Spray drying of siRNA-containing PLGA nanoparticles intended for inhalation

Abstract

Local delivery of small interfering RNA (siRNA) to the lungs constitutes a promising new area in drug delivery. The present study evaluated parameters of importance for spray drying of siRNA-loaded poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) into nanocomposite microparticles intended for inhalation. The spray drying process was optimised using a statistical design of experiment and by evaluating powder characteristics upon systematic variation of the formulation parameters. Concentration, carbohydrate excipient (trehalose, lactose and mannitol) and the ratio of NP to excipient were varied to monitor the effects on moisture content, particle morphology, particle size and powder yield. The identified optimum conditions were applied for spray drying of siRNA-loaded nanocomposite microparticles, resulting in a product with a low water content (0.78% w/w) and an aerodynamic particle diameter considered suitable for inhalation. The use of mannitol in the formulation allowed a significantly lower moisture content than trehalose and lactose. The inclusion of 50% (w/w) or higher amounts of NPs resulted in a marked change in the surface morphology of the spray-dried particles. Importantly, the integrity and biological activity of the siRNA were preserved during the spray drying process. In conclusion, the present results show that spray drying is a suitable technique for producing nanocomposite microparticles comprising siRNA-containing PLGA NPs for potential use in inhalation therapy.

The role of microRNAs in chronic respiratory disease: recent insights

“…Moreover, studies involving intratracheal delivery of siRNAs show mixed results, likely due to the presence of mucus, mucociliary clearance pathways, and complicated branching structure of the lungs that impair uptake (Lam et al, 2012). Ideally, technology allowing for aerosolization would offer the least-invasive delivery method (Jensen et al, 2010), though these have not yet been reported in clinical settings.…”

Lactose characteristics and the generation of the aerosol

“…It is interesting to note that lactose is often used as a bulking agent and stabilising adjuvant in spray-dried formulations of sensitive drugs, peptides and proteins to provide some protection during the manufacturing process against shear forces and increased temperatures in particular [200][201][202][203][204][205]. The structure and activity of dried proteins are protected by hydrogen bonding with lactose, which enables the production of stable particles of a size suitable for inhalation and allows a rapid release of the drug in the lung.…”

“…After reaching the alveoli, the microparticles were decomposed to nanoparticles, as lactose is soluble in the alveolar lining fluid [205,[212][213][214].…”

Formulation of pH responsive peptides as inhalable dry powders for pulmonary delivery of nucleic acids

“…Dry powder aerosol formulation are preferred for macromolecules due to their higher stability during storage, better sterility, easy transportation compared with liquid formulations, and have been successfully used in formulation of other therapeutic macromolecules [23][24][25][26]. To prepare inhalable powder formulations of nucleic acids, either spray drying (SD) or spray freeze drying (SFD) are employed [27][28][29][30]. In the spray drying process, liquids are atomized into sprays which are rapidly evaporated by hot air-stream to give dry particles.…”