CN115279363A - 治疗糖尿病的方法 - Google Patents
治疗糖尿病的方法 Download PDFInfo
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- CN115279363A CN115279363A CN202180020954.7A CN202180020954A CN115279363A CN 115279363 A CN115279363 A CN 115279363A CN 202180020954 A CN202180020954 A CN 202180020954A CN 115279363 A CN115279363 A CN 115279363A
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Abstract
本发明涉及一种治疗糖尿病的方法。该方法包括以有效量向有需要的受试者施用达泮舒腈或其药学上可接受的溶剂化物。口服施用是优选的施用途径。
Description
技术领域
本发明涉及使用达泮舒腈(dapansutrile)或其药学上可接受的溶剂化物治疗糖尿病。
背景技术
糖尿病是重大的公共卫生问题。在美国，有超过1000万糖尿病患者。糖尿病是由相对或绝对缺乏胰岛素引起的综合征。临床上，其特征是有症状的葡萄糖不耐受以及脂质和蛋白质代谢的改变。正常血糖水平的维持通过几种激素的作用来实现，最显著的是胰岛素，但也包括胰高血糖素，肾上腺素，皮质类固醇，和生长激素。高血糖症的例子是血液中葡萄糖浓度高于正常浓度。胰腺产生胰岛素，胰岛素随着血糖浓度的升高而释放。胰岛素通过刺激细胞摄取葡萄糖来降低血糖水平。葡萄糖用于细胞代谢以产生能量，或转化为糖原储存在肝脏和肌肉中，或用于产生甘油三酯和脂肪。
在2型糖尿病(T2D)患者中，心力衰竭，心血管发病，肾功能不全，和视网膜病变的发生率高得令人无法接受。作为T2D并发症，心力衰竭的发生早于心肌梗死或中风。肾病是T2D患者透析和肾移植的主要原因。视网膜病变通常需要令人讨厌的眼内注射，并且是西方社会几十年来失明的主要原因。
已有的抗糖尿病药物主要用作降糖药物，而不直接靶向微血管炎症，微血管炎症已被证明是上述并发症发展的关键因素。
先天免疫系统的激活在糖尿病及其并发症发展的所有阶段都很明显。这包括β细胞功能受损，胰岛素抵抗，心血管疾病，心力衰竭，非酒精性脂肪性肝炎，肾病，多发性神经病，疲劳，视网膜病变，和黄斑水肿。
免疫系统的病理学激活在越来越多的疾病中发挥关键作用，其中一些与糖尿病相关联，如类风湿性关节炎，痛风，银屑病，和癌症。
为了治疗与糖尿病有关的病症，除了降糖药物外，还开出了几种药物。这种多药物方式通常与患者依从性(compliance)降低相关联，因为开出的药片数量与治疗依从性(adherence)成反比。
需要一种治疗糖尿病的有效方法；该方法不仅可以缓解高血糖症，还可以预防疾病进展，并有利于靶向糖尿病微血管和大血管并发症。
附图简要说明
图1示出了示例1的研究设计。从第1天到第14天，队列1每天接受500mg治疗，队列2每天两次接受500mg治疗，队列3每天4次接受500mg治疗。在第1，14，和28天进行了药效动力学(PD)研究；也就是说，抽取了血液和尿液并测试了生物标志物，包括离体分析。
图2示出了示例1的研究过程。
发明详述
本发明涉及治疗糖尿病，特别是2型糖尿病(T2D)的方法，2型糖尿病(T2D)增加心力衰竭，心血管发病，肾功能不全，和视网膜病变的发生率。该方法不仅降低了患者的血糖水平，而且通过治疗患者的微血管炎症预防疾病进展。
该方法包括施用有效量的达泮舒腈或其药学上可接受的溶剂化物以治疗糖尿病的步骤。
达泮舒腈抑制NLRP3炎性小体的寡聚化，进而阻止caspase-1的激活以及pro-IL-1β和pro-IL-18分别成熟为其活性形式IL-1β和IL-18。发明人已经发现达泮舒腈有效降低糖尿病患者的血糖水平。达泮舒腈靶向代谢综合征和T2D患者的IL-1，这不仅可以改善血糖，同时还可以预防微血管和心血管发病。
化合物
本发明使用纯化的达泮舒腈(3-甲磺酰基丙腈)化合物或其药学上可接受的溶剂化物：
如本文所用，“药学上可接受的溶剂化物”是保留母体化合物的想要的生物学活性并且不赋予不想要的毒理学效应的溶剂化物。溶剂化物是其中化合物与可接受的共溶剂以某种固定比例结合的加成配合物。共溶剂包括但不限于水，乙酸乙酯，月桂醇乳酸酯，肉豆蔻醇乳酸酯，十六醇乳酸酯，肉豆蔻酸异丙酯，甲醇，乙醇，1-丙醇，异丙醇，1-丁醇，异丁醇，叔丁醇，丙酮，甲乙酮，乙腈，苯，甲苯，二甲苯，乙二醇，二氯甲烷，1，2-二氯乙烷，N-甲基甲酰胺，N，N-二甲基甲酰胺，N-甲基乙酰胺，吡啶，二恶烷，和乙醚。
药学组合物
本发明提供包含一种或多种药学上可接受的载体和达泮舒腈的活性化合物或其药学上可接受的盐或溶剂化物的药学组合物。药学组合物中的活性化合物或其药学上可接受的盐或溶剂化物通常的量，对于外用制剂为约0.01-20％，或0.05-20％，或0.1-20％，或0.2-15％，或0.5-10％，或1-5％(w/w)；对于注射制剂为约0.1-5％，对于贴剂制剂为约0.1-5％，对于片剂制剂为约1-90％，对于胶囊制剂为约1-100％。药学组合物中使用的活性化合物通常为至少90％，优选95％，或98％，或99％(w/w)纯。
在一个实施例中，药学组合物为剂型，如片剂，胶囊剂，颗粒剂，细颗粒剂，粉剂，糖浆剂，栓剂，可注射溶液剂，贴剂等。在另一个实施例中，将活性化合物掺入任何可接受的载体，包括乳膏，凝胶，洗剂，或其他类型的悬浮液，其可稳定活性化合物并通过外用应用将其递送至受影响区域。上述药学组合物可以通过常规方法制备。
非活性成分的药学上可接受的载体可由本领域技术人员使用常规标准选择。药学上可接受的载体包括但不限于非水基溶液，悬浮液，乳液，微乳液，胶束溶液，凝胶，和软膏。药学上可接受的载体还可能包含成分，该成分包括但不限于盐水和电解质水溶液；离子和非离子渗透剂，如氯化钠，氯化钾，甘油，和右旋糖；pH调节剂和缓冲剂，如氢氧化物盐，磷酸酯/盐，柠檬酸酯/盐，乙酸酯/盐，硼酸酯/盐；和三乙醇胺；抗氧化剂，如亚硫酸氢盐，亚硫酸盐，偏亚硫酸盐，硫代亚硫酸盐，抗坏血酸，乙酰半胱氨酸，半胱氨酸，谷胱甘肽，丁基羟基苯甲醚，丁基羟基甲苯，生育酚，和抗坏血酸棕榈酸酯的盐，酸，和/或碱；表面活性剂，如卵磷脂，磷脂，包括但不限于磷脂酰胆碱，磷脂酰乙醇胺，和磷脂酰肌醇；泊洛沙姆和泊洛沙胺(poloxamines)，聚山梨酯类，如聚山梨酯80，聚山梨酯60，和聚山梨酯20，聚醚，如聚乙二醇和聚丙二醇；乙烯类聚合物，如聚乙烯醇和聚维酮；纤维素衍生物，如甲基纤维素，羟丙基纤维素，羟乙基纤维素，羧甲基纤维素，羟丙基甲基纤维素及其盐；石油衍生物，如矿物油和白凡士林；脂肪，如羊毛脂，花生油，棕榈油，大豆油；甘油单酯，甘油二酯，和甘油三酯；丙烯酸聚合物，如羧基聚亚甲基凝胶，和疏水改性的交联丙烯酸酯共聚物；多糖，如葡聚糖，和糖胺聚糖，如透明质酸钠。此类药学上可接受的载体可以使用已知的保存剂来保存以防止细菌污染，这些保存剂包括但不限于苯扎氯铵，乙二胺四乙酸及其盐，苄索氯铵，氯己定，氯丁醇，对羟基苯甲酸甲酯，硫柳汞，和苯乙醇，或可配制成用于单次或多次使用的非保存制剂。
例如，活性化合物的片剂制剂或胶囊制剂可能包含没有生物活性且不与该活性化合物反应的其他赋形剂。片剂的赋形剂可包括填充剂，粘合剂，润滑剂，和助流剂，崩解剂(disintegrators)，润湿剂，和释放速率调节剂。粘合剂促进制剂颗粒的粘附，对片剂制剂很重要。粘合剂的示例包括但不限于羧甲基纤维素，纤维素，乙基纤维素，羟丙基甲基纤维素，甲基纤维素，刺梧桐胶，淀粉，淀粉，和黄着胶，聚(丙烯酸)，和聚乙烯吡咯烷酮。
例如，活性化合物的贴剂制剂可能包含一些非活性成分，如1，3-丁二醇，二羟基氨基乙酸铝，依地酸二钠，D-山梨醇，明胶，高岭土，对羟基苯甲酸甲酯，聚山梨酯80，聚维酮(聚乙烯吡咯烷酮)，丙二醇，对羟基苯甲酸丙酯，羧甲基纤维素钠，聚丙烯酸钠，酒石酸，二氧化钛，和纯净水。贴剂制剂还可包含皮肤渗透性增强剂，如乳酸酯(例如，月桂醇乳酸酯)或二甘醇单乙醚。
包括活性化合物的外用制剂可以是凝胶，乳膏，洗剂，液体，乳液，软膏，喷雾，溶液，和悬浮液的形式。外用制剂中的非活性成分例如包括但不限于月桂醇乳酸酯(润肤剂/促渗剂)，二甘醇单乙醚(润肤剂/促渗剂)，DMSO(溶解性增强剂)，有机硅弹性体(流变学/纹理改性剂)，辛酸/癸酸甘油三酯，(润肤剂)，水杨酸辛酯，(润肤剂/UV过滤剂)，有机硅流体(润肤剂/稀释剂)，角鲨烯(润肤剂)，葵花油(润肤剂)，和二氧化硅(增稠剂)。
使用方法
本发明涉及治疗糖尿病的方法。该方法包括以下步骤：首先识别患有糖尿病的受试者，并以有效治疗糖尿病的量向该受试者施用达泮舒腈。如本文所用，“有效量”是通过改善病理学状况或减轻疾病症状而有效治疗疾病的量。
在一个实施例中，该方法降低患者的空腹血糖水平。
在一个实施例中，该方法降低血液中血红蛋白A1C(HbA1c)水平
在一个实施例中，该方法增加葡萄糖摄取并调节血糖。
在一个实施例中，该方法降低患者过去2至3个月的平均血糖水平。
在一个实施例中，该方法增加患者的葡萄糖摄取并调节血糖水平。
本发明的药学组合物可以通过全身施用和局部施用来应用。全身施用包括口服，肠胃外(如静脉内，肌肉内，皮下，或直肠)，和其他全身施用途径。在全身施用中，活性化合物首先到达血浆，然后分布至靶组织。局部施用包括外用施用。
组合物的给药量可以基于疾病的程度和每个患者的个体反应而变化。对于全身施用，所递送的活性化合物的血浆浓度可以变化；但通常为0.1-1000μg/mL或1-100μg/mL。
在一个实施例中，药学组合物经口服施用于受试者。口服施用剂量通常为至少1mg/kg/天且小于100mg/kg/天。例如，对于人受试者，口服施用剂量为1-100，或5-50，或10-50mg/kg/天。例如，对于人受试者，口服施用剂量为100-10,000mg/天，优选500-2000，500-4000，500-4000，1000-5000，2000-5000，2000-6000，或2000-8000mg/天。该药物可以每天口服一次，两次，三次，或四次。患者每天接受治疗持续1个月，2个月，或3个月，或直至患者的生命期限。例如，患者接受治疗3-6个月，3-9个月，或6-12个月。
在一个实施例中，将药学组合物静脉内施用于受试者。静脉推注或静脉输注的剂量通常为0.03至20mg/kg/天或0.03至10mg/kg/天。
在一个实施例中，将药学组合物经皮下施用于受试者。皮下施用的剂量通常为0.3-20mg/kg/天或0.3-3mg/kg/天。
本领域技术人员将认识到，多种递送机制也适用于本发明。
本发明可能与一种或多种降低血糖水平的其他治疗联合使用。
本发明用于治疗哺乳动物受试者，如人，马，牛，狗，和猫。本发明特别适用于治疗人。
以下示例进一步说明本发明。这些示例仅旨在说明本发明而不应被解释为限制性的。
示例
示例1 NYHA II-III收缩性心力衰竭受试者口服施用达泮舒腈胶囊的临床研究。
方法
本研究是单中心，随机，双盲，剂量递增试验，旨在评估口服施用达泮舒腈胶囊对患有NYHA II-III收缩性心力衰竭的受试者的安全性和药效动力学。纳入的主要标准：
·18岁或以上的男性和女性受试者
·症状稳定的心力衰竭(NYHAII-III级)，左心室射血分数降低(LVEF≤40％，入组(enrollment)6个月内测量-过去2个月内心脏药物或新装置植入无变化)
·峰值运动受限于呼吸短促并且与呼吸交换率(RER)＞1.00(反映最大有氧运动)相关联
·在基线按年龄/性别将峰值有氧运动能力(峰值VO2)降低至低于预测值的80％
·筛选时血浆CRP或hsCRP水平＞2mg/L
·项目负责人认为可接受的总体医疗状况可安全入组并完成研究(特别是心血管，肾，和肝脏状况)
·在启动任何与研究有关的过程之前提供书面知情同意书的能力，以及项目负责人认为理解和遵守研究的所有要求的能力
排除的主要标准：
·有生育能力的女性，或一位或多位性伴侣是有生育能力的女性的男性，他们：
о正在或打算在研究期间怀孕(包括使用生育药物)
о正在哺乳
о在完成所有后续过程之前不使用可接受的高效避孕方法
·CPX期间发生的血压或心率反应异常，心绞痛，或ECG变化(缺血或心律失常)
·自身免疫性病症的存在或已知病史
·基线访视前的活动性或近期(2周内)感染
·HIV，乙型肝炎表面抗原或丙型肝炎病毒抗体的病史或已知阳性
·项目负责人认为会损害受试者安全参与试验和/或完成方案要求的任何其他伴随的医疗或精神状况，疾病，或先前的手术
·通过Cockcroft-Gault方法计算的肾损害和/或肌酐清除率低于50mL/min的已知病史
·活动性恶性肿瘤或过去6个月内接受过化疗治疗的近期恶性肿瘤
·基线访视前30天内入组任何试验和/或使用任何研究产品或装置
·之前暴露于研究产品
·使用违禁药物
·基线访视时活动性肺结核(TB)感染的病史或证据
剂量和施用方式：
研究设计示于图1。每个队列由10名患者组成；8名患者接受了达泮舒腈治疗，2名患者接受了安慰剂治疗。从第1天到第14天，队列1每天接受500mg治疗，队列2每天两次接受500mg治疗(每天共1000mg)，队列3每天4次接受500mg治疗(每天共2000mg)。研究方案示于图2。在第1天(基线)，第4天，第8天，第14天，和第28天测试了每位患者的空腹血糖。
结果
30名患者中，19人基于病史确定为糖尿病，多见于心力衰竭患者。19名糖尿病受试者在第14天和第28天的空腹血糖结果汇总于表1。表1示出了接受500mg，1000mg，和2000mg达泮舒腈治疗的受试者，合并所有接受治疗的受试者，和合并安慰剂受试者在第14天(治疗的最后一天)和第28天的血糖值与基线水平的变化。结果显示对达泮舒腈治疗的剂量反应趋势。
在2000mg治疗中，平均空腹血糖水平从基线水平降低了43.5mg/dL。在第14天，所有接受达泮舒腈治疗的受试者的血糖水平从基线血糖水平显著降低，p值为0.029。在第28天，也就是最后一次治疗后的第14天，药效消失了。
示例2临床研究(预言性示例)
目的：为了证明达泮舒腈治疗与安慰剂相比在26周降低HbA1c(糖化血红蛋白)的功效。
方法
本研究是多中心，随机，平行组，安慰剂对照的临床试验，旨在评估2000mg/天达泮舒腈与安慰剂相比对患有2型糖尿病的患者的益处。
纳入的主要标准：
符合纳入本研究资格的患者必须满足以下所有标准：
-诊断为2型糖尿病(美国糖尿病协会标准)。
-筛选时年龄≥18岁。
-HbA1c水平为7.5％至10.5％。
-CRP≥2mg/L
-存在以下至少一项：心力衰竭病史或NTproBNP＞125mg，OCT显示有黄斑水肿征象的糖尿病视网膜病变或血管造影术显示微血管病变，GFR≤60 GFR ml/min/1.7或大量白蛋白尿(≥300mg/24h)
-愿意在试验期间维持饮食和锻炼方案。
排除的主要标准：
满足以下任何标准的患者不符合纳入本试验的资格：
-孕妇或哺乳期(泌乳期)女性，孕期定义为女性在受孕后直至妊娠终止的状态，经hCG实验室检测阳性(>5mIU/ml)证实
-肾病变综合征或肾移植(无论肾功能如何)
-已知的活动性或复发性肝病(包括肝硬化，乙型肝炎和丙型肝炎，或经确认的ALT/AST水平＞3倍ULN或总胆红素＞2倍ULN)
-会干扰试验进行的消遣性药物使用和酒精依赖。
-对研究产品配方的任何成分过敏或反应的已知病史。
-与GLP-1激动剂或SGLT2抑制剂的伴随治疗
-任何靶向免疫系统的药物(例如，TNF阻滞剂，阿那白滞素，利妥昔单抗，阿巴西普，托珠单抗，或类固醇激素)
-预期寿命＜5年的任何危及生命的病症，但可能阻止患者完成研究的血管疾病除外。
剂量和施用方式：
受试者被随机分配至2000mg/天达泮舒腈或安慰剂组。每名患者每天接受达泮舒腈或安慰剂治疗，持续26周。在第1天，第2天，然后每月一次，和最后一次治疗后抽取血液进行给药前测试。
临床试验持续时间：
试验持续时间为26周。
用于评估的临床活动结果：
主要功效结果测量是：
·HbA1C
次要功效结果测量是：
·标准化混合餐食或OGT(O-连接的N-乙酰氨基葡萄糖(GlcNAc)转移酶)与推注葡萄糖，+arg/+胰高血糖素刺激后的C肽(峰值，AUC)。
现在以如此全面，清晰，简明，和准确的术语描述本技术以及制造和使用其的方式和过程，以至于本技术所属领域的任何技术人员能够制造和使用本技术。应当理解，前面描述了本技术的优选实施例，在不脱离如权利要求所述的本发明范围的情况下可以对其进行修改。为了明确指出并清楚地要求保护被视为发明的主题，以下权利要求对说明书进行了总结。
Claims (7)
1.一种治疗糖尿病的方法，包括以下步骤：
向患有糖尿病的受试者施用有效量的达泮舒腈或其药学上可接受的溶剂化物。
2.根据权利要求1所述的方法，其中，所述方法降低受试者血液中的血红蛋白A1C(HbA1c)水平。
3.根据权利要求1所述的方法，其中，所述方法降低受试者的血糖水平。
4.根据权利要求1所述的方法，其中，所述方法还通过治疗受试者的微血管炎症预防疾病进展。
5.根据权利要求1所述的方法，其中，所述受试者患有心力衰竭。
6.根据权利要求1所述的方法，其中，达泮舒腈通过全身施用施用。
7.根据权利要求5所述的方法，其中，达泮舒腈通过口服施用施用。
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