Sibeum Lee

Physicochemical properties and oral bioavailability of amorphous atorvastatin hemi-calcium using spray-drying and SAS process

The objective of the study was to prepare amorphous atorvastatin hemi-calcium using spray-drying and supercritical antisolvent (SAS) process and evaluate its physicochemical properties and oral bioavailability. Atorvastatin hemi-calcium trihydrate was transformed to anhydrous amorphous form by spray-drying and SAS process. With the SAS process, the mean particle size and the specific surface area of amorphous atorvastatin were drastically changed to 68.7+/-15.8nm, 120.35+/-1.40m2/g and 95.7+/-12.2nm, 79.78+/-0.93m2/g from an acetone solution and a tetrahydrofuran solution, respectively and appeared to be associated with better performance in apparent solubility, dissolution and pharmacokinetic studies, compared with unprocessed crystalline atorvastatin. Oral AUC0-8h values in SD rats for crystalline and amorphous atorvastatin were as follow: 1121.4+/-212.0ngh/mL for crystalline atorvastatin, 3249.5+/-406.4ngh/mL and 3016.1+/-200.3ngh/mL for amorphous atorvastatin from an acetone solution and a tetrahydrofuran solution with SAS process, 2227.8+/-274.5 and 2099.9+/-339.2ngh/mL for amorphous atorvastatin from acetone and tetrahydrofuran with spray-drying. The AUCs of all amorphous atorvastatin significantly increased (P<0.05) compared with crystalline atorvastatin, suggesting that the enhanced bioavailability was attributed to amorphous nature and particle size reduction. In addition, the SAS process exhibits better bioavailability than spray-drying because of particle size reduction with narrow particle size distribution. It was concluded that physicochemical properties and bioavailability of crystalline atorvastatin could be improved by physical modification such as particle size reduction and generation of amorphous state using spray-drying and SAS process. Further, SAS process was a powerful methodology for improving the physicochemical properties and bioavailability of atorvastatin.

Preparation and characterization of solid dispersions of itraconazole by using aerosol solvent extraction system for improvement in drug solubility and bioavailability.

The objective of this study was to elucidate the feasibility to improve the solubility and bioavailability of poorly water-soluble itraconazolevia solid dispersions by using supercritical fluid (SCF). Solid dispersions of itraconazole with hydrophilic polymer, HPMC 2910, were prepared by the aerosol solvent extraction system (ASES) under different process conditions of temperature/pressure. The particle size of solid dispersions ranged from 100 to 500 nm. The equilibrium solubility increased with decrease (15 to 10 MPa) in pressure and increase (40 to 60°C) in temperature. The solid dispersions prepared at 45°C/15 MPa showed a slight increase in equilibrium solubility (approximately 27-fold increase) when compared to pure itraconazole, while those prepared at 60°C/10 MPa showed approximately 610-fold increase and no endothermic peaks corresponding to pure itraconazole were observed, indicating that itraconazole might be molecularly dispersed in HPMC 2910 in the amorphous form. The amorphous state of itraconazole was confirmed by DSC/XRD data. The pharmacokinetic parameters of the ASES-processed solid dispersions, such as Tmax, Cmax, and AUC0–24h were almost similar to Sporanox® capsule which shows high bioavailability. Hence, it was concluded that the ASES process could be a promising technique to reduce particle size and/or prepare amorphous solid dispersion of drugs in order to improve the solubility and bioavailability of poorly water-soluble drugs.

Cefuroxime axetil solid dispersions prepared using solution enhanced dispersion by supercritical fluids

Cefuroxime axetil (CA) solid dispersions with HPMC 2910/PVP K‐30 were prepared using solution enhanced dispersion by supercritical fluids (SEDS) in an effort to increase the dissolution rate of poorly water‐soluble drugs. Their physicochemical properties in solid state were characterized by differential scanning calorimeter (DSC), powder X‐ray diffraction (PXRD), Fourier transform infrared spectrometry (FT‐IR) and scanning electron microscopy. No endothermic and characteristic diffraction peaks corresponding to CA were observed for the solid dispersions in DSC and PXRD. FTIR analysis demonstrated the presence of intermolecular hydrogen bonds between CA and HPMC 2910/PVP K‐30 in solid dispersions, resulting in the formation of amorphous or non‐crystalline CA. Dissolution studies indicated that the dissolution rates were remarkably increased in solid dispersions compared with those in the physical mixture and drug alone. In conclusion, an amorphous or non‐crystalline CA solid dispersion prepared using SEDS could be very useful for the formulation of solid dosage forms.

Controlled release tamsulosin hydrochloride from alginate beads with waxy materials.

The objective of this study was to develop oral controlled release delivery systems for tamsulosin hydrochloride (TSH) using alginate beads with various waxy materials, such as Compritol 888 ATO, Precirol ATO 5 and Gelucires. The beads were prepared from sodium alginate—waxy material—TSH slurry dropped onto calcium chloride to form spherical beads. The effects of the addition of various waxy materials to alginate beads on the drug encapsulation efficiency, bead size and morphology were investigated. The drug encapsulation efficiency significantly increased with the addition of waxy materials. The TSH‐loaded alginate beads with and without waxy materials were almost spherical particles with an average diameter of 1.44 and 1.22mm, respectively. In dissolution study, the TSH‐loaded alginate beads with waxy materials exhibited controlled release behaviour over a 6‐h period, while beads without waxy materials showed release of 100% TSH within 2h. These results may be attributed to the formation of a more rigid alginate matrix structure due to incorporated waxy materials. From the Dunnetts t‐test and the f2 factor, the release of TSH from alginate beads, a similar dissolution pattern to that of the marketed product (Harunal capsules) could be achieved by adding Gelucire 50/13 into TSH‐loaded alginate beads. From these results, oral controlled release of TSH could be achieved with loading in alginate beads with waxy materials, such as Compritol 888 ATO, Precirol ATO 5 and Gelucires.

The influence of surelease and sodium alginate on the in-vitro release of tamsulosin hydrochloride in pellet dosage form

The objective of this study was to prepare controlled‐release pellets containing 0.2 mg tamsulosin hydrochloride using a pelletizer‐equipped piston extruder and double‐arm counter‐rotating rollers with Surelease and sodium alginate. The release of tamsulosin HCl from pellets coated with the commercial aqueous ethylcellulose dispersion (Surelease) was investigated at different coating loads. In addition, the effect of sodium alginate on drug release was investigated by varying the ratio of sodium alginate to microcrystalline cellulose (MCC). Dissolution studies were first performed in 500 mL simulated gastric fluid (pH 1.2) containing 0.003% (w/w) polysorbate 80 and then in simulated intestinal fluids (pH 7.2). The morphology of pellet surfaces and cross sections were examined by scanning electron microscopy (SEM). Apparently, the spherical pellets were prepared using a pelletizer‐equipped piston extruder and double‐arm counter‐rotating rollers. The release profiles of tamsulosin HCl from Surelease‐coated pellets were significantly affected by changing the content of Surelease, the pH of the dissolution medium and the ratio of sodium alginate to MCC. The drug release rates not only decreased with increase in the coating load, but also increased when the pH of the dissolution medium was increased from 1.2 to 7.2 regardless of the sodium alginate‐to‐MCC ratio. Moreover, the drug release rate at pH 7.2 was gradually increased by increasing the ratio of sodium alginate to MCC. SEM showed smooth surfaces of Surelease‐coated pellets. These results suggest that Surelease and sodium alginate would be useful excipients in the preparation of controlled‐release pellets with the desired release profiles.

Influence of water soluble additives and HPMCP on drug release from sureleaseê-coated pellets containing tamsulosin hydrochloride

The objective of this study was to investigate the influence of various water-soluble additives and HPMCP as an enteric polymer into Sureleaseê for the developement of oral controlled release system containg tamsulosin hydrochloride. The drug loaded pellets were coated with only Sureleaseê or Sureleaseê containing HPMC, PEG 4000, mannitol and HPMCP (20% w/ w). In case of HPMC and PEG 4000 as additives into Sureleaseê film, the rapid drug release was observed in pH 1.2 while the higher drug release was achieved by adding HPMCP into Sureleaseê as well as by increasing the amount of HPMCP (10, 20, and 30% w/w) in pH 7.2. The incorporation of HPMCP into Sureleaseê showed pH-denpendent drug release due to its pH-dependent nature. Therefore, the incorporation of HPMCP into Sureleaseê based on aqueous coating formulation is an effective way to develop oral controlled release delivery systems containing tamsulosin hydrochloride.

Optimization of tamsulosin hydrochloride controlled release pellets coated with Surelease and neutralized HPMCP

This study was to optimize the coating level in the development of controlled release pellets coated with Surelease and neutralized hydroxypropyl methylcellulose phthalate (HPMCP) by a computer optimization technique based on a response surface methodology utilizing polynomial equation. A full factorial 32 design was used for the optimization procedure with coating level (X1) and HPMCP content (X2) as the independent variables. The drug release percent at 2, 3 and 5 h were the target responses, which were restricted to 12–39% (Y1), 44–70% (Y2) and 70–100% (Y3), respectively. The quadratic model was well fitted to the data, and the resulting equation was used to predict the responses in the optimal region. It was shown that the optimized coating formulation was achieved at the ratio of 3:1 (Surelease: neutralized HPMCP) with 20% coating level. The optimized formulation showed release profiles and responses, which were close to predicted responses. Therefore, a full factorial 32 design and optimization technique can be successfully used in the development of optimized coating formulations based on Surelease and neutralized HPMCP to achieve a controlled release drug delivery system containing tamsulosin hydrochloride.

LC-MS determination and bioavailability study of imidapril hydrochloride after the oral administration of imidapril tablets in human volunteers

The purpose of the present study was to develop a standard protocol for imidapril hydrochloride bioequivalence testing. For this reason, a specific LC-MS method was developed and validated for the determination of imidapril in human plasma. A solid-phase extraction cartridge, Sep-pak® C18, was used to extract imidapril and ramipril (an internal standard) from deproteinized plasma. The compounds were separated using a XTerra MS® C18 column (3.5 μm, 2.1x150 mm) and acetonitrile-0.1% formic acid (67:33, v/v) adjusted to pH 2.4 by 2 mmol/L ammonium formic acid, as mobile phase at 0.3 mL/min. Imidapril was detected asm/z406 at a retention time of ca. 2.3 min, and ramipril asm/z 417 at ca. 3.6 min. The described method showed acceptable specificity, linearity from 0.5 to 100 ng/mL, precision (expressed as a relative standard deviation of less than 15%), accuracy, and stability. The plasma concentration-versus-time curves of eight healthy male volunteers administered a single dose of imidapril (10mg), gave an AUC12hrOf imidapril of 121.48 ± 35.81 ng mL-1 h, and Cmax and Tmax values of 32.59 ± 9.76 ng/mL and 1.75 ± 0.27 h. The developed method should be useful for the determination of imidapril in plasma with sufficient sensitivity and specificity in bioequivalence study.

Preparation and Characterization of Lysozyme Nanoparticles using Solution Enhanced Dispersion by Supercritical Fluid (SEDS) Process

The micron or nano-sized lysozyme as a model protein drug was prepared using solution enhanced dispersion by supercritical fluid (SEDS) process at various conditions (e.g., solvent, temperature and pressure) to investigate the feasibility of pulmonary protein drug delivery. The lysozyme particles prepared were characterized by laser diffraction particle size analyzer, scanning electron microscopy (SEM) and powder X-ray diffractometry (PXRD). The biological activity of lysozyme particles after/before SEDS process was also examined. Lysozyme was precipitated as spherical particles. The precipitated particles consisted of 100 - 200 nm particles. Particle size showed the precipitates to be agglomerates with primary particles of size . The biological activity varied between 38 and 98% depending on the experimental conditions. There was no significant difference between untreated lysozyme and lysozyme after SEDS process in PXRD analysis. Therefore, the SEDS process could be a novel method to prepare micron or nano-sized lysozyme particles, with minimal loss of biological activity, for the pulmonary delivery of protein drug.

Preparation of controlled release spheronized beads by a simple extrusion and modified spheronization process

Beads loaded with the water-soluble drug, phenylpropanolamine HCI (PPA), were prepared using an extruder and double arm counter-rotating roller modified from a traditional pill machine. The mean diameter of the cylindrical rod-like extrudate from the ram extruder was 3 mm; that of the uncoated bead after cutting and spheronization by the modified double arm counter-rotating roller was 3.26–3.28 mm. Although the surface of the beads was moderately rough and irregular, some exhibited hump-shaped protrusions, the sphericity was acceptable (roundness 1.15) and adequate for the subsequent coating process. An increase in mean diameter of the coated beads and improvements in friability and sphericity were observed in proportion to the amount of coating material applied (ethylcellulose or Eudragit® RS 100). It was also found that the release rate of PPA from the coated beads could be controlled by the amount and type of coating materials applied or with the incorporation of Eudragit® RS 100 into the core matrix. Further modifications to the double arm counter-rotating roller, including adjustment of the rotation speed and distance between the rollers, would yield smaller uncoated beads with improved roundness and surface roughness. In conclusion, the present method could be potentially applied to prepare controlled release drug delivery beads or pellet dosage forms.