Volumetric printing and non-destructive drug quantification of water-soluble supramolecular hydrogels

Abstract

Vat photopolymerisation 3D printing is being actively explored for manufacturing personalised medicines due to its high dimensional accuracy and lack of heat application. However, several challenges have hindered its clinical translation, including the inadequate printing speeds, the lack of resins that give soluble matrices, and the need for non-destructive quality control measures. In this study, for the first time, a rapid approach to producing water-soluble vat photopolymerised matrices and a means of non-destructively verifying their drug content were investigated. Volumetric printing, a novel form of vat photopolymerisation, was used to fabricate personalised warfarin-loaded 3D-printed tablets (printlets). Eight different formulations containing varying amounts of warfarin (0.5–6.0% w/w) were used to print two different sized torus-shaped printlets within 6.5 to 11.1 s. Nuclear magnetic resonance (NMR) spectroscopy revealed the presence of only trace amounts of unreacted acrylate monomers, suggesting that the photopolymerisation reaction had occurred to near completion. All printlets completely solubilised and released their entire drug load within 2.5 to 7 h. NIR spectroscopy (NIRS) was used to non-destructively verify the dose of warfarin loaded into the vat photopolymerised printlets. The partial least square regression model built showed strong linearity (R² = 0.980), and high accuracy in predicting the drug loading of the test sample (RMSEP = 0.205%). Therefore, this study advances pharmaceutical vat photopolymerisation by demonstrating the feasibility of producing water-soluble printlets via volumetric printing and quantifying the drug load of vat photopolymerised printlets with NIRS.

Introduction

Personalised medicine is a modern practice in healthcare where medical care and interventions are tailored to individual patients as opposed to a “one-size-fits-all” approach based on population means [1, 2]. While personalised medicines emerged in the past two decades following notable advancements in molecular genetics, personalising a patient’s drug treatments has been and remains in practice since the 1960s in the form of therapeutic drug monitoring (TDM) [3,4,5]. TDM is the clinical practice of adjusting a patient’s drug regime based on their serum, plasma, or whole blood drug concentration [5]. This is primarily applied to drugs that have small differences in their therapeutic and toxic dose, i.e., narrow therapeutic index (NTI) drugs. For example, warfarin is an NTI anti-coagulant drug where individual dose requirements can vary significantly, based on the patient’s age, body mass index, and genetic variations in enzymes (cytochrome P450) that metabolise the drug [6]. Consequently, a patient’s prescribed dose of warfarin is based on their international normalised ratio (INR), which indicates the time it takes for blood to clot. With growing pharmacogenomic evidence and emerging healthcare technologies, the practice of TDM and medicines personalisation is expected to see improvements in dose optimisation, therapeutic outcomes, and accessibility.

3D printing (3DP), or additive manufacturing, is one such technology that is being actively explored in the pharmaceutical field for its ability to fabricate personalised medical devices and medicines [7,8,9,10,11]. Specific to the latter, the technology allows medicines to be tailored in terms of dose, drug release profile, and geometry according to the patient’s therapeutic needs. Amongst the various categories of 3D printing, vat photopolymerisation affords high spatial resolution without necessitating the application of heat [12,13,14]. Vat photopolymerisation-based technologies, such as stereolithography (SLA), digital light processing (DLP) and liquid crystal display (LCD), use light to induce photopolymerisation and hence solidification of a liquid photosensitive resin [15, 16]. Owing to its high dimensional accuracy and compatibility with heat labile drugs, this technology has been explored for numerous pharmaceutical and healthcare applications, such as dental implants [17,18,19], personalised tablets (printlets) [20,21,22,23], patient-tailored drug-eluting devices [24,25,26], and microneedles [27,28,29]. However, due to the layer-by-layer means of fabrication, SLA, DLP, and LCD 3DP may not be able to provide the printing speeds required to keep up and be deployed in fast-paced clinical settings.

Volumetric printing, or volumetric additive manufacturing, is a novel type of vat photopolymerisation printing that affords significantly faster printing speeds [30,31,32]. Unlike SLA and DLP, volumetric printing does not produce the desired 3D geometry layer-by-layer; instead, the entire object is fabricated simultaneously through the accumulation of light patterns derived from images of the object viewed from different angles. In the pharmaceutical space, volumetric printing has been used to fabricate paracetamol-loaded tablets in as little as 7 s, which is significantly faster than DLP and SLA that requires the same time to polymerise a single layer [33,34,35]. However, as with other vat photopolymerisation printing technologies, drug delivery devices and dosage forms fabricated in this way have been insoluble in water. Consequently, applications have been limited to sustained release medicines and drug-eluting medical devices that do not require solubilisation of the printed matrix. Recently, our group reported a novel vat photopolymerisable formulation that produced water-soluble paracetamol-loaded matrices printed through DLP 3DP [36]. Preliminary evidence from a single-dose acute toxicity animal study on matrices derived from this formulation also provided early evidence on the safety of the photopolymerised polymers. However, as volumetric printing has resin requirements that are distinct from DLP and SLA printing (e.g., resin transparency), the feasibility of printing matrices with this novel formulation with volumetric printing remains to be investigated.

Another barrier to the clinical translation of vat photopolymerisation 3DP, and other pharmaceutical 3DP technologies, is the challenge of safeguarding and validating the quality of made-to-order medicines [37]. As these personalised medicines are not made in excess, conventional quality control measures that are destructive, such as drug quantification via high performance liquid chromatography or UV spectroscopy assays, are not suitable. Near infra-red spectroscopy (NIRS) is an analytical technology that has been explored for non-destructive dose verification of 3D printed medicines [38, 39]. Every compound has a unique NIR spectrum, where the intrinsic peaks of the compound can be correlated to its concentration through multivariate modelling. Thus, quantitative multivariate models can be built to determine the percentage content of a drug within a 3D printed matrix. This has successfully been used for drug quantification in selective laser sintering printed tablets [40, 41], inkjet-printed devices [42], and direct powder extrusion printed medicines [43]. A drawback of NIRS is that the analyte signals can be easily overwhelmed by the strong overtone and combination bands of vibrations arising from water molecules, as water strongly absorbs energy in the IR region [44, 45]. Consequently, quantifying the drug load of vat photopolymerised hydrogels (herein referred to as printlets) with NIRS could be a challenge given the common inclusion of water as a non-reactive diluent.

Therefore, this study aims to investigate the feasibility of using volumetric printing to fabricate personalised warfarin sodium-loaded water-soluble printlets via volumetric printing using the novel water-soluble matrix formulation. This study represents the first-time water-soluble warfarin-loaded printlets have been fabricated using vat photopolymerization. The amount of warfarin sodium loaded into the resin mixture and the size of the printlets were varied to demonstrate the potential to personalise printlets according to the patient’s INR. NIRS was used to non-destructively quantify the weight% of warfarin sodium loaded into the printlets, representing the first time NIRS is used for dose verification of vat photopolymerised printlets.

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Materials

[2-(Acryloyloxy)ethyl]trimethylammonium chloride solution (TMAEA) (80 wt% in water), lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP, MW 294.21 g/mol, ≥ 95%), 2-propanol (isopropanol, puriss, ≥ 99.8%), acetonitrile (ACN) for HPLC (gradient grade, ≥ 99.9%), and deuterium oxide (99.9 atom % D) were purchased from Sigma-Aldrich (Dorset, UK). Warfarin sodium clathrate (MW 330.31 g/mol, > 98.0%) was purchased from LKT Laboratories Inc. (St. Paul MN, USA). Red food colorant (Kroma Kolors, Kopykake, Torrance, CA, USA) was purchased from Shesto Limited (Watford, UK). Sodium acetate (MW 82.03 g/mol) was purchased from VWR Chemicals (Leuven, Belgium). Glacial acetic acid (MW 60.05 g/mol) was purchased from Severn Biotech Ltd. (Worcestershire, UK). Hydrochloric acid 1 M solution was purchased from LP Chemicals Ltd (Winsford, UK). All materials were used as received.

Ong, J.J., Jørgensen, A.K., Zhu, Z. et al. Volumetric printing and non-destructive drug quantification of water-soluble supramolecular hydrogels. Drug Deliv. and Transl. Res. (2024). https://doi.org/10.1007/s13346-024-01723-6

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