Hyaluronic Acid-Dexamethasone Nanoparticles for Local Adjunct Therapy of Lung Inflammation.

The delivery of a dexamethasone formulation directly into the lung appears as an appropriate strategy to strengthen the systemic administration, reducing the dosage in the treatment of lung severe inflammations. For this purpose, a hyaluronic acid-dexamethasone formulation was developed, affording an inhalable reconstituted nanosuspension suitable to be aerosolized. The physico-chemical and biopharmaceutical properties of the formulation were tested: size, stability, loading of the spray-dried dry powder, reconstitution capability upon redispersion in aqueous media. Detailed structural insights on nanoparticles after reconstitution were obtained by light and X-ray scattering techniques. (1) The size of the nanoparticles, around 200 nm, is in the proper range for a possible engulfment by macrophages. (2) Their structure is of the core-shell type, hosting dexamethasone nanocrystals inside and carrying hyaluronic acid chains on the surface. This specific structure allows for nanosuspension stability and provides nanoparticles with muco-inert properties. (3) The nanosuspension can be efficiently aerosolized, allowing for a high drug fraction potentially reaching the deep lung. Thus, this formulation represents a promising tool for the lung administration via nebulization directly in the pipe of ventilators, to be used as such or as adjunct therapy for severe lung inflammation.

Inhibition of Pro-Fibrotic Molecules Expression in Idiopathic Pulmonary Fibrosis-Derived Lung Fibroblasts by Lactose-Modified Hyaluronic Acid Compounds.

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory and fibrotic pathological condition with undefined effective therapies and a poor prognosis, partly due to the lack of specific and effective therapies. Galectin 3 (Gal-3), a pro-fibrotic ß-galactoside binding lectin, was upregulated in the early stages of the pathology, suggesting that it may be considered a marker of active fibrosis. In the present in vitro study, we use Hylach®, a lactose-modified hyaluronic acid able to bind Gal-3, to prevent the activation of lung myofibroblast and the consequent excessive ECM protein cell expression. Primary human pulmonary fibroblasts obtained from normal and IPF subjects activated with TGF-ß were used, and changes in cell viability, fibrotic components, and pro-inflammatory mediator expression at both gene and protein levels were analyzed. Hylach compounds with a lactosylation degree of about 10% and 30% (Hylach1 and Hylach 2), administrated to TGF-ß-stimulated lung fibroblast cultures, significantly downregulated α-smooth muscle actin (α-SMA) gene expression and decreased collagen type I, collagen type III, elastin, fibronectin gene and protein expression to near baseline values. This anti-fibrotic activity is accompanied by a strong anti-inflammatory effect and by a downregulation of the gene expression of Smad2 for both Hylachs in comparison to the native HA. In conclusion, the Gal-3 binding molecules Hylachs attenuated inflammation and TGF-ß-induced over-expression of α-SMA and ECM protein expression by primary human lung fibroblasts, providing a new direction for the treatment of pulmonary fibrotic diseases.

Mannitol Polymorphs as Carrier in DPIs Formulations: Isolation Characterization and Performance.

The search for best performing carriers for dry powder inhalers is getting a great deal of interest to overcome the limitations posed by lactose. The aerosolization of adhesive mixtures between a carrier and a micronized drug is strongly influenced by the carrier solid-state properties. This work aimed at crystallizing kinetically stable D-mannitol polymorphs and at investigating their aerosolization performance when used in adhesive mixtures with two model drugs (salbutamol sulphate, SS, and budesonide, BUD) using a median and median/high resistance inhaler. A further goal was to assess in vitro the cytocompatibility of the produced polymer-doped mannitol polymorphs toward two lung epithelial cell lines. Kinetically stable (up to 12 months under accelerate conditions) α, and δ mannitol forms were crystallized in the presence of 2% w/w PVA and 1% w/w PVP respectively. These solid phases were compared with the ß form and lactose as references. The solid-state properties of crystallized mannitol significantly affected aerosolization behavior, with the δ form affording the worst fine particle fraction with both the hydrophilic (9.3 and 6.5%) and the lipophilic (19.6 and 32%) model drugs, while α and ß forms behaved in the same manner (11-13% for SS; 53-58% for BUD) and better than lactose (8 and 13% for SS; 26 and 39% for BUD). Recrystallized mannitol, but also PVA and PVP, proved to be safe excipients toward lung cell lines. We concluded that, also for mannitol, the physicochemical properties stemming from different crystal structures represent a tool for modulating carrier-drug interaction and, in turn, aerosolization performance.