A Novel Approach for the Fabrication of Nanoparticle Agglomerates for Pulmonary Drug Delivery

Abstract

Purpose: Recent advances in nanoparticle technology have prompted the development of various nanoparticle-based pulmonary drug formulations that offer enhanced dissolution, targeted therapy, reduced immunogenicity, and/or sustained therapeutic action [1, 2]. However, formulation instability and tendency to exhale low-inertia nanoparticles remain the major hurdles that have to be overcome in such formulation development [3]. This study was aimed at assessing the utility of combining spray-drying and thermal gelation as a novel approach for the controlled production of redispersible drug nanoparticle agglomerates with the appropriate aerodynamic size range (2-3 µm) and stability for deep lung delivery. To this end, itraconazole (ITZ), a poorly water-soluble antifungal agent, was chosen as a model drug for the formulation development work. A gel-forming polymer, methylcellulose (MC) M20 (viscosity ~20mPaS, Tgel ~48°C) was employed as a protectant for ITZ nanoparticles during agglomeration by spray-drying (≥ 100°C). The impact of critical formulation and spray drying parameters on the redispersibility and aerosol performance of the resulting agglomerates was evaluated. Methods: ITZ nanosuspension with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as primary stabilizer and cholesterol (CLT) as a hydrophobic co-stabilizer (ITZ:TPGS:CLT = 1:1:0.2 w/w/w; ITZ = 0.25 mg/ml) was prepared by Flash Nanoprecipitation using a four-stream multi-inlet vortex mixer, as reported previously [4]. The resulting ITZ nanosuspension was diluted with MC M20 solution [with or without dimethylformamide (DMF)] in 1:1 volumetric ratio, followed by spray-drying in a Büchi B-191 spray-dryer with the aspiration rate and atomizing air flow set at 100% and 600 L/h, respectively. Particle size of primary nanoparticles was measured using a dynamic light scattering nanosizer. In vitro aerosol performance of the spray-dried product was evaluated using a next generation impactor and an Osmohaler® device. The morphology and surface features of the agglomerates were examined by scanning electron microscopy (SEM). Results: Thermal gelation by co-spray drying with MC was capable of entrapping ITZ nanoparticles to form redispersible nanoparticle agglomerates, while other conventional protectants tested (mannitol, sucrose, lactose, and hydroxypropyl-β-cyclodextrin) failed to preserve the nanoparticle integrity during spray-drying. Increasing the DMF content up to 5% v/v reduced the growth of primary nanoparticles, whereas higher DMF concentrations tended to reverse this effect (p < 0.05; Figure 1). At 5% v/v DMF, an increase in ITZ:MC M20 ratio from 1:20 to 1:10 w/w lowered the Sf/Si ratio (ratio of the size of primary nanoparticles following spray-drying and reconstitution in water to the initial particle size of the nanosuspension before spray-drying) from 1.33 ± 0.08 to 1.13 ± 0.05 (Figure 1). However, non-redispersible products were obtained when the ITZ:MC M20 ratio was raised to 1:5 w/w, indicative of an optimal amount of protectant being required for nanoparticle stabilization. The optimal spray-drying conditions for constraining the size change of primary nanoparticles (Sf/Si = 1.02 ± 0.03) were achieved with an inlet temperature of 110°C and a feed rate of ~1.5 ml/min. While the aerosol performance of the agglomerates showed no apparent correlation with the DMF content, ITZ:MC M20 ratio, and feed rate of spray-dryer, an ascending trend in mass median aerodynamic diameter (MMAD) with increasing inlet temperature was observed (Figure 2). Doubling the concentrations for both drug nanoparticles and MC M20 in the suspension for spray drying also tended to impair the aerosol performance (i.e., larger MMAD and lower FPF; p < 0.05, Figure 2). Nevertheless, all spray-dried formulations displayed superior aerosol performance (with a device removal efficiency >90%, fine particle fraction (FPF) >50%, and an MMAD of 2-3 μm), which can be attributed to a decrease in interparticulate contact area with buckled shells as well as the hollow structure of the ITZ nanoparticle agglomerates (Figure 3). Conclusion: The present study has clearly demonstrated the utility of thermal gelation by co-spray drying with MC for producing hollow drug nanoparticle agglomerates with the desired redispersibility and aerosol performance for deep lung delivery. An Sf/Si of unity, i.e., 1.02 ± 0.03, indicative of almost full preservation of nanoparticles, can be achieved by optimizing the formulation and spray-drying processing parameters. References: 1. Rabinow, B.E. Nanosuspensions in drug delivery. Nat. Rev. Drug Discov., 2004, 3, 785-796. 2. Merisko-Liversidge, E.M. and Liversidge, G.G. Drug nanoparticles: formulating poorly water-soluble compounds. Toxicol. Pathol., 2008, 36, 43-48. 3. Sung, J.C., Pulliam, B.L., Edwards, D.A. Nanoparticles for drug delivery to the lungs. Trends Biotechnol., 2007, 25, 563-570. 4. Wan, K.Y., et al., Impact of molecular rearrangement of amphiphilic stabilizers on physical stability of itraconazole nanoparticles prepared by flash nanoprecipitation. Int. J. Pharm., 2018, 542, 221-231.