Zhang Yumin, Zhang Aoxue, Chen Dongmei, Xie Shuyu
National Reference Laboratory of Veterinary Drug Residues (HZAU), Wuhan, Hubei 430070, China.
National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
Curr Drug Deliv. 2024 Aug 13. doi: 10.2174/0115672018276382231207103955.
Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is one of the leading causes of death and an immense financial burden on healthcare systems. Rifaximin (RFX) has good antibacterial activity against MRSA, but its clinical application is limited due to its poor oral absorption. Solid lipid nanoparticles have good biocompatibility, high drug loading, sustained release performance, and the inertia of lipids in gastric acid, which facilitates oral drug delivery.
In order to improve the oral bioavailability of rifaximin and expand the clinical application of RFX for MRSA pneumonia, this study developed RFX-loaded myristic acid solid lipid nanoparticles (RFX-SLNs).
This study first prepared RFX-SLNs through hot melt emulsification and ultrasonic methods and selected the optimal formula of RFX-SLNs through single-factor screening. Afterward, the particle size, zeta potential, and polydispersity index (PDI) of the RFX-SLNs were measured, the morphology of RFX-SLNs was observed by transmission electron microscopy, and the encapsulation efficiency (EE) and drug loading capacity (LC) of RFX-SLNs were detected by high-performance liquid chromatography. Then, the sustained release ability and oral bioavailability of RFX-SLNs were studied through in vitro release and pharmacokinetics. Finally, the therapeutic effect of RFX-SLNs on MRSA pneumonia infection was studied by using a mouse MRSA pneumonia infection model.
The optimal formulation of RFX-SLNs was 1% RFX with water (3% PVA) and oil (myristic acid) ratio of 1:19. RFX-SLNs were spherical in shape with a smooth surface and uniform size. The EE and LC of three different batches of RFX-SLNs were 89.35±2.47%, 90.45±3.69%, 88.72±1.18%, and 9.50 ± 0.01%, 10.09±0.01%, and 9.68±0.00%, respectively. In vitro release and pharmacokinetic studies showed that the myristic acid solid lipid nanoparticles showed excellent sustained release as expected and increased the oral bioavailability of RFX by 2.18 times. This indicates that RFX-SLNs can be used for the oral treatment of bacterial infections. Compared to RFX, RFX-SLNs showed good therapeutic effects in a mouse MRSA pneumonia infection model.
This study indicates that the myristic acid solid lipid nanoparticles might be an effective way to enhance the oral absorption and therapy effects of RFX and other insoluble drugs. This not only opens up avenues for the clinical application of RFX but also provides a way for the development of new dosage forms of water-soluble drugs and the expansion of their clinical application scope.
耐甲氧西林金黄色葡萄球菌（MRSA）肺炎是主要死亡原因之一，给医疗系统带来巨大经济负担。利福昔明（RFX）对MRSA具有良好的抗菌活性，但由于其口服吸收差，临床应用受限。固体脂质纳米粒具有良好的生物相容性、高载药量、缓释性能以及在胃酸中脂质的惰性，有利于口服给药。
为提高利福昔明的口服生物利用度，扩大RFX在MRSA肺炎中的临床应用，本研究制备了载有利福昔明的肉豆蔻酸固体脂质纳米粒（RFX-SLNs）。
本研究首先通过热熔乳化法和超声法制备RFX-SLNs，并通过单因素筛选确定RFX-SLNs的最佳配方。随后，测定RFX-SLNs的粒径、zeta电位和多分散指数（PDI），通过透射电子显微镜观察RFX-SLNs的形态，并用高效液相色谱法检测RFX-SLNs的包封率（EE）和载药量（LC）。然后，通过体外释放和药代动力学研究RFX-SLNs的缓释能力和口服生物利用度。最后，利用小鼠MRSA肺炎感染模型研究RFX-SLNs对MRSA肺炎感染的治疗效果。
RFX-SLNs的最佳配方为1% RFX，水（3%聚乙烯醇）与油（肉豆蔻酸）的比例为1:19。RFX-SLNs呈球形，表面光滑，尺寸均匀。三批不同的RFX-SLNs的EE和LC分别为89.35±2.47%、90.45±3.69%、88.72±1.18%和9.50±0.01%、10.09±0.01%、9.68±0.00%。体外释放和药代动力学研究表明，肉豆蔻酸固体脂质纳米粒如预期显示出优异的缓释性能，使RFX的口服生物利用度提高了2.18倍。这表明RFX-SLNs可用于口服治疗细菌感染。与RFX相比，RFX-SLNs在小鼠MRSA肺炎感染模型中显示出良好的治疗效果。
本研究表明，肉豆蔻酸固体脂质纳米粒可能是提高RFX和其他难溶性药物口服吸收及治疗效果的有效途径。这不仅为RFX的临床应用开辟了道路，也为水溶性药物新剂型的开发及其临床应用范围的扩大提供了一种方法。
