Zhou Yaxin, Dai Guonian, Xu Jing, Xu Weibing, Li Bing, Chen Shulin, Zhang Jiyu
Key Laboratory of New Animal Drug Project of Gansu Province, Lanzhou 730050, China.
Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou 730050, China.
Pharmaceutics. 2025 Jul 24;17(8):957. doi: 10.3390/pharmaceutics17080957.
Trimethoprim (TMP), a sulfonamide antibacterial synergist, is widely used in antimicrobial therapy owing to its broad-spectrum activity and clinical efficacy in treating respiratory, urinary tract, and gastrointestinal infections. However, its application is limited due to poor aqueous solubility, a short elimination half-life (t), and low bioavailability. In this study, we proposed TMP loaded by PEG-PLGA polymer nanoparticles (NPs) to increase its efficacy. We synthesized and thoroughly characterized PEG-PLGA NPs loaded with TMP using an oil-in-water (O/W) emulsion solvent evaporation method, denoted as PEG-PLGA/TMP NPs. Drug loading capacity (LC) and encapsulation efficiency (EE) were quantified by ultra-performance liquid chromatography (UPLC). Comprehensive investigations were conducted on the stability of PEG-PLGA/TMP NPs, in vitro drug release profiles, and in vivo pharmacokinetics. The optimized PEG-PLGA/TMP NPs displayed a high LC of 34.0 ± 1.6%, a particle size of 245 ± 40 nm, a polydispersity index (PDI) of 0.103 ± 0.019, a zeta potential of -23.8 ± 1.2 mV, and an EE of 88.2 ± 4.3%. The NPs remained stable at 4 °C for 30 days and under acidic conditions. In vitro release showed sustained biphasic kinetics and enhanced cumulative release, 86% at pH 6.8, aligning with first-order models. Pharmacokinetics in rats revealed a 2.82-fold bioavailability increase, prolonged half-life 2.47 ± 0.19 h versus 0.72 ± 0.08 h for free TMP, and extended MRT 3.10 ± 0.11 h versus 1.27 ± 0.11 h. PEG-PLGA NPs enhanced the solubility and oral bioavailability of TMP via high drug loading, stability, and sustained-release kinetics, validated by robust in vitro-in vivo correlation, offering a promising alternative for clinical antimicrobial therapy.
甲氧苄啶（TMP）是一种磺胺类抗菌增效剂，因其具有广谱活性以及在治疗呼吸道、泌尿道和胃肠道感染方面的临床疗效，而被广泛用于抗菌治疗。然而，由于其水溶性差、消除半衰期（t）短以及生物利用度低，其应用受到限制。在本研究中，我们提出用聚乙二醇-聚乳酸-羟基乙酸共聚物（PEG-PLGA）聚合物纳米粒（NPs）负载TMP以提高其疗效。我们采用水包油（O/W）乳液溶剂蒸发法合成并全面表征了负载TMP的PEG-PLGA NPs，记为PEG-PLGA/TMP NPs。通过超高效液相色谱（UPLC）对载药量（LC）和包封率（EE）进行了定量分析。对PEG-PLGA/TMP NPs的稳定性、体外药物释放曲线和体内药代动力学进行了全面研究。优化后的PEG-PLGA/TMP NPs显示出34.0±1.6%的高载药量、245±40 nm的粒径、0.103±0.019的多分散指数（PDI）、-23.8±1.2 mV的zeta电位以及88.2±4.3%的包封率。这些纳米粒在4℃下30天以及在酸性条件下均保持稳定。体外释放显示出持续的双相动力学和增强的累积释放，在pH 6.8时为86%，符合一级模型。大鼠体内药代动力学显示生物利用度提高了2.82倍，半衰期延长，游离TMP的半衰期为0.72±0.08小时，而PEG-PLGA/TMP NPs为2.47±0.19小时，平均驻留时间延长，游离TMP为1.27±0.11小时，而PEG-PLGA/TMP NPs为3.10±0.11小时。PEG-PLGA NPs通过高载药量、稳定性和缓释动力学提高了TMP的溶解度和口服生物利用度，通过可靠的体外-体内相关性得到验证，为临床抗菌治疗提供了一种有前景的替代方案。
