Targeting of Inhaled Therapeutics to the Small Airways: Nanoleucine Carrier Formulations.

Danforth P. Miller,Thomas E. Tarara,Jeffry G. Weers

doi:10.3390/pharmaceutics13111855

Abstract

Current dry powder formulations for inhalation deposit a large fraction of their emitted dose in the upper respiratory tract where they contribute to off-target adverse effects and variability in lung delivery. The purpose of the current study is to design a new formulation concept that more effectively targets inhaled dry powders to the large and small airways. The formulations are based on adhesive mixtures of drug nanoparticles and nanoleucine carrier particles prepared by spray drying of a co-suspension of leucine and drug particles from a nonsolvent. The physicochemical and aerosol properties of the resulting formulations are presented. The formulations achieve 93% lung delivery in the Alberta Idealized Throat model that is independent of inspiratory flow rate and relative humidity. Largely eliminating URT deposition with a particle size larger than solution pMDIs is expected to improve delivery to the large and small airways, while minimizing alveolar deposition and particle exhalation.

Highlights

The respiratory tract is divided into two principal regions, the upper respiratory tract (URT) comprising the mouth, larynx, and pharynx, and the lower respiratory tract (LRT) comprising the trachea, bronchi, and lungs
The LRT has been divided into two principal regions: (1) the conducting airways comprising the large airways, bronchioles and terminal bronchioles which extend from generation 0 to generation 15, and (2) the respiratory zone comprising the respiratory bronchioles in generations 16–19 and the alveolar ducts and alveoli in generations
The leucine carrier particles utilized in the manufacture of the Ciclesonide Powder for Inhalation (CPI) batch described had a median geometric diameter (X50 ) of 2.21 μm and a tapped density of

Summary

Introduction

The respiratory tract is divided into two principal regions, the upper respiratory tract (URT) comprising the mouth, larynx, and pharynx, and the lower respiratory tract (LRT) comprising the trachea, bronchi, and lungs. For therapeutics administered via oral inhalation, the LRT is generally the target. Drug deposited in the URT may contribute to systemic adverse events. Regional deposition within the LRT may be critical for effective drug delivery [1]. The LRT has been divided into two principal regions: (1) the conducting airways comprising the large airways, bronchioles and terminal bronchioles which extend from generation 0 to generation 15, and (2) the respiratory zone comprising the respiratory bronchioles in generations 16–19 and the alveolar ducts and alveoli in generations

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