CN113559088A - 一种含二甲双胍和西格列汀的复方降糖药物制剂 - Google Patents
一种含二甲双胍和西格列汀的复方降糖药物制剂 Download PDFInfo
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Abstract
本发明涉及一种含二甲双胍和西格列汀的复方降糖药物制剂，包括二甲双胍、格列美脲和西格列汀，所述二甲双胍、格列美脲和西格列汀的份数比为2.35～5.67：1.23～3.54：11.89～14.63。该含二甲双胍和西格列汀的复方降糖药物制剂还包括B族维生素，所述B族维生素为维生素B2、维生素B6、维生素B12或生物素中的一种或两种组合。该含二甲双胍和西格列汀的复方降糖药物制剂在降糖和控糖的同时可以抑制糖尿病人的并发症。
Description
技术领域
本发明涉及一种药物组合物技术领域，特别涉及一种含二甲双胍和西格列汀的复方降糖药物制剂。
背景技术
糖尿病发病率仍在逐年增加。根据世界卫生组织(WHO)提供的数据，发达国家糖尿病患病率已高达5％～10％，在我国则为3％左右，全世界有1.3亿糖尿病患者；到2030年，全世界糖尿病患者人数将比2000年翻一番。值得注意的是，糖尿病患病率在发展中国家增加速度特别快，尤其是在那些从穷变富的发展中国家。糖尿病不只是一个富贵病，在经济和生活水平发生剧变的地区，现实地存在着糖尿病爆发流行的危险。我国糖尿病正处于爆发性流行。糖尿病可发生于任何年龄，随着病程延长，容易并发全身神经、微血管和大血管病变等组织病理损害，并可导致心、脑、肾、神经及眼等组织器官的慢性、进行性病变。患者从葡萄糖糖耐量正常(NGT)，经过糖耐量减低(IGT)进入糖尿病，往往经过一段相当长的时期(推算为7～11年)的亚临床阶段，而后转为显性临床阶段。由于长时期高血糖而没有临床症状，待临床确诊时已有大约半数病人有不同程度的糖尿病慢性并发症存在。一般认为，IGT患者虽然不发生糖尿病慢性并发症，但是有大血管病变和高血压发生率增高的现象，而一旦进入糖尿病阶段，大血管、微血管和神经病变发生率随着病程迁延和血糖、血脂控制不能达到理想标准而迅速发展。糖尿病的危害主要来自糖尿病的并发症。糖尿病并发症困扰着患者和医务界，同时糖尿病得不到适当的控制并发肾病、视网膜病变、外周神经病变、心脏病变的几率很高，严重影响生活质量；我国每年用于糖尿病的直接医疗成本超过180亿，占医疗总费用的4％；尽管患者数量如此之多，但较低的诊断率，疾病的慢性病程，对联合治疗的需要，缺少有效的长程治疗糖尿病的口服药物以及与注射治疗相关联的较差的患者依从性，均意味着目前在该领域中，仍有许多需求未得到满足。近年来医药工作者开展了大量有关糖尿病药物研发的工作，解决了糖尿病治疗中的一些问题，同时也潜在地改变了这种疾病的治疗模式。
在用于2型糖尿病治疗的口服抗糖尿病药物方面，已打破了坚守治疗40余年的磺酰脲类与双胍类的化学结构，新结构、新类型及新作用机制的药物不断涌现。20世纪90年代末先后上市了非磺酰脲类的刺激胰岛β细胞分泌胰岛素的药物瑞格列奈(repaglinide)是苯甲酸类衍生物，那格列奈(nateglinide)是苯丙氨酸衍生物，具有起效快，作用短的特点，被称为“一餐一剂”的降血糖药，便于患者灵活掌握用餐时间。近年来研究开发与使用胰岛素增敏剂，对于改善2型糖尿病患者的胰岛素抵抗状态(insulinresistance)，纠正患者异常的糖及脂质代谢有重要意义，因此在治疗2型糖尿病的领域中受到极大的关注。噻唑烷二酮类化合物(thiazolinedine，TZD)是这类药物的代表，其中罗格列酮(rosiglitazone)及匹格列酮(pioglitazone)先后于1999年上市。但该类药物属于比较单一的控制血糖的药物，对于一些已经有多种并发病的糖尿病人得需要同时服用多种药物。
因此，有必要开发一种含二甲双胍和西格列汀的复方降糖药物制剂，在降糖和控糖的同时可以抑制糖尿病人的并发症。
发明内容
本发明要解决的技术问题是，针对现有的不足，提供一种高含二甲双胍和西格列汀的复方降糖药物制剂，在降糖和控糖的同时可以抑制糖尿病人的并发症。
为了解决上述技术问题，本发明采用的技术方案是，该含二甲双胍和西格列汀的复方降糖药物制剂，其特征在于，该含二甲双胍和西格列汀的复方降糖药物制剂包括二甲双胍、格列美脲和西格列汀，所述二甲双胍、格列美脲和西格列汀的份数比为2.35～5.67：1.23～3.54：11.89～14.63。
采用上述技术方案，所提供的含二甲双胍和西格列汀的复方降糖药物制剂的配伍机理如下所述：磺脲类降糖药物是一种促胰岛素分泌剂，在临床应用已有50余年；对于大多数新诊断的2型糖尿病患者，磺脲类降糖药物可以使空腹血糖下降50～80mg/dl，使糖化血红蛋白(HbA1c)下降1.0％～2.5％。因为2型糖尿病患者的β细胞功能随时间而衰减，磺脲类降糖药物对临床上新诊断的糖尿病患者血糖降低十分有效。各种磺脲类降糖药物主要是通过关闭β细胞膜上三磷酸腺苷敏感性钾离子(KATP)通道来增加内源性胰岛素分泌。磺脲类降糖药物与KATP通道的磺脲受体1(SUR1)结合关闭K+通道，使细胞膜上的部分区域去极化引起电压依赖性L-型Ca2+通道开放，Ca2+进入细胞内，胞浆中Ca2+浓度升高，从而刺激胰岛素分泌。磺脲类降糖药物正作为非超重或非肥胖2型糖尿病患者治疗的一线用药。临床上广泛应用的磺脲类降糖药物包括格列本脲(Glibenclamide)、格列波脲(Glibornuride)、格列环脲(Glycyclamide)、格列己脲(Glyhexamide)、格列沙脲(Glisamuride)、格列生脲(Glisentide)、格列索脲(Glisolamide)、格列辛脲(Glyoctamide)、格列齐特(Gliclazide)、格列吡嗪(Glipizide)、格列喹酮(Gliquidone)和格列美脲(Glimepiride)。噻唑烷二酮类降糖药物亦称胰岛素增敏剂，包括罗格列酮(rosiglitazone)、吡格列酮(匹格列酮，pioglitazone)、二甲双胍(troglitazone)、恩格列酮(englitazone)、环格列酮(cightazone)等。该类药物为细胞核过氧化酶体增殖因子活化受体(PPAR-γ)的配体，能增加外周组织清除葡萄糖的能力，降低肝糖输出，增加糖负荷时的肝糖摄取，从而有效降低血糖，改善胰岛素敏感性。噻唑烷二酮类药物的降糖作用是通过增强胰岛素的效应而实现的，故不易产生低血糖。该类药物可以单独应用，也可以与其他类型的口服降糖药及胰岛素合用。磺脲类降糖药物与噻唑烷二酮类降糖药物合用对2型糖尿病疗效好，该复方产品明显优于单用磺脲类组及安慰剂组，并且对老年糖尿病患者疗效及安全性亦很好；格列美脲和噻唑烷二酮类药物联合应用能显著改善2型糖尿病的代谢综合征患者大多数代谢指标：空腹血糖、清晨静息状态下血压、甘油三酯和LDL-C均有明显降低，HDL-C明显升高，腰围和体重指数有降低趋势；然而，现有的磺脲类降糖药物与噻唑烷二酮类降糖药物的合用并不能减轻同型半胱氨酸(Hcy)对糖尿病患者带来的危害；同时本技术方案中添加了西格列汀，磷酸西格列汀一水合物是一种白色或类白色，结晶，非吸湿性粉末。易溶于水和N，N-二甲基甲酰胺，微溶于甲醇，极微溶于乙醇，丙酮，乙腈，和不溶于异丙醇和乙酸异丙酯。磷酸西格列汀二甲双胍片是将两种作用机制互补的降血糖药物联合起来，用于改善2型糖尿病患者的血糖控制：药物成分中的西格列汀是一种二肽基肽酶4(DPP-4)抑制剂，而二甲双胍一种是双胍类降血糖药物。西格列汀二甲双胍片可以直击2型糖尿病的3大缺陷——胰岛受损导致的胰岛素缺乏、胰岛素抵抗和肝糖过度输出，为患者提供了一个优化的治疗选择。与传统治疗方案相比，本品可帮助2型糖尿病患者实现强效降糖、持久控制血糖，同时提高患者治疗的依从性，减轻一定的疾病经济负担；将西格列汀和格列美脲、二甲双胍三者联合用药提高了疗效，方便了患者用药；该含二甲双胍和西格列汀的复方降糖药物制剂通过三种不同降血糖药物的科学组合，达到机制互补、相互协同、提高疗效、合理用药的目的；特别是抑制和减少对糖尿病导致的视网膜病变等疾病；该含二甲双胍和西格列汀的复方降糖药物制剂用于临床上血糖水平尤其是餐后血糖控制不佳，产生胰岛素抵抗的患者；或者用于糖耐量低减者，肥胖糖尿病患者的治疗；经过大量的动物试验，取得了很好的效果。
作为本发明的优选技术方案，该含二甲双胍和西格列汀的复方降糖药物制剂还包括B族维生素，所述B族维生素为维生素B2、维生素B6、维生素B12或生物素中的一种或两种组合。B族维生素包括维生素B2(核黄素)、维生素B6(吡哆醇)、维生素B12(氰钴胺)及生物素，都是人体健康不可缺少的微量营养素。对于B族维生素的研究，目前倍受关注的是叶酸、维生素B12和维生素B6。B族维生素对新陈代谢、红细胞形成、保持神经系统和免疫系统功能具有重要作用，B族维生素的缺乏可导致许多不良的后果，包括肌肉无力、瘫痪、精神混乱、神经系统紊乱、消化障碍、皮肤皱裂及鳞皮、严重的贫血和心脏损害；而B族维生素在本发明的技术方案中添加的作用是减轻Hcy对糖尿病患者带来的危害，保护神经系统，同时避免糖尿病患者服药后可能呕吐的副作用。
作为本发明的优选技术方案，该含二甲双胍和西格列汀的复方降糖药物制剂还包括多种辅料，所述辅料包括稀释剂、稳定剂和缓释剂。
作为本发明的优选技术方案，所述二甲双胍、格列美脲和西格列汀的份数比为3.86：2.72：12.94。
作为本发明的优选技术方案，所述B族维生素的份数占比为所述二甲双胍、格列美脲和西格列汀的份数总和的0.5％～1.36％。
作为本发明的优选技术方案，所述稀释剂为山梨醇、甘露醇和纤维素中的一种，所述稀释剂的份数占比为所述二甲双胍、格列美脲和西格列汀的份数总和的3％～5％。
作为本发明的优选技术方案，所述稳定剂为alpha-D-吡喃葡萄基-alpha-D-吡喃葡萄苷，所述稳定剂的份数占比为所述二甲双胍、格列美脲和西格列汀的份数总和的1％～6％。
作为本发明的优选技术方案，所述缓释剂为乙基纤维素和醋酸纤维素的组合，所述缓释剂的份数占比为所述二甲双胍、格列美脲和西格列汀的份数总和的3％～6％，其中乙基纤维素和醋酸纤维素的份数比为1～3:4～8。
作为本发明的优选技术方案，该含二甲双胍和西格列汀的复方降糖药物制剂制成胶囊剂或片剂。
作为本发明的优选技术方案，所述片剂包括普通片、缓释片和肠溶片。
具体实施方式
实施例1：该含二甲双胍和西格列汀的复方降糖药物制剂由下列成分按重量份数配比组成：二甲双胍2.35份、格列美脲3.54份、西格列汀12.53份、维生素B6 10.21份、山梨醇90份、alpha-D-吡喃葡萄基-alpha-D-吡喃葡萄苷30份、乙基纤维素19份、醋酸纤维素45份。
制备工艺：按上述配比称取原材料(其中原材料均为购买的现有的)，将二甲双胍、格列美脲和西格列汀三者分别过筛100目，再将维生素B6过筛90目，再将山梨醇、alpha-D-吡喃葡萄基-alpha-D-吡喃葡萄苷、乙基纤维素和醋酸纤维素过筛80目，将所有过筛后的原材料放入球磨机进行搅拌混合均匀，并控制含水量为3～5％，取出检测含量后，放入压片机压制成片，进行包装，避光保存。
实施例2：该含二甲双胍和西格列汀的复方降糖药物制剂由下列成分按重量份数配比组成：二甲双胍3.86份、格列美脲2.72份、西格列汀12.94份、维生素B6 17.57份、山梨醇78份、alpha-D-吡喃葡萄基-alpha-D-吡喃葡萄苷58.56份、乙基纤维素20份、醋酸纤维素50份。
制备方法同实施例1。
实施例3：该含二甲双胍和西格列汀的复方降糖药物制剂由下列成分按重量份数配比组成：二甲双胍5.66份、格列美脲1.23份、西格列汀14.63份、维生素B6 28份、山梨醇65份、alpha-D-吡喃葡萄基-alpha-D-吡喃葡萄苷90份、乙基纤维素15份、醋酸纤维素75份。
制备方法同实施例1。
实施例4：该含二甲双胍和西格列汀的复方降糖药物制剂由下列成分按重量份数配比组成：二甲双胍3.86份、格列美脲2.72份、西格列汀12.94份、维生素B2 17.57份、甘露醇78份、alpha-D-吡喃葡萄基-alpha-D-吡喃葡萄苷58.56份、乙基纤维素20份、醋酸纤维素50份。
制备方法同实施例1。
实施例5：该含二甲双胍和西格列汀的复方降糖药物制剂由下列成分按重量份数配比组成：二甲双胍3.86份、格列美脲2.72份、西格列汀12.94份、维生素B12 17.57份、纤维素78份、alpha-D-吡喃葡萄基-alpha-D-吡喃葡萄苷58.56份、乙基纤维素20份、醋酸纤维素50份。
制备方法同实施例1。
实施例6：动物实验；体重200g左右(体重偏差在正负10g)的白鼠，雌雄各半，先喂以高脂高糖饲料(蛋白选质5％、碳水化合物60％其中蔗糖为30％、脂肪32％，其中炼猪油为30％)；4周后，白鼠禁食18h；腹腔注射0.6％链脲霉素(STZ)30mg/kg，STZ溶于PH4.0，0.1mol/L柠檬酸-柠檬酸钠缓冲液中，每次药量在10min内用完。空白组大鼠腹腔注射等体积柠檬酸-柠檬酸钠缓冲液，正常饲养。5天后断尾取血测全血糖，以血糖值水平＞10.0mmol/L者为造模成功。
将造模成功大鼠按照血糖水平随机分为模型组，阳性对照组，二甲双胍组，格列美脲组，二甲双胍、格列美脲和西格列汀复方组、二甲双胍、格列美脲、西格列汀和B族维生素组，每组8只；各组分别灌胃给予上述实施例1～5的原料，空白组和对照组给予相同体积的生理盐水；每天一次，连续10周；采血测定空腹血糖，进食后2h的血糖，糖化血红蛋白(HbAlc)。
血糖的测定：将造模成功大鼠随机分组后，按剂量灌胃给药，连续10周，正常饲养。所有大鼠分别于治疗前和治疗后4周内每周取尾静脉血检测空腹血糖(FBG)，进食后2h血糖(PBG)。将取出的血样放入蛋白沉淀剂中，室温放置7min后，离心5min(3000r/min)，取上清液，用葡萄糖氧化酶法测全血糖。
实验结果：无论是空腹血糖还是餐后2h血糖，二甲双胍组，格列美脲组，二甲双胍、格列美脲和西格列汀复方组和二甲双胍、格列美脲、西格列汀和B族维生素组与模型组比较都有极显著性差异，结果表明格列美脲组，二甲双胍、格列美脲和西格列汀和B族维生素复方制剂能有效降低餐后血糖且减少Hey糖尿病带来的影响。
最后，还需要注意的是，以上列举的仅是本发明的若干个具体实施例。显然，本发明不限于以上实施例，还可以有许多变形。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形，均应认为是本发明的保护范围。
Claims (10)
1.一种含二甲双胍和西格列汀的复方降糖药物制剂，其特征在于，该含二甲双胍和西格列汀的复方降糖药物制剂包括二甲双胍、格列美脲和西格列汀，所述二甲双胍、格列美脲和西格列汀的份数比为2.35～5.67：1.23～3.54：11.89～14.63。
2.根据权利要求1所述的含二甲双胍和西格列汀的复方降糖药物制剂，其特征在于，该含二甲双胍和西格列汀的复方降糖药物制剂还包括B族维生素，所述B族维生素为维生素B2、维生素B6、维生素B12或生物素中的一种或两种组合。
3.根据权利要求2所述的含二甲双胍和西格列汀的复方降糖药物制剂，其特征在于，该含二甲双胍和西格列汀的复方降糖药物制剂还包括多种辅料，所述辅料包括稀释剂、稳定剂和缓释剂。
4.根据权利要求2所述的含二甲双胍和西格列汀的复方降糖药物制剂，其特征在于，所述二甲双胍、格列美脲和西格列汀的份数比为3.86：2.72：12.94。
5.根据权利要求2所述的含二甲双胍和西格列汀的复方降糖药物制剂，其特征在于，所述B族维生素的份数占比为所述二甲双胍、格列美脲和西格列汀的份数总和的0.5％～1.36％。
6.根据权利要求3所述的含二甲双胍和西格列汀的复方降糖药物制剂，其特征在于，所述稀释剂为山梨醇、甘露醇和纤维素中的一种，所述稀释剂的份数占比为所述二甲双胍、格列美脲和西格列汀的份数总和的3％～5％。
7.根据权利要求3所述的含二甲双胍和西格列汀的复方降糖药物制剂，其特征在于，所述稳定剂为alpha-D-吡喃葡萄基-alpha-D-吡喃葡萄苷，所述稳定剂的份数占比为所述二甲双胍、格列美脲和西格列汀的份数总和的1％～6％。
8.根据权利要求3所述的含二甲双胍和西格列汀的复方降糖药物制剂，其特征在于，所述缓释剂为乙基纤维素和醋酸纤维素的组合，所述缓释剂的份数占比为所述二甲双胍、格列美脲和西格列汀的份数总和的3％～6％，其中乙基纤维素和醋酸纤维素的份数比为1～3:4～8。
9.根据权利要求3所述的含二甲双胍和西格列汀的复方降糖药物制剂，其特征在于，该含二甲双胍和西格列汀的复方降糖药物制剂制成胶囊剂或片剂。
10.根据权利要求9所述的含二甲双胍和西格列汀的复方降糖药物制剂，其特征在于，所述片剂包括普通片、缓释片和肠溶片。
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| WO2020194046A1 (en) * | 2019-03-25 | 2020-10-01 | The George Institute for Global Health | Low-dose triple combination formulation |
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