Despite its relatively limited resolution, FDM 3D printing proved to be a suitable platform for a single-process fabrication of delayed release tablets. This work reveals the potential of dual FDM 3D printing as a unique platform for personalising delayed release tablets to suit an individual patient's needs.

Hypertension and dyslipidaemia are modifiable risk factors associated with cardiovascular diseases (CVDs) and often require a complex therapeutic regimen. The administration of several medicines is commonly associated with poor levels of adherence among patients, to which World Health Organisation (WHO) proposed a fixed-dose combination unit (polypill) as a strategy to improve adherence. In this work, we demonstrate the fabrication of patient-specific polypills for the treatment of CVDs by fused deposition modelling (FDM) 3D printing and introduce a novel solution to meet critical quality attributes. The construction of poly(vinyl alcohol) (PVA)-based polypills containing four model drugs (lisinopril dihydrate, indapamide, rosuvastatin calcium and amlodipine besylate) was revealed for the first time. The impact of tablet architecture was explored using multi-layered and unimatrix structures. The novel approach of using distilled water as a 'temporary co-plasticiser' is reported and was found to significantly lower the extruding (90°C) and 3D printing (150°C) temperatures from 170°C and 210°C respectively, with consequent reduction in thermal stress to the chemicals. XRD indicated that lisinopril dihydrate and amlodipine besylate maintained their crystalline form while indapamide and rosuvastatin calcium were essentially amorphous in the PVA tablets. From the multilayer polypills, the release profile of each drug was dependent on its position in the multilayer.In addition to the multilayer architecture offering a higher flexibility in dose titration and a more adaptive solution to meet the expectations of patient-centred therapy, we identify that it also allows orchestrating the release of drugs of different physicochemical characteristics. Adopting such an approach opens up a pathway towards low-cost multidrug delivery systems such as tablets, stents or implants for wider range of globally approved actives.

Polypharmacy is often needed for the management of cardiovascular diseases and is associated with poor adherence to treatment. Hence, highly flexible and adaptable systems are in high demand to accommodate complex therapeutic regimens. A novel design approach was employed to fabricate highly modular 3D printed 'polypill' capsules with bespoke release patterns for multiple drugs. Complex structures were devised using combined fused deposition modelling 3D printing aligned with hotfilling syringes. Two unibody highly modular capsule skeletons with 4 separate compartments were devised: i) concentric format: two external compartments for early release whilst two inner compartments for delayed release, or ii) parallel format: where non-dissolving capsule shells with free-pass corridors and dissolution rate-limiting pores were used to achieve immediate and extended drug releases, respectively. Controlling drug release was achieved through digital manipulation of shell thickness in the concentric format or the size of the rate limiting pores in the parallel format. Target drug release profiles were achieved with variable orders and configurations, hence confirming the modular nature with capacity to accommodate therapeutics of different properties. Projection of the pharmacokinetic profile of this digital system capsules revealed how the developed approach could be applied in dose individualization and achieving multiple desired pharmacokinetic profiles.

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On demand manufacturing of patient-specific oral doses provides significant advantages to patients and healthcare staff. Several 3D printing (3DP) technologies have been proposed as a potential digital alternative to conventional manufacturing of oral tablets. For additive manufacturing approach to be successful for on-demand preparation, a facile process with minimal preparation steps and training requirements is needed. A novel hybrid approach to the 3D printing process is demonstrated here based on combined solvent and heating elements/factors/aspects to facilitate extrusion. The system employed a moderate elevated temperature range of (65-100 o C), a brief drying period, and a simple set-up. In this approach, a compact powder cylinder is used as a pharmaceutical ink to be extruded in a temperaturecontrolled metal syringe. The process proved compatible with hygroscopic polymers [Poly(vinyl alcohol (PVA) and poly(vinyl pyridine) (PVP)] and a number of pharmaceutical fillers (lactose, sorbitol and mannitol). The fabricated tablets demonstrated compendial acceptable weight and content uniformity as well as mechanical resistance. In vitro drug release of theophylline from 3D printed tablets was dependant on the nature of the polymer and its molecular weight. This reported approach offers significant advantages compared to other 3DP technologies: simplification of pre-product, the use of a moderate temperature range, a minimal drying period, and avoiding the use of mechanically complicated direct extruder machinery. In the future, we envisage the use of this low-cost and facile approach to fabricate small batches of bespoke tablets.

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