Kenechukwu Franklin Chimaobi, Isaac God'spower Tochukwu, Nnamani Daniel Okwudili, Momoh Mumuni Audu, Attama Anthony Amaechi
Drug Delivery and Nanomedicines Research Group, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka 410001, Enugu State, Nigeria.
Heliyon. 2022 Mar 15;8(3):e09100. doi: 10.1016/j.heliyon.2022.e09100. eCollection 2022 Mar.
Metformin hydrochloride (MTH) has been associated with poor/incomplete absorption (50-60%), low bioavailability, short half-life (0.4-0.5 h), high dosage and dose-related side effects. To overcome these barriers and improve oral bioavailability and efficacy of MTH, surface-modified nanostructured lipid carriers (NLCs) were developed. Lipid matrices composed of rational blends of beeswax and Phospholipon® 90H (as solid lipids) and Capryol-PGE 860 (as liquid lipid) were prepared by fusion, and the resultant lipid matrices were PEGylated to give 10, 20 and 40% PEGylated lipid matrices. MTH-loaded non-PEGylated and PEGylated NLCs were prepared via high-shear hot homogenization and characterized regarding particle properties and physicochemical performance. The encapsulation efficiencies (EE%) and loading capacities (LC) of the MTH-loaded NLCs were determined while the drug release was evaluated in phosphate buffered saline (PBS, pH 7.4). Antidiabetic and pharmacokinetics properties of the NLCs were ascertained in an alloxan-induced diabetic rats model after oral administration. The MTH-loaded NLCs were nanomeric (particle size: 184.8-882.50 nm) with low polydispersity index (0.368-0.687) and zeta potential (26.5-34.2 mV), irregular shape, amorphous nature with reduced crystallinity. The EE% and LC were >90 % and 16%, respectively. The formulations showed >65 % release over 12 h in a greater sustained manner than marketed MTH formulation (Glucophage®) as well as enhanced pharmacokinetics properties and sustained blood glucose lowering effect, even at reduced doses with PEGylated NLCs than Glucophage®. Thus, PEGylated NLC is a promising approach for improved delivery and oral bioavailability of MTH thus encouraging further development of the formulation.
盐酸二甲双胍（MTH）存在吸收不良/不完全（50 - 60%）、生物利用度低、半衰期短（0.4 - 0.5小时）、剂量高以及与剂量相关的副作用等问题。为克服这些障碍并提高MTH的口服生物利用度和疗效，研发了表面改性的纳米结构脂质载体（NLCs）。通过融合制备了由蜂蜡和磷脂酰胆碱90H（作为固体脂质）以及辛酸甘油三酯860（作为液体脂质）的合理混合物组成的脂质基质，并将所得脂质基质进行聚乙二醇化处理，得到10%、20%和40%聚乙二醇化脂质基质。通过高剪切热均质法制备了载有MTH的非聚乙二醇化和聚乙二醇化NLCs，并对其颗粒性质和物理化学性能进行了表征。测定了载有MTH的NLCs的包封率（EE%）和载药量（LC），同时在磷酸盐缓冲盐水（PBS，pH 7.4）中评估了药物释放情况。在口服给药后，在四氧嘧啶诱导的糖尿病大鼠模型中确定了NLCs的抗糖尿病和药代动力学性质。载有MTH的NLCs为纳米级（粒径：184.8 - 882.50 nm），多分散指数低（0.368 - 0.687），zeta电位（26.5 - 34.2 mV），形状不规则，为无定形性质且结晶度降低。EE%和LC分别>90%和16%。这些制剂在12小时内的释放率>65%，比市售MTH制剂（格华止®）具有更强的持续释放方式，以及增强的药代动力学性质和持续的降血糖作用，即使使用聚乙二醇化NLCs的剂量降低时也优于格华止®。因此，聚乙二醇化NLC是一种有前景的方法，可改善MTH的递送和口服生物利用度，从而推动该制剂的进一步开发。
