Development of microneedles for propolis delivery: The effect on the production of reactive oxygen species and in vitro immunostimulating activity

Microneedles (MN) constitute a technological strategy to break the skin barrier in a minimally invasive way. MN can enhance the availability of drugs in the deeper layers of the skin. Propolis (PROP) is a gum-resin produced by Apis mellifera L. bees and displays several properties like antioxidant and immunostimulating actions. PROP extracts are utilized on therapeutics, exhibiting disadvantages like unpleasant and strong taste, aromatic odor, high solvent concentration, problems of bioavailability. These result in difficulties for administration and pose challenges to the patient compliance to the therapeutics, showing the need for the development of improved systems for PROP delivery. Therefore, the aim of this work was to prepare and optimize MN composed of poloxamer 407, polyvinyl alcohol and polyvinylpyrrolidone, for controlled delivery of ethanolic or glycolic extract of PROP, and evaluate their biological properties. The optimization of MN formulations involved utilizing various PROP extracts and polymers, followed by the characterization of their hardness and in vitro drug release. Moreover, the formulations were evaluated for ex vivo skin permeation and in vitro generation of reactive oxygen species. As a result, MN containing PROP ethanolic extract displayed better structuring than those containing glycolic extract of PROP. The selected formulations presented quicker disintegration, which enabled the confirmation of the skin permeation of PROP extract in the epidermis and dermis. The optimized MN could produce reactive oxygen species and stimulate neutrophils and macrophages in vitro. In addition, they can be used as platforms for local administration of PROP, in order to enable the increased skin drug delivery, and provide antioxidant and immunostimulating action. Further studies are needed to evaluate these properties in vivo.