Development of metformin HCl granules using brown flaxseed mucilage as a retardant polymer: effects of polymer and drug ratio

Abstract Flaxseed (Linum usitatissimum L.) is the seed of a multipurpose plant of pharmaceutical interest, as its mucilage can be used as a natural matrix to develop extended-release dosage forms and potentially replace synthetic polymers. In this study, a 3² factorial design with two replicates of the central point was applied to optimize the development of extended-release granules of metformin HCl. The total fiber content of the mucilage as well as the friability and dissolution of the formulations were evaluated. The lyophilized mucilage presented a high total fiber content (42.63%), which suggests a high efficiency extraction process. Higher concentrations of the mucilage and metformin HCl yielded less friable granules. In addition, lower concentrations of metformin HCl and higher concentrations of the mucilage resulted in slower drug release during the dissolution assays. The release kinetics for most formulations were better represented by the Hixson-Crowell model, while formulations containing a higher concentration of the mucilage were represented by the Korsmeyer-Peppas model. Nonetheless, five formulations showed a longer release than the reference HPMC formulation. More desirable results were obtained with a higher concentration of the mucilage (13-18%) and a lower concentration of metformin (40%).

摘要：亚麻籽（Linum usitatissimum L.）是一种兼具多种用途且具有药用价值的植物种子，其所含的粘液质可作为天然基质用于开发缓释制剂，有望替代合成高分子材料。本研究采用3²析因设计（3² factorial design），并设置两个中心点重复实验，以优化盐酸二甲双胍（metformin HCl）缓释颗粒的制备工艺。本研究测定了该粘液质的总纤维含量，同时对各制剂的脆碎度与溶出特性进行了评价。冷冻干燥制备的粘液质总纤维含量达42.63%，表明其提取工艺具有较高效率。提高粘液质与盐酸二甲双胍的投料浓度，可获得脆碎度更低的颗粒。此外，降低盐酸二甲双胍的投料浓度并提高粘液质的投料浓度，可在溶出试验中实现更缓慢的药物释放。多数制剂的释药动力学更符合Hixson-Crowell模型，而高粘液质投料浓度的制剂则更符合Korsmeyer-Peppas模型。不过，有5种制剂的释药时长均长于羟丙基甲基纤维素（HPMC）参比制剂。当粘液质投料浓度为13%~18%、盐酸二甲双胍投料浓度为40%时，可获得更理想的试验结果。