Full Length ArticleStereolithography (SLA) 3D printing of an antihypertensive polyprintlet: Case study of an unexpected photopolymer-drug reaction
Graphical abstract
Introduction
Three-dimensional (3D) printing is forecasted to be a disruptive manufacturing technique from its ability to fabricate bespoke objects of virtually any shape and size in a layer-by-layer manner. Structures can be created from a digital 3D file using computer-aided design (CAD) software or imaging techniques to manufacture individualised entities on-demand [1]. 3D printing technologies have transformed a boundless field of applications including the aerospace industry [2], food sciences [3], robotics [4] and tissue and organ modelling [5] since its introduction.
From its advent in the pharmaceutical arena, 3D printing has already caused a paradigm shift in medicine manufacture. In 2016, the Food and Drug Administration (FDA) approved the first 3D printed tablet, Spritam®, which exploited the advantages of the 3D printing binder jet technique to produce orodispersible tablets for the treatment of epilepsy [6]. 3D printing technologies can be used to fabricate advanced oral dosage forms including orally disintegrating tablets [7], formulations with different geometries and size [[8], [9], [10]], and innovative structures [[11], [12], [13]] complemented with unique functions [[14], [15], [16], [17], [18], [19], [20]] which are otherwise challenging or near impossible to manufacture with conventional pharmaceutical techniques. Moreover, the fabrication of oral dosage forms by 3D printing allows the inclusion of multiple drug compounds in a single oral product with different configurations, such as the duoCaplet [21] or miniprintlets where doses and drug release profiles can be specifically tailored [22].
Several 3D printing technologies have proved their amenability in the pharmaceutical field, including fused deposition modelling (FDM), selective laser sintering (SLS), binder jetting and semi-solid extrusion [23]. Vat photopolymerisation techniques such as stereolithography (SLA) [24], digital light processing (DLP) [25] and continuous liquid interface production (CLIP) [26] are processes that utilise light irradiation (e.g. laser beam, UV and visible light) to create solid objects from a photoreactive liquid resin. Such methods offer several advantages including great feature resolution, a smooth surface finish and avoidance of drug thermal degradation [27,28]. Generally, there are two main photopolymerisation systems including i) free radical and ii) ionic reactions. In both mechanisms, a photoinitiator system is responsible to generate reactive species (free radical, cations or anions) in order to initiate photopolymerisation [29]. Methacrylate- and acrylate-based monomers are most widely used in the free radical system, demonstrating fast reaction rates and tunable mechanical properties [30]. Free radical photopolymerisation is an attractive and versatile platform for the development of pharmaceutical products as the active components can simply be blended with photocurable monomers prior to printing and become trapped in the polymeric cross-linked network. Previously, controlled-release drug-loaded hydrogels were successfully prepared using poly(ethylene glycol) diacrylate as the main photocurable monomers and riboflavin as a non-toxic photoinitiator via SLA 3D printing [31]. SLA technology has also demonstrated its success in the fabrication of a single oral dosage forms incorporating up to six drugs [32].
Combination therapy has gained momentum with the aim of improving therapeutic outcomes currently achieved by polypharmacy. The concurrent use of multiple medications by a patient, however, is an ongoing concern due to the high pill burden, patient non-adherence and increasing risk of medication errors [33,34]. To overcome such limitations, “polypills”, the concept of incorporating more than one active pharmaceutical ingredient in a single dosage form, was devised as an optimised therapeutic approach for treatments such as cardiovascular disease (CVD) [35]. Recently, a high-impact clinical study investigated the therapeutic outcome of a single polypill containing four antihypertensive drugs [36] (atenolol, hydrochlorothiazide, irbesartan and amlodipine) and demonstrated that a single polypill achieved a greater reduction in high blood pressure when compared with the standard dose of each medication alone.
This study aimed to explore the amenability of SLA 3D printing to fabricate a multi-layer antihypertensive polypill (herein coined as a polyprintlet) of four antihypertensive drugs (irbesartan, atenolol, hydrochlorothiazide and amlodipine) with a secondary aim to study the unexpected chemical reaction between the photopolymers and drugs.
Section snippets
Materials
Hydrochlorothiazide (MW 297.74 g/mol), poly(ethylene glycol) diacrylate (PEGDA, average Mn 575 g/mol) and diphenyl(2, 4, 6-trimethyl-benzoyl) phosphine oxide (TPO) were purchased from Sigma-Aldrich, UK. Irbesartan (MW 428.53 g/mol) was obtained from Sun Pharmaceutical Industries Ltd., India. Amlodipine (MW 408.88 g/mol) and atenolol (MW 266.34 g/mol) were purchased from LKT Laboratories Inc., USA. Poly(ethylene glycol) (PEG 300, average MW 300 g/mol) was acquired from Acros Organics, UK.
Results and discussion
The study herein demonstrates the amenability to incorporate the selected drugs in a resin to be 3D printed via SLA. Pure amlodipine and hydrochlorothiazide readily dissolved in the photopolymer solution although a longer time was required to completely dissolve atenolol and irbesartan. Hydrochlorothiazide and amlodipine solutions were clear, although both of the printed layers appeared off-white. A white solution was achieved following the homogenous dispersion of pure atenolol in the
Conclusion
In this study, we successfully report the fabrication of a multi-layer antihypertensive polyprintlet that could potentially deliver a low-dose combination therapy utilising a novel SLA 3D printing approach. Notably, reactions between photocrosslinkable monomers (PEGDA) and one of the drugs (amlodipine) were demonstrated and confirmed using FTIR and NMR spectroscopy. To the best of our knowledge, the findings from our case study was the first to describe the unexpected drug-polymer reactions in
CRediT authorship contribution statement
Xiaoyan Xu: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Resources, Data curation, Writing - original draft, Writing - review & editing. Pamela Robles-Martinez: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Resources, Data curation, Writing - review & editing, Visualization. Christine M. Madla: Conceptualization, Methodology, Resources, Writing - review & editing. Fanny Joubert: Conceptualization, Methodology,
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgement
This research was funded by the Engineering and Physical Sciences Research Council (EPSRC) UK, grant number EP/L01646X.
References (48)
- et al.
Extrusion-based food printing for digitalized food design and nutrition control
J. Food Eng.
(2018) - et al.
3D bioprinting for drug discovery and development in pharmaceutics
Acta Biomater.
(2017) - et al.
Fabricating 3D printed orally disintegrating printlets using selective laser sintering
Int. J. Pharm.
(2018) - et al.
Patient acceptability of 3D printed medicines
Int. J. Pharm.
(2017) - et al.
Direct powder extrusion 3D printing: fabrication of drug products using a novel, single-step process
Int. J. Pharm.
(2019) - et al.
3D printing of drug-loaded gyroid lattices using selective laser sintering
Int. J. Pharm.
(2018) - et al.
3D printed oral theophylline doses with innovative ‘radiator-like’ design: impact of polyethylene oxide (PEO) molecular weight
Int. J. Pharm.
(2019) - et al.
Channelled tablets: an innovative approach to accelerating drug release from 3D printed tablets
J. Control. Release
(2018) - et al.
Anti-tuberculosis drug combination for controlled oral delivery using 3D printed compartmental dosage forms: from drug product design to in vivo testing
J. Control. Release
(2017) - et al.
‘Temporary Plasticiser’: a novel solution to fabricate 3D printed patient-centred cardiovascular ‘Polypill’ architectures
Eur. J. Pharm. Biopharm.
(2019)
3D printed multi-compartment capsular devices for two-pulse oral drug delivery
J. Control. Release
PET/CT imaging of 3D printed devices in the gastrointestinal tract of rodents
Int. J. Pharm.
Pharmaceutical 3D printing: design and qualification of a single step print and fill capsule
Int. J. Pharm.
Automated therapy preparation of isoleucine formulations using 3D printing for the treatment of MSUD: first single-centre, prospective, crossover study in patients
Int. J. Pharm.
3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles
J. Control. Release
Reshaping drug development using 3D printing
Drug Discov. Today
Stereolithographic (SLA) 3D printing of oral modified-release dosage forms
Int. J. Pharm.
Digital light processing (DLP) 3D-printing technology and photoreactive polymers in fabrication of modified-release tablets
Eur. J. Pharm. Sci.
Controlling release from 3D printed medical devices using CLIP and drug-loaded liquid resins
J. Control. Release
Low temperature fused deposition modeling (FDM) 3D printing of thermolabile drugs
Int. J. Pharm.
3D scanning and 3D printing as innovative technologies for fabricating personalized topical drug delivery systems
J. Control. Release
Tough and degradable photopolymers derived from alkyne monomers for 3D printing of biomedical materials
Polym. Chem.
Fabrication of drug-loaded hydrogels with stereolithographic 3D printing
Int. J. Pharm.
3D printing pharmaceuticals: drug development to frontline care
Trends Pharmacol. Sci.
Cited by (150)
Systematic screening of photopolymer resins for stereolithography (SLA) 3D printing of solid oral dosage forms: Investigation of formulation factors on printability outcomes
2024, International Journal of PharmaceuticsStereolithographic 3D printing: Formulation design based on percolation thresholds
2023, Journal of Drug Delivery Science and TechnologyDrug delivery and testing via 3D printing
2023, BioprintingAdditive manufacturing technologies with emphasis on stereolithography 3D printing in pharmaceutical and medical applications: A review
2023, International Journal of Pharmaceutics: XA comparison of droplet deposition modelling, fused filament fabrication, and injection moulding for the production of oral dosage forms containing hydrochlorothiazide
2023, International Journal of Pharmaceutics