A Comprehensive Review on the Advanced Transdermal Drug Delivery Systems for Donepezil and Memantine

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioural disturbances, representing the most common cause of dementia worldwide. Current pharmacotherapy relies primarily on two cornerstone agents: Donepezil hydrochloride, a selective acetylcholinesterase inhibitor, and Memantine hydrochloride, a noncompetitive NMDA receptor antagonist. These drugs provide symptomatic relief by enhancing cholinergic neurotransmission and modulating glutamatergic excitotoxicity, respectively. However, oral administration of Donepezil and Memantine is associated with significant limitations, including gastrointestinal side effects, hepatic first pass metabolism, poor patient compliance, and fluctuating plasma concentrations. These drawbacks compromise therapeutic efficacy and quality of life, particularly in elderly patients with swallowing difficulties and polypharmacy challenges. Transdermal drug delivery systems (TDDS) have emerged as a promising alternative to overcome these limitations. By delivering drugs across the skin into systemic circulation, TDDS bypasses the gastrointestinal tract and liver, thereby enhancing bioavailability and reducing systemic toxicity. Moreover, transdermal patches offer controlled and sustained release, maintaining steady state plasma concentrations and minimizing peaks and troughs associated with oral dosing. Patient centered benefits include non-invasive administration, simplified dosing schedules, improved adherence, and reduced caregiver burden. Advanced TDDS technologies—such as bilayered patches, nanostructured lipid carriers (NLCs), microneedles, iontophoresis, and permeation enhancers—further expand the potential of transdermal delivery. These innovations improve drug loading, enhance skin penetration, and prolong stability, making them particularly suitable for dual drug therapy. Bilayer patches, for instance, can incorporate Donepezil in an immediate release layer and Memantine in a sustained release matrix, achieving complementary pharmacological effects and superior therapeutic outcomes compared to monotherapy. Published studies between 2020 and 2026 have demonstrated the feasibility of TDDS for Donepezil and Memantine. Optimization using polymeric films and design of experiment approaches has yielded flexible patches with sustained release beyond 24 hours. Iontophoresis has been shown to enhance permeation flux, particularly for hydrophilic Memantine, while microneedle arrays provide painless, minimally invasive delivery suitable for elderly patients. Nanocarrier systems, including NLCs and ethosomes, have improved entrapment efficiency and controlled release, overcoming physicochemical barriers. Analytical validation methods, such as HPLC quantification, ensure reproducibility and regulatory compliance, critical for clinical translation. Collectively, these findings highlight the transformative potential of TDDS in Alzheimer’s pharmacotherapy. In conclusion, advanced transdermal drug delivery systems for Donepezil and Memantine represent a significant advancement in the management of Alzheimer’s disease. By addressing the limitations of oral therapy, TDDS offers sustained release, improved bioavailability, reduced side effects, and enhanced patient compliance. Future directions should focus on integrating biosensor enabled smart patches, personalized dosing strategies, and large-scale clinical trials to establish long term safety and efficacy. The convergence of pharmacological innovation and patient centered care positions TDDS as a promising platform to improve therapeutic outcomes and quality of life for millions of Alzheimer’s patients worldwide.