Design, development and biopharmaceutical considerations of modular 3D printed ‘polypills’ for personalised cardiovascular disease therapy

Carrapiço Pereira, Beatriz (2020) Design, development and biopharmaceutical considerations of modular 3D printed ‘polypills’ for personalised cardiovascular disease therapy. Doctoral thesis, University of Central Lancashire.

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The use of fixed dose combinations (also known as polypills) in chronic conditions such as cardiovascular disease (CVD) has been linked with improved adherence to the associated complex therapeutic regimens. Despite this merit, customisation of such drug dosage forms is yet to be achieved through traditional manufacturing techniques. To address this, fused deposition modelling (FDM) 3D printing could be utilised for its applicability in the production of on-demand solid dosage forms due to its unmatched flexibility of design and consequent ease of drug dose and release profile manipulation. The aim of this work is to employ this technology for the development of patient-specific multidrug tablets and capsules comprising four clinically relevant drugs (lisinopril dihydrate, amlodipine besylate, indapamide and rosuvastatin calcium) used in the treatment of CVD.

High temperatures have been recognised as the main drawback associated with FDM 3D printing, which can lead to degradation of thermolabile drugs. Therefore, a new method is needed, which was developed to address this issue and increase the number of drugs suitable for additive manufacturing. An aspect of this study established the use of distilled water as a ‘temporary plasticiser’. This novel solution proved to successfully reduce extrusion (from 170 to 90
°C) and 3D printing (from 210 to 150 °C) temperatures when compared with formulations without this plasticiser. Such drop-in processing temperatures was associated with lower degradation levels of the four model drugs used. Polypills with unimatrix and multilayer structures were developed to study the impact of tablet architecture on drug release. In general, drug release from the 3D printed tablets was dependent on drug solubility. The multilayer approach proved to allow variation of each drug release according to layer positioning.

This study further explored formulating these model drugs as single 3D printed multidrug capsules. Previously developed 3D printed capsules have been associated with leakage and/or compatibility issues between the infill and the shell. In addition, a more complex system comprising a larger number of drugs is yet to be explored. Therefore, highly modular multidrug capsule systems were developed using two different polymeric shells and different design approaches. Multicompartment capsules with concentric format consisted of a water-soluble (PVA) shells with varying walls thickness for extended and delayed drug release. On the other hand, multicompartment capsules with parallel format contained a water-insoluble (PLA) shell, where drug release was dependent on rate- limiting pores size. These capsules yielded immediate and extended drug release profiles. In addition, a novel fast dissolving capsule filling compatible with both 3D printed polymeric shells was developed.

Intestinal permeability is widely recognised as a determinant for the extent of drug absorption and it is generally expressed by the apparent permeability coefficient (Papp). In vitro Caco-2 permeability assays demonstrated no significant difference in Papp values for lisinopril dihydrate and indapamide formulated individually or in combination with the other model drugs. On the other hand, amlodipine besylate and rosuvastatin calcium had significantly lower Papp values when tested in the combination of the four drugs. This change in permeability is believed to be caused by a molecular interaction between these two drugs, due to ionization of rosuvastatin calcium and formation of a complex of amlodipine and calcium ion. The 3D printing process and the presence of excipients did not seem to influence drug permeability. Pharmacokinetic simulation of the developed 3D printed tablets and capsules was then explored using GastroPlus®, a physiologically-based pharmacokinetic modelling software. Results from this demonstrated how drug release and permeability can affect the absorption profile of the model drugs.

Adopting such highly modular approaches with minimal starting materials to achieve complex therapeutic regimens will allow health professionals to access an on-demand treatment by conveniently timing each drug administration with a desired peak drug plasma concentration to achieve optimal clinical outcomes. The coordination of customised 3D printed polypills and pharmacokinetic simulation technologies holds a promise of a paradigm shift in an integrated digital solution in medicines optimisation.

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