International Journal of Nanomedicine (Dec 2018)
A high bioavailability and sustained-release nano-delivery system for nintedanib based on electrospray technology
Abstract
Hongfei Liu,1,2 Kunyu Du,1 Dongli Li,2 Yi Du,2 Jumei Xi,3 Ying Xu,1 Yan Shen,4 Tao Jiang,5 Thomas J Webster6 1School of Pharmacy, Jiangsu University, Zhenjiang 212013, China; 2School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China; 3Health of Nepstar Drugstore Chain Company Limited, Wuxi 214000, China; 4State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China; 5The Pharmacy Department, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China; 6Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA Background: Nintedanib is a new tyrosine kinase inhibitor and growth factor antagonist. It can be used to treat idiopathic pulmonary fibrosis diseases. Nintedanib has poor solubility in the intestinal tract environment, which leads to low bioavailability of just 4.7%. Methods: In this study, a nintedanib solid dispersion was prepared by electrospray technology with an optimized formula (nintedanib:PVPK30:Soybean lecithin=1:5:0.25) and electrospray parameters (21 kV voltage, 18 cm receiving distance, 0.3 mL/h solution flow rate, 0.5 mm pinhole inner diameter). Results: The accumulative release rate of the optimized solid dispersion was more than 60% in 30 minutes and 100% in 60 minutes. The size distribution was uniform and the surface observed with scanning electron microscopy (SEM) was smooth. The DSC and X-ray diffraction results showed that nintedanib existed in the solid dispersion through an amorphous form. Nintedanib solid dispersion sustained-release capsules were prepared to prolong drug release, improve patient compliance and reduce side effects. The accumulative release rate from the sustained release capsules was 35.17%, 54.78%, 70.58%, and 93.93% after 2 h, 6 h, 8 h, and 12 h, respectively, having obvious sustained release effects in vitro. The release behavior of solid dispersion sustained-release capsules in vitro was in accordance with the Ritger-Peppas model. The in vivo studies of nintedanib soft capsules, solid dispersion and nintedanib sustained release capsules in SD rats were investigated; the results showed that the Tmax of the soft capsule, solid dispersion and sustained release capsules were 3 h, 2 h, and 6 h, respectively. The Cmax were 2.945 mg/mL, 5.32 mg/mL, and 3.75 mg/mL, respectively, while the AUC0–24 h was 15.124 mg·h/mL, 23.438 mg·h/mL, and 24.584 mg·h/mL, respectively. The relevant bioavailability of the sustained-release capsules was 162.55% compared to the nintedanib soft capsule and 104.89% compared to the nintedanib solid dispersion.Conclusion: The results suggested superior bioavailability and a sustained-release effect from nintedanib sustained-release capsules, as compared to the reference (commercial nintedanib soft capsule). Keywords: nintedanib, electrospray technology, solid dispersion, sustained release capsule, pharmacokinetics
