• cyclodextrins
• hydroxypropilated
• mucoadhesive excipients
• posphorylated
• solubility
• sulphobutylated
• thiolated cyclodextrins

NOVEL SYNTHESIS OF PERTHIOLATED CYCLODEXTRINS TO INCREASE THE ORAL BIOAVAILABILITY OF DEXAMETHASONE
Drug administration via the oral route is the most commonly used medication administration route, since is economically convenient and well accepted by patients. The primary site of drug absorption is usually the small intestine, and the bioavailability of the A.P. is influenced by the amount of drug absorbed across the intestinal epithelium: this is coated with a mucus gel layer, that acts as a barrier to the passage of orally administered drugs. Once the A.P. has successfully crossed the mucus gel layer and reached the intestinal epithelium, it can be absorbed into the bloodstream and reach the action site.
Delivery systems constituted by excipients able to adhere to the mucus gel layer could, therefore, be an interesting solution to increase bioavailability, by counteracting the GI transit that physiologically carries the drug away from the absorption site.
Among many, this thesis focused on thiolated excipients, which mechanism of mucoadhesion is represented by the formation of disulfide bonds between the delivery system itself and the cysteine rich domains of the mucins contained in the mucus layer, via simple oxidation or thiol/disulfide exchange reactions.
This thesis also focused on increasing the bioavailability of lipophilic, poorly soluble drugs at the absorption site by keeping them into solution with the use of cyclodextrins, cyclic oligosaccharides, characterized by a peculiar truncated cone shape. Composed by (α-1,4)-linked α-D-glucopyranose units, their three-dimensional shape forces the hydroxyl groups on the outside of the cone, giving it a polar nature, whereas the skeletal carbon and ethereal oxygens face the inside of the cone, making it hydrophobic. This duality in its chemical nature, makes the cyclodextrin the perfect host for lipophilic drugs: these inclusion complexes keep the AP in solution and carry it to the absorption site. They also increase its stability, protecting it from hydrolysis, oxidation, heat and light.
The bioavailability increasing solutions involved in this thesis are, ultimately, two: delivery systems that lead to a higher drug solubility and a higher mucoadhesive ability, the conjunction of which, therefore, is thiolated cyclodextrins.
On top of that, this thesis focused on two critical issues concerning thiolated CDs:
1. The amount of thiol groups - Needless to say, the more thiol groups are present on a cyclodextrin, the more mucoadhesive the cyclodextrin will be, being able to form cross links with the mucus. A novel synthesis for per-thiolated cyclodextrins was carried out, with the aim of substituting with thiol groups all of the hydroxyl groups available.
2. The solubility - Natural cyclodextrins have a poor water solubility, because of the intramolecular hydrogen bonds that easily form given these molecules’ structures; in fact, it has been extensively proven that substitutions at the 2, 3, and 6 hydroxyl sites, even with just methyl groups, increase solubility. Then, of course, if the nature of the substitution is also hydrophilic, that would greatly benefit the complex’s solubility in the aqueous medium. Moreover, β-Cyclodextrins are especially difficult in terms of solubility because of their rigid structure, but are often preferred in drug formulations because they benefit from the perfect cavity size for complexation with a majority of active principles. That’s why, in this work, three β-cyclodextrins with polar substitutions were chosen for the purpose of per-thiolation: hydroxypropylated, phosphated and sulfobutylated β-Cyclodextrins
Indeed, the first step of the experimental part of this work, was the synthesis, which consisted in the thiolation of hydroxypropilated, sulphobutylated and posphorylated β-cyclodextrins. The thiolation was carried out with an innovative synthesis method that, involving thiolating agent phosphorous pentasulfide, should lead to per-thiolated cyclodextrins, meaning that all of the -OH groups available are substituted with -SH groups, and, therefore, obtaining highly mucoadhesive products.
The purification occurred via dialysis, followed by chemical studies of thiol content quantification, via Ellman’s and Disulfide tests.
Then, cytotoxicity studies and haemolysis studies were carried out to assess the effect of the obtained products on human cells, as well as rheology and cell permeation studies to establish if the products actually exhibit mucoadhesive properties.
The last part of this work involved complexation studies with model drug dexamethasone, to determine the ability of both unmodified and thiolated cyclodextrins to solubilize the otherwise poorly soluble DMS.
From this screening, HP-β-CD-SH displayed the highest degree of thiolation and led to interesting results in all the performed assays, seeming to be the most promising of the CDs analysed; it could, therefore, constitute an interesting new way of improving oral bioavailability of DMS, both by increasing its solubility and prolonging its residence time on the intestinal mucus gel layer.