Dual phytoconstituent-loaded cubosomal gel for enhanced topical delivery: design, optimization by central composite design, in vitro and ex-vivo evaluation

Curcumin (CUR) and Quercetin (QUR) possess well-documented anti-inflammatory and antioxidant activities that make them promising candidates for the management of rheumatoid arthritis. However, their clinical application is limited by poor aqueous solubility, low bioavailability, and inadequate skin permeation. Therefore, Curcumin–Quercetin-loaded cubosomes were prepared to enhance topical delivery. The cubosomal formulation was developed using the top-down technique and optimized using Response Surface Methodology by applying Central Composite Design (CCD) to evaluate the influence of glycerol monooleate (25–50% w/v) and Poloxamer 407 (2.5–10% w/v) on vesicle size and entrapment efficiency. Following numerical optimization, the optimized cubosomes exhibited a vesicle size of 150.120 ± 2.18 nm, a polydispersity index (PDI) of 0.21 ± 0.03, zeta potential of −24.40 ± 1.25 mV, and entrapment efficiencies of 86.20 ± 1.35% and 90.10 ± 1.20% for Curcumin and Quercetin, respectively. The optimized cubosomes were characterized by FTIR, DSC, XRD, and transmission electron microscopy (TEM), which confirmed the successful formation of uniformly distributed spherical vesicles without any significant drug–excipient interaction. The optimized formulation demonstrated sustained drug release over 12 h, with cumulative releases of 93.37 ± 3.96% for Curcumin and 81.26 ± 3.62% for Quercetin. For convenient topical application, the optimized cubosomes were incorporated into a Carbopol 934 gel and evaluated for physicochemical properties, ex vivo skin permeation, and stability. The cumulative drug permeated from the cubosomal gel was approximately 81.36 ± 2.14% for curcumin and 77.92 ± 1.98% for quercetin, which was significantly higher (p < 0.05) than that of the conventional gel (∼39.74 ± 2.03%). The enhanced permeation observed with the cubosomal system (approx. 2.37-fold increase). Furthermore, the optimized cubosomal formulation remained physicochemically stable throughout three months of storage. These findings suggest that the Curcumin–Quercetin-loaded cubosomal gel represents a promising nanocarrier system for improving the topical delivery of phytoconstituents and may serve as an effective therapeutic approach for the management of rheumatoid arthritis.