CN1327840C - Medicinal composition and its use in treatment of diabetes - Google Patents

Medicinal composition and its use in treatment of diabetes Download PDF

Info

Publication number
CN1327840C
CN1327840C CN 200410019483 CN200410019483A CN1327840C CN 1327840 C CN1327840 C CN 1327840C CN 200410019483 CN200410019483 CN 200410019483 CN 200410019483 A CN200410019483 A CN 200410019483A CN 1327840 C CN1327840 C CN 1327840C
Authority
CN
China
Prior art keywords
pioglitazone
metformin
hydrochloride
sheet
pharmaceutical composition
Prior art date
Application number
CN 200410019483
Other languages
Chinese (zh)
Other versions
CN1582928A (en
Inventor
王杏林
徐维钰
张宗鹏
陈学民
郑家通
田义红
Original Assignee
天津药物研究院
连云港德源药业有限责任公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 天津药物研究院, 连云港德源药业有限责任公司 filed Critical 天津药物研究院
Priority to CN 200410019483 priority Critical patent/CN1327840C/en
Publication of CN1582928A publication Critical patent/CN1582928A/en
Application granted granted Critical
Publication of CN1327840C publication Critical patent/CN1327840C/en

Links

Abstract

本发明公开了一种药物组合物,该组合物含有5mg~60mg吡格列酮或其药学上可接受的盐,和不超过3000mg的二甲双胍或其药学上可接受的盐及一种或一种以上的药学上可接受的载体。 The present invention discloses a pharmaceutical composition, the composition comprising a pharmaceutically 5mg ~ 60mg of pioglitazone or a pharmaceutically acceptable salt thereof, and a pharmaceutically no more than 3000mg of metformin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier. 通过制成不同配比的复方制剂,改善服药方式,减少了服药次数,每日一次,方便患者长期服用。 Compound preparation made by different proportions, improved medication the way, reducing the number of medication once a day for the convenience of patients long-term use. 本发明同时也公开了该组合物在制备用于治疗和/或预防糖尿病、与糖尿病有关的疾病及其某些并发症中的应用。 The present invention is also disclosed and / or applications associated with diabetes mellitus and certain complications in diseases of the composition for the treatment prophylaxis of diabetes.

Description

一种药物组合物及其在制备用于治疗糖尿病中的应用 A pharmaceutical composition for the treatment and its application in diabetic

技术领域 FIELD

本发明属于治疗糖尿病药物领域,更具体地说是涉及一种吡格列酮和二甲双胍的药物组合物,以及该组合物制备在用于治疗和/或预防糖尿病、与糖尿病有关的疾病及其某些并发症中的应用。 The present invention is in the field of diabetes treatment drugs, and more particularly relates to the preparation of pioglitazone and metformin pharmaceutical compositions, and compositions for the treatment and / or prophylaxis of diabetes mellitus, diseases associated with diabetes mellitus and certain complications of application.

背景技术 Background technique

糖尿病是一组由遗传和环境因素相互作用而引起的临床综合症。 Diabetes is a group of genetic and environmental factors interact to cause the clinical syndrome. 据流行病学调查估计目前全球糖尿病患者总数已逾一亿,其中90%左右为II型糖尿病,其发病机理为胰岛素抵抗为主,伴有胰岛素分泌缺陷或胰岛素分泌缺陷为主,伴胰岛素抵抗和肝脏葡萄糖产生增加。 According to epidemiological survey estimated that the total number of people with diabetes worldwide for more than one hundred million, of which about 90% of type II diabetes, insulin resistance and its pathogenesis is mainly associated with defects in insulin secretion or insulin secretory defect mainly associated with insulin resistance and hepatic glucose production increases. II型糖尿病患者常伴有肥胖、高血压、高脂血症、脂肪肝及冠心病等疾病。 Patients with type II diabetes is often accompanied by obesity, hypertension, hyperlipidemia, fatty liver and coronary heart disease.

美国专利第3174901号公开了双胍类抗高血糖药二甲双胍,其控制血糖的辅助机制是抑制肝脏产生葡萄糖和增加外周摄取葡萄糖,由此降低胰岛素抗性。 U.S. Patent No. 3,174,901 discloses a biguanide antihyperglycemic agent metformin, glycemic control mechanisms assist to suppress hepatic glucose production and increasing peripheral glucose uptake, thereby reducing insulin resistance.

日本专利昭61-267580,欧洲专利Ep193256,美国专利US4687777公开了噻唑烷二酮类胰岛素增敏剂吡格列酮的抗高血糖和调节脂代谢作用,其作用机制与胰岛素存在有关,可减少外周组织和肝脏的胰岛素抗性,增加依赖胰岛素的葡萄糖处理,并减少肝糖的输出。 Japanese Patent No. Sho 61-267580, in European Patent Ep193256, U.S. Patent No. US4687777 discloses a thiazolidine diones insulin sensitizer pioglitazone antihyperglycemic and regulate lipid metabolism, the mechanism of which the presence of insulin may be directed to reduce the peripheral tissues and liver insulin resistance, increase insulin-dependent glucose disposal and reduce hepatic glucose output is. 下列文献公开了吡格列酮与二甲双胍联合应用的实例:(1)Einhorn D等Pioglitazonehydrochloride in combination with metformin in the treatment of type 2 diabetesmellitus:a randomized,placebo-controlled study.Clin Ther.2000Dec;22(12):1395-409.公开了在单独使用二甲双胍血糖控制不佳时,与盐酸吡格列酮联合应用的治疗效果和耐受性。 The following discloses example pioglitazone and metformin of: (1) Einhorn D like Pioglitazonehydrochloride in combination with metformin in the treatment of type 2 diabetesmellitus: a randomized, placebo-controlled study.Clin Ther.2000Dec; 22 (12): 1395 -409. when used alone, it discloses a poor blood glucose control with metformin, and pioglitazone hydrochloride combined therapeutic effect and tolerability.

(2)Suzuki M等Effects of combined pioglitazone and metformin on diabetes andobesity in Wistar fatty rats.Clin Exp Pharmacol Physiol.2002 Apr;29(4):269-74.公开了盐酸吡格列酮和盐酸二甲双胍联合应用,对高血糖、高甘油酯血、高酮血的Wistar肥胖大鼠的治疗效果。 (2) Suzuki M, etc. Effects of combined pioglitazone and metformin on diabetes andobesity in Wistar fatty rats.Clin Exp Pharmacol Physiol.2002 Apr; 29 (4): 269-74 discloses pioglitazone hydrochloride and metformin hydrochloride combined, hyperglycemia. high blood glycerides, high blood ketone Wistar rats of obesity treatment.

(3)潘长玉等在《盐酸二甲双胍治疗II型糖尿病的有效性和安全性的多中心临床研究》中公开了盐酸吡格列酮与磺脲类或双胍类联合应用时降糖效果和安全性。 (3) Pan Changyu like "metformin hydrochloride multicenter study of the efficacy and safety of treatment of type II diabetes," discloses pioglitazone when sulfonylureas or biguanides in combination with a hypoglycemic effect and safety of hydrochloric acid.

吡格列酮是一种噻唑烷酮类胰岛素抵抗改善剂,降低胰岛素抵抗,保护β细胞功能,能有效治疗非胰岛素依赖性糖尿病肥胖患者的糖、脂异常。 Pioglitazone is a thiazolidinone insulin resistance improving agents, reducing insulin resistance, β cell function protection, effective in the treatment of glucose non-insulin dependent diabetes mellitus in obese patients and lipid abnormalities. 二甲双胍现已被广泛接受为轻、中度型糖尿病患者特别是肥胖患者的首选抗高血糖药物。 Metformin is now widely accepted as mild to moderate in patients with diabetes especially in obese patients preferred antihyperglycemic drugs. 甚至对于II型糖尿病的中间阶段-IGT(葡萄糖耐量减低),亦有干预作用,可阻止或延缓由IGT状态进入糖尿病阶段。 Even for intermediate stage -IGT type II diabetes (impaired glucose tolerance), also intervention can prevent or delay diabetes by the IGT state to enter the stage.

胰岛素抵抗是II型糖尿病初始阶段的主要缺陷。 Insulin resistance is a major drawback in the initial stage of type II diabetes. 胰岛素抵抗贯穿于II型糖尿病的发生、发展全过程,而噻唑烷二酮类盐酸吡格列酮与二甲双胍皆具降低胰岛素抵抗效果,但二者的作用机制不同,二者的作用部位也有差别,吡格列酮主要促进外周组织(骨骼肌)摄取葡萄糖,可用于II型糖尿病的胰岛素耐受性,而二甲双胍主要抑制肝葡萄糖输出,故二者合用,作用集中在代谢缺陷,抗糖尿病效果可加强,有助于较单独使用二甲双胍达到更好的控制血糖。 Insulin resistance throughout the occurrence of type II diabetes, the development of the entire process, and thiazolidine diones hydrochloride pioglitazone and metformin Jieju reduce insulin resistance effect, but with different mechanisms of action between the two, the site of action of both there are differences, pioglitazone major promoter peripheral tissues (skeletal muscle) uptake of glucose, insulin resistance can be used for type II diabetes, metformin mainly inhibit hepatic glucose output, so the two combined, concentrated on the role of metabolic defects, can enhance the antidiabetic effects, alone contribute more metformin achieve better control of blood sugar.

发明内容 SUMMARY

现在,有令人惊奇的现实表明,吡格列酮与二甲双胍的联合药物形式可提供特别有益的血糖控制作用而没有观察到副作用,观察到的协同作用在于低血糖的显著改善,因此这种联合药物形式特别可用于治疗糖尿病,尤其是II型糖病和与糖尿病有关的疾病。 Now, surprisingly, reality shows, combination drug form pioglitazone and metformin may provide particularly beneficial glycemic control action without side effects were observed synergy observed that significant improvement in low blood sugar, so this combination drug form is particularly useful for the treatment of diabetes, particularly type II diabetes disease and saccharide-related diseases.

因此,本发明提供了一种哺乳动物如人的糖尿病的治疗方法,该方法包含给予需要这种治疗的哺乳动物有效、无毒且药学上可接受量的胰岛素增敏剂如吡格列酮或其药学上可接受的盐,和双胍类抗高血糖剂如二甲双胍或其药学上可接受的盐的药物组合物,其中,吡格列酮或其药学上可接受的盐的用量为5-60mg,二甲双胍或其药学上可接受的盐的用量为不超过3000mg。 Accordingly, the present invention provides a method of treating diabetes in a mammal such as a human, which method comprises administering to a mammal in need of such treatment an effective, non-toxic and pharmaceutically acceptable amount of an insulin sensitizer such as pioglitazone or a pharmaceutically acceptable acceptable salt thereof, and a biguanide antihyperglycaemic agent, such as metformin or a pharmaceutically acceptable salt thereof in a pharmaceutical composition, wherein the amount of pharmaceutically pioglitazone or a pharmaceutically acceptable salt thereof is 5-60 mg, metformin or a pharmaceutically acceptable salt amounts to no more than 3000mg.

应当理解,吡格列酮和二甲双胍是分别以其药学上可接受的形式做为适当的相关药物活性剂给药的,包括其药学上可接受的衍生物如药学上可接受的盐、酯和溶剂化物。 It should be understood, Pioglitazone and Metformin are their pharmaceutically acceptable administration form as appropriate, relevant pharmaceutically active agent, comprising a pharmaceutically acceptable derivative thereof Pharmaceutically acceptable salts, esters and solvates thereof such as. 应理解,本发明包括活性剂本身的所有药学上可接受的形式。 It should be understood, the present invention includes all pharmaceutically acceptable forms of the active agent itself. 二甲双胍的合适的药学上可接受的形式是酸加成盐,如盐酸盐、乙酸盐、苯甲酸盐、甲磺酸盐、马来酸盐等,然而,优选使用二甲双胍本身或其盐酸盐。 Suitable pharmaceutically acceptable form of metformin is an acid addition salt, such as hydrochloride, acetate, benzoate, methanesulfonate, maleate and the like, however, preferably metformin or a salt thereof per se salt. 参照US3174901方法通过二甲双胍与相应的酸反应得到二甲双胍的可药用盐。 Referring US3174901 method of metformin resulting acid with a corresponding pharmaceutically acceptable salt of metformin.

吡格列酮合适的药学上可接受的盐包括盐酸盐、甲酸盐、富马酸盐、乙酸盐、苯甲酸盐、甲磺酸盐、硫酸盐、马来酸盐等,然而,优选使用吡格列酮本身或其盐酸盐。 Pharmaceutically pioglitazone Suitable pharmaceutically acceptable salts include hydrochloride, formate, fumarate, acetate, benzoate, methanesulfonate, sulfate, maleate and the like, however, it is preferred to use pioglitazone or its hydrochloride salt itself. 参照EP193256方法可制备吡格列酮的可药用盐。 Pioglitazone pharmaceutically acceptable salts can be prepared with reference to EP193256 method.

在一个特定方面,该方法包含给予5~60mg吡格列酮或盐酸吡格列酮,尤其是当每天给药时。 In a particular aspect, the method comprises administering 5 ~ 60mg or pioglitazone pioglitazone hydrochloride, especially when administered per day.

特别是,该方法包含每天给予5~15、15~30、30~45、45~60mg吡格列酮或盐酸吡格列酮。 In particular, the method comprises administering 5 ~ 15,15 ~ 30,30 ~ 45,45 ~ 60mg or pioglitazone pioglitazone hydrochloride per day topiramate.

特别是,该方法包含每天给予5~15mg吡格列酮或盐酸吡格列酮,尤其是当每天给药时。 In particular, the method comprises administering 5 ~ 15mg per day pioglitazone hydrochloride, rosiglitazone or pioglitazone, especially when administered per day.

特别是,该方法包含每天给予15~30mg吡格列酮或盐酸吡格列酮,尤其是当每天给药时。 In particular, the method comprises administering a daily 15 ~ 30mg pioglitazone hydrochloride, rosiglitazone or pioglitazone, especially when administered per day.

特别是,该方法包含每天给予30~45mg吡格列酮或盐酸吡格列酮,尤其是当每天给药时。 In particular, the method comprises administering 30 ~ 45mg per day pioglitazone hydrochloride, rosiglitazone or pioglitazone, especially when administered per day.

特别是,该方法包含每天给予45~60mg吡格列酮或盐酸吡格列酮,尤其是当每天给药时。 In particular, the method comprises administering 45 ~ 60mg per day pioglitazone hydrochloride, rosiglitazone or pioglitazone, especially when administered per day.

优选的是,该方法包含每天给予5mg吡格列酮或盐酸吡格列酮,尤其是当每天给药时。 Preferably, the method comprises administering to 5mg per day or pioglitazone pioglitazone hydrochloride, especially when administered per day.

优选的是,该方法包含每天给予10mg吡格列酮或盐酸吡格列酮,尤其是当每天给药时。 Preferably, the method comprises administering to 10mg per day or pioglitazone pioglitazone hydrochloride, especially when administered per day.

优选的是,该方法包含每天给予15mg吡格列酮或盐酸吡格列酮,尤其是当每天给药时。 Preferably, the method comprises administering to 15mg per day or pioglitazone pioglitazone hydrochloride, especially when administered per day.

优选的是,该方法包含每天给予30mg吡格列酮或盐酸吡格列酮,尤其是当每天给药时。 Preferably, the method comprises administering to 30mg per day or pioglitazone pioglitazone hydrochloride, especially when administered per day.

优选的是,该方法包含每天给予45mg吡格列酮或盐酸吡格列酮,尤其是当每天给药时。 Preferably, the method comprises administering to 45mg per day or pioglitazone pioglitazone hydrochloride, especially when administered per day.

优选的是,该方法包含每天给予60mg吡格列酮或盐酸吡格列酮,尤其是当每天给药时。 Preferably, the method comprises administering to 60mg per day or pioglitazone pioglitazone hydrochloride, especially when administered per day.

在一个特定方面,该方法包含给予不超过3000mg的二甲双胍或盐酸二甲双胍,尤其是当每天给药时。 In a particular aspect, the method comprises administering to no more than 3000mg of metformin or metformin hydrochloride, especially when administered per day. 特别优选的是,二甲双胍或盐酸二甲双胍的用量为250mg、750mg、1000mg,尤其是当每天给药时。 Particularly it preferred that the amount of metformin or metformin hydrochloride is 250mg, 750mg, 1000mg, especially when administered per day.

本发明解决了糖尿病患者需要长期多次服药的烦恼,通过制成不同配比的复方制剂,改善服药方式,减少了服药次数,每日一次,方便患者长期服用。 The invention solves the long-term diabetic patients need several doses of trouble, made by different proportions of compound preparation, improved medication the way, reducing the number of medication once a day for the convenience of patients long-term use.

另一方面,本发明提供了一种吡格列酮与二甲双胍在制备用于治疗和/或预防糖尿病、与糖尿病有关的疾病,及其某些并发症中的应用,特别是,治疗糖尿病尤其是II型糖尿病和与糖尿病有关的疾病的方法中的应用。 Another aspect, the present invention provides a pioglitazone and metformin for the treatment and / or prophylaxis of diabetes, diseases associated with diabetes and its application in some complications, in particular, the treatment of diabetes, particularly type II diabetes applications and diabetes-related diseases of the methods. 该方法包含将吡格列酮与二甲双胍同时给药。 The method comprises simultaneous administration of metformin and pioglitazone. 同时给药包括给予吡格列酮与二甲双胍的制剂,或者将每种活性剂的单独制剂基本上同时给药。 Simultaneous administration includes administering the formulation pioglitazone and metformin, or separate formulations of each active agent administered substantially simultaneously.

经大量的临床研究已证实,II型糖尿病诊断后3年内若只用一种药治疗,葡萄糖控制进展性下降,有互补作用的两药联合治疗经常被用来得到最大治疗效应和减小副作用。 The large number of clinical studies have confirmed diagnosis of Type II diabetes after three years, if only by a drug treatment, progressive decline in glucose control, are complementary two-drug combination therapy is often used to obtain the maximum therapeutic effect and reduce side effects. 吡格列酮与二甲双胍两药联合应用不仅有效地控制血糖、降低胰岛素抵抗、保护β细胞功能,同时降低了低血糖的发生率,起到了协同作用。 Pioglitazone and metformin combination of both drugs is not only effective glycemic control, decreasing insulin resistance, β cell function protection, while reducing the incidence of hypoglycemia, has played a synergistic effect. 两药联合应用可延缓和阻止疾病的发展,预防糖尿病的长期并发症,如心脏病、失明、截肢和肾衰竭。 Two drugs in combination can delay and prevent the development of disease, prevention of long-term complications of diabetes, such as heart disease, blindness, amputation and kidney failure.

本文中使用的术语“与糖尿病有关的疾病”包括与前驱糖尿病状态有关的那些疾病、与糖尿病自身有关的疾病和与糖尿病有关的并发症。 The term used herein 'disorders associated with diabetes "includes those disease states associated with prediabetes, diabetes-related diseases and their complications associated with diabetes.

本文中使用的术语“与前驱糖尿病状态有关的那些疾病”包括诸如胰岛素抵抗疾病,包括遗传性胰岛素抵抗、葡萄糖耐量减弱和高胰岛素血。 The term used herein "those diseases associated with the pre-diabetic state" includes diseases such as insulin resistance, including hereditary insulin resistance, impaired glucose tolerance, and hyperinsulinemia.

本文中使用的术语“与糖尿病自身有关的疾病”包括高血糖,胰岛素抵抗,包括后天胰岛素抵抗和肥胖。 The term used herein 'disorders associated with diabetes mellitus itself "include hyperglycaemia, insulin resistance, including acquired insulin resistance and obesity. 其他与糖尿病有关的疾病包括高血压和心血管疾病,尤其是动脉粥样硬化和与胰岛素有关的疾病。 Other diseases associated with diabetes include hypertension and cardiovascular disease, especially atherosclerosis and diseases associated with insulin. 与胰岛素有关的疾病包括多囊性卵巢综合征和类固醇诱导的胰岛素抵抗和妊娠糖尿病。 Insulin-related diseases include polycystic ovarian syndrome and steroid induced insulin resistance and gestational diabetes.

“与糖尿病有关的并发症”包括肾脏疾病,尤其是与II型糖尿病有关的肾脏疾病,神经病和视网膜病。 "Complications associated with diabetes' includes renal disease, especially type II diabetes associated with kidney disease, neuropathy and retinopathy.

与II型糖尿病有关的肾脏疾病包括肾病,肾小球肾炎,肾小球硬化症,肾病综合征,高血压性肾硬化和晚期肾脏疾病。 Associated with type II diabetes, kidney diseases, including nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.

本文中所用的术语“药学上可接受的”包含任何兽医用途:例如术语“药学上可接受的”包含兽医学上可接受的化合物。 As used herein, the term "pharmaceutically acceptable" encompasses any veterinary use: for example the term "pharmaceutically acceptable" includes veterinarily acceptable compound.

通过本发明治疗提供的特别有益的血糖控制作用,指示为相对于对照的协同作用,该对照预期为单独的活性药剂的作用总和。 Particularly advantageous action of glycemic control provided by the treatment of the invention, indicating a synergistic effect relative to the control, the control action is expected to be the sum of the individual active agent.

在一个优选的方面,当根据本发明治疗而使用时,所用的各种活性剂的剂量水平将小于达到单纯加和的血糖控制作用可能需要的剂量。 In a preferred aspect, when used in accordance with the present invention the treatment, various dosage levels of active agent employed will be less than the simple sum of the dose to achieve glycemic control action may be required.

再一方面,本发明提供了一种含有吡格列酮与二甲双胍的药物组合物。 Another aspect, the present invention provides a pharmaceutical composition comprising pioglitazone and metformin. 该组合物含有5~60mg吡格列酮或盐酸吡格列酮和不超过3000mg,二甲双胍或盐酸二甲双胍及一种或一种以上的药学上可接受的载体。 The composition comprises a carrier 5 ~ 60mg pioglitazone pioglitazone hydrochloride, or does not exceed 3000mg, metformin or metformin hydrochloride acceptable and one or more pharmaceutically.

通常该组合物适于口服给药,但是,它们也适合其他的给药方式,例如胃肠外给药、舌下给药或经皮给药。 Typically, this composition is suitable for oral administration, however, they are also suitable for other modes of administration, for example parenteral administration, sublingual or transdermal administration.

为了达到给药的一致性,本发明组合物优选为单剂形式。 In order to achieve consistency of administration, the compositions of the present invention is preferably a single agent.

用于口服给药的单剂表示形式可以是片剂和胶囊,可含有以下赋性剂诸如填充剂,乳糖、蔗糖、淀粉、微晶纤维素、山梨醇、磷酸钙;粘合剂,例如糖浆、明胶、羟丙基甲基纤维素、聚乙烯吡咯烷酮、淀粉、糊精;崩解剂,例如微晶纤维素、羧甲基淀粉钠、羧甲基纤维素钠、交联聚乙烯吡咯烷酮;润滑剂,例如硬脂酸镁;高分子骨架材料,例如羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素、巴西棕榈蜡、氢化植物油、丙烯酸树脂;成膜材料,例如羟丙基甲基纤维素、聚乙烯吡咯烷酮、丙烯酸树脂等。 Single dose for oral administration may be a representation of tablets and capsules, may contain the following excipients such as fillers, lactose, sucrose, starch, microcrystalline cellulose, sorbitol, calcium phosphates; binders, for example syrup, gelatin, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, dextrin; disintegrants such as microcrystalline cellulose, sodium carboxymethyl starch, sodium carboxymethyl cellulose, crosslinked polyvinylpyrrolidone; lubricants such as magnesium stearate; a polymer matrix material, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, carnauba wax, hydrogenated vegetable oil, an acrylic resin; film forming materials, such as hydroxypropyl methyl cellulose, polyvinylpyrrolidone, acrylic resin or the like.

本发明优选的药物组合物的制备方法,可制成含5~60mg速释吡格列酮或其药用盐和不超过3000mg缓释二甲双胍或其药用盐的上下双层片,或可制成内层为不超过3000mg缓释二甲双胍或其药用盐,外层为含5~60mg速释的吡格列酮或其药用盐的双层片。 The preferred method of preparing the pharmaceutical compositions of the present invention, can be prepared to contain 5 ~ 60mg immediate release pioglitazone or a pharmaceutically acceptable salt thereof and a sustained release of no more than 3000mg of metformin or a pharmaceutically acceptable salt thereof bunk sheet, or inner layer can be made pioglitazone or a pharmaceutically acceptable salt thereof for the bilayer tablet does not exceed 3000mg extended release metformin or a pharmaceutically acceptable salt thereof, an outer layer containing 5 ~ 60mg immediate release.

本发明中二甲双胍或其药用盐制成每天只需服用一次的缓释片,能在体内缓慢释放,维持血药浓度平稳,半衰期延长,安全、高效、低毒、服用方便,副作用和配伍禁忌较少,并方便与吡格列酮或其药用盐制成不同配比的复方制剂,且病人服用方便,不易漏服,增加了用药的顺从型。 In the present invention, metformin or a pharmaceutically acceptable salt thereof is made only once-daily sustained-release tablets, slow release in the body, to maintain stable plasma concentration, half-life, safety, efficiency, low toxicity, easy to take, incompatibility, and side effects less convenient and different ratio of compound preparation of the pioglitazone or a pharmaceutically acceptable salt thereof is made, and patients taking convenient, easily missed, an increase of drug-compliant.

这些组合物优选以与相关日剂量适宜的量制成单位剂型。 The composition is preferably associated with a suitable amount of daily dosage unit dosage form.

合适的吡格列酮的单位剂量包含5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45mg吡格列酮。 Suitable pioglitazone unit dosage comprising 5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26 , 27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45mg pioglitazone.

本发明的组合物可以每天给药1~3次,但优选每天给药1或2次。 The composition of the present invention may be administered 1 to 3 times a day, but preferably 1 or 2 times per day of administration.

吡格列酮特定剂量是5mg/天,10mg/天,15mg/天,30mg/天,45mg/天、60mg/天。 Pioglitazone specific dose is 5mg / day, 10mg / day, 15mg / day, 30mg / day, 45mg / day, 60mg / day.

二甲双胍合适的剂量包括每天不超过3000mg,优选以250mg、500mg、1000mg、1500mg或2000mg的单位剂量给药,二甲双胍剂量的一个例子是每次1000mg、每日一次。 Suitable dosages of metformin include not more than 3000 mg of per day, preferably 250mg, 500mg, 1000mg, 1500mg or 2000mg example of a unit dose, metformin per dose is lOOOmg, once a day.

吡格列酮和二甲双胍合适的单位剂量还包括这些化合物的已知剂量,如参考书中国药典、美国药典、英国药典、欧洲药典及PHYSICINS'DESK REFERENCE中描述或提到的。 Pioglitazone and metformin suitable unit doses also include known dosage of such compounds, reference books such as the Chinese Pharmacopoeia, United States Pharmacopoeia, the British Pharmacopoeia, the European Pharmacopoeia and PHYSICINS'DESK REFERENCE described or mentioned.

以下通过药理的急性、毒性实验,药代动力学实验,药效学实验进一步阐述本发明。 The following pharmacological by acute toxicity test, pharmacokinetic experiments, pharmacodynamic experiments further illustrate the present invention.

一、复方二甲双胍/吡格列酮急性毒性试验:1、试验目的:观察复方二甲双胍/吡格列酮不同配比(500∶7.5、500∶15、500∶30)单次口服给药后小鼠产生的急性毒性反应及死亡分布情况,计算LD50值。 First, the compound metformin / pioglitazone acute toxicity test: 1, Test Objective: acute toxicity compound metformin / pioglitazone different ratio (500:7.5,500:15,500:30) after single oral administration to mice and death distribution, calculated LD50 value. 为药效学试验、多次反复给药的毒性试验的复方配比和剂量设计及临床安全性提供参考。 As pharmacodynamics, toxicity test compound administered repeatedly and dose ratio clinical safety and design reference.

2、实验材料:(1)实验动物昆明种小鼠,雌雄各半,体重18-22g。 2 Experimental Materials: (1) Test Animals Kunming mice, male and female, weighing 18-22g. 实验动物设施:二级;合格证号:津实动设施准第012号;实验动物合格证:WJ津实动质R准字第001号。 Experimental Animal: two; qualified No: move Azumi facility registration No. 012; laboratory animals certificate: WJ Azumi movable mass 001 No. R-word. 实验环境和条件:室温22±4℃,湿度60±20%。 And experimental environment conditions: temperature 22 ± 4 ℃, humidity of 60 ± 20%. 中央空调自动通风。 Automatic central air conditioning and ventilation. 光照12小时。 Light for 12 hours. 自由摄食和饮用自来水。 Free access to food and drinking water. 每日换水一次。 Changing the water once a day.

(2)实验药物复方二甲双胍/吡格列酮,药物用1%CMC配制成100mg/ml的混悬药液。 (2) Test drug combination metformin / pioglitazone, drugs formulated with 1% CMC suspended liquid 100mg / ml of.

3、实验方法和结果:(1)实验方法:昆明种小鼠50只,雌雄各半,按性别随机分为5组,分别为5000、4000、3200、2560、2048mg/kg五个剂量组。 3. Testing methods and results: (1) Experimental Method: 50 Kunming mice, male and female, were randomly divided into 5 groups according to sex, were 5000,4000,3200,2560,2048mg / kg five dose groups. 动物禁食6小时给药。 Animals were fasted 6 hours of administration. 将药物用1%CMC混悬配制成100mg/ml的药液,采用等浓度不等体积的方式给药,给药体积分别为0.50、0.40、0.32、0.26、0.20ml/10g。 Administration of the drug suspended in 1% CMC with formulated chemical 100mg / ml, using isocratic manner unequal volumes, respectively dosing volume 0.50,0.40,0.32,0.26,0.20ml / 10g. 药后观察动物的毒性反应及其发生时间,死亡情况及时间,死亡动物进行解剖学检查,必要时进行组织学检查;存活动物连续观察14天,在试验的0、1、3、7、14天称体重,在第14天对部分存活动物进行解剖观察。 Animals were observed and the time after the drug toxicity occurs, time and death, dead animals were dissected examination, histological examination, if necessary; surviving animals were observed for 14 consecutive days 0,1,3,7,14 in the test day weighed on the part of the surviving animals were dissected observed on day 14. 统计动物死亡情况,计算半数致死量和动物体重的变化。 Animal mortality statistics, calculate the change in the median lethal dose and weight of the animal.

(2)实验结果:复方二甲双胍/吡格列酮(500∶7.5)口服给药急性毒性试验:口服给予复方二甲双胍/吡格列酮(500∶7.5),药后10-30分钟动物出现活动减少,部分动物出现闭眼(1-6/10);药后1小时,5只动物出现腹泻;药后2小时,10只动物出现腹泻。 (2) Results: compound metformin / pioglitazone (500:7.5) Acute toxicity test for oral administration: for oral administration of compound metformin / pioglitazone (500:7.5), 10 to 30 minutes after the drug appears to reduce the activity of animals, some animals with eyes closed appears (1-6 / 10); 1 hour after administration, five animals diarrhea; 2 hours after administration, 10 animals diarrhea. 毒性反应发生的时间、动物数及严重程度与给药剂量呈正相关。 Toxicity occurred at a time, the number of animals and the severity of dose positive correlation. 动物死亡最早出现在药后5小时,所有动物死亡均发生在药后18小时内。 Animals died first appeared in five hours after the drug, death occurred in all animals within 18 hours after the drug. 对死亡动物剖检,可见部分动物(6只)轻度肺出血,其它脏器未见任何明显病变。 Necropsy of dead animals, the visible part of the animal (6) mild pulmonary hemorrhage, other organs did not show any obvious lesions. 药后18小时,所有存活动物基本恢复正常活动。 18 hours after the drug, all surviving animals returned to normal activity. 存活动物在14天的观察期内未见死亡,动物体重增长未受明显影响。 Surviving animals were no deaths during the 14-day observation period, the animal weight gain was unaffected. 第14天取部分存活动物剖检未见明显病变。 A portion of day 14 no significant lesions necropsy of surviving animals. 小鼠口服给药的半数致死量为3137.3mg/kg。 The median lethal dose for oral administration to mice 3137.3mg / kg. (结果见表1、2)。 (Results shown in Table 2).

表1.小鼠单次口服给予复方二甲双胍/吡格列酮(500∶7.5)对存活动物体重的影响(g) Table 1. Mice given a single oral Compound metformin / pioglitazone Effect (500:7.5) on survival of animal body weight (g)

注:0d动物体重为禁食后体重,动物数为各组存活动物数,见表2。 NOTE: 0d animal body weight after fasting body weight, the number of animals in each group the number of surviving animals (Table 2).

表2.小鼠单次口服给予复方二甲双胍/吡格列酮(500∶7.5)LD50测定结果 Table 2. Compound administered orally to mice, metformin / pioglitazone (500:7.5) LD50 measurement result

复方二甲双胍/吡格列酮(500∶15)口服给药急性毒性试验:口服给予复方二甲双胍/吡格列酮(500∶15),药后10-30分钟动物出现活动减少,部分动物出现闭眼(1-4/10);药后1小时,3只动物出现腹泻,1只动物后肢无力,步态不稳;药后2小时,9只动物出现腹泻,1只动物濒死。 Compound Metformin / pioglitazone (500:15) Acute toxicity test for oral administration: for oral administration of compound metformin / pioglitazone (500:15), 10 to 30 minutes after the drug appears to reduce the activity of animals, some animals appear with eyes closed (1-4 / 10 ); 1 hour after administration, three animals developed diarrhea, an animal hind limb weakness, ataxia; 2 hours after drugs, diarrhea 9 animals, one animal dying. 毒性反应发生的时间、动物数及严重程度与给药剂量呈正相关。 Toxicity occurred at a time, the number of animals and the severity of dose positive correlation. 动物死亡最早出现在药后4小时,所有动物死亡均发生在药后18小时内。 Animals died first appeared in 4 hours after drug deaths occurred in all animals within 18 hours after the drug. 对死亡动物剖检,可见部分动物(4只)轻度肺出血,其它脏器未见任何明显病变。 Necropsy of dead animals, the visible part of the animal (4) mild pulmonary hemorrhage, other organs did not show any obvious lesions. 药后18小时,所有存活动物基本恢复正常活动。 18 hours after the drug, all surviving animals returned to normal activity. 存活动物在14天的观察期内未见死亡,动物体重增长未受明显影响。 Surviving animals were no deaths during the 14-day observation period, the animal weight gain was unaffected. 第14天取部分存活动物剖检未见明显病变。 A portion of day 14 no significant lesions necropsy of surviving animals. 小鼠口服给药的半数致死量为3348.8mg/kg。 The median lethal dose for oral administration to mice 3348.8mg / kg. (结果见表3、4)。 (Results shown in Table 3 and 4).

表3.小鼠单次口服给予复方二甲双胍/吡格列酮(500∶15)对存活动物体重的影响(g) Table 3. Compound of mice administered a single oral metformin / pioglitazone Effect (500:15) on survival of animal body weight (g)

注:0d动物体重为禁食后体重,动物数为各组存活动物数,见表4。 NOTE: 0d animal body weight after fasting body weight, the number of surviving animals Number of animals in each group (Table 4).

表4.小鼠单次口服给予复方二甲双胍/吡格列酮(500∶15)LD50测定结果 Table 4. Mice single oral administration of compound metformin / pioglitazone (500:15) LD50 measurement result

复方二甲双胍/吡格列酮(500∶30)口服给药急性毒性试验:口服给予复方二甲双胍/吡格列酮(500∶30),药后10-30分钟动物活动减少,部分动物闭眼(1-4/10);药后1小时,4只动物腹泻;药后2小时,1只动物步态不稳,7只动物腹泻。 Compound Metformin / pioglitazone (500:30) Acute toxicity test for oral administration: for oral administration of compound metformin / pioglitazone (500:30), 10-30 minutes after drug reduce animal activity, the animals eyes closed portion (1-4 / 10); 1 hour after drug, 4 diarrhea in animals; 2 hours after administration, an unsteady gait animals, 7 animals diarrhea. 毒性反应发生的时间、动物数及严重程度与给药剂量呈正相关。 Toxicity occurred at a time, the number of animals and the severity of dose positive correlation. 动物死亡最早出现在药后5小时,所有动物死亡均发生在药后18小时内。 Animals died first appeared in five hours after the drug, death occurred in all animals within 18 hours after the drug. 对死亡动物剖检,可见部分动物(10只)轻度肺出血,其它脏器未见任何明显病变。 Necropsy of dead animals, the visible part of the animal (10) mild pulmonary hemorrhage, other organs did not show any obvious lesions. 药后18小时,所有存活动物基本恢复正常活动。 18 hours after the drug, all surviving animals returned to normal activity. 存活动物在14天的观察期内未见死亡,动物体重增长未受明显影响。 Surviving animals were no deaths during the 14-day observation period, the animal weight gain was unaffected. 第14天取部分存活动物剖检未见明显病变。 A portion of day 14 no significant lesions necropsy of surviving animals. 小鼠口服给药的半数致死量为3726.7mg/kg。 The median lethal dose for oral administration to mice 3726.7mg / kg. (结果见表5、6)。 (Results shown in Table 5, 6).

表5.小鼠单次口服给予复方二甲双胍/吡格列酮(500∶30)对存活动物体重的影响(g) Table 5. Compound of mice administered a single oral metformin / pioglitazone Effect (500:30) on survival of animal body weight (g)

注:0d动物体重为禁食后体重,动物数为各组存活动物数,见表6。 NOTE: 0d animal body weight after fasting body weight, the number of animals in each group the number of surviving animals (Table 6).

表6.小鼠单次口服给予复方二甲双胍/吡格列酮(500∶30)LD50测定结果 Table 6. Compound of mice administered a single oral metformin / pioglitazone (500:30) LD50 measurement result

4、结论:小鼠单次口服给予三种配比的复方二甲双胍/吡格列酮出现的毒性反应基本一致,给药后10-30分钟部分动物活动减少、闭眼,药后1小时部分动物腹泻、步态不稳,毒性反应发生的动物数及严重程度与给药剂量呈正相关。 4. Conclusion: The three kinds of mice administered a single oral stoichiometric Compound Metformin / pioglitazone toxicity appeared consistent, reducing 10 to 30 minutes after administration of active part of the animal, with eyes closed, one hour after the drug portion diarrhea in animals, step unstable state, and the severity of the number of animals dose toxicity occurred positive correlation. 动物死亡最早出现在药后4-5小时,所有动物死亡均发生在药后18小时内。 Animals died first appeared in 4-5 hours after injection, all animals death occurred within 18 hours after the drug. 对死亡动物剖检,可见部分动物轻度肺出血,其它脏器未见任何明显病变。 Necropsy of dead animals, the visible part of the animal mild pulmonary hemorrhage, other organs did not show any obvious lesions. 药后18小时,所有存活动物基本恢复正常活动。 18 hours after the drug, all surviving animals returned to normal activity. 存活动物在14天的观察期内未见死亡,动物体重增长未受明显影响。 Surviving animals were no deaths during the 14-day observation period, the animal weight gain was unaffected. 第14天取部分存活动物剖检未见明显病变。 A portion of day 14 no significant lesions necropsy of surviving animals. 小鼠口服给予复方二甲双胍/吡格列酮不同配比(500∶7.5、500∶15、500∶30)的半数致死量分别为3137.3、3348.8、3726.7mg/kg。 Mice were orally administered compound metformin / pioglitazone different ratio (500:7.5,500:15,500:30) median lethal dose were 3137.3,3348.8,3726.7mg / kg.

二、复方二甲双胍/吡格列酮降糖的药代动力学研究:复方降糖是双胍类降糖药二甲双胍和噻唑烷酮类降糖药吡格列酮的复方制剂,简称复方降糖(500∶30,w/w),由于作用机理不同,配伍以期达到更佳的降糖效果。 Second, pharmacokinetic studies compound metformin / pioglitazone hypoglycemic: antidiabetic compound is metformin, a biguanide hypoglycemic agents and hypoglycemic agents thiazolidinone pioglitazone FDC, referred hypoglycemic compound (500:30, w / w ), due to the different mechanism of action, in order to achieve better compatibility hypoglycemic effect. 本试验旨在通过大鼠的吸收试验阐明复方制剂与单方制剂之间吸收的异同。 The test compound is intended to clarify the differences and similarities between the absorbent formulation prescribed preparations by absorption test in rats.

1、材料 1, material

(1)药物:二甲双胍:临用前以水溶解成15mg/ml,给药容量为1ml/100g体重,相当于150mg/kg。 (1) Drug: Metformin: water immediately before use to dissolve 15mg / ml, dosing capacity of 1ml / 100g body weight, equivalent to 150mg / kg.

吡格列酮:临用前以1%CMCNa混悬成0.9mg/ml,给药容量为1ml/100g体重,相当于9mg/kg。 Pioglitazone: immediately before use was suspended in 1% CMCNa to 0.9mg / ml, dosing capacity of 1ml / 100g body weight, corresponding to 9mg / kg.

复方降糖:临用前以1%CMCNa混悬成15mg二甲双胍和0.9mg吡格列酮/ml,给药容量为1ml/100g体重,相当于150mg/kg二甲双胍和9mg/kg吡格列酮。 Compound Hypoglycemic: immediately prior to suspension in 1% CMCNa 15mg metformin and pioglitazone 0.9mg / ml, dosing capacity of 1ml / 100g body weight, equivalent to 150mg / kg of metformin and 9mg / kg pioglitazone.

(2)试剂:甲醇:优级纯,天津市康科德科技有限公司产品,批号031204。 (2) Reagents: methanol: excellent pure, Tianjin Concord Technology Co., Ltd, batch number 031,204. 磷酸二氢钾:AR,北京红星化工厂产品,批号851011-1。 Potassium dihydrogen phosphate: AR, Beijing Red Star Chemical Plant, batch number 851011-1. B7:天津市化学试剂二厂产品。 B7: Tianjin Chemical Reagent Factory products. 乙腈:AR,天津市康科德科技有限公司产品,批号031015。 Acetonitrile: AR, Tianjin Concord Technology Co., Ltd, batch number 031,015. 乙酸钠:天津石英钟厂霸州市化工分厂产品,批号980303。 Sodium acetate: quartz plant in Tianjin branch Bazhou chemical products, lot number 980303.

(3)仪器:NL-200TPA分析天平:日本岛津公司。 (3) Instruments: NL-200TPA analytical balance: Shimadzu Corporation.

TGL-16C高速台式离心机:上海安亭科学仪器厂。 TGL-16C high-speed desktop centrifuge: Shanghai Anting Scientific Instrument Factory.

HPLC:WATERS 515泵;717自动进样器;RAININ紫外检测器;ANASTAR色谱数据工作站。 HPLC: WATERS 515 pumps; 717 autosampler; RAININ UV detector; ANASTAR chromatography data station.

(4)动物:健康Wistar大鼠,雌性,体重约210g,实验动物设施合格证“津实验动物设施准第013号”由天津市实验动物管理委员会颁发,符合一级标准。 (4) Animals: healthy Wistar rats, female, weighing about 210g, Laboratory Animal Facility Certificate "Jin quasi experimental animal facility No. 013" issued by the Tianjin Experimental Animal Management Committee, in line with a standard. 正常饲养三天后供试。 After three days of normal feeding test.

2、方法:(1)样品采集与处理:健康Wistar大鼠12只,雌性,禁食16小时,按体重平均分为三组,即吡格列酮9mg/kg组,二甲双胍150mg/kg组和复方降糖组。 2. Method: (1) Sample collection and processing: 12 healthy Wistar rats, females, fasted for 16 hours were divided into three groups according to body weight, i.e., pioglitazone 9mg / kg group, metformin 150mg / kg group and the compound Hypoglycemic group. 于早晨8:00分别口服灌胃上述药物,于药后0.33,0.66,1.0,1.5,2.0,4.0,6.0,12.0,24.0和36.0小时分别眼眶采血0.5ml,离心分离血清。 8:00 to these drugs were oral gavage at 36.0 hours post-drug 0.33,0.66,1.0,1.5,2.0,4.0,6.0,12.0,24.0 each orbital blood 0.5ml, centrifuged serum.

定量吸取二甲双胍组和复方降糖组动物的血清50μl,加入等体积10%高氯酸,充分振摇沉淀蛋白,离心,上清液20μl进样,HPLC分析。 Quantitative suction metformin hypoglycemic and serum 50μl compound group of animals, the addition of an equal volume of 10% perchloric acid, shaken well protein precipitation, centrifugation, 20μl supernatant sample, HPLC analysis. 用空白血清复管操作配制标准血清样品,浓度分别为0,0.5,1,2,5,10和20μg/ml,作为标准曲线,处理方法同上。 Complex formulated with blank serum pipehandling standard serum sample, and 0,0.5,1,2,5,10 concentrations of 20μg / ml, as a standard curve, the process as above.

定量吸取吡格列酮组和复方降糖组动物的血清150μl,加入1ml二氯甲烷,充分振摇,离心,取800μl下层有机相置于另一个离心管中,空气吹干,75μl流动相复溶,离心20μl进样,HPLC分析。 Quantitative suction 150μl serum ketone group and compound antidiabetic pioglitazone group of animals, was added 1ml of dichloromethane, shaken, centrifuged and 800μl lower organic phase was placed in another centrifuge tube, air dried, 75 l of mobile phase solvent, centrifugation 20μl injection, HPLC analysis. 用空白血清复管操作配制标准血清样品,浓度分别为0,0.1,0.5,1,5和10μg/ml,作为标准曲线,处理方法同上。 Complex formulated with blank serum pipehandling standard serum sample, and 0,0.1,0.5,1,5 concentrations of 10μg / ml, as a standard curve, the process as above.

(2)色谱条件:二甲双胍:固定相:C18ODS柱,4.6×250mm,10μ,柱号22I25117流动相∶甲醇∶0.005M磷酸二氢钾(pH2.5)=10∶90柱温:40℃UV检测:233nm吡格列酮:固定相:C10ODS柱,4.6×100mm,5μ,柱号22K10040流动相∶乙腈∶0.1M乙酸钠(pH4.5)=39∶61柱温:30℃UV检测:269nm(3)结果:二甲双胍:血清标准曲线(0~20μg/ml)的线性方程是:C=0.0000353A+0.10355(r=0.9992)。 (2) Chromatographic conditions: Metformin: stationary phase: C18ODS column, 4.6 × 250mm, 10μ, No 22I25117 column Mobile phase: methanol :0.005M potassium dihydrogen phosphate (pH2.5) = 10:90 Column temperature: 40 ℃ UV detection : 233nm pioglitazone: stationary phase: C10ODS column, 4.6 ×, 5μ 22K10040 flow 100mm, column No. phase: acetonitrile :0.1M sodium acetate (pH4.5) = 39:61 column temperature: 30 ℃ UV detection: 269nm (3) results : metformin: serum standard curve (0 ~ 20μg / ml) is a linear equation: C = 0.0000353A + 0.10355 (r = 0.9992). 回收率为95.04%。 Recovery was 95.04%. 大鼠口服二甲双胍和复方降糖后不同时间的血药浓度见表7,药时曲线见图1;平均达峰时间分别为1.1和1.0小时;峰浓度分别为19.6和20.4μg/ml;AUC分别为239.8和249.9μg·h/ml。 Metformin and oral administration of compound plasma concentrations at different times of the glucose in Table 7, the concentration-time curve shown in Figure 1; the mean time to peak were 1.1 and 1.0 hours; peak concentrations were 19.6 and 20.4μg / ml; AUC, respectively to 239.8 and 249.9μg · h / ml. 复方相对于单方的生物利用度为101.7%。 Compound with respect to bioavailability was 101.7% unilaterally.

表7.大鼠口服二甲双胍和复方降糖后不同时间的血药浓度 Table oral hypoglycemic metformin and the blood concentration of Compound 7. rats at different times

吡格列酮:血清标准曲线(0~10μg/ml)的线性方程是:C=0.0000310A-0.1488(r=0.9988)。 Pioglitazone: serum standard curve (0 ~ 10μg / ml) is a linear equation: C = 0.0000310A-0.1488 (r = 0.9988). 回收率为71.7%。 Recovery was 71.7%. 大鼠口服吡格列酮和复方降糖后不同时间的血药浓度见表8,药时曲线见图2;平均达峰时间分别为4.0和3.9小时;峰浓度分别为6.8和5.3μg/ml;AUC分别为80.4和85.0μg·h/ml。 Oral administration of pioglitazone and plasma concentrations at different times after the hypoglycemic compound are shown in Table 8, the concentration-time curve of Figure 2; average peak time was 4.0 and 3.9 hours; peak concentrations of 6.8 and 5.3μg / ml; AUC, respectively 80.4 and 85.0μg · h / ml. 复方相对于单方的生物利用度为105.7%。 Compound with respect to bioavailability was 105.7% unilaterally.

表8.大鼠口服吡格列酮和复方降糖后不同时间的血药浓度 Table 8. oral rat pioglitazone and the compound hypoglycemic serum concentration time

3、结论:大鼠口服给药单方二甲双胍和复方降糖后平均达峰时间分别为1.1和1.0小时;峰浓度分别为19.6和20.4μg/ml;AUC分别为239.8和249.9μg·h/ml。 3 Conclusion: orally dosed rats after unilateral metformin and hypoglycemic compound peak time average of 1.1 and 1.0 hours; peak concentrations were 19.6 and 20.4μg / ml; AUC, respectively 239.8 and 249.9μg · h / ml. 复方相对于单方的生物利用度为101.7%。 Compound with respect to bioavailability was 101.7% unilaterally. 大鼠口服吡格列酮和复方降糖后的平均达峰时间分别为4.0和3.9小时;峰浓度分别为6.8和5.3μg/ml;AUC分别为80.4和85.0μg·h/ml。 Oral administration of pioglitazone and average peak time after hypoglycemic compound were 4.0 and 3.9 hours; peak concentrations of 6.8 and 5.3μg / ml; AUC were 80.4 and 85.0μg · h / ml. 复方相对于单方的生物利用度为105.7%。 Compound with respect to bioavailability was 105.7% unilaterally. 复方降糖中所包含的两种降糖药的大鼠体内吸收基本无干扰,与单方无显著性差异。 Compound hypoglycemic rats contained two absorbing substantially hypoglycemic agents without interference with unilateral no significant difference.

附图说明 BRIEF DESCRIPTION

图1为大鼠口服给药二甲双胍和复方制剂后药时曲线;图2为大鼠口服给药吡格列酮和复方制剂给药后药时曲线。 Figure 1 is a rat after oral administration of metformin and a pharmaceutical preparation of Compound concentration-time curve; FIG. 2 rats oral administration of pioglitazone and after administration of the formulation when the drug compound curve.

三、复方二甲双胍/吡格列酮药效学试验:1.实验材料1.1实验动物:Wistar大鼠,体重140-160g。 Third, the compound metformin / pioglitazone Pharmacodynamic: 1 Experimental Materials 1.1 Animals:. Wistar rats, weighing 140-160g. 实验动物合格证:WJ津实动质R准字第001号。 Experimental Animals Certificate: WJ Azumi dynamic quality R-word No. 001.

1.2实验环境及条件实验动物设施二级,合格证号:津实动设施准第012号;室温22±4℃,湿度60±20%。 1.2 Experimental Animal Facility Environment and two experimental conditions, qualified No: move Azumi facility registration No. 012; room temperature for 22 ± 4 ℃, humidity of 60 ± 20%. 中央空调自动通风。 Automatic central air conditioning and ventilation. 光照12小时。 Light for 12 hours. 自由摄食和饮用自来水。 Free access to food and drinking water. 每日换水一次。 Changing the water once a day.

1.3药物:盐酸二甲双胍;盐酸吡格列酮。 1.3 Drug: Metformin hydrochloride; pyrazol pioglitazone hydrochloride. 将两药研磨成粉末混匀后,用1%CMC配制成混悬液。 After mixing the two drugs ground into a powder, with 1% CMC formulated as a suspension.

1.4试剂及仪器: 1.4 Reagents and Instruments:

链脲佐菌素(Streptozotocin,STZ),Sigma,S-0130,进口分装,北京欣经科生物技术公司提供。 Streptozotocin (Streptozotocin, STZ), Sigma, S-0130, import-packing, by Beijing Xin Bioscience companies. 规格:1g/瓶。 Specifications: 1g / bottle. 纯度:98%。 Purity: 98%.

京都血糖仪(SUPER GLUCOCARD II)及检测试纸条,日本生产,北京麦邦生物工程技术公司提供。 Kyoto blood glucose meter (SUPER GLUCOCARD II) and test strip, produced in Japan, Beijing Maibang biotechnology companies.

胰岛素试剂盒:天津舒普生物工程技术公司提供。 Insulin kit: Tianjin Shope biotechnology companies. 批号:06043-ASUNRISE遥控酶标仪,TECAN产品。 Lot: 06043-ASUNRISE remote microplate reader, TECAN products.

2.实验方法及结果Wistar大鼠,雄性,300只,140g-160g,禁食16hr,腹腔注射30mg/kg的STZ(4℃冰浴中溶于0.1mol/L的PH值4.4的柠檬酸缓冲液,配后立即使用),每天1次,连续3次,给药2周后喂以高脂高糖饲料(基础饲料55%,猪油25%,蔗糖20%),喂养6周后测大鼠FBG(测前禁食12h),挑选FBG≥12.0mmol/L的大鼠64只,随机分为8组,每组8只,分别设为模型对照组和复方300∶1.5组、复方300∶3组、复方300∶4.5组、复方300∶6组、复方300∶6.75组、复方300∶9组、复方300∶27组。 2. Experimental methods and results Wistar rats, male, 300, 140g-160g, 16 hr fast, by intraperitoneal injection of 30mg / kg of STZ (4 ℃ was dissolved in an ice bath and 0.1mol / L citrate buffer PH value of 4.4 solution immediately after use with), once a day, 3 times, 2 weeks after the administration feeding large measure to high fat and sugar diet (basal diet 55%, lard 25%, 20% sucrose), feeding 6 weeks the FBG mice (fasted 12h prior to measurement), the selection FBG≥12.0mmol / L of 64 rats were randomly divided into 8 groups of 8 mice in each group and the model control set 300:1.5 compound groups, the compound 300: 3 group, compound 300:4.5 group, compound 300:6 group, compound 300:6.75 group, compound 300:9 group, compound 300:27 group. 另取8只正常雄性Wistar大鼠(与上述大鼠同批领取,FBG≤5.0mmol/L)作为生理对照组。 Another eight normal male Wistar rats (rat above with batch collection, FBG≤5.0mmol / L) as the physiological control group. 生理对照和模型对照组灌胃给予1%CMC,7个复方组依次灌胃给予300mg∶1.5mg/kg、300mg∶3mg/kg、300mg∶4.5mg/kg、300mg∶6mg/kg、300mg∶6.75mg/kg、300mg∶9mg/kg、300mg∶27mg/kg的复方药物(盐酸二甲双胍∶盐酸吡格列酮)。 Physiological control and model control group was given 1% CMC, 7 th group are sequentially intragastric administration of Compound 300mg:1.5mg / kg, 300mg:3mg / kg, 300mg:4.5mg / kg, 300mg:6mg / kg, 300mg:6.75 mg / kg, 300mg:9mg / kg, 300mg:27mg / kg of the drug compound (metformin hydrochloride: pioglitazone hydrochloride). 将受试药物用1%CMC配制成不同浓度的混悬液,每日上午ig给药,给药体积均为1ml/100g,生理对照和模型对照组灌胃给予等体积的1%CMC。 The test drug was formulated with 1% CMC suspension at different concentrations, every morning, ig, are administered volume 1ml / 100g, physiological control and model control group was given an equal volume of 1% CMC. 连续给药21d,第22d早上9:00用毛细玻璃管从眼底静脉丛取血(取血前禁食12h)1滴,用血糖检测仪测FBG,另取血1ml,离心取血清,按试剂盒说明方法采用ELASE法测空腹血清胰岛素(FINS)。 Continuous administration of 21 d, 22d 9:00 am with the first glass capillary blood from venous plexus of the fundus (fasted before blood 12h) 1 drop, as measured by blood glucose monitoring device FBG, another blood 1ml, centrifuged to obtain serum, according to reagent methods described method cartridge ELASE fasting serum insulin (FINS). 计算:给药前后降糖绝对值(降糖绝对值=给药21dFBG-给药前FBG)、降糖百分率(降糖百分率=[(给药21dFBG-给药前FBG)/给药前FBG×100%])及胰岛素抵抗指数(IR)(IR=FBG×FINS/22.5)。 Calculated: the absolute value of hypoglycemic (antidiabetic = absolute value 21dFBG- administered before administration FBG) before and after administration, the percentage of hypoglycemic (antidiabetic percentage = [(pre-dose administration 21dFBG- FBG) / predose FBG × 100%]) and insulin resistance index (IR) (IR = FBG × FINS / 22.5). 各项数据以平均值±标准差表示,各组与模型对照组采用组间t检验进行比较。 The data are expressed as mean ± standard deviation, groups with the model control group t test between the two groups were compared. 结果:各个比例的复方药物均可不同程度的降低高血糖大鼠的FBG,复方300mg∶3mg/kg以上剂量与模型对照组比较,降糖绝对值及降糖百分率有显著差异,且有一定的剂量相关性;各个比例的复方药物均可明显降低高血糖大鼠的FINS与IR水平。 Results: The ratio of each compound may be different levels of the drug decreased FBG hyperglycemic rats comparing Compound 300mg:3mg / kg dose than with the control group, the percentage of hypoglycemic and antidiabetic absolute values ​​were significantly different, and there is a certain dose-dependent; the proportion of each combination drugs could decrease the level of IR and FINS hyperglycemic rats. 见表9、10。 Table 9 and 10.

表9复方盐酸二甲双胍-吡格列酮对大鼠空腹血糖的影响 Table 9 metformin combination - Effects of pioglitazone on fasting blood glucose in rats

注:与模型对照组比较,*p<0.05,**p<0.01,***p<0.001表10复方盐酸二甲双胍-吡格列酮对大鼠空腹胰岛素及胰岛素抵抗的影响 Effects of pioglitazone on fasting insulin and insulin resistance - with the model control group, * p <0.05, ** p <0.01, *** p <0.001 Table 10 Compound Metformin Hydrochloride: Note

注:与模型对照组比较,*p<0.05,**p<0.01,***p<0.0013.实验结论复方盐酸二甲双胍-吡格列酮(300mg∶1.5mg/kg、300mg∶3mg/kg、300mg∶4.5mg/kg、300mg∶6mg/kg、300mg∶6.75mg/kg、300mg∶9mg/kg、300mg∶27mg/kg)分别连续灌胃给药21d,各个比例的复方药物均可不同程度的降低高血糖大鼠的FBG、FINS与IR水平,对FINS与IR的降低尤其明显。 Note: Compared with the model group, * p <0.05, ** p <0.01, *** p <0.0013 Experimental results metformin combination - pioglitazone (300mg:1.5mg / kg, 300mg:3mg / kg, 300mg:4.5 mg / kg, 300mg:6mg / kg, 300mg:6.75mg / kg, 300mg:9mg / kg, 300mg:27mg / kg) were administered intragastrically 21d, the respective proportions of different degrees of combination drug may reduce hyperglycemia FBG, FINS and IR levels in rats, to decrease the IR FINS is particularly evident.

具体实施方式 Detailed ways

下面结合实施例对本发明做进一步的描述,但这些实施例并非对本发明的限制。 Below in connection with embodiments of the present invention will be further described, these embodiments do not limit the present invention. 为了更充分的解释本发明的实施,提供下述制剂实施例。 In order to more fully explain the embodiment of the present invention, the following formulation examples. 制剂可以采用本发明中的任意一个组合物的形式。 Formulations may be in any form of a composition of the present invention is employed. 特选复方二甲双胍/吡格列酮不同配比(1)500∶15(2)750∶15(3)1000∶15为代表。 Selected compound metformin / pioglitazone different ratio (1) 500:15 (2) 750:15 (3) 1000:15 represented.

制剂1上下双层片剂: Vertical bilayer tablet formulation:

制备方法:盐酸吡格列酮颗粒制备方法:将活性成分、乳糖、微晶纤维素过筛,并充分混合,用聚乙烯吡咯烷酮溶液与上述的粉混合,过筛,制得湿颗粒于50-60℃干燥,将羧甲基淀粉钠,硬脂酸镁和滑石粉预先过筛,然后加入到上述的颗粒中。 Preparation: Preparation of pioglitazone hydrochloride particles pyrazol Method: The active ingredient, lactose, microcrystalline cellulose, sieved, and mixed with a solution of polyvinylpyrrolidone is mixed with the above powder, sieved to obtain wet granules dried at 50-60 deg.] C , sodium carboxymethyl starch, magnesium stearate, and talc, previously sieved, and then added to the granules.

盐酸二甲双胍颗粒制备方法:将活性成分、羟丙基甲基纤维素过筛,并充分混合,用聚乙烯吡咯烷酮乙醇溶液与上述的粉混合,过筛,制得湿颗粒于50-60℃干燥,加入硬脂酸镁到上述的颗粒中。 The method of preparing the particles of metformin hydrochloride: The active ingredient, hydroxypropyl methyl cellulose sieved and mixed, the mixed powder described above with an ethanol solution of polyvinylpyrrolidone, sieved to obtain wet granules dried at 50-60 ℃, magnesium stearate was added to the above granules.

将上述颗粒置双层片压片机压片。 The pellets opposing bilayer tablet press tableting.

制剂2内外双层片剂: 2 the inner and outer bilayer tablet formulation:

制备方法:盐酸二甲双胍缓释片芯制备方法:将活性成分、羟丙基甲基纤维素过筛,并充分混合,用聚乙烯吡咯烷酮乙醇溶液与上述的粉混合,过筛,制得湿颗粒于50-60℃干燥,加入硬脂酸镁到上述的颗粒中,压片。 Preparation: Preparation of metformin hydrochloride extended release core Method: The active ingredient, hydroxypropyl methyl cellulose sieved and mixed, the mixed powder described above with an ethanol solution of polyvinylpyrrolidone, sieved to obtain wet granules 50-60 ℃ dried, magnesium stearate was added to the above granules, tableting.

盐酸吡格列酮包衣液:将盐酸吡格列酮与羟丙基甲基纤维素混合均匀,取适量聚乙二醇400加入水中溶解,搅拌下,缓缓加入上述混合物,使成混悬液,包衣液固体含量约为9%。 Pyrazole hydrochloride pioglitazone coating solution: pioglitazone hydrochloride and hydroxypropyl methylcellulose mixed, an appropriate amount of polyethylene glycol 400 dissolved in water was added, with stirring, gradually added to the mixture to make into a suspension, the solid coating liquid content of about 9%.

混悬液过80目筛,适宜条件下包衣,控制增重量,使每片约含盐酸吡格列酮15mg。 Suspension over 80 mesh sieve, coatings, controlling weight gain under suitable conditions, so that each tablet containing about pioglitazone hydrochloride 15mg.

尽管本发明结合它的专门的实施例已做了详细的描述,但是很明显对本技术领域的熟练人来说仍能做出各种各样的变化和改进,都不会偏离本发明的精神实质和保护范围。 Although the invention in conjunction with its specific embodiments have been described in detail, it is clear to the skilled person in the art, it can still make a variety of changes and improvements, are not departing from the spirit of the invention and the scope of protection.

Claims (9)

1.一种药物组合物,其特征在于:含有15mg盐酸吡格列酮和500mg或750mg盐酸二甲双胍及一种或多种药学上可接受的载体,所述组合物是双层片,分为速释层和缓释层,速释层含盐酸吡格列酮,缓释层含盐酸二甲双胍,所述双层片为上下双层片剂或内外双层片剂;所述内外双层片剂的内层为二甲双胍缓释层,外层为盐酸吡格列酮速释层。 1. A pharmaceutical composition, comprising: containing pioglitazone hydrochloride 15mg and 500mg or 750mg of metformin hydrochloride, and one or more pharmaceutically acceptable carriers, said composition is a bilayer tablets, immediate-release layer and into sustained release layer, the immediate release layer containing a pyrazole pioglitazone hydrochloride, metformin hydrochloride-containing sustained-release layer, the upper and lower double sheet inner and outer bilayer tablet or bilayer tablet; and outside the inner layer of the bilayer tablet metformin layer, the outer immediate release layer pyrrolidone hydrochloride Gleevec.
2.如权利要求1的药物组合物,其特征在于其中所述组合物含有500mg盐酸二甲双胍。 2. A pharmaceutical composition as claimed in claim 1, characterized in that said composition contains 500mg of metformin hydrochloride.
3.如权利要求1的药物组合物,其特征在于其中所述组合物含有750mg盐酸二甲双胍。 3. A pharmaceutical composition as claimed in claim 1, characterized in that said composition contains 750mg of metformin hydrochloride.
4.如权利要求1的药物组合物,其特征在于其中所述双层片为上下双层片,其中每片上层含有:盐酸吡格列酮 15mg微晶纤维素 55mg乳糖 45mg聚乙烯吡咯烷酮 3mg羧甲基淀粉钠 4.5mg硬脂酸镁 0.5mg滑石粉 1mg每片下层含有:盐酸二甲双胍 500mg羟丙基甲基纤维素 190mg聚乙烯吡咯烷酮 14mg硬脂酸镁 7.1mg。 4. A pharmaceutical composition as claimed in claim 1, characterized in that wherein the sheet is a bunk bilayer tablets, wherein each of the upper layer sheet comprising: pioglitazone hydrochloride 15mg Lactose 45mg Microcrystalline cellulose 55mg polyvinylpyrrolidone carboxymethyl starch 3mg sodium 4.5mg magnesium stearate 0.5mg talc 1mg per tablet layer contains: 500mg metformin hydrochloride 190mg hydroxypropylmethylcellulose polyvinylpyrrolidone 14mg magnesium stearate 7.1mg.
5.如权利要求1的药物组合物,其特征在于其中所述双层片为上下双层片,其中每片上层含有:盐酸吡格列酮 15mg微晶纤维素 55mg乳糖 45mg聚乙烯吡咯烷酮 3mg羧甲基淀粉钠 4.5mg硬脂酸镁 0.5mg滑石粉 1mg每片下层含有:盐酸二甲双胍 750mg羟丙基甲基纤维素 205mg聚乙烯吡咯烷酮 19.1mg硬脂酸镁 9.7mg。 5. A pharmaceutical composition as claimed in claim 1, characterized in that wherein the sheet is a bunk bilayer tablets, wherein each of the upper layer sheet comprising: pioglitazone hydrochloride 15mg Lactose 45mg Microcrystalline cellulose 55mg polyvinylpyrrolidone carboxymethyl starch 3mg sodium 4.5mg magnesium stearate 0.5mg talc 1mg per tablet layer contains: 205mg metformin 750mg hydroxypropylmethylcellulose polyvinylpyrrolidone 19.1mg magnesium stearate 9.7mg hydrochloric acid.
6.如权利要求1的药物组合物,其特征在于,所述双层片为内外双层片,其中每片内层含有:盐酸二甲双胍 500mg羟丙基甲基纤维素 190mg聚乙烯吡咯烷酮 14.0mg硬脂酸镁 7.1mg每片外层含有:盐酸吡格列酮 15mg羟丙基甲基纤维素 43.6mg聚乙二醇-400 4.5mg。 6. A pharmaceutical composition as claimed in claim 1, wherein said sheet is a double external double sheet, wherein each sheet comprises an inner layer: Metformin hydrochloride 190mg 500mg hydroxypropylmethylcellulose hard 14.0mg Polyvinylpyrrolidone magnesium stearate 7.1mg per tablet layer comprising: pioglitazone hydrochloride pyrazol hydroxypropylmethylcellulose 15mg 43.6mg polyethylene glycol -400 4.5mg.
7.如权利要求1的药物组合物,其特征在于,所述双层片为内外双层片,其中每片内层含有:盐酸二甲双胍 750mg羟丙基甲基纤维素 205mg聚乙烯吡咯烷酮 19.1mg硬脂酸镁 9.7mg每片外层含有:盐酸吡格列酮 15mg羟丙基甲基纤维素 43.6mg聚乙二醇-400 4.5mg。 7. A pharmaceutical composition as claimed in claim 1, wherein said sheet is a double external double sheet, wherein each sheet comprises an inner layer: Metformin hydrochloride 750mg hydroxypropylmethylcellulose Polyvinylpyrrolidone 19.1mg 205mg Hard an outer layer comprising magnesium stearate 9.7mg per tablet: pioglitazone hydrochloride 15mg 43.6mg hydroxypropylmethylcellulose polyethylene glycol -400 4.5mg.
8.一种制备权利要求1-7中任一权利要求的药物组合物的方法,其包括:(1)上下双层片剂的制备:(A)盐酸吡格列酮颗粒的制备:将活性成分、乳糖、微晶纤维素过筛并充分混合得混合物;用聚乙烯吡咯烷酮溶液与上述混合物混合,过筛,制得的湿颗粒于50-60℃干燥;将羧甲基淀粉钠、硬脂酸镁和滑石粉预先过筛,然后加入到上述的颗粒中;(B)盐酸二甲双胍颗粒的制备:将活性成分、羟丙基甲基纤维素过筛并充分混合得混合物过筛,制得湿颗粒于50-60℃干燥,加入硬脂酸镁到上述的颗粒中;(C)将上述(A)和(B)的颗粒置于双层压片机中压片,得到双层片;或(2)内外双层片剂制备:(A)盐酸二甲双胍缓释片芯的制备:将活性成分和羟丙基甲基纤维素过筛,并充分混合,得混合物;用聚乙烯吡咯烷酮的乙醇溶液与上述混合物混合,过筛,制得的湿颗粒于50-60℃干燥 The pharmaceutical composition of any one of claims 1-7 8. A preparation as claimed in claim, comprising: preparing tablets bunk (1): Preparation of pioglitazone (A) particles rosiglitazone hydrochloride: The active ingredient, the lactose , microcrystalline cellulose, sifted and mixed to obtain a mixture; with a solution of polyvinylpyrrolidone is mixed with the above mixture, sieved to prepare wet granules dried at 50-60 deg.] C; sodium carboxymethyl starch, magnesium stearate, and talc, previously sieved, and then added to the granules; (B) preparation of granules of metformin hydrochloride: the active ingredient, hydroxypropyl methyl cellulose is sieved and mixed thoroughly resulting mixture was sieved to obtain wet granules at 50 -60 ℃ dried, magnesium stearate was added to the above granules; (C) to (a) and the above-described particles (B) was placed bilayer tablet tableting machine to obtain bilayer tablets; or (2) inner and outer bilayer tablets prepared: (a) preparation of metformin hydrochloride core: the active ingredient and hydroxypropyl methylcellulose sieved, and mixed to obtain a mixture; polyvinylpyrrolidone in ethanol solution with the mixture mixing, sieving, to obtain wet granules dried at 50-60 deg.] C 加入硬脂酸镁到上述的颗粒中,压片得到片芯;(B)盐酸吡格列酮包衣液的制备:将盐酸吡格列酮与羟丙基甲基纤维素混合均匀,得混合物;取聚乙二醇-400加入水中溶解,搅拌下,缓缓加入上述的混合物,使成混悬液,过80目筛,得到盐酸吡格列酮包衣液;(C)用上述(B)的包衣液对(A)的片芯包衣,控制增重量,使每片含预定量的盐酸吡格列酮。 Magnesium stearate was added to the above granules and tableted to obtain tablets core; (B) Preparation of pioglitazone hydrochloride of coating solution: The pyrazol pioglitazone hydrochloride and hydroxypropyl methylcellulose mixed to obtain a mixture; taken polyethylene glycol -400 added to the water dissolved, with stirring, gradually added to the above mixture, making into a suspension, over 80 mesh sieve, pioglitazone hydrochloride obtained coating solution; (C) with the above coating solution (B) to (a) the tablet cores are coated, controlling weight gain, so that each sheet containing a predetermined amount of hydrochloric acid pioglitazone.
9.权利要求1-7中任一项的药物组合物在制备治疗糖尿病药物中的应用。 9. The use of a pharmaceutical composition according to 1-7 in the manufacture of any of a medicament for treating diabetes claims.
CN 200410019483 2004-06-08 2004-06-08 Medicinal composition and its use in treatment of diabetes CN1327840C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 200410019483 CN1327840C (en) 2004-06-08 2004-06-08 Medicinal composition and its use in treatment of diabetes

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 200410019483 CN1327840C (en) 2004-06-08 2004-06-08 Medicinal composition and its use in treatment of diabetes

Publications (2)

Publication Number Publication Date
CN1582928A CN1582928A (en) 2005-02-23
CN1327840C true CN1327840C (en) 2007-07-25

Family

ID=34600526

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 200410019483 CN1327840C (en) 2004-06-08 2004-06-08 Medicinal composition and its use in treatment of diabetes

Country Status (1)

Country Link
CN (1) CN1327840C (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104490921A (en) * 2014-12-09 2015-04-08 成都恒瑞制药有限公司 Solid oral preparation containing metformin hydrochloride and colesevelam hydrochloride

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7959946B2 (en) 2002-09-20 2011-06-14 Watson Pharmaceuticals, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US9060941B2 (en) 2002-09-20 2015-06-23 Actavis, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US8084058B2 (en) 2002-09-20 2011-12-27 Watson Pharmaceuticals, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US7785627B2 (en) 2002-09-20 2010-08-31 Watson Pharmaceuticals, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
CN101347511B (en) 2008-09-05 2011-08-17 刘全胜 Medicament composition with function for reducing blood sugar
CN102008472B (en) * 2010-10-18 2012-08-22 中国科学院上海药物研究所 Compound pioglitazone hydrochloride/metformin hydrochloride bilayer osmotic pump controlled release preparation and preparation method thereof
CN103432131A (en) * 2013-09-11 2013-12-11 中国药科大学 Compound preparation containing pioglitazone hydrochloride and metformin hydrochloride and preparing method thereof
CN106138061A (en) * 2015-04-03 2016-11-23 中国人民解放军第三军医大学第三附属医院 Complex for preventing or weakening pulmonary fibrosis, preparation prepared from complex and application of complex

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1145783A (en) * 1995-06-20 1997-03-26 武田药品工业株式会社 Pharmaceutical composition
CN1260716A (en) * 1997-06-18 2000-07-19 史密丝克莱恩比彻姆有限公司 Treatment of diabetes with thiazolidinedione and metformin
CN1348369A (en) * 1998-11-12 2002-05-08 史密丝克莱恩比彻姆有限公司 Pharmaceutical composition for modified release of an insulin sensitiser and another antidiabetic agent

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1145783A (en) * 1995-06-20 1997-03-26 武田药品工业株式会社 Pharmaceutical composition
CN1260716A (en) * 1997-06-18 2000-07-19 史密丝克莱恩比彻姆有限公司 Treatment of diabetes with thiazolidinedione and metformin
CN1429551A (en) * 1997-06-18 2003-07-16 史密丝克莱恩比彻姆有限公司 Treating diabetes by thiazolidine-diketo and dimethylbiguanide
CN1348369A (en) * 1998-11-12 2002-05-08 史密丝克莱恩比彻姆有限公司 Pharmaceutical composition for modified release of an insulin sensitiser and another antidiabetic agent

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104490921A (en) * 2014-12-09 2015-04-08 成都恒瑞制药有限公司 Solid oral preparation containing metformin hydrochloride and colesevelam hydrochloride

Also Published As

Publication number Publication date
CN1582928A (en) 2005-02-23

Similar Documents

Publication Publication Date Title
AU2008324878B2 (en) Dual-acting pharmaceutical compositions based on superstructures of angiotensin receptor antagonist/blocker (ARB) and neutral endopeptidase (NEP) inhibitor
JP5456795B2 (en) Linagliptin and pharmaceutical compositions containing sglt2 inhibitor optionally and use thereof
EP3295936A1 (en) Pharmaceutical formulation comprising one or more fumaric acid esters in an erosion matrix
DK2482806T3 (en) A pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods of treatment and uses thereof
USRE37330E1 (en) Glibenclamide-metformin combination for the treatment of diabetes mellitus of type II
CN1245158C (en) Tablet compositions
US20170020907A1 (en) Pharmaceutical composition, methods for treating and uses thereof
JP4865975B2 (en) New compositions and use
CN1212117C (en) Medicine composition for treating diabetes mellitus
US20070172525A1 (en) Anti-diabetic combinations
CA1125656A (en) Pharmaceutical tablet for oral administration and process for its manufacture
CN1230162C (en) Pharmaceutical composition for modified release of an insulin sensitizing agent and another antidiabetic agent
EP1962827A2 (en) Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with metformin
CN1114404C (en) Treatment of diabetes with thiazolidinedione and melbine
CN1414862A (en) Antidiabetic formulation and method
US20120034274A1 (en) Pharmaceutical composition comprising one or more fumaric acid esters
US20180185291A1 (en) Pharmaceutical compositions
CN104220049A (en) Pharmaceutical compositions comprising metformin and DPP -4 inhibitor or SGLT-2 inhibitor
CN101234105A (en) Pharmaceutical composition containing diabetosan and vildagliptin and preparation thereof
JP4787446B2 (en) Glyburide compositions
US7732492B2 (en) Nateglinide-containing preparation
KR20100012867A (en) Solid dosage forms comprising tadalafil
US20090163580A1 (en) Anti-aging composition containing resveratrol and method of administration
EP2029134B1 (en) Stabilized pharmaceutical compositions comprising fesoterodine
JP4633469B2 (en) Oral solid pharmaceutical

Legal Events

Date Code Title Description
C06 Publication
C10 Request of examination as to substance
C14 Granted
LIC Patent license contract for exploitation submitted for record

Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2009.7.18 TO 2014.7.18; CHANGE OF CONTRACT

Name of requester: JIANGSU DEYUAN MEDICINE CO., LTD.

Effective date: 20090807

LICC Enforcement, change and cancellation of record of contracts on the license for exploitation of a patent
ASS Succession or assignment of patent right

Owner name: JIANGSU DEYUAN PHARMACEUTICAL CO., LTD.

Free format text: FORMER OWNER: LIANYUNGANG DEYUAN PHARMACEUTICAL CO., LTD.

Effective date: 20131211

C41 Transfer of the right of patent application or the patent right
C56 Change in the name or address of the patentee

Owner name: TIANJIN PHARMACEUTICAL INSTITUTE CO., LTD.

Free format text: FORMER NAME: TIANJIN INSTITUTE OF PHARMACEUTICAL RESEARCH