4.7 Article

Optimization of Tilmicosin-Loaded Nanostructured Lipid Carriers Using Orthogonal Design for Overcoming Oral Administration Obstacle

Journal

PHARMACEUTICS
Volume 13, Issue 3, Pages -

Publisher

MDPI
DOI: 10.3390/pharmaceutics13030303

Keywords

tilmicosin; nanostructured lipid carriers; orthogonal design; intestinal absorption; MDCK-chAbcg2; Abcb1 cell monolayer

Funding

  1. National Key Research and Development Program of China [2016YFD0501306]
  2. Fundamental Research Funds for the Central Universities [KYGD202002, Y0201800847]
  3. Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
  4. UHK project [VT2019-2021]

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The study optimized TMS-loaded nanostructured lipid carriers (TMS-NLCs) using an orthogonal experimental design, resulting in excellent stability and sustained release properties. In cell models, TMS-NLCs showed enhanced cellular uptake and inhibition of drug efflux transporters, indicating their potential to overcome oral administration obstacles for TMS.
Tilmicosin (TMS) is widely used to treat bacterial infections in veterinary medicine, but the clinical effect is limited by its poor solubility, bitterness, gastric instability, and intestinal efflux transport. Nanostructured lipid carriers (NLCs) are nowadays considered to be a promising vector of therapeutic drugs for oral administration. In this study, an orthogonal experimental design was applied for optimizing TMS-loaded NLCs (TMS-NLCs). The ratios of emulsifier to mixed lipids, stearic acid to oleic acid, drugs to mixed lipids, and cold water to hot emulsion were selected as the independent variables, while the hydrodynamic diameter (HD), drug loading (DL), and entrapment efficiency (EE) were the chosen responses. The optimized TMS-NLCs had a small HD, high DL, and EE of 276.85 +/- 2.62 nm, 9.14 +/- 0.04%, and 92.92 +/- 0.42%, respectively. In addition, a low polydispersity index (0.231 +/- 0.001) and high negative zeta potential (-31.10 +/- 0.00 mV) indicated the excellent stability, which was further demonstrated by uniformly dispersed spherical nanoparticles under transmission electron microscopy. TMS-NLCs exhibited a slow and sustained release behavior in both simulated gastric juice and intestinal fluid. Furthermore, MDCK-chAbcg2/Abcb1 cell monolayers were successfully established to evaluate their absorption efficiency and potential mechanism. The results of biodirectional transport showed that TMS-NLCs could enhance the cellular uptake and inhibit the efflux function of drug transporters against TMS in MDCK-chAbcg2/Abcb1 cells. Moreover, the data revealed that TMS-NLCs could enter the cells mainly via the caveolae/lipid raft-mediated endocytosis and partially via macropinocytosis. Furthermore, TMS-NLCs showed the same antibacterial activity as free TMS. Taken together, the optimized NLCs were the promising oral delivery carrier for overcoming oral administration obstacle of TMS.

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