DoE-based Development of Transdermal Risedronate-laden Cubosomes: In Vitro Characterization, Drug Deposition, and In...

Risedronate, a bisphosphonate widely prescribed for osteoporosis, suffers from poor oral bioavailability and gastrointestinal adverse effects. To overcome these limitations, risedronate-laden cubosomes were developed for transdermal delivery. Cubosomes were fabricated using the top-down approach and optimized via Central Composite Design to assess the influence of glyceryl monooleate, Poloxamer 407, and the impact of sonication time on critical quality attributes. The optimized formulation exhibited a particle size of 61.45 ± 7.26 nm, PDI of 0.312 ± 0.04, zeta potential of -24.27 ± 2.27 mV, and entrapment efficiency of 90.65 ± 0.06%. In vitro release demonstrated 90.81 ± 3.17% drug release over 24 h. FTIR analysis confirmed the absence of drug-excipient interactions and successful drug encapsulation, while SAXS verified a cubic D-type (Pn3m) structure. Transmission electron microscopy further revealed uniform nano-sized cubic particles. The optimized cubosomes were incorporated into a Carbopol 934-based gel to facilitate transdermal application. Ex vivo permeation across rat skin showed a flux of 0.184 ± 0.005 mg/cm².h for the cubosomal gel, markedly higher than plain risedronate (0.0069 ± 0.002 mg/cm²/h). Skin irritation studies confirmed biocompatibility, and drug deposition studies revealed a 2-fold increase in skin retention with the cubosomal gel compared to plain gel. In vivo pharmacokinetic evaluation demonstrated a 1.39-fold enhancement in bioavailability relative to plain risedronate and a 3-fold improvement compared to marketed oral tablets. Collectively, these findings establish risedronate-laden cubosomal gel as a promising patient-friendly transdermal delivery system for long-term management of osteoporosis.