CN103702668A - 治疗糖尿病的组合物和方法 - Google Patents
治疗糖尿病的组合物和方法 Download PDFInfo
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- CN103702668A CN103702668A CN201280021319.1A CN201280021319A CN103702668A CN 103702668 A CN103702668 A CN 103702668A CN 201280021319 A CN201280021319 A CN 201280021319A CN 103702668 A CN103702668 A CN 103702668A
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Abstract
本发明涉及通过绕过上消化道递送丁酸、胆汁酸、长链脂肪酸或谷氨酰胺至结肠治疗II型糖尿病的方法。该组合物通过或者相同或者不同的给药途径与DPP-IV抑制剂诸如维格列汀联合。
Description
本申请要求2011年5月2日提交的美国临时申请号61/481,268的优先权,并通过全文引用结合于本文中。
版权标记
本专利的一部分公开含有受到版权保护的素材。版权拥有者并不反对具有专利文献或专利公开的任何人复制,如其在专利和商标事务所的专利档案或纪录中呈现的那样,但在另一方面保留所有版权。
发明背景。
发明领域
本发明涉及治疗糖尿病、代谢综合征、高甘油三脂血症、多囊性卵巢综合征(PCOS)和肥胖症的新方法和组合方法。具体说来,本发明涉及通过将与二肽基肽酶抑制剂联合的特定的天然存在的化合物传递至下消化道,以诱导分泌的内源性胃肠激素分泌和防止分泌的内源性肠激素降解的方式治疗糖尿病、代谢综合征、高甘油三脂血症、多囊性卵巢综合征(PCOS)和肥胖症。
相关领域的描述
减肥手术(bariatric surgery)的应用是受欢迎的并是治疗肥胖症非常有效的方法。
糖尿病是越来越严重的世界性健康威胁,并被认为即是发达国家又是发展中国家的主要健康风险。II型糖尿病占绝大部分涉及糖尿病的病例,并被视作美国的第七大主要死因。看来,II型糖尿病发病的主要促成因素是超重。仅在美国,就估计超过1760万人患有糖尿病,估计另外570万人不知道他们患有糖尿病。此外,有约5700万美国人被认为处于糖尿病前期。
也把II型糖尿病称为非胰岛素依赖的糖尿病。其通常表现为其本身不能适当地调节血糖水平。这与特征在于在胰腺生成胰岛素方面有缺陷的I型糖尿病相反。换句话说,II型糖尿病个体似乎患有胰岛素抵抗。已经证实促进II型糖尿病发展的因素包括肥胖症、遗传背景、年龄、膳食和缺乏运动中的一种或多种。II型通常称为“成年发病型”,然而由于膳食是一种因素,其在几乎任何年龄均可能发生。
II型糖尿病可引起血和尿中的葡萄糖水平升高,这依次可引起饥饿、排尿、干渴和代谢问题。如果该疾病不治疗,最常见的严重结果包括心脏病、肾病和失明。目前采用几种治疗。因为肥胖症往往是糖尿病的致病因子,食物和运动通常是前线防御。治疗剂也用作第二道防御线,包括采用降低葡萄糖的血和尿水平的胰岛素或药物。
目前用于II型糖尿病的几种药物包括胰岛素促分泌剂、葡萄糖降低效应物(effectors)、GLP-1类似物、DPPIV抑制剂、过氧化物酶体增殖物(proliferator)激活剂活化的受体-γ的激活剂和α-葡萄糖苷酶抑制剂。用DPP-IV抑制剂治疗的一个特殊的问题是阻断通过GLP-1和相关的胃肠激素(PYY、GLP-2、泌酸调节肽)的释放的反馈机制的众所周知的问题。由于目前这些治疗具有与它们相关的几个问题,仍需要供选择的治疗方法以治疗II型糖尿病。
胃肠激素是一种类型的胃肠激素,其中,它在饮食后,甚至在血糖水平升高前,使自胰岛(islets of Langerhans)的β细胞释放的胰岛素的量增加。它们以其最高水平自结肠中的L-细胞分泌。它们还通过减轻胃排空减缓进入血流中的营养素的吸收速度,并可直接减少食物摄取。它们还抑制胰高血糖素自胰岛的α细胞释放。胰高血糖素如肽-1 (GLP-1),其常常被称为肠降血糖素,是经L细胞分泌的胃肠激素。胰高血糖素样肽-1 (GLP-1) (肠降血糖素)已经被确认为如果刺激其分泌可能用来治疗糖尿病的一种组合物。
GLP-1是自肠内分泌L细胞分泌的肽并具有在过去二十年间在许多出版物中已经描述过的多种生理学作用。最近,大量研究已经集中于GLP-1在治疗疾病和障碍诸如糖尿病、紧张状态、肥胖症、食欲控制和饱满感、阿尔茨海默病、炎症和中枢神经系统疾病方面的用途。然而,由于难以给药和缺乏充分的体内稳定性,肽在临床治疗中的用途严重受限。因此,已经认为能直接模拟GLP- 1的效用或能增加GLP-1分泌的小分子是在治疗上述各种疾病或障碍,即糖尿病和肥胖症中增加肠降血糖素生成的治疗选择。
PYY是胃肠激素(肽YY),它是经回肠和结肠中的细胞响应食物摄取而释放出的短(36个氨基酸)蛋白。它降低人的食欲。PYY发现于胃肠道尤其是回肠和结肠的粘膜中的L-细胞。在食道、胃、十二指肠和空肠中也有少量(约1-10%)的PYY。PYY在血液循环中的浓度餐后(食物摄取后)增加并因禁食而下降。
GLP-2 (胃肠激素)是与GLP-1一起自小肠和大肠中的肠内分泌细胞共同分泌的33个氨基酸肽。其中,GLP-2刺激小肠和大肠的粘膜生长,抑制胃排空和胃酸分泌,减少肠渗透性和刺激肠血液流动。
泌酸调节肽(胃肠激素)是与GLP-1一起自L-细胞共同分泌的37个氨基酸肽,其模拟GLP-1和GLP-2对胃酸分泌和胃肠蠕动的作用,抑制正常人的食欲和减少食物摄取并减少能量摄取约17%,对于超重和肥胖人受治者的水摄取完全没有作用。
丁酸是以酯的形式出现于动物脂肪和植物油中的天然存在的脂肪酸。例如,丁酸的甘油三酯组成3%-4%的黄油。它发现于酸败食物(rancid foods)诸如变质黄油和变质奶酪中,并具有极为讨厌的气味和味道。它是称为短链脂肪酸的脂肪酸亚组的重要成员。
胆汁酸(也称为胆盐)是主要发现于哺乳动物的胆汁中的甾烷酸(steroid acids)。人的牛磺胆酸和甘氨胆酸(胆汁酸的衍生物)代表着全部胆汁酸的约80%。两种主要的胆汁酸是胆酸和鹅去氧胆酸。它们、它们的共轭物及其7-α-去羟基化衍生物全部发现于人肠胆汁中。随着胆汁酸的增加的分泌,胆汁流动表现出增加。胆汁酸的主要功能是促进胶束的形成,其促进膳食脂肪处理。胆盐组成由甾族结构与4个环、终结于羧酸的5或8个碳侧链组成并存在和定位有不同数量的羟基的分子大家族。4个环从左至右标记为(按照通常绘制的) A、B、C和D,其中一个碳连着的D-环比其它三个更小。2位上的羟基有一个选择,或者上(或者外),称为β(通常按惯例画成实线),或者下,称为α(在图中表示为虚线)。全部胆汁酸在3位具有羟基,其衍生自母体分子胆固醇。在胆固醇中,4个甾族环是平的,且3-羟基的位置是β。
长链脂肪酸(LCFA)是具有16个或更多个碳的脂肪族末端的脂肪酸。脂肪酸是衍生于或包含于动物或植物脂肪、油或蜡中的酯化形式的脂族单羧酸。天然脂肪酸通常具有可以是饱和或不饱和的4-28个碳(通常无支链和偶数个成员)的链。
谷氨酰胺是用作治疗多种疾病,包括癌症的营养补充剂的氨基酸。谷氨酰胺是人体中最大量的游离氨基酸,除了其作为蛋白组分的作用外,它还在身体中发挥多种功能。由于其由身体细胞制备,它是非必需氨基酸。此外,大部分膳食蛋白含有足量的谷氨酰胺,健康人通常在其膳食中得到它们需要的全部额外的谷氨酰胺。
特别难以给予以上天然存在的产物,因为这些产物的味道极不适口,而且它们在消化道中易于降解和/或吸收。
肥胖症是遍及世界上多个国家的人群中达到流向比例的医学疾病。它也是涉及或介导扰乱生命活力和生活方式的其它疾病或病症的疾病。肥胖症公认为其它疾病和病症,诸如糖尿病、高血压和动脉硬化的严重风险因素,并可促成血液中的胆固醇水平升高。还公认,由于肥胖症的增加的体重会给关节,诸如膝关节带来负担,引起关节炎、疼痛和僵硬。肥胖症可引起某些皮肤病诸如特应性皮炎和褥疮。由于吃得过多和肥胖症在普通人群中已经成为这样一个问题,许多人现在对体重减轻、减少体重和/或保持健康体重和生活方式感兴趣。
高甘油三脂血症(hTG)是美国的常见病。该病由于不受控制的糖尿病、肥胖症和久坐习惯而加重,与发展中国家相比,所有这些加重更加流行于工业化社会,尤其是在美国。在流行病学和干预研究中,高甘油三脂血症是冠状动脉疾病的风险因素(CAD)。通过限制膳食中的碳水化合物和脂肪,以及用烟酸、贝特类和他汀类(三类药物),治疗高甘油三脂血症。增加的鱼油摄取可大大降低个体的甘油三酯。
显然存在有许多设计来递药至下消化道的组合物。这类组合物包括诸如于2008年10月7日授权于Villa等的美国专利7,431,943公开的三组分基质结构,其通过全文引用结合于本文中。
正在试验表现出刺激胃肠激素诸如GPR 120、TGR5、GPR 41 和GPR 43受体的刺激受体的多种新途径。在专利申请:2008年6月5日出版的WO/2008/067219;2007年11月8日出版的US2007/060759;2006年3月9日出版的JP2006-630 4A和2006年3月2日出版的JP 2006-56881 A中,公开已被设计来刺激TGR5受体、胆汁酸 G-蛋白偶联受体的几类小分子激动剂。
包括直链淀粉包衣片剂、肠溶衣壳聚糖片剂、基质或多基质系统中的基质或多糖包衣片剂的多种不同制剂,可有效递送想要的组合物至结肠。多基质控释系统的一个实例公开于2008年10月7日授权于Villa等的美国专利号7,431,943中,其通过引用结合于本文中。所公开的是基质设计中的基质,其中的亲脂相(lipophlic phase)和两亲相(amphiphilic phase)结合在内基质中,且至少一部分活性成分被结合进两亲相。
二肽基肽酶4 (DDP-IV)抑制剂是一类通过阻断DPP-IV而起作用的口服降血糖药并可用于治疗II型糖尿病。据认为它们的作用机制是由GLP-1抑制剂的降解而产生的,其依次增加胰岛素分泌,减少胃排空和减少血糖水平。这些化合物具有的共同缺点是,它们防止因进食诱导的内源性胃肠激素的分泌。上市的或在临床试验中的此类药物的实例包括西格列汀、维格列汀、沙格列汀、利拉利汀、度格列汀、吉格列汀、阿格列汀和小蘖碱(小蘖碱是一种草本膳食补剂,其已知具有抗-高血糖药物活性,但不用于这样的治疗而出售)。
发明概述
本发明涉及这样的发现,即某些天然存在的组合物可被递送至结肠 或直肠,以便绕过胃和上消化系统并增加来自L细胞的某些胃肠激素的生成。这可在以结肠靶向制剂与二肽基肽酶4 (DDP-IV)抑制剂联合使用时用来治疗II型糖尿病。这些组合是不同的、口服给予的二肽基肽酶4(DDP-IV)抑制剂。口服给予的DDP-IV抑制剂被快速吸收,导致高的血浆水平,其可维持最多24小时的长时间。以DPP IV抑制剂的血浆水平将不达到显著水平的方式选择本发明的组合物,因而将允许酶(DPP IV)用于延迟处理血浆中的GLP-1并在餐后将不减少胃肠激素的释放。GLP-1 9-36的额外增加的水平(其被报道具有有益的心血管作用)将存在于系统循环中。
在本发明的一个实施方案中,存在治疗个体的II型糖尿病的病症的方法,其包括:
a) 从包含丁酸、胆汁酸、长链脂肪酸和谷氨酰胺的组中选择使胃肠激素自L-细胞分泌的药物,所配制的组合物在人结肠靶向递送系统中或在直肠释放系统中释放;
b) 选择DPP-IV抑制剂;和
c) 经结肠靶向递送系统给予个体与DPP-IV抑制剂组合的药物,所述药物引起结肠同时释放所述药物和足以使胃肠激素自个体结肠中的L-细胞释放的抑制剂,其中所述抑制剂抑制所述药物的降解。
在本发明的又一个实施方案中,存在用于治疗II型糖尿病的药用组合物,其包含;
a) 用于诱导自L-细胞释放胃肠激素的组分,其选自丁酸、胆汁酸、长链脂肪酸和谷氨酰胺;和
b) DPP-IV抑制剂;
其中配制所述组合物和抑制剂用于同时释放至结肠。
发明详述
该详述的说明书本文所用的术语的含义,并按顺序为本领域的技术人员具体描述实施方案以实现本发明。
术语“约”和“基本上”意指±10%。
术语“包含”并不打算限制本发明至仅用这样的包含语言要求的本发明的范围。使用术语包含的任何本发明可以使用“由…构成”或“由…组成”的权利要求语言分成一个或多个权利要求且有意如此。
如本文用的术语"一"或者"一个"被定义为一个或定义为不止一个。如本文用的术语"多个"被定义为两个或定义为不止两个。如本文用的术语"另一个"被定义为至少第二个或更多个。如本文用的术语"包括"和/或"具有"被定义为包含(即,开放语言)。如本文用的术语"偶联"被定义为连接,尽管不一定是直接的,也不一定是物理上的。
提到遍及本文件的"一个实施方案"、"某些实施方案"和“某实施方案"或类似术语时意指与该实施方案有关的所述具体特征、结构或特性被包括在至少一个本发明实施方案中。因此,出现在整个说明书中不同位置的这类短语不一定都指同一实施方案。而且,可毫无限制地以任何适用方式将具体特征、结构或特性组合在一个或多个实施方案中。
如本文用的术语"或"被解释为包括或者意指任何一种或任何组合。因此,"A、B或C"意指下列中任一种:"A; B; C; A和B; A和C; B和C; A、B和C"。仅当要素、功能、步骤或作用在某些方式上固有地互相排斥时,才会出现该定义的例外。
在一个操作的现在分词前的术语“方式”指,存在一个或多个实施方案的想要的功能,即,实现想要的功能的一种或多种方法、装置或器具,和本领域技术人员可就本文的公开从这些或它们的等价物中选择,术语“途径”的使用并非旨在限制。
如本文用的术语"治疗"指缓解特定的疾病、消除或减轻疾病的症状、减缓或消除疾病的发展并预防或延缓受治者疾病的初发或先前受折磨的受治者的疾病的复发。
如本文采用的“病症”或“障碍”指哺乳动物例如人类等的II型糖尿病,在餐后增加自L细胞生成的胃肠激素,同时用DPP IV抑制剂治疗将对哺乳动物具有正面影响。
在本发明中,通常为响应肠中营养素的出现,存在于结肠中的L-细胞中的胃肠激素分泌受到刺激。这种作用在用DPP-IV抑制剂治疗II型糖尿病时可被部分地或严重地抑制,因此当使用这些类型的组合物时有助于改善所述病症的治疗。尽管这样的L-细胞也存在于消化道的其它部分和有机体的其它部分,但它们在结肠中的浓度最高。刺激结肠中的L-细胞使胃肠激素最有效的生成成为可能,从而产生最有效的治疗。本发明的来自L-细胞的胃肠激素包括但不限于GLP-1、GP-2、PYY 和泌酸调节肽。肠降血糖素诸如GLP-1,具体说来,是一个实施方案中感兴趣的胃肠激素。
刺激胃肠激素释放的本发明化合物是选自丁酸、胆汁酸、长链脂肪酸和谷氨酰胺的天然化合物。应理解,其分别包括这些化合物的组合以及每种化合物。
如本文采用的术语“DPP-IV抑制剂”指为一类口服降血糖药的组合物,其通过阻断DPP-IV起作用并可被用于治疗II型糖尿病。据认为它们的作用机理是由抑制胰高血糖素的释放,增加胰岛素分泌,减少胃排空和减少血糖水平的GLP-1的高维持水平产生的。这些化合物具有的共同缺点是,它们防止因进食诱导的内源性胃肠激素的分泌。上市的和/或在临床试验中的此类药物的实例包括西格列汀、维格列汀、沙格列汀、利拉利汀、度格列汀、吉格列汀、阿格列汀和小蘖碱(小蘖碱是一种草本膳食补剂,其已知具有抗-高血糖药物活性,但不用于这样的治疗而出售)。
如本文用的,本发明的"化合物”包括本文所述的全部化合物。
本发明化合物可以不止一种型式结晶,典型地称为多晶现象,这类多晶型形式("多晶型物")在本发明范围内。多晶现象通常会随着对温度、压力或二者的变化的响应而发生。多晶现象也可源自结晶过程。可通过本领域已知的各种物理特性,诸如x射线衍射图、溶解度和熔点,区分多晶型物。
本文所述的某些化合物含有一个或多个手性中心,或者可能除此之外能够作为多种立体异构体存在。本发明的范围包括各立体异构体的混合物以及纯化的对映异构体或对映异构/非对映异构富集的混合物。包括在本发明范围中的还有本发明化合物的各单一异构体,及其完全或部分平衡的任何混合物。本发明还包括作为与其异构体的混合物的上式表示的化合物的各单一异构体,其中一或多个手性中心被翻转。
一般,但并非绝对,本文的化合物包括本发明组合物的盐,并包括药学上可接受的盐。涵盖于术语"药学上可接受的盐"中的盐指本发明化合物的无毒盐。本发明化合物的盐可包括酸加成盐。代表性的盐包括醋酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、乙二胺四乙酸钙、樟磺酸盐、碳酸盐、克拉维酸盐、柠檬酸盐、二盐酸盐、乙二磺酸盐、依托酸盐(estolate)、乙磺酸盐、富马酸盐、葡庚糖酸盐(gluceptate)、葡糖酸盐、谷氨酸盐、对羟乙酰氨基苯胂酸盐(glycollyl arsanilate), 已基间苯二酚盐、海巴明、氢溴酸盐、盐酸盐、羟萘酸盐、碘化物、羟乙基磺酸盐(isethionate)、乳酸盐、乳糖酸盐(lactobionate)、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、马来酸氢钾(monopotassium maleate)、粘酸盐、萘磺酸盐、硝酸盐、N-甲基葡萄糖胺、草酸盐、双羟萘酸盐(扑酸盐)、棕榈酸盐、泛酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸盐、钾、水杨酸盐、钠、硬脂酸盐、碱式乙酸盐、琥珀酸盐、硫酸盐、单宁酸盐、酒石酸盐、茶氯酸盐、甲苯磺酸盐、thethiodide、三甲基铵(thmethylammonium)和戊酸盐。非药学上可接受的其它盐可用于本发明化合物的制备,应认为这些形成本发明的其它方面。
“同时给予”、“同时释放”,以及“同时传递”来自L-细胞的胃肠激素的刺激组合物指刺激组合物和DPP-IV抑制剂组合物同时向结肠的联合传递。如本文所用的“传递至结肠”指口服或直肠给予本发明的组合物,其中活性组合物被传递至结肠。如本文别处描述的,这样配制的各化合物可口服并绕过上消化道和胃递送至结肠,或者经直肠递送组合物至结肠。
“给予”本发明组合物可指经口、直肠等,且除了作为完整组合物传递至结肠外,并不依赖于任何特定的给药方式。DPP-IV抑制剂与胃肠激素刺激组合物同时地给予,而不管给药途径。DPP-IV抑制剂可经与肠降血糖素刺激组合物相同的途径给予。本发明给予的DPP-IV抑制剂量是用于防止结肠对胃肠激素分泌刺激组合物的降解并直至其到达肝的量。在那一点上说,DPP-IV抑制剂将被代谢而提供GLP-1的正常代谢过程。本领域技术人员将能确定准确的量,该量取决于具体的DPP-IV抑制剂以及参与本发明的疗法的个体。在本发明的用DPP-IV抑制剂维格列汀的治疗中,在一个实施方案中,平均剂量将为约0.01 mg/kg至约1 mg/kg。在同时给予的组合物中,L-细胞刺激组合物的有效量为100 mg至约2 g。
如本文所用的,术语"有效量"指能引起例如研究者或临床医生寻求的组织、系统、动物或人的生物学或医学响应的药物或药剂的量。
术语"治疗有效量"意指作为与未接受这样的量的相应受治者相比,产生疾病、障碍、副作用改善的治疗、康复、预防、改进,或疾病或障碍的发展速度下降的任何量。术语还在其范围内包括有效促进正常生理学功能的量。治疗有效量将产生“治疗效果”。
针对治疗用途,治疗有效量的本发明化合物及其盐呈现为被配制来在结肠靶向递送系统中释放的药用组合物。
本发明提供包含有效量的如本文描述的化合物或它的盐和一种或多种药学上可接受的载体、稀释剂或赋形剂的药用组合物。就与制剂中的其它成分相容和不有害于药用组合物的接受者和与给药方式,即经口或直肠一致而言,载体、稀释剂或赋形剂必须是可接受的。
根据本发明的另一方面,还提供药用制剂的制备方法,其包括使本发明化合物或它的盐与一种或多种药学上可接受的载体、稀释剂或赋形剂混合。
本发明化合物的治疗有效量将取决于多个因素。例如,接受者的物种、年龄和体重,需要治疗的确切疾病及其严重性,制剂的性质和结肠靶向递送系统的类型是要考虑的全部因素。治疗有效量最终应由护理者、医师或兽医判断。无论如何,针对患有糖尿病或超重病症和相关疾病的人的治疗的本发明肠降血糖素刺激化合物的有效量通常应该在0.01-100 mg/kg接受者体重(哺乳动物)每日的范围内。更频繁地,有效量应该在0.3-30 mg/kg体重每日的范围内。因此,对于70 kg成年哺乳动物,每日实际量将通常为21-2100 mg。可以每日单次剂量或以每日多个(诸如2、3、4、5或更多个)亚剂量给予该量,以便总日剂量为相同的。可按照本发明化合物本身的有效量的比例确定盐或其溶剂合物的有效量。类似剂量应适于治疗本文提及的其它疾病。
药用制剂可呈每单位剂量含有预定量的活性成分的单位剂量形式。作为非限制性实例,根据要治疗的疾病、给药途径和患者的年龄、体重和状况,这样的单位可含有0.5mg-1g的本发明肠降血糖素刺激化合物。优选单位剂量制剂是含有活性成分的如上文列举的日剂量或亚剂量或其适当部分的那些。可通过制药领域熟知的任何方法制备这类药用制剂。
通过靶向递药系统给予本发明化合物或它的盐。在一个实施方案中,可针对靶向递药至结肠和绕过上消化系统和胃,采用递药系统。这类递药系统包括共价连接的组合物、聚合物包衣组合物、包埋于基质中的组合物、定时释放组合物、氧化还原敏感聚合物组合物、生物粘附组合物、微粉包衣组合物和渗透递送组合物。适用的组合物包括含有多糖,诸如壳聚糖、果胶、硫酸软骨素、环糊精、右旋糖酐、瓜尔胶、菊糖、淀粉酶和刺槐豆胶的那些。化合物也可与可溶解聚合物偶合。这类聚合物可包括聚乙烯基吡咯烷酮(PVP)、吡喃共聚物、聚羟丙基甲基丙烯酰胺-酚、聚羟乙基-天冬酰胺酚(aspartamidephenol)或被棕榈酰残基取代的聚氧化乙烯聚赖氨酸。而且,化合物可与一类可生物降解的聚合物偶合;例如,聚乳酸、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲嵌段共聚物。本发明中特别有效的那些包括多基质靶向系统的实施方案。本发明特别有效的为基质系统中的靶向基质,其包含亲水的第一种基质的制剂、包含亲脂相和两亲相,其中的亲脂相和两亲相共同处于第二种基质中,第二种基质完全分散于亲水的第一种基质中,其中的药用组合物含有至少部分地结合进两亲相的化合物。某些基质制剂中的基质的实例公开于如上提及的美国专利7,431,943。本领域技术人员应意识到为靶向递送本发明化合物或其盐至要治疗的受治者的结肠而采用这类组合物。就该公开而言,靶向递送这类组合物制剂的方法在本领域的技术范围内。
可单独或与其它治疗剂联合采用本发明的化合物或其盐。在一个实施方案中,它们与用来治疗II型糖尿病的其它药物组合。当分开给予时,可同时或按任何顺序相继给予。为达到想要的联合治疗效果,将选择给予本发明化合物和其它药用活性剂的量和相应的时间安排。本发明化合物或其盐或溶剂合物与其它治疗剂联合给予可通过同时给予以下的组合:(1) 包含两种化合物的单一药用组合物;(2)各自包含一种化合物的分开的药用组合物。作为选择,可以相继的方式分别给予,其中先给予一种治疗剂,再给予另外的第二种,反之亦然。这样的相继给药可以接近的的时间或者相隔较长的时间进行。
也可将化合物配制成直肠组合物例如含有常规栓剂基质诸如可可脂或其它甘油酯的栓剂或滞留型灌肠剂。除了直肠给药可能影响的其它区域之外,这样配制的组合物还将被设计为给予结肠有效剂量。
本发明化合物可用于治疗II型糖尿病。本发明化合物本身可与用于治疗这种病症的多种其它治疗剂联合采用。如以上简单讨论的,目前的糖尿病疗法包括食物、运动、胰岛素、胰岛素促泌剂、降血糖效应物(glucose-lowering effectors)、PPAR-γ激动剂和α-葡萄糖苷酶抑制剂。本发明化合物可与这些或其它医学治疗联合,以治疗和/或预防糖尿病和相关障碍和疾病,包括但不限于,I和II型糖尿病、肥胖症、葡萄糖耐受不良、胰岛素抵抗、代谢综合征、高脂血症、高胆固醇血症、动脉硬化、神经变性病和其它适应症诸如炎症和中风。
实施例
实施例1
如文献1中所述制备作为灌肠剂或栓剂递送的药物(含有1g谷氨酰胺)。对10位整夜禁食的II型糖尿病患者以一种栓剂(或灌肠剂)直肠给药。给药后30分钟,使患者接受口服葡萄糖耐量试验(OGTT)或标准餐。于以下时间点采集血样:-30、0、5、10、15、30、60、90和120分钟。分析血样的以下水平:葡萄糖、胰岛素、GLP-1、PYY、其它激素和脂质。治疗方案后测量葡萄糖和脂质(标准餐后)水平,显示有下降。
实施例2
如文献1中所述制备作为灌肠剂或栓剂递送的药物(含有2g丁酸)。对10位整夜禁食的II型糖尿病患者以一种栓剂(或灌肠剂)直肠给药。给药后30分钟,使患者接受口服葡萄糖耐量试验(OGTT)或标准餐。于以下时间点采集血样:-30、0、5、10、15、30、60、90和120分钟。分析血样的以下水平:葡萄糖、胰岛素、GLP-1、PYY、其它激素和脂质。治疗方案后测量葡萄糖和脂质(标准餐后)水平,显示它们的水平下降。
实施例3
如文献2中描述的制备用MMX技术配制的片剂(含有1g谷氨酰胺)。于上午8:00给予10位整夜禁食的II型糖尿病患者一片MMX片剂。给药后4小时,使患者接受口服葡萄糖耐量试验(OGTT)或标准餐。于以下时间点采集血样:-30、0、5、10、15、30、60、90和120分钟。分析血样的以下水平:葡萄糖、胰岛素、GLP-1、PYY、其它激素和脂质。治疗方案后测量葡萄糖和脂质(标准餐后)水平,显示它们的水平下降。
实施例4
如文献2中描述的制备用MMX技术配制的片剂(含有2g丁酸)。于上午8:00给予10位整夜禁食的II型糖尿病患者一片MMX片剂。给药后4小时,使患者接受口服葡萄糖耐量试验(OGTT)或标准餐。于以下时间点采集血样:-30、0、5、10、15、30、60、90和120分钟。分析血样的以下水平:葡萄糖、胰岛素、GLP-1、PYY、其它激素和脂质。治疗方案后测量葡萄糖和脂质(标准餐后)水平,显示它们的水平下降。
实施例5
如文献2中描述的制备用MMX技术配制的片剂(含有1g谷氨酰胺)。在首次进食前于上午8:00给予10位II型糖尿病患者一片MMX片剂6周。在治疗前和在开始治疗后的1、2和6周,测量HbA1c,禁食葡萄糖和胰岛素。此外,在这些时间使患者接受口服葡萄糖耐量试验(OGTT)或标准餐。于以下时间点采集血样:-30、0、5、10、15、30、60、90和120分钟。分析血样的以下水平:葡萄糖、胰岛素、GLP-1、PYY、其它激素和脂质。治疗方案后,测量出葡萄糖水平下降。治疗也使甘油三酯水平低于治疗前水平。
实施例6
使以上各实施例与每日一次给予(MMX)一片(1)定时释放的5 mg维格列汀(Galvus, Novartis)片剂联合。II型糖尿病患者用联合疗法治疗并在急性实验中再次测试OGTT的葡萄糖处置并在慢性实验中检测HbA1c水平。已观察到联合疗法导致改善的II型糖尿病病症(当与单一药物的情况比较时),即仅需要较低剂量的药物(与使用单一的药物比较)达到相同的功效,或者使用与单一药物疗法相同的量,如在长期给药后经降低HbA1c所测定的达到较高的疗效。
以下参考文献通过全文引用结合于本申请中。
1. Mayo Clin. Proc. 1993, 68卷, 978页,通过引用结合于本文中,
2. 美国专利7,431,943 B1,通过引用结合于本文中,
3. Diabetes, Obesity and Metabolism, 9 (增刊1), 2007, 23–31 通过引用结合于本文中,
4. Toft-Nielsen MB, Damholt MB, Madsbad S等. 2型糖尿病患者的胰高血糖素样肽-1的受损的分泌的决定因素. J Clin Endocrinol Metab 2001;86:3717-3723,
5. Rask E, Olsson T, Soderberg S等. 非糖尿病男性混合餐后的受损的肠降血糖素响应与胰岛素抵抗相关. Diabetes Care 2001;24:1640-1645,
6. 2009年1月12日提交的临时专利申请(BIOK001PR) 61/143,951和2010年1月11日提交的临时专利申请(BIOK001PR-C) 61/293,773,均通过引用以其全文结合于本文中。
7. BIOK001-C-PCT申请号PCT/US2010/020629,通过引用以其全文结合于本文中。
Claims (17)
1.一种治疗个体的II型糖尿病的病症的方法,其包括:
a) 从包含丁酸、胆汁酸、长链脂肪酸和谷氨酰胺的一组中选择使胃肠激素自L细胞分泌的药物,所配制的组合物在人结肠靶向递送系统中或直肠释放系统中释放;
b) 选择DPP-IV抑制剂;和
c) 经结肠靶向递送系统给予所述个体与DPP-IV抑制剂组合的药物,其引起结肠同时释放所述药物和足以引起自个体结肠中的L细胞释放胃肠激素的抑制剂,其中所述抑制剂抑制所述药物的降解。
2.根据权利要求1的方法,其中的药物包含谷氨酰胺。
3.根据权利要求1的方法,其中的药物包含丁酸。
4.根据权利要求1的方法,其中的结肠靶向递送系统是基质递送系统中的基质。
5.根据权利要求4的方法,其中的结肠靶向递送系统是包含亲脂相和两亲相的亲水的第一种基质的控释制剂,其中的亲脂相和两亲相共同处于第二种基质中,且所述第二种基质被充分分散于亲水的第一种基质中,其中的药用组合物至少部分地结合进两亲相中。
6.根据权利要求1的方法,其中所述靶向递送系统是同时直肠给予的。
7.根据权利要求1的方法,其中的DPP-IV抑制剂选自西格列汀、维格列汀、沙格列汀、利拉利汀、度格列汀、吉格列汀、阿格列汀和小蘖碱。
8.根据权利要求7的方法,其中所述抑制剂是维格列汀。
9.根据权利要求1的方法,其中来自L-细胞的胃肠激素选自GLP-1、GLP-2、PYY和泌酸调节肽。
10.一种用于治疗II型糖尿病的药用组合物,其包含:
a) 用于诱导从L-细胞释放胃肠激素的组分,所述组分选自丁酸、胆汁酸、长链脂肪酸和谷氨酰胺;和
b) DPP-IV抑制剂;
其中所述组分和抑制剂被配制用于同时传递至结肠。
11.根据权利要求10的组合物,其中的组合物被配制成结肠靶向递药系统。
12.根据权利要求10的组合物,其中的组合物为直肠给药而配制。
13.根据权利要求10的组合物,其中的药用组合物包含谷氨酰胺。
14.根据权利要求10的组合物,其中的药用组合物包含丁酸。
15.根据权利要求10的组合物,其中的结肠靶向递送系统是在基质系统中的基质。
16.根据权利要求15的组合物,其中的结肠靶向递送系统是包含亲脂相和两亲相的亲水的第一种基质的控释制剂,其中的亲脂相和 两亲相共同处于第二种基质中,并且所述第二种基质被充分分散于亲水的第一种基质中,其中的药用组合物至少部分地结合进两亲相。
17.根据权利要求10的组合物,其中的DPP-IV抑制剂选自西格列汀, 维格列汀, 沙格列汀, 利拉利汀, 度格列汀, 吉格列汀, 阿格列汀和小蘖碱,根据权利要求11的组合物,其中的胃肠激素选自GLP-1、GLP-2、PYY和泌酸调节肽。
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CL2013003154A1 (es) | 2014-07-18 |
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CA2834885C (en) | 2020-03-10 |
HK1259004A1 (zh) | 2019-11-22 |
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