Development of a Novel and Customizable Two-Solution Mixing Type Spray Nozzle for One-Step Preparation of Nanoparticle-Containing Microparticles

Abstract

Production of drug nanoparticles is an effective strategy to enhance solubility and oral absorption of water-insoluble drugs. The handling of drug nanoparticles has been an important issue in drug formulation because nanoparticles easily aggregate each other and redispersion of these particles is very difficult. In the present study, we developed a unique two-solution mixing type spray nozzle that can prepare drug nanoparticles in microparticles in one step without any common solvent and surfactant, and then, the prepared formulation were evaluated. Ethylcellulose (EC) and mannitol (MAN) were used as a model polymer of water-insoluble compound and a water-soluble carrier, respectively. We characterized the EC/MAN microparticles produced by the novel spray nozzle when customizing the nozzle parts to mix EC and MAN solution. Relatively smaller EC nanoparticles (<110 nm) in MAN microparticles (approximately 3 µm) were obtained by changing the customizable parts in the nozzle. In addition, the core of EC nanoparticles (<50 nm) was also observed by atomic force microscopy. We also found that the mixing time in the nozzle parts affected the size and the standard deviation of EC nanoparticles. These results suggest that the size of EC nanoparticles in MAN microparticles is controllable by using this unique nozzle. After all, we could prepare MAN microparticles containing EC nanoparticles in one step by using the novel nozzle. The drug/MAN microparticles formulation produced by the nozzle may be useful for the handling of drug nanoparticles.Key words two-solution mixing type nozzle; spray drier; composite particle; anti-solvent effect; one-step preparation Improvement of water-insoluble drugs has been an important issue as increasing the promising drug candidates. The use of nano-sized drugs is an effective strategy to enhance drug solubility.1-5) Several methods have been extensively employed to prepare smaller particles from large drug particles, such as the use of ball and jet mills, crystallization by evaporating the drug in an organic solvent, and preparation of emulsions and liposomes. Although these methods have advantages and disadvantages, the handling of nano-sized drug powders has been an important factor. Nanoparticles can easily aggregate with each other because of their great surface energy; hence, redispersion of these aggregates is very difficult and the effective properties derived from nanoparticles are lost. Therefore, technologies to preserve nanoparticles have been pursued.In a previous study, we developed a four-fluid nozzle spray dryer to produce microparticles containing nano-sized drug particles.6-11) This nozzle has two liquid and two gas passages that allow two compounds (e.g., a water-insoluble drug in organic solvent and a water-soluble carrier in aqueous solution) to be dissolved in separate solvents, thereby overcoming the problems of finding and using a common solvent. Although the detailed mechanism of the production of drug nanoparticles/water-soluble carrier microparticles by using the...

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