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首页> 外文期刊>The Internet Journal of Pharmacology >Site-specific oral controlled release metformin tablets - development, in vitro, ex vivo and in vivo evaluation
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Site-specific oral controlled release metformin tablets - development, in vitro, ex vivo and in vivo evaluation

机译：定点口服控释二甲双胍片剂-研发，体外，离体和体内评估

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Oral absorption of metformin is confined to the upper part of intestine posing problems in the formulation of extended release tablets. Therefore, the objective of the present study was to develop controlled-release mucoadhesive core tablets and confine the tablets to the specific site in the gastrointestinal tract. A projective coat protects the core tablets from mucoadhesion till the targeted site is reached. Once the tablet reaches the specific site, the coat dissolves exposing the core tablet for mucoadhesion. In vitro coat intactness test and ex vivo tablet bioadhesion test confirmed that the tablets were targeted and contained in the upper intestine. Further, the pharmacokinetic parameters obtained for metformin from the site-specific coated formulation were better (P<0.05) than that of the non-site-specific uncoated formulation in the in vivo studies. Standardized formulation was stable during the stability studies conducted as per ICH Q1C guidelines. INTRODUCTION Metformin is a widely used biguanide anti-diabetic drug for the management of non-insulin dependent diabetes mellitus. Oral absorption of Metformin is confined to the upper part of the intestine, i.e., the duodenum, jejunum and to a lesser extent ileum1. Therefore, the bioavailability of this drug even from aqueous solution or rapidly dissolving tablets is relatively low2. A pharmacokinetic-pharmacodynamic rationale for development of metformin controlled release formulations was established and concluded that clinical advantage could be obtained from gastro-retentive systems3. However, only a 15% increase in bioavailability was produced by gastro-retentive swelling tablets based on high molecular weight polyethylene oxide compared to the currently marketed immediate release products4. In yet another study, compressed matrix tablets were prepared using pH-sensitive polyethylene oxide-eudragit-L100 compounds by a co-evaporation process, which gave a gradual and complete release of metformin from stomach to jejunum without getting affected by gastric pH fluctuations5. But the drug release was limited to only 4 hours with such a formulation. Hence to optimize oral metformin therapy, there is a need for development of metformin tablets, which confine to specific site in the upper intestine. Therefore, in the present study, an attempt was made to develop oral mucoadhesive controlled release metformin hydrochloride (MH) tablets using hydroxypropylmethyl cellulose (HPMC). These mucoadhesive tablets were intended to target the upper part of the intestine by pH sensitive polymer coating with eudragit-L100. As eudragit-L100 is soluble only above pH 6, coat dissolves upon reaching upper intestine and releases the core tablet to adhere at the specific site thus facilitating drug release for an extended duration of time. Materials And Methods Materials MH was supplied as a gift sample by Micro Labs Ltd., Hosur, India and eudragit-L100 by Degussa, Goa, India. All other materials used were of analytical grade and were obtained from s.d.fine-chemicals limited, Mumbai-25, India. Animal studies were conducted in accordance to the Institutional Animal Ethics Committee of Al-Ameen College of Pharmacy (Ref. No: AACP/P-05; Date: 07/07/2002), Bangalore, India. MethodsMethod of preparation of the mucoadhesive core tabletsMetformin controlled release mucoadhesive core tablets each containing 500mg dose of drug were prepared by conventional wet granulation as well as by direct compression methods. Polyvinylpyrrolidone–K30D (PVP-K30D) was used as a binding agent and microcrystalline cellulose (MCC) was included as filler, both of which improve the compressibility of MH. Colloidal silicon dioxide and magnesium stearate were used as lubricants. In case of wet granulation method, the drug MH, 30% of total quantity of the HPMCs and other ingredients except colloidal silicon dioxide and talc were blended together thoroughly after passing through 60 mesh. The powder blend was wetted with 95%
机译：二甲双胍的口服吸收仅限于缓释片剂配方中肠道上部的问题。因此，本研究的目的是开发控释粘膜粘附性核心片剂并将片剂限制在胃肠道的特定部位。投射涂层可保护核心片剂免受粘膜粘连，直至到达目标部位。片剂到达特定部位后，包衣溶解，使核心片剂粘膜粘​​附。体外被膜完整性测试和离体片剂生物粘附测试证实了片剂是靶向的并且包含在上肠中。此外，在体内研究中，由二甲双胍从位点特异性包衣制剂获得的药代动力学参数比非位点特异性未包衣制剂更好（P <0.05）。在按照ICH Q1C指南进行的稳定性研究中，标准化制剂是稳定的。简介二甲双胍是一种广泛使用的双胍类抗糖尿病药物，用于治疗非胰岛素依赖型糖尿病。二甲双胍的口服吸收仅限于肠的上部，即十二指肠，空肠，回肠的程度较小。因此，即使从水溶液或快速溶解的片剂中，该药物的生物利用度也相对较低2。建立了二甲双胍控释制剂开发的药代动力学-药效学原理，并得出结论，可以从胃固性系统获得临床优势3。但是，与目前市售的速释产品相比，基于高分子量聚环氧乙烷的胃滞留溶胀片仅产生15％的生物利用度4。在另一项研究中，通过共蒸发过程使用pH敏感的聚环氧乙烷-eudragit-L100化合物制备了压缩基质片剂，该片剂可从胃向空肠逐渐完全释放二甲双胍，而不受胃pH波动的影响5。但是用这样的制剂，药物的释放仅限于4小时。因此，为了优化口服二甲双胍治疗，需要开发二甲双胍片剂，其限于上肠道的特定部位。因此，在本研究中，尝试使用羟丙基甲基纤维素（HPMC）开发口服粘膜粘附控释盐酸二甲双胍（MH）片剂。这些粘膜粘附片剂旨在通过用eudragit-L100进行pH敏感的聚合物包衣来靶向肠的上部。由于eudragit-L100仅在pH高于6时才可溶，因此当包衣到达上层肠道时会溶解，并释放核心片剂以粘附在特定部位，从而延长药物释放时间。材料和方法材料MH由印度Hosur的Micro Labs Ltd.和印度果阿Degussa的eudragit-L100作为礼物样品提供。使用的所有其他材料均为分析纯，并从印度孟买25的s.d.fine-chemicals limited获得。动物研究根据印度班加罗尔Al-Ameen药学院的机构动物伦理委员会（Ref。No：AACP / P-05; Date：07/07/2002）进行。方法制备粘膜粘附性核心片剂的方法通过常规湿法制粒和直接压片法制备二甲双胍控释粘膜粘附性核心片剂，每片含500mg药物。聚乙烯吡咯烷酮-K30D（PVP-K30D）被用作粘合剂，微晶纤维素（MCC）被用作填充剂，两者均提高了MH的可压缩性。胶体二氧化硅和硬脂酸镁用作润滑剂。在湿法制粒的情况下，药物MH，HPMC总量的30％和除胶体二氧化硅和滑石粉外的其他成分在通过60目后彻底混合在一起。将粉末混合物用95％湿润

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