Hongfei Liu1, Jiaao Mei1, Ying Xu1, Lei Tang1, Daquan Chen2, Yating Zhu1, Shuguang Huang1, Thomas J Webster3, Hui Ding4. 1. College of Pharmacy, Jiangsu University, Zhenjiang 212013, People's Republic of China. 2. School of Pharmacy, Yantai University, Yantai 264005, People's Republic of China. 3. Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA. 4. Department of Respiratory and Critical Care Medicine, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu 214200, People's Republic of China.
Abstract
OBJECTIVE: Nintedanib (NDNB) is a triple receptor tyrosine kinase inhibitor with poor solubility in neutral conditions and low bioavailability. A self-microemulsifying drug delivery system (SMEDDS) of NDNB was developed to improve drug solubility in physical conditions and absorption in vivo. METHODS: The NDNB-SMEDDS formulation was optimized via pseudo-ternary phase diagrams. The physicochemical properties of NDNB-SMEDDS, viz., morphological observation, droplet size, stability, compatibility and in vitro release were investigated. The permeability of NDNB-SMEDDS was detected using both a Caco-2 cell monolayer in vitro and an intestinal perfusion study in vivo. Furthermore, the pharmacokinetic characteristics of NDNB-SMEDDS were evaluated. RESULTS: The optimal formulation was composed of MCT as an oil phase, RH 40 as a surfactant and ethylene glycol as a co-surfactant. The average droplet size of the microemulsion was about 23 nm with good stability within 30 days. The formulation did not exhibit any obvious cytotoxic effect on Caco-2 cells. Permeability of nintedanib in a Caco-2 cell monolayer was enhanced by 2.8-fold upon incorporation in SMEDDS compared with the drug solution. The intestinal perfusion study demonstrated that the P app of NDNB-SMEDDS increased by 3.0-fold in the entire intestine and 3.2-fold in the colon in comparison with the drug solution. The pharmacokinetics study showed that the AUC of the NDNB-SMEDDS increased significantly. CONCLUSION: This study showed that the self-microemulsion formulations could improve the absorption of nintedanib, and can thus serve as a promising carrier for the oral delivery of nintedanib.
OBJECTIVE: Nintedanib (NDNB) is a triple receptor tyrosine kinase inhibitor with poor solubility in neutral conditions and low bioavailability. A self-microemulsifying drug delivery system (SMEDDS) of NDNB was developed to improve drug solubility in physical conditions and absorption in vivo. METHODS: The NDNB-SMEDDS formulation was optimized via pseudo-ternary phase diagrams. The physicochemical properties of NDNB-SMEDDS, viz., morphological observation, droplet size, stability, compatibility and in vitro release were investigated. The permeability of NDNB-SMEDDS was detected using both a Caco-2 cell monolayer in vitro and an intestinal perfusion study in vivo. Furthermore, the pharmacokinetic characteristics of NDNB-SMEDDS were evaluated. RESULTS: The optimal formulation was composed of MCT as an oil phase, RH 40 as a surfactant and ethylene glycol as a co-surfactant. The average droplet size of the microemulsion was about 23 nm with good stability within 30 days. The formulation did not exhibit any obvious cytotoxic effect on Caco-2 cells. Permeability of nintedanib in a Caco-2 cell monolayer was enhanced by 2.8-fold upon incorporation in SMEDDS compared with the drug solution. The intestinal perfusion study demonstrated that the P app of NDNB-SMEDDS increased by 3.0-fold in the entire intestine and 3.2-fold in the colon in comparison with the drug solution. The pharmacokinetics study showed that the AUC of the NDNB-SMEDDS increased significantly. CONCLUSION: This study showed that the self-microemulsion formulations could improve the absorption of nintedanib, and can thus serve as a promising carrier for the oral delivery of nintedanib.
Authors: Frank Hilberg; Ulrike Tontsch-Grunt; Anke Baum; Anh T Le; Robert C Doebele; Simone Lieb; Davide Gianni; Tilman Voss; Pilar Garin-Chesa; Christian Haslinger; Norbert Kraut Journal: J Pharmacol Exp Ther Date: 2017-12-20 Impact factor: 4.030
Authors: Guru R Valicherla; Kandarp M Dave; Anees A Syed; Mohammed Riyazuddin; Anand P Gupta; Akhilesh Singh; Kalyan Mitra; Dipak Datta; Jiaur R Gayen Journal: Sci Rep Date: 2016-05-31 Impact factor: 4.379