Nanostructured lipid carriers for oral delivery of silymarin: improving its absorption and in vivo efficacy in type 2 diabetes and metabolic syndrome model

Silymarin (SLM) is a mixture of flavonolignans extracted from the fruit of Silybum marianum L. Gaertn. which has been used for decades as a hepatoprotector. Silymarin has recently been proposed to be beneficial in type 2 diabetic patients. Constituents of SLM are poorly water-soluble and low permeable compounds, with consequently limited oral bioavailability. This study aimed to investigate the possibility of delivery of SLM via nanostructured lipid carriers (NLCs) to overcome these issues and for preparation of an oral dosage form. NLCs were prepared through an emulsion/evaporation/solidifying method. Cetyl palmitate:Lauroglycol 90 was selected as the lipid mixture and Brij S20 as surfactant. NLCs were chemically and physically characterized. Encapsulation efficiency was more than 92%. The storage stability of the NLC suspension was also investigated and the freeze-drying process was taken into consideration. After assessing the stability of the formulation in a simulated gastrointestinal environment, the release of SLM was monitored in different pH conditions. In vitro experiments with artificial membranes (PAMPA) and Caco-2 cells revealed that the NLCs enhanced the permeation of SLM. Active processes are involved in the internalization of NLCs, as evidenced by cellular uptake studies. After preliminary toxicological studies, the formulation was studied in vivo in a streptozotocin (STZ)-induced diabetic mouse model in the presence of metabolic syndrome. The formulation was also compared to an NLC containing stearic acid:Capryol 90, to evaluate the effect of the lipid matrix on the in vivo performance of nanocarriers. Finally, hepatic histopathological analyses were also conducted. Both SLM-loaded NLCs exhibited in vivo a significant down-regulation of blood glucose and triglyceride levels better than free SLM, with a liver-protective effect. Furthermore, both formulations showed a significant anti-hyperalgesic effect on STZ-induced neuropathy.