Nanostructured Zinc Oxide as drug carrier for pharmaceutical applications

In this PhD thesis nanostructured ZnO (NsZnO) was studied to develop innovative drug carriers for future dermatological applications. In particular the novelty of the research was the use of a green organic-solvent free route both for the production of the NsZnO and for the loading of of the Active Pharmaceutical Ingredients (API), by means of supercritical carbon dioxide (scCO2) technology. The first chapter deals with a general overview of the ZnO properties and applications in the biomedical field, offering a detailed description of the current state-of-art related to the use of ZnO nanostructures as drug delivery systems. Particular attention is focused on the existing studies of NsZnO in skin applications. The second chapter presents the scCO2 technology as an innovative and greener approach to perform the drug loading of a delivery system. The fundamental properties of the scCO2 are described in order to understand the mechanism of scCO2-mediated drug impregnation, since it is the drug loading method selected in this PhD research project. The third chapter illustrates the development of a green organic-solvent-free route to prepare ZnO-based drug carriers. Two NsZnO materials with different morphologies were synthesized using wet organic-solvent-free processes and they were characterized to elucidate their morphological and physico-chemical properties. In this investigation, Clotrimazole (CTZ) and Ibuprofen (IBU) were selected as the drug models. For the first time, scCO2-mediated drug impregnation was used in the loading of NsZnO materials. The fourth chapter describes the study of a third ZnO nanostructure, which consists in mesoporous ZnO particles. A simple synthesis was carried out, based on the on the hydrolysis of a zinc salt in basic alcoholic solutions. A material with a significant high surface area and a morphology suitable for the biomedical applications was obtained. Also in this case the scCO2 technology was studied as a greener alternative technology to carry out the drug loading of the mesoporous NsZnO. CTZ was selected as the drug model. The fifth chapter is focused on the study of the three developed NsZnOs from a biological point of view, in order to highlight their intrinsic biological properties. Particularly, their antimicrobial activity against different microbial strains were investigated, and the results were correlated with their physico-chemical parameters. Also the in vitro Zn2+ release profiles from the NsZnO matrices were evaluated, simulating a release to the skin. The sixth chapter presents the research work carried out at the Lancaster University (UK). The main aim was the study of innovative materials for wound healing. Particularly, this section describes the development of biocompatible in-situ-forming composite hydrogels, based on natural polysaccharides, where one of the previously synthetized NsZnO was used as inorganic nanofiller. The crosslinking mechanism, structure, morphology and swelling behavior of the in situ forming composite hydrogels were studied. Moreover, in vitro release of Zn2+from the formulations was simulated on synthetic skin and the cytotoxicity of the different component was carried out on a HaCat cell line. The seventh chapter describes the main results of a parallel research project carried out within my PhD studies. In particular, the proof of concept of an innovative dermatological formulation containing ordered mesoporous silica (OMS) was successfully demonstrated. The possibility to obtain a drug reservoir system, combining API-loaded OMS with a saturated solution of the same API was investigated obtaining outstanding results from both a physical-chemical and biological point of view. The innovative formulation resulted in a sustained release of the drug lasting two times with respect to the commercial gel, which opens the possibility of reducing the daily number of administrations during a real treatment.