Synthesis, Comprehensive Characterization, and Development of Therapeutic Peptides and Glycopeptides for Targeted Respiratory Drug Delivery as Inhalation Aerosols

Abstract

Central nervous system (CNS) disorders, including neurodegeneration and chronic pain, and many respiratory diseases would greatly benefit from the specific and potent peptide pharmaceuticals and their low inherent toxicity. The delivery of peptides to target the brain is challenging, principally due to peptides' low metabolic stability, which decreases their duration of action, poor penetration of the blood-brain barrier (BBB), and their incompatibility with oral administration, typically resulting in the need for parenteral administration. These challenges limit the clinical application of peptides and explain the interest for alternative routes of peptide administration, particularly: delivery to the respiratory tract (upper and lower). Upper to target the brain through the olfactory route bypassing the blood-brain barrier (BBB), i.e., needle-free nose-to-brain delivery (N-to-B), which offers protein and peptide drugs the possibility to reach the brain noninvasively. N-to-B delivery can be a convenient method for rapidly targeting the CNS, bypassing the BBB, and minimizing systemic exposure. In addition, delivery to the lower respiratory tract as inhalation aerosol offers attractive advantages in delivering the drug locally to treat lung diseases; and to the CNS to treat its disorders at a low dose while minimizing systemic adverse effects. The lung is a low metabolic organ compared to the gastrointestinal (GI) tract. It allows rapid and high drug absorption due to the large surface area, the high blood flow, and the absence of the first-pass metabolism. In this study, several peptides and glycopeptides with different pharmacological mechanisms were developed. Some of these compounds were synthesized using the SPPS strategy and formulated as dry powders with characteristics tailored to target the respiratory tract (upper and/or lower) to treat various CNS and lung diseases. Advanced organic closed mode spray drying technique was used to produce microparticulate/ nanoparticulate formulations utilizing sugar-based excipients. The solubility and lipophilicity of all included compounds were determined computationally using molecular operating environment (MOE) software and experimentally using the shake-flask method (SFM). The raw and formulated compounds were comprehensively characterized in the solid-state. The safety of all peptides and glycopeptides covered in this dissertation was evaluated in vitro using the human nasal, brain, and pulmonary cell lines. The in vitro aerosol dispersion of the raw and spray-dried compounds was tested using an FDA-approved human inhaler device, and the influence of spray drying process conditions on the aerosol dispersion was evaluated.