Nint is a potent small molecule that inhibits tyrosine kinases receptors (RTKs), including receptors of fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) that exerts anti-inflammatory and anti-fibrotic effects [1]. The U.S. Food and Drug Administration (FDA) authorized Nint for the therapy of idiopathic pulmonary fibrosis (IPF) in 2014. Nint was recently permitted to treat chronic fibrosing interstitial lung disorders (ILDs) with a progressive phenotype and interstitial lung disease linked with scleroderma (SSc-ILD) [2]. Inhibition of multiple receptor tyrosine kinases has also been associated with blocking angiogenesis, which makes Nint an useful anticancer agent [3]. Due to its activity against multiple RTKs, Nint has also been licensed by the European Union as second-line chemotherapy in combination with docetaxel for non-small-cell lung cancer (NSCLC) in patients with advanced adenocarcinoma [4]. Several recent studies have tested Nint as a viable candidate for treating a rare pleural cavity cancer, namely malignant pleural mesothelioma. While preclinical and Phase II results were encouraging [5], Phase III study failed to meet the clinical endpoints [6].

Currently, Nint is available as oral capsules (Ofev® and Vargatef®), usually taken at 150 mg or 200 mg twice daily for the treatment of IPF [7,8]. However, due to safety concerns over its known adverse effects including diarrhea, nausea, and abnormal liver functioning, further oral dose escalation for potentially improved efficacy is not an option [9,10]. Other clinical trials in patients with systemic sclerosis-associated interstitial lung disease found the adverse-event profile of Nint was similar to those observed in patients with IPF; gastrointestinal adverse effects, including diarrhea were more common with Nint than with placebo [11,12]. Pharmacokinetically, Nint oral capsule is reported to have very low bioavailability (<5 %) contributed by P-glycoprotein (P-gp)-mediated efflux, low aqueous solubility, and substantial first-pass metabolism [1,13]. Due to its unwanted systemic side effects and low bioavailability, there is an urgent requirement to explore targeted treatments to enhance the local accumulation of Nint in the lungs and improve its therapeutic efficacy while circumventing the orally delivered adverse effects.

Recently, the inhalation route of administration has demonstrated a unique direction in treating respiratory diseases [14]. This non-invasive technique delivers the medication directly into the lungs' airways and respiratory area via oral or nasal administration. That leads to high patient compliance, enhanced lung bioavailability, and rapid onset of drug action while circumventing the limitations of conventional routes of administration like unwanted systemic effects and hepatic first-pass metabolism [15]. Although pulmonary delivery ensures local delivery into the airways, limited therapeutic effects of these agents are still often observed as a result of poor lung deposition and mucociliary or macrophage clearance [16]. To address these issues, numerous nanocarriers have been developed to further enhance the efficiency of pulmonary delivery. In particular, PLGA-based nanoparticles have been explored extensively for inhalation therapy [[17], [18], [19], [20]]. A study by Bai et al. [17] designed an inhalable and mucus-penetrating siRNA-loaded nanosystem against interleukin-11 (IL11), a profibrotic cytokine that drives the underlying pathogenesis of IPF. The nanoparticles were formulated using cationic lipid-like components G0-C14 and PLGA-PEG di-block copolymer to enable efficient transmucosal delivery of siIL11 [17]. Moreover, a report verified nanocarriers <200 nm can be small enough to avoid mucociliary clearance by rapid penetration through surfactant and mucosal lining layers, which helps to prevent recognition from macrophage phagocytosis in the alveoli [16]. Another study suggested that inhalable particles with 2–5 μm aerodynamic diameter should be desired for deep-lung delivery [21].

Although nanotechnology has shown to be a powerful and customizable tool that can overcome biological and chemical barriers in the human body, designing nanoparticles is a difficult achievement regarding reproducibility of size and mono-dispersity [22]. Similarly, more knowledge of scale-up technologies is needed to translate promising nanoparticle technologies into commercial production [23,24]. The nanoparticle production method relies on numerous aspects, such as purpose of the application, materials utilized in the formulation, properties of the bioactive ingredients, etc. Nanoparticle development requires a proper selection of materials and appropriate strategies, as the in-vitro and in-vivo interpretation of the strategies depends on them [22]. High-pressure homogenization (HPH), a nanoparticle development approach, has recently drawn much interest because of its scalability and effectiveness in reproducing results. HPH enables a seamless transition from a small laboratory scale to a pilot scale manufacturing of emulsion, suspension, and nanoparticle [25]. During the HPH process, the formulation is pushed under pressure through a very narrow aperture or channel. The formulation is then invaded by a hard-impact ring or a second high-velocity stream of one phase flowing from the opposite direction [26]. Therefore, The formulation is exposed to high pressure and mechanical forces, including turbulence, cavitation, and impact shear [27], resulting in reproducible nanoparticles with tiny particle sizes and high drug loading [28]. This study utilized HPH to achieve Nint-NPs of nanoscale particle size (<200 nm) and higher stability.

Nint is one of the promising candidates for treatment of multiple lung ailments, there, unfortunately, isn't much literature regarding its encapsulation in sustained delivery carriers. A recent study by Park et al. discussed development of systemically administered Nint-encapsulated PLGA microparticles for IPF treatment [29]. Another study by Shukla et al., investigated inhaled niosomes for Nint delivery [30]. The present study was intended to design scalable and inhalable Nint-loaded PLGA nanoparticles using HPH technique to achieve small particle size (<200 nm) and good stability. This is the first study investigating Nint-loaded inhaled PLGA nanoparticles for localized lung accumulation of therapeutics by utilizing a scalable fabrication approach.