After three years of doctoral thesis, Annalisa Rosso is pleased to inform you that her thesis defense, entitled
“Hybrid nanosystems for intestinal delivery”
will take place on Wednesday 16 December at 9:30 am.
The defense will be fully video-conferenced.
Oral delivery of drugs and biologics has challenged the development of hybrid delivery devices that combine nanoparticles and polymeric systems. Such combination allows to merge the technological advantages of the two formulations and to improve their pharmaceutical performance which is usually limited by multifaceted biological challenges.
The aim of the present work was the development of hybrid polymeric-lipid systems based on nanoemulsions (NE) loaded into a chitosan sponges and supersaturable self-microemulsifying drug delivery systems (S-SMEDDS). Both systems were designed for improving intestinal residence time following oral administration and to increase local or systemic drug absorption.
In the first part of this thesis, mucopenetrating NE have been designed and optimized by mean of an experimental design. Stable NE showing a droplet size of 100 nm and a neutral surface charge were obtained. NE were efficiently dried using spray-drying and freeze-drying overcoming major challenges related with the production of dry powders from oil based systems. Then, an original structural characterization of NE, with an in-depth focus on the NE shell crystalline and fluid nature was performed via X-ray diffraction, differential scanning calorimetry (DSC) and a novel polarity-sensitive fluorophore. NE proved to be non-toxic on Caco-2 cells at concentration higher than 1 mg/mL, while a time- and concentration-dependent inhibition of cell viability was observed on HCT 116 cells being the threshold of toxicity at 313 μg·mL1 after 24 h. The NEs mucopenetrating potential was confirmed by the absence of surface affinity and thermodynamic interactions with mucins, together with the rapid diffusion in a preformed mucins network. The natural polymer chitosan was used as mucoadhesive macrosystem to load mucopenetrating NE and prepare nanocomposite sponges by freeze-drying. The sponge matrix allowed to sustainably release NE in simulated biorelevant fluids (FaSSIF-V2) showing 28% release in 2 h followed by a plateau at 50% until 72 h. Moreover, in vivo intestinal residence time was enhanced for sponges compared to NE alone when orally administered to mice.
As a second part of this work, SMEDDS intended for the solubility and bioavailability enhancement of a hydrophobic anticancer model benzoimidazole drug were formulated and optimized. The hydroxypropyl cellulose (HPC) polymer was added as precipitation inhibitor to create supersaturable SMEDDS (S-SMEDDS). S-SMEDDS improved drug loading and system stability in simulated intestinal fluids compared to SMEDDS. Systems enhanced epithelial permeability in intestinal Caco-2 cell monolayers via a transient and reversible opening of tight junctions. Moreover, plasmatic drug concentrations in mice after oral gavage indicated that S-SMEDDS provided sustained drug absorption and slower elimination rate compared to free drug dispersion in HPC, thanks to their ability in maintaining the drug in a supersaturated state over time.
Overall, this thesis provided an extensive investigation on hybrid formulation strategies aimed at overcoming the biological hurdles for intestinal delivery. The combination of nanosystems with additional delivery approaches proved to be a winning strategy for a complete control over oral administration in view of both local and systemic treatment.