Characterization of a Riboflavin Non-aqueous Nanosuspension Prepared by Bead Milling for Cutaneous Application

Abstract

The purpose of this study was to characterize the non-aqueous nanosuspension of a hydrophilic drug prepared by bead milling for cutaneous application. Riboflavin was used as the model hydrophilic drug. The non-aqueous nanosuspensions were prepared by grinding riboflavin with zirconia beads using eight nonaqueous bases. The mean particle size of riboflavin in the suspensions ranged from 206 to 469 nm, as determined by the dynamic light scattering method. Among the well-dispersed samples, riboflavin nanosuspension prepared in oleic acid was selected for evaluation of the drug permeability through rat skin. The cumulative amount and permeation rate of riboflavin from the nanosuspension were approximately three times higher than those for unprocessed riboflavin in oleic acid. Fluorescence imaging of the riboflavin nanosuspension suggested improved penetration of riboflavin into the stratum corneum. Furthermore, the addition of polysorbate 65 or polyglyceryl-6 polyricinoleate to the nanosuspension prepared in oleic acid markedly improved the riboflavin dispersibility. These results show that the preparation of a nanosuspension in a non-aqueous base by bead milling is one of the simple methods to improve the skin permeability of hydrophilic drugs.Key words bead milling; riboflavin; non-aqueous nanosuspension; oleic acid; stabilization; skin permeabilityThe skin permeability of hydrophilic drugs is generally known to be low, 1,2) due to the existence of lipophilic stratum corneum. It is difficult to obtain sufficient skin permeation to obtain a pharmacological effect without skin irritation, even with the use of chemical enhancers.3) Application of hydrophilic drugs by iontophoresis 4,5) and microneedle, 6,7) known as physical enhancers, allows dramatic improvement of the skin permeation, but these devices are expensive, and the safety of their long-term use still needs to be evaluated.In recent years, application of the preparations for cutaneous with the use of nanoparticles has been reported. Polymer nanoparticles composed of poly(DL-lactic-co-glycolic acid) 8,9) or chitosan 9,10) are considered to enhance the skin permeation of drugs by improving the polymer penetration into hair follicles. Solid-in-oil (S/O) nanosuspension is reported to enhance the skin permeation of hydrophilic drugs via penetration of the nanoparticles into the stratum corneum, 11) and penetration into the stratum corneum of latex-beads nanoparticles has been confirmed.12) In addition, solid-lipid nanoparticles and nanostructured lipid carriers enhance drug permeation by forming a film on the skin, improving the skin hydration. 13)However, the presence of nanoparticles in the receptor fluid was not shown in these reports.Nanosuspensions are bothersome to produce via as the process involves emulsification, drying/evaporation/centrifugation, and redispersion. Especially, preparation of uniformly dispersed nanosuspensions is difficult because of the agglomeration forces between nanoparticles after the drying/evaporation/centrifugation process. In ...

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