Inhalable Nanoparticles/Microparticles of an AMPK and Nrf2 Activator for Targeted Pulmonary Drug Delivery as Dry Powder Inhalers

Maria F Acosta,David Encinas-Basurto,Jeffrey R Fineman,Heidi M Mansour,Michael D Abrahamson,Stephen M Black

doi:10.1208/s12248-020-00531-3

Abstract

Metformin is an activator of the AMPK and Nrf2 pathways which are important in the pathology of several complex pulmonary diseases with unmet medical needs. Organic solution advanced spray drying in the absence of water in closed-mode was used to design and develop respirable dry powders. Following comprehensive characterization, the influence of physicochemical properties was correlated with performance as aerosols using inertial impaction and three different human dry powder inhaler (DPI) devices varying in device properties. In vitro cell assays were conducted to test safety in 2D human pulmonary cell lines and in 3D small airway epithelia comprising primary cells at the air-liquid interface (ALI). In addition, in vitro transepithelial electrical resistance (TEER) was carried out. Metformin remained crystalline following advanced spray drying under these conditions. All SD powders consisted of nanoparticles/microparticles in the solid state. In vitro aerosol dispersion performance showed high aerosolization for all SD metformin powders with all DPI devices tested. High emitted dose for all powders with all three DPI devices was measured. Differences in other aerosol performance parameters and the interplay between the properties of different formulations produced at specific pump rates and the three different DPI devices were correlated with spray drying pump rate and device properties. Safety over a wide metformin dose range was also demonstrated in vitro. Aerosol delivery of metformin nanoparticles/microparticles has the potential to be a new “first-in-class” therapeutic for the treatment of a number of pulmonary diseases including pulmonary vascular diseases such as pulmonary hypertension.

Highlights

Metformin has long been used to treat type-2 diabetes mellitus and is a known AMP-activated protein kinase (AMPK) activator that is unrelated to its hypoglycemic actions [1]
For the first time, a systematic study demonstrating that inhalable solid-state nanoparticles/microparticles of metformin, an AMPK and nuclear factor erythroid-related factor 2 (Nrf2) activator, can be successfully designed and produced using advanced spray drying conditions in closed mode
We were able to demonstrate that these inhalable solid-state nanoparticles/ microparticles have the essential particle properties needed for delivery as dry powder inhaler (DPI) with efficient aerosolization and high aerosol dispersion performance

Summary

Introduction

Metformin has long been used to treat type-2 diabetes mellitus and is a known AMP-activated protein kinase (AMPK) activator that is unrelated to its hypoglycemic actions [1]. Since mitochondrial glucose oxidation is inhibited in patients with pulmonary hypertension (PH) and glucose levels are increased in endothelial and smooth muscle cells, metformin has been reported to have positive effects in the treatment of PH [2]. Pulmonary hypertension affects adult and children [3]. In addition to being an AMPK activator, metformin is a Nrf activator [11], increasing Nrf nuclear concentrations, affecting senescence, and delaying aging [11]. Metformin has been shown to improve mitochondrial function by activating transcription of nuclear factor erythroid-related factor 2 (Nrf2) [12].

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