Characterization and aerosol dispersion performance of advanced spray-dried chemotherapeutic PEGylated phospholipid particles for dry powder inhalation delivery in lung cancer

Abstract

Pulmonary inhalation chemotherapeutic drug delivery offers many advantages for lung cancer patients in comparison to conventional systemic chemotherapy. Inhalable particles are advantageous in their ability to deliver drug deep in the lung by utilizing optimally sized particles and higher local drug dose delivery. In this work, spray-dried and co-spray dried inhalable lung surfactant-mimic PEGylated lipopolymers as microparticulate/nanoparticulate dry powders containing paclitaxel were rationally designed via organic solution advanced spray drying (no water) in closed-mode from dilute concentration feed solution. Dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine poly(ethylene glycol) (DPPE-PEG) with varying PEG chain length were mixed with varying amounts of paclitaxel in methanol to produce co-spray dried microparticles and nanoparticles. Scanning electron microscopy showed the spherical particle morphology of the inhalable particles. Thermal analysis and X-ray powder diffraction confirmed the retention of the phospholipid bilayer structure in the solid-state following spray drying, the degree of solid-state molecular order, and solid-state phase transition behavior. The residual water content of the particles was very low as quantified analytically Karl Fisher titration. The amount of paclitaxel loaded into the particles was quantified which indicated high encapsulation efficiencies (43-99%). Dry powder aerosol dispersion performance was measured in vitro using the Next Generation Impactor (NGI) coupled with the Handihaler dry powder inhaler device and showed mass median aerodynamic diameters in the range of 3.4-7 μm. These results demonstrate that this novel microparticulate/nanoparticulate chemotherapeutic PEGylated phospholipid dry powder inhalation aerosol platform has great potential in lung cancer drug delivery.

Keywords: Biocompatible biodegradable lipopolymers; Dry powder inhaler (DPI); Lung surfactant; Nanomedicine; Nanotechnology; Respiratory drug delivery.

Figure 1

SEM micrographs of co-spray dried (co-SD) PEGylated phospholipid particles with varying PEG chain length containing 5% paclitaxel (PTX): (a) co-SD 5PTX:95DPPC; (b) co-SD 5PTX:95DPPC/DPPE-PEG2k; (c) co-SD 5PTX:95DPPC/DPPE-PEG3k; and (d) co-SD 5PTX:95DPPC:DPPE-PEG5k. Magnification for all samples was 10,000×.

Figure 2

SEM micrographs of co-spray dried (co-SD) PEGylated phospholipid particles with varying PEG chain length containing 25% paclitaxel (PTX): (a) co-SD 25PTX:75DPPC; (b) co-SD 25PTX:75DPPC/DPPE-PEG2k; (c) co-SD 25PTX:75DPPC/DPPE-PEG3k; and (d) co-SD 25PTX:75DPPC/DPPE-PEG5k. Magnification for all samples was 10,000×.

Figure 3

SEM micrographs of co-spray dried (co-SD) PEGylated phospholipid particles with varying PEG chain length containing 50% paclitaxel (PTX): (a) co-SD 50PTX:50DPPC; (b) co-SD 50PTX:50DPPC/DPPE-PEG2k; (c) co-SD 50PTX:50DPPC/DPPE-PEG3k; and (d) co-SD 50PTX:50DPPC/DPPE-PEG5k. Magnification for all samples was 10,000×.

Figure 4

SEM micrographs of co-spray dried (co-SD) PEGylated phospholipid particles with varying PEG chain length containing 75% paclitaxel (PTX): (a) co-SD 75PTX:25DPPC; (b) co-SD 75PTX:25DPPC/DPPE-PEG2k; (c) co-SD 75PTX:25DPPC/DPPE-PEG3k; and (d) co-SD 75PTX:25DPPC/DPPE-PEG5k. Magnification for all samples was 10,000×.

Figure 5

SEM micrographs of spray-dried (SD) 100% paclitaxel particles (100PTX) following spray drying at three pump rates (Low P, Med P, and High P) for: (a) Raw paclitaxel (PTX); (b) SD 100PTX (Low P); (c) SD 100PTX (Med P); and (d) SD 100PTX (High P). Magnification for all samples was 10,000×.

Figure 6

DSC thermograms of spray-dried (SD) and co-spray-dried (co-SD) particles with varying PTX content and PEG chain lengths for: (a) co-SD 5PTX:95 DPPC vs. co-SD 5PTX:95 DPPC/DPPE-PEG; (b) co-SD 25 PTX:75 DPPC vs. co-SD 25 PTX:75 DPPC/DPPE-PEG; (c) co-SD 50PTX:50 DPPC vs. co-SD 50 PTX:50 DPPC/DPPE-PEG; (d) co-SD 75PTX:25 DPPC vs. co-SD 75PTX:25DPPC/DPPE-PEG; (e) SD 100PTX from three pump rates vs. raw PTX; and (f) insert of co-SD 75PTX:25 DPPC vs. co-SD 75PTX:25DPPC/DPPE-PEG for T_g transition visualization.

Figure 7

X-ray powder diffractograms of spray-dried (SD) and co-spray-dried (co-SD) particles with varying PTX content and PEG chain lengths for: (a) co-SD 5PTX:95 DPPC vs. co-SD 5PTX:95 DPPC/DPPE-PEG; (b) co-SD 25 PTX:75 DPPC vs. co-SD 25 PTX:75 DPPC/DPPE-PEG; (c) co-SD 50PTX:50 DPPC vs. co-SD 50 PTX:50 DPPC/DPPE-PEG; (d) co-SD 75PTX:25 DPPC vs. co-SD 75PTX:25DPPC/DPPE-PEG; and (e) SD 100PTX at three pump rates vs. raw PTX.

Figure 8

Representative ATR-FTIR spectra of co-spray-dried (co-SD) PTX:DPPC/DPPE-PEG3k particles in comparison to raw DPPC and raw paclitaxel.

Figure 9

Representative HSM micrographs of co-spray dried (co-SD) for: (a) co-SD 5PTX:95DPPC/DPPE-PEG3k; and (b) co-SD 50PTX:50DPPC/DPPE-PEG3k particles (scale bar = 3 mm).

Figure 10

Representative HSM micrographs of spray-dried (SD): (a) SD 100PTX (High P) particles; and (b) raw paclitaxel. (Scale bar = 3 mm).

Figure 11

Aerosol dispersion performance as % deposited on each stage of the Next Generation Impactor™ (NGI™) for spray-dried (SD) and co-spray-dried (co-SD) particles with varying PTX content and PEG chain lengths for: a) co-SD 5PTX:95 DPPC vs. co-SD 5PTX:95 DPPC/DPPE-PEG; b) co-SD 25 PTX:75 DPPC vs. co-SD 25 PTX:75 DPPC/DPPE-PEG; c) co-SD 50PTX:50 DPPC vs. co-SD 50 PTX:50 DPPC/DPPE-PEG; d) co-SD 75PTX:25 DPPC vs. co-SD 75PTX:25DPPC/DPPE-PEG; and e) SD 100PTX particles spray-dried at three pump rates (Low P, Med P, and High P). For Q= 60 L/minute, the effective cutoff diameters for each NGI™ impaction stage are as follows: Stage 1 (8.06 µm); Stage 2 (4.46 µm); Stage 3 (2.82 µm); Stage 4 (1.66 µm); Stage 5 (0.94 µm); Stage 6 (0.55 µm); and Stage 7 (0.34 µm). (n = 3, Ave ± SD)