Design and DoE-Based Optimization of Hybrid Nano-in-Nanofiber Systems for Sustained Delivery of Metformin and Sitagliptin

Abstract

Conventional type 2 diabetes therapies (e.g., metformin, sitagliptin) often suffer from short half-lives, frequent dosing, and side effects. To address this, we developed a hybrid “nano-in-nanofiber” system: metformin encapsulated in solid lipid nanoparticles (SLNs) and sitagliptin in niosomes, both embedded within electrospun polymeric nanofibers. A statistical Design of Experiments (DoE) approach (factorial design and response surface methodology) was used to optimize key formulation variables (e.g. polymer ratio, nanoparticle loading) for minimal particle size and maximal drug entrapment. Optimized SLNs (~195 nm) and niosomes (~150 nm) showed narrow size distributions and high entrapment efficiencies. The hybrid nanofiber mats (fiber diameter ~500 nm) retained discrete nanoparticulate reservoirs (confirmed by SEM/TEM). In vitro release studies demonstrated sustained biphasic release: an initial moderate release followed by extended slow release (much slower than plain fibers or free drug), as shown in Fig.1. The DoE-guided optimization significantly reduced the initial burst and extended the release duration, potentially enabling multi-day glycemic control. This systematic DoE-driven development illustrates the advantages of combining polymeric fibers with nano-carriers to create multifunctional drug delivery platforms.