Tailored on demand anti-coagulant dosing: Anin vitroandin vivoevaluation of 3D printed purpose-designed oral dosage forms

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Abstract

Coumarin therapy has been associated with high levels of inter- and intra-individual variation in the required dose to reach a therapeutic anticoagulation outcome. Therefore, a dynamic system that is able to achieve accurate delivery of a warfarin dose is of significant importance. Here we assess the ability of 3D printing to fabricate and deliver tailored individualised precision dosing using in-vitro and in-vivo models. Sodium warfarin loaded filaments were compounded using hot melt extrusion (HME) and further fabricated via fused deposition modelling (FDM) 3D printing to produce capsular-ovoid-shaped dosage forms loaded at 200 or 400 μg dose. The solid dosage forms and comparator warfarin aqueous solutions were administered by oral gavage to Sprague–Dawley rats. A novel UV imaging approach indicated that the erosion of the methacrylate matrix was at a rate of 16.4 and 15.2 μm/min for horizontal and vertical planes respectively. In vivo, 3D printed forms were as proportionately effective as their comparative solution form in doubling plasma exposure following a doubling of warfarin dose (184% versus 192% respectively). The 3D printed ovoids showed a lower Cmax of warfarin (1.51 and 3.33 mg/mL versus 2.5 and 6.44 mg/mL) and a longer Tmax (6 and 3.7 versus 4 and 1.5 h) in comparison to liquid formulation. This work demonstrates for the first time in vivo, the potential of FDM 3D printing to produce a tailored specific dosage form and to accurately titrate coumarin dose response to an individual patient.

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