A Nasal Hydrogel Combining Metformin and Curcumin for Potential Nose-to-Brain Therapy in Neurodegenerative Disorders

Neurodegenerative disorders such as Alzheimer's and Parkinson's disease remain a significant therapeutic challenge due to the restrictive nature of the blood-brain barrier (BBB) and the limited efficacy of current pharmacological treatments. Intranasal administration has emerged as a promising noninvasive strategy that enables direct drug delivery to the brain by bypassing the BBB. This study aimed to design and optimize a dual-drug nasal hydrogel containing metformin hydrochloride, a hydrophilic AMP-activated protein kinase activator, and curcumin, a lipophilic antioxidant and anti-amyloid agent, and to provide synergistic neuroprotection. The formulation was prepared using carbopol as the gel matrix and characterized in terms of physicochemical stability, drug content uniformity, rheology, in vitro release, and excipient compatibility. A Box-Behnken design was used to systematically evaluate the effects of carbopol, glycerin, and curcumin concentrations on critical quality attributes. The optimized hydrogel exhibited acceptable pH, viscosity suitable for nasal administration, and sustained biphasic drug release with a cumulative 6-h release of approximately 85% for metformin and 39% for curcumin according to the Higuchi drug release model (R² > 0.98). Collectively, these results highlight the feasibility of an integrative intranasal hydrogel platform to overcome the bioavailability challenges of both agents. The proposed system offers a patient-friendly, noninvasive approach for potential nose-to-brain therapy in neurodegenerative disorders and warrants further preclinical and in vivo investigation.