Yun-Seok Rhee

Physical properties and in vivo bioavailability in human volunteers of isradipine using controlled release matrix tablet containing self-emulsifying solid dispersion.

Poorly water-soluble drug with a short half-life such as isradipine (IDP) offer challenges in the controlled release formulation because of low dissolution rate and poor bioavailability. Self-emulsifying solid dispersions (SESD) of IDP consisted of surfactant and fatty acid in poloxamer 407 (POX 407) as a carrier and were manufactured by the melting method. Then, controlled release HPMC matrix tablet containing SESD were prepared via direct compression. The dissolution behaviors and in vivo bioavailability of controlled release matrix tablet in healthy human volunteers were investigated. The physical properties of solid dispersion were also examined using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). It was shown that structure of IDP was amorphous in the solid dispersion. The dissolution rate of IDP from SESD was markedly enhanced because of increased solubility and wetting effect. Controlled release HPMC matrix tablets containing SESD released drug in a controlled manner and were stable during storage over 3 months at 40 °C/75% RH. Furthermore, the tablet containing 5mg IDP SESD showed significantly increased oral bioavailability and extended plasma concentration compared with the marketed 5 mg Dynacirc(®) capsule. A combined method of solid dispersion and controlled release technology could provide versatile dosage formulations containing IDP with poor water solubility and short half-life.

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.

Preparation of sildenafil citrate microcapsules and in vitro/in vivo evaluation of taste masking efficiency

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 in 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.

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.

Formulation and in vivo human bioavailability of dissolving tablets containing a self-nanoemulsifying itraconazole solid dispersion without precipitation in simulated gastrointestinal fluid.

To investigate the performance of a solid-state self-nanoemulsifying system with no precipitation in gastric and intestinal fluid, itraconazole (ITZ) was selected as a model drug because of its practically insoluble nature in intestinal fluid. A self-nanoemulsifying ITZ solid dispersion (SNESD) system was prepared as follows: (1) establishment of self-nanoemulsifying composition via the hot melting method, (2) solidification with fumed silicon dioxide (Aerosil 300) via adsorption to prepare SNESD and (3) preparation of a directly compressible tablet containing SNESD. This SNESD was easily formulated in the form of a dissolving tablet and provided a favourable nanoemulsifying microenvironment with no precipitation in the testing media. The SNESD and SNESD-loaded tablet displayed highly enhanced dissolution via nanomisation (266.8 nm and 258.3 nm at 60 min and 120 min, respectively), whereas the drug alone or a reference ITZ Sporanox® capsule displayed very low dissolution and precipitated immediately in intestinal fluid. Drug precipitation in intestinal fluid may affect the in vivo performance of poorly soluble weakly basic drugs and was estimated according to the crystal growth theory. The superdisintegrant and surfactant in the formulation of the tablet were very crucial to the dissolution of the SNESD-loaded tablet. The drug contents and dissolution rates of the SNESD-loaded tablets were also stable during storage in terms of dissolution and drug content. The SNESD-loaded tablet displayed significantly increased oral bioavailability in healthy human volunteers compared with the reference Sporanox® capsule. The current solid-state SNESD-loaded tablet could provide an alternative to liquid-based emulsifying preparations for various poorly water-soluble drugs without precipitation in testing media.

Investigation of physicochemical factors affecting the stability of a pH-modulated solid dispersion and a tablet during storage

The stability of solid dispersions (SD) during storage is of concern. We prepared the pH-modulated SD (pSD) and compressed tablets consisting of polyethylene glycol (PEG) 6000 as a carrier, drug and MgO (alkalizer). Telmisartan (TEL), an ionizable poorly water-soluble drug, was chosen as a model drug. The changes in physicochemical factors such as the dissolution rate, drug crystallinity, microenvironmental pH (pH(M)) and intermolecular interactions of the pSD and the tablets were investigated over 3 months under different temperature and relative humidity (RH) conditions: refrigerator (5-8 °C), 25 °C/32% RH, 25 °C/55% RH, 25 °C/75% RH, 40°C/32% RH, 40 °C/55% RH, and 40 °C/75% RH. Differential scanning calorimetry (DSC) analysis of all samples revealed no distinct changes in the drug melting point. In contrast, powder X-ray diffraction (PXRD) diffractograms revealed that samples stored at 40 °C/75% RH for 1 month, 25 °C/75% RH for 3 months and 40 °C at all humidity conditions for 3 months showed gradual recrystallization of the drug. Fourier transform infrared (FTIR) spectra indicated a reduced intensity of intermolecular interactions between TEL and MgO in the pSD and tablet. The pH(M) also gradually decreased. These altered physicochemical factors under the stressed conditions resulted in decreased dissolution profiles in intestinal fluid (pH 6.8). In contrast, the dissolution rate in gastric fluid (pH 1.2) was almost unchanged because of the high intrinsic solubility of TEL at this pH.

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).

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 evaluation of dual-mode floating gastroretentive tablets containing itraconazole.

Abstract The aims of the present study were to prepare new dual-mode floating gastroretentive tablets (DF-GRT) containing itraconazole (ITR) and to evaluate influence of the dosage forms on pharmacokinetic parameters of ITR. The solubility of ITR was enhanced around 200 times (from 1.54 to 248.38 µg/mL) by preparing solid dispersion (SD) with hydroxypropylmethyl cellulose. Buoyancy of DF-GRT containing ITR-SD was established by both camphor sublimation and gas generation. Camphor sublimation decreased density of DF-GRT by making pores in tablet matrix, which led to elimination of lag time for floating. Carbon dioxide generated by sodium bicarbonate and citric acid helped to maintain buoyancy of DF-GRT. Therefore DF-GRT floated on the medium without lag time until disintegrated entirely during in vitro release study. They released 89.11% of the drug at 2 h. Residual camphor was <0.5 wt% after sublimation. The pharmacokinetics of DF-GRT was evaluated in six miniature pigs and compared to immediate release tablets (IRT). Mean AUC ratio of GRT/IRT was 1.36 but there was no statistical difference between AUC values. However delayed tmax, increased MRT and equivalent Cmax of DF-GRT supposed it could be a promising tool for gastroretentive drug delivery system containing ITR.

Release kinetics of highly porous floating tablets containing cilostazol

&NA; This study focuses on developing a highly porous floating tablet containing cilostazol. The underlying release mechanism of cilostazol from porous and floating tablets in dissolution media containing surfactants was investigated. The tablets were prepared by compressing granules and excipients with a sublimating agent, followed by sublimation under vacuum. The volatile material for the sublimating agent was chosen based on its flow properties using conventional methods as well as the twisted blade method. Resultant tablets could float immediately and had significantly higher tensile strengths than conventional tablets of similar porosities, holding a promising potential for increasing gastroretentive properties. Fitting the release profiles to the Korsmeyer‐Peppas equation indicated Super Case II, Case II and non‐Fickian kinetics, which implied that the release was affected by both floating behavior and matrix erosion. Abrupt changes in release kinetic parameters and erosional behaviors were found between the tablets containing different amounts of HPMC, indicating the existence of an excipient percolation threshold. Neither the surfactant in the media nor the porosity affected the dominant release mechanism, which was matrix erosion. Understanding the dominant release mechanism and percolation threshold allows for tuning the formulation to obtain various release profiles. Graphical abstract Figure. No caption available.