https://orcid.org/0000-0002-1895-8562
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ABSTRACT
Introduction
Nintedanib (N.T.B) is an orally administered tyrosine kinase inhibitor that has been approved recently by U.S.F.D.A for idiopathic pulmonary fibrosis (I.P.F) and systemic sclerosis-associated interstitial lung disease (S.Sc-I.L.D). N.T.B is also prescribed in COVID-19 patients associated with I.P.F. However, it has an extremely low bioavailability of around 4.7%, and hence, researchers are attempting to address this drawback by different approaches.
Areas covered
This review article focuses on enlisting all the formulation attempts explored by researchers to increase the bioavailability of N.T.B while also providing meaningful insight into the unexplored areas in formulation development, such as targeting of the lymphatic system and transdermal delivery. All the patents on the formulation development of N.T.B have also been summarized.
Expert opinion
N.T.B has the potential to act on multiple diseases that are still being discovered, but its extremely low bioavailability is a challenge that is to be dealt with for obtaining the full benefit. Few studies have been performed aiming at improving the bioavailability, but there are unexplored areas that can be used, a few of which are explained in this article. However, the ability to reproduce laboratory results when scaling up to the industry level is the only factor to be taken into consideration.
Article highlights
Nintedanib is a novel tyrosine kinase inhibitor that is used in the treatment of idiopathic pulmonary fibrosis and systemic sclerosis-associated interstitial lung disease, approved by USFDA in 2014 and 2019, respectively.
It has an extremely low bioavailability of around 4.7% when administered orally due to first-pass metabolism and P-gp inhibition. This is being addressed by formulating various drug carriers.
Orally administered self-emulsifying drug delivery systems, solid dispersion, cyclodextrin complexes, and nanostructured lipid carriers are being currently explored by researchers, while the nasal route of administration via nebulized drug solutions is also being explored.
We have suggested few alternative drug delivery options such as transdermal and lymphatic systems targeted to obtain better bioavailability.
This box summarizes key points contained in the article.
Abbreviations
| Nintedanib (N.T.B) | = | Phosphatidylinositol phosphate (P.I.P) |
| Idiopathic pulmonary fibrosis (I.P.F) | = | Mitogen-activated protein kinase (M.E.K) |
| Systemic sclerosis-associated interstitial lung disease (S.Sc-I.L.D) | = | Phospholipase C-γ (PLC- γ) |
| Vascular endothelial growth factor (V.E.G.F) | = | Growth factor receptor-bound protein-2 (GRB2) |
| Fibroblasts growth factor receptor (F.G.F.R) | = | Non-small cell lung cancer (N.S.C.L.C) |
| Platelet-derived growth factor receptor (P.D.G.F) | = | Death-associated protein kinase (DAPk) |
| Non-small cell lung cancer (N.S.C.L.C) | = | O(6)-methylguanine-DNA methyltransferase (M.G.M.T) |
| Interstitial lung diseases (I.L.Ds) | = | Tissue inhibitor metalloprotease 3 (TIMP3) |
| Biopharmaceutical Classification System (B.C.S) | = | Angiotensin converting enzyme II (ACE II) |
| Platelet derived growth factor receptor (P.D.G.F.R) | = | Self-microemulsion drug delivery systems (S.M.E.D.D.S) |
| Toll-like receptors (T.L.R) | = | Poly dispersibility index (P.D.I) |
| T-helper 2 (Th2) cells | = | Area Under the Curve (A.U.C) |
| Connective tissue growth factor (C.T.G.F) | = | Solid dispersions (S.D) |
| Vascular endothelial growth factor receptor (V.E.G.F.R) | = | Cyclodextrin complex (C.D) |
| Epithelial growth factor receptor (E.G.F.R) | = | Nano structured lipid carriers (N.L.Cs) |
| Anaplastic lymphoma kinase (A.L.K) | = | Hydrophilic lipophilic balance (H.L.B) |
| Reactive oxidation species (R.O.S) | = | P-glyco protein (P-gp) |
| Extracellular signal-regulating kinase (E.R.K) | = | Disposable Cartridge Jet injector (D.C.J.I) |
| Son of sevenless (S.O.S) | = | Multi-use nozzle jet injector (M.U.N.J.Is) |
| Focal adhesion kinase (F.A.K) | = | Gastrointestinal tract (G.I.T) |
| Protein kinase C (P.K.C) | = | Phosphatidylinositol phosphate (P.I.P) |
Acknowledgement
Authors are thankful to Manipal Academy of Higher Education (MAHE), Manipal, India, for providing Dr TMA Pai Fellowship to Varalakshmi Velagacherla and Akhil Suresh. Also thankful to Indian Council for Medical Research for providing Senior Research Fellowship (45/33/2019/PHA/BMS) to Chetan H Mehta.
Disclosure statement
The author(s) have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.