Purpose: In the United States, up to 40% of the population has expressed difficulty swallowing traditional tablets. These numbers are even higher in pediatric and geriatric populations. From a patient-centric perspective, it was desired to create a convenient and easy-to-swallow dosage form. To accomplish this goal, a commercially viable manufacturing process for rapidly disintegrating levetiracetam dosage forms was developed that utilized three-dimensional printing (3DP).
Methods: Rapidly disintegrating levetiracetam (BCS Class I) dosage forms (ZipDose™) were developed using a 3DP manufacturing process. Levetiracetam was formulated with excipients into a powder blend, which was spread by a controlled process in thin layers while a binding fluid was printed in a prescribed image onto each layer. The dosage forms were then dried at 50°C, resulting in powder binding and the formation of a porous, three-dimensional structure that rapidly disintegrates when wetted. Different dose strengths (250 mg, 500 mg, 750 mg, and 1000 mg) were produced by varying both the size of the printed images and the number of powder layers, resulting in suitably sized dosage forms. Taste-masking was accomplished by the addition of sweetening and flavoring agents to increase palatability. The disintegration rates of the levetiracetam ZipDose™ dosage forms at the various doses were tested using a USP disintegration apparatus and compared to commercially available orally disintegrating tablets.
Results: Rapidly disintegrating levetiracetam ZipDose™ dosage forms were produced in 250 mg, 500 mg, 750 mg, and 1000 mg dose strengths, using a 3DP manufacturing process. Successful manufacture of eight registration batches resulted in FDA approval and subsequent commercialization. Each of the dose strengths was produced with consistent mass throughout a batch and between batches. Variability of the average mass (n=10) measured throughout the batches ranged from 0.7% to 1.1% relative standard deviation (n ranged from 22 to 36). The average mass between batches of the same dose strength was 412 mg ± 0.1 mg for the three 250 mg batches and 1635 mg ± 9 mg for the three 1000 mg batches. Uniformity of dosage units met the USP specification for all batches, with acceptance values ranging from 4.5 to 12.3. Despite the high drug load, each of the dose strengths disintegrated within 10 seconds when tested according to USP <701>. Compared to commercialized orally disintegrating products, these 3D printed ZipDose™ dosage forms achieved faster disintegration times while simultaneously delivering higher doses of drug. Dissolution was rapid for all batches, with no less than 99% of the labeled amount of levetiracetam dissolved in 15 minutes in any batch.
Conclusion: This unique, 3DP manufacturing process allows the creation of a dosage form that can disintegrate in seconds when taken in the mouth with a sip of liquid, which can help improve the patient experience. Acceptable mass control and content uniformity have been demonstrated for the levetiracetam ZipDose™ dosage units produced by the commercial manufacturing process. Furthermore, the ZipDose™ dosage form has been shown to deliver up to 1000 mg of drug in this rapidly-disintegrating format.
Lauren Beach– Senior Product Development Scientist, Aprecia Pharmaceuticals, East Brunswick, New Jersey
Norman Coyle– Emerson Resources
Ratilal Patel– Director of Quality Control and Analytical Development, Aprecia Pharmaceuticals
Thomas Bradbury– Vice President Development Engineering, Aprecia Pharmaceuticals
Jules Jacob– Tiziana Life Sciences PLC and Rasna Therapeutics