Comparative Pharmacokinetics/Pharmacodynamics of Fixed-Dose Combination of Esomeprazole and Calcium Carbonate (AD-206) to the Conventional Esomeprazole.

PURPOSE: Proton pump inhibitors (PPIs) are used for the treatment of acid-related disorders. Demands for enhanced stability and faster onset led to the development of AD-206, a fixed-dose combination of a PPI (esomeprazole) with an antacid salt (calcium carbonate). This study compared the pharmacokinetics (PKs) and pharmacodynamics (PDs) of AD-206 (Addpharma) with conventional esomeprazole (Nexium®, AstraZeneca). MATERIALS AND METHODS: A randomized, open-label, two-treatment, two-sequence crossover study was conducted with 2 different doses of esomeprazole at 20 and 40 mg with a fixed calcium carbonate dose of 600 mg in AD-206. Forty-four subjects were included in each dose group and randomly received either AD-206 or the conventional esomeprazole for 7 consecutive days in each period. After a single- and multiple-dose, blood samples for the PK analysis were analyzed, and 24-hour intragastric pH monitoring was conducted. RESULTS: The systemic exposure of esomeprazole after a multiple-dose of AD-206 was similar to that of the conventional esomeprazole in both doses, but the time to reach the peak concentration was faster in AD-206. The percentage decrease from baseline in the integrated gastric acidity for a 24-hour interval after the dose was not significantly different between the AD-206 and the conventional esomeprazole after a single- and multiple-dose for both doses, and the time to reach pH 4 was faster for AD-206. CONCLUSION: AD-206 showed a similar systemic exposure and suppression of gastric acid secretion after a multiple-dose compared to the conventional esomeprazole.

Characterization and therapeutic efficacy evaluation of glimepiride and L-arginine co-amorphous formulation prepared by supercritical antisolvent process: Influence of molar ratio and preparation methods.

The glimepiride/L-arginine (GA) binary systems were prepared at various molar ratios by using a supercritical antisolvent (SAS) process. For comparison, the GA system was also prepared by physical mixing (PM), melt quenching (MQ), and solvent evaporation (SE) methods. Analyses by DSC and PXRD showed that only the GA binary mixture at 1:1 M ratio prepared by the SAS process was a pure co-amorphous mixture with an excellent content uniformity. On the other hand, GA mixture prepared by PM and SE were not pure co-amorphous systems and contained crystalline eutectic mixture, and MQ method at 170 °C induced the decrease in drug content due to decomposition of glimepiride. The positive deviation of experimentally measured glass transition temperature (Tg) compared to predicted Tg by the Gordon Taylor equation suggests specific molecular interactions between glimepiride and L-arginine in solid-state GA co-amorphous (GACA) mixture. The intermolecular interactions between glimepiride and L-arginine in GACA system were characterized by FT-IR and solid-state NMR analyses. Improved glimepiride dissolution rate of GACA formulation were confirmed using the solubility test, contact angle measurement, and dissolution test. Furthermore, the evaluation of pharmacodynamic hypoglycemic effect demonstrated that GACA prepared by the SAS process significantly improved the therapeutic efficacy of glimepiride.

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.

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

Statistical optimization of tamsulosin hydrochloride controlled release pellets coated with the blend of HPMCP and HPMC.

The objective of the present study was to evaluate three coating parameters for the application of a blend of HPMCP and HPMC in ethylcellulose aqueous dispersions (Surelease) in order to obtain controlled release of tamsulosin hydrochloride. The selected independent variables, HPMCP content (X1), HPMC content (X2) and coating level (X(3)), were optimized with a three-factor, three-level Box-Behnken design. The selected dependent variables were the cumulative percentage values of tamsulosin hydrochloride that had dissolved after 2, 3 and 5 h. Various dissolution profiles of the drug from controlled release pellets were obtained. Optimization was performed for X1, X2 and X3 using the following target ranges; 15% < or = Y1 < or= 30%; 50% < or = Y2 < or = 65%; 80% < or = Y3 < or = 95%. Results of the optimization procedure indicated that the optimized levels of HPMCP content (X1), HPMC content (X2) and coating level (X3) were 30%, 15% and 25%, respectively. Controlled release pellets coated with the optimized formulation provided a release profile that was close to predicted values. In addition, the dissolution profiles of the controlled release pellets coated with the optimized formulation were similar to those of the commercial product Harunal capsule (f1 = 4.6, f2 = 78.7).

Development and optimization of a novel oral controlled delivery system for tamsulosin hydrochloride using response surface methodology.

The purpose of this study was to develop and optimize oral controlled-release formulations for tamsulosin hydrochloride using a combination of two cellulose ester derivatives, hydroxypropyl methylcellulose (HPMC) and hydroxypropyl methylcellulose phthalate (HPMCP), with Surelease as a coating material. A three-factor, three-level Box-Behnken design was used to prepare systematic model formulations, which were composed of three formulation variables, the content of HPMC (X(1)) and HPMCP (X(2)) and the coating level (X(3)), as independent variables. The response surface methodology (RSM) and multiple response optimization utilizing the polynomial equation were used to search for the optimal coating formulation with a specific release rate at different time intervals. The drug release percentages at 2, 3 and 5h were the target responses and were restricted to 15-30% (Y(1)), 50-65% (Y(2)) and 80-95% (Y(3)), respectively. The optimal coating formulation was achieved with 10% HPMC and 20% HPMCP at a coating level of 25%, and the observed responses coincided well with the predicted values from the RSM optimization technique. The drug release from pellets coated with the optimized formulation showed a controlled-release pattern (zero-order), in comparison with a commercial product (Harunal capsule). In conclusion, a novel, oral, controlled-release delivery system for tamsulosin hydrochloride was successfully developed by incorporating HPMC and HPMCP as coating additives into Surelease aqueous ethylcellulose dispersion.

Preparation and characterization of simvastatin/hydroxypropyl-beta-cyclodextrin inclusion complex using supercritical antisolvent (SAS) process.

In the present study, the practically insoluble drug, simvastatin (SV), and its inclusion complex with hydroxypropyl beta-cyclodextrin (HP-beta-CD) prepared using supercritical antisolvent (SAS) process were investigated to improve the aqueous solubility and the dissolution rate of drug, thus enhancing its bioavailability. Inclusion complexation in aqueous solution and solid state was evaluated by the phase solubility diagram, differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), Fourier-transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). The phase solubility diagram with HP-beta-CD was classified as A(L)-type at all temperatures investigated, indicating the formation of 1:1 stoichiometric inclusion complex. The apparent complexation constants (K(1:1)) calculated from phase solubility diagram were 774, 846 and 924 M(-1) at 25, 37 and 45+/-0.5 degrees C, respectively. No endothermic and characteristic diffraction peaks corresponding to SV was observed for the inclusion complex in DSC and PXRD. FT-IR study demonstrated the presence of intermolecular hydrogen bonds between SV and HP-beta-CD in inclusion complex, resulting in the formation of amorphous form. Aqueous solubility and dissolution studies indicated that the dissolution rates were remarkably increased in inclusion complex, compared with the physical mixture and drug alone. Moreover, SV/HP-beta-CD inclusion complex performed better than SV in reducing total cholesterol and triglyceride levels. This could be primarily attributed to the improved solubility and dissolution associated with inclusion complex between drug and HP-beta-CD. In conclusion, SAS process could be a useful method for the preparation of the inclusion complex of drug with HP-beta-CD and its solubility, dissolution rate and hypolipidemic activity were significantly increased by complexation between SV and HP-beta-CD.

Recrystallization of fluconazole using the supercritical antisolvent (SAS) process.

The supercritical antisolvent (SAS) process was used to modify solid state characteristics of fluconazole. Fluconazole was recrystallized at various temperatures (60-80 degrees C) and pressures (8-16MPa) using dichloromethane (DCM) as a solvent. Acetone and ethanol were also employed as solvents. The fluconazole polymorphs prepared by the SAS process were characterized by differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). Furthermore, the equilibrium solubility of the samples in aqueous solution was determined. Fluconazole anhydrate form I was obtained at low temperature (40 degrees C) and anhydrate form II was obtained at high temperature (80 degrees C). The variation of pressure during the SAS process may influence the preferred orientation. Anhydrate forms I and II were also obtained using various solvents. Therefore, it was shown that solid state characteristics of fluconazole, including the polymorphic form and preferred orientation, can be controlled by changing operating conditions of the SAS process such as temperature, pressure, and solvent.

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 3(2) design was used for the optimization procedure with coating level (X(1)) and HPMCP content (X(2)) as the independent variables. The drug release percent at 2, 3 and 5 h were the target responses, which were restricted to 12-39% (Y(1)), 44-70% (Y(2)) and 70-100% (Y(3)), 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 3(2) 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.

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 1.22 mm, 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 2 h. These results may be attributed to the formation of a more rigid alginate matrix structure due to incorporated waxy materials. From the Dunnett's 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.

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.

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 itraconazole via 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 degrees C) in temperature. The solid dispersions prepared at 45 degrees C/15 MPa showed a slight increase in equilibrium solubility (approximately 27-fold increase) when compared to pure itraconazole, while those prepared at 60 degrees 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 AUC(o-24 h) 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.

Improved physicochemical characteristics of felodipine solid dispersion particles by supercritical anti-solvent precipitation process.

Solid dispersions of felodipine were formulated with HPMC and surfactants by the conventional solvent evaporation (CSE) and supercritical anti-solvent precipitation (SAS) methods. The solid dispersion particles were characterized by particle size, zeta potential, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), solubility and dissolution studies. The effects of the drug/polymer ratio and surfactants on the solubility of felodipine were also studied. The mean particle size of the solid dispersions was 200-250 nm; these had a relatively regular spherical shape with a narrow size distribution. The particle size of the solid dispersions from the CSE method increased at 1 h after dispersed in distilled water. However, the particle sizes of solid dispersions from the SAS process were maintained for 6 h due to the increased solubility of felodipine. The physical state of felodipine changed from crystalline to amorphous during the CSE and SAS processes, confirmed by DSC/XRD data. The equilibrium solubility of the felodipine solid dispersion prepared by the SAS process was 1.5-20 microg/ml, while the maximum solubility was 35-110 microg/ml. Moreover, the solubility of felodipine increased with decreasing drug/polymer ratio or increasing HCO-60 content. The solid dispersions from the SAS process showed a high dissolution rate of over 90% within 2 h. The SAS process system may be used to enhance solubility or to produce oral dosage forms with high dissolution rate.

Reparation of controlled release spheronized beads by simple extrusion and modified spheronization process.

Beads loaded with the water-soluble drug, phenylpropanolamine HCl (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.

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.

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 microm, 2.1 x 150 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 as m/z 406 at a retention time of ca. 2.3 min, and ramipril as m/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 (10 mg), gave an AUC12hr of 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.

LC-MS determination and bioavailability study of loperamide hydrochloride after oral administration of loperamide capsule in human volunteers.

The purpose of the present study was to develop a standard protocol for loperamide hydrochloride bioequivalence testing. For this purpose, a simple rapid and selective LC-MS method utilizing a single quadrupole mass spectrometer was developed and validated for the determination of loperamide hydrochloride in human plasma, and we followed this with a bioavailability study. Methyl tert-butylether (MTBE) was used to extract loperamide hydrochloride and ketoconazole (internal standard (IS)) from an alkaline plasma sample. LC separation was performed on a Zorbax RX C18 column (5 microm, 2.1 mm x 150 mm) using acetonitrile-water-formic acid (50:50:0.1 (v/v)) as a mobile phase. The retention times of loperamide hydrochloride and IS were 1.2 and 0.8 min, respectively. Quadrupole MS detection was by monitoring at m/z 477 (M + 1) corresponding to loperamide hydrochloride and at m/z 531 (M + 1) for IS. The described assay method showed acceptable precision, accuracy, linearity, stability, and specificity. The bioavailability of loperamide hydrochloride was evaluated in eight healthy male volunteers. The following pharmacokinetic parameters were elucidated after administering a single dose of four 2mg capsules of loperamide: the area under the plasma concentration versus time curve from time 0 to 72 h (AUC72 h) 19.26 +/- 7.79 ng h/ml; peak plasma concentration (Cmax) 1.18 +/- 0.37 ng/ml; time to Cmax (Tmax) 5.38 +/- 0.74 h; and elimination half-life (t1/2) 11.35 +/- 2.06 h. The developed method was successfully used to study the bioavailability of a low dose (8 mg) of loperamide hydrochloride.