CN101103993B - Hypoglycemic medicine composition - Google Patents

Hypoglycemic medicine composition Download PDF

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CN101103993B
CN101103993B CN2006100990276A CN200610099027A CN101103993B CN 101103993 B CN101103993 B CN 101103993B CN 2006100990276 A CN2006100990276 A CN 2006100990276A CN 200610099027 A CN200610099027 A CN 200610099027A CN 101103993 B CN101103993 B CN 101103993B
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rosiglitazone
glimepiride
folic acid
pioglitazone
content
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CN2006100990276A
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CN101103993A (en
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戴成祥
王文艳
李华
陈明侠
王燕
于多
陈光亮
徐希平
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北京华安佛医药研究中心有限公司
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Abstract

The invention relates to a newly-developed medicine compound for diabetes which contains sulfonylureas drug for diabetes or a bioactive metabolite of the sulfonylureas drug for diabetes or pharmaceutical salt of the sulfonylureas drug for diabetes, and thiazolidinedione drug for diabetes or pharmaceutical salt and vitamin B of the thiazolidinedione drug for diabetes. The compound contains the sulfonylureas drug for diabetes of therapy dose or the bioactive metabolite of the sulfonylureas drug for diabetes or the pharmaceutical salt of the sulfonylureas drug for diabetes, the thiazolidinedionedrug for diabetes of therapy dose or the pharmaceutical salt and therapy dose of vitamin B of the thiazolidinedione drug for diabetes or compound which is related to the thiazolidinedione drug for diabetes and has similar bioactivity and pharmaceutical carrier or excipient. The invention also relates to the purpose of the compound in preparation of drug for treating diabetes or preventing diabetes complication, belonging to the pharmaceutical field.

Description

降糖药物组合物 Hypoglycemic pharmaceutical composition

技术领域 FIELD

[0001] 本发明涉及一种含有磺脲类降糖药物、噻唑烷二酮类降糖药物及B族维生素的药物组合物,以及该组合物在制备治疗糖尿病或预防糖尿病并发症的药物中的用途。 [0001] The present invention relates to a drug containing sulfonylureas, thiazolidine diones hypoglycemic drugs and B vitamins pharmaceutical compositions, and compositions for treating or preventing diabetes, diabetic complications in use. 本发明属于医药领域。 The present invention is in the field of medicine.

背景技术 Background technique

[0002] 糖尿病是一种多病因的代谢疾病,其特点是慢性高血糖,伴随因胰岛素分泌和/ 或作用缺陷引起的糖、脂肪和蛋白质代谢紊乱。 [0002] Diabetes is a metabolic disease of multiple etiology, characterized by chronic hyperglycemia, sugar, fat and protein metabolism disorders accompanied by insulin secretion and / or action defect. 目前糖尿病严重泛滥,2003年,全世界有1. 94亿人患有糖尿病,年龄从20岁至79岁不等,到2025年这一数字可能会增长72%而达到3. 33亿,且大约80%的病例将分布在贫困的工业发展中国家。 Currently diabetes severe flooding in 2003, there are 194 million people worldwide suffer from diabetes, aged from 20 to 79 years ranging from 2025 this figure is likely to grow by 72 percent to reach 333 million, and about 80% of cases will be distributed in poor industries in developing countries. 我国为糖尿病总人数最多的3个国家之一。 Our country is one of three countries most of the total number of diabetes. 2004年10月12日卫生部、科技部和国家统计局公布的《中国居民营养与健康现状》的报告中指出:我国18岁及以上居民糖尿病患病率为2.6%,空腹血糖受损率为1.9%。 October 12, 2004 report, "China National Nutrition and Health Status," the Ministry of Health, Ministry of Science and the National Bureau of Statistics pointed out: My Residents aged 18 and over 2.6% prevalence of diabetes, impaired fasting glucose rate 1.9%. 估计全国糖尿病现患病人数2000多万,另有近2000万人空腹血糖受损。 The number of diabetic patients in China is estimated more than 20 million, impaired fasting glucose and nearly 20 million. 城市患病率明显高于农村,与1996年糖尿病抽样调查资料相比,大城市20岁以上糖尿病患病率由4. 6%上升到6. 4%、中小城市由3. 4%上升到3. 9%。 City prevalence was significantly higher than in rural areas, compared with 1996 sample survey of diabetes, major cities over the age of 20 diabetes prevalence rate from 4.6 percent to 6.4 percent rise, medium and small cities increased from 3.4% to 3 . 9%. 糖尿病仍是中国一个严重的公共卫生问题。 Diabetes is China still a serious public health problem.

[0003] 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。 [0003] diabetes can occur at any age, with the extension of the course, easy to concurrent systemic histopathological damage nerves, microvascular and macrovascular disease and other tissues and organs and can lead to chronic heart, brain, kidneys, nerves and eyes and so on, progressive lesions. 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。 From glucose in patients with normal glucose tolerance (NGT), impaired glucose tolerance through (IGT) into the diabetes, often after quite a long period of time (estimated 7 to 11 years) of sub-clinical stage, then turned overt clinical stage. 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。 Due to prolonged high blood sugar but no clinical symptoms, has about half of the patients have varying degrees of chronic complications of diabetes there is to be clinically diagnosed. 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【朱禧星.现代糖尿病学.上海:复旦大学出版社.2000年5 月.第299-371页】。 Is generally believed, IGT patients with chronic complications of diabetes, although not happen, but there is a large vessel disease and hypertension increased incidence of the phenomenon, but once into the stage diabetes, macrovascular, microvascular and neuropathy increases with prolonged course and blood sugar, blood lipids control can not achieve the desired standard and the rapid development of diabetes [Zhu Xi-modern science. Shanghai: Fudan University Press, 2000. pp. 299-371.]. 糖尿病的危害主要来自糖尿病的并发症。 Mainly from the hazards of diabetes complications of diabetes. 对中国30个省、市、自治区住院患者糖尿病慢性并发症十年回顾分析(1991年1月1日至2000年12月31日),发现糖尿病并发症患病率分别为:高血压31. 9%、脑血管并发症12. 2%、心血管并发症15. 9%、下肢血管并发症5. 0%、眼部并发症34. 3%、肾脏并发症33. 6%、神经病变60. 3%,总患病率为73. 2%【中华医学会糖尿病分会慢性并发症调查组.1991-2000年全国住院糖尿病患者慢性并发症及相关大血管病变回顾性分析.中国医学科学院学报,2002,24(5) :447-451】。 Recalling the chronic complications of diabetes in China's 30 provinces, municipalities and autonomous regions analyzed inpatient years (January 1991 to December 31, 2000 1), we found that the prevalence of diabetes complications were: hypertension 31.9 %, 12.2% cerebrovascular complications, cardiovascular complications 15.9%, 5.0% lower extremity vascular complications, ocular complications of 34.3%, 33.6% renal complications, neuropathy 60. 3% of the total prevalence rate of 73.2% [Chinese diabetes Society chronic complications investigation team 1991--. 2000 national chronic complications of diabetes and related hospitalization in patients with vascular disease large retrospective analysis of Chinese Academy of Medical Sciences, 2002 24 (5): 447-451].

[0004] 糖尿病的患病率呈逐年上升趋势。 [0004] The prevalence of diabetes increased year by year. 糖尿病是一种非感染性慢性病,需要终身防治。 Diabetes is a non-infectious chronic diseases, the need for lifelong control. 由于目前人类对糖尿病的病因和发病机制未充分了解,尚缺乏针对病因的有效治疗手段。 Due to the current human etiology and pathogenesis of diabetes is not fully understood, no effective treatment for the cause. 目前强调早期治疗、长期治疗和综合治疗的原则。 Current emphasis on the principle of early treatment, long-term treatment and comprehensive treatment. 治疗的目标是使血糖达到或接近正常水平,纠正代谢紊乱,消除糖尿病症状,防止或延缓并发症,维持健康、劳动和学习能力,保障儿童生长发育,延长寿命,降低病死率。 The goal of treatment is to make the blood sugar at or near normal levels, to correct metabolic disorders, eliminate diabetes symptoms and prevent or delay complications, maintain health, labor and learning capacity and to ensure the growth and development of children, to extend the life and reduce mortality. 具体措施以控制饮食治疗和适当的体育锻炼为基础,根据不同病情予以药物(口服抗糖尿病药、胰岛素)治疗。 Specific measures to control diet and appropriate physical exercise therapy is based, to be a drug (oral anti-diabetic drugs, insulin) treatment under different conditions. 糖尿病病人中90%以上为2型糖尿病,在发病初期70 %〜85 %的病人需要使用口服降糖药物治疗,仅有15 %〜30 %病人可用单纯饮食加运动治疗达到满意控制的标准。 More than 90% of diabetic patients with type 2 diabetes, in the early stages of 70% ~ 85% of patients require the use of oral hypoglycemic drugs, only 15% ~ 30% of patients diet plus exercise treatment alone can be used to achieve satisfactory control of the standard. 后者在以后的1〜3年中,多半也需加用口服降糖药物才能使血糖控制满意【李春霖.糖尿病的口服降糖药物治疗.人民军医, 2004,47(9) :544-547】。 The latter after 1 to 3 years, most also be added with oral hypoglycemic drugs to control blood sugar satisfaction [Li Chunlin diabetes oral hypoglycemic medications People's Medical, 2004, 47 (9): 544-547] . 因此,口服降糖药物在糖尿病治疗中的重要性不言而喻。 Therefore, the importance of oral hypoglycemic drugs in the treatment of diabetes self-evident. 目前临床常用的口服抗糖尿病药物包括磺酰脲类降糖药、双胍类降糖药、α-葡萄糖苷酶抑制剂、噻唑烷二酮类(格列酮类)降糖药、非磺酰脲类促胰岛素分泌剂等。 Commonly used in clinical oral antidiabetic hypoglycemic agents include sulfonylureas, biguanides hypoglycemic agents, alpha] -glucosidase inhibitor, a thiazolidine diones (glitazones) antidiabetic drugs, non-sulfonylurea class insulinotropic agents.

[0005] 近年来的研究显示,糖尿病和血浆高同型半胱氨酸(Homocysteine,Hcy)水平密切相关。 [0005] In recent years, studies have shown, it is closely related to diabetes and high plasma homocysteine ​​(Homocysteine, Hcy) levels. 早在1992年日本人Ohtsuka首次研究报道糖尿病合并肾病患者高Hcy血症在血糖控制好后Hcy水平可明显下降,认为糖尿病和血浆高Hcy水平有关。 As early as 1992 the Japanese Ohtsuka first reported consolidated patients with diabetic nephropathy high Hcy blood Hcy levels significantly decreased after good glycemic control, diabetes and think that high plasma Hcy levels. 之后,许多研究均证实糖尿病患者特别是合并有慢性并发症者,其血浆Hcy明显升高。 After that, many studies have confirmed that patients with diabetes are especially associated with chronic complications, plasma Hcy significantly increased. Montalescot G等人【Montalescot G,et al. Plasma homocysteine and the extent of atherosclerosis in patients with coronaryartery disease. Int J Cardiol. 1997,60(3) :295_300]石if 究发现合并大血管病变的2型糖尿病患者血浆总Hey、游离Hcy的水平均明显高于无大血管病变组和健康对照组,认为Hcy也是糖尿病大血管病变的独立危险因素。 .. Montalescot G et al [Montalescot G, et al Plasma homocysteine ​​and the extent of atherosclerosis in patients with coronaryartery disease Int J Cardiol 1997,60 (3):. 295_300] stone study if found in type 2 diabetes with macrovascular disease plasma total Hey, free of Hcy levels were significantly higher than those without large vessel disease group and the healthy control group that Hcy is an independent risk factor for macrovascular disease. Stabler SP等人石if究[Stabler SP, et al. Totalhomocysteine is associated with nephropathy in non-insulin-dependent diabetesmellitus. Metabolism. 1999,48(9) :1096_1101]认为同型半胱氨酸与糖尿病神经病变有关。 Stabler SP if Stone et al study [. Stabler SP, et al Totalhomocysteine ​​is associated with nephropathy in non-insulin-dependent diabetesmellitus Metabolism 1999,48 (9):.. 1096_1101] that homocysteine ​​and related to diabetic neuropathy. Hofmann MA等【Hofmann MA,et al. Hyperhomocyst (e) inemia and endothelial dysfunction in IDDM. Diabetes Care. 1997,20 (12): 1880-1886】排除了吸烟、肥胖、高血压、高血脂、糖化血红蛋白(HbAlc)等重要危险因素, 研究了Hcy与微血管病变的关系,发现合并高Hcy血症的糖尿病患者尿蛋白(Alb)、血栓调节蛋白(thrombomodulin TM)均比Hcy正常的糖尿病患者高,糖尿病性肾病(75% 对33% ),视网膜病变(69%对51% ),神经病变(57%对41% )的发病率显著增加,认为高Hcy血症可能是糖尿病微血管病变的重要危险因素。 Etc. [Hofmann MA... Hofmann MA, et al Hyperhomocyst (e) inemia and endothelial dysfunction in IDDM Diabetes Care 1997,20 (12): 1880-1886] for smoking, obesity, hypertension, hyperlipidemia, glycosylated hemoglobin ( HbAlc) and other important risk factors, the relationship between Hcy and microvascular disease, found that the combined high Hcy blood urine protein (Alb) diabetic patients, thrombomodulin (thrombomodulin TM) higher than normal Hcy diabetes, diabetic nephropathy (75% vs. 33%), retinopathy (69% vs. 51%), neuropathy (57% vs. 41%) significant increase in the incidence of that high Hcy blood may be an important risk factor for diabetic microangiopathy. 其它研究也得出同样的结论【Araki A, et al. Plasma homocysteine concentrationsin Japanese patients with non-insulin-dependent diabetes mellitus :effect of parenteral methylcobalamin treatment. Atherosclerosis. 1993,103(2) :149-157 ;Robillon JF, et al.Type 1 diabetes mellitus and homocyst(e)ine. Diabete Metab. 1994 Sep-Oct,20 (5) :494-496 ; Hultberg B, et al. Poor metabolic control, early ageatonset, and marginal folate deficiency are associated with increas2ing levels ofplasma homocysteine in insulin-dependent diabetesmellitus. A five-year follow-upstudy. Scand J Clin Lab Invest.1997,57 (7) :595_600】。 Other studies have reached similar conclusions [Araki A, et al Plasma homocysteine ​​concentrationsin Japanese patients with non-insulin-dependent diabetes mellitus: effect of parenteral methylcobalamin treatment Atherosclerosis 1993,103 (2): 149-157; Robillon JF... , et al.Type 1 diabetes mellitus and homocyst (e) ine diabete Metab 1994 Sep-Oct, 20 (5):... 494-496; Hultberg B, et al Poor metabolic control, early ageatonset, and marginal folate deficiency are associated with increas2ing levels ofplasma homocysteine ​​in insulin-dependent diabetesmellitus A five-year follow-upstudy Scand J Clin Lab Invest.1997,57 (7):.. 595_600].

[0006] 总之,高tHcy血症不仅是心脑血管疾病的独立危险因素,也存在于糖尿病患者中,重视对糖尿病患者tHcy水平的监测,采取干预措施预防和降低血浆Hcy的水平,对推迟2型糖尿病患者多种并发症特别是血管病变发生的时间、降低并发症的严重程度有重要意义。 [0006] In short, not only hyperlipidemia high tHcy is an independent risk factor for cardiovascular disease, but also in patients with diabetes, the importance of monitoring tHcy levels in patients with diabetes, interventions to prevent and reduce the level of plasma Hcy, to postpone 2 It is important in patients with a variety of complications, especially diabetic vascular lesions of the time, reducing the severity of complications.

[0007] 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。 [0007] The drug is a sulfonylurea insulin secretagogues, more than 50 years in clinical applications. 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(HbAlc)下降1.0%〜2.5%。 For the majority of type 2 diabetic patients newly diagnosed, sulfonylureas can cause decreased fasting glucose 50~80mg / dl, glycated hemoglobin (HbAIc) decreased by 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。 Because the β-cell function in patients with type 2 diabetes and decay over time, sulfonylurea drugs clinically newly diagnosed diabetic patients reduced blood very effective. 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。 Various sulfonylureas by closing down the β cell membrane ATP-sensitive potassium (Katp) channel to increase endogenous insulin secretion. 磺脲类降糖药物与Katp通道的磺脲受体I(SURl)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。 Sulfonylurea receptor I sulfonylureas and Katp channel (sURL) K + channel binding off, so that part of the region on the membrane to cause the voltage-dependent L- type Ca2 + channel opening polarization, Ca2 + into the cell, the cytoplasm the Ca2 + concentration, thereby stimulating insulin secretion. 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。 As a non-sulfonylurea drugs are the treatment of overweight or obese patients with type 2 diabetes in first-line treatment. 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(Glim印iride)。 Clinically sulfonylureas widely used include glibenclamide (Glibenclamide), glibornuride (Glibornuride), Glenn cyclic urea (Glycyclamide), Glenn glipizide (Glyhexamide), Ge Liesha urea (Glisamuride ), Glenn raw urea (Glisentide), glisolamide (glisolamide), Ge Liexin urea (Glyoctamide), gliclazide (gliclazide), glipizide (A combination of glipizide), gliquidone (gliquidone) and glimepiride (Glim India iride).

[0008] 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)、曲格列酮(troglitazone)、恩格列酮(englitazone)、环格列酮(cightazone)等。 [0008] thiazole TZDs hypoglycemic drugs, also known as insulin sensitizers include rosiglitazone (rosiglitazone), pioglitazone (pioglitazone, of pioglitazone), troglitazone (of troglitazone), englitazone ( englitazone), ciglitazone (cightazone) and the like. 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。 These drugs nuclear peroxisome proliferation-activated receptor ligands (PPAR-γ), and can increase the capacity of clearance of glucose in peripheral tissues, reducing hepatic glucose output, increased glycogen uptake during glucose load, thereby effectively lowering blood glucose improve insulin sensitivity. 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。 Thiazole TZDs hypoglycemic effect by enhancing the effects of insulin is achieved, it is not easy to produce hypoglycemia. 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。 These drugs may be used alone or in combination with other types of insulin and oral hypoglycemic agents.

[0009] B族维生素包括叶酸、维生素B12 (氰钴胺)、维生素B6 (吡哆醇)、维生素Bl (硫胺)、维生素B2 (核黄素)、维生素B3 (烟酸)、泛酸及生物素,都是人体健康不可缺少的微量营养素。 [0009] B vitamins including folic acid, vitamin B12 (cyanocobalamin), vitamin B6 (pyridoxine), vitamin Bl (thiamine), vitamin B2 (riboflavin), Vitamin B3 (niacin), pantothenic acid and biological Su, is human health indispensable micronutrients. 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。 For the study of B vitamins, currently much attention is folic acid, vitamin B12 and vitamin 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。 B vitamins on metabolism, red blood cell formation, maintaining the nervous system and the immune system plays an important role, vitamin B deficiency can lead to many adverse consequences, including muscle weakness, paralysis, mental confusion, nervous system disorders, digestive disorders, skin wrinkle cracked and scaly skin, severe anemia and heart damage.

[0010] 机体摄入的叶酸、维生素B12、维生素B6不足可造成体内维生素叶酸缺乏,而维生素B12、维生素B6又分别是胱硫醚β合成酶及蛋氨酸合成酶的辅酶,叶酸是体内甲基的间接供体,两者的缺乏既阻碍了蛋氨酸的再合成,同时也造成Hcy的蓄积,血浆同型半胱氨酸升高,从而导致同型半胱氨酸血症及心血管相关疾病的发生,严重威胁到生命体的健康;外源性适量补充叶酸可降低血浆中的Hcy,其有效剂量为0. 4〜5mg/day。 [0010] The body's intake of folate, vitamin B12, vitamin B6 deficiency can cause vitamin folic acid deficiency, vitamin B12, vitamin B6 and are cystathionine β synthase and methionine synthase coenzyme, methyl folate in vivo indirect donor, both lack not only hinder the re-synthesis of methionine, but also result in accumulation of plasma homocysteine ​​Hcy increased, leading to the occurrence of homocysteine ​​and cardiovascular disease, serious a threat to the health of the living body; exogenous supplement of folic acid may reduce plasma Hcy, the effective dose of 0. 4~5mg / day. 一项包括12 项研究,1114例受试者的分析表明,在标化治疗前血浆叶酸浓度为12nmol/L和Hcy水平在12μπι01/1的前提下,0. 5〜5mg叶酸有相似的降同型半胱氨酸效果,大约可降低1/5〜 1/3(如12umol/L至8〜9μ mo 1/L)【Homocysteine Lowering Trialists'Collaboration. Lowering bloodhomocysteine with folic acid based supplements :meta_analysis of randomized trials. BMJ. 1998,316 :894_898】。 12 includes a study, analysis of 1114 cases indicate that the subject, prior to treatment standard plasma folate concentrations of 12nmol / L, and Hcy levels premise 12μπι01 / 1's, 0. 5~5mg reduced folate similar isotype cysteine ​​effect, can be reduced to about 1 / -5 to 1/3 (e.g., 12umol / L to 8~9μ mo 1 / L) [homocysteine ​​Lowering Trialists'Collaboration Lowering bloodhomocysteine ​​with folic acid based supplements:. meta_analysis of randomized trials. . BMJ 1998,316: 894_898]. John P Forman[Forman JP,et al. Folate intake and the riskof incident hypertension among US women. JAMA. 2005 Jan 19, 293(3) :320-329】报道的资料共观察93803名年青妇女和62260名老年妇女,在2年一次的问卷中,共有7373名年青妇女(NHSII)和12347名老年妇女(NHSI)报告有高血压(由一名临床医生诊断),年青妇女中摄叶酸≥1000 μ g/天者比摄叶酸< 200 μ g/天者的高血压危险低46% ;老年妇女,高叶酸摄量者的高血压危险低于低摄量者18%,叶酸摄量> 1000 μ g/天者高血压危险低于摄量不足当前美国的建议400 μ g/天者40%。 John P Forman [Forman JP, et al Folate intake and the riskof incident hypertension among US women JAMA 2005 Jan 19, 293 (3):... 320-329] reported data were observed 93 803 62 260 young women and older women in two years time the survey, a total of 7373 young women (NHSII) and 12,347 older women (NHSI) reported hypertension (clinical diagnosis by a physician), young women in the folic acid intake ≥1000 μ g / day were <low risk of hypertension 200 μ g / day 46% of those; dangerous hypertensive elderly women, folate intake and the amount of those below the low intake by 18%, the amount of folic acid intake> folate intake than 1000 μ g / day by high blood pressure and the risk of inadequate intake and lower than the current US proposal 400 μ g / day in 40%. 有研究表明, 低水平叶酸和VB6促进动脉粥样硬化的发展【Robinson K,et al. Low circulating folateand vitamin B6 concentrations :riskfactors for stroke, peripheral vascular disease, and coronary artery disease :uropeanC0MAC Group. Circulation. 1998,97 : 437-443】。 Studies have shown that low levels of folic acid and VB6 promote the development of atherosclerosis sclerosis [Robinson K, et al Low circulating folateand vitamin B6 concentrations:. Riskfactors for stroke, peripheral vascular disease, and coronary artery disease:.. UropeanC0MAC Group Circulation 1998, 97: 437-443].

[0011] 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,美国FDA已经批准葛兰素史克公司(GSK)的新型复方产品Avandaryl (马来酸罗格列酮/格列美脲) 上市销售,用于治疗2型糖尿病,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。 [0011] sulfonylureas and thiazolidine diones good hypoglycemic drugs combined effect of type 2 diabetes, the FDA has approved GlaxoSmithKline (GSK) new combination products Avandaryl (rosiglitazone maleate ketone / glimepiride) marketed for the treatment of type 2 diabetes, the combination product is superior to alone sulfonylurea group and the placebo group, and the efficacy and safety of elderly patients with diabetes is also very good. 另外,两类药物合用的文献和专利报道也很多:对于患有代谢综合征的2型糖尿病患者,噻唑烷二酮类和格列美脲联合治疗可明显改善长期血压控制,降低姨岛素抵抗【Derosa G,et al. Thiazolidinedione effects on blood pressure in diabeticpatients with metabolic syndrome treated with glimepiride. Hypertens Res. 2005,28(11) :917_924】;格列美脲和吡格列酮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【田景伦等.格列美脲和吡格列酮联合治疗代谢综合征合并2型糖尿病临床观察.实用医院临床杂志,2005,2(4) :33-34】;罗格列酮与格列齐特联合使用较单用格列齐特能更好地控制血糖,降低糖化血红蛋白(HbA1C)、 TG,同时不增加空腹胰岛素(FIN)水平【顾芹等.罗格列酮 Further, two drug combination is also reported in the literature and many patents: For patients with type 2 diabetes with metabolic syndrome, thiazolidine diones and glimepiride combination therapy can significantly improve long-term control of blood pressure reducing Insulin resistance aunt [. Derosa G, et al Thiazolidinedione effects on blood pressure in diabeticpatients with metabolic syndrome treated with glimepiride Hypertens Res 2005,28 (11): 917_924..]; glimepiride and pioglitazone in combination can significantly improve the metabolism of type 2 diabetes most patients with metabolic syndrome indicators: fasting blood glucose, blood pressure early in the morning resting state, and triglycerides were significantly lower LDL-C, HDL-C increased significantly, waist circumference and body mass index tended to decrease [Tianjing Lun, etc. Glenn. clinical observation of type 2 diabetes, glimepiride and pioglitazone combination therapy of metabolic syndrome complicated Journal of Applied clinical hospital, 2005,2 (4): 33-34]; rosiglitazone in combination with gliclazide column together than alone grid Patent better glycemic control, reduced glycosylated hemoglobin (HbA1C), TG, while not increasing the fasting insulin (FIN) [Gu horizontal celery etc. rosiglitazone 与格列齐特联合治疗2型糖尿病的临床疗效.中国临床药学杂志,2003,12(3) :144-146】;每天1次的文迪雅与格列齐特联合应用具有良好的耐受性,且文迪雅能降低胰岛素的抵抗,所以文迪雅能够协同格列齐特有效地控制血糖,未发现有肝功能损害等不良反应,有良好的安全性【孙晓晖.罗格列酮和格列齐特联合应用治疗2型糖尿病38例临床观察.华中医学杂志,2004,28(2) :129】;另外,专利CN200410022514. 3中公开罗格列酮与格列美脲的组合物,二者对高血糖具有协同作用;专利CN98807319. 6中公开了磺脲类降糖药物与噻唑烷二酮类降糖药物和双胍类降糖药物的组合物用于治疗糖尿病;等等。 Clinical efficacy and Gliclazide in the treatment of type 2 diabetes in Chinese Journal of Clinical Pharmacy, 2003,12 (3): 144-146]; Avandia once a day in combination with gliclazide well tolerated. resistance, and Avandia reduce insulin resistance, it is possible synergistic gliclazide Avandia effectively control blood glucose showed no liver damage and other adverse reactions, has good security [Sunxiao Hui. rosiglitazone and gliclazide combination of 38 cases of type 2 diabetes central Medicine, 2004, 28 (2): 129]; Further, disclosed in patent CN200410022514 3 rosiglitazone and glimepiride composition, having a synergistic effect on both hyperglycemia; patent CN98807319 6 discloses sulfonylureas and thiazolidine diones biguanide hypoglycemic drugs and hypoglycemic pharmaceutical composition for the treatment of diabetes; and the like.

[0012] 然而,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Hcy对糖尿病患者带来的危害。 [0012] However, in combination with sulfonylureas thiazolidine diones hypoglycemic drugs can not reduce the harm caused by diabetes Hcy. 在临床实践或是已经发表的科研文献中,我们尚没有发现磺脲类降糖药物、噻唑烷二酮类降糖药物及B族维生素三种药物联合应用的研究报道。 In clinical practice or published scientific literature, we have not found yet reported sulfonylureas, thiazolidinediones TZDs hypoglycemic drugs and B vitamins combination of three drugs. 我们经过大量试验研究发现,磺脲类降糖药物、噻唑烷二酮类降糖药物及B族维生素三种药物联合应用可有效控制血糖,减轻胰岛素抵抗,减轻糖尿病患者特别是合并有慢性并发症的糖尿病患者血浆同型半胱氨酸升高,并可以协同或相加的减少糖尿病慢性并发症的发生,保护内皮细胞功能;同时亦可减轻患者经济负担,提高患者对治疗的依从性,从而进一步改善糖尿病患者的生活质量。 After extensive testing we have found, sulfonylureas, thiazolidine diones hypoglycemic drugs and B vitamins triple drug combinations can effectively control blood sugar, reduce insulin resistance, in particular diabetes alleviate chronic complications associated with plasma homocysteine ​​to diabetes, and may be synergistic or additive reduce chronic complications of diabetes, protection of endothelial cell function; but will also reduce the financial burden of patients to improve patient compliance with the treatment, further improve the quality of life of diabetes patients.

发明内容 SUMMARY

[0013] 本发明的目的在于提供一种有效治疗糖尿病或预防糖尿病并发症的药物组合物, 该组合物可有效降低血糖,防止糖尿病患者特别是合并有慢性并发症的糖尿病患者血浆同型半胱氨酸升高,降低糖尿病慢性并发症的发生率,保护内皮细胞功能,具有有效治疗糖尿病或预防糖尿病慢性并发症的作用。 [0013] The object of the present invention is to provide an effective treatment for the prevention of diabetes or diabetic complications pharmaceutical composition, the composition may effectively reduce blood sugar, prevent plasma homocysteine ​​cysteinyl especially associated with diabetic chronic complications of diabetes acid increased, reduce the incidence of chronic complications of diabetes, protection of endothelial cell function, has the effect of effectively preventing or treating diabetic chronic complications of diabetes.

[0014] 本发明提供的药物组合物含有药用剂量的磺脲类降糖药物中的一种或该磺脲类降糖药物的活性代谢产物或该磺脲类降糖药物的可药用盐、药用剂量的噻唑烷二酮类降糖药物中的一种或该噻唑烷二酮类降糖药物的可药用盐、药用剂量的B族维生素或与其相关的具有相似生物活性的化合物,以及可药用载体或赋形剂。 [0014] The active metabolite of the present invention, one kind of sulfonylureas provides a pharmaceutical composition comprising a pharmaceutically acceptable amount of the drug or the sulfonylurea or the sulfonylurea drugs may be acceptable salt thereof , B vitamins pharmaceutically acceptable dosage thiazolidine diones hypoglycemic medicament or one of the thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt, or a pharmaceutically acceptable dose of a compound associated with similar biological activity and a pharmaceutically acceptable carrier or excipient.

[0015] 本发明提供的药物组合物中的磺脲类降糖药物选自格列本脲、格列波脲、格列环脲、格列己脲、格列美脲、格列平脲、格列沙脲、格列生脲、格列索脲、格列辛脲、格列齐特、格列吡嗪和格列喹酮,优选格列本脲、格列美脲、格列齐特、格列喹酮或格列吡嗪,更加优选格列美脲。 [0015] The pharmaceutical compositions of the present invention provides sulfonylureas selected from glibenclamide, glibornuride, Glenn cyclic ureas, Glenn glipizide, glimepiride, glipizide flat urea, Ge Liesha urea, urea raw Glenn, glisolamide, Ge Liexin urea, gliclazide, glipizide and gliquidone, preferably glyburide, glimepiride, gliclazide , gliquidone or glipizide, more preferably glimepiride.

[0016] 本发明提供的药物组合物中的噻唑烷二酮类降糖药物选自罗格列酮(rosiglitazone)、吡格列酮(匹格列酮,pioglitazone)、曲格列酮(troglitazone)、恩格列酮(englitazone)、环格列酮(cightazone)等,优选罗格列酮或吡格列酮。 [0016] thiazolidine provides pharmaceutical compositions of the invention in the selected diketones hypoglycemic drugs rosiglitazone (rosiglitazone), pioglitazone (pioglitazone, pioglitazone), troglitazone (troglitazone), Engel rosiglitazone (englitazone), ciglitazone (cightazone) and the like, preferably rosiglitazone or pioglitazone.

[0017] 本发明提供的药物组合物中的噻唑烷二酮类降糖药物的可药用盐包括但不限于马来酸罗格列酮、酒石酸罗格列酮、罗格列酮钠、盐酸罗格列酮、盐酸吡格列酮等,优选马来酸罗格列酮或盐酸吡格列酮。 [0017] hypoglycemic thiazolidine diones pharmaceutical composition of the present invention provides a pharmaceutical composition in pharmaceutically acceptable salts include but are not limited to rosiglitazone maleate, tartrate rosiglitazone, sodium rosiglitazone hydrochloride rosiglitazone, pioglitazone hydrochloride and the like, preferably rosiglitazone maleate or pioglitazone hydrochloride.

[0018] 本发明提供的药物组合物中的B族维生素选自叶酸、维生素B12(氰钴胺)、维生素B6 (吡哆醇)、维生素Bl (硫胺素)、维生素B2 (核黄素)、维生素B3 (烟酸)、泛酸及生物素,优选叶酸、维生素B12或维生素B6,更加优选叶酸。 [0018] B vitamins according to the present invention provides a pharmaceutical composition in the selected folic acid, vitamin B12 (cyanocobalamin), vitamin B6 (pyridoxine), vitamin Bl (thiamine), vitamin B2 (riboflavin) , vitamin B3 (niacin), pantothenic acid and biotin, preferably folic acid, vitamin B12 or vitamin B6, folic acid is more preferable.

[0019] 在本发明中,与B族维生素相关的具有相似生物活性的化合物是指B族维生素盐、 B族维生素的不同亚基取代物或在体内代谢或生成与B族维生素具有生物等效性的物质, 上述物质与B族维生素具有相似的生物活性,但与B族维生素具有不同的存在或表现形式。 [0019] In the present invention, vitamin B-related compounds having similar biological activity refers to salts of the different subunits B vitamins, vitamin B group substituted or metabolized in vivo bioequivalence B vitamins or generate the substance of the substance B vitamins have similar biological activity, but having a different B vitamins presence or manifestation. 其中,与叶酸相关的具有相似生物活性的化合物,如甲酰四氢叶酸、甲基四氢叶酸、亚甲基四氢叶酸、叶酸盐、叶酸或叶酸盐的活性代谢产物和可在体内代谢和/或生成叶酸的物质等;与维生素B12相关的具有相似生物活性的化合物,如钴胺素、甲钴胺素、5'-脱氧腺苷钴胺素、羟钴胺素及上述物质的衍生物和可在体内代谢和/或生成该类化合物的物质;与维生素B6相关的具有相似生物活性的化合物,如吡哆醛、吡哆胺、磷酸吡哆醇、磷酸吡哆醛、 磷酸吡哆胺及上述物质的衍生物和可在体内代谢和/或生成该类化合物的物质。 Wherein the folic acid related compounds having similar biological activity, such as active metabolites leucovorin methyl tetrahydrofolate, methylene-tetrahydrofolate, folate, folic acid or folate in vivo, and metabolic and / or folic acid generating substances; vitamin B12-related compounds having similar biological activity, such as cobalamin, methyl cobalamin, adenosyl cobalamin 5'-deoxy, hydroxocobalamin and the foregoing and derivatives may be metabolized in vivo and / or generating substance such compounds; vitamin B6 related compound with similar biological activity, such as pyridoxal, pyridoxamine, pyridoxine phosphate, pyridoxal phosphate, phosphate-pyrazole pyridoxamine and derivatives thereof, and such compounds may be metabolized in the body material and / or generated.

[0020] 应当认识到,上述说明并非对本发明的限制,凡是以磺脲类降糖药物包括格列本脲、格列波脲、格列环脲、格列己脲、格列美脲、格列平脲、格列沙脲、格列生脲、格列索脲、格列辛脲、格列齐特、格列吡嗪和格列喹酮、或以磺脲类降糖药物为活性成分的化合物为一个组成成分,以噻唑烷二酮类降糖药物包括罗格列酮、吡格列酮、曲格列酮、恩格列酮、或环格列酮等、或以噻唑烷二酮类降糖药物为活性成分的化合物为另一个组成成分,以B族维生素或与其相关的具有相似生物活性的化合物为第三个组成成分所构成的药物组合物,都是本发明保护的范围。 [0020] It should be appreciated that the above description is not intended to limit the invention, to all sulfonylureas include glyburide, glibornuride, Glenn cyclic ureas, Glenn glipizide, glimepiride, grid LP urea, Ge Liesha urea, urea raw Glenn, glisolamide, Ge Liexin urea, gliclazide, glipizide and gliquidone, or sulfonylureas as active ingredient as a component of compounds, thiazole TZDs hypoglycemic drugs include rosiglitazone, pioglitazone, troglitazone, englitazone, ciglitazone or the like, or hypoglycemic thiazolidine diones pharmaceutical active ingredient is a compound of another composition, B vitamins to or associated with the pharmaceutical composition of the third composition consisting of a compound having a biological activity similar to the range, the protection of the present invention are present.

[0021] 本发明提供的药物组合物中,磺脲类降糖药物优选格列美脲、格列本脲、格列齐特、格列喹酮或格列吡嗪,其中上述物质在存在时的含量分别为:格列美脲Img〜4mg,格列本脲Img〜15mg,格列齐特20mg〜160mg,格列喹酮15mg〜60mg,格列吡嗪Img〜15mg ; 噻唑烷二酮类降糖药物或其可药用盐优选罗格列酮、吡格列酮、马来酸罗格列酮或盐酸吡格列酮,其中上述物质在存在时的含量分别为:罗格列酮Img〜8mg,吡格列酮7. 5mg〜 45mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮;B族维生素优选叶酸、维生素B12或维生素B6,其中上述物质在存在时的含量分别为:叶酸0. Img〜7. 5mg,维生素B120. 005mg〜2mg,维生素B62mg〜75mg。 [0021] The pharmaceutical compositions provided by the invention, the drug is preferably sulfonylurea glimepiride, glibenclamide, gliclazide, gliquidone or glipizide, wherein said material in the presence of the contents were: glimepiride Img~4mg, glibenclamide Img~15mg, gliclazide 20mg~160mg, gliquidone 15mg~60mg, glipizide Img~15mg; thiazolidine diones hypoglycemic drugs, or a pharmaceutically acceptable salt thereof preferably rosiglitazone, pioglitazone, maleic acid, rosiglitazone or pioglitazone hydrochloride, rosiglitazone, wherein the content of the substance, if present, are: rosiglitazone Img~8mg, pioglitazone 7. 5mg~ 45mg, rosiglitazone content of rosiglitazone maleate is equivalent Img~8mg rosiglitazone, pioglitazone pyrazole hydrochloride corresponds to an amount of 7. 5mg~45mg of pioglitazone; preferably B vitamins folic acid, vitamin B12 or vitamin B6, wherein the content of the substance, if present, are: folate 0. Img~7 5mg, vitamin B120 005mg~2mg, vitamin B62mg~75mg..

[0022] 更确切的说,本发明提供的药物组合物优选格列美脲、罗格列酮和叶酸的组合,格列美脲、吡格列酮和叶酸的组合,格列本脲、罗格列酮和叶酸的组合,格列本脲、吡格列酮和叶酸的组合,格列齐特、罗格列酮和叶酸的组合,格列齐特、吡格列酮和叶酸的组合,格列喹酮、罗格列酮和叶酸的组合,格列喹酮、吡格列酮和叶酸的组合,格列吡嗪、罗格列酮和叶酸的组合,格列吡嗪、吡格列酮和叶酸的组合中的一种。 [0022] More specifically, the combination of the present invention provides a pharmaceutical composition is preferably glimepiride, rosiglitazone and folic acid, glimepiride, pioglitazone and folic acid, glyburide, rosiglitazone and a combination of folic acid, a combination of glibenclamide, pioglitazone and folic acid, gliclazide, and rosiglitazone in combination folic acid, a combination of gliclazide, pioglitazone and folic acid, gliquidone, rosiglitazone and a combination of folic acid, a combination of gliquidone, pioglitazone and folic acid, glipizide, and rosiglitazone in combination folic acid, a combination of glipizide, pioglitazone and a folate.

[0023] 本发明提供的药物组合物中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为叶酸。 [0023] The pharmaceutical compositions provided by the invention, the drug is a sulfonylurea glimepiride, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and folic acid. 在该组合物中,格列美脲的含量为Img〜4mg,罗格列酮的含量为Img〜8mg,叶酸的含量为0. Img〜7. 5mg。 In this composition, the amount of glimepiride is Img~4mg, rosiglitazone content Img~8mg, folic acid content is 0. Img~7. 5mg.

[0024] 本发明提供的药物组合物中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为叶酸。 [0024] The pharmaceutical compositions provided by the invention, the drug is a sulfonylurea glimepiride, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B vitamins was folic acid. 在该组合物中,格列美脲的含量为Img〜4mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,叶酸的含量为0. Img〜 7. 5mg0 In this composition, the amount of glimepiride is Img~4mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, folic acid content is 0. Img~ 7. 5mg0

[0025] 本发明提供的药物组合物中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为叶酸。 [0025] The pharmaceutical compositions provided by the invention, the drug is a sulfonylurea glimepiride, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and folic acid. 在该组合物中,格列美脲的含量为Img〜4mg,吡格列酮的含量为7. 5mg〜45mg,叶酸的含量为0. Img〜7. 5mg。 In this composition, the amount of glimepiride is Img~4mg, the content of pioglitazone 7. 5mg~45mg, folic acid content is 0. Img~7. 5mg.

[0026] 本发明提供的药物组合物中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为叶酸。 [0026] The pharmaceutical compositions provided by the invention, the drug is a sulfonylurea glimepiride, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and folic acid. 在该组合物中,格列美脲的含量为Img〜4mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,叶酸的含量为0. Img 〜7. 5mg0 In this composition, the amount of glimepiride is Img~4mg, pioglitazone hydrochloride pyrazole in an amount of equivalent of 7. 5mg~45mg pioglitazone, folic acid content is 0. Img ~7. 5mg0

[0027] 本发明提供的药物组合物中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为维生素B12。 [0027] The pharmaceutical compositions provided by the invention, the drug is a sulfonylurea glimepiride, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and vitamin B12. 在该组合物中,格列美脲的含量为Img〜4mg,罗格列酮的含量为Img〜8mg,维生素B12的含量为0. 005mg〜2mg。 In this composition, the amount of glimepiride is Img~4mg, rosiglitazone content Img~8mg, vitamin B12, 0. 005mg~2mg.

[0028] 本发明提供的药物组合物中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为维生素B12。 [0028] The pharmaceutical compositions provided by the invention, the drug is a sulfonylurea glimepiride, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B vitamins was vitamin B12. 在该组合物中,格列美脲的含量为Img〜4mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,维生素B12的含量为0. 005mg 〜2mg。 In this composition, the amount of glimepiride is Img~4mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, vitamin B12, 0. 005mg ~2mg.

[0029] 本发明提供的药物组合物中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为维生素B12。 [0029] The pharmaceutical compositions provided by the invention, the drug is a sulfonylurea glimepiride, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and vitamin B12. 在该组合物中,格列美脲的含量为Img〜4mg,吡格列酮的含量为7. 5mg〜45mg,维生素B12的含量为0. 005mg〜2mg。 In this composition, the amount of glimepiride is Img~4mg, the content of pioglitazone 7. 5mg~45mg, vitamin B12, 0. 005mg~2mg.

[0030] 本发明提供的药物组合物中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为维生素B12。 [0030] The pharmaceutical compositions provided by the invention, the drug is a sulfonylurea glimepiride, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and vitamin B12. 在该组合物中,格列美脲的含量为Img〜4mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,维生素B12的含量为0. 005mg 〜2mg。 In this composition, the amount of glimepiride is Img~4mg, pioglitazone hydrochloride in an amount of equivalent of 7. 5mg~45mg pioglitazone, vitamin B12, 0. 005mg ~2mg.

[0031] 本发明提供的药物组合物中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为维生素B6。 [0031] The pharmaceutical compositions provided by the invention, the drug is a sulfonylurea glimepiride, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and vitamin B6. 在该组合物中,格列美脲的含量为Img〜4mg,罗格列酮的含量为Img〜8mg,维生素B6的含量为2mg〜75mg。 In this composition, the amount of glimepiride is Img~4mg, rosiglitazone content Img~8mg, vitamin B6 is 2mg~75mg.

[0032] 本发明提供的药物组合物中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为维生素B6。 [0032] The pharmaceutical compositions provided by the invention, the drug is a sulfonylurea glimepiride, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B vitamins was vitamin B6. 在该组合物中,格列美脲的含量为Img〜4mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,维生素B6的含量为2mg 〜75mg。 In this composition, the amount of glimepiride is Img~4mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, vitamin B6 is 2mg ~75mg.

[0033] 本发明提供的药物组合物中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为维生素B6。 [0033] The pharmaceutical compositions provided by the invention, the drug is a sulfonylurea glimepiride, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and vitamin B6. 在该组合物中,格列美脲的含量为Img〜4mg,吡格列酮的含量为7. 5mg〜45mg,维生素B6的含量为2mg〜75mg。 In this composition, the amount of glimepiride is Img~4mg, the content of pioglitazone 7. 5mg~45mg, vitamin B6 is 2mg~75mg.

[0034] 本发明提供的药物组合物中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为维生素B6。 [0034] The pharmaceutical compositions provided by the invention, the drug is a sulfonylurea glimepiride, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and vitamin B6. 在该组合物中,格列美脲的含量为Img〜4mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,维生素B6的含量为2mg 〜75mg。 In this composition, the amount of glimepiride is Img~4mg, pioglitazone hydrochloride in an amount of equivalent of 7. 5mg~45mg pioglitazone, vitamin B6 is 2mg ~75mg.

[0035] 本发明提供的药物组合物中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为叶酸。 [0035] The pharmaceutical compositions provided herein, the sulfonylurea drug is glyburide, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and folic acid. 在该组合物中,格列本脲的含量为Img〜15mg,罗格列酮的含量为Img〜8mg,叶酸的含量为0. Img〜7. 5mg。 In this composition, the content of glibenclamide is Img~15mg, rosiglitazone content Img~8mg, folic acid content is 0. Img~7. 5mg.

[0036] 本发明提供的药物组合物中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为叶酸。 [0036] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glyburide, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B vitamins was folic acid. 在该组合物中,格列本脲的含量为Img〜15mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,叶酸的含量为0. Img 〜7. 5mg0 In this composition, the content of glibenclamide is Img~15mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, folic acid content is 0. Img ~7. 5mg0

[0037] 本发明提供的药物组合物中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为叶酸。 The pharmaceutical compositions [0037] The present invention provides, a sulfonylurea drug is glyburide, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and folic acid. 在该组合物中,格列本脲的含量为Img〜15mg,吡格列酮的含量为7. 5mg〜45mg,叶酸的含量为0. Img〜7. 5mg。 In this composition, the content of glibenclamide is Img~15mg, the content of pioglitazone 7. 5mg~45mg, folic acid content is 0. Img~7. 5mg.

[0038] 本发明提供的药物组合物中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为叶酸。 [0038] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glyburide, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and folic acid. 在该组合物中,格列本脲的含量为Img〜15mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,叶酸的含量为0. Img 〜7. 5mg0 In this composition, the content of glibenclamide is Img~15mg, pioglitazone hydrochloride pyrazole in an amount of equivalent of 7. 5mg~45mg pioglitazone, folic acid content is 0. Img ~7. 5mg0

[0039] 本发明提供的药物组合物中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为维生素B12。 [0039] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glyburide, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and vitamin B12. 在该组合物中,格列本脲的含量为Img〜15mg, 罗格列酮的含量为Img〜8mg,维生素B12的含量为0. 005mg〜2mg。 In this composition, the content of glibenclamide is Img~15mg, rosiglitazone content Img~8mg, vitamin B12, 0. 005mg~2mg.

[0040] 本发明提供的药物组合物中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为维生素B12。 [0040] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glyburide, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B vitamins was vitamin B12. 在该组合物中,格列本脲的含量为Img〜15mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,维生素B12的含量为0. 005mg 〜2mg。 In this composition, the content of glibenclamide is Img~15mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, vitamin B12, 0. 005mg ~2mg.

[0041] 本发明提供的药物组合物中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为维生素B12。 [0041] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glyburide, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and vitamin B12. 在该组合物中,格列本脲的含量为Img〜15mg, 吡格列酮的含量为7. 5mg〜45mg,维生素B12的含量为0. 005mg〜2mg。 In this composition, the content of glibenclamide is Img~15mg, the content of pioglitazone 7. 5mg~45mg, vitamin B12, 0. 005mg~2mg.

[0042] 本发明提供的药物组合物中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为维生素B12。 [0042] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glyburide, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and vitamin B12. 在该组合物中,格列本脲的含量为Img〜15mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,维生素B12的含量为0. 005mg 〜2mg。 In this composition, the content of glibenclamide is Img~15mg, pioglitazone hydrochloride in an amount of equivalent of 7. 5mg~45mg pioglitazone, vitamin B12, 0. 005mg ~2mg.

[0043] 本发明提供的药物组合物中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为维生素B6。 [0043] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glyburide, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and vitamin B6. 在该组合物中,格列本脲的含量为Img〜15mg,罗格列酮的含量为Img〜8mg,维生素B6的含量为2mg〜75mg。 In this composition, the content of glibenclamide is Img~15mg, rosiglitazone content Img~8mg, vitamin B6 is 2mg~75mg.

[0044] 本发明提供的药物组合物中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为维生素B6。 [0044] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glyburide, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B vitamins was vitamin B6. 在该组合物中,格列本脲的含量为Img〜15mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,维生素B6的含量为2mg 〜75mg。 In this composition, the content of glibenclamide is Img~15mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, vitamin B6 is 2mg ~75mg.

[0045] 本发明提供的药物组合物中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为维生素B6。 [0045] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glyburide, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and vitamin B6. 在该组合物中,格列本脲的含量为Img〜15mg,吡格列酮的含量为7. 5mg〜45mg,维生素B6的含量为2mg〜75mg。 In this composition, the content of glibenclamide is Img~15mg, the content of pioglitazone 7. 5mg~45mg, vitamin B6 is 2mg~75mg.

[0046] 本发明提供的药物组合物中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为维生素B6。 [0046] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glyburide, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and vitamin B6. 在该组合物中,格列本脲的含量为Img〜15mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,维生素B6的含量为2mg 〜75mg。 In this composition, the content of glibenclamide is Img~15mg, pioglitazone hydrochloride in an amount of equivalent of 7. 5mg~45mg pioglitazone, vitamin B6 is 2mg ~75mg.

[0047] 本发明提供的药物组合物中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为叶酸。 [0047] The pharmaceutical compositions provided by the invention, the sulfonylurea drugs gliclazide, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and folic acid. 在该组合物中,格列齐特的含量为20mg〜160mg,罗格列酮的含量为Img〜8mg,叶酸的含量为0. Img〜7. 5mg。 In this composition, the amount of gliclazide is 20mg~160mg, rosiglitazone content Img~8mg, folic acid content is 0. Img~7. 5mg.

[0048] 本发明提供的药物组合物中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为叶酸。 [0048] The pharmaceutical compositions provided by the invention, the sulfonylurea drugs gliclazide, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B vitamins was folic acid. 在该组合物中,格列齐特的含量为20mg〜160mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,叶酸的含量为0. Img 〜7. 5mg0 In this composition, the amount of gliclazide is 20mg~160mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, folic acid content is 0. Img ~7. 5mg0

[0049] 本发明提供的药物组合物中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为叶酸。 [0049] The pharmaceutical compositions provided by the invention, the sulfonylurea drugs gliclazide, thiazolidine diones as hypoglycemic agent is folic pioglitazone, B vitamins. 在该组合物中,格列齐特的含量为20mg〜160mg,吡格列酮的含量为7. 5mg〜45mg,叶酸的含量为0. Img〜7. 5mg。 In this composition, the amount of gliclazide is 20mg~160mg, the content of pioglitazone 7. 5mg~45mg, folic acid content is 0. Img~7. 5mg.

[0050] 本发明提供的药物组合物中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为叶酸。 [0050] The pharmaceutical compositions provided by the invention, the sulfonylurea drugs gliclazide, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and folic acid. 在该组合物中,格列齐特的含量为20mg〜160mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,叶酸的含量为0. Img 〜7. 5mg0 In this composition, the amount of gliclazide is 20mg~160mg, pioglitazone hydrochloride pyrazole in an amount of equivalent of 7. 5mg~45mg pioglitazone, folic acid content is 0. Img ~7. 5mg0

[0051] 本发明提供的药物组合物中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为维生素B12。 [0051] The pharmaceutical compositions provided by the invention, the sulfonylurea drugs gliclazide, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and vitamin B12. 在该组合物中,格列齐特的含量为20mg〜160mg, 罗格列酮的含量为Img〜8mg,维生素B12的含量为0. 005mg〜2mg。 In this composition, the amount of gliclazide is 20mg~160mg, rosiglitazone content Img~8mg, vitamin B12, 0. 005mg~2mg.

[0052] 本发明提供的药物组合物中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为维生素B12。 [0052] The pharmaceutical compositions provided by the invention, the sulfonylurea drugs gliclazide, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B vitamins was vitamin B12. 在该组合物中,格列齐特的含量为20mg〜160mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,维生素B12的含量为0. 005mg〜2mg。 In this composition, the amount of gliclazide is 20mg~160mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, vitamin B12, 0. 005mg~2mg.

[0053] 本发明提供的药物组合物中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为维生素B12。 [0053] The pharmaceutical compositions provided by the invention, the sulfonylurea drugs gliclazide, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and vitamin B12. 在该组合物中,格列齐特的含量为20mg〜160mg, 吡格列酮的含量为7. 5mg〜45mg,维生素B12的含量为0. 005mg〜2mg。 In this composition, the amount of gliclazide is 20mg~160mg, the content of pioglitazone 7. 5mg~45mg, vitamin B12, 0. 005mg~2mg.

[0054] 本发明提供的药物组合物中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为维生素B12。 [0054] The pharmaceutical compositions provided by the invention, the sulfonylurea drugs gliclazide, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and vitamin B12. 在该组合物中,格列齐特的含量为20mg〜160mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,维生素B12的含量为0. 005mg〜2mg。 In this composition, the amount of gliclazide is 20mg~160mg, pioglitazone hydrochloride in an amount of equivalent of 7. 5mg~45mg pioglitazone, rosiglitazone, vitamin B12, 0. 005mg~2mg.

[0055] 本发明提供的药物组合物中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为维生素B6。 [0055] The pharmaceutical compositions provided by the invention, the sulfonylurea drugs gliclazide, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and vitamin B6. 在该组合物中,格列齐特的含量为20mg〜160mg, 罗格列酮的含量为Img〜8mg,维生素B6的含量为2mg〜75mg。 In this composition, the amount of gliclazide is 20mg~160mg, rosiglitazone content Img~8mg, vitamin B6 is 2mg~75mg.

[0056] 本发明提供的药物组合物中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为维生素B6。 [0056] The pharmaceutical compositions provided by the invention, the sulfonylurea drugs gliclazide, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B vitamins was vitamin B6. 在该组合物中,格列齐特的含量为20mg〜160mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,维生素B6的含量为2mg〜75mg。 In this composition, the amount of gliclazide is 20mg~160mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, vitamin B6 is 2mg~75mg.

[0057] 本发明提供的药物组合物中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为维生素B6。 The pharmaceutical compositions provided herein [0057] In the present, sulfonylurea drugs gliclazide, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and vitamin B6. 在该组合物中,格列齐特的含量为20mg〜160mg, 吡格列酮的含量为7. 5mg〜45mg,维生素B6的含量为2mg〜75mg。 In this composition, the amount of gliclazide is 20mg~160mg, the content of pioglitazone 7. 5mg~45mg, vitamin B6 is 2mg~75mg.

[0058] 本发明提供的药物组合物中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为维生素B6。 [0058] The pharmaceutical compositions provided by the invention, the sulfonylurea drugs gliclazide, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and vitamin B6. 在该组合物中,格列齐特的含量为20mg〜160mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,维生素B6的含量为2mg 〜75mg。 In this composition, the amount of gliclazide is 20mg~160mg, pioglitazone hydrochloride in an amount of equivalent of 7. 5mg~45mg pioglitazone, rosiglitazone, vitamin B6 is 2mg ~75mg. [0059] 本发明提供的药物组合物中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为叶酸。 [0059] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and folic acid. 在该组合物中,格列喹酮的含量为15mg〜60mg,罗格列酮的含量为Img〜8mg,叶酸的含量为0. Img〜7. 5mg。 In this composition, the content of gliquidone is 15mg~60mg, rosiglitazone content Img~8mg, folic acid content is 0. Img~7. 5mg.

[0060] 本发明提供的药物组合物中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为叶酸。 [0060] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B vitamins was folic acid. 在该组合物中,格列喹酮的含量为15mg〜60mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,叶酸的含量为0. Img 〜7. 5mg0 In this composition, the content of gliquidone is 15mg~60mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, folic acid content is 0. Img ~7. 5mg0

[0061] 本发明提供的药物组合物中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为叶酸。 [0061] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and folic acid. 在该组合物中,格列喹酮的含量为15mg〜60mg,吡格列酮的含量为7. 5mg〜45mg,叶酸的含量为0. Img〜7. 5mg。 In this composition, the content of gliquidone is 15mg~60mg, the content of pioglitazone 7. 5mg~45mg, folic acid content is 0. Img~7. 5mg.

[0062] 本发明提供的药物组合物中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为叶酸。 [0062] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and folic acid. 在该组合物中,格列喹酮的含量为15mg〜60mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,叶酸的含量为0. Img 〜7. 5mg0 In this composition, the content of gliquidone is 15mg~60mg, pioglitazone hydrochloride pyrazole in an amount of equivalent of 7. 5mg~45mg pioglitazone, folic acid content is 0. Img ~7. 5mg0

[0063] 本发明提供的药物组合物中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为维生素B12。 [0063] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and vitamin B12. 在该组合物中,格列喹酮的含量为15mg〜60mg, 罗格列酮的含量为Img〜8mg,维生素B12的含量为0. 005mg〜2mg。 In this composition, the content of gliquidone is 15mg~60mg, rosiglitazone content Img~8mg, vitamin B12, 0. 005mg~2mg.

[0064] 本发明提供的药物组合物中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为维生素B12。 [0064] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B vitamins was vitamin B12. 在该组合物中,格列喹酮的含量为15mg〜60mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,维生素B12的含量为0. 005mg〜2mg。 In this composition, the content of gliquidone is 15mg~60mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, vitamin B12, 0. 005mg~2mg.

[0065] 本发明提供的药物组合物中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为维生素B12。 [0065] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and vitamin B12. 在该组合物中,格列喹酮的含量为15mg〜60mg, 吡格列酮的含量为7. 5mg〜45mg,维生素B12的含量为0. 005mg〜2mg。 In this composition, the content of gliquidone is 15mg~60mg, the content of pioglitazone 7. 5mg~45mg, vitamin B12, 0. 005mg~2mg. [0066] 本发明提供的药物组合物中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为维生素B12。 [0066] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and vitamin B12. 在该组合物中,格列喹酮的含量为15mg〜60mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,维生素B12的含量为0. 005mg 〜2mg。 In this composition, the content of gliquidone is 15mg~60mg, pyridine hydrochloride in an amount of pioglitazone pioglitazone 7. 5mg~45mg corresponds to one column, vitamin B12, 0. 005mg ~2mg.

[0067] 本发明提供的药物组合物中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为维生素B6。 [0067] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and vitamin B6. 在该组合物中,格列喹酮的含量为15mg〜60mg, 罗格列酮的含量为Img〜8mg,维生素B6的含量为2mg〜75mg。 In this composition, the content of gliquidone is 15mg~60mg, rosiglitazone content Img~8mg, vitamin B6 is 2mg~75mg.

[0068] 本发明提供的药物组合物中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为维生素B6。 [0068] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B vitamins was vitamin B6. 在该组合物中,格列喹酮的含量为15mg〜60mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,维生素B6的含量为2mg 〜75mg。 In this composition, the content of gliquidone is 15mg~60mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, vitamin B6 is 2mg ~75mg.

[0069] 本发明提供的药物组合物中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为维生素B6。 [0069] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and vitamin B6. 在该组合物中,格列喹酮的含量为15mg〜60mg, 吡格列酮的含量为7. 5mg〜45mg,维生素B6的含量为2mg〜75mg。 In this composition, the content of gliquidone is 15mg~60mg, the content of pioglitazone 7. 5mg~45mg, vitamin B6 is 2mg~75mg.

[0070] 本发明提供的药物组合物中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为维生素B6。 [0070] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and vitamin B6. 在该组合物中,格列喹酮的含量为15mg〜60mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,维生素B6的含量为2mg 〜75mg。 In this composition, the content of gliquidone is 15mg~60mg, pioglitazone hydrochloride in an amount of equivalent of 7. 5mg~45mg pioglitazone, rosiglitazone, vitamin B6 is 2mg ~75mg.

[0071] 本发明提供的药物组合物中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为叶酸。 [0071] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and folic acid. 在该组合物中,格列吡嗪的含量为Img〜15mg,罗格列酮的含量为Img〜8mg,叶酸的含量为0. Img〜7. 5mg。 In this composition, the amount of glipizide is Img~15mg, rosiglitazone content Img~8mg, folic acid content is 0. Img~7. 5mg.

[0072] 本发明提供的药物组合物中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为叶酸。 [0072] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B vitamins was folic acid. 在该组合物中,格列吡嗪的含量为Img〜15mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,叶酸的含量为0. Img 〜7. 5mg0 In this composition, the amount of glipizide is Img~15mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, folic acid content is 0. Img ~7. 5mg0

[0073] 本发明提供的药物组合物中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为叶酸。 [0073] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and folic acid. 在该组合物中,格列吡嗪的含量为Img〜15mg,吡格列酮的含量为7. 5mg〜45mg,叶酸的含量为0. Img〜7. 5mg。 In this composition, the amount of glipizide is Img~15mg, the content of pioglitazone 7. 5mg~45mg, folic acid content is 0. Img~7. 5mg.

[0074] 本发明提供的药物组合物中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为叶酸。 [0074] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and folic acid. 在该组合物中,格列吡嗪的含量为Img〜15mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,叶酸的含量为0. Img 〜7. 5mg0 In this composition, the amount of glipizide is Img~15mg, pioglitazone hydrochloride pyrazole in an amount of equivalent of 7. 5mg~45mg pioglitazone, folic acid content is 0. Img ~7. 5mg0

[0075] 本发明提供的药物组合物中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为维生素B12。 [0075] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and vitamin B12. 在该组合物中,格列吡嗪的含量为Img〜15mg, 罗格列酮的含量为Img〜8mg,维生素B12的含量为0. 005mg〜2mg。 In this composition, the amount of glipizide is Img~15mg, rosiglitazone content Img~8mg, vitamin B12, 0. 005mg~2mg.

[0076] 本发明提供的药物组合物中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为维生素B12。 [0076] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B vitamins was vitamin B12. 在该组合物中,格列吡嗪的含量为Img〜15mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,维生素B12的含量为0. 005mg 〜2mg。 In this composition, the amount of glipizide is Img~15mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, vitamin B12, 0. 005mg ~2mg. [0077] 本发明提供的药物组合物中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为维生素B12。 [0077] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and vitamin B12. 在该组合物中,格列吡嗪的含量为Img〜15mg, 吡格列酮的含量为7. 5mg〜45mg,维生素B12的含量为0. 005mg〜2mg。 In this composition, the amount of glipizide is Img~15mg, the content of pioglitazone 7. 5mg~45mg, vitamin B12, 0. 005mg~2mg.

[0078] 本发明提供的药物组合物中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为维生素B12。 [0078] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and vitamin B12. 在该组合物中,格列吡嗪的含量为Img〜15mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,维生素B12的含量为0. 005mg 〜2mg。 In this composition, the amount of glipizide is Img~15mg, pioglitazone hydrochloride in an amount of equivalent of 7. 5mg~45mg pioglitazone, vitamin B12, 0. 005mg ~2mg.

[0079] 本发明提供的药物组合物中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为维生素B6。 [0079] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and vitamin B6. 在该组合物中,格列吡嗪的含量为Img〜15mg,罗格列酮的含量为Img〜8mg,维生素B6的含量为2mg〜75mg。 In this composition, the amount of glipizide is Img~15mg, rosiglitazone content Img~8mg, vitamin B6 is 2mg~75mg.

[0080] 本发明提供的药物组合物中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为维生素B6。 [0080] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B vitamins was vitamin B6. 在该组合物中,格列吡嗪的含量为Img〜15mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,维生素B6的含量为2mg 〜75mg。 In this composition, the amount of glipizide is Img~15mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, vitamin B6 is 2mg ~75mg.

[0081] 本发明提供的药物组合物中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为维生素B6。 [0081] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and vitamin B6. 在该组合物中,格列吡嗪的含量为Img〜15mg,吡格列酮的含量为7. 5mg〜45mg,维生素B6的含量为2mg〜75mg。 In this composition, the amount of glipizide is Img~15mg, the content of pioglitazone 7. 5mg~45mg, vitamin B6 is 2mg~75mg.

[0082] 本发明提供的药物组合物中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为维生素B6。 [0082] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and vitamin B6. 在该组合物中,格列吡嗪的含量为Img〜15mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,维生素B6的含量为2mg 〜75mg。 In this composition, the amount of glipizide is Img~15mg, pioglitazone hydrochloride in an amount of equivalent of 7. 5mg~45mg pioglitazone, vitamin B6 is 2mg ~75mg.

[0083] 根据本发明,药物组合物包含三个基本组分,其中一个组分来自于磺脲类降糖药物中的一种药物或该磺脲类降糖药物的活性代谢产物或该磺脲类降糖药物的可药用盐,一个组分来自于噻唑烷二酮类降糖药物中的一种药物或该噻唑烷二酮类降糖药物的可药用盐,另一个组分来自于B族维生素中的一种或一种与B族维生素相关的具有相似生物活性的化合物。 [0083] According to the present invention, the pharmaceutical composition comprises three essential components, wherein one component from a pharmaceutical sulfonylureas or the sulfonylureas of the sulfonylurea active metabolite or class of antidiabetic drugs pharmaceutically acceptable salt thereof, a component from a pharmaceutical thiazolidine diones hypoglycemic medicament or the thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt, derived from a further component compound with similar biological activity of one or one and B vitamins in the B vitamins associated with. 该药物组合物可以制成包括药学上可以接受的任何剂型,例如将含有磺脲类降糖药物或该磺脲类降糖药物的活性代谢产物或该磺脲类降糖药物的可药用盐、噻唑烷二酮类降糖药物或该噻唑烷二酮类降糖药物的可药用盐和B族维生素或与其相关的具有相似生物活性的化合物的组合物制成普通片剂、双层片剂、多层片剂、缓释片剂、单室控释片剂、 双室控释片剂、微孔型控释片剂、舌下含片、口腔速崩片、分散片、肠溶片、颗粒剂、丸剂、肠溶胶囊、延迟释放片、定时/位释放片、普通胶囊、缓释胶囊、控释胶囊、含有微丸或小片的胶囊、含有微丸或小片的PH依赖型胶囊、口服液、膜剂或贴剂等。 The pharmaceutical composition may be in any pharmaceutically acceptable dosage forms including, e.g. containing an active metabolite of the sulfonylureas or sulfonylurea drugs or sulfonylureas of the pharmaceutically acceptable salt , thiazolidine diones hypoglycemic drugs or the thiazolidine diones hypoglycemic drugs and pharmaceutically acceptable salts of B vitamins or associated with a biologically active composition comprising a compound having a similar made of ordinary tablets, double-layer tablets agents, multilayer tablets, sustained-release tablet, controlled release tablet single chamber, dual chamber controlled release tablet, controlled release tablet microporous, sublingual tablets, orally rapidly disintegrating tablets, dispersible tablets, enteric-coated tablets , granules, pills, enteric-coated capsules, delayed release tablets, the timing / bit release tablets, ordinary capsules, sustained-release capsules, controlled release capsules, pellets or capsules containing small pieces, pellets or tablets containing PH dependent-capsule, oral solution, film formers or stickers and the like. 应该特别指出的是,将含有磺脲类降糖药物或该磺脲类降糖药物的活性代谢产物或该磺脲类降糖药物的可药用盐、 同时含有噻唑烷二酮类降糖药物或该噻唑烷二酮类降糖药物的可药用盐和B族维生素或与其相关的具有相似生物活性的化合物的组合物制成片剂或胶囊。 It should be particularly pointed out that the active metabolite, or medicament containing the sulfonylurea sulfonylureas or the sulfonylureas pharmaceutically acceptable salts, containing both thiazolidine diones hypoglycemic drugs or the thiazolidine diones hypoglycemic drugs and pharmaceutically acceptable salts of B vitamins or associated with a biologically active composition comprising a compound having a similar form of tablets or capsules.

[0084] 在本发明中,术语“药用剂量”是本领域的常用术语,是指以疾病的治疗为目的而使用的药物的剂量,作为公开的常识,磺脲类降糖药物和噻唑烷二酮类降糖药物的药用剂量是现有技术,每种药物剂量,可以参考《新编药物学》、《新编医院药物大全》、《临床用药指南》、《临床用药双向指南》、《临床实用新药手册》、《新药临床应用手册》和《新编临床用药手册》等。 [0084] In the present invention, the term "pharmaceutical dosage" is a common term of art, refers to a dosage to treat the disease for the purpose of drug used, as disclosed knowledge, sulfonylureas and thiazolidine medicinal dose TZDs hypoglycemic drugs is prior art, each drug dose, can refer to the "New Pharmacology", "New Encyclopedia of hospital drugs", "clinical guidelines", "clinical guidelines bi" "The clinical utility of new drugs Manual", "New drug application Manual" and "New clinical drug Handbook".

[0085] 在本发明中,术语“可药用载体或赋形剂”是指在本领域已知的可在片剂、丸剂、胶囊等中充当充填剂或载体原料的那些物质。 [0085] In the present invention, the term "pharmaceutically acceptable carrier or excipient" refers to those materials which may act as filler or carrier material in tablets, pills, capsules and the like are known in the art. 通常这些物质是获得卫生行政机构批准用于此目的的,而且作为药学试剂它们是无活性的。 These substances are generally obtain health administrative approval for this purpose, and as pharmaceutical agents which are inactive. 《药学赋形剂手册》(A. Wade和PJ Weller主编,第二版,美国药学会、华盛顿和药学出版社,伦敦出版,1994年)编辑了可药用载体和赋形剂。 "Pharmaceutically acceptable excipient Handbook" (A. Wade and PJ Weller eds., Second Edition, American Pharmaceutical Association, Washington and The Pharmaceutical Press, published in London, 1994) edited pharmaceutically acceptable carriers and excipients. 特别是,乳糖、淀粉、纤维素衍生物等等,以及它们的混合物可用作本发明组合物活性组分的载体。 In particular, lactose, starch, cellulose derivatives and the like, and mixtures thereof may be used as carrier composition of the present invention the active ingredient.

[0086] 在本发明中,可药用载体或赋形剂可制成普通口服制剂,包括普通片剂、普通胶囊、颗粒剂等,制成片剂时所述可药用载体包括有助于将活性化合物配制成药用制剂的赋形剂和辅料,如微晶纤维素、无机盐类、乳糖、氯化钠、柠檬酸、亚硫酸钠、淀粉、纤维素衍生物、预胶化淀粉,羧甲基淀粉钠,羟丙基淀粉,低取代羟丙基纤维素,交联羧甲基淀粉钠,交联聚乙烯吡咯烷酮,蔗糖、糊精、糖粉、葡萄糖等的一种或几种物质的组合物,属于本领域常识。 [0086] In the present invention, pharmaceutically acceptable carriers or excipients for oral preparations can be made common, including ordinary tablets, ordinary capsules, granules, etc., is made the tablet may include pharmaceutically acceptable carriers facilitate the active compounds are formulated into pharmaceutical excipients and formulation excipients, such as microcrystalline cellulose, inorganic salts, lactose, sodium chloride, citric acid, sodium sulfite, starch, cellulose derivatives, pregelatinized starch, carboxymethyl sodium starch glycolate, hydroxypropyl starch, low-substituted hydroxypropylcellulose, cross-linked sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, sucrose, dextrin, powdered sugar, glucose and the like of one or several material composition , belonging to the knowledge in the art.

[0087] 在本发明中,可药用载体或赋形剂可制成缓释制剂,包括赋形剂和辅料等。 [0087] In the present invention, pharmaceutically acceptable carrier or excipient may be sustained release formulations, comprising excipients and adjuvants, etc. 所述的赋形剂和辅料包括起缓释作用的辅料为羟丙甲基纤维素和/或乙基纤维素和/或聚丙烯酸树脂类和/或聚羧乙烯类和/或海藻酸的可溶性/不溶性盐和/或乙基纤维素和/或其他起缓释作用的辅料,羟丙甲纤维素采用内含羟丙甲基纤维素(HPMC)的各种商品,乙基纤维素采用内含乙基纤维素(EC)的各种商品,聚丙烯酸树脂采用内含聚丙烯酸树脂II、III类或类似物如各种规格的丙烯酸树脂(Eudragit)。 Comprising excipients and auxiliaries of the sustained release excipient is from hydroxypropyl methylcellulose and / or ethylcellulose soluble and / or polyacrylic acid resins and / or carbopol-based and / or alginic acid / insoluble salts and / or ethyl cellulose and / or sustained release action of the other starting materials, using hypromellose containing hydroxypropylmethyl cellulose (HPMC) of various commodities, using ethyl cellulose containing ethyl cellulose (EC) of various commodities, using polyacrylic resin containing a polyacrylic resin II, III, or the like, such as a variety of acrylic resin (Eudragit). 上述的辅料为致孔剂、粘合剂、润滑剂、乳化剂、膜材料、发泡剂、助漂剂、溶剂或其他辅料,致孔剂可采用蔗糖、甘露醇、淀粉、滑石粉、 二氧化硅等;粘合剂可采用乙醇_水溶液;润滑剂可采用硬脂酸、硬脂酸镁、滑石粉、淀粉、 石蜡等;增溶剂可采用酒石酸、柠檬酸等;乳化剂可采用span80\span85等;膜材料可采用聚乙烯醇、羟甲纤维素、羟乙纤维素、羟乙甲纤维素、甲基纤维素等;发泡剂可采用碱式碳酸镁、碳酸氢钠等;助漂剂可采用十六醇、十八醇、蜂蜡等;溶剂可采用无水乙醇、乙醇、水等。 Above porogen excipients, binders, lubricants, emulsifiers, film material, a foaming agent, rinse aid, solvents or other excipients, the porogen can be sucrose, mannitol, starch, talc, titanium silicon oxide; _ aqueous ethanol may be employed a binder; lubricants employed stearate, magnesium stearate, talc, starch, paraffin and the like; solubilizing agents may be employed tartaric acid, citric acid and the like; emulsifier employed Span80 \ span85 like; polyvinyl alcohol film material may be employed, hydroxymethyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl acetate, methyl cellulose, methyl cellulose and the like; blowing agent can be basic magnesium carbonate, sodium hydrogencarbonate and the like; rinse aid agents may be employed cetyl alcohol, stearyl alcohol, beeswax and the like; solvent can be ethanol, ethanol, water and the like.

[0088] 在本发明中,可药用载体或赋形剂可制成控释制剂,包括活性药物及起控释作用的辅料。 [0088] In the present invention, a pharmaceutically acceptable carrier or excipient may be made a controlled release formulation, including the active drug release and play the role of adjuvant. 上述起控释作用的辅料为聚氧乙烯和/或羟丙甲纤维素和/或乙基纤维素和/或氯化钠和/或乳糖和/或甘露醇和/或果糖和/或葡萄糖和/或蔗糖或低取代羟丙基纤维素和/或交联羧甲基纤维素钠和/或交联聚乙烯吡咯烷酮和/或醋酸纤维素。 Controlled release from the above-described excipients polyoxyethylene and / or hydroxypropylmethyl cellulose and / or ethyl cellulose and / or sodium chloride and / or lactose and / or mannitol and / or fructose and / or glucose and / or sucrose, or low-substituted hydroxypropylcellulose and / or crosslinked sodium carboxymethyl cellulose and / or crosslinked polyvinylpyrrolidone and / or cellulose acetate. 上述的辅料为药物载体、膨胀材料、助渗剂、增溶剂、粘合剂、润湿剂、润滑剂、着色剂、致孔剂、膜材料、 抗粘剂、增塑剂、避光剂、溶剂。 Accessories for the above-described pharmaceutical carrier, the expandable material, penetration aids, solubilizers, binders, wetting agents, lubricants, colorants, porogen, a film material, anti-sticking agents, plasticizers, dark agent, solvent. 药物载体、膨胀材料可采用聚氧乙烯、羟丙甲纤维素、乙基纤维素、羟丙基纤维素,甲基纤维素、山嵛酸甘油酯类等;助渗剂可采用氯化钠、乳糖、甘露醇等;增溶剂可采用十二烷基硫酸钠或泊洛沙姆等;粘合剂可采用聚乙烯吡咯烷酮、羟丙甲纤维素、甲壳胺、海藻酸钠、甲基纤维素,乙基纤维素,淀粉浆,阿拉伯胶,明胶,蔗糖,聚乙烯醇等;润湿剂可采用无水乙醇、水、各种浓度的乙醇-水溶液;润滑剂可采用硬脂酸、硬脂酸镁、滑石粉、淀粉、石蜡等;着色剂可采用胭脂红、苋菜红、柠檬黄、亮兰、靛兰、棕红色氧化铁等天然色素和合成色素等等;致孔剂可采用蔗糖、甘露醇、聚乙二醇、二氧化钛、滑石粉、二氧化硅等;膜材料可采用醋酸纤维素、乙基纤维素、羟丙基甲基纤维素醋酸琥珀酸酯、邻苯二甲酸醋酸纤维素、聚邻苯二甲酸乙酸乙烯 Pharmaceutical carrier, the expandable material may be employed polyethylene oxide, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose, glycerol behenate the like; sodium chloride may be employed penetration aids, lactose, mannitol and the like; sodium lauryl sulfate may be employed solubilizer poloxamer or the like; binders can be polyvinylpyrrolidone, hydroxypropylmethyl cellulose, chitosan, sodium alginate, methyl cellulose, ethyl cellulose, starch paste, gum arabic, gelatin, sucrose, polyvinyl alcohol and the like; wetting agent may be used ethanol, water, and various concentrations of ethanol - water; lubricants employed stearate, stearic acid magnesium, talc, starch, paraffin and the like; colorant employed carmine, amaranth, tartrazine, brilliant blue, indigo, red iron oxide brown pigment and other natural and synthetic pigments and the like; porogen employed sucrose, mannitol alcohols, polyethylene glycol, titanium dioxide, talc, silica and the like; film material can be cellulose acetate, ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, poly vinyl acetate phthalate 纤维素、羟丙基纤维素、羟乙基纤维素等;溶剂可采用丙酮、无水乙醇、乙醇、水等。 Cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and the like; solvent can be acetone, ethanol, ethanol, water and the like. [0089] 在本发明中,可药用载体或赋形剂可制成舌下含片、口腔速崩片或分散片等;包括赋形剂和辅料等。 [0089] In the present invention, pharmaceutically acceptable carriers or excipients, etc. can be made sublingual tablets, orally rapidly disintegrating tablets or dispersible tablets; comprising excipients and adjuvants, etc. 所述的赋形剂和辅料由甘露醇、木糖醇、低取代羟丙基甲基纤维素、微晶纤维素、羧甲基淀粉钠、交联羧甲纤维素钠、交联聚乙烯吡咯烷酮、处理琼脂、环糊精、甘草酸、甜菊苷、柠檬酸、薄荷油、桉叶油、丁香油、柠檬油、桔子油以及其它一些用微囊包裹的矫味剂等。 By the excipient and the excipient mannitol, xylitol, low-substituted hydroxypropylmethyl cellulose, microcrystalline cellulose, sodium carboxymethyl starch, croscarmellose sodium, cross-linked polyvinyl pyrrolidone processing agar, cyclodextrin, glycyrrhizin, stevioside, citric acid, peppermint oil, eucalyptus oil, clove oil, lemon oil, orange oil, and the other with the microencapsulated flavoring agents.

[0090] 在本发明中,可药用载体或赋形剂可制成肠溶片或肠溶胶囊等,包括赋形剂和辅料等,所述的赋形剂和辅料有淀粉、微晶纤维素、无机盐类、羟丙基甲基纤维素、乙基纤维素、聚丙烯酸树脂类、聚羧乙烯类、海藻酸的可溶性/不溶性盐类、十八醇、十八酸、氯化钠、 半胱氨酸、柠檬酸和亚硫酸钠等的一种或几种物质的组合物,肠溶包衣材料包括:虫胶、醋酸纤维素酞酸酯、丙烯酸树脂类(如Eudragit L和S型等)、聚醋酸乙烯苯二甲酸酯、邻苯二甲酸羟丙甲纤维素酯、琥珀酸醋酸羟丙甲基纤维素,以及增塑剂(如邻苯二甲酸二乙酯、 聚乙二醇、丙二醇、甘油三乙酸酯、邻苯二甲酸二甲酯、癸二酸二丁酯、柠檬酸三乙酯、柠檬酸三丁酯、乙酰基柠檬酸三乙酯、蓖麻油和各种百分比的乙酰化单酸甘油酯等)与致孔剂(如PEG6000)等多种药剂学辅料。 [0090] In the present invention, pharmaceutically acceptable carrier or excipient may be made enteric-coated tablets or enteric capsules or the like, and the like comprising excipients and auxiliaries, excipients and auxiliaries of the starch, microcrystalline cellulose Su, inorganic salts, hydroxypropylmethyl cellulose, ethyl cellulose, polyacrylic acid resins, carbopol-based, alginic acid soluble / insoluble salts, stearyl alcohol, stearic acid, sodium chloride, cysteine, citric acid, sodium sulfite and the like of one or several material composition, the enteric coating materials include: shellac, cellulose acetate phthalate, acrylic resins (e.g. Eudragit L and S, etc.) , polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate, hydroxypropylmethyl cellulose acetate succinate, and a plasticizer (e.g. diethyl phthalate, polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, castor oil and varying percentages of acetylated monoglycerides and the like) with porogen (e.g. of PEG6000), and other pharmaceutical adjuvants.

[0091] 在本发明中,可药用载体或赋形剂可制成延迟释放片或定时(位)释放片,包括赋形剂和辅料,所述的赋形剂和辅料有淀粉、微晶纤维素、无机盐类、羟丙基甲基纤维素、乙基纤维素、聚丙烯酸树脂类、聚羧乙烯类、海藻酸的可溶性/不溶性盐类、十八醇、十八酸、 氯化钠、半胱氨酸、柠檬酸和亚硫酸钠等的一种或几种物质的组合物,所述的起延迟释放或定时(位)释放的包衣材料包括:虫胶、醋酸纤维素酞酸酯、乙基纤维素、羟丙基甲基纤维素、羟丙基纤维素、丙烯酸树脂类(如Eudragit L和S型等)、聚醋酸乙烯苯二甲酸酯、邻苯二甲酸羟丙甲纤维素酯、琥珀酸醋酸羟丙甲基纤维素、聚醋酸乙烯苯二甲酸酯、以及增塑剂(如邻苯二甲酸二乙酯、聚乙二醇、丙二醇、甘油三乙酸酯、邻苯二甲酸二甲酯、癸二酸二丁酯、柠檬酸三乙酯、柠檬酸三丁 [0091] In the present invention, pharmaceutically acceptable carrier or excipient may be made of a sheet or delayed release timing (position) release tablet comprising excipients and auxiliaries, excipients and auxiliaries according starch, microcrystalline cellulose, inorganic salts, hydroxypropylmethyl cellulose, ethyl cellulose, polyacrylic acid resins, carbopol-based, alginic acid soluble / insoluble salts, stearyl alcohol, stearic acid, sodium , cysteine, citric acid, sodium sulfite and the like of one or several composition of matter, or delayed release from the timing (position) release coating materials include: shellac, cellulose acetate phthalate, ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, acrylic resins (e.g. Eudragit L and S, etc.), polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate esters, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, and a plasticizer (e.g. diethyl phthalate, polyethylene glycol, propylene glycol, triacetin, phthalic dicarboxylate, dibutyl sebacate, triethyl citrate, tributyl citrate 、乙酰基柠檬酸三乙酯、蓖麻油和各种百分比的乙酰化单酸甘油酯等)与致孔剂(如PEG1000、PEG4000、PEG6000)等多种药剂学辅料。 , Acetyl triethyl citrate, castor oil and varying percentages of acetylated monoglycerides and the like) with a porogen (e.g., PEG1000, PEG4000, PEG6000) and other pharmaceutical adjuvants.

[0092] 在本发明中,可药用载体或赋形剂可制成缓释胶囊、控释胶囊,含有微丸或小片的胶囊,含有微丸或小片的PH依赖型胶囊等,包括赋形剂和辅料,所述的赋形剂和辅料有淀粉、微晶纤维素、无机盐类、羟丙基甲基纤维素、乙基纤维素、聚丙烯酸树脂类、聚羧乙烯类、 海藻酸的可溶性/不溶性盐类、十八醇、十八酸、氯化钠、半胱氨酸、柠檬酸和亚硫酸钠等的一种或几种物质的组合物,包衣材料包括:虫胶、醋酸纤维素酞酸酯、乙基纤维素、羟丙基甲基纤维素、羟丙基纤维素、丙烯酸树脂类(如Eudragit L和S型等)、聚醋酸乙烯苯二甲酸酯、邻苯二甲酸羟丙甲纤维素酯、琥珀酸醋酸羟丙甲基纤维素、聚醋酸乙烯苯二甲酸酯、以及增塑剂(如邻苯二甲酸二乙酯、聚乙二醇、丙二醇、甘油三乙酸酯、邻苯二甲酸二甲酯、癸二酸二丁酯、柠檬酸三乙酯、柠 [0092] In the present invention, pharmaceutically acceptable carrier or excipient may be sustained release capsules, controlled release capsules, capsules containing pellets or tablets, the pellets or small tablets containing PH dependent capsules and the like, comprising a shaped agents and excipients, said excipients and auxiliaries starch, microcrystalline cellulose, inorganic salts, hydroxypropylmethyl cellulose, ethyl cellulose, polyacrylic acid resins, carbopol-based, alginic acid soluble / insoluble salts, stearyl alcohol, stearic acid, sodium chloride, cysteine, citric acid, sodium sulfite and the like of one or several material composition, coating material comprising: shellac, cellulose acetate phthalate, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, acrylic resins (e.g. Eudragit L and S, etc.), polyvinyl acetate phthalate, hydroxypropyl phthalate methylcellulose acetate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, and a plasticizer (e.g. diethyl phthalate, polyethylene glycol, propylene glycol, glycerol triacetate esters, dimethyl phthalate, dibutyl sebacate, triethyl citrate, citraconic 檬酸三丁酯、乙酰基柠檬酸三乙酯、蓖麻油和各种百分比的乙酰化单酸甘油酯等)与致孔剂(如PEG6000)等多种药剂学辅料。 Citric acid tributyl, triethyl acetyl citrate, castor oil and varying percentages of acetylated monoglycerides and the like) with a porogen (e.g. of PEG6000), and other pharmaceutical adjuvants.

[0093] 在本发明中,可药用载体或赋形剂可制成口服液、膜剂、贴剂等剂型。 [0093] In the present invention, pharmaceutically acceptable carrier or excipient may be made of oral, films, patches and the like dosage forms. 制成贴剂膜剂时所述药学上可接受的载体包括有助于将活性化合物配制成药用制剂的赋形剂和辅料, 如聚乙烯醇、三醋酸纤维素、乙烯一醋酸乙烯共聚物、聚乙烯呲咯烷酮、聚丙烯酰胺、聚乙丁烯类压敏胶、丙烯酸树脂类压敏胶、硅酮类压敏胶等,以及聚氯乙烯、聚乙烯、铝箔、聚丙烯、 聚酯等背衬材料,聚乙烯、聚苯乙烯、聚丙烯等保护膜等的一种或几种物质的组合物。 When the patch preparation of the film former comprises pharmaceutically acceptable carriers facilitate active compounds are formulated into pharmaceutical excipients and auxiliaries of the formulation, such as polyvinyl alcohol, cellulose triacetate, ethylene-vinyl acetate copolymer, bared polyvinyl pyrrolidone, polyacrylamide, polyethylene butenes pressure-sensitive adhesive, acrylic resin pressure-sensitive adhesive, silicone-based pressure-sensitive adhesive and the like, as well as polyvinyl chloride, polyethylene, aluminum foil, polypropylene, polyester like backing material, polyethylene, polystyrene, polypropylene, one or several substances like a protective film composition. [0094] 根据本发明,药物组合物中磺脲类降糖药物或该磺脲类降糖药物的活性代谢产物或该磺脲类降糖药物的可药用盐、噻唑烷二酮类降糖药物或该噻唑烷二酮类降糖药物的可药用盐和B族维生素或与其相关的具有相似生物活性的化合物三个组成成分也可以分别制成制剂,做成联合包装形式给药;或者是任意两个组成成分做成制剂与第三个组成成分做成的制剂的联合包装形式。 [0094] According to the present invention, the active metabolite of a pharmaceutical composition of the sulfonylureas or sulfonylurea drugs or sulfonylureas the pharmaceutically acceptable salts, hypoglycemic thiazolidine diones the drug or thiazolidine diones hypoglycemic drugs and pharmaceutically acceptable salts of B vitamins or related compounds having biological activity similar three components may be formulated separately, administration made joint packaging; or any two joint components is made in the form of packaged formulation third formulation components made of.

[0095] 本发明提供的药物组合物中的化合物以相同的制剂形式可以同时施与患病个体, 也可分别地相继施与患病个体。 [0095] The pharmaceutical compositions of the present invention is provided in the same form preparations may be administered simultaneously diseased individuals, may be separately administered sequentially diseased individuals. 若是相继施与患病个体,则后两个(或附加的)活性成分施与的延迟不应当导致活性成分联合带来的有益效果的损失。 If the administration have been diseased individuals, the latter two (or additional) active ingredient administered delay should not lead to loss of active ingredient beneficial effects of the joint. 若是同时施与患病个体,组合物中的化合物可以混合存在于同一个药物制剂形式中,也可以以同样的制剂形式分别独立存在。 If diseased individuals administered simultaneously, the compounds in the composition may be mixed in the same form of pharmaceutical preparations may be in the same form preparations exist individually. 若是以同样的制剂形式分别独立存在,则药物组合物可以变通的以“组合药盒”形式存在。 If the preparations are in the same form of independent existence, the pharmaceutical compositions may be present in varying "combination kit" form. “组合药盒”是一种盒状容器,内置一种或多种剂量形式的药物组合,及其使用说明书。 "Combination kit" is a box-like container, one or more built-dosage form pharmaceutical compositions, and instructions for use. 在本发明中优选所述的药用剂量的磺脲类降糖药物中的一种或该磺脲类降糖药物的活性代谢产物或该磺脲类降糖药物的可药用盐、药用剂量的噻唑烷二酮类降糖药物中的一种或该噻唑烷二酮类降糖药物的可药用盐、药用剂量的B族维生素或与其相关的具有相似生物活性的化合物组成的复方片剂。 In the present invention, one kind of active metabolites in pharmaceutical doses of sulfonylureas in the preferred or the sulfonylureas of the sulfonylureas or a pharmaceutically acceptable salt, pharmaceutically acceptable one dose thiazolidine diones hypoglycemic medicament or the thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt, pharmaceutical dosage of B vitamins or related compound with similar biological activity of the compound having the composition tablet.

[0096] 本发明提供的药物组合物中的化合物以不相同的制剂形式可以同时施与患病个体,也可分别地相继施与患病个体。 [0096] The pharmaceutical compositions of the present invention are not provided in the same form preparations may be administered simultaneously diseased individuals, may be separately administered sequentially diseased individuals. 若是相继施与患病个体,则后两个(或附加的)活性成分施与的延迟不应当导致活性成分联合带来的有益效果的损失。 If the administration have been diseased individuals, the latter two (or additional) active ingredient administered delay should not lead to loss of active ingredient beneficial effects of the joint. 若是同时施与患病个体, 组合物中的化合物以不同的制剂形式独立存在,药物组合物也可以变通的以“组合药盒”形式存在。 If diseased individuals administered simultaneously, the compounds exist independently in the composition in various preparation forms, there are present pharmaceutical compositions may also work in "combination kit" form. “组合药盒”是一种盒状容器,内置一种或多种剂量形式的药物组合,及其使用说明书。 "Combination kit" is a box-like container, one or more built-dosage form pharmaceutical compositions, and instructions for use.

[0097] 在实验研究中,我们惊奇地发现,以上述药用剂量的磺脲类降糖药物或该磺脲类降糖药物的活性代谢产物或该磺脲类降糖药物的可药用盐、药用剂量的噻唑烷二酮类降糖药物或该噻唑烷二酮类降糖药物的可药用盐和药用剂量的B族维生素或与其相关的具有相似生物活性的化合物为组分的药物组合物对治疗糖尿病或预防糖尿病并发症具有显著的效果。 [0097] In the experimental study, we have surprisingly found that the active metabolite sulfonylureas or dose of the aforementioned pharmaceutical sulfonylureas of the sulfonylureas or a pharmaceutically acceptable salt , the pharmaceutical dosage thiazolidine diones hypoglycemic drugs or the thiazolidine diones hypoglycemic drugs may B vitamins pharmaceutically acceptable salts and its dosage or related compounds having similar biological activity as the component the pharmaceutical composition has a significant effect complications of diabetes treating or preventing diabetes.

[0098] 本发明提供的药物组合物中的组分之一是磺脲类降糖药物。 [0098] one of the components of the pharmaceutical compositions of the invention are provided sulfonylureas. 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(HbAlc)下降1.0%〜2.5%。 For the majority of type 2 diabetic patients newly diagnosed, sulfonylureas can cause decreased fasting glucose 50~80mg / dl, glycated hemoglobin (HbAIc) decreased by 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。 Because the β-cell function in patients with type 2 diabetes and decay over time, sulfonylurea drugs clinically newly diagnosed diabetic patients reduced blood very effective. 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。 Various sulfonylureas by closing down the β cell membrane ATP-sensitive potassium (Katp) channel to increase endogenous insulin secretion. 磺脲类降糖药物与Katp通道的磺脲受体1 (SURl)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。 Sulfonylureas and Katp channel sulfonylurea receptor 1 (SURl) K + channel binding off, so that part of the region on the membrane to cause the voltage-dependent L- type Ca2 + channel opening polarization, Ca2 + into the cell, the cytoplasm the Ca2 + concentration, thereby stimulating insulin secretion. 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。 As a non-sulfonylurea drugs are the treatment of overweight or obese patients with type 2 diabetes in first-line treatment. 本发明提供的药物组合物中的组分之二是噻唑烷二酮类降糖药物,临床上用于治疗2型糖尿病。 The two-component pharmaceutical compositions of the invention are provided thiazolidine diones hypoglycemic drugs, used clinically for the treatment of type 2 diabetes. 该类药物亦称胰岛素增敏剂,为细胞核过氧化酶体增殖因子活化受体(PPAR-Y)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。 When the liver of these drugs, also known as insulin sensitizers, peroxisome proliferating cell nuclear factor ligand receptor activation (PPAR-Y), the ability to increase the clearance of glucose in peripheral tissues, reducing hepatic glucose output, increased glucose load sugar intake, so as to effectively lower blood sugar, improve insulin sensitivity. 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,故在胰岛素缺乏时单独使用该药不能降血糖。 Thiazole TZDs hypoglycemic effect by enhancing the effects of insulin is achieved, it is used alone in the absence of the drug can not be insulin hypoglycemic. 本发明提供的药物组合物中的组分之三是B族维生素中的一种,B族维生素是人体必需的营养素,对生命体新陈代谢、红细胞形成、保持神经系统和免疫系统功能具有重要作用,更为重要的是对同型半胱氨酸具有降低作用。 The three-component pharmaceutical compositions of the invention are provided in a B vitamin A, B vitamins are essential nutrients for living body metabolism, red blood cell formation, maintaining nervous system and the immune system plays an important role, more importantly, with a lowering effect on homocysteine.

[0099] 在临床实践或者是已经发表的文献中,我们尚没有发现磺脲类降糖药物或该磺脲类降糖药物的活性代谢产物或该磺脲类降糖药物的可药用盐、噻唑烷二酮类降糖药物或该噻唑烷二酮类降糖药物的可药用盐与B族维生素或与其相关的具有相似生物活性的化合物三种组分联合应用用于治疗糖尿病或预防糖尿病并发症的报道。 [0099] In clinical practice or published literature, we have not yet found that the active metabolite of sulfonylurea drugs or the sulfonylurea medicine or the sulfonylureas pharmaceutically acceptable salt, thiazolidine diones hypoglycemic drugs or the thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt, or B vitamins associated therewith a compound having biological activity similar three components in combination for treating diabetes or prophylaxis of diabetes complications were reported. 在实验研究中,我们惊奇地发现,以药用剂量的磺脲类降糖药物或该磺脲类降糖药物的活性代谢产物或该磺脲类降糖药物的可药用盐、药用剂量的噻唑烷二酮类降糖药物或该噻唑烷二酮类降糖药物的可药用盐和药用剂量的B族维生素或与其相关的具有相似生物活性的化合物为活性成分的药物组合物可以明显降低2型糖尿病患者的血糖,同时补充体内叶酸和B12等维生素水平, 有效改善2型糖尿病患者胰岛素抵抗状态及血浆同型半胱氨酸水平,而且三药单独应用均不能达到此三种物质联合应用的效果。 In the experimental study, we have surprisingly found that the active metabolite sulfonylureas or the pharmaceutically acceptable doses of sulfonylureas of the sulfonylureas or a pharmaceutically acceptable salt, pharmaceutical dosage the thiazolidine diones hypoglycemic drugs or the thiazolidine diones B vitamins hypoglycemic drugs pharmaceutically acceptable salts and pharmaceutically acceptable amount of a compound similar to or associated with the biological activity of the active ingredients of the pharmaceutical compositions can significantly lower blood glucose in type 2 diabetic patients, and vitamin B12 and folic acid levels, improve insulin resistance in type 2 diabetic patients and plasma homocysteine ​​levels, and three drugs alone can not achieve this joint three substances the effect of the application. 试验结果表明,磺脲类降糖药物或该磺脲类降糖药物的活性代谢产物或该磺脲类降糖药物的可药用盐、噻唑烷二酮类降糖药物或该噻唑烷二酮类降糖药物的可药用盐与B族维生素或与其相关的具有相似生物活性的化合物三种物质联合应用除可有效控制糖尿病患者血糖外,可协同保护内皮细胞功能,并可减少糖尿病慢性并发症的发生,优于任一药物单用或任两个药物合用,具有有效治疗糖尿病或预防糖尿病并发症的作用(见实施例)。 The results showed that the active metabolite of the sulfonylureas or sulfonylurea drugs or sulfonylureas the pharmaceutically acceptable salts, thiazolidine diones hypoglycemic drugs or the thiazolidinedione class of antidiabetic drugs a pharmaceutically acceptable salt B vitamins or related compound with similar biological activity three materials in combination in addition to effectively control blood sugar in diabetic patients, the endothelial cells may be synergistic protection, and reduce the diabetic chronic complicated disease occurs, than either alone or in combination of any two drugs, an effective therapeutic prevention of diabetes or a diabetic complication drugs effects (see Examples).

[0100] 内皮细胞的功能被赋予特殊的临床意义是因为:(1)内皮细胞参与动脉粥样硬化形成的各期;(2)许多典型的危险因素和非典型的心血管疾病的危险因素与内皮功能失调有关;(3)内皮功能失调在大动脉粥样硬化前已发生,且可预示动脉粥样硬化的发生。 [0100] endothelial cell function has been given a special clinical significance because: (1) endothelial cells involved in atherosclerosis each kind of hardening is formed; risk factors (2) number of typical and atypical risk factors for cardiovascular disease and For endothelial dysfunction; (3) endothelial dysfunction in atherosclerosis occurs in the aorta before curing, and may indicate the occurrence of atherosclerosis. 内皮细胞损伤与高血压、糖尿病的发生、发展密切相关;有学者将高血压、冠心病、脑梗塞(脑动脉硬化)、糖尿病等列为“血管内皮细胞功能障碍性疾病”,认为这四种病的临床改变、发病机理、病理改变及治疗方法虽不尽相同,但均存在血管内皮细胞障碍,主要表现为血清NO 减低。 Endothelial cell damage and high blood pressure, diabetes, closely related to development; some scholars have high blood pressure, coronary heart disease, cerebral infarction (cerebral arteriosclerosis), diabetes as a "vascular endothelial cell function disorders" that these four change of clinical disease, pathogenesis, pathology and treatment, though not the same, but the obstacles are present in vascular endothelial cells, mainly to reduce the level of NO. 本发明提供的药物组合物可协同改善内皮细胞功能,减少并发症的发生,更好保护患者靶器官,同时该组合物亦可减轻患者经济负担,提高患者对治疗的依从性,因而对该组合物的深入开发具有重要的社会意义和经济价值。 The present invention provides a pharmaceutical composition synergistically improve endothelial function, reduce the incidence of complications, the patient to better protect the target organ, the composition may also simultaneously reduce the financial burden of patients to improve patient compliance with the treatment, and thus the composition in-depth development of material has important social significance and economic value.

[0101] 根据本发明,在该组合物对治疗糖尿病或预防糖尿病并发症的作用机制的研究中,我们发现:本发明提供的药物组合物药用效果并非是组成成分药效的简单相加,而是通过三类活性成分与生命体的相互作用改变原有有益效应而发挥药效的。 [0101] According to the present invention, in the study of the mechanism of action of the compositions for treating diabetes or the prevention of diabetic complications, we find: The pharmaceutical compositions of the present invention provides a pharmaceutical effect is not a simple sum of components efficacy, but changing the original three beneficial effects by interacting with the active ingredient of life on the efficacy of play. 其作用机制尚不清楚,可能和三者合用后可更好发挥抗氧化、作用于内皮细胞功能不同环节等机制有关。 Its mechanism of action is unclear, and may be better to play after three combined antioxidant concerned with the effects on endothelial cell function and other aspects of different mechanisms. 本发明中公开的药物组合物的用途是用于制备治疗糖尿病或预防糖尿病并发症的药物。 Pharmaceutical composition of the present invention is disclosed in the preparation of a medicament for the treatment or prevention of diabetic complications of diabetes.

[0102] 在本发明中,所述的糖尿病是指一组由于胰岛素分泌缺陷和/或其生物学作用障碍引起的以高血糖为特征的代谢性疾病,包括胰岛素依赖型糖尿病(IDDM,1型)、非胰岛素依赖型糖尿病(NIDDM,2型)、营养不良性糖尿病(MRDM,3型)、继发性糖尿病、糖耐量减低(IGT)及妊娠糖尿病(GDM),尤指2型糖尿病。 [0102] In the present invention, the diabetes is a group due to the defects in insulin secretion and / or biological action due to disorder characterized by hyperglycemia metabolic disorders, including insulin dependent diabetes mellitus (of IDDM, Type 1 ), non-insulin dependent diabetes mellitus (of NIDDM, type 2), malnutrition, diabetes (MRDM, 3 type), secondary diabetes, impaired glucose tolerance (IGT) and gestational diabetes mellitus (of GDM), especially type 2 diabetes.

[0103] 在本发明中,所述的糖尿病并发症包括慢性并发症和急性并发症,尤指慢性并发症;所述慢性并发症包括糖尿病心血管并发症、糖尿病肾病、糖尿病神经病变、糖尿病视网膜病变、糖尿病足、糖尿病皮肤病变等。 [0103] In the present invention, the diabetic complications include acute complications and chronic complications, especially chronic complications; the chronic complications of diabetes including cardiovascular complications, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy lesions, diabetic foot, diabetes and other skin lesions. [0104] 本发明所述的生命体是指对拥有生命的个体的一种描述,尤其指哺乳类动物,特别指人类。 [0104] living body according to the present invention refers to a description of the individual's own life, especially of mammals, particularly refers to a human.

[0105] 本发明的另一目的在于提供药物组合物在制备治疗糖尿病的药物中的用途;本发明的第三个目的在于提供药物组合物在制备预防糖尿病并发症的药物中的用途。 [0105] Another object of the present invention is to provide pharmaceutical compositions for use in a medicament for the treatment of diabetes; third object of the present invention is to provide a pharmaceutical composition in the manufacture of a medicament in the prevention of diabetic complications.

[0106] 本发明提供的用途中涉及的药物组合物的组分之一是磺脲类降糖药物,包括格列本脲、格列波脲、格列环脲、格列己脲、格列美脲、格列平脲、格列沙脲、格列生脲、格列索脲、 格列辛脲、格列齐特、格列吡嗪、和格列喹酮,优选格列本脲、格列美脲、格列齐特、格列喹酮或格列吡嗪,更加优选格列美脲;组分之二是噻唑烷二酮类降糖药物,包括罗格列酮、吡格列酮、曲格列酮、恩格列酮、环格列酮、马来酸罗格列酮、酒石酸罗格列酮、罗格列酮钠、盐酸罗格列酮、盐酸吡格列酮等,优选罗格列酮、马来酸罗格列酮、吡格列酮或盐酸吡格列酮;组分之三是B族维生素中的至少一种,所述B族维生素包括叶酸、维生素B12 (氰钴胺)、维生素B6 (吡哆醇)、维生素Bl (硫胺素)、维生素B2 (核黄素)、维生素B3 (烟酸)、泛酸及生物素,优选叶酸、维生素 [0106] The present invention provides the use of one of the components involved in the pharmaceutical composition is a sulfonylurea drugs, including glibenclamide, glibornuride, Glenn cyclic ureas, Glenn glipizide, glibenclamide glimepiride, glipizide flat urea, Ge Liesha urea, urea raw Glenn, glisolamide, Ge Liexin urea, gliclazide, glipizide, gliquidone and, preferably glyburide, glimepiride, gliclazide, gliquidone or glipizide, more preferably glimepiride; it is of the two-component thiazolidine diones hypoglycemic drugs, including rosiglitazone, pioglitazone, Qu glitazone, englitazone, ciglitazone, rosiglitazone maleate, tartrate rosiglitazone, rosiglitazone sodium, rosiglitazone hydrochloride, pioglitazone hydrochloride and the like, preferably rosiglitazone, maleate rosiglitazone, pioglitazone or hydrochloride pioglitazone; third component of at least one of the B vitamins in the B vitamins including folic acid, vitamin B12 (cyanocobalamin), vitamin B6 (pyridoxine) , vitamin Bl (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), pantothenic acid and biotin, preferably folic acid, vitamin B12和维生素B6,更加优选叶酸。 B12 and vitamin B6, folic acid is more preferable.

[0107] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为叶酸。 Pharmaceutical compositions [0107] The present invention provides, a sulfonylurea agent is glimepiride, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and folic acid. 在该组合物中,格列美脲的含量为1mg〜4mg,罗格列酮的含量为1mg〜8mg,叶酸的含量为0. 1mg〜7. 5mg。 In this composition, the amount of glimepiride is 1mg~4mg, rosiglitazone content 1mg~8mg, folic acid content is 0. 1mg~7. 5mg.

[0108] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为叶酸。 [0108] The pharmaceutical compositions provided by the invention, the drug is a sulfonylurea glimepiride, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B Group vitamin folic acid. 在该组合物中,格列美脲的含量为1mg〜4mg,马来酸罗格列酮的含量为相当于1mg〜8mg的罗格列酮,叶酸的含量为0. 1mg 〜7. 5mg0 In this composition, the amount of glimepiride is 1mg~4mg, rosiglitazone maleate content corresponds 1mg~8mg rosiglitazone, folic acid content is 0. 1mg ~7. 5mg0

[0109] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为叶酸。 [0109] The pharmaceutical compositions provided by the invention, the drug is a sulfonylurea glimepiride, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and folic acid. 在该组合物中,格列美脲的含量为1mg〜4mg,吡格列酮的含量为7. 5mg〜45mg,叶酸的含量为0. 1mg〜7. 5mg。 In this composition, the amount of glimepiride is 1mg~4mg, the content of pioglitazone 7. 5mg~45mg, folic acid content is 0. 1mg~7. 5mg.

[0110] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列美脲,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为叶酸。 [0110] The pharmaceutical compositions provided by the invention, the drug is a sulfonylurea glimepiride, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and folic acid. 在该组合物中,格列美脲的含量为1mg〜4mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,叶酸的含量为0. 1mg 〜7. 5mg0 In this composition, the amount of glimepiride is 1mg~4mg, pioglitazone hydrochloride pyrazole in an amount of equivalent of 7. 5mg~45mg pioglitazone, folic acid content is 0. 1mg ~7. 5mg0

[0111] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为叶酸。 [0111] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glyburide, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and folic acid. 在该组合物中,格列本脲的含量为1mg〜15mg, 罗格列酮的含量为1mg〜8mg,叶酸的含量为0. 1mg〜7. 5mg。 In this composition, the content of glibenclamide is 1mg~15mg, rosiglitazone content 1mg~8mg, folic acid content is 0. 1mg~7. 5mg.

[0112] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为叶酸。 [0112] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glyburide, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B Group vitamin folic acid. 在该组合物中,格列本脲的含量为1mg〜15mg,马来酸罗格列酮的含量为相当于1mg〜8mg的罗格列酮,叶酸的含量为0. 1mg 〜7. 5mg0 In this composition, the content of glibenclamide is 1mg~15mg, rosiglitazone maleate content corresponds 1mg~8mg rosiglitazone, folic acid content is 0. 1mg ~7. 5mg0

[0113] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为叶酸。 [0113] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glyburide, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and folic acid. 在该组合物中,格列本脲的含量为1mg〜15mg, 吡格列酮的含量为7. 5mg〜45mg,叶酸的含量为0. 1mg〜7. 5mg。 In this composition, the content of glibenclamide is 1mg~15mg, the content of pioglitazone 7. 5mg~45mg, folic acid content is 0. 1mg~7. 5mg.

[0114] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列本脲,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为叶酸。 [0114] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glyburide, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and folic acid. 在该组合物中,格列本脲的含量为Img〜15mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,叶酸的含量为0. Img 〜7. 5mg0 In this composition, the content of glibenclamide is Img~15mg, pioglitazone hydrochloride pyrazole in an amount of equivalent of 7. 5mg~45mg pioglitazone, folic acid content is 0. Img ~7. 5mg0

[0115] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为叶酸。 [0115] The pharmaceutical compositions provided by the invention, the sulfonylurea drugs gliclazide, thiazolidine diones as hypoglycemic drugs rosiglitazone, rosiglitazone, B vitamins and folic acid. 在该组合物中,格列齐特的含量为20mg〜160mg, 罗格列酮的含量为Img〜8mg,叶酸的含量为0. Img〜7. 5mg。 In this composition, the amount of gliclazide is 20mg~160mg, rosiglitazone content Img~8mg, folic acid content is 0. Img~7. 5mg.

[0116] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为叶酸。 [0116] The pharmaceutical compositions provided by the invention, the sulfonylurea drugs gliclazide, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B Group vitamin folic acid. 在该组合物中,格列齐特的含量为20mg〜160mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,叶酸的含量为0. Img 〜7. 5mg0 In this composition, the amount of gliclazide is 20mg~160mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, folic acid content is 0. Img ~7. 5mg0

[0117] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为叶酸。 Pharmaceutical compositions provided herein [0117] In the present, sulfonylurea drugs gliclazide, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and folic acid. 在该组合物中,格列齐特的含量为20mg〜160mg, 吡格列酮的含量为7. 5mg〜45mg,叶酸的含量为0. Img〜7. 5mg。 In this composition, the amount of gliclazide is 20mg~160mg, the content of pioglitazone 7. 5mg~45mg, folic acid content is 0. Img~7. 5mg.

[0118] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列齐特,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为叶酸。 [0118] The pharmaceutical compositions provided by the invention, the sulfonylurea drugs gliclazide, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and folic acid. 在该组合物中,格列齐特的含量为20mg〜160mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,叶酸的含量为0. Img 〜7. 5mg0 In this composition, the amount of gliclazide is 20mg~160mg, pioglitazone hydrochloride pyrazole in an amount of equivalent of 7. 5mg~45mg pioglitazone, folic acid content is 0. Img ~7. 5mg0

[0119] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为叶酸。 [0119] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and folic acid. 在该组合物中,格列喹酮的含量为15mg〜60mg, 罗格列酮的含量为Img〜8mg,叶酸的含量为0. Img〜7. 5mg。 In this composition, the content of gliquidone is 15mg~60mg, rosiglitazone content Img~8mg, folic acid content is 0. Img~7. 5mg.

[0120] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为叶酸。 [0120] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B Group vitamin folic acid. 在该组合物中,格列喹酮的含量为15mg〜60mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,叶酸的含量为0. Img 〜7. 5mg0 In this composition, the content of gliquidone is 15mg~60mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, folic acid content is 0. Img ~7. 5mg0

[0121] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为叶酸。 [0121] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and folic acid. 在该组合物中,格列喹酮的含量为15mg〜60mg, 吡格列酮的含量为7. 5mg〜45mg,叶酸的含量为0. Img〜7. 5mg。 In this composition, the content of gliquidone is 15mg~60mg, the content of pioglitazone 7. 5mg~45mg, folic acid content is 0. Img~7. 5mg.

[0122] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列喹酮,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为叶酸。 [0122] The pharmaceutical compositions provided by the invention, the sulfonylureas of gliquidone, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and folic acid. 在该组合物中,格列喹酮的含量为15mg〜60mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,叶酸的含量为0. Img 〜7. 5mg0 In this composition, the content of gliquidone is 15mg~60mg, pioglitazone hydrochloride pyrazole in an amount of equivalent of 7. 5mg~45mg pioglitazone, folic acid content is 0. Img ~7. 5mg0

[0123] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物为罗格列酮,B族维生素为叶酸。 [0123] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones as hypoglycemic drugs rosiglitazone, B vitamins and folic acid. 在该组合物中,格列吡嗪的含量为Img〜15mg, 罗格列酮的含量为Img〜8mg,叶酸的含量为0. Img〜7. 5mg。 In this composition, the amount of glipizide is Img~15mg, rosiglitazone content Img~8mg, folic acid content is 0. Img~7. 5mg.

[0124] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物的可药用盐为马来酸罗格列酮,B族维生素为叶酸。 [0124] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones hypoglycemic drugs pharmacologically acceptable salt is rosiglitazone maleate, B Group vitamin folic acid. 在该组合物中,格列吡嗪的含量为Img〜15mg,马来酸罗格列酮的含量为相当于Img〜8mg的罗格列酮,叶酸的含量为0. Img 〜7. 5mg0 In this composition, the amount of glipizide is Img~15mg, rosiglitazone maleate content corresponds Img~8mg rosiglitazone, folic acid content is 0. Img ~7. 5mg0

[0125] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物为吡格列酮,B族维生素为叶酸。 [0125] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones as hypoglycemic agents pioglitazone, B vitamins and folic acid. 在该组合物中,格列吡嗪的含量为Img〜15mg,吡格列酮的含量为7. 5mg〜45mg,叶酸的含量为0. 1mg〜7. 5mg。 In this composition, the amount of glipizide is Img~15mg, the content of pioglitazone 7. 5mg~45mg, folic acid content is 0. 1mg~7. 5mg.

[0126] 本发明提供的药物组合物的用途中,磺脲类降糖药物为格列吡嗪,噻唑烷二酮类降糖药物的可药用盐为盐酸吡格列酮,B族维生素为叶酸。 [0126] The pharmaceutical compositions provided by the invention, the sulfonylurea drug is glipizide, thiazolidine diones hypoglycemic drugs a pharmaceutically acceptable salt of pioglitazone hydrochloride, B vitamins and folic acid. 在该组合物中,格列吡嗪的含量为Img〜15mg,盐酸吡格列酮的含量为相当于7. 5mg〜45mg的吡格列酮,叶酸的含量为0. 1mg 〜7. 5mg0 In this composition, the amount of glipizide is Img~15mg, pioglitazone hydrochloride pyrazole in an amount of equivalent of 7. 5mg~45mg pioglitazone, folic acid content is 0. 1mg ~7. 5mg0

[0127] 本发明的有益效果: [0127] Advantageous effects of the invention:

[0128] 本发明提供了含有磺脲类降糖药物或该磺脲类降糖药物的活性代谢产物或该磺脲类降糖药物的可药用盐、噻唑烷二酮类降糖药物或该噻唑烷二酮类降糖药物的可药用盐和B族维生素或与其相关的具有相似生物活性的化合物的药物组合物。 [0128] The present invention provides an active metabolite or the sulfonylureas containing sulfonylureas or sulfonylurea drug the pharmaceutically acceptable salts, thiazolidine diones or the antidiabetic drugs thiazolidine diones hypoglycemic drugs and pharmaceutically acceptable salts of B vitamins or related compounds with similar biological activity pharmaceutical composition. 磺脲类降糖药物、 噻唑烷二酮类降糖药物和B族维生素的三种物质联合应用的效果并不是各个活性物质的各自作用的简单加和,该药物组合物可有效控制血糖,协同保护内皮细胞功能,减轻糖尿病患者特别是合并有慢性并发症的糖尿病患者血浆同型半胱氨酸升高,并可减少糖尿病并发症的发生,具体实施方式提供的试验说明,三种物质联合应用在各自技术效果的基础上,能发挥三种物质单独不具有的技术效果,因而达到协同作用。 Sulfonylureas, simple summation, the pharmaceutical composition is effective glycemic control between the three substances thiazolidine diones hypoglycemic drugs and B vitamins are not combined action of the respective individual active substances, synergistic protection of endothelial cells, especially to alleviate chronic complications associated with the diabetic plasma homocysteine ​​increased diabetes, diabetes complications and reduce the test illustrate specific embodiments provided by the three substances in combination on the basis of their technical effect can play three substances alone does not have the technical effect, thus achieving a synergistic effect. 本发明提供的药物组合物在抗糖尿病的有效治疗效果上,具有明显的预防糖尿病并发症的有益效果,因此是更适宜的抗糖尿病药物,为治疗糖尿病或预防糖尿病并发症提供了一种可行、安全的治疗方案。 The present invention provides a pharmaceutical composition in an effective anti-diabetic treatment effect, with obvious beneficial effect of preventing the diabetic complications, and is therefore more suitable antidiabetic agents for the treatment of diabetes or preventing diabetic complications is provided a viable, safe treatment options.

[0129] 下面结合具体实施方式对本发明做进一步说明,并非对本发明的限定,凡依照本发明内容进行的任何本领域的等同替换,均属于本发明的保护范围。 [0129] DETAILED DESCRIPTION The following embodiments of the present invention will be further described, the present invention is not limited to, any equivalents of the present art where conducted in accordance with the present invention, all fall within the scope of the present invention.

具体实施方式 Detailed ways

[0130] 以下药物制剂实施例的制剂制备过程和制剂所用物质或制剂所用物质的用量不限于文字表述,凡含有本发明提供的药物组合物的制剂方法,均属于本发明的保护范围,具体的实验方法可参考药物制剂常用参考书,如《药剂辅料应用与制备》、《药剂学》、《生物药剂学与药物动力学》等。 [0130] the substance or formulation amount of the substance is not limited to a textual representation of a manufacturing process and Formulation Formulation Example formulations following drugs are used, where the preparation method of a pharmaceutical composition of the present invention is provided, all fall within the scope of the present invention, the specific experimental methods used reference can refer to a pharmaceutical formulation, such as "application and preparation of pharmaceutical excipients", "pharmaceutical", "Biopharmaceutics and pharmacokinetics" and the like.

[0131] 实施例1制备复方格列美脲罗格列酮叶酸(0.4mg)片(1000片量) Preparation of Compound glimepiride rosiglitazone folic acid (0.4mg) tablets (1,000 amount) [0131] Example 1

[0132] 配方:格列美脲 1g[0133] 罗格列酮 4g[0134] 叶酸 0. 4g[0135] 淀粉 20g[0136] 微晶纤维素 40g[0137] 羧甲基淀粉钠 40g[0138] 低取代羟丙基纤维素 20g[0139] 聚维酮乙醇溶液 适量[0140] 硬脂酸镁 0. 5% [0132] Formulation: glimepiride 1g [0133] Rosiglitazone 4g [0134] Folic acid 0. 4g [0135] Starch 20g [0136] Microcrystalline cellulose 40g [0137] The sodium carboxymethyl starch 40g [0138] low-substituted hydroxypropylcellulose 20g [0139] povidone-ethanol solution suitable amount [0140] magnesium stearate 0.5%

[0141] 制备方法:将辅料粉碎过80目筛,干燥备用。 Preparation [0141] Method: The crushed materials 80 mesh sieve, and dried for use. 取Ig格列美脲、4g罗格列酮、0.4g叶酸按照等量递增法混合均勻,按照处方量分别加入淀粉、微晶纤维素、羧甲基淀粉钠和低取代羟丙基纤维素,按等量递增法均勻混合,用5%聚维酮K29/30-95%乙醇溶液制成软材, 20目筛制粒,40°C干燥约2h,18目筛整粒,控制颗粒的含水量为2-3%,将干燥后的颗粒与硬脂酸镁混合均勻,半成品进行检测,测定含量,用压片机压制成1000片。 Ig take glimepiride, 4g rosiglitazone, 0.4 g of folic acid were uniformly mixed in equivalent incremental method, as prescribed amount of starch were added, microcrystalline cellulose, sodium carboxymethyl starch and low substituted hydroxypropylcellulose, by mixing equal amounts gradually increasing uniformly with 5% povidone K29 / 30-95% ethanol solution made of soft material, granulated 20 mesh sieve, 40 ° C and dried for about 2h, 18 mesh sieve, control particles containing 2-3% of water, the particles are dried with magnesium stearate uniformly mixed, semi detection, determination of, compressed into 1000 with a tableting machine. 制成的片剂需铝塑泡罩包装,避光保存。 Tablet blister packages made required, and stored. 制成的复方片剂中每片含格列美脲lmg、罗格列酮4mg、叶酸0. 4mg, 其质量比为1 : 4 : 0.4。 Compound tablets made in each tablet containing glimepiride lmg, rosiglitazone 4mg, folic of 0. The 4mg, mass ratio of 1: 4: 0.4.

[0142] 实施例2〜实施例8制备含有不同含量配比的格列美脲罗格列酮叶酸片 [0142] Example 2 ~ embodiment glimepiride rosiglitazone Example 8 was prepared containing different ratios of the content of folic acid tablets rosiglitazone

[0143] 制备方法与实施例1相同,按照表1所示配方获得的颗粒制成片剂。 [0143] prepared in the same manner as in Example 1, in accordance with the formulation shown in Table 1 to obtain particles made into tablets.

[0144] 实施例9制备复方格列美脲罗格列酮维生素B12(2mg)片(1000片量) [0144] (2mg) sheet (1000 amount) of the compound prepared in Example glimepiride rosiglitazone embodiment vitamin B12 9

[0145] 实施例10制备复方格列美脲罗格列酮维生素B6 (IOmg)片(1000片量) [0145] Example 10 Preparation of Compound glimepiride rosiglitazone Vitamin B6 (IOmg) Embodiment sheet (1000 amount)

[0146] 实施例9〜10的制备方法与实施例1相同,按照表1所示配方获得的颗粒制成片剂。 [0146] Preparation Example 9 to 10 is the same as in Example 1, in accordance with the formulation shown in Table 1 to obtain particles made into tablets.

[0147] 表1实施例2〜10片剂配方组成 [0147] Table 1 Example Composition embodiment 2~10 tablet formulation

[0148] [0148]

Figure CN101103993BD00211

[0149] 实施例2制成的复方格列美脲罗格列酮叶酸片剂中每片含格列美脲2mg、罗格列酮4mg、叶酸0.4mg,其质量比为2 : 4 : 0. 4。 [0149] Compound Example 2 is made glimepiride rosiglitazone folate tablets each containing glimepiride 2mg, rosiglitazone 4mg, folic acid 0.4mg, mass ratio of 2: 4: 0 4.

[0150] 实施例3制成的复方格列美脲罗格列酮叶酸片剂中每片含格列美脲4mg、罗格列酮4mg、叶酸0.4mg,其质量比为4 : 4 : 0. 4。 Compound each containing glimepiride 4mg, rosiglitazone 4mg, 0.4mg folic acid glimepiride tablets rosiglitazone folic acid [0150] Example 3 is made of the embodiment, the mass ratio of 4: 4: 0 4.

[0151] 实施例4制成的复方格列美脲罗格列酮叶酸片剂中每片含格列美脲lmg、罗格列酮4mg、叶酸0.8mg,其质量比为1 : 4 : 0.8。 [0151] Example Compound glimepiride per tablet LMG glimepiride, rosiglitazone 4mg, 0.8mg folate folate one tablet of rosiglitazone 4 is made, the mass ratio of 1: 4: 0.8 .

[0152] 实施例5制成的复方格列美脲罗格列酮叶酸片剂中每片含格列美脲lmg、罗格列酮4mg、叶酸l.Omg,其质量比为1 : 4 : 1.0。 Compound rosiglitazone, glimepiride per tablet LMG glimepiride, rosiglitazone 4mg, folic acid, folic l.Omg one tablet [0152] Example 5 is made of the embodiment, the mass ratio of 1: 4: 1.0.

[0153] 实施例6制成的复方格列美脲罗格列酮叶酸片剂中每片含格列美脲4mg、罗格列酮2mg、叶酸0.4mg,其质量比为4 : 2 : 0. 4。 Compound Glimepiride each containing glimepiride 4mg, rosiglitazone 2mg, 0.4mg folic acid, folic acid tablets rosiglitazone [0153] Example 6 is made of the embodiment, the mass ratio of 4: 2: 0 4.

[0154] 实施例7制成的复方格列美脲罗格列酮叶酸片剂中每片含格列美脲4mg、罗格列酮lmg、叶酸0.4mg,其质量比为4 : 1 : 0. 4。 Compound Glimepiride each containing glimepiride 4mg, LMG rosiglitazone, rosiglitazone 0.4mg folate folate tablets [0154] Example 7 made of embodiments, the mass ratio of 4: 1: 0 4.

[0155] 实施例8制成的复方格列美脲罗格列酮叶酸片剂中每片含格列美脲4mg、罗格列酮8mg、叶酸0.4mg,其质量比为4 : 8 : 0. 4。 Compound Glimepiride each containing glimepiride 4mg, rosiglitazone 8mg, 0.4mg folate folate tablets rosiglitazone [0155] Example 8 is made of the embodiment, the mass ratio of 4: 8: 0 4.

[0156] 实施例9制成的复方格列美脲罗格列酮维生素B12片剂中每片含格列美脲lmg、 罗格列酮4mg、维生素B12 2mg,其质量比为1 : 4 : 2。 [0156] Compound of Example 9 is made embodiment glimepiride rosiglitazone Vitamin B12 tablets each containing glimepiride lmg, rosiglitazone 4mg, vitamin B12 2mg, mass ratio of 1: 4: 2.

[0157] 实施例10制成的复方格列美脲罗格列酮维生素B6片剂中每片含格列美脲lmg、 罗格列酮4mg、维生素B6 10mg,其质量比为1 : 4 : 10。 [0157] Example embodiments of the compound 10 prepared glimepiride rosiglitazone vitamin B6 tablets each containing glimepiride lmg, rosiglitazone 4mg, Vitamin B6 10mg, mass ratio of 1: 4: 10.

[0158] 实施例11〜15制备含有不同含量配比的格列美脲吡格列酮叶酸片 [0158] Example 11~15 prepared containing glimepiride Pioglitazone tablets with different content ratios of folic acid

[0159] 制备方法与实施例1相同,按照表2所示配方获得的颗粒制成片剂。 [0159] prepared in the same manner as in Example 1, in accordance with the formulation shown in Table 2 to obtain particles made into tablets.

[0160] 实施例16制备复方格列美脲吡格列酮维生素B12(2mg)片(1000片量) (1000 amount) Example 16 Preparation of Compound glimepiride pioglitazone Vitamin B12 (2mg) sheet [0160] Embodiment

[0161] 实施例17制备复方格列美脲呲格列酮维生素B6 (IOmg)片(1000片量) [0161] Preparation of Compound glimepiride bared glitazone Vitamin B6 (IOmg) Example 17 sheets (amount 1000)

[0162] 实施例16、17的制备方法与实施例1相同,按照表2所示配方获得的颗粒制成片剂。 [0162] Example 16 and 17 prepared in Example 1 of the same, according to the formulation shown in Table 2 to obtain the particles made into tablets.

[0163] 表2实施例11〜17片剂配方组成 [0163] Table 2 Composition Examples 11~17 tablet formulation

[0164] [0164]

Figure CN101103993BD00221

[0165] 实施例11制成的复方格列美脲吡格列酮叶酸片剂中每片含格列美脲lmg、吡格列酮15mg、叶酸0. 4mg,其质量比为1 : 15 : 0.4。 [0165] The compound prepared in Example 11 glimepiride pioglitazone folate tablets each containing glimepiride lmg, pioglitazone 15mg, folic acid 0. 4mg, the mass ratio of 1: 15: 0.4.

[0166] 实施例12制成的复方格列美脲吡格列酮叶酸片剂中每片含格列美脲2mg、吡格列酮15mg、叶酸0. 4mg,其质量比为2 : 15 : 0.4。 [0166] Example 12 Compound prepared glimepiride pioglitazone folate tablets each containing glimepiride 2mg, pioglitazone 15mg, folic acid 0. 4mg, the mass ratio of 2: 15: 0.4.

[0167] 实施例13制成的复方格列美脲吡格列酮叶酸片剂中每片含格列美脲4mg、吡格列酮15mg、叶酸0. 4mg,其质量比为4 : 15 : 0.4。 [0167] The compound prepared in Example 13 embodiment glimepiride pioglitazone folate tablets each containing glimepiride 4mg, pioglitazone 15mg, folic of 0. The 4mg, the mass ratio of 4: 15: 0.4.

[0168] 实施例14制成的复方格列美脲呲格列酮叶酸片剂中每片含格列美脲lmg、呲格列酮15mg、叶酸0. 8mg,其质量比为1 : 15 : 0.8。 [0168] Example 14 Compound glimepiride per tablet glimepiride lmg, bared glitazone 15mg, folic acid 0. 8mg, the mass ratio of one folate tablets prepared bared glibenclamide is 1: 15: 0.8.

[0169] 实施例15制成的复方格列美脲吡格列酮叶酸片剂中每片含格列美脲lmg、吡格列酮15mg、叶酸l.Omg,其质量比为1 : 15 : 1.0。 Compound glimepiride pioglitazone each containing LMG glimepiride, pioglitazone 15mg, folic acid, folic l.Omg one tablet [0169] Example 15 is made of the embodiment, the mass ratio of 1: 15: 1.0. [0170] 实施例16制成的复方格列美脲吡格列酮维生素B12片剂中每片含格列美脲lmg、 吡格列酮15mg、维生素B12 2mg,其质量比为1 : 15 : 2。 Compound glimepiride pioglitazone Vitamin B12 tablets [0170] prepared in Example 16 in each tablet containing glimepiride lmg, pioglitazone 15mg, vitamin B12 2mg, the mass ratio of 1: 15: 2.

[0171] 实施例17制成的复方格列美脲吡格列酮维生素B6片剂中每片含格列美脲lmg、 吡格列酮15mg、维生素B6 10mg,其质量比为1 : 15 : 10。 Compound glimepiride pioglitazone vitamin B6 tablet [0171] Example 17 is made of embodiments in each tablet containing glimepiride lmg, pioglitazone 15mg, Vitamin B6 10mg, the mass ratio of 1: 15: 10.

[0172] 实施例18制备复方格列美脲罗格列酮叶酸(0. 4mg)胶囊(1000粒量) [0172] Preparation of Compound glimepiride rosiglitazone folic acid (0. 4mg) of the capsule (1,000 amount) Example 18

[0173] 配方:格列美脲 Ig [0173] Recipe: glimepiride Ig

[0174] 罗格列酮 4g [0174] Rosiglitazone 4g

[0175] 叶酸 0. 4g [0175] folic acid 0. 4g

[0176] 微晶纤维素 30g [0176] Microcrystalline cellulose 30g

[0177] 羧甲基淀粉钠20g [0177] The sodium carboxymethyl starch 20g

[0178] 聚维酮乙醇溶液适量 [0178] povidone-ethanol solution suitable amount

[0179] 微粉硅胶 [0179] Aerosil

[0180] 硬脂酸镁 [0180] Magnesium stearate

[0181] 制备方法:将原辅料粉碎过80目筛,干燥备用。 Preparation [0181] Method: pulverizing raw materials through a 80 mesh sieve, and dried for use. 取4g罗格列酮、0.4g叶酸、微晶纤维素、羧甲基淀粉钠按照等量递增法混合均勻,用5%聚维酮乙醇溶液制成软材,30目筛制粒,18目筛整粒,控制颗粒的含水量为2-3%;将制好的颗粒与格列美脲混合均勻,加入微粉硅胶和硬脂酸镁充分混合均勻,测定含量,装入空心胶囊即得。 Take 4g rosiglitazone, 0.4 g of folic acid, microcrystalline cellulose, sodium carboxymethyl starch were uniformly mixed in equivalent incremental method, washed with 5% povidone-ethanol solution made of soft material, granulated 30 mesh, 18 mesh whole screen, controlling a water content of 2-3% of the particles; and the prepared granules were mixed glimepiride, aerosil and magnesium stearate was added mixed well, determine the content, that was loaded into hollow capsules. 制成的胶囊需铝塑泡罩包装,避光保存。 Capsule need blister package made, and stored. 制成的胶囊中每粒含格列美脲lmg、罗格列酮4mg、叶酸0. 4mg,其质量比为1 : 4 : 0.4。 Capsules made of glimepiride each containing lmg, rosiglitazone 4mg, folic of 0. The 4mg, mass ratio of 1: 4: 0.4.

[0182] 实施例19〜实施例25制备含有不同含量配比的格列美脲罗格列酮叶酸胶囊 [0182] Example 25 Example 19~ prepared containing different ratios of content glimepiride rosiglitazone folate capsule

[0183] 制备方法与实施例18相同,按照表3所示配方获得的颗粒制成胶囊。 [0183] A method same as in Example 18, in Table 3 Granular formulations into capsules obtained in FIG.

[0184] 实施例26制备复方格列美脲罗格列酮维生素B12(2mg)胶囊(1000粒量) [0184] Example 26 Preparation of Compound glimepiride rosiglitazone Vitamin B12 (2mg) Capsule (1,000 amount)

[0185] 实施例27制备复方格列美脲罗格列酮维生素B6 (IOmg)胶囊(1000粒量) [0185] Capsules (1000 amount) of the compound prepared glimepiride rosiglitazone Vitamin B6 (IOmg) Example 27

[0186] 实施例26、27的制备方法与实施例18相同,按照表3所示配方获得的颗粒制成胶囊剂。 Preparation Method [0186] Examples 26 and 27 is the same as in Example 18. The obtained granular formulations shown in Table 3. capsules made.

[0187] 表3实施例19〜27胶囊剂配方组成 19~27 capsules Formulation Example [0187] Table 3 Composition

[0188] [0188]

Figure CN101103993BD00241

[0189] 实施例19制成的复方格列美脲罗格列酮叶酸胶囊中每粒含格列美脲2mg、罗格列酮4mg、叶酸0.4mg,其质量比为2 : 4 : 0. 4。 Compound glimepiride rosiglitazone [0189] Example 19 is made of one embodiment of a column folate capsules each containing glimepiride 2mg, rosiglitazone 4mg, folic acid 0.4mg, mass ratio of 2: 4: 0. 4.

[0190] 实施例20制成的复方格列美脲罗格列酮叶酸胶囊中每粒含格列美脲4mg、罗格列酮4mg、叶酸0.4mg,其质量比为4 : 4 : 0. 4。 Compound glimepiride rosiglitazone [0190] Example 20 is made of one embodiment of a column folate capsules each containing glimepiride 4mg, rosiglitazone 4mg, folic acid 0.4mg, mass ratio of 4: 4: 0. 4.

[0191] 实施例21制成的复方格列美脲罗格列酮叶酸胶囊中每粒含格列美脲lmg、罗格列酮4mg、叶酸0.8mg,其质量比为1 : 4 : 0.8。 [0191] Example 21 Compound glimepiride rosiglitazone, rosiglitazone prepared folate capsules each containing glimepiride lmg, rosiglitazone 4mg, folic acid 0.8mg, mass ratio of 1: 4: 0.8.

[0192] 实施例22制成的复方格列美脲罗格列酮叶酸胶囊中每粒含格列美脲lmg、罗格列酮4mg、叶酸l.Omg,其质量比为1 : 4 : 1.0。 Compound glimepiride rosiglitazone [0192] Example 22 prepared Rosiglitazone embodiment folate capsules each containing glimepiride lmg, rosiglitazone 4mg, folic l.Omg, mass ratio of 1: 4: 1.0 .

[0193] 实施例23制成的复方格列美脲罗格列酮叶酸胶囊中每粒含格列美脲4mg、罗格列酮2mg、叶酸0.4mg,其质量比为4 : 2 : 0. 4。 Compound glimepiride rosiglitazone [0193] prepared in Example 23 Rosiglitazone folate capsules each containing glimepiride 4mg, rosiglitazone 2mg, folic acid 0.4mg, mass ratio of 4: 2: 0. 4.

[0194] 实施例24制成的复方格列美脲罗格列酮叶酸胶囊中每粒含格列美脲4mg、罗格列酮lmg、叶酸0.4mg,其质量比为4 : 1 : 0. 4。 Compound glimepiride rosiglitazone [0194] Example 24 is made of Rosiglitazone embodiment folate capsules each containing glimepiride 4mg, rosiglitazone lmg, folic acid 0.4mg, mass ratio of 4: 1: 0. 4.

[0195] 实施例25制成的复方格列美脲罗格列酮叶酸胶囊中每粒含格列美脲lmg、罗格列酮8mg、叶酸0.4mg,其质量比为1 : 8 : 0.4。 Compound glimepiride rosiglitazone [0195] Example 25 prepared Rosiglitazone embodiment folate capsules each containing glimepiride lmg, rosiglitazone 8mg, folic acid 0.4mg, mass ratio of 1: 8: 0.4.

[0196] 实施例26制成的复方格列美脲罗格列酮维生素B12胶囊中每粒含格列美脲lmg、 罗格列酮4mg、维生素B12 2mg,其质量比为1 : 4 : 2。 Compound glimepiride rosiglitazone Capsule Vitamin B12 [0196] Example 26 prepared in the embodiment glimepiride each containing lmg, rosiglitazone 4mg, vitamin B12 2mg, mass ratio of 1: 4: 2 .

[0197] 实施例27制成的复方格列美脲罗格列酮维生素B6胶囊中每粒含格列美脲lmg、 罗格列酮4mg、维生素B6 10mg,其质量比为1 : 4 : 10。 Compound glimepiride rosiglitazone Capsule Vitamin B6 [0197] Example 27 prepared in the embodiment glimepiride each containing lmg, rosiglitazone 4mg, Vitamin B6 10mg, mass ratio of 1: 4: 10 .

[0198] 实施例28〜32制备含有不同含量配比的格列美脲吡格列酮叶酸胶囊 Glimepiride pioglitazone folate content of capsules containing different ratios of Preparation Example 28~32 [0198] Embodiment

[0199] 制备方法与实施例18相同,按照表4所示配方获得的颗粒制成胶囊剂。 [0199] A method same as in Example 18, the particles obtained according to the formulations shown in Table 4 to give a capsule.

[0200] 实施例33制备复方格列美脲吡格列酮维生素B12 (2mg)胶囊(1000粒量) [0200] Compound glimepiride pioglitazone EXAMPLE 33 Preparation of vitamin B12 (2mg) Capsule (1,000 amount)

[0201] 实施例34制备复方格列美脲呲格列酮维生素B6 (IOmg)胶囊(1000粒量) [0201] Capsules (1000 amount) of the compound prepared glimepiride bared glitazone vitamin B6 Example 34 (IOmg) Embodiment

[0202] 实施例33、34的制备方法与实施例18相同,按照表4所示配方获得的颗粒制成胶囊剂。 Preparation [0202] Example 33 is the same as in Example 18, the particles obtained according to the formulations shown in Table 4 to give a capsule. [0203] 表4实施例28〜34胶囊剂配方组成 [0203] Example 28~34 TABLE 4 Composition Formulation Capsules

[0204] [0204]

Figure CN101103993BD00251

[0205] 实施例28制成的复方格列美脲吡格列酮叶酸胶囊中每粒含格列美脲lmg、吡格列酮15mg、叶酸0. 4mg,其质量比为1 : 15 : 0.4。 Compound glimepiride pioglitazone folate capsule [0205] Example 28 prepared in the embodiment glimepiride each containing lmg, pioglitazone 15mg, folic acid 0. 4mg, the mass ratio of 1: 15: 0.4.

[0206] 实施例29制成的复方格列美脲吡格列酮叶酸胶囊中每粒含格列美脲2mg、吡格列酮15mg、叶酸0. 4mg,其质量比为2 : 15 : 0.4。 Compound glimepiride pioglitazone folate capsule [0206] Example 29 prepared in the embodiment each containing glimepiride 2mg, pioglitazone 15mg, folic acid 0. 4mg, the mass ratio of 2: 15: 0.4.

[0207] 实施例30制成的复方格列美脲吡格列酮叶酸胶囊中每粒含格列美脲4mg、吡格列酮15mg、叶酸0. 4mg,其质量比为4 : 15 : 0.4。 Compound glimepiride pioglitazone folate capsule [0207] Example 30 prepared in the embodiment each containing glimepiride 4mg, pioglitazone 15mg, folic of 0. The 4mg, the mass ratio of 4: 15: 0.4.

[0208] 实施例31制成的复方格列美脲吡格列酮叶酸胶囊中每粒含格列美脲lmg、呲格列酮15mg、叶酸0. 8mg,其质量比为1 : 15 : 0.8。 Compound glimepiride pioglitazone folate capsule [0208] Example 31 prepared in the embodiment glimepiride each containing lmg, bared glitazone 15mg, folic acid 0. 8mg, the mass ratio of 1: 15: 0.8.

[0209] 实施例32制成的复方格列美脲吡格列酮叶酸胶囊中每粒含格列美脲lmg、吡格列酮15mg、叶酸l.Omg,其质量比为1 : 15 : 1.0。 Compound glimepiride pioglitazone folate capsule [0209] Example 32 prepared in the embodiment glimepiride each containing lmg, pioglitazone 15mg, folic l.Omg, the mass ratio of 1: 15: 1.0.

[0210] 实施例33制成的复方格列美脲吡格列酮维生素B12胶囊中每粒含格列美脲lmg、 吡格列酮15mg、维生素B12 2mg,其质量比为1 : 15 : 2。 Compound glimepiride pioglitazone Capsule Vitamin B12 [0210] Example 33 prepared in the embodiment glimepiride each containing lmg, pioglitazone 15mg, vitamin B12 2mg, the mass ratio of 1: 15: 2.

[0211] 实施例34制成的复方格列美脲呲格列酮维生素B6胶囊中每粒含格列美脲lmg、 Compound glimepiride bared glitazone Capsule Vitamin B6 [0211] Example 34 is made in the embodiment glimepiride each containing lmg,

吡格列酮15mg、维生素B6 10mg,其质量比为1 : 15 :10。 Pioglitazone 15mg, Vitamin B6 10mg, the mass ratio of 1: 15: 10. [0212] 实施例35制备复方格列苯脲罗格列酮叶酸 (0. 4mg) 片 (1000片量[0213] 实施例36制备复方格列苯脲吡格列酮叶酸 (0. 4mg) 片 (1000片量[0214] 实施例37制备复方格列齐特罗格列酮叶酸 (0. 4mg) 片 (1000片量[0215] 实施例38制备复方格列齐特吡格列酮叶酸 (0. 4mg) 片 (1000片量[0216] 实施例39制备复方格列喹酮罗格列酮叶酸 (0. 4mg) 片 (1000片量[0217] 实施例40制备复方格列喹酮吡格列酮叶酸 (0. 4mg) 片 (1000片量[0218] 实施例41制备复方格列吡嗪罗格列酮叶酸 (0. 4mg) 片 (1000片量[0219] 实施例42制备复方格列吡嗪吡格列酮叶酸 (0. 4mg) 片 (1000片量[0220] 实施例35〜42的制备方法与实施例1相同,按照表5所示配方获得的颗粒制成片剂。 [0212] Example 35 Preparation of Compound glibenclamide rosiglitazone folic acid (0. 4mg) sheet (1000 Volume [0213] 36 Preparation of Compound glibenclamide pioglitazone folic acid (0. 4mg) Embodiment sheet (1000 the amount of [0214] Example 37 preparation of compound 格列齐特罗格 rosiglitazone folic acid (0. 4mg) sheet (the amount of 1000 [0215] Example 38 preparation of compound gliclazide pioglitazone folate embodiment (0. 4mg) sheet (1000 sheet amount [0216] Example 39 preparation of compound gliquidone rosiglitazone folic acid (0. 4mg) tablets (1,000 amount of [0217] embodiment 40 preparation of compound gliquidone pioglitazone folic acid (0. 4mg) tablets ( 1,000 the amount of [0218] Example 41 preparation of compound glipizide rosiglitazone folic acid (0. 4mg) sheet (the amount of 1000 [0219] Example 42 preparation of compound glipizide pioglitazone folic acid (0. 4mg) sheet (1000 Volume [0220] preparation Example 35~42 embodiment same as in Example 1, particles in accordance with formulations shown in table 5 were made into tablets.

[0221 ] 表5实施例35〜42片剂配方组成[0222] Example 35~42 tablet formulation [0221] Table 5 Composition [0222]

Figure CN101103993BD00261

[0223] 实施例35制成的复方格列苯脲罗格列酮叶酸片剂中每片含格列苯脲2. 5mg、罗格列酮4mg、叶酸0.4mg,其质量比为2. 5 : 4 : 0. 4。 [0223] Example 35 Compound glibenclamide made of urea rosiglitazone folate tablets each containing glibenclamide 2. 5mg, rosiglitazone 4mg, folic acid 0.4mg, mass ratio of 2.5 : 4: 0.4.

[0224] 实施例36制成的复方格列苯脲吡格列酮叶酸片剂中每片含格列苯脲2. 5mg、吡格列酮15mg、叶酸0.4mg,其质量比为2. 5 : 15 : 0.4。 Compound glyburide [0224] Example 36 prepared embodiment of pioglitazone folate tablets each containing glibenclamide 2. 5mg, pioglitazone 15mg, folic acid 0.4mg, mass ratio of 2.5: 15: 0.4.

[0225] 实施例37制成的复方格列喹酮罗格列酮叶酸片剂中每片含格列喹酮30mg、罗格列酮4mg、叶酸0. 4mg,其质量比为30 : 4 : 0. 4。 Compound gliquidone rosiglitazone [0225] Example 37 is made of one embodiment of a column of folic acid tablets each containing gliquidone 30mg, rosiglitazone 4mg, folic of 0. The 4mg, mass ratio of 30: 4: 0.4.

[0226] 实施例38制成的复方格列喹酮吡格列酮叶酸片剂中每片含格列喹酮30mg、吡格列酮15mg、叶酸0. 4mg,其质量比为30 : 15 : 0.4。 Compound glibenclamide quinoline [0226] Example 38-one prepared embodiment pioglitazone tablets each containing folate gliquidone 30mg, pioglitazone 15mg, folic acid 0. 4mg, mass ratio of 30: 15: 0.4.

[0227] 实施例39制成的复方格列齐特罗格列酮叶酸片剂中每片含格列齐特50mg、罗格列酮4mg、叶酸0. 4mg,其质量比为50 : 4 : 0. 4。 [0227] Example 39 Compound 格列齐特罗格 rosiglitazone folic acid tablets made in each tablet containing Gliclazide 50mg, rosiglitazone 4mg, folic of 0. The 4mg, mass ratio of 50: 4: 0.4.

[0228] 实施例40制成的复方格列齐特吡格列酮叶酸片剂中每片含格列齐特50mg、吡格列酮15mg、叶酸0. 4mg,其质量比为50 : 15 : 0.4。 Compound gliclazide folate tablet Pioglitazone [0228] Example 40 is made in each tablet containing embodiment Gliclazide 50mg, pioglitazone 15mg, folic acid 0. 4mg, mass ratio of 50: 15: 0.4.

[0229] 实施例41制成的复方格列吡嗪罗格列酮叶酸片剂中每片含格列吡嗪5mg、罗格列酮4mg、叶酸0.4mg,其质量比为5 : 4 : 0. 4。 Compound glipizide rosiglitazone [0229] Example 41 is made of one embodiment of a column folate tablets each containing glipizide 5mg, rosiglitazone 4mg, folic acid 0.4mg, mass ratio of 5: 4: 0 4.

[0230] 实施例42制成的复方格列吡嗪吡格列酮叶酸片剂中每片含格列吡嗪5mg、吡格列酮15mg、叶酸0. 4mg,其质量比为5 : 15 : 0.4。 [0230] Example 42 Compound glipizide made Pioglitazone tablets each containing folate glipizide 5mg, pioglitazone 15mg, folic acid 0. 4mg, the mass ratio of 5: 15: 0.4.

[0231] 实施例43格列美脲、罗格列酮和叶酸组合物对糖尿病大鼠血糖、同型半胱氨酸、内皮细胞功能和肾脏病变的影响 Homocysteine, Effects [0231] Example 43 glimepiride, rosiglitazone and folic acid compositions for diabetic rats, endothelial cells and renal lesions

[0232] 链脲佐菌素溶液:称取1200mg链脲佐菌素临用前溶于200ml新配制的柠檬酸缓冲液(0. lmmol/L, ρΗ4· 5)中,配成6mg/ml 的溶液。 [0232] streptozotocin solution: citrate buffer 1200mg streptozotocin taken immediately before use is dissolved in 200ml of freshly prepared (0. lmmol / L, ρΗ4 · 5), the dubbed 6mg / ml of solution.

[0233] 取健康大鼠,随机选取10只大鼠作为空白对照,其余大鼠尾静脉快速注射链脲佐菌素溶液(60mg/kg),空白组大鼠给予正常饮食,试验组大鼠给予高脂饲料喂养诱导胰岛素抵抗。 [0233] Taking the healthy rats, 10 rats were randomly selected as the control, the remaining rat tail vein injection of streptozotocin solution (60mg / kg), rats were given normal diet control group, the test group of rats administered fat diet induced insulin resistance. 2周后眶静脉采血测定空腹血糖值,筛选血糖值超过16. 7mmol/L的大鼠制成糖尿病模型大鼠用于后续实验。 After 2 weeks the orbital venous blood fasting glucose level, blood glucose level exceeds filter 16. 7mmol / L in rats made diabetic rat model used in subsequent experiments.

[0234] 将糖尿病大鼠随机分为模型组、格列美脲组、罗格列酮组、叶酸组、格列美脲+叶酸组、罗格列酮+叶酸组、格列美脲+罗格列酮组、格列美脲+罗格列酮+叶酸组,每日分别灌胃给予等量相应受试物,每日一次。 [0234] The diabetic rats were randomly divided into model group, groups glimepiride, rosiglitazone, folic acid group, glimepiride and the folic acid group, rosiglitazone group folic acid, glimepiride Lo + glitazone group, glimepiride + rosiglitazone + folic group, daily oral administration of the same amount, respectively corresponding to the test substance, once daily. 连续给药6周后,进行血糖(GLU)、血浆同型半胱氨酸(Hcy)、心肌组织中乳酸脱氢酶(LDH)、丙二醛(MDA)、一氧化氮(NO)测定,并对肌酐(Cr)、尿素氮(BUN)及24h尿蛋白指标进行测定。 After 6 weeks of continuous administration, blood glucose (GLU), plasma homocysteine ​​(of Hcy), myocardial lactate dehydrogenase (of LDH), malondialdehyde (of MDA), was measured nitric oxide (NO), and to creatinine (Cr), urea nitrogen (BUN) and urinary protein were measured and 24h. 每组10只大鼠测得的上述结果以(平均值士标准差)(又士S)表示,样本均数间的多重比较采用单因素方差分析,应用SPSS10.0软件进行统计分析,详见表6。 The results measured in each group 10 rats (mean ± standard deviation) (Shi and S), said multiple samples were used to compare between ANOVA, SPSS10.0 application software for statistical analysis, see table 6.

[0235] 表6格列美脲、罗格列酮和叶酸组合物对糖尿病大鼠的作用(又士s,n=10) [0235] Table 6 glimepiride, rosiglitazone and folic acid compositions of diabetic rats (Shi and s, n = 10)

[0236] [0236]

Figure CN101103993BD00271

[0237] 注:对照组与模型组比较,flP < 0. 05,flflP < 0. 01,###P < 0. 001 ;各给药组与模型组比较,*P < 0. 05,**P <0.01, ***P < 0. 001 ;各给药组与格列美脲+罗格列酮+叶酸组比较,ΔΡ < 0. 05,δδΡ < 0. 01,ΔΔΔΡ < 0. 001。 [0237] Note: Compared with model control group, flP <0. 05, flflP <0. 01, ### P <0. 001; compare each treatment group and the model group, * P <0. 05, * * P <0.01, *** P <0. 001; in each treatment group and the glimepiride + rosiglitazone comparison folic acid group, ΔΡ <0. 05, δδΡ <0. 01, ΔΔΔΡ <0. 001 .

[0238] 续表6格列美脲、罗格列酮和叶酸组合物对糖尿病大鼠的作用〈又士S, η=ιο) [0238] Continued Table 6 glimepiride, rosiglitazone, and the role of folic acid compositions diabetic rats <persons and S, η = ιο)

[0239] [0239]

Figure CN101103993BD00281

[0240] 注:对照组与模型组比较,flP < 0. 05,flflP < 0. 01,###P < 0. 001 ;各给药组与模型组比较,*P < 0. 05,**P <0.01, ***P < 0. 001 ;各给药组与格列美脲+罗格列酮+叶酸组比较,ΔΡ < 0. 05,δδΡ < 0. 01,ΔΔΔΡ < 0. 001。 [0240] Note: Compared with model control group, flP <0. 05, flflP <0. 01, ### P <0. 001; compare each treatment group and the model group, * P <0. 05, * * P <0.01, *** P <0. 001; in each treatment group and the glimepiride + rosiglitazone comparison folic acid group, ΔΡ <0. 05, δδΡ <0. 01, ΔΔΔΡ <0. 001 .

[0241] 结论:上述结果表明,格列美脲、罗格列酮和叶酸组合物可显著降低糖尿病大鼠的血糖、同型半胱氨酸水平,保护糖尿病引起的内皮细胞损伤及肾脏病变(ρ <0.01或0. 001),格列美脲+罗格列酮+叶酸组合物降糖作用优于单方格列美脲及叶酸(P < 0. 05 或0.001);降同型半胱氨酸水平优于单方格列美脲及罗格列酮(P <0.01或0.001);对糖尿病引起的内皮细胞功能损伤及肾脏病变的保护作用也明显优于单方或任两种组份的组合(P <0.05或0.01)。 [0241] Conclusion: The above results show, glimepiride, rosiglitazone and folic acid compositions can be significantly reduced blood glucose in diabetic rats, homocysteine ​​levels, protection of endothelial cell damage caused by diabetes, and renal lesions ([rho] <0.01 or 0.001), glimepiride + rosiglitazone folic acid composition hypoglycemic effect than single square glimepiride and folate (P <0. 05 or 0.001); homocysteine-lowering over single horizontal grid glimepiride and rosiglitazone (P <0.01 or 0.001); injury of endothelial cells and the protective effect of diabetic kidney disease significantly better than the unilateral or any combination of two components ( P <0.05 or 0.01). 说明格列美脲、罗格列酮和叶酸组合物对糖尿病大鼠血糖、同型半胱氨酸、内皮细胞功能和肾脏病变均具有良好的治疗效果。 He said Minge glimepiride, rosiglitazone and folic acid compositions for diabetic rats, homocysteine, endothelial cell function and renal lesions have a good therapeutic effect.

[0242] 实施例44格列美脲、吡格列酮和叶酸组合物对糖尿病大鼠血糖、同型半胱氧酸、 内皮细胞功能和肾脏病变的影响 Oxygen homocysteic acid, Effects [0242] Example 44 glimepiride, pioglitazone and folic acid compositions for diabetic rats, endothelial cells and renal lesions

[0243] 实验方法同实施例43。 [0243] Example 43 the same experimental procedure. 结果见表7。 The results are shown in Table 7.

[0244] 表7格列美脲、吡咯列酮和叶酸组合物对糖尿病大鼠的作用(S士S, η=,ο) [0244] Table 7 glimepiride, pioglitazone and folic acid composition on diabetic rats (S Shi S, η =, ο)

[0245] [0245]

Figure CN101103993BD00291

[0246] 注:对照组与模型组比较,flP < 0. 05,flflP < 0. 01,###P < 0. 001 ;各给药组与模型组比较,*P < 0. 05,**P <0.01, ***P < 0. 001 ;各给药组与格列美脲+吡咯列酮+叶酸组比较,ΔΡ < 0. 05,δδΡ < 0. 01,ΔΔΔΡ < 0. 001。 [0246] Note: Compared with model control group, flP <0. 05, flflP <0. 01, ### P <0. 001; compare each treatment group and the model group, * P <0. 05, * * P <0.01, *** P <0. 001; in each treatment group and the glimepiride + pioglitazone + folic group comparison, ΔΡ <0. 05, δδΡ <0. 01, ΔΔΔΡ <0. 001.

[0247] 续表7格列美脲、吡咯列酮和叶酸组合物对糖尿病大鼠的作用(又土S,n=1Q) [0247] Continued Table 7 role glimepiride, pioglitazone and folic acid compositions diabetic rats (soil and S, n = 1Q)

[0248] [0248]

Figure CN101103993BD00292

[0249] 注:对照组与模型组比较,flP < 0. 05,flflP < 0. 01,###Ρ < 0. 001 ;各给药组与模型组比较,*Ρ < 0. 05,**Ρ <0.01, ***Ρ < 0. 001 ;各给药组与格列美脲+吡咯列酮+叶酸组比较,ΔΡ < 0. 05,δδΡ < 0. 01,ΔΔΔΡ < 0. 001。 [0249] Note: Compared with model control group, flP <0. 05, flflP <0. 01, ### Ρ <0. 001; compare each treatment group and the model group, * Ρ <0. 05, * * Ρ <0.01, *** Ρ <0. 001; in each treatment group and the glimepiride + pioglitazone + folic group comparison, ΔΡ <0. 05, δδΡ <0. 01, ΔΔΔΡ <0. 001.

[0250] 结论:上述结果表明,格列美脲、吡咯列酮和叶酸组合物可显著降低糖尿病大鼠的血糖、同型半胱氨酸水平,保护糖尿病引起的内皮细胞损伤及肾脏病变(P <0.01或0. 001),格列美脲+吡咯列酮+叶酸组合物降糖作用优于单方格列美脲及叶酸(P < 0. 05 或0. 001);降同型半胱氨酸水平优于单方格列美脲及吡咯列酮(P < 0. 01或0. 001);对糖尿病引起的内皮细胞功能损伤及肾脏病变的保护作用也明显优于单方或任两种组份的组合(P <0.05或0.01)。 [0250] Conclusion: The above results show, glimepiride, pioglitazone and folic acid compositions can significantly reduce blood glucose in diabetic rats, homocysteine ​​levels, protection of endothelial cell injury and renal lesions (P caused by diabetes < 0.01 or 0.001), glimepiride + pioglitazone + folic acid composition hypoglycemic effect than single square glimepiride and folate (P <0. 05 or 0.001); homocysteine-lowering over single horizontal grid glimepiride and pioglitazone (P <0. 01 or 0.001); injury of endothelial cells and the protective effect of renal lesions caused by diabetes was obviously better than any of the two components or unilaterally combination (P <0.05 or 0.01). 说明格列美脲、吡咯列酮和叶酸组合物对糖尿病大鼠血糖、同型半胱氨酸、内皮细胞功能和肾脏病变均具有良好的治疗效果。 He said Minge glimepiride, pioglitazone and folic acid compositions for diabetic rats, homocysteine, endothelial cell function and renal lesions have a good therapeutic effect.

[0251] 实施例45格列苯脲、罗格列酮和叶酸组合物对糖尿病大鼠血糖、同型半胱氨酸、 内皮细胞功能和肾脏病变的影响 [0251], homocysteine, Example 45 Effect of glibenclamide, folic acid and rosiglitazone compositions for diabetic rats embodiment of endothelial cells and renal lesions

[0252] 实验方法同实施例43。 [0252] Example 43 the same experimental procedure. 结果见表8。 The results are shown in Table 8.

[0253] 表8格列苯脲、罗格列酮和叶酸组合物对糖尿病大鼠的作用(又士S,n=10) [0253] Table 8 glibenclamide, rosiglitazone and folic acid compositions of diabetic rats (Shi and S, n = 10)

[0254] [0254]

Figure CN101103993BD00301

[0255] 注:对照组与模型组比较,flP < 0. 05,flflP < 0. 01,###Ρ < 0. 001 ;各给药组与模型组比较,*Ρ < 0. 05,**Ρ <0.01, ***Ρ < 0. 001 ;各给药组与格列苯脲+罗格列酮+叶酸组比较,ΔΡ < 0. 05,δδΡ < 0. 01,ΔΔΔΡ < 0. 001。 [0255] Note: Compared with model control group, flP <0. 05, flflP <0. 01, ### Ρ <0. 001; compare each treatment group and the model group, * Ρ <0. 05, * * Ρ <0.01, *** Ρ <0. 001; in each treatment group and the glyburide + rosiglitazone comparison folic acid group, ΔΡ <0. 05, δδΡ <0. 01, ΔΔΔΡ <0. 001 .

[0256] 续表8格列苯脲、罗格列酮和叶酸组合物对糖尿病大鼠的作用(叉士S,η=10) [0256] Table 8 Continued glibenclamide, and the role of folate rosiglitazone compositions diabetic rats (fork Shi S, η = 10)

[0257] [0257]

Figure CN101103993BD00311

[0258] 注:对照组与模型组比较,flP < 0. 05,flflP < 0. 01,###P < 0. 001 ;各给药组与模型组比较,*P < 0. 05,**P <0.01, ***P < 0. 001 ;各给药组与格列苯脲+罗格列酮+叶酸组比较,ΔΡ < 0. 05,δδΡ < 0. 01,ΔΔΔΡ < 0. 001。 [0258] Note: Compared with model control group, flP <0. 05, flflP <0. 01, ### P <0. 001; compare each treatment group and the model group, * P <0. 05, * * P <0.01, *** P <0. 001; in each treatment group and the glyburide + rosiglitazone comparison folic acid group, ΔΡ <0. 05, δδΡ <0. 01, ΔΔΔΡ <0. 001 .

[0259] 结论:上述结果表明,格列苯脲、罗格列酮和叶酸组合物可显著降低糖尿病大鼠的血糖、同型半胱氨酸水平,保护糖尿病引起的内皮细胞损伤及肾脏病变(ρ <0.01或0. 001),格列苯脲+罗格列酮+叶酸组合物降糖作用优于单方格列苯脲及叶酸(P < 0. 05 或0.001);降同型半胱氨酸水平优于单方格列苯脲及罗格列酮(P <0.01或0.001);对糖尿病引起的内皮细胞功能损伤及肾脏病变的保护作用也明显优于单方或任两种组份的组合(P <0.05或0.01)。 [0259] Conclusion: The above results show, glibenclamide, rosiglitazone and folic acid compositions can significantly reduce blood glucose in diabetic rats, homocysteine ​​levels, protection of endothelial cell damage caused by diabetes, and renal lesions ([rho] <0.01 or 0.001), glibenclamide + rosiglitazone folic acid composition hypoglycemic effect than single column grid phenyl urea and folate (P <0. 05 or 0.001); homocysteine-lowering level over single column grid-phenylurea and rosiglitazone (P <0.01 or 0.001); injury of endothelial cells and the protective effect of diabetic kidney disease significantly better than the unilateral or any combination of two components ( P <0.05 or 0.01). 说明格列苯脲、罗格列酮和叶酸组合物对糖尿病大鼠血糖、同型半胱氨酸、内皮细胞功能和肾脏病变均具有良好的治疗效果。 Minge said column phenylurea, rosiglitazone and folic acid compositions for diabetic rats, homocysteine, endothelial cell function and renal lesions have a good therapeutic effect.

[0260] 实施例46格列喹酮、罗格列酮和叶酸组合物对糖尿病大鼠血糖、同型半胱氨酸、 内皮细胞功能和肾脏病变的影响 [0260], homocysteine, Example 46 Effect gliquidone, folic acid and rosiglitazone compositions for diabetic rats embodiment of endothelial cells and renal lesions

[0261] 实验方法同实施例43。 [0261] Example 43 the same experimental procedure. 结果见表9。 The results are shown in Table 9.

[0262] 表9格列喹酮、罗格列酮和叶酸组合物对糖尿病大鼠的作用(又士S,η=10) [0262] Table 9 gliquidone, rosiglitazone and folic acid compositions of diabetic rats (Shi and S, η = 10)

[0263] [0263]

Figure CN101103993BD00321

[0264] 注:对照组与模型组比较,flP < 0. 05,flflP < 0. 01,###P < 0. 001 ;各给药组与模型组比较,*P < 0. 05,**P <0.01, ***P < 0. 001 ;各给药组与格列喹酮+罗格列酮+叶酸组比较,ΔΡ < 0. 05,δδΡ < 0. 01,ΔΔΔΡ < 0. 001。 [0264] Note: Compared with model control group, flP <0. 05, flflP <0. 01, ### P <0. 001; compare each treatment group and the model group, * P <0. 05, * * P <0.01, *** P <0. 001; in each treatment group and gliquidone + rosiglitazone comparison folic acid group, ΔΡ <0. 05, δδΡ <0. 01, ΔΔΔΡ <0. 001 .

[0265] 续表9格列喹酮、罗格列酮和叶酸组合物对糖尿病大鼠的作用(交士S, η=10) [0265] Continued action 9 gliquidone, rosiglitazone and folic acid compositions diabetic rats (cross-Shi S, η = 10)

[0266] [0266]

Figure CN101103993BD00322

[0267] 注:对照组与模型组比较,flP < 0. 05,flflP < 0. 01,###P < 0. 001 ;各给药组与模型组比较,*P < 0. 05,**P <0.01, ***P < 0. 001 ;各给药组与格列喹酮+罗格列酮+叶酸组比较,ΔΡ < 0. 05,δδΡ < 0. 01,ΔΔΔΡ < 0. 001。 [0267] Note: Compared with model control group, flP <0. 05, flflP <0. 01, ### P <0. 001; compare each treatment group and the model group, * P <0. 05, * * P <0.01, *** P <0. 001; in each treatment group and gliquidone + rosiglitazone comparison folic acid group, ΔΡ <0. 05, δδΡ <0. 01, ΔΔΔΡ <0. 001 .

[0268] 结论:上述结果表明,格列喹酮、罗格列酮和叶酸组合物可显著降低糖尿病大鼠的血糖、同型半胱氨酸水平,保护糖尿病引起的内皮细胞损伤及肾脏病变(P <0.01或0. 001),格列喹酮+罗格列酮+叶酸组合物降糖作用优于单方格列喹酮及叶酸(P < 0. 05 或0.001);降同型半胱氨酸水平优于单方格列喹酮及罗格列酮(P <0.01或0.001);对糖尿病引起的内皮细胞功能损伤及肾脏病变的保护作用也明显优于单方或任两种组份的组合(P <0.05或0.01)。 [0268] Conclusion: The above results show, gliquidone, rosiglitazone and folic acid compositions can significantly reduce blood glucose in diabetic rats, homocysteine ​​levels, protection of endothelial cell injury and renal lesions (P caused by diabetes <0.01 or 0.001), gliquidone rosiglitazone + folic acid composition hypoglycemic effect than single square gliquidone and folate (P <0. 05 or 0.001); homocysteine-lowering over single horizontal grid gliquidone and rosiglitazone (P <0.01 or 0.001); injury of endothelial cells and the protective effect of diabetic kidney disease significantly better than the unilateral or any combination of two components ( P <0.05 or 0.01). 说明格列喹酮、罗格列酮和叶酸组合物对糖尿病大鼠血糖、同型半胱氨酸、内皮细胞功能和肾脏病变均具有良好的治疗效果。 He said Minge gliquidone, rosiglitazone and folic acid compositions for diabetic rats, homocysteine, endothelial cell function and renal lesions have a good therapeutic effect.

[0269] 实施例47格列齐特、罗格列酮和叶酸组合物对糖尿病大鼠血糖、同型半胱氨酸、 内皮细胞功能和肾脏病变的影响 Example 47 Effect of homocysteine ​​gliclazide, rosiglitazone and folic acid compositions for diabetic rats, endothelial cell function and renal disease [0269] Embodiment

[0270] 实验方法同实施例43。 [0270] Example 43 the same experimental procedure. 结果见表10。 The results are shown in Table 10.

[0271] 表10格列齐特、罗格列酮和叶酸组合物对糖尿病大鼠的作用(又士S,n=10) [0271] Table 10 gliclazide, rosiglitazone and folic acid compositions of diabetic rats (Shi and S, n = 10)

[0272] [0272]

Figure CN101103993BD00331

[0273] 注:对照组与模型组比较,flP < 0. 05,flflP < 0. 01,###P < 0. 001 ;各给药组与模型组比较,*P < 0. 05,**P <0.01, ***P < 0. 001 ;各给药组与格列齐特+罗格列酮+叶酸组比较,ΔΡ < 0. 05,δδΡ < 0. 01,ΔΔΔΡ < 0. 001。 [0273] Note: Compared with model control group, flP <0. 05, flflP <0. 01, ### P <0. 001; compare each treatment group and the model group, * P <0. 05, * * P <0.01, *** P <0. 001; in each treatment group and gliclazide + rosiglitazone comparison folic acid group, ΔΡ <0. 05, δδΡ <0. 01, ΔΔΔΡ <0. 001 .

[0274] 续表10格列齐特、罗格列酮和叶酸组合物对糖尿病大鼠的作用(又士S,η=10) [0274] Continued Table 10 effect of gliclazide, rosiglitazone and folic acid compositions diabetic rats (Shi and S, η = 10)

[0275][0276] [0275] [0276]

Figure CN101103993BD00341

[0277] 注:对照组与模型组比较,flP < 0. 05,flflP < 0. 01,###P < 0. 001 ;各给药组与模型组比较,*P < 0. 05,**P <0.01, ***P < 0. 001 ;各给药组与格列齐特+罗格列酮+叶酸组比较,ΔΡ < 0. 05,δδΡ < 0. 01,ΔΔΔΡ < 0. 001。 [0277] Note: Compared with model control group, flP <0. 05, flflP <0. 01, ### P <0. 001; compare each treatment group and the model group, * P <0. 05, * * P <0.01, *** P <0. 001; in each treatment group and gliclazide + rosiglitazone comparison folic acid group, ΔΡ <0. 05, δδΡ <0. 01, ΔΔΔΡ <0. 001 .

[0278] 结论:上述结果表明,格列齐特、罗格列酮和叶酸组合物可显著降低糖尿病大鼠的血糖、同型半胱氨酸水平,保护糖尿病引起的内皮细胞损伤及肾脏病变(P <0.01或0. 001),格列齐特+罗格列酮+叶酸组合物降糖作用优于单方格列齐特及叶酸(P < 0. 05 或0. 001);降同型半胱氨酸水平优于单方格列齐特及罗格列酮(P < 0. 01或0. 001);对糖尿病引起的内皮细胞功能损伤及肾脏病变的保护作用也明显优于单方或任两种组份的组合(P <0.05或0.01)。 [0278] Conclusion: The above results show, gliclazide, rosiglitazone and folic acid compositions can significantly reduce blood glucose in diabetic rats, homocysteine ​​levels, protection of endothelial cell injury and renal lesions (P caused by diabetes <0.01 or 0.001), gliclazide rosiglitazone + folic acid composition and hypoglycemic effect than unilateral gliclazide folate (P <0. 05 or 0.001); drop homocysteic gliclazide acid levels lower than unilateral and rosiglitazone (P <0. 01 or 0.001); injury of endothelial cells and the protective effect of diabetic kidney disease significantly better than any two or unilaterally parts of a combination of species group (P <0.05 or 0.01). 说明格列齐特、罗格列酮和叶酸组合物对糖尿病大鼠血糖、同型半胱氨酸、内皮细胞功能和肾脏病变均具有良好的治疗效果。 He said 明格列齐特, rosiglitazone and folic acid compositions for diabetic rats, homocysteine, endothelial cell function and renal lesions have a good therapeutic effect.

[0279] 实施例48格列吡嗪、罗格列酮和叶酸组合物对糖尿病大鼠血糖、同型半胱氨酸、 内皮细胞功能和肾脏病变的影响 Homocysteine, Effects [0279] Example 48 glipizide, rosiglitazone and folic acid compositions for diabetic rats, endothelial cells and renal lesions

[0280] 实验方法同实施例43。 [0280] Example 43 the same experimental procedure. 结果见表11。 The results are shown in Table 11.

[0281] 表11格列吡嗪、罗格列酮和叶酸组合物对糖尿病大鼠的作用(文士S, η=10) [0281] Table 11 glipizide, rosiglitazone and folic acid composition on diabetic rats (scribes S, η = 10)

[0282] [0282]

Figure CN101103993BD00351

[0283] 注:对照组与模型组比较,flP < 0. 05,flflP < 0. 01,###P < 0. 001 ;各给药组与模型组比较,*P < 0. 05,**P <0.01, ***P < 0. 001 ;各给药组与格列吡嗪+罗格列酮+叶酸组比较,ΔΡ < 0. 05,δδΡ < 0. 01,ΔΔΔΡ < 0. 001。 [0283] Note: Compared with model control group, flP <0. 05, flflP <0. 01, ### P <0. 001; compare each treatment group and the model group, * P <0. 05, * * P <0.01, *** P <0. 001; in each treatment group and glipizide + rosiglitazone + folic group, ΔΡ <0. 05, δδΡ <0. 01, ΔΔΔΡ <0. 001 .

[0284] 续表11格列吡嗪、罗格列酮和叶酸组合物对糖尿病大鼠的作用士S, η=10) [0284] Continued Table 11 glipizide, rosiglitazone and folic acid composition effect on diabetic rats Christie S, η = 10)

[0285] [0285]

Figure CN101103993BD00352

[0286] 注:对照组与模型组比较,flP < 0. 05,flflP < 0. 01,###P < 0. 001 ;各给药组与模型组比较,*P < 0. 05,**P <0.01, ***P < 0. 001 ;各给药组与格列吡嗪+罗格列酮+叶酸组比较,ΔΡ < 0. 05,δδΡ < 0. 01,ΔΔΔΡ < 0. 001。 [0286] Note: Compared with model control group, flP <0. 05, flflP <0. 01, ### P <0. 001; compare each treatment group and the model group, * P <0. 05, * * P <0.01, *** P <0. 001; in each treatment group and glipizide + rosiglitazone + folic group, ΔΡ <0. 05, δδΡ <0. 01, ΔΔΔΡ <0. 001 .

[0287] 结论:上述结果表明,格列吡嗪、罗格列酮和叶酸组合物可显著降低糖尿病大鼠的血糖、同型半胱氨酸水平,保护糖尿病引起的内皮细胞损伤及肾脏病变(P <0.01或0. 001),格列吡嗪+罗格列酮+叶酸组合物降糖作用优于单方格列吡嗪及叶酸(P < 0. 05 或0. 001);降同型半胱氨酸水平优于单方格列齐特及罗格列酮(P < 0. 01或0. 001);对糖尿病引起的内皮细胞功能损伤及肾脏病变的保护作用也明显优于单方或任两种组份的组合(P <0.05或0.01)。 [0287] Conclusion: The above results show, glipizide, rosiglitazone and folic acid compositions can significantly reduce blood glucose in diabetic rats, homocysteine ​​levels, protection of endothelial cell injury and renal lesions (P caused by diabetes <0.01 or 0.001), glipizide + rosiglitazone folic acid composition hypoglycemic effect than single grid glipizide and folate (P <0. 05 or 0.001); drop homocysteic gliclazide acid levels lower than unilateral and rosiglitazone (P <0. 01 or 0.001); injury of endothelial cells and the protective effect of diabetic kidney disease significantly better than any two or unilaterally parts of a combination of species group (P <0.05 or 0.01). 说明格列吡嗪、罗格列酮和叶酸组合物对糖尿病大鼠血糖、同型半胱氨酸、内皮细胞功能和肾脏病变均具有良好的治疗效果。 He said Minge glipizide, rosiglitazone and folic acid compositions for diabetic rats, homocysteine, endothelial cell function and renal lesions have a good therapeutic effect.

Claims (5)

1. 一种降糖药物组合物,由药用剂量的磺脲类降糖药物中的一种、药用剂量的噻唑烷二酮类降糖药物中的一种、药用剂量的B族维生素中的一种及可药用载体或赋形剂组成, 其特征在于:所述噻唑烷二酮类降糖药物是罗格列酮,含量为Img〜8mg ;所述B族维生素是叶酸,含量为0. Img〜7. 5mg ;所述磺脲类降糖药物是格列美脲、格列本脲、格列齐特、格列喹酮或格列吡嗪,其中,格列美脲的含量为Img〜4mg,格列本脲的含量为Img〜15mg,格列齐特的含量为20mg〜160mg,格列喹酮的含量为15mg〜60mg,格列吡嗪的含量为Img〜 15mg。 A hypoglycemic pharmaceutical composition from a pharmaceutical dosage sulfonylureas in a pharmaceutically acceptable dosage thiazolidine diones hypoglycemic drugs, pharmaceutical dosage vitamin B of one and a pharmaceutically acceptable carrier or excipient, characterized in that: said thiazolidine diones rosiglitazone antidiabetic drugs, an amount of Img~8mg; the B vitamins folate content is 0. Img~7 5mg;. the sulfonylureas are glimepiride, glibenclamide, gliclazide, gliquidone or glipizide, wherein the glimepiride content Img~4mg, glibenclamide content is Img~15mg, gliclazide content is 20mg~160mg, gliquidone content is 15mg~60mg, glipizide content is Img~ 15mg.
2. 一种降糖药物组合物,由药用剂量的磺脲类降糖药物中的一种、药用剂量的噻唑烷二酮类降糖药物中的一种、药用剂量的B族维生素中的一种及可药用载体或赋形剂组成, 其特征在于:所述噻唑烷二酮类降糖药物是吡格列酮,含量为7. 5mg〜45mg ;所述B族维生素是叶酸,含量为0. Img〜7. 5mg ;所述磺脲类降糖药物是格列美脲,含量为Img〜4mg。 A hypoglycemic pharmaceutical composition from a pharmaceutical dosage sulfonylureas in a pharmaceutically acceptable dosage thiazolidine diones hypoglycemic drugs, pharmaceutical dosage vitamin B a medium and a pharmaceutically acceptable carrier or excipient, characterized in that: said hypoglycemic thiazolidine diones drug is pioglitazone, an amount of 7. 5mg~45mg; the B vitamins folate, an amount of 0. Img~7 5mg;. the sulfonylureas are glimepiride, content Img~4mg.
3.权利要求1至2任何一项所述的药物组合物,其特征在于:所述的药物组合物的剂型为片剂或胶囊剂。 1 2 any pharmaceutical composition according to any one of claim 1, wherein: the pharmaceutical dosage composition is a tablet or capsule.
4.权利要求1至3中任何一项所述的药物组合物在制备治疗糖尿病的药物中的用途。 1 to 3, any one of the pharmaceutical compositions for use in the manufacture of a medicament for treating diabetes in a claim.
5.权利要求1至3中任何一项所述的药物组合物在制备预防糖尿病并发症的药物中的用途。 1 to 3, a pharmaceutical composition of any one of the manufacture of a medicament for the prevention of diabetic complications in claim.
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Publication number Priority date Publication date Assignee Title
CN1263467A (en) 1997-07-18 2000-08-16 史密丝克莱恩比彻姆有限公司 Treatment of diabetes with thiazolidinedione, insulin secretagogue and alpha glucocidase inhibitor

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1263467A (en) 1997-07-18 2000-08-16 史密丝克莱恩比彻姆有限公司 Treatment of diabetes with thiazolidinedione, insulin secretagogue and alpha glucocidase inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
刘蜀宝."药剂学" 2004年8月第1版.郑州大学出版社,2004,第197-198页,第507页.

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