You are on page 1of 33

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

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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

powder bed. and fused deposition modeling (FDM) (Alhnan et al. the production of 3D-printed drugs on demand may contribute to the field of personalized medicine (Sandler and Preis. Powder-based 3D printing technology that can produce a 3D 3 . semi-solid extrusion. powder jetting. Patient-friendly 3D-printed therapeutics can improve patient compliance to treatment and thus would be cost effective (Choonara et al. 2015. 2016). 2016). For example. Stingl and Viviani. such as stereolithographic. Individual patients have diverse drug pharmacokinetics/pharmacodynamics profiles because each patient exhibits a different biological response.. 2012. 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. Zhang et al.. 2016).1. due to gene polymorphism (Mannino and Sesti. There are many types of 3D printers. such as drug metabolism and toxicity. 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).. 2017) and deteriorating hepatic and renal function due to aging (Tan et al. 3D-printed drugs may meet needs unmet by conventional mass-produced drugs.. selective laser sintering. The use of 3D printers for pharmaceutical applications remains limited to several types of printers. 2015).

Muppalaneni and Omidian. PLA has been used for 4 . European Pharmacopoeia. The polymers.structure by spraying a binder solution onto powder has been used for the preparation of 3D-printed fast melt formulations (Boudriau et al. PVA has favorable properties. and Japanese pharmaceutical excipients.. FDM-type 3D printers use polymer filaments as printer ink. PVAs have been used as excipients (e. 2009b)..g. and drug delivery systems and tablet excipients) (Gaaz et al. sugar coating. 2015..). 2016. etc. 2013). Skowyra et al. and PVAs are listed in United States Pharmacopeia. are melted by heating.. Yu et al. 2015). extruded from the nozzle as ink. synthetic tear eye-drops. contact lenses. coating agent. surgical sponges. FDM is a popular and cost-effective type of 3D printer for domestic use. 2016). Goyanes et al. 2014. solubilizer. naturally organic acid is biodegradative. such as polylactic acid (PLA) and acrylonitrile butadiene styrene. 2015a. thickener. PVA-based tablets prepared using a FDM-type 3D printer have recently been reported (Goyanes et al. 2009a... PLA which is derived from lactic acid. adhesive. 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. 2016. base. and then laminated on the printer stage to produce a 3D object. stabilizer. binder. On the other hand.g... Long et al. and thus has been used for biomedical and pharmaceutical applications (e.. such as biocompatibility. PLA which is a bio-friendly polymer is used in biomedical fields (Bergström and Hayman. Yu et al.

The dual nozzle head can extrude two types of samples in preparation to produce “composite tablets”. We recently reported the preparation of PVA-based tablets using an FDM-type 3D printer (Tagami et al. The characteristics of the composite 5 . 2015.. However. For example. stents. thickness and weight of the resulting tablets. 2017). polypills containing multiple drugs were designed as composite tablets providing different release profiles for different drugs (Khaled et al. In this study.. for example containing the polymer Eudragit. and PLA. such as printing temperature and flow rate. a water-insoluble polymer. affected the diameter. 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 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. Sadia et al. The printing conditions were important for good formability of the tablets and several parameters. we focused on the fabrication of 3D-printed composite tablets consisting of a drug and a filler component to control drug release. and tissue engineering scaffold.. there is little information about the preparation of composite tablets by using 3D printer. 2015). Other 3D printing filaments. drug delivery system. PVA. Composite tablets should support various drug release profiles..sutures. were used as the polymer filler components. a water-soluble polymer. 2016). have recently found pharmaceutical application (Pietrzak et al.

Regents Calcein (Bis[N.. PVA (Gohsenol EG-05P. CA. Ltd. (Kumamoto. rate of extrusion amount. N-bis(carboxymethyl)-aminomethyl] fluorescein) was purchased from Dojindo Laboratories. Inc. The printing parameters were set by using 6 . Japan).tablets and the dissolution profiles of the drug (calcein) were investigated.. Shizuoka. the structure of the composite tablets was designed using 123D Design 3D CAD software (Autodesk Inc.. 2. The calcein-PVA filament was prepared using a hot melt extruder. Japan). 2. The experimental condition was following: Temperature pattern.75 mm) was obtained by using twin screw extruder (L/D ratio = 60. China).5kg/hr.75 mm) was purchased from Polymaker (Shanghai. PVA filament with or without calcein (1. (Osaka. Nippon Synthetic Chemical Industry Co. USA). Osaka. Japan). 1.1. San Rafael. Preparation of 3D-printed composite tablets The tablets were prepared using an FDM-type 3D printer (FDM-200W. Materials and Methods 2. Japan) as described in our previous report. screw diameter = 15 mm) from Nippon Synthetic Chemical Industry Co. PLA filament (1. Ltd. with modifications (Tagami et al. 2017). Briefly. NinjaBot. C1/ C2/ C3/ C4/ C5/ C6/ C7/ C8/ D = 90/ 120/ 180/ 190/ 200/ 200/ 200/ 205/ 210°C.2...) was used to prepared PVA-filament.

2. Japan) as described previously. The ends of the calcein-loaded PVA filament. 120%.. 190°C.4. bed temperature. layer height. In brief. Niigata. 2017).3. Dissolution profiles of the 3D-printed composite tablets Drug dissolution was evaluated using a dissolution apparatus (NTR-6200A. Osaka. the vessels were filled with 500 ml of water and their temperature was maintained at 7 . The printing condition was the same for both filaments and nozzles: printing temperature. Geldermalsen. with modifications (Tagami et al. Ultimaker. fill density. 0. The weight of each tablet was measured using an electronic balance. GNU General Public License). 100%. print speed.. 60°C. Formability of 3D-printed composite tablets The mean diameter and thickness of each composite tablet was measured using a digital caliper (Niigata Seiki Co.. 2017). 20 mm/s. the Netherlands). and PVA filament or PLA filament. Ltd.slicer software (Cura 3D printing slicing software. flow. 2. 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. 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. Japan) as described previously (Tagami et al. In brief. Toyama Sangyo.2 mm.

. Japan). Calcein powder samples supplied from manufacturer were used without treatment.6. This relatively high-speed stirring allowed 1) vigorous stirring of tablets and dissolution of tablets from all direction and 2) decreased measuring time. The dissolution rate (mg/min) was calculated by subtracting the amount of dissolved calcein-PVA at each time point. Samples (2-3 mg) were accurately weighed. Ltd. calcein-PVA and PVA filament were pulverized for the analysis. and crimped with a cover for DSC analysis.37°C. Heat scan was conducted from 30°C to 300°C at 10°C/min. Calcein-PVA filament was dissolved in water. 2018). Waltham.5.. the tablets were placed in the vessels and stirred with a paddle at 250 rpm. Japan). 2. 2.. and the solution was used to generate a calibration curve.. Kyoto. MA. Then. Inc. ex. samples were withdrawn and transferred to wells of a 96-well plate. USA. The samples were scanned from 2θ = 3° to 45° using CuKα radiation. X-ray powder diffraction (XRPD) XRPD patterns were obtained by using X-ray diffractometer (Rint-Ultima. 535 nm) (Fuse et al. At appropriate times. Differential Scanning Calorimetry (DSC) Thermal analysis was performed by using a Shimadzu DSC-50 (Shimadzu. Samples of PVA. put in an aluminum pan. Fluorescence was measured using a Wallac 1420 ARVO plate reader (PerkinElmer. em. 355 nm. Tokyo. Rigaku Co. 8 .

We designed the tablets with simple designs which have different surface areas experimentally. The composite tablets were designed to have a drug component/filler component ratio of 2/3 (v/v). Eight kinds of calcein-loaded PVA/PVA composite tablets and four kinds of calcein-loaded PVA/PLA tablets were designed using the 3D printer. Vvarious composite tablets were designed using 3D CAD software (Fig. two types of polymers (PVA and PLA) were used as the filler component for the tablets. 2012). The drug was pre-incorporated into water-soluble PVA. Results and Discussion At the beginning of study. If PVA/PLA composite tablets were administrated. cCalcein was used both as a fluorescence marker and a model drug. as shown below. In contrast. In this study. 1A).3. The proportion of drug component and filler component was fixed to allow comparison of drug dissolution. PLA is a bio-friendly resin used in biomedical fields (Lasprilla et al. The information of surface area of calcein-PVA was described in Table 1. 9 . 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. and PLA component would be discharged by bowel movement finally. 2012) and was used as a coating that can completely exclude water.. Then. PLA is a water-insoluble polymer and degrades slowly (over several months) (Lasprilla et al. drug-PVA component would be dissolved in alimentary tract..

surface area/volume ratio. The composite tablets were designed to have a drug component/filler component ratio of 2/3 (v/v). yet showed different drug dissolution profiles.We observed various drug release profiles from the various designs of composite tablets fabricated using a 3D printer (Fig. The appearance of the composite tablets is shown in Figure 1B. cylinder. Goyanes et al. or weight.9162. Despite their different designs. 2A & B)..9164). the same group reported a 3D-printed PVA 10 . R2 = 0. Additionally. Formability was evaluated by measuring the mean diameter. 2C). pyramid. fabricated different shapes of 3D-printed PVA tablets (cube. the composite tablets typically had the intended shape. thickness and weight of the tablets (Table 1). R2 = 0. 2015b). sphere and torus) containing paracetamol (Goyanes et al. as shown below. 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. They reported that the five tablets had the same surface area. calcein-PVA/PLA composite tablets. The proportion of drug component and filler component was fixed to allow comparison of drug dissolution. Eight kinds of calcein-loaded PVA/PVA composite tablets and four kinds of calcein-loaded PVA/PLA tablets were generated using the 3D printer. A proportional relationship was obtained (calcein-PVA/PVA composite tablets.

the amount of released drug increased. we used simplified composite tablets in which the exposed drug component retained a constant surface area during drug dissolution. tablets with high porosity likely have a larger surface area. We then confirmed that the surface area of the exposed drug component was reflected in the drug dissolution rate.tablet with high porosity that quickly released drugs (fluorescein (Goyanes et al. a water-soluble polymer that swells. we further found that the surface area of the drug component clearly affected initial drug release (Fig. Next. 3B): as the surface area increased. 3D). 20π. 2015a)). 16π. Goyanes et al. facilitating drug dissolution. Tablets were prepared with different top surface areas of the exposed drug component (12π. showing proportionality between the surface area of the exposed drug component and dissolution rate (Fig. The drug dissolution rate was very similar for all groups (zero-order drug release. During dissolution.. Fig. the relationship between the surface area of the exposed drug component and drug dissolution was confirmed. 3A). 2014) and aminosalicylic acid (Goyanes et al. Here. The use of a filler component could simplify the relationship between drug release and surface area. and 24π mm2) while the bottom side was coated with PLA (Fig. 2C). In our case.. 3C). also mentioned that dissolution of PVA. The amount of released drug was dependent on the surface area of the drug component (Fig. could affect both drug dissolution and structure characteristics of the tablets. 11 . Similar factors could be at play with the composite tablets prepared in the present study.

. 2012) to achieve a constant release rate from conventional tablets. we designed drug-PVA/PLA filler composite tablets providing different exposed surface areas during drug dissolution. 4B). A plot of the relationship between drug dissolution rate and time (Fig.Zero-order drug release is useful for delivering the drug at a constant release rate. 1A. Geomatrix®. 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.g. These results showing a linear change in dissolution rate demonstrated that the composite tablets exhibited the desired drug release characteristics.. We prepared composite tablets exhibiting zero-order drug release by combining a simplified design with 3D printer fabrication (Fig. To extend the application of composite tablets 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. VersaTab®) (Moodley et al. Elaborate drug formulation design is typically required using various technologies (e. Fig. the top side of the tablet comprised the drug and the other side was surrounded with PLA filler. 2A. 4C) showed that the drug dissolution rate decreased linearly for a tablet whose surface area decreased linearly. 1B. and Fig. As shown in Figure 4A. 12 . while the drug dissolution rate increased linearly for a tablet whose surface area increased linearly. composite tablet B) when fabricated using a 3D printer. Smartrix®. 3).

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. A composite tablet in which the surface area of the exposed drug component decreased initially released drug quickly and then more gradually. 5B). then tended to increase rapidly (one data point was an outlier). 2015). The relationship between drug dissolution rate and time is shown in Fig. while a tablet whose surface area increased released drug at a constant rate. They first prepared a mold for forming composite tablets using a poured polymer solution. 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. the drug release rate of tablets whose surface area increased remained essentially constant. except near the end of the experiment (Fig. Compared with the tablet design shown in Fig. Sun et al. then decreased slowly with large deviations. The drug dissolution rate of composite tablets whose surface area decreased initially rapidly decreased. 13 . these tablets were designed so that the exposed surface area on the top side dramatically changed with time (Fig. 4. 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. In contrast. 5C. 5). 5A).

3D-printed composite tablets were produced by surrounding the drug compartment with a PVA shell of different thicknesses (Fig.7 ± 8. including a UV-irradiation step. at 105 min). it might be possible to prepare tablets showing more reproducible drug release profiles. at 15 min.3 ± 6. pH sensitivity. at 60 min.5%. Such tablets could be useful for releasing drugs at appropriate times and at desired sites. 1 mm thick. For example. the resulting tablets exhibiting desired drug release characteristics hold promise for tailor-made drugs. 14 . 6C). 2 mm thick. 6).Although the method is time consuming and requires complex steps. 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.9%.6 ± 2.2%. These tablets started to release drug at different time points (Fig. such as the lower gastrointestinal tract. The peak drug dissolution rates were 15 min (0 mm). The relationship between drug dissolution and the time of drug release was plotted (Fig. 27. 20. Composite tablets with different lag times for drug release were prepared (Fig. 6A. if an FDM-type 3D printer equipped with multiple nozzle heads (≥ 3 nozzles) were used. 75 min (1 mm). 28. and a polymer coating have been used to control the timing of drug release from conventional tablets. In our study. perhaps due to the 3D printing resulting in slight heterogeneity in the thickness of the PVA shell. Thus. osmotic stress. and 135 min (2 mm). 0 mm thick as bare calcein-PVA tablet. and 1 mm and 2 mm thick). 6B) (0 mm thick.

2012). PVA filament.. 2015c) and showed that the inner caplet containing caffeine released drug with a lag time whereas the outer layer containing paracetamol released drug immediately. Composite tablets with similar shapes have been fabricated using conventional technologies.. the temperature below 300ºC was scanned because FDM-type 3D printer is operated below 300ºC typically. and PLA filament was shown in Figure 7B. and PLA filament was shown as physical property (Fig. The XRPD pattern of calcein. PVA filament. calcein-PVA filament. DSC pattern of calcein. Regarding calcein sample. which means the peak derived from water. where a caplet is a capsule-shaped tablet) (Goyanes et al. 7A).. The melting point of calcein was 200 ºC from the literature (Sabnis. In this case. We fabricated composite tablets containing drug in one step by using a 3D printer. These tablets aim to provide programmed drug delivery (i. The result of calcein suggested that the crystallinity of calcein was weak. One of the reason is that melted calcein was incorporated into PVA as solid dispersion. The marked peak derived from calcein was not found in calcein-PVA. calcein-PVA filament. but the endothermic peak was not found around the temperature.e. Another group prepared a 3D-printed PVA-based DuoCaplet (caplet in caplet. endothermic peak was found around 100ºC. chronotherapy) (Moodley et al. This could be due to the low crystallinity of 15 . 2010).

calcein (Fig. 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. Our present results will help extend the applications of 3D-printed therapeutics. 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. In contrast. the pattern of calcein PVA was vary similar to that of PVA. 3D printing technology can create various composite tablets on demand. 4. Calcein which is a derivative of fluorescein has melting point more than 300ºC (from the information of manufacturer’s page). Regarding calcein-PVA sample. 7A). The results suggested that amorphous state of calcein may be incorporated into PVA filament. and composite tablets with different release characteristics for different drugs will be useful in the future for individualized therapy. Conclusion In conclusion. Our finding is that tThe use of a polymer filler component was effective in controlling drug release. which may suggest the crystallization of calcein. The exothermic peak was observed around 210ºC in calcein sample. 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. 16 .

2 487.8 ± 8.9 ± 4.8 0 0.0 ± 1.8 133.7 ± 21.1 62.8 62.8 468.7 461.4 ± 2.4 1.7 141.5 ± 1.5 95.1 464.4 J 103.2 ± 0.2 ± 2.8 ± 14.7 1.7 479.1 (B) Diameter (%) Thickness (%) Weight (mg) Surface area of Initial release calcein-PVA (mm2) rate (mg/min) I 102.5 ± 2.3 D 102.3 ± 21.6 ± 1.6 ± 1. (A) Diameter (%) Thickness (%) Weight (mg) Surface area of Initial release calcein-PVA (mm2) rate (mg/min) A 99.7 1.5 E 102.3 133.6 97.5 1.2 465.8 0.6 125.8 97.5 474.0 97.0 ± 3.3 ± 2.1 93.2 F 100.5 474.3 ± 2.3 97.0 98.4 G 100.5 ± 0.5 ± 8. Composite tablets 10 mm in diameter and 5 mm thick were designed.0 466.9 C 100.8 219. Table 1.2 ± 1.6 ± 1.4 ± 12.7 ± 1.9 98.Declaration of Conflict of Interest The authors declare no conflicts of interest.0 125. Data are the mean ± SD (n=5). Characteristics of 3D-printed composite tablets.6 B 99. (A) Calcein-loaded PVA/PVA composite tablets and (B) Calcein-loaded PVA/PLA composite tablets.4 1.7 17 .6 ± 1.8 98.0 ± 1.2 ± 2.8 141.9 ± 1.9 2.7 ± 1.1 ± 24.8 474.7 H 100.4 1.8 0.1 ± 10.5 98.7 ± 1.

8 L 102. and 24π mm2). 1. Fig. while aqua blue component means PVA filler (actual printed color.6 96. (B) Drug release profiles of calcein-PVA/PLA composite tablets. (B) The amount of calcein-PVA released from the composite tablets.1 462.5 ± 1.4 98.8 12.6 0.3 ± 1. Calcein-loaded PVA/PVA composite tablets and calcein-PVA/PLA tablets. (C) Relationship between the surface area of exposed calcein-PVA in the tablets and their dissolution rate during the first 30 min.9 ± 5. 20π.5 ± 1. (A) Composite tablets designed using 3D CAD software.2 Figure Legends Fig. 3.8 0. Fig. (A) 3D-designed composite tablets with different surface area of the exposed drug component (12π.1 62. (C) The 18 . (A) Drug release profiles of calcein-PVA/PVA composite tablets. (B) Photos of 3D-printed composite tablets 10 mm in diameter and 5 mm thick. Calcein-PVA/PLA composite tablets with zero-order drug release. Red component of 3D designed-composite tablets means calcein-PVA.0 ± 0.1 ± 4. The design and appearance of each type of composite tablet is shown in Fig. translucent white) and PLA filler (actual printed color.K 102. Data are the mean ± SD (n=5).6 489. Dissolution drug profiles from various designs of composite tablets. white). 16π. 1. 2.

PVA. (A) 3D-designed composite tablets coated with a PVA shell of different thickness (0 mm.relationship between the surface area of the exposed drug component and the dissolution rate. 7. (B) Drug release profiles of the composite tablets. Data are the mean ± SD (n=5). Fig. (A) 3D-designed composite tablets with an increasing or decreasing surface area of exposed drug component. (A) XRPD patterns and (B) DSC peaks of calcein. Data are the mean ± SD (n=5). (C) The relationship between dissolution rate and dissolution time of the tablets. (A) 3D-designed composite tablets with an increasing or decreasing surface area of exposed drug component. Fig. (C) The relationship between dissolution rate and dissolution time of the tablets. 19 . Calcein-PVA/PLA composite tablets with rapidly changing drug release rate. Data are the mean ± SD (n=5). (C) The relationship between dissolution rate and dissolution time of the tablets. 6. Fig. 4. (B) Drug release profiles of the composite tablets. Calcein-PVA/PLA composite tablets with constantly changing drug release rates. (B) Drug release profiles of the composite tablets. Calcein-PVA/PVA composite tablets with a drug release lag time. XRPD and thermal analysis. 1 mm and 2 mm). (D) Drug release profiles of the composite tablets. Fig. 5. Data are the mean ± SD (n=5).

2016.E.. Al-Amiery. Gaaz. Kadhum.. T.B. 2016.. Effective light-triggered contents release from helper lipid-incorporated liposomes co-encapsulating gemcitabine and a water-soluble photosensitizer. 1817-1832. Massicotte.. A.. K. Hanzel.. T.. Drugs R D 16. Pharm Res 33. S. P. T. Arafat. Emergence of 3D Printed Dosage Forms: Opportunities and Challenges.. Wan. Randomized Comparative Bioavailability of a Novel Three-Dimensional Printed Fast-Melt Formulation of Levetiracetam Following the Administration of a Single 1000-mg Dose to Healthy Human Volunteers Under Fasting and Fed Conditions.. Pillay.. Ahmed. W.. Tane.. Kondiah. Tagami. J.calcein-PVA. 23-32. Int J Pharm 540. 229-238. M. An Overview of Mechanical Properties and Material Modeling of Polylactide (PLA) for Medical Applications.N. Fuse. Sulong. B.. References Alhnan.W. Bergström J. Y. Boudriau.A.. Wang.A. A... P... Okwuosa. and PLA.. Mohamad.. Akhtar. L. Kumar. A. L. T. Sadia. Ozeki. 330-40. Choonara..B. du Toit.P. M. M.. Hayman D. T. 2016.. 3D-printing and the effect on medical costs: a new era? Expert Rev Pharmacoecon Outcomes Res 16.C. 20 . Sayegh. 50-56..S. 2018.. Lefebvre. Ann Biomed Eng 44. M.S. C. 2016.. J.. V. M.A... A.C.

2016. S. Buanz. R. A. 4077-4084... C. Martinez.. 3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. Curr Pharm Des. Hatton.J.. J. Martinez-Pacheco.W.. A. H. C..J. 2014. A... Telford. Filho. A. Wang. Basit. 2015c. Int J Pharm 476.W.H.L. 657-663. 3D Printing of Medicines: Engineering Novel Oral Devices with Unique Design and Drug Release Characteristics. 2012.. Yang. A. Biotechnol Adv 30. Khaled. A. Lasprilla. B. Goyanes... 2015b. Lu. Halloysite Nanotubes and Their Nanocomposites. Long....A. Gaisford. Basit.. A. J. S. Buanz..... Poly-lactic acid synthesis for application in biomedical devices . Basit. Mol Pharm 12. A. A. Gaisford. Properties and Applications of Polyvinyl Alcohol. Lunelli. Review: Application of Fused Deposition Modelling (FDM) Method of 3D Printing in Drug Delivery.2015. J. A. 3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles.. Robles Martinez.. S.R. Effect of geometry on drug release from 3D printed tablets.. P. Gaisford. Alexander. R..C.A. R.a review. Goyanes. 88-92. Fused-filament 3D printing (3DP) for fabrication of tablets.B. Eur J Pharm Biopharm 89. S.. J Control Release 217. Jardini.. Bunt. A. 308-314. A. Basit.B. G. S... A.. Burley. 321-328.W.. A.M. Goyanes.. 21 . 22833-22847. 2015. Int J Pharm 494. 157-162.. Buanz. A. J. Seyfoddin.. J... Roberts. G... 2015a.W. Molecules 20. Gaisford. Goyanes. Gholizadeh. M. Buanz.B.

G. R.C..A. M. Smyth.Mannino. 2010.... J Develop Drugs 2... M. L.. Isreb.. Bawa.. W. Mol Diagn Ther 16.A. Pillay. Kumar. M.W.. Alhnan.. K. M... Drug Dev Ind Pharm 42. 2016. Prasad. 2015. S. 1070-1080... 2016. A John Wiley & Sons.C. Alhnan.... V. Preis.A. A. p71.. Eur J Pharm Biopharm 96. Int J Pharm 513. 659-668. Pietrzak. 18-43. 2013. Handbook of biological dyes and stains: Synthesis and industrial applications.. L. 1019-1031. Moodley.. V. 3D Printing technologies for drug delivery: a review. H. A. A. H. Kelarakis. P. S. du Toit.. K. Skowyra.. A flexible-dose dispenser for immediate and extended release 3D printed tablets. 2012. Pietrzak. K.K. Sadia.. P. M.. J. Individualized therapy for type 2 diabetes: clinical implications of pharmacogenetic data. Fabrication of extended-release 22 . Adaptation of pharmaceutical excipients to FDM 3D printing for the fabrication of patient-tailored immediate release tablets. 2012. 1000112. Y. Sesti. 2016. Cooppan.. Int J Mol Sci 13. Printed Drug-Delivery Systems for Improved Patient Treatment. B. 380-387... Ahmed. N. Sabnis. Inc. Muppalaneni. Omidian.. A. Sandler. G. Choonara. Alhnan. Oral drug delivery systems comprising altered geometric configurations for controlled drug delivery. Sosnicka. Ndesendo. 2015. Arafat.. Isreb. Trends Pharmacol Sci 37.E. 285-302. Polyvinyl alcohol in medicine and pharmacy: a perspective..M.

Drugs Aging 32.G. Y. Biol Pharm Bull 40.. X..M. Y. Yang. Branford-White. 167-177..... Li. 2015. Age-Related Changes in Hepatic Function: An Update on Implications for Drug Therapy.X.M. Poudel.. Zhu. Ozeki.E. Pharmacokinetic and Pharmacodynamic 23 . J Pharm Pharmacol 61.W.. R. L. 2017.. E.. 1530-1536. Welbeck. J. D. Soh.. Yu. Hubbard. T. 2015.P. White. K.L.J. 7847-7853. Shen.. Tagami. Y. L. in the metabolism of psychotropic drugs. T. 2009b. Eur J Pharm Sci 68. 2015. C.. D.. Hayashi. J..G. Tan.P. M. Chen. Yu. X.. C. Stingl.L. members of the cytochrome P450 mixed-function oxidase system. K. 3D Printing Factors Important for the Fabrication of Polyvinylalcohol Filament-Based Tablets. 11-17.. Yang. J. Zhu. Zhang. Printing tablets with fully customizable release profiles for personalized medicine... Drug Dev Ind Pharm 35....C. S. Tang. J Intern Med 277. Yang.. 2009a.G... Sun. 323-329. A novel fast disintegrating tablet fabricated by three-dimensional printing.L.. E. A. Eastment. X.. Ogawa. J. Branford-White.. Advanced Materials 27. 357-364. Novel oral fast-disintegrating drug delivery devices with predefined inner structure fabricated by Three-Dimensional Printing. R. 2017. 999-1008.. Viviani.patient-tailored prednisolone tablets via fused deposition modelling (FDM) 3D printing. X. Polymorphism in CYP2D6 and CYP2C19. Fukushige. N.

Int J Environ Res Public Health 14.Responses to Clopidogrel: Evidences and Perspectives. 24 .

. 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.

Tagami et al. 2 (A) (B) (C) 26 .. Fig.

3 (A) (B) SA=12π SA=16π SA=20π SA=24π (C) (D) 27 .Tagami et al. Fig..

Tagami et al.. 4 (A) Tablet with increasing SA Tablet with decreasing SA (B) (C) 28 . Fig.

Fig. 5 (A) Tablet with increasing SA Tablet with decreasing SA (B) (C) 29 ..Tagami et al.

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 .. Fig.Tagami et al.

.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 .