CN110141557A - 氢化可的松控制释放制剂 - Google Patents
氢化可的松控制释放制剂 Download PDFInfo
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- CN110141557A CN110141557A CN201910452557.1A CN201910452557A CN110141557A CN 110141557 A CN110141557 A CN 110141557A CN 201910452557 A CN201910452557 A CN 201910452557A CN 110141557 A CN110141557 A CN 110141557A
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- hydrocortisone
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Abstract
本公开涉及包含氢化可的松的药物制剂及其在治疗疾病状况中的应用,所述疾病状况为受益于氢化可的松的延迟释放的疾病状况,特别是诸如肾上腺功能不全、炎性状况和抑郁症的疾病状况。
Description
本申请是2013年02月12日提交的发明名称为“氢化可的松控制释放制剂”的第201380008921.6号中国专利申请的分案申请。
技术领域
本公开涉及包含氢化可的松的药剂及其在治疗疾病状况中的应用,所述疾病状况将从氢化可的松的控制释放中获益,特别是诸如肾上腺功能不全、炎性状况和抑郁症的疾病状况。
发明背景
在哺乳动物中,生理节律或中枢生物钟的基本振荡器位于视交叉上核中。该主控振荡器负责醒睡周期和激素节律(例如,皮质醇和褪黑素)。已经了解到,周边组织如免疫细胞和肝也具有时钟基因及其自身的分子振荡能力。基因表达、生理和行为的日节律维持在恒定条件下,并因此,必须由称为生物钟的自我维持生物振荡器来驱动。生物钟仅能大约地计算时间,并必需每天通过光周期进行调整,以与外界保持一致。
需要研发药物递送方式以提供受控的药物释放,特别是与患者的生理节律保持一致的方式。存在可从该治疗方案获益的多种疾病状况,例如肾上腺衰竭,原发性、二发性、三发性肾上腺功能不全和类固醇停药综合征,炎性疾病如风湿性关节炎,以及抑郁症和相关抑郁病治疗中的疾病状况,包括慢性疲劳和肌痛性脑炎(ME)。
肾上腺衰竭发病于约1/10,000的人群。其可能是由于原发性肾上腺衰竭或二发性肾上腺衰竭(其发病是由于可能由脑垂体瘤或手术造成的脑垂体衰竭)。在原发性肾上腺衰竭中,来自脑垂体的ACTH水平将会升高,而在二发性肾上腺衰竭中,ACTH水平不恰当地偏低。给予外源性糖皮质激素或如在库欣氏症候群(Cushing’s syndrome)中过量的内源性糖皮质激素分泌造成下丘脑-脑垂体-肾上腺(HPA)轴的抑制,并且发生于来自下丘脑、脑垂体和肾上腺的所有水平。这被称为三发性肾上腺功能不全。这意味着在过度糖皮质激素暴露后,患者将具有低皮质醇水平,并遭受临时的或偶发的恒定皮质醇缺陷(三发性肾上腺功能不全),其导致疲乏、体重减轻和肾上腺危机倾向。
长效合成糖皮质激素如泼尼松龙和地塞米松,相比氢化可的松更可能造成肾上腺抑制。氢化可的松具有短半衰期(约3小时)优势,为天然糖皮质激素,并能以低剂量给予。然而,氢化可的松的当前制剂不能再造皮质醇的生理节律。为了将HPA的恢复最大化,糖皮质激素剂量不应当超过正常每日需要量,并还应允许启动正常皮质醇节律。如果即时释放的糖皮质激素在夜间给予,则其通常将阻止HPA轴的夜间活性。HPA轴的抑制可由于以外源性糖皮质激素过度处理而发生,如在治疗炎性状况如风湿性关节炎和哮喘中。类似地,已被广泛认识到,由脑垂体或产生异位肿瘤的ACTH或产生肾上腺肿瘤的皮质醇引起的库欣氏症候群可造成肾上腺抑制。
炎症是身体响应其细胞和带血管组织损伤的复杂反应。炎症可为急性的或慢性的。急性炎症反应为免疫系统对有害试剂的即时反应。该反应包括血管膨胀、内皮和嗜中性细胞激活。急性炎症反应将会消退或发展成慢性炎症。慢性炎症为较长时间长度的炎症反应,其持续数周、数月或甚至无期限,其延长的时间进程由针对组织中炎症的诱发性刺激的持续引起。炎性过程必然造成组织损伤。慢性炎症的具体性质、程度和时间进程是可变的,并取决于病原体和身体将其清除的尝试之间的平衡。产生慢性炎症的发病原因包括但不限于:能躲避或抵抗宿主防御并因此在组织中存留较长时间的感染性生物体;并非天然抵抗但存留于损伤区域的感染性生物体,在该处它们被保护而免于暴露于宿主防御;不能被酶分解或吞噬作用清除的刺激性非生命外来物质;或其中该刺激物为“正常”组织成分,造成自身免疫疾病。
糖皮质激素通常用于治疗炎性疾病。常见副作用为皮质醇的内源性生理节律的抑制。结果在撤除糖皮质激素期间患者可能需要断药,并且在该断药期间,他们可能会出现疾病的爆发,或经历短暂的可能引起他们疾病爆发的皮质醇缺陷。抑制起因于其作用为抑制皮质醇的生理节律的外源性糖皮质激素的引发。该抑制发生于所有的下丘脑-脑垂体-肾上腺轴水平。替代性的治疗方案为使用类固醇治疗炎性状况。类固醇如泼尼松龙被用于治疗风湿性关节炎,并可有效减少炎症。如果使用类固醇较长时间,则它们的副作用包括骨质疏松症、皮肤变薄、体重增加和库欣氏症候群的肌肉萎缩所有特征。另外,给予类固醇抑制了皮质醇从肾上腺腺体的内源性节律分泌,并且这可对用类固醇治疗的患者产生影响。
已被广泛认识到,抑郁症与正常皮质醇生理节律的丧失相关。同样已被广泛认识到,库欣氏症候群(其中肿瘤造成皮质醇的生理节律丧失)造成抑郁症[例如,生理节律的丧失造成疾病]。造成抑郁症或全身不适的疾病状况是公知的。这些包括但不限于:临床抑郁症、反应性抑郁症、产后抑郁症、大手术引起的抑郁症、慢性疲劳、肌痛性脑炎和诸如时差综合征的疾病状况。抑郁状况还可由自我施加的外部效应引起,例如抑郁症可在人因努力减肥而节食或在人尝试治疗上瘾如吸烟或可卡因成瘾时产生。还存在严重性较低的造成全身不适疾病状况,例如非正常工作时间(unsociable hour)工作的轮班工作人员由于其正常睡眠模式破坏,可能变得疲劳和压抑。还已知一年的某些时段可引起抑郁症,例如圣诞节和季节性情绪失调(SAD)。抑郁症的生理效应有差异。然而,一些普遍特性包括:造成高皮质醇水平、皮质醇生理节律丧失和睡眠障碍与早醒的下丘脑-脑垂体-肾上腺轴活性过高。夜间或入睡时的高糖皮质激素水平还可自身破坏睡眠。
在WO2003/015793和WO2010/032006中,我们公开了在控制肾上腺功能不全和其他疾病状况中以延迟和缓释方式递送糖皮质激素的药物延迟和缓释制剂。本公开涉及施用延迟释放制剂,其令人吃惊地还可用于治疗可从糖皮质激素如氢化可的松的节律递送获益的疾病状况,如原发性、二发性和三发性肾上腺功能不全、炎性疾病和状况以及抑郁症和抑郁病。
发明内容
根据本发明的一个方面,提供了适于经口给药的药物组合物,其包含:包含氢化可的松和载体的核,以及与所述核接触的包含延迟释放聚合物的层,其中所述延迟释放聚合物为pH敏感性肠溶聚合物,并且适于从所述核延迟释放氢化可的松。
根据本发明的一个方面,提供了适于经口给药的药物组合物,其包含:包含氢化可的松和载体的核,以及与所述核接触的包含延迟释放聚合物的层,其中所述延迟释放聚合物为单一的或混合的pH敏感性肠溶聚合物,并且适于从所述核延迟释放氢化可的松,特征在于所述核包含微晶纤维素,其为组合物的75-85%w/w。
因此,对于重建该节律的药物,当在夜间作为最后一件事于约20:00时-24:00时服用时,药物将需要2-5h的释放延迟,并在06:00时-09:00时释放而提供峰值水平,并直到约19:00时维持皮质醇水平高于100nmol/l。天然地,该药物可在晚间早些时候或更晚服用,这取决于对象的正常睡眠模式,并且接着可恰当地相位提前或延迟其节律。
在本发明的优选实施方案中,所述载体为亲水性分子。
在本发明的优选实施方案中,所述亲水性分子或聚合物选自:甘露醇、木糖醇、蔗糖或葡萄糖。
优选地,所述亲水分子为糖珠形式。
在本发明的替代性优选实施方案中,所述载体为亲水聚合物。
在本发明的优选实施方案中,所述亲水聚合物为羟丙甲基纤维素或羟丙乙基纤维素。
在本发明的替代性优选实施方案中,所述载体为疏水性聚合物或小分子。
优选地,所述疏水性聚合物为微晶纤维素或磷酸二钙。
在本发明的优选实施方案中,所述载体包含微晶纤维素颗粒,其中所述颗粒的直径为200μm-1200μm。
优选地,所述颗粒的直径为500μm-800μm。
在本发明的优选实施方案中,所述载体包含组合物的75-85%w/w的微晶纤维素,或基本上由组合物的75-85%w/w的微晶纤维素组成。
优选地,所述载体包含80-82%w/w的微晶纤维素;最优选地,组合物的约81%w/w的微晶纤维素。
在本发明的优选实施方案中,氢化可的松在所述载体中或在所述载体上存在的浓度为组合物的2-10%w/w。
更优选地,氢化可的松在所述载体中或在所述载体上的浓度为组合物的5-8%w/w。
在本发明的更优选的实施方案中,氢化可的松的浓度为组合物的约6%w/w。
在本发明的优选实施方案中,氢化可的松在所述载体中或在所述载体上与粘合剂如聚维酮一起存在。
优选地,聚维酮的浓度为组合物的0.5-4%w/w。
更优选地,聚维酮的浓度为组合物的1.5-3%w/w。
在本发明的优选实施方案中,提供的聚维酮的浓度为组合物的约1.8%w/w。
在本发明的优选实施方案中,所述延迟释放层为肠溶聚合物,其中所述组合物在pH 5.5-7.0溶解;优选在pH 6.0-6.8溶解。
在本发明的优选实施方案中,所述肠溶聚合物选自:丙烯酸和/或聚[甲基]丙烯酸聚合物、醋酸琥珀酸纤维素或聚乙烯醋酸酯邻苯二甲酸酯。
优选地,所述肠溶聚合物为甲基丙烯酸衍生物;优选为Eudragit L100和/或Eudragit S100。
在本发明的优选实施方案中,所述肠溶聚合物为Eudragit S100。
在本发明的替代性优选实施方案中,所述层基本上由Eudragit S100和EudragitL100的混合物组成。
在本发明的优选实施方案中,Eudragit S100与Eudragit L100的比例为约4:1。
在本发明的优选实施方案中,提供的所述肠溶聚合物为组合物的5-10%w/w,优选6-8%w/w,最优选约7%w/w。
在本发明的优选实施方案中,所述肠溶聚合物层包含增塑剂如癸二酸二丁酯。
优选地,所述肠溶聚合物层中存在的癸二酸二丁酯为组合物的0.5-1.0%w/w。
更优选地,所述肠溶聚合物层中存在的癸二酸二丁酯为组合物的约0.7%w/w。
根据本发明的一个方面,提供了适于经口给药的药物组合物,其包含:
包含氢化可的松和载体的核;
包含与所述核接触的延迟释放聚合物的层,其中所述延迟释放聚合物为pH敏感性肠溶聚合物,其为组合物的约6-7%w/w的Eudragit L100和Eudragit S100[1:4]的混合物,其适于从所述核延迟释放氢化可的松。
在本发明的优选实施方案中,所述组合物基本上由核和表1所示的延迟释放层组成。
在本发明的优选实施方案中,所述组合物包含每单位剂量1-30mg的氢化可的松或醋酸可的松;优选每单位剂量约5、10、20或30mg的氢化可的松。
在本发明的优选实施方案中,所述组合物被压缩在片剂中,或填充至外部胶囊中,或塑造成可经口给药的合适剂量形式。
当给药时,氢化可的松制剂以药学可接受的制剂给药。此类制剂可常规地含有药学可接受的稀释剂、载体或加工助剂如无机盐、赋形剂填充物、缓冲剂、防腐剂和相容性载体。
此类数量当然取决于处理的具体条件、疾病状况的严重性、个体患者参数包括年龄、身体状况、体积和重量、治疗时长、同时治疗(若存在)的性质等健康从业者知识和专业范围内的因素。这些因素为本领域技术人员熟知,并可仅使用常规实验解决。通常优选地,可使用单独组分或其组合的最大剂量,即根据合理的医学判断的最高安全剂量。所用的氢化可的松制剂含有有效量的药物,用于以适于给予至患者的单位重量或体积产生期望的反应。
可根据不同的参数,特别是对象的状态以及他们的重量挑选给予至对象的氢化可的松的剂量。其他因素包括期望的治疗时长。在施用起始剂量时对象中的反应不足的情况下,可采用患者耐受性允许程度的较高剂量(或通过不同的、更局部化的递送途径的有效更高剂量)。
给予氢化可的松制剂至除人外的哺乳动物(例如,用于检测目的或兽医治疗目的),在基本上与上述相同的条件下进行,尽管剂量将根据治疗动物的大小而变化。如本文所用,对象为哺乳动物,优选为人,并且包括非人的灵长类、牛、马、猪、绵羊、山羊、狗、猫或啮齿类。
给药时,氢化可的松制剂以药学可接受的量和药学可接受的组合物给药。术语“药学可接受的”指不干扰活性成分的生物活性效力的无毒物质。此类制剂可常规地含有盐、缓冲剂、防腐剂、相容性载体以及任选的其他治疗剂。当用于药物时,所述盐应当是药学可接受的,但非药学可接受的盐可常规地用于制备其药学可接受的盐,并且不排除在本发明范围外。此类药理学和药学可接受的盐包括但不限于从以下酸制备的那些:盐酸、氢溴酸、硫酸、硝酸、磷酸、马来酸、醋酸、水杨酸、柠檬酸、甲酸、丙二酸、琥珀酸等。另外,药学可接受的盐可制备为碱金属盐或碱土盐如钠盐、钾盐或钙盐。
如有需要,氢化可的松制剂可与药学可接受的载体组合。如本文所用,术语“药学可接受的载体”指一种或多种相容性固体或液体填充物、稀释剂或包封物质,其适于给予至人,且通常为惰性的。术语“载体”表示有机或无机成分,其为天然的或合成的,与活性成分组合以促进应用。药物组合物的成分还能以彼此之间不产生实质上损害所需药物效力的相互作用的方式,与氢化可的松彼此融合。
多颗粒核基质可与药学可接受的赋形剂组合,所述赋形剂可包括:(a)填充物如乳糖、甘露糖、磷酸二钙、微晶纤维素、淀粉、预凝胶化淀粉;(b)粘合剂如羟丙基纤维素、聚乙烯吡咯烷酮、聚醋酸乙烯酯;(c)粉末增流剂如胶状二氧化硅;(d)润滑剂如硬脂酸镁、硬脂酰富马酸钠;(e)崩解剂如淀粉乙醇酸钠和聚乙烯吡咯烷酮,和(f)抗粘着剂如滑石。
氢化可的松制剂可含有合适的溶解增强剂和缓冲剂。氢化可的松制剂还可任选地含有本领域技术人员已知的相容性防腐剂或化学和物理稳定剂。
在本发明的替代性优选实施方案中,氢化可的松可替代醋酸可的松。
根据本发明的另一方面,提供了本发明的用于治疗肾上腺功能障碍的药物组合物。
优选地,肾上腺功能障碍由选自以下的疾病状况引起:原发性或二发性或三发性肾上腺衰竭、先天性肾上腺增生、迟发性先天性肾上腺增生、多囊卵巢衰竭、糖皮质激素可抑制性醛固酮增多症(GRA)。
在本发明的优选实施方案中,所述疾病状况为三发性肾上腺功能不全。
三发性肾上腺功能不全为由先前的类固醇治疗或库欣氏症候群引起的肾上腺功能不全。对于三发性肾上腺功能不全,治疗方案可用于传统的肾上腺功能不全,但同时可能需要使对象停止使用类固醇,并尝试恢复脑垂体肾上腺通路,例如类固醇撤药。在该情形下,治疗方案将在夜间给予本发明的延迟制剂,以再造皮质醇的夜间分泌并逐渐停用剂量来允许恢复脑垂体肾上腺通路。这类方案可应用于不同的适应证,例如针对炎性疾病如风湿性关节炎或在癌症治疗中具有一段时间的高剂量类固醇的患者。通常,治疗方案将允许从三发性肾上腺功能不全或脑垂体肾上腺通路的部分抑制恢复。
在本发明的优选实施方案中,肾上腺功能障碍由先天性肾上腺功能障碍引起。
在本发明的优选实施方案中,所述组合物在20:00时-24:00时给药;优选地,第二组合物在06:00时-10:00时给药。
根据本发明的一个方面,提供了治疗对象中的肾上腺功能不全的方法,所述对象具有肾上腺皮质醇分泌缺陷或患有糖皮质激素可抑制性醛固酮增多症(GRA),所述方法包括如下或由如下组成:
i)在20:00时-24:00时给予本发明的第一组合物;和
ii)在06:00时-10:00时给予本发明的第二组合物,其中第一和第二组合物的组合再造皮质醇分泌的正常生理节律,从而以生理方式控制肾上腺功能不全。
根据本发明又一个方面,提供了治疗肾上腺功能不全或糖皮质激素抑制性醛固酮增多症的治疗方案,包括如下或由如下组成:提供本发明的第一组合物至患有肾上腺功能不全的对象并在20:00时-24:00时给予所述第一组合物;以及提供本发明的第二组合物并在06:00时-10:00时给予至所述相同的对象,用于控制肾上腺功能不全。
在本发明的优选方法或用途中,所述第一和第二组合物包含1-60mg的氢化可的松;优选约5-40mg的氢化可的松;优选在夜间给予三分之二,并在早晨给予三分之一,例如夜间50-70%和早晨30-50%。
在本发明的优选方法或用途中,肾上腺功能不全由选自以下的疾病状况引起:原发性或二发性或三发性肾上腺衰竭、先天性肾上腺增生、迟发性先天性肾上腺增生、多囊卵巢衰竭或阿狄森氏病。
根据本发明的其他方面,提供了本发明的药物组合物用于治疗炎性疾病或状况。
优选地,所述炎性疾病或状况由自身免疫疾病引起。
存在大量的展现慢性炎性组分的疾病。这些包括但不限于:炎性关节病(例如,风湿性关节炎、风湿性多肌痛(PMR)骨关节炎、多发性关节炎和痛风)、慢性炎性结缔组织病(例如,全身性红斑狼疮、硬皮病、干燥综合征(Sjorgen’s Syndrome)、多肌炎和皮肌炎、血管炎、混合性结缔组织病(MCTD)、肌腱炎、滑膜炎、细菌性心内膜炎、骨髓炎和牛皮癣);慢性炎性肺病(例如,哮喘、慢性呼吸道疾病、肺炎、纤维性肺泡炎、慢性支气管炎、慢性阻塞性肺病(COPD)、支气管扩张、气肿、硅肺和其他尘肺病和结核病);慢性炎性肠病和胃肠道炎性疾病(例如,溃疡性结肠炎和克罗恩氏病);慢性神经性炎性疾病(例如,慢性炎性脱髓鞘多神经根神经病、慢性炎性脱髓鞘多神经病、多发性硬化、格林巴利综合征(Guillan-BarreSyndrome)和重症肌无力(myasthemia gravis));其他炎性疾病(例如,乳腺炎、蹄叶炎、喉炎、慢性胆囊炎、桥本氏甲状腺炎、炎性乳腺病);伤口中植入的外来体引起的慢性炎症;并且包括慢性炎性肾脏疾病,包括新月体性肾小球肾炎、狼疮性肾炎、ANCA相关的肾小球性肾炎、局灶性节段性坏死肾小球性肾炎、IgA肾病、膜增生性肾小球肾炎、冷球蛋白血症和肾小管间质性肾炎。糖尿病性肾病还可具有慢性炎性组分,并且慢性炎性反应涉及移植器官的排斥。显然许多疾病具有炎性组分,其中许多为自身免疫疾病。
在本发明的优选实施方案中,所述炎性疾病为风湿性关节炎或风湿性多肌痛。
在本发明的替代性实施方案中,所述炎性疾病为炎性肠病。
在本发明的优选实施方案中,所述炎性肠病选自:克罗恩氏病、溃疡性结肠炎、胶原性结肠炎、淋巴细胞性结肠炎、缺血性结肠炎、改道性结肠炎、白塞氏(Behcet’s)结肠炎。
在本发明的优选实施方案中,所述炎性肠病为克罗恩氏病。
在本发明的其他优选实施方案中,所述炎性肠病为溃疡性结肠炎。
在本发明的优选实施方案中,所述组合物在睡觉前给药,例如在20:00时-24:00时。
根据本发明的一个方面,提供了治疗对象中的炎性疾病或状况的方法,所述对象患有所述疾病或状况,所述方法包括如下或由如下组成:在睡觉前给予有效量的至少一种本发明的组合物,其中所述一种或多种组合物不抑制皮质醇分泌的正常生理节律,并控制所述炎性疾病或状况。
在本发明的优选方法中,所述疾病为风湿性关节炎。
在本发明的替代性优选实施方案中,所述疾病为炎性肠病。
优选地,炎性肠病为克罗恩氏病或溃疡性结肠炎。
在本发明的优选方法或用途中,所述第一和第二组合物包含1-60mg的氢化可的松;优选约5-40mg的氢化可的松;最优选20-30mg的氢化可的松。
在本发明的优选方法中,本发明的所述组合物每夜提供一次。
根据本发明的又一个方面,提供了本发明的药物组合物,其中所述组合物提供了氢化可的松的延迟释放,以重置和重新调整皮质醇在治疗抑郁症或抑郁症相关疾病状况中的生理节律。
可从重新调整皮质醇分泌获益的疾病或状况包括但不限于:抑郁症、睡眠障碍、疲乏、饮食异常、成瘾、焦虑、免疫反应、炎症、关节炎、哮喘、时差综合征。
在本发明的优选实施方案中,所述应用为治疗抑郁症或造成抑郁症的状况,或类似疾病状况。
在本发明的优选实施方案中,所述抑郁症为临床抑郁症。
在本发明又一优选实施方案中,所述抑郁症为反应性抑郁症。
在本发明还一优选实施方案中,所述抑郁症为产后抑郁症。
在本发明又一优选实施方案中,所述疾病状况或不适选自:慢性疲劳综合征;肌痛性脑炎;时差综合征;轮班工作综合征、人过胖导致的抑郁症;节食导致的抑郁症;治疗烟癖导致的抑郁症;治疗酒癖导致的抑郁症;治疗药瘾(例如,可卡因、海洛因)导致的抑郁症;治疗季节性情绪失调或类似疾病状况。
在本发明的其他优选实施方案中,所述疾病状况由给予抗精神病药引起。
在本发明的优选方法中,所述抗精神病药选自:氯氮平、奥氮平、利培酮、喹硫平或舍吲哚。
根据本发明又一个方面,提供了制备延迟释放氢化可的松制剂的方法,包括以下步骤:
i)配制悬液,其在含有媒介物中包含氢化可的松和粘合剂;
ii)提供微粒载体;
iii)将氢化可的松悬液涂覆于微粒载体以包被所述载体;
iv)干燥氢化可的松包被的微粒载体;
v)提供包含延迟释放聚合物的胶体溶液,其中所述延迟释放聚合物为单一的或混合的pH敏感性肠溶聚合物、溶剂或溶剂混合物、抗粘着剂/助流剂和增塑剂;
vi)将(v)中形成的溶液涂覆于干燥的vii)中的微粒载体;以及任选地
viii)将完成的制剂包封成单位剂量形式。
在本发明的优选方法中,所述粘合剂包括聚维酮。
在本发明的优选方法中,所述微粒载体为微晶纤维素或糖珠。
在本发明的优选方法中,所述混合的延迟释放聚合物包含Eudragit S100和Eudragit L100的混合物。
优选地,Eudragit S100和Eudragit L100以约4:1的比例混合。
在本发明的优选方法中,所述增塑剂为癸二酸二丁酯。
在本发明的优选方法中,所述抗粘着剂/助流剂为滑石。
在本发明的优选方法中,氢化可的松和粘合剂溶液作为喷雾剂施用。
在本发明方法的优选方法中,所述延迟释放聚合物溶液作为喷雾剂施用。
根据本发明又一个方面,提供了根据本发明方法制备的药物制剂。
在本发明的优选实施方案中,提供的氢化可的松终浓度为通过本方法形成的组合物的2-10%w/w、5-8%w/w或约6%w/w。
在本申请文件的整个说明书和权利要求中,词语“包括(comprise)”和“含有(contain)”以及这些词语的变形,例如“包括(comprising)”和“包括(comprises)”意指“包括但不限于”,并且不试图(且不)排除其他部分、添加物、组分、整数或步骤。
在本申请文件的整个说明书和权利要求中,单数形式包括复数,除非上下文另有要求。具体而言,当使用不定冠词时,申请文件应当理解为包括复数以及单数形式,除非上下文另有要求。
结合本发明的具体方面、实施方案或实例描述的特征、整数、特性、化合物、化学部分或基团应当理解为适用于本文描述的任何其他方面、实施方案或实例,除非与其不相容。
现在将仅通过实例并参照以下附图描述本发明的实施方案:
图1:阐示了健康志愿者的24小时节律谱分析;
图2A:阐示了延迟和缓释氢化可的松制剂[DIURF-001]相比图2B(其阐示了延迟释放氢化可的松制剂[DIURF-006])的体外溶解图谱;
图3:阐示了延迟和缓释氢化可的松制剂与延迟释放氢化可的松制剂的药代动力学比较;和
图4为延迟氢化可的松图谱相比正常节律图谱,以阐示使用氢化可的松的延迟制剂来重建皮质醇的节律释放。
图5:对于夜间(23:00时)以单一剂量5mg、10mg和20mg给药的氢化可的松平均血浆浓度相对于时间的曲线图。
图6:对于以30mg的累积剂量(夜间(23:00时)给药20mg,且早晨(7:00时)给药10mg)给药的氢化可的松平均血浆浓度相对于时间的曲线图。对皮质醇(Debono et al.,2009)和氢化可的松即时释放片剂(来自研究DIUR-001)的标准公布数据进行比较。
图7:针对涵盖5mg-30mg剂量范围的曲线(AUC0-t)下面积,比较从制剂暴露的氢化可的松。
定义
“控制释放”是通过剂量形式递送的药物释放谱,通常通过零级或一级,目的是维持血流中的药物水平,其在给药间隔中随时间保持不变。
“延迟释放”是通过剂量形式递送的药物释放谱,其特征在于在主要的药物释放阶段前的起始阶段完全无药物释放或非常低的药物释放,通常小于或等于剂量形式中10%的总剂量。
“缓释”是通过剂量形式递送的药物释放谱,通常通过一级或假一级,目的是维持持续释放以便给药频率小于或等于以即时释放剂量形式得到的一半。
“肠溶聚合物”是同聚物或共聚物或它们的混合物,其在含水介质中具有pH依赖性溶解性,特征通常在于在酸性条件(pH 1-4)下具低水溶性,且在弱酸性条件及更高(pH>5)下具较高水溶性。目的是保护药剂在肠的酸性胃部环境中免于聚合物溶解介导的释放。
“Eudragit L100”是定义的聚甲基丙烯酸酯[CAS号:2506-15-1]与化学组合物:聚(甲基丙烯酸、甲基甲基丙烯酸酯)以1:1比例的混合物。
“Eudragit S100”是定义的聚甲基丙烯酸酯[CAS号:25086-15-1]与化学组合物:聚(甲基丙烯酸、甲基甲基丙烯酸酯)以1:2比例的混合物。
术语“多颗粒”和“微粒”可互换使用,且在形式和功能上彼此等同。
材料和方法
制备方法
制剂DIURF-001的制备方法包括步骤1-4。
制剂DIURF-006的制备方法仅包括步骤1、3和4。
工艺步骤1:制备氢化可的松包被的
的描述
·称出相关量的所需物质。
·将聚维酮加至水中,并使用顶置式搅拌器混合约5分钟。
·向聚维酮溶液中加入氢化可的松,并使用合适的拌匀器拌匀。混合直到均匀(约30分钟)。
·去除拌匀器并用顶置式搅拌器替代。确保悬液在整个喷射过程中得到混合。
·以Wurster附加装置和保留篮装配流化床干燥器(例如:Glatt GPCG3)。
·将放入流化床干燥器中,并流化直到产物温度超过20℃。
·将Wurster附加装置设定至25mm高,同时流化
·使用以下参数喷射API溶液:-
雾化空气=~1.8bar
过滤振荡器=15秒每30秒
入口空气温度=40℃
入口空气体积=60m3/sec
泵速=~15g/min(对于最初30分钟),其后为~18g/min。
[使用:对于上述操作,400μm保留篮]
·以重量计根据悬液喷射在样品批次上的量来确定终点。
·在喷射过程完成后,将氢化可的松包被的保持流化30分钟,以允许它们充分干燥。
·通过1.4mm筛来筛选氢化可的松包被的这将去除任何团聚体。
工艺步骤2:缓释涂层的描述
·称出相关量的所需物质。
·以足以制造出漩涡但不溢出的速度,使用顶置式搅拌器将异丙醇、丙酮、Eudragit RL100/RS100混合在一起。混合直到得到溶液。
·向所述溶液中加入癸二酸二丁酯、纯净水和滑石,并在整个包被过程中继续混合以保持滑石悬浮。
·用Wurster附加装置和保留篮装配流化床干燥器。
·将氢化可的松包被的(来自单元工艺1)放入流化床干燥器中,并流化直到产物温度达到20℃-25℃。
·将Wurster附加装置设定至25mm高,同时流化氢化可的松包被的
·使用以下参数喷射聚合物悬液:-
雾化空气=~1.8bar
过滤振荡器=15秒每30秒
入口空气温度=25℃
入口空气体积=60m3/sec
泵速=~15g/min(对于最初30分钟)。其后为~18g/min。
[使用:对于上述操作,400μm保留篮]
·以重量计根据悬液喷射在样品批次上的量来确定终点。
·一旦达到终点,即停止喷射悬液,并从流化床干燥器去除氢化可的松缓释包被的
·通过1.4mm筛来筛选氢化可的松缓释包被的这将去除任何团聚体。
·将约1%重量的滑石加入至氢化可的松缓释包被的以降低任何粘着的可能性。
工艺步骤3:肠溶(延迟释放)涂层的描述
·称出相关量的所需物质。
·以足以制造出漩涡但不溢出的速度,使用顶置式搅拌器将异丙醇、丙酮、Eudragit S100和L100混合在一起。混合直到得到溶液。
·向溶液中加入癸二酸二丁酯、水和滑石,并在整个包被过程中继续混合以保持滑石悬浮。
·用Wurster附加装置和保留篮装配流化床干燥器。
·将氢化可的松缓释包被的放入流化床干燥器中,并流化直到产物温度达到20℃-25℃。
·将Wurster附加装置设定至25mm高,同时流化氢化可的松缓释包被的
·使用以下参数喷射聚合物悬液:-
雾化空气=~1.8bar
过滤振荡器=15秒每30秒
入口空气温度=25℃
入口空气体积=60m3/sec
泵速=~15g/min(对于最初30分钟)。其后为~18g/min。
[使用:对于上述操作,400μm保留篮]
·以重量计根据悬液喷射在样品批次上的量来确定终点。
·一旦达到终点,即停止喷射悬液,并从流化床干燥器去除氢化可的松缓释和延迟释放包被的
·通过1.4mm筛来筛选氢化可的松延迟释放和缓释包被的这将去除任何团聚体。
·将约1%重量的滑石加入至氢化可的松延迟释放和缓释包被的以降低任何粘着的可能性。
工艺步骤4:封装、散货包装和标记的描述
·装配封装机器。
·用氢化可的松延迟释放和缓释包被的(来至单元工艺3)填充料斗。
·用空大小00胶囊壳填充胶囊固定器。
将机器设定为填充所需的填充重量。
溶解方法
使用USP装置I(篮)进行氢化可的松控制释放多颗粒的溶解检测,采用总共900mL的溶解介质,包括随后两次依次进行的介质改变,并且篮速为100rpm。最初在700mL的模拟胃液(USP,pH 1.2)中进行溶解2小时,然后进一步在调节至pH 6.0(通过加入150mL预热的0.18M正磷酸三钠十二水合物缓冲液)的850mL介质中溶解1小时,然后在调节至pH 7.2(通过加入50mL预热的0.23M正磷酸三钠十二水合物缓冲液)的900mL介质中溶解。
氢化可的松的检测
使用以下方法测定在多颗粒形式中的和在溶解评估期间释放的氢化可的松的浓度。将氢化可的松溶液稀释在包含四氢呋喃/水(20:80v/v)的流动相溶液中。将产生的溶液载入HPLC,以Phenomenex Luna柱C18(2),5μm,150mm x 4.6mm装配,在45℃平衡。使用等度条件采用四氢呋喃/水(20:80v/v)作为流动相以1.5mL/分钟的流速运行样品。通过UV在254nm的波长下检测。
实施例
实施例1
在健康志愿者中分析了人对象中皮质醇的节律分泌。通过液相色谱–质谱(LC-MS)测量皮质醇。计算了皮质醇水平的几何平均数(黑线);参见图1。顶部灰线为几何平均数的第90百分位数,并且底部灰线为几何平均数的第10百分位数。样品以20min间隔获得。使用Waters Xevo质谱仪用Acquity uPLC系统(定量限为0.01μg/dl或0.3nmol/l,且低皮质醇水平处相对标准偏差<15%,而中等和高皮质醇水平处<10%)测量了28名健康志愿者的24h皮质醇谱。皮质醇分泌的生理节律得到清晰显示,其峰值水平在06:00-09:00时,皮质醇水平维持在高于100nmol/l直到约19:00时;参见图1。
实施例2
图2阐示了缓释且延迟释放氢化可的松制剂与延迟释放制剂的体外溶解。图2A显示了药物释放开始前约3小时延迟时间,随后为约8-10小时的药物缓释阶段。相反,在图2B中,延迟释放氢化可的松制剂的体外溶解图谱显示了药物释放开始前类似的3小时延迟时间,其后为氢化可的松的即时释放。
实施例3
图3中阐示了在健康人志愿者(n=6)中,30mg仅延迟的氢化可的松制剂相比30mg延迟-缓释的氢化可的松制剂的体外药代动力学比较。分析通过LC-MS进行,且针对已在图1中显示的正常节律皮质醇谱进行比较。比较阐述如下:
正常:
·AUC/生物利用度=4697nM.hr
·C最大=451.5nMol/l
·T最大=07:52h
延迟释放制剂:
·延迟的AUC/生物利用度=4595nm.hr(98%相比正常)
·C最大=507.0nMol/l
·T最大=08:00h
延迟-缓释制剂:
·AUC/生物利用度=1628nM.hr(35%相比正常)
·C最大=159nMol/l
·T最大=05:00h
相比延迟和缓释制剂,延迟释放氢化可的松制剂具有更大的C最大、更晚的T最大和更大的AUC。这些结果基于图2A和2B中显示的以及现有技术中的体外溶解数据是预期不到的,现有技术教导了为氢化可的松制剂提供必需的释放谱以再造皮质醇分泌的生理节律需要提供延迟和缓释制剂。可以预期,相比延迟和缓释制剂,仅延迟制剂将产生更早的C最大和非持续性的吸收谱。然而,相比延迟-缓释制剂,于体内,在人中,仅延迟的制剂具有更晚的T最大、更持久的吸收和更大的AUC,并重复了正常夜间皮质醇谱。这图示在图4中,其显示了30mg延迟制剂的几何平均值和第10及第90百分位数皮质醇水平,该水平与正常皮质醇水平(也显示为几何平均值和第10及第90百分位数)重叠。
实施例4
在28名健康志愿者中进行了开放标记的、随机化的、单次剂量交叉研究,以定征(制剂DIURF-006)的药代动力学,以证明与皮质醇的生理节律拟合的紧密度。筛选健康志愿者并登记入研究。基本的入选标准为健康男性对象年龄为18-60岁,其不轮班工作且没有临床显著的全身感染和/或氢化可的松/地塞米松的过敏/敏感史。每名对象接受4次(制剂DIURF-006),间隔1周清除期。在每次给予的剂量为以下之一:5mg、10mg或20mg(在23:00时给予)或30mg(在23:00时给予20mg,和在第二天7:00时给予10mg)。在每次给予前,对每名对象给予地塞米松(1mg,约4-6次每小时间隔)以抑制皮质醇的内源性释放。在确定的时间点进行药代动力学取样,在每次给药后经过约24小时的时间。
使用验证的高压液相色谱质谱仪(LC-MS)检测确定氢化可的松的血浆浓度。使用WinNonlin Professional(版本5.2.1)进行药代动力学参数分析。针对氢化可的松即时释放片剂(来自研究DIUR-001的历史内部数据)和健康个体的参考性标准皮质醇谱(由Debonoet al.,2009发表),进行的药代动力学谱比较。
以单次剂量的5mg、10mg和20mg(在23:00时)给予的药代动力学谱显示在图5中。所有谱图均显示特征性的给药后最初2-4小时的延迟释放时段,然后为血浆浓度逐渐上升达到最大浓度(C最大),通常在给药后7小时左右。
以30mg的累积剂量(23:00时,20mg和7:00时,10mg)给予的药代动力学谱显示在图6中。在相同的图中比较了与健康个体中皮质醇的标准节律谱拟合的紧密度。还显示了氢化可的松即时释放片剂的参考药代动力学谱,以阐示相比常规的氢化可的松即时释放制剂,与标准皮质醇谱拟合的紧密度的显著改善。
来自不同剂量的的氢化可的松暴露比例显示在图7中。可以看到在5mg-30mg的剂量范围中,来自制剂的氢化可的松暴露基本上为线性的。
表1延迟释放制剂[DIURF-006]氢化可的松修饰的释放胶囊制剂,剂量强度:5mg、10mg、20mg和30mg
延迟释放涂层
()-加工期间去除的,在终产物中不出现,所需的量显示在括号中
1包被用制剂中包含的作为抗粘合剂的滑石
2包含在颗粒外的作为抗粘合剂的滑石,且在制备过程中去除
表2延迟和缓释制剂[DIURF-001]氢化可的松修饰的释放胶囊制剂,剂量强度:5mg、10mg和20mg
缓释涂层
延迟释放涂层
()-加工期间去除的,在终产物中不出现,所需的量显示在括号中
1包被用制剂中包含的作为抗粘合剂的滑石
2包含在颗粒外的作为抗粘合剂的滑石,且在制备过程中去除
Claims (16)
1.适于经口给药的第一药物组合物和第二药物组合物在制备用于治疗肾上腺功能障碍的药物中的用途,其中所述第一药物组合物和第二药物组合物包含:
包含氢化可的松、粘合剂和载体的核;以及
包含延迟释放聚合物的延迟释放层,
其中所述第一药物组合物在20:00时-24:00时给药,并且所述第二药物组合物在06:00时-10:00时给药。
2.如权利要求1所述的用途,其中所述氢化可的松的浓度为所述组合物的5-8%w/w。
3.如权利要求1或2所述的用途,其中所述包含延迟释放聚合物的延迟释放层与所述核接触,其中所述延迟释放聚合物是(i)1:1比例的聚(甲基丙烯酸、甲基丙烯酸甲酯)和(ii)1:2比例的聚(甲基丙烯酸、甲基丙烯酸甲酯)的混合物,其中(i)和(ii)的比例为1:4,并且为所述组合物的6-7%w/w。
4.如权利要求1-3中任一项所述的用途,其中所述载体包含微晶纤维素颗粒,以及其中所述载体为所述组合物的75-85%w/w。
5.如权利要求4所述的用途,其中所述核由80-82%w/w的微晶纤维素颗粒组成。
6.如权利要求5所述的用途,其中所述核由约81%w/w的微晶纤维素颗粒组成。
7.如权利要求1-6中任一项所述的用途,其中所述核包含微晶纤维素颗粒,其中所述颗粒的直径为200μm-1200μm或500μm-800μm。
8.如权利要求1-7中任一项所述的用途,其中氢化可的松的浓度为所述组合物的约6%w/w。
9.如权利要求1-8中任一项所述的用途,其中所述粘合剂为聚维酮,并且聚维酮的浓度为所述组合物的1.5-3.0%w/w。
10.如权利要求9所述的用途,其中提供的聚维酮浓度为所述组合物的约1.8%w/w。
11.如权利要求1-10中任一项所述的用途,其中提供的所述延迟释放聚合物层为所述组合物的约7%w/w。
12.如权利要求1-11中任一项所述的用途,其中所述延迟释放聚合物层包含癸二酸二丁酯,并且癸二酸二丁酯为所述组合物的约0.7%w/w。
13.如权利要求1-12中任一项所述的用途,其中所述第一药物组合物的药核包含20mg氢化可的松,以及所述第二药物组合物的药核包含10mg氢化可的松,其中当与延迟-缓释的氢化可的松制剂的相对生物利用度相比,在所述第一药物组合物和第二药物组合物中的总共30mg氢化可的松的相对生物利用度是增加的,以及其中施用所述第一药物组合物和第二药物组合物重现皮质醇的正常生理释放。
14.如权利要求1所述的用途,其中所述组合物由以下组成:
81.36%w/w的微晶纤维素球,
6.09%w/w的氢化可的松,
1.83%w/w的聚维酮,
5.37%w/w的Eudragit S100,
1.34%w/w的Eudragit L100,
3.34%w/w的滑石,
0.67%w/w的癸二酸二丁酯。
15.如权利要求1-14中任一项所述的用途,其中肾上腺功能障碍由选自以下的疾病状况引起:原发性或二发性或三发性肾上腺衰竭、先天性肾上腺增生、迟发性先天性肾上腺增生、多囊卵巢衰竭、糖皮质激素可抑制性醛固酮增多症(GRA)。
16.如权利要求15所述的用途,其中肾上腺功能障碍由先天性肾上腺增生引起。
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