Improving solubility and oral bioavailability of a novel antimalarial prodrug: comparing spray-dried dispersions with self-emulsifying drug delivery systems.

To improve the solubility and oral bioavailability of a novel antimalarial agent ELQ-331(a prodrug of ELQ-300), spray-dried dispersions (SDD) and a self-emulsifying drug delivery system (SEDDS) were developed. SDD were prepared with polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) polymer carrier and Aeroperl® 300 Pharma and characterized by differential scanning calorimetry, powder X-ray diffraction. For SEDDS, solubility in oils, surfactants, and co-surfactants was determined and ternary phase diagram was constructed to show self-emulsifying area. SEDDS were characterized for spontaneous emulsification and droplet size distribution. The amorphous ELQ-331 SDD improved the solubility to 10× in fast-state simulated intestinal fluid and addition of sodium lauryl sulphate externally to SDDs further improved the solubility to ∼28.5× versus non-formulated drug. SEDDS had good self-emulsifying characteristics with small emulsion droplet sizes and narrow particle distribution. Oral pharmacokinetic studies for SDD and SEDDS formulations were performed in rats. The ELQ-331 rapidly converted to ELQ-300 soon after oral administration in rats. Exposure levels of ELQ-300 were about 1.4-fold higher (based on AUC) in SEDDS than SDD formulations. Poorly soluble drugs like ELQ-331 can be formulated using SDD or SEDDS to improve solubility and oral bioavailability.

Evaluating the toxicity of novel Zn-DTPA tablet formulation in dogs and rats.

The purpose of this research work is to evaluate toxicity of diethylenetriamine pentaacetic acid zinc trisodium salt (Zn-DTPA) tablets, a novel oral solid dosage form containing permeation enhancers in beagle dogs and Sprague Dawley rats. (Zn-DTPA) in tablet dosage form was administered once daily for 7 days to beagle dogs at low (840 mg/dog/day), mid (2520 mg/dog/day), or high (7560 mg/dog/day). On day 8, all treated and control groups were necropsied. The novel Zn-DTPA tablet formulation showed rapid absorption with the T(max) at 1 h. Plasma concentrations as high as 270 µg/mL were observed after 7 days of administration. Exposure to DTPA, based on area under the curve (AUC(last)) and maximum concentration (C(max)), was dose dependent but not dose proportional. No biologically relevant changes in hematology or clinical chemistry that were related to DTPA exposure were observed, and there were no changes in body weight in treated dogs compared with controls. Zn-DTPA was well tolerated, with minor toxicological effects of emesis and diarrhea, following oral tablet administration for 7 consecutive days. Based on the endpoints evaluated in this study, the maximum tolerated dose is considered to be greater than 7560 mg/dog/day (2535 µmol/kg/day, 1325 mg/kg/day), and the no-observed-adverse-effect level (NOAEL) is considered to be approximately 1325 mg/kg/day per oral when given to male and female beagle dogs. For rats, the NOAEL was estimated to be greater than 1000 mg/kg/day when administered by oral gavage of the crushed Zn-DTPA tablets as suspension once daily (qd) to male and female Sprague Dawley rats.

Development and validation of a liquid chromatography/tandem mass spectrometry assay for the simultaneous determination of nateglinide, cilostazol and its active metabolite 3,4-dehydro-cilostazol in Wistar rat plasma and its application to pharmacokinetic study.

Nateglinide (NTG), an insulin secretogogue, has been studied in rats for drug-drug interaction with cilostazol (CLZ), an antiplatelet agent commonly used in diabetics. We developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) based method that is capable of simultaneous monitoring plasma levels of nateglinide, cilostazol, and its active metabolite 3,4-dehydro-cilostazol (DCLZ). All analytes including the internal standard (Repaglinide) were chromatographed on reverse phase C(18) column (50 mm x 4.6mm i.d., 5 microm) using acetonitrile: 2mM ammonium acetate buffer, pH 3.4 (90:10, v/v) as mobile phase at a flow rate 0.4 ml/min in an isocratic mode. The detection of analyte was performed on LC-MS/MS system in the multiple reaction monitoring (MRM) mode. The quantitations for analytes were based on relative concentration. The method was validated over the concentration range of 20-2000 ng/ml and the lower limit of quantitation was 20 ng/ml. The recoveries from spiked control samples were >79% for all analytes and internal standard. Intra- and inter-day accuracy and precision of validated method were with in the acceptable limits of <15% at all concentration. The quantitation method was successfully applied for simultaneous estimation of NTG, CLZ and DCLZ in a pharmacokinetic drug-drug interaction study in Wistar rats.

Validated high performance liquid chromatographic method for simultaneous determination of rosiglitazone, cilostazol, and 3,4-dehydro-cilostazol in rat plasma and its application to pharmacokinetics.

A high performance liquid chromatographic (HPLC) method for simultaneous determination of rosiglitazone, CAS 122320-73-4, RSG), cilostazol (CAS 73963-72-1, CLZ) and its active metabolite 3, 4-dehydro-cilostazol (DCLZ), using pioglitazone (PIO) as internal standard (IS), in rat plasma is described. The plasma was extracted with methyl t-butyl ether, the dry extract was reconstituted in mobile phase and the aliquot was injected. The eluent drugs were detected by UV at dual wavelength of 226 nm (RSG and DCLZ) and 257 nm (CLZ). The mobile phase consisting of acetonitrile:potassium di-hydrogen phosphate buffer (35:65 v/v) was used at the flow rate of 1.2 ml/min on a reverse phase C18 column. The absolute recovery was above 90% of all analytes over the concentration range of 25-2500 ng/ml for RSG and CLZ and 20-2000 ng/ ml for DCLZ. The relative standard deviation (RSD) of the inter-day and intra-day precision ranged from 2.8 to 8.4% and 0.9 to 5.9%, respectively. The method is simple, rapid, accurate and sensitive and was applied to pharmacokinetic studies.