Abstract
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.
Highlights
Nanostructured lipid carriers (NLCs), the second-generation lipid-based nano drug delivery system, are derived from an admixture of solid lipid and liquid lipid and regarded as an effective oral carrier in virtue of their possibility to increase the solubility and oral bioavailability of poorly water-soluble drugs [1,2,3]
Carriers with particle size less than 300 nm are more suitable for the intestinal transport in order to reduce capture by the reticuloendothelial system [29]
According to the R values, in which a higher R value represents more significant effect [20], the effect of four factors decreased in the following order: C > B > A > D (Table 2), indicating C, i.e., the ratio of drug to mixed lipids, was the most important effect among these four factors set in this study
Summary
Nanostructured lipid carriers (NLCs), the second-generation lipid-based nano drug delivery system, are derived from an admixture of solid lipid and liquid lipid and regarded as an effective oral carrier in virtue of their possibility to increase the solubility and oral bioavailability of poorly water-soluble drugs [1,2,3]. It is easy to cause an acute cardiotoxic effect when administered by injection owing to its transient high drug concentration [13]; oral administration would be a more suitable delivery method for TMS, but this administration route suffers from problems such as poor water solubility, sensitivity to gastric acid, bitterness, and low bioavailability [14]. It is reported SLNs [13], silica nanoparticles [15], alginate–
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