Seyfoddin, AliNagaraj, Anushree2026-05-042026-05-042026http://hdl.handle.net/10292/21017The resurgence of interest in plant-derived therapeutics has positioned cannabinoids, particularly Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), as promising pharmacological agents with demonstrated analgesic, anti-inflammatory, antiemetic, and neuroprotective effects. However, their clinical translation remains hindered by low aqueous solubility, extensive hepatic first-pass metabolism, and poor oral bioavailability (<10–20%). Conventional oral and oromucosal dosage forms, including oils, capsules, and sprays such as Sativex, often yield variable absorption and unpredictable pharmacokinetics, leading to inconsistent therapeutic responses and unwanted psychoactive effects. These limitations underscore the need for alternative delivery systems capable of bypassing hepatic metabolism, enhancing cannabinoid absorption, and ensuring controlled drug release. This thesis aimed to develop and optimize buccal cannabinoid delivery systems, including thermoresponsive mucoadhesive in-situ gels, ion-activated in-situ gels, and extrusion-based 3D bioprinted mucoadhesive films to address the abovementioned shortcomings. Buccal delivery offers a non-invasive and patient-friendly route that enables direct absorption into the systemic circulation, allowing for rapid onset of action and improved bioavailability. Two distinct in-situ gelling mechanisms were employed in the development of cannabinoid formulations, with the gelling polymers combined with either hydroxypropyl methylcellulose (HPMC) or Carbopol 934 to produce mucoadhesive in-situ gels. The first approach involved the formulation of thermoresponsive in-situ gels using Poloxamer 407, optimized through factorial design to achieve ideal sol–gel transition temperatures, appropriate viscosity, and mucoadhesive strength. These formulations exhibited reversible sol–gel behaviour, transitioning from a free-flowing liquid at room temperature to a cohesive semi-solid gel at 37°C. The second formulation platform focused on ion-activated in-situ gels, utilizing gellan gum, κ-carrageenan, and a novel κ/ι-carrageenan blend that gelled upon exposure to salivary cations. The κ/ι-carrageenan system formed a synergistic polymeric network balancing rigidity and flexibility, resulting in enhanced gel strength, elasticity, and mucoadhesion compared to single-polymer systems. Both thermoresponsive and ion-activated gels demonstrated prolonged mucosal residence, with Carbopol-based formulations exhibiting superior mechanical strength, mucoadhesion, and physicochemical properties compared to HPMC-based gels. The systems displayed biphasic release profiles, characterised by an initial lag phase (~15–30 minutes) followed by sustained cannabinoid release over 4 hours. To further improve stability and storage properties, ion-induced in-situ gels containing Carbopol were developed into freeze-dried formulations that could be readily rehydrated before administration These lyophilized systems retained their gelling capacity and preserved over 94% of cannabinoid content after six months, offering improved storage stability and eliminating the need for strict cold-chain conditions. The third approach involved using 3D bioprinting to fabricate extrusion-based mucoadhesive films composed of HPMC and Carbopol matrices, enabling precise control over geometry, thickness, and cannabinoid loading. HPMC-based films demonstrated excellent mechanical integrity, uniform drug distribution, and sustained cannabinoid release over 2 hours. This work demonstrated the feasibility of employing bioprinting techniques for producing individualized cannabinoid dosage forms with enhanced pharmacokinetic predictability. This work also introduced a novel formulation strategy integrating multiple terpenes as permeation enhancers with hydroxypropyl-β-cyclodextrin inclusion complexes of cannabinoids within the developed buccal systems, providing a complementary mechanism to enhance both solubility and buccal absorption. This thesis provided a comprehensive foundation for buccal delivery of cannabinoids by integrating formulation optimization, physicochemical and rheological characterization, ex vivo permeation, and stability evaluation. The findings underscore the potential of mucoadhesive buccal systems to overcome the pharmacokinetic limitations of oral cannabinoids, reduce required doses, enhance patient compliance, and support the clinical translation of cannabinoid therapies for conditions such as chemotherapy-induced nausea, appetite stimulation, chronic pain, and multiple sclerosis.enThesisOpenAccess