Chitosan (CS) is a linear polysaccharide obtained by the deacetylation of chitin, which, after cellulose, is the second biopolymer most abundant in nature, being the primary component of the exoskeleton of crustaceans and insects. Since joining the pharmaceutical field, in the early 1990s, CS attracted great interest, which has constantly increased over the years, due to its several beneficial and favorable features, including large availability, biocompatibility, biodegradability, non-toxicity, simplicity of chemical modifications, mucoadhesion and permeation enhancer power, joined to its capability of forming films, hydrogels and micro- and nanoparticles. Moreover, its cationic character, which renders it unique among biodegradable polymers, is responsible for the ability of CS to strongly interact with different types of molecules and for its intrinsic antimicrobial, anti-inflammatory and hemostatic activities. However, its pH-dependent solubility and susceptibility to ions presence may represent serious drawbacks and require suitable strategies to be overcome. Presently, CS and its derivatives are widely investigated for a great variety of pharmaceutical applications, particularly in drug delivery. Among the alternative routes to overcome the problems related to the classic oral drug administration, the mucosal route is becoming the favorite non-invasive delivery pathway. This review aims to provide an updated overview of the applications of CS and its derivatives in novel formulations intended for different methods of mucosal drug delivery.

Topical administration of celecoxib proved to be an effective mean of preventing skin cancer development and improving anticancer drugs effectiveness in skin tumors treatment. The aim of this study was the development of an effective topical formulation of celecoxib, able to promote drug skin delivery, providing its in depth penetration through the skin layers. Three kinds of vesicular formulations have been investigated as drug carriers: liposomes containing a surfactant, or transfersomes and ethosomes, containing suitable edge activators. Firstly, the effect of membrane composition variations on the system performance has been evaluated for each vesicle type. Selected formulations were characterized for particle size, polydispersity index and encapsulation efficiency. The best formulations were subjected to ex vivo permeation studies through excised human skin. All vesicular formulations markedly (p < 0.001) improved the drug amount penetrated into the skin with respect to an aqueous suspension, from 2.0 to 6.5, up to 9.0 folds for liposomes, transfersomes and ethosomes, respectively. In particular, ethosomes containing Tween 20 as edge activator not only showed the best vesicle dimensions and homogeneity, and the highest encapsulation efficacy (54.4%), but also enabled the highest increase in drug penetration through the skin, probably due to the simultaneous presence in their composition of ethanol and Tween 20, both acting as permeation enhancers. Therefore, among the various vesicular formulations examined in the study, Tween 20-ethosomes can be considered the most promising one as carrier for topical celecoxib applications aimed to prevent skin cancer development and increase the anticancer drugs effectiveness against skin tumors.

The hydrochlorothiazide (HCT) low solubility and permeability give rise to limited and variable bioavailability; its low stability makes it difficult to develop stable aqueous liquid formulations; its low dose makes the achievement of a homogeneous drug distribution very difficult. Thus, the aim of this study was to investigate the effectiveness of a strategy based on the development of nanostructured lipid carriers (NLC) as an innovative oral pediatric formulation of HCT with improved therapeutic efficacy. The performance of various synthetic and natural liquid lipids was examined and two different preparation methods were employed, i.e. homogenization-ultrasonication (HU) and microemulsion (ME), in order to evaluate their influence on the NLC properties in terms of size, polydispersity index, ζ-potential, entrapment efficiency, gastric stability, and drug release properties. Precirol®ATO5 was used as solid lipid and Tween^®80 and Pluronic^®F68 as surfactants, formerly selected in a previous study focused on the development of HCT-solid lipid nanoparticles (SLNs). The presence of Pluronic^®F68 did not allow ME formation. On the contrary, using Tween^®80, the ME method enabled a higher entrapment efficiency than the HU. Regardless of the preparation method, NLCs exhibited great entrapment efficiency values clearly higher than previous SLNs. Moreover, NLC-ME formulations provided a prolonged release, which lasted for 6 h. In particular, NLC-ME containing Tween^®20 as Co-Surfactant showed the best performances, giving rise to a complete drug release, never achieved with previous SLN formulations, despite their successful results. In vivo studies on rats confirmed these results, displaying their best diuretic profile. Moreover, all HCT-loaded NLC formulations showed higher stability than the corresponding SLNs.

The aim of this study was the optimization of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in terms of physicochemical and biopharmaceutical properties, to develop effective and stable aqueous liquid formulations of hydrochlorothiazide, suitable for paediatric therapy, overcoming its low-solubility and poor-stability problems. Based on solubility studies, Precirol^® ATO5 and Transcutol^® HP were used as solid and liquid lipids, respectively. The effect of different surfactants, also in different combinations and at different amounts, on particle size, homogeneity and surface-charge of nanoparticles was carefully investigated. The best formulations were selected for drug loading, and evaluated also for entrapment efficiency and release behaviour. For both SLN and NLC series, the use of Gelucire^® 44/14 as surfactant rather than PluronicF68 or Tween^® 80 yielded a marked particle size reduction (95–75 nm compared to around 600–400 nm), and an improvement in entrapment efficiency and drug release rate. NLC showed a better performance than SLN, reaching about 90% entrapped drug (vs. 80%) and more than 90% drug released after 300 min (vs. about 65%). All selected formulations showed good physical stability during 6-month storage at 4 °C, but a higher loss of encapsulated drug was found for SLNs (15%) than for NLCs (<5%). Moreover, all selected formulations revealed the absence of any cytotoxic effect, as assessed by a cell-viability test on Caco-2 cells and are able to pass the intestinal epithelium as suggested by Caco-2 uptake experiments.