Development of a novel dry powder delivery system for delivery of inhaled corticosteroids to the small airways of pediatric asthma patients

Respira Therapeutics, Inc., Albuquerque NM

Investigators

Abstract

ABSTRACT Asthma is prevalent in over 9% of the pediatric population, with most pediatric patients uncontrolled or poorly controlled in their disease. Extensive inflammation of the airways in asthma is treated using inhaled corticosteroids (ICS) as a maintenance therapy. However, these drugs can suppress growth in children, and fear of this outcome can lead to non-adherence in pediatric patients. This results in severe complications. To minimize the risk of growth suppression, recommendations are that ICS therapy be titrated to the lowest effective dose. However, this is complicated by the poor delivery efficiency of currently marketed inhalers, which deposit the majority of the dose (>70%) in the upper respiratory tract (URT). This often results in delivery of sub-therapeutic doses and leads to unwanted local side effects. In children, this is further complicated by decreased inspiratory effort and lung volume. The issues with poor delivery efficiency become magnified when one considers that the small airways contribute substantially to asthma. Unfortunately, the poor delivery efficiency of marketed DPIs means that only a small fraction of the nominal dose (<10%) reaches the small airways. There is an unmet need for a consistent, high-efficiency inhaled therapy. The objective of this project is to develop an inhaled drug product that enables efficient and reproducible delivery of inhaled corticosteroids to the small airways of pediatric asthma patients, thereby addressing important causes of poor control. Our approach consists of minimizing URT deposition by engineering low-density, fine particles that can be readily dispersed at flow rates achievable by pediatric patients using a high-resistance device. We will create novel, aerodynamically small (??< 0.7 µm) leucine carrier particles and form adhesive mixtures of these particles with nano-sized ICS particles. Leucine carrier particles have micromeritic properties that fundamentally differ from the standard adhesive mixtures of micronized drug with coarse lactose carrier particles. Here, the agglomerates of drug and carrier remain respirable and have a small impaction parameter. Characterization: For aerosol performance testing we will use Respira?s proprietary AOS? DPI, a portable, passive, capsule-based inhaler with a high resistance, enhancing delivery. To assess aerosol deposition in the URT, we will use the Alberta Idealized Throat (AIT) model, which provides excellent in vitro-in vivo correlations. We aim to achieve the following milestones: 1) Demonstrate that ?? values of the leucine carrier particles are < 0.7 µm, preferably less than 0.5 µm. 2) Demonstrate efficient aerosol delivery of ICS with >90% of the delivered dose delivered past the AIT. 3) Demonstrate that drug delivery using this approach has low flow rate dependence. 4) Demonstrate environmental robustness, with comparable aerosol performance at 40% and 75% RH. Our ultimate goal is the development of a new drug product, with increased and consistent delivery to the entire respiratory tree and decreased off-target effects, thus improving the health of asthma patients.