Natural products have been used as a major source of drugs for millennia, and about half of the pharmaceuticals in use today are derived from natural products. However, their efficacy can be limited because of their low hydrophilicity and intrinsic dissolution rate(s), or physical/chemical instability. In addition, they can present scarce absorption, poor pharmacokinetics and bioavailability, scarce biodistribution, first-pass metabolism, trivial penetration and accumulation in the organs of the body, or low targeting efficacy. Novel nanoformulations based on drug delivery systems, namely nanoparticles, micelles, and vesicles, offer significant promise in overcoming these limitations. Nowadays, nanomedicine is crucial in developing appropriate therapeutic treatments of essential drugs, specifically antitumor and antiparasistic agents (i.e., Taxol, vincristine, camptothecin, doxorubicin, artemisinin) and other emerging molecules with pleiotropic functions (i.e., resveratrol, curcumin, salvianolic acid B, honokiol). Additionally, the number of nanoformulations developed with flavonoids, in particular rutin, quercetin, silymarin, and green tea catechins, is constantly increasing, and a significant number of publications have appeared in the last decade pertaining to nanoformulations based on extracts and essential oils. Most of these studies report very promising nanoformulations with sustained release and improved bioavailability at much lower doses than conventional preparations, and in many cases, also a better safety profile.

Natural products are fascinating molecules in drug discovery for their exciting structure variability and also for their interaction with various targets. Drugs multi-targeting effect represents a more realistic approach to develop successful medications for many diseases. However, besides a large number of successful in vitro and in vivo studies, most of the clinical trials fail. This is generally related to the scarce water solubility, low lipophilicity and inappropriate molecular size of natural compounds, which undergo structural instability in biological milieu, rapid clearance and high metabolic rate. Additionally, some molecules are destroyed in gastric juice or suffer to a massive pre-systemic metabolism in the liver, when administered orally, limiting their clinical use. A reduced bioavailability can also be linked to drug distribution/accumulation in non-targeted tissues and organs that increase the side effects lowering the therapeutic efficacy and patient compliance. Nanomedicine represents a favourable tool to increase bioavailability and activities of natural products. Generally, nanovectors provide a large surface area and can overcome anatomic barriers. Each nanovector has its own advantages, disadvantages, and characteristics. In this review, different nanocarriers made of compounds which are Generally Recognized As Safe (GRAS) for the delivery of natural products, marketed as food supplements and medicines are reported.

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.

The purpose of this study was to develop new formulation for an improved oral delivery of Vitex agnus-castus (VAC) extract. After the optimization and validation of analytical method for quali-quantitative characterization of extract, nanoemulsion (NE) was selected as lipid-based nanocarrier. The composition of extract-loaded NE resulted in triacetin as oil phase, labrasol as surfactant, cremophor EL as co-surfactant and water. NE contains until 60 mg/mL of extract. It was characterized by DLS and TEM analyses and its droplets appear dark with an average diameter of 11.82 ± 0.125 nm and a polydispersity index (PdI) of 0.117 ± 0.019. The aqueous solubility of the extract was improved about 10 times: the extract is completely soluble in the NE at the concentration of 60 mg/mL, while its solubility in water results less than 6 mg. The passive intestinal permeation was tested by using parallel artificial membrane permeation assay (PAMPA) and the permeation across Caco-2 cells after preliminary cytotoxicity studies were also evaluated. NE shows a good solubilizing effect of the constituents of the extract, compared with aqueous solution. The total amount of constituents permeated from NE to acceptor compartment is greater than that permeated from saturated aqueous solution. Caco-2 test confirmed PAMPA results and they revealed that NE was successful in increasing the permeation of VAC extract. This formulation could improve oral bioavailability of extract due to enhanced solubility and permeability of phytocomplex.