Samiei Beni-Suef University Journal of Basic and Applied Sciences (2020) 9:12

https://doi.org/10.1186/s43088-020-00040-4
Beni-Suef University Journal of
Basic and Applied Sciences

REVIEW Open Access

Recent trends on applications of 3D

printing technology on the design and
manufacture of pharmaceutical oral
formulation: a mini review
Nasim Samiei1,2

Abstract
Background: Three-dimensional printing (3DP) is an emerging technology used to describe 3D products
manufactured on a digital design platform and in a layer by layer fashion. 3D printing technology has appeared as
a major technological revolution of the recent years leading to the manufacturing and production of novel medical
products and devices in pharmaceutical industry. The new technology has gained considerable attraction when the
first commercial 3D tablet Spiratam® (levetiracetam) was approved by FDA in August 2015.
Main text: The key aspect of printing technology in the field of drug delivery is its versatility to create potential
novel oral dosage forms. It also enables rapid, safe, and low-cost development in the production process which
consequently leads to wide applications of this new technology in pharmaceutical fields. 3D printing also enhances
patient convenience to further improve the medication compliance.
Among various technical trends for fabricating 3D objects, extrusion-based printing, powder-based binding, and
inject printing methods are of particular interest to the pharmaceutical industry which are discussed briefly in this
paper. This study also provides different applications of 3D printing technology and highlights the impact of 3D
printing as an innovative promising technology through presenting some examples as experimental studies in the
fabrication of oral drug delivery systems.
Conclusions: Through reviewing some experimental studies, this mini review has shown that 3D printing
technique can be successfully used on a small scale to produce tailored doses of drug products and has great
advantages experimentally in the production of oral doses forms. Concerning the future of 3D printing, the new
technology is likely to focus on production in hospitals and pharmacies for individuals or niche groups with specific
needs.
3D printing may also offer an attractive new research and development opportunity to improve drug formulation
and administration of existing active pharmaceutical ingredients.
Keywords: 3D printing technology, 3D drug product, Customized medicine, Enabling technology, Customized
release profile, Local fabrication

Correspondence: [email protected]
1
FakherPharma Pharmaceutical, P.O. Box 14155-6153, Tehran, Iran
2
Department of Pharmaceutics, Pharmaceutical Sciences Branch, Islamic Azad
University (IAUPS), Tehran, Iran

© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
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Samiei Beni-Suef University Journal of Basic and Applied Sciences (2020) 9:12 Page 2 of 12

1 Background While a comprehensive review of the recent literature

Three-dimensional printing (3DP) is an emerging tech- of this field is beyond the scope of this manuscript, this
nology used to describe 3D products manufactured on a mini review aims to briefly review the 3D printing tech-
digital design platform in a layer by layer fashion. 3D nology as an innovative enabling technology and its
printing was originally developed with industrial applica- applications in pharmaceutical industry. The methods
tion purposes and has progressively become a promising used in this study encompasses targeted literature
technology within past few years. Emergence of 3D searches focused upon emerge of three-dimensional
printing in the pharmaceutical industry has led to radical printing (3DP) technology in the pharmaceutical indus-
shifts in the manufacturing process of drug products try and its contribution in the fabrication of novel oral
and has markedly enabled non-digitalized medical prod- drug delivery systems in main databases such as
ucts to turn into digital 3D content [1–3]. On the other PubMed, Scopus, and Web of Science. Peer-reviewed
hand, there is a co-existence between physical and published articles were chosen from established and
digital production which leads to manufacturing diverse well-regarded recent scientific journals.
models of 3D medical products. 3D printing technology The suitability of 3D printing was assessed as an enab-
has appeared as a major technological revolution of the ling technology through investigation of printing different
recent years in pharmaceutical industry in terms of ranges of drug products from poorly water-soluble drugs
process innovation in the fabrication of 3D medical and proteins. Different manufacturing processes such as
products [4–6]. The major shift toward development of extrusion-based printing, powder bed, and injection print-
3D printing technology in the pharmaceutical industry ing technologies which are widely used in fabrication of
was initiated in the early 90s at MIT (Massachuset Insti- oral solid dosage forms, will also be discussed.
tute Technology, Cambridge, MA, USA) with a rapid
prototyping method invented and patented by Sachs 2 Main text
et al. entitled as “three-dimensional printing techniques.” 2.1 Interplay between 3D printing and conventional
Despite the slow growth and adoption of the new tech- manufacturing technique
nology, the first commercial 3D tablet Spiratam® (leveti- Solid oral dosage forms such as tablet and capsule are
racetam) was approved by the USA Food and Drug common routes of drug administration. Traditionally,
Administration (FDA) in August 2015 and was released they are produced by mass fabrication which involves
to the market. The new 3D tablet enables epileptic multiples processes such as blending, mixing, milling,
patients to use a high dose tablet in emergency situa- and finally compression into tablets. Furthermore, the
tions with no water and with a fast onset of action [7, 8]. conventional manufacturing techniques are intended to
Nowadays, pharmaceutical 3D printing is gaining be a large-scale mass production with a one-dose-fit-all
considerable attention as a potential technology enhan- approach which may not necessarily consider the indi-
cing efficacy, preciseness, and individualisation while vidual needs of a patient. The major disadvantages of
reducing wastage cost. The new technology also enables the traditional manufacturing process include being
creation of novel oral dosage forms and medical devices time-consuming and costly while also requiring highly
which are otherwise challenging to be produced using skilled technicians [19, 20].
conventional manufacturing technologies [9–11]. The The 3D printing technology seems to be a revolution
ambitious goal of extensive research of 3D printing is to in pharmaceutical manufacturing processes which is fun-
develop a technology which is capable of replacing all or damentally different from the traditional mass produc-
most parts of conventional fabrication process of med- tion methods. With the introduction of 3D printing in
ical products. The technology is highly disruptive and the pharmaceutical industry, it is possible to curtail the
can lead to remarkable innovation in different processes process of manufacturing drug products from days to a
of drug development [12, 13]. matter of hours. Speeding up the production process
The advent of 3D printing technology in the pharma- can lead to more rapid release of the drug product into
ceutical industry has made it possible to design and the market. In addition, the ability of 3D printing to rap-
manufacture novel complex drug products, as well as idly manufacture a drug product causes a substantial
multiple active drug pharmaceutical ingredients (API) cost reduction in the production process, which is highly
into one dosage form with customized release trends favorable to the pharmaceutical industry. Further, it pro-
and individualized design adapted to patients’ specific motes creativity, innovation, and customization [21–23].
needs. These individualized dosage forms can be directly The fabrication steps with 3D printing are clean and the
fabricated in a pharmacy on a local 3D printer or even material waste is negligible allowing for previously dis-
at home by the patient. Indeed, the main advantage of carded raw materials to be further explored, while also
the 3D printing is its flexibility to design and fabricate increasing compliance and accessibility of drugs. Now-
diverse medical products [14–18]. adays, the number of research with 3D technique is
Samiei Beni-Suef University Journal of Basic and Applied Sciences (2020) 9:12 Page 3 of 12

growing which intends to leverage the arising profit of Hence, 3D medical products should meet the same
this technique in the pharmaceutical field [24]. quality and standard of conventional dosage forms
In regard to manufacturing tailor-made medicine via with Good Manufacturing Practices (GMP) guidelines
traditional methods, general approaches involve utilization [24, 27].
of high chain polymeric materials or waxy lipids to embed Nevertheless, 3D printing technology is still an imma-
the drug substance for prolonging its release rate [25]. ture technique and has not yet been fully exploited due
Development of such modified release products such as to its limitations. The fabrication of 3D products require
matrix embedment, core-coat, and multi-compartment sys- different types of technologies in particular those used in
tems may have few disadvantages such as accidental burst pharmaceutical production, which are often rarely avail-
release of the drug from the dosage form which can lead to able in the pharma industry [20].
toxicity and adverse side effects. In this regard, 3D printing Some important advantages of 3D printing technology
technique enables alternative manufacturing routes for ad- in oral drug delivery system are highlighted in Fig. 1.
vanced drug delivery systems with flexibility in the creation
of oral dosage forms with a complex geometry. This can 2.2 Manufacturing trends for fabrication of 3D printed
potentially address the issues related to the traditional medical products
modified release dosage forms and ultimately enables more A 3D printing medical product can be generated by a set
effective way of personalized medications [26]. of different processes that replace the ink with a desir-
The ability of the technique in rapid production through able formulation of drug and then jet that onto a suit-
a computer-aided design (CAD) allows for fast fabrication able substrate in an additive process. The substrate may
of a medicine with stability issues during the production be an edible sheet with a functionalized structure of spe-
process thus affording the opportunity of using the medi- cific hydrophobicity/hydrophilicity, porosity, and perme-
cation right after its immediate production [9, 14]. ability. The main challenge of 3D printing technique is

Fig. 1 Main advantages of 3D printing technology in the pharmaceutical applications

Samiei Beni-Suef University Journal of Basic and Applied Sciences (2020) 9:12 Page 4 of 12

to convert the starting materials (drug and excipients) as rapid prototyping, solid free form fabrication, and
into a “curable ink” or a printable material [19, 28]. additive manufacturing have also emerged as other
The first step of manufacturing a 3D object involves names and can be referred to as 3D printing. These
designing a digital model of the desired 3D product by a terms have been introduced by manufacturing compan-
special CAD (the software comes in many forms and ies to reflect a special design for 3D products [8]. A
licenses). Next, the digital design is exported to a readable summary of 3D printing process is represented in Fig. 2.
format for a system which is mainly a stereo lithography
(STL) file. Afterwards, a slicer (3D printing software) 2.3 3D technology adoption in the pharmaceutics
transfers the STL file into a series of thin layers with the There are a number of technical trends for fabricating
instruction tailored to generate the 3D object. 3D printing products which can be used in the pharma-
Then, during the course of printing, the printer head ceutical industry and correspond to different applica-
moves and the formulation ink decomposes onto succes- tions and materials. These various methods vary in their
sive layers on a built tray which will create the basis for function and productivity, where the key difference be-
the object. The process continues until the desired 3D tween them is the way a layer deposits on another layer.
product is constructed. In addition, speed, accuracy, quality, and material prop-
Finally, the 3D product may require movement of erties are the major criteria which should be considered
solvent residues, excess powder, polishing, and sintering in selecting a suitable method for 3D printing [5, 29].
which occur in the post-printing step [11, 19]. The main characteristic of a 3D medical product such as
3D printing has a potential to process versatile mate- drug load and its release rate can be precisely modified
rials such as polymers, waxes, metals, and hydrogels. by printing parameters such as manipulating the num-
The technique is even used for the production of objects bers of printed layers for a given area or changing the
made from a single material or a combination of mate- entire area of printing [19].
rials, where each material may be deposited by a separ- Through reviewing some literature, a brief overview is
ate print head or other deposition steps [5]. presented about the most relevant 3D printing techniques
While 3D printing is widely used for the products adopted in the pharmaceutical industry such as extrusion-
which have been created layer by layer, other terms such based technique, powder bed, and material jetting.

Fig. 2 A schematic representation of different processing steps involved in fabrication of 3D printing objects
Samiei Beni-Suef University Journal of Basic and Applied Sciences (2020) 9:12 Page 5 of 12

2.3.1 Extrusion-based printing layer by layer upon leaving the printer. The fused depos-
The trend of using extrusion printing technology started ition technique is also known as fussed filament (FF) in
in 1980 and became operational in 1990. Extrusion the literature. In comparison with the hot melt extrusion
printing technique is governed by two types of printing printing, in fused deposition modeling, the mechanical
methods including hot melt extrusion (HME) technique properties of 3D products and the drug load are lower.
and fused deposition modeling [30, 31]. Further, the fused filament method can be efficiently
In the case of HME technique, a homogenous solid used as a 3D printer for local or home-fabricated
dispersion of pharmaceutical excipients such as poly- products for personalized medicine at the point of
meric materials and plasticizers are prepared in a molten use [35, 36]. Figure 3 displays a schematic illustration
form of polymer and a drug substance is introduced in of the extrusion technique [37].
the polymeric composition. Next, the formulation ink Both of the methods have gained popularity for fabri-
can be extruded directly through a die under high pres- cating 3D drug products in the pharmaceutical industry.
sure and elevated temperature, then fused and solidified The main advantage of the 3D extrusion printing
after printing, thereby generating a 3D product of uni- technique is its high flexibility to develop a novel formu-
form shape with a high quality and drug content [32]. lation of solid oral dosage forms with a different geom-
The advantage of hot melt extrusion is that it is a etry, complexity and hallow structure product and
solvent-free method which eliminates the need for a various drug release profiles, and the ability to print a
rigorous solvent selection step, making it an environ- different range of polymers. Also, the extrusion tech-
mentally friendly method of production [11, 25]. nique is a promising way to printing materials in an
In the late 1990, with emergence of thermoplastic amorphous form which enhances the dissolution rate
polymers such as polylactic acid (PLA), polyvinyl alcohol thereby improving the bioavailability of poorly soluble
(PVA), and ethylvinyl acetate, 3D printing was intro- drugs [27, 38–40].
duced as a great adaptation in the pharmaceutical indus-
try [33, 34]. 2.3.2 Powder-based binding method
Concerning the fused deposition method, the drug Rapid prototyping with a powder-based method is of
substance is loaded in a thermoplastic polymeric fila- particular interest to the pharmaceutical industry as it
ment for example via passive diffusion from solutions has many parallels with current manufacturing processes
and used as starting materials. Next, it is extruded by a and may offer a more efficient longer-term printing
gear system in a continuous profile through the heated solution [12]. Multilayers of 3D printing products are
printer head onto a surface and immediately hardens constructed by spraying a solution of binder or drug

Fig. 3 Schematic representation of fused deposition modeling, reused from free copyright website RapRap (https://reprap.org/wiki/File:FFF.png)
Samiei Beni-Suef University Journal of Basic and Applied Sciences (2020) 9:12 Page 6 of 12

with additional excipients in small droplets from an X-Y droplets. Then, the droplets are directed to an electric-
print head (in two-dimensional manners) over a powder ally charged element to obtain the desired charge.
bed on a built platform. Then, it is lowered along Z-axis Finally, the formed droplets reach onto the substrate
based on the height of layers until the subsequent layer is and create the 3D product.
constructed. The layers could be bonded via adhesion or In the DOD printing system, the pharmaceutical-based
welding in a liquid solution or suspension (Fig. 4) [19, 25]. ink is converted to a droplet form by applying a voltage to
Finally, the residual of the solvent and unbound powder is a piezoelectric crystal transducer to vibrate the materials
removed under appropriate conditions, allowing for the or heating the formulation to the temperature higher than
3D product to develop properly (post-printing step) [14]. the boiling temperature thereby creating droplets. Then,
Powder bed 3D printing method is fast and compatible the dots of the solution are driven from an orifice to the
for printing a wide range of pharmaceutical substances. printer head’s nozzle and solidified dropwise. The main
Further, the quality of fabricated 3D products is high criterion in developing a formula of API for printing in
and contributes to a considerable reduction in the the inject print system is the performance of the carrier
production cost. The method has great potentials for formulation during printing, which is strongly influenced
fabricating high dose formulations of drug substance, by rheological parameters such as fluid viscosity, velocity,
controlled and immediate release drug formulation, and and surface tension [43–45]. Likewise, the release profile
multilayer tablets containing different and precise active of the formulation can be modified given the deposition
substances. These advantages have led to wide adoption pattern of droplets onto the substrate.
of this technique in pharmaceutical applications [41]. The main advantage of inject printing method in the
Selecting a suitable binder and concentration can re- pharmaceutical application is its high accuracy in creat-
sult in the appropriate integrity of 3D drug products. ing 3D drug products. The technology also opens up
Further, the particle size of the powder is another new possibility for usage of new active pharmaceutical
major factor which affects the quality of the final 3D ingredients and personalisation in drug discovery [35].
products [19]. Experimental studies have shown potential applications
of inject printing approach for fabricating oral dosage
2.3.3 Inject printing forms such as poorly soluble and potent drugs [12, 46].
Another adoption of 3D printing in pharmaceutics is in- The factors affecting the fabrication of 3D drug prod-
ject printing. This approach is particularly suitable when ucts contributing to the material and manufacturing
the formulation of starting materials is liquid [42]. Inject process are listed in Table 1.
printing is classified into two categories: continuous in-
ject printing (CIJ) and drop on demand (DOD) based on 2.4 Challenges associated with different 3D printing
the direction of droplets (Fig. 5a,b) [31]. In the case of techniques
CIJ, the drops are formed by a transducer or a droplet Although there are many advantages associated with the pro-
loading apparatus producing a continuous stream of duction of pharmaceuticals products using 3D technology,

Fig. 4 Schematic illustration of powder bed binding technique

Samiei Beni-Suef University Journal of Basic and Applied Sciences (2020) 9:12 Page 7 of 12

Fig. 5 Inject printing technique (a) continuous (CIJ), (b) drop on demand (DOD). Permission to reprint the figure has been obtained from Image
Permanence Institute (http://www.imagepermanenceinstitute.org)

each technique has its own challenges which can restrict the and poor drug loading may limit its usage for low-dosed
application of the method. A significant drawback of drugs [36].
extrusion-based printing method is usage of high energy in- Considering the limitation of 3D printing via the pow-
put in this technique (typical temperature printing, 200–260) der bed technique, 3D printed products usually require
which has raised concern over degradation of thermo- additional drying steps to remove residual solvents and
sensitive materials, thus limiting it mostly to thermo-stable improve the physical resistance. Furthermore, a remark-
materials. The fabricated 3D product may collapse during able wastage of powder is produced during the fabrica-
3D printing if a constructed layer cannot harden sufficiently tion process. Also, there is less flexibility in terms of
to withstand the weight of the successive layers, which could mistake improvement for 3D products during the fabri-
lead to a low hardness and highly friable 3D product. Also, cation process [41].
controlling the flow of semi-solid materials is difficult Finally, inject printing has few limitations: the droplet
through the nozzle and the resolution of printing is limited size is 10–50 μm which may limit the printing efficacy
by the nozzle size [14, 21]. and as a result the manipulation of the drug load.
In the case of fused filament technique, filaments Obtaining higher doses will otherwise imply numerous
should be prepared before loading the drug substance by printings on a particular area, which could lead to a
a specific method and the technique is confined to longer drying time and potential instabilities. Also, the
thermoplastic polymers. Drug loading in the filament is materials should be dissolved in a safe volatile solvent,
usually achieved through incubation in organic solvents, which is another restriction for this method [12].

Table 1 Main critical factors affecting the manufacturing a 3D printing product

Methods Range of material Process critical factors Material critical factors References
Extrusion based Liquid, past, Nozzle orifice diameter, extrusion temperature, Type of polymer, molecular weight, viscosity, [36, 37, 47, 48]
printing gel, slurry cooling rate extrusion pressure, speed of glass transition temperature, strength,
traveling printing profile, feeding rate, fill toughness, type of plasticizer and its
percentage concentration, polymer to drug ratio, Filament
Line spacing. diameter.
Kind of solvent to load drug into filament.
Powder bed Powder, liquid Printer head shape, number, speed, and its Powder particle size, shape and density , [14, 19, 27]
technique binder movement pattern layer thickness moisture content.
Powder bed spreading speed, powder bed Binder concentration, viscosity, surface tension,
temperature thermal capacity, electrical Conductivity,
Speed of drying of powder bed between droplet volume.
layers
Temperature of heater in post printing step.
Material jetting Liquid Droplet flight path Droplet cauterization like size concentration/ [1, 12, 19]
Surface wetting viscosity/ionic strength and stability, Kind of
Jetting heating system and its temperature. solvent.
Samiei Beni-Suef University Journal of Basic and Applied Sciences (2020) 9:12 Page 8 of 12

2.5 Disruptive effect of 3D printing technique in drug processes and assesses their result via in vitro or in vivo
delivery systems evaluation from 3D oral drug products with some exam-
The significant ability of 3D printing in the fabrication ples of recent literature. Other examples of 3D oral dos-
of solid oral dosage forms is its flexibility, which can age forms manufactured with 3D printing technology
potentially promote creativity and innovation. The new are tabulated in Table 2.
technology enables possibilities to create unique new
oral drug products, which traditional methods fail to
emulate [49, 50]. 3D printing most likely corresponds to 2.5.1 3D printing of tablets with various geometries to
novel architectural innovation and enables designing and achieve a tailored function
fabricating oral dosage forms with different geometrics, Goyanes et al. explored the feasibility of using a fused
complex features such as tablets with a designed internal filament method to fabricate tablets of different shapes
structure, porosity gradients, torture channels, and and sizes. Acetaminophen-loaded filaments of PVA were
multi-compartment systems such as poly-pills contain- prepared by introducing an aqueous solution of para-
ing multiple API in one dosage forms. These features cetamol (2% w/w) in small pieces of PVA with Varicut
may enable the control of drug release rate by obtaining as a plasticizer. Then, the formula was printed with dif-
specific and complex release patterns in response to the ferent shapes as cube, pyramid, cylinder, sphere, and
patient’s needs, thereby enhancing the drug efficacy [51]. torus using a single-screw filament extruder. The printed
Concerning customized medicine, clinical pharmacists geometries were considered to be reproducible, precise,
or doctors may need patient’s individual information and printable at a size suited to mass production.
such as age, gender, body mass index, and metabolism They found that manipulation of the printed geometry
in order to develop the optimum medical dose. In this of acetaminophen tablets resulted in varying drug release
way, the patient can receive accurate personalized treat- rates, allowing for a high degree of personalisation. The
ment regimen matching their particular medical profile pyramid-shaped tablet of acetaminophen which had the
[46]. Current research into 3D printing technology as a largest surface area to volume ratio revealed the fastest re-
tool within pharmaceutical research and production lease rate, while the cylinder-shaped tablet with the smal-
has focused on small scale manufacturing to enable lest ratio indicated the slowest release rate of the drug.
individualisation and utilization, as well as to increase Further, their study proved that different-shaped
compliance. tablets had a great impact on transit time in vivo which
The following section thoroughly discusses the impact may also be beneficial for developing targeted drug de-
of 3D printing technique in various manufacturing livery systems to a specific gastro-intestine site [37].

Table 2 Proprietary 3D printing drug products

Drug product Fabrication technique Dosage Form Characteristics References
Acetaminophen controlled release tablet Hot melt extrusion Specific 3D structure with different inner core [52]
densities and outer shell thickness.
Warfarin fast disintegrating tablet Powder based method Highly porous structure which disintegrates [53]
very fast in oral cavity.
Aripiprazoleoro dispersible films Fused filament method Printed film with a porous structure and [54]
amorphization of the drug substance.
Colon delivery tablet of aminosalicylate Hot melt extrusion Monolithic controlled release tablet as [55]
(4- ASA and 5-ASA) patient-tailored medicine.
Theophylline immediate and extended Hot melt extrusion A combination of different release [56]
release tablet mechanisms into a single system with digital
control of excipients.
Fluorescein 3D printing tablet Fused filament method Monolithic tablet for personalized [36]
dosemedicine and specific release profile.
Prednisolone extended release 3D tablet Fused filament method Amorphization of prednisolone in formulation [57]
/personalized dose medicine.
Ritonavir 3D tablet Hot melt extrusion Solid dispersion of drug in hydrophilic [24]
polymer to improve the drug solubility and
bioavailability.
3D tablet containing nanocapsule of Fused filament method Combination of two technology; 3D printing [58]
deflazacort and nanotechnology to create innovative
formulation.
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2.5.2 3D printing of tablets with honeycomb architecture as general circulation. Also, this kind of formulation can
different levels of complexity to control and tuneable drug open up a new way in designing dosage forms for
release rate patients who struggle to swallow a tablet [14, 46].
Kyobulaa et al. developed a modified release tablet of
fenofibrate with 3D inject printing technique using mol- 2.5.4 3D hollow structure tablets to improve the solubility
ten beeswax (FDA approved wax) as a hydrophobic drug and bioavailability and extend the release pattern
carrier. Application of beeswax in the formulation of A novel enabling strategy to increase the solubility and
tablets is generally safe and provides a means for bioavailability of the poorly soluble drug “domperidone”
controlling the release of active ingredient from the dos- with 3D printing technique was introduced by Chai
age form. The molten combination of fenofibrate and et al. The developed 3D tablet represented a new
beeswax was prepared using a magnetic stirrer hotplate concept as a gastro-retentive system with an extended
at 90 °C and then printed in a honeycomb architecture release pattern using the fused disposition modeling.
without using any solvent. The main characteristic of Domperidone was loaded onto a hydrophilic carrier of
this type of 3D tablet is its potential to provide custom- hydroxypropyl cellulose (HPC) filament as solid disper-
ized drug loading and facilitating the drug distribution sion and printed into a hollow structure tablet. The
within the tablet which may ultimately enhance the drug shape of the hallow structure was controlled with two
release rate. This result is based on the fact that by ma- main factors including the numbers of shell and infill
nipulating key geometric parameters such as cell size, percentage which may affect the outline and inner part
wall surface area, and shell thickness, the drug dissol- of the 3D object, respectively. Increasing the number of
ution rate will also be affected. shells will add the weight and strength of the tablet. On
The results of this study suggested that the increase in the other hand, reducing the infill percentage during the
honeycomb diameter and surface led to an increase in printing leads to increased porosity of the tablet, thereby
the amount of released drug in the case of honeycomb improving the dissolution rate. The result of their study
with a middle-sized channel. Tablets with the smallest showed that the proposed formulation of the 3D tablet
and widest dimension honeycombs showed a reduction with two shells, zero percent infill and density of 0.77 g/
in the dissolution rate of the drug due to insufficient cm3, had a rigid hallow internal structure which could
penetration of dissolution medium and lower surface dissociate slowly and provide sustained release rate with
area respectively, when compared with a middle-sized a floating ability up to 10 h both in vitro and in vivo.
channel. Further, the benefits of this system include its The enhanced concentration of the drug with less fluc-
flexibility for manipulation of different geometries for tuations in the rabbit plasma and consequently improved
personalized medicines or a pattern for different drugs, oral bioavailability of domperidone after oral administra-
without the need to change the basic formulation com- tion of single-dose of the tablet to the rabbit revealed
position, processing parameters, and the manufacturing that the 3D gastro floating tablet had a potential to
equipment. In addition, this system has a potential to reduce the frequency of drug administration and to
mask the bad taste of the drug. The study also found improve the drug’s efficacy [47].
inkjet printing system to be a more precise and effective
method for fabricating different doses of poorly soluble 2.5.5 Nanosuspension strategy for accurate dosing of
drugs [59]. poorly water-soluble drugs in personalized medicine
Jana et al. worked on an approach to develop a nanosus-
2.5.3 3D tablets for systemic effect with a fast onset of pension system for folic acid as a model of poorly water-
action soluble drug. They employed inkjet printing system to
Spirtam® (levapiracetam) is the first 3D commercial produce personalized medicines. A 10% of folic acid sus-
tablet produced by Aprecia Pharmaceuticals (the first pension was prepared by mortar and pestle of folic acid
Pharmaceutical which started to integrate 3D printing in in the presence of 3% (w/w) Tween 20. The nanosuspen-
one of its products) and approved by FDA in August sion was then created using a special homogenizer under
2015. It is a complex, pyramid-shaped and immediate- controlled pressure. The particle size distribution of folic
release 3D tablet manufactured by powder bed binding acid in the nanosuspension formulation was determined
technique without applying compression. The 3D tablet below 5 μm by a laser diffractometry system. A piezo-
has a highly porous scaffold even at high doses (1000 mg electric inkjet printer system with a nozzle apparatus of
of API) enabling fast disintegration in the patient’s 100 μm was employed for printing. The result of their
mouth with a little amount of water. The new 3D tablet study indicated that the saturated solubility and dissol-
offers the advantage of reducing the lag time for the ution rate of folic acid nanosuspension significantly in-
onset of action since a large proportion of the drug is creased by up to 57% and 12.5%, respectively, compared
available for absorption via the oral mucosa into the to folic acid microsuspension. The authors concluded
Samiei Beni-Suef University Journal of Basic and Applied Sciences (2020) 9:12 Page 10 of 12

that faster and more accurate dissolution profiling can tablet, thereby improving compliance for pediatric
be adjusted via formulating the nanosuspension of folic patients. The results of the dissolution study showed
acid using an inject printing method. Also, the printed immediate release of indomethacin within 60 min, re-
dosage forms were found to be chemically and physically gardless of the printed shape of tablets [62].
stable under ambient conditions [60].
2.6 3D printing role in local and home fabrication
2.5.6 3D printed buccal film for oral delivery of protein and The final stage of adoption of 3D printing in the
peptide pharmaceutical application is local or home fabrication
Biomedical molecules such as protein and peptides 3D printers in a mini-dispenser unit which first emerged
represent great pharmaceutical challenges which cannot in 2010. The fabrication of 3D medical products is per-
be processed and administered via oral delivery routes. formed directly by patients themselves with a personal
The major issue related to insufficient efficacy and bio- 3D printing device at home or a local printer in different
availability is attributed to their retention of structure situations such as pharmacy, clinic, or an emergency
and instability in gastrointestinal fluids. In a study con- condition only with a single fabrication run. The starting
ducted by Miguel et al., they developed a printed buccal material should be provided in mass-production for the
oral film of two kinds of proteins including lysozyme final manufacturing step by the customer. In this case,
and ribonuclease-A which were extracted from egg the medical care providers and patients must be edu-
chicken and bovine pancreas. They employed thermal cated well enough on how to use the printer and how to
inkjet printing system adapted for printing biological evaluate the quality defects which may appear in the
materials. The ink formula for printing contained a pro- printed product. This kind of adoption will enable
tein solution in water and glycerine (a viscosity modifier) bypassing the distribution stage which would be more
with a ratio of 70:30. Sodium deoxycholate was also economical to manufacture a smaller batch of a medi-
added into the ink formulation as a permeation enhan- cine rapidly. Tissue engineering scaffolds and wound-
cer. The printed films were evaluated by different ana- healing gels are two practical examples for application of
lysis methods to test the protein quantity, structure, local printing technique which are mostly performed via
efficacy, and enzyme activity. The results of their study the extrusion technique by a doctor [13, 26, 63].
indicated that the 3D buccal film was successfully According to recent literature review, the number of
printed by a conventional printer. No changes occurred local or home 3D printing devices is limited and re-
in the protein structure nor in their enzyme activity after stricted mainly to engineering studies. Further, apart
the printing process. The study concluded that the ther- from the importance of the value and potential of 3D
mal ink jet printing can be used as an efficient and prac- printing in pharmaceutical development, there is much
tical approach for preparing biological buccal oral films more debate about home fabrication which can be per-
without compromising the protein activity [61]. formed by patients themselves. The reasons about the
unsuitability of this technique at home or other local
2.5.7 Pediatric-printed tablets places include low quality product, high cost, and lim-
Scoutaris et al. managed to fabricate a 3D tablet of indo- ited materials which can be used. One of the drawbacks
methacin in the form of Starmix® designs for pediatrics. which can raise concerns over the product responsibility
Indomethacin was incorporated onto hypromellose acet- would be related to granting permission of license of
ate succinate (HMPCAS) thermoplastic polymer and production for the desired drug product from the
transformed into a 3D tablet via the extrusion method. pharmaceutical company to pharmacies and patients
The study involved coupling both extrusion systems, who intend to produce the product locally. This may
HME and the FDM, to fabricate chewable tablets of raise the problem of adverse incidence or claims of
Starmix form. The printing method with HME can mask product defects. In addition to the on-demand 3D print-
the bitter taste of the drug substance. Through choosing ing production outside the pharmaceutical companies by
a suitable taste-masking polymer via solid dispersion healthcare centers or pharmacies, another concern is
with API, and as FDM can fabricate any shape of 3D hackers making alternative drug formulations which can
product, a combination of two methods led to fabrica- cause serious implications for the patient [63, 64].
tion of tablets with a favorite shape and taste, being
more attractive and desired by children. 3 Conclusion
Their research team proposed that the printing tech- 3D printing technology represents a great potential in
nology enables fabricating 3D tablets of indomethacin in drug development, formulation, and administration due
the form of a heart, ring, bottle, ring, bear, and lion- to its great flexibility and efficacy in innovation and cre-
shape combined with effective sweetening. This may be ation of novel medical products. In addition, the suitabil-
a promising substitute for indomethacin conventional ity of the technology as a tool for drug individualisation
Samiei Beni-Suef University Journal of Basic and Applied Sciences (2020) 9:12 Page 11 of 12

is massive given its ability to manipulate high degrees of Received: 5 November 2019 Accepted: 7 February 2020
drug deposition pattern to assess different release pro-
files. The new technique allows for reformulating and
remanufacturing a medical formulation to distinguish it References
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