Formulation development of itraconazole PEGylated nano-lipid carriers for pulmonary aspergillosis using hot-melt extrusion technology

Abstract

Pulmonary delivery is a promising alternative for the oral treatment of pulmonary aspergillosis. This study aimed to develop continuous and scalable itraconazole PEGylated nano-lipid carriers (ITZ-PEG-NLC) for inhalation delivery. The feasibility of preparing NLCs utilizing hot-melt extrusion (HME) coupled with probe sonication was investigated. The process parameters for HME and sonication were varied to optimize the formulation. ITZ-PEG-NLC (particle size, 101.20 ± 1.69 nm; polydispersity index, 0.26 ± 0.01) was successfully formulated. The drug entrapment efficiency of ITZ-PEG-NLC was 97.28 ± 0.50%. Transmission electron microscopy was used to characterize the shape of the particles. The developed formulations were evaluated for their aerodynamic properties for pulmonary delivery. The lung deposition of ITZ-PEG-NLC was determined using an Anderson Cascade Impactor and Philips Respironics Sami the Seal Nebulizer Compressor. In vitro cytotoxicity studies were performed using A549 cells. A burst-release pattern was observed in ITZ-PEG-NLC with a drug release of 41.74 ± 1.49% in 60 min. The in vitro aerosolization of the ITZ-PEG-NLC formulation showed a mass median aerodynamic diameter of 3.51 ± 0.28 μm and a geometric standard deviation of 2.44 ± 0.49. These findings indicate that HME technology could be used for the production of continuous scalable ITZ-PEG-NLC.

Keywords: Hot-melt extrusion; Inhalation; Itraconazole; Nanostructured lipid carriers; PEGylation; Pulmonary drug delivery.

Graphical abstract

Fig. 1

Schematic illustration of ITZ-PEG-NLC formulation using hot melt extrusion technology and probe sonication.

Fig. 2

Modified screw configuration utilized for the preparation of ITZ-PEG-NLC with hot-melt extrusion technology.

Fig. 3

Differential Scanning Calorimetry thermograms.

Fig. 4

Effect of parameters on attributes of the formulation. 3a- Effect of parameters on the particle size of formulation. 3b- Effect of parameters on the PDI of the formulation. 3c- Effect of parameters on the zeta potential of the formulation.

Fig. 5

PXRD Diffractograms of pure ITZ, ITZ-PEG-NLC formulation (F-2) and placebo formulation.

Fig. 6

In vitro release of ITZ-PEG-NLC in 10 mL of 20% (w/v) 2-hydroxypropyl-beta cyclodextrin (mean ± SD, n = 3).

Fig. 7

Viscosity against the speed of spindle (CPE 44) using the Brookfield cone and plate viscometer, (each error bar represents standard deviation, n = 3).

Fig. 8

Particle size and PDI of the ITZ-PEG-NLC before and after nebulization using Philips Respironics Sami the Seal Nebulizer Compressor, (each error bar represents standard deviation, n = 3).

Fig. 9

a-Amount of ITZ deposited on each stage of Anderson cascade impactor using the Philips Respironics Sami the Seal Nebulizer Compressor, b-Cumulative mass deposition versus the Anderson Cascade Impactor effective cut-off diameters, (each error bar represents standard deviation, n = 3).

Fig. 10

Cell viability measured by the crystal violet assay for the ITZ-PEG-NLC against A549 cell line. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 11

Tandem Electron Microscopy of ITZ-PEG-NLC formulation F2.