Optimization of Tilmicosin-Loaded Nanostructured Lipid Carriers Using Orthogonal Design for Overcoming Oral Administration Obstacle
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...
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MDPI AG
2021-02-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/3/303 |
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| author | Jia Wen Xiuge Gao Qian Zhang Benazir Sahito Hongbin Si Gonghe Li Qi Ding Wenda Wu Eugenie Nepovimova Shanxiang Jiang Liping Wang Kamil Kuca Dawei Guo |
| author_facet | Jia Wen Xiuge Gao Qian Zhang Benazir Sahito Hongbin Si Gonghe Li Qi Ding Wenda Wu Eugenie Nepovimova Shanxiang Jiang Liping Wang Kamil Kuca Dawei Guo |
| author_sort | Jia Wen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T00:31:26Z |
| format | Article |
| id | doaj.art-6ae593eb59ae44638b57b6e932799f29 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T00:31:26Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-6ae593eb59ae44638b57b6e932799f292023-12-11T18:28:11ZengMDPI AGPharmaceutics1999-49232021-02-0113330310.3390/pharmaceutics13030303Optimization of Tilmicosin-Loaded Nanostructured Lipid Carriers Using Orthogonal Design for Overcoming Oral Administration ObstacleJia Wen0Xiuge Gao1Qian Zhang2Benazir Sahito3Hongbin Si4Gonghe Li5Qi Ding6Wenda Wu7Eugenie Nepovimova8Shanxiang Jiang9Liping Wang10Kamil Kuca11Dawei Guo12Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, ChinaCenter for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, ChinaCenter for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, ChinaCenter for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, ChinaCollege of Animal Science and Technology, Guangxi University, 100 Daxuedong Road, Nanning 530004, ChinaCollege of Animal Science and Technology, Guangxi University, 100 Daxuedong Road, Nanning 530004, ChinaSchool of Pharmacy, Bengbu Medical College, 2600 Donghai Avenue, Bengbu 233030, ChinaCenter for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, ChinaDepartment of Chemistry, Faculty of Science, University of Hradec Kralove, 50003 Hradec Kralove, Czech RepublicCenter for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, ChinaCenter for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, ChinaDepartment of Chemistry, Faculty of Science, University of Hradec Kralove, 50003 Hradec Kralove, Czech RepublicCenter for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, ChinaTilmicosin (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.https://www.mdpi.com/1999-4923/13/3/303tilmicosinnanostructured lipid carriersorthogonal designintestinal absorptionMDCK-chAbcg2/Abcb1 cell monolayer |
| spellingShingle | Jia Wen Xiuge Gao Qian Zhang Benazir Sahito Hongbin Si Gonghe Li Qi Ding Wenda Wu Eugenie Nepovimova Shanxiang Jiang Liping Wang Kamil Kuca Dawei Guo Optimization of Tilmicosin-Loaded Nanostructured Lipid Carriers Using Orthogonal Design for Overcoming Oral Administration Obstacle Pharmaceutics tilmicosin nanostructured lipid carriers orthogonal design intestinal absorption MDCK-chAbcg2/Abcb1 cell monolayer |
| title | Optimization of Tilmicosin-Loaded Nanostructured Lipid Carriers Using Orthogonal Design for Overcoming Oral Administration Obstacle |
| title_full | Optimization of Tilmicosin-Loaded Nanostructured Lipid Carriers Using Orthogonal Design for Overcoming Oral Administration Obstacle |
| title_fullStr | Optimization of Tilmicosin-Loaded Nanostructured Lipid Carriers Using Orthogonal Design for Overcoming Oral Administration Obstacle |
| title_full_unstemmed | Optimization of Tilmicosin-Loaded Nanostructured Lipid Carriers Using Orthogonal Design for Overcoming Oral Administration Obstacle |
| title_short | Optimization of Tilmicosin-Loaded Nanostructured Lipid Carriers Using Orthogonal Design for Overcoming Oral Administration Obstacle |
| title_sort | optimization of tilmicosin loaded nanostructured lipid carriers using orthogonal design for overcoming oral administration obstacle |
| topic | tilmicosin nanostructured lipid carriers orthogonal design intestinal absorption MDCK-chAbcg2/Abcb1 cell monolayer |
| url | https://www.mdpi.com/1999-4923/13/3/303 |
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