Microfabricated engineered particle systems for respiratory drug delivery and other pharmaceutical applications

Abstract

Particle Replication in Non-Wetting Templates (PRINT(®)) is a platform particle drug delivery technology that coopts the precision and nanoscale spatial resolution inherently afforded by lithographic techniques derived from the microelectronics industry to produce precisely engineered particles. We describe the utility of PRINT technology as a strategy for formulation and delivery of small molecule and biologic therapeutics, highlighting previous studies where particle size, shape, and chemistry have been used to enhance systemic particle distribution properties. In addition, we introduce the application of PRINT technology towards respiratory drug delivery, a particular interest due to the pharmaceutical need for increased control over dry powder characteristics to improve drug delivery and therapeutic indices. To this end, we have produced dry powder particles with micro- and nanoscale geometric features and composed of small molecule and protein therapeutics. Aerosols generated from these particles show attractive properties for efficient pulmonary delivery and differential respiratory deposition characteristics based on particle geometry. This work highlights the advantages of adopting proven microfabrication techniques in achieving unprecedented control over particle geometric design for drug delivery.

Figure 1

Schematic illustration of the PRINT process. (a) Features on a hard silicon master template are replicated with high fidelity (b) to obtain a soft, polymeric mold with micro- and nanocavities that can then be (c) filled with relevant particle matrix and (d) extracted out of the mold and onto a harvest array for (e) particle collection and purification.

Figure 2

SEM micrographs of diverse PRINT aerosols. (a) BSA/Lactose 200 × 200 nm cylinders; (b) IgG/Lactose10 μm pollen; (c) 30 K PLGA 3 μm cylinders; (d) itraconazole 1.5 μm torus; (e) itraconazole 3 μm torus; (f) itraconazole 6 μm torus; (g) zanamivir 1.5 μm torus; (h) DNAse 1.5 μm torus; (i) siRNA 1.5 μm torus.

Figure 3

Aerodynamic characterization of PRINT aerosols. (a) SEM micrographs and aerodynamic performance of 1.5 μm, 3 μm, and 6 μm particles by APS. PRINT affords precise control over particle geometric size and aerodynamic size. (b) SEMs and aerodynamic distributions of jet-milled itraconazole aerosols compared to 1 μm PRINT cylinder particles made out of itraconazole. PRINT-itraconazole particles result in a narrower size distribution and higher available respirable fraction.

Figure 4

Favorable properties of PRINT aerosols for dry powder pharmaceutical use. (a, b) Comparison of 1.5 μm torus PRINT-zanamivir particles against the marketed product Relenza (active pharmaceutical ingredient zanamivir) using an NGI. (b) PS: preseparator; RSD: relative standard deviation. (c) Whole lung deposition by gamma scintigraphy in canine shows increased whole-lung deposition of 1.5 μm (right, 1.3 μm MMAD) torus aerosols versus 6.0 μm (left, 4.6 μm MMAD) torus aerosols.