Anti-Inflammatory Activity of 1,6,7-Trihydroxy-2-(1,1-dimethyl-2-propenyl)-3-methoxyxanthone Isolated from Cudrania tricuspidata via NF-κB, MAPK, and HO-1 Signaling Pathways in Lipopolysaccharide-Stimulated RAW 264.7 and BV2 Cells.

Neuroinflammation activated by microglia affects inflammatory pain development. This study aimed to explore the anti-inflammatory properties and mechanisms of 1,6,7-trihydroxy-2-(1,1-dimethyl-2-propenyl)-3-methoxyxanthone (THMX) from Cudrania tricuspidata in microglia activation-mediated inflammatory pain. In RAW 264.7 and BV2 cells, THMX has been shown to reduce lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory mediators and cytokines, including nitric oxide (NO), prostaglandin (PG) E2, interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α). THMX also decreased LPS-induced phosphorylation of mitogen-activated protein kinase (MAPK) and the activation of p65 nuclear factor kappa B (NF-κB). Interestingly, THMX also activated heme oxygenase (HO)-1 expression. These findings suggest that THMX is a promising biologically active compound against inflammation through preventing MAPKs and NF-ĸB and activating HO-1 signaling pathways.

Accelerated Oral Healing by Angelica gigas Nakai from Hot Melt Extrusion Technology: An In Vitro Study.

Background and Objectives: In spite of the oral environment being healing-prone, its dynamic changes may affect wound healing. The purpose of this study was to assess the oral wound healing effect of Angelica gigas Nakai (AG) prepared by hot-melt extrusion. Materials and Methods: Human gingival fibroblast (HGF) cells were treated with AG or AG via hot-melt extrusion (AGH) for 24 h to determine the optimal concentration. For evaluating the anti-inflammatory effect of AG and AGH, a nitric oxide assay was performed under lipopolysaccharide (LPS) stimulation. The wound-healing effects of AG and AGH were evaluated using cell proliferation/migration assays and wound-healing marker expression through qRT-PCR. Results: Both AG and AGH showed no cytotoxicity on HGH cells. Regarding nitric oxide production, AGH significantly decreased LPS-induced nitric oxide production (p < 0.05). AGH showed a significantly positive result in the cell proliferation/cell migration assay compared with that in AG and the control. Regarding wound healing marker expression, AGH showed significantly greater VEGF and COL1α1 expression levels than those in the others (p < 0.05), whereas α-SMA expression was significantly different among the groups. Conclusions: Within the limits of this study, AGH accelerated oral wound healing in vitro.

Biodegradable Nanoparticles-Loaded PLGA Microcapsule for the Enhanced Encapsulation Efficiency and Controlled Release of Hydrophilic Drug.

Recently, nano- and micro-particulate systems have been widely utilized to deliver pharmaceutical compounds to achieve enhanced therapeutic effects and reduced side effects. Poly (DL-lactide-co-glycolide) (PLGA), as one of the biodegradable polyesters, has been widely used to fabricate particulate systems because of advantages including controlled and sustained release, biodegradability, and biocompatibility. However, PLGA is known for low encapsulation efficiency (%) and insufficient controlled release of water-soluble drugs. It would result in fluctuation in the plasma levels and unexpected side effects of drugs. Therefore, the purpose of this work was to develop microcapsules loaded with alginate-coated chitosan that can increase the encapsulation efficiency of the hydrophilic drug while exhibiting a controlled and sustained release profile with reduced initial burst release. The encapsulation of nanoparticles in PLGA microcapsules was done by the emulsion solvent evaporation method. The encapsulation of nanoparticles in PLGA microcapsules was confirmed by scanning electron microscopy and confocal microscopy. The release profile of hydrophilic drugs can further be altered by the chitosan coating. The chitosan coating onto alginate exhibited a less initial burst release and sustained release of the hydrophilic drug. In addition, the encapsulation of alginate nanoparticles and alginate nanoparticles coated with chitosan in PLGA microcapsules was shown to enhance the encapsulation efficiency of a hydrophilic drug. Based on the results, this delivery system could be a promising platform for the high encapsulation efficiency and sustained release with reduced initial burst release of the hydrophilic drug.

An Enhanced Water Solubility and Stability of Anthocyanins in Mulberry Processed with Hot Melt Extrusion.

Mulberry fruits are rich sources of anthocyanins that exhibit beneficial biological activity. These anthocyanins become instable in an aqueous media, leading to their low bioavailability. In this study, a colloidal dispersion was produced by processing mulberry samples with hot-melt extrusion. In this process, hydrophilic polymer matrices were used to disperse the compound in an aqueous media. Mulberry samples were processed with hot-melt extrusion and in the presence of an ionization agent and sodium alginate to form mulberry-extrudate solid formulations. The particle size of mulberry-extrudate solid formulations decreased, while the total phenol content, the total anthocyanin content, and solubility increased. Fourier transform infrared spectroscopy (FT-IR) revealed that mulberry-extrudate solid formulations now contained new functional groups, such as -COOH group. We investigated whether mulberry-extrudate solid formulations had a positive impact on the stability of anthocyanins. The non-extrudate mulberry sample and mulberry-extrudate solid formulations were incubated with a simulated gastric fluid system and an intestinal fluid system. The number of released anthocyanins was determined with HPLC. We found that anthocyanins were released rapidly from non-extrudate mulberry extract. Mulberry-extrudate solid formulations contained a large number of available anthocyanins even after being incubated for 180 min in the intestinal fluid system. Thus, hot-melt extrusion enhanced water solubility and stability of anthocyanins with the prolonged release.

Pharmacokinetic/Pharmacodynamic Modeling To Predict the Antiplatelet Effect of the Ticagrelor-Loaded Self-Microemulsifying Drug Delivery System in Rats.

Ticagrelor (TCG) has been used as an antiplatelet agent for acute coronary syndrome patients. The aim of this research was to establish a population pharmacokinetic/pharmacodynamic (PK/PD) model of TCG and to apply the model for predicting the PD response of the TCG-loaded self-microemulsifying drug delivery system (TCG-SME) in rats. Pure TCG and TCG-SME (2, 5, and 10 mg/kg of TCG) were orally administered to male Sprague-Dawley rats. Plasma samples were collected at scheduled time-points and then analyzed for TCG plasma concentrations and antiplatelet effects. The inhibition of platelet aggregation of TCG was measured as a PD response. The PK profiles of pure TCG and TCG-SME could be well-explained with a two-compartment PK model. The accuracy of the PK model was assessed with a goodness-of-fit plot and conditional weight residual error (CWRES). Also, the visual predictive check was investigated based on the predictions. A population PK/PD model for pure TCG was established as an indirect response Emax model linked to the two-compartment PK model of pure TCG. The PK/PD model proposed a suitable fitting to link the plasma concentration of TCG simultaneously with platelet aggregation. Based on the PK data of TCG-SME, as well as the established PK/PD model of pure TCG, the PD profiles of TCG-SME were simulated. TCG-SME was more effective in inducing the antiplatelet effect than pure TCG at equivalent doses of TCG. The accuracy of the simulation was verified by comparing the simulated PD profile with the profile observed in rats. The observations were close to the model simulations. In addition, the values of CWRES were almost within ±2. In conclusion, the PK/PD modeling approach can provide a way for predicting mathematically the PD responses from PK profiles of other TCG formulations and a conceptual prediction for future clinical assessment.

Development of Houttuynia cordata Extract-Loaded Solid Lipid Nanoparticles for Oral Delivery: High Drug Loading Efficiency and Controlled Release.

Houttuynia cordata (H. cordata) has been used for diuresis and detoxification in folk medicine as well as a herbal medicine with antiviral and antibacterial activities. H. cordata extract-loaded solid lipid nanoparticles (H-SLNs) were prepared with various concentration of poloxamer 188 or poloxamer 407 by a hot homogenization and ultrasonication method. H-SLNs dispersion was freeze-dried with or without trehalose as a cryoprotectant. The physicochemical characteristics of H-SLNs were evaluated by dynamic laser scattering (DLS), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM). Additionally, the in vitro release and in vitro cytotoxicity of H-SLNs were measured. Encapsulation efficiencies of H-SLNs (as quercitrin) were 92.9-95.9%. The SEM images of H-SLNs showed that H-SLNs have a spherical morphology. DSC and FT-IR showed that there were no interactions between ingredients. The increased extent of particle size of freeze-dried H-SLNs with trehalose was significantly lower than that of H-SLNs without trehalose. H-SLNs provided sustained release of quercitrin from H. cordata extracts. Cell viability of Caco-2 cells was over 70% according to the concentration of various formulation. Therefore, it was suggested that SLNs could be good carrier for administering H. cordata extracts.

Multi-Drug-Loaded Microcapsules with Controlled Release for Management of Parkinson's Disease.

Parkinson's disease (PD) is a progressive disease of the nervous system, and is currently managed through commercial tablets that do not sufficiently enable controlled, sustained release capabilities. It is hypothesized that a drug delivery system that provides controlled and sustained release of PD drugs would afford better management of PD. Hollow microcapsules composed of poly-l-lactide (PLLA) and poly (caprolactone) (PCL) are prepared through a modified double-emulsion technique. They are loaded with three PD drugs, i.e., levodopa (LD), carbidopa (CD), and entacapone (ENT), at a ratio of 4:1:8, similar to commercial PD tablets. LD and CD are localized in both the hollow cavity and PLLA/PCL shell, while ENT is localized in the PLLA/PCL shell. Release kinetics of hydrophobic ENT is observed to be relatively slow as compared to the other hydrophilic drugs. It is further hypothesized that encapsulating ENT into PCL as a surface coating onto these microcapsules can aid in accelerating its release. Now, these spray-coated hollow microcapsules exhibit similar release kinetics, according to Higuchi's rate, for all three drugs. The results suggest that multiple drug encapsulation of LD, CD, and ENT in gastric floating microcapsules could be further developed for in vivo evaluation for the management of PD.

Effect of hot-melt extruded Morus alba leaves on intestinal microflora and epithelial cells.

Although rutin and isoquercitrin have many effects, they are insoluble substances, making it difficult to obtain pure substances. This study was to investigate whether Morus alba leaves containing rutin and isoquercitrin could improve intestinal health by making a sustained-release formulation through a hot-melt extrusion (HME) process with improved stability and solubility and determine whether it could upregulate the balance of intestinal microorganisms and intestinal epithelial cells. A sustained-release formulation was prepared by the HME process using Morus alba leaves and a hydrophilic polymer matrix. Antibacterial activities of pathogenic microorganisms (Escherichia coli, Streptococcus aureus, Enterococcus faecalis) and proliferative effect of probiotics (Lactobacillus rhamnosus, Pediococcus pentosaceus) were tested against intestinal microorganisms. Regarding intestinal epithelial cells, a co-culture model of Caco-2 cells and RAW 264.7 cells was used. It was confirmed that the extrudate exhibited high antibacterial activities against pathogenic microorganisms and affected the proliferation of probiotics. Furthermore, after inducing inflammation through LPS, it recovered transepithelial electrical resistance-increased levels of tight junction proteins and decreased expression levels of pro-inflammatory cytokines. HME of Morus alba leaves containing rutin and isoquercitrin can upregulate intestinal microbial balance and intestinal epithelial cells.

Enhanced Minor Ginsenoside Contents of Nano-Sized Black Korean Ginseng through Hot Melt Extrusion.

Black ginseng (BG), a traditional medicinal herb produced through a nine-stage steaming and drying process, exhibits stronger pharmacological efficacy, including antioxidant, anti-inflammatory, and anti-cancer properties, when compared to white and red ginseng. The ginsenosides in BG are classified as major and minor types, with minor ginsenosides demonstrating superior pharmacological properties. However, their low concentrations limit their availability for research and clinical applications. In this study, hot melt extrusion (HME) was utilized as an additional processing technique to enhance the content of minor ginsenoside in BG, and the physicochemical properties of the formulation were analyzed. Ginsenoside content in BG and HME-treated BG (HME-BG) was analyzed using high-performance liquid chromatography (HPLC), while their physicochemical properties were evaluated through dynamic light scattering (DLS), electrophoretic light scattering (ELS), X-ray diffraction (XRD), thermogravimetric analysis (TGA), and Fourier-transform infrared spectroscopy (FT-IR). HME treatment resulted in a significant increase in minor ginsenosides Rg3 and compound K (CK) by 330% and 450%, respectively, while major ginsenosides Rg1 and Rb1 decreased or were not detected. Additionally, HME-BG demonstrated reduced particle size, improved PDI, and decreased crystallinity. HME treatment effectively converts major ginsenosides in BG into minor ginsenosides, enhancing its pharmacological efficacy and showing great potential for research and development applications.

Green Synthesis of Silver Nanoparticle Using Black Mulberry and Characterization, Phytochemical, and Bioactivity.

Synthesis of silver nanoparticles (AgNPs) using plant extracts has been proposed as a more advantageous and environmentally friendly alternative compared to existing physical/chemical methods. In this study, AgNPs were synthesized from silver nitrate using black mulberry (BM) extract. The biosynthesized AgNPs were characterized through an UV-visible spectrometer, X-ray diffraction, and transmission electron microscopy. Additionally, BM-AgNPs were subjected to antioxidant, antibacterial, anti-inflammatory, and anticancer activities. AgNPs biosynthesized from BM extract were dark brown in color and showed a strong peak at 437 nm, confirming that AgNPs were successfully synthesized. The size of AgNPs was 170.17 ± 12.65 nm, the polydispersity index was 0.281 ± 0.07, and the zeta potential value was -56.6 ± 0.56 mV, indicating that the particles were stable. The higher total phenol, flavonoid, and anthocyanin content of BM-AgNPs compared to BM extract indicates that the particles contain multiple active substances due to the formation of AgNPs. The DPPH and ABTS assays showed decreased IC50 values compared to BM extract, demonstrating improved antioxidant activity. AgNPs inhibited the growth of S. aureus and E. coli at 600 µg/mL, with minimum bactericidal concentrations determined to be 1000 and 1200 µg/mL, respectively. The anti-inflammatory activity was 64.28% at a BM-AgNPs concentration of 250 µg/mL. As the concentration increased, the difference from the standard decreased, indicating the inhibitory effect of AgNPs on bovine serum albumin denaturation. The viability of MCF-7 cells treated with BM-AgNPs was found to be significantly lower than that of cells treated with BM extract. The IC50 value of BM-AgNPs was determined to be 96.9 µg/mL. This study showed that BM-AgNPs have the potential to be used in the pharmaceutical industry as antioxidant, antibacterial, anti-inflammatory, and anticancer agents.

Fabrication and evaluation of chitosan-coated nanostructured lipid carriers for co-delivery of paclitaxel and PD-L1 siRNA.

This study aimed to develop a nanostructured lipid carrier (NLC) capable of co-delivering paclitaxel (PTX) and programmed death-ligand 1 (PD-L1) small interfering RNA (siRNA) to enhance PTX bioavailability and bolster immunity through PD-L1 knockdown. We prepared a PTX-loaded NLC (P-NLC) and coated it with positively charged chitosan (Chi) to create P-NLC-Chi, which was subsequently conjugated to siRNA (P-NLC-Chi-siRNA). The P-NLC-Chi formulation was optimized using the Box-Behnken design. P-NLC-Chi measured 123.8 ± 0.52 nm (zeta potential, 22.71 ± 0.49 mV). By verifying the gel retardation assay and observing changes in the zeta potential, the optimal binding ratio of NLC to PD-L1 siRNA was identified as 50:1. The P-NLC-Chi-siRNA particle size was 181.97 ± 0.67 nm, with a zeta potential of 18.66 ± 0.23 mV. siRNA stability was observed in serum over a 24-h period. Enhanced cytotoxicity and intracellular uptake of the complex were evident in breast cancer cells and breast cancer-resistant cells (MCF-7 and MCF-7/ADR cells, respectively). Evaluation of P-glycoprotein-mediated efflux demonstrated that NLC mitigated drug efflux in MCF-7/ADR cells. Subcutaneous injection of P-NLC-Chi-siRNA into tumor-bearing BALB/c nude mice injected with MCF-7/ADR cells revealed a reduction in tumor size. In vitro and in vivo experiments indicated a significant reduction in PD-L1 mRNA expression levels. Additionally, an in vivo study revealed tumor-specific CD4 + and CD8 + T cell responses within the tumor tissue following the injection of P-NLC-Chi-siRNA. Our findings suggest that Chi-coated NLC for the co-delivery of PTX and PD-L1 siRNA has great potential as an innovative delivery system for chemoimmunotherapy.

Practical Manipulation for the Preparation of Mesoporous Silica Nanoparticles for Drug Delivery Vehicles.

BACKGROUND: Optimization of MSNs is the most important process for efficient and safe drug delivery systems. OBJECTIVE: In this study, the physicochemical properties of MSNs were evaluated using various compositions of individual reagents. METHODS: MSNs were synthesized according to a modified Stöber method. The physicochemical properties of MSNs were evaluated. Spherical uniform particles were observed in the scanning electron microscope (SEM) and transmission electron microscopy (TEM) image and the meso-structure of MSNs was confirmed. The amorphous and specific hexagonal structure of MSNs was confirmed through Xray diffraction (XRD) and SAXRD. RESULTS: The particle size and surface area according to changes in amounts of reagents ranged from 34.5 ± 2.3 to 216.0 ± 17.1 nm and from 549.79 to 1154.26 m2/g, respectively. A linear relationship was found between the surface area of MSNs and the adsorption rate of methylene blue (MB). MSNs exhibited no apparent cytotoxic effect on Caco-2 cell up to 200 µg/mL. The amounts of tetramethyl ammonium silicate and tetraethyl ortho silicate (TEOS), NaOH, and hexadecyl trimethyl ammonium bromide (CTAB) were adjusted to control the particle size and surface area of MSNs, and it was found that the amounts of synthetic reagents affected the physicochemical properties such as particle size and surface area of MSNs. MSNs with a large surface area adsorbed a large amount of MB. CONCLUSION: These results indicated that drug adsorption is related to the surface area of MSNs. MSNs did not show cytotoxicity to Caco-2 cells. MSNs may be a promising nanomaterial that could be applied as a carrier for various drugs.

Surface-modified gemcitabine with mucoadhesive polymer for oral delivery.

Gemcitabine microparticles were prepared using chitosan, polyethylene oxide or carbopol as the mucoadhesive polymer and eudragit L100-55 as the enteric polymer by a double emulsion method. The particle size and zeta potential changed from 1338.3 ± 254.1 nm to 2459.4 ± 103.6 nm and -5.16 ± 1.62 mV to 2.84 ± 0.65 mV, respectively, with increasing chitosan to gemcitabine weight ratio from 0.25 to 1. The gemcitabine-loaded microparticles without mucoadhesive polymer (F50) showed the particle size and zeta potential of 671.3 ± 58.3 nm and - 16.7 ± 1.82 mV, respectively. The cellular uptake of gemcitabine into Caco-2 cells from gemcitabine-loaded microparticles with chitosan increased with increasing incubation time in Caco-2 cells compared to that of gemcitabine-loaded microparticles with polyethylene oxide or carbopol, suggesting that chitosan might be the optimal mucoadhesive polymer. Gemcitabine microparticles will be tested to identify whether the oral absorption could be increased in the future.

The Effect of Hot-Melt Extrusion of Mulberry Leaf on the Number of Active Compounds and Antioxidant Activity.

The aim of this study is to compare the functions of the physiologically active compounds of three types of mulberry leaf by cultivar, and to confirm the changes using hot-melt extrusion (HME-ML). The active components of mulberry leaf were analyzed using the HPLC system, and total phenolic content (TPC), total flavonoid content (TFC), and antioxidant activity were measured. Among the three varieties, the highest contents of rutin and isoquercetin were detected in Cheongil, of TPC in Cheongol, and of TFC in Cheongil. It was confirmed that this bio-accessibility was increased in HME-ML compared with the control. The DPPH radical scavenging activity of Cheongol showed greater antioxidant properties, and HME showed improvement in the antioxidant properties of all mulberry leaves. These results suggest that the application of HME technology can improve the biological activities of mulberry leaf.

Green Synthesis of Silver Nanoparticles (AgNPs) of Angelica Gigas Fabricated by Hot-Melt Extrusion Technology for Enhanced Antifungal Effects.

Green synthesis for synthesizing silver nanoparticles (AgNPs) has been suggested as an environmentally friendly alternative to conventional physical/chemical methods. In this study, we report the green synthesis of AgNPs using a hot-melt extrusion-processed Angelica gigas Nakai (AGN) (HME-AGN) extract as a reducing agent to increase the water solubility of the active ingredient compared to the existing AGN. The mixture of the AGN extract and AgNO3 at about 420 nm could not confirm the formation of AgNPs. The synthesis of AgNPs was found to be most advantageous at 60 °C when the mixing ratio of the HME-AGN extract was 9:1 (AgNO3-extract, v/v) using 3 mM AgNO3. The physicochemical properties of the optimized AgNPs were characterized by UV-Vis spectrophotometer, dynamic light scattering (DLS), zeta potential, transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS), Fourier-transform infrared spectroscopy (FT-IR), and X-ray diffractometer (XRD). DLS showed the particle size average of 102.3 ± 1.35 nm and polydispersity index (PDI) value of 0.314 ± 0.01. The particle surface charge was -35 ± 0.79 mV, confirming the stability of the particles. The particle shape was spherical, as shown through TEM analysis, and the presence of silver ions was confirmed through the EDS results. FT-IR data showed functional groups of biomolecules of the extract involved in the synthesis of AgNPs. The face-centered cubic (FCC) lattice of AgNPs was confirmed in the XRD pattern. The AgNPs had an effective antifungal activity against Candida albicans (C. albicans) that was better than that of the HME-AGN extract. In conclusion, this study suggests that the synthesis of AgNPs was improved by using the HME-AGN extract with increased water solubility through HME. In addition, it was suggested that the synthesized AgNPs can be used as an improved antifungal agent compared with the HME-AGN extract with antifungal activity.

Hot-Melt Extrusion Enhances Antioxidant Effects of Mulberry on Probiotics and Pathogenic Microorganisms.

Mulberry is a rich source of anthocyanins (ACNs) known to possess biological activities. However, these ACNs are unstable in high pH, heat, and aqueous environments with a low bioavailability. In this study, a colloidal dispersion was prepared by hot melt extrusion with proper excipients. In this process, a hydrophilic polymer matrix was used to confirm the stability of the compound in high pH, high temperature, and aqueous media. It was confirmed that the particle size and the polydispersity index value were reduced, thereby improving the solubility. In vitro release studies revealed that the extrudate had a sustained release compared to a non-extruded product. As a result of measuring changes of intestinal microorganisms (Lacticaseibacillus rhamnosus, Pediococcus pentosaceus, Escherichia coli, Enterococcus faecalis, and Staphylococcus aureus), contents of probiotics were found to be increased whereas contents of pathogenic microorganisms were decreased. Thus, hot-melt extrusion could enhance the stability of ACN with prolonged release. The processed formulation exhibited probiotic properties and antimicrobial activities against pathogenic intestinal microflora.

Enhancement of S(+)-zaltoprofen oral bioavailability using nanostructured lipid carrier system.

Zaltoprofen is a nonsteroidal anti-inflammatory drug with poor oral bioavailability. S(+)-zaltoprofen (SZPF)-loaded nanostructured lipid carriers (NLCs) were prepared to enhance oral bioavailability. SZPF-loaded NLCs (NLC-SZPF) were prepared using the hot-melting homogenization method and optimized using the Box-Behnken design. The characterization of optimized NLC-SZPF, in vitro release, cytotoxicity, cellular uptake, ex vivo permeability, and pharmacokinetic parameters were evaluated to confirm the advantages of NLC formulation. NLC-SZPF with a diameter of 105.5 ± 1.2 nm had a high encapsulation efficiency of 99.84 ± 0.01%. NLC-SZPF showed a sustained-release profile, high biocompatibility, and high permeability across the intestinal tract. The relative bioavailability of NLC-SZPF was 431.3% compared with that of SZPF after oral administration to experimental rats. NLC-SZPF was successfully optimized using experimental designs to enhance the oral bioavailability of SZPF. Hence, NLC-SZPF could be a promising approach to overcome the poor oral bioavailability of SZPF.

Development and Evaluation of Tannic Acid-Coated Nanosuspension for Enhancing Oral Bioavailability of Curcumin.

Curcumin (CUR) has been used in the treatment of various diseases such as cough, fever, skin disease, and infection because of various biological benefits such as anti-inflammatory, antiviral, antibacterial, and antitumor activity. However, CUR is a BCS class 4 group and has a limitation of low bioavailability due to low solubility and permeability. Therefore, the purpose of this study is to prepare a nanosuspension (NSP) loaded with CUR (CUR-NSP) using a statistical design approach to improve the oral bioavailability of CUR, and then to develop CUR-NSP coated with tannic acid to increase the mucoadhesion in the GI tract. Firstly, the optimized CUR-NSP, composed of sodium dodecyl sulfate (SDS) and polyvinylpyrrolidone/vinyl acetate (PVP/VA), was modified with tannic acid (TA). The particle size and polydispersity index of the formulation measured by laser scattering analyzer were 127.7 ± 1.3 nm and 0.227 ± 0.010, respectively. In addition, the precipitation in distilled water (DW) was 1.52 ± 0.58%. Using a differential scanning calorimeter and X-ray diffraction analysis, the stable amorphous form of CUR was confirmed in the formulation, and it was confirmed that CUR-NSP formulation was coated with TA through a Fourier transform-infrared spectroscopy. In the mucoadhesion assay using the turbidity, it was confirmed that TA-CUR-NSP had higher affinity for mucus than CUR-NSP under all pH conditions. This means that the absorption of CUR can be improved by increasing the retention time in the GI tract of the formulation. In addition, the drug release profile showed more than 80% release, and in the cellular uptake study, the absorption of the formulation (TA-CUR-NSP) containing TA acting as an inhibitor of P-gp was increased by 1.6-fold. In the evaluation of antioxidant activity, the SOD activity of TA-CUR-NSP was remarkably high due to TA, which improves cellular uptake and has antioxidant activity. In the pharmacokinetic evaluation, the maximum drug plasma concentration of the TA-coated NSP formulation was 7.2-fold higher than that of the pure drug. In all experiments, it was confirmed that the TA-CUR-NSP is a promising approach to overcome the low oral bioavailability of CUR.

Lipid-Polymer Hybrid Nanoparticles Enhance the Potency of Ampicillin against Enterococcus faecalis in a Protozoa Infection Model.

Enterococcus faecalis (E. faecalis) biofilms are implicated in endocarditis, urinary tract infections, and biliary tract infections. Coupled with E. faecalis internalization into host cells, this opportunistic pathogen poses great challenges to conventional antibiotic therapy. The inability of ampicillin (Amp) to eradicate bacteria hidden in biofilms and intracellular niches greatly reduces its efficacy against complicated E. faecalis infections. To enhance the potency of Amp against different forms of E. faecalis infections, Amp was loaded into Lipid-Polymer hybrid Nanoparticles (LPNs), a highly efficient nano delivery platform consisting of a unique combination of DOTAP lipid shell and PLGA polymeric core. The antibacterial activity of these nanoparticles (Amp-LPNs) was investigated in a protozoa infection model, achieving a much higher multiplicity of infection (MOI) compared with studies using animal phagocytes. A significant reduction of total E. faecalis was observed in all groups receiving 250 µg/mL Amp-LPNs compared with groups receiving the same concentration of free Amp during three different interventions, simulating acute and chronic infections and prophylaxis. In early intervention, no viable E. faecalis was observed after 3 h LPNs treatment whereas free Amp did not clear E. faecalis after 24 h treatment. Amp-LPNs also greatly enhanced the antibacterial activity of Amp at late intervention and boosted the survival rate of protozoa approaching 400%, where no viable protozoa were identified in the free Amp groups at the 40 h postinfection treatment time point. Prophylactic effectiveness with Amp-LPNs at a concentration of 250 µg/mL was exhibited in both bacteria elimination and protozoa survival toward subsequent infections. Using protozoa as a surrogate model for animal phagocytes to study high MOI infections, this study suggests that LPN-formulated antibiotics hold the potential to significantly improve the therapeutic outcome in highly complicated bacterial infections.

Novel self-floating tablet for enhanced oral bioavailability of metformin based on cellulose.

Metformin has several problems such as low bioavailability, short half-life, and narrow absorption window, sustained and site-specific drug delivery system is required. Floating drug delivery systems are very useful to achieve these purposes. However, conventional floating systems have several limitations; lag time, a high proportion of excipient in the tablet, using non-biocompatible excipient, and requirement of a complicated procedure. To overcome these obstacles, we developed a hollow-core floating tablet (HCFT). The HCFT immediately floated in pH 1.2, 4.0, 6.8 medium, and even distilled water. The floating duration time of HCFT was>24 h. From the in vitro release study, it was confirmed that HCFT showed the sustain release profile of metformin for 12 h. Water uptake and matrix erosion were evaluated for predicting the buoyancy and drug release kinetics of HCFT in the body. Factor analysis was applied to optimize the formulation. There were significant (p < 0.05) differences in metformin plasma concentration of 4 h and 6 h between two groups. Compared with Glucophage® XR, the relative bioavailability of metformin HCFT was 123.81 ± 3.52%. The X-ray imaging of optimized formulation revealed that HCFT was constantly floating in the stomach region of the rabbit, thereby indicating improved gastric retention for>6 h. Consequently, all the findings indicate that HCFT could be an effective gastric retention system and applied extensively to other drugs with narrow absorption windows.