ABSTRACT
This work gives a brief overview of carrier materials currently used in pharmaceutical studies on the three-dimensional (3D) semi-solid extrusion (SSE) printing of medicines for pediatrics. The suitability of using these carrier materials in pediatric formulations, concerning safety and toxicity, was reviewed by consulting the 'Safety & Toxicity of Excipients for Pediatrics' (STEP) database and the Food and Drug Administration (FDA) regulations. In the second part of this work, carrier materials were tested on their ability to form a semi-solid mixture with lactose by dual asymmetric centrifugation (DAC) and printing by SSE. With the combination of theoretical and experimental studies, this work will guide research toward grounded decision-making when it comes to carrier material selection for pharmaceutical pediatric 3D SSE printing formulations.
ABSTRACT
Oral dosage forms are by far the most common prescription and over-the-counter pharmaceutical dosage forms used worldwide. However, many patients suffer from adverse effects caused by their use of "one-size fits all" mass produced commercially available solid dosage forms, whereby they do not receive dedicated medication or dosage adjusted to their specific needs. The development of 3D printing paves the way for personalised medicine. This work focuses on personalised therapies for hypertensive patients using nifedipine as the model drug. 3D printed full solid and channelled spherical mini-tablets with enhanced surface area (1.6-fold higher) were printed using modified PVA commercial filaments loaded by passive diffusion (PD), and Kollidon VA64 (KVA) and ethylcellulose (EC) based filaments prepared by hot-melt extrusion (HME). Drug loading ranged from 3.7% to 60% based on the employed technique, with a 13-fold higher drug loading achieved with the HME compared to PD. Composition was found to have a more significant impact on drug dissolution than geometry and surface area. Both KVA and EC-based formulations exhibited a biphasic zero-order drug-release profile. Physicochemical characterization revealed that nifedipine was in the amorphous form in the KVA-based end-products which led to a greater dissolution control over a 24 h period compared to the EC-based formulations that exhibited low levels of crystallinity by PXRD. The proposed 3D printed spherical mini-tablets provide a versatile technology for personalised solid dosage forms with high drug loading and dissolution control, easily adaptable to patient and disease needs.
Subject(s)
Excipients , Technology, Pharmaceutical , Drug Liberation , Humans , Printing, Three-Dimensional , Solubility , TabletsABSTRACT
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).
