Randomized Comparative Bioavailability of a Novel Three-Dimensional Printed Fast-Melt Formulation of Levetiracetam Following the Administration of a Single 1000-mg Dose to Healthy Human Volunteers Under Fasting and Fed Conditions.

BACKGROUND: Rapidly disintegrating or 'fast-melt' oral formulations have been developed recently to facilitate drug intake among patients. Even though these formulations have helped to improve therapy adherence, some of their limitations include: the dissolution time, their facility to be swallowed, and the dosage strengths that may be accommodated. To overcome these limitations, a novel, porous, quickly disintegrating, and easier-to-swallow fast-melt formulation based on powder-liquid, three-dimensional printing (3DP) technology has been developed. OBJECTIVE: To determine and compare the relative bioavailability of a novel 3DP fast melt containing levetiracetam in healthy male and female subjects. METHODS: This study included 33 subjects in a three-way crossover design. The 3DP fast-melt formulation was compared against the conventional immediate-release tablet of levetiracetam (Keppra(®)) after a single 1000-mg dose administration under fasting conditions following the bioequivalence criteria used by the US Food and Drug Administration. This study also evaluated the food effect on the bioavailability of the levetiracetam 3DP fast melt. A small sip of liquid was used to administer the fast-melt formulation. RESULTS: The novel 3DP fast melt showed rapid oral disintegration (mean duration of 11 s from a sip of water to completion of swallowing) following its administration, and did not affect the pharmacokinetic profile of levetiracetam. A lower absorption peak was observed after administration of the 3DP fast melt under fed conditions, as expected. In addition, time of maximum measured plasma concentration was delayed by approximately 3.5 h under fed conditions. These effects are unlikely to be of clinical significance with long-term administration, and may help reduce the adverse events and facilitate compliance. Finally, no change in the oral mucosa was observed with the 3DP fast melt while being as safe and well tolerated as the standard levetiracetam tablet. CONCLUSION: This study quantified the rapid disintegration of the 3DP levetiracetam fast melt and confirmed its equivalent rate and extent of absorption to the conventional immediate-release tablet in the fasted state, using standard bioequivalence criteria.

Enantioselective analysis of levetiracetam and its enantiomer R-alpha-ethyl-2-oxo-pyrrolidine acetamide using gas chromatography and ion trap mass spectrometric detection.

A gas chromatographic-mass spectrometric method was developed for the enantioselective analysis of levetiracetam and its enantiomer (R)-alpha-ethyl-2-oxo-pyrrolidine acetamide in dog plasma and urine. A solid-phase extraction procedure was followed by gas chromatographic separation of the enantiomers on a chiral cyclodextrin capillary column and detection using ion trap mass spectrometry. The fragmentation pattern of the enantiomers was further investigated using tandem mass spectrometry. For quantitative analysis three single ions were selected from the enantiomers, enabling selected ion monitoring in detection. The calibration curves were linear from 1 microM to 2 mM for plasma samples and from 0.5 mM to 38 mM for urine samples. In plasma and urine samples the inter-day precision, expressed as relative standard deviation was around 10% in all concentrations. Selected ion monitoring mass spectrometry is suitable for quantitative analysis of a wide concentration range of levetiracetam and its enantiomer in biological samples. The method was successfully applied to a pharmacokinetic study of levetiracetam and (R)-alpha-ethyl-2-oxo-pyrrolidine acetamide in a dog.

Determination of carphedon in human urine by solid-phase microextraction using capillary gas chromatography with nitrogen-phosphorus detection.

Carphedon is a phenyl derivative of nootropil and is effective in increasing physical endurance and cold resistance, and is used for amnesia treatment. Carphedon was extracted from human urine samples by solid-phase microextraction with a 65 microns carbowax-divinylbenzene-coated fiber. This analysis was performed by using capillary gas chromatography with nitrogen-phosphorus detection and optimized at pH 9.6, 30% NaCl, immersion time 10 min and desorption in the GC injector at 250 degrees C for 3 min. The regression equation for carphedon showed good linearity in the range from 0.1 to 10 micrograms ml-1 for human urine samples. The limit of detection was 0.01 microgram ml-1. The developed method is more sensitive and simpler in sample preparation than liquid-liquid extraction and can be applied to doping analysis for stimulants.

[Fast thin-layer densitometric determination of the nootropic piracetam in biological material]. / Rasche dünnschicht-densitometrische Bestimmung des Nootropikums Piracetam in biologischem Material.

After oral doses of piracetam this drug is detectable in serum as well as in urine after formation of the red Fe(III)-hydroxamatecomplex by thin-layer densitometry. Detection in serum requires extraction with a mixture of dichloromethane/ methanol, while urine can be used directly after dilution. The limit of quantification in urine is 100 micrograms/ml and in serum 4.0 micrograms/ml. The new method was validated by HPLC. The coefficient of correlation was 0.9999% for determination in urine and 0.9986% for determination in serum.

Compliance testing by measurement of piracetam in urine--a possible method of compliance control for piracetam intakers. An empirical investigation.

All teams of investigators concerned with compliance rate have come to the conclusion that one can seldom rely on patients to take their tablets as prescribed. In case of long-term medication the problem becomes even more acute. A method for checking on compliance is, therefore, of great help in controlling medical therapy as well as in judging the effectiveness of pharmaceuticals. The results of this study imply that diachronic determination of piracetam concentration in patients' urine is an especially simple way of testing compliance without undue strain on the patient.

[Pharmacokinetics of piracetam during delivery]. / Zur Pharmakokinetik von Piracetam während der Geburt.

The excretion of Piracetam was monitored by measuring the concentrations in maternal and fetal substrates during labor in nine volunteers. Piracetam was tolerated without side-effects and injected in the maternal cubital vein. Consecutively, maternal plasma and urine samples as well as amniotic fluid portions were collected during labor. at delivery, fetal blood from placenta and the first fetal urines were collected. Biostatistical methods showed that approximately 50% of Piracetam were eliminated 80 minutes after the injection of the drug. In amniotic fluid a continuous rise of Piracetam concentrations was monitored until delivery. In fetal plasma and urines the substance could be detected. The rapid excretion of Piracetam during labor was obviously typical for the situation sub partu; reasons are discussed.