Anyang, South Korea
Anyang, South Korea

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Seo Y.G.,Yeungnam University | Kim D.-W.,Hanyang University | Yeo W.H.,Yeungnam University | Ramasamy T.,Yeungnam University | And 10 more authors.
Pharmaceutical Research | Year: 2013

Purpose: To investigate the potential of thermosensitive and biadhesive nanomicelles in improving the bioavailability of docetaxel (DCT) and its chemotherapeutic effect. Method: DCT-loaded nanomicelles were prepared by emulsufication and characterized in terms of physico-chemical and visco-elastic parameters. The optimzed formulation was evaluated for in vivo localization, pharmacokinetic and anti-tumor efficacy. Results: The hydrodynamic size of DCT-loaded nanomicelles was approximately 13 nm and the nanomicelles exhibited a sufficient gelation strength (9250 mPa·s) and bioadhesive force (2100 dyn/cm2) to be retained in the upper part of rectum. We observed a high rectal bioavailability of 29% DCT compared to that following oral administration in rats, as it successfully evaded the multidrug efflux transporters and hepatic first-pass metabolism. Plasma concentration around ∼50 ng/mL was maintained throughout the study period (12 h) while Taxotere® attained subtherapeutic range within 4 h of drug administration. Results also revealed that the rectally administered DCT-loaded nanomicelles exhibited a significant anti-tumor effect (200 mm3) with a reduced toxicity profile when compared to orally administered DCT (950 mm3). Furthermore, histological study showed that the rectal mucosa was completely intact with no signs of irritation upon treatment with DCT-loaded nanomicelles. Conclusions: Taken together, our novel thermosensitive and biadhesive nanomicelles demonstrated the ability to improve the bioavailability and chemotherapeutic potential of DCT in vivo. To the best of our knowledge, this is the first report describing the rectal delivery of DCT-loaded nanomicelles. © 2013 Springer Science+Business Media New York.


Lee H.S.,Seoul National University | Lee H.S.,Samil Pharmaceutical Co. | Son W.-C.,University of Ulsan | Ryu J.-E.,University of Ulsan | And 2 more authors.
Molecules | Year: 2014

The aim of this study was to examine the effect of standardized extract of Salvia miltiorrhiza (SME) on gene and protein expression of non-alcoholic steatohepatitis (NASH)-related factors in activated human hepatic stellate cells (HSC), and in mice with steatohepatitis induced by a methionine-choline deficient (MCD) diet. Male C57BL/6J mice were placed on an MCD or control diet for 8 weeks and SME (0, 0.1, 0.5 and 1 mg/kg body weight) was administered orally every other day for 4 or 6 weeks. HSCs from the LX-2 cell line were treated with transforming growth factor β-1 (TGF-β1) or TGF-β1 plus SME (0.1-10 μg/mL). To investigate the effect of SME on reactive oxygen species (ROS)-induced condition, LX-2 cells were treated with hydrogen peroxide (H2O2) or H2O2 plus SME (0.1-100 μg/mL). MCD administration for 12 weeks increased mRNA expression of tumor necrosis factor (TNF-α), TGF-β1, interleukin-1β (IL-1β), C-reactive protein (CRP), α-smooth muscle actin (α-SMA), type I collagen, matrix metalloproteinase-2 (MMP-2) and MMP-9. TGF-β1-induced LX-2 cells exhibited similar gene expression patterns. SME treatment significantly reduced the mRNA and protein expression of NASH-related factors in the mouse model and HSCs. Histopathological liver analysis showed improved non-alcoholic fatty liver disease (NAFLD) activity and fibrosis score in SME-treated mice. The in vivo studies showed that SME had a significant effect at low doses. These results suggest that SME might be a potential therapeutic candidate for NAFLD treatment. © 2014 by the authors.


Lee H.S.,Seoul National University | Lee H.S.,Samil Pharmaceutical Co. | Jun J.-H.,Samil Pharmaceutical Co. | Jung E.-H.,Samil Pharmaceutical Co. | And 2 more authors.
Molecules | Year: 2014

Epigalloccatechin-3-gallate (EGCG) is the main polyphenol component of green tea (leaves of Camellia sinensis). EGCG is known for its antioxidant, anti-inflammatory, antiviral, and anti-carcinogenic properties. Here, we identify EGCG as a new inhibitor of ocular angiogenesis and its vascular permeability. Matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) play a key role in the processes of extracellular matrix (ECM) remodeling and microvascular permeability during angiogenesis. We investigated the inhibitory effects of EGCG on ocular neovascularization and vascular permeability using the retina oriented cells and animal models induced by VEGF and alkaline burn. EGCG treatment significantly decreased mRNA and protein expression levels of MMP-9 in the presence of 12-O-tetradecanoylphorbol-13- acetate (TPA) and tumor necrosis factor alpha (TNF-α) in human retinal pigment epithelial cells (HRPECs). EGCG also effectively protected ARPE-19 cells from cell death and attenuated mRNA expressions of key angiogenic factors (MMP-9, VEGF, VEGF Receptor-2) by inhibiting generation of reactive oxygen species (ROS). EGCG significantly inhibited proliferation, vascular permeability, and tube formation in VEGF-induced human retinal microvascular endothelial cells (HRMECs). Furthermore, EGCG significantly reduced vascular leakage and permeability by blood-retinal barrier breakdown in VEGF-induced animal models. In addition, EGCG effectively limited upregulation of MMP-9 and platelet endothelial cell adhesion molecule (PECAM/CD31) on corneal neovascularization (CNV) induced by alkaline burn. Our data suggest that MMP-9 and VEGF are key therapeutic targets of EGCG for treatment and prevention of ocular angiogenic diseases such as age-related macular degeneration, diabetic retinopathy, and corneal neovascularization. © 2014 by the authors.


Epigalloccatechin-3-gallate (EGCG) is the main polyphenol component of green tea (leaves of Camellia sinensis). EGCG is known for its antioxidant, anti-inflammatory, antiviral, and anti-carcinogenic properties. Here, we identify EGCG as a new inhibitor of ocular angiogenesis and its vascular permeability. Matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) play a key role in the processes of extracellular matrix (ECM) remodeling and microvascular permeability during angiogenesis. We investigated the inhibitory effects of EGCG on ocular neovascularization and vascular permeability using the retina oriented cells and animal models induced by VEGF and alkaline burn. EGCG treatment significantly decreased mRNA and protein expression levels of MMP-9 in the presence of 12-O-tetradecanoylphorbol-13-acetate (TPA) and tumor necrosis factor alpha (TNF-) in human retinal pigment epithelial cells (HRPECs). EGCG also effectively protected ARPE-19 cells from cell death and attenuated mRNA expressions of key angiogenic factors (MMP-9, VEGF, VEGF Receptor-2) by inhibiting generation of reactive oxygen species (ROS). EGCG significantly inhibited proliferation, vascular permeability, and tube formation in VEGF-induced human retinal microvascular endothelial cells (HRMECs). Furthermore, EGCG significantly reduced vascular leakage and permeability by blood-retinal barrier breakdown in VEGF-induced animal models. In addition, EGCG effectively limited upregulation of MMP-9 and platelet endothelial cell adhesion molecule (PECAM/CD31) on corneal neovascularization (CNV) induced by alkaline burn. Our data suggest that MMP-9 and VEGF are key therapeutic targets of EGCG for treatment and prevention of ocular angiogenic diseases such as age-related macular degeneration, diabetic retinopathy, and corneal neovascularization.


PubMed | Samil Pharmaceutical Co., University of Ulsan and Seoul National University
Type: Journal Article | Journal: Molecules (Basel, Switzerland) | Year: 2014

The aim of this study was to examine the effect of standardized extract of Salvia miltiorrhiza (SME) on gene and protein expression of non-alcoholic steatohepatitis (NASH)-related factors in activated human hepatic stellate cells (HSC), and in mice with steatohepatitis induced by a methionine-choline deficient (MCD) diet. Male C57BL/6J mice were placed on an MCD or control diet for 8 weeks and SME (0, 0.1, 0.5 and 1 mg/kg body weight) was administered orally every other day for 4 or 6 weeks. HSCs from the LX-2 cell line were treated with transforming growth factor -1 (TGF-1) or TGF-1 plus SME (0.1-10 g/mL). To investigate the effect of SME on reactive oxygen species (ROS)-induced condition, LX-2 cells were treated with hydrogen peroxide (H2O2) or H2O2 plus SME (0.1-100 g/mL). MCD administration for 12 weeks increased mRNA expression of tumor necrosis factor (TNF-), TGF-1, interleukin-1 (IL-1), C-reactive protein (CRP), -smooth muscle actin (-SMA), type I collagen, matrix metalloproteinase-2 (MMP-2) and MMP-9. TGF-1-induced LX-2 cells exhibited similar gene expression patterns. SME treatment significantly reduced the mRNA and protein expression of NASH-related factors in the mouse model and HSCs. Histopathological liver analysis showed improved non-alcoholic fatty liver disease (NAFLD) activity and fibrosis score in SME-treated mice. The in vivo studies showed that SME had a significant effect at low doses. These results suggest that SME might be a potential therapeutic candidate for NAFLD treatment.


Park Y.-J.,Samil Pharmaceutical Co. | Xuan J.J.,Yeungnam University | Oh D.H.,Yeungnam University | Balakrishnan P.,Yeungnam University | And 5 more authors.
Archives of Pharmacal Research | Year: 2010

To develop a novel itraconazole-loaded solid dispersion without crystalline change with improved bioavailability, various itraconazole-loaded solid dispersions were prepared with water, polyvinylpyrroline, poloxamer and citric acid. The effect of carriers on aqueous solubility of itraconazole was investigated. Their physicochemical properties were investigated using SEM, DSC, and powder X-ray diffraction. The dissolution, bioavailability in rats and stability of solid dispersions were evaluated. Unlike conventional solid dispersion system, the itraconazole-loaded solid dispersion with relatively rough surface did not change crystalline form of drug. Our DSC and powder X-ray diffraction results suggested that this solid dispersion was formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting in conversion of the hydrophobic drug to hydrophilic form. The itraconazole-loaded solid dispersion at the weight ratio of itraconazole/ polyvinylpyrroline/poloxamer of 10/2/0.5 gave maximum drug solubility of about 20 μg/mL. It did not change the crystalline form of drug for at least 6 months, indicating that it was physically stable. It gave higher AUC, C max and T max compared to itraconazole powder and similar values to the commercial product, suggesting that it was bioequivalent to commercial product in rats. Thus, it would be useful to deliver a poorly water-soluble itraconazole without crystalline change with improved bioavailability. © 2010 The Pharmaceutical Society of Korea and Springer Netherlands.


Park Y.-J.,Samil Pharmaceutical Co. | Park Y.S.,Chung - Ang University | Chung Z.C.,Chung - Ang University | Nam Y.S.,Chung - Ang University | And 10 more authors.
Biomolecules and Therapeutics | Year: 2011

The present study was undertaken to determine whether combined treatment with prokinetic trimebutine and mosapride has a synergic effect on gastrointestinal motility and visceral pain associated with gastrointestinal dysfunction. To develop effective gastroprokinetic agents with greater potencies than trimebutine or mosapride for the treatment of gastrointestinal tract disease, a mixture of trimebutine and mosapride was designed and prepared. In the present study, treatment with trimebutine alone showed a dose-dependent effect on propelling movements of normal small and large intestine in mice, whereas mosapride effected only small intestine motility. Co-administration of trimebutine with mosapride, a well-established prokinetic drug, produced a synergistic infl uence on normal small intestine motility, but demonstrated an unclear effect on large intestine motility, with a slight tendency to reduce the propelling time. In a stress model, the small and large intestine motilities were signifi cantly decreased. The reduction of intestine motility was restored to a normal level and the restoring effect was more pronounced in the combined treatment with trimebutine plus mosapride than treatment with trimebutine or mosapride alone. Furthermore, treatment with trimebutine plus mosapride signifi cantly decreased acute visceral pain which was not controlled by trimebutine or mosapride alone. These data suggest that combination therapy with trimebutine plus mosapride has a synergic effect on small and large intestine motility and visceral pain control in gastrointestinal disorders. © 2011 The Korean Society of Applied Pharmacology.


Lee J.S.,Yeungnam University | Park S.-Y.,Yeungnam University | Thapa D.,Yeungnam University | Choi M.K.,Yeungnam University | And 5 more authors.
Experimental and Molecular Medicine | Year: 2010

TNF-α is a major cytokine involved in inflammatory bowel disease (IBD). In this study, water extract of Grifola frondosa (GFW) was evaluated for its protective effects against colon inflammation through the modulation of TNF-α action. In coculture of HT-29 human colon cancer cells with U937 human monocytic cells, TNF-α-induced monocyte adhesion to HT-29 cells was significantly suppressed by GFW (10, 50, 100 μg/ml). The reduced adhesion by GFW correlated with the suppressed expression of MCP-1 and IL-8, the major IBD-associated chemokines. In addition, treatment with GFW significantly suppressed TNF-α-induced reactive oxygen species production and NF-κB transcriptional activity in HT-29 cells. In differentiated U937 monocytic cells, LPS-induced TNF-α production, which is known to be mediated through NF-κB activation, was significantly suppressed by GFW. In an in vivo rat model of IBD, oral administration of GFW for 5 days (1 g/kg per day) significantly inhibited the trinitrobenzene sulfonic acid (TNBS)-induced weight loss, colon ulceration, myeloperoxidase activity, and TNF-α expression in the colon tissue. Moreover, the effect of GFW was similar to that of intra-peritoneal injection of 5-aminosalicylic acid (5-ASA), an active metabolite of sulfasalazine, commonly used drug for the treatment of IBD. The results suggest that GFW ameliorates colon inflammation by suppressing production of TNF-α as well as its signaling through NF-κB leading to the expression of inflammatory chemokines, MCP-1 and IL-8. Taken together, the results strongly suggest GFW is a valuable medicinal food for IBD treatment, and thus may be used as an alternative medicine for IBD.


Joe J.H.,Yeungnam University | Lee W.M.,Yeungnam University | Park Y.-J.,Samil Pharmaceutical Co. | Joe K.H.,Yeungnam University | And 6 more authors.
International Journal of Pharmaceutics | Year: 2010

Three solid dispersions containing poorly water-soluble tacrolimus were prepared with hydroxypropyl-β-cyclodextrin (HP-β-CD) and dioctyl sulfosuccinate (DOSS) using a spray-drying technique via the solvent-evaporation method with a methylene chloride/ethanol mixture, the solvent-wetting method with ethanol and the surface-attached method with water, respectively. The solubility and dissolution of the drug in the three solid dispersions were evaluated compared to drug powder. Furthermore, their physicochemical properties were investigated using SEM, DSC and powder X-ray diffraction. The solubility and dissolution of the drug were significantly improved in the order of the tacrolimus-loaded solid dispersion prepared by: solvent-evaporation method > solvent-wetting method > surface-attached method. The solid dispersions prepared by solvent evaporation appeared as an aggregated form with the amorphous form. In particular, the solid dispersion prepared by the solvent-evaporation method improved solubility about 900-fold and dissolution of tacrolimus 15-fold because of its reduced particle size, increased surface area and close contact between the hydrophilic carrier and the drug. In the solvent-wetting method, the drug, which was changed to an amorphous form, was attached onto the surface of undissolved carriers. However, the solid dispersion prepared by the surface-attached method gave an unchanged crystalline form. In this solid dispersion, the carriers were attached to the surface of the undissolved drug, resulting in changing the drug from being hydrophobic to hydrophilic. As the crystal form of drug in this solid dispersion was not converted to the amorphous form unlike other solid dispersions, it gave relatively less solubility and dissolution of the drug than did the others. Thus, in the development of a solid-dispersion system containing poorly water-soluble drugs, the method of preparation plays an important role in the solubility and crystallinity of the drugs. © 2010.


PubMed | Samil Pharmaceutical Co.
Type: Comparative Study | Journal: Archives of pharmacal research | Year: 2010

To develop a novel itraconazole-loaded solid dispersion without crystalline change with improved bioavailability, various itraconazole-loaded solid dispersions were prepared with water, polyvinylpyrroline, poloxamer and citric acid. The effect of carriers on aqueous solubility of itraconazole was investigated. Their physicochemical properties were investigated using SEM, DSC, and powder X-ray diffraction. The dissolution, bioavailability in rats and stability of solid dispersions were evaluated. Unlike conventional solid dispersion system, the itraconazole-loaded solid dispersion with relatively rough surface did not change crystalline form of drug. Our DSC and powder X-ray diffraction results suggested that this solid dispersion was formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting in conversion of the hydrophobic drug to hydrophilic form. The itraconazole-loaded solid dispersion at the weight ratio of itraconazole/polyvinylpyrroline/poloxamer of 10/2/0.5 gave maximum drug solubility of about 20 microg/mL. It did not change the crystalline form of drug for at least 6 months, indicating that it was physically stable. It gave higher AUC, C(max) and T(max) compared to itraconazole powder and similar values to the commercial product, suggesting that it was bioequivalent to commercial product in rats. Thus, it would be useful to deliver a poorly water-soluble itraconazole without crystalline change with improved bioavailability.

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