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The feasibility of preparing microparticles with high insulin loading suitable for needle-free ballistic drug delivery by spray-freeze-drying (SFD) was examined in this study. The aim was to manufacture dense, robust particles with a diameter of around 50 mm, a narrow size distribution and a high content of insulin. Atomization using ultrasound atomizers showed improved handling of small liquid quantities as well as narrower droplet size distributions over conventional two-fluid nozzle atomization. Insulin nanoparticles were produced by SFD from solutions with a low solid content (,10 mg ml 21 ) and subsequent ultra-turrax homogenization. To prepare particles for needle-free ballistic injection, the insulin nanoparticles were suspended in matrix formulations with a high excipient content (.300 mg ml 21) consisting of trehalose, mannitol, dextran (10 kDa) and dextran (150 kDa) (abbreviated to TMDD) in order to maximize particle robustness and density after SFD. With the increase in insulin content, the viscosity of the nanosuspensions increased. Liquid atomization was possible up to a maximum of 250 mg of nano-insulin suspended in a 1.0 g matrix. However, if a narrow size distribution with a good correlation between theoretical and measurable insulin content was desired, no more than 150 mg nano-insulin could be suspended per gram of matrix formulation. Particles were examined by laser light diffraction, scanning electron microscopy and tap density testing. Insulin stability was assessed using size exclusion chromatography (SEC), reverse phase chromatography and Fourier transform infrared (FTIR) spectroscopy. Densification of the particles could be achieved during primary drying if the product temperature (T prod ) exceeded the glass transition temperature of the freeze concentrate (T g 0 ) of 229.48C for TMDD (3 : 3 : 3 : 1) formulations. Particles showed a collapsed and wrinkled morphology owing to viscous flow of the freeze concentrate. With increasing insulin loading, the d (v, 0.5) of the SFD powders increased and particle size distributions got wider. Insulin showed a good stability during the particle formation process with a maximum decrease in insulin monomer of only 0.123 per cent after SFD. In accordance with the SEC data, FTIR analysis showed only a small increase in the intermolecular b-sheet of 0.4 per cent after SFD. The good physical stability of the polydisperse particles made them suitable for ballistic injection into tissue-mimicking agar hydrogels, showing a mean penetration depth of 251.3 + 114.7 mm.

Needle-free injection is a novel technique for transdermal drug and vaccine delivery, the efficacy of which depends on the number density and mean penetration depth of particles beneath the skin. To date, these parameters have been assessed optically, which is time-consuming and unsuitable for use in vivo. The present work describes the development of a scanning acoustic microscopy technique to map and size particle distributions following injection. Drug particles were modeled using a polydisperse distribution of polystyrene spheres, mean diameter 30.0 mum, and standard deviation 16.7 mum, injected into agar-based tissue-mimicking material, and later, as polydisperse stainless steel spheres, mean diameter 46.0 mum, and standard deviation 13.0 mum, injected both into agar and into porcine skin. A focused broadband immersion transducer (10-75 MHz), driven in pulse-echo mode, was scanned over the surface of the injected samples. Recorded echo signals were post-processed to deduce particle penetration depth (30-300 mum). Furthermore, post-injection size distribution of the spheres was calculated using a novel, automated spectral analysis technique. Experimental results were validated optically and found to predict penetration depth and particle size accurately. The availability of simultaneous particle penetration depth and particle size information makes it possible for the first time to optimize particle design for specific drug delivery applications.

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