Emergence of 3D Printed Dosage Forms: Opportunities and Challenges

The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such an extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and its potential yet to be fully explored. This paper presents various 3D printing technologies such as stereolithographic, powder based, selective laser sintering, fused deposition modelling and semi-solid extrusion 3D printing. It also provides a comprehensive review of previous attempts at using 3D printing technologies on the manufacturing dosage forms with a particular focus on oral tablets. Their advantages particularly with adaptability in the pharmaceutical field have been highlighted, which enables the preparation of dosage forms with complex designs and geometries, multiple actives and tailored release profiles. An insight into the technical challenges facing the different 3D printing technologies such as the formulation and processing parameters is provided. Light is also shed on the different regulatory challenges that need to be overcome for 3D printing to fulfil its real potential in the pharmaceutical industry.

[1]  Gordon G Wallace,et al.  3-dimensional (3D) fabricated polymer based drug delivery systems. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[2]  H. M. Nielsen,et al.  Three-dimensional printing of drug-eluting implants: preparation of an antimicrobial polylactide feedstock material. , 2015, Journal of pharmaceutical sciences.

[3]  Dong-Woo Cho,et al.  Development of 3D PPF/DEF scaffolds using micro-stereolithography and surface modification , 2009, Journal of materials science. Materials in medicine.

[4]  K. Cooper,et al.  Fused Deposition Modeling , 2001 .

[5]  Marc E. Nelson,et al.  Bioresorbable airway splint created with a three-dimensional printer. , 2013, The New England journal of medicine.

[6]  Federico Parietti,et al.  3D printing by fused deposition modeling (FDM) of a swellable/erodible capsular device for oral pulsatile release of drugs , 2015 .

[7]  Udayabhanu M. Jammalamadaka,et al.  Antibiotic and chemotherapeutic enhanced three-dimensional printer filaments and constructs for biomedical applications , 2015, International journal of nanomedicine.

[8]  Jean-Pierre Kruth,et al.  On the difference in material structure and fatigue properties of nylon specimens produced by injection molding and selective laser sintering , 2013 .

[9]  Qixin Zheng,et al.  The controlled-releasing drug implant based on the three dimensional printing technology: Fabrication and properties of drug releasing in vivo , 2009 .

[10]  Xuanhui Qu,et al.  Preparation and properties of porous Ti-10Mo alloy by selective laser sintering. , 2013, Materials science & engineering. C, Materials for biological applications.

[11]  Simon Gaisford,et al.  3D Printing of Medicines: Engineering Novel Oral Devices with Unique Design and Drug Release Characteristics. , 2015, Molecular pharmaceutics.

[12]  Adam Froats,et al.  The use of a low cost 3D scanning and printing tool in the manufacture of custom-made foot orthoses: a preliminary study , 2014, BMC Research Notes.

[13]  Vinod P. Shah,et al.  Analysis of in Vitro Dissolution of Whole vs. Half Controlled-Release Theophylline Tablets , 2004, Pharmaceutical Research.

[14]  V. K. Popov,et al.  Laser stereolithography and supercritical fluid processing for custom-designed implant fabrication , 2004, Journal of materials science. Materials in medicine.

[15]  Sara McMains Layered manufacturing technologies , 2005, CACM.

[16]  M. Alexander,et al.  3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[17]  J. Ford,et al.  An assessment of dose‐uniformity of samples delivered from paediatric oral droppers , 2004, Journal of clinical pharmacy and therapeutics.

[18]  Niklas Sandler,et al.  Inkjet printing of drug substances and use of porous substrates-towards individualized dosing. , 2011, Journal of pharmaceutical sciences.

[19]  Benard P Dreyer,et al.  Parents' medication administration errors: role of dosing instruments and health literacy. , 2010, Archives of pediatrics & adolescent medicine.

[20]  Michael Schmidt,et al.  Selective laser sintering of PEEK , 2007 .

[21]  Deng-Guang Yu,et al.  A novel fast disintegrating tablet fabricated by three-dimensional printing , 2009, Drug development and industrial pharmacy.

[22]  K. Karlage,et al.  Analysis of drug content and weight uniformity for half-tablets of 6 commonly split medications. , 2009, Journal of managed care pharmacy : JMCP.

[23]  Colleen L Flanagan,et al.  Bone tissue engineering using polycaprolactone scaffolds fabricated via selective laser sintering. , 2005, Biomaterials.

[24]  K. H. Low,et al.  Characterization of microfeatures in selective laser sintered drug delivery devices , 2002, Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine.

[25]  Walter E. Haefeli,et al.  Difficulties swallowing solid oral dosage forms in a general practice population: prevalence, causes, and relationship to dosage forms , 2012, European Journal of Clinical Pharmacology.

[26]  Jörg Kotzerke,et al.  [Structured review]. , 2014, Nuklearmedizin. Nuclear medicine.

[27]  A. Basit,et al.  Fused-filament 3D printing (3DP) for fabrication of tablets. , 2014, International journal of pharmaceutics.

[28]  M. A. Alhnan,et al.  A flexible-dose dispenser for immediate and extended release 3D printed tablets. , 2015, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[29]  A. Basit,et al.  Effect of geometry on drug release from 3D printed tablets. , 2015, International journal of pharmaceutics.

[30]  J David Spence,et al.  Polypill: For Pollyanna* , 2008, International journal of stroke : official journal of the International Stroke Society.

[31]  Deepak Saxena,et al.  Effect of Pollypill on cardiovascular parameters: Systematic review and meta-analysis. , 2013, Journal of cardiovascular disease research.

[32]  Jaedeok Yoo,et al.  Development of Near Zero-Order Release Dosage Forms Using Three-Dimensional Printing (3-DP™) Technology , 2006, Drug development and industrial pharmacy.

[33]  Chee Kai Chua,et al.  Building Porous Biopolymeric Microstructures for Controlled Drug Delivery Devices Using Selective Laser Sintering , 2006 .

[34]  C K Chua,et al.  Fabrication of porous polymeric matrix drug delivery devices using the selective laser sintering technique , 2001, Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine.

[35]  Satu Lakio,et al.  Continuous manufacturing of extended release tablets via powder mixing and direct compression. , 2015, International journal of pharmaceutics.

[36]  Steven Teerenstra,et al.  The accuracy, precision and sustainability of different techniques for tablet subdivision: breaking by hand and the use of tablet splitters or a kitchen knife. , 2014, International journal of pharmaceutics.

[37]  Kevin Outterson,et al.  Regulating compounding pharmacies after NECC. , 2012, The New England journal of medicine.

[38]  Abdul W. Basit,et al.  Personalised dosing: Printing a dose of one's own medicine. , 2015, International journal of pharmaceutics.

[39]  J. Erramouspe,et al.  Effect on Dissolution from Halving Methylphenidate Extended-Release Tablets , 1997, The Annals of pharmacotherapy.

[40]  I. Ursan,et al.  Three-dimensional drug printing: a structured review. , 2013, Journal of the American Pharmacists Association : JAPhA.

[41]  Uwe Gbureck,et al.  Low temperature direct 3D printed bioceramics and biocomposites as drug release matrices. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[42]  M. Alexander,et al.  Desktop 3D printing of controlled release pharmaceutical bilayer tablets. , 2014, International journal of pharmaceutics.

[43]  Duc Truong Pham,et al.  A comparison of rapid prototyping technologies , 1998 .

[44]  L. Froyen,et al.  Fundamentals of Selective Laser Melting of alloyed steel powders , 2006 .

[45]  Richard A Black,et al.  The design and production of Co-Cr alloy implants with controlled surface topography by CAD-CAM method and their effects on osseointegration. , 2005, Biomaterials.

[46]  Adnan Nasir,et al.  Polyglycolic acid microneedles modified with inkjet-deposited antifungal coatings. , 2015, Biointerphases.

[47]  Peter A Meléndez,et al.  Thermal inkjet application in the preparation of oral dosage forms: dispensing of prednisolone solutions and polymorphic characterization by solid-state spectroscopic techniques. , 2008, Journal of pharmaceutical sciences.

[48]  N. Jawahar,et al.  Influence of layer thickness on mechanical properties in stereolithography , 2006 .

[49]  Deng Guang Yu,et al.  Three-dimensional printing in pharmaceutics: promises and problems. , 2008, Journal of pharmaceutical sciences.

[50]  D. Cho,et al.  3D printing of cell-laden constructs for heterogeneous tissue regeneration , 2013 .

[51]  Rachmat Mauludin,et al.  Influence of β-cyclodextrin on Cefixime Stability in Liquid Suspension Dosage Form , 2014 .

[52]  W. Habib,et al.  Accuracy of tablet splitting: Comparison study between hand splitting and tablet cutter. , 2014, Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society.

[53]  M. Alexander,et al.  3D printing of tablets containing multiple drugs with defined release profiles. , 2015, International journal of pharmaceutics.

[54]  Niklas Sandler,et al.  Towards fabrication of 3D printed medical devices to prevent biofilm formation. , 2014, International journal of pharmaceutics.

[55]  Jianhua Sun,et al.  A programmed release multi-drug implant fabricated by three-dimensional printing technology for bone tuberculosis therapy , 2009, Biomedical materials.

[56]  J S Cohen,et al.  Ways to minimize adverse drug reactions. Individualized doses and common sense are key. , 1999, Postgraduate medicine.

[57]  Dennis Douroumis,et al.  Inkjet printing of transdermal microneedles for the delivery of anticancer agents. , 2015, International journal of pharmaceutics.

[58]  Guixing Qiu,et al.  [Selective Laser Sintering-produced porous titanium alloy scaffold for bone tissue engineering]. , 2014, Zhonghua yi xue za zhi.

[59]  Chee Kai Chua,et al.  Characterization of SLS parts for drug delivery devices , 2001 .

[60]  J. Farrar,et al.  Isoniazid, Pyrazinamide and Rifampicin Content Variation in Split Fixed-Dose Combination Tablets , 2014, PLoS ONE.

[61]  Kaufui Wong,et al.  A Review of Additive Manufacturing , 2012 .

[62]  Siowling Soh,et al.  Printing Tablets with Fully Customizable Release Profiles for Personalized Medicine , 2015, Advanced materials.

[63]  Julia Will,et al.  Three-dimensional printing of flash-setting calcium aluminate cement , 2011 .

[64]  L. Tahaineh,et al.  Tablet Splitting and Weight Uniformity of Half-Tablets of 4 Medications in Pharmacy Practice , 2012, Journal of pharmacy practice.

[65]  Niklas Sandler,et al.  A step toward development of printable dosage forms for poorly soluble drugs. , 2013, Journal of pharmaceutical sciences.

[66]  Gianaurelio Cuniberti,et al.  Three-dimensional printing of hierarchical and tough mesoporous bioactive glass scaffolds with a controllable pore architecture, excellent mechanical strength and mineralization ability. , 2011, Acta biomaterialia.

[67]  Emanuel M. Sachs,et al.  Solid free-form fabrication of drug delivery devices , 1996 .

[68]  Shaochen Chen,et al.  Projection printing of 3-dimensional tissue scaffolds. , 2012, Methods in molecular biology.

[69]  Syed H. Masood,et al.  Application of fused deposition modelling in controlled drug delivery devices , 2007 .

[70]  Woong-Chul Kim,et al.  In vitro evaluation of the bond strength between various ceramics and cobalt-chromium alloy fabricated by selective laser sintering , 2015, The journal of advanced prosthodontics.

[71]  M. Cima,et al.  Multimechanism oral dosage forms fabricated by three dimensional printing. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[72]  A Piattelli,et al.  Direct laser metal sintering as a new approach to fabrication of an isoelastic functionally graded material for manufacture of porous titanium dental implants. , 2008, Dental materials : official publication of the Academy of Dental Materials.

[73]  Gordon G. Wallace,et al.  Extrusion printed polymer structures: a facile and versatile approach to tailored drug delivery platforms. , 2012, International journal of pharmaceutics.

[74]  Liang Hou,et al.  Additive manufacturing and its societal impact: a literature review , 2013 .

[75]  H. Seitz,et al.  Three-dimensional printing of porous ceramic scaffolds for bone tissue engineering. , 2005, Journal of biomedical materials research. Part B, Applied biomaterials.

[76]  Jan Feijen,et al.  A poly(D,L-lactide) resin for the preparation of tissue engineering scaffolds by stereolithography. , 2009, Biomaterials.

[77]  I. Hutchings,et al.  Adult rat retinal ganglion cells and glia can be printed by piezoelectric inkjet printing , 2013, Biofabrication.

[78]  Abdul W. Basit,et al.  Preparation of Personalized-dose Salbutamol Sulphate Oral Films with Thermal Ink-Jet Printing , 2011, Pharmaceutical Research.

[79]  M. Alexander,et al.  Inkjet printing as a novel medicine formulation technique. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[80]  A. Basit,et al.  3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. , 2015, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[81]  Wei Dong Huang,et al.  Tablets with material gradients fabricated by three-dimensional printing. , 2007, Journal of pharmaceutical sciences.

[82]  S. Helmy,et al.  Tablet splitting: is it worthwhile? Analysis of drug content and weight uniformity for half tablets of 16 commonly used medications in the outpatient setting. , 2015, Journal of managed care & specialty pharmacy.

[83]  Huibi Xu,et al.  Levofloxacin implants with predefined microstructure fabricated by three-dimensional printing technique. , 2007, International journal of pharmaceutics.

[84]  K. Leong,et al.  Scaffold development using selective laser sintering of polyetheretherketone-hydroxyapatite biocomposite blends. , 2003, Biomaterials.

[85]  Scott J Hollister,et al.  A paradigm for the development and evaluation of novel implant topologies for bone fixation: implant design and fabrication. , 2012, Journal of biomechanics.

[86]  Dominik Rietzel,et al.  Additive Processing of Polymers , 2008 .

[87]  R. Inführ,et al.  Photopolymers for rapid prototyping , 2007 .

[88]  Manfred Schubert-Zsilavecz,et al.  Dosing accuracy of measuring devices provided with antibiotic oral suspensions , 2007 .

[89]  Jamil Awad Shibli,et al.  Early human bone response to laser metal sintering surface topography: a histologic report. , 2010, The Journal of oral implantology.

[90]  Roger J. Narayan,et al.  Stereolithography in tissue engineering , 2014, Journal of Materials Science: Materials in Medicine.

[91]  F. Melchels,et al.  A review on stereolithography and its applications in biomedical engineering. , 2010, Biomaterials.

[92]  M. A. Alhnan,et al.  Fabrication of extended-release patient-tailored prednisolone tablets via fused deposition modelling (FDM) 3D printing. , 2015, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[93]  Xiaofeng Cui,et al.  Application of inkjet printing to tissue engineering , 2006, Biotechnology journal.

[94]  Deng-Guang Yu,et al.  Novel oral fast-disintegrating drug delivery devices with predefined inner structure fabricated by Three-Dimensional Printing. , 2009, The Journal of pharmacy and pharmacology.

[95]  Shuvo Roy,et al.  Rapid and low-cost prototyping of medical devices using 3D printed molds for liquid injection molding. , 2014, Journal of visualized experiments : JoVE.

[96]  M. Cima,et al.  Oral dosage forms fabricated by three dimensional printing. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[97]  M. Suzuki,et al.  Fabrication of microneedles precisely imitating mosquito's proboscis by nanoscale tree dimensional laser lithography and its characterization , 2015, 2015 Transducers - 2015 18th International Conference on Solid-State Sensors, Actuators and Microsystems (TRANSDUCERS).

[98]  Richard Lewanczuk,et al.  More medications, fewer pills: combination medications for the treatment of hypertension. , 2007, The Canadian journal of cardiology.

[99]  Deng-Guang Yu,et al.  Novel drug delivery devices for providing linear release profiles fabricated by 3DP. , 2009, International journal of pharmaceutics.

[100]  Chee Kai Chua,et al.  Introduction to rapid prototyping of biomaterials , 2020, Rapid Prototyping of Biomaterials.

[101]  Jerry Y. H. Fuh,et al.  Processing and characterising photo-sensitive polymer in the rapid prototyping process , 1999 .

[102]  Ph. Bertrand,et al.  Ceramic components manufacturing by selective laser sintering , 2007 .

[103]  Byung Kook Lee,et al.  Fabrication of drug-loaded polymer microparticles with arbitrary geometries using a piezoelectric inkjet printing system. , 2012, International journal of pharmaceutics.

[104]  M. Rimsza,et al.  Parents can dose liquid medication accurately. , 1997, Pediatrics.

[105]  Malcolm N. Cooke,et al.  Use of stereolithography to manufacture critical-sized 3D biodegradable scaffolds for bone ingrowth. , 2003, Journal of biomedical materials research. Part B, Applied biomaterials.