Polymeric Matrix-Based Transdermal Drug Delivery Systems for Brexpiprazole: A Review of Formulation Strategies, Release Kinetics, Skin Permeation, and Stability

Brexpiprazole is a second-generation atypical antipsychotic and serotonin–dopamine activity modulator approved for schizophrenia and as adjunctive therapy in major depressive disorder. Although the molecule is well absorbed after oral dosing, its clinical use in chronic psychiatric disease is constrained by the well-documented problem of poor long-term medication adherence, by fluctuations in plasma concentration associated with once-daily oral regimens, and by the practical difficulties of sustained tablet-taking in this patient population. Its very long elimination half-life makes it an attractive candidate for a delivery system that maintains steady systemic exposure with minimal user intervention. The present review critically examines the rationale, scientific principles, formulation strategies, and evaluation framework for a polymeric matrix-based transdermal drug delivery system (TDDS) of brexpiprazole. The structure and barrier properties of the skin, the principal pathways of percutaneous transport, and the quantitative descriptors of permeation are discussed in relation to the physicochemical profile of the drug. Matrix-type patch architecture, film-forming polymers, plasticizers, and chemical permeation enhancers are reviewed alongside solubility-enhancement strategies appropriate to a lipophilic, poorly water-soluble molecule. The role of the solvent-casting technique and its critical process parameters, the in-vitro release and ex-vivo permeation testing framework, mathematical modelling of release kinetics, and the application of Design of Experiments (DoE) and Quality-by-Design (QbD) principles for systematic optimization are described. Stability considerations under International Council for Harmonisation (ICH) conditions and local skin tolerability are also addressed. The review concludes that a rationally engineered polymeric matrix patch, optimized through DoE and supported by mechanistic release–permeation correlation and ICH-compliant stability data, represents a scientifically sound route toward improving adherence and therapeutic consistency in long-term brexpiprazole therapy.