EVALUATION OF PHARMACEUTICAL AND COSMETIC USE OF EXCIPIENTS OBTAINED FROM CITRUS PROCESSING WASTE PRODUCTS
Depletion of natural resources and pollution are pushing society towards the development of models based on sustainability and recycling. In recent years, the use of food industry waste as new materials in pharmaceuticals and cosmetics has attracted increasing interest. In this circular economy perspective, bergamot peel waste is an established source of high-value components such as essential oils, flavonoids, pectin, and ascorbic acid. After the extraction of such phytochemicals, the remaining biomasses can be further used to recover residual lipid traces that have not been investigated so far. This doctoral thesis aimed to investigate whether bergamot lipid components (BLCs) remaining in the bergamot discarded biomass could be a functional excipient for the preparation of dosage forms for pharmaceutical or cosmetic purposes. Keeping in mind this aim, a suitable extraction method was developed and the composition of the obtained BLCs extract was determined by using Gas Chromatography with Mass Selection Detector (GC/MS) and ATR-FTIR spectroscopy. The raw extract was predominantly composed of long and medium-chain fatty acids with 70 % saturated and 30 % unsaturated acids. ATR-FTIR spectroscopy suggested that the extract appeared to be primarily composed of waxes and, to a lesser extent, free fatty acids. Since waxes are among the most used components—alongside triglycerides—in the preparation of solid lipid nanoparticles (SLNs), the possible application of BLCs as main components of SLNs was investigated. However, SLNs have limitations such as low drug encapsulation efficiency and poor long-term stability, often due to lipid polymorphic transitions. Therefore, in addition to formulating SLNs using only BLCs, the production of nanostructured lipid carriers (NLCs) by incorporating a liquid lipid, which can prevent the crystallization of primary lipid, was also investigated. The most promising formulations were finally evaluated for delivering solid or liquid drug through the skin and pre-gastric mucosae. For what concerns transdermal drug delivery, these nanosystems were found to be effective skin penetration enhancer due to their ability to induce a conformational change in stratum corneum lipids, shifting them from an ordered configuration to a liquid-like organization upon penetration of BLCs. The hypothesis of perturbation of the stratum corneum lipid network was further demonstrated by a second set of in vitro permeation studies performed by the co-administration of placebo BLCs nanosystems added to ibuprofen solutions or gels. The co-administration did not lead to significant differences compared to drug-loaded nanosystems but highlighted a significant increase in drug skin penetration compared to the corresponding dosage forms (solution and gel). Finally, the lack of interaction with keratins, as confirmed by the ATR spectra, suggested that the perturbation of the human stratum corneum occurred in a reversible manner, ensuring the BLCs safety. To definitively confirm that the mechanism of action of BLCs was exclusively based on the perturbation of the packing of the stratum corneum, the performance of BLCs nanosystems loaded with curcumin was also tested after application on another stratified epithelium, namely the oesophagus, using liposomes as references. As expected, the penetration of porcine oesophageal mucosa occurred be less efficient than the liposomal formulations. Besides clarifying the skin penetration effect of BLCs, the results also elucidated other technological aspects of BLCs related to the formulation of lipid nanosystems. Firstly, monodispersed nanoparticles can be easily obtained at relatively low temperatures (60-70°C) by a melting and emulsification method assisted by ultrasounds without the use of stabilizers, which are necessarily required in the formulation of SLNs and NLCs prepared with other excipients. Secondly, the peculiar composition of BLCs led to a characteristic lipid-shell structure which was able to accommodate large amounts of drug, avoiding drug leakage phenomena over time. Finally, the data also proved that BLCs can be used in the formulation of nanoemulsions capable of carrying large quantities of liquid drugs. Indeed, BLCs proved to be an optimal stabilizer of these colloidal systems even when the drug/BLCs ratio was 6/1, as in the case of perfluorodecalin. In conclusion, BLCs appear to be a promising chemical skin penetration enhancer which can also be advantageously used in the formulation of lipid nanosystems to be applied on the skin.
circular economy, transdermal delivery, skin, esophagu, skin penetration enhancer, solid lipid nanoparticle, nanostructured lipid carrier, nanoemulsion, liposome, lipid based nanosystems, Settore CHEM-08/A - Tecnologia, socioeconomia e normativa dei medicinali e dei prodotti per il benessere e per la salute
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