CN105722854B - 用于治疗疾病和病症的降钙素模拟物 - Google Patents
用于治疗疾病和病症的降钙素模拟物 Download PDFInfo
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- CN105722854B CN105722854B CN201480062032.2A CN201480062032A CN105722854B CN 105722854 B CN105722854 B CN 105722854B CN 201480062032 A CN201480062032 A CN 201480062032A CN 105722854 B CN105722854 B CN 105722854B
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Abstract
具有根据SEQ ID NO:8或SEQ ID NO:53的氨基酸序列的降钙素模拟肽可用作用于治疗以下的药物:糖尿病(I型和/或II型)、体重过重、过度食物摄入、代谢综合征、类风湿性关节炎、非酒精性脂肪肝病、骨质疏松症或骨关节炎、血糖水平调节不良、针对葡萄糖耐量测试之响应调节不良或摄食调节不良,所述氨基酸序列各自可在其N‑末端羧基化,或者以其他方式修饰以降低第一个氨基酸的正电荷,并且独立于此可在其C‑末端酰胺化,并且在每个所述氨基酸序列中,1位和7位的半胱氨酸残基可一起被α‑氨基辛二酸(Asu)替换。
Description
技术领域
本发明涉及降钙素的模拟物,并且延伸至其作为药物在治疗多种疾病和病症(包括但不限于糖尿病(I型和II型)、体重过重、过度食物摄入和代谢综合征)、调节血糖水平、调节针对葡萄糖耐量测试之响应、调节摄食、治疗骨质疏松症和治疗骨关节炎中的用途。
全世界约有2.5亿糖尿病患者,并且预计在接下来的二十年内该数据将加倍。该群体中有超过90%患有2型糖尿病(type 2diabetes mellitus,T2DM)。据估计,患有T2DM或处于明显T2DM之前阶段的人中只有50%至60%目前得到诊断。
T2DM是以碳水化合物和脂肪代谢异常为特征的异质性疾病。T2DM的原因是多因素的并且包括影响组织(例如肌肉、肝、胰和脂肪组织)中的β细胞功能和胰岛素敏感性的遗传和环境要素二者。结果是,观察到胰岛素分泌受损并且伴随着进行性的β细胞功能降低和慢性胰岛素抵抗。内分泌胰腺不能够补偿外周胰岛素抵抗导致高血糖和临床糖尿病的发生。目前,认为针对胰岛素介导的葡萄糖摄取的组织抗性是T2DM的主要病理生理学决定因素。
最佳T2DM介入的成功标准是血糖水平降低,其可以是血糖水平长期降低和在食物摄入后耐受高血糖水平的能力提高二者,它们由较低的峰值葡萄糖水平和较快的清除来描述。这两种情形对β-细胞胰岛素输出和功能的压力都较小。
I型葡萄糖的特征在于:其丧失响应于摄食而产生胰岛素的能力并且因此不能将血糖调节至正常生理学水平。
骨的物理结构可因为多种因素(包括疾病和损伤)而受到损害。最常见的骨疾病之一是骨质疏松症,其以骨组织的低骨量和结构退化(structural deterioration)为特征,从而导致特别是髋部、脊柱和腕的骨脆性和骨折易感性提高。骨质疏松症发生于存在这样的不平衡时:骨吸收速率超过骨形成速率。已表明,施用有效量的抗吸收剂(例如降钙素)防止骨吸收。
炎性或退行性疾病可由于疼痛和关节破坏而导致移动性显著丧失,所述炎性或退行性疾病包括关节疾病,例如骨关节炎(osteoarthritis,OA)、类风湿性关节炎(rheumatoid arthritis,RA)或幼年型类风湿性关节炎(juvenile rheumatoidarthritis,JRA),并且包括由自身免疫应答引起的炎症,例如狼疮、强直性脊柱炎(ankylosing spondylitis,AS)或多发性硬化(multiple sclerosis,MS)。关节内覆盖并缓冲(cushion)骨的软骨可随时间变得退化,因此不期望地允许两块骨直接接触,从而可在关节运动期间限制一块骨相对于另一块的运动和/或通过另一块骨对一块骨造成损伤。恰好位于软骨之下的软骨下骨也可退化。施用有效量的抗吸收剂(例如降钙素)可防止骨吸收。
WO2013/067357公开了天然降钙素的合成变体,其具有旨在提供经改善特性的经修饰氨基酸序列。
降钙素在很多种物种间高度保守。全长天然降钙素的长度为32个氨基酸。下面示出了天然降钙素实例的序列(在每种情况下,所述序列均具有C-末端酰胺化-未示出):
多种天然降钙素与来自WO2013/067357的UGP302的氨基酸序列比较如下:
表1
1SEQ ID NO:1
2SEQ ID NO:2
3SEQ ID NO:3
4SEQ ID NO:4
本文中还以名称KBP-042提及WO2013/067357的肽UGP302。
仍然需要开发这样的降钙素类似物,其特别是在胰淀素(amylin)和降钙素受体激动作用方面具有更进一步改善的特性,或者至少提供改善天然存在降钙素之特性的作为替代的人工序列,同时消除CGRP-受体激动作用,并因此确保最佳的体内效力与安全性比例。
相关的肽序列包括:
表2
其中,独立地,Xa是V或M;Xb是K或R;Xc是D或E;Xd是K或R;Xe是T或S;Xf是F或Y;Xg是K或R;并且Xh是P或Y,优选P。
其他的目标肽序列示于下表中:
表2a
其中Xc是D或E,并且Xe独立地是F或Y,并且所述序列各自可在其N-末端羧基化,或者以其他方式修饰以降低第一个氨基酸的正电荷,并且独立于此可在其C-末端酰胺化,并且在所述序列中,其各自1位和7位的半胱氨酸残基可一起被α-氨基辛二酸(Asu)替换。
表2b
表3
表4a
其中Xc是D或E,并且Xe独立地是F或Y。
表4b
因此,本发明目前提供了具有表2a或表4a中的任一氨基酸序列的肽,所述氨基酸序列各自可在其N-末端羧基化,或者以其他方式修饰以降低第一个氨基酸的正电荷,并且独立于此可在其C-末端酰胺化,在每个所述氨基酸序列中,1位和7位的半胱氨酸残基可一起被α-氨基辛二酸(Asu)替换。
本发明包括具有表3中的任一氨基酸序列的肽。
本发明还包括具有表2b或表4b中的任一氨基酸序列的肽,所述氨基酸序列各自可在其N-末端羧基化,或者以其他方式修饰以降低第一个氨基酸的正电荷,并且独立于此可在其C-末端酰胺化,在每个所述氨基酸序列中,1位和7位的半胱氨酸残基可一起被α-氨基辛二酸(Asu)替换。
在对天然降钙素之众多32-氨基酸类似物的活性进行研究,特别是研究高效激活受体介导的响应需要哪些氨基酸之后,我们已发现编号为11、15、18、22、24、30和31的氨基酸在氨基酸类型方面更为严格,其中优选的值为:11位是K或R,15位是D或E,18位是K或R,22位是Y或F,24位优选是K但是R也有效,30位是N,并且31位是A。
所述肽可配制成作为药物施用,并且可配制成用于经肠(enteral)或肠胃外(parenteral)施用。优选的制剂是可注射的,优选用于皮下注射,然而所述肽可与载体一起配制成用于经口施用,并且任选地其中所述载体提高该肽的经口生物利用度。合适的载体包括含有5-CNAC、SNAD或SNAC的那些。
任选地,所述肽配制成含有经包衣柠檬酸颗粒的用于经口施用的药物组合物,并且其中所述经包衣柠檬酸颗粒提高该肽的经口生物利用度。
本发明包括本发明的肽,其用作药物。所述肽可用于治疗糖尿病(I型和/或II型)、体重过重(excess bodyweight)、过度食物摄入(excessive food consumption)、代谢综合征、类风湿性关节炎、非酒精性脂肪肝病(non-alcoholic fatty liver disease)、骨质疏松症或骨关节炎、血糖水平调节不良(poorly regulated blood glucose level)、针对葡萄糖耐量测试之响应调节不良(poorly regulated blood glucose level)或食物摄入调节不良(poorly regulated of food intake)。特别地,所述肽可用于降低不期望高的空腹血糖水平或者降低不期望高的HbA1c或者降低不期望高的针对葡萄糖耐量测试的响应。
在一些实施方案中,上文中讨论的降钙素模拟物的N-末端侧经修饰以降低第一个氨基酸的正电荷。例如,可在半胱氨酸-1上进行乙酰基、丙酰基或琥珀酰基取代。在表3中,“Ac”指乙酰基修饰。表3中的每个‘Ac’可替换成“Pr”,这称为丙酰基修饰;或者替换成“Succ”,这成为琥珀酰基修饰。“NH2”指酰胺化的C-末端羧酸基团。降低正电荷的作为替代的方式包括但不限于基于聚乙二醇的PEG化(PEGylation)或在N-末端添加其他氨基酸,例如谷氨酸或天冬氨酸。或者,可向上文中讨论的肽的N-末端添加其他氨基酸,包括但不限于赖氨酸、甘氨酸、甲酰基甘氨酸、亮氨酸、丙氨酸、乙酰基丙氨酸和二丙氨酰。本领域技术人员将认识到,具有多个半胱氨酸残基的肽常常在两个这样的半胱氨基酸残基之间形成二硫键。本文中所示的所有此类肽限定为任选地特别是在Cys1至Cys7的位置包含一个或更多个这样的二硫键。模拟这一情况,1位和7位的半胱氨酸残基可共同被α-氨基辛二酸连接替换。本文中公开的具有KBP-0##编号的所有肽均具有这样的二硫键。
尽管本公开内容的降钙素模拟物可以以游离酸形式存在,但是优选地C-末端氨基酸被酰胺化。申请人预期,这样的酰胺化可有助于肽的有效性和/或生物利用度。用于制备本公开内容的降钙素模拟物的酰胺化形式的优选技术是:根据已知的技术在肽基甘氨酸α-酰胺化单加氧酶存在下使前体反应(用甘氨酸替代所期望酰胺化产物的C-末端氨基),其中所述前体在反应中被转化为酰胺化产物,这描述于例如US4708934以及EP0308067和EP0382403中。
重组产生对于前体和催化前体转化为鲑鱼降钙素的酶二者而言都是优选的。这样的重组产生由Ray MV、Van Duyne P、Bertelsen AH、Jackson-Matthews DE、Sturmer AM、Merkler DJ、Consalvo AP、Young SD、Gilligan JP、Shields PP.在Biotechnology,Vol.11(1993)第64-70页中进行了讨论,其还描述了前体向酰胺化产物的转化。在此报道的重组产物与天然鲑鱼降钙素以及使用溶液相和固相化学肽合成产生的鲑鱼降钙素相同。
酰胺化产物的产生还可使用下述的方法和酰胺化酶来实现:Consalvo,等,US7445911;Miller等,US2006/0292672;Ray等,2002,Protein Expression andPurification,26:249-259;和Mehta,2004,Biopharm.International,7月,第44-46页。
优选酰胺化肽的产生可如下进行:例如,作为具有谷胱甘肽-S-转移酶的可溶性融合蛋白在大肠杆菌(E.coli)中产生甘氨酸延伸的前体(glycine-extended precursor),或者根据US6103495中所述的技术直接表达该前体。这样的甘氨酸延伸前体除C-末端之外具有与所期望酰胺化产物相同的分子结构(其中所述产物以--X--NH2为末端,而所述前体以--X-gly为末端,X为所述产物的C-末端氨基酸残基)。上述公开中所述的α-酰胺化酶催化前体转化为产物。所述酶优选地在中国仓鼠卵巢(Chinese Hamster Ovary,CHO)细胞中重组产生,如上文引用的Biotechnology and Biopharm.文章中所述。
本公开内容的肽活性剂的游离酸形式可以以类似方式产生,不同之处在于“前体”上不包含C-末端甘氨酸,所述前体作为替代是最终的肽产物并且无需酰胺化步骤。
除非另有说明,否则本公开内容的降钙素模拟物的优选剂量对于治疗目的和预防目的二者来说是相同的。期望的剂量在下文进行更详细的讨论,并且根据施用方式而不同。
除非另有注明或由上下文显而易见,否则本文中的剂量指未受药用赋形剂、稀释剂、载体或其他成分影响或者将其扣除的活性化合物的重量,尽管期望这样的其他成分包含在内。医药工业中常规用于递送肽活性剂的任何剂型(胶囊剂、片剂、注射剂等)均适用于本文,并且术语“赋形剂”、“稀释剂”或“载体”包括这样的非活性成分,如在工业中通常与活性成分一起包含在这样的剂型中。优选的经口剂型在下文中更详细地讨论,但不应认为是施用本公开内容的活性剂的唯一方式。
本公开内容的降钙素模拟物可施用于患者以治疗多种疾病或病症。本文中使用的术语“患者”意指属于动物界的任何生物。在一个实施方案中,术语“患者”指脊椎动物,更优选哺乳动物,包括人。
因此,本公开内容包括所述肽在以下方法中的用途:治疗I型糖尿病、II型糖尿病或代谢综合征、肥胖,或者食欲抑制,或者用于减轻胰岛素抵抗,或者用于降低不期望高的空腹血糖水平,或者用于降低不期望高的峰值血糖水平,或者用于降低不期望高的峰值血清胰岛素水平,或者用于降低针对葡萄糖耐量测试之不期望大的响应,或者用于治疗骨质疏松症,或者用于治疗骨关节炎。
基于许多因素例如性别、年龄和身高,存在许多本领域公认的正常体重范围的量度。需要本文中所示的治疗或预防方案的患者包括体重超过公认标准的患者,或者由于遗传、环境因素或其他公认风险因素而处于比一般群体更高的变得超重或肥胖的风险的患者。根据本公开内容,考虑所述降钙素模拟物可以用于治疗糖尿病,其中重量控制是治疗的一个方面。
在一个实施方案中,所述方法包括向有此需要的患者经肠施用药学上有效量的本文中所述的任一种肽以治疗所述病症。
在一个实施方案中,所述方法包括向有此需要的患者肠胃外施用药学上有效量的本文中所述的任一种肽以治疗所述病症。对于肠胃外施用(包括腹膜内、皮下、静脉内、皮内或肌内注射),可以采用例如本公开内容之肽在芝麻油或花生油或者在水性丙二醇中的溶液剂。如果需要的话,水溶液剂应适当缓冲(优选pH大于8),并且液体稀释剂首先变得等渗。这些水溶液剂适合用于静脉内注射目的。油性溶液剂适合用于关节内、肌内和皮下注射目的。所有这些溶液剂在无菌条件下的制备容易通过本领域技术人员公知的标准制药技术来实现。对于肠胃外应用,合适制剂的实例包括溶液剂(优选油性或水性溶液剂)以及混悬剂、乳剂或植入剂,包括栓剂。肽可以以多剂量或单剂量形式以无菌形式配制,例如分散在流体载体(例如注射剂通常使用的无菌生理盐水或5%盐水葡萄糖溶液)中。
所述方法可包括确定患者是否患有所述病症的预备步骤,和/或确定所述治疗在所述患者中减轻所述病症的有效程度的后续步骤,例如,在每种情况中,均进行经口葡萄糖耐量测试或静息血糖水平(resting blood sugar level)。
为了改善对患者体重的控制以使体重减轻或避免体重增长,活性化合物优选地以每天一次或更多(例如每天至少两次,例如每天2至4次)施用。活性化合物的制剂可包含适于这样的施用方案的单位剂量。活性化合物可考虑控制正接受糖尿病或代谢综合征治疗之患者的体重来施用。
与含在口中使得通过舌下或含服途径运输至血流的制剂相对,经口的经肠制剂用于通过吞咽摄取以随后在胃之下的肠内释放并由此通过门静脉递送至肝。
用于本公开内容的合适剂型包括片剂、小片剂(mini-tablet)、胶囊剂、颗粒剂、丸剂、散剂(powder)、泡腾固体和可咀嚼的固体制剂。这样的制剂可以包含明胶,其优选为经水解的明胶或低分子量明胶。这样的制剂可如下获得:冷冻干燥包含降钙素或者其片段或缀合物和经水解明胶或低分子量明胶的均质水溶液,并将得到固体材料进一步加工成所述经口药物制剂,并且其中明胶的平均分子量可以是1000至15000道尔顿。这样的制剂可包含保护性载体化合物,例如5-CNAC或本文中公开的其他化合物。
虽然经口制剂(例如片剂和胶囊剂)是优选的,但是用于本公开内容的组合物还可采用以下形式:糖浆剂、酏剂等以及栓剂等。经口递送一般是首选的递送途径,因为其方便、相对容易并且一般无痛,从而相对于其他递送方式产生较大的患者顺从性。然而,生物、化学和物理屏障(例如胃肠道内的不同pH、强效的消化酶和活性剂不可渗透的胃肠膜)使得向哺乳动物经口递送降钙素样肽成为问题,例如经口递送为由哺乳动物中的甲状腺滤泡旁细胞以及由鸟类和鱼类的后腮腺(ultimobranchial gland)分泌之长链多肽激素的降钙素最初证实是困难的,这至少部分地归因于降钙素在胃肠道内的稳定性不足以及降钙素不能容易地通过肠壁转运至血流。
然而,合适的经口制剂在下文中描述。
患者的治疗
在一个实施方案中,本公开内容的降钙素模拟物以使该模拟物在患者中的血清水平维持在以下的足够剂量施用:5皮克至500纳克/毫升,优选50皮克至250纳克,例如1至100纳克/毫升。血清水平可通过本领域中已知的放射免疫测定技术来测量。主治医生可监测患者响应,并且可随后根据个体患者的代谢和响应来在一定程度上改变剂量。通过将本公开内容的所有组分作为单个丸剂或胶囊剂施用最佳地实现近乎同时释放。然而,本公开内容还包括例如将所需量的降钙素模拟物分配在两个或更多个片剂或胶囊剂中,其可一起施用使得其一起提供必须量的所有成分。本文中使用的“药物组合物”包括但不限于适合特别施用于患者的完全剂量,无论一个或更多个片剂或胶囊剂(或其他剂型)是否在给定施用时推荐。
本公开内容的降钙素模拟物可使用在Unigene产品中采用的方法配制成用于经口施用。这些可包括如在美国专利No.5,912,014、美国专利No.6,086,918、美国专利No.6,673,574、美国专利No.7,316,819、美国专利No.8,093,207和美国公开No.2009/0317462中所述的方法。特别地,其可包括以下用途:将化合物与膜转位蛋白(membrane translocator)(例如HIV TAT蛋白的蛋白质转导结构域)缀合、与一种或更多种蛋白酶抑制剂和/或可被包衣的pH降低剂和/或抗酸性保护性载剂和/或可以是表面活性剂的吸收增强剂共配制。
在一个实施方案中,本公开内容的降钙素模拟物优选地以美国专利公开No.2009/0317462中已知的方式配制成用于经口递送。根据本公开内容的一种优选经口剂型示于下表5中:
表5-固体剂型制剂的组分
活性剂或赋形剂 | 功能 |
选自SEQ ID NO:1至8之一的降钙素模拟物 | 活性剂 |
经包衣的柠檬酸颗粒 | 蛋白质抑制剂 |
月桂酰肉碱 | 吸收增强剂 |
非离子聚合物 | 子包衣(Subcoat) |
Eudragit L30D-55 | 肠溶衣 |
在一个实施方案中,本公开内容的降钙素模拟物可通过与合适的载体化合物混合而配制成用于经肠(尤其是经口)施用。合适的载体化合物包括美国专利No.5,773,647和美国专利No.5866536中所述的那些,并且在这些中5-CNAC(N-(5-氯水杨酰基)-8-氨基辛酸,通常作为其二钠盐)特别有效。另一些优选的载体或递送剂为SNAD(10-(2-羟基苯甲酰氨基)癸酸的钠盐)和SNAC(将N-(8-[2-羟基苯甲酰基]氨基)辛酸的钠盐)。在一个实施方案中,本公开内容的药物组合物包含递送有效量的载体(例如5-CNAC),即足以递送化合物达到期望效果的量。一般来说,载体(例如5-CNAC)以总组合物的按重量计2.5%至99.4%、更优选按重量计25%至50%的量存在。
此外,WO 00/059863公开了式I的二钠盐及其特别有效地用于经口递送活性剂(例如降钙素,例如鲑鱼降钙素)的水合物和溶剂合物,并且这些可用于本公开内容中:
其中
R1、R2、R3和R4独立地是氢、-OH、-NR6R7、卤素、C1-C4烷基或C1-C4烷氧基;
R5是经取代或未经取代的C2-C16亚烷基、经取代或未经取代的C2-C16亚烯基、经取代或未经取代的C1-C12烷基(亚芳基),或者经取代或未经取代的芳基(C1-C12亚烷基);并且R6和R7独立地为氢、氧或C1-C4烷基。
使用任选地微粉化5-CNAC的优选经肠制剂一般可如WO2005/014031中所描述。
所述化合物可使用在Bone Medical Limited的Capsitonin产品中采用之方法配制成用于经口施用。这些可以包括在Axcess制剂中并入的方法。更特别地,活性成分可包封入能够经受通过胃运送的经肠胶囊剂中。这可以含有活性化合物和亲水性芳香醇吸收增强剂,例如如WO02/028436中所述。在已知的方式中,肠溶衣可以以pH敏感性方式(例如在3至7的pH下)变成可渗透。WO2004/091584也描述了使用芳香醇吸收增强剂的合适配制方法。
所述化合物可使用参见Oramed产品中的方法配制,其可包括与ω-3脂肪酸的配制,如参见WO2007/029238中或US 5102666中所述。
一般来说,可使用这些载体或递送剂的可药用盐(尤其是单钠盐或二钠盐)、溶剂合物(例如醇溶剂合物)和水合物。
根据本公开内容的药物组合物的经口施用可有规律地完成,例如每日或每周一次或更多次;间歇性地完成,例如在一天或一周期间不规律;或周期性地完成,例如几天或几周的时间内有规律,随后一段时间不施用。目前公开的一些实施方案之药物组合物的剂型可以是任何已知的形式,例如液体或固体剂型。液体剂型包括溶液乳剂、混悬剂、糖浆剂和酏剂。除活性化合物和载体(例如5-CNAC)外,液体制剂还可包含本领域中常用的惰性赋形剂,例如增溶剂,例如乙醇;油类,例如棉籽油、蓖麻油和芝麻油;润湿剂;乳化剂;助悬剂;甜味剂;矫味剂;和溶剂,例如水。固体剂型包括胶囊剂、软凝胶胶囊剂、片剂、囊片剂、散剂、颗粒剂或其他固体经口剂型,其全部可通过本领域中公知的方法制备。所述药物组合物还可包含常规用量的添加剂,包括但不限于pH调节剂、防腐剂、食用香料(flavorant)、掩味剂、芳香剂(fragrance)、湿润剂、张力调节剂(tonicifier)、着色剂、表面活性剂、增塑剂、润滑剂(例如硬脂酸镁)、助流剂、压制助剂、增溶剂、赋形剂、稀释剂(例如微晶纤维素,例如由FMC公司供应的Avicel PH 102),或其任意组合。其他的添加剂可包括磷酸缓冲盐、柠檬酸、二醇类及其他分散剂。所述组合物还可包含一种或更多种酶抑制剂,如放线酰胺素(actinonin)或表放线酰胺素(epiactinonin)及其衍生物;抑肽酶(aprotinin)、Trasylol和Bowman-Birk抑制剂。此外,本公开内容的组合物中可存在转运抑制剂,即[ρ]-糖蛋白,例如Ketoprofin。本公开内容的固体药物组合物可通过常规方法制备,例如如下制备:将活性化合物、载体(例如5-CNAC)和任意其他成分的混合物共混,揉捏并填充到胶囊中,或者不填充到胶囊中,而是模制随后进一步制片或压制模制以得到片剂。此外,可通过已知方法形成固体分散体,随后进一步加工以形成片剂或胶囊剂。优选地,本公开内容的药物组合物中的成分在整个固体剂型中均质或均匀混合。
或者,活性化合物可配制为与所述载体的缀合物,其可以是如US2003/0069170中所述的寡聚体,例如:
如其中所述,这样的缀合物可与脂肪酸和胆盐组合施用。
可使用与聚乙二醇(PEG)的缀合物,如例如在Mansoor等中所述。
或者,活性化合物可以与亚硝基-N-乙酰基-D,L-青霉胺(SNAP)和卡波姆溶液混合或者与牛磺胆酸盐和卡波姆溶液混合以形成粘膜粘附性乳剂。
活性化合物可通过如Prego等中所公开的装入壳聚糖纳米胶囊(任选地经PEG修饰,如Prego Prego C,Torres D,Fernandez-Megia E,Novoa-Carballal R,E,,Alonso MJ.中)中或者如Garcia-Fuentes等中所公开的装入壳聚糖或PEG包衣的脂质纳米颗粒来配制。用于这一目的的壳聚糖纳米颗粒可以如Guggi等中所述经亚氨基四氢噻吩(iminothiolane)修饰。其可如Dogru等中所述配制成水/油/水型乳剂。如Sinko等或Song等中所述,通过使用牛磺脱氧胆酸盐或月桂酰肉碱可提高活性化合物的生物利用度。一般来说,作为载体的合适纳米颗粒在de la Fuente等中进行了讨论并且可用于本公开内容。
用于经口制剂的其他合适策略包括如Chiasma Ltd.的WO2005/094785中所述使用瞬时透性增强剂(transient permeability enhancer,TPE)系统。TPE利用固体亲水性颗粒在疏水性介质中的油性混悬液来保护药物分子免受因为不利的胃肠(GI)环境而失活,并且同时作用于GI壁以诱导其所载药物分子的渗透。
还包括如US2008/0200563中所述使用谷胱甘肽或含有很多硫醇基团的化合物来抑制粘膜上流出泵的作用。这样的技术的应用实例还在以下中进行了描述:Caliceti,P.Salmaso,S.,Walker,G.和Bernkop-Schnürch,A.(2004)‘Development and in vivoevaluation of an oral insulin-PEG delivery system.’Eur.J.Pharm.Sci.,22,315-323;Guggi,D.,Krauland,A.H.和Bernkop-Schnürch,A.(2003)‘Systemic peptidedelivery via the stomach:in vivo evaluation of an oral dosage form for salmoncalcitonin’.J.Control.Rel.92,125-135;以及Bernkop-Schniirch,A.,Pinter,Y.,Guggi,D.,Kahlbacher,H.,G.,Schuh,M.,Schmerold,I.,Del Curto,M.D.,D′Antonio,M.,Esposito,P.and Huck,Ch.(2005)‘The use of thiolated polymers ascarrier matrix in oral peptide delivery’-Proof of concept.J.Control.Release,106,26-33。
可如WO2004/084870所述将活性化合物配制成无缝微球,其中活性药物成分增溶成为乳剂、微乳剂或混悬剂,配制成小球(mini-sphere);并不定地通过常规或新颖的包衣技术进行包衣。所得物是“预先增溶”形式的经包封药物,其在经口施用时沿胃肠道向特定位置并以特定速率提供所述活性药物的预定的立即或持续释放。实质上,药物的预先增溶增强了其动力学谱的可预测性,同时增强了渗透性和药物稳定性。
可如US2009/0074824中所述采用壳聚糖包衣的纳米胶囊。用该技术施用的活性分子在纳米胶囊内得到保护,这是因为纳米胶囊对于胃液作用来说是稳定的。此外,该系统的粘膜粘附特性延长粘附到肠壁的时间(已证实,这些系统在胃肠运送中存在延迟),有助于更有效地吸收活性分子。
可使用由TSR1 Inc.开发的方法。这些包括亲水增溶技术(HydrophilicSolubilization Technology,HST),其中明胶(带有正电荷和负电荷二者的天然来源的胶原提取物)包被包含在卵磷脂胶束中的活性成分颗粒并阻止其聚集或结块。这通过极性相互作用导致疏水药物颗粒可湿性提高。此外,两亲性卵磷脂降低溶解流体和颗粒表面之间的表面张力。
活性成分可用瓜环(cucurbituril)作为赋形剂来配制。
或者,可采用Merrion Pharmaceuticals的GIPET技术来生产包含活性成分和吸收增强剂的肠溶衣片剂,所述吸收增强剂可如US2007/0238707中所述为中链脂肪酸或中链脂肪酸衍生物或者如US7268214中所述为膜转位肽。
可采用GIRESTM技术,其由在可膨胀袋中的控制释放剂型组成,所述可膨胀袋放置在用于经口施用的药物胶囊中。胶囊溶解后,产气系统在胃中膨胀所述袋。在临床试验中,已证明该袋在胃中存留16至24小时。
或者,活性物可与使其抵抗胃中酶促降解并便于其吸收的保护性调节剂缀合。所述活性物可与单分散性短链甲氧基聚乙二醇糖脂衍生物共价缀合,其在纯化后结晶并冷冻干燥成为干燥的活性药物成分。这样的方法在US5438040和www.biocon.com中描述。
还可采用肝定向囊泡(hepatic-directed vesicle,HDV)来进行活性物递送。HDV可由包封活性物的脂质体(直径≤150nm)组成,所述脂质体还在其脂质双层中包含肝细胞靶向分子。所述靶向分子指导包封的活性物递送到肝细胞,并因此起效需要相对少量的活性物。这样的技术在US2009/0087479中并进一步在www.diasome.com中描述。
如涉及胰岛素的US2002/0115592所述,可以将活性物与中链偏甘油酯(任选地与长链PEG物质混合)联合并入另外包含基本无水的亲水性介质(包含醇和潜溶剂)的组合物中。
或者,可如Shen Z,Mitragotri S,Pharm Res.2002Apr;19(4):391-5“Intestinalpatches for oral drug delivery”中所述利用肠贴剂(intestinal patch)。
可如美国专利No.7189414所述将活性物并入可侵蚀基质中,所述基质由混合有疏水性聚合物的水凝胶形成。
用于待治疗成人的合适经口剂量水平可以是0.05至5mg,优选约0.1至2.5mg。
患者的剂量治疗频率可以是每天1至6次,例如每天2至4次。理想地治疗将维持至少6周,优选至少6个月,优选至少1年,并任选地终生的长时间。
针对相关疾病的联合治疗可使用根据本公开内容的组合物并独立施用一种或更多种其他治疗剂来进行。或者,根据本公开内容的组合物可引入一种或更多种其他治疗剂来进行联合施用。
根据本公开内容的联合治疗包括所述活性化合物与胰岛素、GLP-2、GLP-1、GIP或胰淀素,或者一般地与其他抗糖尿病剂的组合。因此,包括共制剂的联合治疗可用以下进行:胰岛素增敏剂,包括双胍类(例如,二甲双胍、丁双胍和苯乙双胍)、TZD类(PPAR)(例如,巴格列酮、吡格列酮、来格列酮、罗格列酮和曲格列酮)、双重PPAR激动剂(例如,阿格列扎、莫格他唑和替赛格列他),或者促分泌素(包括磺酰脲类,例如氨磺丁脲、氯磺丙脲、格列齐特、甲苯磺丁脲、妥拉磺脲、格列吡嗪、格列本脲、优降糖、格列喹酮、格列吡脲和格列美脲)、美格列奈类/格列奈类(K+)(例如,那格列奈、瑞格列奈和米格列奈)、GLP-1类似物(例如,艾塞那肽、利拉鲁肽和阿必鲁泰)、DPP-4抑制剂(例如,阿格列汀、利拉利汀、沙格列汀、西他列汀和维格列汀)、胰岛素类似物或特殊制剂(例如,(快速起效的)赖脯胰岛素、门冬胰岛素、赖谷胰岛素,(长效的)甘精胰岛素、地特胰岛素,吸入性胰岛素-Exubra和NPH胰岛素),以及其他,包括α-葡萄糖苷酶抑制剂(例如,阿卡波糖、米格列醇和伏格列波糖)、胰淀素类似物(例如,普兰林肽)、SGLT2抑制剂(例如,达格列净、瑞格列净和舍格列净)以及其他药物,包括苯氟雷司和托瑞司他。
另一些组合包括与瘦素的共施用或共制剂。瘦素抗性是2型糖尿病的得到确认的组成;然而,迄今为止,瘦素的注射未能改善这一病症。相比之下,有证据支持胰淀素以及由此具有胰淀素样能力的分子(如鲑鱼降钙素模拟物)能够提高瘦素敏感性。胰淀素/瘦素组合已显示出对体重和摄食以及胰岛素抵抗的协同作用[Kusakabe T等]。
目前公开的一些实施方案在以下实施例中进行了描述,列出所述实施例是为了帮助理解本公开内容,并且不应解释为以任何方式限制所附权利要求书中限定的公开内容的范围。阐述以下实施例以向本领域普通技术人员提供全部公开内容以及如何制备和使用所述一些实施方案的描述,并且不旨在限制本公开内容的范围,也不旨在表示下面的实验是所进行的全部或仅有实验。已努力确保所用数字(例如量、温度等)的准确度,但一些实验误差和偏差应予以考虑。除非另有说明,否则份数是重量份数,分子量是重均分子量,温度是摄氏度,压力是大气压或接近大气压。
结果示于附图中,如下:
图1:显示在不同时间点时表3的KBP对CTR的活性与sCT和UGP302/KBP-042不相上下的原始数据。
图2:作为时间的函数之固定浓度的不同配体对CTR的活化。
图3:当添加至表达AMY-R的细胞系时,AMY-R之针对不同配体的剂量响应性活化。
图4:受试化合物在表达CTR(上图)和AMY-R(下图)之细胞上的竞争性结合,其中pIC50数据在表中。
图5:CGRP-R之针对不同配体的剂量响应性活化。
图6:单剂量的KBP-056对摄食、体重和PPG的作用。
图7:用UGP302/KBP-042、KBP-023、KBP-056和KBP.088进行三周处理对FPG和HbA1c的作用。
图8:KBP化合物对I型胶原的吸收(上图)以及对II型胶原的吸收(下图)的作用。
图9示出了比较化合物KBP-088和KBP-089对肥胖大鼠中摄食之作用的在实施例7中获得的结果。
图10示出了在比较本发明的肽KBP-089和已知肽KBP-042中在实施例7中获得的短期摄食测量结果。
图11示出了这些肽的长期摄食测量结果(上图)和体重变化(下图)。
图12A至12F示出了通过作用于降钙素受体(图12A、B和E)和胰淀素受体(图D和E)进行cAMP诱导的在实施例1中获得的进一步结果,并且示出了在摄食测量中在实施例7中获得的进一步结果(图12F)。
实施例
在以下实施例中,采用以下材料和方法。
细胞及细胞系
购买表达降钙素、胰淀素和CGRP受体的以下细胞系并且根据制造商的说明进行培养。
1.降钙素受体(CTR):来自DiscoveRx的U2OS-CALCR(目录号:93-0566C3)。
2.胰淀素受体(AMY-R):来自DiscoveRx的CHO-K1CALCR+RAMP3(目录号:93-0268C2)。
3.CGRP受体(CGRP-R):来自DiscoveRx的CHO-K1 CALCRL+RAMP1(目录号:93-0269C2)。
在独立的生物测定中,根据指定时间点用递增剂量的sCT、UGP-302/KBP-042或表3中鉴定的KBP(0、0.001、0.01、0.1、1、10和100nM)处理CTR、AMY-R和CGRP-R细胞。
实施例1:β-抑制蛋白(β-Arrestin)测定
PathHunter β-抑制蛋白GPCR测定是全细胞的功能性测定,其通过检测β-抑制蛋白与活化的GPCR的相互作用来直接测量配体激活GPCR的能力。由于抑制蛋白募集独立于G-蛋白信号传导,因此这些测定提供可用于几乎任何Gi、Gs或Gq偶联受体的强大且通用的筛选和分析(profiling)平台。
在该系统中,将GPCR与小酶片段ProLinkTM框内融合并在稳定地表达β-抑制蛋白和β-gal之较大N-末端缺失突变体(称为酶受体或EA)的融合蛋白的细胞中共表达。GPCR的活化刺激β-抑制蛋白与ProLink标记的GPCR结合并且促使两个酶片段互补,从而导致形成活性β-gal酶。这一相互作用导致酶活性提高,其可通过使用化学发光检测试剂进行测量。
该测定在白色的384孔板(Greiner Bio-One,784080)中进行。在实验前的当天,将细胞以2500个细胞/孔接种在10μL的细胞类型特异性培养基中。为了量化GPCR介导的β-抑制蛋白募集,使用PathhunterTM检测试剂盒(93-0001,DiscoverX)并根据生产商的说明进行测定。
结果见图1、2和3。如图1所见,肽在活性方面非常类似;然而,随着时间的延长,KBP-056表现出优越的激活CTR并维持其活化的能力。这在图2中可更好地看出,其中各个配体以一个给定的浓度并作为时间的函数进行绘图。在此,显而易见的是KBP-056在降钙素受体活化方面优于其他肽。
这类分子的另一重要特征是激活胰淀素受体AMY-R的能力,如图3所见,KBP完全能够激活该受体,并且KBP-088比经典的AMY-R激动剂sCT更有效。
在附图的亚组中,使用β-抑制蛋白测定来评估延长的受体活化。这使用以下降钙素受体(CTR)来进行:来自DiscoveRx细胞系的U2OS-CALCR(目录号:93-0566C3),并且与经典的3小时输出相反,进行24、48和72小时的β-抑制蛋白累积,然后分析。
用于本发明的肽根据其体外激活CTR和AMY-R的能力以降序进行排列,如下:
*比较的
实施例2:竞争性配体结合
在该实施例中,我们证明受试化合物结合降钙素和胰淀素受体的相对能力。对应于β-抑制蛋白诱导实验,我们使用表达CTR和AMY-R的细胞进行竞争性配合结合实验。在研究细胞上的配体结合中,将15.000个CTR或AMY-R细胞接种在96孔板中并将细胞在37℃下在未经标记的KBP存在或不存在下用0.1nM125I-缀合的sCT以递增剂量处理60分钟。在孵育之后,除去上清液并将细胞在200μl PBS中清洗两次。使用RIPA缓冲液(30mM M NaCl、50mMTris-HCl、5mM EDTA、1%脱氧胆酸、10%SDS、蛋白酶抑制剂小片(1片:10ml))裂解细胞,并还收集裂解液以用于用γ-计数器进行测量。
结果见图4。首先,我们发现所有的配体均与两种受体高效结合;然而,就亲和力而言,KBP-088比其他配体更优,特别是对于AMY-R。
实施例3:对CGRP-受体测试的β-抑制蛋白募集
由于已表明能够激活胰淀素受体的肽活化CGRP-R(可对化合物的整体效果不利的作用),因此我们对KBP是否激活CGRP-受体进行评估。如图5所见,不同于鲑鱼降钙素,KBP化合物均不激活CGRP-R。
实施例4:对体重的体内活性测试
为了确保这类肽的体内活性,进行KBP-056与UGP302/KBP-042相比之降低摄食、体重和餐后葡萄糖的能力的急性测试。向雄性Sprague-Dawley大鼠饲喂高脂膳食8周以诱发肥胖,然后使其暴露于5μg/kg皮下单剂量的KBP-056、UGP302/KBP-042或载剂(盐水)(每组5只大鼠),并评估对摄食、体重和血糖的作用。在18小时的给药之后,从尾静脉收集血液。用Avia血糖仪(Roche Diagnostics,Rotkreuz,Switzerland)确定全血糖水平。
如图6所见,KBP-056在18小时期间强烈降低摄食,这也在显著重量减轻中得到证明。有趣的是,该重量减轻显示超过由UGP302/KBP-042引起的重量减轻。最后,观察到餐后葡萄糖水平显著降低,从而证实这类新型肽表现出显著的体内活性。
实施例5:对空腹血糖和HbA1c的体内活性测试
为了评估肽对于调节血糖水平的作用,用3种最有前景的KBP(023、056和088)和活性比较物(UGP302/KBP-042)处理雄性ZDF大鼠(2型糖尿病的金标准模型)3周。雄性ZDF(fa/fa)于7周龄时从Charles River Laboratories(Kisslegg,Deutschland)获得。将所有动物圈养在Nordic Bioscience的动物设施:恒温(21℃至23℃)和相对湿度(55%-65%),12小时的光照/黑暗周期,自由获取Purina 5008大鼠食物(Brogaarden,Lynge,Denmark)和自来水。在8周龄时,基于空腹血糖和体重将动物随机分成5组,每组8只大鼠(载剂(盐水)、UGP302/KBP-042 5μg/kg/天、KBP-023 5μg/kg/天、KBP-056 5μg/kg/天和KBP-088 5μg/kg/天),并每日一次地皮下给药。将动物处理总共3周以评估肽对空腹血糖的作用。使用Avia监测系统(Roche Diagnostics,Rotkreuz,Switzerland)监测血糖并且通过DCA VantageTM分析仪(Siemens Healthcare Diagnostics,Deerfield,IL)监测HbA1c水平。
空腹血糖和HbA1c在3周后进行评估,并且如图7所见,KBP-056和KBP-088二者在降低FPG和HbA1c方面均具有高活性,并且有趣的是,其表现出优于UGP302/KBP-042,表明氨基酸替换提高效力,如在体外数据中也可看出。
实施例6:KBP-056对骨吸收和软骨降解的作用
鉴于KBP与不同降钙素之间的关系以及鲑鱼降钙素的公知骨和软骨保护作用,在以HFD为食的雄性大鼠中分析KBP-056对骨吸收(通过CTX-I测量)和软骨降解(通过CTX-II评估)的作用。如图8所见,KBP-056剂量和时间依赖性地降低CTX-I和CTX-II二者,其中在给药后3小时且剂量超过1μg/kg/天时达到最大抑制。这证实,KBP尽管氨基酸改变但仍保留其对骨和软骨的有益作用。另外,基于其在其他测试中的优越性,我们预期这些作用同样优越。
实施例7:KBP 088和KBP 089对肥胖大鼠中摄食的比较性作用
在实验之前,向大鼠饲喂高脂膳食(High-Fat-Diet)14周以诱发肥胖。然后,将大鼠随机分成7组(载剂(0.9%NaCl)、KBP-089(剂量:1.25、2.5、5μg/kg)和KBP-088(剂量:1.25、2.5、5μg/kg)。将大鼠禁食过夜,然后在早晨利用皮下施用用单剂量的肽或载剂进行处理。在以下时间间隔内监测摄食(0至4小时、4至24小时和24至48小时)。如图9所见,KBP-088和KBP-089二者均导致摄食在4小时间隔内降低,并且该效果维持至24小时。在24至48小时的间隔内,仅KBP-089导致摄食降低,表明该分子优于KBP-088。
在图12F中,根据本发明之更宽范围的肽表现出类似测试结果。
在不同时间段并且用不同的肽进行其他类似研究,并且结果见图10和图11。将KBP089在72小时内抑制摄食的能力与作为对照的KBP042进行比较,并且结果见图10。
为了进一步研究KBP-089相对于KBP-042的效力,对肥胖大鼠如下给药:以2.5μg/kg/天给予皮下注射KBP-089或KBP-042,然后是两个对照组:载剂组和卡路里限制组,在卡路里限制组中,摄食与KBP-089组的摄食匹配以显示是否可观察到独立于摄食的作用。
在图11中:肽在8周处理期期间对摄食和体重的作用分别示于上图和下图中。可以看出,如所预期的,两种肽在开始时均显著降低摄食,在此之后效果降低,并且摄食逐渐正常。对体重的作用示于图11的下图中,其中明显看出这两种肽均导致体重显著减轻;然而由KBP-089引起的体重减轻大于由KBP-042引起的体重减轻,表现出优越性。另外,当将KBP-089与在研究期间与KBP-089组接受完全相同量食物的卡路里限制对照组(成对饲喂)进行比较时,明显的是重量减轻不仅受限制摄食的调节,而且还受其他作用的调节。
在本说明书中,除非另外明确地指出,使用词语“或/或者”的意义是当满足所陈述条件之一或都满足时,返回一个真值的操作,而不是要求只满足一个条件的“排他的或”的操作。使用的词语“包含”的意义是“包括”而不是“由......组成”。上文提及的所有现有教导均通过参考并入本文。不承认本文中的任何在先发表的文献应被理解为承认或表示其教导在澳大利亚或其他地区在其发表之日为公知常识。
Claims (9)
1.由以下组成的肽:
a)根据SEQ ID NO:43的氨基酸序列,或者
b)通过在其N-末端羧基化、乙酰化、丙酰化、琥珀酰化或PEG化,和/或通过在其C-末端酰胺化,和/或通过使得1位和7位的半胱氨酸残基一起被α-氨基辛二酸(Asu)替换而修饰的根据SEQ ID NO:43的氨基酸序列。
2.如权利要求1所述的肽,其由SEQ ID NO:44组成。
3.如权利要求1或2所述的肽,其配制成用于经肠施用。
4.如权利要求1或2所述的肽,其配制成用于肠胃外施用。
5.如权利要求4所述的肽,其配制成用于注射。
6.如权利要求1至3中任一项所述的肽,其与载体一起配制成用于经口施用。
7.如权利要求6所述的肽,其中所述载体包含5-CNAC、SNAD或SNAC。
8.如权利要求1至3、6或7中任一项所述的肽,其中所述肽配制成包含经包衣柠檬酸颗粒的用于经口施用的药物组合物,并且其中所述经包衣柠檬酸颗粒提高所述肽的经口生物利用度。
9.如权利要求1至8中任一项所述的肽在制备用于治疗I型糖尿病、II型糖尿病、体重过重、代谢综合征、类风湿性关节炎、非酒精性脂肪肝病、骨质疏松症或骨关节炎、血糖水平调节不良、针对葡萄糖耐量测试之响应调节不良或摄食调节不良的药物中的用途。
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