[Show abstract][Hide abstract]ABSTRACT: The aim of this study was to observe the effects of different test conditions on the flexural properties of root canal post. Metal- and fiber-reinforced composite root canal posts of various diameters were measured to determine flexural properties using a threepoint bending test at different conditions. In this study, the span length/post diameter ratio of root canal posts varied from 3.0 to 10.0. Multiple regression models for maximum load as a dependent variable were statistically significant. The models for flexural properties as dependent variables were statistically significant, but linear regression models could not be fitted to data sets. At a low span length/post diameter ratio, the flexural properties were distorted by occurrence of shear stress in short samples. It was impossible to obtain high span length/post diameter ratio with root canal posts. The addition of parameters or coefficients is necessary to appropriately represent the flexural properties of root canal posts.
Preview · Article · Jan 2016 · Dental Materials Journal
[Show abstract][Hide abstract]ABSTRACT: Albumin is considered an attractive dug carrier for hydrophobic drugs to target inflamed joints of rheumatoid arthritis. This study focused on the pharmaceutical potential of albumin-based nanoparticles (NPs) on delivery of tacrolimus (TAC) to enhance targetability and anti-arthritic efficacy. TAC-loaded human serum albumin (HSA) nanoparticles (TAC HSA-NPs) were prepared using the nab™ technology. The resulting NPs were 185.8±6.8nm in diameter and had a zeta potential value of -30.5±1.1mV, as determined by dynamic light scattering. Particles were uniformly spherical in shape as determined by transmission electron microscopy. The encapsulation efficacy of TAC was 79.3±3.7% and the water solubility was over 46 times greater than that of free TAC. TAC was gradually released from NPs over 24hours, which is sufficient time for targeting and treatment of the NPs in inflamed arthritis via intravenous injection. In vitro study using splenocytes excised from spleens of mice following induction of arthritis using collagen clearly demonstrated the anti-proliferative activity of TAC HSA-NPs on activated T cells compared with non-activated T cells. Furthermore, TAC HSA-NPs displayed significantly more anti-arthritis activity than TAC formulations including intravenously administered TAC solution or oral TAC suspension, as reflected by the incidence of arthritis and clinical score (1.6 vs. 3.2 and 5.0, respectively). These improvements were due to the targetability of HSA that facilitated the accumulation of TAC HSA-NPs at inflamed arthritis sites. TAC HSA-NPs are a promising drug delivery system to enhance water solubility and increase accumulation in joints for treatment of rheumatoid arthritis.
Full-text · Article · Dec 2015 · International Journal of Pharmaceutics
[Show abstract][Hide abstract]ABSTRACT: Purpose:
We developed a new nanoparticle formulation comprised of human serum albumin (HSA) for co-delivery of doxorubicin (Dox) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with the goal of apoptotic synergy in the treatment of colon cancer.
TRAIL (0.2, 0.4, 1.0%)- and Dox-loaded HSA nanoparticles (TRAIL/Dox HSA NPs) were prepared by using the nab(TM) technology. Morphological and physicochemical characterizations were investigated by dynamic light scattering and transmission electron microscopy. Synergistic cytotoxicity, apoptotic activity, and potential penetration into mass tumor were determined in HCT116 cell-based systems. Furthermore, antitumor efficacy and tumor targeting were also investigated.
TRAIL/Dox HSA NPs were uniformly spherical with sizes of 60 ~ 120 nm. The encapsulation efficacy of Dox and TRAIL was 68.9-77.2% and 80.4-86.0%, respectively. TRAIL 1.0%/Dox HSA NPs displayed the best inhibition of HCT116 colon cancer cells; inhibition was 6 times higher than achieved with Dox HSA NPs. The TRAIL 1.0%/Dox HSA NPs formulation was studied further. Flow cytometry analysis and TUNEL assay revealed that TRAIL 1.0%/Dox HSA NPs had markedly greater apoptotic activity than Dox HSA NPs. In HCT116 tumor-bearing BALB/c nu/nu mice, TRAIL 1.0%/Dox HSA NPs had significantly higher antitumor efficacy than Dox HSA NPs (tumor volume; 933.4 mm(3) vs. 3183.7 mm(3), respectively). TRAIL 1.0%/Dox HSA NPs penetrated deeply into tumor masses in a HCT116 spheroid model and localized in tumor sites after tail vein injection.
Data indicate that TRAIL 1.0%/Dox HSA NPs offer advantages of co-delivery of Dox and TRAIL in tumors, with potential synergistic apoptosis-based anticancer therapy.
Full-text · Article · Nov 2015 · Pharmaceutical Research
[Show abstract][Hide abstract]ABSTRACT: The objectives of this study were to prepare itraconazole (ITZ) nanoparticles using a Shirasu porous glass (SPG) membrane and to characterize the effects of diverse preparation parameters on the physical stability of nanoparticles. SPG membrane technology was used for the antisolvent precipitation method. The preparation of nanoparticles was carried out over a wide range of continuous-phase factors (type of surfactant, surfactant concentration), dispersed-phase factors (solvent type, solvent volume used to dissolve ITZ), and technical factors (pressure, membrane pore size, stirring speed in the continuous phase, temperature). Improved physical stability of nanoparticles was observed when surfactant with a lower molecular weight and higher hydrophilic segment ratio was used. The water miscibility of the solvent also had an effect on the physical stability. N,N-Dimethylacetamide contributed to creating a well-rounded shape and narrow size distribution due to high miscibility. Concentration of the surfactant and solvent volume used for dissolving ITZ were related to instability of nanoparticles, resulting from depletion attraction and Ostwald ripening. In addition to these factors, technical factors changed the environment surrounding ITZ nanoparticles, such as the physicochemical equilibrium between surfactant and ITZ nanoparticles. Therefore, the appropriate continuous-phase factors, dispersed-phase factors, and technical factors should be maintained for stabilizing ITZ nanoparticles.
No preview · Article · Oct 2015 · CHEMICAL & PHARMACEUTICAL BULLETIN
[Show abstract][Hide abstract]ABSTRACT: Recently, much effort has been made to develop effective dermatological depigmenting compounds. In this study, we investigated the novel candidate compound, AP736 (an adamantyl benzylbenzamide derivative), and its effects on melanogenesis in B16F10 melanoma cells, as well as the mechanisms involved. AP736 has been reported to exert anti-melanogenic effects in melanocytes in vitro and in artificial skin equivalents through the inhibition of key melanogenic enzymes and the suppression of the cAMP-protein kinase A (PKA)-cAMP response element‑binding protein (CREB) signaling pathway. Thus, we examined another pathway of melanogenesis involving the effects of AP736 on the glycogen synthesis kinase 3β (GSK3β) pathway. Melanin content and tyrosinase activity were measured using a spectrophotometer after the cells were treated with AP736. The AP736-induced activation of signaling pathways was examined by western blot analysis. We confirmed that AP736 decreased melanin production in a dose-dependent manner; however, it did not directly inhibit tyrosinase, the rate-limiting melanogenic enzyme. The expression of microphthalmia-associated transcription factor, tyrosinase, and related signal transduction pathways was also investigated. The Wnt signaling pathway is deeply involved in melanogenesis; therefore, phosphorylation by GSK3β was assessed following treatment with AP736. AP736 induced GSK3β phosphorylation (inactivation), but it did not alter the level of β-catenin. Furthermore, the expression of α-melanocyte-stimulating hormone-induced tyrosinase was downregulated by AP736. Our data suggest that AP736 exerts hypopigmentary effects through the downregulation of tyrosinase via GSK3β phosphorylation.
No preview · Article · Sep 2015 · International Journal of Molecular Medicine
[Show abstract][Hide abstract]ABSTRACT: This paper focuses on the development and physicochemical characterization of a self-microemulsifying drug delivery system (SMEDDS) containing a fixed-dose combination of atorvastatin (ATR) and ezetimibe (EZT). The solubility of both drugs was determined in excipient screening studies. Ternary-phase diagrams were drawn for 27 systems composed of different surfactants, cosurfactants, and oils at different surfactant-to-cosurfactant (S/CoS) ratios, and the system exhibiting the largest percentage area of the self-microemulsifying region was selected. The optimum oil ratio in the SMEDDS was selected by evaluating the mean droplet size of the resultant microemulsions. The underlying mechanism of the lower ATR loading capacity compared with EZT was elucidated by measurement of the zeta potential and UV absorption analysis. The results implied that ATR was located exclusively in the surfactant-cosurfactant layer, whereas EZT was located both in the microemulsion core and the surfactant-cosurfactant layer. In vitro dissolution studies showed that the SMEDDS had higher initial dissolution rates for both drugs when compared with marketed products. More importantly, EZT had a significantly increased dissolution profile in distilled water and pH 4.0 acetate buffer, implying enhanced bioavailability.
No preview · Article · Jun 2015 · Chemical & pharmaceutical bulletin
[Show abstract][Hide abstract]ABSTRACT: The main objective of this study was to develop novel orally administrable tablets containing solid dispersion granules (SDG) of amorphous paclitaxel (PTX) prepared by fluid bed technology, and to evaluate its in vitro dissolution and in vivo pharmacokinetics (PK) in beagle dogs. The SDG were prepared using optimized composition by fluid bed technology, and characterized for solid-state properties. The release study of SDG tablet (SDG-T) in simulated gastric fluid showed a rapid release of PTX, reaching maximum dissolution within 20 min. Finally, the PK profile of SDG-T and a reference formulation Oraxol™ (oral solution formulation used in Phase I clinical study) at a dose of 60 mg orally with co-administration of P-gp inhibitor HM38101, and Taxol® at a dose of 10 mg intravenously (i.v.) was investigated in beagle dogs. The mean absolute BA% of PTX following SDG-T and Oraxol™ solution was 8.23 and 6.22% in comparison to i.v. administration of Taxol®. The relative BA% of PTX from SDG-T in comparison to Oraxol™ solution was 132.25% at a dose of 60 mg following oral administration. In conclusion, we have successfully prepared PTX tablets with solid dispersion granules (SDG) of amorphous PTX using fluid bed technology that could provide plasma PTX concentration in the range of 10-150 ng/mL for a period of 24 h following oral administration in dogs with a P-gp inhibitor. Hence, this could be a promising formulation for PTX oral delivery and could be used in our intended clinical studies following pre-clinical efficacy studies.
Full-text · Article · Mar 2015 · Drug Development and Industrial Pharmacy
[Show abstract][Hide abstract]ABSTRACT: The aim of present study was to design oxycodone once-a-day controlled-release (CR) tablets and to perform in vitro/in vivo characterizations. Release profiles to achieve desired plasma concentration versus time curves were established by using simulation software and reported pharmacokinetic parameters of the drug. Hydroxypropyl methylcellulose (HPMC) 100,000 mPa·s was used as a release modifier because the polymer was found to be resistant to changes in conditions of the release study, including rotation speed of paddle and ion strength. The burst release of the drug from the CR tablets could be suppressed by applying an additional HPMC layer as a physical barrier. Finally, the oxycodone once-a-day tablet was comprised of two layers, an inert HPMC layer and a CR layer containing drug and HPMC. Commercial products, either 10 mg bis in die (bid [twice a day]) or once-a-day CR tablets (20 mg) were administered to healthy volunteers, and calculated pharmacokinetic parameters indicated bioequivalence of the two different treatments. The findings of the present study emphasize the potential of oxycodone once-a-day CR tablets for improved patient compliance, safety, and efficacy, which could help researchers to develop new CR dosage forms of oxycodone.
Preview · Article · Jan 2015 · Drug Design, Development and Therapy
[Show abstract][Hide abstract]ABSTRACT: A mu-zero resonator with an effective zero permeability is presented for efficient wireless power transfer (WPT) using resonant inductive coupling (RIC). An N-cell mu-zero resonator is modified to maintain a fixed size and resonance frequencies that are important design factors of WPT using RIC because they are related to the magnetic coupling coefficient and Q-factor. The resonator has many resonant modes with the extraordinary phenomena of metamaterials such as an infinite wavelength wave and backward-wave propagation. An analysis of the resonant modes and a design of the N-cell mu-zero resonator is performed by theory and full-wave simulation based on a dispersion diagram and magnetic field distribution. The power transfer efficiencies of one-cell and two-cell mu-zero resonators are simulated and measured. To optimise the transfer efficiency of the WPT system using the mu-zero resonance (MZR) mode, which supports stronger coupling than the other modes, an equivalent circuit of mu-zero resonator is analysed for a high Q-factor. The theoretical, simulated, and measured results of a one-cell resonator with optimum values confirm that an efficient WPT system can be successfully designed by the MZR mode.
No preview · Article · Sep 2014 · IET Microwaves Antennas & Propagation
[Show abstract][Hide abstract]ABSTRACT: The aim of this study was to design and evaluate extended-release formulations of a model drug, nicorandil, in order to achieve the desired steady-state plasma concentration of drug in vivo. Simulation was employed to estimate optimum dissolution and absorption rate of nicorandil. The dissolution test was employed using pH 1.2, 4.0, 6.8 buffer solution, or water, to measure the in vitro release behaviors of nicorandil formulations. A single dose (15 mg) of each formulation was orally administered to four beagle dogs under fasted conditions, and the pharmacokinetic parameters were calculated. The in vitro/in vivo relationship of the extended-release formulation was confirmed using in vitro dissolution profiles and plasma concentrations of drug in beagle dogs. Nicorandil was released completely within 30 min from the immediate-release tablets and released for 24 hr from the extended-release tablets. The nicorandil plasma concentration could be modified by adjusting the drug release rate from the extended-release formulation. The release rate of nicorandil was the rate-limiting step in the overall absorption of drug from the extended-release formulations. These results highlight the potential of a nicorandil extended-release formulation in the treatment of angina pectoris.
Full-text · Article · Sep 2014 · Asian Journal of Pharmaceutical Sciences
[Show abstract][Hide abstract]ABSTRACT: In the present study, controlled-release microparticles for orally disintegrating tablets (ODT) were prepared using two different processes, spray drying and fluidized bed coating processes. Pramipexole dihydrochloride monohydrate (PRM), an anti-Parkinson's disease agent, was selected as a model drug. The in vitro release rate and morphology of microparticles were evaluated and compared. The size of microparticles prepared by spray drying (SD microparticles) and fluidized bed coating (FC microparticles) was around 10 and 200 µm, respectively. The latter size was defined by the size of an inert core bead. The release behavior of SD microparticles was characterized by a large initial burst release prior to slow release. In the case of FC microparticles, the initial burst release was smaller than that of SD microparticles and the compression process damaged the release-controlling layer, which led to a change in release rate. The results indicated the importance of carefully considering the manufacturing process for microparticles during the design of controlled-release ODT.
No preview · Article · May 2014 · Drying Technology
[Show abstract][Hide abstract]ABSTRACT: An injectable liquid crystal-forming system (LCFS) was prepared by using sorbitan monooleate (SMO) as a new liquid crystal-forming material for injections, and its potential use of clinically available sustained-release formulation was evaluated. LCFS was prepared using SMO mixed with phosphatidyl choline and tocopherol acetate, and contained 3.75mg of leuprolide acetate as a monthly dose in 90μl of a liquid form. The semi-solid mesophase was formed from the liquid LCFS when it contacted water. The mesophase showed typical characteristics of the liquid crystalline phase, which was classified as the hexagonal phase. The safety of the LCFS was studied by an in vitro extraction colony assay and by examining the injection site in rats and white rabbits after an autopsy. Both in vitro release test and in vivo pharmacokinetic and pharmacodynamic studies showed a sustained release of leuprolide. When compared with a commercial depot formulation of leuprolide, the LCFS showed a similar AUClast value and significantly reduced initial burst with the sufficient suppression of testosterone after subcutaneous injections in rats and dogs. The LCFS can serve as a new type of sustained-release injection formulations for its safety, ease of preparation, and sustained release properties.
No preview · Article · Apr 2014 · Journal of Controlled Release
[Show abstract][Hide abstract]ABSTRACT: The objective of this study was to evaluate the healing effects of a chitosan-based, film-forming gel containing tyrothricin (TYR) in various rat wound models, including burn, abrasion, incision, and excision models. After solidification, the chitosan film layer successfully covered and protected a variety of wounds. Wound size was measured at predetermined timepoints after wound induction, and the effects of the film-forming gel were compared with negative (no treatment) and positive control groups (commercially available sodium fusidate ointment and TYR gel). In burn, abrasion and excision wound models, the film-forming gel enabled significantly better healing from 1 to 6 days after wound induction, compared with the negative control. Importantly, the film-forming gel also enabled significantly better healing compared with the positive control treatments. In the incision wound model, the breaking strength of wound strips from the group treated with the film-forming gel was significantly increased compared with both the negative and positive control groups. Histological studies revealed advanced granulation tissue formation and epithelialization in wounds treated with the film-forming gel. We hypothesize that the superior healing effects of the film-forming gel are due to wound occlusion, conferred by the chitosan film. Our data suggest that this film-forming gel may be useful in treating various wounds, including burn, abrasion, incision and excision wounds.
No preview · Article · Apr 2014 · Archives of Pharmacal Research
[Show abstract][Hide abstract]ABSTRACT: The aim of the present study was to prepare the particulate taste-masking system to mask the bitter taste of sildenafil citrate (SC), a well-known phosphodiesterase-5 inhibitor used for erectile dysfunction (ED) and pulmonary artery hypertension (PAH). It was evaluated for the taste masking efficiency by the in vitro measurement using electronic tongue (e-tongue) system and the in vivo human panel sensory test. Microcapsules were prepared by microencapsulation with a gastro-soluble polymer, Eudragit(®) E100 (E100), using a spray drying technique at four different weight ratios (2:1, 1:1, 1:2, and 1:3). Characters of prepared microcapsules and the effect of polymer ratio on the taste masking were investigated. The particle morphology and the distribution of SC in microcapsules were observed by SEM-EDS and physical properties were evaluated by PXRD, Raman spectroscopy, and DSC. By drug dissolution studies at pH 1.2 buffer and DW, it was found that E100 was not able to alter the drug release at stomach. As the result of taste evaluation studies, there were a good correlation (R(2)=0.9867) between the weight ratio of polymer and the taste masking efficiency expressed in the distances on the PCA map of the e-tongue data, and a relevance of the e-tongue measurement with the result of sensory test.
No preview · Article · Mar 2014 · International Journal of Pharmaceutics
[Show abstract][Hide abstract]ABSTRACT: Homosalate (HMS) is an ultraviolet (UV) filtering agent used in sunscreens and other cosmetics for skin protection purposes. Despite the widespread use of these products, absorption, disposition, and in vivo endocrine disrupting potential of HMS have not been characterized. Thus, the aim of this study was to examine the percutaneous absorption, disposition, and exposure assessment of HMS in rats. Initially, sunscreen preparations of petrolatum jelly, oily solution, lotion, and gel were prepared and evaluated for in vitro permeation of HMS across excised rat skin. Dermal permeability was greatest for gel, and this preparation was used in subsequent in vivo topical application investigations. After iv injection (0.5, 2, or 5 mg/kg), the pharmacokinetics of HMS was linear and was characterized by a large Vd ss (13.2-17 L/kg), high Cls (4.5-6.1 L/h/kg), and long t1/2 (6.1-8.4 h). After topical application of gel, the bioavailability of HMS was 5.4 ± 1.1 and 4.2 ± 0.6% for high and low doses (10 and 20 mg), respectively. Consistent with the prolonged absorption (T max 11.2 ± 1.8 and 12 ± 0 h for low and high doses, respectively), the terminal t 1/2 was longer after topical application (23.6-26.1 h) compared to iv injection. A population pharmacokinetic model was further developed to simultaneously fit the time courses of plasma concentrations and dermal content data after iv injection and topical application. Findings of this study may be useful to further examine the relationship between exposure and endocrine disrupting potential of HMS in risk assessment.
No preview · Article · Feb 2014 · Journal of Toxicology and Environmental Health Part A
[Show abstract][Hide abstract]ABSTRACT: The aims of the present study were to prepare hydroxypropylmethyl cellulose (HPMC)-based porous matrix tablets for gastroretentive drug delivery and to characterize their physicochemical properties. Gabapentin (GBP) was used as a model drug. Paste containing GBP, HPMC and water was molded and freeze-dried to prepare freeze-dried gastroretentive matrix tablet (FD-GRT). In vitro drug release and erosion studies were also performed. Although FD-GRT exhibited porous structure, they had good tablet strength and friability. Density of FD-GRT ranged from 0.402 to 0.509 g/cm3 and thus they could float on the medium surface without any lag time. FD-GRT was remained floated until the entire matrix erosion or end of drug release during in vitro release test. Release behavior of GBP could be modulated by the amount and the viscosity grade of HPMC. However, large amount and high viscosity of HPMC caused trouble in molding prior to freeze-drying. Addition of ethylcellulose could retard the release rate of GBP, with relatively low increase in viscosity of paste. Since pores generated by freeze drying imparted buoyancy for gastric retention to FD-GRT, additional materials for buoyancy was not necessary and FD-GRT had no lag time for buoyancy due to low density. Therefore it could be a promising tool for gastroretentive drug delivery.