Idiopathic pulmonary fibrosis (IPF) is a type of idiopathic interstitial pneumonia and a chronic pulmonary disease characterized by progressively abnormal reprogramming following damage to the lung (Ballester et al., 2019, Sgalla et al., 2018). Although IPF has variation in rate of progression, after the onset of symptoms, fatal respiratory failure and death typically occurs within 1–3 years (Ley et al., 2011). Currently, extensive research efforts are focused on elucidating the pathogenesis of IPF and developing new therapeutic strategies to improve patient quality of life and survival rates.

Nintedanib (NIN, Fig. 1A) is an oral tyrosine kinase inhibitor with a structure that enables it to effectively bind to the ATP pocket, competitively inhibiting vascular endothelial growth factor, fibroblast growth factor receptors, and platelet-derived growth factor receptors (Wongkarnjana et al., 2019). NIN can effectively inhibit the progression of pulmonary fibrosis and reduce the loss of lung capacity in patients. In 2019, it was approved by the Food and Drug Administration (FDA) for the treatment of IPF and interstitial lung disease associated with systemic sclerosis (Otsubo et al., 2022). However, the bioavailability of NIN is only 4.7 %, likely due to its low solubility and slow dissolution in the intestinal tract, a consequence of the weakly basic nature of the molecule (Qin et al., 2022). Classified as a Biopharmaceutical Classification System (BCS) class II drug, NIN exhibits low solubility and high permeability characteristics. The NIN ethanesulfonate salt, used as an active pharmaceutical ingredient in commercial formulation, enhances the dissolution of NIN in acidic fluids. However, it exhibits instability and low solubility in the intestinal tract (Vaidya et al., 2019). Many researchers have attempted to improve the solubility of NIN in the intestine using cyclodextrin inclusion, nanocrystals, self-microemulsifying drug delivery systems (SMEDDS), and amorphous solid dispersions (ASD). Nevertheless, the dissolution-enhancing effect of cyclodextrin inclusion is highly drug-specific because binding constants vary widely among compounds, and the improvement can differ drastically from one drug to another (Jambhekar and Breen, 2016, Tsunoda et al., 2023). While both nanocrystals and SMEDDS exhibit poor physical stability (Liu et al., 2019, Yun et al., 2024), these formulation technologies still face numerous challenges in achieving commercial viability.

Hot-melt extrusion (HME) is a solvent-free and environmentally friendly technology that allows continuous, large-scale production of ASDs; because no organic solvents are used, HME generates substantially lower carbon emissions and far less chemical waste than solvent-based processes (Patil et al., 2024). Compared to spray drying, hot melt extrusion offers several advantages, including no need for solvents, lower costs, environmental friendliness, and ease of scale-up production. Although spray drying is a well-established method, its disadvantages include high equipment and production costs, high solvent recovery and treatment demands, poor sustainability of the process environment, and potential issues such as uneven distribution of components in the product and poor subsequent formulation processing performance (Qin et al., 2022). The solubility of drugs with a high tendency to crystallize can be significantly enhanced by dispersing them, whether in molecular or crystalline form, within a suitable polymer material that exhibits solubilizing effects and crystallization inhibition properties. This approach breaks the lattice energy of the crystalline drug and maintains the relatively high free energy state of the amorphous drug, ensuring a sustained supersaturated concentration in the dissolution medium (Chiang et al., 2023, Lalge et al., 2023). The sustained supersaturated concentration can reduce drug precipitation in the gastrointestinal tract, thereby enhancing the drug’s oral bioavailability (Ghezzi et al., 2021, Joshi and Sangamwar, 2022, Tripathi et al., 2023, Yarlagadda et al., 2023).

Soluplus® (Fig. 1B), the trade name for polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol, is a graft copolymer with an average molecular weight of 90,000–140,000 g/mol (Pignatello et al., 2022). This amphiphilic polymer exhibits excellent wettability and solubilizing capabilities, along with strong crystallization inhibition properties (Tousif et al., 2019). These characteristics make it an ideal polymer carrier for enhancing drug solubility and improving bioavailability by HME technology (Wang et al., 2022b). Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS) is another polymer carrier commonly used in HME, which synthesized through the esterification of hydroxypropyl methylcellulose (HPMC) with acetic anhydride and succinic anhydride (Fig. 1C). The average molecular weight of HPMCAS is 18,000, with acetyl content of 9 % and succinoyl content of 11 %. HPMCAS exhibits adjustable hydrophilicity, low hygroscopicity, strong intermolecular interactions between the drug and the polymer, and high supersaturation concentrations during drug dissolution in alkaline conditions (Friesen et al., 2008, Monschke and Wagner, 2020). The rapidly dissolves in the intestine will facilitate drug absorption. In this study, Soluplus® was chosen as one polymer matrix to leverage its pH-independent drug release characteristics. By comparing Soluplus® (pH-independent) with HPMCAS (pH-dependent enteric polymer), we aimed to evaluate how different polymer types influence the dissolution and absorption of NIN-ASDs.

In this study, we introduce several innovative aspects that distinguish our work from previous research. First, while previous studies have focused mainly on the use of enteric polymers such as HPMCAS, we introduce Soluplus®, a novel pH-independent amphiphilic polymer, and compare it with HPMCAS (Qin et al., 2022). This comparison allows us to evaluate the unique advantages of Soluplus® in enhancing Nintedanib dissolution and absorption, an aspect that has not been extensively explored.Furthermore, we expand the scope of our research by incorporating both in vitro dissolution and pharmacokinetic studies in rats, while also investigating the antifibrotic effects of the ASD formulation in a pulmonary fibrosis rat model, which involves evaluating the drug’s therapeutic efficacy. This comprehensive approach, combining pharmacokinetics and pharmacodynamics, provides a more thorough understanding of the potential therapeutic benefits of Nintedanib-ASDs, distinguishing our work from studies that primarily focus on dissolution and pharmacokinetics.