Absorption from 3D-printed pediatric carvedilol tablets: insights from in vitro, in vivo, and in silico approaches

There is a lack of age-appropriate dosage forms of carvedilol, a poorly water-soluble substance requiring dose adjustment when treating congestive heart failure in children. Here, 3D-printed carvedilol tablets intended for pediatric use were produced, and the tablet performance was evaluated in vitro and in vivo, with in silico methods used to increase the understanding of formulation properties. Tablets were 3D-printed using semi-solid extrusion of emulsion gels containing a lipid-based formulation (LBF) and cellulose-based polymers. In vitro digestion-permeation assays were performed to assess the absorption across an artificial lipid membrane and were contrasted to a clinically utilized marketed product. A crossover study in juvenile pigs was performed to evaluate in vivo exposure of carvedilol from the 3D-printed tablets relative to the product. Coarse-grained molecular dynamics simulations were conducted to investigate how the LBF influenced carvedilol transport across a phosphatidylcholine membrane model, mimicking the artificial membrane used in vitro. The 3D-printed tablets demonstrated significantly higher in vitro permeation across the artificial lipid membrane compared to the marketed product. In vivo, slightly higher, although not statistically different, carvedilol exposure of the 3D-printed tablets was observed. In silico simulations suggested that LBF facilitates transport of the free drug, and that LBF digestion products integrate into the membrane, resulting in enhanced carvedilol permeation. The combination of in vitro, in vivo and in silico approaches provide a platform for rational formulation design, with molecular-level insights guiding future optimization. Overall, the results demonstrate the feasibility of 3D printing individualized and dose-adjusted pediatric tablets with promising absorption characteristics.