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Design and characterization of a novel 3D printed pressure-controlled drug delivery system
Journal Pre-proof Design and characterization of a novel 3D printed pressurecontrolled drug delivery system
Julius Krause, Malte Bogdahn, Felix Schneider, Mirko Koziolek, Werner Weitschies PII:
S0928-0987(19)30331-8
DOI:
https://doi.org/10.1016/j.ejps.2019.105060
Reference:
PHASCI 105060
To appear in:
European Journal of Pharmaceutical Sciences
Received date:
13 September 2018
Revised date:
17 July 2019
Accepted date:
29 August 2019
Please cite this article as: J. Krause, M. Bogdahn, F. Schneider, et al., Design and characterization of a novel 3D printed pressure-controlled drug delivery system, European Journal of Pharmaceutical Sciences(2019), https://doi.org/10.1016/j.ejps.2019.105060
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© 2019 Published by Elsevier.
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Design and characterization of a novel 3D printed pressure-controlled drug delivery system Julius Krause, Malte Bogdahn, Felix Schneider, Mirko Koziolek, Werner Weitschies* University of Greifswald, Institute of Pharmacy, Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport, Felix-Hausdorff-
Prof. Dr. Werner Weitschies
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* Corresponding author:
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Str. 3, D-17487 Greifswald, Germany
Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption
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and Transport, University of Greifswald, Greifswald, Germany Felix-Hausdorff-Str. 3, D-17487 Greifswald, Germany Tel +49 3834 4204813
[email protected]
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Abstract The aim of the present work was to explore the feasibility of 3D printing via fused deposition modeling (FDM) in the manufacturing of a pressure-controlled drug delivery system. Eudragit® RS, a brittle polymer with pH-independent solubility, was chosen to be a suitable excipient for the 3D printing of a pressure-sensitive, capsule-like dosage form. A selfconstructed piston extruder was used for hot melt extrusion (HME) of filaments made from Eudragit® RS that could be used for 3D printing. Subsequently, the printing parameters were experimentally optimized with the aid of a self-programmed software. This G-code generator allowed the simple adjustment of printing speed, temperature, extrusion multiplier and layer
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height. By this, capsule-shaped dosage forms with the desired mechanical properties could be
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obtained. The effect of physiological pressure events on the drug release behaviour from the novel dosage form was finally tested by using a biorelevant stress test device. These in vitro
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experiments demonstrated the rapid and quantitative release of the probe drug after applying realistic pressure events. This work illustrated that 3D printing can be an interesting technique
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for the production of pressure-controlled dosage forms as a new concept of oral drug delivery.
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1. Introduction The targeted delivery of orally administered drugs to specific sites of the human gastrointestinal (GI) tract can offer various advantages over conventional drug delivery such as increased oral bioavailability or reduced local side effects. The underlying formulation concepts are typically based on physiological parameters or phenomena specific for a certain region of the GI tract such as luminal pH, enzymatic activity or transit time. In the past, research was mainly focused on the targeted delivery of drugs to the colon (colon targeting) whilst the targeting to the upper intestine was often overlooked although it may
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provide certain advantages for oral pharmacotherapy (Barakat et al., 2011; Hu et al., 2000; Jeong et al., 2001). At the moment, passive diffusion is assumed to be the main driver of
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absorption for the majority of drugs. Thus, achieving high drug concentrations in the small intestine at the main site of absorption should result in better absorption and thus, increased
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oral bioavailability. However, the luminal concentration of a drug in the upper small intestine
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is hardly predictable as it is the result of the interplay of various processes. These include dosage form disintegration and drug dissolution, gastric emptying, intestinal peristalsis,
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distribution of luminal fluids in the small intestine, presence of efflux transporters as well as oral, gastric and intestinal secretions (Higaki et al., 2008; Mudie et al., 2010; Mudie et al.,
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2014; Nokhodchi and Asare-Addo, 2014; Schiller et al., 2005; Steingoetter et al., 2006; Weitschies et al., 2005). In case of conventional dosage forms, for which disintegration and
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drug dissolution occurs mainly in the stomach, the easiest way to increase the luminal drug concentration for a certain formulation would be to reduce the amount of co-administered fluid. The lower the volume of co-administered fluid, the higher is the luminal concentration (Koziolek et al., 2016). Even though this approach may seem to be a valid strategy to increase luminal concentrations in the small intestine, one should note that the co-administered fluid is also important for esophageal transit of the dosage form, disintegration and dissolution as well as for gastric emptying (Weitschies et al., 2005). Thus, the volume of co-administered fluid should not be changed arbitrarily and reliable formulation strategies are needed. For pharmaceutical scientists, the most obvious approach would be the application of an entericcoated dosage form. An enteric coating is typically based on a polymer with a pH-dependent solubility, which shall prevent drug release in the stomach. Upon emptying from the stomach into the duodenum, drug release is triggered by the rapid increase in luminal pH. This concept works nicely in vitro, but in reality the limited availability of fluids in the upper small intestine causes a lag time of drug release due to delayed disintegration and/or dissolution (Schiller et al., 2005). Additionally, the transit through the duodenum is very rapid and thus,
Journal Pre-proof the drug has already passed the site that provides optimum conditions for drug release (Yuen, 2010). This approach is therefore not suitable for drug targeting of the proximal small intestine. In a recent publication, Wilde and colleagues described the development of a pressuresensitive drug delivery system that shall release small volumes of a highly concentrated drug solution directly into the small intestine (Wilde et al., 2014a; Wilde et al., 2014b). The trigger for drug release into the duodenum is the high pressure in the antropyloric region. In a recent SmartPill® study we could show that these pressures can be up to 500 mbar and that their occurrence is closely linked with gastric emptying (Koziolek et al., 2015; Schneider et al.,
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2016). The pressure-sensitive capsules were made from triglycerides and filled with a liquid
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solution of the drug. It was the idea that during gastric emptying, the high pressures cause rupture of the capsule shell and thus, to release the liquid content. The suitability of this
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concept was confirmed in vitro with the aid of the dissolution stress test device, an in vitro tool that enables the simulation of gastrointestinal pressures for biorelevant dissolution testing
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(Garbacz et al., 2008). The major drawback of this novel drug delivery system is the
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complexity of its production and the resulting poor reproducibility. Nonetheless, Wilde and co-workers could demonstrate that the applied pharmaceutical excipients were suitable for the
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production of a pressure-controlled drug delivery system. The aim of this study was to produce pressure-controlled dosage forms by 3D printing as this
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technology was expected to enable a fast and reproducible development of objects with desired properties. For this purpose, we used fused deposition modeling (FDM) technique as one of the most common 3D printing techniques for pharmaceutical applications. In FDM, a thermoplastic filament is moved into a heated nozzle which is movable in three dimensions relative to a build plate. The polymer is then molten and applied layer by layer until a threedimensional object results. FDM was already applied in pharmaceutical technology for the production of tablets containing multiple drugs, of capsules with pulsatile drug release as well of personalized implants (Kempin et al., 2017; Khaled et al., 2015; Melocchi et al., 2015). In the present work, the pressure-controlled drug delivery system should be produced by using filaments of Eudragit® RS for 3D printing. The use of Eudragit® RS as polymer for 3D printing was already examinated by Kempin and colleagues (Kempin et al., 2017). For this study, Eudragit® RS was chosen due to its water insoluble properties, its pH independent swelling properties and the low permeability. After assessing the optimal printing parameters, the drug release behavior of the 3D printed dosage forms should be tested under biorelevant conditions with the aid of the modified dissolution stress test device.
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2. Materials and methods 2.1 Materials Acetaminophen and mannitol were purchased from Caelo (Hilden, Germany). Fumed silica was obtained from Fagron (Barsbüttel, Germany). Eudragit® RS 100 (granule) was gratefully donated by Evonik (Essen, Germany). 2.2 Methods 2.2.1 Preparation of the filaments Filaments of Eudragit® RS were produced using a self-constructed extruder. It consisted of a
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barrel and a piston. The barrel was heatable using resistance wire (diameter 0.3 mm,
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6.93 Ω/m, BLOCK Transformatoren-Elektronik GmbH, Germany) controlled by a temperature sensor (Fluke multisensor detector 179, Fluke Cooperation, USA). The piston
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could be moved forward via a stepper motor (NANOTEC PD4-N60, Nanotec GmbH & Co. KG, Germany) connected to a drive screw. For extrusion of Eudragit® RS filaments the
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polymer granules were transferred into the barrel of the piston extruder and heated to 120 °C.
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The molten polymer was extruded through a round nozzle (diameter 3 mm) and stretched afterwards. The stretching was automatically done using a second stepper motor turning a spool. A string connected to the spool was attached to the extrudate. By this, the extrudate
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was drawn at constant speed in direction of the spool. The speed of both stepper motors was set via the software NanoProV version 2.71. The speed was adjusted so that an approximate
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filament diameter of 2.85 mm resulted. 2.2.2 Filament characterization
The diameter of the produced filament was determined every 10 mm by use of a digital caliper (Powerfix, Kompernass Handels GmbH, Germany, accuracy ±0.02 mm). Furthermore, the filament strands were controlled visually to discard those containing gas bubbles or other impurities. For this purpose, a reflected-light microscope was used (Zeiss Stemi 2000-C with light source Zeiss CL 1500 ECO, camera Zeiss AxioCam and AxioVision software, all Carl Zeiss Microscopy GmbH, Germany). 2.2.3 3D printing 3D printing was performed using a modified Mendel Max 2.5 (German RepRap GmbH, firmware Marlin, Germany). Various modifications were necessary to enable the printing of the brittle Eudragit® RS filament. For instance, the use of the standard feeder resulted in the breakage of the strands during the forward movement. This was avoided by placing the
Journal Pre-proof strands into a straight, rigid tube that was connected to the hot end of the 3D printer. As can be seen from Figure 1, commercially available polylactic acid (PLA) filament was also fed into the tube via a bulldog extruder XL (Reprapdiscount Yang, China) in order to push the Eudragit® RS filament into the hot end. The nozzle diameter was either 0.25 mm or 0.4 mm. Scotch tape (type 2090, 3M Germany GmbH, Germany) was used for better adhesion of the
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printed objects.
Figure 1. Schematic representation of the 3D printer (A: build plate; B: printed dosage form; C: nozzle; D: hot end; E: water cooling system; F: filament input; Green: Eudragit® RS filament; Blue: driving filament).
2.2.3.1 Optimization of the printing parameters In order to determine the optimal printing temperature and speed for Eudragit® RS filament, single line walls with a height 30 mm and a wide of 30 mm were printed at different temperatures (160 °C, 165 °C, 170 °C, 175 °C and 180 °C). Furthermore, the effect of printing speeds (400 mm/min, 600 mm/min and 800 mm/min) was assessed. The usage of print bed heating was not necessary. The resulting objects were investigated for optical defects (e.g. gas bubbles, unattached layers) using a reflected-light microscope (Zeiss Stemi
Journal Pre-proof 2000-C with light source Zeiss CL 1500 ECO, camera Zeiss AxioCam and AxioVision software, all Carl Zeiss Microscopy GmbH, Germany). 2.2.3.2 3D printing of pressure-controlled drug delivery systems In common 3D printing workflow, the G-code will be generated by dedicated software by dedicated slicing software. The contour of a computer-aided design (CAD) model will be imported as an STL file which only describes the surface of the object by means of vertices forming a triangle mesh. The contour will be divided in horizontal parts corresponding to the targeted layer height and the slicing software calculates the toolpath for the perimeter as well for the infill for each layer. Simultaneously the amount of material needed to print the object
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is determined. This information is translated into G-code. Since the slicing software has no
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information about the application and the intended function of the printed structure the G-
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code will be optimized for low printing time and mechanical strength. Due to these limitations, the G-code for the 3D printing process was generated by a self-
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written Python script (Figure 2).
Figure 2. Picture of the self-programmed software (left: G-code-Generator with editable parameters; right: schematic drawing of the dosage form).
This allowed us to have full control over important printing parameters (e.g. temperature, layer height, printing speed, extrusion multiplier and thus extrusion rate). The capsule was printed in an upright position, so that the layers were oriented in parallel with the circular cross section of the cylinder. The capsule was printed single-walled and without any support structure or infill in order to obtain a pressure-sensitive object. To control the pressuresensitivity, the extrusion multiplier of the cylindrical part of the capsule was varied. By this, the amount of extruded polymer during the process of printing, i.e. the extrusion rate, was
Journal Pre-proof defined. The wall thickness was examined using a digital caliper. The usage of print bed heating was not necessary. The dimensions of the pressure-induced drug delivery system (height: 25.1 mm, diameter: 12.7 mm) were chosen to be equal to the SmartPill®, a telemetric capsule that is able to measure intraluminal temperature, pH and pressure during its gastrointestinal transit. Therefore, we were able to compare stresses experienced by a SmartPill® with the stresses experienced by the novel dosage form. 2.2.3.3 Assessment of the pressure sensitivity of the 3D printed systems
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Empty capsules were printed at different wall thicknesses to characterize their mechanical properties. To assess at which pressure the capsules break in vitro, a test setup based on the
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dissolution stress test device by Garbacz and colleagues (Garbacz et al., 2008; Garbacz et al.,
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2009) was developed (Figure 3). In brief, it consisted of a transparent shell in which the 3D printed capsule could be placed. The shell was closed by a cap which contained a balloon that
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was connected to a nozzle. Via the nozzle, pressurized air could be introduced, which inflated the balloon and led to realistic stresses on the tested object (Garbacz et al., 2008; Garbacz et
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al., 2009). At the test beginning the balloon was inflated with 200 mbar for 5 s and deflated again. Subsequently, we increased the pressure in steps of 50 mbar and repeated the
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aforementioned procedure until capsule break could be observed. All tests were performed in
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absence of liquid and in triplicate.
Figure 3. Test device for pressure-controlled drug delivery systems (Left: capsule before testing; middle: broken capsule after testing; right: pieces of the broken capsule).
Journal Pre-proof 2.2.4 Assessing the pressure-controlled drug delivery of the 3D printed systems The capsules were filled with 0.5 g of a powder mixture consisting of 5% (w/w) acetaminophen, 94.5% (w/w) mannitol and 0.5% (w/w) fumed silica to confirm successful pressure-controlled drug delivery. The acetaminophen represents a model drug that can be analyzed via UV/Vis spectrophotometry. For capsule filling the printer nozzle moved to a parking position after printing the convex bottom part and cylinder of the capsule. After powder filling, the printer continued the printing process from its last position and finished the capsule. For the in vitro drug dissolution testing under realistic gastrointestinal conditions in terms of pressures we used the dissolution stress test device. A thorough description of this
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device can be found elsewhere (Garbacz et al., 2008). As dissolution medium 1100 ml simulated gastric fluid sine pepsin (SGF sp) pH 1.2 at a temperature of 37 °C were used. The
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speed of the impeller was set to 75 rpm. To assure the homogeneity of the medium we
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additionally used a peristaltic pump (ISM404B, Ismatec, Germany) at a flow rate of 150 mL/min to circulate the fluid from the bottom of the vessel to the top. The analytics were
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done using an UV/Vis spectrophotometer (Varian Cary® 50 Bio UV/Vis Spectrophotometer, Agilent Technologies, USA) in combination with fiber optics (2 mm probe tips).
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Measurements were done at 243 nm every 2 min. The first 60 min no pressure events were applied to assess the permeability of the capsule shell. After this time, the balloon was
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inflated with 200 mbar for 5 s and deflated again. This procedure was repeated applying a pressure increased by 50 mbar until the maximum pressure of 500 mbar was reached or the
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breakage of all dosage forms could be observed. Data acquisition was done with the Cary WinUV software (Varian UV Dissolution Application Version 4.00). All tests were performed in triplicate.
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3. Results 3.1 Preparation and characterization of Eudragit® RS filaments The self-constructed piston extruder was suitable for the fabrication of filament containing Eudragit® RS. It was possible to produce filaments of homogenous quality with a diameter of approximately 2.7 mm that could be used in 3D printing. Extrusion temperatures around 120 °C proved to be appropriate for the filament preparation. Higher temperatures led to inhomogeneous filament with poor quality. Though the filament diameter was not uniform over the length of each fabricated filament, it was possible to select filament segments with low variations. Variations in the diameter of 0.05 mm were defined as the limiting value.
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3.2.1 Optimization of the printing parameters
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Filaments with greater variations were excluded from farther testing.
The optimization of the printing process was successfully carried out by printing single line
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walls at variable printing speed and printing temperature. Figure 4 shows exemplary microscopic images of the printed single line walls. Unevenly aligned layers could be
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detected in the microscopic images as well as strings facing outwards. Irregular arranged whitish spots were visible and indicated insufficient bonding. A printing temperature of
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170 °C led to uniform objects. It can be seen that all layers were stacked evenly. Neither defects between the layers nor hair like extensions of the individual layer were visible in the
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microscopic images. Process temperatures above 170 °C lead to thermal degradation of the used material and could be recognized by large whitish areas in the print as well as by disconnected layer. In the microscopic images, large gaps between the individual layers were observable.
Journal Pre-proof Figure 4. Microscopic image of the single layer objects as a function of the printing temperature (printing speed 800 mm/min; top row: close-up view 40x magnification; bottom row: overview 10x magnification).
3.2.2 3D printing of the pressure controlled drug delivery systems For the printing of the dosage forms, we used filament segments with uniform diameter and uniform appearance. The actual diameter was considered in the generation of the G-code. The self-programmed G-code generator was found useful for easy editing of the printing parameters and allowed a simple and transparent G-code generation. An optimization of the
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printer settings for every part of the capsule (bottom, cylinder and top) was necessary. In
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Figure 5, the process of optimizing the top is shown exemplarily.
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Figure 5. Optimization of the top (Red arrows indicate faults, 6,5x magnification).
In this case, more than 35 adjustments were necessary to finally obtain a closed top. The red
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arrows in Figure 5 indicate printing voids that could lead to permeable dosage forms. Mostly changed printing parameters were the printing speed, the extrusion multiplier that defines the amount of extruded material and the number of lines. For the sake of clarity, the exact printing parameters are not shown. After the optimization of the printing process of the capsule parts, the further printing parameters were optimized. Since the breakage of the dosage form depended on the cylindrical part of the capsule, only the printing parameters of this part were varied. 3.2.3 Assessment of the pressure sensitivity of the 3D printed systems By amendment of the printing parameters, fifteen batches could be manufactured. The corresponding properties are displayed in Table 1. By adjusting the printing parameters, capsules with different breaking behavior could be produced. Thereby, the obtained breaking pressures ranged from about 200 mbar up to 900 mbar.
Journal Pre-proof Table 1. Properties of pressure-sensitive capsules and the applied 3D printing conditions. Batch # Nozzle
1
2
3
4
5
6
7
8
9
10
11
12
0.4
0.4
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
2.5
2.4
0.2
0.25
0.3
0.4
0.2
0.21
0.225
0.3
0.2
0.225
0.5
0.5
800
800
(mm) Extrusion multiplier Layer
0.075 0.075 0.075 0.075 0.075 0.075 0.075 0.075 0.075 0.075
height (mm) Printing
400
400
400
400
400
400
800
800
0.404 0.364 0.342 0.387 0.393 0.492 0.327 0.335 0.362 0.393 0.338 0.336 ±
±
±
±
±
±
±
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(g)
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(mm/min) Weight
800
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speed
800
±
±
±
±
±
0.013 0.005 0.007 0.007 0.025 0.009 0.006 0.007 0.009 0.013 0.012 0.023 0.55
0.42
0.24
0.29
thickness
±
±
±
±
(mm)
0.04
0.02
0.02
0.02
Breaking
760
367
233
pressure
±
±
±
(mbar)
146
131
47
0.29
0.33
0.24
0.26
0.29
0.35
0.25
0.26
±
±
±
±
±
±
±
±
0.02
0.03
0.02
0.04
0.04
0.03
0.03
0.03
300
683
841
208
333
580
900
300
730
±
±
±
±
±
±
±
±
±
112
73
19
111
196
153
58
150
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Wall
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110
It can be seen from Figure 6 that the breaking pressures nicely correlates with the wall thickness. The wall thickness which depends on the extrusion multiplier is the determining parameter for the burst pressure.
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Figure 6. Breaking pressure of the 3D printed capsules depending on wall thickness for the batches 710 printed with a nozzle of 0.25 mm and a printing speed of 800 mm/min, but with varying extrusion
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multipliers.
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By adjusting the printing parameters of the cylindrical part, capsules with different mechanical properties could be produced. Since in later dissolution tests the reproducible
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tightness of the capsules could be doubted for the above stated printing properties, we further optimized the 3D printing process. Therefore, capsules from batches 13-15 were printed with
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the properties stated in Table 2 and led to the best results in dissolution stress tests (cfr. section 3.2.4). The printing properties were comparable to batches 1 and 2.
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Table 2. Critical breaking pressures for different batches measured in the modified dissolution stress test (printing parameters: 0.4 mm nozzle, layer height 0.075 mm, printing speed 800 mm/min). 13
14
15
1.525
1.55
1.6
Capsule 1
250
250
300
Capsule 2
300
250
450
Capsule 3
400
450
500
8.00
8.67
9.33
Batch #
Extrusion multiplier Breaking pressure (mbar)
t85% released (min)
Furthermore, we used the actual filament diameter from the measurements for the calculation of the extrusion multiplier for batches 13-15, which led to clearly reduced values. Comparing batches 13-15, it can be seen that an increased extrusion multiplier again led to increased breaking pressure.
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Figure 7 shows exemplary the dissolution profile from batch 13.
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Figure 7. Batch 13 - Cumulative release of Acetaminophen (0.4 mm nozzle, extrusion multiplier
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1.525, layer height 0.075 mm, printing speed 800 mm/min).
In this batch, the tested dosage forms showed no drug release within 60 min. After applying a
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pressure of 200 mbar, no drug release was observed. However, applying a pressure of 250 mbar caused the beginning of drug release in one capsule. Drug release from the other capsules started after applying 300 mbar and 400 mbar, respectively. All dosage forms released 85% of their content within 8 min after breaking.
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4. Discussion In this work, pressure-sensitive dosage forms as described recently by Wilde and co-workers were successfully produced from Eudragit® RS by 3D printing. Eudragit® RS was chosen as the wall material as it possesses ideal properties for the production of brittle capsule shells that are able to break at a certain pressure. Moreover, it shows a pH-independent swelling behavior and low permeability. Prior to 3D printing, filaments of Eudragit® RS were produced with the aid of a self-made hot melt extruder since commercial filaments of this polymer are not available. The use of Eudragit® RS for the production of filament for 3D printing has already been described by other groups (Kempin et al., 2017; Pietrzak et al.,
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2015; Yu et al., 2007). After optimizing the extrusion process, we were able to obtain
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filaments that could be used in 3D printing. These showed only small variations in terms of their diameter. Generally, a variation of maximum 5% is regarded as acceptable (Melocchi et
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al., 2015). Higher variation of the filament diameter can lead to non-homogenous prints
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(Zhang et al., 2017).
In order to be able to obtain dosage forms that break upon certain pressures, it was our
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primary task to optimize the printing parameters (e.g. printing temperature, printing speed). For 3D printing, a temperature of 170 °C was found to be optimal. However, at this
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temperature Eudragit® RS also starts to degrade (Parikh et al., 2014), which can cause gas bubbles to be formed in the hot end. These can interrupt the flow of molten material leaving
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the nozzle. By this, the contact between adjacent material strings is hampered and therefore, the proper formation of bonded connections is inhibited. The optimal printing temperature determined in these experiments was much higher than in comparable hot melt extrusion processes (Albarahmieh et al., 2016; Schilling et al., 2007; Wu and McGinity, 2003). A reason for this observation might be the absence of any plasticizer in the filaments as the addition of plasticizer like triethyl citrate would have resulted in filament that did not possess the optimal brittle properties. As opposed to temperatures above 170 °C lower printing temperatures led to insufficient layer bonding. In order to optically assess the printing process, single-line walls were printed at different temperatures. By using this simple geometry and high printing speeds, we could easily evaluate the optimal printing temperature for the 3D printing of the pressure-sensitive capsule shells. The rectangular shape also made it possible to characterize the test objects by optical methods. These experiments clearly revealed that the temperature had a dramatic effect on the properties of the printed objects.
Journal Pre-proof After defining the optimum printing temperature, the further printing parameters such as layer height, printing speed and extrusion multiplier were optimized. For this purpose, a selfwritten software tool was used. To our knowledge, this is the first study in pharmaceutics that does not use common slicing software for 3D printing of pharmaceutical dosage forms. The G-code generator enabled an easy adjustment of the printing parameters like printing speed, printing temperature or extrusion multiplier. A further advantage is the separate adaption of any part of the printed capsule so that the different parts can be printed with different parameters. The variations of the nozzle diameter or the extrusion multiplier enabled the printing of capsules with variable pressure sensitivity. The breaking pressure of the pressure-
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controlled dosage forms could be easily adjusted by changing the wall thickness of the capsules. In comparison to previous works by Wilde et al., this procedure was found to be
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faster and led to pressure controlled systems that are independent from the gastric transit time
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(Wilde et al., 2014a; Wilde et al., 2014b). In the works by Wilde et al. they produced coated hard fat spheres, which should melt at body temperature and leave a pressure sensitive
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cellulose acetate coating. Depending on the polymer load that was applied during coating they could determine the crushing strength of the drug release system. However, since the hard fat
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has to be melted, the fasted state intake of the system could lead to a rapid emptying into the duodenum along with insufficient pressure control of the drug release. Our approach to use
this issue.
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the highly reproducible process of FDM printing for prototyping of the capsules addressed
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Subsequently, drug-release from the pressure-controlled drug delivery system was evaluated under biorelevant conditions with the aid of a modified dissolution stress test device. In these tests, a gastric transit time of 1 h was simulated, which was followed by the simulation of gastric emptying. Earlier studies with the SmartPill® have shown that high pressures can arise during gastric emptying (Cassilly et al., 2008; Koziolek et al., 2015; Schneider et al., 2016). These high pressures (200 – 500 mbar) could be realistically simulated by the modified version of the stress test device (Garbacz et al., 2008; Garbacz et al., 2009). The applied modifications enabled a better distribution of the media in order to rapidly detect the release of acetaminophen. It should be noted that compendial dissolution test apparatuses cannot be used to demonstrate the suitability of this dosage form as they are not able to generate such high pressures (Schneider et al., 2017). In our tests, drug release before application of the pressures was not observed, but the simulation of realistic pressures caused release of the entire dose within a short time. This observation confirmed our hypothesis of a pressure-controlled drug release from this novel
Journal Pre-proof formulation. After breakage, the capsule shell disintegrated into many small particles and 85% of the probe drug acetaminophen was detected within 8 minutes. The content is probably released faster, but the dissolution of the powder mixture and the homogenous distribution of the acetaminophen in the medium took some time. In contrast to earlier publications by Wilde and colleagues which produced pressure-sensitive capsules using glyceryl tristearate, it was possible to control the breaking pressure of the capsule with the aid of the 3D printing process (Wilde et al., 2014a). In particular, the extrusion rate, defined by the extrusion multiplier, was found to be highly important. The more material was extruded per layer, the higher was the mean breaking pressure. Further
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experiments and improvement of the printing process will be necessary to manufacture
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capsules with homogenous breaking profiles. Such pressure-controlled dosage forms might bring benefits for drugs with a narrow absorption window like metformin, levodopa or
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acyclovir (Bardonnet et al., 2006; Davis, 2005; Murakami, 2017; Murphy et al., 2012). Pressure-controlled dosage forms filled with liquids of peptides or proteins could also be a
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possibility for drug delivery of proteins. Thereby, the drug is protected against proteases and a
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high concentrated solution can be released in the small upper intestine to probably improve absorption. Of course, to test this hypothesis in vivo experiments are necessary. Furthermore, the 3D printing as well as the extrusion process have to be further optimized. The variation of
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the pressure needed to break the capsules was higher than expected. To some extent these variations could be explained by variations in the filament diameter arising from the used
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extrusion process.
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5. Conclusion This work demonstrated the possibility of using 3D printing via fused deposition modeling for the fabrication of pressure-controlled dosage forms. Customized G-code generation enabled the printing of objects with an adjustable wall thickness without the need of support structures. By small variations of the extrusion rate via the extrusion multiplier, capsules with different mechanical properties could be obtained. Since a high uniformity in filament diameter is needed for reproducible 3D printing, the extrusion process was another critical process step for the production of this pressure-controlled drug delivery system. In this study, Eudragit® RS filament without any plasticizer was successfully manufactured by hot melt
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extrusion with the aid of a self-constructed piston extruder. The proof-of-concept was
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demonstrated by the application of a biorelevant stress test device that enabled dissolution testing under conditions realistic for the upper human GI tract. Physiological pressure events
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delivery concept.
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6. References Albarahmieh, E., Qi, S., Craig, D.Q.M., 2016. Hot melt extruded transdermal films based on amorphous solid dispersions in Eudragit RS PO: The inclusion of hydrophilic additives to develop moisture-activated release systems. International Journal of Pharmaceutics 514 (1), 270–281. Barakat, N.S., Al-Suwayeh, S.A., Taha, E.I., Bakry Yassin, A.E., 2011. A new pressure-controlled colon delivery capsule for chronotherapeutic treatment of nocturnal asthma. Journal of Drug Targeting 19 (5), 365–372. Bardonnet, P.L., Faivre, V., Pugh, W.J., Piffaretti, J.C., Falson, F., 2006. Gastroretentive dosage forms: Overview and special case of Helicobacter pylori. Journal of Controlled Release 111 (1-2),
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Cassilly, D., Kantor, S., Knight, L.C., Maurer, A.H., Fisher, R.S., Semler, J., Parkman, H.P., 2008. Gastric emptying of a non-digestible solid: assessment with simultaneous SmartPill pH and
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pressure capsule, antroduodenal manometry, gastric emptying scintigraphy. Neurogastroenterology and Motility 20 (4), 311–319.
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Davis, S.S., 2005. Formulation strategies for absorption windows. Drug discovery today 10 (4), 249–
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Garbacz, G., Golke, B., Wedemeyer, R.-S., Axell, M., Soderlind, E., Abrahamsson, B., Weitschies, W., 2009. Comparison of dissolution profiles obtained from nifedipine extended release once a
Sciences 38 (2), 147–155.
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day products using different dissolution test apparatuses. European Journal of Pharmaceutical
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Garbacz, G., Wedemeyer, R.-S., Nagel, S., Giessmann, T., Monnikes, H., Wilson, C.G., Siegmund, W., Weitschies, W., 2008. Irregular absorption profiles observed from diclofenac extended release tablets can be predicted using a dissolution test apparatus that mimics in vivo physical stresses. European Journal of Pharmaceutics and Biopharmaceutics 70 (2), 421–428. Higaki, K., Choe, S.Y., Lobenberg, R., Welage, L.S., Amidon, G.L., 2008. Mechanistic understanding of time-dependent oral absorption based on gastric motor activity in humans. European Journal of Pharmaceutics and Biopharmaceutics 70 (1), 313–325. Hu, Z., Mawatari, S., Shibata, N., Takada, K., Yoshikawa, H., Arakawa, A., Yosida, Y., 2000. Application of a biomagnetic measurement system (BMS) to the evaluation of gastrointestinal transit of intestinal pressure-controlled colon delivery capsules (PCDCs) in human subjects. Pharmaceutical Research 17 (2), 160–167. Jeong, Y.I., Ohno, T., Hu, Z., Yoshikawa, Y., Shibata, N., Nagata, S., Takada, K., 2001. Evaluation of an intestinal pressure-controlled colon delivery capsules prepared by a dipping method. Journal of Controlled Release 71 (2), 175–182.
Journal Pre-proof Kempin, W., Franz, C., Koster, L.-C., Schneider, F., Bogdahn, M., Weitschies, W., Seidlitz, A., 2017. Assessment of different polymers and drug loads for fused deposition modeling of drug loaded implants. European Journal of Pharmaceutics and Biopharmaceutics 115, 84–93. Khaled, S.A., Burley, J.C., Alexander, M.R., Yang, J., Roberts, C.J., 2015. 3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles. Journal of Controlled Release 217, 308–314. Koziolek, M., Grimm, M., Schneider, F., Jedamzik, P., Sager, M., Kuhn, J.-P., Siegmund, W., Weitschies, W., 2016. Navigating the human gastrointestinal tract for oral drug delivery: Uncharted waters and new frontiers. Advanced Drug Delivery Reviews 101, 75–88.
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Koziolek, M., Schneider, F., Grimm, M., Modebeta, C., Seekamp, A., Roustom, T., Siegmund, W., Weitschies, W., 2015. Intragastric pH and pressure profiles after intake of the high-caloric, high-
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fat meal as used for food effect studies. Journal of Controlled Release 220 (Pt A), 71–78.
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Melocchi, A., Parietti, F., Casati, F., Maroni, A., Gazzaniga, A., Zema, L., 2015. 3D printing by fused deposition modeling of capsular devices for oral pulsatile release based on swellable/erodible
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Mudie, D.M., Amidon, G.L., Amidon, G.E., 2010. Physiological parameters for oral delivery and in vitro testing. Molecular Pharmaceutics 7 (5), 1388–1405. Mudie, D.M., Murray, K., Hoad, C.L., Pritchard, S.E., Garnett, M.C., Amidon, G.L., Gowland, P.A.,
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Spiller, R.C., Amidon, G.E., Marciani, L., 2014. Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted state. Molecular Pharmaceutics 11
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(9), 3039–3047.
Murakami, T., 2017. Absorption sites of orally administered drugs in the small intestine. Expert opinion on drug discovery 12 (12), 1219–1232. Murphy, C., Pillay, V., Choonara, Y.E., Du Toit, L.C., Ndesendo, V.M.K., Chirwa, N., Kumar, P., 2012. Optimization of a dual mechanism gastrofloatable and gastroadhesive delivery system for narrow absorption window drugs. AAPS PharmSciTech 13 (1), 1–15. Nokhodchi, A., Asare-Addo, K., 2014. Drug release from matrix tablets: Physiological parameters and the effect of food. Expert Opinion on Drug Delivery 11 (9), 1401–1418. Parikh, T., Gupta, S.S., Meena, A., Serajuddin, A.T., 2014. Investigation of thermal and viscoelastic properties of polymers relevant to hot melt extrusion - III: Polymethacrylatesand polymethacrylic acid based polymers. Journal of Excipients and Food Chemicals 5 (1). Pietrzak, K., Isreb, A., Alhnan, M.A., 2015. A flexible-dose dispenser for immediate and extended release 3D printed tablets. European Journal of Pharmaceutics and Biopharmaceutics 96, 380–387.
Journal Pre-proof Schiller, C., Frohlich, C.-P., Giessmann, T., Siegmund, W., Monnikes, H., Hosten, N., Weitschies, W., 2005. Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging. Alimentary Pharmacology & Therapeutics 22 (10), 971–979. Schilling, S.U., Shah, N.H., Malick, A.W., Infeld, M.H., McGinity, J.W., 2007. Citric acid as a solidstate plasticizer for Eudragit RS PO. The Journal of Pharmacy and Pharmacology 59 (11), 1493– 1500. Schneider, F., Beeck, R., Hoppe, M., Koziolek, M., Weitschies, W., 2017. In vitro simulation of realistic gastric pressure profiles. European Journal of Pharmaceutical Sciences 107, 71–77. Schneider, F., Grimm, M., Koziolek, M., Modess, C., Dokter, A., Roustom, T., Siegmund, W.,
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Weitschies, W., 2016. Resolving the physiological conditions in bioavailability and bioequivalence studies: Comparison of fasted and fed state. European Journal of Pharmaceutics
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Steingoetter, A., Fox, M., Treier, R., Weishaupt, D., Marincek, B., Boesiger, P., Fried, M., Schwizer, W., 2006. Effects of posture on the physiology of gastric emptying: A magnetic resonance
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Weitschies, W., Kosch, O., Monnikes, H., Trahms, L., 2005. Magnetic Marker Monitoring: An application of biomagnetic measurement instrumentation and principles for the determination of the gastrointestinal behavior of magnetically marked solid dosage forms. Advanced Drug Delivery
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Wilde, L., Bock, M., Glockl, G., Garbacz, G., Weitschies, W., 2014a. Development of a pressure-
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sensitive glyceryl tristearate capsule filled with a drug-containing hydrogel. International Journal of Pharmaceutics 461 (1-2), 296–300. Wilde, L., Bock, M., Wolf, M., Glockl, G., Garbacz, G., Weitschies, W., 2014b. Development of pressure-sensitive dosage forms with a core liquefying at body temperature. European Journal of Pharmaceutics and Biopharmaceutics 86 (3), 507–513. Wu, C., McGinity, J.W., 2003. Influence of methylparaben as a solid-state plasticizer on the physicochemical properties of Eudragit RS PO hot-melt extrudates. European Journal of Pharmaceutics and Biopharmaceutics 56 (1), 95–100. Yu, D.G., Yang, X.L., Huang, W.D., Liu, J., Wang, Y.G., Xu, H., 2007. Tablets With Material Gradients Fabricated by Three-Dimensional Printing. Journal of Pharmaceutical Sciences 96 (9), 2446–2456. Yuen, K.-H., 2010. The transit of dosage forms through the small intestine. International Journal of Pharmaceutics 395 (1-2), 9–16.
Journal Pre-proof Zhang, J., Feng, X., Patil, H., Tiwari, R.V., Repka, M.A., 2017. Coupling 3D printing with hot-melt extrusion to produce controlled-release tablets. International Journal of Pharmaceutics 519 (1-2),
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Graphical abstract
Julius Krause, Malte Bogdahn, Felix Schneider, Mirko Koziolek, Werner Weitschies PII:
S0928-0987(19)30331-8
DOI:
https://doi.org/10.1016/j.ejps.2019.105060
Reference:
PHASCI 105060
To appear in:
European Journal of Pharmaceutical Sciences
Received date:
13 September 2018
Revised date:
17 July 2019
Accepted date:
29 August 2019
Please cite this article as: J. Krause, M. Bogdahn, F. Schneider, et al., Design and characterization of a novel 3D printed pressure-controlled drug delivery system, European Journal of Pharmaceutical Sciences(2019), https://doi.org/10.1016/j.ejps.2019.105060
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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.
© 2019 Published by Elsevier.
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Design and characterization of a novel 3D printed pressure-controlled drug delivery system Julius Krause, Malte Bogdahn, Felix Schneider, Mirko Koziolek, Werner Weitschies* University of Greifswald, Institute of Pharmacy, Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport, Felix-Hausdorff-
Prof. Dr. Werner Weitschies
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* Corresponding author:
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Str. 3, D-17487 Greifswald, Germany
Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption
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and Transport, University of Greifswald, Greifswald, Germany Felix-Hausdorff-Str. 3, D-17487 Greifswald, Germany Tel +49 3834 4204813
[email protected]
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Abstract The aim of the present work was to explore the feasibility of 3D printing via fused deposition modeling (FDM) in the manufacturing of a pressure-controlled drug delivery system. Eudragit® RS, a brittle polymer with pH-independent solubility, was chosen to be a suitable excipient for the 3D printing of a pressure-sensitive, capsule-like dosage form. A selfconstructed piston extruder was used for hot melt extrusion (HME) of filaments made from Eudragit® RS that could be used for 3D printing. Subsequently, the printing parameters were experimentally optimized with the aid of a self-programmed software. This G-code generator allowed the simple adjustment of printing speed, temperature, extrusion multiplier and layer
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height. By this, capsule-shaped dosage forms with the desired mechanical properties could be
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obtained. The effect of physiological pressure events on the drug release behaviour from the novel dosage form was finally tested by using a biorelevant stress test device. These in vitro
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experiments demonstrated the rapid and quantitative release of the probe drug after applying realistic pressure events. This work illustrated that 3D printing can be an interesting technique
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for the production of pressure-controlled dosage forms as a new concept of oral drug delivery.
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1. Introduction The targeted delivery of orally administered drugs to specific sites of the human gastrointestinal (GI) tract can offer various advantages over conventional drug delivery such as increased oral bioavailability or reduced local side effects. The underlying formulation concepts are typically based on physiological parameters or phenomena specific for a certain region of the GI tract such as luminal pH, enzymatic activity or transit time. In the past, research was mainly focused on the targeted delivery of drugs to the colon (colon targeting) whilst the targeting to the upper intestine was often overlooked although it may
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provide certain advantages for oral pharmacotherapy (Barakat et al., 2011; Hu et al., 2000; Jeong et al., 2001). At the moment, passive diffusion is assumed to be the main driver of
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absorption for the majority of drugs. Thus, achieving high drug concentrations in the small intestine at the main site of absorption should result in better absorption and thus, increased
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oral bioavailability. However, the luminal concentration of a drug in the upper small intestine
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is hardly predictable as it is the result of the interplay of various processes. These include dosage form disintegration and drug dissolution, gastric emptying, intestinal peristalsis,
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distribution of luminal fluids in the small intestine, presence of efflux transporters as well as oral, gastric and intestinal secretions (Higaki et al., 2008; Mudie et al., 2010; Mudie et al.,
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2014; Nokhodchi and Asare-Addo, 2014; Schiller et al., 2005; Steingoetter et al., 2006; Weitschies et al., 2005). In case of conventional dosage forms, for which disintegration and
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drug dissolution occurs mainly in the stomach, the easiest way to increase the luminal drug concentration for a certain formulation would be to reduce the amount of co-administered fluid. The lower the volume of co-administered fluid, the higher is the luminal concentration (Koziolek et al., 2016). Even though this approach may seem to be a valid strategy to increase luminal concentrations in the small intestine, one should note that the co-administered fluid is also important for esophageal transit of the dosage form, disintegration and dissolution as well as for gastric emptying (Weitschies et al., 2005). Thus, the volume of co-administered fluid should not be changed arbitrarily and reliable formulation strategies are needed. For pharmaceutical scientists, the most obvious approach would be the application of an entericcoated dosage form. An enteric coating is typically based on a polymer with a pH-dependent solubility, which shall prevent drug release in the stomach. Upon emptying from the stomach into the duodenum, drug release is triggered by the rapid increase in luminal pH. This concept works nicely in vitro, but in reality the limited availability of fluids in the upper small intestine causes a lag time of drug release due to delayed disintegration and/or dissolution (Schiller et al., 2005). Additionally, the transit through the duodenum is very rapid and thus,
Journal Pre-proof the drug has already passed the site that provides optimum conditions for drug release (Yuen, 2010). This approach is therefore not suitable for drug targeting of the proximal small intestine. In a recent publication, Wilde and colleagues described the development of a pressuresensitive drug delivery system that shall release small volumes of a highly concentrated drug solution directly into the small intestine (Wilde et al., 2014a; Wilde et al., 2014b). The trigger for drug release into the duodenum is the high pressure in the antropyloric region. In a recent SmartPill® study we could show that these pressures can be up to 500 mbar and that their occurrence is closely linked with gastric emptying (Koziolek et al., 2015; Schneider et al.,
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2016). The pressure-sensitive capsules were made from triglycerides and filled with a liquid
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solution of the drug. It was the idea that during gastric emptying, the high pressures cause rupture of the capsule shell and thus, to release the liquid content. The suitability of this
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concept was confirmed in vitro with the aid of the dissolution stress test device, an in vitro tool that enables the simulation of gastrointestinal pressures for biorelevant dissolution testing
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(Garbacz et al., 2008). The major drawback of this novel drug delivery system is the
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complexity of its production and the resulting poor reproducibility. Nonetheless, Wilde and co-workers could demonstrate that the applied pharmaceutical excipients were suitable for the
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production of a pressure-controlled drug delivery system. The aim of this study was to produce pressure-controlled dosage forms by 3D printing as this
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technology was expected to enable a fast and reproducible development of objects with desired properties. For this purpose, we used fused deposition modeling (FDM) technique as one of the most common 3D printing techniques for pharmaceutical applications. In FDM, a thermoplastic filament is moved into a heated nozzle which is movable in three dimensions relative to a build plate. The polymer is then molten and applied layer by layer until a threedimensional object results. FDM was already applied in pharmaceutical technology for the production of tablets containing multiple drugs, of capsules with pulsatile drug release as well of personalized implants (Kempin et al., 2017; Khaled et al., 2015; Melocchi et al., 2015). In the present work, the pressure-controlled drug delivery system should be produced by using filaments of Eudragit® RS for 3D printing. The use of Eudragit® RS as polymer for 3D printing was already examinated by Kempin and colleagues (Kempin et al., 2017). For this study, Eudragit® RS was chosen due to its water insoluble properties, its pH independent swelling properties and the low permeability. After assessing the optimal printing parameters, the drug release behavior of the 3D printed dosage forms should be tested under biorelevant conditions with the aid of the modified dissolution stress test device.
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2. Materials and methods 2.1 Materials Acetaminophen and mannitol were purchased from Caelo (Hilden, Germany). Fumed silica was obtained from Fagron (Barsbüttel, Germany). Eudragit® RS 100 (granule) was gratefully donated by Evonik (Essen, Germany). 2.2 Methods 2.2.1 Preparation of the filaments Filaments of Eudragit® RS were produced using a self-constructed extruder. It consisted of a
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barrel and a piston. The barrel was heatable using resistance wire (diameter 0.3 mm,
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6.93 Ω/m, BLOCK Transformatoren-Elektronik GmbH, Germany) controlled by a temperature sensor (Fluke multisensor detector 179, Fluke Cooperation, USA). The piston
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could be moved forward via a stepper motor (NANOTEC PD4-N60, Nanotec GmbH & Co. KG, Germany) connected to a drive screw. For extrusion of Eudragit® RS filaments the
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polymer granules were transferred into the barrel of the piston extruder and heated to 120 °C.
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The molten polymer was extruded through a round nozzle (diameter 3 mm) and stretched afterwards. The stretching was automatically done using a second stepper motor turning a spool. A string connected to the spool was attached to the extrudate. By this, the extrudate
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was drawn at constant speed in direction of the spool. The speed of both stepper motors was set via the software NanoProV version 2.71. The speed was adjusted so that an approximate
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filament diameter of 2.85 mm resulted. 2.2.2 Filament characterization
The diameter of the produced filament was determined every 10 mm by use of a digital caliper (Powerfix, Kompernass Handels GmbH, Germany, accuracy ±0.02 mm). Furthermore, the filament strands were controlled visually to discard those containing gas bubbles or other impurities. For this purpose, a reflected-light microscope was used (Zeiss Stemi 2000-C with light source Zeiss CL 1500 ECO, camera Zeiss AxioCam and AxioVision software, all Carl Zeiss Microscopy GmbH, Germany). 2.2.3 3D printing 3D printing was performed using a modified Mendel Max 2.5 (German RepRap GmbH, firmware Marlin, Germany). Various modifications were necessary to enable the printing of the brittle Eudragit® RS filament. For instance, the use of the standard feeder resulted in the breakage of the strands during the forward movement. This was avoided by placing the
Journal Pre-proof strands into a straight, rigid tube that was connected to the hot end of the 3D printer. As can be seen from Figure 1, commercially available polylactic acid (PLA) filament was also fed into the tube via a bulldog extruder XL (Reprapdiscount Yang, China) in order to push the Eudragit® RS filament into the hot end. The nozzle diameter was either 0.25 mm or 0.4 mm. Scotch tape (type 2090, 3M Germany GmbH, Germany) was used for better adhesion of the
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printed objects.
Figure 1. Schematic representation of the 3D printer (A: build plate; B: printed dosage form; C: nozzle; D: hot end; E: water cooling system; F: filament input; Green: Eudragit® RS filament; Blue: driving filament).
2.2.3.1 Optimization of the printing parameters In order to determine the optimal printing temperature and speed for Eudragit® RS filament, single line walls with a height 30 mm and a wide of 30 mm were printed at different temperatures (160 °C, 165 °C, 170 °C, 175 °C and 180 °C). Furthermore, the effect of printing speeds (400 mm/min, 600 mm/min and 800 mm/min) was assessed. The usage of print bed heating was not necessary. The resulting objects were investigated for optical defects (e.g. gas bubbles, unattached layers) using a reflected-light microscope (Zeiss Stemi
Journal Pre-proof 2000-C with light source Zeiss CL 1500 ECO, camera Zeiss AxioCam and AxioVision software, all Carl Zeiss Microscopy GmbH, Germany). 2.2.3.2 3D printing of pressure-controlled drug delivery systems In common 3D printing workflow, the G-code will be generated by dedicated software by dedicated slicing software. The contour of a computer-aided design (CAD) model will be imported as an STL file which only describes the surface of the object by means of vertices forming a triangle mesh. The contour will be divided in horizontal parts corresponding to the targeted layer height and the slicing software calculates the toolpath for the perimeter as well for the infill for each layer. Simultaneously the amount of material needed to print the object
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is determined. This information is translated into G-code. Since the slicing software has no
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information about the application and the intended function of the printed structure the G-
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code will be optimized for low printing time and mechanical strength. Due to these limitations, the G-code for the 3D printing process was generated by a self-
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written Python script (Figure 2).
Figure 2. Picture of the self-programmed software (left: G-code-Generator with editable parameters; right: schematic drawing of the dosage form).
This allowed us to have full control over important printing parameters (e.g. temperature, layer height, printing speed, extrusion multiplier and thus extrusion rate). The capsule was printed in an upright position, so that the layers were oriented in parallel with the circular cross section of the cylinder. The capsule was printed single-walled and without any support structure or infill in order to obtain a pressure-sensitive object. To control the pressuresensitivity, the extrusion multiplier of the cylindrical part of the capsule was varied. By this, the amount of extruded polymer during the process of printing, i.e. the extrusion rate, was
Journal Pre-proof defined. The wall thickness was examined using a digital caliper. The usage of print bed heating was not necessary. The dimensions of the pressure-induced drug delivery system (height: 25.1 mm, diameter: 12.7 mm) were chosen to be equal to the SmartPill®, a telemetric capsule that is able to measure intraluminal temperature, pH and pressure during its gastrointestinal transit. Therefore, we were able to compare stresses experienced by a SmartPill® with the stresses experienced by the novel dosage form. 2.2.3.3 Assessment of the pressure sensitivity of the 3D printed systems
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Empty capsules were printed at different wall thicknesses to characterize their mechanical properties. To assess at which pressure the capsules break in vitro, a test setup based on the
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dissolution stress test device by Garbacz and colleagues (Garbacz et al., 2008; Garbacz et al.,
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2009) was developed (Figure 3). In brief, it consisted of a transparent shell in which the 3D printed capsule could be placed. The shell was closed by a cap which contained a balloon that
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was connected to a nozzle. Via the nozzle, pressurized air could be introduced, which inflated the balloon and led to realistic stresses on the tested object (Garbacz et al., 2008; Garbacz et
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al., 2009). At the test beginning the balloon was inflated with 200 mbar for 5 s and deflated again. Subsequently, we increased the pressure in steps of 50 mbar and repeated the
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aforementioned procedure until capsule break could be observed. All tests were performed in
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absence of liquid and in triplicate.
Figure 3. Test device for pressure-controlled drug delivery systems (Left: capsule before testing; middle: broken capsule after testing; right: pieces of the broken capsule).
Journal Pre-proof 2.2.4 Assessing the pressure-controlled drug delivery of the 3D printed systems The capsules were filled with 0.5 g of a powder mixture consisting of 5% (w/w) acetaminophen, 94.5% (w/w) mannitol and 0.5% (w/w) fumed silica to confirm successful pressure-controlled drug delivery. The acetaminophen represents a model drug that can be analyzed via UV/Vis spectrophotometry. For capsule filling the printer nozzle moved to a parking position after printing the convex bottom part and cylinder of the capsule. After powder filling, the printer continued the printing process from its last position and finished the capsule. For the in vitro drug dissolution testing under realistic gastrointestinal conditions in terms of pressures we used the dissolution stress test device. A thorough description of this
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device can be found elsewhere (Garbacz et al., 2008). As dissolution medium 1100 ml simulated gastric fluid sine pepsin (SGF sp) pH 1.2 at a temperature of 37 °C were used. The
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speed of the impeller was set to 75 rpm. To assure the homogeneity of the medium we
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additionally used a peristaltic pump (ISM404B, Ismatec, Germany) at a flow rate of 150 mL/min to circulate the fluid from the bottom of the vessel to the top. The analytics were
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done using an UV/Vis spectrophotometer (Varian Cary® 50 Bio UV/Vis Spectrophotometer, Agilent Technologies, USA) in combination with fiber optics (2 mm probe tips).
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Measurements were done at 243 nm every 2 min. The first 60 min no pressure events were applied to assess the permeability of the capsule shell. After this time, the balloon was
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inflated with 200 mbar for 5 s and deflated again. This procedure was repeated applying a pressure increased by 50 mbar until the maximum pressure of 500 mbar was reached or the
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breakage of all dosage forms could be observed. Data acquisition was done with the Cary WinUV software (Varian UV Dissolution Application Version 4.00). All tests were performed in triplicate.
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3. Results 3.1 Preparation and characterization of Eudragit® RS filaments The self-constructed piston extruder was suitable for the fabrication of filament containing Eudragit® RS. It was possible to produce filaments of homogenous quality with a diameter of approximately 2.7 mm that could be used in 3D printing. Extrusion temperatures around 120 °C proved to be appropriate for the filament preparation. Higher temperatures led to inhomogeneous filament with poor quality. Though the filament diameter was not uniform over the length of each fabricated filament, it was possible to select filament segments with low variations. Variations in the diameter of 0.05 mm were defined as the limiting value.
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3.2.1 Optimization of the printing parameters
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Filaments with greater variations were excluded from farther testing.
The optimization of the printing process was successfully carried out by printing single line
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walls at variable printing speed and printing temperature. Figure 4 shows exemplary microscopic images of the printed single line walls. Unevenly aligned layers could be
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detected in the microscopic images as well as strings facing outwards. Irregular arranged whitish spots were visible and indicated insufficient bonding. A printing temperature of
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170 °C led to uniform objects. It can be seen that all layers were stacked evenly. Neither defects between the layers nor hair like extensions of the individual layer were visible in the
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microscopic images. Process temperatures above 170 °C lead to thermal degradation of the used material and could be recognized by large whitish areas in the print as well as by disconnected layer. In the microscopic images, large gaps between the individual layers were observable.
Journal Pre-proof Figure 4. Microscopic image of the single layer objects as a function of the printing temperature (printing speed 800 mm/min; top row: close-up view 40x magnification; bottom row: overview 10x magnification).
3.2.2 3D printing of the pressure controlled drug delivery systems For the printing of the dosage forms, we used filament segments with uniform diameter and uniform appearance. The actual diameter was considered in the generation of the G-code. The self-programmed G-code generator was found useful for easy editing of the printing parameters and allowed a simple and transparent G-code generation. An optimization of the
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printer settings for every part of the capsule (bottom, cylinder and top) was necessary. In
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Figure 5, the process of optimizing the top is shown exemplarily.
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Figure 5. Optimization of the top (Red arrows indicate faults, 6,5x magnification).
In this case, more than 35 adjustments were necessary to finally obtain a closed top. The red
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arrows in Figure 5 indicate printing voids that could lead to permeable dosage forms. Mostly changed printing parameters were the printing speed, the extrusion multiplier that defines the amount of extruded material and the number of lines. For the sake of clarity, the exact printing parameters are not shown. After the optimization of the printing process of the capsule parts, the further printing parameters were optimized. Since the breakage of the dosage form depended on the cylindrical part of the capsule, only the printing parameters of this part were varied. 3.2.3 Assessment of the pressure sensitivity of the 3D printed systems By amendment of the printing parameters, fifteen batches could be manufactured. The corresponding properties are displayed in Table 1. By adjusting the printing parameters, capsules with different breaking behavior could be produced. Thereby, the obtained breaking pressures ranged from about 200 mbar up to 900 mbar.
Journal Pre-proof Table 1. Properties of pressure-sensitive capsules and the applied 3D printing conditions. Batch # Nozzle
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2
3
4
5
6
7
8
9
10
11
12
0.4
0.4
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
2.5
2.4
0.2
0.25
0.3
0.4
0.2
0.21
0.225
0.3
0.2
0.225
0.5
0.5
800
800
(mm) Extrusion multiplier Layer
0.075 0.075 0.075 0.075 0.075 0.075 0.075 0.075 0.075 0.075
height (mm) Printing
400
400
400
400
400
400
800
800
0.404 0.364 0.342 0.387 0.393 0.492 0.327 0.335 0.362 0.393 0.338 0.336 ±
±
±
±
±
±
±
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(g)
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(mm/min) Weight
800
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speed
800
±
±
±
±
±
0.013 0.005 0.007 0.007 0.025 0.009 0.006 0.007 0.009 0.013 0.012 0.023 0.55
0.42
0.24
0.29
thickness
±
±
±
±
(mm)
0.04
0.02
0.02
0.02
Breaking
760
367
233
pressure
±
±
±
(mbar)
146
131
47
0.29
0.33
0.24
0.26
0.29
0.35
0.25
0.26
±
±
±
±
±
±
±
±
0.02
0.03
0.02
0.04
0.04
0.03
0.03
0.03
300
683
841
208
333
580
900
300
730
±
±
±
±
±
±
±
±
±
112
73
19
111
196
153
58
150
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Wall
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It can be seen from Figure 6 that the breaking pressures nicely correlates with the wall thickness. The wall thickness which depends on the extrusion multiplier is the determining parameter for the burst pressure.
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Figure 6. Breaking pressure of the 3D printed capsules depending on wall thickness for the batches 710 printed with a nozzle of 0.25 mm and a printing speed of 800 mm/min, but with varying extrusion
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multipliers.
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By adjusting the printing parameters of the cylindrical part, capsules with different mechanical properties could be produced. Since in later dissolution tests the reproducible
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tightness of the capsules could be doubted for the above stated printing properties, we further optimized the 3D printing process. Therefore, capsules from batches 13-15 were printed with
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the properties stated in Table 2 and led to the best results in dissolution stress tests (cfr. section 3.2.4). The printing properties were comparable to batches 1 and 2.
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Table 2. Critical breaking pressures for different batches measured in the modified dissolution stress test (printing parameters: 0.4 mm nozzle, layer height 0.075 mm, printing speed 800 mm/min). 13
14
15
1.525
1.55
1.6
Capsule 1
250
250
300
Capsule 2
300
250
450
Capsule 3
400
450
500
8.00
8.67
9.33
Batch #
Extrusion multiplier Breaking pressure (mbar)
t85% released (min)
Furthermore, we used the actual filament diameter from the measurements for the calculation of the extrusion multiplier for batches 13-15, which led to clearly reduced values. Comparing batches 13-15, it can be seen that an increased extrusion multiplier again led to increased breaking pressure.
Journal Pre-proof 3.2.4 Assessing the pressure-controlled drug delivery of the 3D printed systems
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Figure 7 shows exemplary the dissolution profile from batch 13.
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Figure 7. Batch 13 - Cumulative release of Acetaminophen (0.4 mm nozzle, extrusion multiplier
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1.525, layer height 0.075 mm, printing speed 800 mm/min).
In this batch, the tested dosage forms showed no drug release within 60 min. After applying a
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pressure of 200 mbar, no drug release was observed. However, applying a pressure of 250 mbar caused the beginning of drug release in one capsule. Drug release from the other capsules started after applying 300 mbar and 400 mbar, respectively. All dosage forms released 85% of their content within 8 min after breaking.
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4. Discussion In this work, pressure-sensitive dosage forms as described recently by Wilde and co-workers were successfully produced from Eudragit® RS by 3D printing. Eudragit® RS was chosen as the wall material as it possesses ideal properties for the production of brittle capsule shells that are able to break at a certain pressure. Moreover, it shows a pH-independent swelling behavior and low permeability. Prior to 3D printing, filaments of Eudragit® RS were produced with the aid of a self-made hot melt extruder since commercial filaments of this polymer are not available. The use of Eudragit® RS for the production of filament for 3D printing has already been described by other groups (Kempin et al., 2017; Pietrzak et al.,
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2015; Yu et al., 2007). After optimizing the extrusion process, we were able to obtain
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filaments that could be used in 3D printing. These showed only small variations in terms of their diameter. Generally, a variation of maximum 5% is regarded as acceptable (Melocchi et
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al., 2015). Higher variation of the filament diameter can lead to non-homogenous prints
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(Zhang et al., 2017).
In order to be able to obtain dosage forms that break upon certain pressures, it was our
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primary task to optimize the printing parameters (e.g. printing temperature, printing speed). For 3D printing, a temperature of 170 °C was found to be optimal. However, at this
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temperature Eudragit® RS also starts to degrade (Parikh et al., 2014), which can cause gas bubbles to be formed in the hot end. These can interrupt the flow of molten material leaving
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the nozzle. By this, the contact between adjacent material strings is hampered and therefore, the proper formation of bonded connections is inhibited. The optimal printing temperature determined in these experiments was much higher than in comparable hot melt extrusion processes (Albarahmieh et al., 2016; Schilling et al., 2007; Wu and McGinity, 2003). A reason for this observation might be the absence of any plasticizer in the filaments as the addition of plasticizer like triethyl citrate would have resulted in filament that did not possess the optimal brittle properties. As opposed to temperatures above 170 °C lower printing temperatures led to insufficient layer bonding. In order to optically assess the printing process, single-line walls were printed at different temperatures. By using this simple geometry and high printing speeds, we could easily evaluate the optimal printing temperature for the 3D printing of the pressure-sensitive capsule shells. The rectangular shape also made it possible to characterize the test objects by optical methods. These experiments clearly revealed that the temperature had a dramatic effect on the properties of the printed objects.
Journal Pre-proof After defining the optimum printing temperature, the further printing parameters such as layer height, printing speed and extrusion multiplier were optimized. For this purpose, a selfwritten software tool was used. To our knowledge, this is the first study in pharmaceutics that does not use common slicing software for 3D printing of pharmaceutical dosage forms. The G-code generator enabled an easy adjustment of the printing parameters like printing speed, printing temperature or extrusion multiplier. A further advantage is the separate adaption of any part of the printed capsule so that the different parts can be printed with different parameters. The variations of the nozzle diameter or the extrusion multiplier enabled the printing of capsules with variable pressure sensitivity. The breaking pressure of the pressure-
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controlled dosage forms could be easily adjusted by changing the wall thickness of the capsules. In comparison to previous works by Wilde et al., this procedure was found to be
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faster and led to pressure controlled systems that are independent from the gastric transit time
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(Wilde et al., 2014a; Wilde et al., 2014b). In the works by Wilde et al. they produced coated hard fat spheres, which should melt at body temperature and leave a pressure sensitive
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cellulose acetate coating. Depending on the polymer load that was applied during coating they could determine the crushing strength of the drug release system. However, since the hard fat
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has to be melted, the fasted state intake of the system could lead to a rapid emptying into the duodenum along with insufficient pressure control of the drug release. Our approach to use
this issue.
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the highly reproducible process of FDM printing for prototyping of the capsules addressed
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Subsequently, drug-release from the pressure-controlled drug delivery system was evaluated under biorelevant conditions with the aid of a modified dissolution stress test device. In these tests, a gastric transit time of 1 h was simulated, which was followed by the simulation of gastric emptying. Earlier studies with the SmartPill® have shown that high pressures can arise during gastric emptying (Cassilly et al., 2008; Koziolek et al., 2015; Schneider et al., 2016). These high pressures (200 – 500 mbar) could be realistically simulated by the modified version of the stress test device (Garbacz et al., 2008; Garbacz et al., 2009). The applied modifications enabled a better distribution of the media in order to rapidly detect the release of acetaminophen. It should be noted that compendial dissolution test apparatuses cannot be used to demonstrate the suitability of this dosage form as they are not able to generate such high pressures (Schneider et al., 2017). In our tests, drug release before application of the pressures was not observed, but the simulation of realistic pressures caused release of the entire dose within a short time. This observation confirmed our hypothesis of a pressure-controlled drug release from this novel
Journal Pre-proof formulation. After breakage, the capsule shell disintegrated into many small particles and 85% of the probe drug acetaminophen was detected within 8 minutes. The content is probably released faster, but the dissolution of the powder mixture and the homogenous distribution of the acetaminophen in the medium took some time. In contrast to earlier publications by Wilde and colleagues which produced pressure-sensitive capsules using glyceryl tristearate, it was possible to control the breaking pressure of the capsule with the aid of the 3D printing process (Wilde et al., 2014a). In particular, the extrusion rate, defined by the extrusion multiplier, was found to be highly important. The more material was extruded per layer, the higher was the mean breaking pressure. Further
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experiments and improvement of the printing process will be necessary to manufacture
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capsules with homogenous breaking profiles. Such pressure-controlled dosage forms might bring benefits for drugs with a narrow absorption window like metformin, levodopa or
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acyclovir (Bardonnet et al., 2006; Davis, 2005; Murakami, 2017; Murphy et al., 2012). Pressure-controlled dosage forms filled with liquids of peptides or proteins could also be a
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possibility for drug delivery of proteins. Thereby, the drug is protected against proteases and a
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high concentrated solution can be released in the small upper intestine to probably improve absorption. Of course, to test this hypothesis in vivo experiments are necessary. Furthermore, the 3D printing as well as the extrusion process have to be further optimized. The variation of
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the pressure needed to break the capsules was higher than expected. To some extent these variations could be explained by variations in the filament diameter arising from the used
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extrusion process.
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5. Conclusion This work demonstrated the possibility of using 3D printing via fused deposition modeling for the fabrication of pressure-controlled dosage forms. Customized G-code generation enabled the printing of objects with an adjustable wall thickness without the need of support structures. By small variations of the extrusion rate via the extrusion multiplier, capsules with different mechanical properties could be obtained. Since a high uniformity in filament diameter is needed for reproducible 3D printing, the extrusion process was another critical process step for the production of this pressure-controlled drug delivery system. In this study, Eudragit® RS filament without any plasticizer was successfully manufactured by hot melt
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extrusion with the aid of a self-constructed piston extruder. The proof-of-concept was
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demonstrated by the application of a biorelevant stress test device that enabled dissolution testing under conditions realistic for the upper human GI tract. Physiological pressure events
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during gastric transit were shown to be able to initiate drug release from this novel drug
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delivery concept.
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6. References Albarahmieh, E., Qi, S., Craig, D.Q.M., 2016. Hot melt extruded transdermal films based on amorphous solid dispersions in Eudragit RS PO: The inclusion of hydrophilic additives to develop moisture-activated release systems. International Journal of Pharmaceutics 514 (1), 270–281. Barakat, N.S., Al-Suwayeh, S.A., Taha, E.I., Bakry Yassin, A.E., 2011. A new pressure-controlled colon delivery capsule for chronotherapeutic treatment of nocturnal asthma. Journal of Drug Targeting 19 (5), 365–372. Bardonnet, P.L., Faivre, V., Pugh, W.J., Piffaretti, J.C., Falson, F., 2006. Gastroretentive dosage forms: Overview and special case of Helicobacter pylori. Journal of Controlled Release 111 (1-2),
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Cassilly, D., Kantor, S., Knight, L.C., Maurer, A.H., Fisher, R.S., Semler, J., Parkman, H.P., 2008. Gastric emptying of a non-digestible solid: assessment with simultaneous SmartPill pH and
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Garbacz, G., Wedemeyer, R.-S., Nagel, S., Giessmann, T., Monnikes, H., Wilson, C.G., Siegmund, W., Weitschies, W., 2008. Irregular absorption profiles observed from diclofenac extended release tablets can be predicted using a dissolution test apparatus that mimics in vivo physical stresses. European Journal of Pharmaceutics and Biopharmaceutics 70 (2), 421–428. Higaki, K., Choe, S.Y., Lobenberg, R., Welage, L.S., Amidon, G.L., 2008. Mechanistic understanding of time-dependent oral absorption based on gastric motor activity in humans. European Journal of Pharmaceutics and Biopharmaceutics 70 (1), 313–325. Hu, Z., Mawatari, S., Shibata, N., Takada, K., Yoshikawa, H., Arakawa, A., Yosida, Y., 2000. Application of a biomagnetic measurement system (BMS) to the evaluation of gastrointestinal transit of intestinal pressure-controlled colon delivery capsules (PCDCs) in human subjects. Pharmaceutical Research 17 (2), 160–167. Jeong, Y.I., Ohno, T., Hu, Z., Yoshikawa, Y., Shibata, N., Nagata, S., Takada, K., 2001. Evaluation of an intestinal pressure-controlled colon delivery capsules prepared by a dipping method. Journal of Controlled Release 71 (2), 175–182.
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Mudie, D.M., Amidon, G.L., Amidon, G.E., 2010. Physiological parameters for oral delivery and in vitro testing. Molecular Pharmaceutics 7 (5), 1388–1405. Mudie, D.M., Murray, K., Hoad, C.L., Pritchard, S.E., Garnett, M.C., Amidon, G.L., Gowland, P.A.,
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Murakami, T., 2017. Absorption sites of orally administered drugs in the small intestine. Expert opinion on drug discovery 12 (12), 1219–1232. Murphy, C., Pillay, V., Choonara, Y.E., Du Toit, L.C., Ndesendo, V.M.K., Chirwa, N., Kumar, P., 2012. Optimization of a dual mechanism gastrofloatable and gastroadhesive delivery system for narrow absorption window drugs. AAPS PharmSciTech 13 (1), 1–15. Nokhodchi, A., Asare-Addo, K., 2014. Drug release from matrix tablets: Physiological parameters and the effect of food. Expert Opinion on Drug Delivery 11 (9), 1401–1418. Parikh, T., Gupta, S.S., Meena, A., Serajuddin, A.T., 2014. Investigation of thermal and viscoelastic properties of polymers relevant to hot melt extrusion - III: Polymethacrylatesand polymethacrylic acid based polymers. Journal of Excipients and Food Chemicals 5 (1). Pietrzak, K., Isreb, A., Alhnan, M.A., 2015. A flexible-dose dispenser for immediate and extended release 3D printed tablets. European Journal of Pharmaceutics and Biopharmaceutics 96, 380–387.
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Graphical abstract