Preparation and in vitro/in vivo Evaluation of Lacidipine by Adsorption onto Fumed Silica Using Supercritical Carbon Dioxide.

The aim of this study was to design a silica-supported solid dispersion of lacidipine (LCDP) to enhance the dissolution rate and oral absorption using supercritical CO2 (scCO2) as a solvent. The formulation was characterized using differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy and fourier transformed infrared spectroscopy. In the dissolution test, LCDP-scCO2 formulation showed a significantly enhanced dissolution compared with LCDPsilica physical mixture and a faster dissolution rate than Lacipil® under different dissolution conditions. In an in vivo test, the area under concentration-time curve and Cmax of LCDP-scCO2 formulation was 9.23 and 23.78 fold greater than LCDP-silica physical mixture (1:15, w/w), respectively, whereas the corresponding values were 1.92 and 2.80 fold greater than Lacipil®, respectively. Our results showed that the solid dispersion prepared by supercritical fluids technology is a feasible method to enhance the oral bioavailability of LCDP.

Improved Oral Bioavailability of Lacidipine Using Nanosuspension Technology: Inferior in vitro Dissolution and Superior in vivo Drug Absorption versus Lacipil®.

Improved dissolution is a better way of increasing the oral absorption of lacidipine (LCDP) because it is a BCS II class drug. The purpose of this study is to improve the oral bioavailability of LCDP by applying nanosuspension technology. LCDP nanosuspensions were prepared by a hybrid method of microprecipitation and high pressure homogenization. The effects of the production parameters (shearing rate and time, the stabilizers and their concentrations, homogenization pressure and number of cycles) were investigated to optimize the preparation process. In vitro characterizations (X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy and dissolution measurement) were carried out and an oral pharmacokinetic study was performed in beagle dogs. LCDP was transformed into an amorphous state during the preparation process, and the mean particle size was about 714.0 ± 12.7 nm. The dissolution rate of LCDP nanosuspensions was faster than that of physical mixtures, but slower than that of Lacipil® (the commercial tablet). Regarding the in vivo pharmacokinetics, the key pharmacokinetic parameters (Cmax and AUC0-∞) of the nanosuspensions were statistically significantly higher than those of both the commercial tablet and physical mixtures. So, this is an efficient drug delivery strategy to facilitate the oral administration of LCDP by using nanosuspension technology, and should be generally applicable to many poorly water-soluble drugs with dissolution rate-limited absorption.

In-vitro and in-vivo study of amorphous spironolactone prepared by adsorption method using supercritical CO2.

OBJECTIVE: The aim of this study was to improve the oral bioavailability of spironolactone (SP). METHOD: SP was adsorbed on the fumed silica using supercritical CO2 (scCO2) technology and further compressed into tablets. The morphology was observed by scanning electron microscopy (SEM), and the crystalline form was investigated by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The dissolution test was performed in water, 0.1 M HCl solution, pH 4.5 acetate buffers and pH 6.8 phosphate buffers using the paddle method. The pharmacokinetics was undertaken in six dogs in a crossover fashion. RESULTS: SP was successfully prepared into tablets and presented in amorphous state. SP-silica scCO2 tablets displayed higher dissolution profiles than SP-silica physical mixtures tablets in different media. The AUC0-t and Cmax of SP-silica supercritical CO2 was 1.61- and 1.52-fold greater than those of SP-silica physical mixtures (p < 0.05), respectively. CONCLUSION: It is a promising method in improving dissolution and bioavailability by adsorbing SP, a poorly soluble drug, on the fumed silica using rapid expansion of supercritical solutions.

Development of a supercritical fluid chromatography-tandem mass spectrometry method for the determination of lacidipine in beagle dog plasma and its application to a bioavailability study.

A simple, novel, rapid and sensitive supercritical fluid chromatography-tandem mass spectrometry (SFC-MS/MS) method was developed and validated for the determination of lacidipine in beagle dog plasma with nimodipine as internal standard. The method involved a simple liquid-liquid extraction method with tert-butyl methyl ether. The analytes were analyzed on an Acquity UPC(2) with a HSS C18 SB column (3mm×100mm, 1.8µm) set at 50°C. The mobile phase was carbon dioxide (≥99.99%) and methanol (92:8, v/v) at a flow rate of 2ml/min, the compensation solvent was methanol with 2% formic acid at a flow rate of 0.2ml/min and a total analysis time of 1.5min for each sample. The multiple reaction-monitoring mode was used for quantification of ion transitions at m/z 473.32→354.10 and 419.00→343.10 for lacidipine and internal standard, respectively. The linearity range of proposed method was 0.10-100ng/ml) (r(2)≥0.9990). The intra- and inter-day precision values were less than 15% and accuracy was from -0.83% to 3.27% at all quality control levels. The proposed method was successfully applied to a pharmacokinetic study of lacidipine in beagle dogs.

An HPLC-MS/MS method for simultaneous determination of decitabine and its valyl prodrug valdecitabine in rat plasma.

A simple and sensitive HPLC-MS/MS method was developed and validated for the simultaneous determination of decitabine and valdecitabine in rat plasma. The analytes were separated on a C(18) column (150mm×4.6mm, 3.5µm) and a triple-quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source was applied for detection. A clean solid-phase extraction procedure with cation exchange cartridge was employed to extract the analytes from rat plasma with high recovery of decitabine (>82%). The calibration curves were linear over a concentration range of 10-10,000ng/mL for decitabine and 5-500ng/mL for valdecitabine. The lower limit of quantitation (LLOQ) of decitabine and valdecitabine was 10 and 5ng/mL, respectively. The intra-day and inter-day precisions were less than 15% and the relative error (RE) was all within ±15%. The validated method was successfully applied to a pharmacokinetics study in rats after either decitabine or valdecitabine orally administrated to the Sprague-Dawley rats.