A high bioavailability and sustained-release nano-delivery system for nintedanib based on electrospray technology
Authors: Dongli Li
Hongfei Liu
Yi Du
Yan Shen
Ying Xu
Kunyu Du
Jumei Xi
Tao Jiang
Thomas J Webster
Journal: International Journal of Nanomedicine (2018)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: electrospray technology; nintedanib; pharmacokinetics; solid dispersion; sustained release capsule.

Abstract:  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). 

Retracted: No

PubPeer comments:
 It is unclear to me if these images in Fig 3 4 be the same (see red and green boxes). Other readers on social media are more certain they should not, as they represent different treatments, but Iu2019m getting different answers from different people. Apologies if I have misunderstood. *** ![file] , 
 Thank you for pointing this out and we are currently investigating this - Tom Webster , 
 Common authors on this paper: https: pubpeer.com publications 2F557CA7AF9B31C3976083FCE5C839 , 
 #2 Is there an update on this investigation? Emails to this corresponding author (who is also the journalu2019s Editor in Chief) are currently generating an auto reply: u201cThank you for your message. I am currently on a leave of absence. Should you require immediate assistance please contact....u201d , 
 June 2021 Erratum found here: https: www.dovepress.com corrigendum-a-high-bioavailability-and-sustained-release-nano-delivery-peer-reviewed-fulltext-article-IJN  The authors wish to provide an explanation for the duplicated images observed in Figure 3 and Figure 4B, and revise Figures 2 and 3 accordingly (by providing the prescription parameters for each sample). The dissolution curves shown in Figure 2 and SEM images shown in Figure 3 provide a one-to-one correspondence. For example, the blue curve (0.3 mL h) in Figure 2A corresponds to the SEM image in Figure 3Ai. The authors can confirm that the dissolution curves shown in Figure 2, for samples sharing the same parameters are the same. For example, the red curve (15 cm) in Figure 2B and the red curve (21 kV) of Figure 2C are the same. These dissolution curves correlate to the SEM images shown in Figure 3Bii and 3Cii, respectively. In order to be more intuitive, the authors have marked the corresponding SEM image shown in Figure 3 to each dissolution curve in Figure 2, as shown below. In order to provide more clarity to the SEM images shown the authors have also provided the prescription parameters corresponding to each SEM image on the right side of Figure 3. Thus, Figure 3Ai, Figure 3Biii, Figure 3Diii and Figure 4B are the same sample and share the same parameters and SEM image. Figure 3Bii and Figure 3Cii are also the same sample and share the same parameters and SEM image, as shown below. The authors wish to apologize for any confusion caused. New Figure 3: ![file] ,