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This study evaluated the moisturizing effect of serine-loaded solid lipid nanoparticles (serine-SLN) and polysaccharide-rich reed (Phragmites communis) root extract (RRE) incorporated in hydrogel bases. The hydrogels with serine-SLN and/or RRE were carefully applied on the volar forearm of human volunteers. Their moisturizing efficacy was evaluated by monitoring conductance values using a skin surface hygrometer. The values of the area under the normalized conductance-time curve (AUCC) were developed and compared as a parameter for the water holding capacity of the skin. Hydrogels with serine-SLN did not significantly moisturize the skin, while hydrogel containing 0.25% RRE produced a significant increase in the moisture content of the skin. However, adding more than 0.25% of RRE into the hydrogel base decreased the moisturizing effect due to the marked reduction of viscosity. Significantly enhanced moisturizing effect was observed with the hydrogel containing 0.25% RRE and 3% serine-SLN, with AUCC increased 2.21 times compared to than blank hydrogel. The results imply that effective delivery of serine into the skin is possible using lipid-based nanocarriers and RRE, which could be a promising strategy to moisturize the skin effectively.

The ocean contains numerous marine organisms, including algae, animals, and plants, from which diverse marine polysaccharides with useful physicochemical and biological properties can be extracted. In particular, fucoidan, carrageenan, alginate, and chitosan have been extensively investigated in pharmaceutical and biomedical fields owing to their desirable characteristics, such as biocompatibility, biodegradability, and bioactivity. Various therapeutic efficacies of marine polysaccharides have been elucidated, including the inhibition of cancer, inflammation, and viral infection. The therapeutic activities of these polysaccharides have been demonstrated in various settings, from in vitro laboratory-scale experiments to clinical trials. In addition, marine polysaccharides have been exploited for tissue engineering, the immobilization of biomolecules, and stent coating. Their ability to detect and respond to external stimuli, such as pH, temperature, and electric fields, has enabled their use in the design of novel drug delivery systems. Thus, along with the promising characteristics of marine polysaccharides, this review will comprehensively detail their various therapeutic, biomedical, and miscellaneous applications.

Multicellular layers (MCL) of cancer cells is an in vitro 3-dimensional (3D) model that mimics avascular microregions of human solid tumors and has been shown to be useful in pharmacokinetic-pharmacodynamic studies of anticancer agents. We investigated whether Ki-67, which is widely used as a proliferation marker, can be used to evaluate changes in proliferative fractions following drug exposure in MCL of HT-29 human colorectal cancer cells. Ki-67 expression was monitored and compared between cancer cells cultured as monolayers or MCL. Drug distribution and Ki-67 expression were evaluated within MCL following exposure to doxorubicin and paclitaxel. Ki-67 expression was observed in the nuclei of proliferating cells in monolayers, tumor xenograft, and multicellular spheroids. In MCL, however, Ki-67 expression was detected in the membrane/cytoplasm as well as in the nucleus throughout MCL. Neither the location nor the level of expression changed following drug exposure, whereas drug-induced apoptosis increased. Our data show that membranous/cytoplasmic Ki-67 may not be valid as a marker for the proliferative activity of cells grown as MCL. Studies for non-nuclear localization and its mechanism in 3D in vitro models of other cell lines are warranted.

Poly(organophosphazene), a novel thermosensitive hydrogel, is an injectable drug delivery system (DDS) that transforms from sol to gel at body temperature. Paclitaxel (PTX) is a mitotic inhibitor used in the treatment of various solid tumors. Due to its poor solubility in water and efflux systems in the gastrointestinal tract, PTX is a good candidate for local DDS. Here, we evaluated the penetration kinetics of PTX released from the PTX-poly(organophosphazene) hydrogel mixture in multicellular layers (MCLs) of human cancer cells. We also investigated the tumor pharmacokinetics of PTX (60 mg/kg) when administered as an intratumoral injection using poly(organophosphazene) in mice with human tumor xenografts. When PTX was formulated at 0.6 % w/w into a 10 % w/w hydrogel, the in vitro and in vivo release were found to be 40 and 90 % of the dose, respectively, in a sustained manner over 4 weeks. Exposure of MCLs to PTX-hydrogel showed time-dependent drug penetration and accumulation. In mice, the hydrogel mass was well retained over 6 weeks, and the PTX concentration in the tumor tissue was maximal at 14 days, which rapidly decreased and coincided with rebound tumor growth after 14 days of suppression. These data indicate that PTX-hydrogel should be intratumorally injected every 14 days, or drug release duration should be prolonged in order to achieve a long-term antitumor effect. Overall, poly(organophosphazene) represents a novel thermosensitive DDS for intratumoral delivery of PTX, which can accommodate a large dose of the drug in addition to reducing its systemic exposure by restricting biodistribution to tumor tissue alone.

Sparassis crispa (SC) is an edible mushroom that harbours β-glucans reported to possess immunostimulatory and anticancer properties. The role of SC in regulating the functional activation of macrophages is yet to be fully elucidated. The objective of this study was to investigate the molecular mechanism underlying the immune-stimulatory function of Sparassis crispa soluble β-glucan (Sc-SG) on macrophages. According to this study, Sc-SG was able to stimulate nitric oxide (NO) production as well as enhance the expression of inducible NO synthase (iNOS) from macrophage-like RAW264.7 cells. NO production was strongly suppressed by mitogen-activated protein kinase (MAPK) inhibitors such as U0126, extracellular signal-regulated kinase, SB203580, a p38 inhibitor, and SP600125, a c-Jun N-terminal kinase inhibitor. Thus, indicating that Sc-SG-induced NO release is possibly mediated by MAPK. Sc-SG induced phosphorylation of extracellular signal-regulated kinase, p38, and JNK in a time-dependent manner. Moreover, Sc-SG triggered the phosphorylation and translocation of c-Jun and c-Fos, components of the transcription factor AP-1, activated by MAPK. The results of this study suggest that MAPK may be a major signaling enzyme that regulates the Sc-SG-mediated NO production in macrophages.

Saponins are valuable principles found in various herbal medicine with pharmaceutical, cosmetical and nutraceutical merits. In this study, we evaluated the protective role of saponin fraction (Cl-SF), prepared from Codonopsis lanceolata, an ethnopharmacologically famous plant in Korea, China and Japan, on water immersion stress-induced liver damage and radical generation. Cl-SF clearly decreased the up-regulated levels of serum glutamate-oxalacetate transaminase and glutamate-pyruvate-transaminase induced by water-immersed stress conditions. Furthermore, Cl-SF seemed to block the stress-induced radicals. Thus, Griess and DPPH assays revealed that Cl-SF significantly suppressed both radical generation in sodium nitroprusside-treated RAW264.7 cells and nitric oxide production in LPS-treated RAW264.7 cells. Therefore, these results suggest that Cl-SF may be considered as a promising stress-regulatory principle with radical scavenging actions.

Saponin components are known to be pharmaceutically, cosmetically and nutraceutically valuable principles found in various herbal medicine. In this study, we evaluated the inhibitory role of saponin fraction (SF), prepared from C. lanceolata, an ethnopharmacologically famous plant, on various inflammatory responses managed by monocytes, macrophages, lymphocytes and mast cells. SF clearly suppressed the release of nitric oxide (NO) and tumor necrosis factor (TNF)-alpha, but not prostaglandin E(2) (PGE(2)). While this fraction did not scavenge the reactivity of SNP-induced radicals in RAW264. 7 cells, it negatively modulated the phagocytic uptake of macrophages treated with FITC-dextran. Interestingly, SF completely diminished cell-cell adhesion events induced by both CD29 and CD43, but not cell-fibronectin adhesion. Concanavalin (Con) A [as well phytohemaglutinin A (PHA)]-induced proliferation of splenic lymphocytes as well as interferon (IFN)-gamma production were also clearly suppressed by SF treatment. Finally, SF also significantly blocked the degranulation process of mast cell line RBL-2H3 cell as assessed by DNP-BSA-induced beta-hexosaminidase activity. The anti-inflammatory activities of SF on NO production seemed to be due to inhibition of nuclear factor (NF)-kappaB activation signaling, since it blocked the phosphorylation of inhibitor of kappaB (IkappaB)alpha as well as inducible NO synthase (iNOS) expression. Therefore, these results suggest that SF may be considered as a promising herbal medicine with potent anti-inflammatory actions.

The aim of the present study was to evaluate the effects of two phospholipid permeation enhancers, lysophosphatidylcholine (LPC) and didecanoylphosphatidylcholine (DDPC), along with a fusidic acid derivative, sodium taurodihydrofusidate (STDHF) and ethanol (EtOH) on the buccal transport of propranolol hydrochloride (PPL) using an ex vivo buccal diffusion model. The permeation rate of [3H]PPL as measured by steady-state fluxes increased with increasing EtOH concentration. A significant flux enhancement (P0.05) was achieved by EtOH at 20 and 30 %v/v concentrations. At a 0.5 %w/v permeation enhancer concentration, the buccal permeation of [3H]PPL was significantly enhanced by all the enhancers studied (i.e., LPC, DDPC and STDHF) compared to the control (phosphate-buffered saline pH 7.4, PBS). LPC and DDPC displayed a greater degree of permeation enhancement compared with STDHF and EtOH-PBS mixtures with an enhancement ratio of 3.2 and 2.9 for LPC and DDPC, respectively compared with 2.0 and 1.5 for STDHF and EtOH:PBS 30:70 %v/v mixture, respectively. There was no significant difference between LPC and DDPC for the flux values and apparent permeability coefficients of [3H]PPL. These results suggest that phospholipids are suitable as permeation enhancers for the buccal delivery of drugs.

In order to enhance the dissolution profile and oral bioavailability of megestrol acetate (MA), solid dispersions of MA (MASDs) were formulated with copovidone and crystal sugar as a hydrophilic polymeric carrier and an inert core bead, respectively. Solvent evaporation method and fluidized bed coating technique were employed. MASDs were categorized as crystalline solid dispersion by the characterization of differential scanning calorimetry and X-ray diffraction. The mass-median diameters of MASDs were in a range of 1.4 to 2.6 μm. Based on drug to polymer ratio, MASD (1:1) and (1:2) were considered as optimized formulations, resulting in a smooth-surfaced homogeneously coated layer with enhanced dissolution rate. Dissolution of MASD was gradually increased up to 15 min, after which it reached a plateau. For the initial period, dissolution rates were in the decreasing order of MASD (1:2) ≥ MASD (1:1) > MASD (1:3) > MASD (1:5) > MASD (1:0.5) > MA powder. In the comparative pharmacokinetic study with Megace OS, a reference drug product, MASD (1:1) showed improved bioavailability of over 220% with 2-fold higher Cmax and 30% faster Tmax. We conclude that MASD (1:1) is a good candidate for the development of oral solid dosage forms.

Olmesartan medoxomil (OLM) is an antihypertensive angiotensin II receptor blocker. OLM has a low bioavailability (BA), approximately 26% in humans, due to its low water solubility and efflux by drug resistance pumps in the gastrointestinal tract. Self-microemulsifying drug delivery system (SMEDDS), which is easily emulsified in aqueous media under gentle agitation and digestive motility, was formulated to increase the oral BA of OLM. Among the surfactants and oils studied, Capryol 90, Tween 20, and Tetraglycol were chosen and combined at a volume ratio of 1:6:3 on the basis of equilibrium solubility and phase diagram experiments. The mean droplet size of SMEDDS was 15 nm. In an oral absorption study in rats, SMEDDS formulation brought faster absorption compared to suspension, showing a T(max) value of 0.2 hr. The C(max) and AUC values of SMEDDS formulation were significantly higher than those of suspension, revealing a relative BA of about 170%. Our study demonstrated the potential usefulness of SMEDDS for the oral delivery of poorly absorbable compounds, including OLM.

Mushroom-derived polysaccharides (beta-glucans) are considered as a valuable biopharmaceutical principle without displaying side effects. Although Tricholoma matsutake is well-known mushroom in Korea, Japan and China, the immunoregulatory roles of T. matsutake-derived polysaccharides were not fully elucidated yet. In this study, we continued to evaluate the immunomodulatory effect of T. matsutake-derived polysaccharide fraction (TmC-2) using functional activation models of macrophages, monocytes and splenic lymphocytes. TmC-2 treatment strongly increased the production of NO and TNF-alpha. Phagocytic uptake and ROS generation was also up-regulated by TmC-2. Interestingly, TmC-2 stimulated CD29-mediated cell-cell or cell-finbronectin adhesions in monocytes, while CD43-mediated cell adhesion was down-regulated. Interestingly, the enhancement of proliferation and IFN-gamma production was striking observed in TmC-2-treated splenic lymphocytes. The activation seemed to be mediated by up-regulating intracellular signaling cascades such as PI3K/Akt and MAPK (ERK and p38) and by the involvement of surface receptors (dectin-1 and TLR-2). Therefore, our results suggest that this TmC-2 from T. matsutake can be developed as a promising immunostimulatory principle, applicable to people with lowered immunomodulatory potentials.

As an initial step to develop the transdermal delivery system of glucosamine hydrochloride (GL-HCl), the permeation study across the rat skin in vitro was performed to identify the most efficient vehicle with regard to the ability to deliver GL-HCl transdermally. The GL-HCl formulations such as o/w cream, liposome suspension, liposomal gel, and liquid crystalline vehicles were prepared and compared for transdermal flux of GL-HCl. The liquid crystalline vehicles were more effective in increasing the skin permeation of GL-HCl than o/w cream and liposomal vehicles. Of the liquid crystalline vehicles tested, the permeation enhancing ability of the cubic phase was greater than that of the hexagonal phase when the nanoparticle dispersion was used. The skin permeation enhancing ability of the cubic nanoparticles for GL-HCl was further increased by employing both oleic acid and polyethylene glycol 200. Therefore, the cubic liquid crystalline nanodispersion containing oleic acid and PEG 200 can provide a possibility of clinical application of transdermal GL-HCl.

The purpose of the present study was to determine whether Pluronic F127 polymeric micelles could improve the oral bioavailability of a poor water-soluble drug, such as genistein. Genistein is a phytoestrogen that has estrogenic activity. F127 triblock copolymer consists of PEO100-PPO65-PEO100. Genistein was incorporated in the Pluronic F127 polymeric micelles by a solid dispersion method. The genistein release of genistein-loaded polymeric micelles was studied in vitro (in pH 1.2 and pH 6.8). And the oral bioavailabilities of genistein powder and genistein-loaded micelles were estimated at a dose of 4.0 mg/kg as genistein in rats. Drug loading amount and drug loading efficiency were 11.18% and 97.41%, respectively. The average size of the genistein-loaded polymeric micelles was 27.76 nm. And genistein release of the genistein-loaded polymeric micelles in vitro was 58% (pH 1.2) and 82% (pH 6.8). The bioavailability of genistein-loaded polymeric micelles was better than genistein powder. Consequently, Pluronic F127 polymeric micelles are an effective delivery system for the oral administration of genistein.

An O/W microemulsion system was developed to enhance the skin permeability of aceclofenac. Of the oils studied, Labrafil® M 1944 CS was chosen as the oil phase of the microemulson, as it showed a good solubilizing capacity. Pseudo-ternary phase diagrams were constructed to obtain the concentration range of oil, surfactant, Cremophor® ELP, and co-surfactant, ethanol, for micoemulsion formation. Eight different formulations with various values of oil of 6–30%, water of 0–80%, and the mixture of surfactant and co-surfactant (at the ratio of 2) of 14–70%. Thein vitro transdermal permeability of aceclofenac from the microemulsions was evaluated using Franz diffusion cells mounted with rat skin. The level of aceclofenac permeated was analyzed by HPLC and the droplet size of the microemulsions was characterized using a Zetasizer Nano-ZS. Terpenes were added to the microemulsions at a level of 5%, and their effects on the skin permeation of aceclofenac were investigated. The mean diameters of the microemulsions ranged between approximately 10≈100 nm, and the skin permeability of the aceclofenac incorporated into the microemulsion systems was 5-fold higher than that of the ethanol vehicle. Of the various terpenes added, limonene had the best enhancing ability. These results indicate that the microemulsion system studied is a promising tool for the percutaneous delivery of aceclofenac.

Research in this paper focuses on the kinetic evaluation of swelling of the liquid crystalline phases of glyceryl monooleate (GMO). Swelling of the lamellar and cubic liquid crystalline phases of GMO was studied using two in vitro methods, a total immersion method and a Franz cell method. The swelling of the lamellar phase and GMO having 0 %w/w initial water content was temperature dependent. The swelling ratio was greater at 20 degrees C than 37 degrees C. The water uptake increased dramatically with decreasing initial water content of the liquid crystalline phases. The swelling rates obtained using the Franz cell method with a moist nylon membrane to mimic buccal drug delivery situation were slower than the total immersion method. The swelling was studied by employing first-order and second-order swelling kinetics. The swelling of the liquid crystalline phases of GMO could be described by second-order swelling kinetics. The initial stage of the swelling (t4 h) followed the square root of time relationship, indicating that this model is also suitable for describing the water uptake by the liquid crystalline matrices. These results obtained from the current study demonstrate that the swelling strongly depends on temperature, the initial water content of the liquid crystalline phases and the methodology employed for measuring the swelling of GMO.

The impact of storage conditions on the permeability of porcine buccal mucosa to [3H]water and [14C]mannitol was assessed. The fresh porcine buccal tissue (fresh tissue) was obtained by utilizing pig heads within 24 hours of slaughter. The stored and frozen porcine buccal tissues (stored tissue and frozen tissue) were obtained after the storage of the tissue intact in the pig heads at 4 degrees C or -20 degrees C, respectively, for 24 h. The results demonstrated that the barrier properties of the porcine buccal mucosa were maintained with regard to [3H]water permeability when stored at 4 degrees C for 24 h. However, freezing the tissue resulted in tissue damage illustrated by a significant increase in [3H]water permeability. [14C]Mannitol does not appear to be a suitable model solute to assess the ex vivo permeability of porcine buccal mucosa due to its extremely low permeability.