Nanocochleates for Oral Delivery of Antidiabetic Therapeutics: Formulation Strategies, Mechanistic Basis, Characterization, Bioavailability and Translational Challenges

Diabetes mellitus is a chronic metabolic disorder requiring prolonged pharmacological intervention, while the effectiveness of treatment is frequently influenced by bioavailability, dosing frequency, adverse effects and patient adherence. Oral delivery is particularly attractive because of its convenience and potential to improve treatment acceptance; however, the gastrointestinal tract presents substantial physicochemical, enzymatic and epithelial barriers to the absorption of poorly soluble drugs and macromolecular therapeutics. Nanocochleates are non-vesicular, multilamellar lipid-based carriers formed primarily through the interaction of negatively charged phospholipids with multivalent cations. Their compact, highly organized architecture distinguishes them from conventional liposomes and provides opportunities for improving drug protection, controlled release and biological performance. This review critically examines the application of nanocochleates to oral antidiabetic drug delivery, with emphasis on their structural basis, lipid and cation composition, preparation approaches, drug-encapsulation mechanisms, characterization requirements, gastrointestinal behavior and pharmacokinetic implications. Particular attention is given to published evidence involving resveratrol, insulin, glipizide and metformin, together with broader evidence supporting cochleate-based delivery of bioactive molecules. Current studies demonstrate promising improvements in drug stability, controlled release and selected pharmacokinetic parameters; however, the evidence remains predominantly preclinical and is characterized by considerable heterogeneity in formulation composition, preparation methodology, analytical characterization and experimental models. Important translational barriers include reproducible large-scale manufacture, batch-to-batch control, long-term physical stability, gastrointestinal fate, safety evaluation, regulatory characterization and demonstration of clinically meaningful benefits. Future development should therefore move beyond particle-size optimization alone toward quality-by-design approaches integrating critical material attributes, critical process parameters, biorelevant dissolution, intestinal transport studies, pharmacokinetic–pharmacodynamic relationships and standardized long-term safety assessment. Nanocochleates represent a promising but still investigational platform for oral antidiabetic delivery, and systematic validation is required before their potential can be translated into clinically useful products.