Development and characterization of the voriconazole loaded lipid-based nanoparticles

Purpose: Topical fungal infections, including ocular mycoses, are increasing, and voriconazole (VCZ) is an effective antifungal but has poor water solubility, limiting liquid ophthalmic formulations. Lipid-based nanoparticles (LNPs/SLNs) may improve VCZ solubility, loading, and topical delivery.

Hypothesis: If VCZ is encapsulated into solid lipid nanoparticles using a suitable lipid such as Witespol W35 via high-pressure homogenisation, then an optimised nanosuspension with small particle size, low polydispersity, good entrapment efficiency, and retained antifungal activity can be produced for potential ophthalmic use.

Aims: Formulate VCZ-loaded solid lipid nanoparticles (VCZ-SLN) by high-pressure homogenisation (HPH). - Optimise critical parameters: lipid type, lipid amount, VCZ concentration, and number of homogenisation cycles. - Characterise VCZ-SLN by particle size, PDI, entrapment efficiency, DSC, FTIR, and in vitro release. - Evaluate antifungal efficacy against Candida glabra and Aspergillus flavus.

Delivery system: Platform: Solid lipid nanoparticles / lipid-based nanoparticles. - Selected lipid: Witespol W35; stearic acid and Compritol 888 ATO were also tested but not suitable. - Surfactants/stabilizers: L-α-phosphatidylcholine (PPC) and polysorbate 80. - Payload: Voriconazole (VCZ), a triazole antifungal. - Preparation: High-pressure homogenisation at 600 bar for 3–5 cycles after Ultra-Turrax prehomogenization. - Targeting ligand: None. - Intended route: Topical/ophthalmic delivery.

Approach: Formulation screen: 12 SLN formulations (SLN1–SLN12) varying Witespol W35 (0.25, 0.50, 0.75 g) and VCZ (0, 50, 100, 150 mg); n = 3. - Optimisation: Particle size, PDI, and entrapment efficiency used to select lead formulation. - Controls: Blank SLNs without VCZ. - Antifungal test: Disc diffusion against C. glabra and A. flavus; blank SLN as negative control. - No in vivo or cell-culture studies were performed.

Key methods: Photocorrelation spectroscopy / DLS for particle size and PDI. - HPLC-UV for VCZ quantification and entrapment efficiency after ultrafiltration. - Differential scanning calorimetry (DSC) for physical state. - FTIR spectroscopy for chemical interactions. - Dialysis test for in vitro VCZ release. - Paper disc diffusion assay for antifungal activity.

Key results: Optimised formulation (SLN2): Witespol W35 0.25 g + VCZ 50 mg; particle size 182 ± 4.1 nm, PDI 0.269 ± 0.01, entrapment efficiency 78.79 ± 3.4%. - Five homogenisation cycles at 600 bar reduced PDI by ~36.5% compared with fewer cycles. - Stearic acid and Compritol 888 ATO produced particles >0.5 µm with PDI >0.8, unsuitable for the target size range. - DSC showed no crystalline VCZ peak in VCZ-SLN; FTIR showed no new characteristic peaks and no change in VCZ chemical structure. - In vitro release: 22.98 ± 0.23% cumulative VCZ release in first 60 min; about 50% released over 24 h. - Antifungal inhibition zones: 42 ± 1.5 mm (SLN2) and 44 ± 2 mm (SLN6), not significantly different (p > 0.05); blank SLN showed no inhibition.

Interpretation: VCZ was successfully encapsulated into SLN by HPH. DSC and FTIR supported nanoparticle formation without changing VCZ chemical structure. The optimised VCZ-SLN released drug and inhibited fungal growth, suggesting a promising alternative carrier for ophthalmic/topical antifungal therapy.

Limitations: No in vivo, ex vivo, or corneal toxicity/irritation studies. - Only two fungal strains tested. - No long-term physical stability data. - No comparison with marketed VCZ formulations or an optimised VCZ eye drop. - Surfactants were used, and the optimised PDI (0.269) was still relatively high. - Entrapment efficiency was moderate (~79%) for the selected formulation. - No pharmacokinetic or biodistribution evaluation.