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Selective laser sintering (SLS) 3D printing is a revolutionary 3D printing technology that has been found capable of creating drug products with varied release profiles by changing the laser scanning speed. Here, SLS 3D printed formulations (printlets) loaded with a narrow therapeutic index drug (theophylline) were produced using SLS 3D printing at varying laser scanning speeds (100-180 mm/s). The use of reflectance Fourier Transform - Near Infrared (FT-NIR) spectroscopy was evaluated as a non-destructive approach to predicting 3D printed tablet density and drug release at 2 h and 4 h. The printed drug products formulated with a higher laser speed exhibited an accelerated drug release and reduced density compared with the slower laser scanning speeds. Univariate calibration models were developed based on a baseline shift in the spectra in the third overtone region upon changing physical properties. For density prediction, the developed univariate model had high linearity (R2 value = 0.9335) and accuracy (error < 0.029 mg/mm3). For drug release prediction at 2 h and 4 h, the developed univariate models demonstrated a linear correlation (R2 values of 0.9383 and 0.9167, respectively) and accuracy (error < 4.4%). The predicted vs. actual dissolution profiles were found to be statistically similar (f2 > 50) for all of the test printlets. Overall, this article demonstrates the feasibility of SLS 3D printing to produce drug products containing a narrow therapeutic index drug across a range of drug release profiles, as well as the potential for FT-NIR spectroscopy to predict the physical characteristics of SLS 3D printed drug products (drug release and density) as a non-destructive quality control method at the point-of-care.
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Selective laser sintering (SLS) 3D printing is capable of revolutionising pharmaceutical manufacturing, by producing amorphous solid dispersions in a one-step manufacturing process. Here, 3D-printed formulations loaded with a model BCS class II drug (20% w/w itraconazole) and three grades of hydroxypropyl cellulose (HPC) polymer (-SSL, -SL and -L) were produced using SLS 3D printing. Interestingly, the polymers with higher molecular weights (HPC-L and -SL) were found to undergo a uniform sintering process, attributed to the better powder flow characteristics, compared with the lower molecular weight grade (HPC-SSL). XRPD analyses found that the SLS 3D printing process resulted in amorphous conversion of itraconazole for all three polymers, with HPC-SSL retaining a small amount of crystallinity on the drug product surface. The use of process analytical technologies (PAT), including near infrared (NIR) and Raman spectroscopy, was evaluated, to predict the amorphous content, qualitatively and quantitatively, within itraconazole-loaded formulations. Calibration models were developed using partial least squares (PLS) regression, which successfully predicted amorphous content across the range of 0-20% w/w. The models demonstrated excellent linearity (R2 = 0.998 and 0.998) and accuracy (RMSEP = 1.04% and 0.63%) for NIR and Raman spectroscopy models, respectively. Overall, this article demonstrates the feasibility of SLS 3D printing to produce solid dispersions containing a BCS II drug, and the potential for NIR and Raman spectroscopy to quantify amorphous content as a non-destructive quality control measure at the point-of-care.
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Digitalisation of the healthcare sector promises to revolutionise patient healthcare globally. From the different technologies, virtual tools including artificial intelligence, blockchain, virtual, and augmented reality, to name but a few, are providing significant benefits to patients and the pharmaceutical sector alike, ranging from improving access to clinicians and medicines, as well as improving real-time diagnoses and treatments. Indeed, it is envisioned that such technologies will communicate together in real-time, as well as with their physical counterparts, to create a large-scale, cyber healthcare system. Despite the significant benefits that virtual-based digital health technologies can bring to patient care, a number of challenges still remain, ranging from data security to acceptance within the healthcare sector. This review provides a timely account of the benefits and challenges of virtual health interventions, as well an outlook on how such technologies can be transitioned from research-focused towards real-world healthcare and pharmaceutical applications to transform treatment pathways for patients worldwide.
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Inteligência Artificial , Tecnologia Digital/métodos , Indústria Farmacêutica/organização & administração , Setor de Assistência à Saúde/organização & administração , Tecnologia Biomédica , Ensaios Clínicos como Assunto , Desenvolvimento de Medicamentos/organização & administração , Descoberta de Drogas/organização & administração , Troca de Informação em Saúde , Humanos , Aprendizado de Máquina , Aplicativos Móveis , Tecnologia de Sensoriamento Remoto/métodos , Projetos de Pesquisa , Fatores de Tempo , Estados Unidos , United States Food and Drug Administration , Realidade VirtualRESUMO
Now more than ever, traditional healthcare models are being overhauled with digital technologies of Healthcare 4.0 increasingly adopted. Worldwide, digital devices are improving every stage of the patient care pathway. For one, sensors are being used to monitor patient metrics 24/7, permitting swift diagnosis and interventions. At the treatment stage, 3D printers are under investigation for the concept of personalised medicine by allowing patients access to on-demand, customisable therapeutics. Robots are also being explored for treatment, by empowering precision surgery, rehabilitation, or targeted drug delivery. Within medical logistics, drones are being leveraged to deliver critical treatments to remote areas, collect samples, and even provide emergency aid. To enable seamless integration within healthcare, the Internet of Things technology is being exploited to form closed-loop systems that remotely communicate with one another. This review outlines the most promising healthcare technologies and devices, their strengths, drawbacks, and opportunities for clinical adoption.
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Tecnologia Biomédica , Tecnologia Digital , Assistência ao Paciente , HumanosRESUMO
Three-dimensional (3D) printing is a revolutionary technology that is disrupting pharmaceutical development by enabling the production of personalised printlets (3D printed drug products) on demand. By creating small batches of dose flexible medicines, this versatile technology offers significant advantages for clinical practice and drug development, namely the ability to personalise medicines to individual patient needs, as well as expedite drug development timelines within preclinical studies through to first-in-human (FIH) and Phase I/II clinical trials. Despite the widely demonstrated benefits of 3D printing pharmaceuticals, the clinical potential of the technology is yet to be realised. In this timely review, we provide an overview of the latest cutting-edge investigations in 3D printing pharmaceuticals in the pre-clinical and clinical arena and offer a forward-looking approach towards strategies to further aid the translation of 3D printing into the clinic.
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Desenvolvimento de Medicamentos/métodos , Impressão Tridimensional , Tecnologia Farmacêutica/métodos , Animais , Sistemas de Liberação de Medicamentos , Humanos , Medicina de Precisão/métodos , Pesquisa Translacional Biomédica/métodosRESUMO
Intravesical instillation therapy is an alternative approach to oral medications for the treatment of severe bladder diseases, offering high drug concentrations at the site of action while minimising systemic side effects. However, therapeutic efficacy is often limited because of the short residence time of the drug in the bladder and the need for repeated instillations. This study reports, for the first time, the use of stereolithography (SLA) 3D printing to manufacture novel indwelling bladder devices using an elastic polymer to achieve extended and localised delivery of lidocaine hydrochloride. The devices were designed to be inserted into and retrieved from the bladder using a urethral catheter. Two types of bladder devices (hollow and solid) were prepared with a resilient material (Elastic Resin) incorporating three drug loads of lidocaine hydrochloride (10% w/w, 30% w/w and 50% w/w); a drug frequently used to treat interstitial cystitis and bladder pain. All of the devices showed acceptable blood compatibility, good resistance to compressive and stretching forces and were able to recover their original shape immediately once external forces were removed. In vitro drug release studies showed that a complete release of lidocaine was achieved within 4 days from the hollow devices, whereas the solid devices enabled sustained drug release for up to 14 days. SLA 3D printing therefore provides a new manufacturing route to produce bladder-retentive drug delivery devices using elastic polymers, and offers a revolutionary and personalised approach for clinical intravesical drug delivery.
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Preparações Farmacêuticas , Estereolitografia , Sistemas de Liberação de Medicamentos , Impressão Tridimensional , Bexiga UrináriaRESUMO
Visual impairment and blindness affects 285 million people worldwide, resulting in a high public health burden. This study reports, for the first time, the use of three-dimensional (3D) printing to create orally disintegrating printlets (ODPs) suited for patients with visual impairment. Printlets were designed with Braille and Moon patterns on their surface, enabling patients to identify medications when taken out of their original packaging. Printlets with different shapes were fabricated to offer additional information, such as the medication indication or its dosing regimen. Despite the presence of the patterns, the printlets retained their original mechanical properties and dissolution characteristics, wherein all the printlets disintegrated within ~5 s, avoiding the need for water and facilitating self-administration of medications. Moreover, the readability of the printlets was verified by a blind person. Overall, this novel and practical approach should reduce medication errors and improve medication adherence in patients with visual impairment.
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Three-dimensional printing (3DP) is a revolutionary technology in pharmaceuticals, enabling the personalisation of flexible-dose drug products and 3D printed polypills (polyprintlets). A major barrier to entry of this technology is the lack of non-destructive quality control methods capable of verifying the dosage of multiple drugs in polyprintlets at the point of dispensing. In the present study, 3D printed films and cylindrical polyprintlets were loaded with flexible, therapeutic dosages of two distinct drugs (amlodipine and lisinopril) across concentration ranges of 1-5% w/w and 2-10% w/w, respectively. The polyprintlets were non-destructively analysed for dose content using a portable near infrared (NIR) spectrometer and validated calibration models were developed using partial least squares (PLS) regression, which showed excellent linearity (R2 Pred = 0.997, 0.991), accuracy (RMSEP = 0.24%, 0.24%) and specificity (LV1 = 82.77%, 79.55%) for amlodipine and lisinopril, respectively. X-ray powder diffraction (XRPD) and thermogravimetric analysis (TGA) showed that sintering partially transformed the phase of both drugs from the crystalline to amorphous forms. For the first time, we report a non-destructive method for quality control of two separate active ingredients in a single 3D printed drug product using NIR spectroscopy, overcoming a major barrier to the integration of 3D printing into clinical practice.
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Anlodipino/administração & dosagem , Lisinopril/administração & dosagem , Impressão Tridimensional , Tecnologia Farmacêutica , Anlodipino/química , Química Farmacêutica , Cristalização , Lisinopril/química , Controle de Qualidade , Espectroscopia de Luz Próxima ao Infravermelho , Termogravimetria , Difração de Raios XRESUMO
Introduction: Three-dimensional (3D) printing is a relatively new, rapid manufacturing technology that has found promising applications in the drug delivery and medical sectors. Arguably, never before has the healthcare industry experienced such a transformative technology. This review aims to discuss the state of the art of 3D printing technology in healthcare and drug delivery. Areas covered: The current and future applications of printing technologies within drug delivery and medicine have been discussed. The latest innovations in 3D printing of customized medical devices, drug-eluting implants, and printlets (3D-printed tablets) with a tailored dose, shape, size, and release characteristics have been covered. The review also covers the state of the art of 3D printing in healthcare (covering topics such as dentistry, surgical and bioprinting of patient-specific organs), as well as the potential of recent innovations, such as 4D printing, to shape the future of drug delivery and to improve treatment pathways for patients. Expert opinion: A future perspective is provided on the potential for 3D printing in healthcare, covering strategies to overcome the major barriers to integration that are faced today.
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Atenção à Saúde/métodos , Sistemas de Liberação de Medicamentos/tendências , Impressão Tridimensional/tendências , Animais , Humanos , Medicina de Precisão , ComprimidosRESUMO
Printing technologies have been forecast to initiate a new era of personalised medicine in pharmaceuticals. To facilitate integration, a non-destructive and robust method of product authenticity is required. This study reports, for the first time, the interface between 3D printing and 2D inkjet printing technologies in order to fabricate a drug-loaded 3D printed tablet (printlet) with a unique track-and-trace measure in a single step process. In particular, quick response (QR) codes and data matrices were printed onto the surface of polymeric-based printlets for scanning using a smartphone device, and were designed to encode tailored information pertaining to the drug product, patient and prescriber. Moreover, a novel anti-counterfeit strategy was designed, which involved the deposition of a unique combination of material inks for detection using Raman spectroscopy. The inks were characterised for printability by measuring surface tension, viscosity and density, and each was successfully detected on the 3D printed tablet post-printing. Overall, this novel approach will enable an enhanced transparency and tracking of 3D printed medicines across the supply chain, leading to a safer treatment pathway for patients.
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Tinta , Impressão Tridimensional , Tecnologia Farmacêutica/métodos , Fraude/prevenção & controle , Medicina de Precisão , ComprimidosRESUMO
Three-dimensional printing (3DP) has demonstrated great potential for multi-material fabrication because of its capability for printing bespoke and spatially separated material conformations. Such a concept could revolutionise the pharmaceutical industry, enabling the production of personalised, multi-layered drug products on demand. Here, we developed a novel stereolithographic (SLA) 3D printing method that, for the first time, can be used to fabricate multi-layer constructs (polypills) with variable drug content and/or shape. Using this technique, six drugs, including paracetamol, caffeine, naproxen, chloramphenicol, prednisolone and aspirin, were printed with different geometries and material compositions. Drug distribution was visualised using Raman microscopy, which showed that whilst separate layers were successfully printed, several of the drugs diffused across the layers depending on their amorphous or crystalline phase. The printed constructs demonstrated excellent physical properties and the different material inclusions enabled distinct drug release profiles of the six actives within dissolution tests. For the first time, this paper demonstrates the feasibility of SLA printing as an innovative platform for multi-drug therapy production, facilitating a new era of personalised polypills.
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Three-dimensional (3D) printing is revolutionising how we envision manufacturing in the pharmaceutical field. Here, we report for the first time the use of direct powder extrusion 3D printing: a novel single-step printing process for the production of printlets (3D printed tablets) directly from powdered materials. This new 3D printing technology was used to prepare amorphous solid dispersions of itraconazole using four different grades of hydroxypropylcellulose (HPC - UL, SSL, SL and L). All of the printlets showed good mechanical and physical characteristics and no drug degradation. The printlets showed sustained drug release characteristics, with drug concentrations higher than the solubility of the drug itself. The printlets prepared with the ultra-low molecular grade (HPC - UL) showed faster drug release compared with the other HPC grades, attributed to the fact that itraconazole was found in a higher percentage as an amorphous solid dispersion. This work demonstrates the potential of this innovate technology to overcome one of the major disadvantages of fused deposition modelling (FDM) 3D printing by avoiding the need for preparation of filaments by hot melt extrusion (HME). This novel single-step technology could revolutionise the preparation of amorphous solid dispersions as final formulations and it may be especially suited for preclinical studies, where the quantity of drugs is limited and without the need of using traditional HME.
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Impressão Tridimensional , Tecnologia Farmacêutica/métodos , Celulose/análogos & derivados , Celulose/química , Liberação Controlada de Fármacos , Itraconazol/química , PósRESUMO
Selective laser sintering (SLS) is a single-step three-dimensional printing (3DP) process that can be leveraged to engineer a wide array of drug delivery systems. The aim of this work was to utilise SLS 3DP, for the first time, to produce small oral dosage forms with modified release properties. As such, paracetamol-loaded 3D printed multiparticulates, termed miniprintlets, were fabricated in 1 mm and 2 mm diameters. Despite their large surface area compared with a conventional monolithic tablet, the ethyl cellulose-based miniprintlets exhibited prolonged drug release patterns. The possibility of producing miniprintlets combining two drugs, namely paracetamol and ibuprofen, was also investigated. By varying the polymer, the dual miniprintlets were programmed to achieve customised drug release patterns, whereby one drug was released immediately from a Kollicoat Instant Release matrix, whilst the effect of the second drug was sustained over an extended time span using ethyl cellulose. Herein, this work has highlighted the versatility of SLS 3DP to fabricate small and intricate formulations containing multiple active pharmaceutical ingredients with distinct release properties.
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Three-dimensional printing (3DP) has the potential to cause a paradigm shift in the manufacture of pharmaceuticals, enabling personalised medicines to be produced on-demand. To facilitate integration into healthcare, non-destructive characterisation techniques are required to ensure final product quality. Here, the use of process analytical technologies (PAT), including near infrared spectroscopy (NIR) and Raman confocal microscopy, were evaluated on paracetamol-loaded 3D printed cylindrical tablets composed of an acrylic polymer (Eudragit L100-55). Using a portable NIR spectrometer, a calibration model was developed, which predicted successfully drug concentration across the range of 4-40% w/w. The model demonstrated excellent linearity (R2â¯=â¯0.996) and accuracy (RMSEPâ¯=â¯0.63%) and results were confirmed with conventional HPLC analysis. The model maintained high accuracy for tablets of a different geometry (torus shapes), a different formulation type (oral films) and when the polymer was changed from acrylic to cellulosic (hypromellose, HPMC). Raman confocal microscopy showed a homogenous drug distribution, with paracetamol predominantly present in the amorphous form as a solid dispersion. Overall, this article is the first to report the use of a rapid 'point-and-shoot' approach as a non-destructive quality control method, supporting the integration of 3DP for medicine production into clinical practice.
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Acetaminofen/química , Analgésicos não Narcóticos/química , Impressão Tridimensional , Tecnologia Farmacêutica/métodos , Acetaminofen/administração & dosagem , Resinas Acrílicas/química , Administração Oral , Analgésicos não Narcóticos/administração & dosagem , Composição de Medicamentos , Excipientes/química , Derivados da Hipromelose/química , Microscopia Confocal , Modelos Químicos , Microscopia Óptica não Linear , Espectroscopia de Luz Próxima ao Infravermelho , ComprimidosRESUMO
Hypothyroidism is a chronic and debilitating disease that is estimated to affect 3% of the general population. Clinical experience has highlighted the synergistic value of combining triiodothyronine (T3) and thyroxine (T4) for persistent or recurrent symptoms. However, thus far a platform that enables the simultaneous and independent dosing of more than one drug for oral administration has not been developed. Thermal inkjet (TIJ) 2D printing is a potential solution to enable the dual deposition of T3 and T4 onto orodispersible films (ODFs) for therapy personalisation. In this study, a two-cartridge TIJ printer was modified such that it could print separate solutions of T3 and T4. Dose adjustments were achieved by printing solutions adjacent to each other, enabling therapeutic T3 (15-50⯵g) and T4 dosages (60-180⯵g) to be successfully printed. Excellent linearity was observed between the theoretical and measured dose for both T3 and T4 (R2â¯=â¯0.982 and 0.985, respectively) by changing the length of the print objective (Y-value). Rapid disintegration of the ODFs was achieved (<45â¯s). As such, this study for the first time demonstrates the ability to produce personalised dose combinations by TIJ printing T3 and T4 onto the same substrate for oral administration.
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Hipotireoidismo/tratamento farmacológico , Impressão Tridimensional , Tecnologia Farmacêutica/métodos , Tiroxina/administração & dosagem , Tri-Iodotironina/administração & dosagem , Administração Oral , Combinação de Medicamentos , Composição de Medicamentos , Cálculos da Dosagem de Medicamento , Liberação Controlada de Fármacos , Desenho de Equipamento , Humanos , Cinética , Impressão Tridimensional/instrumentação , Solubilidade , Tecnologia Farmacêutica/instrumentação , Tiroxina/química , Tri-Iodotironina/químicaRESUMO
Three-dimensional printing (3DP) is a highly disruptive technology with the potential to change the way pharmaceuticals are designed, prescribed and produced. Owing to its low cost, diversity, portability and simplicity, fused deposition modeling (FDM) is well suited to a multitude of pharmaceutical applications in digital health. Favourably, through the combination of digital and genomic technologies, FDM enables the remote fabrication of drug delivery systems from 3D models having unique shapes, sizes and dosages, enabling greater control over the release characteristics and hence bioavailability of medications. In turn, this system could accelerate the digital healthcare revolution, enabling medicines to be tailored to the individual needs of each patient on demand. To date, a variety of FDM 3D printed medical products (e.g. implants) have been commercialised for clinical use. However, within pharmaceuticals, certain regulatory hurdles still remain. This article reviews the current state-of-the-art in FDM technology for medical and pharmaceutical research, including its use for personalised treatments and interconnection within digital health networks. The outstanding challenges are also discussed, with a focus on the future developments that are required to facilitate its integration within pharmacies and hospitals.
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Impressão Tridimensional , Tecnologia Farmacêutica/instrumentação , Animais , Humanos , Modelos Teóricos , Preparações Farmacêuticas/química , Plásticos/química , TelemedicinaRESUMO
The pharmaceutical industry stands on the brink of a revolution, calling for the recognition and embracement of novel techniques. 3D printing (3DP) is forecast to reshape the way in which drugs are designed, manufactured, and used. Although a clear trend towards personalised fabrication is perceived, here we accentuate the merits and shortcomings of each technology, providing insights into aspects such as the efficiency of production, global supply, and logistics. Contemporary opportunities for 3DP in drug discovery and pharmaceutical development and manufacturing are unveiled, offering a forward-looking view on its potential uses as a digitised tool for personalised dispensing of drugs.
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Descoberta de Drogas/métodos , Preparações Farmacêuticas/síntese química , Impressão Tridimensional , Animais , Composição de Medicamentos , Humanos , Estrutura Molecular , Preparações Farmacêuticas/provisão & distribuição , Relação Estrutura-AtividadeRESUMO
Three-dimensional printing (3DP) is gaining momentum in the field of pharmaceuticals, offering innovative opportunities for medicine manufacture. Selective laser sintering (SLS) is a novel, high resolution and single-step printing technology that we have recently introduced to the pharmaceutical sciences. The aim of this work was to use SLS 3DP to fabricate printlets (3D printed tablets) with cylindrical, gyroid lattice and bi-layer structures having customisable release characteristics. Paracetamol-loaded constructs from four different pharmaceutical grade polymers including polyethylene oxide, Eudragit (L100-55 and RL) and ethyl cellulose, were created using SLS 3DP. The novel gyroid lattice structure was able to modulate the drug release from all four polymers. This work is the first to demonstrate the feasibility of using SLS to achieve customised drug release properties of several polymers, in a swift, cost-effective manner, avoiding the need to alter the formulation composition. By creating these constructs, it is therefore possible to modify drug release, which in practice, could enable the tailoring of drug performance to the patient simply by changing the 3D design.
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Lasers , Impressão Tridimensional , Tecnologia Farmacêutica/métodos , Acetaminofen/química , Resinas Acrílicas/química , Celulose/análogos & derivados , Celulose/química , Liberação Controlada de Fármacos , Polietilenoglicóis/química , Polímeros/química , ComprimidosRESUMO
3D printing (3DP) is forecast to be a highly revolutionary technology within the pharmaceutical sector. In particular, the main benefits of 3DP lie in the production of small batches of medicines, each with tailored dosages, shapes, sizes and release characteristics. The manufacture of medicines in this way may finally lead to the concept of personalised medicines becoming a reality. In the shorter term, 3DP could be extended throughout the drug development process, ranging from preclinical development and clinical trials, through to frontline medical care. In this review, we provide a timely perspective on the motivations and potential applications of 3DP pharmaceuticals, as well as a practical viewpoint on how 3DP could be integrated across the pharmaceutical space.