School of Pharmacy, The University of Queensland, Woolloongabba 4102, Australia; Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Woolloongabba 4102, QLD, Australia.
School of Pharmacy, The University of Queensland, Woolloongabba 4102, Australia.
Int J Pharm. 2021 Mar 15;597:120280. doi: 10.1016/j.ijpharm.2021.120280. Epub 2021 Feb 1.
Meropenem (MER) is one of the last resort antibiotics used to treat resistant bacterial infections. However, the clinical effectiveness of MER is hindered due to chemical instability in aqueous solution and gastric pH, and short plasma half-life. Herein, a novel multi-material delivery system based on γ-cyclodextrin (γ-CD) and poly lactic-co-glycolic acid (PLGA) is demonstrated to overcome these challenges. MER showed a saturated solubility of 14 mg/100 mL in liquid CO and later it was loaded into γ-CD to form the inclusion complex using the liquid CO method. The γ-CD and MER inclusion complex (MER-γ-CD) was encapsulated into PLGA by the well-established double emulsion solvent evaporation method. The formation of the inclusion complex was confirmed using FTIR, XRD, DSC, SEM, and H NMR and docking study. Further, MER-γ-CD loaded PLGA nanoparticles (MER-γ-CD NPs) were characterized by SEM, DLS, and FTIR. The drug loading and entrapment efficiency for MER-γ-CD were 21.9 and 92. 2% w/w, respectively. However, drug loading and entrapment efficiency of MER-γ-CD NPs was significantly lower at up to 3.6 and 42.1% w/w, respectively. In vitro release study showed that 23.6 and 27.4% of active (non-degraded drug) and total drug (both degraded and non-degraded drug) were released from MER-γ-CD NPs in 8 h, respectively. The apparent permeability coefficient (Papp) (A to B) for MER, MER-γ-CD, and MER-γ-CD NPs were 2.63 × 10 cm/s, 2.81 × 10 cm/s, and 2.92 × 10 cm/s respectively. For secretory transport, the Papp (B to A) were 1.47 × 10 cm/s, 1.53 × 10 cm/s, and 1.58 × 10 cm/s for MER, MER-γ-CD and MER-γ-CD NPs respectively. Finally, the MER-γ-CD inclusion complex and MER-γ-CD NPs retained MER's antibacterial activities against Staphylococcus aureus and Pseudomonas aeruginosa. Overall, this work demonstrates the significance of MER-γ-CD NPs to protect MER from gastric pH with controlled drug release, while retaining MER's antibacterial activity.
美罗培南（MER）是一种用于治疗耐药细菌感染的最后手段抗生素。然而，由于在水溶液中化学不稳定和胃 pH 值以及血浆半衰期短，MER 的临床效果受到阻碍。本文展示了一种基于 γ-环糊精（γ-CD）和聚乳酸-共-羟基乙酸（PLGA）的新型多材料递送系统，以克服这些挑战。MER 在液态 CO 中显示出 14 mg/100 mL 的饱和溶解度，随后将其加载到 γ-CD 中，通过液态 CO 法形成包合物。γ-CD 和 MER 包合物（MER-γ-CD）通过成熟的双乳液溶剂蒸发法封装到 PLGA 中。使用傅里叶变换红外光谱（FTIR）、X 射线衍射（XRD）、差示扫描量热法（DSC）、扫描电子显微镜（SEM）和 H 核磁共振（NMR）以及对接研究证实了包合物的形成。进一步，通过 SEM、DLS 和 FTIR 对载有 MER-γ-CD 的 PLGA 纳米粒子（MER-γ-CD NPs）进行了表征。MER-γ-CD 的载药量和包封效率分别为 21.9%和 92.2%（w/w）。然而，MER-γ-CD NPs 的载药量和包封效率分别显著降低至 3.6%和 42.1%（w/w）。体外释放研究表明，MER-γ-CD NPs 在 8 小时内分别释放了 23.6%和 27.4%的活性（未降解药物）和总药物（降解和未降解药物）。MER、MER-γ-CD 和 MER-γ-CD NPs 的表观渗透系数（Papp）（A 到 B）分别为 2.63×10-5 cm/s、2.81×10-5 cm/s 和 2.92×10-5 cm/s。对于分泌转运，MER、MER-γ-CD 和 MER-γ-CD NPs 的 Papp（B 到 A）分别为 1.47×10-5 cm/s、1.53×10-5 cm/s 和 1.58×10-5 cm/s。最后，MER-γ-CD 包合物和 MER-γ-CD NPs 保留了 MER 对金黄色葡萄球菌和铜绿假单胞菌的抗菌活性。总体而言，这项工作表明，MER-γ-CD NPs 具有保护 MER 免受胃 pH 值影响并控制药物释放的重要意义，同时保留了 MER 的抗菌活性。
