Kwang-Ho Cha

Enhanced dissolution of megestrol acetate microcrystals prepared by antisolvent precipitation process using hydrophilic additives

Microcrystals of megestrol acetate (MA), a poorly water-soluble drug, were successfully prepared using an antisolvent precipitation technique for improving the dissolution rate. The effective hydrophilic polymers and surfactants used were screened for their abilities to produce smaller particle sizes. Raw micronized MA and processed MA microcrystals were ranked by the Student-Newman-Keuls test in order of increasing particle size and SPAN values as follows: processed MA microcrystals in the presence of polymer and surfactant (mean diameter 1048nm)<processed MA microcrystals in the presence of polymer (1654nm)<processed MA microcrystals in the absence of polymer and surfactant (3491nm)<raw micronized MA (4352nm). The order of BET surface area was reversely ranked. Processed MA microcrystals in the presence of polymer and surfactant slightly decreased crystallinity and altered crystal habit and preferred orientation without change in polymorph. In addition, the dissolution properties of the processed MA microcrystals in the presence of polymer and surfactant were significantly enhanced as compared to that of the raw micronized MA. This effect is mainly due to a reduction in particle size resulting in an increased surface area. Therefore, it was concluded that the antisolvent precipitation technique in mild conditions could be a simple and useful technique to prepare poorly water-soluble drug particles with reduction in particle size, a narrow particle size distribution and enhanced dissolution properties.

Preparation and pharmaceutical characterization of amorphous cefdinir using spray-drying and SAS-process.

The aim of this study was to investigate the effects of micronization and amorphorization of cefdinir on solubility and dissolution rate. The amorphous samples were prepared by spray-drying (SD) and supercritical anti-solvent (SAS) process, respectively and their amorphous natures were confirmed by DSC, PXRD and FT-IR. Thermal gravimetric analysis was performed by TGA. SEM was used to investigate the morphology of particles and the processed particle had a spherical shape, while the unprocessed crystalline particle had a needle-like shape. The mean particle size and specific surface area were measured by dynamic light scattering (DLS) and BET, respectively. The DLS result showed that the SAS-processed particle was the smallest, followed by SD and the unprocessed cefdinir. The BET result was the same as DLS result in that the SAS-processed particle had the largest surface area. Therefore, the processed cefdinir, especially the SAS-processed particle, appeared to have enhanced apparent solubility, improved intrinsic dissolution rate and better drug release when compared with SD-processed and unprocessed crystalline cefdinir due not only to its amorphous nature, but also its reduced particle size. Conclusions were that the solubility and dissolution rate of crystalline cefdinir could be improved by physically modifying the particles using SD and SAS-process. Furthermore, SAS-process was a powerful methodology for improving the solubility and dissolution rate of cefdinir.

Design of pH-independent extended release matrix tablets of minocycline hydrochloride for the treatment of dementia.

The aim of this study was to develop a pH-independent extended release matrix tablet of minocycline HCl for the treatment of dementia. The matrix tablets were prepared by wet granulation technique using Eudragit L and S as release modifiers at different w/w ratios (1:0, 1:1 and 0:1) and PEO as a matrix former. In the case of the matrix tablet without any release modifiers, the drug release rate at pH 1.2 was much higher than that of pH 7.4. By adding the release modifier, the drug release rate at pH 7.4 increased close to that of pH 1.2 and the pH-independent release was obtained. In addition, it was shown that lubricants containing a divalent cation such as Mg stearate inhibited minocycline release in basic medium. Therefore, the incorporation of Eudragit L and S (1:1 ratio) as release modifiers and Na stearyl fumarate as a lubricant into PEO-based matrix tablets effectively produced pH-independent minocycline release profiles.

Quantitative determination of sirolimus in dog blood using liquid chromatography-tandem mass spectrometry, and its applications to pharmacokinetic studies.

A rapid, sensitive method of detecting sirolimus in blood was developed and applied in pharmacokinetic studies employing deionized water for hemolysis and a weakly basic mobile phase to enhance chromatographic peak intensity. Dog blood samples were processed via liquid-liquid extraction and the amounts of sirolimus and tacrolimus, an internal standard, were quantified by LC-MS/MS. Specificity, the lower limit of quantification, linearity, accuracy, precision, dilution, recovery, matrix effects, robustness and stability were within the acceptable range for assay validation. The concentration of sirolimus was quantifiable in blood samples for up to 36 h after the dog had received a 3 mg/kg dose of sirolimus. These observations suggest that sirolimus can be detected at low levels in dog blood using a basic mobile phase and metal-free hemolysis. This method is therefore applicable to pharmacokinetic studies in dogs.

Development of Self-microemulsifying Drug Delivery System for Enhancing the Bioavailability of Atorvastatin

The objective of the study was to prepare self-microeulsifying drug delivery system (SMEDDS) incor- porating atorvastatin calcium and evaluate its properties and oral bioavailability. Solubility of atorvastatin in various vehicles was determined. Pseudo-ternary phase diagrams were constructed to identify the good self-emulsification region. The drop- let size distributions of the resultant emulsions were determined by dynamic light scattering measurement. The mean droplet size of chosen formulation (20% ethyl oleate, 40% tween-80, 40% Carbitol ® ) was 23.4±1.3 nm. The SMEDDS incor- porating atorvastatin calcium appeared to be associated with better performance in dissolution and pharmacokinetic studies, compared with raw atorvastatin calcium. In dissolution test, the release percentage of atorvastatin from SMEDDS mixture could rapidly reach more than 95% within 3 min. Oral AUC0→8hrvalues in SD rats was 1994±335 ng·hr/mL, which signi- ficantly increased (P<0.05) compared with raw atorvastatin calcium. The SMEDDS formulation was relatively stable when stored at 4 o C during 3 months. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic com- pounds, such as atorvastatin, by the oral route. Key wordsAtorvastatin calcium, SMEDDS, Phase diagram, Bioavailability, Stability Atorvastatin, as a synthetic lipid-lowering agent, is an inhib- itor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosyn- thesis(Lennernas, 2003). Atorvastatin is currently used as cal- cium salt for the treatment of hypercholesterolemia. Atorvastatin calcium ((R-(R*,R*))-2-(4-fluorophenyl)-b,d-dihydroxy-5-(1-

Pharmacokinetic and bioequivalence study of itopride HCl in healthy volunteers.

In the present study two different formulations containing 50 mg itopride HCl (N-[4-12-(dimethylamino)ethoxylbenzyl]-3,4-dimethoxybenzamide HCl, CAS 122898-67-3) were compared in 28 healthy male volunteers in order to compare the bioavailability and prove the bioequivalence. The study was performed in an open, single dose randomized, 2-sequence, crossover design in 28 healthy male volunteers with a one-week washout period. Blood samples for pharmacokinetic profiling were drawn at selected times during 24 h. The serum concentrations of itopride HCl were determined using a specific and sensitive HPLC method with fluorescence detection. The detection limit of itopride HCl was 5 ng/ml and no endogenous compounds were found to interfere with analysis. The mean AUC(0-4h), AUC(0 --> infinity), C(max), T(max) and T1/2 were 865.28 ng x h/ml, 873.04 ng x h/ml, 303.72 ng/ml, 0.75 h, and 2.95 h, respectively, for the test formulations, and 833.00 ng x h/ml, 830.97 ng x h/ml, 268.01 ng/ml, 0.78 h, and 2.83 h, respectively, for the reference formulation. Both primary target parameters AUC(0 --> infinity) and C(max) were log-transformed and tested parametrically by analysis of variance (ANOVA). 90% confidence intervals of AUC(0 --> infinity) and C(max) were 100.57%-109.56% and 105.46%-121.18%, respectively, and were in the range of acceptable limits of bioequivalence (80-125%). Based on these results, the two formulations of itopride HCl are considered to be bioequivalent.

pH-independent sustained release matrix tablet containing doxazosin mesylate: Effect of citric acid

The aim of this study was to develop a pH-independent sustained release matrix tablets of doxazosin mesylate. The matrix tablets were prepared by direct compression technique using polyethylene oxide, sodium alginate and citric acid as a pH modifier. Formulations were evaluated for an in vitro drug release study, erosion study, and the microenvironmental pH was studied using the pH indicator methyl red. For formulations without citric acid, the extent and rate of drug release in simulated gastric fluid were much higher than those in simulated intestinal fluid. By adding the citric acid, the drug release rate in simulated intestinal fluid was increased, and microenvironmental pH values within the tablets were maintained at low pH during drug release. Furthermore, drug release from the matrix tablet containing 20% w/w citric acid was comparable to that from a commercial product, Cardura® XL, and a pHindependent release could be achieved. Therefore, the incorporation of citric acid as a pH modifier to Polyethylen oxide-sodium alginate matrix tablets effectively produced pHindependent doxazocin mesylate release profiles.

Microencapsulation of Fish Oil by Spray Drying using Different Wall Materials

The aim of this study was to investigate the effect of different wall material on the microencapsulation efficiency of microcapsules containing fish oil. The present work reports on the microencapsulation of fish oil by spray drying using hydroxypropyl methylcellulose (HPMC) 2910, maltodextrin, gelatin, sodium caseinate as wall materials. The emulsion stability was assessed by emulsion stability index value (ESI). The microstructural properties of microcapsules was evaluated by scanning electron microscopy (SEM) and microencapsulation efficiency (ME) was assessed by soxhlet method. The highest ESI and ME were observed in the case of a 1:1 gelatin/sodium caseinate ratio and 1:1 glycerin fatty acid ester/lecithin ratio, and ME of microcapsules was increased with increasing the ESI of emulsion. Thus, the stability of emulsion was a critical factor for the encapsulation of fish oil.

Pharmacokinetic and Bioequivalence Study of Zolpidem Tartate in Healthy Volunteers

In this study simple and sensitive high performance liquid chromatographic method using a commercially available column, was developed and validated for the determination of zolpidem tartrate in human plasma. The developed method with suitable validation was applied to a bioequivalence study of two different kinds of zolpidem tartrate. Two different formulations containing 10 mg of zolpidem tartate (CAS: 99294-93-6) were compared in 24 healthy male volunteers in order to compare the bioavailability and prove the bioequivalence. The study was performed in an open, single dose randomized, 2-sequence, cross-over design in 24 healthy male volunteers with a one-week washout period. Blood samples for pharmacokinetic profiling were drawn at selected times during 12 h. The mean AUC0-12h, Cmax, Tmax and T1/2 were 676.6±223.4 ng·h·mL-1, 177.4±34.2 ng·mL-1, and 0.8±0.4 and 3.5±2.1, respectively, for the test formulations, and 640.7±186.6 ng·h·mL-1, 193.0±64.5 ng·mL-1, and 0.9±0.4 and 2.7±0.9, respectively, for the reference formulation. Both primary target parameters AUC0-12h and Cmax were log-transformed and tested parametrically by analysis of variance (ANOVA). 90% confidence intervals of AUC0-12h and Cmax were in the range of acceptable limits of bioequivalence (80- 125%). Based on these results, the two formulations of zolpidem tartate are considered to be bioequivalent.