Nano-Structured Lipid Carriers for Co-Delivery of Linagliptin and Canagliflozin in Type 2 Diabetes: A Critical Review and Conceptual Framework

Type 2 diabetes mellitus (T2DM) affects 537 million adults worldwide, a figure projected to reach 783 million by 2045, necessitating novel combinatorial therapeutic strategies. Dipeptidyl peptidase-4 (DPP-4) and sodium-glucose cotransporter-2 (SGLT2) inhibitors act via complementary mechanisms, yet co-encapsulation of linagliptin and canagliflozin within nanostructured lipid carriers (NLCs) has not previously been reported. This review is structured to critically evaluate existing NLC formulation strategies using the Quality by Design (QbD) methodology, assess the pharmacological rationale for dual-agent delivery, and propose a biphasic dual-drug NLC framework addressing the marked disparity in elimination half-lives and lipophilicity between the two agents. Preclinical evidence for individually formulated NLCs demonstrates 3-5-fold bioavailability enhancement and sustained release extending to 96 hours; however, no experimental data exist for the proposed combination. Drug-drug-lipid interactions, long-term stability, and clinical translational feasibility are identified as critical uncertainties. A conceptual framework is presented, positioning this dualdrug NLC as a theoretically justified but experimentally unvalidated formulation strategy.