线照片。所见的特征包括关节间隙狭窄、软骨下骨硬化和软骨下囊肿,如本领域所公知的。
侵蚀性手骨关节炎是特征在于在普通射线照片中在指间关节处存在软骨下骨侵蚀的手骨关节炎的子集。通常来说,侵蚀性手骨关节炎具有突然发作、更快的进展、更具侵袭性的疾病进程,具有明显的疼痛和炎症以及降低的手功能性。滑膜炎和腱鞘炎在侵蚀性手骨关节炎中也是频繁的。
如在实施例4和5中所公开的,出人意料的是孟鲁司特在患有侵蚀性手骨关节炎的患者中对于改善临床症状、对于减轻疼痛、改善手功能性以及对于改善放射学特征是显著有效的。
此外,这些研究中包含的患有侵蚀性手骨关节炎的患者之前已用采用镇痛剂和/或采用抗炎剂的常规治疗进行治疗,并且对这样的治疗无响应。
本发明的一个实施方案涉及对采用镇痛剂和/或抗炎剂的治疗无响应的患有侵蚀性手骨关节炎的患者的治疗。
如普通实践者所公知的,对治疗无响应的患者是在采用治疗的情况下未显示出其症状的改善或者改善不足的那些。
在本发明的上下文中,提及手骨关节炎,并且特别在提及侵蚀性手骨关节炎的术语“治疗(treatment)”或“治疗(treating)”涉及对与例如以下的疾病相关的一种或更多种症状或表现的消除、减轻、改善或使其稳定(即不使其恶化):软骨退化、关节间隙狭窄、软骨下骨侵蚀、软骨下硬化、骨赘形成、骨增大(例如形成结节,例如涉及远指间关节的海伯顿结节和/或涉及近指间关节的布夏达结节)、滑膜炎、腱鞘炎、疼痛、压痛、僵硬、炎症、肿胀、握力和手功能性减弱。
一些症状通过放射学测试来评价,而另一些通过临床评估例如中度至重度疼痛和手功能性来评价。
治疗方法包括向对象施用治疗有效量的孟鲁司特、其药用盐。
治疗的持续时间取决于数个因素,主要取决于病症的严重程度及其演变。由于其是与年龄相关的退行性疾病,因此可能需要长期施用。
孟鲁司特
孟鲁司特是指定给化合物2-[1-[[(1R)-1-[3-[(E)-2-(7-氯喹啉-2-基)乙烯基]苯基]-3-[2-(2-羟基丙烷-2-基)苯基]丙基]硫烷基甲基]环丙基]乙酸(CAS号:158966-92-8)的国际非专有名称(International Nonproprietary Name,INN)。
药理学上,孟鲁司特是在用于治疗哮喘和变态反应的治疗中使用的选择性半胱氨酰白三烯1型(cysteinyl leukotriene type 1,Cys-LT1)受体拮抗剂。其作为用于治疗哮喘和季节性变态反应的药物中的钠盐(孟鲁司特钠)可商购获得,例如以商标名销售。
孟鲁司特的制备在例如文章Labelle et al.,Discovery of MK-0476,a potentand orally active leukotriene D4 receptor antagonist devoid of peroxisomalenzyme induction,Bioorg.Med.Chem.Lett,1995,5(3),283-288中公开。孟鲁司特也可从商业来源广泛获得。
化学上,孟鲁司特分子包含羧酸基团。在本发明的范围内,孟鲁司特可作为游离酸或以其可药用盐形式使用。
“可药用”意指所述盐适合于制备药物组合物,因为其是无毒的并且不是生物学上不期望的。
孟鲁司特作为酸性化合物可与有机或无机碱形成碱性加成盐。形成合适盐的无机碱尤其包括碱和碱土金属氢氧化物,例如氢氧化锂、氢氧化钠、氢氧化钾、氢氧化钙或氢氧化镁,以分别形成孟鲁司特锂盐、孟鲁司特钠盐、孟鲁司特钾盐、孟鲁司特钙盐或孟鲁司特镁盐。孟鲁司特还可与胺形成盐,例如与氨形成孟鲁司特铵,或者与其他有机胺形成盐。
孟鲁司特的任何可药用盐均涵盖在本发明的范围内。
在一个优选实施方案中,孟鲁司特作为可药用盐使用。
在本发明一个实施方案中,孟鲁司特可药用盐选自碱金属盐或碱土金属盐,优选地选自孟鲁司特锂、孟鲁司特钠、孟鲁司特钾、孟鲁司特钙或孟鲁司特镁,并且更优选地是孟鲁司特钠。
在一个优选实施方案中,孟鲁司特作为孟鲁司特钠使用。
根据本发明的用途,孟鲁司特可经口或表面(topically)施用。
在本发明一个实施方案中,孟鲁司特或其可药用盐经口施用。
当施用是经口时,孟鲁司特或其可药用盐以通常为1至200mg/天的剂量施用,所述剂量以孟鲁司特的当量剂量(equivalent dose)表示。
在实施例4中公开的临床研究中,以日剂量为10mg经口孟鲁司特在患有侵蚀性手骨关节炎的患者中是显著有效的,并且减轻了疼痛并改善了临床和放射学症状。
此外,在实施例5中公开的研究中,每日将20mg孟鲁司特给予选自先前研究的对采用每日10mg孟鲁司特的治疗无响应的9位患者。出人意料地发现,在仅治疗数天之后,该治疗在疼痛减轻和改善手功能这两方面均是显著有效的。
已知孟鲁司特是安全且良好耐受的药物,其甚至在高剂量(例如200mg/天)下也不引起不良作用(Stroms et al.,Clinical safety and tolerability of montelukast,aleukotriene receptor antagonist,in controlled clinical trials in patientsaged≥6 years,Clin.Exp.Allergy,2001,31,77-87)。
因此,根据本发明的治疗允许针对每位患者的特定病症和针对疾病的严重程度调整待施用的孟鲁司特的剂量以及治疗的持续时间。
孟鲁司特的优选经口剂量为2至80mg/天。孟鲁司特的更优选经口剂量为5至70mg/天。孟鲁司特的还更优选的经口剂量为10至50mg/天。
在一个实施方案中,孟鲁司特的剂量为5至15mg/天,优选地为7至13mg/天,更优选地为9至11mg/天,并且还更优选地该剂量为约10mg/天。
在一个实施方案中,孟鲁司特的剂量为7至25mg/天,优选地为10至20mg/天,更优选地为14至16mg/天,并且还更优选地该剂量为约15mg/天。
在一个实施方案中,孟鲁司特的剂量为10至30mg/天,优选地为15至25mg/天,更优选地为19至21mg/天,并且还更优选地该剂量为约20mg/天。
在一个实施方案中,孟鲁司特的剂量为12至37mg/天,优选地为20至30mg/天,更优选地为24至36mg/天,并且还更优选地该剂量为约25mg/天。
在一个实施方案中,孟鲁司特的剂量为15至45mg/天,优选地为25至35mg/天,更优选地为29至31mg/天,并且还更优选地该剂量为约30mg/天。
在一个实施方案中,孟鲁司特的剂量为20至60mg/天,优选地为35至45mg/天,更优选地为39至41mg/天,并且还更优选地该剂量为约40mg/天。
在一个实施方案中,孟鲁司特的剂量为25至75mg/天,优选地为45至55mg/天,更优选地为49至51mg/天,并且还更优选地该剂量为约50mg/天。
孟鲁司特的合适经口日剂量为,例如约5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50mg。其他更高的剂量,多至200mg/天也是合适的。
根据本发明一个方面,基于孟鲁司特的治疗被认为是个性化治疗,并且根据患者对处方初始孟鲁司特剂量的响应以及根据专业标准开具处方。
以上剂量是孟鲁司特或其可药用盐的剂量,但总是以孟鲁司特的当量剂量表示。
因此,在本说明书以及权利要求书中,孟鲁司特的剂量作为孟鲁司特游离酸的当量剂量表示,不论其是否作为游离酸或作为盐施用。
当孟鲁司特作为盐施用时,调整剂量以提供孟鲁司特游离酸的所需当量剂量。
这样的日剂量可根据每日一次方案(q.d.)以一次单一施用来施用,或者可在一天期间将其分为数次施用,例如每日两次(b.i.d.)、每日三次(t.i.d)或每日四次(q.i.d.)。
当孟鲁司特的日剂量被分为两次或更多次施用(即,b.i.d.、t.i.d.或q.i.d.)来施用时,优选地,将总日剂量分为相等的部分剂量。例如,根据b.i.d.方案将12mg日剂量以约6mg的两个相等剂量施用;或根据t.i.d.以约4mg的三个相等剂量施用。
优选地,孟鲁司特根据每日一次方案或每日两次方案施用,并且更优选地,孟鲁司特根据每日一次施用方案来施用。
在本发明另一个实施方案中,孟鲁司特或其可药用盐表面施用。
表面施用包括将有效量的孟鲁司特以合适的表面药物制剂的形式施加至手的受影响部位处的皮肤,特别是受影响关节附近的皮肤。
本文中使用的表面施用等同于“经皮(transdermal)”、“由皮(transcutaneous)”、“透皮(percutaneous)”施用,并且意指通过皮肤施用以将孟鲁司特递送至皮肤下受影响的组织。
当表面施用孟鲁司特时其剂量取决于受影响患者中疾病的程度和严重程度而变化。
就孟鲁司特全身吸收衍生的可能不良作用而言,表面施用甚至是更安全的。因此,与在经口施用中相比,在表面施用的情况下的剂量可以更不受限制。
在表面施用时,剂量可以为每只受影响手每日1至200mg。优选地,剂量范围为每只受影响手每日2至80mg,更优选5至70mg,并且还更优选10至50mg。
这些剂量可以以每日一次单一施用来施用,或者将其分为每日数次施用。
根据本发明的用途,用孟鲁司特进行治疗的持续时间可以为约一周至数年不等,这取决于疾病的演变。孟鲁司特是基本上没有不良作用的安全药物,并因此长期治疗是合适的(如果需要的话)。熟练的实践者将毫无困难地调整每种情况下的治疗持续时间,这取决于疾病的严重程度以及患者的演变。
药物组合物
根据本发明用途的孟鲁司特或其可药用盐通常以包含活性成分,即孟鲁司特或其可药用盐以及至少一种可药用赋形剂和/或载剂的药物组合物的形式施用。
因此,本发明的另一个方面涉及用于在人对象中治疗侵蚀性手骨关节炎的包含孟鲁司特或其可药用盐的药物组合物。
本发明的另一个方面是在患者中治疗侵蚀性手骨关节炎的方法,其包括向有此需要的患者施用有效量的包含孟鲁司特或其可药用盐以及至少一种可药用赋形剂和/或载剂的药物组合物的步骤。
本发明的另一个方面是包含孟鲁司特或其可药用盐以及至少一种可药用赋形剂和/或载剂的药物组合物用于制备用于在人对象中治疗侵蚀性手骨关节炎的药物的用途。
根据本发明应用的药物组合物是可使用药物制剂技术人员公知的方法制备的任何常规制剂,所述方法如在药物技术手册中,例如在书籍J.P Remington and A.R.Genaro,Remington The Science and Practice of Pharmacy,第20版,Liρpincott,Williams&Wilkins,Philadelphia,2000[ISBN:0-683-306472]中,或在书籍M.E.Aulton andK.M.G.Taylor,Aulton’s Pharmaceutics,the design and manufacture of medicines,第4版,Churchill Livingstone Elsevier,2013[ISBN:978-0-7020-4290-4]中,或在书籍A.K.Dash,S.Singh and J.Tolman,Pharmaceutics.Basic principles and applicationto pharmacy practice,Academic Press,Elsevier,2014[ISBN:978-0-12-386890-9]中公开的那些。
适合于用于本发明药物组合物的赋形剂也是药物技术的技术人员公知的,并且在例如书籍R.C.Rowe,P.J.Sheskey and P.J.Weller,Handbook of PharmaceuticalExcipients,第六版,Pharmaceutical Press,2009中描述。
适合于根据本发明用途的药物组合物是适合于经口或表面施用的所有那些。
在本发明一个实施方案中,药物组合物是适合于经口施用的组合物。适合于经口施用的任何药物形式均包含在根据本发明的用途内,优选固体组合物,或任一种液体,例如以溶液剂、混悬剂或糖浆剂形式。
固体剂型通常包含片剂、胶囊剂、颗粒剂和散剂。
用于根据本发明用途的包含孟鲁司特或其可药用盐的片剂可使用本领域公知的标准技术来配制。这样的片剂可被配制为常规压缩片剂、口含片剂、舌下片剂、可咀嚼片剂、泡腾片剂、肠溶包衣片剂、膜包衣片剂、缓释片剂或经口崩解片剂,通过选择合适的赋形剂和药物制剂技术人员公知的程序来进行。
或者,孟鲁司特或其可药用盐可以以胶囊剂形式配制。如本领域公知的,在胶囊剂中,活性成分通常与至少一种可药用赋形剂一起被包封在硬或软的可溶性壳内。胶囊壳的主要组分是明胶,而另一些组分包括水、着色剂、增塑剂(例如甘油或山梨糖醇)和乳浊剂。羟丙甲纤维素可替代地用作胶囊壳材料。
根据本发明的孟鲁司特制剂也可以是用于经口施用的散剂或颗粒剂的形式。其可直接施用于口腔,或者其可在被摄取之前预先溶解或分散在水或其他液体中。其也可以是泡腾散剂或颗粒剂。
散剂是干燥细碎的药物与一种或更多种赋形剂一起的紧密混合物。通常来说,对散剂进行混合过程以获得匀质混合物,例如通过本领域公知的研磨(trituration)、调拌(spatulation)、筛理(sifting)或滚揉(tumbling)程序。
颗粒剂由已聚集形成较大颗粒的粉末颗粒组成,并且其通常通过本领域也公知的干法制粒或湿法制粒程序来制备。
此外,颗粒剂可以是包衣颗粒剂、胃抗性颗粒剂(gastro-resistantgranule)或调释颗粒剂(modified-release granule)。
可用于制备固体形式(例如片剂、胶囊剂、颗粒剂或散剂)的经口药物组合物的可药用赋形剂是本领域技术人员公知的,并且包括例如,稀释剂,例如碳酸钙、磷酸钙、硫酸钙、乙酸纤维素、葡萄糖结合剂(dextrate)、糊精、右旋糖、乙基纤维素、果糖、明胶、硬脂酸棕榈酸甘油酯、异麦芽酮糖醇(isomalt)、高岭土(kaolin)、乳糖醇、乳糖、碳酸镁、氧化镁、麦芽糖糊精、麦芽糖、微晶或粉状纤维素、聚甲基丙烯酸酯、预胶化淀粉、淀粉、碳酸钠、氯化钠、山梨糖醇或蔗糖等,及其混合物;润滑剂,例如硬脂酸钙、山嵛酸甘油酯、硬脂酸棕榈酸甘油酯、氢化蓖麻油、硬脂酸镁、聚乙二醇、苯甲酸钠、十二烷基硫酸钠、硬脂富马酸钠、硬脂酸或滑石等,及其混合物;崩解剂,例如褐藻酸、交聚维酮、交联羧甲基纤维素钠、羟基乙酸淀粉钠、淀粉、低取代羟丙基纤维素等,及其混合物;黏合剂,例如阿拉伯树胶(acacia)、邻苯二甲酸乙酸纤维素、葡萄糖结合剂、糊精、乙基纤维素、瓜尔胶(guar gum)、羟乙基纤维素、羟乙基甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素甲基纤维素、麦芽糖糊精、微晶纤维素、蔗糖、聚维酮、预胶化淀粉、羧甲基纤维素钠、淀粉或硬脂酸等,及其混合物;助流剂,例如磷酸三钙、粉状纤维素、胶体二氧化硅、氧化镁、硅酸镁、三硅酸镁、二氧化硅或滑石等,及其混合物;甜味剂,例如山梨糖醇、麦芽糖醇、甘露糖醇、右旋糖、异麦芽酮糖醇、麦芽糖、木糖醇、糖精、蔗糖、三氯蔗糖、阿斯巴甜(aspartame)、乙酰磺胺酸钾或海藻糖等,及其混合物;矫味剂,例如麦芽酚、香兰素、乙基香兰素、薄荷醇、柠檬酸、富马酸、乙基麦芽酚、酒石酸、薄荷、人工或天然水果芳香剂等,及其混合物;着色剂,例如姜黄素、核黄素、铁氧化物(红色、黄色或黑色)、焦糖、磷酸核黄素、胭脂虫红、二氧化钛或胡萝卜素等,及其混合物;或者其混合物。
在一个实施方案中,根据本发明应用的孟鲁司特或其可药用盐为选自片剂、胶囊剂、散剂或颗粒剂的用于经口施用的药物组合物的形式。在一个优选实施方案中,为片剂形式。在另一个优选实施方案中,为胶囊剂形式,优选地为硬胶囊剂形式。在另一个优选实施方案中,为颗粒剂形式。在另-个优选实施方案中,为散剂形式。
在本发明一个实施方案中,孟鲁司特或其可药用盐作为散剂或颗粒剂组合物使用并且以包含单位剂量的活性成分的单剂量小袋剂(sachet)的形式存在。这些小袋剂可由纸或者铝或塑料叠层中的任一者制成。
当包含在片剂、或胶囊剂、或者以散剂或颗粒剂形式的组合物的单剂量小袋剂中的孟鲁司特或其可药用盐的单位剂量旨在用于每日一次剂量方案时,其可以是合适的日剂量;或者当其旨在用于每日两次剂量方案时,其可以是日剂量的一半;或者当其旨在用于每日三次剂量方案时,其可以是日剂量的三分之一;或者当其旨在用于每日四次方案时,其可以是日剂量的四分之一。
在一个实施方案中,每个片剂、胶囊剂或散剂或颗粒剂单剂量小袋剂包含孟鲁司特或其可药用盐为1至200mg,优选地为2至80mg,更优选地为5至70mg,并且更优选地为10至50mg的剂量,所述剂量以孟鲁司特的当量剂量表示。当孟鲁司特作为盐使用时,优选的单位剂量可选自,例如约5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29和30mg,其以孟鲁司特的当量剂量表示。在每个片剂、胶囊剂或单剂量小袋剂中,优选的剂量为约5、约10、约15、约20mg和约30mg的孟鲁司特或其可接受盐,所述剂量以孟鲁司特的当量剂量表示。当孟鲁司特作为盐使用时,所述剂量以孟鲁司特的当量剂量表示。
适合于根据本发明用途的孟鲁司特或其药用盐的液体经口剂型包括例如溶液剂、混悬剂或糖浆剂。
经口溶液剂包含溶解于载剂中的活性物质,该载剂通常是水,任选地具有另外的共助溶剂。糖浆剂是包含高浓度的蔗糖或其他糖的经口水溶液剂。不含糖的糖浆剂通过用例如氢化葡萄糖、甘露糖醇、山梨糖醇或木糖醇代替蔗糖来获得。在经口混悬剂中,活性物质分散在液体介质中。经口溶液剂和/或混悬剂的制剂包含一种或更多种另外的赋形剂,例如增溶剂、稳定剂、缓冲剂、抗氧化剂、防腐剂、矫味剂、着色剂和甜味剂等。
在经口溶液剂和混悬剂中更常见的载剂是水;另一些合适的共溶剂包括乙醇、丙二醇、聚乙二醇300或400和甘油等,及其混合物。如本领域公知的,用于经口溶液剂和/或混悬剂中的另一些合适的赋形剂包括缓冲剂,例如二乙醇胺、磷酸氢二钠、磷酸二氢钠、柠檬酸钾、碳酸氢钠、柠檬酸钠二水合物等,及其混合物;表面活性剂,例如聚氧乙烯蓖麻油衍生物和脱水山梨糖醇酯;防腐剂,例如苯扎氯铵、苄醇、溴硝醇、对羟基苯甲酸酯、苯甲酸钠、丙酸钠、山梨酸、度米芬溴化物(domifen bromide)或硫柳汞等,及其混合物;抗氧化剂,例如亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、丁羟甲苯(butylated hydroxytoluene,BHT)、丁基羟基茴香醚(butylated hydroxyanisole,BHA)、没食子酸丙酯,及其混合物;黏度调节剂,例如阿拉伯树胶、褐藻酸、膨润土、卡波姆(carbomer)、卡拉胶(carrageenan)、明胶、甘油、羟乙基纤维素、羟乙基甲基纤维素、羟丙基纤维素、麦芽糖糊精、聚乙烯醇、褐藻酸钠、西黄蓍胶(tragacanth)或黄原胶等,及其混合物;助悬剂,例如黄原胶、瓜尔胶、褐藻酸、膨润土、卡波姆、羧甲基纤维素钠或羧甲基纤维素钙、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟丙基藻酸盐、微晶或粉状纤维素、无水胶体二氧化硅、糊精、明胶、高岭土、硅酸铝镁、麦芽糖醇、聚维酮、脱水山梨糖醇酯或西黄蓍胶等,及其混合物;矫味剂,例如麦芽酚、香兰素、乙基香兰素、薄荷醇、柠檬酸、富马酸、乙基麦芽酚、酒石酸、薄荷、人工或天然水果芳香剂等,及其混合物;甜味剂,例如山梨糖醇、麦芽糖醇、甘露糖醇、右旋糖、异麦芽酮糖醇、麦芽糖、木糖醇、糖精、蔗糖、三氯蔗糖、阿斯巴甜、乙酰磺胺酸钾或海藻糖等,及其混合物;着色剂,例如姜黄素、核黄素、焦糖、磷酸核黄素、胭脂虫红或胡萝卜素等,及其混合物。
在一个实施方案中,根据本发明应用的孟鲁司特或其可药用盐为选自溶液剂和混悬剂的用于经口施用的液体药物组合物的形式。
通常来说,用于经口使用的这样的液体剂型可作为多剂量或作为单剂量制剂提供。来自多剂量容器的每个剂量通过适合于测量处方体积的装置来施用。测量装置可以是,例如如匙、杯、经口注射器或滴管。
每个测量的剂量通常包含孟鲁司特或其可药用盐为1至200mg,优选地为2至80mg,更优选地为5至70mg,并且还更优选地为10至50mg的量,所述量以孟鲁司特的当量剂量表示。当孟鲁司特作为盐使用时,优选的单位剂量可选自例如为约5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29和30mg,其以孟鲁司特的当量剂量表示。在液体组合物的每个测量的剂量中,优选的剂量为约5、约10、约15、约20mg和约30mg的孟鲁司特或其可接受盐,所述剂量以孟鲁司特的当量剂量表示。
在本发明另一个实施方案中,药物组合物适合于表面施用。适合于表面施用的任何药物形式均包含在本发明的用途内,通常以液体或半固体的形式。适合于表面施用的液体组合物可通过将孟鲁司特或其可药用盐溶解或分散在合适的载体(例如如水、醇、二醇或其混合物)中来制备,并且是例如洗剂、搽剂或酊剂;或者另外地可使用该液体组合物来浸渍施加至受影响区域的以敷料或绷带形式的支持物;或者作为替代地,可使用泵式喷淋器(sprayer)或喷雾器(aerosol)将液体组合物喷洒至受影响的区域上。
表面施用的另一些形式是包含其中溶解孟鲁司特或其可药用盐、使其乳化、分散或悬浮的可药用的载体或载剂的半固体组合物,例如乳膏剂、凝胶剂、软膏剂或糊剂。
如药物技术的技术人员公知的,乳膏剂是半固体乳剂,其可以是由油相、水相和乳化剂配制的水包油(oil-in-water,o/w)类型或油包水(water-in-oil,w/o)类型。凝胶剂从通过添加流变剂或胶凝剂而凝胶化的液体中获得。软膏剂是包含溶解的或以分散形式的活性成分的半固体脂肪制剂。软膏剂可用多种载剂,例如石蜡、塑基(plastibase)(聚乙烯与一系列碳氢化合物的混合物)或植物油来配制。糊剂类似于软膏剂来制备,并且其显示出更多的固体稠度,因为其包含更多量的不溶性固体。
表面组合物中的载剂可以是水或另一些水溶性或水混溶性载剂,例如低级醇(例如乙醇或异丙醇)、二醇(例如乙二醇、丙二醇或聚乙二醇300)或甘油等,或其混合物。合适的油性载剂包括杏仁油、玉米油、芝麻油、蓖麻油、豆油、石蜡油、花生油、橄榄油、棉籽油、羊毛脂(lanolin)、单硬脂酸甘油酯或亚麻籽油等,或其混合物。另外的赋形剂包括:乳化剂,例如硬脂酸钙、硬脂酸、鲸蜡醇、硬脂酸棕榈酸乙二醇酯、单硬脂酸甘油酯、卵磷脂、磷脂、油酸、泊洛沙姆(poloxamer)、十二烷基硫酸钠、脱水山梨糖醇酯、聚氧乙烯蓖麻油衍生物或乳化蜡等,及其混合物;胶凝剂,例如卡拉胶、瓜尔胶、西黄蓍胶、槐豆胶(locust bean gum)、黄原胶、果胶、琼脂、褐藻酸、卡波姆、羧甲基纤维素、甲基纤维素、羟乙基纤维素、羟丙基甲基纤维素和聚乙二醇等,及其混合物;软化剂(emollient),例如矿脂、矿物油、肉豆蔻(myristyl)醇、鲸蜡醇、硬脂醇、鲸蜡硬脂醇、单硬脂酸甘油酯、单油酸甘油酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、胆固醇、羊毛脂醇和甘油等,及其混合物;增稠剂或增黏剂,例如卡波姆、羧甲基纤维素钠、羧甲基纤维素钙、透明质酸、羟乙基纤维素、羟乙基甲基纤维素、羟丙基甲基纤维素、阿拉伯树胶、瓜尔胶、黄原胶、褐藻酸、膨润土、卡拉胶、黏土、明胶、藻酸钠、西黄蓍胶等,及其混合物;抗氧化剂,例如抗坏血酸、抗坏血酸棕榈酸酯、丁基羟基茴香醚、丁羟甲苯、螯合剂、柠檬酸一水合物、富马酸、苹果酸、焦亚硫酸钾、没食子酸丙酯、抗坏血酸钠、亚硫酸氢钠、焦亚硫酸钠、亚硫酸钠、硫代硫酸钠等,及其组合;防腐剂,例如苯扎氯铵、苄醇、溴硝醇、氯己定、咪脲、对羟基苯甲酸酯、苯氧乙醇、苯甲酸钠、丙酸钠、山梨酸或硫柳汞等,及其混合物;缓冲剂和pH调节剂,例如硼酸、柠檬酸一水合物、二乙醇胺、磷酸氢二钠、苹果酸、马来酸、磷酸二氢钠、柠檬酸钾、乙酸钠、碳酸钠、碳酸氢钠、柠檬酸钠二水合物、硼酸钠、氢氧化钠、乳酸钠、三乙醇胺等,及其混合物;香料剂(perfume agent),例如薄荷、草本植物、可可脂和花露油芳香剂(floral oil fragrance)等;以及适合于药物用途的着色剂;等,及其混合物。
在一个实施方案中,根据本发明应用的孟鲁司特或其可药用盐为选自乳膏剂、凝胶剂、软膏剂和糊剂的用于表面施用的组合物的药物组合物的形式。
药物组合物中孟鲁司特或其可药用盐的百分比可根据特定的药物剂型和预期的特定剂量而变化。通常来说,经口固体药物组合物中的活性成分的百分比为0.1至50w/w%,其作为相对于组合物总重量的孟鲁司特的当量量(equivalent amount)表示。
在经口液体药物组合物中,孟鲁司特或其可药用盐的浓度也可取决于具体制剂和期望的浓度而广泛变化,例如,为0.1至20%w/v,其作为100ml组合物中孟鲁司特的当量克表示。
在表面组合物中,孟鲁司特或其药用盐的量可以为例如0.5至50w/w%,所述量作为相对于组合物总重量的孟鲁司特的当量量表示。
本发明涉及以下实施方案:
1.孟鲁司特或其可药用盐,其用于在人对象中治疗侵蚀性手骨关节炎。
2.根据实施方案1所述应用的孟鲁司特的可药用盐。
3.根据实施方案2所述应用的孟鲁司特的可药用盐,其特征在于所述孟鲁司特可药用盐选自碱金属盐或碱土金属盐。
4.根据实施方案3所述应用的孟鲁司特的可药用盐,其特征在于所述孟鲁司特可药用盐选自孟鲁司特锂、孟鲁司特钠、孟鲁司特钾、孟鲁司特钙和孟鲁司特镁。
5.根据实施方案4所述应用的孟鲁司特的可药用盐,其特征在于所述孟鲁司特可药用盐是孟鲁司特钠。
6.根据实施方案1至5中任一个所述应用的孟鲁司特或其可药用盐,其特征在于孟鲁司特或其可药用盐用于经口施用。
7.根据实施方案6所述应用的孟鲁司特或其可药用盐,其特征在于孟鲁司特或其可药用盐的剂量为1至200mg/天,优选地为2至80mg/天,更优选地为5至70mg/天,并且还更优选地为10至50mg/天,所述剂量以孟鲁司特的当量剂量表示。
8.根据实施方案6所述应用的孟鲁司特或其可药用盐,其特征在于孟鲁司特或其可药用盐的剂量为5至15mg/天,优选地为7至13mg/天,更优选地为9至11mg/天,并且还更优选地,所述剂量为约10mg/天,所述剂量以孟鲁司特的当量剂量表示。
9.根据实施方案6所述应用的孟鲁司特或其可药用盐,其特征在于孟鲁司特或其可药用盐的剂量为7至25mg/天,优选地为10至20mg/天,更优选地为14至16mg/天,并且还更优选地,所述剂量为约15mg/天,所述剂量以孟鲁司特的当量剂量表示。
10.根据实施方案6所述应用的孟鲁司特或其可药用盐,其特征在于孟鲁司特或其可药用盐的剂量为10至30mg/天,优选地为15至25mg/天,更优选地为19至21mg/天,并且还更优选地,所述剂量为约20mg/天,所述剂量以孟鲁司特的当量剂量表示。
11.根据实施方案6所述应用的孟鲁司特或其可药用盐,其特征在于孟鲁司特或其可药用盐的剂量为12至37mg/天,优选地为20至30mg/天,更优选地为24至36mg/天,并且还更优选地,所述剂量为约25mg/天,所述剂量以孟鲁司特的当量剂量表示。
12.根据实施方案6所述应用的孟鲁司特或其可药用盐,其特征在于孟鲁司特或其可药用盐的剂量为15至45mg/天,优选地为25至35mg/天,更优选地为29至31mg/天,并且还更优选地,所述剂量为约30mg/天,所述剂量以孟鲁司特的当量剂量表示。
13.根据实施方案6所述应用的孟鲁司特或其可药用盐,其特征在于孟鲁司特或其可药用盐的剂量为20至60mg/天,优选地为35至45mg/天,更优选地为39至41mg/天,并且还更优选地,所述剂量为约40mg/天,所述剂量以孟鲁司特的当量剂量表示。
14.根据实施方案6所述应用的孟鲁司特或其可药用盐,其特征在于孟鲁司特或其可药用盐的剂量为25至75mg/天,优选地为45至55mg/天,更优选地为49至51mg/天,并且还更优选地,所述剂量为约50mg/天,所述剂量以孟鲁司特的当量剂量表示。
15.根据实施方案7至14中任一个所述应用的孟鲁司特或其可药用盐,其特征在于日剂量根据选自以下的剂量方案进行施用:每日一次(q.d)、每日两次(b.i.d.)、每日三次(t.i.d)和每日四次(q.i.d.),优选地,所述剂量方案选自每日一次和每日两次,并且更优选地,所述剂量方案为每日一次。
16.根据实施方案7至15中任一个所述应用的孟鲁司特或其可药用盐,其特征在于剂量根据患者对治疗的响应而调整。
17.根据实施方案1至5中任一个所述应用的孟鲁司特或其可药用盐,其特征在于孟鲁司特或其可药用盐用于表面施用。
18.根据实施方案1至5中任一个所述的孟鲁司特或其可药用盐,其特征在于孟鲁司特或其可药用盐为包含孟鲁司特或其可药用盐以及至少一种可药用赋形剂和/或载剂的药物组合物的形式。
19.根据实施方案18所述应用的孟鲁司特或其可药用盐,其特征在于孟鲁司特或其可药用盐为用于经口施用的固体药物组合物的形式,优选地选自片剂、胶囊剂、散剂和颗粒剂。
20.根据实施方案18所述应用的孟鲁司特或其可药用盐,其特征在于孟鲁司特或其可药用盐为用于经口施用的液体药物组合物的形式,优选地选自溶液剂和混悬剂。
21.根据实施方案19或20所述应用的孟鲁司特或其可药用盐,其特征在于每个单剂量,优选地,每个片剂、胶囊剂、散剂或颗粒剂单剂量小袋剂或液体测量单剂量包含孟鲁司特或其可药用盐为1至200mg,优选地为2至80mg,更优选地为5至70mg,并且还更优选地为10至50mg的剂量,所述剂量以孟鲁司特的当量剂量表示。
22.根据实施方案18所述应用的孟鲁司特或其可药用盐,其特征在于孟鲁司特或其可药用盐为用于表面施用的药物组合物的形式,优选地选自乳膏剂、凝胶剂、软膏剂和糊剂。
23.根据实施方案22所述应用的孟鲁司特或其可药用盐,其特征在于所述组合物中孟鲁司特或其可药用盐的量为0.5至50w/w%,所述量作为相对于所述组合物总重量的孟鲁司特的当量量表示。
接下来,出于举例说明本发明而不是限制本发明的目的,提供了一些实施例。
实施例
实施例1.-孟鲁司特口腔分散散剂(orodispersible powder)的制备
散剂形式的组合物使用下表中包含的重量浓度范围内的以下组分来制备:
将所有成分均置于合适的容器中并在转筒(rotating drum)中将其混合10至30分钟。将获得的混合物引入到单剂量小袋剂中。每个单剂量小袋剂包含200mg至500mg的组合物。
实施例2.-孟鲁司特片剂的制备
片剂形式的组合物使用以下组分来制备:
所述组合物根据以下程序制备:首先,将形成片剂的核心的所有成分筛分。然后,将活性成分与核心的剩余组分混合30分钟以达到均质。接下来,添加硬脂酸镁,并使混合物继续持续5至10分钟。将在压缩过程之后获得的片剂用包衣组分包衣所需的时间以达到适当的包覆。每个片剂包含200mg至500mg的组合物。
实施例3.-用于表面施用的水性凝胶稠度制剂的制备
凝胶剂形式的组合物使用以下组分来制备:
所述组合物根据以下程序制备:将孟鲁司特钠溶解于由纯化水、异丙醇、乙醇、肉豆蔻酸异丙酯和丁基羟基甲苯构成的混合物中。对混合物进行连续搅拌以获得均质。当混合物均质时,添加羟乙基纤维素,并搅拌混合物直至聚合物溶胀并且得到具有水性凝胶稠度的均质混合物。然后,添加香料并通过使用盐酸和氢氧化钠将pH调节至用于表面施用的适当值(5.5至8.0)。最后,将混合物搅拌至均质。
实施例4.-在患有侵蚀性手骨关节炎的患者中每日经口10mg孟鲁司特的临床研究
在患有侵蚀性手骨关节炎的患者中进行了初步的临床观察研究。
选择在用镇痛剂和/或抗炎剂治疗之后无响应或具有有限响应的患有侵蚀性手骨关节炎的50位患者以进行研究。根据每日一次剂量方案,使用如实施例1中所公开制备的经口可分散组合物,通过经口途径每日向患者施用10mg孟鲁司特。
治疗持续时间为3至16个月。
以下参数用于评价治疗效力:(i)临床症状的改善;(ii)疼痛减轻的效力;以及(iii)放射学评价的改善。所有评估均集中在患者的一只手上。
临床症状的改善通过评价使患者生活品质得到改善之受影响手的症状,例如功能性、僵硬和畸形的改善来评估。
对于评估疼痛减轻的效力,要求患者在治疗之前和在治疗期结束时两种情况下使用视觉模拟评分(visual analogue scale,VAS)方法评价他们感受到的疼痛。当基于0至10的评分,在治疗之后观察到至少2个单位的降低时,则认为该治疗对疼痛减轻是有效的。
对于评估该治疗在手放射学参数中的效力,对受影响关节的以下特征进行评价:a)水肿,b)软骨下侵蚀,c)滑膜炎和d)腱鞘炎。这些特征通过在治疗期之前和之后进行的手后前位射线照片来放射学评估。如果所评估特征的至少两个具有可观察到的改善并且其余特征未恶化,则认为该治疗提供了放射学改善。
在治疗期之后,32位患者显示临床症状改善。
在开始治疗之前,50位患者中的45位就已报道了疼痛。在治疗期之后,患有疼痛的那些45位患者中的28位报道了有效的疼痛减轻。
在放射学评价之后,28位患者显示出改善:28位显示出滑膜炎改善,18位显示出腱鞘炎改善,19位显示出水肿改善,以及14位显示出侵蚀改善。在这些患者中的大多数中,所评估的放射学特征的改善是显著的。此外,10位另外的患者显示出所评估的放射学参数未恶化。
实施例5.-在患有侵蚀性手骨关节炎的患者中每日经口20mg孟鲁司特的临床研究
对于该研究,从先前研究(实施例4)中在对治疗(每日10mg孟鲁司特)无响应的那些中选择了9位患者。
在本研究中,根据每日一次剂量方案,还使用如实施例1中所公开制备的经口可分散组合物,通过经口途径向患者施用20mg孟鲁司特的日剂量。患者的年龄为52至78岁。
与先前研究一样,对于评估疼痛减轻的效力,使用了视觉模拟评分(VAS)方法,其中疼痛针对0至10的评分进行评估。
对于评估手功能改善的效力,还使用了同样为0至10的视觉模拟评分(VAS),其中0意指完全功能性,即完全能够握住物体,并且10意指不存在功能性,即不能握住任何物体。
下表总结了该研究的结果:
任何经治疗患者均未报道不良作用。
“初始”值意指开始治疗之前的值,并且“最终”值意指完成治疗之后的值。
最小至最大范围示出了针对患者群体中的每个评估参数发现的个体最小值和最大值。
在疼痛方面,所有所选择患者在治疗之前均患有中度至重度的疼痛,因为通常认为VAS值高于4意指显著的疼痛。
在疼痛减轻和改善手功能性两个方面中,发现对每日20mg孟鲁司特的响应均高度显著,如前表中所示。
发现在治疗开始和结束时的两个变量均存在显著差异(在两种情况下均p<<0.0005),其中疼痛平均降低3.89±0.54并且手功能性平均改善4.56±0.39。对每日采用10mg孟鲁司特的治疗无响应的患者中的几乎70%当接受每日20mg孟鲁司特时均显示出为55%的疼痛减轻。所有患者当接受每日20mg孟鲁司特时均显示出手功能性显著改善(35%改善)。
实施例6.-在患有侵蚀性手骨关节炎的患者中表面孟鲁司特的效力
招募诊断为患有侵蚀性手骨关节炎的一位患者进行该研究,所述患者已用表面肾上腺皮质激素甲基泼尼松龙乙丙酸酯(methylprednisolone aceponate)治疗12周(每日一次),在疼痛减轻(使用VAS方法在0至10评分内仍具有高于5的评分)或在放射学评估(在治疗期间显示出疾病进展)两方面中均没有任何改善。
在数周的洗涤期(wash-up period)之后,患者开始用如实施例3中所公开制备的表面制剂进行治疗,其中剂量为每只手每日约10mg,涂抹在受影响区域上持续12周的时期。在治疗之后,患者显示出显著的疼痛减轻和骨关节炎临床症状的改善。
Claims (17)
1.孟鲁司特或其可药用盐用于制备用于在人对象中治疗侵蚀性手骨关节炎的药物的用途。
2.孟鲁司特的可药用盐用于制备用于在人对象中治疗侵蚀性手骨关节炎的药物的用途。
3.根据权利要求2所述的孟鲁司特的可药用盐的用途,其特征在于所述孟鲁司特可药用盐选自碱金属盐或碱土金属盐。
4.根据权利要求3所述的孟鲁司特的可药用盐的用途,其特征在于所述孟鲁司特可药用盐为孟鲁司特钠。
5.根据权利要求1所述的孟鲁司特或其可药用盐的用途,其特征在于孟鲁司特或其可药用盐用于经口施用。
6.根据权利要求5所述的孟鲁司特或其可药用盐的用途,其特征在于孟鲁司特或其可药用盐的剂量为1至200mg/天,所述剂量以孟鲁司特的当量剂量表示。
7.根据权利要求6所述的孟鲁司特或其可药用盐的用途,其特征在于孟鲁司特或其可药用盐的剂量为5至15mg/天,所述剂量以孟鲁司特的当量剂量表示。
8.根据权利要求6所述的孟鲁司特或其可药用盐的用途,其特征在于孟鲁司特或其可药用盐的剂量为7至25mg/天,所述剂量以孟鲁司特的当量剂量表示。
9.根据权利要求6所述的孟鲁司特或其可药用盐的用途,其特征在于孟鲁司特或其可药用盐的剂量为10至30mg/天,所述剂量以孟鲁司特的当量剂量表示。
10.根据权利要求6所述的孟鲁司特或其可药用盐的用途,其特征在于孟鲁司特或其可药用盐的剂量为15至45mg/天,所述剂量以孟鲁司特的当量剂量表示。
11.根据权利要求1所述的孟鲁司特或其可药用盐的用途,其特征在于孟鲁司特或其可药用盐用于表面施用。
12.根据权利要求1所述的孟鲁司特或其可药用盐的用途,其特征在于孟鲁司特或其可药用盐为包含孟鲁司特或其可药用盐以及至少一种可药用赋形剂和/或载剂的药物组合物的形式。
13.根据权利要求12所述的孟鲁司特或其可药用盐的用途,其特征在于孟鲁司特或其可药用盐为选自片剂、胶囊剂、散剂或颗粒剂的用于经口施用的固体药物组合物的形式。
14.根据权利要求13所述的孟鲁司特或其可药用盐的用途,其特征在于所述散剂或颗粒剂为单剂量小袋剂的形式,并且特征在于每个片剂、胶囊剂或散剂或颗粒剂单剂量小袋剂包含1至200mg剂量的孟鲁司特或其可药用盐,所述剂量以孟鲁司特的当量剂量表示。
15.根据权利要求12所述的孟鲁司特或其可药用盐的用途,其特征在于孟鲁司特或其可药用盐为用于表面施用的药物组合物的形式。
16.根据权利要求15所述的孟鲁司特或其可药用盐的用途,其特征在于所述用于表面施用的药物组合物为乳膏剂、凝胶剂、软膏剂或糊剂。
17.根据权利要求15所述的孟鲁司特或其可药用盐的用途,其特征在于所述组合物中孟鲁司特或其可药用盐的量为0.5至50w/w%,所述量以相对于所述组合物总重量的孟鲁司特的当量的量表示。
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AU2019386235A1 (en) | 2021-07-01 |
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