Accepted Manuscript

Defined drug release from 3D-printed composite tablets consisting of drug-loa-

ded polyvinylalcohol and a water-soluble or water-insoluble polymer filler

Tatsuaki Tagami, Noriko Nagata, Naomi Hayashi, Emi Ogawa, Kaori

Fukushige, Norihito Sakai, Tetsuya Ozeki

PII: S0378-5173(18)30204-7
DOI: https://doi.org/10.1016/j.ijpharm.2018.03.057
Reference: IJP 17400

To appear in: International Journal of Pharmaceutics

Received Date: 27 November 2017

Revised Date: 26 March 2018
Accepted Date: 28 March 2018

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

polyvinylalcohol and a water-soluble or water-insoluble polymer filler

Authors: Tatsuaki Tagami1, Noriko Nagata1, Naomi Hayashi1, Emi Ogawa1, Kaori

Fukushige1,†, Norihito Sakai2, and Tetsuya Ozeki1*

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,

Osaka 530-0018, Japan.

†
Current address: Department of Anatomy, Aichi Medical University, 1-1 Yazakokarimata,

Nagakute, Aichi 480-1195, Japan.

*Corresponding Author: Tetsuya Ozeki, PhD

Tel: +81-52-836-3463; Fax: +81-52-836-3464; E-mail: ozekit@phar.nagoya-cu.ac.jp

Keywords: Composite tablet, Controlled release, Fused deposition modeling (FDM)-type 3D

printer, Polylactic acid (PLA), Polyvinylalcohol (PVA), 3D-printed therapeutic drug.

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

using a fused deposition modeling-type 3D printer. Polyvinylalcohol (PVA) polymer

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,

respectively. Various kinds of drug-PVA/PVA and drug-PVA/PLA composite tablets were

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

conventional mass-produced drugs. For example, the production of 3D-printed drugs on

demand may contribute to the field of personalized medicine (Sandler and Preis, 2016).

Individual patients have diverse drug pharmacokinetics/pharmacodynamics profiles because

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

of individualized therapy. Patient-friendly 3D-printed therapeutics can improve patient

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

to several types of printers. Powder-based 3D printing technology that can produce a 3D

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.

Polyvinylalcohol (PVA) is a water-soluble polymer that can be washed out with

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,

European Pharmacopoeia, and Japanese pharmaceutical excipients. PLA which is a

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

application (Pietrzak et al., 2015; Sadia et al., 2016).

We recently reported the preparation of PVA-based tablets using an FDM-type 3D

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. Materials and Methods

2.1. Regents

Calcein (Bis[N, N-bis(carboxymethyl)-aminomethyl] fluorescein) was purchased

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

filament (1.75 mm) was purchased from Polymaker (Shanghai, China).

2.2. Preparation of 3D-printed composite tablets

The tablets were prepared using an FDM-type 3D printer (FDM-200W, NinjaBot,

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).

2.3. Formability of 3D-printed composite tablets

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

weight of each tablet was measured using an electronic balance.

2.4. Dissolution profiles of the 3D-printed composite tablets

Drug dissolution was evaluated using a dissolution apparatus (NTR-6200A; Toyama

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

subtracting the amount of dissolved calcein-PVA at each time point.

2.5. X-ray powder diffraction (XRPD)

XRPD patterns were obtained by using X-ray diffractometer (Rint-Ultima, Rigaku

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.

2.6. Differential Scanning Calorimetry (DSC)

Thermal analysis was performed by using a Shimadzu DSC-50 (Shimadzu, Kyoto,

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

(Lasprilla et al., 2012).

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

(calcein-PVA/PVA composite tablets, R2 = 0.9162; calcein-PVA/PLA composite tablets, R2 =

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

fabrication (Fig. 3).

To extend the application of composite tablets with PLA filler, we designed

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.

12
 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.

13
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

reproducible drug release profiles.

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

resulting in slight heterogeneity in the thickness of the PVA shell.

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

3D printer. Another group prepared a 3D-printed PVA-based DuoCaplet (caplet in caplet,

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

paracetamol released drug immediately.

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

FDM-type 3D printer is operated below 300ºC typically. Regarding calcein sample,

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

In conclusion, 3D-printed composite tablets consisting of a drug-PVA component and

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

present results will help extend the applications of 3D-printed therapeutics.

16
Declaration of Conflict of Interest

The authors declare no conflicts of interest.

Table 1. Characteristics of 3D-printed composite tablets. (A) Calcein-loaded PVA/PVA

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

calcein-PVA (mm2) rate (mg/min)

A 99.6 ± 1.8 97.5 ± 0.8 468.1 ± 10.8 141.4 1.6

B 99.7 ± 1.8 98.0 ± 1.7 461.3 ± 21.1 62.8 0.9

C 100.5 ± 2.5 95.5 ± 1.0 466.5 ± 8.7 141.4 1.3

D 102.9 ± 1.3 97.4 ± 2.7 479.1 ± 24.8 133.5 1.5

E 102.0 ± 1.5 98.3 ± 2.2 487.8 ± 8.0 125.7 1.2

F 100.6 ± 1.6 97.6 ± 1.5 474.4 ± 12.8 62.8 0.4

G 100.2 ± 0.9 98.3 ± 2.5 474.8 ± 14.8 219.9 2.7

H 100.7 ± 1.0 98.6 ± 1.1 464.7 ± 21.8 0 0.1

(B)

Diameter (%) Thickness (%) Weight (mg) Surface area of Initial release

calcein-PVA (mm2) rate (mg/min)

I 102.2 ± 2.1 93.7 ± 1.2 465.0 ± 3.3 133.4 1.4

J 103.2 ± 1.0 97.2 ± 2.8 474.9 ± 4.6 125.7 1.7

17
K 102.3 ± 1.4 98.0 ± 0.6 489.9 ± 5.1 62.8 0.8

L 102.5 ± 1.6 96.5 ± 1.1 462.1 ± 4.8 12.6 0.2

Figure Legends

Fig. 1. Calcein-loaded PVA/PVA composite tablets and calcein-PVA/PLA tablets. (A)

Composite tablets designed using 3D CAD software. (B) Photos of 3D-printed composite

tablets 10 mm in diameter and 5 mm thick. Red component of 3D designed-composite tablets

means calcein-PVA, while aqua blue component means PVA filler (actual printed color,

translucent white) and PLA filler (actual printed color, white).

Fig. 2. Dissolution drug profiles from various designs of composite tablets. (A) Drug release

profiles of calcein-PVA/PVA composite tablets. (B) Drug release profiles of calcein-PVA/PLA

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)

Calcein-loaded PVA/PVA composite tablet

Calcein-loaded PVA/PLA composite tablet

(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

Tablet with decreasing SA

(B)

(C)

28
Tagami et al., Fig. 5
(A)
Tablet with increasing SA

Tablet with decreasing 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

The design of 3D printing composite tablets

for future tailor-made medicine

Drug/PLA filler composite tablets with Drug/PVA filler composite

zero-order and varying drug release tablets with lag time

32