Quercetin solid lipid microparticles: a flavonoid for inhalation lung delivery

Abstract

Purpose: The aim of the present work was to develop solid lipid microparticles (SLMs), as dry powders containing quercetin for direct administration to the lung.

Methods: Quercetin microparticles were prepared by o/w emulsification via a phase inversion technique, using tristearin as the lipid component and phosphatidylcholine as an emulsifier. The quercetin SLMs were characterised for morphology, drug loading (15.5%±0.6, which corresponded to an encapsulation efficiency of 71.4%), particle size distribution, response to humidity, crystallinity, thermal behaviour and in vitro respirable fraction. Furthermore, the toxicity and the in vitro transport of the SLMs on an air liquid interface model of the Calu-3 cell line were also investigated using a modified twin-stage impinger apparatus.

Results: Results showed that quercetin SLMs could be formulated as dry powder suitable for inhalation drug delivery (20.5±3.3% fine particle fraction ≤4.46μm) that was absorbed, via a linear kinetic model across the Calu-3 monolayer (22.32±1.51% over 4h). In addition, quercetin SLMs were shown to be non-toxic at the concentrations investigated. Interestingly, no apical to basolateral transport of the micronised quercetin was observed over the period of study.

Conclusions: These observations suggest quercetin diffusion was enhanced by the presence of the lipid/emulsifying excipients in the SLMs; however further studies are necessary to elucidate the exact mechanisms.

Graphical abstract

Fig. 1

Particle size distribution of raw quercetin and quercetin SLM measured using dry dispersion system of laser diffraction. Data represent mean ± SD (n = 3).

Fig. 2

Scanning electron micrographs of quercetin SLMs (A) and raw quercetin (B).

Fig. 3

Differential scanning calorimetric thermograms of quercetin SLM, quercetin raw material, phosphatidylcholine and tristearin.

Fig. 4

The X-ray powder diffractogram of raw quercetin and quercetin SLMs.

Fig. 5

Mass change as a function of time for quercetin SLM, quercetin, phosphatidylcholine and tristearin (A) DVS isotherm of the first cycle sorption for quercetin SLM, quercetin, phosphatidylcholine and tristearin (B). Zoomed in area in front view.

Fig. 6

Quercetin SLMs aerosol deposition by next generation impaction. S1–S8 represents NGI stages cut off diameters: S1 > 8.06; S2 > 4.46; S3  > 2.82; S4 > 1.66; S5 > 0.94; S6 > 0.55; S7  > 0.34; S8 > 0.34 μm, respectively.

Fig. 7

The effect of quercetin SLMs on Calu-3 cell viability after 72 h drug treatment. Data represent mean ± SD (n = 3).

Fig. 8

Release profiles of quercetin SLMs using a modified TSI air-interface Calu-3 cell model. Data represent mean ± SD (n = 3).

Fig. 9

Percentage of total drug remaining on the cell surface, inside the cells or transported to the basal chamber after 4 hours. Data represent mean ± SD (n = 3).