Carrier-free high-dose formulations for dry powder inhalers: optimization through particle modulation

Abstract

This project systematically develops and evaluates high-dose, carrier-free heparin sodium (HS) microparticles for pulmonary delivery, aiming to overcome the limitations of traditional parenteral administration. Given heparin’s anticoagulant, anti-inflammatory, antiviral, and emerging anticancer activities, delivering HS directly to the lungs offers a promising non-invasive strategy for treating pulmonary infections, thromboembolic events, and lung malignancies.

The study first selects capsule-based dry powder inhalers (DPIs) as the optimal delivery platform for carrier-free high dose formulations due to their superior dose capacity, manufacturability, and patient convenience. Building on this, carrier-free HS microparticles were prepared via co-jet-milling with minimal magnesium stearate (MgSt<1%), achieving exceptionally high API content (>99%), excellent aerosolization (FPF>70%, E-FPF>60%), and robust long-term stability. Crucially, inverse gas chromatography (IGC) revealed for the first time that in carrier-free DPI systems, total surface energy (SE) shows a strong linear correlation (R²≈0.90) with emitted rate (ER), with higher SE significantly reducing capsule and device retention while exerting minimal influence on FPF. This discovery provides a novel mechanistic principle for optimizing delivery efficiency in high-purity DPI formulations.

The research then explores binary co-spray-dried HS formulations incorporating L-leucine (Leu), which improved powder dispersibility and reduced hygroscopicity compared to pure HS, albeit with slightly lower drug content (60–75%). Notably, these systems further validated the general applicability of the SE–ER relationship across different manufacturing techniques, highlighting its relevance as a universal design parameter. Finally, by integrating chitosan (CT) with Leu through ternary co-spray-drying, the study pioneered the first carrier-free inhalable HS microparticles with sustained-release functionality. These ternary systems achieved a biphasic, non-Fickian release profile and ~50% cumulative release over 180 min, balancing prolonged lung residence with deep pulmonary deposition.

Together, this work presents the first comprehensive development of carrier-free inhalable HS formulations spanning co-jet-milling and co-spray-drying approaches. It establishes a robust scientific framework linking SE to delivery efficiency, offers practical strategies for achieving high-dose pulmonary targeting, and lays the groundwork for future clinical translation of inhaled heparin therapies in pulmonary and systemic diseases.

Date of Award	15 Nov 2025
Original language	English
Awarding Institution	University of Nottingham
Supervisor	Binjie Hu (Supervisor), Yuanyuan Shao (Supervisor) & Xiaoyang Wei (Supervisor)