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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.

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.

(1) Background: Andrographolide (AG) is a natural compound effective for the treatment of inflammation-mediated neurodegenerative disorders. The aim of this investigation was the preparation of liposomes to enhance the penetration into the brain of AG, by modifying the surface of the liposomes by adding Tween 80 (LPs-AG) alone or in combination with Didecyldimethylammonium bromide (DDAB) (CLPs-AG). (2) Methods: LPs-AG and CLPs-AG were physically and chemically characterized. The ability of liposomes to increase the permeability of AG was evaluated by artificial membranes (PAMPA) and hCMEC/D3 cells. (3) Results: Based on obtained results in terms of size, homogeneity, ζ-potential and EE%. both liposomes are suitable for parenteral administration. The systems showed excellent stability during a month of storage as suspensions or freeze-dried products. Glucose resulted the best cryoprotectant agent. PAMPA and hCMEC/D3 transport studies revealed that LPs-AG and CLPs-AG increased the permeability of AG, about an order of magnitude, compared to free AG without alterations in cell viability. The caveolae-mediated endocytosis resulted the main mechanism of up-take for both formulations. The presence of positive charge increased the cellular internalization of nanoparticles. (4) Conclusions: This study shows that developed liposomes might be ideal candidates for brain delivery of AG.

(1) Background: Andrographolide (AN), the main diterpenoid constituent of Andrographis paniculata, has a wide spectrum of biological activities. The aim of this study was the development of nanocochleates (NCs) loaded with AN and based on phosphatidylserine (PS) or phosphatidylcholine (PC), cholesterol and calcium ions in order to overcome AN low water solubility, its instability under alkaline conditions and its rapid metabolism in the intestine. (2) Methods: The AN-loaded NCs (AN–NCs) were physically and chemically characterised. The in vitro gastrointestinal stability and biocompatibility of AN–NCs in J77A.1 macrophage and 3T3 fibroblasts cell lines were also investigated. Finally, the uptake of nanocarriers in macrophage cells was studied. (3) Results: AN–NCs obtained from PC nanoliposomes were suitable nanocarriers in terms of size and homogeneity. They had an extraordinary stability after lyophilisation without the use of lyoprotectants and after storage at room temperature. The encapsulation efficiency was 71%, while approximately 95% of AN was released in PBS after 24 h, with kinetics according to the Hixson–Crowell model. The in vitro gastrointestinal stability and safety of NCs, both in macrophages and 3T3 fibroblasts, were also assessed. Additionally, NCs had extraordinary uptake properties in macrophages. (4) Conclusions: NCs developed in this study could be suitable for both AN oral and parental administration, amplifying its therapeutic value.

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The present study explores the potential of nanoemulsion, a lipid drug delivery system, to improve solubility and oral absorption of extract. The optimized formulation contained 40 mg/mL of commercial extract (4 % w/w) and it was composed of 2.5 g labrasol (20 %) as the oil phase, 1.5 g cremophor EL as the surfactant, and 1 g labrafil as the cosurfactant (mixture surfactant/cosurfactant, 20 %).The system was characterized by dynamic light scattering, transmission electron microscopy, and HPLC-DAD analyses in order to evaluate size, homogeneity, morphology, and encapsulation efficiency. Physical and chemical stabilities were assessed during 40 days at 4 °C and 3 months at 25 °C. Stability in simulated gastric fluid followed by simulated intestinal conditions was also considered. permeation studies were performed to determine the suitability of the prepared nanoemulsion for oral delivery. Different models such as the parallel artificial membrane permeability assay and Caco-2 cell lines were applied.The nanoemulsion showed a good solubilizing effect of the extract, with a pronounced action also on its permeability, in respect to a saturated aqueous solution. The Caco-2 test confirmed the parallel artificial membrane permeability assay results and they revealed the suitability of the prepared nanoemulsion for oral delivery.

Background: Silymarin is the extract from seeds of Silybum marianum L. Gaertn. and it has been used for decades as hepatoprotectant. Recently, it has been proposed to be beneficial in type 2 diabetes patients. However, silymarin is a poorly water soluble drug with limited oral bioavailability. In this study, nanostructured lipid carriers were proposed to enhance its solubility and intestinal absorption. Methods: Nanostructured lipid carriers were made of Stearic acid:Capryol 90 as lipid mixtures and Brij S20 as surfactant. Formulations were physically and chemically characterized. Stability and in vitro release studies were also assessed. In vitro permeability and Caco-2 cellular uptake mechanism were investigated. Results: Obtained results were based on size, homogeneity, ζ-potential and EE%. Nanostructured lipid carriers could be orally administered. No degradation phenomena were observed in simulated gastrointestinal fluids. Storage stability of suspensions and lyophilized products was also tested. Glucose was selected as best cryoprotectant agent. About 60% of silymarin was released in 24 h in phosphate buffered saline. In vitro parallel artificial membrane permeability assay experiments revealed that the nanocarrier enhanced the permeation of Silymarin. Caco-2 study performed with fluorescent nanoparticles revealed the ability of carrier to enhance the permeation of a lipophilic probe. Cellular uptake studies indicated that active process is involved in the internalization of the formulation. Conclusions: The optimized nanostructured lipid carriers showed excellent chemical and physical stability and enhanced the absorption of silymarin.