Design and optimization of cannabidiol nanoplatforms to unlock bioavailability and therapeutic potential across different administration pathways

The formulation of natural bioactive compounds represents a crucial step toward unlocking their full bioavailability and therapeutic potential. Many of these molecules, despite showing remarkable pharmacological activity in vitro, fail to achieve therapeutic concentrations in vivo due to their unfavorable biopharmaceutical profile. Among them, cannabidiol (CBD) was selected in this thesis as a model compound. CBD is a natural phytocannabinoid of high biomedical relevance, known for its anti-inflammatory, neuroprotective and analgesic effects. However, its poor water solubility, chemical instability and extensive first-pass metabolism lead to low and highly variable bioavailability, which significantly limits its clinical use. The overarching goal of this thesis was to design and develop nanotechnological delivery systems capable of overcoming these limitations and improving the pharmacokinetic and therapeutic performance of CBD. The research was structured around two main strategies. The first focused on enhancing CBD stability and solubilization within the gastrointestinal tract, with the aim of increasing its bioaccessibility and consequently its oral bioavailability. The second explored alternative routes of administration, such as the topical (ocular) and nose-to-brain pathways, which can bypass first-pass metabolism and offer more direct or localized delivery to target tissues. Within this framework, nanocarriers were selected as a versatile tool with which to address the intrinsic challenges of CBD. Their nanoscale dimensions, high surface area and tunable physicochemical properties make them ideal for keeping poorly soluble drugs in a molecularly dispersed state and protecting labile compounds from chemical or enzymatic degradation. They can also improve or maintain permeation across biological barriers by interacting with epithelial membranes and provide controlled or sustained release while maintaining biocompatibility and stability. In this thesis, polymeric micelles, self-microemulsifying drug delivery systems (SMEDDS), ultradeformable vesicles, cationic vesicles, and chitosan-coated vesicles were formulated, depending on the administration route and therapeutic goal. In some cases, these nanocarriers were incorporated into thermosensitive or thermosensitive-mucoadhesive hydrogels to enhance viscosity and adhesion to biological tissues, as well as to obtain semi-solid dosage forms suitable for nasal or ocular application. A Design of Experiments (DoE) approach was used to rationally guide some of the formulation development, identifying the optimal composition. Moreover, molecular dynamics (MD) simulations, performed using the Martini 3 coarse-grained force field, were applied to study the molecular interactions and dynamic behavior of vesicular system, providing insight into the relationship between formulation composition and structural properties such as bilayer fluidity, packing, and drug partitioning. The overall aim of this thesis was to establish a comprehensive framework for developing, optimizing and understanding the mechanisms of nanocarrier-based systems for CBD delivery. Through the integration of experimental formulation design, molecular-level simulation and biopharmaceutical evaluation across various administration routes, the study wanted to address the critical limitations of CBD and offer transferable strategies to enhance the delivery of other poorly soluble natural compounds with therapeutic potential.