Dry powder for inhalation of single and fixed dose combinations of nintedanib, pirfenidone and mycophenolic acid prepared by thin-film freezing technology

Date

2023-04-19

Authors

Praphawatvet, Tuangrat

Journal Title

Journal ISSN

Volume Title

Publisher

Abstract

Dry powder for inhalation (DPI) exhibits a non-invasive drug delivery that has been developed to achieve the therapeutic efficacies and undesirable side effects of oral administration. Particle engineering technologies have developed inhaled micro- and nanoparticles to achieve sufficient aerodynamic performance for inhalation. The first chapter presents inhaled-nanoparticle properties that overcome the limitation of drug delivery to lung tissue for local or systemic effects. The second chapter presents the thin-film freezing (TFF) process that potentially produces pharmaceutical powders with physical properties to improve oral and pulmonary delivery. The TFF process, a particle engineering technology, produces stable and aerosolized powders of small molecules for inhalation. TFF powders exhibit brittle matrix structures with high surface area, enhancing aerosol characteristics and achieving drug solubility and bioavailability limitations. The third chapter found that the TFF process produces inhaled nintedanib powder with high aerodynamic performance. Moreover, the process parameters, including drug loading and excipients, can affect physical properties and aerodynamic performance. The brittle-matrix characters of the TFF powders, including surface area, powder brittleness and moisture content, were significantly correlated to aerodynamic performance. The fourth chapter presents the development of inhaled fixed-dose combinations of nintedanib, pirfenidone and mycophenolic acid for idiopathic pulmonary fibrosis (IPF) to improve efficacy and safety over oral administration. In this study, we found that the TFF process achieved the challenges in producing inhaled fixed-dose combinations of two- and three-drug formulations with homogenous brittle-matrix powders to provide acceptable aerosol properties for inhalation. The last chapter presents the TFF process improved aerodynamic performance of pirfenidone by cocrystal formation. We found that pirfenidone is glass-forming class 1 that is easily recrystallized during preparation or storage. Therefore, pirfenidone exhibited very low aerosolization that cannot be delivered to lungs. The cocrystal formation of pirfenidone and dicarboxylic acid changed pirfenidone morphology and limited recrystallization that enhanced aerodynamic performance. In conclusion, the TFF process can overcome the challenges in developing dry powder for inhalation of single and fixed dose combinations of nintedanib, pirfenidone and mycophenolic acid.

Description

LCSH Subject Headings

Citation