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Oleanolic acid has been used only as a subsidiary agent in cosmetic products. The aim of the study is to show the effect of oleanolic acid as an active ingredient for the alleviation of wrinkles in humans and to develop a polymeric micelle formulation that enables poorly soluble oleanolic acid to be used as a main ingredient in cosmetic products for reducing wrinkles. The solubility of oleanolic acid was evaluated in solubilizers, surfactants, and polymers. The particle sizes and shapes of polymeric micelles containing oleanolic acid were evaluated by electrophoretic light scattering spectrophotometer and scanning electron cryomicroscopy. Encapsulation efficiency and skin permeation were measured by HPLC. Stability of the polymeric micelles stored at 40 °C for 3 months was evaluated by visual observation, particle size measurement, and oleanolic acid content measurement. Polymeric micelles in final product ampoule form were applied around the eyes of 23 female subjects for 8 weeks. Five skin parameters were evaluated by optical profilometry every 4 weeks for 8 weeks. In addition, professionals made visual observations of the skin and a human skin irritation study was conducted. Polymeric micelles of oleanolic acid with a particle size of less than 100 nm were prepared using Capryol 90® and poloxamer. The skin permeation rate of the oleanolic acid in the polymeric micelles was higher than that in the other solutions made of oleanolic acid dispersed in 2 different surfactants. No significant changes in particle size, color, or oleanolic acid content were observed, and the polymeric micelles stored at 40 °C for 3 months did not undergo phase separation. After 8 weeks of application, skin irritation had not developed and all five parameters evaluated by optical profilometry as well as the visual evaluation scores were significantly improved. This study showed that the polymeric micelles of oleanolic acid prepared in this study were stable and effective at alleviating wrinkles in humans as the principal active ingredient. Based on these findings, it is expected that polymeric micelles of oleanolic acid can be widely used in cosmetic applications.

A new theranostic ultrasmall superparamagnetic iron oxide nanoparticle (USPIONP)—consisting of an iron oxide nanoparticle (IONP) core, amphiphilic poly(aspartic acid) graft copolymer (P), and a model anticancer drug, epirubicin (EPI)—was developed and characterized. The graft copolymer P, poly(2-hydroxyethylaspartamide)-mPEG-C16, was synthesized by a polysuccinimide ring-opening reaction. The P-IONP, the IONP core of which was coated with polymer P, was synthesized using a co-precipitation method. The P-IONP was a USPIONP with an IONP core of diameter 6–9 nm and a hydrodynamic diameter of 41 nm. The EPI-loaded P-IONP (EPI-P-IONP) had a hydrodynamic diameter of 53 nm. The remarkably high relaxivity, r2, of 605.5 s−1 mM−1 of EPI-P-IONP corresponded to magnetic resonance contrast enhancement 2.7-fold that of a commercial contrast agent. The EPI encapsulation efficiency was 81%, and EPI was released from EPI-P-IONP in a sustained manner. P-IONP had negligible cytotoxicity against HeLa cells, while cytotoxicity increased in an EPI-dose-dependent manner after 4 h incubation with EPI-P-IONP. Cellular uptake of EPI from EPI-P-IONP was comparable to that of free EPI, as determined by flow cytometry. Confocal microscopy confirmed nuclear uptake of EPI released from EPI-P-IONP. These results suggest that the P-IONP has potential as an imaging agent and a therapeutic agent, and thus as a theranostic agent.

Organic-free MnO2 aerogels with ultralow density have been achieved by self-assembly of two dimensional MnO2 nanosheets via an ice-templating approach., Self-assembling inorganic nanoparticles (NPs) into macroscopic three dimensional (3D) architectures often requires the assistance of organic components, leaving residual organics in the resultant. In this work, organic-free MnO2 aerogels with ultralow density have been achieved by the self-assembly of two dimensional (2D) MnO2 nanosheets via an ice-templating approach. To the authors' best knowledge, it is the first reported case of constructing a high-purity inorganic aerogel from preformed NPs without using any functionalization or stabilization agents. Moreover, it has been demonstrated that an ultralight MnO2 aerogel with a density as low as ∼0.53 mg cm–3, which is the lightest metal oxide aerogel to date, can be well obtained by such an approach. The successful formation of the aerogel can be attributed to the enhanced van der Waals force between the 2D building blocks that have been more orderly arranged by the squeezing of ice crystals during the freezing process. Hence, this work shows a pioneering example of assembling inorganic NPs into aerogels relying only on the weak interactions between NPs (e.g. van der Waals forces). It has also been demonstrated that the obtained MnO2 aerogel can function as an effective absorbent for toxic reducing gas, owing to its strong oxidation ability and high porosity. The strategy presented herein holds good potential to be applied to the fabrication of other high-purity inorganic aerogels, especially those with 2D building blocks readily available.

Root-induced changes play a crucial role in influencing the fate and speciation of potentially toxic elements (PTEs) in contaminated soils, but their role in the phytostabilization of waste slag sites remain unclear. The aim of this study was to determine the effect of four phytostabilization plants, Broussonetia papyrifera, Arundo donax, Robinia pseudoacacia, and Cryptomeria fortunei, planted in a zinc smelting waste slag site for 5 years on PTEs speciation and the mineral and aggregation characteristics at the interface of the waste slag-plant system. The results showed that the presence of a higher content of oxalic acid in the rhizosphere slags of the four plant species than in the bare slag. Revegetation of the waste slag with the four plant species significantly changed the mineral composition and morphology of the waste slag. The mass percentage of large particles (1-5 mm) and small particles (0.5-1 mm, 0.25-0.5 mm, and0.25 mm) in the rhizosphere slags decreased and increased, respectively. The PTEs (Cu, Pb, Zn, and Cd) in most of the rhizosphere slags were mainly distributed within the small particles, and the enrichment coefficients of PTEs in the large particles and small particles were less than and greater than 1, respectively. The bioavailability of the PTEs in the waste slag increased with decreasing particle size. Root-induced the transformation of acid-soluble PTEs into their reducible, oxidizable, and residual forms in the different waste slag particles weathered in the rhizosphere. These results suggested that there are root-induced changes in the aggregation characteristics and geochemical behaviours of PTEs in waste slag fractions during the phytoremediation of waste slag sites.

To prevent Cr poisoning of the cathode and to retain high conductivity during solid oxide fuel cell (SOFC) operation, Cu or La doped Co-Mn coatings on a metallic interconnect is deposited and followed by oxidation at 750 °C. Microstructure and composition of coatings after preparation and oxidation is analyzed by X-ray diffraction (XRD) and scanning electron microscopy (SEM). High energy micro arc alloying process, a low cost technique, is used to prepare Cu or La doped Co-Mn coatings with the metallurgical bond. When coatings oxidized at 750 °C in air for 20 h and 100 h, Co3O4 is the main oxide on the surface of Co-38Mn-2La and Co-40Mn coatings, and (Co,Mn)3O4 spinel continues to grow with extended oxidation time. The outmost scales of Co-33Mn-17Cu are mainly composed of cubic MnCo2O4 spinel with Mn2O3 after oxidation for 20 h and 100 h. The average thickness of oxide coatings is about 60–70 μm after oxidation for 100 h, except that Co-40Mn oxide coatings are a little thicker. Area-specific resistance of Cu/La doped Co-Mn coatings are lower than that of Co-40Mn coating. (Mn,Co)3O4/MnCo2O4 spinel layer is efficient at blocking the outward diffusion of chromium and iron.

종양 조직으로 약물을 효과적으로 전달하기 위하여 리포솜의 개발이 활발이 연구되고 있다. 그러나 리포솜이 종양조직에 효과적으로 축적됨에도 불구하고, 낮은 약물 방출 때문에 리포솜의 치료 효과가 제한적이다. 따라서 우리는 외부 자극에 의하여 약물방출을 최대화 시킬 수 있는 온도민감성 리포솜을 개발하였다. 모델약물인 독소루비신은 pH 전위차 방법에 의하여 리포솜 내부에 봉입하였다. 리포솜의 입자 크기는 $142.0{\pm}6.24nm$ 이었고, 표면전하는 $-10.55{\pm}1.12mV$ 이었다. 온도민감성 리포솜으로부터 약물의 방출은 형광광도계로 측정하였으며 $42^{\circ}C$ 이상에서 5분 이내에 80% 이상의 방출률을 나타냈다. 초음파에 의해 온도민감성 리포솜으로부터 방출된 독소루비신의 세포독성은 초음파를 조사하지 않은 온도민감성 리포솜보다 월등히 우세하였다. 이번 연구에서 우리는 초음파에 의하여 온도민감성 리포솜으로부터 온도에 민감한 약물방출을 증명하였고, 이것은 외부 자극에 의한 종양조직의 약물 농도를 증가시킬 수 있는 암치료에 효과적일 것이다. 【Development of liposomes has been actively studied for effective delivery of drug at tumor site. However, despite their preferential accumulation at tumor site, the therapeutic efficacy of such liposomal drug has been limited because of low drug release. Therefore, we developed a temperature-sensitive liposome (TSL), which can be made to maximize release of drug by external stimulation such as ultrasound. Doxorubicin (DOX) as a model drug was encapsulated into TSL by a pH gradient method. The particle size of the TSL was $142.0{\pm}6.24nm$ . Surface charge was $-10.55{\pm}1.12mV$ . Release of drug from TSLs was up to 80% within 15 min at over $42^{\circ}C$ measured by fluorescence intensity. Cytotoxicity of released DOX from TSLs with ultrasound was highly increased compared to TSLs without ultrasound. Taken together, we demonstrate that temperature sensitive drug release from TSLs with ultrasound, which may be useful for cancer therapy to increase drug concentration at tumor site by external stimulation.】

Junsung Park,1,2,* Wonkyung Cho,1,2,* Hee Jun Park,1,2 Kwang-Ho Cha,1,2 Dae-Chul Ha,2,5 Youn-Woong Choi,5 Ha-Young Lee,3 Sun-Hang Cho,5 Sung-Joo Hwang1,41Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea; 2College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea; 3Biomaterials Laboratory, Korea Research Institutes of Chemical Technology, Daejeon, Republic of Korea; 4College of Pharmacy, Yonsei University, Incheon, Republic of Korea; 5Korea United Pharm Inc, Seoul, Republic of Korea *These authors contributed equally to this workObjectives: The purpose of this study was to observe the pharmacokinetic behavior of newly synthesized biocompatible polymers based on polyhydroxyethylaspartamide (PHEA) to be used to coat an iron oxide core to make superparamagnetic iron oxide nanoparticles (SPION).Materials and methods: The isotopes [14C] and [59Fe] were used to label the polymer backbone (CLS) and iron oxide core (FLS), respectively. In addition, unradiolabeled cold superparamagnetic iron oxide nanoparticles (SPION/ULS) were synthesized to characterize particle size by dynamic light scattering, morphology by transmission electron microscopy, and in vivo magnetic resonance imaging (MRI). CLS and FLS were used separately to investigate the behavior of both the synthesized polymer and [Fe] in Sprague Dawley (SD) rats, respectively. Because radioactivity of the isotopes was different by β for CLS and γ for FLS, synthesis of the samples had to be separately prepared.Results: The mean particle size of the ULS was 66.1 nm, and the biodistribution of CLS concentrations in various organs, in rank order of magnitude, was liver > kidney > small intestine > other. The biodistribution of FLS concentrations was liver > spleen > lung > other. These rank orders show that synthesized SPION mainly accumulates in the liver. The differences in the distribution were caused by the SPION metabolism. Radiolabeled polymer was metabolized by the kidney and excreted mainly in the urine; [59Fe] was recycled for erythrocyte production in the spleen and excreted mainly in the feces. The MR image of the liver after intravenous injection demonstrated that [Fe] effectively accumulated in the liver and exhibited high-contrast enhancement on T2-weighted images.Conclusion: This newly synthesized, polymer-coated SPION appears to be a promising candidate for use as a liver-targeted, biocompatible iron oxide MR imaging agent.Keywords: SPION, radiolabeled, polyhydroxyethylaspartamide, pharmacokinetic, liverCorrigendum for this paper has been published

Red ginseng (the steamed root of Panax ginseng C. A. Mayer), which contains ginsenosides as its main constituents, is frequently used to treat tumor, inflammation, diabetes, stress and acquired immunodeficiency syndrome in Asian countries. Ginsenoside Rhl, a bacterial metabolite of ginsenoside Rgl, is a protopanaxatriol type of ginsenosides. Liposomes do not deeply penetrate the skin and remain confined to the stratum corneum.Thus, new vesicular colloidal carriers such as ethosomes and transfersomes have been developed as an enhanced type of liposomes, recently. The aim of this study was to improve the topical delivery of ginsenoside Rhl isolated from red ginseng employing new vesicular system of ethosomes and transfersomes compared to conventional liposome. Characterization of ginsenoside Rhl-loaded vesicles were prepared and evaluated for particle size, zeta potential, entrapment efficiency (% EE), and transmission electron microscopy (TEM) studies. In addition, skin permeation profile was obtained using frantz diffusion cells and rat dorsal skin treated with ethosome and transfersome compared with conventional iposome. The size of vesicles range from 108.5 to 322.9 nm, and negatively charged from -20.95 to -31.37 mV. The % EE of ginsenoside Rh1 was obtained between 45.0 to 65.0%. Transfersomes provided a significantly higher skin permeation of ginsenoside Rhl compared to ethosome and conventional liposome. Therefore, based on the current study, ginsenoside Rhl-loaded transfersomes can act as a topical therapeutic effects potential.

Liposomes, which can deliver payload at target site, have been studied as drug carrier. However, conventional liposomes have limitation for drug release at target site. Therefore, we developed hydroxyapatite (HA) coated ultrasound sen- sitive liposomes to increase drug release at target site and to enhance stability in blood stream. Control liposome was prepared using hydrogenated soy phosphatidylcholine (HSPC) and cholesterol, and then we assessed HA coating on the surface of con- trol liposomes using calcium acetate, phosphoric acid, and 25% ammonium solution. Doxorubicin was used as a model drug. Size of HA coated liposomes was 120 nm and encapsulation efficiency of doxorubicin in liposomes was up to 95%. Size of HA coated liposomes are not changed in 30% serum solution, however, the control liposomes was 1.4 fold increased. After ultrasound triggered drug release from liposomes, intracellular efficiency of drug released from HA coated liposomes was 3 fold increased compared to control liposomes. In this study, we developed ultrasound sensitive liposomes to enhance drug release, which will be applied in controlled drug release at disease site.

Development of dual functional liposome has been studied for cancer theragnostics. Therefore, we focused on ultrasound-sensitive liposomes with doxorubicin (DOX) and gadolinium (Gd) as a theragnostic carrier having a potential for cancer therapy and diagnosis. In this study, Gd(III)-DOTA-modified sonosensitive liposomes (GL) was developed using chemically synthesized Gd(III)-DOTA-DPPE lipid. Sonosensitivity of GL to 1 MHz ultrasound induced 25% of DOX release. The relaxivities () of GL were , which was higher than that of MR-bester. Intracellular delivery of DOX from GL by ultrasound irradiation was evaluated according to ultrasound intensity, resulting in increase of uptake of DOX released from ultrasound-triggered GLs compared to GL3 or Doxil without ultrasound. Taken together, this study shows that the paramagnetic and sonosensitive liposomes, GL, is a novel and highly effective delivery system for drug with the potential for broad applications in human disease.

The Pluronic/poly(ethylene glycol) composite nanoparticles (NPs) composed of Pluronic F-68, liquid poly(ethylene glycol) (PEG; molecular weight, 400) and human growth hormone (hGH) were stabilized with the vesicle fusion. When hGH-loaded Pluronic/PEG composite NPs were mixed with vesicles in the aqueous medium, hGH-loaded Pluronic/PEG composite NPs were incorporated into vesicles to form multi-core vesicle NPs. The morphology and size distribution of multi-core vesicle NPs were observed using field emission scanning electron microscopy, cryo-transmission electron microscopy, and a particle size analyzer. When multi-core vesicle NPs were applied as a delivery system for the protein drug, a sustained release pattern of hGH was observed.

In this study, poly(ethylene glycol) (PEG) was used as a hydrophilic polymer carrier to develop solid dispersion formulations for enhancing solubility and dissolution rate of pranlukast, one of poorly soluble drugs that has been broadly used for the treatment of asthma. PEG based solid dispersions with or without poloxamer were prepared by hot melting and solvent evaporation methods. The resultant solid dispersions were characterized by DSC and powder X-ray measurements, and their morphological properties were observed to be partially changed to amorphous state with reduced crystallinity. Dissolution and solubility tests showed that the solubility and dissolution rate of the solid dispersions were significantly enhanced. The solid dispersion formulation prepared by the hot melting method with a chemical composition of pranlukast:PEG:poloxamer = 1:5:1 demonstrated the most enhanced solubility and dissolution rate. The results suggest that the solid dispersions based on PEG and poloxamer are promising systems for the enhancement of solubility and bioavailability of pranlukast.

We described the preparation of the glycol chitosan/heparin immobilized iron oxide nanoparticles (composite NPs) as a magnetic resonance imaging agent with a tumor-targeting characteristic. The iron oxide nanoseeds used clinically as a magnetic resonance imaging agent were immobilized into the glycol chitosan/heparin network to form the composite NPs. To induce the ionic interaction between the iron oxide nanoseeds and glycol chitosan, gold was deposited on the surface of iron oxide nanoseeds. After the immobilization of gold-deposited iron oxide NPs into the glycol chitosan network, the NPs were stabilized with heparin based on the ionic interaction between cationic glycol chitosan and anionic heparin. FE-SEM (field emission-scanning electron microscopy) and a particle size analyzer were used to observe the formation of the stabilized composite NPs, and a Jobin-Yvon Ultima-C inductively coupled plasma-atomic emission spectrometer (ICP-AES) was used to measure the contents (%) of formed iron oxide nanoseeds as a function of reaction temperature and formed gold deposited on the iron oxide nanoparticles. We also evaluated the time-dependent excretion profile, in vivo biodistribution, circulation time, and tumor-targeting ability of the composite NPs using a noninvasive NIR fluorescence imaging technology. To observe the MRI contrast characteristic, the composite NPs were injected into the tail veins of tumor-bearing mice to demonstrate their selective tumoral distribution. The MR images were collected with conventional T(2)-weighted spin echo acquisition parameters.

We prepared nanoparticles by a temperature-induced phase transition in a mixture of Pluronic F-68 and liquid PEG (polyethylene glycol, molecular weight: 400) containing paclitaxel (PTX) with a fast, simple, continuous and solvent-free process. The liquid PEG is used as solubilizer of PTX and the polymer for the encapsulation of PTX is composed of Pluronic F-68. At the phase transition temperature, the polymer mixture was changed to the liquid phase, and stirring the liquid polymer mixture formed emulsions composed of PEG containing PTX and liquidized Pluronic F-68. On the nanometer scale, PEG containing PTX was encapsulated by Pluronic F-68 by cooling to 0 °C to form Pluronic nanoparticles. The morphology and size distribution of the prepared Pluronic nanoparticles were observed using FE-SEM and TEM, and a particle size analyzer and cryo-TEM were used to observe the shape of paclitaxel-loaded Pluronic nanoparticles in an aqueous state. To apply Pluronic nanoparticles as a delivery system for cancer therapy, the release pattern of PTX, a model anti-cancer drug, was observed and the tumor growth was monitored by injecting the PTX-loaded Pluronic nanoparticles into the tail veins of tumor-bearing mice. We also evaluated the time-dependent excretion profile, in vivo biodistribution, circulation time, and tumor targeting ability of PTX-loaded Pluronic nanoparticles using non-invasive live animal imaging technology. In the early stage within 7 h of release, the loaded PTX was rapidly released and the sustained release was observed for up to 48 h. In vivo studies, PTX-loaded Pluronic nanoparticles were observed with higher anti-tumor efficacy compared with PTX formulated in Cremophor EL.

Core/shell nanoparticles with lipid core were prepared and characterized as pH-sensitive delivery system of anticancer drug. The lipid core is composed of drug-loaded lecithin and the polymeric shell is composed of Pluronics (poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) tri-block copolymer, F-127). Based on the preparation method in the previous report by us, the freeze-drying of drug-loaded lecithin was performed in the F-127 aqueous solution containing trehalose used as a cryoprotectant to form stabilized core/shell nanoparticles. For the application of core/shell nanoparticles as a pH-sensitive drug delivery system for anticancer drug, doxorubicin was loaded into the core/shell nanoparticles and the drug loading amount and drug release behavior in response to pH change were observed.

Biocompatible poly-[N-(2-hydroxyethyl)-d,l-aspartamide]-methoxypoly(ethyleneglycol)-hexadecylamine (PHEA-mPEG-C16) conjugated with 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid-gadolinium (DOTA-Gd) via ethylenediamine (ED) was synthesized as a magnetic resonance imaging (MRI) contrast agent. Amphiphilic PHEA-mPEG-C16-ED-DOTA-Gd forms micelle in aqueous solution. All the synthesized materials were characterized by proton nuclear magnetic resonance (1H NMR). Micelle size and shape were examined by dynamic light scattering (DLS) and atomic force microscopy (AFM). Micelles with PHEA-mPEG-C16-ED-DOTA-Gd showed higher relaxivities than the commercially available gadolinium contrast agent. Moreover, the signal intensity of a rabbit liver was effectively increased after intravenous injection of PHEA-mPEG-C16-ED-DOTA-Gd.

Osteoporosis was traditionally defined by the occurrence of nontraumatic fractures, especially of the spine, in the setting of low bone mass. Bisphosphonates are an important group of therapeutic agents for the management of osteoporosis, as they inhibit bone resorption and increase bone density, thereby potentially decreasing fracture risk. Risedronate sodium is a bisphosphonate class used by oral formulation. In this study, risedronate was transdermally delivered by iontophoresis. Effects of polarity, pH, current density, and drug concentration were studied using a side-by-side diffusion cell including the hairless mice skin. In addition we studied effect of enhancers. The flux was evaluated by HPLC/UV system. The amount of transported drug under iontophoretic delivery was approximately 186 fold higher than that under passive delivery. Flux was proportional to the increase of drug concentration and current density. The flux was observed about 0.68mg/ when the amout of Propyleneglycol monolaurate (PGML) used 1% as enhancer. Results indicated that iontophoresis is an effective method for transdermal administration of risedronate sodium

Liposomes have been used as one of the efficient carriers for drug delivery. In this study, anionic liposomes of which surface was modified by using both electrostaic interaction between anionic liposomes and cationically charged BSA molecules at lower pH than isoelectric point (pI) of BSA and denaturation of the BSA-coated liposomes by thermal treatment. The thermally denatured BSA-coated liposomes (DBAL) had mean particle diameter of 125.21.7 nm and zeta potential value of -22.44.5 mV. Loading efficiency of model drug, doxorubicin (DOX), into liposomes was 83.02.6%. Results of in vitro stability study of DBAL in blood plasma showed that the mean particle diameter of DBAL 400 did not increase in blood plasma and adsorption of plasma protein was much less than plain or anionic liposomes. Intracellular uptake of DBAL 400 evaluated by confocal microscopy observation was higher than that of PEG liposomes.

PHEA (hydroxyethyl-aspartamide)-mPEG (methoy-polyethyleneglycol)- (hexadecylamine)-ED (ethylenediamine) was prepared as a drug delivery carrier. The structure and molecular weight of polymers were characterized by -NMR and gel permeation chromatography. Micelle size and shape were measured by electro-photometer light scattering and transmission electron microscope. The mean diameter of micelles was 23 nm in aqueous solution. To evaluate the potential of these polymeric micelles as a drug carrier, PSI-mPEG--ED was conjugated with Cy5.5 for Near-Infrared Fluorescent (NIRF) based optical imaging. PSI-mPEG--ED-Cy5.5 was injected intravenously into mice (n=5) and in vivo NIRF imaging was performed during 48 h after injection. The biodistribution study at 24 h after injection showed the longcirculation property of PSI-mPEG--ED-Cy5.5. Therefore, PSI-mPEG--ED micelles could be a promising drug carrier and imaging agent.

Liposomes as one of the efficient drug carriers have some shortcomings such as their relatively short blood circulation time, fast clearance from human body by reticuloendothelial system (RES) and limited intracellular uptake to target cells. In this study, polyethylene glycol (PEG)-complexed cationic liposomes (PCL) were prepared by ionic complex of cationically charged liposomes with carboxylated polyethylene glycol (mPEG-COOH). The cationic liposomes had approximately 98.6+/-1.0 nm of mean particle diameter and 45.5+/-1.1 mV of zeta potential value. While, the PCL had 110.1+/-1.2 nm of mean particle diameter and 18.4+/-0.8 mV of zeta potential value as a result of the ionic complex of mPEG-COOH with cationic liposomes. Loading efficiency of model drug, doxorubicin, into cationic liposomes or PCL was about 96.0+/-0.7%. Results of intracellular uptake evaluated by flow cytometry and fluorescence microscopy studies showed higher intracellular uptake of PCL than that of Doxil. In addition, in vitro cytotoxicity of PCL was comparable to cationic liposomes. In pharmacokinetic study in rats, PCL showed slightly lower plasma level of DOX than that of Doxil. In vivo antitumor activity of DOX-loaded PCL was comparable to that of Doxil against human SKOV-3 ovarian adenocarcinoma xenograft rat model. Consequently, the PCL, of which surface was complexed with PEG by ionic complex may be applicable as drug delivery carriers for increasing therapeutic efficacy of anticancer drugs.

Alfuzosin, an Alphal-adrenoceptor antagonist is used for the treatment of patients with voiding and in a lesser extent storage lower urinary tract symptoms (LUTS) associated to benign prostatic hyperplasia (BPH). The objective of this study was to formulate sustained release alfuzosin HCl granules and assess their formulation variables. The as a polymer, sustained release membrane, and dibutyl sebacate (DBS) as a plasticizer were used. Multi-coated alfuzosin HCl delivery systems composed of sugar sphere, various excipients, and HPMC (hydroxy propyl methyl cellulose), Cellulose Acetate were prepared by fluid-bed coater. Membrane layer were used RS PO and NE 30D. And the alfuzosin HCl coated beads were coated immediate release drug layer for initial burst. Its dissolution test was carried out compared to conventional products ( XL). The release rate of drug from coated beads was higher than that from XL in pH 6.8.

Liposomes are spherical vesicles composed of lipid bilayer membranes. However, the conventional liposomes have been found to be plagued by rapid opsonization and taken up by the reticuloendothelial system (RES), resulting in shortened circulation time and limited intracellular uptake to target cell. In this study, polyethyleneglycol-cationic liposomes (PCL) containing cationic lipid and DSPE-mPEG were prepared by thin film cast-hydration method. The PEG liposomes had approximately of mean particle diameter and of zeta potential value. PCL had of mean particle diameter and of zeta potential value with a decrease of about 10 mV compared to the PEG liposomes. Loading of model drug, doxorubicin (DOX), in liposomes were carried out by using remote loading method and the loading efficiency of DOX in liposomes was about . Intracellular uptake and cytotoxicity of PCL were higher than that of PEG liposomes to murine B16F10 melanoma cells. In addition, anti-tumor activity of PCL was similar to that of PEG liposomes on growth of A549 human lung carcinoma in BALB/c mice. Consequently, PCL modified with cationic lipid may be applicable as anticancer drug carriers that can increase intracellular uptake and therapeutic efficacy.

Indapamide (4-chloro-N-(2-methyl-1-indolinyl)-3-sulfamoyl-benz-amide) is an oral antihypertensive diuretic agent indicated for the treatment of hypertensive. The diuretic and natriuretic effects are mainly due to the structure of o-chlorobenzenesulfonamide. The objective of this study was to formulate sustained release indapamide granules and assess their formulation variables. Granules were prepared by fluid bed coating method and consist of drug layer and membrane layer. The granules were coated with HPC and ethyl cellulose along with plasticizer dibuthyl sebacate. The release of indapamide depended on the type of Eudragit such as RS and NE 30 D used in the formulation controlled release layer. These results obtained clearly suggest that the sustained release oral delivery system for indapamide could be designed with satisfying drug release profile approved.

Composite nanoparticles were prepared and characterized as a sustained delivery system for paclitaxel, an anticancer drug. Gold nanoparticles were used as building blocks for constructing the composite nanoparticles. An ionic interaction between the anionic gold nanoparticles and cationic chitosan was induced to form the composite nanoparticles. Particle size analysis, field emission scanning electron microscopy, transmittance electron microscopy, and ultraviolet–visible were used to observe the formation of the composite nanoparticles. For the application of the composite nanoparticles as a drug carrier, paclitaxel was loaded into the composite nanoparticles, and the drug-release pattern was observed. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008

Liposomes as one of the efficient drug carriers have some shortcomings such as their short circulation time, fast clearance from human body by reticuloendothelial system (RES) and limited intracellular uptake to target cell. In this study, polyethylenglycol (PEG)-incorporated cationic liposomes were prepared by ionic complexation of positively charged liposomes with carboxylated polyethyleneglycol (mPEG-COOH). The cationic liposomes had approximately of mean particle diameter and of zeta potential value. The PEG-incorporated cationic liposomes had of mean particle diameter with an increase of about 10 nm compared to the cationic liposomes. Zeta potential value of them was indicating 30mV decrease of cationic charge compared to the cationic liposomes. The amount of PEG which was incorporated onto the cationic liposomes was assayed by using picrate assay method and the incorporation efficiency was . Loading efficiency of model drug, doxorubicin, into cationic liposomes or PEG-incorporated cationic liposomes was about . Results of intracellular uptake which were evaluated by flow cytometry analysis of doxorubicin loaded liposomes showed that intracellular uptake of PEG-incorporated cationic liposomes was higher than the cationic liposomes or DSPE-mPEG liposomes. In addition, cytotoxicity of PEG-incorporated cationic liposomes was comparable to cationic liposomes. Consequently, the PEG-incorporated cationic liposomes of which surface was incorporated with PEG by ionic complex may be applicable as anticancer drug carriers that can increase therapeutic efficacy.

The chemical formula of indapamide is 3-(aminosulfonyl)-4-chloro-N-(2,3-dihydro-2-methyl-1H-indol-l-yl)-benzamide, Indapamide is an oral antipertensive diuretic agent indicated for the treatment of hypertensive and edema. Indapamide inhibits carbonic anhydrase enzyme. Transdermal drug delivery systems, as compared to their corresponding classical oral or injectable dosage form counterparts, offer many advantages. The most important advantages are improved systemic bioavailability of the pharmaceutical active ingredients (PAI), because the first-pass metabolism by the liver and digestive system are avoided; and the controlled, constant drug delivery profile (that is, controlled zero-order absorption). Also of importance is the reduced dose frequency compared to the conventional oral dosage forms (that is, once-a-day, twice-a-week or once-a-week). Other benefits include longer duration of therapeutic action from a single application, and reversible action. For example, patches can be removed to reverse any adverse effects that may be caused by overdosing. In order to evaluate the effects of vehicles and penetration enhancers on skin permeation of Indapamide, the skin permeation rates of Indapamide from vehicles of different composition were determined using Franz cells fitted with excised hairless skins. Solubility of Indapamide in various solvents was investigated to select a vehicle suitable for the percutaneous absorption of Indapamide, The solvents used were Tween80, Tween20, Labrasol, Lauroglycol90 (LG90) and Peceol. Lauroglycol90 increase the permeability of indapamide approximately 3.75-fold compared with the control. Tween80, Tween20, Labrasol, Lauroglycol90 (LG90) and Peceol showed flux of , respectively.

To enhance the stability of liposomes in systemic circulation, a number of liposomes modified with hydrophilic polymer such as poly(ethylene oxide) have been developed. In this study, the comb-type copolymer was prepared as a surface modifier of liposome and the polymer was anchored onto the lipid bi-layer via hydrophobic interaction between aliphatic chain of phospholipids and hydrophobic chain of the polymer. The comb-type copolymer was synthesized by radical polymerization of octadecyl acrylate (ODA), hydroxy-poly-(oxyethylene) methacrylate (HPOEM) and 2-Hydroxyethyl methacrylate (HEMA). The structure of the comb-type copolymer was confirmed by 1H-NMR analysis. The stability of the comb-type copolymer-incorporated liposomes (CCIL) in serum was investigated by measuring the amount of protein adsorbed onto liposomes. The CCIL showed a much lower amount of adsorbed protein than the other liposomes. Those results indicated that the stability of CCIL in serum was higher than those of the other liposomes. Thus, the comb-type copolymer composed of ODA-HPOEM-HEMA can be a promising surface modifier for enhancement of the stability of liposomes in systemic circulation.

Venlafaxine, 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride is a novel, nontricyclic antidepressant. venlafaxine is a unique antidepressant that differs structurally from other currently available. The aim ot the study was to formulate sustained-release venlafaxine granules and assess their formulation variables. It consists of two layers, venlafaxine drug layer and sustained release coating layer and manufactured by fluidized bed process. The sustained release of drug could be increased by double-control rising various components in venlafaxine drug layer and sustained-release layer. The drug-containing granules were coated with cellulose acetate, cetyl alcohol and Eudragit RS along with plastisizer such as dibuthyl sebacate as an nano-pore former The release oi venlafaxine depended on the type of Eudragit such as RS, and RL used in the formulation of controlled release layer. These results obtained clearly suggest that the sustained release oral delivery system for venlafaxine could be designed with satisfying drug release profile approved.

Liposomes having particle size from several tens to hundreds nanometers are efficient carriers for injectable drug delivery. Enhancement of liposome stability in bloodstream has been studied because of its relatively short circulation time and fast clearance from human body by reticuloendothelial system (RES) in blood vessel. In this study, new disaccharide-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) derivatives in which lactose or sucrose as the disaccharide molecule was conjugated covalently to DSPE were synthesized. Liposomes of which surface had disaccharide molecules were prepared by incorporating the disaccharide-DSPE into liposomes as one of their lipid components. Particle size of the prepared liposomes was approximately 100 nm. The liposomes of which surface were modified with the disaccharide-DSPE showed -25 mV of zeta potential value due to the presence of hydroxyl groups on their surface, while the unmodified control liposomes showed -10 mV of zeta potential value. Loading efficiency of model drug, doxorubicin, into liposomes was about 90%. Stability of the disaccharide-modified liposomes in vitro was evaluated by monitoring the amount of protein adsorption and particle size of the liposomes in serum. Disaccharide-modified liposomes were more stable in serum than unmodified control liposomes or polyethyleneglycol (PEG)-modified liposomes due to less adsorption of serum protein and hence less increase of their particle size. The liposomes of which surface was modified with disaccharide-DSPE conjugate can be used as long-circulating carriers for drugs having high toxicity or short half-life time due to their enhanced stability in blood circulatory system.

Fluoroquinolone antibiotics with concentration-dependent killing effects and a well-established broad spectrum of activity are used commonly to treat infectious diseases caused by bacteria. However, frequent and excessive administration of these antibiotics is a serious problem, and leads to increased number of drug-resistant bacteria. Thus, there is an urgent need for novel fluoroquinolone antibiotic formulations that minimize the risk of resistance while maximizing their efficacy. In this study, we developed intramuscularly injectable polymeric microparticles (MPs) that encapsulated with marbofloxacin (MAR) and were composed of poly(D,L-lactide-co-glycolic acid) (PLGA) and poloxamer (POL). MAR-encapsulated MP (MAR-MP) had a spherical shape with particle size ranging from 80 μm to 120 μm. Drug loading efficiency varied from 55 to 85% (w/w) at increasing amount of hydrophilic agent, POL. Drug release from MAR-MP demonstrated a significant and sustained increase at increased ratios of POL to PLGA. These results indicate that MAR-MP is an improved drug delivery carrier for fluoroquinolone antibiotics, which can reduce the number of doses needed and sustain a high release rate of MAR for 2-3 days. As a novel and highly effective drug delivery platform, MAR-MP has great potential for use in a broad range of applications for the treatment of various veterinary diseases.

Stimulus-triggered drug release based on the liposomal drug delivery platform has been studied vigorously to increase drug release at the target site. Although the delivery system has been developed, an effective carrier system is needed to achieve effective therapeutic efficacy. Therefore, we focused on the development of gold cluster bound thermosensitive liposomes (G-TSL), which are capable of triggered drug release when stimulated by external near-infrared (NIR) irradiation in the tumor microenvironment. The size of doxorubicin (DOX)-loaded G-TSL (DOX/G-TSL) was 171.5 ± 8.3 nm, and the efficiency of DOX encapsulation was up to 90%. The release of DOX from DOX/G-TSL was increased 70% by NIR irradiation (1.50 W/cm(2) for 0.5 min) compared to non-gold-coated TSL. Consequentially, the gold cluster on the TSL enabled the light-controlled DOX release through the photothermal conversion of the energy of NIR-absorbed light, leading to membrane destabilization. Cell cytotoxicity of DOX/G-TSL was also increased by their NIR irradiation-triggered DOX release compared to non-NIR-irradiated DOX/G-TSL. In addition, we demonstrated the therapeutic efficacy of DOX/G-TSL against the MDA-MB-231 tumor model. The NIR-irradiated DOX/G-TSL treatment showed greater therapeutic efficacy than that of the non-NIR-irradiated DOX/G-TSL and control (p

Polyvinylpyrrolidone (PVP)-coated iron oxide nanoparticles were prepared by the thermal decomposition of Fe(CO)(5) (iron pentacarbonyl) in one step. X-ray diffraction (XRD), transmission electron microscopy (TEM), electrophoretic light scattering (ELS), infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) together with the variation of the molar ratio of PVP/Fe(CO)(5), solvent, and molecular weight of PVP, were used to characterize the PVP-coated iron oxide nanoparticles. Fifty to hundred nanometer-sized iron oxide nanoclusters with a spherical shape were formed in dimethylformamide (DMF), used as a solvent, and exhibited an enhanced stability in the aqueous media. Their magnetic properties were investigated by superconducting quantum interface device (SQUID). The in vitro cytotoxicity test revealed that the PVP-coated iron oxide nanoparticles exhibited excellent biocompatibility by MTT assay. Magnetic resonance imaging (MRI) effect was observed with the administration of PVP-coated iron oxide nanoparticles through the marginal vein of rabbit, resulting in improved detection of the liver lesions.

Tamsulosin or a salt thereof such as its hydrochloride salt has been known to have an adrenaline receptor blocking action for urethra and prostate areas. It has been widely used as a drug which lowers the prostate pressure and improves urinary disturbance accompanied by prostate-grand enlargement, thus for the treatment of prostatic hyperplasia. To avoid dose-dependent side effects of tamsulosin upon oral administration, the development of sustained-release delivery system is essentially required, that can maintain therapeutic drug levels for a longer period of time. The aim of this study was therefore to formulate sustained-release tamsulosin granules and assess their formulation variables. We designed entric coated sustained-release tamsulosin granules for this purpose. Nano-pores in the outer controlled release membrane were needed in order to obtain initial tamsulosin release even in an acidic environment such as gastric region. In our sustained release osmotic granule system, hydroxypropylmethylcellulose in a drug-containing layer was used as a rate controller. The drug-containing granules were coated with hydroxypropylmethylcellulose phthalate (HPMCP) and Eudragit, along with glycerol triacetate as an aqueous nano-pore former. The release of tamsulosin depended heavily on the type of Eudragit such as RS, RL, NE 30D, used in the formulation of controlled release layer. These results obtained clearly suggest that the sustained-release oral delivery system for tamsulosin could be designed with satisfying drug release profile approved by the Korean Food and Drug Administration.

MPEG–PCL diblock copolymers consisting of methoxy polyethylene glycol (MPEG) and poly(ϵ-caprolactone) (PCL) as drug carriers were synthesized by ring-opening polymerization. It is possible to control the balance between hydrophilic and hydrophobic by changing the MPEG and the ratio of ϵ-CL to MPEG. Implantable wafers were easily fabricated by the direct compression method after physical mixing of diblock copolymers and bovine serum albumin–fluorescein isothiocyanate (BSA-FITC) as a model protein drug. The BSA release from wafers prepared by MPEG–PCL diblock copolymers were higher than that from PCL with the physical blending of MPEG. The wafers prepared by a variety of MPEG–PCL diblock copolymers exhibited the controlled BSA release profiles with a dependence on MPEG–PCL diblock copolymer compositions. In addition, the changing of MPEG and PCL molecular weights within MPEG–PCL diblock copolymer controlled the initial burst of BSA. We confirmed that the diblock copolymers could be served as protein delivery carrier in implantable wafer form. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102:1561–1567, 2006

A novel preparation method for core/shell nanoparticles with a drug-loaded lipid core was designed and characterized. The lipid core is composed of lecithin and a drug, and the polymeric shell is composed of Pluronics (poly(ethylene oxide)-poly (propylene oxide)-poly(ethylene oxide) triblock copolymer, F-127). For the formation of stabilized core/shell nanoparticles, freeze-drying was performed in the presence of trehalose used as a cryoprotectant. Cryogenic transmittance electron microscopy (cryo-TEM), differential scanning calorimetry (DSC), and a particle size analyzer were used to observe the formation of the stabilized core/shell nanoparticles. For the application of the core/shell nanoparticles as a drug carrier, paclitaxel, a potent anticancer drug, was loaded into the core/shell nanoparticles, and the drug loading amount and the drug release pattern were observed.

A novel preparation method for core/shell nanoparticles with hydrophilic polymeric shell was designed and characterized. The core is composed of poly(lactide-co-glycolide) and polymeric shell is composed of pluronics (poly (ethylene oxide)-poly (propylene oxide)-poly(ethylene oxide) triblock copolymer, F-127) and hyaluronic acid (HA). The role of core is to provide the nucleus for the stable formation of hydrophilic polymeric shell by physical adsorption and that of polymeric shell is to provide the hydrophilic network for protein loading. Lysozyme, which was used as a model drug and protonated in the physiological pH, was successfully loaded into polymeric shell up to 7 wt% via ionic interaction between HA and lysozyme and the sustained release pattern was observed, which was due to the stable immobilization of lysozyme in the polymeric shell.

The main objective of this study was to develop an optimal paclitaxel microemulsion prepared by self-microemulsifying drug delivery system (SMEDDS) which is a mixture of paclitaxel, tetraglycol, Cremophor ELP, and Labrafil 1944 and a paclitaxel microemulsion containing poly( d , l -lactide-co-glycolide) (PLGA) in order to offer controlled release of paclitaxel. To achieve this goal, paclitaxel and PLGA were dissolved by solubilizer like tetraglycol. There was not observed any change in molecular weight of PLGA after being solubilized by tetraglycol. The droplet size for all of the formulation of microemulsion was found in the range of 45–270 nm by dynamic light scattering (DLS). It was observed that the droplet size of microemulsion without PLGA was smaller than that of microemulsion containing PLGA by transmission electron microscopy (TEM). The droplet of microemulsion containing PLGA was almost of spherical shape with smooth surface and there was no aggregation or adhesion among droplet of microemulsion by atomic force microscopy (AFM). The release behaviour of paclitaxel from microemulsion containing PLGA having various molecular weights (8K, 33K, and 90K) exhibited a biphasic pattern characterized by a fast initial release during the first 48 h, followed by a slower and continuous release for 144 h, in contrast that the release of paclitaxel from microemulsion without PLGA was finished during 24 h. This result was identical with the result of anti-tumor activity in vitro of paclitaxel from microemulsion containing PLGA against human breast cancer cell line MCF7 and this formulation enhanced anti-tumor activity in vivo compared with microemulsion without PLGA against SKOV-3 human ovarian cancer cells bearing nude mice model.

Acyclovir (ACV) is one of the most effective and selective agents against viruses of the herpes group. Because of low solubility, bioavailability of ACV has shown below 30% with oral dosage form. In our previous study, we reported that the fabrication of solid dispersion of ACV was possible and the solid dispersion of ACV and PVP was the most useful in all samples. In this study, we examined the effect of mixture ratio of polymers (PEG and PVP) to ACV. Solubility of ACV was dramatically increased up to 25 mg/ml in distilled water. So water was used as a solvent to eliminate problem of residual solvent. Spray drying method was used for the solid dispersion of ACV as solvent extraction. Different scanning calorimeter was used to check degradation of drug. Polymer carriers were PEG 6,000 and PVP. In summary, ACV-PVP (1:3) showed the best solubility in distilled water.

Acyclovir(ACV) is an important antiviral drug used extensively against infections caused by herpes viruses, especially herpes simplex and varicella zoster. Because of high crystallinity and large particle size, solubility of intact ACV is very low in water(1.3 mg/ml). The goal of this work is to enhance the solubility of ACV. To make solid dispersion, Polyethyleneglycol, Hydroxyprophylmethylcelluose and Polyvinylpyrrolidone were used as polymer carriers in this work. Polymer carriers and drug were dissolved in acetic acid. And then spray drying method and freeze drying method were used as solvent extraction. Morphology, crystallization and functional group were characterized using SEM, XRD and FT-IR. The result of in vitro test showed the sample using PVP as polymer carrier had higher dissolution rate(up to 466%) than intact ACV.

The main purpose of this work is to prepare self-microemulsifying drug delivery system (SMEDDS) for oral bioavailability enhancement of a poorly water soluble drug, simvastatin. Solubility of simvastatin was determined in various vehicles. SMEDDS is mixture of oils, surfactants, and cosurfactants, which are emulsified in aqueous media under conditions of gentle agitation and digestive motility that would be encountered in the gastro-intestinal (GI) tract. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsification region and particle size distributions of the resultant microemulsions were determined using a laser diffraction sizer. Optimized formulations for in vitro dissolution and bioavailability assessment were Carpryol 90 (37%), Cremophor EL (28%), and Carbitol (28%). The release rate of simvastatin from SMEDDS was significantly higher than the conventional tablet. The prepared SMEDDS was compared with the conventional tablet (Zocor®) by administering the prefilled hard capsules to fasted beagle dogs. The absorption of simvastatin acid from SMEDDS form resulted in about 1.5-fold increase in bioavailability compared with the conventional tablet. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds, such as simvastatin by the oral route.

Ibuprofen (IBU), is a non-steroidal anti-inflammatory drug, used to treat rheumatoid arthritis, removal of fever and mild to moderate pain. Because of small dosage and very low accumulation in the body, IBU has been used to heal children's fever. However, IBU was very low solubility in a low pH and water (in water mg/ml). A nanoemulsion containing IBU by means of self-microemulsion drug delver system (SMEDDS) was prepared in order to enhance the solubility of IBU. The SMEDDS was composed of cosurfactant, oil and surfactant The solubility of IBU in various components such as cosurfactant, oil and surfactant was examined. as a cosurfactant, M1944CS as an oil and RH-40 as a surfactant were used in this study for preparing SMEDDS. Optimized formulation of SMEDDS was obtained by phase diagram which express the section of nanoemulsion formation. The SMEDDS containing IBU had higher dissolution rate than conventional IBU sirups. Thus the SMEDDS was a potential candidate of stable conventional and effective oral dosage form for IBU.

Diblock copolymers consisting of methoxy poly(ethylene glycol) (MPEG) and poly(ϵ-caprolactone) (PCL), poly(δ-valerolactone) (PVL), poly(L-lactic acid) (PLLA), or poly(lactic-co-glycolic acid) (PLGA) as biodegradable polyesters were prepared to examine the phase transition of diblock copolymer solutions. MPEG–PCL and MPEG–PVL diblock copolymers and MPEG–PLLA and MPEG–PLGA diblock copolymers were synthesized by the ring-opening polymerization of ϵ-caprolactone or δ-valerolactone in the presence of HCl · Et2O as a monomer activator at room temperature and by the ring-opening polymerization of L-lactide or a mixture of L-lactide and glycolide in the presence of stannous octoate at 130 °C, respectively. The synthesized diblock copolymers were characterized with 1H NMR, IR, and gel permeation chromatography. The phase transitions for diblock copolymer aqueous solutions of various concentrations were explored according to the temperature variation. The diblock copolymer solutions exhibited the phase transition from gel to sol with increasing temperature. As the polyester block length of the diblock copolymers increased, the gel-to-sol transition moved to a lower concentration region. The gel-to-sol transition showed a dependence on the length of the polyester block segment. According to X-ray diffraction and differential scanning calorimetry thermal studies, the gel-to-sol transition of the diblock copolymer solutions depended on their degrees of crystallinity because water could easily diffuse into amorphous polymers in comparison with polymers with a crystalline structure. The crystallinity markedly depended on both the distinct character and composition of the block segment. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 5784–5793, 2004

The objectives of this study were to investigate the influence of gamma irradiation for sterilization on poly(D,L-lactide-co-glycolide) (PLGA) with different molecular weight and the effect of gamma irradiation on the release behavior of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, carmustine) from PLGA wafer with various irradiation doses. The effect of gamma irradiation on PLGA was evaluated by gel permeation chromatography (GPC), differential scanning calorimetry (DSC), and electron paramagnetic resonance (EPR). The weight average molecular weight (M w) and glass transition temperature (T g) of PLGA decreased after gamma irradiation. The extent ofM w reduction was dependent on irradiation dose and PLGA molecular weight. Using EPR spectroscopy, we successfully detected gamma irradiation induced free radicals in PLGA. The gamma irradiation increased the release rate of BCNU from PLGA wafer at applied irradiation doses except 2.5 Mrad of irradiation dose in this study.

Melatonin (MT) is an indole amide pineal hormone. It has not only very short half-life but also pH-sensitive property. The sustained release dosage form which delivers MT in a circadian fashion over 8 h is clinical value. The purpose of this study is to prepare sugar beads using multiple coating methods and enteric-coated in a sustained release to evaluate in vitro release characteristics in simulated gastric and intestinal fluids. The as a polymer, sustained release membrane, and triethylcitrate (TEC) as a plasticzer were used. Multi-coated melatonin delivery system was composed of sugar, various excipients, and enteric materials (e.g. hydroxy propyl methyl cellulose phthalate, HPMCP), and prepared by fluid bed coater. The dissolution test was carried out using the basket method at a stirring speed of 100 rpm at in simulated gastric (pH 1.2) and intestinal fluid (pH 7.4). The released amount of MT was determined by High performance liquid chromatography method. The morhologies of surface and cross section of multi-coated beads were observed by scanning electron microscope. Size of multi-coated sugar beads was ranged over . The release rate of MT from coated beads was limited in simulated gastric fluid (pH 1.2), but it was sustained in intestinal fluid (pH 7.4) during hours. The MT beads may provide small-intestine-targeted device for oral delivery. Studies on animal and relative experiment are in process.

For last five years, we are developing the novel local drug delivery devices using biodegradable polymers, especially polylactide (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) due to its relatively good biocompatibility, easily controlled biodegradability, good processability and only FDA approved synthetic degradable polymers. The relationship between various kinds of drug [water soluble small molecule drugs : gentamicin sulfate (GS), fentanyl citrate (FC), BCNU, azidothymidine (AZT), pamidronate (ADP), 1,25(OH)2 vitamin D3, water insoluble small molecule drugs : fentanyl, ipriflavone (IP) and nifedipine, and water soluble large peptide molecule drug : nerve growth factor (NGF), and Japanese encephalitis virus (JEV)], different types of geometrical devices [microspheres (MSs), microcapsule, nanoparticle, wafers, pellet, beads, multiple-layered beads, implants, fiber, scaffolds, and films], and pharmacological activity are proposed and discussed for the application of pharmaceutics and tissue engineering. Also, local drug delivery devices proposed in this work are introduced in view of preparation method, drug release behavior, biocompatibility, pharmacological effect, and animal studies. In conclusion, we can control the drug release profiles varying with the preparation, formulation and geometrical parameters. Moreover, any types of drug were successfully applicable to achieve linear sustained release from short period (1∼3 days) to long period (over 2 months). It is very important to design a suitable formulation for the wanting period of bioactive molecules loaded in biodegradable polymers for the local delivery of drug. The drug release is affected by many factors such as hydrophilicity of drug, electric charge of drug, drug loading amount, polymer molecular weight, the monomer composition, the size of implants, the applied fabrication techniques, and so on. It is well known that the commercialization of new drug needs a lot of cost of money (average: over 10 million US dollar per one drug) and time (average: above 9 years) whereas the development of DDS and high effective generic drug might be need relatively low investment with a short time period. Also, one core technology of DDS can be applicable to many drugs for the market needs. From these reasons, the DDS research on potent generic drugs might be suitable for less risk and high return.

The objective of this study was to solidify the simvastatin self-microemulsifying drug delivery system (SMEDDS) and to improve the encapsulation efficiency of solidified alginate beads using sodium alginate. Typical simvastatin SMEDDS was composed of various oils, surfactants and cosurfactants. Also solidified-alginate beads was prepared by crosslinking liquid emulsion mixtures containing sodium alginate and other excipients (cetylpyridinum chloride (CP-Cl), hydroxypropyl methylcellulose, starch and so on). in solution, it has been investigated that the drug release pattern and encapsulation efficiency were varied with the ratio of cationic lipid (CP-Cl). Solidified sodium alginate beads containing simvastatin SMEDDS were redispersed into media without re-aggregation. Oil droplet size of redispersed solidified-beads in media produced smaller than the initial size. The density of beads and drug loading amount were increased with increasing cationic lipid content. These systems have advantages of storage stability and predictability of drug release rate.

The controlled delivery of anticancer agents using biodegradable polymeric implant has been developed to solve the problem of penetration of blood brain barrier and severe systemic toxicity. This study was performed to prepare 5-FU-loaded poly(L-lactide-co-glycolide) (PLGA) wafer fabricated microparticles prepared by two different method and to evaluate their release profile for the application of the treatment of brain tumor. 5-FU-loaded PLGA microparticles were characterized by scanning electron microscopy (SEM), powder X-ray diffraction (XRD), and differential scanning calorimetry (DSC). SEM observation of the 5-FU-loaded PLGA microparticles prepared by rotary solvent evaporation method showed that 5-FU was almost surrounded by PLGA and significant reduction of crystallinity of 5-FU was confirmed by XRD. In case of release profile of 5-FU from 5-FU-loaded PLGA wafer fabricated microparticles prepared by mechanical mixing, the release profile of 5-FU followed near first order release kinetics. In contrast to the above result, release profile of 5-FU from 5-FU-loaded PLGA wafer fabricated microparticles prepared by rotary solvent evaporation method followed near zero order release kinetics. These results indicate that preparation method of the 5-FU-loaded PLGA microparticles to fabricate into wafers was contributed to drug release profile.

A polymeric emulsion bead, which consists of core and capsule, was prepared. The core is composed of lipid nanoparticles containing lipophilic drug and semi-interpenetrating networks (semi-IPNs) are prepared to provide the capsule composed of sodium alginate and hydroxypropylmethyl cellulose (HPMC). The lipid nanoparticles were encapsulated into the polymeric emulsion bead with high drug loading efficiency, and lovastatin was used as a model drug. For the application as an oral drug delivery system, the enteric coating was performed with polymeric emulsion bead. The drug release pattern was controlled by the composition of capsule materials and environmental pH.