Development of nintedanib nanosuspension for inhaled treatment of experimental silicosis

Abstract

Silicosis is an irreversible and progressive fibrotic lung disease caused by massive inhalation of crystalline silica dust at workplaces, affecting millions of industrial workers worldwide. A tyrosine kinase inhibitor, nintedanib (NTB), has emerged as a potential silicosis treatment due to its inhibitory effects on key signaling pathways that promote silica‐induced pulmonary fibrosis. However, chronic and frequent use of the oral NTB formulation clinically approved for treating other fibrotic lung diseases often results in significant side effects. To this end, we engineered a nanocrystal‐based suspension formulation of NTB (NTB‐NS) possessing specific physicochemical properties to enhance drug retention in the lung for localized treatment of silicosis via inhalation. Our NTB‐NS formulation was prepared using a wet‐milling procedure in presence of Pluronic F127 to endow the formulation with nonadhesive surface coatings to minimize interactions with therapy‐inactivating delivery barriers in the lung. We found that NTB‐NS, following intratracheal administration, provided robust anti‐fibrotic effects and mechanical lung function recovery in a mouse model of silicosis, whereas a 100‐fold greater oral NTB dose given with a triple dosing frequency failed to do so. Importantly, several key pathological phenotypes were fully normalized by NTB‐NS without displaying notable local or systemic adverse effects. Overall, NTB‐NS may open a new avenue for localized treatment of silicosis and potentially other fibrotic lung diseases.

Nanosuspension-Based Drug Delivery Systems for Topical Applications

“…17,73 In contrast, the pulmonary route has gained increasing attention as a potential method for systemic drug delivery due to the extensive alveolar surface area, the delicate epithelial barrier, and the significant vascularization conducive to drug absorption. [75][76][77][78] Furthermore, drugs administered via the pulmonary route bypass the first-pass metabolism of the gastrointestinal tract, enter the systemic circulation, and may eliminate barriers associated with patient compliance. 5,19,79 However, the effectiveness of drug delivery through this route depends significantly on factors such as aerosol particle size, particle shape and geometry, surface adhesive properties, and the mechanism and rate of removal from the respiratory system.…”

From Basic Research to Clinical Practice: Considerations for Treatment Drugs for Silicosis

“…For instance, antifibrotic drugs like pirfenidone and nintedanib, which are commonly prescribed for IPF [146], have demonstrated efficacy in reducing lung inflammation and fibrotic changes in animal models of silicosis [147][148][149]. Due to the significant side effects of nintedanib, it has not been an option for silicosis treatment, but recently an experiment engineered a nanocrystal-based suspension formulation of nintedanib possessing specific physicochemical properties to enhance drug retention in the lung for localized treatment of silicosis [150], bringing new hope to nintedanib for treating silicosis and highlighting that overcoming the side effects of existing clinical drugs can provide a new direction for the treatment of silicosis. Therefore, insights gained from antifibrosis drugs utilized in IPF could offer potential avenues for treating silicosis.…”

Telmisartan Nanosuspension for Inhaled Therapy of COVID-19 Lung Disease and Other Respiratory Infections

“…However, universal use of oral ARB formulations poses safety concerns due to the established systemic adverse effects, particularly for those with normal blood pressure or hypotension. − Additionally, unlike the original use for systemic pressure-reducing effects, a very high oral dose is likely needed to achieve desirable therapeutic concentrations in the lung tissue to yield meaningful clinical outcomes. Inhalable formulations may elegantly enhance dose flexibility as well as reduce overall dose and/or dosing frequency, therefore minimizing undesired systemic exposure of drug payloads. , To this end, we have developed and extensively characterized an inhalable nanosuspension formulation of a clinically used ARB, telmisartan, which can be administered directly into the lung via nebulization. Of note, nebulized nanoformulations, such as drug nanosuspensions, can effectively reach the deep lung when appropriate aerodynamic properties are achieved. , …”

“…Inhalable formulations may elegantly enhance dose flexibility as well as reduce overall dose and/or dosing frequency, therefore minimizing undesired systemic exposure of drug payloads. 14,15 To this end, we have developed and extensively characterized an inhalable nanosuspension formulation of a clinically used ARB, telmisartan, which can be administered directly into the lung via nebulization. Of note, nebulized nanoformulations, such as drug nanosuspensions, can effectively reach the deep lung when appropriate aerodynamic properties are achieved.…”