CN104856970B - A method of treating diabetes type Ⅱ vildagliptin tablet - Google Patents

A method of treating diabetes type Ⅱ vildagliptin tablet Download PDF

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CN104856970B
CN104856970B CN201510349305.8A CN201510349305A CN104856970B CN 104856970 B CN104856970 B CN 104856970B CN 201510349305 A CN201510349305 A CN 201510349305A CN 104856970 B CN104856970 B CN 104856970B
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vildagliptin
tablet according
gluconic acid
lubricant
method
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CN104856970A (en
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张磊
谷燕
朱娅梅
王娜
陈淑芳
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张磊
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Abstract

本发明属于医药制剂技术领域,公开了一种治疗Ⅱ型糖尿病的维格列汀片剂,该片剂是将原辅料混匀后直接压片而得,所述的原辅料包括维格列汀、葡萄糖酸、崩解剂和润滑剂。 The present invention belongs to the technical field of pharmaceutical preparations, discloses a method of treating diabetes type Ⅱ vildagliptin tablets which is the original direct tableting obtained by mixing materials, the raw materials comprising vildagliptin , gluconic acid, disintegrants, and lubricants. 本发明在制备和储存过程中所含维格列汀基本无降解,质量稳定;制备方法采用直接压片法,工艺简单易控,易于工业化大生产。 The present invention is substantially free of degradation during storage and preparation contained vildagliptin, quality and stability; prepared by direct compression method, the process is simple and easy to control and easy industrial production.

Description

一种治疗Π型糖尿病的维格列订片剂 Π for treating diabetes Ludwig column set tablets

技术领域 FIELD

[0001] 本发明属于药物制剂技术领域,具体而言,涉及一种高稳定性的固体口服制剂,尤其涉及一种含有维格列汀的片剂及其制备方法。 [0001] The present invention belongs to the technical field of pharmaceutical formulation, in particular, relates to a high stability solid oral formulations, and in particular relates to a method for preparing a tablet containing vildagliptin.

背景技术 Background technique

[0002] 葡萄糖依赖性促胰岛素多肽(GIP)和胰高血糖素样多肽-I (GLP-I)是维持体内葡萄糖浓度的重要激素,都具有肠促胰岛素作用。 [0002] Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide -I (GLP-I) is an important hormone to maintain the glucose concentration in the body, having incretin effect. Π型糖尿病患者GIP的促胰岛素分泌作用受损,仅有GLP-I能发挥促胰岛激素分泌作用,它通过作用于胰岛B细胞膜上的受体,促进胰岛素的分泌。 Insulin secretion in patients with diabetes mellitus type Π damaged GIP, GLP-I can only play insulinotropin secretion, which by acting on the pancreatic B cell membrane receptors, and promote insulin secretion. GLP-I还可抑制胰高血糖素的分泌以及抑制胃排空从而增加饱足感(抑制食欲)。 GLP-I also inhibit the secretion of glucagon and inhibiting gastric emptying thereby increasing satiety (appetite suppression). DPP-IV与蛋白结合存在于许多组织中,如肾、肝、小肠膜的刷状边缘、胰管、淋巴细胞、内皮细胞,其能通过水解GLP-I的N端第2位丙氨酸迅速使其失活,从而达到治疗Π型糖尿病的目的。 DPP-IV binding protein present in many tissues, such as the brush-like kidney, liver, small intestine edges of the film, pancreatic duct, lymphocytes, endothelial cells, which GLP-I by hydrolysis of the N-terminal alanine at position 2 rapidly inactivated, so as to achieve the treatment of diabetes mellitus type Π.

[0003] 维格列汀是一种具有选择性、竞争性、可逆的DPP-IV抑制剂,给药后能快速抑制DPP-4活性,使空腹和餐后内源性血糖素GLP-I (胰高血糖素多肽-1)和GIP (葡萄糖依赖性促胰岛素多肽)的水平升高,进而增加细胞对葡萄糖的敏感性,促进葡萄糖依赖性胰岛素的分泌。 [0003] Vildagliptin is a selective, competitive, reversible inhibitors of DPP-IV after administration of DPP-4 inhibition of rapid activity, fasting and the postprandial glucagon endogenous GLP-I ( glucagon levels of peptide-1) and the GIP (glucose-dependent insulinotropic polypeptide) is increased, thereby increasing the sensitivity of cells to glucose, the glucose-dependent insulin secretion promoting. 通过增加内源性GLP-I水平,维格列汀还能够增加α细胞对葡萄糖的敏感性,使葡萄糖水平与胰高血糖素的分泌量契合度提高。 By increasing the endogenous levels of GLP-I, α vildagliptin also increase the sensitivity of cells to glucose, and glucose level secretion of glucagon improved fit. 在高血糖期间,维格列汀通过升高肠降血糖素水平,增加胰岛素/胰高血糖素的比率,导致空腹和餐后肝脏葡萄糖生成量减少,进而降低血糖。 During hyperglycemia, vildagliptin by increasing incretin levels, increasing the ratio of insulin / glucagon, resulting in fasting and postprandial hepatic glucose production reduced, thereby reducing blood glucose. 该药物的化学名为1_[[ (3-羟基-1-金刚烷基)氨基]乙酰基]-2-氰基-(5)-四氢吡咯烷, 结构式如下: The pharmaceutical chemical name 1 _ [[(3-hydroxy-1-adamantyl) amino] acetyl] -2-cyano - (5) - alkoxy pyrrolidine, the following structural formula:

Figure CN104856970BD00031

[0005] 维格列汀对湿热极不稳定,故在其制剂的生产过程中,多采用干法制粒或干粉直压的工艺,然而经长期储存后依然降解严重,造成药品质量下降。 [0005] vildagliptin is very unstable to heat, so in the production process of the preparation thereof, the use of dry granulation or dry direct compression process, but after long-term storage is still severe degradation, resulting in decreased quality of pharmaceuticals.

[0006] CN101618216B公开了一种将二肽基肽酶IV (DPP-IV)抑制剂(即维格列汀)化合物直接压片所形成的片剂、其制备方法、及药物配方。 [0006] CN101618216B discloses a dipeptidyl peptidase IV (DPP-IV) inhibitor (i.e. vildagliptin) compound tablets formed by direct compression methods for their preparation, and pharmaceutical formulations. 但其所采用的润滑剂硬脂酸镁与活性成分发生配位使活性成分发生降解反应,包括关环、水解等,导致其在制备或贮存中稳定性的降低。 However, their use of the lubricant magnesium stearate is coordinated with the active ingredient active ingredient degradation reactions occur, including cyclization, hydrolysis, leading to reduced stability in the manufacture or storage. CN104161752 A润滑剂选用硬脂富马酸钠,工艺为直接压片,以延缓药物水解,然而该制剂采用不常用的其它润滑剂,增加了物料的采购成本和药品的生产成本。 CN104161752 A lubricant selected stearyl sodium fumarate, a direct compression process, to retard hydrolysis of the drug, however, that other formulations of the lubricant is not used, the production cost increases and the cost of purchasing pharmaceutical materials.

发明内容 SUMMARY

[0007] 鉴于现有技术的不足,本发明的目的在于提供一种生产成本低、质量稳定的维格列汀片剂。 [0007] In view of the deficiencies of the prior art, an object of the present invention is to provide a low production cost, quality and stability of vildagliptin tablet.

[0008] 为了实现本发明的目的,发明人经过大量试验对辅料进行筛选研究,意外地发现葡萄糖酸能抑制维格列汀的水解发生,尤其可以抑制硬脂酸镁与维格列汀发生配位导致的降解反应,从而大幅度提尚制剂的稳定性。 [0008] To achieve the object of the present invention, the inventors screened for materials research through extensive testing, gluconic surprisingly found possible to suppress the occurrence of the hydrolysis of vildagliptin, in particular, can be suppressed with the occurrence of magnesium stearate with vildagliptin bit causes degradation reaction, thus greatly still provide stability of the formulation.

[0009] 具体而言,本发明的目的是通过如下技术方案实现的:一种治疗Π型糖尿病的维格列汀片剂,该片剂是将原辅料混匀后直接压片而得,所述的原辅料包括维格列汀、葡萄糖酸、崩解剂和润滑剂。 [0009] Specifically, the object of the present invention is achieved by the following technical solution: a method of treating diabetes Π vildagliptin tablets which is the original mixing materials obtained by direct compression, by said raw materials comprising vildagliptin, gluconic acid, disintegrants, and lubricants.

[0010] 优选地,如上所述的维格列汀片剂,其中的原辅料还可以包含填充剂,填充剂的加入更有利于片剂的压制成型。 [0010] Preferably, vildagliptin tablet as described above, wherein the raw materials may also contain a filler, the filler is added more conducive to forming compressed tablets.

[0011] 在本发明所优选的实施例中,如上所述的维格列汀片剂,其中的原辅料由维格列汀、葡萄糖酸、填充剂、崩解剂和润滑剂组成。 [0011] In the preferred embodiment of the present invention, vildagliptin tablet as described above, wherein the raw materials of vildagliptin, gluconic acid, a filler, a disintegrant and a lubricant.

[0012] 进一步优选地,如上所述的维格列汀片剂,其中的维格列汀与葡萄糖酸的重量比为1: (0.4〜3.0)。 [0012] Further preferably, vildagliptin tablet as described above, wherein the weight ratio of vildagliptin and gluconic acid is 1: (0.4~3.0). 再进一步优选地,其中的维格列汀与葡萄糖酸的重量比为1: (0.8〜1.5)。 Still further preferably, the weight of vildagliptin and gluconic acid wherein the ratio of 1: (0.8~1.5).

[0013] 本发明所述的维格列汀片剂,所述的崩解剂选自交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素和交联羧甲基纤维素钠中的一种或几种。 [0013] vildagliptin tablet according to the present invention, the disintegrant is selected from cross-linked povidone, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose and crosslinked carboxymethylcellulose one or more of sodium. 所述的填充剂选自乳糖、微晶纤维素、甘露醇、糊精、蔗糖和预胶化淀粉中的一种或多种。 Said filler is selected from lactose, microcrystalline cellulose, mannitol, dextrin, sucrose, and one or more of pregelatinized starch. 所述的润滑剂选自硬脂酸镁、硬脂酸富马酸钠和滑石粉中的一种或几种。 Said lubricant is selected from magnesium stearate, sodium stearate, fumaric acid and one or more of talc.

[0014] 本发明还提供了上述维格列汀片剂的制备方法,该方法包括如下步骤:将维格列汀过筛,加入葡萄糖酸、微晶纤维素、羧甲基淀粉钠混合均匀,加入润滑剂,混合均匀,直接压片而成。 [0014] The present invention further provides a method for preparing the vildagliptin tablet, the method comprising the steps of: vildagliptin sieved, added gluconic acid, microcrystalline cellulose, sodium carboxymethyl starch are mixed uniformly, lubricant was added, mixed, direct tableting formed.

[0015] 与现有技术相比,本发明涉及的维格列汀片剂及其制备方法具有如下优点和显著进步性:(1)制剂在制备和储存过程中所含维格列汀基本无降解,质量稳定;(2)制剂处方中可以采用成本更低且更常用的润滑剂硬脂酸镁,同时有利于质量控制; [0015] Compared with the prior art, vildagliptin tablet and preparation method of the present invention and has the advantage of significant progress: (1) in the formulation during storage and preparation contained substantially no vildagliptin degradation, stable quality; (2) lower cost and more pharmaceutical formulations commonly used lubricant magnesium stearate may be employed, while facilitating quality control;

[0016] (3)制备方法简单,易于工业化大生产。 [0016] Preparation of (3) The method is simple and easy industrial production.

具体实施方式 Detailed ways

[0017] 现通过以下实施例来进一步描述本发明的制备过程和实施效果,但本发明的保护范围并不局限于以下实施例。 [0017] Example embodiments now be further described by the following embodiments and effects of the manufacturing process of the present invention, but the scope of the present invention is not limited to the following embodiments.

[0018] 实施例1 维格列汀50g 葡萄糖酸120g [0018] Example 1 120g embodiment gluconate 50g vildagliptin

[0019] 微晶纤维素200g 羧甲基淀粉钠IOg 硬脂酸镁3.6g [0019] Microcrystalline cellulose 200g Sodium carboxymethyl starch Magnesium stearate 3.6g IOg

[0020]制备方法: [0020] Preparation:

[0021] 将维格列汀过100目筛,加入处方量过80目筛的葡萄糖酸、微晶纤维素、羧甲基淀粉钠混合均匀,加入硬脂酸镁,混合均匀,直接压片而成。 [0021] The vildagliptin than 100 mesh, the amount of formulation added through a sieve of 80 mesh gluconic acid, microcrystalline cellulose, sodium carboxymethyl starch mixed, magnesium stearate was added, mixed, direct tabletting to make.

[0022] 实施例2 维格列汀_50g 葡萄糖酸20g [0022] Example 2 20g embodiment gluconate vildagliptin _50g

[0023] 微晶纤维素10% 交联聚维酮Sg 硬脂酸镁2 Ig [0023] Microcrystalline Cellulose 10% cross-linked povidone Sg Magnesium stearate 2 Ig

[0024]制备方法: [0024] Preparation:

[0025] 将维格列汀过100目筛,加入处方量过100目筛的葡萄糖酸、微晶纤维素、交联聚维酮混合均匀,加入硬脂酸镁,混合均匀,直接压片而成。 [0025] The vildagliptin than 100 mesh, the amount of formulation added through a 100 mesh sieve gluconic acid, microcrystalline cellulose, cross-linked povidone mixed, magnesium stearate was added, mixed, direct tabletting to make.

[0026] 实施例3 维格列汀50g 葡萄糖酸极% Example 3 50g glucose vildagliptin acid [0026] The pole%

[0027] 微晶纤维素130g 交联聚维酮IOg 硬脂酸镁2:.5g [0027] Microcrystalline cellulose 130g cross-linked povidone IOg Magnesium stearate 2: .5g

[0028]制备方法: [0028] Preparation:

[0029] 将维格列汀过80目筛,加入处方量过100目筛的葡萄糖酸、微晶纤维素、交联聚维酮混合均匀,加入硬脂酸镁,混合均匀,直接压片而成。 [0029] The vildagliptin through 80 mesh sieve, was added 100 mesh sieve prescribed amount of gluconic acid, microcrystalline cellulose, cross-linked povidone mixed, magnesium stearate was added, mixed, direct tabletting to make.

[0030] 对比例1 维格列汀5%: 微晶纤维素:2(% [0030] Comparative Example 1 5% of vildagliptin: microcrystalline cellulose: 2 (%

[0031] 交联聚维酮IOg 硬脂酸镁2.:2g [0031] The cross-linked povidone, magnesium stearate 2.:2g IOg

[0032]制备方法: [0032] Preparation:

[0033] 将维格列汀过80目筛,加入处方量过100目筛的微晶纤维素、交联聚维酮混合均匀,加入硬脂酸镁,混合均匀,压片而成。 [0033] The vildagliptin through 80 mesh sieve, were added through a 100 mesh sieve prescribed amounts of microcrystalline cellulose, crosslinked povidone mixed, magnesium stearate was added, mixed well, tabletting is made.

[0034] 对比例2 维格列汀50g: 枸橼酸60g [0034] Comparative Example 2 vildagliptin 50g: citric acid 60g

[0035] 微晶纤维素130g 交联聚维酮IOg 硬脂酸镁2.5g [0035] Microcrystalline cellulose 130g cross-linked povidone, magnesium stearate 2.5g IOg

[0036]制备方法: [0036] Preparation:

[0037]将维格列汀过80目筛,加入处方量过100目筛的枸橼酸、微晶纤维素、交联聚维酮混合均匀,加入硬脂酸镁,混合均匀,压片而成。 [0037] The vildagliptin through 80 mesh screen, added to the amount of 100 mesh pass prescription citrate, microcrystalline cellulose, cross-linked povidone mixed, magnesium stearate was added, mixed well, tabletting to make.

[0038] 实施例4:加速试验前后维格列汀片的有关物质检测试验 [0038] Example 4: Accelerated testing related substances before the test piece 后维格列汀

[0039] 取实施例1-3及对比例1-2制备的维格列汀片剂各6片作为样品,分别置IOOml量瓶中,加稀释剂适量,振摇使维格列汀溶解,用稀释剂稀释至刻度,摇匀,滤过,取续滤液作为供试品溶液。 [0039] Examples 1-3 taken and the proportion of vildagliptin tablets prepared in each six 1-2 as a sample, are set IOOml flask, add appropriate amount of diluent, shaking vildagliptin is dissolved, It was diluted with a diluent, shaken, filtered, the filtrate taken as the test solution. 取维格列汀对照品适量,精密称定,用稀释剂溶解并稀释制成每Iml中约含2.5 yg的溶液作为对照品溶液。 Take vildagliptin reference standard amount, accurately weighed, dissolved with a diluent and made every Iml containing about 2.5 yg solution was diluted as the reference solution. 照高效液相色谱法(中国药典2010年版二部附录VD)测定,用十八烷基硅烷键合硅胶为填充剂;0.02mol/L磷酸二氢钠溶液(取二水合磷酸二氢钠3.12g,加水IOOOml使溶解,加三乙胺lml,混匀,用磷酸调节pH值至2.8)-乙腈(96: 4)为流动相A, 0.02mol/L磷酸二氢钠溶液-乙腈(75: 25)为流动相B;按下表进行梯度洗脱,流速为每分钟1.0ml,检测波长为2IOnm,柱温为35 °C。 High performance liquid chromatography (China Pharmacopoeia 2010 Appendix VD) was measured, using octadecyl silane bonded silica gel as a filler; 0.02mol / L sodium dihydrogen phosphate (sodium dihydrogen phosphate dihydrate takes 3.12g , water was added to dissolve IOOOml, lml of triethylamine, mixing, adjusting the pH to 2.8 with phosphoric acid) - acetonitrile (96: 4) as mobile phase A, 0.02mol / L sodium dihydrogen phosphate - acetonitrile (75: 25 ) as the mobile phase B; gradient elution in the table, the flow rate of 1.0ml per minute, detection wavelength was 2IOnm, column temperature was 35 ° C.

[0040] 取系统适用性溶液20μ1,注入液相色谱仪,记录色谱图,精密量取供试品溶液和对照品溶液各20μ1,分别注入液相色谱仪,记录色谱图。 [0040] The system suitability solution was taken 20μ1, into the liquid chromatograph, record the chromatograms, the precise amount of the test solution and reference solution 20μ1, were injected into the liquid chromatograph, record the chromatograms. 单个杂质不得过0.2%。 Single impurity not more than 0.2%. 记录并计算各组样品有关物质的含量均值。 And recording for each set of samples to calculate the mean content of related substances.

[0041] 表1:各实施例测定结果 [0041] Table 1: results of the measurements in Example

[0042] [0042]

Figure CN104856970BD00061

[0043] 从表1的试验统计结果中可知,本发明实施例1-3制备的维格列汀片,经加速考察后,有关物质基本不变;而对比例1的辅料中未加入匍甸糖酸,有关物质增加明显;对比例2 采用枸橼酸代替葡萄糖酸,效果更不好。 [0043] apparent from the test results shown in Table 1, statistically, vildagliptin tablets prepared according to Examples 1-3 of the present invention, after investigation accelerated, substantially constant related substances; whereas materials of Comparative Example 1 was not added creeping Austin sugar acids, the relevant substances which increase significantly; Comparative Example 2 using citric acid instead of glucose, the effect is worse.

Claims (7)

1. 一种治疗Π型糖尿病的维格列汀片剂,该片剂是将原辅料混匀后直接压片而得,其特征在于,所述的原辅料包括维格列汀、葡萄糖酸、崩解剂和润滑剂,维格列汀与葡萄糖酸的重量比为1: (0.4〜3.0)。 1. A method of treating diabetes Π vildagliptin tablets which is the original mixing materials obtained by direct compression, characterized in that said raw materials comprising vildagliptin, gluconic acid, disintegrant and a lubricant, the weight ratio of vildagliptin and gluconic acid is 1: (0.4~3.0).
2. 根据权利要求1所述的维格列汀片剂,其特征在于,所述的原辅料还包括填充剂。 Vildagliptin tablet according to claim 1, wherein said raw materials further include a filler.
3. 根据权利要求1所述的维格列汀片剂,其特征在于,所述的原辅料由维格列汀、葡萄糖酸、填充剂、崩解剂和润滑剂组成。 Vildagliptin tablet according to claim 1, wherein said raw materials of vildagliptin, gluconic acid, a filler, a disintegrant and a lubricant.
4. 根据权利要求1所述的维格列汀片剂,其特征在于,维格列汀与葡萄糖酸的重量比为1: (0.8〜1.5) 〇 Vildagliptin tablet according to claim 1, wherein the weight ratio of vildagliptin and gluconic acid is 1: (0.8~1.5) square
5. 根据权利要求1所述的维格列汀片剂,其特征在于,所述的崩解剂选自交联聚维酮、 羧甲基淀粉钠、低取代羟丙基纤维素和交联羧甲基纤维素钠中的一种或几种。 Vildagliptin tablet according to claim 1, wherein said disintegrant is selected from cross-linked povidone, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose and crosslinked one or more of sodium carboxymethyl cellulose.
6. 根据权利要求2所述的维格列汀片剂,其特征在于,所述的填充剂选自乳糖、微晶纤维素、甘露醇、糊精、蔗糖和预胶化淀粉中的一种或多种。 Vildagliptin tablet according to claim 2, wherein said filler is selected from one of lactose, microcrystalline cellulose, mannitol, dextrin, sucrose, and pregelatinized starch or more.
7. 根据权利要求1所述的维格列汀片剂,其特征在于,所述的润滑剂选自硬脂酸镁、硬脂酸富马酸钠和滑石粉中的一种或几种。 Vildagliptin tablet according to claim 1, wherein said lubricant is selected from magnesium stearate, sodium stearate, fumaric acid and one or more of talc.
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