PHARMACEUTICAL APPLICATIONS OF NEXT GENERATION PRINTING TECHNOLOGIES: A BRIEF LITERATURE REVIEWHTML Full Text
PHARMACEUTICAL APPLICATIONS OF NEXT GENERATION PRINTING TECHNOLOGIES: A BRIEF LITERATURE REVIEW
O. Baisya * 1, S. Bhowmick 1, C. Sengupta 1 and A. Das Bhowmik 2
Department of Pharmaceutics 1, Netaji Subhas Chandra Bose Institute of Pharmacy, Chakdaha - 741222, West Bengal, India.
Diagnostics Facility 2, AIC-Centre for Cellular & Molecular Biology, Hyderabad - 500039, Telangana, India.
ABSTRACT: Next-generation printing or commonly known as three-dimensional (3D) printing (3DP), is a fabrication process of construction of a 3D object using a computer-aided design or digital 3D model. The 3D object is created layer by layer by depositing, joining, or solidifying a feedstock material such as thermoplastic polymer under the control of a computer-designed program. It is considered the latest technology that has the potential to address complex medical and pharmaceutical problems, such as prototyping essential medical devices, equipment, and novel drug delivery systems. The ability of 3DP to produce medications with accurate specifications tailored to the needs of individual patients has indicated the possibility of developing personalized medicines. The technology allows dosage forms to be precisely printed in various shapes, sizes, and textures, in a limited time period. In spite of many potential medical and economic benefits of 3DP, some technical and regulatory challenges are associated with the widespread application of 3DPin the pharmaceutical sector; those need to be addressed by proper research so that the benefit of this technology can be utilized fully. Along with 3DP, more advanced and sophisticated printing technologies like 4D/5D printing are also introduced and have already been explored in biomedical applications. However, the utility of these technologies in the pharmaceutical drug manufacturing process is still in the early experimental phase and gradually evolving. This review article illustrates the recent trends, challenges, and future prospects of 3D Pin pharmaceutical applications, along with the highlights of the ongoing transition from 3D to 4D/5D printing.
Three-dimensional printing, Computer-aided design, Thermoplastic polymer, Novel drug delivery systems, 4D/5D printing
INTRODUCTION: Three-dimensional printing (3DP) is nowadays a well known advanced additive manufacturing technology used widely in various fields of technology, art, and science, however most importantly used in various pharmaceutical and medical applications like regenerative medicine, diagnosis, implants, developments of artificial tissues and organs, etc. Fig. 1.
The fastest-growing demand for customized pharmaceuticals and medical devices makes the impact of 3DP technology increased rapidly in recent years.
The technique prints or manufactures one or more entities in a layer-by-layer manner with a 3D printer, and by adjusting the size and shape of each individual layer, a complex, solid object is formed from a digital model. It applies the additive shaping principle and based on that principle; it builds the physical 3D structures by successive addition of material 1, 2. The main advantages of 3DP include high reproducibility, fast and accurate manu-facturing, personalized product series, superficial modifications of a product at a designed level with no restrictions on its spatial arrangement, and convenient, cost-effective manufacture 3. The most significant applications are found in regenerative medicine, artificial tissue, and organ generation, ophthalmological implants, 3D printed drugs, customized prosthetics, medical phantoms, and cancer research 1, 4. There are mainly 3 types of 3D printing systems that are commonly used in pharmaceutical developments; printing-based inkjet system, nozzle-based deposition systems, and laser-based writing systems 5.
These printing technologies mostly differ in speeds and resolutions, but the main operating systems are based on either extrusion or powder/liquid solidification 4. Among all these printing processes, extrusion-based printing like fused deposition modeling (FDM) and pressure-assisted micro-synringes (PAM)are widely used by researchers and manufacturers due to several advantages like low cost, ability to fabricate hollow objects, ability to print using a range of polymers with or without drug, ability to sustain drug release by altering the geometry and polymer, ability to print at room temperature, etc. 6 However each of these techniques have their specific advantages and limitations. Regardless of these differences in material deposition mechanism, the basic method of function is the same. A computer-aided design (CAD) file is prepared based on the desired 3D model, then the 3D printer follows the instructions of the CAD file and builds the object in a specific shape and size by moving the print head along the 3Ddirections 7. The materials used as ink formulation covers a wide range of compounds from plastics, metals, ceramics or a combination thereof, making the process highly versatile 2.
Within the last decade, patient-centric personalized drug development has been under considerable attention. It was focused on novel dosage forms and technological processes. Growing demand for customized devices combined with an expansion of technological innovation drives the major progress in personalized medicine to meet the anatomical needs of patients 4. Within many discoveries introduced into the pharmaceutical and biomedical market, 3DP technology has revolutionized the area of personalized medicine. 3DP offers many novel strategies and approaches in the field of novel drug delivery systems in suitable dosage forms, and gradually it is becoming of much interest in the pharmaceutical industry. Recently engineered solid dosage forms with complex inner structures, geometries, surface texture, multiple combinations of drugs, and many different types of drug delivery systems like oral control released systems, microchip, pills, implants, rapidly dissolving tablets, multiphase release dosage forms, etc. have been developed using this technology 8-13. 3DP technology showed many industrial benefits over conventional technologies in designing and fabricating novel drug delivery dosage forms. However, there are some technical and regulatory challenges and limitations associated with the widespread application of this technology in the pharmaceutical sector 14.
The main disadvantage of 3DP is that this only takes into account the initial state of the printed structure and considers it static and inanimate 15. To solve this problem, a new concept called 4D printing (4DP) was launched in 2013, allowing bioengineered constructs to be pre-programmed to evolve in a particular way after printing 16, 17. Along with 4DP, 4D bio-printing or laser-assisted bioprinting has also recently emerged, which is a dedicated extension of 3D bio-printing that restructure the biochemical and biophysical compositions, in addition to the hierarchical morphology of different tissues using stimuli-responsive biomaterials and cells 18. The major drawback of 4D printing is not able to print complex shapes having curved surfaces 1. To overcome this problem, another new concept5D, printing (5DP) was introduced in 201619. 5DP technology is an extension of 3DP, also known as five-axis 3D printing, where the print head has the capability to move around from 5 different angles due to a movable flat terrain. This creates arched layers which are stronger than the traditional3D/4D printed flat layers 20.
This review describes the latest developments of some 3DP technologies suitable for pharmaceutical manufacturing, their advantages, and disadvantages associated with its utility based on current and future perspectives. The parallel development of higher next-generation printing technologies like 4D/5D printing technologies and their applications in medical and pharmaceutical manufacturing is also discussed briefly. Lastly, it briefly summarizes the application of this technology in the ongoing crisis-response efforts to take on the COVID-19 pandemic situation generated worldwide for the past few months.
FIG. 1: DIFFERENT APPLICATIONSOF 3D PRINTING TECHNOLOGY IN MEDICAL AND PHARMACEUTICAL FIELDS
Applications of 3DP Technology in Novel Drug Development and Delivery: The principle application of 3DP technology in pharmaceutical developments pertains to novel drug development and delivery with correct dosage forms. The wide spread use of this application benefited mostly the rapidly growing personalized medicine field. Using this technology, various drug delivery systems can be developed with high accuracy and in short time, such as tablets, capsules, multilayered drug delivery systems, nano-suspensions, orodispersible films, transdermal systems, wound healing patches, vaginal and rectal delivery systems etc. 21-26 The most commonly used pharmaceutical active ingredients in these, include steroidal anti-inflammatory drugs, acetaminophen, caffeine, salicylic acid, antibiotics, paclitaxel, prednisolone, folic acid, insulin, captopril, curcumin etc. 4, 26 The ink formulations in 3D printers have been obtained from a number of both natural polymers like alginate, HA, collagen, chitosan etc. and synthetic polymers like PCL, PLA, PEG, PGA, diacrylate, PVP, PVAc, cellulose derivatives etc. 4 The main advantage of using synthetic polymers over natural polymers is that the synthetic polymers can be easily modified to meet specific requirements by optimizing mechanical and physicochemical properties, pH and temperature responses and they can be functionalized with various biomolecules. Sometimes blended polymers (natural+synthetic) are also used as bioinks to enhance and adapt cellular responses within 3D construct 1. PLA is a biocompatible synthetic polymer that has recently been approved by the US Food and Drug Administration (FDA) biomedical applications such as tissue engineering, controlled drug delivery systems and orthopaedicim plants 27. Many recent studies focus on the mechanical and biocompatibility / bioactivity properties of PLA or its blends after 3Dprinting 28, 29.
The first known 3D printed drug in tablet form, that was approved by FDA and was commercialized for the treatment of epilepsy is Spritam® by Aprecia Pharmaceuticals30. The drug (levitiracetam) was made by the layer-by-layer production system using ZipDose technique based on power bed fusion 31. A year after Clark et. al., 32 in association with a British pharmaceutical company Glaxo-SmithKline conducted a study where inkjet 3D printing and ultraviolet (UV) curing were used to create a tablet Ropinirole HCL, a dopamine agonist drug used for the treatment of Parkinson’s disease and restless legs syndrome. Using this set-up, batches of 25 tablets with a 5 mm diameter were produced.
Total printing time was 1.5 h or approximately 4 minutes per tablet. Curing time was an additional 7.5 min per batch. The researchers concluded that “UV inkjet printing has been demonstrated as a platform to produce solid oral dosage forms for the first time 32.” Nose-shaped masks, filled with salicylic acid, used as anti-acne agents, had been developed in a short and competent manner 33. These are known as personalized tropical treatment devices. 3DP technology has also been used in chemotherapy for cancer treatment to reduce its side effects 34. A construction of patches loaded with 5-fluorouracil, poly (lactic-coglycolic) acid and PCL had been successfully and efficiently printed and implanted directly into pancreatic cancer 35. Another commercial use of 3DP technology has been seen in designing 3D printed polypill 36, 37. Polypills are single personalized tablets made in combination of several drugs. These drugs are mostly designed for elderly persons who use poly medicines. Table 1 summarizes the 3DP technologies applied in the development of pharmaceutical drug delivery systems and the suitable polymers exploited with various dosage forms 9, 32, 33, 35, 37, 38-68.
TABLE 1: SUMMARY OF DIFFERENT 3DP TECHNOLOGIES EXPLORED FOR THE DEVELOPMENT OF NOVEL DRUG DELIVERY SYSTEMS
|3D Printing technology||Dosage forms||Polymers used||Model drugs used||Reference|
|Hydrogel||Polyethyleneglycol (PEG), Diacrylate
|UV-Inkjet 3D printed tecnology||Tablets||Cross-linked Poly(ethylene glycol diacrylate)(PEGDA)||Ropinirole||32|
|3D printer||Tablets||Polyvinyl alcohol l(PVA)||Paracetamol||39|
|3D extrusion printer||Multi-active solid dosage form (polypill)||Polyvinylpyrrolidine (PVP), Sodium starch glycolate, Hydroxypropyl methylcelloluse (HPMC)||Aspirin, Hydrochlorothiazide Pravastatin, Atenolol & Ramipril||36|
|(FDM) and Hot Melt Extrusion (HME)||Tablets||Hydroxy propyl cellulose (HPC)||Domperidone||41|
|Fused deposition 3D printing||Extended release tablet||Polyvinyl alcohol(PVA)||Prednisolone||42|
|3D printer||Tablet implant||Methacrylicester copolymer (EudragitÒ E-100), cellulose powder (Avicel PH301)||Isoniazide||43|
|FDM and Hot Melt Extrusion (HME)||Compartmentalized shells||Polylactic acid||Rifampicin, Isoniazid||45|
|Fused deposition 3D printer||Oral pulsatile capsule||Polylactic acid (PLA) filament (L-PLA natural, ø 1.75 mm; MakerBot
®), Hydroxypropyl cellulose (HPC,
Klucel®), Polyethylene glycol 1500 (PEG, Clariant Masterbatches, I)
|FDM and HME||Three compartment hallow cylinder||Polyvinyl alcohol (PVA) and Polylactic acid (PLA)||Hydrochlorthaizide, Mannitol||9|
|Ink-jet printer||Solid dispersion||Polyvinyl pyrollidone (PVP) k30||Felodipine||48|
|Desktop 3D printer||Bi-layer matrix tablet||Hydroxypropyl methyl cellulose(HPMC), Microcrystalline cellulose||Guaifenesin||49|
|Laboratory scale 3-DP™ machine||Capsule with immediate release core and a release rate regulating shell||Kollidon SR and
hydroxypropylmethyl cellulose (HPMC), ethanolic
triethyl citrate (TEC), PVP K17
|Fused deposition 3D printer||Modified-release drug loaded tablet||Polyvinyl alcohol(PVA)||5-Aminosalicylic acid & 4-Aminosalicylic acid||37|
|Extrusion-based printer||Multi-active tablets (Polypill)||Polyethylene glycol 6000, Hydroxypropyl methylcelloluse (HPMC 2910) (hypromellose®),Croscarmellose
sodium (CCS) (Primellose®),microcrystalline cellulose (MCC) (Pharmacel® 102) and sodium starch
glycolate (SSG) (Primojel®)
|Captopril, Nifedipine & Glipizide||51|
|3D printer||Complex matrix tablet with ethylcellulose gradients||Ethylcellulose(EC), Eudragit RS-100, Hydroxypropyl methyl cellulose (HPMC)||Acetaminophen||52|
|Inkjet printer||Implant with lactic acid polymer matrix||Poly(L-lacticacid)(L-PLA)||Levofloxacin||53|
|3D printer||Multi-layered concentric implant||Poly(D,L-Lactic acid)(PDLLA)||Rifampicin and Isoniazid||54|
|Micro-drop Inkjet 3DP||Nanosuspension||Tagat S, TPGS, Solutrol HS15, Cremophor EL, Cremophor RH 40, Lutrol F68||Folic Acid||55|
|Thermal Inkjet printer||Dosing drug Solutions onto oral films||Potato starch||Salbutamol sulphate||56|
|Commercial inkjet printer||Nanocomposite structure||Dimethyl sulfoxide (DMSO), poly(D,L-lactic-co-glycolic)acid (PLGA), Biphasic calcium phosphate(BCP)||Rifampicin and Calcium phosphate||57|
|3D Extrusion printer||Drug encapsulated film of PLGA and PVA||DL-lactic/glycolic copolymer (PLGA, 85:15), poly(vinyl alcohol)(PVP), dichloromethane (DCM)||Dexamethasone||58|
|Thermal Inkjet printer||Oral solid dosage forms||1,2,3-propanetriol (glycerol), ALPHAGLAS PTFE- coated fiberglass film(premium grade, B903)||Prednisolone||59|
|3D printer||Microfluidic pump||Polylactic acid bioplastic, Polydimethylsiloxane, polymer base
|Stereolithography printer||Anti-acne patch||Polyethylene glycol diacrylate||Salicylic acid||33|
|3D printer||Biodegradable patch||Poly(lactide-co-glycolide), polycaprolactone||5-Fluorouracil||35|
|Fused deposition 3D printer||Immediate-release tablets||Methacrylic polymer (Eudragit E-100)||5-Aminosalicylic acid, Captopril, Theophylline & Prednisolone||61|
|Fused-deposition printer||T-shaped intrauterine systems and subcutaneous rods||Different grades of the EVA copolymer (ATEVA 1070, 1075A, 1081G,
1241, 1641, 1821A, 1850A, 1880A, 2821A, 3325A), polycarbonate (PC), polyetherimide (PEI) resin, polyphenylsulfone
(PPSF), polyamides (Nylon), high-impact polystyrene (HIPS), high-density
polyethylene (HDPE), polymethylmethacrylate (PMMA) and
poly(ε-caprolactone) (PCL) (CAPA™ 6500)
|Electro hydrodynamic atomization technique||Patterned micron scaled structures||Polyvinylpyrrolidone(PVP), Polyethylene oxide(PEO)||Tetracycline hydrochloride||63|
|Fused deposition printer||Capsules for immediate and modified release||Hydroxypropyl methyl cellulose (HPMC),Ethyl cellulose(EC)
|Acetaminophen and Furosemide||64|
|3D printer||Biofilm disk||Hydroxypropylmethylcellulose (Metolose), Polylactic acid, Methylcellulose||Nitrofurantoin||65|
|Multi-nozzle 3D printer||Capsule-shaped solid devices||Polyvinyl alcohol(PVA)||Acetaminophen & Caffeine||66|
|Fused-deposition printer||Capsule-shaped tablets||Polyvinyl alcohol (PVA), Budesonide powder, Eudragit1 L100, Triethyl citrate (TEC)||Budesonide||67|
|Stereolithographic 3D printer||Modified-release tablets||Polyethylene glycol diacrylate||4-aminosalicylic acid & Paracetamol||68|
Challenges of 3D Printing in Novel Drug Development and Delivery Systems: Even though the 3DP technology offers several advantages in designing pharmaceutical products over conventional manufacturing methods, there are also some limitations that can hinder the progression of this technology to commercialize. It faces technical challenges like optimization process, improving the performance of the product for versatile use, selections of appropriate raw materials, post-treatment measures, etc. 69 There are concerns include technical difficulties associated with printing of large volumes of materials, slow printing times, availability of materials are limited at present because of the recent arrival of this technology and high cost of the 3D printers1. Also, to attain the quality of 3D products, some essential technical parameters are required to be optimized like printing rate, printing passes, line velocity of the print head, interval time between two printing layer, the distance between the nozzles and the powder layer, etc. 70, 71 It is also important for post-processing after prototyping like drying methods, as it has major impact on the quality of the finished 3D printed products 72-74. To increase the drug loading capacity in 3D printed processed tablet, uniaxial compression and suspension dispersed methodologies are adopted, but this technique suffers from increased complexity and clogging of spray nozzle 75, 76.
For bio-printing, it is also essential to further develop more detailed in-vitro and in-vivo studies to assess the efficacy and, most importantly the safety concerns associated with the widespread application of 3D printed drugs, tissues, organs, and medical devices1. Since the technology is mostly based on computer-generated machine learning and most recently artificial intelligence-based models, technical, operational and systemical errors cannot be avoided. One has to take care and ensure the utmost accuracy in designing these models.
Despite these limitations and uncertainties, we have to understand that this technology is still in an early development phase and can be seen as a research subject. Till date, the only known 3D printed drug that was commercialized is known as Spritam® by Aprecia Pharmaceuticals, used for the treatment of epilepsy 30.
Future Prospects of 3D Printing: The initial developments and research studies clearly show the utility of 3DP technology in different medical fields, including the pharmaceutical sector. It depicts a prospective future of this technology in drug manufacturing. The significance of this technology in the pharmaceutical sector is growing inevitably. The technology has great potential in compiling personalized dosage forms that can play a remarkable role in personalized medicine 77. Also, patients will reduce their medication load to one polypill per day, which will produce patient conformity 36, 37. 3D printing technologies can change the pharmacy practice by allowing individualized medication and tailored specifically to each patient, although there are technical and regulatory hurdles that have to overcome 1, 69-76, 78. Drug manufacturing and distribution is usually a costly process in the pharmaceutical industry. 3D printed tablet production can be done in localized conditions within the clinic or in the local pharmacies 79, 80. Recently approved 3D printed tablet called Spritam® has created a benchmark for the pharmaceutical companies 30. Many such investigations are already underway as many scientific articles can be seen in recent times to discuss 3DP technology or highlighting recent findings of 3DP technology. In a recent update, a coaxial needle extrusion 3D technology was used to print active pharmaceutical components and create combinations of controlled release of drugs 81.
Transition from 3D to 4D/5D Printing: Although the 3DP technology has several advantages in designing pharmaceutical products over conventional manufacturing methods, there are also some technical challenges that exist with the technology that has been already discussed in the previous section. Various methods have been developed to overcome these technical challenges and can be classified according to the formula applied to assemble the material or its physical state 82. The most commonly used methods for processing pure polymers and polymer nano-composites for biomedical applications include stereolithography, inkjet, micro-extrusion, and laser-based printing 83. Even after that, each of these methods has its own limitations1. The main disadvantage of 3DP technology itself is that this only considers the initial state of the printed structure and considers it as static and inanimate 15, thus unable to build complex bio-structures 4. DP technology was arrived primarily to overcome this limitation and also to take care of some of the technical difficulties associated with the 3DP17.4DP has the capacity to reshape or self-assemble with respect to time. It has 4 dimensions i.e., x, y, z-axis, and a fourth dimension which is time. Unlike 3DP, 4DP uses the ability of shape and functionality transformation over time when exposed to intrinsic/external stimuli allowing a more precise replication of the dynamics of the indigenous issues and is based on the combination of smart biomaterials 16, 84-86.
4D printed material has the ability to act on certain parameters with respect to the environment like humidity, temperature, etc., and it changes its shape according to the environment. 4DP technology has also included few technological advances over 3DP for printing adaptable objects 1, 87. There are a few difficulties and limitations that also exist for the 4DP technology. The major disadvantage is that it is unable to print complex shapes having curved surface 1. Also, it is observed that 4D printed materials are less stable with respect to environment temperature88. To overcome these difficulties of 4DP, another advanced printing technology was evolved based on 5 dimensions, known as 5D printing (5DP) 19. 5DP is the latest printing technology in additive manufacturing in which both the print head and printable object rotate along with x, y, and z-axis altogether with five degrees of freedom89. It can produce curved layers or dipped shapes very precisely as per design restraints. In this process, the printed part simultaneously move while the printer head prints along the five axis. The printbed moves forward and backward along with x, y, z axis which allows the object to be printed from all 5 axes instead from only one point of printing 20, 88, 89.
4DP method is mainly used in manufacturing next-generation medical devices for targeted drug delivery, by enhancing the capability of already established 3DP technology in this field, where personalized medical treatments are important such as dentistry, implants, prosthetics, etc. 90 4D-printed devices can contain pharmaceutical drugs and release them when the environment of the targeted location provides the correct stimulus. Few examples of such devices are 4D-printed containers 91, theragrippers that were particularly tested for the controlled release of drugs in the gastrointestinal tract 92, different types of stents 93-95, and splints 96-98 used in surgical procedures. 5DP technology is currently tested for manufacturing medical or surgical tools like mosquito forceps, monopolar diathermy, debakey forceps, deaver retractor, etc., those having complex curved-like structures 88. 5DP can also be used to manufacture artificial body parts like hands, legs, lower jaw, teeth that have complex shapes of implants with high strength, as prosthetic implants 19, 88, 89. Wide-scale applications of both 4D and 5D printing technologies are still in their infancy, and most of the activity now is still under research and development.
Application of 3DP Technology in Healthcare against COVID19: The global uncertainty created by the novel COVID-19 pandemic has pushed the world into a severe crisis that is still unfolding and gradually evolving. Healthcare systems are on a war footing path to handle the pandemic situation by increasing supplies of medicines, protective materials, and trained workers. Crisis-generated efforts are in action to assuage the shortages of essential medical supplies.
There is a need for more pharmaceutical factories to manufacture on-demand medicines and medical devices for a range of essential services in healthcare. In this context, a flexible advanced manufacturing network with mostly computational approach enabled by a distribution of 3D-printing factories has become a great potential, especially at this time of social distancing practices.
3DP technology has shown its capabilities in response to COVID19 by demonstrating its competitive advantage in this emergency situation 99-102. It has stepped up to become a vital technology to support improved healthcare and our general response to the emergency at the present pandemic situation. The eminent manufacturers and researchers implicated the potential of 3DP technologies and channeled them for developing personal protective equipment like face masks, face shields, respirators, medical devices like ventilator valves, emergency respiration devices, testing devices, sample collecting devices like naso-pharyngeal swabs, etc. and other gadgets 101, 102.
Different types of 3DP technologies were used for this purpose like fused filament fabrication (FFF), FDM, selective laser sintering (SLS), stereo lithography (SLA), etc. 101, 102 As the vaccine development process against novel coronavirus are currently undergoing different stages, the healthcare professionals are treating their patients with the existing medical drugs.
To use the available drugs in the best way, it has been emphasized by the various professionals to adopt the novel3DP technologies in delivering controlled healing chemical and organic compounds. Formulations based on micro-sized structures used for drug delivery using 3DP technologies are believed to be highly effective in curing patients suffering from pandemic 10, 53, 57, 70.
It is believed that long-standing health problems, generally observed in pandemic condition, may be solved by these systems that allow synchronized use of multiple drug components and other spatial models of drug deposition within the hydrogel or polymer matrix 33, 101, 102.
Focusing on COVID-19, these revelations of 3DP technologies can be lined up well with the current demands of personalized medicine in the pharmaceutical sector 100-105. Although at present there are no specific antivirals drugs for the treatment of COVID-19, several already present and well-characterized antiviral drugs are being considered for therapies 106. Soon, it may be possible to use these technologies to effectively and rapidly print drugs like lopinavir/ritonavir, remdesivir, hydroxyl-chloroquine, etc., that are often being used now for the symptomatic treatment of COVID-19 patients and also as preventive medicine for health workers.
Although at present, very few studies are focused on the treatment of the COVID-19 patients as the current regulations are highly stringent due to the risk level, but this technology definitely has the potential to revolutionize the pharmaceutical industry by making faster research, development and production of drugs applicable to patients with COVID-19. The research activities will endeavor to categorize the 3DP technologies based on their superiorities in the fabrication of drug delivery systems as well as the formulation.
CONCLUSION: The utility of 3D/4D/5D printing technologies described in this review article shows the benefits of these technologies in the pharma-ceutical industry, especially for the development of novel drug delivery systems. Although the development of these methods in the field of pharmacy is only in its early phase, but in the near future, these approaches will surely be utilized to fabricate and wangle various novel dosage forms to achieve optimized drug release profiles, develop effective personalized medicines, evade incompatibilities between multiple drugs, design multiple-release dosage forms, limit degradation of biological molecules and for many other purposes. Although commercial production of such novel dosage forms is still in a challenging phase, the scientists and researchers are certain that the modern pharmaceutical industry is seeing a turning point and that the 3DP of solid dosage forms are set to revolutionize the drug delivery systems.
ACKNOWLEDGEMENT: None. This review is compiled by the four authors based on the latest developments.
CONFLICTS OF INTEREST: Authors have no conflict of interest.
- Ghilan A, Chiriac AP, Nita LE, Rusu AG, Neamtu I and Chiriac VM: Trends in 3D printing processes for biomedical field: opportunities and challenges. Journal of Polymers and the Environment 2020; 28: 1345-67.
- ISO/ASTM 52900:2015(en) Additive manufacturing - General principles – Terminology. 2020 August 08. Available from: https://www.iso.org/obp/ui/#iso:std:iso-astm:52900:ed-1:v1:en.
- Douroumis D: 3D printing of pharmaceutical and medical applications: a new era. Pharmaceutical Research 2019; 36: 41-42.
- Jamróz W, Szafraniec J, Kurek M and Jachowicz R: 3D printing in pharmaceutical and medical applications - recent achievements and challenges. Pharmaceutical Research 2018; 35: 176.
- Murphy SV and Atala A: 3D bioprinting of tissues and organs. Nature Biotechnology 2014; 32:7 73-85.
- Azad MA, Olawuni D, Kimbell G, Badruddoza AZM, Hossain MS and Sultana T: Polymers for extrusion-based 3D printing of pharmaceuticals: a holistic materials-process perspective. Pharmaceutics 2020; 12: 124.
- De Mori A, Peña Fernández M, Blunn G, Tozzi G and Roldo M: 3D printing and electrospinning of composite hydrogels for cartilage and bone tissue engineering. Polymers 2018; 10: 285
- Katstra W, Palazzolo R, Rowe C, Giritlioglu B, Teung P and Cima MJ: Oral dosage forms fabricated by three dimensional printing. Journal of Controlled Release 2000; 66: 1-9.
- Gioumouxouzis CI, Katsamenis O, Bouropoulos N and Fatouros DG: 3D printed oral solid dosage forms containing hydrochlorothiazide for controlled drug delivery. J of Drug Deli Sci and Tech 2017; 40: 164-71.
- Santini JT, Cima MJ and Langer R: A controlled-release microchip. Nature 1999; 397: 335-38.
- Cima LG and Cima MJ: Preparation of medical devices by solid free-form fabrication methods. Google Patents (EP0724428B1) 1996.
- Monkhouse D, Sandeep K, Rowe C and Yoo J: A computer-aided fabrication process for rapid designing, prototyping and manufacturing. Google Patents (WO2000029202A9) 2000.
- Monkhouse D, Yoo J, Sherwood JK, Cima MJ and Bornancini E: Dosage forms exhibiting multi-phasic release kinetics and methods of manufacture thereof. Google patents (US6280771B1) 2003.
- Park BJ, Choi JH, Moon SJ, Kim SJ, Bajracharya R, Youn Min J and Han HK: Pharmaceutical applications of 3D printing technology: current understanding and future perspectives. J of Pharm Investigation 2019; 49: 575-85.
- Gao B, Yang Q, Zhao X, Jin G, Ma Y and Xu F: 4D bioprinting for biomedical applications. Trends in Biotechnology 2016; 34: 746-56.
- Tibbits S: 4D printing: multi-material shape change. Architectural Design 2014; 84: 116-21.
- Wu J, Huang L, Zhao Q and Xie T: 4D printing: history and recent progress. Chinese Journal of Polymer Science 2017; 36: 563-75.
- Yang G, Yeo M, Koo Y and Kim G: 4D bioprinting: technological advances in biofabrication. Macromolecular Bioscience 2019; 19: 1800441.
- Zeijderveld JV. 5D printing: a new branch of additive manufacturing. Sculpteo report. https://www.sculpteo. com/blog/2018/05/07/5d-printing-a-new-branch-of-additive-manufacturing/ 2018. [Accessed on 10.09.2020].
- Kumar P, Tech M, Roy S, Hegde H, Bharti S and Kumar: 4D and 5D Printing: Healthcare’s New Edge, In: Ahmad N, Gopinath P, Dutta R (eds) 3D Printing Technology in Nanomedicine 2019; 143-63.
- Norman J, Madurawe R, Moore C, Khan M and Khairuzzaman A: A new chapter in pharmaceutical manufacturing: 3D-printed drug products. Advanced Drug Delivery Reveiws 2017; 108: 39–50.
- Fu J, Yu X andJin Y. 3D printing of vaginal rings with personalized shapes for controlled release of progesterone. International Journal of Pharmaceutics 2018; 539: 75-82.
- Ehtezazi T, Algellay M, Islam Y, Roberts M, Dempster N and Sarker S: The application of 3D printing in the formulation of multilayered fast dissolving oral films. Journal of Pharmceutical Science 2018; 107: 1076-85.
- Öblom H, Zhang J, Pimparade M, Speer I, Preis M, Repka M and Sandler N: 3D-Printed Isoniazid Tablets for the Treatment and Prevention of Tuberculosis-Personalized Dosing and Drug Release. AAPS Pharm Sci Tech 2019; 20: 52.
- Kotta S, Nair A and Alsabeelah N: 3D printing technology in drug delivery: recent progress and application. Current Pharmceutical Design 2019; 24: 5039-48.
- Maulvi FA, Shah MJ, Solanki BS, Patel AS and Soni TG: Application of 3D printing technology in the development of novel drug delivery systems. International Journal of Drug Development and Research 2017; 9: 44-49.
- Subramaniam SR, Samykano M, Selvamani SK, Ngui WK, Kadirgama K, Sudhakar K and Idris MS: 3D printing: overview of PLA progress AIP Conference Proceedings 2019; 2059: 020015.
- Kandasamy J: A case study of 3D printed PLA and Its mechanical properties. Mat Tod Procee 2018; 5: 11219-26.
- Aveen KP, Vishwanath Bhajathari F and Jambagi Sudhakar C: 3D printing & mechanical characteristion of polylactic aid and bronze filled polylactic acid components. IOP Conference Series: Materials Science and Engineering 2018; 376: 012042.
- Brooks M: FDA Clears First 3D-Printed Drug (Spritam [Levetiracetam]) [Last accessed on 09.09.2020]. Available from: https://www.medscape.com/viewarticle/848971.
- Yoo J, Bradbury TJ, BebbTj, Iskra J, Suprenant HL and West TG: Aprecia Pharmaceuticals LLC, Three-dimensional printing system and equipment assembly. Google Patents (US20140065194A1) 2014.
- Clark EA, Alexander MR, Irvine DJ, Roberts CJ, Wallace MJ, Sharpe S, Yoo J, Hague RJM, Tuck CJ and Wildman RD: 3D printing of tablets using inkjet with UV photoinitiation. Int Journal of Pharma 2017; 529: 523-30.
- Goyanes A, Det-Amornrat U, Wang J, Basit AW and Gaisford S: 3D scanning and 3D printing as innovative technologies for fabricating personalized topical drug delivery systems. J of Controlled Rele 2016; 234: 41-48.
- Einhorn LH and Donohue J: Cis-diamminedichloro-platinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Annals of Internal Medicine 1977; 87: 293-98.
- Yi H-G, Choi Y-J, Kang KS, Hong JM, Pati RG, Park MN, Shim KI, Lee CM, Kim SC and Cho DW: A 3D-printed local drug delivery patch for pancreatic cancer growth suppression. J of Control Rele 2016; 238: 231-41.
- Khaled SA, Burley JC and Alexander MR: 3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles. Journal of Controlled Release 2015; 217: 308-14.
- Goyanes A, Buanz AB and Hatton GB: 3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. European Journal of Pharmaceutics and Biopharmaceutics 2015; 89: 157-62.
- Martinez PR, Goyanes A, Basit AW and Gaisford S: Fabrication of drug-loaded hydrogels with stereolitho-graphic 3D printing. Int J of Pharma 2017; 532: 313-17.
- Goyanes A, Martinez PR, Buanz A, Basit AW and Gaisford S: Effect of geometry on drug release from 3D printed tablets. Int J of Pharmaceutics 2015; 494: 657-63.
- Solanki NG, Tahsin M, Shah AV and Serajuddin ATM: Formulation of 3D Printed Tablet for Rapid Drug Release by Fused Deposition Modeling: Screening Polymers for Drug Release, Drug-Polymer Miscibility and Printability. Journal of Pharmaceutical Sciences 2018; 107: 390-01.
- Chai X, Chai H, Wang X, Yang J, Li J, Zhao Y, Cai W, Tao T and Xiang X: Fused Deposition Modeling (FDM) 3D Printed Tablets for Intragastric Floating Delivery of Domperidone. Scientific Reports 2017; 7: 2829.
- Skowyra J, Pietrzak K andAlhnan MA: Fabrication of extended-release patient-tailored prednisolone tablets via fused deposition modelling (FDM) 3D printing. European Journal of Pharmaceutical Sciences 2015; 68: 11-17.
- Wu G, Wu W, Zheng Q, Li J, Zhou J and Hu Z: Experimental study of PLLA/ INH slow release implant fabricated by three dimensional printing technique and drug release characteristics in-vitro. Biomedical Engineering Online 2014; 13: 97.
- Beck RCR, Chaves PS, Goyanes A, Vucosavljevic B, Buanz A, Windbergs M, Basit AW and Gaisford S: 3D printed tablets loaded with polymeric nanocapsules: An innovative approach to produce customized drug delivery systems. Int Journal of Pharmaceutics 2017; 528: 268-79.
- Genina N, Boetker JP, Colombo S, Harmankaya N, Rantanen J and Bohr A: Anti-tuberculosis drug combination for controlled oral delivery using 3D printed compartmental dosage forms: From drug product design to in-vivo Journal of Controlled Release 2017; 268: 40-48.
- Melocchi A, Parietti F, Loreti G, Maroni A, Gazzaniga A and Zema L: 3D printing by fused deposition modeling (FDM) of a swellable/erodible capsular device for oral pulsatile release of drugs. Journal of Drug Delivery Science and Technology 2015; 30: 360-67.
- Sadia M, Arafat B, Ahmed W, Forbes RT and Alhnan MA: Channelled tablets: An innovative approach to accelerating drug release from 3D printed tablets. Journal of Controlled Release 2018; 269: 355-63.
- Scoutaris N, Alexander MR, Gellert PR and Roberts CJ: Inkjet printing as a novel medicine formulation technique. Journal of Controlled Release 2011; 156: 179-85.
- Khaled SA, Burley JC, Alexander MR and Roberts CJ: Desktop 3D printing of controlled release pharmaceutical bilayer tablets. International Journal of Pharmaceutics 2014; 461: 105-11.
- Wang CC, Tejwani MR, Roach WJ, Kay JL, Yoo J, Suprenant HL, Monkhouse DC and Pryor TJ: Development of near zero-order release dosage forms using three-dimensional printing (3-DP™) technology. Drug Development and Industrial Pharmacy 2006; 32: 367-76.
- Khaled SA, Burley JC, Alexander MR, Yang J and Roberts CJ: 3D printing of tablets containing multiple drugs with defined release profiles. International Journal of Pharmaceutics 2015; 494: 643-50.
- Yu DG, Yang XL, Huang WD, Liu J, Wang YG and Xu H: Tablets with material gradients fabricated by three-dimensional printing. Journal of Pharmaceutical Sciences 2007; 96: 2446-56.
- Huang W, Zheng Q, Sun W, Xu H and Yang X: Levofloxacin implants with predefined microstructure fabricated by three-dimensional printing technique. International Journal of Pharmaceutics 2007; 339: 33-38.
- Wu W, Zheng Q, Guo X, Sun J and Liu Y: A programmed release multi-drug implant fabricated by three-dimensional printing technology for bone tuberculosis therapy. Biomedical Materials 2009; 4: 065005.
- Pardeike J, Strohmeier DM, Schrödl N, Voura C, Gruber M, Khinast JG and Zimmer A: Nano suspensions as advanced printing ink for accurate dosing of poorly soluble drugs in personalized medicines. International Journal of Pharma-ceutics 2011; 420: 93-00.
- Buanz AB, Saunders MH, Basit AW and Gaisford S: Preparation of personalized-dose salbutamol sulphate oral films with thermal ink-jet printing. Pharmaceutical Research 2011; 28: 2386-92.
- Gu Y, Chen X, Lee JH, Monteiro DA, Wang H and Lee WY: Inkjet printer antibiotic-and calcium-eluting bio-resorbable nanocomposite micropatterns for orthopedic implants. Acta biomaterialia 2012; 8: 424-31.
- Rattanakit P, Moulton SE, Santiago KS, Liawruangrath S and Wallace GG: Extrusion printed polymer structures: a facile and versatile approach to tailored drug delivery platforms. Int J of Pharmaceutics 2012; 422: 254-63.
- Meléndez PA, Kane KM, Ashvar CS, Albrecht M and Smith PA: Thermal inkjet application in the preparation of oral dosage forms: Dispensing of prednisolone solutions and polymorphic characterization by solid-state spectroscopic techniques. Journal of Pharmaceutical Sciences 2008; 97: 2619-36.
- Thomas D, Tehrani Z and Redfearn B: 3-D printed composite microfluidic pump for wearable biomedical applications. Additive Manufacturing 2016; 9: 30-38.
- Sadia M, Sośnicka A, Arafat B, Isreb A, Ahmed W, Kelarakis A and Alhnan MA: Adaptation of pharmaceutical excipients to FDM 3D printing for the fabrication of patient-tailored immediate release tablets. International Journalof Pharmaceutics 2016; 513: 659-68.
- Genina N, Holländer J, Jukarainen H, Mäkilä E, Salonen J and Sandler N: Ethylene vinyl acetate (EVA) as a new drug carrier for 3D printed medical drug delivery devices. European Journal of Pharmaceutical Sciences 2015; 90: 53-63.
- Wang JC, Chang MW, Ahmad Z and Li JS: Fabrication of patterned polymer-antibiotic composite fibers via electrohydrodynamic (EHD) printing. Journal of Drug Delivery Science and Technology 2016; 35: 114-23.
- Melocchi A, Parietti F, Maroni A, Foppoli A, Gazzaniga A andZema L: Hot-melt extruded filaments based on pharmaceutical grade polymers for 3D printing by Fused Deposition Modeling. International Journal of Pharmaceutics 2016; 509: 255-63.
- Boetker J, Water JJ, Aho J, Arnfast L, Bohr A and Rantanen J: Modifying release characteristics from 3D printed drug-eluting products. European Journal of Pharmaceutical Sciences 2016; 90: 47-52.
- Goyanes A, Wang J, Buanz A, Martínez-Pacheco R, Telford R, Gaisford S and Basit AW: 3D printing of medicines: engineering novel oral devices with unique design and drug release characteristics. Molecular Pharmaceutics 2015; 12: 4077-84.
- Goyanes A, Chang H, Sedough D, Hatton GB, Wang J, Buanz A, Gaisford S and Basit AW: Fabrication of controlled-release budesonide tablets via desktop (FDM) 3D printing. International Journalof Pharmaceutics 2015; 496: 414-20.
- Wang J, Goyanes A, Gaisford S and Basit AW: Stereolithographic (SLA) 3D printing of oral modified-release dosage forms. International Journalof Pharma-ceutics 2016; 503: 207-12.
- Srinivas L, Jaswitha M, Manikanta V, Bhavya B and Deva himavant B: 3d printing in pharmaceutical technology: a review. International Research Journal of Pharmacy 2019; 10: 2230-07.
- Wu BM and Cima MJ: Effects of solvent-particle interaction kinetics on microstructure formation during three-dimensional printing. Polymer Engineering and Science 1999; 39: 249-60.
- Kulkarni P, Marsan A and Dutta D: A review of process planning techniques in layered manufacturing. Rapid Prototyping Journal 2000; 6: 18-35.
- Fukai J, Ishizuka H, Sakai Y, Kaneda M, Morita M and Takahara A: Effects of droplet size and solute concentration on drying process of polymer solution droplets deposited on homogeneous surfaces. International Journal of Heat and Mass Transfer 2006; 49: 3561-67.
- Utela B, Storti D, Anderson R and Ganter M: A review of process development steps for new material systems in three dimensional printing (3DP). Journal of Manufacturing Processes 2008; 10: 96-04.
- Sachs E, Cima M, Williams P, Brancazio D and Cornie J: Three dimensional printing: rapid tooling and prototypes directly from a CAD model. Journal of Manufacturing Science and Engineering 1992; 114: 481-88.
- Rowe C, Lewis WP, Cima M, Bornancini E and Sherwood J: Printing or dispensing a suspension such as three-dimensional printing of dosage forms. Google Patents (US20030099708A1) 2001.
- Lewis WP, Rowe CW, Cima MJ and Materna PA: System and method for uniaxial compression of an article, such as a three-dimensionally printed dosage form. Google Patents (US20030143268A1) 2011.
- Serra T, Mateos-Timoneda MA, Planell JA and Navarro M. 3D printed PLA-based scaffolds: A versatile tool in regenerative medicine. Organogenesis 2013; 9: 239-44.
- Fina F, Madla CM, Goyanes A, Zhang J, Gaisford S and Basit AW: Fabricating 3D printed orally disintegrating printlets using selective laser sintering. International Journal of Pharmaceutics 2018; 541: 101-07.
- Bhusnure O, Gholve V and Sugave B: 3D printing & pharmaceutical manufacturing: opportunities and challenges. Int Journal of Bioassays 2016; 5: 4723-38.
- Awad A, Trenfield SJ and Gaisford S: 3D printed medicines: A new branch of digital healthcare. International Journal of Pharmaceutics 2018; 548: 586-96.
- Yu I and Chen RK: A feasibility study of an extrusion-based fabrication process for personalized drugs. Journal of Personalized Medicine 2020; 10: 16.
- Teoh S, Goh B and Lim J: Three-Dimensional printed polycaprolactone scaffolds for bone regeneration-success and future perspective. Tissu Eng Part A 2019; 25: 931-35.
- Ghidini T: Regenerative medicine and 3D bioprinting for human space exploration and planet colonisation. Journal of Thoracic Disease 2018; 10:S2363–S2375.
- Javaid M and Haleem A: 4D printing applications in medical field: A brief review. Clinical Epidemiology and Global Health 2019; 7: 317-21.
- Miao S, Castro N, Nowicki M, Xia L, Cui H, Zhou X and Zhang LG: 4D printing of polymeric materials for tissue and organ regeneration. Mat Today 2017; 20: 577-91.
- Studart AR: Additive manufacturing of biologically inspired materials. Chem Soci Reviews 2016; 45: 359-76.
- Khan FA, Celik HK, Oral O and Rennie AEW: A short review on 4d printing. International Journal of3D Printing Technologies and Digital Industry 2018; 2: 59-67.
- HAJ SS and Patil PP: Review on 4D and 5D printing technology. International Research Journal of Engineering and Technology 2020; 7: 744-51.
- Haleem A, Javaid M and Vaishya R: 5D printing and its expected applications in Orthopaedics. Journal of Clinical Orthopaedics and Trauma 2019; 10: 809-10.
- Zhang Z, Demir KG and Gu GX: Developments in 4D-printing: a review on current smart materials, technologies, and applications. International Journal of Smart Nano Materials 2019; 10:2 05-24.
- Azam A, Laflin KE, Jamal M, Fernandes R and Gracias DH: Self-folding micro-patterned polymeric containers. Biomedical Microdevices 2011; 13: 51-58.
- Malachowski K, Breger J, Kwag H, Wang M, Fisher J and Selaru F: Stimuli-responsive theragrippers for chemo-mechanical controlled release. Angewandte Chemie 2014; 126: 8183-87.
- Bodaghi M, Damanpack AR and Liao WH: Self-expanding/shrinking structures by 4D printing. Smart Materialsand Structures 2016; 25: 105034.
- Wei H, Zhang Q, Yao Y, Liu L, Liu Y, Leng J. Direct-Write Fabrication of 4D Active Shape-Changing Structures Based on a Shape Memory Polymer and Its Nanocomposite. ACS Applied Materials & Interfaces 2017; 9: 876-83.
- Ge Q, Sakhaei AH, Lee H, Dunn CK, Fang NX and Dunn ML: Multimaterial 4D Printing with Tailorable Shape Memory Polymers. Scientific Reports 2016; 6: 31110.
- Morrison RJ, Hollister SJ, Niedner MF, Mahani MG, Park AH, Mehta DK, Ohye RG and Green GE. Mitigation of tracheobronchomalacia with 3D-printed personalized medical devices in pediatric patients. Science Translational Medicine 2015; 7: 285ra64.
- Miao S, Cui H, Nowicki M, Xia L, Zhou X, Lee SJ, Zhu W, Sarkar K, Zhang Z and Zhang LG: Stereolithographic 4D Bioprinting of Multiresponsive Architectures for Neural Engineering. Adv Biosystems 2018; 2: 1800101.
- Miao S, Zhu W, Castro N, Nowicki M, Zhou X, Cui H, Fisher JP and Zhang LG: 4D printing smart biomedical scaffolds with novel soybean oil epoxidized acrylate. Scientific Reports 2016; 6: 27226.
- Italian hospital saves Covid-19 patients lives by 3D printing valves for reanimation devices. https://www. 3dprintingmedia.network/covid-19-3dprinted-valve-for-eanimation-device/. Accessed on 09.09.2020.
- 3D printing community RESPONDS to COVID-19 and coronavirus RESOURCES (Dated: 13-04-2020), https:// 3dprintingindustry.com/news/3d-printing-community-responds-to-covid-19-and-coronavirus-resources-169143/.
- Larraneta E, Dominguez-Robles J and Lamprou DA: Additive Manufacturing Can Assist in the Fight against COVID-19 and Other Pandemics and Impact on the Global Supply Chain. 3D Printing and Additive Manufacturing 2020; 7: 100-03.
- Singh S, Prakash C and Ramakrishna S: Three-dimensional printing in the fight against novel virus Covid-19: Technology helping society during an infectious disease pandemic. Tech in Soc 2020; 62: 101305.
- Ishack S and Lipner SR: Applications of 3D Printing Technology to Address COVID-19-Related Supply Shortages. Am Journal of Medicine 2020; 133: 771-73.
- Choong YYC, Tan HW, Patel DC, Choong WTN, Chen CH, Low HY, Tan MJ, Patel CD and Chua CK: The global rise of 3D printing during the COVID-19 pandemic. Nature Review Materials 2020; 5: 637-39.
- Tino R, Moore R, Antoline S, Ravi P, Wake N, Ionita CN, Morris JM, Decker SJ, Sheikh A, Rybicki FJ and Chepelev LL: COVID-19 and the role of 3D printing in medicine. 3D Printing in Medicine 2020; 6: 11.
- Cascella M, Rajnik M, Cuomo A, Dulebohn SC and Di Napoli R: Features, Evaluation, and Treatment of Coronavirus (COVID-19). In: StatPearls. Treasure Island (FL): StatPearls Publishing; August 10, 2020.
How to cite this article:
Baisya O, Bhowmick S, Sengupta C and Bhowmik AD: Pharmaceutical applications of next generation printing technologies: a brief literature review. Int J Pharm Sci & Res 2021; 12(6): 2995-05. doi: 10.13040/IJPSR.0975-8232.12(6).2995-05.
All © 2013 are reserved by the International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
O. Baisya *, S. Bhowmick, C. Sengupta and A. D. Bhowmik
Department of Pharmaceutics, Netaji Subhas Chandra Bose Institute of Pharmacy, Chakdaha, Nadia, West Bengal, India.
09 October 2020
27 April 2021
12 May 2021
01 June 2021