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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Optimization of Mesoporous Silica Nanoparticles through Statistical Design of Experiment and the Application for the Anticancer Drug.

The synthesis process or composition of mesoporous silica nanoparticles (MSNs) affects the physicochemical properties. Using these properties, MSNs were synthesized through the Box-Behnken design (BBD) among statistical experimental methods. The effect of the amounts of synthetic reagents, hexadecyl triethyl ammonium bromide (CTAB), tetraethyl orthosilicate (TEOS), and 2 N sodium hydroxide (NaOH), was studied using the reaction surface design. Surface area, particle size, and zeta potential were set as response values. The physicochemical properties of the optimized MSNs were evaluated, and the effect as a drug delivery system was evaluated by loading doxorubicin hydrochloride (DOX). Nano-sized MSNs were successfully prepared with 0.617 g of CTAB, 8.417 mL of TEOS, and 2.726 mL of 2 N NaOH and showed excellent physicochemical properties. The optimized MSNs showed negligible toxicity in MCF-7 cells. The drug release profile from DOX-loaded MSNs (MSN@DOX) showed an increased rate of release with decreasing pH of the medium, with the release profile sustained for 48 h. In the cytotoxicity test, the sustained drug release mechanism of MSN@DOX was confirmed. This study proposed a new statistical approach to the synthesis of MSNs.

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.

Development and evaluation of TPGS/PVA-based nanosuspension for enhancing dissolution and oral bioavailability of ticagrelor.

In this study, we developed ticagrelor-dispersed nanosuspension (TCG-NSP) to enhance the dissolution and oral bioavailability of ticagrelor (TCG) through a statistical design approach. TCG, a reversible P2Y12 receptor antagonist, is classified as a biopharmaceutics classification system (BCS) class IV drug with low solubility and permeability, resulting in low oral bioavailability. Nanosuspension (NSP) is an efficient pharmaceutical technique for overcoming the disadvantages. First, we optimized TCG-NSP consisting of D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) and polyvinyl alcohol (PVA), which exhibited homogeneously dispersed TCG particle (233 nm) and low precipitation (3%). Characterization studies demonstrated that TCG-NSP provided amorphous TCG particles and supersaturation effect, resulting in higher dissolution than a commercial product. In addition, everted gut sac and pharmacokinetic studies confirmed that TCG-NSP improved the gastrointestinal permeation of TCG by 2.8-fold compared to commercial product, thereby enhancing the oral bioavailability (2.2-fold). These results suggested that TCG-NSP could be successfully used as an efficient pharmaceutical formulation to achieve the enhanced dissolution and oral bioavailability of TCG.

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.

Achyranthis radix Extract-Loaded Eye Drop Formulation Development and Novel Evaluation Method for Dry Eye Treatment.

Recently, Achyranthis radix extract has been studied as a therapeutic agent for dry eye disease that occurs from fine dust. The aim of this study was the development of Achyranthis radix extract-loaded eye drop formulations using lubricants, generally used for artificial tear eye drops. Ecdysterone was used as a marker compound for Achyranthis radix extract and 1% Achyranthis radix extract solution contained 14.37 ± 0.04 µg/mL of ecdysterone. Before formulation studies, a new method was performed to evaluate pigmentation, which might be caused by eye drops of herbal extract. A comparative study of the water retention ability of each formulation and ability to prevent the death of conjunctival epithelial cells in dry conditions was conducted. Moreover, treatment of Achyranthis radix extract (USL) eye drop formulation exhibited a significant inhibitory effect on inflammation in a concentration-dependent manner. The long-term and accelerated stability tests showed that lubricants could contribute to the stability of herbal extracts in solution. In conclusion, hyaluronic acid showed a good effect on the development of eye drop formulation using Achyranthis radix extracts for treating dry eye disease.

Extended Intake of Mulberry Leaf Extract Delayed Metformin Elimination via Inhibiting the Organic Cation Transporter 2.

Diabetes mellitus (DM) has become a major health problem in most countries of the world. DM causes many complications, including hyperglycemia, diabetic ketoacidosis, and death. In Asia, mulberry has been used widely in the treatment of DM. Combination of drugs with herbal medicine may reduce the unwanted side effects caused by drugs. In this study, the influence of extended mulberry leaves extract (MLE) intake on metformin (Met) was evaluated in terms of pharmacokinetics and pharmacodynamics in DM-induced rats. Three week-treatment of MLE alone produced the anti-hyperglycemic effect (around 24%) if compared to the control. Interestingly, Met administration after MLE treatment for 3 weeks enhanced about 49% of the anti-hyperglycemic effect of Met. In addition, the extended intake of MLE potentiated the anti-hyperglycemic effect of Met on various concentrations. This potentiated anti-hyperglycemic effect of Met appears to be due to the pharmacokinetic change of Met. In this study, 3 week-treatment of MLE reduced the elimination of Met in DM-induced rats. In addition, MLE reduced the human organic cation transporter 2 (hOCT2) activity in a concentration-dependent manner. Thus, these findings suggest that MLE lowered the elimination of Met via inhibiting the hOCT2.

A thorough analysis of the effect of surfactant/s on the solubility and pharmacokinetics of (S)-zaltoprofen.

Until now, there are no publications about the preformulation studies on (S)-zaltoprofen ((S)-ZPF). Hence, we first investigated the solubility of (S)-ZPF, screened solubilizers and performed the pharmacokinetic study of (S)-ZPF in the presence of the solubilizers. The measurement of the solubility of (S)-ZPF in 26 different solvents was carried out, including d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), 2-hydroxypropyl-ß-cyclodextrin (HPCD), and mixtures of individual solvent. The plasma concentration of (S)-ZPF and the amount of (S)-ZPF retained in stomach were determined after oral (35.0 mg/kg) and intravenous (5.0 mg/kg) administration. The solubility of (S)-ZPF showed an increase of 484-fold in TPGS compared to its aqueous solubility. There was a significant increase of AUC0-24   h for pure (S)-ZPF in the TPGS group (813.59 ±â€¯64.17 µg⋅h/ml) in comparison with AUC0-24   h in the HPCD group (595.57  ±â€¯71.76 µg⋅h/ml) and water group (465.57 ±â€¯90.89 µg⋅h/ml). In addition, the Tmax of (S)-ZPF in the TPGS group was 2 h, much faster than that in the HPCD or water groups (5.50 or 5.67 h, respectively). This suggested that TPGS played a significant role in the increase of solubility and bioavailability of (S)-ZPF.

Improved Bioavailability of Levodopa Using Floatable Spray-Coated Microcapsules for the Management of Parkinson's Disease.

Oral administration of levodopa (LD) is the gold standard in managing Parkinson's disease (PD). Although LD is the most effective drug in treating PD, chronic administration of LD induces levodopa-induced dyskinesia. A continuous and sustained provision of LD to the brain could, therefore, reduce peak-dose dyskinesia. In commercial oral formulations, LD is co-administrated with an AADC inhibitor (carbidopa) and a COMT inhibitor (entacapone) to enhance its bioavailability. Nevertheless, patients are known to take up to five tablets a day because of poor sustained-releasing capabilities that lead to fluctuations in plasma concentrations. To achieve a prolonged release of LD with the aim of improving its bioavailability, floatable spray-coated microcapsules containing all three PD drugs were developed. This gastro-retentive delivery system showed sustained release of all PD drugs, at similar release kinetics. Pharmacokinetics study was conducted and this newly developed formulation showed a more plateaued delivery of LD that is void of the plasma concentration fluctuations observed for the control (commercial formulation). At the same time, measurements of LD and dopamine of mice administered with this formulation showed enhanced bioavailability of LD. This study highlights a floatable, sustained-releasing delivery system in achieving improved pharmacokinetics data compared to a commercial formulation.