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Drug delivery using thermosensitive liposomes (TSL) has significant potential for tumor drug targeting and can be combined with local hyperthermia to trigger drug release. Although TSL-mediated drug delivery can be effective by itself, we developed doxorubicin (DOX)-containing CO2 bubble-generating TSL (TSL-C) that were found to enhance the antitumor effects of DOX owing to the synergism between burst release of drug and hyperthermia-induced CO2 generation. An ultrasound imaging system was used to monitor hyperthermia-induced CO2 generation in TSL-C and the results revealed that hyperthermia-induced CO2 generation in TSL-C led to increased DOX release compared to that observed for non-CO2-generating TSL. Moreover, TSL-C significantly inhibited the tumor growth in MDA-MB-231 tumor-bearing mice compared to TSL (p

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.】

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.

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.

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

Ketrorolac tromethamine (KT), a nonsteroidal anti-inflammatory drug (NSAID) is required repeated administration due to its short blood half-life. To avoid dose-dependent side effects of KT, sustained-release pellets containing KT were prepared by coating with Eudragit RS 100 and Eudragit NE 30D. The in vitro and in vivo drug release behavior of KT from Eudragit RS 100 and NE 30D coated pellet (SR-A), Eudragit RS 100 coated pellet (SR-B) and conventional commercial immediate-release tablet (IR) was investigated. KT from SR-A and SR-B was slowly released over several hours, whereas IR showed rapid initial release in vitro. The pharmacokinetic study in vivo was performed by oral administration in beagle dogs. 5 mg IR was administered 3 times at intervals 5 hr. Five milligrams of IR was administered 3 times at intervals of 5 hr and 15 mg of SR-A and SR-B did once. After administering IR, KT concentration in blood showed high peak- trough fluctuation and stomach ulcer were discovered. On the other hand, SR-A and SR-B sustainedly released KT and reduced the occurrence of stomach ulcer. There sustained-release pellets will be effective system to minimize dosedependent of side effect and improve patient compliance.

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.

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.

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.

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.

Summary Background Superficial fungal infections are a very common problem in dermatological clinics. The diagnostic method of fungal culture is time-consuming and has inconsistent sensitivity. Therefore, a practical method for rapid and accurate identification of the species causing superficial fungal infections is needed. Aim To compare PCR–reverse blot hybridization assay (PCR-REBA) with conventional fungal diagnostic methods so as to determine the reliability of PCR-REBA for the diagnosis and species identification in superficial fungal infections. Methods Potassium hydroxide (KOH) preparation, fungal culture, conventional real-time PCR and PCR-REBA were used to assess 83 specimens, and the results from each method were compared. Results Of the 83 specimens, 44 specimens that were positive by fungal culture had 62.7% agreement with PCR-REBA. Compared with real-time PCR, there was 68.7% agreement with fungal culture, but 91.6% agreement with PCR-REBA. When the comparison was made using the 55 specimens that gave positive results in both KOH preparation and fungal culture, there was 85.5% agreement with real-time PCR for fungal culture, but 94.5% agreement with PCR-REBA. Conclusions Compared with KOH preparation or fungal culture, PCR-REBA has higher sensitivity and specificity. Therefore, PCR-REBA could be a useful method in clinical settings because it can identify species quickly and accurately, and can also determine the existence of pathogens.

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.

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.

Purpose: Actual delivered dose of moving tumors treated with gated volumetric arc therapy (VMAT) may significantly differ from the planned dose assuming static target. In this study, we developed a method which reconstructs actual delivered dose distribution of moving target by taking into account both tumor motion and dynamic beam delivery of gated VMAT, and applied to abdominal tumors. Methods: Fifteen dual-arc VMAT plans (Eclipse, Varian Medical Systems) for 5 lung, 5 pancreatic, and 5 liver cancer patients treated with gated VMAT stereotactic body radiotherapy (SBRT) were studied. For reconstruction of the delivered dose distribution, we divided each original arc beam into control-point-wise sub-beams, and applied beam isocenter shifting to each sub-beam to reflect the tumor motion. The tumor positions as a function of beam delivery were estimated by synchronizing the beam delivery with the respiratory signal which acquired during treatment. For this purpose, an in-house program (MATLAB, Mathworks) was developed to convert the original DICOM plan data into motion-involved treatment plan. The motion-involved DICOM plan was imported into Eclipse for dose calculation. The reconstructed delivered dose was compared to the plan dose using the dose coverage of gross tumor volume (GTV) and dose distribution of organs at risk (OAR). Results: The mean GTV dose coverage difference between the reconstructed delivered dose and the plan dose was 0.2 % in lung and pancreas cases, and no difference in liver cases. Mean D1000cc of ipsilateral lungs was reduced (0.8 ± 1.4cGy). Conclusion: We successfully developed a method of delivered dose reconstruction taking into account both respiratory tumor motion and dynamic beam delivery, and applied it to abdominal tumors treated with gated VAMT. No significant deterioration of delivered dose distribution indicates that interplay effect would be minimal even in the case of gated SBRT. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2015038710)

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.

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.

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.

A self-microemulsifying drug delivery system (SMEDDS) was developed to increase the dissolution rate, solubility, and ultimately bioavailability of a poorly water soluble drug, lovastatin. SMEDDS was the mixtures of oils, surfactants, and cosurfactants, which emulsify under conditions of gentle agitation, similar to those which would be encountered in the gastro-intestinal (GI) tract. Various types of self-emulsifying formulations were prepared using four types of oil (Capryol 90, Lauroglycol 90, Labrafil M 1944 CS and Labrafil M 2125), two surfactants (Cremophor EL and Tween 80), and three cosurfactants (Carbitol, PEG 400 and propylene glycol). The efficiency of emulsification was studied using a laser diffraction size analyzer to determine particle size distributions of the resultant emulsions. Optimized formulations selected for bioavailability assessment were Carpryol 90 (40%), Cremophor EL (30%) and Carbitol (30%). SMEDDS containing lovastatin (20 mg and 5 mg) were compared to a conventional lovastatin tablet by the oral administration as prefilled hard gelatin capsules to fasted beagle dogs for in vivo study. The area under the serum concentration-time curve from time zero to the last measured time in serum, , was significantly greater in SMEDDS, suggesting that bioavailability increase 130% and 192% by the SMEDDS, respectively. The self-emulsifying formulations of lovastatin afforded the improvement in absolute oral bioavailability relative to previous data of lovastatin tablet formulation. These data indicate the utility of dispersed self-emulsifying formulations for the oral delivery of lovastatin and potentially other poorly absorbed drugs.

Temperature-induced phase transition of polymer shows the bulk swelling change in the polymer network, which may induce the change of polymer surface properties. The contact angle measurements at the polymer–water interface were performed to observe the temperature-induced phase transition at the polymer–water interface using two-liquid technique. The dispersive and nondispersive components of surface free energy of polymer were measured above or below the phase transition temperature (lower critical solution temperature). A semi-interpenetrating polymer networks composed of sodium alginate and poly(N,N-dimethylaminoethyl methacrylate-co-ethyl acrylamide) were used as a model polymer system.

Polymer membranes composed ofN,N-dimethylaminoethyl methacrylate (DMAEMA) and acrylamide (AAm) (or ethyl acrylamide (EAAm)) were prepared to demonstrate the thermocontrol of solute permeation. Poly DMEMA has a lower critical solution temperature (LCST) at around 50°C in water. With the copolymerization of DMAEMA with AAm (or EAAm), a shift in the LCST to a lower temperature was observed, probably due to the formation of hydrogen bonds between the amide andN,N-dimethylamino groups. However, the temperature-induced phase transition of poly (DMAEMA-co-EAAm) did not show a similar trend to that of poly (DMAEMA-co-AAm) in the gel state. The hydrogen bonds in poly (DMAEMA-co-EAAm) were significantly disrupted with the formation of a gel network, which led to a difference in the swelling behavior of polymer gels in response to temperature. To apply these polymers to temperature-sensitive solute permeation, polymer membranes were prepared. The permeation pattern of hydrocortisone, used as the model solute, was explained based on the temperature-sensitive swelling behavior of the polymer membranes.

Polymer gels composed of N,N-dimethylaminoethyl methacrylate (DMAEMA) and acrylamide (AAm) (or ethyl acrylamide (EAAm)) were prepared to observe temperature-sensitive swelling behavior. The temperature dependence of equilibrium swelling of poly (DMAEMA-co-AAm) gel was in accordance with the change of the lower critical solution temperature (LCST) of poly (DMAEMA-co-AAm) aqueous solution as a function of chemical composition. However, poly (DMAEMA-co-EAAm) gel did not show the similar trend to poly (DMAEMA-co-AAm) gel. In the case of poly (DMAEMA-co-AAm), the hydrogen bond, which played an important role in controlling the LCST, was maintained with the formation of the gel network. However, the hydrogen bond in poly (DMAEMA-co-EAAm) was disrupted significantly with the formation of the gel network. This led to the difference in swelling behavior of polymer gels in response to temperature.

An important target of many controlled release systems is to properly modify the drug release behaviour in response to some external stimuli like temperature or pH changes. The copolymer gels made up by poly(N,N-dimethylaminoethyl methacrylate (DMAEMA)-co-acrylamide (AAm)), being thermosensitive, are suitable systems for the thermocontrol of the solute release. Modifying the ratio DMAEMA/AAm, one may select the copolymer systems showing desired swelling properties. In order to better design such systems and in order to understand better the solute transport through the copolymer membrane, a mathematical model has been developed. The model employs suitable flux equations for the water uptake or release and for the solute (hydrocortisone) diffusion. With the condition of knowing the copolymer swelling kinetics, the model is able to describe in a reasonably good manner the solute transport across a DMAEMA-AAm membrane undergoing step temperature changes.

A novel semi-interpenetrating networks (IPNs) system was developed in an attempt to investigate the feasibility of a polymer system as a biodegradable absorbent material. This system consisted of two chemically independent polymers. The first network consisted of sodium alginate which disintegrated by a natural erosive force. The other was a polyacrylic acid which provided a high swelling capacity to the polymer system. Swelling and DSC experiments were performed to characterize the physical properties of the model polymer system. These showed the characteristic swelling behaviors of absorbent materials. Fungi resistance tests were conducted to observe the biodegradability of the model polymer system, suggesting that the model polymer system would be attacked by a soil microorganism which would cause disintegration by a natural erosive force.

A pH-sensitive drug delivery system has been prepared using an O W emulsion, which consists of a core and capsule. The core consists of oil and dispersed drug. A novel semi-interpenetrating networks (semi-IPNs) system has been developed to provide a capsule network which shows pH-sensitive swelling behavior. The first network consists of sodium alginate which disintegrates in the intestinal fluid. The other is a polyacrylic acid which provides pH-sensitive swelling capacity to the capsule network. The drug delivery system in this study showed a pH-sensitive drug release pattern which was due both to the diffusion of drug through the capsule network and to the escape of drug from the surface which underwent disintegration after swelling depending on the chemical composition of the capsule network and the pH of release media.

Ultrasound-sensitive (sonosensitive) liposomes for tumor targeting have been studied in order to increase the antitumor efficacy of drugs and decrease the associated severe side effects. Liposomal contrast agents having Gd(III) are known as a nano-contrast agent system for the efficient and selective delivery of contrast agents into pathological sites. The objective of this study was to prepare Gd(III)-DOTA-modified sonosensitive liposomes (GdSL), which could deliver a model drug, doxorubicin (DOX), to a specific site and, at the same time, be capable of magnetic resonance (MR) imaging. The GdSL was prepared using synthesized Gd(III)-DOTA-1,2-distearoyl-sn-glycero-3-phosphoethanolamine lipid. Sonosensitivity of GdSL to 20-kHz ultrasound induced 33% to 40% of DOX release. The relaxivities (r 1) of GdSL were 6.6 to 7.8 mM−1 s−1, which were higher than that of MR-bester®. Intracellular uptake properties of GdSL were evaluated according to the intensity of ultrasound. Intracellular uptake of DOX for ultrasound-triggered GdSL was higher than that for non-ultrasound-triggered GdSL. The results of our study suggest that the paramagnetic and sonosensitive liposomes, GdSL, may provide a versatile platform for molecular imaging and targeted drug delivery.

The purpose of this study was to synthesize biocompatible polyvinylpyrrolidone (PVP)-coated iron oxide (PVP-IO) nanoparticles and to evaluate their efficacy as a magnetic resonance imaging (MRI) contrast agent. The PVP-IO nanoparticles were synthesized by a thermal decomposition method and characterized by x-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light scattering (DLS), and a superconducting quantum interface device (SQUID). The core size of the particles is about 8-10 nm and the overall size is around 20-30 nm. The measured r(2) (reciprocal of T(2) relaxation time) and r2∗ (reciprocal of T2∗ relaxation time) are 141.2 and 338.1 (s mM)(-1), respectively. The particles are highly soluble and stable in various buffers and in serum. The macrophage uptake of PVP-IO is comparable to that of Feridex as measured by a Prussian blue iron stain and phantom study. The signal intensity of a rabbit liver was effectively reduced after intravenous administration of PVP-IO. Therefore PVP-IO nanoparticles are potentially useful for T(2)-weighted MR imaging.

Heparin-immobilized Pluronic (F-68)/Polyvinylalcohol (PVA) composite microparticles were designed and characterized for the sustained drug delivery of ionic drug. Venlafaxine, antidepressant medication, was used as a model drug. For the efficient loading of ionic drug, heparin was immobilized into F-68/PVA composite microparticles. Differential scanning calorimetry (DSC) was used to understand the intra/intermolecular interactions in the heparin-immobilized F-68/PVA composite gels containing model drug. For the application as a sustained drug delivery system, the loading amount and release pattern of loaded drug were measured using high performance liquid chromatography (HPLC).

Purpose: To generate a synthetic mammogram from a digital breast tomosynthesis (DBT) image which will be comparable to an actual mammogram. Methods: Prior to reconstruction of the DBT image, the obtained projections undergo preprocessing by modifying the distribution of pixel values in each projection. After reconstruction using filtered back-projection with the processed projections, the forward projection and maximum intensity projection of the reconstructed image are taken using the ray-driven scheme. The forward projection and maximum intensity projection are then put through a low-pass and high-pass filter respectively to obtain relevant information. The two filtered images are then added together to generate the synthetic mammogram. Results: Modifying the pixel value distribution in the projections prior to reconstruction improves contrast in the DBT image and therefore in the final synthetic image as well. This makes structures of interest such as microcalcification structures and mass lesions more readily identifiable. The downside to this approach is that noise is also amplified which can be partly mitigated by use of a low-pass filter. In the synthetic image generated using the proposed method, structures of interest are just as visible as in the actual mammograms upon visual inspection. Combining the forward and maximum intensity projections after filtering gave better results that were visually more similar to the actual mammogram than using just the forward projection or maximum intensity projection alone. Conclusion: The results show that images generated using the proposed method are comparable to actual mammograms upon initial inspection, although further study of its diagnostic performance is needed.

A novel method for preparing the PLGA nanospheres with hydrophilic surface has been designed and characterized. Because of good solubility of tetraglycol in water, PLGA (poly(lactide-co-glycolide)) nanospheres were formed by spraying the PLGA/tetraglycol solution into water. The size of PLGA nanospheres was manipulated by changing the concentration of PLGA/tetraglycol solution. Based on the hydrophobic interaction between PLGA and poly(propylene oxide) domain of F-127 (one of Pluronics, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer, F-127-coated PLGA nanospheres was prepared to enhance the stability of PLGA nanospheres in the aqueous media. For the application as a drug delivery vehicle, it was characterized by measuring the loading amount, the encapsulation efficiency and the release pattern of drug. Paclitaxel used as a potent anti-cancer drug was selected as a model drug.

The purpose of the present study was to develop implantable BCNU-loaded poly(D,L-lactide-co-glycolide) (PLGA) wafer for the controlled release of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and to evaluate its in vitro and in vivo antitumor activity. The release rate of BCNU from PLGA wafer increased with the increase of BCNU amount loaded and the release was continued until 7 days. In vitro and in vivo antitumor activity of BCNU-loaded PLGA wafer was investigated using in vitro cytotoxicity against 9L gliosarcoma cells and a subcutaneous (s.c.) solid tumor model of 9L gliosarcoma, respectively. The wafers containing BCNU showed more effective cytotoxicity than BCNU powder due to its short half-life and inhibited the proliferation of 9L gliosarcoma cells. BCNU-loaded PLGA wafer delayed the growth of the tumors significantly and increasing the dose of BCNU in the wafer resulted in a substantial regression of the tumor. These results of antitumor activity of BCNU-loaded PLGA wafer demonstrate the feasibility of the wafers for clinical application.

Purpose: The purpose of our study is to reduce imaging radiation dose while maintaining image quality of region of interest (ROI) in X-ray fluoroscopy. A low-dose real-time ROI fluoroscopic imaging technique which includes graphics-processing-unit- (GPU-) accelerated image processing for brightness compensation and noise filtering was developed in this study. Methods: In our ROI fluoroscopic imaging, a copper filter is placed in front of the X-ray tube. The filter contains a round aperture to reduce radiation dose to outside of the aperture. To equalize the brightness difference between inner and outer ROI regions, brightness compensation was performed by use of a simple weighting method that applies selectively to the inner ROI, the outer ROI, and the boundary zone. A bilateral filtering was applied to the images to reduce relatively high noise in the outer ROI images. To speed up the calculation of our technique for real-time application, the GPU-acceleration was applied to the image processing algorithm. We performed a dosimetric measurement using an ion-chamber dosimeter to evaluate the amount of radiation dose reduction. The reduction of calculation time compared to a CPU-only computation was also measured, and the assessment of image quality in terms of image noise and spatial resolution wasmore » conducted. Results: More than 80% of dose was reduced by use of the ROI filter. The reduction rate depended on the thickness of the filter and the size of ROI aperture. The image noise outside the ROI was remarkably reduced by the bilateral filtering technique. The computation time for processing each frame image was reduced from 3.43 seconds with single CPU to 9.85 milliseconds with GPU-acceleration. Conclusion: The proposed technique for X-ray fluoroscopy can substantially reduce imaging radiation dose to the patient while maintaining image quality particularly in the ROI region in real-time.« less

Objectives Childhood allergic diseases are a major concern because they lead to a heavy economic burden and poor quality of life. The purpose of this study was to investigate the prevalence of childhood atopic dermatitis, asthma, allergic rhinitis, and the comorbidity of allergic diseases in Seoul, Korea. Methods We conducted a cross-sectional survey between May and October 2010 to evaluate the prevalence of childhood allergic diseases, including atopic dermatitis, asthma, and allergic rhinitis, using a questionnaire from the International Study of Asthma and Allergies in Childhood group. Each questionnaire was completed by the parent or guardian of a child. Results In the 31,201 children studied, the prevalence of atopic dermatitis symptoms in the past 12 months was 19.3% in children 0 to 3 years of age, 19.7% in children 4 to 6 years of age, 16.7% in children 7 to 9 years of age, and 14.5% in children 10 to 13 years of age (p for trend < 0.001). The prevalence of asthma in these age groups was 16.5%, 9.8%, 6.5%, and 5.4%, respectively (p for trend < 0.001). The prevalence of allergic rhinitis in these age groups was 28.5%, 38.0%, 38.5%, and 35.9%, respectively (p for trend = 0.043). The percentage of subjects with both atopic dermatitis and asthma, both asthma and allergic rhinitis, or both atopic dermatitis and allergic rhinitis was 2.5%, 4.7%, and 8.7%, respectively. The prevalence of comorbid allergic diseases decreased with age (p for trend < 0.001). Conclusions Our study revealed that the prevalence of some allergic diseases, such as atopic dermatitis and asthma, was relatively high in very young children and that all of the principal allergic diseases in children often co-exist.

Purpose: To reduce imagingradiationdose to the patient in cone‐beam CT(CBCT) for image‐guidedradiation therapy via intensity‐weighted region‐of‐interest (IWROI) imaging with a half‐fan geometry. Methods: An intensity‐weighting (IW) filter made of copper was mounted on the X‐ray tube unit of the on‐board imager (OBI) for CBCTdata acquisition. Since a half‐fan full‐scan mode is the choice of scanning for most treatment sites including the chest and the abdomen due to its enlarged field‐of‐view (FOV), the half‐fan scan mode has been used in this study. Accordingly, the IW filter was placed asymmetrically to cover outer part of the FOV. As a result, the region corresponding to the outer FOV was illuminated by the filtered beam during the scan. By sacrificing the image quality of the outer ROI‐region, one can reduce the overall imagingradiationdose to the patient dramatically. A humanoid abdomen phantom was used for the IWROI imaging experiment. Both the Feldkamp‐Davis‐Kress (FDK) and the chord‐ based backprojection‐filtration (BPF) algorithms were used for image reconstruction, and the results were compared. Correction of image artifacts caused by the edge of filter and the heterogeneity in beam‐quality was also made. Results: FDK algorithm produced images with artifacts when truncated data were used, whereas the BPF algorithm was capable of reconstructing exact ROI images without truncation artifacts from the truncated cone‐beam data. Dosimetric measurements are in progress to assess quantitative evaluation of imagingdose reduction. In addition, a feasibility study of image registration using the ROI images obtained by the proposed method is also going to be presented. Conclusions: The proposed half‐fan‐based IWROI imaging technique can be a valuable option for CBCT in IGRT applications, considering the substantial radiationdose imposed by the repeated use of conventional CBCT.