Drug Design, Development and Therapy (May 2022)
Reduced the Food Effect and Enhanced the Oral Bioavailability of Ivacaftor by Self-Nanoemulsifying Drug Delivery System (SNEDDS) Using a New Oil Phase
Abstract
Yanfei Miao,1 Shihua Zhao,1 Jian Zuo,1 Jiqin Sun,1 Jingnan Wang2 1College of Chemistry and Chemical Engineering, Taishan University, Tai’an, People’s Republic of China; 2School of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, People’s Republic of ChinaCorrespondence: Yanfei Miao, College of Chemistry and Chemical Engineering, Taishan University, Tai’an 271000, People’s Republic of China, Tel/Fax +86-0538-6713958, Email [email protected]: The purpose of this work was to develop an ivacaftor self-nanoemulsion drug delivery system (IVA-SNEDDS) using the newly developed double headed miscellaneous lipid (DHML) as oil phase to reduce the food effect and inter-individual absorption variability of IVA.Methods: The lipids with the greatest solubility to IVA were selected as the oil phase of IVA-SNEDDS by saturation solubility method. Then, among different surfactants and co-surfactants, those with good emulsifying ability for the selected oil phase were selected, and the proportion of surfactant and co-surfactant was further selected by pseudo-ternary phase diagram. The prepared IVA-SNEDDS were screened and evaluated in vitro and in beagle dogs.Results: The optimized IVA-SNEDDS formulation consisting of DHML, Tween 80, and Transcutol HP with the weight ratio of 2:2:1 was physically stable and it was easy to disperse in water, pH 1.2 hydrochloric acid and pH 6.8 phosphate buffer solution, and generated a fine homogeneous nanoemulsion, with mean globule size less than 75 nm regardless of dilution ratio. In vitro drug release studies showed that the drug in IVA-SNEDDS could be completely released in a short time, while the drug release in IVA-suspension was less than 1% at 60 min. In vivo, using IVA-suspension (Fed) as a reference, the relative oral bioavailability of IVA-suspension (Fasted), IVA-SNEDDS (Fasted), and IVA-SNEDDS (Fed) were 23.35%, 153.63%, and 149.89%, respectively. This showed that IVA-SNEDDS could eliminate the positive food effect, improve the oral bioavailability, and reduce the IVA absorption difference between individuals.Conclusion: As the oil phase of SNEDDS, DHML can significantly improve the drug solubility and drug loading of IVA-SNEDDS. Moreover, DHML was easily emulsified and can effectively form a nanoemulsion in vivo and in vitro. The prepared IVA-SNEDDS can reduce the inter-individual absorption variability of IVA, eliminate its food effect and improve its oral bioavailability.Keywords: ivacaftor, food effect, self-nanoemulsion drug delivery system (SNEDDS), oral bioavailability, oil phase
