Effetti delle ciclodestrine modificate sulle proprietà carrier di nanoparticelle di chitosano preparate per gelazione ionotropica

Chitosan nanoparticles (CH-NPs) show good properties for drug administration through different routes. The ionotropic gelation process is a way of CH-NPs preparation that takes place entirely in aqueous solution. NPs are obtained as a consequence of the electrostatic interaction between a polyanion and cationic polymer. The drugs must have adequate solubility in water to be encapsulated and permit the formation of NPs containing high percentages of active ingredient during gelation. High lipophilic drugs can not be encapsulated into NPs prepared by a process entirely performed in aqueous solution because of their low water solubility. Although, a very water soluble molecule can be encapsulated but is quickly released from the system. In this research work, CH-NPs were produced by ionotropic gelation induced by sulfobutylether-β-cyclodextrin (CH/SBE-β-CYD-NPs). In the specific, it has been evaluated the effect of the macrocycle on the physico-chemical and morphological properties, carrying capacity and in vitro release properties of CH-NPs, considering that drugs with different hydrophilicity and therapeutic activity interact differently with the macrocycle and with the polymeric matrix. Levofloxacin hydrochloride (LVF) and Idebenone (IDE) have been chosen as drug models. LVF is an antibacterial drug approved for the treatment of ocular infections. However, high doses of LVF are required due to the low ocular bioavailability which causes bacterial resistance. IDE is an antioxidant drug that acts in the central nervous system, but its poor water solubility limits its clinical application. We characterized CH/SBE-β-CYD-NPs loading LVF in terms of encapsulation parameters, morphology, and sizes, in comparison to CH-NPs produced without the macrocycle. Nuclear magnetic resonance and UV-VIS spectroscopy studies have demonstrated that SBE-β-CYD is able to complex LVF and influence encapsulation parameters of CH-NPs, producing high encapsulation efficiency and LVF loading. The NPs were homogenous in size, with an hydrodynamic radius between 80 and 170 nm and a positive zeta potential (ζ) values. This surface property promotes the interaction of CH-NPs with the negatively charged ocular tissue, increasing their residence time and consequently, LVF efficacy. In vitro antibacterial activity against Gram-positive and Gram-negative bacteria showed an activity of CH/SBE-β-CYD-NPs loading LVF doubled compared to the free drug. SBE-β-CYD is able to include within its cavity IDE, forming a 1:1 complex, maintaining its ability to interact with CH to obtain NPs. We demonstrated that the drug can be successfully encapsulated within the CH-NPs based on SBE-β-CYD. Overloaded CH/SBE-β-CYD-NPs were obtained by adding an excess of drug as soluble inclusion complex with hydroxypropyl-β-cyclodextrin (HP-β-CYD). In this way, we obtained CH-NPs suitable in sizes and homogeneity for intranasal administration. They showed excellent technological parameters above all in terms of loading of IDE and prolonged release over time. CH/SBE-β-CYD-NPs loading IDE showed antioxidant activity higher than free drug on human glioblastoma cells (U373). Good permeation of IDE through excited bovine nasal mucosa was observed for all systems compared to free drug, improving its clinic efficacy in the treatment of diseases of the central nervous system. Although further in vitro and in vivo studies are necessary, these excellent results suggest that CH-NPs based on CYDs developed in this research could be a promising carrier for the targeting of LVF in the treatment of ocular bacterial infections, and of IDE for nose-brain targeting in Alzheimer's disorders.