Personalised 3D Printed Medicines: Optimising Material Properties for Successful Passive Diffusion Loading of Filaments for Fused Deposition Modelling of Solid Dosage Forms.

Jose R Cerda,Aikaterini Lalatsa,Anne Marie Healy,Sejad Ayyoubi,Talaya Arifi,Maria Paloma Ballesteros,Peter Knief,Dolores R Serrano,William Keeble,Eugen Barbu

doi:10.3390/pharmaceutics12040345

Jose R Cerda, Aikaterini Lalatsa + Show 8 more

Open Access

https://doi.org/10.3390/pharmaceutics12040345

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Abstract

Although not readily accessible yet to many community and hospital pharmacists, fuse deposition modelling (FDM) is a 3D printing technique that can be used to create a 3D pharmaceutical dosage form by employing drug loaded filaments extruded via a nozzle, melted and deposited layer by layer. FDM requires printable filaments, which are commonly manufactured by hot melt extrusion, and identifying a suitable extrudable drug-excipient mixture can sometimes be challenging. We propose here the use of passive diffusion as an accessible loading method for filaments that can be printed using FDM technology to allow for the fabrication of oral personalised medicines in clinical settings. Utilising Hansen Solubility Parameters (HSP) and the concept of HSP distances (Ra) between drug, solvent, and filament, we have developed a facile pre-screening tool for the selection of the optimal combination that can provide a high drug loading (a high solvent-drug Ra, >10, and an intermediate solvent–filament Ra value, ~10). We have identified that other parameters such as surface roughness and stiffness also play a key role in enhancing passive diffusion of the drug into the filaments. A predictive model for drug loading was developed based on Support Vector Machine (SVM) regression and indicated a strong correlation between both Ra and filament stiffness and the diffusion capacity of a model BCS Class II drug, nifedipine (NFD), into the filaments. A drug loading, close to 3% w/w, was achieved. 3D printed tablets prepared using a PVA-derived filament (Hydrosupport, 3D Fuel) showed promising characteristics in terms of dissolution (with a sustained release over 24 h) and predicted chemical stability (>3 years at 25 °C/60% relative humidity), similar to commercially available NFD oral dosage forms. We believe FDM coupled with passive diffusion could be implemented easily in clinical settings for the manufacture of tailored personalised medicines, which can be stored over long periods of time (similar to industrially manufactured solid dosage forms).

Highlights

Modern 3D printing (3DP) techniques have opened a wide range of possibilities for the manufacture of solid dosage forms, in particular where there are clear benefits derived from adjusting the drug dose to the needs of each patient
Passive diffusion overcomes some of the issues highlighted above that are associated with the HME approach to preparing drug-loaded filaments, one of the main reasons why there has been a move away from this approach in recent years, and towards HME as a more routine method for loading filaments [9,10], is because lower drug loadings have typically been achieved compared to those obtained by HME
Finding a suitable combination of drug solvent–filament is crucial to ensure the manufacture of 3DP tablets with characteristics similar to those of commercially available solid dosage forms

Summary

Introduction

Modern 3D printing (3DP) techniques have opened a wide range of possibilities for the manufacture of solid dosage forms, in particular where there are clear benefits derived from adjusting the drug dose to the needs of each patient. Dose personalisation is known to maximise the therapeutic efficacy of drugs [1] and to reduce the incidence of undesirable effects, which are critical for drugs with a low therapeutic index (such as anticoagulants e.g., warfarin), cytostatic drugs, or very potent actives [2]. To complement these advantages, 3DP allows for easy personalisation of medicines in terms of composition, colour, and dosage form size [3]. We believe the loading process can be significantly improved by optimally combining a biocompatible and extrudable polymeric material with a suitable

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