BackgroundRapidly 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.ObjectiveTo determine and compare the relative bioavailability of a novel 3DP fast melt containing levetiracetam in healthy male and female subjects.MethodsThis 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.ResultsThe 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.ConclusionThis 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.

AimsTo evaluate the effects of food and formulation on the pharmacokinetics of bismuth biskalcitrate, metronidazole and tetracycline when combined in a new 3-in-1 single capsule (BMT) for eradication of Helicobacter pylori . MethodsIn a randomized, 3 ¥ 3 cross-over design, 23 healthy males received one dose of BMT in the fed and fasting states and equivalent doses of the three drugs g iven together but as separate capsules while fasting. Bioequivalence was evaluated according to 90% confidence intervals (CIs) of ratios of geometric least square means for C max , AUC t , and AUC • . ResultsWith respect to food, none of the three drugs met bioequivalence guidelines. Bismuth had lower limit CIs ranging from 12% for C max to 25% for AUC • . The corresponding values for tetracycline were 59% and 51%. Metronidazole had a lower limit CI of 74% for C max . With respect to formulation, bismuth had lower limits of CIs rang ing from 39% for C max to 50% for AUC t and higher limits of 146% for AUC t , metronidazole met bioequivalence guidelines, and tetracycline had lower limits of CIs between 72% for AUC t and 74% for AUC • . ConclusionsFood significantly decreased the relative bioavailability of each drug but formulation was without effect. This decrease may be beneficial when a local gastric action is needed, as confirmed by a near 90% eradication rate when this combined capsule is administered with food to treat gastro-duodenal local infection by H. pylori .

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The objective of this study was to determine the impact of omeprazole on bismuth (Bi) bioavailability when given in a three-in-one capsule containing bismuth biskalcitrate, metronidazole, and tetracycline. Thirty-four healthy volunteers were randomly assigned to receive three capsules (each containing bismuth biskalcitrate 140 mg + metronidazole 125 mg + tetracycline 125 mg) qid alone x 6 days or the same treatment + omeprazole (OM) 20 mg bid. Blood was drawn at intervals for 24 hours after the last dose. After the last dose, mean (CV) C(min) for plasma bismuth was 2882 pg/mL (36%) and 1195 pg/mL (23%) (p< 0.001), with and without OM, respectively. Mean (CV) C(max) was 25493 pg/mL (69%) and 8061 pg/mL (28%) (p < 0.001) with and without OM, respectively. AUC(0-24) increased by 2.9 in presence of OM (p < 0.001). Adverse events in both groups were usually mild and of a gastrointestinal nature, and all had resolved by the end of the trial. This study confirms an interaction between Bi biskalcitrate and OM. Risk of Bi toxicity, seen after long-term use of Bi compounds, is minimal here because plasma levels of Bi remained well below the toxic levels of 50 microg/L, and the treatment period with this triple capsule + OM is only 10 days, a substantially lower number of days compared to that which might produce Bi toxicity.