Abstract :
[en] Pulmonary drug delivery is a promising strategy for treating chronic respiratory
diseases, as it enables high local drug concentrations while minimizing systemic
side effects. However, its effectiveness is often limited by physiological barriers that
hinder drug deposition and therapeutic efficiency. To address this, liposomes have
emerged as attractive carriers, enabling the encapsulation of active pharmaceutical
ingredients, their protection from degradation and improved bioavailability,
although their limited aqueous stability remains a major challenge.
In this context, formulating liposomes as dry powders for inhalation represents a
relevant approach to enable efficient pulmonary delivery and improve stability.
Spray-drying, a widely used technique to produce respirable particles, allows control
over powder properties but may also compromise liposome integrity and induce
premature drug leakage. This thesis therefore aimed to evaluate the feasibility of
developing optimized inhalable liposome-based dry powder formulations.
A Quality by Design approach supported by Design of Experiments was
implemented to assess the feasibility of spray-drying liposomes and to identify
critical formulation and process parameters. This work provided fundamental
insights into the impact of drying conditions and liquid feed composition on
liposome integrity and powder properties. Liposome stability during spray-drying
was shown to depend on a complex interplay of factors, where active ingredient
properties influence susceptibility to leakage, while lipid composition, excipient
environment and process conditions govern membrane response to stress and
powder properties. These findings highlight the need to consider liposomal systems
as integrated formulations. Additionally, optimized spray-drying conditions were
identified and validated, enabling the production of inhalable powders with
preserved liposome integrity, limited drug leakage and suitable aerodynamic
properties, resulting in high in vitro lung deposition (FPF ~70%).
Subsequently, optimized inhalable dry powder formulations were developed,
incorporating an innovative combination of ciclesonide and indacaterol for asthma
treatment, which is not currently available on the pharmaceutical market in this
form. The spray-drying conditions identified were successfully applied to liposomes
designed to co-encapsulate this combination for pulmonary delivery, yielding
inhalable powders with preserved liposome integrity, enhanced lung deposition and
satisfactory stability under refrigerated conditions. In parallel, the same drug
combination was formulated into non‐liposomal inhalable dry powders, including a
clinically relevant optimized formulation and a reference formulation matched in
composition and drug content to the optimized liposome‐based DPI, enabling
assessment of the added value of liposomal incorporation.
Overall, this work demonstrates the feasibility of developing liposome-based
inhalable dry powders, highlights the challenges associated with their formulation
and provides a better understanding of the parameters governing their
performance. These findings establish a solid foundation for the design of next
generation inhalable formulations and open new perspectives for the development
of more efficient and targeted therapeutic strategies for the treatment of respiratory
diseases.
