Combination of co-amorphization with SNEDDS outperforms Ofev® in the oral absorption of nintedanib

[Display omitted] Nintedanib (NTD), approved for the treatment of idiopathic pulmonary fibrosis and advanced non-small cell lung cancer, is one of brick dusts with high melting point. Although NTD has been marketed as Ofev®, a soft capsule of NTD ethanesulfonate (NTD-ESA) suspended in oil components...

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Bibliographic Details
Published in:International journal of pharmaceutics 2024-05, Vol.657, p.124197-124197, Article 124197
Main Authors: Inoue, Tomoya, Maehara, Seito, Maruyama, Masato, Higaki, Kazutaka
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biological Availability
Brick dust
Co-amorphous
Indoles - administration & dosage
Indoles - chemistry
Indoles - pharmacokinetics
Intestinal Absorption
Male
Nintedanib
Ofev
Oral absorption
Rats
Rats, Sprague-Dawley
SNEDDS
Solubility
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Summary:[Display omitted] Nintedanib (NTD), approved for the treatment of idiopathic pulmonary fibrosis and advanced non-small cell lung cancer, is one of brick dusts with high melting point. Although NTD has been marketed as Ofev®, a soft capsule of NTD ethanesulfonate (NTD-ESA) suspended in oil components, the oral bioavailability is quite low and highly variable. To improve the oral absorption behavior of NTD, we prepared SNEDDS formulation containing NTD-(+)-10-camphorsulfonic acid (CSA) complex with 2% HPMCP-50. CSA disrupted the high crystallinity of NTD-ESA and the formed complex, NTD-CSA, was found to be amorphous by DSC and XRPD. NTD-CSA provided solubilities in various vehicles much higher than NTD-ESA. Under the gastric luminal condition, NTD-CSA SNEDDS with or without 2% HPMCP-50 and NTD-CSA powder indicated very good dissolution of NTD from early time periods, while NTD was gradually dissolved until around 60 min from NTD-ESA and Ofev®. Under the small intestinal luminal condition, in contrast, both NTD-CSA SNEDDS formulations almost completely dissolved NTD throughout the experiments, while Ofev®, NTD-CSA, and NTD-ESA exhibited a very poor dissolution of NTD. In the in vivo absorption study, NTD-CSA SNEDDS with 2% HPMCP-50 significantly improved NTD absorption and reduced the inter-individual variation in oral absorption behavior compared with Ofev®.
ISSN:0378-5173
1873-3476
DOI:10.1016/j.ijpharm.2024.124197