Optimizing glycerosome formulations via an orthogonal experimental design to enhance transdermal triptolide delivery

Triptolide exerts strong anti-inflammatory and immunomodulatory effects; however, its oral administration might be associated with side effects. Transdermal administration can improve the safety of triptolide. In this study, glycerosomes were prepared as the transdermal vehicle to enhance the transdermal delivery of triptolide. With entrapment efficiency and drug loading as dependent variables, the glycerosome formulation was optimized using an orthogonal experimental design. Phospholipid-to-cholesterol and phospholipid-to-triptolide mass ratios of 30:1 and 5:1, respectively and a glycerol concentration of 20 % (v/v) were used in the optimization. The glycerosomes prepared with the optimized formulation showed good stability, with an average particle size of 153.10 ± 2.69 nm, a zeta potential of –45.73 ± 0.60 mV and an entrapment greater than 75 %. Glycerosomes significantly increased the transdermal delivery of triptolide compared to conventional liposomes. As efficient carriers for the transdermal delivery of drugs, glycerosomes can potentially be used as an alternative to oral triptolide administration

Measurement and correlation study of silymarin solubility in supercritical carbon dioxide with and without a cosolvent using semi-empirical models and back-propagation artificial neural networks

The solubility data of compounds in supercritical fluids and the correlation between the experimental solubility data and predicted solubility data are crucial to the development of supercritical technologies. In the present work, the solubility data of silymarin (SM) in both pure supercritical carbon dioxide (SCCO2) and SCCO2 with added cosolvent was measured at temperatures ranging from 308 to 338 K and pressures from 8 to 22 MPa. The experimental data were fit with three semi-empirical density-based models (Chrastil, Bartle and Mendez-Santiago and Teja models) and a back-propagation artificial neural networks (BPANN) model. Interaction parameters for the models were obtained and the percentage of average absolute relative deviation (AARD%) in each calculation was determined. The correlation results were in good agreement with the experimental data. A comparison among the four models revealed that the experimental solubility data were more fit with the BPANN model with AARDs ranging from 1.14% to 2.15% for silymarin in pure SCCO2 and with added cosolvent. The results provide fundamental data for designing the extraction of SM or the preparation of its particle using SCCO2 techniques

Immunosuppressive dead cell as lung-targeting vehicle and cytokine absorption material for cytokine storm attenuation of pneumonia

Effectively controlling cytokine storm is important to reduce the mortality of severe pneumonia. In this work a bio-functional dead cell was engineered by one-time quick shock of live immune cells in liquid nitrogen, and the obtained immunosuppressive dead cell could server as both lung-targeting vehicle and cytokine absorption material. After loading the anti-inflammatory drugs of dexamethasone (DEX) and baicalin (BAI), the drug-loaded dead cell (DEX&BAI/Dead cell) could first passively target to the lung after intravenous administration and quickly release the drugs under high shearing stress of pulmonary capillaries, realizing drug enrichment in the lung. Then, the immunosuppressive dead cell acted as the camouflage of normal immune cells with various cytokine receptors exposing on their surface, to “capture” the cytokines and further reduce the state of inflammation. With above formulation design, a synergic anti-inflammatory effect between drugs and carrier could be achieved. In a lipopolysaccharide-induced pneumonia mice model, this system could calm down the cytokine storm with high efficacy and elongate the survival of mice

Hyaluronic Acid Coating Reduces the Leakage of Melittin Encapsulated in Liposomes and Increases Targeted Delivery to Melanoma Cells

Melittin is a promising antitumor substance; however, it is a nonspecific cytolytic peptide, which limits its clinical application. In this study, melittin liposomes (Mel-Lip) and hyaluronic acid (HA)-modified Mel-Lip (Mel-HA-Lip) were designed to reduce the toxicity and increase the anti-tumor effects of melittin. The optimal preparation procedure was evaluated using a uniform design based on the single factor method, and the concentration of HA was determined based on the cellular uptake of coumarin 6 labeled HA-Lip. Liposomes and HA-modified liposomes were evaluated in vitro by assessing cytotoxicity, cellular uptake, and release behavior. Liposomes prepared in the optimum formulation improved stability, with a particle size of 132.7 ± 1.55 nm, zeta potential of −11.5 ± 1.51 mV, entrapment efficiency of 86.25 ± 1.28%, and drug-loading efficiency of 3.91 ± 0.49%. Cellular uptake tests revealed that the uptake of nanoparticles significantly increased with HA modification, suggesting that HA modification enhanced the internalization of liposomes within cells, which was consistent with the results of the cytotoxicity analysis. Furthermore, in vitro release experiments showed that Mel-HA-Lip possessed a stronger sustained-release effect compared with Mel-Lip. The results of this experiment provide insight into the potential tumor-targeting effects of melittin

Correction: Zhao, J., et al. Podophyllotoxin-Loaded Nanostructured Lipid Carriers for Skin Targeting: In Vitro and In Vivo Studies. Molecules 2016, 21, 1549

The authors wish to make the following correction to their paper [1]

Diethylene glycol monoethyl ether-mediated nanostructured lipid carriers enhance trans-ferulic acid delivery by Caco-2 cells superior to solid lipid nanoparticles

This work aimed to compare the performance of trans-ferulic acid-encapsulated nanostructured lipid carriers (NLCs) and solid lipid nanoparticles (SLNs) for transport by Caco-2 cells. The NLC particles (diameter: 102.6 nm) composed of Compritol® 888 ATO, ethyl oleate, Cremophor® EL, and Transcutol® P were larger than the SLNs (diameter: 86.0 nm) formed without liquid lipid (ethyl oleate), and the former had a higher encapsulation efficiency for trans-ferulic acid (p < 0.05). In vitro cultured Caco-2 cell transport was used to simulate intestinal absorption, and the cellular uptake of NLCs was higher than that of SLNs (p < 0.05). Compared to SLNs, NLCs greatly enhanced trans-ferulic acid permeation through the MillicellTM membrane (p < 0.05). This work confirms that NLCs have better properties than SLNs in terms of increasing drug transport by Caco-2 cells. This helps to comprehend the approach by which NLC-mediated oral bioavailability of trans-ferulic acid is better than that mediated by SLNs, as shown in our previous report

Improved dissolution and bioavailability of silymarin delivered by a solid dispersion prepared using supercritical fluids

The objective of this study was to improve the dissolution and bioavailability of silymarin (SM). Solid dispersions (SDs) were prepared using solution-enhanced dispersion by supercritical fluids (SEDS) and evaluated in vitro and in vivo, compared with pure SM powder. The particle sizes, stability, and contents of residual solvent of the prepared SM-SDs with SEDS and solvent evaporation (SE) were investigated. Four polymer matrix materials were evaluated for the preparation of SM-SD-SEDS, and the hydrophilic polymer, polyvinyl pyrrolidone K17, was selected with a ratio of 1:5 between SM and the polymer. Physicochemical analyses using X-ray diffraction and differential scanning calorimetry indicated that SM was dispersed in SD in an amorphous state. The optimized SM-SD-SEDS showed no loss of SM after storage for 6 months and negligible residual solvent (ethanol) was detected using gas chromatography. In vitro drug release was increased from the SM-SD-SEDS, as compared with pure SM powder or SM-SD-SE. In vivo, the area under the rat plasma SM concentration-time curve and the maximum plasma SM concentration were 2.4-fold and 1.9-fold higher, respectively, after oral administration of SM-SD-SEDS as compared with an aqueous SM suspension. These results illustrated the potential of using SEDS to prepare SM-SD, further improving the biopharmaceutical properties of this compound

Podophyllotoxin-Loaded Nanostructured Lipid Carriers for Skin Targeting: In Vitro and In Vivo Studies

Nanostructured lipid carriers (NLC) exhibit high skin targeting efficiency and good safety. They are promising vehicles for topical drug delivery. This study aims to increase the skin distribution of podophyllotoxin (POD) by incorporating it into NLCs. Two kinds of POD-loaded NLCs (POD-NLCs)—POD-NLCformulation 1 and POD-NLCformulation 2—were prepared and characterized. Their skin targeting efficiencies were compared by conducting in vitro and in vivo experiments. Obviously smaller mean particle size was observed for POD-NLCformulation 1 (106 nm) than POD-NLCformulation 2 (219 nm), whereas relatively low POD loadings (less than 0.5%) were observed for both POD-NLCformulation 1 (0.33%) and POD-NLCformulation 2 (0.49%). Significantly higher in vitro and in vivo rat skin deposit amounts of POD (p ˂ 0.01) were detected after the topical application of POD-NLCformulation 1 compared to POD-NLCformulation 2. To visualize the skin distribution behavior of hydrophobic active pharmaceutical ingredients (APIs) when NLCs were used as carriers, POD was replaced with Nile red (NR—a hydrophobic fluorescent probe), and the distribution behavior of NR-NLCformulation 1 and NR-NLCformulation 2 in rat skin in vivo was observed using confocal laser scanning microscopy (CLSM). Higher fluorescent intensity was observed in rat skin after the topical application of NR-NLCformulation 1 than NR-NLCformulation 2, suggesting that higher skin targeting efficiency might be obtained when NLCs with smaller mean particle size were used as carriers for hydrophobic APIs. This result was in accordance with those of skin distribution evaluation experiments of POD-NLCs. Skin irritation property of POD-NLCformulation 1 was investigated and no irritation was observed in intact or damaged rabbit skin, suggesting it is safe for topical use. Our results validated the safety of NLCs when applied topically. More importantly, mean particle size might be an important parameter for formulation optimization when NLCs are used as carriers for hydrophobic APIs for topical application, considering that their loading is relatively low

D-α-tocopherol polyethylene glycol succinate and Poloxamer 188 modified liposomal chrysin hydrogel for enhanced topical treatment of ultraviolet-induced skin photoaging damage

Chrysin (CHR) has a wide range of pharmacological and physiological activities and low toxicity, however, its clinical application is hampered by its insolubility in water, low intestinal absorption and reduced activity due to rapid carbonylation and metabolism of the hydroxyl groups at positions 5 and 7. Here, we describe a new preparation of CHR-loaded liposomal gel (CHR-Lip-Gel) with good physicochemical stability and efficient antiphotoaging properties. The CHR-loaded liposomes (CHR-Lip) was hybridized with D-α-tocopherol polyethylene glycol succinate and Poloxamer 188, and dispersed in sodium hyaluronate-formed hydrogel to obtain CHR-Lip-Gel. The resulting CHR-Lip in the hydrogel had a complete vesicle structure, with a particle size of 143.50 ± 8.20 nm. CHR-Lip-Gel significantly (p < 0.01) increased skin permeability and skin retention of chrysin compared with CHR aqueous dispersion (CHR group). Cellular uptake in human immortalized keratinocytes (HaCaT) revealed the superiority of the liposomal formulations over the free drug (p < 0.01). CHR-Lip-Gel markedly (p < 0.01) reduced the reactive oxygen species content and showed a dose dependency after UV irradiation on HaCaT cells in vitro. Additionally, both CHR-Lip-Gel and CHR-Lip groups decreased malondialdehyde and increased the contents of superoxide dismutase, hydroxyproline and glutathione peroxidase significantly (p < 0.05) in the UV-treated HaCaT cells in vitro compared with CHR group. Anti-photoaging studies in UV-injured rats showed that CHR-Lip-Gel observably increased the preventive and therapeutic effects compared with CHR-Lip, CHR, or epigallocatechin gallate. All the administration groups inhibited the expression of matrix metalloprotein-1 and promoted the expression of transforming growth factor-β1; however, only CHR-Lip-Gel and epigallocatechin gallate showed statistically significant differences (p < 0.01) in regulating both of these proteins in contrast with the model control group. This newly developed carrier effectively increased the skin permeation of chrysin, thereby significantly enhancing its efficacy. In summary, our study suggests that CHR-Lip-Gel is a superior anti-photoaging system