Erratum to: Effects of metal- and fiber-reinforced composite root canal posts on flexural properties.

Erratum to: Dental Materials Journal 2016; 35(1): 138­146. doi:10.4012/dmj.2015-193 JOI JST.JSTAGE/dmj/2015-193. Figure 1, 2 and 3 (a) should be corrected as below.

Effects of metal- and fiber-reinforced composite root canal posts on flexural properties.

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.

Designing of the fixed-dose gastroretentive bilayer tablet for sustained release of metformin and immediate release of atorvastatin.

Patients with type 2 diabetes mellitus have a high risk of cardiovascular disease mainly caused by dyslipidemia. Metformin and atorvastatin are preferentially used to treat type 2 diabetes mellitus and dyslipidemia, respectively. The aim of this study was to develop a once-a-day fixed-dose combination tablet containing metformin and atorvastatin. For this purpose, we designed gastroretentive bilayer tablets consisting of 500 mg metformin in a sustained release layer and 10 mg atorvastatin in an immediate release layer. In addition, we modified the formulation to maintain a dual release pattern for the kinetically different layers for once-daily dosing. The gastroretentive bilayer tablet was developed using polyethylene oxide as a swellable polymer and ammonium methacrylate copolymer as a granule-coating polymer with minimal use of excipients. In vitro release patterns of metformin and atorvastatin from the developed formulation were similar to those of the reference drugs, Glucophage XR for metformin and Lipitor for atorvastatin, with satisfactory dissolution similarity factor (f2) values. The pharmacokinetic study showed the sustained and immediate absorptions of metformin and atorvastatin, respectively, in beagle dogs. The 90% confidence intervals of the ratios of ln values of AUCs of test formulation F3 and respective reference formulations of metformin and atorvastatin were 0.93-1.12 and 0.89-1.17, respectively, compared with their respective reference drugs. This formulation could contribute to improving the compliance and therapeutic outcome of patients with metabolic diseases.

Preparation and evaluation of sustained-release doxazosin mesylate pellets.

Doxazosin mesylate (DXM) sustained release pellets were prepared by an extrusion-spheronization and fluid-bed coating technique. The core pellets containing DXM were prepared by extrusion-spheronization technique, and coated by a fluid-bed coater to control the release of DXM. The factors affecting to properties of pellets, such as diluent content, type and coating level of coating agents and plasticizers were studied in the present study. Polymethacrylate derivatives (Eudragit® RS PO and RL PO) were used for coating agents, and polyethylene glycol 6000 (PEG 6000), triethyl citrate (TEC) and castor oil were as plasticizers. To evaluate the properties of prepared pellets, the size of prepared pellets was investigated by sieve analysis technique and the morphology of pellets was evaluated by scanning electron microscopy. Through the dissolution test, factors that have an effect on the dissolution of the drug were evaluated. As the content ratio of microcrystalline cellulose (MCC) had increased, the dissolution was proportionally sustained. Eudragit® RS PO had more marked sustaining effect on the dissolution rate than Eudragit® RL PO, and the effect was more pronounced with the increased coating level. PEG 6000 was an appropriate plasticizer for DXM pellets, and increasing the content of PEG 6000, was also slightly decreasing the dissolution rate.

Preparation of highly porous gastroretentive metformin tablets using a sublimation method.

The present investigation is aimed to formulate floating gastroretentive tablets containing metformin using a sublimation material. In this study, the release of the drug from a matrix tablet was highly dependent on the polymer concentrations. In all formulations, initial rapid drug release was observed, possibly due to the properties of the drug and polymer. The effect of the amount of PEO on swelling and eroding of the tablets was determined. The water-uptake and erosion behavior of the gastroretentive (GR) tablets were highly dependent on the amount of PEO. The water-uptake increased with increasing PEO concentration in the tablet matrix. The weight loss from tablets decreased with increasing amounts of PEO. Camphor was used as the sublimation material to prepare GR tablets that are low-density and easily floatable. Camphor was changed to pores in the tablet during the sublimation process. SEM revealed that the GR tablets have a highly porous morphology. Floating properties of tablets and tablet density were affected by the sublimation of camphor. Prepared floating gastroretentive tablets floated for over 24 h and had no floating lag time. However, as the amount of camphor in the tablet matrix increased, the crushing strength of the tablet decreased after sublimation. Release profiles of the drug from the GR tablets were not affected by tablet density or porosity. In pharmacokinetic studies, the mean plasma concentration of the GR tablets after oral administration was greater than the concentration of glucophase XR. Also, the mean AUC(0-∞) values for the GR tablets were significantly greater than the plasma concentrations of glucophase XR.

Physicochemical, pharmacokinetic and pharmacodynamic evaluations of novel ternary solid dispersion of rebamipide with poloxamer 407.

This study was conducted primarily to improve the solubility of rebamipide, a poorly water-soluble anti-ulcer drug, using novel ternary solid dispersion (SD) systems and secondly to evaluate the effect of solubility enhancement on its pharmacokinetic (PK) and pharmacodynamic (PD) profile. After dissolving the three components in aqueous medium, ternary SD containing the drug, sodium hydroxide (NaOH) and PVP-VA 64 was achieved by spray drying method, which was used as primary SD. Poloxamer 407, a surfactant polymer, was incorporated in this primary SD by four different methods: co-grinding, physical mixing, melting or spray drying. SD was then characterized by dissolution test, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR). The spray dried SD of poloxamer 407 together with primary SD displayed highest dissolution rate of the drug of about 70% after 2 h. DSC, PXRD and FT-IR characterized the amorphous state and molecular dispersion of the drug in the SD. PK and PD studies in Sprague-Dawley rats revealed that the bioavailability of the drug using optimal SD was about twofold higher than that of reference product, and the irritation area of stomach was significantly reduced in the ulcer-induced rat model using optimal SD as compared to the reference product.

Preparation and valuation of a topical solution containing eutectic mixture of itraconazole and phenol.

The purposes of this study were to prepare a topical solution containing itraconazole (ITR)-phenol eutectic mixture and to evaluate its ex vivo skin permeation, in vivo deposition and in vivo irritation. The eutectic mixture was prepared by agitating ITR and phenol (at a weight ratio of 1:1) together at room temperature. The effects of additives on the skin permeation of ITR were evaluated using excised hairless mouse skin. The in vivo skin deposition and skin irritation studies were performed in Sprague-Dawley rat and New Zealand white rabbit model. The permeability coefficient of ITR increased with addition of oleic acid in the topical solution. Otherwise, the permeability coefficient was inversely proportional to the concentration of the thickening agent, HPMC. The optimized topical solution contained 9 wt% of the ITR-phenol eutectic mixture, 9.0 wt% of oleic acid, 5.4 wt% of hydroxypropylmethyl cellulose and 76.6 wt% of benzyl alcohol. The steady-state flux and permeability coefficient of the optimized topical solution were 0.90 ± 0.20 µg/cm(2)·h and 22.73 ± 5.73 × 10(6) cm/h, respectively. The accumulated of ITR in the epidermis and dermis at 12 h was 49.83 ± 9.02 µg/cm(2). The topical solution did not cause irritation to the skins of New Zealand white rabbits. Therefore, the findings of this study indicate the possibilities for the topical application of ITR via an external preparation.

Phase behavior of itraconazole-phenol mixtures and its pharmaceutical applications.

The aims of this study were to examine the phase behavior of itraconazole-phenol mixtures and assess the feasibility of topical formulations of itraconazole using eutectic mixture systems. Itraconazole-phenol eutectic mixtures were characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy, (1)H-nuclear magnetic resonance, and powder X-ray diffractometry. The skin permeation rates of itraconazole-phenol eutectic formulations were determined using Franz diffusion cells fitted with excised hairless mouse skins. Itraconazole can form eutectic compounds with phenol, and the hydrogen-bonding interactions between the carbonyl group in the itraconazole and hydroxyl group in phenol play a major role in itraconazole-phenol eutectic formation. Despite its high molecular weight and hydrophobicity, the drug (i.e., itraconazole) can be permeated through excised hairless mouse skins from itraconazole-phenol eutectic formulations. The findings of this study emphasize the capabilities of the topical application of itraconazole via external preparations.

Investigation of formulation factors affecting in vitro and in vivo characteristics of a galantamine transdermal system.

Because of low treatment compliance with the Alzheimer disease patients, there have been clinical needs for the alternative administration route to effective and well-tolerated approaches of galantamine (Small and Dubois, 2007). In this study, drug-in-adhesive transdermal patches with galantamine were prepared and evaluated in vitro and in vivo. The in vitro permeation studies indicated that DT-2510 was the most suitable pressure-sensitive-adhesive and oleic acid was the most promising enhancer for galantamine drug-in-adhesive patch. The optimized galantamine drug-in-adhesive patch could be physicochemically stable for 28 days at 40 °C/75% RH. The in vivo studies of the optimized galantamine drug-in-adhesive patch showed high absolute bioavailability of around 80% and sustained effect on the drug plasma levels for 24 h. The in vitro and in vivo studies of galantamine drug-in-adhesive patches with different pressure-sensitive-adhesive functional groups showed a strong correlation between the skin permeation rate and the area under the curve. The results suggest that the transdermal application of galantamine drug-in-adhesive patches might be the alternative dosage form to have good efficacy and tolerability for the treatment of Alzheimer disease.

Investigation of an active film coating to prepare new fixed-dose combination tablets for treatment of diabetes.

The aim of the present study was to formulate new fixed-dose combination tablets (FCTs) by coating a glimepiride (GLM) immediate-release (IR) layer on a metformin hydrochloride (MTF) extended-release (ER) core tablet using perforated film coating equipment. Composition of GLM-IR coating suspension for homogeneity was studied and application of near-infrared spectroscopy (NIR) to determine the end-point of the coating process was also investigated. The final product was administered to healthy male volunteers and its pharmacokinetic parameters were analyzed. GLM-IR coating suspension was prepared with a ratio of SLS to GLM at 0.75 for homogeneity. An inert mid-layer was introduced to prevent contact between MTF-ER core tablet and GLM-IR layer, which led to an increased release rate of GLM in pH 7.8 medium. The proportional correlation was confirmed between analytical results of GLM determined by NIRS and those by HPLC-UV. Thus, the end-point of the GLM coating process was determined by NIRS, the fast and non-destructive method. New FCTs were confirmed to be bioequivalent to the marketed product.

Preparation and in vivo evaluation of spray dried matrix type controlled-release microparticles of tamsulosin hydrochloride for orally disintegrating tablet.

The objective of this study was to achieve an optimal formulation of spray dried matrix type controlled-release (MTCR) microparticles containing tamsulosin hydrochloride for orally disintegrating tablet. To control the release rate of tamsulosin hydrochloride, Acrylate-methacrylate copolymer (Eudragit(®) L-100 or Eudragit(®) S-100) and ethylcellulose were employed on the composition of MTCR microparticles. Physicochemical properties of MTCR microparticles such as particle size and SEM were characterized. Pharmacokinetic parameters of tamsulosin hydrochloride were evaluated in the rats after oral administration. MTCR microparticles were spherical microparticles of around 10 µm diameter with a corrugated surface. ODTs containing MTCR microparticles were disintegrated within 30 s and MTCR microparticles were able to control the release rate of tamsulosin hydrochloride following Fickian diffusion mechanism. The in vitro release rates of tamsulosin hydrochloride from MTCR microparticles were proportional to the ratio of Acrylate-methacrylate copolymer to ethylcellulose. Moreover, MTCR microparticles retarded the in vivo release rate of tamsulosin hydrochloride without reducing the bioavailability. Our results suggest that MTCR microparticles may be potential oral dosage forms to control the release and to improve the bioavailability of tamsulosin hydrochloride.

Formulation of solid dispersion of rebamipide evaluated in a rat model for improved bioavailability and efficacy.

OBJECTIVES: Rebamipide, a novel anti-ulcer agent, is listed in biopharmaceutics classification class IV because of its low aqueous solubility and permeability. Consequently, the bioavailability of rebamipide is under 10% in humans. The aim of this study was to increase the solubility and determine the effect of solubility enhancement on the bioavailability and efficacy of rebamipide (RBM). METHODS: After taking into account the physiochemical properties of RBM (solubility, melting point, dosage etc.), solid dispersion was chosen as the solubility enhancement method. A rebamipide solid dispersion system containing the drug, l-lysine, PVP-VA 64 and poloxamer 407 was obtained from a spray-drying method. Solubility enhancement of RBM from the solid dispersion was determined by a dissolution test in 900 ml at pH 1.2. The bioavailability and efficacy of RBM solid dispersion were evaluated in a rat model. KEY FINDINGS: The aqueous solubility of RBM was improved 62.17 times by solid dispersion. The oral bioavailability of the drug was also increased 1.74-fold from solid dispersion compared with the reference product in a rat model. With regard to the anti-ulcer effect, the percentage inhibition of the solid dispersion was 2.71 times higher than that of the reference product in the ulcer-induced rat model. CONCLUSIONS: A solid dispersion of rebamipide was successfully formulated using the spray-drying method. Bioavailability and efficacy of rebamipide were increased significantly by solubility enhancement of the drug.

Effect of electrokinetic stabilizers on the physicochemical properties of propofol emulsions.

The aims of the present study were to elucidate the potential mechanism of propofol emulsion destabilization following the addition of lidocaine, and to evaluate the effects of various electrokinetic stabilizers on the physicochemical properties of lidocaine-propofol emulsions. The assessments included pH observations and determination of the maximum globule diameter (MGD) and zeta potential (ZP). The MGD of propofol emulsions increased up to several tens mum following the addition of 50 mg of lidocaine to 200mg of propofol, and the proposed destabilization mechanism involves localization of protonated lidocaine molecules between lecithin molecules in propofol emulsions, which consequently leads to increased ZP. The ZP of propofol emulsions containing acidic amino acid or neutral amino acid increased following the addition of lidocaine, and a charge reversal occurred. Therefore, the MGD of emulsions increased to several tens (m. However, the MGD of emulsions that contained basic amino acids or basic compounds remained below 5 (m, despite the addition of large amounts lidocaine (50 mg), and the ZP did not pass through the point of zero charge. In conclusion, our results provide not only further insight into the physical stability of propofol emulsions containing lidocaine, but also a better understanding of the administration of propofol in existing applications.

In Vitro/in vivo relationship of gabapentin from a sustained-release tablet formulation: a pharmacokinetic study in the beagle dog.

The aim of this study was to examine the in vitro/in vivo relationship of the drug release behavior of a sustained-release formulation of gabapentin. The immediate-release formulation was used as the reference formulation. The dissolution test was employed using pH 1.2, 4.0, or 6.8 buffer solution, or water, to determine the in vitro release behaviors of gabapentin tablets. Gabapentin was released completely within 1 h from the immediate-release tablet and released for 12 h from the sustained-release tablet. A single dose (600 mg) of each formulation was orally administered to four beagle dogs under fasted conditions, and the pharmacokinetic parameters were calculated. Although the sustained-release tablet did not disintegrate and had slow drug release characteristics, it showed similar pharmacokinetic parameters to the immediate-release tablet, which rapidly disintegrated and showed fast drug release. Thus, the in vivo release of gabapentin did not correlate with in vitro release of drug.

Investigation of the relationship between in vitro and in vivo release behaviors of acamprosate from enteric-coated tablets.

Acamprosate calcium is a highly soluble drug with low permeability that is used to maintain abstinence in alcohol-dependent patients. The aim of this study was to investigate the relationship between in vitro and in vivo behaviors of acamprosate from enteric-coated tablets. The in vitro release behavior of acamprosate tablets in pH 6.8 buffer solution was determined in three dissolution conditions, 50 and 150 rpm (paddle method) and 180 rpm (basket method). The results of this in vitro experiment indicated that acamprosate tablets hardly disintegrated, and drug dissolution was retarded despite the extremely hydrophilic nature of the drug. A single dose (333 mgx2 tablets) of each formulation was orally administered to four beagle dogs under fasting conditions, and the pharmacokinetic parameters were calculated. The mean AUC0-48, Cmax, Tlag and Tmax for the two types of tablets ranged from 41.5-53.6 microg.h/mL, 4.3-4.5 microg/mL, 2.0-2.5 h and 3.8-4.0 h, respectively. In conclusion, it is suggested that retarded drug release from the tablets and the low drug permeability may result in poor absorption and erratic bioavailability of this drug in humans.