Developing Advanced Formulation Strategies for Efficient Topical and Transdermal Cannabinoid Delivery: Leveraging Hydrogel Systems and Ultradeformable Nano Vesicles

Abstract

As natural and herbal treatments gain popularity in modern medicine, cannabinoids such as ∆-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have emerged as promising therapeutic agents. Derived from the cannabis plant, cannabinoids have been used medicinally for thousands of years, though their applications have fluctuated due to societal, regulatory, and scientific factors. Modern analytical advancements have shed light on their complex chemistry and biochemistry, enabling the exploration of their therapeutic potential.

Cannabinoids show promise in treating conditions such as cancers, neurological diseases, chronic pain, and dermatological disorders. Despite their potential, challenges persist due to their poor pharmacokinetics, including low aqueous solubility, limited absorption, and extensive first-pass metabolism, which compromise their bioavailability. Conventional delivery routes, such as oral and pulmonary administration, exhibit limitations like delayed onset and unpredictable absorption. This necessitates the investigation of alternative delivery systems.

This thesis addresses these challenges by developing innovative transdermal delivery (TD) systems for cannabinoids, aiming to enhance bioavailability and provide sustained drug release. Cannabinoids' high lipophilicity hinders skin permeation, a challenge overcome in this study through optimised solvent systems and permeation enhancers. A computationally optimised hydrogel was developed, exhibiting uniform distribution of cannabinoids and efficient drug content throughout the formulation. This hydrogel, evaluated using a Franz diffusion cell study, demonstrated a flux of 496.98 ± 2.79 µg/cm² and a lag time under 2 hours, highlighting its potential for managing local pain, neurological disorders, and dermatological conditions.

For systemic delivery, nanotechnology was employed to create ultradeformable vesicular (UDV) systems optimised for TD of CBD and THC. By incorporating bilayer softening agents into the rigid liposome structure, five UDV types were developed and characterised. These systems exhibited small vesicle sizes (61.76–107.98 nm), low PDI (<0.25), and high encapsulation efficiency (78.94–92.66%). Stability studies confirmed their robustness for at least three months under standard conditions. In vitro permeation tests demonstrated flux enhancement ratios between 47.40 and 93.24 compared to traditional liposomes. Drug release studies showed an initial burst release followed by sustained delivery over 24 hours, maintaining therapeutic levels for extended durations. These formulations hold potential for treating conditions like epilepsy, multiple sclerosis, chronic pain, and inflammatory skin diseases.

A notable innovation introduced in this thesis is the "Transethocamphosome," a novel UDV combining camphor's permeation-enhancing properties with optimised bilayer design. This nanocarrier demonstrated superior physicochemical characteristics and permeation profiles, suggesting potential applications for other lipophilic drugs.

This thesis emphasises the application of Quality by Design (QbD) principles in developing cannabinoid delivery systems, ensuring rigorous optimisation and regulatory readiness. In addition to addressing significant clinical challenges, the study provides a comprehensive reference for future research, offering detailed methodologies and comparative analyses of UDV systems. By advancing cannabinoid delivery strategies, this work contributes to improving therapeutic outcomes for a wide range of conditions.