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

Abstract

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.

Three-Dimensional Printing of Medicinal Products and the Challenge of Personalized Therapy

“…Hence, it deals with a dosage form produced on a large-scale and approved via the regulatory procedure currently in use. A recent study also demonstrated bioequivalence of this product in the fasted state to the conventionally fabricated immediate-release tablets available on the market 80 .…”

Current formulation approaches in design and development of solid oral dosage forms through three-dimensional printing

“…High porosity also characterises Spritam®, the first medicine fabricated through a 3D printing process-known as ZipDose®-to gain Food and Drug Administration approval in 2015, marketed by Aprecia Pharmaceuticals [25]. Spri-tam® is an antiseizure drug containing the active ingredient levetiracetam and the rationale behind its development is that the highly porous structure allows the tablet to disintegrate in a mean of 11 s, allowing a fast onset of action [26,27].…”

Utility of extracellular matrix powders in tissue engineering

“…35 Drug conjugation to powder has been used to create 3D printed drugs, such as levetiracetam. 36 3DP allows for control of spatial drug distribution and accurate drug dispense at low volumes, thereby reducing waste in manufacturing drugs and creating a highly tunable release profile. 37,38 ECM powders have not been used in drug 3DP, but their separate uses in drug delivery and 3DP indicates potential future application in drug 3DP.…”