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PII: S0378-5173(18)30204-7
DOI: https://doi.org/10.1016/j.ijpharm.2018.03.057
Reference: IJP 17400
Please cite this article as: T. Tagami, N. Nagata, N. Hayashi, E. Ogawa, K. Fukushige, N. Sakai, T. Ozeki, Defined
drug release from 3D-printed composite tablets consisting of drug-loaded polyvinylalcohol and a water-soluble or
water-insoluble polymer filler, International Journal of Pharmaceutics (2018), doi: https://doi.org/10.1016/
j.ijpharm.2018.03.057
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Title: Defined drug release from 3D-printed composite tablets consisting of drug-loaded
Authors: Tatsuaki Tagami1, Noriko Nagata1, Naomi Hayashi1, Emi Ogawa1, Kaori
Affiliations:
1
Drug Delivery and Nano Pharmaceutics, Graduate School of Pharmaceutical Sciences,
Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
2
The Nippon Synthetic Chemical Industry Co., Ltd., 2-4, Komatsubara-cho, Kita-ku,
†
Current address: Department of Anatomy, Aichi Medical University, 1-1 Yazakokarimata,
1
Abstract (189200/200 words)
3D-printed tablets are a promising new approach for personalized medicine. In this
study, we fabricated composite tablets consisting of two components, a drug and a filler, by
containing calcein (a model drug) was used as the drug component and PVA or polylactic acid
(PLA) polymer without drug was used as the water-soluble or water-insoluble filler,
designed, and the 3D-printed tablets exhibited good formability. The surface area of the
exposed drug component is highly correlated with the initial drug release rate. Composite
tablets with an exposed top and a bottom covered with a PLA layer were fabricated. These
tablets showed zero-order drug release by maintaining the surface area of the exposed drug
component during drug dissolution. In contrast, the drug release profile varied for tablets
whose exposed surface area changed. Composite tablets with different drug release lag times
were prepared by changing the thickness of the PVA filler coating the drug component. These
results which used PVA and PLA filler will provide useful information for preparing the
tablets with multi-components and tailor-made tablets with defined drug release profiles using
3D printers.
2
1. Introduction
There has been increased interest in the development and manufacture of 3D-printed
therapeutic drugs since a 3D-printed tablet was approved by the US Food and Drug
Administration (Prasad and Smyth, 2016). 3D-printed drugs may meet needs unmet by
demand may contribute to the field of personalized medicine (Sandler and Preis, 2016).
each patient exhibits a different biological response, such as drug metabolism and toxicity,
due to gene polymorphism (Mannino and Sesti, 2012; Stingl and Viviani, 2015; Zhang et al.,
2017) and deteriorating hepatic and renal function due to aging (Tan et al., 2015). The design
of a customizable drug tablet formulation whose release is carefully controlled for individual
patients and its generation on-demand using a 3D printer would aid effective implementation
compliance to treatment and thus would be cost effective (Choonara et al., 2016).
There are many types of 3D printers, such as stereolithographic, powder bed, powder
jetting, selective laser sintering, semi-solid extrusion, and fused deposition modeling (FDM)
(Alhnan et al., 2016). The use of 3D printers for pharmaceutical applications remains limited
3
structure by spraying a binder solution onto powder has been used for the preparation of
3D-printed fast melt formulations (Boudriau et al., 2016; Yu et al., 2009a; Yu et al., 2009b).
On the other hand, FDM is a popular and cost-effective type of 3D printer for domestic use.
FDM-type 3D printers use polymer filaments as printer ink. The polymers, such as polylactic
acid (PLA) and acrylonitrile butadiene styrene, are melted by heating, extruded from the
nozzle as ink, and then laminated on the printer stage to produce a 3D object.
water and is commonly used as the supporting material for 3D products. PVA-based tablets
prepared using a FDM-type 3D printer have recently been reported (Goyanes et al., 2014;
Goyanes et al., 2015a; Long et al., 2016; Skowyra et al., 2015). PVA has favorable properties,
such as biocompatibility, and thus has been used for biomedical and pharmaceutical
applications (e.g., contact lenses, synthetic tear eye-drops, surgical sponges, and drug delivery
systems and tablet excipients) (Gaaz et al., 2015; Muppalaneni and Omidian, 2013). PVAs
have been used as excipients (e.g. stabilizer, solubilizer, base, binder, coating agent, sugar
coating, adhesive, thickener, etc.), and PVAs are listed in United States Pharmacopeia,
bio-friendly polymer is used in biomedical fields (Bergström and Hayman, 2016). PLA which
is derived from lactic acid, naturally organic acid is biodegradative. PLA has been used for
4
sutures, stents, drug delivery system, and tissue engineering scaffold. Other 3D printing
filaments, for example containing the polymer Eudragit, have recently found pharmaceutical
printer (Tagami et al., 2017). The printing conditions were important for good formability of
the tablets and several parameters, such as printing temperature and flow rate, affected the
diameter, thickness and weight of the resulting tablets. The present study aimed to extend the
possible applications of 3D-printed tablets and thus tablets were prepared using a 3D printer
equipped with dual nozzles. The dual nozzle head can extrude two types of samples in
preparation to produce “composite tablets”. Composite tablets should support various drug
release profiles. For example, polypills containing multiple drugs were designed as composite
tablets providing different release profiles for different drugs (Khaled et al., 2015). However,
there is little information about the preparation of composite tablets by using 3D printer. In
this study, we focused on the fabrication of 3D-printed composite tablets consisting of a drug
and a filler component to control drug release. PVA, a water-soluble polymer, and PLA, a
water-insoluble polymer, were used as the polymer filler components. There are few studies
that focused on the use of fillers with different properties for the preparation of composite
tablets by using FDM-type 3D printer as far as we know. The characteristics of the composite
5
tablets and the dissolution profiles of the drug (calcein) were investigated.
2.1. Regents
from Dojindo Laboratories, Inc. (Kumamoto, Japan). PVA (Gohsenol EG-05P, Nippon
Synthetic Chemical Industry Co., Ltd., Osaka, Japan).) was used to prepared PVA-filament.
PVA filament with or without calcein (1.75 mm) was obtained by using twin screw extruder
(L/D ratio = 60, screw diameter = 15 mm) from Nippon Synthetic Chemical Industry Co., Ltd.
(Osaka, Japan). The experimental condition was following: Temperature pattern, C1/ C2/ C3/
C4/ C5/ C6/ C7/ C8/ D = 90/ 120/ 180/ 190/ 200/ 200/ 200/ 205/ 210°C; rate of extrusion
amount, 1.5kg/hr. The calcein-PVA filament was prepared using a hot melt extruder. PLA
Shizuoka, Japan) as described in our previous report, with modifications (Tagami et al., 2017).
Briefly, the structure of the composite tablets was designed using 123D Design 3D CAD
software (Autodesk Inc., San Rafael, CA, USA). The printing parameters were set by using
6
slicer software (Cura 3D printing slicing software; Ultimaker; Geldermalsen, the Netherlands).
The printing condition was the same for both filaments and nozzles: printing temperature,
190°C; bed temperature, 60°C; print speed, 20 mm/s; flow, 120%; fill density, 100%; layer
height, 0.2 mm. The ends of the calcein-loaded PVA filament, and PVA filament or PLA
filament, were set in each nozzle head of the 3D printer and the dual nozzle produced tablets
under the control of the 3D printing host software (Pronterface; GNU General Public
License).
The mean diameter and thickness of each composite tablet was measured using a
digital caliper (Niigata Seiki Co., Ltd; Niigata, Japan) as described previously (Tagami et al.,
2017). In brief, the diameter and thickness at three random points on each tablet were
measured and the average value was taken as the mean diameter and mean thickness. The
Sangyo; Osaka, Japan) as described previously, with modifications (Tagami et al., 2017). In
brief, the vessels were filled with 500 ml of water and their temperature was maintained at
7
37°C. Then, the tablets were placed in the vessels and stirred with a paddle at 250 rpm. This
relatively high-speed stirring allowed 1) vigorous stirring of tablets and dissolution of tablets
from all direction and 2) decreased measuring time. At appropriate times, samples were
withdrawn and transferred to wells of a 96-well plate. Fluorescence was measured using a
Wallac 1420 ARVO plate reader (PerkinElmer, Inc., Waltham, MA, USA; ex. 355 nm, em.
535 nm) (Fuse et al., 2018). Calcein-PVA filament was dissolved in water, and the solution
was used to generate a calibration curve. The dissolution rate (mg/min) was calculated by
Co., Ltd., Tokyo, Japan). Samples of PVA, calcein-PVA and PVA filament were pulverized for
the analysis. Calcein powder samples supplied from manufacturer were used without
treatment. The samples were scanned from 2θ = 3° to 45° using CuKα radiation.
Japan). Samples (2-3 mg) were accurately weighed, put in an aluminum pan, and crimped
with a cover for DSC analysis. Heat scan was conducted from 30°C to 300°C at 10°C/min.
8
3. Results and Discussion
At the beginning of study, Vvarious composite tablets were designed using 3D CAD
software (Fig. 1A). In this study, Eight kinds of calcein-loaded PVA/PVA composite tablets
and four kinds of calcein-loaded PVA/PLA tablets were designed using the 3D printer.
cCalcein was used both as a fluorescence marker and a model drug. The drug was
pre-incorporated into water-soluble PVA. We designed the tablets with simple designs which
have different surface areas experimentally. The information of surface area of calcein-PVA
was described in Table 1. The composite tablets were designed to have a drug
component/filler component ratio of 2/3 (v/v). The proportion of drug component and filler
component was fixed to allow comparison of drug dissolution, as shown below. Then, two
types of polymers (PVA and PLA) were used as the filler component for the tablets. PVA will
likely prevent dissolution of the drug component by physical blocking but this blockage will
decrease with time due to its water-soluble property. In contrast, PLA is a water-insoluble
polymer and degrades slowly (over several months) (Lasprilla et al., 2012) and was used as a
coating that can completely exclude water. If PVA/PLA composite tablets were administrated,
drug-PVA component would be dissolved in alimentary tract, and PLA component would be
discharged by bowel movement finally. PLA is a bio-friendly resin used in biomedical fields
9
The appearance of the composite tablets is shown in Figure 1B. Eight kinds of
calcein-loaded PVA/PVA composite tablets and four kinds of calcein-loaded PVA/PLA tablets
were generated using the 3D printer. Formability was evaluated by measuring the mean
diameter, thickness and weight of the tablets (Table 1). Despite their different designs, the
composite tablets typically had the intended shape. The composite tablets were designed to
have a drug component/filler component ratio of 2/3 (v/v). The proportion of drug component
and filler component was fixed to allow comparison of drug dissolution, as shown below.We
observed various drug release profiles from the various designs of composite tablets
fabricated using a 3D printer (Fig. 2A & B). We also investigated the relationship between
initial drug release rate and surface area of the exposed calcein-PVA in the composite tablets
(Table 1) and plotted the relationship (Fig. 2C). A proportional relationship was obtained
0.9164).
Goyanes et al. fabricated different shapes of 3D-printed PVA tablets (cube, pyramid,
cylinder, sphere and torus) containing paracetamol (Goyanes et al., 2015b). They reported that
the five tablets had the same surface area, surface area/volume ratio, or weight, yet showed
different drug dissolution profiles. Additionally, the same group reported a 3D-printed PVA
10
tablet with high porosity that quickly released drugs (fluorescein (Goyanes et al., 2014) and
aminosalicylic acid (Goyanes et al., 2015a)). During dissolution, tablets with high porosity
likely have a larger surface area, facilitating drug dissolution. Goyanes et al. also mentioned
that dissolution of PVA, a water-soluble polymer that swells, could affect both drug
dissolution and structure characteristics of the tablets. Similar factors could be at play with the
composite tablets prepared in the present study. In our case, we further found that the surface
area of the drug component clearly affected initial drug release (Fig. 2C). The use of a filler
component could simplify the relationship between drug release and surface area.
Next, the relationship between the surface area of the exposed drug component and
drug dissolution was confirmed. Here, we used simplified composite tablets in which the
exposed drug component retained a constant surface area during drug dissolution. Tablets
were prepared with different top surface areas of the exposed drug component (12π, 16π, 20π,
and 24π mm2) while the bottom side was coated with PLA (Fig. 3A). The amount of released
drug was dependent on the surface area of the drug component (Fig. 3B): as the surface area
increased, the amount of released drug increased, showing proportionality between the surface
area of the exposed drug component and dissolution rate (Fig. 3C). We then confirmed that
the surface area of the exposed drug component was reflected in the drug dissolution rate. The
drug dissolution rate was very similar for all groups (zero-order drug release, Fig. 3D).
11
Zero-order drug release is useful for delivering the drug at a constant release rate. Elaborate
drug formulation design is typically required using various technologies (e.g., Geomatrix®,
Smartrix®, VersaTab®) (Moodley et al., 2012) to achieve a constant release rate from
conventional tablets. Composite tablets with similar designs (drug component core and a PVA
layer on each side) also appears to show zero-order-like drug release (Fig. 1A, Fig. 1B, and
Fig. 2A; composite tablet B) when fabricated using a 3D printer. We prepared composite
tablets exhibiting zero-order drug release by combining a simplified design with 3D printer
drug-PVA/PLA filler composite tablets providing different exposed surface areas during drug
dissolution. As shown in Figure 4A, the top side of the tablet comprised the drug and the
other side was surrounded with PLA filler. Tablets whose exposed surface area of drug
component decreased with time released drug faster than tablets whose overall surface area
decreased increased (Fig. 4B). A plot of the relationship between drug dissolution rate and
time (Fig. 4C) showed that the drug dissolution rate decreased linearly for a tablet whose
surface area decreased linearly, while the drug dissolution rate increased linearly for a tablet
whose surface area increased linearly. These results showing a linear change in dissolution
rate demonstrated that the composite tablets exhibited the desired drug release characteristics.
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Drug-PVA/PLA composite tablets with a changing drug release rate were designed to
change the surface area of exposed calcein-PVA with time during dissolution (Fig. 5).
Compared with the tablet design shown in Fig. 4, these tablets were designed so that the
exposed surface area on the top side dramatically changed with time (Fig. 5A). A composite
tablet in which the surface area of the exposed drug component decreased initially released
drug quickly and then more gradually, while a tablet whose surface area increased released
drug at a constant rate, except near the end of the experiment (Fig. 5B). The relationship
between drug dissolution rate and time is shown in Fig. 5C. The drug dissolution rate of
composite tablets whose surface area decreased initially rapidly decreased, then decreased
slowly with large deviations. In contrast, the drug release rate of tablets whose surface area
increased remained essentially constant, then tended to increase rapidly (one data point was
an outlier). The observed variation in the data is probably due to water inefficiently dissolving
the PVA component near the end of the experiment due to its location deep in the PLA
component.
Sun et al. prepared 3D-printed composite tablets with varying drug release rates and
with pulsed drug release rates by using three types of polymers (Sun and Soh, 2015). They
first prepared a mold for forming composite tablets using a poured polymer solution.
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Although the method is time consuming and requires complex steps, including a
UV-irradiation step, the resulting tablets exhibiting desired drug release characteristics hold
promise for tailor-made drugs. Thus, if an FDM-type 3D printer equipped with multiple
nozzle heads (≥ 3 nozzles) were used, it might be possible to prepare tablets showing more
Composite tablets with different lag times for drug release were prepared (Fig. 6).
Such tablets could be useful for releasing drugs at appropriate times and at desired sites, such
as the lower gastrointestinal tract. For example, pH sensitivity, osmotic stress, and a polymer
coating have been used to control the timing of drug release from conventional tablets. In our
study, 3D-printed composite tablets were produced by surrounding the drug compartment
with a PVA shell of different thicknesses (Fig. 6A; 0 mm thick as bare calcein-PVA tablet, and
1 mm and 2 mm thick). These tablets started to release drug at different time points (Fig. 6B)
(0 mm thick, 27.6 ± 2.2%, at 15 min; 1 mm thick, 28.3 ± 6.5%, at 60 min; 2 mm thick, 20.7 ±
8.9%, at 105 min). The relationship between drug dissolution and the time of drug release was
plotted (Fig. 6C). The peak drug dissolution rates were 15 min (0 mm), 75 min (1 mm), and
135 min (2 mm). Composite tablets with a 2-mm-thick shell of PVA filler showed drug
release comparable to that of tablets with a 1-mm-thick shell, perhaps due to the 3D printing
14
Composite tablets with similar shapes have been fabricated using conventional
technologies. These tablets aim to provide programmed drug delivery (i.e., chronotherapy)
(Moodley et al., 2012). We fabricated composite tablets containing drug in one step by using a
where a caplet is a capsule-shaped tablet) (Goyanes et al., 2015c) and showed that the inner
caplet containing caffeine released drug with a lag time whereas the outer layer containing
The XRPD pattern of calcein, PVA filament, calcein-PVA filament, and PLA filament
was shown as physical property (Fig. 7A). The result of calcein suggested that the
crystallinity of calcein was weak. The marked peak derived from calcein was not found in
calcein-PVA. One of the reason is that melted calcein was incorporated into PVA as solid
dispersion. DSC pattern of calcein, PVA filament, calcein-PVA filament, and PLA filament
was shown in Figure 7B. In this case, the temperature below 300ºC was scanned because
endothermic peak was found around 100ºC, which means the peak derived from water. The
melting point of calcein was 200 ºC from the literature (Sabnis. 2010), but the endothermic
peak was not found around the temperature. This could be due to the low crystallinity of
15
calcein (Fig. 7A). In contrast, Calcein which is a derivative of fluorescein has melting point
more than 300ºC (from the information of manufacturer’s page). The exothermic peak was
observed around 210ºC in calcein sample, which may suggest the crystallization of calcein.
Regarding calcein-PVA sample, the pattern of calcein PVA was vary similar to that of PVA.
The results suggested that amorphous state of calcein may be incorporated into PVA filament.
4. Conclusion
a PVA or PLA filler component were characterized by using FDM-type 3D printer with
double head nozzles. Our finding is that tThe use of a polymer filler component was effective
in controlling drug release. The composite tablets showed the various drug release profile not
only by using PVA filler as water-soluble and time-limiting filler and but also by using PLA
filler as poorly water-soluble and stable filler. The surface area of the exposed drug
component was closely related with the drug release rate and was an important factor for
controlling drug release from various designs of composite tablets. 3D printing technology
can create various composite tablets on demand, and composite tablets with different release
characteristics for different drugs will be useful in the future for individualized therapy. Our
16
Declaration of Conflict of Interest
composite tablets and (B) Calcein-loaded PVA/PLA composite tablets. Composite tablets 10
mm in diameter and 5 mm thick were designed. Data are the mean ± SD (n=5).
(A)
Diameter (%) Thickness (%) Weight (mg) Surface area of Initial release
(B)
Diameter (%) Thickness (%) Weight (mg) Surface area of Initial release
17
K 102.3 ± 1.4 98.0 ± 0.6 489.9 ± 5.1 62.8 0.8
Figure Legends
Composite tablets designed using 3D CAD software. (B) Photos of 3D-printed composite
means calcein-PVA, while aqua blue component means PVA filler (actual printed color,
Fig. 2. Dissolution drug profiles from various designs of composite tablets. (A) Drug release
composite tablets. (C) Relationship between the surface area of exposed calcein-PVA in the
tablets and their dissolution rate during the first 30 min. The design and appearance of each
type of composite tablet is shown in Fig. 1. Data are the mean ± SD (n=5).
Fig. 3. Calcein-PVA/PLA composite tablets with zero-order drug release. (A) 3D-designed
composite tablets with different surface area of the exposed drug component (12π, 16π, 20π,
and 24π mm2). (B) The amount of calcein-PVA released from the composite tablets. (C) The
18
relationship between the surface area of the exposed drug component and the dissolution rate.
(D) Drug release profiles of the composite tablets. Data are the mean ± SD (n=5).
Fig. 4. Calcein-PVA/PLA composite tablets with constantly changing drug release rates. (A)
3D-designed composite tablets with an increasing or decreasing surface area of exposed drug
component. (B) Drug release profiles of the composite tablets. (C) The relationship between
dissolution rate and dissolution time of the tablets. Data are the mean ± SD (n=5).
Fig. 5. Calcein-PVA/PLA composite tablets with rapidly changing drug release rate. (A)
3D-designed composite tablets with an increasing or decreasing surface area of exposed drug
component. (B) Drug release profiles of the composite tablets. (C) The relationship between
dissolution rate and dissolution time of the tablets. Data are the mean ± SD (n=5).
Fig. 6. Calcein-PVA/PVA composite tablets with a drug release lag time. (A) 3D-designed
composite tablets coated with a PVA shell of different thickness (0 mm, 1 mm and 2 mm). (B)
Drug release profiles of the composite tablets. (C) The relationship between dissolution rate
and dissolution time of the tablets. Data are the mean ± SD (n=5).
Fig. 7. XRPD and thermal analysis. (A) XRPD patterns and (B) DSC peaks of calcein, PVA,
19
calcein-PVA, and PLA.
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Tagami et al., Fig. 1
(A)
(B)
Calcein-loaded PVA/PVA composite tablet
Calcein-loaded PVA/PLA
composite tablet
25
Tagami et al., Fig. 2
(A)
(B)
(C)
26
Tagami et al., Fig. 3
(A) (B)
SA=12π SA=16π
SA=20π SA=24π
(C) (D)
27
Tagami et al., Fig. 4
(A)
Tablet with increasing SA
(B)
(C)
28
Tagami et al., Fig. 5
(A)
Tablet with increasing SA
(B)
(C)
29
Tagami et al., Fig. 6
(A)
0 mm
(no PVA coating) 1 mm
2 mm
(B)
(C)
30
Tagami et al., Fig. 7
(A)
Calcein
PVA
Calcein-PVA
PLA
(B)
Calcein
PVA
Calcein-PVA
PLA
31
Tagami et al., Graphical Abstract
32