Design and development of innovative microparticulate/nanoparticulate inhalable dry powders of a novel synthetic trifluorinated chalcone derivative and Nrf2 agonist

Priya Muralidharan,Brielle Jones,Graham Allaway,Heidi M Mansour,Shyam S Biswal

doi:10.1038/s41598-020-76585-2

Abstract

Chalcone derivatives are shown to possess excellent anti-inflammatory and anti-oxidant properties which are of great interest in treating respiratory diseases such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF). This study successfully designed and developed dry powder inhaler (DPI) formulations of TMC (2-trifluoromethyl-2′-methoxychalone), a new synthetic trifluorinated chalcone and Nrf2 agonist, for targeted pulmonary inhalation aerosol drug delivery. An advanced co-spray drying particle engineering technique was used to design and produce microparticulate/nanoparticulate formulations of TMC with a suitable excipient (mannitol) as inhalable particles with tailored particle properties for inhalation. Raw TMC and co-spray dried TMC formulations were comprehensively characterized for the first time using scanning electron microscopy (SEM) with energy dispersive X-ray (EDX) spectroscopy, thermal analysis, X-ray powder diffraction (XRPD), and molecular fingerprinting as dry powders by ATR-FTIR spectroscopy and Raman spectroscopy. Further, biocompatibility and suitability of formulations were tested with in vitro cellular transepithelial electrical resistance (TEER) in air-interface culture (AIC) using a human pulmonary airway cell line. The ability of these TMC formulations to perform as aerosolized dry powders was systematically evaluated by design of experiments (DOEs) using three different FDA-approved human inhaler devices followed by interaction parameter analyses. Multiple spray drying pump rates (25%, 75%, and 100%) successfully produced co-spray dried TMC:mannitol powders. Raw TMC exhibited a first-order phase transition temperature at 58.15 ± 0.38 °C. Furthermore, the results demonstrate that these innovative TMC dry powder particles are suitable for targeted delivery to the airways by inhalation.

Highlights

Airways are continuously exposed to environmental insults that trigger inflammation consistent with the body’s natural response to a stimulus such as smoke, infection, pollutants, and allergens
The mediocre performance of the 75% spray drying pump rate particles can be related to the physicochemical properties of the powder. This systematic and comprehensive study reports for the first time on innovative dry powder inhaler formulations of the novel synthetic trifluorinated Nuclear factor (erythroid-derived 2)—like 2 (Nrf2)-agonist TMC molecularly mixed with a d-mannitol in the solid-state
This study is the first to report on the comprehensive characterization of the physicochemical properties of TMC including Tm, crystalline phase, and spectroscopy molecular fingerprinting by both Attenuated total reflectance (ATR)-FTIR and Raman spectroscopy

Summary

Introduction

Airways are continuously exposed to environmental insults that trigger inflammation consistent with the body’s natural response to a stimulus such as smoke, infection, pollutants, and allergens. The study synthesized about 59 derivatives of chalcone and systematically screened their Nrf[2] activity by testing in normal pulmonary epithelial cell line and mouse model. Reported is the Nrf2/ARE cellular pathway activation efficacy of chalcone and its derivatives in different cell lines such as mouse embryonic fibroblast cells[38], neural and microglial cells[39,40], AREc32 cells[41], gastric epithelial cells[42], lung epithelial cells[21], and colon cells[43]. The main objective of this systematic study was to design, develop and optimize dry powder inhaler (DPI) formulations of TMC (Fig. 1) to treat inflammatory and fibrotic lung diseases directly through targeted lung delivery to the airways. The influence of different human DPI devices on the aerosol properties of the formulations was quantified and correlated with DPI device properties and formulation properties

Methods

Results

Discussion

Conclusion