Formulation of Nanomicelles to Improve the Solubility and the Oral Absorption of Silymarin

Abstract

Two novel nanomicellar formulations were developed to improve the poor aqueous solubility and the oral absorption of silymarin. Polymeric nanomicelles made of Soluplus and mixed nanomicelles combining Soluplus with d-α-tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS) were prepared using the thin film method. Physicochemical parameters were investigated, in particular the average diameter, the homogeneity (expressed as polydispersity index), the zeta potential, the morphology, the encapsulation efficiency, the drug loading, the critical micellar concentration and the cloud point. The sizes of ~60 nm, the narrow size distribution (polydispersity index ≤0.1) and the encapsulation efficiency >92% indicated the high affinity between silymarin and the core of the nanomicelles. Solubility studies demonstrated that the solubility of silymarin increased by ~6-fold when loaded into nanomicelles. Furthermore, the physical and chemical parameters of SLM-loaded formulations stored at room temperature and in refrigerated conditions (4 °C) were monitored over three months. In vitro stability and release studies in media miming the physiological conditions were also performed. In addition, both formulations did not alter the antioxidant properties of silymarin as evidenced by the 1,1-Diphenyl-2-picrylhydrazyl radical (DPPH) assay. The potential of the nanomicelles to increase the intestinal absorption of silymarin was firstly investigated by the parallel artificial membrane permeability assay. Subsequently, transport studies employing Caco-2 cell line demonstrated that mixed nanomicelles statistically enhanced the permeability of silymarin compared to polymeric nanomicelles and unformulated extract. Finally, the uptake studies indicated that both nanomicellar formulations entered into Caco-2 cells via energy-dependent mechanisms.

Comparison of Chitosan Nanoparticles and Soluplus Micelles to Optimize the Bioactivity of Posidonia oceanica Extract on Human Neuroblastoma Cell Migration

“…In particular, POE had no cytotoxic effects on cell viability as well as cells showed no signs of toxicity in the presence of NP-POE. As for PM-POE, cell viability value was about 80% due to the very low cytotoxicity ascribed to PM as just reported [21] ( Figure S1, in Supplementary Material). Therefore, considering that SH-SY5Y cell viability was maintained over 80% up to 24 h of POE, NP-POE, and PM-POE treatments, cell migration was evaluated by the wound healing assay and compared to their vehicles.…”

“…Furthermore, while in an aqueous solution the extract remains completely undissolved, the micellar solution is able to solubilize about 2 mg/mL of POE and it becomes colored in yellow, proof of a change in solubility of the extract. As reported in literature, the nanomicelles have achieved good results in improving the solubility of extracts, such as the silymarin phytocomplex [21]. For the first time in this work Soluplus nanomicelles have been used to increase the solubility of a phytocomplex of marine origin.…”

“…The dissolution medium was 0.01 M PBS (pH 7.4, NaCl 0.138 M, KCl 0.0027 M). At different time points, 1 mL of the release medium was taken and replaced with the same volume of PBS to maintain the sink condition [21,37]. The experiment was conducted for 24 h and 72 h for NP-POE and MP-POE, respectively.…”

“…For example, it has been seen that the use of Soluplus micelles significantly improves the solubility of silymarin, extracted from the fruits of Silybum marianum (L.) Gaertn. (Asteraceae), increasing its solubility and its intestinal permeability [21]. Other applications described the use of Soluplus for doxorubicin delivery in the treatment of resistant tumors [20] or to increase acyclovir permeability across the cornea and sclera [22] or even to enhance oral bioavailability and hypouricemic activity of scopoletin [23].…”

“…The authors developed mixed polymeric micelles of Soluplus/TPGS-Vit. E for the formulation of silymarin [21].…”