Development of a novel rapamycin loaded nano- into micro-formulation for treatment of lung inflammation

Abstract

It has recently emerged that drugs such as the mTOR inhibitor rapamycin (Rapa) may play a key role in the treatment of airway inflammation associated with lung diseases, such as chronic obstructive pulmonary disease, asthma, and cystic fibrosis. Nevertheless, Rapa clinical application is still prevented by its unfavorable chemical-physical properties, limited oral bioavailability, and adverse effects related to non-specific biodistribution. In this paper, the design and production of a novel formulation of Rapa based on nano into micro (NiM) particles are detailed. To achieve it, Rapa-loaded nanoparticles were produced by nanoprecipitation of an amphiphilic pegylated poly-ɛ-caprolactone/polyhydroxyethyl aspartamide graft copolymer. The obtained nanoparticles that showed a drug loading of 14.4 wt% (corresponding to an encapsulation efficiency of 82 wt%) did not interact with mucins and were able to release and protect Rapa from degradation in simulated lung and cell fluids. To allow their local administration to the lungs as a dry powder, particle engineering at micro-sized level was done by embedding nanoparticles into mannitol-based microparticles by spray drying. Obtained NiM particles had a mean diameter of about 2-µ, spherical shape and had good potential to be delivered to the lungs by a breath-activated dry powder inhalers. Rheological and turbidity experiments showed that these NiM particles can dissolve in lung simulated fluid and deliver the Rapa-loaded pegylated nanoparticles, which can diffuse through the mucus layer. Graphical abstract

Inhalable Formulation Based on Lipid–Polymer Hybrid Nanoparticles for the Macrophage Targeted Delivery of Roflumilast

“…Nanoparticle powders are not suitable for direct inhalation due to their dimensions, which are not appropriate for bronchial deposition. 13 One of the most promising approaches to turning nanoparticles into inhalable dry powders is the nano-into-micro strategy (NiM), where nanoparticles are entrapped into water-soluble microparticles. Ideally, when deposited on lung fluids (e.g., mucus), NiM should rapidly dissolve and release embedded colloidal particles, which could efficiently diffuse along the respiratory membranes reaching the epithelial surface.…”

“…Ideally, when deposited on lung fluids (e.g., mucus), NiM should rapidly dissolve and release embedded colloidal particles, which could efficiently diffuse along the respiratory membranes reaching the epithelial surface. 13 …”

“…The interactions between Man-LPHFNPs (or LPHFNPs as control samples) and mucin were determined by turbidimetry. , Briefly, we prepared dispersions of LPHFNPs or Man-LPHFNPs (0.2 mg/mL) and mucin (2 mg/mL) in PBS. Then, equal volumes of each dispersion were mixed and kept under magnetic stirring for 1 min.…”

“…To achieve an inhalable formulation, the nano-into-micro (NiM) strategy was followed. 12 , 13 In particular, an inhalable powder consisting of microparticles based on poly(vinyl alcohol) (PVA) and l -leucine (Leu), where LPHNPs were homogenously dispersed, was obtained by spray-drying. 14 …”

“…Preliminary in vitro studies were carried out to evaluate the absence of cell toxicity and determine the targeting function of mannose toward the macrophages. To achieve an inhalable formulation, the nano-into-micro (NiM) strategy was followed. , In particular, an inhalable powder consisting of microparticles based on poly­(vinyl alcohol) (PVA) and l -leucine (Leu), where LPHNPs were homogenously dispersed, was obtained by spray-drying …”